Corticotropin-release inhibitory factor

BRIEF REVIEWS Corticotropin-Release Inhibitory Factor Evidence for Dual Stimulatory and Inhibitory Hypothalamic Regulation Over Adrenocorticotropin Secretion and Biosynthesis Dennis Engler, Jun-Ping Liu, Iain J. Clarke, and John W. Funder

The hypothalamus is currently thought to stimulate the synthesis and secretion of ACTH uniquely by secreting neuropeptides into the hypophysial-portal circulation, of which the most important are CRH and arginine vasopressin. However, analysis of the effects of pituitary isolation on the pituitary-adrenal axis in a variety of species suggests that the hypothalamus exerts both stimulator-y and inhibitory regulation over ACTH secretion and POMC biosynthesis, and that the inhibitory control is dominant. Because none of the currently known inhibitory factors in the hypophysial-portal circulation consistently decreases basal ACTH secretion and POMC mRNA levels in normal anterior pituitary cells, it is suggested that this inhibition is mediated by a currently unidentified hypothalamic substance, presumably a neuropeptide, which we have termed corticotropin-release inhibitory factor (CRIF). The possible roles in clinical medicine of agonists and antagonists of this putative CRIF are discussed. (Trends Endocrinol Metab 1994;5:272-283) ??

Hypothalamic Stimulation of ACM-I Release and Biosynthesis

It is currently thought that the hypothalamus uniquely stimulates the secretion and synthesis of ACTH by the anterior pituitary (AP) by secreting a number of peptides into the hypophysial-portal circulation, the most important of which are CRH and arginine vasopressin (AVP) (Plotsky 199 1, Antoni 1993). In humans and in rats, CRH is the most potent ACTH secretagogue and the only neuropeptide known to stimulate POMC

Dennis Engler, Jun-Ping Liu, Iain J. Clarke, and John W. Funder are at Prince Henry’s Institute of Medical Research and the Molecular Embryology and Birth Defects LaboratoIy, Monash Medical Centre, Clayton, Victoria 3168, Australia.

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biosynthesis. In the rat, the ability of CRH to stimulate ACTH release is potentiated by the weaker secretagogues AVP, oxytocin, angiotensin II, norepinephrine (NE), and epinephrine (EPI). However, none of these weaker agonists exerts any effect on POMC biosynthesis, nor enhances the effect of CRH on the rat POMC gene. However, CRH may not be the dominant ACTH secretagogue in all species, as CRH and AVP appear equipotent in their ability to release ACTH from bovine AP cells (Schwartz and Vale 1989) and in the sheep, AW is a more potent stimulus than CRH of ACTH secretion in vivo and in vitro (Pradier et al. 1986, Fan&u-i et al. 1989, Liu et al. 1990). The paraventricular nucleus of the hypothalamus (PVH) contains the CRH and AVP neurons that project to the 01994, ElsevierScienceInc., 1043-2760/94/$7.00

external zone of the median eminence and to other brain areas (Swanson et al. 1983) This heterogeneous structure contains three magnocellular and five parvocellular subdivisions and is situated on either side of the third ventricle. The tuberoinfundibular CRH and AVP neurons are mainly located in the medial parvocellular subdivision (PVHmp), and recent immunohistochemical studies in the rat indicate that pro-AW-expressing (CRH+/AVP+) and pro-AVP-deficient (CRH+/AW_) CRH perikarya are found in almost equal proportion in this region (Whit&l 1988). Although comparable studies have yet to be performed in other species, it appears likely that a similar cytoarchitecture might be found. The CRH, /AVP+neurons are densely innervated by dopamine+hydroxylase (DBH), phenylethanolamine-N-methyltransferase (PNMT), and neuropeptide Y (NPY) axon terminals (Figure 1). The DBH-immunoreactive (ir) axons are derived from noradrenergic cell bodies located in the nucleus of the tractus solitarius (NTS, A2 area), the ventrolateral medulla (Al area), and the locus coeruleus (A6 area), whereas the PNMTir fibers originate from the Cl, C2, and C3 brainstem adrenergic cell groups. The NPY-ir fibers are predominantly derived from the hypothalamic arcuate nucleus, although some axons originate in the brainstem, where the peptide is extensively colocalized within the Cl, C2, and C3 adrenergic cell groups (Sawchenko et al. 1985). DBH-ir, PNMT-ir, and NPY-ir axon terminals all make direct synaptic contacts with CRH-ir perikarya in the PVH, raising the possibility that they may all be involved in regulating CRH and AVP secretion and/ or synthesis. As previously mentioned, CRH and AVP are released into the hypophysialportal circulation and regulate corticotrope function. The corticotropes of the rat and ovine anterior pituitary synthesize POMC and process the prohonnone to generate ACTH, p-endorphin @EP), and p-lipotropin (Smith and Funder 1988), although the ovine anterior pituitary also contains some a-MSH. The melanotropes of the intermediate lobe also synthesize TEA4 Vol. 5, No. 7, 1994

