Progestin

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Progestins are synthetic[1] progestogens that have progestogenic effects similar to those of progesterone.[2] The two most common uses of progestins are for hormonal contraception (either alone or with an estrogen), and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy. Progestins are also used to treat secondary amenorrhea, dysfunctional uterine bleeding and endometriosis, and as palliative treatment of endometrial cancer, renal cell carcinoma, breast cancer, and prostate cancer. High-dose megestrol acetate is used to treat anorexia, cachexia, and AIDS-related wasting.

Progesterone (or sometimes dydrogesterone or hydroxyprogesterone caproate) is used for luteal support in IVF protocols, questionably for treatment of recurrent pregnancy loss, and for prevention of preterm birth in pregnant women with a history of at least one spontaneous preterm birth.[3]

Progestins are also used in judicial chemical castration of sex offenders and in the treatment of individuals suffering from unwanted sexual urges (e.g., from hypersexuality, paraphilias, etc.) due to their antigonadotropic and thus functional antiandrogen effects.

Examples[edit]

Some examples of progestins that are used in hormonal contraceptives are norethisterone (many brand names, most notably Ortho-Novum and Ovcon), norgestimate (Ortho Tricyclen, Ortho-Cyclen), norgestrel, levonorgestrel (Alesse, Trivora-28, Plan B, Mirena), medroxyprogesterone acetate (Provera, Depo-Provera), cyproterone acetate (Diane-35), desogestrel, etonogestrel (Nexplanon), and drospirenone (Yasmin, Yasminelle, YAZ).

History[edit]

The recognition of progesterone's ability to suppress ovulation during pregnancy spawned a search for a similar hormone that could bypass the problems associated with administering progesterone (e.g. low bioavailability when administered orally and local irritation and pain when continually administered parenterally) and, at the same time, serve the purpose of controlling ovulation. The many synthetic hormones that resulted are known as progestins.

The first orally active progestin, ethisterone (pregneninolone, 17α-ethynyltestosterone), the 17α-ethynyl analog of testosterone, was synthesized in 1938 from dehydroandrosterone by ethynylation, either before or after oxidation of the 3-OH group, followed by rearrangement of the 5,6 double bond to the 4,5 position. The synthesis was designed by chemists Hans Herloff Inhoffen, Willy Logemann, Walter Hohlweg and Arthur Serini at Schering AG in Berlin and was marketed in Germany in 1939 as Proluton C and by Schering in the U.S. in 1945 as Pranone.[4][5][6][7][8]

A more potent orally active progestin, norethisterone (norethindrone, 19-nor-17α-ethynyltestosterone), the 19-nor analog of ethisterone, synthesized in 1951 by Carl Djerassi, Luis Miramontes, and George Rosenkranz at Syntex in Mexico City, was marketed by Parke-Davis in the U.S. in 1957 as Norlutin, and was used as the progestin in some of the first oral contraceptives (Ortho-Novum, Norinyl, etc.) in the early 1960s.[5][5][6][7][8][9]

Noretynodrel, an isomer of norethisterone, was synthesized in 1952 by Frank B. Colton at Searle in Skokie, Illinois and used as the progestin in Enovid, marketed in the U.S. in 1957 and approved as the first oral contraceptive in 1960.[5][6][7][8][10]

Mechanism of action[edit]

Progestins act by binding to and activating the progesterone receptor (PR). Major targets of action include the uterus, the breasts, and the brain. By activating PRs in the hypothalamus and pituitary gland, progestins suppress the secretion of gonadotropins and thereby function as antigonadotropins at sufficient dosages.

Comparison of structural classes[edit]

The different structural classes of progestins have different pharmacological profiles. 19-Norprogesterone and retroprogesterone derivatives tend to be pure progestogens. 17α-Hydroxyprogesterone derivatives tend to have antiandrogen and glucocorticoid properties. Notable exceptions include hydroxyprogesterone caproate, which is a pure progestogen, and medroxyprogesterone acetate, which has weak androgenic actions. 17α-Ethynyltestosterone and 19-nortestosterone derivatives tend to possess weak androgenic actions.[11][12] Gestodene is a 19-nortestosterone derivative with antimineralocorticoid properties. 17α-Spirolactones tend to have antimineralocorticoid and antiandrogen actions. Progesterone itself has potent antimineralocorticoid properties and very weak glucocorticoid actions.

