Progestogen | |
---|---|
Drug class | |
Class identifiers | |
Synonyms | Progestins; Progestagens; Gestagens, |
Use | Contraception, menopause, hypogonadism, transgender women, others |
ATC code | G03D |
Biological target | Progesterone receptors (PRA, PRB, PRC, mPRs (e.g., mPRα, mPRβ, mPRγ, mPRδ, others)) |
External links | |
MeSH | D011372 |
Legal status | |
In Wikidata |
Progestogens, also sometimes written progestins, progestagens or gestagens, [1] are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). [2] [3] Progesterone is the major and most important progestogen in the body. The progestogens are named for their function in maintaining pregnancy (i.e., progestational), although they are also present at other phases of the estrous and menstrual cycles. [2] [3]
The progestogens are one of three types of sex hormones, the others being estrogens like estradiol and androgens/anabolic steroids like testosterone. In addition, they are one of the five major classes of steroid hormones, the others being the androgens, estrogens, glucocorticoids, and mineralocorticoids, as well as the neurosteroids. All endogenous progestogens are characterized by their basic 21-carbon skeleton, called a pregnane skeleton (C21). In similar manner, the estrogens possess an estrane skeleton (C18), and androgens, an androstane skeleton (C19).
The terms progesterone, progestogen, and progestin are mistakenly used interchangeably both in the scientific literature and in clinical settings. [1] [4] [5] Progestins are synthetic progestogens and are used in medicine. [2] Major examples of progestins include the 17α-hydroxyprogesterone derivative medroxyprogesterone acetate and the 19-nortestosterone derivative norethisterone. The progestins are structural analogues of progesterone and have progestogenic activity similarly, but differ from progesterone in their pharmacological properties in various ways. [5]
In addition to their roles as natural hormones, progestogens are used as medications, for instance in menopausal hormone therapy and transgender hormone therapy for transgender women; for information on progestogens as medications, see the progesterone (medication) and progestogen (medication) articles.
The most important progestogen in the body is progesterone (P4). [6] [7] Other endogenous progestogens, with varying degrees of progestogenic activity, include 16α-hydroxyprogesterone (16α-OHP), [8] 17α-hydroxyprogesterone (17α-OHP) (very weak), [9] 20α-dihydroprogesterone (20α-DHP), [10] [11] 20β-dihydroprogesterone (20β-DHP), [11] 5α-dihydroprogesterone (5α-DHP), [12] 5β-dihydroprogesterone (5β-DHP) (very weak), [13] [14] 3β-dihydroprogesterone (3β-DHP), [15] [16] 11-deoxycorticosterone (DOC), [17] and 5α-dihydrodeoxycorticosterone (5α-DHDOC). [18] They are all metabolites of progesterone, lying downstream of progesterone in terms of biosynthesis.
The major tissues affected by progestogens include the uterus, vagina, cervix, breasts, testes, and brain. The main biological role of progestogens in the body is in the female reproductive system, and the male reproductive system, [19] with involvement in regulation of the menstrual cycle, maintenance of pregnancy, and preparation of the mammary glands for lactation and breastfeeding following parturition in women; in men progesterone affects spermiogenesis, sperm capacitation, and testosterone synthesis. Progestogens also have effects in other parts of the body. Unlike estrogens, progestogens have little or no role in feminization. [20]
Progesterone is produced from cholesterol with pregnenolone as a metabolic intermediate. In the first step in the steroidogenic pathway, cholesterol is converted into pregnenolone, which serves as the precursor to the progestogens progesterone and 17α-hydroxyprogesterone. These progestogens, along with another steroid, 17α-hydroxypregnenolone, are the precursors of all other endogenous steroids, including the androgens, estrogens, glucocorticoids, mineralocorticoids, and neurosteroids. Thus, many tissues producing steroids, including the adrenal glands, testes, and ovaries, produce progestogens.
In some tissues, the enzymes required for the final product are not all located in a single cell. For example, in ovarian follicles, cholesterol is converted to androstenedione, an androgen, in the theca cells, which is then further converted into estrogen in the granulosa cells. Fetal adrenal glands also produce pregnenolone in some species, which is converted into progesterone and estrogens by the placenta (see below). In the human, the fetal adrenals produce dehydroepiandrosterone (DHEA) via the pregnenolone pathway.
