Estradiol benzoate butyrate

Not to be confused with Estradiol benzoate or Estradiol enantate.

Estradiol benzoate butyrate

Clinical data
Trade names	Neolutin N, Redimen, Soluna, Unijab (all combinations)
Other names	EBB; Estradiol 3-benzoate 17β-n-butyrate; Estra-1,3,5(10)-triene-3,17β-diol 3-benzoate 17β-n-butyrate
Routes of administration	Intramuscular injection
Drug class	Estrogen; Estrogen ester
Identifiers
IUPAC name [(8R,9S,13S,14S,17S)-17-butanoyloxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate
CAS Number	63042-18-2
PubChem CID	67081
ChemSpider	60431
UNII	ZE4IGI4UMH
CompTox Dashboard (EPA)	DTXSID20978979
ECHA InfoCard	100.057.989
Chemical and physical data
Formula	C29H34O4
Molar mass	446.587 g·mol^−1
3D model (JSmol)	Interactive image
SMILES CCCC(=O)O[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=C3C=CC(=C4)OC(=O)C5=CC=CC=C5)C
InChI InChI=1S/C29H34O4/c1-3-7-27(30)33-26-15-14-25-24-12-10-20-18-21(32-28(31)19-8-5-4-6-9-19)11-13-22(20)23(24)16-17-29(25,26)2/h4-6,8-9,11,13,18,23-26H,3,7,10,12,14-17H2,1-2H3/t23-,24-,25+,26+,29+/m1/s1 Key:MKYFGNOOEKZNPW-ZRJUGLEFSA-N

Estradiol benzoate butyrate (EBB), sold under the brand names Neolutin N, Redimen, Soluna, and Unijab and formerly known under the developmental code name Unimens, is an estrogen medication which is used in hormonal birth control for women.^[1][2] It is formulated in combination with dihydroxyprogesterone acetophenide (DHPA; algestone acetophenide), a progestin, and is used specifically as a combined injectable contraceptive.^[1][2] EBB is not available for medical use alone.^[3] The medication, in combination with DHPA, is given by injection into muscle once a month.^[1][2]

Side effects of EBB include breast tenderness, breast enlargement, nausea, headache, and fluid retention.^[4] EBB is an estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol.^[5][6] It is an estrogen ester and a prodrug of estradiol in the body.^[6][5] Because of this, it is considered to be a natural and bioidentical form of estrogen.^[6]

EBB was first described in 1938.^[7] It was developed for use as a form of birth control in the 1970s^[8][1] and was introduced for medical use for this indication by the 1980s.^[9][10] The medication is used in combination with DHPA as a combined injectable contraceptive in Peru and Singapore.^[11][12]

Medical uses

EBB is used in combination with DHPA as a once-a-month combined injectable contraceptive to prevent pregnancy in women.^{[1][11][12][2][13]}

Available forms

See also: Estradiol benzoate butyrate/dihydroxyprogesterone acetophenide

The combination of EBB and DHPA contains 10 mg estradiol benzoate butyrate (EBB), an estrogen, and 150 mg algestone acetophenide (dihydroxyprogesterone acetophenide; DHPA), a progestin.^[11][12]

Side effects

The combination of EBB and DHPA is said to be associated with poor control of menstrual bleeding when used as a once-a-month combined injectable contraceptive.^[1][14]

Pharmacology

Estradiol, the active form of EBB.

Pharmacodynamics

See also: Pharmacodynamics of estradiol

EBB is an estradiol ester, or a prodrug of estradiol.^[6][5] As such, it is an estrogen, or an agonist of the estrogen receptors.^[6][5] EBB is of about 64% higher molecular weight than estradiol due to the presence of its C3 benzoate and C17β butyrate esters. Because EBB is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.^[6]

The estrogenic potency of oral ethinylestradiol is approximately 30-fold higher than that of parenteral EBB.^[1] In accordance, 50 μg/day oral ethinylestradiol has been reported to be about 3 times stronger in estrogenic effect than once-a-month injections of 10 mg EBB.^[1]

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Potencies and durations of natural estrogens by intramuscular injection

