Differential expression of a cutaneous corticotropin-releasing hormone system

We completed the mapping of a cutaneous CRH signaling system in two species with widely different determinants of skin functions, humans and mice. In human skin, the CRH receptor (CRH-R) 1 was expressed in all major cellular populations of epidermis, dermis, and subcutis with CRH-R1alpha being the most prevalent isoform. The CRH-R2 gene was expressed solely in hair follicle keratinocytes and papilla fibroblasts, whereas CRH-R2 antigen was localized predominantly in hair follicles, sebaceous and eccrine glands, muscle and blood vessels. In mouse skin, the CRH-R2 gene and protein were widely expressed in all cutaneous compartments and in cultured normal and malignant melanocytes. CRH-binding protein mRNA was present in dermal fibroblasts, melanoma cells, and sc fat of human skin and undetectable in mouse skin. The urocortin II gene was expressed equally in mouse and human skin. Taken together with our previous investigations, the present studies document the preferential expression of CRH-R1 in human skin, which mirrors CRH-R2 expression patterns in human and mouse skin. They are likely reflecting different functional activities of human and mouse skin. The adnexal location of CRH-R2 suggests a role for the receptor in hair growth. The differential interspecies CRH signaling expression pattern probably reflects adaptation to species-specific skin function determinants.     

Aging-related changes in release of growth hormone and luteinizing hormone in female rhesus monkeys

A decline in somatic function with aging in women is associated with a decrease in GH release and a loss of estrogen after menopause. As an initial step to establish a monkey model for the neuroendocrine mechanisms underlying somatopause and menopause, we have conducted three experiments in unrestrained aged (approximately 25.7-yr-old) and young (approximately 5.4-yr-old) female rhesus monkeys. GH release was pulsatile, and mean GH release and pulse amplitude were significantly lower in aged monkeys than in young monkeys. Injection of GHRH alone, GH-releasing peptide-2 alone, or the combination of both induced an increase in GH release in both age groups. The mean LH level, pulse amplitude, and baseline LH levels were significantly higher in aged animals than in young animals. Both estrogen and IGF-I levels were lower in aged than young monkeys. These results suggest that in female rhesus monkeys 1) there is a clear decline in circulating GH and IGF-I levels with aging; 2) GHRH and GH-releasing peptide-2 stimulate GH release synergistically; and 3) circulating LH levels increase as estrogen decreases with aging. These results indicate that the rhesus monkey is an excellent model for studies of the neuroendocrine mechanisms of aging.     

Impaired beta-endorphin response to human corticotropin-releasing hormone in obese children

In order to evaluate the secretion of beta-endorphin in obese children and adolescents, we measured plasma beta-endorphin, ACTH and cortisol levels before and following administration of CRH (1 microgram/kg). Fourteen normal weight and 22 obese subjects (weight excess ranging from 30 to 98%) were studied. Plasma hormone levels were measured by radioimmunoassay directly in plasma (cortisol, ACTH) and after silicic acid extraction and Sephadex G-75 column chromatography (beta-endorphin). Basal beta-endorphin levels in obese children were significantly higher than in controls (14.7 +/- 1.8 vs 6.0 +/- 0.6 pmol/l; mean +/- SEM). No differences were found in basal ACTH and cortisol levels. CRH administration significantly increased beta-endorphin, ACTH and cortisol levels in normal subjects and ACTH and cortisol levels in obese subjects. Plasma beta-endorphin levels in obese children and adolescents did not show any significant increment. These data confirm the higher than normal beta-endorphin plasma levels in obese subjects in childhood and demonstrate that CRH is unable to increase beta-endorphin levels, suggesting an impairment of the hypothalamo-pituitary control mechanisms or an extra-anterior pituitary source.     

