Progestin




This article is about progestogens as medications. For the role of progestogens as hormones, see Progestogen.





































Progestin
Drug class

Medroxyprogesterone acetate.svg

Medroxyprogesterone acetate (Provera, Depo-Provera), a progesterone derivative and one of the most widely used progestins.

Class identifiers
Synonyms Synthetic progestogens
Use
Hormonal birth control, hormone therapy, gynecological disorders, fertility and pregnancy support, sex hormone suppression, others
ATC code G03
Biological target
Progesterone receptors (PR-A, PR-B, PR-C)
Chemical class Steroids (pregnanes, norpregnanes, androstanes, estranes)
Clinical data
Drugs.com Drug Classes
External links
MeSH D011372
In Wikidata

A progestin is a type of medication which is used most commonly in hormonal birth control and menopausal hormone therapy.[1] They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications.[1] Progestins are used alone or in combination with estrogens.[1] They are available in a wide variety of formulations and for use by many different routes of administration.[1]


Side effects of progestins include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth, and changes in liver protein production among others.[1][2] Other side effects of progestins include an increased risk of breast cancer, cardiovascular disease, and blood clots.[2] At high dosages, progestins can cause low sex hormone levels and associated side effects like sexual dysfunction and an increased risk of bone fractures.[3]


Progestins are synthetic progestogens and have similar effects to those of the natural hormone progesterone.[1] They act as agonists of the progesterone receptor, and have important effects in the female reproductive system (uterus, cervix, and vagina), the breasts, and the brain.[1] In addition, many progestins also have other hormonal activities, such as androgenic, antiandrogenic, estrogenic, glucocorticoid, or antimineralocorticoid activity.[1] They also have antigonadotropic effects and at sufficiently high dosages can strongly suppress sex hormone production.[1] Progestins mediate their contraceptive effects both by inhibiting ovulation and by thickening cervical mucus, thereby preventing fertilization.[4][5] They have functional antiestrogenic effects in certain tissues like the endometrium, and this underlies their use in menopausal hormone therapy.[1]


Progestins were first introduced for medical use in 1939.[6][7][8] They 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] Progestins are available widely throughout the world and are used in all forms of hormonal birth control and in most menopausal hormone therapy regimens.[9][10][12][11][1]


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Contents






  • 1 Medical uses


    • 1.1 Birth control


    • 1.2 Hormone therapy


    • 1.3 Gynecological disorders


      • 1.3.1 Gynecological cancers




    • 1.4 Fertility and pregnancy


    • 1.5 Sex-hormone suppression


    • 1.6 Appetite stimulation


    • 1.7 Available forms




  • 2 Contraindications


  • 3 Side effects


  • 4 Overdose


  • 5 Interactions


  • 6 Pharmacology


    • 6.1 Pharmacodynamics


      • 6.1.1 Antigonadotropic effects


      • 6.1.2 Androgenic activity


      • 6.1.3 Estrogenic activity


      • 6.1.4 Glucocorticoid activity


      • 6.1.5 Antimineralocorticoid activity


      • 6.1.6 Neurosteroid activity




    • 6.2 Pharmacokinetics




  • 7 Chemistry


  • 8 History


  • 9 Society and culture


    • 9.1 Generations


    • 9.2 Availability




  • 10 Research


  • 11 See also


  • 12 References


  • 13 Further reading





Medical uses



Birth control


Progestins are used in a variety of different forms of hormonal birth control for women, 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]


Progestins mediate their contraceptive effects by multiple mechanisms, including prevention of ovulation via their antigonadotropic effects; thickening of cervical mucus, making the cervix largely impenetrable to sperm; preventing capacitation of sperm due to changes in cervical fluid, thereby making sperm unable to penetrate the ovum; and atrophic changes in the endometrium, making the endometrium unsuitable for implantation.[20][21][22][23] They may also decrease tubal motility and ciliary action.[23]


Combined androgen and progestogen birth control methods for men have been extensively studied but have yet to be approved or marketed.[24]



Hormone therapy


Progestins are commonly used as a component of menopausal hormone therapy in women to prevent endometrial hyperplasia and increased risk of endometrial cancer from unopposed estrogen therapy. They are also used in transgender hormone therapy, including in both feminizing hormone therapy for transgender women (e.g., cyproterone acetate and medroxyprogesterone acetate to help suppress testosterone levels) and masculinizing hormone therapy in transgender men (e.g., medroxyprogesterone acetate to help suppress menses).


