Adrenocorticotropin Hormone Responses Research Articles

The Diagnostic Approach to Central Adrenocortical Insufficiency (CAI) in Thalassemia.

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The effects of smoked nicotine on measures of subjective states and hypothalamic-pituitary-adrenal axis hormones in women during the follicular and luteal phases of the menstrual cycle.

To determine the acute effects of cigarette smoking on hypothalamic-pituitary-adrenal (HPA) axis hormones and subjective states as a function of the menstrual cycle in nicotine-dependent women. Seventeen healthy nicotine-dependent women were studied during the follicular and/or luteal phase of the menstrual cycle. Because of observation of a possible bimodal distribution of progesterone levels within the luteal phase group, we performed a set of a posteriori analyses. Therefore, we divided the luteal group into a low progesterone and a high progesterone groups. Smoked nicotine activated HPA, measured by adrenocorticotropin hormone (ACTH), cortisol, and dehydroepiandrosterone (DHEA) response and affected subjective states in both follicular and luteal phases, with increased "High," "Rush," and decreased "Craving." The HPA stimulation revealed a blunting of ACTH response. There was only modest evidence for a blunting of subjective state responses in the luteal phase. However, upon post hoc analyses, the high progesterone luteal group showed a marked blunting of measures of subjective states and a blunted ACTH response. Examining the association between hormone and measures of subjective states revealed tentative associations of ACTH stimulation with increased "Rush" and "Craving," and DHEA stimulation with increased "Craving." This pilot study suggests that menstrual cycle phase differences in progesterone levels may attenuate nicotine's addictive effects via diminution of its reinforcing properties and augmentation of its aversive effects interfering with the pleasure associated with cigarette smoking.

Dissociation between ACTH and cortisol response in DEX–CRH test in patients with panic disorder

Panic disorder (PD) has been associated with the altered circadian rhythm of the hypothalamic-pituitary-adrenocortical (HPA) axis. The findings regarding the stress-specific functioning of the HPA-system are inconsistent. It is also unclear whether the HPA-system response after the Corticotropin-Releasing-Hormone (CRH) challenge becomes altered. For this study, the dexamethasone-corticotropin-releasing-hormone (DEX-CRH) test was implemented to assess the HPA-axis reactivity indicated by the plasma adreno-corticotropin-hormone (ACTH) and the cortisol release. The sample included 32 patients diagnosed with PD in a Structured Clinical Interview (SCID). Fourteen male and eighteen female patients, [mean age = 33.50 years, SD = 12.76] were matched with 32 healthy controls by age and gender. Moreover, a sample of patients with unipolar depression (n = 21, ten females) was examined as a clinical control group. In healthy controls as well as in patients with PD and patients with unipolar depression, the ACTH and the cortisol response increased significantly due to the CRH injection after dexamethasone pre-treatment. There were differences between the healthy controls and the patients with PD in the plasma cortisol response pattern, however, not in the ACTH. The patients with PD showed a decreased CRH-induced plasma cortisol response. A median-split gave evidence that patients suffering from PD longer than two years showed a remarkably higher HPA-axis reactivity under CRH-injection than patients suffering from PD two years or less. These findings provide strong evidence that patients with PD show some dissociation between ACTH and cortisol response under the DEX-CRH test with strong indicators that the length of the duration of the psychopathology is a risk factor for an increased reactivity of the HPA-axis in patients with PD.

Effects of sex and early maternal abuse on adrenocorticotropin hormone and cortisol responses to the corticotropin-releasing hormone challenge during the first 3 years of life in group-living rhesus monkeys.

In this study we investigated the development of the hypothalamic-pituitary-adrenal (HPA) axis in 21 group-living rhesus monkeys infants that were physically abused by their mothers in the first few months of life and in 21 nonabused controls. Cortisol and adrenocorticotropin hormone (ACTH) responses to a corticotropin-releasing hormone (CRH) challenge were assessed at 6-month intervals during the subjects' first 3 years of life. Abused infants exhibited greater cortisol responses to CRH than controls across the 3 years. Abused infants also exhibited blunted ACTH secretion in response to CRH, especially at 6 months of age. Although there were no significant sex differences in abuse experienced early in life, females showed a greater cortisol response to CRH than males at all ages. There were no significant sex differences in the ACTH response to CRH, or significant interactions between sex and abuse in the ACTH or cortisol response. Our findings suggest that early parental maltreatment results in greater adrenocortical, and possibly also pituitary, responsiveness to challenges later in life. These long-term alterations in neuroendocrine function may be one the mechanisms through which infant abuse results in later psychopathologies. Our study also suggests that there are developmental sex differences in adrenal function that occur irrespective of early stressful experience. The results of this study can enhance our understanding of the long-term effects of child maltreatment as well as our knowledge of the development of the HPA axis in human and nonhuman primates.

