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Infertility and PCOS.

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Presentation on theme: "Infertility and PCOS."— Presentation transcript:

1 Infertility and PCOS

2 How common is PCOS A. 1-2% of women B. 3-5% of women C. 5-10% of women
D. 7-12% of women

3 Answer C. 5-10% of women

4 What % of women have infertility and how is it defined
A. 8% of women of reproductive age infertile and Classically defined as failing to, become pregnant after 1 yr of trying B. 5% of women of reproductive age infertile and Classically defined as failing to, become pregnant after 2 yr of trying C. 10% of women of reproductive age infertile and Classically defined as failing to, become pregnant after 6 mo of trying

5 Answer A. 8% of women of reproductive age infertile and Classically defined as failing to, become pregnant after 1 yr of trying

6 If semen analysis is abnormal consider checking?
A. high follicle-stimulating hormone (FSH; >15 mIU/mL), low testosterone (common in obesity), and fasting blood sugar and hemglobin AIC B. Lipid profil, low testosterone (common in obesity), and prolactin level C. consider testicular failure, high follicle-stimulating hormone (FSH; >15 mIU/mL), low testosterone (common in obesity), and prolactin level

7 Answer C. consider testicular failure, high follicle-stimulating hormone (FSH; >15 mIU/mL), low testosterone (common in obesity), and prolactin level

8 Which of the following can decrease fertility in women
Which of the following can decrease fertility in women?  A) Endometriosis  B) Fibroids  C) Tubal disease  D) All the above

9 Answer  D) All the above

10 On semen analysis, which of the following is an abnormal finding
On semen analysis, which of the following is an abnormal finding?  A) Sperm count, 10 million/mL  B) 50% of sperm appear motile  C) 50% of sperm appear normal on World Health Organization sperm morphology classification  D) 15% of sperm appear normal on strict morphology criteria (ie, 1000-fold magnification)

11 Answer  A) Sperm count, 10 million/mL

12 Which of the following is a sign of low ovarian reserve
Which of the following is a sign of low ovarian reserve?  A) Regular menstrual cycles lasting <25 days  B) Follicle-stimulation hormone level >15 mIU/mL on third day of cycle  C) Progesterone level >15 mIU/mL on third day of cycle  D) Dysmenorrhea

13 Answer  B) Follicle-stimulation hormone level >15 mIU/mL on third day of cycle

14 All women with polycystic ovary syndrome should undergo hysterosalpingography before being treated with clomiphene.  A) True  B) False

15 Answer B) False

16 Polycystic ovary syndrome (PCOS) is a reproductive disorder characterized by _______ and _______. (A) Anovulation; obesity (B) Anovulation; hyperandrogenemia (C) Amenorrhea; insulin resistance (D) Infertility; hyperlipidemia

17 Answer (B) Anovulation; hyperandrogenemia

18 Beta–cell dysfunction in patients with PCOS is largely determined by presence or absence of a first-degree relative with: (A) Type 2 diabetes (B) Obstructive sleep apnea (C) Hyperlipidemia (D) Vitamin D deficiency

19 Answer (A) Type 2 diabetes

20 Which of the following components of metabolic syndrome appears least common in women with PCOS? (A) Increased waist circumference (B) Low high-density lipoprotein level (C) High triglyceride level (D) Hypertension

21 Answer (D) Hypertension

22 Which of the following groups is at highest risk for components of metabolic syndrome? (A) White men (B) Hispanic women (C) White women (D) Black women

23 Answer (D) Black women

24 Which of the following is the strongest predictor of sleep-disordered breathing? (A) High body mass index (B) High testosterone level (C) Insulin resistance (D) Daytime sleepiness

25 Answer (C) Insulin resistance

26 Vitamin D deficiency is associated with: (A) Decreased serum calcium levels (B) Rickets (C) Increased parathyroid hormone levels (PTH) (D) All the above

27 Answer (D) All the above

28 Which of the following affects vitamin D production
Which of the following affects vitamin D production? (A) Sunscreen (B) Age (C) Skin pigmentation (D) All the above

