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Biomedical subjects

A Winokur

Publications and source records attributed to A Winokur.

At least 37 records · Page 2Linked to original sources
PubMed1989

Enhanced adrenocortical sensitivity to submaximal doses of cosyntropin (alpha1-24-corticotropin) in depressed patients.

There is evidence that excessive cortisol secretion in depressed patients might result, in part, from an enhanced adrenocortical sensitivity to corticotropin. This phenomenon has been examined using the cosyntropin (alpha1-24-corticotropin) stimulation test. Most studies have used supramaximal doses of cosyntropin administered in the morning, when adrenal sensitivity to corticotropin is at its maximum. This could partially obscure subtle differences in adrenocortical sensitivity in depression that might otherwise be evident at lower cosyntropin doses given later in the day. To test this hypothesis, we administered two consecutive cosyntropin tests on separate occasions employing a submaximal 0.05-microgram/kg dose and a maximal 0.2-microgram/kg dose. The cortisol centered cumulative response over 240 minutes was measured after each test in 12 depressed patients (7 melancholic, 5 nonmelancholic) and 6 healthy volunteers. When the difference in mean cortisol centered cumulative response values was determined, healthy controls demonstrated a significant increase in cortisol centered cumulative response, while the nonmelancholic patients had a less robust increase in cortisol centered cumulative response. In contrast, the melancholic patients demonstrated cortisol responses similar to those of the healthy subjects after each cosyntropin dose, suggesting an enhanced adrenocortical sensitivity to corticotropin. These data support the hypothesis that increased glucocorticoid secretion in depression may result from abnormalities at several sites within the hypothalamic-pituitary-adrenocortical axis.

Adrenal Cortex↗
PubMed1989

Multiple hormone responses to clonidine administration in depressed patients and healthy volunteers.

Abnormalities in several hypothalamic-pituitary-target organ axes in depression may reflect alterations in central neurotransmitter receptor function. As the alpha 2-adrenergic receptor has been implicated in a variety of neuroendocrine abnormalities in depression, we assessed the role of alpha 2-adrenoceptor dysfunction in mediating response abnormalities of growth hormone, cortisol, and prolactin after intravenous clonidine administration (an alpha 2-adrenergic receptor agonist) in 18 patients with major depression (12 with melancholic features, 6 without melancholic symptoms) and 9 healthy volunteers. In particular, we examined the hypothesis that these abnormalities might be more evident in patients with DSM-III melancholic depression. After clonidine, the mean growth hormone response was significantly lower in melancholic depressives compared to controls (p = 0.02), and the shape of the growth hormone response profile was also significantly different in melancholic patients (p = 0.04). There was an overall decrease in the mean cortisol concentration after clonidine in melancholic patients and control subjects (p = 0.02), as well as a larger cumulative prolactin response in melancholic patients compared to those without melancholic features (p = 0.02). The present results confirm prior observations of a blunted growth hormone response after clonidine and suggest that alterations in alpha 2-adrenergic receptor activity might also contribute to several neuroendocrine abnormalities in patients with melancholic depression.

Adult↗
PubMed1989

The assessment of abnormalities in hormonal responsiveness at multiple levels of the hypothalamic-pituitary-adrenocortical axis in depressive illness.

A substantial body of data suggests that excessive cortisol secretion in depression may result from dysregulation at several sites within the hypothalamic-pituitary-adrenocortical (HPA) axis. The alterations in regulatory mechanisms are thought to result from a limbic system-hypothalamic "overdrive" of corticotropin-releasing hormone (CRH). We also have demonstrated that excessive secretion of cortisol may result from an abnormal adrenocortical responsiveness to adrenocorticotropic hormone (ACTH), and we have postulated that corticotropic cells within the pituitary mediate between excessive secretion of CRH from the hypothalamus and hypercortisolemia secondary to adrenocortical hyperplasia and enhanced sensitivity to ACTH at the adrenal cortex. The present report describes a series of clinical experiments utilizing several neuroendocrine probes, as well as computer-assisted tomography, to examine the complexities of the HPA axis dysregulation in depression. These studies support the hypothesis that a limbic system-hypothalamic disturbance results in excessive CRH secretion as well as enhanced adrenocortical activity, and that these factors contribute to excessive cortisol secretion in patients with depression. These data further support the hypothesis that endogenous affective disorders are best characterized in the framework of a generalized biological disturbance of HPA axis function which involves both central and peripheral endocrine sites.

Adrenocorticotropic Hormone↗
PubMed1989

Factors contributing to erythrocyte lithium-sodium countertransport activity in lithium-treated bipolar patients.

