clomiphene citrate & dexamethazone in treatment of clomiphene citrate resistant pcos

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A Elnashar, E abdelmageed, M Fayed, M Sharaf Benha University Hospital, Egypt Aboubakr Elnashar

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A Elnashar, E abdelmageed, M Fayed, M Sharaf

Benha University Hospital, Egypt

Aboubakr Elnashar

C C is the traditional first-line treatment for

chronic anovulation that characterizes PCOS

(Lidor et al, 2000).

However, 25% of PCOS women fail to ovulate

with incremental doses of CC. In addition, clinical

data revealed a discrepancy between ovulation

rates (75%) and conception rates (35%) during

CC treatment (Yen, 1991).

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The use of corticosteroid for the treatment of

ovulatory dysfunction was first reported in 1953

by Jones et al & Greenblatt (Azziz et al, 1999).

Parsanenzhad et al, (2002) had reported the

novel use of the Dexa (high dose, short course)

for inducing ovulation in anovulatory women with

PCOS & normal DHEAS.

Dexa therapy during the follicular phase has been

described without any side effects or serious

sequelae (Edwards et al, 1996).

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Objective

was to evaluate the efficacy of adding Dexa (high dose, short course) to CC in CC- resistant PCOS

with normal DHEAS.

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Patients and Methods

Sample size was calculated

80 infertile women with CC- resistant PCOS were included.

Our inclusion criteria:

1- Age: between 18-39 years.

2- Period of infertility > 2 years.

3- Serum DHEAS within normal levels (80-400 ug/dl).

4- No treatment was taken during the last 2 months prior to

the Dexa treatment.

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Patients were randomly assigned into 2

groups.

Group I (40 women): CC 100 mg/d from D3 to 7

of the cycle combined with Dexa 2 mg /d, in two

divided doses, from D 3 to 12 of the cycle.

Group II(40 women): Same protocol of CC

combined with placebo.

HCG (10.000 U) was given when at least one

follicle measured 18 mm & timed intercourse was

advised.

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Outcome Measures

The primary outcome was the ovulation rate in the treatment

cycle.

Secondary outcomes included number of follicles of >18

mm, endometrial thickness & pregnancy rate.

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Results

•Dexa was very well tolerated as no patients

complained of any side effect.

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Baseline features & clinical outcomes of the two treatment groups

P value Group II

(n=40)

Group I

(n=40)

Variable

0.05 25.1502.3783 23.3803.5941 Age (Y)

>0.05 3.17101.3896 2.11000.9882 Duration of infertility (Y)

>0.05 29.5955.7958 29.3815.1195 Body mass index (Kg/m2)

>0.05 0.96270.0851 0.89480.0940 Waist /Hip ratio

0.05

0.05

32 (80%)

8 (20%)

31 (77.5%)

9 (22.5%)

Menstrual pattern: Oligomenorrhea or Amenorrhea

Eumenorrhea

0.05 (13) 32.5% (11) 27.5% Hirsutism

0.05 107.7885.15 93.3781.52 DHEA-S (ug/dl)

0.05 7.03000.7409 8.82001.4906 Endometrial thickness (mm)

0.05 12.500.71 12.501.61 Day of HCG administration

<0.05 0.15±0.04 1.25±0.67 Follicles >18 mm

<0.001 (6) 15% (30) 75% Ovulation rate

<0.05 (2) 5% (16) 40% Pregnancy

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Characteristics of both Dexa responders and non-responders

Significance Non-

responders

(n=10)

Responders

(n=30)

Variable

NS (a) 25.22.4 23.43.6 Age of patients (Ys)

NS (a) 3.21.39 2.10.98 Duration of infertility (y)

NS (a) 29.65.8 29.45.1 BMI (kgm/m2)

NS (a) 0.960.09 0.890.09 W/H ratio

S (b) 6 (60.0%) 25 (83.3%) Oligomenorrhea or

Amenorrhea (n=31)

S (b) 4 (40.0%) 7 (23.3%) Hirsutism (n=11) S= significant NS= not significant (a) t test (b) X2 test

•Responders were more often amenorrheic than non-responders. •About hirsutism, the population sample (n=11) was too small to allow statistical analysis.

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Discussion

•Several mechanisms have been proposed

Ovarian function:

•Dexa acts directly on the pituitary gland to suppress the

action of E2, which may be involved in the process of induction of ovulation by Dexa-CC treatment (Terkawa,1985).

•Dexa lowers hypothalamo-pituitary LH secretion (Suter & Schwartz,

1985; Saketos et al 1993)

•Dexa acts indirectly by increasing GH (Casaneuva et aL, 1990), serum

IGF-1 (Miell et aL, 1993) & consequently follicular fluid IGF-1.

•Dexa suppress adrenal androgen production (T & DHEAS)

(Haning et al, 1985) and therefore reduce circulating androgen levels in hyperandrogenic women (Karpas

et al, 1984; Ho Yuen & Mincey, 1983).

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•Reducing ovarian androgen production while

suppressing circulating DHEAS as a prehormone for ovarian

steroidogenesis (Haning et al, 1985) presumably lowers elevated intrafollicular androgen levels, which appear to impair folliculogenesis.

•Dexa may directly enhance follicular

development (Smith et aL, 2000). •Dexa may enhance the FSH-stimulated follicular

progesterone production (Roy et al, 2003).

The endometrial thickness:

The adverse endometrial effect seen with CC, are

not seen with Dexa. The endometrium was of

adequate thickness to allow implantation.

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•High dose, short course Vs Low dose, long

course of Dexa (0.5 mg/day for one month) (Diamant

& Evron, 1981; Lobo 1982; Daly 1984; Hoffman, et al., 1985; Trott, et al., 1996; Isaacs, 1997).

Low dose, long course: Favourable endometrial effect is unlikely (Polak de Fried

et al, 1993)

Ovulation rates: 55% to 80%

Pregnancy rates: 8.3% to 49%.

•The high dose, short course regimen:

higher ovulation & pregnancy rates &

more convenient to the patient.

•Although the high dose, short course is more

appropriate, further studies comparing the two

regimen are required (Beck et al, 2005, Systematic review of the Cochrane

library ).

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Conclusion

1. Induction of ovulation by adding Dexa (high

dose, short course) to CC in CC- resistant

PCOS with normal DHEAS is associated with:

no adverse antiestrogenic effect on the

endometrium

ovulation and pregnancy rates in a significant

number of patients.

2. It is an effective, inexpensive & safe method &

may be tried before gonadotropins or

laparoscopic ovarian drilling. Aboubakr Elnashar

Thank You

Aboubakr Elnashar Aboubakr Elnashar