Trimegestone

Last updated
Trimegestone
Trimegestone.svg
Clinical data
Trade names Ginotex, Lovelle, Minique, Ondeva, Totelle, others
Other namesTMG; RU-27987; 21(S)-Hydroxypromegestone; 21β-Hydroxypromegestone; 21(S)-Hydroxy-17α,21-dimethyl-9-dehydro-19-norprogesterone; 21(S)-Hydroxy-17α,21-dimethyl-19-norpregna-4,9-dien-3,20-dione; 17β-(S)-Lactoyl-17α-methylestra-4,9-dien-3-one; 17β-((S)-2-Hydroxypropanoyl)-17α-methylestra-4,9-dien-3-one
Routes of
administration 		By mouth
Drug class Progestogen; Progestin
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100% [1]
Protein binding 98% (to albumin) [2]
Metabolism Mainly hydroxylation [2]
Elimination half-life Range: 12–20 hours [3]
Mean: 13.8–15.6 hours [2] [4]
Identifiers
  • (8S,13S,14S,17S)-17-[(2S)-2-hydroxypropanoyl]-13,17-dimethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.189.099 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H30O3
Molar mass 342.479 g·mol−1
3D model (JSmol)
  • C[C@@H](C(=O)[C@]1(CC[C@@H]2[C@@]1(CCC3=C4CCC(=O)C=C4CC[C@@H]23)C)C)O
  • InChI=1S/C22H30O3/c1-13(23)20(25)22(3)11-9-19-18-6-4-14-12-15(24)5-7-16(14)17(18)8-10-21(19,22)2/h12-13,18-19,23H,4-11H2,1-3H3/t13-,18+,19-,21-,22+/m0/s1
  • Key:JUNDJWOLDSCTFK-MTZCLOFQSA-N

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. [4] [2] [3] It was also under development for use in birth control pills to prevent pregnancy, but ultimately was not marketed for this purpose. [5] The medication is available alone or in combination with an estrogen. [6] [7] It is taken by mouth. [2]

Contents

Side effects of trimegestone include headache, breast tenderness, nervousness, abdominal pain, bloating, muscle cramps, nausea, depression, and vaginal bleeding among others. [8] [4] Trimegestone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. [2] [4] It has weak antiandrogenic and antimineralocorticoid activity and no other important hormonal activity. [2] [4]

Trimegestone was first described in 1979 and was introduced for medical use in 2001. [9] [10] [11] It is sometimes described as a "fourth-generation" progestin. [12] [13] The medication is marketed throughout Europe and Latin America. [14] [6] It is not available in the United States or Canada. [15] [14] [6]

Medical uses

Trimegestone is used in menopausal hormone therapy in the treatment of menopausal symptoms such as hot flashes and vaginal atrophy and in the prevention of postmenopausal osteoporosis. [16] [10] [3] [7]

Available forms

Trimegestone is available both alone (as Ondeva) and in combination with estradiol (as Ginotex, Lovelle, Minique, Totelle), both of which are approved for the treatment of menopausal symptoms and prevention of postmenopausal osteoporosis. [7] [17] Preparations of trimegestone are oral tablets and contain 0.1 to 0.5 mg of the medication. [18]

Side effects

The most common side effects of trimegestone alone at dosages of 0.25 to 0.5 mg/day include breast tenderness (40.7–43.0%), abdominal pain (13.9–16.7%), headache (16.0–19.4%), nervousness (12.7–16.0%), bloating (10.3–16.0%), muscle cramps (12.3–13.9%), nausea (4.8–12.3%), and depression (3.0–3.1%). [8] The most common side effects of the combination of 1 mg/day estradiol and 0.125–0.25 mg/day trimegestone include headache (26.4%), breast pain (15–20%), abdominal pain (18%), and vaginal bleeding (9–18%), and metrorrhagia (18.8%). [4]

Pharmacology

Pharmacodynamics

Trimegestone is a progestogen, or an agonist of the progesterone receptor (PR). [19] [2] [20] It has very high affinity for the PR, about 588 to 660% of that of progesterone. [19] [2] [20] This is greater than that of almost all other widely used progestins, with the exception of the 19-nortestosterone derivative gestodene (which has about 864% of the affinity of progesterone). [19] [21] [2] [20] In accordance with its very high affinity for the PR, trimegestone is described as a very potent progestogen, showing secretory transformation of the estrogen-treated endometrium at a dosage of only 0.1 mg/day, and is the most potent progestin of the 19-norprogesterone group. [16] [2] Like other progestogens, trimegestone has functional antiestrogenic effects in certain tissues such as the endometrium and has antigonadotropic effects. [2] [22] The endometrial transformation dosage of trimegestone is 0.25 to 0.5 mg/day and its ovulation-inhibiting dosage is 0.5 mg/day. [21] [2]

