Progesterone 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, in through the vagina, and by injection into muscle or fat, among other routes. A progesterone vaginal ring form used for birth control also exists 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 drug is a naturally occurring progestogen and hence is an agonist of the progesterone receptor (PR), 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 (OMP), 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 (MPA) and norethisterone.
Video Progesterone (medication)
Medical uses
The use of progesterone and its analogues have many medical applications, both to address acute situations and to address the long-term decline of natural progesterone levels. Because of the poor bioavailability of progesterone when taken by mouth, many synthetic progestins have been designed with improved bioavailability by mouth and have been used long before progesterone formulations became available. Uses of progesterone include hormone replacement therapy, birth control, support of fertility and pregnancy (e.g., prevention of preterm birth and miscarriage), and treatment of gynecological conditions.
Hormone therapy
Menopause
Progesterone is used in combination with an estrogen as a component of menopausal hormone therapy for the treatment of menopausal symptoms. A progestogen is needed to prevent endometrial hyperplasia and increased risk of endometrial cancer caused by unopposed estrogens in women who have an intact uterus. In addition, progestogens, including progesterone, are able to treat and improve hot flashes. 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.
Transgender women
Progesterone is used as a component of feminizing hormone therapy for transgender women in combination with estrogens and antiandrogens. However, the addition of progestogens to HRT for transgender women is controversial and their role is unclear. Some patients and clinicians believe that progesterone may enhance breast development, improve mood, and increase sex drive. However, there is a lack of evidence 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 MPA.
Because some believe that progestogens are necessary for full breast development, progesterone is often used in transgender women with the intention of enhancing breast development. However, a 2014 review concluded that "Current evidence does not provide evidence that progestogens enhance breast development in [transgender] women. Neither do they prove the absence of such an effect." Aside from a theoretical involvement in breast development, progestogens are not otherwise known to be involved in physical feminization.
Birth control
A progesterone vaginal ring is available for birth control when breastfeeding in a number of areas of the world. An intrauterine device containing progesterone has also been marketed under the brand name Progestasert for birth control, including previously in the United States.
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.
Fertility support
Progesterone is used for luteal support in assisted reproductive technology (ART) cycles such as in vitro fertilization (IVF). It is also used to prepare uterine lining in infertility therapy and to support early pregnancy.
Gynecological disorders
Progesterone is used to control persistent anovulatory bleeding. 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. The progesterone is taken orally for a short time (usually one week), after which the progesterone is discontinued and bleeding should occur.
Other uses
Historically, progesterone has been widely used in the treatment of premenstrual syndrome. A 2012 Cochrane review found insufficient evidence for or against the effectiveness of progesterone for this indication. 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.
Progesterone can be used to treat catamenial epilepsy by supplementation during certain periods of the menstrual cycle.
Maps Progesterone (medication)
Contraindications
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. 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. 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. Use of progesterone is not recommended during pregnancy and breastfeeding. 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. Some progesterone formulations contain benzyl alcohol, and this may cause a potentially fatal "gasping syndrome" if given to premature infants.
Side effects
Progesterone is well-tolerated and many clinical studies have reported no side effects. Side effects of progesterone may include abdominal cramps, back pain, breast tenderness, constipation, nausea, dizziness, edema, vaginal bleeding, hypotension, fatigue, dysphoria, depression, and irritability. 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). The same may be true for side effects of progesterone including dysphoria, depression, anxiety, irritability, and decreased friendliness, 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. Also, progesterone may be taken before bed to avoid these side effects and/or to help with sleep.
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. Intramuscular injection may cause mild-to-moderate pain at the site of injection. High intramuscular doses of progesterone have been associated with increased body temperature, which may be alleviated with paracetamol treatment.
