module 7 - pharmacotherapy for endocrine and exocrine disorders

Geriatric Pharmacy Review

Module 07: Pharmacotherapy for Endocrine and Exocrine Disorders

Copyright 2011 American Society of Consultant Pharmacists

Accreditation Information

ASCP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

This home study web activity has been assigned 5 credit hours.

ACPE UPN: 0203-0000-10-040-H01-P

Release Date: 4/1/2010

Expiration Date: 4/1/2013

To receive continuing education credit for this course, participants must complete an on-line evaluation form and pass the on-line assessment with a score of 70% or better. If you do not receive a minimum score of 70% or better on the assessment, you are permitted 4 retakes. After passing the assessment, you can print and track your continuing education statements of credit online.

Geriatric Pharmacy Review courses have not yet been approved for Florida consultant pharmacy continuing education.


Content Experts

Mary Caputi, PharmD, CDE, BC-ADM, CGP Department of Veterans Affairs Hickory Outpatient Clinic

Dennis J. Chapron, MS, RPh Medication Safety Officer Saint Francis Hospital and Medical Center

Sean M. Jeffery, PharmD, CGP, FASCP Associate Clinical Professor University of Connecticut School of Pharmacy & Clinical Pharmacy Specialist Geriatrics and Extended Care Connecticut VA Healthcare System

Jennifer M. Voisine, PharmD, BCPS Geriatrics Pharmacy Resident Connecticut VA Healthcare System & Adjunct Assistant Professor University of Connecticut School of Pharmacy

Marie Parker, PharmD, BCPS Clinical Pharmacist Humana Pharmacy Solutions

Jennifer J. Lee, PharmD, BCPS, CDE Assistant Clinical Professor University of Connecticut School of Pharmacy & Clinical Pharmacist in Ambulatory Care/Women’s Health Connecticut Healthcare System

Legacy Expert:

Stephen M. Setter, PharmD, CDE, CGP, DVM College of Pharmacy Department of Pharmacotherapy Washington State University


Content Expert Disclosure

Mary Caputi has no relevant financial relationships to disclose.

Dennis J. Chapron has no relevant financial relationships to disclose.

Sean M. Jeffery has no relevant financial relationships to disclose.

Jennifer J. Lee has no relevant financial relationships to disclose.

Jennifer M. Voisine has no relevant financial relationships to disclose.

Marie Parker has no relevant financial relationships to disclose.

Stephen Setter has no relevant financial relationships to disclose.


Diabetes Mellitus: Clinical Picture

Learning Objectives

By the end of this Review Concept you should be able to:

•  Compare and contrast the epidemiology, pathology, and clinical presentation of diabetes mellitus type 2 in the younger versus older individual.

•  Describe microvascular, macrovascular, and other complications which can occur in a patient with diabetes and how they may present differently in the older patient.


Incidence of Diabetes Mellitus

Annual Number (in Thousands) of New Cases of Diagnosed Diabetes Among Adults Aged 18–79 Years, United States, 1980–2007

From 1980 through 2007, the number of adults aged 18–79 years with newly diagnosed diabetes almost tripled from 493,000 in 1980 to more than 1.5 million in 2007 in the United States. The number of new cases of diabetes has increased sharply since the early 1990s.

www.cdc.gov/diabetes/statistics/incidence/fig1.htm.



Distribution of Age at Diagnosis of Diabetes Among Adult Incident Cases Aged 18–79 Years, United States, 2006

In 2006, about one half (47%) of the adult incident cases (i.e., cases diagnosed within past year) of diabetes were diagnosed between the age of 45 and 59 years. About 10% were diagnosed before the age of 35 and about 18% were diagnosed at age 65 years or older.

http://www.cdc.gov/diabetes/statistics/age/fig1.htm

Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2007. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2008.



Median of Diabetes Duration Among Adults Aged 18–79 Years, by Age, United States, 1997–2007 From 1997 to 2007, the median of diabetes duration for adults aged 18–79 years was longest among adults aged 65–79 years, and shortest among adults aged 18–44 years. During this time period, there were no clear age-specific trends.

http://www.cdc.gov/diabetes/statistics/duration/fig4.htm.



The incidence and prevalence of type 2 diabetes continues to increase throughout the world. Coincident with the aging of the population and the increase in obesity, the incidence of Diabetes will likely increase in those >65 years of age. This trend has already been documented.

There are two types of diabetes; type 1 and type 2. Type 1 diabetes is associated with beta cell destruction because of either an autoimmune or idiopathic process which eventually leads to absolute insulin deficiency. This can occur at any age including the older patient. Type 1 accounts for approximately 5% of diabetes cases.

In comparison, type 2 diabetes accounts for approximately 90 to 95 percent of reported cases. Type 2 diabetes is characterized by a combination of insulin resistance and beta-cell secretory defects. Progressive beta-cell dysfunction can lead to absolute insulin deficiency. Type 2 diabetes historically occurred more frequently in adults but recent statistics report increased frequency in adolescents and young adults.

Management of type 1 diabetes requires exogenous insulin while type 2 diabetes management includes lifestyle changes [diet, exercise], oral medications and injectable products such as insulin, exenatide and pramlintide.

Complications of type 1 and type 2 diabetes can be life-threatening, occur in multiple organ systems, and result in loss of quality and quantity of life. Management of complications results in significant healthcare burden. Total cost of care will increase as the population ages, diabetes occurs more frequently in the younger population, and the duration of diabetes increases. Prevention of diabetes, early detection and aggressive management of diabetes are key components to reducing complications and health costs.


Pre-Diabetes

Recently the American Diabetes Association added a new category to the classification of diabetes. Glucose abnormalities include impaired fasting glucose [IFG] and impaired glucose tolerance [IGT]. Individuals with IFG and IGT are considered to have Pre-diabetes and are at greater risk of progressing to diabetes and developing heart disease and stroke

• Pre-diabetes Population Trends

• In 1988–1994, among U.S. adults aged 40–74 years, 33.8% had IFG, 15.4% had IGT, and 40.1% had pre-diabetes (IGT or IFG or both).

• In 2003–2006, 25.9% of U.S. adults aged 20 years or older had IFG (35.4% of adults aged 60 years or older). Applying this percentage to the entire U.S. population in 2007 yields an estimated 57 million American adults aged 20 years or older with IFG, suggesting that at least 57 million American adults had prediabetes in 2007.

• After adjusting for population age and sex differences, IFG prevalence among U.S. adults aged 20 years or older in 2003–2006 was 21.1% for non-Hispanic blacks, 25.1% for non-Hispanic whites, and 26.1% for Mexican Americans.

http://www.cdc.gov/diabetes/pubs/general07.htm#impaired


Pre-Diabetes

People with pre-diabetes can have impaired fasting glucose or “IFG”, impaired glucose tolerance or “IGT” or both IFG and IGT. The classification of pre-diabetes is based on a fasting glucose result and the results of a 2-hour glucose tolerance test.

In those with IFG the fasting blood sugar level is 100 to 125 milligrams per deciliter (mg/dL) after an overnight fast. This level is higher than normal but not high enough to be classified as diabetes.

In those with IGT the blood sugar level is 140 to 199 mg/dL after a 2-hour oral glucose tolerance test. This level is higher than normal but not high enough to be classified as diabetes.

Management of those with pre-diabetes includes lifestyle changes, emphasizing dietary modification and increasing activity levels. Medication such as metformin can be added to management but dietary and activity changes provide the greatest benefits.


Complications of Diabetes for the older adult in the United States

Diabetes is associated with an increased risk for a number of serious, sometimes life-threatening complications and certain populations experience an even greater threat. Good diabetes control can help reduce risk, however many people are not even aware that they have diabetes until they develop one of its complications. Complications include:

• Heart disease and stroke • High blood pressure • Blindness • Kidney Disease • Nervous system disease • Amputations • Dental disease • Sexual Dysfunction • Other Complications

Heart Disease and stroke Heart disease and stroke account for about 65% of deaths in people with diabetes. Adults with diabetes have heart disease death rates about 2 to 4 times higher than adults without diabetes. The risk for stroke is 2 to 4 times higher and the risk of death from stroke is 2.8 times higher among people with diabetes.

High Blood Pressure About 73% of adults with diabetes have blood pressure greater than or equal to 130/80 millimeters of mercury (mm Hg) or use prescription medications for hypertension.



Blindness Diabetic retinopathy causes 12,000 to 24,000 new cases of blindness each year making diabetes the leading cause of new cases of blindness in adults 20-74 years of age.

Kidney Disease Diabetes is the leading cause of kidney failure. In 2002, a total of 178,689 people with End Stage Renal Disease due to diabetes were receiving chronic dialysis or with a kidney transplant. Diabetes accounted for 44% of new cases in 2005. In 2005, 46,739 people with diabetes began treatment for end-stage renal disease (ESRD).

Nervous System Disease Approximately 60% to 70% of people with diabetes have mild to severe forms of nervous system damage or neuropathy. Neuropathy can include impaired sensation or pain in the feet or hands, slowed digestion of food in the stomach, carpal tunnel syndrome, and other nerve problems. Almost 30% of people with diabetes aged 40 years or older have impaired sensation in the feet (at least one area that lacks feeling) and severe forms of diabetic nerve disease are a major contributing cause of lower-extremity amputations. An addition concern is cognitive changes which can result from persistent hyperglycemia.

Amputations More than 60% of non-traumatic lower-limb amputations occur in people with diabetes. In 2004, about 71,000 lower-limb amputations were performed in people with diabetes and the rate of amputation in diabetics is 10 times higher than those without diabetes.

Dental Disease Periodontal (gum) disease is more common in people with diabetes. Among young adults, those with diabetes have about twice the risk of those without diabetes. Almost one-third of people with diabetes have severe periodontal disease with loss of attachment of the gums to the teeth measuring 5 millimeters or more. Persons with poorly controlled diabetes (hemoglobin A1C > 9%) were nearly 3 times more likely to have severe periodontitis than those without diabetes.



Sexual Dysfunction Diabetes significantly increases the risk for sexual dysfunction in both men and women.

Other Complications Uncontrolled diabetes often leads to biochemical imbalances that can cause acute life-threatening events, such as diabetic ketoacidosis and hyperosmolar (nonketotic) coma. People with diabetes are more susceptible to many other illnesses and, once developed, often have worse prognoses.

It is estimated that 18.2 million Americans have the endocrine disorder known as diabetes mellitus. Of the six hundred twenty-five thousand new cases per year, about fifty percent of them occur in individuals over fifty-five years of age.

There are two primary or main types of diabetes mellitus that differ in terms of when they are diagnosed and how they are controlled and managed. Five to ten percent of diabetes patients have Type 1, and are dependent on exogenous insulin for survival. This type of diabetes is generally diagnosed before age thirty. The other ninety to ninety-five percent of patients with diabetes have Type 2, which may be controlled with diet (medical nutrition therapy), exercise (physical activity), oral agents and/or insulin.

http://www.diabetes.org/diabetes-statistics/complications.jsp


Normal Regulation of Blood Glucose

Normal Fuel Physiology in Response to Food Intake:

• Carbohydrate & protein intake • Increased insulin secretion from beta cells • Glycogenesis and glycolysis • Glycogenolysis prevented

Normal Fuel Physiology in The Fasting State:

• Plasma glucose 70- - 110 mg/dL • Decreased serum insulin • Increased glucagon • Glucose provided via

• glycogenolysis (75%) • gluconeogenesis (25%).

• Lipolysis results when glucose is not available • Fats -> free fatty acids -> keto acids

Diabetes mellitus is characterized by changes in the metabolism of carbohydrate, protein and fat. To understand these changes , it is important to understand normal regulation of blood glucose.

After food intake, metabolism of carbohydrate and protein results in increased blood glucose, and in turn, increased insulin secretion from the beta cells. Increased insulin levels facilitate glucose transport into peripheral cells. Blood glucose is also stored in the liver as glycogen through glycogenesis. Glycogenolysis, the breakdown of glycogen to glucose, is inhibited. These processes maintain normal blood glucose.

In the fasting state, plasma glucose levels are maintained by regulation of hepatic glucose production and peripheral glucose utilization. When serum insulin levels fall, glucagon stimulates hepatic glucose production [through glycogenolysis and gluconeogenesis] to raise blood glucose levels. If glucose is unavailable, fats are converted to free fatty acids and ultimately keto acids.


Glucose abnormalities in Diabetes

Diabetes is characterized by • Hyperglycemia • Hyperinsulinemia • Insulin receptor defects • Beta-cell secretory defects

Fasting hyperglycemia is diagnostic for type 2 diabetes and is evidence of beta-cell loss/failure. Fasting plasma insulin levels are elevated as a result of insulin resistance and up-regulation of beta-cells in an attempt to overcome it. Early in diabetes this can compensate for the hyperglycemia but, eventually, insulin production is insufficient to maintain normal glucose levels.

As fasting blood glucose levels rise the rapid first phase insulin response to oral glucose is lost but late phase insulin release is normal or increased. As the level of glycemia increases further, insulin secretion is impaired [beta-cell dysfunction] and hepatic glucose production [glycogenolysis/gluconeogenesis] becomes prominent. Insulin resistance is seen in muscle and adipose tissues.

Post-prandial hyperglycemia stimulates insulin secretion in an attempt to normalize plasma glucose. Insulin receptor and post-receptor binding defects result in further increases in insulin levels. Beta-cell dysfunction reduces insulin secretion and hyperglycemia worsens.

Lipolysis becomes an energy source when glucose transport into cells is reduced. Free-fatty acid production further impairs insulin sensitivity and hyperglycemia worsens.


Etiology of Insulin Resistance in the Older Adult

Insulin resistance is a central component of the metabolic syndrome and it significantly increases the risk of cardiovascular morbidity and mortality. Insulin resistance is present when large amounts of insulin (endogenous or exogenous) are required for a normal biologic response.

The insulin resistance that triggers this series of events can be due to tissue and cellular defects. Obesity is often seen in type 2 diabetes and may directly contribute to insulin resistance. Adipose cells can be considered an endocrine organ because it influences insulin action through release of free fatty acids and secretion of proinflammatory mediators such as Tumor Necrosis Factor-alpha, and Interleukin-6. It also modulates hormones such as adiponection, leptin, and resistin. Research is ongoing on the impact of these hormones and their role in the development of diabetes.

Target cell defects, such as the mutation of the insulin–receptor gene, problems with intracellular glucose transporters and cellular inhibitors worsen the relative glucose deficiency. In the older adult, stress and hormone disorders can also affect target cells and contribute to insulin resistance. Hormones implicated include corticosteroids, growth hormone, catecholamines, glucagon and thyroid hormone.

• Target cell defects •  • Stress •  • Counter-regulatory hormone disorders


Signs and Symptoms of Diabetes Mellitus

Global symptoms: • Unexplained weight loss • Fatigue • Cataracts • Recurrent infections, esp. urinary tract

Classic symptoms (may be less noticeable or nonexistent elderly):

• Frequent urination(polyuria) • Excessive thirst (polydipsia) • Extreme hunger (polyphagia) • Unusual weight loss • Increased fatigue • Irritability • Blurry vision

Macrovascularcomplications:

• Coronary artery disease • Cerebrovascular disease (stroke) • Peripheral vascular disease (PVD)

Microvascular complications

• Retinopathy • Nephropathy • Neuropathy


Signs and Symptoms of Diabetes Mellitus

Type 1 diabetes usually presents in acute or subacute manner with classic symptoms of frequent urination (polyuria), excessive thirst (polydipsia), extreme hunger (polyphagia), and unusual weight loss.

In the younger person with type 2 diabetes, classic symptoms may or may not be present at the time of diagnosis. The only symptoms reported may be fatigue or vision changes.

In the older individual, symptoms reported may be minimal and include fatigue and lethargy. An increased frequency of urinary tract infections or vaginal yeast infections may be seen in this population . The onset of diabetes in the older patient is frequently insidious and can be accompanied by cognitive changes.

Diabetes is diagnosed by fasting hyperglycemia. Unfortunately, type 2 diabetes can be asymptomatic for 4-7 years prior to diagnosis. During this lag time microvascular complications may develop as a result of persistent hyperglycemia. At the time of diagnosis, up to 21% of patients have retinopathy. Other complications at diagnosis may include some degree of neuropathy and microalbuminuria

The American Diabetes Association Clinical Practice Guidelines 2009 include criteria for pre-diabetes and diabetes testing in asymptomatic adults. Initial evaluation of a newly diagnosed patient includes baseline evaluation for retinopthy, neuropathy, nephropathy, cardiovascular disease, cerebrovascular disease and peripheral arterial disease. Referrals for Diabetes self-management education, medical nutrition therapy and dilated eye exam should be considered.


Macrovascular Complications of Diabetes

Coronary Artery Disease (CAD) • silent ischemia • angina • myocardial infarction

Cerebrovascular Disease (CVD) • Stroke (CVA) • TIA (Transischemic attack)

Peripheral Vascular Disease (PVD) • diabetic foot • intermittent claudication

Cadiovascular disease [CVD] is a major cause of morbidity and mortality in patients with Diabetes. Hypertension and dyslipidemia are often present in patients with diabetes and confer additional risk beyond that of diabetes. Aggressive lifestyle change and medication for blood pressure and cholesterol are required to reduce cardiovascular and cerebrovascular risk.

Peripheral vascular disease, neuropathy and impaired circulation increase risk of foot infections and limb amputations. These contribute to morbidity, disability, and reduced quality of life in people with diabetes.

As reviewed previously, diabetes is the leading cause of limb amputations and End Stage Renal Disease requiring dialysis. Early recognition and management of risk factors can prevent or delay complications..

More Information Additional information regarding testing, diagnosis and management of macrovascular complications review the Standards of Medical Care in Diabetes – 2009 [Reference below].


Microvascular Complications of Diabetes

While the macrovascular complications of diabetes are the ones most likely to result in death, it is the microvascular complications that result in the greatest impact on the person’s quality of life and degree of disability. Up to 70% of people with diabetes will experience nervous system damage in their lifetime. The pain and discomfort caused by diabetic neuropathy, at a minimum, contributes to a diminished quality of life. At its worst, diabetic neuropathy is a major contributing cause of lower-limb amputation.

Macrovascular Complications:

• Retinopathy • Nephropathy • Neuropathy

Retinopathy Diabetic retinopathy is the leading cause of legal blindness in people with Diabetes in the United States. Retinopathy occurs as a result of elevated glucose levels which cause structural, physiological and biochemical changes that alter cellular metabolism, retina blood flow and retinal capillary function.

The first manifestation of diabetic retinopathy is abnormalities in the retinal blood vessels such as microaneurysms. If these are detected, more are likely to occur. If these are not addressed, diabetic retinopathy can progress from a mild, asymptomatic form to severe, rapidly progressing retinopathy. In addition to diabetic retinopathy, cataracts and glaucoma are also leading causes of blindness.

The development and progression of diabetic retinopathy correlate strongly with glycemic control and duration of diabetes. Modifiable risk factors for retinopathy include hyperglycemia and blood pressure. Intensive management of both are important in slowing the progression of retinopathy.



Retinopathy is divided into two categories: Non-proliferative retinopathy and proliferative retinopathy.

Non-proliferative retinopathy is characterized by microaneurysms, venous loops, retinal hemorrhages, hard exudates and soft exudates.

Proliferative retinopathy is defined as presence of new blood vessels with or without vitreous hemorrhage. Proliferative retinopathy represents progression of non-proliferative retinopathy.

Patients with type 1 diabetes should have a comprehensive, dilated eye examination within the first year after diagnosis. In contrast, patients with type 2 diabetes should have an initial dilated eye examination shortly after diagnosis. All patients should have an annual follow-up examination; if the examination is normal, follow-up may be scheduled every two to three years. If retinopathy is present, more frequent examinations may be needed.

Nephropathy Diabetic nephropathy is defined by macroalbuminuria:

• urinary albumin excretion of more than 300 milligrams in a 24-hour collection or • macroalbuminuria and abnormal renal function characterized by abnormal serum creatinine, calculated creatinine clearance, or glomerular filtration rate (GFR).

Diabetic nephropathy if the most common cause of end-stage kidney disease in the United states. Approximately one-quarter to one-third of patients with type 1 or type 2 diabetes develop this to some degree.

The American Diabetes Association recommends the random spot urine collection for nephropathy screening. All patients with Diabetes should be tested annually for the presence of microalbuminuria [trace levels of albumin in the urine, an indicator of early nephropathy].



In patients with type 1 diabetes, annual screening should begin 5 years after the diagnosis. In patients with type 2 diabetes, annual screening should start at the time of diagnosis.

The most precise evaluation of albuminuria [microalbuminuria or macroalbuminuria] is a twenty-four hour urine sample to measure creatinine clearance and protein loss.

Classification of Urine Albumin Excretion – Random Spot Urine Test Results

• Normal result: less than thirty micrograms per milligram of creatinine • Microalbuminuria: between thirty and two hundred ninety nine micrograms per milligram of creatinine • Macroalbuminuria: three hundred or more micrograms per milligram of creatinine

Because of variability in urine albumin excretion, two of three specimens collected over three to six months should be abnormal before the diagnosis of microalbuminuria is made. Factors which can cause false positives include febrile illness, exercise within the previous twenty-four hours, infection, hematuria, menstruation, marked hyperglycemia and pronounced hypertension.

Neuropathy Neuropathy is a heterogeneous condition that is associated with nerve pathology. It is classified by the affected nerves and can be focal, diffuse, sensory, motor, or autonomic. While the macrovascular complications of diabetes are the ones most likely to result in death, microvascular complications result in significant disability and diminished quality of life.

Diabetic neuropathy is prevalent in the diabetic population; and up to 70% of people with diabetes will develop some degree of neuropathy and impairment.



Diabetes-related neuropathies have been classified based on clinical manifestations and anatomical findings. Classification of neuropathy includes:

• rapidly reversible neuropathy [hyperglycemic neuropathy] • Generalized symmetrical polyneuropathy • autonomic neuropathy • focal and multifocal neuropathies

Generalized symmetrical polyneuropathy includes acute sensory neuropathy and chronic sensorimotor neuropathy [distal polyneuropathy]. Acute sensory neuropathy is characterized by severe pain, weight loss, depression and erectile dysfunction. Patients report burning, deep, sharp, stabbing, “shock-like sensations” in the lower limbs. It is usually associated with poor glycemic control and may be seen with rapid improvement of glucose levels.

Sensorimotor neuropathy can be either small-fiber or large-fiber neuropathy and can be either diffuse [progresses with increasing duration of diabetes] or focal [usually remits completely].

Autonomic neuropathy can be either functional [gastroparesis with hyperglycemia and ketoacidosis] or organic, where nerve fibers are lost. Autonomic neuropathy can affect any system in the body and can occur as early as the first year after diagnosis. Manifestations can be seen in the cardiovascular, gastrointestinal, and genito-urinary systems.

Symptoms of autonomic neuropathy commonly include reduced exercise tolerance, edema, supine or nocturnal hypotension, and heat intolerance.

Additional information on the complications and testing please review the Standards of Medical Care in Diabetes – 2009 [Reference below].



About 60-70% of people with diabetes have mild to severe forms of nervous system damage that can result in the following symptoms:

• Paresthesias, impaired sensation or pain in the feet or hands known or abnormal sensations such as burning, tingling, pricking

• Gastroparesis, slowed digestion of food in the stomach • Carpal tunnel syndrome • Muscle weakness • Impotence • Postural hypotension • Diarrhea

The microvascular complications of diabetes arise from long term complications of diabetes affecting small blood vessels. These classically have included retinopathy, nephropathy and neuropathy. Retinopathy is divided into two main categories. Non-proliferative retinopathy and proliferative retinopathy. Non-proliferative retinopathy can be recognized by development of microaneurysms, venous loops, retinal hemorrhages, hard exudates and soft exudates. Proliferative retinopathy is defined as presence of new blood vessels with or without vitreous hemorrhage. Proliferative retinopathy represents a progression of non-proliferative retinopathy.

Diabetic nephropathy is defined as the presence of persistent proteinuria >0.5 gms/24 hours. Overt nephropathy is characterized by progressive decline in renal function resulting in end stage renal disease.

Neuropathy is a heterogenious condition that is associated with nerve pathology. The condition is classified according to the nerves affected. The classification of neuropathy includes focal, diffuse, sensory, motor and autonomic neuropathy.


Other Complications of Diabetes Mellitus

Diabetic ketoacidosis (DKA) Hyperglycemic, hyperosmolar nonketotic syndrome (HHNS) Congitive Impairment Depression

Risk Factors: • Age • Hydration status • Concurrent medications • Level of glycemic control

Life-threatening complications of diabetes include DKA (diabetic kito acidous) and HHNS (hypersmolar hyperglycemic non-ketotic syndrome). Insulin deficiency, either relative or absolute, and elevated levels of stress-responding, hormones (e.g., glucagon, catecholamines, growth hormone, and cortisol) are involved in the development of these conditions.

These complications can be seen in type 1 or type 2 diabetes. DKA is usually seen in patients with type 1 diabetes and HHNS in patients with type 2 disease. The clinical management of these syndromes involves careful evaluation and correction of the metabolic and volume status of the patient, identification and treatment of precipitating and comorbid conditions, implementation of a treatment regimen and a plan to prevent recurrence.


Other Complications of Diabetes Mellitus

Risk factors contributing to development of HHNS include increased age, inadequate hydration, especially when ill, and medications such as steroids. HHNS can have an insidious onset and may not be detected until severe hyperglycemia and mental status changes are present. Elderly patients should have a sick-day plan to ensure that medications are continued and hydration is adequate.

Other complications of diabetes in the elderly include cognitive impairment and depression. Cognitive dysfunction has been associated with both type 1 and type 2 diabetes. In older patients with type 2 diabetes, the risk of Alzheimer’s disease is increased.

Cognitive dysfunction may make it difficult for patients to follow nutrition, medication, and activity regimens. This can result in increased risk of hypoglycemia as well as progression of diabetes complications. It is important to consider cognitive deficits when designing treatment regimens.

Elderly persons with diabetes also have a high risk of depression. Untreated depression is associated with poor glycemic control. Treating depression improves the patient’s ability to self-manage diabetes. This can resulted in improved glycemic control and quality of life.


Screening Guidelines for High Risk Patients

The American Diabetes Association [ADA] Standards of Medical Care in Diabetes—2009 have established screening criteria for pre-diabetes and diabetes in asymptomatic, high-risk adults. Because age is a major risk factor for diabetes, testing of those without other risk factors should begin no later than age 45 years.

Asymptomatic patients and those at high-risk of developing diabetes should be screened according to the 2009 ADA Standards. Testing should be considered in all adults who are overweight (Body Mass Index greater than 25 kilograms per meter squared) and have additional risk factors such as physical inactivity and family history. In the absence of any specific risk factors, testing for pre-diabetes and diabetes should begin at the age of 45 years. If results are normal, testing should be repeated at 3-year intervals, with more frequent testing depending on initial results and risk status.

The American Diabetes Association [ADA] Standards of Medical Care in Diabetes—2009 have established screening criteria for pre-diabetes and diabetes in asymptomatic, high-risk adults. Because age is a major risk factor for diabetes, testing of those without other risk factors should begin no later than age 45 years.

Asymptomatic patients and those at high-risk of developing diabetes should be screened according to the 2009 ADA Standards. Testing should be considered in all adults who are overweight (Body Mass Index greater than 25 kilograms per meter squared) and have additional risk factors such as physical inactivity and family history. In the absence of any specific risk factors, testing for pre-diabetes and diabetes should begin at the age of 45 years. If results are normal, testing should be repeated at 3-year intervals, with more frequent testing depending on initial results and risk status.


Screening Guidelines for High Risk Patients

Screening

1. Testing should be considered in all adults who are overweight (Body Mass Index greater than 25 kilograms per meter squared) and have additional risk factors:

• physical inactivity • first-degree relative with diabetes • members of a high-risk ethnic population (e.g., African American, Latino, Native American, Asian American, Pacific Islander) • women who delivered a baby weighing 9 pounds or more or were diagnosed with Gestational Diabetes Mellitus • hypertension (140/90 millimeters mercury or on therapy for hypertension) • HDL cholesterol level lower than 35 milligrams per deciliter (0.90 millimoles per liter) and/or a triglyceride level greater than 250 milligrams per deciliter (2.82 millimoles per liter) • women with polycystic ovarian syndrome (PCOS) • Impaired Glucose Tolerance or Impaired Fasting Glucose on previous testing • other clinical conditions associated with insulin resistance (for example severe obesity, acanthosis nigricans) • history of Cardiovascular disease

2. In the absence of the above criteria, testing for pre-diabetes and diabetes should begin at the age of 45 years

3. If results are normal, testing should be repeated at least at 3-year intervals, with more frequent testing depending on initial results and risk status.

http://care.diabetesjournals.org/content/32/Supplement_1/S15.full.pdf+html


Diagnostic Criteria for Diabetes

There are three laboratory tests available to diagnose diabetes:

1. Fasting Plasma Glucose greater than 126 milligrams per deciliter (7.0 millimoles per liter)*. Fasting is defined as no caloric intake for at least 8 h.

OR

2. Symptoms of hyperglycemia and a casual (random) plasma glucose _200 milligrams per deciliter (11.1 millimoles per liter). Casual (random) is defined as any time of day without regard to time since last meal. The classic symptoms of hyperglycemia include polyuria, polydipsia, and unexplained weight loss.

OR

3. A two-hour plasma glucose greater than 200 milligrams/deciliter (11.1 millimoles per liter) during an Oral Glucose Tolerance Test. The test should be performed as described by the World Health Organization using a glucose load containing the equivalent of 75-grams of anhydrous glucose dissolved in water.*

*In the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat testing on a different day

http://care.diabetesjournals.org/content/32/Supplement_1/S14.full.pdf+html



Diagnosis Criteria

For the diagnosis of diabetes:

● The A1C assay is an accurate, precise measure of chronic glycemic levels and correlates well with the risk of diabetes complications.

● The A1C assay has several advantages over laboratory measures of glucose.

● Diabetes should be diagnosed when A1C is greater than 6.5 percent Diagnosis should be confirmed with a repeat A1C test. Confirmation is not required in symptomatic subjects with plasma glucose levels greater than_200 milligrams per deciliter (11.1 millimoles per liter).

● If A1C testing is not possible, previously recommended diagnostic methods (for example Fasting Plasma Glucose or 2 Hour Post Glucose load, with confirmation) are acceptable.

● A1C testing is indicated in children in whom diabetes is suspected but the classic symptoms and a casual plasma glucose greater 200 milligrams per deciliter (11.1 millimoles per liter) are not found.

For the identification of those at high risk for diabetes:

● The risk for diabetes based on levels of glycemia is a continuum; therefore, there is no lower glycemic threshold at which risk clearly begins. ● The categorical clinical states pre-diabetes, Impaired Fasting Glucose, and Impaired Glucose Tolerance fail to capture the continuum of risk and will be phased out of use as A1C measurements replace glucose measurements.



●As for the diagnosis of diabetes, the A1C assay has several advantages over laboratory measures of glucose in identifying individuals at high risk for developing diabetes.

● Those with A1C levels below the threshold for diabetes but geater than or equal to 6.0% should receive demonstrably effective preventive interventions. Those with A1C below this range may still be at risk and, depending on the presence of other diabetes risk factors, may also benefit from prevention efforts.

● The A1C level at which population-based prevention services begin should be based on the nature of the intervention, the resources available, and the size of the affected population.

Retrieved from: http://care.diabetesjournals.org/content/32/7/1327.full.pdf+html

Another recent change is the American Diabetes Association recommendation to use the estimated average glucose, or eAG when reporting the A1C to patients.



Another recent change is the American Diabetes Association recommendation to use the estimated average glucose, or eAG when reporting the A1C to patients.

Correlation of A1C with average glucose:

A1C (%) Mean plasma glucose mg/dl mmol/l 6 126 7.0 7 154 8.6 8 183 10.2 9 212 11.8 10 240 13.4 11 269 14.9 12 298 16.5

A calculator for converting A1C results into eAG, in either mg/dl or mmol/l,and other professional and patient information materials are available at http://professional.diabetes.org/eAG

Retreived from http://care.diabetesjournals.org/content/32/Supplement_1/S13.full.pdf+html


Factors Predisposing the Elderly to Diabetes

• Physiologic changes • Lifestyle • Medical Conditions • Pharmacotherapy

There are many factors which contribute to the development of diabetes in the elderly. These include physiologic changes associated with the normal aging process such as reduced beta-cell volume and function, insulin resistance, and hypertension. Lifestyle risk factors include obesity, diet, and decreased physical activity or mobility concerns.

Multiple comorbid illnesses and the pharmacotherapy for these conditions may precipitate hyperglycemia and increase the risk of diabetes. For example, persons who require corticosteroid treatment to control diseases such as Rheumatoid Arthritis, Chronic Obstructive Lung Disease or other acute conditions treated with intermittent steroid use may be prone to hyperglycemia.

