Estradiol

Not to be confused with 17α-estradiol.
Estradiol
Systematic (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
Clinical data
Trade names Climara, Menostar
AHFS/Drugs.com monograph
Pregnancy
category
  • US: X (Contraindicated)
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: -only
  • (Prescription only)
Routes of
administration
Oral, transdermal
Pharmacokinetic data
Bioavailability 97–99% is bound
Metabolism Liver
Biological half-life ~13-17 hours
Excretion Urine and sweat glands
Identifiers
CAS Number 50-28-2 YesY
ATC code G03CA03
PubChem CID 5757
IUPHAR/BPS 1013
DrugBank DB00783 YesY
ChemSpider 5554 YesY
UNII 4TI98Z838E YesY
KEGG D00105 YesY
ChEBI CHEBI:16469 YesY
ChEMBL CHEMBL135 YesY
Synonyms (17β)-Estra-1,3,5(10)-triene-3,17-diol
Chemical data
Formula C18H24O2
Molar mass 272.38 g/mol
  (verify)

Estradiol, or more precisely, 17β-estradiol, is a steroid and estrogen sex hormone, and the primary female sex hormone. It is named for and is important in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is essential for the development and maintenance of female reproductive tissues[1] but it also has important effects in many other tissues including bone. While estrogen levels in men are lower compared to women, estrogens have essential functions in men as well. Estradiol is found in most vertebrates as well as many crustaceans, insects, fish, and other animal species.[2][3]

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 the 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).[5] One principle pathway then converts progesterone to its 17-hydroxy derivative, 17-hydroxyprogesterone, and then to Δ4-androstenedione via sequential cytochrome P450-catalyzed oxidations. Action of aromatase on Δ4-androstenedione generates estrone, and action of a dehydrogenase on this gives the title compound, 17β-estradiol. Alternatively, Δ4-androstenedione can be converted into the androgen, testosterone, which in turn can be converted directly into 17β-estradiol.

Effects

Female reproduction

In the female, estradiol acts as a growth hormone for tissue of the reproductive organs, supporting the lining of the vagina, the cervical glands, the endometrium, and the lining of the fallopian tubes. It enhances growth of the myometrium. Estradiol appears necessary to maintain oocytes in the ovary. During the menstrual cycle, estradiol produced by the growing follicle triggers, via a positive feedback system, the hypothalamic-pituitary events that lead to the luteinizing hormone surge, inducing ovulation. In the luteal phase, estradiol, in conjunction with progesterone, prepares the endometrium for implantation. During pregnancy, estradiol increases due to placental production. In baboons, blocking of estrogen production leads to pregnancy loss, suggesting estradiol has a role in the maintenance of pregnancy. Research is investigating the role of estrogens in the process of initiation of labor. Actions of estradiol are required before the exposure of progesterone in the luteal phase.

Sexual development

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 produces 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.

Male reproduction

The effect of estradiol (and estrogens in general) 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.[6] It functions (in vitro) to prevent apoptosis of male sperm cells.[7] While some studies in the early 1990s claimed a connection between globally declining sperm counts and estrogen exposure in the environment,[8] later studies found no such connection, nor evidence of a general decline in sperm counts.[9][10] Suppression of estradiol production in a subpopulation of subfertile men may improve the semen analysis.[11]

Males with certain sex chromosome genetic conditions, such as Klinefelter's syndrome, will have a higher level of estradiol.[12]

Bone

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.[13] Also, women past menopause experience an accelerated loss of bone mass due to a relative estrogen deficiency.[14]

Liver

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.

Brain

Estrogens can be produced in the brain from steroid precursors. As antioxidants, they have been found to have neuroprotective function.[15]

The positive and negative feedback loops of the menstrual cycle involve ovarian estradiol as the link to the hypothalamic-pituitary system to regulate gonadotropins.[16] (See Hypothalamic–pituitary–gonadal axis.)

