Gestodene

Last updated
Gestodene
Gestodene.svg
Gestodeno3D.png
Clinical data
Trade names Femodene, Femodette, Gynera, Harmonet, Meliane, Minesse, Minulet, others
Other namesGSD; SHB-331; δ15-Norgestrel; 15-Dehydronorgestrel; 17-hydroxy-18a-homo-19-nor-17α-pregna-4,15-dien-20-yn-3-one; 17α-Ethynyl-18-methyl-19-nor-δ15-testosterone; 17α-Ethynyl-18-methylestra-4,15-dien-17β-ol-3-one; 13β-Ethyl-18,19-dinor-17α-pregna-4,15-dien-20-yn-17β-ol-3-one
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • X
Routes of
administration 		By mouth
Drug class Progestogen; Progestin
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 96% (87–111%) [1] [2] [3]
Protein binding 98% (64% to SHBG Tooltip sex hormone-binding globulin, 34% to albumin, 2% free) [4]
Metabolism Liver (reduction, hydroxylation) [4]
Elimination half-life 12–15 hours [2] [4]
Excretion Urine
Identifiers
  • (8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-17-hydroxy-1,2,6,7,8,9,10,11,12,14-decahydrocyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.056.478 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H26O2
Molar mass 310.437 g·mol−1
3D model (JSmol)
Melting point 197.9 °C (388.2 °F)
  • O=C4\C=C3/[C@@H]([C@H]2CC[C@]1([C@@H](/C=C\[C@]1(C#C)O)[C@@H]2CC3)CC)CC4
  • InChI=1S/C21H26O2/c1-3-20-11-9-17-16-8-6-15(22)13-14(16)5-7-18(17)19(20)10-12-21(20,23)4-2/h2,10,12-13,16-19,23H,3,5-9,11H2,1H3/t16-,17+,18+,19-,20-,21-/m0/s1 Yes check.svgY
  • Key:SIGSPDASOTUPFS-XUDSTZEESA-N Yes check.svgY
   (verify)

Gestodene, sold under the brand names Femodene and Minulet among others, is a progestin medication which is used in birth control pills for women. [5] [6] It is also used in menopausal hormone therapy. [7] The medication is available almost exclusively in combination with an estrogen. [8] It is taken by mouth. [6] [9]

Contents

Side effects of the combination of an estrogen and gestodene include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, and others.[ citation needed ] Gestodene is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. [10] [11] It has weak androgenic activity, weak antimineralocorticoid activity, and weak glucocorticoid activity. [10] [11]

Gestodene was discovered in 1975 and was introduced for medical use, specifically in birth control pills, in 1987. [4] [12] It was subsequently introduced for use in menopausal hormone therapy as well. [7] [8] Gestodene is sometimes referred to as a "third-generation" progestin. [13] It is marketed in birth control pills widely throughout the world, whereas it is available for use in menopausal hormone therapy only a few countries. [8] [7] Gestodene is not approved in the United States. [14] [15]

Medical uses

Gestodene is neutral in terms of androgenic activity, meaning that contraceptive pills containing gestodene do not exhibit the androgenic side effects (e.g., acne, hirsutism) sometimes associated with second-generation contraceptive pills such as those containing levonorgestrel. [16]

The estrogen dosage in third-generation contraceptive pills (including those containing gestodene) is lower than that in second-generation oral contraceptives, reducing the likelihood of weight gain, breast tenderness, and migraine. [17]

Third-generation oral contraceptives are also suitable for use in patients with diabetes or lipid disorders because they have minimal impact on blood glucose levels and the lipid profile. [18]

Gestodene is also available in combination with estradiol for use in menopausal hormone therapy. [7] [8]

Available forms

Contraceptive products containing gestodene include:

Contraindications

Side effects

Women who take oral contraceptives containing gestodene are 5.6 times as likely to develop venous thromboembolism than women who do not take any contraceptive pill, and 1.6 times as likely to develop venous thromboembolism compared to women taking oral contraceptives containing levonorgestrel. [20]

Overdose

Contraindications

Pharmacology

Pharmacodynamics

Gestodene is a highly potent progestogen, and also possesses weak androgenic, antimineralocorticoid, and glucocorticoid activity. [9] [10] [11] Due to its progestogenic activity, it has antigonadotropic and functional antiestrogenic effects. [9] The medication has little or no estrogenic and no antiandrogenic activity. [9]