Increased response of plasma allopregnanolone to corticotropin-releasing hormone in obese patients

Allopregnanolone is a neuroactive steroid present in the brain, but also measurable in systemic circulation. It exhibits anxiolytic and anticonvulsant effects and is able to produce hyperphagia. Since eating behavior disturbances and increased peripheral basal sympathetic activity have been reported in obese subjects, the present study investigated allopregnanolone and catecholamine (epinephrine and norepinephrine) responses to corticotropin-releasing hormone (CRH) in obese subjects. Blood was sampled from 39 obese (14 men and 25 women) and 57 normal-weight subjects (20 men and 37 women) and assayed for cortisol, allopregnanolone and catecholamines concentrations. In addition, 13 obese patients (5 men and 8 women) and 18 control subjects (9 men and 9 women) were submitted to a CRH test. Plasma allopregnanolone and norepinephrine levels were significantly higher in obese than in control subjects (p < 0.01), but plasma cortisol and epinephrine concentrations were comparable in both groups. No correlation was found in any group between plasma allopregnanolone and norepinephrine or epinephrine levels. Acute CRH administration significantly stimulated allopregnanolone secretion, with peak levels at 15 min in obese subjects, whereas maximal concentrations were reached after 60 min only in controls. In obese patients the allopregnanolone secretory incremental area was significantly higher than in controls (p < 0.02). CRH injection increased cortisol levels to a comparable extent in both groups. Plasma norepinephrine or epinephrine levels did were not significantly affected by CRH test in either group. In conclusion, obese subjects present higher allopregnanolone levels and a greater response to CRH than normal subjects. Since allopregnanolone has hyperphagic effects in rats, hypersecretion of the hormone in obese patients may represent one of the mechanisms underlying obesity.     

Morphine inhibits the pituitary-adrenal response to ovine corticotropin-releasing hormone in normal subjects

To determine the locus of opiate modulation of ACTH secretion, 11 normal subjects were given ovine corticotropin-releasing hormone (CRH) 30 min after receiving either placebo or morphine sulfate. Plasma ACTH, cortisol, arginine vasopressin (AVP), epinephrine, norepinephrine, and CRH were measured 30 min before and up to 150 min after CRH administration. Morphine blunted the ACTH response for the first 60 min and cortisol response for the first 90 min after CRH administration. Morphine did not lower arginine vasopressin or catecholamine levels. To determine whether morphine's effect on ACTH and cortisol was due to a direct action on the corticotroph cell, dispersed rat pituitary cells were perifused with medium containing 1 microgram/ml morphine sulfate or medium alone. Morphine had no effect on the ACTH response of these cells to 10 nM CRH pulses. Similarly, morphine had no effect on ACTH production by dispersed rat pituitary cells in monolayer culture in response to 90- and 180-min incubations with 5 nM CRH. We conclude that morphine blunts the early response of the pituitary gland to CRH in vivo. Based on the lack of a direct effect of morphine on rat pituitary cells in vitro, we postulate that morphine given in vivo may modulate the pituitary ACTH response to CRH through other suprapituitary factors.     

The corticotropin-releasing hormone system in the regulation of energy balance in obesity

The view that energy balance is regulated has gained acceptance in recent years. An important role in this regulation is played by brain circuitries involved in the control of energy intake (food intake) and energy expenditure (thermogenesis) that are capable of integrating peripheral signals, produced by perturbations of adipose tissue mass, into messages to effectors of food intake and energy expenditure, so as to prevent substantial variations in the level of energy reserves. More than one neurosystem has been reported to genuinely participate in the regulation of energy balance. Among them is the corticotropin-releasing hormone (CRH) system. This system, with its numerous clusters of brain neurons, its closely related peptide urocortin, its two receptor types and its binding protein, all generally widely distributed throughout the brain, forms a network of neuronal pathways capable of interacting with the circuitries controlling food intake and energy expenditure. In addition, CRH and urocortin's anorectic and thermogenic actions appear to be coordinated to optimize energy losses. Finally, the CRH system seems to demonstrate a certain degree of plasticity in obesity and in response to food deprivation that is consistent with its action on food intake and thermogenesis. The observations have been made that food deprivation and obesity can blunt the expression of the CRH type 2alpha receptor in the ventromedial hypothalamic nucleus and can induce the expression of the CRH-binding protein (a CRH-inactivating protein) in brain areas involved in the anorectic and thermogenic actions of CRH.     

