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

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

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

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

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

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

7. No.
Balen et al. Hum Repord 1995

8. Obesity
Insulin
SHBG
Free testosterone

9. 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

10. PCOD in Obese and non-obese patients Possible pathophysiological mechanism
Age (range 23-31)
Oligomenorrhea
LH/FSH
Hirsutism (7 Pat.)
U/S diagnosed PCO
4 Pat.
4 Pat.
Obese
Non-obese
BMI
BMI

11. 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

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

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

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

15. 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

16. Insulin resistant and non-resistant PCOS18
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

17. 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

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

19. 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

20. Clinical Data Normo-insulinemic patients Hyper-insulinemic patients
No. of pat. 14 20
Obese
Lean
Obese
Lean 3 11 14 6
BMI.
P<0.05
SHBG
P<0.001
FAI (Tx100)/SHBG
P<0.005
Fulghesu et al. J.C.E.M. 1997

21. 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

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

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

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

25. 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

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

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

28. 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

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

30. 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

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

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

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

34. 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

35. 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

36. 6.3+4.2 p<0.001 100 50 2 1 Months Clark et al. Hum Reprod 1995-0
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

37. 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.

38. 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

39. 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

40. 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
P<0.03
Nestler et al. N Engl J Med 1998

41. 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.

42. 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

43. 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.