Ovulation induction with clomiphene citrate
- Emre Seli, MD
Emre Seli, MD
- Associate Professor of Obstetrics, Gynecology & Reproductive Sciences
- Yale University School of Medicine
- Aydin Arici, MD
Aydin Arici, MD
- Professor of Obstetrics, Gynecology & Reproductive Sciences
- Yale University School of Medicine
Clomiphene citrate (CC) has been the most widely used treatment for fertility enhancement for the past 40 years. Clomiphene was a revolutionary advance in reproductive medicine and quickly became popular for induction of ovulation because of its ease of administration and minimal side effects. Ironically, it was initially synthesized as a synthetic estrogen for possible use as a contraceptive.
The pharmacology, indications, and administration of CC will be reviewed here. Other drugs for induction of ovulation are discussed elsewhere. (See "Overview of ovulation induction" and "Strategies for improving the efficacy of clomiphene induction of ovulation" and "Ovulation induction with letrozole".)
PHARMACOLOGY/MECHANISMS OF ACTION
Clomiphene is a nonsteroidal triphenylethylene derivative distantly related to diethylstilbestrol. It acts as a selective estrogen receptor modulator (SERM), similar to tamoxifen and raloxifene. All three drugs are competitive inhibitors of estrogen binding to estrogen receptors (ERs) and have mixed agonist and antagonist activity, depending upon the target tissue. (See "Mechanisms of action of selective estrogen receptor modulators".)
The commercially available form of clomiphene is the dihydrogen citrate salt (clomiphene citrate [CC]). It contains two stereoisomers: zu-clomiphene (38 percent) and en-clomiphene (62 percent), which were originally called the cis-isomer and trans-isomer, respectively. En-clomiphene is cleared rapidly, while zu-clomiphene has a long half-life . The two clomiphene isomers have mixed estrogenic and antiestrogenic effects that vary among species. En-clomiphene is the more potent isomer with greater antiestrogenic activity and the one primarily responsible for inducing follicular development .
Clomiphene is cleared through the liver and excreted in feces. Over fifty percent of an oral dose of 14C-labeled CC is excreted after five days, but traces of radioactivity from the labeled clomiphene appear in the feces up to six weeks after administration. Although this observation raises concerns about fetal exposure to clomiphene, most studies suggest that the frequency of congenital malformations is not increased . (See 'Perinatal outcome' below.)
- Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women: a committee opinion. Fertil Steril 2013; 100:341.
- Glasier AF, Irvine DS, Wickings EJ, et al. A comparison of the effects on follicular development between clomiphene citrate, its two separate isomers and spontaneous cycles. Hum Reprod 1989; 4:252.
- Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod Update 1996; 2:483.
- Kettel LM, Roseff SJ, Berga SL, et al. Hypothalamic-pituitary-ovarian response to clomiphene citrate in women with polycystic ovary syndrome. Fertil Steril 1993; 59:532.
- Jorgensen SE, Starup J, Roos J, Micic S. Studies on the mode of action of clomiphene citrate. Acta Obstet Gynecol Scand 1976; 55:337.
- Kerin JF, Liu JH, Phillipou G, Yen SS. Evidence for a hypothalamic site of action of clomiphene citrate in women. J Clin Endocrinol Metab 1985; 61:265.
- Hsueh AJ, Erickson GF, Yen SS. Sensitisation of pituitary cells to luteinising hormone releasing hormone by clomiphene citrate in vitro. Nature 1978; 273:57.
- Kessel B, Hsueh AJ. Clomiphene citrate augments follicle-stimulating hormone-induced luteinizing hormone receptor content in cultured rat granulosa cells. Fertil Steril 1987; 47:334.
- Eden JA, Place J, Carter GD, et al. The effect of clomiphene citrate on follicular phase increase in endometrial thickness and uterine volume. Obstet Gynecol 1989; 73:187.
- Dehbashi S, Parsanezhad ME, Alborzi S, Zarei A. Effect of clomiphene citrate on endometrium thickness and echogenic patterns. Int J Gynaecol Obstet 2003; 80:49.
- Bonhoff AJ, Naether OG, Johannisson E. Effects of clomiphene citrate stimulation on endometrial structure in infertile women. Hum Reprod 1996; 11:844.
- Sereepapong W, Suwajanakorn S, Triratanachat S, et al. Effects of clomiphene citrate on the endometrium of regularly cycling women. Fertil Steril 2000; 73:287.
- Li TC, Warren MA, Murphy C, et al. A prospective, randomised, cross-over study comparing the effects of clomiphene citrate and cyclofenil on endometrial morphology in the luteal phase of normal, fertile women. Br J Obstet Gynaecol 1992; 99:1008.