Unlike various progestins, progesterone lacks off-target hormonal side effects caused by, for instance, androgenic, antiandrogenic, glucocorticoid, or estrogenic activity. Conversely, it can still produce side effects related to its antimineralocorticoid and neurosteroid activity. The neurosteroid side effects of progesterone are notably not shared with progestins and hence are unique to progesterone. Compared to the progestin MPA, there are fewer reports of breast tenderness with progesterone and the magnitude and duration of vaginal bleeding is reported to be lower. Whereas all assessed progestins except the atypical progestin dydrogesterone are associated with a significantly increased risk of breast cancer when used in combination with an estrogen in menopausal hormone therapy, the combination of an estrogen with progesterone in menopausal women is associated with no change in breast cancer risk.
Overdose
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. 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. There is a case report of progesterone misuse with 6,400 mg per day. Administration of as much as 1,000 mg progesterone via 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.
Interactions
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 5?-dihydroprogesterone and allopregnanolone via activation of 3?-HSD. Progesterone potentiates the sedative effects of benzodiazepines and alcohol. Notably, there is a case report of progesterone abuse alone with very high doses. 5?-Reductase inhibitors such as finasteride and dutasteride, as well as inhibitors of 3?-HSD such as MPA, inhibit the conversion of progesterone into its inhibitory neurosteroid metabolites, and for this reason, may have the potential to block or reduce its sedative effects.
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. As such, progesterone may have the potential to accelerate the clearance of various drugs, especially with oral administration (which results in supraphysiological levels of progesterone in the liver), as well as with the high concentrations achieved with sufficient injection dosages.
Pharmacology
Pharmacodynamics
Progesterone is a progestogen, or an agonist of the nuclear progesterone receptors (PRs), the PRA, PRB, and PRC. In addition to the PR, progesterone is an agonist of the membrane progesterone receptors (mPRs), including the mPR?, mPR?, mPR?, mPR?, and mPR?. It is also a potent antimineralocorticoid (antagonist of the mineralocorticoid receptor (MR)), as well as a very weak glucocorticoid (agonist of the glucocorticoid receptor). Progesterone does not bind to the androgen receptor (AR) or to the estrogen receptor (ER). In addition to its activity as a steroid hormone, progesterone is a neurosteroid. Specifically, it is an antagonist of the sigma ?1 receptor, a negative allosteric modulator of nicotinic acetylcholine receptors, and, via its active metabolites allopregnanolone and pregnanolone, a potent positive allosteric modulator of the GABAA receptor, the major signaling receptor of the inhibitory neurotransmitter ?-aminobutyric acid (GABA).
Effects in the body and brain
The PRs are expressed widely throughout the body, including in the uterus, cervix, vagina, fallopian tubes, breasts, fat, skin, pituitary gland, hypothalamus, and elsewhere throughout the brain. Through activation of the PRs (as well as the mPRs), progesterone has many effects, including the following:
- Induces endometrial secretory transformation in preparation for pregnancy
- Prevents estrogen-induced endometrial hyperplasia and increased endometrial cancer risk
- Maintains pregnancy via effects in endometrium (with withdrawal resulting in miscarriage)
- Reduces amount and fibrosity of cervical mucus and causes cervix to become firmer and more tightly closed
- Controls motility and composition of fluid in the fallopian tubes
- Reduced cornification and maturation of the vaginal lining
- Causes water retention in the breasts resulting in temporary enlargement during the menstrual cycle
- Mediates lobuloalveolar development of the breasts necessary for lactation
- Suppresses lactation initiation and triggers lactation upon withdrawal (as with parturition)
- Modulates central nervous system function and has effects on the psyche
- Inhibits gonadotropin secretion from the pituitary gland, including mid-cycle gonadotropin surge
- Increases basal body temperature (by 0.3-0.6 °C (0.5-1.0 °F) relative to preovulation) via the hypothalamus
- Reduces hot flashes via the hypothalamus
- Stimulates respiration via the hypothalamus and/or respiratory center
- Maintains skin health, integrity, appearance, and hydration and slows the rate of aging of the skin
It should be noted that many of the effects of progesterone require estrogen, as estrogens prime tissues for progesterone by inducing expression of the PRs.
Progesterone also lowers blood pressure and reduces water and salt retention among other effects via its antimineralocorticoid activity.
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.
