Pharmacodynamics Selective estrogen receptor modulator activity<unk>  is a nonsteroidal triphenylethylene derivative that acts as a selective estrogen receptor modulator (SERM). It consists of a racemic mixture of zuclomifene (~38%) and enclomifene (~62%), each of which has unique pharmacologic properties. It is a mixed agonist and antagonist of the estrogen receptor (ER).<unk>  activates the ERα in the setting of low baseline estrogen levels and partially blocks the receptor in the context of high baseline estrogen levels. Conversely, it is an antagonist of the ERβ.<unk>  has antiestrogenic effects in the uterus. There is little clinical research on the influence of<unk>  in many target tissues, such as lipids, the cardiovascular system, and the breasts. Positive effects of<unk>  on bone have been observed.<unk>  has been found to decrease insulin-like growth factor 1 (IGF-1) levels in women.<unk>  is a long-acting ER ligand, with a nuclear retention of greater than 48 hours.<unk>  is a prodrug being activated via similar metabolic pathways as the related triphenylethylene SERMs tamoxifen and toremifene. The affinity of<unk>  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<unk> , 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<unk>  and its metabolites for the ERα were ~100 nM for<unk> , ~2.4 nM for 4-hydroxyclomifene, ~125 nM for N-desmethylclomifene, and ~1.4 nM for 4-hydroxy-N-desmethylclomifene. Even though<unk>  has some estrogenic effect, the antiestrogenic property is believed to be the primary source for stimulating ovulation.<unk>  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). In normal physiologic female hormonal cycling, at 7 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. If fertilization does not occur in the post-ovulation period the corpus luteum disintegrates due to a lack of human chorionic gonadotropin (hCG). This would normally be produced by the embryo in the effort of maintaining progesterone and estrogen levels during pregnancy. Therapeutically,<unk>  is given early in the menstrual cycle. It is typically prescribed beginning on day 3 and continuing for 5 days. By that time, FSH levels are rising steadily, causing the development of a few follicles. Follicles, in turn, produce the estrogen, which circulates in serum. In the presence of<unk> , the body perceives a low level of estrogen, similar to day 22 in the previous cycle. 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. (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.) 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<unk> . In normal men, 50 mg/day<unk>  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. Estradiol levels increased by 62 pg/mL in younger men and by 40 pg/mL in elderly men. These findings suggest that the progonadotropic effects of<unk>  are stronger in younger men than in older men. In men with hypogonadism,<unk>  has been found to increase testosterone levels by 293 to 362 ng/dL and estradiol levels by 5.5 to 13 pg/mL. In a large clinical study of men with low testosterone levels (<400 ng/dL), 25 mg/day<unk>  increased testosterone levels from 309 ng/dL to 642 ng/dL after 3 months of therapy. No significant changes in HDL cholesterol, triglycerides, fasting glucose, or prolactin levels were observed, although total cholesterol levels decreased significantly. Other activities<unk>  is an inhibitor of the conversion of desmosterol into cholesterol by the enzyme 24-dehydrocholesterol reductase. Concerns about possible induction of desmosterolosis and associated symptoms such as cataracts and ichthyosis with extended exposure precluded the use of<unk>  in the treatment of breast cancer. Continuous use of<unk>  has been found to increase desmosterol levels by 10% and continuous high doses of<unk>  (200 mg/day) have been reported to produce visual disturbances. Pharmacokinetics<unk>  produces N-desmethylclomifene,<unk> xide<unk>  N-oxide), 4-hydroxyclomifene, and 4-hydroxy-N-desmethylclomifene as metabolites.<unk>  is a prodrug most importantly of 4-hydroxyclomifene and 4-hydroxy-N-desmethylclomifene, which are the most active of its metabolites. In one study, the peak levels after a single 50 mg dose of<unk>  were 20.37 nmol/L for<unk> , 0.95 nmol/L for 4-hydroxyclomifene, and 1.15 nmol/L for 4-hydroxy-N-desmethylclomifene.<unk>  has an onset of action of 5 to 10 days following course of treatment and an elimination half-life about 5 days. In one study, after a single 50 mg dose of<unk> , the half-life of<unk>  was 128 hours (5.3 days), of 4-hydroxyclomifene was 13 hours, and of 4-hydroxy-N-desmethylclomifene was 15 hours. Individuals with the CYP2D6*10 allele showed longer half-lives for 4-hydroxyclomifene and 4-hydroxy-N-desmethylclomifene. Most<unk>  metabolism occurs in the liver, where it undergoes enterohepatic recirculation.<unk>  and its metabolites are excreted primarily through feces (42%), and excretion can occur up to 6 weeks after discontinuation.
Clomifene
Enclomifene
Esthiomene
Intonjane
Brodifacoum
Plerixafor
Lisocabtagene maraleucel
Toremifene