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 major progestogen in the body. Progesterone has a variety of important functions in the body. It is also a crucial metabolic intermediate in the production of other endogenous steroids, including the sex hormones and the corticosteroids, and plays an important role in brain function as a neurosteroid.
Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineralocorticoids. In addition, pregnenolone is biologically active in its own right, acting as a neurosteroid.
Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term neurosteroid was coined by the French physiologist Étienne-Émile Baulieu and refers to steroids synthesized in the brain. The term, neuroactive steroid refers to steroids that can be synthesized in the brain, or are synthesized by an endocrine gland, that then reach the brain through the bloodstream and have effects on brain function. The term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy. In addition to their actions on neuronal membrane receptors, some of these steroids may also exert effects on gene expression via nuclear steroid hormone receptors. Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy and traumatic brain injury. Ganaxolone, a synthetic analog of the endogenous neurosteroid allopregnanolone, is under investigation for the treatment of epilepsy.
Allopregnanolone, also known as brexanolone, is a naturally produced steroid that acts on the brain. As a medication, it is sold under the brand name Zulresso and used to treat postpartum depression. It is used by injection into a vein over a 60-hour period under medical supervision.
5α-Dihydroprogesterone is an endogenous progestogen and neurosteroid that is synthesized from progesterone. It is also an intermediate in the synthesis of allopregnanolone and isopregnanolone from progesterone.
In pharmacology, GABAA receptor positive allosteric modulators are positive allosteric modulator (PAM) molecules that increase the activity of the GABAA receptor protein in the vertebrate central nervous system.
Membrane progesterone receptors (mPRs) are a group of cell surface receptors and membrane steroid receptors belonging to the progestin and adipoQ receptor (PAQR) family which bind the endogenous progestogen and neurosteroid progesterone, as well as the neurosteroid allopregnanolone. Unlike the progesterone receptor (PR), a nuclear receptor which mediates its effects via genomic mechanisms, mPRs are cell surface receptors which rapidly alter cell signaling via modulation of intracellular signaling cascades. The mPRs mediate important physiological functions in male and female reproductive tracts, liver, neuroendocrine tissues, and the immune system as well as in breast and ovarian cancer.
A neurosteroidogenesis inhibitor is a drug that inhibits the production of endogenous neurosteroids. Neurosteroids include the excitatory neurosteroids pregnenolone sulfate, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S), and the inhibitory neurosteroids allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 3α-androstanediol, among others. By inhibiting the synthesis of endogenous neurosteroids, neurosteroidogenesis inhibitors have effects in the central nervous system.
5β-Dihydroprogesterone is an endogenous neurosteroid and an intermediate in the biosynthesis of pregnanolone and epipregnanolone from progesterone. It is synthesized from progesterone by the enzyme 5β-reductase.
A progestogen ester is an ester of a progestogen or progestin. The prototypical progestogen is progesterone, an endogenous sex hormone. Esterification is frequently employed to improve the pharmacokinetics of steroids, including oral bioavailability, lipophilicity, and elimination half-life. In addition, with intramuscular injection, steroid esters are often absorbed more slowly into the body, allowing for less frequent administration. Many steroid esters function as prodrugs.
Progesterone (P4) is a medication and naturally occurring steroid hormone. It is a progestogen and is used in combination with estrogens mainly in hormone therapy for menopausal symptoms and low sex hormone levels in women. It is also used in women to support pregnancy and fertility and to treat gynecological disorders. Progesterone can be taken by mouth, in through the vagina, and by injection into muscle or fat, among other routes. A progesterone vaginal ring and progesterone intrauterine device used for birth control also exist in some areas of the world.
Progesterone 3-acetyl enol ether, also known as progesterone acetate, as well as 3-acetoxypregna-3,5-dien-20-one, is a progestin which was never marketed. It was reported to possess similar potency to progesterone and hydroxyprogesterone caproate in the rabbit endometrial carbonic anhydrase test, a bioassay of progestogenic activity. In addition, it was able to maintain pregnancy in animals. Progesterone 3-acetyl enol ether is closely related to quingestrone, which is also known as progesterone 3-cyclopentyl enol ether and was formerly marketed as an oral contraceptive.
EIDD-1723, also known as EPRX-01723 or as progesterone 20E-[O-[(phosphonooxy)methyl]oxime] sodium salt, is a synthetic, water-soluble analogue of progesterone and a neurosteroid which was developed for the potential treatment of traumatic brain injury. It is a rapidly converted prodrug of EIDD-036, which is considered to be the active form of the agent. Previous C3 and C20 oxime derivatives of progesterone, such as P1-185, were also developed and studied prior to EIDD-1723.
EIDD-036, also known as EPRX-036, as well as progesterone 20-oxime (P4-20-O) or 20-(hydroxyimino)pregn-4-en-3-one, is a synthetic, water-soluble analogue of progesterone, a neurosteroid, and the active metabolite of EIDD-1723 (EPRX-01723), a medication developed for the potential treatment of traumatic brain injury.
VOLT-02 is a water-soluble conjugate of progesterone and a neurosteroid which is under development by Levolta Pharmaceuticals for the treatment of traumatic brain injury, gynecological disorders, and menstrual disorders. As of March 2017, it is in phase II clinical trials for these indications. The chemical structure of VOLT-02 does not appear to have been released yet.
Progesterone carboxymethyloxime, or progesterone 3-(O-carboxymethyl)oxime (P4-3-CMO), is a progestin which was never marketed. It is an oral prodrug of progesterone with improved pharmacokinetic properties. The compound was developed in an attempt to address the poor oral pharmacokinetics of progesterone, including its very low bioavailability and short biological half-life. These properties of progesterone are thought to be caused by its low water solubility and high metabolic clearance rate due to rapid degradation in the intestines and liver. Drugs with low aqueous solubility are not absorbed well in the intestines because their dissolution in water is limited.
Progesterone dioxime, or progesterone 3,20-dioxime (P4-3,20-DO), also known as 3,20-di(hydroxyimino)pregn-4-en-3-one, is a progesterone derivative which was never marketed. It is a progestogen oxime – specifically, the C3 and C20 dioxime of the progestogen progesterone. Progesterone C3 and C20 oxime conjugates have been found to be water-soluble prodrugs of progesterone and pregnane neurosteroids.
Progesterone 3-oxime (P4-3-O), also known as 3-(hydroxyimino)pregn-4-en-3-one, is a progesterone derivative which was never marketed. It is a progestogen oxime – specifically, the C3 oxime of the progestogen progesterone. Progesterone C3 and C20 oxime conjugates, like progesterone 3-(O-carboxymethyl)oxime, have been found to be water-soluble prodrugs of progesterone and pregnane neurosteroids.
