CC

50%: ovulate using the 50-mg/d

Another 25%: ovulate if the dosage increased to

100 mg/d

(Hughes et al., 2000).

Most CC-induced pregnancies occur within the

first 3 cycles.

There is no benefit to increase dosage once

ovulation has occurred or to continuing beyond 6

ms

Derman et al., 1995). Aboubakr Elnashar

CC should be discontinued if the patient is anovulatory after

the dose has been increased in 3 consecutive cycles up to

100 mg (Balen, ,1999).

•150 mg or more confer no benefit (Kousta et al., 1997) &

only worsen the side effects:

thickened cervical mucus

antiestrogenic effect on the endometrium

(Sereepapong et al., 2000).

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CC Resistant PCOS

Incidence:

20%

Define

No ovulation (Absence of follicular development on TVS with concomitant failure of E2 levels to rise) after treatment with CC, {100 mg, for 5 days in 3 cycles} (Coelingh Bennink, 1998).

Causes:

hyperandrogenic

Obese

Severe insulin resistance (Murakawa et al., 1999; Speroff et al., 1999).

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CC failure

Define:

No pregnancy despite of ovulation with CC

Causes:

cervical and endometrial changes

low fertilization rate,

variable implantation rate and

deficient corpus luteum function (Speroff et al., 1999)

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I

1. Life style changes: Weight reduction,

Exercise,

stop smoking

2. CC + corticosteroids if DHEAS > 2ug/ml

II

Alternatives

1. Tamoxifen

2. Letrozole

3. Metformin

Adjuvants

1. Corticosteroid

2. NAC

3. Prett with COC

Bromocriptine

Extended CC.

Antiandrogens:

a. Ketoconazole b. Aldactone c. cyproterone acetate Naltrexone

Prett with progesterone Aboubakr Elnashar

Alternatives

1. Tamoxifen •No evidence of a difference in effect between CC

& tamoxifen (Cochrane library, 2005)

The recent NICE report (NICE 2004) regarded both CC & tamoxifen as equally

effective agents for ovulation induction. •CC in combination with tamoxifen has no effect

on PR when compared to CC alone (Cochrane library, 2005)

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2. Insulin sensitizers

Types:

1. Metformin

2. D-Chiro-inositol: induced ovulation sucessfully with no serious side effects, but limted studies

3. Rosiglitazone, Pioglitazone: limited studies

4. Troglitazone: Withdrawn by FDA because of liver toxicity & other side effects

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Metformin: oral biguanide

Mechanism of action:

A. Decrease blood glucose level by:

a.Mainly: decrease hepatic glucose production

b.To lesser extent: increases peripheral glucose uptake.

B.Increases insulin sensitivity at the post-receptor level

Unlike S. urea it does not cause hypoglycaemia because it does not increase insulin secretion.

C. Directly inhibits human ovarian steroidogenesis (Mansfield et al,2000)

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Side effects:

diarrhea, n,v, abd bloating, metallic taste, v. rare lactic acidosis

Contraindications:

1. Renal (creatinine >1.4mg/dl) or hepatic impairment

2. Cardiac or respiratory disease.

Dose:

500 mg/d for 1 w then 500 mg bid for 1 w then 500 mg tds then 850 mg bid

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Effects:

1. Increase SHBG,decrease insulin, A, FT, LH. These improvements occurred in absence of any change in body weight (Iurno & Nestler,2001)

2. Increase both spontaneous & CC induced ovulation rate (Nestler,1998)

3. Enhance the response to induction with FSH injection (Deleo et al, 1999)

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4. As adjunctive during COH: Improvement in oocyte quality, fertilization rate, embryo development (Geusa et al,2002), implantation & clinical pregnancy rates (Kahraman et al,2002)

5. Reduces FSH stimulated aromatase activity in PCOS (De Leo et al,2002)

6. Improves the features of syndrome X e.g hypertension & obesity.

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Uses:

1. In PCOS:

a. Induction of ovulation in:

Insulin resistant PCOS: Both obese & lean with hyperinsluinaemia respond to metformin (Speroff,1999)

CCR PCOS (ASRM, 2002)

PCOS: as a first line drug (Sharma, 2005)

b. To prevent OHSS in PCOS induced by gonadotrophin (Visnova et al,2002)

c. To reduce the doses of gonadotrophin in PCOS patients undergoing ovarian stimulation (Atassi et al,2002)

d. In adolescent PCOS: Use for 1 year to prevent full picture (Hassan & Yousef, 2002)

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2. IN PCOS during pregnancy

a. Prevent early pregnancy loss (Jakubowicz et al,2000, Gluek et al,2001): by decreasing platelet activator inhibitor

b. Prevent Gestational D.M (Glueck et al,2002). 2.55 g/d, 10 fold decrease in GDM

c. Treatment of DM after the first trimester (Coetze et al,1979; Hellmuth et al,2000). It is not teratogenic (category B,FDA)

d. Prevent fetal virilization with increased androgen (Sarlis et al, 1999)

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The Cochrane Database of Systematic Reviews 2005 Issue 4, Lord et al •Metformin has a significant effect in reducing fasting

insulin & LDL. There was no evidence of effect on BMI

or WHR.

