Reversing the odds: Advanced and emerging therapeutic strategies for male infertility

Abstract

Male infertility is a complex and multifaceted condition that has substantial consequences, highlighting the importance and necessity of viable sperm for conception. Despite all the advances in assisted reproductive technologies, pharmacological therapies are still critically needed for the effective management of male infertility. Fortunately, hormone-based therapies, including gonadotropins, selective estrogen receptor modulators (SERMs), and aromatase inhibitors (AIs), show increasing promises in the restoration of hormonal balance and stimulating spermatogenesis, especially in conditions like hypogonadotropic hypogonadism. Other pharmacologic and nonpharmacologic approaches are currently being investigated, with some offering a bit (or more) of a blue sky. In Pharmacological Reviews, Rambhatla et al (2025) provide an in-depth discussion of male infertility. They discussed its diverse causes including the underlying endocrine disturbances, genetic abnormalities, infections, and idiopathic factors. The authors focused on the hypothalamic-pituitary-testicular axis, which regulates male reproduction. Highlighting that testosterone production is key for spermatogenesis, the authors remind us that the ruling exogenous testosterone can impair fertility by suppressing gonadotropins. For men to maintain fertility, other treatments like gonadotropin-releasing hormone or human chorionic gonadotropin (hCG) can provide some hope by virtue of their ability to stimulate spermatogenesis. The manuscript also addressed hypogonadotropic hypogonadism (HH), a condition in reduced which gonadotropin levels impair testosterone production. Treatment for hypogonadotropic hypogonadism includes gonadotropin-releasing hormone therapy, hCG, and follicle-stimulating hormone (FSH), which help restore fertility. Dopamine agonists are used to treat prolactinomas, which can suppress gonadotropins. Eugonadotropic hypogonadism is another condition in which testosterone levels are low despite normal gonadotropin levels. Medications like selective SERSMs and AIs can stimulate gonadotropins and improve testosterone and sperm production. In a separate section, the authors discussed hypergonadotropic hypogonadism (HrH), which is a morphic deficiency due to testicular dysfunction. This dysfunction leads to reduced testosterone production and spermatogenesis impairment, albeit elevated or normal levels of lutinizing hormone and FSH. Importantly, for inferile men with HrH who wish to conceive, testosterone replacement therapy is contraindicated as it suppresses sperm production. Alternative therapies include hCG, human menopausal gonadotropin, FSH, and AIs, which aim