Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an
endogenous
Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell.
For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...
steroid
A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration.
Steroids have two principal biological functions: as important components of cell membranes t ...
and
precursor/
metabolic intermediate
Metabolic intermediates are compounds produced during the conversion of substrates (starting molecules) into final products in biochemical reactions within cells.
Although these intermediates are of relatively minor direct importance to cell ...
in the
biosynthesis
Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...
of most of the
steroid hormone
A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Wit ...
s, including the
progestogens,
androgen
An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
s,
estrogen
Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
s,
glucocorticoid
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...
s, and
mineralocorticoid
Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary ...
s.
In addition, pregnenolone is
biologically active in its own right, acting as a
neurosteroid.
In addition to its role as a natural hormone, pregnenolone has been used as a
medication
Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
and
supplement; for information on pregnenolone as a medication or supplement, see the
pregnenolone (medication) article.
Biological function
Pregnenolone and its 3β-
sulfate
The sulfate or sulphate ion is a polyatomic anion with the empirical formula . Salts, acid derivatives, and peroxides of sulfate are widely used in industry. Sulfates occur widely in everyday life. Sulfates are salts of sulfuric acid and many ...
,
pregnenolone sulfate, like
dehydroepiandrosterone
Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It funct ...
(DHEA),
DHEA sulfate, and
progesterone
Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
, belong to the group of
neurosteroids that are found in high concentrations in certain areas of the brain, and are synthesized there. Neurosteroids affect synaptic functioning, are
neuroprotective, and enhance
myelin
Myelin Sheath ( ) is a lipid-rich material that in most vertebrates surrounds the axons of neurons to insulate them and increase the rate at which electrical impulses (called action potentials) pass along the axon. The myelinated axon can be lik ...
ization. Pregnenolone and its sulfate ester may improve cognitive and
memory
Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembe ...
function.
In addition, they may have protective effects against
schizophrenia
Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
.
Biological activity
Neurosteroid activity
Pregnenolone is an allosteric
endocannabinoid, as it is a
negative allosteric modulator of the
CB1 receptor.
Pregnenolone is involved in a natural
negative feedback
Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused ...
loop against CB
1 receptor activation in animals. It prevents CB
1 receptor
agonist
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
s like
tetrahydrocannabinol
Tetrahydrocannabinol (THC) is a cannabinoid found in cannabis. It is the principal psychoactive constituent of ''Cannabis'' and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) de ...
, the main active constituent in
cannabis
''Cannabis'' () is a genus of flowering plants in the family Cannabaceae that is widely accepted as being indigenous to and originating from the continent of Asia. However, the number of species is disputed, with as many as three species be ...
, from fully activating the CB
1. A related compound
AEF0117 has been derived from pregnenolone and is more specific for this type of activity.
Pregnenolone has been found to bind with high,
nanomolar
Molar concentration (also called molarity, amount concentration or substance concentration) is the number of moles of solute per liter of solution. Specifically, It is a measure of the concentration of a chemical species, in particular, of a so ...
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Pa ...
to
microtubule-associated protein 2 (MAP2) in the brain.
In contrast to pregnenolone, pregnenolone sulfate did not bind to
microtubule
Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nanometer, nm and have an inner diameter bet ...
s.
However, progesterone did and with similar affinity to pregnenolone, although unlike pregnenolone, it did not increase binding of MAP2 to
tubulin
Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytosk ...
.
Pregnenolone was found to induce tubule polymerization in neuronal cultures and to increase
neurite growth in PC12 cells treated with
nerve growth factor
Nerve growth factor (NGF) is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons. It is perhaps the prototypical growth factor, in that it was ...
.
As such, pregnenolone may control formation and stabilization of microtubules in neurons and may affect both
neural development
The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field ...
during
prenatal development
Prenatal development () involves the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal de ...
and
neural plasticity during
aging
Ageing (or aging in American English) is the process of becoming Old age, older until death. The term refers mainly to humans, many other animals, and fungi; whereas for example, bacteria, perennial plants and some simple animals are potentiall ...
