Estradiol
Updated: Feb 18, 2020
Author: Alina G Sofronescu, PhD, NRCC-CC, FAAC; Chief Editor: Eric B Staros, MD
Depending on the method of evaluation, reference intervals can vary from one clinical lab to another. In addition, the reference range of estradiol (E2) varies by age and sex.
The conversion factor is shown below.
Estradiol: pg/mL x 3.676 = pmol/L (molecular weight = 272)
Child < 10 years old: < 15 pg/mL[1]
Adult male: 10-50 pg/mL[1]
Adult female[1] :
Child < 10 years old: 0-6[1]
Adult male: 0-6[1]
Adult female[1] :
In women, serum estradiol evaluation is an essential component of reproductive function assessment, including evaluation of infertility, oligomenorrhea, and menopause. Estradiol testing is also used to monitor induction of ovulation induction and to plan steps of IVF.
In these circumstances, modestly sensitive estradiol assays suffice. However, numerous other clinical applications warrant the use of estradiol assays with extra sensitivity, simultaneous estrone testing, or both. These include the following:
Inborn errors of sex steroid metabolism
Puberty disorders
Estrogen deficiency in men
Assessment of fracture risk in menopausal women
Therapeutic drug monitoring (an increasing indication, eg, antiestrogen treatment, female hormone replacement therapy at low doses)
Evaluating serum estradiol (E2) levels is most useful in the following situations:
Testing for developmental disorders in children
Assessing reproductive function and assisted reproduction in premenopausal women
Testing for feminizing disorders in men
Evaluating for tumors that secrete estrogen (both sexes)
In young females, an estradiol level below the premenopausal reference range indicates hypogonadism. Elevated follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels indicate primary gonadal failure. The main causes are as follows:
Heredity (eg, Turner syndrome, familial premature ovarian failure)
Autoimmunity (eg, autoimmune ovarian failure, possibly as part of autoimmune polyglandular endocrine failure syndrome type II)
Toxicity (eg, related to chemotherapy or radiation therapy used to treat malignancy)
Functional etiologies may account for low or inappropriately "normal" LH or FSH levels that result in a diagnosis of hypogonadotrophic hypogonadism. Starvation, overexercise, severe physical or emotional stress, and heavy drug and/or alcohol use are potential causes. Organic disease of the hypothalamus or pituitary is also potentially etiologic. Additional workup steps, typically including testing of pituitary hormones (especially prolactin) and MRI in some cases, are usually required.
Absent or irregular menstrual periods in the setting of normal or high estradiol levels indicate possible polycystic ovarian syndrome, androgen-producing tumors, or estrogen-producing tumors. Additional workup steps are required, usually including assessment of total and bioavailable testosterone, androstenedione, dehydroepiandrosterone (sulfate), and sex hormone–binding globulin, as well as imaging studies in some cases.
During the menstrual cycle, estradiol levels fluctuate significantly, as follows:
Postmenses: Estradiol levels may drop to as low as 15 pg/mL.
Follicular phase to a preovulatory peak: Estradiol levels rise considerably, typically to more than 300 pg/mL.
Luteal phase: Levels fall.
Menses: Estradiol levels range from 50-100 pg/mL.
Analysis of estradiol levels may aid in establishing time of ovulation and optimal time for conception, which is 48-72 hours after estradiol levels peak at midcycle. Over several days, serial specimens must be drawn to assess baseline and peak total estrogen (estrone [E1] plus estradiol) levels. An anovulatory cycle is indicated by (1) low baseline levels and absence of elevation and (2) persistently high levels without an elevation at midcycle.
Low levels (~30 pg/mL) are critical before ovarian stimulation is performed as part of in vitro fertilization (IVF), since higher values are commonly associated with poor stimulation cycles.
The goal of estrogen replacement in women of reproductive age is to replicate natural estrogen levels as closely as possible. Estradiol levels should be within the premenopausal reference range (and ideally higher than estrone levels), and LH/FSH levels should be within the reference range.
