Estradiol (medication)

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Estradiol
Estradiol.svg
Estradiol 3D ball.png
Clinical data
Pronunciation/ˌɛstrəˈdl/ ES-trə-DY-ohl[1][2]
Trade namesNumerous
Other namesOestradiol; E2; 17β-Estradiol; Estra-1,3,5(10)-triene-3,17β-diol
AHFS/Drugs.comMonograph
Pregnancy
category
  • AU: B1
  • US: X (Contraindicated)
Routes of
administration
By mouth (tablet)
Sublingual (tablet)
Intranasal (nasal spray)
Transdermal (patch, gel, cream, emulsion, spray)
Vaginal (tablet, cream, suppository, insert, ring)
IM injection (oil solution)
SC injection (aq. soln.)
Subcutaneous implant
Drug classEstrogen
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityOral: <5%[3]
IM: 100%[4]
Protein binding~98%:[3][5]
Albumin: 60%
SHBG: 38%
• Free: 2%
MetabolismLiver (via hydroxylation, sulfation, glucuronidation)
MetabolitesMajor (90%):[3]
Estrone
Estrone sulfate
Estrone glucuronide
Estradiol glucuronide
Elimination half-lifeOral: 13–20 hours[3]
Sublingual: 8–18 hours[6]
Transdermal (gel): 37 hours[7]
IM (as EV): 4–5 days[4]
IM (as EC): 8–10 days[8]
IV (as E2): 1–2 hours[4]
ExcretionUrine: 54%[3]
Feces: 6%[3]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC18H24O2
Molar mass272.388 g·mol−1
3D model (JSmol)
  (verify)

Estradiol (E2) is a medication and naturally occurring steroid hormone.[9][10][11] It is an estrogen and is used mainly in menopausal hormone therapy and to treat low sex hormone levels in women.[9][12] It is also used in hormonal birth control for women, in hormone therapy for transgender women, and in the treatment of hormone-sensitive cancers like prostate cancer in men and breast cancer in women, among other uses.[13][14][15][16][17] Estradiol can be taken by mouth, held and dissolved under the tongue, as a gel or patch that is applied to the skin, in through the vagina, by injection into muscle or fat, or through the use of an implant that is placed into fat, among other routes.[9]

Side effects of estradiol in women include breast tenderness, breast enlargement, headache, fluid retention, and nausea among others.[9][18] Men and children who are exposed to estradiol may develop symptoms of feminization, such as breast development and a feminine pattern of fat distribution, and men may also experience low testosterone levels and infertility.[19][20] Estradiol may increase the risk of endometrial hyperplasia and endometrial cancer in women with intact uteruses if it is not taken together with a progestogen such as progesterone.[9] The combination of estradiol with a progestin, though not with oral progesterone, may increase the risk of breast cancer.[21][22] Estradiol should not be used in women who are pregnant or breastfeeding or who have breast cancer, among other contraindications.[18]

Estradiol is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol.[9] Due to its estrogenic activity, estradiol has antigonadotropic effects and can inhibit fertility and suppress sex hormone production in both women and men.[23][24] Estradiol differs from non-bioidentical estrogens like conjugated estrogens and ethinylestradiol in various ways, with implications for tolerability and safety.[9]

Estradiol was discovered in 1933.[25][26] It became available as a medication that same year, in an injectable form known as estradiol benzoate.[27][28][29] Forms that were more useful by mouth, estradiol valerate and micronized estradiol, were introduced in the 1960s and 1970s and increased its popularity by this route.[30][31][32] Estradiol is also used as other prodrugs, like estradiol cypionate.[9] Related estrogens such as ethinylestradiol, which is the most common estrogen in birth control pills, and conjugated estrogens (brand name Premarin), which is used in menopausal hormone therapy, are used as medications as well.[9] In 2016, estradiol was the 59th most prescribed medication in the United States, with more than 13 million prescriptions.[33]

Medical uses[edit]

Hormone therapy[edit]

Menopause[edit]

Estradiol is used in menopausal hormone therapy to prevent and treat moderate to severe menopausal symptoms such as hot flashes, vaginal dryness and atrophy, and osteoporosis (bone loss).[9] As unopposed estrogen therapy (using estrogen alone without progesterone) increases the risk of endometrial hyperplasia and endometrial cancer in women with intact uteruses, estradiol is usually combined with a progestogen like progesterone or medroxyprogesterone acetate to prevent the effects of estradiol on the endometrium.[9][34] This is not necessary if the woman has undergone a hysterectomy (surgical removal of the uterus).[9] A 2017 meta-analysis found that estradiol had no effect on depressive symptoms in peri- and postmenopausal women.[35]

Estrogen dosages for menopausal hormone therapy

Route/form Estrogen Low Standard High
Oral Estradiol 0.5–1 mg/day 1–2 mg/day 2–4 mg/day
Estradiol valerate 0.5–1 mg/day 1–2 mg/day 2–4 mg/day
Estradiol acetate 0.45–0.9 mg/day 0.9–1.8 mg/day 1.8–3.6 mg/day
Conjugated estrogens 0.3–0.45 mg/day 0.625 mg/day 0.9–1.25 mg/day
Esterified estrogens 0.3–0.45 mg/day 0.625 mg/day 0.9–1.25 mg/day
Estropipate 0.75 mg/day 1.5 mg/day 3 mg/day
Estriol 1–2 mg/day 2–4 mg/day 4–8 mg/day
Ethinylestradiola 5–10 μg/day
Nasal spray Estradiol 150 μg/day 300 μg/day 600 μg/day
Transdermal patch Estradiol 25 μg/dayb 50 μg/dayb 100 μg/dayb
Transdermal gel Estradiol 0.5 mg/day 1–1.5 mg/day 2–3 mg/day
Vaginal Estradiol 25 μg/day
Estriol 30 μg/day 0.5 mg 2x/week 0.5 mg/day
IM or SC injection Estradiol valerate 4 mg 1x/4 weeks
Estradiol cypionate 1 mg 1x/3–4 weeks 3 mg 1x/3–4 weeks 5 mg 1x/3–4 weeks
Estradiol benzoate 0.5 mg 1x/week 1 mg 1x/week 1.5 mg 1x/week
SC implant Estradiol 25 mg 1x/6 months 50 mg 1x/6 months 100 mg 1x/6 months
Footnotes: a = No longer used or recommended, due to health concerns. b = As a single patch applied once or twice per week (worn for 3–4 days or 7 days), depending on the formulation. Note: Dosages are not necessarily equivalent. Sources: See template.

