Progesterone (medication)
Progesterone, sold under the brand name Prometrium among others, is a medication and naturally occurring steroid hormone. It is a progestogen and is used in combination with estrogens mainly in hormone therapy for menopausal symptoms and low sex hormone levels in women. It is also used in women to support pregnancy and fertility and to treat gynecological disorders. Progesterone can be taken by mouth, vaginally, and by injection into muscle or fat, among other routes. A progesterone vaginal ring and progesterone intrauterine device used for birth control also exist in some areas of the world.
Progesterone is well tolerated and often produces few or no side effects. However, a number of side effects are possible, for instance mood changes. If progesterone is taken by mouth or at high doses, certain central side effects including sedation, sleepiness, and cognitive impairment can also occur. The medication is a naturally occurring progestogen and hence is an agonist of the progesterone receptor, the biological target of progestogens like endogenous progesterone. It opposes the effects of estrogens in various parts of the body like the uterus and also blocks the effects of the hormone aldosterone. In addition, progesterone has neurosteroid effects in the brain.
Progesterone was first isolated in pure form in 1934. It first became available as a medication later that year. Oral micronized progesterone, which allowed progesterone to be taken by mouth, was introduced in 1980. A large number of synthetic progestogens, or progestins, have been derived from progesterone and are used as medications as well. Examples include medroxyprogesterone acetate and norethisterone. In 2023, it was the 117th most commonly prescribed medication in the United States, with more than 5million prescriptions.
Medical uses
Menopause
Progesterone is used in combination with an estrogen as a component of menopausal hormone therapy for the treatment of menopausal symptoms in peri- and postmenopausal women. It is used specifically to provide endometrial protection against unopposed estrogen-induced endometrial hyperplasia and cancer in women with intact uteruses. A 2016 systematic review of endometrial protection with progesterone recommended 100 mg/day continuous oral progesterone, 200 mg/day cyclic oral progesterone, 45 to 100 mg/day cyclic vaginal progesterone, and 100 mg alternate-day vaginal progesterone. Twice-weekly 100 mg vaginal progesterone was also recommended, but more research is needed on this dose and endometrial monitoring may be advised. Transdermal progesterone was not recommended for endometrial protection.The REPLENISH trial was the first adequately powered study to show that continuous 100 mg/day oral progesterone with food provides adequate endometrial protection. 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 trial. However, the PEPI trial was not adequately powered to fully quantify endometrial hyperplasia or cancer risk. No adequately powered studies have assessed endometrial protection with vaginal progesterone. In any case, the Early versus Late Intervention Trial with Estradiol found that cyclic 45 mg/day vaginal progesterone gel showed no significant difference from placebo in endometrial cancer rates. Due to the vaginal first-pass effect, low doses of vaginal progesterone may allow for adequate endometrial protection. Although not sufficiently powered, various other smaller studies have also found endometrial protection with oral or vaginal progesterone. There is inadequate evidence for endometrial protection with transdermal progesterone cream.
Oral progesterone has been found to significantly reduce hot flashes relative to placebo. The combination of an estrogen and oral progesterone likewise reduces hot flashes. Estrogen plus oral progesterone has been found to significantly improve quality of life. The combination of an estrogen and 100 to 300 mg/day oral progesterone has been found to improve sleep outcomes. Moreover, sleep was improved to a significantly better extent than estrogen plus medroxyprogesterone acetate. This may be attributable to the sedative neurosteroid effects of progesterone. Reduction of hot flashes may also help to improve sleep outcomes. Based on animal research, progesterone may be involved in sexual function in women. However, very limited clinical research suggests that progesterone does not improve sexual desire or function in women.
The combination of an estrogen and oral progesterone has been found to improve bone mineral density to a similar extent as an estrogen plus medroxyprogesterone acetate. Progestogens, including progesterone, may have beneficial effects on bone independent of those of estrogens, although more research is required to confirm this notion. The combination of an estrogen and oral or vaginal progesterone has been found to improve cardiovascular health in women in early menopause but not in women in late menopause. Estrogen therapy has a favorable influence on the blood lipid profile, which may translate to improved cardiovascular health. The addition of oral or vaginal progesterone has neutral or beneficial effects on these changes. This is in contrast to various progestins, which are known to antagonize the beneficial effects of estrogens on blood lipids. Progesterone, both alone and in combination with an estrogen, has been found to have beneficial effects on skin and to slow the rate of skin aging in postmenopausal women.
In the French E3N-EPIC observational study, the risk of diabetes was significantly lower in women on menopausal hormone therapy, including with the combination of an oral or transdermal estrogen and oral progesterone or a progestin.
Transgender women
Progesterone is used as a component of feminizing hormone therapy for transgender women in combination with estrogens and often antiandrogens. However, the addition of progestogens to HRT for transgender women is controversial and their role is unclear. Some patients and clinicians believe anecdotally that progesterone may enhance breast development, improve mood, regulate sleep, and increase sex drive. However, there is a lack of evidence from well-designed studies to support these notions at present. In addition, progestogens can produce undesirable side effects, although bioidentical progesterone may be safer and better tolerated than synthetic progestogens like medroxyprogesterone acetate.Because some believe that progestogens are necessary for full breast development, progesterone is sometimes used in transgender women with the intention of enhancing breast development. However, a 2014 review concluded the following on the topic of progesterone for enhancing breast development in transgender women:
Our knowledge concerning the natural history and effects of different cross-sex hormone therapies on breast development in women is extremely sparse and based on low quality of evidence. Current evidence does not provide evidence that progestogens enhance breast development in women. Neither do they prove the absence of such an effect. This prevents us from drawing any firm conclusion at this moment and demonstrates the need for further research to clarify these important clinical questions.
Data on menstruating women shows there is no correlation between water retention, and levels of progesterone or estrogen. Despite this, some theorise progesterone might cause temporary breast enlargement due to local fluid retention, and may thus give a misleading appearance of breast growth. Aside from a hypothetical involvement in breast development, progestogens are not otherwise known to be involved in physical feminization.
Pregnancy support
Vaginally dosed progesterone is being investigated as potentially beneficial in preventing preterm birth in women at risk for preterm birth. The initial study by Fonseca suggested that vaginal progesterone could prevent preterm birth in women with a history of preterm birth. 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. The hormone treatment was administered vaginally every day during the second half of a pregnancy. A subsequent and larger study showed that vaginal progesterone was no better than placebo in preventing recurrent preterm birth in women with a history of a previous preterm birth, but a planned secondary analysis of the data in this trial showed that women with a short cervix at baseline in the trial had benefit in two ways: a reduction in births less than 32 weeks and a reduction in both the frequency and the time their babies were in intensive care.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. An editorial by Roberto Romero discusses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment. A meta-analysis published in 2011 found that vaginal progesterone cut the risk of premature births by 42 percent in women with short cervixes. 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.