PCOS Update 2011:

More than Infertility…Definition, Diagnosis and

Management

R. Mimi Secor, MS, M.Ed, FNP, FAANP

Newton Wellesley ObGynNewton, Massachusetts

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R. Mimi Secor, MS, M.Ed, FNP-BC, FAANP

Nurse Practitioner for 34 years Newton Wellesley ObGyn, Newton, Mass Award winning NP Radio Host for

ReachMD Coauthor, Advanced Health Assessment

of Women Skills and procedures, 2010, Springer

Publishing

Fellow in the AANP Visiting Scholar – Boston College Owned private practice for 12 years Worked in Bethel, Alaska for 7 years

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Mimi Secor, MS, M.Ed, FNP-BC, FAANP

Disclosure

None

The speaker did NOT receive an pharmaceutical educational grant for this presentation

PCOS Objectives for Session Upon completion of this session attendees

will be able to:

Discuss epidemiology, pathophysiology, associated risks and complications - 15 minutes

List symptoms, signs & explain diagnostic work-up - 30 minutes

Describe prevention & most current treatment approaches – 30 minutes

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PCOS: Introduction Most common reproductive endocrine

disorder in reproductive-aged women

5 + million women in US 1 in 15 women (6-10%) Familial tendency

Associated with serious sequelae: Cardiovascular Disease, Diabetes, Infertility,

etc.

Increased awareness by clinicians & patients

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PCOS:More Common as Obesity

Rates Rise 1/20 Americans are

Diabetic

47+ million with “Metabolic Syndrome”

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PCOS: Menstrual Irregularities

Classic Clinical Profile Oligomenorrhea to amenorrhea

History since menarche

6 or fewer “menses” per year

BUT may have regular cycles!

Solomon et al. 2001 JAMA;286:2421

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PCOS: Etiology & Associated Risks

PCOS is associated with Insulin Resistance (IR) and Compensatory Hyperinsulinemia

IR plays critical role in pathogenesis of Hyperandrogenism, Chronic Anovulation

Increased Cardiometabolic risks (DM, CVD)

Correlated with High BMI & Obesity

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PCOS Associated withCardioMetabolic Derangements

Prevalence of Type 2 Diabetes 10 x higher By age 30, approx 30-50% have IGT or Type 2

Diabetes

Prevalence of Metabolic Syndrome is 2 - 3 x higher By age 20 approx. 20% have MS

Risk of fatal MI 2 x higher- if severe oligomenorrhea

Ehrmann D et al. Diabetes Care 1999;22:141-6.

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PCOS History & Definition

1935 Stein & Leventhal identified PCOS as a singular clinical entity

“Persistent anovulation” better term

PCOS is a sign, NOT a disease!

New definition…“General health disorder linked to Insulin Resistance which causes PCOS”

PCOS: Symptoms, Signs & Risks

Oligomenorrhea: Highly predictive Hyperandrogenism: Hirsutism , acne,

etc. Obesity: esp. central obesity Infertility (25-37%) & Anovulation Dysfunctional Uterine Bleeding/DUB Uterine Cancer- 3 fold incr. risk Insulin Resistance, Diabetes Type 2

(3-7x risk) Heart Disease, Hypertension,

Dyslipidemia (70%) Mental Health Problems

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Pathophysiology of PCOSRelated Androgen

Symptoms

Increased Insulin lowers SHBG by 50%

Raising Testosterone levels Causing acne, hirsutism, etc.

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Insulin Resistance & PCOS

Pathogenesis

IR & hyperinsulinemia are critical inpathogenesis of hyperandrogenism& chronic anovulation

Improving insulin sensitivity decreases androgens & increases ovulation

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Pathophysiology of PCOS:Hyperinsulinemia

Causes the Pituitary to hyper secrete LH (not All)Tonic levels of LH, FSH, estrogen, testosterone

Estrogen, testosterone slightly elevated, Estrogen reduces pituitary FSH, LH New follicles continuously stimulated,

producing estrogen but don’t fully mature= rare ovulation

LH thickens ovarian theca Insulin suppresses apoptosis: programmed

cell death Hence PCOS develops, vicious cycle!

