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The Corticotropin-Release Inhibitory Factor Hypothesis: A Review of the Evidence for the Existence of Inhibitory as Well as Stimulatory Hypophysiotropic Regulation of Adrenocorticotropin Secretion and Biosynthesis¹

Laboratory of Molecular Genetics and Development (D.E., I.K), Institute of Reproduction and Development, Monash Medical Centre, Clayton, Victoria, Australia 3168; and The Asher Center (E.R), Department of Psychiatry and Behavioral Sciences, Northwestern University Medical School, Chicago, Illinois 60611

	Abstract

Top Abstract I. Introduction II. Hypothalamic Stimulation of... III. Hypothalamic Inhibition of... IV. CRIF: A Consideration... V. Future Directions References

 

I. Introduction

II. Hypothalamic Stimulation of ACTH Release and Biosynthesis

A. Corticotropin-releasing factor (CRF)

B. Arginine vasopressin (AVP)

C. The hypothalamic CRF and AVP neurons and their connections

D. Studies of the secretion of CRF and AVP into the hypophysial-portal circulation

E. Studies of the neural regulation of CRF and AVP secretion and biosynthesis

III. Hypothalamic Inhibition of ACTH Release and Biosynthesis

A. Historic studies

B. Effect of hypothalamo-pituitary disconnection in adult and fetal sheep

C. Effects of the opiate alkaloids and opioid peptides on the HPA axis

D. The role of the posterior pituitary in the regulation of corticotropic function

E. Hypothalamic ACTH release-inhibitory activity

F. Definition of corticotropin release inhibitory factor (CRIF)

IV. CRIF: A Consideration of Possible Candidates

A. Somatostatin (SST)

B. Dopamine

C. Atrial natriuretic peptide (ANP)

D. Prepro-TRH-(178–199)

E. Other substances

V. Future Directions

	I. Introduction

Top Abstract I. Introduction II. Hypothalamic Stimulation of... III. Hypothalamic Inhibition of... IV. CRIF: A Consideration... V. Future Directions References

 
IT HAS been traditionally thought that the hypothalamus only exerts a stimulatory influence upon the secretion and synthesis of ACTH by the anterior pituitary gland and that this is mediated by neuropeptides such as corticotropin-releasing factor (CRF), arginine vasopressin (AVP), and oxytocin (OT), which are secreted into the hypophysial-portal circulation (Refs. 1, 2, 3, 4, 5, 6 and Fig. 1). However, an analysis of the effects on the hypothalamic-pituitary-adrenal (HPA) axis of surgically isolating the anterior pituitary from the hypothalamus suggests that the hypothalamus may exert both inhibitory and stimulatory regulation over ACTH secretion and POMC biosynthesis and that the inhibitory regulation might be mediated by a currently unidentified substance that has been named corticotropin release-inhibitory factor (CRIF) (7, 8). In this review, we will initially summarize some of the recent knowledge of the mechanisms by which the hypothalamus stimulates corticotropic function and describe some of the central neural pathways regulating the HPA axis. We will then review the historical, and more current, literature describing the effects on the HPA axis of surgically isolating the pituitary from the hypothalamus. We outline several postulates that may need to be fulfilled for a substance to qualify as a CRIF, describe studies performed to date to determine the ACTH release-inhibitory activity of a number of possible candidates, and finally point to possible future directions in this emerging area.

View larger version (35K): [in this window] [in a new window]   Figure 1. A schematic representation of the current model by which the hypothalamus is thought to regulate ACTH secretion. This model proposes that the hypothalamus only stimulates ACTH secretion by secreting neuropeptides such as CRF and AVP into the hypophysial-portal circulation. ACTH then stimulates the adrenocortical production of cortisol, which then restrains the secretion of ACTH by exerting negative feedback effects on the anterior pituitary, hypothalamus, and various extrahypothalamic brain sites.

	II. Hypothalamic Stimulation of ACTH Release and Biosynthesis

Top Abstract I. Introduction II. Hypothalamic Stimulation of... III. Hypothalamic Inhibition of... IV. CRIF: A Consideration... V. Future Directions References

View larger version (18K): [in this window] [in a new window]   Figure 2. Effect of synthetic CRF ( and •), purified native ovine CRF ( and ), and 8-Br-cAMP ( and ) on secretion of ACTH (solid line) and ß-endorphin-like immunoactivity (dashed line) by rat anterior pituitary cells in primary culture. Concentrations of synthetic and purified native CRF were determined by amino acid analysis. [Reproduced with permission from W. Vale et al.: Science 213:1394–1397, 1981 (9 ). © American Association for the Advancement of Science.]

View larger version (19K): [in this window] [in a new window]   Figure 3. Concentration-dependent effects of CRF and AVP on ACTH. Ovine anterior pituitary cells (3.3 x 105) were incubated for 4 h with the indicated concentrations of CRF (A) or AVP (B) and ACTH release (), total ACTH accumulation (), and intracellular ACTH content (•) were determined. Results are the means ± SE of triplicate determinations from four experiments. Error bars have been omitted when they were smaller than the symbol size. [Reproduced with permission from J.-P. Liu et al.: J Biol Chem 265:14136–14142, 1990 (15 ).]

View larger version (160K): [in this window] [in a new window]   Figure 4. Color-coded image of [[125I]Tyr]oCRF autoradiographs of representative coronal sections from rostral to caudal of monkey brain. Areas of very high density are shown in red, and densities decrease through yellow, green, and light blue. Dark blue and black correspond to nonspecific background. CC, Cingulate cortex; P, putamen; OC, orbital cortex; C, caudate; OT, olfactory tubercle; Cl, claustrum; TC, temporal cortex; NST, nucleus of stria terminalis; IC, insular cortex; POA, preoptic area; AA, anterior amygdala; NPT, paraventricular nucleus of thalamus; A, amygdala; MDT, medial dorsal thalamus; MN, mamillary nucleus; Hi(gd), hippocampus (gyrus dentatus); SC, superior colliculus; LPTN, lateral posterior thalamic nucleus; LGB, lateral geniculate body; Hi, hippocampus; Cb, cerebellum; ICo, inferior colliculus; LC, locus coeruleus; DPN, dorsal parabrachial nucleus. [Reproduced with permission from M. A. Millan et al.: Proc Natl Acad Sci USA 83:1921–1925, 1986 (51 ).]

The second CRF receptor to be isolated (CRF-R₂) was cloned from mouse heart and rat brain cDNA libraries (63, 64, 65, 66) and consists of two splice variants, CRF-R₂ and CRF-R_2ß, which differ at their N-terminal domain. CRF-R₂ is a 411-amino acid protein cloned from the rat brain (63), whereas CRF-R_2ß is a 431-amino acid protein that was isolated from mouse heart (64, 65, 66). CRF and the nonmammalian peptides, sauvagine and urotensin I, all bind to CRF-R₂ and stimulate adenylate cyclase activity, and the rank order of potency of their interaction (sauvagine > urotensin> rat/human CRF > ovine CRF) differs markedly from their interaction with CRF-R₁. The distribution of CRF-R₂ mRNA in rat brain differs from that of CRF-R₁ mRNA (67) since CRF-R₁ mRNA expression is highest in neocortical, cerebellar, and sensory relay structures, whereas CRF-R₂ mRNA expression is mainly confined to subcortical structures and is most abundant in the lateral septal nucleus, the ventromedial hypothalamus, and choroid plexus (Fig. 5). In further contrast with the CRF-R₁ mRNA, the CRF-R₂ mRNA is in very low abundance within the anterior pituitary.

View larger version (123K): [in this window] [in a new window]   Figure 5. Color-coded digitized images of CRF1 and CRF2 receptor mRNA expression in adjacent horizontal brain sections. Regions exhibiting high levels of mRNA expression are coded in red and orange, while the lowest levels of expression are coded in blue. [Reproduced with permission from D. T. Chalmers et al.: J Neurosci 15:6340–6350, 1995 (67 ).]

B. AVP
The nonapeptide AVP is also secreted into the hypophysial-portal circulation and acts on the anterior pituitary to stimulate ACTH release. AVP is a weak ACTH secretagog in the rat and in man, although it appears to be as potent as CRF in the bovine species and even more potent than CRF in the ovine species. Although CRF and AVP both increase ACTH secretion and total ACTH content in ovine anterior pituitary cells, AVP is clearly the more potent agonist, and these observations gave rise to the hypothesis that both secretagogs might increase POMC gene expression in ovine corticotropes (15). This suggestion initially received little experimental support (73), but a recent study by van de Pavert et al. (74) has demonstrated that AVP, but not CRF, does increase steady-state levels of POMC mRNA in ovine corticotropes. This finding contrasts sharply with the situation in the rat where CRF is the only neuropeptide known to stimulate POMC gene expression and points toward species-specific differences in regulation of the POMC gene. The molecular basis for these differences requires further investigation.

The pituitary AVP receptor (V1b) is clearly different from those AVP receptors found in the liver and on vascular smooth muscle cells (V1) or in the kidney (V2) (75, 76, 77, 78, 79, 80, 81, 82). Adrenalectomy markedly decreases AVP binding in the pituitary, an effect that is prevented by glucocorticoid replacement (78, 79). Moreover, Vlb receptor content is increased or decreased by manipulations that respectively augment or reduce HPA axis activity (83). When taken together, these findings suggest that V1b receptor expression is positively regulated by glucocorticoids. The nucleotide and amino acid sequences of the Vlb receptor were first derived from a human pituitary cDNA library (84). The deduced protein was found to contain 424 amino acid residues and 7 transmembrane domains, and Northern blot analysis showed a single mRNA transcript that was detectable only in the anterior pituitary. However, a subsequent study has predicted a protein of 421 amino acids and shown expression of 2 mRNA species in the anterior pituitary, in several brain regions, and in a number of extrapituitary tissues (85). The precise basis for these different findings awaits further elucidation.

