Clomiphene Citrate

Potential Benefits of Clomiphene citrate

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

What is 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

Clomiphene citrate stimulates the pituitary gland in the brain to increase the production of follicle stimulating hormone (FSH) and LH (luteinizing hormone). This in turn promotes ovarian follicle growth and thus initiates ovulation.

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.

Chemical Structure of Clomiphene citrate

Research on 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 womenfound that clomiphene citrate does not increasethe risk for fetal malformations. [2]
2. A 2004 study published in the Gynecological Endocrinologyfound that clomiphene citratedose 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 citratefor 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 Medicinefound thatclomiphene 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 C. 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]

B. 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]

Associated Side Effects of Clomiphene citrate

Clomiphene citrate side effects are very uncommon. There have been some side effects associated with the use of this drug wherein the patient had one of the issues listed below at some point while being on clomiphene citrate. However, these side effects weren’t confirmed to be associated with the treatment and could have been a coincidence and not related to the use of clomiphene citrate. Despite this, it was listed as a side effect associated with clomiphene citrate even though these associated side effects are very uncommon.

Side effects associated with clomiphene citrate may include the following:

• Abdominal/pelvic fullness
• Bloating
• Breast tenderness
• Dizziness
• Flushing (“hot flashes”)
• Headache
• Stomach upset

