Negative Feedback Sensitivity Research Articles

Early environmental programming hypothalamic-pituitary-adrenal responses to stress

This paper summarizes the effects of various early environmental manipulations (infantile handling, maternal separation, neonatal immune challenge) on the development of hypothalamic-pituitary-adrenal (HPA) responses to stressful stimuli. Each manipulation results in a permanent effect on HPA responsivity to stress, although the effects qualitatively are quite different. In each case the effects are apparent in terms of different levels of activity of the corticotrophin-releasing hormone/arginine vasopressin neurons in the paraventricular nucleus of the hypothalamus. These effects, in turn, seem to be derived from changes in forebrain corticosteroid receptor systems which determine glucocorticoid negative feedback sensitivity. We feel that these effects represent examples of early environmental 'programming' of CNS function and reflect naturally-occurring plasticity in neuroendocrine defense systems. This programming also seems to have important implications for health in later life by determining vulnerability to certain forms of pathology.

Periodic maternal deprivation-induced potentiation of the negative feedback sensitivity to glucocorticoids to inhibit stress-induced adrenocortical response persists throughout the animal's life-span

In this study, it was clearly demonstrated that the enhanced negative feedback sensitivity to glucocorticoids to inhibit stress-induced adrenocortical response, which was produced by periodic maternal deprivation (PMD) treatment for the first 3 weeks of life, did persist in rats tested at 66 and 92 weeks of life, suggesting that some stressful experience during early life permanently alters the adrenocortical response to stressful stimuli. This effect of PMD was not accompanied by an increased density of glucocorticoid receptor binding sites in the hippocampus from 93-week-old rats.

Enhanced suppression of cortisol following dexamethasone administration in posttraumatic stress disorder.

The authors investigated the possibility of enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis in posttraumatic stress disorder (PTSD) by using a low dose of dexamethasone. Baseline blood samples were obtained at 8:00 a.m., and 0.5 mg of dexamethasone was administered to 21 male patients with PTSD and 12 normal age-comparable men at 11:00 p.m. Cortisol and dexamethasone levels were measured 9 and 17 hours after dexamethasone administration. After correction for differences in dexamethasone levels, the PTSD patients showed greater suppression of cortisol in response to dexamethasone than did the normal subjects. This was true even in patients meeting concurrent diagnostic criteria for major depression. The data support earlier studies showing that HPA abnormalities in PTSD are different from those seen in depression and suggest that the low-dose dexamethasone suppression test may be a potentially useful tool for differentiating the two syndromes and further exploring differences in their pathophysiology.

The effect of testosterone on serum gonadotropins of castrated rats kept under different lighting conditions.

Testosterone feedback sensitivity was measured as the ability of testosterone propionate to decrease serum LH and FSH of long-term castrated (4 wk) rats under four different lighting conditions: periodic light (12L:12D), constant light (LL), constant darkness (DD), and dim night illumination (1 lx) with a 12L:12D photoperiod. Rats were exposed to the different lighting conditions for 1 wk, during which they received daily testosterone propionate (125 micrograms or 250 micrograms s.c.). At the end of the experiment the rats were decapitated at 1100 h, and serum gonadotropin levels were measured by RIA. Serum LH of the rats kept under LL was reduced to the level of the intact rats with the smaller testosterone dose (125 micrograms/day). Under all other lighting conditions only the large dose (250 micrograms/day) was able to restore the serum LH concentration to the level of the intact rats. Serum FSH was restored only partially, and the effect was the same with both doses and similar under all lighting conditions. We conclude that the increase in testosterone negative feedback sensitivity was not caused by the lack of periodicity of illumination alone, but that sufficient intensity of lighting throughout the 24 h was needed as well.

Basal ACTH, corticosterone and corticosterone-binding globulin levels over the diurnal cycle, and age-related changes in hippocampal type I and type II corticosteroid receptor binding capacity in young and aged, handled and nonhandled rats.