Certain progestins, including megestrol acetate, medroxyprogesterone acetate, cyproterone acetate, and chlormadinone acetate have been used to reduce hot flashes in men with prostate cancer.[25][26][27]



Gynecological disorders


Progestins are used to treat gynecological disorders such as secondary amenorrhea, dysfunctional uterine bleeding, and endometriosis.[17][18] In a normal menstrual cycle, declining levels of progesterone triggers menstruation. Norethisterone acetate and medroxyprogesterone acetate may be used to artificially induce progestogen-associated breakthrough bleeding.[28]


Progestogens are also used to treat benign breast disorders.[29][30] They are associated not only with a reduction in breast pain, but also a decrease in breast cell proliferation, a decrease in breast gland size, and a disappearance of breast nodularity.[29][30][31] Progestogens that have been used for such purposes include topical progesterone, dydrogesterone, promegestone, lynestrenol, medroxyprogesterone acetate, dienogest, and medrogestone.[29][30][32][31]



Gynecological cancers


Progestins were first found to be effective at high dosages in the treatment of endometrial hyperplasia and endometrial cancer in 1959.[33][34][35] Subsequently, high-dosage gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate were approved for the treatment of endometrial cancer.[36][37][38]


Progestins, such as megestrol acetate and medroxyprogesterone acetate, are effective at high dosages in the treatment of advanced postmenopausal breast cancer.[39][40] They have been extensively evaluated as a second-line therapy for this indication.[39] However, they produce various side effects, such as dyspnea, weight gain, vaginal bleeding, nausea, fluid retention, hypertension, thrombophlebitis, and thromboembolic complications.[39][40] In addition, megestrol acetate has been found to be significantly inferior to aromatase inhibitors in the treatment of breast cancer, and in relation to this, progestins have been moved down in the sequential therapy of the disease.[39] Megestrol acetate is the only Food and Drug Administration-approved progestin for breast cancer.[39] The mechanism of action of progestins in the treatment of breast cancer is unknown, but may be related to their functional antiestrogenic and/or antigonadotropic effects.[39]



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.[41]


Certain progestins are used to support pregnancy, including hydroxyprogesterone caproate, dydrogesterone, and allylestrenol. They are used questionably for treatment of recurrent pregnancy loss and for prevention of preterm birth in pregnant women with a history of at least one spontaneous preterm birth.[41]



Sex-hormone suppression


Certain progestins are used at high dosages as antigonadotropins to suppress sex hormone production and levels as a form of medical castration for a variety of androgen and estrogen-dependent conditions. Examples of indications include treating prostate cancer, benign prostatic hyperplasia, blocking precocious puberty and puberty in transgender youth, lowering sex hormone levels in transgender people and reducing libido in men with sexual deviance such as in sex offenders, paraphilias, and hypersexuality. Progestins that have been used for such purposes include allylestrenol, chlormadinone acetate,[42]cyproterone acetate, gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone acetate,[43]megestrol acetate, and oxendolone.[44] The progestins that have been used to treat prostate cancer include chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, and megestrol acetate.[45][46] However, only chlormadinone acetate and cyproterone acetate have been approved or commonly used for the treatment of prostate cancer.[46]


Some progestins are also antiandrogens, for instance cyproterone acetate, and can be used to treat androgen-dependent conditions like acne and hirsutism in women.



Appetite stimulation


Certain progestins can be used at very high dosages to increase appetite in conditions like cachexia, anorexia, and 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 drugs 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.[47][48] The mechanism of action of the appetite-related effects of these two drugs is unknown and may not be related to their progestogenic activity.



Available forms


Progestins are available in the form of oral tablets, solutions and suspensions for intramuscular or subcutaneous injection, and a number of other forms (e.g., transdermal patches, vaginal rings, intrauterine devices, subcutaneous implants).
















































































































































































































































































































































































































































































































































