Sex | Sex hormone | Reproductive phase | Blood production rate | Gonadal secretion rate | Metabolic clearance rate | Reference range (serum levels) | |
---|---|---|---|---|---|---|---|
SI units | Non-SI units | ||||||
Men | Androstenedione | – | 2.8 mg/day | 1.6 mg/day | 2200 L/day | 2.8–7.3 nmol/L | 80–210 ng/dL |
Testosterone | – | 6.5 mg/day | 6.2 mg/day | 950 L/day | 6.9–34.7 nmol/L | 200–1000 ng/dL | |
Estrone | – | 150 μg/day | 110 μg/day | 2050 L/day | 37–250 pmol/L | 10–70 pg/mL | |
Estradiol | – | 60 μg/day | 50 μg/day | 1600 L/day | <37–210 pmol/L | 10–57 pg/mL | |
Estrone sulfate | – | 80 μg/day | Insignificant | 167 L/day | 600–2500 pmol/L | 200–900 pg/mL | |
Women | Androstenedione | – | 3.2 mg/day | 2.8 mg/day | 2000 L/day | 3.1–12.2 nmol/L | 89–350 ng/dL |
Testosterone | – | 190 μg/day | 60 μg/day | 500 L/day | 0.7–2.8 nmol/L | 20–81 ng/dL | |
Estrone | Follicular phase | 110 μg/day | 80 μg/day | 2200 L/day | 110–400 pmol/L | 30–110 pg/mL | |
Luteal phase | 260 μg/day | 150 μg/day | 2200 L/day | 310–660 pmol/L | 80–180 pg/mL | ||
Postmenopause | 40 μg/day | Insignificant | 1610 L/day | 22–230 pmol/L | 6–60 pg/mL | ||
Estradiol | Follicular phase | 90 μg/day | 80 μg/day | 1200 L/day | <37–360 pmol/L | 10–98 pg/mL | |
Luteal phase | 250 μg/day | 240 μg/day | 1200 L/day | 699–1250 pmol/L | 190–341 pg/mL | ||
Postmenopause | 6 μg/day | Insignificant | 910 L/day | <37–140 pmol/L | 10–38 pg/mL | ||
Estrone sulfate | Follicular phase | 100 μg/day | Insignificant | 146 L/day | 700–3600 pmol/L | 250–1300 pg/mL | |
Luteal phase | 180 μg/day | Insignificant | 146 L/day | 1100–7300 pmol/L | 400–2600 pg/mL | ||
Progesterone | Follicular phase | 2 mg/day | 1.7 mg/day | 2100 L/day | 0.3–3 nmol/L | 0.1–0.9 ng/mL | |
Luteal phase | 25 mg/day | 24 mg/day | 2100 L/day | 19–45 nmol/L | 6–14 ng/mL | ||
Notes and sources Notes: "The concentration of a steroid in the circulation is determined by the rate at which it is secreted from glands, the rate of metabolism of precursor or prehormones into the steroid, and the rate at which it is extracted by tissues and metabolized. The secretion rate of a steroid refers to the total secretion of the compound from a gland per unit time. Secretion rates have been assessed by sampling the venous effluent from a gland over time and subtracting out the arterial and peripheral venous hormone concentration. The metabolic clearance rate of a steroid is defined as the volume of blood that has been completely cleared of the hormone per unit time. The production rate of a steroid hormone refers to entry into the blood of the compound from all possible sources, including secretion from glands and conversion of prohormones into the steroid of interest. At steady state, the amount of hormone entering the blood from all sources will be equal to the rate at which it is being cleared (metabolic clearance rate) multiplied by blood concentration (production rate = metabolic clearance rate × concentration). If there is little contribution of prohormone metabolism to the circulating pool of steroid, then the production rate will approximate the secretion rate." Sources: See template. |
Progesterone is the major progestogen produced by the corpus luteum of the ovary in all mammalian species. Luteal cells possess the necessary enzymes to convert cholesterol to pregnenolone, which is subsequently converted into progesterone. Progesterone is highest in the diestrus phase of the estrous cycle.
