[39][40][37][41] Cyclic 200 mg/day oral progesterone has also been found to be effective in the prevention of endometrial hyperplasia, for instance in the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial.

[39] In any case, the Early versus Late Intervention Trial with Estradiol (ELITE) found that cyclic 45 mg/day vaginal progesterone gel showed no significant difference from placebo in endometrial cancer rates.

[55][21] Some patients and clinicians believe anecdotally that progesterone may enhance breast development, improve mood, regulate sleep, and increase sex drive.

[61] According to a recent study, women with a short cervix that received hormonal treatment with a progesterone gel had their risk of prematurely giving birth reduced.

[64] In another trial, vaginal progesterone was shown to be better than placebo in reducing preterm birth prior to 34 weeks in women with an extremely short cervix at baseline.

[65] An editorial by Roberto Romero discusses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.

[67][68] The meta-analysis, which pooled published results of five large clinical trials, also found that the treatment cut the rate of breathing problems and reduced the need for placing a baby on a ventilator.

[26] An intrauterine device containing progesterone has also been marketed under the brand name Progestasert for birth control, including previously in the United States.

[94][95] In addition to approved pharmaceutical products, progesterone is available in unregulated custom compounded and over-the-counter formulations like systemic transdermal creams and other preparations.

[45][46][98] Contraindications of progesterone include hypersensitivity to progesterone or progestogens, prevention of cardiovascular disease (a Black Box warning), thrombophlebitis, thromboembolic disorder, cerebral hemorrhage, impaired liver function or disease, breast cancer, reproductive organ cancers, undiagnosed vaginal bleeding, missed menstruations, miscarriage, or a history of these conditions.

[110][111] It should also be used with caution in patients with anemia, diabetes mellitus, a history of depression, previous ectopic pregnancy, and unresolved abnormal Pap smear.

[28] Side effects of progesterone may include abdominal cramps, back pain, breast tenderness, constipation, nausea, dizziness, edema, vaginal bleeding, hypotension, fatigue, dysphoria, depression, and irritability, among others.

[20][28] These side effects may include drowsiness, sedation, sleepiness, fatigue, sluggishness, reduced vigor, dizziness, lightheadedness, confusion, and cognitive, memory, and/or motor impairment.

[126] The conclusions for progesterone were the same in a 2019 meta-analysis of the worldwide epidemiological evidence by the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC).

[137] Administration of as much as 500 mg progesterone by intravenous infusion in humans was uneventful in terms of toxicity, but did induce deep sleep, though the individuals were still able to be awakened with sufficient stimulation.

Certain selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, and sertraline may increase the GABAA receptor-related central depressant effects of progesterone by enhancing its conversion into 5α-dihydroprogesterone and allopregnanolone via activation of 3α-HSD.

[141][142][143] Progesterone is a weak but significant agonist of the pregnane X receptor (PXR), and has been found to induce several hepatic cytochrome P450 enzymes, such as CYP3A4, especially when concentrations are high, such as with pregnancy range levels.

[153] The PRs are expressed widely throughout the body, including in the uterus, cervix, vagina, fallopian tubes, breasts, fat, skin, pituitary gland, hypothalamus, and in other areas of the brain.

[20][155] In addition, progesterone can produce sedative, hypnotic, anxiolytic, euphoric, amnestic, cognitive-impairing, motor-impairing, anticonvulsant, and even anesthetic effects via formation of sufficiently high concentrations of its neurosteroid metabolites and consequent GABAA receptor potentiation in the brain.

[107][190][191][189] However, subcutaneous pellet implants of progesterone were later studied as a form of birth control in women in the 1980s and early 1990s, though no preparations were ultimately marketed.

[107] An aqueous solution of progesterone complexed with cyclodextrin to increase its water solubility was introduced for use by once-daily subcutaneous injection in Europe under the brand name Prolutex in the mid-2010s.

[245][246][247] A sublingual tablet formulation of progesterone has been approved under the brand name Luteina in Poland and Ukraine and remains marketed today.

[235][254] They included Pincus (in conjunction with John Rock, who did not attend the conference); a nine-member Japanese group led by Masaomi Ishikawa; and the two-member team of Abraham Stone and Herbert Kupperman.

[258][259][260] 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.

[248][263] At the 1955 Tokyo conference, Pincus had also presented the first findings of ovulation inhibition by oral progestins in animals, specifically 19-nortestosterone derivatives like noretynodrel and norethisterone.

[266][267] 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.

[94][163] Examples of major brand names under which progesterone has been marketed include Crinone, Crinone 8%, Cyclogest, Endogest, Endometrin, Estima, Geslutin, Gesterol, Gestone, Luteina, Luteinol, Lutigest, Lutinus, Microgest, Progeffik, Progelan, Progendo, Progering, Progest, Progestaject, Progestan, Progesterone, Progestin, Progestogel, Prolutex, Proluton, Prometrium, Prontogest, Strone, Susten, Utrogest, and Utrogestan.

[93] An oral combination formulation of micronized progesterone and estradiol in oil-filled capsules (brand name Bijuva) is marketed in the United States for the treatment of menopausal symptoms and endometrial hyperplasia.

[312][314] In other studies, 50 mg/day progesterone by intramuscular injection for 10 weeks in men produced azoospermia, decreased testicular size, markedly suppressed libido and erectile potency, and resulted in minimal semen volume upon ejaculation.

[312][313][315][316] An oil and water nanoemulsion of progesterone (particles of <1 mm in diameter) using micellar nanoparticle technology for transdermal administration known as Progestsorb NE was under development by Novavax for use in menopausal hormone therapy in the 2000s.