Trengestone

Last updated
Trengestone
Trengestone.svg
Clinical data
Trade names Reteroid, Retroid, Retrone
Other namesRo 4-8347; Triengestone; 1,6-Didehydro-6-chlororetroprogesterone; 6-Chloro-9β-10α-pregna-1,4,6-triene-3,20-dione
Routes of
administration 		By mouth
Drug class Progestogen; Progestin
ATC code
  • None
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability ≥41–46% (based on urinary excretion) [1]
Metabolism Liver [2] [3]
Metabolites • 20α-Dihydrotrengestone [1]
Elimination half-life • Trengestone: very short [1]
• 20α-DHTG: 8–14 hours [1]
Excretion Urine: 41–46% [1]
Feces: 30% (unchanged) [1]
Identifiers
  • (8S,9S,10R,13S,14S,17S)-17-acetyl-6-chloro-10,13-dimethyl-8,9,11,12,14,15,16,17-octahydrocyclopenta[a]phenanthren-3-one
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
ECHA InfoCard 100.023.617 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H25ClO2
Molar mass 344.88 g·mol−1
3D model (JSmol)
  • CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2C=C(C4=CC(=O)C=C[C@]34C)Cl)C
  • InChI=1S/C21H25ClO2/c1-12(23)15-4-5-16-14-11-19(22)18-10-13(24)6-8-21(18,3)17(14)7-9-20(15,16)2/h6,8,10-11,14-17H,4-5,7,9H2,1-3H3/t14-,15+,16-,17-,20+,21+/m0/s1
  • Key:USXVMPAWZOOYDE-HGUQNLGYSA-N

Trengestone, sold under the brand names Reteroid, Retroid, and Retrone, is a progestin medication which was formerly used to treat menstrual disorders but is now no longer marketed. [4] [5] [6] [7] [8] It is taken by mouth. [9]

Contents

Side effects of trengestone include headache, fatigue, and breast tenderness among others. [7] Trengestone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. [7] It is not androgenic or estrogenic. [7]

Trengestone was introduced for medical use in 1974. [5] It is no longer available. [8]

Medical uses

Trengestone was used in the treatment of menstrual disorders. [8] It has also been used to induce ovulation, with about a 50% success rate on average. [7]

Side effects

Side effects of trengestone include headache, fatigue, and breast tenderness among others. [7] It is not androgenic and does not cause masculinization. [7]

Pharmacology

20a-Dihydrotrengestone, the main active form of trengestone. 20a-Dihydrotrengestone.svg
20α-Dihydrotrengestone, the main active form of trengestone.

Pharmacodynamics

Trengestone is a progestogen, or an agonist of the progesterone receptor. [7] It is an atypical progestogen similarly to dydrogesterone. [7] For instance, unlike other progestogens, trengestone and dydrogesterone do not increase body temperature (i.e., have no hyperthermic effect). [7] [10] [11] In addition, whereas other progestogens are antigonadotropic and inhibit ovulation, dydrogesterone is neither antigonadotropic nor progonadotropic and does not affect ovulation, and trengestone appears to be progonadotropic and can be used to induce ovulation. [7] [11] [12] Similarly to dydrogesterone and progesterone, trengestone has no androgenic or estrogenic activity. [7] [11]

Pharmacokinetics

Trengestone appears to be a prodrug of 20α-dihydrotrengestone (20α-DHTG), as it is largely transformed into this major metabolite upon oral administration. [1] [13] 20α-DHTG has potent progestogenic activity, with peak levels of this metabolite occurring at 2 to 4 hours following administration of trengestone and with a biological half-life of 8 to 14 hours. [1] Trengestone is excreted 41 to 46% in urine and up to 30% unchanged in feces, suggesting that a significant portion of the medication is not absorbed from the gastrointestinal tract. [1] The metabolism and pharmacokinetics of trengestone have been reviewed. [2] [3]