PCOS OvaryClassic “string of

pearls”

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PCOS PathophysiologyNormal Cycle versus

PCOS

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Pathophysiological Characteristics of the Polycystic Ovary Syndrome (PCOS)

Nestler J. N Engl J Med 2008;358:47-54

Android Obesity: Apple Shape

Visceral Fat Is more active metabolically

Producing free fatty acids Delivered to liver via portal vein

Causing “Insulin Resistance” in the liver

Associated hyperglycemia Increased lipid levels Androgens inhibit hepatic and

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PCOS, IR & Risk of DM3 to 7 fold incr. risk of Type

2 DMRotterdam consensus group. Revised 2003

consensus criteria. Fertil Steril 2004 Jan;81:19-25.

Most women with PCOS have IR (64%) Worsened by obesity (esp.

visceral fat) 31-35% Prevalence of IGT 8-10% Type 2 Diabetes

Conversion from IGT to Type 2 DM 5 to 10 fold increased risk

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Cardiovascular Risk and PCOS

PCOS is a unique, independent risk factor for CVD

Young women w/ PCOS had higher prevalence of coronary artery calcium (CAC) as marker of CAD than controls

Evidence of asymptomatic vascular disease Incr. uterine pulsatility & opthalmic artery back

pressure Elevated triglycerides, total cholesterol Elevated atherogenic plasma index

Shroff R et al. Young obese women with PCOS have evidence of early coronary atherosclerosis. J Cl Endocr Metab 2007 Dec;92:4609. n = 24 plus controls

Battaglia C et al. Vasc risk in young women w PCOS. Obst Gynecol 2008 Feb;111:385. N 28+c

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PCOS and Pregnancy Risks

More challenging to conceive, takes longer

High risk for spontaneous abortion /SAB 25-73% With or without fertility induction

treatment

> 3 times incr. risk of Gestational Diabetes

Mental Health Issues and PCOS

2,100 citations since 1990

Wide range of mental health issues: Depression, anger, aggression Body dissatisfaction, eating

disorders Sexual and Relationship Issues

Management must address these risks

Himelein & Thatcher. A Review. Ob Gyn Survey 2006; 61 (11): 723-730

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Diagnosis of PCOS Clinical presentation

sufficient

If NO virilizing symptoms

BUT Rule out associated

conditions

AND Variable presentation

common!

Rotterdam Criteria 20042 of 3 required

Oligo or anovulation Hyperandrogenism:

Acne, hirsutism, central obesity

Polycystic ovaries on Ultrasound: 12 follicles 2-9 mm or increased volume >10ml in >1

ovary 25% of NORMAL women have

ovarian cysts!

Rotterdam consensus group. Revised 2003 consensus criteria. Fertil Steril 2004 Jan;81:19-25.

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Hirsutism Diagnostic Work-up:

Rapid Onset, Rule out Pathology Testosterone

Prolactin: if galactorrhea TSH 17 hydroxyprogesterone (17-

OHP)• Rule out Cushing’s Syndrome

24 hr urinary free Cortisol (10-90 ug)• Or serum fasting Cortisol (4-22 ug/dl)

• IV ACTH if indicated

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Testosterone: If Rapid Virilizing Sx

Total Testosterone Normal 20-80

ng/dl PCOS >60

Rule out tumor >200

Free T normal ~ 1% PCOS > 2%Increases with degree of

obesity

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PCOS Lab Work-upNo Need to Order Routinely

PCOS pts may have: Elevated LH levels Increased LH/FSH ratios > 3

40% with PCOS have normal ratios !!!

Androstenedione levels elevated Testosterone mildly elevated Dehydroepiandrosterone Sulfate

(DHEAS) Spiroff 2007

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PCOS Diagnostic Work-up

Body weight, BMI (>30) Height Waist circumference (>35 inches) Blood pressure Pelvic ultrasound: preferred

Check Ovaries and Uterus for hyperplasia >10mm

CBC, TSH, Lipids Fasting glucose, GTT, Hgb-a1C (KEY) Testosterone Other labs as indicated, LFTs, “Fatty

liver”

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Diagnosis of MS in PCOS pts

Requires 3 Criteria B/P >130/85 Abdominal obesity >35 inches Triglycerides >150 mg/dl HDL Cholesterol < 50 mg/dl Fasting Glucose 100-126

mg/dl >95 suspicious !!!

