Progesterone (medication)

Source: Wikipedia, the free encyclopedia.
This article is about progesterone as a medication. For its role as a hormone, see progesterone.
Not to be confused with medroxyprogesterone acetate, a synthetic progestogen.

Progesterone
Antimineralocorticoid; Neurosteroid
ATC code
Legal status
Legal status
IVTooltip Intravenous injection: 3–90 minutes[17]
ExcretionBile and urine[18][19]
Identifiers
  • (8S,9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one
dioxane, β-form)
Melting point126 °C (259 °F)
  • CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=CC(=O)CC[C@]34C)C
  • 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 checkY
  (verify)

Progesterone (P4), sold under the brand name Prometrium among others, is a

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

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.

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

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

transdermal progesterone cream.[29][22][45][46]

Oral progesterone has been found to significantly reduce

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

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

See also: Feminizing hormone therapy § Progestogens

Progesterone is used as a component of

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 [transgender] women is extremely sparse and based on low quality of evidence. Current evidence does not provide evidence that progestogens enhance breast development in [transgender] 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.

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

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%

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

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

See also: Estradiol/progesterone, Estradiol benzoate/progesterone, and Estradiol hemisuccinate/progesterone

Progesterone is available in a variety of different forms, including

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

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]

Available forms of progesterone[sources 1][a]
Route Form Dose Brand name Availability[b]
Oral Capsule 100, 200, 300 mg Prometrium[c] Widespread
Tablet (SR) 200, 300, 400 mg Dubagest SR[c] India
Sublingual Tablet 10, 25, 50, 100 mg Luteina[c] Europe[d]
Transdermal
 Gel[e] 1% (25 mg) Progestogel Europe
Vaginal
 Capsule 100, 200 mg Utrogestan Widespread
Tablet 100 mg Endometrin[c] Widespread
Gel 4, 8% (45, 90 mg) Crinone[c] Widespread
Suppository 200, 400 mg Cyclogest Europe
Ring 10 mg/day[f] Fertiring[c] South America[g]
Rectal Suppository 200, 400 mg Cyclogest Europe
Uterine
 IUD 38 mg Progestasert Discontinued
Intramuscular
injection
 Oil solution 2, 5, 10, 20, 25,
50, 100 mg/mL		 Proluton[c] Widespread
Aq. susp. 12.5, 30, 100 mg/mL Agolutin[c] Europe[h]
Emulsion 5, 10, 25 mg/mL Di-Pro-Emulsion Discontinued
Microsph. 20, 100 mg/mL ProSphere[c] Mexico
Subcutaneous Aq. soln. (inj.) 25 mg/vial Prolutex Europe
Implant 50, 100 mg Proluton[c] Discontinued
Intravenous
 Aq. soln. (inj.) 20 mg/mL Primolut Discontinued
Sources and footnotes:
  1. ^ Sources: [99][100][101][102][103][104][105][106][107][108][109]
  1. ^ This table only includes products where progesterone is the sole active ingredient.
  2. ^ See also: Progesterone (medication) § Availability
  3. ^ a b c d e f g h i j Other brand names exist.
  4. ^ Specifically in Poland and Ukraine.
  5. ^ For local application to the breasts; negligible systemic effect.
  6. ^ One progesterone vaginal ring provides 10mg of progesterone each day for 3 months.
  7. ^ Specifically in Chile, Ecuador, and Peru.
  8. ^ Specifically the Czech Republic and Slovakia.

Contraindications

premature infants.[110]

Side effects

Progesterone is well tolerated, and many clinical studies have reported no side effects.

cognitive/memory impairment, can also occur.[28][20]

Vaginal progesterone may be associated with

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

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 depression

Progesterone can produce

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

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 cancer

Breast cell proliferation has been found to be significantly increased by the combination of an

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

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.

powered for quantifying breast cancer risk.[126][132]

Worldwide epidemiological evidence on breast cancer risk with menopausal hormone therapy (CGHFBC, 2019)
Therapy <5 years 5–14 years 15+ years
Cases
RRTooltip Adjusted relative risk (95% CI
Tooltip confidence interval) 		Cases
RRTooltip Adjusted relative risk (95% CI
Tooltip confidence interval) 		Cases
RRTooltip Adjusted relative risk (95% CI
Tooltip confidence interval)
Estrogen alone 1259 1.18 (1.10–1.26) 4869 1.33 (1.28–1.37) 2183 1.58 (1.51–1.67)
    By estrogen
        Conjugated estrogens 481 1.22 (1.09–1.35) 1910 1.32 (1.25–1.39) 1179 1.68 (1.57–1.80)
        Estradiol 346 1.20 (1.05–1.36) 1580 1.38 (1.30–1.46) 435 1.78 (1.58–1.99)
        Estropipate (estrone sulfate) 9 1.45 (0.67–3.15) 50 1.09 (0.79–1.51) 28 1.53 (1.01–2.33)
        Estriol 15 1.21 (0.68–2.14) 44 1.24 (0.89–1.73) 9 1.41 (0.67–2.93)
        Other estrogens 15 0.98 (0.46–2.09) 21 0.98 (0.58–1.66) 5 0.77 (0.27–2.21)
    By route
        Oral estrogens – – 3633 1.33 (1.27–1.38) – –
        
