HPA Axis Dysfunction in ME/CFS is NOT Related to Testosterone Use
The low cortisol levels and HPA axis dysfunction observed in ME/CFS patients are intrinsic features of the disease itself, caused by hypothalamic-pituitary autoimmunity and neuroinflammation—not by exogenous testosterone administration. 1, 2
Understanding the Pathophysiology
The HPA axis dysfunction in ME/CFS is characterized by:
- Low cortisol production without compensatory ACTH elevation, indicating central (hypothalamic-pituitary) rather than adrenal pathology 1
- High prevalence of antipituitary (56%) and antihypothalamic (33%) antibodies in ME/CFS patients, with higher antibody titers correlating with more severe disease and lower ACTH/cortisol levels 2
- Underlying neuroinflammatory processes affecting hypothalamic CRH-producing neurons, leading to reduced HPA axis activity 1, 3
- Attenuated diurnal cortisol variation and enhanced negative feedback to the HPA axis 4, 5
Why Testosterone is Not the Culprit
The evidence clearly demonstrates that:
- ME/CFS-associated HPA dysfunction predates and is independent of hormone replacement therapy 1
- The cortisol abnormalities are documented in ME/CFS patients more than 1 year into symptom duration, representing a core disease feature 1
- Reduced adrenal responsiveness to ACTH exists in some ME/CFS patients, similar to secondary adrenal insufficiency patterns 6
- The dysfunction stems from autoimmune attack on hypothalamic-pituitary structures, not from exogenous hormone suppression 2
Critical Clinical Caveat
However, initiating testosterone therapy in a patient with unrecognized or inadequately treated adrenal insufficiency could precipitate adrenal crisis. 1, 7, 8
This occurs because:
- Other hormones (including testosterone) accelerate cortisol clearance, unmasking or worsening existing adrenal insufficiency 1, 7
- Cortisol replacement must always precede testosterone or other hormone therapy when multiple endocrine deficiencies are present 1, 7
Diagnostic Approach for This Patient
Evaluate the HPA axis independently of testosterone use:
- Obtain morning (8 AM) cortisol and ACTH levels together to determine if this is primary versus secondary adrenal insufficiency 7, 8
- Low cortisol with low or inappropriately normal ACTH confirms central (secondary) adrenal insufficiency, consistent with ME/CFS pathophysiology 1, 8
- Consider ACTH stimulation testing (250 mcg cosyntropin) if morning cortisol is indeterminate (5-18 mcg/dL), with peak cortisol <18 mcg/dL at 30 or 60 minutes confirming adrenal insufficiency 7, 8
- Assess for antipituitary and antihypothalamic antibodies, as these are present in the majority of ME/CFS patients with HPA dysfunction 2
Management Algorithm
If adrenal insufficiency is confirmed:
- Initiate hydrocortisone 15-20 mg daily in divided doses (typically 10 mg morning, 5 mg afternoon) for mild symptoms 7, 8
- For moderate symptoms, use 2-3 times maintenance dosing (hydrocortisone 30-50 mg total daily) 7, 8
- Do not adjust or discontinue testosterone unless there are other clinical indications, as the HPA dysfunction is disease-related, not testosterone-induced 1, 2
Patient education is mandatory:
- Teach stress dosing (double or triple usual dose during illness, fever, injury) 1, 7, 8
- Provide emergency injectable hydrocortisone 100 mg IM kit with self-injection training 7, 8
- Medical alert bracelet indicating adrenal insufficiency 1, 8
Monitoring Considerations
Assess for signs of glucocorticoid over-replacement:
- Bruising, thin skin, edema, weight gain, hypertension, hyperglycemia 7
- Use the lowest effective hydrocortisone dose, as average daily doses >7.5 mg prednisone equivalent may be associated with reduced survival in some contexts 1
The absence of correlation between morning and afternoon cortisol levels may be a more representative marker of HPA axis disturbance in ME/CFS than single-time hormone measurements 5