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Overview of CAS-50-28-2

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4TI98Z838E
PharmaCompass
  • Chemistry
4TI98Z838E
Also known as: Beta-estradiol, 50-28-2, 17beta-estradiol, Oestradiol, Dihydrofolliculin, Estrace
Molecular Formula
C18H24O2
Molecular Weight
272.388  g/mol
InChI Key
VOXZDWNPVJITMN-ZBRFXRBCSA-N
FDA UNII
4TI98Z838E

Estradiol (also known as E2 or 17β-estradiol) is a naturally occurring hormone that circulates endogenously within the human body. It is the most potent form of mammalian estrogenic steroids and acts as the major female sex hormone. As such, estradiol plays an essential role in the regulation of the menstrual cycle, in the development of puberty and secondary female sex characteristics, as well as in ageing and several hormonally-mediated disease states. Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects [A31620]. Estradiol is commercially available in several hormone therapy products for managing conditions associated with reduced estrogen production such as menopausal and peri-menopausal symptoms as well as hypoestrogenism. It is also used in transgender hormone therapy, as a component of oral contraceptive pills for preventing pregnancy (most commonly as [DB00977], a synthetic form of estradiol), and is sometimes used for the palliative treatment of some hormone-sensitive cancers like breast and prostate cancer. Estradiol is available in a number of formulations including oral, transdermal, and injectable. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. However, after menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulphate conjugated form, estrone sulphate, are the most abundant circulating estrogens in postmenopausal women [FDA Label]. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level. Because of the difference in potency between estradiol and estrone, menopause (and a change in primary hormone from estradiol to estrone) is associated with a number of symptoms associated with this reduction in potency and in estrogenic effects. These include hot flashes, vaginal dryness, mood changes, irregular menses, chills, and sleeping problems. When used for oral or IM administration, estradiol is commonly synthesized as a pro-drug ester (such as [DB13952], [DB13953], [DB13954], [DB13955], and [DB13956]). It is commonly produced with an ester side-chain as endogenous estradiol has very low oral bioavailability on its own (2-10%). First-pass metabolism by the gut and the liver quickly degrades the estradiol molecule before it gets a chance to enter the systemic circulation and exert its estrogenic effects [A12102]. Esterification of estradiol aims to improve absorption after oral administration (such as with Estradiol valerate) or to sustain release from intramuscular depot injections (such as with Estradiol Cypionate) through improved lipophilicity [T84]. Following absorption, the esters are cleaved, resulting in the release of endogenous estradiol, or 17β-estradiol. Recommendations for treatment of menopausal symptoms changed drastically following the release of results and early termination of the Women's Health Initiative (WHI) studies in 2002 as a number of concerns were raised regarding the use of estrogen [A31626]. Specifically, the combined estrogen–progestin arm was discontinued after approximately five years of follow up due to a statistically significant increase in invasive breast cancer and in cardiovascular events [A31627]. Following extensive critique of the WHI results in the years following its release, Hormone Replacement Therapy (HRT) is now recommended to be used only for a short period (for 3-5 years post-menopause) in low doses, and in women without a history of breast cancer or at increased risk of cardiovascular or thromboembolic disease [A31628]. Notably, use of estrogen for menopausal symptoms should always be accompanied by a progestin component due to estrogen's effects on the endometrium; in women with an intact uterus, unopposed estrogen has been shown to promote the growth of the endometrium which can lead to endometrial hyperplasia and possibly cancer in the long-term. [DB00977] (EE) is a synthetic form of estradiol commonly used as the estrogenic component of most combination Oral Contraceptive Pills (OCPs). Ethinyl Estradiol differs from Estradiol in that it has improved biovailability and greater resistance to metabolism, making it more suitable for oral administration.
Estradiol is an Estrogen. The mechanism of action of estradiol is as an Estrogen Receptor Agonist. The chemical classification of estradiol is Estradiol Congeners.
1 2D Structure

4TI98Z838E

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
(8R,9S,13S,14S,17S)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol
2.1.2 InChI
InChI=1S/C18H24O2/c1-18-9-8-14-13-5-3-12(19)10-11(13)2-4-15(14)16(18)6-7-17(18)20/h3,5,10,14-17,19-20H,2,4,6-9H2,1H3/t14-,15-,16+,17+,18+/m1/s1
2.1.3 InChI Key
VOXZDWNPVJITMN-ZBRFXRBCSA-N
2.1.4 Canonical SMILES
CC12CCC3C(C1CCC2O)CCC4=C3C=CC(=C4)O
2.1.5 Isomeric SMILES
C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2O)CCC4=C3C=CC(=C4)O
2.2 Other Identifiers
2.2.1 UNII
4TI98Z838E
2.3 Synonyms
2.3.1 MeSH Synonyms