Transdermal
estrogens 		– – 919 1.35 (1.25–1.46) – –
        
Vaginal
estrogens 		– – 437 1.09 (0.97–1.23) – –
Estrogen and progestogen 2419 1.58 (1.51–1.67) 8319 2.08 (2.02–2.15) 1424 2.51 (2.34–2.68)
    By progestogen
        (Levo)norgestrel 343 1.70 (1.49–1.94) 1735 2.12 (1.99–2.25) 219 2.69 (2.27–3.18)
        Norethisterone acetate 650 1.61 (1.46–1.77) 2642 2.20 (2.09–2.32) 420 2.97 (2.60–3.39)
        Medroxyprogesterone acetate 714 1.64 (1.50–1.79) 2012 2.07 (1.96–2.19) 411 2.71 (2.39–3.07)
        Dydrogesterone 65 1.21 (0.90–1.61) 162 1.41 (1.17–1.71) 26 2.23 (1.32–3.76)
        Progesterone 11 0.91 (0.47–1.78) 38 2.05 (1.38–3.06) 1 –
        Promegestone 12 1.68 (0.85–3.31) 19 2.06 (1.19–3.56) 0 –
        Nomegestrol acetate 8 1.60 (0.70–3.64) 14 1.38 (0.75–2.53) 0 –
        Other progestogens 12 1.70 (0.86–3.38) 19 1.79 (1.05–3.05) 0 –
    By progestogen frequency
        
