Polycystic Ovarian Syndrome Refresher Course for the Family Physician Lauren Coyne, MD Clinical Assistant Professor Department of Obstetrics and Gynecology

PCOS - Outline Background Incidence and Etiology Clinical manifestations Differential Diagnosis Clinical Considerations

Background Endocrinopathy characterized by Future metabolic sequelae Hyperandrogenism Ovulatory dysfunction Polycystic ovaries Future metabolic sequelae Cardiovascular disease Diabetes

Definition Signs/Symptom NIH Criteria (Both required) Rotterdam Criteria (2 of 3 required) Androgen Excess Society Hyperandrogenism R NR Oligomenorrhea/ Amenorrhea Polycystic ovaries by ultrasound -

Definition Signs/Symptom NIH Criteria (Both required) Rotterdam Criteria (2 of 3 required) Androgen Excess Society Hyperandrogenism R NR Oligomenorrhea/ Amenorrhea Polycystic ovaries by ultrasound -

Hyperandrogenism Clinical findings Acne Hirsutism Androgenic alopecia Acanthosis nigracans

Hyperandrogenism Laboratory findings Total testosterone, SHBG Bioavailable and free testosterone Exclude other causes of hyperandrogenemia TSH Prolactin 17-hydroxyprogesterone 17-oh p to rule out nonclassical congenital adrenal hyperplasia due to 21 hydrozylase deficincy

Oligomenorrhea/Amenorrhea Oligomenorrhea – Bleeding that occurs less frequently than every 35 days Amenorrhea – Absence of menses for more than 3 cycles

Polycystic Ovaries Present in one or both ovaries 12 or more follicles measuring 2-9mm in diameter Increase ovarian volume >10cc

Transvaginal sonography displays multiple small hypoechoic cysts Transvaginal sonography displays multiple small hypoechoic cysts. (Used with permission from Dr. Elysia Moschos.) Source: Polycystic Ovarian Syndrome and Hyperandrogenism, Williams Gynecology, 3e Citation: Hoffman BL, Schorge JO, Bradshaw KD, Halvorson LM, Schaffer JI, Corton MM. Williams Gynecology, 3e; 2016 Available at: http://accessmedicine.mhmedical.com/content.aspx?bookid=1758&sectionid=118170024 Accessed: February 14, 2017 Copyright © 2017 McGraw-Hill Education. All rights reserved

Exaggerated PCOS Ovarian Hyperthecosis HAIRAN Syndrome Severe form of PCOS Nest of luetinized theca cells throughout ovarian stroma Severe hyperandrogenism and frank virilization Greater degree of insulin resistance and acanthosis nigricans HAIRAN Syndrome Hyperandrogenic-insulin resistant acanthosis nigracans Severe insulin resistance PCOS variant vs genetic syndrome Virilzation – Clitoromegaly, temporal balding, voice deepeing

Incidence/Etiology Affects 4-12% of female population Equally affects all races and nationalities Multifactorial and polygenic basis is suspected Obesity may amplify the effects Symptoms of androgens excess may affect different races/nationalities differently Obesity is not a diagnostic criterion and 20% of patient are not obese

Pathophysiology Increased LH level Increased degree of insulin resistance and compensatory hyperinsulinemia Both insulin and LH stimulate androgen production by ovarian theca cells Decreased levels of sex hormone binding globulin Less circulating androgen is bound and more is therefore free to bind end organ receptors (more can be converted to estrone by aromatase in adipose) Total testosterone can be in normal range, free testosterone levels elevated (clinically hyperandrogenic) Anovulation Altered GnRH pulsatility, inappropriate gonoadotropin secretion, insulin resistance (why metformin may benefit)

Consequences Short term Long Tern Obesity Infertility Depression Sleep apnea Irregular menses Abnormal lipid levels NASH Hisutism/Acne/ Alopcia Insulin resistance/acanthosis nigracans Long Tern Diabetes mellitus (2-5 fold increase) Endometrial cancer Cardiovascular disease

Clinical Manifestations Menstrual dysfunction Amenorrhea, oligomenorrhea, episodic menorrhagia (can result in iron deficiency anemia) Hyperandrogenism Hirsutism, acne, androgenic hirsutism Infertility Increased risk for ovarian hyperstimulation and multifetal pregnancy Pregnancy complications Insulin resistance Obstructive sleep apnea Metabolic syndrome/cardiovascular disease

Metabolic Syndrome Two or more criteria present Elevated blood pressure Greater or equal to 130/85 Increased waist circumference >35 inches Elevated fasting blood glucose >100 mg/dL Reduced HDL Less than or equal to 50 mg/dL Elevated triglyceride level Greater than or equal to 150 mg/dL

Differential Diagnosis Androgen secreting tumor Exogenous androgens Cushing syndrome Screen only if coexisting signs of Cushing (moon facies, buffalo hump, abdominal striae, centripetal fat distribution, htn) Nonclassical congenital adrenal hyperplasia Acromegaly Genetic defects in insulin action Primary hypothalamic amenorrhea Primary ovarian failure Thyroid disease Prolactin disorders