The role of the placenta in progestogen production varies by species. In the sheep, horse, and human, the placenta takes over the majority of progestogen production, whereas in other species the corpus luteum remains the primary source of progestogens. In the sheep and human, progesterone is the major placental progestogen.
The equine placenta produces a variety of progestogens, primarily 5α-dihydroprogesterone and 5α,20α-tetrahydroprogesterone, beginning on day 60. A complete luteo-placental shift occurs by day 120–150.
The endogenous progestogens are naturally occurring pregnane steroids with ketone and/or hydroxyl groups at the C3 and C20 positions.
Progestogens, including both progesterone and progestins, are used medically in hormonal birth control, hormone therapy, to treat gynecological disorders, to suppress sex hormone levels for various purposes, and for other indications.
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.
Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and signaling cascades. The polypeptide hormones luteinizing hormone, follicle-stimulating hormone and gonadotropin-releasing hormone – each associated with the gonadotropin axis – are usually not regarded as sex hormones, although they play major sex-related roles.
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.
17α-Hydroxyprogesterone (17α-OHP), also known as 17-OH progesterone (17-OHP), or hydroxyprogesterone (OHP), is an endogenous progestogen steroid hormone related to progesterone. It is also a chemical intermediate in the biosynthesis of many other endogenous steroids, including androgens, estrogens, glucocorticoids, and mineralocorticoids, as well as neurosteroids.
Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.
Ethisterone, also known as ethinyltestosterone, pregneninolone, and anhydrohydroxyprogesterone and formerly sold under the brand names Proluton C and Pranone among others, is a progestin medication which was used in the treatment of gynecological disorders but is now no longer available. It was used alone and was not formulated in combination with an estrogen. The medication is taken by mouth.
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.
Medrogestone, sold under the brand name Colprone among others, is a progestin medication which has been used in menopausal hormone therapy and in the treatment of gynecological disorders. It is available both alone and in combination with an estrogen. It is taken by mouth.
Epipregnanolone, also known as 3β-hydroxy-5β-pregnan-20-one, 3β,5β-tetrahydroprogesterone, or 3β,5β-THP, is an endogenous neurosteroid. It acts as a negative allosteric modulator of the GABAA receptor and reverses the effects of potentiators like allopregnanolone. Epipregnanolone is biosynthesized from progesterone by the actions of 5β-reductase and 3β-hydroxysteroid dehydrogenase, with 5β-dihydroprogesterone as the intermediate in this two-step transformation.
20α-Dihydroprogesterone (20α-DHP), also known as 20α-hydroxyprogesterone (20α-OHP), is a naturally occurring, endogenous progestogen. It is a metabolite of progesterone, formed by the 20α-hydroxysteroid dehydrogenases (20α-HSDs) AKR1C1, AKR1C2, and AKR1C3 and the 17β-hydroxysteroid dehydrogenase (17β-HSD) HSD17B1. 20α-DHP can be transformed back into progesterone by 20α-HSDs and by the 17β-HSD HSD17B2. HSD17B2 is expressed in the human endometrium and cervix among other tissues. In animal studies, 20α-DHP has been found to be selectively taken up into and retained in target tissues such as the uterus, brain, and skeletal muscle.
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.
3α-Dihydroprogesterone (3α-DHP), also known as 3α-hydroxyprogesterone, as well as pregn-4-en-3α-ol-20-one, is an endogenous neurosteroid. It is biosynthesized by 3α-hydroxysteroid dehydrogenase from progesterone. 3α-DHP has been found to act as a positive allosteric modulator of the GABAA receptor and is described as being as active as allopregnanolone in regard to this action. In accordance, it has anxiolytic effects in animals. 3α-DHP has also been found to inhibit the secretion of follicle-stimulating hormone (FSH) from the rat pituitary gland, demonstrating possible antigonadotropic properties. Unlike the case of most other inhibitory neurosteroids, 3α-DHP production is not blocked by 5α-reductase inhibitors like finasteride. No data were available on the progestogenic activity of 3α-DHP as of 1977. Levels of 5α-DHP have been quantified.