Continuous
 – – 3948 2.30 (2.21–2.40) – –
        
Intermittent
 – – 3467 1.93 (1.84–2.01) – –
Progestogen alone 98 1.37 (1.08–1.74) 107 1.39 (1.11–1.75) 30 2.10 (1.35–3.27)
    By progestogen
        Medroxyprogesterone acetate 28 1.68 (1.06–2.66) 18 1.16 (0.68–1.98) 7 3.42 (1.26–9.30)
        Norethisterone acetate 13 1.58 (0.77–3.24) 24 1.55 (0.88–2.74) 6 3.33 (0.81–13.8)
        Dydrogesterone 3 2.30 (0.49–10.9) 11 3.31 (1.39–7.84) 0 –
        Other progestogens 8 2.83 (1.04–7.68) 5 1.47 (0.47–4.56) 1 –
Miscellaneous
    Tibolone – – 680 1.57 (1.43–1.72) – –
Notes:
menopausal hormone therapy and breast cancer risk by the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC). Fully adjusted relative risks
for current versus never-users of menopausal hormone therapy. Source: See template.
Risk of breast cancer with menopausal hormone therapy in large observational studies (Mirkin, 2018)
Study Therapy Hazard ratio (95% CITooltip confidence interval)
E3N-EPIC: Fournier et al. (2005) Estrogen alone 1.1 (0.8–1.6)
Estrogen plus progesterone
    Transdermal estrogen
    Oral estrogen		 0.9 (0.7–1.2)
0.9 (0.7–1.2)
No events
Estrogen plus progestin
    Transdermal estrogen
    Oral estrogen		 1.4 (1.2–1.7)
1.4 (1.2–1.7)
1.5 (1.1–1.9)
E3N-EPIC: Fournier et al. (2008) Oral estrogen alone 1.32 (0.76–2.29)
Oral estrogen plus progestogen
    Progesterone
    Dydrogesterone
    Medrogestone
    Chlormadinone acetate
    Cyproterone acetate
    Promegestone
    Nomegestrol acetate
    Norethisterone acetate
    Medroxyprogesterone acetate
Not analyzeda
0.77 (0.36–1.62)
2.74 (1.42–5.29)
2.02 (1.00–4.06)
2.57 (1.81–3.65)
1.62 (0.94–2.82)
1.10 (0.55–2.21)
2.11 (1.56–2.86)
1.48 (1.02–2.16)
Transdermal estrogen alone 1.28 (0.98–1.69)
Transdermal estrogen plus progestogen
    Progesterone
    Dydrogesterone
    Medrogestone
    Chlormadinone acetate
    Cyproterone acetate
    Promegestone
    Nomegestrol acetate
    Norethisterone acetate
    Medroxyprogesterone acetate
1.08 (0.89–1.31)
1.18 (0.95–1.48)
2.03 (1.39–2.97)
1.48 (1.05–2.09)
Not analyzeda
1.52 (1.19–1.96)
1.60 (1.28–2.01)
Not analyzeda
Not analyzeda
E3N-EPIC: Fournier et al. (2014) Estrogen alone 1.17 (0.99–1.38)
Estrogen plus progesterone or dydrogesterone 1.22 (1.11–1.35)
Estrogen plus progestin 1.87 (1.71–2.04)
CECILE: Cordina-Duverger et al. (2013) Estrogen alone 1.19 (0.69–2.04)
Estrogen plus progestogen
    Progesterone
    Progestins
        Progesterone derivatives
        Testosterone derivatives		 1.33 (0.92–1.92)
0.80 (0.44–1.43)
1.72 (1.11–2.65)
1.57 (0.99–2.49)
3.35 (1.07–10.4)
Footnotes: a = Not analyzed, fewer than 5 cases. Sources: See template.
Risk of breast cancer with menopausal hormone therapy by duration in large observational studies (Mirkin, 2018)
Study Therapy Hazard ratio (95% CITooltip confidence interval)
E3N-EPIC: Fournier et al. (2005)a Transdermal estrogen plus progesterone
    <2 years
    2–4 years
    ≥4 years
0.9 (0.6–1.4)
0.7 (0.4–1.2)
1.2 (0.7–2.0)
Transdermal estrogen plus progestin
    <2 years
    2–4 years
    ≥4 years
1.6 (1.3–2.0)
1.4 (1.0–1.8)
1.2 (0.8–1.7)
Oral estrogen plus progestin
    <2 years
    2–4 years
    ≥4 years
1.2 (0.9–1.8)
1.6 (1.1–2.3)
1.9 (1.2–3.2)
E3N-EPIC: Fournier et al. (2008) Estrogen plus progesterone
    <2 years
    2–4 years
    4–6 years
    ≥6 years
0.71 (0.44–1.14)
0.95 (0.67–1.36)
1.26 (0.87–1.82)
1.22 (0.89–1.67)
Estrogen plus dydrogesterone
    <2 years
    2–4 years
    4–6 years
    ≥6 years
0.84 (0.51–1.38)
1.16 (0.79–1.71)
1.28 (0.83–1.99)
1.32 (0.93–1.86)
Estrogen plus other progestogens
    <2 years
    2–4 years
    4–6 years
    ≥6 years
1.36 (1.07–1.72)
1.59 (1.30–1.94)
1.79 (1.44–2.23)
1.95 (1.62–2.35)
E3N-EPIC: Fournier et al. (2014) Estrogens plus progesterone or dydrogesterone
    <5 years
    ≥5 years
1.13 (0.99–1.29)
1.31 (1.15–1.48)
Estrogen plus other progestogens
    <5 years
    ≥5 years
1.70 (1.50–1.91)
2.02 (1.81–2.26)
Footnotes: a = Oral estrogen plus progesterone was not analyzed because there was a low number of women who used this therapy. Sources: See template.

Blood clots

Whereas the combination of estrogen and a progestin is associated with increased risk of

venous thromboembolism (VTE) relative to estrogen alone, there is no difference in risk of VTE with the combination of estrogen and oral progesterone relative to estrogen alone.[130][133] Hence, in contrast to progestins, oral progesterone added to estrogen does not appear to increase coagulation or VTE risk.[130][133] The reason for the differences between progesterone and progestins in terms of VTE risk are unclear.[134][130][129] However, they may be due to very low progesterone levels and relatively weak progestogenic effects produced by oral progesterone.[130][129] In contrast to oral progesterone, non-oral progesterone—which can achieve much higher progesterone levels—has not been assessed in terms of VTE risk.[130][129]

Overdose

Progesterone is likely to be relatively safe in

deep sleep, though the individuals were still able to be awakened with sufficient stimulation.[119][17][120][121]

Interactions

There are several notable

abuse alone with very high doses.[140] 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.[141][142][143]

Progesterone is a weak but significant agonist of the pregnane X receptor (PXR), and has been found to induce several hepatic cytochrome P450 enzymes, such as CYP3A4, especially when concentrations are high, such as with pregnancy range levels.[144][145][146][147] As such, progesterone may have the potential to accelerate the metabolism of various medications.[144][145][146][147]

Pharmacology

Pharmacodynamics

Main article: Pharmacodynamics of progesterone

Progesterone is a progestogen, or an

γ-aminobutyric acid (GABA).[153]

The PRs are expressed widely throughout the body, including in the

antigonadotropic effects due to its progestogenic activity, and can inhibit ovulation and suppress gonadal sex hormone production.[20]

The activities of progesterone besides those mediated by the PRs and mPRs are also of significance.

