Clomifene has been found to decrease insulin-like growth factor 1 (IGF-1) levels in women.Clomifene is a long-acting ER ligand, with a nuclear retention of greater than 48 hours. Clomifene is a prodrug being activated via similar metabolic pathways as the related triphenylethylene SERMs tamoxifen and toremifene. 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%). 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-7 breast cancer cells, respectively. The ER affinities of the isomers of 4-hydroxyclomifene were 285% for (E)-4-hydroxyclomifene and 16% for (Z)-4-hydroxyclomifene relative to estradiol. 4-Hydroxy-N-desmethylclomifene has similar affinity to 4-hydroxyclomifene for the ER. 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.Even though clomifene has some estrogenic effect, the antiestrogenic property is believed to be the primary source for stimulating ovulation. Clomifene appears to act mostly in the hypothalamus where it depletes hypothalamic ERs and blocks the negative feedback effect of circulating endogenous estradiol, which in turn results in an increase in hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency and circulating concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
Clinical studies were conducted under an Investigational New Drug Application; clomifene was third drug for which an IND had been filed under the 1962 Kefauver Harris Amendment to the Federal Food, Drug, and Cosmetic Act that had been passed in response to the thalidomide tragedy. It was approved for marketing in 1967 under the brand name Clomid. It was first used to treat cases of oligomenorrhea but was expanded to include treatment of anovulation when women undergoing treatment had higher than expected rates of pregnancy.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".The company was acquired by Dow Chemical in 1980, and in 1989 Dow Chemical acquired 67 percent interest of Marion Laboratories, which was renamed Marion Merrell Dow. In 1995 Hoechst AG acquired the pharmaceutical business of Marion Merrell Dow. Hoechst in turn became part of Aventis in 1999,: 9–11  and subsequently a part of Sanofi. It became the most widely prescribed drug for ovulation induction to reverse anovulation or oligoovulation.