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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
or 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-
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-
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-
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.
2. Lord JM, Flight IH, Norman RJ. Insulin-sensitising
drugs (metformin, troglitazone, rosiglitazone, pioglita-
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.
Irreducible Constituents of Monomial CharactersHTTP://SCIENZE-COMO.UNINSUBRIA.IT/PREVITALIH:= a subgroup of finite index, say n, of a group G;T := a right transversal of H in G, thus G =We assume that G be a subgroup of Sym(n);T × T becomes G-set via (s, t) · g := (s · g, t · g);The G-orbits on T × T are called orbitals;X := (T × T )//G a set of representatives of (H, H)-cosets;defin
Veterinary Recommendations for Anesthesia and Analgesia This Guidance Document is to establish recommendations for anesthesia and analgesia for use in research animals. PRINCIPLES OF ANESTHESIA AND ANALGESIA 1. The proper anesthetic and analgesic agents must be used in order to eliminate or reduce the potential for pain and distress during the peri-operative period. 2. Witholding