Stress Induced Hypothalamus-Pituitary-Adrenal Axis Responses and Disturbances in Psychological Profiles in Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome

Chronic pelvic pain in men has a strong relationship with biopsychosocial stress and central nervous system sensitization may incite or perpetuate the pain syndrome. We evaluated patients and asymptomatic controls for psychological factors and neuroendocrine reactivity under provoked acute stress conditions. Men with pain (60) and asymptomatic controls (30) completed psychological questionnaires including the Perceived Stress, Beck Anxiety, Type A behavior and Brief Symptom Inventory for distress from symptoms. Hypothalamic-pituitary-adrenal axis function was measured during the Trier Social Stress Test with serum adrenocorticotropin hormone and cortisol reactivity at precise times, before and during acute stress, which consisted of a speech and mental arithmetic task in front of an audience. The Positive and Negative Affective Scale measured the state of emotions. Patients with chronic pelvic pain had significantly more anxiety, perceived stress and a higher profile of global distress in all Brief Symptom Inventory domains (p <0.001), scoring in the 94th vs the 49th percentile for controls (normal population). Patients showed a significantly blunted plasma adrenocorticotropin hormone response curve with a mean total response approximately 30% less vs controls (p = 0.038) but no differences in any cortisol responses. Patients with pelvic pain had less emotional negativity after the test than controls, suggesting differences in cognitive appraisal. Men with pelvic pain have significant disturbances in psychological profiles compared to healthy controls and evidence of altered hypothalamic-pituitary adrenal axis function in response to acute stress. These central nervous system observations may be a consequence of neuropsychological adjustments to chronic pain and modulated by personality.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome.

Enhanced stress responsiveness has been implicated as a potential mechanism contributing to the pathophysiology of irritable bowel syndrome (IBS), and should be reflected in altered function of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Both of these systems can modulate mucosal immune function. The aims of this study were: (i) to characterize the basal circadian rhythm of adrenocorticotropin hormone (ACTH) and cortisol in IBS vs healthy controls; (ii) to compare stimulated ACTH, cortisol and noradrenaline responses to a pelvic visceral stressor (sigmoidoscopy) in IBS and controls; and (iii) to correlate neuroendocrine responses with colonic mucosal cytokine expression and symptoms in IBS. Two separate studies were conducted in women. In Study 1, basal cortisol levels were analysed in 41 IBS and 25 controls using 24-h collections of plasma ACTH and cortisol (q10 min sampling). In Study 2, 10 IBS patients with diarrhoea (IBS-D) and 10 controls underwent sigmoidoscopy with measurements of stimulated neuroendocrine responses and cytokine mRNA expression in colonic tissue. Basal ACTH levels were significantly blunted (P < 0.05), while basal and stimulated plasma cortisol levels were higher in patients. Basal cortisol levels prior to an experimental visceral stressor positively correlated with anxiety symptoms (P < 0.004), but not IBS symptoms. Irritable bowel syndrome patients with diarrhoea had significantly decreased mRNA expression of mucosal cytokines [interleukin (IL)-2, IL-6] in the sigmoid colon vs controls (P < 0.05). Although dysregulations in stress-responsive systems such as the HPA axis and mucosal immune function are demonstrated in IBS, they do not appear to have a primary role in modulating IBS severity and abdominal pain.

Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamus

Selective serotonin reuptake inhibitors (SSRIs), such as Prozac®, are used to treat mood disorders. SSRIs attenuate (i.e. desensitize) serotonin 1A (5-HT1A) receptor signaling, as demonstrated in rats through decreased release of oxytocin and adrenocorticotropin hormone (ACTH) following 5-HT1A receptor stimulation. Maximal therapeutic effects of SSRIs for treatment of mood disorders, as well as effects on hypothalamic 5-HT1A receptor signaling in animals, take 1 to 2 weeks to develop. Estradiol also attenuates 5-HT1A receptor signaling, but, in rats, these effects occur within 2 days; thus, estrogens or selective estrogen receptor modulators may serve as useful short-term tools to accelerate desensitization of 5-HT1A receptors in response to SSRIs if candidate estrogen receptor targets in the hypothalamus are identified. We found high levels of GPR30, which has been identified recently as a pertussis-toxin (PTX) sensitive G-protein-coupled estrogen receptor, in the hypothalamic paraventricular nucleus (PVN) of rats. Double-label immunohistochemistry revealed that GPR30 co-localizes with 5-HT1A receptors, corticotrophin releasing factor (CRF) and oxytocin in neurons in the PVN. Pretreatment with PTX to the PVN before peripheral injections of 17-β-estradiol 3-benzoate completely prevented the reduction of the oxytocin response to the 5-HT1A receptor agonist, (+)-8-hydroxy-2-dipropylaminotetralin (DPAT). Treatment with the selective GRP30 agonist, G-1, attenuated 5-HT1A receptor signaling in the PVN as measured by an attenuated oxytocin (by 29%) and ACTH (by 31%) response to DPAT. This study indicates that a putative extra-nuclear estrogen receptor, GPR30, may play a role in estradiol-mediated attenuation of 5-HT1A receptor signaling, and potentially in accelerating the effects of SSRIs in treatment of mood disorders.

The role of CRF in individual differences in response to social defeat: neuroendocrine, behavior, and viscera

Individual differences in response to stress may determine vulnerability to adverse psychological consequences. During a 30 minute social defeat paradigm, Sprague Dawley intruders exhibited individual differences in average latency to be defeated (exhibiting a supine posture) by an aggressive resident Long Evans during 7 daily defeats. Rats responding submissively exhibited short latencies (SL; 197±15 sec) whereas those displaying defensive behaviors exhibited greater latencies (LL; 438±12 sec). All defeated rats exhibited blunted weight gain and adrenal hypertrophy, however when challenged with restraint, LL rats exhibited facilitated adrenocorticotropin hormone response whereas SL exhibited blunted release vs control. SL rats also displayed increased immobility during Porsolt forced swim vs control. As previously reported in mice, SL rats also developed bladder hypertrophy. Corticotropin‐releasing factor (CRF), in addition to its initiating role in the HPA axis and anxiogenic effects, inhibits micturition via barrington's nucleus, thereby inhibiting urination and, in extreme cases, promotes bladder hypertrophy. Immunohistochemical analysis revealed increased CRF‐expressing cells in barrington's of SL. The results implicate a role of individual differences in coping strategy in determining neuroendocrine, neuropeptide, behavioral and visceral repercussions of repeated defeat.

Chronic voluntary wheel running facilitates corticosterone response habituation to repeated audiogenic stress exposure in male rats

Voluntary exercise is associated with the prevention and treatment of numerous physical and psychological illnesses, yet the mechanisms by which it confers this protection remain unclear. In contrast, stress, particularly under conditions of prolonged or repeated exposure when glucocorticoid levels are consistently elevated, can have a devastating impact on health. It has been suggested that the benefits of physical exercise may lie in an ability to reduce some of the more deleterious health effects of stress and stress hormones. The present series of experiments provides evidence that voluntary exercise facilitates habituation of corticosterone but not adrenocorticotropin hormone responses to repeated stress presentations. After 6 weeks of running wheel access or sedentary housing conditions, rats were exposed to 11 consecutive daily 30 min presentations of 98 dB noise stress. Similar corticosterone responses in exercised rats and sedentary controls were observed following the first, acute stress presentation. While both groups demonstrated habituation of corticosterone secretory responses with repeated noise stress exposures, the rate of habituation was significantly facilitated in exercised animals. These results suggest that voluntary exercise may reduce the negative impact of prolonged or repeated stress on health by enhancing habituation of the corticosterone response ultimately reducing the amount of glucocorticoids the body and brain are exposed to.

