Clinical Information

Estrogens are involved in development and maintenance of the female
phenotype, germ cell maturation, and pregnancy. They also are
important for many other, nongender-specific processes, including
growth, nervous system maturation, bone metabolism/remodeling,
and endothelial responsiveness. The 2 major biologically active
estrogens in nonpregnant humans are estrone (E1) and estradiol (E2).
A third bioactive estrogen, estriol (E3), is the main pregnancy
estrogen,but plays no significant role in nonpregnant women or men.
 
E2 is produced primarily in ovaries and testes by aromatization of
testosterone. Small amounts are produced in the adrenal glands and
some peripheral tissues, most notably fat. By contrast, most of the
circulating E1 is derived from peripheral aromatization of
androstenedione (mainly adrenal). E2 and E1 can be converted into
each other, and both can be inactivated via hydroxylation and
conjugation. E2 demonstrates 1.25-5 times the biological potency of
E1.
 
E2 circulates at 1.5-4 times the concentration of E1 in premenopausal,
nonpregnant women. E2 levels in men and postmenopausal women
are much lower than in nonpregnant women, while E1 levels differ less,
resulting in a reversal of the premenopausal E2:E1 ratio. E2 levels in
premenopausal women fluctuate during the menstrual cycle. They are
lowest during the early follicular phase. E2 levels then rise
graduallyuntil 2-3 days before ovulation, at which stage they start
to increase much more rapidly and peak just before the
ovulation-inducinglutenizing hormone (LH)/follicle stimulating hormone (FSH)
surge at 5-10 times the early follicular levels. This is followed by a
modest decline during the ovulatory phase. E2 levels then increase
again gradually until the midpoint of the luteal phase and thereafter
decline to trough, early follicular levels.
 
Measurement of serum E2 forms an integral part of the assessment of
reproductive function in females, including assessment of infertility,
oligo-amenorrhea and menopausal status. In addition, it is widely used
for monitoring ovulation induction, as well as during preparation for
in vitro fertilization (IVF). For these applications E2 measurements
with modestly sensitive assays suffice. However, extra sensitive E2
 
assays or simultaneous measurement of E1, or both are needed in a
number of other clinical situations. These include inborn errors of
sex steroid metabolism, disorders of puberty, estrogen deficiency in
men, fracture risk assessment in menopausal women, and increasingly,
therapeutic drug monitoring, either in the context of low-dose female
hormone replacement therapy or antiestrogen treatment.
 
Useful For:
As part of the diagnosis and work-up of precocious and delayed
puberty in females, and, to a lesser degree, males.
 
As part of the diagnosis and work-up of suspected disorders of sex
steroid metabolism, e.g., aromatase deficiency and 17 alpha-
hydroxylase deficiency
 
As an adjunct to clinical assessment, imaging studies and bone
mineral density measurement in the fracture risk assessment of
postmenopausal women, and, to a lesser degree, older men
 
Monitoring low-dose female hormone replacement therapy in
 
post-menopausal women
 
Monitoring antiestrogen therapy (e.g., aromatase inhibitor therapy)
 
Interpretation:
Irregular or absent menstrual periods with normal or high E2 levels
(and often high E1 levels) are indicative of possible polycystic
ovarian syndrome, androgen producing tumors, or estrogen producing tumors.
 
Further work-up is required and usually includes measurement of total
and bioavailable testosterone, androstenedione,
dehydroepiandrosterone (sulfate), sex hormone-binding globulin, and
possibly imaging.
 
Estrogen replacement in reproductive age women should aim to mimic
natural estrogen levels as closely as possible. E2 levels should be
within the reference range for premenopausal women, LH/FSH should
be within the normal range, and E2 levels should ideally be higher
than E1 levels.
 
Postmenopausal women and older men in the lowest quartile of E2
levels are at increased risk of osteoporotic fractures. E2 levels are
typically < 5 pg/mL in these patients.
 
The current recommendations for postmenopausal female hormone
replacement are to administer therapy in the smallest beneficial
doses for as briefly as possible. Ideally, E2 and E1 levels should be
held below, or near, the lower limit of the premenopausal female
reference range.
 
Antiestrogen therapy with central or peripheral acting agents that are
not pure receptor antagonists usually aims for complete suppression
of E2 production, and in the case of aromatase inhibitors, complete
E1 and E2 suppression.
 
Gynecomastia or other signs of feminization in males may be due to
an absolute or relative (in relation to androgens) surplus of
estrogens.
 
Gynecomastia is common during puberty in boys. Unless E1, E2, or
 
testosterone levels exceed the adult male reference range, the
condition is usually not due to hormonal disease (though it sometimes
may still result in persistent breast tissue, which later needs to be
surgically removed). For adults with gynecomastia, the work-up should
include testosterone and adrenal androgen measurements, in
addition to E2 and E1 measurements. Causes for increased E1 or E2
levels include:
 
-High androgen levels caused by tumors or androgen therapy
 (medical or sport performance enhancing), with secondary elevations
 in E1 and E2 due to aromatization
 
-Obesity with increased tissue production of E1
 
-Decreased E1 and E2 clearance in liver disease
 
-Estrogen producing tumors
 
-Estrogen ingestion
 
Normal male E1 and E2 levels also may be associated with feminization
or gynecomastia if bioavailable testosterone levels are low due to
primary/secondary testicular failure. This may occur, for example,
whe patients are receiving antiandrogen therapy or other drugs with
antiandrogenic effects (e.g., spironolactone, digitalis
preparations).
 
The gonadotrophin-releasing hormone (GnRH) stimulation test
remains the central part of the work-up for precocious puberty.
However, baseline sex steroid and gonadotrophin measurements also are
important. Prepubertal girls have E2 levels <10 pg/mL (most
<5 pg/mL). Levels in prepubertal boys are less than half the levels
seen in girls. LH/FSH are very low or undetectable. E1 levels also
are low, but may rise slightly in obese children after onset of
adrenarche.
E2, which is produced in the gonads, should remain low in these children.
Intrue precocious puberty, both E2 and LH/FSH levels are elevated above
the prepubertal range. Elevation of E2 or E1 alone suggests pseudo
precocious puberty, possibly due to a sex steroid-producing tumor.
 
In delayed puberty, estrogens and gonadotrophins are in the
prepubertal range. A rise over time predicts the spontaneous onset of
puberty. Persistently low estrogens and elevated gonadotrophins
suggest primary ovarian failure, while low gonadotrophins suggest
hypogonadotrophic hypogonadism. In this latter case, Kallman's
syndrome (or related disorders) or hypothalamic/pituitary tumors
should be excluded in well-nourished children.
 
Inherited disorders of sex steroid metabolism are usually associated
with production abnormalities of other steroids, most notably a lack
of cortisol. Aromatase deficiency is not associated with cortisol
abnormalities and usually results in some degree of masculinization in
affected females, as well as primary failure of puberty. Males may
show delayed puberty and delayed epiphyseal closure, as well as
low bone-density. E2 and E1 levels are very low or undetectable.
 
Various forms of testicular feminization are due to problems in
androgen signaling pathways and are associated with female (or
feminized) phenotypes in genetic males. E2 and E1 levels are above
the male reference range, usually within the female reference range,
 
and testosterone levels are very high.