Estradiol hexahydrobenzoate

Estradiol hexahydrobenzoate
Clinical data
Trade names	Benzo-Ginoestril A.P., BenzoGynoestryl Retard, Ginestryl-15-Depot, Menodin, Tardoginestryl
Other names	EHHB; Estradiol cyclohexanecarboxylate; ECHC; Oestradiol hexahydrobenzoate; Estradiol 17β-hexahydrobenzoate; Estradiol 17β-cyclohexanecarboxylate; Estradiol hexabenzoate
Routes of; administration	Intramuscular injection
Drug class	Estrogen; Estrogen ester
Identifiers
	IUPAC name (3-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl) cyclohexanecarboxylate;
CAS Number	15140-27-9;
PubChem CID	85808;
ChemSpider	77397;
UNII	DI3496530P;
CompTox Dashboard (EPA)	DTXSID80934253 ;
ECHA InfoCard	100.035.623
Chemical and physical data
Formula	C25H34O3
Molar mass	382.544 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC12CCC3C(CCc4cc(O)ccc34)C1CCC2OC(=O)C5CCCCC5;
	InChI InChI=1S/C25H34O3/c1-25-14-13-20-19-10-8-18(26)15-17(19)7-9-21(20)22(25)11-12-23(25)28-24(27)16-5-3-2-4-6-16/h8,10,15-16,20-23,26H,2-7,9,11-14H2,1H3; Key:IVRCALGRJCHPRV-UHFFFAOYSA-N;

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.^[3]^[5]^[6]^[7]

Side effects of EHHB include breast tenderness, breast enlargement, nausea, headache, and fluid retention.^[8] EHHB is an estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol.^[9]^[10] It is an estrogen ester and a prodrug of estradiol in the body.^[10]^[9] Because of this, it is considered to be a natural and bioidentical form of estrogen.^[10]

EHHB was first described in 1956,^[11]^[12] and was introduced for medical use by 1957.^[6] It was used in France.^[6] 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.^[3]^[6]^[13]

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.^[3]^[5]^[6]^[7] Use of EHHB for feminizing hormone therapy in transgender women has been reported.^[14] 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.^[15]^[16]^[17] Its indications include menopausal hormone therapy and the treatment of functional uterine bleeding.^[15] The combination is administered typically once per month by intramuscular injection.^[15]

Pharmacology

Pharmacodynamics

EHHB is an estradiol ester, or a prodrug of estradiol.^[10]^[9]^[18] As such, it is an estrogen, or an agonist of the estrogen receptors.^[10]^[9] EHHB is of about 40% higher molecular weight than estradiol due to the presence of its C17β cyclohexanecarboxylate ester.^[1] Because EHHB is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.^[10]

Pharmacokinetics

A combination of EHHB and norgestrel as a combined injectable contraceptive reportedly has a duration of action of about 3 weeks.^[19]

Chemistry

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.^[1]^[2]^[3]^[4] It is specifically the C17β cyclohexanecarboxylate (hexahydrobenzoate) ester of estradiol.^[1]^[2]

History

EHHB was first described and characterized in 1956.^[11]^[12] It was developed in France.^[11]^[12] The medication was introduced for medical use in France by 1957.^[6] 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.^[20]^[21]^[22] The woman died due to breast cancer 10 months after the diagnosis.^[20]^[22]

Society and culture

Generic names

Estradiol hexahydrobenzoate is the generic name of the drug and its INNTooltip International Nonproprietary Name), while oestradiol hexahydrobenzoate is its BANMTooltip British Approved Name.^[1]^[2]^[3]^[4] The medication is also known as estradiol cyclohexanecarboxylate (ECHC).^[1]^[2]^[3]^[4]

Brand names

EHHB has been marketed under the brand names Benzo-Ginoestril A.P., BenzoGynoestryl Retard, Ginestryl-15-Depot, Menodin, and Tardoginestryl.^[1]^[2]^[3]^[4]^[5]

Availability

EHHB was previously marketed in France.^[6]

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.^[23]^[24]^[25]^[26]^[27]^[19]