3β-Dihydroprogesterone (3β-DHP), also known as 3β-hydroxyprogesterone, or pregn-4-en-3β-ol-20-one, is an endogenous steroid. It is biosynthesized by 3β-hydroxysteroid dehydrogenase from progesterone. Unlike 3α-dihydroprogesterone (3α-DHP), 3β-DHP does not act as a positive allosteric modulator of the GABAA receptor, which is in accordance with the fact that other 3β-hydroxylated progesterone metabolites such as isopregnanolone and epipregnanolone similarly do not act as potentiators of this receptor and instead inhibit it as well as reverse the effects of potentiators like allopregnanolone. 3β-DHP has been reported to possess about the same potency as progesterone in a bioassay of progestogenic activity, whereas 3α-DHP was not assessed.
Retroprogesterone, also known as 9β,10α-progesterone or as 9β,10α-pregn-4-ene-3,20-dione, is a progestin which was never marketed. It is a stereoisomer of the naturally occurring progestogen progesterone, in which the hydrogen atom at the 9th carbon is in the α-position instead of the β-position and the methyl group at the 10th carbon is in the β-position instead of the α-position. In other words, the atom positions at the two carbons have been reversed relative to progesterone, hence the name retroprogesterone. This reversal results in a "bent" configuration in which the plane of rings A and B is orientated at a 60° angle below the rings C and D. This configuration is ideal for interaction with the progesterone receptor, with retroprogesterone binding with high affinity to this receptor. However, the configuration is not as ideal for binding to other steroid hormone receptors, and as a result, retroprogesterone derivatives have increased selectivity for the progesterone receptor relative to progesterone.
16α-Hydroxyprogesterone (16α-OHP), also known as 16α-hydroxypregn-4-ene-3,20-dione, is a minor endogenous progestogen steroid hormone and a metabolite of progesterone that is formed in lower amounts than 17α-hydroxyprogesterone (17α-OHP). It occurs in micromolar concentrations and its physiological relevance hence is questionable. However, it may accumulate in target tissues and could have a physiological role in the reproductive system and mammary gland development as well as the cardiovascular and central nervous systems.
5α-Dihydronorethisterone is a major active metabolite of norethisterone (norethindrone). Norethisterone is a progestin with additional weak androgenic and estrogenic activity. 5α-DHNET is formed from norethisterone by 5α-reductase in the liver and other tissues.
Steroidogenic enzymes are enzymes that are involved in steroidogenesis and steroid biosynthesis. They are responsible for the biosynthesis of the steroid hormones, including sex steroids and corticosteroids, as well as neurosteroids, from cholesterol. Steroidogenic enzymes are most highly expressed in classical steroidogenic tissues, such as the testis, ovary, and adrenal cortex, but are also present in other tissues in the body.
20β-Dihydroprogesterone (20β-DHP), also known as 20β-hydroxyprogesterone (20β-OHP), is an endogenous metabolite of progesterone which is formed by 20β-hydroxysteroid dehydrogenase (20β-HSD). It is a progestogen similarly to progesterone, with about 20 to 50% of the progestogenic activity of progesterone. It can be converted by 20β-HSD into progesterone in the uterus. The effects of 20β-HSD on the uterus, mammary glands, and in maintaining pregnancy have been studied. The progestogenic activity of 20β-HSD has also been characterized in women.
The pharmacology of progesterone, a progestogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.
In addition to progesterone, 20α- and 20β-hydroxyprogesterone (20α- and 20β-hydroxy-4-pregnene-3-one) also are found. These compounds have about one-fifth the progestational activity of progesterone in humans and other species.
In the Clauberg bioassay the 3β-hydroxy-4-pregnen-20-one shows about the same potency as progesterone (34). In regard to the biological activity of the 3α epimer no data are available.
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: CS1 maint: multiple names: authors list (link) (the Women's Health, Osteoporosis, Progestin, Estrogen study)