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Premium member Presentation Transcript Polycystic Ovarian Syndrome : Polycystic Ovarian Syndrome INTRODUCTION : INTRODUCTION Most common cause of infertility in women Classic syndrome originally described by Stein and Levanthal Hyperandrogenism Menstrual irregularity Polycystic ovaries Central adiposity Syndrome, not a disease—multiple potential etiologies with variable clinical expression History : History Originally described by Stein and Leventhal in 1935, first known as the “Stein-Leventhal syndrome” 7 women with amenorrhea, hirsutism, and obesity, found to have a polycystic appearance to their ovaries. What is PCOS? : What is PCOS? Disorder characterized by 2 of the following: Hyperandrogenism Oligoovulation or chronic anovulation Polycystic ovaries In the absence of pituitary or adrenal disease It is a syndrome, ie., no single test can establish the diagnosis. Why is PCOS important? : Why is PCOS important? Affects 4-12% of women of reproductive age Significant association between obesity, insulin resistance, and PCOS. Huge impact on the reproductive, metabolic, and cardiovascular health of affected women. Pathogenesis : Pathogenesis INTRAOVARIAN ANDROGEN EXCESS Pathogenesis : Pathogenesis 1. Hyperandrogenism 2. Insulin resistance Slide 8: Ehrmann NEJM 2005 Pathogenesis: Hyperandrogenism : Pathogenesis: Hyperandrogenism Symptoms of androgen excess Reduced sex-hormone-binding globulin (SHBG) more free testosterone Insulin insensitivity Lipid abnormalities Abdominal obesity Pathogenesis: Insulin resistance : Pathogenesis: Insulin resistance Favors anovulation, androgen excess, reduced SHBG Metabolic syndrome Abdominal obesity Insulin resistance in PCOS: it’s not just a theory : Insulin resistance in PCOS: it’s not just a theory Insulin resistance in PCOS is independent of obesity Obese women with PCOS tend to be more insulin resistant than nml-wt counterparts. Obesity is an independent risk factor for glucose intolerance or DM in PCOS 3-fold increased incidence of metabolic syndrome in PCOS, vs general population, independent of obesity. Insulin resistance ≠ glucose intolerance Many insulin resistant PCOS pts have normal glucose tolerance 30-40% prevalence of glucose intolerance in PCOS women 7-10% prevalence of type 2 DM in PCOS women Insulin resistance worsens over time Increased risk for impaired glucose tolerance and type 2 DM Abnormal Pituitary Function—Altered Negative Feedback Loop : Abnormal Pituitary Function—Altered Negative Feedback Loop Increased GnRH from hypothalamus Excessive LH secretion relative to FSH by pituitary gland LH stimulates ovarian thecal cells-- androgen production Ineffective suppression of the LH pulse frequency by estradiol and progesterone Androgen excess increases LH by blocking the hypothalamic inhibitory feedback of progesterone Slide 14: hypothalamus pituitary ovary GnRH LH androgens Androgens block inhibitory effect of progesterone X Abnormal steroidogenenesis : Abnormal steroidogenenesis Intraovarian androgen excess results in excessive growth of small ovarian follicles Follicular maturation is inhibited Excess androgen causes thecal and stromal hyperplasia HYPERINSULINEMIA : HYPERINSULINEMIA Excess insulin production and insulin resistance Genetic link Hyperandrogenism vs. hyperinsulinemia Which came first? DIAGNOSTIC CRITERIA AND CLINICAL MANIFESTATIONS : DIAGNOSTIC CRITERIA AND CLINICAL MANIFESTATIONS Slide 18: NIH Criteria ** Menstrual irregularity due to anovulation or oligo-ovulation Evidence of clinical or biochemical hyperandrogenism Hirsutism, acne, male pattern baldness High serum androgen levels Exclusion of other causes (CAH, tumors, hyperprolactinemia) Slide 19: Rotterdam Criteria (2 out of 3) Menstrual irregularity due to anovulation oligo-ovulation Evidence of clinical or biochemical hyperandrogenism Polycystic ovaries by US presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter and/or increased ovarian volume MENSTRUAL DYSFUNCTION : MENSTRUAL DYSFUNCTION Oligo or amenorrhea Menstrual irregularity typically begins in the peripubertal period Delayed menarche Reduction in ovulatory events leads to deficient progesterone secretion Chronic estrogen stimulation of the endometrium with no progesterone for differentiation—intermittent breakthrough bleeding or dysfunctional uterine bleeding Increased