Decline of clomiphene
for PCOS-related infertility

Metformin and aromatase inhibitors may promise fewer spontaneous abortions and multiple gestations formin 850 mg twice daily for 6 months orclomiphene 150 mg for cycle days 3 to 7 Robert L. Barbieri, MD
For decades clomiphene citrate has
been the first-line agent for ovulationinduction in women with PCOS, but and aromatase inhibitors are superior.
(31/45) in the metformin group and 34%(16/47) in the clomiphene group. The rate Metformin effective as first-line agent
of spontaneous abortion was significantly Based on consistent clinical trial results, many specialists now use metformin as the formin (38% vs 10%, P<.05). The authors first-line agent for anovulatory infertility in more effective than 6 cycles of clomiphene.
betes mellitus. It is an insulin sensitizer that suppresses hepatic glucose output, decreas- FAST TRACK
A randomized trial
increases insulin-mediated glucose utiliza- through the first trimester to reduce risk of spontaneous abortion, and then discontin- found a higher
ue the medication so that they can be test- pregnancy rate
and lower abortion
resumption of ovulation in oligomenorrhe- rate with metformin ic women with PCOS.1 Major side effects Aromatase inhibitors promising
include diarrhea, nausea or vomiting, flatu- lence, indigestion, and abdominal discom- matase inhibitors induce ovulation in these multiple gestations and spontaneous abor- A meta-analysis of more than a dozen ran-
treatment of hormone-sensitive breast can- cer. Aromatase inhibitors block conversion A recent randomized trial found a higher
circulating estradiol levels. When given to the reduction of circulating estradiol causes an increase in pituitary secretion of follicle- the presence of oligomenorrhea and hyper- stimulating hormone, resulting in follicular Stepwise treatment options
For the treatment of anovulatory infertility been reported on the efficacy of aromatase clearly indicate that, when given for cycle days 3 to 7 after a progestin-induced with- drawal bleed, they often cause ovulation in • If metformin is not effective as a single were randomized to either letrozole 2.5 mg daily or anastrozole 1 mg daily, for cycle • Alternatively, clinicians might contin- days 3 to 7. The ovulation rate was signif- icantly higher in the letrozole group (84% vs 60%, P<.05) and the pregnancy rate has reported on the efficacy of clomipheneversus aromatase inhibitors for ovulationinduction in women with anovulatory infertility caused by PCOS. Cohort studiesreport that multiple gestation occurs less in R E F E R E N C E S
pregnancy induced by aromatase inhibitors 1. Barbieri RL. Metformin for the treatment of polycystic ovary syndrome. Obstet Gynecol. 2003;101:785–793.
For PCOS-related
2. Lord JM, Flight IH, Norman RJ. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglita- anovulatory
zone, D-chiro-inositol) for polycystic ovary syndrome.
Cochrane Database Syst Rev. 2003;(3):CD003053.
3. Palomba S, Orio F Jr, Falbo A, et al. Prospective par- allel randomized, double-blind, double-dummy con-trolled clinical trial comparing clomiphene citrate Newborn and childhood outcomes
and metformin as the first-line treatment for ovula- A major deficit in the literature on ovula- tion induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab.
matase inhibitors is the relatively small 4. Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P. Continuing metformin throughout pregnancyin women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril. 2001;75:46–52.
5. Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA, appears to be associated with a higher rate Nestler JE. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J ClinEndocrinol Metab. 2002;87:524–529.
6. Al-Omari WR, Sulaiman WR, Al-Hadithi N. Comparison of two aromatase inhibitors in women withclomiphene-resistant polycystic ovary syndrome. Int J given the strong relationship between mul- tiple gestation and adverse pregnancy out- 7. Mitwally MF, Biljan MM, Casper RF. Pregnancy outcome come, it is likely that metformin and aro- after the use of an aromatase inhibitor for ovarian stim-ulation. Am J Obstet Gynecol. 2005;192:381–386.
matase inhibitors will be associated with 8. Al-Fozan H, Al-Khadouri M, Tan SL, Tulandi T. A ran- better overall newborn and childhood out- domized trial of letrozole versus clomiphene citratein women undergoing superovulation. Fertil Steril.

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