Hypogonadism[edit]

Estrogen is responsible for the mediation of puberty in females, and in girls with delayed puberty due to hypogonadism (low-functioning gonads, which can result in low sex hormone levels) such as in Turner syndrome, estradiol is used to induce the development of and maintain female secondary sexual characteristics such as breasts, wide hips, and a female fat distribution.[36][12][37] It is also used to restore estradiol levels in adult premenopausal women with hypogonadism, for instance those with premature ovarian failure or who have undergone oophorectomy.[12][37] It is used to treat women with hypogonadism due to hypopituitarism as well.[37][12]

Transgender women[edit]

Estradiol is used as part of feminizing hormone therapy for transgender women.[38][15] The drug is used in higher dosages prior to sex reassignment surgery or orchiectomy to help suppress testosterone levels; after this procedure, estradiol continues to be used at lower dosages to maintain estradiol levels in the normal premenopausal female range.[38][15]

Birth control[edit]

Although almost all combined oral contraceptives contain the synthetic estrogen ethinylestradiol,[39] natural estradiol itself is also used in some hormonal contraceptives, including in estradiol-containing oral contraceptives and combined injectable contraceptives.[13][14] It is formulated in combination with a progestin such as dienogest, nomegestrol acetate, or medroxyprogesterone acetate, and is often used in the form of an ester prodrug like estradiol valerate or estradiol cypionate.[13][14] Hormonal contraceptives contain a progestin and/or estrogen and prevent ovulation and thus the possibility of pregnancy by suppressing the secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the peak of which around the middle of the menstrual cycle causes ovulation to occur.[40]

Hormonal cancer[edit]

Prostate cancer[edit]

Estradiol is used as a form of high-dose estrogen therapy to treat prostate cancer and is similarly effective to other therapies such as androgen deprivation therapy with castration and antiandrogens.[16][11][41][42] It is used in the form of long-lasting injected estradiol prodrugs like polyestradiol phosphate, estradiol valerate, and estradiol undecylate,[11][41][43] and has also more recently been assessed in the form of transdermal estradiol patches.[41][44] Estrogens are effective in the treatment of prostate cancer by suppressing testosterone levels into the castrate range, increasing levels of sex hormone-binding globulin (SHBG) and thereby decreasing the fraction of free testosterone, and possibly also via direct cytotoxic effects on prostate cancer cells.[45][46][47] Parenteral estradiol is largely free of the cardiovascular side effects of the high oral dosages of synthetic estrogens like diethylstilbestrol ad ethinylestradiol that were used previously.[41][48][49] In addition, estrogens may have advantages relative to castration in terms of hot flashes, sexual interest and function, osteoporosis, cognitive function, and quality of life.[41][49][46][50] However, side effects such as gynecomastia and feminization in general may be difficult to tolerate and unacceptable for many men.[41]

Estrogen dosages for prostate cancer

Route/form Estrogen Dosage
Oral Estradiol 1–2 mg 3x/day
Conjugated estrogens 1.25–2.5 mg 3x/day
Ethinylestradiol 0.15–2 mg/day
Ethinylestradiol sulfonate 1–2 mg 1x/week
Diethylstilbestrol 1–3 mg/day
Dienestrol 5 mg/day
Hexestrol 5 mg/day
Fosfestrol 120–480 mg 1–3x/day
Chlorotrianisene 12–24 mg/day
Quadrosilan 900 mg/day
Estramustine phosphate 140–1400 mg/day
Transdermal patch Estradiol 2–6x 100 μg/day
Scrotal: 1x 100 μg/day
IM or SC injection Estradiol benzoate 1.66 mg 3x/week
Estradiol dipropionate 5 mg 1x/week
Estradiol valerate 10–40 mg 1x/1–2 weeks
Estradiol undecylate 100 mg 1x/4 weeks
Polyestradiol phosphate Alone: 160–320 mg 1x/4 weeks
With oral EE: 40–80 mg 1x/4 weeks
Estrone 2–4 mg 2–3x/week
IV injection Fosfestrol 300–1200 mg 1–7x/week
Estramustine phosphate 240–450 mg/day
Note: Dosages are not necessarily equivalent. Sources: See template.

Breast cancer[edit]

High-dose estrogen therapy is effective in the treatment of about 35% of cases of breast cancer in women who are at least 5 years menopausal and has comparable effectiveness to antiestrogen therapy with medications like the selective estrogen receptor modulator (SERM) tamoxifen.[17][51][52] Although estrogens are rarely used in the treatment of breast cancer today and synthetic estrogens like diethylstilbestrol and ethinylestradiol have most commonly been used, estradiol itself has been used in the treatment of breast cancer as well.[17][18][53] It has been used orally at very high doses (30 mg/day) in the treatment of therapy-naive breast cancer and orally at low doses (2 to 6 mg/day) in the treatment of breast cancer in women who were previously treated with and benefited from but acquired resistance to aromatase inhibitors.[17][54][18] Polyestradiol phosphate is also used to treat breast cancer.[55][56]

Estrogen dosages for breast cancer

Route/form Estrogen Dosage
Oral Estradiol 10 mg 3x/day
AI-resistant: 2 mg 1–3x/day
Estradiol valerate AI-resistant: 2 mg 1–3x/day
Conjugated estrogens 10 mg 3x/day
Ethinylestradiol 0.5–1 mg 3x/day
Diethylstilbestrol 5 mg 3x/day
Dienestrol 5 mg 3x/day
IM or SC injection Estradiol benzoate 5 mg 2–3x/week
Estradiol dipropionate 5 mg 2–3x/week
Estradiol valerate 30 mg 1x/2 weeks
Polyestradiol phosphate 40–80 mg 1x/4 weeks
Estrone 5 mg ≥3x/week
Notes: (1) Only in women who are at least 5 years postmenopausal. (2) Dosages are not necessarily equivalent. Sources: See template.