risk for endometrial hyperplasia and/or endometrial CA HYPERANDROGENISM : HYPERANDROGENISM Hirsutism, acne, male pattern balding, alopecia 50-90% patients have elevated serum androgen levels Free testosterone levels most sensitive Rare: increased muscle mass, deepening voice, clitormegaly (should prompt search for underlying neoplasm) Diagnosis : Diagnosis Hyperandrogenism (cont’d) Laboratory features Elevated total testosterone Most values in PCOS <150 ng/dl (if >200 ng/dl, consider ovarian or adrenal tumor) Free testosterone assays not reliable yet DHEA-S Most normal or slightly high in PCOS If >800 mcg/dl, consider adrenal tumor LH/FSH ratio Levels vary over menstrual cycle, released in pulsatile fashion, affected by OCPs LH/FSH ratio >2 has little diagnostic sensitivity and need not be documented Diagnosis : Diagnosis 2. Oligoovulation or anovulation Oligomenorrhea or amenorrhea Dysfunctional uterine bleeding Infertility 30-50% 1st trimester miscarriage rate 3-fold increased risk endometrial carcinoma Diagnosis : Diagnosis Polycystic Ovaries Criteria by ultrasound Increased ovarian area (>5.5 cm2) or volume (>11 ml) w/ presence of >12 follicles measuring 2-9 mm in diameter Polycystic ovaries not specific for PCOS > 20% normal women have incidental polycystic ovaries OVARIAN ABNORMALITIES : OVARIAN ABNORMALITIES Thickened sclerotic cortex Multiple follicles in peripheral location 80% of women with PCOS have classic cysts INFERTILITY : INFERTILITY Intermittent ovulation or anovulation Inherent ovarian disorder—studies show reduced rated of conception despite therapy with clomid Diagnosis : Diagnosis 4. Absence of other disorders to account for these symptoms. Pregnancy pregnancy test Hypothyroidism TSH Hyperprolactinemia prolactin Late onset congenital adrenal hyperplasia 17-hydroxyprogesterone (r/o if <200 ng/dl) Ovarian tumor total testosterone (esp if >200 ng/dl) Adrenal tumor DHEA-S (esp if > 800 mcg/dl) Cushing’s syndrome salivary cortisol, 24 hr urine cortisol Diagnosis : Diagnosis 5. Supportive of insulin resistance “Syndrome XX”: 3 or more of the following criteria: Waist circumference > 88 cm Triglycerides > 150 mg/dl HDL <50 mg/dl BP > 130/85 Fasting glucose >110 mg/dl ACOG and ADA suggest screening all women w/ PCOS for glucose intolerance, type 2 DM. Oral glucose tolerance test more sensitive than fasting glucose. Personal or family history of DM Acanthosis nigricans OBESITY : OBESITY Prevalence of obesity varies from 30-75% 2/3 of patients with PCOS who are not obese have excessive body fat and central adiposity Obese patients can be hirsute and/or have menstrual irregularities without having PCOS OBESITY AND INSULIN RESISTANCE : OBESITY AND INSULIN RESISTANCE ½ patients with PCOS are obese > 80% are hyperinsulinemic and have insulin resistance (independent of obesity) Hyperinsulinemia contributes to hyperandrogenism through production in the theca cell and through its suppressive effects on sex hormone binding globulin production by the liver ASSOCIATED MEDICAL CONDITIONS : ASSOCIATED MEDICAL CONDITIONS Increased risk of developing Type 2 Diabetes and Gestational diabetes Low HDL and high triglycerides Sleep apnea Nonalcoholic steatohepatitis Metabolic syndrome—43% of PCOS patients (2 fold higher than age-matched population) Elevated CRP and heart disease Advanced atherosclerosis DIFFERENTIAL DIAGNOSIS : DIFFERENTIAL DIAGNOSIS Hyperprolactinemia Prominent menstrual dysfunction Little hyperandrogenism 2. Congenital Adrenal Hyperplasia morning serum 17-hydroxyprogesterone concentration greater than 200 ng/dL in the early follicular phase strongly suggests the diagnosis confirmed by a high dose (250 mcg) ACTH stimulation test: post-ACTH serum 17-hydroxyprogesterone value less than 1000 ng/dL Slide 35: 3. Ovarian and adrenal tumors serum testosterone concentrations are always higher than 150 ng/dL adrenal tumors: serum DHEA-S concentrations higher than 800 mcg/dL LOW serum LH concentrations 4. Cushing’s syndrome 5. Drugs: danazol; OCPs with high androgenicity TESTING : TESTING Serum HCG Serum prolactin Thyroid panel FSH: r/o ovarian failure Serum luteinizing hormone (LH)—elevated Serum estradiol—normal Serum estrone—elevated TESTING : TESTING Fasting glucose: elevated 2 hour OGTT: elevated Fasting insulin: elevated Free testosterone: elevated DHEA-S: normal 17-hydroxyprogesterone: normal