A progestin is a type of medication which is used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestins are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration.
Side effects of progestins include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth, and changes in liver protein production among others. Other side effects of progestins include an increased risk of breast cancer, cardiovascular disease, and blood clots. At high dosages, progestins can cause low sex hormone levels and associated side effects like sexual dysfunction and an increased risk of bone fractures.
Progestins are synthetic progestogens and have similar effects to those of the natural hormone progesterone. They act as agonists of the progesterone receptor and have important effects in the female reproductive system (uterus, cervix, and vagina), the breasts, and the brain. In addition, many progestins also have other hormonal activities, such as androgenic, antiandrogenic, estrogenic, glucocorticoid, or antimineralocorticoid activity. They also have antigonadotropic effects and at sufficiently high dosages can strongly suppress sex hormone production. Progestins mediate their contraceptive effects both by inhibiting ovulation and by thickening cervical mucus, thereby preventing fertilization. They have functional antiestrogenic effects in certain tissues like the endometrium and this underlies their use in menopausal hormone therapy.
Progestins were first introduced for medical use in 1939. They started to be used in birth control in the 1950s. Around 60 progestins have been marketed for clinical use in humans or use in veterinary medicine. These progestins can be grouped into different classes and generations. Progestins are available widely throughout the world and are used in all forms of hormonal birth control and in most menopausal hormone therapy regimens.
Video Progestin
Medical uses
Birth control
Progestins are used in a variety of different forms of hormonal birth control, including combined estrogen and progestogen forms like combined birth control pills, patches, and combined injectables; progestogen-only forms like progestin-only pills, implants, and intrauterine devices; and mixed forms like rings.
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 intramuscular injection every several months or released over time by diffusion from an implant or an intrauterine device depending on their solubility characteristics.
Combined androgen and progestin birth control regimens have been studied for use in men.
Hormone therapy
Progestins are commonly used as a component of menopausal hormone therapy in women to prevent endometrial hyperplasia and increased risk of endometrial cancer from unopposed estrogen therapy. They are also used in transgender hormone therapy, including in both feminizing hormone therapy for transgender women (e.g., cyproterone acetate and medroxyprogesterone acetate to help suppress testosterone levels) and masculinizing hormone therapy in transgender men (e.g., medroxyprogesterone acetate to help suppress menses).
Certain progestins, including megestrol acetate, medroxyprogesterone acetate, cyproterone acetate, and chlormadinone acetate have been used to reduce hot flashes in men with prostate cancer.
Gynecological disorders
Progestins are used to treat gynecological disorders such as secondary amenorrhea, dysfunctional uterine bleeding, and endometriosis. 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.
Fertility medicine
Progestogens are used in fertility medicine for women. For example, progesterone (or sometimes dydrogesterone or hydroxyprogesterone caproate) is used for luteal support in in-vitro fertilization protocols.
Pregnancy support
Certain progestins are used to support pregnancy, including hydroxyprogesterone caproate, dydrogesterone, and allylestrenol. They are used 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.
Sex-hormone suppression
Certain progestins are used at high doses to suppress sex hormone production and levels as a form of medical castration for a variety of androgen and estrogen-dependent conditions. Examples of indications include treating hormone-sensitive cancers (e.g., breast cancer, prostate cancer, endometrial cancer), benign prostatic hyperplasia, blocking precocious puberty and puberty in transgender youth, lowering sex hormone levels in transgender people and reducing sex drive in men with sexual deviance such as in sex offenders, paraphilias, and hypersexuality. Progestins that have been used for such purposes include chlormadinone acetate, cyproterone acetate, gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate.
Some progestins are also antiandrogens, for instance cyproterone acetate, and can be used to treat androgen-dependent conditions like acne and hirsutism in women.
Appetite stimulation
Certain progestins can be used at very high dosages to increase appetite in conditions like cachexia, anorexia, and wasting syndromes. In general, they are used in combination with certain other steroid medications 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. The mechanism of action of the appetite-related effects of these two drugs is unknown and may not be related to their progestogenic activity.
Available forms
Progestins are available in the form of oral tablets, solutions and suspensions for intramuscular or subcutaneous injection, and a number of other forms (e.g., transdermal patches, vaginal rings, intrauterine devices, subcutaneous implants).
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), levonorgestrel (Alesse, Trivora-28, Plan B, Mirena), medroxyprogesterone acetate (Provera, Depo-Provera), cyproterone acetate (Diane-35), desogestrel, etonogestrel (Nexplanon), and drospirenone (Yasmin, Yasminelle, YAZ).