Other uses[edit]

Infertility[edit]

Estrogens may be used in treatment of infertility in women when there is a need to develop sperm-friendly cervical mucous or an appropriate uterine lining.[57][58]

It is also commonly used during in vitro fertilization (IVF). Estrogen helps maintains the endometrial lining of the uterus and help prepare for pregnancy. Research shows higher pregnancy rate if the mother takes estrogen in addition to progesterone.[59] Estradiol is the predominant form of estrogen during reproductive years and is most commonly prescribed.[59]

Lactation suppression[edit]

Estrogens can be used to suppress and cease lactation and breast engorgement in postpartum women who do not wish to breastfeed.[60][51] They do this by directly decreasing the sensitivity of the alveoli of the mammary glands to the lactogenic hormone prolactin.[51]

Tall stature[edit]

Estrogens have been used to limit final height in adolescent girls with tall stature.[61] They do this by inducing epiphyseal closure and suppressing growth hormone-induced hepatic production and by extension circulating levels of insulin-like growth factor-1 (IGF-1), a hormone that causes the body to grow and increase in size.[61] Although ethinylestradiol and conjugated estrogens have mainly been used for this purpose, estradiol can also be employed.[62][63]

Breast enhancement[edit]

Estrogens are involved in breast development and estradiol may be used as a form of hormonal breast enhancement to increase the size of the breasts.[64][65][66][67][68] Both polyestradiol phosphate monotherapy and pseudopregnancy with a combination of high-dosage intramuscular estradiol valerate and hydroxyprogesterone caproate have been assessed for this purpose in clinical studies.[64][65][66][67] However, acute or temporary breast enlargement is a well-known side effect of estrogens, and increases in breast size tend to regress following discontinuation of treatment.[64][66][67] Aside from those without prior established breast development, evidence is lacking for a sustained increases in breast size with estrogens.[64][66][67]

Schizophrenia[edit]

Estradiol has been found to be effective in the adjunctive treatment of schizophrenia in women.[69][70][71] It has been found to significantly reduce positive, negative, and cognitive symptoms, with particular benefits on positive symptoms.[69][70][71][72] Other estrogens, as well as selective estrogen receptor modulators (SERMs) like raloxifene, have been found to be effective in the adjunctive treatment of schizophrenia in women similarly.[69][73][74] Estrogens may be useful in the treatment of schizophrenia in men as well, but their use in this population is limited by feminizing side effects.[75][76] SERMs, which have few or no feminizing side effects, have been found to be effective in the adjunctive treatment of schizophrenia in men similarly to in women and may be more useful than estrogens in this sex.[75][73][74]

Sexual deviance[edit]

Estradiol has been used at high doses in the treatment of sexual deviance, such as paraphilias, in men.[77][78] It has specifically been used for this indication in the form of subcutaneous pellet implants of estradiol and intramuscular injections of estradiol undecylate.[77][78]

Available forms[edit]

Estradiol is available in a variety of different formulations, including oral, intranasal, transdermal/topical, vaginal, injectable, and implantable preparations.[9][79] An ester may be attached to one or both of the hydroxyl groups of estradiol to improve its oral bioavailability and/or duration of action with injection.[9] Such modifications give rise to forms such as estradiol acetate (oral and vaginal), estradiol valerate (oral and injectable), estradiol cypionate (injectable), estradiol benzoate (injectable), estradiol undecylate (injectable), and polyestradiol phosphate (injectable; a polymerized ester of estradiol), which are all prodrugs of estradiol.[9][79][80]

Available forms of estradiol

Route Ingredient Form Dose Major brand names
Oral Estradiol Tablets 0.1, 0.2, 0.5, 1, 2, or 4 mg per tablet Estrace, Ovocyclin
Estradiol acetateb Tablets 0.45, 0.9, or 1.8 mg per tablet Femtrace
Estradiol valerate Tablets 0.5, 1, 2, or 4 mg per tablet Progynova
Intranasal Estradiolb Nasal sprays 150 µg per spray (60 sprays per bottle) Aerodiol
Transdermal Estradiol Patches 14, 25, 37.5, 50, 60, 75, or 100 µg E2 per 24 hours for 3–4 or 7 days Climara, Estraderm, Vivelle
Gel dispensers 0.06% (0.87 or 1.25 g gel or 0.52 or 0.75 mg E2 per activation) Elestrin, EstroGel
Gel packets 0.1% (0.25, 0.5, or 1.0 g gel or 2.5, 5, or 10 mg E2 per packet) DiviGel, Sandrena
Emulsions 0.14% (1.74 g emulsion or 4.35 mg E2 per pouch; delivers 50 µg E2 per day) Estrasorb
Sprays 1.53 mg per spray Evamist
Vaginal Estradiol Tablets 10 or 25 µg per tablet Vagifem
Creams 0.01% (0.1 mg E2 per 1.0 g cream) Estrace
Suppositoriesb 4 or 40 μg per suppository Ovocyclin
Inserts 4 or 10 µg per insert (replaced daily for 2 weeks and then twice weekly) Imvexxy
Rings 2 mg per ring (provides 7.5 µg E2 per 24 hours for 3 months) Estring
Estradiol acetate Rings 12.4 or 24.8 mg per ring (provide 50 or 100 µg E2 per 24 hours for 3 months) Femring
Intramuscular
injection
Estradiola Ampoules 1.0 mg/mL Juvenum E
Estradiol benzoate Vials/ampoules 0.167, 0.2, 0.333, 1, 1.67, 2, 5, 10, 20, or 25 mg/mL Progynon-B
Estradiol cypionate Vials/ampoules 1, 3, or 5 mg/mL Depo-Estradiol
Estradiol dipropionateb Vials/ampoules 0.1, 0.2, 0.5, 1, 2.5, or 5 mg/mL Di-Ovocylin, Progynon-DP
Estradiol enantate Vials/ampoules 5 or 10 mg/mL (available only in combination with a progestin) Perlutal, Topasel
Estradiol undecylateb Vials/ampoules 100 mg/mL Delestrec, Progynon Depot 100
Estradiol valerate Vials/ampoules 5, 10, 20, or 40 mg/mL Delestrogen, Progynon Depot
Polyestradiol phosphate Vials/ampoules 40 or 80 mg per vial/ampoule Estradurin
Subcutaneous Estradiolc Implants 20, 25, 50, or 100 mg per implant (usually replaced every 6 months) Estradiol Implants, Meno-Implant
Abbreviations: E2 = Estradiol. Footnotes: a = Encapsulated in microspheres. b = Discontinued. c = Mostly discontinued. Notes: (1): This table does not include combination products, for instance estradiol formulated in combination with a progestogen or androgen. (2): This table does not include compounded estradiol products; only approved pharmaceutical preparations are included. (3): The availability of pharmaceutical estradiol products differs by country (see Estradiol (medication) § Availability). (4): Some of these formulations have been marketed previously but may no longer be available. Sources: See template.