Pelvic US Lipids TREATMENT : TREATMENT Management : Management Immediate/Acute issues Hirsutism Regulation of menses Fertility issues Long-term issues Insulin resistance Cardiovascular risk Obstructive sleep apnea Malignancy risk WEIGHT LOSS : WEIGHT LOSS Weight loss Weight loss Weight loss Management:Immediate/Acute Issues : Management:Immediate/Acute Issues Control of hirsutism Medical (need a trial of 6-12 mos before deemed ineffective) Decrease testosterone production (predominantly from ovary) OCPs (improvement scores 33%) -Increase SHBG Lifestyle modification/weight loss Metformin (improvement scores 10-13%) Glucocorticoids? -Theory: ACTH stimulates adrenal androgen synthesis. So, suppress ACTH via glucocorticoids. -Study by Vanky, et al- dexamethasone 0.25 mg/day vs placebo—reduction in testosterone, androstenedione, DHEA-S by 25-50%. No significant change in BMI, glucose, insulin, lipids -problematic Management:Immediate/Acute Issues : Management:Immediate/Acute Issues Control of hirsutism (cont’d) Decrease testosterone action Antiandrogens Spironolactone (start 50 mg bid 100 mg bid) -Reduction in hirsutism 45% -Preferred use w/ OCPs, 75% response Drospirenone (analogue of spironolactone, approved in Yasmin) 5α-reductase inhibitors (ex. Finasteride) Lifestyle modification/weight loss Metformin Management:Immediate/Acute Issues : Management:Immediate/Acute Issues Control of hirsutism (cont’d) Mechanical Plucking/shaving/electrolysis/laser Vaniqa cream (eflornithine hydrochloride 13.9%) Mechanism: slows growth of hair by inhibiting L-ornithine decarboxylase (enzyme involved in hair growth) 58% demonstrated some improvement in hair growth vs 32% with placebo Hair growth rates return to nml 8 wks off therapy Not covered by most insurance policies Hirsutism : Hirsutism Mechanical hair removal Vaniqa (eflornithine hydrochloride) OCPs with minimal androgenicity OCP plus antiandrogen (spironolactone) Spironolactone, 50-200 mg per day Flutamide Potential hepatic dysfunction Management:Immediate/Acute Issues : Management:Immediate/Acute Issues Regulation of menses Oral contraceptives Periodic progesterone withdrawal Medroxyprogesterone 10 mg/day x 7-10 days, every 3 months (approx 4 menses annually) Lifestyle modification/weight loss Metformin- ie., hitting the “root cause” 500-1000 mg bid, 6 month trial reasonable for improvement of menses Oligomenorrhea : Oligomenorrhea Combination estrogen-progestin pill first line when fertility is not desired Decrease in LH secretion and decrease in androgen production Increase in hepatic production of sex-hormone binding globulin Decreased bioavailablity of testosterone Decreased adrenal androgen secretion Regular withdrawal bleeds Prevention of endometrial hyperplasia Management:Immediate/Acute Issues : Management:Immediate/Acute Issues Fertility issues Lifestyle modification/weight loss Loss of >5% body wt, calorie-restricted diet, and exercise associated with improvement in spontaneous pregnancy rates (7.5-15% improvement) Clomiphene citrate Most women with PCOS do not respond to normal dose—20% ovulation rate! Management:Immediate/Acute Issues : Management:Immediate/Acute Issues Fertility issues (cont’d) Metformin OR 3.88 in achieving fertility (compared to placebo), 4.4 (for metformin+clomiphene compared to clomiphene alone) Improved outcomes with in vitro fertilization (reduced risk of ovarian hyperstimulation when treated with FSH) Reduction in 1st trimester spontaneous abortions Thiazolidinediones Early studies w/ rosiglitazone prior to conception 30% improvement in fertility rates. TREATMENT—no fertility desired : TREATMENT—no fertility desired Monophasic antiandrogenic OCP ON 1/35 (norethindrone) Orthocyclen (norgestimate) Desogen or Orthocept (desogestrel) Yasmin Slide 50: Metformin will restore ovulation and menses in > 50% of patients Treat with cyclic progestin to reduce endometrial hyperplasia if regular menses not attained 10 mg for 7 to 10 days every two to four months METFORMIN : METFORMIN Decreases hepatic glucose production Reduces need for insulin secretion Improves insulin sensitivity (increases peripheral glucose uptake and utilization) Antilipolytic effect—reduces fatty acid concentrations and reduces gluconeogenesis SIDE EFFECTS : SIDE EFFECTS Diarrhea, nausea, vomiting, flatulence, indigestion, abdominal discomfort Caused by lactic acid in