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.[28][112][113][156]

There are differences between progesterones and progestins, such as medroxyprogesterone acetate and norethisterone, with implications for pharmacodynamics and pharmacokinetics, as well as for efficacy, tolerability, and safety.[20]

Pharmacokinetics

Main article: Pharmacokinetics of progesterone

The

subcutaneous injection.[157][16][159]

inserts, gels, suppositories or pessaries, and rings.[16]

The bioavailability of progesterone was commonly overestimated due to the immunoassay method of analysis failing to distinguish between progesterone itself and its metabolites.[160][129][130] Newer methods have adjusted the oral bioavailbility estimate from 6.2 to 8.6%[161] down to less than 2.4%.[5]

Chemistry

Steroids

Progesterone is a

dione), one at the C3 position and the other at the C20 position.[162][163] 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.

Derivatives

See also: Progestogen ester, List of progestogens § Progesterone derivatives, List of progestogen esters § Esters of progesterone derivatives, and List of neurosteroids

A large number of

19-nortestosterone derivatives, exemplified by norethisterone (norethindrone) and levonorgestrel, are not derived from progesterone but rather from testosterone.[20]

A variety of synthetic

water-soluble prodrugs of progesterone and its neurosteroid metabolites.[165][166][167][168][169][170]

Synthesis

Chemical syntheses of progesterone have been published.[171]

History

Discovery and synthesis

The hormonal action of progesterone was discovered in 1929.[30][31][172] Pure crystalline progesterone was isolated in 1934 and its chemical structure was determined.[30][31] Later that year, chemical synthesis of progesterone was accomplished.[31][173] Shortly following its chemical synthesis, progesterone began being tested clinically in women.[31][102]

Injections and implants

In 1933 or 1934,

pharmaceutical formulation of progesterone to be marketed for medical use.[176] It was initially a corpus luteum extract, becoming pure synthesized progesterone only subsequently.[177][178][174][179] A clinical study of the formulation was published in 1933.[174][180][178] Multiple formulations of progesterone in oil solution for intramuscular injection, under the brand names Proluton, Progestin, and Gestone, were available by 1936.[177][181] A parenteral route was used because oral progesterone had very low activity and was thought to be inactive.[22][175][179] Progesterone was initially very expensive due to the large doses required.[182] However, with the start of steroid manufacturing from diosgenin in the 1940s, costs greatly decreased.[183]

Subcutaneous pellet implants of progesterone were first studied in women in the late 1930s.[184][185][186][187][188] They were the first long-acting progestogen formulation.[189] Pellets were reported to be extruded out of the skin within a few weeks at high rates, even when implanted beneath the deep fascia, and also produced frequent inflammatory reactions at the site of implantation.[107][186][190] In addition, they were absorbed too slowly and achieved unsatisfactorily low progesterone levels.[107] Consequently, they were soon abandoned, in favor of other preparations such as aqueous suspensions.[107][190][191][189] However, subcutaneous pellet implants of progesterone were later studied as a form of birth control in women in the 1980s and early 1990s, though no preparations were ultimately marketed.[192][193][194][195]

oil solutions, have limited the clinical use of aqueous suspensions of progesterone and other steroids.[201][202][203] Today, a preparation with the brand name Agolutin Depot remains on the market in the Czech Republic and Slovakia.[204][205] A combined preparation of progesterone, estradiol benzoate, and lidocaine remains available with the brand name Clinomin Forte in Paraguay as well.[206] In addition to aqueous suspensions, water-in-oil emulsions of steroids were studied by 1949,[207][208][209] and long-acting emulsions of progesterone were introduced for use by intramuscular injection under the brand names Progestin and Di-Pro-Emulsion (with estradiol benzoate) by the 1950s.[199][210][211][212][213] Due to lack of standardization of crystal sizes, crystalline suspensions of steroids had marked variations in effect.[107] Emulsions were said to be even more unreliable.[107]

combined injectable contraceptives (with estradiol) by the late 1980s and early 1990s but were never marketed.[214][215][216][217][218]

subcutaneous injection in Europe under the brand name Prolutex in the mid-2010s.[221][16]

In the 1950s, long-acting parenteral

progestins such as hydroxyprogesterone caproate, medroxyprogesterone acetate, and norethisterone enanthate were developed and introduced for use by intramuscular injection.[189][222][223] They lacked the need for frequent injections and the injection site reactions associated with progesterone by intramuscular injection and soon supplanted progesterone for parenteral therapy in most cases.[223][222][224]

Oral and sublingual

The first study of oral progesterone in humans was published in 1949.