Chemistry

Trengestone, also known as 1,6-didehydro-6-chlororetroprogesterone or as 6-chloro-9β,10α-pregna-1,4,6-triene-3,20-dione, is a synthetic pregnane steroid and a derivative of progesterone and retroprogesterone. [4] [7] [14] Retroprogesterone derivatives like trengestone are analogues of progesterone in which the hydrogen atom at the 9th carbon has been switched from the α-position (below the plane) to the β-position (above the plane) and the methyl group at the 10th carbon has been switched from the β-position to the α-position. [7] This results in a "bent" configuration in which the plane of rings A and B is orientated at a 60° angle below the rings C and D. [11] Analogues of trengestone include dydrogesterone (6-dehydroretroprogesterone) and Ro 6-3129 (16α-ethylthio-6-dehydroretroprogesterone). [4]

History

Trengestone was synthesized in 1964 and was introduced for medical use by Roche in 1974. [4] [5] [6]

Society and culture

Generic names

Trengestone is the generic name of the drug and its INN Tooltip International Nonproprietary Name. [4] [6] It is also known by its former developmental code name Ro 4-8347. [4] [6]

Brand names

Trengestone was marketed under the brand names Reteroid, Retroid, and Retrone. [4]

Availability

Trengestone is no longer marketed and hence is no longer available in any country. [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">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">Dydrogesterone</span> Chemical compound

Dydrogesterone, sold under the brand name Duphaston among others, is a progestin medication which is used for a variety of indications, including threatened or recurrent miscarriage during pregnancy, dysfunctional bleeding, infertility due to luteal insufficiency, dysmenorrhea, endometriosis, secondary amenorrhea, irregular cycles, premenstrual syndrome, and as a component of menopausal hormone therapy. It is taken by mouth.

<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">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">Cyproterone</span> Chemical compound

Cyproterone, also known by its developmental code name SH-80881, is a steroidal antiandrogen which was studied in the 1960s and 1970s but was never introduced for medical use. It is an analogue of cyproterone acetate (CPA), an antiandrogen, progestin, and antigonadotropin which was introduced instead of cyproterone and is widely used as a medication. Cyproterone and CPA were among the first antiandrogens to be developed.

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

Delmadinone acetate (DMA), sold under the brand name Tardak among others, is a progestin and antiandrogen which is used in veterinary medicine to treat androgen-dependent conditions such as benign prostatic hyperplasia. It must be used with care as it has the potential to cause adrenal insufficiency via inhibition of adrenocorticotropic hormone (ACTH) secretion from the pituitary gland. DMA is the C17α acetate ester of delmadinone, which, in contrast to DMA, was never marketed for medical use.

<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">Osaterone acetate</span> Chemical compound

Osaterone acetate, sold under the brand name Ypozane, is a medication which is used in veterinary medicine in Europe in the treatment of enlarged prostate in dogs. It is given by mouth.

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

Retroprogesterone, also known as 9β,10α-progesterone or as 9β,10α-pregn-4-ene-3,20-dione, is a progestin which was never marketed. It is a stereoisomer of the naturally occurring progestogen progesterone, in which the hydrogen atom at the 9th carbon is in the α-position instead of the β-position and the methyl group at the 10th carbon is in the β-position instead of the α-position. In other words, the atom positions at the two carbons have been reversed relative to progesterone, hence the name retroprogesterone. This reversal results in a "bent" configuration in which the plane of rings A and B is orientated at a 60° angle below the rings C and D. This configuration is ideal for interaction with the progesterone receptor, with retroprogesterone binding with high affinity to this receptor. However, the configuration is not as ideal for binding to other steroid hormone receptors, and as a result, retroprogesterone derivatives have increased selectivity for the progesterone receptor relative to progesterone.

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

Quingestrone, also known as progesterone 3-cyclopentyl enol ether (PCPE) and sold under the brand name Enol-Luteovis, is a progestin medication which was previously used in birth control pills in Italy but is now no longer marketed. It is taken by mouth.

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

Dimethandrolone (DMA), also known by its developmental code name CDB-1321, is an experimental androgen/anabolic steroid (AAS) and progestogen medication which is under investigation for potential clinical use.

