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Clomiphene Citrate: An Old Favourite Lives On
Timothy Rowe, MB BS, FRCSC
It’s a simple truism, but nothing beats experience. Those (forsome hormoneassays) and possibly endovaginalultra-
of us in contemporary practice are fortunate indeed to
sound examination before polycystic ovary syndrome
have the experience of our clinical forebears to depend on.
(PCOS) is diagnosed and treatment discussed. In the greatmajority of cases, such treatment would be medical rather
Consider the work done by Stein and Leventhal, summa-
than surgical. The risks associated with such treatment are
rized in their paper “Amenorrhea associated with bilateral
minimal and well known. And if such women were seeking
polycystic ovaries,” which was read at a meeting of the Cen-
pregnancy, standard practice for 30 years was to offer them
tral Association of Obstetricians and Gynecologists in New
Orleans in November 1934.1 In this report they describe thecases of seven young women, four of whom had chief com-
This impressively resilient and effective medication has
plaints of “sterility and amenorrhea” and the others a com-
actually been used to induce ovulation since 1965.2
bination of amenorrhea, irregular menses, abnormal hair
Although initial impressions were that it had potential to
inhibit fertility, because much of its clinical action is
Much time and effort (and, I’m sure, head scratching) must
anti-estrogenic, it subsequently proved to have real poten-
have gone into the clinical management of these women.
tial to induce ovulation in anovulatory women. Random-
All of them had undergone transabdominal or transuterine
ized trials of clomiphene therapy compared with placebo or
pneumoperitoneum with subsequent X-ray in order to
no treatment in women with oligo-ovulation and infertility
allow some visualization of the ovaries, as well as the other
showed the likelihood of ovulation increased almost seven
pelvic structures. Initially their management had consisted
times and the pregnancy rate per treated cycle increased
of injections of “estrogenic hormone preparations . . .
reputed to be more or less potent,” but ultimately all seven
So treatment with clomiphene in women with PCOS will
women underwent surgery. The surgical procedures were
increase the potential for such women to conceive. But
described as wedge resections, although the authors
women with PCOS also experience higher than average
acknowledge that in fact they resected from one half to
rates of early pregnancy loss,4 later pregnancy complica-
three quarters of each ovary, followed by suture of the hilus
tions,5 and obesity,6 leading to the frustrating conclusion
using “the finest catgut.” Postoperatively, all the women
that induction of ovulation does not address the root cause
developed regular and apparently ovulatory cycles, and two
of the condition. The recognition that women with PCOS
of them (at the time of the report) had successfully
have significant insulin resistance that is independent of
obesity, changes in body composition, and impairment of
Contrast this with how these women would be managed
glucose tolerance,7 and that insulin resistance in PCOS
today, leaving aside the possibility that they would make
appears to arise from a defect in the insulin receptor or in
their own diagnosis and provide their own management via
postreceptor signal transduction8 raised the possibility that
Internet sources. Not for them the pain and uncertainty of
PCOS was essentially a metabolic syndrome based on
induction of a pneumoperitoneum or the hazards of
reduced insulin sensitivity. Whether or not this is so
laparotomy under general anaesthesia. Depending on their
remains unresolved, partly because there is no universally
wishes regarding pregnancy and contraception, women pre-
agreed set of diagnostic criteria for PCOS. Most North
senting with amenorrhea and signs of hyperandrogenism
American investigators use the National Institutes of
would be unlikely to experience more than venepuncture
Health (1990) criteria of hyperandrogenism, oligo-ovulation, and exclusion of known disorders, but many oth-ers use the Rotterdam (2003) criteria, which require two of
J Obstet Gynaecol Can 2007;29(8):617–618
oligo-ovulation or anovulation, clinical or biochemical signsof hyperandrogenism, and ultrasound demonstration of
AOÛT 2007 l
polycystic ovaries (assuming that other causes have been
appear to increase the risk of fetal abnormalities and does
excluded).9 This lack of certainty has not, however, stopped
numerous investigators and primary care providers from
So it appears that clomiphene citrate has a viable challenger
treating women with PCOS with insulin sensitizers such as
for its position as drug of choice in primary management of
anovulatory infertility; letrozole is at least a potentially
Nevertheless, so far as infertility is concerned, it looks as
effective alternative therapy if clomiphene fails. What
though clomiphene is still the preferable treatment. In a
clomiphene does have, however, is a 40-year history of clin-
ical use. In this evidence-based era, that is a very reassuring
clomiphene citrate (or a combination) treatment in 626
women with PCOS and infertility, women treated withmetformin for up to six months had a live-birth rate of
7.2%, and the rate in those treated with clomiphene was
1. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic
ovaries. Am J Obstet Gynecol 1935;29:181–91.