1. 17 Beta Estradiol

2. 17 Beta Oestradiol

3. 17 Beta-estradiol

4. 17 Beta-oestradiol

5. Aerodiol

6. Delestrogen

7. Estrace

8. Estraderm Tts

9. Estradiol 17 Alpha

10. Estradiol 17 Beta

11. Estradiol 17beta

12. Estradiol Anhydrous

13. Estradiol Hemihydrate

14. Estradiol Hemihydrate, (17 Alpha)-isomer

15. Estradiol Monohydrate

16. Estradiol Valerate

17. Estradiol Valeriante

18. Estradiol, (+-)-isomer

19. Estradiol, (-)-isomer

20. Estradiol, (16 Alpha,17 Alpha)-isomer

21. Estradiol, (16 Alpha,17 Beta)-isomer

22. Estradiol, (17-alpha)-isomer

23. Estradiol, (8 Alpha,17 Beta)-(+-)-isomer

24. Estradiol, (8 Alpha,17 Beta)-isomer

25. Estradiol, (9 Beta,17 Alpha)-isomer

26. Estradiol, (9 Beta,17 Beta)-isomer

27. Estradiol, Monosodium Salt

28. Estradiol, Sodium Salt

29. Estradiol-17 Alpha

30. Estradiol-17 Beta

31. Estradiol-17beta

32. Oestradiol

33. Ovocyclin

34. Progynon Depot

35. Progynon-depot

36. Progynova

37. Vivelle

2.3.2 Depositor-Supplied Synonyms

1. Beta-estradiol

2. 50-28-2

3. 17beta-estradiol

4. Oestradiol

5. Dihydrofolliculin

6. Estrace

7. Ovocyclin

8. Progynon

9. Dihydrotheelin

10. Dihydroxyestrin

11. Aquadiol

12. Diogynets

13. Gynergon

14. Gynoestryl

15. Vivelle

16. Diogyn

17. Oestroglandol

18. Aerodiol

19. Corpagen

20. Dimenformon

21. Estrovite

22. Femestral

23. Follicyclin

24. Ginosedol

25. Macrodiol

26. Oestergon

27. Ovahormon

28. Ovasterol

29. Ovastevol

30. Perlatanol

31. Primofol

32. Profoliol

33. Altrad

34. Bardiol

35. Climara

36. Divigel

37. Evorel

38. Femogen

39. Lamdiol

40. Syndiol

41. Vagifem

42. Dihydromenformon

43. Estradiol-17beta

44. Cis-estradiol

45. Estraderm Tts

46. Estraderm

47. Estraldine

48. Estroclim

49. Trocosone

50. Estrogel

51. Menorest

52. Nordicol

53. Zumenon

54. Systen

55. D-oestradiol

56. D-estradiol

57. Progynon Dh

58. Climaderm

59. Compudose

60. Dermestril

61. Estrasorb

62. Ovocycline

63. Encore

64. Estring

65. Menest

66. Oesclim

67. Dihydroxyoestrin

68. Sk-estrogens

69. Progynon-dh

70. Gynestrel

71. Microdiol

72. Oestrogynal

73. Ovociclina

74. Ovocylin

75. Tradelia

76. Estroclim 50

77. Innofem

78. Macrol

79. Zerella

80. 17beta-oestradiol

81. Alora

82. Oestradiol R

83. Estring Vaginal Ring

84. Dihydrofollicular Hormone

85. Trial Sat

86. Theelin, Dihydro-

87. Elestrin

88. Estreva

89. Estrifam

90. Extrasorb

91. Fempatch

92. Femtran

93. Ginedisc

94. Gynodiol

95. Oestrogel

96. Esclim

97. Compudose 200

98. Compudose 365

99. Gynpolar

100. Estrofem Forte

101. Profoliol B

102. Sandrena Gel

103. Sisare Gel

104. Estrofem 2

105. Oestradiolum

106. Estradiol-17-beta

107. Estradiolum

108. Estradot

109. Gelestra

110. 3,17-epidihydroxyestratriene

111. Evamist

112. Zesteem

113. Dihydroxyesterin

114. Cis-oestradiol

115. Estraderm Tts 50

116. Climara Forte

117. Estrogens, Esterified

118. Oestradiol Berco

119. Estraderm Mx

120. Vivelle-dot

121. Epiestriol 50

122. 17beta Oestradiol

123. Oestradiol-17beta

124. Estrapak 50

125. 17-beta-estradiol

126. 17 Beta-estradiol

127. Estradiol-17 Beta

128. Estradiolum [inn]

129. Estradiolo [dcit]

130. Oestradiol-17-beta

131. Amnestrogen

132. Femanest

133. Femestrol

134. Estra-1,3,5(10)-triene-3,17beta-diol

135. Estradiol-3,17beta

136. B-estradiol

137. 17-beta-oh-estradiol

138. 3,17-beta-estradiol

139. Nsc-9895

140. 3,17-beta-oestradiol

141. 3,17-epidihydroxyoestratriene

142. D-3,17beta-estradiol

143. 17b-oestradiol

144. Sandrena 1

145. E(sub 2)

146. Estraderm (tn)

147. [3h]-estradiol

148. Estrogel (tn)

149. Climara (tn)

150. Divigel (tn)

151. Estrace (tn)

152. Estring (tn)

153. Innofem (tn)

154. Vagifem (tn)

155. Vivelle (tn)

156. 17.beta.-estradiol

157. 17.beta.-oestradiol

158. 17-beta-oh-oestradiol

159. 3,17.beta.-estradiol

160. D-3,17beta-oestradiol

161. Estrodiolum [inn-latin]

162. (17beta)-estra-1,3,5(10)-triene-3,17-diol

163. D-3,17-beta-estradiol

164. D-3,17-beta-oestradiol

165. .beta.-estradiol

166. .beta.-oestradiol

167. [3h]]estradiol

168. 17

169. A-oestradiol

170. Ccris 280

171. Unii-4ti98z838e

172. Estradiol, .beta.-

173. Estradiol-17.beta.

174. Chebi:16469

175. Estra-1,3,5(10)-triene-3,17-diol (17beta)-

176. Oestradiol-17.beta.

177. Hsdb 3589

178. Estradiol Hemihydrate

179. Oestra-1,3,5(10)-triene-3,17beta-diol

180. C18h24o2

181. Estrasorb (tn)

182. 17.beta.-oh-estradiol

183. 17.beta.-oh-oestradiol

184. 17beta Estradiol (e2)

185. Einecs 200-023-8

186. 17beta-estra-1,3,5(10)-triene-3,17-diol

187. 1,3,5-estratriene-3,17-beta-diol

188. Chembl135

189. D-3,17.beta.-estradiol

190. Dimenformon Prolongatum

191. D-3,17.beta.-oestradiol

192. 3,17beta-dihydroxyestra-1,3,5-triene

193. Estra-1,3,5(10)-triene-3,17-diol, (17beta)-

194. 3,17beta-dihydroxyoestra-1,3,5-triene

195. 3,17-beta-dihydroxyoestra-1,3,5-triene

196. Mls000069494

197. (8r,9s,13s,14s,17s)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol

198. Estra-1,3,5(10)-triene-3,17-beta-diol

199. Oestra-1,3,5(10)-triene-3,17-beta-diol

200. 3,17-beta-dihydroxyestra-1,3,5(10)-triene

201. 3,17-beta-dihydroxy-1,3,5(10)-oestratriene

202. Voxzdwnpvjitmn-zbrfxrbcsa-n

203. 17-beta-estra-1,3,5(10)-triene-3,17-diol

204. 17beta-oestra-1,3,5(10)-triene-3,17-diol

205. 4ti98z838e

206. (17beta)-estra-1(10),2,4-triene-3,17-diol

207. 17-beta-oestra-1,3,5(10)-triene-3,17-diol

208. 1,3,5-estratriene-3,17beta-diol

209. [3h]e2

210. Mfcd00003693

211. Ncgc00091544-04

212. Beta-estradiol, 98%

213. Estrodiolum

214. Polyestradiol

215. Estradiolo

216. Smr000059126

217. 3,17b-dihydroxyestra-1,3,5(10)-triene

218. Dsstox_cid_573

219. 3,17beta-dihydroxy-1,3,5(10)-estratriene

220. 3,17beta-dihydroxyestra-1,3,5(10)-triene

221. Dsstox_rid_75666

222. Benzogynestry

223. Dsstox_gsid_20573

224. Estropause

225. Estasorb

226. (8r,9s,13s,14s,17s)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6h-cyclopenta[a]phenanthrene-3,17-diol

227. [2,4,6,7-3h]-e2

228. E 2

229. Oestradiol-17beta And Esters [steroidal Oestrogens]

230. Destradiol

231. Minivelle

232. Yuvvexy

233. Zesteen

234. Estradiol [usan:inn]

235. 17b-estradiol

236. Activella (salt/mix)

237. Combipatch (salt/mix)

238. (1s,10r,11s,14s,15s)-15-methyltetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadeca-2(7),3,5-triene-5,14-diol

239. Component Of Menrium

240. Estradiol-17 Alpha

241. Climara Pro (salt/mix)

242. 3,17beta-estradiol

243. 3,17-.beta.-oestradiol

244. Estraderm Tts 100

245. 3,3,5(10)-triene

246. Sr-01000075866

247. 17-.beta.-estradiol

248. Estra-1,3,5(10)-triene-3,17-diol (17.beta.)-

249. (+)-3,17.beta.-estradiol

250. Oestrodiol

251. Estradiol [usp:inn:ban]

252. Elestrim

253. Delta-estradiol

254. Dihydro-theelin

255. Delta-oestradiol

256. Tx-004hr

257. Estradiol Complex

258. Unii-125dp6010h

259. Estrogel Hbf

260. 1jgl

261. 1lhu

262. 1qkt

263. 1qku

264. [3h]estradiol

265. Climara, Menostar

266. 1,3,5-estratriene-3,17.beta.-diol

267. Cas-50-28-2

268. .alpha.-oestradiol

269. Cpd000059126

270. Prestwick_207

271. 3,17b-estradiol

272. Bio-e-gel

273. Fem7

274. [3h]-estrogen

275. 17 ?-estradiol

276. 3,17.beta.-dihydroxyestra-1,3,5-triene

277. 3,17.beta.-dihydroxyoestra-1,3,5-triene

278. Cmc_11154

279. 17-beta

280. 1,3,5,(10)-estratrien-3,17.beta.-diol

281. Sl-1100

282. Estra-1,3,5(10)-triene-3,17.beta.-diol

283. Oestra-1,3,5(10)-triene-3,17.beta.-diol

284. 2j7x

285. 3,17.beta.-dihydroxy-1,3,5(10)-estratriene

286. 3,17.beta.-dihydroxy-1,3,5(10)-oestratriene

287. 3,17.beta.-dihydroxyestra-1,3,5(10)-triene

288. 3,3,5-triene

289. [3h]17beta-estradiol

290. (17?)-estra-1,3,5(10)-triene-3,17-diol

291. 17.beta.-estra-1,3,5(10)-triene-3,17-diol

292. 17.beta.-oestra-1,3,5(10)-triene-3,17-diol

293. Opera_id_1688

294. Prestwick0_000441

295. Prestwick1_000441

296. Prestwick2_000441

297. Prestwick3_000441

298. Spectrum5_002055

299. 17beta-estradiol (e2)

