Can High-Dose Testosterone Cause HPA Axis Dysfunction and Low Cortisol in ME/CFS?
High-dose testosterone therapy is unlikely to be the primary cause of HPA axis dysfunction and low cortisol in your patient with ME/CFS, as the underlying disease itself is strongly associated with hypothalamic-pituitary-adrenal axis dysfunction independent of hormone replacement therapy. However, exogenous testosterone can theoretically suppress the HPA axis through aromatization to estrogen and subsequent negative feedback, though this is not the dominant mechanism in ME/CFS patients.
The ME/CFS-HPA Axis Connection
The evidence strongly supports that HPA axis dysfunction is intrinsic to ME/CFS pathophysiology:
Recent reports indicate low blood cortisol levels in patients with long COVID and ME/CFS compared with controls, more than 1 year into symptom duration, with low cortisol production by the adrenal gland not compensated by increased ACTH production, supporting hypothalamus-pituitary-adrenal axis dysfunction 1
A 2021 study found that 33% of ME/CFS patients had antihypothalamic antibodies and 56% had antipituitary antibodies, with those having high antibody titers showing significantly lower ACTH/cortisol levels and more severe forms of ME/CFS 2
The mainstream research evidence indicates that CFS patients have mild hypocortisolism, weakened daily variation in cortisol, a weakened response to the HPA axis, and an increase in negative feedback of the HPA axis 3
Testosterone's Potential Role (Secondary at Best)
While exogenous steroids can suppress the HPA axis, the evidence specific to testosterone in this context is limited:
Exogenous steroids including therapeutic hormones can suppress the hypothalamic-pituitary-adrenal axis and cause iatrogenic secondary adrenal insufficiency 4
However, the pattern in ME/CFS is distinct from typical iatrogenic adrenal suppression—it involves central HPA axis dysfunction with impaired ACTH response rather than simple suppression from negative feedback 1, 2
Male ME/CFS patients showed lower circulating levels of cortisol and corticosterone compared to healthy controls, suggesting the disease process itself drives cortisol abnormalities 5
Distinguishing the Cause
To determine if testosterone is contributing:
Measure both morning (7:30-8:00 AM) cortisol AND ACTH simultaneously—if ACTH is low with low cortisol, this suggests secondary adrenal insufficiency which could be medication-related; if ACTH is inappropriately normal or the response is blunted despite low cortisol, this points to the ME/CFS-related HPA dysfunction 4, 6
The relationship between ACTH and cortisol distinguishes primary from secondary causes, with ME/CFS typically showing central dysfunction where ACTH fails to rise appropriately despite low cortisol 1, 4
Consider a cosyntropin stimulation test (0.25 mg IV/IM with cortisol at 30 and 60 minutes)—a peak cortisol <500 nmol/L (<18 mcg/dL) confirms adrenal insufficiency, but the pattern of ACTH response helps distinguish ME/CFS-related dysfunction from medication-induced suppression 4, 6
Critical Clinical Pitfall
Do not attribute all symptoms to testosterone without proper evaluation—the autoimmune hypothalamic-pituitary dysfunction documented in ME/CFS patients, particularly those with severe disease, represents a distinct pathophysiological process that requires specific recognition and management 2. The presence of antihypothalamic or antipituitary antibodies at high titers is associated with significantly lower ACTH/cortisol levels and more severe ME/CFS manifestations 2.
Practical Approach
If you suspect testosterone is contributing, temporarily discontinuing it requires careful monitoring—never abruptly stop hormone replacement without endocrine consultation and a proper weaning protocol 4
Laboratory confirmation of the cause should not be attempted while the patient is on multiple hormonal therapies without proper washout periods and specialist guidance 4, 6
The evidence suggests that ME/CFS-related HPA dysfunction is likely the primary driver, with testosterone potentially playing a minor contributory role at most through standard negative feedback mechanisms 1, 2, 3