Nutrition, activity level, and obesity are modifiable risk factors in comparison to age and beta-cell loss. It is important to provide education on lifestyle changes which reduce the risk of developing diabetes. A modest weight loss of 5-7% of body weight can reduce the risk of diabetes and improve blood pressure and cholesterol. In patients with diabetes, the same weight loss can reduce insulin resistance and improve glycemic control. Older persons should be encouraged to start an activity program such as walking if medically approved.


Resources

For additional information, see:

American Diabetes Association. Position Statement. Standards of Medical Care in Diabetes. Diabetes Care 32:S13-S61, © 2009 by the American Diabetes Association American Association of Diabetes Educators: Position Statement: Special considerations for the education and management of older adults with diabetes. The Diabetes Educator 2002;26:37-39.

The Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med, 2002 346 6:393-403.

The Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001 344[18]: 1343-1350.

Gallagher EJ, LeRoith d, Karnieli E. The Metabolic Syndrome-from Insulin Resistance to Obesity and Diabetes. Endocrinol Metabol Clin N Am 2008 37;559-579.

Gregg EW, Gu Q,Cheng YJ, Narayan, KM, Cowie CC. Mortality Trends in Men and Women with Diabetes, 1971 to 2000. Ann Intern Med. 2007 June 18 147:149-155.

Holman RR, Paul SK, Bethel MA, Matthews DR, Neil AW. 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Engl J Med 2008;359:1577-89.

The International Expert Committee. International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes. Diabetes Care July 2009 32:1327-1334.


Resources

Liebovitz, HE; editor. Therapy for Diabetes Mellitus and Related Disorders. 4th ed. Alexandria [VA]: American Diabetes Association; 2004.

Meneilly GS. Diabetes in the elderly. Med Clin N Am 2006 90:909-923.

Mensing C. editor in chief, Cypress M, Halstenson C, McLaughlin s, Walker EA, section editors. The Art and Science of Diabetes Self-Management Education, A Desk Reference for Healthcare Professionals.Chicago, American Association of diabetes Educators; 2006.

Pan X-R, Li G-W, Wang J-X, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:537-44.

Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-50.


Resources

The American Diabetes Association: http://www.diabetes.org

The American Association of Clinical Endocrinologists http://www.aace.com.

American Association of Diabetes Educators, http://www.diabeteseducator.org

The American Geriatrics Society: Guidelines for Improving the Care of the Older Person with Diabetes Mellitus . California Healthcare Foundation/American Geriatrics Society Panel on Improving Care for Elders with Diabetes [JAGS 51:S265–S280, 2003 © 2003 by the American Geriatrics Society]. URL: http://www.americangeriatrics.org/products/positionpapers/JAGSfinal05.pdf

The Centers for Disease Control and Prevention. http://www.cdc.gov/diabetes/index.htm

The National Diabetes Education Program : http://ndep.nih.gov/

The National Institute for Diabetes & Digestive & Kidney Disease; http://www2.niddk.nih.gov/


Diabetes Mellitus: Treatment

Learning Objectives:

By the end of this Review you should be able to:

• Classify an older adult as having diabetes mellitus given clinical presentation and laboratory data.

• Construct a treatment plan for an elderly individual given a patient case, taking into account patient and age-related variables.

•  Educate an elderly individual on the non-pharmacologic and pharmacologic management of their diabetes.


Factors to Consider when Establishing Therapeutic Goals for Diabetic Patients

• Coexisting medical conditions • Life expectancy • Patient’s desires and goals • Social and financial support • Cognitive function • Medication regimen complexity

When managing diabetes in the elderly, treatment goals must be established with the patient, their social support team, and other members of the health care team. The treatment plan must be patient-centered. Factors to be considered are listed on your screen. One of the first is the presence of coexisting health problems such as depression, visual impairment, arthritic changes, movement disorders, neuropathy, and renal and hepatic function. The patient’s life expectancy is also a consideration in the aggressiveness of the treatment plan.

It is important to be aware of financial implications of the medications and the patient’s economic resources when developing a cost-effective, individualized treatment plan.

Cognitive impairment and lack of social support can affect regimen adherence, for this reason, treatment approaches should be formulated with “simplicity” in mind. Often, a less aggressive treatment approach is preferable in patients with advanced diabetes complications, limitations in their activities of daily living, impaired cognitive function, limited social support, and other neuropsychiatric disorders.

When selecting medications for the elderly patient, consideration must be given to the individual’s risk of hypoglycemia. Cognitive impairment and autonomic changes can result in hypoglycemia unawareness and inability to respond appropriately to symptoms of hypoglycemia. Hence, the treatment plan must be developed with this in mind.


ADA Glycemic Control Guidelines

Table-1: 2009 ADA Clinical Practice Recommendations

Key concepts in setting glycemic goals:

• A1C is the primary target for glycemic control.

• Goals should be individualized based on: • duration of diabetes • age/life expectancy • comorbid conditions • known Cardiovascular Disease or advanced microvascular complications • hypoglycemia unawareness • individual patient considerations

• More or less stringent glycemic goals may be appropriate for individual patients.

• Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial glucose goals.

Summary of glycemic recommenda1ons for non-‐pregnant adults with diabetes

A1C <7.0%*

Preprandial capillary plasma glucose 70–130 mg/dl (3.9–7.2 mmol/l)

Peak postprandial capillary plasma glucose <180 mg/dl (<10.0 mmol/l)


ADA Glycemic Control Guidelines

Referenced to a nondiabetic range of 4.0–6.0% using a DCCT-based assay. Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally peak levels in patients with diabetes.

Diabetes Care 32:S13-S61, 2009. I: 10.2337/dc09-S013 © 2009 by the American Diabetes Association

The American Diabetes Association recommendations for glycemic control can be found above. These goals may be appropriate for some elderly individuals but, frequently, treatment goals must be adjusted to facilitate improved control with less risk of hypoglycemia.


Options for Treating Diabetes Mellitus

Non-Pharmacologic Options: • Diet (medical nutrition therapy) • Exercise (physical activity, resistance training)

Pharmacologic Options • Oral agents

• Hypoglycemics [secretogogues] • Sulfonylureas • Meglitinides

• Antihyperglycemics • Sensitizers

• Biguanides • Thiazolidinediones

• DPP-4 Inhibitors • Alpha-glucosidase Inhibitors • Bile Acid Sequestrant

• Insulin • GLP-1 Analog

• Amylin Analog



Management of hyperglycemia in type 2 diabetes -‐ Summary of An1diabe1c Interven1ons

Interven1on Expected Decrease in A1C [%]

Advantages -‐ Disadvantages

Step 1: IniGal Lifestyle changes to decrease weight and increase acGvity

1-‐2 Advantages:

-‐ Low cost, benefits beyond weight loss

Disadvantages: -‐ IntervenGons fail for most paGents within the first year

MeGormin 1.5 Advantages: -‐ Weight neutral -‐  Inexpensive

Disadvantages: -‐ ProblemaGc GastrointesGnal side effects -‐ Rare lacGc acidosis -‐  LimitaGons based on serum creaGnine






Step 2: Addi1onal Therapy

Insulin 1.5-‐2.5 Advantages: -‐ No dose limitaGon -‐ Inexpensive [depends on product selecGon] -‐ Improvements in Lipid Profile

Disadvantages: -‐ InjecGons -‐ Frequent monitoring -‐ PotenGal for hypoglycemia -‐ Weight gain -‐  Frequent glucose tesGng

Sulfonylureas 1.5 Advantages: -‐ Inexpensive

Disadvantages: -‐ Weight gain -‐ Hypoglycemia [relaGvely infrequent]*






Thiazolidinediones 0.5–1.4 Advantages: - Improvements in Lipid Profile

Disadvantages: - Fluid retenGon - Weight gain - High cost - LimitaGons due to co-‐morbid diagnoses such as Heart Failure

Alpha-‐glucosidase Inhibitors 0.5 – 0.8

Advantages: - Weight neutral

Disadvantages: - GastrointesGnal side effects [flatulence] - Three Gmes a day dosing - High cost

Megli1nides** 1-‐1.5 Advantages: - short duraGon of acGon

Disadvantages: - Three Gmes a day dosing before meals - High cost






DPP-‐IV Inhibitors 0.48-‐0.85 Advantages: - Once daily dosing - Minimal risk of hypoglycemia as monotherapy - Improvements in fasGng and post-‐prandial glucose levels - Lack of weight gain - RelaGvely mild side-‐effect profile

Disadvantages: - Cost - CauGon when used in renal dysfuncGon

Exena1de 0.5 – 1.0 Advantages: - Weight loss

Disadvantages: - InjecGons - Frequent gastrointesGnal side effects - High cost - Scant long-‐term use data



*Severe hypoglycemia is relatively infrequent with sulfonylurea therapy. The longer-acting agents (e.g. chlorpropamide, glyburide, and sustained release glipizide) are more likely to cause hypoglycemia than glipizide, glimepiride

.**Repaglinide is more effective at lowering A1C than nateglinide

Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy. Diabetes Care 31: 174, © 2008 by the American Diabetes Association, Inc., and Springer.




Pramlin1de 0.5-‐1.0 Advantages: - Weight loss

Disadvantages: - MulGple daily injecGons [pre-‐meal] - GastrointesGnal side effects - High cost - Scant long-‐term data



While medications can be initiated at the time of diagnosis, Lifestyle changes such as weight loss and increased activity are still the cornerstone of diabetes care and should be included in the initial and ongoing diabetes management plan. Recent clinical trials have documented the benefit of Lifestyle changes in improving diabetes control.

Selection of initial pharmacotherapy should be based on an evaluation of medication-specific contraindications, dosing schedule, organ function, the side effect profile, drug interactions, comorbid diagnoses, and cost. The above table provides a summary of available options for monotherapy and the expected reduction in the A1C. The patient’s baseline A1C and the therapeutic goal must be considered when deciding on the initial medication regimen.

A comprehensive pharmacotherapy plan must include a schedule for monitoring medication safety, tolerability, and efficacy for each pharmacologic agent. This plan must be communicated with all members of the healthcare team as well as the patient and his or her social support system/caregiver.


First Generation Sulfonylureas

Chlorpropamide [Diabinese®]:

Indications: • Management of type 2 diabetes

Contraindications/Precautions: • Diabetic ketoacidosis and type 1 diabetes • Avoid in elderly, renal dysfunction, debilitation, malnourished and Heart Failure.

Mechanism of Action: • Stimulation of pancreatic insulin secretion • Peak action 2-4 hours • Duration of action: 24-72 hours; half-life 24-48 hours • Metabolites: active or unchanged • Excretion: urine

Dosing: • Initial dose 250 mg daily, after 5-7 days increase by 50-125 mg every 3-5 days to desired level of glucose

control • In the elderly or debilitated patient initiate at 100-125 mg daily • Take with morning meal



Adverse Drug Reactions: • severe, prolonged hypoglycemia • diarrhea, nausea, vomiting • photosensitivity reaction • disulfiram-like reactions

Significant Drug Interactions: • Alcohol may increase hypoglycemic risk and precipitate a disulfiram-like reaction • Beta-blockers may potentiate hypoglycemia and mask symptoms of hypoglycemia • Corticosteroids may increase risk of hyperglycemia • Antihypertensive agents [calcium channel blockers, diuretics] may increase risk of hyperglycemia • Coumarins may potentiate hypoglycemia

Tolbutamide [Orinase®]:

Indications: • Management of type 2 diabetes

Contraindications/Precautions: • Diabetic ketoacidosis and type 1 diabetes • Hypoglycemia risk in the elderly, debilitated or malnourished



Mechanism of Action: • Stimulation of pancreatic insulin secretion • Peak action 3-4 hours • Duration of action: 6-10 hours; half-life: 5-7 hours • Metabolites: inactive • Excretion: urine

Dosing: • Initial dose 1000-2000 mg daily; adjust dose based upon glucose response • Maintenance dose 250-3000 mg; maximum daily dose 3000 mg daily • In the elderly use lower doses to minimize hypoglycemia

Adverse Drug Reactions: • Hypoglycemia • Nausea heartburn • Allergic skin reactions • Blood dyscrasias • Rare disulfiram-like reactions • Hyponatremia • Taste disturbances

Significant Drug Interactions: • Similar to chlorpropamide

First generation sulfonylureas are rarely used in the elderly because of the long duration of action, hypoglycemia risk, and the availability of safer medications.


Second Generation Sulfonylureas

Glyburide [Diabeta®]:

Indications: • Management of type 2 diabetes as monotherapy or as add-on therapy to reduce blood glucose

Contraindications/Precautions: • Diabetic ketoacidosis and type 1 diabetes • Hypoglycemia risk in those with renal and/or hepatic disease, elderly, debilitated or malnourished patients • In acute illness [fever, trauma, stress] insulin may be needed to control glucose

Mechanism of Action: • Stimulation of pancreatic insulin secretion • Peak action 4 hours • Duration of action: 12-24 hours; half-life: 10 hours • Metabolites: inactive and weakly active • Excretion: urine 50%; feces 50%

Dosing: • Initial dose 2.5 mg daily with breakfast or first main meal [reduce dose to 1.25 mg if prone to hypoglycemia];

adjust dose based upon glucose response. Increase dose by 2.5 mg daily at weekly intervals • Maintenance dose: 1.25 - 20 mg daily or in divided doses. Doses of 10 mg daily or more may be given twice

daily; doses above 10 mg daily do not offer increased A1C reduction compared to 20 mg daily • In the elderly: initial dose 1.25 mg daily, titrate slowly in lower increments



Dosing - Micronized glyburide [Glynase Pres Tab®]: • Initial dose: 1.5 – 3 mg daily with breakfast or first main meal • In elderly/debilitated: initial dose of 0.75 mg daily • Titration: increase dose by no more than 1.5 mg per day at weekly intervals. • Maintenance dose: 0.75-12 mg once daily or in divided doses. • Maximum dose: 12 mg/day given daily or twice daily

Adverse Drug Reactions: • Hypoglycemia • Nausea heartburn • Allergic skin reactions • Blood dyscrasias • Rare disulfiram-like reactions • Hyponatremia • Hepatic function abnormalities

Significant Drug Interactions: • Similar to first-generation sulfonylurea agents • Coumarins: glyburide may increase or decrease anticoagulant effects



Glipizide [Glucotrol®]

Indications • Management of type 2 diabetes as monotherapy or as add-on therapy to reduce blood glucose levels

Contraindications/Precautions • Diabetic ketoacidosis and type 1 diabetes • Hypoglycemia risk in elderly, debilitated or malnourished patients • In acute illness [fever, trauma, stress] insulin may be needed to control glucose

Mechanism of Action • Stimulation of pancreatic insulin secretion • Peak action: 1-3 hours • Duration of action: 12-14 hours; half-life: 2-4 hours • Metabolites: inactive • Excretion: urine 80%; feces 20%

Dosing – glipizide immediate-release • Initial dose 5 mg daily with breakfast or first main meal [reduce dose to 2.5 mg if prone to hypoglycemia]; adjust

dose based upon glucose response. Increase dose by 2.5-5 mg daily after several days • Maintenance dose: 5-10 mg daily or in divided doses. Doses of 10 mg daily or more may be given twice daily;

doses above 10 mg daily do not offer increased A1C reduction compared to 20 mg daily • Administer dose 30 minutes prior to a meal • In the elderly: initial dose 2.5 mg daily, titrate in 2.5-5 mg increments after several days • Maximum dose: 40 mg/day



Dosing – glipizide extended-release [Glucotrol-XL®] • Initial dose: 5 mg daily with breakfast or first main meal • In elderly/debilitated: initial dose of 2.5 mg daily • Titration: increase by 2.5 – 5 mg per day at weekly intervals. • Maintenance dose: 5-10 mg once daily • Maximum dose: 20 mg/day; doses >15 mg should be divided [twice daily]

Adverse Drug Reactions • Hypoglycemia • Nausea, heartburn • Allergic skin reactions • Blood dyscrasias • Rare disulfiram-like reactions • Hyponatremia • Hepatic function abnormalities

Significant Drug Interactions • Similar to first-generation sulfonylurea agents • Coumarins: may potentiate hypoglycemia



• Coumarins: may potentiate hypoglycemia

Sulfonylurea combination products: • Glimepiride/Pioglitazone • Glimepiride/Rosiglitazone • Glipizide/Metformin • Glyburide/Metformin

Oral sulfonylureas are a cost-effective choice for controlling hyperglycemia. They are indicated for use in type 2 diabetes when hyperglycemia is not controlled after an adequate trial of diet and exercise. They can be used as monotherapy or in combination with other oral agents.

All sulfonylureas stimulate the release of insulin from pancreatic beta cells and enhance beta cell sensitivity to glucose. Because these agents increase insulin release, they are also known as secretagogues.

The side effect and drug interaction profile of the second generation agents is similar to that of the first generation products. Hypoglycemia is the side effect of main concern for both types. This can be prolonged and more severe than insulin-induced hypoglycemia because of the longer half-life and duration of action of the sulfonylureas. Renal function and pharmacokinetic parameters must be considered when selecting a sulfonylurea for use in an elderly individual.



Sulfonylurea therapy is monitored by finger-stick testing as well as periodic evaluation of the A1C. Home testing frequency is determined by the intensity of the regimen. The A1C is monitored quarterly until at goal, then it can be evaluated every 6-12 months.

Elderly patients and the caregiver or household members must be educated regarding signs and symptoms of hypoglycemia, treatment of hypoglycemia and the need to test before treating if hypoglycemia is suspected.

A precaution to consider when using sulfonulyreas is the warning that the administration of oral antidiabetic agents has been reported to be associated with increased risk of cardiovascular mortality when compared to treatment with nutrition therapy alone or nutrition therapy with insulin. This stems from the results of the University Group Diabetes Program prospective long-term clinical trial. The only sulfonylurea included in this trial was tolbutamide, however, this warning may apply to other members of the class because of the similar mechanism of action. Subsequently, the United Kingdom Prospective Diabetes Study [UKPDS] did not document an increase in cardiovascular mortality with sulfonylureas. The risk has been debated since then.

Glimepiride binds to a different site on the sulfonylurea receptor and has selective effects on the potassium ATP channels. These channels are of interest because they could theoretically reduce the risk of cardiovascular mortality that has been ascribed to the sulfonylureas. The blood glucose-lowering effect of glimepiride is similar to other sulfonylureas.

Both glimepiride and glipizide are safer in the elderly and those with renal impairment because of differences in metabolic and excretory pathways. In comparison to first-generation sulfonylureas, the second generation agents have fewer side effects and drug interactions. Because of the long duration of action and renally-excreted active metabolites, glyburide should be used cautiously in the elderly patient or those with renal insufficiency.



Approximately 20%-25% of patients with newly diagnosed type diabetes do not respond to initial therapy with a sulfonylurea [primary failure]. In contrast, 3-5% of patients who initially achieved goal glucose experience worsening control each year [secondary failures].

The natural history of diabetes is one of progressive loss of beta-cell function and increasing hyperglycemia which necessitates changes in treatment. Worsening control while adhering to a sulfonylurea regimen may not be due to patient nonadherence but to the pregressive beta-cell decline. Other considerations in secondary failure include presence of insulin resistance, weight gain, and sedentary lifestyle.


Meglitinides

Repaglinide [Prandin®]

Indications • Adjunct to nutrition and exercise to lower blood glucose in patients with type 2 diabetes who have not met goals

through lifestyle changes • Use in combination with metformin or thiazolidinedione

Contraindications/Precautions • Patients with ketoacidosis and/or type 1 diabetes • Increased risk of hypoglycemia in the elderly or those with renal or hepatic impairment • Secondary failure may occur over time • Not indicated for use with NPH insulin

Mechanism of Action • Meglitinides are structurally unrelated to sulfonulyreas but they lower glucose levels by stimulating insulin release from

the pancreas.

• Insulin release is dependent on functioning beta-cells and is also dependent on glucose levels. Insulin release decreases at lower glucose concentrations. • Peak action: 1 hour • Duration of action; half-life: 1 hour • Metabolites: inactive • Excretion: urine 0.1% excreted unchanged; feces 90%


Meglitinides

Dosing: • Administer at the start of the meal or within 15-30 minutes before the meal • If an extra meal is eaten or a meal is skipped, a dose should be added or omitted. • If A1C <8% and treatment naive: 0.5 mg initial dose before the meal • If A1C >8% previously treated: initial dose 1-2 mg before each meal • Dose adjustments are guided by glucose response and can be increased until goal glycemic control is achieved • Adjustments should be done at weekly intervals or longer

• Maximum dose: • Prandial dose: 4 mg • Total daily dose: 16 mg/day • Renal dysfunction [CrCl 20-40 mg/dL]:

• Initial dose: 0.5 mg with careful titration

Adverse Drug Reactions: • Hypoglycemia • Upper respiratory infections, bronchitis, sinusitis, rhinitis • Nausea, diarrhea, constipation, vomiting, dyspepsia • Headache, chest pain

Significant Drug Interactions: • CYP2C8 inhibitors: may inhibit repaglinide metabolism • CYP3A4 inducers: may increase repaglinide metabolism • Gemfibrozil: may increase glucose levels and inhibit metabolism; avoid concomitant use • Other interactions are similar to the sulfonylureas


Meglitinides

Nateglinide [Starlix®]

Indications: • Adjunct to nutrition and exercise to lower blood glucose in patients with type 2 diabetes who have not met goals

through lifestyle changes • Use in combination with metformin or thiazolidinedione

Contraindications/Precautions: • Patients with ketoacidosis and/or type 1 diabetes • Increased risk of hypoglycemia in the elderly or debilitated • Secondary failure may occur in prolonged therapy

Mechanism of Action: • Similar to repaglinide.

• Peak action: ½ -1 hour • Duration of action; half-life: 1 hour • Metabolites: inactive • Excretion: urine 16% excreted unchanged

Dosing • Administer 1-30 minutes before meals • Similar to repaglinide, an extra dose of nateglinide should be added or omitted if an additional meal is eaten or

skipped. • Initial and maintenance: 120 mg three times daily as monotherapy or in combination with metformin or

thiazolidinedione • If A1C is close to goal the dose can be reduced to 60 mg three times daily


Meglitinides

Adverse Drug Reactions: • Hypoglycemia • Upper respiratory infections • Dizziness, diarrhea, back pain • Jaundice, cholestatic hepatitis, elevated liver enzymes

Significant Drug Interactions: • Similar to the sulfonylureas and repaglinide

Combination products: • Repaglinide/Metformin

The meglitinides differ from sulfonylureas in their rapid peak and short half-life. This contributes to a reduced risk of hypoglycemia which may be beneficial in the elderly or those predisposed to hypoglycemia. In addition, these may be appropriate for the patient who eats only two meals a day or those with a varied meal plan such as patients with Dementia where meals may be erratic.

Disadvantages of meglitinides include less reduction in the A1C and greater cost compared to sulfonylureas. This class also has the risk of secondary failure with prolonged use. Advantages include use as an alternative to sulfonyureas in patients with a true sulfa allergy and easier dosing with nateglinide compared to repaglinide because dose titration per se is not needed.


Oral Antihyperglycemic Agents

• Biguanides • Thiazolidinediones • Alpha-glucosidase inhibitors • Bile Acid Sequestrants • DPP-4 Inhibitors

Available oral antihyperglycemic agents include the biguanide metformin, alpha-glucosidase inhibitors such as acarbose and miglitol, thiazolidinediones, such as rosiglitazone and pioglitazone, the bile acid sequestrant colesevelam, and the DPP-4 inhibitors, sitagliptin and saxagliptin [approved 7/31/09]. These agents are referred to as antihyperglycemic agents because they do not directly affect insulin levels and thus are less prone to precipitating hypoglycemia when used as monotherapy.

Colesevelam is FDA approved as adjunctive therapy to improve glycemic control in adults with type 2 diabetes. It can be added to metformin, sulfonylureas, or insulin monotherapy and can be used in combination with other antidiabetic agents. This treatment option addresses two major cardiovascular risk factors; elevated LDL cholesterol and blood glucose in patients with type 2 diabetes.

If the A1C is above 8.5-9%, it may be necessary to consider initiating insulin because oral agents generally will not reduce the A1C to goal at this level of glycemia. In addition, at higher A1C levels, secretagogues may not be efficacious because of the level of glucotoxicity. This is a patient-specific consideration. Generally patients are started on an oral agent and subsequent pharmacotherapy is determined by the individual’s glycemic response to oral agents.


Biguanides Metformin

Indications:

• Monotherapy for those unable to achieve glycemic goals after a trial of diet and exercise. • Combination therapy with oral agents and insulin

Contraindications/Precautions:

• Contraindicated in males with serum creatinine >1.5 mg/dL and in females with serum creatinine >1.4 mg/dL; and in patients with abnormal creatinine clearance • Acute or chronic metabolic acidosis • Congestive heart failure class 3 or 4 • Age >80 years, unless serum creatinine indicates normal renal function. • Chronic alcohol intake • Monitoring should include baseline serum creatinine with periodic follow-up testing

Mechanism of Action:

• Primary: reduction of hepatic basal glucose production by suppression of gluconeogenesis and glycogenolysis • Secondary: improve insulin stimulated glucose transport in skeletal muscle • Peak action: 1-2 hours • Half-Life: 1.5 -4.9 hours • Metabolism: none • Elimination: urine – 90%



Dosing: • Immediate Release [IR] Formulation [Glucophage®] • Initial dose: 500 mg or 850 mg once daily before the largest meal • Dose titration: increase by 500 mg on a weekly basis up to 2500 mg/day. If using 850 mg tablets a three times

daily schedule should be used. If using 1000 mg tablets it should be dosed twice daily • In the elderly patient, metformin should not be titrated to maximum dose • Extended Release [XR] formulation [Glucophage XR®] • Initial dose: 500 mg once daily with evening meal. • Dose titration: 500 mg/week • Maximum dose of 2,000 mg

Adverse Drug Reactions • Gastrointestinal side effects

• Diarrhea, nausea, vomiting • Bloating, flatulence • Anorexia and dysgeusia or altered taste

• Lactic Acidosis • Occurs primarily in patients with predisposing conditions which may compromise renal function (e.g., MI, CHF, sepsis). • Incidence: Rare; 0.03 cases/1000 patients-years of use • Mortality rate: ~ 50% of cases result in death



Significant Drug Interactions

• Cationic drugs [eg. digoxin, amiloride, morphine , ranitidine, vancomycin]: may increase metformin serum levels • Corticosteroids and estrogen: may decrease metformin effect when given with medications that can cause

hyperglycemia • Thiazides: may cause hyperglycemia

Available Combination Products

• Metformin/glipizide • Metformin/glyburide • Metformin/pioglitazone • Metformin/rosiglitazone • Metformin/repaglinide • Metformin/sitagliptin

The most common side effects of metformin are gastrointestinal in nature. While these can be problematic, they are usually transient and resolve with continued therapy. Administering metformin with meals and gradual dose titration can reduce the occurence of of these side effects. Metformin may not be appropriate in elderly patients which

Gastrointestinal disorders such as Irritable Bowel Syndrome or Crohn’s Disease because it may worsen the bowel dysfunction. Patient education should include the reason for slow dose titration, take with meals, inform their healthcare provider if diarrhea or other intolerable side effects occur. Metformin XL may be an option in those who experience diarrhea.



Metformin can result in improvements in the lipid profile, specifically in triglycerides and the low-density lipoprotein fraction. Unlike the thiazolidinediones and sulfonyllurea agents, metformin is unlikely to cause weight gain, and many patients will have mild weight loss.

Although it is rare, the most serious potential side effect of metformin use is lactic acidosis which can occur in patients with risk factors such as renal dysfunction. For this reason, metformin is contraindicated in patients with predisposing conditions such as cardiovascular collapse, acute myocardial infarction, severe infection, use of iodinated contrast media in radiologic tests, and major surgical procedures. Other risk factors for lactic acidosis include liver dysfunction, a history of alcohol abuse or binge drinking, and acute or chronic metabolic acidosis.

Metformin should be stopped in patients undergoing major surgery. Therapy can be resumed post-procedure after oral intake resumes and renal function is normal. This should be discussed with the patient prior to procedures so he/she is aware that it will be stopped temporarily and they should keep in contact with their prescriber regarding when it is appropriate to resume


Thiazolidinediones (TZDs)

Indications

• Use alone, or in combination with insulin, sulfonylurea, metformin, sitagliptin

• Treatment of polycystic ovarian syndrome

Contraindications/Precautions

• Contraindicated in patients with Heart Failure Class III or IV

• Active liver disease or serum ALT concentrations of more than 2.5 times the upper limit of normal [ULN]. Discontinue TZD if ALT is more than 3 times the ULN on therapy.

• TZD’s may cause pre-menopausal women who are insulin resistant and anovulatory. These patients may be at risk for pregnancy if contraception methods are not used.

• Reduction in hemoglobin and hematocrit possibly due to volume expansion. This may occur within the first 4-8 weeks and persist for at least 2 years. Percent reduction varies with the TZD used.

• Monitor Liver Function at baseline and every 2 months for the first 12 months, then periodically thereafter



Mechanism of Action: • Primary – improve glycemic control by increasing insulin sensitivity through direct stimulation of the peroxisome-proliferator-activated receptor-gamma [PPAR γ] on the nuclear surface of cells responsible for modulating lipid homeostasis, adipocyte differentiation, and insulin action.

• Secondary - decreased hepatic glucose production

• Peak concentration: Pioglitazone: 2 hours, Rosiglitazone: 1 hour

• Elimination: pioglitazone - urine 15-30%; rosiglitazone – urine 64%; feces 23%

• Half-life: pioglitazone 16-24 hours; rosiglitazone – 103-158 hours

Dosing

Rosiglitazone [Avandia®] •  Initial dose: 4 mg once daily or 2 mg twice daily • Dose titration: after 8-12 weeks the dose may be increased to 8 mg given once daily or 4 mg twice daily [twice daily dosing may be more effective than once daily dosing]

• Maximum dose: • Monotherapy or with metformin: 8 mg/day • In combination with insulin or sulfonylurea: 4 mg/day. Adjust insulin dose as needed based on glucose response



• Pioglitazone [Actos®]

• Initial dose: 15 or 30 mg once daily • Dose titration: in 8-12 weeks increase to a maximum dose of 45 mg once daily • In combination therapy the maximum dose is 30 mg/day with a 10-25% reduction in insulin dose based upon glucose response

• Adverse Effects

• Weight gain, edema • Upper respiratory infections, sinusitis • Headache • Anemia [pioglitazone] • Changes in liver function tests • Increased incidence of bone fractures in females • Cardiovascular events [controversial at this time] • New onset or worsening of diabetic macular edema [pioglitazone]

• Significant Drug Interactions • Rosiglitazone

• Increased risk of hypoglycemia when administered with insulin or secretagogues

• Pioglitazone • Estrogen and norethindrone: pioglitazone may reduce contraceptive efficacy • Other interactions similar to rosiglitazone



Available Combination Products • Pioglitazone/glimepiride • Pioglitazone/metformin • Rosiglitazone/glimepiride • Rosiglitazone/metformin

Thiazolidinediones can be used as monotherapy or in combination with sulfonylureas, metformin, or insulin [pioglitazone]. As with other oral agents, the degree of A1C reduction required is a consideration when selecting pharmacotherapy. Metformin and sulfonylureas provide a slightly greater benefit in A1C reduction than the TZD’s and may be a cost-effective choice.

Recently several studies have suggested a link between TZD’s and reductions in bone density and fractures. The use of TZD’s in patients at risk for osteoporosis may result in an increased fracture rate. This should be considered if these are prescribed in elderly patients, especially females.

The TZD’s have differing effects on the Lipid profile. Pioglitazone is associated with reductions in triglyceride levels and increases in HDL. However, both agents can raise the LDL.

Another recent development related to the TZD’s are conflicting reports of cardiovascular mortality in patients receiving rosiglitazone. Several meta-analyses have suggested a 30-40% relative increase in risk for myocardial infarction with rosiglitazone. In comparison, the Prospective Pioglitazone Clinical Trial in macrovascular events [PROactive] did not demonstrate significant effects of pioglitazone compared to placebo on the primary cardiovascular outcome after 3 years of follow-up. Pioglitazone was associated with a 16% reduction in death, myocardial infarction and stroke [a secondary endpoint reported to have marginal statistical significance].

Meta-analyses have supported a possible beneficial effect of pioglitazone on cardiovascular risk. Recently, the American Diabetes Association [ADA] and the European Association for the Study of Diabetes [EASD] released a Consensus Statement Update advising against use of rosiglitazone since other options are available.