29 Answer (D) All the above

30 It is recommended that current standards for vitamin D supplementation for most adults be increased to: (A) 200 to 400 IU/day (B) 400 to 600 IU/day (C) 1000 to 2000 IU/day (D) 4000 to 6000 IU/day

31 Answer (C) 1000 to 2000 IU/day

32 Choose the correct statement about vitamin D toxicity
Choose the correct statement about vitamin D toxicity. (A) Need 40,000 IU/day to cause hypercalcemia (B) Indicated by 25-hydroxyvitamin D level >100 ng/mL (C) 4000 IU/day reported to cause renal impairment (D) 1000 to 2000 IU/day risky in patients with normal PTH level

33 Answer (A) Need 40,000 IU/day to cause hypercalcemia

34 Blocking aldosterone production can have a dramatic effect on blood pressure control in obese individuals. (A) True (B) False

35 Answer (A) True

36 Which of the following is not one of the 3 Rotterdam criteria for diagnosis of polycystic ovary syndrome (PCOS)? (A) Oligo-ovulation or anovulation (B) Clinical or laboratory evidence of hyperandrogenism (C) Polycystic ovaries (D) Presence of acanthosis nigricans

37 Answer (D) Presence of acanthosis nigricans

38 Which of the following statements about treatment of infertility with clomiphene and metformin is incorrect? (A) A meta-analysis found that a combination of the 2 drugs was most effective (B) In a randomized trial, the chance of conception over 6 mo was much higher with clomiphene (C) Metformin is associated with a lower rate of miscarriage (D) Metformin may take longer to work than clomiphene

39 Answer (C) Metformin is associated with a lower rate of miscarriage

40 Which of the following is not a predictor of successful fertility therapy in women with PCOS? (A) High educational level (B) Younger age (C) Lower body mass index (D) Lower hirsutism score

41 Answer (A) High educational level

42 Lean women with PCOS have a lower probability of developing type 2 diabetes than obese women without PCOS. (A) True (B) False

43 Answer (A) True

44 Infertility: common 8% of women of reproductive age infertile
25% of couples concerned with infertility (only 15% seek medical care due to embarrassment) Classically defined as failing to become pregnant after 1 yr of trying treat factors that may be reducing fecundity and normal conception rate for age

45 Age-related infertility
women—growing concern Associated with social demands and changes factors that decrease female fertility include fibroids, endometriosis, comorbidities, and lack of partner availability in women 25 yr of age, likelihood of failing to become pregnant after1 yr of trying, 10% (90% in women 42 yr of age) men— fertility decreases with age; may be due to changes in semen parameters, varicoceles, medical illness and conditions, and increased rate of nondisjunction in sperm etiologies—endometriosis or tubal disease consider both female and male factors (perform semen analysis) Ovulation defects unexplained infertility

46 Evaluation of men history—ask about mumps, urologic factors (eg, infection), industrial exposure, chemotherapy, and marijuana smoking semen analysis—check sperm count (20 million/mL normal) evaluate sperm motility (50% should appear motile) assess sperm morphology, based on World Health Organization morphology classification criteria (50% should appear normal) or strict morphology (ie, examine sperm at 1000-fold magnification; 15% should appear normal) check for liquefaction, white cells (sign of infection), and antisperm antibodies (risk factors include history of trauma, vasectomy reversal, or prostatitis) requires abstinence for 2 to 5 days if 1 factor on semen analysis abnormal, repeat in 2 mo if 3 factors (eg, motility, count, morphology) abnormal, refer to urologist consider testicular failure, high follicle-stimulating hormone (FSH; >15 mIU/mL), low testosterone (common in obesity), and prolactin level if semen analysis markedly abnormal, work up or refer to urologist Physical examination—measure testicular size to rule out testicular failure check for varicocele (usually on left side Simple outpatient surgery corrects varicocele and restores normal semen analysis) drug history—long-term use of sulfonamides, sulfonamide-based drugs, and chemotherapy can affect semen analysis and fertility

