Progestogen (medication)

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This article is about progestogens as medications. For the role of progestogens as hormones, see Progestogen.
Progestogen (medication)
retropregnanes, androstanes, estranes)
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A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of

bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.[1]

blood clots.[2] At high doses, progestogens can cause low sex hormone levels and associated side effects like sexual dysfunction and an increased risk of bone fractures.[3]

Progestogens are

fertilization.[4][5] They have functional antiestrogenic effects in certain tissues like the endometrium, and this underlies their use in menopausal hormone therapy.[1]

Progesterone was first introduced for medical use in 1934 and the first progestin, ethisterone, was introduced for medical use in 1939.[6][7][8] More potent progestins, such as norethisterone, were developed and started to be used in birth control in the 1950s.[6] Around 60 progestins have been marketed for clinical use in humans or use in veterinary medicine.[9][10][11][12][13] These progestins can be grouped into different classes and generations.[1][14][15] Progestogens are available widely throughout the world and are used in all forms of hormonal birth control and in most menopausal hormone therapy regimens.[1][9][10][12][11]

Medical uses

Available forms

Progestogens marketed for clinical or veterinary use
Generic name Class[a] Brand name Route[b] Intr.
Acetomepregenol P[i][ii] Diamol POTooltip Oral administration 1981
Algestone acetophenide P[i][iii] Deladroxate[c] IMTooltip Intramuscular injection 1964
Allylestrenol T[iv][v] Gestanin[c] PO 1961
Altrenogest[d] T[iv][v] Regumate[c] PO 1980s
Chlormadinone acetate P[i][ii] Belara[c] PO 1965
Cyproterone acetate P[i][ii] Androcur[c] PO, IM 1973
Danazol T[v] Danocrine PO 1971
Delmadinone acetate[d] P[i][ii] Tardak PO 1972
Desogestrel T[iv][vi] Cerazette[c] PO 1981
Dienogest T[iv][v] Natazia[c] PO 1995
Drospirenone S[vii] Angeliq[c] PO 2000
Dydrogesterone RPTooltip retroprogesterone Duphaston PO 1961
Etonogestrel T[iv][vi] Implanon (SC), NuvaRing (V)
V
Tooltip Vaginal administration		 1998
Etynodiol diacetate T[iv][v][ii] Demulen[c] PO 1965
Flugestone acetate[d] P[i][ii] Chronogest PO 1960s
Gestodene T[iv][vi] Femodene[c] PO 1987
Gestonorone caproate P[i][viii][ii] Depostat[c] IM 1968
Gestrinone T[iv][vi] Dimetriose[c] PO 1986
Hydroxyprogesterone caproate P[i][ii] Makena[c] IM 1954
Levonorgestrel T[iv][vi] Plan B[c] PO, TDTooltip Transdermal,
IUD, SC		 1970
Lynestrenol T[iv][v] Exluton[c] PO 1961
Medrogestone P[ix] Colprone PO 1966
Medroxyprogesterone acetate P[i][ii] Provera[c] PO, IM, SC 1958
Megestrol acetate P[i][ii] Megace PO, IM 1963
Melengestrol acetate[d] P[i][ii] Heifermax[c] IM 1960s
Nomegestrol acetate P[viii][ii] Lutenyl[c] PO 1986
Norelgestromin T[iv][vi] Evra[c] TD patch 2002
Norethisterone T[iv][v] Aygestin[c] PO 1957
Norethisterone acetate T[iv][v][ii] Primolut-Nor PO, TD patch 1964
Norethisterone enanthate T[iv][v][ii] Noristerat[c] IM 1957
Norgestimate T[iv][vi][ii] Ortho-Cyclen[c] PO 1986
Norgestomet[d] P[viii][ii] Syncro-Mate B PO 1970s
Norgestrel T[iv][vi] Ovral PO 1966
Normethandrone T[iv][v] Metalutin PO 1957
Osaterone acetate[d] P[i][ii] Ypozane PO 2007
Oxendolone T[iv][v] Prostetin[c] IM 1981
Progesterone BI Prometrium[c] PO, V, IM 1934
Proligestone[d] P[i][iii] Corvinan[c] PO 1975
Promegestone P[viii] Surgestone PO 1983
Segesterone acetate P[i][ii] Elcometrine[c] SC, V 2000
Tibolone T[iv][v] Livial[c] PO 1988
Trimegestone P[viii] Lovelle[c] PO 2001
Legend for class of molecule
  1. ^ a b c d e f g h i j k l m n 17α-hydroxy
  2. ^ a b c d e f g h i j k l m n o p q r Ester
  3. ^ a b Cyclic ketal
  4. ^
    19-nor
  5. ^ a b c d e f g h i j k l estrane
  6. ^ a b c d e f g h Gonane
  7. ^ Spironolactone
  8. ^
    19-nor
  9. ^ 17α-methyl
  1. ^ Classes: P = progesterone derivative, T = testosterone derivative
  2. vaginal
  3. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab Also marketed under other brand names.
  4. ^ a b c d e f g Veterinary use only.

Progestogens are available in many different

subcutaneous injection, and various others (e.g., transdermal patches, vaginal rings, intrauterine devices, subcutaneous implants
).

Dozens of different progestogens have been marketed for

clinical and/or veterinary
use.

Birth control

Progestogens are used in a variety of different forms of hormonal birth control for females, including combined estrogen and progestogen forms like combined oral contraceptive pills, combined contraceptive patches, combined contraceptive vaginal rings, and combined injectable contraceptives; and progestogen-only forms like progestogen-only contraceptive pills ("mini-pills"), progestogen-only emergency contraceptive pills ("day-after pills"), progestogen-only contraceptive implants, progestogen-only intrauterine devices, progestogen-only contraceptive vaginal rings, and progestogen-only injectable contraceptives.[16][17][18][19]

Progestogens mediate their contraceptive effects by multiple mechanisms, including prevention of

ciliary action.[23]

Hormone therapy

Menopause and hypogonadism

Progestogens are used in combination with

menopausal hormone therapy in women. They are also used in combination with estrogens in hormone therapy for hypogonadism and delayed puberty in girls and women. They are used mainly to prevent endometrial hyperplasia and increased risk of endometrial cancer
from unopposed estrogen therapy.

Transgender hormone therapy

Progestogens are used as a component of

menses. Progestogens have also been used to delay puberty in transgender boys and girls
.

Other uses

Certain progestogens, including megestrol acetate, medroxyprogesterone acetate, cyproterone acetate, and chlormadinone acetate, have been used at high doses to reduce hot flashes in men undergoing androgen deprivation therapy, for instance to treat prostate cancer.[24][25][26]

Gynecological disorders

Menstrual disorders

Progestogens are used to treat

breakthrough bleeding.[27]

The progestogen challenge test or progestogen withdrawal test is used to diagnose amenorrhea. Due to the availability of assays to measure estrogen levels, it is now rarely used.

Uterine disorders

Progestogens are used in the prevention and treatment of

uterine fibroids, and uterine hypoplasia
.

Breast disorders

Progestogens are used to treat

topical progesterone, dydrogesterone, promegestone, lynestrenol, medroxyprogesterone acetate, dienogest, and medrogestone.[28][29][31][30]

Progestogens are used in the treatment of

lobuloalveolar development of the breasts, which is required for lactation and breastfeeding
.

Enlarged prostate

Progestogens have been used at high doses to treat

prostate gland
.

