Infusion of fluoxetine, a serotonin reuptake inhibitor, in the shell region of the nucleus accumbens increases blood glucose concentrations in rats.

The brain is well known to regulate blood glucose, and the hypothalamus and hindbrain, in particular, have been studied extensively to understand the underlying mechanisms. Nuclei in these regions respond to alterations in blood glucose concentrations and can alter glucose liver output or glucose tissue uptake to maintain blood glucose concentrations within strict boundaries. Interestingly, several cortico-limbic regions also respond to alterations in glucose concentrations and have been shown to project to hypothalamic nuclei and glucoregulatory organs. For instance, electrical stimulation of the shell of the nucleus accumbens (sNAc) results in increased circulating concentrations of glucose and glucagon and activation of the lateral hypothalamus (LH). Whether this is caused by the simultaneous increase in serotonin release in the sNAc remains to be determined. To study the effect of sNAc serotonin on systemic glucose metabolism, we implanted bilateral microdialysis probes in the sNAc of male Wistar rats and infused fluoxetine, a serotonin reuptake inhibitor, or vehicle after which blood glucose, endogenous glucose production (EGP) and glucoregulatory hormones were measured. Fluoxetine in the sNAc for 1h significantly increased blood glucose concentrations without an effect on glucoregulatory hormones. This increase was accompanied by a higher EGP in the fluoxetine infused rats compared to the controls. These data provide further evidence for a role of sNAc-serotonin in the regulation of glucose metabolism.

The Role of Hypothalamic NF-κB Signaling in the Response of the HPT-Axis to Acute Inflammation in Female Mice.

A large proportion of critically ill patients have alterations in the hypothalamus-pituitary-thyroid (HPT) axis, collectively known as the nonthyroidal illness syndrome. Nonthyroidal illness syndrome is characterized by low serum thyroid hormone (TH) concentrations accompanied by a suppressed central component of the HPT axis and persistent low serum TSH. In hypothalamic tanycytes, the expression of type 2 deiodinase (D2) is increased in several animal models of inflammation. Because D2 is a major source of T3 in the brain, this response is thought to suppress TRH expression in the paraventricular nucleus via increased local bioavailability of T3. The inflammatory pathway component RelA (the p65 subunit of nuclear factor-κB) can bind the Dio2 promoter and increases D2 expression after lipopolysaccharide (LPS) stimulation in vitro. We aimed to determine whether RelA signaling in tanycytes is essential for the LPS-induced D2 increase in vivo by conditional elimination of RelA in tanycytes of mice (RelA(ASTKO)). Dio2 and Trh mRNA expression were assessed by quantitative in situ hybridization 8 or 24 hours after saline or LPS injection. At the same time points, we measured pituitary Tshß mRNA expression and serum T3 and T4 concentrations. In RelA(ASTKO) mice the LPS-induced increase in Dio2 and decrease in Trh mRNA levels in the hypothalamus were reduced compared with the wild-type littermates, whereas the drop in pituitary Tshß expression and in serum TH concentrations persisted. In conclusion, RelA is essential for the LPS-induced hypothalamic D2 increase and TRH decrease. The central changes in the HPT axis are, however, not required for the down-regulation of Tshß expression and serum TH concentrations.

Hepatic denervation and dyslipidemia in obese Zucker (fa/fa) rats.

Human and animal studies increasingly point toward a neural pathogenesis of the metabolic syndrome, involving hypothalamic and autonomic nervous system dysfunction. We hypothesized that increased very-low-density lipoprotein-triglyceride (VLDL-TG) secretion by the liver in a rat model for dyslipidemia, that is, the obese Zucker (fa/fa) rat, is due to relative hyperactivity of sympathetic, and/or hypoactivity of parasympathetic hepatic innervation. To test the involvement of the autonomic nervous system, we surgically denervated the sympathetic or parasympathetic hepatic nerve in obese Zucker rats. Our results show that cutting the sympathetic hepatic nerve lowers VLDL-TG secretion in obese rats, finally resulting in lower plasma TG concentrations after 6 weeks. In contrast, a parasympathetic denervation results in increased plasma total cholesterol concentrations. The effect of a sympathetic or parasympathetic denervation of the liver was independent of changes in humoral factors or changes in body weight or food intake. In conclusion, a sympathetic denervation improves the lipid profile in obese Zucker rats, whereas a parasympathetic denervation increases total cholesterol levels. We believe this is a novel treatment target, which should be further investigated.

