[Development of Cushing's syndrome during phytotherapy]. / Entwicklung eines Cushing-Syndroms während einer Phytotherapie.

UNLABELLED: HISTORY AND INITIAL FINDINGS: In a 75-year-old woman with unclear weight gain and typical signs of Cushing's syndrome, a pituitary microadenoma and hyperplasia of the left adrenal gland were diagnosed. She was referred for preoperative diagnostics. Her clinical appearance suggested hypercortisolism. INVESTIGATIONS: The lab test suggested external glucocorticoid application. Basal ACTH and cortisol were low. DIAGNOSIS, TREATMENT AND FURTHER COURSE: The patients' phytotherapeutics received from a masseuse were analyzed in a special lab. The analysis showed that the pills were enriched with cortisone and hydrocortisone and were causal for the development of Cushing's syndrome and the symptoms of secondary adrenal insufficiency. CONCLUSION: Symptoms of Cushing's syndrome develop during chronic exposure to glucocorticoids. The development of Cushing's syndrome depends on the patient's sensitivity and on the duration and dose of the glucocorticoid application. Clinical and laboratory studies precede imaging.

Effects of hyperlipidaemia on glucocorticoid metabolism: results of a randomized controlled trial in healthy young women.

OBJECTIVE: It is well established that the hypothalamic-pituitary-adrenal (HPA) axis is altered in obese individuals. Hyperlipidaemia with elevated levels of free fatty acids (FFAs) is also frequently seen in obesity and in the metabolic syndrome. We hypothesized, therefore, that hyperlipidaemia may alter the activity of the HPA axis. PATIENTS AND METHODS: The effects of hyperlipidaemia, including increased circulating FFAs, on ACTH secretion and cortisol metabolism were analysed in 13 healthy young women during the early follicular phase of two subsequent cycles. We administered a 20% lipid/heparin (LHI) or a saline/heparin infusion (SHI) using a crossover design in random order for 330 min. A detailed characterization of glucocorticoid metabolism was performed by measurement of plasma ACTH, cortisol and urinary excretion rates of adrenal glucocorticoids and the glucocorticoid metabolites. RESULTS: We observed that LHI-induced hyperlipidaemia elevated serum cortisol levels compared to SHI. No changes in plasma ACTH levels, daily urinary excretion rates of adrenal glucocorticoids, glucocorticoid precursors/metabolites and the calculated activities of the 5α-reductase, 3ß-hydroxysteroid dehydrogenase (HSD), 11-, 17-, 21-hydroxylase and 11ß-HSD 1 or 2 were found. CONCLUSION: Our randomized controlled trial suggests that the adrenal sensitivity to ACTH may be enhanced by LHI-induced hyperlipidaemia in normal-weight healthy young women. This effect might contribute to the disturbances of the HPA axis described in women with abdominal obesity and impaired lipid metabolism.

Blockade of tachykinin NK1/NK2 receptors in the brain attenuates the activation of corticotrophin-releasing hormone neurones in the hypothalamic paraventricular nucleus and the sympathoadrenal and pituitary-adrenal responses to formalin-induced pain in the rat.

Evidence from pharmacological studies has implicated substance P (SP), a natural ligand of tachykinin NK(1) receptors which can also interact with NK(2) receptors, in the generation of pressor and tachycardic responses to stress. Using selective blockade of brain NK(1) and NK(2) receptors, we tested in conscious rats the hypothesis that SP initiates, within the neuronal brain circuits, the sympathoadrenal, hypothalamic-pituitary-adrenal (HPA) and behavioural responses to noxious stimuli. Formalin injected s.c. through a chronically implanted catheter in the area of the lower leg was used as a pain stimulus. Rats were pretreated i.c.v. with vehicle or the selective, nonpeptide antagonists of tachykinin NK(1) and NK(2) receptors, RP 67580 and SR 48968, respectively. Ten minutes thereafter, formalin was injected s.c. and the cardiovascular responses were recorded, plasma concentrations of catecholamines, adrenocorticotrophic hormone (ACTH) and corticosterone were determined and the expression of the inducible transcription factor c-Fos in the paraventricular (PVN) and supraoptic nuclei was detected to identify neurones which were activated during pain stimulation. Blockade of NK(1) and NK(2) receptors attenuated the formalin-induced increases in mean arterial pressure and heart rate, adrenaline and ACTH concentrations in plasma, and completely abolished the pain-induced c-Fos expression in corticotrophin-releasing hormone neurones localised in the parvocellular division of the PVN. The results obtained provide pharmacological evidence that tachykinins, most probably SP, act as mediators within the neuronal circuits linked to the initiation and control of the cardiovascular, sympathoadrenal, HPA and behavioural responses to pain stimuli and provide an excitatory input to corticotrophin-releasing hormone neurones in the PVN to activate the HPA axis. Our data demonstrating the inhibition of the complex response pattern to noxious stimuli and stress are consistent with the proposed anxiolytic and antidepressant activity of NK(1) and NK(2) receptor antagonists.