47 Evaluation of women family history—endometriosis
Recurrent spontaneous abortion fragile X syndrome Early menopause medical history—pelvic inflammatory disease (PID); abdominal surgery; ectopic pregnancy; ruptured appendix; menstrual history—regular menstrual cycles <25 days or >35 days highly associated with infertility (indicates low progesterone level) only 2% of women of reproductive age have regular 28-day cycles evaluate patients with bleeding concerns severe dysmenorrhea sign of endometriosis coital function—ask about coital frequency,

48 Evaluation of women pain during intercourse
use of vaginal lubricants (olive oil, canola oil, and saliva safe) coital and ejaculatory dysfunction in partner tests—endocrine testing for women with irregular menstrual cycles timed progesterone test Postcoital test check for ovulation; luteal phase defect test imaging—transvaginal ultrasonography to determine size of ovaries

49 Ovarian reserve number of eggs remaining
check for elevated (>15 mIU/mL) FSH on third day of cycle

50 Ovulatory dysfunction
caused by hypothyroidism and elevated prolactin treated with clomiphene (eg, Clomid)

51 Clomiphene safe; reliable use first-line for 2 cycles
Maintain lowest dose needed to induce ovulation for 3 cycles If ineffective after 3 cycles, refer to specialist for midcycle monitoring study showed midcycle monitoring and checking estradiol levels do not add value to improving conception in first 4 cycles clomiphene challenge test no longer used elevated FSH on day 3 indicates low ovarian reserve

52 Assessment of ovulation
basal body temperature (30% of women with flat basal body temperature for 1 yr ovulate normally) single progesterone level 6 to 8 days after detection of ovulation with luteinizing hormone surge (if >15 ng/mL, no further testing needed; <3 ng/mL, indicates lack of ovulation; if <10 ng/mL, patient may benefit from clomiphene)

53 Hysterosalpingography
in women with history of ectopic pregnancy, check for open tubes women with 5 menstrual periods per year and polycystic ovary syndrome, may be treated with clomiphene without undergoing hysterosalpingography if pelvic examination normal findings may include hydrosalpinx, salpingitis isthmica nodosum (sign of chlamydial infection), and divot in uterus (may explain infertility or be linked to miscarriage)

54 Polycystic ovary syndrome (PCOS)
reproductive disorder characterized by anovulation (manifests as oligomenorrhea or amenorrhea, infertility, or endometrial carcinoma) and hyperandrogenemia (manifests as hirsutism, acne refractory to treatment, and male-pattern hair loss) Associated metabolic and cardiovascular derangements— obesity Insulin resistance Beta-cell dysfunction (results in impaired glucose tolerance [IGT] and increased risk for type 2 diabetes) Hyperlipidemia Hypercoagulability hypertension endothelial dysfunction obstructive sleep apnea (OSA; can both precipitate and be exacerbated by some metabolic disorders)

55 Prevalence of IGT in PCOS
35% of women 28 yr of age who have PCOS have impaired glucose tolerance (5%-10% frankly diabetic) prevalence of IGT in PCOS nearly identical to prevalence of IGT in Pima Indian women (ie, group with highest risk, prevalence, and incidence of type 2 diabetes) women with PCOS at higher risk of developing diabetes at early age risk for diabetes significantly lower in white women without PCOS in United States, estimated prevalence of PCOS, 5% to 8% (6-9 million women; nearly 1 million diabetic, and slightly over 3 million have IGT)

56 Obesity and insulin resistance
study of obese and lean women with and without PCOS saw highest insulin resistance in obese women with PCOS obese women in control group significantly less insulin-resistant despite identical body mass index (BMI) and body fat composition Lean women with PCOS more insulin-resistant than women in control group obese women in control group and lean women with PCOS similarly insulin-resistant suggests involvement of other factor(s) in development of insulin-resistance in PCOS

