Women can experience masculinization as a result of excess adrenal androgen, which can be caused by adrenal tumors, Cushing's syndrome, or congenital adrenal hyperplasia. This can involve the masculinization of external genitalia, such as an enlarged clitoris, during fetal development, as well as excessive facial and body hair (known as hirsutism) and acne in adult women. Excessive adrenal androgens also play a role in ovarian dysfunction and ovulation, specifically in polycystic ovary syndrome.

It is important to note that neither adrenal androgens nor their more potent metabolites (such as testosterone, dihydrotestosterone, and estradiol-17β) negatively feedback on adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH). This means that an enzymatic defect associated with the synthesis of cortisol, like CYP21B deficiency, can lead to a dramatic increase in both ACTH (due to the lack of negative feedback from cortisol) and adrenal androgens. This "loophole" in the hypothalamic-pituitary-adrenal axis gives rise to congenital adrenal hyperplasia (CAH).

The primary regulator of the zona reticularis, the outer layer of the adrenal cortex, is ACTH. Both dehydroepiandrosterone (DHEA) and androstenedione follow the same diurnal rhythm as cortisol, while DHEA sulfate (DHEAS) does not due to its long circulating half-life. Although adrenarche occurs with constant ACTH and cortisol levels, the rise and decline of DHEAS do not align with a similar pattern of ACTH or cortisol production. The other factors that regulate adrenal androgen function, whether extraadrenal or intraadrenal, are currently unknown.

The zona glomerulosa, the thin outermost zone of the adrenal, primarily produces the mineralocorticoid aldosterone, which regulates salt and volume homeostasis. ACTH has minimal influence on the zona glomerulosa. Instead, it is primarily regulated by the renin-angiotensin system, plasma potassium levels, and atrial natriuretic peptide (ANP).

It is worth noting that the zona glomerulosa does not express CYP17, which means it does not produce cortisol or any form of adrenal androgens. Pregnenolone is converted to progesterone and deoxycorticosterone (DOC) by 3β-HSD and CYP21, respectively.
Duringadrenalandrogenexcess(e.g.,adrenaltumor,Cushing’ssyndrome,congenitaladrenalhyperplasia),masculinization of women canoccur.Thisinvolvesmasculinizationoftheexternalgenitalia(e.g.,enlargedclitoris)inuteroandexcessivefacialandbodyhair(calledhirsutism)andacneinadultwomen.Excessiveadrenalandrogensalsoappeartoplayaroleinovariandysovulation(i.e.,polycysticovariansyndrome).
Acrucialclinicalaspectofregulationofthezonareticularisisthatneitheradrenalandrogensnortheirmorepotentmetabolites(e.g.,testosterone,dihydrotestosterone,estradiol-17β)negativelyfeedbackonACTHorCRH(
Fig.
43.14 ).Thismeansthatanenzymaticdefectassociatedwiththesynthesisofcortisol(e.g.,CYP21Bdeficiency)isassociatedwithadramaticincreaseinbothACTH(nonegativefeedbackfromcortisol)andadrenalandrogens(becauseoftheelevatedACTH).Itisthis“loophole”inthehypothalamic-pituitary-adrenalaxisthatgivesriseto congenital adrenal hyperplasia (CAH).
Regulation of Zona Reticularis Function
ACTH is the primary regulator of the zona reticularis. Both DHEA and androstenedione display the same diurnal rhythm as cortisol (DHEAS does not because of its long circulating half-life). Moreover, the zona reticularis shows the same atrophic changes as the zona fasciculata in conditions typified by little or no ACTH. However, other factors must regulate adrenal androgen function. Adrenarche occurs in the face of constant ACTH and cortisol levels, and the rise and decline of DHEAS is not associated with a similar pattern of ACTH or cortisol production. However, the other factors, whether extraadrenal or intraadrenal, remain unknown.
The thin outermost zone of the adrenal, the zona glomerulosa, produces the mineralocorticoid aldosterone, which regulates salt and volume homeostasis (see ). The zona glomerulosa is minimally influenced by ACTH. Rather it is regulated primarily by the reninangiotensin system, plasma [K+], and atrial natriuretic peptide (ANP).
An important feature in the steroidogenic capacity of the zona glomerulosa is that it does not express CYP17. Therefore zona glomerulosa cells never make cortisol, nor do they make adrenal androgens in any form. Pregnenolone is converted to progesterone and DOC by 3β-HSD and •Fig. 43.13 Steroidogenicpathwaysinthezonareticularis.Thefirstcommonreactioninthepathway,conversionofcholesteroltopregnenolonebyCYP11A1,isnotshown.Expressionof3β-hydroxysteroiddehydrogenase(3β-HSD)isrelativelylowinthezonareticularis,soandrostenedioneisaminorproductincomparisontoDHEAandDHEAS.Thezonareticularisalsomakesasmallamountoftestosteroneandestrogens(notshown).(ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby;2013.)
CYP21, respectively (