300. E0025

301. Alpha-estradiol (obsolete)

302. Beta-estradiol, >=98%

303. Bmse000642

304. Epitope Id:136018

305. (+)-3,17b-estradiol

306. E 8875

307. Ec 200-023-8

308. Ac1l1l2k

309. Schembl8049

310. (+)-3,17beta-estradiol

311. Estradiol (jan/usp/inn)

312. Bidd:pxr0065

313. Lopac0_000503

314. S-21400

315. Bspbio_000482

316. Bspbio_001065

317. Kbiogr_000405

318. Kbiogr_002269

319. Kbioss_000405

320. Kbioss_002270

321. Oestradiol-17beta And Esters

322. Mls000758312

323. Mls001076331

324. Mls001424022

325. Bidd:er0125

326. Spbio_002421

327. Bpbio1_000532

328. Gtpl1012

329. Gtpl1013

330. Dtxsid0020573

331. Bdbm17292

332. Kbio2_000405

333. Kbio2_002269

334. Kbio2_002973

335. Kbio2_004837

336. Kbio2_005541

337. Kbio2_007405

338. Kbio3_000769

339. Kbio3_000770

340. Kbio3_002749

341. Aob5963

342. Nsc9895

343. 1a52

344. 1g50

345. 2d06

346. Cmap_000005

347. Molport-001-794-632

348. Bio1_000403

349. Bio1_000892

350. Bio1_001381

351. Bio2_000363

352. Bio2_000843

353. Hms1362e07

354. Hms1569i04

355. Hms1792e07

356. Hms1990e07

357. Hms2051c17

358. Hms2090e18

359. Hms2096i04

360. Hms2236h04

361. Hms3261f07

362. Hms3403e07

363. Hms3713i04

364. Beta-estradiol, Analytical Standard

365. (8s,9s,13s,14s,17s)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol

366. Acn-s003579

367. Bcp08579

368. Hy-b0141

369. Tox21_111148

370. Tox21_202057

371. Tox21_300288

372. Tox21_500503

373. 1,5-estratriene-3,17.beta.-diol

374. Lmst02010001

375. Ls-137

376. S1709

377. Zinc13520815

378. [2,4,6,7-3h]-17beta-estradiol

379. Akos015896570

380. 125dp6010h

381. An-6628

382. Ccg-100808

383. Cs-1938

384. Db00783

385. Lp00503

386. Nc00058

387. Idi1_002118

388. Smp1_000121

389. 1,3,5(10)-estratriene-3,17b-diol

390. Ncgc00091544-00

391. Ncgc00091544-01

392. Ncgc00091544-02

393. Ncgc00091544-05

394. Ncgc00091544-06

395. Ncgc00091544-07

396. Ncgc00091544-09

397. Ncgc00091544-10

398. Ncgc00091544-11

399. Ncgc00091544-12

400. Ncgc00091544-13

401. Ncgc00091544-14

402. Ncgc00091544-15

403. Ncgc00091544-16

404. Ncgc00179321-01

405. Ncgc00179321-02

406. Ncgc00254177-01

407. Ncgc00259606-01

408. Ncgc00261188-01

409. 17-e

410. 73459-61-7

411. Ac-22346

412. Aj-64042

413. As-13729

414. Bc200811

415. Sc-25771

416. Estra-1,3,5(10)-triene-3,17b-diol

417. Oestra-1,3,5(10)-triene-3,17b-diol

418. Wln: L E5 B666ttt&j E1 Fq Oq

419. Ab0012866

420. Ab2000237

421. Estra-1,5(10)-triene-3,17.beta.-diol

422. Estradiol, Meets Usp Testing Specifications

423. 3,17beta-dihydroxyestra-1,3,5(10)-trien

424. Estra-1,3,5(10)-triene -3,17beta-diol

425. Eu-0100503

426. Oestra-1,5(10)-triene-3,17.beta.-diol

427. 3,17-dihydroxy-delta(1,3,5-10)-estratriene

428. C00951

429. D00105

430. J10189

431. Z-4415

432. (17b)-estra-1,3,5(10)-triene-3,17-diol

433. 13b-methyl-1,3,5(10)-gonatriene-3,17b-ol

434. 17-decahydrocyclopenta[a]phenanthrene-3,17-diol

435. 17.beta.-estra-1,5(10)-triene-3,17-diol

436. 17.beta.-oestra-1,5(10)-triene-3,17-diol

437. Estra-1,3,5(10)-triene-3,17-diol(17b)-

438. 003e693

439. 17-beta-estradiol 100 Microg/ml In Acetonitrile

440. Sr-01000721892

441. 13beta-methyl-1,3,5(10)-gonatriene-3,17beta-ol

442. Estra-1,5(10)-triene-3,17-diol (17.beta.)-

443. I06-2405

444. Q-201503

445. Sr-01000075866-1

446. Sr-01000075866-4

447. Sr-01000721892-3

448. Brd-k18910433-001-04-4

449. Brd-k18910433-001-43-2

450. Estra-1(10),2,4-triene-3,17-diol, (17beta)-

451. Estra-1,5(10)-triene-3,17-diol, (17.beta.)-

452. 17

453. A-estradiol;oestradiol;17

454. A-oestradiol;

455. A-estradiol

456. Z1847670481

457. B8b5aef5-4957-49eb-a14f-444a8212c482

458. Beta-estradiol, Bioreagent, Powder, Suitable For Cell Culture

459. Estra-1,3,5(10)-triene-3,17-diol (17beta)-, Homopolymer

460. Estradiol, United States Pharmacopeia (usp) Reference Standard

461. Beta-estradiol, Powder, Gamma-irradiated, Suitable For Cell Culture

462. (9beta,13alpha,14beta,17alpha)-estra-1,3,5(10)-triene-3,17-diol

463. Estradiol, Pharmaceutical Secondary Standard; Certified Reference Material

464. (13s,17s)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6h-cyclopenta[a]phenanthrene-3,17-beta-diol

465. (1s,10r,11s,14s,15s)-15-methyltetracyclo[8.7.0.0(2),.0(1)(1),(1)]heptadeca-2,4,6-triene-5,14-diol

466. (1s,10r,11s,14s,15s)-15-methyltetracyclo[8.7.0.0;{2,7}.0;{11,15}]heptadeca-2,4,6-triene-5,14-diol

467. (8''r'',9''s'',13''s'',14''s'',17''s'')-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[''a'']phenanthrene-3,17-diol

468. 1050677-52-5

469. 1206475-11-7

470. 17beta-estradiol Solution, 1.0 Mg/ml In Acetonitrile, Ampule Of 1 Ml, Certified Reference Material

471. 873662-39-6

2.4 Create Date
2004-09-16
3 Chemical and Physical Properties
Molecular Weight 272.388 g/mol
Molecular Formula C18H24O2
XLogP34
Hydrogen Bond Donor Count2
Hydrogen Bond Acceptor Count2
Rotatable Bond Count0
Exact Mass272.178 g/mol
Monoisotopic Mass272.178 g/mol
Topological Polar Surface Area40.5 A^2
Heavy Atom Count20
Formal Charge0
Complexity382
Isotope Atom Count0
Defined Atom Stereocenter Count5
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Therapeutic Uses

Estradiol tablets are indicated in the treatment of moderate to severe vasomotor symptoms associated with the menopause. /Included in US product label/

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


Estradiol tablets are indicated in the treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered. /Included in US product label/

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


Estradiol tablets are indicated in the treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure. /Included in US product label/

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


Estradiol tablets are indicated in the treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease. /Included in US product label/

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


Estradiol tablets are indicated in the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only). /Included in US product label/

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


Estradiol tablets are indicated in the prevention of osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. /Included in US product label/

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


Estradiol is used to suppress postpartum breast engorgement in patients who do not desire to breast feed.

