Progesterone is a medication and naturally occurring steroid hormone.[14] 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.[14][15] It is also used in women to support pregnancy and fertility and to treat gynecological disorders.[16][17][18][19] Progesterone can be taken by mouth, in through the vagina, and by injection into muscle or fat, among other routes.[14] A progesterone vaginal ring and progesterone intrauterine device used for birth control also exist in some areas of the world.[20][21] Progesterone is well-tolerated and often produces few or no side effects.[22] However, a number of side effects are possible, for instance mood changes.[22] If progesterone is taken by mouth or at high doses, certain central side effects including sedation, sleepiness, and cognitive impairment can also occur.[22][14] The drug is a naturally occurring progestogen and hence is an agonist of the progesterone receptor (PR), the biological target of progestogens like endogenous progesterone.[14] It opposes the effects of estrogens in various parts of the body like the uterus and also blocks the effects of the hormone aldosterone.[14][23] In addition, progesterone has neurosteroid effects in the brain.[14] Progesterone was first isolated in pure form in 1934.[24][25] It first became available as a medication later that year.[26][27] Oral micronized progesterone (OMP), which allowed progesterone to be taken by mouth, was introduced in 1980.[27][16][28] A large number of synthetic progestogens, or progestins, have been derived from progesterone and are used as medications as well.[14] Examples include medroxyprogesterone acetate and norethisterone.[14] Progesterone is used in combination with an estrogen as a component of menopausal hormone therapy for the treatment of menopausal symptoms.[14] A progestogen is needed to prevent endometrial hyperplasia and increased risk of endometrial cancer caused by unopposed estrogens in women who have intact uteruses.[14] In addition, progestogens, including progesterone, are able to treat and improve hot flashes.[14] Progesterone, both alone and in combination with an estrogen, also has beneficial effects on skin health and is able to slow the rate of skin aging in postmenopausal women.[29][30] Based on animal research, progesterone may be involved in sexual function in women.[31][32] However, very limited clinical research suggests that progesterone does not improve sexual desire or function in women.[33] Progesterone is used as a component of feminizing hormone therapy for transgender women in combination with estrogens and antiandrogens.[34][15] However, the addition of progestogens to HRT for transgender women is controversial and their role is unclear.[34][15] Some patients and clinicians believe anecdotally that progesterone may enhance breast development, improve mood, and increase sex drive.[15] However, there is a lack of evidence from well-designed studies to support these notions at present.[15] In addition, progestogens can produce undesirable side effects, although bioidentical progesterone may be safer and better tolerated than synthetic progestogens like medroxyprogesterone acetate.[34][35] 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.[34][36][35] However, a 2014 review concluded the following on the topic of progesterone for enhancing breast development in transgender women:[36] While the influence of progesterone on breast development is uncertain, it is known that progesterone can cause temporary breast enlargement due to local fluid retention in the breasts, and this may give a misleading appearance of breast growth.[37][38] Aside from a hypothetical involvement in breast development, progestogens are not otherwise known to be involved in physical feminization.[35][34] 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.[39] 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.[40] 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,[41] 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.[42] 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.[43] An editorial by Roberto Romero discusses the role of sonographic cervical length in identifying patients who may benefit from progesterone treatment.[44] A meta-analysis published in 2011 found that vaginal progesterone cut the risk of premature births by 42 percent in women with short cervixes.[45] 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.[46] Progesterone is used for luteal support in assisted reproductive technology (ART) cycles such as in vitro fertilization (IVF).[18][47] 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.[48][49] A progesterone vaginal ring is available for birth control when breastfeeding in a number of areas of the world.