Antiestrogenic effects
Progesterone, like all progestogens, has antiestrogenic effects in certain tissues such as the uterus, cervix, and vagina and possibly also the breasts and brain. These effects are mediated by activation of the PR in these tissues. Progesterone does not have antiestrogenic effects in the more conventional sense of binding to and antagonizing the ER or binding to and inhibiting enzymes involved in estrogen biosynthesis. Instead, for instance in the endometrium, progesterone causes downregulation of the ER and upregulation of the estrogen-inactivating enzymes 17?-hydroxysteroid dehydrogenase 2 (converts estradiol into estrone) and estrone sulfotransferase (converts estrone into estrone sulfate). In the breasts, progesterone similarly downregulates the ER as well as the estrogen-activating enzymes steroid sulfatase (converts estrone sulfate into estrone) and 17?-hydroxysteroid-dehydrogenase 1 (converts estrone into estradiol) and upregulates estrone sulfotransferase. The antiestrogenic effects of progesterone and other progestogens form the basis for their only approved indication in menopausal HRT: prevention of long-term unopposed estrogen-induced endometrial hyperplasia and increased endometrial cancer risk in women with intact uteruses.
It has been hypothesized that progestogens may counteract various effects of estrogens in the brain such as stimulatory and excitatory effects on neuronal activity. Progesterone moreover has a special position among progestogens concerning such actions due to its inhibitory neurosteroid metabolites and their central depressant effects. It has been suggested that these actions of progestogens may explain the unfavorable effects on mood that have been observed with these drugs in some women. However, the mutual interactions of estrogens and progestogens in the brain in general are controversial and require more research.
Progesterone can also have global antiestrogenic effects at very high doses in both women and men via its antigonadotropic effects and consequent suppression of gonadal estrogen production (see below). These antigonadotropic effects are mediated by hyperactivation of the PR.
Antigonadotropic effects
Progestogens have antigonadotropic effects at sufficiently high dosages via activation of the PR and consequent negative feedback on and hence suppression of the hypothalamic-pituitary-gonadal axis. This results in suppression of gonadotropin secretion and by extension interference with fertility and gonadal sex hormone production. The minimum ovulation-inhibiting (i.e., contraceptive) dosage of OMP in women, this effect being the result of suppression of the mid-cycle surge in gonadotropin secretion, is 300 mg/day. Conversely, treatment with a high dosage of OMP of 100 mg four times per day (or 400 mg/day total) in men for 10 days that resulted in approximately mid-luteal phase levels of progesterone (7.9-9.4 ng/mL) did not cause any change in testosterone levels, suggesting that progesterone has little or no antigonadotropic effect in males at typical clinical dosages. On the other hand, a single 50 mg intramuscular injection of progesterone, which is associated with very high progesterone levels of approximately 50 ng/mL (or early- to mid-pregnancy levels), resulted in substantial (50-60%) suppression of luteinizing hormone, follicle-stimulating hormone, and testosterone levels in men. Progestogens in general are able to suppress gonadal testosterone production by a maximum of about 70 to 80% or just above castrate levels when used at sufficiently high doses in men.
Antimineralocorticoid activity
Progesterone is a potent antimineralocorticoid. It has higher affinity for the MR than aldosterone, the major endogenous agonist of the receptor. Progesterone produces antimineralocorticoid effects such as natriuresis (excretion of sodium in the urine) at normal physiological concentrations. A 200 mg dose of OMP is considered to be approximately equivalent in antimineralocorticoid effect to a 25 to 50 mg dose of the potent antimineralocorticoid spironolactone, which itself is a derivative of progesterone. The antimineralocorticoid effects of progesterone underlie its ability to lower blood pressure and reduce water and salt retention and its potential application in the treatment of hypertension. An active metabolite of progesterone, 11-deoxycorticosterone (21-hydroxyprogesterone), is a precursor of aldosterone and has strong mineralocorticoid activity (i.e., is a strong agonist of the MR). However, it is formed in relatively small amounts, and any such effects produced by it are usually outweighed by the antimineralocorticoid activity of progesterone.
