Cortisol production by the zona fasciculata is regulated by a standard hypothalamic-pituitary-adrenal axis involving corticotropin-releasing hormone (CRH), ACTH, and cortisol (see ). The hypothalamus and pituitary stimulate cortisol production, and cortisol negatively feeds back on the hypothalamus and pituitary to maintain its set point. Both neurogenic (e.g., fear) and systemic (e.g., hypoglycemia, hemorrhage, cytokines) forms of stress stimulate release of CRH. CRH is also under strong diurnal rhythmic regulation emerging from the suprachiasmatic nucleus, such that cortisol levels surge during the early predawn and morning hours and then continually decline throughout the day and evening. CRH acutely stimulates release of ACTH and chronically increases proopiomelanocortin (POMC) gene expression and corticotrope hypertrophy and proliferation. Some parvicellular neurons coexpress CRH and ADH, which potentiates the actions of CRH.
ACTH binds to the melanocortin 2 receptor (MC2R) located on cells in the zona fasciculata (
Fig. 43.11 ). The effects of ACTH can be subdivided into three phases: 1.
The acute effects of ACTH occur within minutes. Cholesterol is rapidly mobilized from lipid droplets by posttranslational activation of cholesterol ester hydrolase and transported to the outer mitochondrial membrane. ACTH both rapidly increases StAR protein gene expression and activates StAR protein through protein kinase A (PKA)-dependent phosphorylation. Collectively, these acute actions of ACTH increase pregnenolone levels.
2.
The chronic effects of ACTH occur over a period of several hours. These effects involve increasing transcription of the genes encoding the steroidogenic enzymes and their coenzymes. ACTH also increases expression of the LDL receptor and scavenger receptor BI (SR-BI; the HDL receptor).
3.
The trophic actions of ACTH on the zona fasciculata and zona reticularis occur over a period of weeks and •Fig. 43.11 OverviewoftheactionsofACTHontargetadrenocorticalcells.Notethatthemajorsecondmessenger,cAMP,activatesimmediateproteinmediatorsandalsoinducesproductionoflaterproteinmediators.HDL,high-densitylipoprotein;LDL,low-densitylipoprotein.
months. This effect is exemplified by atrophy of the zona fasciculata in patients receiving therapeutic (i.e., supraphysiological) levels of glucocorticoid analogues for at least 3 weeks. Under these conditions the exogenous corticosteroids completely repress CRH and ACTH production, thereby resulting in atrophy of the zona fasciculata and a decline in endogenous cortisol production (
Fig. 43.12 ). At the end of therapy, these patients need to be slowly weaned off exogenous glucocorticoids to allow the hypothalamic-pituitary-adrenal axis to reestablish itself and the zona fasciculata to enlarge and produce adequate amounts of cortisol. Cortisol inhibits both POMC gene expression at the corticotropes and pro-CRH gene expression at the hypothalamus. However, intense stress can override the negative-feedback effects of cortisol at the hypothalamus and reset the “set point” at a higher level.
The innermost zone, the zona reticularis, begins to appear after birth at about 5 years of age. Adrenal androgens, especially DHEAS, the main product of the zona reticularis, become detectable in the circulation at about 6 years of age. This onset of adrenal androgen production is called adrenarche, and it contributes to the appearance of axillary and pubic hair at about age 8. DHEAS levels continue to increase, peak during the mid-20s, and then progressively decline with age.