[20] An intrauterine device containing progesterone has also been marketed under the brand name Progestasert for birth control, including previously in the United States.[50] Progesterone is used to control persistent anovulatory bleeding.[51][52][53] It is used in non-pregnant women with a delayed menstruation of one or more weeks, in order to allow the thickened endometrial lining to slough off. This process is termed a progesterone withdrawal bleed. Progesterone is taken orally for a short time (usually one week), after which it is discontinued and bleeding should occur.[citation needed] 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.[54][55][56] It is not approved for systemic therapy.[57][54] 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.[56] Historically, progesterone has been widely used in the treatment of premenstrual syndrome.[58] A 2012 Cochrane review found insufficient evidence for or against the effectiveness of progesterone for this indication.[59] 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.[58][60] Progesterone can be used to treat catamenial epilepsy by supplementation during certain periods of the menstrual cycle.[61] 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.[62][14] A 1% topical progesterone gel is approved for local application to the breasts to treat breast pain, but is not indicated for systemic therapy.[57][54] Progesterone was previously available as an intrauterine device for use in hormonal contraception, but this formulation was discontinued.[62] Progesterone is also limitedly available in combination with estrogens such as estradiol and estradiol benzoate for use by intramuscular injection.[63][64] 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.[65][66][67][68][69] The systemic efficacy of transdermal/topical progesterone is controversial and has not been demonstrated.[67][68][69] 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.[75][76] 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.[75][76] It should also be used with caution in patients with anemia, diabetes mellitus, a history of depression, previous ectopic pregnancy, venereal disease, and unresolved abnormal Pap smear.[75][76] Use of progesterone is not recommended during pregnancy and breastfeeding.[76] However, the drug 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.[75] Some progesterone formulations contain benzyl alcohol, and this may cause a potentially fatal "gasping syndrome" if given to premature infants.[75] Progesterone is well-tolerated and many clinical studies have reported no side effects.[22] Side effects of progesterone may include abdominal cramps, back pain, breast tenderness, constipation, nausea, dizziness, edema, vaginal bleeding, hypotension, fatigue, dysphoria, depression, and irritability.[22] Side effects including drowsiness, sedation, sleepiness, fatigue, sluggishness, reduced vigor, dizziness, lightheadedness, decreased mental acuity, confusion, and cognitive, memory, and/or motor impairment may occur with oral ingestion and/or at high doses of progesterone, and are due to progesterone's neurosteroid metabolites (namely allopregnanolone).[22][77][78] The same may be true for side effects of progesterone including dysphoria, depression, anxiety, and irritability, and both the adverse cognitive/sedative and emotional side effects of progesterone may be reduced or avoided by parenteral routes of administration such as vaginal or intramuscular injection.[10][79] Also, progesterone may be taken before bed to avoid these side effects and/or to help with sleep.[77] 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.[22] Intramuscular injection may cause mild-to-moderate pain at the site of injection.[22] High intramuscular doses of progesterone have been associated with increased body temperature, which may be alleviated with paracetamol treatment.[22] Unlike various progestins, progesterone lacks off-target hormonal side effects caused by, for instance, androgenic, antiandrogenic, glucocorticoid, or estrogenic activity.[14] Conversely, it can still produce side effects related to its antimineralocorticoid and neurosteroid activity.[14] The neurosteroid side effects of progesterone are notably not shared with progestins and hence are unique to progesterone.[14] Compared to the progestin medroxyprogesterone acetate, there are fewer reports of breast tenderness with progesterone, and the magnitude and duration of vaginal bleeding with progesterone is reported to be lower.[22] The combination of an estrogen and progesterone has not been found to increase the risk of breast cancer in postmenopausal women.[80][81][82][83] In contrast, all assessed progestins except the atypical progestin dydrogesterone have been associated with a significantly increased risk of breast cancer when used in combination with an estrogen in menopausal hormone therapy.