POMC, but process ACTH further to yield a-MSH and corticotropinlike intermediate lobe peptide [ACTH( 1g-39)]. ACTH is secreted in a pulsatile manner, and this ultradian rhythm appears to be the major determinant of the normal cortisol rhythm. &EP and a-MSH are also secreted in a pulsatile fashion in sheep, and this rhythm appears to be due to the synchronous and asynchronous release of both peptides from the anterior and intermediate lobes (Engler et al. 1989a). In recent studies in the conscious ewe (Engler et al. 1989b), we demonstrated that the hypothalamus secretes CRH and AVP in a pulsatile manner and that the CRH and AVP pulse patterns are markedly heterogeneous in the basal state (Figure 2). Moreover, only 45%80% of all the POMC-peptide pulses were strictly correlated with a pulse of CRH and/or AVP, although a positive correlation was found between the levels of CRH and AVP in hypophysial-portal blood and the concentrations of ACTH and cortisol in the systemic circulation. An audiovisual stimulus and insulininduced hypoglycemia both caused a rapid activation of the hypothalamicpituitary-adrenal axis, although hypoglycemia was the more intense stimulus (Figure 2). Because the audiovisual stimulus activates the auditory and visual cortex whereas hypoglycemia primarily activates several subcortical brain areas, these findings show that the CRH and AVP neurons within the PVH may be

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Figure 1. Schematic drawing of a sagittai section through the rat brain to indicate the dominant biochemical makeup and distribution of catecholaminergic and NPYimmunoreactive inputs from the brainstem to the PVH. Adrenergic (E) projections arise from the Cl, 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 coexuieus and A2 ceil groups are also distributed primarily to the parvicehuiar division, but are, for the most part, NPY negative. A heterogeneous input arises from the Al region and is distributed to both the parvicellular division and preferentially to those parts of the magnocelluiar division in which vasopressinergic neurons (V) predominate over oxytocinergic ones (0). One component appears also to contain NPY immunoreactivity, whereas a second one does not. Reproduced with permission from Sawchenko et al. (1985).

activated by different neural inputs. These stressful stimuli also caused a consistently greater rise in AVP than CRH, thereby increasing the AVP-CRH molar ratio. The large increase in AW secretion during stress may be due to activation of both parvocellular and magnocellular neurons in the PVH, a conclusion that is supported by studies in the rat which indicate that most of the AVP in hypophysial-portal plasma is derived from magnocellular secretion (Antoni 1993). Taken together, the results strongly suggest that AVP is an important dynamic modulator of the stress response.

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Evidence that Activation of the CentralNoradrenergic, Adrenergic, or Neuropeptide Y Pathways May Reset the Hypothalamic-PituitaryAdrenal Axis: Potential Clinical Implications

Experimental

Studies

The studies were aimed initially at deter-

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mining how insulin-induced hypoglycemia stimulates CRH and AVP secretion. The PVH does not appear to contain glucose-sensitive neurons, but a number of other brain regions such as the nucleus of the tractus solitarius (NTS), the lateral hypothalamic area (LHA), and the ventromedial hypothalamus (VMH) do contain neurons that respond to changes in glucose concentration by altering their firing rates. Therefore, the effect of hypoglycemia on CRH and AVP release is likely to be indirect and secondary to a primary activation of one or more of the aforementioned glucose-sensitive sites. The experiments were based on the finding that hypoglycemia increases the hypothalamic turnover of NE (Smythe et al. 1984) and on the previously described anatomic relationships that exist in the rat between the PVH and the brainstem catecholaminergic and peptidergic cell groups. We hypothesized that the effect of hypoglycemia on neuronal firing in the NTS might be translated into an increased synthesis of NE within the nu-

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2. A representativeexample of the secretion of CRF (=CRH), AVF’, the three POMC peptides,and cortisol in a conscious ewe. Shown also are the secretoryresponsesto a 3-min audiovisualstress(hatchedarea) and insulin-inducedhypoglycemia (arrow). In this and the subsequent figure, the triangles (v) depict significant hormone pulses. Reproduced with permissionfrom Engleret al. (1989b).

Figure

cleus or within the Al and A6 areas, because all three regions are interconnected. This conceptual framework would then explain the increased hypothalamic turnover of NE during hypoglycemia and predict that NE (and possible EPI) might stimulate the release of CRH and/or AVP. When these experiments were begun, it was widely accepted that NE inhibited ACTH release, a view based on a large body of data from Ganong’s laboratory in the 1970s (Weiner and Ganong 1978).

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When NE and EPI were injected into the lateral cerebral ventricle of conscious sheep, both NE and EPI caused an acute and sustained increase in ACTH and cortisol secretion, and NE appeared to be the more potent agonist (Liu et al. 1991). NE and EPI released only very modest amounts of ACTH from cultured AP cells, suggesting that they were acting mainly on suprahypophysial brain sites to increase CRH and AW release. This prediction was tested by determining the effects of intracerebroventricular (i.c.v.)

