1. Obesity has a negative impact on fertility
Obesity is a major health problem; also, together with increasing age of aspiring parents, it constitutes a challenge for fertility
In large Finnish and US cohorts 1, 2, an inverse U-shaped association between BMI and number of children was demonstrated in both women and men
Part of this association is mediated by marital status
In women, the effect of obesity appears to be stronger than that of underweight
Jokela et al, Epidemiology 2007; 18:
Jokela et al, Am J Clin Nutr 2008; 88:

2. Data from US National Longitudinal Survey of Youth (5982 women)
Cumulative probability of having a first child in women of different body weight until 47 years of age
Data from US National Longitudinal Survey of Youth (5982 women)
Jokela et al, Am J Clin Nutr 2008; 88:

3. Obesity leads to insulin resistance (IR)
Positive energy balance → IR and basal hyperinsulinemia :
- liver: portal insulin↑ →triglyceride-deposition (“fatty liver”) & unrestrained glucose production →relative hyperglycemia
- skeletal muscle: impaired capillary recruitment (microvascular perfusion) and glucose delivery/uptake; TG deposition
- visceral adipose tissue: unrestrained lipolysis (→FFA) and abnormal adipokine profile
Progressive islet TG-deposition →β-cell dysfunction and loss→basal hyperglycemia (type 2-diabetes)
IR and β-cell dysfunction are also determined by genetic factors (polygenic)

4. Natural history of type 2 diabetes: time-scale
Positive energy balance
Accelerated progression of insulin resistance: lifelong or years
Increased liver fat: years
Increased plasma triglycerides: years
Unrestrained liver glucose production: few years
Initial elevation of plasma glucose: few years
Excess exposure of islets to fatty acids: months to years
Decreased insulin secretion in response
to glucose: months to years
Hyperglycemia: months
Irreversible beta cell loss and dysfunction: >2 years
Taylor, Diabetologia 2008; 51:

5. The metabolic syndrome as a clinical expression of IR
At least three of five criteria (2001 NCEP ATP III):
Central fat accumulation: waist circumference ≥88 (80) cm in women
Raised blood pressure (≥130/85 mm Hg)
Elevated fasting plasma glucose (≥5.6 mmol/l,100 mg/dl), or on treatment for raised glucose
Elevated triglycerides (≥1.7 mmol/l,150 mg/dl), or on treatment for raised triglycerides
Reduced HDL-cholesterol (<1.3 mmol/l, 50 mg/dl), or on treatment for reduced HDL

6. Hum Reprod 2008; 23:

7. IR/hyperinsulinemia leads to reproductive dysfunction
Principal mechanism = elevated free (bioavailable) testosterone
- hyperinsulinemia →SHBG-production by liver↓ →free T↑
- hyperinsulinemia →increased androgen production by theca-cells and stroma (17-OH-P, Δ4A, T) in some women
Women with obesity/type 2 diabetes are more likely to be anovulatory and to have irregular cycles; conversely, irregular cycles or PCOS is independent predictor of subsequent type 2-diabetes
Women with obesity/type 2 diabetes are more likely to be hirsute (“le diabète de la femme à barbe”)
There is no evidence of IR at the ovary or endometrium in obese or PCOS women

8. Insulin stimulates ovarian growth
In extreme congenital IR (insulin receptor mutation), ovaries are enlarged even before puberty
The IR associated with normal puberty stimulates ovarian growth, especially in girls with underlying IR
Mechanisms involved are only partly elucidated:
- direct: activation of insulin receptors; upregulation and activation of IGF1 receptors or “hybrid” insulin-IGF1 receptors
- indirect: portal insulin↑ →IGFBP-1 in liver↓ →more bioavailable IGF1
Excessive ovarian growth is reversible with insulin-sensitizing agents

9. Insulin-sensitizing treatments: an overview
All treatments that result in reversal of positive energy balance:
- exercise →skeletal muscle insulin sensitivity↑ (“vascular fitness”)
- any hypocaloric diet
- anti-obesity drugs: orlistat, sibutramine
- anti-obesity (bariatric) surgery: gastric banding, gastric bypass, biliopancreatic diversion
Specific pharmacological anti-IR treatments :
- metformin
- thiazolidinediones (TZDs) or glitazones (pioglitazone, rosiglitazone)

10. Hypocaloric diets with or without exercise in overweight PCOS patients are helpful
Weight loss of 5-10% improves cardiometabolic (insulin, SHBG, HDL-cholesterol) and hormonal (total/free testosterone) indices
Adding aerobic or combined aerobic-resistance exercise offers advantages in terms of body composition (fat mass or %) (1)
At least 40-50% (44-92%) of anovulatory women resume spontaneous ovulation(s) after weight loss of 5-10 kg, with improvement of menstrual cyclicity (1)
Effect on hirsutism is poorly studied, and probably moderate
Several studies (DPP etc) show that diet+exercise reduces type-2 diabetes incidence by 58% in high-risk individuals, although <60% of participants met the targets (2)
Thomson et al, J Clin Endocrinol Metab 2008; 93:
Knowler et al, N Engl J Med 2002; 346:

11. Yet lifestyle intervention in PCOS women is not without problems
Requires a continued commitment from the patient (“conversion of Paul” moment)
Rapid weight loss should be avoided → time needed for improvement of hirsutism or/and ovulation rate may be substantial
While inherently cheap, diet and exercise programs supervised by health workers are not without costs for patient and society alike
Weight cycling and weight gain after initial loss may rapidly undo any hard-won improvements

12. Pharmacotherapy: metformin
Biguanide antidiabetic agent with “second life” after US registration in 1995
Mode of action: improves insulin sensitivity in liver (ie, relieves unrestrained glucose production); possibly, improves glucose uptake by muscle and AT; does not increase insulin secretion
Usual dose: mg in two or three doses, strictly with meals; increase dose slowly
Side-effects: gastrointestinal (nausea, diarrhea, abdominal pain) in ≤50% of users
Safe in young persons; lactic acidosis (1/30,000) occurs in patients with hepatic or renal impairment, heart failure, alcoholism

13. Metformin is a useful “holistic” treatment strategy in PCOS patients with the metabolic syndrome: arguments pro
Variable, on average small beneficial effect on body weight →IR↓
Any beneficial effect on BW may be an incentive for lifestyle intervention
Improvement in cardiometabolic (insulin, SHBG, HDL-C), hormonal (free/total T) and endothelial function (flow-mediated vasodilation) IR parameters
Improvement in ovulation rate compared to placebo: RR = 2.94 ( ); gradual improvement in menstrual cyclicity (6-12 months)
Moderate improvement in hirsutism after 8 months, although less than anti-androgen treatment with cyproterone acetate
In patients at high risk for type-2 diabetes, metformin 1700 mg/d reduces diabetes incidence by 31%, especially in young and overweight individuals (DPP); benefits persist even after stopping metformin (UKPDS)
No risk of hypoglycemia
No teratogenicity demonstrated as yet
Possible benefits during pregnancy: reduced miscarriage rate?? reduced GDM rate? (Glueck, Rowan)
Very cheap

14. Effect of metformin on body weight in PCOS (studies with at least 6 months duration)
Duration Treatment(s) N Mean change in BW Ref.
(months)
Metformin % Hoeger 2004
Lifestyle+Metformin -8.9%
Metformin1500mg/d kg Harborne 2005
Metformin2500mg/d -3.7kg
Metformin kg Tang 2006
6 Metformin kg Pasquali 2000
Metformin kg/m2 Moghetti 2000
Modified from Golay A: Metformin and body weight. Int J Obes 2008; 32: 61-72

15. Effect of metformin on ovulation: meta-analysis of metformin compared with placebo (left); CC + metformin compared with CC and placebo (right)
Creanga et al, Obstet Gynecol 2008; 111:

16. Metformin vs. clomiphene citrate (CC) for ovulation induction: the time issue
Two randomized trials (Legro, Moll) showed that 1) metformin alone resulted in a lower live birth rate than CC alone after 6 months; 2) metformin+CC confers no added benefits compared to CC alone
Comments to studies: poor medication adherence? suboptimal dose ( mg/d)? short time (6 months)? subgroup analyses? Still higher multiple pregnancy rate with CC
Poor adherence with metformin does not explain the results (1)
However, in a post-hoc analysis (2), pregnancy rates were higher in patients treated with combination (CC+metformin) if they were ≥28y old and had a WHR ≥0.85
Pretreatment with metformin is still an option if 1) PCOS + metabolic syndrome and 2) time-scale for fertility >6 months (3)
No place for metformin in lean PCOS
1. McGovern et al, Fertil Steril 2008; 90: ; 2. Moll et al, Hum Reprod 2008; 23:
3. Nestler, Fertil Steril 2008; 90: 14-6

17. Kaplan–Meier curves for live birth in infertile women with PCOS randomized to metformin, clomiphene, or the combination of both
Legro et al, N Engl J Med 2007; 356: 560

18. There is no place for TZDs in PCOS
Pharmacological agonists (ligands) of PPARγ receptor (differentiation of fat cells)
Mechanism of TZDs: improved peripheral glucose disposal; smaller fat cells, with less lipolysis; no stimulation of insulin secretion
Troglitazone has been tested extensively in PCOS, but has been withdrawn (liver toxicity)
Preliminary data with pioglitazone and rosiglitazone (no liver toxicity) in PCOS
Same benefits as metformin on metabolic, hormonal, endothelial function parameters; on ovulation rate and cyclicity; on hirsutism
But: weight gain (more sc fat and ECF); risk of cardiac failure; more cardiovascular morbidity/mortality (rosiglitazone); deleterious effect on bones (accelerated aging) with more fractures; potentially teratogenic; expensive, PCOS is not an indication

19. In sum…
The metabolic syndrome is on the rise and has a negative impact on fertility
The principal mechanism is by increasing androgen availability and reducing ovulation rate
Metabolic screening is useful in fertility practice
Reversal of the positive energy balance (hypocaloric diet, exercise) is the primary goal, but requires patients’ commitment
Anti-obesity drugs and surgery may be helpful in selected cases
Metformin is a useful adjunct in PCOS+metabolic syndrome, both for fertility reasons and for long-term metabolic outcome; however, a time-scale of 6-12 months is required for fertility indications
There is no place for TZDs (or other antidiabetic agents) in PCOS