Infertility and PCOS

How common is PCOS

• A. 1-2% of women

• B. 3-5% of women

• C. 5-10% of women

• D. 7-12% of women

Answer

• C. 5-10% of women

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

Answer

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

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

Answer

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

Which of the following can decrease fertility in

women? A) Endometriosis

 B) Fibroids C) Tubal disease D) All the above

Answer

•  D) All the above

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)

Answer

•  A) Sperm count, 10 million/mL

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

Answer

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

All women with polycystic ovary syndrome should

undergo hysterosalpingography

before being treated with clomiphene.

 A) True B) False

Answer

• B) False

Polycystic ovary syndrome (PCOS) is a reproductive disorder characterized by _______ and _______.

(A) Anovulation; obesity (B) Anovulation;

hyperandrogenemia (C) Amenorrhea; insulin

resistance (D) Infertility; hyperlipidemia

Answer

• (B) Anovulation; hyperandrogenemia

Beta–cell dysfunction in patients with PCOS is largely determined by presence or absence of a first-

degreerelative with:

(A) Type 2 diabetes (B) Obstructive sleep apnea

(C) Hyperlipidemia (D) Vitamin D deficiency

Answer

• (A) Type 2 diabetes

Which of the following components of metabolic syndrome appears least

common in women withPCOS?

(A) Increased waist circumference (B) Low high-density lipoprotein

level (C) High triglyceride level

(D) Hypertension

Answer

• (D) Hypertension

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

Answer

• (D) Black women

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

Answer

• (C) Insulin resistance

Vitamin D deficiency is associated with:

(A) Decreased serum calcium levels

(B) Rickets (C) Increased parathyroid

hormone levels (PTH) (D) All the above

Answer

• (D) All the above

Which of the following affects vitamin D production?

(A) Sunscreen (B) Age

(C) Skin pigmentation (D) All the above

Answer

• (D) All the above

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

Answer

• (C) 1000 to 2000 IU/day

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

Answer

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

Blocking aldosterone production can have a dramatic effect on

blood pressure control in obeseindividuals.

(A) True (B) False

Answer

• (A) True

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

Answer

• (D) Presence of acanthosis nigricans

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

Answer

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

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

Answer

• (A) High educational level

Lean women with PCOS have a lower probability of developing

type 2 diabetes than obese women without

PCOS.(A) True (B) False

Answer

• (A) True

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

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

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

Evaluation of womenfamily 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,

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

Ovarian reserve• number of eggs remaining

• check for elevated (>15 mIU/mL) FSH on third day of cycle

Ovulatory dysfunction• caused by hypothyroidism and elevated

prolactin

• treated with clomiphene (eg, Clomid)

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

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)

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)

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)

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)

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

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

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

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

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

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

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

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

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)

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)

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

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

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

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

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

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

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

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)

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

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)

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

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

Rotterdam criteria• allow 4 potential PCOS phenotypes with

differing combinations of 3 features

• implications of each phenotype currently under investigation

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

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

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

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

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)

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

Predictors of fertility success

• Youth

• lower BMI

• Lower hirsutism score

• unclear if specific subgroups benefit from metformin

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

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

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