Dr. Mitra Basu Chhillar, M.D.,M.B.A.,F.A.M.
Functional & Regenerative Medicine Specialist
Medical Director, SOMA Wellness Clinic

Introduction

In an era where chronic fatigue, hormonal imbalance, anxiety, and burnout have become distressingly common, there is an increasing need to revisit powerful yet underutilized tools in functional and regenerative medicine. One such tool is pregnenolone, often called the “mother of all hormones.”

Discovered in the 1930s, pregnenolone is a naturally occurring steroid hormone synthesized primarily in the adrenal glands, brain, and gonads. It serves as a precursor for the synthesis of other crucial hormones such as DHEA, cortisol, progesterone, estrogen, and testosterone. In recent years, interest has resurged around this foundational molecule for its role in adrenal health, cognitive vitality, anti-aging, stress resilience, hormonal rebalancing, and overall wellbeing.

At SOMA Wellness Clinic, we use sublingual pregnenolone drops in a carefully guided protocol that bypasses common limitations of oral administration. This article explores the scientific rationale, clinical indications, method of use, and emerging research supporting the thoughtful use of pregnenolone in today’s overstressed and hormonally depleted population.

Why Sublingual Pregnenolone?

The method of delivery dramatically influences a hormone’s effectiveness. Oral pregnenolone undergoes extensive first-pass metabolism in the liver, significantly reducing its bioavailability. Various studies suggest that oral pregnenolone has a bioavailability of only 10-15%, with most of it being converted to inactive metabolites before reaching systemic circulation.

Sublingual delivery, on the other hand, allows the hormone to bypass the liver, entering the bloodstream directly through the rich network of capillaries under the tongue. This increases bioavailability up to 70-80%, enabling a lower dose to achieve physiological effectiveness.

At SOMA Wellness Clinic, our patients are advised to:

• Shake the bottle well before each use.
• Place 3 to 4 drops under the tongue, early in the morning.
• Avoid using pregnenolone in the evening, as it can increase mental alertness and potentially disturb sleep.

Biochemistry of Pregnenolone

Pregnenolone is synthesized from cholesterol via the mitochondrial enzyme P450scc (CYP11A1). It is the first step in the steroidogenic cascade and gives rise to glucocorticoids, mineralocorticoids, androgens, and estrogens through various enzymatic pathways.

It has multiple roles:

• As a neurosteroid, it directly modulates GABA-A receptors, NMDA receptors, and sigma-1 receptors in the brain.
• In peripheral tissues, it contributes to downstream synthesis of DHEA, progesterone, and cortisol.
• It acts as a regulatory switch that governs the balance between anabolic and catabolic hormone production.

Clinical Indications and Benefits

1. Adrenal Exhaustion and Chronic Stress

Chronic stress overactivates the HPA axis, leading to adrenal dysregulation and downstream hormonal imbalances. In adrenal fatigue, pregnenolone levels often plummet, resulting in reduced DHEA, cortisol, and other steroid hormones.

Supplementing pregnenolone helps recharge adrenal function, restoring the body’s capacity to handle physical and psychological stressors. It also stabilizes mood and reduces anxiety by modulating neurosteroids in the brain.

2. Cognitive Function and Mood

Pregnenolone enhances:

• Memory and learning by modulating NMDA and AMPA receptors.
• Mood stabilization by influencing GABAergic tone and dopamine sensitivity.

Studies show pregnenolone’s potential in supporting patients with depression, bipolar disorder, schizophrenia, and age-related cognitive decline.

3. Anti-aging and Cellular Vitality

Low pregnenolone is associated with:

• Cellular senescence
• Mitochondrial dysfunction
• Reduced hormone synthesis

Supplementation restores cellular resilience, boosts mitochondrial output, and supports neurogenesis. As a result, patients report increased energy, motivation, skin glow, and muscular strength.

4. Hormonal Rebalancing in Men and Women

Pregnenolone is a critical precursor for both estrogen and testosterone. In men and women suffering from low testosterone, estrogen dominance, or progesterone deficiency, pregnenolone restores upstream balance, facilitating endogenous production of downstream hormones.