Androgenic and antiandrogenic activities
Progesterone does not bind to the AR, the biological target of androgens like testosterone and dihydrotestosterone (DHT), and hence does not possess any direct androgenic or antiandrogenic activity. This is in contrast to many progestins, such as 19-nortestosterone derivatives (e.g., norethisterone, levonorgestrel, dienogest) and 17?-hydroxyprogesterone derivatives (e.g., cyproterone acetate, MPA), which do bind to the AR and have been associated with androgenic or antiandrogenic effects depending on the progestin in question.
Although progesterone does not bind directly to the AR, it is a precursor and intermediate, albeit distant, in the biosynthesis of androgens from cholesterol. For this reason, there has been some speculation that exogenous progesterone could be transformed into androgens by certain tissues that express the requisite enzymes. Progesterone is converted by 17?-hydroxylase into 17?-hydroxyprogesterone, 17?-hydroxyprogesterone is converted by 17,20-lyase into androstenedione, and androstenedione is converted by 17?-hydroxysteroid dehydrogenases into testosterone. CYP17A1, the cytochrome P450 gene that encodes 17?-hydroxylase and 17,20-lyase, is expressed mainly in the gonads (ovaries and testes) and the adrenal glands. Despite the reasoning that progesterone could be converted into androgens however, clinical studies in which women were treated with 100 to 300 mg/day OMP have found no or only a small increase in levels of 17?-hydroxyprogesterone and no change in androgen levels, including those of dehydroepiandrosterone, androstenedione, and testosterone. In these studies, levels of estradiol and cortisol, which progesterone is also a precursor of, did not change either, although levels of 11-deoxycorticosterone did increase significantly. In accordance with the lack of changes in androgen levels, progesterone, unlike various progestins, has not been associated with androgenic effects in clinical studies, including changes in the blood lipid profile or sex hormone-binding globulin levels, acne, skin oiliness, hirsutism, or voice deepening, or induction of teratogenicity (i.e., virilization of female fetuses).
Progesterone is a substrate for 5?-reductase and has been said to be a competitive inhibitor of this enzyme. 5?-Reductase is expressed in the skin, hair follicles, and prostate gland, and is responsible for the transformation of testosterone into the several-fold more potent androgen DHT. As such, it has been said that progesterone may possess some antiandrogenic effects via acting as a 5?-reductase inhibitor. However, while congenital 5?-reductase 2 deficiency is associated with ambiguous genitalia in male fetuses, progesterone levels increase by up to 100-fold during normal pregnancy and yet such defects do not develop.
Fluctuations in neurosteroid levels
Progesterone is extensively converted into allopregnanolone (as well as pregnanolone) upon oral ingestion due to a large first-pass effect (>90% metabolism), and allopregnanolone has a relatively short elimination half-life in the circulation. For these reasons, there are dramatic and highly supraphysiological spikes in allopregnanolone concentrations followed by steep declines with each oral intake of progesterone. Hence, allopregnanolone levels fluctuate substantially (e.g., 15-fold) and in an unphysiological manner with oral progesterone during treatment. Moreover, consumption of food with oral progesterone increases its absorption by two-fold, which may further compound fluctuations in neurosteroid levels if food intake with progesterone is not consistent from dose to dose.
Similarly to other GABAA receptor positive allosteric modulators such as benzodiazepines, barbiturates, and alcohol, tolerance has been found to develop with exposure to increased levels of allopregnanolone and related inhibitory neurosteroids. This includes downregulation and desensitization of the GABAA receptor, reduced effects of allopregnanolone and other GABAA receptor activators (e.g., GABA and benzodiazepines), and rebound or withdrawal effects upon falls in allopregnanolone levels. Moreover, changes in allopregnanolone levels have been implicated in adverse neuropsychiatric effects associated with the menstrual cycle (e.g., dysphoria, depression, anxiety, irritability) and postpartum period (e.g., postpartum depression), as well as in catamenial epilepsy (seizures).
