POLYCYSTIC OVARIAN SYNDROME

WHERE WE ARE AT IN 2018

PCOS:WHERE WE ARE AT IN 2018

Nancy Arquette, MD Premier Women’s Health

6135 Trust Drive #114

Holland, OH 43528

February 3, 2018 Kalahari Resorts

ME

• General OB-GYN (2007)

• Specialize in Robotic Minimally Invasive Surgery

• Still deliver babies

• Born and raised in Toledo, Ohio

• College: Wittenberg University (BA)

• Post Graduate: Bowling Green State University (MS in Cell Biology)

• Medical School: Wright State University (MD)

• Residency: Johns Hopkins Hospital (crazy)

• I have no financial disclosures

PCOS - A SYNDROME, NOT A DISEASE

• Clinical presentations of PCOS • Labs and imaging studies • Targeted treatment options • PCOS in the older woman • PCOS and infertility • Question and Answer period

CLINICAL PRESENTATIONS OF PCOS

• My periods are all over the place

• I have facial hair

• I have acne

• My hair is falling out

• I can’t get pregnant

• I can’t lose weight

MENSTRUAL IRREGULARITIES

• Cycles < 19 days or > 90 days are abnormal

• During first post-menarcheal year

• 75% of cycles range from 21-45 days

• By five years after starting menses

• 95% achieve 21-40 day cycles

MENSTRUAL DYSFUNCTIONS SUGGESTING ABNORMAL OVULATION

• Primary amenorrhea – no period by age 15, or > 3 years after onset of breast development

• Secondary amenorrhea - > 90 days without a menstrual period

• Oligomenorrhea

• Within first year after starting menses - < 4 periods in a year

• After first year of starting menses - < 6 periods in a year

• 2 – 5 years after starting menses - < 8 periods in a year (avg cycle length > 45 days)

• 6 years and beyond - < 9 periods a year (avg cycle length > 38-40 days)

MENSTRUAL DYSFUNCTIONS SUGGESTING ABNORMAL OVULATION

• Excessive uterine bleeding

• Bleeding more frequently than every 21 days

• Bleeding lasting more than 7 days

• Soaking a pad or tampon more than every 1-2 hours

• Shedding of endometrium exposed to insufficient progesterone

ADOLESCENTS

• Use caution in labeling hyperandrogenic adolescents as having PCOS if the menstrual abnormality has not persisted for 2 years or more

• Instead use “at-risk for PCOS” to avoid misdiagnosing physiological pubertal changes

Consider in adolescent

girls with treatment

resistant acne

DEFINING PCOS

•Ovulatory dysfunction • Hyperandrogenism • Polycystic ovaries

PCOS

• No universally accepted definition • Several expert generated diagnostic criteria

• Hyperandrogenism, anovulation, polycystic ovaries by USN

• (insulin resistance is not included)

• All require more than 1 sign or symptom

DEFINING PCOS

• Unknown etiology – complex trait arising from interaction of genetic and environmental factors

• Congenitally programmed predisposition

• Manifests in presence of a provocative factor (usually hyperinsulinism/obesity)

• Heritability of PCOS estimated at over 70%

• Treatment is symptom based

• Poses greater risk for diabetes and cardiovascular disease

DIFFERENTIAL DIAGNOSIS

• Androgen secreting tumor

• Exogenous androgens

• Cushing syndrome

• Non classical congenital adrenal hyperplasia (Ashkenazi Jewish, Hispanic)

• Acromegaly

• Genetic defects in insulin action

• Primary hypothalamic amenorrhea

• Primary ovarian failure

• Thyroid disease

• Prolactin disorders

LABS AND IMAGING STUDIES PHYSICAL EXAM

• Suggested evaluation (ACOG) • Physical

• BP

• BMI (Important to keep in mind – 20% patients with PCOS are NOT obese)