Neuroscience of glucose homeostasis.

Plasma glucose concentrations are homeostatically regulated and maintained within strict boundaries. Several mechanisms are in place to increase glucose output when glucose levels in the circulation drop as a result of glucose utilization, or to decrease glucose output and increase tissue glucose uptake to prevent hyperglycemia. Although the term homeostasis mostly refers to stable levels, the blood glucose concentrations fluctuate over the day/night cycle, with the highest concentrations occurring just prior to the activity period in anticipation of increased caloric need. In this chapter we describe how the brain, particularly the hypothalamus, is involved in both the daily rhythm of plasma glucose concentrations and acute glucose challenges.

Expression of 11ß-hydroxysteroid dehydrogenase type 1 in the human hypothalamus.

The hypothalamus is a major target for glucocorticoids and a key structure for hypothalamic-pituitary-adrenal (HPA) axis setpoint regulation. The enzyme 11ß hydroxysteroid dehydrogenase type 1 (11ßHSD1) modulates glucocorticoid signalling in various tissues at the prereceptor level by converting biologically inactive cortisone to its active form cortisol. The present study aimed to assess 11ßHSD1 expression in the human hypothalamus. We studied 11ßHSD1 expression in five frozen and four formalin-fixed, paraffin-embedded human hypothalami (obtained from the Netherlands Brain Bank) by the polymerase chain reaction and immunocytochemistry, respectively. 11ßHSD1 mRNA was expressed in the area of the suprachiasmatic nucleus, which is the biological clock of the brain, in the supraoptic nucleus and paraventricular nucleus (PVN), and in the infundibular nucleus, which is the human homologue of the rodent arcuate nucleus. 11ßHSD1 was detected by immunocytochemistry in the same nuclei. In the PVN, neuronal 11ßHSD1 immunoreactivity colocalised with corticotrophin-releasing hormone (CRH), arginine vasopressin and oxytocin, as shown by dual fluorescence staining. Our data demonstrate that 11ßHSD1 is widely expressed in the human hypothalamus. Its colocalisation with CRH in the PVN suggests a role in modulation of glucocorticoid feedback of the HPA axis, whereas the expression of 11ßHSD1 in additional and functionally diverse hypothalamic nuclei points to a role for the enzyme in the regulation of metabolism, appetite and circadian rhythms.

Intrahypothalamic estradiol modulates hypothalamus-pituitary-adrenal-axis activity in female rats.

Estrogen plays an important role in the regulation of the hypothalamus-pituitary-adrenal (HPA)-axis, but the neuroendocrine pathways and the role of estrogen receptor (ER) subtypes involved in specific aspects of this interaction remain unknown. In a first set of experiments, we administered estradiol (E2) intravenously, intracerebroventricularly, and by intrahypothalamic microdialysis to ovariectomized rats to measure plasma corticosterone (CORT) concentrations from carotid artery blood. Systemic infusion of E2 did not increase plasma CORT, but intracerebroventricular E2 induced a 3-fold CORT increase (P = 0.012). Local E2 infusions in the hypothalamic paraventricular nucleus (PVN) significantly increased plasma CORT (P < 0.001). A similar CORT increase was seen after PVN infusion of the ERα agonist propylpyrazoletriol, whereas the ERß agonist diarylpropiolnitrile had no effect. In a second set of experiments, we investigated whether E2 modulates the HPA-axis response to acute stress by administering E2 agonists or its antagonist ICI 182,780 into the PVN during restraint stress exposure. After 30 min of stress exposure, plasma CORT had increased 5.0-fold (P < 0.001). E2 and propylpyrazoletriol administration in the PVN enhanced the stress-induced plasma CORT increase (8-fold vs. baseline), whereas ICI 182,780 and diarylpropiolnitrile reduced it, as compared with both E2 and vehicle administration in the PVN. In conclusion, central E2 modulates HPA-axis activity both in the basal state and during restraint stress. In the basal condition, the stimulation is mediated by ERα-sensitive neurons, whereas during stress, it is mediated by both ERα and ERß.

