Smarter Decisions,
Better Care

UpToDate synthesizes the most recent medical information into evidence-based practical recommendations clinicians trust to make the right point-of-care decisions.

  • Rigorous editorial process: Evidence-based treatment recommendations
  • World-Renowned physician authors: over 5,100 physician authors and editors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

Choose from the list below to learn more about subscriptions for a:

Subscribers log in here

Ovulation induction with clomiphene citrate


Clomiphene citrate 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 clomiphene citrate 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".)


Clomiphene is a triphenylethylene derivative distantly related to diethylstilbestrol. It acts as a selective estrogen receptor modulator, similar to tamoxifen and raloxifene. All three drugs are competitive inhibitors of estrogen binding to estrogen receptors 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). 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. Zu-clomiphene appears to have greater estrogenic activity than en-clomiphene [1].

14C-labeled clomiphene citrate is absorbed by the gastrointestinal tract. Fifty percent of the oral dose is excreted after five days, but radioactivity from labeled clomiphene appears in the feces up to six weeks after administration. However, the pharmacologic effect of clomiphene citrate is brief [2].


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2014. | This topic last updated: Sep 22, 2014.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2014 UpToDate, Inc.
  1. 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.
  2. Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod Update 1996; 2:483.
  3. 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.
  4. Jorgensen SE, Starup J, Roos J, Micic S. Studies on the mode of action of clomiphene citrate. Acta Obstet Gynecol Scand 1976; 55:337.
  5. 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.
  6. Hsueh AJ, Erickson GF, Yen SS. Sensitisation of pituitary cells to luteinising hormone releasing hormone by clomiphene citrate in vitro. Nature 1978; 273:57.
  7. 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.
  8. 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.
  9. 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.
  10. Bonhoff AJ, Naether OG, Johannisson E. Effects of clomiphene citrate stimulation on endometrial structure in infertile women. Hum Reprod 1996; 11:844.
  11. Sereepapong W, Suwajanakorn S, Triratanachat S, et al. Effects of clomiphene citrate on the endometrium of regularly cycling women. Fertil Steril 2000; 73:287.
  12. 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.
  13. Thomson JL. Effect of two non-steroidal antifertility agents on pregnancy in mice. II. Effects on tubal transport rate and implantation. J Reprod Fertil 1968; 16:363.
  14. 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.
  15. Gelety TJ, Buyalos RP. The effect of clomiphene citrate and menopausal gonadotropins on cervical mucus in ovulatory cycles. Fertil Steril 1993; 60:471.
  16. Roumen FJ. [Decreased quality of cervix mucus under the influence of clomiphene: a meta-analysis]. Ned Tijdschr Geneeskd 1997; 141:2401.
  17. Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in women. Fertil Steril 2003; 80:1302.
  18. Gorlitsky GA, Kase NG, Speroff L. Ovulation and pregnancy rates with clomiphene citrate. Obstet Gynecol 1978; 51:265.
  19. 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.
  20. Kousta E, White DM, Franks S. Modern use of clomiphene citrate in induction of ovulation. Hum Reprod Update 1997; 3:359.
  21. Glasier AF. Clomiphene citrate. Baillieres Clin Obstet Gynaecol 1990; 4:491.
  22. 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.
  23. Brown J, Farquhar C, Beck J, et al. Clomiphene and anti-oestrogens for ovulation induction in PCOS. Cochrane Database Syst Rev 2009; :CD002249.
  24. Guzick DS, Sullivan MW, Adamson GD, et al. Efficacy of treatment for unexplained infertility. Fertil Steril 1998; 70:207.
  25. Reindollar RH, Regan MM, Neumann PJ, et al. A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial. Fertil Steril 2010; 94:888.
  26. Glazener CM, Coulson C, Lambert PA, et al. Clomiphene treatment for women with unexplained infertility: placebo-controlled study of hormonal responses and conception rates. Gynecol Endocrinol 1990; 4:75.
  27. Deaton JL, Gibson M, Blackmer KM, et al. A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertil Steril 1990; 54:1083.
