Beta-estradiol, 17beta-estradiol, Estrace, Dihydrofolliculin, Oestradiol, Dihydrotheelin

Overview

  • CHEMISTRY

    View chemical information of Estradiol

  • chemwerth-inc-m-2019-06-17

Also known as: Beta-estradiol, 17beta-estradiol, Estrace, Dihydrofolliculin, Oestradiol, Dihydrotheelin
Molecular Formula
C18H24O2
Molecular Weight
272.38196  g/mol
InChI Key
VOXZDWNPVJITMN-ZBRFXRBCSA-N
FDA UNII
4TI98Z838E

Generally refers to the 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. In humans, it is produced primarily by the cyclic ovaries and the PLACENTA. It is also produced by the adipose tissue of men and postmenopausal women. The 17-alpha-isomer of estradiol binds weakly to estrogen receptors (RECEPTORS, ESTROGEN) and exhibits little estrogenic activity in estrogen-responsive tissues. Various isomers can be synthesized.
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

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. Estrace

7. Estraderm Tts

8. Estradiol 17 Alpha

9. Estradiol 17 Beta

10. Estradiol 17beta

11. Estradiol Hemihydrate

12. Estradiol Hemihydrate, (17 Alpha)-isomer

13. Estradiol Monohydrate

14. Estradiol Orion Brand

15. Estradiol, (+-)-isomer

16. Estradiol, (-)-isomer

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

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

19. Estradiol, (17-alpha)-isomer

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

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

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

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

24. Estradiol, Monosodium Salt

25. Estradiol, Sodium Salt

26. Estradiol-17 Alpha

27. Estradiol-17 Beta

28. Estradiol-17beta

29. Novartis Pharmaceuticals Brand Of Estradiol

30. Oestradiol

31. Orion Brand Of Estradiol

32. Ovocyclin

33. Vivelle

2.3.2 Depositor-Supplied Synonyms

1. Beta-estradiol

2. 17beta-estradiol

3. Estrace

4. Dihydrofolliculin

5. Oestradiol

6. Dihydrotheelin

7. Dihydroxyestrin

8. Divigel

9. Vivelle

10. Progynon

11. Diogynets

12. Femestral

13. Gynoestryl

14. Ovocyclin

15. Aerodiol

16. Aquadiol

17. Climara

18. Estradiol-17beta

19. Estrogel

20. Gynergon

21. Diogyn

22. Estraderm Tts

23. Oestroglandol

24. Corpagen

25. Dimenformon

26. Estrasorb

27. Estrovite

28. Follicyclin

29. Ginosedol

30. Macrodiol

31. Oestergon

32. Ovahormon

33. Ovasterol

34. Ovastevol

35. Perlatanol

36. Primofol

37. Profoliol

38. Altrad

39. Bardiol

40. Estring

41. Evorel

42. Femogen

43. Lamdiol

44. Syndiol

45. Vagifem

46. Dihydromenformon

47. Cis-estradiol

48. Progynon Dh

49. Climaderm

50. Compudose

51. Dermestril

52. Estraderm

53. Estraldine

54. Estroclim

55. Menorest

56. Nordicol

57. Trocosone

58. Encore

59. Innofem

60. Systen

61. Zumenon

62. Alora