[80][82][81][83] On the other hand, progesterone is associated with a significantly increased risk of endometrial cancer in combination with an estrogen, while this is not true with any progestin.[84][83] However, this does not appear to be the case with vaginal progesterone, which achieves high local concentrations of progesterone in the uterus that are likely fully sufficient for endometrial protection.[84] Whereas the combination of an estrogen and a progestin is associated with an increased risk of venous thromboembolism relative to estrogen alone, there is no further increase in the risk of venous thromboembolism with the combination of an estrogen and progesterone relative to estrogen only.[84] The reasons for these differences between progesterone and progestins is not entirely clear, but may be due to the relatively low potency of oral progesterone and a potentially inadequate progestogenic effect of this medication.[84][83] Progesterone is likely to be relatively safe in overdose. Levels of progesterone during pregnancy are up to 100-fold higher than during normal menstrual cycling, although levels increase gradually over the course of pregnancy.[85] Oral dosages of progesterone of as high as 3,600 mg/day have been assessed in clinical trials, with the main side effect being sedation.[86] There is a case report of progesterone misuse with an oral dosage of 6,400 mg per day.[87] Administration of as much as 1,000 mg progesterone by intramuscular injection in humans was uneventful in terms of toxicity, but did induce extreme sedation and somnolence accompanied by nearly unarousable sleep, though the individuals were still able to be awakened with sufficient physical stimulation.[88] There are several notable drug interactions with progesterone. 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.[89] Progesterone potentiates the sedative effects of benzodiazepines and alcohol.[90] Notably, there is a case report of progesterone abuse alone with very high doses.[91] 5α-Reductase inhibitors such as finasteride and dutasteride inhibit the conversion of progesterone into the inhibitory neurosteroid allopregnanolone, and for this reason, may have the potential to reduce the sedative and related effects of progesterone.[92][93][94] 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.[95][96][97][98] As such, progesterone may have the potential to accelerate the metabolism of various drugs.[95][96][97][98] Progesterone is a progestogen, or an agonist of the nuclear progesterone receptors (PRs), the PR-A, PR-B, and PR-C.[14] In addition, progesterone is an agonist of the membrane progesterone receptors (mPRs), including the mPRα, mPRβ, mPRγ, mPRδ, and mPRϵ.[99][100] Aside from the PRs and mPRs, progesterone is a potent antimineralocorticoid, or antagonist of the mineralocorticoid receptor, the biological target of the mineralocorticoid aldosterone.[101][102] In addition to its activity as a steroid hormone, progesterone is a neurosteroid.[103] Among other neurosteroid activities, and via its active metabolites allopregnanolone and pregnanolone, progesterone is a potent positive allosteric modulator of the GABAA receptor, the major signaling receptor of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).[104] 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.[14][105] In accordance, progesterone has numerous effects throughout the body.[14] Among other effects, progesterone produces changes in the female reproductive system, the breasts, and the brain.[14][105] Progesterone has functional antiestrogenic effects due to its progestogenic activity, including in the uterus, cervix, and vagina.[14] The effects of progesterone may influence health in both positive and negative ways.[14] In addition to the aforementioned effects, progesterone has antigonadotropic effects due to its progestogenic activity, and can inhibit ovulation and suppress gonadal sex hormone production.[14] The activities of progesterone besides those mediated by the PRs and mPRs are also of significance.[14] Progesterone lowers blood pressure and reduces water and salt retention among other effects via its antimineralocorticoid activity.[14][106] In addition, progesterone can produce sedative, hypnotic, anxiolytic, euphoric, cognitive-, memory-, and 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.[22][77][78][107] There are differences between progesterone and other progestogens, such as progestins like medroxyprogesterone acetate and norethisterone, with implications for pharmacodynamics and pharmacokinetics as well as efficacy, tolerability, and safety.[14] The pharmacokinetics of progesterone are dependent on its route of administration. The drug is approved in the form of oil-filled capsules containing micronized progesterone for oral administration, termed oral micronized progesterone or OMP.