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]

Not to be confused with Estrogen ester or Conjugated estrogens.
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 sulfateEstrogen
Sodium equilin sulfateEstrogen
Clinical data
Trade namesEstratab, Menest, others
Other namesEsterified oestrogens; EEs; Esterified equine estrogens; Esterified equine oestrogens; EEEs
Routes of
administration		By mouth[1]
Drug classEstrogen
ATC code
  • None
Identifiers
PubChem SID
DrugBank
UNII

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/formEstrogenLowStandardHigh
OralEstradiol0.5–1 mg/day1–2 mg/day2–4 mg/day
Estradiol valerate0.5–1 mg/day1–2 mg/day2–4 mg/day
Estradiol acetate0.45–0.9 mg/day0.9–1.8 mg/day1.8–3.6 mg/day
Conjugated estrogens0.3–0.45 mg/day0.625 mg/day0.9–1.25 mg/day
Esterified estrogens0.3–0.45 mg/day0.625 mg/day0.9–1.25 mg/day
Estropipate0.75 mg/day1.5 mg/day3 mg/day
Estriol1–2 mg/day2–4 mg/day4–8 mg/day
Ethinylestradiola2.5–10 μg/day5–20 μg/day–
Nasal sprayEstradiol150 μg/day300 μg/day600 μg/day
Transdermal patchEstradiol25 μg/dayb50 μg/dayb100 μg/dayb
Transdermal gelEstradiol0.5 mg/day1–1.5 mg/day2–3 mg/day
VaginalEstradiol25 μg/day––
Estriol30 μg/day0.5 mg 2x/week0.5 mg/day
IMTooltip Intramuscular or SC injectionEstradiol valerate––4 mg 1x/4 weeks
Estradiol cypionate1 mg 1x/3–4 weeks3 mg 1x/3–4 weeks5 mg 1x/3–4 weeks
Estradiol benzoate0.5 mg 1x/week1 mg 1x/week1.5 mg 1x/week
SC implantEstradiol25 mg 1x/6 months50 mg 1x/6 months100 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
See also: Conjugated estrogens § Side effects, and Estrogen (medication) § Side effects

Pharmacology
See also: Pharmacodynamics of estradiol and Pharmacokinetics of estradiol

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
EstrogenHFTooltip Hot flashesVETooltip Vaginal epitheliumUCaTooltip Urinary calciumFSHTooltip Follicle-stimulating hormoneLHTooltip Luteinizing hormoneHDLTooltip High-density lipoprotein-CTooltip CholesterolSHBGTooltip Sex hormone-binding globulinCBGTooltip Corticosteroid-binding globulinAGTTooltip AngiotensinogenLiver
Estradiol1.01.01.01.01.01.01.01.01.01.0
Estrone ? ? ?0.30.3 ? ? ? ? ?
Estriol0.30.30.10.30.30.2 ? ? ?0.67
Estrone sulfate ?0.90.90.8–0.90.90.50.90.5–0.71.4–1.50.56–1.7
Conjugated estrogens1.21.52.01.1–1.31.01.53.0–3.21.3–1.55.01.3–4.5
Equilin sulfate ? ?1.0 ? ?6.07.56.07.5 ?
Ethinylestradiol12015040060–150100400500–600500–6003502.9–5.0
Diethylstilbestrol ? ? ?2.9–3.4 ? ?26–2825–37205.7–7.5
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 UCaTooltip urinary calcium. FSH = Suppression of FSHTooltip follicle-stimulating hormone levels. LH = Suppression of LHTooltip luteinizing hormone 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
CompoundRBATooltip Relative binding affinity to
SHBGTooltip sex hormone-binding globulin (%)		Bound to
SHBG (%)		Bound to
albumin (%)		Total
bound (%)		MCRTooltip Metabolic clearance rate
(L/day/m2)
17β-Estradiol50376198580
Estrone121680961050
Estriol0.3191921110
Estrone sulfate00999980
17β-Dihydroequilin30 ? ? ?1250
Equilin82613 ?2640
17β-Dihydroequilin sulfate0 ? ? ?375
Equilin sulfate0 ? ? ?175
Δ8-Estrone ? ? ? ?1710
Notes: RBA for SHBG (%) is compared to 100% for testosterone. Sources: See template.

Chemistry
See also: List of estrogens, Estrogen ester, and List of estrogen esters

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 USPTooltip United States Pharmacopeia.[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
See also: List of estrogens available in the United States

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

References
  1. Sherif K (14 May 2013). Hormone Therapy: A Clinical Handbook. Springer Science & Business Media. pp. 120–. ISBN 978-1-4614-6268-2.
  2. Sweetman SC, 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. "Esterified estrogens".
  4. 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.
  5. Weiner CP, Rope K (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 NL, Heckbert SR, Lemaitre RN, Reiner AP, Lumley T, Rosendaal FR, Psaty BM (December 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. 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. Vol. 69. Northwest Medical Pub. Association. 1970.
  9. Ebadi M (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. Morley JE, van den Berg L (5 November 1999). Endocrinology of Aging. Springer Science & Business Media. pp. 172–. ISBN 978-1-59259-715-4.
  12. Fritz MA, Speroff L (28 March 2012). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. 752–. ISBN 978-1-4511-4847-3.
  13. Parker-Pope T (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 NL, Heckbert SR, Lemaitre RN, Reiner AP, Lumley T, Weiss NS, et al. (October 2004). "Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis". JAMA. 292 (13): 1581–1587. doi:10.1001/jama.292.13.1581. PMID 15467060.
  15. Lemaitre RN, Weiss NS, Smith NL, Psaty BM, Lumley T, Larson EB, Heckbert SR (February 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. PMID 16505258.
  16. "Estrogens, Esterified (USP) - Searchable synonyms, formulas, resource links, and other chemical information". ChemIDplus. U.S. Library of Medicine. D042724000.
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