Basal corticosterone (B) levels increase with age in the rat, a result of decreased negative-feedback inhibition of hypothalamic-pituitary-adrenal (HPA) activity. Postnatal handling increases CNS negative-feedback sensitivity and appears to attenuate some of the changes occurring in the HPA axis in later life. In the experiments described here, we have examined basal HPA function in young (6-8 months) and old (22 months), handled (H) and nonhandled (NH) rats in relation to changes in corticosteroid receptor binding. Among young animals, there were no group differences in basal adrenocorticotropin (ACTH) or B levels at any point in the diurnal cycle. In contrast, plasma ACTH and B levels during the PM phase were significantly higher in old NH animals in comparison to old H animals and to both groups of young animals. The H and NH groups did not differ in in vivo adrenal responsiveness to exogenous ACTH. As expected, ACTH sensitivity was greater in all groups during the PM phase and in general, old animals showed a greater response to ACTH regardless of the treatment group. There were no differences across the groups in AM plasma corticosterone-binding globulin (CBG) levels. However, during the PM phase of the cycle, CBG levels were significantly lower and the percentage of B in the free form was significantly higher in the old NH animals. As expected, levels of free B during the PM phase of the cycle were significantly higher in the old NH animals. Thus, there is a significant increase in the PM corticoid signal in the old NH animals that occurs as a function of elevated B and decreased CBG levels; these age-related changes in basal HPA activity were not seen in the old H animals. Type I (mineralocorticoid-like) receptor binding in the hippocampus did not differ as a function of handling and was significantly reduced with age in both H and NH animals. Type II (glucocorticoid) receptor binding decreased as a function of age in both H and NH animals, but was consistently higher in the H animals. There were no differences in type II receptor binding in the hypothalamus or pituitary as a function of age or handling. These data suggest that the increase in basal HPA activity occurring in aged rats is largely restricted to the dark phase of the cycle and is attenuated by postnatal handling, a treatment that increases hippocampal type II corticosteroid receptor binding.

Lymphocyte glucocorticoid receptor number in posttraumatic stress disorder

The authors' objective was to investigate the possibility that glucocorticoid receptor changes may be involved in the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in posttraumatic stress disorder (PTSD). They measured the number of lymphocyte cytosolic glucocorticoid receptors and plasma cortisol concentrations in 15 consecutively admitted male combat Vietnam veterans with PTSD and in a normal comparison group of 11 subjects. Both the patients and the normal comparison subjects showed a morning-to-afternoon decline in glucocorticoid receptor concentrations, paralleling the normal diurnal decline in cortisol levels. The number of glucocorticoid receptors was 63% greater in the morning and 26% greater in the afternoon in the patients with PTSD than in the normal subjects. No group differences in cortisol levels were observed, nor were glucocorticoid receptor number and cortisol levels correlated. The number of morning glucocorticoid receptors was positively correlated with symptoms of PTSD and anxiety. These results provide further evidence for a dysregulation of the HPA axis in PTSD. The finding that patients with PTSD had a substantially greater number of lymphocyte glucocorticoid receptors than normal comparison subjects is consistent with the authors' previous observations of low 24-hour urinary cortisol excretion in subjects with PTSD. Furthermore, the receptor changes observed are opposite of those reported in major depressive disorder. The present data, along with other findings of HPA abnormalities in PTSD, support the possibility of a greater negative feedback sensitivity at one or more levels of the HPA axis.

Evidence that desensitization of the negative feedback of oestrogen and priming for the positive feedback of oestrogen depend upon a common mechanism of oestrogen action in rats

Oestrogen priming of the central nervous system is required for the positive feedback of oestrogen, and the sensitivity of the negative feedback of oestrogen can be reduced by oestrogen itself. Using adult female and male rats we examined the possibility that these effects depend upon a common mechanism of oestrogen action that is mediated by the medial preoptic area (MPOA). Guide cannulae were implanted in the MPOA of 4-day cyclic rats which were ovariectomized during the evening of day 1 of dioestrus. Glass capillary tubes containing different substances were placed in the cannulae between 09.00 and 12.00 h on the presumptive day 2 of dioestrus. The effectiveness of oestrogen priming was evaluated by examining whether an s.c. implant of oestradiol-17 beta (OE2) induced an LH surge, and the inhibitory effect of oestrogen on tonic LH secretion was investigated by injecting the rats with 3 micrograms oestradiol benzoate (OB)/100 g body weight. The priming effect of an s.c. implant of OE2 could be imitated by the bilateral implantation in the MPOA of a mixture of OB and cholesterol at a ratio of 1:360 for 3 h only. Similar medial preoptic oestrogen implantation also significantly reduced the LH-inhibiting effect of OB. In accord with findings obtained in former studies on desensitization of the negative oestrogen feedback, oestrogen priming resulting from the s.c. administration of OE2 could be suppressed by short-term medial preoptic implantation of clomiphene citrate or apomorphine; bilateral electrical stimulation of the medial amygdaloid nucleus induced an increase in the serum concentration of LH in ovariectomized females implanted with OB in the MPOA, but not in castrated males pretreated and implanted with OB.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in Glucocorticoid Receptor Number in the Hypothalamus and Pituitary of the Sheep Fetus with Gestational Age and after Adrenocorticotropin Treatment*

