DHEA-S & Pregnenolone: Upstream Hormones on TRT

Last Updated: OCTOBER 2023

Men with total testosterone below 300 ng/dL have a significantly increased risk of adverse health outcomes, with a meta-analysis of prospective observational studies showing an elevated risk of major cardiovascular events and all-cause mortality. For instance, data indicates a 1.25-fold higher risk of all-cause mortality in men with low testosterone compared to those with normal levels (Xu et al., European Journal of Preventive Cardiology, 2018). While optimizing testosterone is foundational for men on TRT, true hormonal well-being extends beyond a single number. Many individuals find that addressing upstream hormones like DHEA-S and Pregnenolone can be crucial for resolving persistent symptoms such as brain fog, fatigue, and mood disturbances, even when their testosterone levels are within an optimal range. These adrenal steroids are integral to the broader endocrine system and act as vital neurosteroids, directly impacting brain function and overall quality of life.

The Adrenal-Gonadal Connection on TRT

When you introduce exogenous testosterone, the body’s natural testosterone production via the hypothalamic-pituitary-gonadal (HPG) axis is suppressed. This suppression can have downstream effects, as the body’s steroidogenic pathway, starting from cholesterol, is a cascade. Cholesterol is converted to pregnenolone, which is then a precursor to DHEA, progesterone, and ultimately to testosterone, cortisol, and estrogens. While TRT directly replaces testosterone, it doesn’t always account for the potential disruption or suppression of these other critical steroid pathways. The adrenal glands are primary producers of DHEA and DHEA-S, and also play a role in pregnenolone synthesis. Monitoring these hormones helps ensure that the entire hormonal orchestra is playing in harmony, not just the testosterone section.

Why DHEA-S Matters

Dehydroepiandrosterone sulfate (DHEA-S) is the most abundant steroid hormone in the human body. Primarily produced by the adrenal glands, it serves as a crucial precursor for both androgenic and estrogenic hormones in various tissues. Its role extends beyond simple precursor activity; DHEA and DHEA-S are recognized neurosteroids, directly influencing brain function.

On TRT, some men may experience a natural decline in their endogenous DHEA production. While not universally suppressed, it’s common enough to warrant consideration. Low DHEA-S levels can manifest as:

• Persistent fatigue and low energy
• Reduced libido, even with optimized testosterone
• Mood disturbances, including anxiety or depression
• Compromised immune function
• Dry skin and reduced overall vitality

Maintaining DHEA-S within an optimal range is about providing the body with the building blocks it needs for balanced hormonal health. Optimal DHEA-S levels on TRT generally fall within the mid-to-upper quartile of reference ranges, often aiming for levels seen in healthy young adults. For most labs, this translates to roughly 250–450 µg/dL for men, though individual needs can vary. It’s not about hitting an arbitrary number, but about resolving symptoms and achieving symptomatic relief within a healthy range.

For those considering DHEA supplementation, typical dosages range from 25–100mg per day, taken orally. Starting low and titrating up while monitoring blood levels and symptoms is a prudent approach. It’s important to understand that DHEA can convert to both testosterone and estrogen, so monitoring total testosterone, free testosterone, and estradiol (E2) is essential.

Why Pregnenolone Matters

Often referred to as the “mother hormone,” pregnenolone is the direct precursor to virtually all other steroid hormones, including DHEA, progesterone, testosterone, and cortisol. Synthesized primarily in the adrenal glands, but also in the brain and gonads, pregnenolone is also a potent neurosteroid. It plays a significant role in neuronal excitability, memory formation, and stress response.

The recent interest in pregnenolone on TRT stems from its connection to persistent neurological and cognitive symptoms, particularly “brain fog.” Many men on TRT report optimized T levels but still struggle with mental clarity, focus, or even sleep issues. This can sometimes be attributed to suboptimal pregnenolone levels, as the body, while receiving exogenous testosterone, might not be adequately producing its precursors. “These neurosteroids [pregnenolone, DHEA] are involved in a variety of physiological functions, including learning and memory, stress response, neuroprotection, and mood regulation, suggesting their potential therapeutic utility,” as noted by Maninger et al. in Frontiers in Endocrinology, 2018.

Optimal pregnenolone levels on TRT are often aimed at the mid-to-upper range for healthy adults, typically around 150–250 ng/dL. Below this, individuals might experience:

• Brain fog, difficulty concentrating
• Memory issues
• Fatigue, despite good sleep
• Anxiety or irritability
• Low libido and overall low energy

When supplementing pregnenolone, common dosages range from 25–100mg per day, typically taken orally. As with DHEA, a cautious approach starting with a lower dose and adjusting based on symptom response and lab work is recommended. Monitoring the conversion to downstream hormones, especially DHEA and progesterone, can be insightful.

Comprehensive Lab Work for TRT Optimization

A truly optimized TRT protocol goes beyond merely achieving a target total testosterone number. The antiquated lower bound of 264 ng/dL for total testosterone, for instance, was derived from studies in the 1970s that included men who were elderly and often suffering from significant comorbidities. Relying solely on such outdated markers ignores the complex interplay of the entire endocrine system. Real optimization involves a broader perspective, ensuring all key hormones are balanced for optimal health and well-being. This broader perspective often includes monitoring neurosteroids and adrenal hormones.

A comprehensive TRT lab panel should include:

• Total Testosterone: A general measure of testosterone in the blood.
• Free Testosterone: The bioavailable form of testosterone, crucial for its effects on tissues. Aim for 15–25 pg/mL.
• Estradiol (E2): To monitor for potential aromatization of testosterone. Aim for 20–40 pg/mL on TRT.
• Sex Hormone Binding Globulin (SHBG): Impacts free testosterone levels.
• Prolactin: Can sometimes be elevated with hypogonadism or certain medications.
• Hematocrit: To monitor for erythrocytosis, a potential side effect of TRT.
• Lipid Panel: To monitor cardiovascular health markers.
• Prostate Specific Antigen (PSA): For prostate health monitoring.
• DHEA-S: As discussed, typically aiming for 250–450 µg/dL.
• Pregnenolone: As discussed, typically aiming for 150–250 ng/dL.
• LH/FSH (Luteinizing Hormone/Follicle-Stimulating Hormone): Useful at baseline to diagnose primary vs. secondary hypogonadism, though often suppressed on TRT.
• Progesterone: An important neurosteroid and precursor; sometimes elevated or low when other steroids are imbalanced.

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