the bowel wall Minimized by slow increase in dosage Lactic acidosis—rare Avoid in CHF, renal insufficiency, sepsis Discontinue for procedures using contrast (withhold X 48 hours) Temporarily suspend for all surgical procedures that involve fluid restriction Cimetidine causes increased metformin levels INFERTILITY TREATMENT : INFERTILITY TREATMENT Metformin 500 mg daily Increase by 500 mg each week until: Normal menses Reached max dose Side-effects Clomid 50 mg days 3-7 for 3 months 100 mg days 3-7 for 3 months METFORMIN DOSING : METFORMIN DOSING Target—1500-2550 mg per day Clinically significant responses not regularly observed at doses less than 1000 mg per day Extended release formulations—fewer side-effects. Entire dose should be given with dinner Infertility : Infertility Weight loss—reduction in serum testosterone concentration and resumption of ovulation Clomid: 80% will ovulate, 50% will conceive Metformin: when added to clomid, improves ovulatory rates FSH injections Laparoscopic surgery: wedge resections, laparoscopic ovarian laser electrocautery IVF Clomid Challenge Test : Clomid Challenge Test Day 3 FSH and estradiol levels 100 mg of Clomid on cycle days 5-9 Day 10 FSH levels The test is abnormal if either the day 3 or day 10 FSH values are elevated (greater than 10) or if the day 3 estradiol is greater than 80 Management:Long-Term Issues : Management:Long-Term Issues Insulin resistance Metformin Function Lowers hepatic glucose production by reducing gluconeogenesis Increases peripheral glucose uptake by skeletal muscle and adipose tissue Reduces intestinal glucose absorption Outcomes Estimated 31% reduction in development of type II DM over mean period 3 years Taken during pregnancy, reduction in gestational diabetes and major fetal complications Management:Long-Term Issues : Management:Long-Term Issues Insulin resistance Thiazolidinediones Function Selective ligands of the nuclear transcription PPARγ, expressed in adipose tissue, pancreatic beta cells, vascular endothelium, macrophages, HPO axis. “fatty acid steal” hypothesis Promote fatty acid uptake and storage in adipose tissue, sparing other tissues (muscle, liver) from harmful metabolic effects of free fatty acids (high levels in PCOS) Increased expression of adiponectin (adipocytokine with an insulin sensitivity effect) Decreased expression of 11β-hydroxysteroid dehydrogenase type 1 (enzyme converts inactive cortisone to active cortisol) Outcomes Management:Long-Term Issues : Management:Long-Term Issues Cardiovascular Risk Increased prevalence of HTN Dyslipidemia (↑ TG, ↓ HDL, ↑ LDL) Predisposition to macrovascular disease and thrombosis Nurses’ health study: 20-60% increased risk of CAD events Studies of pts undergoing coronary angiography: women with significant h/o hirsutism or polycystic ovaries more likely to have CAD, and if they had it, more extensive CAD, compared to female controls. Aggressive management…”CHAMP”? Management:Long-Term Issues : Management:Long-Term Issues Obstructive Sleep Apnea 30-fold increased risk of OSA, not explained by obesity alone. Insulin resistance strongest predictor of OSA (not BMI, age, testosterone) Consider polysomnography if at risk Management:Long-Term Issues : Management:Long-Term Issues Risk for malignancy 3X increased risk endometrial carcinoma in PCOS Increased risk of ovarian and breast cancer Warrants regular screening, low threshold for endometrial biopsy Other issuesRole of epilepsy? : Other issuesRole of epilepsy? Increased incidence of reproductive disorders in patients with epilepsy Pts on valproic acid may have higher levels of insulin, testosterone, and TG New things on the horizon… : New things on the horizon… Somatostatin analogs Function Blunts LH response to GnRH Decreases GH secretion by pituitary Inhibits pancreatic insulin release Outcomes: limited studies 7 d administration octreotide in PCOS women decreased fasting and glucose-stimulated insulin levels Reduced LH, androgen, IGF-1 levels Short half-life (80-110 min) requiring multiple injections Extended release octreotide (octreotide-LAR)- inject IM Q28 days- results in improvement in GH, insulin, IGF-1, hirsutism Not approved yet RCOG Guidelines (May 2003) : RCOG Guidelines (May 2003) Evidence based guidelines for reduction of long-term PCOS consequences Guidelines (RCOG, May 2003) : Guidelines (RCOG, May 2003) Patients