Clinical and biochemical factors related to the activity of the erythrocyte lithium-sodium countertransport (LSC) system were investigated during lithium prophylaxis in 27 patients (13 male, 14 female) with bipolar affective illness. No relationship was found between erythrocyte LSC and such factors as age, gender, duration of lithium prophylaxis, quality of prophylactic lithium response, and family history of affective illness. There was a significant negative correlation between the activity of LSC and the magnitude of the erythrocyte lithium ratio both in whole group and in female patients. In seven patients with concomitant hypertension, the relationship between high activity of LSC and hypertension was not demonstrated. The levels of total cholesterol, HDL cholesterol, triglycerides, and potassium related neither to LSC activity nor to hypertension. Erythrocyte LSC in patients with lower TSH levels were significantly reduced compared to patients with higher TSH. The values of TSH were negatively correlated with T4 but not with T3. Concentrations of T3 were positively correlated with plasma total cholesterol levels. These results are discussed in the view of recent findings on erythrocyte LSC.

Adult↗
PubMed1989

TRH and TRH receptors in the spinal cord.

Over the past 12 years, substantial progress has been made in delineating the localization of TRH and TRH receptors in spinal cord. High concentrations of both the peptide and its receptor have been observed in the ventral horn in the region of the motoneurons and in the dorsal horn in the substantia gelatinosa. As noted, pharmacological effects of TRH administration on various parameters of spinal cord function have been reported in a number of studies. To date, however, substantial questions remain regarding the physiological role of TRH in the spinal cord. Nevertheless, it is hoped that the extensive information that has been obtained on localization of TRH and TRH receptors in spinal cord will provide a basis for answering these complex questions.

Animals↗
PubMed1988

Organization of dopamine D1 and D2 receptors in human striatum: receptor autoradiographic studies in Huntington's disease and schizophrenia.

The technique of quantitative autoradiography was used to examine the effects of Huntington's disease (HD) and schizophrenia on the organization of striatal dopamine (DA) D1 and D2 receptors. Whereas the striatum of HD cases showed a reduction in the density of D1 ([3H]SCH 23390) and D2 ([3H]spiroperidol) receptors, the patterning of D2 receptor loss did not match that of the D1 receptor loss. The HD loss of D1 D1 receptors (65%) is far greater than the loss of D2 receptors (28%). Whereas there was a dorsal-ventral gradient of effect on both receptor subtypes, the effects of HD on D2 receptors in the ventral putamen (PUT) and nucleus accumben septi (NAS) were minimal. Similarly, muscarinic M1 and M2 receptors demonstrate different patterns of alteration in HD. The M2 subtype, labeled with [3H]N-methylscopolamine (in the presence of excess pirenzepine to occlude M1 sites), was depleted far more than the M1 receptor subtype, labeled with [3H]pirenzepine. Although the effects of HD on [3H]mazindol labeling of DA terminals were more heterogeneous, there appeared to be a relative preservation of this afferent input to the striatum of the HD cases. In the schizophrenic cases, our autoradiographic studies confirm previous reports of an elevation of D2 receptor density in the striata of many schizophrenics. This increase was evident even though two of the three cases were known to have not been treated with neuroleptics, and the third case may also have been drug naive. However, the increase was far greater in the NAS (164%) and ventral PUT (173%) than more dorsally in the striatum (68%). The density of D1 receptors and DA terminals labeled with [3H]mazindol in the striatum of schizophrenics was not significantly different from that of control cases. Thus in both HD and schizophrenia, the ratio of D2/D1 receptors is altered in favor of the D2 population, particularly in the NAS.

Aged↗
PubMed1988

Characterization of thyrotropin-releasing hormone in the central nervous system of African lungfish.

Central administration of thyrotropin-releasing hormone (TRH) produces potent effects on various physiological parameters, such as arousal, respiration, and cardiovascular function, in several species. As part of an investigation into the evolution of this tripeptide as a central modulator of these parameters, we examined its distribution in the central nervous system of the African lungfish (Protopterus). Lungfish brains were dissected into three regions: telencephalon, diencephalon, and medulla. Each region was assayed for TRH by radioimmunoassay and for norepinephrine, dopamine, and serotonin by HPLC/electrochemical methods. TRH immunoreactivity (IR-TRH) was present in all regions of lungfish brain examined. The telencephalon contained the highest concentrations of TRH, the diencephalon also contained a high concentration of TRH, and the medulla contained a markedly lower concentration. Similar concentration gradients (telencephalon greater than diencephalon greater than medulla) were observed for norepinephrine, dopamine, and serotonin. The identity of IR-TRH as authentic TRH was confirmed by elution profiles on HPLC. The results of this investigation demonstrated that TRH and the monoamine neurotransmitters are present in high concentrations in various regions of lungfish brain. The lungfish may represent a promising model for further studies of the interactions of TRH with these neurotransmitter systems.