.
Although pregnenolone itself does not possess these activities, its
metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
pregnenolone sulfate is a
negative allosteric modulator of the
GABAA receptor as well as a
positive allosteric modulator of the
NMDA receptor
The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...
.
In addition, pregnenolone sulfate has been shown to activate the
transient receptor potential M3 (TRPM3)
ion channel
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...
in
hepatocyte
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, bi ...
s and
pancreatic islets causing
calcium
Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
entry and subsequent
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
release.
Nuclear receptor activity
Pregnenolone has been found to act as an
agonist
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
of the
pregnane X receptor.
Pregnenolone has no
progestogenic,
corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invo ...
,
estrogen
Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
ic,
androgen
An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
ic, or
antiandrogen
Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking t ...
ic activity.
Biochemistry
Biosynthesis
Pregnenolone is
synthesized from
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
. This
conversion involves
hydroxylation of the
side chain
In organic chemistry and biochemistry, a side chain is a substituent, chemical group that is attached to a core part of the molecule called the "main chain" or backbone chain, backbone. The side chain is a hydrocarbon branching element of a mo ...
at the C20 and C22 positions, with
cleavage
Cleavage may refer to:
Science
* Cleavage (crystal), the way in which a crystal or mineral tends to split
* Cleavage (embryo), the division of cells in an early embryo
* Cleavage (geology), foliation of rock perpendicular to stress, a result of ...
of the
side chain
In organic chemistry and biochemistry, a side chain is a substituent, chemical group that is attached to a core part of the molecule called the "main chain" or backbone chain, backbone. The side chain is a hydrocarbon branching element of a mo ...
. The
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
performing this task is
cytochrome P450scc, located in the
mitochondria
A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
,
and controlled by
anterior pituitary
The anterior pituitary (also called the adenohypophysis or pars anterior) is a major Organ (anatomy), organ of the endocrine system. The anterior pituitary is the glandular, Anatomical terms of location#Usage in human anatomy, anterior lobe that t ...
trophic hormones, such as
adrenocorticotropic hormone
Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...
,
follicle-stimulating hormone
Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, puberty, pubertal maturat ...
, and
luteinizing hormone
Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (G ...
, in the
adrenal gland
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer adrenal corte ...
s and
gonad
A gonad, sex gland, or reproductive gland is a Heterocrine gland, mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gon ...
s.
There are two
intermediates in the transformation of cholesterol into pregnenolone,
22''R''-hydroxycholesterol and
20α,22''R''-dihydroxycholesterol, and all three steps in the transformation are catalyzed by P450scc.
Pregnenolone is produced mainly in the
adrenal gland
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer adrenal corte ...
s, the
gonad
A gonad, sex gland, or reproductive gland is a Heterocrine gland, mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gon ...
s, and the
brain
The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
.
Although pregnenolone is also produced in the gonads and brain, most circulating pregnenolone is derived from the
adrenal cortex
The adrenal cortex is the outer region and also the largest part of the adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. I ...
.
To assay conversion of cholesterol to pregnenolone, radiolabeled cholesterol has been used.
Pregnenolone product can be separated from cholesterol substrate using Sephadex LH-20 minicolumns.
Distribution
Pregnenolone is
lipophilic
Lipophilicity (from Greek language, Greek λίπος "fat" and :wikt:φίλος, φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are c ...
and readily crosses the
blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...
.
This is in contrast to
pregnenolone sulfate, which does not cross the blood–brain barrier.
Metabolism
Pregnenolone undergoes further steroid
metabolism
Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
in one of several ways:
* Pregnenolone can be converted into
progesterone
Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
. The critical enzyme step is two-fold using a
3β-hydroxysteroid dehydrogenase and a
Δ5-4 isomerase. The latter transfers the
double bond
In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
from C5 to C4 on the A ring. Progesterone is the entry into the Δ
4 pathway, resulting in production of
17α-hydroxyprogesterone and
androstenedione, precursor to
testosterone
Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
and
estrone.
