Oncocytic lesions of the neuroendocrine system.

Oncocytic tumors are rare tumors that have been described in many organs throughout the body, mainly in salivary, parathyroid, thyroid, and adrenal glands and in the kidney. A wide spectrum of benign and malignant oncocytic tumors can arise in various organs of the neuroendocrine system. They are usually defined as tumors that are composed predominantly or exclusively of oncocytic cells. A majority of these tumors are benign; however, in some endocrine organs such as the thyroid the diagnosis of oncocytic/Hürthle cell carcinoma portends a more aggressive clinical course than non-Hürthle cell follicular carcinoma. Therefore, it is important to follow strict criteria to diagnose and differentiate between benign and malignant oncocytic tumors. In this review we will discuss the clinicopathologic features of various oncocytic tumors of the endocrine glands.     

Influence of medial preoptic-anterior hypothalamic area stimulation of the excitability of mediobasal hypothalamic neurones in the rat.

1. Extracellular action potentials recorded from 798 neurones in the mediobasal hypothalamus (MBH) of pentobarbitone anaesthetized male rats were analysed for a change in excitability following stimulation in the medial preoptic and anterior hypothalamic areas. 2. An increase in excitability characteristic of orthodromic excitation was observed from 11-5% (n=92) of MBH neurones. Latencies for excitation were shorter for cells tested with anterior hypothalamic area stimulation (n=42; mean 5-4 +/- 2-6 msec S.D.) than for cells tested with medial preoptic stimulation (n=50; mean 15-2 +/- 7-2 msec S.D.). With spontaneously active neurones, excitation was followed by a decrease in excitability lasting 150-250 msec. An initial decrease in excitability, suggestive of post-synaptic inhibition, over a wide latency range (4-30 msec) and with duration of 100-400 msec was observed from 3-6% of MBH neurones. 3. Features of antidromic invasion were observed from 149 MBH neurones. From the medial preoptic area, the latency range was 0-5-38 msec (mean 7-8 +/- 5-5); from the anterior hypothalamic area the latency range was 0-4-9-5 msec (mean 3-1 +/- 2-3). Occasionally an abrupt decrease in latency followed an increase in stimulus intensity. Most cells followed paired stimuli at frequencies up to 500 Hz. Axon conduction velocities were estimated to be under 2-0 m/sec. Antidromic invasion was usually followed by a decrease in excitability lasting approximately 100-150 msec. 4. Twenty MBH neurons displayed antidromic invasion from both the medial preoptic or anterio hypothalamic areas and one other stimulation site: the median eminence (five cells); the amygdala (six cells); the region of thalamic nucleus medialis dorsalis (three cells) and the midbrain periaqueductal gray (six cells). Interaction studies indicated that the axons of these cells branched close to the origin of the axon itself. 5. Antidromic invasion from the surface of the median eminence identified thirty-nine tuberoinfundibular neurones. Stimulation in the medial preoptic and anterior hypothalamic area produced orthodromic excitatory (n = 5) and inhibitory (n = 4) actions on HVM neurones, but was without an action on most other neurones (n = 30). Tuberoinfundibular neurones in the ventromedial nucleus also responded to stimulation in the amygdala, but usually at latencies greater than that for medial preoptic area evoked responses. 6. These observations indicate a close relationship between MBH neurones and cells located in both the amygdala and the medial preoptic-anterior hypothalamic area. The data for tuberoinfundibular neurones indicates that several extrahypothalamic areas may send fibres to these cells. These pathways may be important for the adaptive neuroendocrine responses reported in the literature.     

The neuroendocrine system of the gastrointestinal tract.

The use of increasingly refined techniques in endocrinologic research resulted in a challenge to the classical concept of hormones. The regulatory activity of the highly complicated neuroendocrine system is mediated not only by hormones but by neurotransmitters, paracrine substances, and possibly by substances secreted into the gastrointestinal lumen as well. The system is divided into the central and peripheral nervous system and the endocrine system. The latter consists of the endocrine glands and the disseminated endocrine system. Research into the activities of the system will result in important advances in the fields of physiology, pathophysiology and pathology.     

Metabolic and neuroendocrine indices one month after lateral hypothalamic area lesions.

