From Wikipedia, the free encyclopedia
Jump to: navigation, search
Not to be confused with 17α-estradiol. ‹See Tfd›
Systematic (IUPAC) name
Clinical data
Trade names Climara, Menostar
AHFS/ monograph
Pregnancy cat. X (USA)
Routes Oral, transdermal
Pharmacokinetic data
Bioavailability 97–99% is bound
Metabolism Liver
Half-life ~13-17 hours
Excretion Urine, and sweat glands
CAS number 50-28-2 YesY
ATC code G03CA03
PubChem CID 5757
IUPHAR ligand 1012
DrugBank DB00783
ChemSpider 5554 YesY
UNII 4TI98Z838E YesY
KEGG D00105 YesY
ChEBI CHEBI:16469 YesY
Chemical data
Formula C18H24O2 
Mol. mass 272.38 g/mol
 YesY (what is this?)  (verify)


Estradiol or oestradiol (American or British English usages), derives from estra-, Gk. οἶστρος (oistros, literally meaning "verve or inspiration")[4] and -diol, a chemical name and suffix indicating that this form of steroid and sex hormone is a type of alcohol bearing two hydroxyl groups.

Estradiol is produced especially within the follicles of female ovaries, but also in other endocrine (i.e., hormone-producing) and non-endocrine tissues (e.g., including fat, liver, adrenal, breast, and neural tissues). Estradiol is biosynthesized from progesterone (arrived at in two steps from cholesterol, via intermediate pregnenolone).[citation needed] One principle pathway then converts progesterone to its 17-hyroxy-derivative, and then to androstenedione via sequential cytochrome P450-catalyzed oxidations.[citation needed] Action of aromatase on this dione generates estrone, and action of a dehydrogenase on this gives the title compound, 17β-estradiol.[citation needed]


Female reproduction[edit]


Sexual development[edit]

The development of secondary sex characteristics in women is driven by estrogens, to be specific, estradiol. These changes are initiated at the time of puberty, most are enhanced during the reproductive years, and become less pronounced with declining estradiol support after the menopause. Thus, estradiol enhances breast development, and is responsible for changes in the body shape, affecting bones, joints and fat deposition. Fat structure and skin composition are modified by estradiol.[citation needed]

Male reproduction[edit]

The effect of estradiol (and estrogens) upon male reproduction is complex. Estradiol is produced by action of aromatase mainly in the Leydig cells of the mammalian testis, but also by some germ cells and the Sertoli cells of immature mammals.[5] It functions (in vitro) to prevent apoptosis of male sperm cells.[6]

Several studies have noted sperm counts have been declining in many parts of the world, and estrogen exposure in the environment has been postulated to be the cause.[7] Suppression of estradiol production in a subpopulation of subfertile men may improve the semen analysis.[8]

Males with sex chromosome genetic conditions, such as Klinefelters syndrome, will have a higher level of estradiol.[9]


Estradiol has a profound effect on bone. Individuals without it (or other estrogens) will become tall and eunuchoid, as epiphyseal closure is delayed or may not take place. Bone structure is affected also, resulting in early osteopenia and osteoporosis.[10] Also, women past menopause experience an accelerated loss of bone mass due to a relative estrogen deficiency.[11]


Estradiol has complex effects on the liver. It can lead to cholestasis. It affects the production of multiple proteins, including lipoproteins, binding proteins, and proteins responsible for blood clotting.[citation needed]



The positive and negative feedback loops of the menstrual cycle involve ovarian estradiol as the link to the hypothalamic-pituitary system to regulate gonadotropins.[13] (See Hypothalamic–pituitary–gonadal axis.)


Recently, the volumes of sexually dimorphic brain structures in phenotypical males were found to change and approximate typical female brain structures when exposed to estradiol over a period of months,[16] suggesting estradiol has a significant part to play in sex differentiation of the brain, both prenatally and throughout life.