References

1. Beall SA, DeCherney A. History and challenges surrounding ovarian stimulation in the treatment of infertility. Fertil Steril. 2012;97(4):795–801. doi:10.1016/j.fertnstert.2012.02.030.
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. GynecolEndocrinol. 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 GynecolObstet Hum Reprod. 2017;46(7):575-577.
5. Venn A, Lumley J. Clomiphene citrate and pregnancy outcome. Aust N Z J ObstetGynaecol. 1994;34(1):56-66.
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 ClinEndocrinolMetab. 2013;98(12):4565–92.
11. Legro RS, Barnhart HS, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356(6):551–66.
12. Richard JP, Steiner AZ, Terplan M. Comparison of tamoxifen and clomiphene citratefor ovulation induction: a meta-analysis. Hum Reprod. 2005;20:1511–1515.
13. Fisher SA, Reid RL, Van vugt DA, Casper RF. A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women. Fertil Steril. 2002;78(2):280-5.
14. Sipe CS, Davis WA, Maifeld M, Van voorhis BJ. A prospective randomized trial comparing anastrozole and clomiphene citrate in an ovulation induction protocol using gonadotropins. Fertil Steril. 2006;86(6):1676-81.
15. Bayar U, Tanriverdi HA, Barut A, Ayoğlu F, Ozcan O, Kaya E. Letrozole vs. clomiphene citrate in patients with ovulatory infertility. Fertil Steril. 2006;85(4):1045-8.
16. Hughes E, Collins J, Vandekerckhove P. WITHDRAWN: Clomiphene citrate for ovulation induction in women with oligo-amenorrhoea. Cochrane Database Syst Rev. 1996;(1):CD000056.
17. Zain MM, Jamaluddin R, Ibrahim A, Norman RJ. Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction, achievement of pregnancy, and live birth in Asian women with polycystic ovary syndrome: a randomized controlled trial. FertilSteril. 2009;91(2):514-21.
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. FertilSteril. 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 ObstetGynecol 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.
27. 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 Apr;93(1):44-8. doi: 10.1016/j.ijgo.2005.10.015. Epub 2006 Mar 10. PMID: 16530767.
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.
31. Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome [published correction appears in N Engl J Med. 2014 Oct 9;317(15):1465]. N Engl J Med. 2014;371(2):119-129. doi:10.1056/NEJMoa1313517.
32. Mukherjee S, Sharma S, Chakravarty BN. Comparative evaluation of pregnancy outcome in gonadotrophin-clomiphene combination vs clomiphene alone in polycystic ovarian syndrome and unexplained infertility-A prospective clinical trial. J Hum Reprod Sci. 2010;3(2):80-84. doi:10.4103/0974-1208.69341.
33. Hajishafiha M, Dehghan M, Kiarang N, Sadegh-Asadi N, Shayegh SN, Ghasemi-Rad M. Combined letrozole and clomiphene versus letrozole and clomiphene alone in infertile patients with polycystic ovary syndrome [published correction appears in Drug Des Devel Ther. 2017 Apr 28;11:1367]. Drug Des Devel Ther. 2013;7:1427-1431. Published 2013 Dec 3. doi:10.2147/DDDT.S50972.
34. Bae SA, Joo JK, Choi JR, Kim SS, Lee KS. Clinical outcomes of three- or five-day treatment with clomiphene citrate combined with gonadotropins and a timed intercourse cycle in polycystic ovary syndrome patients. Clin Exp Reprod Med. 2015;42(3):106-110. doi:10.5653/cerm.2015.42.3.106.
35. Nasseri S, Ledger WL. Clomiphene citrate in the twenty-first century. Hum Fertil (Camb). 2001;4(3):145-51. doi: 10.1080/1464727012000199212. PMID: 11591271.
36. Hammond MG, Halme JK, Talbert LM. Factors affecting the pregnancy rate in clomiphene citrate induction of ovulation. Obstet Gynecol. 1983 Aug;62(2):196-202. PMID: 6866363.
37. Willets AE, Corbo JM, Brown JN. Clomiphene for the treatment of male infertility. Reprod Sci. 2013;20(7):739-44.
38. Patankar SS, Kaore SB, Sawane MV, Mishra NV, Deshkar AM. Effect of clomiphene citrate on sperm density in male partners of infertile couples. Indian J PhysiolPharmacol. 2007;51(2):195-8.
39. Sharma D, Zillioux J, Khourdaji I, et al. Improvements in semen parameters in men treated with clomiphene citrate-A retrospective analysis. Andrologia. 2019;51(5):e13257.
40. Schellen TM. Clomiphene treatment in male infertility. Int J Fertil. 1982;27(3):136-45.
41. Ghanem H, Shaeer O, El-segini A. Combination clomiphene citrate and antioxidant therapy for idiopathic male infertility: a randomized controlled trial. FertilSteril. 2010;93(7):2232-5.
42. Hayashi N, Sugimura Y, Hori N, et al. [Clomiphene citrate therapy in idiopathic male infertility]. Hinyokika Kiyo. 1988;34(5):847-50.
43. Roth LW, Ryan AR, Meacham RB. Clomiphene citrate in the management of male infertility. SeminReprod Med. 2013;31(4):245-50.
44. Sokol RZ, Steiner BS, Bustillo M, Petersen G, Swerdloff RS. A controlled comparison of the efficacy of clomiphene citrate in male infertility. FertilSteril. 1988;49(5):865-70.
45. Allag IS, Alexander NJ. Clomiphene citrate therapy for male infertility. Urology. 1979;14(5):500-3.
46. Bendre SV, Murray PJ, Basaria S. Clomiphene Citrate Effectively Increases Testosterone in Obese, Young, Hypogonadal Men. ReprodSyst Sex Disord. 2015;4(4):155. doi:10.4172/2161-038X.1000155.
47. Abel BJ, Carswell G, Elton R, et al. Randomised trial of clomiphene citrate treatment and vitamin C for male infertility. Br J Urol. 1982;54(6):780-4.
48. Emperaire JC, Riviere J, Ruffie A, Audebert AJ. Clomiphene test and clomiphene therapy in idiopathic male infertility. Arch Androl. 1979;2(3):223-31.
49. Krzastek SC, Sharma D, Abdullah N, et al. Long-Term Safety and Efficacy of Clomiphene Citrate for the Treatment of Hypogonadism. J Urol. 2019;202(5):1029-1035.
50. Elsheikh MG, Hosny MB, Elshenoufy A, Elghamrawi H, Fayad A, Abdelrahman S. Combination of vitamin E and clomiphene citrate in treating patients with idiopathic oligoasthenozoospermia: A prospective, randomized trial. Andrology. 2015;3(5):864-7.
51. Moradi M, Moradi A, Alemi M, et al. Safety and efficacy of clomiphene citrate and L-carnitine in idiopathic male infertility: a comparative study. Urol J. 2010;7(3):188-93.
52. Surbone A, Vaucher L, Primi MP, et al. Clomiphene citrate effect on testosterone level and semen parameters in 18 infertile men with low testosterone level and normal/low gonadotropines level. Eur J ObstetGynecolReprod Biol. 2019;238:104-109.
53. Patel DP, Brant WO, Myers JB, et al. The safety and efficacy of clomiphene citrate in hypoandrogenic and subfertile men. Int J Impot Res. 2015;27(6):221-4.
54. Paulson DF, Wacksman J. Clomiphene citrate in the management of male infertility. J Urol. 1976;115(1):73-6.
55. Wu C, Forbes E, Jarvi KA. Clomiphene citrate rescue of spermatogenesis in men with infertility while remaining on finasteride: A case report. Can UrolAssoc J. 2017;11(3-4):E122–E123. doi:10.5489/cuaj.4191.
56. Check JH, Chase JS, Nowroozi K, Wu CH, Adelson HG. Empirical therapy of the male with clomiphene in couples with unexplained infertility. Int J Fertil. 1989;34(2):120-2.