Hypothalamic Syndrome Research Articles

Relationship of thyroid hormones and norepinephrine to the lateral hypothalamic syndrome

The role of thyroid hormones and norepinephrine in the elevated thermogenesis seen following lateral hypothalamic (LH) lesions was investigated by measuring serum thyroid hormone levels and urinary norepinephrine excretion during the 24 hours following placement of LH lesions and again one month later when body weight had stabilized at a reduced level. During the first 24 hours following LH lesions, serum thyroxine (T 4) and triiodothyronine (T 3) were significantly depressed. By one month postlesion, both T 4 and T 3 had returned to normal. In contrast, urinary excretion of norepinephrine (NE) was increased 100% during the 24 hours following LH lesions. By one month postlesion, NE had returned to normal levels. These results indicate that the elevated thermogenesis seen shortly following LH lesions does not reflect enhanced thyroid activity, but is probably a consequence of sympathetic nervous system stimulation. The return of NE to normal levels after one month is consistent with the observation that LH-lesioned rats are by one month postlesion no longer hypermetabolic, but display levels of heat production appropriate to the reduced body weight they then maintain.

Control of sensorimotor function by dopaminergic nigrostriatal neurons: Influence on eating and drinking

The literature on the effects of lesions of the lateral hypothalamic area (LHA) on eating and drinking is reviewed in an effort to understand the function of the neural substrate destroyed. The data suggest that damage to the dopaminergic nigrostriatal neurons that course through the LHA results in a decrease in sensorimotor facilitation; that is, an increase in the threshold for responding to stimuli that elicit orientation, approach and consumption. This increase results in decreased consumption of food and water. Evidence is also reviewed suggesting the possibility that striatal dopaminergic activity may mediate a negative feedback signal related to blood glucose level that influences responsiveness to food, and therefore eating. There is no evidence that the nigrostriatal system mediates a similar signal related to water balance and drinking. A second deficit associated with LHA lesions, caused by damage to the pallidofugal neurons that descend through this area, is a dysfunction of motor control of the head and mouth. This results in an increase in the effort required to consume food and water, also leading to decreased consumption. These two behavioral factors: an increased threshold for responding to the sensory properties of food and water and an increase in the effort required to eat and drink are used to explain the symptoms making up the lateral hypothalamic syndrome without postulating changes in physiological regulatory (set point) mechanisms.

40 hGH RESPONSE TO GH-RH 1–44 IN OBESITY OF VARIOUS ETIOLOGIES

Fourteen juveniles with obesity were tested with i.v. GH-RH 1-44 (1 mcg/kg). Seven had simple obesity and in the other 7 the obesity was associated with the following syndromes: Prader-Willi (n=4); Laurence Moon Biedle (n=1); hypothalamic syndrome (n=2). The overweight (Owt) SDS was calculated by substracting height SDS from weight SDS. The subjects were grouped according to the diagnosis and Owt SDS (Table). In simple obesity (Gr. 1+2) there was a good response of hGH to GH-RH (11.8±5.8 ng/m1) whereas in the syndromes (Gr. 3+4) there was a poor response (3.2±2.1 ng/ml p < 0.01). In groups 2 & 3 there was a similar Owt SDS, but different etiologies of the obesity with a significantly reduced hGH response in the syndromes (Gr. 3; p < 0.01). Though the blunted response of hGH to pharmacologic stimuli as well as to sleep and GH-RH in obesity is related to the degree of Owt, it is concluded that additional factors contribute to the pattern of hGH secretion and response in obesity.

Ventromedial and dorsomedial hypothalamic syndromes in the weanling rat: Is the “center” concept really outmoded?