Hormone-sensitive cancers

Endometrial cancer

Progestogens were first found to be effective at high doses in the treatment of endometrial hyperplasia and endometrial cancer in 1959.[32][33][34] Subsequently, high-dose gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate were approved for the treatment of endometrial cancer.[35][36][37]

Breast cancer

Progestogens, such as megestrol acetate and medroxyprogesterone acetate, are effective at high doses in the treatment of

antigonadotropic effects.[38]

Prostate cancer

Certain progestogens, particularly those with antiandrogenic properties, have been used at high doses in the treatment of

tumors
.

Fertility and pregnancy

Progestogens are used in

fertility medicine for women. For example, progesterone (or sometimes dydrogesterone or hydroxyprogesterone caproate) is used for luteal support in in-vitro fertilization protocols.[42]

Certain progestogens are used to support

preterm birth in pregnant women with a history of at least one spontaneous preterm birth.[42]

Puberty suppression

Progestogens have been used to treat precocious puberty in both boys and girls. They have also been used to delay puberty in transgender youth.

Sexual deviance

Certain progestogens, such as

erectile function and ability to attain orgasm
.

Skin and hair conditions

Progestogens are used to treat

scalp hair loss, and hidradenitis suppurativa
. They act by suppressing testosterone levels and, in the case of antiandrogenic progestogens, by directly blocking the actions of androgens.

Androgen excess

Progestogens are used to treat hyperandrogenism, such as due to polycystic ovary syndrome and congenital adrenal hyperplasia, in women. Examples include cyproterone acetate and chlormadinone acetate.

Appetite stimulation

Certain progestins can be used at very high doses to

wasting syndromes. In general, they are used in combination with certain other steroid medications such as dexamethasone. Their effects take several weeks to become apparent, but are relatively long-lived when compared to those of corticosteroids. Furthermore, they are recognized as being the only medications to increase lean body mass. Megestrol acetate is the lead drug of this class for the management of cachexia, and medroxyprogesterone acetate is also used.[43][44] The mechanism of action of the appetite-related effects of these two medications is unknown and may not be related to their progestogenic activity. Very high doses of other progestogens, like cyproterone acetate
, have minimal or no influence on appetite and weight.

Contraindications

venous thromboembolism among others.[45][citation needed
]

Side effects

Progestogens have relatively few

premenopausal women.[3]

Results of the Women's Health Initiative (WHI) menopausal hormone therapy randomized controlled trials
Clinical outcome Hypothesized
effect on risk 		Estrogen and progestogen
(CEsTooltip conjugated estrogens 0.625 mg/day p.o. + MPATooltip medroxyprogesterone acetate 2.5 mg/day p.o.)
(n = 16,608, with uterus, 5.2–5.6 years follow up) 		Estrogen alone
(CEsTooltip Conjugated estrogens 0.625 mg/day p.o.)
(n = 10,739, no uterus, 6.8–7.1 years follow up)
HRTooltip Hazard ratio 95% CITooltip Confidence interval
AR
Tooltip Attributable risk 		HRTooltip Hazard ratio 95% CITooltip Confidence interval
AR
Tooltip Attributable risk
Coronary heart disease
 Decreased 1.24 1.00–1.54 +6 / 10,000 PYs 0.95 0.79–1.15 −3 / 10,000 PYs
Stroke Decreased 1.31 1.02–1.68 +8 / 10,000 PYs 1.37 1.09–1.73 +12 / 10,000 PYs
Pulmonary embolism Increased 2.13 1.45–3.11 +10 / 10,000 PYs 1.37 0.90–2.07 +4 / 10,000 PYs
Venous thromboembolism
 Increased 2.06 1.57–2.70 +18 / 10,000 PYs 1.32 0.99–1.75 +8 / 10,000 PYs
Breast cancer Increased 1.24 1.02–1.50 +8 / 10,000 PYs 0.80 0.62–1.04 −6 / 10,000 PYs
Colorectal cancer Decreased 0.56 0.38–0.81 −7 / 10,000 PYs 1.08 0.75–1.55 +1 / 10,000 PYs
Endometrial cancer – 0.81 0.48–1.36 −1 / 10,000 PYs – – –
Hip fractures Decreased 0.67 0.47–0.96 −5 / 10,000 PYs 0.65 0.45–0.94 −7 / 10,000 PYs
Total fractures Decreased 0.76 0.69–0.83 −47 / 10,000 PYs 0.71 0.64–0.80 −53 / 10,000 PYs
Total mortality Decreased 0.98 0.82–1.18 −1 / 10,000 PYs 1.04 0.91–1.12 +3 / 10,000 PYs
Global index – 1.15 1.03–1.28 +19 / 10,000 PYs 1.01 1.09–1.12 +2 / 10,000 PYs
Diabetes – 0.79 0.67–0.93 0.88 0.77–1.01
Gallbladder disease Increased 1.59 1.28–1.97 1.67 1.35–2.06
Stress incontinence – 1.87 1.61–2.18 2.15 1.77–2.82
Urge incontinence
 – 1.15 0.99–1.34 1.32 1.10–1.58
Peripheral artery disease – 0.89 0.63–1.25 1.32 0.99–1.77
Probable dementia Decreased 2.05 1.21–3.48 1.49 0.83–2.66
Abbreviations: CEs =
coronary heart disease, stroke, pulmonary embolism, breast cancer, colorectal cancer, endometrial cancer (estrogen plus progestogen group only), hip fractures, and death
from other causes. Sources: See template.

Mood changes

Birth control

The available evidence on the risk of

bleeding may positively influence mood.[48]

A 2018

confounding factors, but overall show no association of hormonal birth control with depression.[50][51] Randomized controlled trials typically do not find clinically significant influences of hormonal birth control on mood.[50][51] Reviews from before 1980 reported a high incidence of adverse mood effects with combined birth control pills.[48] However, doses of estrogens and progestogens in birth control pills before 1980 were considerably higher than those used today, and these doses frequently caused unpleasant side effects that may have unfavorably influenced mood.[48][55]

Mood with birth control pills may be better with monophasic and continuous formulations than with triphasic and cyclic formulations.

androgenic or antiandrogenic progestins like desogestrel, gestodene, and drospirenone may have a more favorable influence on mood than birth control with more androgenic progestins like levonorgestrel.[48][52] However, androgen supplementation with hormonal birth control has also been reported to improve mood.[48]

Hormonal birth control that suppresses

postpartum period.[61]

Studies suggest a

stress response with hormonal birth control in some women.[59][50]

Hormone therapy

Estrogen therapy appears to have a beneficial influence on mood in

perimenopausal women.[62][63][64] Conversely, research on combined estrogen and progestogen therapy for depressive symptoms in menopausal women is scarce and inconclusive.[62][63] Some researchers contend that progestogens have an adverse influence on mood and reduce the benefits of estrogens on mood,[65][66][2] whereas other researchers maintain that progestogens have no adverse influence on mood.[67][68] Progesterone differs from progestins in terms of effects in the brain and might have different effects on mood in comparison.[2][69][1] The available evidence, although limited, suggests no adverse influence of progesterone on mood when used in menopausal hormone therapy.[70]

Sexual function

In most women, sexual desire is unchanged or increased with combined birth control pills.[71] This is despite an increase in sex hormone-binding globulin (SHBG) levels and a decrease in total and free testosterone levels.[71][72] However, findings are conflicting, and more research is needed.[73]

Blood clots

Physiological levels of estrogen and/or progesterone may also influence risk of VTE—with late menopause (≥55 years) being associated with greater risk than early menopause (≤45 years).[79][80]

