Progestogen (medication)

Progestogen (medication)
	Drug class
	Progesterone (Prometrium, Utrogestan), the natural progestogen in the body and one of the most widely used progestogen medications.
Class identifiers
Synonyms	Progestagen; Gestagen; Gestogen; Progestin (synthetic progestogen); Progesterone receptor agonist
Use	Hormonal birth control, hormone therapy, gynecological disorders, fertility medicine and pregnancy support, sex-hormone suppression, others
ATC code	G03
Biological target	Progesterone receptors (PR-A, PR-B, PR-C); Membrane progesterone receptors (mPRα, mPRβ, mPRγ, mPRδ, mPRε); Progesterone receptor membrane components (PGRMC1, PGRMC2)
Chemical class	Steroids (pregnanes, norpregnanes, retropregnanes, androstanes, estranes)
Clinical data
Drugs.com	Drug Classes
External links
MeSH	D011372
	In Wikidata

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body.[1] A progestin is a synthetic progestogen.[1] Progestogens are 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] Progestogens 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] Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.[1]

Side effects of progestogens 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 progestogens may include an increased risk of breast cancer, cardiovascular disease, and 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 agonists of the progesterone receptors (PRs) and produce progestogenic or progestational effects.[1] They have important effects in the female reproductive system (uterus, cervix, and vagina), the breasts, and the brain.[1] In addition, many progestogens also have other hormonal activities, such as androgenic, antiandrogenic, estrogenic, glucocorticoid, or antimineralocorticoid activity.[1] They also have antigonadotropic effects and at high doses can strongly suppress sex hormone production.[1] Progestogens 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]

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.[9][10][12][11][1]

Medical uses

Birth control

Progestogens 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]

Progestogens 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

Progestogens 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 progestogens, 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

Progestogens 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]

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.

Gynecological cancers

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

Progestogens, such as megestrol acetate and medroxyprogesterone acetate, are effective at high doses 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, progestogens have been moved down in the sequential therapy of the disease.[39] Megestrol acetate is the only Food and Drug Administration-approved progestogen for breast cancer.[39] The mechanism of action of progestogens 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 progestogens are used to support pregnancy, including progesterone, 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 progestogens are used at high doses 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. Progestogens 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 progestogens 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 progestogens 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 doses 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

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

Progestogens marketed for clinical or veterinary use
Generic name	Class	Brand name(s)	Route(s)	Launch	Status	Hits^a
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; 17α-MP	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; 17α-OHP; Ester	Depostat, Primostat	IM	1968	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; 17α-OHP; 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; 17α-OHP; 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; 17α-MP	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; 17α-OHP; 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; 17α-MP	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 progestogens may include breast cancer and a history of venous thromboembolism among others.[49]

Side effects

Progestogens have relatively few side effects at typical dosages.[50] Side effects of progestogens may include tiredness, dysphoria, depression, mood changes, menstrual irregularities, hypomenorrhea, edema, vaginal dryness, vaginal atrophy, headaches, nausea, breast tenderness, decreased libido.[1][2][50] 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][50] Other side effects of progestogens may include an increased risk of breast cancer, cardiovascular disease, and blood clots, among others.[2] Some of the side effects of progestogens are due not to their progestogenic activity but rather due to off-target activities (e.g., androgenic activity, glucocorticoid activity, antimineralocorticoid activity).[1][51] At high doses, due to their antigonadotropic effects, progestogens 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 controlled trials for its review.[52] This is in contrast to other research which found a relationship between hormonal contraceptive use and subsequent prescription antidepressant use.[53]

Overdose

Progestogens are relatively safe in acute overdose.

Interactions

Inhibitors and inducers of cytochrome P450 enzymes and other enzymes such as 5α-reductase may interact with progestogens.

Pharmacology

Pharmacodynamics

Progestogens act by binding to and activating the progesterone receptors (PRs), including the PR-A, PR-B, and PR-C.[1][54][55] Major tissues affected by progestogens include the uterus, cervix, vagina, breasts, and brain.[1] By activating PRs in the hypothalamus and pituitary gland, progestogens suppress the secretion of gonadotropins and thereby function as antigonadotropins at sufficiently high doses.[1] Progesterone interacts with membrane progesterone receptors, but interaction of progestins with these receptors is less clear.[56][57] Progestogens 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] 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.[58]

In addition to their progestogenic activity, many progestogens have off-target activities such as androgenic, antiandrogenic, estrogenic, glucocorticoid, or antimineralocorticoid activity.[1][2][51] Such actions can contribute both to their beneficial or desirable effects and to their side effects.[1][2][59]

