The Pharmacology of PCOS

The Pharmacology of PCOS G. Wright Bates, Jr., M.D. Director Reproductive Endocrinology & Infertility University of Alabama at Birmingham Objectives Review the diagnosis of PCOS Highlight lifestyle modifications Discuss the Pharmacology of PCOS treatment options including: Selective Estrogen Receptor Modulators Oral antihyperglycemics Aromatase Inhibitors Oral Contraceptives Glucocorticoids Causes of Infertility Diagnostic Evaluation 15% 1% 5% 35% Tubal Male Unknown Others Essential TSH Prolactin Semen Analysis Progestin challenge and FSH if amenorrhea Anatomy (HSG) Semen Analysis Recommend Day 3 FSH or clomid challenge test, AMH? Hysterosalpingogram Consider Androgens: Testosterone 17-OH progesterone, DHEAS 35% Methods Used to Assess REGULAR CYCLE / Moliminal Symptoms Basal body temperature chart Midluteal phase serum progesterone (> 3 ng/ml, ideally greater than 1) Luteal phase endometrial biopsy Detection of LH in the urine Cervical Mucous Ultrasound observation of follicular development and/or rupture Electronic monitoring

Urinary LH Testing Begin testing based on shortest cycle in last 6 months 28 day cycle begin day 1 12 21 days cycle begin day 5-7 35+ day cycle begin day 16-18 Delay testing until 3 days after CC Optimum time for testing is late afternoon (4: pm) Clearblue Easy Fertility Monitor RCT of 653 women trying to conceive Most effective in women trying to conceive <6 months 25 2 15 % 1 5 Cycle 1 Cycle 2 Combo Robinson JE et al. Fertil Steril 27;87:329 CB Easy Control.4.35.3.25.2.15.1.5 Timing of Intercourse and Probability of Conception 221 patients, a total of 625 normal menstrual -6-5 -4-3 -2-11 +1 Days Wilcox AJ, et al. N Engl J Med 1995;333:517 Pregnancy and Female Age Dunson DB, et al, Hum Reprod 22;1399 Ovulatory Dysfunction Ovulatory disturbances (25% of couples with infertility) PCO most common etiology of ovulatory dysfunction (7%) PCO (6% of reproductive age women) ACOG Practice Bulletin, 22:34 and 41 World Health Organization Classification of Anovulation WHO I-I anovulation with low gonadotropin levels Low endogenous estrogen, usually do not bleed with a progestin challenge Usually need gonadotropin to ovulate WHO II- anovulation with normal gonadotropins Have significant endogenous estrogen, progestin challenge bleeding WHO III- anovulation with elevated gonadotropins Ovarian Failure- Do not respond to fertility medications World Health Organization Scientific Group. Report No. 514. 1976

PCOS Definition 23 ESHRE- ASRM Consensus (requires 2 of 3) Irregular or Absent Clinical and/or biochemical signs of androgen excess At least one ovary with 12 or more follicles (2 9mm) and increased ovarian volume (at least 1 ml) Rotterdam Workshop, Hum Reprod, 24;19:41 Thyroid Pituitary PCOS: CONSIDER other endocrinopathies Androgen Excess Total and free T, DHEAS Adrenal CAH (17-OH progesterone) Cushing s s (24 hr urine cortisol) PCOS Features Menstrual irregularities (8%) amenorrhea, oligomenorrhea (most common), dysfunctional uterine bleeding Polycystic Ovaries (75-9%) Hyperandrogenism (7%) Hirsutism (6-75%) Obesity- (65-75%) Insulin resistance (5-7%) Rare- acanthosis nigricans,, male-pattern balding Azziz R, et al. Fertil Steril 29;91:456 Obesity and Reproduction Oligoovulation and infertility Increased risks Miscarriage Congenital anomalies Pregnancy complication Balen AH, Hum Fertil 27 1(4):195 Treatment of Obese PCOS Patients with Anovulation Weight loss remains first line therapy Improves hormonal profiles Lowers androgens Lower glucose and lipid levels Improves spontaneous resumption of menses and pregnancy Improves response to ovulation induction PCOS and Exercise 3 month exercise regimen (92 min / week) 5% reduction in BMI and improved glucose dynamics 6% had return of menstrual cycle Vigorito C, JCEM 27;92:1379 24 week exercise regimen or high protein diet Higher rates of menses and ovulation in the exercise group Improved insulin resistance and androgen levels Palomba S, Hum Reprod 28;23:642

