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1 Polycystic Ovarian Syndrome (PCOS) Ma qianhong Ob/Gyn Department LOGO

2 Contents Epidemiology and Definition Pathophysiology, Endocrinological Features Diagnostic Criteria Treatment Prognosis

3 Introduction Definition and epidermiology: polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 5-10% of reproductive-age women and characterized by hyperandrogenemia,polycystic ovary by ultrasound and irregular menses. It also associated with insulin resistance, pancreatic β-cell dysfunction, obesity etc. PCOS was also called Stein-Leventhal syndrome because these two scientists first described all the signs of this disease. It confers a substantially increased risk for metabolic syndrome and type 2 diabetes mellitus(t2d). These reproductive and metabolic abnormalities are heritable, and male as well as female first-degree relatives are at risk for metabolic syndrome and T2D.

4 Pathophysiology and Endocrine features Endocrine features (dysfunction): Androgen excess Excessive estrone Hypersecretion/elevation of luteining hormone, maybe increased LH/FSH Insulin resistance(ir) or hyperinsulinemia

5 Pathophysiology and Endocrine features Pathophysiology Androgen and estrone excess 1 Hypothalamus-pituitory-ovarian axis (HPO axis) disorder: pulse amplitude and freqiuency of LH secretion in pituitary, lack of negative feedback ( serum progesterone?) 2 Ovarian production: LH results in theca hyperplasia, resulting in testosterone(t), androstenedione(a4), dehydroepitestosterone(dhea), dehydroepitestosterone sulfate(dhea-s), 17-hydroxyprogesterone(17-OHP) and estrone(e1), ovarian estradiol (E2) production is unchanged. 3 Adrenal is a secondary source of elevated serum androgen. 4 sex hormone-binding globulin (SHBG) in blood leads to free androgen and estrogen, lowering follicle-stimulating hormone (FSH) relative to LH

6 Pathophysiology and Endocrine features Pathophysiology IR / Hyperinsulinemia 1 IR/ Hyperinsulinemia leads to SHBG in liver, IGF-binding protein (IGFBP)-Ⅰand free androgen. 2 Total serum IGF-Ⅰlevels are normal in PCOS, but IGFBP-Ⅰ concentrations can lead to free IGF-I. 3 IGF-Ⅰand -Ⅱ LH stimulation of androgens in theca cells. 4 Insulin may also androgen production directly or may LH secretion from the pituitary. 5 Waist-hip ratio>0.85(central obesity) is significantly related to insulin sensitivity, but body mass index (BMI) is not.

7 Pathophysiology and Endocrine features Pathophysiology Organ dysfunction: Ovary 1 LH levels stimulate theca cells, thickening the ovarian stroma, and local androgen production within the ovary, which in turn prevents follicular maturation. 2 Low-normal circulating FSH levels maintain a continuous stimulation for follicular growth. High levels of local androgens may inhibit maturation of follicles. 3 Atretic follicles continuously being replaced by new follicles of limited growth potential, none of which matures to become a dominant, ovulatory follicle 4 High levels of local androgens may inhibit maturation of follicles.

8 Pathophysiology and Endocrine features Pathophysiology Organ dysfunction: pituitary 1 Androgen excess may cause LH excess by counteracting the LH-suppressive effect of P4.

9 Pathophysiology and Endocrine features Pathophysiology Organ dysfunction: endometrium No ovulation no progesterone production proferative endometrium risk of endometrial hyperplasia and/or cancer Organ dysfunction: adrenal gland 50% of patients with PCOS also have a characteristic type of adrenal dysfunction that consists of moderately excess response of 17-ketosteroids (DHEA, DHEA-S) to adrenocorticotropic hormone(acth), possibly due to activity of p450c17α(aromatase).

10 Diagnostic criteria Rotterdam Criteria (2003 ESHRE): 2 out of 3 1 Oligo- and /or anovulation 2 Clinical and /or biochemical signs of hyperandrogenis m 3 Polycystic ovaries by ultrasound ( 12 follicles[2-9mm diameter] in each ovary) Exclusion of other etiologies( e.g., nonclassic congenital adrenal hyperplasia, hyperprolactinemia, Cushing s syndrome, and androgen-secreting tumors)

11 Clinical signs and symptoms Menstrual dysfunction: onset at menarche: oligo/ amenorrhea Infertility: because of ovulation dysfunction Hirsutism: Onset usually with puberty, gradual onset over months to years Dark, coarse hairs in androgen-dependent locations, such as in vulva Associated with hyperandrogenemia (classic PCOS) and idiopathic increased end organ sensitivity Obesity: Obesity occurs in 35-65% of women with PCOS(>80% are obese before puberty) Androgens convert to E1 in peripheral fat and can contribute to endometrial hyperplasia. Fat contributes to insulin insensitivity.

