Progesterone

Clinical data
Trade names	Prometrium, Utrogestan, Endometrin, others
Other names	P4; Pregnenedione; Pregn-4-ene-3,20-dione[1]
AHFS/Drugs.com	Monograph
MedlinePlus	a604017
Routes of administration	By mouth, sublingual, topical, vaginal, rectal, intramuscular, subcutaneous, intrauterine
Drug class	Progestogen; Antimineralocorticoid; Neurosteroid
ATC code	G03DA04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only[2][3][4] In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	Oral: <2.4%[5] Vaginal (micronized insert): 4–8%[6][7][8]
Protein binding	98–99%:[9][10] • Albumin: 80% • CBGTooltip Corticosteroid-binding globulin: 18% • SHBGTooltip Sex hormone-binding globulin: <1% • Free: 1–2%
Metabolism	Mainly liver: • 5α- and 5β-reductase • 3α-Tooltip 3α-Hydroxysteroid dehydrogenase and 3β-HSDTooltip 3β-Hydroxysteroid dehydrogenase • 20α-Tooltip 20α-Hydroxysteroid dehydrogenase and 20β-HSDTooltip 20β-Hydroxysteroid dehydrogenase • Conjugation • 17α-Hydroxylase • 21-Hydroxylase • CYPsTooltip CYP (e.g., CYP3A4)
Metabolites	• Dihydroprogesterones • Pregnanolones • Pregnanediols • 20α-Hydroxyprogesterone • 17α-Hydroxyprogesterone • Pregnanetriols • 11-Deoxycorticosterone (and glucuronide/sulfate conjugates)
Elimination half-life	• Oral: 5 hours (with food)[11] * Sublingual: 6–7 hours[12] • Vaginal: 14–50 hours[13][12] • Topical: 30–40 hours[14] • IM: 20–28 hours[15][13][16] • SC: 13–18 hours[16] • IVTooltip Intravenous injection: 3–90 minutes[17]
Excretion	Bile and urine[18][19]
Identifiers
IUPAC name (8S,9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopentaphenanthren-3-one
CAS Number	57-83-0 Y
PubChem CID	5994
IUPHAR/BPS	2377
DrugBank	DB00396 Y
ChemSpider	5773 Y
UNII	4G7DS2Q64Y
KEGG	D00066 Y
ChEBI	CHEBI:17026 Y
ChEMBL	ChEMBL103 Y
Chemical and physical data
Formula	C21H30O2
Molar mass	314.469 g·mol−1
3D model (JSmol)	Interactive image
Specific rotation	D25 = +172 to +182° (2% in dioxane, β-form)
Melting point	126 °C (259 °F)
SMILES CC(=O)1CC21(CC32CCC4=CC(=O)CC34C)C
InChI InChI=InChI=1S/C21H30O2/c1-13(22)17-6-7-18-16-5-4-14-12-15(23)8-10-20(14,2)19(16)9-11-21(17,18)3/h12,16-19H,4-11H2,1-3H3/t16-,17+,18-,19-,20-,21+/m0/s1 N Key:RJKFOVLPORLFTN-LEKSSAKUSA-N Y
(verify)

Progesterone (P4), sold under the brand name Prometrium among others, is a medication and naturally occurring steroid hormone.^[20] 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.^[20][21] It is also used in women to support pregnancy and fertility and to treat gynecological disorders.^{[22][23][24][25]} Progesterone can be taken by mouth, vaginally, and by injection into muscle or fat, among other routes.^[20] A progesterone vaginal ring and progesterone intrauterine device used for birth control also exist in some areas of the world.^[26][27]

Progesterone is well tolerated and often produces few or no side effects.^[28] However, a number of side effects are possible, for instance mood changes.^[28] If progesterone is taken by mouth or at high doses, certain central side effects including sedation, sleepiness, and cognitive impairment can also occur.^[28][20] The medication is a naturally occurring progestogen and hence is an agonist of the progesterone receptor (PR), the biological target of progestogens like endogenous progesterone.^[20] It opposes the effects of estrogens in various parts of the body like the uterus and also blocks the effects of the hormone aldosterone.^[20][29] In addition, progesterone has neurosteroid effects in the brain.^[20]

Progesterone was first isolated in pure form in 1934.^[30][31] It first became available as a medication later that year.^[32][33] Oral micronized progesterone (OMP), which allowed progesterone to be taken by mouth, was introduced in 1980.^[33][22][34] A large number of synthetic progestogens, or progestins, have been derived from progesterone and are used as medications as well.^[20] Examples include medroxyprogesterone acetate and norethisterone.^[20] In 2021, it was the 167th most commonly prescribed medication in the United States, with more than 3 million prescriptions.^[35][36]