The concentrations of ACTH and cortisol both rise in the plasma of fetal lambs during late pregnancy, reflecting maturation of the fetal hypothalamic-pituitary-adrenal axis and providing the stimulus for parturition. The failure of rising cortisol to suppress plasma ACTH may be due to altered sensitivity of glucocorticoid negative feedback. To examine the possibility that this effect might be mediated through changes in the number of glucocorticoid receptors (GR) in the fetal hypothalamus and pituitary, we measured changes in GR number in these tissues from fetuses at discrete times of pregnancy between day 60 and term (day 145) and from newborn lambs and adult sheep. We also determined the effect of intrafetal ACTH administration in amounts known to produce premature parturition on GR number in fetuses at days 125-130 of gestation. Binding of [1,2,4-N-3H]triamcinolone acetonide to dispersed cell preparations of fetal pituitary and hypothalamus was saturable, temperature dependent, glucocorticoid specific, and of high affinity (2-3 X 10(-9) M). The number of GR in the pituitary always exceeded that in the hypothalamus. In both tissues GR number rose between days 60-70 to highest values on days 100-110, then decreased until day 125. GR number in the pituitary rose again at term, paradoxically at a time of rising endogenous glucocorticoid levels. However, after ACTH administration, there was a significant decrease in GR number in both hypothalamus and pituitary. These results indicate that altered efficacy of glucocorticoid negative feedback in term fetuses is not due to a decrease in pituitary or hypothalamic GR number. The rise in GR number at term and the fall after intrafetal ACTH treatment raises the possibility that mechanisms exist in the fetus allowing normal autoregulation of GR to be overridden at term.

Opiate-Thyroid Hormone Interactions in the Regulation of Thyrotropin Secretion in the Rat

Studies were performed to determine the role of thyroid hormone in the suppression of thyrotropin (TSH) by opiates. Serum samples were collected by decapitation 1, 3, 6, 12, 24, or 48 h after rats were implanted with 1 sustained-release morphine (75 mg) or placebo pellet. Morphine decreased TSH by 44% at 1 h and by 83% at 3 h, and TSH remained significantly depressed by 38% through 48 h. Thyroxine (T4) levels were significantly reduced from 12 to 24 h after morphine, but triiodothyronine (T3) levels were not affected. When control or thyroidectomized (THX) rats were implanted with morphine or placebo 24 h before serum collection, morphine significantly decreased TSH, T3 and T4 in controls but had no effect on TSH in THX rats. Thus, it appears that the morphine-induced suppression of TSH release requires circulating thyroid hormone. When THX rats were chronically treated with morphine or placebo, then injected subcutaneously with saline or 1, 10 or 100 micrograms T4/kg body weight 24 h prior to serum collection, morphine treatment alone did not affect TSH in THX rats. T4 replacement caused a dose-dependent decrease in serum TSH in both morphine and placebo rats; however, TSH was suppressed significantly more in morphine than in placebo rats. Thus, while chronic morphine treatment is ineffective in suppressing in TSH in THX rats, morphine interacts with thyroid hormone to reduce TSH release. These data suggest that morphine may exert its inhibitory effect on TSH secretion by increasing the negative feedback sensitivity to thyroid hormones.

Effect of food manipulation on the GnRH-LH-estradiol axis of young female rats.