•Metformin was associated with a significantly higher

incidence of GIT disturbance

•Metformin is an effective treatment for anovulation in

women with PCOS.

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Its choice as a first line agent seems justified.

•Ovulation rates are higher when combined with CC

(76% Vs 46% when used alone)

•It should be used as an adjuvant to general lifestyle

improvements, and not as a replacement for increased

exercise and improved diet.

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Systematic review of metformin Vs CC in PCOS (Kashyap, 2004).

•Metformin plus CC are 3-4-fold superior to CC

alone for ovulation induction and pregnancy.

•No RCTs directly compare metformin to CC but

the need for such a trial exists.

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3. Aromatase inhibitors

Mechanism

1. Release the pituitary/hypothalamic axis from

the estrogenic negative feedback, increase Gnt

secretion, stimulate ovarian follicle development

(Mitwally & Casper, 2001).

2. locally in the ovary: increase the follicular

sensitivity to FSH (Vendola et al,1998).

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Advantages

1. No adverse antiestrogenic effect on the

endometrium or cervical mucus

a. absence of estrogen receptor depletion.

b. Rapid elimination from the body (half-life of 45

hours)

2. Limited number of mature follicles (decrease

OHSS & multiple pregnancy).

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Dose

• Letrozole:

2.5 -5 mg/ day on day 3 to 7 or

Single dose of 20 mg on day 3

(Mitwally & Casper,2001).

•Anstrazole:

1-2 mg/day

The comparison between two AIs (letrozole and

anastrozole) did not find any evidence of a

difference in effect on pregnancy rate

(Cochrane library, 2005)

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b. The largest study (44 patients) done by

Elnashar et al (MEFS J; 2004):

Induction of ovulation with Letrozole in CC R

PCOS is associated with ovulation rate

(54.6%) and pregnancy rate (25%)

No significant difference between letrozole

responders & non-responders as regards the

age, period of infertility, BMI, W.C., LH, FSH or

LH/FSH (Elnashar et al, Fertil Steril; Feb, 2006).

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Adjuvants

1. N-acetyl cysteine

Effects of NAC on PCOS

NAC: 1.8 g/d for 5-6 W (Fulghesu et al, 2002) 1. In hyperinsulinemic subjects:

• Significant increase in insulin sensitivity

Significant reduction in insulin levels

• Significant reduction in T & FAI

2. In normoinsulinemie & placebo-treated

subjects:

No significant changes

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Effects

A. Metabolic:

1. Antioxidant:

in non-insulin dependent DM (De Mattia, et al., 1998).preserve vascular integrity (Sekhon et al. 2003) & protect against focal ischemia.

2. Insulin sensitizer:

Increase peripheral insulin sensitivity (Moghetti et al., 2000).

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B. Biological effects:

Antiapoptotic (Odetti et al., 2003). Anticytokines (inhibit proinflammatory cytokine release)

(Lappas et al. 2003) Inhibition of phosopholipid metabolism& Protease

activity.

NAC may exert the same effects at the ovarian level

which may be important in inducing ovulation

Mucolytic.

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Dose:

1.2 gm/day with CC 100mg/day for 5 days

Advantages:

safe, well tolerated, inexpensive.

NAC alone is not an effective drug in inducing ovulation

in CC resistant PCOS

(Elnashar et al, 2005)

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Results:

1. CCPCOS:

The combination of CC and NAC significantly increased

both ovulation and pregnancy rate (49.3&21.3%

respectively)

(Rizk et al,2004)

2. PCOS:

NAC is effective , adjuvant to the CC for ovulation

induction in PCOS even in the absence of insulin

resistance

(Badawy, Elnashar, Totongy, 2005)

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2. Corticosteroids

Regimen:

1.Small dose long course: Dexamethazone: 0.5

mg at night daily

Prednisone: 5 mg/d

2. High dose short course: Dexamethazone 2 mg

from D3-12 &

CC from D 3 to 7 (100 mg /day)

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Mechanism of action

1. Inhibits adrenal androgens (DHEAS, T) Act as a prehormone for T (Ray et al., 1984) and the reduction in this prehormone leads to a decrease in T level

2.Reduces circulating LH, and LH/FSH ratio (Baldwin, 1974; Karpas, 1984;Speroff, 1990).

3. Acts directly

a. on the pituitary to suppress the action of E2, which my

be involved in the process of induction of ovulation

(Terkawa, 1985). b. influence follicular development (Smith et aL, 2000).

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4. Acts indirectly

a. by increasing serum GH (Casaneuva et aL, 1990), serum IGF-1 (Miell et aL, 1993) & consequently

follicular fluid IGF-1 concentrations.

b. Enhances the FSH-stimulated follicular steroid

production (Roy et al, 2003).

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•DEX high dose, short course therapy combined with CC

in the follicular phase can improve folliculogenesis,

ovulation, & PR (Parsanenzhad, et al., 2003; Elnashar et

al, 2005).