Mature male rats received bilateral electrolytic lateral hypothalamic area lesions (LHAL) or were sham-operated fed ad lib (CON-ADLIB) or sham-operated pair-fed/gained (CON-PF) to LHAL rats. One month later all rats were sacrificed. Rats with LHAL were hypophagic and had reduced body carcass fat, testes, livers, epididymal fat pads (PADS), diaphragms (DIA), and body weight compared to CON-ADLIB. In the liver, LHAL rats incorporated more C14-U-glucose carbon (GLUCINC) into lipid and glycogen than both CON groups, but GLUCINC was similar among CON groups. In PADS, LHAL rats oxidized more glucose carbon (GLUCOX) than CON-ADLIB but less than CON-PF/PG. The latter showed greater GLUCOX than CON-ADLIB. In DIA, LHAL and CON-PF/PG showed reduced GLUCINC into glycogen vs. CON-ADLIB. Plasma glucose was similar among groups, but insulin was lower in LHAL and CON-ADLIB than in CON-PF/PG. Rats with LHAL had lower plasma T3 concentrations than CON-ADLIB, but similar T3 levels compared to CON-PF/PG. Several of the metabolic changes in LHAL rats could be due to hypophagia; however, four out of nine metabolic indices, glucose carbon incorporation into liver lipid and glycogen and epididymal fat pad lipid and oxidation, were significantly different from CON-PF/PG, i.e., they were independent of food intake. Possibly then, they are due to a lesion effect other than on feeding mechanisms. Some aspects of metabolism that were previously found to be altered 48 h after LHAL were recovered, whereas others apparently were not.     

Adrenal epinephrine in hyperuricemia induced by hypothalamic stimulation of the rat.

Peripheral neurological mechanisms involved in hyperuricemia following ventromedial hypothalamic electrical stimulation was studied in the conscious rat. The intensity of 0.2 mA was near the maximum intensity of stimulation current producing a linear increase in plasma uric acid throughout the 15-min period of stimulation, as well as a subsequent rise and fall of plasma allantoin. Bilateral adrenal demedullation abolished the stimulation-induced hyperuricemia and markedly impaired the accompanying rise of allantoin. Prior treatment of the animal with hexamethonium significantly inhibited the uric acid increase, but did not reduce the allantoin elevation so markedly. Moreover, propranolol eliminated both responses of these plasma purine metabolites, whereas phentolamine greatly increased the response. It is concluded therefore that the hypothalamic stimulation-induced rise of plasma uric acid is the result of acceleration of epinephrine release from the adrenal medulla and that, whereas some unknown extra-adrenal mechanism may be partially involved, the primary part of the accompanying allantoin elevation is explained by the combined effects of the increased uric acid and the hepatic uricase.     

Depression of delayed-type hypersensitivity in mice with hypothalamic lesion induced by monosodium glutamate: involvement of neuroendocrine system in immunomodulation.

Delayed-type hypersensitivity (DTH) was depressed in mice that had been treated with monosodium glutamate (MSG) in their suckling period. Analysis of the DTH depression by use of the macrophage migration inhibition assay showed dysfunction of DTH effector T cells. The neuronal loss of nuclei in the hypothalamus, which elaborates the corticotropin-releasing factor and the hypersecretion of adrenocorticotrophic hormone, was observed in the MSG-treated mice. Therefore, DTH response may be modulated by the neuroendocrine system.     

Sympathetic hyperresponsiveness to hypothalamic stimulation in young hypertensive rats.

The possible occurrence of central sympathetic dysfunction during development of spontaneous hypertension was studied by recording aortic pressure and sympathetic nerve activity concurrently during electrical stimulation of the posterior hypothalamus in 9-wk-old Kyoto-Wistar rats. Even at this early age, basal levels for both measurements were already elevated significantly in those with spontaneous hypertension. Increases in sympathetic neural firing induced by graded hypothalamic stimulation were always followed by corresponding increases in blood pressure; magnitude of both effects was appreciably larger in spontaneously hypertensive than in normotensive rats, as was the vasodepression caused by blocking autonomic ganglia with pentolinium. By contrast, pressor responses to injected norepinephrine were almost equal thereby suggesting that cardiovascular reactivity was unaltered and that enhanced responsiveness to hypothalamic stimulation was directly due to the concomitant increase in sympathetic nerve activity. Although the exact site from which sympathetic hyperactivity originates was unidentified, our results support the interpretation that sympathetic mechanisms involving the posterior hypothalamus participate in elevating blood pressure during development of spontaneous hypertension in rats.     

Aftereffects of rewarding lateral hypothalamic brain stimulation and feeding behavior.

The aftereffects of rewarding lateral hypothalamic brain stimulation are shown to depress the speed with which rats will initiate consumption of various foods. The strength of this depression was positively correlated (r_xy = 0.60) with the rate of self-stimulation on that electrode. Seemingly paradoxical relations between this finding and other known characteristics of lateral hypothalamic stimulation are discussed.     

