Endocrine and obstetrics

Tom Archer, MD, MBA

UCSD Anesthesia

“Hormone”

• From the Greek– “to stimulate or excite”

• My version of the theme is “SIGNALING.”

http://casestudies.med.utah.edu/med1/diabetes2/images/web/Insulin_signalling_pathways.jpg

Long term anabolic effects

Short term effect of glucose uptake into muscle

Insulin is an ANABOLIC hormone

• Insulin affects gene transcription, promoting tissue growth and health.

Google images

Insulin is NOT just about blood glucose control!

Insulin

• Anticoagulant

• Vasodilatory

• Anti-inflammatory

• Anabolic

• Insulin even reduces augmentation index!

http://www.eng.vt.edu/warelab/images/Klages%20Machine%20Shop.jpg

Are hormones building new machinery (e.g. tissue growth)?

(Slow)

Or are hormones turning on pre-existing machinery (e.g. glucose uptake into muscle)?

(Fast)

Hormones…

• Do they act slowly or quickly?

• Do they rapidly control pre-existing machinery such as contracting smooth muscle cells (e.g. angiotensin II), or…

• Do they slowly make new structures, such as hypertrophied cardiac or vascular muscle (e.g. angiotensin II or aldosterone)?

Hormones

• Can have multiple sites of action and

• Multiple time courses and mechanisms of action.

Examples of hormones having multiple sites of action:

• Dobutamine: inotrope AND improves microcirculation in septic shock.

• Insulin regulates uptake of glucose into muscle (at multiple sites) AND supports tissue growth and protein synthesis AND supports vasodilation AND…

• Angiotensin II causes vasoconstriction AND causes vascular stiffening and cardiac hypertrophy.– Stiff aorta causes increased pulse wave velocity and aortic

pressure augmentation.– ACE inhibitors reduce heart damage (CHF) and renal damage.

• AVP (ADH) causes vasoconstriction (V1) AND free water retention (V2).

The sophisticated physician…

• Will appreciate the multiple actions of hormones– many that are still unknown!

Complex action of hormones

• Short term, catecholamines and RAAS help the CV system to handle stress (“fight or flight”).

• Long term, they hurt CV system by causing “remodeling” (cardiac and vascular stiffness due to fibrosis and smooth muscle hypertrophy).

Many current agents appear to block long term bad effects of sympathetic and RAAS

systems on heart and kidney:

• Beta blockers

• ACE inhibitors

• ARBs

• Aldosterone blockers

• Insulin

• Statins

ACEIs, ARBs, CCBs, Statins, aldosterone antagonists…

• Reverse stiffening of aorta.

• Reverse or arrest aortic pressure augmentation.

• Reverse or arrest cardiac and renal damage.

Hormones…

• Do they work on the outside of the cell membrane by activating signal transduction pathways (such as insulin or epinephrine), or…

• Do they cross cell membranes and modulate transcription of DNA in the nucleus (like thyroid and sex hormones).

Two Signal Transduction Pathways

Cell does some thing fast with existing machinery

mRNA Protein

Cell makes new machineryThyroid hormone

Epinephrine

Transcription factor

Hormones…

• Do they affect apoptosis (normal organ formation and maintenance)– like glucose?

• Do they affect organ maturation (lung, brain blood vessels, GI tract)– like glucose?

Eghbali M (Trends Cardiovasc Med 2006;16:285–291)

Non-pregnant vs late pregnant mouse hearts. Note hypertrophy and conduction disturbance (QRS prolongation) in LP mouse heart.

Eghbali M (Trends Cardiovasc Med2006;16:285–291)

Cardiac hypertrophy requires activation of signal transduction pathways for transcription and translation.

Different pathways are activated in different types of hypertrophy.

This is demonstrated by production of different mRNA profiles (gene fingerprinting).

www.pitt.edu/~super1/lecture/lec9691/018.htm

Pressure overload eg AS Volume overload eg pregnancy or athletics

Hyperglycemia

Obesity

Inflammation

Insulin resistance

Atherosclerosis

Nephropathy

Retinopathy

Neuropathy

Immune dysfunction

Poor wound healing

Pancreatic beta cell damage

Decreased insulin output

Genetic

predisposition

Two vicious cycles

of type II DM:

#1

#2

“Glucotoxicity”

Wasserman DH Clin and Exp Pharm Phys 2005

Insulin can affect three different steps

of muscle glucose uptake

arteriole

Pre-capillary sphincter

G = glucose Insulin mediated process

Muscle cell

Mitochondrion

G6P

G

G

GLUT 4 transport proteinAuto- regulation of

microcirculation

Hexokinase

G

GG

G GG G

G

G

GG

G

G

G

G

G

GGG

G

G

G

G

G

G

G

G

G

Insulin enables three distinct stages of glucose utilization:

capillary

Hyperglycemia “cries wolf” to the innate immune system– activating it when it is not needed and weakening its capacity to respond to a real infection.

portland.indymedia.org accessed on Google images

Hyperglycemia damages (“activates”) the endothelium.

