Clomifene (particularly the purified enclomiphene isomer) has also been found to have a powerful ability to boost or restore testosterone levels in hypogonadal men.[11]
Clomifene is one of several alternatives for ovulation induction in those who are infertile due to anovulationoroligoovulation.[12] Evidence is lacking for the use of clomifene in those who are infertile without a known reason.[13] In such cases, studies have observed a clinical pregnancy rate 5.6% per cycle with clomifene treatment vs. 1.3%–4.2% per cycle without treatment.[12]
Clomifene is sometimes used in the treatment of male hypogonadism as an alternative to testosterone replacement therapy.[15][non-primary source needed] It has been found to increase testosterone levels by 2- to 2.5-times in hypogonadal men at such dosages.[15][16] Despite the use of questionnaires in testosterone replacement comparator trials being called into question, clomifene's lower cost, therapeutic benefits, and greater value towards hypogonadism improvement have been noted.[17][non-primary source needed]
Clomifene consists of two stereoisomers in equal proportion: enclomifene and zuclomifene. Zuclomifene has pro-estrogenic properties, whereas enclomifene is pro-androgenic, i.e. it promotes testosterone production through stimulation of the HPG axis. For this reason, purified enclomifene isomer has been found to be twice as effective in boosting testosterone compared to the standard mix of both isomers.[11] Additionally, enclomifene has a half-life of just 10 hours,[4] but zuclomifene has a half-life on the order of several days to a week, so if the goal is to boost testosterone, taking regular clomifene may produce far longer-lasting pro-estrogenic effects than pro-androgenic effects.[18]
Clomifene has been used in the treatment of gynecomastia.[19] It has been found to be useful in the treatment of some cases of gynecomastia but it is not as effective as tamoxifenorraloxifene for this indication.[20] It has shown variable results for gynecomastia (probably because the zuclomifene isomer is estrogenic), and hence is not recommended for treatment of the condition.[21] Pure enclomifene isomer is likely to be more effective than clomifene at treating gynecomastia, because of the lack of the zuclomifene isomer (as noted above).[medical citation needed]
Due to its long half-life, zuclomifene can be detected in urine for at least 261 days after discontinuation[22] (261 days after discontinuation with a half-life of 30 days, there is still 0.24% of the peak level of zuclomifene being excreted, whereas with a half-life of 10 hours, enclomifene reaches the same 0.24% level in less than 4 days[medical citation needed]).
Because of its potential for boosting testosterone, clomifene is listed as banned for use by competitive sportsmen, both in and out of competition, by the World Anti-Doping Agency, absent an organic etiology of primary hypogonadism.[citation needed]
Contraindications include an allergy to the medication, pregnancy, prior liver problems, abnormal vaginal bleeding of unclear cause, ovarian cysts other than those due to polycystic ovarian syndrome, unmanaged adrenal or thyroid problems, and pituitary tumors.[7]
Clomifene can lead to multiple ovulation, hence increasing the chance of twins (10% of births instead of ~1% in the general population) and triplets.[medical citation needed]
Rates of birth defects and miscarriages do not appear to change with the use of clomifene for fertility.[7] Clomifene has been associated with liver abnormalities and a couple of cases of hepatotoxicity.[23]
Some studies have suggested that clomifene if used for more than a year may increase the risk of ovarian cancer.[13] This may only be the case in those who have never been and do not become pregnant.[24] Subsequent studies have failed to support those findings.[12][25]
Clomifene has been shown to be associated with an increased risk of malignant melanomas and thyroid cancer.[3] Thyroid cancer risk was not associated with the number of pregnancies carried to viability.[26]
Clomifene is a long-acting ER ligand, with a nuclear retention of greater than 48 hours.[31] Clomifene is a prodrug being activated via similar metabolic pathways as the related triphenylethylene SERMs tamoxifen and toremifene.[32][33] The affinity of clomifene for the ER relative to estradiol ranges from 0.1 to 12% in different studies, which is similar to the range for tamoxifen (0.06–16%).[34][35][36] 4-Hydroxyclomifene, a major active metabolite of clomifene, and afimoxifene (4-hydroxytamoxifen), a major active metabolite of tamoxifen, show 89–251% and 41–246% of the affinity of estradiol for the ER in human MCF-7breast cancercells, respectively.[37][38] The ER affinities of the isomers of 4-hydroxyclomifene were 285% for (E)-4-hydroxyclomifene and 16% for (Z)-4-hydroxyclomifene relative to estradiol.[37] 4-Hydroxy-N-desmethylclomifene has similar affinity to 4-hydroxyclomifene for the ER.[33] In one study, the affinities of clomifene and its metabolites for the ERα were ~100 nM for clomifene, ~2.4 nM for 4-hydroxyclomifene, ~125 nM for N-desmethylclomifene, and ~1.4 nM for 4-hydroxy-N-desmethylclomifene.[33]