presenting with PCOS particularly if they are obese, should be offered measurement of fasting blood glucose and urine analysis for glycosuria. Abnormal results should be investigated by a glucose tolerance test. Such patients are at increased risk of developing type II diabetes Women who have been diagnosed as having PCOS before pregnancy (eg those requiring ovulation induction for conception) should be screened for gestational diabetes in early pregnancy, with referral to a specialized obstetric diabetic service if abnormalities are detected Guidelines (RCOG, May 2003) : Guidelines (RCOG, May 2003) Measurement of fasting cholesterol, lipids and triglycerides should be offered to patients with PCOS, since early detection of abnormal levels might encourage improvement in diet and exercise. Olig- and amenorrhoeic women with PCOS may develop endometrial hyperplasia and later carcinoma. It is good practice to recommend treatment with progestogens to induce withdrawal bleed at least every 3-4 months. 4- Guidelines (RCOG, May 2003) : Guidelines (RCOG, May 2003) A body of evidence has accumulated demonstrating safety and in some studies efficacy of insulin-sensitizing agents in the management of short-term complications of PCOS, particularly anovulation. Long-term use of these agents for avoidance of metabolic complications of PCOS can not as yet be recommended . No clear consensus has yet emerged concerned regular screening of women with PCOS for later development of diabetes and dyslipidemia but obese women with a strong family history of cardiac disease or diabetes should be assessed regularly. 6- Guidelines (RCOG, May 2003) : Guidelines (RCOG, May 2003) Young women diagnosed with PCOS should be informed of the possible long-term risks to health that are associated with their condition. They should be advised regarding weight and exercise. AACE Position statement2005 : AACE Position statement2005 Guidelines-2005 : Guidelines-2005 Well-defined published data indicate a high risk for development of T2DM and CVD in women with PCOS. In view of the lack of protective effect of female sex on CVD risk in patients with diabetes, the associated risks of CVD are magnified in women with diabetes who have PCOS. Clearly, this situation means that PCOS is a general health disorder of young women, with potential for reversal of some of the associated risk with early diagnosis and treatment. Guidelines-2005 : Guidelines-2005 Lifestyle modification with weight loss and exercise, avoidance of tobacco, correction of lipid abnormalities, and use of metformin may be of value. Metformin therapy not only reduces hyperinsulinism and improves steroidogenic dysfunction but also is helpful in achieving better regularity of menses and fertility potential. Thiazolidinediones have also been shown to decrease androgen levels, improve ovulation, and reduce progression to overt T2DM in patients with PCOS and IGT. Guidelines-2005 : Guidelines-2005 Early recognition of the syndrome. Lifestyle modification, with emphasis on the need for controlled eating patterns and regular aerobic exercise. Encouragement should be offered by an empathic physician, who will monitor the patient carefully during the course of treatment. Measurement of glucose (and possibly insulin levels). An oral glucose challenge may be considered, particularly in obese women with PCOS and those with a family history of T2DM. Guidelines: Lipids and BP : Guidelines: Lipids and BP Detection and treatment of lipid abnormalities, with dietary measures first and then use of appropriate medications, such as a statin, fibrate, niacin, or ezetimibe (or some combination of these agents), as necessary. Careful attention to and treatment of blood pressure abnormalities. Measurement of atherogenic markers (C-reactive protein [CRP], fibrinogen, and possibly homocysteine). Guidelines: Metformin : Guidelines: Metformin Consideration of metformin therapy as the initial intervention in most women with PCOS, particularly in those who are overweight or obese. Metformin improves many metabolic abnormalities in PCOS and may improve menstrual cyclicity and the potential for pregnancy. Of note, metformin has not been approved by the US Food and Drug Administration for use in PCOS, although abundant medical literature supports its efficacy. Guidelines: OC and Anti-Androgen : Guidelines: OC and