57 Beta–cell dysfunction
contributes to development of type 2 diabetes normal obese person can produce sufficient insulin to compensate for degree of insulin resistance and maintain normal glucose tolerance once glucose levels rise above normal, Beta cells unable to compensate in order to maintain normal glucose tolerance as insulin resistance worsens, Beta cells must produce more insulin to maintain normal blood glucose patients with early gestational diabetes tend to have Bet-cell dysfunction Beta-cell dysfunction in patients with PCOS largely determined by presence or absence of first degree relative with type 2 diabetes women with negative family history of diabetes tend to have better Beta-cell function (suggests role of genetic factors in ability to secrete insulin to maintain normal glucose tolerance) women with PCOS and positive family history of diabetes unable to compensate as glucose levels rise, compared to women with PCOS and negative family history

58 Metabolic syndrome increased waist circumference (>88 cm) common in women with PCOS visceral adiposity more significant risk factor for diabetes than peripheral or subcutaneous adiposity women with PCOS tend to have more android, male-type body fat distribution high prevalence of low high-density lipoprotein (HDL) and high triglyceride levels fasting blood glucose (FBG) levels elevated in 10% 10% may be diabetic hypertension not as common (may be due to younger age of women with PCOS women followed over time found to develop hypertension) prevalence of hypertension in PCOS questionably elevated

59 Family history and ethnicity
average waist circumference of patient with PCOS and first-degree relative with type 2 diabetes 4.8 cm greater than patient with negative family history whites and Hispanics relatively protected from some metabolic abnormalities overweight black women with positive family history of type 2 diabetes at highest risk for individual components of metabolic syndrome stratify risk in women with first-degree relative with type 2 diabetes, and black women

60 Obstructive sleep apnea
electroencephalography (EEG) slowwave activity sleep associated with risk for diabetes Sleep loss, sleep fragmentation, and hypoxia contribute to insulin resistance; higher prevalence of OSA in men may be due to testosterone women tend to have more slow-wave activity (protective against OSA) studies—1) looked at small group of women with PCOS, and control group of women matched identically by age and BMI polysomnography used to quan tify apnea-hypopnea index (AHI; number of apneic or hypopneic events per hour of sleep) mean AHI in women with PCOS, 22 (in control group, 7 <5 normal; 5-15 considered intermediate or moderate; >15 severe; >30 extremely severe) twice as many women with PCOS had OSA compared to control group severe OSA 8 times higher in women with PCOS 2) subsequent study showed women with PCOS 30 times more likely to have sleep-disordered breathing or OSA, and 9 times more likely to have daytime sleepiness (after statistically controlling for BMI) insulin resistance stronger predictor of sleep-disordered breathing than age, BMI, or testosterone level effect of reducing slow-wave sleep—OSA characterized by frequent microarousals (ie, awakenings determined by EEG changes, but not by conscious awakenings) and reductions in slow-wave sleep study selectively disrupting slowwave sleep for 3 nights in normal individuals saw significant reduction in glucose tolerance (as defined by intravenous [IV] glucose tolerance testing) and reduction in insulin sensitivity study of women with PCOS 18 to 40 yr of age—>50% of women with PCOS had OSA, compared to 19% in control group (prevalence in general population, 4%-8%); after adjusting for BMI, body fat distribution, family history of diabetes, and ethnicity, patients with PCOS found 7 times more likely to have OSA than patients without PCOS as severity of OSA increases, prevalence of glucose intolerance increases

61 PCOS effect of treatment of OSA on fertility or ovulation—indirect studies looking at sex steroid levels in response to stimulation before and after treatment with continuous positive airway pressure (CPAP) under way screening women with PCOS for OSA—after PCOS diagnosed, consider performing oral glucose tolerance testing morning after performing sleep study Overweight women at higher risk for OSA predictive value of Berlin questionnaire (eg, “do you snore?; do you have morning headaches?”) fairly good CPAP and insulin resistance— most published studies in non-PCOS populations show evidencethat CPAP results in some improvement in insulin sensitivity in short-term insulin sensitivity in obese women tends to be so low that changes in insulin sensitivity may not be remarkable (ie, IV glucose tolerance test may be too insensitive to show improvement) some studies show glucose intolerance and insulin resistance improve with longterm use of CPAP