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

Flumedroxone acetate, sold under the brand names Demigran and Leomigran, is a progestin medication which is or has been used as an antimigraine agent. It is taken by mouth.

<span class="mw-page-title-main">Ro 6-3129</span> Chemical compound

Ro 6-3129, also known as 16α-ethylthio-6-dehydroretroprogesterone or as 16α-ethylthio-9β,10α-pregna-4,6-diene-3,20-dione, as well as 16α-ethylthiodydrogesterone, is a progestogen of the retroprogesterone group which was developed by Roche but was never marketed. It shows greater potency than dydrogesterone in bioassays.

<span class="mw-page-title-main">11-Dehydroprogesterone</span> Chemical compound

11-Dehydroprogesterone, also known as pregna-4,11-diene-3,20-dione, is a steroidal progestin that was never marketed. It was found to be 2- to 3-fold as potent as progesterone as a progestogen in animal bioassays, although other studies found them to be equivalent in potency. 11-Dehydroprogesterone has been studied in women. It was discovered in the 1930s or 1940s, and was one of the earliest synthetic progestogens.

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

Gestadienol acetate an orally active progestin which was described in the literature in 1967 and was never marketed. It has no androgenic or estrogenic effects. The effects of gestadienol acetate on the endometrium and its general pharmacology were studied in a clinical trial in women. It has also been studied in a clinical trial for benign prostatic hyperplasia in men, but was ineffective.

<span class="mw-page-title-main">20α-Dihydrotrengestone</span> Chemical compound

20α-Dihydrotrengestone (20α-DHTG), also known as 20α-hydroxytrengestone, as well as 6-chloro-20(S)-hydroxy-9β,10α-pregna-1,4,6-trien-3-one, is a progestin and the major active metabolite of trengestone. It appears that trengestone is a prodrug of 20α-DHTG, as it is largely transformed into this metabolite when given orally in humans. 20α-DHTG has potent progestogenic activity similarly to trengestone.

<span class="mw-page-title-main">DU-41164</span> Chemical compound

DU-41164, also known as 1,2β-methylene-6-fluoro-17α-acetoxy-δ6-retroprogesterone, is a progestin which was developed by Philips-Duphar in the 1970s and was never marketed. It is a combined derivative of 17α-hydroxyprogesterone and retroprogesterone. The drug shows extremely high potency as a progestogen in animals; it was reported to possess 500 times the affinity of progesterone for the progesterone receptor expressed in rabbit uterus, and showed 600 times the progestogenic potency of subcutaneous progesterone when given orally in animals. The affinity of DU-41164 for the progesterone receptor was described in 1974 as "probably the highest reported for any steroid-receptor interaction". The drug showed no androgenic, anabolic, antiandrogenic, estrogenic, or corticosteroid activity in animals. Although highly potent in animals, DU-41164 produced little or no progestogenic effect at dosages of 50 and 200 µg/day in women, suggesting major species differences. A closely related compound, DU-41165, has been developed as a photoaffinity label for the progesterone receptor.

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

Ethinylandrostenediol, also known as 17α-ethynyl-5-androstenediol, is a synthetic estrogen, progestogen, and androgen which was never marketed. It is the C17α ethynyl derivative of the androgen precursor and prohormone 5-androstenediol.

