Polycystic Ovary Syndrome HEATHER BURKS, MD OU PHYSICIANS REPRODUCTIVE MEDICINE SEPTEMBER 21, 2018

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1 Polycystic Ovary Syndrome HEATHER BURKS, MD OU PHYSICIANS REPRODUCTIVE MEDICINE SEPTEMBER 21, 2018

2 Learning Objectives At the conclusion of this lecture, learners should: 1) Know the various diagnostic criteria for polycystic ovary syndrome 2) Know the initial evaluation for a patient suspected to have polycystic ovary syndrome 3) Understand the long-term health implications of polycystic ovary syndrome 4) Understand key elements of the management of polycystic ovary syndrome

3 Polycystic Ovary Syndrome (PCOS) First described by Stein and Leventhal in 1935 Series of 7 patients with: Amenorrhea Hirsutism Enlarged, multi-cystic ovaries Am J Ob Gyn, 1935

4 Male pattern hair growth Coarse terminal hair

5 Male pattern hair growth Coarse terminal hair

6 PCOS: First series of 7 patients Treated with ovarian wedge resection All 7 resumed normal menses 2 of 7 became pregnant Stein, Leventhal. Am J Ob Gyn, 1935

9 PCOS - Pathophysiology Cysts Actually follicles Follicles arrested in development accumulate in the ovary PCOS women do not throw away their old follicles

10 Normal ovulation: Selection of dominant follicle

11 PCOS: Follicle arrest

12 Menstrual cycle changes: PCOS Normal PCOS

13 PCOS: Definition 3 different sets of criteria created by 3 different meetings National Institutes of Health 1990 Rotterdam ESHRE/ASRM Consensus 2003 Androgen Excess Society 2006

14 PCOS: Definition NIH major criteria (all 3 required): 1. Chronic anovulation (oligo- or amenorrhea) 2. Clinical and/or biochemical evidence of hyperandrogenism 3. Exclusion of other causes of anovulation and hyperandrogenism Zawadsky JK, Dunaif A., Blackwell Scientific 1992

15 PCOS: Definition NIH minor criteria: Insulin resistance Perimenarchal onset of hirsutism and obesity Elevated LH/FSH ratio Ultrasonographic evidence of polycystic ovaries Zawadsky JK, Dunaif A., Blackwell Scientific 1992

16 PCOS: Definition R = required; NR = not required ACOG Practice Bulletin: PCOS 2018

17 So what IS PCOS?? A heterogeneous disorder of unclear etiology An important cause of menstrual irregularity and androgen excess in women

18 Classic PCOS When fully expressed, manifestations include: Ovulatory dysfunction Androgen excess Polycystic Ovaries Obesity

19 PCOS: Prevalence Affects 6-8% of reproductive age women Most common cause of female infertility in the United States Onset is likely pre-pubertal but difficult to detect until late adolescence

20 Diagnostic tests Anovulation: Menstrual history < 9 menses/year or > 3 consecutive months without menses Hyperandrogenism: Physical exam: Hirsutism, acne Serum androgen levels: Testosterone (T), Free T, DHEA-S Pelvic Ultrasound DIAGNOSIS OF EXCLUSION

21 Pitfalls: ultrasound alone is not enough Normal ovary Polycystic ovary Controversy is due to high prevalence (up to 68%) of PCOM in normal young women

22 Differential diagnosis Androgen secreting tumor Exogenous androgens Cushing syndrome Nonclassical congenital adrenal hyperplasia Acromegaly Genetic defects in insulin action Primary hypothalamic amenorrhea Primary ovarian failure Thyroid disease Prolactin disorders

23 Diagnostic tests of exclusion Pregnancy: HCG Congenital Adrenal Hyperplasia: 17-OH progesterone In high-risk populations Hyperprolactinemia: Prolactin Thyroid abnormalities: TSH Androgen secreting tumor: DHEAS, Testosterone Suspected if T > 200 ng/dl or DHEAS > 700 mcg/dl + Cushings syndrome: 24 hour urinary cortisol

24 Risk factors for PCOS in adolescents Low birth weight: < 2500 g Premature pubarche: Onset before 8yo Family history (1 st degree relative) Obesity

25 Health implications

26 PCOS: Clinical Manifestations Sam & Dunaif Trends Endocrinol Metab 2003.

27 Insulin sensitivity and obesity Insulin resistance is a feature of PCOS in obese and non-obese women

28 Effects of Hyperinsulinemia Activation of insulin receptor (IGF) in the ovary: augmented thecal androgen response to LH Suppression of hepatic SHBG production: increased free androgen proportion Direct stimulation of LH secretion by insulin Sensitization of LH secreting cells to GnRH

29 Insulin Resistance IR itself is not enough to cause PCOS Only about 25% of reproductive-aged women with type 2 diabetes have PCOS Screening for IR is indicated in patients with PCOS