Hyperglycemia causes inflammation.

Reinhart K 2002, Dandona P 2005 J Clin Invest, Dandona P 2003 Curr Drug Targets

Hyperglycemia, sepsis and pre-eclampsia all “activate” (damage) endothelium, white cells and platelets, leading to white cell adhesion and infiltration, thrombosis and edema (inflammation).

Hyperglycemia, sepsis or pre-eclampsia

WBC

Platelet

Protein (edema)

WBC

Platelets

Archer TL 2006 unpublished

vasodilatory signals (NO, prostacyclin)

vasoconstrictive signals (thromboxane, endothelin)

Endothelial cells send molecular signals to surrounding smooth muscle

Vessel lumen

Insulin makes endothelium produce

Glucose makes endothelium produce

Archer TL 2006 unpublished, Idea from Dandona P 2004

Hyperglycemia damages mitochondria

H+

H+

Electron transport chain creates H+ gradient

ATPH+

H+ gradient flowing through ATP synthase converts ADP to ATP.

Chemo-osmosis in inner mitochondrial membrane produces ATP

Outer mitochondrial membrane

Inner mitochondrial membrane

Glucose

NADH and NADPH (electrons)

Cytochromes of electron transport chain

½ O2 +

H2O

E-

E-

E-

E-

O2

O2- superoxide

Superoxides damage mitochondria.

Hyperglycemia increases flow of electrons through mitochondrial electron transport chain, with increased leakage to form ROS, which damage mitochondria.

Appropriate ATP generation

Leakage of “excess” electrons to form ROS.

2H+ and 2e-

Hyperglycemia makes mitochondria “peel out”: too much energy produces destructive debris

Reactive oxygen species

(ROS)

Mitochondria exposed to too much NADPH (electron energy).

Google images

Hormonal Yin and Yang

• Normal glucose metabolism is a balance between

• the anabolic effects of insulin and

• the catabolic effects of epinephrine, cortisol, glucagon and growth hormone.

Absence / deficiency of insulin

glucose does not enter muscle and liver cells and accumulates in the blood-

hyperglycemia and dehydration due to osmotic diuresis once renal threshold for glucose reabsorption is surpassed.

Acute complications of insulin deficiency (and Rx):

DKA (associated with DM type 1).

Hyperosmolar hyperglycemic nonketotic coma (associated with DM type 2).

Hypoglycemia from excessive insulin Rx.

Enormous dangers of hyperglycemia in pregnant patients!

• HG alters DNA transcription, causing:

– “Diabetic embryopathy”-- birth defects.

– “Diabetic fetopathy”– macrosomia and organ immaturity for gestational age (e.g. lung).

– Placental vascular disease (IUGR, chronic malnutrition / hypoxia)

– Non-specific inflammation, vasoconstriction, coagulation and fibrosis.

– Decreased neutrophil / monocyte function.

– Neonatal hypoglycemia

DKA in pregnancy (8% of diabetic pregnancies):

Occurs in Type 1 DM.

30-70% chance of fetal death with DKA.

Maternal acidosis appears to decrease uterine artery blood flow.

Causes of DKA in pregnancy:

Patient noncompliance with insulin Rx.

Infection.

Steroid therapy for lung maturation in premies.

Beta agonist tocolysis therapy stimulates glucagon release.

Questions about DKA

• Why does a high glucose cause a low Na+?

• Why do we give NS and not LR?

• Why can cerebral edema develop with rapid reduction of blood sugar, especially in kids?

Hypoglycemia

Always a danger, particularly with the tight glycemic control that is recommended nowadays before and during pregnancy.

Chronic complications of hyperglycemia:

Microvascular complications (retinopathy, nephropathy and neuropathy).

Macrovascular (MI, CVA, and PVD)

Perioperative complications (of hyperglycemia):• Poor wound healing.• Increased infections.• Increased neurological damage with brain trauma and

CPB.• Increased mortality in ICU patients.• Worse results in acute MI patients, short and long term.

Types of DM:

• Type 1: genetic and autoimmune etiologies (often in the young). ABSENCE OF INSULIN.

• Type 2: obesity and genetic predisposition. RESISTANCE TO INSULIN.

Gestational DM:

Appears in 4% of pregnancies. Possibly due to inability to make enough insulin to counteract the “counteregulatory hormones” which increase in pregnancy—placental lactogen, progesterone, placental GH and cortisol.

Gestational DM tends to recur in subsequent pregnancies. Gestational DM increases risk for type 2 DM later in life.

Pregestational DM:

Insulin requirements increase rapidly after the 26th week of gestation. Insulin requirement at term is about 50% more than pre-pregnant requirements.

Insulin requirements fall during first stage of labor, but rise during second stage of labor.

Insulin requirement falls up to 40% the day after delivery. Placental hormones are “diabetogenic”.