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Progestogens marketed for clinical or veterinary use
Generic name Class Brand name(s) Route(s) Launch Status
Hitsa
Acetomepregenol 17α-OHP; Ester Diamol Oral 1981 Available 2,400
Algestone acetophenide 17α-OHP; Cyclic ketal Deladroxate, others IM 1964 Available 52,200
Allylestrenol 19-NT; Estrane Gestanin, others Oral 1961 Available 61,800
Altrenogest 19-NT; Estrane Regumate, Matrix Veterinary 1980s Veterinary 68,400
Anagestone acetate 17α-OHP; Ester Anatropin Oral 1968 Discontinued 19,500
Chlormadinone acetate 17α-OHP; Ester Belara, others Oral 1965 Available 220,000
Chlormethenmadinone acetate 17α-OHP; Ester Biogest, Agelin Oral 1960s Discontinued 328
Cyproterone acetate 17α-OHP; Ester Androcur, Diane Oral, IM
 1973 Available 461,000
Danazol T; Estrane Danocrine Oral 1971 Available 1,610,000
Delmadinone acetate 17α-OHP; Ester Tardak Veterinary 1972 Veterinary 42,600
Demegestone 19-NP Lutionex Oral 1974 Discontinued 39,000
Desogestrel 19-NT; Gonane Cerazette, Mircette Oral 1981 Available 714,000
Dienogest 19-NT; Estrane Natazia, Qlaira Oral 1995 Available 220,000
Dimethisterone T; Estrane Lutagan, Secrosteron Oral 1959 Discontinued 43,100
Drospirenone SPL Angeliq, Yasmin Oral 2000 Available 570,000
Dydrogesterone RP Duphaston Oral 1961 Available 225,000
Ethisterone T; Estrane Pranone, Proluton-C Oral, sublingual 1939 Discontinued 59,400
Etonogestrel 19-NT; Gonane Implanon, NuvaRing Implant, vaginal (ring) 1998 Available 266,000
Etynodiol diacetate 19-NT; Estrane; Ester Demulen, others Oral 1965 Available 335,400
Flugestone acetate 17α-OHP; Ester Chronogest Veterinary 1960s Veterinary 63,900
Flumedroxone acetate 17α-OHP; Ester Demigran, Leomigran Oral 1960s Discontinued 32,600
Gestodene 19-NT; Gonane Femodene, others Oral 1987 Available 186,000
Gestonorone caproate 19-NP; Ester Depostat, Primostat IM 1973 Available 119,000
Gestrinone 19-NT; Gonane Dimetriose, others Oral 1986 Available 55,300
Haloprogesterone 17α-BP Prohalone Oral 1961 Discontinued 4,520
Hydroxyprogesterone acetate 17α-OHP; Ester Prodox Oral 1957 Discontinued 48,300
Hydroxyprogesterone caproate 17α-OHP; Ester Makena, Proluton IM 1954 Available 438,000
Hydroxyprogesterone heptanoate 17α-OHP; Ester H.O.P., Lutogil A.P. IM 1950s Discontinued 4,950
Levonorgestrel 19-NT; Gonane Plan B, others Oral, patch, IUD, implant 1970 Available 2,310,000
Lynestrenol 19-NT; Estrane Exluton, Ministat Oral 1961 Available 76,600
Medrogestone 17α-MP Colprone Oral 1966 Available 84,700
Medroxyprogesterone acetate 17α-OHP; Ester Provera, Depo-Provera Oral, IM, SC
 1958 Available 1,250,000
Megestrol acetate 17α-OHP; Ester Megace Oral, IM
 1963 Available 510,000
Melengestrol acetate 17α-OHP; Ester Heifermax, MGA Veterinary 1960s Veterinary 81,300
Methenmadinone acetate 17α-OHP; Ester Superlutin, Antigest Oral 1960s Discontinued 4,800
Nomegestrol acetate 19-NP; Ester Lutenyl, Zoely Oral 1986 Available 106,000
Norelgestromin 19-NT; Gonane Evra, Ortho Evra Transdermal (patch) 2002 Available 83,400
Norethisterone 19-NT; Estrane Aygestin, Primolut N Oral 1957 Available 881,000
Norethisterone acetate 19-NT; Estrane; Ester Primolut-Nor Oral, transdermal (patch) 1964 Available 348,000
Norethisterone enanthate 19-NT; Estrane; Ester Noristerat, Norigest IM 1957 Available 104,000
Noretynodrel 19-NT; Estrane Enovid Oral 1957 Discontinued 158,000
Norgesterone 19-NT; Estrane Vestalin Oral 1960s Discontinued 7,130
Norgestimate 19-NT; Gonane; Ester Ortho-Cyclen, Sprintec Oral 1986 Available 361,000
Norgestomet 19-NP; Ester Syncro-Mate B Veterinary 1970s Veterinary 101,000
Norgestrel 19-NT; Gonane Ovral Oral 1966 Available 319,000
Norgestrienone 19-NT; Estrane Ogyline, Planor Oral 1960s Discontinued 57,300
Normethandrone 19-NT; Estrane Metalutin Oral 1957 Available 68,100
Norvinisterone 19-NT; Estrane Neoprogestin, others Oral 1960s Discontinued 22,100
Osaterone acetate 17α-OHP; Ester Ypozane Veterinary 2007 Veterinary 87,600
Oxendolone 19-NT; Estrane Prostetin, Roxenone IM 1981 Available 36,100
Pentagestrone acetate 17α-OHP; Ester Gestovis, Gestovister Oral 1961 Discontinued 3,440
Progesterone P4 Prometrium, others Oral, vaginal, IM, others 1934 Available 11,000,000
Proligestone 17α-OHP; Cyclic ketal Corvinan, Delvosteron Veterinary 1975 Veterinary 22,100
Promegestone 19-NP Surgestone Oral 1983 Available 98,700
Quingestanol acetate 19-NT; Estrane; Ester; Ether Demovis, Pilomin Oral 1972 Discontinued 37,700
Quingestrone P4; Ether Enol-Luteovis Oral 1962 Discontinued 27,600
Segesterone acetate 19-NP; Ester Elcometrine, Nestorone Implant, vaginal (ring) 2000 Available 88,900
Tibolone 19-NT; Estrane Livial, Tibofem Oral 1988 Available 247,000
Trengestone RP Retrone Oral 1974 Discontinued 3,520
Trimegestone 19-NP Lovelle, others Oral 2001 Available 64,500

Footnotes: a = Hits = Google Search hits (as of February 2018). Class: P4 = Progesterone. 17α-OHP = 17α-Hydroxyprogesterone. 17α-MP = 17α-Methylprogesterone. 17α-BP = 17α-Bromoprogesterone. 19-NP = 19-Norprogesterone. RP = Retroprogesterone. T = Testosterone. 19-NT = 19-Nortestosterone. SPL = Spirolactone. Sources: See individual articles.