63. 50-28-2

64. D-oestradiol

65. D-estradiol

66. Estroclim 50

67. Ovocycline

68. Elestrin

69. Oesclim

70. Ovocylin

71. Tradelia

72. Zerella

73. Menest

74. Dihydroxyoestrin

75. Dihydrofollicular Hormone

76. Sk-estrogens

77. Progynon-dh

78. Trial Sat

79. 17beta-oestradiol

80. Theelin, Dihydro-

81. Compudose 200

82. Compudose 365

83. Estrifam

84. Extrasorb

85. Fempatch

86. Femtrace

87. Ginedisc

88. Gynestrel

89. Gynodiol

90. Microdiol

91. Oestrogel

92. Oestrogynal

93. Ovociclina

94. Esclim

95. Estreva

96. Evamist

97. Femtran

98. Macrol

99. Estring Vaginal Ring

100. Gynpolar

101. Estrofem Forte

102. Oestradiol R

103. Sandrena Gel

104. Profoliol B

105. Estraderm Mx

106. Sisare Gel

107. Vivelle-dot

108. Estrofem 2

109. Estradiol-17 Beta

110. Amnestrogen

111. Estraderm Tts 50

112. Estradiolum

113. Oestradiolum

114. Estradot

115. Femestrol

116. Femring

117. Gelestra

118. Menostar

119. Zesteem

120. Dihydroxyesterin

121. Cis-oestradiol

122. Climara Forte

123. 3,17-epidihydroxyestratriene

124. B-estradiol

125. Oestradiol Berco

126. 17b-oestradiol

127. Sandrena 1

128. Epiestriol 50

129. 17beta Oestradiol

130. Estraderm (tn)

131. Oestradiol-17beta

132. [3h]-estradiol

133. 17

134. A-estradiol

135. 17

136. A-oestradiol

137. Estrapak 50

138. 17-beta-estradiol

139. Estrogel (tn)

140. 17 Beta-estradiol

141. Climara (tn)

142. Divigel (tn)

143. Estrace (tn)

144. Estradiol-17-beta

145. Estring (tn)

146. Innofem (tn)

147. Vagifem (tn)

148. Vivelle (tn)

149. Estradiolum [inn]

150. Estradiolo [dcit]

151. Oestradiol-17-beta

152. Nsc-9895

153. Estradiol-3,17beta

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

155. Destradiol

156. Estradiolo

157. Estrodiolum

158. Polyestradiol

159. 17-beta-oh-estradiol

160. 3,17-beta-estradiol

161. Femanest

162. Zesteen

163. 3,17-beta-oestradiol

164. D-3,17beta-estradiol

165. Chebi:16469

166. E(sub 2)

167. 1jgl

168. 1qkt

169. 1qku

170. .beta.-estradiol

171. .beta.-oestradiol

172. Estrasorb (tn)

173. [3h]]estradiol

174. .alpha.-oestradiol

175. Ccris 280

176. Prestwick_207

177. Bio-e-gel

178. 3,17-epidihydroxyoestratriene

179. Component Of Menrium

180. Unii-4ti98z838e

181. 17-beta

182. 17.beta.-estradiol

183. 3,17beta-estradiol

184. Estradiol, .beta.-

185. Estradiol-17.beta.

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

187. S1709_selleck

188. 17.beta.-oestradiol

189. Dimenformon Prolongatum

190. Oestradiol-17.beta.

191. Estraderm Tts 100

192. Hsdb 3589

193. 17-beta-oh-oestradiol

194. Estradiol [usan:inn]

195. 3,17.beta.-estradiol

196. D-3,17beta-oestradiol

197. 17-.beta.-estradiol

198. Prestwick0_000441

199. Prestwick1_000441

200. Prestwick2_000441

201. Prestwick3_000441

202. Spectrum5_002055

203. 17beta Estradiol (e2)