In contrast to oral administration, parenteral progesterone, such as with vaginal administration, avoids the first-pass effect, and is not associated with supraphysiological concentrations of neurosteroid metabolites, nor with spikes or marked fluctuations in neurosteroid levels. Parenteral routes can be used instead of oral administration to avoid neurosteroid-related adverse effects if they prove to be problematic. Lower doses of oral progesterone (100 mg/day) are also associated with relatively reduced rates of conversion into neurosteroid metabolites and may similarly help to alleviate such side effects. The 5?-reductase inhibitor dutasteride, which blocks the production of allopregnanolone from progesterone, has been found to diminish symptoms of premenstrual syndrome.
Pharmacokinetics
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. It is also available in the form of vaginal or rectal suppositories or pessaries, topical creams and gels, oil solutions for intramuscular injection, and aqueous solutions for subcutaneous injection.
Routes of administration that progesterone has been used by include oral, intranasal, transdermal/topical, vaginal, rectal, intramuscular, subcutaneous, and intravenous injection. Oral progesterone has been found to be inferior to vaginal and intramuscular progesterone in terms of absorption (low) and clearance rate (rapid). Intravaginal progesterone is available in the forms of progesterone gel, rings, and suppositories or pessaries. Advantages of intravaginal progesterone over oral administration include high bioavailability, rapid absorption, avoidance of first-pass metabolism, sustained plasma concentrations, and a local endometrial effect, while advantages of intravaginal progesterone relative to intramuscular injection include greater convenience and lack of injection site pain.
Intranasal progesterone as a nasal spray has been found to be effective in achieving therapeutic levels, and was not associated with nasal irritation, but was associated with an unpleasant taste of the spray. Rectal, intramuscular, and intravenous routes may be inconvenient, especially for long-term treatment. Plasma levels of progesterone are similar after vaginal and rectal administration in spite of the different routes of administration, and rectal administration is an alternative to vaginal progesterone in conditions of vaginal infection, cystitis, recent childbirth, or when barrier contraception methods are used. Intramuscular injection of progesterone may achieve much higher levels of progesterone than normal luteal phase concentrations and levels achieved with other routes.
For comparison purposes, luteal phase levels of progesterone are 4 to 30 ng/mL (with levels of 5 to 9 ng/mL during the mid-luteal phase), while follicular phase levels of progesterone are 0.02 to 0.9 ng/mL, menopausal levels are 0.03 to 0.3 ng/mL, and levels of progesterone in men are 0.12 to 0.3 ng/mL. During pregnancy, levels of progesterone in the first 4 to 8 weeks are 25 to 75 ng/mL, and levels are typically around 140 to 200 ng/mL at term. Production of progesterone in the body in late pregnancy is approximately 250 mg per day, 90% of which reaches the maternal circulation.
Oral administration
The oral bioavailability of progesterone is very low, requiring very high doses to produce significant effects, and the hormone must be micronized in order to confer oral activity at practical dosages. As progesterone could not be used orally for many decades (until the introduction of OMP in 1980), the poor activity of oral progesterone prompted the development of progestins (i.e., synthetic progestogens), which, in contrast to oral progesterone, have improved metabolic stability and high oral bioavailability. OMP is almost completely absorbed from the gastrointestinal tract, but its bioavailability is very low at less than 10% (relative to intramuscular injection) due to extensive first-pass metabolism in the liver. There is wide interindividual variability in the bioavailability of OMP, and its absorption is increased approximately two-fold when it is taken with food.
The terminal half-life of progesterone in circulation is only approximately 5 minutes. However, with OMP, peak concentrations of progesterone are seen about 2 to 3 hours after ingestion and the terminal half-life is extended at about 16 to 18 hours. Significantly elevated serum levels of progesterone are maintained for about 12 hours and levels do not return to baseline until at least 24 hours have passed. In any case, due to the relatively short terminal half-life/duration of action of OMP, it is often prescribed in divided doses of two or even three times daily.
A dosage of 150 mg oral progesterone achieves mid-luteal phase levels, while higher doses of 300 to 1,200 mg achieve supraphysiological or pregnancy concentrations of progesterone.