  28. Arici A, Byrd W, Bradshaw K, et al. Evaluation of clomiphene citrate and human chorionic gonadotropin treatment: a prospective, randomized, crossover study during intrauterine insemination cycles. Fertil Steril 1994; 61:314.
  29. Hughes E, Collins J, Vandekerckhove P. Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev 2000; :CD000057.
  30. Bohnet HG, Kato K, Trapp M, et al. Different hormonal patterns in human menopausal gonadotropin-treated, clomiphene citrate-treated, and untreated conception cycles. Fertil Steril 1986; 45:469.
  31. Wu CH, Winkel CA. The effect of therapy initiation day on clomiphene citrate therapy. Fertil Steril 1989; 52:564.
  32. 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.
  33. Lobo RA, Gysler M, March CM, et al. Clinical and laboratory predictors of clomiphene response. Fertil Steril 1982; 37:168.
  34. Rostami-Hodjegan A, Lennard MS, Tucker GT, Ledger WL. Monitoring plasma concentrations to individualize treatment with clomiphene citrate. Fertil Steril 2004; 81:1187.
  35. O'Herlihy C, De Crespigny LJ, Robinson HP. Monitoring ovarian follicular development with real-time ultrasound. Br J Obstet Gynaecol 1980; 87:613.
  36. 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.
  37. 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.
  38. Rossing MA, Daling JR, Weiss NS, et al. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994; 331:771.
  39. Homburg R. Clomiphene citrate--end of an era? A mini-review. Hum Reprod 2005; 20:2043.
  40. Shoham Z, Borenstein R, Lunenfeld B, Pariente C. Hormonal profiles following clomiphene citrate therapy in conception and nonconception cycles. Clin Endocrinol (Oxf) 1990; 33:271.
  41. Macgregor AH, Johnson JE, Bunde CA. Further clinical experience with clomiphene citrate. Fertil Steril 1968; 19:616.
  42. Scialli AR. The reproductive toxicity of ovulation induction. Fertil Steril 1986; 45:315.
  43. Kurachi K, Aono T, Minagawa J, Miyake A. Congenital malformations of newborn infants after clomiphene-induced ovulation. Fertil Steril 1983; 40:187.
  44. Dickey RP, Taylor SN, Curole DN, et al. Incidence of spontaneous abortion in clomiphene pregnancies. Hum Reprod 1996; 11:2623.
  45. 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.
  46. REPROTOX: An information system on environmental hazards to human reproduction and development. Agent #1242 (Accessed on August 20, 2008).
  47. 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.
  48. 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.
  49. 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.
  50. 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.
  51. 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.
  52. 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.
  53. Källén B, Olausson PO, Nygren KG. Neonatal outcome in pregnancies from ovarian stimulation. Obstet Gynecol 2002; 100:414.
  54. 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.
  55. Jones GS, De Moraes-Ruehsen M. Induction of ovulation with human gonadotropins and with clomiphene. Fertil Steril 1965; 16:461.
  56. Purvin VA. Visual disturbance secondary to clomiphene citrate. Arch Ophthalmol 1995; 113:482.
  57. 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.
  58. 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.
  59. Althuis MD, Moghissi KS, Westhoff CL, et al. Uterine cancer after use of clomiphene citrate to induce ovulation. Am J Epidemiol 2005; 161:607.
  60. Palomba S, Falbo A, Giallauria F, et al. Six weeks of structured exercise training and hypocaloric diet increases the probability of ovulation after clomiphene citrate in overweight and obese patients with polycystic ovary syndrome: a randomized controlled trial. Hum Reprod 2010; 25:2783.
  61. O'Herlihy C, Pepperell RJ, Robinson HP. Ultrasound timing of human chorionic gonadotropin administration in clomiphene-stimulated cycle. Obstet Gynecol 1982; 59:40.
  62. 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.
  63. 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.
  64. 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.
  65. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril 2008; 89:505.
  66. 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.
  67. 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.
  68. Sönmez AS, Yasar L, Savan K, et al. Comparison of the effects of acarbose and metformin use on ovulation rates in clomiphene citrate-resistant polycystic ovary syndrome. Hum Reprod 2005; 20:175.