Understanding the Role of Neurosteroids, Upstream Hormones, and Practical Solutions
Curated By Nelson Vergel | ExcelMale.com
Curated By Nelson Vergel | ExcelMale.com
Introduction: The TRT Paradox
One of the most frustrating experiences reported by men on testosterone replacement therapy (TRT) is the persistence of anxiety and brain fog despite achieving optimal testosterone levels. As one ExcelMale forum member described:"I've been on TRT for almost 5 weeks... Most of my social anxiety went away and I started experiencing a calm focus that felt amazing. I even started for the first time in my life to want to actually do things, to have some thirst and enthusiasm for life. These positive changes however only lasted for about a week or so and 5-6 days ago I started feeling even more anxiety than I ever did before."
This paradox—adequate testosterone but persistent neuropsychiatric symptoms—has puzzled both patients and clinicians alike. The answer lies not in testosterone itself, but in what happens to the hormones "upstream" of testosterone when exogenous testosterone is administered.
The Hidden Hormonal Cascade: Understanding Neurosteroids
To understand why TRT can sometimes cause or fail to resolve anxiety and brain fog, we must first understand the steroid hormone cascade and a critical class of molecules called neurosteroids.What Are Neurosteroids?
Neurosteroids are steroid hormones that act directly on the brain to modulate neural activity. The most important of these for mood and cognition is allopregnanolone (ALLO), a potent GABAergic neurosteroid derived from progesterone. ALLO acts on GABA-A receptors—the same receptors targeted by benzodiazepines like Xanax and Valium—to produce calming, anxiolytic effects.The synthesis pathway is straightforward: Pregnenolone → Progesterone → Allopregnanolone (via 5-alpha reductase)
As noted in research discussed on ExcelMale.com: "Pregnenolone supports several routes, not simply progesterone. Direct progesterone bypasses upstream neurosteroid balancing, thereby perhaps causing an excess in one area and a deficit in others."
The Critical Role of 5-Alpha Reductase
The enzyme 5-alpha reductase (5AR) is essential for producing both dihydrotestosterone (DHT) from testosterone AND allopregnanolone from progesterone. This creates a potential problem: when testosterone levels are high (as with TRT), the 5AR enzyme may become preferentially occupied converting testosterone to DHT, leaving less enzymatic capacity available for the critical progesterone → allopregnanolone conversion.This "enzyme competition" hypothesis helps explain why some men with excellent testosterone and DHT levels still experience anxiety and cognitive issues—their neurosteroid production has been inadvertently compromised.
How TRT Disrupts Upstream Hormone Production
When a man takes exogenous testosterone, several hormonal changes occur that can negatively impact neurosteroid production:1. Suppression of LH and FSH
TRT suppresses the pituitary's release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) through negative feedback. As explained in ExcelMale research: "When you take exogenous testosterone, your pituitary gland reduces LH secretion. In men, LH normally stimulates the testes not only to produce testosterone but also to produce pregnenolone and progesterone as intermediate steps in steroidogenesis. With low LH, testicular output of pregnenolone/progesterone drops, and the adrenal glands may not fully compensate."2. Reduced Testicular Steroidogenesis
The testes are a significant source of pregnenolone and progesterone—the precursors needed for allopregnanolone synthesis. When LH is suppressed by TRT, the testes essentially "go to sleep," producing minimal amounts of these crucial upstream hormones. This is why testicular atrophy is so common in men on TRT without hCG—the cells that produce these hormones literally shrink from disuse.3. Lower Neurosteroid Precursors
Research has consistently shown that men on TRT commonly have lower pregnenolone, progesterone, and DHEA compared to age-matched controls not on TRT. One forum discussion noted: "Over time, men on TRT might have plenty of testosterone and DHT, but unusually low levels of pregnenolone, progesterone, and even DHEA compared to pre-TRT or age-matched non-TRT men. This scenario can contribute to symptoms like anxiety or reduced stress tolerance."4. The 5AR Competition Effect
High testosterone levels from TRT increase the demand on 5-alpha reductase to convert testosterone to DHT. This may reduce the enzyme's availability for converting progesterone to allopregnanolone. The result: adequate androgens but deficient neurosteroids, leading to anxiety and brain fog despite "optimal" testosterone levels.Real-World Experiences from ExcelMale.com
The ExcelMale forum contains thousands of discussions about anxiety, brain fog, and mood issues related to TRT. Several patterns emerge:The Initial Honeymoon Followed by Decline
