Diagnosing and differential diagnosis of hyperandrogenism (in

conjunction with measurements of other sex steroids).

An initial screen in adults might include dehydroepiandrosterone

(DHEA)/ dehydroepiandrosterone sulfate (DHEAS) and

bioavailable testosterone measurement. Depending on results,

this may be supplemented with measurements of sex hormone-

binding globulin and occasionally other androgenic steroids

(eg, 17-hydroxyprogesterone).

An adjunct in the diagnosis of congenital adrenal hyperplasia

(CAH); DHEA/DHEAS measurements play a secondary

role to the measurements of cortisol/cortisone, 17

alpha-hydroxyprogesterone, and androstenedione.

Diagnosing and differential diagnosis of premature adrenarche.

Dehydroepiandrosterone (DHEA) is the principal human C-19

steroid. DHEA has very low androgenic potency, but serves as

the major direct or indirect precursor for most sex steroids. DHEA

is secreted by the adrenal gland and production is at least partly

controlled by adrenocorticotropic hormone (ACTH). The bulk of

DHEA is secreted as a 3-sulfoconjugate dehydroepiandrosterone

sulfate (DHEAS). Both hormones are albumin bound, but DHEAS

binding is much tighter. As a result, circulating concentrations of

DHEAS are much higher (greater than 100-fold) compared to

DHEA. In most clinical situations, DHEA and DHEAS results can

be used interchangeably. In gonads and several other tissues,

most notably skin, steroid sulfatases can convert DHEAS back

to DHEA, which can then be metabolized to stronger androgens

and to estrogens.

During pregnancy, DHEA/DHEAS and their 16-hydroxylated

metabolites are secreted by the fetal adrenal gland in large

quantities. They serve as precursors for placental production of

the dominant pregnancy estrogen, estriol. Within weeks after birth,

DHEA/DHEAS levels fall by 80% or more and remain low until

the onset of adrenarche at age 7 or 8 in girls and age 8 or 9 in boys.

Adrenarche is a poorly understood phenomenon peculiar to

higher primates, that is characterized by a gradual rise in

adrenal androgen production. It precedes puberty, but is not

casually linked to it. Early adrenarche is not associated with

early puberty or with any reduction in final height or overt andro-

genization. However, girls with early adrenarche may be at

increased risk of polycystic ovarian syndrome as adults and

some boys may develop early penile enlargement.

Following adrenarche, DHEA/DHEAS levels increase until the

age of 20 to a maximum roughly comparable to that observed

at birth. Levels then decline over the next 40 to 60 years to around

20% of peak levels. The clinical significance of this age-related

drop is unknown and trials of DHEA/DHEAS replacement in the

elderly have not produced convincing benefits. However, in

young and old patients with primary adrenal failure, the addition

of DHEA/DHEAS to corticosteroid replacement has been shown

in some studies to improve mood, energy, and sex drive.

Elevated DHEA/DHEAS levels can cause symptoms or signs of

hyperandrogenism in women. Men are usually asymptomatic, but

through peripheral conversion of androgens to estrogens can

occasionally experience mild estrogen excess. Most mild-to-

moderate elevations in DHEAS levels are idiopathic. However,

pronounced elevations of DHEA/DHEAS may be indicative of

androgen-producing adrenal tumors. In small children, congenital

adrenal hyperplasia (CAH) due to 3 beta-hydroxysteroid dehydro-

genase deficiency is associated with excessive DHEA/DHEAS

production. Lesser elevations may be observed in 21-hydroxylase

deficiency (the most common form of CAH) and 11 beta-hydroxylase

deficiency. By contrast, steroidogenic acute regulatory protein

(STAR) or 17 alpha-hydroxylase deficiency is characterized by

low DHEA/DHEAS levels.

Premature: <40 ng/mL*

0-1 day: <11 ng/mL*

2-6 days: <8.7 ng/mL*

7 days-1 month: <5.8 ng/mL*

>1-23 months: <2.9 ng/mL*

2-5 years: <2.3 ng/mL

6-10 years: <3.4 ng/mL

11-14 years: <5.0 ng/mL

15-18 years: <6.6 ng/mL

19-30 years: <13 ng/mL

31-40 years: <10 ng/mL

41-50 years: <8.0 ng/mL

51-60 years: <6.0 ng/mL

> or =61 years: <5.0 ng/mL

(NIH units)

Premature: <4,000 ng/dL*

0-1 day: <1,100 ng/dL*

2-6 days: <870 ng/dL*

7 days-1 month: <580 ng/dL*

>1 month-23 months: <290 ng/dL*

2-5 years: <230 ng/dL

6-10 years: <340 ng/dL

11-14 years: <500 ng/dL

15-18 years: <660 ng/dL

19-30 years: <1,300 ng/dL

31-40 years: <1,000 ng/dL

41-50 years: <800 ng/dL

51-60 years: <600 ng/dL

> or =61 years: <500 ng/dL 

*Source: Dehydroepiandrosterone. In Pediatric Reference

Ranges. 5th edition. Edited by SJ Soldin, C Brugnara, EC Wong.

Washington, DC, AACC Press, 2005, p 75

Elevated DHEA/DHEAS levels indicate increased adrenal androgen

production. Mild elevations in adults are usually idiopathic, but levels

>5-fold or more of the upper limit of normal can suggest the presence

of an androgen-secreting adrenal tumor. DHEA/DHEAS levels are

elevated in >90% of patients with such tumors. This is particularly

true for androgen-secreting adrenal carcinomas, as they have typically

lost the ability to produce downstream androgens, such as

testosterone. By contrast, androgen-secreting adrenal adenomas

may also produce excess testosterone and secrete lesser amounts

of DHEA/DHEAS.

Patients with CAH may show very high levels of DHEA/DHEAS,

often 5- to 10-fold elevations. However, with the possible exception

of 3 beta-hydroxysteroid dehydrogenase deficiency, other steroid

analytes offer better diagnostic accuracy than DHEA/DHEAS

measurements. Consequently, DHEA/DHEAS testing should not

be used as the primary tool for CAH diagnosis. Similarly,

discovering a high DHEA/DHEAS level in an infant or child with

symptoms or signs of possible CAH should prompt additional

testing, as should the discovery of very high DHEA/DHEAS levels

in an adult. In the latter case, adrenal tumors need to be excluded

and additional adrenal steroid profile testing may assist in

diagnosing nonclassical CAH.

Currently the correlation of serum DHEA/DHEAS level with

human well-being or disease risk factors have not been

completely established.

There are currently no established guidelines for DHEA/DHEAS

replacement/supplementation therapy or its biochemical

monitoring. In most settings, the value of DHEA/DHEAS therapy

is doubtful. However, if DHEAS therapy is used, then it seems

prudent to avoid overtreatment, with its associated

hyperandrogenic effects. These are particularly likely to

occur in postmenopausal females if DHEA/DHEAS levels

approach or exceed the upper reference range. Most

supplements contain DHEA, but the in vivo conversion to

DHEAS allows monitoring of either DHEA or DHEAS.

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