The anterior pituitary AVP receptor is coupled to the phosphatidylinositol (PI) pathway (86, 87, 88), and hormone binding therefore stimulates PI hydrolysis and increases the production of inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (Refs. 89, 90, 91 and Fig. 6). The diacylglycerol is required for the activation of protein kinase C, which then causes the phosphorylation of a number of cellular substrates such as the myristoylated alanine-rich C kinase substrate (MARCKS) protein (15, 37, 92, 93, 94, 95, 96). The IP₃ causes the liberation of Ca²⁺ from intracellular stores and, together with the influx of extracellular Ca²⁺, causes the rise in intracellular Ca²⁺ that is required to mediate ACTH release (33, 40). Since the pituitary AVP receptor is not linked to the adenylate cyclase, it does not increase cAMP levels in this site (36, 97, 98, 99). However, it does potentiate the cAMP response to CRF, an effect that is due to the activation of protein kinase C since it is also mimicked by phorbol esters (36, 98, 99).

View larger version (48K): [in this window] [in a new window]   Figure 6. A schematic representation of the subcellular mechanisms activated by the binding of AVP to the anterior pituitary V1b receptor. A, A unified hypothesis of the spatiotemporal aspects of calcium signaling, based on ideas concerning calcium oscillations and the propagation of calcium waves. A typical response begins with an agonist (such as AVP) generating Ins(1 4 5 )P3, which then mobilizes calcium from an Ins(1 4 5 )P3-sensitive calcium store and also promotes the entry of external calcium to give an initial calcium signal. In some cells, this Ins(1 4 5 )P3-induced calcium signal can act as a "primer" to drive a process of calcium-induced calcium release from the Ins(1 4 5 )P3-insensitive pools to produce a spike that might be organized in the form of a wave, thereby spreading the signal throughout the cell. [Reproduced with permission from M. J. Berridge and R. F. Irvine: Nature 341:197–205, 1989 (86 ). © Macmillan Magazines, Ltd.] B, Schematic representation of proposed mechanisms of protein kinase C (PKC) activation. There are two pathways leading to the activation of intracellular PKC from the extracellular environment: (a) by the receptor-mediated production of diacylglycerol (DAG) via a G protein-coupled phospholipase C; and (b) by direct pharmacological activation with phorbol esters. Both DAG and phorbol esters [such as phorbol 12-myristate 13-acetate (PMA)] bind to the C1 region of the PKC-regulatory subunit that causes physical association of PKC with the plasma membrane (translocation). DAG promotes the formation of a PKC-phosphatidylserine (PS)-Ca2+ complex, whereas phorbol esters cause plasma membrane insertion of the kinase and its subsequent down-regulation. Both DAG and phorbol esters induce a conformational change in the structure of PKC so that the inhibitory pseudosubstrate sequence moves away from the substrate binding site. This then permits PKC substrates to bind to the kinase and to be phosphorylated. (1 ) Receptor activation; (2 ) translocation; (3 ) down-regulation; (4 ) membrane insertion; and (5 ) substrate phosphorylation. [Reproduced with permission from J. P. Liu: Mol Cell Endocrinol 116:1–29, 1996 (88 ). © Elsevier Science.]

View larger version (18K): [in this window] [in a new window]   Figure 7. A schematic diagram to show the major cell groups of the paraventricular nucleus of the hypothalamus in the rat, as viewed from above. The three parts of the magnocellular division are shown in stipple,and are embedded in the parvocellular division, which consists of five parts. The abbreviations are as follows: am, anterior magnocellular; ap, anterior parvocellular; dp, dorsal parvocellular; lp, lateral parvocellular; mm, medial magnocellular; mp, medial parvocellular; pm, posterior magnocellular; pv, periventricular. [Reproduced with permission from L. W. Swanson et al.: J Comp Neurol 196:271–285, 1981 (129 ). © Wiley-Liss, Inc., a division of John Wiley & Sons, Inc.]

View larger version (17K): [in this window] [in a new window]   Figure 8. A schematic illustration of the major CRF-stained cell groups (black dots) and fiber systems in the rat brain. Most of the immunoreactive cells and fibers appear to be associated with systems that regulate the output of the pituitary and the autonomic nervous system, and with cortical interneurons. Most of the longer central fibers course either ventrally through the medial forebrain bundle and its caudal extension in the reticular formation, or dorsally through a periventricular system in the thalamus and brainstem central gray. The direction of fibers in these systems is unclear because they appear to interconnect regions that contain CRF-stained cell bodies. Thus, for example, three adjacent CRF-stained cell groups, the laterodorsal tegmental nucleus (LDT), locus ceruleus (LC), and parabrachial nucleus (PB), lie in the dorsal pons. However, it is uncertain which of these cell groups contributes to each of the pathways shown, and which of them receives inputs from the same pathways. Abbreviations: HIP, hippocampus; SEPT, septal region; BST, bed nucleus of the stria terminalis; SI, substantia innominata; CeA, central nucleus of the amygdala; PVH, paraventricular hypothalamic nucleus; MPO, medial preoptic area; ME, median eminence; PP, posterior pituitary; LHA, lateral hypothalamic area; MID THAL, midline thalamic nuclei; POR, perioculomotor nucleus; CG, central gray; DR, dorsal raphe; MR, median raphe; LDT, laterodorsal tegmental nucleus; LC, locus ceruleus; PB, parabrachial nucleus; MVN, medial vestibular nucleus; DVC, dorsal vagal complex; A1, A5, noradrenergic cell groups; ac, anterior commissure; cc, corpus callosum; st, stria terminalis; mfb, medial forebrain bundle. [Reproduced with permission from L. W. Swanson et al.: Neuroendocrinology 36:165–186, 1983 (111 ). © Karger, Basel.]

The PVH is also connected with a number of brain regions, and prominent among these are the forebrain, the limbic system, and the brainstem. For example, the parvocellular part of the PVH receives moderately dense projections arising from all areas of the hypothalamus (except the supraoptic nucleus, the medial and lateral mamillary nuclei, and the magnocellular preoptic nucleus), from the subfornical organ, and the bed nucleus of the stria terminalis, but the magnocellular division of the PVH receives relatively few inputs from these structures (123). Although a large amount of physiological and functional evidence indicates that several parts of the limbic system (septum, amygdala, and hippocampal formation) may regulate the activity of the PVH, detailed autoradiographic studies have failed to detect direct projections from any of these areas to the PVH or the supraoptic nucleus (124, 125, 126). Rather, these structures may give rise to pathways that end in cell groups lying immediately adjacent to the PVH. The only exception to this statement is the projection from the ventral subiculum, which may interact directly with the PVH by means of a relay in the bed nucleus of the stria terminalis (127). As noted, the PVH is densely innervated by aminergic and peptidergic axon terminals that arise from cell bodies located in brainstem nuclei. The aminergic terminals contain NE, EPI, dopamine (DA), and serotonin and, to date, the noradrenergic and adrenergic projections have been subjected to the most detailed analysis (128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139).

The noradrenergic input to the PVH arises almost exclusively from three interrelated cell groups in the brainstem, namely the A2 region in the nucleus of the tractus solitarius (NTS), the A1 region in the ventrolateral medulla, and the A6 area in the locus ceruleus (Fig. 9). The projections from the A1 region are almost entirely directed toward the magnocellular division and terminate preferentially on vasopressinergic cell bodies. The fibers originating from the A2 region are primarily distributed throughout the parvocellular division and are most dense in the dorsal medial part, a region known to contain a large population of CRF-immunoreactive neurons. The projections arising from the A6 area are almost entirely distributed to the parvocellular PVH, and their most prominent input is localized to the periventricular zone, an area known to contain DA-, somatostatin (SST)-, and TRH-staining neurons (138). When taken together, these findings suggest that the A1, A2, and A6 noradrenergic cell groups may each regulate the activity of anatomically and functionally distinct groups of neurosecretory neurons.

View larger version (14K): [in this window] [in a new window]   Figure 9. Schematic drawing of a sagittal section through the rat brain to indicate the dominant biochemical makeup and distribution of catecholaminergic and NPY-immunoreactive inputs from the brainstem to the PVH. Adrenergic (E) projections arise from the C1, C2, and C3 regions, are distributed overwhelmingly to the parvicellular (pc) division of the nucleus, and generally stain positive for NPY immunoreactivity. Noradrenergic (NE) projections from the locus coeruleus and A2 cell groups are also distributed primarily to the parvicellular division, but are, for the most part, NPY negative. A heterogeneous input arises from the A1 region and is distributed to both the parvicellular division and preferentially to those parts of the magnocellular division in which vasopressinergic neurons (V) predominate over oxytocinergic ones (o). One component appears also to contain NPY immunoreactivity, whereas a second one does not. [Reproduced with permission from P. E. Sawchenko et al.: J Comp Neurol 24:138–153, 1985 (149 ). © Wiley-Liss, Inc., a division of John Wiley & Sons, Inc.]

As stated above, the PVH is also innervated by peptidergic axon terminals, and those that stain for neuropeptide Y (NPY) appear particularly prominent (140, 141). NPY-stained perikarya and axon terminals are widely distributed within the brain, and the PVH and hypothalamic arcuate nucleus, respectively, contain the highest density of NPY-stained axon terminals and perikarya within the brain (142, 143, 144, 145, 146). NPY is extensively colocalized within brainstem adrenergic neurons that project to the PVH, while its expression in noradrenergic neurons appears limited to a subpopulation of cells in the A1 group (147, 148, 149, 150, 151). NPY-stained projections are most dense in the anterior and medial parvocellular parts of the PVH, and these areas are known to contain CRF- and TRH-stained neurons (Fig. 10). Furthermore, the ultrastructural demonstration of direct synaptic contacts between NPY-stained axon terminals and CRF-stained perikarya in the PVH provides the anatomical basis for considering NPY a potentially important regulator of the HPA axis (152).