There is also evidence the programming of adult male sexual behavior in many vertebrates is largely dependent on estradiol produced during prenatal life and early infancy.[17] It is not yet known whether this process plays a significant role in human sexual behavior, although evidence from other mammals tends to indicate a connection.[18]

Blood vessels[edit]

Estrogen affects certain blood vessels. Improvement in arterial blood flow has been demonstrated in coronary arteries.[19]


Estrogen is suspected to activate certain oncogenes, as it supports certain cancers, notably breast cancer and cancer of the uterine lining. In addition, several benign gynecologic conditions are dependent on estrogen, such as endometriosis, leiomyomata uteri, and uterine bleeding.[citation needed]



Medical uses[edit]

Nolvadex (tamoxifen) 20 mg
Arimidex (anastrozole) 1 mg
See also: Estrogen patch

Hormonal contraception[edit]

A chemical derivative of estradiol, ethinyl estradiol with maximum dosage 200 µg,[20] is a major component of hormonal contraceptive devices. Combined forms of hormonal contraception contain ethinyl estradiol and a progestin, which both contribute to the inhibition of GnRH, LH, and FSH, which accounts for the ability of these birth control methods to prevent ovulation and thus prevent pregnancy. Other types of hormonal birth control contain only progestins and no ethinyl estradiol.[21]

Hormone replacement therapy[edit]

If severe side effects of low levels of estradiol in a woman's blood are experienced (commonly at the beginning of menopause or after oophorectomy), hormone replacement therapy may be prescribed. Such therapy is usually combined with a progestin to reduce the risk of endometrial cancer.[22]

Estrogen therapy may be used in treatment of infertility in women when there is a need to develop sperm-friendly cervical mucus or an appropriate uterine lining. This is often prescribed in combination with clomifene.[citation needed]

Estrogen therapy can also be used to treat advanced prostate cancer, as well as to relieve symptoms of breast cancer.[23][24]

Estrogen therapy is also used as part of the hormone replacement therapy for trans women. Either oral or transdermal estradiol is used in higher concentrations during initial treatment and transition; estradiol is continued in lower doses to maintain female-level hormones following gender reassignment surgery.[25]

Not all products are available worldwide. Estradiol is also part of conjugated estrogen preparations, such as Premarin, though it is not the major ingredient. (Premarin consists of a large number of estrogen derivatives. As the name indicates, it comes from pregnant mares' urine.)[26]

Blocking estrogens[edit]

Inducing a state of hypoestrogenism may be beneficial in certain situations where estrogens are contributing to unwanted effects, e.g., certain forms of breast cancer, gynecomastia, and premature closure of epiphyses. Estrogen levels can be reduced by inhibiting production using gonadotropin-releasing factor agonists (GnRH agonists) or blocking the aromatase enzyme using an aromatase inhibitor, such as anastrozole, or with an estrogen receptor antagonist, such as tamoxifen.

Estradiol medications[edit]

Estrogen is marketed in a number of ways to address issues of hypoestrogenism. Thus, there are oral, transdermal, topical, injectable, and vaginal preparations. Furthermore, the estradiol molecule may be linked to an alkyl group at C17 (sometimes also at C3) position to facilitate the administration. Such modifications give rise to estradiol acetate (oral and vaginal applications) and to estradiol cypionate (injectable).

Oral preparations are not necessarily predictably absorbed, and are subject to a first pass through the liver, where they can be metabolized, and also initiate unwanted side effects. Therefore, alternative routes of administration that bypass the liver before primary target organs are hit have been developed. Transdermal and transvaginal routes are not subject to the initial liver passage.

Ethinyl estradiol, the most common estrogen ingredient in combined oral contraceptive pills, is a more profound alteration of the estradiol structure.