Expression of the kcnk3 potassium channel gene lessens the injury from cerebral ischemia, most likely by a general influence on blood pressure.

We examined the possible protective effect of TASK-1 (TWIK-related acid-sensitive potassium channel-1, kcnk3) and -3 potassium channels during stroke. TASK-1 and TASK-3, members of the two pore domain (K2P or kcnk) potassium channel family, form hetero or homodimers and help set the resting membrane potential. We used male TASK-1 and TASK-3 knockout mice in a model of focal cerebral ischemia, permanent middle cerebral artery occlusion (pMCAO). Infarct volume was measured 48 h after pMCAO. The TASK-1 knockout brains had larger infarct volumes (P=0.004), and those in TASK-3 knockouts were unchanged. As the TASK-1 gene is expressed in adrenal gland, heart and possibly blood vessels, the higher infarct volumes in the TASK-1 knockout mice could be due to TASK-1 regulating blood vessel tone and hence blood pressure or influencing blood vessel microarchitecture and blood flow rate. Indeed, we found that male TASK-1 knockout mice had reduced blood pressure, likely explaining the increased brain injury seen after pMCAO. Thus to make precise conclusions about how TASK-1 protects neurons, neural- or organ-specific deletions of the gene will be needed. Nevertheless, a consequence of having TASK-1 channels expressed (in various non-neuronal tissues and organs) is that neuronal damage is lessened when stroke occurs.

Saliva as a medium for aldosterone measurement in repeated sampling studies.

BACKGROUND: Saliva is a readily available biological fluid, making it convenient in diagnosis of diseases and in multi-sampling protocols. Several salivary steroids give a useful index of free plasma levels. Increased incidence of primary aldosteronism (PA) in approximately 10% of the hypertensive population has increased interest in the mineralocorticoid aldosterone. METHODS: A biotinylated-aldosterone tracer and a commercially available antibody are used in a time-resolved fluorescence immunoassay (TR-FIA) to measure salivary aldosterone (SA). Saliva was collected in various multi-sampling protocols: Investigation of diurnal rhythm in healthy and PA patients, ACTH stimulation test and posture test in healthy subjects. RESULTS: Method validation showed a sensitivity of 19 ng/L and intra-/inter-assay precision between 7.2-10.1% and 8.7-15.7%, respectively. SA correlated significantly (y = 0.2995x +/- 0.01, r(2)=0.60) to plasma aldosterone measured by a commercial radioimmunoassay. SA (median; 95%CI) was at 111 (95-127)ng/L in PA (n=84) and 50 (44-56)ng/L in healthy subjects (n=60). After change in posture, aldosterone increased in both, saliva (57 (47-63)ng/L to 95 (84-117)ng/L) and plasma (26 (26-41)ng/L to 135 (110-181)ng/L). Peak levels were reached after 1h, and were higher in females than in males. CONCLUSIONS: SA correlates well to plasma aldosterone and mirrors responses during conditions of stress. SA is significantly higher in PA, and the diurnal rhythm seen in the healthy is blunted in PA. We additionally found gender-dependent differential responses to posture, with higher increases in females. Measurement of aldosterone in saliva presents a useful and convenient method for application in multi-sampling studies.

[Endurance capabilities of triathlon competitors with type 1 diabetes mellitus]. / Ausdauer-Leistungsfähigkeit von Triathlon-Athleten mit Typ-1-Diabetes.

