Diagnosis and differential diagnosis of hyperandrogenism (in

conjunction with measurements of other sex-steroids). An initial

work-up in adults might also include total and bioavailable

testosterone (#80065 "Testosterone, Total and Bioavailable, Serum")

measurements. Depending on results, this may be supplemented

with measurements of sex hormone binding globulin (#9285 "Sex

Hormone Binding Globulin [SHBG], Serum") and, occasionally other

androgenic steroids (e.g., 17-hydroxyprogesterone).

As an adjunct in the diagnosis of CAH

Diagnosis 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 adrenocorticotrpic hormone (ACTH). The bulk of

DHEA is secreted as a 3-sulfoconjugate (DHEA-S). Both hormones

are albumin bound, but binding of DHEA-S is much tighter. In gonads

and several other tissues, most notably skin, steroid sulfatases can

convert DHEA-S back to DHEA, which can then be metabolized to

stronger androgens and to estrogens.

During pregnancy, DHEA-S and its 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-S levels fall by 80%

or more and remain low until the onset of adrenarche at age 7 or 8 in

boys. Adrenarche is a poorly understood phenomenon peculiar to

higher primates, which is characterized by a gradual rise in adrenal

androgen production. It precedes puberty but is not causally linked to

it. Early adrenarche is not associated with early puberty or with any

reduction in final height or overt androgenization and is generally

regarded as a benign condition, not needing intervention. However,

girls with early adrenarche may be at increased risk of polycystic

ovarian syndrome (PCOS) as adults, and some boys may develop

early penile enlargement.

Following adrenarche, DHEA-S levels increase until the age of 20 to

a maximum roughly comparable to that observed at birth.  Levels then

decline over the next 40-60 years to around 20% of peak levels. The

clinical significance of this age-related drop is unknown and trials of

DHEA-S replacement in the elderly have not produced convincing

benefits. However, in young and old patients with primary adrenal

failure, the addition of DHEA-S to corticosteroid replacement has

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

Elevated DHEA-S 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 DHEA-S levels are idiopathic. However,

pronounced elevations of DHEA-S may be indicative of androgen-

producing adrenal tumors. In small children, congenital adrenal

hyperplasia (CAH) due to 3 beta-hydroxysteroid deficiency is

associated with excessive DHEA-S 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 deficiencies are characterized by low DHEA-S levels.

MALES

1-14 days: DHEA-S levels in newborns are very elevated at birth

                      but will fall to prepubertal levels within a few days.

*Tanner Stage:  Mean Age           Reference Range (ug/dL)

Stage I:                 >14 days              <15-120

Stage II:                11.5 years            <15-333

Stage III:               13.6 years            <15-312

Stage IV:              15.1 years              29-412

Stage V:               18.0 years              89-457

*Puberty onset (transition from Tanner stage I to Tanner stage II)

occurs for boys at a median age of 11.5 ( /-) 2 years. For boys,

there is no proven relationship between puberty onset and

body weight or ethnic origin. Progression through Tanner stages is

variable. Tanner stage V (adult) is usually reached by age 18.

18-29 years: 89-457 ug/dL

30-39 years: 65-334 ug/dL

40-49 years: 48-244 ug/dL

50-59 years: 35-179 ug/dL

> or =60 years: 25-131 ug/dL

FEMALES

1-14 days: DHEA-S levels in newborns are very elevated at birth 

                     but fall to prepubertal levels within a few days.

*Tanner Stage:  Mean Age           Reference Range (ug/dL)

Stage I:                 >14 days              16-96

Stage II:                10.5 years            22-184

Stage III:               11.6 years            <15-296

Stage IV:              12.3 years            17-343

Stage V:               14.5 years            44-332

*Puberty onset (transition from Tanner stage I to Tanner stage II)

occurs for girls at a median age of 10.5 ( /-) 2 years. There is

evidence that it may occur up to 1 year earlier in obese girls and

in African-American girls. Progression through Tanner stages is

variable. Tanner stage V (adult) is usually reached by age 18.

