Clomiphene citrate: A potential alternative for testosterone therapy in hypogonadal males

Abstract

Background Hypogonadism is a worldwide problem among men causing sexual, physical and mental problems. Testosterone therapy is the first‐choice treatment for male hypogonadism, with several side effects, that is, subfertility. Clomiphene citrate (CC) is an alternative off‐label therapy for a certain group of hypogonadal males, especially for those with an active or future child wish. There is scarce literature in usage of CC for men with hypogonadism. The aim of this retrospective study was to evaluate the effectiveness and safety of CC for hypogonadal males. Methods In this single‐centre study, men treated with CC for hypogonadism were evaluated retrospectively. Primary outcome was hormonal evaluation including total testosterone (TT), free testosterone (FT), luteinizing hormone (LH) and follicle stimulating hormone (FSH). Secondary outcomes were hypogonadal symptoms, metabolic and lipid parameters, haemoglobin (Hb), haematocrit (Ht), prostate specific antigen (PSA), side effects, the effect of a trial without medication and potential predictors for biochemical and clinical response. Results In total, 153 hypogonadal men were treated with CC. Mean TT, FT, LH and FSH increased during treatment. TT increased from 9 to 16 nmol/L, with a biochemical increase in 89% of the patients. In patients who continued CC treatment, an increased level of TT persisted after 8 years of treatment. With CC treatment, 74% of the patients experienced hypogonadal symptom improvement. LH at the lower normal range before CC treatment was predictive for better TT response. During CC therapy, few side effects were reported and no clinical important changes in PSA, Hb and Ht were found. Conclusion Clomiphene citrate is an effective therapy on short and long term, improving both clinical symptoms and biochemical markers of male hypogonadism with few side effects and good safety aspects.

Clomiphene Citrate Administered in Periconception Phase Causes Fetal Loss and Developmental Impairment in Mice

“…Anogenital distance is a common marker of endocrine disruption and potential for subsequent testicular dysfunction, by virtue of association with serum testosterone levels in animal models ( 57 , 58 ). The increased anogenital distance observed in both male and female progeny from clomiphene citrate–treated dams in the current study might reflect increased testosterone levels ( 59 ), consistent with clinical reports that clomiphene increases circulating testosterone ( 60 ). The reduction in fat deposition we observed in male progeny of clomiphene citrate–treated dams is also consistent with an endocrine and/or metabolic perturbation ( 61 ).…”

Clomiphene Citrate in the Management of Infertility in Oligospermic Obese Men with Hypogonadism: Retrospective Pilot Study

“…CC is a selective estrogen receptor modulator (SERM) and blocks the negative feedback loop that estrogen usually exerts on the HPG axis, which in turn stimulates the release of hormones, such as LH and FSH, from the pituitary gland [26]. These hormones are crucial in signaling the testes to produce more testosterone [27]. The rise in FSH levels due to CC treatment also supports the process of spermatogenesis, which is particularly beneficial for men with conditions like low sperm count or oligospermia.…”

“…CC is an anti-estrogenic drug that competes with estrogen upon binding to estrogen receptors in the hypothalamus. CC is used as a medication for treating obesity-related hypogonadism to boost the testosterone levels by increasing LH and FSH levels [27,28]. Further, CC is also used as a treatment option for men with oligospermia to improve their semen parameters [25].…”

Identification and synthesis of (Z)‐3′‐hydroxy clomiphene as a new potential doping‐relevant metabolite of clomiphene

“…1 If used by males, it results in an increased testosterone production, which is the reason for using clomiphene an off-label medication to treat male infertility and hypogonadism. 2,3 Because it is a widely used drug, its metabolism has been subject to multiple studies, many of which have focused on the differences between the two isomers of clomiphene. [4][5][6][7][8] These differences include the shorter half-life of (E)-clomiphene due to its higher affinity for the phase I enzyme cytochrome P450 2D6.…”