Non-classical CAH Late onsent Adult presentation of anovulation and hirsutism Genetic defect in 21 hydroxylase (CYP21) Ashkenazi Jews, Hispanics, Yugoslavs, Native American Inuits in Alasaka, Italians If in high risk groups screen with morning, fasting 17-hydrocyprogesterone level If elevated, ACTH stimulation test (adrenocorticotropic)

Benefit of Weight loss? Lower circulating androgen levels Resumption of menses Improved pregnancy rates Decreased hirsutism Better glucose and lipid levels See normalization of reproductive and metabolic abnormalities with as little as 5% loss of initial weight Pharmacologic/surgical weight loss modalities may be beneficial Unknown if helpful in normal weight patients

Type II Diabetes Screening With diagnosis of PCOS Fasting glucose level and 2 hour glucose challenge after 75g glucose load Insulin level testing is of little utility

Cardiovascular disease screening Dyslipidemia present in 70% of PCOS patients Early onset of cardiovascular disease is suspected but not proven Premenopausal PCOS patients have increased prevalence of subclinical atherosclerosis Risk assess with BMI, fasting lipid and lipoprotein levels, and metabolic syndrome risk factors Screen periodically Regular exercise and weight control are best methods to reduce CV risk

How treat menstrual disorders? Combination hormonal contraceptives Suppress LH, suppress ovarian androgen secretion, increase SHBG “Most effective” combination of hormonal contraception unknown Progestin Cyclic oral progesterone or progesterone containing IUD decrease endometrial cancer risk Optimal regimen unknown Insulin-sensitizing agents

How treat menstrual disorders? Insulin – sensitizing agents Metformin used most commonly Tend to decrease weight Improving insulin sensitivity is associated with a decrease in circulating androgen levels, improved ovulation rate, and improved glucose tolerance Ovulation rates likely improve – discuss contraception! No antidiabetic agent is FDA approved for PCOS related menstrual dysfunction Unknown endometrial protective effects

Risk reducing medical therapy – Pregnancy not desired Lifestyle modification Increase exercise Dietary changes – calorie restriction (no benefit of any other dietary modifications) Insulin-sensitizing agents - Metformin Beneficial if impaired glucose tolerance or metabolic syndrome is present Used in conjunction with lifestyle changes Commonly dosed 1500 – 2000 mg daily in divided doses

Risk reducing medical therapy – Pregnancy not desired Statins Increasing evidence of benefit of cardiovascular and endocrine benefit with PCOS Long-term effects in preventing CV disease in young women with PCOS is unknown Combined hormonal contraceptives and progestins Dose dependent effects on insulin sensitivity of cOCP Low-dose hormonal contraceptive is recommended See increase in triglyceride and HDL Consider additional cardiovascular risk factors such as hypertension, obesity, clotting history, cigarette use Effect of progestins alone on metabolic risk factors vary and is not well understood

Ovulation Induction Associated with an increase in multiple birth 10% increased risk of twin gestation with use of clomiphene Greater even with exogenous gonadotropins May be higher with PCOS patients Related obstetric and neonatal risks Preterm birth Hypertensive disorders Gestational diabetes Discordant growth Fetal malpresentation

Ovulation Induction Clomiphene Citrate Gonadotropins First line Live birth rates 20-40% 50% will conceive at starting dose (50mg) 20% will conceive at 100mg dose Adding dexamethasone has been found to increase both rates of ovulation and pregnancy Gonadotropins Option if clomid fails Low dose is optimal (higher rate of ovulation and monofollicular development with lower risk of ovarian hyperstim)

Ovulation Induction Ovarian drilling Aromatase inhibitors (Letrozole) 2nd line option Beniefits may be temporary and medical induction may still be needed Lower rate of multiples Aromatase inhibitors (Letrozole) Not FDA approved Results similar to Clomid May have lower multiple rates, higher implantation rates Metformin May increase pregnancy rates when used with clomid No increase in pregnancy loss

Treating hirsutism Combined hormonal contraceptives Not FDA approved Improvement has been noted No optimal pill Effects may be additive with usage of spironolactone

Treating hirsutism Antiandrogens Teratogenic, best when combined with OCP Spironolactone Inhibits ovarian and adrenal steroidogenesis Competes at androgen receptors in hair follicles Inhibits 5 alpha reductase Dose 25-100mg twice daily May take 6 months for maximum effect May see increased menstrual frequency Flutamide Androgen receptor agonist Optimal use with lifestyle changes and metformin Finasteride Well tolerated

Treating hirsutism Insulin-sensitizing agents Elfornithin Additional data needed Elfornithin Ornithine decarboxylase inhibitor FDA approved Cream applied twice daily

Cosmetic management of hirsutism Mechanical removal No evidence to support that shaving increases hair follicle number or size Avoid folliculitis Laser Dark hair, light skin are best candidates Repeat treatments may be necessary

Citations Hoffman BL, Schorge JO, Bradshaw KD, Halvorson LM, Schaffer JI, Corton MM.Polycystic Ovarian Syndrome and Hyperandrogenism. In: Hoffman BL, Schorge JO, Bradshaw KD, Halvorson LM, Schaffer JI, Corton MM. eds. Williams Gynecology, 3e. New York, NY: McGraw-Hill; 2016. http://accessmedicine.mhmedical.com/content.aspx?bookid=1758&sectionid=118170024. Accessed February 15, 2017. PB 108 PB 128