menstrual disturbances by Upjohn, though it saw limited use.[236][237] Another preparation, which contained progesterone alone, was Synderone (trademark registered by Chemical Specialties in 1952).[238][239][240]

Sublingual progesterone in women was first studied in 1944 by Robert Greenblatt.[241][242][190][225][243][229] Buccal progesterone tablets were marketed by Schering under the brand name Proluton Buccal Tablets by 1949.[244] Sublingual progesterone tablets were marketed under the brand names Progesterone Lingusorbs and Progesterone Membrettes by 1951.[245][246][247] A sublingual tablet formulation of progesterone has been approved under the brand name Luteina in Poland and Ukraine and remains marketed today.[94][95]

Progesterone was the first progestogen that was found to inhibit ovulation, both in animals and in women.

pseudopregnancy" therapy with a combination of high doses of diethylstilbestrol and oral progesterone prevented ovulation and pregnancy in women.[232][261][262][263][264][265]

Unfortunately, the use of oral progesterone as a hormonal contraceptive was plagued by problems.

19-nortestosterone derivatives like noretynodrel and norethisterone.[263][235] These progestins were far more potent than progesterone, requiring much smaller doses orally.[263][235] By December 1955, inhibition of ovulation by oral noretynodrel and norethisterone had been demonstrated in women.[263] These findings as well as results in animals were published in 1956.[266][267] Noretynodrel and norethisterone did not show the problems associated with oral progesterone—in the studies, they fully inhibited ovulation and did not produce menstruation-related side effects.[263] Consequently, oral progesterone was abandoned as a hormonal contraceptive in women.[248][263] The first birth control pills to be introduced were a noretynodrel-containing product in 1957 and a norethisterone-containing product in 1963, followed by numerous others containing a diversity of progestins.[268] Progesterone itself has never been introduced for use in birth control pills.[269]

More modern clinical studies of oral progesterone demonstrating elevated levels of progesterone and end-organ responses in women, specifically progestational endometrial changes, were published between 1980 and 1983.[270][271][272][273] Up to this point, many clinicians and researchers apparently still thought that oral progesterone was inactive.[273][274][275] It was not until almost half a century after the introduction of progesterone in medicine that a reasonably effective oral formulation of progesterone was marketed.[103] Micronization of progesterone and suspension in oil-filled capsules, which allowed progesterone to be absorbed several-fold more efficiently by the oral route, was first studied in the late 1970s and described in the literature in 1982.[276][272][277] This formulation, known as oral micronized progesterone (OMP), was then introduced for medical use under the brand name Utrogestan in France in 1982.[272][34][33][22] Subsequently, oral micronized progesterone was introduced under the brand name Prometrium in the United States in 1998.[161][278] By 1999, oral micronized progesterone had been marketed in more than 35 countries.[161] In 2019, the first combination of oral estradiol and progesterone was introduced under the brand name Bijuva in the United States.[11][279]

A

Madison Pharmacy Associates in Madison, Wisconsin in the United States.[280][281]

Vaginal, rectal, and uterine

Vaginal progesterone suppositories were first studied in women by Robert Greenblatt in 1954.

assisted reproduction and was approved in Latin America by 2007.[294][295]

Development of a progesterone-containing intrauterine device (IUD) for contraception began in the 1960s.[296] Incorporation of progesterone into IUDs was initially studied to help reduce the risk of IUD expulsion.[296] However, while addition of progesterone to IUDs showed no benefit on expulsion rates, it was unexpectedly found to induce endometrial atrophy.[296] This led in 1976 to the development and introduction of Progestasert, a progesterone-containing product and the first progestogen-containing IUD.[73][296][27] Unfortunately, the product had various problems that limited its use.[296][27][73] These included a short duration of efficacy of only one year, a high cost, a relatively high 2.9% failure rate, a lack of protection against ectopic pregnancy, and difficult and sometimes painful insertions that could necessitate use of a local anesthetic or analgesic.[296][27][73] As a result of these issues, Progestasert never became widely used, and was discontinued in 2001.[296][27][73] It was used mostly in the United States and France while it was marketed.[27]

Transdermal and topical

A topical gel formulation of progesterone, for direct application to the breasts as a local therapy for breast disorders such as

over-the-counter without a prescription in the United States.[45][46][98] However, these preparations are unregulated and have not been adequately characterized, with low and unsubstantiated effectiveness.[45][22]

Society and culture

Generic names

Progesterone is the

INNTooltip INN, USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, DCITTooltip Denominazione Comune Italiana, and JANTooltip Japanese Accepted Name, while progestérone is its name in French and its DCFTooltip Dénomination Commune Française.[94][162][163][302] It is also referred to as progesteronum in Latin, progesterona in Spanish and Portuguese, and progesteron in German.[94][163]

Brand names

"Prometrium" redirects here. For the chemical element, see Promethium.
Prometrium 100 mg oral capsule.