Progestogen monotherapy

Progestogens when used by themselves at typical clinical dosages, for instance in

statistical artifact of preferential prescription of depot medroxyprogesterone acetate to women at risk for VTE.[90] Alternatively, medroxyprogesterone acetate may be an exception among progestogens in terms of influence on VTE risk,[88][92][81][94] possibly due to its partial glucocorticoid activity.[1][6][81] In contrast to depot medroxyprogesterone acetate, no increase in VTE risk has been observed with moderately high doses of the related progestin chlormadinone acetate (10 mg/day for 18–20 days/cycle), though based on limited data.[94][95]

Very-high-dose progestogen therapy, including with medroxyprogesterone acetate, megestrol acetate, and cyproterone acetate, has been associated with activation of coagulation and a dose-dependent increased risk of VTE.[82][87][96][97][98][99] In studies with high-dose cyproterone acetate specifically, the increase in VTE risk has ranged from 3- to 5-fold.[96][98][99] The incidence of VTE in studies with very-high-dose progestogen therapy has been found to range from 2 to 8%.[82][100][101] However, the relevant patient populations, namely aged individuals with cancer, are already predisposed to VTE, and this greatly amplifies the risk.[82][87][102]

Estrogen plus progestogen therapy

In contrast to progestogen-only birth control, the addition of progestins to

first-pass effect in the liver.[1][89] Research is mixed on whether addition of progestins to transdermal estradiol is associated with a greater risk of VTE, with some studies finding no increase in risk and others finding higher risk.[103][92][106] Unlike the case of transdermal estradiol, VTE risk is not lower with ethinylestradiol-containing contraceptive vaginal rings and contraceptive patches compared to combined birth control pills with ethinylestradiol.[76][108][81] This is thought to be due to the resistance of ethinylestradiol to hepatic metabolism.[1][109][89][81]

The type of progestin in combined birth control may modulate the risk of VTE.

confounding factors like new-user bias.[113][81] As such, it is unclear whether the higher risk of VTE with newer-generation birth control pills is a real finding or a statistical artifact.[113] Androgenic progestins have been found to antagonize to some degree the effect of estrogens on coagulation.[83][84][75][114][81] First-generation progestins are more androgenic, while newer-generation progestins are weakly androgenic or antiandrogenic, and this might explain the observed differences in risk of VTE.[104][115][75][114] The type of estrogen also influences VTE risk.[109][116][117] Birth control pills containing estradiol valerate are associated with about half the VTE risk of birth control pills with ethinylestradiol.[116][117]

The type of progestogen in combined menopausal hormone therapy may also modulate VTE risk.

vaginal or injectable progesterone, which can achieve luteal-phase levels of progesterone and associated progestogenic effects, has not been characterized in terms of VTE risk.[122]

A 2012

body weight, lower physical activity, and smoking are all associated with a higher risk of VTE with oral estrogen and progestogen therapy.[89][122][123][124] Women with thrombophilia have a dramatically higher risk of VTE with estrogen and progestogen therapy than women without thrombophilia.[76][108] Depending on the condition, risk of VTE can be increased as much as 50-fold in such women relative to non-use.[76][108]

Estrogens induce the production of

estradiol/nomegestrol acetate, and high-dose parenteral polyestradiol phosphate therapy have both been found to increase SHBG levels by about 1.5-fold.[81][134][132][131]

transgender women has been associated with a 20- to 45-fold higher risk of VTE relative to non-use.[102][123] The absolute incidence was about 6%.[102][123] Conversely, the risk of VTE in transgender women is much lower with oral or transdermal estradiol plus high-dose cyproterone acetate.[102][123] Ethinylestradiol is thought to have been primarily responsible for the VTE risk, but cyproterone acetate may have contributed as well.[102] Ethinylestradiol is no longer used in transgender hormone therapy,[135][136][137] and doses of cyproterone acetate have been reduced.[138][139]

Risk of venous thromboembolism (VTE) with hormone therapy and birth control (QResearch/CPRD)
Type Route Medications Odds ratio (95% CITooltip confidence interval)
Menopausal hormone therapy
 Oral Estradiol alone
    ≤1 mg/day
    >1 mg/day		 1.27 (1.16–1.39)*
1.22 (1.09–1.37)*
1.35 (1.18–1.55)*
Conjugated estrogens alone
    ≤0.625 mg/day
    >0.625 mg/day		 1.49 (1.39–1.60)*
1.40 (1.28–1.53)*
1.71 (1.51–1.93)*
Estradiol/medroxyprogesterone acetate 1.44 (1.09–1.89)*
Estradiol/dydrogesterone
    ≤1 mg/day E2
    >1 mg/day E2		 1.18 (0.98–1.42)
1.12 (0.90–1.40)
1.34 (0.94–1.90)
Estradiol/norethisterone
    ≤1 mg/day E2
    >1 mg/day E2		 1.68 (1.57–1.80)*
1.38 (1.23–1.56)*
1.84 (1.69–2.00)*
Estradiol/norgestrel or estradiol/drospirenone
 1.42 (1.00–2.03)
Conjugated estrogens/medroxyprogesterone acetate 2.10 (1.92–2.31)*
Conjugated estrogens/norgestrel
    ≤0.625 mg/day CEEs
    >0.625 mg/day CEEs		 1.73 (1.57–1.91)*
1.53 (1.36–1.72)*
2.38 (1.99–2.85)*
Tibolone alone 1.02 (0.90–1.15)
Raloxifene alone 1.49 (1.24–1.79)*
Transdermal
 Estradiol alone
   ≤50 μg/day
   >50 μg/day		 0.96 (0.88–1.04)
0.94 (0.85–1.03)
1.05 (0.88–1.24)
Estradiol/progestogen 0.88 (0.73–1.01)
Vaginal
 Estradiol alone 0.84 (0.73–0.97)
Conjugated estrogens alone 1.04 (0.76–1.43)
Combined birth control
 Oral Ethinylestradiol/norethisterone 2.56 (2.15–3.06)*
Ethinylestradiol/levonorgestrel 2.38 (2.18–2.59)*
Ethinylestradiol/norgestimate
 2.53 (2.17–2.96)*
Ethinylestradiol/desogestrel 4.28 (3.66–5.01)*
Ethinylestradiol/gestodene 3.64 (3.00–4.43)*
Ethinylestradiol/drospirenone 4.12 (3.43–4.96)*
Ethinylestradiol/cyproterone acetate 4.27 (3.57–5.11)*
Notes: (1)
Bioidentical progesterone was not included, but is known to be associated with no additional risk relative to estrogen alone. Footnotes: * = Statistically significant
(p < 0.01). Sources: See template.