[108] It is also available in the form of vaginal or rectal suppositories or pessaries, topical creams and gels,[109] oil solutions for intramuscular injection, and aqueous solutions for subcutaneous injection.[108][10][110] Routes of administration that progesterone has been used by include oral, intranasal, transdermal/topical, vaginal, rectal, intramuscular, subcutaneous, and intravenous injection.[10] Vaginal progesterone is available in the form of progesterone capsules, tablets or inserts, gels, suppositories or pessaries, and rings.[10] Progesterone is a naturally occurring pregnane steroid and is also known as pregn-4-ene-3,20-dione.[111][112] It has a double bond (4-ene) between the C4 and C5 positions and two ketone groups (3,20-dione), one at the C3 position and the other at the C20 position.[111][112] Due to its pregnane core and C4(5) double bond, progesterone is often abbreviated as P4. It is contrasted with pregnenolone, which has a C5(6) double bond and is often abbreviated as P5. A large number of progestins, or synthetic progestogens, have been derived from progesterone.[111][14] They can be categorized into several structural groups, including derivatives of retroprogesterone, 17α-hydroxyprogesterone, 17α-methylprogesterone, and 19-norprogesterone, with a respective example from each group including dydrogesterone, medroxyprogesterone acetate, medrogestone, and promegestone.[14] The progesterone ethers quingestrone (progesterone 3-cyclopentyl enol ether) and progesterone 3-acetyl enol ether are among the only examples that do not belong to any of these groups.[105][113] Another major group of progestins, the 19-nortestosterone derivatives, exemplified by norethisterone (norethindrone) and levonorgestrel, are not derived from progesterone but rather from testosterone.[14] A variety of synthetic inhibitory neurosteroids have been derived from progesterone and its neurosteroid metabolites, allopregnanolone and pregnanolone.[111] Examples include alfadolone, alfaxolone, ganaxolone, hydroxydione, minaxolone, and renanolone.[111] In addition, C3 and C20 conjugates of progesterone, such as progesterone carboxymethyloxime (progesterone 3-(O-carboxymethyl)oxime; P4-3-CMO), P1-185 (progesterone 3-O-(L-valine)-E-oxime), EIDD-1723 (progesterone 20E-[O-[(phosphonooxy)methyl]oxime] sodium salt), EIDD-036 (progesterone 20-oxime; P4-20-O), and VOLT-02 (chemical structure unreleased), have been developed as water-soluble prodrugs of progesterone and neurosteroids.[114][115][116][117][118][119] Chemical syntheses of progesterone have been published.[120] The hormonal action of progesterone was discovered in 1929.[24][25][121] Pure crystalline progesterone was isolated in 1934 and its chemical structure was determined.[24][25] Later that year, chemical synthesis of progesterone was accomplished.[25][122] Shortly following its chemical synthesis, progesterone began being tested clinically in women.[25] In 1934, Schering introduced progesterone as a pharmaceutical drug under the brand name Proluton.[26][27] It was administered by intramuscular injection because it is rapidly metabolized when taken by mouth and hence required very high oral doses to produce effects.[16][123] It was not until almost half a century later that a non-injected formulation of progesterone was marketed.[124] Micronization, similarly to the case of estradiol, allowed progesterone to be absorbed effectively via other routes of administration, but the micronization process was difficult for manufacturers for many years.[125] OMP was finally marketed in France under the brand name Utrogestan in 1980,[27][16][28] and this was followed by the introduction of OMP in the United States under the brand name Prometrium in 1998.[125] In the early 1990s, vaginal micronized progesterone (brand names Crinone, Utrogestan, Endometrin)[126] was also marketed.[124] Progesterone was approved by the United States Food and Drug Administration as a vaginal gel on 31 July 1997,[127] a capsule to be taken by mouth on 14 May 1998,[128] in an injection form on 25 April 2001,[129] and as a vaginal insert on 21 June 2007.[130] Progesterone is the generic name of the drug in English and its INN, USAN, USP, BAN, DCIT, and JAN, while progestérone is its name in French and its DCF.[63][111][112][131] It is also referred to as progesteronum in Latin, progesterona in Spanish and Portuguese, and progesteron in German.[63][112] Progesterone is marketed under a large number of brand names throughout the world.[63][112] Examples of major brand names under which progesterone has been marketed include Crinone, Crinone 8%, Cyclogest, Endogest, Endometrin, 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.