Lifestyle Recommendations Stop smoking/limit alcohol and caffeine Weight Reduction Low caloric diet, 1-12 12 kcal/day 1% body weight reduction in 6 months Exercise Regular physical exercise Minimum 3 min moderate intensity 3 times/week Medical treatment/bariatric Surgery Clomiphene Citrate Approved for clinical use in 1967 Predominately an estrogen antagonist Utilizes normal endocrine pathway Indicated for: Anovulatory women Normal thyroid and prolactin Evidence of endogenous estrogen Unexplained infertility Luteal phase defect Fertil Steril 28;9:21 Clomiphene Citrate Begin with lowest dose (5mg) 5 days Take days 5 9 of cycle (Rule of 5s) May begin treatment earlier, day 2-42 Increase dose if anovulatory,, up to 15mg day Maintain dose if evidence of ovulation Minimal or intensive monitoring appropriate Clomiphene Citrate rates approximately 75% Cycle fecundity is approximately 15% in anovulatory women who respond to treatment 3 5% cumulative pregnancy rate Most conceptions occur within the first six ovulatory 88% conceive at 15 mg or less (52% at 5 mg) Imani B, JCEM 1999;84:1617 Fertil Steril 22; 77:91 Clomid / IUI** Clomid / IUI 12% 8% 4% % 2351 (983) 947 (422) 614 (265) 165 (81) 12 (55) <35 35-37 38-4 41-42 >42 Maternal Age (y) **(intent to treat analysis) Dovey S, Fertil Steril, 28;9:2281 Dovey S, Fertil Steril, 28;9:2281

Clomiphene Citrate Side Effects Incidence of multiple gestation is between 5%-1% Vasomotor symptoms up to 2% Mood swings, breast tenderness, headaches, nausea 2 5% Visual disturbance <2% Rare Ovarian Hyperstimulation Syndrome No increase in congenital anomalies, birth defects, ovarian or breast cancer Induction Monitoring CC 5-15mg cycle days 5-95 First ultrasound day 1-12 12 hcg 1, IU intramuscularly when lead follicle > 2 mm IUI 36 hours after hcg ASRM, Committee Opinion, June 23 35 3 25 2 15 1 5 HCG trigger vs. LH monitoring for CC/IUI 1 2 3 Lewis V, Fertil Steril 26: 85; 41 hcg LH surge RCT of 15 ovulatory infertile women LH surge group underwent IUI later Cancellation rates higher in LH group (31 vs 11%) biguanide antihyperglycemic agent approved for the management of type 2 diabetes decrease blood glucose levels suppress hepatic glucose output decrease intestinal absorption of glucose enhance peripheral glucose uptake and utilization Target dose 15-255 mg Barbieri RL. Obstet Gynecol 23;11:785 Most common side effects are diarrhea, nausea or vomiting, flatulence, indigestion, and abdominal discomfort 5% discontinuation rate due to side effects Barbieri RL. Obstet Gynecol 23;11:785. XL formulation has lower GI side effects Blonde L, et al. Curr Med Res Opin 24;2:565 Consider liquid formulation - Riomet Excreted by the kidney Rare instance of lactic acidosis, increased in patients with renal insufficiency (creatinine( > 1.4 mg/dl dl) ) of liver dysfunction. Should be temporarily suspended prior to surgery or radiologic procedures that involve IV administration of iodinated contrast Barbieri RL. Obstet Gynecol 23;11:785 No cases of lactic acidosis in 48, patient years of metformin use Cochrane Systemic Review, November 25.

Effects In Women With PCOS For Menstrual Irregularity and Anovulation Decreases insulin secretion levels & LH Increased SHBG Decreases androgens Total T 38% Free T 58% Androstenedione 58% Nestler J. N Engl J Med 1996;335:617 Hass DA. Fertil Steril 23;79:469. Maciel GA, Fertil Steril 24;81(2):355 Small reduction in BMI Some women will have spontaneous ovulation and pregnancy Other long-term studies have found that women with PCOS and irregular menses given metformin alone for six months, typically 5% resumed regular menses In adolescents with PCOS treated with metformin,, most individuals required 4-64 6 months before ovulatory menses occurred Barbieri RL. Obstet Gynecol 23;11:785. in Obese Women with Clomid in Nonobese Women 61 women mean BMI = 32.3 Randomized to 34 days of metformin 5 mg tid or placebo day 35 ovulation induction with CC 5mg days 5-9, 5 metformin or placebo continued ovulation by serum progesterone (>8ng) 9 8 7 6 5 4 3 2 1 Pregnancy Nestler JE, et al. N Engl J Med 1998; 38:1876 Placebo Placebo /CC /CC 1 with PCOS and infertility BMI < 3 Randomized placebo and metformin 85 mg bid or CC 15 mg (days 3 7) and placebo 1 9 8 7 6 5 4 3 2 1 446 evaluated % Palomba S, et al. JCEM, 25;9:468 SAB CC/ Placebo Placebo/ 1 9 8 7 6 5 4 3 2 1 with Clomid in Nonobese women Preg Cycle Total Preg Palomba S, et al. JCEM, 25;9:468 Nml Menses CC/ Placebo Placebo/ vs. Clomid or Combination RCT of 626 women with PCOS Oligo or anovulation Elevated androgens Randomized to, Clomiphene Citrate or combination for 6 stopped with positive BhCG Significantly better pregnancy rate with CC or combination No significant difference in SAB rate Higher multiple rate with CC (6%) Legro RS, et al. N Engl J Med 27;356:551