Cardiovascular health

Progestogens may influence the risk of

venous thromboembolic events.[148] It is thought that androgenic progestins like medroxyprogesterone acetate and norethisterone may antagonize the beneficial effects of estrogens on biomarkers of cardiovascular health (e.g., favorable lipid profile changes).[118][149] However, these findings are mixed and controversial.[149] Differences of progestogens on cardiovascular health and risk have been reviewed and summarized:[118]

"Unfortunately, there are few long-term clinical studies comparing different progestogens used in [hormone therapy] with respect to cardiovascular outcomes. However, some aspects of potential cardiovascular risk have been examined, namely effects on lipids, vascular function/blood pressure, inflammation, thrombosis, and carbohydrate metabolism. [...] Although progestins have differing effects on aspects of cardiovascular risk, in general, those more similar to progesterone have been associated with a lower impact than the more androgenic progestins on the beneficial effects of concomitant estrogen therapy. However, the limited number of long-term clinical studies makes it difficult to extrapolate the short-term effects on various markers of cardiovascular risk to long-term cardiovascular morbidity."[118]

Route of administration might also influence the cardiovascular health effects of progestogens, but more research is needed similarly.[150]

Breast cancer

Estrogen alone, progestogen alone, and combined estrogen and progestogen therapy are all associated with increased risks of breast cancer when used in

postmenopausal women relative to non-use.[151][152][153] These risks are higher for combined estrogen and progestogen therapy than with estrogen alone or progestogen alone.[151][153] In addition to breast cancer risk, estrogen alone and estrogen plus progestogen therapy are associated with higher breast cancer mortality.[154] With 20 years of use, breast cancer incidence is about 1.5-fold higher with estrogen alone and about 2.5-fold higher with estrogen plus progestogen therapy relative to non-use.[151] The increase in breast cancer risk with estrogen and progestogen therapy was shown to be causal with conjugated estrogens plus medroxyprogesterone acetate in the Women's Health Initiative randomized controlled trials.[122][155]

Breast cancer risk with combined estrogen and progestogen therapy may differ depending on the progestogen used.

oral progesterone and dydrogesterone with short-term use (<5 years) may be associated with lower risk of breast cancer relative to other progestins.[152][151][118][156] In the long-term however (>5 years), oral progesterone and dydrogesterone have been associated with significantly increased breast cancer risk similarly to other progestogens.[151][157] The lower risk of breast cancer with oral progesterone than with other progestogens may be related to the very low progesterone levels and relatively weak progestogenic effects it produces.[158][122][6]

The risk of breast cancer with estrogen and progestogen therapy in peri- and postmenopausal women is dependent on the duration of treatment, with more than 5 years of use being associated with significantly greater risk than less than five years of use.[151][152] In addition, continuous estrogen and progestogen therapy is associated with a higher risk of breast cancer than cyclic use.[151][152]

A nationwide

cisgender women.[159][160][161][162] The extent to which the increase in breast cancer risk was related to estrogen versus cyproterone acetate is unknown.[159][160][161][162]

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.

Overdose

Progestogens are relatively safe in acute

overdose.[citation needed
]

Interactions

5α-reductase may interact with progestogens.[citation needed
]

Pharmacology

Pharmacodynamics

See also: Pharmacodynamics of progesterone

Progestogens act by binding to and activating the

antimineralocorticoid activity.[1][2][47]

Progestogens mediate their contraceptive effects in women both by inhibiting

fertilization of the ovum by sperm.[4][5] Progestogens have functional antiestrogenic effects in various tissues like the endometrium via activation of the PR, and this underlies their use in menopausal hormone therapy (to prevent unopposed estrogen-induced endometrial hyperplasia and endometrial cancer).[1] The PRs are induced in the breasts by estrogens, and for this reason, it is assumed that progestogens cannot mediate breast changes in the absence of estrogens.[167] The off-target activities of progestogens can contribute both to their beneficial effects and to their adverse effects.[1][2][58]

Pharmacodynamics of progestogens
Progestogen Class Off-target activities
Relative binding affinities
(%)
ES
AN
Tooltip Androgenic
AA
Tooltip Antiandrogenic		 GCTooltip Glucocorticoid
AM
Tooltip Antimineralocorticoid		 PRTooltip Progesterone receptor ARTooltip Androgen receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor SHBGTooltip Sex hormone-binding globulin
CBG
Tooltip Corticosteroid binding globulin
Allylestrenola Estrane – ± – – – 1 0 0 0 ? 0 ?
Chlormadinone acetate Pregnane – – + + – 67 5 0 8 0 0 0
Cyproterone acetate Pregnane – – ++ + – 90 6 0 6 8 0 0
Demegestone Norpregnane – – – – – 115 1 0 5 1–2 ? ?
Desogestrela Gonane – + – ± – 1 0 0 0 0 0 0
Dienogest Gonane – – + – – 5 10 0 1 0 0 0
Drospirenone Spirolactone – – + – + 35 65 0 6 230 0 0
Dydrogesteronea Pregnane – – – – ± 75 0 ? ? ? ? ?
Ethisterone Androstane – + – – – 18 0 0 0 0 ? ?
Etonogestrel Gonane – + – ± – 150 20 0 14 0 15 0
Etynodiola,b Estrane + + – – – 1 0 11–18 0 ? ? ?
Etynodiol diacetatea Estrane + + – – – 1 0 0 0 0 ? ?
Gestodene Gonane – + – + + 90–432 85 0 27–38 97–290 40 0
Gestonorone caproate Pregnane – – – – – ? ? ? ? ? ? ?
Hydroxyprogesterone caproate Pregnane – – – – ± ? ? ? ? ? ? ?
Levonorgestrel Gonane – + – – – 150–162 45 0 1–8 17–75 50 0
Lynestrenola Estrane + + – – – 1 1 3 0 0 ? ?
Medrogestone Pregnane – – ± – – ? ? ? ? ? ? ?
Medroxyprogesterone acetate Pregnane – ± – + – 115–149 5 0 29–58 3–160 0 0
Megestrol acetate Pregnane – ± + + – 65 5 0 30 0 0 0
Nomegestrol acetate Norpregnane – – + – – 125 42 0 6 0 0 0
Norelgestromin Gonane – ± – – – 10 0 ? ? ? 0 ?
Norethisterone Estrane + + – – – 67–75 15 0 0–1 0–3 16 0
Norethisterone acetatea Estrane + + – – – 20 5 1 0 0 ? ?
Norethisterone enanthatea Estrane + + – – – ? ? ? ? ? ? ?
Noretynodrela Estrane + ± – – – 6 0 2 0 0 0 0
Norgestimatea Gonane – + – – – 15 0 0 1 0 0 0
Progesterone Pregnane – – ± + + 50 0 0 10 100 0 36
Promegestonea Norpregnane – – – + – 100 0 0 5 53 0 0
Segesterone acetate Norpregnane – – – – – 136 0 0 38 ? 0 ?
Tibolonea Estrane + ++ – – – 6 6 1 ? ? ?
Δ4-Tiboloneb Estrane – ++ – – – 90 35 1 0 2 1 0
Trimegestone Norpregnane – – ± – ± 294–330 1 0 9–13 42–120 ? ?
Footnotes: a =
CBGTooltip Corticosteroid-binding globulin: Cortisol
= 100%. Sources: See template.
Oral potencies of progestogens[data 1]
Compound Doses for specific uses (mg/day)[a]
OID TFD MDT BCPD ECD
Cycle Daily
Allylestrenol 25 150–300 - 30 – -
Bromoketoprogesterone[b] - - 100–160 - – -
Chlormadinone acetate 1.5–4.0 20–30 3–10 1.0–4.0 2.0 5–10
Cyproterone acetate 1.0 20–30 1.0–3.0 1.0–4.0 2.0 1.0
Desogestrel 0.06 0.4–2.5 0.15 0.25 0.15 0.15
Dienogest 1.0 6.0–6.3 - - 2.0–3.0 2.0
Drospirenone 2.0 40–80 - - 3.0 2.0
Dydrogesterone >30 140–200 10–20 20 – 10
Ethisterone - 200–700 50–250 - – -
Etynodiol diacetate 2.0 10–15 - 1.0 1.0–20 -
Gestodene 0.03 2.0–3.0 - - 0.06–0.075 0.20
Hydroxyprogest. acetate - - 70–125 - 100 -
Hydroxyprogest. caproate - 700–1400 70 - – -
Levonorgestrel 0.05 2.5–6.0 0.15–0.25 0.5 0.1–0.15 0.075
Lynestrenol 2.0 35–150 5.0 10 - -
Medrogestone 10 50–100 10 15 – 10
Medroxyprogest. acetate 10 40–120 2.5–10 20–30 5–10 5.0
Megestrol acetate >5[c] 30–70 - 5–10 1.0–5.0 5.0
Nomegestrol acetate 1.25–5.0 100 5.0 - 2.5 3.75–5.0
Norethandrolone[b] - - 10 - – -
Norethisterone 0.4–0.5 100–150 5–10 10–15 0.5 0.7–1.0
Norethisterone acetate 0.5 30–60 2.5–5.0 7.5 0.6 1.0
Norethist. acetate (micron.) - 12–14 - - – -
Noretynodrel 4.0 150–200 - 14 2.5–10 -
Norgestimate 0.2 2.0–10 - - 0.25 0.09
Norgestrel 0.1 12 - 0.5–2.0 - -
Normethandrone - 150 10 - – -
Progesterone (non-micron.) >300[d] - - - - -
Progesterone (micronized) - 4200 200–300 1000 – 200
Promegestone 0.5 10 0.5 - – 0.5
Tibolone 2.5 - - - – -
Trengestone - 50–70 - - – -
Trimegestone 0.5 - 0.25–0.5 - – 0.0625–0.5
Notes and sources
  1. ^ [168][169][170][171][172][173][174][175][176][177][178][179][180][181][182][183][184][185][186][187]
  1. ^ Dosages are expressed in mg/day unless otherwise noted
  2. ^ a b Never marketed as a progestogen.
  3. ^ The exact OID of MGA is unknown, but it is known to be greater than 5 mg/day.[188][189][190]
  4. ^ Ovulation inhibition rate with 300 to 1,000 mg/day oral non-micronized P4 was incomplete.[191][182][192][193][194][195]
Parenteral potencies and durations of progestogens[a][b]
Compound Form Dose for specific uses (mg)[c] DOA[d]
TFD[e] POICD[f] CICD[g]
Algestone acetophenide Oil soln. - – 75–150 14–32 d
Gestonorone caproate Oil soln. 25–50 – – 8–13 d
Hydroxyprogest. acetate[h] Aq. susp. 350 – – 9–16 d
Hydroxyprogest. caproate Oil soln. 250–500[i] – 250–500 5–21 d
Medroxyprog. acetate Aq. susp. 50–100 150 25 14–50+ d
Megestrol acetate Aq. susp. - – 25 >14 d
Norethisterone enanthate Oil soln. 100–200 200 50 11–52 d
Progesterone Oil soln. 200[i] – – 2–6 d
Aq. soln. ? – – 1–2 d
Aq. susp. 50–200 – – 7–14 d
Notes and sources:
  1. ^ Sources: [196][197][198][199][200][201][202][203][204][205][206][207][208][209][210][211][212][213][214]
  2. subcutaneous injection
    .
  3. OID
    Tooltip ovulation-inhibiting dose of OHPC is 250 to 500 mg/month.
  4. ^ Duration of action in days.
  5. ^ Usually given for 14 days.
  6. ^ Usually dosed every two to three months.
  7. ^ Usually dosed once monthly.
  8. ^ Never marketed or approved by this route.
  9. ^ a b In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4).

