Enclomiphene, also known as Androxal, is a selective estrogen receptor modulator (SERM) that has been developed as a potential treatment for male hypogonadism. The compound is structurally similar to clomiphene citrate, a drug that has been widely used for several decades as an infertility treatment for women.
The history of enclomiphene can be traced back to the mid-20th century, when clomiphene citrate was first synthesized and tested as a potential contraceptive. Clomiphene citrate works by binding to the estrogen receptors in the hypothalamus and pituitary gland, thereby blocking the negative feedback of estrogens on the hypothalamic-pituitary-gonadal (HPG) axis. This leads to an increase in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion, which stimulates ovulation in women.
In the 1990s, researchers began to investigate the potential use of clomiphene citrate as a treatment for male infertility. It was thought that the compound could increase testosterone levels by blocking the negative feedback of estrogens on the HPG axis, as it does in women. However, the results of early studies were disappointing, and clomiphene citrate was found to have little effect on testosterone levels in men.
In the early 2000s, a new form of clomiphene citrate called enclomiphene was developed as a potential treatment for male hypogonadism. Unlike clomiphene citrate, enclomiphene is a stereoisomer of the original compound, meaning that its molecular structure is slightly different. This change in structure gives enclomiphene a different affinity for estrogen receptors, allowing it to selectively bind to the receptors in the testes rather than in the hypothalamus and pituitary gland.
The development of enclomiphene was based on the idea that by selectively targeting the estrogen receptors in the testes, the compound could increase testosterone levels by blocking the negative feedback of estrogens on the HPG axis. This would lead to an increase in FSH and LH secretion, which would stimulate testosterone production in the testes.
In clinical trials, enclomiphene was found to be effective in increasing testosterone levels in men with hypogonadism. The compound was well tolerated, with a good safety profile and minimal side effects. These positive results led to the filing of a New Drug Application (NDA) with the US Food and Drug Administration (FDA) in 2014, seeking approval for the use of enclomiphene as a treatment for male hypogonadism.
However, the FDA ultimately rejected the NDA, citing concerns about the potential for enclomiphene to increase the risk of prostate cancer and other safety issues. Despite this setback, the developers of enclomiphene continued to pursue the development of the compound, and in 2019, the FDA granted tentative approval for the use of enclomiphene as a treatment for male hypogonadism.
Today, enclomiphene is still being studied as a potential treatment for male hypogonadism, and there is ongoing research into its safety and efficacy. While the compound has not yet been approved for use in the US, it is being tested in clinical trials in other countries and continues to show promise as a treatment for male hypogonadism.