BACKGROUND AND OBJECTIVE: Treatment of type 1 diabetes mellitus (DM) aims to prevent complications by strictly optimizing blood glucose levels. Although physical exercise is an important part of metabolic control, endurance sports are considered hazardous for patients with type 1 diabetes because of the extreme physiological stress they represent. To further elucidate the metabolic challenge this form of exercise presented we investigated the performance of triathlon competitors with type 1 diabetes. PATIENTS AND METHODS: Ten patients (32-61 years) with type 1 diabetes (disease duration 2-35 years) were followed for three years, during which each year they participated in one triathlon long-distance competitions (2.4 miles swimming, 26.2 miles running and 112 miles cycling; Ironman Germany 2005-2007). Glucose, cortisol, aldosterone, renin, thyroid hormones, testosterone, growth hormone and catecholamines were measured in blood and saliva. Five non-diabetic competitors served as controls. RESULTS: The performance equalled those of age-matched healthy athletes. Several participants experienced hyperglycemia early in the bike leg, whereas all of them developed low blood glucose levels during the marathon leg. Basal insulin supply was reduced up to 50 % on race day. Hormone levels in athletes with type 1 DM and healthy controls were similar. CONCLUSIONS: Patients with type 1 DM can successfully sustain extreme endurance challenges. Physiological alterations of the metabolic state complicated by type 1 DM can readily be compensated by adapting intensified insulin therapy and nutritional modifications. Thus 1 DM should not be regarded a contraindication to participating in high endurance sports.

Serum concentrations of cortisol and cortisone in healthy dogs and dogs with pituitary-dependent hyperadrenocorticism treated with trilostane.

The serum concentrations of cortisol and cortisone were measured in 19 healthy dogs and in 13 dogs with pituitary-dependent hyperadrenocorticism (PDH) before and one hour after an injection of synthetic adrenocorticotropic hormone (ACTH). In the dogs with pdh, the cortisol and cortisone concentrations were measured before and after one to two weeks and three to seven weeks of treatment with trilostane. The dogs with PDH had significantly higher baseline and poststimulation concentrations of cortisol and cortisone, and higher baseline cortisol:cortisone ratios than the healthy dogs. During the treatment with trilostane, the poststimulation cortisol, the baseline and poststimulation cortisone concentrations, and the baseline and poststimulation cortisol:cortisone ratios decreased significantly. The decrease in poststimulation cortisone was significantly smaller than the decrease in cortisol.

Intravenous lipid and heparin infusion-induced elevation in free fatty acids and triglycerides modifies circulating androgen levels in women: a randomized, controlled trial.

BACKGROUND: The polycystic ovarian syndrome (PCOS) is characterized by hyperandrogenism and associated with obesity and impaired glucose metabolism. Despite the high prevalence of PCOS and the considerable clinical impact, the precise interplay between metabolism and hyperandrogenemia is not entirely clear. OBJECTIVE: The objective of the study was to analyze the effects of iv lipid and heparin infusion on circulating androgen levels in healthy women. DESIGN: This was a randomized, controlled, crossover trial. SETTING: The study was conducted at an endocrinology center. PATIENTS: Patients included 12 healthy young women during the early follicular phase of two subsequent cycles. INTERVENTION: After an overnight fast, a 20% lipid/heparin or a saline/heparin infusion was administered in random order for 330 min. MAIN OUTCOME MEASURES: A detailed characterization of androgen metabolism was performed. RESULTS: Elevations in free fatty acids and triglycerides, induced by lipid/heparin infusion, elevates the levels of androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), testosterone, 5alpha-dihydrotestosterone, estrone, and 17beta-estradiol. Urinary excretion of DHEA, DHEAS, 5-androstene-3beta,17beta-diol, and the sum of urinary excreted DHEA and its 16-hydroxylated downstream metabolites, 16alpha-hydroxy-DHEA and 5-androstene-3beta,16alpha,17beta-triol, were reduced. CONCLUSION: The mechanism of iv lipid and heparin infusion-induced elevation of circulating androgens described here might contribute to the development of hyperandrogenism in women with PCOS and suggests that lowering of hyperlipidemia might be a potential therapeutic target in patients with PCOS to treat hyperandrogenemia.

Evaluation of cortisol precursors for the diagnosis of pituitary-dependent hypercortisolism in dogs.