Maps Progestin
Side effects
Progestogens have relatively few side effects at typical dosages. Side effects of progestins include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth, and changes in liver protein production among others. Other side effects of progestins include an increased risk of breast cancer, cardiovascular disease, and blood clots among others. Some of the side effects of progestins are due not to their progestogenic activity but rather due to off-target activities (e.g., androgenic activity, glucocorticoid activity). At high dosages, due to their antigonadotropic effects, progestins can cause low sex hormone levels and associated side effects like diminished secondary sexual characteristics, sexual dysfunction (e.g., reduced sex drive and erectile dysfunction), reversible infertility, reduced bone mineral density, and an increased risk of bone fractures, both in men and in premenopausal women.
Pharmacology
Progestins act by binding to and activating the progesterone receptors (PRs), including the PR-A, PR-B, and PR-C. Major tissues affected by progestogens include the uterus, cervix, vagina, breasts, and brain. By activating PRs in the hypothalamus and pituitary gland, progestins suppress the secretion of gonadotropins and thereby function as antigonadotropins at sufficiently high dosages. Interaction of progestins with membrane progesterone receptors is less clear. Progestins mediate their contraceptive effects in women both by inhibiting ovulation (via their antigonadotropic effects) and by thickening cervical mucus, thereby preventing the possibility of fertilization of the ovum by sperm. Progestins have functional antiestrogenic effects in various tissues like the endometrium via activation of the PR, and this underlies their use in menopausal hormone therapy (to prevent unopposed estrogen-induced endometrial hyperplasia and endometrial cancer).
Antigonadotropic effects
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 PR in the pituitary gland. This effect is a form of negative feedback on the hypothalamic-pituitary-gonadal axis (HPG axis) and takes advantage of the mechanism that the body uses to prevent sex hormone levels from becoming too high. Accordingly, progestogens, both endogenous and exogenous (i.e., progestins), have antigonadotropic effects, and progestins in sufficiently high amounts can markedly suppress the body's normal production of progestogens, androgens, and estrogens as well as inhibit fertility (ovulation in women and spermatogenesis in men).
Progestins have been found to maximally suppress circulating testosterone levels in men by up to 70 to 80% at sufficiently high dosages. This is notably less than that achieved by GnRH analogues, which can effectively abolish gonadal production of testosterone and suppress circulating testosterone levels by as much as 95%. It is also less than that achieved by high-dose estrogen therapy, which can suppress testosterone levels into the castrate range similarly to GnRH analogues.
Dydrogesterone is an atypical progestin and does not have antigonadotropic effects nor inhibit ovulation even at very high dosages. It is the only clinically used progestin that is known to lack such effects, and also shows a number of other atypical properties. This may be related to selective agonism of the PR-B.
Off-target activities
In addition to their progestogenic activity, functional antiestrogenic effects, and antigonadotropic effects, many progestins have off-target activities such as androgenic, antiandrogenic, estrogenic, glucocorticoid, or antimineralocorticoid activity. Such actions can contribute both to their beneficial or desirable effects and to their side effects.
Androgenic activity
Some progestins have androgenic activity and can produce androgenic side effects such as increased sebum production (oilier skin), acne, and hirsutism (excessive facial/body hair growth), as well as changes in liver protein production. Only certain progestins are androgenic however, these being the testosterone derivatives and, to a lesser extent, the 17?-hydroxyprogesterone derivatives medroxyprogesterone acetate and megestrol acetate. No other progestins have such activity (though some, conversely, possess antiandrogenic activity). 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.
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. The androgenic activity of many androgenic progestins is offset by combination with ethinylestradiol, which robustly increases SHBG levels, and most oral contraceptives in fact markedly reduce free testosterone levels and can treat or improve acne and hirsutism. An exception is progestin-only contraceptives, which do not also contain an estrogen.
The androgenic activity of testosterone-derivative progestins and progestins that have androgenic activity can be roughly ranked as follows:
- Very high: danazol, ethisterone, gestrinone, normethandrone, norvinisterone
- High: levonorgestrel, norgestrel, norgestrienone, tibolone
- Moderate: norethisterone and its prodrugs (norethisterone acetate, norethisterone enanthate, etynodiol diacetate, lynestrenol, quingestanol acetate)
- Low: desogestrel, etonogestrel, gestodene, norgestimate
- Very low or negligible: allylestrenol, dimethisterone, medroxyprogesterone acetate, megestrol acetate, norelgestromin, noretynodrel, norgesterone
- Antiandrogenic: dienogest, oxendolone
It should be noted however that the clinical androgenic and anabolic activity of the androgenic progestins listed above is still far lower than that of conventional androgens and anabolic steroids like testosterone and nandrolone esters. As such, they are only generally associated with such effects in women and often only at high dosages. In men, due to their concomitant progestogenic activity and by extension antigonadotropic effects, these progestins can have potent functional antiandrogenic effects via suppression of testosterone production and levels.