Female rats were prevented from growing and developing reproductively by restricting their food intake from the time they reached 80-85 g (27-29 days of age) until they were 2 mo old. A return to ad libitum feeding then typically yielded the pubertal ovulation during the third or fourth dark period. Ad libitum feeding for 48 h increased the frequency of luteinizing hormone (LH) pulsing in ovariectomized females. This treatment also depressed the level of circulating estradiol in ovariectomized females implanted with Silastic capsules. It had no effect on the rate at which estradiol was cleared from the blood in a 1-h test, however, nor did it affect the pool of assayable gonadotropin-releasing hormone (GnRH) in the hypothalamus, the pool of assayable LH in the pituitary, the response of the pituitary to GnRH, or the rate at which LH was cleared from the blood. In toto, the present results suggest that food restriction inhibits pubertal development by acting rather specifically on GnRH secretion via an ovarian steroid-independent pathway. The presumed supplemental role for enhanced negative-feedback sensitivity could not be evaluated because of the aberrant results with encapsulated estradiol.

The endocrine function of rat gonads with reduced number of germ cells following busulphan treatment.

The endocrine function of rat gonads with an experimentally reduced number of germ cells was examined to analyse the effect of germ cells on the surrounding somatic endocrine cells. Pregnant Wistar rats received a single i.v. injection of 10 mg/kg B.W. of Busulphan on day 15 of gestation to prevent fetal primordial germ cells from starting mitotic division. The gonadal growth and the number of germ cells in Busulphan-treated rats (B-rats) were severely arrested. Almost a normal testicular structure was formed in the males, while few follicular structures were formed in the females, suggesting that the presence of oocytes in the fetal ovary is a prerequisite to the formation of the follicle. The meiotic division of spermatogonia in B-rats, which started on day 20 as in controls, stopped before the completion of spermatogenesis, and germ cells disappeared by day 50. The remaining germ cells and the associated follicles in female B-rats also disappeared by day 60 after repeating irregular estrous cycles for approximately 1 month. Thereafter the ovary consisted of fibroblasts and morphologically interstitial-like cells. Vaginal opening occurred in B-rats on day 28-30, a-week earlier than in controls. Changes in serum GTH after ovariectomy and the estradiol treatment suggested the maturation of the negative feedback sensitivity to estradiol in this period, and besides, earlier estradiol production with less dependency on gonadotropin. The vaginal epithelium of B-rats was cornified continuously after day 60. The ovarian cells in this period did not luteinize either morphologically or functionally in response to an ovulatory dose of hCG. During the same period, the conversion rate from progesterone to estradiol in ovarian homogenates of B-rats was considerably higher than those of controls at any stage of the estrous cycle. High content of estradiol was detected in the testes of B-rats at any age. In male B-rats, both LH and FSH levels in serum were higher than controls. The serum testosterone concentration in B-rats was lower than the normal, while the testicular testosterone content was greater. In conclusion, with a decreased number of germ cells, the rat gonads of both sexes secrete estradiol very efficiently.

Photoperiod-dependent negative feedback effects of thyroid hormones in Fundulus heteroclitus

In Fundulus heteroclitus, an annual cycle in the response of the thyroid to ovine thyroidstimulating hormone (oTSH) is characterized by maximal thyroxin (T 4) secretion in midwinter and minimal T 4 secretion in summer. Four daily injections of oTSH, given in winter caused serum T 4 to plateau at elevated levels for several days, while in summer fish similar treatment resulted in far more fluctuating titers of serum T 4; maximum levels were similar in both groups. The difference in sustenance rather than magnitude of Peak T 4 led to an examination of the negative feedback effects of thyroid hormones as they might relate to these seasonal changes. Radioiodine uptake by thyroid follicles served as a simple, but effective bioassay for endogenous TSH. Fish collected in summer were more sensitive to negative feedback of T 3 than those collected in winter; feedback effects of T 4 in the two groups were not significantly different. The effects of specific photoperiods on negative feedback sensitivity to T 3 and T 4 were also tested. Exposure of winter fish for one month to long days (LD 14:10) enhanced the degree of reduction of iodine uptake caused by T 4 in the aquarium water (10 μg/100 ml). Negative feedback in short-day (LD 8:16) winter fish was not demonstrated. It is concluded that long days increase and short days diminish the negative feedback sensitivity of the hypothalamus-pituitary axis to thyroid hormones in F. heteroclitus. Such photoperiodically induced changes may act to aid in the year-round maintenance of T 4 levels necessary for seasonal adaptation and survival.