As for postmenopausal female hormone replacement, the current recommendation is to administer the smallest dose in the shortest duration as is beneficial. Estradiol and estrone levels should ideally be maintained at below or near the lower limit of the reference range for premenopausal females.[2, 3]
Osteoporotic fractures are more common in older men and postmenopausal women whose estradiol levels are in the lowest quartile,[4] typically below 5 pg/mL.
The goal of anti-estrogen therapy with central or peripheral-acting agents (not pure receptor antagonists) is usually complete estradiol suppression, whereas the goal of therapy with aromatase inhibitors is complete suppression of both estradiol and estrone.
In males, gynecomastia (which is common during puberty) or other signs of feminization may result from a surplus of estrogens, either absolute or relative (compared with androgen levels). In most cases, gynecomastia does not result from hormonal disease except in males in whom estrone, estradiol, or testosterone levels are above the reference ranges for men. Nonetheless, the condition may result in persistent breast tissue that requires surgery for removal.
Gynecomastia in adults should prompt additional workup, including assessment of testosterone and adrenal androgen, as well as estradiol and estrone.[5]
Increased estrone or estradiol levels may be caused by the following:
Aromatization of increased androgen levels due to tumors or androgen therapy (medical or performance enhancing), which secondarily elevates estrone and estradiol levels
Increased tissue production of estrone associated with obesity
Reduced estrone and estradiol clearance in association with liver disease
Estrogen-producing tumors
Ingestion of estrogen
Feminization or gynecomastia may be associated with normal estrone and estradiol levels in males with low bioavailable testosterone levels caused by primary or secondary testicular failure. This scenario may occur in patients undergoing antiandrogen therapy or receiving other medications with anti-androgenic effects (eg, digitalis preparations, spironolactone).
The principal component of the workup for precocious puberty remains the gonadotrophin-releasing hormone (GnRH) stimulation test, although assessments of baseline sex steroid and gonadotrophin are other important components.
Estradiol levels are less than 10 pg/mL in prepubertal girls (most < 5 pg/mL), while values in prepubertal boys are less than half of those in prepubertal girls. LH and FSH levels are undetectable or very low in this population. Estrone levels are also low but may be slightly higher in in obese children after adrenarche develops. Levels of estradiol, which is produced in the gonads, usually remain low in these children.
In individuals with true precocious puberty, estradiol, LH, and FSH levels exceed the prepubertal range. Elevations of estradiol or estrone alone suggest pseudo-precocious puberty, possibly caused by a sex steroid–producing tumor.[3]
Patients with delayed puberty have prepubertal levels of gonadotrophins and estrogens.[6] A gradual rise of these values suggests that puberty will spontaneously occur. Persistently decreased estrogen levels and increased gonadotrophin levels suggest primary ovarian failure, while decreased gonadotrophin levels suggest hypogonadotrophic hypogonadism. If the latter occurs in well-nourished children, hypothalamic/pituitary tumors or Kallmann syndrome (or related disorders) should be ruled out.
Abnormalities in the production of other steroids, particularly those that result in an absence of cortisol, are usually associated with inherited disorders of sex steroid metabolism.
Aromatase deficiency, which is not associated with cortisol abnormalities, usually results in masculinization to some degree in females, in addition to primary puberty failure. Males with aromatase deficiency may present with delayed puberty, delayed epiphyseal closure, and decreased bone density. Estradiol and estrone levels in persons with aromatase deficiency are undetectable or very low.
Various types of testicular feminization result from disorders involving androgen-signaling pathways and lead to female (or feminized) phenotypes in genetic males. In such individuals, estradiol and estrone levels exceed the reference range for males and typically rise into the reference range for females, while testosterone levels are also significantly elevated.
Clinical laboratory can evaluate and report estradiol results in few forms:
Free (unbound) estradiol
Total estradiol (free and bound)
Percentage free estradiol (%fE2): (fE2/tE2) X 100
SHBG and albumin can also be measured in the same sample and used for further calculations/evaluation of estrogens.
Estradiol can be estimated in the clinical laboratory using different analytical methods. Depending on these, sample requirements can vary from one lab to another.