204. Einecs 200-023-8

205. Estrodiolum [inn-latin]

206. D-3,17-beta-estradiol

207. Bmse000642

208. Chembl135

209. D-3,17-beta-oestradiol

210. Ac1l1l2k

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

212. Lopac0_000503

213. Bidd:pxr0065

214. Ncgc00091544-04

215. Bspbio_000482

216. Bspbio_001065

217. Kbiogr_000405

218. Kbiogr_002269

219. Kbioss_000405

220. Kbioss_002270

221. Bidd:er0125

222. Bio-0812

223. E1024_sigma

224. E1132_sigma

225. E2257_sigma

226. E2758_sigma

227. E8875_sigma

228. Spbio_002421

229. Mls000069494

230. Mls000758312

231. Mls001076331

232. Bpbio1_000532

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

234. Kbio2_000405

235. Kbio2_002269

236. Kbio2_002973

237. Kbio2_004837

238. Kbio2_005541

239. Kbio2_007405

240. Kbio3_000769

241. Kbio3_000770

242. Kbio3_002749

243. 2d06

244. Cmap_000005

245. Cpd-352

246. Nsc9895

247. 17beta-estra-1,3,5(10)-triene-3,17-diol

248. .alpha.-estradiol

249. Bio1_000403

250. Bio1_000892

251. Bio1_001381

252. Bio2_000363

253. Bio2_000843

254. Hms1362e07

255. Hms1569i04

256. Hms1792e07

257. Hms1990e07

258. Hms2051c17

259. Hms2090e18

260. (17beta)-estra-1(10),2,4-triene-3,17-diol

261. C18h24o2

262. 1,3,5-estratriene-3,17beta-diol

263. Cmc_11154

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

265. Lmst02010001

266. Ls-137

267. 1,3,5-estratriene-3,17-beta-diol

268. Db00783

269. E2

270. Sl-1100

271. Idi1_002118

272. Smp1_000121

273. 3,17beta-dihydroxyestra-1,3,5-triene

274. Ncgc00091544-00

275. Ncgc00091544-01

276. Ncgc00091544-02

277. Ncgc00091544-05

278. Ncgc00091544-06

279. Ncgc00091544-07

280. Ncgc00091544-09

281. Ncgc00091544-12

282. Ncgc00179321-01

283. Ncgc00179321-02

284. 17-e

285. 3,17beta-dihydroxyoestra-1,3,5-triene

286. Ac-10460

287. Cpd000059126

288. Sam001247032

289. Smr000059126

290. 3,17-beta-dihydroxyoestra-1,3,5-triene

291. 3,17b-dihydroxyestra-1,3,5(10)-triene

292. Dsstox_cid_573

293. E0025

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

295. Eu-0100503

296. 3,17beta-dihydroxy-1,3,5(10)-estratriene

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

298. 3,17-beta-dihydroxyestra-1,3,5(10)-triene

299. C00951

300. D00105

301. E 8875

302. 17beta-oestra-1,3,5(10)-triene-3,17-diol

303. 3,17-beta-dihydroxy-1,3,5(10)-oestratriene

304. Dsstox_rid_75666

305. 17-beta-estra-1,3,5(10)-triene-3,17-diol

306. 17-beta-oestra-1,3,5(10)-triene-3,17-diol

307. Dsstox_gsid_20573

308. S-21400

309. [2,4,6,7-3h]-e2

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

311. (8r,9s,13s,14s,17s)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol

312. 17e

313. 73459-61-7

314. 873662-39-6

315. E 2

316. 3,3,5(10)-triene

317. Oestrodiol

318. Elestrim

319. Minivelle

320. Delta-estradiol

321. Dihydro-theelin

322. 17

323. A-estradiol, Oestradiol, 17

324. A-oestradiol,

325. A-estradiol , Estradiol

326. Estrogel Hbf

327. 1lhu

328. [3h]estradiol

329. 17b-estradiol

330. Cid5757

331. Climara, Menostar

332. Lio-oid

333. Cas-50-28-2

334. Ncgc00091544-08

335. Estradiol - Acrux

336. 3,17b-estradiol

337. [3h]-estrogen

338. Nchembio.76-comp2

339. Nchembio775-comp2

340. Nchembio794-comp6

341. Nchembio860-comp1

342. Nchembio.168-comp3

343. 2j7x

344. 3,3,5-triene

345. [3h]17beta-estradiol

346. Surecn8049

347. 17.beta.-oh-estradiol

348. 17.beta.-oh-oestradiol

349. 17beta-estradiol (e2)

350. Alpha-estradiol (obsolete)

351. Epitope Id:136018

352. (+)-3,17b-estradiol

353. D-3,17.beta.-estradiol

354. (+)-3,17beta-estradiol

355. D-3,17.beta.-oestradiol

356. Estradiol (jan/usp/inn)

357. Estradiol [usp:inn:ban]

358. Oestradiol-17beta And Esters

359. Mls001424022

360. Gtpl1012

361. Gtpl1013

362. Hmdb00151

363. 1a52

364. 1g50

365. Molport-001-794-632

366. 4ti98z838e

367. Hms2096i04

368. Hms2236h04

369. Hms3261f07

370. (8s,9s,13s,14s,17s)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol

371. Acn-s003579

372. Delta-oestradiol;estradiol-17-beta

373. Hy-b0141

374. Tox21_111148

375. Tox21_202057

376. Tox21_300288

377. [3h]e2

378. 1,5-estratriene-3,17.beta.-diol

379. Dap000854

380. Dnc000620

381. Zinc13520815

382. Akos015896570

383. Ccg-100808

384. Cs-1938

385. Estradiol-supplied By Selleck Chemicals

386. Lp00503

387. Nc00058

388. 1,3,5(10)-estratriene-3,17b-diol

389. Ncgc00091544-10

390. Ncgc00091544-11

391. Ncgc00091544-13

392. Ncgc00091544-14

393. Ncgc00091544-15

394. Ncgc00091544-16

395. Ncgc00254177-01

396. Ncgc00259606-01

397. Bc200811

398. H061

399. Sy017569

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

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

402. Wln: L E5 B666ttt&j E1 Fq Oq

403. Ab2000237

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

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

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

407. 3,17beta-dihydroxyestra-1,3,5(10)-triene

408. 3,17-dihydroxy-delta(1,3,5-10)-estratriene

409. Z-4415

410. (17b)-estra-1,3,5(10)-triene-3,17-diol

411. 13b-methyl-1,3,5(10)-gonatriene-3,17b-ol

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

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

414. 13beta-methyl-1,3,5(10)-gonatriene-3,17beta-ol

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

416. I06-2405

417. Brd-k18910433-001-04-4

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

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

420. 17

421. A-estradiol;oestradiol;17

422. A-oestradiol;

423. A-estradiol

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

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

426. (13s,17s)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6h-cyclopenta[a]phenanthrene-3,17-beta-diol