18-29 years: 44-332 ug/dL

30-39 years: 31-228 ug/dL

40-49 years: 18-244 ug/dL

50-59 years: <15-200 ug/dL

> or =60 years: <15-157 ug/dL

Elevated DHEA-S levels indicate increased adrenal androgen

production. Mild elevations in adults are usually idiopathic, but

levels of 600 ug/dL or more can suggest the presence of an

androgen-secreting adrenal tumor. DHEA-S levels are elevated

in more than 90% of patients with such tumors, usually well above

600 ug/dL. This is particularly true for androgen-secreting adrenal

carcinomas, as they have typically lost the ability to produce down-

stream androgens, such as testosterone. By contrast, androgen-

secreting adrenal adenomas may also produce excess

testosterone and secrete lesser amounts of DHEA-S.

Patients with CAH may show very high levels of DHEA-S, often 5-10-

fold elevations. However, with the possible exception of 3 beta-

hydroxysteroid dehydrogenase deficiency, other steroid analytes

offer better diagnostic accuracy than DHEA-S measurements.

Consequently, DHEA-S testing should not be used as the primary

tool for CAH diagnosis. Similarly, discovering a high DHEA-S 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-S 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.

Girls below the age of 7-8 and boys before age 8-9, who present with

early development of pubic hair, or, in boys, penile enlargement, may

be suffering from either premature adrenarche or premature puberty,

or both. Measurement of DHEA-S, DHEA (#8567 "17-Ketosteroid

Fractionation, Urine"), and androstenedione (#9709 "Androstenedione,

Serum"), alongside determination of sensitive estradiol (#81816

"Estradiol, Enhanced, Serum"), testosterone and bioavailable

(#80065 "Testosterone, Total and Bioavailable, Serum"), or free

testosterone (#8508 "Testosterone, Total and Free, Serum"),

SHBG (#9285 "Sex Hormone Binding Globulin [SHBG], Serum"),

and LH (#8663 "Luteinizing Hormone [LH], Serum")/FSH

(#8670 "Follicle-Stimulating Hormone [FSH], Serum") levels will allow

correct diagnosis in most cases. In premature adrenarche, only the

adrenal androgens, chiefly DHEA-S, will be above prepubertal levels,

whereas early puberty will also show a fall in SHBG levels and

variable elevations of gonadotropins and gonadal sex-steroids

above the pre-puberty reference range.

Levels of DHEA-S do not show significant diurnal variation.

There are currently no established guidelines for DHEA-S

replacement/supplementation therapy or its biochemical monitoring.

In most settings, the value of DHEA-S therapy is doubtful. However,

if DHEA-S therapy is used, then it seems prudent to avoid over-

treatment, with its associated hyperandrogenic effects. These are

particularly likely to occur in postmenopausal females if DHEA-S

levels approach or exceed the upper reference range. Most

supplements contain DHEA, but the in vivo conversion to DHEA-S

allows monitoring of either DHEA or DHEA-S.

Many drugs and hormones can result in changes in DHEA-S levels.

Whether any of these secondary changes in DHEA-S levels are of

clinical significance and how they should be related to the established

normal reference ranges is unknown. In most cases, the drug-induced

changes are not large enough to cause diagnostic confusion, but when

interpreting mild abnormalities in DHEA-S levels, drug and hormone

interactions should be taken into account.

Examples of drugs/hormones that can reduce DHEA-S levels include:

insulin, oral contraceptive drugs, corticosteroids, central nervous

system agents that induce hepatic enzymes (e.g., carbamazepine,

clomipramine, imipramine, phenytoin), many antilipemic drugs (e.g.,

statins, cholestyramine), domapinergic drugs (e.g., levodopa/

dopamine, bromocryptine), fish oil, and vitamin E.

Drugs that may increase DHEA-S levels include: metfomin, troglitazone,

prolactin (and by indirect implication many neuroleptic drugs), danazol,

calcium channel blockers (e.g., diltiazem, amlodipine), and nicotine.

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