Attenuation of a convulsive syndrome in the rat by lateral hypothalamic stimulation.

Modification of a behaviorally suppressive syndrome produced by cholinergic activation of the amygdala was compared under automatically delivered electrical stimulation in rats which had previously been implanted with a bipolar electrode in the medial forebrain bundle (MFB) and preselected for high or low self-stimulation rates. Carbachol was applied bilaterally to the amygdaloid complex to precipitate a convulsive syndrome. Concurrently, brain stimulation pulses were applied unilaterally to the medial forebrain bundle at the lateral hypothalamic level at predetermined current intensities and frequency in two program combinations: ON-OFF-ON and OFF-ON-OFF. The rats were assigned scores on 5 measures of the carbachol-induced syndrome, as well as on a locomotion measure. An irritability test was also administered 6 times during the test hour. The frequency of clonic seizures was found to be significantly lower for all self-stimulators, especially those in the ON-OFF-ON order of ICS. Greater locomotor activity was found for experimental self-stimulators. Non-self-stimulators were most characterized by muscular hypertonus and seizure activity, and were indistinguishable from the carbachol-only controls on the locomotion measure. Other aspects of the syndrome appeared to be unaffected. The results are discussed in relation to the concept of a behavioral facilitative-suppressive model, and a possible neuroanatomical substrate consisting of mutually-antagonistic noradrenergic and cholinergic systems.     

Compensatory effects of hypothalamic rewarding stimulation during concomitant painful footshock.

Rats exhibiting steady self-stimulation behavior were allowed to regulate the duration of hypothalamic stimulation during concomitant painful footshock. Results show that the mean duration of bar pressing increases with the incrementation of the footshock voltage. Furthermore, the incrementation of the brain stimulation depends on the rewarding value elicited by the hypothalamic stimulation. The less the intracranial stimulation is rewarding, the more the animal increases brain stimulation, and vice versa. Several hypotheses are presented to explain the mechanism underlying the compensation behavior by increasing the consummation of rewarding electrical stimuli during concomitant footshock. Finally, the verification of three conditions supports the hypothesis of an attenuation of nociceptive effects by the stimulation of rewarding brain area. These conditions are the following: (1) the rewarding brain region and the region responsible for pain-suppression, when excited, had to be separated; (2) the painful stimulation must stay aversive despite the rewarding brain stimulation; (3) a close relationship between the rewarding intensity elicited and the intensity of the nociceptive stimulation.     

Activation of the retrotrapezoid nucleus by posterior hypothalamic stimulation

The retrotrapezoid nucleus (RTN) contains chemically defined neurons (ccRTN neurons) that provide a pH-regulated excitatory drive to the central respiratory pattern generator. Here we test whether ccRTN neurons respond to stimulation of the perifornical hypothalamus (PeF), a region that regulates breathing during sleep, stress and exercise. PeF stimulation with gabazine increased blood pressure, phrenic nerve discharge (PND) and the firing rate of ccRTN neurons in isoflurane-anaesthetized rats. Gabazine produced an approximately parallel upward shift of the steady-state relationship between ccRTN neuron firing rate and end-tidal CO₂, and a similar shift of the relationship between PND and end-tidal CO₂. The central respiratory modulation of ccRTN neurons persisted after gabazine without a change in pattern. Morphine administration typically abolished PND and reduced the discharge rate of most ccRTN neurons (by 25% on average). After morphine administration, PeF stimulation activated the ccRTN neurons normally but PND activation and the central respiratory modulation of the ccRTN neurons were severely attenuated. In the same rat preparation, most (58%) ccRTN neurons expressed c-Fos after exposure to hypercapnic hyperoxia (6–7% end-tidal CO₂; 3.5 h; no hypothalamic stimulation) and 62% expressed c-Fos under hypocapnia (∼3% end-tidal CO₂) after PeF stimulation. Under baseline conditions (∼3% end-tidal CO₂, hyperoxia, no PeF stimulation) few (11%) ccRTN neurons expressed c-Fos. In summary, most ccRTN neurons are excited by posterior hypothalamic stimulation while retaining their normal response to CNS acidification. ccRTN neurons probably contribute both to the chemical drive of breathing and to the feed-forward control of breathing associated with emotions and or locomotion.     

Vascular responses in canine subcutaneous adipose tissue to hypothalamic stimulation.

