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 Heritability of PCOS estimated at over 70% Treatment is symptom based Poses greater risk for diabetes and cardiovascular disease (usually hyperinsulinism/obesity)
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 obese) (Important to keep in mind 20% patients with PCOS are NOT 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 2 nd hour < 140 normal 2 nd hour 140-199 impaired 2 nd 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 2 nd 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 BARBIERI APRIL 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 1 st 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 SYNDROME 33% 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