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PubMed2006

Neuropeptide S stimulates the hypothalamo-pituitary-adrenal axis and inhibits food intake.

Neuropeptide S (NPS) is a recently discovered peptide shown to be involved in the modulation of arousal and fear responses. It has also been shown that lateral ventricle administration of NPS causes a significant decrease in food intake. Neuropeptides involved in the modulation of arousal have been shown to be involved in the regulation of the hypothalamo-pituitary adrenal (HPA) axis and food intake. In this study, we have examined the effect of intracerebroventricular (ICV) administration of NPS on behavior, regulation of the HPA axis, and food intake. ICV NPS significantly increased plasma ACTH and corticosterone 10 and 40 min after injection, respectively. A single ICV injection of NPS caused a significant increase in rearing activity as well as ambulatory movement for up to 45 min after injection. We then studied the effect of paraventricular nucleus (PVN) administration of NPS on the regulation of the HPA axis, behavior, and food intake. There was a significant increase in plasma ACTH and corticosterone after a single NPS PVN injection. Incubation of hypothalamic explants with increasing concentrations of NPS caused a significant increase in CRH and arginine vasopressin release. In addition, PVN administration of NPS dose-dependently inhibited food intake in the first hour after injection, although no effect on food intake was seen after this time. PVN administration of NPS caused a significant increase in rearing activity. These data demonstrate a novel role for NPS in the stimulation of the HPA axis.

Animals↗

PubMed1990

Abnormal regulation of the hypothalamo-pituitary-adrenal axis in the genetically obese fa/fa rat.

Adrenalectomy has been shown to reverse most facets of the syndrome of the genetically obese fa/fa rat. However, a detailed analysis of the hypothalamo-pituitary-adrenal (HPA) axis in these animals is lacking. In the present study, morning corticosteronemia was higher in obese rats of both sexes than in lean ones, whereas evening corticosteronemia was higher only in obese male rats. The HPA axis was further investigated using stressful stimuli. Immobilization, ether, and cold stresses resulted in greater corticosterone levels in obese than in lean animals. These abnormalities consisted in upward shifts of the corticosterone response in obese females and absolute increases in that of obese males, indicating that such alterations were more pronounced in obese male than obese female rats. Due to this, the putative origin of the increased corticosterone output of obese rats was studied in males. Greater levels of ACTH were reached in obese than in lean rats when submitted to a cold stress (6 C). Dexamethasone produced a complete suppression of corticosterone output in both lean and obese rats. During the recovery from such suppression, corticosterone levels rose to higher values in obese than in lean rats. This observation together with the greater cold-induced ACTH output in obese rats suggest that the increased activity of the HPA axis of these animals is of central origin. Whatever its precise etiology within the central nervous system, it is proposed that the increased HPA axis activity in obese rats and its resultant hypercorticism play a role in the establishment and maintenance of their syndrome.

Animals↗

PubMed1992

Feedback sensitivity of the rat hypothalamo-pituitary-adrenal axis and its capacity to adjust to exogenous corticosterone.

Chronic stress causing elevated morning (AM) corticosterone (B) concentrations of 2-8 micrograms B/dl does not appear to inhibit subsequent activity in the hypothalamic-pituitary-adrenal (HPA) axis, a surprising finding in view of the known depression in AM basal ACTH by only 3 micrograms B/dl in adrenalectomized rats. To distinguish between the possibilities that either intact rats are less sensitive to B feedback than adrenalectomized rats, or that chronic stress facilitates responses in the HPA axis, we elevated basal B levels in young male rats with slow-release B pellets in the absence of stress. Between 4-6 days after implantation of B pellets at three doses that elevated basal AM (diurnal trough) plasma B to approximately 1.2, 4, and 10 micrograms/dl, we studied basal ACTH and B at trough (AM) and peak evening (PM) times of the diurnal cycle, as well as the responses to the stress of restraint and blood collection from the tail at each time of day. We also determined mean daily plasma B, insulin, and glucose from samples collected at six intervals during the day. Adrenal, thymus, and body wts were measured as were transcortin (CBG) and adrenal phenylethanolamine-N-methyl transferase activity. Compared to controls implanted with wax pellets, all doses of B inhibited adrenal wt and AM stress responses and tended to inhibit pituitary ACTH content and adrenal phenylethanolamine-N-methyl transferase activity. Inhibition with the middle dose B pellet was close to maximally effective for these endpoints. Plasma glucose and thymus wt were significantly decreased and insulin was significantly increased in the middle and highest B pellet groups, with significantly greater effects at the highest dose. The gain in body wt and transcortin concentrations were significantly decreased only in the highest dose groups, in which mean daily plasma B was approximately 10 micrograms/dl, a level that clearly overwhelmed the capacity of the adrenocortical system to respond to any stimulus tested. By contrast, rats with low and middle dose B pellets appeared to adjust HPA axis function by decreasing the peak diurnal increase in B, so that 24-h mean B levels did not differ from control, and were maintained at approximately 5 micrograms/dl. Both of these groups also had inhibited ACTH responses to stress applied during the diurnal trough (AM). By contrast, neither group had inhibited ACTH responses to stress applied during the diurnal peak (PM). We conclude that: 1) The HPA axis of intact rats is extremely sensitive to exogenous B.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Glands↗

