Adrenal Androgens

Adrenal androgens are steroid hormones produced by the adrenal cortex, predominantly within the zona reticularis. The major adrenal androgenic steroids are dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione. These hormones have relatively weak intrinsic androgenic activity compared with testosterone and dihydrotestosterone, but they are important because they can be converted into more potent androgens or estrogens in peripheral tissues.

The adrenal glands produce androgenic steroids in both males and females. Their physiological importance differs according to sex, age, gonadal function, and the ability of peripheral tissues to convert adrenal precursors into biologically active sex steroids. Adrenal androgen production becomes particularly prominent during adrenarche in childhood and contributes to the development of pubic and axillary hair.

Adrenal androgen synthesis is closely related to cortisol synthesis because both pathways begin with cholesterol and share several steroidogenic intermediates. Production is influenced primarily by adrenocorticotropic hormone (ACTH), although the regulation of adrenal androgen secretion is not identical to that of cortisol.

Site of Production

Adrenal androgens are produced within the adrenal cortex, particularly the zona reticularis.

The adrenal cortex is organized into three major zones:

• Zona glomerulosa
• Zona fasciculata
• Zona reticularis

Adrenal Cortical Zones

Zone	Major Hormonal Products
Zona glomerulosa	Mineralocorticoids, especially aldosterone
Zona fasciculata	Glucocorticoids, especially cortisol
Zona reticularis	Adrenal androgens, particularly DHEA and DHEAS

Zona Reticularis

The zona reticularis is the innermost layer of the adrenal cortex and lies immediately external to the adrenal medulla.

Its steroidogenic cells are arranged in an interconnected network and contain the enzymes required for substantial production of androgen precursors.

Major Adrenal Androgens

The principal androgenic steroids produced directly or indirectly by the adrenal cortex include:

• Dehydroepiandrosterone (DHEA)
• Dehydroepiandrosterone sulfate (DHEAS)
• Androstenedione

Small quantities of other androgenic steroids may also be produced.

Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) is an important steroid produced by the zona reticularis.

DHEA itself has relatively weak androgenic activity but serves as an important precursor from which peripheral tissues can synthesize more potent androgens and estrogens.

Dehydroepiandrosterone Sulfate

Dehydroepiandrosterone sulfate (DHEAS) is the sulfated form of DHEA and is produced in large quantities by the adrenal cortex.

DHEAS circulates at substantially higher concentrations than DHEA and has a longer circulating half-life, making it a useful clinical marker of adrenal androgen production.

Androstenedione

Androstenedione is another androgen precursor produced by the adrenal glands as well as the gonads.

Peripheral tissues can convert androstenedione into testosterone or estrogens depending on the enzymes expressed within those tissues.

Comparison of Major Adrenal Androgens

Hormone	Major Feature
DHEA	Weak androgen and important steroid precursor
DHEAS	Sulfated adrenal androgen with high circulating concentration and long half-life
Androstenedione	Precursor capable of conversion to testosterone and estrogens

Steroid Hormone Synthesis

Like all adrenal cortical steroid hormones, adrenal androgens are synthesized from cholesterol.

Cholesterol is transported into mitochondria, where steroidogenesis begins with its conversion to pregnenolone.

Cholesterol

Cholesterol is the common precursor for mineralocorticoids, glucocorticoids, and adrenal androgens.

Adrenal cortical cells obtain cholesterol from circulating lipoproteins and intracellular stores and can also synthesize cholesterol.

Transport Into the Mitochondria

A critical early step in steroidogenesis is the movement of cholesterol to the inner mitochondrial membrane.

The steroidogenic acute regulatory protein (StAR) plays an important role in facilitating this process.

Pregnenolone Formation

Within mitochondria, cholesterol is converted to pregnenolone by the cholesterol side-chain cleavage enzyme.

Pregnenolone then serves as a precursor for several adrenal steroidogenic pathways.

Androgenic Steroid Pathway

In the zona reticularis, steroidogenesis is directed substantially toward formation of C19 androgen precursors.

A simplified pathway is:

Cholesterol → Pregnenolone → 17-Hydroxypregnenolone → DHEA → Androstenedione → Peripheral sex steroids

CYP17A1

The enzyme CYP17A1 has both 17α-hydroxylase and 17,20-lyase activities and is essential for adrenal androgen synthesis.

Its 17,20-lyase activity facilitates formation of DHEA from 17-hydroxypregnenolone.

17,20-Lyase Activity

Enhanced 17,20-lyase activity within the zona reticularis favors production of androgen precursors rather than directing all available steroid intermediates toward glucocorticoid synthesis.

