PCOD: Critical analysis of medical and surgical management

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PCOD Critical analysis of medical and surgical
management
Zeev Shoham M.D.
Dep. Of OB/GYN Kaplan Hospital, Rehovot, Israel
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PCOD Various treatment modalities
Pharmacological Treatment
Surgical Treatment
CC
Wedge resection
Hyperinsulinemia? Insulin sensitizer
Gonadotropins
hMG uFSH HP-FSH rec-FSH
GnRH-analogs
Electro cauterization
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Cycle evaluation during CC treatment
Ov. Endo.
Foll. Endo.
36 h
5 days
Menses
Day 5 to 9
Day 13-14
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Anovulatory infertility in PCOS

• 50-80 will ovulate on CC
• Only 40-50 will conceive

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FSH administration regimens
Chronic Low Dose (CLD) S. Franks et al. Step
Down (SD) B. Fauser et al. Sequential (SE) J.N.
Hugues et al.
hCG
150 IU
112.5 IU
75 IU
75 IU
Days
7
14
21
28
150 IU
112.5 IU
hCG
75 IU
Foll. ? 10 mm
½
150 IU
112.5 IU
75 IU
75 IU
hCG
6
12
Foll. ? 14 mm
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Ovarian Hyperstimulation Syndrome
Multiple pregnancy
Prevention ?
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Patients at Risk
PCOD
hCG (Exo/Endo)
High serum E2
Multiple follicles
Younger age lt32
Lean Habitus
GnRH-a Protocols
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Strategies for prevention
Withholding hCG administration Reduced dose of
hCG Administration of native GnRH or
GnRH-a Administration of rec-LH Freeze all embryos
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Prevention of OHSS


Replacing hCG with rec-LH or GnRH-a
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Spontaneous LH surge
hCG
Endogenous surge triggered by GnRH-a
IU/L
Periovulatory phase (hrs)
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LH Serum Concentration versus Time
400 IU/kg IV
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r-LH u-LH p-LH
1
Normalized LH serum level (I/L)
0.1
0.01
0.001
48
24
60
36
12
72
84
0
96
Time
le Cotonnec and Porchet 1993
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Multiple Gestation
From curiosity to epidemic
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Multiple Gestation
Rate

• Japan 6.7/1000
• U.S/Europe 11/1000
• Africa 40/1000
• Monozygous 3.5/1000
• O.I./ART 370/1000

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How to minimize the risk of multiple gestation


Optimize Follicular Development?
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Multiple pregnancy rate related to the number of
follicles gt 16 mm on hCG day
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How to minimize the risk of multiple birth


Strict criteria for hCH administration.
Optimize Follicular Development? The use of
different doses of rec-LH
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The use of rec-LH to facilitate monofollicular
developmentEuropean r-hLH Research Group
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United Kingdom
Holland
Italy
Israel
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Study design
To assess the efficacy of two doses of r-hLH
225
450
Given at the late follicular phase to FSH treated
PCOS patients
if
? 4 foll. 8-13 mm
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• 17 PCOS patients enrolled
• Placebo 5 patients
• r-hLH 225 IU/day 4 patients
• r-hLH 450 IU/day 8 patients

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PRIOR TO STUDY patients received FSH
stimulation.
When at least one follicle of ? 18 mm and ? 3
follicles of ? 11 mm gt hCG 5000 IU
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Mean total number of follicles at baseline(?
8-13 mm) and on day of hCG (? 14 mm)
Placebo
225 IU r-hLH
450 IU r-hLH
18
14
14
9.75
8.88
10
No. of follicles
8-13
6
2
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Summary

• This study supports the hypothesisadding high
  dose LH during the late follicular phase, induces
  atresia of growing follicles.

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How to minimize the risk of multiple birth and
still achieve a good pregnancy rate/ per started
cycle?


Adjust the No. of embryos transferred depending
on risk factors for multiple gestation.
Age.
A good freezing program
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Conclusion
Identify patients who will benefit from single
blastocyst transfer. We have to adopt a strategy
where we try to retrieve multiple oocytes,
replace one blastocyst and freeze the others .
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Compensatory Hyperinsulinemia
Insulin resistance
?
Ovary
Cause-and-effect relationship
Androgens
Serum insulin
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Impact of insulin secretion on ovarian response
to FSH stimulation in PCOS
Relationship between Circulating insulin
levels Follicular growth Ovarian
hormone secretion
Fulghesu et al., J Clin Endocrinol Metab 1997
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Clinical Data
Normo-insulinemic patients
Hyper-insulinemic patients
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20
No. of pat.
Obese
Obese
Lean
Lean
11
14
6
3
BMI.
Plt0.05
23.24.1
27.85.3
FAI (Tx100)/SHBG
Plt0.005
4.121.9
11.395.4
Fulghesu et al. J.C.E.M. 1997
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Treatment protocol
Fulghesu et al. J.C.E.M. 1997
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Stimulation outcome
Normo-insulinemic patients
Hyper-insulinemic patients
No. of Cy.
Dose/BMI
FSH dose
Ovul. rate
OHSS
Plt0.05
Pregnancy
Abortion
Fulghesu et al. J.C.E.M. 1997
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Plt0.01
Fulghesu et al. J.C.E.M. 1997
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Diameter gt12 mm and lt 16 mm
Number of follicles
Plt0.01
Days from hCG injection
Fulghesu et al. J.C.E.M. 1997
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Conclusion
Insulin resistance may be an important marker for
poor outcome and for high risk for development
of the ovarian hyperstimulation syndrome.
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Hyperinsulinemic PCOS patients management

• Weight loss diet, exercise, life-style changes
• Insulin lowering agents
• Induction of ovulation

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Metformin

• Dimethylbiguanide
• Multiple mechanisms of action
• Inhibition of gluconeogenesis in the liver
• Enhanced peripheral uptake of glucose
• Increased intestinal use of glucose
• Decreased fatty acid oxidation

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61women with BMI gt28
USA
Venezuela
Italy
PCOS
26 women received - Placebo
1 ovulated
Plt0.001
35 women received - Metformin 1500 mg/day
14 ovulated
1
14
28
35
Prog. gt25 nmol/L
Nestler et al., New Engl J Med 1998
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CC 50 mg
25 women received - Placebo
2 ovulated
Plt0.001
21 women received - Metformin 1500 mg/day
19 ovulated
1
5
10
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Area under the curve (micU/ml/min) 75 g of
glucose (0,60,120 min)
Pre-
Post
Metformin Placebo
65981267 65581030
3479455 510055
Plt0.03
Nestler et al., New Engl J Med 1998
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Conclusions Effects of metformin
on gonadotropin-induced ovulation in PCOS

• Reduction of follicles gt 15 mm in diameter
• Reduction in E2 levels on hCG day
• Reduction in cycle cancellation (hCG withholding)
• Lower incidence of OHSS

De Leo et al., Fertil Steril 1999 72282-5
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A major challenge for every physician is to
balance the immediate gain of a pregnancy against
the potential long term negative impact of the
treatment, mainly OHSS and multiple gestation.