PubMed1993

Lack of a role of the hypothalamic-pituitary-adrenal axis in the fasting-induced suppression of luteinizing hormone secretion in adult male rhesus monkeys (Macaca mulatta).

One day of fasting suppresses pulsatile LH secretion in adult male rhesus monkeys. In the present study, we determined whether the hypothalamic-pituitary-adrenal (HPA) axis is activated by 1 day of fasting, and if there is any evidence that an increase in the activity of the HPA axis causes the fasting-induced suppression of LH secretion. In the first experiment, blood samples were collected at 15-min intervals from nine monkeys for 24 h (0800-0800 h) on a day of normal feeding (animals fed a single daily meal at 1100 h) and again on a day of fasting (animals not fed their daily meal) to assess changes in LH and cortisol secretion caused by fasting. LH secretion on the day of fasting (4.44 +/- 0.85 LH pulses/24 h) was significantly suppressed compared to that on a day of normal feeding (7.67 +/- 0.74 LH pulses/24 h; P < or = 0.01), and there was a slight, but significant, rise in plasma cortisol levels from 17.86 +/- 2.29 to 25.14 +/- 2.74 micrograms/dl (measured at 1400 h) that was evident soon after the meal was missed on the day of fasting. However, within individual animals, there was no correlation between the rise in plasma cortisol levels and the decrease in LH secretion observed on a day of fasting (r = 0.37). A second experiment was performed to determine whether the small rise in plasma cortisol levels that occurred on a day of fasting was capable of suppressing LH secretion. Hydrocortisone acetate (HCA) was administered to six normally fed monkeys, creating a rise in plasma cortisol levels somewhat greater than the levels occurring during fasting (HCA treatment, 44.51 +/- 1.48 micrograms/dl; fasting, 18.42 +/- 1.62 micrograms/dl; measured between 1100-2400 h). However, HCA treatment had no effect on LH secretion, suggesting that the rise in cortisol that occurs during fasting does not cause LH suppression. To determine whether increased secretion of the neuropeptides that provide the central drive to the adrenal axis causes the suppression of LH secretion during fasting, six animals were treated with dexamethasone (0.25 mg/kg, im) on a day of fasting to inhibit the activity of the glucocorticoid-sensitive CRH neurons of the adrenal axis via increased glucocorticoid negative feedback. Dexamethasone treatment caused a marked suppression of circulating cortisol levels (to approximately 1.0 micrograms/dl), but it did not prevent the fasting-induced suppression of pulsatile LH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗

PubMed1994

Regulation of activity in the hypothalamo-pituitary-adrenal axis is integral to a larger hypothalamic system that determines caloric flow.

We have previously reported that there are diurnal rhythms in the magnitude of ACTH responses to stressors and in the sensitivity of stress-induced ACTH responses to facilitation induced by prior stress and to corticosterone (B) feedback induced by exogenous B. In all cases ACTH was more responsive in the morning than in the evening in nocturnally feeding rats. We have also shown in adrenalectomized rats that an overnight fast reduces ACTH responses to restraint in the morning compared with rats fed ad libitum, and we have shown that calorie-containing gavage during the fast increases the amplitude of ACTH responses to restraint in fasted rats. Therefore, this diurnal rhythm is not associated with B feedback and is associated with calories. In these studies we asked whether young, male intact rats that were deprived of food overnight had: 1) hypothalamo-pituitary-adrenal (HPA) axis responses during the fasting period; 2) altered basal activity in the HPA axis; 3) altered responsivity of ACTH to restraint; and 4) altered sensitivity of restraint-induced ACTH responses to facilitation or B feedback. Our results show that food deprivation: 1) induces marked ACTH and B responses during the fast that mirrors the pattern of food intake in fed rats, with an approximately 3-h lag; 2) results in essentially no change in basal ACTH in the morning; 3) reduces ACTH responsivity to stress in the morning; and 4) reduces ACTH responsivity to prior stress-induced facilitation and exogenous B-induced feedback. We conclude that: 1) the HPA axis serves as a default pathway to feeding when food is not available; 2) the diurnal rhythms in restraint-induced ACTH secretion are determined by food intake; and 3) the HPA axis is integral to a larger hypothalamic system that mediates energy flow.