References

  1. 1 2 3 4 5 6 7 8 9 Dixon R, Tormey P, Darragh A (March 1975). "Disposition of the retro-steroid progestogen, 6-chloro-9beta, 10alpha-pregna-1,4,6-triene-3,20-dione (Ro 4-8347), in man". Contraception. 11 (3): 339–346. doi:10.1016/0010-7824(75)90042-6. PMID   1116370.
  2. 1 2 Darragh A (October 1970). "The metabolism of the synthetic progestational compound Ro 4-8347". Bulletin der Schweizerischen Akademie der Medizinischen Wissenschaften. 25 (4–6): 337–348. PMID   5510163. Archived from the original on 2018-03-01. Retrieved 2018-03-01.
  3. 1 2 Breuer H (October 1970). "Metabolism of progesterone and synthetic progestational agents". Bulletin der Schweizerischen Akademie der Medizinischen Wissenschaften. 25 (4–6): 300–315. PMID   5510160. Archived from the original on 2018-03-01. Retrieved 2018-03-01.
  4. 1 2 3 4 5 6 7 Elks J (14 November 2014). "6-Chloro-9β-10α-pregna-1,4,6-triene-3,20-dione". The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 259–. ISBN   978-1-4757-2085-3. C-00276.
  5. 1 2 3 Brudon P, Brudon-Jakobowicz P (1983). Médicaments pour tous en l'an 2000?: les multinationales pharmaceutiques suisses face au tiers monde : l'exemple du Mexique. Editions d'en bas. pp. 93–. ISBN   978-2-8290-0039-3.
  6. 1 2 3 4 Morton I, Morton IK, Hall JM (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 279–. ISBN   978-0-7514-0499-9.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Horsky J (6 December 2012). "Therapy of Anovulation". In Horsky J, Presl J (eds.). Ovarian Function and its Disorders: Diagnosis and Therapy. Springer Science & Business Media. pp. 329–. ISBN   978-94-009-8195-9.
  8. 1 2 3 4 "Micromedex". Merative US L.P.
  9. ↑ Popper TL, Watnick AS (1971). "Chapter 17. Steroids and Biologically Related Compounds". Annual Reports in Medicinal Chemistry. Vol. 6. Academic Press. pp. 162–181. doi:10.1016/S0065-7743(08)60972-0. ISBN   9780120405060. ISSN   0065-7743. Ro 4-8347 (21), a potent orally active progestagen, when given at the dose of 4 mg/day in the second half of the cycle, was found clinically useful in anovulatory women with decreased ovarian function.109
  10. ↑ Taubert HD (1978). "Luteal phase insufficiency". Contributions to Gynecology and Obstetrics. 4: 78–113. doi:10.1159/000401245. ISBN   978-3-8055-2791-0. PMID   679688. Fig. 17. Lack of hyperthermic effect of retroprogesterone derivative (Trengestone).
  11. 1 2 3 4 Kuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 (Suppl 1): 3–63. doi:10.1080/13697130500148875. PMID   16112947. S2CID   24616324.
  12. ↑ James VH, Martini L, eds. (1971). Hormonal Steroids: Proceedings of the Third International Congress on Hormonal Steroids, Hamburg, 7-12 September 1970. Vol. 3. Excerpta Medica. pp. 873–874, 876. ISBN   978-90-219-0144-2. Trengestone, contrary to [dydrogesterone], not only does not inhibit ovarian activity while exerting a progestation effect, but it stimulates the former. One tablet per day is administered from the 5th [...] Both dydrogesterone and trengestone can inhibit ovulation in the rat and rabbit, but only the latter compound can do so in women — at doses far above the therapeutic range. Various clinical reports have suggested, on the basis of quite unrelated findings, that trengestone may, despite lack of inherent estrogenicity, somehow cause an indirect stimulation of the production of endogenous estrogens. Numerous investigators (Stamm et al., 1968; Dapunt and Windbichler, 1970) have satisfied themselves that the compound may stimulate ovulation in women with certain endocrinologic imbalances or deficiencies [...]
  13. ↑ Breuer H, Kime DE, Knuppen R (September 1973). "Metabolism of 6-chloro-9 beta, 10 alpha-pregna-1,4,6-triene-3,20-dione in rat, rabbit, monkey and man". Acta Endocrinologica. 74 (1): 127–143. doi:10.1530/acta.0.0740127. PMID   4202495.
  14. ↑ Andreoli C, Fiorentino F, Lenzi G (September 1970). "[Clinical studies and endometrial histomorphological findings by means of a new retroprogesterone derivative: 1,6 bis dehydro-6-chloro-retroprogesterone (Trengestone)]". Minerva Ginecologica (in Italian). 22 (18): 874–879. PMID   4925556.
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