Antiandrogenic activity
Some progestins have antiandrogenic activity in addition to their progestogenic activity. These progestins, with varying degrees of potency as antiandrogens, include chlormadinone acetate, cyproterone acetate, dienogest, drospirenone, medrogestone, megestrol acetate, nomegestrol acetate, osaterone acetate (veterinary), and oxendolone. The relative antiandrogenic activity in animals of some of these progestins has been ranked as follows: cyproterone acetate (100%) > nomegestrol acetate (90%) > dienogest (30-40%) >= chlormadinone acetate (30%) = drospirenone (30%). Antiandrogenic activity in certain progestins may help to improve symptoms of acne, seborrhea, hirsutism, and other androgen-dependent conditions in women.
Estrogenic activity
A few progestins have weak estrogenic activity. These include the 19-nortestosterone derivatives norethisterone, noretynodrel, and tibolone, as well as the norethisterone prodrugs norethisterone acetate, norethisterone enanthate, lynestrenol, and etynodiol diacetate. The estrogenic activity of norethisterone and its prodrugs are due to metabolism into ethinylestradiol. High dosages of norethisterone and noretynodrel have been associated with estrogenic side effects such as breast enlargement in women and gynecomastia in men, but also with alleviation of menopausal symptoms in postmenopausal women. In contrast, non-estrogenic progestins were not found to be associated with such effects.
Glucocorticoid activity
Some progestins, mainly certain 17?-hydroxyprogesterone derivatives, have weak glucocorticoid activity. This can result, at sufficiently high dosages, in side effects such as symptoms of Cushing's syndrome, steroid diabetes, adrenal suppression and insufficiency, and neuropsychiatric symptoms like depression, anxiety, irritability, and cognitive impairment. Progestins with the potential for clinically relevant glucocorticoid effects include the 17?-hydroxyprogesterone derivatives chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, and megestrol acetate and the testosterone derivative gestodene. Conversely, hydroxyprogesterone caproate possesses no such activity, while progesterone itself has very weak glucocorticoid activity.
Antimineralocorticoid activity
Certain progestins, including drospirenone and gestodene and to a lesser extent dydrogesterone and trimegestone, have varying degrees of antimineralocorticoid activity. Progesterone itself has potent antimineralocorticoid activity. No clinically used progestins are known to have mineralocorticoid activity. Progestins with potent antimineralocorticoid activity like drospirenone may have properties more similar to those of natural progesterone, such as counteraction of cyclical estrogen-induced sodium and fluid retention, edema, and associated weight gain; lowered blood pressure; and possibly improved cardiovascular health.
Chemistry
All currently available progestins are steroids. They include the pregnanes (e.g., dydrogesterone, medroxyprogesterone acetate) and norpregnanes (e.g., nomegestrol acetate), which are derivatives of progesterone, and the androstanes (e.g., danazol, ethisterone) and estranes (e.g., norethisterone, levonorgestrel), which are testosterone derivatives. These groups can be further divided into various subgroups.
History
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, 17?-ethynyltestosterone), the 17?-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.
A more potent orally active progestin, norethisterone (norethindrone, 19-nor-17?-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.
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.
Society and culture
Generations
Progestins used in birth control are sometimes grouped, somewhat arbitrarily and fairly inconsistently, into generations. One definition of these generations is as follows:
- First generation: Approved for marketing before 1973. Examples: noretynodrel, norethisterone (norethindrone), lynestrenol, levonorgestrel.
- Second generation: Approved for marketing between 1973 and 1989. Examples: desogestrel, nomegestrol acetate, norgestimate.
- Third generation: Approved for marketing between 1990 and 2000. Examples: dienogest, etonogestrel.
- Fourth generation: Approved for marketing after 2000. Examples: drospirenone, norelgestromin, segesterone acetate (nestorone).
Alternatively, estranes such as noretynodrel and norethisterone are classified as first-generation while gonanes such as norgestrel and levonorgestrel are classified as second-generation, with less androgenic gonanes such as desogestrel, norgestimate, and gestodene classified as third-generation and newer progestins like drospirenone classified as fourth-generation. Yet another classification system considers there to be only first- and second-generation progestins.
Availability
Progestins are available widely throughout the world in many different forms. They are present in all birth control pills.
Research
A variety of progestins have been studied for use as potential male hormonal contraceptives in combination with androgens in men. These include the pregnanes medroxyprogesterone acetate and cyproterone acetate, the norpregnane segesterone acetate, and the estranes norethisterone acetate, norethisterone enanthate, levonorgestrel, levonorgestrel butanoate, desogestrel, and etonogestrel. The androgens that have been used in combination with these progestins include testosterone, testosterone esters, androstanolone (dihydrotestosterone), nandrolone esters, and trestolone.
See also
- Comparison of progestogens
- Phytoprogestogen
- Progestin challenge
References
Source of the article : Wikipedia
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