Clomiphene for Male Hypogonadism and Oligospermia
Clomiphene citrate is prescribed to men with hypogonadism or oligospermia primarily when fertility preservation is desired, as it increases endogenous testosterone production without suppressing spermatogenesis—unlike exogenous testosterone which causes azoospermia. 1
Mechanism of Action
Clomiphene is a selective estrogen receptor modulator (SERM) that blocks estrogen receptors in the hypothalamus and pituitary gland, preventing the negative feedback of estrogen on gonadotropin secretion. 2, 3 This blockade stimulates increased secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn stimulates the testes to produce more endogenous testosterone and supports spermatogenesis. 2, 3
The critical advantage over testosterone replacement therapy is that clomiphene preserves the hypothalamic-pituitary-gonadal axis and maintains intratesticular testosterone production, which is essential for sperm production. 3
Primary Clinical Indications
Hypogonadism with Fertility Preservation
Men with low testosterone who desire current or future fertility should receive clomiphene rather than exogenous testosterone, which suppresses FSH and LH through negative feedback and causes azoospermia that can take months to years to recover. 1
Clomiphene is particularly effective in men with secondary (hypogonadotropic) hypogonadism who have functioning pituitary glands but low testosterone levels. 1
Select patients with adult-onset idiopathic hypogonadotropic hypogonadism may respond to clomiphene alone, with increases in testosterone, FSH, and LH levels. 4
Oligospermia and Male Infertility
Clomiphene is prescribed for men with oligospermia (low sperm count) to improve semen parameters, including sperm concentration, motility, and morphology. 5, 6
In oligospermic obese hypogonadal men, clomiphene treatment significantly improved baseline sperm concentration (from 4.5 ± 6.8 × 10⁶/mL to 11.4 ± 15.5 × 10⁶/mL) and motility (from 31.5% ± 21.5% to 42.6% ± 14.7%). 5
Clomiphene has been used in the management of unexplained infertility, oligo and asthenospermia, and nonobstructive azoospermia, though results are mixed. 6
Guideline Perspective on Efficacy
The 2021 AUA/ASRM guidelines explicitly state that the benefits of SERM administration (including clomiphene) in men with idiopathic infertility are small and outweighed by the distinct advantages of assisted reproductive technologies like IVF, which offer higher pregnancy rates and earlier conception timeframes. 1
However, clomiphene remains clinically useful in specific scenarios:
For men with normal testosterone levels and idiopathic infertility, the therapeutic aim is improving semen parameters, though benefits are limited. 1
For men with non-obstructive azoospermia, clomiphene has been used off-label to optimize reproductive hormones before surgical sperm retrieval, though evidence is limited and studies are typically uncontrolled. 1
Clinical Outcomes
Testosterone Improvement
In oligospermic hypogonadal obese men, clomiphene substantially improved baseline serum testosterone levels from 193.8 ± 59.3 ng/dL to 332.7 ± 114.8 ng/dL. 5
Many studies show clomiphene reduces hypogonadal symptoms, with improvements in erectile function, bone mineral density, and reduction in body mass index. 3
Fertility Outcomes
A meta-analysis of studies investigating fertility rates in hypogonadal men treated with clomiphene showed significant improvement in fertility rates. 3
In men with adult-onset idiopathic hypogonadotropic hypogonadism, two out of three men achieved pregnancies with clomiphene alone. 4
Safety Profile
Clomiphene is generally considered safe and well-tolerated, with a lower risk profile compared to testosterone replacement therapy, which is associated with adverse effects such as polycythemia. 2, 3
Reported adverse effects include:
Critical Clinical Caveat
The 2025 European Association of Urology guidelines classify clomiphene as causing "drug-induced estrogen receptor blockade," which can alter the hormonal feedback mechanisms. 1 This is the intended therapeutic mechanism but underscores that clomiphene is a hormonal intervention that requires appropriate patient selection and monitoring.
When NOT to Use Clomiphene
Men with primary testicular failure (elevated LH/FSH with low testosterone) are unlikely to respond, as their testes cannot respond to increased gonadotropin stimulation. 1
Men not interested in fertility preservation may be better served by testosterone replacement therapy for symptom relief, though clomiphene remains an option. 2
The cost-to-benefit ratio is questionable in idiopathic infertility, as men typically require treatment for 3 months or more, and the incremental increase in pregnancy rates is small compared to IVF. 1