Pregnenolone & Its Metabolites

CARRIE DECKER, ND 

When we speak of hormones, we often think of those that play a role in mediating sexual function: estrogen, testosterone, and progesterone. These hormones come from the common base molecule of cholesterol, and all 3 derive from the mother hormone, pregnenolone (PREG), while estrogen and testosterone are also both downstream from dehydroepiandrosterone, commonly known as DHEA.  

PREG is upstream of DHEA; it gives rise not only to DHEA but also to progesterone, cortisol, and other intermediary metabolites. The synthesis and metabolism of PREG primarily takes place in the adrenals, with the specific pathways and products varying by the adrenal location.1 Smaller amounts of PREG are also made in the gonads as well as the brain.2–4  

Although we all are quite familiar with PREG as a mother hormone, many of us are not as familiar with the neurosteroid effects of PREG and its metabolites.  

Peripherally and in the brain, PREG is metabolized to progesterone (PROG) and further converted to allopregnanolone (ALLO-P).5 Similar to DHEA and its sulfated form, DHEA-S, PREG also exists in a sulfated form, PREG-S, throughout the body including the brain.6 PREG, PROG, and ALLO-P each have been demonstrated to have neuroprotective effects.7 ALLO-P interacts with gamma-aminobutyric acid (GABA) receptors as an allosteric agonist; this may be a primary mechanism by which both PREG and PROG exert central nervous system (CNS) calming effects.8,9  

As we grow in our understanding of the actions that PREG and its metabolites have in the brain, we see them increasingly being studied as therapies for conditions associated with neuroinflammation and CNS hyperexcitability, including epilepsy,10,11 schizophrenia,12 anxiety,13 depression,14 and traumatic brain injury,15 many of which we will look at further herein.  

Age-Related Memory Decline  

PREG and its derivatives may serve as a buffer for age-related hormonal decline, enhancing learning and memory, reducing dementia risk, enhancing locomotor activity, and promoting the growth and survival of brain cells.16,17 Much like other hormones, PREG declines with increasing age after it reaches its maximum levels at around 20 years of age.18,19   

Memory formation and cognitive function, much like all things, rely on an appropriate balance of excitation and inhibition. In contrast to PREG and ALLO-P, PREG-S has GABA-inhibitory effects, which may be the mechanism by which the injection of PREG-S into rats’ brains was found to improve memory.20 A significant correlation between PREG-S and cognitive performance has been shown in animal models: rats with memory impairment tend to have much lower concentrations of the neurohormone as compared to rats with normal memory, whereas restoration of normal levels reversed memory deficits.17 PREG-S mediates many aspects of synaptic plasticity, that is, the connections between neurons that are responsible for their communication, the learning of new skills, and the formation of memory.21 

As compared with healthy controls, patients with Alzheimer’s disease (AD) were found to have lower levels of PREG and its primary products, as well as DHEA-S (another downstream metabolite of PREG), in their brains.22,23 The sex steroids estrogen and testosterone also have been shown to be significantly lower in individuals with AD, particularly older females.24 Higher levels of the proteins, β-amyloid and hyperphosphorylated tau (proteins characteristic of AD25), are correlated with lower levels of the neurosteroids in certain regions of the brain.25 Animal studies have indicated that these neurosteroids may also reduce the damage that these proteins cause, thereby improving cellular survival.25  

Although there are no studies to date specifically looking at PREG as a therapy for cognitive decline associated with aging, there are studies investigating its cognitive impact in other populations. We do see one small study point to the positive impact DHEA may have on brain health with aging: when taken at a dose of 25 mg daily for 6 months, DHEA was found to enhance cognitive function in women with mild-to-moderate cognitive impairment.26  

In patients with schizophrenia, supplementation with PREG at escalating doses up to 500 mg/day for 8 weeks led to significant improvements in negative symptoms, with serum increases in PREG and ALLO-P predicting improvements in cognitive scores.27 A subsequent study in patients with recent-onset schizophrenia also found that supplementation of PREG at only 50 mg/day improved multiple markers of attention as well as executive function.28  

Medications that specifically stimulate the brain’s production of PREG, PROG, and ALLO-P are currently under investigation as a treatment or prevention strategy for AD.29  

