Progestin

Examples

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).

Generations

Contraceptive progestins are sometimes grouped, somewhat arbitrarily and very inconsistently, into generations. One definition of these generations is as follows:

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.

In women

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

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.

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.

Contraceptive methods

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 IUD (Intra-Uterine-Device) (intrauterine system) depending on their solubility characteristics.

As antiandrogens

In addition to their progestogenic activity, some progestins are antagonists of the androgen receptor and can be used therapeutically as antiandrogens. 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.

As antigonadotropins

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. Accordingly, progestogens, both endogenous and exogenous (i.e., progestins), have antigonadotropic effects, and progestins in sufficient amounts can markedly suppress the body's normal production of progestogens, androgens, and estrogens, as well as, in theory, neurosteroids. As such, certain progestins, including chlormadinone acetate, cyproterone acetate, gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate, 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, prostate cancer, endometrial cancer), benign prostatic hyperplasia, suppressing precocious puberty and puberty in transgender youth, suppressing sex hormone production in transgender patients, and reducing sex drive in sex offenders and individuals with paraphilias or hypersexuality. Cyproterone acetate and gestonorone caproate have been found to suppress circulating testosterone levels by up to 70–80% in men at sufficient dosages. This is notably less than that achieved by GnRH analogues, which effectively abolish gonadal production of testosterone and suppress circulating testosterone levels by as much as 95%. In addition, it is less than that achieved by estrogens, which can suppress testosterone levels into the castrate range at sufficiently high dosages similarly to GnRH analogues.

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.

Adverse effects

Agonists of the PR have relatively few side effects at typical dosages. Many of the side effects of progestins are due not to their progestogenic activity but rather to off-target activity, namely activity at other steroid hormone receptors like the androgen, estrogen, and glucocorticoid receptors (described below). At high dosages, progestins also have potent antigonadotropic effects via PR hyperactivation, and can produce prominent side effects related to hypogonadism in premenopausal women and in men.

Androgenic

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. Only certain progestins are androgenic however, these being the testosterone (19-nortestosterone and 17α-ethynyltestosterone) derivatives and, to a lesser extent, medroxyprogesterone acetate; no other progestins have such activity (though some, conversely, possess antiandrogen activity (see above)). 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, in contrast, increases SHBG levels, and most oral contraceptives in fact 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.

Among the testosterone derivatives, and in no particular order, levonorgestrel, norgestrel, norgestrienone, ethisterone, gestrinone, danazol, tibolone, normethandrone, and norvinisterone have the greatest androgenic activity, while norethisterone and its prodrugs (norethisterone acetate, norethisterone enanthate, lynestrenol, etynodiol diacetate, and quingestanol acetate) have moderate activity. Testosterone derivatives with low (but potentially still significant) androgenic activity include desogestrel, etonogestrel, gestodene, and norgestimate, while norelgestromin, noretynodrel, norgesterone, allylestrenol, and dimethisterone appear to have negligible activity. Dienogest and oxendolone are unique among the testosterone derivatives in that they are potent antiandrogens.

Estrogenic

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. 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

Some progestins, mainly certain 17α-hydroxyprogesterone derivatives, have 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, and irritability. Progestins with the potential for clinically relevant glucocorticoid effects include the 17α-hydroxyprogesterone derivatives chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, and megestrol acetate. Hydroxyprogesterone caproate (another 17α-hydroxyprogesterone derivative), in contrast, possesses no such activity.

Mechanism of action

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.

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, 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.

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.

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.