Antigonadotropic effects

Progestogens, similarly to the androgens and estrogens through their own respective

antigonadotropic effects,[218] and progestogens in sufficiently high amounts can markedly suppress the body's normal production of progestogens, androgens, and estrogens as well as inhibit fertility (ovulation in women and spermatogenesis in men).[217]

Progestogens have been found to maximally suppress circulating testosterone levels in men by up to 70 to 80% at sufficiently high doses.

high-dose estrogen therapy, which can suppress testosterone levels into the castrate range similarly to GnRH analogues.[222]

The

progonadotropic effects, and is actually able to induce ovulation, with about a 50% success rate on average.[223] These progestins also show other atypical properties relative to other progestogens, such as a lack of a hyperthermic effect.[1][223]

Androgenic activity

See also: Progestin-induced virilization

Some progestins have

17α-hydroxyprogesterone derivatives medroxyprogesterone acetate and megestrol acetate.[227][225][228] No other progestins have such activity (though some, conversely, possess antiandrogenic activity).[225][228] Moreover, the androgenic activity of progestins within the testosterone derivatives also varies, and while some may have high or moderate androgenic activity, others have only low or no such activity.[21][229]

The androgenic activity of androgenic progestins is mediated by two mechanisms: 1) direct binding to and activation of the androgen receptor; and 2) displacement of testosterone from sex hormone-binding globulin (SHBG), thereby increasing free (and thus bioactive) testosterone levels.[230] The androgenic activity of many androgenic progestins is offset by combination with ethinylestradiol, which robustly increases SHBG levels, and most oral contraceptives in fact markedly reduce free testosterone levels and can treat or improve acne and hirsutism.[230] An exception is progestin-only contraceptives, which do not also contain an estrogen.[230]

The relative androgenic activity of testosterone-derivative progestins and other progestins that have androgenic activity can be roughly ranked as follows:

The clinical androgenic and

nandrolone esters
. As such, they are only generally associated with such effects in women and often only at high doses. In men, due to their concomitant progestogenic activity and by extension antigonadotropic effects, these progestins can have potent functional antiandrogenic effects via suppression of testosterone production and levels.

Antiandrogenic activity

Some progestogens have

seborrhea, hirsutism, and other androgen-dependent conditions in women.[1][248]

Estrogenic activity

A few progestins have weak estrogenic activity.[1] These include the 19-nortestosterone derivatives norethisterone, noretynodrel, and tibolone, as well as the norethisterone prodrugs[251] norethisterone acetate, norethisterone enanthate, lynestrenol, and etynodiol diacetate.[1] The estrogenic activity of norethisterone and its prodrugs are due to metabolism into ethinylestradiol.[1] High doses of norethisterone and noretynodrel have been associated with estrogenic side effects such as breast enlargement in women and gynecomastia in men, but also with alleviation of menopausal symptoms in postmenopausal women.[252] In contrast, non-estrogenic progestins were not found to be associated with such effects.[252]

Glucocorticoid activity

Some progestogens, mainly certain

neuropsychiatric symptoms like depression, anxiety, irritability, and cognitive impairment.[253][254][255] Progestogens with the potential for clinically relevant glucocorticoid effects include the 17α-hydroxyprogesterone derivatives chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate, promegestone, and segesterone acetate and the testosterone derivatives desogestrel, etonogestrel, and gestodene.[1][254][256][257] Conversely, hydroxyprogesterone caproate possesses no such activity, while progesterone itself has very weak glucocorticoid activity.[258][1]

Glucocorticoid activity of selected steroids in vitro
Steroid Class TRTooltip Thrombin receptor (↑)a GRTooltip glucocorticoid receptor (%)b
Dexamethasone Corticosteroid ++ 100
Ethinylestradiol Estrogen – 0
Etonogestrel Progestin + 14
Gestodene Progestin + 27
Levonorgestrel Progestin – 1
Medroxyprogesterone acetate Progestin + 29
Norethisterone Progestin – 0
Norgestimate Progestin – 1
Progesterone Progestogen + 10
Footnotes: a =
RBATooltip Relative binding affinity (%) for the glucocorticoid receptor (GR). Strength: – = No effect. + = Pronounced effect. ++ = Strong effect. Sources: [259]