List of estradiol medications[edit]

  • Gel: Estrogel, Estrasorb, Estraderm
  • Oral versions: estradiol (Estrace), estradiol hemihydrate (Estrofem), estradiol acetate (Femtrace), estradiol valerate (Estrofem, Progynova)
  • Transdermal patches: Alora, Climara, Minivelle, Vivelle-Dot, Menostar, Estraderm
  • Topical Spray: EvaMist
  • Ointments: Divigel, Estrasorb Topical, Elestrin
  • Injection: estradiol benzoate, estradiol cypionate, estradiol valerate
  • Vaginal ointment: Estrace Vaginal Cream
  • Vaginal ring: Estring (estradiol), Femring (estradiol acetate)
  • Vaginal tablet: Vagifem (estradiol hemihydrate)
  • Estradiol combined with a progestin: CombiPatch (transdermal), Activella (oral), AngeliQ (oral)

Estradiol hemihydrate[edit]

Estradiol hemihydrate (INN; brand names Climara, Estraderm, Estralis, Estrasorb, Estreva, Estring, Estrofem, Estrogel, Vagifem, many others), or oestradiol hemihydrate, is the hemihydrate form of estradiol.[27] In terms of activity and bioequivalence, estradiol and its hemihydrate are identical, with the only disparities being an approximate 1% difference in potency by weight (due to the presence of water molecules in the hemihydrate form of the substance) and a slower rate of release with certain formulations of the hemihydrate.[28][29] This is because estradiol hemihydrate is more hydrated than anhydrous estradiol, and for that reason, is highly insoluble in water in comparison, which results in slower absorption rates with specific formulations such as Vagifem, a vaginal tablet form of the drug.[29] Estradiol hemihydrate has also been shown to result in less systemic absorption as a vaginal tablet formulation relative to other topical estradiol formulations such as vaginal creams.[30]

Adverse effects[edit]




Estradiol has been tied to the development and progression of cancers such as breast cancer, ovarian cancer and endometrial cancer. Estradiol effects target tissues by interacting with two nuclear hormone receptors called estrogen receptor α (ERα) and estrogen receptor β (ERβ).[33][34] One of the functions of these estrogen receptors is gene expression. Once the hormone binds to the estrogen receptors, the hormone-receptor complexes then bind to specific DNA sequences, possibly causing damage to the DNA and an increase in cell division and DNA replication. Eukaryotic cells respond to damaged DNA by stimulating or impairing G1, S, or G2 phases of the cell cycle to initiate DNA repair. As a result, cellular transformation and cancer cell proliferation occurs.[35]


St John's wort, phenobarbital, carbamazepine and rifampicin decrease the levels of estrogens, such as estradiol, by speeding up its metabolism, whereas erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may slow down metabolism, leading to increased levels in the blood plasma.[31]


Estradiol should be avoided when there is undiagnosed abnormal genital bleeding, known, suspected or a history of breast cancer, current treatment for metastatic disease, known or suspected estrogen-dependent neoplasia, deep vein thrombosis, pulmonary embolism or history of these conditions, active or recent arterial thromboembolic disease such as stroke, myocardial infarction, liver dysfunction or disease. Estradiol should not be taken by people with a hypersensitivity/allergy or those who are pregnant or are suspected pregnant.[31]

Synthesis and localization[edit]

Conversion of testosterone to estradiol

Estradiol, like other steroids, is derived from cholesterol. After side chain cleavage and using the delta-5 or the delta-4 pathway, androstenedione is the key intermediary. A fraction of the androstenedione is converted to testosterone, which in turn undergoes conversion to estradiol by an enzyme called aromatase. In an alternative pathway, androstenedione is aromatized to estrone, which is subsequently converted to estradiol.[36]


Estradiol is not produced in the gonads only, in particular, fat cells produce active precursors to estradiol, and will continue to do so even after menopause.[22] Estradiol is also produced in the brain and in arterial walls, though it cannot be readily transferred from the circulatory system into the brain.[37] However, as one of the two active metabolites of testosterone in males (the other being dihydrotestosterone), it can be produced from this hormone within the brain.