Mental Health 

Because of the impact neurosteroids have on CNS excitability and neural function, their role in anxiety and depression has also been studied.30 Interesting research has shown that ALLO-P and DHEA additionally modulate amygdala connectivity and our response to conditions that promote the emotion of fear.31  

In a mouse study, lower serum levels of DHEA-S were observed in animals displaying a conditioned fear response, while administration of both DHEA-S and PREG-S (separately) dose-dependently reduced the anxiety response to conditioned fear.32 This sheds light on the impact these neurosteroids may have on conditioned fears – a factor in post-traumatic stress disorder (PTSD) – as well as on our arousal state and response to stress. Although the fear response is important and preserves our lives at times, we all can probably think of an instance in which being stoic and more functional in the face of our fears would be desired! 

The effects of PREG on the emotional response has also been studied in humans in a task designed to assess emotional processing and regulation.33 When given 2 hours prior to performing the task, 400 mg of PREG altered multiple brain patterns (assessed by functional magnetic resonance imaging) prompted by the task. As compared to placebo, PREG reduced activity in the amygdala and insula, increased activity in the dorsal medial frontal cortex, and increased functional connectivity between the dorsal medial frontal cortex and the amygdala. These effects were associated with a reduction in self-reported anxiety.33 

In young, otherwise-healthy unmedicated men with generalized anxiety disorder, lower serum levels of PREG-S were found, as compared to healthy controls.34 Lower serum ALLO-P levels were also observed in the men with anxiety; however, the difference was not significant; there was also no difference in DHEA-S levels between the 2 groups.34 Levels of ALLO-P have been shown to be significantly lower in men and women with PTSD and to be inversely correlated with PTSD and dysphoria symptoms.35  

Treatment with PREG, at a dose of 100 mg/day for 8 weeks, was shown to have a positive impact on mood (but not cognition) in abstinent individuals being treated for substance use disorder, with trends toward greater improvement in scores for both manic and depressive symptoms.36 In a population of men and women with bipolar disorder not known to have substance use issues, PREG, titrated to 500 mg/day and taken for 12 weeks, also positively impacted depression remission rates compared to placebo, suggesting it may prove to be useful in this difficult-to-treat population.37 

Studies also suggest PREG and its metabolites may have a positive impact on alcohol use disorder (AUD) specifically. Research has shown that plasma levels of ALLO-P are markedly lower in alcoholic subjects in early stages of withdrawal as compared to control subjects.38 In an animal model of AUD, self-administration of alcohol in rats with a preference for alcohol was significantly decreased by PREG.39 Additional animal research suggests that ALLO-P may help reduce alcohol use,40 giving rise to interest in further study of how this research may translate to humans as well.41 Low levels of PREG also have been observed in individuals with cocaine use disorder.42  

Menstrual Cycle Disorders 

Not surprisingly, PREG and its metabolites have also been investigated in women with hormonal-related mood disorders. In women with premenstrual syndrome, significantly lower serum levels of both ALLO-P and PROG were observed in the women during the luteal phase, as compared to controls.43,44 In women with post-partum depression, significantly lower levels of ALLO-P were shown, as compared to control women post-partum, with levels of ALLO-P and PREG both showing a significant negative correlation with Hamilton Rating Scale for Depression scores.45  

One setting for which the underlying etiology suggests PREG may worthy of a therapeutic trial is hypothalamic amenorrhea, particularly as it pertains to women struggling with or in recovery from anorexia nervosa (AN). Hypothalamic amenorrhea is more common after intense metabolic, physical, or psychological stresses, of which AN is one.46 In women diagnosed with hypothalamic amenorrhea who have a normal body weight, lower levels of ALLO-P have been shown,47 and in those specifically in recovery from AN, a low DHEA-S to cortisol ratio also appears to be common.48 Research examining DHEA as a therapy for restoring the menstrual cycle in this population looks promising.49 Considering the general anxiety and fear-“dampening” effects of PREG and its downstream products, PREG also may be worthy of consideration. 