427. (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

428. 1050677-52-5

429. 1206475-11-7

2.3.3 Other Synonyms

1. Angeliq-1

2. Climara Pro

3. Combipatch

4. Estradiol And Norethindrone Acetate

5. Estradiol And Norgestimate

6. Estratab

7. Menrium 10-4-1

2.4 Create Date
2004-09-16
3 Chemical and Physical Properties
Molecular Weight 272.38196 g/mol
Molecular Formula C18H24O2
XLogP34
Hydrogen Bond Donor Count2
Hydrogen Bond Acceptor Count2
Rotatable Bond Count0
Exact Mass272.17763 g/mol
Monoisotopic Mass272.17763 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 Drug Information
1 of 38  
Drug NameAlora
PubMed HealthEstradiol
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Hormonal Contraceptive, Musculoskeletal Agent
Drug LabelAlora (Estradiol Transdermal System, USP) is designed to deliver estradiol continuously and consistently over a 3 or 4-day interval upon application to intact skin. Four strengths of Alora are available, having nominal in vivo delivery rates of 0.025...
Active IngredientEstradiol
Dosage FormFilm, extended release
Routetransdermal; Transdermal
Strength0.025mg/24hr; 0.05mg/24hr; 0.1mg/24hr; n/a; 0.075mg/24hr
Market StatusPrescription
CompanyWatson Labs

2 of 38  
Drug NameClimara
PubMed HealthEstradiol
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Hormonal Contraceptive, Musculoskeletal Agent
Drug LabelClimara (estradiol transdermal system), is designed to release estradiol continuously upon application to intact skin. Six (6.5, 9.375, 12.5, 15, 18.75 and 25 cm2) systems are available to provide nominal in vivo delivery of 0.025, 0.0375, 0.05, 0.06...
Active IngredientEstradiol
Dosage FormFilm, extended release
RouteTransdermal
Strength0.025mg/24hr; 0.05mg/24hr; 0.0375mg/24hr; 0.1mg/24hr; 0.075mg/24hr; 0.06mg/24hr
Market StatusPrescription
CompanyBayer Hlthcare

3 of 38  
Drug NameDivigel
PubMed HealthEstradiol (Absorbed through the skin)
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Musculoskeletal Agent
Drug LabelDivigel (estradiol gel) 0.1% is a clear, colorless gel, which is odorless when dry. It is designed to deliver sustained circulating concentrations of estradiol when applied once daily to the skin. The gel is applied to a small area (200 cm2) of the...
Active IngredientEstradiol
Dosage FormGel
RouteTransdermal
Strength0.1% (1gm/packet); 0.1% (0.25gm/packet); 0.1% (0.5gm/packet)
Market StatusPrescription
CompanyVertical Pharms

4 of 38  
Drug NameElestrin
PubMed HealthEstradiol (Vaginal)
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent
Drug LabelElestrin (estradiol gel) contains 0.06% estradiol in a hydroalcoholic gel base. The gel is applied onto the skin in a thin layer. The recommended area of application is the upper arm to shoulder (approximately 320 cm2). One pump actuation delivers...
Active IngredientEstradiol
Dosage FormGel, metered
RouteTransdermal
Strength0.06% (0.87gm/activation)
Market StatusPrescription
CompanyMeda Pharms

5 of 38  
Drug NameEstrace
PubMed HealthEstradiol
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Hormonal Contraceptive, Musculoskeletal Agent
Drug LabelEach gram of ESTRACE (estradiol vaginal cream, USP, 0.01%) contains 0.1 mg estradiol in a nonliquefying base containing purified water, propylene glycol, stearyl alcohol, white ceresin wax, mono- and di-glycerides, hypromellose 2208 (4000 cps), sod...
Active IngredientEstradiol
Dosage FormCream
RouteVaginal
Strength0.01%
Market StatusPrescription
CompanyWarner Chilcott Us

6 of 38  
Drug NameEstraderm
PubMed HealthEstradiol (Absorbed through the skin)
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Musculoskeletal Agent
Drug LabelEstraderm (estradiol transdermal system) is designed to release estradiol through a rate-limiting membrane continuously upon application to intact skin.Two systems are available to provide nominal in vivo delivery of 0.05 or 0.1 mg of estradi...
Active IngredientEstradiol
Dosage FormFilm, extended release
RouteTransdermal
Strength0.05mg/24hr; 0.1mg/24hr
Market StatusPrescription
CompanyNovartis

7 of 38  
Drug NameEstradiol
PubMed HealthEstradiol
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Hormonal Contraceptive, Musculoskeletal Agent
Drug LabelVivelle-Dot (estradiol transdermal system) contains estradiol in a multipolymeric adhesive. The system is designed to release estradiol continuously upon application to intact skin. Five dosage strengths of Vivelle-Dot are available to p...
Active IngredientEstradiol
Dosage FormTablet; Film, extended release
Routetransdermal; Transdermal; Oral
Strength0.05mg/24hr; 0.025mg/24hr; 0.0375mg/24hr; 0.5mg; 0.1mg/24hr; 2mg; 0.075mg/24hr; 1mg; 0.06mg/24hr
Market StatusPrescription
CompanyWatson Labs; Usl Pharma; Mylan Technologies; Barr Labs; Mylan