Estrogen is considered to play a significant role in women’s mental health, with links suggested between the hormone level, mood and well-being. Sudden drops or fluctuations in, or long periods of sustained low levels of estrogen may be correlated with significant mood-lowering. Clinical recovery from depression postpartum, perimenopause, and postmenopause was shown to be effective after levels of estrogen were stabilized and/or restored.[17][18]

Recently, the volumes of sexually dimorphic brain structures in trans women were found to change and approximate typical female brain structures when exposed to estradiol over a period of months,[19] suggesting that 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.[20] 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.[21]

Blood vessels

Estrogen affects certain blood vessels. Improvement in arterial blood flow has been demonstrated in coronary arteries.[22]

Oncogene

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

Pregnancy

The effect of estradiol, together with estrone and estriol, in pregnancy is less clear. They may promote uterine blood flow, myometrial growth, stimulate breast growth and at term, promote cervical softening and expression of myometrial oxytocin receptors.

Medical uses

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

Hormonal contraception

A more potent chemical derivative of estradiol, ethinyl estradiol is a major component of hormonal contraceptives.[23] Combined forms of hormonal contraception contain ethinyl estradiol and a progestin, which both contribute to the inhibition of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (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.[24]

Hormone replacement therapy

Menopausal

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 (HRT) may be prescribed. Such therapy is usually combined with a progestin to reduce the risk of endometrial cancer.[25]

Transgender women

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 sex reassignment surgery.[26]

Other uses

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.

Estrogen therapy can also be used to treat advanced prostate cancer, as well as to relieve symptoms of breast cancer.[27][28]

Estradiol is also used as an agent of stimulating female puberty induction, as in the treatment of delayed puberty caused by hypogonadism or Turner's syndrome.

Estrogen deprivation

See also: Antiestrogen

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, premature closure of epiphyses, and inhibiting feminization in hormone replacement therapy for trans men. Estrogen levels can be reduced by inhibiting production using GnRH analogues or blocking the enzyme aromatase using an aromatase inhibitor, such as anastrozole, or with an estrogen receptor antagonist, such as tamoxifen or fulvestrant.

Medical formulations

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 the C17 (sometimes also at C3) position to facilitate the administration. Such modifications give rise to forms such as estradiol acetate (oral and vaginal applications) and to estradiol cypionate (injectable), which behaves as a prodrug to estradiol.

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.

Not all products are available worldwide. Estradiol is also part of conjugated estrogen preparations, such as Premarin, though it is present only in small quantities in a conjugated form (sodium estradiol sulfate) and is not the major ingredient. (Premarin consists of a large number of estrogen derivatives. As its name alludes to, Premarin is isolated from the urine of pregnant mares.)[29]

Comparison of routes of administration

Different routes of administration of estradiol produce different effects in the body due to differences in the amount of estradiol that is exposed to the liver.[30]

When taken orally, most estradiol is converted into estrone in the liver during first-pass metabolism.[31][32] Estrone is approximately 10-fold less potent relative to estradiol as an estrogen,[33] and also has a different binding profile relative to estradiol, for instance, lacking affinity to the GPER.[34] In addition, the resulting supraphysiological levels of estrogen in the liver (4 to 5-fold higher relative to the circulation)[35] increase the risk of blood clots,[36] suppress growth hormone (GH)-mediated insulin-like growth factor 1 (IGF-1) production,[37][38] and increase levels of a variety of binding proteins including thyroid binding globulin (TBG), cortisol binding globulin (CBG), sex hormone binding globulin (SHBG), growth hormone binding protein (GHBP),[39] insulin-like growth factor-binding proteins (IGFBPs),[40] and copper binding protein (CBP),[31][41] but also produce positive blood lipid changes.[32][42] Micronized estradiol tablets can be taken sublingually instead of orally.[43] Sublingual ingestion mostly bypasses the liver and hence first-pass metabolism.[44] It has been found to result in levels of estradiol and an estradiol-to-estrone ratio that are significantly higher in comparison to oral ingestion.[45]

Transdermal estradiol, in the form of patches or gel, bypasses the liver and hence first-pass metabolism in a similar but more complete manner relative to sublingual administration. Estradiol patches have been found not to increase the risk of blood clots[36] and to not affect hepatic IGF-1, SHBG, GHBP,[39] IGFBP,[40] or other protein production.[37][38][41] Similar results have been found for vaginal estradiol administration.[46]