Anti-Inflammatory Effects 

Interesting research as far back as 1950 suggested that PREG may be useful for decreasing fatigue and treating inflammatory conditions such as ankylosing spondylarthritis [sic] and rheumatoid arthritis.50,51 Physicians at the time were already aware that the more potent glucocorticoids had several unwanted effects; hence, they had great interest in PREG as alternative anti-inflammatory treatment.52  

Fast-forward to our modern, medication-laden era, and we still see research with PREG as a natural therapy for reducing pain. In fact, a 2019 study specifically details the many mechanisms by which PREG may impact pain and other inflammatory pathology via interactions with the innate immune system.53 PREG is not an immunosuppressant; however, similar to many of our other endogenous hormones, it acts to modulate inflammation and the immune system’s response to it. 

ALLO-P levels have been shown to be inversely related to symptoms of pain in male veterans.54,55 This association was not limited to muscle pain; it included chest pain as well. Interestingly, a very strong association was also shown between a history of traumatic brain injury and muscle soreness, suggesting that some aspect of this symptomology may be centrally mediated. As the research discussed so far strongly supports the central anti-inflammatory effects of PREG, it is no surprise that this neurohormone has been studied in this special population, especially given the concomitant issues of PTSD, for which PREG may also be of benefit.56  

A 2020 randomized, double-blind, placebo-controlled trial considered escalating doses of PREG (1 week at 100 mg/day, 1 week at 300 mg/day, and 2 weeks at 500 mg/day) for low back pain in Iraq- and Afghanistan-era military veterans.56 The population of veterans in this study was approximately 90% male and ranged in age from 18 to 65. Compared to placebo, PREG was shown to significantly reduce pain as well as the effects pain had on participation in other activities, including work. Both pain recall and pain diary scores progressively decreased and were significantly lower in the PREG group than in the placebo group by the study’s completion. Serum PREG levels approximately doubled after taking 100 mg for 1 week, and were almost 5 times greater after taking 500 mg for 2 weeks. ALLO-P and PREG levels increased more than 10-fold by the study’s completion as well. The intervention was well tolerated, with no significant adverse events being reported.56   

Recent preclinical research suggests the PREG downstream metabolites, ALLO-P and PROG, may also improve neuropathic pain, another condition that is often difficult to treat.57,58  

Potential Contraindications & Adverse Effects  

With hormone precursors such as PREG or DHEA, adverse effects are generally not seen acutely, but may be with prolonged use. In the studies discussed herein, adverse effects related to PREG use were not seen despite the fairly high dosage; however, clinically, dysmenorrhea and mastalgia have been reported. With DHEA, adverse effects are mild and may include complaints of oily skin, hair growth, acne, and body odor59,60 – signs we typically associate with increased testosterone levels. Hair loss can also occur, as DHEA converts to more potent androgens in the follicle, which can interfere with hair growth.61 Studies suggest that the epidermal effects of DHEA may be related to steroidal production in the skin,62 which oral supplementation additionally enhances and to which some individuals may be more sensitive. Adverse symptoms may be averted by ensuring normal-to-low levels of hormones prior to initiation of treatment with the “mother hormones.” 

It is worthwhile mentioning that the doses of PREG used in many of these studies are higher than practitioners typically use in clinical practice. Often, PREG or DHEA will be initiated at a low dose, and, if there are no complaints, the dose is gradually increased to levels shown to be effective. Micronization and dissolution into a lipid matrix supports the absorption of fat-soluble substances such as these63; hence, with such a preparation, clinical results may achieved at lower doses. 

Closing Comments 

Given the pleotropic actions of hormones, particularly those that are mother hormones to many others (such as PREG is), it is no surprise that we see such a broad range of biological effects. The research on PREG as an intervention for pain is quite unique, and given the positive findings discussed in the 2020 publication, it is likely we will see further research in this arena. Similarly, the findings supporting the use of PREG in addiction medicine and mental health are quite recent and are already being followed up by additional clinical trials.64,65  

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Carrie Decker, ND graduated with honors from the National College of Natural Medicine (now the National University of Natural Medicine) in Portland, OR. Prior to becoming a naturopathic physician, Dr Decker was an engineer and obtained graduate degrees in biomedical and mechanical engineering from the University of Wisconsin-Madison and University of Illinois at Urbana-Champaign, respectively. She continues to enjoy academic research and writing and uses these skills to support integrative medicine education as a writer and contributor to various resources. Dr Decker supports Allergy Research Group as a member of their education and product development teams.   

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