Briggs, G.G, R.K. Freeman, S.J. Yaffe. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 4th ed. Baltimore, MD: Williams & Wilkins 1994., p. 339


4.2 Drug Warning

ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER- Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of "natural" estrogens results in a different endometrial risk profile than "synthetic" estrogens at equivalent estrogen doses.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


CARDIOVASCULAR AND OTHER RISKS- Estrogens with or without progestins should not be used for the prevention of cardiovascular disease.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


Estrogens should not be used in individuals with any of the following conditions: Undiagnosed abnormal genital bleeding; Known, suspected or history of cancer of the breast except in appropriately selected patients being treated for metastatic disease; Known or suspected estrogen-dependent neoplasia; Active deep vein thrombosis, pulmonary embolism or history of these conditions; Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction); Liver dysfunction or disease.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


ESTRACE should not be used in patients with known hypersensitivity to its ingredients. ESTRACE (estradiol tablets, USP), 2 mg, contain FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


Some women have experienced moving or gliding of ESTRING within the vagina. Instances of ESTRING being expelled from the vagina in connection with moving the bowels, strain, or constipation have been reported. If this occurs, ESTRING can be rinsed in lukewarm water and reinserted into the vagina by the patient.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


ESTRING may not be suitable for women with narrow, short, or stenosed vaginas. Narrow vagina, vaginal stenosis, prolapse, and vaginal infections are conditions that make the vagina more susceptible to ESTRING-caused irritation or ulceration. Women with signs or symptoms of vaginal irritation should alert their physician.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


Vaginal infection is generally more common in postmenopausal women due to the lack of the normal flora of fertile women, especially lactobacillus, and the subsequent higher pH. Vaginal infections should be treated with appropriate antimicrobial therapy before initiation of ESTRING. If a vaginal infection develops during use of ESTRING, then ESTRING should be removed and reinserted only after the infection has been appropriately treated.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


A few cases of toxic shock syndrome (TSS) have been reported in women using vaginal rings. TSS is a rare, but serious disease that may cause death. Warning signs of TSS include fever, nausea, vomiting, diarrhea, muscle pain, dizziness, faintness, or a sunburn-rash on face and body.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


A few cases of ring adherence to the vaginal wall, making ring removal difficult, have been reported. Vaginal wall ulceration or erosion should be carefully evaluated. If an ulceration or erosion has occurred, consideration should be given to leaving the ring out and not replacing it until healing is complete in order to prevent the ring from adhering to the healing tissue.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


A few cases of bowel obstruction and vaginal ring use have been reported. Persistent abdominal complaints consistent with obstruction should be carefully evaluated.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


Removal of the system should be done carefully and slowly to avoid irritation of the skin. Should any adhesive remain on the skin after removal of the system, allow the area to dry for 15 minutes. Then gently rubbing the area with an oil-based cream or lotion should remove the adhesive residue. Used patches still contain some active hormones. Each patch should be carefully folded in half so that it sticks to itself before throwing it away.

US Natl Inst Health; DailyMed. Current Medication Information ESTRADIOL patch (September 2009). Available from, as of February 23, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=12806


Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Estradiol Transdermal System Continuous Delivery (Once-Weekly) is administered to a nursing woman.

US Natl Inst Health; DailyMed. Current Medication Information ESTRADIOL patch (September 2009). Available from, as of February 23, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=12806


FDA Pregnancy Risk Category: X /CONTRAINDICATED IN PREGNANCY. Studies in animals and or humans, or investigational or post-marketing reports, have demonstrated positive evidence of fetal abnormalities or risk which clearly outweighs any possible benefit to the patient./

US Natl Inst Health; DailyMed. Current Medication Information ESTRING (estradiol) ring (October 2009). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=11686


Nausea has been frequently associated with estrogen therapy. Other adverse GI effects include vomiting, abdominal cramps, bloating, and diarrhea. Changes in appetite and changes in weight may also occur. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3126


In patients with hypertriglyceridemia, estrogen therapy may be associated with further increases in plasma triglycerides resulting in pancreatitis and other complications. If acute pancreatitis occurs, estrogens should be discontinued. The risk of gallbladder disease appears to be increased 2- to 4-fold in postmenopausal women receiving estrogen replacement therapy. In one study, an increased risk of gallbladder disease occurred after 2 years of use of the drugs and doubled after 4 or 5 years of use. In another study, an increased risk of gallbladder disease was apparent between 6-12 months of use. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3126


The most frequent adverse dermatologic reaction associated with estrogen therapy is chloasma or melasma. Women who have had melasma during pregnancy appear to be most susceptible. Irregular brown macules may develop slowly on the face within 1 month to 2 years following initiation of estrogen therapy. The macules fade more slowly than in melasma gravidarum and may be permanent. Other dermatologic reactions include erythema multiforme, erythema nodosum, and hemorrhagic eruption. Hirsutism and alopecia have also occurred. Porphyria cutanea has reportedly been adversely affected in some women receiving estrogen therapy. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3126


While results from earlier observational studies indicated that estrogen replacement therapy or combined estrogen/progestin therapy was associated with cardiovascular benefit in postmenopausal women, results of the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women's Health Initiative (WHI) study indicate that use of estrogen replacement therapy (ERT) or combined estrogen/progestin replacement therapy (hormone replacement therapy, HRT) does not decrease the incidence of cardiovascular disease. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3124


There is no evidence that estrogen replacement therapy in postmenopausal women is associated with elevated blood pressure; in fact, unopposed estrogen therapy in postmenopausal women has been associated with blood pressure reductions in some studies. However, increases in blood pressure may occur in some women receiving estrogens, particularly if high dosages are used. Blood pressure elevations are usually minor, but clinically important hypertension may occur in some women. Elevated blood pressure may gradually decrease or persist after discontinuance of estrogen therapy. The precise cause of increased blood pressure is not known, but it may result from a stimulatory effect of estrogen on the renin-angiotensin system. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3126


Women receiving high dosages of estrogens or those with a history of hypertension, preexisting renal disease, a history of toxemia or elevated blood pressure during pregnancy, a familial tendency toward hypertension or its consequences, or a history of excessive weight gain or fluid retention during the menstrual cycle may be at increased risk of developing elevated blood pressure during estrogen therapy and, therefore, should be monitored closely. Even though elevated blood pressure may remain within the normal range, the clinical implications of elevations should be considered in all patients. All women, but particularly those with other risk factors for cardiovascular disease or stroke and those receiving high dosages of estrogens, should have blood pressure measurements before an estrogen is prescribed and at regular intervals during therapy. Estrogens should be discontinued if the patient becomes hypertensive during therapy. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3126


Results of a recent controlled study (WHI study) indicate that hormone replacement therapy, specifically conjugated estrogens 0.625 mg in conjunction with medroxyprogesterone acetate 2.5 mg daily, is associated with a small increase in the risk of cardiovascular disease. In the WHI estrogen plus progestin study, there was a 29% increase in the incidence of heart disease in postmenopausal women receiving hormone replacement therapy compared with those receiving placebo. The number of coronary heart disease (CHD) events (eg, myocardial infarction) per 10,000 patient-years of exposure was 37 or 30 in women receiving hormone replacement therapy or placebo, respectively. In the WHI estrogen-alone study, ERT did not affect the incidence of CHD. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3126


Estrogen replacement therapy and hormone (estrogen/progestin) replacement therapy are associated with an increased risk of venous thromboembolic events. Results of some studies indicate that the risk of venous thromboembolic events with estrogen or hormone replacement therapy is about 2-3 times greater than that in women not receiving such therapy. In the WHI estrogen plus progestin study, the rate of venous thromboembolism, deep-vein thrombosis, or pulmonary embolism in women receiving hormone replacement therapy was twice the rate of these events in women receiving placebo. The number of cases of venous thromboembolism per 10,000 patient-years of exposure was 34 or 16 in women receiving hormone replacement therapy or placebo, respectively. In the WHI estrogen-alone study, the incidence of deep-vein thrombosis was increased in women receiving estrogen compared with women receiving placebo. Venous thrombosis is more likely to occur during the first year of therapy; patients with risk factors for thrombosis are at increased risk of venous thrombosis. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3126