The biosynthesis of estradiol has been observed in various other species, as indicated above, but also in such species as Phaseolus vulgaris.[relevant? ][38]

Mechanism of action[edit]

Estradiol acts primarily as an agonist of the estrogen receptor (ER), a nuclear steroid hormone receptor. There are two subtypes of the ER, ERα and ERβ, and estradiol potently binds to and activates both of these receptors. The result of ER activation is a modulation of gene transcription and expression in ER-expressing cells, which is the predominant mechanism by which estradiol mediates its biological effects in the body. Estradiol also acts as an agonist of the intracellular membrane receptor GPER, a recently-discovered non-nuclear estrogen receptor, through which it can mediate a variety of rapid, non-genomic effects.[39] Unlike the case of the ER, GPER appears to be selective for estradiol, and shows very low affinities for other endogenous estrogens, such as estrone and estriol.[40]


In plasma, estradiol is largely bound to sex hormone-binding globulin, also to albumin. Only a fraction of 2.21% (± 0.04%) is free and biologically active, the percentage remaining constant throughout the menstrual cycle.[41] Deactivation includes conversion to less-active estrogens, such as estrone and estriol. Estriol is the major urinary metabolite. Estradiol is conjugated in the liver by sulfate and glucuronide formation and, as such, excreted via the kidneys. Some of the water-soluble conjugates are excreted via the bile duct, and partly reabsorbed after hydrolysis from the intestinal tract. This enterohepatic circulation contributes to maintaining estradiol levels.

In the liver, estradiol is non-specifically metabolized by CYP1A2, CYP3A4, and CYP2C9 via 2-hydroxylation into 2-hydroxyestradiol, and by CYP2C9, CYP2C19, and CYP2C8 via 17β-hydroxy dehydrogenation into estrone,[42] with various other cytochrome P450 (CYP) enzymes and metabolic transformations also being involved.[43] As a result, cimetidine, a known, non-selective inhibitor of CYP450 enzymes, can increase the levels of exogenous, orally-ingested estradiol.[42]

Levels and potency of estrogens[edit]

As the name implies, estradiol, sometimes abbreviated E2, has two hydroxyl groups in its molecular structure; its relatives estrone (E1) and estriol (E3) have one and three, respectively.[citation needed] Based on its unique chemcial structure, estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect.[citation needed] During the reproductive years of the human female, its serum levels are somewhat higher than that of estrone, except during the early follicular phase of the menstrual cycle; thus, estradiol may be considered the predominant estrogen during human female reproductive years in terms of absolute serum levels and estrogenic activity.[citation needed] During pregnancy estriol becomes the predominant circulating estrogen, while during menopause, estrone predominates (both based on serum levels).[citation needed] The estradiol produced by male humans, from testosterone, is present at serum levels roughly comparable to postmenopausal women (14-55 versus <35 pg/mL, respectively).[citation needed]





Reference ranges for the blood content of estradiol during the menstrual cycle
Reference ranges for serum estradiol
Patient type Lower limit Upper limit Unit
Adult male 50[44] 200[44] pmol/L
14 55 pg/mL
Adult female (follicular
, day 5)
95% PI (standard)
95% PI
90% PI (used
in diagram)
90% PI
30 (90% PI) 60 (90% PI)
Adult female (preovulatory
400[44] 1500[44] pmol/L
110 410 pg/mL
Adult female
(luteal phase)
70[44] 600[44] pmol/L
19 160 pg/mL
Adult female - free
(not protein bound)
0.5[46][original research?] 9[46][original research?] pg/mL
1.7[46][original research?] 33[46][original research?] pmol/L
Post-menopausal female N/A[44] < 130[44] pmol/L
N/A < 35 pg/mL



See also[edit]