This report juxtaposes findings from weanling rats with precise lesions in the Ventromedial (VMNL rats) to data of weanling rats with lesions in the dorsomedial (DMNL) hypothalamic nuclei. Despite the proximity of the two nuclei their destruction produces opposite effects in most cases but similar responses in other parameters. Absolute and relative food intake are normal in VMNL rats yet they become obese in the face of normal body weight gains. DMNL rats show both reduced absolute food intake and body weight but normal relative food intake and body composition. Both VMNL and DMNL cause reduced linear growth and running wheel activity. DMNL rats defend their lower body weight set point against various challenges and maintain normal body composition. Organ growth in both absolute and relative terms is reduced in VMNL rats. In DMNL rats relative organ growth is normal. Pancreatic growth, protein/pancreas and content and concentrations of several pancreatic enzymes are normal in DMNL but reduced in VMNL rats. Mean 24-hour plasma growth hormone (GH) and corticosterone (B) levels are reduced and insulin levels are greatly elevated in VMNL rats; prolactin (PRL) levels are normal. In DMNL rats. GH, B, insulin and somatomedin activity are normal but PRL is elevated. Circadian rhythms of GH, insulin and triiodothyronine are normal in DMNL rats but B levels are disrupted, as they are in VMNL rats. Glucose incorporation and oxidation in adipose tissue of VMNL rats are enhanced in VMNL rats but normal in DMNL rats. Gluconeogenesis in VMNL rats is enhanced as early as 4 hours post-operatively; in DMNL rats it is normal at this time and several weeks thereafter. Basal lipolysis in epididymal fat pads is elevated in both VMNL and DMNL rats but epinephrine-stimulated lipolysis is elevated in VMNL and decreased in DMNL rats. Both VMNL and DMNL rats show normal basal and epinephrine-stimulated lipolysis in interscapular brown adipose tissue. Several hepatic enzymes are normal in DMNL and depressed in VMNL rats. The above data suggest that the DMN and its circuitry are part of an “organismic” set point system with a “true” body weight and not fat set point, as seems to be the case in the VMNL rat.

Effects of intragastric hyperalimentation on pair-fed rats with ventromedial hypothalamic lesions

The present study was undertaken to determine the relative contributions of altered metabolic responses and excess food intake to the obesity and hyperinsulinemia of the ventromedial hypothalamic (VMH) syndrome. This experiment, employing an intragastric hyperalimentation protocol, was also designed to address the related issue of whether altered energy utilization serves as a compensatory strategy for reducing energy retention in the face of excess intake. Separate groups of VMH-lesioned and sham-lesioned female rats were fed, either orally or intragastrically, up to 200% of the calories ingested by a normally feeding intact rat. Both VMH-lesioned and intact rats became obese and hyperinsulinemic when hyperalimented for 30 days, but rats with lesions deposited 25% more fat than intact animals receiving an identical number of calories. Estimates of total carcass energy indicated that rats with lesions required 11% less calories than intact rats to retain identical levels of energy. Furthermore, intact hyperalimented rats failed to evidence the caloric wastage that has been reported to occur in orally fed rats that overeat cafeteria diets.

Hypodipsia, osmoreceptor dysfunction, early puberty and abnormal behaviour in two boys

Two unrelated boys (A 13yrs B 18yrs) presenting with early puberty and episodes of aggressive behaviour were found to have hypernatraemia(Na 147-160 mmol/l, osmolality 298-323mosmol/kg) and hypodipsia. Plasma vasopressin(AVP) levels were in the range seen in diabetes insipidus(<2pmol/l), yet 24hr urinary volumes were <1 litre and the maximal urinary osmolality 1232 in A and 950 in B. Plasma renin activity was elevated (>2000mg/AI/l/hr)and aldosterone normal. Excretion of a water load(20ml/kg)was delayed(minimal urinary osmolality A-166 at 300mins,B-392 at 360mins)but plasma renin and aldosterone fell with increased naturesis. An infusion of 4.5% saline produced a rise in AVP(2.8pmol/l)in A but not in B. Insulin and hypotension resulted in release of AVP. (A 6.1pmol/l, B 4.8 pmol/1) suggesting a selective defect of osmoreceptor function. Hyperprolactinaemia and an exaggerated PRL response to TRH were also noted but no intracranial lesion was demonstrable on CT scan. These boys appear to have a hypothalamic syndrome with early puberty, hyperprolactinaemia, hypodipsia and osmoreceptor dysfunction which may be associated with aggressive behaviour.