Estradiol, in an ester prodrug form such as estradiol cypionate or estradiol valerate, can be administered via depot injection.[47][48] Subcutaneous and intramuscular injections of estradiol cypionate have similar potency and pharmacokinetics (e.g., duration).[48] However, subcutaneous injections may be easier and less painful to perform, and hence result in improved patient compliance.[48]

Dosages and levels

Oral micronized estradiol, at a daily dosage of 1 mg, results in plasma concentrations of estradiol and estrone that are 30–50 pg/mL and 150–300 pg/mL, respectively, while a daily dosage of 2 mg produces serum levels of 50–180 pg/mL and 300–850 pg/mL of estradiol and estrone, respectively.[49] Vaginal micronized estradiol achieves a far higher estradiol-to-estrone ratio in comparison, with a daily dosage of 0.5 mg resulting in estradiol and estrone levels of 250 pg/mL and 130 pg/mL, respectively.[49] For other non-oral routes, the ratio of estradiol to estrone is similarly improved. With transdermal administration, estradiol patches delivering a daily dosage of 0.05 mg (50 µg) achieve estradiol and estrone levels of 30–65 pg/mL and 40–45 pg/mL, while 0.1 mg (100 µg) attains respective levels of 50–90 pg/mL and 30–65 pg/mL of estradiol and estrone.[49] Another transdermal formulation, estradiol gel, with a daily dosage of 1.5 mg, produces estradiol levels of 40–100 pg/mL and estrone levels of 90 pg/mL, while 3 mg/daily results in respective estradiol and estrone levels of 60–140 pg/mL and 45–155 pg/mL.[49] Oral estradiol administration produces a plasma estradiol-to-estrone ratio of about 1:5 to 1:7,[50] while transdermal administration of estradiol via patch or gel results in a ratio of about 1:1.[51]

A single 4 mg intramusuclar (i.m.) injection of estradiol cypionate or estradiol valerate results in maximal plasma levels of estradiol of about 250 pg/mL and 390 pg/mL, respectively, with levels declining to 100 pg/mL (which was baseline for estradiol cypionate) by 12–14 days.[52][53] A single 2.5 mg intramuscular injection of estradiol benzoate in individuals being treated with a GnRH analogue (and hence having minimal baseline levels of estrogen) was found to result in serum estradiol levels of >400 pg/mL at 24 hours post-administration.[47] The differences in the serum levels of estradiol achieved with these different estradiol esters may be explained by their different rates of absorption, as their durations and levels attained appear to be inversely proportional. For instance, estradiol benzoate, which has the shortest duration (4–5 days with a single i.m. dose of 5 mg), produces the highest levels of estradiol, while estradiol cypionate, which has the longest duration (~11 days with a single i.m. dose of 5 mg), produces the lowest levels of estradiol).[47] Estradiol valerate was found to have a duration of 7–8 days after a single i.m. dose of 5 mg.[47]

A study of combined high-dose i.m. estradiol valerate and hydroxyprogesterone caproate in women (described as a "pseudopregnancy" regimen), with specific dosages of 40 mg weekly and 250 mg weekly, respectively, was found to result in serum estradiol levels of 3028–3226 pg/mL after three months and 2491–2552 pg/mL after six months of treatment from a baseline of 27.8–34.8 pg/mL.[54]

In comparison to the above-described levels, normal menstrual cycle serum levels of estradiol in premenopausal women are 40 pg/mL in the early follicular phase to 250 pg/mL at the middle of the cycle and 100 pg/mL during the mid-luteal phase.[49] Serum estrone levels during the menstrual cycle range from 40 to 170 pg/mL, which parallels the serum levels of estradiol.[49] The estradiol-to-estrone ratio in premenopausal women is higher than 1:1.[49] In postmenopausal women, the serum levels of estradiol are below 15 pg/ml and the average levels of estrone are about 30 pg/ml; the estradiol-to-estrone ratio is reversed to less than 1:1.[49]

List of formulations

Estradiol hemihydrate

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.[55] 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.[56][57] 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.[57] 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.[31]