Aging-related changes in myocardial purine metabolism and ischemic tolerance

Impaired tolerance to ischemia-reperfusion in older hearts may stem in part from alterations in purine catabolism, impacting on maintenance of energy state and protective signaling via extracellular adenosine. We characterized effects of aging on normoxic and post-ischemic purine metabolism in hearts from young (2-4 month), middle-aged (12 month), old (18 month), and senescent (24-28 month) C57/Bl6 mice.Normoxic function was similar in all age groups while normoxic purine efflux increased gradually with age. This was the result of enhanced efflux of hypoxanthine, xanthine and uric acid, with extracellular accumulation of adenosine and inosine remaining unchanged. While total purine washout during 60 min reperfusion following 20 min global ischemia was unaltered by aging (1057+/-109 nmoles/g in young vs. 1221+/-127 nmoles/g in senescent hearts), selective changes in purine catabolism were evident. Accumulation of adenosine and inosine were reduced by 50 and 80%, respectively, matched by 400 and 300% elevations in hypoxanthine and xanthine accumulation, respectively. Uric acid remained unchanged. Thus, while adenosine and inosine represented 15+/-2 and 47+/-3% of total purine efflux in young hearts, these values decreased to only 6+/-1 and 9+/-2% in senescent hearts. Efflux of IMP also increased 500% with aging whereas 5'-AMP was unaltered. These changes were associated with a substantial fall in ischemic tolerance, with left ventricular developed pressure recovering to 46+/-3% in young hearts vs. only 24+/-6, 16+/-4, and 19+/-4% in middle-age, old and senescent hearts, respectively.Our data collectively support a pronounced shift in purine catabolism, with reduced accumulation of salvageable and cardioprotective adenosine, and enhanced accumulation of poorly salvaged (and potentially injurious) hypoxanthine and xanthine. Mechanisms underlying this shift have yet to be determined. However, this may play a role in the marked decline in myocardial tolerance to ischemia with aging and senescence.     

犬肺静脉肌袖电生理随龄性改变

目的对比研究老龄和成年犬肺静脉肌袖电生理特性.方法采用经导管房间隔穿刺技术,应用程序刺激和短阵快速起搏分别对正常自然老龄和成年实验犬肺静脉、上腔静脉、左房、右房、以及冠状静脉窦的有效不应期、激动传导及心房颤动诱发阈值进行标测.结果老龄犬的左、右心房,上腔静脉,冠状静脉窦和肺静脉的有效不应期较成年犬均有不同程度的缩短,其中左心房,上腔静脉和肺静脉有效不应期的随龄性变化有统计学差异(P＜0.01).老龄犬的肺静脉不应期较其左房的不应期明显缩短,而成年犬肺静脉与左房的不应期则无显著性差异.老龄犬的肺静脉和上腔静脉内激动传导呈显著递减性传导.在多数老龄犬的肺静脉、左心房和上腔静脉,快速短阵起搏及程序刺激能诱发持续时间＞30s的房颤.结论老龄犬肺静脉肌袖有易于房颤发生的电生理变化,提示心脏老龄化可能是房颤发生的潜在基质.     

Aging-related changes in the iron status of skeletal muscle

The rise in non-heme iron (NHI) concentration observed in skeletal muscle of aging rodents is thought to contribute to the development of sarcopenia. The source of the NHI has not been identified, nor have the physiological ramifications of elevated iron status in aged muscle been directly examined. Therefore, we assessed plantaris NHI and heme iron (HI) levels in addition to expression of proteins involved in iron uptake (transferrin receptor-1; TfR1), storage (ferritin), export (ferroportin; FPN), and regulation (iron regulatory protein-1 (IRP1) and -2 (IRP2)) of male F344xBN F1 rats (n = 10/group) of various ages (8, 18, 28, 32, and 36 months) to further understand iron regulation in aging muscle. In a separate experiment, iron chelator (pyridoxal isonicotinoyl hydrazone; PIH) or vehicle was administered to male F344xBN F1 rats (n = 8/group) beginning at 30 months of age to assess the impact on plantaris muscle mass and function at ~ 36 months of age. Principle findings revealed the increased NHI concentration in old age was consistent with concentrating effects of muscle atrophy and reduction in HI levels, with no change in the total iron content of the muscle. The greatest increase in muscle iron content occurred during the period of animal growth and was associated with downregulation of TfR1 and IRP2 expression. Ferritin upregulation did not occur until senescence and the protein remained undetectable during the period of muscle iron content elevation. Lastly, administration of PIH did not significantly (p > 0.05) impact NHI or measures of muscle atrophy or contractile function. In summary, this study confirms that the elevated NHI concentration in old age is largely due to the loss in muscle mass. The increased muscle iron content during aging does not appear to associate with cytosolic ferritin storage, but the functional consequences of elevated iron status in old age remains to be determined.     