•CC plus Dex treatment resulted in a significant

improvement in PR when compared to CC alone

(Cochrane library, 2005)

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Side effects:

There is no evidence that glucocorticoid treatment has

any important side effects or risks when used in the

doses & durations indicated

(Sperof & Fritz, 2005)

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3. Pretreatment with COC

Suppression of the HPO axis for 2 months with COC

followed by CC results in:

excellent rates of ovulation and pregnancy in women

who had previously failed to ovulate on CC alone

(Genazzani et al, 1997; Branigan and Estes, 1999).

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Effects:

1. lower the LH/FSH level

2. improve the androgen environment of the ovaries, by

increasing Levels of SHBG while decreasing androgen

secretion induced by the increased LH

(Branigan and Estes, 1999). So, it reduces the free testosterone

(Sheu et al, 1994).

3. suppress androgen production, thus ameliorating skin

androgenic symptoms and improving menstrual

dysfunction.

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Disadvantages:

•Exacerbates insulin resistance and since many patients

are overweight & obesity is a relative contraindication,

this treatment may be unsuitable (Sheu et al, 1994).

#

1. The negative influence on insulin sensitivity is not

expressed in non-obese patients (Vrbíková and Cibula, 2005) . 2.Impairment of glucose tolerance is reversible.

3. Lipid levels usually remain within the reference limits.

4. COC with weight reduction or insulin sensitizers

suppress androgen levels and improve metabolic

parameters.

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Advantages: an effective, reasonable, inexpensive, and low-risk alternative before Gnt therapy (Branigan and Estes, 1999). COC are the most often used treatment modality for PCOS (Vrbíková and Cibula, 2005) . Pretreatment with COC followed by CC results in excellent rates of ovulation (Cochrane library, 2005)

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. Bromocriptin not recommended unless prolactin concentration are

consistently elevated

(Zacur , et al ., 1992).

For CC plus bromocriptine Vs CC no evidence of a

difference in effect on pregnancy rate was found

(Cochrane library,2005)

Two methods:

1.2.5mg bid until the patient is pregnant as judged by

the BBT chart.

2.Follicular phase, and the drug is stopped when BBT

rise indicates that ovulation has occurred

(Ginsburg et al, 1992).

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. Extended CC therapy •Increase the duration to 10 days:

previously unresponsive women ovulate in 65% of 48

cycles

(Fluker et al., 1996).

•Extend the duration of CC until a follicle of 18 mm

diameter (on ultrasound), then administer HCG

(Speroff et al., 1999).

•The basic idea behind this therapy is to use more CC.

It is not commonly used {little success & significant side

effects}

(Branigan & Estes, l999).

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. Pretreatment with Progesterone 50 mg/day IM for 5 Days (Homburg et al ,1988). FSH were reduced

LH were reduced LH (in 70%).

Following the withdrawal bleeding, these patients

became responsive to CC as shown by ovulation.

Short-term progesterone treatment improves the

efficiency & results of CC treatment in PCOS (Balen, 1999).

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. Antiandrogens

a. Ketoconazole

is a CYP17a Inhibitor. It inhibits a different part of the

cytochrome P450 complex to AIs.

Mechanism of action:

1. Inhibition of the hydroxylase-lyase enzyme in the

ovary, adrenal gland and liver. This inhibits

steroidogenesis.

2. Inhibits aromatase activity in the gonads (Hassan

2001; Parsanezhad 2003). It therefore may have

similar effects to AIs with added anti-androgenic

effects.

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CC (up to 150 mg) plus ketoconazole (400 mg) Vs CC

(up to 150 mg) (Cochrane library,2005)

PR: no evidence of a difference between groups

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b. Spironolactone A. Alone

Dose: 50-200 mg daily for 6 cycles Advantages: (Kidson, 1998). safety, availability, and low cost. does not cause weight gain Ovulation is commonly restored in 85% slightly reduces insulin resistance

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Effects:

(Evron et al, 1981).

1.Significant decrease in LH, testosterone, prolactin, and 17-ketosteroid

2.Ovulation in 85%

3.Improvement of hirsutism in 70%

4.Restoration of regular cycles in 85%

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Side effects

mild and did not lead to interruption of the treatment. polymenorrhoea.

Antiandrogenic properties of spironolactone render it a suitable agent in the treatment of anovulatory, oligomenorrheic, and hyperandrogenic women.

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Spironolactone (50 mg/d) Vs metformin (1000 mg/d) in

adolescent and young women with PCOS for 6 months

(Ganie et al, 2004).

Both groups showed improvement in glucose tolerance

and insulin sensitivity, although the metformin effect was

significant in the latter.

Serum LH/FSH and testosterone decreased in both

groups.

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Both drugs are effective in the management of PCOS.

Spironolactone appears better than metformin in the

treatment of hirsutism, menstrual cycle frequency, and

hormonal derangements and is associated with fewer

adverse events.

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B. Combined with CC

Three treatment groups CC plus dexamethasone or

sprinolactone or cyproterone acetate

(Koloszar et al, 1996).

The highest ovulation & PR in the group treated with

cyproterone acetate.

Adjuvant antiandrogen treatment with cyproterone

acetate advisable in the cases of hyperandrongenic

conditions.

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