Estradiol is responsible for the regulation of the
estrous and menstrual female reproductive cycles and for the development
and maintenance of female secondary sex characteristics.3,4
Estradiol plays a key role in germ cell maturation and numerous other,
non-gender-specific processes, including growth, bone metabolism,
nervous system maturation, and endothelial responsiveness. Estrogens are
crucial for the normal development and maintenance of the breasts and
the uterus.5 However, excessive estrogen levels can promote
cell proliferation and may increase the risk of developing breast and
uterine cancer as well as uterine endometriosis.5
The
three major naturally occurring estrogens in women are estrone (E1),
estradiol (E2), and estriol (E3). E2 is the predominant estrogen during
reproductive years, both in terms of absolute serum levels as well as in
terms of estrogenic activity.3 During menopause, a dramatic
drop in E2 production leaves estrone as the predominant circulating
estrogen. Estriol is the main pregnancy estrogen, but it does not play a
significant role in nonpregnant women or men.3 The
concentration of E2 in men is much lower than in women of reproductive
age. All estrogens are synthesized from androgen precursors by the
enzyme aromatase.3,5 Aromatase converts the androgenic
substrates androstenedione, testosterone, and 16-hydroxytestosterone to
the corresponding estrogens: estrone, estradiol, and estriol.5 E2 is produced primarily in ovaries and testes by aromatization of testosterone.3
A lesser amount of E2 is produced in the adrenal glands and some
peripheral sites, most notably adipose tissue. Most of the circulating
estrone is derived from peripheral aromatization of androstenedione
(mainly in the adrenal gland). E2 and E1 can be converted to each other,
and both are inactivated via hydroxylation and conjugation. E2
demonstrates two to five times the biological potency of E1.3
The
importance of E2 testing and the need for reliable and accurate
estradiol measurements throughout the analytic range are emphasized in
several recent publications.6-8 LabCorp offers a sensitive estradiol by LC/MS (140244).
Measurement of serum E2 serves an integral role in the assessment of
reproductive function in females and in the assessment of infertility,
oligomenorrhea, and menopausal status. E2 is commonly measured for
monitoring ovulation induction, as well as during preparation for in
vitro fertilization. Because of the relatively high serum concentrations
of E2 in these patients, readily available automated immunoassay
methods with modest sensitivity meet the clinical requirements.
Adult female.
In premenopausal women, E2 levels, along with luteinizing hormone (LH)
and follicle-stimulating hormone (FSH) levels, delineate the stage of
the menstrual cycle.3 E2 levels are lowest during the early
follicular phase and rise gradually. Two to three days before ovulation,
estradiol levels start to increase much more rapidly to a peak just
before ovulation. This dramatic increase in circulating E2 levels
induces a surge in LH and FSH. E2 levels decline modestly during the
ovulatory phase and then increase again gradually until the midpoint of
the luteal phase and ultimately decline back to early follicular levels.
Assessment
of E2 levels is useful for the evaluation of hypogonadism and
oligomenorrhea in women. Decreased ovarian estrogen production is
classified as hypergonadotropic or hypogonadotropic, depending on
whether the disease is of gonadal or pituitary/hypothalamic origin.9-11
Measurement of gonadotropins (LH and FSH) is fundamental in
differentiating these two low estradiol states. The main causes of
primary gonadal failure (hypergonadotropic) are genetic (Turner
syndrome, familial premature ovarian failure), autoimmune (autoimmune
ovarian failure, autoimmune polyglandular endocrine failure syndrome
type II), and toxic (related to chemotherapy or radiation therapy for
malignant disease).