Contraindications


Contraindications of progestins may include breast cancer and a history of venous thromboembolism among others.[citation needed]



Side effects


Progestogens have relatively few side effects at typical dosages.[49] Side effects of progestins may include tiredness, dysphoria, depression, mood changes, menstrual irregularities, hypomenorrhea, edema, vaginal dryness, vaginal atrophy, headaches, nausea, breast tenderness, decreased libido.[1][2][49] Progestins with androgenic activity, namely 19-nortestosterone derivatives, can also cause acne, hirsutism, seborrhea, voice deepening, changes in liver protein production (e.g., decreased HDL cholesterol, sex hormone-binding globulin), increased appetite, and weight gain, among others.[1][49] Other side effects of progestins include an increased risk of breast cancer, cardiovascular disease, and blood clots, among others.[2] Some of the side effects of progestins are due not to their progestogenic activity but rather due to off-target activities (e.g., androgenic activity, glucocorticoid activity).[1][50] At high dosages, due to their antigonadotropic effects, progestins can cause low sex hormone levels and associated side effects like diminished secondary sexual characteristics, sexual dysfunction (e.g., reduced sex drive and erectile dysfunction), reversible infertility, reduced bone mineral density, and an increased risk of bone fractures, both in men and in premenopausal women.[3]


A 2018 systematic review found no association between progestogen-only contraception and depression in women. However, the systematic review did not use Randomized Placebo-Controlled double blind trials for its review.[51] This is in contrast to other research which found a relationship between hormonal contraceptive use and subsequent prescription antidepressant use.[52]



Overdose


Progestins are relatively safe in acute overdose.[citation needed]



Interactions


Inhibitors and inducers of cytochrome P450 enzymes and other enzymes such as 5α-reductase may interact with progestins.[citation needed]



Pharmacology



Pharmacodynamics


Progestins act by binding to and activating the progesterone receptors (PRs), including the PR-A, PR-B, and PR-C.[1][53][54] Major tissues affected by progestogens include the uterus, cervix, vagina, breasts, and brain.[1] By activating PRs in the hypothalamus and pituitary gland, progestins suppress the secretion of gonadotropins and thereby function as antigonadotropins at sufficiently high dosages.[1] Interaction of progestins with membrane progesterone receptors is less clear.[55][56] Progestins mediate their contraceptive effects in women both by inhibiting ovulation (via their antigonadotropic effects) and by thickening cervical mucus, thereby preventing the possibility of fertilization of the ovum by sperm.[4][5] Progestins 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.[57]


In addition to their progestogenic activity, many progestins have off-target activities such as androgenic, antiandrogenic, estrogenic, glucocorticoid, or antimineralocorticoid activity.[1][2][50] Such actions can contribute both to their beneficial or desirable effects and to their side effects.[1][2][58]

















































































































































































































































































































































































































































































































































































































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Pharmacodynamics of progestogens
Progestogen Class Off-target activities Relative binding affinities (%) Refs
ES AN AA GC AM PR AR ER GR MR SHBG
CBG

Allylestrenola
 Estrane – ± – – – 1 0 0 0 ? 0 ?
[59][60]
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 ? ?
[61][62][63][64]

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 ? ?
[63][64]
Etonogestrel Gonane – + – ± – 150 20 0 14 0 15 0

Etynodiola,b
 Estrane + + – – – 1 0 11–18 0 ? ? ? [65]

Etynodiol diacetatea
 Estrane + + – – – 1 0 0 0 0 ? ?
Gestodene Gonane – + – + + 90–432 85 0 27–38 97–290 40 0 [66]
Gestonorone caproate Pregnane – – – – – ? ? ? ? ? ? ?
Hydroxyprogesterone caproate Pregnane – – – – ± ? ? ? ? ? ? ?
[67][68][69]
Levonorgestrel Gonane – + – – – 150–162 45 0 1–8 17–75 50 0 [66]

Lynestrenola
 Estrane + + – – – 1 1 3 0 0 ? ?
Medrogestone Pregnane – – ± – – ? ? ? ? ? ? ?
Medroxyprogesterone acetate Pregnane – ± – + – 115–149 5 0 29–58 3–160 0 0 [66]
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 [66]

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 ? ? [66]

Footnotes: a = Prodrug. b = Metabolite (non-marketed). Class: Pregnane = Progesterone derivative. Norpregnane = 19-Norprogesterone derivative. Androstane = Testosterone derivative. Estrane = 19-Nortestosterone derivative. Gonane = 13β-Ethylgonane = 18-Methyl-19-nortestosterone derivative. Spirolactone = Spirolactone derivative. Magnitude: ++ = High. + = Moderate. ± = Low. – = None. Activity: ES = Estrogenic. AN = Androgenic. AA = Antiandrogenic. GC = Glucocorticoid. AM = Antimineralocorticoid. Binding: PR: Promegestone = 100%. AR: Metribolone = 100%. ER: Estradiol = 100%. GR: Dexamethasone = 100%. MR: Aldosterone = 100%. SHBG: DHT = 100%. CBG: Cortisol = 100%. Sources: [70][1][71][72][73][74]

























































































































