DHEA Sulfation

DHEA can undergo sulfation to form DHEAS.

This reaction is catalyzed primarily by the sulfotransferase enzyme SULT2A1, which is highly expressed in the zona reticularis.

Steroidogenic Characteristics of the Zona Reticularis

The enzyme expression pattern of the zona reticularis favors production of DHEA and DHEAS.

This biochemical specialization distinguishes the zona reticularis from the neighboring zona fasciculata, which is primarily specialized for cortisol production.

Adrenal Androgen Synthesis

Step	Product or Process
Initial substrate	Cholesterol
First steroid intermediate	Pregnenolone
Important hydroxylated intermediate	17-Hydroxypregnenolone
Major adrenal androgen	DHEA
Sulfated product	DHEAS
Additional androgen precursor	Androstenedione

Regulation by ACTH

Adrenocorticotropic hormone (ACTH) is an important regulator of adrenal androgen production.

ACTH is secreted by corticotroph cells of the anterior pituitary and acts on cells of the adrenal cortex.

Hypothalamic-Pituitary-Adrenal Axis

The hypothalamic-pituitary-adrenal axis provides the principal endocrine pathway regulating ACTH secretion.

Corticotropin-releasing hormone from the hypothalamus stimulates ACTH release from the anterior pituitary, which subsequently stimulates the adrenal cortex.

ACTH Receptors

ACTH binds to melanocortin 2 receptors on adrenal cortical cells.

Receptor activation stimulates intracellular signaling pathways that promote cholesterol availability and steroid hormone synthesis.

ACTH and Steroidogenesis

ACTH increases steroidogenic activity by influencing several steps involved in cholesterol transport and steroid synthesis.

Because the zona reticularis is responsive to ACTH, changes in ACTH secretion can alter adrenal androgen production.

Regulation Compared With Cortisol

Both cortisol and adrenal androgen production are influenced by ACTH. However, their developmental patterns and detailed regulation are not identical.

Adrenal androgen production undergoes characteristic age-related changes that are particularly evident during adrenarche.

Adrenarche

Adrenarche is the developmental increase in adrenal androgen production that occurs during childhood, typically before the full activation of gonadal puberty.

It is associated with maturation of the zona reticularis and increasing secretion of DHEA and DHEAS.

Adrenarche and Puberty

Adrenarche and gonadal puberty are related developmental processes but are not identical.

Adrenarche reflects increased adrenal androgen production, whereas gonadal puberty is driven primarily by activation of the hypothalamic-pituitary-gonadal axis.

Effects of Adrenarche

Increasing adrenal androgen production contributes to several secondary changes during childhood and adolescence.

These can include:

• Development of pubic hair
• Development of axillary hair
• Increased activity of apocrine glands
• Changes in body odor
• Increased sebaceous gland activity

Pubarche

Pubarche refers to the appearance of pubic hair associated with increasing androgen action.

Adrenal androgens are important contributors to pubarche, particularly during normal adrenarche.

Adrenal Androgens Across the Lifespan

Adrenal androgen production changes substantially with age.

Levels are relatively low during early childhood, rise during adrenarche, reach high concentrations during early adulthood, and generally decline progressively with advancing age.

DHEAS and Age

DHEAS concentrations show a particularly prominent age-related pattern.

After increasing during adrenarche and reaching relatively high levels in young adulthood, circulating DHEAS generally decreases progressively later in life.

Physiological Actions

The direct androgenic potency of DHEA and DHEAS is relatively weak.

Much of their physiological importance results from their ability to act as precursors for locally produced testosterone, dihydrotestosterone, and estrogens.

Peripheral Conversion

Adrenal androgen precursors can be taken up by peripheral tissues and converted enzymatically into more active sex steroids.

The final hormonal effect therefore depends partly on the enzymes expressed within individual tissues.

Conversion to Testosterone

Androstenedione can be converted into testosterone by enzymes present in peripheral tissues.

DHEA can also contribute indirectly to testosterone production after conversion through intermediate steroids.

Conversion to Dihydrotestosterone

Testosterone derived from adrenal androgen precursors can undergo further conversion to dihydrotestosterone (DHT) in tissues expressing 5α-reductase.

DHT is a potent androgen acting through the androgen receptor.

Conversion to Estrogens

Androstenedione and testosterone derived from adrenal precursors can undergo aromatization to form estrogens.

Adrenal androgens therefore contribute not only to androgenic activity but also to peripheral estrogen production.

Intracrine Conversion

Some tissues convert circulating adrenal androgen precursors into active sex steroids locally and use those hormones within the same tissue.