12 Clinical signs and symptoms Variable other signs and symptoms Acne: no known correlation between the severity of acne and plasma-free T. Acanthosis nigricans: usually seen with significant insulin resistance; called the hyperandrogenism, insulin resistance-acanthosis nigricans (HAIR-AN) syndrome. Dermal hyperkeratosis and papillomatosis presenting as a brown or gray, velvety, occasionally verrucous, hyper-pigmented area over the vulva (most common), axillae, groin, umbilicus, and submammary areas. IR: ~30%, or non-insulin-dependent diabetes millitus(niddm,~8%) Skin tags Polycystic-appearing ovaries: present in 30% of population, not necessarily a prerequisite for diagnosis.

13 Assistant examination Basal body temperature: usually single-phase Pelvic ultrasound: enlarged ovarian volume, polycystic ovary (uni-and/ or bilateral, 12 follicles [2~9mm in diameter], like necklace) Endometrium(curettage D&C): proliferative change, no secretive phase Laparoscopy: enlarged ovarian volume with thickening capsule, more follicles, no ovulation sign, no corpus luteum

14 Endocrine features Testosterone slightly, DHEA, DHEA-S normal or slightly. Serum FSH and LH: may be LH/FSH 2~3, no LH surge because no ovulation. Serum estrogen: E1, E2 or normal (early follicle phase) Serum prolactin: normal or slightly 24-hour urinary cortisol: slightly Oral glucose tolerance test and insulin releasing test: one or more items are abnormal, esp in patients with central obesity hyperlipidemia

15 Differential diagnosis Virilizing ovarian tumor Serum T significantly Tumor be showed by ultrasound, CT or MRI. Adrenal tumor Serum DHEA-S (twice or more than normal) Tumor be showed by ultrasound, CT or MRI. Adrenal hyperplasia ACTH stimulating test + Serum DHEA-S (twice or more than normal) Dexamethasone inhibing rate 0.7 Theca cell hyperplasia Severe hirsutism, no PCO signs on ovary Serum T significantly, DHEA-S normal

16 Treatment Goals Prevent endometrial hyperplasia / cancer Restore normal menstruation Resolution of anovulation / infertility Improve hirsuitism and acne

17 Treatment General treatment: weight reduction low calorie diet, increasing physical activity, insulin sensitizing drugs benefits: As little as 5~7% of body weight reduction can reduce hyperandrogenism, improve insulin sensitivity, and restore spontaneous ovulation and fertility in 75% of women with PCOS

18 Treatment Drug treatment: regulating menstruation 1 oral contraceptives (OC) Method of action: SHBG, suppression of LH, inhibition of 5 α -reductase and androgen receptor binding, inhibition of endometrial hyperplasia Duration : 3-6 months for one treatment cycle Greatest efficacy against acne 2 progestins Give progestins in the latter-half cycles Protecting endometrium, suppression of LH

19 Treatment Drug treatment: antiandrogens 1 corticosteroid: inhibiting the secretion of DHEA-S 2 cyproterone acetate Androgen receptor antagonist, decreases 5 α -reductase activity, impairs androgen synthesis 3 spironolactone: Aldosterone antagonist inhibits steroidogenic enzymes and binds the DHT receptor at the hair follicles Can cause irregular uterine bleeding (combining with OCs can avoid this side effect)

20 Treatment Drug treatment: improving insulin sensitivity 1 metaformin hepatic gluconeogenesis, intestinal glucose absoption, peripheral glucose uptake and utilization; no change in insulin secretion but fasting insulin levels, LH, free T 50% have improved menstrual function 2 other drugs: rosiglitazone and pioglitazone Use under the guidance of endocrinological doctors

21 Treatment Drug treatment: ovulation induction based on improving lifestyle, regulating menstruation, improving insulin sensitivity, decreasing serum androgen First-line drugs: 1 clomiphene citrate(cc) 2 aromatase inhibitor Second-line drugs: 1 follicle-stimulating hormone (FSH) 2 luteinizing hormone (LH) #need ovulation monitoring by ultrosound

22 Treatment Surgery: laparoscopic ovarian drilling (LOD) Benefit: restores spontaneous ovulation in ~50% of CC resistant hyperandrogenic patients Side effects: postoperative adhension formation, general endotrachael anesthesia, latrogenic diminished ovarian reserve

23 Treatment 3 rd line treatment method: IVF-ET Repeated failure of above treatment, some abnormal index of hasband

24 LOGO

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

Polycystic Ovary Syndrome HEATHER BURKS, MD OU PHYSICIANS REPRODUCTIVE MEDICINE SEPTEMBER 21, 2018 Learning Objectives At the conclusion of this lecture, learners should: 1) Know the various diagnostic