Data are conflicting on whether estrogen therapy alone or in combination with progestins is associated with an increased risk of stroke. While some studies suggest that estrogen replacement therapy may be associated with both an increased and a decreased risk of stroke in postmenopausal women, results from a large prospective study (the Nurses' Health Study) indicate no association between risk of stroke and use of estrogen replacement therapy either alone or in combination with progestins. In the WHI estrogen plus progestin study, there was a 41% increase in the incidence of stroke in postmenopausal women receiving hormone replacement therapy compared with those receiving placebo. The number of cases of stroke per 10,000 patient-years of exposure was 29 or 21 in women receiving hormone replacement therapy or placebo, respectively. In the WHI estrogen-alone study, there was a 39% increase in the incidence of stroke in women receiving estrogen compared with those receiving placebo. Approximately 80% of all strokes in the WHI estrogen-alone study were ischemic strokes. The number of cases of stroke per 10,000 patient-years of exposure was 44 or 32 in women receiving ERT or placebo, respectively; this represents an absolute excess risk of 12 additional strokes per 10,000 patient-years. The American Heart Association (AHA) states that hormone therapy should not be used to prevent stroke in postmenopausal women. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3126


In a study in men, large dosages (ie, 5 mg daily) of conjugated estrogens have been shown to increase the risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3126


The clinician and the patient using estrogens should be alert to the earliest signs and symptoms of thromboembolic and thrombotic disorders (eg, thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, coronary occlusion, retinal thrombosis, mesenteric thrombosis). Estrogen therapy should be discontinued immediately when any of these disorders occurs or is suspected. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3126


Estrogens may cause some degree of fluid retention and edema. Estrogen therapy should therefore be used with caution in patients with conditions that might be aggravated by fluid retention. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3126


Endocrine function test results (eg, glucose tolerance, thyroid function) may be altered in patients receiving large dosages of estrogens. Decreased glucose tolerance has occurred in women receiving estrogen-containing oral contraceptives and may occur in patients receiving large dosages of estrogens. Prediabetic and diabetic patients should be carefully monitored during estrogen therapy. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3126


Estrogens have reportedly caused severe hypercalcemia in patients with breast cancer and bone metastases. If severe hypercalcemia occurs, estrogen therapy should be discontinued and appropriate therapy to decrease serum calcium concentration should be instituted. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3127


Cholestasis is manifested by the development of malaise, anorexia, and pruritus about 2 weeks to 2 months after the start of therapy. Occasionally, arthralgia, fever, and rash may occur. Serum bilirubin may range from 3-10 mg/dL and is mostly conjugated. Women with a history of jaundice during pregnancy have an increased risk of jaundice recurrence while receiving estrogen-containing oral contraceptives. If jaundice occurs during estrogen therapy, the drug should be discontinued. Estrogens may precipitate hepatic forms of porphyria, and the drugs probably should not be used by women who have a familial history of hepatic porphyrias, since the occurrence of these conditions appears to be genetically determined. Steroid hormones (including estrogens) may be poorly metabolized in patients with hepatic dysfunction; therefore, estrogens should be administered with caution to these individuals. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3127


Liver tumors have been associated with use of estrogen-containing oral contraceptives. Liver tumors have been benign or malignant and have occurred during short-term and long-term use of oral contraceptives. Most commonly, liver tumors are benign hepatocellular adenomas and occur only rarely in oral contraceptive users; however, they may result in death because their vascularity predisposes them to rupture and cause massive hemorrhage. Although benign hepatocellular adenomas have not been reported to date with estrogens, the possibility of a liver tumor should be considered in any patient receiving an estrogen who develops sudden severe abdominal pain or shock. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3127


Changes in cervical erosion and secretions may occur during estrogen therapy. In addition, preexisting uterine leiomyoma may increase in size in women receiving estrogens. A cystitis-like syndrome has been reported but has not been definitely attributed to estrogens. An increased incidence of Candida vaginitis has been associated with estrogen therapy. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3127


The possibility that estrogen replacement therapy in postmenopausal women, particularly prolonged use, may be associated with an increased risk of endometrial or ovarian cancer should be considered. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3127


Mental depression may occur in patients receiving estrogens. In a few women receiving estrogen-containing oral contraceptives, mental depression was severe and led to suicidal behavior. Patients with a history of mental depression should be observed carefully and estrogens discontinued if severe depression recurs during use. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3127


Dizziness, changes in libido, and chorea have been reported in patients receiving estrogens.Headache, especially migraine headache, may occur during estrogen therapy. Estrogens should be discontinued and the cause evaluated when migraine occurs or is exacerbated, or when a new headache pattern develops that is recurrent, persistent, and/or severe. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3127


Estrogens have been reported to produce keratoconus (steepening of corneal curvature) and intolerance to contact lenses. Contact lens wearers who develop visual disturbances or changes in lens tolerance during estrogen therapy should be assessed by an ophthalmologist; temporary or permanent cessation of contact lens wear should be considered. Although neuro-ocular lesions such as optic neuritis or retinal thrombosis have been associated with use of estrogen-containing oral contraceptives, these lesions have not been reported to date with estrogens. If unexplained, sudden or gradual, partial or complete loss of vision; proptosis or diplopia; papilledema; or retinal vascular lesions occur during therapy with an estrogen, the drug should be discontinued and appropriate diagnostic and therapeutic measures instituted. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3127


Changes in various blood factors and blood components have been observed in women receiving estrogen-containing oral contraceptives and may occur in patients receiving estrogens; however, further studies are required before the clinical importance of these changes can be established. Estrogen (ERT) and hormone replacement therapy (estrogen/progestin, HRT) are associated with an increased risk of venous thromboembolic events in postmenopausal women. Increases in prothrombin and blood coagulation factors VII, VIII, IX, and X levels may occur in patients receiving estrogens; decreases in antithrombin III activity and decreased fibrinolysis also have been reported. In a clinical study in patients receiving conjugated estrogens in conjunction with medroxyprogesterone acetate, factors VII and X concentrations and plasminogen activity were increased and antithrombin III activity usually was decreased following 1 year of therapy. Estrogens may also enhance norepinephrine-induced platelet aggregation. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3127


Breast changes, including tenderness, enlargement, and secretion, may occur during estrogen therapy. The incidence of breast pain may be increased in patients receiving estrogens in conjunction with progestins compared with those receiving estrogens alone; breast pain was reported in about 33% of women receiving conjugated estrogens concomitantly with medroxyprogesterone acetate compared to 12% of women receiving unopposed conjugated estrogen therapy. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3127


Because of the potential increased risk of cardiovascular events, breast cancer, and venous thromboembolic events, estrogen and estrogen/progestin therapy should be limited to the lowest effective doses and shortest duration of therapy consistent with treatment goals and risks for the individual woman. Estrogen and estrogen/progestin therapy should be periodically reevaluated. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3127