Decreased Adrenocorticotropic Hormone and Cortisol Responses to Stress in Healthy Adults Reporting Significant Childhood Maltreatment

Preclinical research findings suggest that exposure to stress and concomitant hypothalamus-pituitary-adrenal (HPA) axis activation during early development can have permanent and potentially deleterious effects. A history of early-life abuse or neglect appears to increase risk for mood and anxiety disorders. Abnormal HPA response to stress challenge has been reported in adult patients with major depressive disorder and posttraumatic stress disorder. Plasma adrenocorticotropin hormone (ACTH) and cortisol reactivity to the Trier Social Stress Test were examined in healthy adults (n = 50) without current psychopathology. Subjects with a self-reported history of moderate to severe childhood maltreatment (MAL) (n = 23) as measured by the Childhood Trauma Questionnaire were compared with subjects without such a history (CTL) (n = 27). Compared with CTLs, MAL subjects exhibited significantly lower cortisol and ACTH baseline-to-peak deltas. A significant group effect was seen in the (repeated measures) cortisol response to the stress challenge, reflecting lower concentrations among MAL subjects. A significant group x time effect characterized the relatively blunted ACTH response of the MAL group. Emotional neglect (-.34, p = .02) and sexual abuse (.31, p = .03) strongly predicted maximal cortisol release. In adults without diagnosable psychopathology, childhood maltreatment is associated with diminished HPA axis response to a psychosocial stressor. Possible explanations for the finding are discussed.

Corticotropin-releasing factor test in melancholic patients in depressed state versus recovery: A comparative study

Purpose Basal adrenocorticotropin hormone (ACTH) and cortisol levels and their response to corticotropin-releasing factor (CRF) test were studied in melancholic depressive patients in depressed state and recovery, and compared with healthy controls. Methods Fifty-four outpatients diagnosed with unipolar depressive disorder with melancholic features according to DSM-IV and 23 healthy controls were included in the study. The Structured Clinical Interview for DSM-IV (SCID-IV) was used for diagnosis. Twenty-nine patients were in recovery, while 25 were in depressed state at the moment of the administration of the CRF test. Findings No differences were found between the recovered and depressed groups with respect to CRF test. Lower ACTH and higher cortisol levels with significant differences were shown in the neuroendocrine variables at 15, 30, and 60 min, and in peak response and increase, in the ACTH and cortisol response curves to CRF challenge between the groups of melancholic patients, both recovered and depressed, compared with the healthy control subjects. Moreover, recovered and depressed melancholic patients had a higher whole cortisol area under the curve with significant differences than the healthy control subjects. Conclusions The crossover clinical status at the moment of the CRF test doesn't differentiate changes in the HPA axis in melancholic patients, while we did find significant differences in the group of healthy controls in comparison with the groups of melancholic patients both in depressive state and recovery. This supports the hypothesis that hypothalamic pituitary adrenal (HPA) axis shows alterations that remain in depressive patients even after recovery.

Effects of early life stress on adult male aggression and hypothalamic vasopressin and serotonin

Early life stress in humans enhances the risk for psychopathologies, including excessive aggression and violence. In rodents, maternal separation is a potent early life stressor inducing long-lasting changes in emotional and neuroendocrine responsiveness to stress, associated with depression- and anxiety-like symptoms. However, effects of maternal separation on adult male aggression and underlying neurobiological mechanisms remain unknown. Therefore, we investigated the effects of maternal separation on adult intermale aggression in Wistar rats and on hypothalamic arginine vasopressin (AVP) mRNA expression, and AVP and serotonin (5-HT) immunoreactivity, as both AVP and 5-HT have been implicated in stress-coping and aggression. We showed that maternal separation induced depression-like behaviour (increased immobility) and higher adrenocorticotropin hormone responses to an acute stressor (forced swimming). Intermale aggression (lateral threat, offensive upright and keep down) was significantly higher in maternally separated rats compared with control rats. AVP mRNA expression and AVP immunoreactivity were higher in the hypothalamic paraventricular and supraoptic nuclei upon resident-intruder test exposure, whereas 5-HT immunoreactivity was decreased in the anterior hypothalamus of maternally separated rats. Moreover, 5-HT immunoreactivity in the anterior hypothalamus and supraoptic nucleus correlated negatively with aggression. These findings show that exposure to early life stress increases adult male aggression in an animal model of maternal separation. Furthermore, the maternal separation-induced changes in hypothalamic AVP and 5-HT systems may underlie these behavioural alterations.

