Zona Reticularis

The zona reticularis is the innermost layer of the adrenal cortex, located adjacent to the adrenal medulla. It is primarily responsible for the synthesis of adrenal androgens, including dehydroepiandrosterone (DHEA) and androstenedione, which function as precursors to more potent sex hormones like testosterone and estrogen. While adrenal androgens have minor roles in adult males, they are important for the development of secondary sexual characteristics in females and children, and for contributing to libido.

Histological Features

Compared to the outer cortical layers, the zona reticularis has a distinctive structure:

• Cell arrangement: Irregular, branching network (reticulated pattern)

• Cell morphology: Smaller, darker-staining cells with less cytoplasmic lipid

• Appearance: Compact cords of cells separated by sinusoidal capillaries

• Staining: More basophilic than the lipid-rich zona fasciculata

The sinusoids in the zona reticularis carry blood inward toward the medulla, allowing direct interaction between cortical hormones and the medullary chromaffin cells — a feature important in adrenal paracrine signaling.

Hormone Production

The zona reticularis synthesizes weak androgens, which serve as precursors to more active sex steroids in peripheral tissues:

Primary Hormones:

• DHEA (dehydroepiandrosterone) – the major adrenal androgen

• DHEA-S (DHEA-sulfate) – a more stable, sulfated form for transport

• Androstenedione – precursor to testosterone and estrone

Functions:

• Converted peripherally to testosterone or estrogen depending on the target tissue

• In females: contributes to pubic and axillary hair growth, libido, and minor estrogen production after menopause

• In both sexes: contributes to adrenarche (early childhood androgen surge)

Regulation

The regulation of androgen synthesis in the zona reticularis is less clearly defined than that of cortisol and aldosterone, but ACTH is the primary stimulant.

• ACTH (adrenocorticotropic hormone): Stimulates both cortisol and androgen synthesis

• CRH (corticotropin-releasing hormone): Indirectly stimulates via ACTH

• No feedback inhibition: Unlike cortisol, adrenal androgens do not inhibit ACTH via negative feedback, making their output more persistent under ACTH stimulation

Other proposed modulators include:

• LH-like activity in fetal and postmenopausal adrenal function

• Unknown local peptides and cytokines that may fine-tune androgen production

Enzymes Involved in Androgen Synthesis

The biosynthetic pathway of adrenal androgens involves several key enzymes:

• CYP11A1: Converts cholesterol to pregnenolone

• CYP17A1 (17α-hydroxylase/17,20-lyase): Crucial enzyme for androgen synthesis

• 3β-HSD: Converts DHEA → androstenedione

• SULT2A1: Sulfates DHEA to form DHEA-S

Note: The zona reticularis expresses high levels of CYP17A1 but relatively low levels of 21-hydroxylase and 11β-hydroxylase, pushing precursors toward androgen rather than cortisol production.

Developmental and Functional Significance

Fetal Development:

• In the fetus, a large “fetal adrenal cortex” produces high levels of DHEA-S for placental estrogen synthesis

• This regresses after birth and is replaced by the adult zona reticularis postnatally

Adrenarche:

• Occurs ~6–8 years of age when the zona reticularis matures

• Marked by an increase in DHEA and DHEA-S production independent of gonadal puberty

• Leads to development of body odor, skin oiliness, and initial pubic/axillary hair

Postmenopause:

• In females, adrenal androgens become the main source of estrogen via peripheral conversion

Clinical Significance

Congenital Adrenal Hyperplasia (CAH)

• Most commonly caused by 21-hydroxylase deficiency

• ↓ Cortisol → ↑ ACTH → adrenal hyperplasia and excess androgen production

• Leads to virilization in females, early puberty in males

Adrenocortical Tumors

• Can originate from the zona reticularis and secrete excessive androgens

• Feminizing tumors: Rare, secrete estrogens in males

• Virilizing tumors: More common, cause hirsutism, deepened voice, clitoromegaly in females

Androgen Excess in PCOS

• While primarily ovarian in origin, the adrenal zona reticularis may contribute to hyperandrogenemia in some women with polycystic ovary syndrome (PCOS)

Addison’s Disease

• Destruction of the adrenal cortex leads to deficiency of cortisol, aldosterone, and adrenal androgens

• In women, this may result in loss of libido and decreased axillary/pubic hair

Laboratory and Diagnostic Relevance

• DHEA-S levels: Commonly measured as a marker of adrenal androgen production

• ACTH stimulation test: Can help differentiate primary vs secondary adrenal insufficiency

• Androgen-secreting tumors: Confirmed by elevated DHEA, DHEA-S, or androstenedione with suppressed ACTH

Pharmacological Notes

• Ketoconazole: Antifungal that inhibits steroidogenesis, used off-label in androgen excess

• Mitotane: Adrenolytic drug used in adrenocortical carcinoma

Anatomical Relations

• The zona reticularis lies immediately superficial to the adrenal medulla

• It shares vascular drainage into the central adrenal vein, allowing for some paracrine interaction with chromaffin cells of the medulla