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Pharmacodynamics of progestin metabolites
Progestogen Class
RBA (%)
PR AR
ER
Norethisterone Estrane 67–75 15 0
  5α-Dihydronorethisterone
 Estrane 25 27 0
Levonorgestrel Gonane 150–162 34c, 45 0
  5α-Dihydrolevonorgestrel
 Gonane 50 38c
 0

Norgestimatea
 Gonane 15 0 0
  Norelgestrominb
 Gonane 10 0 ?
  Levonorgestrel
 Gonane 150 45 0
  Levonorgestrel 17β-acetate
 Gonane 135 ? 0

Desogestrela
 Gonane 1 0 0
  Etonogestrelb
 Gonane 150 20 0
  3β-Hydroxydesogestrel Gonane 13 3 2
  5α-Dihydroetonogestrel Gonane 9 17 0
Dienogest Estrane 5 10 0
  9α,10β-Dihydrodienogest Estrane 26 13 ?
  3α,5α-Tetrahydrodienogest Estrane 19 16 ?

Tibolonea
 Estrane 6 6 1
  Δ4-Tiboloneb
 Estrane 90 35 1
  3α-Hydroxytibolone
 Estrane 0 3 4
  3β-Hydroxytibolone
 Estrane 0 4 3

Foototes: a = Prodrug. b = Main active metabolite. Binding: PR: Promegestone = 100%. AR: Metribolone (c = Mibolerone) = 100%. ER: Estradiol = 100%. Sources: [1][70][66][75][76]




































































































































































































































































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Oral potencies of progestogens
Progestogen Class
OID
(mg/day)
TFD
(mg/cycle)
TFD
(mg/day)
MDT
(mg/day)
ODP
(mg/day)
ECD
(mg/day)
Allylestrenol Estrane 25 150–250 ? ? – ?
Chlormadinone acetate Pregnane 1.5–2.0 20–30 3.0–10 1.0–4.0 2.0 5–10
Cyproterone acetate Pregnane 1.0 20–30 1–3 1.0–4.0 2.0 1.0
Desogestrel Gonane 0.06 0.4–2.5 0.15 0.25 0.15 0.15
Dienogest Gonane 1.0 6.0–6.3 ? ? 2.0–3.0 2.0
Drospirenone Spirolactone 2.0 40–80 ? ? 3.0 2.0
Dydrogesterone Pregnane >30 140–200 10–20 20 – 10
Etynodiol diacetate Estrane 2.0 10–15 ? 1.0 ? ?
Gestodene Gonane 0.03 2.0–3.0 ? ? 0.06–0.075 0.20
Levonorgestrel Gonane 0.05 2.5–6.0 0.15–0.25 0.5 0.1–0.15 0.075
Lynestrenol Estrane 2.0 50–150 5.0 10 ? ?
Medrogestone Pregnane 10 50–100 10 15 – 10
Medroxyprogesterone acetate Pregnane 10 40–120 3–10 20–30 ? 5.0
Megestrol acetate Pregnane ? 40–50 ? 10 ? 5.0
Nomegestrol acetate Pregnane 1.25–5.0 100 5.0 ? 2.5 3.75–5.0
Norethisterone Estrane 0.4–0.5 100–150 ? 15 0.5 0.7–1.0
Norethisterone acetate Estrane 0.5 30–60 5.0 7.5 0.6 1.0
Noretynodrel Estrane 4.0 150 ? 14 2.5–10 ?
Norgestimate Gonane 0.2 2.0–10 ? ? 0.25 0.09
Norgestrel Gonane 0.1 12 ? 0.5–2.0 ? ?
Progesterone (micronized) Pregnane >10; 300 4200 200–300 1000 – 200
Promegestone Pregnane 0.5 10 0.5 ? – 0.5
Tibolone Estrane 2.5 ? ? ? – ?
Trimegestone Pregnane 0.5 ? 0.25–0.5 ? – 0.0625–0.5

Abbreviations: OID = Ovulation-inhibiting dosage (antigonadotropic effect; without an estrogen); TFD = Endometrial transformation dosage; ODP = Oral dosage in commercial contraceptive preparations; ECD = Estimated comparable dosage; MDT = Menstrual delay test (Greenblatt). Sources: [70][6][49][72][77][78][79][80][81][82]













































































































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Parenteral potencies and durations of progestogens
Progestogen Type Class
TFD
(14 days)
MDT
(week)
OID
(month)
POIC-D
(2–3 months)
CIC-D
(month)
 Duration
Algestone acetophenide Synthetic Pregnane ND ND ND NA 75–150 mg
ND
Gestonorone caproate Synthetic Norpregnane ND ND ND NA NA
ND
Hydroxyprogesterone caproate Synthetic Pregnane 250–500 mg 25 mg 250–500 mg NA 250–500 mg 250 mg ≈ 10 days
Medroxyprogesterone acetate Synthetic Pregnane 50–100 mg ND ND 150 mg 25 mg 50 mg ≈ 14 days
Megestrol acetate Synthetic Pregnane ND ND ND NA 25 mg
ND
Norethisterone enanthate Synthetic Estrane ND ND ND 200 mg 50 mg
ND

Progesterone (oil soln.)		 Bioidentical Pregnane 200 mg ND ND NA NA 25 mg ≈ 2–3 days