Adrenocorticotropic Hormone↗

PubMed1995

The fetal somatotropic axis during long term maternal undernutrition in sheep: evidence for nutritional regulation in utero.

Nutrition is a major determinant of the somatotropic axis during postnatal life. However, little is known about the response of the fetal somatotropic axis to nutritional limitation. From day 100 of gestation (term = 147 days), singleton-bearing ewes were fed either ad libitum (control; n = 6) or 25% of the recommended energy and protein requirements (restricted; n = 7). Ewes and fetuses were chronically catheterized on day 110. On day 120, paired maternal and fetal blood samples were taken over a 6-h period at 15-min intervals. Forty-eight hours later, fetuses were given a 20-micrograms GRF bolus (i.v.), and samples were collected for 48 h. Undernourished mothers and fetuses had higher GH concentrations (P < 0.05). Although plasma GH profiles were independent in mothers and their fetuses, both maternal and fetal GH peak and nadir levels were increased (P < 0.05) by nutritional restriction, but the peak/nadir ratio and the number of pulses remained unaltered. Deconvolution analysis showed that the GH mass secreted per burst was higher in nutritionally restricted animals, whereas basal GH secretion and GH serum half-life were not influenced by undernutrition. Both maternal and fetal insulin-like growth factor-I levels were reduced (P < 0.01 and P < 0.05), whereas insulin-like growth factor-II concentrations were not influenced by the feed restriction. Fetuses from restricted mothers had higher peak GH concentrations after a GRF challenge (P < 0.001), but after correction The specific binding of [125I]ovine placental lactogen ([125I]oPL) or [125I]oGH to maternal or fetal hepatic microsomal membrane preparations was not changed by the maternal undernutrition. Maternal oPL concentrations showed considerable short term fluctuations, whereas fetal oPL levels revealed no major fluctuations. Mean maternal oPL levels tended (P < 0.06) to be elevated, whereas fetal oPL concentrations tended (P < 0.06) to be decreased in restricted animals. These results provide evidence that the somatotropic axis is functional in utero and suggest that the fetal somatotropic axis plays an active role during adaptation of the fetus to nutritional limitation.

Animal Nutritional Physiological Phenomena↗

PubMed1998

Neuroendocrine and immunocytochemical demonstrations of decreased hypothalamo-pituitary-adrenal axis responsiveness to restraint stress after long-term social isolation.

We have studied the effects of long-term social isolation of male Wistar rats, after early weaning (16 days), on the activity of the hypothalamo-pituitary-adrenal (HPA) axis. In addition to studying basal HPA activity, the response of the HPA axis to 15 min of immobilization stress was examined. Plasma corticosterone concentrations were measured, and the relative weights of adrenal glands, thymus, and testes were obtained, the latter to check whether gonadal function was affected by the isolation paradigm. Moreover, we carried out a quantitative immunohistochemical study of pituitary ACTH and its hypothalamic secretagogues: CRF, arginine vasopressin (AVP), and oxytocin (OT), both at the level of the synthesizing cell bodies in the hypothalamic paraventricular nucleus and of the releasing fibers in the median eminence (ME). Body weight and daily consumption of food and water were not altered, but social isolation caused a reduction in plasma corticosterone levels, both under basal and stress-stimulated conditions; this was correlated with an increased thymus weight, without affecting adrenal or testicular weights. The immunohistochemical study revealed that isolation caused a smaller increase in the number of ACTH-immunoreactive cells in the pars distalis of the anterior pituitary after exposure to restraint stress, as compared with control animals. This result indicates that fewer corticotrophs were activated by restraint stress in isolated animals, such cells being smaller and exhibiting a smaller ACTH-immunoreactive area than in control animals. Isolated animals also showed an increase in the content of CRF-ir fibers in the ME and a smaller decrease in the neuropeptide immunoreactivity after stress than that observed in control animals. This result could indicate a reduced release of CRF into the portal vasculature in response to acute stress and may partially explain the reduced activation of corticotrophs observed in the pituitary of isolated animals. However, no changes were found in the content of CRF, AVP, or OT within the paraventricular nucleus, nor of the AVP or OT content in the ME. The results of this study show that long-term social isolation after early weaning caused a hypofunction of the HPA axis in the adult rat. This hypofunction was particularly evident after exposure to an acute stressor, suggesting a desensitization of this axis to stressful stimuli.