In addition to its affinity for the PR, trimegestone has moderate affinity for the mineralocorticoid receptor (42–120% of that of aldosterone), weak to very weak affinity for the glucocorticoid and androgen receptors (9–13% of that of dexamethasone and 1–2.4% of that of testosterone, respectively), and no affinity for the estrogen receptor (less than 0.02% of that of estradiol). [19] [2] [20] In accordance, it possesses weak antimineralocorticoid activity, very weak antiandrogenic activity, and no androgenic, estrogenic, glucocorticoid, antiglucocorticoid, or mineralocorticoid activity. [2] [19] [4] [20] As such, it is a selective and mostly pure progestogen. [16] [2] Unlike progesterone, trimegestone does not metabolize into neurosteroids and hence does not influence GABAA receptor signaling or produce sedative side effects. [19]

The antiandrogenic potency of trimegestone in animals is about 30% of that of cyproterone acetate. [23]

Pharmacokinetics

The oral bioavailability of trimegestone is about 100%. [1] [3] Following a single oral dose of trimegestone, peak serum concentrations occur within 0.5 hours and are 12–15 ng/mL (35–44 nmol/L) for a 0.5 mg dose and 25 ng/mL (73 nmol/L) for a 1 mg dose. [2] [3] Circulating levels of trimegestone increase proportionally across dosages of 0.25 to 1 mg/day. [3] Steady-state levels of trimegestone are achieved within 3 days of daily administration. [3] The plasma protein binding of trimegestone is 98%; it is bound to albumin. [2] Trimegestone is metabolized mainly via hydroxylation. [2] [22] The 1β- and 6β-hydroxy metabolites of trimegestone are progestogens with considerable potency similarly and show little or no affinity to other steroid hormone receptors. [22] The elimination half-life of trimegestone is between 12 and 20 hours, with an average of about 13.8 to 15.6 hours. [2] [3] [4]

Chemistry

Trimegestone, also known as 21(S)-hydroxy-17α,21-dimethyl-δ9-19-norprogesterone or as 21(S)-hydroxy-17α,21-dimethyl-19-norpregna-4,9-dien-3,20-dione, is a synthetic norpregnane steroid and a derivative of progesterone. [24] [2] It is specifically a combined derivative of 17α-methylprogesterone and 19-norprogesterone, or of 17α-methyl-19-norprogesterone. [24] [2] Related derivatives of 17α-methyl-19-norprogesterone include demegestone and promegestone. [24] [2]

History

Trimegestone was first described in 1979 and was introduced for medical use in 2001. [9] [10] [11] It was discovered as an active metabolite of promegestone. [9] [21] [25] The medication originated by Sanofi-Aventis in France, where promegestone was developed, and was first marketed by Wyeth in Sweden. [26]

Society and culture

Generic names

Trimegestone is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, and BAN Tooltip British Approved Name, while trimégestone is its DCF Tooltip Dénomination Commune Française. [24] [6] [27] It is also known by its developmental code name RU-27987. [24] [6] [27]

Brand names

Trimegestone under the brand names Ginotex, Lovelle, Lovelle Ciclico, Lovelle Continuo, Minique, Ondeva, Totelle, Totelle Ciclico, Totelle Ciclo, Totelle Continuo, Totelle Cycle, Totelle Cyclo, Totelle Secuencial, and Totelle Sekvens. [14] [6] [27] [11] [3] [28] With the exception of Ondeva, which is formulated alone, all of these products are formulated in combination with estradiol. [14] [6] [27]

Availability

Trimegestone is or has been marketed in Europe and Latin America, including in Argentina, Austria, Belgium, Brazil, Chile, Denmark, Finland, France, Italy, Lithuania, Mexico, Norway, Sweden, and Venezuela. [14] [6] [26] [3] [27] It is not available in any predominantly English-speaking countries, including the United States, Canada, the United Kingdom, Ireland, Australia, New Zealand, or South Africa. [15] [14] [6]

Research

The oral combination of trimegestone and ethinylestradiol was under development by Wyeth in the United States as a birth control pill to prevent pregnancy and the oral combination of trimegestone and conjugated estrogens was under development by Wyeth in the United States to treat menopausal syndrome and to prevent postmenopausal osteoporosis, but the development of both formulations was discontinued and they were never marketed. [5] [29] A transdermal patch with the developmental code name PSK-3987 containing estradiol and trimegestone was under development by ProStrakan for the treatment of menopausal syndrome, but it too never completed development and hence was not marketed. [30]

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">Desogestrel</span> Medication

Desogestrel is a progestin medication which is used in birth control pills for women. 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">Norgestimate</span> Chemical compound

Norgestimate, sold under the brand names Ortho Tri-Cyclen and Previfem 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">Tibolone</span> Chemical compound

Tibolone, sold under the brand name Livial among others, is a medication which is used in menopausal hormone therapy and in the treatment of postmenopausal osteoporosis and endometriosis. The medication is available alone and is not formulated or used in combination with other medications. It is taken by mouth.

