The synthesis of androgens by the zona reticularis differs from that of the zona fasciculata in several ways. Firstly, the expression of 3β-HSD is very low in the zona reticularis, leading to the predominance of the Δ5 pathway. Secondly, the zona reticularis expresses cofactors that enhance the 17,20-lyase function of CYP17, resulting in the production of the androgen precursor molecule dehydroepiandrosterone (DHEA) from 17-hydroxypregnenolone. Additionally, DHEA sulfotransferase (SULT2A1 gene) is expressed in the zona reticularis, which converts DHEA into DHEAS. Some androstenedione is also produced in the zona reticularis. However, most active sex steroids are primarily produced from the peripheral conversion of DHEAS and androstenedione.

DHEAS can be converted back to DHEA by peripheral sulfatases, and both DHEA and androstenedione can be converted to active androgens (testosterone, dihydrotestosterone) peripherally in both males and females. DHEA has a low affinity for binding to albumin and other globulins in the blood, resulting in efficient excretion by the kidney. Its half-life is 15 to 30 minutes. On the other hand, DHEAS binds to albumin with high affinity and has a longer half-life of 7 to 10 hours.

In men, adrenal androgens make a negligible contribution to active androgens. However, in women, the adrenal glands contribute to approximately 50% of circulating active androgens, which are necessary for the growth of axillary and pubic hair as well as libido.

The role of the zona reticularis in adult humans, apart from providing androgen precursors, is not fully understood. DHEAS is the most abundant circulating hormone in young adults, reaching its peak in the mid-20s and then declining gradually. Its potential role in the aging process has sparked interest, although its function in young adults and the impact of its decline on aging are still poorly understood. It is worth noting that the decline in DHEA and DHEAS with age has led to the use of these steroids as dietary supplements, despite recent studies suggesting no beneficial effects.
Androgen Synthesis by the Zona Reticularis
The zona reticularis differs from the zona fasciculata in several important ways with respect to steroidogenic enzyme activity (see
Fig. 43.8 ). First, 3β-HSD is expressed at very low levels in the zona reticularis; thus the Δ5 pathway predominates in the zona reticularis. Second, the zona reticularis expresses cofactors or conditions that enhance the 17,20-lyase function of CYP17, thereby generating the 19-carbon androgen precursor molecule dehydroepiandrosterone (DHEA) from 17-hydroxypregnenolone. Additionally the zona reticularis expresses DHEA sulfotransferase (SULT2A1 gene), which converts DHEA into DHEAS (
Fig. 43.13 ). A limited amount of the Δ4 androgen androstenedione is also made in the zona reticularis. Although small amounts of potent androgens (e.g., testosterone) or 18-carbon estrogens are normally produced by the human adrenal cortex, most active sex steroids are produced primarily from peripheral conversion of DHEAS and androstenedione.
Metabolism and Fate of DHEAS and DHEA
DHEAS can be converted back to DHEA by peripheral sulfatases, and DHEA and androstenedione can be converted to active androgens (testosterone, dihydrotestosterone) peripherally in both sexes. DHEA binds to albumin and other globulins in blood with low affinity, so it is excreted efficiently by the kidney. The half-life of DHEA is 15 to 30 minutes. In contrast, DHEAS binds to albumin with very high affinity and has a half-life of 7 to 10 hours.
Quiescent HPA axis in patient undergoing long-term (>3 wk) Normal HPA axis treatment with glucocorticoid
Hypothalamus CRH ACTH Pituitary Zona fasciculata Atrophied zona fasciculata Cortisol Exogenous corticosteroid (supraphysiological levels) Biological actions Biological actions and therapeutic actions (e.g., antiinflammatory or immunosuppressive) Pituitary Hypothalamus (–) (–) (–) (–) •Fig. 43.12 Comparisonofanormalhypothalamic-pituitary-adrenal(HPA)axistoaquiescentHPAaxisinindividualreceivingexogenousglucocorticoidtherapy.Thelattercausesthezonafasciculatatoatrophyafter3weeks,thusrequiringacarefulwithdrawalregimentoallowrebuildingoftheadrenaltissuebeforetotalcessationofexogenouscorticosteroidadministration.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby;2013.)
Physiological Actions of Adrenal Androgens
In men the contribution of adrenal androgens to active androgens is negligible. However, in women the adrenal contributes to about 50% of circulating active androgens, which are required for the growth of axillary and pubic hair and for libido.
Apart from providing androgen precursors, it is not clear what other role or roles if any the zona reticularis plays in adult humans. DHEAS is the most abundant circulating hormone in young adults. It increases steadily until it peaks in the mid-20s and then steadily declines thereafter. Thus there has been considerable interest in the possible role of DHEAS in the aging process. However, the function of this abundant steroid in young adults and the potential impact of its gradual disappearance on aging are still poorly understood. It should be noted that the age-related decline in DHEA and DHEAS has led to the popular use of these steroids as dietary supplements, even though recent studies indicate no beneficial effects.