2 hr GTT (75 gm load) 140-199 mg/dl

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Glucose Testing GTT for ALL abnormal

values Random elevations suggest a

trend Fasting & Oral GTT required Fast 8 hours: 65-99 mg/dl =

normal • 100-125 = Impaired fasting glucose • > 95 suspicious

• > 126, suspect DM, retest different day

• >140 mg/dl x 2 = Probable diabetes

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PCOS Diagnostic Work-upPer Speroff 2007

2- hour Glucose Response GTT (75 gm load) >140, < 200 mg/dl = Impaired

Glucose Tolerance > 200 mg/dl = Non-insulin-dependent

DM

GTT abnormal: 2-8 years before DM develops !!! Better than FBS

Speroff. PCOS. Dialogues in Contraception 2007;11(1): 5-7.

Diabetes Care 2004;27: S11-14.

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New Hgb A1C Guidelines per ADA

for Diabetes Diagnosis: 2010

Predictive screening tool !

5.6-6.4 = “At risk” > 6.5 = Diabetes

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Insulin Resistance Testing: NOT Recommended by Rotterdam

Group

Fasting Glucose to Insulin Tests NOT RecommendedBecause no validated clinical

test exists Due to variations among ethnic groups And 40% with PCOS have

normal labs

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PCOS Differential Diagnosis

Cushings………………

Androgen-secreting tumors………………….

Hyperprolactinemia…..

Adrenal Hyperplasia….

Hypothyroidism……….

Pregnancy…………….

Ovarian failure………..

24 hr urine cortisol, IV ACTH

DHEA-S, total T, estradiolFasting morning Prolactin17-hydroxyprogesteroneTSH, free T4HCG FSH >30 suggestive

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EMB: When to Perform? Not Based on Age

Duration of exposure to unopposed estrogen?

If long standing anovulation then…Risk of hyperplasia, atypia, cancer

When in doubt: Do an endometrial biopsy! “Low threshold” regardless of age Don’t trust an ultrasound

Ultrasound: If Endometrial Stripe > 10 mm

Must do EMB: Not Based on Age!

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Before PCOS Management

Discuss plans for future pregnancy

Shouldn’t wait until age 35 to have 1st baby

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PCOS and Pregnancy

40% of female infertility is from anovulation

Mainly due to PCOS

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Team Approach to PCOS

Primary care ObGyn Infertility Cardiovascular Diabetes/

Endocrine

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Made in Taiwan, Raised in America

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Principles in Managing Infertility

OB /GYN implications are huge:harder/longer  to get pregnant, more

SAB’s Metformin XR recommended: better tolerance/compliance

Check HgbA1C: since IR is hard to diagnose Obese: Always give Metformin Not clear lean PCOS pts are IR, some may be… US all anovulatory pt:s Check ovaries numerous tiny

follicles perimeter and to rule out uterine hyperplasia,

common if NOT taking oc’s or provera to induce occasional bleeds Easy to achieve ovulation with various fertility drugs

But ovulation doesn’t equal pregnancy and PCOS pts take longer Referral to Reproductive Endocrinology/ Infertility

Expert is KEY

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Infertility in Obese pts with PCOS:

Lifestyle Approaches 1st Line

Weight loss: (>10%) • Increases insulin sensitivity • Improves ovulation & fertility

This addresses role of hyperinsulinemia in pathogenesis of anovulation

Contraception: must address!