Estrogen	Form	Dose (mg)		Duration by dose (mg)
		EPD	CICD
Estradiol	Aq. soln.	?	–	<1 d
	Oil soln.	40–60	–	1–2 ≈ 1–2 d
	Aq. susp.	?	3.5	0.5–2 ≈ 2–7 d; 3.5 ≈ >5 d
	Microsph.	?	–	1 ≈ 30 d
Estradiol benzoate	Oil soln.	25–35	–	1.66 ≈ 2–3 d; 5 ≈ 3–6 d
	Aq. susp.	20	–	10 ≈ 16–21 d
	Emulsion	?	–	10 ≈ 14–21 d
Estradiol dipropionate	Oil soln.	25–30	–	5 ≈ 5–8 d
Estradiol valerate	Oil soln.	20–30	5	5 ≈ 7–8 d; 10 ≈ 10–14 d; 40 ≈ 14–21 d; 100 ≈ 21–28 d
Estradiol benz. butyrate	Oil soln.	?	10	10 ≈ 21 d
Estradiol cypionate	Oil soln.	20–30	–	5 ≈ 11–14 d
	Aq. susp.	?	5	5 ≈ 14–24 d
Estradiol enanthate	Oil soln.	?	5–10	10 ≈ 20–30 d
Estradiol dienanthate	Oil soln.	?	–	7.5 ≈ >40 d
Estradiol undecylate	Oil soln.	?	–	10–20 ≈ 40–60 d; 25–50 ≈ 60–120 d
Polyestradiol phosphate	Aq. soln.	40–60	–	40 ≈ 30 d; 80 ≈ 60 d; 160 ≈ 120 d
Estrone	Oil soln.	?	–	1–2 ≈ 2–3 d
	Aq. susp.	?	–	0.1–2 ≈ 2–7 d
Estriol	Oil soln.	?	–	1–2 ≈ 1–4 d
Polyestriol phosphate	Aq. soln.	?	–	50 ≈ 30 d; 80 ≈ 60 d
Notes and sources Notes: All aqueous suspensions are of microcrystalline particle size. Estradiol production during the menstrual cycle is 30–640 µg/d (6.4–8.6 mg total per month or cycle). The vaginal epithelium maturation dosage of estradiol benzoate or estradiol valerate has been reported as 5 to 7 mg/week. An effective ovulation-inhibiting dose of estradiol undecylate is 20–30 mg/month. Sources: See template.

Pharmacokinetics

See also: Pharmacokinetics of estradiol

A single 10 mg intramuscular injection of EBB has a duration of approximately 3 weeks.^[1][2][15] Its duration is shorter than that of estradiol enantate.^[1][2] A preliminary study of the duration of EBB relative to other estradiol esters was conducted in 1952.^[16]

Chemistry

See also: Estrogen ester and List of estrogen esters § Estradiol esters

EBB is a synthetic estrane steroid and the C3 benzoate (benzenecarboxylate) and C17β butyrate (butanoate) diester of estradiol.^[17] It is also known as estradiol 3-benzoate 17β-n-butyrate or as estra-1,3,5(10)-triene-3,17β-diol 3-benzoate 17β-n-butyrate.^[17]

The experimental octanol/water partition coefficient (logP) of EBB is 6.3.^[18]

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Structural properties of selected estradiol esters