Relative affinities (%) of gestodene
Compound PR Tooltip Progesterone receptor AR Tooltip Androgen receptor ER Tooltip Estrogen receptor GR Tooltip Glucocorticoid receptor MR Tooltip Mineralocorticoid receptor SHBG Tooltip Sex hormone-binding globulin CBG Tooltip Corticosteroid binding globulin
Gestodene90–43285027–3897–290400
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PR Tooltip progesterone receptor, metribolone for the AR Tooltip androgen receptor, E2 for the ER Tooltip estrogen receptor, DEXA Tooltip dexamethasone for the GR Tooltip glucocorticoid receptor, aldosterone for the MR Tooltip mineralocorticoid receptor, DHT Tooltip dihydrotestosterone for SHBG Tooltip sex hormone-binding globulin, and cortisol for CBG Tooltip Corticosteroid-binding globulin. Sources: [9]

Progestogenic activity

Gestodene is a progestogen, and hence is an agonist of the progesterone receptor. [9] Based on the dosage necessary to inhibit ovulation in women, gestodene is the most potent of all of the currently used oral contraceptive progestogens. [21] [22] [23] The oral dosage of gestodene required for ovulation inhibition is 30 or 40 μg per day. [22] [24] This is about 10,000 times lower than the oral dosage of progesterone required to inhibit ovulation (300 mg/day). [11] [9] A dosage of gestodene of 75 μg/day is used in contraceptives. [23]

Androgenic activity

Gestodene has relatively high affinity for the androgen receptor (AR), with twice that of levonorgestrel (which is known to be one of the more androgenic 19-nortestosterone derivatives). [25] However, the ratio of progestogenic to androgenic effects of gestodene is distinctly higher than that of levonorgestrel, and the increase in sex hormone-binding globulin (SHBG) levels (a marker of androgenicity) produced by oral contraceptives containing gestodene is slightly less than that produced by oral contraceptives containing desogestrel (which is known to be one of the more weakly androgenic 19-nortestosterone derivatives). [25] In addition, no difference in acne incidence has been observed with oral contraceptives containing gestodene and oral contraceptives containing desogestrel. [26] Gestodene may also act to some extent as a 5α-reductase inhibitor. [9] [25] Taken together, like desogestrel, gestodene appears to have a low potential for androgenic effects. [25]

Glucocorticoid activity

Gestodene has relatively high affinity for the glucocorticoid receptor, about 27% of that of the corticosteroid dexamethasone. [9] It has weak glucocorticoid activity. [9]

Glucocorticoid activity of selected steroids in vitro
SteroidClass TR Tooltip Thrombin receptor (↑)a GR Tooltip glucocorticoid receptor (%)b
Dexamethasone Corticosteroid++100
Ethinylestradiol Estrogen–0
Etonogestrel Progestin+14
GestodeneProgestin+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 Tooltip Relative binding affinity (%) for the glucocorticoid receptor (GR). Strength: – = No effect. + = Pronounced effect. ++ = Strong effect. Sources: [27]

Antimineralocorticoid activity

Gestodene has very high affinity for the mineralocorticoid receptor (MR), but has only a relatively weak antimineralocorticoid effect that is comparable to that of progesterone. [25]

Other activities

Although gestodene does not bind to the estrogen receptor itself, the drug may have some estrogenic activity, and this would appear to be mediated by its weakly estrogenic metabolites 3β,5α-tetrahydrogestodene and to a lesser extent 3α,5α-tetrahydrogestodene. [28]

Gestodene binds to SHBG with relatively high affinity; it is 75% bound to the protein in circulation. [11] [25]

Gestodene shows some inhibition of cytochrome P450 enzymes in vitro , and has greater potency in this action compared to other progestins (IC50 Tooltip half-maximal inhibitory concentration = 5.0 μM). [9] [1] The medication also shows some inhibition of 5α-reductase in vitro (14.5% at 0.1 μM, 45.9% at 1.0 μM). [9] Like with cytochrome P450 inhibition, gestodene was more potent in this action compared to other progestins, including desogestrel and levonorgestrel. [9] [25]

Pharmacokinetics

The oral bioavailability of gestodene has been found to range from 87 to 111%, with a mean of 96%. [1] [2] [3] [4] Unlike other third-generation progestins like desogestrel and norgestimate, gestodene is not a prodrug. [1] [29] Peak levels of gestodene occur within 1 to 4 hours after an oral dose, but usually within 1 to 2 hours. [1] The plasma protein binding of gestodene is 98%. [4] It is bound 64% to sex hormone-binding globulin and 34% to albumin, with 2% circulating freely. [4] Gestodene is metabolized in the liver via reduction of the δ4-3-keto group to form 3,5-tetrahydrogenated metabolites (major pathway) and via hydroxylation at the C1, C6, and C11 positions (substantial). [4] [1] In spite of differing from it only by the presence of an additional double bond between the C15 and C16 positions, gestodene is not metabolized into levonorgestrel in the body. [1] The biological half-life of gestodene is 12 to 15 hours. [2] [4] Gestodene is eliminated 50% in urine and 33% in feces. [1] Of gestodene excreted in urine, 25% is in the form of glucuronide conjugates, 35% is as sulfate conjugates, and 25% is unconjugated. [1]