Pituitary and adrenal response to ovine corticotropin-releasing hormone in women with polycystic ovarian syndrome

It has been hypothesized that there is an adrenal abnormality in the polycystic ovary syndrome (PCO). This study was undertaken to examine this hypothesis in a more physiological way, by enhancing the ACTH secretion in response to ovine corticotropin releasing hormone (oCRH) injection so that adrenal androgen and glucocorticoid responsiveness to endogenous stimulation could be examined. Plasma ACTH and the ACTH and cortisol (F) response to oCRH were normal. The plasma T and dehydroepiandrosterone (DHEA) responses were also normal. The androstenedione (A) response, however, was exaggerated. This study supports the hypothesis that the adrenal gland in patients with PCO produces increased amounts of androstenedione in response to ACTH stimulation.     

Aging-related changes of intracellular Ca2+ stores and contractile response of intestinal smooth muscle

In this study, we investigated the effect of aging on intracellular Ca2+ stores, as sarcoendoplasmic reticulum (SR) and mitochondria, and the influence of these compartments on contraction of rat colon smooth muscle [Bitar, K.N., 2003. Aging and neural control of the GI tract V. Aging and gastrointestinal smooth muscle: from signal transduction to contractile proteins. Am. J. Physiol. Gastrointest. Liver. Physiol. 284(1), G1-G7; Marijic, J., Li, Q.X., Song, M., Nishimaru, K., Stefani, E., Toro, L., 2001. Decreased expression of voltage-and Ca2+-activated K+ channels in coronary smooth muscle during aging. Circ. Res. 88, 210-234; Rubio, C., Moreno, A., Briones, A. Ivorra, M.D., D'Ocon, P., Vila, E., 2002. Alterations by age of calcium handling in rat resistance arteries. J. Cardiovasc. Pharmacol. 40(6), 832-840]. Calcium stores and contraction were evaluated by simultaneous measurements of fluorescence and tension in smooth muscle strips loaded with fura-2. Results showed that activation of muscarinic receptors by methylcholine (MCh, 10 microM), induced a greater contraction in aged rats than in adult animals. The inhibition of Ca2+ ATPase by thapsigargin (TG, 1 microM) did not prevent the refilling of SR either in adult or aged rats. MCh, in the presence of TG, induced an increase in transient fluorescence, indicating a release of Ca2+ from TG-insensitive compartment. The mitochondrial uncoupler, FCCP (5 microM), caused a greater increase in intracellular Ca2+ and tension in aged rats, indicating that mitochondria may accumulate more Ca2+ during aging. The present results show that changes in intracellular Ca2+ stores, such as mitochondria and SR, affect contraction and may cause dysfunctions during aging that could culminate in severe alterations of Ca2+ homeostasis and cell damage.     

Neurotransmitter-induced hypothalamic-pituitary-adrenal axis responsiveness is defective in inflammatory disease-susceptible Lewis rats: in vivo and in vitro studies suggesting globally defective hypothalamic secretion of corticotropin-releasing hormone.

The susceptibility of female Lewis (LEW/N) rats to the development of streptococcal cell wall (SCW)-induced arthritis and other autoimmune phenomena is associated with the inability of their hypothalamic-pituitary-adrenal (HPA) axis to adequately respond to inflammatory stimuli. In contrast, resistance to the development of SCW-induced arthritis and other inflammatory autoimmune manifestations in histocompatible female Fischer rats (F344/N) is related to their intact HPA axis response to inflammatory mediators. To evaluate the mechanism and the specificity of the HPA axis defect in LEW/N rats, we examined the ability of three major excitatory neurotransmitter systems to activate the HPA axis in both Lewis and Fisher rats. The responsiveness of plasma ACTH and corticosterone to the cholinergic muscarinic receptor agonist arecoline, the alpha 1-adrenergic receptor agonist methoxamine and the serotonin (5-HT) type 2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane were significantly blunted and/or abolished in LEW/N compared to F344/N rats. To localize the HPA axis defect to the hypothalamic CRH neuron, we evaluated the ability of explanted hypothalami from the two strains to secrete immunoreactive CRH in vitro, in response to acetylcholine (ACh), norepinephrine (NE), 5-HT and the 5-HT agonist quipazine. LEW/N hypothalami released less immunoreactive CRH (iCRH) in response to ACh, NE, 5-HT and quipazine than F344/N hypothalami. The dose-response curves of these compounds in the former were shifted to the right and/or abolished, suggesting decreased sensitivity of LEW/N hypothalami to these neurotransmitters.(ABSTRACT TRUNCATED AT 250 WORDS)     