Transdermal estradiol patches marketed in the United States

Brand
name
Forms (µg/day) Duration Type Size (cm2)a Estradiol (mg) Levels
(pg/mL)
Launch
(year)
Hits
Alora 25, 50, 75, 100 3–4 days Matrix 9, 18, 27, 36 0.77, 1.5, 2.3, 3.1 43–144 1996 42,300
Climara 25, 37.5, 50, 60, 75, 100 7 days Matrix 6.5, 9.375, 12.5, 15, 18.75, 25 2, 2.85, 3.8, 4.55, 5.7, 7.6 17–174 1994 110,000
Climara Prob E2 (45) + LNG (15) 7 days Matrix 22 4.4 27–54 2003 23,400
CombiPatchb E2 (50) + NETA (14, 25) 3–4 days Matrix 9, 16 0.62, 0.51 27–71 1998 33,500
Esclim 25, 37.5, 50, 75, 100 3–4 days Matrix 11, 16.5, 22, 33, 44 5, 7.5, 10, 15, 20 16–124 1998 31,800
Estraderm 50, 100 3–4 days Reservoir 10, 20 E2 (4, 8 mg) + EtOH (0.3, 0.6 mL) 32–73 1986 60,200
Estradiolc 25, 37.5, 50, 75, 100 3–4 days Matrix 2.5, 3.75, 5, 7.5, 10 0.41, 0.62, 0.82, 1.23, 1.64 30–145 1996
Estradiolc 25, 37.5, 50, 75, 100 7 days Matrix 7.75, 11.625, 15.5, 18.6, 23.25, 31 0.97, 1.46, 1.94, 2.33, 2.91, 3.88 17–174 2000
FemPatch 25 7 days Matrix 30 ? 16–31 1996 18,200
Menostar 14 7 days Matrix 3.25 1 13–21 2004 21,300
Minivelle 25, 37.5, 50, 75, 100 3–4 days Matrix 1.65, 2.48, 3.3, 4.95, 6.6 0.41, 0.62, 0.83, 1.24, 1.65 30–117 2012 15,100
Vivelle 25, 37.5, 50, 75, 100 3–4 days Matrix 7.25, 11, 14.5, 22, 29 2.17, 3.28, 4.33, 6.57, 8.66 30–145 2000 91,900
Vivelle-Dot 25, 37.5, 50, 75, 100 3–4 days Matrix 2.5, 3.75, 5, 7.5, 10 0.39, 0.585, 0.78, 1.17, 1.56 30–145 1996 68,900
Abbreviations: E2 = Estradiol. LNG = Levonorgestrel. NETA = Norethisterone acetate. EtOH = Ethanol. Notes: Strikethrough = Discontinued. Footnotes: a = For size-comparison purposes, a United States quarter has an area of about 4.6 cm2 (0.72 in2). b = Combined with a progestin. c = Generic (of Vivelle-Dot, Climara; by Mylan). Sources: See template.

Combined injectable contraceptives marketed for clinical use

Composition Dose Vehicle Brand Names Availability
• Estradiol valerate /
• Norethisterone enantate
5 mg EV
50 mg NETE
Oil solution Chinese Injectable No. 3, Efectimes, Ginediol, Mesigyna, Mesilar, Meslart, Mesocept, Mesygest, Nofertyl, Nofertyl Lafrancol, Noregyna, Norestrin, Norifam, Norigynon, Nostidyn, Sexseg, Solouna Approved in at least 36 countries, including Argentina, the Bahamas, Barbados, Bolivia, Brazil, Chile, Colombia, Costa Rica, the Dominican Republic, Ecuador, Egypt, El Salvador, Ghana, Grenada, Guatemala, Guyana, Haiti, Honduras, Jamaica, Kenya, Mexico, Nicaragua, Panama, Paraguay, Peru, St. Lucia, Turkey, Uruguay, Venezuela, and Zimbabwe
• Estradiol cypionate /
• Medroxyprogesterone acetate
5 mg EC
25 mg MPA
Aqueous suspension with defined particle size range Ciclofem, Ciclofemina, Cyclofem, Cyclofemina, Cyclogeston, Femelin, Femydrol, Gestin, Harmonis, Lunella, Lunelle, Novafem Approved in at least 18 countries, including Bolivia, Brazil, Chile, China, Colombia, Costa Rica, El Salvador, Guatemala, Hong Kong, Indonesia, Malaysia, Mexico, Panama, Peru, Puerto Rico, Thailand, the United States, and Zimbabwe
• Estradiol enantate /
• Algestone acetophenide
a
10 mg E2-EN
150 mg DHPA
Oil solution Acefil, Agurin, Atrimon, Ciclomes, Ciclovar, Ciclovular, Cicnor, Clinomin, Cycloven, Daiva, Damix, Deladroxate§, Deprans, Deproxone, Exuna, Ginestest, Ginoplan, Gynomes, Horprotal, Listen, Luvonal, Neogestar, Neolutin, Nomagest, Nonestrol, Normagest, Normensil, Novular, Oterol, Ovoginal, Patector, Patectro, Perludil, Perlumes, Perlutal, Perlutale, Perlutan, Perlutin, Perlutin-Unifarma, Permisil, Preg-Less, Pregnolan, Primyfar, Progestrol, Protegin, Proter, Seguralmes, Synovular, Topasel, Unigalen, Uno-Ciclo, Vagital Approved in at least 19 countries, including Argentina, Belize, Brazil, Chile, Colombia, Costa Rica, the Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Hong Kong, Mexico, Nicaragua, Panama, Paraguay, Peru, Portugal, and Spain
5 mg E2-EN
75 mg DHPA
Oil solution Anafertin, Patector NF, Yectames Approved at least 9 countries, including Costa Rica, the Dominican Republic, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, and Spain
10 mg E2-EN
120 mg DHPA
Oil solution Unalmes, Yectuna Approved in at least 3 countries, including Brazil, Chile, and Paraguay
10 mg E2-EN
75 mg DHPA
Oil solution Ova Repos Discontinued (firm was in Spain)
• Estradiol benzoate butyrate /
• Algestone acetophenide
10 mg EBB
150 mg DHPA
Oil solution? Redimen, Soluna, Unijab, Unimens§ Approved in Peru and Singapore
• Estradiol valerate /
• Hydroxyprogesterone caproate
5 mg EV
250 mg OHPC
Oil solution Chinese Injectable No. 1 Approved in China
• Estradiol /
• Megestrol acetate
3.5 mg E2
25 mg MGA
Aqueous suspension with defined particle size range Chinese Injectable No. 2, Mego-E Approved in China
• Estradiol cypionate /
• Hydroxyprogesterone caproate
5 mg EC
250 mg OHPC
Oil solution? Sinbios Discontinued (firm was in Mexico)
• Estradiol valerate /
• Estradiol benzoate /
• Hydroxyprogesterone caproate
10 mg EV
1 mg EB
250 mg OHPC
Oil solution? Sin-Ol Discontinued (firm was in Mexico)
Notes: All are given by intramuscular injection once a month. Footnotes: = Discontinued. § = Never marketed. a = Unsorted brand names (doses unknown; for E2-EN/DHPA): Evitas and Femineo. Sources: See template.