Progesterone is metabolized into allopregnanolone and pregnanolone (conversions that are catalyzed by the enzymes 5?- and 5?-reductase and 3?-hydroxysteroid dehydrogenase and occurs in the liver, reproductive endocrine tissues, skin, and the brain), which are neurosteroids and potent potentiators of GABAA receptors. It is for this reason that common reported side effects of progesterone include dizziness, drowsiness or sedation, sleepiness, and fatigue. Both oral and sufficiently high doses of intramuscular progesterone can produce these sedative effects, indicating that first-pass metabolism in the liver is not essential for the conversion to take place. Moreover, the sedative effects occur in both men and women, indicating a lack of sex-specificity of the effects.
Vaginal administration
Progesterone for vaginal administration is available in the form of a gel or insert (suppository). With vaginal and rectal administration, a 100 mg dose of progesterone results in peak levels at 4 hours and 8 hours after dosing, respectively, with the levels achieved being in the luteal phase range. Following peak levels, there is a gradual decline in circulating concentrations, and after 24 hours, levels typical of the follicular phase are reached.
Topical administration
Progesterone for topical administration is not approved by the FDA in the United States but is available from custom compounding pharmacies and is also notably available over-the-counter without a prescription in this country. It is available from these sources in the form of creams and gels. Topical progesterone has been used as a component of menopausal HRT to treat thousands of women in the United States and Europe. However, these products are unregulated and have not been clinically tested, often with little being known about their pharmacokinetics. Moreover, the effectiveness of topical progesterone for systemic therapy, as in menopausal HRT, is controversial. Clinical studies have found only very low levels (<3.5 ng/mL) of progesterone in circulation with the use of topical progesterone, and these levels are thought to be insufficient to confer endometrial protection from unopposed estrogen.
Although very low levels of progesterone have been observed in venous blood, very high and in fact greatly supraphysiological levels of progesterone have been found in saliva and capillary blood with topical progesterone. In one study, the levels of progesterone in saliva and capillary blood were 10- and 100-fold greater than levels in venous blood, respectively. These findings suggest that in spite of the fact that progesterone levels in circulation remain low, and for reasons that are poorly understood, systemic distribution with topically administered progesterone is occurring somehow and there may be substantial exposure of tissues, such as the endometrium, to the hormone. However, the few clinical studies that have assessed the effects of topical progesterone on the endometrium have had mixed findings, and further research is needed to determine whether topical progesterone can confer adequate endometrial protection in menopausal HRT.
Topical progesterone is usually supplied in the form of creams and water-based gels, and the studies in which very low levels of progesterone in circulation were observed with topical progesterone used these formulations. However, a study of topical progesterone in the form of an alcohol-based gel found relatively high concentrations of progesterone in circulation that corresponded to luteal phase levels, and were theoretically sufficient to confer endometrial protection.
A study that investigated the pharmacokinetics of topical progesterone using a hydrophilic (gel), lipophilic, or emulsion-type base found that in all three cases the time to peak concentrations was around 4 hours and the elimination half-life was in the range of 30 to 40 hours. The venous blood levels observed were very low.
Topical application of progesterone with the intention of systemic therapy should not be equated with local treatment. Despite the fact that it is not approved for use in menopausal HRT, topical progesterone is registered in some countries under the brand name Progestogel as a 1% gel for direct local application to the breasts to treat premenstrual mastodynia (breast pain). 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. The effectiveness of topical progesterone for this indication may be related in part to the fact that the site of application of topical progesterone has been found to significantly influence its absorption. A study observed a significant increase in serum levels of progesterone when it was applied as a topical ointment to the breasts but not when it was applied to other areas like the thigh or abdomen.
Some unregulated topical progesterone products contain "wild yam extract" derived from Dioscorea villosa, but there is no evidence that the human body can convert its active ingredient (diosgenin, the plant steroid that is chemically converted to produce progesterone industrially) into progesterone.