Many men report feeling fantastic during the first few weeks of TRT, followed by a decline in mood and cognitive function. This timeline corresponds to the gradual suppression of natural hormone production. As one member explained: "Your testosterone levels aren't stable yet and to top it off your natural production is getting shut down... It's about this time when your natural production is circling the drain and you are waiting for the cypionate to build up in your system. I often hear week 3 can be the toughest time for guys."Low DHEA-S Despite TRT
Forum members frequently discover low DHEA-S levels even while on TRT. One member shared: "I am on TRT 200mg cyp weekly... my bloodwork after commencing TRT indicated low DHEA-S levels, so I am thinking about talking to doctor about adding this." This finding supports the theory that TRT alone doesn't maintain the full spectrum of upstream hormones.The hCG Difference
Many forum members report significant mood improvements when hCG is added to their TRT protocol. Research discussed on the forum notes: "Emerging research suggests that HCG may have broader implications beyond fertility, possibly influencing cognitive function and neurosteroids... Some men report feeling calmer and an improved sense of well-being when hCG is included—possibly because it's helping restore some of the pregnenolone → progesterone → allopregnanolone conversion that was suppressed."Individual Variability
Not all men experience these issues. As one member noted: "TRT affects everyone differently, some it increases anxiety while others report the opposite. TRT cures all mood problems for me." Genetic variations in enzymes like MAO-A, COMT, and 5-alpha reductase may explain why some men are more susceptible to neurosteroid deficiency than others.Critical Warning: Avoid 5-Alpha Reductase Inhibitors
If neurosteroid deficiency is contributing to anxiety and brain fog in men on TRT, then 5-alpha reductase inhibitors like finasteride and dutasteride (used for hair loss and prostate enlargement) should be absolutely avoided. These drugs block the very enzyme needed to convert progesterone to allopregnanolone.Research published on ExcelMale.com details the potential underlying mechanisms: "The key possible effect of 5-ARIs is an alteration of neuroactive steroids, specifically allopregnanolone and 5-alpha reductase products. The alterations in neuroactive steroids have close causation with the dysfunction of the dopaminergic system and an alteration in brain receptor function."
Post-Finasteride Syndrome (PFS) is a devastating condition affecting some men who have used these medications. Symptoms include depression, anxiety, brain fog, and sexual dysfunction that can persist for years after stopping the medication. The FDA has added warnings about persistent sexual dysfunction and depression to finasteride's label.
For men on TRT concerned about hair loss, safer alternatives should be explored with a knowledgeable physician, such as topical anti-androgens that don't significantly affect systemic neurosteroid production.
Practical Solutions for TRT Patients
If you're experiencing anxiety or brain fog on TRT despite good testosterone levels, consider the following evidence-based approaches:1. Monitor Upstream Hormones
Standard TRT panels typically include total testosterone, free testosterone, and estradiol. However, to fully assess neurosteroid status, also request:• Pregnenolone
• Progesterone
• DHEA-S
• DHT (to assess 5AR activity)
These are not included in standard panels but can reveal deficiencies that explain persistent symptoms.
2. Consider hCG Add-Back Therapy
Human chorionic gonadotropin (hCG) mimics LH and stimulates the testes to maintain their function. Typical dosing is 500-1500 IU two to three times per week. Benefits include:• Maintains testicular steroidogenesis (pregnenolone, progesterone production)
• Preserves testicular size
• Maintains fertility
• May improve libido and cognitive function
As noted on ExcelMale.com: "Nelson Vergel discusses how his productivity and brain function have improved since starting HCG."
3. Supplement Precursor Hormones
If blood tests confirm deficiencies, supplementation may help:Pregnenolone (25-50 mg daily): This "mother hormone" can convert to multiple downstream hormones including progesterone and allopregnanolone. Forum research notes: "Treatment with oral pregnenolone elevated allopregnanolone serum levels fivefold... elevated progesterone serum levels more than fourfold and DHEAS levels by approximately 16%."
DHEA (25-50 mg daily): May help support the broader neurosteroid milieu. Some practitioners recommend combining DHEA with pregnenolone as they share metabolic pathways.
Considerations: Start low and titrate up. Pregnenolone has a short half-life (3-4 hours), though its sulfated form lasts longer. Sublingual or transdermal administration may provide more consistent levels than oral dosing. Some men respond better to pulsed dosing (every other day or 2-3 times weekly) rather than daily.