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New Book 2010:The PCOS Diet

A Natural Approach to Health for Women with Polycystic Ovary Syndrome

By Hillary Wright

PCOS, Dietand Infertility Nancy Dunne

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Infertility and PCOSOvulation Doesn’t Equal

Pregancy

Easy to stimulate ovulation with various meds

Referral to Reproductive Endocrinology is KEY

Early esp. with PCOS And if “Older” (30-35 and esp. if

>40)

SUMMARY of PCOS Studies: Metformin & Clomiphene

40-60% of women with PCOS treated with metformin for 3 to 6 months will have regular menses and ovulate

Clomiphene + Metformin for 8-9 months results in 66 % ovulation and 34 % chance of pregnancy

Clomiphene + Metformin in resistant patients results in 40% chance ovulation and 25 % chance of pregnancy

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Infertility, Obesity and PCOS:If Lifestyle Changes Fail, AND

IR ! Consider Insulin-sensitizing drugs

• To improve insulin sensitivity• Reduce plasma insulin levels

• Improving ovulation/fertility• 40-50% within 3- 6 months regular

menses & ovulate• Facilitates weight loss

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Infertility and PCOS: If Lifestyle Fails, IR, Especially

if Obese Metformin therapyOften given to everyone, BUT not everyone benefits

Benefits if significant insulin resistance Evaluate infertility causes unrelated to

anovulation Combination therapy with Clomiphene

(CC) Or alternative Letrozole (AI)

Nestler. NEJM 2008;358:47-54.Speroff. Spring 2007, PCOS, Dialogues in Contraception;

11(1): 5-7.Baillargeon et al, Clin ObGyn 2003;46:325

PCOS: Cochrane Review 2010

Metformin Fertility Effects Benefits pregnancy & ovulation rates

But NO evidence of improves live birth rates, used alone or in combination with clomiphene, or when compared with clomiphene

Use of metformin to improve reproductive outcomes in women with PCOS appears limited

2010 Jan 20;(1):CD003053.

Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH.

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Clinical use: ovulation

Clomiphene is a good first choice drug when:1. Ovaries are capable of

functioning normally2. Hypothalamus and pituitary

are also capable of producing their hormones

• In short, the woman's reproductive engine is in working order, but needs some “revving up”

Clomiphene Citrate: Clomid

Synthetic drug Agonist-antagonist action Stimulates hypothalamus to release

more GnRH Pituitary releases more LH and FSH Stimulates ovary to produce a mature

egg/eggs Side effects

Moodiness, etc. Reduced cervical mucus, thinning of

uterine lining Stimulates multiple follicles

Clomiphene:Mechanism of Action

Structurally like estrogen, it binds to brain receptors where estrogen normally attaches, fooling body into thinking E2 is too low

Estrogen receptorClomiphene

Estrogen

Clomiphene

O V U L A T I O N I N D U C T I ON

Standard of Care BUT May NOT be Best

~ Clomiphene citrate

50-150 mg per day orally5 days: cycle days 3-7Ovulate approx 10 days after last doseMonitor for LH surge starting day 12Adverse: hot flashes, vision disturbances,

moodiness

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Aromatase Inhibitors: Alternatives to

Clomiphene Letrozole/ Femara OFF LABEL BUT preferred by infertility experts

as 1st line: Better tolerated, few side effects Mono follicular response PCOS pts highly responsive to fertility

meds Letrozole makes 1 follicle or IVF

single embryo Dosing; 5-7.5 mg daily, Day 2-6, x 5

days

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NOT Desiring Pregnancy: PCOS Treatment Approaches

Life Style Changes: Weight loss, Diet, Exercise

50% reduction in IR

Combination Hormonal Contraceptives

Use low-androgen progestins; NGM, LNG, DSN

Insulin sensitizers: Metformin, TZDs30% reduction in IR

Combination therapy

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Weight Loss

5% loss improves insulin sensitivity

Reduces Testosterone levels Improving acne, hirsutism

Lowers BP, improves labs Enhances fertility! Return of regular menses Thus reducing uterine cancer

risk

Hirsutism and PCOS

Spironolactone: Category C, less prescribed BUT inexpensive & effective

Combined hormonal contraceptives Insulin sensitizers

Various hair removal techniques

Eflornithine HCL (Vaniqa) topical cream “Hair growth retardant” Apply thin film twice daily, rub in

thoroughly Do NOT wash area for 4 hours Category C: do NOT use in pregnancy

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NOT Desiring Pregnancy:Combination Hormonal

Methods To induce menses Prevent uterine cancer Suppress ovarian androgen

production Provides symptom relief For oligomenorrhea, acne &

hirsutism Improved BMI, glucose tolerance &

basal insulin

No evidence at higher risk for CV events

If BMI > 30, VTE risk increased by x 3.5 fold

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Combination Hormonal Contraceptives:

For PCOS Range of options- doses, formulations Drospirenone & ethinyl estradiol (EE),

(Yaz, Yazmin)Analog of Spironolactone,

antiandrogenicPossible slight increased risk of VTE

(NEW)

Norgestimate and ethinyl estradiol (EE), (Ortho Cyclen, Ortho TriCyclen and Generics)

Continuous regimens, EE Vaginal Ring (Nuvaring), generics,

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Progestin Only Methods and PCOS

Medroxyprogesterone Acetate, (Depo-Provera) An option esp. if estrogen is

contraindicated May be associated with weight gain Possible impact of high-dose progestin

on IR? Levonorgestrel IUS (Mirena)

Local endometrial effects only so probably OK

Etonogestrel Implant (Implanon) Very low systemic effects, so probably

OK

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NOT Desiring Pregnancy: Combination Therapy for

PCOS Contraceptives

Combination hormonal methods Progestin only

Plus Insulin sensitizers

Metformin TZDs: Scant research, Category C in

pregnancy

Nestler J. NEJM Jan 2009;358;1

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Metformin Slows Progression to DM:

But, No PCOS Studies

Reduced relative risk of progression to DM

By 26%, 31% respectively

Ramachandran et al. Diabetologia 2006;49:289-97.Diabetes prevention program research group. NEJM 2002;346:393-403.

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Treatment Options: Metformin

Metformin, (Glucophage), = Biguanide Worldwide use commonly for 4+ decades Not FDA approved for PCOS BUT widely

used Insulin sensitizing effect

Decreases risk of progression from IGG to DM

Increases ovulation esp. w/ clomiphene

Category B in pregnancy; no teratogenic risk

Side effects & toxicity well studied Must check liver and renal function

before use

Metformin

Decreased hepatic production of glucose

increased glucose uptake

Dose- 500 tid- qid

nausea, diarrhea, bloating

weight loss or no change

Potential Uses for Metformin

Adjunct to Clomiphene for CC-resistant patients

First line agent for ovulation Alternative to OC for cycle

regulation in PCOS Treatment of PCOS associated

hirsutism Reduction of miscarriage in patients

with PCOS

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Metformin XR:

Dose 500 – 850 mg Oral TID daily with food

Improved lipid profile: Triglycerides, HDL, LDL

No change in CRP

Weight loss especially with higher doses!

XR: Less GI Side Effects XR: May dose at bedtime

Harborne et al. JClin Endocrinol Metab 2005; 90:4593

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Dosing of Metformin: “Start Low, Go Slow”

Starting dose 500 mg daily with food/dinner x 1 wk 500 mg twice daily; breakfast, dinner x1 week 500 mg am, 1,000 mg pm x 1 week 1,000 mg BID; breakfast, dinner Increasing q 1- 2 weeks to max 2+ gms day

Maximum 2250 mg total daily; 850 mg tid Garber et al. Am J Med 1997;103:491-7.

Ovulation improves w Single or Combination therapy

NEW: Research supports benefits even if NOT

seeking pregnancy

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Metformin Effective in Obese Teens with PCOS

DeLeo et al. Human Reprod 2006; 21: 2252-2256, n = 16, no controls

Given Metformin 1700 mg qd x 6 months, follow-up x 6 mo

Findings of Small Study (n of 16): Improved menstrual cyclicity within 1

month, ovulatory Decreased hirsutism, improved acne Lower BMI, fasting insulin levels improved Results persisted after only 6 months of

therapy

Cycle Resumption in PCOSMetformin Treatment

• Metformin~ Biguanide~ Decreased peripheral glucose uptake, hepatic gluconeogenesis, altered fatty acid/cholesterol metabolism

• Return of normal cyclesResumption of menses

in 25% after 3 months in 50-90% by 6 months

Ovulation inductionin 46% with metformin alonein 76% receiving metformin and clomiphene

**Consensus: safe in pregnancy and reduces SABs.

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Metformin: Adverse Effects

Lactic Acidosis rare: 0.3 /10,000 patient years

GI distress, 10-25%, nausea, diarrhea Usually transient Lower GI side effects with “XR”