30 PCOS and metabolic syndrome (MBS) Associated with significant risk for early cardiovascular disease Criteria for diagnosis (3 of 5): Abdominal obesity > 88 cm Triglycerides > 150 mg/dl HDL-C < 50 mg/dl Blood pressure > 130/>85 mmhg OGTT: mg/dl and/or mg/dl

31 Endometrial hyperplasia or malignancy Without regular ovulations: Endometrium is exposed to estrogen from the ovaries and adipose tissue No or infrequent exposure to progesterone Over time this can lead to endometrial hyperplasia or even malignancy

32 Recommended workup

33 Physical examination Blood pressure Height/weight for BMI Waist circumference Signs of hyperandrogenism Acne, hirsutism, alopecia Signs of insulin resistance Acanthosis nigricans

34 Laboratory evaluation Document hyperandrogenemia: testosterone or free T Exclude other causes TSH Prolactin 17-hydroxyprogesterone Screen for other problems based on physical exam (Cushing s, acromegaly)

35 Additional evaluation Ultrasound examination FSH/LH levels 24-hour urinary free cortisol or overnight dexamethasone suppression test if Cushing syndrome suspected IGF-1 if acromegaly supsected

36 Screening for long term health consequences 2 hour oral glucose tolerance test or Hemoglobin A1C Fasting lipid profile Blood pressure Endometrial biopsy

37 Management of PCOS

38 Symptom-dependent treatment Infertility Skin manifestations, hirsutism Dysfunctional uterine bleeding, endometrial cancer prevention Obesity, diabetes prevention

39 Infertility treatment Ovulation induction WEIGHT LOSS: as little as 5% can resume ovulation Clomiphene citrate Approximately 50-80% ovulate with clomid alone Aromatase inhibitors Letrozole is now considered FIRST LINE by ACOG but remains an off-label use Injectable gonadotropins Laparoscopic ovarian drilling Insulin-lowering medications - Metformin

40 Insulin sensitizers in PCOS In women with PCOS: Improves menstrual cyclicity, restores spontaneous ovulation (up to 30% ovulate with metformin alone) Improves symptoms of hyperandrogenism May improve body composition (BMI, WHR) and lipid profile

41 Hyperandrogenism Symptoms Increased terminal hair growth Acne Excess androgen production comes from the ovary Increased theca cell volume Increased expression of LH receptors on theca cells Exaggerated androgen production occurs when LH binds to receptors on the theca cells of the ovary

42 Skin manifestations, hirsutism treatment Oral contraceptives Anti-androgens Spironolactone Flutamide Finasteride Topical eflornithine

43 Oral contraceptives Currently considered first line therapy for those not currently desiring fertility Use low dose estrogen (20-30 mcg ethinyl estradiol) and non-androgenic progestin (e.g. desogestrel or drospirenone)

44 Oral contraceptives Increases SHBG production in the liver Decreases bio-available androgen Decreases hirsutism, acne Restores regular menstrual cycles if taken cyclically Provides effective contraception

45 Anti-androgens Effectively reduces biochemical and clinical hyperandrogenism May be more effective in treating hirsutism than metformin 1 Improves menstrual cyclicity 2 No improvement in metabolic abnormalities 2 1 Ganie et al. JCEM Zulian et al. J Endocrinol Investig 2005

46 Dysfunctional uterus bleeding Due to anovulation, which causes unopposed estrogen exposure Endometrial biopsy!! Rule out hyperplasia/malignancy Combat with progestins Oral contraceptives Progestin only therapy Oral (cyclic or continuous) Intramuscular Intrauterine device Implantable contraception

47 Obesity, diabetes prevention Obesity Lifestyle management Diet and exercise: Shown to effectively prevent diabetes in high risk groups* Effects: Testosterone Insulin levels SHBG Metformin

48 Lifestyle intervention and weight loss Importance is emphasized, but difficult to achieve Current recommendation is combination of lifestyle modification with pharmacologic therapy Refer for bariatric surgery evaluation if applicable and patient is amenable Would need to wait usually months to try for pregnancy

49 Summary: PCOS Initial evaluation: H&P Total T, DHEA-S, 17-hydroxyprogesterone, Prolactin, TSH, LH, FSH Pelvic ultrasound

50 Summary: PCOS Periodic screening once diagnosis is established: 2 hour oral glucose tolerance test Lipid profile Blood pressure + Endometrial biopsy

51 Summary: PCOS Treatment: Depends on symptoms and goals Encourage healthy diet and exercise Ovulation induction with clomid if pregnancy is desired Oral contraceptive pills if pregnancy is not desired Obese and IR patients: Metformin Marked hirsutism refractory to OCPs: Consider spironolactone Lifelong therapy may be necessary

Polycystic Ovary Syndrome (PCOS):

Polycystic Ovary Syndrome (PCOS): Current diagnosis and treatment Anatte E. Karmon, MD Disclosures- Anatte Karmon, MD No financial relationships to disclose 2 Objectives At the end of this presentation,