Hypothalamic-Pituitary-Testicular Axis Effects and Urinary Detection Following Clomiphene Administration in Males

Abstract

Context Clomiphene is a performance-enhancing drug commonly abused by males in sport, but the extent to which testosterone increases in healthy males following its use is unknown. In addition, evidence suggests that clomiphene, a mixture of cis- and trans-isomers zuclomiphene and enclomiphene, is detectable in urine for months following use; the isomer-specific urinary detection window has yet to be characterized in a controlled study. Objective To determine the effect of once-daily, 30-day clomiphene treatment on serum testosterone and gonadotropin levels in the subject population studied and the urinary clearance and detection window of clomiphene isomers following administration for antidoping purposes. Participants and Design Twelve healthy males aged 25 to 38 years, representing a recreational athlete population, participated in this open-label, single-arm study. Intervention Oral clomiphene citrate (50 mg) was self-administered once daily for 30 days. Serum and urine samples were collected at baseline and at days 7, 14, 21, 28, 30, 32, 35, 37, 44, 51, and 58; urine collections continued periodically up to day 261. Results Mean testosterone, LH, and FSH levels increased 146% (SEM, ±23%), 177% (±34%), and 170% (±33%), respectively, during treatment compared with baseline. Serum drug concentrations and urinary excretion were nonuniform among individuals as isomeric concentrations varied. The zuclomiphene urinary detection window ranged from 121 to >261 days. Conclusions Clomiphene significantly raised serum testosterone and gonadotropin levels in healthy men and thus can be abused as a performance-enhancing drug. Such abuse is detectable in urine for ≥4 months following short-term use.

High‐throughput liquid chromatography tandem mass spectrometry assay as initial testing procedure for analysis of total urinary fraction

“…In agreement with earlier findings 41–43 in 77% of the samples where the metabolite was identified, LGD4033 was not detectable at all. On the contrary, cis‐clomiphene was often detected alone or present in much higher concentration than 4‐hydroxyclomiphene, corroborating observations of Guddat et al 44 and Miller et al 45 Only one sample was found to contain 4‐hydroxyclomiphene in the absence of parent drug, which may be ascribed to administration of enclomiphene 46,47 …”

Medical Treatment in Men with Infertility Can Be Misinterpreted as Doping Practice: A Case of Unintentional World Anti-doping Agency (WADA) Code Violation

“…Clomiphene has been shown to increase testosterone by 150% for multiple weeks after use, and it also increases two other types of androgens, epitestosterone, and 4androstenedione (3,14). These effects are mostly seen in males while females show a smaller effect, because most female androgens are made by non-gonadal organs, and these productions are independent of pituitary hormones (14).…”

“…Clomiphene has several markers and metabolites which can be found in urine; 4-hydroxyclomiphene and 3-methoxy-4hydroxyclomiphene being the most common metabolites being tested in doping labs as well as clomiphene isomers, namely Zuclomiphene and Enclomiphene (3,15,16). In a study in 2019, Miller et al showed that Zuclomiphene can be found in urine for an average of 98 days and, in some cases, up to 8 months after the final dose of clomiphene (3).…”

“…These two isomers are usually found in clomiphene preparations with cis:trans ratio of 2:3. Enclomiphene with a half-life of 5 hours demonstrates estrogen antagonist activities, while Zuclomiphene with a half-life of roughly 24 hours exerts estrogen agonist and antagonist activities (3,4).…”

Hormone supply to the pituitary gland: A comprehensive investigation of female‑related tumors (Review)

“…In addition, clomiphene citrate, an estrogen receptor regulator, increases the secretion of GnRH in the hypothalamus by inhibiting the negative feedback regulation of estrogen. In addition to treating female ovulation dysfunction, clomiphene citrate also improves the levels of testosterone and GnRH in men (155)(156)(157). Aromatase inhibitors, which are estrogen receptor regulators, promote the release of GnRH by modulating estrogen levels.…”