62 Metabolic pathway of vitamin D
vitamin D3 synthesized in skin in response to UV light, then quantitatively transferred to 25-hydroxyvitamin D in liver small amount of vitamin D in blood 25-hydroxyvitamin D hydroxylated to form 1,25-dihydroxyvitamin D (calcitriol renal conversion regulated by hormonal factors in response to body requirements for calcium [eg, during adolescence, pregnancy]) Degradative deactivation processes to 24-hydroxylate and 1,25-dihydroxyvitamin D can be inactivated by conversion to 25- hydroxyvitamin D vitamin D2—ergocalciferol Derived from plants potent in humans not biologically active unless 25-hydroxylation and 1-hydroxylation occur Vitamin D3—cholecalciferol occurs naturally; biologically inert until hydroxylated

63 Sources of vitamin D sun exposure—affected by seasons
in midwestern United States, no vitamin D made in skin between late October and late March in Chicago, vitamin D blood levels drop by 50% between late September and early April vitamin D production depends on duration of sun exposure and skin pigmentation (less vitamin D made with greater pigmentation) in older age, skin less efficient in converting precursor to cholecalciferol (by age 70 yr, little or no vitamin D produced) disease or dysfunction of liver disrupts metabolic pathway of conversion food— only 100 IU of vitamin D in 8 fl oz of milk found in fatty fish and fortified cereal, but also in inadequate amounts supplements—most calcium supplements contain vitamin D multivitamins contain 200 or 400 IU over-the-counter gel capsules or tablets; prescribed calcitriol

64 Consequences of vitamin D deficiency
decline in intestinal calcium absorption, leading to decreased serum calcium increase in parathyroid hormone (PTH) secretion (leads to increased bone resorption and decreased bone density Particularly noticeable during winter months) increase in 1,25-dihydroxyvitamin D production reestablishes intestinal calcium absorption (if sufficient 25-hydroxyvitamin D present) upward deflection of PTH seen when serum level of 25-hydroxyvitamin D 27 to 39 ng/mL (30 ng/mL important threshold for preventing rise in PTH)

65 Identifying vitamin D deficiency
measure serum 25-hydroxyvitamin D to prevent bone loss, be vigilant about identifying deficiency before patients become symptomatic prevalence of rickets in children increased in North America children have low levels long before showing clinical signs of deficiency measure vitamin D in at-risk children in Europe, most cases of hip fractures associated with deficiency and changes in bone architecture consistent with osteomalacia 25-hydroxyvitamin D 10 ng/mL classified as deficiency (10-30 ng/mL classified as insufficiency 30 ng/mL, normal)

66 Predisposing factors black ethnicity (levels 10 ng/mL seen in nearly 30%) older age; 30% of Mexican American men vitamin D insufficient (rate of depletion higher in women) 30% of white women vitamin D insufficient; attributed to inadequate supplementation (ie, <400 IU/day; however, 45% of those who take >400 IU/day have low vitamin D levels) national standards clearly inadequate

67 Correlation between deficiency and incidence of fractures:
results in decreased femoral neck bone density (predisposing factor for hip fracture) low trauma fractures (97% have serum 25-hydroxyvitamin D levels <30 ng/mL, 80% have <20 ng/mL) 50% of people with hip fractures in United States have 25-hydroxyvitamin D level <30 ng/mL bone biopsy studies found 25% of patients with hip fractures have osteomalacia

68 Management sun exposure—sun exposure for 1 day can increase vitamin D level to 32 ng/mL (depletes after 1 wk without additional sun exposure) no benefit of sun exposure when sunscreen used (when lowest strength sunscreen used, low level [eg, 8 ng/mL] may be sustained) supplementation—400 IU/day recommended for newborns and older children into adolescence 1000 to 2000 IU/day recommended for adults single dose of vitamin D2 peaks in 5 days and returns to baseline in 2 wk metabolic response to 50,000-IU capsule of vitamin D2 highly variable Halflife of vitamin D3 >30 days patients with vitamin D level 20 to 30 ng/mL—give vitamin D3, 4000 IU/day for 4 days, then decrease to 2000 IU/day recheck 25-hydroxyvitamin D, PTH, and calcium periodically patients with vitamin D level <20 ng/mL—give 4000 IU/day for 10 days, then decrease to maintenance dose; monitor levels

