The hypothalamus and the anterior lobe of the pituitary gland are connected through a neurovascular link. Within the hypothalamus, there are parvicellular "hypophysiotropic" neurosecretory neurons that project axons to the median eminence. In the median eminence, these neurons secrete releasing hormones (RHs). The RHs flow through the hypothalamohypophyseal portal vessels to reach the anterior pituitary. The RHs, along with release-inhibiting hormones, regulate the secretion of tropic hormones from the five cell types in the anterior pituitary.

ACTH, a hormone that circulates freely, has a short half-life of approximately 10 minutes. It binds to the melanocortin-2 receptor (MC2R) on cells in the adrenal cortex. This binding leads to an increase in cortisol and adrenal androgen production by upregulating the expression of genes encoding steroidogenic enzymes. ACTH also promotes the growth and survival of specific zones within the adrenal cortex in the long term.

The secretion of ACTH is controlled by the hypothalamus. A subgroup of parvocellular hypothalamic neurons produces procorticotropin-releasing hormone (pro-CRH), which is further processed into CRH, a 41-amino acid peptide. CRH stimulates the acute secretion of ACTH and enhances the transcription of the POMC gene. These CRH-expressing neurons also produce ADH, which enhances the action of CRH on corticotropes. ACTH secretion follows a diurnal pattern, peaking in the early morning and reaching a nadir.

Excess levels of ACTH can cause darkening of the skin, as seen in conditions like Cushing's disease. The POMC gene is expressed in keratinocytes in the basal layer of the epidermis, but instead of ACTH, it is processed into α-MSH. Upon exposure to ultraviolet light, keratinocytes secrete α-MSH, which acts as a paracrine factor on neighboring melanocytes to darken the skin. α-MSH binds to the MC1R receptor on melanocytes. At very high levels, ACTH can cross-react with the MC1R receptor on skin melanocytes, leading to increased skin pigmentation.

Furthermore, the secretion of CRH and ACTH occurs in a pulsatile manner. The hypothalamic-pituitary-adrenal (HPA) axis, which regulates the release of these hormones, is influenced by various factors, many of which are mediated through the central nervous system. Both neurogenic and systemic stressors can affect the HPA axis.

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740 SECTION8Berne & Levy Physiology •Fig. 41.7 Neurovascularlinkbetweenthehypothalamusandtheanteriorlobe(parsdistalis)ofthepitu-itary.Parvicellular“hypophysiotropic”neurosecretoryneuronswithinvarioushypothalamicnucleiprojectaxonstothemedianeminence,wheretheysecretereleasinghormones(RHs).RHsflowdownthepituitarystalkinthehypothalamohypophysealportalvesselstotheanteriorpituitary.RHs(andrelease-inhibitinghormones[seetext])regulatesecretionoftropichormonesfromthefivecelltypesoftheanteriorpituitary.(FromLarsenPRetal[eds].Williams Textbook of Endocrinology. 10thed.Philadelphia:Saunders;2003.)Hormone-secreting cells Anterior lobe of pituitary Capillary beds Hypothalamohypophyseal portal vessels Hypothalamus Median eminence Parvocellular neurosecretory cells Hypophysiotropic hormones released Hormone transport in axons Hormone transport in blood Hormone transport in blood Stimulation or inhibition of anterior pituitary hormone release Action on endocrine glands
ACTH circulates as an unbound hormone and has a short half-life of about 10 minutes. It binds to the melanocortin-2 receptor (MC2R) on cells in the adrenal cortex (
Fig. 41.9 ). ACTH acutely increases cortisol and adrenal androgen production by increasing expression of steroidogenic enzyme genes. In the long term, ACTH promotes growth and survival of two zones within the adrenal cortex (see
ACTH is under stimulatory control by the hypothalamus. A subset of parvocellular hypothalamic neurons expresses the peptide procorticotropin-releasing hormone (pro-CRH) (see
Table 41.1).
Pro-CRH is processed to CRH, an amidated 41–amino acid peptide. CRH acutely stimulates ACTH secretion and increases transcription of the POMC gene. The parvocellular neurons that express CRH also express ADH, which potentiates the action of CRH on corticotropes. ACTH secretion has a pronounced diurnal pattern, with a peak in early morning and a nadir
Atsupraphysiologicallevels,ACTH causesdarkeningoftheskin(e.g.,inCushing’sdisease).KeratinocytesinthebasallayeroftheepidermisalsoexpressthePOMCgenebutprocessittoα-MSH insteadofACTH.Keratinocytessecreteα-MSHinresponsetoultravioletlight,andα-MSHactsasaparacrinefactoronneighboringmelanocytestodarkentheskin.α-MSHbindstotheMC1R onmelanocytes.Atveryhighlevels,ACTHcancross-reactwiththeMC1Rreceptoronskinmelanocytes(see
Fig.41.9 ).ThusincreasedskinpigmentationisoneindicatorofexcesscirculatingACTH.
Fig. 41.10).
In addition, secretion of CRH—and hence secretion of ACTH—is pulsatile.
There are multiple regulators of the HPA axis, and many of them are mediated through the CNS (
Fig. 41.11). Many types of stress, both neurogenic (e.g., fear) and systemic
TABLE 41.1