Thyroid function after subtotal thyroidectomy in patients with Graves' hyperthyroidism.

BACKGROUND: Subtotal thyroidectomy is a surgical procedure, in which the surgeon leaves a small thyroid remnant in situ to preserve thyroid function, thereby preventing lifelong thyroid hormone supplementation therapy. AIM: To evaluate thyroid function after subtotal thyroidectomy for Graves' hyperthyroidism. SUBJECTS AND METHODS: We retrospectively reviewed the medical records of all patients (n = 62) who underwent subtotal thyroidectomy for recurrent Graves' hyperthyroidism between 1992 and 2008 in our hospital. Thyroid function was defined according to plasma TSH and free T4 values. RESULTS: Median followup after operation was 54.6 months (range 2.1-204.2 months). Only 6% of patients were euthyroid after surgery. The majority of patients (84%) became hypothyroid, whereas 10% of patients had persistent or recurrent hyperthyroidism. Permanent recurrent laryngeal nerve palsy and permanent hypocalcaemia were noted in 1.6% and 3.2% of patients, respectively. CONCLUSION: In our series, subtotal thyroidectomy for Graves' hyperthyroidism was associated with a high risk of postoperative hypothyroidism and a smaller, but significant, risk of persistent hyperthyroidism. Our data suggest that subtotal thyroidectomy seems to provide very little advantage over total thyroidectomy in terms of postoperative thyroid function.

Circadian rhythms in the hypothalamo-pituitary-adrenal (HPA) axis.

The pronounced daily variation in the release of adrenal hormones has been at the heart of the deciphering and understanding of the circadian timing system. Indeed, the first demonstration of an endocrine day/night rhythm was provided by Pincus (1943), by showing a daily pattern of 17-keto-steroid excretion in the urine of 7 healthy males. Twenty years later the adrenal gland was one of the very first organs to show, in vitro, that circadian rhythmicity was maintained. In the seventies, experimental manipulation of the daily corticosterone rhythm served as evidence for the identification of respectively the light- and food-entrainable oscillator. Another 20 years later the hypothalamo-pituitary-adrenal (HPA)-axis was key in furthering our understanding of the way in which rhythmic signals generated by the central pacemaker in the hypothalamic suprachiasmatic nuclei (SCN) are forwarded to the rest of the brain and to the organism as a whole. To date, the adrenal gland is still of prime importance for understanding how the oscillations of clock genes in peripheral tissues result in functional rhythms of these tissues, whereas it has become even more evident that adrenal glucocorticoids are key in the resetting of the circadian system after a phase-shift. The HPA-axis thus still is an excellent model for studying the transmission of circadian information in the body.

Acute inflammation increases pituitary and hypothalamic glycoprotein hormone subunit B5 mRNA expression in association with decreased thyrotrophin receptor mRNA expression in mice.

The biological function of thyrostimulin, consisting of the GPA2 and GPB5 subunit, is currently poorly understood. The recent observation that pro-inflammatory cytokines up-regulate the transcription of GPB5 in vitro suggested a role for thyrostimulin in the nonthyroidal illness syndrome, a state of altered thyroid hormone metabolism occurring during illness. In the present study, we used GPB5 knockout (GPB5(-/-) ) and wild-type (WT) mice to evaluate the role of GPB5 in the pituitary and hypothalamus during acute inflammation induced by lipopolysaccharide (LPS, bacterial endotoxin) administration. We evaluated serum thyroid hormones and mRNA expression of genes involved in thyroid hormone metabolism in the pituitary and in two hypothalamic regions; the periventricular region (PE) and the arcuate nucleus/median eminence region. As expected, LPS administration increased deiodinase type 2 mRNA in the PE, at the same time as decreasing pituitary thyrotrophin (TSH)ß mRNA and serum thyroxine and triiodothyronine both in GPB5(-/-) and WT mice. GPB5 mRNA, but not GPA2 mRNA, markedly increased after LPS in the pituitary (200-fold) and hypothalamus of WT mice. In addition, we found large (>50%) suppression of TSH receptor (TSHR) mRNA in the pituitary and hypothalamus of WT mice but not in GPB5(-/-) mice. In conclusion, our results demonstrate in vivo regulation of central GPB5 transcription during acute illness. The observed differences between GPB5(-/-) and WT mice point to a distinct role for GPB5 in pituitary and hypothalamic TSHR suppression during acute illness.

