Progesterone is an endogenous steroid and sex hormone involved in the menstrual cycle, pregnancy and embryogenesis of humans and other species. Progesterone is a natural substance, which is produced by the corpus luteum for maintenance of pregnancy. It acts on the endometrium, decreases estrogen receptors and mitotic activity and develops the stromal component of the endometrium. This prepares the endometrium for future prostaglandin production, permitting complete uniform shedding at the time of progesterone withdrawal. In larger doses it decreases the effect of estrogen which includes epithelial stimulation of endometrium, breast and metabolic activities. The parent compound has limitations for clinical utility because of poor absorption, rapid hepatic inactivation and transient intramuscular action. Various progesterone like or progestational agents have been synthesized and called progestogens, progestins or gestagens. While the progestins are structural analogues of progesterone, they are not functional analogues, and differ from progesterone considerably in their properties.1,2
Progestogens, are a class of steroid hormones that bind to and activate the progesterone receptor (PR).3 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.4,5 They are one of three types of sex hormones, the others being estrogens like estradiol and androgens/anabolic steroids like testosterone. The progestogens are one of the five major classes of steroid hormones, in addition to 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 most important progestogen in the body is progesterone (P4).6,7 Other endogenous progestogens include 16α-hydroxyprogesterone, 17α-hydroxyprogesterone, 20α-dihydroprogestero, 5α-dihydroprogesterone, 11-deoxycorticosterone, and 5α-dihydrodeoxycorticosterone.8-13
Major examples of progestins include the 17α-hydroxyprogesterone derivative medroxyprogesterone acetate and the 19-nortestosterone derivative norethisterone (norethindrone).
It is on the WHO model list of “Essential Medicines”, the most important medications needed in a basic health system. Progestins are widely used for various indications from menarche to pregnancy and menopause. A wide variety of progestational compounds are existing in the market and different agents are used for different medical conditions and indications. This monogram is an endeavor to elucidate the rational choice and use of progestins in various gynecological disorders.
It was in 1923 that the hormonal action of progesterone was discovered.14-16 It was then known by the name of luteosterone, as it was known to be produced by the corpus luteum of ovaries. Purification of progesterone was the work of several investigators between 1928 and 1934. WM Allen, an American gynecologist and GW Corner, his Anatomy professor isolated the hormone progesterone in 1929 while working in embryology laboratory at the University of Rochester. They are credited with the discovery and the first isolation of pure progesterone from the waxy material obtained by high-vacuum distillation from the corpus luteum extracts of animals. In 1930 they pioneered and used corpus luteum extracts to maintain pregnancy after early ablation of rabbit ovaries.
By 1932, crystalline material of high progestational activity had been isolated from the corpus luteum of animals. By 1934, the extraction of progesterone from urine was accomplished and the chemical structure of progesterone was determined by professor Adolf Butenandt at the Chemisches Institute of Technical University in Gdańsk, Poland.14,15,17 Later that year it was chemically synthesized from stigmasterol and pregnanediol.15,18 Professor Butenandt received the Nobel Prize for Chemistry in 1939 for the discovery and identification of progesterone, estrogen and androsterone. He initially rejected the award in accordance with government policy, but accepted it in 1949 after World War II.
In 1935, in the Second International Conference on the Standardization of Sex Hormones in London, England, organized under the chairmanship of Sir Henry Dale to discuss the terminology and standard tests for the “second” female sex hormone, the name progesterone (derived from the three words—progestational steroidal ketone) was accepted for common use in scientific literature.14,19
Shortly after this, progesterone began being tested clinically in women.15 In 1934, Schering introduced progesterone, as a pharmaceutical drug, under the brand name Proluton, along with estradiol (brand name Progynon) and testosterone (brand names Testoviron, Proviron).20,21 The parent compound had its limitations for clinical utility viz. poor oral absorption, rapid hepatic inactivation and transient intramuscular action. With the aim to overcome these limitations, synthesis of progesterone-like or progestational agents was attempted and 17-hydroxy-progesterone caproate was the first progestin obtained. It required parenteral administration.
In 1943, Russel Marker, an American chemist, synthesized progesterone from diosgenin derived from Mexican yam roots which considerably brought down its cost. In 1950, synthesis of C-21 steroid medroxyprogesterone acetate and related compounds megestrol acetate and chlormadinone yielded highly potent and orally active agents. It was demonstrated in 1951 that removal of the 19-carbon from ethisterone to form norethindrone changed its hormonal effect from androgenic to that of a progestational agent which is orally active. These compounds were appropriately termed as 19-nortestosterones and they were not totally free from androgenic and anabolic properties. In 1952, chemists in USA and Mexico synthesized derivatives of 17-ethinyl-19-nortestosterone, which yielded powerful orally active progestogens. Substitutions of an 18-ethyl group are among the most widely used progestogens today.
The process of micronization of progesterone allowed its better and more effective absorption via other routes of administration. Oral micronized progesterone was marketed in 1980 in France under the brand name Utrogestan and this was followed by the introduction of oral micronized progesterone in the United States under the brand name Prometrium in 1998.21-24 In the early 1990s, vaginal micronized progesterone (brand names Crinone, Utrogestan, Endometrin) was also marketed.25,26
Progesterone was approved by the United States Food and Drug Administration (USFDA) as vaginal gel on July 31, 1997, an oral capsule on May 14, 1998 in an injection form on April 25, 2001 and as a vaginal insert on June 21, 2007.27-30
Progesterone is marketed under a large number of different brand names throughout the world.31 Progesterone, when taken orally, has very poor pharmacokinetics, including low bioavailability (only about 10–15% reaches the bloodstream) and a half-life of only about 5 minutes, unless it is micronized.7,11,32 As such, it is sold in the form of oil-filled capsules containing micronized progesterone for oral use (Utrogestan, Prometrium, Microgest), termed oral micronized progesterone (OMP).7,31
Progesterone is also available in the forms of vaginal or rectal suppositories or pessaries (Cyclogest), transdermally-administered gels or creams (Crinone, Endometrin, Progestogel, Prochieve), or via intramuscular or subcutaneous injection of a vegetable oil solution (Progesterone, Strone).7,31,33,34
Transdermal products made with progesterone United States Pharmacopeia (i.e. “natural progesterone”) do not require a prescription. Some of these products also contain “wild yam extract” derived from Dioscorea villosa, but there is no evidence that the human body can convert its active ingredient (diosgenin, the plant steroid that is chemically converted to produce progesterone industrially) into progesterone.35-37