Andropause is a condition surrounded by controversies in both diagnosis and management, and as understanding of hypogonadism pathophysiology evolves, perspectives on the risks and benefits of testosterone replacement therapy have shifted.
Key Findings
Background
Testosterone levels decline with age, but there is no consensus on the precise threshold defining hypogonadism.
Testosterone levels decline at approximately 1-2% per year after age 30.
The American Urological Association (AUA) defines hypogonadism as a total testosterone level below 300 ng/dL, while other societies use different thresholds.
Symptoms of hypogonadism are nonspecific and overlap with normal aging, making clinical diagnosis challenging.
Two separate morning testosterone measurements are recommended to confirm diagnosis due to diurnal variation.
Results
Early concerns about testosterone replacement therapy (TRT) and cardiovascular risk were based on flawed studies, and more recent evidence suggests TRT may be cardiovascularly neutral or beneficial.
The 2010 Basaria et al. trial was halted early due to increased cardiovascular events in the TRT group, raising initial alarms.
Subsequent larger studies and meta-analyses have not consistently confirmed elevated cardiovascular risk with TRT.
The TRAVERSE trial was designed as a large, randomized controlled trial to definitively assess cardiovascular safety of TRT.
Low testosterone itself has been associated with increased cardiovascular mortality, complicating the interpretation of TRT risk.
Results
The historical contraindication of TRT in men with a history of prostate cancer is being reconsidered based on the saturation model.
The saturation model proposes that androgen receptors become saturated at relatively low testosterone levels (~250 ng/dL), above which additional testosterone does not further stimulate prostate tissue.
Multiple studies have shown no significant increase in prostate cancer recurrence in carefully selected hypogonadal men with a history of low-risk prostate cancer who receive TRT.
TRT remains contraindicated in men with metastatic or high-risk prostate cancer.
PSA monitoring is recommended for all men on TRT.
Results
TRT is associated with an increased risk of venous thromboembolism (VTE), particularly in the early period after initiation.
The FDA issued a warning in 2014 regarding the potential risk of VTE associated with testosterone products.
Polycythemia, a known side effect of TRT, may contribute to increased thrombotic risk by elevating hematocrit.
Hematocrit should be monitored regularly in men on TRT, and therapy should be adjusted or discontinued if hematocrit exceeds 54%.
The absolute risk increase for VTE remains relatively low, and causality has not been definitively established.
Results
TRT has demonstrated beneficial effects on metabolic parameters including insulin sensitivity and body composition in hypogonadal men.
Hypogonadism is associated with increased visceral adiposity, insulin resistance, and metabolic syndrome.
TRT has been shown to reduce fat mass and increase lean muscle mass in hypogonadal men.
Studies have demonstrated improvements in HbA1c and insulin sensitivity with TRT in men with type 2 diabetes and hypogonadism.
The relationship between testosterone and diabetes appears bidirectional, as obesity and diabetes can suppress the hypothalamic-pituitary-gonadal axis.
Results
Exogenous anabolic-androgenic steroid (AAS) abuse causes suppression of the hypothalamic-pituitary-gonadal (HPG) axis, leading to secondary hypogonadism that may be prolonged.
AAS abuse suppresses endogenous LH and FSH secretion, resulting in testicular atrophy and reduced spermatogenesis.
Recovery of the HPG axis after cessation of AAS can take months to years and may be incomplete in some users.
Human chorionic gonadotropin (hCG) and selective estrogen receptor modulators (SERMs) such as clomiphene are used to stimulate endogenous testosterone recovery.
AAS abuse is increasing in non-athletic populations, including men seeking antiaging or cosmetic effects.
Results
TRT negatively impacts male fertility by suppressing spermatogenesis, and alternative treatments should be offered to hypogonadal men who desire fertility.
Exogenous testosterone suppresses FSH and LH, leading to reduced intratesticular testosterone and impaired spermatogenesis.
Clomiphene citrate and hCG are used as alternatives to TRT in hypogonadal men who wish to preserve fertility.
Clomiphene acts as a SERM at the hypothalamus, increasing endogenous LH and FSH secretion and consequently testosterone production.
Men should be counseled about fertility implications prior to initiating TRT.
Results
The antiaging benefits of TRT, including improvements in sexual function, mood, and bone density, are supported by evidence but must be weighed against potential risks.
The Testosterone Trials (TTrials) demonstrated improvements in sexual desire, erectile function, and physical performance in older hypogonadal men receiving TRT.
TRT has been shown to increase bone mineral density in hypogonadal men, potentially reducing fracture risk.
Improvements in mood, energy, and cognitive function have been reported with TRT, though evidence for cognitive benefits remains inconsistent.
The TTrials enrolled men aged 65 and older with confirmed low testosterone and at least one symptom of hypogonadism.
Mian A, Yang D, Kohler T. (2022). Current Management and Controversies Surrounding Andropause.. The Urologic clinics of North America. https://doi.org/10.1016/j.ucl.2022.07.003