Progesterone (cryst. susp.)		 Bioidentical Pregnane 50–100 mg ND ND NA NA 50 mg ≈ 14 days

Notes: All by intramuscular injection. Abbreviations: TFD = Endometrial transformation dose. MDT = Menstrual delay test dose (Greenblatt). OID = Ovulation-inhibiting dose (antigonadotropic effect; without an estrogen). POIC-D = Progestogen-only injectable contraceptive dose(s). CIC-D = Combined injectable contraceptive dose(s). Sources: [83][84][85][86][87]


Antigonadotropic effects


Progestogens, similarly to the androgens and estrogens through their own respective receptors, inhibit the secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) via activation of the PR in the pituitary gland. This effect is a form of negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis) and takes advantage of the mechanism that the body uses to prevent sex hormone levels from becoming too high.[88][42][89] Accordingly, progestogens, both endogenous and exogenous (i.e., progestins), have antigonadotropic effects,[44] and progestins 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).[89]


Progestins have been found to maximally suppress circulating testosterone levels in men by up to 70 to 80% at sufficiently high dosages.[90][91] This is notably less than that achieved by GnRH analogues, which can effectively abolish gonadal production of testosterone and suppress circulating testosterone levels by as much as 95%.[92] It is also less than that achieved by high-dose estrogen therapy, which can suppress testosterone levels into the castrate range similarly to GnRH analogues.[93]


The retroprogesterone derivatives dydrogesterone and trengestone are atypical progestogens and unlike all other clinically used progestogens do not have antigonadotropic effects nor inhibit ovulation even at very high dosages.[1][94] In fact, trengestone may have progonadotropic effects, and is actually able to induce ovulation, with about a 50% success rate on average.[94] These progestins also show other atypical properties relative to other progestogens, such as a lack of a hyperthermic effect.[1][94]



Androgenic activity


See also: Progestin-induced virilization

Some progestins have androgenic activity and can produce androgenic side effects such as increased sebum production (oilier skin), acne, and hirsutism (excessive facial/body hair growth), as well as changes in liver protein production.[95][96][97] Only certain progestins are androgenic however, these being the testosterone derivatives and, to a lesser extent, the 17α-hydroxyprogesterone derivatives medroxyprogesterone acetate and megestrol acetate.[98][96][70] No other progestins have such activity (though some, conversely, possess antiandrogenic activity).[96][70] 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][99]


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.[100] 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.[100] An exception is progestin-only contraceptives, which do not also contain an estrogen.[100]


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



  • Very high: danazol, ethisterone, gestrinone, normethandrone, norvinisterone[101][102][103][104]

  • High: levonorgestrel, norgestrel, norgestrienone, tibolone[21][99][101][7][105][106][1]

  • Moderate: norethisterone and its prodrugs (norethisterone acetate, norethisterone enanthate, etynodiol diacetate, lynestrenol, quingestanol acetate)[107][21][99][105][108]

  • Low: desogestrel, etonogestrel, gestodene, norgestimate[105][108][109]

  • Very low or negligible: allylestrenol, dimethisterone, medroxyprogesterone acetate, megestrol acetate, norelgestromin, noretynodrel, norgesterone[1][110][111][112][113][114][115][116]

  • Antiandrogenic: dienogest, oxendolone[117][1]


It should be noted however that the clinical androgenic and anabolic activity of the androgenic progestins listed above is still far lower than that of conventional androgens and anabolic steroids like testosterone and nandrolone esters. As such, they are only generally associated with such effects in women and often only at high dosages. 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.



On the other hand, some progestins have antiandrogenic activity in addition to their progestogenic activity.[118] These progestins, with varying degrees of potency as antiandrogens, include chlormadinone acetate, cyproterone acetate, dienogest, drospirenone, medrogestone, megestrol acetate, nomegestrol acetate, osaterone acetate (veterinary), and oxendolone.[118][117][119][120] The relative antiandrogenic activity in animals of some of these progestins has been ranked as follows: cyproterone acetate (100%) > nomegestrol acetate (90%) > dienogest (30–40%) ≥ chlormadinone acetate (30%) = drospirenone (30%).[1][121] Antiandrogenic activity in certain progestins may help to improve symptoms of acne, seborrhea, hirsutism, and other androgen-dependent conditions in women.[1][118]



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[122]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 dosages 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.[123] In contrast, non-estrogenic progestins were not found to be associated with such effects.[123]



Glucocorticoid activity


Some progestins, mainly certain 17α-hydroxyprogesterone derivatives, have weak glucocorticoid activity.[124] This can result, at sufficiently high dosages, in side effects such as symptoms of Cushing's syndrome, steroid diabetes, adrenal suppression and insufficiency, and neuropsychiatric symptoms like depression, anxiety, irritability, and cognitive impairment.[124][125][126] Progestins 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][125][127][128] Conversely, hydroxyprogesterone caproate possesses no such activity, while progesterone itself has very weak glucocorticoid activity.[129][1]







































































