Polycystic ovarian syndrome Obesity and Insulin resistance Zeev Shoham, M.D. Department of Obstetrics and Gynecology, Kaplan Hospital, Rehovot, Israel

Polycystic ovary syndrome is a poorly understood disorder Clinically: Menstrual disorder Hirsutism Obesity Infertility PCO

Clinical features of 1557 patients with PCOS Clinically: Hirsutism 63.9% Acne 31.6% Infertility 24.8% Menstrual cycle status Regular 25.0% Oligo. 51.5% Amen. 23.0% Acanthosis nigricans 3.6% Balen et al. Hum Repord 1995

POLYCYSTIC OVARY SYNDROME Obesity and insulin resistance Pathophysiology Clinical implications Proposed treatment

Hyperinsulinemic state Hypothalamic Adrenal Ovary Inherent defect in androgen-secreting tissue Obesity Insulin resistance Hyperinsulinemic state

Ovary ? Insulin resistance Compensatory Hyperinsulinemia Cause-and-effect relationship Androgens Serum insulin

No. Balen et al. Hum Repord 1995

Obesity Insulin SHBG Free testosterone

PCOD in obese and non-obese patients Possible pathophysiological mechanism Hypothesis PCOD is a multifactorial disease in which the full clinical expression is the result of a synergistic pathological action of several different systems. It results from triggering by one factor, which stimulates an abnormal response by other systems. Insler et al. Hum Reprod. 1993

PCOD in Obese and non-obese patients Possible pathophysiological mechanism Age - 26.4 (range 23-31) Oligomenorrhea LH/FSH - 3.5+0.3 Hirsutism (7 Pat.) U/S diagnosed PCO 4 Pat. 4 Pat. Obese Non-obese BMI - 34.7 + 2.3 BMI - 20.5 + 0.8

PCOD in Obese and non-obese patients Possible pathophysiological mechanism Protocol On day 5 (spontaneous or gestagen induced cycle), blood samples were collected every 20 min over a period of 8 h, starting at 23:00 h. Insler et al. Hum Reprod 1993

Different hormone concentrations in obese and non-obese PCO patients (184 samp.) Insler et al. Hum Reprod. 1993

Different hormone concentrations in obese and non-obese PCO patients Insler et al. Hum Reprod. 1993

Different hormone concentrations in obese and non-obese PCO patients Obese patients LH SHBG GH IGFBP-I Insulin Insler et al. Hum Reprod. 1993

Different hormone concentrations in obese and non-obese PCO patients Hypothesis In patients with PCOD, hyperandrogenism results from hyperinsulinemia in obese women, or is caused by high concentrations of GH and LH in the non-obese women. Insler et al. Hum Reprod. 1993

Insulin resistant and non-resistant PCOS 18 35 patients 19 Insulin resistant Non-insulin resistant P<0.0001 P<0.017 P=NS P<0.02 P<0.027 Weight/height 2 40 40 20 20 BMI LH Andr Test SHBG Estrad Meirow et al. Hum Reprod 1995

Insulin resistance Hyperinsulinemia PCOD Non-obese Obese GH Insulin resistance Hyperinsulinemia LH LH and IGF-I effect on theca cells IGFBP-I IGF-I Cytochrome p-450c 17-alpha activity SHBG Androgen secretion

POLYCYSTIC OVARY SYNDROME Obesity and insulin resistance Pathophysiology Clinical implications Proposed treatment

Circulating insulin levels Follicular growth Ovarian hormone secretion Study objective relationship between Circulating insulin levels Follicular growth Ovarian hormone secretion in patients with PCOD Fulghesu et al. J.C.E.M. 1997

Clinical Data Normo-insulinemic patients Hyper-insulinemic patients No. of pat. 14 20 Obese Lean Obese Lean 3 11 14 6 BMI. 23.2+4.1 P<0.05 27.8+5.3 SHBG P<0.001 48.47+29.3 23.29+8.2 FAI (Tx100)/SHBG 4.12+1.9 P<0.005 11.39+5.4 Fulghesu et al. J.C.E.M. 1997

Treatment protocol E 2 12 4 amps. 1 Fulghesu et al. J.C.E.M. 1997 Menses hCG 5,000 12 4 amps. 1 FSH 8 14 18 E 2 Fulghesu et al. J.C.E.M. 1997

Stimulation outcome Normo-insulinemic patients Hyper-insulinemic patients No. of Cy. 21 57.7+18.7 23.8% 85.7% 28.5% 16.6% 1395+472 31 54+18 64.5% 83.8% 16% 20% 1507+727 Dose/BMI FSH dose Ovul. rate OHSS P<0.05 Pregnancy Abortion Fulghesu et al. J.C.E.M. 1997