This local production and action is often described as intracrine steroid metabolism.

Adrenal Androgens in Females

Adrenal androgens represent an important component of androgen production in females.

They contribute to androgen-dependent features such as pubic and axillary hair and provide precursors for peripheral androgen and estrogen synthesis.

Adrenal Androgens in Males

In adult males with normal testicular function, the testes produce much larger quantities of potent androgen, particularly testosterone.

Consequently, adrenal androgen secretion generally contributes a smaller proportion of total androgenic activity than it does in females.

Adrenal Versus Gonadal Androgens

Feature	Adrenal Androgens	Major Gonadal Androgens
Major source	Zona reticularis	Primarily testes in males, with ovarian androgen production in females
Representative hormones	DHEA, DHEAS, androstenedione	Testosterone
Intrinsic androgenic potency	Generally weak	Greater
Major regulatory pathway	ACTH-related regulation	Gonadotropin regulation
Important role	Peripheral sex steroid precursors	Direct systemic androgen action

Transport in Blood

Adrenal androgenic steroids circulate in different forms and with different degrees of protein binding.

DHEAS is highly water soluble relative to unconjugated steroid hormones because of its sulfate group and circulates at much higher concentrations than DHEA.

DHEAS as a Circulating Reservoir

The relatively high concentration and long half-life of DHEAS allow it to function as a substantial circulating pool of adrenal androgen precursor.

Peripheral tissues capable of steroid metabolism can participate in conversion of adrenal precursors into biologically active hormones.

DHEAS as a Clinical Marker

Because DHEAS is produced predominantly by the adrenal glands and has relatively stable circulating concentrations, measurement of DHEAS can help assess whether androgen excess is likely to have an adrenal component.

Androgen Excess

Excessive adrenal androgen production can produce signs of androgen excess, particularly in females and children.

The manifestations depend on the patient's age, sex, severity of hormone excess, and specific steroids produced.

Clinical Features of Androgen Excess

Potential manifestations include:

• Premature development of pubic or axillary hair
• Hirsutism
• Acne
• Menstrual disturbance
• Virilization in severe androgen excess
• Accelerated growth and skeletal maturation in children

Hirsutism

Hirsutism refers to excessive terminal hair growth in androgen-sensitive areas in females.

Adrenal androgen excess is one possible contributor, although hirsutism has multiple potential endocrine and non-endocrine causes.

Virilization

Virilization describes the development of more pronounced androgenic features resulting from substantial androgen exposure.

Rapid or marked virilization can indicate significant androgen excess and warrants evaluation of both adrenal and gonadal sources.

Premature Adrenarche

Premature adrenarche refers to an earlier-than-expected increase in adrenal androgen production.

It may present with premature pubic or axillary hair, body odor, or other androgen-dependent changes without complete activation of gonadal puberty.

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) comprises inherited disorders of adrenal steroidogenesis caused by deficiencies of specific steroidogenic enzymes.

Some forms reduce cortisol synthesis and redirect steroid precursors toward androgen production, producing adrenal androgen excess.

21-Hydroxylase Deficiency

21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia.

Reduced cortisol synthesis decreases normal negative feedback on ACTH secretion. Increased ACTH stimulation and accumulation of steroid precursors can result in excessive adrenal androgen production.

ACTH in Congenital Adrenal Hyperplasia

When cortisol synthesis is impaired, reduced negative feedback can increase ACTH secretion.

Chronic ACTH stimulation promotes adrenal cortical hyperplasia and increases steroid production upstream of the enzymatic block.

Androgen Pathway Diversion

In some forms of CAH, steroid intermediates that cannot proceed efficiently through the normal cortisol pathway are diverted toward androgen synthesis.

This biochemical rerouting explains the association between certain enzyme deficiencies and androgen excess.

Adrenal Androgen-Producing Tumors

Adrenal cortical tumors can occasionally produce excessive quantities of androgenic steroids.

Markedly elevated adrenal androgen concentrations, particularly when accompanied by rapid clinical progression, can prompt investigation for an adrenal source.

Adrenocortical Carcinoma

Adrenocortical carcinoma can produce cortisol, androgens, mineralocorticoids, estrogens, or combinations of steroid hormones.

Androgen secretion from an adrenal cortical neoplasm may produce rapidly developing signs of androgen excess.

Cushing Syndrome and Adrenal Androgens

Disorders associated with excessive ACTH stimulation can affect multiple steroidogenic pathways within the adrenal cortex.

Depending on the underlying cause, adrenal androgen concentrations may therefore change together with cortisol production.