Pharmacodynamics of progestogens
Progestogen	Class	Off-target activities					Relative binding affinities (%)
Progestogen	Class	ES	AN	AA	GC	AM	PR	AR	ER	GR	MR	SHBG	CBG
Allylestrenol^a	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	?	?
Desogestrel^a	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
Dydrogesterone^a	Pregnane	–	–	–	–	±	75	0	?	?	?	?	?
Ethisterone	Androstane	–	+	–	–	–	18	0	0	0	0	?	?
Etonogestrel	Gonane	–	+	–	±	–	150	20	0	14	0	15	0
Etynodiol^a,b	Estrane	+	+	–	–	–	1	0	11–18	0	?	?	?
Etynodiol diacetate^a	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
Lynestrenol^a	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 acetate^a	Estrane	+	+	–	–	–	20	5	1	0	0	?	?
Norethisterone enanthate^a	Estrane	+	+	–	–	–	?	?	?	?	?	?	?
Noretynodrel^a	Estrane	+	±	–	–	–	6	0	2	0	0	0	0
Norgestimate^a	Gonane	–	+	–	–	–	15	0	0	1	0	0	0
Progesterone	Pregnane	–	–	±	+	+	50	0	0	10	100	0	36
Promegestone^a	Norpregnane	–	–	–	+	–	100	0	0	5	53	0	0
Segesterone acetate	Norpregnane	–	–	–	–	–	136	0	0	38	?	0	?
Tibolone^a	Estrane	+	++	–	–	–	6	6	1	?	?	?
Δ⁴-Tibolone^b	Estrane	–	++	–	–	–	90	35	1	0	2	1	0
Trimegestone	Norpregnane	–	–	±	–	±	294–330	1	0	9–13	42–120	?	?
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: See template.

Pharmacodynamics of selected progestogen metabolites
Progestogen	Class	RBA (%)
Progestogen	Class	PR	AR	ER
Norethisterone	Estrane	67–75	15	0
5α-Dihydronorethisterone	Estrane	25	27	0
Levonorgestrel	Gonane	150–162	34^c, 45	0
5α-Dihydrolevonorgestrel	Gonane	50	38^c	0
Norgestimate^a	Gonane	15	0	0
Norelgestromin^b	Gonane	10	0	?
Levonorgestrel	Gonane	150	45	0
Levonorgestrel 17β-acetate	Gonane	135	?	0
Desogestrel^a	Gonane	1	0	0
Etonogestrel^b	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	?
Tibolone^a	Estrane	6	6	1
Δ⁴-Tibolone^b	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: See template.

Oral potencies of progestogens
Progestogen	Class	OID (mg/day)	TFD (mg/cycle)	TFD (mg/day)	MDT (mg/day)	BCP-D (mg/day)	ECD (mg/day)
Allylestrenol	Estrane	25	150–300	?	30	–	?
Bromoketoprogesterone^a	Pregnane	?	?	100–160	?	–	?
Chlormadinone acetate	Pregnane	1.5–4.0	20–30	3–10	1.0–4.0	2.0	5–10
Cyproterone acetate	Pregnane	1.0	20–30	1.0–3.0	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	Retropregnane	>30	140–200	10–20	20	–	10
Ethisterone	Androstane	?	200–400	50–250	?	–	?
Etynodiol diacetate	Estrane	2.0	10–15	?	1.0	1.0–20	?
Gestodene	Gonane	0.03	2.0–3.0	?	?	0.06–0.075	0.20
Hydroxyprogesterone acetate	Pregnane	?	?	70–125	?	100	?
Hydroxyprogesterone caproate	Pregnane	?	?	70	?	–	?
Levonorgestrel	Gonane	0.05	2.5–6.0	0.15–0.25	0.5	0.1–0.15	0.075
Lynestrenol	Estrane	2.0	35–150	5.0	10	?	?
Medrogestone	Pregnane	10	50–100	10	15	–	10
Medroxyprogesterone acetate	Pregnane	10	40–120	2.5–10	20–30	5–10	5.0
Megestrol acetate	Pregnane	>5^b	30–70	?	5–10	1.0–5.0	5.0
Nomegestrol acetate	Pregnane	1.25–5.0	100	5.0	?	2.5	3.75–5.0
Norethandrolone^a	Estrane	?	?	10	?	–	?
Norethisterone	Estrane	0.4–0.5	100–150	5–10	10–15	0.5	0.7–1.0
Norethisterone acetate	Estrane	0.5	30–60	2.5–5.0	7.5	0.6	1.0
Norethisterone acetate (micronized)	Estrane	?	12–14	?	?	–	?
Noretynodrel	Estrane	4.0	150–200	?	14	2.5–10	?
Norgestimate	Gonane	0.2	2.0–10	?	?	0.25	0.09
Norgestrel	Gonane	0.1	12	?	0.5–2.0	?	?
Normethandrone	Estrane	?	150	10	?	–	?
Progesterone (micronized)	Pregnane	>300^c	4200	200–300	1000	–	200
Promegestone	Pregnane	0.5	10	0.5	?	–	0.5
Tibolone	Estrane	2.5	?	?	?	–	?
Trengestone	Retropregnane	?	50–70	?	?	–	?
Trimegestone	Pregnane	0.5	?	0.25–0.5	?	–	0.0625–0.5
Footnotes: ^a = Never marketed as a progestogen. ^b = The OID of MGA is unknown, but is >5 mg/day. ^c = Ovulation inhibition rate with 300 mg/day oral non-micronized P4 was ≥50%. Sources: See template.