8 of 38  
Drug NameEstrasorb
PubMed HealthEstrogen (Oral route, Parenteral route, Topical application route, Transdermal route)
Drug ClassesAntineoplastic Agent, Endocrine-Metabolic Agent, Musculoskeletal Agent
Drug LabelEstrasorb (estradiol topical emulsion) is designed to deliver estradiol to the blood circulation following topical application of an emulsion. Each gram of Estrasorb contains 2.5 mg of estradiol hemihydrate USP, EP, which is encapsulated using a...
Active IngredientEstradiol hemihydrate
Dosage FormEmulsion
RouteTopical
Strength0.25%
Market StatusPrescription
CompanyMedicis

9 of 38  
Drug NameEstring
PubMed HealthEsterified Estrogens (By mouth)
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Hormonal Contraceptive, Musculoskeletal Agent
Drug LabelESTRING (estradiol vaginal ring) is a slightly opaque ring with a whitish core containing a drug reservoir of 2 mg estradiol. Estradiol, silicone polymers and barium sulfate are combined to form the ring. When placed in the vagina, ESTRING releases...
Active IngredientEstradiol
Dosage FormInsert, extended release
RouteVaginal
Strength0.0075mg/24hr
Market StatusPrescription
CompanyPharmacia And Upjohn

10 of 38  
Drug NameEstrogel
PubMed HealthEstradiol
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Hormonal Contraceptive, Musculoskeletal Agent
Drug LabelEstroGel (estradiol gel) contains 0.06 percent estradiol in an absorptive hydroalcoholic gel base for topical application. It is a clear, colorless gel, which is odorless when dry. One pump depression of EstroGel delivers 1.25g of gel containing 0....
Active IngredientEstradiol
Dosage FormGel, metered
RouteTransdermal
Strength0.06% (1.25gm/activation)
Market StatusPrescription
CompanyAscend Theraps Us

11 of 38  
Drug NameEvamist
PubMed HealthEstradiol
Drug ClassesEndocrine-Metabolic Agent, Musculoskeletal Agent
Drug LabelEvamist (estradiol transdermal spray) is designed to deliver estradiol to the blood circulation following topical application to the skin of a rapidly drying solution from a metered-dose pump.Evamist is a homogeneous solution of 1.7% estradiol USP (a...
Active IngredientEstradiol
Dosage FormSpray
RouteTransdermal
Strength1.53mg/spray
Market StatusPrescription
CompanyLumara Health

12 of 38  
Drug NameFemring
PubMed HealthEstrogen (Oral route, Parenteral route, Topical application route, Transdermal route)
Active IngredientEstradiol acetate
Dosage FormInsert, extended release
RouteVaginal
Strengtheq 0.05mg base/24hr; eq 0.1mg base/24hr
Market StatusPrescription
CompanyWarner Ireland

13 of 38  
Drug NameFemtrace
PubMed HealthEstradiol Patch (Absorbed through the skin)
Active IngredientEstradiol acetate
Dosage FormTablet
RouteOral
Strength0.45mg; 1.8mg; 0.9mg
Market StatusPrescription
CompanyWarner Chilcott

14 of 38  
Drug NameMenest
Drug LabelMenostar (estradiol transdermal system) is designed to provide nominal in vivo delivery of 14 mcg of estradiol per day continuously upon application to intact skin. The period of use is 7 days. The transdermal system has a contact surface area of 3.2...
Active IngredientEstrogens, esterified
Dosage FormTablet
RouteOral
Strength2.5mg; 1.25mg; 0.625mg; 0.3mg
Market StatusPrescription
CompanyMonarch Pharms

15 of 38  
Drug NameMenostar
Drug LabelMINIVELLE (estradiol transdermal system) contains estradiol in a multipolymeric adhesive. The system is designed to release estradiol continuously upon application to intact skin.Five dosage strengths of MINIVELLE are available to provide nominal in...
Active IngredientEstradiol
Dosage FormFilm, extended release
RouteTransdermal
Strength0.014mg/24hr
Market StatusPrescription
CompanyBayer Hlthcare

16 of 38  
Drug NameMinivelle
Drug LabelVagifem 10 mcg (estradiol vaginal tablets) are small, white, film-coated tablets containing 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. Vagifem 25 mcg (estradiol vaginal tablets) are small, white, film-coated tablets containi...
Active IngredientEstradiol
Dosage FormFilm, extended release
RouteTransdermal
Strength0.05mg/24hr; 0.0375mg/24hr; 0.1mg/24hr; 0.075mg/24hr
Market StatusPrescription
CompanyNoven

