Clomiphene and anti-oestrogens for ovulation induction in PCOS.
BACKGROUND
Subfertility due to anovulation is a common problem in women. First-line oral treatment is with anti-oestrogens, for example clomiphene citrate, but resistance (failure to ovulate) may be apparent with clomiphene. Alternative and adjunctive treatments have been developed such as tamoxifen, dexamethasone, and bromocriptine.


OBJECTIVE
To determine the relative effectiveness of anti-oestrogen agents alone or in combination with other medical therapies in women with subfertility associated with anovulation, possibly caused by polycystic ovarian syndrome (PCOS).


METHODS
A search was conducted using the Cochrane Menstrual Disorders and Subfertility Group Trials Register (May 2009), CENTRAL (The Cochrane Library 2009, Issue 2), MEDLINE (1966 to May 2009), and EMBASE (1980 to May 2009) for identification of relevant randomised controlled trials (RCTs). The United Kingdom National Institute for Clinical Excellence (NICE) guidelines and the references of relevant reviews and RCTs were searched.


METHODS
RCTs comparing oral anti-oestrogen agents for ovulation induction (alone or in conjunction with medical therapies) in anovulatory subfertility were considered. Insulin sensitising agents, aromatase inhibitors, and hyperprolactinaemic infertility were excluded.


METHODS
Data extraction and quality assessment were done independently by two review authors. The primary outcome was live birth; secondary outcomes were pregnancy, ovulation, miscarriage, multiple pregnancy, overstimulation, ovarian hyperstimulation syndrome, and women reported adverse effects.


RESULTS
This is a substantive update of a previous review. Fifteen RCTs were included. One trial reported live birth. Miscarriage, multiple pregnancy rates and adverse events were poorly reported.Clomiphene was effective in increasing pregnancy rate compared to placebo (OR 5.8, 95% CI 1.6 to 21.5) as was clomiphene plus dexamethasone treatment (OR 9.46, 95% CI 5.1 to 17.7) compared to clomiphene alone. No evidence of a difference in effect was found between clomiphene versus tamoxifen or clomiphene in conjunction with human chorionic gonadotrophin (hCG) versus clomiphene alone.The remaining results had only one study in each comparison. A significant improvement in the pregnancy rate was reported for clomiphene plus combined oral contraceptives versus clomiphene alone. No evidence of a difference in effect on pregnancy rate was found with any of the other comparisons.


CONCLUSIONS
This review shows evidence supporting the effectiveness of clomiphene citrate and clomiphene in combination with dexamethasone for pregnancy rate only. There is limited evidence on the effects of these drugs on outcomes such as miscarriage. Evidence in favour of these interventions is flawed due to the lack of evidence on live births.
Brown
Julie
J
Obstetrics and Gynaecology, University of Auckland, FMHS, Auckland, New Zealand.
Farquhar
Cindy
C
Beck
James
J
Boothroyd
Clare
C
Hughes
Edward
E
D000858:Anovulation / Q000150:complications* / Q000188:drug therapy; D002996:Clomiphene / Q000627:therapeutic use; D003277:Contraceptives, Oral, Combined / Q000627:therapeutic use; D003907:Dexamethasone / Q000627:therapeutic use; D004359:Drug Therapy, Combination / Q000379:methods; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007247:Infertility, Female / Q000188:drug therapy* / Q000209:etiology; D011085:Polycystic Ovary Syndrome / Q000150:complications; D016032:Randomized Controlled Trials as Topic; D013629:Tamoxifen / Q000627:therapeutic use
D003277:Contraceptives, Oral, Combined; D004965:Estrogen Antagonists; D013629:Tamoxifen; D002996:Clomiphene; D003907:Dexamethasone