In normal physiologic female hormonal cycling, at seven days past ovulation, high levels of estrogen and progesterone produced from the corpus luteum inhibit GnRH, FSH, and LH at the hypothalamus and anterior pituitary.[medical citation needed] If fertilization does not occur in the post-ovulation period the corpus luteum disintegrates due to a lack of human chorionic gonadotropin (hCG).[medical citation needed] This would normally be produced by the embryo in the effort of maintaining progesterone and estrogen levels during pregnancy.[medical citation needed]
Therapeutically, clomifene is given early in the menstrual cycle to produce follicles.[medical citation needed] Follicles, in turn, produce the estrogen, which circulates in serum.[medical citation needed] In the presence of clomifene, the body perceives a low level of estrogen, similar to day 22 in the previous cycle.[medical citation needed] Since estrogen can no longer effectively exert negative feedback on the hypothalamus, GnRH secretion becomes more rapidly pulsatile, which results in increased pituitary gonadotropin release.[medical citation needed] (More rapid, lower amplitude pulses of GnRH lead to increased LH and FSH secretion, while more irregular, larger amplitude pulses of GnRH leads to a decrease in the ratio of LH to FSH.[medical citation needed]) Increased FSH levels cause the growth of more ovarian follicles, and subsequently rupture of follicles resulting in ovulation. Ovulation occurs most often 6 to 7 days after a course of clomifene.[medical citation needed]
In normal men, 50 mg/day clomifene for 8 months has been found to increase testosterone levels by around 870 ng/dL in younger men and by around 490 ng/dL in elderly men.[16]Estradiol levels increased by 62 pg/mL in younger men and by 40 pg/mL in elderly men.[16] These findings suggest that the progonadotropic effects of clomifene are stronger in younger men than in older men.[16] In men with hypogonadism, clomifene has been found to increase testosterone levels by 293 to 362 ng/dL and estradiol levels by 5.5 to 13 pg/mL.[16] In a large clinical study of men with low testosterone levels (<400 ng/dL), 25 mg/day clomifene increased testosterone levels from 309 ng/dL to 642 ng/dL after 3 months of therapy.[39] No significant changes in HDL cholesterol, triglycerides, fasting glucose, or prolactin levels were observed, although total cholesterol levels decreased significantly.[16][39]
Effect:+ = Estrogenic / agonistic. ± = Mixed or neutral. – = Antiestrogenic / antagonistic. Note: SERMs generally increase gonadotropin levels in hypogonadal and eugonadal men as well as premenopausal women (antiestrogenic) but decrease gonadotropin levels in postmenopausal women (estrogenic). Sources: See template.
Clomifene produces N-desmethylclomifene, clomifenoxide (clomifene N-oxide), 4-hydroxyclomifene, and 4-hydroxy-N-desmethylclomifene as metabolites.[2][44] Clomifene is a prodrug most importantly of 4-hydroxyclomifene and 4-hydroxy-N-desmethylclomifene, which are the most active of its metabolites.[32][33] In one study, the peak levels after a single 50 mg dose of clomifene were 20.37 nmol/L for clomifene, 0.95 nmol/L for 4-hydroxyclomifene, and 1.15 nmol/L for 4-hydroxy-N-desmethylclomifene.[2]
Clomifene has an onset of action of 5 to 10 days following course of treatment and an elimination half-life about 4 - 7days.[2][4] In one study, after a single 50 mg dose of clomifene, the half-life of clomifene was 128 hours (5.3 days), of 4-hydroxyclomifene was 13 hours, and of 4-hydroxy-N-desmethylclomifene was 15 hours.[2] Individuals with the CYP2D6*10 allele showed longer half-lives for 4-hydroxyclomifene and 4-hydroxy-N-desmethylclomifene.[2] Primarily due to differences in CYP2D6 genetics, steady state concentrations and individual response to clomifene are highly variable.[45]
Most clomifene metabolism occurs in the liver, where it undergoes enterohepatic recirculation. Clomifene and its metabolites are excreted primarily through feces (42%), and excretion can occur up to 6 weeks after discontinuation.[27]
Clomifene is a triphenylethylene derivative. It is a mixture of two geometric isomers, the cis enclomifene ((E)-clomifene) form and trans zuclomifene ((Z)-clomifene) form. These two isomers contribute to the mixed estrogenic and antiestrogenic properties of clomifene.[10] The typical ratio of these isomers after synthesis is 38% zuclomiphene and 62% enclomiphene.[4] The United States Pharmacopeia specifies that clomifene preparations must contain between 30% and 50% zuclomiphene.[4]