View larger version (91K): [in this window] [in a new window]   Figure 10. Darkfield photomicrographs of avidin-biotin immunoperoxidase preparations to show the distribution of fibers and varicosities stained for phenylethanolamine-N-methyltransferase (PNMT), dopamine-ß-hydroxylase (DBH), and neuropeptide Y (NPY) immunoreactivity at a similar level through the paraventricular nucleus (PVH; the third ventricle is at the extreme left of each micrograph). At this midcaudal level, basic similarities and differences in the distribution and density of each input may be appreciated, although in these thicker (30–35 µM) sections, details of the distributions cannot necessarily be inferred. Note that the distribution of PNMT-stained elements is largely limited to a discrete part of the parvicellular division of the nucleus; few are seen in the magnocellular division. The DBH-stained projection encompasses and exceeds that localized with anti-PNMT, providing a prominent input to the magnocellular division, which is located at the right-hand margin of the nucleus at this level. The NPY-stained input encompasses and exceeds the distribution and density provided by DBH-immunoreactive inputs, providing perhaps the most prominent chemically specified input to the PVH yet described. [Reproduced from P. E. Sawchenko et al.: J Comp Neurol 241:138–153,1985 (149 ). © Wiley-Liss, Inc., a division of John Wiley & Sons, Inc.]

In the 1980s and l990s, in vivo studies were performed in the rat, the sheep, and the horse, which demonstrated that CRF, AVP, and OT were secreted into the hypophysial-portal circulation (154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186). The first studies to appear were performed in the anesthetized rat (154, 155, 156, 157, 158), and when they are compared with those subsequently performed in the conscious sheep and horse, it is apparent that the stress of the anesthesia, and perhaps the surgical procedure itself, elevated the baseline levels of these peptides. Nevertheless, the studies in the rat demonstrated that maneuvers such as chemical adrenalectomy, volume depletion, nitroprusside-induced hypotension, insulin-induced hypoglycemia, the intracerebroventricular administration of NE, and transection of the fornix all increased CRF concentrations in portal blood (157, 158, 161, 162, 163, 166, 173, 174). Furthermore, manipulations such as exposure to glucocorticoid-negative feedback, the surgical or chemical destruction of the hypothalamic noradrenergic input, and surgical lesions of the PVN all decreased the basal or stress-induced increments in CRF concentrations in portal plasma (155, 160, 168, 176, 177, 178).

These experimental manipulations were also found to exert effects on the levels of AVP and OT in portal plasma. Volume depletion, hypoglycemia, and fornix transection increased portal AVP and OT concentrations (157, 158, 174), nitroprusside-induced hypotension did not alter either of their levels (177), and chemical adrenalectomy had no discernible effect on OT (161). In contrast, the exposure to glucocorticoids also decreased portal levels of AVP and OT (176, 177), but destruction of the hypothalamic noradrenergic input or the PVN itself had no effect on portal AVP concentrations (168, 176). These findings have given rise to the concept that a substantial proportion of the AVP in portal plasma may be of magnocellular origin (176).

Finally, recent studies in the rat employing the technique of microdialysis have shown that emotional stress may also increase the release of AVP into the PVH (187). However, it appears that AVP, when released into the PVH, exerts an inhibitory, rather than a stimulatory, effect on the HPA axis. Although the mechanisms by which this inhibitory effect is mediated were not elucidated, the findings indicate that the same neuropeptide may exert opposite effects on the HPA axis at the level of the PVH and anterior pituitary gland.

In the late 1980s, several studies appeared in which portal CRF and AVP concentrations were measured in conscious, unanesthetized animals (159, 167, 169, 170, 171, 175, 185). In our studies, ovine pituitary portal blood was collected by the technique developed by Clarke and Cummins (188). This method allowed portal blood to be collected in the conscious animal at 5- to 10-min intervals and thereby permitted the first evaluation of the normal ultradian secretion of the hypothalamic releasing factors and their responses to stressful stimuli. These studies, and those of Caraty et al. (169, 175) performed in conscious rams, demonstrated that CRF and AVP were secreted in a pulsatile manner, that the two peptides were secreted synchronously or asynchronously, that their basal concentrations were generally less than 100 pg/ml, and that their basal secretory patterns differed in each individual animal (Fig. 11). They also showed that volume depletion, a fear-associated audiovisual stimulus, or insulin-induced hypoglycemia all increased CRF and AVP levels in portal plasma and generally increased the AVP:CRF molar ratio. Since fear-associated audiovisual stimuli initially activate the auditory and visual cortices, respectively, and subsequently activate the limbic system whereas hypoglycemia primarily activates several subcortical brain areas, these findings showed that the CRF and AVP neurons within the PVN may be activated by different neural inputs. When sheep were treated with dexamethasone, the basal levels of CRF, ACTH, and cortisol were decreased, the pituitary-adrenal response to an audiovisual stimulus was inhibited, and the HPA response to hypoglycemia was attenuated (171).

View larger version (23K): [in this window] [in a new window]   Figure 11. A representative example of the secretion of CRF, AVP, three POMC-peptides [ACTH, ir-ß-endorphin (ir-ß-EP), and ir--MSH (ir-- MSH)], and cortisol in a conscious ewe. Shown also are the secretory responses to a 3-min audiovisual stress (hatched area) and insulin-induced hypoglycemia (arrow). The triangles () depict significant hormone pulses. [Reproduced with permission from D. Engler et al.: Neuroendocrinology 49:367–381, 1989 (170 ). © Karger, Basel.]

E. Studies of the neural regulation of CRF and AVP secretion and biosynthesis
1. The central noradrenergic and adrenergic pathways. The early studies of Krieger and Krieger (190) that were performed in the conscious cat suggested that centrally administered catecholamines activated the pituitary-adrenal axis. However, throughout the 1970s and early 1980s, it was generally accepted that central NE inhibited ACTH release, and this view was based on experiments by Ganong and co-workers (191, 192) that were performed in the anesthetized dog . However, in the late 1980s and early 1990s, studies in conscious animals (rat, sheep) and in man appeared that strongly supported the view that central catecholamines stimulate the pituitary-adrenal axis (193, 194, 195, 196, 197, 198, 199, 200, 201, 202). The diametrically opposed findings of Ganong et al. (191, 192) may be due to the use of anesthesia and are reconciled with all these studies when one considers that anesthesia may cause a single, centrally administered agonist to exert opposite effects on brainstem NE release and/or biosynthesis (203).

Our studies in the conscious sheep were initiated to determine how insulin-induced hypoglycemia might stimulate CRF and AVP secretion into the hypophysial-portal circulation. The PVH does not appear to contain glucose-sensitive neurons, but the NTS, the lateral hypothalamic area, and the ventromedial hypothalamus do contain neurons that respond to changes in glucose concentration by altering their firing rates (204, 205, 206). Therefore, the effect of hypoglycemia on CRF and AVP release is likely to be secondary to a primary activation of one or more of these glucose-sensitive sites. The experiments were based on the finding that hypoglycemia increases the hypothalamic turnover of NE (207), and the anatomic relationships that exist between the PVH and the brainstem catecholaminergic and peptidergic cell groups. It was hypothesized that the effect of hypoglycemia on neuronal activity in the NTS might increase NE synthesis within the nucleus or within the Al and A6 areas, since all three regions are interconnected (131). This conceptual framework would explain the increased hypothalamic turnover of NE during hypoglycemia and would also predict that NE, and possibly EPI, might stimulate the release of CRF and/or AVP.

When NE or EPI was injected into the lateral cerebral ventricle of the conscious sheep, an acute and sustained increase in ACTH and cortisol secretion was observed, and NE appeared to be the more potent agonist (202). The finding that NE and EPI released only very modest amounts of ACTH from cultured anterior pituitary cells suggested that both amines were mainly acting on suprahypophysial brain sites to increase CRF and AVP release. This prediction was tested by determining the effects of intracerebroventricular (icv) NE on the secretion of CRF and AVP into the hypophysial-portal circulation of the conscious sheep (Ref. 185 and Fig. 12). The icv injection of 50 µg NE acutely increased CRF and AVP concentrations in portal plasma and activated the pituitary-adrenal axis. In addition, NE caused sustained hypersecretion of CRF and AVP even though plasma cortisol levels were greatly elevated. This observation suggested that activation of the central noradrenergic system might override the normal glucocorticoid negative feedback on those areas of the brain concerned with regulation of the HPA axis. This concept of "acquired glucocorticoid resistance" has been recently addressed by De Kloet et al. (208), and the following subcellular mechanisms may underly this phenomenon.

View larger version (24K): [in this window] [in a new window]   Figure 12. The effect of an icv injection of 50 µg norepinephrine on plasma CRF, AVP, ACTH, and cortisol in three ewes. The arrow () depicts the time of injection. [Reproduced with permission from J.-P. Liu et al.: J Clin Invest 93:1439–1450, 1994 (185 ). © The American Society for Clinical Investigation.]