Anti-Androgen The use of a nonandrogenic oral contraceptive agent and an antiandrogen such as spironolactone for the skin manifestations of PCOS. The presence of hair thinning requires the maximal dose of spironolactone in conjunction with an oral contraceptive agent. Ancillary use of electrolysis and laser therapy may also be helpful. Guidelines: TZD : Guidelines: TZD The use of these agents to improve hyperandrogenism and ovulation is considered only investigational at this time. Thiazolidinediones are category C drugs; their use is contraindicated during pregnancy. Recommendations ACOG 2009 : Recommendations ACOG 2009 Grades of Recommendations : Grades of Recommendations A- Requires at least one randomized controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation. (Evidence levels Ia, Ib) B- Requires the availability of well controlled clinical studies but no randomized clinical trials on the topic of recommendations (Evidence levels IIa, IIb, III) C- Requires evidence obtained from expert committee reports or opinions and/ or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality. (Evidence level IV) The following recommendations and conclusions are based on good and consistent scientific evidence (Level A): : The following recommendations and conclusions are based on good and consistent scientific evidence (Level A): An increase in exercise combined with dietary change has consistently been shown to reduce diabetes risk comparable to or better than medication. Improving insulin sensitivity with insulin-sensitizing agents is associated with a decrease in circulating androgen levels, improved ovulation rate, and improved glucose tolerance. The recommended first-line treatment for ovulation induction remains the antiestrogen clomiphene citrate. The addition of eflornithine to laser treatment is superior in the treatment of hirsutism than laser alone. The following recommendations and conclusions are based on limited and inconsistent scientific evidence (Level B): : The following recommendations and conclusions are based on limited and inconsistent scientific evidence (Level B): Women with a diagnosis of polycystic ovary syndrome (PCOS) should be screened for type 2 diabetes and impaired glucose tolerance with a fasting glucose level followed by a 2-hour glucose level after a 75-g glucose load. Women with PCOS should be screened for cardiovascular risk by determination of body mass index (BMI), fasting lipid and lipoprotein levels, and metabolic syndrome risk factors. Reduction in body weight has been associated with improved pregnancy rates and decreased hirsutism, as well as improvements in glucose tolerance and lipid levels. There may be an increase in pregnancy rates by adding clomiphene to metformin, particularly in obese women with PCOS. If clomiphene citrate use fails to result in pregnancy, the recommended second-line intervention is either exogenous gonadotropins or laparoscopic ovarian surgery. The following recommendations and conclusions are based primarily on consensus and expert opinion (Level C): : The following recommendations and conclusions are based primarily on consensus and expert opinion (Level C): Combination low-dose hormonal contraceptives are most frequently used for long-term management and are recommended as the primary treatment of menstrual disorders. Women in groups at higher risk for nonclassical congenital adrenal hyperplasia and a suspected diagnosis of PCOS should be screened to assess the 17- hydroxyprogesterone value. A low-dose regimen is recommended when using gonadotropins in women with PCOS. There is no clear primary treatment for hirsutism in PCOS. Management of PCOS : Management of PCOS Diet and Exercise : Diet and Exercise In patients with PCOS who are obese, endocrine-metabolic parameters markedly improve after 4-12 weeks of dietary restriction. Their SHBG levels rise and free testosterone levels fall by 2-fold. Serum insulin and IGF-1 levels also decrease. Weight loss in patients with PCOS who are obese is associated with a reduction of hirsutism and a return of ovulatory cycles in 30% of women. Moran LJ, Pasquali R, et all Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril. Dec 3 2008; Diet and Exercise : Diet and Exercise A moderate amount of daily exercise increases of levels of IGF-1 binding protein and decreases IGF-1 levels by 20%. Modest weight