Animals↗
PubMed1988

Effects of thyroid hormones on skeletal muscle bioenergetics. In vivo phosphorus-31 magnetic resonance spectroscopy study of humans and rats.

The pathophysiology of the myopathy in dysthyroid states is poorly understood. We therefore tested the effects of thyroid hormones on muscle bioenergetics in humans and rats, using in vivo 31P NMR. Two hypothyroid patients had: low phosphocreatine to inorganic phosphate ratio (PCr/Pi) at rest, increased PCr depletion during exercise and delayed postexercise recovery of PCr/Pi. Eight thyroidectomized rats did not show abnormalities at rest, but muscle work induced by nerve stimulation resulted in a significantly (P less than 0.0001) lower PCr/Pi (35-45% of control) at each of the three stimulation frequencies tested (0.25, 0.5, and 1.0 Hz). Recovery rate was markedly slowed to one-third of normal values. Thyroxine therapy reversed these abnormalities in both human and rat muscle. Five patients and six rats with hyperthyroidism did not differ from normal controls during rest and exercise but had an unusually rapid recovery after exercise. The bioenergetic abnormalities in hypothyroid muscle suggest the existence of a hormone-dependent, reversible mitochondrial impairment in this disorder. The exercise intolerance and fatigue experienced in hypothyroid muscle may be due to such a bioenergetic impairment. The changes in energy metabolism in hyperthyroid muscle probably do not cause the muscular disease in this disorder.

Adult↗
PubMed1988

Insulin resistance after oral glucose tolerance testing in patients with major depression.

An association between affective disorders and alterations in glucose utilization has been recognized. The authors administered a 5-hour oral glucose tolerance test (GTT) to 28 depressed patients and 21 healthy volunteer control subjects and measured serum glucose as well as plasma insulin and glucagon responses. Depressed patients demonstrated significantly higher basal glucose levels, greater cumulative glucose responses after the GTT, and larger cumulative insulin responses after the GTT than control subjects. Values for cumulative glucagon did not significantly differ between groups. These findings indicate the presence of a functional state of insulin resistance during major depressive illness and suggest the presence of a more generalized biological disturbance in some depressed patients.

Administration, Oral↗
PubMed1988

Alterations in receptors for thyrotropin-releasing hormone, serotonin, and acetylcholine in amyotrophic lateral sclerosis.

We utilized quantitative autoradiography to examine thyrotropin-releasing hormone (TRH) receptors, serotonin type 1A (5-HT1A) receptors, muscarinic cholinergic receptors, choline uptake sites, beta-adrenergic receptors, and norepinephrine uptake sites in discrete laminae of spinal cord from patients with amyotrophic lateral sclerosis (ALS) and non-neurologic controls. We found decreases of over 50% in the concentration of TRH receptors in lamina IX of cervical, thoracic, and lumbar spinal cord from ALS patients. Similar reductions were noted in concentrations of muscarinic cholinergic receptors in lamina IX of spinal cords from ALS patients. Significant increases of up to 140% in 5-HT1A receptor densities were noted in lamina IX of spinal cords from ALS patients. No differences were noted between the concentrations of beta-adrenergic receptors or norepinephrine uptake sites in patients with ALS and controls. These findings suggest that TRH and 5-HT may be involved in the pathophysiology of ALS, and act in a comodulatory role in the normal spinal cord.

Amyotrophic Lateral Sclerosis↗
PubMed1987

Pituitary and adrenocortical responses to the ovine corticotropin releasing hormone in depressed patients and healthy volunteers.

It has been suggested that limbic system-hypothalamic "overdrive" may be the underlying mechanism causing an augmented secretion of corticotropin releasing hormone (CRH), heightened adrenocortical responsiveness to corticotropin (adrenocorticotropic hormone) (ACTH), and alteration in cortisol feedback regulatory mechanisms as demonstrated by the dexamethasone suppression test. We examined pituitary and adrenocortical responses after morning administration of ovine CRH (oCRH) in 26 depressed patients and 11 healthy volunteers. Basal plasma ACTH concentrations were similar in both groups, whereas patients had a significantly diminished cumulative ACTH response after administration of oCRH. In contrast, basal total cortisol concentrations and cumulative cortisol responses to oCRH were similar in depressed patients and controls. Patients with melancholic features demonstrated the most profound ACTH blunting after oCRH, whereas patients separated according to dexamethasone suppression test results had similar ACTH and cortisol responses to oCRH. The present results extend data from prior studies utilizing oCRH in the evening and demonstrate a dysregulation of the functional integrity of the hypothalamic-pituitary-adrenocortical axis in depressive illness after a morning oCRH test at both central and peripheral hypothalamic-pituitary-adrenocortical axis sites.