% vs. Clomid or Combination 3 25 2 15 CC 1 Combo 5 Pregnancy SAB Metabolic Syndrome Abdominal obesity (waist circumference) Men>12 cm (>4 in) Women>88 cm (>35 in) Triglycerides 15 mg/dl HDL cholesterol Men<4 mg/dl Women<5 mg/dl Blood pressure >13/ 85 mm Hg Fasting glucose >11 mg/dl Legro RS, et al. N Engl J Med 27;356:551 National Cholesterol Education Program Adult Treatment Panel III vs. Clomid April 28 Meta-Analysis Review of 17 studies, 1639 women Compared metformin vs. placebo metformin vs. clomiphene citrate Suggested metformin increased ovulation metformin and clomid increased ovulation and pregnancy rate and Metabolic Syndrome 71 women 35 Mean age 31.2 3 Mean follow up 31 25 months 2 Decline in BMI, DBP 15 Increased HDL 1 5 SBP, TG, fasting glucose favorable trend Metabolic Syndrome Baseline After Creanga, et.al, and Polycystic Ovary Syndrome. Obstet Gynecol April 28 Cheang KI, World Congress on the Insulin Resistance Syndrome 27. vs. Weight Loss RCT of 143 subjects (BMI> 3) Diet + 85 mg Bid vs placebo reduced androgens and truncal obesity Only weight loss normalized Tang T, et al, Hum Reprod, 26;21:8 16% reduction in weight results in a 2% increase in glucose clearance Niskanen L, J Obes Relat Metab Disord 1996;2:154 OCPs vs. Acne Menses Hirsutism Type II DM

and Pregnancy Category B Preliminary studies of women with PCOS who continue metformin in pregnancy 1. May lower incidence of first trimester losses 2. No adverse affect on birth weight, growth or motor development through 18 months 3. Reduced development of gestational diabetes vs. Insulin (Pregnancy) 751 women randomized at 2 33 weeks of gestation No difference in fasting blood sugar Lower 2 hr postprandial blood sugar with metformin No difference in pre-eclampsis eclampsis Glueck CJ, et al. Hum Reprod 24;19:1323. Jakubowicz DJ, et al. JCEM 22;87:524 Rowan, JA, et al. N Engl J Med 28;358:23-15 Nicholson, W, et al. Obstetrics & Gynecology 29; 113(1):193-25 vs. Insulin (Pregnancy) Lower neonatal hypoglycemia in metformin group (3.3% vs. 8.1%) Preterm birth more common in group (12.1% vs. 7.6%) No difference in delivery complications or composite neonatal outcomes Observational studies agreed. Rowan, JA, et al. N Engl J Med 28;358:23-15 Nicholson, W, et al. Obstetrics & Gynecology 29; 113(1):193-25 Aromatase Inhibitors Mechanism Holzer, H, et al, Fertil Steril, 26;85:277 Letrozole FDA approval First line for advanced or adjuvant for receptor positve breast CA in postmenopausal women Extended adjuvant therapy in postmenopausal women with prior tamoxifen therapy Second line in postmenopausal after anti- estrogen therapy failure Aromatase Inhibitors (letrozole, anastrozole) Exemestane Irreversible blockage of Aromatase Anastrozole Letrozole Unlike Tamoxifen,, AI have reduced incidence of vaginal bleeding, endometrial cancer and thrombosis ACOG Committee Opinion, 28;112(2),45-47