Indications[edit]

In women[edit]

Progestins are used in a variety of different forms of hormonal contraception, including birth control pills, implants, and the intrauterine devices.[13][14]

In women, progestogens are commonly used to prevent endometrial hyperplasia from unopposed estrogen during hormone replacement therapy. They also used to treat secondary amenorrhea, dysfunctional uterine bleeding and endometriosis.[13][14]

In a normal menstrual cycle, declining levels of progesterone triggers menstruation. Norethisterone acetate and medroxyprogesterone acetate may be used to artificially induce progestogen-associated breakthrough bleeding.[15]

Methods of contraception[edit]

It has been found that the most effective method of hormonal contraception is with a combination of an estrogen and a progestin. This can be done in a monophasic, biphasic, or triphasic manner. In the monophasic method, both an estrogen and a progestin are administered for 20 or 21 days and stopped for a 7- or 8-day period that includes the 5-day menstrual period. Sometimes, a 28-day regimen that includes 6 or 7 inert tablets is used. Newer biphasic and triphasic methods are now used to more closely simulate the normal menstrual cycle. Yet another method is to administer a small dose of progestin only (no estrogen) in order to decrease certain risks associated with administering estrogen, but a major side-effect is irregular bleeding usually observed during the first 18 months of such therapy.

Some progestins can be delivered by intra-muscular injection every several months or released over time by diffusion from an implant or an IUD (Intra-Uterine-Device) (intrauterine system) depending on their solubility characteristics.

As antiandrogens[edit]

Main article: Antiandrogen

In addition to their progestogen properties, some progestins are antagonists of the androgen receptor, and can be used clinically as antiandrogens.[16] Examples include chlormadinone acetate, cyproterone acetate, dienogest, drospirenone, megestrol acetate, nomegestrol acetate,[17] and oxendolone.[18][16]

As antigonadotropins[edit]

Progestogens, similarly to the androgens and estrogens through their own respective receptors, inhibit the secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) via activation of the progesterone receptor. This effect is a form of negative feedback on the hypothalamic-pituitary-gonadal (HPG) axis that the body uses to prevent sex hormone levels from becoming too elevated.[19][20][21] Accordingly, progestogens, both endogenous and exogenous (i.e., progestins), have antigonadotropic effects,[22] and progestins in sufficient amounts can markedly suppress the body's normal production of progestogens, androgens, and estrogens, as well as, in theory, neurosteroids.[21] As such, some of the more potent progestins, including chlormadinone acetate,[20] cyproterone acetate, medroxyprogesterone acetate,[23] and megestrol acetate[22] are sometimes used to suppress sex hormone levels in a variety of androgen and estrogen-associated conditions. Examples of indications include treating sex hormone-sensitive cancers (e.g., breast cancer), suppressing precocious puberty and puberty in transgender youth, and reducing sex drive in sex offenders and individuals with paraphilias or hypersexuality.

Cachexia[edit]

Further information: Cachexia

In many people suffering from solid malignancy, especially gastric and pancreatic cancer, high doses of certain progestins can be employed to improve appetite and reduce wasting. In general, they are used in combination with certain other steroids such as dexamethasone. Their effects take several weeks to become apparent, but are relatively long-lived when compared to those of corticosteroids. Furthermore, they are recognized as being the only drugs to increase lean body mass. Megestrol acetate is the lead drug of this class for the management of cachexia, and medroxyprogesterone acetate is also used.[24][25]

Adverse effects[edit]

Androgenic[edit]

Some progestins have androgenic activity and can produce androgenic side effects such as acne, hirsutism, and weight gain, as well as changes in hepatic protein production.[26][27][28] Only certain progestins are androgenic however, these being the testosterone (19-nortestosterone and 17α-ethynyltestosterone) derivatives and, to a lesser extent, medroxyprogesterone acetate;[29] no other progestins have such activity (though some, conversely, possess antiandrogen activity (see above)).[27][30] Moreover, the androgenic activity of progestins within the testosterone derivatives also varies, and while some may have high or moderate androgenic activity, others have only low or no such activity.[31][32]

The androgenic activity of androgenic progestins is mediated by two mechanisms: 1) direct binding to and activation of the androgen receptor; and 2) displacement of testosterone from sex hormone-binding globulin (SHBG), thereby increasing free (and thus bioactive) testosterone levels.[33] The androgenic activity of many androgenic progestins is offset by combination with ethinyl estradiol, which, in contrast, increases SHBG levels, and most oral contraceptives in fact reduce free testosterone levels and can treat or improve acne and hirsutism.[33] An exception is progestin-only contraceptives, which do not also contain an estrogen.[33]

