Progestin

Progestins are synthetic progestogens that have progestogenic effects similar to those of progesterone. 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.

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.).

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 (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, synthesized in 1938 from dehydroandrosterone by adding acetylene either before or after oxidation of the 3-OH group to the ketone, with rearrangement of the 5,6 double bond to the 4,5 position, by Hans Herloff Inhoffen, Willy Logemann, Walter Hohlweg and Arthur Serini at Schering AG in Berlin, 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.

Examples

Some examples of progestins that have been used in hormonal contraceptives are noretynodrel (Enovid), 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), desogestrel, etonogestrel (Nexplanon), and drospirenone (Yasmin, Yasminelle, YAZ).

Progestins have been somewhat inconsistently grouped into "generations" in the medical literature based on when they were introduced:

• First: ethisterone, norethisterone, norethisterone acetate, noretynodrel, etynodiol diacetate, medroxyprogesterone acetate, megestrol acetate
• Second: norgestrel, levonorgestrel
• Third: norgestimate, norelgestromin, desogestrel, etonogestrel, gestodene
• Fourth: dienogest, drospirenone, nestorone, nomegestrol acetate, trimegestone

New, non-steroidal progestins such as tanaproget, with improved potency and selectivity for the PR, have also been recently discovered, and are being investigated for clinical use.

Classification by structure

Progestins used clinically (and/or in veterinary medicine) can be broadly categorized by chemical structure as follows:

• Retroprogesterone: dydrogesterone, trengestone
• 17α-Hydroxyprogesterone: algestone, algestone acetophenide, chlormadinone acetate, cyproterone acetate, delmadinone acetate, hydroxyprogesterone acetate, hydroxyprogesterone caproate, hydroxyprogesterone heptanoate, medroxyprogesterone, medroxyprogesterone acetate, megestrol acetate, melengestrol acetate
  • Other substitutions: haloprogesterone (17α-bromo), medrogestone (17α-methyl), proligestone (14α,17α-propylidenedioxy)
• 19-Norprogesterone: demegestone, gestonorone caproate, nestorone, nomegestrol acetate, norgestomet, promegestone, trimegestone
• 17α-Ethynyltestosterone: dimethisterone, ethisterone
• 19-Nortestosterone: allylestrenol, altrenogest, desogestrel, dienogest, etonogestrel, etynodiol diacetate, gestodene, gestrinone, levonorgestrel, lynestrenol, norelgestromine, norethandrolone, norethisterone (norethindrone), norethisterone acetate, norethisterone enanthate, noretynodrel, norgesterone, norgestimate, norgestrel, norgestrienone, normethandrone (methylestrenolone), norvinisterone, quingestanol acetate, tibolone, trenbolone
• 17α-Spirolactone: canrenone, drospirenone, potassium canrenoate, spironolactone

Comparison

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. A notable exception is hydroxyprogesterone caproate, which is a pure progestogen. Another notable exception is medroxyprogesterone acetate, which has weak androgenic actions. 17α-Ethynyltestosterone and 19-nortestosterone derivatives often possess weak androgenic actions. Gestodene is a 19-nortestosterone derivative with antimineralocorticoid properties. Spirolactones tend to have antimineralocorticoid and antiandrogen actions. Progesterone itself has antimineralocorticoid properties and very weak glucocorticoid actions.

Methods of progestin-based contraception

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.

See also

• Diethylstilbestrol
• List of steroid abbreviations
• Progesterone receptor
• Progestin challenge
• Progestin implant
• Progestin-induced virilisation
• Progestin-only pill
• Progestogen only contraception
• Phytoprogestogen