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NE on the secretion of CRH and AVP into the hypophysial-portal circulation of conscious sheep. Because the distribution of NPY-stained axon terminals in the PVH encompasses the DBH input, the effect of i.c.v. NPY on the activity of the entire axis was also assessed. The i.c.v. injection of 50 pg NE acutely increased AVP and CRF concentrations in portal plasma, increased the AVPCRH molar ratio, and caused an acute activation of the pituitary-adrenal axis (Figure 3). Moreover, hypothalamicpituitary-adrenal activation was also apparent at 4 h after injection. Similar but somewhat less marked changes in hypothalamic-pituitary-adrenal activity were also produced by 50 pg NPY, but, in contrast to NE, NPY did not release ACTH from AP cells, indicating that its effect on the HPA axis is mediated exclusively at a suprahypophysial site (Liu et al. 1994). It is likely that NE and NPY directly activate parvocellular CRH and AVP neurons in the PVH, although the finding that the increases in portal AVP and CRH levels were not temporally coincident supports the suggestion that NE and NPY may have also activated the magnocellular AVP system. The finding that NE is capable of increasing CRH secretion into the ovine hypophysialportal circulation is consistent with a number of in vivo and in vitro studies in the rat (Plotsky 1987, Calogero et al. 1988). However, of perhaps greater importance was the observation that i.c.v. NE and NPY both caused sustained hypersecretion of AVP and CRH even though plasma cortisol levels were greatly elevated. This observation suggests that activation of the central noradrenergic or NPY systems may also override the normal glucocorticoid-negative feedback on those areas of the brain concerned with regulation of the hypothalamicpituitary-adrenalaxis. Although the subcellular mechanisms that underly this phenomenon cannot be elucidated by an in vivo approach, we suggest that the following mechanisms may be involved. First, i.c.v. NE might activate a CRH neuronal subpopulation that is relatively insensitive to glucocorticoid-negative feedback, a possibility that is supported by the finding of a CRH neuronal subpopulation in the PVHmp that does not appear to express glucocorticoid receptors (Agnati et al. 1985). Second, the activation of hypothalamic adrenergic

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receptors by i.c.v. NE (or NPY receptors by NPY) might stimulate CRH and AVP biosynthesis to such an extent that the inhibitory effect of the glucocorticoid on CRH (and AVP) gene expression is overcome. The suggestion that the central noradrenergic pathways might stimulate CRH biosynthesis in vivo is supported by the observations that insulin-induced hypoglycemia increases both the turnover of NE and the level of CRH mRNA expression in the hypothalamus (Smythe et al. 1984, Suda et al. 1988). NE also stimulates the in vitro release and biosynthesis of CRH in fetal rat hypothalamic cells, an effect that involves the activation of both the A and C protein kinases and is mimicked by the phorbol ester TPA. TPA activates protein kinase C and increases the expression of the two major constituents of the AP-1 transcription factor complex, namely, the protooncogene products Fos and Jun (Sheng and Greenberg 1990). In this regard, it is relevant that the overexpression of either Fos or Jun may disrupt the binding of the glucocorticoid receptor (GR) to various regulatory elements in a number of systems, and thus block glucocorticoid inhibitory effects on gene expression (Schtile et al. 1990, Yang-Yen et al. 1990 ). A similar interaction also occurring in PVH CRH, IAVP, neurons in response to NE (and NPY) might partly explain the persistent CRH and AVP hypersecretion occurring in the presence of sustained hypercortisolemia. The physiologic and clinical relevance of these observations is discussed later. Endogenous

Depression

The observation that i.c.v. NE may reset the hypothalamic-pituitary-adrenal axis may be of relevance in that subgroup of patients with endogenous depression who display hypercortisolemia (Gold et al. 1986). These patients show a marked increase in ACTH pulse frequency, although the ACTH pulse amplitude and mean ACTH concentrations are normal. The hypercortisoiemia is associated with cortisol pulses of increased amplitude and duration, and these changes may be

Figure 3. The effect of an intracerebroventricular injection of 50 pg norepinephrine on plasma CRP (=CRH), AVP, ACTH, and cortisol levels in three ewes. The arrow (-1) depicts the time of injection. Reproduced with permission from Liu et al. ( 1994).

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d Figure 4. The effect of a 3-min audiovisual emotional stress on plasma POMC peptide and

cortisol levels in the hy-pothalamopituitary-disconnected (HPD) ewe. The time of exposure to the stress is designated by the hatched area. The sham-HPD animals are represented by closed symbols and continuous lines and the HPD ewes are represented by closed symbols and discontinuous lines. a, ACTH (m); b, ir-p-EP (A); c, ir-a-MSH (0); and d, cortisol (V). Reproduced with permission from Engler et al. (1988).

partly due to increased adrenocortical sensitivity to ACTH. However, the finding that plasma cortisol levels fail to suppress into the subnormal range on the morning after the administration of dexamethasone (1 mg, 2300 hours) implies a coexistent central dysregulation of the hypothalamic-pituitary-adrenal axis. When compared with depressed “cortisol suppressor” patients and control subjects, depressed ‘cortisol nonsuppressor” patients also have increased CSF levels of the NE metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and an increased urinary excretion of NE and normetanephrine (Roy et al. 1988). These patients also show an increased rate of entry of NE into plasma 276

