Adrenal androgens (DHEA and androstenedione)

The adrenal androgens DHEA (dehydroepiandrosterone), its sulfate ester DHEAS (dehydroepiandrosterone sulfate), and androstenedione form an endocrine system in which biological “potency” derives less from the secretion of a single final hormone than from the availability of steroid precursors that flexibly support the peripheral biosynthesis of androgens and estrogens. The adrenal cortex, particularly the zona reticularis, produces large quantities of DHEA and especially DHEAS. These molecules have limited direct receptor activity but considerable physiological relevance because they act as a circulating reservoir of substrates available to target tissues. Within this model, the “androgen signal” does not necessarily correspond to a circulating testosterone concentration, but rather to the ability of peripheral tissues to convert adrenal precursors into active steroids through local production.

The physiology of adrenal androgens is a paradigmatic example of the integration between organ endocrinology, steroidogenic biology, and tissue-specific regulation of hormonal activity. Biosynthesis depends on an enzymatic sequence that directs steroid flux from cholesterol toward C19 steroids. Key steps include cytochrome P450 17A1 (CYP17A1), which possesses 17α-hydroxylase and 17,20-lyase activities, support from cofactors such as cytochrome b5, and the relative reduction in 3β-hydroxysteroid dehydrogenase (3β-HSD) activity within the zona reticularis, which favors DHEA production. Systemic metabolism includes sulfation and desulfation, oxidation-reduction conversions between DHEA and androstenedione and between androstenedione and testosterone, and transformation into more active or inactive steroids according to the tissue involved. This page describes DHEA and androstenedione throughout their entire functional pathway, from adrenal production to the intracellular regulation of biological activity.

Adrenal androgens follow a different physiological logic from endocrine axes centered on a single effector hormone. The adrenal gland secretes primarily DHEAS and, to a lesser extent, DHEA and androstenedione, molecules that mainly act as precursors. Because of its sulfate group, DHEAS is highly hydrophilic, circulates at high concentrations, and has a relatively long half-life, forming a stable plasma reservoir. DHEA and androstenedione, which are more rapidly interconvertible, instead contribute to a dynamic flow of substrates that tissues can readily use to produce active steroids according to local biological requirements.

The decisive feature is that androgen activity in many peripheral tissues is dominated by the intracellular production of active hormones from adrenal precursors. This concept, commonly described as intracrinology, implies that the target tissue possesses its own set of enzymes capable of converting DHEA and androstenedione into more potent androgens or estrogens. The locally produced fraction may act within the tissue without being proportionally reflected in the circulation. Consequently, circulating measurements of precursors and final hormones provide useful but incomplete information about the biological state of signaling within individual tissues.

An additional level of control is provided by the alternation between activation and inactivation of signaling through tissue metabolic pathways. Conversion into more potent steroids may be counterbalanced by transformation into less active metabolites or excretable conjugates. This balance explains the flexibility of the system. In some settings, the availability of adrenal substrates supports reproductive and metabolic functions. In others, it may contribute to androgen excess, whereas systemic stress or changes in enzyme expression may reduce active steroid production even when the plasma reservoir appears preserved.

Three principles explain why DHEA and androstenedione are “precursors” whose biological effects vary markedly among tissues:

• a circulating DHEAS reservoir, characterized by high concentrations and prolonged availability;
• local conversion within peripheral tissues, which transform precursors into active androgens or estrogens according to their enzyme profile;
• intracellular regulation of the effect through activating and inactivating enzymes, nuclear receptors, and tissue coregulators.

This organization clarifies why understanding adrenal androgens requires starting from adrenocortical biosynthesis. The specialization of the zona reticularis and its enzymatic profile determine the amount and chemical form of the precursors released, thereby establishing the reservoir that will subsequently be remodeled by target tissues.

Adrenal androgen production begins with cholesterol, which is transferred into the mitochondria of adrenocortical cells and converted into pregnenolone by cytochrome P450 family 11 subfamily A member 1 (CYP11A1). From this point, steroid flux can be directed toward glucocorticoids, mineralocorticoids, or sex steroids according to the enzyme repertoire of the cortical compartment. C19 steroid production requires CYP17A1, an enzyme with two activities: 17α-hydroxylation and 17,20-lyase activity. The first generates 17-hydroxylated precursors, whereas the second cleaves the side chain to produce C19 steroids, including DHEA.