Adrenocorticotropic Hormone↗
PubMed1987

Assessment of adrenal gland volume by computed tomography in depressed patients and healthy volunteers: a pilot study.

Excessive adrenocortical activation in depression has been postulated to be the result of overactivity of limbic system-hypothalamic function. In contrast, several studies have suggested the possibility that excessive secretion of cortisol might also result, in part, from a heightened adrenocortical responsiveness to adrenocorticotropic hormone (ACTH), or even a mild adrenal hyperplasia. Because computed tomography (CT) may provide a method for assessing an increase in adrenal size, we performed CT scans of the adrenal glands in depressed patients and healthy volunteers, who also received the dexamethasone suppression test. Eight out of 16 patients (50%) had adrenal volumes in excess of the 95th percentile value of the control distribution for adrenal volume. These observations suggest that there may be demonstrable adrenal hypertrophy during depressive illness.

Adrenal Glands↗
PubMed1987

The ACTH stimulation test before and after clinical recovery from depression.

Excessive cortisol secretion after cosyntropin (adrenocorticotropic hormone; ACTH) infusion in some depressed patients has suggested the possibility that the adrenal cortex may have heightened responsiveness to ACTH, and that this may contribute, in part, to activation of the hypothalamic-pituitary-adrenocortical axis. We administered an ACTH test and dexamethasone suppression test (DST) to 32 patients before and after treatment. Maximal cortisol response to ACTH demonstrated a significant decrease after treatment in the subgroup of melancholic/DST nonsuppressors (p = 0.04). When the cumulative cortisol response (CCR) to ACTH was examined, the DST nonsuppressors had a greater CCR decrease than suppressors (p = 0.03), and the melancholics a greater decrease than nonmelancholics (p = 0.02). The melancholic/DST nonsuppressor subgroup had the largest CCR decrease after treatment (p = 0.03), and these patients may represent a group of depressives with altered adrenocortical function that tends to "normalize" with clinical recovery.

Adrenocorticotropic Hormone↗
PubMed1987

Neuroendocrine responses to cold stress in normal subjects and depressives.

In order to assess the effects of cold stress on neuroendocrine function in persons with affective disorders, 11 normal subjects and eight depressed patients were subjected to a well-defined thermal stress in a cold chamber at 10 degrees C. Metabolic rate, skin and rectal temperature, and TSH, T4, T3, growth hormone, prolactin, and cortisol were measured simultaneously for 45 minutes prior to cold exposure and for 60 minutes in the cold. All subjects experienced robust changes in skin temperature and metabolic rate during cold exposure, while maintaining core temperature throughout. There were no changes in any of the neuroendocrine parameters during exposure to cold stress in either the controls or the depressives, although depressives had somewhat higher T4 and lower T3, TSH, and GH throughout the study. These findings indicate that hormones of these neuroendocrine axes are unresponsive to acute, moderate cold stress in normal man and that depressives show no greater reactivity than normals.

Acclimatization↗
PubMed1987

Treatment of experimental spinal trauma with thyrotropin-releasing hormone: central serotonergic and vascular mechanisms of action.

The sites and mechanisms by which thyrotropin-releasing hormone (TRH) may ameliorate the effects of spinal cord contusion were studied in the rabbit. We have examined the actions of an effective intravenous TRH infusion on the spinal content and utilization of the monoamine neurotransmitters (norepinephrine [NE], dopamine [DA], and serotonin [5-HT]) in both control and injured animals. The ability of TRH to penetrate the blood-brain barrier was determined by the measurement of spinal cord TRH immunoreactivity and the effect of TRH upon the development of traumatic edema was evaluated. TRH was found to enter the spinal cord to a large extent in approximately half the animals, but to a lesser degree in the remainder. This indicates the potential for a central site of action. In this regard, TRH induced a significant increase in the metabolism or utilization of 5-HT above the injury site. This effect was not observed in control animals. Finally, TRH was able to cancel the formation of edema at the injury site. These results are correlated with previously described mechanisms and are discussed in terms of the co-existence of TRH and 5-HT in raphe-spinal neurons descending from the medulla.

Animals↗