Hypothalamic control of energy metabolism via the autonomic nervous system.

The hypothalamic control of hepatic glucose production is an evident aspect of energy homeostasis. In addition to the control of glucose metabolism by the circadian timing system, the hypothalamus also serves as a key relay center for (humoral) feedback information from the periphery, with the important role for hypothalamic leptin receptors as a striking example. The hypothalamic biological clock uses its projections to the preautonomic hypothalamic neurons to control the daily rhythms in plasma glucose concentration, glucose uptake, and insulin sensitivity. Euglycemic, hyperinsulinemic clamp experiments combined with either sympathetic-, parasympathetic-, or sham-denervations of the autonomic input to the liver have further delineated the hypothalamic pathways that mediate the control of the circadian timing system over glucose metabolism. In addition, these experiments clearly showed both that next to the biological clock peripheral hormones may "use" the preautonomic neurons in the hypothalamus to affect hepatic glucose metabolism, and that similar pathways may be involved in the control of lipid metabolism in liver and white adipose tissue.

Vasopressin and the output of the hypothalamic biological clock.

The physiological effects of vasopressin as a peripheral hormone were first reported more than 100 years ago. However, it was not until the first immunocytochemical studies were carried out in the early 1970s, using vasopressin antibodies, and the discovery of an extensive distribution of vasopressin-containing fibres outside the hypothalamus, that a neurotransmitter role for vasopressin could be hypothesised. These studies revealed four additional vasopressin systems next to the classical magnocellular vasopressin system in the paraventricular and supraoptic nuclei: a sexually dimorphic system originating from the bed nucleus of the stria terminalis and the medial amygdala, an autonomic and endocrine system originating from the medial part of the paraventricular nucleus, and the circadian system originating from the hypothalamic suprachiasmatic nuclei (SCN). At about the same time as the discovery of the neurotransmitter function of vasopressin, it also became clear that the SCN contain the main component of the mammalian biological clock system (i.e. the endogenous pacemaker). This review will concentrate on the significance of the vasopressin neurones in the SCN for the functional output of the biological clock that is contained within it. The vasopressin-containing subpopulation is a characteristic feature of the SCN in many species, including humans. The activity of the vasopressin neurones in the SCN shows a pronounced daily variation in its activity that has also been demonstrated in human post-mortem brains. Animal experiments show an important role for SCN-derived vasopressin in the control of neuroendocrine day/night rhythms such as that of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes. The remarkable correlation between a diminished presence of vasopressin in the SCN and a deterioration of sleep-wake rhythms during ageing and depression make it likely that, also in humans, the vasopressin neurones contribute considerably to the rhythmic output of the SCN.

Thyroid hormone receptor ß mediates acute illness-induced alterations in central thyroid hormone metabolism.