17 of 38  
Drug NameVagifem
Drug LabelVivelle-Dot (estradiol transdermal system) contains estradiol in a multipolymeric adhesive. The system is designed to release estradiol continuously upon application to intact skin. Five dosage strengths of Vivelle-Dot are available to p...
Active IngredientEstradiol
Dosage FormTablet
RouteVaginal
Strength10mcg
Market StatusPrescription
CompanyNovo Nordisk

18 of 38  
Drug NameVivelle
Drug LabelVivelle-Dot (estradiol transdermal system) contains estradiol in a multipolymeric adhesive. The system is designed to release estradiol continuously upon application to intact skin. Five dosage strengths of Vivelle-Dot are available to p...
Active IngredientEstradiol
Dosage FormFilm, extended release
Routetransdermal; Transdermal
Strength0.05mg/24hr; 0.1mg/24hr
Market StatusPrescription
CompanyNovartis

19 of 38  
Drug NameVivelle-dot
Active IngredientEstradiol
Dosage FormFilm, extended release
RouteTransdermal
Strength0.05mg/24hr; 0.0375mg/24hr; 0.1mg/24hr; 0.025mg/24hr; 0.075mg/24hr
Market StatusPrescription
CompanyNovartis

20 of 38  
Drug NameAlora
PubMed HealthEstradiol
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Hormonal Contraceptive, Musculoskeletal Agent
Drug LabelAlora (Estradiol Transdermal System, USP) is designed to deliver estradiol continuously and consistently over a 3 or 4-day interval upon application to intact skin. Four strengths of Alora are available, having nominal in vivo delivery rates of 0.025...
Active IngredientEstradiol
Dosage FormFilm, extended release
Routetransdermal; Transdermal
Strength0.025mg/24hr; 0.05mg/24hr; 0.1mg/24hr; n/a; 0.075mg/24hr
Market StatusPrescription
CompanyWatson Labs

21 of 38  
Drug NameClimara
PubMed HealthEstradiol
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Hormonal Contraceptive, Musculoskeletal Agent
Drug LabelClimara (estradiol transdermal system), is designed to release estradiol continuously upon application to intact skin. Six (6.5, 9.375, 12.5, 15, 18.75 and 25 cm2) systems are available to provide nominal in vivo delivery of 0.025, 0.0375, 0.05, 0.06...
Active IngredientEstradiol
Dosage FormFilm, extended release
RouteTransdermal
Strength0.025mg/24hr; 0.05mg/24hr; 0.0375mg/24hr; 0.1mg/24hr; 0.075mg/24hr; 0.06mg/24hr
Market StatusPrescription
CompanyBayer Hlthcare

22 of 38  
Drug NameDivigel
PubMed HealthEstradiol (Absorbed through the skin)
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Musculoskeletal Agent
Drug LabelDivigel (estradiol gel) 0.1% is a clear, colorless gel, which is odorless when dry. It is designed to deliver sustained circulating concentrations of estradiol when applied once daily to the skin. The gel is applied to a small area (200 cm2) of the...
Active IngredientEstradiol
Dosage FormGel
RouteTransdermal
Strength0.1% (1gm/packet); 0.1% (0.25gm/packet); 0.1% (0.5gm/packet)
Market StatusPrescription
CompanyVertical Pharms

23 of 38  
Drug NameElestrin
PubMed HealthEstradiol (Vaginal)
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent
Drug LabelElestrin (estradiol gel) contains 0.06% estradiol in a hydroalcoholic gel base. The gel is applied onto the skin in a thin layer. The recommended area of application is the upper arm to shoulder (approximately 320 cm2). One pump actuation delivers...
Active IngredientEstradiol
Dosage FormGel, metered
RouteTransdermal
Strength0.06% (0.87gm/activation)
Market StatusPrescription
CompanyMeda Pharms

24 of 38  
Drug NameEstrace
PubMed HealthEstradiol
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Hormonal Contraceptive, Musculoskeletal Agent
Drug LabelEach gram of ESTRACE (estradiol vaginal cream, USP, 0.01%) contains 0.1 mg estradiol in a nonliquefying base containing purified water, propylene glycol, stearyl alcohol, white ceresin wax, mono- and di-glycerides, hypromellose 2208 (4000 cps), sod...
Active IngredientEstradiol
Dosage FormCream
RouteVaginal
Strength0.01%
Market StatusPrescription
CompanyWarner Chilcott Us

25 of 38  
Drug NameEstraderm
PubMed HealthEstradiol (Absorbed through the skin)
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Musculoskeletal Agent
Drug LabelEstraderm (estradiol transdermal system) is designed to release estradiol through a rate-limiting membrane continuously upon application to intact skin.Two systems are available to provide nominal in vivo delivery of 0.05 or 0.1 mg of estradi...
Active IngredientEstradiol
Dosage FormFilm, extended release
RouteTransdermal
Strength0.05mg/24hr; 0.1mg/24hr
Market StatusPrescription
CompanyNovartis