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

Norethisterone, also known as norethindrone and sold under many brand names, 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">Gestodene</span> Progestin medication

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

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

Gestonorone caproate, also known as gestronol hexanoate or norhydroxyprogesterone caproate and sold under the brand names Depostat and Primostat, is a progestin medication which is used in the treatment of enlarged prostate and cancer of the endometrium. It is given by injection into muscle typically once a week.

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

Ethisterone, also known as ethinyltestosterone, pregneninolone, and anhydrohydroxyprogesterone and formerly sold under the brand names Proluton C and Pranone among others, is a progestin medication which was used in the treatment of gynecological disorders but is now no longer available. It was used alone and was not formulated in combination with an estrogen. The medication is taken by mouth.

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

Dienogest, sold under the brand name Visanne among others, is a progestin medication which is used in birth control pills and in the treatment of endometriosis. It is also used in menopausal hormone therapy and to treat heavy periods. Dienogest is available both alone and in combination with estrogens. It is taken by mouth.

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

Chlormadinone acetate (CMA), sold under the brand names Belara, Gynorelle, Lutéran, and Prostal among others, is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy, as a component of menopausal hormone therapy, in the treatment of gynecological disorders, and in the treatment of androgen-dependent conditions like enlarged prostate and prostate cancer in men and acne and hirsutism in women. It is available both at a low dose in combination with an estrogen in birth control pills and, in a few countries like France and Japan, at low, moderate, and high doses alone for various indications. It is taken by mouth.

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

Medrogestone, sold under the brand name Colprone among others, is a progestin medication which has been used in menopausal hormone therapy and in the treatment of gynecological disorders. It is available both alone and in combination with an estrogen. It is taken by mouth.

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

Promegestone, sold under the brand name Surgestone, is a progestin medication which is used in menopausal hormone therapy and in the treatment of gynecological disorders. It is taken by mouth.

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

Demegestone, sold under the brand name Lutionex, is a progestin medication which was previously used to treat luteal insufficiency but is now no longer marketed. It is taken by mouth.

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

Nomegestrol acetate (NOMAC), sold under the brand names Lutenyl and Zoely among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. It is available both alone and in combination with an estrogen. NOMAC is taken by mouth. A birth control implant for placement under the skin was also developed but ultimately was not marketed.

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

Segesterone acetate (SGA), sold under the brand names Nestorone, Elcometrine, and Annovera, is a progestin medication which is used in birth control and in the treatment of endometriosis in the United States, Brazil, and other South American countries. It is available both alone and in combination with an estrogen. It is not effective by mouth and must be given by other routes, most typically as a vaginal ring or implant that is placed into fat.

<span class="mw-page-title-main">19-Norprogesterone</span> Chemical compound

19-Norprogesterone, also known as 19-norpregn-4-ene-3,20-dione, is a steroidal progestin and close analogue of the sex hormone progesterone, lacking only the C19 methyl group of that molecule. It was first synthesized in 1944 in the form of a mixture that also included unnatural stereoisomers of progesterone, and this mixture was found to be at least equivalent to progesterone in terms of progestogenic activity. Subsequent investigations revealed that 17-isoprogesterone and 14-iso-17-isoprogesterone are devoid of progestogenic activity. 19-Norprogesterone was resynthesized in 1951 with an improved method, and was confirmed to be the component of the mixture synthesized in 1944 that was responsible for its progestogenic activity. In 1953, a paper was published showing that 19-norprogesterone possessed 4- to 8-fold the activity of progesterone in the Clauberg assay in rabbits, and at the time of this discovery, 19-norprogesterone was the most potent progestogen known.

<span class="mw-page-title-main">Estetrol (medication)</span> Estrogen medication

Estetrol (E4) is an estrogen medication and naturally occurring steroid hormone which is used in combination with a progestin in combined birth control pills and is under development for various other indications. These investigational uses include menopausal hormone therapy to treat symptoms such as vaginal atrophy, hot flashes, and bone loss and the treatment of breast cancer and prostate cancer. It is taken by mouth.

<span class="mw-page-title-main">18-Methylsegesterone acetate</span> Chemical compound

18-Methylsegesterone acetate is a progestin medication of the 19-norprogesterone group which was never marketed. It was first described in a patent in 1997 and then in a literature paper in 2003. 18-Methyl-SGA is the C18 methyl or C13β ethyl derivative of segesterone acetate, and shows 3 to 10 times the progestogenic potency of SGA in bioassays. This is analogous to the case of the 19-nortestosterone progestin norethisterone and its 18-methyl derivative levonorgestrel, the latter showing substantially increased potency relative to the former similarly. As SGA is already one of the most potent progestins to have been developed, with 100-fold the potency of progesterone and 10-fold the potency of levonorgestrel in bioassays, 18-methyl-SGA is an extremely potent progestogen, among if not the most potent known.

The pharmacology of progesterone, a progestogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

References

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  30. ↑ "Estradiol/trimegestone transdermal patch - ProStrakan". AdisInsight. Springer Nature Switzerland AG.

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