loss of 2-5% of total body weight can help restore ovulatory menstrual periods in obese patients with PCOS. A daily 500-1000 calorie deficit with 150 minutes of exercise per week can cause ovulation. The Androgen Excess and Polycystic Ovary Syndrome Society recommends lifestyle management as the primary therapy in overweight and obese women with PCOS for the treatment of metabolic complications. Moran LJ, Pasquali R, et all Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril. Dec 3 2008; Metformin : Metformin This anti-diabetic drug improves insulin resistance and decreases hyperinsulinemia in patients with PCOS. Metformin also has a small but beneficial effect on metabolic syndrome. Ascertain that kidney and liver function are normal and that the patient does not have advanced congestive heart failure before starting metformin. The usual starting dose is 500 mg given orally twice a day. Inform patients that they have a high likelihood of having ovulatory cycles while taking metformin. The US Food and Drug Administration has not approved metformin for this indication; therefore, this use is off label Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ. Oct 25 2003;327(7421):951-3. [Medline]. Metformin and Anovulation : Metformin and Anovulation Evidence suggests that metformin frequently—but not universally—improves ovulation rates in women with PCOS.a In addition, pretreatment with metformin has been shown to enhance the efficacy of clomiphene for inducing ovulation.b Whether short-course metformin pretreatment (less than 4 weeks) is as effective as conventional long-course metformin remains uncertain.c N-acetylcysteine may also enhance the effect of clomiphene.d Hirsutism : Hirsutism Hair removal: Short-term non-pharmacologic treatments of hirsutism include shaving and use of chemical depilatories and/or bleaching cream.e Plucking or waxing unwanted hair can result in folliculitis and ingrown hairs. Long-term measures include techniques such as electrolysis and laser treatment of unwanted hairs. Weight reduction: Weight reduction decreases androgen production in women who are obese; therefore, losing weight can slow hair growth. Hirsutism : Hirsutism Oral contraception: Women who do not wish to become pregnant can be effectively treated for hirsutism with oral contraceptives.f Oral contraceptives slow hair growth in 60-100% of women with hyperandrogenemia. Therapy can be started with a preparation that has a low dose of estrogen and a nonandrogenic progestin. Preparations that have norgestrel and levonorgestrel should be avoided because of their androgenic activity. Hirsutism : Hirsutism Spironolactone: Antiandrogens, such as spironolactone, are effective for hirsutism.g Spironolactone 50-100 mg twice daily is an effective primary therapy for hirsutism. Because of the potential teratogenic effects of spironolactone, patients require an effective form of contraception (eg, an oral contraceptive). Adverse effects of spironolactone include GI discomfort, and irregular menstrual bleeding (which can be managed by adding an oral contraceptive). Hirsutism : Hirsutism Eflornithine: Eflornithine (Vaniqa) is a topical cream that can be used to slow hair growth. Eflornithine works by inhibiting ornithine decarboxylase, which is essential for the rapidly dividing cells of hair follicles Menstrual irregularity : Menstrual irregularity This is treated with an oral contraceptive, which not only inhibits ovarian androgen production but also increases SHBG production. Pregnancy should be excluded before therapy with oral contraceptives is started. Surgical Management : Surgical Management Aimed mainly at restoring ovulation. Ovarian wedge resection: This procedure has fallen out of favor because of postoperative adhesion formation and the introduction of ovulation-inducing medications. Laparoscopic surgery: Various laparoscopic methods, including electrocautery, laser drilling, and multiple biopsy, have been used with the goal of creating focal areas of damage in the ovarian cortex and stroma. Potential complications include formation of adhesions and ovarian atrophy. Multiple pregnancy rates are lower with ovarian drilling than with gonadotrophin treatment (1% versus 16%), but there are ongoing concerns about the long-term effects on ovarian function.28 You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.