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Clomiphene

Clomiphene citrate

Clomiphene citrate, also known by its brand name Clomid, is a U.S. Food and Drug Administration (FDA)-approved drug for infertility in both men and women. It’s touted as the “first-line” fertility medication recommended for the treatment of irregular ovulation and low sperm count. Clomiphene citrate has a proven safety record. In fact, the first successful clinical trials for this fertility medication date back in 1967 where it was used for ovulation induction. [1] People with fertility problems can benefit from clomiphene citrate by taking its oral form or via injections.

How Clomiphene citrate Works for Women?

In women, clomiphene citrate works by blocking the production of the hormone estrogen. This mechanism stimulates the hypothalamus and pituitary glands in the brain to produce several hormones necessary for maturation of the egg follicles, such as follicle stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH), and luteinizing hormone (LH). As the egg matures, the chances of ovulation and getting pregnant are usually higher.

How Clomiphene citrate Works for Men?

In men, clomiphene citrate also boosts the production of FSH and LH. These hormones are also present in men and are important for fertility. Specifically, LH stimulates the release of testosterone while FSH is required in the first stage of sperm production (spermatogenesis). With increased testosterone levels, the sperm can move properly through female reproductive tract to reach the matured egg (motility). In addition, testosterone increases sex drive and sexual function.

Overall Benefits of Clomiphene citrate

  • Increases pregnancy rate [2-36]
  • Improves sperm quality [37-56]

Proven Health Benefits of Clomiphene citrate

Increases Pregnancy Rate

An overwhelming body of clinical evidence supports the beneficial effects of clomiphene citrate on fertility. Studies show that this fertility medication increases the chance of pregnancy:

  1. A study involving 114 961 pregnant women found that clomiphene citrate does not increase the risk for fetal malformations. [2]
  2. A 2004 study published in the Gynecological Endocrinology found that clomiphene citrate dose of 150-250 mg/day does not appear to increase adverse pregnancy outcomes. [3]
  3. In patients with polycystic ovary syndrome (PCOS), a condition characterized by irregular menstruation and difficulty getting pregnant, clomiphene citrate treatment for 3 months significantly improved ovulation rate. [4]
  4. A 1994 study published in the Australian & New England Journal of Obstetrics and Gynecology found that clomiphene citrate treatment is associated with higher rates of pregnancy. [5]
  5. In women trying to conceive, administration of clomiphene citrate for at least 6 cycles is recommended in order to get pregnant. [6]
  6. Data from the Yale-New Haven Medical Center showed that clomiphene citrate is associated with 50% conception rate after 3 ovulations. [7]
  7. A 2016 study published in the Iranian Journal of Reproductive Medicine found that clomiphene citrate has higher pregnancy rate compared to other fertility medications such as tamoxifen and letrozole. [8]
  8. Most studies recommend clomiphene citrate as first-line therapy for women with PCOS. [9-10]
  9. In women with PCOS, clomiphene citrate treatment is associated with 6% multiple pregnancies. [11]
  10. In women with anovulation (failure of ovaries to release egg), clomiphene citrate induced ovulation in 80% of the subjects but only 40% became pregnant. [12]
  11. A 2002 study published in Fertility and Sterility reported that clomiphene citrate treatment resulted in stimulation of ovarian folliculogenesis (maturation of the ovarian follicle) without any adverse effects on thickness of the uterine lining. [13]
  12. In infertile women, administration of 100 mg clomiphene citrate for 5 days increased pregnancy rate by 20%. [14]
  13. In patients with ovulatory infertility, clomiphene citrate had higher pregnancy rate compared with letrozole. [15]
  14. In women with irregular ovulation, clomiphene citrate administration at doses between 50 to 250 milligrams daily effectively induced ovulation and improved fertility. [16]
  15. In women with anovulation associated with PCOS, clomiphene citrate treatment is associated with higher ovulation and pregnancy rate compared with metformin. [17]
  16. When combined with metformin, clomiphene citrate is associated with a higher pregnancy rate in women who do not respond to other fertility medications. [18-19]
  17. In women with unexplained infertility, administration of 100 mg of clomiphene citrate daily resulted in favorable pregnancy outcomes. [20]
  18. When combined with letrozole, clomiphene citrate produces higher ovulation rate in women with polycystic ovary syndrome. [21]
  19. When combined with racemosa rhizome dry extract, clomiphene citrate induces higher pregnancy rate and cycle outcomes. [22]
  20. When combined with dexamethasone, clomiphene citrate increases the number and diameter of follicles, endometrial thickness, ovulation rate, and pregnancy outcome in PCOS patients. [23]
  21. In women with PCOS, administration of clomiphene citrate significantly increased ovulation and pregnancy rates with no side effects. [24-34]
  22. Studies show that clomiphene citrate can help restore the normal ovulation cycle. [35-36]