Antimineralocorticoid activity

Certain progestogens, including

antimineralocorticoid activity.[1][58] Other progestins might also have significant antimineralocorticoid activity.[260] Progesterone itself has potent antimineralocorticoid activity.[1] No clinically used progestogens are known to have mineralocorticoid activity.[1]

Progestins with potent antimineralocorticoid activity like drospirenone may have properties more similar to those of natural progesterone, such as counteraction of cyclical estrogen-induced

cardiovascular health.[261][262][263][264]

Neurosteroid activity

Progesterone has

positive allosteric modulators of the GABAA receptor.[1] As a result, it has associated effects such as sedation, somnolence, and cognitive impairment.[1] No progestin is known to have similar such neurosteroid activity or effects.[1] However, promegestone has been found to act as a non-competitive antagonist of the nicotinic acetylcholine receptor similarly to progesterone.[265]

Other activities

Certain progestins have been found to stimulate the

progesterone receptor membrane component-1 (PGRMC1).[266] Norethisterone, desogestrel, levonorgestrel, and drospirenone strongly stimulate proliferation and medroxyprogesterone acetate, dienogest, and dydrogesterone weakly stimulate proliferation, whereas progesterone, nomegestrol acetate, and chlormadinone acetate act neutrally in the assay and do not stimulate proliferation.[266][267] It is unclear whether these findings may explain the different risks of breast cancer observed with progesterone, dydrogesterone, and other progestins such as medroxyprogesterone acetate and norethisterone in clinical studies.[268]

Pharmacokinetics

See also: Pharmacokinetics of progesterone

Transdermal administration of progesterone in the form of creams or gels achieves only very low levels of progesterone and weak progestogenic effects.[278][279]

Due to the poor oral activity of progesterone and its short duration with intramuscular injection, progestins were developed in its place both for oral use and for parenteral administration.

aqueous suspension, have durations in the range of weeks to months.[273][274][275][276][277]

Pharmacokinetics of progestogens
Progestogen Class Dosea Bioavailability
Half-life
Tooltip Elimination half-life
Allylestrenol Estrane NA ? Prodrug
Chlormadinone acetate Pregnane 2 mg ~100% 80 hours
Cyproterone acetate Pregnane 2 mg ~100% 54–79 hours
Desogestrel Gonane 0.15 mg 63% Prodrug
Dienogest Gonane 4 mg 96% 11–12 hours
Drospirenone Spirolactone 3 mg 66% 31–33 hours
Dydrogesterone Pregnane 10 mg 28% 14–17 hours
Etynodiol diacetate Estrane NA ? Prodrug
Gestodene Gonane 0.075 mg 88–99% 12–14 hours
Hydroxyprogesterone caproate Pregnane ND – 8 daysb
Levonorgestrel Gonane 0.15–0.25 mg 90% 10–13 hours
Lynestrenol Estrane NA ? Prodrug
Medrogestone Pregnane 5 mg ~100% 35 hours
Medroxyprogesterone acetate Pregnane 10 mg ~100% 24 hours
Megestrol acetate Pregnane 160 mg ~100% 22 hours
Nomegestrol acetate Pregnane 2.5 mg 60% 50 hours
Norethisterone Estrane 1 mg 64% 8 hours
Norethisterone acetate Estrane NA ? Prodrug
Noretynodrel Estrane NA ? Prodrug
Norgestimate Gonane NA ? Prodrug
Progesterone (micronized) Pregnane 100–200 mg <2.4% 5 hours
Promegestone Pregnane NA ? Prodrug
Tibolone Estrane NA ? Prodrug
Trimegestone Pregnane 0.5 mg ~100% 15 hours
Notes: All by oral administration, unless otherwise noted. Footnotes: a = For the listed pharmacokinetic values. b = By intramuscular injection. Sources: See template.

Chemistry

See also: List of progestogens, Progestogen ester, and List of progestogen esters

All currently available progestogens are

substitutions (see progestogen ester) which result in greater lipophilicity and in some cases cause the progestins in question to act as prodrugs in the body.[1]

