Gestodene

Gestodene
Clinical data
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • X
Routes of
administration		 Oral
ATC code G03AA10 (WHO) G03AB06 (WHO) (only combinations with estrogens)
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 87–99%[1]
Biological half-life 12–14 hours[1]
Excretion Urine
Identifiers
Synonyms SHB-331
CAS Number 60282-87-3 YesY
PubChem (CID) 3033968
DrugBank DB06730 YesY
ChemSpider 2298532 YesY
UNII 1664P6E6MI YesY
KEGG D04316 YesY
ChEMBL CHEMBL1213583 YesY
Chemical and physical data
Formula C21H26O2
Molar mass 310.430 g/mol
3D model (Jmol) Interactive image
  (verify)

Gestodene (INN, USAN, BAN), also known as Δ15-norgestrel or 15-dehydronorgestrel,[2][3] as well as 17α-ethynyl-18-methylestra-4,15-dien-17β-ol-3-one, is a steroidal progestin of the 19-nortestosterone group related to norgestrel and levonorgestrel that is used in combination with ethinyl estradiol as a hormonal contraceptive.[4][5] It is marketed in Europe but is not available in the United States.[6][7]

Medical uses

Contraception

Gestodene is androgenically neutral, meaning that contraceptive pills containing gestodene do not exhibit the androgenic side effects (e.g. acne, hirsutism, weight gain) often associated with second-generation contraceptive pills, such as those containing levonorgestrel.[8]

The synthetic 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.[9]

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.[10]

Available forms

Products containing gestodene include:

Side effects

Women who take oral contraceptives containing gestodene are 5.6 times as likely to develop thromboembolism than women who do not take any contraceptive pill, and 1.6 times as likely to develop thromboembolism compared to women taking oral contraceptives containing levonorgestrel.[12]

Pharmacology

Gestodene is a potent progestogen, and also possesses weak androgenic, antimineralocorticoid, and glucocorticoid activity.[13][14] It has relatively high affinity for the androgen receptor (AR), with twice that of levonorgestrel (which is known to be one of the more highly androgenic 19-nortestosterone derivatives).[15] 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).[15] In addition, no difference in acne incidence has been observed with oral contraceptives containing gestodene and oral contraceptives containing desogestrel.[16] Moreover, gestodene has been found to strongly inhibit 5α-reductase in vitro (14.5% and 45.9% inhibition at 0.1 μM and 1 μM, respectively),[17] and this action was substantially greater than that of desogestrel or levonorgestrel.[15] Taken together, like desogestrel, gestodene appears to have a low potential for androgenic effects.[15] In addition to the AR, gestodene has very high affinity for the mineralocorticoid receptor (MR), but only a relatively weak antimineralocorticoid effect that is comparable to that of progesterone.[15] Gestodene binds to SHBG with relatively high affinity, and is 75% bound to the protein in circulation.[14][15]

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.[18]

Based on the dosage necessary to inhibit ovulation in women, gestodene is the most potent of all of the currently used contraceptive progestogens.[19][20][21] The oral dosage of gestodene required for ovulation inhibition is 30 or 40 μg per day.[20][22] This is about 10,000 times lower than the oral dosage of progesterone required to inhibit ovulation (300 mg/day).[14][23] A dosage of gestodene of 75 μg/day is used in contraceptives.[21]

Chemistry

Gestodene is an estrane (C18) steroid and is also known as 17α-ethynyl-18-methyl-19-nor-δ15-testosterone or as 17α-ethynyl-18-methylestra-4,15-dien-17β-ol-3-one (as well as 13β-ethyl-18,19-dinor-17α-pregna-4,15-dien-20-yn-17β-ol-3-one). It is almost structurally identical with norgestrel (and levonorgestrel), differing only in having an additional double bond between the C15 and C16 positions. As such, it is also known as Δ15-norgestrel or as 15-dehydronorgestrel.[2][3]

History

Gestodene was introduced in 1987.[24]