- Thompson LA, Barratt CL, Thornton SJ, et al. The effects of clomiphene citrate and cyclofenil on cervical mucus volume and receptivity over the periovulatory period. Fertil Steril 1993; 59:125.
- Gelety TJ, Buyalos RP. The effect of clomiphene citrate and menopausal gonadotropins on cervical mucus in ovulatory cycles. Fertil Steril 1993; 60:471.
- Roumen FJ. [Decreased quality of cervix mucus under the influence of clomiphene: a meta-analysis]. Ned Tijdschr Geneeskd 1997; 141:2401.
- Vause TD, Cheung AP, Sierra S, et al. Ovulation induction in polycystic ovary syndrome. J Obstet Gynaecol Can 2010; 32:495.
- Wu CH, Winkel CA. The effect of therapy initiation day on clomiphene citrate therapy. Fertil Steril 1989; 52:564.
- Dehbashi S, Vafaei H, Parsanezhad MD, Alborzi S. Time of initiation of clomiphene citrate and pregnancy rate in polycystic ovarian syndrome. Int J Gynaecol Obstet 2006; 93:44.
- Rossing MA, Daling JR, Weiss NS, et al. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994; 331:771.
- ACOG Committee on Practice Bulletins-Gynecology. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists number 34, February 2002. Management of infertility caused by ovulatory dysfunction. American College of Obstetricians and Gynecologists. Obstet Gynecol 2002; 99:347.
- O'Herlihy C, De Crespigny LJ, Robinson HP. Monitoring ovarian follicular development with real-time ultrasound. Br J Obstet Gynaecol 1980; 87:613.
- Miller PB, Soules MR. The usefulness of a urinary LH kit for ovulation prediction during menstrual cycles of normal women. Obstet Gynecol 1996; 87:13.
- Kousta E, White DM, Franks S. Modern use of clomiphene citrate in induction of ovulation. Hum Reprod Update 1997; 3:359.
- Vause TD, Cheung AP, Sierra S, et al. Ovulation induction in polycystic ovary syndrome: No. 242, May 2010. Int J Gynaecol Obstet 2010; 111:95.
- Smith YR, Randolph JF Jr, Christman GM, et al. Comparison of low-technology and high-technology monitoring of clomiphene citrate ovulation induction. Fertil Steril 1998; 70:165.
- Gorlitsky GA, Kase NG, Speroff L. Ovulation and pregnancy rates with clomiphene citrate. Obstet Gynecol 1978; 51:265.
- 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.
- Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014; 371:119.
- Dickey RP, Matis R, Olar TT, et al. The occurrence of ectopic pregnancy with and without clomiphene citrate use in assisted and nonassisted reproductive technology. J In Vitro Fert Embryo Transf 1989; 6:294.
- Glasier AF. Clomiphene citrate. Baillieres Clin Obstet Gynaecol 1990; 4:491.
- Rostami-Hodjegan A, Lennard MS, Tucker GT, Ledger WL. Monitoring plasma concentrations to individualize treatment with clomiphene citrate. Fertil Steril 2004; 81:1187.
- Homburg R. Clomiphene citrate--end of an era? A mini-review. Hum Reprod 2005; 20:2043.
- Imani B, Eijkemans MJ, te Velde ER, et al. Predictors of chances to conceive in ovulatory patients during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab 1999; 84:1617.
- Macgregor AH, Johnson JE, Bunde CA. Further clinical experience with clomiphene citrate. Fertil Steril 1968; 19:616.
- O'Herlihy C, Pepperell RJ, Robinson HP. Ultrasound timing of human chorionic gonadotropin administration in clomiphene-stimulated cycle. Obstet Gynecol 1982; 59:40.
- Brown J, Farquhar C, Beck J, et al. Clomiphene and anti-oestrogens for ovulation induction in PCOS. Cochrane Database Syst Rev 2009; :CD002249.
- Deaton JL, Clark RR, Pittaway DE, et al. Clomiphene citrate ovulation induction in combination with a timed intrauterine insemination: the value of urinary luteinizing hormone versus human chorionic gonadotropin timing. Fertil Steril 1997; 68:43.
- Zreik TG, García-Velasco JA, Habboosh MS, et al. Prospective, randomized, crossover study to evaluate the benefit of human chorionic gonadotropin-timed versus urinary luteinizing hormone-timed intrauterine inseminations in clomiphene citrate-stimulated treatment cycles. Fertil Steril 1999; 71:1070.
- Kosmas IP, Tatsioni A, Fatemi HM, et al. Human chorionic gonadotropin administration vs. luteinizing monitoring for intrauterine insemination timing, after administration of clomiphene citrate: a meta-analysis. Fertil Steril 2007; 87:607.