A Role for Amine Accumulation in the Syndrome of Ingestive Deficits following Lateral Hypothalamic Lesions

Lesions of the lateral hypothalamus produce ascending catecholamine neuron degeneration which results in terminal depletion and proximal accumulation above the lesions. The occurrence of deficits in ingestive behaviour has been attributed traditionally to the loss of functional dopamine neurotransmitter in the terminal fields. However, release of functional amines may occur in the lateral hypothalamus at areas of accumulation, to produce at least some of the behavioural symptoms characterizing the lateral hypothalamic syndrome. Recovery from behavioural deficits as a result of various pharmacological treatments, after dopamine-depleting lesions, may be mediated by changes in amine release or modified sensitivity of receptors affected by released amines. We conclude that amine accumulation should be considered when interpreting experiments implicating central catecholamine systems in the control of consumatory behaviour and the regulation of body weight.

We should De-emphasize the Importance of the Role we give Amines in the LH Syndrome

Once amines were implicated in the lateral hypothalamic syndrome, it became accepted that the dominant cause of many of its symptoms was an alteration in amines. We suggest that corticofugal fiber damage may produce some of the behavioral symptoms usually attributed to amine alterations.

Influence of sympathectomy on the lateral hypothalamic lesion syndrome.

Influence of sympathectomy on the lateral hypothalamic lesion syndrome.

Influence of sympathectomy on the lateral hypothalamic lesion syndrome.

Sympathetic involvement in the lateral hypothalamic (LH) lesion syndrome was examined. Male rats were surgically or chemically sympathectomized and then given LH lesions. At 24 hr postlesion, lesion-induced hyperglycemia but not hyperthermia was attenuated by splanchnicectomy and celiac ganglionectomy. Hyperthermia but not hyperglycemia was attenuated by adrenal demedullation, adrenalectomy, and neonatal guanethidine treatment. Guanethidine-sympathectomized rats also displayed lower basal temperatures, more perilesion chromatolysis, and severer external symptoms than their controls. No form of sympathectomy affected lesion-induced gastric pathology, plasma gastrin concentrations, or body weight loss. Nor did any sympathectomy influence the recovery of ingestive behavior, daily food intake, the feeding response to 2-deoxy-D-glucose, or body weight maintenance in recovered LH-lesion subjects. These results suggest that sympathetic hyperactivity contributes to some aspects of the acute LH syndrome: Hyperglycemia results from sympathetic outflow to the abdomen, whereas hyperthermia is determined by circulating catecholamines and extraabdominal sympathetic innervation. The results fail to support the hypothesis that chronic increases in sympathetic tone are responsible for the reduced food intake and body weight of the LH-lesion rat.

Hypothalamic Syndrome in Childhood

Hypothalamic Syndrome in Childhood

Aphagia and adipsia after kainic acid lesioning of the dorsomedial hypothalamic area.

Unlike rats which have electrolytic dorsomedial hypothalamic area lesions and are hypophagic and hypodipsic, the rats of the present study with dorsomedial hypothalamic area, kainic acid lesions (KAL) were postoperatively aphagic and adipsic. Subsequently, KAL rats rejected chow or a high-fat diet but ate a 30% sucrose-chow diet. Similarly the KAL rats were adipsic but drank a 30% sucrose solution. Slowly most of the KAL rats began to eat chow and drink tap water but remained hypophagic and hypodipsic. When tested for glucoprivic-induced feeding using 2-deoxy-D-glucose (200 or 400 mg/kg) the KAL rats, in contrast to the sham-operated controls, did not increase their food intake. During water deprivation the recovered KAL rats that would drink tap water ate, and following it they responded with an adequate increase in water consumption. During food deprivation the KAL rats, whether eating chow or sucrose-chow diet, drank, and subsequently the normally hypophagic rats actually ate more than the controls. Although the growth rate (linear and ponderal) of KAL rats was reduced compared with that of the controls, their body composition by indirect measurement was normal. The present data indicate that most of the dorsomedial hypothalamic syndrome results from damage to DMHA neurons and not to fibers of passage.