Sublingual administration
Though no formulation of progesterone is approved for use via sublingual administration, a few studies have investigated the use of progesterone by this route. A study of sublingual progesterone for luteal support in patients undergoing embryo transfer found that after sublingual administration of 50 or 100 mg progesterone dissolved in a 1 mL suspension, peak levels of progesterone were reached in 30 to 60 minutes and were on average 17.61 ng/mL with the 100-mg dose. However, the duration was short and re-administration had to be done two or three times per day for adequate circulating levels of progesterone to be maintained throughout the day. Another study found that sublingual progesterone had to be administered at a dose of 400 mg every 8 hours to achieve circulating levels similar to those produced by 100 mg/day intramuscular progesterone. Further clinical research is necessary to evaluate the effectiveness of progesterone via the sublingual route of administration.
Intramuscular injection
With intramuscular injection of 10 mg progesterone in vegetable oil, maximum plasma concentrations (Cmax) are reached at approximately 8 hours after administration, and serum levels remain above baseline for about 24 hours. Doses of 10 mg, 25 mg, and 50 mg via intramuscular injection result in mean maximum serum concentrations of 7 ng/mL, 28 ng/mL, and 50 ng/mL, respectively. With intramuscular injection, a dose of 25 mg results in normal luteal phase serum levels of progesterone within 8 hours, and a 100 mg dose produces mid-pregnancy levels. At these doses, serum levels of progesterone remain elevated above baseline for at least 48 hours, with an elimination half-life of about 22 hours.
Due to the high concentrations achieved, progesterone by intramuscular injection at the usual clinical dose range is able to suppress gonadotropin secretion from the pituitary gland, demonstrating antigonadotropic efficacy (and therefore suppression of gonadal sex steroid production).
Intramuscular progesterone irritates tissues and is associated with injection site reactions such as changes in skin color, pain, redness, transient indurations (due to inflammation), ecchymosis (bruising/discoloration), and others.
An intramuscular suspension formulation of progesterone contained in microspheres is marketed under the brand name ProSphere in Mexico. It is far longer-lasting than regular intramuscular progesterone and is administered once weekly or once monthly, depending on the indication.
Subcutaneous injection
Progesterone can also be administered alternatively via subcutaneous injection, with the aqueous formulation Prolutex in Europe being intended specifically for once-daily administration by this route. This formulation is rapidly absorbed and has been found to result in higher serum peak progesterone levels relative to intramuscular oil formulations. In addition, subcutaneous injection of progesterone is considered to be easier, safer (less risk of injection site reactions), and less painful relative to intramuscular injection. The terminal half-life of this formulation is 13 to 18 hours, which is similar to the terminal half-lives of OMP and intramuscular progesterone.
Metabolism
With oral administration, progesterone is rapidly metabolized in the gastrointestinal tract and liver. As many as 30 different metabolites have been found to be formed from progesterone with oral ingestion. Regardless of the route of administration, 5?-reductase is the major enzyme involved in the metabolism of progesterone and is responsible for approximately 60 to 65% of its metabolism. 5?-Reductase is also a major enzyme in the metabolism of progesterone. 5?-Reduction of progesterone occurs predominantly in the intestines (specifically the duodenum), whereas 5?-reduction occurs almost exclusively in the liver. The metabolites of progesterone produced by 5?-reductase and 5?-reductase (after further transformation by 3?-hydroxysteroid dehydrogenase) are allopregnanolone and pregnanolone, respectively. With oral administration of progesterone, they occur in circulation at very high and in fact supraphysiological concentrations that are well in excess of those of progesterone itself (peak concentrations of 30 ng/mL for allopregnanolone and 60 ng/mL for pregnanolone versus 12 ng/mL for progesterone at 4 hours after a single 200-mg oral dose of progesterone).
The percentage constitutions of progesterone and its metabolites as reflected in serum levels have been determined for a single 100 mg dose of oral or vaginal progesterone. With oral administration, progesterone accounts for less than 20% of the dose in circulation while 5?- and 5?-reduced products like allopregnanolone and pregnanolone account for around 80%. With vaginal administration, progesterone accounts for around 50% of the dose and 5?- and 5?-reduced metabolites for around 40%.