26 of 38  
Drug NameEstradiol
PubMed HealthEstradiol
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Hormonal Contraceptive, Musculoskeletal Agent
Drug LabelVivelle-Dot (estradiol transdermal system) contains estradiol in a multipolymeric adhesive. The system is designed to release estradiol continuously upon application to intact skin. Five dosage strengths of Vivelle-Dot are available to p...
Active IngredientEstradiol
Dosage FormTablet; Film, extended release
Routetransdermal; Transdermal; Oral
Strength0.05mg/24hr; 0.025mg/24hr; 0.0375mg/24hr; 0.5mg; 0.1mg/24hr; 2mg; 0.075mg/24hr; 1mg; 0.06mg/24hr
Market StatusPrescription
CompanyWatson Labs; Usl Pharma; Mylan Technologies; Barr Labs; Mylan

27 of 38  
Drug NameEstrasorb
PubMed HealthEstrogen (Oral route, Parenteral route, Topical application route, Transdermal route)
Drug ClassesAntineoplastic Agent, Endocrine-Metabolic Agent, Musculoskeletal Agent
Drug LabelEstrasorb (estradiol topical emulsion) is designed to deliver estradiol to the blood circulation following topical application of an emulsion. Each gram of Estrasorb contains 2.5 mg of estradiol hemihydrate USP, EP, which is encapsulated using a...
Active IngredientEstradiol hemihydrate
Dosage FormEmulsion
RouteTopical
Strength0.25%
Market StatusPrescription
CompanyMedicis

28 of 38  
Drug NameEstring
PubMed HealthEsterified Estrogens (By mouth)
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Hormonal Contraceptive, Musculoskeletal Agent
Drug LabelESTRING (estradiol vaginal ring) is a slightly opaque ring with a whitish core containing a drug reservoir of 2 mg estradiol. Estradiol, silicone polymers and barium sulfate are combined to form the ring. When placed in the vagina, ESTRING releases...
Active IngredientEstradiol
Dosage FormInsert, extended release
RouteVaginal
Strength0.0075mg/24hr
Market StatusPrescription
CompanyPharmacia And Upjohn

29 of 38  
Drug NameEstrogel
PubMed HealthEstradiol
Drug ClassesEndocrine-Metabolic Agent, Female Reproductive Agent, Hormonal Contraceptive, Musculoskeletal Agent
Drug LabelEstroGel (estradiol gel) contains 0.06 percent estradiol in an absorptive hydroalcoholic gel base for topical application. It is a clear, colorless gel, which is odorless when dry. One pump depression of EstroGel delivers 1.25g of gel containing 0....
Active IngredientEstradiol
Dosage FormGel, metered
RouteTransdermal
Strength0.06% (1.25gm/activation)
Market StatusPrescription
CompanyAscend Theraps Us

30 of 38  
Drug NameEvamist
PubMed HealthEstradiol
Drug ClassesEndocrine-Metabolic Agent, Musculoskeletal Agent
Drug LabelEvamist (estradiol transdermal spray) is designed to deliver estradiol to the blood circulation following topical application to the skin of a rapidly drying solution from a metered-dose pump.Evamist is a homogeneous solution of 1.7% estradiol USP (a...
Active IngredientEstradiol
Dosage FormSpray
RouteTransdermal
Strength1.53mg/spray
Market StatusPrescription
CompanyLumara Health

31 of 38  
Drug NameFemring
PubMed HealthEstrogen (Oral route, Parenteral route, Topical application route, Transdermal route)
Active IngredientEstradiol acetate
Dosage FormInsert, extended release
RouteVaginal
Strengtheq 0.05mg base/24hr; eq 0.1mg base/24hr
Market StatusPrescription
CompanyWarner Ireland

32 of 38  
Drug NameFemtrace
PubMed HealthEstradiol Patch (Absorbed through the skin)
Active IngredientEstradiol acetate
Dosage FormTablet
RouteOral
Strength0.45mg; 1.8mg; 0.9mg
Market StatusPrescription
CompanyWarner Chilcott

33 of 38  
Drug NameMenest
Drug LabelMenostar (estradiol transdermal system) is designed to provide nominal in vivo delivery of 14 mcg of estradiol per day continuously upon application to intact skin. The period of use is 7 days. The transdermal system has a contact surface area of 3.2...
Active IngredientEstrogens, esterified
Dosage FormTablet
RouteOral
Strength2.5mg; 1.25mg; 0.625mg; 0.3mg
Market StatusPrescription
CompanyMonarch Pharms

34 of 38  
Drug NameMenostar
Drug LabelMINIVELLE (estradiol transdermal system) contains estradiol in a multipolymeric adhesive. The system is designed to release estradiol continuously upon application to intact skin.Five dosage strengths of MINIVELLE are available to provide nominal in...
Active IngredientEstradiol
Dosage FormFilm, extended release
RouteTransdermal
Strength0.014mg/24hr
Market StatusPrescription
CompanyBayer Hlthcare