69 Vitamin D toxicity need 40,000 IU/day to cause hypercalcemia and renal impairment vitamin D intoxication indicated by 25-hydroxyvitamin D level >200 ng/mL 4000 IU/day not associated with hypercalcemia or impairment in renal function 1000 to 2000 IU/day safe, inexpensive, and effective

70 Vitamin D treat patients with low (7-10 ng/mL) levels, even if PTH normal less frequent dosing for older patient loading patients with vitamin D3 once weekly may be effective monitor levels

71 Metabolic syndrome compilation of cardiovascular risk factors (eg, abdominal obesity, elevated triglycerides, elevated blood pressure [BP], impaired glucose tolerance) that signify dramatically increased risk for cardiovascular disease

72 Epidemiology in 2000, 64 million adult Americans had metabolic syndrome 1 in 4 adults has diabetes or metabolic syndrome high risk groups include blacks and Hispanics important to consider many (some estimates as high as 4 million) patients with impaired FBG have undiagnosed diabetes prevalence of metabolic syndrome increases with age, especially in men; at age 50 yr prevalence in men and women similar at age 70 yr, prevalence in women exceeds that of men

73 Aldosterone adipocyte recognized as endocrine organ
recent data demonstrate blocking aldosterone dramatically affects BP in obese individuals metabolism of obese individuals without primary hyperaldosteronism behaves as intermediate phenotype o hyperaldosteronism Human subcutaneous adipocytes induce extracellular signal-related kinases (ERK1/2 mitogen-activated protein [MAP] kinases), which causes upregulation of steroidogenic acute regulatory proteins and sensitization of angiotensin II in adrenal cortical cells results in mild increase in aldosterone production aldosterone increases to high normal level, or 1 SD above upper limit of normal BP control beneficial in obese patients (most dramatic effect on BP control seen in obese black women)

74 Metabolic syndrome and early hypertension
Propensity for atherosclerosis starts earlier profound atherosclerotic disease noted in studies of Vietnam War veterans 23 to 27 yr of age

75 Overview characterized by oligo-ovulation, hirsutism, other signs of hyperandrogenism, and polycystic ovaries Affects 5% to 10% of reproductive-aged women pathogenesis— possible role of pituitary, androgens, and insulin Probably polygenic (ie, familial clustering suggests underlying genetic etiology, but environmental factors also implicated)

76 Diagnosis 2003 Rotterdam criteria—now used in place of 1990 National Institutes of Health criteria patients must have 2 of 3 1) oligo-ovulation or anovulation 2) clinical or laboratory evidence of hyperandrogenism 3) polycystic ovaries exclude other etiologies oligo-ovulation—<8 menses per year unpredictable onset or heavy bleeding and spotting hyperandrogenism—clinical diagnosis based on hirsutism, acne, and male-pattern alopecia laboratory diagnosis based on elevated total testosterone, free testosterone, or dehydroepiandrosterone (testosterone assays not accurate in women) ovarian characteristics—12 follicles in 1 ovary (controversial) increased ovarian volume Other findings not part of criteria—obesity acanthosis nigricans

77 Diagnostic exclusions
congenital adrenal hyperplasia Thyroid disease Hyperprolactinemia Cushing’s syndrome— consider excluding in patient with features of PCOS and elevated blood pressure, striae, and lipodystrophy ("buffalo hump") androgen-producing tumors—excluded with testosterone level functional hypothalamic amenorrhea— consider if patient exercises frequently and has negative progesterone withdrawal test

78 Rotterdam criteria allow 4 potential PCOS phenotypes with differing combinations of 3 features implications of each phenotype currently under investigation

79 Management of PCOS Control of menstrual cycle
educate patient on importance of progesterone in preventing uterine hyperplasia due to unopposed estrogen cyclic progestin—once every 2 mo for 1 wk oral contraceptive (OC)—easiest added benefits hormone-releasing intrauterine device (eg, Mirena)— acceptable alternative