Animals↗

PubMed1999

Interleukin-11 stimulates proopiomelanocortin gene expression and adrenocorticotropin secretion in corticotroph cells: evidence for a redundant cytokine network in the hypothalamo-pituitary-adrenal axis.

We recently characterized leukemia inhibitory factor (LIF) as an important modulator of hypothalamo-pituitary-adrenal (HPA) axis activity. We now describe the role of interleukin (IL)-11, another member of the IL-6 cytokine family, in the neuro-immuno-endocrine modulation of the HPA axis. In murine hypothalamus, pituitary and corticotroph AtT-20 cells, IL-11 messenger RNA (mRNA) was detectable by RT-PCR only, whereas IL-11R mRNA transcripts were demonstrated by Northern blot. Using RT-PCR, IL-11 and IL-11R gene expression were also detected in normal human pituitaries, as well as in corticotropic and nonfunctioning pituitary adenomas. Incubation of AtT-20 cells for 24 h with 10(-9) M IL-11 stimulated ACTH secretion 1.4 +/- 0.1-fold (P < 0.01), whereas LIF at the same concentration caused a 1.5 +/- 0.1-fold increase (P < 0.001). POMC mRNA expression was induced by IL-11 (0.5 x 10(-9) M) and LIF (0.5 x 10(-9) M) 1.5 +/- 0.18-fold (P < 0.05) and 1.7 +/- 0.13-fold (P < 0.01), respectively. POMC promoter activity, assayed by a -706/+64 rat POMC promoter-luciferase construct, was stimulated by 0.5 x 10(-9) M IL-11 (1.9 +/- 0.06-fold; P < 0.001) and 5 mM Bu2cAMP (7.1 +/- 0.52-fold, P < 0.001), and combined treatment of IL-11 plus Bu2cAMP caused a synergistic 11.7+/-0.71-fold increase ofluciferase activity (P < 0.001 vs. Bu2cAMP alone). Gene expression of SOCS-3, an intracellular inhibitor of cytokine action, peaked as early as 60 min after incubation with IL-11 (0.5 x 10(-9) M) and was induced 3.5-fold. In comparison to mock-transfected AtT-20 cells (AtT-20M), stable overexpression of SOCS-3 (AtT-20S) resulted in significant inhibition of ACTH secretion induced by IL-11 alone (1.5 +/- 0.09 vs. 1.1 +/- 0.04-fold induction, P < 0.01) and IL-11 plus Bu2cAMP (2.1 +/- 0.21 vs. 1.5 +/- 0.06-fold, P < 0.05), but not by Bu2cAMP alone (1.5 +/- 0.12 vs. 1.4 +/- 0.06). In summary, human and murine pituitary express IL-11 and IL-11R transcripts. In murine corticotroph AtT-20 cells, IL- 11 induces POMC gene transcription and ACTH secretion. IL-11 induction of SOCS-3 indicates an intracellular negative feedback control of cytokine-induced POMC expression and ACTH secretion. Thus, IL-11 regulates the HPA axis similarly to LIF, providing further evidence for a redundant cytokine network in the neuro-immuno-endocrine regulation of the HPA axis.

Adenoma↗

PubMed1999

Nonresponsiveness of the rat hypothalamo-pituitary-adrenocortical axis to parturition-related events: inhibitory action of endogenous opioids.

During the last 2 days of pregnancy in rats, basal corticosterone secretion is enhanced, although the response of the hypothalamo-pituitary-adrenocortical (HPA) axis to emotional and physical stressors is blunted, independent of the action of endogenous opioids. In this study, alterations in the reactivity of the HPA axis, which may accompany parturition-related stimuli, and the involvement of endogenous opioids were examined in chronically catheterized rats. In vehicle-treated controls (n = 9), ACTH and corticosterone secretion decreased in preparation for birth (P < 0.01) and further declined immediately after delivery of the second pup (P < 0.01), remaining low for 150 min. In contrast, in animals injected with the opiate antagonist naloxone (5 mg ml(-1) kg(-1), i.v., n = 6) after delivery of the second pup, ACTH and corticosterone release were enhanced within 20 min (ACTH, 5.0-fold; corticosterone, 2.3-fold; P < 0.01 vs. controls) and returned to control levels after 90 min. In confirmation of previous reports, oxytocin secretion into blood was elevated in control rats after the onset of parturition (P < 0.01) and was further enhanced in the naloxone group (1.4-fold, P < 0.01 vs. control). Plasma lactate concentration was increased, 30 min after the onset of delivery (1.9-fold, P < 0.01), independent of the treatment. The data indicate that parturition-related events do not trigger HPA axis hormone release because of an effective inhibition by endogenous opioids. This nonresponsiveness of the HPA axis is likely to protect the pups' well-being during birth.