(“increased NE spillover rate”), but do not have symptoms and signs of increased sympathetic nervous system activity. These findings, together with the recent demonstration of unidirectional spillover of NE from the brain to the systemic circulation, suggest that the apparent increase in NE spillover in endogenous depression may be due to enhanced central noradrenergic activity rather than to an increased release of NE from sympathetic nerve endings (Esler et al. 1990). In the context of the findings in conscious sheep, we suggest that central noradrenergic activation may be an early event in depressed “cortisol nonsuppressor” patients, contributing to hypothalamic-pituitary-adrenal dysreg01994,

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TIME

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ulation by causing hypersecretion CRH and AW.

of

Anorexia Nervosa

The finding that NPY also resets the hypothalamic-pituitary-adrenal axis may be of clinical relevance in anorexia nervosa. This condition is characterized by hypercortisolemia and increased CSF levels of NPY, and both of these variables decline to normal with the resumption of a normal body weight (Kaye et al. 1990). NPY is one of the most potent appetite stimulants in the brain, because an i.c.v. or paraventricular injection of NPY markedly stimulates feeding and overrides satiety and body weight control (Stanley and Leibowitz 1984). Moreover, shortterm starvation in the rodent increases endogenous NPY secretion into the PVH that is reversed by refeeding, suggesting that food deprivation may selectively activate the ARC-PVH NPY system (Kalra et al. 199 1). Although it is surprising that NPY levels are also increased in the CSF TEM Vol. 5, No. 7, 1994

of underweight patients with anorexia nervosa, this paradox might be partly reconciled by the observation that these patients are hungry, but they experience a dysphoria during food ingestion that overrides their hunger and results in reduced food intake. Given the effect of i.c.v. NPY on the ovine hypothalamicpituitary-adrenal axis, ARC-PVH NPY activity may be increased in anorexia nervosa and partly account for the elevated CSF NPY levels and HPA dysregulation that characterizes this disorder. Critical Illness The i.c.v. NE injections mimicked even more closely the pituitary-adrenal secretory pattern that occurs in a variety of critical illnesses. Critically ill patients display chronic elevations of plasma cortisol levels that are positively correlated with the severity of the illness and are associated with elevated, or normal, levels of ACTH. The resetting of the hypothalamic-pituitary-adrenal axis in these patients may also be due partly to an attenuation of the normal glucocorticoid feedback, because morning plasma ACTH and cortisol concentrations are only reduced minimally by dexamethasone (3 mg, 2300 hours). Although the pituitary-adrenal response to dexamethasone during critical illness is similar to that observed in patients with endogenous depression, the maximum ACTH response to CRH in the two clinical states differs, because the response is blunted in depression and augmented in critical illness (Reincke et al. 1993).

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Evidence for Hypothalamic Inhibition of ACTH Release and Biosynthesis

Effect of Hypothalamopituitary Disconnection Studies from this laboratory have provided novel and compelling evidence that necessitates a revision of the current concept of ACTH regulation by the hypothalamus. The results were obtained from studies in sheep subjected to surgical hypothalamopituitary disconnection (HPD). This procedure essentially removes the hypothalamic-releasing and release-inhibiting factors from the hypophysial-portal circulation and severs the innervation to the intermediate and pos-

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Figure 5. The effect of HPD and dexamethasone on sheep anterior pituitary POMC mRNA levels. Hybridization of 3*P-labeled human POMC DNA to a Northern blot of 25 pg anterior pituitary total RNA from control (lanes l-3), dexamethasone-treated (lanes 46), OVX-HPD (lanes 7-9), and OVX-HPD dexamethasone-treated (lanes 10-12) sheep. Reproduced with permission from Mercer et al. (1989). terior pituitary lobes (Clarke et al. 1983). However, in contrast to pituitary stalk section, which commonly compromises the blood supply to the AP and thus causes infarction of the gland, HPD preserves the blood supply to the adenohypophysis. HPD causes no obvious histologic abnormality of the anterior lobe, but results in marked hypertrophy of the intermediate lobe and atrophy of the posterior pituitary. This procedure has now been performed in both adult and fetal sheep, with essentially identical histologic findings. As expected, the removal of GnRH horn portal plasma by HPD causes plasma LH and FSH concentrations to become undetectable after 1 week (Clarke et al. 1983). By analogy, if the hypothalamus simply stimulated ACTH release, the removal of CRH and AVP from the hypophysial-portal circulation by the HPD would also be expected to cause a decline in plasma ACTH and cortisol concentrations to subnormal, or undetectable, levels and to abolish their response to stress. In accordance with this prediction, HPD virtually abolishes the rise in ACTH, l3-EP, and a-MSH in response to an audiovisual stimulus and insulin-induced hypoglycemia, suggesting that CRH and AW are essential to mount an adequate pituitary-adrenal response to stress (Figure 4). However, HPD actually increases the basal plasma concentrations of ACTH, fi-EP, a-MSH, and cortisol, and also increases POMC mRNA levels in the AP (Figure 5). Although the increased plasma f!-EP and a-MSH levels may be partly ascribed to their hypersecretion from an intermedi-

