Four groups in the mid-1930s, almost simultaneously, were involved in the isolation of progesteroneCitation1. Most notably, Butenandt in 1934 isolated progesterone, established its structure and synthesized itCitation2. In 1943, Russel Marker, working in Mexico, was able to synthesize 4.5 pounds of progesterone using as starting material the Dioscorea plant (yam). This opened the field to large-scale synthetic proceduresCitation1.
For many years, because of limited oral bioavailability, the intramuscular route of administration of progesterone was most commonCitation3. In 1980, an oral micronized form of progesterone suspended in oil became available in France. The geometric mean diameter of the progesterone particle was less than 10 micronsCitation2,Citation4. In part, because of the difficulties in achieving oral progesterone bioavailability, it has proven to be most difficult to combine progesterone and 17β-estradiol with acceptable oral bioavailability. Most recently, this has been accomplished and submitted for regulatory approval. In addition to oral and intramuscular progesterone administration, it has also been administered vaginally for over 20 yearsCitation5, by implantCitation3, subcutaneouslyCitation5 and rectallyCitation4. Transdermal delivery of progesterone has also been exploredCitation5.
Over the years following its isolation, progesterone has been studied or utilized for a variety of indications including assisted reproduction, threatened and habitual abortion, prevention of premature birth, progestational insufficiency, dysfunctional uterine bleeding, premenstrual syndrome, dysmenorrhea, endometriosis, menopausal vasomotor symptoms, bone metabolism, for the prevention of endometrial hyperplasia with menopausal hormone therapy, and others, although not all successfullyCitation5,Citation6.
The molecular biology story continued in the 1960s and 1970s with the recognition of receptors for estrogen and progesterone and then approximately two decades later with the understanding that these receptors could interact with both co-activators and co-repressorsCitation7. The increasing understanding of the mechanisms of steroid hormone receptor action in the latter part of the 20th century opened the door for the development of progesterone receptor antagonists and mixed-function selective progesterone receptor modulators (SPRMs).
We have devoted this issue of Climacteric to a variety of topics relevant to a consideration of the clinical role of progesterone and its biology. Authors explore the preclinical data, the role of progesterone in pregnancy loss, cognition, and treatment of menopausal symptoms and bone health. Micronized progesterone is explored as well as the very recent data from a randomized clinical trial of oral progesterone and 17β-estradiol. Safety considerations related to progesterone, including thrombosis, breast, endometrium and ovary, are presented. The use of vaginal progesterone and the vaginal first-pass effect are discussed and some of the applications of SPRMs are reviewed.
Conflict of interest
Dr Pickar has consulted for Pfizer, Shionogi and TherapeuticsMD and has stock options with TherapeuticsMD.
Source of funding
Nil.
References
- Diczfalusy E. Gregory Pincus and steroidal contraception: a new departure in the history of mankind. J Steroid Biochem 1979;11:3–11
- Sitruk-Ware R, Bricaire C, de Lignieres B, Yaneva H, Mauvais-Jarvis P. Oral micronized progesterone. Bioavailability pharmacokinetics, pharmacological and therapeutic implications–a review. Contraception 1987;36:373–402
- Swyer GIM. Progestogens and their clinical uses: Part I. Br Med J 1960;1:48–9
- de Lignières B. Oral micronized progesterone. Clin Therapeut 1999;21:41–60
- Ruan X, Mueck AO. Systemic progesterone therapy–oral, vaginal, injections and even transdermal? Maturitas 2014;79:248–55
- Swyer GIM. Progestogens and their clinical uses: Part II. Br Med J 1960;1:121–2
- O’Malley BW. Origins of the field of molecular endocrinology: a personal perspective. Molec Endocrinol 2016;30:1015–18