Testosterone Replacement Therapy and Adrenal Laboratory Values
Testosterone replacement therapy (TRT) does affect certain adrenal hormone laboratory values, specifically causing decreases in DHEA, DHEAS, and androstenedione levels, while also suppressing CRH-stimulated cortisol responses, though these changes do not appear to cause clinically significant adrenal dysfunction.
Direct Effects on Adrenal Androgens
TRT causes measurable changes in adrenal androgen production:
DHEA and DHEAS decrease by approximately 20-28% within the first year of testosterone therapy 1, 2. In transgender women receiving feminizing therapy (which includes testosterone suppression), DHEA decreased by 7.4 nmol/L (28%) and DHEAS by 1.8 µmol/L (20.1%) after one year 2.
Androstenedione (A4) levels decrease by approximately 36.5% after 3 months of therapy and remain stable thereafter 2.
These changes occur early in treatment and then plateau, remaining stable during continued therapy 2.
Effects on HPA Axis Function
The relationship between testosterone and adrenal cortisol production is more complex:
Testosterone suppresses CRH-stimulated cortisol secretion in men. When men received testosterone replacement during induced hypogonadism, CRH-stimulated cortisol levels, peak cortisol, and cortisol excursion were all significantly lower compared to the hypogonadal state 3.
Paradoxically, ACTH levels may actually increase during testosterone replacement, while cortisol decreases, suggesting testosterone acts primarily at the adrenal level to reduce cortisol output 3.
The cortisol:ACTH ratio decreases, indicating reduced adrenal sensitivity to ACTH stimulation 3.
However, one study in opioid-induced hypogonadism found no significant changes in ACTH-stimulated cortisol levels after 6 months of TRT 1, suggesting the clinical significance may be limited in certain populations.
Clinical Implications for Laboratory Monitoring
Based on the major guidelines and FDA labeling:
Standard monitoring does NOT include routine adrenal function testing 4, 5, 6. The established monitoring protocol focuses on:
- Serum testosterone levels
- Hematocrit/hemoglobin
- PSA and digital rectal examination
- Lipid profile (optional)
Adrenal labs are not part of routine TRT monitoring because:
- The decreases in adrenal androgens do not cause symptomatic adrenal insufficiency
- Free cortisol levels remain in normal range despite changes in stimulated responses 3
- No clinical evidence suggests these changes require intervention
When to Consider Adrenal Testing
Consider checking adrenal function only if:
- Patient develops symptoms suggestive of adrenal insufficiency (fatigue, hypotension, electrolyte abnormalities) that cannot be explained by other causes
- Patient has pre-existing adrenal disease or is on medications affecting adrenal function
- Patient is on concurrent glucocorticoid therapy
Important Caveats
Do not confuse the physiologic changes in adrenal androgens with adrenal insufficiency. The decreases in DHEA, DHEAS, and androstenedione represent feedback suppression of adrenal androgen production, not global adrenal failure. Cortisol production capacity remains adequate for physiologic needs 1, 3.
The FDA labeling mentions that androgens may decrease thyroxine-binding globulin, resulting in decreased total T4 levels, but free thyroid hormone levels remain unchanged with no clinical thyroid dysfunction 6. This is analogous to the adrenal changes—laboratory values shift but clinical function is preserved.