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ate lobe that has been deprived of its inhibitory innervation, the rise in plasma ACTH and cortisol suggests that HPD also removes a hypothalamic inhibitory influence over ACTH secretion and biosynthesis (Clarke et al. 1986, Engler et al. 1988 and 1990, Mercer et al. 1989). Historic Studies The demonstration of ACTH hypersecretion by the surgically isolated ovine AP is consistent with the early in vivo studies performed in the dog, rat, and monkey (Egdahl 1960, Halasz and Pupp 1965, Halkz et al. 1967, Kendall and Roth 1969). In 1960, Egdahl first reported that surgical isolation of the canine pituitary increased adrenal venous 17-hydroxysteroid secretion and that additional trauma (burning the hind leg or laparotomy) further increased this secretion (Figure 6). Subsequently, Hal&sz et al. documented that total hypothalamic deafferentation in the rat increased morning plasma corticosterone levels to those seen in the afternoon, thus abolishing the normal diurnal corticosterone rhythm. In addition, the anterior pituitary content of ACTH and adrenal gland weight increased. Kendall and Roth also noted that the adrenal venous secretion of 11 -hydroxycorticosteroids was acutely increased after forebrain removal or pituitary stalk section in the monkey. Therefore, pituitary isolation causes similar effects on the pituitary-adrenal axis of the dog, rat, monkey, and sheep, strongly suggesting that the observations made in the sheep are not unique to this species. Analysis of even earlier studies of pituitary stalk section also supports the sug-

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ACTH concentrations, and the ACTH response to an audiovisual stimulus, serotonin, and insulin-induced hypoglycemia are unaffected by this procedure. These findings indicate that the posterior pituitary regulates PRL secretion in sheep, but does not regulate ACTH release in this species. These findings provide further support for the suggestion that any putative hypothalamic ACTH release-inhibitory factor must be secreted into the long portal vessels by median eminence nerve terminals to regulate ovine corticotropic function.

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Hypothalamic Regulation of the Other Anterior Pituitary Hormones

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It is theoretically possible that the AP could be regulated both by factors secreted from median eminence nerve terminals and the posterior pituitary, because its blood supply 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 (Porter et al. 1973). Indeed, studies in the rat indicate that posterior lobectomy increases plasma LH and PRL concentrations, and abolishes the PRL response to 5-hydroxytryptophan and suckling (Froehlich et al. 1984, Murai and Ben-Jonathan 1984). Posterior lobectomy in the sheep also causes a transient rise in plasma PRL, abolishes its response to hypoglycemia, and attenuates its rise in response to chlorpromazine (Thomas et al. 1989). However, basal LH, FSH, and

The suggestion that the hypothalamus might both stimulate and inhibit ACTH secretion and synthesis implies that the regulation of ACTH may be analogous to that of GH, TSH, and PRL, each of which is regulated by hypothalamic-releasing and release-inhibiting factors. For example, GH secretion and synthesis are stimulated by GHRH, whereas somatostatin (SST) inhibits both the basal and GHRHstimulated increase in GH release (Barinaga et al. 1985). However, SST exerts little, if any, effect on GH gene expression, the dominant inhibitory influence on GH mRNA levels being exerted by IGF-I (Namba et al. 1989). Plasma GH and GH mRNA levels also decline after HPD, providing in vivo evidence that the hypothalamus mainly stimulates GH secretion and synthesis (Fletcher et al. 1994). TSH release and biosynthesis are stimulated by TRH and both dopamine (DA) and SST attenuate TRH-induced TSH secretion (Morley 1981). In addition, DA interacts with TRH to decrease the transcription of both the a and B subunits of TSH (Shupnik et al. 1986). PRL release and gene expression are stimulated by TRH and vasoactive intestinal peptide (VIP) whereas DA inhibits PRL secretion and gene transcription (Abe et al. 1985, Lamberts and Macleod 1990, Maurer 1990). Moreover, plasma PRL levels rise after pituitary isolation, indicating that the hypothalamus dominantly inhibits PRL secretion and synthesis (Thomas et al. 1986). Because pituitary isolation also increases plasma ACTH and POMC mRNA, it is suggested that tonic inhibition is also the major hypothalamic influence over ACTH secretion and synthesis. This interpretation is in complete contrast with the prevailing concept which proposes that

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Figure 6. The effect of brain removal on adrenal venous corticosteroid outptit in the dog. Resting level of corticosteroid output in this animal ranged from 2.2 to 5 g/min. The increase in output was comparable to that obtained following exogenous ACTH. Reproduced with permission from Egdahl(l960). 0 The Endocrine Society. gestion that hypothalamic stimulation of ACTH secretion may not entirely explain

all of the experimental evidence. Most of these studies were performed between 1940 and 1960 and thus antedate Egdahl’s observations. Two outstanding studies of this em are those of Keller et al. (1954) and Fortier et al. (1957), who performed experiments in the dog and rabbit, respectively. For-tier et al. demonstrated that permanent interruption of the hypophysialportal vessels reduced, or abolished, the lymphopenic response to restraint and cold exposure, but exerted little effect on the response to subcutaneous epinephrine or laparotomy. Keller et al. demonstrated that stalk section and destruction of the ventral half of the hypothalamus increased adrenal gland weight (when expressed as mg/kg body weight) and adrenal cholesterol content (when expressed as mgikg body weight), and did not affect the animal’s ability to withstand further surgery (unilateral sympathectomy, pancreatectomy). The authors concluded that “excitation of the adenohypophysis is not dependent upon direct hypothalamic humoral or neurogenic influence,” but the 278

findings could be also interpreted as providing support for the idea that pituitary stalk section removes a dominant inhibitory influence over ACTH release. Role of the Posterior Pituitary in the Regulation of Anterior Pituitary Function