The activation of the cAMP/protein kinase A pathway and the cAMP-regulatory element binding protein (CREB) may constitute one of the intracellular mechanisms that mediates the effect of NE on CRF biosynthesis. The cAMP-regulatory element (CRE), generally represented by the palindromic motif 5'-TGACGTCA-3', binds a number of transcription factors including CREB, an intranuclear PKA substrate protein that is phosphorylated upon activation of the cAMP-PKA pathway (213, 214, 215, 216, 217). The CRE is also present in the rat, ovine, and human CRF genes (218, 219, 223, 224) and is likely to be physiologically important since activation of the cAMP-PKA pathway increases CRF mRNA levels in vitro (220, 221, 222), and mutation of the CRE site completely abolishes this effect (224). Moreover, the cAMP-PKA pathway is also important in stimulating CRF gene expression in vivo since 8-bromo-cAMP, when microinjected into the PVH, increases CRF mRNA in the hypothalamus, increases POMC mRNA in the anterior pituitary, and increases plasma ACTH concentrations (225). Furthermore, the increase in CRF mRNA that occurs as a consequence of insulin-induced hypoglycemia can be attenuated by the prior injection into the PVN of a CREB antisense oligonucleotide. Since insulin-induced hypoglycemia also increases NE turnover in the hypothalamus, these findings point toward a major role for CREB in mediating the stimulatory effect of the ascending catecholaminergic pathways on CRF gene expression.

2. Neuropeptide Y. A number of studies have assessed the role of Neuropeptide Y in the regulation of the HPA axis (185, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235). This 36-residue peptide is widely distributed within the brain, and it exerts its effects by acting on five receptor subtypes (designated Y1-Y5) (236, 237). The cDNAs encoding all except the Y3 receptor have been isolated (238, 239, 240, 241, 242, 243, 244), each one is expressed in the brain, and the Y2 and Y5 receptor mRNAs seem restricted to this site (240, 244). NPY mimics the action of icv NE on the pituitary-adrenal axis when injected into the cerebral ventricles of the rat, dog, and sheep, and the studies in the conscious sheep indicate that the effect is mediated at one or more suprahypophysial sites since NPY increases the release of CRF and AVP into the hypophysial-portal circulation, but does not increase the release of ACTH from cultured ovine anterior pituitary cells (185). Like NE, NPY also stimulates CRF biosynthesis since icv NPY increases CRF mRNA in the rat hypothalamus (233). Although these effects of NPY on CRF are likely to be mediated by binding of the peptide to NPY receptors in the PVH, the exact NPY receptor subtype responsible for this action is currently unclear. Moreover, the finding that a broad range of NPY-related peptides increase plasma ACTH when administered icv raises the possibility that multiple NPY receptor subtypes are involved in mediating this effect (245).

3. CRF. Recent studies suggest that CRF may also exert an ultrashort positive feedback regulation on its own biosynthesis within the PVN (246). When injected icv in the rat, CRF initially increases the PVN expression of the immediate-early genes c-fos and NGFI-B and subsequently increases CRF mRNA in the nucleus. Since these effects are markedly attenuated by the prior icv injection of the CRF antagonist, -helical CRF(9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41), they are likely to be mediated by binding of the peptide to specific CRF receptors located either on CRF neurons within the PVN or in other brain areas. The brainstem catecholaminergic neurons could represent an alternative site of CRF binding since the peptide could be transported to these neurons by the cerebrospinal fluid after icv injection and since icv CRF has been shown to increase c-fos expression in the A1 and C1 cell groups. The activated brainstem catecholaminergic cell groups could then signal to the PVH and other brain areas by means of the ascending catecholaminergic pathways to increase neuronal c-fos expression in these sites.

	III. Hypothalamic Inhibition of ACTH Release and Biosynthesis

Top Abstract I. Introduction II. Hypothalamic Stimulation of... III. Hypothalamic Inhibition of... IV. CRIF: A Consideration... V. Future Directions References

 
A. Historic studies
Although the vast bulk of the studies related to the HPA axis can be adequately explained by assuming the hypothalamus only exerts a stimulatory influence upon ACTH release and biosynthesis, an analysis of the early studies employing pituitary stalk section and other ablative surgical procedures suggests that hypothalamic stimulation of ACTH secretion may not completely explain all of the experimental evidence. The earliest studies showed that pituitary stalk section in the rat and the dog failed to prevent the adrenal hypertrophy that occurs as a consequence of cold exposure (247, 248, 250). The surgery also failed to prevent the adrenal depletion of ascorbic acid in response to unilateral adrenalectomy in the rat (249), failed to prevent cold-induced adrenal cholesterol depletion in the guinea pig (251), and reduced, or abolished, the rabbit’s lymphopenic response to restraint and cold exposure while exerting little effect on this animal’s response to subcutaneous EPI or laparotomy (252). In 1954, Keller et al. (253) sectioned the pituitary stalk and destroyed the ventral hypothalamus in the dog and noted that the procedure resulted in a chronic decrease in insulin tolerance, but did not prevent the animals from withstanding further surgery such as a unilateral adrenalectomy or pancreatectomy. Furthermore, the adrenal gland weights (mg/kg body weight) and adrenal cholesterol contents (mg/kg body weight) were also increased by the hypothalamectomy (Fig. 13). In most instances, the hypothalamectomy also caused an acute eosinopenia, and a drastic eosinopenia was elicited by further surgery. The authors concluded that their experiments "add crucial support to the conclusion drawn by others that excitation of the adenohypophysis is not dependent upon direct hypothalamic humoral or neurogenic influence," but the findings could also be interpreted as providing support for the idea that pituitary stalk section removed a dominant inhibitory influence over ACTH secretion.

View larger version (38K): [in this window] [in a new window]   Figure 13. Adrenal data for four groups of animals: a) 10 dogs having hypophysectomies of varying magnitude (insulin dosages they were able to tolerate ranged from 1/40 to 1/10 U/kg of body weight, the mean being 1/20 U; b) 7 normal dogs which were terminated without being duressed previously in any way; c) 9 normal dogs which were terminated at varying time intervals after a major surgical procedure (in most instances a pancreatectomy); and d) 8 ventral hypothalamectomized dogs which were either terminated during some sort of duress or were found dead. Open bars represent individual animals; the crossed bars represent the group averages. Although there was considerable variability surrounding this data—varying size dogs and the difficulty in quantitating the magnitude of any particular duressed state—the data graphed clearly demonstrate a) the absence of adrenal atrophy and b) a normal range in cholesterol content of these animals. The suspicion of a tendency to adrenal hypertrophy (on the basis of gross inspection) in the hypothalamectomized dog is also verified by the composite data. [Reproduced with permission from A. D. Keller et al.: Am J Physiol 179:5–14, 1954 (253 ).]

View larger version (25K): [in this window] [in a new window]   Figure 14. The effect of brain removal on adrenal venous corticosteroid output in the dog. Resting level of corticosteroid output in this animal ranged from 2.2 to 5 g/min. Burns on five different occasions resulted in sharp increases in corticosteroid output. The increase in output following burning was comparable to that obtained following exogenous ACTH. [Reproduced with permission from R. H. Egdahl: Endocrinology 66:200–216, 1960 (254 ). © The Endocrine Society.]

View larger version (21K): [in this window] [in a new window]   Figure 15. Dog C-2 (total brain removal, total spinal cord removal with isolated pituitary). Fourteen hours after this operation adrenal cortical hypersecretion was still present. [Reproduced with permission from R. H. Egdahl: Endocrinology 71:926–935, 1962 (256 ). © The Endocrine Society.]

View larger version (44K): [in this window] [in a new window]   Figure 16. B-303 (isolated pituitary with brain removal to pons and bilateral nephrectomy). The kidneys are not essential to the increased pituitary adrenal activity observed in dogs with isolated pituitaries. [Reproduced with permission from R. H. Egdahl: Endocrinology 71:926–935, 1962 (256 ). © The Endocrine Society.]

View larger version (76K): [in this window] [in a new window]   Figure 17. a, d, And g, schematic sagittal drawings of the hypothalamo-pituitary complex to demonstrate the different deafferentations of the medial basal hypothalamus. b, e, and h, The knife cuts as seen from the base of the brain. Heavy line indicates the cut; broken lines with arrow indicate the level of the histological sections presented in c.f. - c, f, i. Microphotographs of rat hypothalamus showing the knife cut (arrows). c, Complete deafferentation (coronal section); f, incomplete deafferentation (coronal section); g, frontal cut (horizontal section) (x25). Abbreviations: AC, anterior commissure; AL, anterior lobe of pituitary; ARC, arcuate nucleus; ME, median eminence; MM, medial mamillary nucleus: OC, optic chiasm; ON, optic nerve; PED, cerebral peduncle; PL, posterior lobe of pituitary; PV, paraventricular nucleus; SC, suprachiasmatic nucleus; V, third ventricle; VM, ventromedial nucleus. [Reproduced with permission from B. Halász et al.: Neuroendocrinology 2:43–55, 1967 (258 ). © Karger, Basel.]

View larger version (31K): [in this window] [in a new window]   Figure 18. Upper, Diurnal variation in plasma corticosterone levels. Lower left, Pituitary-adrenal response to stress. Lower right, Adrenal compensatory hypertrophy in animals with partial or total deafferentation of the medial basal hypothalamus. S, Sham operated; CD, complete deafferentation; ID, incomplete deafferentation; FC, frontal cut. The drawings at the top of this figure show, in schematic sagittal section, the type of deafferentation (heavy line) in the groups below. AM, Rats sacrificed in the morning; PM, sacrificed in the afternoon. Adrenal compensatory hypertrophy: I, weight of the adrenal removed first; II, weight of the second adrenal 30 days later. [Reproduced with permission from B. Halász et al.: Neuroendocrinology 2:43–55, 1967 (258 ). © Karger, Basel.]

B. Effect of hypothalamo-pituitary disconnection in adult and fetal sheep
The hypothalamo-pituitary disconnection (HPD) procedure was first described by Clarke et al. (267), and it essentially removes the hypothalamic-releasing and release-inhibiting factors from the hypophysial-portal circulation and severs the innervation to the intermediate and posterior pituitary lobes. However, in contrast to stalk section, which often compromises the blood supply to the anterior pituitary and causes infarction of the gland, HPD preserves the blood supply to the adenohypophysis. The procedure causes no apparent histological alteration of the anterior lobe, but results in marked hypertrophy of the intermediate lobe and atrophy of the posterior pituitary.

