Segesterone acetate

Segesterone acetate
Clinical data
Trade namesNestorone, Elcometrine, Annovera
Other namesSGA; SA; Nestorone; Nestoron; Elcometrine; ST-1435; AC-6844; CS-0411; 16-Methylene-17α-acetoxy-19-norprogesterone; 16-Methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione
Routes of
administration		Subcutaneous implant, vaginal ring, transdermal patch[1]
Drug classProgestogen; Progestin; Progestogen ester
ATC code
  • None
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityOral: 10%[1][2]
Protein binding95% (to albumin and not to SHBGTooltip sex hormone-binding globulin[1][3][4]
MetabolismHydroxylation (CYP3A4), reduction (5α-reductase)
Elimination half-lifeVaginal ring: 4.5 hours[4]
Parenteral: 24–72 hours[5][6]
Oral: 1–2 hours[1]
Identifiers
  • [(8R,9S,10R,13S,14S,17R)-17-acetyl-13-methyl-16-methylidene-3-oxo-2,6,7,8,9,10,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-17-yl] acetate
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC23H30O4
Molar mass370.489 g·mol−1
3D model (JSmol)
  • O=C4\C=C2/[C@@H]([C@H]1CC[C@@]3([C@](OC(=O)C)(C(=C)\C[C@H]3[C@@H]1CC2)C(=O)C)C)CC4
  • InChI=1S/C23H30O4/c1-13-11-21-20-7-5-16-12-17(26)6-8-18(16)19(20)9-10-22(21,4)23(13,14(2)24)27-15(3)25/h12,18-21H,1,5-11H2,2-4H3/t18-,19+,20+,21-,22-,23-/m0/s1
  • Key:CKFBRGLGTWAVLG-GOMYTPFNSA-N

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.[1][4][7] It is available both alone and in combination with an estrogen.[1][4][7] 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.[1][4][8]

Side effects of SGA are similar to those of other progestins. SGA is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[1][3][9][10] It has some affinity for the glucocorticoid receptor and has no other important hormonal activity.[1][3][9][10]

SGA was developed by the Population Council and was introduced for medical use by 2000.[7][11] It is under development in the United States and Europe as a gel in combination with estradiol or testosterone for use as a method of birth control in women and in men, respectively.[12][13][14][15] On August 10, 2018, a first-of-its-kind one-year contraceptive vaginal ring containing segesterone acetate in combination with ethinyl estradiol was approved in the United States.[4][16] It is marketed under the brand name Annovera and is reusable for up to one year as a method of birth control in women. Annovera does not require refrigeration which is very useful for low resource areas.[4][17]

Medical uses

[edit]

SGA is used as a hormonal contraceptive and in the treatment of endometriosis.[1][4][7]

Available forms

[edit]
See also: Ethinylestradiol/segesterone acetate

Side effects

[edit]
See also: Progestin § Side effects

Side effects of SGA are similar to those of other progestins.[citation needed]

Pharmacology

[edit]

Pharmacodynamics

[edit]

SGA acts primarily as a high-affinity agonist of the progesterone receptor (272% of the affinity of progesterone and 136% of that of promegestone).[3] It does not bind significantly to the androgen receptor, estrogen receptor, or mineralocorticoid receptor.[3][9] As such, SGA does not have estrogenic, androgenic, antiandrogenic, or antimineralocorticoid activity.[5] However, SGA does have significant affinity for the glucocorticoid receptor (38% of that of dexamethasone), but in spite of its relatively high affinity for the glucocorticoid receptor, it either does not have any glucocorticoid effects or shows glucocorticoid effects only at exceptionally high doses in animals.[1][3][10] SGA has no antiglucocorticoid activity in animals either.[10] The ovulation-inhibiting dosage of parenteral SGA has been reported to be 150 μg per day, while the endometrial transformation dosage has been reported to be 600 μg per cycle.[5] SGA has antigonadotropic effects and functional antiestrogenic effects via its progestogenic activity similarly to other progestogens.[3][5] In healthy young men, SGA alone at a dose of 2 to 3 mg/day as a transdermal gel (delivering 200–300 μg/day SGA) for 2 weeks suppressed testosterone levels from ~581 ng/dL to ~276 ng/dL (–52%).[18]

Pharmacokinetics

[edit]

SGA is only weakly active orally, and is instead given as a subcutaneous implant.[8] The oral bioavailability of SGA has been reported to be only 10%.[1][2] However, it has also been reported that the medication is more than 100-fold as potent when delivered via subcutaneous implant relative to oral administration in rats.[1][3] It has been estimated that SGA administered at a dose of 2 to 3 mg/day in the form of a transdermal gel delivers approximately 200 to 300 μg/day SGA based on a transdermal bioavailability of about 10 to 12%.[18] SGA is bound to albumin.[1][3] It does not bind to sex hormone-binding globulin.[1][3] Segesterone, the deacetylated form of SGA, is a metabolite of the medication.[19] The biological half-life of parenteral SGA has been reported to be 24 to 72 hours.[5][6] One study specifically reported a biological half-life of 26.8 hours.[6] It has been reported that the biological half-life of SGA with oral administration is only 1 to 2 hours.[1] In contrast to all of the preceding however, the Food and Drug Administration (FDA) label for Annovera, a one-year vaginal ring containing ethinylestradiol and SGA, lists a circulating half-life of SGA of 4.5 hours.[4]