Responses of plasma adrenocorticotropin, cortisol, and dehydroepiandrosterone to ovine corticotropin-releasing hormone in healthy aging men

To assess the effects of age on both the pituitary ACTH response to corticotropin-releasing hormone (CRH) and the secretory responses of cortisol (F) and dehydroepiandrosterone (DHEA) to endogenous rises in ACTH, we measured evening basal and ovine CRH (oCRH; 1 mu/kg)-stimulated plasma concentrations of ACTH,F, and DHEA in 49 healthy men, aged 21-86 yr. By analysis of variance, we found no change with age in either the basal concentration of ACTH or the magnitude of the peak ACTH response to oCRH. Older men had higher basal F levels (P less than 0.05), while basal plasma levels of CBG and ratios of F to CBG did not vary significantly with age (P greater than 0.1). We also found no significant increase with age in the magnitude of the peak F response to oCRH (P greater than 0.2), although peak F responses occurred significantly earlier (P less than 0.03) in the older men. Basal plasma levels of DHEA decreased significantly with age (P less than 0.001), as did the magnitude of peak DHEA responses to endogenous ACTH rises (P less than 0.01). There was no alteration in the timing of the peak DHEA response with age (P greater than 0.7). We conclude that while ACTH and F responses to evening injections of oCRH are well maintained in healthy aging men, that of DHEA is discordantly decreased. The present findings are compatible with the hypotheses that there is a diminished sensitivity of ACTH secretion to negative feedback regulation by glucocorticoids in older men, and there is an ACTH-independent age-related diminution in adrenal androgen secretion.     

Aging-related growth hormone (GH) decrease is a selective hypothalamic GH-releasing hormone pulse amplitude mediated phenomenon

BACKGROUND: Aging is accompanied by declining growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels. The neuroendocrine mechanisms of this decline have been studied previously, but the interpretation of the data was confounded by the imprecision in GH measurements and by the intervening variables of altered body composition and decreased gonadal steroid milieu in the elderly subjects of both sexes. METHODS: To study the contribution of aging per se, we evaluated discrete parameters of GH pulsatility in young (n = 8 women, n = 8 men) and elderly (n = 11 women, in 10 men) subjects closely matched for body mass index. Blood samples for GH were obtained every 10 minutes for 24 hours. Plasma GH was measured by a sensitive chemiluminescent assay. GH pulsatility was assessed using cluster analysis. RESULTS: The elderly subjects had plasma IGF-I levels and integrated GH concentrations that were 32% to -56% of their sex-matched younger counterparts. The age-associated attenuation in GH was due to a decrease in GH pulse amplitude, whereas pulse frequency and nadir levels were unchanged. The majority of the young subjects (81%) reached their peak GH during the "lights off" period, whereas the majority of the elderly subjects (62%) peaked during the "lights on" period (p = .01). CONCLUSIONS: We conclude that aging in both sexes is accompanied by profound decreases in GH output and in plasma IGF-I concentrations. This effect is separate from the alterations in body mass index that accompany the normal aging process. Attenuation of GH output associated with aging is related solely to the lower GH and, by inference, GH-releasing hormone (GHRH) pulse amplitude.     

Immunoreactive corticotropin-releasing hormone in the hypothalamoinfundibular tract

Ovine corticotropin-releasing hormone (CRF)-like immunoreactivity has been examined in the rat hypothalamus by light microscopy. Immunoreactivity was found in nerve fibers of the median eminence, mainly in the external zone around the portal vessels. In rats pretreated with colchicine or with hypothalamic knife cuts, small to moderate sized cells with two (bipolar) or rarely more (multipolar) dendrites, showing CRF-like immunoreactivity were present in the anterior and medial parvocellular subdivisions of the paraventricular nucleus. Scattered CRF-like immunopositive cells were found in the periventricular and medial preoptic nuclei. CRF-like immunoreactivity was clearly enhanced in the median eminence and paraventricular nucleus 8-10 days after bilateral adrenalectomy. A variety of hypothalamic transections had to be performed to determine reliably the topography of CRF-like nerve fibers projecting to the stalk-median eminence. Axons left the paraventricular nucleus in a lateral direction, turned ventrally in the lateral hypothalamus then medially as they approached the base of the hypothalamus above and behind the optic chiasm (lateral retrochiasmatic area). Fibers reached the median eminence by traveling caudally and medially from the rostral half of the lateral retrochiasmatic area. Scattered fibers were present in the retroinfundibular (posterior) portion of the median eminence. No immunoreactive fibers remained in the stalk-median eminence 1 or 4 weeks after transection of that loop-like pathway of CRF-containing fibers in the lateral retrochiasmatic area.     