Chemistry

Gestodene, also known as 17α-ethynyl-18-methyl-19-nor-δ15-testosterone, as well as 17α-ethynyl-18-methylestra-4,15-dien-17β-ol-3-one or 13β-ethyl-18,19-dinor-17α-pregna-4,15-dien-20-yn-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone. [5] [8] It is more specifically a derivative of norethisterone (17α-ethynyl-19-nortestosterone) and is a member of the gonane (18-methylestrane) subgroup of the 19-nortestosterone family of progestins. [30] Gestodene is almost identical to levonorgestrel in terms of chemical structure, differing only in having an additional double bond between the C15 and C16 positions, and for this reason is also known as δ15-norgestrel or as 15-dehydronorgestrel. [31] [32]

History

Gestodene was first synthesized in 1975. [4] It was introduced for medical use, specifically in combination with ethinylestradiol as a combined oral contraceptive, in 1987. [12] The medication was introduced for use in menopausal hormone therapy in combination with estradiol in some countries such as in Europe and Latin America years later. [7] [8]

Society and culture

Generic names

Gestodene is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, BAN Tooltip British Approved Name, and DCF Tooltip Dénomination Commune Française. [5] [6] [8] It is also known by its developmental code name SHB-331. [5] [8]

Brand names

Gestodene is marketed as a contraceptive in combination with ethinylestradiol under a variety of brand names including Femoden, Femodene, Femodette, Gynera, Harmonet, Lindynette, Logest, Meliane, Millinette, Minesse, Minulet, Mirelle, and Triadene as well as many others. [8] It is marketed for use in menopausal hormone therapy in combination with estradiol under the brand names Avaden, Avadene, and Convaden. [7] [8]

Availability

Gestodene is marketed in the United Kingdom, Ireland, elsewhere throughout Europe, South Africa, Australia, Latin America, Asia, and elsewhere in the world. [8] It is not listed as being marketed in the United States, Canada, New Zealand, Japan, South Korea, India, or certain other countries. [8] Gestodene is marketed for use specifically in menopausal hormone therapy only in a few countries, including Colombia, Ecuador, Mexico, Peru, and Portugal. [8]

Related Research Articles

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

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. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. 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. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Levonorgestrel</span> Hormonal medication used for birth control

Levonorgestrel is a hormonal medication which is used in a number of birth control methods. It is combined with an estrogen to make combination birth control pills. As an emergency birth control, sold under the brand names Plan B One-Step and Julie, among others, it is useful within 72 hours of unprotected sex. The more time that has passed since sex, the less effective the medication becomes, and it does not work after pregnancy (implantation) has occurred. Levonorgestrel works by preventing ovulation or fertilization from occurring. It decreases the chances of pregnancy by 57–93%. In an intrauterine device (IUD), such as Mirena among others, it is effective for the long-term prevention of pregnancy. A levonorgestrel-releasing implant is also available in some countries.

<span class="mw-page-title-main">Ethinylestradiol</span> Estrogen medication

Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disorders, and certain hormone-sensitive cancers. It is usually taken by mouth but is also used as a patch and vaginal ring.

Extended or continuous cycle combined oral contraceptive pills are a packaging of combined oral contraceptive pills (COCPs) that reduce or eliminate the withdrawal bleeding that would occur once every 28 days in traditionally packaged COCPs. It works by reducing the frequency of the pill-free or placebo days. Extended cycle use of COCPs may also be called menstrual suppression, although other hormonal medications or medication delivery systems may also be used to suppress menses. Any brand of combined oral contraceptive pills can be used in an extended or continuous manner by simply discarding the placebo pills; this is most commonly done with monophasic pills in which all of the pills in a package contain the same fixed dosing of a synthetic estrogen and a progestin in each active pill.

<span class="mw-page-title-main">Desogestrel</span> Medication

Desogestrel is a progestin medication which is used in birth control pills. It is also used in the treatment of menopausal symptoms in women. The medication is available and used alone or in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Drospirenone</span> Medication drug

Drospirenone is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses. It is available both alone under the brand name Slynd and in combination with an estrogen under the brand name Yasmin among others. The medication is an analog of the drug spironolactone. Drospirenone is taken by mouth.