Chemistry

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

SGA, also known as 16-methylene-17α-acetoxy-19-norprogesterone or as 16-methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione, is a synthetic norpregnane steroid and a derivative of progesterone. It is a combined derivative of 17α-hydroxyprogesterone and 19-norprogesterone, or a derivative of gestronol (17α-hydroxy-19-norprogesterone). The medication is the C17α acetate ester of segesterone, which, in contrast, was never marketed.[19] Other 19-norprogesterone derivatives include demegestone, gestonorone caproate (norhydroxyprogesterone caproate), nomegestrol acetate, promegestone, and trimegestone.[3] SGA is a derivative of 16-methylene-17α-hydroxyprogesterone acetate, and is the analogue of methenmadinone acetate without the C19 methyl group or the C6 double bond.[20] A derivative of SGA with even greater progestogenic potency in comparison to SGA is 18-methylsegesterone acetate.[21][22][23]

History

[edit]

SGA was developed by the Population Council.[11] It has been marketed since at least 2000.[7]

Society and culture

[edit]

Generic names

[edit]

Segesterone acetate is the generic name of the drug and its USANTooltip United States Adopted Name.[24][25] It is also known by its brand names nestorone and elcometrine,[26] as well as by its former developmental code names ST-1435, AC-6844, and CS-0411.[citation needed]

Brand names

[edit]

SGA is marketed alone under the brand names Nestorone and Elcometrine and in combination with ethinylestradiol under the brand name Annovera.[4][7]

Availability

[edit]

SGA is available alone in several South American countries, including Brazil.[1] It is available in the United States as a contraceptive vaginal ring in combination with ethinylestradiol.[4]

Research

[edit]

A combination of SGA and the estrogen estradiol is under development in a transdermal gel formulation for use as a contraceptive in women by the Population Council in conjunction with Antares Pharma in the United States and Europe.[12][14] As of December 2017, it is in phase III clinical trials for this indication.[12] The medication has the tentative brand name NestraGel.[12] A combination of SGA and the estrogen ethinylestradiol in a vaginal ring formulation for use as a one-year contraceptive was developed by the Population Council in multiple regions including Latin America, Europe, and Australia.[17] It completed phase III clinical trials and [17] was approved in the United States in August 2018.[4][16]

A combination of SGA and the androgen testosterone is under development as a transdermal gel formulation for use as a hormonal contraceptive in men by the Population Council.[13][15] As of December 2017, it is in phase II clinical studies for this purpose.[15][27] In a trial, 100 couples used segesterone/testosterone dermal gel as the sole contraception method, which resulted in no pregnancy. Side effects were described as mild, comprising acne, weight gain and nocturnal sweating.[28]

See also

[edit]