The zona reticularis possesses a functional combination of enzymes that favors DHEA production over conversion toward C21 steroids. A key element is the support provided to the 17,20-lyase activity of CYP17A1 by cytochrome b5 and redox cofactors, which increase the efficiency of C19 steroid generation. At the same time, the relatively lower availability of 3β-hydroxysteroid dehydrogenase within the zona reticularis reduces the conversion of Δ5 precursors into the Δ4 pathway, leaving more substrate available for DHEA production. This arrangement is essential for understanding why the zona reticularis is the principal source of adrenal androgens in humans.

The production of androstenedione may result from the conversion of DHEA through 3β-HSD or from cellular pathways in which the enzyme profile allows more efficient progression toward Δ4 steroids. Within the adrenal gland, androstenedione is generally produced in smaller quantities than DHEA and DHEAS, but it remains an important immediate precursor of testosterone and estrogens within peripheral tissues. Functionally, DHEA and androstenedione are not redundant. They provide two distinct entry points into peripheral steroidogenesis and depend differently on specific enzyme families.

Zonal organization and enzyme expression are not static. Maturation of the zona reticularis during development, accompanied by a progressive increase in DHEA and DHEAS production, underlies adrenarche. Conversely, the progressive decline in DHEA and DHEAS secretion with age demonstrates that the biosynthetic capacity of the zona reticularis is regulated throughout life, with consequences for the availability of precursors used in intracrine steroidogenesis.

The next step is to understand how biosynthesis is packaged into a circulating output dominated by the sulfated form, and how trophic stimulation and sulfation systems determine the stability of the plasma reservoir.

A distinctive characteristic of adrenal androgens is that their quantitatively predominant product is DHEAS, which is generated through DHEA sulfation. Sulfation is catalyzed primarily by sulfotransferase family 2A member 1 (SULT2A1), an enzyme highly expressed within the zona reticularis that transfers a sulfate group to DHEA, making it more hydrophilic and stabilizing its persistence in the circulation. This transformation is not merely a chemical detail, but a regulatory mechanism. DHEAS acts as a reservoir, reduces fluctuations in signaling, and ensures substrate availability to peripheral tissues even when adrenal secretion varies over short periods.

The balance between DHEA secretion and DHEAS production depends on sulfation capacity and on the availability of DHEA as a substrate. In practical terms, sulfation allows the adrenal gland to export a large store of precursors that can subsequently be reconverted into DHEA within tissues through steroid sulfatase. This system, involving upstream sulfation and downstream desulfation, is one of the principal mechanisms regulating the compartmentalized activity of steroids.

Adrenal androgen secretion is substantially influenced by adrenocorticotropic hormone (ACTH), with circadian rhythmicity and a stress response component shared with the broader physiology of the adrenal cortex. However, androgen output is not simply a reproduction of the cortisol profile. The zona reticularis has its own regulatory features related to zonal maturation, enzyme availability, and local signals that modulate steroidogenesis. This explains why DHEAS concentrations are relatively stable over time compared with those of other steroids and why DHEAS is frequently used in clinical practice as an indicator of adrenal androgen precursor production.

After secretion, signaling enters another decisive phase involving plasma transport and the biologically accessible fraction. Correct interpretation of measurements and understanding of how substrates reach tissues require consideration of plasma protein binding and of the relationship between total concentrations and bioavailability.

Within the bloodstream, DHEA and androstenedione circulate partly bound to plasma proteins, mainly albumin and, to a variable extent, sex hormone-binding globulin (SHBG). Protein binding helps stabilize circulating concentrations and regulates the fraction immediately available for tissue uptake. Because of its more hydrophilic nature, DHEAS has distinct transport characteristics. Its high concentration and relatively long half-life make it a true circulating reservoir that is less susceptible to rapid fluctuations than free DHEA or androstenedione.

The concept of a “free” fraction has a functional meaning similar to that observed in other endocrine systems, since this fraction is more readily accessible to tissues and more directly connected with intracellular conversion. In the adrenal androgen system, however, the decisive parameter is not only the strictly free fraction, but the combination of reservoir availability, particularly DHEAS, with the tissue capacity for uptake and transformation. Bioavailability is therefore the result of a balance between plasma transport, cellular access, and intracellular metabolism.