metformin had more gastrointestinal side effects but no
2. Kistner RW. Induction of ovulation with clomiphene citrate. Obstet
Gynecol Surv 1965;Dec 20(6):873–900.
multiple pregnancies; the multiple pregnancy rate in women
3. Hughes E, Collins J, Vandekerckhove P. Clomiphene citrate for ovulation
taking clomiphene alone was 6%. It is evident from the
induction in women with oligo-amenorrhea. Cochrane Database Syst Rev
findings of this study that women with PCOS who wish to
conceive and who seek treatment should first be offered
4. Homburg R, Armar NA, Eshel A, Adams J, Jacobs HS. Influence of serum
luteinising hormone concentrations on ovulation, conception, and earlypregnancy loss in polycystic ovary syndrome. BMJ 1988;297:1024–6.
But the consistent gap between ovulation rates and preg-
5. Boomsma CM, Eijkemans MJ, Hughes EG, Visser GH, Fauser BC,
nancy rates in anovulatory women treated with clomiphene
Macklon NS. A meta-analysis of pregnancy outcomes in women withpolycystic ovary syndrome. Hum Reprod Update 2006;12:673–83.
has always vexed clinicians and clinical investigators. This
6. Barber TM, McCarthy MI, Wass JA, Franks S. Obesity and polycystic ovary
has most commonly been attributed to the relatively
syndrome. Clin Endocrinol (Oxf) 2006;65:137–45.
long-lasting anti-estrogenic effect of clomiphene, in the
7. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral
endometrium especially,11 although other factors could be
insulin resistance, independent of obesity, in polycystic ovary syndrome.
involved. The effect of clomiphene in the endometrium has
been one of the key reasons behind the search for
8. Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T.
Evidence for distinctive and intrinsic defects in insulin action in polycystic
anti-estrogenic agents that either have no atrophic effect in
ovary syndrome. Diabetes 1992;41:1257–66.
the endometrium or have a short half-life. This search
9. Azziz R. Diagnosis of polycystic ovary syndrome: the Rotterdam criteria are
resulted in the introduction of letrozole, an aromatase
premature. J Clin Endocrinol Metab 2006;91:781–5.
inhibitor, for inducing ovulation. So far, letrozole appears
10. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA,
to have similar efficacy to clomiphene citrate in achieving
et al. Clomiphene, metformin, or both for infertility in the polycystic ovarysyndrome. N Engl J Med 2007;356:551–66.
pregnancy in both anovulatory12 and ovulatory13 women.
But concerns have persisted about fetal safety with use of
11. Palomba S, Russo T, Orio F, Falbo A, Manguso F, Sammartino A, et al.
Uterine effects of clomiphene citrate in women with polycystic ovary
syndrome: a prospective controlled study. Hum Reprod
In the present issue, Rachel Forman and colleagues describe
the history of using letrozole for ovulation induction in
12. Bayar U, Basaran M, Kiran S, Coskun A, Gezer S. Use of an aromatase
inhibitor in patients with polycystic ovary syndrome: a prospective
both ovulatory and anovulatory women and the contro-
randomized trial. Fertil Steril 2006;86:1447–51.
versy about the relative safety to the fetus of letrozole and
13. Al-Fozan H, Al-Khadouri M, Tan SL, Tulandi T. A randomized trial of
clomiphene citrate. On the basis of their study, they con-
letrozole versus clomiphene citrate in women undergoing superovulation.
clude that the use of letrozole to induce ovulation does not
l AUGUST JOGC
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