White classification

• Developed by Dr. Priscilla White in 1949—shows positive correlation between duration of DM, severity of vascular complications and morbidity and mortality for the fetus.

Hyperglycemia in pregnancy

Women need to get in tight glycemic control BEFORE they get pregnant to minimize chance of fetal anomalies!

Chestnut’s textbook states that, “…only 36% of women with known pregestational DM receive appropriate medical care before conception.”

Hyperglycemia in pregnancy

Hyperglycemia causes placental vascular degeneration: an accelerated version of what happens (ASCVD) over the lifetime of a hyperglycemic individual.

Leads to chronic placental insufficiency, IUGR and fetal distress with labor.

Can cause IUFD.

Hyperglycemia in pregnancy

Organs do not mature properly due to effects on transcription, translation.

Hyperglycemia causes premature birth, respiratory distress syndrome, intraventricular hemorrhage and hyperbilirubinemia.

Hyperglycemia in pregnancy

Causes macrosomia (big baby with risk of CPD or shoulder dystocia).

Glycemic control during labor

• Prevents hyperinsulinemia in the fetus and rebound hypoglycemia in the fetus after delivery.

• Pediatrician may need to feed with D5W or start IV for glucose Rx in hypoglycemic neonate.

Obstetric management:

A balancing act which tries to avoid BOTH:

Premature baby with immature organs (RDS or brain hemorrhage), and

IUFD due to placental insufficiency late in gestation.

Obstetric management:

• Prevention of problems: screening and glycemic control before conception.

• Universal screening for DM at 24-28 weeks.

• Skilled ultrasound at 24 weeks can pick up major malformations.

• Oral hypoglycemic agents were NOT used in pregnancy (this appears to be changing– Xenakis research)

Obstetric management:• Non-stress tests and other types of “biophysical

profiles” are used to watch activity of fetus as term approaches.

• Amniotic fluid analysis for L/S ratio and PG can help determine surfactant levels (lung maturity).

• If lungs are mature, baby is delivered. If not, obstetrician can give betamethasone to assist lung maturation.

• Macrosomia would be a factor in favor of C/S.

Anesthetic management:

Remember autonomic and somatic neuropathy (gastroparesis, orthostatic hypotension, positioning-related neuropathy, or attribution of DM neuropathy to regional anesthesia).

Stiff joint syndrome—difficult intubation due to stiff atlanto-occipital joint.

High “index of suspicion” for problems with DM mothers.

Thyroid disease in pregnancy

• Even mild maternal thyroid hormone deficiency may lead to neurodevelopment complications in the fetus.

• Universal screening? Not yet.

Thyroid disease in pregnancy

• Think about it!

• Second most common endocrine problem area in pregnancy (after DM).

Two syndromes in pregnancy

• Post-partum thyroiditis

• Gestational transient thyrotoxicosis

Thyroid tests made simple:

Measure free T4 and TSH. Period.

Someone who looks hyperthyroid should have a high free T4 and a non-measurable TSH.

Someone who looks hypothyroid should have a low free T4 and a high TSH.

Etiologies of hyperthyroidism (~1% prevalence):

Graves’ Disease in 70-90% of the cases.

Autoimmune disease, with antibodies to TSH receptors, which turn them on.

Thyroiditis—5%

Toxic adenoma – 5%

Toxic multinodular goiter—5%

Rare causes: TSH secreting tumor, thyroid ingestion, gestational trophoblastic tissue (hyperemesis gravidarum and hyperthyroidism can coexist), ectopic thyroid tissue.

Medical and Surgical Therapy (non-pregnant patients):

RAI.

Propylthiouracil or methimazole (block organification of iodine).

Surgery (subtotal thyroidectomy).

Thyroid storm (pregnant patient or not):

Precipitated by infection, stress, surgery, childbirth, other acute disease.

Rx with: General support: fluids, vitamins, cooling, O2, etc.

• Steroids (general support, blocks TSH release from pituitary and peripheral conversion of T3T4).

• PTU (blocks organification of iodine).• Na iodide (blocks release of T3 and T4 from thyroid

gland). Give NaI one hour after starting PTU.• Beta blockers.

Hyperthyroidism in pregnancy:

No RAI—would enter fetus!

PTU at low dose to minimize fetal thyroid suppression.

Surgery reserved for when PTU fails.Preparation for surgery with agents above as for

storm.

Woman who has had thyroidectomy because of Grave’s disease can still have anti-thyroid antibodies (which act like TSH) and which cross the placenta and stimulate the fetal thyroid, causing fetal hyperthyroidism.

Obstetric management of hyperthyroidism:

• Beta blockers could precipitate labor.

• Fetal goiter could cause difficulty with birth and airway problems.

Hypothyroidism in pregnancy:

Hx neck radiation or RAI Rx.

Rx with lithium, iodine, amiodarone or antithyroid meds.

Hx of thyroid surgery.

Hypothyroidism in pregnancy:

TSH is best screening test for hypothyroidism.

Rx is thyroid replacement.

The End