Clomiphene citrate for men with hypogonadism: a systematic review and meta‐analysis

Abstract

Background: Male hypogonadism is a clinical and biochemical androgen insufficiency syndrome, becoming more prevalent with age. Exogenous testosterone is first-choice therapy, with several side effects, including negative feedback of the hypothalamicpituitary-gonadal axis, resulting in suppression of intratesticular testosterone production and spermatogenesis. To preserve these testicular functions while treating male hypogonadism, clomiphene citrate is used as off-label therapy. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of clomiphene citrate therapy for men with hypogonadism. Methods:The EMBASE, PubMed, Cochrane databases were searched in May 2021, for effectiveness studies of men with hypogonadism treated with clomiphene citrate. Both intervention and observational studies were included. The Effective Public Health Practice Project Quality Assessment Tool, a validated instrument, was used to assess methodological study quality. The primary outcome measure was the evaluation of serum hormone concentration. Secondary outcomes were symptoms of hypogonadism, metabolic and lipid profile, side effects, safety aspects. Results:We included 19 studies, comprising four randomized controlled trials and 15 observational studies, resulting in 1642 patients. Seventeen studies were included in the meta-analysis, with a total of 1279 patients. Therapy and follow-up duration varied between one and a half and 52 months. Total testosterone increased with 2.60 (95% CI 1.82-3.38) during clomiphene citrate treatment. An increase was also seen in free testosterone, luteinizing hormone, follicle stimulating hormone, sex hormone-binding globulin and estradiol. Different symptom scoring methods were used in the included studies. The most frequently used instrument was the Androgen Deficiency in Aging Males questionnaire, whose improved during treatment. Reported side effects were only prevalent in less than 10% of the study populations and no serious adverse events were reported.

Elevated HCG and retroperitoneal adenopathy after clomiphene therapy for infertility

“…It has been used off-label for men in subfertility and hypogonadism as the US Food and Drug Administration did not approve the medication, because of unclear effectiveness 4. In a systemic review and meta-analysis of men on CC for hypogonadism, Huijben et al 5 reported the side effects of CC to be seen in 4%–11% of patients ranging from mood changes, blurred vision, breast/nipple tenderness and fatigue.…”

Efficacy and Safety of Human Chorionic Gonadotropin Monotherapy for Men With Hypogonadal Symptoms and Normal Testosterone

“…In addition, hCG has been utilized in patients with isolated hypogonadotropic hypogonadism with a significant response to testicular volume, testosterone levels, and sperm production [ 9 ]. Finally, there has been conflicting literature that has shown that clomid or anastrozole may or may not benefit patients with hypogonadal symptoms in men with T<300 ng/dL [ 12 - 14 ]. All of the studies above explore the use of hCG for fertility and sperm production; however, its use in hypogonadism has not been elucidated.…”

Hypogonadisme en een kinderwens, hebben we opties om te behandelen?

“…De ADAM-score verbeterde met gemiddeld 3 punten. Daarnaast werd er een verbetering van de spermakwaliteit gezien [14]. Bijwerkingen werden bij 10% van de mannen beschreven, alle reversibel na het stoppen van de clomifeencitraat.…”

“…In de verschillende studies bij mannen is dit risico niet gemeld als veel voorkomende bijwerking. Tijdens het gebruik van clomifeencitraat werd er geen verslechtering van de semenparameters gezien; er werd zelfs een verbetering gezien bij semenanalyse [14]. Clomifeencitraat wordt gebruikt in tabletvorm in een dosis van 25 mg om de dag tot 50 mg per dag.…”