Estrogen	Structure	Ester(s)				Relative mol. weight	Relative E2 content^b	log P^c
		Position(s)	Moiet(ies)	Type	Length^a
Estradiol		–	–	–	–	1.00	1.00	4.0
Estradiol acetate		C3	Ethanoic acid	Straight-chain fatty acid	2	1.15	0.87	4.2
Estradiol benzoate		C3	Benzoic acid	Aromatic fatty acid	– (~4–5)	1.38	0.72	4.7
Estradiol dipropionate		C3, C17β	Propanoic acid (×2)	Straight-chain fatty acid	3 (×2)	1.41	0.71	4.9
Estradiol valerate		C17β	Pentanoic acid	Straight-chain fatty acid	5	1.31	0.76	5.6–6.3
Estradiol benzoate butyrate		C3, C17β	Benzoic acid, butyric acid	Mixed fatty acid	– (~6, 2)	1.64	0.61	6.3
Estradiol cypionate		C17β	Cyclopentylpropanoic acid	Cyclic fatty acid	– (~6)	1.46	0.69	6.9
Estradiol enanthate		C17β	Heptanoic acid	Straight-chain fatty acid	7	1.41	0.71	6.7–7.3
Estradiol dienanthate		C3, C17β	Heptanoic acid (×2)	Straight-chain fatty acid	7 (×2)	1.82	0.55	8.1–10.4
Estradiol undecylate		C17β	Undecanoic acid	Straight-chain fatty acid	11	1.62	0.62	9.2–9.8
Estradiol stearate		C17β	Octadecanoic acid	Straight-chain fatty acid	18	1.98	0.51	12.2–12.4
Estradiol distearate		C3, C17β	Octadecanoic acid (×2)	Straight-chain fatty acid	18 (×2)	2.96	0.34	20.2
Estradiol sulfate		C3	Sulfuric acid	Water-soluble conjugate	–	1.29	0.77	0.3–3.8
Estradiol glucuronide		C17β	Glucuronic acid	Water-soluble conjugate	–	1.65	0.61	2.1–2.7
Estramustine phosphate^d		C3, C17β	Normustine, phosphoric acid	Water-soluble conjugate	–	1.91	0.52	2.9–5.0
Polyestradiol phosphate^e		C3–C17β	Phosphoric acid	Water-soluble conjugate	–	1.23^f	0.81^f	2.9^g
Footnotes: ^a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic or cyclic fatty acids. ^b = Relative estradiol content by weight (i.e., relative estrogenic exposure). ^c = Experimental or predicted octanol/water partition coefficient (i.e., lipophilicity/hydrophobicity). Retrieved from PubChem, ChemSpider, and DrugBank. ^d = Also known as estradiol normustine phosphate. ^e = Polymer of estradiol phosphate (~13 repeat units). ^f = Relative molecular weight or estradiol content per repeat unit. ^g = log P of repeat unit (i.e., estradiol phosphate). Sources: See individual articles.

History

EBB, along with a variety of other estradiol esters, was first described in 1938 by Karl Miescher and colleagues of Ciba in Basel, Switzerland.^{[7][19][20][21]} It was developed in combination with DHPA as a combined injectable contraceptive in the 1970s.^{[8][1][22][23][24][25]} The combination was marketed for use as a combined injectable contraceptive in Peru by 1987.^[9][10]

Society and culture

Brand names

EBB is marketed in combination with DHPA under the brand names Neolutin N, Redimen, Soluna, and Unijab.^{[1][11][12][26][27][28]} It was originally developed under the tentative brand name Unimens, but ultimately was not marketed under this particular brand name.^{[1][2][13][8][29]}

Availability

The combination of EBB and DHPA is available only in Peru and Singapore.^[11][12]

