Strategies for improving the efficacy of clomiphene induction of ovulation
- Mark D Hornstein, MD
Mark D Hornstein, MD
- Professor of Obstetrics, Gynecology & Reproductive Biology
- Harvard Medical School
- William E Gibbons, MD
William E Gibbons, MD
- Division of Reproductive Endocrinology
- Department of Obstetrics and Gynecology
- Baylor College of Medicine
- Chief of Reproductive Medicine for the Pavilion for Women
- Texas Children's Hospital
Clomiphene citrate is the fertility medication most widely prescribed by gynecologists. Its use results in ovulation and pregnancy rates of 80 and 40 to 50 percent, respectively, when given at standard doses . The US Food and Drug Administration (FDA) has approved use of clomiphene at doses of 50 or 100 mg daily for five days per cycle.
Women who ovulate but who do not conceive should not be considered "clomiphene citrate failures." In one series, 88 percent of women who ovulated with no other infertility factor conceived, while only 8 percent of those with concurrent infertility factors conceived. This observation highlights the importance of performing an evaluation of fertility factors in women who ovulate but do not conceive before moving to other therapies .
Current guidelines from a consensus group recommend that women who do not become pregnant with clomiphene should be treated with gonadotropin injections (follicle-stimulating hormone [FSH] or FSH and luteinizing hormone [LH]) or laparoscopic ovarian surgery to reduce androgen secretion by the ovary. As a trend, the use of gonadotropin injections in the treatment of polycystic ovarian disease outside of in vitro fertilization (IVF) is diminishing because of the risk of multiple gestations. Thus, it is worthwhile to review less complex, alternative approaches to treating these women before referring them for resource-intensive interventions. Some of these strategies (eg, weight loss) can also be considered at the initial course of clomiphene therapy. (See "Laparoscopic surgery for ovulation induction in polycystic ovary syndrome" and "In vitro fertilization" and "Diagnosis of polycystic ovary syndrome in adults" and "Treatment of polycystic ovary syndrome in adults".)
Strategies for fertility treatment in the 50 to 60 percent of women with ovulatory infertility who do not become pregnant when treated with clomiphene as a single agent will be reviewed here. An optimal sequence for these strategies has not been determined; the sequence described below reflects our typical approach to these patients. A general overview of ovulation induction with clomiphene citrate is presented elsewhere. (See "Ovulation induction with clomiphene citrate".)
REVIEW THE CAUSE OF INFERTILITY
If pregnancy has not occurred after three cycles of clomiphene treatment, it is worthwhile to review the diagnostic studies that were completed by the infertile couple and consider further investigation.
- Adashi EY. Clomiphene citrate initiated ovulation. Semin Reprod Endocrinol 1986; 4:255.
- Gysler M, March CM, Mishell DR Jr, Bailey EJ. A decade's experience with an individualized clomiphene treatment regimen including its effect on the postcoital test. Fertil Steril 1982; 37:161.
- Mahran A, Abdelmeged A, El-Adawy AR, et al. The predictive value of circulating anti-Müllerian hormone in women with polycystic ovarian syndrome receiving clomiphene citrate: a prospective observational study. J Clin Endocrinol Metab 2013; 98:4170.
- Bates GW, Bates SR, Whitworth NS. Reproductive failure in women who practice weight control. Fertil Steril 1982; 37:373.
- Murakawa H, Hasegawa I, Kurabayashi T, Tanaka K. Polycystic ovary syndrome. Insulin resistance and ovulatory responses to clomiphene citrate. J Reprod Med 1999; 44:23.
- Daly DC, Walters CA, Soto-Albors CE, et al. A randomized study of dexamethasone in ovulation induction with clomiphene citrate. Fertil Steril 1984; 41:844.
- Pasquali R, Antenucci D, Casimirri F, et al. Clinical and hormonal characteristics of obese amenorrheic hyperandrogenic women before and after weight loss. J Clin Endocrinol Metab 1989; 68:173.
- Bates GW, Whitworth NS. Effect of body weight reduction on plasma androgens in obese, infertile women. Fertil Steril 1982; 38:406.
- Guzick DS, Wing R, Smith D, et al. Endocrine consequences of weight loss in obese, hyperandrogenic, anovulatory women. Fertil Steril 1994; 61:598.
- Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab 1999; 84:1470.
- Barbieri RL. Induction of ovulation in infertile women with hyperandrogenism and insulin resistance. Am J Obstet Gynecol 2000; 183:1412.
- Barbieri RL, Ryan KJ. Hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features. Am J Obstet Gynecol 1983; 147:90.
- Barbieri RL, Makris A, Randall RW, et al. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab 1986; 62:904.
- Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril 2008; 89:505.
- Isaacs JD Jr, Lincoln SR, Cowan BD. Extended clomiphene citrate (CC) and prednisone for the treatment of chronic anovulation resistant to CC alone. Fertil Steril 1997; 67:641.
- Parsanezhad ME, Alborzi S, Motazedian S, Omrani G. Use of dexamethasone and clomiphene citrate in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome and normal dehydroepiandrosterone sulfate levels: a prospective, double-blind, placebo-controlled trial. Fertil Steril 2002; 78:1001.
- Brown J, Farquhar C, Beck J, et al. Clomiphene and anti-oestrogens for ovulation induction in PCOS. Cochrane Database Syst Rev 2009; :CD002249.
- Elnashar A, Abdelmageed E, Fayed M, Sharaf M. Clomiphene citrate and dexamethazone in treatment of clomiphene citrate-resistant polycystic ovary syndrome: a prospective placebo-controlled study. Hum Reprod 2006; 21:1805.
- REVIEW THE CAUSE OF INFERTILITY
- WHO CLASSIFICATION OF ANOVULATION
- OPTIONS FOR WOMEN WITH WHO TYPE II ANOVULATORY INFERTILITY
- Optimize body mass index
- Combination therapy with insulin sensitizers
- - Metformin
- - Thiazolidinediones
- Combination therapy with glucocorticoids
- Comparisons with letrozole
- SUMMARY AND RECOMMENDATIONS