Reactivity of normal and VMH-lesion rats to quinine-adulterated foods: negative evidence for negative finickiness.

Much of the evidence for the existence of a negative finickiness component in the ventromedial hypothalamic (VMH) syndrome comes from studies comparing the relative reactivities of VMH and normal rats to quinine adulteration. The present experiments addressed two major questions regarding the response of normal and VMH animals to quinine: (a) Do the anorexic properties of quinine depend on quinine's sensory properties (i.e., its bitter taste) or on its postingestive effects; (b) do VMH rats in fact overrespond to quinine adulteration? These issues were examined by comparing the feeding adjustments to quinine by VMH and normal animals in a sham-feeding situation and under normal feeding circumstances, on animals' initial exposure to this drug. The results were consistent with the view that the sensory properties of quinine alone were sufficient to induce large changes of food intake in both groups. In terms of whether lesion rats were more reactive to the taste of quinine, it is argued that previous research had measured reactivity in two dissimilar ways. The present data were used to illuminate how use of these two procedures for measuring reactivity lead to diametrically opposed conclusions regarding the existence of negative finickiness in the VMH syndrome. It is suggested that when the more appropriate measure of reactivity is adopted and when the confound of body weight differences between normal and VMH animals is eliminated, little evidence exists for a conclusion that VMH rats are more reactive than normals to quinine-adulterated foods.

Paraventricular hypothalamic lesions and medial hypothalamic knife cuts produce similar hyperphagia syndromes.

The hyperphagia/obesity syndrome produced by paraventricular hypothalamic (PVH) lesions and that produced by medial hypothalamic (MH) knife cuts were compared in adult female rats. Each treatment produced hyperphagia and overweight on a chow diet, although the PVH effect was less than the knife-cut effect. Each treatment also produced qualitatively similar ingestive responses to unpalatable quinine- and sucrose octaacetate-adulterated diets and to palatable dextrose and fat diets during the dynamic and static weight-gain phases. The PVH lesions and MH cuts disrupted day/night feeding patterns and elevated water intakes but not water/food intake ratios. However, PVH lesions, unlike MH cuts, did not increase emotional reactivity. The relation of the PVH syndrome to the classic hypothalamic hyperphagia syndrome is discussed. Also considered is the neuroanatomical substrate responsible for the PVH hyperphagic effect.

Clinical aspects of neuroendocrinology.

Recent studies have identified structures of most of the hypothalamic hormones and clarified their actions. In addition, the importance of a variety of classical and peptide neurotransmitters or neuromodulators in the regulation of pituitary hormone secretion and other hypothalamic functions has been partly elucidated. These advances in the physiological aspects of the hypothalamus have greatly helped our understanding of the pathogenesis of a variety of hypothalamic syndromes.

Endocrinology and metabolism: an annotated bibliography of recent literature. References to journal articles and other papers.

Endocrinology and metabolism: an annotated bibliography of recent literature. References to journal articles and other papers.

A hypothalamic syndrome characterized by hypernatremia, adipsia, hyperprolactenemia and high threshhold for vasopressin release