35 of 38  
Drug NameMinivelle
Drug LabelVagifem 10 mcg (estradiol vaginal tablets) are small, white, film-coated tablets containing 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. Vagifem 25 mcg (estradiol vaginal tablets) are small, white, film-coated tablets containi...
Active IngredientEstradiol
Dosage FormFilm, extended release
RouteTransdermal
Strength0.05mg/24hr; 0.0375mg/24hr; 0.1mg/24hr; 0.075mg/24hr
Market StatusPrescription
CompanyNoven

36 of 38  
Drug NameVagifem
Drug LabelVivelle-Dot (estradiol transdermal system) contains estradiol in a multipolymeric adhesive. The system is designed to release estradiol continuously upon application to intact skin. Five dosage strengths of Vivelle-Dot are available to p...
Active IngredientEstradiol
Dosage FormTablet
RouteVaginal
Strength10mcg
Market StatusPrescription
CompanyNovo Nordisk

37 of 38  
Drug NameVivelle
Drug LabelVivelle-Dot (estradiol transdermal system) contains estradiol in a multipolymeric adhesive. The system is designed to release estradiol continuously upon application to intact skin. Five dosage strengths of Vivelle-Dot are available to p...
Active IngredientEstradiol
Dosage FormFilm, extended release
Routetransdermal; Transdermal
Strength0.05mg/24hr; 0.1mg/24hr
Market StatusPrescription
CompanyNovartis

38 of 38  
Drug NameVivelle-dot
Active IngredientEstradiol
Dosage FormFilm, extended release
RouteTransdermal
Strength0.05mg/24hr; 0.0375mg/24hr; 0.1mg/24hr; 0.025mg/24hr; 0.075mg/24hr
Market StatusPrescription
CompanyNovartis

4.2 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


4.3 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


4.4 Drug Indication

For the treatment of urogenital symptoms associated with post-menopausal atrophy of the vagina (such as dryness, burning, pruritus and dyspareunia) and/or the lower urinary tract (urinary urgency and dysuria).


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.


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.


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

G03CA03 - Estradiol < G03CA - Natural and semisynthetic estrogens, plain < G03C - Estrogens < G03 - Sex hormones and modulators of the genital system < G - Genito urinary system and sex hormones



5.5 Absorption, Distribution and Excretion

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 <table border="1"><b><center>PHARMACOKINETIC MEAN ESTIMATES FOLLOWING SINGLE ESTRING APPLICATION</center></b> <br><tr><th>Estrogen </th><th>Cmax (pg/mL) </th><th>Css-48 hr (pg/mL) </th><th>Css-4weeks (pg/mL) </th><th>Css-12weeks (pg/mL) </th></tr><tr><td>Estradiol (E2) </td><td>63.2 </td><td>11.2 </td><td>9.5 </td><td>8.0 </td></tr><tr><td>Baseline-adjusted E2 </td><td>55.6 </td><td>3.6 </td><td>2.0 </td><td>0.4 </td></tr><tr><td>Estrone (E1) </td><td>66.3 </td><td>52.5 </td><td>43.8 </td><td>47.0 </td></tr><tr><td>Baseline-adjusted E1 </td><td>20.0 </td><td>6.2 </td><td>-2.4 </td><td>0.8 </td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr></table>

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 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%). <table border="1"><b><center>Single-dose Pharmacokinetic Summary (Mean Estradiol Values)</center></b> <br><tr><th>Estradiol Delivery Rate (mg) </th><th>Surface Area (sq cm) </th><th>Application Site </th><th>Cmax (pg/mL) </th><th>Cavg (pg/mL) </th></tr><tr><td>0.025 </td><td>7.75 </td><td>Abdomen </td><td>32 </td><td>22 </td></tr><tr><td>0.05 </td><td>15.5 </td><td>Abdomen </td><td>71 </td><td>41 </td></tr><tr><td>0.1 </td><td>31 </td><td>Abdomen </td><td>147 </td><td>87 </td></tr><tr><td>0.1 </td><td>31 </td><td>Buttock </td><td>174 </td><td>106 </td></tr><tr><td></td><td></td><td></td><td></td><td></td></tr></table>

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


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 Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/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 Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/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 Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/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.

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.

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


Absorption

43%


Route of Elimination

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


5.6 Metabolism/Metabolites

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

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.


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

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.


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

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 Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V21 308 (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 Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/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 Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V21 (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 Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V21 310 (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 Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V21 310 (1979)

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


5.7 Biological Half-Life

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

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


36 hours

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


5.8 Mechanism of Action

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


Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. 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.

IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: http://monographs.iarc.fr/index.php, p. V21 287 (1979)


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