Contraindications[edit]

Estrogens like estradiol have a number of contraindications.[81][26][82][83] Estradiol should be avoided when there is undiagnosed abnormal vaginal 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.[18]

Side effects[edit]

Common side effects of estradiol in women include headache, breast pain or tenderness, breast enlargement, irregular vaginal bleeding or spotting, abdominal cramps, bloating, fluid retention, and nausea.[18][84][3] Other possible side effects of estrogens may include high blood pressure, high blood sugar, enlargement of uterine fibroids, melasma, vaginal yeast infections, and liver problems.[18] In men, estrogens can cause breast pain or tenderness, gynecomastia (male breast development), feminization, demasculinization, sexual dysfunction (decreased libido and erectile dysfunction), hypogonadism, testicular atrophy, and infertility.[19][20]

Long-term effects[edit]

Uncommon but serious possible side effects of estrogens associated with long-term therapy may include breast cancer, uterine cancer, stroke, heart attack, blood clots, dementia, gallbladder disease, and ovarian cancer.[32] Warning signs of these serious side effects include breast lumps, unusual vaginal bleeding, dizziness, faintness, changes in speech, severe headaches, chest pain, shortness of breath, pain in the legs, changes in vision, and vomiting.[32]

Due to health risks observed with the combination of conjugated estrogens and medroxyprogesterone acetate in the Women's Health Initiative (WHI) studies (see below), the United States Food and Drug Administration (FDA) label for Estrace (estradiol) advises that estrogens should be used in menopausal hormone therapy only for the shortest time possible and at the lowest effective dose.[18] While the FDA states that is unknown if these risks generalize to estradiol (alone or in combination with progesterone or a progestin), it advises that in the absence of comparable data, the risks should be assumed to be similar.[18] When used to treat menopausal symptoms, the FDA recommends that discontinuation of estradiol should be attempted every three to six months via a gradual dose taper.[18]

Despite the recommendations of the FDA however, it appears that the combination of bioidentical transdermal or vaginal estradiol and oral or vaginal progesterone is a safer form of hormone therapy than oral conjugated estrogens and medroxyprogesterone acetate and may not have the same health risks.[85][86][87][88][89][90][91][92][93] Advantages may include reduced or no risk of venous thromboembolism, cardiovascular disease, and breast cancer, among others.[85][86][87][88][89][90][91][92][93]

Health risks in the CEEs/MPA substudy of the Women's Health Initiative

Event Relative Risk CEEs/MPA vs. placebo at 5.2 years (95% CI[note 1]) Placebo
(n = 8102)
CEEs/MPA
(n = 8506)
Absolute Risk per 10,000 Women-Years
Coronary heart disease events
( non-fatal myocardial infarction, death)
1.29 (1.02–1.63)
1.32 (1.02–1.72)
1.18 (0.70–1.97)
30
23
6
37
30
7
Invasive breast cancer[a] 1.26 (1.00–1.59) 30 38
Stroke 1.41 (1.07–1.85) 21 29
Pulmonary embolism 2.13 (1.39–3.25) 8 16
Colorectal cancer 0.63 (0.43–0.92) 16 10
Endometrial cancer 0.83 (0.47–1.47) 6 5
Hip fracture 0.66 (0.45–0.98) 15 10
Death due to causes other than above 0.92 (0.74–1.14) 40 37
Global Index[b] 1.15 (1.03–1.28) 151 170
Deep vein thrombosis[c] 2.07 (1.49–2.87) 13 26
Vertebral fractures[c] 0.66 (0.44–0.98) 15 9
Other osteoporotic fractures[c] 0.77 (0.69–0.86) 170 131
Sources: See template.