ACTH-Dependent Hypercortisolism

When ACTH concentrations are chronically elevated, stimulation of both the zona fasciculata and zona reticularis can increase production of cortisol and adrenal androgen precursors.

ACTH-Independent Cortisol Excess

When cortisol is produced autonomously by an adrenal lesion, suppression of pituitary ACTH may reduce stimulation of nonautonomous adrenal cortical tissue.

Adrenal androgen concentrations may consequently be lower in some ACTH-independent states.

Adrenal Insufficiency

Primary adrenal insufficiency damages the adrenal cortex and can reduce production of cortisol, aldosterone, and adrenal androgens to varying degrees.

Loss of adrenal androgen production can be more clinically apparent in females because adrenal steroids contribute more substantially to their total androgen pool.

Primary Adrenal Insufficiency

In primary adrenal cortical failure, reduced zona reticularis function can decrease DHEA and DHEAS production.

This occurs together with deficiencies involving other adrenal cortical steroid pathways.

Secondary Adrenal Insufficiency

Reduced ACTH stimulation can decrease cortisol and adrenal androgen production.

Mineralocorticoid secretion is comparatively preserved because aldosterone regulation depends predominantly on the renin-angiotensin system and extracellular potassium concentration rather than ACTH.

Laboratory Assessment

Laboratory evaluation of suspected adrenal androgen abnormalities may include measurement of specific circulating steroids and steroid precursors.

The tests selected depend on the clinical presentation and suspected disorder.

DHEAS Measurement

DHEAS is commonly measured when evaluating androgen excess because it is produced predominantly by the adrenal cortex.

Its relatively long half-life and limited short-term fluctuation also make it useful for assessing adrenal androgen production.

DHEA Measurement

DHEA can also be measured, although its circulating concentration varies more than DHEAS and it has a shorter half-life.

Androstenedione Measurement

Androstenedione measurement can provide additional information about androgen synthesis but does not uniquely identify an adrenal source because both the adrenal glands and gonads can produce it.

17-Hydroxyprogesterone

17-Hydroxyprogesterone is an important steroid precursor measured particularly when evaluating suspected 21-hydroxylase deficiency.

Elevated concentrations can indicate impaired progression through the normal steroidogenic pathway.

ACTH Stimulation Testing

ACTH stimulation testing can be used in the evaluation of selected disorders of adrenal steroidogenesis.

Changes in cortisol and steroid precursor concentrations following ACTH administration can help characterize adrenal enzymatic function.

Distinguishing Adrenal and Gonadal Sources

Determining the source of androgen excess requires consideration of the pattern of hormone abnormalities rather than measurement of a single androgen alone.

DHEAS is particularly useful because its production is predominantly adrenal, whereas testosterone and androstenedione can arise from both adrenal and gonadal pathways.

Adrenal Androgen Markers

Hormone	Clinical Interpretation
DHEAS	Useful marker of adrenal androgen production
DHEA	Adrenal androgen precursor with greater short-term variation
Androstenedione	Can originate from adrenal glands or gonads
Testosterone	Potent androgen with important gonadal and peripheral sources
17-Hydroxyprogesterone	Important in assessment of selected steroidogenic enzyme defects

Relationship to Cortisol Synthesis

Adrenal androgen and cortisol synthesis share cholesterol and several early steroidogenic steps.

The final hormonal products depend on the enzymes and cofactors expressed within different zones of the adrenal cortex.

Zona Fasciculata Versus Zona Reticularis

Feature	Zona Fasciculata	Zona Reticularis
Location	Middle adrenal cortical layer	Inner adrenal cortical layer
Major product	Cortisol	DHEA and DHEAS
Major regulator	ACTH	ACTH-related regulation
Principal steroid role	Glucocorticoid activity	Androgen precursor production

Relationship to Aldosterone Synthesis

The zona glomerulosa is specialized for aldosterone production and lacks significant CYP17A1 activity.

It therefore does not normally contribute substantially to adrenal androgen synthesis.

Adrenal Cortex Functional Organization

The functional specialization of adrenal cortical zones reflects differences in steroidogenic enzyme expression.

Although all cortical zones derive steroid hormones from cholesterol, they produce different final products because they express different combinations and activities of enzymes.

Androgen Receptor

Potent androgens derived from adrenal precursors can exert biological effects through the androgen receptor, an intracellular nuclear receptor expressed in numerous tissues.

DHEA and DHEAS themselves have much weaker direct androgenic effects than testosterone or DHT.

Aromatase

The enzyme aromatase converts androgenic steroids into estrogens.

Peripheral aromatization allows adrenal androgen precursors to contribute indirectly to estrogen production.