Aromatase Inhibitors Inhibits androgen conversion to estrogens Indicated for first- line treatment of postmenopausal women with hormone receptor positive or unknown breast CA Thought to induce ovulation by releasing hypothalmus / pituitary from estrogen negative feedback Mitwally MF. Curr Opin Obstet Gynecol 22;14:255 8 7 6 5 4 3 2 1 Letrozole in PCOS Patients With An Inadequate Response to CC % CC 18 letrozole 12 1 8 6 4 2 Endometrial Thickness (mm) Mitwally MFM, Casper RF. Fertil Steril 21;75:35 Letrozole vs Clomid for PCOS RCT Clomid 1mg 5 days 22 women 523 Letrozole 5mg 5 days 218 women 54 Badawy A, et al, Fertil Steril, 28 (epub) 8 7 6 5 4 3 2 1 Clomid Letrozole ovul/cy preg/cy preg/pt Clomid Resistant Patients 64 patient failed 1mg of Clomiphene Citrate Randomized to CC 15 mg vs. Letrozole 7.5 mg Mean estradiol 448 vs. 818 pg/ml Mean endometrial thickness 9. vs. 1.1 mm 7 6 5 4 3 2 1 Begum MR et al. Fertil Steril 28 (epub) OV Preg CC Letrozole Letrozole: : Is it Safe? Aromatase inhibitor Blocks conversion of androgens to estrogens Potential to interfere with fetal genital tract /? CNS development if used while pregnant Short half life 3-6 hours Shorter than clomiphene citrate (5-7 7 days) In theory then: Problematic if given while fetal genitalia are in development (GA wks 8 to 14) but not otherwise. Letrozole: : is it safe? Montreal Fertility Clinic 15 babies after letrozole 5 mg days 3 to 7 4.7% rate of major anomalies vs. 1.8% rate in controls (low risk OB service) Multicenter Canadian Study 514 babies after letrozole,, 397 babies after clomid Letrozole 1.2% major malformations, 2.4% total Clomid 3.% major, 4.8% total Biljan N, et al. Fertil Steril 25;84(supp) Tulandi, et al. Fertil Steril 26;85:1761

Letrozole: : where are we? Equal efficacy to clomiphene with fewer side effects Unsafe if taken while pregnant (like Provera) Not demonstrated to be unsafe when used pre-conceptually I continue to use it Confirm not pregnant each cycle before prescribing Discuss off-label use Consider Consent Form Gonadotropins Higher pregnancy rates Consider OCP suppression prior to stimulation Low dose (75 to 15 IU daily) Consider recombinant FSH adjust based on age, previous response start slow, AVOID increasing dose Close monitoring, hcg trigger combine with IUI Significant Risk (Multiples, OHSS (?...>13 pg/ml ml) Follicle number (overall & >14 16 mm) Oral Contraceptive Pretreatment Clomid Resistance with Elevated Adrenal Androgens 48 patient with CC resistance 89 CC 1 mg 5-95 alone vs. OCPs followed by CC Ultrasound monitoring, hcg 8 7 6 5 4 3 2 1 % Ov Cycles CC OCP + CC DHEAS levels > 2. ug/ ml Dexamethasone.5 mg daily (Prednisone 5. mg may be used) 1 9 8 7 6 5 4 3 2 1 PREG Clomid CC + Dex Branigan EF, Am J Ob Gynecol 23;188:1424 Daly DC, Fertil Steril 1984; 41:844 Isaac JD, Fertil Steril 1997; 67:641 High Dose Dex in CC resistant women with normal DHEAS Clomid 1 mg days 3-7 Dexamethasone 2mg or placebo days 3-123 hcg > 18 mm follicle, timed intercourse 8 women up to 6 treatment 8 7 6 5 4 3 2 1 Elnashar A,Hum Reprod 26;185:26 PREG CC + Placebo CC + Dex ESHRE / ASRM-Sponsored Sponsored PCOS Consensus Workshop Lifestyle Modifications are key Weight Reduction Exercise Stop smoking Limit alcohol Fertil Steril 28;89:25

ESHRE / ASRM-Sponsored Sponsored PCOS Consensus Workshop First Line: 2 nd Line : 3 rd Line: Clomiphene Citrate Gonadotropins L/S Ovarian Surgery IVF for glucose intolerance Insufficient data to recommend letrozole Fertil Steril 28;89:25 PCOS Treatment Approach (Age Dependant) Lifestyle modification CC or Letrozole 3 cycle with OPK and TI 3 with ultrasound monitoring and IUI IUI earlier in unexplained or mild male factor Consider adjuctive therapy Dexamethasone Gonadotropins / IUI Ovarian Drilling IVF (3 rd or 4 th line therapy) Summary Recommendations Alone Insulin resistance Women interested in restoring menses or ovulation without ovulation induction While on weight loss program prior to starting ovulation induction Prevention of Metabolic Syndrome? Hirsutism?, Acne? Summary Recommendations Letrozol CC resistant patients and/or women with thin endometrial thickness on CC First line? /CC or /Letrozole CC resistant patients with PCOS Gonadotropins Careful Risk Benefit Analysis Intensive monitoring