Estradiol hexahydrobenzoate explained

Estradiol hexahydrobenzoate (EHHB), sold under a number of brand names including Benzo-Ginoestril A.P., BenzoGynoestryl Retard, Ginestryl-15-Depot, Menodin, and Tardoginestryl, is an estrogen medication which was previously used for indications such as menopausal hormone therapy and gynecological disorders.[1] [2] [3] [4] [5] EHHB is given by injection into muscle at regular intervals, for instance once every few weeks.

Side effects of EHHB include breast tenderness, breast enlargement, nausea, headache, and fluid retention.[6] EHHB is an estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol.[7] It is an estrogen ester and a prodrug of estradiol in the body. Because of this, it is considered to be a natural and bioidentical form of estrogen.[8]

EHHB was first described in 1956, and was introduced for medical use by 1957. It was used in France. The medication should not be confused with estradiol benzoate (EB), which has been marketed under similar brand names including Benzo-Ginestryl, Benzo-Ginoestril, and Benzo-Gynoestryl.[9]

Medical uses

EHHB was marketed in France in a 5 mg/mL oil solution in ampoules for intramuscular injection at regular intervals, for instance once every few weeks.[10] Use of EHHB for feminizing hormone therapy in transgender women has been reported.[11] A combination of 3 mg EHHB, 75 mg hydroxyprogesterone caproate, and 100 mg testosterone hexahydrobenzoate in 2 mL oil solution provided in ampoules has been marketed under the brand name Trinestril AP in Brazil.[12] [13] [14] Its indications include menopausal hormone therapy and the treatment of functional uterine bleeding. The combination is administered typically once per month by intramuscular injection.

Pharmacology

Pharmacodynamics

See also: Pharmacodynamics of estradiol.

EHHB is an estradiol ester, or a prodrug of estradiol.[15] As such, it is an estrogen, or an agonist of the estrogen receptors. EHHB is of about 40% higher molecular weight than estradiol due to the presence of its C17β cyclohexanecarboxylate ester. Because EHHB is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.

Pharmacokinetics

See also: Pharmacokinetics of estradiol.

A combination of EHHB and norgestrel as a combined injectable contraceptive reportedly has a duration of action of about 3 weeks.

Chemistry

See also: Estrogen ester.

EHHB, also known as estradiol cyclohexanecarboxylate (ECHC) as well as estradiol 17β-hexahydrobenzoate or estradiol 17β-cyclohexanecarboxylate, is a synthetic estrane steroid and an estrogen ester. It is specifically the C17β cyclohexanecarboxylate (hexahydrobenzoate) ester of estradiol.

History

EHHB was first described and characterized in 1956.[16] [17] It was developed in France. The medication was introduced for medical use in France by 1957.[18] A publicized case report of a rapidly growing breast cancer tumor in a 53-year-old woman 10 days after initiation of therapy with 5 mg/month EHHB by intramuscular injection for hot flashes was published in 1962.[19] [20] [21] The woman died due to breast cancer 10 months after the diagnosis.

Society and culture

Generic names

Estradiol hexahydrobenzoate is the generic name of the drug and its), while oestradiol hexahydrobenzoate is its . The medication is also known as estradiol cyclohexanecarboxylate (ECHC).

Brand names

EHHB has been marketed under the brand names Benzo-Ginoestril A.P., BenzoGynoestryl Retard, Ginestryl-15-Depot, Menodin, and Tardoginestryl.

Availability

EHHB was previously marketed in France.

Research

A combination of 5 mg EHHB in peanut oil solution and 25 mg norgestrel in aqueous suspension as a once-monthly combined injectable contraceptive was studied, but this formulation was ultimately never marketed.[22] [23] [24] [25] [26] [27]