Structural aspects of progestogens used in clinical and veterinary medicine
Class Subclass Progestogen Structure Chemical name Features
Pregnane Progesterone Progesterone
Pregn-4-ene-3,20-dione –
Quingestrone
Progesterone 3-cyclopentyl enol ether Ether
17α-Hydroxyprogesterone Acetomepregenol
3-Deketo-3β,17α-dihydroxy-6-dehydro-6-methylprogesterone 3β,17α-diacetate Ester
Algestone acetophenide
16α,17α-Dihydroxyprogesterone 16α,17α-(cyclic acetal with acetophenone)
Cyclic acetal
Anagestone acetate
3-Deketo-6α-methyl-17α-hydroxyprogesterone 17α-acetate Ester
Chlormadinone acetate
6-Dehydro-6-chloro-17α-hydroxyprogesterone 17α-acetate Ester
Chlormethenmadinone acetate
6-Dehydro-6-chloro-16-methylene-17α-hydroxyprogesterone 17α-acetate Ester
Cyproterone acetate
1,2α-Methylene-6-dehydro-6-chloro-17α-hydroxyprogesterone 17α-acetate Ester; Ring-fused
Delmadinone acetate
1,6-Didehydro-6-chloro-17α-hydroxyprogesterone 17α-acetate Ester
Flugestone acetate
9α-Fluoro-11β,17α-dihydroxyprogesterone 17α-acetate Ester
Flumedroxone acetate
6α-(Trifluoromethyl)-17α-hydroxyprogesterone 17α-acetate Ester
Hydroxyprogesterone acetate
17α-Hydroxyprogesterone 17α-acetate Ester
Hydroxyprogesterone caproate
17α-Hydroxyprogesterone 17α-hexanoate Ester
Hydroxyprogesterone heptanoate
17α-Hydroxyprogesterone 17α-heptanoate Ester
Medroxyprogesterone acetate
6α-Methyl-17α-hydroxyprogesterone 17α-acetate Ester
Megestrol acetate
6-Dehydro-6-methyl-17α-hydroxyprogesterone 17α-acetate Ester
Melengestrol acetate
6-Dehydro-6-methyl-16-methylene-17α-hydroxyprogesterone 17α-acetate Ester
Methenmadinone acetate
6-Dehydro-16-methylene-17α-hydroxyprogesterone 17α-acetate Ester
Osaterone acetate
2-Oxa-6-dehydro-6-chloro-17α-hydroxyprogesterone 17α-acetate Ester
Pentagestrone acetate
17α-Hydroxyprogesterone 3-cyclopentyl enol ether 17α-acetate Ester; Ether
Proligestone
14α,17α-Dihydroxyprogesterone 14α,17α-(cyclic acetal with propionaldehyde) Cyclic acetal
Other 17α-substituted progesterone Haloprogesterone
6α-Fluoro-17α-bromoprogesterone –
Medrogestone
6-Dehydro-6,17α-dimethylprogesterone –
Spirolactone Drospirenone
6β,7β:15β,16β-Dimethylenespirolactone Ring-fused
Norpregnane
 19-Norprogesterone;
17α-Hydroxyprogesterone 		Gestonorone caproate
17α-Hydroxy-19-norprogesterone 17α-hexanoate Ester
Nomegestrol acetate
6-Dehydro-6-methyl-17α-hydroxy-19-norprogesterone 17α-acetate Ester
Norgestomet
11β-Methyl-17α-hydroxy-19-norprogesterone 17α-acetate Ester
Segesterone acetate
16-Methylene-17α-hydroxy-19-norprogesterone 17α-acetate Ester
19-Norprogesterone;
Other 17α-substituted progesterone 		Demegestone
9-Dehydro-17α-methyl-19-norprogesterone –
Promegestone
9-Dehydro-17α,21-dimethyl-19-norprogesterone –
Trimegestone
9-Dehydro-17α,21-dimethyl-19-nor-21β-hydroxyprogesterone –
Retropregnane
 Retroprogesterone Dydrogesterone
6-Dehydro-9β,10α-progesterone –
Trengestone
1,6-Didehydro-6-chloro-9β,10α-progesterone –
Androstane
17α-Ethynyltestosterone
 Danazol
2,3-d-Isoxazol-17α-ethynyltestosterone Ring-fused
Dimethisterone
6α,21-Dimethyl-17α-ethynyltestosterone –
Ethisterone
17α-Ethynyltestosterone –
Estrane
19-Nortestosterone
;
17α-Ethynyltestosterone 		Etynodiol diacetate
3-Deketo-3β-hydroxy-17α-ethynyl-19-nortestosterone 3β,17β-diacetate Ester
Lynestrenol
3-Deketo-17α-ethynyl-19-nortestosterone –
Norethisterone
17α-Ethynyl-19-nortestosterone –
Norethisterone acetate
17α-Ethynyl-19-nortestosterone 17β-acetate Ester
Norethisterone enanthate
17α-Ethynyl-19-nortestosterone 17β-heptanoate Ester
Noretynodrel
5(10)-Dehydro-17α-ethynyl-19-nortestosterone –
Norgestrienone
9,11-Didehydro-17α-ethynyl-19-nortestosterone –
Quingestanol acetate
17α-Ethynyl-19-nortestosterone 3-cyclopentyl enol ether 17β-acetate Ester; Ether
Tibolone
5(10)-Dehydro-7α-methyl-17α-ethynyl-19-nortestosterone –
19-Nortestosterone;
Other 17α-substituted testosterone
(and 16β-substituted testosterone) 		Allylestrenol
3-Deketo-17α-allyl-19-nortestosterone –
Altrenogest
9,11-Didehydro-17α-allyl-19-nortestosterone –
Dienogest
9-Dehydro-17α-cyanomethyl-19-nortestosterone –
Norgesterone
5(10)-Dehydro-17α-vinyl-19-nortestosterone –
Normethandrone
17α-Methyl-19-nortestosterone –
Norvinisterone
17α-Vinyl-19-nortestosterone –
Oxendolone
16β-Ethyl-19-nortestosterone –
Gonane 19-Nortestosterone;
17α-Ethynyltestosterone;
18-Methyltestosterone 		Desogestrel
3-Deketo-11-methylene-17α-ethynyl-18-methyl-19-nortestosterone –
Etonogestrel
11-Methylene-17α-ethynyl-18-methyl-19-nortestosterone –
Gestodene
15-Dehydro-17α-ethynyl-18-methyl-19-nortestosterone –
Gestrinone
9,11-Didehydro-17α-ethynyl-18-methyl-19-nortestosterone –
Levonorgestrel
17α-Ethynyl-18-methyl-19-nortestosterone –
Norelgestromin
17α-Ethynyl-18-methyl-19-nortestosterone 3-oxime Oxime
Norgestimate
17α-Ethynyl-18-methyl-19-nortestosterone 3-oxime 17β-acetate Oxime; Ester
Norgestrel
rac-13-Ethyl-17α-ethynyl-19-nortestosterone –

History

Historical progestogens no longer marketed for use
Generic name Class[a] Brand name Route[b] Intr.
Anagestone acetate P[i][ii] Anatropin PO 1968
Chlormethenmadinone acetate P[i][ii] Biogest[c] PO 1960s
Demegestone P[iii] Lutionex PO 1974
Dimethisterone T[iv] Lutagan[c] PO 1959
Ethisterone T[iv] Pranone[c] PO,
SL
Tooltip Sublingual		 1939
Flumedroxone acetate P[i][ii] Demigran[c] PO 1960s
Haloprogesterone P[v] Prohalone PO 1961
Hydroxyprogesterone acetate P[i][ii] Prodox PO 1957
Hydroxyprogesterone heptanoate P[i][ii] H.O.P.[c] IM 1950s
Methenmadinone acetate P[i][ii] Superlutin[c] PO 1960s
Noretynodrel T[vi][iv] Enovid PO 1957
Norgesterone T[vi][iv] Vestalin PO 1960s
Norgestrienone T[vi][iv] Ogyline[c] PO 1960s
Norvinisterone T[vi][iv] Neoprogestin[c] PO 1960s
Pentagestrone acetate P[i][ii] Gestovis[c] PO 1961
Quingestanol acetate T[vi][vii][ii][viii] Demovis[c] PO 1972
Quingestrone P[viii] Enol-Luteovis PO 1962
Trengestone RP Retrone PO 1974
Legend for class of molecule
  1. ^ a b c d e f g 17α-hydroxy
  2. ^ a b c d e f g h Ester
  3. 19-nor
  4. ^ a b c d e f estrane
  5. ^ 17-bromo
  6. ^
    19-nor
  7. ^ Gonane
  8. ^ a b ether
  1. ^ Classes: P = progesterone derivative, T = testosterone derivative
  2. vaginal
  3. ^ a b c d e f g h i j Also marketed under other brand names.

The recognition of progesterone's ability to suppress

parenterally
) and, at the same time, serve the purpose of controlling ovulation. The many synthetic hormones that resulted are known as progestins.

The first orally active progestin,

oxidation of the C3 hydroxyl group, followed by rearrangement of the C5(6) double bond to the C4(5) position. The synthesis was designed by chemists Hans Herloff Inhoffen, Willy Logemann, Walter Hohlweg and Arthur Serini at Schering AG in Berlin and was marketed in Germany in 1939 as Proluton C and by Schering in the U.S. in 1945 as Pranone.[282][283][284][285][286]

A more potent orally active progestin, norethisterone (norethindrone, 19-nor-17α-ethynyltestosterone), the C19 nor analogue of ethisterone, synthesized in 1951 by Carl Djerassi, Luis Miramontes, and George Rosenkranz at Syntex in Mexico City, was marketed by Parke-Davis in the U.S. in 1957 as Norlutin, and was used as the progestin in some of the first oral contraceptives (Ortho-Novum, Norinyl, etc.) in the early 1960s.[283][284][285][286][287]

Searle in Skokie, Illinois and used as the progestin in Enovid, marketed in the U.S. in 1957 and approved as the first oral contraceptive in 1960.[283][284][285][286][288]

Society and culture

Generations

Progestins used in birth control are sometimes grouped, somewhat arbitrarily and inconsistently, into generations. One categorization of these generations is as follows:[14]

Alternatively, estranes such as noretynodrel and norethisterone are classified as first-generation while gonanes such as norgestrel and levonorgestrel are classified as second-generation, with less androgenic gonanes such as desogestrel, norgestimate, and gestodene classified as third-generation and newer progestins like drospirenone classified as fourth-generation.[15] Yet another classification system considers there to be only first- and second-generation progestins.[citation needed]

Classification of progestins by generation has been criticized and it has been argued that the classification scheme should be abandoned.[289]

Availability

See also: List of progestogens available in the United States

Progestogens are available widely throughout the world in many different forms. They are present in all birth control pills.