61: Adolescent girls with conduct disorder: HPA axis reactivity in response to psychological stress

Previous work demonstrated HPA axis hypoactivity in the morning in girls with Conduct Disorder (CD) compared to girls with no psychiatric disorder. The purpose of this study was to further characterize HPA axis function in girls with CD, comparing them to girls who had no psychiatric illness (NC) and girls who had depression or anxiety (DEP). This report describes preliminary analyses on the first two sets of assays completed. Girls, ages 15-16 years old and in Tanner Stage V, were recruited from the community. The participants and a parent received a structured psychiatric diagnostic interview and girls were categorized into three groups: CD, n=22; DEP, n=7; NC, n=8. We used the Trier Social Stress Test (TSST) as the psychological stressor. Serum cortisol and plasma adrenocorticotropin hormone (ACTH) levels were assessed at the following times: −90, −60, 0, +15, +30, +60, and +90 minutes (0 was the beginning of the TSST). Response to the stressor was measured with area under the curve (AUC) analysis, and mean AUC was examined for a group effect. All the groups exhibited some activation of the HPA axis in response to the psychological stressor; ANOVA demonstrated a significant difference between the groups in both the ACTH and cortisol response (FACTH= 3.42; p = .05; FCortisol= 4.98; p = .01). Post-hoc analyses indicated that the girls with CD had mean AUC responses for both hormones that were significantly lower than those in the DEP group, but were not different from the NC group. The DEP group mean AUC for ACTH and cortisol were also significantly higher than those in the NC group. These preliminary findings suggest that girls with CD may have HPA axis responses to a psychological stressor that are similar to those found in girls without any psychiatric disorder. The high responsivity of the girls in the DEP group is somewhat surprising since previous studies have reported that adolescent depression is not associated with HPA axis abnormalities. All of our findings need to be further tested in a larger sample to insure generalizability. However, if we continue to find the same associations, this could have important implications in understanding the mechanisms underlying adolescent depression and anxiety in girls.

Non-associative defensive responses of rats to ferret odor

Predators and their odors offer an ethologically valid model to study learning processes. The present series of experiments assessed the ability of ferret odor to serve as an unconditioned stimulus and examined behavioral and endocrine changes in male Sprague–Dawley rats with single or repeated exposures in a defensive withdrawal paradigm or in their home cages. Rats exposed to ferret odor avoided the ferret odor stimulus more, exhibited greater risk assessment and displayed higher adrenocorticotropin hormone (ACTH) and corticosterone release compared with control odor exposed rats and these measures did not significantly habituate over repeated exposures. Ferret odor exposure did not show associative conditioning effects during extinction trials. However, rats that were pre-exposed to ferret odor only once, as compared to control and repeatedly exposed rats, displayed a sensitized ACTH and corticosterone response to an additional ferret odor exposure in small cages. These experiments suggest that ferret odor is a highly potent unconditioned stimulus that has long lasting effects on behavior and endocrine responses, and further suggests the independence of habituation and sensitization processes.

Spontaneous Recovery from Posttraumatic Hypopituitarism

Hypopituitarism is an increasingly recognized complication of traumatic brain injury that can have significant potential to impair recovery and rehabilitation in affected survivors. Although posttraumatic cranial diabetes insipidus is known to be transient in many cases, recovery of established anterior pituitary hormone deficiency is thought to be a very rare event. We report the case of a 25-yr-old man who incurred severe traumatic brain injury in 1997. Sixteen months later, dynamic pituitary stimulation tests revealed severe growth hormone and adrenocorticotropin hormone deficiency. He was treated with recombinant human growth hormone and hydrocortisone. Five years after traumatic brain injury, repeat neuroendocrine assessment, prompted by an increasing serum insulin-like growth factor-1 level, showed normal growth hormone and adrenocorticotropin hormone responses. This is the first case report, to our knowledge, to show that adult posttraumatic growth hormone deficiency can be reversible. The recognition that anterior pituitary dysfunction can recover after traumatic brain injury has implications for the follow-up of patients with hypopituitarism secondary to head trauma to avoid unnecessary, expensive, and potentially harmful therapy.