In women, it helps with:

• Perimenopause and menopause
• Estrogen-progesterone imbalance
• PMS and mood swings

In men, it improves:

• Libido and sexual performance
• Motivation and drive
• Andropause-related fatigue

5. Low Cortisol and Burnout

In individuals with low cortisol levels, pregnenolone offers a safe and physiological method to support the steroidogenic pathway without directly giving exogenous corticosteroids. This is particularly beneficial in:

• Long COVID fatigue
• Post-viral burnout
• Overtraining syndrome

6. Low DHEA-S Levels

DHEA-S is an important marker of vitality and immune resilience. Pregnenolone acts as a parent molecule to DHEA, thus helping restore DHEA-S levels without bypassing upstream regulatory mechanisms.

7. Chronic Fatigue Syndrome and Fibromyalgia

These complex conditions involve neuroinflammation, mitochondrial dysfunction, and HPA axis dysregulation. Pregnenolone’s combined neurosteroid, anti-inflammatory, and mitochondrial-enhancing roles make it an important consideration in their management.

8. Low Libido and Sexual Dysfunction

Sex hormone synthesis, libido, and arousal are deeply influenced by adrenal and gonadal hormone production. Pregnenolone restores foundational endocrine harmony that enhances:

• Desire and performance
• Arousal and stamina
• Emotional connection and energy

Clinical Considerations

• Dose titration should be guided by symptoms and serum hormone levels.
• Periodic monitoring of DHEA-S, cortisol, testosterone, estradiol, and progesterone is recommended.
• Avoid high evening doses, as pregnenolone can increase alertness and interfere with sleep.

Why It’s Often Undiagnosed

Despite its critical role, pregnenolone deficiency is seldom tested in conventional medicine. This is because:

• Labs rarely include pregnenolone in standard hormone panels.
• There is lack of awareness among mainstream practitioners.
• Patients often present with vague symptoms like fatigue, low motivation, anxiety, or insomnia that are misattributed.

Functional and regenerative medicine takes a systems biology view, placing pregnenolone at the center of metabolic, cognitive, and hormonal health.

Contraindications and Cautions

• Pregnant or lactating women should avoid use unless medically supervised.
• Not advised in estrogen-sensitive cancers without guidance.
• May interact with GABAergic medications or mood stabilizers in sensitive individuals.

Scientific Publications and Research Evidence

1. Flood JF, et al. Proc Natl Acad Sci. 1992; “Pregnenolone enhances memory in aged mice.”
2. Marx CE, et al. Biol Psychiatry. 2009; “Pregnenolone in schizophrenia and schizoaffective disorder.”
3. Ritsner MS, et al. Eur Neuropsychopharmacol. 2010; “Pregnenolone as adjunctive therapy for cognitive deficits.”
4. Mellon SH, Griffin LD. Brain Res Brain Res Rev. 2002; “Neurosteroids: biochemistry and clinical significance.”
5. Genazzani AR, et al. Menopause. 2003; “Neurosteroid role in menopausal syndrome.”
6. Goodyer CG, et al. J Clin Endocrinol Metab. 1995; “Age-related changes in steroidogenesis.”
7. Vallee M, et al. J Neurosci. 2001; “Pregnenolone modulates anxiety behavior via GABA-A.”
8. Maninger N, et al. Psychoneuroendocrinology. 2009; “Neurosteroids and stress resilience.”
9. Labrie F. Endocr Rev. 1991; “DHEA and pregnenolone interplay.”
10. Pruessner JC, et al. Neuroimage. 2010; “HPA axis regulation and neurosteroids.”

Final Thoughts: Reimagining Resilience

As modern life continues to challenge our biological resilience, pregnenolone offers a science-backed, elegantly simple way to restore the body’s foundational vitality. Whether it’s reversing burnout, balancing hormones, or supporting cognitive performance, pregnenolone is not merely a supplement—it is a strategic intervention in the art and science of regeneration.

For doctors exploring functional protocols, or individuals seeking a deeper solution to chronic fatigue, low libido, and hormonal disarray, sublingual pregnenolone may prove to be a game-changer.

Disclaimer

This article is intended for informational purposes only. It does not constitute medical advice, diagnosis, or treatment. Always consult your physician or qualified health provider before starting any new supplement or therapy. The use of pregnenolone should be medically supervised, particularly in individuals with complex hormonal conditions or psychiatric histories.

Authored by:

Dr. Mitra Basu Chhillar

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