A team at William S. Merrell Chemical Company led by Frank Palopoli synthesized clomifene in 1956; after its biological activity was confirmed a patent was filed and issued in November 1959.[10][46] Scientists at Merrell had previously synthesized chlorotrianisene and ethamoxytriphetol.[10] Clomifene was studied in the treatment of advanced breast cancer during the period of 1964 to 1974 and was found to be effective but was abandoned due to concerns about desmosterolosis with extended use.[40][47][48] Short-term use (e.g. days to months) did not raise the same concerns and clomifene continued to be studied for other indications.[41][42]
Footnotes:a = "The particular advantage of this drug is the low incidence of troublesome side effects (25)." "Side effects were usually trivial (26)." Sources:[47][49]
The drug is widely considered to have been a revolution in the treatment of female infertility, the beginning of the modern era of assisted reproductive technology, and the beginning of what in the words of Eli Y. Adashi, was "the onset of the US multiple births epidemic".[10][52]
The company was acquired by Dow Chemical in 1980,[53][54] and in 1989 Dow Chemical acquired 67 percent interest of Marion Laboratories, which was renamed Marion Merrell Dow.[53] In 1995 Hoechst AG acquired the pharmaceutical business of Marion Merrell Dow.[55] Hoechst in turn became part of Aventis in 1999,[56]: 9–11 and subsequently a part of Sanofi.[57] It became the most widely prescribed drug for ovulation induction to reverse anovulationoroligoovulation.[58]
Clomifene is included on the World Anti-Doping Agency list of illegal doping agents in sport.[59] It is listed because it is an "anti-estrogenic substance".[citation needed]
Clomifene has been used almost exclusively for ovulation induction in premenopausal women, and has been studied very limitedly in postmenopausal women.[60]
Clomifene was studied for treatment and prevention of breast cancer, but issues with toxicity led to abandonment of this indication, as did the discovery of tamoxifen.[61] Like the structurally related drug triparanol, clomifene is known to inhibit the enzyme24-dehydrocholesterol reductase and increase circulating desmosterol levels, making it unfavorable for extended use in breast cancer due to risk of side effects like irreversible cataracts.[62][63]
^ abcdefghiKim MJ, Byeon JY, Kim YH, Kim SH, Lee CM, Jung EH, et al. (March 2018). "Effect of the CYP2D6*10 allele on the pharmacokinetics of clomiphene and its active metabolites". Archives of Pharmacal Research. 41 (3): 347–353. doi:10.1007/s12272-018-1005-7. PMID29516347. S2CID4034257.
^ abcdeMikkelson TJ, Kroboth PD, Cameron WJ, Dittert LW, Chungi V, Manberg PJ (September 1986). "Single-dose pharmacokinetics of clomiphene citrate in normal volunteers". Fertility and Sterility. 46 (3): 392–396. doi:10.1016/S0015-0282(16)49574-9. PMID3091405.
^ abcdef"Clomiphene Citrate". The American Society of Health-System Pharmacists. Archived from the original on 14 September 2017. Retrieved 8 December 2016.
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^Helo S, Mahon J, Ellen J, Wiehle R, Fontenot G, Hsu K, et al. (January 2017). "Serum levels of enclomiphene and zuclomiphene in men with hypogonadism on long-term clomiphene citrate treatment". BJU International. 119 (1): 171–176. doi:10.1111/bju.13625. PMID27511863. S2CID5538782.
^Gadducci A, Guerrieri ME, Genazzani AR (January 2013). "Fertility drug use and risk of ovarian tumors: a debated clinical challenge". Gynecological Endocrinology. 29 (1): 30–5. doi:10.3109/09513590.2012.705382. PMID22946709. S2CID1240526.
^ abcdObach RS (April 2013). "Pharmacologically active drug metabolites: impact on drug discovery and pharmacotherapy". Pharmacological Reviews. 65 (2): 578–640. doi:10.1124/pr.111.005439. PMID23406671. S2CID720243.
^Fang H, Tong W, Shi LM, Blair R, Perkins R, Branham W, et al. (March 2001). "Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens". Chemical Research in Toxicology. 14 (3): 280–94. doi:10.1021/tx000208y. PMID11258977.
^ abBaumann RJ, Bush TL, Cross-Doersen DE, Cashman EA, Wright PS, Zwolshen JH, et al. (March 1998). "Clomiphene analogs with activity in vitro and in vivo against human breast cancer cells". Biochemical Pharmacology. 55 (6): 841–51. doi:10.1016/s0006-2952(97)00574-1. PMID9586957.
^Sutherland RL, Watts CK, Ruenitz PC (October 1986). "Definition of two distinct mechanisms of action of antiestrogens on human breast cancer cell proliferation using hydroxytriphenylethylenes with high affinity for the estrogen receptor". Biochemical and Biophysical Research Communications. 140 (2): 523–9. doi:10.1016/0006-291x(86)90763-1. PMID3778464.
^US 2,914,563, Allen RE, Palopoli FP, Schumann EL, Van Campen Jr MG, "Therapeutic composition", issued 24 November 1959, assigned to William S Merrill Company
^Holtkamp DE, Greslin JG, Root CA, Lerner LJ (October 1960). "Gonadotrophin inhibiting and anti-fecundity effects of chloramiphene". Proceedings of the Society for Experimental Biology and Medicine. 105: 197–201. doi:10.3181/00379727-105-26054. PMID13715563. S2CID1448466.