These considerations are also crucial because physiological and pathological conditions may alter binding proteins and change total concentrations without producing an equivalent change in tissue activity. Correct interpretation therefore requires integration of the clinical context, metabolic status, and, when necessary, assessment of final hormones or metabolites, bearing in mind that the adrenal gland mainly supplies precursors.

The next step is cellular entry. For intracrinology to occur, DHEA, androstenedione, and DHEAS must reach the intracellular compartment. Access to these substrates depends on transport mechanisms and on the tissue capacity for local desulfation and conversion.

The biological activity of adrenal precursors requires their entry into target cells. DHEA and androstenedione are more lipophilic and can cross membranes more readily than DHEAS, whose negatively charged sulfate group generally requires dedicated transport mechanisms or indirect strategies based on conversion. Functionally, this means that DHEAS is a substantial reservoir but is not automatically “active.” Its biological usefulness depends on the ability of tissues to import it and convert it into DHEA through steroid sulfatase, or to use the non-sulfated DHEA fraction available in the circulation.

Compartmental regulation results from the combination of substrate access and the intracellular enzyme repertoire. A tissue with a high desulfation capacity and enzymes that promote androgen activation can transform the DHEAS reservoir into local active steroid production. Conversely, a tissue that predominantly expresses inactivating enzymes or restricts precursor uptake may attenuate the effect. This mechanism explains both interindividual variability and the tissue specificity of biological responses to adrenal precursors.

Cellular access is closely linked to the principal biochemical conversion pathways. Once available within the cytoplasm, DHEA and androstenedione may be directed toward more potent androgens or toward estrogens, or they may be transformed into inactive metabolites and conjugates. Understanding how active signaling is generated therefore requires consideration of the main enzymatic steps involved in intracellular conversion.

Peripheral conversion of adrenal precursors is the functional core of the system. DHEA can be converted into androstenedione through 3β-HSD, and androstenedione can be converted into testosterone through specific 17β-hydroxysteroid dehydrogenase enzymes. Testosterone can subsequently be converted into dihydrotestosterone (DHT) within tissues expressing 5α-reductase. In parallel, androstenedione can be converted into estrone and testosterone into estradiol through aromatase, demonstrating that adrenal precursors contribute to both the androgenic and estrogenic components of tissue steroidogenesis.

These transformations do not occur uniformly. Enzyme expression differs among the skin and pilosebaceous unit, adipose tissue, bone, muscle, central nervous system, and reproductive system, resulting in distinct patterns of local production. Some tissues predominantly generate active androgens, whereas others favor aromatization into estrogens or the production of metabolites with reduced activity. From this perspective, the adrenal gland supplies a pool of substrates that tissues interpret according to their own biology, thereby creating different endocrine microenvironments.

The same principle explains why adrenal androgens may contribute substantially to the overall steroid balance in certain physiological conditions, whereas their actual contribution is attenuated in others. The final result is determined not only by the quantity secreted by the adrenal gland, but by the combined effects of substrate availability, cellular uptake, the efficiency of activating pathways, inactivation capacity, and receptor density within the tissue.

Alongside the classical conversion pathways, metabolic routes regulate the duration and intensity of signaling through conjugation and transformations that promote clearance. A complete account therefore requires consideration of the principal mechanisms of inactivation and recycling, since they determine how long precursors remain available and how the body limits excessive active steroid production.

Adrenal androgen metabolism includes both reversible and terminal components. Desulfation of DHEAS through steroid sulfatase is a reversible step that restores DHEA as a substrate for intracellular conversion. By contrast, conjugation processes such as glucuronidation and peripheral sulfation can direct steroids toward less active and more readily excretable forms, thereby limiting excess signaling and regulating its duration.

The liver has a central role in the clearance and metabolism of numerous steroids, whereas the kidney contributes to the excretion of water-soluble conjugates and metabolites. These processes connect the adrenal androgen system with hepatic and renal functional status, explaining why disorders affecting these organs can alter biochemical profiles and precursor availability. Elimination physiology is not an incidental detail, since it contributes to reservoir stability and to the predictability of the temporal pattern of DHEAS concentrations.

The existence of inactivation and conjugation pathways emphasizes that androgen signaling is not merely a process of production, but a dynamic balance. Increased adrenal production or peripheral conversion may be partially offset by increased conjugation and clearance, whereas reduced clearance may amplify substrate availability even without changes in secretion. This concept becomes essential when measurements are interpreted within complex clinical settings.

