Enclomiphene is a purified isomer of clomiphene citrate. Enclomiphene is produced in the form enclomiphene citrate, the orally bioavailable citrate salt of enclomiphene, initially under the commercial name Androxal (Repros Therpeutics) and later renamed Encyzix (Allergan). Repros Therapeutic was acquired by Allergan in 2017. Enclomiphene and zuclomiphene are (E) and (Z), two diastereoisomers found in a 60:40 mixture in clomiphene. In the IUPAC naming system for geometric isomers of alkene, E and Z come from German: entgegen means opposite, and zusammen means same side. Enclomiphene is also referred to as the trans-isomer of clomiphene when the cis/trans designation is used. Clomiphene is a triphenyl ethylene stilbene derivative, which acts as an agonist or antagonist of estrogen depending on the target tissue. Enclomiphene citrate is a selective estrogen receptor modulator (SERM).
The structure of enclomiphene and zuclomiphene. Fontenot GK. Adv Tech Clin Microbiol. 2017
Clomiphene was FDA approved in 1976 for the treatment of female infertility, including polycystic ovary syndrome (POS) anovulation or subovulatory function provided there is sufficient estrogen production. Enclomiphene is the more active isomer compared with zuclomiphene and competes with estrogen at the estrogen receptor in the hypothalamus and pituitary gland, which decreases the suppressive effects of estrogen on gonadotropin release. By binding to estrogen receptors and blocking endogenous estrogen, clomiphene/enclomiphene causes the body to behave as if estrogen levels are low. This results in increased levels of the released gonadotropins FSH and LH, which stimulate and initiate ovulation.
Clomiphene citrate treatment usually begins three to five days before the onset of spontaneous menses or withdrawal bleeding induced by progestogen and is taken daily for five days. While clomiphene is taken, levels of LH and FSH rise along with serum estradiol (E2). After the five days of treatment, estradiol levels continue to rise, and negative feedback on the hypothalamic-pituitary axis causes a decrease in FSH and LH, which mimics the late follicular phase of the normal ovulatory cycle. At five to nine days after the last clomiphene tablet is taken, rising levels of estradiol from the dominant follicle have a positive feedback on the pituitary or hypothalamus, which produces a surge in LH and FSH levels. This results in ovulation and luteinization of the follicle. Luteinization is the development of the corpus luteum, a temporary endocrine structure that produces progesterone, a hormone needed during early pregnancy.
Clomiphene citrate and its isomers, including enclomiphene, are potential therapies to address symptoms of hypogonadism. Clomiphene citrate is used off-label to treat secondary male hypogonadism and male infertility that results from this condition. Male hypogonadism is a condition defined by low levels of serum testosterone in association with symptoms such as decreased libido, erectile dysfunction, loss of lean muscle mass, loss of vitality, and depression. Enclomiphene citrate is responsible for raising luteinizing hormone (LH) and follicle stimulating hormone (FSH), while zuclomiphene is thought to cause some of the side effects associated with clomiphene citrate. Zuclomiphene, but not enclomiphene, is responsible for estrogen agonist activity in clomiphene, which can lead to estrogenic side effects in some men. Enclomiphene citrate increases serum testosterone levels by raising LH and FSH levels without having a negative impact on semen. The drug is able to treat testosterone deficiency in men while maintaining fertility. In contrast, the standard treatment for hypogonadism, testosterone therapy, is associated with suppression of spermatogenesis and other adverse effects.
LH stimulates testosterone production in Leydig cells in the testes. FSH stimulates spermatogenesis in Sertoli cells. Negative feedback on testosterone involves estradiol, which is a form of estrogen. In the body, enclomiphene associates with estrogen receptors and competes with estradiol for binding sites. The anti-estrogen effects of enclomiphene citrate are thought to be responsible for inhibiting the negative feedback on testosterone through the hypothalamic-pituitary-gonadal axis. Similar levels of testosterone were found in men treated with enclomiphene compared with topical testosterone. LH and FSH were higher in men taking enclomiphene compared with those taking topical testosterone. The suppression of LH and FSH in men taking testosterone can negatively impact spermatogenesis.
In 2016, the FDA denied the approval of enclomiphene for the treatment of hypogonadism, due to a lack of data to demonstrate the improvement of clinical symptoms in Phase III clinical trials. A reported hurdle to providing high-quality data is that secondary hypogonadism is associated with many non-specific symptoms. The questionnaires used in clinical studies on enclomiphene for treating secondary hypogonadism are difficult to validate. The data showing increases in testosterone levels were not considered sufficient evidence for a non-testosterone therapy for hypogonadism.
Clomiphene was shown to have anti-viral activity against Ebola virus (EBOV) in tissue culture cells and in laboratory mice. Clomiphene was demonstrated to block EBOV entry into the cytoplasm of the host cell after virus particles are transported to endolysosomes. The drug interferes with the fusion of EBOV with the endolysosomal membrane. In surrogate assays for EBOV infection, the isomers enclomiphene and zuclomiphene were found to have similar abilities to block entry and infection of viral-like particles (VLP) and transcription/replication competent viral-like particles (trVLP).