Etymology

Progestogens, also termed progestagens, progestogens, or gestagens, are compounds which act as

19-nortestosterone derivative norethisterone, among many other synthetic progestogens.[118][1] As progesterone is a single compound and has no plural form, the term "progesterones" does not exist and is grammatically incorrect.[143] The terms describing progestogens are often confused.[118][143] However, progestogens have differing activities and effects and it is inappropriate to interchange them.[118][1][143]

Research

A variety of progestins have been studied for use as potential

nandrolone esters.[290] Dual androgens and progestogens such as trestolone and dimethandrolone undecanoate have also been developed and studied as male contraceptives.[294][295] Doses of progestins used in male hormonal contraception have been noted to be in the range of 5 to 12 times the doses used in female hormonal contraception.[296]

See also

References

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  6. ^ a b c d e f g Kuhl H (2011). "Pharmacology of Progestogens" (PDF). J Reproduktionsmed Endokrinol. 8 (1): 157–177.
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    . Ethisterone, the first orally effective progestagen, was synthesized by Inhoffen and Hohlweg in 1938. Norethisterone, a progestogen still used worldwide, was synthesized by Djerassi in 1951. But this progestogen was not used immediately and in 1953 Colton discovered norethynodrel, used by Pincus in the first oral contraceptive. Numerous other progestogens were subsequently synthesized, e.g., lynestrenol and ethynodiol diacetate, which were, in fact, prhormones converted in vivo to norethisterone. All these progestogens were also able to induce androgenic effects when high doses were used. More potent progestogens were synthesized in the 1960s, e.g. norgestrel, norgestrienone. These progestogens were also more androgenic.
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    . Im Prinzip hatten Hohlweg und Inhoffen die Lösung schon 1938 in der Hand, denn ihr Ethinyltestosteron (11) war eine oral wirksame gestagene Verbindung und Schering hatte daraus bereits 1939 ein Medikament (Proluton C®) entwickelt.
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    . Zur Transformation des Endometriums benotigten sie 200-400 mg [ethisterone] pro Cyclus und postulierten eine etwa sechsfach schwachere Wirkung gegenuber dem Progesteron i.m. appliziert.
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    . Table 1 Publications on ovulation inhibition doses of progestins: Progestin: Progesterone. Reference: Pincus (1956). Method: Urinary Pdiol. Daily dose (mg): 300.000. Total number of cycles in all subjects: 61. Total number of ovulation in all subjects: 30. % of ovulation in all subjects: 49.
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    . The anti-ovulatory properties of megestrol acetate 5 mg. plus Mestranol 0.1 mg. were demonstrated in thirty-five women by direct inspection of the ovaries. When given alone, megestrol acetate 5 mg. or Mestranol 0.1 mg. did not prevent ovulation in all cases.
  189. PMID 2471590
    . At 0.25 mg/day MA has no apparent effect on the histology of the endometrium and is not effective as a contraceptive (53). However, at doses of 0.35 and 0.5 mg/day the drug is an effective contraceptive (10). At the 0.5 mg/day dose MA does not inhibit ovulation but does reduce sperm motility in post-coital tests (68).
  190. ISSN 0140-6736
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  191. PMID 945344
    . Early studies on its use as an oral contraceptive showed that, at 300 mg/day (5th to 25th day of the menstrual cycle), progesterone was effective in preventing ovulation through four cycles (263). The related effect of larger doses of progesterone on gonadotropin excretion also has been investigated. Rothchild (264) found that continuous or intermittent intravenously administered progesterone (100-400 mg/day) for 10 days depressed the total amount of gonadotropin excreted into the urine. However, Paulsen et al. (265) found that oral progesterone at 1000 mg/day for 87 days did not have a significant effect on urinary gonadotropin excretion. The efficacy of progesterone as an oral contraceptive was never fully tested, because synthetic progestational agents, which were orally effective, were available.
  192. PMID 13614060
    . Table 1: Effects of oral progesterone on three indexes of ovulation: Medication: Progesterone. Number: 69. Mean cycle length: 25.5 ± 0.59. Per cent positive for ovulation by: Basal temperature: 27. Endometrial biopsy: 18. Vaginal smear: 6. [...] we settled on 300 mg. per day [oral progersterone] as a significantly effective [ovulation inhibition] dosage, and this was administered from the fifth day through the twenty-fourth day of the menstrual cycle. [...] We observed each of 33 volunteer subjects during a control, nontreatment cycle and for one to three successive cycles of medication immediately following the control cycle. As indexes of the occurrence of ovulation, daily basal temperatures and vaginal smears were taken, and at the nineteenth to twenty-second day of the cycle an endometrial biopsy. [...] Although we thus demonstrated the ovulation-inhibiting activity of progesterone in normally ovulating women, oral progesterone medication had two disadvantages: ( l) the large daily dosage ( 300 mg.) which presumably would have to be even larger if one sought 100 per cent inhibition1 [...]
  193. PMID 13394044
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  194. ^ 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.
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  196. ISBN 978-3-662-00942-0
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  197. ISBN 978-3-642-95583-9
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  198. ISBN 978-3-642-96158-8
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  199. ISBN 978-94-009-8195-9
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  200. ISBN 9783110006148
    . 17α-Hydroxyprogesterone caproate is a depot progestogen which is entirely free of side actions. The dose required to induce secretory changes in primed endometrium is about 250 mg. per menstrual cycle.
  201. ISBN 978-3-11-150424-7
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  202. OCLC 278011135
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  203. ISBN 978-0-8247-8291-7
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  211. ^ Chu YH, Li Q, Zhao ZF (April 1986). "Pharmacokinetics of megestrol acetate in women receiving IM injection of estradiol-megestrol long-acting injectable contraceptive". The Chinese Journal of Clinical Pharmacology. The results showed that after injection the concentration of plasma MA increased rapidly. The meantime of peak plasma MA level was 3rd day, there was a linear relationship between log of plasma MA concentration and time (day) after administration in all subjects, elimination phase half-life t1/2β = 14.35 ± 9.1 days.
  212. ISBN 978-3-642-73790-9
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  213. ISBN 978-1-84214-071-0
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  214. ISBN 978-1-284-02542-2
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  218. PMID 368741
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  220. S2CID 5836155
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  224. S2CID 33611807
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    . [Norethisterone] has similar and [norethynodrel] weaker androgenic effects compared to tibolone.
  237. PMID 3543501
    . Similar androgenic potential is inherent to norethisterone and its prodrugs (norethisterone acetate, ethynodiol diacetate, lynestrenol, norethynodrel, quingestanol).
  238. ^
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  239. S2CID 1019532
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  240. ISBN 978-3-540-38916-3
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  241. ISBN 978-0-300-08943-1
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  242. PMID 13753182
    . Pseudohermaphroditism should not be a problem in these patients as it appears that norethynodrel does not possess androgenic properties, but it is believed that Wilkins has now found one such case in a patient who has been on norethynodrel therapy.
  243. S2CID 40426061
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  244. ISSN 0039-128X
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  245. ISBN 978-0-19-860027-5
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    . At the time our studies were initiated, 11 different gestagens have been tested in men. All the oral preparations were used in doses 5 to 12 fold that used in the female oral contraceptive. The only exception was levo-norgestrel which was used in a very low dose, namely 100 µg daily (Fotherby et al. 1972). However, no effect was obtained on sperm count and in vitro sperm penetration.

Further reading
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