Adrenocorticotropic Hormone↗

PubMed2001

Responses of the fetal pituitary-adrenal axis to acute and chronic hypoglycemia during late gestation in the sheep.

We investigated the response of the fetal pituitary-adrenal axis to acute and chronic hypoglycemia before and after the normal prepartum activation of this axis at around 135 days gestation (term = 147 +/- 3 days). Pregnant ewes were either well nourished (control group; n = 22) or undernourished (UN; 50% reduction in maternal nutrient intake; n = 23) during the last 30 days of pregnancy. Acute hypoglycemia was induced by intrafetal administration of insulin between 125 and 130 days gestation (control, n = 7; UN, n = 12) and between 138 and 141 days gestation (control, n = 6; UN = 9). Fetal plasma glucose concentrations were significantly lower (P < 0.005) in the UN compared with the control group throughout the insulin infusion period at both gestational age ranges. In the control group, there was no fetal ACTH response to insulin infusion before 135 days gestation, but there was a significant (P < 0.001) response after 136 days gestation. In the UN group, there was a significant ACTH response to insulin infusion both before and after 135 days gestation, and there was no difference in the fetal ACTH response between the two gestational age ranges. The plasma cortisol responses to insulin were greater (P < 0.001) after 136 days compared with before 135 days gestation in both the UN and control groups. In the control group there was no significant relationship between basal fetal plasma ACTH and glucose concentrations between 115-135 days gestation or between 136-145 days gestation. In the UN group, fetal glucose ranged from 0.5-2.0 mM, and plasma ACTH and glucose concentrations were inversely related at 115-135 days gestation [log ACTH = -0.31 (glucose) + 2.21; r = -0.37; P < 0.001] and at 136-145 days gestation [log ACTH = -0.40 (glucose) + 2.50; r = -0.54; P < 0.001]. When the UN and control groups were combined, fetal plasma ACTH concentrations were significantly greater (F = 13.5; P < 0.05) when plasma glucose concentrations were less than 1.0 mM at either 115-135 days or 136-147 days gestation. Similarly, fetal plasma cortisol concentrations were also significantly greater (F = 18.7; P < 0.05) when plasma glucose concentrations were less than 1.0 mM at each gestational age range. Therefore, there is an increased sensitivity of the fetal hypothalamo-pituitary axis to acute falls in glucose concentrations below 1.2 mM after 135 days compared with earlier in gestation. The fetal hypothalamo-pituitary axis can respond, however, when plasma glucose concentrations fall below 1.0 mM, before and after 135 days gestation, independently of whether the low glucose concentrations are a consequence of insulin-induced hypoglycemia or maternal nutrient restriction.

Adrenocorticotropic Hormone↗

PubMed2003

The growth hormone/insulin-like growth factor-I axis hormones and bone markers in elite athletes in response to a maximum exercise test.