Parenteral potencies and durations of progestogens
Progestogen	Form	Major brand names	Class	TFD (14 days)	POIC-D (2–3 months)	CIC-D (month)	Duration
Algestone acetophenide	Oil solution	Perlutal, Topasel, Yectames	Pregnane	?	–	75–150 mg	100 mg ≈ 14–32 days
Cyproterone acetate	Oil solution	Androcur Depot	Pregnane	?	–	–	300 mg ≈ 20 days
Dydrogesterone^a	Aqueous suspension	–	Retropregnane	?	–	–	100 mg ≈ 16–38 days
Gestonorone caproate	Oil solution	Depostat, Primostat	Norpregnane	50 mg	–	–	25–50 mg ≈ 8–13 days
Hydroxyprogesterone acetate^a	Aqueous suspension	–	Pregnane	350 mg	–	–	150–350 mg ≈ 9–16 days
Hydroxyprogesterone caproate	Oil solution	Delalutin, Proluton, Makena	Pregnane	250–500 mg^b	–	250–500 mg	65–500 mg ≈ 5–21 days
Levonorgestrel butanoate^a	Aqueous suspension	–	Gonane	?	–	–	5–50 mg ≈ 3–6 months
Lynestrenol phenylpropionate^a	Oil solution	–	Estrane	?	–	–	50–100 mg ≈ 14–30 days
Medroxyprogesterone acetate	Aqueous suspension	Depo-Provera	Pregnane	50–100 mg	150 mg	25 mg	50–150 mg ≈ 14–50+ days
Megestrol acetate	Aqueous suspension	Mego-E	Pregnane	?	–	25 mg	25 mg ≈ >14 days^c
Norethisterone enanthate	Oil solution	Noristerat, Mesigyna	Estrane	100–200 mg	200 mg	50 mg	50–200 mg ≈ 11–52 days
Oxogestone phenylpropionate^a	Oil solution	–	Norpregnane	?	–	–	100 mg ≈ 19–20 days
Progesterone	Oil solution	Progestaject, Gestone, Strone	Pregnane	200 mg^b	–	–	25–350 mg ≈ 2–6 days
Progesterone	Aqueous suspension	Agolutin Depot	Pregnane	50–200 mg	–	–	50–300 mg ≈ 7–14 days
Note: All by intramuscular or subcutaneous injection. All are synthetic except for P4, which is bioidentical. P4 production during the luteal phase is ~25 (15–50) mg/day. The OID of OHPC is 250 to 500 mg/month. Footnotes: ^a = Never marketed by this route. ^b = In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4). ^c = Half-life is ~14 days. Sources: Main: See template.

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.[60][42][61] Accordingly, progestogens, both endogenous and exogenous (i.e., progestins), have antigonadotropic effects,[44] 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).[61]

Progestogens have been found to maximally suppress circulating testosterone levels in men by up to 70 to 80% at sufficiently high doses.[62][63] 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%.[64] 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.[65]

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 doses.[1][66] In fact, trengestone may have progonadotropic effects, and is actually able to induce ovulation, with about a 50% success rate on average.[66] These progestins also show other atypical properties relative to other progestogens, such as a lack of a hyperthermic effect.[1][66]

Androgenic activity

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.[67][68][69] 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.[70][68][71] No other progestins have such activity (though some, conversely, possess antiandrogenic activity).[68][71] 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][72]

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.[73] 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.[73] An exception is progestin-only contraceptives, which do not also contain an estrogen.[73]

The relative 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[74][75][76][77]
High: levonorgestrel, norgestrel, norgestrienone, tibolone[21][72][74][7][78][79][1]
Moderate: norethisterone and its prodrugs (norethisterone acetate, norethisterone enanthate, etynodiol diacetate, lynestrenol, quingestanol acetate)[80][21][72][78][81]
Low: desogestrel, etonogestrel, gestodene, norgestimate[78][81][82]
Very low or negligible: allylestrenol, dimethisterone, medroxyprogesterone acetate, megestrol acetate, norelgestromin, noretynodrel, norgesterone[1][83][84][85][86][87][88][89]
Antiandrogenic: dienogest, oxendolone[90][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 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 antiandrogenic activity in addition to their progestogenic activity.[91] These progestogens, with varying degrees of potency as antiandrogens, include chlormadinone acetate, cyproterone acetate, dienogest, drospirenone, medrogestone, megestrol acetate, nomegestrol acetate, osaterone acetate (veterinary), and oxendolone.[91][90][92][93] The relative antiandrogenic activity in animals of some of these progestogens has been ranked as follows: cyproterone acetate (100%) > nomegestrol acetate (90%) > dienogest (30–40%) ≥ chlormadinone acetate (30%) = drospirenone (30%).[1][94] Antiandrogenic activity in certain progestogens may help to improve symptoms of acne, seborrhea, hirsutism, and other androgen-dependent conditions in women.[1][91]