Improves Sperm Quality

Clomiphene citrate can also be used as a therapeutic option for male infertility. Numerous high- quality studies show that clomiphene citrate administration has beneficial effects on sperm quality, thus increasing the chance of fertilization:

  1. A review of several studies found that clomiphene citrate significantly increased sperm concentrations in infertile men. [37]
  2. A 2013 study published in Reproductive Science found that clomiphene citrate increased sperm parameters in males attempting to conceive. [38]
  3. A 2007 study published in Indian Journal of Physiology and Pharmacology found that clomiphene citrate increased sperm count in men with oligospermia (low sperm count) by boosting the levels of testosterone, FSH, and LH. [39]
  4. A 2019 study published in Andrologia reported that men treated with at least 25 mg clomiphene citrate daily for male infertility had significant improvement in sperm concentration million and total motile count. [40]
  5. When administered in men with low sperm count, clomiphene citrate appears to improve semen parameters. [41]
  6. In men with infertility of unknown cause, clomiphene citrate improved sperm count and sperm motility. [42-43]
  7. When administered in infertile men, clomiphene citrate is associated with a higher rate of impregnating partner and higher levels of testosterone, LH, and FSH. [44]
  8. In infertile men, clomiphene citrate administration at 25 mg and 50 mg daily significantly improved semen quality. [45]
  9. In young, obese men who are at high risk for infertility related to testosterone deficiency, clomiphene citrate administration significantly increased testosterone levels. [46]
  10. A study comparing the efficacy of clomiphene citrate and vitamin C at treating male infertility found that both treatments improved sperm density. [47]
  11. Studies found that clomiphene citrate only improves semen quality in infertile men who had increases in testosterone levels after the treatment. [48-49]
  12. When combined with vitamin E, clomiphene citrate significantly improved sperm motility in men with infertility of unknown cause. [50]
  13. A study found that clomiphene citrate treatment is associated with significant improvement in sperm motility percentage and sperm structure. [51]
  14. In infertile men with low testosterone level, clomiphene citrate treatment increased sperm concentration as well as testosterone. [52-53]
  15. Studies found that clomiphene citrate treats male infertility by increasing the number of mature sperm cells (spermatogenesis). [54-55]
  16. A study found that clomiphene citrate treats male fertility by improving the quality of defective sperm. [56]

References:

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  2. Weller A, Daniel S, Koren G, Lunenfeld E, Levy A. The fetal safety of clomiphene citrate: a population-based retrospective cohort study. BJOG. 2017;124(11):1664-1670.
  3. Jain JK, Kuo J. Pregnancy outcomes with increased clomiphene citrate dose. Gynecol Endocrinol. 2004;19(3):141-5.
  4. Elkhateeb RR, Mahran AE, Kamel HH. Long-term use of clomiphene citrate in induction of ovulation in PCO patients with clomiphene citrate resistance. J Gynecol Obstet Hum Reprod. 2017;46(7):575-577.
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  6. Kousta E, White DM, Franks S. Modern use of clomiphene citrate in induction of ovulation. Hum Reprod Update. 1997;3(4):359-65.
  7. Gorlitsky GA, Kase NG, Speroff L. Ovulation and pregnancy rates with clomiphene citrate. Obstet Gynecol. 1978;51(3):265-9.
  8. Seyedoshohadaei F, Zandvakily F, Shahgeibi S. Comparison of the effectiveness of clomiphene citrate, tamoxifen and letrozole in ovulation induction in infertility due to isolated unovulation. Iran J Reprod Med. 2012;10(6):531–536.
  9. SOGC clinical practice guideline. Ovulation induction in polycystic ovarian syndrome. Ottawa, ON: Society of Obstetricians and Gynaecologists of Canada; 2010. Available from: https://docs.google.com/viewerng/viewer?url=http://sogc.org/wp-content/uploads/2013/01/gui242CPG1005E_000.pdf.
  10. Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(12):4565–92.
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  18. Abu hashim H, Shokeir T, Badawy A. Letrozole versus combined metformin and clomiphene citrate for ovulation induction in clomiphene-resistant women with polycystic ovary syndrome: a randomized controlled trial. Fertil Steril. 2010;94(4):1405-9.
  19. Ganesh A, Goswami SK, Chattopadhyay R, Chaudhury K, Chakravarty B. Comparison of letrozole with continuous gonadotropins and clomiphene-gonadotropin combination for ovulation induction in 1387 PCOS women after clomiphene citrate failure: a randomized prospective clinical trial. J Assist Reprod Genet. 2009;26:19–24.
  20. Badawy A, Shokeir T, Allam AF, Abdelhady H. Pregnancy outcome after ovulation induction with aromatase inhibitors or clomiphene citrate in unexplained infertility. Acta Obstet Gynecol Scand. 2009;88(2):187-91.
  21. Mejia RB, Summers KM, Kresowik JD, Van Voorhis BJ. A randomized controlled trial of combination letrozole and clomiphene citrate or letrozole alone for ovulation induction in women with polycystic ovary syndrome. Fertil Steril. 2019;111(3):571-578.e1. doi:10.1016/j.fertnstert.2018.11.030.
  22. Shahin AY, Ismail AM, Zahran KM, Makhlouf AM. Adding phytoestrogens to clomiphene induction in unexplained infertility patients–a randomized trial. Reprod Biomed Online. 2008;16(4):580-588. doi:10.1016/s1472-6483(10)60465-8.
  23. Esmaeilzadeh S, Amiri MG, Basirat Z, Shirazi M. Does Adding Dexamethasone to Clomiphene Citrate Improve Ovulation in PCOS Patients? A Triple – Blind Randomized Clinical Trial Study. Int J Fertil Steril. 2011;5(1):9-12.
  24. Badawy A, Allam A, Abulatta M. Extending clomiphene treatment in clomiphene-resistant women with PCOS: a randomized controlled trial. Reprod Biomed Online. 2008 Jun;16(6):825-9. doi: 10.1016/s1472-6483(10)60148-4. PMID: 18549692.
  25. Dasari P, Pranahita G. The efficacy of metformin and clomiphene citrate combination compared with clomiphene citrate alone for ovulation induction in infertile patients with PCOS. J Hum Reprod Sci. 2009;2(1):18-22. doi:10.4103/0974-1208.51337.
  26. Neveu N, Granger L, St-Michel P, Lavoie HB. Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction and achievement of pregnancy in 154 women with polycystic ovary syndrome. Fertil Steril. 2007 Jan;87(1):113-20. doi: 10.1016/j.fertnstert.2006.05.069. Epub 2006 Nov 1. PMID: 17081535.
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  28. Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ. 2006;332(7556):1485. doi:10.1136/bmj.38867.631551.55.
  29. Kar S. Clomiphene citrate or letrozole as first-line ovulation induction drug in infertile PCOS women: A prospective randomized trial. J Hum Reprod Sci. 2012;5(3):262-265. doi:10.4103/0974-1208.106338.
  30. Brown J, Farquhar C. Clomiphene and other antioestrogens for ovulation induction in polycystic ovarian syndrome. Cochrane Database Syst Rev. 2016;12(12):CD002249. Published 2016 Dec 15. doi:10.1002/14651858.CD002249.pub5.
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