References

^ ^a ^b ^c ^d ^e ^f ^g Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. p. 898. ISBN 978-1-4757-2085-3.
^ ^a ^b ^c ^d ^e ^f Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 114, 206. ISBN 978-94-011-4439-1.
^ ^a ^b ^c ^d ^e ^f ^g ^h Muller A (19 June 1998). European Drug Index: European Drug Registrations, Fourth Edition. CRC Press. pp. 150–. ISBN 978-3-7692-2114-5.
^ ^a ^b ^c ^d ^e Martindale W, Reynolds JE (1993). The Extra Pharmacopoeia. Pharmaceutical Press. p. 1191. ISBN 978-0-85369-300-0. 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.
^ ^a ^b ^c ^d IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 388–. ISBN 978-92-832-1291-1.
^ ^a ^b ^c ^d ^e ^f ^g France (August 1957). Journal officiel de la République française. 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).
^ ^a ^b France (1976). Journal officiel de la République française. Édition des lois et décrets. p. 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) [...]
^ McIver B, Tebben PJ, Shah P (23 September 2010). "Endocrinology". In Ghosh AK (ed.). Mayo Clinic Internal Medicine Board Review. OUP USA. pp. 222–. ISBN 978-0-19-975569-1.
^ ^a ^b ^c ^d 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.
^ ^a ^b ^c ^d ^e ^f Kuhnz W, Blode H, Zimmermann H (6 December 2012). "Pharmacokinetics of exogenous natural and synthetic estrogens and antiestrogens". In Oettel M, Schillinger E (eds.). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. p. 261. ISBN 978-3-642-60107-1. 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.
^ ^a ^b ^c Feyel-Cabanes T (1956). "[A new estrogen with retarded action, estradiol-17-hexahydrobenzoate]" [A new estrogen with retarded action, estradiol-17-hexahydrobenzoate]. Comptes Rendus des Séances de la Société de Biologie et de Ses Filiales (in French). 150 (11): 1881–1883. PMID 13427258.
^ ^a ^b ^c Guiard E (June 1956). "[Physiologic and clinical action of long-acting hormones; 1. testosterone hexahydrobenzoate, 2. estradiol hexahydrobenzoate]" [Physiologic and clinical action of long-acting hormones; 1. testosterone hexahydrobenzoate, 2. estradiol hexahydrobenzoate]. La Presse Médicale (in French). 64 (52): 1223–1224. PMID 13350115.
^ Lewis RJ (13 June 2008). Hazardous Chemicals Desk Reference. John Wiley & Sons. pp. 593–. ISBN 978-0-470-18024-2.
^ Kulick D (12 January 2009). "Becoming a Travesti". Travesti: Sex, Gender, and Culture among Brazilian Transgendered Prostitutes. University of Chicago Press. pp. 64, 244. ISBN 978-0-226-46101-4.
^ ^a ^b ^c "Trinestril AP-Label".
^ Sweetman SC, ed. (2009). "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. pp. 2100, 2124–2125. ISBN 978-0-85369-840-1.
^ "Climatério - Medicamentos". Archived from the original on 2019-06-23. Retrieved 2019-06-11.
^ The Rules Governing Medicinal Products in the European Union. Office for Official Publications of the European Communities. 1996. ISBN 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.
^ ^a ^b Hawkins DF, Elder MG (22 October 2013). "Other hormonal Contraceptive Procedures". Human Fertility Control: Theory and Practice. Elsevier Science. pp. 110–. ISBN 978-1-4831-6361-1.
^ ^a ^b Juret P, Autissier P (September 1962). "[Breast cancer of subacute development discovered after injections of estradiol hexahydrobenzoate]" [Breast cancer of subacute development discovered after injections of estradiol hexahydrobenzoate]. La Presse Médicale (in French). 70 (30): 1813. PMID 13958106.
^ Evaluation of the Potential Carcinogenic Action of a Drug: Proceedings of the Symposium in Lausanne, January 1964. Excerpta Medica Foundation. 1964. p. 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.
^ ^a ^b Carcinogenesis Abstracts. National Cancer Institute. 1973. p. 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.
^ de Souza JC, Coutinho EM (May 1972). "Control of fertility by monthyl injections of a mixture of norgestrel and a long-acting estrogen. A preliminary report". Contraception. 5 (5): 395–399. doi:10.1016/0010-7824(72)90031-5. PMID 4650657.
^ Toppozada MK (April 1994). "Existing once-a-month combined injectable contraceptives". Contraception. 49 (4): 293–301. doi:10.1016/0010-7824(94)90029-9. PMID 8013216.
^ Newton JR, D'arcangues C, Hall PE (1994). "A review of "once-a-month" combined injectable contraceptives". Journal of Obstetrics and Gynaecology. 4 (Suppl 1): S1-34. doi:10.3109/01443619409027641. PMID 12290848.
^ Toppozada MK (1983). "Monthly Injectable Contraceptives". In Alfredo Goldsmith, Mokhtar Toppozada (eds.). Long-Acting Contraception. pp. 93–103. OCLC 35018604.
^ Toppozada M (June 1977). "The clinical use of monthly injectable contraceptive preparations". Obstetrical & Gynecological Survey. 32 (6): 335–347. doi:10.1097/00006254-197706000-00001. PMID 865726.

[Elks2014-1] ^ ^a ^b ^c ^d ^e ^f ^g Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. p. 898. ISBN 978-1-4757-2085-3.

[MortonHall2012-2] ^ ^a ^b ^c ^d ^e ^f Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 114, 206. ISBN 978-94-011-4439-1.

[Muller1998-3] ^ ^a ^b ^c ^d ^e ^f ^g ^h Muller A (19 June 1998). European Drug Index: European Drug Registrations, Fourth Edition. CRC Press. pp. 150–. ISBN 978-3-7692-2114-5.

[MartindaleSciences1993-4] Martindale W, Reynolds JE (1993). The Extra Pharmacopoeia. Pharmaceutical Press. p. 1191. ISBN 978-0-85369-300-0. 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.