Dipeptidyl Peptidase-4 Inhibitors [DPP-4]

Indications:

• Monotherapy if glycemic control is not at goal after a trial of Lifestyle changes • Add-on therapy to a sulfonylurea, metformin, or thiazolidinedione • Saxagliptin is indicated as an adjunct to diet and exercise to improve blood sugar (glycemic) control in adults for the

treatment of type 2 diabetes mellitus or in combination with metformin, sulfonylureas or thiazolidinediones (TZD). It has not been studied in combination with insulin.

Contraindications/Precautions

• Sitagliptin phosphate: Anaphylaxis or angioedema • Sitagliptin phosphate/metformin HCl:

• Serum creatinine >1.5 [males] • Serum creatinine >1.4 [females] • Metabolic acidosis including diabetic ketoacidosis • Discontinue for 48 hours in patients undergoing radiologic studies with intravascular iodinated contrast materials

• Saxagliptin: Assessment of renal function is recommended prior to initiation and periodically thereafter

Mechanism of Action: • DPP-4 inhibitors inhibit the enzymatic degradation of GLP-1 [glucagon-like peptide-1] which augments the effects of endogenous GLP-1 within the body. This results in:

• Stimulation of insulin secretion • Inhibition of glucagon secretion • Stimulation of ß-cell proliferation



Dosing:

Sitagliptin [Januvia®] • Sitagliptin can be taken with or without food • In normal renal function: 100 mg daily • CrCl >30 to <50 ml/min: 50 mg once daily • CrCl <30 ml/min or with end-stage renal disease requiring dialysis: 25 mg once daily • Janumet should be taken twice daily with meals and titrated slowly to minimize metformin gastrointestingl effects

Saxagliptin [Onglyza®] • Once-daily: 2.5 mg or 5 mg that can be taken regardless of meals. • CrCl ≤50 mL/min or severe renal impairment, or end-stage renal disease requiring hemodialysis: 2.5 mg daily.

Adverse Effects • upper respiratory tract infection, headache, nasopharyngitis • urinary tract infection [saxagliptin] • acute pancreatitis (sitagliptin)

Significant Drug Interactions Sitagliptin

• May slightly increase digoxin levels, monitor if sitagliptin is added to regimen • May cause hypoglycemia when co-administered with sulfonylureas

• Saxagliptin dose limited to 2.5 mg when coadministered with strong cytochrome P450 3A4/5 (CYP 3A4/5) inhibitors (e.g., ketoconazole).



Available Formulations: • Sitagliptin: 25 mg, 50 mg, 100 mg tablets • Sitagliptin and metformin respectively: 50/500 mg; 50/1000 mg • Saxagliptin: 2.5 mg, 5 mg tablets

The DPP-4 inhibitors are new agents in the management of type 2 diabetes. They can be used in combination with other oral agents or as monotherapy.. Because of the potential reduction in A1C when compared to the other oral agents, these may be appropriate for individuals with A1C values close to 7%. They appear to be well-tolerated and can be used in patients with renal insufficiency. Once-daily dosing is beneficial in terms of adherence.

The place in diabetes management for these new agents has not been established and cost will likely be an issue in prescribing. Until additional safety data is available, medications with long-standing safety data may be preferable.


Alpha Glucosidase Inhibitors Acarbose [Precose®]

Indications: • Adjunct to diet and exercise • Combination therapy with a sulfonylurea or insulin

Contraindications/Precautions: • Diabetic ketoacidosis • Serum Creatinine > 2.0 mg/dL • Cirrhosis • Inflammatory Bowel Disease, Colonic Ulceration, Partial Intestinal Obstruction • Liver function tests should be monitored every 3 months for the first year then periodically in patients receiving 200-300 mg/day

Mechanism of Action: • Reversible binding to alpha-glucosidase enzymes in the brush border of the small intestine. This binding delays the

absorption of carbohydrates from the gastrointestinal tract, attenuates the rise in blood glucose levels after a meal and results in improvement of post-prandial glucose levels without causing hypoglycemia.

• Peak concentration: 1 hour • Metabolism: occurs in the intestine to at least 13 metabolites • Excretion: intestine: and a small amount of unchanged drug that is absorbed is excreted in urine.



Dosing:

Acarbose • Initial dose: 25 mg once daily with the first bite of the meal. • Dose titration: increase in increments of 25 mg every 4 to 8 weeks up to three times a day dosing • Maximum dose:

• Weight less than 60 kg: 50 mg three times a day; • Weight greater than 60 kg, 100 mg three times a day

Miglitol [Glyset®] • All doses should be taken with the first bite of each main meal • Initial dose: 25 mg three times a day; may give 25 mg once daily to minimize gastrointestinal side effects and gradually increase to three times daily. • Dose titration: after 4-8 weeks incease to 50 mg three times daily [maintenance dose] • Maximum dose: 100 mg three times daily

Adverse Drug Reactions • Hypoglycemia: unlikely to occur when used as monotherapy. If hypoglycemia does occur it must be treated with

glucose • Gastrointestinal effects: flatulence, abdominal distention and pain, diarrhea



Significant Drug interactions

• Increased risk of hypoglycemia when administered with sulfonylureas • Decreased effect when administered with charcoal • Reduced efficacy if administered with Pancreatic enzymes

• Available formulations • Acarbose and miglitol: 25 mg, 50 mg, 100 mg tablets

Alpha glucosidase inhibitors are not widely used because the gastrointestinal side effects are not well-tolerated by most patients. In clinical trials, 25-45% of patients discontinued the alpha-glucosidase inhibitor because of this side effect. In addition, other available oral options for diabetes management provide greater reduction in the hemoglobin A1C and improved tolerance.


Bile Acid Sequestrants [BAS] Colesevelam [Welchol®]

Indications • Per the American Association of Clinical Endocrinologists Road Maps

• Patients with an initial hemoglobin A1C of 7-8% and who should be using combination therapy • It has not been studied as monotherapy or in combination with a DPP-4 inhibitor or with thiazolidinediones

Contraindications/Precautions • Monitor lipid profile prior to initiation of treatment and periodically thereafter • Use cautiously if:

• Triglycerides >300 mg/dL; contraindicated if triglycerides are >500 mg/dL • Dysphagia or swallowing disorders • Gastrointestinal disorders or surgery, bowel obstruction

• BAS may decrease absorption of fat-soluble vitamins A, D, E, and K. • Colesevelam should be administered 4 hours before or after other medications are administered

Mechanism of Action • Proposed mechanism include reduction in glucose absorption or changes in the time-course of glucose absorption in

the gastrointestinal tract • May be attributed to BAS-induced disruption of the entero-hepatic pathway of bile metabolism • Metabolism: not absorbed • Excretion: feces; negligible urinary excretion.


Bile Acid Sequestrants [BAS] Colesevelam [Welchol®]

Dosing • Take with adequate liquid and with a meal • 625 mg tablets: 3 tablets twice daily or 6 tablets daily

Adverse Effects • Dyspepsia, constipation, nausea, bowel obstruction, esophageal obstruction, fecal impaction • Elevated triglycerides, pancreatitis • Increased transaminase enzymes

Significant Drug Interactions • Potential decrease in oral contraceptive efficacy due to reduced hormone levels • May decrease efficacy of glyburide, levothyroxine, phenytoin • May decrease the INR when administered with warfarin


Human Insulin

Recombinant DNA Human insulin has essentially made animal source insulin obsolete. Insulin works by promoting the uptake of glucose, fatty acids, and amino acids by the liver and peripheral tissues. Side effects include weight gain, hypoglycemia, lipoatrophy, and lipodystrophy.

There are numerous insulin formulations from which to choose when designing an insulin regimen. The tables in 07.02.08 provide a summary of the pharmacokinetic properties of the available products, physical characteristics, and injection devices available.

It is important to understand the kinetics of the selected insulin formulation[s] when designing a pharmacotherapy plan, interpreting fingerstick and plasma glucose results, adjusting insulin doses, and minimizing side effects.


Insulin Characteristics

Retrieved from https://secure.pharmacytimes.com/lessons/200510-03.asp


Insulin Characteristics

Prandial insulin products include regular insulin and several rapid-acting insulins. The latter offer the advantage of more rapid onset of action which permits a more flexible injection time in relation to the meal. These products can be injected within 10-15 minutes prior to or within 15 minutes of beginning to eat in comparison to regular insulin or combinations with regular insulin which should be injected 30-45 minutes prior to eating.

The one drawback to the rapid acting insulin formulations is that they can be mixed with NPH insulin but not with insulin glargine or insulin detemir. When prandial insulin is used with insulin glargine or insulin detemir, multiple daily injections will be required. This should be discussed with the patient and their preferences taken into consideration before deciding on an insulin regimen.

The intermediate-acting insulin NPH provides dosing flexibility and is available as a fixed combination or single-entity product. When administered as a mixed dose in combination with regular insulin it must be injected 30-45 minutes prior to eating. If the regimen is composed of NPH and a rapid-acting insulin analog, it can be injected in the same timeframe discussed for rapid-acting analogs and can be mixed in the same syringe with NPH.

Long acting “basal” insulin formulations include insulin glargine [Lantus®] and insulin detemir [Levemir®]. Insulin glargine does not have a “peak action”; it provides a basal release of insulin and is administered once daily. There is no additional benefit gained in A1C control by administering insulin glargine more than once daily. In comparison, insulin detemir has a peak action and 1-2 injections may be required to achieve glycemic control targets. A potential benefit of insulin detemir is less effect on weight and less intra-patient variability in glycemic response.

Unlike NPH insulin, insulin glargine and insulin detemir are clear.solutions. When used in combination with prandial insulin products, there is the potential for medication errors because of administering the incorrect insulin. Patients must be instructed to store the clear insulin products in separate areas or to develop their own system to prevent this potentially dangerous mix-up. Similar to the rapid-acting analogs, insulin glargine and detemir cannot be mixed or diluted with any other solution or any other type of insulin.

When converting to insulin glargine from NPH, the glargine dose should be started at 80% of the total NPH dose and administered once daily.


Insulin Products

Retrieved 8/1/09 from https://secure.pharmacytimes.com/lessons/200510-03.asp


Insulin Products

The above chart provides a summary of available insulin products. When selecting an insulin formulation for the elderly patient, the regimen must be tailored to the persons cognitive skills, risk of hypoglycemia, social and economic factors, renal function, and visual or dexterity impairments.

When financial issues are a concern, NPH insulin is a cost-effective, intermediate-acting, alternative. However, in the elderly with renal insufficiency who require a prandial insulin, a rapid-acting analog should be considered rather than Regular insulin because their excretion is not as dependent on renal function.

Often, it is necessary to only use a basal or intermediate acting formulation without a prandial insulin if hypoglycemia or mental status are a concern. It may also be necessary to use an injection device; this too must be one that the patient or caregiver is able to manipulate. Caregivers may have to calculate prandial insulin dose when used in combination with NPH; in this scenario a fixed-mixed product may be the optimal choice to promote a simplified regimen and adherence. Either of these scenarios may necessitate a less aggressive A1C goal.

Of note, Lente® and Ultralente® insulin are no longer available.


Indications: • Adjunctive therapy to treat type 2 diabetes for patients who have not achieved glycemic goals on a regimen of:

• Metformin • A sulfonylurea • A combination of metformin and sulfonylurea • A combination of metformin and a thiazolidinedione

Contraindications/Precautions: • Patients with type 1 diabetes ot those with diabetic ketoacidosis • Exenatide is not a substitute for insulin • Severe GI disease, especially those with gastroparesis or a history of bowel obstruction • Patients with severe renal impairment [CrCl <30 ml/min] or End-Stage Renal Disease should not receive exenatide

Mechanism of Action: • Exenatide is an incretin mimetic which enhances glucose-dependent insulin secretion by pancreatic ß-cells and

restores first-phase insulin response. • During hyperglycemia, exenatide lowers serum glucagon concentrations which results in reduced hepatic glucose

release and decreased insulin need • Gastric-emptying is delayed, thus reducing meal-related glucose excursions • Food intake is reduced

• It is recommended that sulfonylurea dose reduction is considered when exenatide is initiated

Insulin Products


Glucagon-Like Peptide-1 [GLP-1] Exenatide [Byetta®]

Dosing:

• Dose adjustment is not required in renal dysfunction • Exenatide is not recommended for patients with severe renal impairment or in those with ESRD • Exenatide is administered subcutaneously up to 60 minutes prior to the morning and evening meals [with at least 6 hours between meals] • Exenatide may be injected in the thigh, abdomen, or upper arm • Initiate at 5 mcg twice daily if patient is on metformin or a sulfonylurea • If 5 mcg twice daily is tolerated after 1 month the dose may be increased to 10 mcg twice daily • Exenatide should never be injected after a meal nor should patients “make up a missed dose”

Adverse Effects • Nausea, vomiting, diarrhea, dizziness, headache, dyspepsia

• Nausea is common [40%] but often subsides with continued administration

Significant Drug Interactions • Coadministration of medications whose kinetics are dependent upon normal gastric emptying [i.e digoxin, lisinopril,

lovastatin, acetaminophen, antibiotics, contraceptives]. Oral medications should be administered 1 hour prior to exenatide injection.

• Warfarin effect may be altered if exenatide is initiated; careful monitoring is indicated in this situation.

Available Formulation: • Prefilled Pen [60 doses]: 5 mcg/dose or 10 mcg/dose


Glucagon-Like Peptide-1 [GLP-1] Exenatide [Byetta®]

Exenatide is a novel agent for use in type 2 diabetes. The glycemic benefit of exenatide is due to multiple mechanisms and the effects on weight, delayed gastric emptying, and satiety.

Disadvantages of exenatide include the high incidence of nausea which can result in discontinuation of therapy, injection formulation, and high cost. As with other newer agents, its place in therapy has not clearly been identified.

A small proportion of patients may develop anti-exenatide antibodies which can result in a poor glycemic response. If a suboptimal response occurs or glycemic benefit wanes over time, alternative agents should be considered and exenatide discontinued.

There have been recent reports of pancreatitis in patients using exenatide. Patients should be instructed to contact their healthcare provider if severe abdominal distress or pain with vomiting occurs.

When exenatide is administered in addition to sulfonylureas, hypoglycemia may occur. In these patients the secretagogue dose should be reduced. Additionally, as the patient loses weight, doses of other medications may also need to be adjusted.


Amylin Analog Pramlintide [Symlin®]

Indications • Pramlintide is indicated for use in type 1 and type 2 diabetes as an adjunctive therapy in those who have not achieved glycemic goals despite optimal use of prandial insulin. • In type 2 patients, it can be added if the patient is already injecting mealtime insulin with a sulfonylurea or metformin.

Contraindications/Precautions • Hypersensitivity to pramlintide or any components including metacresol • Confirmed diagnosis of gastroparesis because pramlintide may worsen this condition • Hypoglycemia unawareness

Black Box Warning Use with insulin: risk of severe insulin-induced hypoglycemia, particularly with type 1 diabetes. Severe hypoglycemia usually occurs within three hours of injection Appropriate patient selection, careful patient education, and insulin dose adjustments are necessary to reduce this risk

Mechanism of Action • In patients without diabetes, amylin and insulin are both released in response to elevated blood glucose levels. • Amylin has three major effects on the regulation of blood glucose:

• Slowed gastric emptying which permits more gradual absorption of of carbohydrates thus reducing post-prandial spikes on blood glucose • Reduces the release of glucagon from the pancreas thus helping maintain appropriate balance between glucagon and insulin • Amylin centrally causes satiety, which may decrease the total amount of carbohydrates and calories consumed during a meal. Calorie reduction may promote weight loss which may further help improve glucose control.



Dosing • Prior to initiating pramlintide, the insulin dose should be reduced by 50%. • Monitor glucose frequently and adjust insulin dose once target dose of pramlintide is achieved. • Do not mix with insulin; administer as separate injections • Type 1 Diabetes

• Initial dose: 15 mcg before each major meal [more than 250 calories or 30 grams of carbohydrates] • If the initial dose is tolerated without nausea after three to seven days, the dose can be increased in 15 mcg-increments to a target dose of 30 to 60 mcg with each major meal • If nausea is intolerable after dose increase, it can be decreased to the previously tolerated dose

• Type 2 Diabetes • Initial dose: 60 mcg with each major meal [more than 250 calories or 30 grams of carbohydrates] • If the intial dose is tolerated after three to seven days the dose can be increased to 120 mcg with each major meal

Adverse Effects • Nausea, anorexia, vomiting, abdominal pain • Headache, fatigue, dizziness, coughing, pharyngitis • Hypoglycemia: severe hypoglycemia usually occurs within 3 hours of injection. Patient selection, thorough patient

education, and insulin dose adjustments are necessary to reduce hypoglycemia



Significant Drug Interactions • Agents affecting gastrointestinal motility should not be administered with pramlintide [anticholinergic agents] • Agents which slow intestinal absorption such as alpha-glucosidase inhbitors should not be administered with pramlintide • Rapidly acting oral medications should be administered 1 hour before or 2 hours after the pramlintide injection

Formulation: • Injection: 600 mcg/ml; 5 ml vial • Pen Injector: 1000 mcg/ml; 1.5 ml, 2.7 ml

Similar to exenatide, pramlintide is a relatively new agent for diabetes management. Although it can be used in type 1 or type 2 diabetes, the increased risk of severe hypoglycemia is of concern. Like insulin, it requires multiple daily injections.

As with exenatide, cost is another factor to which will be an impediment for many patients. The elderly patient would likely not be a good candidate for pramlintide because of cost, frequent injections and the significant risk of hypoglycemia.


Algorithm for Treating Diabetes Mellitus

Figure 1: Treatment Algorithm for Management of type 2 Diabetes

Figure 1—Algorithm for the metabolic management of type 2 diabetes. Reinforce lifestyle intervention at every visit. Check A1C every 3 months until 7% and then at least every 6 months.

Associated with increased risk of fluid retention, CHF, and fractures. Rosiglitazone, but probably not pioglitazone, may be associated with an increased risk of myocardial infarction.

Although three oral agents can be used, initiation and intensification of insulin therapy is preferred based on effectiveness and lower expense.

Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy. Diabetes Care 31: 173-175, © 2008 by the American Diabetes Association, Inc., and Springer.



In this module we have reviewed the medications available for treatment of type 2 diabetes. The above algorithm published by the American Diabetes Association offers an approach to diabetes management. The treatment pathway followed will depend on patient characteristics which have been discussed elsewhere in this unit. Of note, basal insulin can be initiated early in treatment is the most effective approach.

Treatment regimens should always include nutrition and activity components in addition to medication. Therapeutic agents which have been well-studied in clinical trials and have favorable risk – benefit profiles should be utilized first. These include insulin, metformin, and sulfonylureas. The hemoglobin A1C gap [current A1C – goal A1C] can be used to guide selection of additional therapy [see 07.02.03 - Management of hyperglycemia in type 2 diabetes - Summary of Antidiabetic Interventions]. While the newer agents have been proven to reduce the hemoglobin A1C; long-term safety and efficacy data are not currently available and cost may limit widespread use.

Of special concern in the elderly patient is the risk of hypoglycemia. Older patients may be more vulnerable to this because of changes in autonomic function, hypoglycemia unawareness, cognitive deficits, and reduced ability to manage hypoglycemia. For this reason, agent selection must take into account the risk of hypoglycemia. Review of the current medication regimen must be completed to minimize the potential for drug interactions which can result in changes in glucose control. Lastly, it is often necessary to target a higher hemoglobin A1C in the frail elderly with multiple diagnoses.

Cardiovascular risk reduction such as smoking cessation, exercise, weight loss, blood pressure control, and cholesterol reduction should be encouraged in the elderly patient.

Because the risk of complications increases with increasing duration of diabetes, health maintenance screening must be kept up-to-date. This includes Eye examinations, Foot examinations, the urine microalbumin/creatinine ratio at least annually [or more frequent in nephropathy], cardiovascular testing, administration of an annual influenza vaccine, and verification of administration of the pneumococcal vaccine.



Medication recommendations include daily aspirin [if no contraindications], administration of an angiotensin converting enzyme inhibitor [ACEI] or an angiotensin receptor blocking agent [ARB], Nutrition Education and Diabetes Self-Management Education and Training when indicated.

While we may be limited in the choice of diabetes medications, there are many non-pharmacologic options available to improve quantity and quality of life in the elderly patient with diabetes. A thorough Pharmacotherapy plan for the elderly patient must include all aspects of diabetes management.


Resources

American Association of Clinical Endocrinology. http://www.aace.com/clin/guidelines/diabetes2007.pdf American Association of Diabetes Educators, http://www.diabeteseducator.org American Diabetes Association. Position Statement. Standards of Medical Care in Diabetes. Diabetes Care 32:S13-S61, © 2009 by the American Diabetes Association The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), http:// www2.niddk.nih.gov

U.S. Food And Drug Administration Approves ONGLYZA™ (saxagliptin) For The Treatment Of Type 2 Diabetes Mellitus In dults. Retreived 8/1/09 from http://www.medicalnewstoday.com/articles/159538.php.

For more information:

American Association of Clinical Endocrinologists. Medical Guidelines for Clinical Practice for The Management of Diabetes Mellitus. Endocrine Practice 2007. 13 [suppl 1], May/June 2007.

The Action to Control Cardiovascular Risk in Diabetes Study Group*. Effects of Intensive Glucose Lowering in Type 2 Diabetes. N Engl J Med 2008;358:2545-59.

Chau D, Edelman SV. Clinical management of diabetes in the elderly. Clinical Diabetes ©2001 19[4]:172-75.

Dormandy JA, Charbonnel B, Eckland DJ, et al; the PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279-1289.

Drab SR, Meece J, Garza H. The 3 R’s of managing seniors with type 2 diabetes: recognition, risks, and remedies. The Consultant Pharmacist ©2009 June;24:1-24.


Resources

Hirsch IB. Drug therapy: Insulin analogues. N Engl J Med 2005;352:174-183.

Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol. Diabetologia. 2005;48:1726-1735.

McEvoy GK, ed. Insulin human and insulin analogue. In: American Hospital Formulary Service. Bethesda, MD: American Society of Health-System Pharmacists; 2005: 2970-2980. retrieved May 3 2009 from https://secure.pharmacytimes.com/lessons/200510-03.asp

Mensing C, editor; Cypress M, Halstenson C, McLaughlin S, Walker EA, section editors. The art and science of diabetes self-management education. Illinois: American Association of Diabetes Educators; ©2006.

Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, et al. Medical management of hyperglycemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2009 Oct 22;52:17-30.

Neumiller JJ, Setter SM, Gates BJ, Sonnett TE, Dobbins EK, Campbell K. Pharmacological management of glycemic control in the geriatric patient with type 2 diabetes mellitus. Consult Pharm. 2009 Jan;24(1):45-63

White J R, Campbell RK. ADA/PDR medications for the treatment of diabetes. Montvale [NJ]: American Diabetes Association and Thomson Reuters, Healthcare; 2008.

Neumiller JJ, Setter SM, Gates BJ, Sonnett TE, Dobbins EK, Campbell K. Pharmacological management of glycemic control in the geriatric patient with type 2 diabetes mellitus. Consult Pharm. 2009 Jan;24(1):45-63


Pharmacotherapy of Thyroid Diseases in the Elderly

Learning Objectives


• Describe the influence of aging on thyroid hormone production and clearance.

• Classify an elderly patient as either hyper- or hypothyroid based on symptoms, signs and other objective data.

• Construct a treatment plan for an elderly patient with either hyperthyroid of hypothyroid given a patient case.

• Discuss the subclinical forms of hyperthyroidism and hypothyroidism.

• List the various types of drug-drug interactions that can occur with L-thyroxine replacement therapy.


The pituitary thyroid axis in health and disease

Figure 1 depicts the classical negative feedback system for maintaining normal circulating concentrations of thyroid hormones. Thyrotropin-releasing hormone (TRH) is secreted by the hypothalamus and stimulates the anterior pituitary to synthesize and release thyrotropin, which is commonly referred to as thyroid-stimulating hormone or TSH. The released TSH stimulates the thyroid gland to synthesize and secrete the thyroid hormones thyroxine and triiodothyronine, often abbreviated as T-4 and T-3 respectively. Some of the released thyroxine enters the liver where is deiodinated to triiodothyronine, which enters the circulating blood.

Approximately 80 % of the circulating T-3 is derived from the hepatic conversion of T-4 to T-3. When adequate circulating concentrations of thyroid hormones are achieved, these hormones feedback negatively to suppress the further release of TRH and TSH. As circulating concentrations of thyroid hormones decline, TRH and TSH are sequentially released to stimulate the release of T-4 and T-3. Biologically, T-3 is about 4 times more potent than T-4.



Figure 2 shows the normal euthyroid state, where TSH is secreted by the pituitary gland and stimulates the thyroid gland to release T-4 and T-3, which in turn feedsback negatively on pituitary TSH secretion.



Figure 3 depicts the situation where the thyroid gland is failing to secrete adequate amount of T-4 and T-3. The resulting lower serum concentrations of thyroid hormones have impaired their negative feedback on pituitary TSH release. Therefore, serum TSH concentrations will rise progressively as thyroid gland failure advances in severity. This is referred to as primary gland failure.



Figure 4 shows the situation where the anterior pituitary gland is losing its capacity to secrete TSH. Diminishing TSH secretion is paralleled by diminishing release of T-4 and T-3 from the thyroid gland. This progressive form of thyroid gland failure secondary to pituitary failure will eventually result in overt hypothyroidism. This form of hypothyroidism is referred to as central or secondary hypothyroidism.



Figure 5 shows a situation where the entire thyroid gland is autonomously secreting excessive amounts of T-4 and T-3 due to a diffusely enlarged gland, as in Graves’ disease or toxic goiter. Discrete nodules may also autonomously secrete excessive amounts of T-4 and T-3. The excess secretion of T-4 and T-3 will markedly suppress pituitary TSH secretion.


Influence of aging on thyroid hormone production and clearance

The synthesis of thyroxine and triiodothyronine and the thyroidal uptake of radioactive iodide are significantly reduced in the elderly. The metabolic clearance of thyroxine and triiodothyronine is also reduced with aging. Because the decreased synthesis of thyroid hormones is balanced by their decreased systemic degradation, the net effect is normal thyroxine and triiodothyronine serum concentrations in the elderly. The elimination half-life of thyroxine in the elderly is about 9 days compared to 7 days in younger persons.

During chronic drug administration, the elimination half-life of a medication is the prime determinant of the time required to achieve a steady-state drug concentration. Medications must be administered for 4 - 5 drug half-lives in order to reach plateau serum drug concentrations. When considering levothyroxine replacement therapy in the elderly, its protracted half-life of 9 days mandates about 4 - 6 weeks of daily therapy to achieve a steady-state serum thyroxine concentration. Thus it is best to evaluate the effects of a dosage adjustment in levothyroxine therapy only after 4 - 6 weeks of continuous use. Because the capacity to metabolically inactivate thyroxine continuously declines with aging, the levothyroxine dose used as replacement therapy will often need to be adjusted downward as the patient advances from “young” elderly to very elderly.


Types of Thyroid Dysfunction

Thyrotoxicosis

Definition: Elevated serum concentrations of thyroxine (T-4) and triiodothyronine (T-3) due to a hyperfunctioning gland (hyperthyroidism) or an inability to store preformed thyroid hormones (thyroiditis)

Incidence/prevalence Occurrence in the general population, up to 2% of women and 0.2% of men; prevalence in the elderly, 0.2 – 0.3 %.

Hypothyroidism:

Definition Low serum concentrations of thyroxine and triiodothyronine due to a hypofunctioning thyroid gland.

Incidence In the Framingham study, the prevalence in patients over 60 years of age was 5.9 % in women and 2.3 % in men. In a general population, the incidence of autoimmune hypothyroidism (most common cause) is about 0.4 % in women and 0.1% in men. The risk for hypothyroidism increases with aging.


Biochemical diagnosis of thyroid disease

Initial screening test • Serum thyrotropin (TSH)

• If an abnormal serum TSH is found, follow-up with an unbound or serum free T-4 and a total T-3. Total serum T-4 (reflecting mostly bound T-4) measurements are less useful in the elderly because of significant serum binding abnormalities seen in this population, most often due to protein malnutrition, chronic illness and medications which effect the production of thyroxine binding proteins.

Laboratory tests to evaluate thyroid function:

• Serum total thyroxine (total) 5-12 ug/dL • Unbound or serum free thyroxine 0.7-1.86 ng/dL • Serum total triiodothyronine 80-220 ng/dL • Serum TSH 0.3-5.0 mU/L • Serum thyroglobulin < 40 ng/mL • Iodide-123 uptake/24hrs 5-35%

Hyperthyroidism is almost always associated with a suppressed serum TSH and elevated serum free T-4 and T-3 concentrations. Hypothyroidism due to primary gland failure is associated with an elevated serum TSH concentration and a low serum free T-4 level. Serum total T-3 concentrations are not helpful in diagnosing hypothyroidism because many non-thyroidal illnesses or conditions decrease its concentration. Serum TSH levels are not useful in suspected hypothyroid patients who have underlying pituitary dysfunction.


Causes of Thyrotoxicosis

Graves’ Disease Toxic multinodular goiter (TMNG) Toxic adenoma Thyroiditis Iodide-induced (Jod-Basedow effect, mostly occurring in patients with underlying nontoxic multinodular goiter when given iodide containing medications TSH-secreting pituitary adenoma Oversupplementation with thyroid hormone replacement therapy

The most common causes of hyperthyroidism in the elderly are Graves’ disease and TMNG, with an approximate equal distribution. The administration of iodide containing medications to patients with underlying Graves’ disease or a multinodular goiter may precipitate acute hyperthyroidism. Oversupplementation with levothyroxine may produce “exogenous” hyperthyroidism, which is easily managed with a dose reduction of levothyroxine.


Clinical manifestations of hyperthyroidism

Symptoms: • Hyperactivity • Irritability • Heat intolerance and sweating • Palpitations • Fatigue and weakness • Loose stools

Signs: • Tachycardia • Tremor • Warm, moist skin • Stare • Goiter • Weight loss • Proximal muscle dysfunction

(both upper and lower limbs)

Many of the common signs and symptoms of hyperthyroidism are not manifest in the elderly. It has been estimated that only about one-third of elderly patients present with typical features of thyrotoxicosis.

Many aged patients who are hyperthyroid exhibit anorexia, weight loss, weakness and proximal muscle wasting leading to a “masked” or ‘apathetic” form of the disease. Cardiac signs are more apparent in the elderly and include atrial fibrillation, angina and refractory heart failure and may be the only presenting signs of hyperthyroidism.

Thyrotoxic atrial fibrillation should be treated with anticoagulants to avoid the risk of an embolic event. Psychiatric manifestations of confusion, agitation and dementia may predominate in aged patients. Hyperthyroidism accelerates bone loss in the elderly and may lead to severe osteoporosis with an attendant risk of fractures.

In the majority of aged patients the thyroid gland is nonpalpable and the classic eye signs are absent.


Treatment of Hyperthyroidism

• Radioactive iodide (ablative therapy) • Thioamides • Surgery (ablative therapy) • Iodides • Beta-adrenergic blockers and calcium channel blockers

There are several treatment options for hyperthyroidism. The treatment of choice for elderly patients with either Graves’ disease or toxic multinodular goiter is radioactive iodide (131 I). This therapy provides a definitive cure. Radioactive iodide is administered orally as the sodium salt in an aqueous solution or a capsule. Once incorporated in the thyroid gland, radioactive iodide slowly destroys it, requiring from 6-18 weeks to induce an euthyroid state. The destruction of the thyroid gland continues indefinitely and hypothyroidism should be an expected outcome of treatment. Salivary gland inflammation and neck pain are potential adverse effects of radioactive iodide (131 I) therapy. In addition, there is recent evidence that radioactive iodine treatment may precipitate hyperparathyroidism, with elderly patients appearing more susceptible to this effect than a younger age group. It is recommended that serum or ionized calcium be measured every 2-3 years in all elderly patients who are treated with radioactive iodine.

Thioamides can also be used as primary therapy in elderly patients.

Surgery is rarely performed in elderly patients, but may be necessary for patients with toxic goiters causing airway obstruction or swallowing problems. Preoperative administration of iodides (usually Lugol’s solution or saturated solution of potassium iodide) is common and has been shown to reduce thyroid vascularity and intraoperative blood loss during thyroidectomy.

Complications of surgery include hypothyroidism, hypoparathyroidism, laryngeal nerve injury, bleeding, jugular vein or carotid artery injury, and infections. Beta-adrenergic blockers or calcium channel blockers may be used to attenuate some of the sympathomimetic-like features of hyperthyroidism.