As expected, the lack of GnRH in the hypophysial-portal circulation in the HPD animal caused a gradual decline in plasma LH and FSH concentrations, and they became undetectable 1 week after the procedure (267). By analogy with the hypothalamic-pituitary-gonadal axis, if the hypothalamus merely stimulated ACTH release, the absence of CRF and AVP in the hypophysial-portal circulation of HPD-treated animals would also be expected to reduce plasma ACTH and cortisol concentrations to subnormal, or undetectable, levels and abolish their response to stress. However, in 1986, Clarke et al. (268) noted that basal ACTH, -MSH, ß-endorphin, and cortisol levels were significantly elevated in those animals subjected to HPD and concluded that the ovine pituitary could function in the absence of hypothalamic influence. In 1988, Engler et al. (269) confirmed the effect of HPD on the basal levels of these POMC peptides and demonstrated that HPD virtually abolished their rise in response to an audiovisual stimulus and insulin-induced hypoglycemia, indicating that CRF and AVP are essential to mount an adequate pituitary-adrenal response to stress (Fig. 19). In addition, these authors also noted that the direction in which plasma ACTH and cortisol levels changed after HPD was identical to that of PRL, since hyperprolactinemia is also a consequence of pituitary isolation in the sheep, the rat, and the monkey (263, 270, 271, 272, 273). The hypothalamus both stimulates and inhibits PRL secretion and synthesis, and the dominant inhibitory regulation is mediated by DA, whereas the stimulatory input is mediated by neuropeptides such as TRH, vasoactive intestinal peptide, OT, and the newly discovered PRL-releasing peptide (271, 272, 274, 275, 276, 277). Since the hyperprolactinemia that follows stalk section is thought to be due to withdrawal of the major inhibitory factor DA (271, 274), it was argued that the increased ACTH secretion by the isolated anterior pituitary might also be due to withdrawal of the corticotropes from the influence of a hypothalamic factor that inhibits ACTH secretion. It was suggested this substance be named corticotropin release inhibitory factor (CRIF) since neither of the two best characterized inhibitory substances in portal plasma, namely SST and DA, seemed to possess the criteria required of such a substance (see below).

View larger version (25K): [in this window] [in a new window]   Figure 19. The effect of a 3-min audiovisual emotional stress on plasma POMC peptide and cortisol levels in the hypothalamopituitary-disconnected (HPD) ewe. The time of exposure to the stress is designated by the hatched area. The sham-operated animals are represented by closed symbols and continuous lines, and the HPD ewes are represented by closed symbols and broken lines. a, ACTH (); b, Ir-ß-endorphin (); c, ir--MSH (•); and d, cortisol (). [Reproduced with permission from D. Engler et al.: Neuroendocrinology 48:551–560, 1988 (269 ). © Karger, Basel.]

View larger version (28K): [in this window] [in a new window]   Figure 20. The POMC peptide and cortisol ultradian rhythm in four hypothalamopituitary disconnected (HPD) ewes. In this figure, the POMC peptides are displayed in the upper panels, and cortisol is shown in the lower panels. Significant hormone pulses are designated by . •, ACTH; , ir-ß-endorphin; , ir--MSH; , cortisol. [Reproduced with permission from D. Engler et al.: Endocrinology 127:1956–1966, 1990 (278 ). © The Endocrine Society.]

View larger version (77K): [in this window] [in a new window]   Figure 21. The effect of hypothalamopituitary disconnection (HPD) and dexamethasone on sheep anterior pituitary POMC mRNA levels. Hybridization of 32P-labeled human POMC DNA to a Northern blot of 25 µg anterior pituitary total RNA from control (lanes 1–3), dexamethasone-treated (lanes 4–6), ovariectomized (OVX)-HPD (lanes 7–9), and OVX-HPD dexamethasone-treated (lanes 10–12) sheep. [Reproduced with permission from J. E. Mercer et al.: Neuroendocrinology 50:280–285, 1989 (281 ). © Karger, Basel.]

C. Effects of the opiate alkaloids and opioid peptides on the HPA axis
An analysis of the in vivo and in vitro effects of opiate agonists and antagonists also provides indirect evidence for the participation of hypothalamic factors in addition to CRF and AVP in regulating the pituitary-adrenal axis (288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319).

The opiate alkaloids and opioid peptides suppress the pituitary-adrenal axis in man since morphine, ß-endorphin, and the met-enkephalin analog DAMME decrease basal plasma cortisol levels (290, 291, 300, 302, 303, 304), and morphine and DAMME also attenuate the ACTH and cortisol responses to CRF (305, 311, 312). These effects are likely to be mediated at a suprahypophysial site since morphine does not affect the release of ACTH from cultured rat anterior pituitary cells (305, 314). Conversely, the opiate receptor antagonist naloxone elevates basal plasma ACTH and cortisol levels, but the effect is only observed when high doses are used, suggesting that its effects are mediated by naloxone-insensitive -opiate receptors (292, 294, 295, 298, 300, 302, 307, 312, 318).

Studies in the rat suggest that the opiates act on distinct receptors to exert both inhibitory and stimulatory effects on the pituitary-adrenal axis, although their stimulatory effect is seen only in the unanesthetized animal (288, 289, 296, 297, 299, 301, 306, 313, 315). For example, the opiate antagonist naloxone and the -receptor agonist MR 2034 increase basal pituitary-adrenal activity in the rat, and these effects are abolished by a CRF antiserum. These findings suggest that the endogenous opiates restrain CRF release by acting on -opiate receptors. This conclusion is also supported by in vitro studies showing that naloxone increases basal CRF release or reverses the ß-endorphin-induced suppression of CRF release from incubated or perifused rat hypothalami (309, 317). By contrast, the µ-receptor agonist morphine also increases pituitary-adrenal activity in the rat, but this effect seems not to be mediated by increased CRF release since it is not affected by a CRF antiserum (313). This conclusion is further supported by in vitro studies that show that opiates decrease both the basal and stimulated release of CRF from cultured or perifused rat hypothalami (309, 314). Taken together, the stimulatory effects of morphine on the rat HPA axis could be explained by postulating that the opiate acts on µ-receptors to inhibit the release of both CRF and a CRIF (317).

The effects of the opiates on the release of CRF and AVP into the hypophysial-portal circulation have been assessed in the anesthetized rat and in the conscious horse (308, 310, 319). When injected into the cerebral ventricles of the rat, ß-endorphin and dynorphin inhibit the basal and hypotension-induced stimulation of CRF release into the hypophysial-portal circulation, whereas naltrexone increases both the spontaneous and stimulated CRF secretion (308). In addition, the intravenous administration of morphine also decreases the release of AVP into rat hypophysial-portal plasma (310). These findings provide direct evidence that the opiates restrain the release of both CRF and AVP into the hypophysial-portal circulation and suggest that their ability to stimulate the HPA axis must involve mechanisms that are independent of CRF and AVP. The effect of naloxone on the secretion of CRF and AVP in the conscious horse has been studied in detail by Alexander and Irvine (319). The administration of high doses of naloxone increases plasma ACTH and cortisol in the horse and also augments the CRF and AVP secretion rates. In contrast, low doses of naloxone also raise plasma ACTH and cortisol but do not alter the CRF and AVP secretion rates (Fig. 22). These findings demonstrate that endogenous opiates also inhibit the equine HPA axis, and the effects of low-dose naloxone provide further reason for speculating that endogenous opioids might also modulate the secretion of a CRIF.

View larger version (32K): [in this window] [in a new window]   Figure 22. Pituitary venous concentrations of CRH (), ACTH (solid line), and AVP in two mares given naloxone, at a low dose rate (0.2 mg/kg iv bolus at the arrow). A, Mare 9; B, mare 10. [Reproduced with permission from S. L. Alexander and C. H. G. Irvine: Endocrinology 136:5139–5147, 1995 (319 ). © The Endocrine Society.]

D. The role of the posterior pituitary in the regulation of corticotropic function
It is theoretically possible that the anterior pituitary could be regulated by factors secreted from nerve terminals located in both the external zone of the median eminence and the posterior pituitary because the blood supply to the adenohypophysis is derived from both the long portal vessels that originate in the median eminence and the short portal vessels that originate from the infundibular process of the posterior pituitary (320, 321).

The studies of Saffran and Schally (322) were among the first to point toward a role for the posterior pituitary in the regulation of ACTH secretion. When rat anterior pituitary tissue was only incubated with the posterior lobe, the release of ACTH was unaltered. However, in the presence of either arterenol, sphingosine, or hypothalamic tissue, the posterior lobe tissue caused the release of a large amount of ACTH. In 1957, McCann (323) injected a variety of agents into rats with transient or chronic diabetes insipidus caused by acute or chronic bilateral hypothalamic lesions. The clearest results were obtained in rats with transient diabetes insipidus and, in these animals, intravenous Pitressin (Parke-Davis, Morris Plains, NJ) caused reproducible ACTH release as judged by the adrenal ascorbic acid depletion assay. The results led McCann to propose that "the evidence obtained in vivo supports the hypothesis that ADH may be the neuro-humor responsible for eliciting ACTH discharge."