  2. ^ Mechoulam R, Brueggemeier RW, Denlinger DL (September 2025). "Estrogens in insects". Cellular and Molecular Life Sciences 40 (9): 942–944. doi:10.1007/BF01946450. 
  5. ^ Carreau S, Lambard S, Delalande C, Denis-Galeraud I, Bilinska B, Bourguiba S (2003). "Aromatase expression and role of estrogens in male gonad : a review". Reproductive Biology and Endocrinology 1: 35. doi:10.1186/1477-7827-1-35. PMC 155680. PMID 12747806. 
  6. ^ Pentikäinen V, Erkkilä K, Suomalainen L, Parvinen M, Dunkel L (2000). "Estradiol acts as a germ cell survival factor in the human testis in vitro". The Journal of Clinical Endocrinology and Metabolism 85 (5): 2057–67. doi:10.1210/jc.85.5.2057. PMID 10843196. 
  7. ^ Sharpe RM, Skakkebaek NE (1993). "Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract?". Lancet 341 (8857): 1392–5. doi:10.1016/0140-6736(93)90953-E. PMID 8098802. 
  8. ^ Raman JD, Schlegel PN (2002). "Aromatase inhibitors for male infertility". The Journal of Urology 167 (2 Pt 1): 624–9. doi:10.1016/S0022-5347(01)69099-2. PMID 11792932. 
  9. ^ Visootsak J, Graham JM (2006). "Klinefelter syndrome and other sex chromosomal anueploidies". Orphanet Journal of Rare Diseases 1 (42): 42. doi:10.1186/1750-1172-1-42. PMC 1634840. PMID 17062147. Retrieved 20 November 2013. 
  10. ^ Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER (1997). "Effect of testosterone and estradiol in a man with aromatase deficiency". The New England Journal of Medicine 337 (2): 91–5. doi:10.1056/NEJM199707103370204. PMID 9211678. 
  11. ^ Albright, Fuller; Smith Patricia H., Richardson Anna M. (31 May 1941). "Postmenopausal Osteoporosis: Its Clinical Features". JAMA 116 (22): 2465–2474. doi:10.1001/jama.1941.02820220007002. Retrieved 20 November 2013. 
  14. ^ Douma SL, Husband C, O'Donnell ME, Barwin BN, Woodend AK (2005). "Estrogen-related mood disorders: reproductive life cycle factors". ANS Adv Nurs Sci 28 (4): 364–75. doi:10.1097/00012272-200510000-00008. PMID 16292022. 
  16. ^ Hulshoff HE, Cohen-Kettenis PT, Van Haren NE, Peper JS, Brans RG, Cahn W, Schnack HG, Gooren LJ Kahn RS (July 2006). "Changing your sex changes your brain: influences of testosterone and estrogen on adult human brain structure". European Journal of Endocrinology 155 (155): 107–114. doi:10.1530/eje.1.02248. 
  17. ^ Harding CF (June 2004). "Hormonal Modulation of Singing: Hormonal Modulation of the Songbird Brain and Singing Behavior". Ann. N.Y. Acad. Sci. (The New York Academy of Sciences) 1016: 524–539. doi:10.1196/annals.1298.030. PMID 15313793. Retrieved 2007-03-07. 
  20. ^ 韋伯顧問醫師 (2011-08-09). "【您應該知道的避孕常識 9】事後緊急避孕" [Common contraception knowledge you shall know (Part 9): Emergency contraception after sex] (in zh-hant). Retrieved 2012-07-02. 
  22. ^ a b Mutschler, Ernst; Schäfer-Korting, Monika (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 434, 444. ISBN 3-8047-1763-2. 
  23. ^ Ockrim JL, Lalani el-N, Kakkar AK, Abel PD (August 2005). "Transdermal estradiol therapy for prostate cancer reduces thrombophilic activation and protects against thromboembolism". J. Urol. 174 (2): 527–33; discussion 532–3. doi:10.1097/01.ju.0000165567.99142.1f. PMID 16006886. 
