Clomiphene citrate (USA trade name Clomid) is a selective estrogen receptor modulator (SERM) that increases production of the body’s gonadotropins via disruption of the natural negative feedback system in the hypothalamus. Clomiphene consists of two bioactive isomers, zuclomifene and enclomiphene. Zuclomifene is responsible for the primary effects of clomiphene, which consists of binding to estrogen receptors for long periods of time. Because the receptors cease recycling (and cannot be reused) for the duration, the hypothalamic estrogen number decreases, meaning the body’s feedback system tells it that there is low estrogen. Estrogen modulation is the body’s primary method of initiating and controlling negative hypothalamic feedback; with perceived low estrogen, GnRH pulsatility is increased and the pituitary releases more luteinizing hormone (LH) and follicle stimulating hormone (FSH).[1]

Clomiphene is primarily used to treat female fertility issues via its ability to increase the body’s gonadotropin release.[1] It is also useful for reasons related to the same mechanisms, as well as novel and newly discovered mechanisms, in treating various forms of male infertility.[1]

Schellen writes and highlights well the diverse uses and progressive versatility shown with clomiphene as a potential treatment for an array of issues:

After the discovery that Clomiphene-citrate (Clomid) increased the secretion of gonadotropins, it was first used to induce ovulation and later on it was also used in males in certain cases of infertility. The effects of Clomid on the hypothalamic-pituitary level made it also possible to use it for a dynamic evaluation of the hypothalamic-pituitary gonadal axis in both females and males. [2]

Clomiphene is often used by bodybuilders who self-administer anabolic-androgenic steroids (AAS) to control undesirable estrogenic side-effects such as gynecomastia, acne, and mood-swings, similar to the way drug tamoxifen and the aromatase inhibitors letrozole, exemestane, and anastrozole are used. Users of AAS also frequently use clomid to exploit its gonadotropin-stimulating effect, in order to increase testosterone levels from a suppressed baseline after a “cycle” of steroids via release of gonadotropin releasing-hormone, follicle stimulating hormone, and luteinizing hormone.

In some cases clomiphene may be preferable over other options such as testosterone therapy for hypogonadism because, as the researches quoted below note, testosterone administration actually causes infertility in many cases; further, as many cases of hypogonadism may be steroid-abuse-induced, testosterone would be ruled out in those cases:

Hypogonadism has a number of important clinical consequences related to androgen deficiency and impaired spermatogenesis. The cause of this condition is multifactorial and can result from hypothalamic, pituitary or gonadal dysfunction as well as factors that affect hormonal signaling along the hypothalamic-pituitary-gonadal axis. While testosterone replacement is the most common treatment, it can paradoxically lead to infertility, and may be a less physiologic therapy for patients with secondary hypogonadism due to pituitary dysfunction. Clomiphene citrate, and its derivatives, may allow for restoration of gonadal function by restoring physiologic pituitary function in a subset of patients with hypogonadism.[3]

Tan and Vasudevan document a case study in which clomiphene successfully treated (by standards of testosterone levels, LH pulsatility, and restoration of pituitary-gonadal axis and feedback system) premature andropause induced by long-term steroid abuse:

Clomiphene citrate is used typically in helping to restore fertility in females. This represents the first case report of the successful use of clomiphene to restore T levels and the pituitary-gonadal axis in a male patient. The axis was previously shut off with multiple anabolic steroid abuse.[4]

Taylor and Levine find clomiphene citrate suitable for long-term use in place of testosterone gel replacement therapy for treating sexual dysfunction and the set of symptoms generally associated with hypogonadism or andropause:

CC represents a treatment option for men with hypogonadism, demonstrating biochemical and clinical efficacy with few side effects and lower cost as compared with TGRT.[5]

Kanayama et al recommend clomiphene as part of a comprehensive treatment program for AAS abusers:

…AAS suppress the male hypothalamic-pituitary-gonadal axis via their androgenic effects, potentially causing hypogonadism during AAS withdrawal. Men experiencing prolonged dysphoric effects or frank major depression from hypogonadism may desire to resume AAS, thus contributing to AAS dependence. AAS-induced hypogonadism may require treatment with human chorionic gonadotropin or clomiphene to reactivate neuroendocrine function, and may necessitate antidepressant treatments in cases of depression inadequately responsive to endocrine therapies alone