The aim of the GH-2000 project is to develop a method for detecting GH doping among athletes. Previous papers in the GH-2000 project have proposed that a forthcoming method to detect GH doping will need specific components from the GH/IGF-I axis and bone markers because these specific variables seem more sensitive to exogenous GH than to exercise. The present study examined the responses of the serum concentrations of these specific variables to a maximum exercise test in elite athletes from selected sports. A total of 117 elite athletes (84 males and 33 females; mean age, 25 yr; range, 18-53 yr) from Denmark, the United Kingdom, Italy, and Sweden participated in the study. The serum concentrations of total GH, GH22 kDa, IGF-I, IGF binding protein (IGFBP)-2, IGFBP-3, acid-labile subunit, procollagen type III (P-III-P), and the bone markers osteocalcin, carboxy-terminal cross-linked telopeptide of type I collagen (ICTP), and carboxy-terminal propeptide of type I procollagen were measured. The maximum exercise test showed, in both genders, a peak concentration of total GH (P < 0.001) and GH22 kDa (P < 0.001) by the time exercise ended compared with baseline, and a subsequent decrease to baseline levels within 30-60 min after exercise. The mean time to peak value for total GH and GH22 kDa was significantly shorter in males than females (P < 0.001). The components of the IGF-I axis showed a similar pattern, with a peak value after exercise compared with baseline for IGF-I (P < 0.001, males and females); IGFBP-3 (P < 0.001, males and females); acid-labile subunit [P < 0.001, males; not significant (NS), females], and IGFBP-2 (P < 0.05, females; NS, males). The serum concentrations of the bone markers ICTP (P < 0.001, males; P < 0.05, females) and P-III-P (P < 0.001, males and females) increased in both genders, with a peak value in the direct post-exercise phase and a subsequent decrease to baseline levels or below within 120 min. The osteocalcin and propeptide of type I procollagen values did not change during the exercise test. Specific reference ranges for each variable in the GH/IGF-I axis and bone markers at specific time points are presented. Most of the variables correlated negatively with age. In summary, the maximum exercise test showed a rather uniform pattern, with peak concentrations of the GH/IGF-I axis hormones and the bone markers ICTP and P-III-P immediately after exercise, followed by a subsequent decrease to baseline levels. The time to peak value for total GH and GH22 kDa was significantly shorter for females compared with males. This paper presents reference ranges for each marker in each gender at specific time points in connection to a maximum exercise test to be used in the development of a test for detection of GH abuse in sports.

Adult↗

PubMed2004

In boys with abnormal developmental tempo, maturation of the skeleton and the hypothalamic-pituitary-gonadal axis remains synchronous.

The primary mechanism that initiates puberty is unknown. One possible clue is that pubertal maturation often parallels skeletal maturation. Conditions that delay skeletal maturation also tend to delay the onset of puberty, whereas conditions that accelerate skeletal maturation tend to hasten the onset of puberty. To examine this relationship, we studied boys with congenital adrenal hyperplasia (n = 13) and familial male-limited precocious puberty (n = 22), two conditions that accelerate maturational tempo, and boys with idiopathic short stature (n = 18) in which maturational tempo is sometimes delayed. In all three conditions, the onset of central puberty generally occurred at an abnormal chronological age but a normal bone age. Boys with the greatest skeletal advancement began central puberty at the earliest age, whereas boys with the greatest skeletal delay began puberty at the latest age. Furthermore, the magnitude of the skeletal advancement or delay matched the magnitude of the pubertal advancement or delay. This synchrony between skeletal maturation and hypothalamic-pituitary-gonadal axis maturation was observed among patients within each condition and also between conditions. In contrast, the maturation of the hypothalamic-pituitary-gonadal axis did not remain synchronous with other maturational processes including weight, height, or body mass index. We conclude that in boys with abnormal developmental tempo, maturation of the skeleton and the hypothalamic-pituitary-gonadal axis remains synchronous. This synchrony is consistent with the hypothesis that in boys, skeletal maturation influences hypothalamic-pituitary-gonadal axis maturation.

Adolescent↗

PubMed1993

The effects of mild ethanol intoxication on the hypothalamic-pituitary-adrenal axis in nonalcoholic men.

Historically, ethanol exposure has been thought to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. However, recent studies have demonstrated decreased responsiveness to metyrapone and insulin-induced hypoglycemia in alcoholic subjects. The present study investigated in more detail the effect of acute ethanol ingestion (0.75 g/kg) on the HPA axis in healthy nonalcoholic men (n = 14). In study 1, plasma ACTH/cortisol levels were determined basally and every 30 min over a 180-min period after the ingestion of placebo or ethanol (n = 8). When the subjects were analyzed as a group, ethanol did not alter ACTH or cortisol levels. However, in two of eight subjects, ethanol ingestion was accompanied by a rise in plasma ACTH. In study 2, ethanol or placebo was ingested over 15 min, and 1 microgram/kg ovine (o) CRH was administered (n = 9). Hormone levels were determined at 20 min before and 0, 15, 30, 60, and 90 min after iv oCRH. Compared to responses to placebo, plasma ACTH responses to oCRH were blunted during the ethanol session [peak ACTH, 14.2 +/- 1.4 vs. 20.3 +/- 3.1 pmol/L (P = 0.036); peak value minus baseline (delta), 7.3 +/- 1.4 vs. 13.4 +/- 2.6 pmol/L (P = 0.017); delta divided by baseline x 100, 131 +/- 28 vs. 197 +/- 29% (P = 0.041); area under the ACTH curve, 1082 +/- 116 vs. 1529 +/- 232 pmol/min.L (P = 0.024)]. Ethanol ingestion also significantly blunted plasma cortisol levels after oCRH compared to placebo treatment. In study 3, ethanol or placebo was ingested over 15 min, and 0.25 microgram ACTH-(1-24) was administered (n = 5). Cortisol levels, determined 20 min before and 0, 30, 60, and 90 min after ACTH treatment, were not altered by ethanol administration. In summary, mildly intoxicating doses of ethanol did not stimulate the HPA axis in six of eight subjects. However, mild intoxication significantly impaired oCRH-stimulated ACTH/cortisol secretion. We speculate that mild intoxication with ethanol may impair the ability of the HPA axis to respond to physiological stressors.