A small amount of progesterone is converted by 21-hydroxylase into 11-deoxycorticosterone. Increases in levels of 11-deoxycorticosterone are markedly higher when progesterone is given orally as opposed to via parenteral routes like vaginal or intramuscular injection. The conversion of progesterone into 11-deoxycorticosterone occurs in the intestines (specifically the duodenum) and in the kidneys. 21-Hydroxylase appears to be absent in the liver, so conversion of progesterone into 11-deoxycorticosterone is thought not to occur in this part of the body.
Chemistry
Progesterone is a pregnane steroid and is also known as pregn-4-ene-3,20-dione. 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.
Derivatives
A large number of progestins (synthetic progestogens) have been derived from progesterone. They can be categorized into several structural groups, including derivatives of retroprogesterone, 17?-hydroxyprogesterone, 17?-methylprogesterone, and 19-norprogesterone, with a respective example from each group including dydrogesterone, MPA, medrogestone, and promegestone. Quingestrone (progesterone 3-cyclopentyl enol ether) is among the only examples that do not belong to any of these groups. Another major group of progestins, the 19-nortestosterone derivatives, exemplified by norethisterone (norethindrone) and levonorgestrel, are not derived from progesterone but rather from testosterone.
History
The hormonal action of progesterone was discovered in 1929. Pure crystalline progesterone was isolated in 1934 and its chemical structure was determined. Later that year, chemical synthesis of progesterone was accomplished. Shortly following its chemical synthesis, progesterone began being tested clinically in women. In 1934, Schering introduced progesterone as a pharmaceutical drug under the brand name Proluton. 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.
It was not until almost half a century later that a non-injected formulation of progesterone was marketed. 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. OMP was finally marketed in France under the brand name Utrogestan in 1980, and this was followed by the introduction of OMP in the United States under the brand name Prometrium in 1998. In the early 1990s, vaginal micronized progesterone (brand names Crinone, Utrogestan, Endometrin) was also marketed.
FDA approvals
Progesterone was approved by the United States Food and Drug Administration as a vaginal gel on 31 July 1997, a capsule to be taken by mouth on 14 May 1998, in an injection form on 25 April 2001, and as a vaginal insert on 21 June 2007.
Society and culture
Generic names
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. It is also referred to as progesteronum in Latin, progesterona in Spanish and Portuguese, and progesteron in German.
Brand names
Progesterone is marketed under a large number of brand names throughout the world. Examples of major brand names under which progesterone has been marketed include Crinone, Crinone 8%, Cyclogest, Endometrin, Geslutin, Gesterol, Gestone, Luteinol, Lutigest, Lutinus, Progeffik, Progelan, Progendo, Progest, Progestaject, Progestan, Progestin, Progestogel, Prolutex, Proluton, Prometrium, Prontogest, Utrogest, and Utrogestan.
Availability
United States
As of November 2016, progesterone is available in the United States in the following formulations:
- Oral capsules: Prometrium - 100 mg, 200 mg, 300 mg
- Vaginal gels: Crinone, Progestasert, Prometrium - 4%, 8%
- Vaginal inserts: Endometrin - 100 mg
- Oil for intramuscular injection: Progesterone - 50 mg/mL
Discontinued:
- Oil for intramuscular injection: Progesterone - 25 mg/mL
- Intrauterine device: Progestasert - 38 mg/device
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.
Progesterone is also available in custom preparations from compounding pharmacies in the United States.
Other countries
Progesterone is widely available in countries throughout the world in a variety of formulations. For an extensive list of countries that it is marketed in along with the associated brand names, see here.
Research
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).
Multiple sclerosis
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.
Brain damage
Studies as far back as 1987 show that female sex hormones have an effect on the recovery of traumatic brain injury. 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. A number of additional animal studies have confirmed that progesterone has neuroprotective effects when administered shortly after traumatic brain injury. Encouraging results have also been reported in human clinical trials.
Combination treatments
Vitamin D and progesterone separately have neuroprotective effects after traumatic brain injury, but when combined their effects are synergistic. 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.
Clinical trials
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. 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. 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.
Addiction
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.
References
Source of the article : Wikipedia
0 Comments