References

[edit]
  1. ^ a b c d e f g h i j k l m n o p q Lemke TL, Williams DA, Roche VT, Zito SW (24 January 2012). "Chapter 41: Women's Health". Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. p. 1403. ISBN 978-1-60913-345-0. Retrieved 13 September 2012.
  2. ^ a b Sitruk-Ware R (15 May 2001). "Progestins and the cardiovascular system". In Genazzani AR (ed.). Hormone Replacement Therapy and Cardiovascular Disease: The Current Status of Research and Practice. CRC Press. pp. 95–. ISBN 978-1-84214-038-3.
  3. ^ a b c d e f g h i j k 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.
  4. ^ a b c d e f g h i j k l "ANNOVERATM (segesterone acetate and ethinyl estradiol vaginal system)" (PDF). Population Council. U.S. Food and Drug Administration. 2018.
  5. ^ a b c d e Rabe T, Goeckenjan M, Ahrendt HJ, Crosignani PG, Dinger JC, Mueck AO, et al. (October 2011). "Oral Contraceptive Pills: Combinations, Dosages and the Rationale behind 50 Years or Oral Hormonal Contraceptive Development" (PDF). Journal für Reproduktionsmedizin und Endokrinologie-Journal of Reproductive Medicine and Endocrinology. 8 (1): 58–129.
  6. ^ a b c Fraser IS, Weisberg E, Kumar N, Kumar S, Humberstone AJ, McCrossin L, et al. (December 2007). "An initial pharmacokinetic study with a Metered Dose Transdermal Systemfor delivery of the progestogen Nestorone as a possible future contraceptive". Contraception. 76 (6): 432–438. doi:10.1016/j.contraception.2007.08.006. PMID 18061700.
  7. ^ a b c d e f Croxatto HB (2000). "Progestin implants". Steroids. 65 (10–11): 681–685. doi:10.1016/S0039-128X(00)00124-0. PMID 11108876. S2CID 42296395.
  8. ^ a b Rajagopalan S, Mukherjee D, Mohler ER (31 August 2004). Manual of Vascular Diseases. Lippincott Williams & Wilkins. p. 803. ISBN 978-0-7817-4499-7. Retrieved 13 September 2012.
  9. ^ a b c Hussain R, El-Etr M, Gaci O, Rakotomamonjy J, Macklin WB, Kumar N, et al. (October 2011). "Progesterone and Nestorone facilitate axon remyelination: a role for progesterone receptors". Endocrinology. 152 (10): 3820–3831. doi:10.1210/en.2011-1219. PMC 6285137. PMID 21828184.
  10. ^ a b c d Kumar N, Koide SS, Tsong Y, Sundaram K (2000). "Nestorone: a progestin with a unique pharmacological profile". Steroids. 65 (10–11): 629–636. doi:10.1016/S0039-128X(00)00119-7. PMID 11108869. S2CID 13722269.
  11. ^ a b Prasad, P. V., & Shrivastav, T. G. (2015). Nestorone®: A new hope for Gynecologists, Andrologists and Neurologists. of, 3, 2.
  12. ^ a b c d "Elcometrine/Estradiol - Population Council/Therapeutics MD - AdisInsight".
  13. ^ a b Ilani N, Roth MY, Amory JK, Swerdloff RS, Dart C, Page ST, et al. (October 2012). "A new combination of testosterone and nestorone transdermal gels for male hormonal contraception". The Journal of Clinical Endocrinology and Metabolism. 97 (10): 3476–3486. doi:10.1210/jc.2012-1384. PMC 3462927. PMID 22791756.
  14. ^ a b "Nestorone®/Estradiol Transdermal Gel Contraception | Population Council".
  15. ^ a b c "Nestorone®/Testosterone Transdermal Gel for Male Contraception | Population Council". 14 September 2022.
  16. ^ a b "FDA approves new vaginal ring for one year of birth control". Food and Drug Administration. 24 March 2020.
  17. ^ a b c "The Nestorone®/Ethinyl Estradiol One-Year Vaginal Contraceptive System". Population Council.
  18. ^ a b Zitzmann M, Rohayem J, Raidt J, Kliesch S, Kumar N, Sitruk-Ware R, Nieschlag E (May 2017). "Impact of various progestins with or without transdermal testosterone on gonadotropin levels for non-invasive hormonal male contraception: a randomized clinical trial". Andrology. 5 (3): 516–526. doi:10.1111/andr.12328. PMID 28189123. S2CID 41502711.
  19. ^ a b Prasad PV, Bashir M, Sitruk-Ware R, Kumar N (March 2010). "Single-dose pharmacokinetics of Nestorone, a potential female-contraceptive". Steroids. 75 (3): 252–264. doi:10.1016/j.steroids.2009.12.011. PMID 20064539. S2CID 205253216.
  20. ^ Milne GW (1 November 2017). Ashgate Handbook of Endocrine Agents and Steroids. Taylor & Francis. pp. 158–. ISBN 978-1-351-74347-1.
  21. ^ Tuba Z, Bardin CW, Dancsi A, Francsics-Czinege E, Molnár C, Csörgei J, et al. (May 2000). "Synthesis and biological activity of a new progestogen, 16-methylene-17alpha-hydroxy-18-methyl-19-norpregn-4-ene-3, 20-dione acetate". Steroids. 65 (5): 266–274. doi:10.1016/S0039-128X(99)00109-9. PMID 10751638. S2CID 37188669.
  22. ^ Sitruk-Ware R, Small M, Kumar N, Tsong YY, Sundaram K, Jackanicz T (November 2003). "Nestorone: clinical applications for contraception and HRT". Steroids. 68 (10–13): 907–913. doi:10.1016/S0039-128X(03)00140-5. PMID 14667982. S2CID 34984413.
  23. ^ Kumar N, Fagart J, Liere P, Mitchell SJ, Knibb AR, Petit-Topin I, et al. (January 2017). "Nestorone® as a Novel Progestin for Nonoral Contraception: Structure-Activity Relationships and Brain Metabolism Studies". Endocrinology. 158 (1): 170–182. doi:10.1210/en.2016-1426. PMC 5412978. PMID 27824503.
  24. ^ "Segesterone acetate" (PDF). Population Council, Inc. American Medical Association.
  25. ^ "7759-35-5 - CKFBRGLGTWAVLG-GOMYTPFNSA-N - Segesterone acetate [USAN] - Similar structures search, synonyms, formulas, resource links, and other chemical information". ChemIDplus. Archived from the original on 2016-08-11. Retrieved 2016-06-17.
  26. ^ Negwer M, Scharnow HG (2001). Organic-chemical drugs and their synonyms: (an international survey). Wiley-VCH. ISBN 978-3-527-30247-5. Retrieved 13 September 2012.
  27. ^ Clinical trial number NCT03452111 for "Clinical Evaluation of Daily Application of Nestorone® (NES) and Testosterone (T) Combination Gel for Male Contraception" at ClinicalTrials.gov
  28. ^ Stöckel M (2022-06-13). "Verhütung für den Mann: Das Hormon-Gel lässt hoffen" [Contraception for men: The hormone gel inspires hope] (in German). Swiss Radio and Television SRF. Retrieved 2022-06-15.
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