Does exogenous testosterone increase androgen exposure in tissues?

Exogenous testosterone therapy effectively increases circulating testosterone levels and intracellular androgen activity in women. By raising the systemic pool of the hormone, therapy ensures a higher concentration of the biologically active fraction available for peripheral tissues.

Clinical effectiveness and serum levels

The administration of exogenous testosterone—via transdermal patches, creams, or subcutaneous pellets—consistently elevates serum total and free testosterone.

• Dose-Response: In postmenopausal women, meta-analyses of over 36 randomized controlled trials (RCTs) involving more than 8,000 participants demonstrate significant increases in total testosterone. For example, low-dose transdermal creams (0.5–2.0 mg) can raise free testosterone from approximately 1.18 pg/mL to 4.16 pg/mL, effectively restoring levels to the upper premenopausal range.
• Protein Binding: Total testosterone in the blood is largely bound to Sex Hormone-Binding Globulin (SHBG). Exogenous androgens often suppress SHBG production in the liver; this reduction, combined with the increase in the total testosterone pool, leads to a disproportionately higher rise in "free" (unbound) testosterone, which is the fraction available for tissue uptake.

Mechanistic explanations of tissue exposure

Higher serum levels translate into increased tissue exposure through established pharmacokinetic and molecular pathways:

• Passive Diffusion: Following the "free hormone hypothesis," only unbound testosterone can cross cell membranes. Increased circulating free testosterone creates a steeper concentration gradient, driving more hormone into target cells such as muscle, bone, and skin.
• Intracellular Conversion: Once inside the cell, testosterone can bind directly to the androgen receptor (AR). In many tissues, it is also converted by the enzyme 5-alpha reductase into dihydrotestosterone (DHT), which has a three- to ten-fold higher affinity for the AR.
• Intracrinology: This local conversion allows tissues to amplify androgenic signals. Clinical evidence of increased tissue exposure is seen in physiological changes such as improved bone mineral density, increased lean muscle mass, and, at higher doses, androgenic side effects like increased sebum production.

Bottom line

Exogenous testosterone therapy reliably raises both total and free serum testosterone. This increases the availability of the hormone to diffuse into target cells, where it drives androgen receptor activation and local conversion to more potent androgens, resulting in enhanced tissue-level exposure.