Acute illness in mice profoundly affects thyroid hormone metabolism in the hypothalamus and pituitary gland. It remains unknown whether the thyroid hormone receptor (TR)-ß is involved in these changes. In the present study, we investigated central thyroid hormone metabolism during lipopolysaccharide (LPS)-induced illness in TRß(-/-) mice compared to wild-type (WT) mice. We administered a sublethal dose of LPS or saline to TRß(-/-) and WT mice. TRß(-/-) mice displayed higher basal levels of serum triiodothyronine (T(3)) and thyroxine (T(4)) compared to WT, reflecting thyroid hormone resistance. In the periventricular area of the hypothalamus, we observed a marked decrease in thyrotrophin-releasing hormone (TRH) mRNA expression in TRß(-/-) and WT mice at t = 4 h, coinciding with the peak in plasma corticosterone. The decrease in TRH mRNA persisted in WT, but not in TRß(-/-) mice at t = 24 h. By contrast, the increase of type 2 deiodinase (D2) mRNA already present at 4 h after LPS remained significant at 24 h in TRß(-/-), but not in WT mice. LPS decreased pituitary thyroid-stimulating hormone ß mRNA expression in WT at 24 h but not in TRß(-/-) mice. The peak in pituitary D2 expression at t = 4 h in WT was absent in TRß(-/-) mice. The relative decrease in plasma T(3) and T(4) upon LPS treatment was similar in both strains, although, at t = 24 h, plasma T(3) tended to be restored in TRß(-/-) mice. Our results suggest that TRß is involved in suppression of the central component of the hypothalamic-pituitary-thyroid axis in acute illness.

Chronic local inflammation in mice results in decreased TRH and type 3 deiodinase mRNA expression in the hypothalamic paraventricular nucleus independently of diminished food intake.

During illness, changes in thyroid hormone metabolism occur, known as nonthyroidal illness and characterised by decreased serum triiodothyronine (T3) and thyroxine (T4) without an increase in TSH. A mouse model of chronic illness is local inflammation, induced by a turpentine injection in each hind limb. Although serum T3 and T4 are markedly decreased in this model, it is unknown whether turpentine administration affects the central part of the hypothalamus-pituitary-thyroid axis (HPT-axis). We therefore studied thyroid hormone metabolism in hypothalamus and pituitary of mice during chronic inflammation induced by turpentine injection. Using pair-fed controls, we could differentiate between the effects of chronic inflammation per se and the effects of restricted food intake as a result of illness. Chronic inflammation increased interleukin (IL)-1beta mRNA expression in the hypothalamus more rapidly than in the pituitary. This hypothalamic cytokine response was associated with a rapid increase in local D2 mRNA expression. By contrast, no changes were present in pituitary D2 expression. TSHbeta mRNA expression was altered compared with controls. Comparing chronic inflamed mice with pair-fed controls, both preproTSH releasing hormone (TRH) and D3 mRNA expression in the paraventricular nucleus were significantly lower 48 h after turpentine administration. The timecourse of TSHbeta mRNA expression was completely different in inflamed mice compared with pair-fed mice. Turpentine administration resulted in significantly decreased TSHbeta mRNA expression only after 24 h while later in time it was lower in pair-fed controls. In conclusion, central thyroid hormone metabolism is altered during chronic inflammation and this cannot solely be attributed to diminished food intake.

Decreased neuropeptide Y (NPY) expression in the infundibular nucleus of patients with nonthyroidal illness.

In patients with a variety of illnesses, serum concentrations of T3 decrease without giving rise to elevated serum levels of TSH, a phenomenon known as the sick euthyroid syndrome or nonthyroidal illness (NTI). Our previous studies in postmortem brain material showed decreased thyrotropin-releasing hormone (TRH) messenger RNA (mRNA) in the paraventricular nucleus (PVN) of patients with NTI, suggesting a role for TRH cells in the persistence of low TSH levels in NTI. In the present study, we hypothesized that changes in neuropeptide Y (NPY) input from the infundibular nucleus (IFN) to TRH cells in the PVN might be a determinant of decreased TRH expression in NTI. We investigated the hypothalamus of nine patients whose endocrine status had been assessed in a serum sample taken less than 24h before death and we examined NPY expression in the IFN by means of immunocytochemistry and mRNA in situ hybridization using an image analysis system. There was a negative correlation (r = -0.88; p = 0.01) between serum leptin concentrations and total NPY mRNA in the IFN. The total amount of NPY immunoreactivity in the IFN correlated with total NPY mRNA (r = 0.69; p = 0.04). In contrast to the situation in food-deprived rodents, total NPY immunoreactivity in the IFN showed a positive correlation with total TRH mRNA in the PVN (r = 0.77; p = 0.02). The results suggest a role for decreased NPY input from the IFN in the resetting of thyroid hormone feedback on hypothalamic TRH cells in NTI.