[63][112] Progesterone is widely available in countries throughout the world in a variety of formulations.[63][64] Progesterone in the form of oral capsules; vaginal capsules, tablets/inserts, and gels; and intramuscular oil have widespread availability.[63][64] The following formulations/routes of progesterone have selective or more limited availability:[63][64] In addition to single-drug formulations, the following progesterone combination formulations are or have been marketed, albeit with limited availability:[63][64] As of November 2016[update], progesterone is available in the United States in the following formulations:[62] A 25 mg/mL concentration of progesterone oil for intramuscular injection and a 38 mg/device progesterone intrauterine device (Progestasert) have been discontinued.[62] An oral combination formulation of micronized progesterone and estradiol in oil-filled capsules (developmental code name TX-001HR) is currently under development in the United States for the treatment of menopausal symptoms and endometrial hyperplasia, though it has yet to be approved or introduced.[134][5] Progesterone is also available in unregulated custom preparations from compounding pharmacies in the United States.[65][66] In addition, transdermal progesterone is available over-the-counter in the United States, although the clinical efficacy of transdermal progesterone is controversial.[67][68][69] Due to its neurosteroid actions, progesterone has been researched for the potential treatment of a number of central nervous system conditions such as multiple sclerosis, brain damage, and drug addiction. Additional uses of progesterone may include treatment of hypertension (due to its antimineralocorticoid activity), chronic obstructive pulmonary disease, and benzodiazepine withdrawal (due to its neurosteroid actions).[22] Progesterone is being investigated as potentially beneficial in treating multiple sclerosis, since the characteristic deterioration of nerve myelin insulation halts during pregnancy, when progesterone levels are raised; deterioration commences again when the levels drop.[citation needed] Studies as far back as 1987 show that female sex hormones have an effect on the recovery of traumatic brain injury.[135] In these studies, it was first observed that pseudopregnant female rats had reduced edema after traumatic brain injury. Recent clinical trials have shown that among patients that have suffered moderate traumatic brain injury, those that have been treated with progesterone are more likely to have a better outcome than those who have not.[136] A number of additional animal studies have confirmed that progesterone has neuroprotective effects when administered shortly after traumatic brain injury.[137] Encouraging results have also been reported in human clinical trials.[138][139] Vitamin D and progesterone separately have neuroprotective effects after traumatic brain injury, but when combined their effects are synergistic.[140] When used at their optimal respective concentrations, the two combined have been shown to reduce cell death more than when alone. One study looks at a combination of progesterone with estrogen. Both progesterone and estrogen are known to have antioxidant-like qualities and are shown to reduce edema without injuring the blood-brain barrier. In this study, when the two hormones are administered alone it does reduce edema, but the combination of the two increases the water content, thereby increasing edema.[141] The clinical trials for progesterone as a treatment for traumatic brain injury have only recently begun. ProTECT, a phase II trial conducted in Atlanta at Grady Memorial Hospital in 2007, the first to show that progesterone reduces edema in humans. Since then, trials have moved on to phase III. The National Institute of Health began conducting a nationwide phase III trial in 2011 led by Emory University.[136] A global phase III initiative called SyNAPSe®, initiated in June 2010, is run by a United States-based private pharmaceutical company, BHR Pharma, and is being conducted in the United States, Argentina, Europe, Israel and Asia.[142][143] Approximately 1,200 patients with severe (Glasgow Coma Scale scores of 3-8), closed-head TBI will be enrolled in the study at nearly 150 medical centers. To examine the effects of progesterone on nicotine addiction, participants in one study were either treated orally with a progesterone treatment, or treated with a placebo. When treated with progesterone, participants exhibited enhanced suppression of smoking urges, reported higher ratings of “bad effects” from IV nicotine, and reported lower ratings of “drug liking”. These results suggest that progesterone not only alters the subjective effects of nicotine, but reduces the urge to smoke cigarettes.[144]