Use of Thioamides in the Treatment of Hyperthyroidism

Methimazole and propylthiouracil:

• Inhibitors of the intrathyroidal biosynthesis of thyroxine and triiodothyronine • Usually 6 weeks of treatment is needed in order to attain a euthyroid state • Once euthyroid, smaller maintenance doses are needed • Large thioamide requirements suggest poor compliance

Methimazole: • Initial or induction dose: 10 – 60 mg (daily or divided depending on GI tolerance) • For small glands or mild hyperthyroidism: 10 – 20 mg daily • More severe forms of hyperthyroidism: 20 – 60 mg daily • Maintenance dose: 5 – 15 mg daily

Propylthiouracil: • Initial or induction dose: 300 – 1200 mg daily in 3 divided doses • For small glands or mild hyperthyroidism: 100 – 150 mg tid • More severe forms of hyperthyroidism: 200 – 400 mg tid • Maintenance dose: 50 – 150 mg twice daily


Use of Thioamides in the Treatment of Hyperthyroidism

Adverse drug reactions:

Common • Rash • Urticaria • Arthralgias • Arthritis • Fever • Myalgias • Nausea/vomiting

Rare • Aganulocytosis (PTU and methimazole) • Hepatotoxicity • Hepatitis (PTU) • Cholestatic jaundice (methimazole) • Hypoprothrombinemia (PTU) • Lupus erythematosus (PTU)

Hyperthyroid elderly patients should be made euthyroid with thionamide therapy prior to the use of radioactive iodide.

Radiation-induced thyroiditis is sometimes a complication of radioactive iodide therapy, resulting in the uncontrolled release of stored thyroid hormones and a brief worsening of the thyrotoxic state.

This complication is reduced significantly if the patient is rendered euthyroid before radioactive iodide therapy is initiated. Elderly patients with hyperthyroidism due to Graves’ disease or toxic multinodular goiter can be restored to a euthyroid state with thioamides alone. This form of therapy is not curative in patients with toxic multinodular goiter and life long treatment will be necessary.

In patients with Graves’ disease there can be a high rate of relapse with stopping the thionamide after a year of use. All patients taking thionamides must be warned of the small risk of agranulocytosis and to immediately contact their physician if they develop a sore throat, mouth sores, or fever and obtain a white blood cell count. Thionamide-induced agranulocytosis is rapidly reversible when the medication is stopped.

Filgrastim administration does not improve recovery outcome.


Subclinical hyperthyroidism


• Defined as a suppressed serum TSH concentration and a normal free serum thyroxine level. Serum triiodothyronine (T-3) must be also be measured to rule out T-3 thyrotoxicosis.

• Estimated population prevalence of 0.9%; more common in women.

• Certain nonthyroidal illnesses may also suppress serum TSH concentrations and must be ruled out.

• In patients without thyroid nodules, suppressed serum TSH may normalize in about 50% of cases. However, in patients with autonomous thyroid nodules, spontaneous normalization of the serum TSH is unusual and advancement to overt hyperthyroidism is considered a strong possibility.

• Risk of new onset atrial fibrillation, accelerated bone loss and dementia is increased.

• Decision to treat should be based on the presence of symptomology (weight loss, psychiatric problems, fatigue) and risk for exacerbating underlying medical problems (osteoporosis, cognitive loss and heart disease). Elderly patients may be treated initially with a thionamide, usually methimazole at a dose of 5 – 10 mg daily. Successful resolution of symptoms indicates a consideration of ablative therapy with radioiodide. If you suspect that subclinical hyperthyroidism is contributing to progressive osteoporosis, cognitive loss and heart disease in the older patient, ablative therapy with radioiodide should be discussed with the patient and family.



Many endocrinologists consider subclinical hyperthyroidism to be the mildest form of hyperthyroidism. The key serum chemistries are a suppressed TSH concentration and normal thyroid hormone levels. Remember that the range for what is considered a normal serum thyroxine concentration is quite wide, from 5 to 12 micrograms per deciliter.

Consider a normal or euthyroid woman who requires a serum thyroxine concentration of 7 micrograms per deciliter for maintaining a desired metabolic state, and which is confirmed by a normal serum TSH concentration. If in this individual the serum thyroxine concentration now rises to 10 micrograms per deciliter because of the development of an autonomously functioning thyroid nodule, she is still in the normal range of serum thyroxine levels, but this level is too high for her metabolic wellbeing, and this is reflected by a suppressed serum TSH concentration.

A scan of the thyroid gland would reveal the nodule and treatment would be indicated if this patient manifested symptoms of weight loss, psychiatric problems, fatigue or risk for aggravating underlying medical problems such as osteoporosis, cognitive loss and heart disease.


Cause of Hypothyroidism

Primary thyroid gland failure: • Laboratory findings: low serum concentrations of thyroxine and triiodothyronine and an elevated serum TSH level.

Etiologies:

• Autoimmune destruction (Hashimoto’s or atrophic thyroiditis) • Prior ablative therapy with radioactive iodide (131 I) • Subtotal or total thyroidectomy • Prior radiation therapy to the neck • Medications: amiodarone, iodides, lithium, • Iodine deficiency • Infiltratrative disorders: amyloidosis, sarcoidosis, • Scleroderma

Pituitary TSH deficiency (secondary or central hypothyroidism):

Laboratory findings: low serum concentrations of thyroxine and triiodothyronine and a normal or reduced serum TSH level

Etiologies: • Hypopituitarism: tumors, prior surgery/radiation, trauma and infiltrative disorders • Hypothalamic dysfunction: tumors, trauma and infiltrative disorders


Cause of Hypothyroidism

The two major categories of hypothyroidism are primary thyroid gland failure and anterior pituitary gland failure. Autoimmune destruction of the thyroid gland is the most common cause of primary hypothyroidism. Autoimmune destruction of the thyroid gland may occur in association with other autoimmune disorders including pernicious anemia, Addison’s disease, multiple sclerosis, and celiac disease. Because the association is particularly strong for pernicious anemia, it is reasonable to screen all elderly patients with a documented or suspected diagnosis of autoimmune-induced hypothyroidism for vitamin B-12 deficiency.

Destruction of the thyroid gland by radiation, often from prior treatment of hyperthyroidism with radioactive iodide (131 I), is also another common cause of primary gland failure. Lithium treatment can cause hypothyroidism primarily by inhibiting the release of thyroid hormones from the gland. Its incidence varies widely, with overt hypothyroidism being reported in up to 20% of patients. Exposure to iodides, usually from radiocontrast agents or from the deiodination of amiodarone, can in susceptible patients cause hypothyroidism.

In normal individuals, excessive exposure to iodides will transiently inhibit the release of thyroid hormones from the gland. However, in patients who have underlying subclinical thyroid gland injury or dysfunction, iodide exposure can induce persistent hypothyroidism. Anterior pituitary gland failure will cause hypothyroidism secondarily due to the loss of TSH secretion. This type of hypothyroidism is referred to as secondary or central hypothyroidism.


Signs and Symptoms of Hypothyroidism

• Cardiac: bradycardia, ischemia, and heart failure • Hematologic: anemia • Dermatologic: alopecia, dry skin, itching, periorbital and peripheral edema • Gastroenterologic: constipation and anorexia • Metabolic: hypercholesterolemia, hypothermia and hyponatremia • Neurologic: weakness, muscle cramps, ataxia, vertigo, hearing loss, hoarseness, delayed relaxation of the deep tendon reflexes, and carpal tunnel syndrome • Psychiatric: depression, psychosis and dementia • Rheumatologic: myalgias, and arthritis-like joint complaints

The signs and symptoms of hypothyroidism are many and varied, develop insidiously, touch upon many subspecialties in medicine and in the elderly are often attributed to the aging process. Nonspecific symptoms such as dry skin, constipation, joint complaints, weakness, and depression are common in the elderly and do not arouse suspicion of an underlying thyroid illness. Global effects of hypothyroidism in the elderly may present as nonspecific as apathy or as a general failing in mobility. Classic features of hypothyroidism occur in the elderly and include periorbital and peripheral edema (myxedema), bradycardia, hypothermia, and hoarseness, and demand immediate attention. All hypercholesterolemic patients should be evaluated for hypothyroidism. Yearly screening of a serum TSH concentration is very helpful in identifying thyroid problems in the elderly.


Levothyroxine Therapy in the Elderly Hypothyroid Patient

Levothyroxine replacement is initiated at 12.5 – 25 mcg/day, with the 12.5-mcg dose being reserved for patients with significant cardiac disease.

In elderly patients with primary thyroid gland failure, the levothyroxine dose is incremented by 12.5 – 25 mcg every 4 - 8 weeks with a serum TSH concentration being measured before each increment. The full replacement dose should be reached in several months as indicated by a normal serum TSH concentration. The normal serum TSH range is wide, 0.3 – 5.0 mU/L, and some patients may feel better with a serum TSH concentrations between 1 – 2 mU/L, rather that between 3 – 5 mU/L. Products containing a combination of levothyroxine and triiodothyronine are not superior to solo therapy with levothyroxine.

In elderly patients with secondary hypothyroidism (pituitary failure), the possibility of coexisting adrenal insufficiency (due to loss of ACTH secretion) must be ruled out. If discovered, glucocorticoid replacement must precede the initiation of thyroid replacement. The levothyroxine titration schedule is similar to patients with primary thyroid gland failure, except that the goal of replacement therapy is determined by achieving a normal serum free thyroxine concentration rather than a normal serum TSH level. Small levothyroxine dose titration within the normal range of serum thyroxine concentrations may be needed in patients still complaining of hypothyroid symptoms.

There are two gastrointestinal disorders that may significantly impair the bioavailability of orally administered levothyroxine. These include celiac disease, which is an autoimmune disorder that causes villous atrophy in the small intestine, and atrophic gastritis, which is caused by parietal cell autoantibodies or chronic H pylori infection. Hypothyroid patients who are maintained euthyroid on unusually large daily doses of levothyroxine should be accessed for these gastrointestinal pathologies.


Levothyroxine Therapy in the Elderly Hypothyroid Patient

▪ There are numerous branded and generic levothyroxine preparations available. In the Orange Book, which is published by the Food and Drug Administration (FDA), products designated with an AB rating have undergone bioavailability testing and are determined to be equivalent to a reference standard. For levothyroxine sodium products an additional number is added to the AB code (AB1, AB2, AB3, AB4) because several products have served as reference standards. In the Orange Book, the FDA has listed these products under four different therapeutic equivalence (TE) codes. A common TE code (ex., AB1) would indicate therapeutic equivalence between products. Furthermore, some preparations fall under two or three TE codes. The Orange Book, which can be accessed at FDA.gov, should be consulted when substituting levothyroxine products.

The methods used to determine bioequivalence between levothyroxine sodium products have been criticized. Because euthyroid patients (normal thyroid function) are used to assess bioequivalence, single dose bioavailability studies require the administration of a 600 mcg dose of levothyroxine sodium in order to increment levothyroxine blood levels high above the patient’s endogenous levothyroxine levels and thus provide a reliable pharmacokinetics assessment. Mathematical techniques to correct for endogenous (ie., baseline) levothyroxine concentrations are applied to the bioavailability data , but appear to be unable to distinguish dosage strengths that differ by 12.5%. Such differences may be clinically significant given that levothyroxine is considered a narrow therapeutic index drug and serum TSH concentrations are very sensitive to modest changes in levothyroxine dose.

It would seem prudent in elderly patients, especially those with underlying cardiovascular disease or on suppressive therapy for thyroid cancer, that adequacy and safety of substitution with another levothyroxine preparation should be confirmed by measuring a serum TSH concentration 6-8 weeks later.


Subclinical Hypothyroidism

• Defined as an elevated serum TSH and a normal serum free thyroxine concentration.

• An estimated population prevalence of 8.5%; more common in women and with aging; in women and men over 74 years of age, a prevalence of 21% and 16% respectively was reported in the Colorado Thyroid Disease Prevalence Study.

• Although most patients have no obvious cause for subclinical hypothyroidism, certain risk factors have been identified and include prior treatment with neck irradiation, type I diabetes mellitus, primary adrenal insufficiency, and medications that may inhibit thyroid gland function (amiodarone, interferon alpha and lithium).

• The risk for advancement to overt hypothyroidism is increased in patients with serum TSH concentrations above 10 mU/L or positive titers for serum thyroid autoantibodies against thyroperoxidase (also referred to as antiTPO or antimicrosomal antibodies).

• Treatment to normalize serum TSH with thyroxine supplementation is advised if:

1. The serum TSH is greater than 10 mU/L 2. Anti-TPO antibodies are present 3. Signs and symptoms consistent with hypothyroidism are present and troublesome 4. Goiter or hypercholesterolemia is present


Subclinical Hypothyroidism

Levothyroxine supplementation for subclinical hypothyroidism in the elderly should begin low at 12.5 or 25 mcg daily because of the risk of associated with evident or occult heart disease. A serum TSH concentration should be measured 4 - 6 weeks after initiating thyroxine therapy. The dose of levothyroxine needed normalize the serum TSH concentration is usually lower that that needed to treat overt hypothyroidism. Levothyroxine requirements may increase over time, as further progression to thyroid failure is possible.


Drug-Drug Interactions Management Issues with Thyroid Replacement Therapy

Drugs that can reduce the bioavailability of co-administered levohyroxine:

• Aluminum hydroxide • Calcium carbonate • Cholestyramine • Colestipol • Iron salts • Sucralfate

Drugs that increase the metabolic degradation of thyroid hormone:

• Carbamazepine • Phenobarbital • Phenytoin • Primidone • Rifampin

Drugs that enhance the serum binding of thyroxine by increasing the hepatic production of thyroid binding globulin:

• Estrogens • Fluorouracil • Methadone • Mitotane • Tamoxifen



Drugs that decrease the serum binding of thyroxine by decreasing the hepatic production of thyroid binding globulin.

•  Anabolic steroids •  Androgens •  Glucocorticoids

Drug interactions involving levothyroxine replacement therapy occur frequently in the elderly. Osteoporosis and iron deficiency anemia from chronic blood loss are common in this age group, thus increasing the probability that calcium or iron supplements will be co-administered with levothyroxine. These interactions can be avoided by always administering the levothyroxine product first and then waiting at least 2 hours before giving the interfering iron or calcium preparation.

Drugs that increase the metabolic degradation of thyroid hormone, often referred to as enzyme inducers, will also increase levothyroxine requirements. Whenever enzyme inducers are started or stopped in patients on levothyroxine therapy, it is important to obtain a serum TSH concentration 6-8 weeks later. With enzyme-inducers, the induction process reaches a steady-state after about 2 weeks of inducer administration. Similarly, when an enzyme-inducer is stopped it take about 2 weeks to fully deinduce.

Always suspect a levothyroxine drug interaction in elderly patients taking doses of 150 mcg or greater per day. The dosage range for levothyroxine replacement in the elderly is usually 50 – 125 mcg per day. The larger doses are often needed for the heavier patients.



Careful monitoring of levothyroxine therapy is necessary with the initiation or discontinuation of estrogen therapy. Estrogens increase the hepatic production of thyroid binding globulin, which subsequently reduces the tissue availability of circulating thyroid hormones, that is, less free or unbound hormone is available for transport into cells.

Thus, serum TSH concentrations may rise when estrogen therapy is added to a medication regimen containing levothyroxine, and may necessitate a small increment in the levothyroxine daily dose. The converse situation may occur when estrogen use is stopped in a patient on levothyroxine supplementation. Similar potential problems must be considered when dealing with medications that decrease serum thyroid binding globulin concentrations.


Adjusting Thyroid Replacement Hormone

Increase dosage to compensate for:

• Drugs that impair intestinal absorption of T4 (aluminum hydroxide, ferrous sulfate and gluconate, sucralfate, cholestyramine) • Drugs that decrease T4 conversion(amiodarone) • Drugs that accelerate T4 clearance (phenytoin, carbamazepine, rifampin) • Drugs that increase the serum concentration of thyroid binding proteins (oral estrogen therapy). Using a transdermal estrogen should circumvent this problem.

Decrease dosage to compensate for:

• Removal of a medication that is interfering with levothyroxine bioavailability. • Discontinuation of a medication that induces the metabolic degradation of levothyroxine. • Discontinuation of a medication that induces the production of serum thyroid binding proteins

There are a number of drugs that interact with levothyroxine therapy. These drugs include a number of agents that decrease the intestinal absorption of levothyroxine. Additionally, amiodarone has been found to decrease T4 conversion to T3.Phenytoin, phenobarbital, carbamazepine and rifampin have been found to accelerate the hepatic clearance of T-4, resulting in lower serum thyroid hormone concentrations.

Orally administered estrogens stimulate the hepatic production of thyroid binding proteins and thus may increase levothyroxine requirements by reducing the unbound serum hormone concentrations. You may need to decrease levothyroxine supplementation therapy when co-administered drugs that interfere with its bioavailability, induce its hepatic clearance or augment its serum protein bind are discontinued.


Resources

Arafah BM. Increased Need for Thyroxine in Women with Hypothyroidism during Estrogen Therapy. N Eng J Med 2001; 344: 1743 – 49.

Arafah BM. Decreased L-thyroxine Requirement in Women with Hypothyroidism During Androgen Therapy for Breast Cancer. Ann Intern Med 1994;121:247-51..

Blakesley V, Awni W, Locke C et al. Are Bioequivalence Studies of Levothyroxine Sodium Formulations in Euthyroid Volunteers Reliable? Thyroid 2004;14:191- 200.

Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado Thyroid Disease Prevalence Study. Arch Intern Med 2000;160:526.

Checchi S, Montanaro A, Pasqui L et al. L-Thyroxine Requirement in Patients with Autoimmune Hypothyroidism and Parietal Cell Antibodies. J Clin Endocrinol Metab 2008;93:465-469.

Clyde PW, Harari AE, Getka, EJ, Shakir KMM. Combined Levothyroxine Plus Liothyronine Compared with Levothyroxine Alone in Primary Hypothyroidism. JAMA 2003;290:2952-58.

Colaco SM, Ming MS, Reiff E et al. Hyperparathyroidism After Radioactive Iodine Therapy. Am J Surg. 2007;194:323-27.

Cooper DS. Subclinical Hypothyroidism. N Engl J Med 2001;345:260-5.


Resources

Hornick TR, Kowal J. Clinical Epidemiology of Endocrine Disorders in the Elderly. Endocrinology and Metabolism Clinics of North America. 1997;26:145

Huber G, Staub J-J, Meier C et al. Prospective Study of the Spontaneous Course of Subclinical Hypothyroidism: Prognostic Value Of Thyrotropin, Thyroid Reserve, and Thyroid Antibodies. J Clin Endocrinol Metab 2002;87:3221-5.

Jenkins RC, Weetman AP. Disease Associations with Autoimmune Thyroid Disease. Thyroid 2002;12:977-88.

Kalmijn S, Mehta KM, Pols HAP, et al. Subclinical Hyperthyroidism and the Risk of Dementia. The Rotterdam Study. Clinical Endocrinol 2000;53:733-7.

Mandel SJ, Brent GA, Larsen PR. Levothyroxine Therapy in Patients with Thyroid Disease. Ann Intern Med 1993;119:492-502.

McDermont JH, Cos A, Walsh CH. Celiac Disease Presenting as Resistant Hypothyroidism. Thyroid 2005;15:386-388.

Surks MI, Ortiz E, Daniels GH, et al. Subclinical Thyroid Disease. Scientific Review and Guidelines for Diagnosis and Management. JAMA. 2004;291:228-38.

Surks MI, Sievert R. Drugs and Thyroid Function. New Engl J Med. 1995;333:1688-94.

Thomas FB, Mazzaferri EL, Skillman TG. Apathetic Thyrotoxicosis: A Distinct Clinical and Laboratory Entity. Ann Internal Med 1970;72:579-85.


Resources

Toft AD. Subclinical Hyperthyroidism. N Engl J Med 2001;345:512-6.

Utiger RD. Estrogen, Thyroxine Binding in Serum, and Thyroxine Therapy. N Engl J Med 2001;344:1784-5.

Walsh JP, Shiels L, Lim EM et al. Combined Thyroxine / Liothyronine treatment dose not improve well-being, quality of life or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab. 2003;88:4543-55.

Websites:

American Thyroid Association

Thyroid Disease Manager

FDA Electronic Orange Book


Disorders of the Adrenal Glands



• Describe the effects of aging on the HPA (hypothalamic pituitary adrenal) axis and the adrenal glands.

• Classify an elderly patient as having either Cushing’s disease or Addison’s disease based on clinical presentation and laboratory values.

• Construct a treatment plan for an elderly patient with either Cushing’s disease or Addison’s disease, given a patient case.


Adrenal Gland Anatomy and Physiology

• Each of the two glands is located extraperitoneally to the upper poles of each kidney. • Adrenal medulla (10% of gland) secretes catecholamines.

Adapted from: Nieman LK, Orth DN. Clinical Manifestations, Diagnosis, and Treatment of Adrenal Insufficiency. UpToDate Online.



Adrenal cortex (90% of gland) is divided into three regions:

• Zona glomerulosa (15%) produces mineralocorticoids such as aldosterone. • Zona fasiculata (60%) is the middle region and is high in cholesterol. Responsible for glucocorticoid production. • Zona reticularis (25%) inner zone is responsible for all androgen production.

Adrenal function in aging: • Structural changes

• Decreased size of the adrenal cortex • Functional changes

• Decreased production and secretion of androgens • Unchanged production and secretion of glucocorticoids (i.e. cortisol) under basal conditions • Decreased resiliency of the HPA axis during stress (blunting of negative feedback) • Decreased production and secretion of mineralocorticoids

Despite being relatively small in size, weighing only 4 gm and measuring 3 cm by 6 cm in length, the adrenal glands are capable of regulating sex steroid production, glucocorticoid production and mineralocorticoid production. Aldosterone is produced in the zona glomerulosa and its function is to help maintain electrolyte and volume homeostasis by altering potassium and magnesium secretion and importantly renal tubular sodium reasborption. Remember, wherever goes sodium, so to goes water!

The zona fasiculata uses cholesterol as the base compound from which glucocorticoids are produced. The primary product is cortisol which is responsible for the regulation of fat, carbohydrate and protein.

The zona reticularis produces the sex hormones testosterone and estradiol which are responsible for primary and secondary sex characteristics.



Advancing age causes several changes to the adrenal glands and the HPA-axis. Aside from the structural changes of decreased size, the function of the adrenal glands changes as well. There is decreased production and secretion of the sex hormones testosterone and estradiol as well as mineralocorticoids.

Although the production and secretion of cortisol is unchanged under normal conditions, the HPA axis has decreased resiliency during stressful events resulting in a reduction of the negative feedback mechanism.It is important to note the function of the adrenal glands depends greatly on the status of the hypothalamus-pituitary-adrenal (HPA) axis. If there are problems with the hypothalamus, pituitary gland, or their hormones, there will most likely be a problem with adrenal gland functioning.


Disorders of Adrenal Hormone Secretion

Cushing’s syndrome: Abnormally high levels of cortisol.

Addison’s disease: Abnormally low levels of cortisol (and sometimes aldosterone).

Pheochromocytoma: Abnormally high levels of catecholamines

Hyperaldosteronism: Abnormally high levels of aldosterone


Disorders of Adrenal Hormone Secretion

Cortisol is the principal glucocorticoid secreted in the human body. It affects not only cell membranes, but the very genes that code for enzymes that regulate enzyme, lipid, carbohydrate and protein metabolism. It is not surprising that disruptions in the level of circulating cortisol can have a profound effect on a variety of metabolic functions.

Two disorders best represent these disruptions in cortisol levels. The first is Cushing’s syndrome, a hormonal disorder characterized by excessive adrenal activity and prolonged exposure of the body’s tissues to high levels of cortisol. The second is Addison’s disease, a hormonal disorder characterized by abnormally low levels of cortisol and, in some cases, aldosterone.

In addition to alteration in cortisol levels, the adrenal glands are also responsible for the secretion of norepinephrine and epinephrine. A pheochromocytoma is a benign neoplasm on the adrenal medulla causing increase in norepinephrine and epinephrine release. While this condition is rare, it should be considered as a cause of resistant hypertension in uncontrolled patients. All patients with sustained hypertension should have the appropriate studies performed to rule out pheochromocytoma. It may be diagnosed by looking at serum levels for increased catecholamines and their metabolites. The treatment of choice in most cases is surgical removal of the adrenal glands.

Aldosterone is the principal mineralocorticoid produced by the adrenal glands. Its secretion is primarily regulated by the renin-angiotension system and by potassium ions. The prevalence of hyperaldosteronism is relatively low at 2%. The classic presentation is a patient with hypertension, hypokalemia, and metabolic alkalosis. This condition is diagnosed by obtaining a patients aldosterone/renin ratio; a value for this ratio >30 is strongly suggestive of hyperaldosteronism. Hyperaldosteronism can be treated by surgical removal of its most common cause, a unilateral aldosterone-producing adenoma. For bilateral adenomas, spironolactone, an aldosterone antagonist, may also be considered.

The remainder of this module will focus on diseases associated with abnormally high and abnormally low levels of cortisol which represent the most common disorders of the adrenal glands.


Onset and Incidence of Cushing’s Syndrome

Incidence: • Spontaneous + Pituitary + Ectopic: 5-25/1,000,000 per year. • Ectopic: mainly from lung cancer; incidence increases with age. • Iatrogenic: high in elderly due to corticosteroid therapy.

Onset: • Spontaneous Cushing’s: childhood and adulthood. • Pituitary Cushing’s: ages 25-45 years. • Ectopic Cushing’s: adulthood. • Iatrogenic or Factitious Cushing’s: after prolonged use of pharmacologic doses of glucocorticoid medications.

Spontaneous or Pituitary Cushing’s syndrome most commonly affects young and middle-aged adults; however, it can strike in the later years. Only about five to twenty-five out of every million people are affected each year. Ectopic Cushing’s, which occurs secondary to tumors, affects a larger percentage of older adults.

A common cause of cortisol excess in the elderly is secondary to supraphysiologic doses of glucocorticoid medications such as prednisone use in COPD patients or rheumatoid arthritis patients. When assessing a patient for suspected iatrogenic Cushing’s disease it is important to ascertain both the total daily dose and the length of time the individual has been exposed to exogenous glucocorticoids. Doses greater than 20 mg of prednisone a day for longer than 3 weeks can result in hypothalamic pituitary axis suppression.


Etiology and Pathogenesis of Cushing’s Syndrome

When the excessive circulation of cortisol is the result of overproduction by the body’s own adrenal glands - pituitary adenomas and other kinds of tumors are usually at fault. Cushing’s Disease is caused by a pituitary adenoma which secretes increased amounts of adrenocorticotropin or A-C-T-H, a hormone that stimulates the adrenal glands to release cortisol into the bloodstream. Ectopic ACTH Syndrome is caused by a tumor that secretes ACTH, which in turn stimulates the release of cortisol from the adrenal glands.

Iatrogenic Cushing’s Syndrome is caused by the administration of supraphysiologic doses of glucocorticoid medications, resulting in suppression of the HPA axis. Adrenal tumors, though relatively rare, can also cause Cushing’s syndrome because they contain cancer cells that secrete increased amounts of cortisol along with other adrenal cortical hormones.


Comparison of Corticosteroids

The physiological dose of prednisone is roughly 5 mg per day. Iatrogenic Cushing’s syndrome can be caused by supraphysiologic doses of glucocorticoid medications. Not all corticosteroids have the same glucocorticoid and mineralocorticoid activity. For instance, the glucocorticoid activity of prednisone 20 mg is equivalent to 3 mg of dexamethasone.


Common Signs and Symptoms of Cushing’s Syndrome

Hirsutism “Buffalo hump” Abdominal Striae

Images from: http://vasculitis.med.jhu.edu/treatments/prednisone.html.


Common Signs and Symptoms of Cushing’s Syndrome

From: Lancet 2001; 357: 783-91

The symptoms of Cushing’s syndrome vary. In younger individuals, the disease usually manifests as upper body or truncal obesity, including rounded face and increased fat around the neck, the so-called “buffalo hump”. The arms and legs become thinner, and the skin becomes fragile and thin. Purplish stretch marks may appear on the abdomen, thighs, buttocks, arms and breasts. The bones are weakened, and routine activities may lead to backaches or rib and spinal fractures. Other symptoms include severe fatigue, weak muscles, high blood pressure, and blood sugar. Irritability, anxiety and depression are also common. Women tend to exhibit excess hair growth and menstrual irregularity. Men have decreased fertility and libido.


Presentation of Cushing’s Syndrome in the Elderly

In Younger Patients:

• Upper body obesity • Thinning arms and legs • Thin and fragile skin • Purplish stretch marks • Weakened bones, muscles • Severe fatigue • Increased blood pressure • Increased blood glucose • Irritability, anxiety, depression

In Older Patients:

• Easy bruising, poor healing • Falls, - risk of fractures • Failure to thrive • Refusal to eat, weight loss • Confusion, dementia, paranoia • Hypochondriasis, psychosis • Compromised immune system

In the elderly, Cushing’s syndrome can exacerbate the physical and psychological changes of aging. Skin, which has already begun to thin, bruises easily and heals poorly. The risk of fractures may be compounded by osteoporosis. The mental status changes associated with Cushing’s syndrome may become more severe, leading to confusion, increasing dementia, paranoia, hypochondriasis, psychosis or threats of suicide.

As their immune system becomes less effective due to the combined effects of aging and excessive cortisol, the elderly patient becomes more susceptible to infections, malignancies, autoimmune disorders and allergies.


Diagnosis of Cushing’s Syndrome

From: Lancet 2001; 357: 783-91

Test for excess cortisol: 24 hr urinary free cortisol; levels > 30-100 mcg/day suggest Cushing’s

Tests for differentiating ACTH and Ectopic Cushing’s:

Dexamethasone suppression test dexamethasone 0.5 mg po qid x 4 days, with 24-hr urine collections on day 0, 1, 2, 3, 4

CRH (corticotropin-releasing hormone) injection to test for ACTH; increased ACTH and cortisol with pituitary adenomas

Dexamethasone + CRH test for patients with delayed onset of Cushing’s symptoms

Petrosal sinus sampling; levels of ACTH in blood from petrosal sinuses are compared with ACTH in forearm vein

Tests for tumor location: X-rays, CT, MRI


Diagnosis of Cushing’s Syndrome

While the classic physical signs of Cushing’s syndrome are striking, these features do not in and of themselves confirm the presence of the disease. Other conditions that can produce a similar appearance include polycystic ovary syndrome, ovarian tumors, congenital adrenal hyperplasia, obesity and alcoholism. Blood and twenty-four hour urine tests will confirm cortisol excess, and a dexamethasone suppression test will determine if the excess is due to overproduction. Tests using corticotropin-releasing hormone and petrosal sinus sampling help to differentiate ACTH dependent and ACTH independent types of Cushing’s syndrome. Finally, localizing techniques such as CT scan or MRI are used to find the tumor.


Treatment of Cushing’s Syndrome

An abdominal CT scan showing an enlarged adrenal gland

Laproscopic adrenolectomy incisions.

Images from: http://www.surgery.wisc.edu/general/patients/endocrine/adrenal.shtml.


Treatment of Cushing’s Syndrome

Surgical removal of tumor • Trans-sphenoidal surgery • Bilateral adrenalectomy

Radiation therapy

Treatment depends on the specific reason for cortisol excess and may include surgery, radiation, chemotherapy or the use of cortisol-inhibiting drugs.

Surgical intervention is the most widely accepted primary therapy for the treatment of Cushing’s syndrome. In the hands of an experienced surgeon, total remission can be achieved in 80 – 90% of cases. Laparoscopic adrenalectomy allows the removal of an adrenal gland through a procedure that allows most patients go home the day after surgery with minimal pain. Prior to laparoscopic adrenalectomy, surgery consisted of a moderate to large incision and a hospital stay of 3 to 7 days. With laparoscopic adrenalectomy the surgery occurs through 3 or 4 small incisions measuring less than 0.5 inches in size. Many patients return to work within 7 to 10 days.

Patients will require glucocorticoid replacement therapy (20 – 30 mg hydrocortisone daily) from the time of surgery until recovery of the hypothalamic-pituitary-adrenal axis, which is 4 – 12 months after surgery inmost cases. Owing to their hypercoaguable state, patients with Cushing’s disease undergoing any type of surgery should receive heparin prophylaxis. Patients who are poor candidates for trans-sphenoidal surgery may benefit from radiation therapy. In one case series patients receiving radiation achieved an 83% remission rate. Bilateral adrenalectomy, which provides the definitive cure in patients for whom cure is not achieved with surgery, radiation, or both, necessitates lifelong continuous monitoring of glucocorticoid and mineralocorticoid replacement therapy. Again, glucocorticoid replacement is 20 – 30 mg hydrocortisone daily and mineralocorticoid replacement with fludrocortisone is 50 – 100 micrograms daily.