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[95] 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.[96] In contrast, non-estrogenic progestins were not found to be associated with such effects.[96]

Glucocorticoid activity

Some progestogens, mainly certain 17α-hydroxyprogesterone derivatives, have weak glucocorticoid activity.[97] This can result, at sufficiently high doses, 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.[97][98][99] 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][98][100][101] Conversely, hydroxyprogesterone caproate possesses no such activity, while progesterone itself has very weak glucocorticoid activity.[102][1]

Glucocorticoid activity of selected steroids *in vitro*
Steroid	Class	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. Sources: See template.

Antimineralocorticoid activity

Certain progestogens, including progesterone, drospirenone, and gestodene, as well as to a lesser extent dydrogesterone and trimegestone, have varying degrees of antimineralocorticoid activity.[1][59] 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 sodium and fluid retention, edema, and associated weight gain; lowered blood pressure; and possibly improved cardiovascular health.[103][104][105][106]

Neurosteroid activity

Progesterone has neurosteroid activity via metabolism into allopregnanolone and pregnanolone, potent positive allosteric modulators of the GABA_A 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.[107]

Pharmacokinetics

Pharmacokinetics of progestogens
Progestogen	Class	Dose^a	Bioavailability	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 days^b
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

All currently available progestogens are steroids.[1] They include the following structural groups:[1]

Progesterone derivatives
- Pregnanes (e.g., medroxyprogesterone acetate)
- Retropregnanes (e.g., dydrogesterone)
- Norpregnanes (e.g., nomegestrol acetate)
- Spirolactones (e.g., drospirenone)
Testosterone derivatives
- Androstanes (e.g., ethisterone)
- Estranes (e.g., norethisterone)
- Gonanes (e.g., levonorgestrel)

Structural characteristics of marketed progestogens
Classes	Progestogen	Chemical name	Features
Progesterone	Progesterone	Pregn-4-ene-3,20-dione	–
Progesterone	Quingestrone	Progesterone 3-cyclopentyl enol ether	Ether
Retroprogesterone	Dydrogesterone	6-Dehydro-9β,10α-progesterone	–
Retroprogesterone	Trengestone	1,6-Didehydro-6-chloro-9β,10α-progesterone	–
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
Other 17α-substituted progesterone	Haloprogesterone	6α-Fluoro-17α-bromoprogesterone	–
	Medrogestone	6-Dehydro-6,17α-dimethylprogesterone	–
	Proligestone	14α,17α-Dihydroxyprogesterone 14α,17α-(cyclic acetal with propionaldehyde)	Cyclic acetal
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	–
Spirolactone	Drospirenone	6β,7β:15β,16β-Dimethylenespirolactone	Ring-fused
17α-Ethynyltestosterone	Danazol	2,3-d-Isoxazol-17α-ethynyltestosterone^?	Ring-fused
	Dimethisterone	6α,21-Dimethyl-17α-ethynyltestosterone	–
	Ethisterone	17α-Ethynyltestosterone	–
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; 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	–
19-Nortestosterone; Other 17α-substituted testosterone (and 16β-substituted)	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	–

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 C17α ethynyl analogue of testosterone, was synthesized in 1938 from dehydroandrosterone by ethynylation, either before or after 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.[108][109][110][111][112]

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.[109][109][110][111][112][113]

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.[109][110][111][112][114]

Introduction of first-generation birth control pills
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: See template.

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]

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.

Availability

Progestogens 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][115][116][117] The androgens that have been used in combination with these progestins include testosterone, testosterone esters, androstanolone (dihydrotestosterone), and nandrolone esters.[24] Dual androgens and progestogens such as trestolone and dimethandrolone undecanoate have also been developed and studied as male contraceptives.[118][119]

References

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.
Wiegratz I, Kuhl H (2004). "Progestogen therapies: differences in clinical effects?". Trends Endocrinol. Metab. 15 (6): 277–85. doi:10.1016/j.tem.2004.06.006. PMID 15358281.
Thibaut F, De La Barra F, Gordon H, Cosyns P, Bradford JM (2010). "The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of paraphilias". World J. Biol. Psychiatry. 11 (4): 604–55. doi:10.3109/15622971003671628. PMID 20459370.
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