Among the testosterone derivatives, levonorgestrel, norgestrel, norgestrienone, ethisterone,[34] gestrinone,[35] danazol,[35] and normethandrone[36] have the greatest androgenic activity,[31][32][37][34][38] while norethisterone and its esters (norethisterone acetate and norethisterone enanthate) and other prodrugs (lynestrenol, etynodiol diacetate, noretynodrel, quingestanol acetate) and tibolone[39] have moderate activity.[31][32][38][40] Testosterone derivatives with low (but potentially still significant) androgenic activity include desogestrel, etonogestrel, gestodene, and norgestimate,[41][38][40] while norelgestromin,[42] allylestrenol,[43] and dimethisterone[44] have negligible activity. Dienogest and oxendolone are unique among the testosterone derivatives in that they are potent antiandrogens.[45][18]

Glucocorticoid[edit]

Some progestins, mainly certain 17α-hydroxyprogesterone derivatives, have glucocorticoid activity.[46] This can result in side effects such as symptoms of Cushing's syndrome, steroid diabetes, adrenal suppression and insufficiency, and neuropsychiatric side effects like depression, anxiety, and irritability at sufficiently high dosages.[46][47][48] Progestins with the potential for clinically relevant glucocorticoid effects include the 17α-hydroxyprogesterone derivatives chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, and megestrol acetate,[49][50][47] while hydroxyprogesterone caproate, in contrast, possesses no such activity.[51]

List of progestins[edit]

Progestogens by Decade of Introduction[52]
1930s 1950s 1960s 1970s 1980s 1990s 2000s
Ethisterone
Progesterone
Hydroxyprogesterone caproate
Norethisterone
Noretynodrel
Normethandrone
Allylestrenol
Anagestone acetate
Chlormadinone acetate
Dimethisterone
Dydrogesterone
Etynodiol diacetate
Levonorgestrel
Lynestrenol
Medroxyprogesterone acetate
Megestrol acetate
Norethisterone acetate
Norethisterone enanthate
Norgesterone
Norgestrel
Norgestrienone
Norvinisterone
Pentagestrone acetate
Quingestrone
Cyproterone acetate
Danazol
Demegestone
Gestonorone caproate
Quingestanol acetate
Trengestone
Desogestrel
Gestodene
Gestrinone
Medrogestone
Nomegestrol acetate
Norgestimate
Oxendolone
Promegestone
Tibolone
Dienogest
Etonogestrel
Drospirenone
Norelgestromin
Segesterone acetate
Trimegestone

Progestogens by chemical structure[edit]

Progestogens used clinically (and/or in veterinary medicine) can be broadly categorized by chemical structure as follows:[53][54]

Group Members
Progesterone ProgesteroneQuingestrone (prodrug to progesterone)
Retroprogesterone DydrogesteroneTrengestone
17α-Hydroxyprogesterone AlgestoneAlgestone acetophenideChlormadinone acetateCyproterone acetateDelmadinone acetateFlugestone acetate (flurogestone acetate)HydroxyprogesteroneHydroxyprogesterone acetateHydroxyprogesterone caproateHydroxyprogesterone heptanoateMedroxyprogesteroneMedroxyprogesterone acetateMegestrol acetateMelengestrol acetateOsaterone acetatePentagestrone acetate
Other 17α substitutions: Haloprogesterone (17α-bromo) • Medrogestone (17α-methyl) • Proligestone (14α,17α-propylidenedioxy)
19-Norprogesterone
(including 17α-substituted)
DemegestoneGestonorone caproate (gestronol hexanoate)Nomegestrol acetateNorgestometPromegestoneSegesterone acetate (nestorone)Trimegestone
17α-Ethynyltestosterone DanazolDimethisteroneEthisterone
19-Nortestosterone
(and closely related)
AllylestrenolAltrenogestDesogestrelDienogestEtonogestrelEtynodiol diacetateGestodeneGestrinoneLevonorgestrelLynestrenolNorelgestrominNorethisterone (norethindrone)Norethisterone acetateNorethisterone enanthateNoretynodrelNorgesteroneNorgestimateNorgestrelNorgestrienoneNormethandrone (methylestrenolone)NorvinisteroneOxendoloneQuingestanol acetateTibolone
17α-Spirolactosteroid CanrenoneDrospirenonePotassium canrenoateSpironolactone

See also[edit]

References[edit]

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