Gestodene

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.

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.

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.

Gestodene is also available in combination with estradiol for use in menopausal hormone therapy.

Available forms

Contraceptive products containing gestodene include:

• Melodene-15, Mirelle, and Minesse which contain 15 μg of ethinylestradiol and 60 μg of gestodene;
• Meliane, Sunya, Femodette, and Millinette 20/75 which contain 20 μg of ethinylestradiol and 75 μg of gestodene; and
• Gynera, Minulet, Femoden, Femodene, Katya and Millinette 30/75 which contain 30 μg of ethinylestradiol and 75 μg of gestodene.

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.

Overdose

Contraindications

Pharmacology

Pharmacodynamics

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

Progestogenic activity

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

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). 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). In addition, no difference in acne incidence has been observed with oral contraceptives containing gestodene and oral contraceptives containing desogestrel. Gestodene may also act to some extent as a 5α-reductase inhibitor. Taken together, like desogestrel, gestodene appears to have a low potential for androgenic effects.

Glucocorticoid activity

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

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.

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.

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

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

Pharmacokinetics

The oral bioavailability of gestodene has been found to range from 87 to 111%, with a mean of 96%. Unlike other third-generation progestins like desogestrel and norgestimate, gestodene is not a prodrug. Peak levels of gestodene occur within 1 to 4 hours after an oral dose, but usually within 1 to 2 hours. The plasma protein binding of gestodene is 98%. It is bound 64% to sex hormone-binding globulin and 34% to albumin, with 2% circulating freely. 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). 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. The biological half-life of gestodene is 12 to 15 hours. Gestodene is eliminated 50% in urine and 33% in feces. Of gestodene excreted in urine, 25% is in the form of glucuronide conjugates, 35% is as sulfate conjugates, and 25% is unconjugated.

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. 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. 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.

Synthesis

A chemical synthesis of gestodene is reported that doesn't involve a microbiological fermentation step. Prior art:

The starting material is called 13-Ethylgon-4-ene-3,17-dione (13-Egedo) [21800-83-9] (1). Condensation with one equivalent of neopentyl glycol gives a mixture of products with the C=C occupying C5C6 (PC11462926) or C5C10 (PC11617672) positions (2). Treatment with Methyl phenyl sulfone [3112-85-4] in the presence of base leads to addition of the sulfinyl group (sulfoxide) to position 16 on the steroid (3). β-elimination upon reflux in the presence of triethylamine to give (4). Organometallic addition of ethynyllithium to the keto group gives (5). Hydrolysis of the ketal protecting group completed the synthesis of gestodene (6).

History

Gestodene was first synthesized in 1975. It was introduced for medical use, specifically in combination with ethinylestradiol as a combined oral contraceptive, in 1987. 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.

Society and culture

Generic names

Gestodene is the generic name of the drug and its , , , and . It is also known by its developmental code name SHB-331.

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. It is marketed for use in menopausal hormone therapy in combination with estradiol under the brand names Avaden, Avadene, and Convaden.

Availability

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

References

References

1. (2002). "Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception". Rev Endocr Metab Disord.
2. (August 1996). "Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy". Contraception.
3. (14 November 2014). "The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies". Springer.
4. (31 October 1999). "Concise Dictionary of Pharmacological Agents: Properties and Synonyms". Springer Science & Business Media.
5. "Estradiol/gestodene - Bayer Healthcare Pharmaceuticals - AdisInsight".
6. (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric.
7. (9 April 2015). "Progestogens in Obstetrics and Gynecology". Springer.
8. (2001). "Principles and Practice of Endocrinology and Metabolism". Lippincott Williams & Wilkins.
9. (25 May 2016). "Benefit-Risk Assessment Methods in Medical Product Development: Bridging Qualitative and Quantitative Assessments". CRC Press.
10. (26 October 2023). "Anti-androgen therapy | DermNet NZ".
11. (2006). "Progestogens in combined oral contraceptives for contraception". The WHO Reproductive Health Library.
12. (November 1999). "Update on oral contraceptive pills". American Family Physician.
13. "prospecto".
14. (October 2011). "Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9". BMJ.
15. (January 1995). "Characterization of the novel progestin gestodene by receptor binding studies and transactivation assays". Contraception.
16. (December 2003). "Classification and pharmacology of progestins". Maturitas.
17. (15 July 1997). "Clinical Perspectives on a New Gestodene Oral Contraceptive Containing 20μg of Ethinylestradiol". CRC Press.
18. (2004). "Clinical profile of contraceptive progestins". Eur J Contracept Reprod Health Care.
19. (6 December 2012). "Contraception". Springer Science & Business Media.
20. (2008). "Classification and pharmacology of progestins". Maturitas.
21. (April 2014). "Gestodene: a review of its pharmacology, potency and tolerability in combined contraceptive preparations". Contraception.
22. (July 2012). "Combined oral contraceptive pills for treatment of acne". The Cochrane Database of Systematic Reviews.
23. (2000). "The oestrogenic effects of gestodene, a potent contraceptive progestin, are mediated by its A-ring reduced metabolites". J. Endocrinol..
24. (10 November 1999). "Progestins and Antiprogestins in Clinical Practice". Taylor & Francis.
25. (2008). "Foye's Principles of Medicinal Chemistry". Lippincott Williams & Wilkins.
26. "Gestodene - Drugs.com".
27. (2009). "Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management". Elsevier Health Sciences.
28. (1996). "Primary care management of adolescent sexual behavior". Curr. Opin. Pediatr..
29. (2011). "Clinical Gynecologic Endocrinology and Infertility". Lippincott Williams & Wilkins.
30. (2004). "A Simple Synthesis of Gestodene from 18-Methyl-4-estren-3,17-dione". Synlett.
31. BE847090 idem H. Hofmeister et al., US4081537 (1978 to Schering AG).
32. Rino Prendin & Silvio Pirovano, EP0700926 (1998 to Industriale Chimica SRL)
33. 王博, 艾荣华 & 洪用剑, CN119751531 (2025 to Zhejiang Xianju Pharmaceutical Co Ltd).
34. (December 1995). "Gestodene-containing contraceptives". Clin Obstet Gynecol.
35. (6 December 2012). "Female Contraception: Update and Trends". Springer Science & Business Media.