Drug Therapy of Cushing’s Syndrome

Compounds acting at hypothalamic-pituitary level: • Serotonin antagonists (cyproheptadine, metergoline, ketanserin, nitanserin) • Dopamine agonists (bromocriptine) • GABA agonists (sodium valproate) • Somatostatin analogues (octreotide)

Compounds acting on adrenal glands • Mitotane • Aminoglutethimide • Metyrapone • Trilostane • Ketoconazole • Etomidate • Glucocorticoid antagonists (mifepristone) • Megestrol acetate

Adapted from Lancet 2001; 357: 783-91

Drug therapy for Cushing’s disease is targeted at the hypothalamic-pituitary level in order to decrease corticotrophin secretion, inhibit cortisol synthesis and the adrenal level or compete with cortisol at the receptor level. Inhibitors of steroid synthesis are effective in most cases in a dose dependent manner.

Medical management of Cushing’s syndrome is reserved for patients who need to have rapid corrections of hypercortisolism, for critical cases and in preparation for surgery, for patients treated with pituitary irradiation, and whenever a definitive treatment is delayed.


Drug Therapy of Cushing’s Syndrome

Drugs acting at the hypothalamic-pituitary level are rarely effective and infrequently used, especially in the elderly who are at increased risk of toxicity from agents like dopamine agonists.

Inhibitors of steroid synthesis such as mitotane, metyrapone, aminoglutethimide and ketoconazole have all shown varying degrees of success. With the exception of mitotane, this group all interferes with steroid metabolism through the cytochrome P-450 system. Because their mechanism of action is non-specific enzyme changes in the P-450 system, their actions are non-selective and extra-adrenal effects are common.

Mitotane possesses adrenocorticolytic effects, can modify steroid peripheral metabolism and directly inhibits steroid biosynthesis. Therapeutic effects require several weeks and because of the extensive inhibition of steroid synthesis replacement therapy requirements are higher than other agents. Because mitotane suppresses cortisol production, it is often used with radiation therapy to speed recovery. Mitotane alone has been found to be successful in thirty to forty percent of such cases. Adverse drug reactions include nausea and vomiting, depression, lethargy, and vertigo.

Ketoconazole inhibits cholesterol side-chain cleavage and therefore steroid synthesis. Daily doses of 600 – 800 mg are needed to maintain urinary cortisol concentrations within the upper limits of normal. Ketoconazole can cause elevations in liver function tests, therefore it is recommended to monitor LFTs during therapy. Additionally, men are likely to develop hypogonadism.


Incidence of Addison’s Disease

Thomas Addison

Addison's sufferer John F. Kennedy. Notice the far thinner face of his brother Robert, behind him. • 1/100,000 people affected

• Affects all age groups • Males and females are affected equally

In 1849, Thomas Addison first described the “melasma suprarenale” in a paper titled “A Remarkable Form of Anaemia.” He chose the term anemia to reflect the chronic fatigue, muscle weakness, anorexia and weight loss that are common in Addison’s disease. What were not recognized at the time were the role of the adrenal glands and the severe or total deficiency of cortisol and other adrenal hormones such as aldosterone. Today Addison’s disease is best known for one of its sufferers, President John Kennedy. While it is now well-known that he had the condition, during his lifetime he went to great lengths to hide his disease.


Etiology and Pathogenesis of Addison’s Disease

The pair of adrenal glands in the bottom are normal. Those at the top come from a patient with adrenal atrophy from with either Addison's disease or long-term corticosteroid therapy.

Primary Adrenal Insufficiency due to:

• Autoimmune disorders (70% of cases in US) • TB (20%) – most common infectious cause in the world • Chronic infections

• HIV- most common infectious cause in US • Cancer metastases • Amyloidosis • Surgical removal of adrenal glands • Inflammation

Secondary Adrenal Insufficiency due to:

• Interruption of glucocorticoid medication

• Surgical removal of ACTH producing tumors

• Pituitary dysfunction


Etiology and Pathogenesis of Addison’s Disease

Tertiary Adrenal Insufficiency due to:

• Interruption of glucocorticoid medication • Iatrogenic suppression of HPA axis • Hypothalmic failure or dysfunction

Addison’s disease affects about one in every one hundred thousand people and occurs in all age groups. It can be the result of primary adrenal insufficiency or secondary to a decline in adrenocorticotropin levels.

Primary adrenal insufficiency due to autoimmune destruction of the adrenal cortex accounts for about seventy percent of Addison’s cases. Tuberculosis accounts for another twenty percent. Secondary adrenal insufficiency may be due to the surgical removal of benign ACTH-producing tumors or pituitary dysfunction.

Tertiary adrenal insufficiency may occur with hypothalamic failure or dysfunction. A temporary form of Addison’s disease occurs when a person who has been receiving glucocorticoid medication suddenly stops or reduces the dose substantially.

This may also occur in a glucocorticoid-dependent patient who become stressed and require additional increased glucocorticoids to maintain stability.


Drugs that Can Inhibit Adrenal Function

High dose steroids (e.g., > 20 mg prednisone for 3 wks) – suppresses the hypothalamic-pituitary-adrenal axis

Mitotane – destroys adrenal cortex, affecting peripheral conversion of cortisol

Aminoglutethimide – inhibits P450scc, resulting in compensatory increase in ACTH

Metyrapone – inhibits P450 C11 hydroxylase, affecting cortisol and aldosterone production

Ketoconazole – inhibits P450 C11 hydroxylase

Etomidate – inhibits P450 C11 hydroxylase

Mifepristone – competitvely inhibits receptor binding

Megestrol Acetate – has slight glucocorticoid activity and may suppress the hypothalamic-pituitary –adrenal axis

Human Growth Hormone- a synthetic analog of a pituitary hormone that has been correlated with adrenal insufficiency

Rifampin- enhances the hepatic metabolism of cortisol

Warfarin- case reports of adrenal hemorrhage from hypocoagulopathy


Drugs that Can Inhibit Adrenal Function

Generally speaking, maintenance doses of steroids carry a very low risk of triggering clinical significant adrenal insufficiency. However, high doses of steroids, which suppress the hypothalamic-pituitary-adrenal axis, can substantially increase this risk. Other drugs that can inhibit adrenal function, causing adrenal insufficiency or other conditions, include agents used to treat Cushing’s syndrome such as mitotane, aminoglutethimide, and metyrapone. Recently, studies have shown a correlation with adrenal insufficiency in adults who had previously received human growth hormone for childhood onset of human growth hormone deficiency.


Common Signs and Symptoms of Addison’s Disease

• Fatigue • Muscle weakness • Loss of appetite and weight loss • Nausea & vomiting • Diarrhea • Orthostatic hypotension • Hyperpigmentation of exposed and nonexposed areas • Irritability and depression • Craving for salty foods • Hypoglycemia • Disruption of menstrual periods

The symptoms of Addison’s disease usually begin gradually. Chronic, worsening fatigue and muscle weakness, loss of appetite, and weight loss are common. Nausea, vomiting, and diarrhea occur in about fifty percent of cases. Blood pressure, which is already lower, falls further when standing, causing dizziness or fainting. Skin changes include possible hyperpigmentation covering exposed and nonexposed parts of the body. Mental status changes include irritability and depression. Patients often have a craving for salty foods.


Addisonian Crisis

Onset caused by: an illness, accident or other stressful event.

Signs and Symptoms: • Sudden penetrating pain in the lower back, abdomen or legs • Severe vomiting and diarrhea, followed by dehydration • Low blood pressure • Loss of consciousness

In its early stages, Addison’s disease can be difficult to diagnose. A review of the patient’s medical history based on the symptoms may lead the clinician to suspect adrenal insufficiency, especially if there is hyperpigmentation. In about twenty-five percent of cases, however, the disease goes undetected until a stressful event such as an illness or accident causes the patient to take a dramatic downturn.

This is called an Addisonian crisis or acute adrenal insufficiency, and is marked by sudden penetrating pain in the lower back, abdomen or legs, severe vomiting and diarrhea, and low blood pressure. If left untreated, an Addisonian crisis can be fatal. Therefore, it is important for patients who may be susceptible adrenal insufficiency to be aware of the signs and symptoms of adrenal crisis and to be monitored for adrenal insufficiency to prevent sudden death from Addisonian crisis.


Diagnosis of Addison’s Disease

• ACTH stimulation test: to determine cortisol production • Insulin-induced hypoglycemia test: to evaluate hypothalamus, pituitary, and adrenals’ response to stress • X-rays: to detect adrenal calcium deposits • CT and MRI: to view pituitary

ACTH S1mula1on Test

Enzyme defect Direct effect Secondary to HPA over ac1vity

21 Hydroxylase increased 170HP, P decreased 11 Deoxy corGsol decreased CorGsol

increased 4-‐Androstenedione

11 Hydroxylase

increased 170HP decreased CorGsol increased DeoxycorGcosterone

increased 4-‐Androstenedione


Diagnosis of Addison’s Disease

As with Cushing’s syndrome, diagnosis of Addison’s disease relies on ACTH stimulation tests and other biochemical assays.

In the ACTH stimulation test, the patient’s blood and/or urine cortisol levels are measured before and after a synthetic ACTH injection. If the patient’s cortisol level does not rise in response to the injection, adrenal insufficiency should be suspected. An insulin-induced hypoglycemia test may be given to determine how the hypothalamus, pituitary, and adrenal glands respond to stress.

X-rays of the abdomen are used to detect calcium deposits in the adrenals; CT scans and MRI are used to view the size and shape of the pituitary.


Treatment of Addison’s Disease

Normal Addison's:

• Hydrocortisone po bid (to replace cortisol) - 2/3 (25 mg) in AM and 1/3 (12.5 mg) in PM before supper – drug of choice for Addison’s

• Fludrocortisone(Florinef ®) 0.1 mg qd to 3 times/week (to replace aldosterone) – to decrease serum potassium, increase serum sodium, or if postural hypotension is present

• Decreased salt intake

Addisonian Crisis:

• Hydrocortisone 100 mg IV immediately and every 6-8 hours for 24-48 hours • IV normal saline and dextrose supplementation to maintain hemodynamic support; then when stable • Hydrocortisone 50 mg PO every 8 hours for 48 hours; taper to 30-50 mg/day

Treatment of Addison’s disease involves replacing, or substituting, the hormones that are not being produced by the adrenal glands. Hydrocortisone tablets, taken once or preferably twice a day, compensate for cortisol deficiency. If twice a day, give two thirds replacement in the morning and one third replacement in the afternoon before supper. Daily oral doses of the mineralocorticoid fludrocortisone acetate replace aldosterone. Patients receiving aldosterone replacement therapy are usually advised to reduce their salt intake. Patients in Addisonian crisis are treated with IV hydrocortisone, saline, and dextrose.


Adrenal Insufficiency in Acutely Ill Patients

Causes of Adrenal Insufficiency in the Acutely Ill

Septicemia and coagulopathy may cause adrenal hemorrhage

High levels of cytokines during inflammation may inhibit adrenal cortisol synthesis and induce systemic corticosteroid resistance

HIV infection can result in adrenal infection and use of various drugs making one susceptible to adrenal insufficiency (rifampin, ketoconazole, megestrol acetate, etc.)

An increase in tissue corticosteroid levels during acute illness is an important protective response. Many diseases and treatments interfere with the normal response of corticosteroids to illness. This adrenal insufficiency in the critically ill is difficult to diagnose because its symptoms are usually attributed to their acute illness. Overall, the role of corticosteroids in the critically ill is controversial. There is evidence to support the use of supplemental corticosteroids in patients with established septic shock who are in an intensive care unit. It has been shown that patients with septic shock treated with hydrocortisone and fludrocortisone had a significant reduction in death from septic shock. Patients in shock may be treated with steroid replacement therapy at diagnosis and should be tested for adrenal insufficiency; treatment can then be removed if adrenal function is intact.


Resources


Annane D, Sebille V, Charpentier C, et al. Effect of Treatment with Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic Shocl. JAMA, 2002; 288: 862-71.

Barnette DJ. Endocrine and metabolic disorders. In: Barnette D, Bressler L, Brouse S, et al. Updates in Therapeutics: The Pharmacotherapy Preparatory Course, Vol. 2, 2008 ed. Lenexa, KS: American College of Clinical Pharmacy, 2008: 187-220.

Boscaro M, Barzon L, Fallo F et al. Cushing’s syndrome.Lancet 2001;357:783-91

Cizza, G. & Chrousos, G. P. Adrenocorticotrophic hormone-dependent Cushing’s syndrome. Cancer Treatment and Research 1997;89: 25-40.

Cook, D. M. & Loriaux, D. L. Cushing’s syndrome. Current Therapy in Endocrinology & Metabolism 1997;6: 161-164.

Cooper MS and Stewart PM. Corticosteroid Insufficiency in Acutely Ill Patients. N Eng J Med 2003; 348: 727-734.

Coursin DB and Wood KE. Corticosteroid Supplementation for Adrenal Insufficiency. JAMA 2002; 287: 236-40.

Failor RA and Capell PT. Hyperaldosteronism and Pheochromocytoma: New Tricks and Tests. Prim Care Clin Office Pract, 2003; 30: 801-20 . Girgis R, Winter J. The effects of glucocorticoid replacement therapy on growth, bone mineral density, and bone turnover markers in children with congenital adrenal hyperplasia. J of Clin Endocrinol and Metab 1997;82:3926-3929.


Resources

Gums JG, Terpening CM. Adrenal gland disorders. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM editors. Pharmacotherapy, a pathophysiologic approach, New York, McGraw-Hill Medical Publishing Division 2002, Chapter 76; 1379-1393

Lange M, Feldt-Rasmussen U, Svedsen OL, et al. High Risk of Adrenal Insufficiency in Adults Previously Treated for Idiopathic Childhood Onset Growth Hormone Deficiency. J of Clin Endocrinol Metab 2003; 88:5784-9.

Mann M, Koller E, Murgo A et al. Glucocorticoidlike Activity of Megestrol: A Summary of Food and Drug Administration Experience and a Review of the Literature. Arch Intern Med 1997; 157: 1651-6.

Mills JL, Schonberger LB, Wysowski DK, et al. Long-Term Mortality in the United States Cohort of Pituitary-Derived Growth Hormone Recipients. J Pediatr 2004; 144: 430-6.

National Adrenal Diseases Foundation http://www.medhelp.org/nadf/: Accessed 4/29/05

National Institute of Diabetes and Digestive and Kidney Diseases: “Addison’s Disease” http://www.niddk.nih.gov/health/endo/pubs/addison/addison.htm: Accessed 4/29/05

National Institute of Diabetes and Digestive and Kidney Diseases: “Cushing’s Syndrome” http://www.niddk.nih.gov/health/endo/pubs/cushings/cushings.htm: Accessed 4/29/05

Meier, C. A. & Biller, C. M. Clinical and biomedical evaluation of Cushing’s syndrome. Endocrinology & Metabolism Clinics of North America, 1997;26(4): 741-762.


Resources

Nieman LK. Diagnostic tests for Cushing’s syndrome. Ann NY Acad Sci 2002;970:112-118

Nieman, L. K. Cushing’s: Medical approach. Current Therapy in Endocrinology & Metabolism, 1997;6: 59-62.

Orth, D. N. Cushing’s syndrome. N Engl J Med, 1995;332: 791-803.

Parker CR. Adrenal function in aging. Current Opion in Endocrinology & Diabetes, 1999; 6(3): 210

Rocha R, Funder JW. The pathophysiology of aldosterone in the cardiovascular system. Ann NY Acad Sci 2002;970:89-100

Timiras PS. Physiological basis of aging and geriatrics. 3rd ed. Informa Health Care, 2002: 172-177.

Tsigos, C. & Chrousos, G. P. Differential diagnosis and management of Cushing’s syndrome. Annual Review of Medicine, 1996;47: 443-461.

Vaughan ED. Diseases of the adrenal gland. Med Clin N Am, 2004; 88:443-66


Paget’s Disease

Learning Objectives


•  Identify the common clinical manifestations and complications associated with Paget’s disease.

• Compare and contrast the pharmacological and non-pharmacological therapies used to treat Paget’s disease

• Prepare a treatment plan for an elderly patient with Paget’s disease given a patient case.


Pathogenesis of Paget’s Disease

Initial Phase: intense osteoclastic activity and bone resorption.

Mixed Phase (Osteolytic-Osteoblastic Phase): active bone resorption & formation of woven bone with ineffective mineralization.

Late Sclerotic Phase: Dense cortical and trabecular bone deposition dominates resulting in weak, chaotic bone that also encroaches on marrow.

Bones Commonly Affected

Bones Percentage

Pelvis 72

Lumbar spine 58

Femur 55

Thoracic spine 45

Skull 42

Tibia 35

Humerus 31

Cervical spine 14

Information from Ooi CG, Fraser WD. Paget’s disease of bone. Postgrad Med J 1997;73:70

In normal bone, the process of remodeling is coupled so that bone resorption occurs at a similar rate to bone formation. The cells responsible for these actions are osteoclasts and osteoblasts, respectively. When this process becomes uncoupled, as in osteoporosis or Paget’s disease, greater resorption occurs resulting in loss of bone mineral density.

Paget’s disease is characterized by intense localized osteoclastic and osteoblastic activity that progresses in three general phases. In the initial phase, there is a localized increase in bone resorption. Numerous osteoblasts overlie previously resorbed bone surfaces and result in increased bone formation. During the mixed phase, in-growth of highly vascularized fibrous tissue occurs. In the sclerotic phase, dense cortical and trabecular bone encroach on the marrow space.

Paget’s disease can affect any bone although the most commonly affected bones are those of the axial skeleton, long bones and pelvis. In the majority of patients, Paget’s disease affects at least two bones; however, up to one-third of patients will only have one bone that is involved.


Etiology of Paget’s Disease

•  Slow-virus infection • Genetics (associated with chromosome 18q) • Hormonal imbalance • Environmental factors, such as dietary calcium intake and exposure to industrial toxins

The exact cause of Paget’s disease still is unknown. Possible causes include a slow virus infection, as evidence of previous infection with measles or respiratory syncytial viruses are often found in Paget’s patients. Other theories implicate hormonal imbalances such as hyperparathyroidism, excess growth hormone secretion, adrenal insufficiency and calcitonin deficiency.

Additionally, genetics may also play a role in the etiology of Paget’s disease as fifteen to forty percent of patients have a positive family history of the disease and at least one first-degree relative with the disorder. Increasingly, there is more information on genetic abnormalities believed to be involved in the pathogenesis of Paget’s. Identification of the genes involved in osteoclastogenesis are mutated in Paget’s. This mutation combined with nongenetic factors, like infection or environmental exposure, form the leading theory on how Paget’s disease occurs. From a clinical standpoint, this new information leads to the question of whether treatment should be started in patients carrying the Paget’s-causing genetic mutations.


Signs & Symptoms of Paget’s Disease

http://eduserv.hscer.washington.edu/hubio553/totrad/SCAR/commonmsk.html

From: http://www.surgeongeneral.gov/library/bonehealth/chapter_3.html

Anterior and posterior whole body images from a radionuclide bone scan. Multiple bones (skull, sternum, humerus, right hemipelvis, and left tibia demonstrate intense uptake, consistent with Paget's disease. Up to 25 % of Paget's patients have no bone pain at the time of diagnosis. Therefore, it is not unusual to first diagnose Paget's disease on images performed for some other completely unrelated reason.



From: http://www.nlm.nih.gov/medlineplus/ency/imagepages/9499.htm

Pain: • Spontaneous • Often in the low back • Related to arthritic hip/knee • Associated with deformity femur/tibia

Deformity: • Kyphosis • Progressive and painless bowing of long bone • Increased head size or curvature of the spine • Shortened or bowed limbs • Frontal bossing of the forehead • Dental abnormality

Neurological: • Deafness • Headache • Spinal cord compression • Brain stem compression • Trigeminal neuralgia

Heart failure

Kidney stones



Fortunately an estimated 70% of Paget’s disease cases are asymptomatic and only identified incidentally on radiographs or by laboratory examination. For those patients who are symptomatic, chronic pain is the most common symptom. Interestingly, pain typically increases with rest especially at night when the extremities are warm. Bone pain can occur in any bone affected by Paget's disease. It often localizes to areas adjacent to the joints. Pain can be exacerbated with weight bearing activities. Paget’s disease can also affect the joint space leading to damage to cartilage and the development of arthritis.

Headaches and hearing loss may occur when Paget's disease affects the skull - owing to a decrease in the size of the neural foramina resulting in compression of the cranial nerves, the brain stem and cerebella from basilar invagination, as well as compressive lesions of the spinal cord and nerve root. In advanced cases head size may increase along with bowing of limbs or curvature of the spine.

Patients with Paget’s disease are also prone to rheumatoid arthritis, and psoriatic and other inflammatory disorders. Osteoarthritis may be the most common source of chronic joint pain and immobility.


Complications of Paget’s Disease

Malignant bone tumors Fractures - tibia, femur, radius, pelvis Paraplegia

Malignant bone tumors are one of the most serious complications of Paget’s Disease. Fortunately this is relatively rare, occurring in about 0.7% to 0.9% of patients with Paget’s disease. Osteosarcomas, chondrosarcomas, and fibrosarcomas may develop in a preexisting pagetic lesion, often obscuring the ability to detect the malignancy early. Increased bone pain or deformity should be followed up by radiologic evaluation, and if necessary, by bone biopsy. Because of this increased risk of osteosarcoma, patients with Paget’s should not be treated with terparatide, according to the product’s “black box” warning.

Another serious complication of Paget’s disease is fractures. These can result in further complications such as reduced mobility, functioning and additional decompensation. If spinal cord compression is involved the patient may also become paraplegic.


Lab Evaluation

Radiologic diagnosis

• Severe localized osteolysis • Osteosclerotic lesions • Widespread osteosclerosis

Radiologic tests

• Bone scintigraphy (Gallium 67) • MRI • Bone biopsy

Biochemical bone markers:

• Serum markers of bone turnover

• Serum alkaline phosphatase • Serum bone-specific alkaline phosphatase • Tartrated-resistant acid phosphatase • Procollagen type I N-terminal peptides (PINP) • Serum bone sialoprotein • Serum osteocalcin • B-carboxyterminal telopeptide of type-I collagen (SCTX)

Urine markers of bone turnover

• Pyridinoline (PYD) • Hydroxyproline (Hyp) • Amino (NTX) & ?-carboxyterminal (CTX) of collagen type I • Deoxypyridinoline (DPD) • Urinary calcium

Markers of bone formation

• Bone-specific alkaline phosphatase • N-terminal and C-terminal extension peptides of

procollagen


Lab Evaluation

As mentioned earlier, most patients are diagnosed incidental to radiographs or a routine laboratory work-up. A conventional bone scan is recommended before and six months after treatment, and every 12 months thereafter depending on the behavior of the Pagetic lesion. Radiographs should be obtained before treatment and every one to two years thereafter to monitor changes in modeling and remodeling. Radionucleotides such as Gallium 67 can help localize Pagetic lesions and may be used to follow the response to drug therapy. Such bone scans should be done on every patient suspected to have Paget’s because they will identify fifteen to thirty percent of lesions not picked up on x-rays. Although rarely done, a bone biopsy is used to evaluate malignancy when MRI indicates mixed osteoblastic and osteolytic vertebral lesions.

Three decades ago it became possible to measure the rate of bone resorption by using urinary hydroxyproline, as well as the rate of bone formation, indicated by plasma alkaline phosphatase. Both are increased considerably by the excess bone turnover of pagetic bone. Since that time there has been an explosion of biochemical bone markers. Historically, the two most important markers in Paget’s disease are total serum alkaline phosphatase and urinary pyridinoline. However, it is now appreciated that hydroxyproline, because of extensive breakdown before excretion, does not reflect collagen turnover accurately. Newer assays of nonmetabolized collagen peptides, including N-telopeptides and pyridinoline crosslink assays, are more sensitive markers of bone resorption and are readily available through commercial laboratories.

Serum markers of bone turnover show lower biological variability than urinary markers and are therefore more sensitive indices of the activity of the disease. Serum alkaline phosphatase can be considered to be a sensitive and inexpensive marker for therapeutic monitoring of Paget’s disease. Patients should be followed by measuring bone markers every three to six months depending on the activity of the Pagetic lesion and the drug used. Treatment should be recommended when remodeling indices rise above the upper limits of normal or by 25% above the previous lowest point.


Indications for Pharmacotherapy

• Bone or articular pain • Bone deformity • Bone, articular, or neurologic complications • Asymptomatic disease, but risk of complications due to site of involvement:

• Base of skull (risk of hearing loss or other neurologic complications) • Spine (risk of neurologic complications) • Long bones of lower limbs (risk of fractures and osteoarthritis)

• Increased bone remodeling (alkaline phosphatase > 25 – 50% over normal or baseline levels) • Preparation for orthopedic surgery

Adapted from Delmas PD, Meunier PJ. The management of Paget’s disease of bone.N Engl J Med 1997;336:558-566

Both symptomatic and asymptomatic patients with increased parameters of bone remodeling are candidates for drug therapy, especially if the alkaline phosphatase level is at least 25% above the baseline level. Bone pain can increase the need for specific drug treatment, especially if it is unrelieved by nonsteroidal anti-inflammatory drugs or acetaminophen. Preparation for orthopedic surgery, and medication complications such as hypercalcemia, hearing loss, and spinal cord or nerve dysfunction are also good indicators for drug therapy. Drug therapy may be recommended to prevent fractures or skeletal deformity in patients with active Paget’s disease. Because Paget’s disease is a chronic disease the goal of therapy is to palliate bone pain and to prevent the progression of the disease.


Pharmacological Treatment of Paget’s Disease

• Bisphosphonates • Calcitonin (human & salmon) • Analgesics

Paget’s disease is a chronic, progressive disease with the potential for severe complications and significant reduction in quality of life. Therefore even asymptomatic patients are considered for treatment if they show active disease as indicated by abnormal biochemical markers. However, there is no conclusive evidence to suggest that complications can be prevented by controlling bone remodeling through drug therapy. Several agents are helpful in treating Paget’s disease and are discussed below

Bisphosphonates are the treatment of choice because they bind to the surface of hydroxyapatite crystals, decreasing bone resorption and disrupting osteoclasts and cellular activity. The main action of bisphosphonates is to induce marked and prolonged inhibition of bone resorption by decreasing osteoclastic activity. Disease activity stays low for months or years after cessation of these medications. Bisphosphonates can cause a 70 percent decrease in biochemical markers in one half of patients. As newer more potent Bisphosphonates are developed the reduction in biochemical markers will likely increase. Bisphosphonates also may demonstrate some analgesic effect for bone pain. Bisphosphonates appear to be more effective than calcitonin in suppressing the histological and biochemical activity in Paget’s disease.

Calcitonin is no longer considered to be the treatment of choice for Paget’s disease. Calcitonin is a product of the thyroid C-cells and its action in the body is to decrease osteoclastic bone resorption. Calcitonin is appropriate for patients who show no response to the bisphosphonates or when used for a few weeks to decrease bone pain.

Analgesics such as acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) may be useful in symptomatic patients to reduce bone pain.


Treatment with Bisphosphonates

Mechanism of Action: induce marked and prolonged inhibition of bone resorption by decreasing osteoclastic activity.

Advantages:

• Long duration of action • Improve in neurologic complications • Lamellar new bone formation rather than woven • Decrease bone turnover • Stabilize hearing loss

Limitation:

• Poorly absorbed from gastrointestinal tract • Osteonecrosis of the Jaw (ONJ) with IV use of Pamidronate and Zolendronic Acid

1st Generation

Etidronate (Didronel®) • Dosing: 5 mg/kg body weight po qd for six months • Side effects:

• Defective mineralization of newly formed bone matrix • Increased risk of fracture



2nd Generation (preferred)

Alendronate (Fosamax®) – available in PO and IV • The recommended dose is 40 mg once daily for six months. Retreatment may be considered, following a six-month post-treatment evaluation period in patients who have relapsed, based on increases in serum alkaline phosphatase or failure to normalize serum alkaline phosphatase (Prod Info Fosamax(R), 2003).

• Side effects: • Esophageal ulceration

Pamidronate (Aredia®) – available in PO and IV Dosing: 30 mg IV over a four hour period on three consecutive days; or 60 mg IV over a two to four hour period for two or more consecutive or nonconsecutive days

Side effects: Venous irritation Transient fever with influenza-like symptoms



3rd Generation

• Tiludronate (Skelid®) • An oral dose of 400 mg once daily for three months is recommended. After completing three months of therapy, an additional three months is necessary to assess the response to therapy (Prod Info Skelid(R), 1997).

• Risedronate (Actonel®) • An oral dose of risedronate 30 mg once daily for two months is recommended. Retreatment may be considered following post-treatment observation of at least two months; for retreatment, dose and duration of therapy are the same as for the initial course.

• Zoledronic Acid (Reclast®) • Dosing: Single 5 mg IV infusion over no less than 15 minutes once yearly

• Ibandronate (Boniva®) • Intravenous ibandronate injections given every three months may be an effective alternative to oral bisphosphonate therapy for post-menopausal women. However, ibandronate is not currently FDA approved for Paget’s disease. • Oral dosing is either 2.5 mg daily or 150 mg tablet once monthly for post-menopausal women.



http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15050907

http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#zometa2 http://www.fda.gov/cder/drug/infopage/bisphosphonates/default.htm http://www.fda.gov/cder/drug/early_comm/bisphosphonates_update_200811.htm

Bisphosphonates are compounds that are structurally similar to that of inorganic pyrophosphate which is an endogenous regulator of bone mineralization. Bisphosphonates are the agents of choice for Paget’s patients that are able to tolerate them. Oral etidronate was initially standard therapy for Paget’s disease. However, etidronate along with tiludronate, have less antiresorptive bone activity than the newer-generation bisphosphonates and were shown to be less effective than alendronate. Resistance to etidronate therapy is also possible.

The oral aminobisphosphonates such as pamidronate and alendronate are associated with esophageal side effects including ulceration and stricture. Therefore IV bisphosphonates such as pamidronate, zoledronic acid and ibandronate are used for patients unable to tolerate other oral bisphosphonates. In patients previously treated with pamidronate, alendronate was shown to be more effective.

Risedronate is a pyridinyl bisphosphonate with potent antiresorptive properties, approximately 1000 times more potent than etidronate and 5 times more potent than alendronate in animals. When compared to etidronate in Paget’s disease patients, risedronate offered a shorter duration of therapy, better and longer-lasting remission, significant reductions in pain and additional remission in patients who failed etidronate.

The increased potency of third generation bisphosphonates results in greater normalization of biochemical markers of bone turnover than first generation agents. However, it is unclear whether the enhanced reduction in biochemical markers will affect the overall course of the illness.



With all of these agents, remission of the disease is possible for up to three years. If the patient’s disease reactivates then additional trials of bisphosphonates are indicated. In cases of disease that have developed resistance to bisphosphonates, both IV pamidronate and oral risedronate are shown to be efficacious, with risedronate having a lower incidence of treatment-related side effects.

The newest bisphosphonates available include zoledronic acid and ibandronate. Zoledronic acid, an intravenous nitrogen-containing bisphosphonate with 100- to 850-fold more potency in bone resorption inhibition than pamidronate, was approved by the FDA in April 2007 for the treatment of Paget’s disease. Studies indicate that patients taking oral alendronate can be directly switched to zoledronic acid and maintain positive bone effects for a full 12 months following the single infusion. Ibandronate is a potent nitrogen-containing oral bisphosphonate that is given monthly for the prevention of post-menopausal osteoporosis. It has not been approved by the FDA for the treatment of Paget’s disease. Data supporting the efficacy of ibandronate is limited; available information warrants further investigation to identify a dose and regimen that will achieve complete normalization and long-term remission of Paget’s disease.

There have been several safety concerns with the use of bisphosphonates, of which the FDA has released recent communications regarding these. In 2005, the FDA notified dental healthcare professionals of revisions to the prescribing information of the intravenous bisphosphonates, Aredia (pamidronate disodium) and Reclast (zoledronic acid) describing the occurence of osteonecrosis of the jaw (ONJ) observed in cancer patients receiving treatment. In 2008, two MedWatch documents were released: one reminding physicians of potential severe and sometimes incapacitating bone, joint and/or muscle pain among patients taking any bisphosphonate, a warning included but potentially overlooked by providers, and the other declaring no clear association between treatment with a bisphosphonate and atrial fibrillation, with the exception being zoledronic acid’s prescribing information that includes a potential increased risk for serious atrial fibrillation.


Side Effects of Bisphosphonates

Watch for:

• Low blood calcium • Esophagitis • GI distress • Diarrhea • Cramps • Headache • Bone pain

Monitor:

• Response to drug • Resolution of symptoms • Alkaline phosphatase and either free

pyridinoline cross-links or telopeptides

One common side effect of bisphosphonates is low blood calcium. Therefore, patients must have adequate intake of Vitamin D and oral calcium. T

The oral aminobisphosphonates such as pamidronate and alendronate as well as risedronate can all cause heartburn, esophageal irritation, esophagitis, abdominal pain, diarrhea and other adverse gastrointestinal effects. Gastrointestinal distress appears to be lessened with third generation agents. To avoid severe esophageal irritation, the tablets must not be chewed or allowed to dissolve in the mouth, and must be taken with eight ounces of plain water while in an upright position. For 30 minutes after taking the drug, the patient must not eat or drink anything other than water and must avoid lying down. Food and vitamin supplements must be withheld for at least two hours after administration.