Establishment of reference values for endocrine tests. II: Hyperprolactinemia.

BACKGROUND: In patients with hyperprolactinemia, the thyrotropin-releasing hormone (TRH) stimulation test is widely applied to distinguish prolactinoma from other causes of hyperprolactinemia. In the present study, we established reference values for the plasma concentration of prolactin (PRL) and its response to TRH. METHODS: Basal PRL and the PRL response to 400 micrograms TRH i.v. was determined in 50 subjects recruited from the general population, equally distributed according to sex and age between 20 and 69 years. PRL was determined by a fluoroimmunometric assay. Reference values are given as the observed range. RESULTS: Plasma concentrations of PRL were 4.0-25 micrograms/l (median: 10.0 micrograms/l) in women and 0.5-19.0 micrograms/l (median: 8.5 micrograms/l) in men (p = 0.11). The peak PRL concentration after stimulation with TRH was slightly higher in women (median: 51 micrograms/l) than in men (median: 41 micrograms/l; p = 0.04) and was reached at t = 20 min in all subjects. The relative increase in plasma PRL (median: 440%) did not show a statistically significant effect of age or sex. In 12 subjects (24%), the relative increase in plasma PRL was lower than 250%, which has traditionally been considered the minimum cutoff for a normal response. There were no effects of smoking and alcohol, but regular ingestion of liquorice was associated with lower basal (p = 0.03) and lower stimulated (p = 0.05) plasma concentrations of PRL. CONCLUSIONS: The present study provides reference values for basal and TRH-stimulated plasma concentrations of PRL.

Physiological and pathophysiological aspects of thyrotropin-releasing hormone gene expression in the human hypothalamus.

Although the tripeptide thyrotropin-releasing hormone (TRH) was the first hypothalamic hormone to be isolated and characterized, only very few data were available on the central component of the hypothalamus-pituitary-thyroid (HPT) axis in the human brain until recently. We used immunocytochemistry to describe, for the first time, the distribution of TRH-containing cells and fibers in the human hypothalamus. Brain material was obtained with a short postmortem delay followed by fixation in paraformaldehyde, glutaraldehyde, and picric acid. Many TRH-containing cells were present in the paraventricular nucleus (PVN), especially in its dorsocaudal part. Some TRH cells were found in the suprachiasmatic nucleus (SCN), which is the circadian clock of the brain, and in the sexually dimorphic nucleus (SDN), which is in agreement with earlier observations in the rat hypothalamus. Dense TRH-containing fiber networks were present not only in the median eminence but also in a number of other hypothalamic areas, suggesting a physiological function of TRH as a neuromodulator or neurotransmitter in the human brain, in addition to its neuroendocrine role in pituitary secretion of thyroid-stimulating hormone (TSH). As a next step, we developed a technique for TRH mRNA in situ hybridization using a [35S] CTP-labeled TRH cRNA antisense probe in formalin-fixed paraffin-embedded sections. Numerous heavily labeled TRH mRNA-containing neurons were detected in the caudal part of the PVN, while some cells were present in the SCN and in the perifornical area. These results demonstrated the value of in situ hybridization for elucidating the chemoarchitecture of the human hypothalamus in routinely fixed autopsy tissue and enabled us to perform quantitative studies. As part of the neuroendocrine response to disease, serum concentrations of thyroid hormone decrease without giving rise to elevated concentrations of TSH, suggesting altered feedback control at the level of the hypothalamus and/or pituitary. In order to establish whether decreased activity of TRH cells in the PVN contributes to the persistence of low TSH levels in nonthyroidal illness (NTI), hypothalamic TRH gene expression was investigated in patients whose plasma concentrations of thyroid hormones had been measured just before death. Quantitative in situ hybridization showed a positive correlation of total TRH mRNA in the PVN and serum concentrations of TSH and triiodothyronine (T3) less than 24 hours before death, supporting our hypothesis. Current experiments aim at elucidating the mechanism by which hypothalamic thyroid hormone feedback control in TRH cells of patients with NTI is changed.