Medical uses

Hormone therapy

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.^[20][37] It is used specifically to provide endometrial protection against unopposed estrogen-induced endometrial hyperplasia and cancer in women with intact uteruses.^[20][37] 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.^[29][38] Twice-weekly 100 mg vaginal progesterone was also recommended, but more research is needed on this dose and endometrial monitoring may be advised.^[29][38] Transdermal progesterone was not recommended for endometrial protection.^[29][38]

The REPLENISH trial was the first adequately powered study to show that continuous 100 mg/day oral progesterone with food provides adequate endometrial protection.^{[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][42][38] However, the PEPI trial was not adequately powered to fully quantify endometrial hyperplasia or cancer risk.^[39] No adequately powered studies have assessed endometrial protection with vaginal progesterone.^[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.^[39][29] Due to the vaginal first-pass effect, low doses of vaginal progesterone may allow for adequate endometrial protection.^[22][43][20] Although not sufficiently powered, various other smaller studies have also found endometrial protection with oral or vaginal progesterone.^{[39][42][38][44]} There is inadequate evidence for endometrial protection with transdermal progesterone cream.^{[29][22][45][46]}

Oral progesterone has been found to significantly reduce hot flashes relative to placebo.^[39][47] The combination of an estrogen and oral progesterone likewise reduces hot flashes.^[39][37] Estrogen plus oral progesterone has been found to significantly improve quality of life.^[39][37] The combination of an estrogen and 100 to 300 mg/day oral progesterone has been found to improve sleep outcomes.^[39][37][47] Moreover, sleep was improved to a significantly better extent than estrogen plus medroxyprogesterone acetate.^[39] This may be attributable to the sedative neurosteroid effects of progesterone.^[39] Reduction of hot flashes may also help to improve sleep outcomes.^[39] Based on animal research, progesterone may be involved in sexual function in women.^[48][49] However, very limited clinical research suggests that progesterone does not improve sexual desire or function in women.^[50]

The combination of an estrogen and oral progesterone has been found to improve bone mineral density (BMD) to a similar extent as an estrogen plus medroxyprogesterone acetate.^[39] Progestogens, including progesterone, may have beneficial effects on bone independent of those of estrogens, although more research is required to confirm this notion.^[51] 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.^[39] Estrogen therapy has a favorable influence on the blood lipid profile, which may translate to improved cardiovascular health.^[39][20] The addition of oral or vaginal progesterone has neutral or beneficial effects on these changes.^[39][37][47] This is in contrast to various progestins, which are known to antagonize the beneficial effects of estrogens on blood lipids.^[20][39] 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.^[52][53]

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.^[54]

Transgender women

Progesterone is used as a component of feminizing hormone therapy for transgender women in combination with estrogens and antiandrogens.^[55][21] However, the addition of progestogens to HRT for transgender women is controversial and their role is unclear.^[55][21] Some patients and clinicians believe anecdotally that progesterone may enhance breast development, improve mood, and increase sex drive.^[21] However, there is a lack of evidence from well-designed studies to support these notions at present.^[21] In addition, progestogens can produce undesirable side effects, although bioidentical progesterone may be safer and better tolerated than synthetic progestogens like medroxyprogesterone acetate.^[55][56]

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.^[55][57][56] However, a 2014 review concluded the following on the topic of progesterone for enhancing breast development in transgender women:^[57]

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.^[57]

Data on menstruating women shows there is no correlation between water retention, and levels of progesterone or estrogen.^[58] 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.^[59][60] Aside from a hypothetical involvement in breast development, progestogens are not otherwise known to be involved in physical feminization.^[56][55]

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.^[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. The hormone treatment was administered vaginally every day during the second half of a pregnancy.^[62] 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,^[63] 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.^[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.^[66] A meta-analysis published in 2011 found that vaginal progesterone cut the risk of premature births by 42 percent in women with short cervixes.^[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.^[69]

Fertility support

Progesterone is used for luteal support in assisted reproductive technology (ART) cycles such as in vitro fertilization (IVF).^[24][70] It is also used to correct luteal phase deficiency to prepare the endometrium for implantation in infertility therapy and is used to support early pregnancy.^[71][72]

Birth control

A progesterone vaginal ring is available for birth control when breastfeeding in a number of areas of the world.^[26] An intrauterine device containing progesterone has also been marketed under the brand name Progestasert for birth control, including previously in the United States.^[73]