Paget’s patients taking bisphosphonates should be monitored for changes in bone resorption indices as well as serum calcium levels. Lab tests for alkaline phosphatase and either free pyridinoline cross-links or telopeptides can help verify if the patient is responding to treatment.


Treatment with Calcitonin

Advantages:

• Relieves bone pain within two weeks • Improves mobility • Decreases blood flow to affected regions • Heals osteolytic lesions • Stabilizes hearing loss

Limitations:

• Acquired resistance possible • Short-lived effects

Types:

Salmon

• Injectable - initial doses 50-100 IU qd for one month, follow three to four days weekly thereafter

• Spray: 200-400 IU qd for one month

Human (Calcimar®)

• Injectable - 50 IU qd for one month, follow three to four days weekly

Although calcitonin is no longer considered the treatment of choice for Paget’s disease, there is still a role for its use. Calcitonin can be used to reduce bone pain associate with pagetic lesions, fractures or the initiation of bisphosphonate therapy. Long-term therapy is limited by the development of resistance.

Over treatment periods of two to three years, one quarter of patients acquire a resistance to calcitonin due to an increased level of neutralizing antibodies and/or by receptor down regulation.

Calcitonin is available in an injectable salmon and human forms and as a nasal spray in salmon form only. With intranasal delivery of calcitonin, there is lower bioavailability; hence the dosage is higher.

Salmon calcitonin may be problematic over human calcitonin due to the production of antibodies that attenuate the effectiveness of the agent in one to two thirds of patients. Those that either do not respond to salmon calcitonin or develop a resistance to it should try the human form.


Side Effects of Calcitonin

• Nausea • Facial flushing • Vomiting • Rhinitis • Perioral paresthesias • Metallic taste sensation • Chills

Side effects are seen in twenty percent of patients. Common symptoms include nausea, vomiting and facial flushing. Rhinitis is experienced in patients with nasal administration.


Nonpharmacological Treatment of Paget’s Disease

Orthopedic intervention may be required due to skeletal complications seen with Paget’s disease. Bowing of the femur and tibia, and delayed fractures are examples of such complications. Complications of elective surgery could bring the risk of infection, hemorrhage and loosening of the prosthetic joint replacement. Calcitonin and bisphosphonates may postpone need for surgery, however, surgery can help improve mobility and decrease the bone pain.


Resources


Ankrom MA, Shapiro JR.Paget’s disease of bone (osteitis deformans).J Am Geriatr Soc 1998;46:1025-33.

Buckler H, Fraser W, Hosking D, et al. Single Infusion of Zoledronate in Paget’s Disease of Cone: A Placebo-Controlled, Dose-Ranging Study. Bone, 1999; 24; 81S-5S.

Cacace E. Ruggiero V. Matulli C. Uras L. Perpignano G. Markers of bone resorption in bisphosphonate therapy of Paget's disease. Clinical & Experimental Rheumatology. 22(4):502, 2004

Coppes-Zantinga AR, Coppes MJ.Sir James Paget (1814-1889): a great academic victorian. J Am Coll Surg 2000;191(1):70-4.

Delmas PD, Meunier PJ.The management of Paget’s disease of bone. N Engl J Med 1997;336(8):558-66.

Grauer A, Heichel S, Knaus J, et al. Ibandronate treatment in Paget’s disease of the bone. Bone. 1999;24(5 Suppl):87S-89S.

Hadjipavlou AG, Gaitanis IN, Kontakis GM. Paget’s disease of the bone and its management. J Bone Joint Surg Br 2002;84-B(2):160-9.

Hamdy RC. Paget’s disease of the bone. Clin Geriatr Med 1994;10(4):719-35.


Resources

Holgado S, Rotes D, Guma M, et al. Paget’s Disease of Bone in Early Life. Ann Rheum Dis, 2005; 64: 306-8.

Hosking D, Meunier PJ, Ringe JD et al.Paget’s disease of bone: diagnosis and management.BMJ 1996;312(7029):491-4.

Kanis JA, McCloskey EV, Beneton MN. Clodronate and osteoporosis. Maturity 1996; 23 Suppl:81-6.

Kurzl RG.Paget’s disease. Sem Dermatol 1996;15(1):60-6.

Langston AL. Ralston SH. Management of Paget's disease of bone. Rheumatology. 43(8):955-9, 2004

Lyles KW. What is "resistance" in Paget's disease of bone? Arthritis & Rheumatism. 48(8):2097-9, 2003

Miller PD, Brown JP, Siris ES et al. A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget’s disease of bone. Am J Med 1999;106:513-20.

Mirra JM, Brien EW, Tehranzadeh J. Paget’s disease of bone: review with emphasis on radiologic features, Part II.Skeletal Radiol 1995;24(3):173-84.

Onishi Y, Ohara K. Ectopic extramammary Paget’s disease affecting the upper abdomen. Br J Dermatol 1996;134(5):958-61.

Paget Foundation, http://www.paget.org/


Resources

Pearce JMS.Sir James Paget: a biographical note.Q J Med 1997;90:235-7.

Product Information: Forteo(TM), teriparatide (rDNA origin) injection. Eli Lilly & Co., Indianapolis, IN (PI revised 2/2004) reviewed 12/2004.

Redina D, Mossetti G, Viceconti, et al. Risedronate and Pamidronate Treatment in the Clinical Management of Patients with Severe Paget’s Disease of Bone and Acquired Resistance to Bisphosphonates. Calcif Tissue Int, 2004; 75: 189-96.

Reid IR, Miller P, Lyles K, et al. Comparison of single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med 2005;353:898-908.

Roodman GD and Windle JJ. Paget Disease of Bone. J Clin Invest, 2005; 115: 200-8.

Schneider D, Hofmann MT, Peterson JA. Diagnosis and treatment of Paget’s disease of bone.Am Fam Physician 2002;65(10):2069-72.

Takata S, Yasui N, Nakatsuka K, et al. Evolution of Understanding of Genetics of Paget’s Disease of Bone and Related Disease. J Bone Miner Metab, 2004; 22: 519-23.

Woitge HW, Oberwittler H, Heichel S, et al. Short and long term effects of ibandronate treatment on bone turnover in Paget disease of the bone. Clin Chem. 2000;46(5):684-90.


Menopause and Hormone Replacement Therapy

Learning Objectives


• Identify a patient experiencing menopausal symptoms, and the signs which would coincide with a diagnosis of menopause.

• Compare and contrast the treatment of the signs and symptoms of menopause historically with how it is treated today.

• Educate a menopausal female on the risks and benefits of certain non-pharmacological and pharmacological therapies for the treatment of symptoms of menopause.

• Suggest a treatment plan for a menopausal female experiencing distressing symptoms of menopause.


Introduction to Menopause

Perimenopause: • Time between menstrual irregularity and menopause

Natural Menopause: • No spontaneous menstrual period (amenorrhea) for 12 consecutive months with no other pathologic or physiologic

cause • Age of onset is between 40 – 60 years • Associated with somatic, physiological, and psychological changes

Premature Menopause: • Onset prior to age 40 years • Caused by genetics, viral infection, smoking

Induced Menopause: • Cessation of menses following hysterectomy with or without bilateral oophorectomy • Iatrogenic ablation of ovarian function (ie. chemotherapy, radiation)


Introduction to Menopause

Menopause is a significant life event for women and can be associated with somatic, physiological, and psychological changes. Since healthy women spend about one-half to one-third of their lives in the menopausal state, it is important for providers caring for aging female patients to have a good overall understanding of the issues surrounding menopause.

Perimenopause is generally defined as the time between menstrual irregularity and menopause. Women experience either a change in menstrual cycle length or skipped menstrual periods. In addition, many women experience similar symptoms as women who are postmenopausal. It is not until a woman experiences no menstrual period for twelve consecutive months that she is considered postmenopausal.

The hallmark of menopause is the major change in estrogen production and metabolism, which causes characteristic symptoms including vasomotor symptoms such as hot flashes and night sweats and genitourinary changes such as vaginal dryness and dyspareunia or painful intercourse. These symptoms may be disabling for some but not all women. Menopause generally occurs between the age of forty to sixty and the median age of onset is between fifty and fifty-two years of age. Premature menopause can be defined as ovarian failure and menstrual cessation prior to the age of 40. Genetic predisposition, viral infection, and smoking can increase the risk for premature menopause. In some instances, menopause may be surgically induced following surgical removal of both ovaries or as a consequence of chemotherapy or radiation.


Biological Role of Estrogen, Progesterone, and Testosterone in Female Reproduction

Estrogen • Promote development of female secondary

sex characteristics • Regulation of the menstrual cycle • 3 types exist in significant quantity:

• 17β-estradiol • Estrone • Estriol

Progesterone • Regulation of the menstrual cycle, pregnancy,

and embryogenesis

Testosterone • Precursor to estrogen synthesis • Promotes sexual functioning

Estrogen, progesterone, and testosterone are endogenous steroids which are synthesized in the ovaries mainly from cholesterol. Progesterone and testosterone are synthesized first during the follicular phase of the ovarian cycle. Before these initial two hormones can leave the ovaries, almost all the testosterone and much of the progesterone are converted into estrogens by the granulosa cells.

The liver conjugates the estrogens to form glucuronides and sulfates. About one-fifth of these conjugated products are excreted in the bile while the remainder is excreted in the urine. The liver converts the potent estrogens, 17β-estradiol (most abundant) and estrone, into the almost totally impotent estrogen estriol. Thus, diminished liver function actually increases the amount of activity of estrogens in the body.


Biological Role of Estrogen, Progesterone, and Testosterone in Female Reproduction

Within a few minutes after secretion, almost all the progesterone is degraded to other steroids that have no progesteronic effect. Again, the liver is vital for the metabolic degradation of progesterone.

Differences exist in hormone release in women during pregnancy. Estrogens are secreted in major quantities primarily by the ovaries in non-pregnant women, while during pregnancy estrogens are secreted from the placenta. In non-pregnant women, progesterone is secreted in significant amounts only during the latter half of each ovarian cycle by the corpus luteum. During pregnancy, especially after the fourth month of gestation, the placenta secretes large amounts of progesterone.


Endocrine Changes Due to Menopause

• Decreased production of inhibin resulting in increased FSH and LH • Loss of oocytes and ovarian follicles resulting in:

• Altered estrogens • Decreased 17β-estradiol • Increased estrone

• Decreased testosterone • Decreased follicular response


Structural and Physiological Changes Due to Menopause

• Ovaries shrink • Stomal cells predominate • Genitourinary tract changes • Breasts become smaller • Endometrium becomes thinner • Mild hirsutism and other androgenic effects are observed

Along with endocrine changes, somatic and physiological changes are noted in women experiencing menopause. To begin with, the ovaries shrink and have a wrinkled appearance. The endometrium thins and may become atrophic, resulting in cystic hyperplasia in up to 20% of cases. Mild hair growth is observed, as well as other androgenic effects such as a deeper voice, acne, increased weight, and sweating and breasts become smaller in size.


Vasomotor and Genitourinary Symptoms Related to Menopause

Vasomotor Symptoms:

• Experienced by 75 – 85% of menopausal women • Most common 12 – 24 months after the last menstrual period • Symptoms: hot flashes, night sweats • Felt in face, neck, and upper trunk • Lasts from 30 seconds to several minutes • Frequency and severity can vary based on:

• Race/ethnicity • Menstrual status (perimenopausal versus postmenopausal) • Body mass index (BMI) • Physical activity • Smoking status

GU Complaints:

• Fluctuating hormone levels resulting in irregular uterine bleeding and eventual amenorrhea (no menstrual period) • Atrophy of urogenital epithelium • Vulvovaginal atrophy resulting in vaginal dryness, dyspareunia (painful intercourse) and increased UTIs • Loss of uterine support resulting in incontinence


Vasomotor and Genitourinary Symptoms Related to Menopause

Vasomotor symptoms, such as hot flashes, can begin prior to complete cessation of menses during perimenopause. These symptoms can range in severity from mild annoyances to true disruptions in everyday life. Frequency of symptoms can also vary with some women experiencing occasional symptoms while other women may experience multiple hot flashes throughout the day. An increase in pulsatile release of gonadotropin-releasing hormone from the hypothalamus is believed to trigger the hot flashes by affecting the adjacent temperature-regulating area of the brain.

Hot flashes tend to be worse in those women who undergo surgical menopause. Women experience hot flashes of the face, neck, and upper trunk. Hot flashes can manifest as perspiration, palpitations, nausea, dizziness, headache, or night sweats. Each hot flash can last from half a minute to several minutes.

Flushing is more pronounced late in the day, during hot weather, after ingestion of hot foods or drinks, or during periods of tension. When occurring at night, hot flashes can cause insomnia which may result in daytime sedation and difficulty concentrating. More than 75% of women report experiencing hot flashes within 2 years surrounding menopause. Among these women, 25% report these symptoms remain for greater than 5 years and 10% report they remain for more than 10 years.

During and after menopause, women will experience urogenital atrophy due to lack of estrogen stimulation. This results in thinning, drying, and loss of elasticity of the vaginal epithelium which can lead to pruritus and dyspareunia. Loss of uterine support also results in increased urinary urgency and frequency, leading to incontinence. In addition, decreased estrogen can increase vaginal pH enabling pathogens to colonize the vagina and predispose women to urinary tract infections.


Other Changes Related to Menopause

• Osteoporosis • Coronary Artery Disease (CAD) • Fatigue • Mood changes (ie. depression, anxiety, irritability) • Sexual dysfunction • Memory loss and impaired concentration • Insomnia

Loss of estrogen in postmenopausal women can increase the risk of osteoporotic fractures due to an increased bone resorption. Additionally, low estrogen concentrations can lead to lipid alterations such as an increase in LDL and a decrease in HDL which can increase risk of cardiovascular problems such as coronary artery disease. In fact, menopause increases a woman’s risk of atherosclerosis to that of a male in the same age group. Increases in fibrinogen and thromboxane, and decreases in PGI2 and nitric oxide may increase vascular stiffness.

Fatigue and mood changes such as depression, along with the physiological changes to the genitourinary tract can cause sexual dysfunction in postmenopausal women leading to further psychological distress. Other potential psychological symptoms include problems with memory, insomnia, anxiety, and irritability.


Essentials of Diagnosis

• Irregular menstrual cycles followed by 1 year of amenorrhea • Additional findings:

• FSH >30mIU/mL • Hot flashes/flushes and night sweats • Decreased vaginal lubrication • Thinned vaginal mucosa (with or without dyspareunia)

Menstrual irregularity preceding cessation of menses for 12 consecutive months is the hallmark feature for menopause diagnosis. In most cases, patients reports of amenorrhea and symptoms commonly associated with menopause are sufficient for a clinical diagnosis.

In some cases, a serum FSH level may be ordered. A rise in serum FSH concentrations, greater than 30mIU/mL, is indicative of menopause. Although LH concentrations also rise in menopause, it is not routinely measured to aid in diagnosis. A Pap smear and pelvic exam can aid in assessing physiologic changes that occur during menopause.


Trends in Hormone Therapy (HT)

Historically • Observational studies suggest a reduction in cardiovascular disease and mortality in HT users compared to

nonusers • All women should receive long-term HT for management of vasomotor symptoms and prevention of chronic disease

• Estrogen • Estrogen-progestin combinations • Androgens

Currently • Randomized, controlled trials suggest nitiation of HT in women over age 60 or more than 10 years since

menopause associated with increased cardiovascular risk • HT should only be prescribed for short-term (<5 years) management of vasomotor symptoms • HT is recommended at the lowest effective dose



More recently, randomized clinical trials were launched to test the hypothesis of estrogen’s potential for cardiovascular prevention. Results of primary and secondary prevention trials such as the Heart and Estrogen/Progestin Replacement Studies (HERS & HERS II) and the Women’s Health Initiative (WHI) now show that estrogen-based therapy may actually increase cardiovascular and other risks.

Early observational studies have shown a 30% to 50% reduction in CHD and total mortality in postmenopausal women using estrogen. Therefore, all women entering menopause received long-term hormone therapy (HT), previously known as hormone replacement therapy (HRT).

The hormone that was in greatest need of replacing, particularly in the elderly, was estrogen. Women with an intact uterus were also prescribed concomitant progesterone to minimize risk for endometrial cancer. In some cases, women were also supplemented with androgens for menopause-related symptoms such as decreased libido.

Although used primarily for management of vasomotor symptoms, HT was marketed to help women maintain their youth and beauty, as well as prevent chronic diseases such as coronary heart disease (CHD), osteoporosis, and Alzheimer’s disease.



The difference in cardiovascular outcomes between observational studies and randomized clinical trials is likely related to differences in the characteristics of the cohorts. In observational studies, women who used hormone therapy were younger, 30 to 55 years of age, recently postmenopausal, were relatively lean, and were using hormone therapy predominantly for management of vasomotor symptoms. In randomized clinical trials, more than 90% of women were over the age of 55, were more than 10 years beyond menopause, were overweight, and had less complaints of vasomotor symptoms.

The America College of Clinical Endocrinologists (AACE), American College of Obstetricians and Gynecologists (ACOG), and North American Menopause Society (NAMS) now recommend hormone therapy for women early in the menopausal transition at the lowest dose and for the shortest duration possible.


Heart and Estrogen/Progestin Replacement Study and Follow-up (HERS and HERS II)

• Randomized, double-blinded, placebo-controlled trial to determine the effects of estrogen plus progestin compared with placebo in older postmenopausal women with coronary heart disease (CHD)

• 2,763 women, average age of 67 with average of 6.8 years of observation (HERS + HERS II) • Women received 0.625 mg conjugated estrogens and 2.5 mg medroxyprogesterone or placebo • Results:

• Increased rates of venous thromboembolism and biliary tract surgery in older women with CHD on HT • No overall effect of HT on cardiovascular disease (CVD) event rates

The Heart and Estrogen/Progestin Replacement Studies, known as the HERS trials were the first randomized, controlled trials in older postmenopausal women with coronary heart disease (CHD) designed to examine the effect of long-term postmenopausal hormone therapy on both cardiovascular and non-cardiovascular disease outcomes. The HERS trial assessed the efficacy of HT for secondary prevention of CHD. Over the 4.1 years of follow-up for the HERS trial there were no overall differences in CHD endpoints between women randomized to placebo or HT. However, there was a trend toward decreasing risk of CHD with increasing duration of HT use. This was believed to result from the increased early thrombotic effects of estrogen during the first years of the trial. Since these results contradicted data from observational studies, many clinicians concluded that a net benefit for HT would have been observed with longer duration of use.

The HERS II trial was a continuation of the original HERS trial with follow-up for an additional 2.7 years in order to allow for longer duration of HT exposure. Surprisingly, the lower rates of CHD events among women in the hormone group in the final years of the first HERS trial did not persist during additional years of follow-up in HERS II. After 6.8 years, HT did not reduce the risk of cardiovascular events in women with CHD. Furthermore, estrogen plus progestin in older women did not produce favorable trends in overall rates of cardiovascular disease, fracture, or death. The lack of benefit of HT in high-risk women has been confirmed in additional trials.

HERS II also failed to show any benefit in preventing ischemic stroke. Non-cardiovascular end points such as overall risk of venous thromboembolism and biliary tract surgery were also significantly higher in HT patients.


Women’s Health Initiative (WHI)

• Randomized, double-blinded, placebo-controlled trial • Enrolled 161,808 generally healthy postmenopausal women • Consisted of a set of clinical trials and an observational study • Hormone therapy trial separated into 2 arms

• Estrogen plus Progestin and Estrogen alone • Enrolled 27,348 women between the ages of 50 and 79

The WHI was a 15 year project sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and National Institutes of Health (NIH) to address common causes of death, disability, and quality of life in postmenopausal women. Launched in 1991, the trial recruited 161,808 postmenopausal women. Women could be enrolled in any or all of the clinical trials including HT, dietary modification, and calcium/vitamin D. In addition, the WHI included an observational study. The HT trial of the WHI is the largest, randomized, primary prevention trial to assess the safety and efficacy of estrogen plus progestin and estrogen alone in reducing risk of cardiovascular disease (CVD), breast and colorectal cancers, and osteoporotic fractures. The HT trial involved 27,348 participants ranging from 50-79 year of age.


Women’s Health Initiative (WHI) Hormone Therapy Trial: Estrogen + Progestin

• Enrolled 16,608 women between the ages of 50 and 79 (mean age 63.2) • Women with intact uterus received 0.625 mg/d conjugated estrogen and 2.5 mg/d medroxyprogesterone or placebo • Prematurely stopped in July 2002 because the overall risks of the intervention outweighed the benefits

Results including Hazard Ratio (HRs): • Increased risk of CHD

• HRs 1.29 (1.02-1.63) with 286 cases of CHD • Increased risk of breast and endometrial cancers

• HRs 1.26 (1.00-1.59) with 290 cases of breast cancer • HRs 0.83 (0.47-1.47) with 47 cases of endometrial cancer

• Increased risk of PE • HRs 2.13 (1.39-3.25) with 101 cases

• Increased risk of stroke • HRs 1.41 (1.07-1.85) with 212 cases

• Decreased risk of colorectal cancer • HRs 0.63 (0.43-0.92) with 112 cases

• Decreased risk of hip fracture • HRs 0.66 (0.45-0.98) with 106 cases of hip fracture

The absolute excess risks per 10,000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures



From: JAMA. 2002;288(3):321-333 (Figure 3).



JAMA. 2002;288(3):321-333 (Figure 3).



8,506 women with an intact uterus were randomized to 0.625 mg/d of conjugated estrogen and 2.5 mg/d of medroxyprogesterone and 8,102 women received placebo. The primary outcome of the study was CHD, both nonfatal myocardial infarction and CHD death, along with invasive breast cancer as the primary adverse outcome. On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin versus placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits.


Women’s Health Initiative (WHI) Hormone Therapy Trial: Estrogen Alone

• Enrolled 10,739 women between the ages of 50 and 79 (mean age 63.6) • Women who had a hysterectomy received 0.625 mg/d conjugated estrogen or placebo • Prematurely stopped in February 2004 because the overall risks of the intervention outweighed the benefits • Results including Hazard Ratio (HRs):

• Decreased risk of CHD • HRs 0.91 (0.75-1.12) with 376 cases of CHD

• Decreased risk of breast cancer • HRs 0.77 (0.59-1.01) with 218 cases of breast cancer

• Increased risk of PE • HRs 1.34 (0.87-2.06) with 85 cases

• Increased risk of stroke • HRs 1.39 (1.10-1.77) with 276 cases

• Increased risk of colorectal cancer • HRs 1.08 (0.75-1.55) with 119 cases

• Decreased risk of hip fracture • HRs 0.61 (0.41-0.91) with 102 cases of hip fracture

• The absolute excess risks per 10,000 person-years attributable to estrogen alone were 12 more strokes, 7 more PEs, and 1 more colorectal cancer, while the absolute risk reductions per 10,000 person-years were 5 fewer CHD events, 7 fewer invasive breast cancers, and 6 fewer hip fractures



JAMA. 2004;291(14):1701-1712 (Figure 3).



The estrogen alone arm of the HT trials was a parallel clinical trial to the estrogen plus progestin arm but was conducted in women who had a hysterectomy. 5,310 women who had a hysterectomy were randomized to 0.625 mg/d of conjugated estrogen and 5,429 women received placebo. The primary outcome was CHD incidence, both nonfatal myocardial infarction or CHD death. Invasive breast cancer incidence was the primary safety outcome.

JAMA. 2004;291(14):1701-1712 (Figure 3).



When the estrogen + progestin arm was stopped early in 2002, participants in the estrogen alone arm were informed that no increase in breast cancer incidence was observed at that point in women taking estrogen alone. However, on February 2, 2004, after a mean of 6.8 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen alone versus placebo because the increased risk of stroke was similar to the risk reported in the estrogen + progestin arm.

Early termination of both the estrogen plus progestin and estrogen alone arms of the WHI caused a great deal of confusion for patients and providers. The conclusions drawn in the early publications of these trials were inaccurate suggesting cardiovascular harm with HT use at any time and at any age. Exaggerated reports by the media caused further alarm and uncertainty for patients and providers. Furthermore, it is important to keep in mind that although hazard ratios may make risks associated with HT use appear alarming, the absolute risk to women may actually be very small. For example, estrogen plus progestin was associated with a 29% increased risk for CHD, however, the absolute risk was 7 additional CHD events per 10,000 person-years compared to placebo.

Since their publication, reanalyses of the original findings from the HT trial of the WHI were conduced to determine risks and benefits of HT use in various subgroups of postmenopausal patients.


Effects of Hormone Therapy on Myocardial Infarction and Stroke

• Observational studies suggest a decreased risk for heart disease among estrogen users early in menopause (Nurses’ Health Study)

• Randomized controlled trials (RCTs) do not show benefit from HT in older women with preexisting CHD (HERS, WHI) • E+P: CHD HR 1.24 (1.00-1.54)

• 6 additional CHD events per 10,000 person-years • E alone: CHD HR 0.95 (0.79-1.16)

• 3 fewer CHD events per 10,000 person-years

• Reanalyses of WHI suggest lower risk for CHD when HT initiated within 10 years of menopause and increased risk for CHD when HT initiated more than 10 years after menopause

• HT is not recommended for primary or secondary cardiovascular protection



NEJM. 2003;349(6):523-534 (Figure 2).

Arch Intern Med. 2006;166:357-365.



• RCTs suggest increased risk for ischemic stroke with HT • E+P: Stroke HR 1.31 (1.02-1.68)

• 8 additional strokes per 10,000 person-years • E alone: Stroke HR 1.39 (1.10-1.77)

• 12 additional strokes per 10,000 person-years • Risk of stroke is less in women aged 50 to 59 and in those within 5 years of menopause • HT is not recommended for primary or secondary prevention of stroke

JAMA. 2003;289(20):2673-2684.



As mentioned earlier, results of observational studies of HT use in young postmenopausal women suggested cardioprotection. However, these findings had yet to be confirmed in randomized clinical trials. The Heart and Estrogen/Progestin Replacement Study (HERS) was a secondary prevention trial that did not show cardioprotection with HT use. Several years later, findings from the WHI also did not show cardioprotection with HT use, but rather an increased risk for heart disease.

After the initial publication of the results of the estrogen plus progestin and estrogen alone arms of the WHI, further analyses regarding the effects of hormone therapy on CHD were conducted. The Kaplan-Meier curve shown in (NEJM. 2003;349(6):523-534 (Figure 2)) illustrates the cumulative hazard rates of coronary heart disease (including nonfatal myocardial infarction or death due to coronary heart disease) in the two groups. The curve indicates there is an elevated risk of CHD with estrogen plus progestin which appeared to emerge during the first year after randomization. The cumulative rates did not begin to converge until year 6. For women taking estrogen alone, the Kaplan-Meier curves shown in (Arch Intern Med. 2006;166:357-365) suggest a lower CHD risk among women age 50-59 while CHD risk increases between years 4 and 5 in women age 60-69 and in year 4 for women age 70-79 of estrogen use.

A recent reanalysis of the WHI across categories of age and years since menopause explored whether timing of initiation of hormone therapy influences its effect of cardiovascular disease (CVD). The authors reported that neither regimen was associated with increased risk in women initiating hormone therapy within 10 years of menopause and/or in the 50-59 year age group. In contrast, the risk significantly increased in women 60-79 years of age. In short, initiation of HT in early postmenopausal women (less than 5 years) is not likely to increase cardiovascular risk. However, risk increases when starting HT 10 or more years beyond menopause.



In addition to increasing cardiovascular risk, the WHI reported that both estrogen plus progestin and estrogen alone increased the risk of ischemic stroke in generally healthy postmenopausal women. Excess risk for all strokes attributed to estrogen plus progestin and estrogen alone appeared to be present in all subgroups of women examined. The increased risk was significant for ischemic but not hemorrhagic stroke, although there were too few hemorrhagic strokes to draw conclusions about the risk for that subtype. Although still at higher risk for stoke, the risk was less in women aged 50 to 59 and in those within 5 years of menopause.

When considering ischemic stroke, estrogen has been believed to have a neuroprotective effect through perfusion-dependent and independent mechanisms and so may be associated with less severe strokes and better stroke outcome; yet, in the WHI study, there were no differences reported based on the Glasgow Outcome Scale. Unlike CHD, the excess risk of stroke in the estrogen plus progestin group was not present in the first year but appeared during the second year and persisted through the fifth year. Based on accumulated data, no HT regimen should be used for primary or secondary prevention of stroke.


Effects of Hormone Therapy on Cancer Risks

Breast cancer

• Conflicting data from RCTs • E+P: Total breast cancers HR 1.24 (1.02-1.54) and Invasive breast cancers HR 1.24 (1.01-1.54)

• 4-6 additional invasive breast cancers per 10,000 person-years • Increased risk with greater than 5 years of use

• E alone: Total breast cancers HR 0.82 (0.65-1.04) and invasive breast cancers HR 0.80 (0.62-1.04) • 8 fewer cases of invasive breast cancer per 10,000 person-years

• Increased risk for breast cancer may appear after more than 5 years of HT • Avoid HT in women with a history of breast cancer

Ovarian cancer • Increased risk with HT

• E+P: HR 1.58 (0.77-3.24) • 15 fewer ovarian cancers per 10,000 person-years

• E: alone • Increase in risk seen in observational studies

Endometrial cancer • Increased risk with unopposed estrogen • Recommend estrogen + progestin in postmenopausal women with a intact uterus



Colorectal cancer

• Possible decreased risk with HT • E+P: HR 0.56 (0.38-0.81)

• 7 fewer colorectal cancers per 10,000 person-years • E alone: HR 1.08 (0.75-1.55)

• 1 more colorectal cancer per 10,000 person-years

The breast cancer results of the WHI were surprising based on the different effects observed with estrogen plus progestin versus estrogen alone. For women taking estrogen plus progestin, there was a significant 24% increase in incidence of total and invasive breast cancers. HT use less than 5 years did not seem to have a major impact on breast cancer risk. Incident breast cancers diagnosed among combined HT users were similar in histology and grade, but larger and at more advanced stage compared to those diagnosed in the placebo group. In contrast, estrogen alone therapy was associated with a nonsignificant 20% decrease in invasive breast cancer. For incident invasive breast cancer cases, no difference in cancer stage or tumor grade was noted.

Differences in findings between estrogen plus progestin and estrogen alone on breast cancer risk may be related to differences in uterine status and baseline characteristics among the study populations. Despite differences in breast cancer incidence, use of both HT regimens was associated with a substantial increase in the number of abnormal mammograms.



Endometrial cancer incidence is significantly increased with unopposed estrogen use in women with a uterus. Addition of progestin to the regimen decreases this risk in women with an intact uterus. In the combined HT arm of the WHI, a nonsignificant decrease in endometrial cancer was noted. For cases of endometrial cancer that occurred, no difference was seen in tumor histology, stage, or grade.

Conflicting data exists regarding risk for colorectal cancer among users of estrogen plus progestin and estrogen alone. A significant decrease in colorectal cancer incidence was reported early after initiation of estrogen plus progestin whereas a nonsignificant increase was reported among estrogen alone users.


Effects of Hormone Therapy on Venous Thromboembolism (VTE)

• Increased risk for VTE with HT • E+P: HR 2.06 (1.57-2.70)

• 18 additional VTE events per 10,000 person-years • E alone: HR 1.32 (0.99-1.75)

• 8 additional VTE events per 10,000 person-years • Greater risk with increasing age, obesity, factor V Leiden mutations, smoking • Avoid HT in women with active or a history of deep venous thrombosis (DVT) or pulmonary embolism (PE)

Observational and randomized controlled trials have shown that postmenopausal women who use hormone therapy are at increased risk for VTE. The risk emerges 1 to 2 years after initiation of therapy and decreases over time. Although still at risk, hormone therapy users less than 60 years of age are at lower risk for VTE. Women with a prior history of VTE or women who possess factor V Leiden are at increased risk for VTE with HT use.