The removal of the neurointermediate lobe (NIL) in the rat also alters the function of the HPA axis (324, 325, 326, 327). For example, Arimura et al. (325) demonstrated that removal of the NIL markedly decreased, or abolished, the ACTH responses to repeated footshock, laparotomy, and the intraperitoneal (ip) or intravenous injection of lysine vasopressin, but basal ACTH concentrations and the ACTH response to ip histamine remained unaffected by the procedure. More recently, Fagin et al. (327) showed that similar surgery increased the mean 24-h CS level, attenuated the pituitary-adrenal response to an auditory stimulus, but did not affect the pituitary-adrenal responses to hemorrhage or insulin-induced hypoglycemia. The data regarding the effect of posterior lobectomy on the ovine HPA axis are much more limited and do not include measurements of plasma cortisol (328). Nevertheless, the procedure appears not to affect basal ACTH concentrations or the ACTH responses to an audiovisual stress, to serotonin, or to insulin-induced hypoglycemia. These findings suggest that the posterior lobe may be of little, if any, importance in regulating ACTH release from the ovine anterior pituitary and imply that any putative hypothalamic CRIF would need to be secreted into the long portal vessels by nerve terminals in the median eminence to regulate ovine corticotropic function.

E. Hypothalamic ACTH release-inhibitory activity
A number of in vitro studies have also suggested that hypothalamic extract contains ACTH release-inhibitory activity, but the precise nature of this activity currently remains uncertain (329, 330, 331, 332). In an effort to define the CRF activity in rat stalk median eminence (SME), Gillies et al. (330) subjected rat SME extract to Sephadex G-50 and BioGel P2 column chromatography and noted that certain fractions eluting on the BioGel P2 column (at 57–63 ml) possessed some ACTH release-inhibitory activity. However, further purification of this activity was not undertaken.

In 1983, Rédei and Endröczi (331) postulated the existence of a corticotropin-inhibiting factor by drawing an analogy with the hypothalamic regulation of PRL and GH secretion. In their initial studies, porcine hypothalamic tissue was purified by Sephadex G-25 column chromatography, preparative TLC, and two-dimensional TLC. These procedures isolated an "inhibitory factor" with a molecular weight that was larger than -aminobutyric acid, methionine enkephalin, and TRH, but smaller than that of SST. When a purified preparation of this "inhibitory factor" (in an amount equivalent to 0.3–1 hypothalamic extract as starting material) was administered intravenously to rats 1 min after their exposure to 10 electric shocks, plasma CS concentrations at 20 min were significantly lower than those in saline-injected animals, but were not significantly different from the control group at 40 min. Moreover, when the inhibitory factor was added to medium perfusing hypothalamic tissue slices, anterior pituitary fragments, or adrenal cortex quarters, it inhibited the effect of CRF at the pituitary level.

In 1989, Redei and Evans (332) reported further studies in which bovine hypothalamic extract was purified by reversed phase and Sephadex G-50 column chromatography. Those fractions that inhibited the release of ACTH from dispersed rat anterior pituitary cells were again purified by reversed phase HPLC (RP-HPLC), the purification-bioassay step was repeated three times, and the final purified material was eluted as a single peak that retained 37% of the ACTH release-inhibitory activity.

The purified "inhibitor" caused a concentration-dependent inhibition of basal ACTH secretion from dispersed rat anterior pituitary cells, although the highest concentration (1:400 dilution of purified factor from 200 g bovine hypothalamic starting material) only decreased ACTH release by approximately 48%. When the cells were incubated with 0.1–10 nM CRF and a 1:1750 dilution of inhibitor, the response to CRF did not differ from control incubations, but when the cells were preincubated (60 min) with the inhibitor, the ACTH response to 10 nM CRF was consistently reduced by up to 45%. When the inhibitor was injected intravenously into rats 5 min before or 1 min after their exposure to an inescapable footshock, plasma CS levels were significantly lower than those in the control group at 20 min. Finally, when the inhibitor was injected intravenously into freely moving, chronically cannulated rats, basal plasma ACTH concentrations were significantly suppressed at 40 min when compared with saline-injected animals.

These series of studies represent the most comprehensive performed to date with a partially purified hypothalamic "inhibitory factor," but the lack of protein sequence of the starting material precludes definitive judgment of their physiological significance.

F. Definition of CRIF
From the foregoing review, we suggest that a substance would need to fulfill the following postulates to qualify as a bona fide CRIF (Table 1).

Second, we postulate that CRIF also inhibits POMC gene expression by an effect on gene transcription and/or translation.

Third, we postulate that blockade of CRIF activity would increase basal ACTH secretion and may potentiate the release of ACTH caused by physiological stimuli.

Fourth, we postulate that CRIF will be present in nerve terminals of the external zone of the median eminence and will be found in hypophysial-portal blood in sufficient concentration to inhibit ACTH secretion.

Fifth, we postulate that CRIF binds to a specific receptor on the anterior pituitary. It is not essential that the receptor possess a specific structure, but it could be linked to one or more G proteins and possess seven transmembrane domains since all the anterior pituitary receptors identified to date possess these characteristics (57, 58, 59, 60, 63, 64, 65, 66, 84, 85, 277, 333, 334, 335, 336, 357).

	IV. CRIF: A Consideration of Possible Candidates

Top Abstract I. Introduction II. Hypothalamic Stimulation of... III. Hypothalamic Inhibition of... IV. CRIF: A Consideration... V. Future Directions References

 
In this section, we summarize the activities of several well characterized substances on the HPA axis and discuss whether they do, or do not, satisfy these postulates.

A. SST
A large number of studies have been performed over the last 20 yr to delineate the neuroendocrinology of SST and to assess its effects on the HPA axis (337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358). The two naturally occurring SST peptides, SST-14 and SST-28, are derived from the posttranslational processing of the prohormone prosomatostatin (pro-SST) in neurons and endocrine cells, and SST-like immunoreactivity has been demonstrated throughout the central nervous system, the gastrointestinal tract, and the pancreatic islet D cells. Within the hypothalamus, SST-containing perikarya are located in the periventricular nucleus, in the parvocellular PVH, the anterior hypothalamic nucleus, the perifornical region, and the lateral hypothalamus, and the most dense aggregation of hypothalamic fibers and terminals is seen in the external zone of the median eminence (341), from where the peptide is secreted into the hypophysial-portal circulation (339, 340, 348, 354). The actions of SST are mediated by five distinct receptor subtypes (SSTR1–5), which are coupled to the adenylyl cyclase, to K⁺ and Ca²⁺ ion channels, and to a protein tyrosine phosphatase (355, 356, 357, 358).

The in vivo studies in normal human subjects have shown that SST does not affect basal ACTH levels or the ACTH response to CRF, suggesting that it does not normally act at the pituitary level to regulate corticotrope function (350, 352). However, SST does decrease basal ACTH secretion in patients with Addison’s disease (337), and it also attenuates the POMC peptide and cortisol response to insulin-induced hypoglycemia, presumably by acting at a suprahypophysial site to attenuate CRF secretion (350).

The in vitro studies have clearly shown that the effects of SST on ACTH secretion are critically dependent upon the use of normal or neoplastic pituitary tissue and on the presence or absence of glucocorticoids in the incubation medium (338, 342, 343, 344, 345, 346, 347, 349, 351, 352). The clonal GH₃ and AtT-20 pituitary cell lines have been used to study the subcellular mechanisms of action of SST on the anterior pituitary and to characterize its effects on ACTH secretion (342, 343, 344, 345, 346, 349). The AtT-20 mouse pituitary tumor cell line responds to SST since it expresses those mRNAs encoding three of the four SST-14-selective receptors, namely SSTR 1, 2, and 4, as well as the mRNA encoding the SST-28-selective receptor SSTR5 (356). SST markedly attenuates the ability of CRF, isoproterenol, vasoactive intestinal peptide, forskolin, and cholera toxin to stimulate cAMP formation in AtT-20 cells (343) and also decreases the [Ca²⁺]_i in both GH₃ and AtT-20 cells by reducing the voltage-dependent Ca²⁺ current (344, 349). In addition, SST (10^-10 to 10^-7 M) inhibits basal ACTH release from AtT-20 cells (343) and the ACTH response to CRF, 50 mM KCl, and hypothalamic extract (342, 343).

However, studies employing normal rat anterior pituitary cells, fragments, or halves have shown that 10^-12 to 10^-6 M SST has no effect on basal ACTH secretion (338, 345, 346, 347, 353). However, Voigt et al. (338) first showed that SST (10^-11 to 10^-5 M) could attenuate the ACTH response to rat stalk median eminence extract or 100 nM AVP in pituitary cells derived from adrenalectomized animals, thereby suggesting that the inhibitory effect requires the absence of glucocorticoids. This finding was confirmed by Lamberts et al. (353), who showed that SST could only inhibit the ACTH response to CRF when normal rat anterior pituitary cells were cultured in glucocorticoid-free medium or were preincubated with the glucocorticoid receptor antagonist RU 38486 (Fig. 23).

View larger version (22K): [in this window] [in a new window]   Figure 23. Effect of somatotropin release-inhibiting hormone (SRIH) on CRH-stimulated (0.1 nM) ACTH release by normal female rat pituitary cells. Upper panel (control), the cells were incubated for 2 days in MEM + 10% FCS and then cultured for 2 days in MEM alone; middle panel, the cells were incubated in MEM + 100 nM RU 38486; lower panel, the cells were cultured in MEM + 5 nM dexamethasone. [Reproduced with permission from S. W. Lamberts et al.: Neuroendocrinology 50:44–50, 1989 (353 ). © Karger, Basel.]

B. Dopamine
The catecholamine dopamine (DA) is the most important PRL-inhibiting hormone, although several studies have suggested that it may also regulate corticotropic function, and for this reason it is considered in this review (359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375). The anterior, intermediate, and posterior pituitary lobes are regulated by three groups of tuberohypophysial DA neurons: one group is located in the rostral arcuate nucleus and innervates the pars intermedia; a second group of cells that lies immediately caudal to the first group innervates the posterior lobe; and a third group of arcuato-infundibular neurons innervates the external layer of the median eminence and the pituitary stalk (359). DA is secreted into the hypophysial-portal circulation (360, 361, 364, 366, 374), binds to adenohypophysial D2 DA receptors (362, 365, 371), and inhibits the secretion and synthesis of PRL by mechanisms that include a reduction in cAMP accumulation and phosphatidylinositol turnover (332, 367, 372, 373, 375).