Adrenocorticotropic Hormone↗

PubMed1993

Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans.

The inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1 alpha and -beta (IL-1 alpha and -beta), and IL-6 can activate the hypothalamic-pituitary-adrenal (HPA) axis. Tumor necrosis factor-alpha and IL-1 have been tested in both experimental animals and humans, but their administration has been limited by significant toxicity, mainly severe hypotension. IL-6, on the other hand, has demonstrated modest toxicity in animals. We evaluated the ability of recombinant IL-6 to stimulate the human HPA axis in patients with cancer and a good performance status, who received daily morning sc injections of 30 micrograms/kg IL-6 for 7 consecutive days, during the course of a phase I trial. IL-6 caused impressively marked and prolonged elevations of plasma ACTH and cortisol on the first day and blunted ACTH responses on the seventh day of treatment, perhaps as a result of increased baseline cortisol levels. The overall cortisol response, however, on the seventh day was of similar magnitude, suggesting that a new equilibrium in the feedback regulation of the HPA axis occurs with chronic IL-6 administration. The toxic effects of IL-6 were modest, suggesting that it might be useful for clinical testing of the HPA axis, as an alternative to the insulin tolerance test.

Adrenocorticotropic Hormone↗

PubMed1994

Interleukin-6 stimulates the hypothalamus-pituitary-adrenocortical axis in man.

A recent study in humans, animal studies, and in vitro data have suggested that interleukin-6 (IL-6) stimulates the secretory activity of the hypothalamus-pituitary-adrenocortical (HPA) axis. In a phase II study, one female and six male patients with metastatic renal cell carcinoma received IL-6 to evaluate a possible antitumor effect of IL-6. This offered the possibility of investigating the influence of IL-6 on the HPA axis in man. The subjects were studied 1 day before, on day 1, and on day 21 of IL-6 therapy (150 micrograms administered sc every day at 0900 h). Blood samples were taken at 0900, 1100, 1300, 1600, and 2000 h the day before, on day 1 of IL-6 therapy, 24 h after the first IL-6 injection, and on day 21 of IL-6 treatment. Plasma ACTH and cortisol levels promptly followed the rise of IL-6, which peaked 4 h after administration. They were significantly (P < 0.05) higher at 1100 and 1300 h on day 1 of IL-6 therapy compared with the corresponding plasma levels the day before IL-6 treatment. Cortisol concentrations remained significantly increased at 1600 and 2000 h after IL-6 administration. Twenty-four hours after the first IL-6 administration, IL-6, ACTH, and cortisol levels had reached preinjection values. Although plasma cortisol levels were similar on days 1 and 21, ACTH levels were lower on day 21 (than on day 1), but significantly elevated at 1100 h compared with levels on the day before the first IL-6 injection. Results confirming the very recent data of another study demonstrate a stimulating effect of IL-6 on the HPA axis in man. They support the notion that IL-6 is one of the cytokines involved in the interaction between the immune system and the HPA axis.

Adrenal Cortex↗

PubMed1997

Estrogen and testosterone, but not a nonaromatizable androgen, direct network integration of the hypothalamo-somatotrope (growth hormone)-insulin-like growth factor I axis in the human: evidence from pubertal pathophysiology and sex-steroid hormone replacement.