Stress-Induced Sensitization of the Hypothalamic-Pituitary Adrenal Axis Is Associated with Alterations of Hypothalamic and Pituitary Gene Expression

We have previously reported that inescapable tail shock (IS) produces persistent changes in hypothalamic-pituitary-adrenal (HPA) axis function. These changes are manifest as an elevation in basal corticosterone (CORT) levels, a sensitization of adrenocorticotropin hormone (ACTH) and CORT responses to subsequent challenge, and a failure of dexamethasone to suppress both the ACTH and CORT responses to a subsequent challenge. The experiments presented here examine IS-induced alterations in the responsiveness of the HPA axis, particularly at the level of the anterior pituitary. The data presented show that adrenalectomy does not abolish the IS-induced sensitization of the HPA axis, suggesting that the sensitization is not solely caused by a defect in glucocorticoid negative feedback. Analysis of gene expression in the anterior pituitary revealed that IS exposure persistently elevated basal levels of proopiomelanocortin (POMC; the precursor to ACTH) mRNA and sensitized the POMC hnRNA and c-fos mRNA response to a subsequent challenge. Analysis of gene expression in the parvocellular division of the paraventricular nucleus of the hypothalamus (pPVN) after IS exposure revealed that basal levels of corticotropin-releasing hormone (CRH) mature mRNA are elevated and the c-fos mRNA response to a subsequent challenge is enhanced. Finally, a blunted in vitro ACTH response to CRH challenge is observed after IS exposure. These data suggest that the ultimate source of the IS-induced sensitization is not the anterior pituitary and implicate an increased drive on the anterior pituitary from the pPVN.

Amygdalar vasopressin mRNA increases in acute cocaine withdrawal: Evidence for opioid receptor modulation

In humans, stress is recognized as a major factor contributing to relapse to drug abuse in abstinent individuals; drugs of abuse themselves or withdrawal from such drugs act as stressors. In the animals, evidence suggests that centrally released arginine vasopressin in both amygdala and hypothalamus plays an important role in stress-related anxiogenic behaviors. The stress responsive hypothalamic–pituitary–adrenal axis is under tonic inhibition via endogenous opioids, and cocaine withdrawal stimulates hypothalamic–pituitary–adrenal activity. The present studies were undertaken to determine whether: (1) 14-day (chronic) “binge” pattern cocaine administration (45mg/kg/day) or its withdrawal for 3 h (acute), 1 day (subacute) or 10 days (chronic) alters arginine vasopressin mRNA levels in amygdala or hypothalamus; (2) the opioid receptor antagonist naloxone (1mg/kg) alters arginine vasopressin mRNA or hypothalamic–pituitary–adrenal hormonal responses in acute cocaine withdrawal; and (3) there are associated changes of mu opioid receptor or proopiomelanocortin mRNA levels. In amygdala, arginine vasopressin mRNA levels were unchanged after chronic “binge” cocaine, but were increased during acute cocaine withdrawal. Naloxone completely blocked this increase. Neither chronic cocaine nor its acute withdrawal altered amygdalar mu opioid receptor mRNA levels. The increase in amygdalar arginine vasopressin mRNA levels was still observed after subacute withdrawal, but not after chronic withdrawal. Although hypothalamic–pituitary–adrenal tolerance developed with chronic “binge” cocaine, there were modestly elevated plasma adrenocorticotropin hormone levels during acute withdrawal. While naloxone produced modest adrenocorticotropin hormone elevations in cocaine-naïve rats, naloxone failed to elicit an adrenocorticotropin hormone response in cocaine-withdrawn rats. In hypothalamus, neither chronic cocaine nor acute withdrawal altered arginine vasopressin, proopiomelanocortin or mu opioid receptor mRNA levels. These results show that: (1) opioid receptors mediate increased amygdalar arginine vasopressin gene expression during acute cocaine withdrawal, and (2) cocaine withdrawal renders the hypothalamic–pituitary–adrenal axis insensitive to naloxone. Our findings suggest a potential role for amygdalar arginine vasopressin in the aversive consequences of early cocaine withdrawal.

HPA axis activation determined by the CRH challenge test in patients with few versus multiple episodes of treatment?refractory depression

In clinical guidelines, risk factors for a malignant illness course include 3 or more lifetime episodes of depression. Our aim was to investigate the activation of the hypothalamic-pituitary-adrenal hormonal axis in treatment-refractory affective disorder in pauciepisodic (one or two episodes) versus multiepisodic (three or more episodes) patients. We evaluated the HPA axis in 37 patients with treatment-refractory affective disorder and in 27 healthy volunteers by measuring adrenocorticotropin hormone (ACTH) and cortisol responses following administration of corticotropin-releasing hormone (CRH). In retrospective life charts was recorded every previous illness episode for each patient. Seven of the patients were pauciepisodic and 30 were multiepisodic. The pauciepisodic patients had significantly larger peak and total ACTH responses to CRH compared to the multiepisodic patients as well as to the control group. Multiepisodic patients showed no difference compared to controls in ACTH secretion pre- and post-CRH. Cortisol secretion was the same in all three groups. The pituitary adrenocortical responses were stronger in pauciepisodic patients than in multiepisodic patients and in volunteers. This cross-sectional study suggests that the HPA axis, in refractory multiepisodic affective disorders, might weaken its original activity as the illness recurs with more episodes.