Effects of Hormone Therapy on Cognition and Dementia

• Strong biological evidence supports the beneficial effects of estrogen on the brain including: • Neurotrophic effects • Reductions in ß-amyloid accumulation • Enhanced neurotransmitter release and action • Protection against oxidative stress damage • Reduction in cortisol levels

• Reduced risk of dementia with long-term estrogen use seen in observational studies

• RCTs do not support beneficial effects of HT on cognition • Women’s Health Initiative Memory Study (WHIMS)

• E+P: HRs 2.05 (1.21-3.48) • 23 more cases of dementia per 10,000 person-years

• E alone: HRs 1.49 (0.83-2.66) • 23 more cases of dementia 45 per 10,000 person-years

• HT for prevention or treatment of dementia is not recommended

For years basic research into estrogens effects on the brain have provided tantalizing evidence of how beneficial estrogen is to the brain of women. In postmenopausal women, the effect of reduced sex hormones, especially estrogen and progesterone, on cognitive decline is of particular interest because of their modulating effects on neurotransmitters, neuroconnectivity, and neuroprotection. In fact, estrogen receptors are widely distributed throughout the brain..


Effects of Hormone Therapy on Cognition and Dementia

Many retrospective and cohort studies have shown an association between either no HT and worsening cognitive function with age, or HT and improved cognitive function with age. However, much like the recent findings of the HERS trials and the WHI on the negative consequences of HT, recent clinical trials of HT for improving cognition have also proved disappointing.

One large study of 120 mildly-to-moderately demented women treated with either conventional doses of CEE 0.625 mg/d or higher doses of 1.25 mg/d CEE versus placebo showed no improvement after one year of treatment. The results of the Women’s Health Initiative Memory Study (WHIMS), which is a substudy of the WHI, now complete the picture of estrogen when used for primary prevention of cognitive decline. Although the number of women with dementia was small, the data presented suggest an increased risk for all types of dementia due to HT. Overall, the WHIMS revealed that hormone therapy increased the risk of dementia. The reported increased risk of probable dementia would lead to an additional 23 cases of dementia per 10,000 women per year for both HT arms. The risk of being diagnosed with mild cognitive impairment, was increased by 37% for women taking estrogen plus progestin and 34% for women taking estrogen alone compared with placebo. Data analysis in both HT arms show that these rates began to separate in the first year.

Some of this increased risk of developing dementia may be related to the increase in vascular dementia secondary to the increase in ischemic strokes seen in the WHI. Regardless of the cause, there is little evidence to suggest that HT can prevent or improve dementia or Alzheimer’s disease.


Effects of Hormone Therapy on Urinary Incontinence

• Oral hormone therapy administration is associated with increased rates of urinary incontinence • 50% increase in mixed urinary incontinence • 80% increase in stress incontinence • 30% increase in urge incontinence • 40% increase in total incontinence

• Inconsistent improvement in urinary incontinence with transdermal or vaginal estrogen administration

• HERS II: • Increased risk of urinary incontinence with estrogen plus progestin therapy

• 3 times more likely to develop urge incontinence • 5 times more likely to have stress incontinence

Once believed to help “tone” the bladder, researchers now feel that estrogen and progestin might actually make matters worse. Oral hormone administration was associated with increased rates or urinary incontinence in most randomized, controlled trials. Inconsistent data exists for postmenopausal women using transdermal or vaginal estrogen preparations on rates of urinary incontinence.

In the HERS II report, incontinence improved in 26% of the women assigned to placebo compared to only 21% of the women assigned to estrogen plus progestin. 39% of the treatment group worsened, whereas only 27% of the placebo group had worsening symptoms.Among women assigned to treatment with hormone therapy, incontinence was more likely to worsen and less likely to improve than among women on placebo. No improvement in the treatment group occurred in the frequency of either stress or urge incontinence, and no reduction in diurnal or nocturnal urinary frequency.


Effects of Hormone Therapy on Osteoporosis

• Estrogen can: • Prevent hip fractures • Prevent vertebral fractures • Prevent other osteoporotic fractures

• RCTs support beneficial effects of HT on increasing bone mineral density (BMD) and reducing fractures • E+P: total fracture HR 0.76; 0.69-0.83.

• Total hip BMD increased 3.7% after 3 years in women taking estrogen plus progestin compared to 0.14% taking placebo

• E Alone • Reduced the rates of fracture by 30-39%

• Hip fracture HR 0.61 (0.41-0.91) • Vertebral fracture HR 0.62 (0.42-0.93) • Total fractures HR 0.70 (0.63-0.79)

• HT should not be used solely for prevention of osteoporosis in postmenopausal women • Safer and more effective agents are available

The results of the WHI did provide some good news in that the results are consistent with the observational data and limited data from clinical trials that estrogen is able to maintain bone mineral density. In fact, estrogen can prevent hip, vertebral and other osteoporotic fractures. While that may not sound surprising, it should be when you consider that the WHI is the first trial with definitive data supporting the ability of postmenopausal hormone to prevent fractures at the hip, vertebrae, and other sites.


Effects of Hormone Therapy on Osteoporosis

Estrogen plus progestin reduced the observed hip and clinical vertebral fracture rates by one third compared with placebo, both nominally significant. The 23% reduction in other osteoporotic fractures and 24% reduction in total fractures were statistically significant. No statistically significant differences were present at baseline in bone mineral density between the treatment and placebo groups of the WHI. Baseline levels of serum calcium, albumin, parathyroid hormone, and 25-hydroxyvitamin D were within the normal range. The results from the estrogen alone arm of the WHI are similar to the findings from the estrogen plus progestin arm.

Although estrogen is FDA approved to prevent postmenopausal osteoporosis, women should not be prescribed HT solely for this reason based on the potential for serious adverse effects associated with its use. Rather, safer and more effective alternatives should be considered.


Effects of Hormone Therapy on Quality of Life

No clinically meaningful effect on health-related quality of life at 3 years

No significant effects on: • General health • Vitality • Mental health • Depressive symptoms • Sexual satisfaction

Statistically significant, but small and not clinically meaningful effect on: • Sleep disturbance • Physical functioning • Bodily pain

All analyses for the WHI Quality of Life study focused on changes in health-related quality of life from baseline to 1 year in relation to study-group assignment. It has been postulated that the positive effects of estrogen plus progestin on health-related quality of life may be masked or delayed during the first year, when some women have bothersome side effects such as bleeding and breast pain. The WHI results showed no evidence that long-term use (over 3 years) of estrogen plus progestin has a more positive effect on health-related quality of life than short-term use.

Sleep disturbance is a common and distressing symptom in postmenopausal women that may be slightly alleviated with the use of estrogen plus progestin.


Effect of Hormone Therapy on Gallbladder Disease

• Observational studies suggest estrogen therapy promotes gallstone formation and cholecystitis • Analysis of data from the WHI support findings that estrogen +/- progestin increases in risk of biliary tract disease

among postmenopausal women using estrogen therapy

Estrogen therapy has been thought to promote gallstone formation and cholecystitis, but most data has been derived from observational studies rather than randomized trials. The study by Cirillo and colleagues, published in the Journal of the American Medical Association in early 2005, looked to determine the effect of estrogen therapy in healthy postmenopausal women on gallbladder disease outcomes through a randomized, placebo-controlled trial. The Women’s Health Initiative (WHI) postmenopausal hormone trial consisted of 2 randomized components, in which women with hysterectomy were randomized to receive estrogen alone or placebo, and those without hysterectomy received either a combination of estrogen and progestin or placebo.

In this part of the WHI, gallbladder and gallstone disease outcomes were directly reported by the participants in the semiannual safety monitoring questionnaire. Related medical records were obtained in the instance that such reports were made. A total of 22,579 women were analyzed, 8,376 of which were in the estrogen only arm and 14,203 in the estrogen PLUS progestin arm.

For the estrogen only arm, the annual incidence rate for any gallbladder event (cholecystitis, cholelithiasis, or cholecystectomy) was 78 per 10,000 person-years versus 47 per 10,000 person-years in the placebo group. The observed annual incidence rate of any gallbladder event was 55 per 10,000 person-years for the estrogen PLUS progestin group versus 35 per 10,000 person-years for the placebo group. Receipt of both estrogen and estrogen PLUS progestin significantly increased the risk for gallbladder procedures, which were predominantly cholecystectomies.

Cirillo and colleagues state, “These WHI findings suggest that oral estrogens are causally associated with gallbladder diseases, and the magnitude of the effect is not influenced greatly by the presence or absence of progestins.”


Estrogen Warnings After the Women’s Health Initiative


Estrogen Warnings After the Women’s Health Initiative

As a result of the recently published findings of the WHI and other trials, the FDA has required new black box warnings be added to estrogen-containing products. The warning includes: (1) Estrogens increase the chances of getting cancer of the uterus; (2) Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes; and, (3) Using estrogens with or without progestins may increase a woman’s chances of getting heart attacks, strokes, breast cancer, and blood clots. A woman and her healthcare provider should talk regularly about whether she still needs treatment with estrogens.


Recommendations for the Use of Hormone Therapy

• Individualize therapy according to the needs, preferences, and risk factors of each patient

• Treatment should be patient specific and appropriate for patient reported menopausal symptoms

• If hormone therapy is used, treatment should be administered using the lowest effective dose for the shortest duration possible

• Maximum recommended duration for hormone therapy is 5 years

• Hormone therapy should not be prescribed for prevention of chronic disease

• Treatment should be monitored at least every 6-12 months to assess need for therapy and side effects

Assessment of symptoms and their impact on quality of life are a key component of the menstrual evaluation. It is important to elicit information regarding the patient’s most bothersome symptoms to determine their desire for treatment and how to appropriately manage these specific symptoms.

The risks and benefits of the available treatment options should be weighed, keeping in mind patient specific factors such as past medical history, family history, social history, and current medication use. In addition, other factors affecting postmenopausal health such as bone density; vaginal, bladder, and sexual function; cardiovascular health; thromboembolic risk; and cancer risk should be included in the assessment. For most women early in their postmenopausal years, which is considered less than 5 years since menopause, HT remains the gold standard for management of vasomotor symptoms according to the American Association of Clinical Endocrinologists and North American Menopause Society. For patients unable or unwilling to take HT, several nonhormonal agents may be considered.


Estrogens

FDA Approved Indications: • Treatment of moderate to severe vasomotor symptoms associated with menopause • Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause • Prevention of postmenopausal osteoporosis

Use: • Gold standard for management of vasomotor symptoms related to menopuse • Administered continuously • Combined with a progestin depending on whether the woman has an intact uterus

Effect: • Effect of estrogen on hot flashes and sleep

Clinical Therapeutics. 1997;19:308 (Figure 2).


Estrogens

Side Effects: • Breast tenderness, bloating, and nausea • Migraine headaches • Cholecystitis • Endometrial cancer • Breast cancer • Stroke • PE • DVT

Oral Estrogen Products

Prepara1ons Brands (®) Dose

Conjugated Equine Estrogen (CEE) Premarin 0.3–1.25 mg/day

SyntheGc Conjugated Estrogens (plant-‐derived) CenesGn, Enjuvia 0.3–1.25 mg/day

Esterified Estrogens Estratab, Menest 0.3–1.25 mg/day

Micronized 17β Estradiol Estrace, Gynodiol 0.5–2.0 mg/day

Estropipate Ogen, Ortho-‐Est 0.75–6 mg/day


Estrogens

Transdermal Estrogen Products


Transdermal 17β Estradiol Alora, Climara, Esclim, Estraderm, Vivelle, Vivelle-‐Dot Menostar

0.025–0.1 mg patch 2x/wk 14 mcg patch every week

Estradiol Gel EstroGel, Elestrin Apply 1.25 g/day

Estradiol Transdermal Spray Evamist 1-‐3 sprays/day

Vaginal Estrogen Products


Conjugated Equine Estrogen Premarin 0.5-‐2 g intravaginally daily (3 wks on and 1 wk off)

Micronized 17β Estradiol Estrace

2-‐4gm intravaginally daily for 2 wks, then ½ dose daily for 2 wks, then 1gm dose 1-‐3x/wk

Estradiol Vaginal Ring Estring Femring

1 ring every 3 months (0.0075 mg) 1 ring every 3 months (0.5-‐1 mg)

Estradiol Vaginal Tablet Vagifem 1 vaginal tablet (25 mcg) 2x/wk


Estrogens

Recommendations:

• Lower doses of systemic estrogen is preferred for management of vasomotor symptoms • 0.3 mg conjugated equine estrogen daily • 0.25-0.5 mg oral micronized 17β estradiol daily • 0.025 mg transdermal 17β estradiol

• Local estrogen therapy is preferred for patients who only complain of vaginal symptoms

Estrogen therapy is FDA approved to manage symptoms related to menopause. Estrogen is 80-90% effective in managing moderate to severe vasomotor symptoms. In addition, estrogen is effective in treating moderate to severe vulvar and vaginal atrophy associated with menopause. However, when used solely for treatment of vaginal symptoms, vaginal creams, gels, rings or tablets are preferred. In women with a uterus, estrogen therapy should be given in combination with a progestin to minimize risk for endometrial cancer. Although estrogen is also approved for prevention of postmenopausal osteoporosis, it should not be used solely for this reason.

Side effects of estrogen therapy include those associated with menstrual cycles such as breast tenderness, bloating, and some nausea. The use of estrogen has also been associated with an increase in cholecystitis. For those women who are prone to migraine headaches, estrogen may increase their frequency. Endometrial cancer has a well-recognized association with hormone therapy. In women receiving both estrogen and progestin the risk of breast cancer was increased but not until 5 years in the WHI trial suggesting that longer duration of use increases the risk.


Estrogens

Estrogens come in many preparations, such as oral, transdermal, intravaginal,and intramuscular forms as well as estrogen-based vaginal rings, creams, and intramuscular shots. Regardless of the estrogen product used, the American College of Obstetrics and Gynecology (ACOG) and the North American Menopause Society (NAMS) recommend use of estrogen products only for the management of vasomotor symptoms related to menopause. Dosage requirements, as always, will depend on the individual and it is best to start with the lowest dose and titrate at a minimum of at least 4 to 8 weeks. Lower estrogen doses have demonstrated nearly equivalent vasomotor symptom relief. Risks and benefits to each individual patient should also be taken into account. Based on available data regarding emergence of cardiovascular and breast cancer risks, HT should not be used beyond 5 years. In addition, it is recommended that women be monitored every 6 to 12 months to assess continued need for HT.

Estrogens are metabolized to inactive compounds in the liver (sulfates and glucuronides) and excreted in the urine and bile. Some reabsorption takes place from the intestine with return to the liver via the portal venous system. Esterified estrogens are rapidly metabolized in the liver and gastrointestinal tract and then excreted in the urine and bile. Estradiol is rapidly metabolized in the liver to the less active estriol and estrone. Oral estradiol undergoes extensive first-pass metabolism. Estradiol is excreted in the urine as the sulfate and glucuronide esters along with a small amount of unchanged drug.

Estriol undergoes rapid glucuronide conjugation after oral doses, with only 1 to 2% appearing in the circulation as unchanged compound. There is no conversion of estriol to estradiol in vivo. Estrone is rapidly metabolized in the liver and undergoes extensive first- pass metabolism to less active products such as estriol. Estropipate is rapidly metabolized and undergoes extensive first-pass metabolism; as a derivative of estrone, the drug is first metabolized to the less potent estrogen, estriol. Topical and transdermal estrogen preparations have the advantage of bypassing first-pass metabolism so lower doses are needed compared to oral estrogens. In addition, they do not increase triglycerides.

In the absence of head-to-head randomized controlled trials, data regarding differences between types and formulations of estrogen are assumed to be the same. There is some evidence that transdermal 17β estradiol may be associated with lower risk of deep venous thrombosis than oral estrogen, however, more research in this area will need to be conducted.


Progestins

Use:

• Decrease risk of endometrial cancer and hyperplasia • Decrease risk of estrogen-induced irregular bleeding • May help in the prevention of osteoporosis • Administered cyclically or continuously

Side Effects:

• Menstrual symptoms • Limited bleeding • Weight gain • Headache • Drowsiness • Altered cholesterol levels

• Decreased HDL • Increased LDL

Prepara1on Brand(s) ® Dose

Medroxyprogesterone acetate Provera 5–10 mg/day for 5-‐10 days

Micronized progesterone Prometrium 200 mg/day on days 1-‐12

Norethindrone acetate AygesGn 2.5–10 mg on days 1–12

Megestrol acetate Megace 20 mg twice daily

Preparations:


Progestins

The primary menopause-related indication for progestin use is endometrial protection from unopposed estrogen in women with an intact uterus. Progestin is generally not indicated when low-dose estrogen is administered locally for vaginal atrophy. In addition, progestin can also decrease the risk of estrogen-induced irregular bleeding. However, it is controversial whether progestin reduces or enhances estrogen’s effect on breast cancer or if it can prevent osteoporosis.

Although progestin may be given cyclically or continuously, intermittent dosing may be preferred to minimize overall hormone exposure. The dose and duration of use affect its ability to prevent endometrial hyperplasia. Bleeding may occur, but will be limited if therapy is continued on a daily basis.

As with estrogen, the side effects of progestin include symptoms associated with the menstrual cycle such as: breast tenderness, bloating, edema, anxiety, and depression. Progestins produce a dose-related increase in blood pressure by causing sodium and water retention. Weight gain, headaches, and drowsiness are also common side effects. Progestin appears to have an impact on lipid parameters, decreasing HDL levels and increasing LDL levels, opposite of its estrogen counterparts.

Medroxyprogesterone acetate is the most commonly used progestin preparation in the United States. Micronized or natural progesterone does not offer a clear-cut advantage, but appears less likely to cause mood changes. If given cyclically, a minimum dosage of five milligrams daily is required, with a minimum duration of ten days per month.


Combination Estrogen-Progestin Products

Oral Combined Hormone Therapy Products


Conjugated estrogens / medroxyprogesterone acetate tablets

Prempro

0.3–0.625 mg / 1.5–5 mg tablets (conjugated estrogens / medroxyprogesterone tablets, respecGvely) 1 tablet daily

Conjugated estrogens and conjugated estrogens / medroxyprogesterone acetate tablets

Premphase

#14 conjugated estrogens 0.625 mg tablets & #14 conjugated estrogens 0.625 mg / MPA 5 mg tablets 1 tablet daily

NorgesGmate and estradiol Ortho Prefest

#15 estradiol 1 mg tablets & #15 estradiol 1 mg / norgesGmate 0.09 mg tablets 1 tablet daily

Estradiol and norethindrone acetate AcGvella

0.5/1 mg tablets & 1/0.5 mg tablets (estradiol / norethindrone, respecGvely) 1 tablet daily



Oral Combined Hormone Therapy Products


Ethinyl estradiol and norethindrone acetate FemHrt

2.5 μg/0.5 mg tablets & 5 μg/1 mg tablets (ethyinyl estradiol/ norethindrone, respecGvely) 1 tablet daily

Estradiol and drospirenone Angeliq

1/0.5 mg tablets (estradiol/ drosperinone, respecGvely) 1 tablet daily

Transdermal Combined Hormone Therapy Products


Estradiol and norethindrone acetate transdermal system CombiPatch

0.05/0.14 mg & 0.05/0.25 mg (estradiol / norethindrone acetate, respecGvely) 1 patch 2x/wk

Estradiol / levonorgestrel transdermal system

Climara Pro Patch

0.045/0.015 mg (estradiol / levonorgestrel, respecGvely) 1 patch weekly



The recommended treatment for vasomotor instability includes administration of oral or transdermal estrogen preparations.

Progestin, which can be administered cyclically or continuously, and estrogen are given together for patients with an intact uterus to protect against endometrial cancer. Recommended dosages are listed.


Androgens

Benefits: • May bone mineral density (BMD) • Increased libido • Increased psychological functioning

Risks: • Virilization / hirsutism • Hepatotoxicity • Decreased HDL cholesterol

Oral Estrogen/Testosterone Prepara1ons:

Prepara1ons Brand(s) ® Dose

Oral Esterified estrogens/ oral methyltestosterone Estratest

1.25 mg/2.5 mg tablets 1 tablet daily (3 wks on and 1 wk off)

Oral Esterified estrogens/ oral methyltestosterone Estratest H.S.

0.625 mg/1.25 mg tablets 1-‐2 tablets at bedGme

Transdermal Testosterone Prepara1ons:


Transdermal testosterone

Androderm, Testoderm, Testoderm TTS

2.5 mg–6 mg/patch Apply 1 patch daily

Topical testosterone packets AndroGel, TesGm

25 mg/2.5 Gm/pkt & 50 mg/ Gm/pkt Apply once daily


Androgens

Injectable Testosterone Prepara1ons:


IM estradiol cypionate / testosterone cypionate

Depotestadiol, Depotestogen, DuoCyp

2 mg/mL / 50 mg/mL vials (estradiol cypionate / testosterone cypionate, respecGvely) Inject monthly

Benefits and risks of androgens have both been demonstrated and various preparaGons have been idenGfied. Benefits of androgens include increased bone mineral density, increased libido, and improved psychological funcGoning for symptoms such as anxiety and depression. Risks of taking androgens as hormone therapy include virilizaGon, or hirsuGsm, which are infrequent and reversible. Hepatotoxicity has been found with high doses of androgens.

Androgens may also decrease high-‐density lipoprotein (HDL) cholesterol. Topical and transdermal testosterone preparaGons are used daily.


Contraindications and Precautions for Hormone Therapy

Contraindications:

• Unexplained vaginal bleeding • Active liver disease or chronic impaired liver function • Active or history of deep vein thrombosis or pulmonary embolism • Active or recent (within the past year) arterial thromboembolic disease (ie. stroke, MI) • Known, suspected, history of breast cancer • Known or suspected estrogen-dependent neoplasm • Endometrial carcinoma • Untreated hypertension

Monitoring (at least annually):

• Blood pressure • Breast exam and mammogram • Bone densitometry • Endometrial hyperplasia • Vision changes • New or worsening migranes • Thromboembolic disorders • Lipid profiles


Contraindications and Precautions for Hormone Therapy

Hormone therapy is contraindicated in a number of diseases and conditions including unexplained vaginal bleeding, liver disease, and vascular thrombosis. Patients undergoing hormone therapy should be evaluated semiannually for blood pressure elevation, breast masses and the development of endometrial hyperplasia. Endometrial biopsy may be needed prior to estrogen therapy and yearly for women on estrogen alone.

As stated earlier, the effects of estrogen plus progestin therapy on breast cancer growth and its ability to hinder diagnosis contraindicates use of HT in women with a history of breast cancer.

Risk of venous thromboembolism among current HT users is reportedly increased. The highest report of DVT occurred during the first year of therapy.

In light of all of the new findings on estrogen and progestins women need to carefully examine the risk to benefit of using HT, even for short term management of postmenopausal symptoms.


Hormone Therapy for Urogenital Atrophy

• Effective for symptoms of vaginal dryness, dyspareunia, incontience

• Topical estrogen creams and gels • Use daily for 1 – 2 weeks, followed by ½ dose daily for 2 more weeks, then maintenance doses 1 – 3 times / week

• Intravaginal estrogen rings • Inserted once every 3 months

• Intravaginal estrogen tablets • Inserted daily for 2 weeks, then twice weekly

For patients with complaints of only vaginal symptoms, treatment should be restricted to localized products. Local estrogen therapy is effective for patients with complaints of vaginal dryness, dyspareunia, and urinary frequency or urgency. Systemic products should be reserved for patients with vasomotor symptoms.


Non-Hormonal Treatment of Menopausal Symptoms

Hot Flashes:

• Nonpharmacologic Management: • Avoid caffeine, alcohol, spicy foods • Adjust room temperature, dress in layers • Maintain a normal weight • Smoking cessation • Regular exercise

• Non-hormonal Pharmacologic Management (limited data) • SSRIs

• Fluoxetine 10-30mg orally daily • 50% symptom reduction compared to 26% for placebo

• Paroxetine 10-37.5mg orally daily • 62-65% symptom reduction compared to 38% for placebo

• SNRIs • Venlafaxine 37.5-75mg orally daily

• 61% symptom reduction compared to 27% for placebo



• Other • Clonidine 0.1-1.5mg orally daily

•  38-78% symptom reduction compared to 24-50% for placebo • Transdermal clonidine (equivalent to 0.1mg daily) weekly patch

• 20-80% symptom reduction compared to 36% for placebo • Gabapentin 900-2,700mg daily in divided doses

• 45% symptom reduction compared to 29% for placebo

GU Atrophy:

• Lubricants, moisturizers, oils • Urinary analgesics

For most symptomatic menopausal women, HT remains the most effective treatment when administered at the lowest effective dose for the shortest duration possible. However, various nonhormonal options are available for treating menopausal symptoms and bone loss in women who are unable or unwilling to take HT. For hot flashes, patients should avoid caffeine, alcohol, and spicy foods. Adjusting room temperature and dressing in layers may help as well.

Although not medically proven, vitamin E and other herbal remedies may help in easing the hot flush symptoms. Case studies have also shown benefit for certain antidepressants like SSRIs and SNRIs since development of vasomotor symptoms seems to be related to the withdrawal of gonadotropins and the instability of serotonin and norepinephrine in the hypothalamus. Most of the studies involving SSRIs for relief of vasomotor symptoms have included paroxetine since it has the highest affinity for the norepinephrine receptor among the SSRIs.



Fluoxetine has also been shown to be effective in reducing frequency and severity of symptoms. Effectiveness of other available SSRIs have also been explored and used in practice for management of vasomotor symptoms. Of the available serotonin-norepinephrine reuptake inhibitors (SNRIs), venlafaxine has been most widely studied for reducing frequency and severity of vasomotor complaints.

In fact, in 2004, the NAMS recognized venlafaxine at doses of 37.5-75mg as a nonhormonal treatment option for vasomotor symptoms. Duloxetine and desvenlafaxine are two other SNRIs that are also being explored for this indication. For both SSRIs and SNRIs, some relief of symtpoms should be observed within 1 to 2 weeks. Other agents like gabapentin, and clonidne have also been studied for menopausal symptom management. Gabapentin may be initiated at a dose of 300mg daily and titrated to effect. In women over 65 years of age, lower doses are recommended. Clonidine should not be recommended for normotensive patients.

For atrophy of the genitourinary tract, coital lubricants and urinary analgesics are recommended. Although non-hormonal drug therapies are available for the treatment of menopause symptoms, they are not generally very helpful.


Nutraceutical Options

• Black cohosh (Cimicifuga racemosa) • Remifenen®

• Red clover isoflavones • Promensil® - 82 mg of isoflavones • Romostil® - 57 mg of isoflavones

• No clinically important effects on hot flashes or other symptoms of menopause

Most studies have failed to show significant, if any, difference between isoflavones such as red clover or the herb black cohosh. One study from by Van de Weijer et al. in 2002 of 80 mg of isoflavones versus placebo for 12 weeks found hot flashes significantly decreased in the treatment group relative to placebo; however, after a 16.7% decrease in hot flashes during a single blind screening phase, there was no further reduction in the placebo group.

Phytoestrogens are substances found in many plants, such as soy plants, that have similar effects to estrogen. The evidence that phytoestrogens are helpful for menopausal women comes mostly from observational studies and epidemiologic studies of cultures whose diet is rich in phytoestrogens. The long-term adverse effects of phytoestrogen consumption are not known.


Soy and Soy Extracts for Hot Flashes

Compilation of related studies:



Endocrinology & Metabolism Clinics of North America. 2004;33:717 (Table 1).



The tables shown here are of randomized controlled trials of soy products versus placebo for vasomotor symptoms. The results from these alternative medicine therapies have consistently found a placebo effect, ranging from approximately 1% to as high as 77%. These findings bring into question studies of complementary and alternative medicine therapies showing treatment effects similar to the reduction seen with placebo, if the study was conducted in the absence of placebo or inactive control. Of note, some of the studies identified a significant effect of soy at 4 weeks, but not at 12 weeks or beyond, indicating that the effect of soy products on vasomotor symptoms is not sustained. Of note, it is important to keep in mind that soy is a weak estrogen and should not be recommended to patients with a history of breast cancer.


Options and Alternatives to Hormone Therapy for Menopause-Related Conditions

Cardiovascular diseases • Aspirin • Lipid-lowering agents • Antihypertensive agents

Vaginal symptoms • Nonhormonal lubricants, moisturizers, oils

Vasomotor symptoms • SSRIs • SNRIs • Clonidine • Gabapentin • Black cohosh • Soy isoflavones

Osteoporosis • Calcium and vitamin D • Bisphosphonates • Calcitonin salmon • Teriparatide • SERMs

• Does not increase risk of breast cancer

This list represents other options to consider instead of estrogen +/- progestin for the management of postmenopausal women.

Close to 40% of postmenopausal women in the United States took hormone therapy prior to the release of the recent landmark trials. The purpose of healthy women taking long-term estrogen/progestin therapy is to preserve health and prevent disease.

The results of these landmark studies provide strong evidence that the opposite is happening for important aspects of women’s health, even if the absolute risks are low.

Certain benefits such as prevention of osteoporosis and treatment of vasomotor symptoms are known and may be benefit from short-term HT. Postmenopausal women who have not had a hysterectomy should not receive estrogen only, as there is an unquestioned increased risk of endometrial cancer, and an increased risk of breast cancer and ovarian cancer as well.


Hormone Therapy: Risk Increase or Decrease?


Conclusion

• Short-term therapy should still be considered for menopausal symptomatic treatment, although careful consideration of the risks and benefits should be observed

• Hormone therapy should not be offered for prevention of chronic disease

• Hormone therapy should not be recommended to women with a high risk of cardiovascular disease

• Long-term treatment is associated with an increased incidence of breast cancer

• All women should be counseled about the risks, benefits, and uncertainties of hormone therapy before deciding to start or stop treatment


Conclusion

The American Association of Clinical Endocrinoogists, American College of Obstetricians and Gynecologists, and the North American Menopause Society recommend against the use of HT for the primary or secondary prevention of chronic disease, especially cardiovascular disease. These organizations recommend caution in using HT solely to prevent osteoporosis and suggest considering alternate therapies. HT can be considered an acceptable treatment option for menopausal symptoms, but advise caution about the prolonged use of HT for the relief of symptoms. The American Heart Association now recommends against the use of HT for primary or secondary prevention of cardiovascular disease.

For older patients who are many years removed from menopause and are still taking HT, consideration should be given to stopping therapy as it is clear that with longer duration of therapy comes increased risk of breast cancer. Although we have more information available regarding the risks and benefits of HT use in postmenopausal women, there are still several unanswered questions. More RCTs will need to be conducted to determine the risks and benefits of HT with regards to dose, formulation, patient population, and appropriate duration of HT among others.


. Resources


Abraham D & Carpenter PC. “Issues concerning androgen replacement therapy in postmenopausal women.” Mayo Clinic Proceedings. 1997; 72:1051-1055.

American Association of Clinical Endocrinologists. “American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Menopause.” Endocr Pract. 2006;12(3):317-337.

American College of Obstetricians and Gynecologists. “Hormone Therapy: Stroke.” Obstet Gynecol. 2004;104(4 suppl):97S-105S.

American College of Physicians. “Guidelines for counseling postmenopausal women about preventive hormone therapy.” Ann Intern Med. 1993;117:1038-1041.

Anderson GL, et al. “Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures.” JAMA. 2003;290(13):1739-1748.

Ascott-Evans BH, et al. “Alendronate Prevents Loss of Bone Density Associated With Discontinuation of Hormone Replacement Therapy.” Arch Intern Med.2003;163:789-794.

Boehringer SK. “Estrogen Patches.” Pharmacist’s Letter. Jan 2004;20:Detail Document #200108.

Cardozo LD & Kelleher CJ. “Sex hormones, the menopause, and urinary problems.” Gynecol Endocrinol. 1995;9(1):75-84.


Resources

Cauley JA, et al. “Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density.” JAMA. 2003;290:1729-1738.

Chlebowski RT, et al. “Estrogen Plus Progestin and Colorectal Cancer in Postmenopausal Women.” NEJM. 2004;350(10):991-1004.

Chlebowski RT, et al. “Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289(24):3243-3253.

Cirillo DJ, et al. “Effect of Estrogen Therapy on Gallbladder Disease.” JAMA. 2005;293(3):330-339.

Curb JD, et al. “Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus.” Arch Intern Med. 2006;166:772-780.

Cushman M, et al. “Estrogen Plus Progestin and Risk of Venous Thrombosis.” JAMA. 2004;292:1573-1580.

Davis SB & Burger HG. “Androgens and the postmenopausal woman.” Journal of Clinical Endocrinology and Metabolism. 1996;82:2759-2763.

Espeland MA, et al. “Conjugated Equine Estrogens and Global Cognitive Function in Postmenopausal Women.” JAMA. 2004;291(24):2959-2968.

Freeman R & Lewis RM. “The therapeutic role of estrogensin postmenopausal women.” Endocrinology and Metabolism Clinics of North America. 2004;33:771-789.


Resources

Hays J, et al. “Effects of Estrogen plus Progestin on Health-Related Quality of Life.” NEJM.2003;348:1839-1854.

Hazzard WR., et al. Principles of geriatric medicine and gerontology. New York: McGraw-Hill. The Menopause and Hormone Replacement Therapy, pp. 867-876.