Aldosterone
Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays ...
and
corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invo ...
s are also derived from progesterone or its derivatives.
* Pregnenolone can be converted to
17α-hydroxypregnenolone by the enzyme 17α-hydroxylase (
CYP17A1). Using this pathway, termed Δ
5 pathway, the next step is conversion to
dehydroepiandrosterone
Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It funct ...
(DHEA) via 17,20-lyase (CYP17A1). DHEA is the precursor of androstenedione.
* Pregnenolone can be converted to
androstadienol
Androstadienol, or androsta-5,16-dien-3β-ol, is a 16-androstene class endogenous steroid, pheromone, and chemical intermediate to several other pheromones that is found in the sweat of both men and women.
Androstadienol and androstadienone ...
by 16-ene synthase (CYP17A1).
* Pregnenolone can be converted to
pregnenolone sulfate by
steroid sulfotransferase, and this conversion can be reversed by
steroid sulfatase.
Levels
Normal circulating levels of pregnenolone are as follows:
* Men: 10 to 200 ng/dL
* Women: 10 to 230 ng/dL
* Children: 10 to 48 ng/dL
* Adolescent boys: 10 to 50 ng/dL
* Adolescent girls: 15 to 84 ng/dL
Mean levels of pregnenolone have been found not to significantly differ in postmenopausal women and elderly men (40 and 39 ng/dL, respectively).
Studies have found that pregnenolone levels are not significantly changed after
surgical
Surgery is a medical specialty that uses manual and instrumental techniques to diagnose or treat pathological conditions (e.g., trauma, disease, injury, malignancy), to alter bodily functions (e.g., malabsorption created by bariatric surgery ...
or
medical castration in men, which is in accordance with the fact that pregnenolone is mainly derived from the adrenal glands.
Conversely, medical castration has been found to partially suppress pregnenolone levels in premenopausal women.
Similarly, an
adrenalectomized premenopausal woman showed incompletely diminished circulating pregnenolone levels.
Chemistry
Pregnenolone is also known chemically as pregn-5-en-3β-ol-20-one.
Like other
steroid
A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration.
Steroids have two principal biological functions: as important components of cell membranes t ...
s, it consists of four interconnected
cyclic hydrocarbons.
The compound contains
ketone
In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...
and
hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
functional group
In organic chemistry, a functional group is any substituent or moiety (chemistry), moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions r ...
s, two
methyl
In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...
branches, and a
double bond
In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
at C5, in the B cyclic hydrocarbon ring.
Like many steroid hormones, it is
hydrophobic
In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, thu ...
. The
sulfated derivative,
pregnenolone sulfate, is water-soluble.
3β-Dihydroprogesterone (pregn-4-en-3β-ol-20-one) is an
isomer
In chemistry, isomers are molecules or polyatomic ions with identical molecular formula – that is, the same number of atoms of each element (chemistry), element – but distinct arrangements of atoms in space. ''Isomerism'' refers to the exi ...
of pregnenolone in which the C5
double bond
In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
has been replaced with a C4 double bond.
History
Pregnenolone was first
synthesized by
Adolf Butenandt
Adolf Friedrich Johann Butenandt (; 24 March 1903 – 18 January 1995) was a German biochemist. He was awarded the Nobel Prize in Chemistry in 1939 for his "work on sex hormones." He initially rejected the award in accordance with government pol ...
and colleagues in 1934.
References
{{Navboxes
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Biological activity
In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...
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, list1 =
{{Cannabinoid receptor modulators
{{Glycine receptor modulators
{{Sigma receptor modulators
{{Xenobiotic-sensing receptor modulators
Sterols
CB1 receptor antagonists
Glycine receptor agonists
Ketones
Neurosteroids
Pregnane X receptor agonists
Pregnanes
Sigma agonists
Steroid hormones
CB1 receptor negative allosteric modulators