5α-Dihydroprogesterone (5α-DHP, allopregnanedione, or 5α-pregnane-3,20-dione) is an endogenous progestogen and neurosteroid that is synthesized from

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 m ...

. It is also an intermediate in the synthesis of allopregnanolone and isopregnanolone from progesterone. 5α-DHP is metabolized by the

aldo-keto reductase The aldo-keto reductase family is a family of proteins that are subdivided into 16 categories; these include a number of related monomeric NADPH-dependent oxidoreductases, such as aldehyde reductase, aldose reductase, prostaglandin F synthase, xy ...

s (AKRs)

AKR1C1 Aldo-keto reductase family 1 member C1 also known as 20α-hydroxysteroid dehydrogenase, 3α-hydroxysteroid dehydrogenase, and dihydrodiol dehydrogenase 1/2 is an enzyme that in humans is encoded by the ''AKR1C1'' gene. This gene encodes a member ...

AKR1C2 Aldo-keto reductase family 1 member C2, also known as bile acid binding protein, 3α-hydroxysteroid dehydrogenase type 3, and dihydrodiol dehydrogenase type 2, is an enzyme that in humans is encoded by the ''AKR1C2'' gene. This gene encodes a m ...

, and AKR1C4 with high catalytic efficiency. AKR1C1 preferentially forms 20α-hydroxy-5α-pregnane-3-one while AKR1C2 preferentially forms allopregnanolone. Similarly AKR1C1 reduces and consequently inactivates allopregnanolone into 5α-pregnane-3α,20α-diol. In contrast to the other AKRs,

AKR1C3 Aldo-keto reductase family 1 member C3 (AKR1C3), also known as 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5, HSD17B5) is a key steroidogenic enzyme that in humans is encoded by the ''AKR1C3'' gene. Function This gene encodes a member of t ...

has low catalytic efficiency for reduction of 5α-DHP. These AKRs are highly expressed in the human

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

and

mammary gland A mammary gland is an exocrine gland in humans and other mammals that produces milk to feed young offspring. Mammals get their name from the Latin word ''mamma'', "breast". The mammary glands are arranged in organs such as the breasts in pri ...

but have relatively modest expression in the human

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

and

uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...

. 5α-DHP is an

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the progesterone receptor and a

positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to ...

of the GABA_A receptor (albeit with an

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 Par ...

for this

receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...

that is regarded as relatively low (in comparison to 3α-hydroxylated progesterone

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 ...

s such as allopregnanolone and pregnanolone)). It has also been found to act as a

negative allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds t ...

of the GABA_A-rho receptor. The steroid has been found to possess 82% of the affinity of progesterone for the progesterone receptor in rhesus monkey

. 5α-Dihydroprogesterone has been said to possess about 33% of the relative progestogenic

potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of how ...

of progesterone. In addition, it is a weak agonist of the

pregnane X receptor In the field of molecular biology, the pregnane X receptor (PXR), also known as the steroid and xenobiotic sensing nuclear receptor (SXR) or nuclear receptor subfamily 1, group I, member 2 (NR1I2) is a protein that in humans is encoded by the ' ...

(PXR) ( EC₅₀ >10,000 μM), with approximately six-fold lower potency relative to its 5β-isomer, 5β-dihydroprogesterone. Allopregnanolone is transformed back into 5α-DHP by 3α-hydroxysteroid oxidoreductase, and conversion of allopregnanolone into 5α-DHP is responsible for the progestogenic activity of allopregnanolone. 5α-DHP, via the progesterone receptor, and allopregnanolone, via the GABA_A receptor, act together to induce

lordosis Lordosis is historically defined as an ''abnormal'' inward curvature of the lumbar spine. However, the terms ''lordosis'' and ''lordotic'' are also used to refer to the normal inward curvature of the lumbar and cervical regions of the human spin ...

in animals. A study found that 41% of allopregnanolone that was administered via injection was transformed into 5α-DHP in the rat brain. Levels of 5α-DHP have been quantified.

Chemistry

References

{{DEFAULTSORT:Dihydroprogesterone, 5α- Neurosteroids Progestogens GABAA receptor positive allosteric modulators GABAA-rho receptor negative allosteric modulators Pregnane X receptor agonists Diketones Pregnanes 5α-Pregnanes

Chemistry

See also

References