Progesterone is marketed under a large number of

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

Availability

Progesterone is widely available in countries throughout the world in a variety of formulations.[94][95] Progesterone in the form of oral capsules; vaginal capsules, tablets/inserts, and gels; and intramuscular oil have widespread availability.[94][95] The following formulations/routes of progesterone have selective or more limited availability:[94][95]

  • A tablet of micronized progesterone which is marketed under the brand name Luteina is indicated for sublingual administration in addition to vaginal administration and is available in Poland and Ukraine.[94][95]
  • A progesterone suppository which is marketed under the brand name Cyclogest is indicated for rectal administration in addition to vaginal administration and is available in Cyprus, Hong Kong, India, Malaysia, Malta, Oman, Singapore, South Africa, Thailand, Tunisia, Turkey, the United Kingdom, and Vietnam.[94][95]
  • An
    subcutaneous injection is marketed under the brand name Prolutex in the Czech Republic, Hungary, Italy, Poland, Portugal, Slovakia, Spain, and Switzerland.[94][95]
  • A non-systemic topical gel formulation of progesterone for local application to the breasts to treat breast pain is marketed under the brand name Progestogel and is available in Belgium, Bulgaria, Colombia, Ecuador, France, Georgia, Germany, Hong Kong, Lebanon, Peru, Romania, Russia, Serbia, Switzerland, Tunisia, Venezuela, and Vietnam.[94][95] It was also formerly available in Italy, Portugal, and Spain, but was discontinued in these countries.[95]
  • A progesterone intrauterine device was previously marketed under the brand name Progestasert and was available in Canada, France, the United States, and possibly other countries, but was discontinued.[95][303]
  • Progesterone vaginal rings are marketed under the brand names Fertiring and Progering and are available in Chile, Ecuador, and Peru.[94][95]
  • A
    sustained-release tablet formulation of oral micronized progesterone (also known as "oral natural micronized progesterone sustained release" or "oral NMP SR") is marketed in India under the brand names Lutefix Pro (CROSMAT Technology), Dubagest SR, Gestofit SR, and Susten SR, among many others.[280][304][305][306][307][308][309][281][94]

In addition to single-drug formulations, the following progesterone combination formulations are or have been marketed, albeit with limited availability:[94][95]

  • A combination pack of progesterone capsules for oral use and estradiol gel for transdermal use is marketed under the brand name Estrogel Propak in Canada.[94][95]
  • A combination pack of progesterone capsules and estradiol tablets for oral use is marketed in an under the brand name Duogestan in Belgium.[94][95]
  • Progesterone and
    aqueous suspension for use by intramuscular injection is marketed under the brand name Cristerona FP in Argentina.[94][95]
  • Progesterone and
    microspheres in an oil solution for use by intramuscular injection is marketed under the brand name Juvenum in Mexico.[94][95][310]
  • Progesterone and estradiol benzoate in an oil solution for use by intramuscular injection is marketed under the brand names Duogynon, Duoton Fort T P, Emmenovis, Gestrygen, Lutofolone, Menovis, Mestrolar, Metrigen Fuerte, Nomestrol, Phenokinon-F, Prodiol, Pro-Estramon-S, Proger F, Progestediol, and Vermagest and is available in Belize, Egypt, El Salvador, Ethiopia, Guatemala, Honduras, Italy, Lebanon, Malaysia, Mexico, Nicaragua, Taiwan, Thailand, and Turkey.[94][95]
  • Progesterone and estradiol hemisuccinate in an oil solution for use by intramuscular injection is marketed under the brand name Hosterona in Argentina.[94][95]
  • Progesterone and estrone for use by intramuscular injection is marketed under the brand name Synergon in Monaco.[94]

United States

See also: List of progestogens available in the United States

As of November 2016, progesterone is available in the United States in the following formulations:[93]

  • Oral: Capsules: Prometrium (100 mg, 200 mg, 300 mg)
  • Vaginal: Tablets: Endometrin (100 mg); Gels: Crinone (4%, 8%)
  • Intramuscular injection: Oil: Progesterone (50 mg/mL)

A 25 mg/mL concentration of progesterone oil for intramuscular injection and a 38 mg/device progesterone intrauterine device (Progestasert) have been discontinued.[93]

An oral combination formulation of micronized progesterone and estradiol in oil-filled capsules (brand name Bijuva) is marketed in the United States for the treatment of menopausal symptoms and endometrial hyperplasia.[311][11]

Progesterone is also available in unregulated custom preparations from

over-the-counter in the United States, although the clinical efficacy of transdermal progesterone is controversial.[45][46][98]

Research

Progesterone was studied as a

combined injectable contraceptives, but were likewise never marketed.[215][217]