Adipsia with high threshhold for vasopressin release was diagnosed in a 9-year-old girl with episodes of muscular weakness,hypernatremia (Na 162-175 mEq/L) ↑ BUN, ↓ Hb and ↓ platelets,and urine osmolality 800-1400 mOsm/L.The levels of serum prolactin,FSH,LH, and estrogens (306 pg/ml) were high.She was obese with normal linear growth,and mentality,and Tanner II pubic hair. Thirst was not sensed even with serum osm.of 365 mOsm/L Prolactin decreased after hypertonic saline infusion (1640 to 1200 mIU/ml) and after L-DOPA (1600 to 600). Thyroid,and adrenal function,and muscle enzymes were normal.CT brain scans,the last one two years after initial symptomatology,were normal.The forcing of fluids (1500 ml/day) resulted in clinical improvement,normalization of serum Na,BUN,Hb and platelets and the appearance of regular menses.Prolactin,LH,and FSH did not change.The pathophysiologic implications will be discussed. It is postulated that the biochemical findings might have been caused by hypothalamitis (autoimmune?) with selective dysfunction of the thirst center,osmolar receptor-vasopressin release complex and the centers for LHRH and prolactin regulation.

Evidence for Increased Dopaminergic and Opioid Activity in Patients with Hypothalamic Hypogonadotropic Amenorrhea

To gain insight into the psychoneuroendocrine basis for the reduced gonadotropin secretion in the hypothalamic hypogonadotropic amenorrhea syndrome, the roles of endogenous opioids and dopamine (DA) on gonadotropin and PRL release were evaluated. Responses of LH, FSH, and PRL to a DA receptor antagonist [metoclopramide (MCP); 10 mg, iv] and to an opioid receptor antagonist (naloxone infusion; 1.6 mg/h for 4 h) were analyzed in eight patients and compared with identical studies carried out in nine normal women during the low estrogen phase of the cycle. Neither MCP administration nor the naloxone infusion induced any changes in serum gonadotropinlevels in normal women. In contrast, four of eight patients responded to both receptor antagonistswith a significant increase in LH levels. The LH increment elicited by naloxone exhibited an amplification of the pulsatile pattern of release, suggesting hypothalamic LRF mediation. The other four patients with prepubertal levels of basal LH and lower concentrations o...

The lateral hypothalamic syndrome: Comparison with the syndrome of anorexia nervosa

The lateral hypothalamic syndrome of feeding disorders may not involve the hypothalamus per se, nor is it simply an impairment of feeding behavior. Recent work has forced revisions in traditional concepts regarding the role of the hypothalamus in the control of feeding. At present, it seems clear that hypothalamic damage disrupts nonspecific contributions to feeding behavior, by damaging dopaminergic and other fibers of passage coursing through the ventral diencephalon, and that the resultant aphagia reflects a general disruption of all voluntary behavior that includes feeding but is not restricted to it. Neurological dysfunctions such as akinesia, catalepsy, and sensory neglect are prominent and indicate a broad activational disorder reminiscent of Parkinson's disease. In the absence of a clear notion of how feeding is controlled by the brain, it seems premature to consider animals with experimental lesions in the hypothalamus (or elsewhere in the brain) as appropriate models of anorexia nervosa.

Cortical activity and sleep in the rat lateral hypothalamic syndrome

Continuous EEG recordings were performed in lateral hypothalamic (LH) damaged rats from day 1 post-lesion when totally aphagic and adipsic until complete recovery of their feeding and drinking. During the early post-operative stage (days 1–3 post-lesion), LH rats showed a complete disorganization of their basal EEG which was characterized by two superimposed activities, a constant rapid low voltage activity modulated by high voltage low frequency waves. Except in the case of intense illumination, several arousing stimuli did not affect this activity. By day 4 post-lesion, the two overlapping activities were replaced by less abnormal waves on top of which the first normal sleep spindles appeared. Sleep increased gradually and normal amounts of both slow-wave and paradoxical sleep were observed during ‘stage 4’ of recovery when rats again ate food and drank water. During this stage, and contrary to normal rats, meal size was correlated only with sleep events occurring within the intermeal interval following the next meal, when most of the ingested nutrients reached the systematic compartment. The effect on sleep of intragastric or intravenous caloric repletion was, at least in part, in agreement with the view of indirect effect of LH lesions on sleep through metabolic impairment. Whatever the mechanism underlying sleep deficits, these are one of the major symptoms of the lateral hypothalamic syndrome.