Adverse effects

Adverse effects, which may occur as a result of use of estradiol and have been associated with estrogen and/or progestin therapy, include changes in vaginal bleeding, dysmenorrhea, increase in size of uterine leiomyomata, vaginitis including vaginal candidiasis, changes in cervical secretion and cervical ectropion, ovarian cancer, endometrial hyperplasia, endometrial cancer, nipple discharge, galactorrhea, fibrocystic breast changes and breast cancer. Cardiovascular effects include chest pain, deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, stroke, and increased blood pressure. Gastrointestinal effects include nausea and vomiting, abdominal cramps, bloating, diarrhea, dyspepsia, dysuria, gastritis, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, or enlargement of hepatic hemangiomas. Skin adverse effects include chloasma or melasma that may continue despite discontinuation of the drug. Other effects on the skin include erythema multiforme, erythema nodosum, otitis media, hemorrhagic eruption, loss of scalp hair, pruritus, or rash. Adverse effects on the eyes include retinal vascular thrombosis, steepening of corneal curvature or intolerance to contact lenses. Adverse central nervous system effects may include headache, migraine, dizziness, chorea, nervousness/anxiety, mood disturbances, irritability, and worsening of epilepsy. Other adverse effects may include changes in weight, reduced carbohydrate tolerance, worsening of porphyria, edema, arthralgias, bronchitis, leg cramps, hemorrhoids, changes in libido, urticaria, angioedema, anaphylactic reactions, syncope, toothache, tooth disorder, urinary incontinence, hypocalcemia, exacerbation of asthma, and increased triglycerides.[58][59]

Estrogen combined with medroxyprogesterone acetate is associated with an increased risk of dementia. It is not known whether estradiol taken alone is associated with an increased risk of dementia. Estrogens should only be used for the shortest possible time and at the lowest effective dose due to these risks. Attempts to gradually reduce the medication via a dose taper should be made every three to six months.[58]

Cancer

Estradiol has been tied to the development and progression of cancers such as breast cancer, ovarian cancer and endometrial cancer. Estradiol effects target tissues mainly by interacting with two nuclear receptors called estrogen receptor α (ERα) and estrogen receptor β (ERβ).[60][61] One of the functions of these estrogen receptors is the modulation of gene expression. Once estradiol binds to the ERs, the 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.[62]

Interactions

St. John's wort, phenobarbital, carbamazepine and rifampicin decrease the levels of estrogens, such as estradiol, by speeding up their metabolism, whereas erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may slow down metabolism, leading to increased levels in the blood plasma.[58]

Contraindications

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.[58]

Biosynthesis and localization

Conversion of testosterone to estradiol

Estradiol, like other steroids, is derived from cholesterol. After side chain cleavage and using the Δ5 or the Δ4- pathway, Δ4-androstenedione is the key intermediary. A portion of the Δ4-androstenedione is converted to testosterone, which in turn undergoes conversion to estradiol by aromatase. In an alternative pathway, Δ4-androstenedione is aromatized to estrone, which is subsequently converted to estradiol.[63]

During the reproductive years, most estradiol in women is produced by the granulosa cells of the ovaries by the aromatization of Δ4-androstenedione (produced in the theca folliculi cells) to estrone, followed by conversion of estrone to estradiol by 17β-hydroxysteroid dehydrogenase. Smaller amounts of estradiol are also produced by the adrenal cortex, and, in men, by the testes.

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.[25] Estradiol is also produced in the brain and in arterial walls.

The biosynthesis of estradiol has been observed in various other species, as indicated above, but also in such species as Phaseolus vulgaris.[64] More often referred to as "beans", consumption may equate to unintentional ingestion of estradiol. In light of this, consumption can be counterproductive to patients undergoing treatment for breast cancer, which usually includes depriving the cancer cells of estrogens. Soybeans are another bean that contains chemicals that act similarly to estrogen in the human body and also cause such interactions.