Gynecological disorders

Progesterone is used to control persistent anovulatory bleeding.^[74][75][76]

Other uses

Progesterone is of unclear benefit for the reversal of mifepristone-induced abortion.^[77] Evidence is insufficient to support use in traumatic brain injury.^[78]

Progesterone has been used as a topical medication applied to the scalp to treat female and male pattern hair loss.^{[79][80][81][82][83]} Variable effectiveness has been reported, but overall its effectiveness for this indication in both sexes has been poor.^{[80][81][84][83]}

Breast pain

Progesterone is approved under the brand name Progestogel as a 1% topical gel for local application to the breasts to treat breast pain in certain countries.^[85][86][22] It is not approved for systemic therapy.^[87][85] It has been found in clinical studies to inhibit estrogen-induced proliferation of breast epithelial cells and to abolish breast pain and tenderness in women with the condition.^[22] However, in one small study in women with cyclic breast pain it was ineffective.^[88] Vaginal progesterone has also been found to be effective in the treatment of breast pain and tenderness.^[88]

Premenstrual syndrome

Historically, progesterone has been widely used in the treatment of premenstrual syndrome.^[89] A 2012 Cochrane review found insufficient evidence for or against the effectiveness of progesterone for this indication.^[90] Another review of 10 studies found that progesterone was not effective for this condition, although it stated that insufficient evidence is available currently to make a definitive statement on progesterone in premenstrual syndrome.^[89][91]

Catamenial epilepsy

Progesterone can be used to treat catamenial epilepsy by supplementation during certain periods of the menstrual cycle.^[92]

Available forms

Progesterone is available in a variety of different forms, including oral capsules; sublingual tablets; vaginal capsules, tablets, gels, suppositories, and rings; rectal suppositories; oil solutions for intramuscular injection; and aqueous solutions for subcutaneous injection.^[93][20] A 1% topical progesterone gel is approved for local application to the breasts to treat breast pain, but is not indicated for systemic therapy.^[87][85] Progesterone was previously available as an intrauterine device for use in hormonal contraception, but this formulation was discontinued.^[93] Progesterone is also limitedly available in combination with estrogens such as estradiol and estradiol benzoate for use by intramuscular injection.^[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.^{[96][97][45][46][98]} The systemic efficacy of transdermal progesterone is controversial and has not been demonstrated.^[45][46][98]

Contraindicationsedit

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] Progesterone should be used with caution in people with conditions that may be adversely affected by fluid retention such as epilepsy, migraine headaches, asthma, cardiac dysfunction, and renal dysfunction.^[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.^[110][111] Use of progesterone is not recommended during pregnancy and breastfeeding.^[111] However, the medication has been deemed usually safe in breastfeeding by the American Academy of Pediatrics, but should not be used during the first four months of pregnancy.^[110] Some progesterone formulations contain benzyl alcohol, and this may cause a potentially fatal "gasping syndrome" if given to premature infants.^[110]

Side effectsedit

Progesterone is well tolerated, and many clinical studies have reported no side effects.^[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.^[28] Central nervous system depression, such as sedation and cognitive/memory impairment, can also occur.^[28][20]

Vaginal progesterone may be associated with vaginal irritation, itchiness, and discharge, decreased libido, painful sexual intercourse, vaginal bleeding or spotting in association with cramps, and local warmth or a "feeling of coolness" without discharge.^[28] Intramuscular injection may cause mild-to-moderate pain at the site of injection.^[28] High intramuscular doses of progesterone have been associated with increased body temperature, which may be alleviated with paracetamol treatment.^[28]

Progesterone lacks undesirable off-target hormonal activity, in contrast to various progestins.^[20] As a result, it is not associated with androgenic, antiandrogenic, estrogenic, or glucocorticoid effects.^[20] Conversely, progesterone can still produce side effects related to its antimineralocorticoid and neurosteroid activity.^[20] Compared to the progestin medroxyprogesterone acetate, there are fewer reports of breast tenderness with progesterone.^[28] In addition, the magnitude and duration of vaginal bleeding with progesterone are reported to be lower than with medroxyprogesterone acetate.^[28]