Activation of the gonadotropic and somatotropic axes in puberty is marked by striking amplification of pulsatile neurohormone secretion. In addition, each axis, as a whole, constitutes a regulated network whose feedback relationships are likely to manifest important changes at the time of puberty. Here, we use the regularity statistic, approximate entropy (ApEn), to assess feedback activity within the somatotropic (hypothalamo-pituitary/GH-insulin-like growth factor I) axis indirectly. To this end, we studied pubertal boys and prepubertal girls or boys with sex-steroid hormone deficiency treated short-term with estrogen, testosterone, or a nonaromatizable androgen in a total of 3 paradigms. First, our cross-sectional analysis of 53 boys at various stages of puberty or young adulthood revealed that mean ApEn, taken as a measure of feedback complexity, of 24-h serum GH concentration profiles is maximal in pre- and mid-late puberty, followed by a significant decline in postpubertal adolescence and young adulthood (P = 0.0008 by ANOVA). This indicates that marked disorderliness of the GH release process occurs in mid-late puberty at or near the time of peak growth velocity, with a return to maximal orderliness thereafter at reproductive maturity. Second, oral administration of ethinyl estradiol for 5 weeks to 7 prepubertal girls with Turner's syndrome also augmented ApEn significantly (P = 0.018), thus showing that estrogen per se can induce greater irregularity of GH secretion. Third, in 5 boys with constitutionally delayed puberty, im testosterone administration also significantly increased ApEn of 24-h GH time series (P = 0.0045). In counterpoint, 5 alpha-dihydrotestosterone, a nonaromatizable androgen, failed to produce a significant ApEn increase (P > 0.43). We conclude from these three distinct experimental contexts that aromatization of testosterone to estrogen in boys, or estrogen itself in girls, is likely the proximate sex-steroid stimulus amplifying secretory activity of the GH axis in puberty. In addition, based on inferences derived from mathematical models that mechanistically link increased disorderliness (higher ApEn) to network changes, we suggest that sex-steroid hormones in normal puberty modulate feedback within, and hence network function of, the hypothalamo-pituitary/GH-insulin-like growth factor I axis.

Adolescent↗

PubMed1997

Chronic imipramine is associated with diminished hypothalamic-pituitary-adrenal axis responsivity in healthy humans.

The hypercortisolism of melancholic depression is thought to reflect hypothalamic hypersecretion of CRH and may be related to the hyperarousal associated with this syndrome. Although chronic administration of imipramine to experimental animals significantly decreases CRH messenger RNA levels in the paraventricular nucleus, it is generally thought that resolution of hypercortisolism following recovery from depression is related to the improvement in mood and decrease in anxiety that accompanies recovery rather than an intrinsic effect of imipramine. The present study was designed to explore whether chronic imipramine administration to healthy, nondepressed volunteers is associated with effects on hypothalamic-pituitary-adrenal (HPA) axis function. We studied basal and provocative measures of HPA axis function in 14 healthy volunteers before and after 6 weeks of imipramine treatment at therapeutic doses. Imipramine was associated with decreased responses in peak ACTH and cortisol to ovine CRH and in peak ACTH to arginine vasopressin (P = 0.02, P = 0.003, and P = 0.02, respectively) without changes in indices of basal HPA axis function. These data are consistent with preclinical findings and support the hypothesis that imipramine has an intrinsic effect on central components of HPA axis function, potentially related to its therapeutic effects.

Adrenocorticotropic Hormone↗

PubMed1998

Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test.

We retrospectively reviewed dynamic ACTH and cortisol responses to insulin hypoglycemia in 193 subjects with suspected ACTH deficiency to ascertain the predictive values of various diagnostic criteria. Based on the achievement of a peak cortisol level of 18 micrograms/dL or above, 133 subjects were classified as having an intact hypothalamic-pituitary-adrenal (HPA) axis, and 60 subjects were determined to have ACTH deficiency. Baseline and peak cortisol concentrations were strongly correlated (r = 0.63; P < 0.0001). Peak cortisol increased in parallel to ACTH increments, but plateaued at approximately 22 micrograms/dL at peak ACTH levels above approximately 75 pg/mL (r = 0.61; P < 0.0001). Basal cortisol values above 17 micrograms/dL or below 4 micrograms/dL were highly predictive of an intact or impaired HPA axis, respectively, but intermediate values had only limited sensitivity and specificity. The criteria of HPA axis integrity, defined as an increment in plasma cortisol of more than 7 micrograms/dL above the baseline or as a doubling of the baseline cortisol value, were associated with high false positive and false negative rates. We conclude that 1) the baseline morning serum cortisol concentration has very limited predictive power in differentiating between normal and impaired HPA function; 2) the use of criteria based on incremental changes in serum cortisol from baseline leads to unacceptably high false positive and false negative rates; and 3) insulin hypoglycemia is still the best indicator of the integrity of the response of the HPA axis to stress.

Adolescent↗