Once active steroids have been generated, their biological effects are mediated mainly by nuclear receptors, with transcriptional control influenced by coregulators. The next step is therefore to describe the genomic action of androgens derived from adrenal precursors and the mechanisms through which tissues translate intracrine production into functional phenotypes.

The biological effects of active androgens generated from DHEA and androstenedione are mediated primarily by the androgen receptor and, when conversion favors aromatization, by estrogen receptors. These receptors belong to the nuclear receptor family and act as ligand-regulated transcription factors. Binding of the active hormone induces conformational changes that promote receptor dimerization, binding to regulatory DNA elements, and recruitment of coregulator complexes that modulate chromatin and transcription.

The biological response depends on the tissue context. Receptor density, coregulator composition, chromatin architecture, and interactions with other endocrine signals determine which genes are regulated and the intensity of that regulation. From this perspective, adrenal precursors provide the substrate, but the tissue determines the response program. Intracrine production of active androgens may support effects on cellular differentiation, skin and pilosebaceous function, modulation of bone and muscle mass, and interactions with energy metabolism. Conversion into estrogens also contributes to effects involving bone, the cardiovascular system, and other tissues.

Genomic regulation generally has a slower time course, with effects developing over hours or days. This is consistent with many physiological functions supported by steroid signaling and explains why chronic changes in precursor availability or in tissue conversion capacity may produce progressive, multisystem phenotypes. The same principle helps explain why circulating precursor measurements do not perfectly predict biological responses, since intracrine production and receptor-mediated signal transduction are decisive steps.

Alongside genomic regulation, steroid signaling may include more rapid responses related to membrane interactions or cytoplasmic pathways. These components do not replace nuclear activity, but may regulate the immediate tissue response and its integration with growth and adaptive signaling.

Sex steroids and their precursors may contribute to rapid responses through mechanisms that are not exclusively transcriptional and that involve interactions with membrane structures and activation of intracellular signaling pathways. In the case of androgens generated locally from adrenal precursors, these pathways may rapidly regulate cellular function and interactions with other systems, including growth signals, catecholamines, and metabolic pathways. Functionally, this broadens the temporal range of the response. In addition to long-term remodeling produced by transcriptional regulation, more rapid modulation of cellular functions may occur.

Integration with adaptive signaling is particularly relevant within the adrenal gland, where trophic stimulation and systemic status can remodel steroidogenesis, and within peripheral tissues, where metabolic stress, inflammation, and changes in the hormonal environment influence intracrine conversion capacity. As a result, the same precursor availability may produce different effects according to the physiological context, tissue enzyme profile, and receptor sensitivity.

These concepts lead to the final synthesis. Adrenal androgen physiology results from adrenal production, sulfation, transport, and tissue-specific conversion, and biochemical measurements have interpretative limitations when considered separately from the clinical context and intracellular biology.

The adrenal androgen system demonstrates that an endocrine axis may be organized around a reservoir of precursors rather than a single effector hormone. The adrenal gland, mainly through the zona reticularis, produces DHEA and especially DHEAS, whereas androstenedione represents an intermediate step connecting these precursors with testosterone production and, through aromatase, estrogen synthesis. Stability is provided by DHEAS sulfation and its long half-life, whereas biological flexibility is provided by the ability of tissues to import, desulfate, and convert precursors into active steroids in a tissue-specific manner.

This organization explains why measurements must be interpreted cautiously. DHEAS is often a robust indicator of adrenal precursor production, but it cannot independently describe the intensity of androgen activity within individual tissues, because the effect depends on intracrine conversion and receptor-mediated signal transduction. Similarly, androstenedione concentrations may reflect different contributions, including peripheral conversion and variations in enzyme expression, and must be interpreted within the clinical context by considering age, sex, metabolic status, hepatic and renal function, and possible conditions of androgen excess.

In conclusion, DHEA and androstenedione are precursors with a central biological role because they enable local regulation of steroid signaling. Their physiology integrates adrenal biosynthesis, sulfation, transport, and tissue-specific conversion into a unified framework that explains both the strength of the system, which can meet different requirements in different tissues, and the limitations of circulating measurements when they are used as direct surrogates of biological activity.