Central depressionedit

Progesterone can produce central nervous system depression as an adverse effect, particularly with oral administration or with high doses of progesterone.^[20][28] These side effects may include drowsiness, sedation, sleepiness, fatigue, sluggishness, reduced vigor, dizziness, lightheadedness, confusion, and cognitive, memory, and/or motor impairment.^{[28][112][113]} Limited available evidence has shown minimal or no adverse influence on cognition with oral progesterone (100–600 mg), vaginal progesterone (45 mg gel), or progesterone by intramuscular injection (25–200 mg).^{[114][39][28][115][116]} However, high doses of oral progesterone (300–1200 mg), vaginal progesterone (100–200 mg), and intramuscular progesterone (100–200 mg) have been found to result in dose-dependent fatigue, drowsiness, and decreased vigor.^{[28][115][114][20][117][116][118]} Moreover, high single doses of oral progesterone (1200 mg) produced significant cognitive and memory impairment.^{[28][117][116][20]} Intravenous infusion of high doses of progesterone (e.g., 500 mg) has been found to induce deep sleep in humans.^{[119][17][120][121]} Some individuals are more sensitive and can experience considerable sedative and hypnotic effects at lower doses of oral progesterone (e.g., 400 mg).^[20][122]

Sedation and cognitive and memory impairment with progesterone are attributable to its inhibitory neurosteroid metabolites.^[20] These metabolites occur to a greater extent with oral progesterone, and may be minimized by switching to a parenteral route.^{[20][16][123]} Progesterone can also be taken before bed to avoid these side effects and to help with sleep.^[112] The neurosteroid effects of progesterone are unique to progesterone and are not shared with progestins.^[20]

Breast canceredit

Breast cell proliferation has been found to be significantly increased by the combination of an oral estrogen plus cyclic medroxyprogesterone acetate in postmenopausal women but not by the combination of transdermal estradiol plus oral progesterone.^[39] Studies of topical estradiol and progesterone applied to the breasts for 2 weeks have been found to result in highly pharmacological local levels of estradiol and progesterone.^[39][124] These studies have assessed breast proliferation markers and have found increased proliferation with estradiol alone, decreased proliferation with progesterone, and no change in proliferation with estradiol and progesterone combined.^[39] In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, the combination of estrogen and cyclic oral progesterone resulted in a higher mammographic breast density than estrogen alone (3.1% vs. 0.9%) but a non-significantly lower breast density than the combination of estrogen and cyclic or continuous medroxyprogesterone acetate (3.1% vs. 4.4–4.6%).^[39] Higher breast density is a strong known risk factor for breast cancer.^[125] Other studies have had mixed findings however.^[126] A 2018 systematic review reported that breast density with an estrogen plus oral progesterone was significantly increased in three studies and unchanged in two studies.^[126] Changes in breast density with progesterone appear to be less than with the compared progestins.^[126]

In large short-term observational studies, estrogen alone and the combination of estrogen and oral progesterone have generally not been associated with an increased risk of breast cancer.^{[39][127][128][38]} Conversely, the combination of estrogen and almost any progestin, such as medroxyprogesterone acetate or norethisterone acetate, has been associated with an increased risk of breast cancer.^{[39][127][38][128][129]} The only exception among progestins is dydrogesterone, which has shown similar risk to that of oral progesterone.^[39] Breast cancer risk with estrogen and progestin therapy is duration-dependent, with the risk being significantly greater with more than 5 years of exposure relative to less than 5 years.^[127] In contrast to shorter-term studies, the longer-term observations (>5 years) of the French E3N study showed significant associations of both estrogen plus oral progesterone and estrogen plus dydrogesterone with higher breast cancer risk, similarly to estrogen plus other progestogens.^[39] Oral progesterone has very low bioavailability and has relatively weak progestogenic effects.^[129][130] The delayed onset of breast cancer risk with estrogen plus oral progesterone is potentially consistent with a weak proliferative effect of oral progesterone on the breasts.^[129][130] As such, a longer duration of exposure may be necessary for a detectable increase in breast cancer risk to occur.^[129][130] In any case, the risk remains lower than that with most progestins.^[39][128] A 2018 systematic review of progesterone and breast cancer concluded that short-term use (<5 years) of an estrogen plus progesterone is not associated with a significant increase in risk of breast cancer but that long-term use (>5 years) is associated with greater risk.^[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).^[131]

Most data on breast density changes and breast cancer risk are with oral progesterone.^[126] Data on breast safety with vaginal progesterone are scarce.^[126] The Early versus Late Intervention Trial with Estradiol (ELITE) was a randomized controlled trial of about 650 postmenopausal women who used estradiol and 45 mg/day cyclic vaginal progesterone.^[126][132] Incidence of breast cancer was reported as an adverse effect.^[126][132] The absolute incidences were 10 cases in the estradiol plus vaginal progesterone group and 8 cases in the control group.^[126][132] However, the study was not adequately powered for quantifying breast cancer risk.^[126][132]