AVP

(ANP), SST,

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Figure 7. A schematic representation of hypothalamic regulation of ACTH secretion based on studies outlined in this review (CRF = CRH). This is a dual model that includes both hypothalamic stimulatory and inhibitory influences. It is suggested that hypothalamic inhibition of ACTH secretion is mediated by secretion of a specific corticotropinrelease inhibitory factor (CRIF). Alternatively, it is possible that a number of substances could be involved in this process. stimu-

Definition of Corticotropin-Release Inhibitory Factor As judged by the in vivo effects of pituitary isolation on the pituitary-adrenal axis, the most important hypothalamic ACTH release inhibitory factor should act on normal corticotropic cells in vivo and in vitro primarily to decrease POMC gene expression and ACTH secretion. Although it is possible that this substance might also attenuate CRH- and/or AVP-induced increases in ACTH release and the CRHinduced increase in POMC gene expression, these activities are probably of subsidiary importance. The main hypothalamic substances that are known to inhibit ACTH release and/or POMC gene expression are atria1 natriuretic peptide

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the inability

of ANP to decrease

basal

ACTH release in normal anterior pituitary cells and its inability to affect both basal and CRF-induced ACTH and cortisol re-

with normal corticotropic

lease in humans

cells. Engler et

Atrial Natriuretic Peptide

-

the hypothalamus predominantly lates corticotrope function.

as dis-

al. (1988) therefore suggested that the effect of pituitary isolation on the pituitaryadrenal axis might be due to removal of the corticotrope from the tonic inhibitory influence of an as yet unidentified hypothalamic substance that is presumably a neuropeptide and was termed corticotropin-release inhibitory factor (CRIF). While the CRIF hypothesis was based on an analysis of the effects of HPD on the HPA axis, Redei and Evans (1989) drew an analogy with the hypothalamic regulation of PRL and GH secretion and independently postulated the a priori existence of a corticotropin-inhibiting factor (CIF). They described the partial purification of a bovine hypothalamic factor which inhibited the in vitro and in vivo release of ACTH in the rat, but the nature of this substance has yet to be determined.

ACTH

CORTISOL

and DA. However,

cussed later, none of these factors entirely satisfies these primary and secondary criteria when experiments are performed

Although ANP is synthesized in the heart and released into the systemic circulation as a 28residue peptide ([ANP( l-28)]), the hypothalamus contains two N-terminally shortened forms of the peptide [ANP(428) and ANP(S-28)]. A number of studies have proposed that hypothalamic ANP is a, or the, CRIF, based on the following evidence (Antoni 1993). First, ir-ANP is present in rat hypophysial-portal plasma in concentrations that are greater than those found in the systemic circulation. Although the precise molecular species remains to be determined, the finding that hypothalamic neurons contain ANP(428) but secrete ANP(S-28) suggests that the ir-ANP in portal plasma might be ANP(5-28). Second, immunoneutralization of endogenous ANP with an ANP antiserum augments the stress-induced ACTH and corticosterone levels in the Wistar and Brattleboro rats, but has little effect on basal ACTH and corticosterone levels. Third, when infused in PVH-lesioned rats, ANP attenuates the ACTH response to CRH and AVP, but has no effect on basal ACTH release. Fourth, ANP may exert modest effects on CRH- and AVPstimulated ACTH release from rat and ovine anterior pituitary cells. Taken together, these data provide the most compelling evidence to date that a neuropep tide may inhibit ACTH release. However,

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(Ur et al. 1991) suggest

that ANP may not be the CRIF. However, it may be an additional inhibitory modulator of the HPA axis.

Somatostatin Several lines of evidence indicate that SST may also exert an inhibitory effect on ACTH secretion at the anterior pituitary level, but the effect is only apparent under nonphysiologic conditions. For example, SST decreases the elevated plasma ACTH levels in patients with autoimmune adrenocortical failure (Addison’s disease) and in Nelson’s syndrome (Fehm et al. 1976). This latter disorder is characterized by a pituitary ACTH-secreting microadenoma or macroadenoma after bilateral adrenalectomy for Cushing’s disease. Moreover, these in vivo effects of SST on ACTH secretion are paralleled by similar effects in vitro, because SST also inhibits ACTH release from normal AP cells when glucocorticoids are removed from the culture medium, and from the mouse AtT-20 pituitary tumor cell line (Lamberts et al. 1989, Reisine 1985). However, in contrast, SST has no effect on the rise in plasma ACTH induced by insulin-induced hypoglycemia in normal humans and has no effect on ACTH release from normal AP cells when glucocorticoids are included in the culture medium. Therefore, the available evidence suggests that SST does not inhibit ACTH release under physiologic conditions and therefore cannot be considered to be a CRIF.