Overdose[edit]

Estrogens are relatively safe in overdose.[80] During pregnancy, levels of estradiol increase to very high concentrations that are as much as 100-fold normal levels.[94][95][96] In late pregnancy, the body produces and secretes approximately 100 mg of estrogens, including estradiol, estrone, and estriol, per day.[94] Serious adverse effects have not been described following acute overdose of large doses of estrogen- and progestogen-containing birth control pills by small children.[80] Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, vaginal bleeding, heavy legs, and leg cramps.[81][80] These side effects can be diminished by reducing the estrogen dosage.[81]

Interactions[edit]

Inducers of cytochrome P450 enzymes like CYP3A4 such as St. John's wort, phenobarbital, carbamazepine and rifampicin decrease the circulating levels of estradiol by accelerating its metabolism, whereas inhibitors of cytochrome P450 enzymes like CYP3A4 such as erythromycin, cimetidine,[97] clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice[98] may slow its metabolism resulting in increased levels of estradiol in the circulation.[18] There is an interaction between estradiol and alcohol such that alcohol considerably increases circulating levels of estradiol during oral estradiol therapy and also increases estradiol levels in normal premenopausal women and with parenteral estradiol therapy.[99][11][100][101] This appears to be due to a decrease in hepatic 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) activity and hence estradiol inactivation into estrone due to an alcohol-mediated increase in the ratio of NADH to NAD in the liver.[100][101] Spironolactone can reduce the bioavailability of oral estradiol.[102]

Pharmacology[edit]

Pharmacodynamics[edit]

Estradiol is an estrogen, or an agonist of the estrogen receptors (ERs), the ERα and ERβ.[9] It is also an agonist of membrane estrogen receptors (mERs), including the GPER, Gq-mER, ER-X, and ERx.[103][104] Estradiol is highly selective for these ERs and mERs, and does not interact importantly with other steroid hormone receptors.[105][106][107] It is far more potent as an estrogen than are other bioidentical estrogens like estrone and estriol.[9][108] Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.[108]

The ERs are expressed widely throughout the body, including in the breasts, uterus, vagina, fat, skin, bone, liver, pituitary gland, hypothalamus, and other parts of the brain.[25] In accordance, estradiol has numerous effects throughout the body.[25][109][110][111][112][113][114][11][45][115][116][117][118] Among other effects, estradiol produces breast development, feminization, changes in the female reproductive system, changes in liver protein synthesis, and changes in brain function.[113][114][11][45][115][116][117][118] The effects of estradiol can influence health in both positive and negative ways.[9] In addition to the aforementioned effects, estradiol has antigonadotropic effects due to its estrogenic activity, and can inhibit ovulation and suppress gonadal sex hormone production.[114][11][45][46][47][23][24] At sufficiently high dosages, estradiol is a powerful antigonadotropic, capable of suppressing testosterone levels into the castrate/female range in men.[45][46][47][23][24]

There are differences between estradiol and other estrogens, such as non-bioidentical estrogens like natural conjugated estrogens and synthetic estrogens like ethinylestradiol and diethylstilbestrol, with implications for pharmacodynamics and pharmacokinetics as well as efficacy, tolerability, and safety.[9]

Pharmacokinetics[edit]

Estradiol can be taken by a variety of different routes of administration.[9] These include oral, buccal, sublingual, intranasal, transdermal (gels, creams, patches), vaginal (tablets, creams, rings, suppositories), rectal, by intramuscular or subcutaneous injection (in oil or aqueous), and as a subcutaneous implant.[9] The pharmacokinetics of estradiol, including its bioavailability, metabolism, biological half-life, and other parameters, differ by route of administration.[9] Likewise, the potency of estradiol, and its local effects in certain tissues, most importantly the liver, differ by route of administration as well.[9] In particular, the oral route is subject to a high first-pass effect, which results in high levels of estradiol and consequent estrogenic effects in the liver and low potency due to first-pass hepatic and intestinal metabolism into metabolites like estrone and estrogen conjugates.[9] Conversely, this is not the case for parenteral (non-oral) routes, which bypass the intestines and liver.[9]

Different estradiol routes and dosages can achieve widely varying circulating estradiol levels.[9] For purposes of comparison with normal physiological circumstances, menstrual cycle circulating levels of estradiol in premenopausal women are 40 pg/mL in the early follicular phase, 250 pg/mL at the middle of the cycle, and 100 pg/mL during the mid-luteal phase.[117] Mean integrated levels of circulating estradiol in premenopausal women across the whole menstrual cycle have been reported to be in the range of 80 and 150 pg/mL, according to some sources.[119][120][121]

Chemistry[edit]

Structures of major endogenous estrogens
Chemical structures of major endogenous estrogens
Estrone (E1)
Estradiol (E2)
Estriol (E3)
The image above contains clickable links
Note the hydroxyl (–OH) groups: estrone (E1) has one, estradiol (E2) has two, estriol (E3) has three, and estetrol (E4) has four.

Estradiol is a naturally occurring estrane steroid.[9][122] It is also known as 17β-estradiol (to distinguish it from 17α-estradiol) or as estra-1,3,5(10)-triene-3,17β-diol.[123][124][9] It has two hydroxyl groups, one at the C3 position and the other at the C17β position, as well as three double bonds in the A ring (the estra-1,3,5(10)-triene core).[122][125] Due to its two hydroxyl groups, estradiol is often abbreviated as E2.[122] The structurally related estrogens, estrone (E1), estriol (E3), and estetrol (E4) have one, three, and four hydroxyl groups, respectively.[122][126]

Hemihydrate[edit]

A hemihydrate form of estradiol, estradiol hemihydrate, is widely used medically under a large number of brand names similarly to estradiol.[124] In terms of activity and bioequivalence, estradiol and its hemihydrate are identical, with the only disparities being an approximate 3% 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.[127][128] This is because estradiol hemihydrate is more hydrated than anhydrous estradiol, and for this reason, is more insoluble in water in comparison, which results in slower absorption rates with specific formulations of the drug such as vaginal tablets.[128] 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.[129] Estradiol hemihydrate is used in place of estradiol in some estradiol products.[130][131][132]

Derivatives[edit]

A variety of C17β and/or C3 ester prodrugs of estradiol, such as estradiol acetate, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enantate, estradiol undecylate, estradiol valerate, and polyestradiol phosphate (an estradiol ester in polymeric form), among many others, have been developed and introduced for medical use as estrogens.[123][124][9][133] Estramustine phosphate is also an estradiol ester, but with a nitrogen mustard moiety attached, and is used as a cytostatic antineoplastic agent in the treatment of prostate cancer.[123][124][134] Cloxestradiol acetate and promestriene are ether prodrugs of estradiol that have been introduced for medical use as estrogens as well, although they are little known and rarely used.[123][124]