Low E2 with low or inappropriately "normal" LH
and/or FSH in young adult females is consistent with hypogonadotrophic
hypogonadism.11-13 This can be caused by hypothalamic or
pituitary failure due to conditions including multiple pituitary hormone
deficiency and Kallmann syndrome. Diagnostic workup includes the
measurement of E2, along with pituitary gonadotropins and prolactin and,
possibly, imaging. This endocrine presentation can be caused by
starvation, overexercise, severe physical or emotional stress, and
drug/alcohol abuse. While early studies suggested that E2 levels could
be used to predict ovarian reserve in women of reproductive age
undergoing assisted reproduction procedures, more recent studies have
found the marker less useful.14 Estradiol measurement is useful in assessing the status of ovulation induction in women with hypogonadotropic hypogonadism,15 and for the prediction and prevention of ovarian hyperstimulation syndrome in patients undergoing assisted reproduction.16
Normal
or high E2 with irregular or absent menstrual periods is suggestive of
possible polycystic ovarian syndrome, androgen producing tumors, or
estrogen producing tumors. In these cases, measurement of total and
bioavailable androstenedione, dehydroepiandrosterone (sulfate), and sex
hormone-binding globulin can aid in differential diagnosis.
The
main site of estrogen biosynthesis in the nonpregnant premenopausal
woman is the ovarian granulosa cells; however, the adipose tissue
becomes a major source of circulating estradiol in postmenopausal women.3 After menopause, androstenedione, secreted by the adrenal gland, is converted into estrone in the adipose tissue.3 The conversion of plasma androstenedione to estrone increases with excess body weight in both pre- and postmenopausal women.3 Estrone is then eventually converted to estradiol by 17-ß-hydroxysteroid dehydrogenase enzymes present in peripheral tissues.3
Measurement
of E2 level, together with FSH and/or anti-Müllerian hormone (AMH) can
be useful in predicting the timing of the transition into menopause.17,18
A large population study (Randolph) found that the mean E2 level
started to decline approximately two years prior to the final menstrual
period (FMP) and exhibited a maximal rate of change at the FMP. The mean
E2 level stabilized a menopausal level approximately two years after
FMP.17 A sensitive estradiol assay is required to measure E2
levels accurately in postmenopausal women. The current recommendations
for postmenopausal female hormone replacement are to administer therapy
in the smallest beneficial doses for as briefly as possible. Estrogen
replacement in reproductive-age women should aim to mimic natural
estrogen levels as closely as possible, while levels in menopausal women
should be held near the lower limit of the premenopausal female
reference range. Postmenopausal women with lower E2 levels are at
increased risk of osteoporotic fractures, while higher estradiol levels
are associated with increased risk of malignancy and cardiovascular
disease.19,20 Accurate measurement of E2 in women receiving hormone replacement may play a role in optimizing therapy.
Gonadotropin
receptor hormone (GNRH) analogues are used therapeutically to reduce
the ovarian production of estradiol in sex hormone-dependent disorders,
including endometriosis and uterine fibroids.21 Aromatase
inhibitors are also used therapeutically to reduce circulating estrogens
(E2 and E1) levels in hyperestrogenic conditions (ie, endometriosis in
women and gynecomastia in men) and in estrogen-sensitive malignancies.22-26
The complete or near complete suppression of estradiol production
induced by these treatments produces low serum levels that can only be
accurately measured by sensitive methods.27 See Estradiol, Sensitive (LC/MS) [140244].
Adult male.
