What are the effects of elevated testosterone levels in males using exogenous testosterone (external testosterone)?

From the Guidelines

High testosterone levels in males using exogenous testosterone can lead to severe adverse effects, including infertility, and therefore, exogenous testosterone therapy should not be prescribed to men who are currently trying to conceive. The most recent and highest quality study, published in 2024, 1, highlights the negative effects of exogenous testosterone on spermatogenesis, resulting in oligospermia or azoospermia. This is further supported by a strong recommendation from the 2018 guideline, 1, which advises against prescribing exogenous testosterone therapy to men trying to conceive due to its interruptive effect on normal spermatogenesis.

Key points to consider:

• Exogenous testosterone therapy inhibits intratesticular testosterone production and suppresses spermatogenesis, impairing fertility 1
• The degree of response to treatment correlates with the size of the testis prior to treatment, and initial treatment with human chorionic gonadotropin (hCG) injections is recommended 1
• Recovery of sperm to the ejaculate may occur after cessation of testosterone therapy, but the time course of recovery can be prolonged, taking months or rarely years 1
• Testosterone therapy can lead to hormonal imbalances, cardiovascular complications, and liver damage, emphasizing the need for regular blood tests and monitoring 1

In light of these findings, it is crucial to avoid exogenous testosterone therapy in males pursuing or planning to pursue family building in the near future, and instead, consider alternative treatments, such as hCG injections, to restore testosterone production and spermatogenesis 1. If testosterone therapy is necessary, patients should be counseled about the potential negative effects on fertility and the importance of regular monitoring and follow-up 1.

From the FDA Drug Label

5.8 Potential for Adverse Effects on Spermatogenesis With large doses of exogenous androgens, including testosterone gel, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count. 5.6 Abuse of Testosterone and Monitoring of Serum Testosterone Concentrations Testosterone has been subject to abuse, typically at doses higher than recommended for the approved indication and in combination with other anabolic androgenic steroids. Anabolic androgenic steroid abuse can lead to serious cardiovascular and psychiatric adverse reactions

If testosterone levels are too high in males on exogenous testosterone, it may lead to:

• Suppression of spermatogenesis: High doses of exogenous testosterone can suppress the production of sperm through feedback inhibition of pituitary follicle-stimulating hormone (FSH).
• Cardiovascular and psychiatric adverse reactions: Abuse of testosterone, typically at doses higher than recommended, can lead to serious cardiovascular and psychiatric adverse reactions 2.
• Other potential risks: High levels of testosterone may also increase the risk of polycythemia, venous thromboembolism, and cardiovascular risk as mentioned in the drug label 2.

From the Research

Effects of High Testosterone Levels in Males on Exogenous Testosterone

• High levels of exogenous testosterone can have various effects on the body, including suppression of spermatogenesis, changes in plasma lipids, and alterations in calcium metabolism 3.
• Exogenous testosterone replacement therapy can increase serum testosterone and estradiol levels, leading to a decrease in high-density lipoprotein (HDL) cholesterol levels and an increase in low-density lipoprotein (LDL) cholesterol levels 3.
• The use of exogenous testosterone can also affect calcium metabolism, with a decrease in serum calcium levels and an increase in parathyroid hormone (PTH) levels 3.
• High-dose exogenous testosterone administration has been associated with an increase in body weight, acne, and a trend towards increased arousal and spontaneous erections, although these effects may not be statistically significant 3.

Risks and Considerations

• Exogenous testosterone replacement therapy can pose risks to fertility due to negative feedback mechanisms on the hypothalamic-pituitary-gonadal (HPG) axis, which is the main regulator of testosterone production and spermatogenesis in males 4.
• The use of exogenous testosterone can also increase the risk of cardiovascular events, although the evidence is limited and of low quality 5.
• Clinicians must consider the unique characteristics of each patient and make necessary adjustments in the management of hypogonadism to provide the safest and most beneficial results 6.

Alternative Approaches

• Alternative pharmacologic therapies, such as selective estrogen receptor modulators, gonadotropins, and aromatase inhibitors, are being used to increase endogenous testosterone levels while attempting to preserve fertility and function of the HPG axis 4.
• These alternative approaches aim to improve endogenous testosterone production and preserve fertility, but are still in the initial stages of development 4.