See also

• Estradiol benzoate butyrate/dihydroxyprogesterone acetophenide

References

1. 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.
2. Toppozada MK (1983). "Monthly Injectable Contraceptives". In Alfredo Goldsmith, Mokhtar Toppozada (eds.). Long-Acting Contraception. pp. 93–103. OCLC 35018604.
3. "Estradiol: Uses, Dosage & Side Effects".
4. Ghosh AK (23 September 2010). Mayo Clinic Internal Medicine Board Review. OUP USA. pp. 222–. ISBN 978-0-19-975569-1.
5. 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.
6. 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. Handbook of Experimental Pharmacology. Vol. 135 / 2. Springer Science & Business Media. pp. 261–322. doi:10.1007/978-3-642-60107-1_15. 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.
7. Miescher K, Scholz C, Tschopp E (April 1938). "The activation of female sex hormones: alpha-Oestradiol and its di-esters". The Biochemical Journal. 32 (4): 725–732. doi:10.1042/bj0320725. PMC 1264097. PMID 16746680.
8. 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.
9. Bonnema J, Dalebout JA (February 1992). "The abuse of high dose estrogen/progestin combination drugs in delay of menstruation: the assumptions and practices of doctors, midwives and pharmacists in a Peruvian city". Social Science & Medicine. 34 (3): 281–289. doi:10.1016/0277-9536(92)90270-Z. PMID 1557669.
10. Thomas DB, Molina R, Rodriguez Cuevas H, Ray RM, Riotton G, Dabancens A, et al. (August 1989). "Monthly injectable steroid contraceptives and cervical carcinoma". American Journal of Epidemiology. 130 (2): 237–247. doi:10.1093/oxfordjournals.aje.a115330. PMID 2665476.
11. 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. 433, 467. ISBN 978-92-832-1291-1.
12. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; International Agency for Research on Cancer (1 January 1999). Hormonal Contraception and Post-menopausal Hormonal Therapy (PDF). IARC. p. 65. ISBN 978-92-832-1272-0. Archived from the original (PDF) on 28 August 2021. Retrieved 17 November 2019.
13. Hafez ES (1980). Human reproduction: conception and contraception. Harper and Row. ISBN 978-0-06-141066-6.
14. 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.
15. Emmens CW, Martin L (5 December 2016). "Estrogens". In Dorfman RI (ed.). Steroidal Activity in Experimental Animals and Man. Elsevier Science. pp. 36–. ISBN 978-1-4832-7299-3.
16. Ferin J (January 1952). "Relative duration of action of natural and synthetic estrogens administered parenterally in women with estrogen deficiency". The Journal of Clinical Endocrinology and Metabolism. 12 (1): 28–35. doi:10.1210/jcem-12-1-28. PMID 14907837.
17. Josephy E, Radt F (1946). Elsevier's Encyclopaedia of Organic Chemistry: Tetracyclic and higher-cyclic compounds. Elsevier. pp. 99, 680.
18. "Β-Estradiol-3-benzoate 17-N-butyrate | C29H34O4 | ChemSpider".
19. Korenchevsky V, Burbank R, Hall K (March 1939). "The action of the dipropionate and benzoate-butyrate of oestradiol on ovariectomized rats". The Biochemical Journal. 33 (3): 366–371. doi:10.1042/bj0330366. PMC 1264384. PMID 16746921.
20. Lockyer NS (1938). Nature. Macmillan Journals Limited. p. 292. The oestradiol benzoate butyrate and dipropionate were supplied by Dr. Miescher (of Ciba Ltd.) who recently described their prolonged effects in rats8.
21. American journal of cancer. 1940. Note: Our thanks are due to Doctor Karl Miescher of Messrs. Ciba in Basel, Switzerland, for a liberal supply of different esters of estradiol used in this work.
22. Minucci D, Arreghini G, Rabasso A (1973). "[Modification of the endometrium during combined therapy with dihydroxyprogesterone acetophenide and estradiol-3-benzoate-17-n-butyrate]" [Modification of the endometrium during combined therapy with dihydroxyprogesterone acetophenide and estradiol-3-benzoate-17-n-butyrate]. Rivista di Ostetricia Ginecologia Pratica e Medicina Perinatale (in Italian). 54 (10): 497–505. PMID 4807299.
23. Cittadini E, Catalano G (1973). "[Use of a new combination: dihydroxyprogesterone acetophenide and estradiol-3-benzoate-17 isobutyrate in gynecology]" [Use of a new combination: dihydroxyprogesterone acetophenide and estradiol-3-benzoate-17 isobutyrate in gynecology]. Rivista di Ostetricia Ginecologia Pratica e Medicina Perinatale (in Italian). 54 (10): 506–512. PMID 4620236.
24. Selvaggi L, Putignano G (December 1975). "[Response of peripheral receptors to the parenteral administration of an association of dihydroxyprogesterone acetophenide and estradiol-3 benzoate-17-n-butyrate. Preliminary note]" [Response of peripheral receptors to the parenteral administration of an association of dihydroxyprogesterone acetophenide and estradiol-3 benzoate-17-n-butyrate. Preliminary note]. Minerva Ginecologica (in Italian). 27 (12): 961–963. PMID 778679.
25. Cappello F (December 1975). "[Use of a parenteral estroprogestin as an inhibitor of ovulation in a single monthly administration]" [Use of a parenteral estroprogestin as an inhibitor of ovulation in a single monthly administration]. Minerva Ginecologica (in Italian). 27 (12): 964–968. PMID 778680.
26. "Farmaco SOLUNA 150 + 10 registrado en Perú".
27. "Unijab Dosage & Drug Information | MIMS Singapore".
28. "SOLUNA". www.corporacionmisalud.com. Archived from the original on 2014-10-05.
29. 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.