The use of a sensitive, LC/MS assay for serum E2 measurement in males
is preferred over direct immunoassays because of its greater sensitivity
and lesser interference by other steroids.28 See LabCorp test Estradiol, Sensitive (LC/MS) [140244]. In males, estradiol is present at low concentrations in blood, but it is extraordinarily high in semen.3
Estradiol plays an important role in epididymal function and sperm
maturation and is essential for normal spermatogenesis and sperm
motility.3
Gynecomastia refers to a syndrome of
abnormal feminization with swelling of the breast tissue in boys or men,
caused by an imbalance of the hormones estrogen and testosterone.29
Gynecomastia is common during puberty in boys and can be seen in older
males due to increased estrogen levels related to obesity (increased
aromatase activity), decreased hepatic clearance, estrogen ingestion,
and estrogen-producing tumors. Asymptomatic gynecomastia is common in
older men, but individuals who present with gynecomastia of recent onset
(associated with pain and tenderness) may require clinical workup.29
Gynecomastia and other signs of male feminization may be caused by an
absolute increase in E2 and/or E1. The testes may directly secrete too
much estradiol due to a Leydig-cell or Sertoli-cell tumor. They may also
secrete estradiol indirectly through the stimulatory effect of a human
chorionic gonadotropin-secreting tumor of gonadal or extragonadal
germ-cell origin.29 Alternatively, men with normal estrogen
levels can develop gynecomastia, if testosterone levels are low due to
primary/secondary testicular failure, resulting in an abnormally
elevated estrogen:androgen ratio. Feminization may also occur in men
treated with antiandrogen therapy or drugs with antiandrogenic effects
(eg, spironolactone, digitalis). Conversely, individuals with elevated
androgen levels will often exhibit gynecomastia caused by
aromatase-catalyzed estrogen production.
Estrogens (and androgens) play an important role in the normal physiology of the skeleton in both sexes.3
Males with diminished estrogen levels (due to congenital aromatase
deficiency) or insensitivity to estrogens (due to estrogen receptor
deficiency) have a characteristic phenotype with regard to bone
development.3,25 These males exhibit significant increased overall height due to lack of estrogen-induced epiphyseal closure.25
The importance of estradiol in bone health is further supported by the
fact that estradiol levels correlate better with bone mineral density
than do testosterone levels in aging men.25 The Endocrine
Society has recently reported that low estradiol levels are associated
with increased fracture risk and accelerated bone loss in older men.30
Children and adolescents.
A sensitive method is required to measure accurately the E2
concentrations found in boys and prepubertal girls. See LabCorp test Estradiol, Sensitive (LC/MS) [140244]. Levels in boys and heavier girls are generally lower than in girls of normal weight.31,32 Adrenal steroids tend to increase prior to gonadal steroids at the beginning of the pubertal transition.31 In girls, E2 concentrations increase just before breast development.31
In precocious puberty (PP), estradiol and the gonadotropins, LH and FSH, tend to be above the prepubertal range.33
E2 measurement in children suspected of having PP is performed to
support the diagnosis and to determine the origin of the condition or
disease. The source of increased estradiol can be exogenous estrogens or
an ovarian cyst that has produced transient estrogens. Elevation of E1
or E2 alone suggests pseudoprecocious puberty, possibly due to a
steroid-producing tumor.
It is not normal for an adolescent to be amenorrheic for greater than three months, even in the early gynecologic years,34 and menstrual cycle duration persistently outside 21 to 45 days in adolescents is unusual.35
Since estrogen deficiency is a risk factor for later development of
osteoporosis and cardiovascular disease, a workup including sensitive E2
measurement is recommended for adolescent girls and women with
potentially disordered hypothalamic-pituitary-gonadal function.11,34
Persistently low estrogens and elevated gonadotropins in children with
delayed puberty suggest primary ovarian failure, while low gonadotropins
suggest hypogonadotrophic hypogonadism. In this latter case, Kallmann
syndrome (or related disorders) or hypothalamic/pituitary tumors should
be excluded in well-nourished children.36 Both E2 and E1 levels are very low or undetectable in children with aromatase deficiency.35
Affected girls have hypergonadotropic hypogonadism, fail to develop
secondary sexual characteristics, and exhibit progressive virilization.35
The affected boys exhibit normal male sexual differentiation and
pubertal maturation. However, boys with aromatase deficiency are
typically extremely tall with eunuchoid proportions and continued linear
growth into adulthood, severely delayed epiphyseal closure, and
osteoporosis due to estrogen deficiency. Highly sensitive E2 measurement
can be of value in the assessment of therapeutic efficacy of estrogen
replacement in hypogonadal girls.32
