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Treatment of WHO 2: Clomiphene Citrate
Introduction
Clomiphene citrate (CC) was first introduced by Greenblatt et al. in 1961 and found to be a safe and efficient way to induce ovulation. The simplicity and inexpensive nature of this treatment have retained CC until today in its position as the first-line treatment for anovulation associated with normal concentrations of endogenous estrogens, (hypothalamic–pituitary dysfunction—WHO Group 2) mainly polycystic ovarian syndrome (PCOS).
By blocking hypothalamic and pituitary estrogen receptors, CC induces a discharge of FSH that is often enough to restore ovulation. Given for 5 days in a dose of 50–150 mg/day, starting from day 2 to 6 of a spontaneous or progestin-induced menstruation, CC will restore ovulation in 73% and induce pregnancy in 36%. Some 20%–25% will not respond at all and are considered to be “clomiphene resistant.” The gap between ovulation and pregnancy rates has mainly been attributed to its anti-estrogen effects on endometrium.
As CC blocks the negative feedback mechanism, rising estradiol levels have no effect in stemming the discharge of FSH, and this may invoke multiple follicle development. The risk of multiple gestation is therefore increased and is estimated at about 8%–10% while the singleton live birth rate is reported around 25%.
The prevalence of congenital abnormalities and spontaneous abortion following CC treatment are no different to those seen in spontaneously conceived pregnancies.
Overview of Existing Evidence
Given the well-established effect of CC on ovulation induction and pregnancy outcome, clinical trials have examined a possible improvement in results by adding adjunctive treatments or attempted to establish a potentially superior replacement.
Fields of interest are summarized as follows:
1. CC + Adjunctive treatments
• CC versus CC + dexamethasone
• CC versus CC + HCG as ovulation trigger
• CC versus CC + metformin
2. Comparison between CC and other treatments
• CC versus placebo
• CC versus metformin
• CC versus letrozole
• CC versus FSH
3. Risk of cancer
In a comparison between CC and a placebo, CC clearly increased the pregnancy rate (OR 9.46, 95% CI 5.1 to 17.7) (1) (LOE 1a).
In order to improve the outcome of treatment with CC, several adjuvants to clomiphene treatment have been suggested.
Clomiphene plus dexamethasone treatment was effective in increasing the pregnancy rate compared to clomiphene alone (1) (LOE 1a). The addition of dexamethasone as an adjunct to clomiphene therapy in a dose of 0.5 mg at bedtime is said to suppress adrenal androgen secretion and induce responsiveness to CC in previous nonresponders, mostly hyperandrogenic women with PCOS and elevated concentrations of dehydroepiandrosterone sulfate (DHEAS). However, glucocorticoid steroid therapy often induces side effects, including increased appetite and weight gain, and should probably be reserved for women who have congenital adrenal hyperplasia as a cause for their anovulation.
The routine addition of hCG at mid-cycle does not improve the conception rates (LOE 1a) (1). In a very powerful randomized control trial (RCT), Legro et al. (2
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