[HumansOrganization2007-5] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 388–. ISBN 978-92-832-1291-1.

[France1957-6] ^ ^a ^b ^c ^d ^e ^f ^g France (August 1957). Journal officiel de la République française. 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).

[France1976-7] France (1976). Journal officiel de la République française. Édition des lois et décrets. p. 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) [...]

[Ghosh2010-8] McIver B, Tebben PJ, Shah P (23 September 2010). "Endocrinology". In Ghosh AK (ed.). Mayo Clinic Internal Medicine Board Review. OUP USA. pp. 222–. ISBN 978-0-19-975569-1.

[pmid16112947-9] 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.

[OettelSchillinger2012-10] ^ ^a ^b ^c ^d ^e ^f Kuhnz W, Blode H, Zimmermann H (6 December 2012). "Pharmacokinetics of exogenous natural and synthetic estrogens and antiestrogens". In Oettel M, Schillinger E (eds.). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. p. 261. ISBN 978-3-642-60107-1. 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.

[pmid13427258-11] Feyel-Cabanes T (1956). "[A new estrogen with retarded action, estradiol-17-hexahydrobenzoate]" [A new estrogen with retarded action, estradiol-17-hexahydrobenzoate]. Comptes Rendus des Séances de la Société de Biologie et de Ses Filiales (in French). 150 (11): 1881–1883. PMID 13427258.

[pmid13350115-12] Guiard E (June 1956). "[Physiologic and clinical action of long-acting hormones; 1. testosterone hexahydrobenzoate, 2. estradiol hexahydrobenzoate]" [Physiologic and clinical action of long-acting hormones; 1. testosterone hexahydrobenzoate, 2. estradiol hexahydrobenzoate]. La Presse Médicale (in French). 64 (52): 1223–1224. PMID 13350115.

[Lewis2008-13] Lewis RJ (13 June 2008). Hazardous Chemicals Desk Reference. John Wiley & Sons. pp. 593–. ISBN 978-0-470-18024-2.

[Kulick2009-14] Kulick D (12 January 2009). "Becoming a Travesti". Travesti: Sex, Gender, and Culture among Brazilian Transgendered Prostitutes. University of Chicago Press. pp. 64, 244. ISBN 978-0-226-46101-4.

[Trinestril_AP-Label-15] "Trinestril AP-Label".

[Martindale2009-16] Sweetman SC, ed. (2009). "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. pp. 2100, 2124–2125. ISBN 978-0-85369-840-1.

[GoPonto-17] "Climatério - Medicamentos". Archived from the original on 2019-06-23. Retrieved 2019-06-11.

[OOPEC1996-18] The Rules Governing Medicinal Products in the European Union. Office for Official Publications of the European Communities. 1996. ISBN 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.

[HawkinsElder2013-19] Hawkins DF, Elder MG (22 October 2013). "Other hormonal Contraceptive Procedures". Human Fertility Control: Theory and Practice. Elsevier Science. pp. 110–. ISBN 978-1-4831-6361-1.

[pmid13958106-20] Juret P, Autissier P (September 1962). "[Breast cancer of subacute development discovered after injections of estradiol hexahydrobenzoate]" [Breast cancer of subacute development discovered after injections of estradiol hexahydrobenzoate]. La Presse Médicale (in French). 70 (30): 1813. PMID 13958106.

[ExcerptaMedica1964-21] Evaluation of the Potential Carcinogenic Action of a Drug: Proceedings of the Symposium in Lausanne, January 1964. Excerpta Medica Foundation. 1964. p. 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.

[NCI1973-22] Carcinogenesis Abstracts. National Cancer Institute. 1973. p. 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.

[pmid4650657-23] Souza JC, Coutinho EM (May 1972). "Control of fertility by monthyl injections of a mixture of norgestrel and a long-acting estrogen. A preliminary report". Contraception. 5 (5): 395–399. doi:10.1016/0010-7824(72)90031-5. PMID 4650657.

[pmid8013216-24] Toppozada MK (April 1994). "Existing once-a-month combined injectable contraceptives". Contraception. 49 (4): 293–301. doi:10.1016/0010-7824(94)90029-9. PMID 8013216.

[pmid12290848-25] Newton JR, D'arcangues C, Hall PE (1994). "A review of "once-a-month" combined injectable contraceptives". Journal of Obstetrics and Gynaecology. 4 (Suppl 1): S1-34. doi:10.3109/01443619409027641. PMID 12290848.

[Toppozada1983-26] Toppozada MK (1983). "Monthly Injectable Contraceptives". In Alfredo Goldsmith, Mokhtar Toppozada (eds.). Long-Acting Contraception. pp. 93–103. OCLC 35018604.

[pmid865726-27] Toppozada M (June 1977). "The clinical use of monthly injectable contraceptive preparations". Obstetrical & Gynecological Survey. 32 (6): 335–347. doi:10.1097/00006254-197706000-00001. PMID 865726.

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