  24. ^ Carruba G, Pfeffer U, Fecarotta E, Coviello DA, D'Amato E, Lo Castro M, Vidali G, Castagnetta L (March 1994). "Estradiol inhibits growth of hormone-nonresponsive PC3 human prostate cancer cells". Cancer Res. 54 (5): 1190–3. PMID 8118804. 
  25. ^
  26. ^ Premarin Official FDA information, side effects and uses.
  27. ^ Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. pp. 406–. ISBN 978-3-88763-075-1. Retrieved 13 September 2012. 
  28. ^ IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research On Cancer (2007). Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. World Health Organization. p. 384. ISBN 978-92-832-1291-1. Retrieved 13 September 2012. 
  29. ^ a b Archana Desai; Mary Lee (7 May 2007). Gibaldi's Drug Delivery Systems in Pharmaceutical Care. ASHP. p. 337. ISBN 978-1-58528-136-7. Retrieved 13 September 2012. 
  30. ^ Rebekah Wang-Cheng; Joan M. Neuner (May 2007). Menopause. ACP Press. p. 96. ISBN 978-1-930513-83-9. Retrieved 13 September 2012. 
  31. ^ a b c d Barr Laboratories, Inc. (March 2008). "ESTRACE TABLETS, (estradiol tablets, USP)" (PDF). Retrieved 27 January 2010. 
  32. ^ Pfizer (August 2008). "ESTRING (estradiol vaginal ring)" (PDF). 
  33. ^ Bulzomi P, Bolli A, Galluzzo P, Leone S, Acconcia F, Marino M (January 2010). "Naringenin and 17β-estradiol coadministration prevents hormone-induced human cancer cell growth". IUBMD Life 62 (1): 51–60. doi:10.1002/iub.279. PMID 19960539. 
  34. ^ Sreeja S, Santhosh Kumar TR, Lakshmi BS, Sreeja S (17 March 2011). "Pomegranate extract demonstrate a selective estrogen receptor modulator profile in human tumor cell lines and in vivo models of estrogen deprivation". Journal of Nutritional Biochemistry 23 (7): 725–32. doi:10.1016/j.jnutbio.2011.03.015. PMID 21839626. 
  35. ^ Thomas CG, Strom A, Lindberg K, Gustafsson JA (22 June 2010). "Estrogen receptor beta decreases survival of p53-defective cancer cells after DNA damage by impairing G2/M checkpoint signaling". Breast Cancer Research and Treatment 127 (2): 417–427. doi:10.1007/s10549-010-1011-z. PMID 20623183. 
  36. ^ Walter F. Boron, Emile L. Boulpaep (2003). Medical Physiology: A Cellular And Molecular Approach. Elsevier/Saunders. p. 1300. ISBN 1-4160-2328-3. 
  37. ^ Pardridge WM, Mietus LJ (July 1979). "Transport of Steroid Hormones through the Rat Blood-Brain Barrier". Journal of Clinical Investigation 64 (1): 145–154. doi:10.1172/JCI109433. PMC 372100. PMID 447850. 
  38. ^ Young, I. J.; Hillman, J. R.; Knights, B. A. (1978). "Endogenous Estradiol-17 β in Phaseolus vulgaris". Zeitschrift für Pflanzenphysiologie 90: 45. doi:10.1016/S0044-328X(78)80223-2. 
  39. ^ Prossnitz ER, Barton M (May 2014). "Estrogen biology: New insights into GPER function and clinical opportunities". Mol. Cell. Endocrinol. 389 (1-2): 71–83. doi:10.1016/j.mce.2014.02.002. PMID 24530924. 
  40. ^ Prossnitz ER, Arterburn JB, Sklar LA (February 2007). "GPR30: A G protein-coupled receptor for estrogen". Mol. Cell. Endocrinol. 265-266: 138–42. doi:10.1016/j.mce.2006.12.010. PMC 1847610. PMID 17222505. 
  43. ^ Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT (August 2003). "Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms". Endocrinology 144 (8): 3382–98. doi:10.1210/en.2003-0192. PMID 12865317. 
  44. ^ a b c d e f g h i j GPNotebook — reference range (oestradiol) Retrieved on September 27, 2009

External links[edit]

Additional images[edit]