Patients receiving estrogens should be informed to notify their physician if signs or symptoms of thromboembolic or thrombotic disorders (eg, thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, coronary occlusion, retinal thrombosis, mesenteric thrombosis) occur, including sudden severe headache or vomiting, disturbance of vision or speech, sudden partial or complete loss of vision, dizziness or faintness, weakness or numbness in an extremity, sharp or crushing chest pain, unexplained cough, hemoptysis, sudden shortness of breath, calf pain, or heaviness in the chest. If signs or symptoms consistent with a thromboembolic or thrombotic disorder occur, hormone replacement therapy (HRT) should be discontinued immediately. Use of ERT or HRT is not advised in women with a history of stroke or transient ischemic attacks. If hormone therapy is initiated or discontinued in a woman receiving oral anticoagulant therapy, effectiveness of the anticoagulant may be altered and dosage adjustment needed. Patients receiving estrogens should also be advised to inform their physician if abdominal pain, swelling, or tenderness (indicating possible gallbladder disease), or an abdominal mass (indicating a possible liver tumor), jaundice, severe mental depression, or unusual bleeding occurs. Since endometrial hyperplasia and endometrial carcinoma have been reported in women receiving estrogen therapy, adequate diagnostic tests should be performed in women with undiagnosed, persistent, or recurring abnormal vaginal bleeding. Women receiving estrogens should be instructed in self-examination of their breasts and should report lumps in the breast to their physician. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3127


Women undergoing surgery and those with fracture or who are immobilized have a relatively high risk of venous thromboembolic events. Therefore, estrogens should be discontinued, whenever feasible, at least 4 weeks prior to surgery that is associated with an increased risk of thromboembolism or prolonged immobilization. The decision as to when to resume estrogen therapy following major surgery or immobilization should be based on the risks of postsurgery thromboembolic complications and the need for such therapy. In addition, some clinicians recommend that women discontinue estrogen replacement therapy during immobilization due to fracture, stroke, or other severe illness; estrogen replacement therapy can be restarted when normal activity is resumed. Since acute pancreatitis, associated with increased triglyceride concentrations, has been reported in a few women receiving estrogens alone or in conjunction with a progestin, it is recommended that serum lipid concentrations be monitored prior to and during estrogen therapy. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3127


Because estrogens influence the metabolism of calcium and phosphorus, the drugs should be used with caution in patients with renal insufficiency and in patients with metabolic bone diseases that are associated with hypercalcemia. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3128


Metabolism of estrogens may be decreased in patients with impaired hepatic function. Caution is advised in patients with a history of cholestatic jaundice associated with estrogen use or pregnancy; if cholestatic jaundice recurs, estrogen therapy should be discontinued. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3128


Estrogens may exacerbate asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3128


Estrogens are contraindicated in patients with known or suspected pregnancy, undiagnosed abnormal genital bleeding, known or suspected breast cancer or a history of breast cancer (except when used for the palliative treatment of metastatic disease in appropriately selected individuals), or known or suspected estrogen-dependent neoplasia. Estrogens also are contraindicated in patients with active deep-vein thrombosis or pulmonary embolism, a history of deep-vein thrombosis or pulmonary embolism, active or recent (within the past year) arterial thromboembolic disease (eg, stroke, myocardial infarction), liver disease or impairment, or known hypersensitivity to estrogen or any ingredient in the formulation. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3128


Estrogen therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay. Safety and efficacy of estrogens in children have not otherwise been established. Estrogen therapy should be used with caution in young individuals in whom bone growth is not yet complete, since estrogens may cause premature closure of the epiphyses. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3128


When the total number of patients studied in the Women's Health Initiative (WHI) study is considered, 44-46% were 65 years of age or older, while 6.6-7.1% were 75 years of age or older. In the estrogen plus progestin WHI study, there was a higher relative risk of nonfatal stoke or breast cancer in women 75 years of age or older compared with women younger than 75 years of age. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3128


4.3 Drug Indication

Estradiol is indicated for the treatment of moderate to severe vasomotor symptoms and vulvar and vaginal atrophy due to menopause, for the treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure, and for the prevention of post-menopausal osteoarthritis. It is also used for the treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease, and for the treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).


FDA Label


Treatment of vaginal atrophy due to oestrogen deficiency in postmenopausal women when at least one lower dose topical oestrogen treatment has failed.


5 Pharmacology and Biochemistry
5.1 Pharmacology

Estradiol, the principal intracellular human estrogen, is substantially more active than its metabolites, estrone and estriol, at the cellular level.


Therapeutic Estradiol is a steroid sex hormone vital to the maintenance of fertility and secondary sexual characteristics in females. Typically esterified, estradiol derivatives are formulated for oral or parenteral administration. As the primary, most potent estrogen hormone produced by the ovaries, estradiol binds to and activates specific nuclear receptors. Estradiol exhibits mild anabolic and metabolic properties, and increases blood coagulability.


Estradiol Hemihydrate is the hemihydrate form of estradiol, the most potent, naturally produced estrogen. Estradiol hemihydrate diffuses through the cell membrane and binds to and subsequently activates the nuclear estrogen receptor found in the reproductive tract, breast, pituitary, hypothalamus, liver, and bone. The activated complex binds to the estrogen response element on the DNA and activates the transcription of genes involved in the functioning of the female reproductive system and secondary sex characteristics.


5.2 MeSH Pharmacological Classification

Estrogens

Compounds that interact with ESTROGEN RECEPTORS in target tissues to bring about the effects similar to those of ESTRADIOL. Estrogens stimulate the female reproductive organs, and the development of secondary female SEX CHARACTERISTICS. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds. (See all compounds classified as Estrogens.)


5.3 FDA Pharmacological Classification
5.3.1 Active Moiety

ESTRADIOL


5.3.2 FDA UNII

4TI98Z838E


5.3.3 Pharmacological Classes

Chemical/Ingredient structural concept [Chemical/Ingredient]

Estradiol Congeners


Established Pharmacologic Class [EPC]

Estrogen


Mechanisms of Action [MoA]

Estrogen Receptor Agonists


5.4 ATC Code

G - Genito urinary system and sex hormones

G03 - Sex hormones and modulators of the genital system

G03C - Estrogens

G03CA - Natural and semisynthetic estrogens, plain

G03CA03 - Estradiol


5.5 Absorption, Distribution and Excretion

Absorption

43%


Route of Elimination

Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates.


Estrogens used in therapeutics are well absorbed through the skin, mucous membranes, and the gastrointestinal (GI) tract. The vaginal delivery of estrogens circumvents first-pass metabolism.

US Natl Inst Health; DailyMed. Current Medication Information ESTRING (estradiol) ring (October 2009). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=11686


The Estradiol Transdermal System Continuous Delivery (Once-Weekly) continuously releases estradiol which is transported across intact skin leading to sustained circulating levels of estradiol during a 7 day treatment period. The systemic availability of estradiol after transdermal administration is about 20 times higher than that after oral administration. This difference is due to the absence of first-pass metabolism when estradiol is given by the transdermal route.

US Natl Inst Health; DailyMed. Current Medication Information ESTRADIOL patch (September 2009). Available from, as of February 23, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=12806


In a Phase I study of 14 postmenopausal women, the insertion of ESTRING (estradiol vaginal ring) rapidly increased serum estradiol (E2) levels. The time to attain peak serum estradiol levels (Tmax) was 0.5 to 1 hour. Peak serum estradiol concentrations post-initial burst declined rapidly over the next 24 hours and were virtually indistinguishable from the baseline mean (range: 5 to 22 pg/mL). Serum levels of estradiol and estrone (E1) over the following 12 weeks during which the ring was maintained in the vaginal vault remained relatively unchanged [See Table #5462 - PHARMACOKINETIC MEAN ESTIMATES FOLLOWING SINGLE ESTRING APPLICATION]

US Natl Inst Health; DailyMed. Current Medication Information ESTRING (estradiol) ring (October 2009). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=11686


Table #5462 - PHARMACOKINETIC MEAN ESTIMATES FOLLOWING SINGLE ESTRING APPLICATION


The initial estradiol peak post-application of the second ring in the same women resulted in ~38 percent lower Cmax, apparently due to reduced systemic absorption via the treated vaginal epithelium. The relative systemic exposure from the initial peak of ESTRING accounted for approximately 4 percent of the total estradiol exposure over the 12-week period.

US Natl Inst Health; DailyMed. Current Medication Information ESTRING (estradiol) ring (October 2009). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=11686


In postmenopausal women, mean dose of estradiol systemically absorbed unchanged from ESTRING is approximately 8 percent [95 percent CI: 2.8-12.8 percent] of the daily amount released locally.

