Medical Studies on Pregnenolone – Basic Facts
Pregnenolone is considered to be the “grandmother” of all steroid hormones and its importance for human health has been acknowledged for decades. However, pregnenolone’s effectiveness is due not only to its metabolites but also to its role as an independent hormone; a role in which it fulfills important tasks – especially in the nervous system.
Pregnenolone is produced in the brain, adrenal glands, liver and skin. Its production follows a daily rhythm, with peak values occurring around 8:00 in the morning and the lowest values present shortly before midnight. Like many other hormones, such as melatonin, pregnenolone levels decrease with age. For example, pregnenolone levels peak between the ages of 20 and 30 and decrease as we age. A 60- to 70-year-old, for example, only maintains 1/10 – 1/20 of the pregnenolone values obtained in younger years.
The metabolism of pregnenolone follows a complex pathway. First, pregnenolone is formed from cholesterol in the mitochondria. Then it is further metabolized into progesterone, for example, and from here again into aldosterone or cortisol. Through another pathway, pregnenolone can become DHEA, where it can subsequently be metabolized into testosterone or estrogen. The conversion pathway pregnenolone takes is determined by the body and depends on various factors, such as isolated hormone deficiency, which causes pregnenolone to be converted in the body either to DHEA or to progesterone.
Interfering Factors in Pregnenolone Production
Age is not the only factor that can lead to a lack of pregnenolone. Chronic stress or illness can also create a deﬁcit. Typical signs of low pregnenolone are fatigue, reduced performance, decreased memory and cognition, autoimmune concerns, or a dysfunctional immune system.
Medical Studies on Pregnenolone – Basic Facts
Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men
Many hormones display distinct circadian rhythms, driven by central regulators, hormonal bioavailability, and half-life. A set of 11-oxygenated C19 steroids (11-oxyandrogens) and pregnenolone sulfate (PregS) are elevated in congenital adrenal hyperplasia and other disorders, but their circadian patterns have not been characterized.
The Expanding Role of Mitochondria, Autophagy and Lipophagy in Steroidogenesis
The fundamental framework of steroidogenesis is similar across steroidogenic cells, especially in initial mitochondrial steps.
De novo neurosteroidogenesis in human microglia: involvement of the 18 kDa translocator protein
Neuroactive steroids are potent modulators of microglial functions and are capable of counteracting their excessive reactivity. This action has mainly been ascribed to neuroactive steroids released from other sources, as microglia have been defined unable to produce neurosteroids de novo.
Clock-controlled mitochondrial dynamics correlates with cyclic pregnenolone synthesis
Neurosteroids are steroids synthetized in the nervous system, with the first step of steroidogenesis taking place within mitochondria with the synthesis of pregnenolone. They exert important brain-specific functions by playing a role in neurotransmission, learning and memory processes, and neuroprotection.
Site of action of brain neurosteroid pregnenolone sulfate at the N-Methyl-D-Aspartate Receptor
N-methyl-D-aspartate receptor (NMDAR) hypofunction has been implicated in several neurodevelopmental disorders. NMDAR function can be augmented by positive allosteric modulators, including endogenous compounds, such as cholesterol and neurosteroid pregnenolone sulfate (PES).
Steroids and TRP channels: a close relationship
Transient receptor potential (TRP) channels are remarkable transmembrane protein complexes that are essential for the physiology of the tissues in which they are expressed. They function as non-selective cation channels allowing for the signal transduction of several chemical, physical and thermal stimuli and modifying cell function. These channels play pivotal roles in the nervous and reproductive systems, kidney, pancreas, lung, bone, intestine, among others.
Pregnenolone and pregnenolone-methyl-ether rescue neuronal defects caused by dysfunctional CLIP170 in a neuronal model of CDKL5 Deficiency Disorder
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene are responsible for the onset of CDKL5 Deficiency Disorder (CDD), a neurological pathology characterised by severe infantile seizures, intellectual disability, impairment of gross motor skills, sleep and gastrointestinal disturbances. CDKL5 is a serine/threonine kinase the molecular network of which is not yet fully understood.
Effect of SULT2B1 genetic polymorphisms on the sulfation of dehydroepiandrosterone and pregnenolone by SULT2B1b allozymes
Pregnenolone and dehydroepiandrosterone (DHEA) are hydroxysteroids that serve as biosynthetic precursors for steroid hormones in human body. SULT2B1b has been reported to be critically involved in the sulfation of pregnenolone and DHEA, particularly in the sex steroid-responsive tissues.
Neuroactive steroids, neurosteroidogenesis and sex
The nervous system is a target and a source of steroids. Neuroactive steroids are steroids that target neurons and glial cells. They include hormonal steroids originated in the peripheral glands, steroids locally synthesized by the neurons and glial cells (neurosteroids) and synthetic steroids, some of them used in clinical practice.
TSPO ligands boost mitochondrial function and pregnenolone synthesis
Translocator protein 18 kDa (TSPO) is located in the mitochondrial outer membrane and plays an important role in steroidogenesis and cell survival. In the central nervous system (CNS), its expression is upregulated in neuropathologies such as Alzheimer's disease (AD).
Uptake and metabolism of sulphated steroids by the blood-brain barrier in the adult male rat
Little is known about the origin of the neuroactive steroids dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulphate (PregS) in the brain or of their subsequent metabolism.
Neurosteroid regulation of central nervous system development
Neurosteroids are a relatively new class of neuroactive compounds brought to prominence in the past 2 decades.
Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor
The N-methyl-D-aspartate (NMDA) receptor is believed to play a major role in learning and in excitotoxic neuronal damage associated with stroke and epilepsy.
Neurosteroid pregnenolone sulfate antagonizes electrophysiological responses to GABA in neurons
Our earlier biochemical studies suggested that the neurosteroid pregnenolone sulfate (PS) may reduce gamma-aminobutyric acid (GABA) action at the Cl- channel associated with GABAA receptors.