• Waist circumference (body fat distribution) >35 inches is abnormal

PHYSICAL EXAM

• Stigmata of hyperandrogenism and insulin resistance

• Acne

• Hirsutism – body hair distribution

• Balding or androgenic alopecia

• Clitoromegaly - beware of other causes, usually something other than PCOS

• Centripetal fat distribution

• Acanthosis nigricans – velvety, mossy, verrucous, hyperpigmented skin

• Associated with insulinomas, malignancy (esp adenocarcinoma of stomach)

LABORATORY

• Total testosterone and sex-hormone binding globulin (can give you the free testosterone)

• Or Free testosterone

• TSH

• Prolactin (mild elevations are normal in women with pcos)

• Fasting 17-hydroxyprogesterone (nonclassical CAH due to 21 hydroxylase deficiency)

• Consider screening for Cushing syndrome, acromegaly (IGF-1) etc

LABORATORY

• Evaluation for metabolic abnormalities

• 2 hr oral glucose tolerance test (75gm)

• Fasting < 110 normal

• Fasting 110 – 125 impaired

• Fasting > 126 = type II DM

• 2nd hour < 140 normal

• 2nd hour 140-199 impaired

• 2nd hour >200 = type II DM

LABORATORY

• Fasting Lipid and Lipoprotein level

• Total cholesterol > 200 abnl

• HDL < 50 abnl

• LDL > 100 abnl

• Triglycerides > 150 abnl

OPTIONAL TESTS TO CONSIDER

• FSH/LH, estradiol, hcg (amenorrhea)

• DHEA-S (cases of rapid virilization, levels over 700)

• Fasting insulin

• Younger women, those with severe stigmata of insulin resistance, hyperandrogenism, or those undergoing OI

• 24hr urinary free-cortisol excretion test (or low dose dexamethasone suppression test)

• Women with late onset PCOS symptoms or stigmata of Cushing syndrome

WHY HYPERANDROGENISM?

• Obesity or increased glucose load or insulin insensitivity

•↑ INSULIN LEVELS

• ↓ SHBG (sex hormone binding globulin)

• ↑ BIOAVAILABLE CIRCULATING ANDROGEN

• TROPHIC STIMULUS TO ANDROGEN PRODUCTION IN THE ADRENAL GLAND AND OVARY

• Insulin can directly affect hypothalamus – creating abnormal appetite stimulation

NON CLASSIC CONGENITAL ADRENAL HYPERPLASIA“LATE ONSET”

• 2nd most common cause of androgen excess that presents in adolescence

• 2-5% of cases of hyperandrogenism in most populations

• It is an autosomal recessive deficiency in the activity of an adrenocortical enzyme step necessary for corticosteroid biosynthesis

• Mild deficiency of 21-hydroxylase

• Mildly hyperandrogenic

• Does not have genital ambiguity which is seen in classical

• Premature pubarche

• Dx is strongly suggested by elevated levels of serum 17-hydroxyprogesterone

CUSHING SYNDROME STIGMATA 1 IN 1,000,000 INDIVIDUALS DUE TO ADRENAL HYPERPLASIA, RARE OCCASIONS ASSOC WITH HYPERANDROGENIC ANOVULATION

A condition that occurs from exposure to high cortisol levels for a long time

Dexamethasone suppression test

IMAGING

• Pelvic Ultrasound • Determination of polycystic ovaries:

• Can be in 1 or both ovaries

• 12 or more follicles measuring 2-9 mm in diameter OR

• Increased ovarian volume ( > 10 cm³ )

• However if there is a follicle > 10mm in diameter, the scan should be repeated during time of ovarian quiescence

IMAGING IN ADOLESCENTS

• USN is not recommended or required for the diagnosis of PCOS in adolescents, because the high frequency of polycystic-appearing ovaries in this age group makes this an unreliable criterion for the diagnosis of pcos

TARGETED TREATMENT OPTIONS

PCOS AND NOT DESIRING PREGNANCY

• TREATING MENSTRUAL DISORDERS

• Combination hormonal contraceptives- recommended as primary treatment

• Suppression of pituitary LH secretion

• Suppression of ovarian androgen secretion

• Increased circulating SHBG (in turn means lower circulating androgen levels)

