Discovery and synthesis The hormonal action of progesterone was discovered in 1929. Pure crystalline progesterone was isolated in 1934 and its
chemical structure was determined. Shortly following its chemical synthesis, progesterone began being tested clinically in women. This was the first
pharmaceutical formulation of progesterone to be marketed for medical use. It was initially a
corpus luteum extract, becoming pure synthesized progesterone only subsequently. A clinical study of the formulation was published in 1933. Multiple formulations of progesterone in oil solution for intramuscular injection, under the brand names Proluton, Progestin, and Gestone, were available by 1936. A parenteral route was used because oral progesterone had very low activity and was thought to be inactive. However, with the start of steroid manufacturing from
diosgenin in the 1940s, costs greatly decreased. Subcutaneous pellet implants of progesterone were first studied in women in the late 1930s. They were the first long-acting progestogen formulation. Pellets were reported to be extruded out of the skin within a few weeks at high rates, even when implanted beneath the
deep fascia, and also produced frequent inflammatory reactions at the site of implantation.
Aqueous suspensions of progesterone
crystals for
intramuscular injection were first described in 1944. These preparations were on the market in the 1950s under a variety of brand names including Flavolutan, Luteosan, Lutocyclin M, and Lutren, among others. Aqueous suspensions of steroids were developed because they showed much longer
durations than intramuscular injection of steroids in
oil solution. However, local
injection site reactions, which do not occur with
oil solutions, have limited the clinical use of aqueous suspensions of progesterone and other steroids. Today, a preparation with the brand name Agolutin Depot remains on the market in the Czech Republic and Slovakia. A combined preparation of progesterone,
estradiol benzoate, and
lidocaine remains available with the brand name Clinomin Forte in Paraguay as well. In addition to aqueous suspensions, water-in-oil
emulsions of
steroids were studied by 1949, and long-acting emulsions of progesterone were introduced for use by intramuscular injection under the brand names Progestin and Di-Pro-Emulsion (with
estradiol benzoate) by the 1950s. Due to lack of standardization of crystal sizes, crystalline suspensions of steroids had marked variations in effect.
Aqueous solutions of water-insoluble steroids were first developed via association with
colloid solubility enhancers in the 1940s. An aqueous solution of progesterone for use by
intravenous injection was marketed by
Schering AG under the brand name Primolut Intravenous by 1962. They lacked the need for frequent injections and the injection site reactions associated with progesterone by intramuscular injection and soon supplanted progesterone for parenteral therapy in most cases.
Oral and sublingual The first study of oral progesterone in humans was published in 1949. It found that oral progesterone produced significant progestational effects in the endometrium in women. Another preparation, which contained progesterone alone, was
Synderone (
trademark registered by Chemical Specialties in 1952). Sublingual progesterone in women was first studied in 1944 by
Robert Greenblatt. Sublingual progesterone tablets were marketed under the brand names
Progesterone Lingusorbs and
Progesterone Membrettes by 1951. A sublingual tablet formulation of progesterone has been approved under the brand name
Luteina in Poland and Ukraine and remains marketed today. Injections of progesterone were first shown to inhibit ovulation in animals between 1937 and 1939. Inhibition of
fertilization by administration of progesterone during the
luteal phase was also demonstrated in animals between 1947 and 1949. Findings on inhibition of ovulation by progesterone in women were first presented at the
Fifth International Conference on Planned Parenthood in Tokyo, Japan in October 1955. Three different research groups presented their findings on this topic at the conference. The conference marked the beginning of a new era in the history of birth control. Rock and Pincus also subsequently described findings from 1952 that "
pseudopregnancy" therapy with a combination of high doses of
diethylstilbestrol and oral progesterone prevented ovulation and pregnancy in women. Unfortunately, the use of oral progesterone as a hormonal contraceptive was plagued by problems. Noretynodrel and norethisterone did not show the problems associated with oral progesterone—in the studies, they fully inhibited ovulation and did not produce menstruation-related side effects. The first birth control pills to be introduced were a noretynodrel-containing product in 1957 and a norethisterone-containing product in 1963, followed by numerous others containing a diversity of progestins. Progesterone itself has never been introduced for use in birth control pills. More modern clinical studies of oral progesterone demonstrating elevated levels of progesterone and end-organ responses in women, specifically progestational endometrial changes, were published between 1980 and 1983. Up to this point, many clinicians and researchers apparently still thought that oral progesterone was inactive. It was not until almost half a century after the introduction of progesterone in medicine that a reasonably effective oral formulation of progesterone was marketed. This formulation, known as oral micronized progesterone (OMP), was then introduced for medical use under the brand name Utrogestan in France in 1982. By 1999, oral micronized progesterone had been marketed in more than 35 countries. A
sustained-release (SR) formulation of oral micronized progesterone, also known as "oral natural micronized progesterone sustained release" or "oral NMP SR", was marketed in India in 2012 under the brand name Gestofit SR. Shortly thereafter, vaginal progesterone suppositories were introduced for medical use under the brand name Colprosterone in 1955. Vaginal micronized progesterone gels and capsules were introduced for medical use under brand names such as Utrogestan and Crinone in the early 1990s. Progesterone was approved in the United States as a vaginal gel in 1997 and as a vaginal insert in 2007. A progesterone contraceptive vaginal ring known as Progering was first studied in women in 1985 and continued to be researched through the 1990s. It was approved for use as a contraceptive in lactating mothers in Latin America by 2004. Development of a progesterone-containing
intrauterine device (IUD) for contraception began in the 1960s. Incorporation of progesterone into IUDs was initially studied to help reduce the risk of IUD expulsion. No transdermal formulations of progesterone for systemic use have been successfully marketed, in spite of efforts of pharmaceutical companies towards this goal. The low potency of transdermal progesterone has thus far precluded it as a possibility. Although no formulations of transdermal progesterone are approved for systemic use, transdermal progesterone is available in the form of
creams and
gels from custom
compounding pharmacies in some countries, and is also available
over-the-counter without a
prescription in the United States. However, these preparations are unregulated and have not been adequately characterized, with low and unsubstantiated effectiveness. ==Society and culture==