<span class="mw-page-title-main">Norethisterone acetate</span> Chemical compound

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.

<span class="mw-page-title-main">Norelgestromin</span> Pharmaceutical drug

Norelgestromin, or norelgestromine, sold under the brand names Evra and Ortho Evra among others, is a progestin medication which is used as a method of birth control for women. The medication is available in combination with an estrogen and is not available alone. It is used as a patch that is applied to the skin.

<span class="mw-page-title-main">Norgestimate</span> Chemical compound

Norgestimate, sold under the brand name Ortho Tri-Cyclen among others, is a progestin medication which is used in birth control pills for women and in menopausal hormone therapy. The medication is available in combination with an estrogen and is not available alone. It is taken by mouth.

<span class="mw-page-title-main">Norgestrel</span> Progestin medication used for birth control

Norgestrel, sold under the brand name Opill among others, is a progestin which is used in birth control pills. It is often combined with the estrogen ethinylestradiol, marketed as Ovral. It is also used in menopausal hormone therapy. It is taken by mouth.

<span class="mw-page-title-main">Norethisterone</span> Progestin medication

Norethisterone, also known as norethindrone and sold under the brand name Norlutin among others, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.

<span class="mw-page-title-main">Norgestrienone</span> Chemical compound

Norgestrienone, sold under the brand names Ogyline, Planor, and Miniplanor, is a progestin medication which has been used in birth control pills, sometimes in combination with ethinylestradiol. It was developed by Roussel Uclaf and has been registered for use only in France. Under the brand name Planor, it has been marketed in France as 2 mg norgestrienone and 50 μg ethinylestradiol tablets. It is taken by mouth.

<span class="mw-page-title-main">Mestranol</span> Chemical compound

Mestranol, sold under the brand names Enovid, Norinyl, and Ortho-Novum among others, is an estrogen medication which has been used in birth control pills, menopausal hormone therapy, and the treatment of menstrual disorders. It is formulated in combination with a progestin and is not available alone. It is taken by mouth.

Combined injectable contraceptives (CICs) are a form of hormonal birth control for women. They consist of monthly injections of combined formulations containing an estrogen and a progestin to prevent pregnancy.

Progestogen-only contraception relies on progestogens alone to achieve contraception. It is one of the two major types of hormonal contraception, with the other major type being combined hormonal contraceptive methods. There are several progestogen only contraceptive methods:

<span class="mw-page-title-main">Norethisterone enanthate</span> Chemical compound

Norethisterone enanthate (NETE), also known as norethindrone enanthate, is a form of hormonal birth control which is used to prevent pregnancy in women. It is used both as a form of progestogen-only injectable birth control and in combined injectable birth control formulations. It may be used following childbirth, miscarriage, or abortion. The failure rate per year in preventing pregnancy for the progestogen-only formulation is 2 per 100 women. Each dose of this form lasts two months with only up to two doses typically recommended.

<span class="mw-page-title-main">Trimegestone</span> Chemical compound

Trimegestone, sold under the brand names Ondeva and Totelle among others, is a progestin medication which is used in menopausal hormone therapy and in the prevention of postmenopausal osteoporosis. It was also under development for use in birth control pills to prevent pregnancy, but ultimately was not marketed for this purpose. The medication is available alone or in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Estradiol/norethisterone</span> Combination drug

Estradiol/norethisterone (E2/NET), tentative brand name Netagen or Netagen 403, was a combination of estradiol (E2), an estrogen, and norethisterone (NET), a progestin, which was studied as a birth control pill to prevent pregnancy in women. It was taken by mouth and contained 4 mg micronized E2 and 3 mg NET per tablet. The medication was developed by Novo Pharmaceuticals in Denmark and was never marketed.

Combined birth control pills that contain natural estradiol or an estradiol ester include:

<span class="mw-page-title-main">Levonorgestrel acetate</span> Chemical compound

Levonorgestrel acetate (LNG-A), or levonorgestrel 17β-acetate, also known as 3-ketonorgestimate, is a progestin which was never marketed. It is a progestogen ester and is the C17β acetate ester and a prodrug of levonorgestrel. Norgestimate is the C3 oxime of LNG-A. The drug is a minor active metabolite of norgestimate, which is a prodrug of norelgestromin and to a lesser extent of levonorgestrel and LNG-A. LNG-A has high affinity for the progesterone receptor, about 135% of that of promegestone. Along with levonorgestrel butanoate, LNG-A was investigated as a hormonal contraceptive by the Population Council.

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Further reading

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