Peripheral Tissues

Tissues capable of metabolizing adrenal androgen precursors include adipose tissue, skin, hair follicles, bone, and reproductive tissues.

The steroid produced locally depends on the combination of steroidogenic enzymes present in the tissue.

Skin and Hair Follicles

Skin and hair follicles contain enzymes capable of metabolizing androgen precursors.

This local metabolism contributes to the effects of adrenal androgens on pubic and axillary hair, sebaceous glands, and other androgen-sensitive structures.

Sebaceous Glands

Increasing androgen activity during adrenarche and puberty stimulates sebaceous gland activity.

This relationship contributes to the association between increasing androgen levels and development of acne.

Apocrine Glands

Adrenal androgen activity contributes to maturation and increased activity of apocrine glands during adrenarche.

This is associated with changes in body odor that commonly accompany this developmental stage.

Adrenal Androgens and Bone

Adrenal androgen precursors can be converted into active sex steroids within peripheral tissues, including bone.

Sex steroids influence skeletal growth, maturation, and maintenance, although gonadal hormones become the dominant sex steroid source during normal puberty.

Fetal Adrenal Androgens

The fetal adrenal gland has a distinctive organization that differs from the adult adrenal cortex.

A prominent fetal zone produces large quantities of DHEA sulfate, which participates in fetoplacental steroid metabolism.

Fetal Zone

The fetal zone forms a large proportion of the fetal adrenal cortex.

It produces androgen precursors, particularly DHEAS, that can be used by the placenta for estrogen synthesis.

Fetoplacental Steroidogenesis

During pregnancy, fetal adrenal DHEAS provides an important precursor for placental estrogen production.

The placenta modifies these fetal adrenal steroids through its own steroidogenic pathways.

After Birth

After birth, the fetal adrenal zone undergoes substantial involution.

The adrenal cortex subsequently develops toward its characteristic postnatal zonation and later undergoes further maturation associated with adrenarche.

Adrenal Androgens Versus Testosterone

Feature	DHEA/DHEAS	Testosterone
Major adrenal source	Zona reticularis	Only limited direct adrenal production
Androgenic potency	Weak	Strong
Role as precursor	Major role	Can itself be converted to DHT or estradiol
Circulating DHEAS form	Very abundant	Not applicable

Adrenal Androgens Versus Dihydrotestosterone

DHT is considerably more potent at the androgen receptor than the major adrenal androgen precursors.

Adrenal steroids can nevertheless contribute indirectly to DHT production after peripheral conversion through intermediate androgens.

Key Features of Adrenal Androgens

Feature	Key Point
Primary site of production	Zona reticularis of adrenal cortex
Major hormones	DHEA, DHEAS and androstenedione
Precursor	Cholesterol
Important enzyme	CYP17A1
DHEA sulfation enzyme	SULT2A1
Major regulatory hormone	ACTH
Developmental increase	Adrenarche
Intrinsic androgenic potency	Relatively weak
Major physiological role	Precursors for peripheral androgen and estrogen synthesis
Useful adrenal marker	DHEAS

Clinical Associations

Condition	Relationship to Adrenal Androgens
Premature adrenarche	Early increase in adrenal androgen production
Congenital adrenal hyperplasia	Some enzyme defects increase androgen synthesis
Adrenal androgen-producing tumor	Can produce marked androgen excess
Primary adrenal insufficiency	Reduced adrenal androgen production
ACTH deficiency	Can reduce adrenal androgen production
Hirsutism or virilization	May prompt evaluation for excessive adrenal androgen production

Anatomical and Physiological Importance

Adrenal androgens represent an important functional product of the zona reticularis of the adrenal cortex. DHEA, DHEAS, and androstenedione are relatively weak androgens compared with testosterone and DHT, but they form an important circulating pool of precursors that can be converted into active androgens and estrogens within peripheral tissues.

Production increases during adrenarche and contributes to pubic and axillary hair development, sebaceous activity, and other androgen-dependent changes. Their relative physiological importance is greater in females because testicular testosterone production dominates androgen activity in adult males with normal gonadal function.

The steroidogenic pathway is also clinically important because abnormalities in adrenal enzyme activity, ACTH regulation, or adrenal cortical growth can substantially alter androgen production. Disorders such as congenital adrenal hyperplasia, adrenal cortical tumors, and adrenal insufficiency can therefore be associated with characteristic changes in adrenal androgen concentrations. Measurement of DHEAS is particularly useful when evaluating the adrenal contribution to androgen excess because circulating DHEAS is produced predominantly by the adrenal cortex.