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 AUGUST JOGC 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 REFERENCES
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 AOÛT 2007


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