- Diamond MP, Kruger M, Santoro N, et al. Endometrial shedding effect on conception and live birth in women with polycystic ovary syndrome. Obstet Gynecol 2012; 119:902.
- Abu Hashim H, Ombar O, Abd Elaal I. Intrauterine insemination versus timed intercourse with clomiphene citrate in polycystic ovary syndrome: a randomized controlled trial. Acta Obstet Gynecol Scand 2011; 90:344.
- Badawy A, Gibreal A. Clomiphene citrate versus tamoxifen for ovulation induction in women with PCOS: a prospective randomized trial. Eur J Obstet Gynecol Reprod Biol 2011; 159:151.
- de Paula Guedes Neto E, Savaris RF, von Eye Corleta H, et al. Prospective, randomized comparison between raloxifene and clomiphene citrate for ovulation induction in polycystic ovary syndrome. Fertil Steril 2011; 96:769.
- Scialli AR. The reproductive toxicity of ovulation induction. Fertil Steril 1986; 45:315.
- McDowell S, Kroon B, Yazdani A. Clomiphene ovulation induction and higher-order multiple pregnancy. Aust N Z J Obstet Gynaecol 2013; 53:395.
- Kurachi K, Aono T, Minagawa J, Miyake A. Congenital malformations of newborn infants after clomiphene-induced ovulation. Fertil Steril 1983; 40:187.
- Dickey RP, Taylor SN, Curole DN, et al. Incidence of spontaneous abortion in clomiphene pregnancies. Hum Reprod 1996; 11:2623.
- Sørensen HT, Pedersen L, Skriver MV, et al. Use of clomifene during early pregnancy and risk of hypospadias: population based case-control study. BMJ 2005; 330:126.
- REPROTOX: An information system on environmental hazards to human reproduction and development. Agent #1242 www.reprotox.org (Accessed on August 20, 2008).
- Reefhuis J, Honein MA, Schieve LA, et al. Use of clomiphene citrate and birth defects, National Birth Defects Prevention Study, 1997-2005. Hum Reprod 2011; 26:451.
- Hack M, Brish M, Serr DM, et al. Outcome of pregnancy after induced ovulation. Follow-up of pregnancies and children born after clomiphene therapy. JAMA 1972; 220:1329.
- Lambalk CB, van Hooff M. Natural versus induced twinning and pregnancy outcome: a Dutch nationwide survey of primiparous dizygotic twin deliveries. Fertil Steril 2001; 75:731.
- Olivennes F, Rufat P, André B, et al. The increased risk of complication observed in singleton pregnancies resulting from in-vitro fertilization (IVF) does not seem to be related to the IVF method itself. Hum Reprod 1993; 8:1297.
- Pregnancies and births resulting from in vitro fertilization: French national registry, analysis of data 1986 to 1990. FIVNAT (French In Vitro National). Fertil Steril 1995; 64:746.
- Källén B, Olausson PO, Nygren KG. Neonatal outcome in pregnancies from ovarian stimulation. Obstet Gynecol 2002; 100:414.
- Gaudoin M, Dobbie R, Finlayson A, et al. Ovulation induction/intrauterine insemination in infertile couples is associated with low-birth-weight infants. Am J Obstet Gynecol 2003; 188:611.
- Jones GS, De Moraes-Ruehsen M. Induction of ovulation with human gonadotropins and with clomiphene. Fertil Steril 1965; 16:461.
- Purvin VA. Visual disturbance secondary to clomiphene citrate. Arch Ophthalmol 1995; 113:482.
- Racette L, Casson PR, Claman P, et al. An investigation of the visual disturbances experienced by patients on clomiphene citrate. Fertil Steril 2010; 93:1169.
- Keenan JA, Herbert CM, Bush JR, Wentz AC. Diagnosis and management of out-of-phase endometrial biopsies among patients receiving clomiphene citrate for ovulation induction. Fertil Steril 1989; 51:964.
- Althuis MD, Moghissi KS, Westhoff CL, et al. Uterine cancer after use of clomiphene citrate to induce ovulation. Am J Epidemiol 2005; 161:607.
- PHARMACOLOGY/MECHANISMS OF ACTION
- PATIENT SELECTION
- Polycystic ovary syndrome
- Other ovulatory disorders
- HOW TO USE CLOMIPHENE CITRATE
- Pretreatment evaluation
- Starting a cycle
- Ovulatory and pregnancy rates
- - Effect of modified regimens
- Higher doses
- Addition of ovulatory dose hCG
- Combination regimens
- Multiple gestation
- Perinatal outcome
- Adverse effects
- - Common side effects
- - Visual disturbances
- - Endometrial effects
- Strategies to prevent thin endometrium
- - Cancer risks
- SUMMARY AND RECOMMENDATIONS