Other Substances The catecholamine DA is secreted into the hypophysial-portal circulation and causes a physiologic inhibition of PRL release and gene transcription. Although DA also decreases basal ACTH release from human corticotropic tumor cells (Ishibashi and Yamaji 1981), it has no significant effect on ACTH release when normal corticotrope cells are used and therefore does not appear to be a CRIF. The inhibins and activins are dimeric peptides that were isolated from ovarian follicular fluid on the basis of their ability, respectively, to inhibit or stimulate FSH secretion (Ying 1988). However, inhibin and activin subunits and their mRNAs have been detected in extragonadal tis-

279

sues, including the pituitary and brain (Meunier et al. 1988). Inhibin B-stained cells are found in the NTS and send ascending projections to the oxytocinergic cells in the magnocellular division of the paraventricular hypothalamus (Sawchenko et al. 1988). Activin mRNA has been detected in the pituitary, raising the possibility that the peptide might also exert an autocrine or paracrine effect on FSH secretion. In addition, activin inhibits POMC mRNA production in mouse AtT-20 corticotropic tumor cells, providing yet another example that the POMC gene may be negatively regulated by a peptide (Bilezikjian et al. 1991). However, ir-activin has not been detected in the hypophysial-portal circulation in concentrations greater than those in the systemic circulation, suggesting that it is not secreted by the hypothalamus and is unlikely to be a candidate CRIF. Finally, it should be noted that neuropeptides in the external zone of the median eminence may not be secreted into the hypophysial-portal circulation in all species. For example, NPY, substance P, and galanin are found in the ovine median eminence, but their concentrations in portal plasma are not consistently greater than those in systemic plasma. Moreover, plasma concentrations of neurokinin A, peptide histidine isoleucine, neurotensin, and cholecystokinin were either undetectable or not greater than those in jugular plasma, thus excluding these known neuropeptides as candidate releasing or release-inhibiting factors in the ovine species (Clarke et al. 1993).

??

Future Directions

Analogues of the two best characterized inhibitory substances in the hypophysialportal circulation (SST and DA) are finding increasing application in clinical medicine. For example, the SST analogue octreotide is used in the management of gastrointestinal tumors that produce watery diarrhea, and in patients with GH (acromegaly) and TSH-secreting pituitary tumors as an alternative, or adjunct, to surgery (Grosman and Simon 1990, Vance and Harris 1991, Chanson et al. 1993). The dopaminergic agonist bromocriptine is the treatment of choice in many patients with PRL microadenomas and macroadenomas and is also used in Parkinson’s disease (Molitch et al. 1985, 280

Calne 1993). By analogy, we suggest that a CRIF agonist might also be a useful medical therapy in patients with Cushing’s disease and Nelson’s syndrome. In addition to the AP as the most obvious direct site of action of a CRIF agonist, a CRIF antagonist might possess a variety of unsuspected applications by virtue of its ultimate effect on plasma cortisol concentrations. In this regard, we speculate that subjects who are predisposed toward the development of autoimmune disease may derive benefit from therapeutic intervention with a CRIF antagonist. This statement is based on studies in animals and humans that indicate that a hyporesponsive hypothalamic-pituitary-adrenal axis may be of central importance in determining an individual’s susceptibility to diseases such as experimental allergic encephalomyelitis (EAE), autoimmune thyroiditis, and rheumatoid arthritis (Chrousos and Gold 1992). For example, EAE causes a reversible hind-leg paralysis in the rat, although susceptibility to this disorder is strain dependent (Mason 1991). In this regard, the Lewis rat is the most susceptible to its development, whereas the PVG strain is resistant. Moreover, when the large increase in plasma corticosterone that occurs at the onset of the disease is prevented by adrenalectomy, spontaneous recovery is prevented, and fatal paralysis ensues. In addition, when the PVG rat is adrenalectomized and plasma corticosterone levels maintained merely at baseline levels, this strain is also rendered susceptible to EAE and develops fatal paralysis. These results lead to the conclusion that spontaneous recovery of the Lewis rat from EAE and resistance to this disease in the PVG strain is critically dependent upon corticosterone secretion. The obese strain (OS) chicken provides a second example of the role of the hypothalamic-pituitary-adrenal axis in the development of autoimmune thyroid disease (Wick et al. 1992). This strain is susceptible to the development of an autoimmune thyroiditis that bears some resemblance to human Hashimoto’s thyroiditis. Compared with normal white leghorn (NWL) chickens that do not develop the disease, the OS strain shows a markedly reduced, or absent, corticosterone response to immunization and to the injection of lymphocyte-conditioned 01994,