Long-term neuro-endocrine sequelae after treatment for childhood medulloblastoma.

The occurrence of neuro-endocrine deficiencies following craniospinal irradiation for medulloblastoma is well known, but data concerning the spectrum and prevalence of endocrine abnormalities in adulthood are scarce. We studied endocrine function in 20 (median age 25 years) adult subjects, 8-25 years (median 16 years) after therapy. The radiation dose to the whole cranium and spinal axis was 35 +/- 2.6 Gray (mean +/- standard deviation) with a boost to the posterior fossa of 18 +/- 3.7 Gray. 13 subjects had received additional chemotherapy. In 15 of 20 (75%) subjects, endocrine abnormalities were observed. In 14 (70%), growth hormone (GH) secretion was impaired; 7 (35%) subjects had an absolute GH deficiency, while 7 (35%) showed subnormal responses to insulin-induced hypoglycaemia. In contrast, only 20% (4) of these subjects showed impairment of the hypothalamus-pituitary-thyroid (HPT) axis, while 15% (3) showed central impairment of hypothalamus-pituitary-gonadal (HPG) function. Central impairment of the HPG axis was associated with impaired GH secretion in all cases. Central adrenal insufficiency was not observed. Basal levels of prolactin were normal in all subjects. Young age at treatment was a determinant of GH deficiency in adulthood (P = 0.014). Neither post-treatment interval, nor the use of chemotherapy were determinants of central endocrine impairment in adulthood. In long-term survivors of medulloblastoma, GH deficiency has a high prevalence. In contrast, impairment of the HPG and HPT axis is less common, while central adrenal insufficiency was not observed.

Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with nonthyroidal illness.

Changes in hypothalamus-pituitary-thyroid function occur in patients with a variety of illnesses and are referred to as the euthyroid sick syndrome or nonthyroidal illness (NTI). In NTI, serum concentrations of T3 decrease to low, or even undetectable, levels without giving rise to elevated concentrations of TSH. We hypothesized that decreased activity of TRH-producing cells in the paraventricular nucleus (PVN) contributes to the persistence of low TSH levels. To test this hypothesis, we collected a series of formalin-fixed, paraffin-embedded hypothalami of patients whose plasma concentrations of T3, T4, and TSH had been measured in a blood sample taken less than 24 h before death. Quantitative TRH messenger RNA in situ hybridization (intraassay coefficient of variation: 13%) was performed in the PVN. Total TRH messenger RNA in the PVN showed a positive correlation with serum T3 (r = 0.66; P < 0.05) and with logTSH (r = 0.64; P < 0.05), but not with T4 (r = -0.02; P = 0.95). This is the first study to correlate premortem serum concentrations of thyroid hormones with postmortem gene expression of identified neurons in the human hypothalamus. The results suggest an important role for TRH cells in the pathogenesis of NTI.

Thyrotropin-releasing hormone gene expression in the human hypothalamus.

We studied the distribution of mRNA coding for thyrotropin-releasing hormone (TRH) in the human hypothalamus by means of in situ hybridization. In 10% formalin-fixed paraffin-embedded tissue sections of five hypothalami, TRH mRNA-containing cells were found in several nuclei and areas. Numerous TRH mRNA-containing cells were detected in the medial region of the caudal part of the paraventricular nucleus. These neurons were heavily labeled and mainly small to medium-sized. Few, lightly- and medium-labeled, small cells were detected in the suprachiasmatic nucleus. In addition, heavily labeled single cells were found in the perifornical area and the anterior- and lateral hypothalamic regions. In the latter region, occasional heavily labeled cells were found just dorsal to the supraoptic nucleus. Neither in the supraoptic nucleus nor in the sexually dimorphic nucleus of the preoptic area were TRH mRNA-containing cells found. This is the first description of TRH mRNA containing cells in the human hypothalamus.