Progesterone has been assessed for the suppression of

testicular size, markedly suppressed libido and erectile potency, and resulted in minimal semen volume upon ejaculation.[312][313][315][316]

An

menopausal hormone therapy in the 2000s.[317][318][319] However, development was discontinued in 2007 and the formulation was never marketed.[317]

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  220. ^ Basic Sex Hormone Therapy. Schering A.G. 1962. p. 93,96. Intravenous: The intravenous injection of sex hormones is restricted mainly to specific circumstances where a speedy elevation of hormone levels is required, for example, in treatment of threatened abortion. [...] Crystalline Suspension: With crystalline suspensions the crystalline size governs the rate of absorption and therefore the duration of action. The lack of standardisation of crystalline size in commercial products plus the limits imposed by needle bore, introduces marked variations in effect. The results from emulsified forms are even more unreliable. [...] Hormone Pellets for Implantation: The subcutaneous implantation of sterile tablets was the first means of achieving prolonged action. Such possible factors as encapsulation or extrusion and diminished absorption as the surface area of the pellet is reduced, may be a drawback. Implantation of testosterone (about eight 100 mg. pellets), repeated 6-monthly, is a satisfactory treatment for eunuchoidism and implantation of oestradiol (a 50 mg. pellet remains active for about a year or more) is sometimes a useful procedure. The implantation of progesterone is best discarded altogether; extrusion of pellets (even when placed beneath the deep fascia) and slowness of absorption, in relation to metabolic requirements, make it unsatisfactory and the new depot hormones should be given preference. [...] Sex Hormone Preparations of Schering A.G. Berlin [...] Trade Name: Primolut intravenous. Chemical Description: Progesterone in aqueous solution. Packing: Ampoules of 1 c. c. = 20 mg.
  221. ^ "Progesterone - IBSA". AdisInsight. Springer Nature Switzerland AG.
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  223. ^
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  236. PMID 13030701
    . Cyclogesterin. A relatively new approach to progesterone therapy, Cyclogesterin establishes that this hormone can be effective by the oral route. Primarily indicated to induce menstruation in secondary amenorrhea by oral therapy, it contains 30 mg. of progesterone and 1 mg. of mixed natural estrogens per tablet. One tablet is given three times daily for five consecutive days and therapy is stopped. Menstruation follows in one to six days in the non-pregnant patient. The product is manufactured by the Upjohn Company.
  237. ^ Gutman J (1958). Modern Drug Encyclopedia and Therapeutic Index. Yorke Medical Group. p. 299.
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  245. ^ Remington JP, Cook EF, Martin EW (1951). Remington's Practice of Pharmacy: A Treatise on the Preparing, Standardizing, and Dispensing of Official and Extemporaneous Pharmaceutical Products, with Descriptions of Medicinal Substances, Their Properties, Uses and Doses. Also a Guide to Other Professional Services Rendered by the Pharmacist in Connection with Community Health. Intended for the Use of Pharmacists and Physicians and as a Textbook for Students. Mack Publishing Company. pp. 936–937.
  246. ^ Welsh AL (1951). Dermatological Formulary: A Guide for Medical Students and Resident Physicians in Dermatology. Educational Publishers. p. 155.
  247. ISBN 978-3-662-25655-8
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  248. ^
    PMID 14232795
    . The original observation of Makepeace et al. (1937) that progesterone inhibited ovulation in the rabbit was substantiated by Pincus and Chang (1953). In women, 300 mg of progesterone per day taken orally resulted in ovulation inhibition in 80% of cases (Pincus, 1956). The high dosage and frequent incidence of breakthrough bleeding limited the practical application of the method. Subsequently, the utilization of potent 19-norsteroids, which could be given orally, opened the field to practical oral contraception.
  249. ^
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    PMID 5848673
    . At the Fifth International Conference on Planned Parenthood in Tokyo, Pincus (1955) reported an ovulation inhibition by progesterone or norethynodrel1 taken orally by women. This report indicated the beginning of a new era in the history of contraception. [...] That the cervical mucus might be one of the principal sites of action was suggested by the first studies of Pincus (1956, 1959) and of Ishikawa et al. (1957). These investigators found that no pregnancies occurred in women treated orally with large doses of progesterone, though ovulation was inhibited only in some 70% of the cases studied. [...] The mechanism of protection in this method—and probably in that of Pincus (1956) and of Ishikawa et al. (1957)—must involve an effect on the cervical mucus and/or endometrium and Fallopian tubes.