The in vivo studies in man indicate that the dopaminergic agonist bromocriptine can lower ACTH concentrations in some patients with Cushing’s disease and Nelson’s syndrome (363, 369), and the in vitro studies have shown that DA (10^-7 M) can decrease the release of ACTH from cultured human corticotropic adenoma cells (Ref. 370 and Fig. 24). However, these findings are more likely due to the aberrant expression of DA receptors by neoplastic corticotropes since DA does not regulate the release of ACTH from normal corticotropic cells (Ref. 370 and Fig. 25) and for this reason is unlikely to be a physiological CRIF.

View larger version (30K): [in this window] [in a new window]   Figure 24. Effect of dopamine (DA) alone or in combination with haloperidol on ACTH secretion by cultured corticotroph adenoma cells obtained from patients with Nelson’s syndrome (patients 1–4) and a patient with Cushing’s disease (patient 5). In one adenoma tissue (no. 4), experiments were repeated on day 5 and on day 13 in culture to ascertain whether the response was reproducible. A minimum of four replicates was used for each variable. Results are expressed as the percentage of change in secretion relative to a preincubation in medium alone. For comparison, the mean values in the control incubation were designated as 100%. Results are the mean ± SEM. *, P < 0.05; **, P < 0.01. [Reproduced with permission from M. Ishibashi and T. Yamaji: J Clin Invest 68:1018–1027, 1981 (370 ). © The American Society for Clinical Investigation.]

View larger version (26K): [in this window] [in a new window]   Figure 25. Effect of cyproheptadine, dopamine, TRH, hydrocortisone, and lysine vasopressin on ACTH secretion by cultured normal human corticotrophs obtained from a patient at the time of hypophysectomy for the palliation of metastatic breast cancer. A minimum of four replicates was used for each variable. Results are expressed as the percentage of change in secretion relative to a preincubation in medium alone. For comparison, the mean value in the control incubation was designated as 100%. Results are the mean ± SEM. **, P < 0.01. [Reproduced with permission from M. Ishibashi and T. Yamaji: J Clin Invest 68:1018–1027, 1981 (370 ). © The American Society for Clinical Investigation.]

Although ANP was originally identified in the heart, ir-ANP has also been demonstrated in neurons and nerve terminals in the brain (386, 387, 393). However, in contrast to the cardiac atrium, the predominant molecular forms of ANP in the brain are ANP(4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) and ANP(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) (392). Although the ir-ANP in hypothalamic neurons is comprised solely of ANP(4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28), the neuron secretes ANP(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28), thereby implying that it processes ANP(4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) to ANP(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) before secretion (403). Within the hypothalamus, the most abundant collection of ir-ANP perikarya is located in the periventricular area that extends caudally from the anteroventral tip of the third ventricle to the mamillary region. At a more caudal level, the periventricular neurons invade the suprachiasmatic nucleus, the arcuate nucleus, and the paraventricular nucleus (PVH). These findings indicate that ir-ANP neurons are present in hypothalamic nuclei that are known to project to the median eminence and to other brain areas. The majority of ir-ANP fibers in the hypothalamus are associated with the wall of the third ventricle, but large populations of fibers also innervate the PVH, the dorsomedial, arcuate, and ventromedial nuclei, and the external zone of the median eminence.

The findings of ir-ANP in some hypothalamic neurons that project to the median eminence and of ir-ANP in nerve terminals in the external zone of the median eminence suggest that ANP could be secreted into the hypophysial-portal circulation (Fig. 26). This suggestion is supported by the finding that rat hypophysial-portal plasma contains ir-ANP in concentrations that are 2.5- to 4.5-fold higher than those found in the systemic circulation (402, 407) and that the predominant molecular species of ANP is ANP(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) (414). The peptide could bind the ANP receptor(s) that are present on the anterior pituitary (385) since the adenohypophysis contains two forms of the ANP receptor, both ANP(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) and ANP(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) demonstrate a similar potency in receptor binding, and both cause a dose-dependent accumulation of cyclic GMP in the anterior pituitary (399). Although ir-ANP is found in tuberoinfundibular neurons and ANP(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28) is present in portal plasma, despite the finding of ANP receptors on the anterior pituitary and the ability of ANP to stimulate the accumulation of cyclic GMP in the anterior pituitary, the available evidence indicates that these events are not coupled to the secretion of any anterior pituitary hormone.

View larger version (106K): [in this window] [in a new window]   Figure 26. Atriopeptin (APir) staining in the median eminence (ME) and arcuate nucleus (ARC). This photomicrograph of a coronal section stained with the immunofluorescent technique shows dense clusters of APir varicosities in the external lamina of the median eminence. A few fibers can be seen traversing the internal lamina. At top are APir neurons in the ventral part of the arcuate nuclues. Scale bar, 50 µm. [Reproduced with permission from D. G. Standaert et al.: J Comp Neurol 253:315–341, 1986 (393 ). © Wiley-Liss, Inc., a division of John Wiley & Sons, Inc.]

The in vivo studies have been performed in the rat and in man and have also yielded diverse findings. Kovåcs and Antoni (404) showed that ANP(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28), when given in an amount sufficient to cause transient hypotension, significantly reduced CRF/AVP-induced ACTH release in intact rats while a higher dose, which produced persistent hypotension, prolonged the CRF/AVP-induced ACTH response. Although the higher dose also caused sustained hypotension in PVN-lesioned animals, it markedly decreased the ACTH response to CRF/AVP (Fig. 27). These findings suggested that ANP may act as a potent inhibitor of stimulated ACTH release, but its ability to cause hypotension may also increase the secretion of ACTH-releasing factors in the intact animal, thereby masking its inhibitory effect on ACTH release. Several studies have used in vivo immunoneutralization to assess the effect of ANP on the pituitary-adrenal axis. In this regard, Fink et al. (406, 409) have used both the Wistar and Brattleboro rat, the latter strain being deficient in AVP and demonstrating a significantly diminished response to stress. In the Wistar rat, the systemic administration of an ovine anti-ANP serum increased basal ACTH and CS levels but did not potentiate the pituitary-adrenal response to an ether stress. In contrast, ether stress failed to increase pituitary-adrenal activity in the Brattleboro rat, but the stimulus was effective in those animals pretreated with an anti-ANP serum. Antoni et al. (410) showed that the intracarotid injection of a rabbit anti-ANP serum in the Wistar rat augmented the ACTH and CS responses to intraperitoneal NaCl but had no effect on baseline pituitary-adrenal activity. Taken together, these findings have suggested that a complete ACTH response to stress may require activation of an hypothalamic stimulatory mechanism that is mediated by CRF and AVP and suppression of an inhibitory hypothalamic mechanism that may involve ANP.

View larger version (25K): [in this window] [in a new window]   Figure 27. The effect of atriopeptin on plasma ACTH in conscious paraventricular nucleus-lesioned male rats injected at time zero with 1 pmol CRF and 10 pmol AVP (CRF/AVP) iv. Atriopeptin was given intravenously as a bolus injection (arrow) followed by a continuous infusion at a rate of 0.005 ml/min (striped bar). Control animals received saline. Data are means ± SEM. *, P < 0.05 when compared with saline-treated controls at the same time point by U test. Inset, Plasma ACTH expressed as the average increase over baseline during a period of 30 min after the injection of CRF/AVP. Data are means ± SEM. *, P < 0.05 by U test. [Reproduced with permission from K. J. Kovåcs and F. A. Antoni: Endocrinology 127:3003–3008, 1990 (404 ). © The Endocrine Society.]

Taken together, the studies with ANP represent the most compelling evidence to date that a neuropeptide may inhibit ACTH release. However, the inability of ANP to consistently decrease basal, or stimulated, ACTH release from normal anterior pituitary cells and its inability to consistently affect the HPA axis in man suggest that ANP may not be the CRIF but it may be a subsidiary modulator of the HPA axis.

D. Prepro-TRH-(178–199)
The hypothalamic tripeptide TRH was identified in 1970 by its ability to stimulate the release of TSH (417, 418) but was subsequently found to be widely distributed within the central nervous system and in extraneural tissues (419, 420, 421, 422, 423). Within the hypothalamus, the largest concentration of TRH-stained perikarya is found in the anterior and medial parvocellular subdivisions of the paraventricular hypothalamus, while the highest concentration of TRH-stained fibers is found in the external zone of the median eminence from where the peptide is secreted into the hypophysial-portal circulation (Fig. 28 and Ref. 424). The rat TRH prohormone (pro-TRH) is a 29,247-Da protein that contains five copies of the TRH progenitor sequence Gln-His-Pro-Gly and additional cleavage sites, which result in the generation of non-TRH peptides (426, 429, 433, 434). In contrast to TRH, which is located in both neuronal perikarya and axon terminals, pro-TRH is largely confined to neuronal cell bodies (425, 427, 435), suggesting that it is rapidly processed within the cell soma and does not undergo significant axoplasmic transport. Moreover, ir-pro-TRH is also found in areas of the brain that contain undetectable amounts of ir-TRH, suggesting that in these sites pro-TRH undergoes alternative modes of posttranslational processing that result in the generation of non-TRH peptides (428, 429, 430, 431).