80 Management of hyperandrogenism
Endocrine Society guidelines on management of hirsutism (2008) treatment based on importance to patient; previously based on modified Ferriman-Gallwey (MFG) score MFG—unfamiliar to many physicians not adjusted to account for varying norms among ethnicities Treatment of hirsutism: mechanical removal—laser, electrolysis, or tweezing pharmacologic—oral contraceptives with antiandrogens (eg, spironolactone, flutamide, finasteride) eflornithine (eg, Vaniqa) mechanisms of OCs—increase sex hormone-binding globulin (SHBG) bind free testosterone directly decrease production of androgens no significant differences seen with different formulations of OCs (choose drug based on side effect profile) takes 6 mo to prevent regrowth acceptable to combine with direct removal consider second agent (eg, spironolactone) after 6 mo

81 Treatment of fertility concerns
anovulation or PCOS Weight loss and lifestyle change clomiphene (eg, Clomid) metformin mechanisms — metformin and weight loss believed to affect insulin sensitivity and function, and thereby improve ovarian function clomiphene triggers brain to increase pituitary production of follicle-stimulating hormone

82 Effect of lifestyle changes
studies found improved ovulation and pregnancy rates with weight loss and exercise weight reduction also reduces complications of pregnancy should be considered first-line

83 Clomiphene first choice if lifestyle changes fail
Synthetic antiestrogen convenient and inexpensive 1998 study— 50% of women ovulated on 50 mg daily additional subsets ovulate with 100 mg or 150 mg daily 45 of 201 patients remained anovulatory, even at 150 mg daily Study of conception—160 patients with anovulatory infertility and successful response to clomiphene 60% conceived after 6 menstrual cycles (70% after 9)

84 Metformin insulin sensitizer
not approved by Food and Drug Administration for treatment of infertility category B for pregnancy 2003 meta-analysis—metformin vs placebo successful (odds ratio [OR] for ovulation 3.8) metformin and clomiphene more effective than clomiphene alone (OR 4.4) Reproductive Medicine Network study (United States)—626 women with PCOS randomized to clomiphene, metformin, or both mean body mass index (BMI) 34 androgenized (ie, high MFG scores) chance of conception highest in clomiphene and metformin group, but difference from clomiphene alone not statistically significant over 6 mo, chance of conception much higher with clomiphene, compared to metformin metformin may take longer to work than clomiphene highest miscarriage rate in metformin group (close to statistical significance) invalidates previous theory that metformin reduced miscarriage rates

85 Predictors of fertility success
Youth lower BMI Lower hirsutism score unclear if specific subgroups benefit from metformin

86 PCOS and Long-Term Health
Insulin resistance Dunaif study (1996)—obese women with PCOS more insulin resistant than obese women without PCOS lean women with PCOS more insulin-resistant than lean women without PCOS, but less so than obese women without PCOS glucose tolerance—found to be impaired in 30% of women with PCOS 10% had type 2 diabetes Metabolic syndrome—common in PCOS 5 criteria (waist circumference, low high-density lipoproteins, high triglycerides, hypertension, and high fasting blood glucose) risk factor for cardiometabolic or cardiovascular disease 33% of women with PCOS found to have metabolic syndrome

87 Metabolic impact of obesity
2001 study—67 women with PCOS and impaired glucose tolerance followed for 6 yr 54% developed type 2 diabetes 15% normalized glucose 31% had no change relative risk for conversion to type 2 diabetes in high BMI group vs low BMI group 10

88 Avoiding type 2 diabetes
Avoiding type 2 diabetes in PCOS (2002 Diabetes Prevention Trial) 4-yr study of individuals with impaired glucose tolerance and family history of diabetes Development of type 2 diabetes—14% of patients on diet and exercise 22% of patients on metformin 29% on placebo recommendations—test glucose tolerance and lipids every 2 yr (modify depending on individual patient’s risk profile) encourage diet and exercise


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