4. Low-Dose Progesterone (Experimental)
Some clinicians are experimenting with low-dose progesterone (5-10 mg oral or cream at bedtime) for men with documented deficiency. As one ExcelMale member reported: "I have been experimenting for a little bit with 5mg micronized cap from Empower, it has a mild sedating effect for me, it helped me with social anxiety better than pregnenolone I believe."However, this should only be done under medical supervision as progesterone can have complex effects on the male hormonal system.
5. Lifestyle Optimization
Several lifestyle factors can support healthy neurosteroid function:Sleep: Poor sleep is strongly associated with brain fog. As one forum member noted, "No one has brought up sleep issues. That and allergies are the main causes of brain fog."
Exercise: Regular physical activity supports overall hormonal health and may influence neurosteroid production.
Diet: Anti-inflammatory diets may support neurosteroid function. One member reported dramatic improvements with an AIP (autoimmune protocol) diet.
Stress management: Chronic stress depletes pregnenolone (the "pregnenolone steal" phenomenon) as the body prioritizes cortisol production.
6. Consider Protocol Adjustments
Some men find that their TRT protocol itself contributes to anxiety. Considerations include:Dose optimization: Higher doses aren't always better. Many forum members report feeling best at moderate doses (60-120 mg/week) rather than aggressive doses that maximize numbers.
Injection frequency: More frequent, smaller injections (e.g., daily or every other day) provide more stable levels and may reduce side effects.
Delivery method: Some men respond differently to various formulations. Creams, especially scrotal application, may result in different hormonal profiles than injections.
When Anxiety and Brain Fog Aren't Hormonal
It's important to recognize that not all anxiety and brain fog in men on TRT is related to neurosteroid deficiency. Other causes to consider include:• Sleep apnea (very common in men on TRT)
• Thyroid dysfunction
• Cortisol abnormalities
• Iron deficiency or excess
• Depression unrelated to hormones
• Life stressors and situational anxiety
• Long-term effects of prior COVID-19 infection
As one forum moderator wisely noted: "If you've noticed a better sex drive, better energy and haven't noticed a reduction or improvement in your anxiety by now, even a little, then that tells me the anxiety isn't hormone related. TRT isn't a panacea, it doesn't always cure all your ills."
Conclusion
The experience of anxiety and brain fog despite optimal testosterone levels is a real phenomenon that affects a subset of men on TRT. The emerging understanding of neurosteroid physiology provides a mechanistic explanation: TRT suppresses the body's natural production of hormones upstream of testosterone, potentially leading to deficiencies in pregnenolone, progesterone, and ultimately allopregnanolone—the brain's natural calming neurosteroid.For men experiencing these symptoms, a comprehensive approach includes:
1. Testing upstream hormones (pregnenolone, progesterone, DHEA-S)
2. Considering hCG add-back therapy to maintain testicular function
3. Supplementing precursor hormones if deficient
4. Absolutely avoiding 5-alpha reductase inhibitors
5. Optimizing lifestyle factors
6. Working with a knowledgeable physician to fine-tune the TRT protocol
The goal of TRT should be optimal well-being, not just optimal numbers. By understanding the full hormonal picture and addressing neurosteroid deficiency when present, men can achieve the comprehensive benefits that TRT promises.
Disclaimer: This article is for educational purposes only and should not be considered medical advice. Always consult with a qualified healthcare provider before making any changes to your hormone therapy protocol. Individual responses to TRT and supplementation vary significantly.
Resources
• ExcelMale.com - Men's Health Forum focused on TRT and hormone optimization• How Can I Increase My Allopregnanolone? - ExcelMale Forum Discussion
• Pregnenolone and Progesterone for Men: Pharmacokinetics and Studies - ExcelMale
• Best HCG Dose for Men on TRT: Two Studies - ExcelMale Forum Discussion
• HCG Use in Men on TRT or as Monotherapy: Over 200 Questions and Answers - ExcelMale
• Pregnenolone in Men: Help Determining Proper Dosage and Frequency - ExcelMale
• Post-Finasteride Syndrome: Current Views and Where Do We Stand? - ExcelMale
• The Connection of 5AR Inhibitors Like Finasteride to Depression - ExcelMale Forum
• Depression and Anxiety on TRT Week 5 After Great Start - ExcelMale Forum
• Anxiety and TRT - ExcelMale Forum Discussion
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