Esterified estrogens

Esterified estrogens (EEs), sold under the brand names Estratab and Menest among others, is an estrogen medication which is used hormone therapy for menopausal symptoms and low sex hormone levels in women, to treat breast cancer in both women and men, and to treat prostate cancer in men.[2][3][4][5][6] It is formulated alone or in combination with methyltestosterone.[2][3] It is taken by mouth.[1]

Esterified estrogens

Estrone sulfate, the primary active component in esterified estrogens (constitutes about 75 to 85% of total content).
Equilin sulfate, the second most major active component in esterified estrogens (constitutes about 6 to 16% of total content).
Combination of
Sodium estrone sulfate	Estrogen
Sodium equilin sulfate	Estrogen
Clinical data
Trade names	Estratab, Menest, others
Other names	Esterified oestrogens; EEs; Esterified equine estrogens; Esterified equine oestrogens; EEEs
Routes of administration	By mouth[1]
Drug class	Estrogen
ATC code	None
Identifiers
PubChem SID	347910451
DrugBank	DB09381
UNII	3ASP8Q3768

Side effects of EEs include nausea, breast tension, edema, and breakthrough bleeding among others.[7] It is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol.[4][2][3] EEs are a prodrug mainly of estradiol and to a lesser extent of equilin.[4]

EEs were introduced for medical use by 1970.[8] They are available in only a few countries, such as Chile and the United States.[2] They have also been marketed in Argentina and Switzerland in the past.[2]

Medical uses

EEs are used in hormone therapy for menopausal symptoms, female hypogonadism, ovariectomy, and primary ovarian failure and in the treatment of breast cancer and prostate cancer.[3][9]

Estrogen dosages for menopausal hormone therapy

Route/form	Estrogen	Low	Standard	High
Oral	Estradiol	0.5–1 mg/day	1–2 mg/day	2–4 mg/day
	Estradiol valerate	0.5–1 mg/day	1–2 mg/day	2–4 mg/day
	Estradiol acetate	0.45–0.9 mg/day	0.9–1.8 mg/day	1.8–3.6 mg/day
	Conjugated estrogens	0.3–0.45 mg/day	0.625 mg/day	0.9–1.25 mg/day
	Esterified estrogens	0.3–0.45 mg/day	0.625 mg/day	0.9–1.25 mg/day
	Estropipate	0.75 mg/day	1.5 mg/day	3 mg/day
	Estriol	1–2 mg/day	2–4 mg/day	4–8 mg/day
	Ethinylestradiol^a	2.5 μg/day	5–15 μg/day	–
Nasal spray	Estradiol	150 μg/day	300 μg/day	600 μg/day
Transdermal patch	Estradiol	25 μg/day^b	50 μg/day^b	100 μg/day^b
Transdermal gel	Estradiol	0.5 mg/day	1–1.5 mg/day	2–3 mg/day
Vaginal	Estradiol	25 μg/day	–	–
	Estriol	30 μg/day	0.5 mg 2x/week	0.5 mg/day
IM or SC injection	Estradiol valerate	–	–	4 mg 1x/4 weeks
	Estradiol cypionate	1 mg 1x/3–4 weeks	3 mg 1x/3–4 weeks	5 mg 1x/3–4 weeks
	Estradiol benzoate	0.5 mg 1x/week	1 mg 1x/week	1.5 mg 1x/week
SC implant	Estradiol	25 mg 1x/6 months	50 mg 1x/6 months	100 mg 1x/6 months
Footnotes: ^a = No longer used or recommended, due to health concerns. ^b = As a single patch applied once or twice per week (worn for 3–4 days or 7 days), depending on the formulation. Note: Dosages are not necessarily equivalent. Sources: See template.

Available forms

EEs are available in the form of 0.3 mg, 0.625 mg, 1.25 mg, and 2.5 mg oral tablets.[10] Estratest is a combination formulation of 1.25 mg EEs with 2.5 mg methyltestosterone.[11]

Side effects

Pharmacology

EEs consist primarily of sodium estrone sulfate and sodium equilin sulfate, and are very similar to conjugated estrogens (CEEs, conjugated equine estrogens; brand name Premarin).[4][6][12][13] However, EEs and CEEs differ in the sources of their contents and in the percentages of their constituents; CEEs consist of approximately 53% sodium estrone sulfate and 25% sodium equilin sulfate, while EEs contain about 75 to 85% sodium estrone sulfate and 6 to 11% sodium equilin sulfate.[4][2][12][14][9] EEs have been found to produce similar serum levels of estrone and estradiol relative to CEEs, although with higher levels of estrone and lower levels of equilin.[4][15] One study found that the risk of venous thrombosis may be less with EEs relative to CEEs.[14][6]

Relative oral potencies of estrogens

Estrogen	HF	VE	UCa	FSH	LH	HDL-C	SHBG	CBG	AGT	Liver
Estradiol	1.0	1.0	1.0	1.0	1.0	1.0	1.0	1.0	1.0	1.0
Estrone	?	?	?	0.3	0.3	?	?	?	?	?
Estriol	0.3	0.3	0.1	0.3	0.3	0.2	?	?	?	0.67
Estrone sulfate	?	0.9	0.9	0.8–0.9	0.9	0.5	0.9	0.5–0.7	1.4–1.5	0.56–1.7
Conjugated estrogens	1.2	1.5	2.0	1.1–1.3	1.0	1.5	3.0–3.2	1.3–1.5	5.0	1.3–4.5
Equilin sulfate	?	?	1.0	?	?	6.0	7.5	6.0	7.5	?
Ethinylestradiol	120	150	400	60–150	100	400	500–600	500–600	350	2.9–5.0
Diethylstilbestrol	?	?	?	2.9–3.4	?	?	26–28	25–37	20	5.7–7.5
Sources and footnotes Notes: Values are ratios, with estradiol as standard (i.e., 1.0). Abbreviations: HF = Clinical relief of hot flashes. VE = Increased proliferation of vaginal epithelium. UCa = Decrease in UCa. FSH = Suppression of FSH levels. LH = Suppression of LH levels. HDL-C, SHBG, CBG, and AGT = Increase in the serum levels of these liver proteins. Liver = Ratio of liver estrogenic effects to general/systemic estrogenic effects (hot flashes/gonadotropins). Sources: See template.