  • v

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  • e

Glucocorticoid activity of selected steroids in vitro
Steroid Type
TR (↑)a
GR (%)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 = Thrombin receptor (TR) upregulation (↑) in vascular smooth muscle cells (VSMCs). b = RBA (%) for the glucocorticoid receptor (GR). Strength: – = No effect. + = Pronounced effect. ++ = Strong effect. Source: [1]


Antimineralocorticoid activity


Certain progestins, including drospirenone and gestodene and to a lesser extent dydrogesterone and trimegestone, have varying degrees of antimineralocorticoid activity.[1][58]Progesterone itself has potent antimineralocorticoid activity.[1] No clinically used progestins 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 sodium and fluid retention, edema, and associated weight gain; lowered blood pressure; and possibly improved cardiovascular health.[130][131][132][133]



Neurosteroid activity


Progesterone has neurosteroid activity via metabolism into allopregnanolone and pregnanolone, potent 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.[134]



Pharmacokinetics



















































































































































































































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Pharmacokinetics of progestogens
Progestogen Class Dose BA Half-life
Refs
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 daysa
 [135]
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
[136][137]
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
[138][139]
Promegestone Pregnane NA ? Prodrug
Tibolone Estrane NA ? Prodrug
Trimegestone Pregnane 0.5 mg ~100% 15 hours

Footnotes: a = By intramuscular injection. Sources: [70][6][140][49][72]


Chemistry


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

All currently available progestins are steroids.[1] They include the pregnanes (e.g., dydrogesterone, medroxyprogesterone acetate) and norpregnanes (e.g., nomegestrol acetate), which are derivatives of progesterone, and the androstanes (e.g., danazol, ethisterone) and estranes (e.g., norethisterone, levonorgestrel), which are testosterone derivatives.[1] These groups can be further divided into various subgroups.[1]



History


The recognition of progesterone's ability to suppress ovulation during pregnancy spawned a search for a similar hormone that could bypass the problems associated with administering progesterone (e.g. low bioavailability when administered orally and local irritation and pain when continually administered 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, ethisterone (pregneninolone, 17α-ethynyltestosterone), the 17α-ethynyl analog of testosterone, was synthesized in 1938 from dehydroandrosterone by ethynylation, either before or after oxidation of the 3-OH group, followed by rearrangement of the 5,6 double bond to the 4,5 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.[141][142][143][144][145]


A more potent orally active progestin, norethisterone (norethindrone, 19-nor-17α-ethynyltestosterone), the 19-nor analog 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.[142][142][143][144][145][146]


Noretynodrel, an isomer of norethisterone, was synthesized in 1952 by Frank B. Colton at 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.[142][143][144][145][147]



























































































































































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Introduction of first-generation oral contraceptives
Progestin Estrogen Brand name Manufacturer U.S. Approval U.K. Approval
Noretynodrel Mestranol Enovid Searle 1960 1963
Norethisterone Mestranol Ortho-Novum, Norinyl
Syntex/Ortho
 1963 1966
Norethisterone Ethinylestradiol Norlestrin
Syntex/Parke-Davis
 1964 1962
Lynestrenol Mestranol Lyndiol Organon N/A 1963
Megestrol acetate Ethinylestradiol Volidan, Nuvacon British Drug Houses N/A 1963
Norethisterone acetate Ethinylestradiol Norlestrin Parke-Davis 1964
N/D
Quingestanol acetate Ethinylestradiol Riglovis Vister N/A N/A
Quingestanol acetate Quinestrol Unovis Warner Chilcott N/A N/A
Medroxyprogesterone acetate Ethinylestradiol Provest Upjohn 1964 N/A
Chlormadinone acetate Mestranol C-Quens Merck 1965 1965
Dimethisterone Ethinylestradiol Oracon British Drug Houses 1965 N/A
Etynodiol diacetate Mestranol Ovulen Searle 1966 1965
Etynodiol diacetate Ethinylestradiol Demulen Searle 1970 1968
Norgestrienone Ethinylestradiol Planor, Miniplanor Roussel Uclaf N/A N/A
Norgestrel Ethinylestradiol Ovral Wyeth 1968 1972
Anagestone acetate Mestranol Neo-Novum Ortho N/A N/A
Lynestrenol Ethinylestradiol Lyndiol Organon N/A 1969

Sources: Main: [148][149][150][151]Supplementary: [152][153][154]


Society and culture



Generations


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



  • First generation: Approved for marketing before 1973. Examples: noretynodrel, norethisterone (norethindrone), lynestrenol, levonorgestrel.

  • Second generation: Approved for marketing between 1973 and 1989. Examples: desogestrel, nomegestrol acetate, norgestimate.

  • Third generation: Approved for marketing between 1990 and 2000. Examples: dienogest, etonogestrel.

  • Fourth generation: Approved for marketing after 2000. Examples: drospirenone, norelgestromin, segesterone acetate.