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media. The site of this immune-endocrine disturbance appears to reside at the hypothalamic-pituitary level, as OS and NWL lymphocyte-conditioned media increase corticosterone secretion equally in the NWL strain. Finally, when freshly hatched OS chickens are treated with cortisol, a dose-dependent prevention of the disease is observed. Recent studies in the rat also point toward a role for the hypothalamicpituitary-adrenal axis in the development of arthritis (Sternberg et al. 1989a and b). The injection of group A streptococcal cell wall peptidoglycan polysaccharide (SCW) in the rat causes an arthritis that resembles human rheumatoid joint disease. However, the development of this disease is also strain dependent, because the female Lewis rat is susceptible to its development, whereas the Fischer strain is resistant. When one compares the hypothalamic-pituitary-adrenal axis of these two strains, the Lewis rat shows markedly impaired plasma ACTH and corticosterone responses to SCW, human IL-IB, the serotonin agonist quipazine, and rat CRH. Because SCW increases PVH CRH gene expression in the Fischer rat but fails to do so in the Lewis strain, the hypothalamus is clearly the locus of the defect in the Lewis animal. These studies in the rat are paralleled by the recent observations of Chicanza et al. (1992) which have shown that patients with active rheumatoid arthritis undergoing joint surgery manifest a defective postoperative rise in plasma cortisol when compared with patients with chronic osteomyelitis or control subjects. Moreover, the site of the defect again appears to reside at the hypothalamic and/or pituitary level of the hypothalamicpituitary-adrenal axis. These three examples illustrate the potential utility of a CRIF antagonist in attenuating a presumably genetic, asymptomatic, hypothalamic-pituitary-adrenal hyporesponsiveness that may predispose one to autoimmune disease. However, such an analogue might also be of use in those disorders in which impaired hypothalamic-pituitary-adrenal activation occurs as the consequence of an acute environmental insult. The chronic fatigue syndrome may be an example of this latter type of disorder and has been defined as a chronic, or relapsing, fatigue of at least six months’ duration occurring in the absence of any definable diagnosis. When

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compared with normal subjects, these patients manifest a reduced 24-h urinary free cortisol excretion, an attenuated net integrated ACTH response to ovine CRH, and reduced CSF levels of the NE metabolite MHFG (Demitrack et al. 1991 and 1992). Although not all aspects of the hypothalamic-pituitary-adrenal dysfunction are easily explained, the findings are consistent with the suggestion that CRH secretion is reduced in this disorder, and that this may be a secondary consequence of impaired central noradrenergic activity. Overall, these examples suggest the possibility that the natural history of these disorders might be favorably altered by augmenting hypothalamic-pituitaryadrenal activity with a CRIF antagonist. However, such hypotheses can only be confirmed or refuted if a substance is isolated that fulfills the aforementioned criteria of a CRIF, and this remains an exciting task for future investigation.

??

Acknowledgments

We are grateful to Dr. Seymour Reichlin for critical reading of the manuscript. In the interest of space, we have cited many review articles and apologize to numerous authors for not having quoted their original work. We thank Mrs. Glenda Hartley and Mrs. Claudette Thiedeman for expert secretarial assistance. The studies were supported by the National Health and Medical Research Council of Australia.

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Autoregulation and Crossregulation of Nuclear Receptor Genes Jamshed R. Tata

Whereas crossregulation of nuclear receptors has been known for some time, recently several examples of autoregulation have been described, especially during development and specific gene expression. In this review, I discuss both these phenomena, based on some studies from our laboratory on amphibian metamorphosis and egg protein gene expression. These include autoinduction of estrogen receptor (ER) accompanying egg protein gene expression in adult and larval Xenopus; autoinduction of thyroid hormone receptor (TR) during metamorphosis and in adult Xenopus; crossregulation by triiodothyronine (T3) and dexamethasone of autoinduction of ER; and inhibition by PRL of autoinduction and crossinduction of TR and ER genes. A dual receptor threshold model to explain the interplay between T3, estrogen and PRL is presented and its significance to the general question of nuclear receptor autoregulation and crossregulation during development is also discussed. (Trends Endocrinol Metab 1994;5;283-290)

Several investigators

studying nuclear re-

ceptors in response to hormones oping

tissues

or during

in devel-

regulation

of

specific hormonal target gene expression have observed the phenomenon of upregulation

of receptor

number.

The

first

Vance ML, Harris AG: 1991. Long-term treatment of 189 acromegalic patients with the somatostatin analog octreotide: results of the International Multicenter Study Group. Arch Intern Med 151:1573-1578.

in multihormonal systems, whereby one hormone would induce or activate the

Weiner RI, Ganong WF: 1978. Role of brain monoamines and histamine in regulation of anterior pituitary secretion. Physiol Rev 58:905-976.

Jamshed R. Tata is at the Laboratory of Developmental Biochemistry, National Institute for Medical Research, The Ridgeway, London NW7 1AA, England.

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observations

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concerned

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receptor for another, or glucocorticoids such as the upregulation by progesterone of estrogen receptor (ER) or in breast cancer cells, during uterine growth, upon egg protein gene activation in the oviduct or during mammary gland development (Baulieu

and Kelly

1990,

Parker

1991,

Tata 1984, Eriksson and Gustafsson 1983). More recently, the phenomenon of upregulation of members of the nuclear steroid/ thyroid hormone receptor gene family by their own ligands has been described in many growth and developmental systems. Here, I shall consider the phenomenon of

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