Mechanism of action

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 membrane estrogen receptors, such as GPER, a recently discovered non-nuclear receptor for estradiol, via which it can mediate a variety of rapid, non-genomic effects.[65] 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.[34]

In the E2 classical pathway or estrogen classical pathway, estradiol enters the cytoplasm, where it causes dissociation of heat-shock protein (HSP). Estradiol then binds to HSP and can homodimerise (form structures of two HSP and two estradiol molecules) and then bind to specific domains on the nucleus (estrogen response element, ERE), allowing for gene transcription which can take place over hours and days.

Metabolism

In plasma, estradiol is largely bound to SHBG, and also to albumin. Only a fraction of 2.21% (± 0.04%) is free and biologically active, the percentage remaining constant throughout the menstrual cycle.[66] 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,[67] with various other cytochrome P450 (CYP) enzymes and metabolic transformations also being involved.[68] As a result, cimetidine, a known, non-selective inhibitor of CYP450 enzymes, can increase the levels of exogenous, orally-ingested estradiol.[67]

Levels and potency of estrogens

As the name implies, estradiol, sometimes abbreviated as E2, has two hydroxyl groups in its molecular structure; its relatives estrone (E1) and estriol (E3) have one and three, respectively, and estetrol (E4) has four. Based on its unique chemical structure, estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect. 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. During pregnancy, estriol becomes the predominant circulating estrogen, and this is the only time at which estetrol occurs in the body, while during menopause, estrone predominates (both based on serum levels). The estradiol produced by male humans, from testosterone, is present at serum levels roughly comparable to those of postmenopausal women (14-55 versus <35 pg/mL, respectively).

Measurement

In women, serum estradiol is measured in a clinical laboratory and reflects primarily the activity of the ovaries. As such, they are useful in the detection of baseline estrogen in women with amenorrhea or menstrual dysfunction, and to detect the state of hypoestrogenicity and menopause. Furthermore, estrogen monitoring during fertility therapy assesses follicular growth and is useful in monitoring the treatment. Estrogen-producing tumors will demonstrate persistent high levels of estradiol and other estrogens. In precocious puberty, estradiol levels are inappropriately increased.

Ranges

Individual laboratory results should always been interpreted using the ranges provided by the laboratory that performed the test.

Reference ranges for the blood content of estradiol during the menstrual cycle
- The ranges denoted By biological stage may be used in closely monitored menstrual cycles in regard to other markers of its biological progression, with the time scale being compressed or stretched to how much faster or slower, respectively, the cycle progresses compared to an average cycle.
- The ranges denoted Inter-cycle variability are more appropriate to use in unmonitored cycles with only the beginning of menstruation known, but where the woman accurately knows her average cycle lengths and time of ovulation, and that they are somewhat averagely regular, with the time scale being compressed or stretched to how much a woman's average cycle length is shorter or longer, respectively, than the average of the population.
- The ranges denoted Inter-woman variability are more appropriate to use when the average cycle lengths and time of ovulation are unknown, but only the beginning of menstruation is given.
Reference ranges for serum estradiol
Patient typeLower limitUpper limitUnit
Adult male 50[69] 200[69] pmol/L
14 55 pg/mL
Adult female (follicular
phase
, day 5)
70[69]
95% PI (standard)
500[69]
95% PI
pmol/L
110[70]
90% PI (used
in diagram)
220[70]
90% PI
19 (95% PI) 140 (95% PI) pg/mL
30 (90% PI) 60 (90% PI)
Adult female (preovulatory
peak)
400[69] 1500[69] pmol/L
110 410 pg/mL
Adult female
(luteal phase)
70[69] 600[69] pmol/L
19 160 pg/mL
Adult female - free
(not protein bound)
0.5[71] 9[71] pg/mL
1.7[71] 33[71] pmol/L
Post-menopausal female N/A[69] < 130[69] pmol/L
N/A < 35 pg/mL

In the normal menstrual cycle, estradiol levels measure typically <50 pg/ml at menstruation, rise with follicular development (peak: 200 pg/ml), drop briefly at ovulation, and rise again during the luteal phase for a second peak. At the end of the luteal phase, estradiol levels drop to their menstrual levels unless there is a pregnancy.

During pregnancy, estrogen levels, including estradiol, rise steadily toward term. The source of these estrogens is the placenta, which aromatizes prohormones produced in the fetal adrenal gland.

See also

References

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