Pharmacokinetics and pharmacodynamic response of methylprednisolone in premenopausal renal transplant recipients.

Chronic glucocorticoid therapy is prescribed in renal transplant recipients according to empiric dose-tapering schedules, which assume a similar pharmacologic response in men and women. The study objectives were (a) to compare the pharmacokinetics of methylprednisolone in premenopausal renal transplant recipients with previously studied male counterparts and (b) to describe the pharmacodynamic response of the hypothalamic-pituitary-adrenal axis during chronic steroid therapy. Thirteen stable premenopausal subjects (ages 30 to </=49 years) receiving chronic glucocorticoid therapy were evaluated for methylprednisolone, cortisol, and adrenocorticotropin hormone (ACTH) over 24 hours after an intravenous infusion of methylprednisolone sodium succinate. Most patients were evaluated during the luteal phase of the menstrual cycle. Pharmacokinetic parameters of methylprednisolone with cortisol and ACTH responses were determined. Results were compared to counterpart male subjects who participated in a prior study. The total clearance of methylprednisolone for the female subjects was 15.6 +/- 5.99 L/h compared to the males with 21.5 +/- 8.67 L/h (P <.05). When normalized for total or lean body weight, no significant difference was noted (P =.614). A 3-fold interpatient variation in weight-adjusted clearance was noted for female subjects. Dose-normalized methylprednisolone a AUC was greater in women (66.1 +/- 19.8 ng*h/mL) than men (46.4 +/- 19.7 ng*h/mL) (P =.174). Total cortisol AUC was not different between groups (P =.599). Despite chronic steroid therapy, 9 of 13 women had a normal cortisol profile and an ACTH AUC of 299 +/- 102 pg*h/mL. It was concluded that methylprednisolone clearance in women was significantly slower compared to men. When drug clearance was normalized for total and lean body weight, no gender difference was noted. These findings are in contrast to prior data indicating a more rapid methylprednisolone clearance in healthy women. These findings suggest that doses of glucocorticoids should be prescribed on a milligram/kilogram basis instead of empiric dosing schedules.

Maternal genotype influences stress reactivity of vasopressin-deficient brattleboro rats.

The role of vasopressin, cosecreted with corticotropin-releasing hormone (CRH), in stress is debated, because both normal as well as reduced adrenocorticotropin hormone (ACTH) rise to an acute challenge has been reported in Brattleboro rats genetically lacking vasopressin (di/di). Because di/di pups could be born either from di/+ (heterozygous) or from di/di mothers, and maternal influence is known to modify adult responsiveness, we investigated whether the influence of maternal genotype could explain the variability. Adult rats from mothers with different genotypes were stressed with 60 min restraint and trunk blood was collected for measuring hormone content by radioimmunoassay at the end of stress. All offspring of di/+ mothers had similar ACTH responses to restraint, while the di/di rats born to, and raised by di/di mothers showed reduced ACTH reactivity to restraint. The di/di rats showed elevated water turnover and required a daily cage cleaning every day, which meant frequent handling. To offset the role of handling, all rats had daily cage cleaning in the next series, but the results were the same as in the first series. To investigate whether lactation, the behaviour of the mother or some other factor during the pregnancy is responsible for the differences, pups from di/+ dams were raised by di/di foster mothers and vice versa. We found that the genotype of parental mother is more important than that of the foster mother. The corticosterone and prolactin elevation normally seen after acute stress was unchanged by family history, maternal or personal genotype. Furthermore, in studies with mutant animals, the rearing conditions should be controlled by the experimenter. In experiments with Brattleboro rats, the use of homozygous and heterozygous rats from the same litters of di/+ dams and di/di males is recommended. Our results suggest that vasopressin is not indispensable for ACTH release, and that the di/di genotype of the parental mother can decrease the stress reactivity of the di/di Brattleboro rats.