Testosterone Physiology in Transgender Men: Endocrine Mechanisms, Measurement, and Clinical Safety Evidence

Testosterone is the primary androgen hormone responsible for the development and maintenance of male reproductive tissues and many secondary sex characteristics. In clinical endocrinology, its biology is best understood as an interplay among steroid synthesis, transport, receptor signaling, and metabolism by hepatic and peripheral enzymes. Testosterone circulates in blood mostly bound to sex hormone–binding globulin (SHBG) and albumin, with only a small fraction remaining biologically active as “free” testosterone. The free fraction can enter target cells, where it binds the androgen receptor (AR) to modulate gene transcription and cellular differentiation. In many tissues, testosterone can also be converted by 5-alpha-reductase to dihydrotestosterone (DHT), a more potent androgen in follicles, prostate, and certain skin compartments. Additionally, aromatase can convert testosterone to estradiol, influencing bone, vascular function, and feedback regulation in the hypothalamic–pituitary–gonadal (HPG) axis.

In transgender men (assigned female at birth who identify as male), endogenous testosterone production is typically lower than in cisgender men, reflecting differences in ovarian steroidogenesis and HPG axis set points. However, gender-affirming hormone therapy (GAHT) with exogenous testosterone can raise circulating testosterone to typical male physiologic ranges. Formulations include intramuscular or subcutaneous injections, transdermal gels, and long-acting preparations. Each route produces different pharmacokinetic profiles: injections may create peaks and troughs, whereas gels tend to yield more stable levels. Clinicians therefore monitor testosterone levels (total testosterone and, when indicated, free testosterone or SHBG), alongside estradiol, hemoglobin/hematocrit, lipids, liver enzymes, and blood pressure.

A key clinical principle is that “testosterone level” should be interpreted in context. Total testosterone may not fully represent androgenic effect because SHBG varies with body composition, insulin sensitivity, liver function, and estrogen exposure. Free testosterone estimation can help when SHBG is abnormal or when total values are discordant with expected clinical response. Measurement timing also matters; for injectable therapy, blood draws are ideally taken at a specified point in the dosing interval to reduce misinterpretation from transient peaks.

Therapeutic goals of GAHT are not to maximize testosterone but to achieve and maintain physiologic male-range androgen exposure while minimizing adverse outcomes. The primary mechanisms of benefit include virilization (increased muscle mass, voice deepening over time, facial and body hair growth, and changes in genital tissues) and reductions in estrogen-driven menstrual function and dysphoria-related endocrine symptoms. Testosterone also affects energy metabolism and fat distribution through androgen receptor signaling and downstream pathways involving insulin sensitivity and adipokine regulation.

Safety considerations are central. Testosterone therapy can increase hemoglobin and hematocrit (erythrocytosis) due to androgen-mediated stimulation of erythropoiesis; this is why periodic complete blood counts are recommended. Lipid changes can occur and vary by baseline risk and route; monitoring cardiovascular risk factors (including smoking status, hypertension, and family history) is advised. Progestogenic and estrogen interactions are relevant because residual estradiol production may be present; clinicians monitor estradiol to ensure suppression consistent with treatment goals. Liver enzymes are monitored, particularly for oral formulations (less commonly used in many settings due to hepatotoxicity risk), while transdermal and parenteral routes generally present a different risk profile.

From a monitoring and evidence standpoint, it is important to understand that comparative statements—such as claims about testosterone “being more than” an entire sports team—are not clinically meaningful. Athletic testosterone varies widely among cisgender male individuals, influenced by age, genetics, time of day, training load, sleep, and acute illness. Moreover, circulating testosterone is not a direct proxy for performance, which is influenced by muscle fiber composition, neuromuscular coordination, training status, and psychological factors. Clinicians treat individual patients using measured hormone levels, symptoms, and laboratory parameters, not population comparisons.

Finally, the endocrine effects of testosterone are reversible to a degree after discontinuation, though some masculinizing changes may persist. Ongoing follow-up supports dose adjustments based on both laboratory monitoring and clinical outcomes, balancing desired masculinization with prevention of long-term complications. Public misconceptions often reduce testosterone to a single number; in reality, androgen exposure is a dynamic endocrine system involving transport proteins, receptor biology, tissue-specific metabolism, and feedback control within the HPG axis.

Source: @3m0ca1llou