Synthetic derivatives of estradiol used as estrogens include ethinylestradiol, ethinylestradiol sulfonate, mestranol, methylestradiol, moxestrol, and quinestrol, all of which are 17α-substituted estradiol derivatives.[123][124][9] Synthetic derivatives of estradiol used in scientific research include 8β-VE2 and 16α-LE2.[135]

Structural properties of selected estradiol esters

Estrogen Structure Ester(s) Relative
mol. weight
Relative
E2 contentb
logPc
Position(s) Moiet(ies) Type Lengtha
Estradiol
Estradiol.svg
1.00 1.00 4.0
Estradiol acetate
Estradiol 3-acetate.svg
C3 Ethanoic acid Straight-chain fatty acid 2 1.15 0.87 2.8–3.9
Estradiol benzoate
Estradiol benzoate.svg
C3 Benzenecarboxylic acid Aromatic fatty acid – (~4–5) 1.38 0.72 4.5–5.7
Estradiol dipropionate
Estradiol dipropionate.svg
C3, C17β Propanoic acid (×2) Straight-chain fatty acid 3 (×2) 1.41 0.71 4.3
Estradiol valerate
Estradiol valerate.svg
C17β Pentanoic acid Straight-chain fatty acid 5 1.31 0.76 5.8–6.0
Estradiol cypionate
Estradiol 17 beta-cypionate.svg
C17β Cyclopentylpropanoic acid Aromatic fatty acid – (~6) 1.46 0.69 6.5–7.1
Estradiol benzoate butyrate
Estradiolbutyratebenzoate structure.png
C3, C17β Benzoic acid, butyric acid Mixed fatty acid – (~6, 2) 1.64 0.61 5.9
Estradiol enantate
Estradiol enanthate.png
C17β Heptanoic acid Straight-chain fatty acid 7 1.41 0.71 7.0
Estradiol dienantate
Estradiol dienanthate.svg
C3, C17β Heptanoic acid (×2) Straight-chain fatty acid 7 (×2) 1.82 0.55 8.1–9.1
Estradiol undecylate
Estradiol undecylate.svg
C17β Undecanoic acid Straight-chain fatty acid 11 1.62 0.62 9.2
Estradiol stearate
Estradiol stearate structure.svg
C17β Octadecanoic acid Straight-chain fatty acid 18 1.98 0.51 12.2
Estradiol distearate C3, C17β Octadecanoic acid (×2) Straight-chain fatty acid 18 (×2) 2.96 0.34 20.2
Estradiol sulfate
Estradiol sulfate.svg
C3 Sulfuric acid Non-fatty acid 1.29 0.77 0.3–3.8
Estradiol glucuronide
Estradiol sulfate.svg
C17β Glucuronic acid Non-fatty acid 1.65 0.61 2.1–2.7
Estramustine phosphated
Estramustine phosphate.svg
C3, C17β Normustine, phosphoric acid Non-fatty acid 1.91 0.52 2.9–5.0
Polyestradiol phosphatee
Polyestradiol phosphate.svg
C3–C17β Phosphoric acid Non-fatty acid 1.23f 0.81f 2.9g
Footnotes: a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic fatty acids. b = Relative estradiol content by weight (i.e., relative estrogenic potency). c = Experimental or predicted octanol/water partition coefficient (i.e., lipophilicity/hydrophobicity). Retrieved from PubChem and DrugBank. d = Also known as estradiol normustine phosphate. e = Polymer of estradiol phosphate (~13 repeat units). f = Relative molecular weight or estradiol content per repeat unit. g = logP of repeat unit (i.e., estradiol phosphate). Sources: See individual articles.

History[edit]

Estradiol was first discovered and synthesized in 1933 via reduction of estrone.[26] Subsequently, estradiol was isolated for the first time in 1935.[25][136] It was also originally known as dihydroxyestrin, dihydrofolliculin, or alpha-estradiol.[125][137] The medication was first introduced for medical use, in the form of estradiol benzoate, an ester prodrug of estradiol administered by intramuscular injection in oil solution, under the brand name Progynon-B in 1933.[27][28][29][138]

Non-esterified estradiol itself was also marketed in the mid-to-late 1930s in oral and other formulations under brand names such as Progynon-DH, Ovocylin, Gynoestryl, and Dimenformon.[125][137][139][140] Due to poor absorption and low potency relative to other estrogens however, oral estradiol was not widely used as late as the early 1970s.[141] Instead, estrogens like conjugated estrogens, ethinylestradiol, and diethylstilbestrol were used for the oral route.[141] In 1966, oral estradiol valerate, another ester prodrug of estradiol, was introduced by Schering for medical use under the brand name Progynova.[30][31][142][143] Esterification of estradiol, as in estradiol valerate, improved its metabolic stability with oral administration.[9][4] In 1972, micronization of estradiol was studied and was likewise found to improve the absorption and potency of estradiol by the oral route.[141] Subsequently, oral micronized estradiol was introduced for medical use in the United States under the brand name Estrace in 1975.[32] Oral micronized estradiol and oral estradiol valerate have similar bioavailability and are both now widely used throughout the world.[9][4]

After the introduction of oral micronized estradiol, vaginal and intranasal micronized estradiol were evaluated in 1977.[144]

The first transdermal estradiol gel, a hydroalcoholic gel known as EstroGel, was initially described in 1980 and was introduced in Europe around 1981.[145] Transdermal estradiol gel did not become available in the United States until 2004, when EstroGel was introduced in this country as well.[145] A transdermal estradiol emulsion, Estrasorb, was marketed in the United States in 2003 as well.[145] One of the earliest reports of transdermal estradiol patches was published in 1983.[145][146] Estraderm, a reservoir patch and the first transdermal estradiol patch to be marketed, was introduced in Europe in 1985 and in the United States in 1986.[147][148] The first transdermal matrix estradiol patches to be introduced were Climara and Vivelle between 1994 and 1996, and were followed by many others.[145][149]

Estradiol benzoate was the first estrogen ester to be marketed.[150] After its introduction, it was followed by many additional esters, for instance injectable estradiol valerate and estradiol cypionate in the 1950s.[124][123][151] Ethinylestradiol was synthesized from estradiol by Inhoffen and Hohlweg in 1938 and was introduced for oral use by Schering in the United States under the brand name Estinyl in 1943.[152][153] It remains widely used in combined birth control pills.[152]