Diurnal variation in the response of plasma adrenocorticotropin and cortisol to intravenous ovine corticotropin-releasing hormone

To determine whether the plasma immunoreactive ACTH (IR-ACTH) and IR-cortisol responses to ovine corticotropin-releasing hormone (oCRH) depend on the time of day, we administered 1 microgram/kg BW synthetic oCRH as an iv bolus dose to five normal men at their usual time of awakening between 0530-0740 h, at 1600 h, and at 2300 h. Mean basal plasma IR-ACTH and IR-cortisol levels were highest upon awakening, intermediate at 1600 h, and lowest at 2300 h, reflecting the diurnal rhythm of ACTH secretion. There was no significant difference in the plasma IR-ACTH response to oCRH at different times of the day. In contrast, the mean maximum plasma IR-cortisol increment and mean integrated response were 2- and 2.6-fold greater (P less than 0.05), respectively, at 2300 h than upon awakening. In another study, oCRH was given in the morning (0700-0900 h) to 22 normal men and in the late afternoon (1600-1800 h) to 24 normal men. Mean basal plasma IR-ACTH and IR-cortisol levels were significantly higher (P less than 0.001) in the morning [24 +/- 3 pg/ml (mean +/- SEM) and 10.6 +/- 0.8 micrograms/dl, respectively] than in the afternoon (13 +/- 2 pg/ml and 5.6 +/- 0.6 micrograms/dl, respectively). Mean peak plasma IR-ACTH was slightly greater in the morning (60 +/- 5.5 pg/ml) than in the afternoon (47 +/- 5.5 pg/ml), the mean maximum plasma IR-ACTH increments were the same (35 +/- 4 and 34 +/- 5 pg/ml, respectively), and the mean integrated IR-ACTH response was slightly less in the morning (2036 +/- 414 vs. 2365 +/- 358 pg . min/ml), but none of these differences was statistically significant. Mean peak plasma IR-cortisol concentrations in the morning and afternoon were similar (18.7 +/- 0.7 and 17.3 +/- 0.9 micrograms/dl, respectively), but the mean maximum plasma IR-cortisol increments (8.1 +/- 0.8 and 11.7 +/- 0.9 micrograms/dl, respectively; P less than 0.005), and the mean integrated IR-cortisol responses (588 +/- 115 and 976 +/- 95 micrograms . min/dl, respectively; P less than 0.01) were greater in the afternoon. There was an inverse correlation between basal plasma IR-cortisol concentration and the integrated IR-ACTH response (P less than 0.05), the maximum IR-cortisol increment (P less than 0.001), and the integrated IR-cortisol response (P less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)     

Role of corticotropin-releasing hormone as a thyrotropin-releasing factor in non-mammalian vertebrates

The finding that thyrotropin-releasing hormone does not always act as a thyrotropin (TSH)-releasing factor in non-mammalian vertebrates has led researchers to believe that another hypothalamic factor may exhibit this function. In representatives of all non-mammalian vertebrate classes, corticotropin-releasing hormone (CRH) appears to be a potent stimulator of hypophyseal TSH secretion, and might therefore function as a common regulator of both the thyroidal and adrenal/interrenal axes. CRH exerts its dual hypophysiotropic action through two different types of CRH receptors. Thyrotropes express type 2 CRH receptors, while CRH-induced corticotropin (ACTH) secretion is mediated by type 1 CRH receptors on the corticotropic pituitary cells. The stimulating effect of CRH on both TSH and ACTH release has profound consequences for the peripheral action of both hormonal axes. The simultaneous stimulation of the thyroidal and adrenal/interrenal axes by CRH, possibly fine-tuned by differential regulation of the expression of the different CRH receptor isoforms, provides a potential mechanism for developmental plasticity.