• Protection against development of endometrial hyperplasia

• Induction of regular uterine withdrawal bleeding

CLINICAL ENDOCRINOLOGY 2016

• OCPS

• Effective at improving hirsutism

• Improving acne

• Improving menstrual cycle irregularities

PCOS AND NOT DESIRING PREGNANCY

• Non-existent or conflicting data on use of: • Depo

• Cyclic progesterone therapy

• Progesterone- containing IUD

• Progesterone only ocps

• However progesterone products can help reduce risk of endometrial hyperplasia

TREATMENT OF METABOLIC DYSFUNCTION CLINICAL ENDOCRINOLOGY 2016

IT IS MORE EFFECTIVE TO PRESCRIBE STRUCTURED EXERCISE TRAINING PROGRAM TO IMPROVE CARDIOVASCULAR RISK FACTORS OF ENDOTHELIAL DYSFUNCTION

SIGNIGICANT IMPROVEMENT IN

LIPID PROFILE

INSULIN SENSTIVITY

CARDIOPULMONARY FUNCTION

INFLAMMATORY MARKERS

SIGNIFICANT REDUCTION IN CAROTID ARTERY INTIMA-MEDIA THICKNESS

SIGNIFICANT INCREASE IN BRACHIAL ARTERY FLOW MEDIATED VASODILATATION

TREATING PCOS: START USING DUAL MEDICAL THERAPY ROBERT BARBIERIAPRIL 2017

• OCPS + metformin (or spironolactone- in women with dermatologic complaints) • Addresses metabolic concerns in conjunction with cycle abnormalities

• Add in diet and exercise for best results

• In his opinion, women that may benefit the most from dual therapy have: • BMI > 30

• Waist to hip ratio > 0.85

• Waist circumference > 35 in

• Acanthosis nigricans

• h/o GDM, Type II DM in first degree relative

• Dx of metabolic syndrome

PCOS AND NOT DESIRING PREGNANCY

None of the antidiabetic agents noted are currently approved by the US FDA for treatment

of PCOS-related menstrual dysfunction, although METFORMIN appears to have the safest

risk-benefit ratio.

METFORMIN • Improves insulin sensitivity

• Decreases circulating androgen levels

• Improves ovulation rates

• Improves glucose tolerance

• Weight loss results inconsistent

TREATING HIRSUTISM

• No clear primary treatment for hirsutism

• No good evidence to support use of ocps to treat unwanted hair

2013 endocrine society clinical practice guidelines on tx of hirsutism suggest ocps as 1st line therapy

• Anti androgens – none were developed to treat hyperandrogenism in women and none are FDA approved

• Spironolactone - a diuretic and aldosterone antagonist

• 25-100mg bid (usual dose is 100mg a day)

• Side effects include orthostatic hypotension, increased menstrual frequency, hyperkalemia- do not need to check K in young women with nml Cr

• clinical effect could take longer than 6 mos

TREATING HIRSUTISM

• Flutamide – androgen receptor agonist

• 125-250 mg/d

• Side effect is dry skin, hepatitis, teratogenicity

• Finasteride – inhibits 5-α-reductase

• 1mg tablet for male alopecia

• Better tolerated but very teratogenic

TREATING HIRSUTISM

• Mechanical hair removal is often front line treatment

• Shaving, plucking, waxing, depilatory creams, electrolysis, laser vaporization

• Eflornithine (Vaniqua)

• FDA approved

• After 6 mos of treatment, 60% of women improved with tx and 1/3 were considered a clinical success

• Applied 2x a day to affected facial areas

• Did not seem to have better results with prior hair removal techniques

• For use indefinitely

PCOS AND DESIRING PREGNANCY

• Addressed below along with infertility considerations

PCOS IN OLDER WOMEN

• Increased risk for • insulin resistance and METABOLIC SYNDROME

• Nonalcoholic fatty liver disease

• Sleep apnea and other obesity related disorders

• Type II DM (2-5 fold increase)

• Cardiovascular disease

• Endometrial cancer ( based on chronic anovulation, centripetal obesity, DM)