Protein binding and metabolic clearance rates of estrogens

Compound	RBA to SHBG (%)	Bound to SHBG (%)	Bound to albumin (%)	Total bound (%)	MCR (L/day/m^2)
17β-Estradiol	50	37	61	98	580
Estrone	12	16	80	96	1050
Estriol	0.3	1	91	92	1110
Estrone sulfate	0	0	99	99	80
17β-Dihydroequilin	30	?	?	?	1250
Equilin	8	26	13	?	2640
17β-Dihydroequilin sulfate	0	?	?	?	375
Equilin sulfate	0	?	?	?	175
Δ^8-Estrone	?	?	?	?	1710
Notes: RBA for SHBG (%) is compared to 100% for testosterone. Sources: See template.

Chemistry

EEs contain synthetic, plant-derived estrogens and are manufactured from soybeans and yams.[5][6]

History

EEs were introduced for medical use by 1970.[8]

Society and culture

Generic names

Estrogens, esterified is the generic name of the drug and its USP.[16] It is also known as esterified estrogens.[3]

Brand names

EEs are marketed under a variety of brand names including Amnestrogen, Estragyn, Estratab, Evex, Femibel, Femogen, Menest, Neo Estrone Tab, and Oestro-Feminal alone, and, in combination with methyltestosterone, under the brand names Covaryx, Delitan, Eemt, Essian, Estratest, Feminova-T, Menogen, and Syntest.[2][5][3]

Availability

EEs are or have been marketed in Argentina, Chile, Switzerland, and the United States.[2] Both EEs and the combination of EEs and methyltestosterone are listed as being marketed only in Chile and the United States as of present.[2]

See also

• Esterified estrogens/methyltestosterone
• Estrogenic substances
• Conjugated estriol
• List of combined sex-hormonal preparations

References

1. Katherine Sherif (14 May 2013). Hormone Therapy: A Clinical Handbook. Springer Science & Business Media. pp. 120–. ISBN 978-1-4614-6268-2.
2. Sweetman, Sean C., ed. (2009). "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. p. 2097. ISBN 978-0-85369-840-1.
3. https://www.drugbank.ca/drugs/DB09381
4. Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
5. Carl P. Weiner, MD; Kate Rope (2 April 2013). The Complete Guide to Medications During Pregnancy and Breastfeeding: Everything You Need to Know to Make the Best Choices for You and Your Baby. St. Martin's Press. pp. 179–. ISBN 978-0-312-67646-9.
6. Smith, N. L.; Heckbert, S. R.; Lemaitre, R. N.; Reiner, A. P.; Lumley, T.; Rosendaal, F. R.; Psaty, B. M. (2006). "Conjugated Equine Estrogen, Esterified Estrogen, Prothrombotic Variants, and the Risk of Venous Thrombosis in Postmenopausal Women". Arteriosclerosis, Thrombosis, and Vascular Biology. 26 (12): 2807–2812. doi:10.1161/01.ATV.0000245792.62517.3b. ISSN 1079-5642. PMID 16973976.
7. Wittlinger, H. (1980). "Clinical Effects of Estrogens". Functional Morphologic Changes in Female Sex Organs Induced by Exogenous Hormones. pp. 67–71. doi:10.1007/978-3-642-67568-3_10. ISBN 978-3-642-67570-6.
8. Northwest Medicine. Northwest Medical Pub. Association. 1970.
9. Manuchair Ebadi (31 October 2007). Desk Reference of Clinical Pharmacology, Second Edition. CRC Press. pp. 249–. ISBN 978-1-4200-4744-8.
10. "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 30 March 2018.
11. John E. Morley; Lucretia van den Berg (5 November 1999). Endocrinology of Aging. Springer Science & Business Media. pp. 172–. ISBN 978-1-59259-715-4.
12. Marc A. Fritz; Leon Speroff (28 March 2012). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. 752–. ISBN 978-1-4511-4847-3.
13. Tara Parker-Pope (9 January 2007). The Hormone Decision: Untangle the Controversy, Understand Your Options, Make Your Own Choices. Rodale. pp. 157–. ISBN 978-1-59486-927-3.
14. Smith, Nicholas L. (2004). "Esterified Estrogens and Conjugated Equine Estrogens and the Risk of Venous Thrombosis" (PDF). JAMA. 292 (13): 1581–7. doi:10.1001/jama.292.13.1581. ISSN 0098-7484. PMID 15467060.
15. Lemaitre, Rozenn N.; Weiss, Noel S.; Smith, Nicholas L.; Psaty, Bruce M.; Lumley, Thomas; Larson, Eric B.; Heckbert, Susan R. (2006). "Esterified Estrogen and Conjugated Equine Estrogen and the Risk of Incident Myocardial Infarction and Stroke". Archives of Internal Medicine. 166 (4): 399–404. doi:10.1001/archinte.166.4.399. ISSN 0003-9926. PMID 16505258.
16. https://chem.nlm.nih.gov/chemidplus/sid/d042724000