Is neurosteroid downregulation a concern in a patient with hypotestosteronemia (low testosterone levels), brain fog, anxiety, and anhedonia, who is being treated with testosterone replacement therapy (TRT)?

Neurosteroid Downregulation with TRT: Not a Clinically Recognized Concern

Neurosteroid downregulation is not identified as a clinical concern in current evidence-based guidelines or high-quality research on testosterone replacement therapy (TRT). The major guidelines from the Endocrine Society and American Urological Association do not mention neurosteroid effects as a contraindication, monitoring parameter, or adverse effect of TRT 1.

What the Evidence Actually Shows About TRT and Neuropsychiatric Symptoms

TRT Improves Depression and Anxiety in Hypogonadal Men

The available research demonstrates that TRT improves rather than worsens neuropsychiatric symptoms in men with confirmed hypogonadism:

• Depression improves with TRT: A prospective placebo-controlled trial of 106 men with testosterone deficiency showed significant decreases in depression scores (Beck Depression Inventory) at 8 months after TRT initiation 2.

• Anxiety symptoms improve: Young hypogonadal men treated with TRT for 6 months showed improvements in Beck Anxiety Inventory scores, though this did not reach statistical significance in one study 3. Another study demonstrated that hypogonadal patients had significantly higher baseline anxiety scores compared to controls, which improved with treatment 3.

• Brain fog and cognitive function: Men with cognitive impairment at baseline (cognitive function score <25) who received TRT showed significant improvement in cognitive function 2. This directly addresses the "brain fog" symptom mentioned in your clinical scenario.

• Anhedonia improves: The improvement in depressive symptoms with TRT includes amelioration of anhedonia, as demonstrated by decreased Beck Depression Inventory scores which assess this symptom 2, 3.

Mechanism of Benefit

Testosterone appears to modulate central nervous system function through multiple pathways, including acting as a modulator of GABAA receptors and inhibiting 5-HT3 receptors centrally 4. This suggests testosterone has direct neuropsychiatric effects beyond simple hormonal replacement.

Clinical Approach for Your Patient

Step 1: Confirm Hypogonadism Diagnosis

• Measure morning total testosterone (8-10 AM) on two separate occasions, with levels <300 ng/dL confirming hypogonadism 5.
• Measure free testosterone by equilibrium dialysis and sex hormone-binding globulin, especially given the neuropsychiatric symptoms 5.
• Obtain LH and FSH to distinguish primary from secondary hypogonadism 5.

Step 2: Rule Out Alternative Causes

Before attributing symptoms solely to hypogonadism, evaluate for:

• Sleep disorders (particularly obstructive sleep apnea) 5
• Thyroid dysfunction 5
• Anemia 5
• Vitamin D deficiency 5
• Metabolic syndrome 5

Step 3: Set Realistic Expectations

For the specific symptoms you mentioned:

• Brain fog/cognitive function: Expect improvement only if baseline cognitive impairment is present (cognitive testing score <25) 2. General cognitive enhancement in men without baseline impairment is not supported 5.

• Anxiety: Expect modest improvement, though evidence is mixed. One study showed significant baseline differences that improved with treatment 3, while another showed non-significant improvement 3.

• Anhedonia/depression: Expect small but significant improvements (standardized mean difference -0.19) 5. Men with more severe testosterone deficiency, mild depression, and those using transdermal testosterone tend to respond best 4.

Step 4: Treatment Selection

First-line recommendation: Transdermal testosterone gel 40.5 mg daily 5, which provides:

• More stable day-to-day testosterone levels 5
• Lower risk of erythrocytosis compared to injectable forms 5
• Better outcomes for neuropsychiatric symptoms based on available evidence 4

Alternative if cost is prohibitive: Testosterone cypionate 100-200 mg every 2 weeks, targeting mid-normal levels (500-600 ng/dL) measured midway between injections 5.

Step 5: Monitoring and Reassessment

• Measure testosterone levels at 2-3 months after initiation 5
• Monitor hematocrit periodically, withholding treatment if >54% 5
• Reassess neuropsychiatric symptoms at 12 months: If no improvement in sexual function or mood symptoms, discontinue TRT to prevent unnecessary long-term exposure without benefit 5

Critical Pitfall to Avoid

Do not initiate TRT based on neuropsychiatric symptoms alone without confirmed biochemical hypogonadism. Approximately 20-30% of men receiving testosterone in the United States do not have documented low testosterone levels before treatment initiation 5. The evidence shows that TRT produces little to no effect on energy, vitality, or cognition in men without confirmed hypogonadism 5.

Bottom Line

The concern about neurosteroid downregulation with TRT lacks evidence-based support. The actual clinical data demonstrates that TRT improves neuropsychiatric symptoms in men with confirmed hypogonadism, including depression, anxiety, cognitive function, and anhedonia 2, 3, 4. However, these improvements are modest, and TRT should only be initiated after confirming biochemical hypogonadism and ruling out alternative causes of symptoms 5.