Preferred specimens are as follows:
Serum
Plasma
Urine - rarely
Saliva - rarely
Red top tube, green top tube (sodium or lithium heparin), serum separator tube (SST), or plasma separator tube (PST)
Specimen volume: 1.2 mL (0.8 mL minimum)
See the list below:
Centrifuge specimens and remove serum or plasma from the cells within 2 hours of collection.
Store at room temperature for 8 hours, or refrigerate at 2-8o C (36-46o F) up to 48 hours.
If assays are not completed within 48 hours, or the separated sample is to be stored beyond 48 hours, samples should be frozen at -20°C or colder. Frozen samples should be thawed only once. Analyte deterioration may occur in samples that are repeatedly frozen and thawed.
Rejection criteria: Severe hemolysis or lipemia
Specimen stability: Refrigerated (preferred) -7 days; frozen -1 year; RT/ambient -7 days
Saliva must be collected after thoroughly rinsing the mouth. The collection must be frozen immediately. This will break down the mucin and make specimen more fluid. After thawing, samples are centrifuged and heated at 56˚C for 2 h to reduce the interferences from saliva matrix.[7]
In clinical laboratories, estradiol is measured in serum samples using different forms of competitive binding immunoassays (with or without pre-extraction): immunoenzymatic assays, RIA, fluorescent labels immunoassay (europium or time-resolved fluorescent immunoassay).
A GC-MS method associated with isotope dilution has also been developed and represents the most accurate and reliable measurement of serum estradiol.
Estradiol can be measured in urine as part of “urine total estrogens” using spectrophotometric methods. Urine total and fractionated estrogens can be evaluated using RIA.
Measurement of estradiol in saliva has more research applications, rather than clinical. Both RIA and immunoenzymatic assays have been developed.[7]
Estrogens are sex hormones, predominantly produced by females and involved in the development and maintenance of female sex organs, secondary sex characteristics, and fertility. More than 20 estrogens have been identified. However only 17 b-estradiol (ie, E2 or simply estradiol) and estriol (ie, E3) are clinically evaluated and used to diagnosis purposes.
Estradiol circulates in few forms:
Free/unbound - 3%
Bound to albumin - 60%
Bound to Steroids Hormone Binding Globulin or SHBG - 37%
The albumin-bound and the free fraction represent the “biological active estradiol.”
In females, estradiol is produced primarily in the ovaries. In males, it is produced by the testes via aromatization of testosterone. In addition, the adrenal glands and some peripheral tissues, most notably fat, produce small amounts of the hormone. Conversely, the majority of estrone in the circulation is derived from peripheral aromatization of androstenedione (mainly adrenal).
Estrone can be converted into estradiol and vice versa, and hydroxylation and conjugation can inactivate both hormones. Estradiol is 1.25-5 times more biologically potent than estrone. In nonpregnant premenopausal women, circulating estradiol levels are 1.5-4 times those of estrone. Estradiol levels in nonpregnant women are much higher than in postmenopausal women and men. Conversely, estrone levels do not vary to the same degree, leading to a reversed premenopausal ratio of estradiol to estrone.
In premenopausal women, estradiol levels fluctuate throughout the menstrual cycle. Estradiol levels are at their lowest point during the early follicular phase and then rise gradually until 2-3 days before ovulation. At this point, they begin to elevate rapidly, peaking just before the ovulation-inducing surge of LH/FSH to 500%-1000% the estradiol levels seen during the early follicular phase. Afterward, levels decline modestly during the ovulatory phase before rising gradually again until the midpoint of the luteal phase. They then decline again to the trough of the early follicular phase.
In addition to their role in the development and maintenance of the female phenotype, germ cell maturation, and pregnancy, estrogens also have important roles in many non–sex-specific processes, including growth, maturation of the nervous system, bone metabolism and remodeling, and endothelial responsiveness.[7]
Serum estradiol (E2) assessment is most useful in the following situations:
Testing for developmental disorders in children (eg, hypogonadism, delayed puberty)
Assessing reproductive function and assisted reproduction in premenopausal women
Testing for feminizing disorders in men
Evaluating for tumors that secrete estrogen (both sexes)
Estriol (E3) is the main estrogen in pregnancy but is insignificant in women who are not pregnant and men.[7]