See also

Footnotes

  1. 1 2 Stanczyk FZ (2002). "Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception". Rev Endocr Metab Disord. 3 (3): 211–24. PMID 12215716.
  2. 1 2 Ellen JM, Irwin CE (1996). "Primary care management of adolescent sexual behavior". Curr. Opin. Pediatr. 8 (5): 442–8. PMID 8946122.
  3. 1 2 Marc A. Fritz; Leon Speroff (2011). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. 966–. ISBN 978-0-7817-7968-5.
  4. ↑ J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 595–. ISBN 978-1-4757-2085-3.
  5. ↑ I.K. Morton; Judith M. Hall (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 132–. ISBN 978-0-7514-0499-9.
  6. ↑ Kenneth L. Becker (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1024–. ISBN 978-0-7817-1750-2.
  7. ↑ Qi Jiang; Weili He (25 May 2016). Benefit-Risk Assessment Methods in Medical Product Development: Bridging Qualitative and Quantitative Assessments. CRC Press. pp. 135–. ISBN 978-1-4822-5937-7.
  8. ↑ http://dermnetnz.org/treatments/antiandrogens.html
  9. ↑ Festin (2006). "Progestogens in combined oral contraceptives for contraception". The WHO Reproductive Health Library.
  10. ↑ Cerel-Suhl (1999). "Update on Oral Contraceptive Pills". American Family Physician. 60 (7): 2073–2084.
  11. ↑ http://www.bayerscheringpharma.es/ebbsc/cms/es/_galleries/download/s_mujer/prospectos/MelodeneS.pdf
  12. ↑ Lidegaard; et al. (2011). "Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses". BMJ. 343: 1–15. doi:10.1136/bmj.d6423. PMC 3202015Freely accessible. PMID 22027398.
  13. ↑ Fuhrmann, Ulrike; Slater, Emily P.; Fritzemeier, Karl-Heinrich (1995). "Characterization of the novel progestin gestodene by receptor binding studies and transactivation assays". Contraception. 51 (1): 45–52. doi:10.1016/0010-7824(94)00003-F. ISSN 0010-7824.
  14. 1 2 3 Schindler, Adolf E; Campagnoli, Carlo; Druckmann, René; Huber, Johannes; Pasqualini, Jorge R; Schweppe, Karl W; Thijssen, Jos H.H (2003). "Classification and pharmacology of progestins". Maturitas. 46: 7–16. doi:10.1016/j.maturitas.2003.09.014. ISSN 0378-5122.
  15. 1 2 3 4 5 6 Stanczyk FZ, Archer DF (2014). "Gestodene: a review of its pharmacology, potency and tolerability in combined contraceptive preparations". Contraception. 89 (4): 242–52. doi:10.1016/j.contraception.2013.12.003. PMID 24485094.
  16. ↑ Arowojolu AO, Gallo MF, Lopez LM, Grimes DA (2012). "Combined oral contraceptive pills for treatment of acne". Cochrane Database Syst Rev (6): CD004425. doi:10.1002/14651858.CD004425.pub5. PMID 22696343.
  17. ↑ Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
  18. ↑ Lemus AE, Zaga V, Santillán R, García GA, Grillasca I, Damián-Matsumura P, Jackson KJ, Cooney AJ, Larrea F, Pérez-Palacios G (2000). "The oestrogenic effects of gestodene, a potent contraceptive progestin, are mediated by its A-ring reduced metabolites". J. Endocrinol. 165 (3): 693–702. PMID 10828854.
  19. ↑ Sven O. Skouby (15 July 1997). Clinical Perspectives on a New Gestodene Oral Contraceptive Containing 20μg of Ethinylestradiol. CRC Press. pp. 19–. ISBN 978-1-85070-786-8.
  20. 1 2 Benagiano G, Primiero FM, Farris M (2004). "Clinical profile of contraceptive progestins". Eur J Contracept Reprod Health Care. 9 (3): 182–93. PMID 15697108.
  21. 1 2 Donna Shoupe; Florence P. Haseltine (6 December 2012). Contraception. Springer Science & Business Media. pp. 62–. ISBN 978-1-4612-2730-4.
  22. ↑ Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH (2008). "Classification and pharmacology of progestins". Maturitas. 61 (1-2): 171–80. PMID 19434889.
  23. ↑ Kuhl H (2011). "Pharmacology of Progestogens" (PDF). J Reproduktionsmed Endokrinol. 8 (1): 157–177.
  24. ↑ Benno Clemens Runnebaum; Thomas Rabe; Ludwig Kiesel (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 13–. ISBN 978-3-642-73790-9.


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