Hodis HN & Mack, WJ. “Postmenopausal Hormone Therapy and Cardiovascular Disease in Perspective. Clin Obstet Gynecol. 2008;51(3):564-580.

Hoeger KM, et al. “The Use of Androgens in Menopause.” Clin Obstet Gynecol. 1999;42(4):883.

Hsia J, et al. “Conjugated Equine Estrogens and Coronary Heart Disease.” Arch Intern Med. 2006;166:357-365.

Hulley S, et al. “Non-cardiovascular disease outcomes during 6.8 years of hormone therapy.” JAMA. 2002;288:58-66.

Hulley S, et al. “Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women: Heart and Estrogen/Progestin Replacement Study (HERS) Research Group.” JAMA. 1998;280:605-613.

Humphries KH and Gill S. “Risks and benefits of hormone replacement therapy: The evidence speaks.” CMAJ.2003;168(8):1001-1010.

Jenkins MR, Sikon AL. “Update on nonhormonal approaches to menopausal management.” Cleve Clin J Med. 2008;75(4):S17-S24.


Resources

Kessel B & Kronenberg F. “The role of complementary and alternative medicine in management of menopausal symptoms.” Endocrinology and Metabolism Clinics of North America. 2004;33:717-739.

Lund KJ. “Menopause and the Menopausal Transition.” Med Clin N Am. 2008;92:1253-1271.

Manson JE, et al. “Estrogen plus Progestin and the Risk of Coronary Heart Disease.” NEJM. 2003;349(6):523-534.

Martino S, Cauley JA, Barrett-Connor E, et al. “Continuing outcomes relevant to Evista (CORE): Breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene.” Journal of the National Cancer Institute. 2004;96:1751-1761.

Nelson HD, et al. “Postmenopausal Hormone Replacement Therapy.” JAMA. 2002;288:872-881.

Palacioz K. “Hormone Replacement Therapy and Urinary Incontinence.” Obstet Gynecol. 2001;97:116. Premarin & Prempro package inserts.

Rapp SR, et al. “Effect of Estrogen Plus Progestin on Global Cognitive Function in Postmenopausal Women.” JAMA. 2003;289(20):2663-2672.

Rossouw JE, et al. “Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause.” JAMA. 2007;297:1465-1477.

Rymer J, et al. “Making decisions about hormone replacement therapy.” BMJ. 2003;326:322-326.


Resources

Scharf MB, et al. “Effects of estrogen replacement therapy on rates of cyclic alternating patterns and hot-flush events during sleep in postmenopausal women: a pilot study.” Clinical Therapeutics. 1997;19:308.

Shamliyan TA, et al. “Systematic Review: Randomized, Controlled Trials of Nonsurgical Treatments for Urinary Incontinence in Women.” Ann Intern Med. 2008;148:459-473.

Shumaker SA, et al. “Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women.” JAMA. 2004;291(24):2947-2958.

Shumaker SA, et al. “Estrogen PLUS Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women.” JAMA. 2003;289(20):2651-2662.

Stefanick ML. “Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy.” JAMA. 2006;295(14):1647-1657.

The North American Menopause Society. “Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society.” Menopause. 2008;15(4):584-603.

The North American Menopause Society. “Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society.” Menopause. 2004;11(1):11-33.


Resources

The Women’s Health Initiative Steering Committee. “Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy.” JAMA. 2004;291(14):1701-1712.

Tice JA, et al. “Phytoestrogen Supplements for the Treatment of Hot Flashes: The Isoflavone Clover Extract (ICE) Study.” JAMA. 2003;290(2):207-214.

Wassertheil-Smoller S, et al. “Effect of Estrogen Plus Progestin on Stroke in Postmenopausal Women.” JAMA. 2003;289:2673-2684.

Writing Group for the Women’s Health Initiative Investigators. “Risks and Benefits of Estrogen Plus Progesterone in Health Postmenopausal Women.” JAMA. 2002;288(3):321-333.

Web Resources:

Micromedex: www.micromedex.com

Nelson H, et al. “Postmenopausal Hormone Replacement Therapy for the Primary Prevention of Chronic Conditions: a summary of the evidence for the U.S. Preventive Services Task Force.” www.preventiveservices.ahrq.gov

North America Menopause Society: www.menopause.org

Women’s Health Initiative website: www.whi.org


Impotence



• Educate an elderly individual on the common clinical manifestations and risk factors for impotence.

• Recognize medications and health-conditions which may be associated with impotence.

• Construct a treatment plan for an elderly individual wishing to use non-pharmacologic/pharmacologic therapies for impotence.


Definition of Impotence and Overall Incidence

• Involves erectile dysfunction (ED), loss of libido, failure of ejaculation • Most common disorder of elderly men • 67% present symptoms by age 70 years • Incidence rapidly increases after age 50 years

The term impotence is often used synonymously with erectile dysfunction. It is important to distinguish between the two in order to understand how the disorder can be effectively treated. The term erectile dysfunction is used to describe the inability to attain or sustain an erection for satisfactory sexual performance. Impotence, on the other hand, is a broader term that includes sexual dysfunction secondary to factors other than the physical inability to achieve an erection, i.e. depression, loss of libido, & ejaculatory problems.


Etiology of Impotence

Psychogenic causes (10-30%)

Vascular disease (70%) • Arterial and venous atherosclerosis • Hypertension

Diabetes mellitus • Endocrinopathy • Neuropathy

Neurological diseases • Multiple sclerosis (MS) • Pelvic surgery • Cerebrovascular accident (CVA) • Parkinson's disease

Alcoholism Obesity1 Hypogonadism (rare) Peyronie’s disease

The incidence of impotence varies depending on its etiology. It is estimated that 322 million men will be diagnosed with ED by the year 2025. Ten to thirty percent of cases are psychogenic in nature and can be treated with proper counseling and guidance. Of the organic causes of impotence, seventy percent are associated with complications of arterial and venous atherosclerosis.

It is also very common to have a combination of psychogenic and organic complications causing erectile dysfunction.

Other causes include hypertension and smoking as both lead to vascular damage. Patients with diabetes have multiple risk factors for impotence, including endocrinopathy and neuropathy. In these patients, the prevalence of impotence rises dramatically with age. Neurological diseases, such as multiple sclerosis, pelvic surgery, CVA, and Parkinson’s disease can induce impotence by interrupting autonomic fibers of the nerve endings.

Peyronie's disease, a condition of uncertain cause, is characterized by a plaque, or hard lump, that forms on the penis. The plaque develops on the upper or lower side of the penis in layers containing erectile tissue. It begins as a localized inflammation and can develop into a hardened scar.


Latrogenic Impotence

Iatrogenic Impotence: occurs in ~ 25% of cases

Classes of medications involved often mirror treatment for conditions known to cause impotence. These include:

From: Baldo O. Diagnosis and investigation of men with erectile dysfunction. J Men's Health Gend - March 2005; 2(1); 79-86


Latrogenic Impotence

Medications are known to interfere with the sexual response by either decreasing libido or the capability to attain an erection. Since the elderly may be taking a number of these agents for various medical conditions, drug-induced impotence can be a very real problem. A drug regimen review should always be performed in patients complaining of impotence.

Iatrogenic impotence occurs in twenty-five percent of cases. It is often the medications used to treat the conditions originally causing impotence that lead to worsening of a patient’s impotence. Medications commonly implicated include antihypertensives, antidepressants, diuretics and anti-psychotics.

While the list of potential impotence causing drugs is a long one, there are alternative regimens recognized as having fewer effects on male sexual function that may be substituted when appropriate. For example, 1st generation antihistamines can be replaced with the 2nd generation agents such as Loratadine. It should be noted that any diuretic that decreases intravascular volume may decrease penile arteriolar flow. Patients taking antihypertensives listed in the table at the end of this text may benefit from changing to ACEIs, alpha1 adrenergic antagonists (Terazosin, Doxazosin), CCBs and ARBs when appropriate.


Physiology of the Sexual Response

From: Lue T. Erectile Dysfunction: N Engl J Med 2000 Jun;(324):24



• Sexual sensory input is processed by hypothalamus

• Signals routed through sympathetic nervous system (SNS) and parasympathetic nervous system (PSNS) to prostate and urethra

• As sexual response heightens, sympathetic activity to penis decreases and parasympathetic activity increases

• Nitrous oxide increases cyclic guanidine monophosphate and depletes intracellular Ca, causing penile muscles to relax

• Penile arterial resistance decreases and inflow to penis increases six-fold.

• Decreased venous outflow produces pressure and erection.



To understand the iatrogenic basis for impotence, it is helpful to review the physiological basis of the sexual response. Recall that an erection results from various neurogenic, vascular, and hormonal inputs.

Sensory stimuli such as sight, sound and smell, are processed by the hypothalamus which routes the input to the sympathetic nervous system and parasympathetic nervous system alike.

Sensory inputs travel via the hypogastric, pelvic & cavernous nerves, and terminate at the prostate and urethra. As a result of these inputs, sympathetic neural activity to the penis decreases, parasympathetic neural activity increases, and nitric oxide is synthesized and released.

Nitric oxide increases cyclic guanidine monophosphate and depletes intracellular calcium, causing smooth muscles to relax. As this occurs, penile arterial resistance decreases and arterial inflow to the penis increases six-fold.

The expansion of the cavernous decreases venous outflow, causes pressure in the penis, and results in an erection.


Physiology of the Sexual Response: 4 Phases

• Arousal

• Plateau

• Orgasmic

• Resolution/refractory

The 4 phases of the sexual response are mediated by an intricate combination of the central, sympathetic and parasympathetic nervous systems. The 3 systems combined are responsible for the genital vasodilation initiated during the arousal phase of the sexual response.

The plateau phase involves lubrication via the parasympathetic nervous system, while the orgasmic phase involves emissions via the sympathetic and parasympathetic nervous systems. Ejaculation is mediated entirely by the sympathetic system.

During the resolution phase, decreases in arterial flow, intracavernosal pressure, and resistance to venous drainage produce flaccidity.


Diagnosing Impotence

Diagnostic testing:

• Blood pressure • Prostate DRE • Nocturnal penile tumescence • Duplex Doppler ultrasound • Somatosensory evoked potentials • Caversonometry and caversonography • Arteriography

The nocturnal penile tumescence (NPT) stamp test is a test that confirms the inability to achieve and maintain an erection.

From: http://www.nlm.nih.gov/medlineplus/ency/imagepages/8894.htm



Lab Studies:

Glucose Testosterone PSA Lipids FSH, LH & prolactin

Psychological assessment

There are several tests available which aid in the diagnosis of impotence in the elderly male. Lab studies should include evaluation of glucose levels for diabetes, testosterone levels for hypogonadism, prostate-specific antigen for prostate cancer, and lipids for vascular disease, especially arthrosclerosis of the penile vasculature. Levels of folicle stimulating hormone, luteinizing hormone and prolactin should also be assessed to rule out pituitary disease.

If the aforementioned tests don’t identify the underlying cause of erectile dysfunction, there are other specialized diagnostic tests are available to specifically target impotence. For example, nocturnal penile tumescence refers to erections that occur at night. The ability to have an erection while sleeping indicates that a man is physically capable of this function. If a man cannot have an erection while awake, the cause may be due to physical problems, psychological factors, or both.

For most men, erections while sleeping are the result of physical processes in the body rather than conscious control. The test is based on the fact that normal men have three to five involuntary night erections. Each erection lasts 20 to 30 minutes and men are often awakened by them. If a man has normal night time erections, it usually means there is no problem with the nerves, blood vessels or hormones.



Doppler ultrasound cavernosography is non invasive and can detect cavernosal abnormalities such as fibrosis and calcifications. During the physical exam, blood pressure and the degree of masculinization should be assessed along with an evaluation of the prostate for vascular and neurological disease.

A detailed medical history should be obtained, noting risk factors such as elevated cholesterol, history of tobacco use, diabetes mellitus, hypertension, and pelvic and spinal trauma. A sexual history should also be documented to determine how long the man has been impotent.


Nonpharmacological Treatment of Impotence: External Vacuum Devices

Advantages:

• Noninvasive • Erection when needed • No significant tissue damaged

Disadvantages:

• Bruising • Pain • Swelling (< 10% of cases) • Interferes with spontaneity • Requires manual dexterity


Nonpharmacological Treatment of Impotence: External Vacuum Devices

The choice of therapy for impotence will depend on whether the condition is caused by neurogenic, psychogenic or hormonal factors. One nonpharmacological treatment option is the use of an external vacuum device.

The vacuum is a hollow tube placed around the penis that is connected to a manual or electric pump. As a vacuum is created, the corpora cavernosa becomes engorged. Advantages of this treatment include relatively low cost and the absence of systemic side effects.

Disadvantages include the possibility of numbness, bruising, swelling and trapped ejaculation. The only contraindications to the vacuum are anticoagulant therapy or bleeding disorder. The external vacuum device may be the treatment of choice for older patients with infrequent sexual intercourse and those who have comorbidities that demand non-invasive drug-free management.


Other Nonpharmacological Treatment of Impotence

Penile Prostheses:

• Silicone-sheathed devices implanted into corpus cavernosa • Possible complications include sepsis, erosion, migration, droop, and perineal pain • Replacement required every 5-10 yrs


Other Nonpharmacological Treatment of Impotence

Vascular Surgery:

• Arterial revascularization • Venous ligation

Sex Therapy:

• Open communication • Partners’ roles and goals • Partners’ expectations

Additional nonpharmacological treatments for impotence include penile prostheses, vascular surgery and sex therapy. Penile prostheses require surgical placement of silicone-sheathed devices into the corpora cavernosa. These devices can either be rigid or malleable and are manually inflated by the patient when an erection is needed.

The disadvantages of prostheses include the requirement for anesthesia and surgery and a high incidence of complications such as sepsis, erosion, migration, droop, necrosis, perineal pain, and leaks. Use of antibacterial-impregnated or hydrophilic-coated prostheses reduces the risk for infection.The implant must also be replaced every 5-10 years.

One of the last resorts for treatment is surgery. Vascular surgery has been more successful in Europe than in the United States, and involves arterial revascularization and venous ligation.

Sex therapy is of course, the least invasive treatment option; focusing on the expectations, communication patterns and defined roles and goals of the couple.


Pharmacological Treatment of Impotence

Selective Phosphodiesterase-5 (PDE-5) Inhibitors:

• Sildenafil • Vardenafil • Tadalafil

• Prostaglandins (intracorporeal or intraurethral) • Papaverine (intracorporeal) • Testosterone therapy

No Longer Recommended:

• Yohimbine • Trazodone



Emerging Therapies

2nd Generation Phosphodiesterase Inhibitors

• AvanafilUdenafil • Mirodenafil • Slx02101

Centrally acting agents

• Bremelanotide

Other agents

•  Topical alprostadil (Topiglan, Alprox-TD) •  Combination of aviptadil and phentolamine for intracavernosal injection (Invicorp)



From: Hatzimouratidis K and Hatzichristou DG. Erectile Dysfunction: Drugs. 2008; 68(2): 231-250.



Pharmacotherapy plays an important role in the treatment of impotence. The phosphodiesterase inhibitor, Sildenafil, emerged as the most popular first line oral agent for ED following its wildly successful introduction to the market in March of 1998. Six million prescriptions were dispensed to 3 million men in the first 9 months following its release. The success of sildenafil naturally led to the research and development of other phosphodiesterase inhibitors with faster onset, longer duration, and fewer side effects.

Other older ED medications like prostaglandins and papaverine are administered via intracorporeal and intra urethral routes. These products are considered highly effective but are generally reserved for PDE-5 inhibitor refractory patients or those with contraindications to PDE-5 inhibitors , i.e. concomitant nitrate use.

Testosterone therapy is normally indicated for impotence if the condition is due to hypogonadism. Advances in therapy for ED means that patients no longer should receive agents with questionable efficacy and known adverse events, such as yohimbine and trazodone.


Phosphodiesterase Inhibitors (Sildenafil, Vardenafil, Tadalafil)

Place in Therapy:

• First line, unless contraindicated • Effective for vascular, neurogenic, and hormonal causes of ED

From: NEJM. 2000;342(24):1802.


Phosphodiesterase Inhibitors (Sildenafil, Vardenafil, Tadalafil)

The American Urological Association supports the use of PDE5 inhibitors as first-line treatment for ED. Sildenafil was originally approved in 1998 as a “breakthrough” treatment for erectile dysfunction. Since then, two other PDE-5 inhibitors, vardenafil and tadalafil, have been approved.

These agents have proven effective in patients with all three types of organic erectile dysfunction (vascular, neurogenic, or hormonal etiologies). There is insufficient evidence on the superiority of one agent over the others. Duration of action, patient-specific side-effects, as well as cost of the drug are usually the deciding factors as to which of these agents to choose.


Phosphodiesterase Inhibitors

Mechanism of Action:

Selective inhibition of PDE5, causing prolonged cyclic guanosine monophophosphate (cGMP), release of nitric oxide, and relaxation of the smooth muscle in the penis.

From: Mayo Clin Proc. 2006;81(3):385-390.



Adverse Drug Reactions:

PDE5 inhibitors can markedly increase the hypotensive effects of nitrates such as nitroglycerin; all of these drugs are contraindicated in patients taking nitrates for angina pectoris.

In addition, they can all cause:

• Lowered blood pressure • Headache • Flushing • Dyspepsia • Mild visual disturbance (sildenafil and vardenafil) • Death (if used with nitrates)

Monitor: BP, Orthostatic Hypotension, EKG changes



The result of PDE5 inhibition is prolonged cyclic guanosine monophosphate (cGMP) activity and the release of nitric oxide and the subsequent relaxation of the smooth muscle in the penis and to form an erection.

All of these drugs have hypotensive properties, and are contraindicated for concurrent use with nitrates. Due to the hypotensive effects of PDE-5 inhibitors, it is recommended that all of these agents be used at the lowest dose possible when used in patients who are also taking non-selective alpha-blockers (doxazosin, terazosin) and the administration of these drugs should be separated by at least 4 hours. PDE5 inhibitors could also add to the hypotensive effect of other antihypertensive drugs.

The risk of hypotension is especially pertinent in older men, many of whom take medications for high blood pressure, prostatic hyperplasia, or may experience angina.


Sildenafil

Initial dose:

• 25 mg in patients > 65 years old • 50 mg in patients < 65 years old

Administered 1 hour before intercourse

High fat meals interfere with absorption

Drug Interactions:

• Nitrates: decreased BP; concomitant use is contraindicated • Alpha-blockers: decreased BP; use the lowest sildenafil dose possible • Cimetidine, erythromycin and ketoconazole all decreased sildenafil metabolism • Rifampin can decrease effectiveness

Can cause visual changes owing to affinity for PDE6 receptors found in high concentrations in the photoreceptor cells of the retina


Sildenafil

The recommended starting dose is for men over 65 years old is 25mg, about 60 minutes before sexual activity. High fat meals may decrease the effect of sildenafil. Duration of effect is approximately 1 hour.

Like all existing PDE-5 inhibitors, concomitant use with nitrates is contraindicated and the risk of hypotension is increased when combined with alpha-blockers or other anti-hypertensives. The drug is metabolized in the liver, primarily by CYP3A4, and is subject to drug interactions when combined with 3A4 inhibitors or inducers. Additionally, sildenafil has some cross-reactivity with PDE-6, which may produce visual side effects.


Vardenafil

Initial dose:

• 5 mg in patients > 65 years old or moderate hepatic impairment • 10 mg in patients < 65 years old • Administered 1 hour before intercourse

Drug Interactions:

• Nitrates: decreased BP; concomitant use is contraindicated • Alpha-blockers: decreased BP; use the lowest vardenafil dose possible • Indinavir, ritonivir, erythromycin and ketoconazole all decreased vardenafil metabolism • QT prolongation; do not use with antiarrhythmics • Can cause visual changes owing to affinity for PDE6 receptors found in high concentrations in the photoreceptor cells of the retina


Vardenafil

The recommended starting dose is 10 mg taken with or without food about 60 minutes before sexual activity. Duration of effect is approximately 1 hour. However, serum concentrations have been higher in men over 65 years old. Therefore a lower starting dose (5mg) should be considered in men > 65 years old. The drug is metabolized in the liver, primarily by CYP3A4 and should be considered in men with moderate hepatic impairment.

Vardenafil may result in a slight prolongation of the QT interval (uncertain if this is clinically significant). Therefore vardenafil should not be used in patients with congenital QT prolongation or taken concurrently with antiarrhythmic drugs such as quinidine, procainamide, amiodarone, or sotalol.

Due to drug interactions with 3A4 inhibitors, the manufacturer recommends using only 5 mg per day with coadministration of erythromycin or 200 mg of ketoconazole or itraconazole, 2.5 mg per day with indinavir, and 2.5 mg once every 3 days with ritonavir.

Like sildenafil, vardenafil has some cross-reactivity with PDE-6, which may produce visual side effects.


Tadalafil

Initial dose:

• As needed use: 10 mg administered 30-60 minutes prior to sexual activity • Once daily use: 2.5 mg daily, without regard to sexual activity

Drug Interactions:

• Nitrates: decreased BP; concomitant use is contraindicated • Alpha-blockers: decreased BP; use the lowest tadalafil dose possible • Ritonivir and erythromycin decreased tadalafil metabolism

Tadalafil is unique because of its prolonged half-life, allowing a much longer time frame in which sexual intercourse can be initiated (24-36 hours). In 2008, the makers of tadalafil began marketing a once daily form, which can be taken every day without regard to timing of sexual activity.

For as needed use, the recommended starting dose is 10 mg taken without regard to meals take 30-60 minutes minutes prior to intercourse.

For once daily use, the recommended starting dose is 2.5 mg taken at approximately the same time every day, without regard to sexual activity. However, dose adjustment may be necessary in patients with renal or hepatic insufficiency.


Tadalafil

Tadalafil can increase hypotension and use is cautioned in patients taking any alpha1–blocker except tamsulosin. Tadalafil apparently does not interact with other antihypertensive drugs.

The potent CYP3A4 inhibitors ketoconazole and ritonavir have been shown to increase serum concentrations of tadalafil; other 3A4 inhibitors such as erythromycin, itraconazole and grapefruit juice probably could do so as well and should be avoided if possible or tadalafil dosage lowered.


Prostaglandins and Papaverine

Alprostadil (Caverject®):

Mechanism of action • Increases cAMP levels

Administration • intracorporeal injection

Initial Dose: • 5 mcg (neurogenic cause) – administers 1.25 mcg of alprostadil10 mcg (vascular cause) - administers 2.5 mcg of alprostadil

Adverse Drug Reactions: • Pain (11-75%) • Prolonged erection (1%)



Papaverine/phentolamine:

Mechanism • Non specific PI, increases cAMP & cGMP

Administration • Intracorporeal injection

Preparation • Must be compounded; 30 mg papaverine/ 1 mg phentolamine per mL (10 mL vial)

Initial Dose: • 0.5 mL (neurogenic cause) • 1 mL (vascular cause) • Maximum dose = 60 mg

Adverse Drug Reactions: • Abnormal liver function tests (40%) • prolonged erection (10%) • Fibrosis (3%)

Monitor • Penile curvature (possible fibrosis secondary to injection or drug itself)



Unfortunately, administration may be difficult in patients who have dexterity issues, which limits its utility in older men. Initial dosages are five or ten micrograms, depending on the etiology of the condition. The dose of Caverject should be individualized to the patient by careful titration under close supervision of a physician. Side effects include pain which can be reduced if the injection is given slowly, over 30-60 seconds. A PGE-Phentolamine combination can be used, dosed at 3-8 micrograms.

This combination, however, may cause painful burning as well. Papaverine is not FDA approved for erectile dysfunction, but has been used effectively for it since 1980. Papaverine also relaxes smooth muscle. Initial dosages may be increased up to sixty milligrams if patient does not respond.

An injection of a vasodilator solution can be self-administered directly into the corpus cavernosus before sex to achieve erection.

No sexual stimulatin is needed, therefore it is the only effective treatment after major pelvic surgery without preservation of the neurovascular bundles of the corpora cavernosa.

Caverject is the most commonly used drug for intracorporeal injections, which cause smooth muscles to relax and vasodilation to occur.

Caverject is also the most effective monotherapy, with an efficacy of greater than 70%.


Prostaglandins (MUSE)

Mechanism of action • Absorbed through urethra, increases cAMP

Administration • Intraurethral suppository

Dosing • 125 mcg to 1000 mcg per erection (use the lowest effective dose)

Adverse Drug Reactions:

• Pain (penile and perineal) • Urethral bleeding • Syncope • Penile burning sensation • Vaginal burning in partner

Monitor • Difficulty voiding (urethral stricture)


Prostaglandins (MUSE)

Intraurethral insertion involves using an applicator with prostaglandin pellets placed in the urethra. Prostaglandin is then absorbed through the urethral mucosa into the corpus cavernosum, producing an erection.

Initial dose titration should be administered under supervision of a physician to evaluate for response, proper technique, and evidence of hypotension. The average dose is five hundred micrograms per erection. The maximum frequency of use is 2 administrations per 24 hours. Side effects include penile pain.


Testosterone Therapy

Mechanism of action • Replenishes body’s lack of natural testosterone in patients with hypogonadism

Administration •  Enanthate or cypionate preparations • Testoderm patch

Dosing • 200 mg IM every 2 weeks • Testoderm patch: app. 6 mg patch daily to scrotum • Testoderm-TSS: app. 5 mg patch daily to upper arm, back, or buttocks (do not apply to scrotum)

Side Effects • Moodiness • Aggression • Excessive hair growth • Lethargy • Prostatic hypertrophy • Oral: hepatic toxicity



Monitor • Weight gain, edema, contact dermatitis (with patches)

Follow-up • Measurement of serum testosterone levels



Testosterone therapy is used to treat hypogonadism and can help improve energy, mood and sense of well being while enhancing erections.

Treatment may be considered in men with ED who have a fasting morning testosterone level less than 220 ng/dL. Use of testosterone therapy is not indicated in patients with a normal serum testosterone level. Men receiving IM injections (which are given every 2-3 weeks) may suffer from changes in mood, energy and efficacy secondary to oscillating testosterone levels.

Patches, on the other hand may be more tolerable by providing the patient with a more consistently normal level of testosterone. Transdermal and parenteral forms are more effective than oral therapy.

Follow up treatment includes measurement of serum testosterone levels one and two weeks after intramuscular depot injection. Hepatic complications and hyperlipidemia are more commonly seen with oral formulations.

The testoderm patch must be applied to a dry shaven scrotum of sufficient surface area to allow adequate adhesion. Men may find this more cumbersome to use than other testosterone patches.


Yohimbine and Trazodone

Place in Therapy

• Questionable efficacy • No longer recommended for use in ED

Adverse Drug Reactions

Yohimbine:

• Nausea • Irritability • Hypertension • Tachycardia

• Trazodone

• Dizziness • Somnolence • Nausea • Orthostatic hypotension


Yohimbine and Trazodone

Due to advances over the past decade and questionable efficacy of these agents, patients should no longer receive yohimbine or trazodone for treatment of ED. Yohimbine was frequently prescribed as an oral treatment for ED prior to the advent of the PDE5 inhibitors.

The American Urological Association and National Institute of Health’s Consumers Panel question its efficacy and discourage its use. Results of a limited number of randomized, placebo-controlled clinical trials with trazodone have failed to show statistically significant efficacy.


Emerging Therapies

2nd Generation Phosphodiesterase Inhibitors

• Avanafil – Phase II • Udenafil – Phase III, approved in Korea • Mirodenafil – Phase III, approved in Korea • SLx-2101 – Phase II

• Possible advantages over existing PDE5 inhibitors:

• Greater specificity for PDE-5, and decreased risk with nitrates (Avanafil) • Longer duration of action (SLx-2101 & Udenafil) • Faster onset of action (Udenafil)


Emerging Therapies

Centrally acting agents • Bremelanotide – Phase II • Mechanism of action: analogue of alpha melanocyte stimulating hormone

Other agents • Topical alprostadil (Topiglan, Alprox-TD) – Phase III

The quest continues for the ideal agent to manage ED. Second generation phosphodiesterase inhibitors are in phase II and III clinical trials. Advantages over the original PDE-5 inhibitors include greater specificity for PDE-5 and altered pharmacokinetics.

A centrally acting compound, bremelanotide, is also being investigated. The effects of bremelanotide on sexual behavior, including penile erection, were demonstrated in laboratory animals.

Because bremelanotide acts in the central nervous system, it will probably have little effect in those patients whose erectile dysfunction is due to neurogenic etiology, such as spinal cord injury. There are also several topical agents that are being investigated.

These agents are designed to administer vasoactive substances without systemic adverse effects and avoiding the invasive nature of intraurethral or intercarvernous administration. In clinical trials, the most common adverse effect of these topical agents has been penile and vaginal irritation.


Summary

• Current therapy has proven highly effective for the management of ED

• PDE-5 inhibitors are recommended for use as first-line therapy, unless contraindicated, for vascular, neurogenic, and hormonal etiologies

• Increased use of medications for ED may risk of transmission of sexually-transmitted diseases in older patients

The current management of ED has proven to be highly effective. However, increasing popularity of these agents have also ushered an unprecedented increase in HIV and sexually-transmitted diseases in a population that is stereotypically viewed as abstinent.

According to the US Center for Disease Control, the incidence of HIV cases in the last decade has risen five-hundred percent among older adults. The rise in HIV and AIDS in older adults has been attributed to two factors: popularity of the PDE-5 inhibitors and lack of education regarding safe sex issues in the elderly.

With this knowledge, pharmacists are encouraged to educate their patients that these agents do not prevent the transmission of sexually transmitted diseases and therefore should use safe-sex practices.


References

AACE Clinical Guidelines – Sexual Dysfunction. http://www.aace.com/clin/guidelines/sexdysguid.pdf

Borer J, Armstrong P. Proceedings of the 99th meeting of the Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee. May 29th and 30th, 2003. Circulation 2003; 107:e9052

Brock G, Bochinski D. Modern pharmacotherapy for erectile dysfunction: Curr Opin Urol 2001; 11:625-630.

Chun J, Carson C. Physician-Patient Dialogue and Clinical Evaluation of Erectile Dysfunction: Urol Clin North Am 2001; 28(2)

Dewire DM.Evaluation and treatment of erectile dysfunction: Am Fam Physician 1996; 53(6): 2101-2106.

Dipiro Joseph T et al. editors. Pharmacotherapy, A Pathophysiologic Approach. 4th Ed New York: McGraw Hill; 2002 1511-1531

Doctor’s Guide – Erectile Dysfunction Information and Resources. http://www.pslgroup.com/ERECTILE.HTM

Eardley I. New oral therapies for the treatment of erectile dysfunction: BJU 1997; 81: 122-127.


References

Esposito, Katherine, MD et al, Effect of Lifestyle Changes on Erectile dysfunction in Obese Men: A Randomized Controlled Trial. JAMA. 2004;291:2978-2984.

Fazio, Luke and Gerald Block. Erectile Dysfunction: Management Update. CMAJ. 2004;170(9) 1429-1437

Fink H et al. Sildenafil for Male Erectile Dysfunction: JAMA 2002; Reprinted in Arch Intern Med 2002 Jun 24; (162).

Gentili A, Mulligan T. Sexual dysfunction in older adults. Clin Geriatr Med 1998; 14(2): 383-393.

Gingell JC. New developments in self-injection therapy for erectile dysfunction. BJU 1998; 81: 599-603.

Godschalk MF, Sison A, Mulligan T. Management of erectile dysfunction by the geriatrician: J Am Geriatr Soc 1997; 45: 1240-1246.

Hakim LS, Goldstein I. Diabetic sexual dysfunction. Endocrinol Metab Clin North Am 1998; 25(2): 379-400.

Hazzard WR, et al. Principles of geriatric medicine and gerontology. New York: McGraw-Hill, Erectile Dysfunction (Impotence), pp. 1251-1258.

Hafez, E. S. E. and S.D. Hafez. Erectile Dysfunction: Anatomical Parameters, Etiology, Diagnosis, and Therapy. Archives of Andrology, 51:15-31, 2005.

Hellstrom W. Sustained Efficacy and Tolerability of Vardenafil, a Highly Potent Slective Posphodiesterase type 5 Inhibitor: Urology Supplement 2003 April; (4A)

Jackson SE, Lue TF. Erectile defection, Therapy health outcomes. New York:Elsevier Science, Inc; 1998.


References

Kloner RA et al, Cardiovascular effects of tadalafil in patients on common antihypertensive therapies. Am J Cardiol 2003; 92 suppl 9A:47M

Lue T. Erectile Dysfunction: N Engl J Med 2000 Jun;(324):24

Neal DR. Update on Pharmacological Causes and Treatment of Erectile Dysfunction: J Am Soc Consult Pharm supp Clinical Consult 1999; 7(14): 7-1 to 7-8.

module 7 - pharmacotherapy for endocrine and exocrine disorders

Documents