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