This alarming reality will inexorably lead to more men and couples seeking medical care for fertility, a process often augmented by or ending in pharmacologic management. Therapies can be multifaceted and are often directed at improving spermatogenesis, enhancing sperm function, facilitating sperm delivery, and hormonally modulating the hypothalamic pituitary testicular (HPT) axis. “Pharmacological therapies for male infertility” by Rambhatla et al provides a comprehensive review of current medical therapies, their indications, dosages, and efficacy.3
Pharmacologic agents are often aimed at ameliorating dysfunction at the different levels of the HPT axis. These include medications for hypogonadotropic -, eugonadotropic -, and hypogonadotropic hypogonadism. Medications for hypergonadotropic hypogonadism and eugonadotropic hypogonadism can include hormonal analogs (like hCG, hMG, recombinant FSH, or LH) or alternatively anti-estrogens (clomiphene citrate, tamoxifen) and aromatase inhibitors (such as anastrozole or letrozole). Hypergonadotropic hypogonadism represents a special circumstance where selective estrogen receptor modulators (SERMs) and LH analogues are not indicated for treatment as gonadotropin levels are already high and a further increase has not been found to lead to improvements in serum or intratesticular testosterone. Aromatase inhibitors alternatively have been shown to improve traditional semen parameters in hypergonadotropic men, specifically in those with a testosterone to estradiol ratio < 10:1.4
There are additionally several pharmacologic therapies targeted at improving sperm function and delivery. Treatment of male accessory gland infections is varied but can include antibiotics, probiotics, steroids, and anti-inflammatory medications. These treatments have variable effects based on the location of the infection (prostate, seminal vesicles, testicles or epididymis) as well as the chronicity of the infections. Retrograde ejaculation and seminal anemission is a well described disorder of sperm delivery and can be due to many etiologies including medication effect (alpha-blockers), polyneuropathy (diabetes), or post-surgical (men undergoing transurethral resection of the prostate or retroperitoneal lymph node dissection). Common medications used for the treatment of retrograde ejaculation include imipramine, ephedrine, and pseudoephedrine as they all modulate the alpha- and beta-adrenergic receptors of the sympathetic nervous system predominantly at the bladder neck.5
Another mainstay in the pharmacologic management of male infertility for many years has been the use of antioxidants and vitamins. However, as delineated, there is an overall lack of standardized protocols for the utilization of these ubiquitous substances, making the interpretation of their efficacy difficult. There have been numerous small studies showing benefits to some fertility parameters, but not until recently has there been high-level evidence showing that antioxidants have a benefit in male infertility. A recent large and well-done meta-analysis of randomized trials by Agarwal et. al demonstrated that there was an improvement in sperm concentration, motility, progressive motility, morphology, and pregnancy rate compared to controls.6
Future directions should aim to identify useful biomarkers for specific aspects of male infertility interventions and better diagnostic algorithms to identify the right patient populations to receive these treatments, coupled with better synergy among the pharmacological strategies to improve sperm parameters and aid in the success of SSR. Pharmacologic therapies play a critical role in the management of male infertility. Further research, and well-done reviews and summations of data are necessary to continue advancing the field and helping men on their way to fatherhood.
Written by: Logan Hubbard,1,2 Amarnath Rambhatla,2,3 Rupin Shah,2,4 and Ashok Agarwal,2,5
- University of Minnesota, Minneapolis, MN, United States
- Global Andrology Forum, Moreland Hills, OH, USA.
- Department of Urology, Henry Ford Health System, Vattikuti Urology Institute, Detroit, MI USA
- Division of Andrology, Department of Urology, Lilavati Hospital and Research Centre, Mumbai, India.
- Cleveland Clinic, Cleveland, OH, USA.
- Levine H, Jørgensen N, Martino-Andrade A, et al. Temporal trends in sperm count: a systematic review and meta-regression analysis of samples collected globally in the 20th and 21st centuries. Hum Reprod Update. Mar 01 2023;29(2):157-176. doi:10.1093/humupd/dmac035
- Levine H, Jørgensen N, Martino-Andrade A, et al. Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update. Nov 01 2017;23(6):646-659. doi:10.1093/humupd/dmx022
- Rambhatla A, Shah R, Pinggera GM, et al. Pharmacological therapies for male infertility. Pharmacol Rev. Oct 21 2024;doi:10.1124/pharmrev.124.001085
- Guo B, Li JJ, Ma YL, Zhao YT, Liu JG. Efficacy and safety of letrozole or anastrozole in the treatment of male infertility with low testosterone-estradiol ratio: A meta-analysis and systematic review. Andrology. Jul 2022;10(5):894-909. doi:10.1111/andr.13185
- Nacchia A, Franco A, Cicione A, et al. Medications Mostly Associated With Ejaculatory Disorders: Assessment of the Eudra-Vigilance and Food and Drug Administration Pharmacovigilance Databases Entries. Urology. Mar 2024;185:59-64. doi:10.1016/j.urology.2023.12.021
- Agarwal A, Cannarella R, Saleh R, et al. Impact of Antioxidant Therapy on Natural Pregnancy Outcomes and Semen Parameters in Infertile Men: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. World J Mens Health. Jan 2023;41(1):14-48. doi:10.5534/wjmh.220067