• Mood disturbances and depression

METABOLIC SYNDROME33% OF WOMEN WITH PCOS 25% OF ADOLESCENTS WITH PCOS

• Elevated blood pressure ( ≥ 130/85 )

• Increased waist circumference ( ≥ 35 in)

• Elevated fasting blood glucose levels ( ≥ 100 )

• Decreased HDL ( ≤ 50 )

• Elevated triglyceride level ( ≥ 150 )

TREATING THE OLDER WOMAN WITH PCOS

• No longer really having menstrual irregularities

• Instead- having irregular bleeding – low threshold for working up DUB, biopsy everyone over 35

• Hirsutism – as suggested in prior slide

• Acne - not typically a problem in this age group

• Metabolic Dysfunction – Most important !

• Healthy diet aimed at heart health, lowering cholesterol, lower in carbohydrates, etc

• Exercise, Exercise, Exercise

• Regular screening for lipid disorder, diabetes and cardiovascular disease

• Stop smoking

PCOS AND INFERTILITY

Obesity contributes substantially to reproductive and metabolic abnormalities

in women with PCOS

PCOS AND INFERTILITY

Weight loss can improve the fundamental aspects of the endocrine syndrome of PCOS by lowering circulating androgen levels and causing spontaneous resumption of menses

PCOS AND INFERTILITY

Reduction in body weight has been associated with improved pregnancy rates,

decreased hirsutism, lower glucose and lipid levels

PCOS AND DESIRING PREGNANCY

• Newest recommendations:

• BEFORE ANY INTERVENTION IS INITIATED, preconception counseling should emphasize the importance of lifestyle, esp weight reduction and exercise in overweight women, smoking cessation, reduced alcohol consumption

• Methods of ovulation induction • NO evidence-based schema to guide the initial and subsequent choices of ovulation

induction methods

OVULATION INDUCTION

• Clomiphene citrate remains first line treatment

• Risks include 10% risk of twins, pre term birth and hypertensive disorders

• 6 month live birth rates range from 20-40%

• 50% of all women who will conceive with clomid do so at the 50mg dose

• 20% conceive at the 100mg dose

• Dexamethasone added to clomid therapy can increase pregnancy rates in clomid-resistant women

• If clomiphene fails to result in pregnancy – second line intervention is either exogenous gonadotropins or laparoscopic ovarian surgery

OVULATION INDUCTION

• Femara • Not FDA approved

• Aromatase inhibitor

• Results are comparable to clomid

• Shorter half life compared to clomid

• Potentially higher implantation rates

• Lower multiple pregnancy rates

• Concerns over small studies showing possible fetal effects

• In obese women with PCOS (BMI >30) it had higher cumulative live birth rates compared to clomid

OVULATION INDUCTION

• Metformin

• Is not used alone in infertility

• Clomiphene is 3x more effective at achieving live birth compared with metformin

• MAY be an increase in pregnancy rates when used together (obese women)

• No known human teratogenic risk

• No solid evidence that its use early in pregnancy prevents pregnancy loss

J CLINICAL ENDOCRINOLOGY AND METABOLISM 2015

216 overweight- obese infertile women with PCOS underwent 4 mos of treatment and then Clomid

low dose ocps lifestyle modification ocps + lifestyle modification

caloric restriction

wt loss med

increased activity

ocps Lifestyle modification

Ocps + Lifestyle modification

% weight loss 1% 6.2% 6.4%

Ovulation rates cumulative

46% 60% 67%

Live birth rates 12% 26% 24%

J CLINICAL ENDOCRINOLOGY AND METABOLISM 2016

Patients with PCOS and low Vitamin D levels (<30 ng/mL) may be at risk for lower live birth rates and

successful ovulation

Goal is Vitamin D level > 40ng/mL

WHEN TO REFER TO SPECIALIST

When it doesn’t work

PCOS AND PREGNANCY

• Increased risk for gestational diabetes

• Increased risk for hypertensive disorders

• Increased risk of pre term birth

• Increased risk of large for gestational age babies

•Questions and Answers