Society and culture[edit]

Generic names[edit]

Estradiol is the generic name of estradiol in American English and its INN, USAN, USP, BAN, DCF, and JAN.[154][124][123][155][156] Estradiolo is the name of estradiol in Italian and the DCIT[154] and estradiolum is its name in Latin, whereas its name remains unchanged as estradiol in Spanish, Portuguese, French, and German.[154][124] Oestradiol was the former BAN of estradiol and its name in British English,[155] but the spelling was eventually changed to estradiol.[154] When estradiol is provided in its hemihydrate form, its INN is estradiol hemihydrate.[124]

Brand names[edit]

Estradiol is marketed under a large number of brand names throughout the world.[124][154] Examples of major brand names in which estradiol has been marketed in include Climara, Climen, Dermestril, Divigel, Estrace, Natifa, Estraderm, Estraderm TTS, Estradot, Estreva, Estrimax, Estring, Estrofem, EstroGel, Evorel, Fem7 (or FemSeven), Imvexxy, Menorest, Oesclim, OestroGel, Sandrena, Systen, and Vagifem.[124][154] Estradiol valerate is marketed mainly as Progynova and Progynon-Depot, while it is marketed as Delestrogen in the U.S.[124][130] Estradiol cypionate is used mainly in the U.S. and is marketed under the brand name Depo-Estradiol.[124][130] Estradiol acetate is available as Femtrace, Femring, and Menoring.[130]

Estradiol is also widely available in combination with progestogens.[154] It is available in combination with norethisterone acetate under the major brand names Activelle, Cliane, Estalis, Eviana, Evorel Conti, Evorel Sequi, Kliogest, Novofem, Sequidot, and Trisequens; with drospirenone as Angeliq; with dydrogesterone as Femoston, Femoston Conti; and with nomegestrol acetate as Zoely.[154] Estradiol valerate is available with cyproterone acetate as Climen; with dienogest as Climodien and Qlaira; with norgestrel as Cyclo-Progynova and Progyluton; with levonorgestrel as Klimonorm; with medroxyprogesterone acetate as Divina and Indivina; and with norethisterone enantate as Mesigyna and Mesygest.[154] Estradiol cypionate is available with medroxyprogesterone acetate as Cyclo-Provera, Cyclofem, Feminena, Lunelle, and Novafem;[14] estradiol enantate with algestone acetophenide as Deladroxate and Topasel;[154][157][158] and estradiol benzoate is marketed with progesterone as Mestrolar and Nomestrol.[154]

Estradiol valerate is also widely available in combination with prasterone enantate (DHEA enantate) under the brand name Gynodian Depot.[154]

Availability[edit]

Estradiol and/or its esters are widely available in countries throughout the world in a variety of formulations.[154][159][160][124][130]

United States[edit]

Vivelle-Dot, an estradiol patch.

As of November 2016, estradiol is available in the United States in the following forms:[130]

  • Oral tablets (Femtrace (as estradiol acetate), Gynodiol, Innofem, generics)
  • Transdermal patches (Alora, Climara, Esclim, Estraderm, FemPatch, Menostar, Minivelle, Vivelle, Vivelle-Dot, generics)
  • Topical gels (Divigel, Elestrin, EstroGel, Sandrena), emulsions (Estrasorb), and sprays (Evamist)
  • Vaginal tablets (Vagifem, generics), creams (Estrace), inserts (Imvexxy), and rings (Estring, Femring (as estradiol acetate))
  • Oil solution for intramuscular injection (Delestrogen (as estradiol valerate), Depo-Estradiol (as estradiol cypionate))

Oral estradiol valerate (Progynova) and other esters of estradiol that are used by injection like estradiol benzoate, estradiol enantate, and estradiol undecylate all are not marketed in the U.S.[130] Polyestradiol phosphate (Estradurin) was marketed in the U.S. previously but is no longer available.[130]

Estradiol is also available in the U.S. in combination with progestogens for the treatment of menopausal symptoms and as a combined hormonal contraceptive:[130]

Estradiol and estradiol esters are also available in custom preparations from compounding pharmacies in the U.S.[163] This includes subcutaneous pellet implants, which are not available in the United States as FDA-approved pharmaceutical drugs.[164] In addition, topical creams that contain estradiol are generally regulated as cosmetics rather than as drugs in the U.S. and hence are also sold over-the-counter and may be purchased without a prescription on the Internet.[165]

Other countries[edit]

Pharmaceutical estradiol subcutaneous pellet implants were formerly available in the United Kingdom and Australia under the brand name Estradiol Implants or Oestradiol Implants (Organon; 25, 50, or 100 mg), but have been discontinued.[124][166][167][168][169] However, an estradiol subcutaneous implant with the brand name Meno-Implant (Organon; 20 mg) continues to be available in the Netherlands.[154][124][170][171] Previously, for instance in the 1970s and 1980s, other subcutaneous estradiol implant products such as Progynon Pellets (Schering; 25 mg) and Estropel Pellets (25 mg; Bartor Pharmacol) were marketed.[172][173][174] It has been said that pharmaceutical estradiol implants have been almost exclusively used in the United Kingdom.[175] Subcutaneous estradiol implants are also available as custom compounded products in some countries.[176][164][177] In 2019 estradiol become “long-term out of stock” in the United Kingdom.[178]

Usage[edit]

Besides ethinylestradiol used in birth control pills, estradiol was the most used estrogen in the U.S. in 2016, with 13.4 million total prescriptions filled.[33] The next most used estrogen in the U.S. in 2016 was conjugated estrogens, with 4.2 million total prescriptions filled.[33]

Research[edit]

Estradiol has been studied in the treatment of postpartum depression and postpartum psychosis.[179][180][181][182][183]

Notes[edit]

  1. ^ Includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer.
  2. ^ A subset of the events was combined in a "global index", defined as the earliest occurrence of coronary heart disease events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.
  3. ^ a b c Not included in Global Index.
  1. ^ Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

References[edit]

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