US Natl Inst Health; DailyMed. Current Medication Information ESTRING (estradiol) ring (October 2009). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=11686


The mean steady-state levels (Cavg) of the estradiol during the application of Estradiol Transdermal System Continuous Delivery (Once-Weekly) 31 sq cm and 15.5 sq cm on the abdomen were about 80 pg/mL and 40 pg/mL, respectively.

US Natl Inst Health; DailyMed. Current Medication Information ESTRADIOL patch (September 2009). Available from, as of February 23, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=12806


In a 3 week multiple application study in 24 postmenopausal women, the 31 sq cm Estradiol Transdermal System Continuous Delivery (Once-Weekly) produced average peak estradiol concentrations (Cmax) of approximately 100 pg/mL. Trough values at the end of each wear interval (Cmin) were approximately 35 pg/mL. Nearly identical serum curves were seen each week, indicating little or no accumulation of estradiol in the body. Serum estrone peak and trough levels were 60 pg/mL and 40 pg/mL, respectively.

US Natl Inst Health; DailyMed. Current Medication Information ESTRADIOL patch (September 2009). Available from, as of February 23, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=12806


In a single-dose, randomized, crossover study conducted to compare the effect of site of application, 38 postmenopausal women wore a single Estradiol Transdermal System Continuous Delivery (Once-Weekly) 31 sq cm system for one week on the abdomen and buttocks. ... Cmax and Cavg values were, respectively, 25% and 17% higher with the buttock application than with the abdomen application. The relative standard deviation of each pharmacokinetic parameter after application to the abdomen averaged 50%, which is indicative of the considerable intersubject variability associated with transdermal drug delivery. The relative standard deviation of each pharmacokinetic parameter after application to the buttock was lower than that after application to the abdomen (e.g., for Cmax 39% vs. 62%, and for Cavg 35% vs. 48%). [See Table #5463 - Single-dose Pharmacokinetic Summary (Mean Estradiol Values)]

US Natl Inst Health; DailyMed. Current Medication Information ESTRADIOL patch (September 2009). Available from, as of February 23, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=12806


Table #5463 - Single-dose Pharmacokinetic Summary (Mean Estradiol Values)


The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


Mean percent dose excreted in the 24-hour urine as estradiol, 4 and 12 weeks post-application of ESTRING in a Phase I study was 5 percent and 8 percent, respectively, of the daily released amount.

US Natl Inst Health; DailyMed. Current Medication Information ESTRING (estradiol) ring (October 2009). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=11686


Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


Estrogens are excreted in milk. Potential for decreased milk volume and decreased nitrogen and protein content ...

Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995., p. 45-25


Various preparations of estradiol, such as crystalline estradiol, micronized estradiol and esterified estradiol (e.g. estradiol valerate, estradiol 3 benzoate, estradiol dipropionate), are used for post menopausal hormonal therapy. The absorption of these estradiol preparations differs, while the route of exposure remains the same. For example, crystalline estradiol applied dermally in a cream diffuses more readily through the skin to the systemic circulation than esterified estradiol, because estradiol is more lipophilic than its ester derivative. Similarly, micronized estradiol is absorbed more rapidly than crystalline estradiol because of its small particle size. The absorption of these estradiol preparations also depends on the dose administered and the route of administration.

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V72 474 (1999)


Daily oral administration of estradiol tablets results in large pulses of estradiol and estrone and exposes women to high concentrations of these compounds. Oral administration of the first estradiol tablet, 2 mg micronized estradiol, to 32 healthy post menopausal women resulted in a maximal plasma estradiol concentration of 1084 pg/mL 49 min after administration, which decreased rapidly during the subsequent 3 hr. Progressive accumulation of estradiol occurred until a steady state was reached. After the fifth tablet, the average concentration of estradiol was about 418 pg/mL, which was 12 times greater than that found when a transdermal patch was used. The estrone concentration reached a peak of 334 pg/mL 4.3 hr after the first administration and reached a steady state after the 14th daily administration. This average concentration of estrone was 9.4 times greater than that found when a transdermal patch was used.

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V72 474 (1999)


A comparison of the pharmacokinetic parameters of oral and sublingual administration of micronized estradiol to post menopausal women revealed that the time to the maximal concentration of estradiol was significantly different by the two routes of administration, being 1 hr or less for sublingual administration and 6.5-7.6 hr for oral administration. The maximal plasma concentration, terminal half life, area under the curve for the integral of the serum concentration over time (area under the curve) and oral clearance were also different with the two routes of administration. For example, after sublingual administration of 1 mg micronized estradiol, the maximal plasma estradiol concentration was 451 pg/mL, the terminal half life was 18 hr, the area under the curve was 2109 pg/mL per hr and the oral clearance was 7.6 L/hr per kg bw; after oral administration, these values were 34 pg/mL, 20.1 h, 823 pg/mL per hr and 27.2 L/hr per kg bw, respectively. The concentrations of estrone were not dependent on route of administration. Sublingual administration resulted in a significantly lower ratio of estrone to estradiol than oral administration during the 24 hr period.

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V72 476 (1999)


The pharmacokinetic parameters of estradiol (E2, CAS 50-28-2), free and total estrone (E1, CAS 53-16-7) were determined in 14 young women following a single oral administration of 2, 4 and 8 mg E2 and a single intravenous administration of 0.3 mg E2 in an open, intraindividual comparison with 4 treatments. The purpose of the study was to determine the absolute bioavailability of orally administered E2 in a larger group of women and to assess the inter- and intraindividual variability of basic pharmacokinetic parameters of E2 and metabolically derived E1. In addition, the outcome of this study should provide a basis for the decision whether E2 could potentially be used in a combination oral contraceptive. There was a dose proportional increase in the AUC-values following the oral administration of 2 mg and 4 mg doses of E2. At the high dose of 8 mg, however, only about 76%, 78% and 70% of the expected values were found for E2, free and total E1, respectively. Especially the reduction in total E1 concentrations points to an incomplete absorption of E2 at the high dose level. The absolute bioavailability of orally administered E2 was calculated based on the 4 mg dose and was found to be 4.9 +/- 5.0%. The mean ratio of free E1 and E2 concentrations in the serum, following parenteral and oral administration of E2 was about 1.0 (i.v.) and between 8.8 to 19.8 (p.o.), respectively. Pharmacokinetic parameters, like AUC, derived from serum level-time curves of E2, free and total E1 showed a high intra- and interindividual variability. PubMed Abstract

Kuhnz W et al; Arzneimittelforschung 43 (9): 966-73 (1993)


This study was designed to evaluate the steady-state pharmacokinetics (PK) of estradiol and its metabolites, estrone and estrone sulfate, following application of a novel estradiol transdermal spray to healthy postmenopausal women. Participants were randomly assigned in parallel to receive 1-, 2-, or 3-spray doses (24 participants/dose level) of a 1.7% estradiol metered-dose transdermal spray (1.53 mg/spray) once daily for 14 days. Blood was collected predose on days 1 to 14 and over 7 days after the last dose. Serum concentrations for all 3 analytes reached steady state by day 7 or 8 and were still slightly above baseline on day 21. Estradiol, estrone, and estrone sulfate serum concentrations generally increased with increasing dose. Mean estradiol and estrone maximum serum concentration (C(max)) following 1, 2, or 3 sprays for 14 days were 36 and 50, 57 and 60, and 54 and 71 pg/mL, respectively. Estradiol time when maximum concentration occurred (t(max)) was 18 to 20 hours. The area under the serum concentration-time curve over 24 hours following the last dose of study drug (AUC(0-24 hr)) on day 14 for the 1-, 2-, and 3-spray groups, respectively, was 471, 736, and 742 pg.hr/mL for estradiol; 886, 1208, and 1367 pg x hr/mL for estrone; and 16,501, 26,515, and 27,971 pg x hr/mL for estrone sulfate. The metered-dose estradiol transdermal spray delivers estradiol at therapeutic levels and produces low serum estrone concentrations. PubMed Abstract

Morton TL et al; J Clin Pharmacol 49 (9): 1037-46 (2009)


5.6 Metabolism/Metabolites

Metabolism

Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens. Estrogens are partially metabolized by cytochrome P450.


Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010:


Variations in estradiol metabolism ... depend upon the stage of the menstrual cycle ... In general, the hormone undergoes rapid hepatic biotransformation with a plasma half-life measured in minutes.

Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1420


Estradiol is primarily converted ... to estriol, which is the major urinary metabolite. A variety of sulfate and glucuronide conjugates also are excreted in the urine.

Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1420


The metabolism of estradiol-17beta and estrone is similar in rats and in humans, in that both species transform these steroids mainly by (aromatic) 2-hydroxylation, and also by 16alpha-hydroxylation. Glucuronides of the various metabolites are excreted in the bile. Differences in the metabolism of estrogens by humans and rats lie mostly in the type of conjugation. A relatively large proportion of administered estrone, estradiol-17beta and estriol is transformed in rats to metabolites oxygenated both at C-2 and C-16. When estriol is administered to rats, glucuronides and, to a lesser extent, sulfates of 16-ketooestradiol and of 2- and 3-methyl ethers of 2-hydroxyoestriol and 2-hydroxy-16-ketooestradiol are excreted in the bile. In contrast, hydroxylations at C-6 or C-7 of ring B of estradiol-17beta and estrone are a minor pathway in rats. 2-Hydroxyoestrogens ('catechol estrogens') are further transformed by various routes, including covalent binding to proteins.

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V21 307 (1979)


Rabbit liver can form 2-hydroxylated estriol. However, the presence of two enzymes unique to this organ leads to an estrogen metabolite pattern that cannot be compared with the human situation: (1) in addition to glucuronyltransferase, rabbit liver microsomes also contain glucosyl and N-acetylglucosaminyl transferases, which transfer glucose from UDP-glucose to the 3-hydroxy group of estrone and estradiol or N-acetylglucosamine from the UDP form to the 17alpha-hydroxy group of estradiol-17alpha; (2) in addition to microsomal and cytoplasmic 17beta-hydroxysteroid dehydrogenase, a 17beta-hydroxysteroid dehydrogenase is found in rabbit liver cytosol. Hence, the major metabolite of estrone or estradiol-17beta in rabbits is estradiol-17alpha, which is mainly conjugated to estradiol-17alpha-N-acetylglucosaminide or to estradiol-3glucuronide-17alpha-N-acetylglucosaminide. These metabolic pathways do not occur in man.

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V21 308 (1979)


Sulfates are the major conjugates of estradiol-17beta and estrone in guinea-pigs, and metabolism by 16alpha-hydroxylation is thought to take place on the estrone 3-sulfate. Glucuronidation, if any, plays only a minor role, in contrast to the human situation; 2-hydroxylation of estrone also occurs. Only small amounts of labelled estrone are converted to estradiol in guinea-pigs.

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V21 308 (1979)


Canine metabolism of estrogens differs greatly from that in humans. Only small amounts of labelled estradiol-17beta are converted to estriol; the bulk of the radioactive dose is excreted in urine as conjugates of estradiol-17beta and estrone. After administration of labelled estriol to dogs, a unique pattern of conjugates was found in bile and urine, probably including polyglucuronides. Furthermore, no significant enterohepatic circulation occurs, in contrast to the distribution of estrogenic hormones in most other species.

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V21 (1979)


Estradiol-17alpha is also a major estrogenic metabolite in some other species, including domestic fowl, bulls and sheep. Liver tissues of pigs contain significant amounts of 17beta-hydroxysteroid dehydrogenase and glucuronyl transferase; in minipigs, oxidoreduction at C-17 is the predominant reaction; whereas, in contrast to humans, hydroxylation of estrogens plays only a minor role. The metabolism of estrogens in these species thus differs markedly from that in humans.

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V21 310 (1979)


5.7 Biological Half-Life

36 hours


... After oral administration ... the terminal half life was 20.1 hr ...

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/ENG/Classification/index.php, p. V72 476 (1999)


5.8 Mechanism of Action

Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects [A31620]. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary.


Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level. ... After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

US Natl Inst Health; DailyMed. Current Medication Information estrace (estradiol) tablet (August 2006). Available from, as of February 22, 2010: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=1485


Estrogens have an important role in the reproductive, skeletal, cardiovascular, and central nervous systems in women, and act principally by regulating gene expression. Biologic response is initiated when estrogen binds to a ligand-binding domain of the estrogen receptor resulting in a conformational change that leads to gene transcription through specific estrogen response elements (ERE) of target gene promoters; subsequent activation or repression of the target gene is mediated through 2 distinct transactivation domains (ie, AF-1 and AF-2) of the receptor. The estrogen receptor also mediates gene transcription using different response elements (ie, AP-1) and other signal pathways. Recent advances in the molecular pharmacology of estrogen and estrogen receptors have resulted in the development of selective estrogen receptor modulators (eg, clomiphene, raloxifene, tamoxifen, toremifene), agents that bind and activate the estrogen receptor but that exhibit tissue-specific effects distinct from estrogen. Tissue-specific estrogen-agonist or -antagonist activity of these drugs appears to be related to structural differences in their estrogen receptor complex (eg, specifically the surface topography of AF-2 for raloxifene) compared with the estrogen (estradiol)-estrogen receptor complex. A second estrogen receptor also has been identified, and existence of at least 2 estrogen receptors (ER-alpha, ER-beta) may contribute to the tissue-specific activity of selective modulators. While the role of the estrogen receptor in bone, cardiovascular tissue, and the CNS continues to be studied, emerging evidence indicates that the mechanism of action of estrogen receptors in these tissues differs from the manner in which estrogen receptors function in reproductive tissue. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3130


Intracellular cytosol-binding proteins for estrogens have been identified in estrogen-responsive tissues including the female genital organs, breasts, pituitary, and hypothalamus. The estrogen-binding protein complex (ie, cytosol-binding protein and estrogen) distributes into the cell nucleus where it stimulates DNA, RNA, and protein synthesis. The presence of these receptor proteins is responsible for the palliative response to estrogen therapy in women with metastatic carcinoma of the breast. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3130


Estrogens have generally favorable effects on blood cholesterol and phospholipid concentrations. Estrogens reduce LDL-cholesterol and increase HDL-cholesterol concentrations in a dose-related manner. The decrease in LDL-cholesterol concentrations associated with estrogen therapy appears to result from increased LDL catabolism, while the increase in triglyceride concentrations is caused by increased production of large, triglyceride-rich, very-low-density lipoproteins (VLDLs); changes in serum HDL-cholesterol concentrations appear to result principally from an increase in the cholesterol and apolipoprotein A-1 content of HDL2- and a slight increase in HDL3-cholesterol. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3130


Estrogens have a weak anabolic effect and may cause sodium retention with associated fluid retention and edema. Estrogens also affect bone by increasing calcium deposition and accelerating epiphyseal closure, following initial growth stimulation. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3130


Other effects of estrogens that may contribute to effects on cardiovascular risk indicators include reduction of insulin and blood glucose concentrations and direct effects on blood vessels. Estrogen receptors have been identified in the heart and coronary arteries, suggesting that estrogens may have specific effects on these tissues. /Estrogen General Statement/

American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 3130


At the cellular level, estrogens increase the cellular synthesis of DNA, RNA, and various proteins in responsive tissues. Estrogens reduce the release of gonadotropin-releasing hormone from the hypothalamus, leading to a reduction in release of follicle-stimulating hormone and luteinizing hormone from the pituitary. /Estrogens/

USP. Convention. USPDI - Drug Information for the Health Care Professional. 19th ed. Volume I.Micromedex, Inc. Englewood, CO., 1999. Content Prepared by the U.S. Pharmacopieal Convention, Inc., p. 1384


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