síndrome de ovario poliquistico y obesidad

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
Menstrual disorder
Hirsutism
Obesity
Infertility
PCO

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

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

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

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

7. 0
50
100
150
200
250
300
16 20 24 28 32 36 40 44
BMI
No.
Balen et al. Hum Repord 1995

8. Obesity
Insulin
Free
testosterone
SHBG

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

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

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. Hormone BMI >25 BMI<25
LH
FSH
8.32+0.84
6.00+0.3
17.24+0.2
6.38+1.0
P=0.0001
P=0.74
SHBG (nmol/L)
Insulin (mU/L)
20.38+0.38
15.68+1.32
51.34+2.33
8.00+1.11
P=0.0001
P=0.0001
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
Hormone BMI >25 BMI<25
GH (ng/mL) 1.50+0.17 2.42+0.24 P=0.002
IGFBP-I (ng/L) 9.37+0.72 51.01+11.8 P=0.001
IGF-I (nmol/L) 27.98+1.83 27.33+1.42 P=0.77

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

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

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

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

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

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

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

21. Menses
hCG 5,000
12
4
4
amps.
1
FSH
8
14
18
E2
Fulghesu et al. J.C.E.M. 1997
Treatment protocol

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

23. Fulghesu et al. J.C.E.M. 1997
0
1000
2000
3000
4000
5000
6000
7000
B
a
s
a
l
-
5
-
4
-
3
-
2
-
1
0
Hyperins
Normoins
Estradiol
(pmol/L)
Days from hCG injection
P<0.01

24. Fulghesu et al. J.C.E.M. 1997
0
1
2
3
4
5
6
7
Basal -5 -4 -3 -2 -1 0
Hyperins
Normoins
Number
of
follicles
Days from hCG injection
P<0.01
Diameter >12 mm and < 16 mm

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

26. Hormone Insulin R. Non-ins R.
LH (IU/L)
FSH (IU/L)
8.3+4.7
5.0+1.5
7.9+3.6
5.1+1.2
Test (nmol/L)
Andro (mU/L)
2.4+0.7
7.0+2.2
2.5+1.2
6.6+3.0
Dale et al. Hum Reprod 1998
Endocrine results on day 4 - 7 of the cycle

27. Hormone Insulin R. Non-ins. R.
SHBG (nmol/L) 21.1+17 34.8+18.6 P=0.05
Fasting insulin
(mIU/L)
27.5+14.7 11.3+3.9 P=0.05
Endocrine results on day 4 - 7 of the cycle
Dale et al. Hum Reprod 1998

28. Dale et al. Hum Reprod 1998
Treatment protocol
Menses
hCG 5,000
17
3
2
amps.
1
8
14
18
E2 < 4
< 1
14 days
75 IU uFSH
37.5

29. Insulin R. Non-ins. R.
No. of cycles
Stimulation (d)
FSH dose (IU)
29
19.2+7.9
2045+1220
41
15.3+6.1
1304+500
P=0.05
P=0.05
Pregnancy
Abortions
2
2
14
5
P=0.05
Clinical results following low-dose protocol
Dale et al. Hum Reprod 1998

30. Homburg et al. Hum Reprod 1996
0
20
40
60
80
100
120
0 20 40 60 80
No.
of
Amps.
Fasting insulin levels
R=0.6, p<0.003

31. Homburg et al. Hum Reprod 1996
0
20
40
60
80
100
120
0 10 20 30 40
No.
of
Amps.
BMI
R=0.6, p<0.004

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

35. Weight loss, ovulation rate and pregnancy in PCOS
patients
Patients: 13
Treatment protocol: - 6 months
Infertility > 2 years
Anovulation
CC resistance
Gradual dietary change
Regular exercise
Clark et al. Hum Reprod 1995

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

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

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

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

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.