  255. ^ Pincus G (1955). "Some Effects of Progesterone and Related Compounds upon Reproduction and Early Development in Mammals". The Fifth International Conference on Planned Parenthood: Theme, Overpopulation and Family Planning: Report of the Proceedings, 24-29 October, 1955, Tokyo, Japan. International Planned Parenthood Federation. pp. 175–184.
  256. ^ Stone A, Kupperman HS (1955). "The Effects of Progesterone on Ovulation: A Preliminary Report". The Fifth International Conference on Planned Parenthood: Theme, Overpopulation and Family Planning: Report of the Proceedings, 24-29 October, 1955, Tokyo, Japan. International Planned Parenthood Federation. p. 185. Archived from the original on 2 May 2019. Retrieved 2 May 2019. The results of testing the effects of progesterone on ovulation in 13 patients at the Margaret Sanger Research Bureau are presented. The patients had normal menstrual cycles and showed clear evidence of ovulation. Each patient was given 1000 [mg] of [oral] progesterone daily during the midperiod for 10 or 12 days during 16 cycles. Ovulation was inhibited in 6 cycles. No disturbance in menstrual rhythm was observed. 3 of 12 patients with longstanding infertility histories became pregnant within 2–4 months after the cessation of progesterone therapy.
  257. ^ Ishikawa M, Kyushiro F, Yoshio F, Takashi K, Masanao M, Michio M, et al. (1955). "Some Effects of Progesterone and Related Compounds upon Reproduction and Early Development in Mammals". The Fifth International Conference on Planned Parenthood: Theme, Overpopulation and Family Planning: Report of the Proceedings, 24-29 October, 1955, Tokyo, Japan. International Planned Parenthood Federation. pp. 186–187.
  258. S2CID 33729147
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  259. ^ Ishikawa M, Fujii K, Furusawa Y, Kobayashi T, Makino T, Matsumoto S, et al. "Unknown". J. Jap. Family Plann. Ass. 2: 51–56.
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    . Ishikawa et al. (1957) employing the same regime of progesterone administration also observed suppression of ovulation in a proportion of the cases taken to laparotomy. Although sexual intercourse was practised freely by the subjects of our experiments and those of Ishikawa el al., no pregnancies occurred. Since ovulation presumably took place in a proportion of cycles, the lack of any pregnancies may be due to chance, but Ishikawa et al. (1957) have presented data indicating that in women receiving oral progesterone the cervical mucus becomes impenetrable to sperm.
  261. S2CID 46312750
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  263. ^
    ISBN 978-1-4696-4001-3
    . [...] Still, neither of the two researchers was completely satisfied with the results. Progesterone tended to cause "premature menses," or breakthrough bleeding, in approximately 20 percent of the cycles, an occurrence that disturbed the patients and worried Rock.17 in addition, Pincus was concerned about the failure to inhibit ovulation in all the cases. Only large doses of orally administered progesterone could insure the suppression of ovulation, and these doses were expensive. The mass use of this regimen as a birth control method was thus seriously imperiled.18 [...]
  264. ISBN 978-1-4214-0208-6
    . 43. The first study used progesterone continuously rather than cyclically. Women began by taking 5 mg of stilbestrol and 50 mg of progesterone, increasing the dose of stilbestrol by 5 mg and of progesterone by 50 mg every two weeks. By the end of twelve weeks, women were taking 30 mg stilbestrol and 300 mg of progesterone. If they had vaginal bleeding at any time, the doses were increased. "Pseudopregnancy," typescript, 15 July 1954, GP-LC. Rock also summarizes his early studies in John Rock, Celso-Ramon Garcia, and Gregory Pincus, "Synthetic Progestins in the Normal Human Menstrual Cycle," Recent Progress in Hormone Research, vol. 13 (New York: Academic Press, 1957), 323-24.
  265. ISBN 978-1-4214-0371-7
    . In the early 1950s, independent of Pincus's work in Worcester, Rock successfully induced pregnancy in previously infertile women by treating them for several months with estrogen and progesterone. Although the steroids prevented pregnancy during the course of therapy, some of the women conceived when the treatment ended; this phenomenon became known as the "Rock rebound effect."58 When Pincus learned of Rock's work, he asked the physician to join forces in the hunt for an ovulation inhibitor, and Rock agreed. Pincus suggested two changes in the experimental regimen: use only progesterone (estrogen promoted cancer in laboratory animals) and administer the hormone for twenty days each month (to allow a period of menstruation). Rock achieved the same rate of success in curing infertility (about 15%), but a significant problem remained: tests indicated that about 15 percent of the women ovulated while taking the progesterone.59 Pincus and Rock needed to find an orally active compound that would completely inhibit ovulation. It was time to test the 19-nor steroids in humans. [...]
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  279. ^ "TherapeuticsMD Announces FDA Approval of TX-001HR: BIJUVA™ (Estradiol and Progesterone) Capsules for the Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause".
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Further reading