Esp. if “start low, go slow” Take with meals Rarely, may have to stop

B12 Deficiency: Long term risk Dose, duration, age

Nestler, NEJM Jan 3, 2008;358:1

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Metformin: Contraindications

Renal impairment: Serum creatinine >1.4 mg/dl

Hepatic dysfunction Severe congestive heart failure History of alcohol abuse

In young women, contraindications rarely an issue

Repeat labs not needed unless illness or condition develop

Nestler J. NEJM Jan 2009; 358:1

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Metformin: Follow-up Visits

3, 6 months after Metformin started Check Testosterone at each visit: Total,

Free T

Document ovulatory cycles w serum Progesterone Check 7 days before next menses Progesterone >4.0 ng/ml = luteal phase and

ovulation

Discuss: Contraception or Conception?

Nestler, NEJM Jan 3, 2008;358:1

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Follow-up for PCOS 1st Year: every 3 months

- To monitor the efficacy of Metformin- Reinforce lifestyle changes - To reduce weight & increase exercise

After 1st year: every 6 to 12 months,- Depending on response to treatment

GTT repeat: Every 2 to 3 years- Even if metformin therapy is used

Nestler. N Engl J Med 2008;358:47-54.

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Insulin resistance and TZDs

“Thia-zolidine-diones” Increase insulin sensitivity of

muscle or adipose tissue Lowers hepatic glucose

production Action depends on presence of

insulin as well as resistance to insulin

Decreases A1c of 0.5% - 1.3%

Dosing: once or twice a day

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TZDs for PCOS Thiazolinediones

TZDs activate the transcription of genes affecting glucose and lipid metabolism

decreasing free fatty acid levels reducing visceral fat mass

2010 Jun 9. Clinical Endocrinology, [Epub ahead of print]Glintborg D, Andersen M.

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Thiazolidinediones for PCOS: Scant Data!

TZDs =“Thia-zolidine-diones” Rosiglitazone (Avandia): Increased

CV Risk FDA 2010 Black Box Warning, 2011: Removed from pharmacies in US

Pioglitazone (Actos): Incr. Bladder Cancer Risk! Decreased CV risk Lowers androgen levels Increase Beta cell function

Side effects/toxicity still being studied Cat. C in Pregnancy!

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May 2011 FDA Restricts Access to Rosiglitazone

Due to Increased Cardiovascular Risks

Rosiglitazone (Avandia): 2010 FDA Black Box warning May 19, 2011: FDA Pharmacy restriction

warningAvandia, Avandamet, Avandaryl

Nov 2011: Will be removed from US pharmacies

To access medications:HCP & Pts must enroll in, Medicines Access Program

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Prevention is KEY Early diagnosis Normalizing labs

Obesity control Exercise Mediterranean

Diet Whole grains Fruits and veggies Lean protein, fish Olive oil

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PCOS References

Nestler, J. PCOS. NEJM Jan 3, 2009; 358:47-54.

Speroff, L. and Mishell, D. PCOS: Management and contraception. Dialogues in Contraception, Spring 2007; 11(1):5-7.

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PCOS Summary: Key Points

Epidemiology: Common Pathophysiology: IR/Insulin problem Risks & complications: MS, DM, CVD,

Ut Ca, etc

Symptoms: Oligomenorrhea, hirsutism, acne Most overweight

Diagnosis: Clinical, +/- labs, possible US

Current treatment options: Life style, Comb Hormonal BC, Insulin

Sensitizers Prevention: Wt loss, exercise, diet, etc Future research: Needed

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PCOS Objectives for Session Upon completion of this session attendees

will be able to:

Discuss epidemiology, pathophysiology, associated risks and complications - 20 minutes

List symptoms, signs & explain diagnostic work-up - 25 minutes

Describe prevention & most current treatment approaches – 30 minutes

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Thank you

Special thanks to Carol Lesser NP, Boston IVF

Patty Duprey NP, Tom Bartol NP

R. Mimi Secor, MS, M.Ed, FNP, FAANP

www. MimiSecor.com