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 (