Interpretation

Estradiol (E2) levels below the premenopausal reference range in young females indicate hypogonadism. If luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels are elevated, primary gonadal failure is diagnosed. The main causes are genetic (eg, Turner syndrome, familial premature ovarian failure), autoimmune (eg, autoimmune ovarian failure, possibly as part of autoimmune polyglandular endocrine failure syndrome type II), and toxic (eg, related to chemotherapy or radiation therapy for malignant disease). If LH/FSH levels are low or inappropriately "normal," a diagnosis of hypogonadotrophic hypogonadism is made. This can have functional causes, such as starvation, overexercise, severe physical or emotional stress, and heavy drug and/or alcohol use. It also can be caused by organic disease of the hypothalamus or pituitary. Further work-up is usually necessary, typically including measurement of pituitary hormones (particularly prolactin), and possibly imaging.

Irregular or absent menstrual periods with normal or high E2 levels (and often high estrone: 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.

E2 analysis may be helpful in establishing time of ovulation and optimal time for conception. Optimal time for conception is within 48 to 72 hours following the midcycle E2 peak. Serial specimens must be collected over several days to evaluate baseline and peak total estrogen (E1 + E2) levels. Low baseline levels and a lack of rise, as well as persistent high levels without midcycle rise are indicative of anovulatory cycles.

For determining the timing of initiation of ovarian stimulation in in vitro fertilization studies, low levels (around 30 pg/mL) before stimulation are critical, as higher values often are associated with poor stimulation cycles.

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.

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.

Postmenopausal women and older men in the lowest quartile of E2 levels are at increased risk of osteoporotic fractures. E2 levels are typically less than 5 pg/mL.

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 workup 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 E1 and E2 levels in males may also be associated with feminization or gynecomastia, if bioavailable testosterone levels are low due to primary/secondary testicular failure. This may occur, for example, when patients are receiving antiandrogen therapy or other drugs with antiandrogenic effects (eg, spironolactone, digitalis preparations).

The gonadotrophin-releasing hormone (GnRH) stimulation test remains the central part of the workup for precocious puberty. However, baseline sex steroid and gonadotrophin measurements also are important. Prepubertal girls have E2 levels less than 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. In true 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 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.

For more information see Steroid Pathways.