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]



Availability


See also: List of progestogens available in the United States

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



Research


A variety of progestins have been studied for use as potential male hormonal contraceptives in combination with androgens in men.[24] These include the pregnanes medroxyprogesterone acetate, megestrol acetate, and cyproterone acetate, the norpregnane segesterone acetate, and the estranes norethisterone acetate, norethisterone enanthate, levonorgestrel, levonorgestrel butanoate, desogestrel, and etonogestrel.[24][155][156][157] The androgens that have been used in combination with these progestins include testosterone, testosterone esters, androstanolone (dihydrotestosterone), and nandrolone esters.[24] Dual androgens and progestins such as trestolone and dimethandrolone undecanoate have also been developed and studied as male contraceptives.[158][159]



See also



  • Pharmacodynamics of progesterone

  • Pharmacokinetics of progesterone

  • Phytoprogestogen

  • Progestin challenge



References





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Further reading





  • Kuhl H (September 1990). "Pharmacokinetics of oestrogens and progestogens". Maturitas. 12 (3): 171–97. doi:10.1016/0378-5122(90)90003-o. PMID 2170822.


  • Lauritzen C (September 1990). "Clinical use of oestrogens and progestogens". Maturitas. 12 (3): 199–214. PMID 2215269.


  • Stanczyk FZ (September 2002). "Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception" (PDF). Rev Endocr Metab Disord. 3 (3): 211–24. doi:10.1023/A:1020072325818. PMID 12215716.


  • Raudrant D, Rabe T (2003). "Progestogens with antiandrogenic properties". Drugs. 63 (5): 463–92. PMID 12600226.


  • Stanczyk FZ (November 2003). "All progestins are not created equal". Steroids. 68 (10–13): 879–90. PMID 14667980.


  • Nieschlag E, Zitzmann M, Kamischke A (November 2003). "Use of progestins in male contraception". Steroids. 68 (10–13): 965–72. PMID 14667989.


  • Wiegratz I, Kuhl H (August 2004). "Progestogen therapies: differences in clinical effects?". Trends Endocrinol. Metab. 15 (6): 277–85. doi:10.1016/j.tem.2004.06.006. PMID 15358281.


  • Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.


  • Sitruk-Ware R (October 2005). "Pharmacology of different progestogens: the special case of drospirenone". Climacteric. 8 Suppl 3: 4–12. doi:10.1080/13697130500330382. PMID 16203650.


  • Wiegratz I, Kuhl H (September 2006). "Metabolic and clinical effects of progestogens". Eur J Contracept Reprod Health Care. 11 (3): 153–61. doi:10.1080/13625180600772741. PMID 17056444.


  • Stanczyk, Frank Z. (2007). "Structure –Function Relationships, Pharmacokinetics, and Potency of Orally and Parenterally Administered Progestogens": 779–798. doi:10.1016/B978-012369443-0/50067-3.


  • Sitruk-Ware R, Nath A (November 2010). "The use of newer progestins for contraception". Contraception. 82 (5): 410–7. doi:10.1016/j.contraception.2010.04.004. PMID 20933114.


  • Kuhl H (2011). "Pharmacology of progestogens" (PDF). Journal für Reproduktionsmedizin und Endokrinologie-Journal of Reproductive Medicine and Endocrinology. 8 (Special Issue 1): 157–176.


  • Lawrie TA, Helmerhorst FM, Maitra NK, Kulier R, Bloemenkamp K, Gülmezoglu AM (May 2011). "Types of progestogens in combined oral contraception: effectiveness and side-effects". Cochrane Database Syst Rev (5): CD004861. doi:10.1002/14651858.CD004861.pub2. PMID 21563141.


  • Endrikat J, Gerlinger C, Richard S, Rosenbaum P, Düsterberg B (December 2011). "Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide". Contraception. 84 (6): 549–57. doi:10.1016/j.contraception.2011.04.009. PMID 22078182.


  • Moore NL, Hickey TE, Butler LM, Tilley WD (June 2012). "Multiple nuclear receptor signaling pathways mediate the actions of synthetic progestins in target cells". Mol. Cell. Endocrinol. 357 (1–2): 60–70. doi:10.1016/j.mce.2011.09.019. PMID 21945474.


  • Stanczyk FZ, Hapgood JP, Winer S, Mishell DR (April 2013). "Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects". Endocr. Rev. 34 (2): 171–208. doi:10.1210/er.2012-1008. PMC 3610676. PMID 23238854.


  • Grimes DA, Lopez LM, O'Brien PA, Raymond EG (November 2013). "Progestin-only pills for contraception". Cochrane Database Syst Rev (11): CD007541. doi:10.1002/14651858.CD007541.pub3. PMID 24226383.


  • Hapgood JP, Africander D, Louw R, Ray RM, Rohwer JM (July 2014). "Potency of progestogens used in hormonal therapy: toward understanding differential actions". J. Steroid Biochem. Mol. Biol. 142: 39–47. doi:10.1016/j.jsbmb.2013.08.001. PMID 23954501.


  • Sitruk-Ware R, El-Etr M (August 2013). "Progesterone and related progestins: potential new health benefits". Climacteric. 16 Suppl 1: 69–78. doi:10.3109/13697137.2013.802556. PMID 23647429.


  • Bińkowska M, Woroń J (June 2015). "Progestogens in menopausal hormone therapy". Prz Menopauzalny. 14 (2): 134–43. doi:10.5114/pm.2015.52154. PMC 4498031. PMID 26327902.















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