Days from hCG injection Estradiol (pmol/L) Days from hCG injection P<0.01 Fulghesu et al. J.C.E.M. 1997

Diameter >12 mm and < 16 mm Number of follicles P<0.01 Days from hCG injection Fulghesu et al. J.C.E.M. 1997

Continues infusion of glucose Non-insulin resistance Impact of insulin resistance on the outcome of ovulation induction in PCOD patients Patients Dale et al. Hum Reprod 1998 42 infertile patients Oligo/Ameno LH/FSH > 2 Hirsutism CC failure Hyperandrogenism U/S diagnosed PCO 17 Pat. 25 Pat. Insulin resistance Continues infusion of glucose Non-insulin resistance

Endocrine results on day 4 - 7 of the cycle Dale et al. Hum Reprod 1998

Endocrine results on day 4 - 7 of the cycle Dale et al. Hum Reprod 1998

Treatment protocol E 2 amps. 2 75 IU uFSH 1 < 1 < 4 14 days 3 17 hCG 5,000 amps. 2 37.5 75 IU uFSH 1 < 1 18 E 2 < 4 14 14 days 8 Menses 3 17 Dale et al. Hum Reprod 1998

Clinical results following low-dose protocol Dale et al. Hum Reprod 1998

Fasting insulin levels R=0.6, p<0.003 No. of Amps. Fasting insulin levels R=0.6, p<0.003 Homburg et al. Hum Reprod 1996

Homburg et al. Hum Reprod 1996 No. of Amps. BMI R=0.6, p<0.004 Homburg et al. Hum Reprod 1996

These studies indicate that insulin resistance may be an important marker of a poor outcome and of patients at high risk for ovarian hyperstimulation.

POLYCYSTIC OVARY SYNDROME Obesity and insulin resistance Pathophysiology Clinical implications Proposed treatment

Management of patients with PCOS Infertility Increase rate of ovulation through the controlled of insulin reduction by diet Suppress elevated LH levels Hyperandrogenism Reduce insulin drive Anti androgen medication Long term complications Correction of metabolic and cardiac risk factors

Weight loss, ovulation rate and pregnancy in PCOS patients Infertility > 2 years Anovulation CC resistance Treatment protocol: - 6 months Gradual dietary change Regular exercise Clark et al. Hum Reprod 1995

6.3+4.2 p<0.001 100 50 2 1 Months Clark et al. Hum Reprod 1995 -0 6.3+4.2 p<0.001 -2 Weight loss (Kg) -4 -6 -8 Insulin -10 -12 Ovulation % 100 50 SHBG 2 Number Pregnancy 1 1 7 8 9 5 4 6 2 3 Months Clark et al. Hum Reprod 1995

Conclusions Out of 13 patients 12 conceived within 12 months (6 spontaneously and 6 during the first or second treatment cycle). Running a group of 14 people is equivalent to the cost of one IVF cycle.

Reduced insulin secretion by drugs: Diazoxide Metformin Triglitazone 140 160 Weight (lb) 50 150 250 cc Lobo et al. Fertil Steril 1982 Associated with Hyperinsulinemia Adversely affect follicular Development by increasing androgen. Account for the poor responsiveness to CC

61women with BMI >28 USA Venezuela Italy PCOS 1 14 28 35 26 women received - Placebo 1 ovulated P<0.001 35 women received - Metformin 1500 mg/day 14 ovulated 1 14 28 35 Prog. >25 nmol/L Nestler et al. N Engl J Med 1998

Area under the curve (micU/ml/min) 75 g of glucose (0,60,120 min) 25 women received - Placebo 2 ovulated P<0.001 21 women received - Metformin 1500 mg/day 19 ovulated 1 CC 50 mg 5 10 18 Area under the curve (micU/ml/min) 75 g of glucose (0,60,120 min) Metformin Placebo 6598+1267 6558+1030 3479+455 5100+55 P<0.03 Nestler et al. N Engl J Med 1998

Conclusions Obesity plays a central role in the development of PCOS leading to hyperinsulinemia in susceptible individuals. This hyperinsulinemia may alter androgen metabolism via a variety of mechanisms, the net result of which is hyperandrogenism.

Conclusions The management of patients with PCOS depends upon the individual patient’s complains Hyperandrogenism are optimally dealt with by reducing insulin drive to the ovary, such as exercise and reducing diet

Conclusions Infertility is treated by increasing the rate of ovulation, in part by reducing insulin drive Ovarian stimulation is used for those patients who do not ovulate, despite losing weight.