View larger version (141K): [in this window] [in a new window]   Figure 28. Coronal sections through the paraventricular nucleus demonstrating the location of ir-TRH in the anterior parvocellular subdivision (A; PVNa), the medial (B; PVNm) and periventricular (P) subdivisions, and the caudal portion of the PVNm (C). In panel B, note the peroxidase-positive cell bodies that appear to be within the ependymal cell wall (open arrows) and the medially directed neuronal processes (closed arrows) toward the third ventricle (III). The high power photomicrograph in the inset depicts an immunoreactive periventricular neuron with extension of a process (small arrow) within the ependymal lining. Clusters of peroxidase-positive neurons are also present in a perifornical distribution (arrows in A and B). D, Extinction of immunoreactive staining after absorption of the antiserum with excess synthetic TRH. Original magnification: A–C, x156; D, x98; inset, x390. F, Fornix; PVNl, magnocellular division of the paraventricular nucleus. [Reproduced with permission from R. M. Lechan and I. M. D. Jackson: Endocrinology 111:55–65, 1982 (424 ). © The Endocrine Society.]

View larger version (83K): [in this window] [in a new window]   Figure 29. Immunocytochemical detection of prepro-TRH-(178–199) in rat hypothalamus and median eminence. Cryostat-cut sections (8 µm) were first incubated with rabbit antiserum to synthetic Ps5 (dilution of 1:200) and then with goat anti-rabbit -globulins conjugated to fluorescein isothiocyanate. A, Section through the median eminence (ME). Magnification x425. B, Section through the paraventricular nucleus of the hypothalamus from a colchicine-treated rat. Immunostaining was detected in numerous cell bodies of the pars parvocellularis of the paraventricular nucleus (PVN). Immunoabsorption of the antiserum with 1 µM Ps5 completely prevented staining. III, Third ventricle. Magnification, x106. [Reproduced with permission from M. Bulant et al.: J Biol Chem 263:17189–17196, 1988 (Ref. 433).]

Isolated ACTH deficiency is a condition in which plasma ACTH concentrations are either low or undetectable and plasma cortisol levels are subnormal (445, 446). In most patients, an autoimmune destruction of the corticotropes is suggested by the findings of lymphocytic infiltration of the anterior pituitary, the presence of antipituitary antibodies in serum, an onset of the condition in the postpartum period, and an association with autoimmune thyroid disease and other autoimmune endocrinopathies. However, the apparent absence of pituitary autoimmunity and the lack of antithyroid antibodies in the serum of some patients with raised TSH concentrations led Redei et al. to propose that primary hypothalamic dysfunction might underlie the disorder in these cases. It was proposed that the elevated TSH level in antibody-negative cases was due to hypersecretion of TRH and that the low ACTH level was due to concomitant hypersecretion of a non-TRH peptide that possessed CRIF activity. However, this hypothesis is open to debate since hypothalamic neuropeptide secretion cannot be determined in man, and the apparent absence of serum antibodies may not entirely exclude an autoimmune pathogenesis.

Nevertheless, to test the hypothesis that the TRH prohormone may contain an ACTH release-inhibiting moiety, mouse AtT-20 pituitary tumor cells were transiently transfected with increasing concentrations of rat prepro-TRH cDNA. A progressive decline in basal and CRF-stimulated ACTH secretion and POMC mRNA levels was observed, and a similar effect on POMC mRNA levels was also seen when the cells were stably transfected with the prepro-TRH cDNA (437). To determine which part of the pro-TRH molecule might possess the CRIF activity, Redei et al. (438) transfected AtT-20 cells with a prepro-TRH cDNA construct lacking the sequence encoding amino acids 119–229. This resulted in the loss of ACTH releasing-inhibiting activity, suggesting that a peptide contained within this region was responsible for the inhibitory activity. When AtT-20 cells were incubated with either 10^-9 to 10^-6 M TRH or the TRH progenitor peptide, prepro-TRH-(115–151), -(160–169), or -(208–220), ACTH secretion remained unaltered. However, 10^-8 to 10^-6 M prepro-TRH-(178–199) inhibited both basal and CRF-stimulated ACTH release, and similar results were observed when rat anterior pituitary cells were used (Fig. 30). These findings, however, have not been confirmed by Nicholson and Orth (Ref. 447 and Fig. 31). These investigators employed cultured rat anterior pituitary cells and demonstrated that neither an acute, nor a prolonged (24 h), exposure of the cells to 500 nM, or graded concentrations, of prepro-TRH-(178–199) was able to affect the basal or CRF-induced ACTH release.

View larger version (32K): [in this window] [in a new window]   Figure 30. CRIF activity of prepro-TRH-(178–199). The amino acid sequence of prepro-TRH-(178–199): Phe-Ile-Asp-Pro-Glu-Leu-Gln-Arg-Ser-Trp-Glu-Glu-Lys-Glu-Gly-Glu-Gly-Val-Leu-Met-Pro-Glu. Primary anterior pituitary cells were used to assess the bioactivity of prepro-TRH-(178–199) on ACTH secretion (A) and POMC mRNA levels (B) in the absence () and presence () of 5 nM CRH. ACTH was measured by RIA, and POMC mRNA levels were determined by Northern blot analysis. The experiment was repeated and also carried out on AtT-20 cells with similar results. [Reproduced with permission from E. Redei et al.: Endocrinology 136:3557–3563, 1995 (438 ). © The Endocrine Society.]

View larger version (20K): [in this window] [in a new window]   Figure 31. Effect of acute exposure to graded concentrations of prepro-TRH-(178–199) on ACTH secretion basally and in response to ovine CRH. The points represent the means of six observations at each prepro-TRH-(178–199) concentration; () prepro-TRH-(178–199) alone; () 5 nM CRH + prepro-TRH(178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 ); (*) significantly less than control, determined by ANOVA followed by Duncan’s multiple range test, P = 0.05. Mean basal ACTH secretion in the experiments depicted here was 1.8 ± 0.2 ng/well/4-h incubation. [Reproduced with permission from W. E. Nicholson and D. N. Orth: Endocrinology 137:2171–2174, 1996 (447 ). © The Endocrine Society.]

View larger version (30K): [in this window] [in a new window]   Figure 32. ACTH, corticosterone, PRL, and TSH secretion in response to 5-min restraint stress. Data are mean and SEM of five to six animals per treatment. The animals were restrained between 1100 and 1300 h. Prepro-TRH178–199 (100 or 200 µg/kg) was infused in the home cage through the indwelling atrial cannula 5 min before restraint. After restraint the cannula was connected immediately with an extender tubing for serial bleeding, and the animals were subsequently returned to the home cage. *,P < 0.05 from both doses of prepro-TRH178–199. [Reproduced with permission from R. F. McGivern et al.: J Neurosci 17:4886–4894, 1997 (448 ).]

Finally, there are neuropeptides in the external zone of the median eminence that may not be secreted into the hypophysial-portal circulation. For example, neuropeptide Y, substance P, and galanin have been demonstrated in the ovine median eminence, but their concentrations in portal plasma are not greater than those in systemic plasma (462). Moreover, portal plasma concentrations of neurokinin A, peptide histidine isoleucine, neurotensin, and cholecystokinin were either undetectable or not greater than those in jugular plasma, thereby excluding these known neuropeptides as potential releasing or release-inhibiting factors in the ovine species.

	V. Future Directions

Top Abstract I. Introduction II. Hypothalamic Stimulation of... III. Hypothalamic Inhibition of... IV. CRIF: A Consideration... V. Future Directions References

 
DA and SST are the two best characterized inhibitory factors in the hypophysial-portal circulation, and their analogs are now in use in clinical medicine. For example, the SST analogs, octreotide and lanreotide, are used as the primary therapy, or as an adjunct to surgery, in the management of gastrointestinal tumors that cause watery diarrhea and in patients with GH- and TSH-secreting pituitary tumors. Moreover, the dopaminergic agonist drugs bromocriptine, pergolide, and cabergoline are usually the treatment of choice in patients with PRL-secreting microadenomas and macroadenomas and are also used to treat Parkinson’s disease. By analogy, it is conceivable that a peptidic or nonpeptidic analog with ACTH release-inhibiting activity might also be of use in the treatment of patients with pituitary ACTH-secreting adenomas that cause Cushing’s disease.

In contrast, an analog with the capacity to antagonize the action of a naturally occurring CRIF, and to thereby raise plasma cortisol concentrations, might also be therapeutically useful in patients with autoimmune or rheumatic diseases. This statement is based on studies in animals and man which indicate that a hyporesponsive HPA axis may increase susceptibility to diseases such as experimental allergic encephalomyelitis, autoimmune thyroiditis, and rheumatoid arthritis. Moreover, such an analog might also be of benefit in reversing the hypercortisolemia that occurs in some psychiatric disorders (anorexia nervosa, endogenous depression), in neurodegenerative diseases (Alzheimer’s disease), and in normal aging. However, these hypotheses can only be tested if a substance, or substances, is isolated that fulfill(s) the proposed criteria of a CRIF (Fig. 33).

View larger version (34K): [in this window] [in a new window]   Figure 33. A conceptual model of the way the hypothalamus may regulate ACTH secretion. This is a model that is based on the studies summarized in this review, and it postulates that the hypothalamus may both stimulate and inhibit ACTH secretion. Moreover, it suggests that the hypothalamic inhibition of ACTH release is mediated by the secretion of a single CRIF. However, it is possible that several substances could cooperate to mediate the inhibition by acting in an analogous fashion to the stimulatory interaction of CRF and AVP.

	Acknowledgments

 
We are indebted to Dr. Seymour Reichlin for continued critical reading of the manuscript and to Ms. Carole Sheppard for secretarial assistance.

	Footnotes

 
Address reprint requests to: Dennis Engler, M.D., Laboratory of Molecular Genetics and Development, Institute of Reproduction and Development, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, Australia 3168.

¹ The studies from the authors’ laboratories were supported by the National Health & Medical Research Council of Australia and the National Institutes of Health, USA.

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