The present studies investigated vascular responses to electrical stimulation of the posterior hypothalamus in isolated but perfused and innervated subcutaneous adipose tissue in adult dogs. Three groups of dogs were distinguished: in one, electrical stimulation elicited vasodilation; in another, vasoconstriction, and in a third, neither significant vasodilation nor vasoconstriction occurred. Histological examination revealed that electrode placements were in the medial posterior hypothalamus, the lateral posterior hypothalamus, and the medial septal region, respectively. Hypothalamic stimulation failed to alter concentrations of free fatty acids or glycerol in venous blood from subcutaneous fat. Local beta-adrenergic block (propranolol) reversed the vasodilation to vasoconstriction while local alpha-adrenergic block (dihydroergotamine) abolished the vaso constrictor response. These results suggest that selective stimulation of the posterior hypothalamus results in neurogenic activation of both alpha- and beta-adrenergic mechanisms in adipose tissue vasculature. beta-Adrenergic vasodilation appears to predominate if the electrode is located medially, and alpha-adrenergic vasoconstriction appears to predominate if the electrode is located in the lateral posterior hypothalamus.     

Naltrexone administration modulates the neuroendocrine control of luteinizing hormone secretion in hypothalamic amenorrhoea

Because endogenous opioids have been considered to be deeplyinvolved as a causal factor of hypothalamic amenorrhoea, thisstudy was designed to evaluate the efficacy of the administrationof naltrexone, an antagonist of opioid receptors, on luteinizinghormone (LH) secretion in patients with hypothalamic amenorrhoea.A total of 30 patients with hypothalamic amenorrhoea were studied.Patients were divided into two groups: group A, hypogonadotrophic(n = 15), and group B, normogonadotrophic (n = 15). All patientswere administered naltrexone at a dose of 50 mg/day per os for6 months. A third group of 10 amenorrhoeic patients was treatedwith placebo per os with the same schedule. All patients wereevaluated for LH spontaneous pulsatile release in baseline conditionsand after 3 and 6 months of treatment. Plasma gonadal steroidconcentrations increased significantly in all patients after3 months of naltrexone therapy, but only hypogonadotrophic patientsshowed a sharp increase in both LH plasma concentrations andLH pulse amplitude within the first 3 months of treatment whichremained unchanged until the sixth month of treatment. Plasmafollicle stimulating hormone concentrations did not change significantlyin any patient. Menstrual bleeding occurred within 90 days ofthe beginning of treatment in 24 out of the 30 patients. Patientstreated with placebo did not show a significant change in gonadotrophinand gonadal steroid plasma concentrations. The results of ourstudy support the efficacy of naltrexone administration on neuroendocrinepathways controlling LH secretion in patients with hypothalamicamenorrhoea.     

Voiced calls evoked by hypothalamic stimulation in the cat

Summary Voiced vocalizations evoked by hypothalamic stimulation were studied in a series of six awake adult cats. Electrical stimulation was found to evoke vocalizations at numerous sites within the hypothalamus, ranging from A+8 to A+16. Regions showing the largest number of responsive sites were the preoptic region, the ventromedial area, the perifornical region, the lateral and the dorso-medial hypothalamus. The form of the evoked calls was generally similar to the spontaneous calls of the same animal. Call latency, duration, and intensity were not significantly affected by changes in stimulus intensity or duration but all three of these call parameters were significantly affected by changes in stimulus frequency. In general, call latency was longest at sites in the rostral hypothalamus and shortest at sites in the caudal hypothalamus. This study is the first to investigate systematically voiced call producing areas in the hypothalamus of awake cats and to document similarities between these calls and spontaneously produced voiced calls.     

Effects of hypothalamic stimulation on gluconeogenesis and glycolysis in rat liver.

Hypothalamic effects on gluconeogenesis and glycosis in rat liver were studied byelectrical stimulations of the ventromedial hypothalamic nucleus (LH) without disturbing the animal's behavior. Stimulation of VMH caused a increase in the activity of phosphoenolpyruvate carboxykinase (PEPCK), a key gluconeogenic enzyme, and marked suppression of pyruvate kinase (PK), a key glycolytic enzyme, of the liver. Stimulationof LH, on the other hand, resulted in a decrease in PEPCK activity but did not alterPK activity. The maximal responses of these enzymes to hypothalamic stimulations were obtained after intermittent stimulations for 4 h. Differential estimations of thetwo isozymes of liver PK (types L and M) were made using antibody against typeM PK. The level of type M enzyme was not altered significantly on stimulation of either VMH or LH. The content of type L enzyme greatly decreased on stimulation of VMH but was not affected by stimulation of LH. The reciprical influences of VMH and LH on hepatic carbohydrate metabolism and their relation to neural-hormonal responses are discussed.