Notes and References

  1. Book: Elks J . The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. 14 November 2014. Springer. 978-1-4757-2085-3. 898.
  2. Book: Morton IK, Hall JM . Concise Dictionary of Pharmacological Agents: Properties and Synonyms. 6 December 2012. Springer Science & Business Media. 978-94-011-4439-1. 114, 206.
  3. Book: Muller A . European Drug Index: European Drug Registrations, Fourth Edition. 19 June 1998. CRC Press. 978-3-7692-2114-5. 150–.
  4. Book: Martindale W, Reynolds JE . The Extra Pharmacopoeia. 1993. Pharmaceutical Press. 978-0-85369-300-0. 1191. Oestradiol Hexahydrobenzoate (13039-d) Oestradiol Hexahydrobenzoate (BANM). Estradiol Hexzihydrobcnzoate (rlNNM). Estra-1,3,5(10)-triene-3,17β-diol 17-cyclohexanecarboxylate. C25H34O3 = 382.5. CAS — 15140-27-9..
  5. Book: IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. World Health Organization. International Agency for Research on Cancer. Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. 2007. World Health Organization. 978-92-832-1291-1. 388–.
  6. Book: McIver B, Tebben PJ, Shah P . Endocrinology . Ghosh AK . Mayo Clinic Internal Medicine Board Review. https://books.google.com/books?id=LS65jBzoD40C&pg=PA222. 23 September 2010. OUP USA. 978-0-19-975569-1. 222–.
  7. Kuhl H . Pharmacology of estrogens and progestogens: influence of different routes of administration . Climacteric . 8 . Suppl 1 . 3–63 . August 2005 . 16112947 . 10.1080/13697130500148875 . 24616324 .
  8. Book: Kuhnz W, Blode H, Zimmermann H . Pharmacokinetics of exogenous natural and synthetic estrogens and antiestrogens . Oettel M, Schillinger E . Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA261. 6 December 2012. Springer Science & Business Media. 978-3-642-60107-1. 261. Natural estrogens considered here include: [...] Esters of 17β-estradiol, such as estradiol valerate, estradiol benzoate and estradiol cypionate. Esterification aims at either better absorption after oral administration or a sustained release from the depot after intramuscular administration. During absorption, the esters are cleaved by endogenous esterases and the pharmacologically active 17β-estradiol is released; therefore, the esters are considered as natural estrogens..
  9. Book: Lewis RJ . Hazardous Chemicals Desk Reference. 13 June 2008. John Wiley & Sons. 978-0-470-18024-2. 593–.
  10. Book: France. Journal officiel de la République française. Édition des lois et décrets. 1976. 1843. Spécialité dénommée BENZO-GYNOESTRYL RETARD, soluté injectable : Laboratoires Roussel, 75323 Paris CEDEX 07. — A. M. M. n" 301063.1 (1 ampoule de 1 ml) [...].
  11. Book: Kulick D . Becoming a Travesti . Travesti: Sex, Gender, and Culture among Brazilian Transgendered Prostitutes. https://books.google.com/books?id=jbZyBfio-hcC&pg=PA64. 12 January 2009. University of Chicago Press. 978-0-226-46101-4. 64,244.
  12. Web site: Trinestril AP-Label .
  13. Book: Sweetman SC . Sex hormones and their modulators . Martindale: The Complete Drug Reference . 36th . 2009 . 2100, 2124–2125 . Pharmaceutical Press . London . 978-0-85369-840-1.
  14. Web site: Climatério - Medicamentos. 2019-06-11. 2019-06-23. https://web.archive.org/web/20190623181304/http://www.drcarlos.med.br/climamed.html. dead.
  15. Book: The Rules Governing Medicinal Products in the European Union. 1996. Office for Official Publications of the European Communities. 978-92-827-6427-5. Oestradiol benzoate, oestradiol valerate and oestradiol hexahydrobenzoate are synthetic esters of the naturally occurring oestrogen oestradiol. After administration the esters are absorbed and subsequently hydrolysed to the active compound oestradiol. Oestradiol is the most active natural oestrogen, which can act at many different sites in both female and male animals..
  16. Feyel-Cabanes T . [A new estrogen with retarded action, estradiol-17-hexahydrobenzoate] . fr . Comptes Rendus des Séances de la Société de Biologie et de Ses Filiales . 150 . 11 . 1881–1883 . 1956 . 13427258 . A new estrogen with retarded action, estradiol-17-hexahydrobenzoate .
  17. Guiard E . [Physiologic and clinical action of long-acting hormones; 1. testosterone hexahydrobenzoate, 2. estradiol hexahydrobenzoate] . fr . La Presse Médicale . 64 . 52 . 1223–1224 . June 1956 . 13350115 . Physiologic and clinical action of long-acting hormones; 1. testosterone hexahydrobenzoate, 2. estradiol hexahydrobenzoate .
  18. Book: France. Journal officiel de la République française. August 1957. BENZOGYNOESTRYL 1, ampoules injectables de 1 cm* A 1 mg (2 ou 10). BENZOGYNOESTRYL 5, ampoules injectables de 1 cm3 à 5 mg (1 ou 10). BENZOGYNOESTRYL-RETARD 5 mg, ampoules injectables Ci/1 cm3)..
  19. Juret P, Autissier P . [Breast cancer of subacute development discovered after injections of estradiol hexahydrobenzoate] . fr . La Presse Médicale . 70 . 30 . 1813 . September 1962 . 13958106 . Breast cancer of subacute development discovered after injections of estradiol hexahydrobenzoate .
  20. Book: Evaluation of the Potential Carcinogenic Action of a Drug: Proceedings of the Symposium in Lausanne, January 1964. 1964. Excerpta Medica Foundation. 96. In 1962, Juret and Antissier described a woman aged 53 who, 10 days after an injection of 5 mg. oestradiol hexahydrobenzoate, showed a rapidly growing mammary carcinoma..
  21. Book: Carcinogenesis Abstracts. 1973. National Cancer Institute.. 900. A rapidly growing lump developed in a 53yr-old woman 1 wk after she had been given estradiol hexahydrobenzoate (5 mg/month) for hot flashes. The patient died of breast cancer 10 months later..
  22. de Souza JC, Coutinho EM . Control of fertility by monthyl injections of a mixture of norgestrel and a long-acting estrogen. A preliminary report . Contraception . 5 . 5 . 395–399 . May 1972 . 4650657 . 10.1016/0010-7824(72)90031-5 .
  23. Toppozada MK . Existing once-a-month combined injectable contraceptives . Contraception . 49 . 4 . 293–301 . April 1994 . 8013216 . 10.1016/0010-7824(94)90029-9 .
  24. Newton JR, D'arcangues C, Hall PE . A review of "once-a-month" combined injectable contraceptives . Journal of Obstetrics and Gynaecology . 4 . Suppl 1 . S1-34 . 1994 . 12290848 . 10.3109/01443619409027641 .
  25. Book: Toppozada MK . Monthly Injectable Contraceptives . 93–103 . Alfredo Goldsmith . Mokhtar Toppozada . Long-Acting Contraception . 1983 . 35018604 .
  26. Toppozada M . The clinical use of monthly injectable contraceptive preparations . Obstetrical & Gynecological Survey . 32 . 6 . 335–347 . June 1977 . 865726 . 10.1097/00006254-197706000-00001 .
  27. Book: Hawkins DF, Elder MG . Other hormonal Contraceptive Procedures . Human Fertility Control: Theory and Practice. https://books.google.com/books?id=1lL0AgAAQBAJ&pg=PA110. 22 October 2013. Elsevier Science. 978-1-4831-6361-1. 110–.

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