The serum concentrations of cortisol, 17alpha-hydroxypregnenolone, 17alpha-hydroxyprogesterone, 21-deoxycortisol and 11-deoxycortisol were measured in 19 healthy dogs, 15 dogs with pituitary-dependent hypercortisolism (pdh) and eight dogs with other diseases before and one hour after an injection of synthetic adrenocorticotrophic hormone (acth). At both times the dogs with pdh had significantly higher concentrations of cortisol, 17alpha-hydroxypregnenolone, 17alpha-hydroxyprogesterone and 21-deoxycortisol than the healthy dogs. Basal 11-deoxycortisol concentrations were also significantly higher in dogs with pdh compared with healthy dogs. When compared with the dogs with other diseases, the dogs with pdh had significantly higher basal and post-acth cortisol and basal 21-deoxycortisol, and significantly lower post-acth 11-deoxycortisol concentrations. The dogs with other diseases had significantly higher post-acth cortisol, 17alpha-hydroxyprogesterone and 11-deoxycortisol concentrations than the healthy dogs. In general, the post-acth concentrations of 17alpha-hydroxypregnenolone, 17alpha-hydroxyprogesterone, 11-deoxycortisol and 21-deoxycortisol were more variable than the post-acth concentrations of cortisol, resulting in large overlaps of the concentrations of these hormones between the three groups. A two-graph receiver operating characteristic (ROC) analysis was used to maximise the sensitivity and specificity of each hormone for diagnosing hypercortisolism; it showed that the post-acth concentration of cortisol had the highest sensitivity and specificity. The overlaps between the healthy dogs, the dogs with pdh and the dogs with other diseases suggested that the individual precursor hormones would not be useful as a screening test for hypercortisolism.

Neuroendocrinological effects of acupuncture treatment in patients with irritable bowel syndrome.

OBJECTIVES: Quality of life (QoL) improvement in patients with irritable bowel syndrome (IBS) during acupuncture (AC) treatment seems to be due to a placebo effect. The aim was to explore if acupuncture has some specific influence on the neuroendocrinic and autonomic nervous system (ANS). DESIGN/SETTING: Patients with IBS were randomly assigned to receive either acupuncture (AC) or sham acupuncture (SAC) using the so-called "Streitberger needle". QoL was measured with the functional quality of life diseases quality of life questionnaire (FDDQL) and SF-36. The effect on ANS was evaluated by measuring salivary cortisol and by cardiovascular responses on a tilt table before and after 10 AC treatments. Complete data sets of tilt table and salivary morning cortisol were available for 9 patients in the AC and 12 in SAC group. RESULTS: QoL increased in both groups (p=0.001) with no group differences. Salivary cortisol decreased in all groups (F=10.55; p=0.006). However, the decrease was more pronounced in the AC group (F=4.07; p=0.033) (ANOVA repeated measures model). Heart rate response decreased during orthostatic stress in the AC group while it increased in the SAC group (F=9.234; p=0.005), indicating an increased parasympathetic tone in the AC group. Improvement of pain was positively associated with increased parasympathetic tone in the AC group (F=10.1; p=0.006), but not in the SAC group. CONCLUSIONS: The acupuncture specific physiological effects are in contrast to the unspecific improvement of QoL in both AC and SAC groups. Thus, different mechanisms seem to be involved in placebo and real-acupuncture driven improvements. The specific mechanism of action of acupuncture on the ANS remains unclear and deserves further evaluation.

[68-year-old female patient with dyspnea and hypokalemic hypertension]. / 68-jährige Patientin mit Dyspnoe und hypokaliämischer Hypertonie.

Ectopic ACTH syndrome is a rare differential diagnosis of hypokalemic hypertension. Patients with ectopic ACTH syndrome due to small cell lung cancer have a poor prognosis. We report on a 68-year-old female patient who presented with dyspnea and hypokalemic hypertension. Endocrine testing was consistent with ectopic ACTH syndrome due to small cell lung cancer. After initiation of chemotherapy with etoposide and carboplatin ACTH and cortisol levels normalized and clinical symptoms impressively improved.

Late diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Congenital adrenal hyperplasia results from 21-hydroxylase deficiency in more than ninety percent of cases. The classical form of 21-hydroxylase deficiency presents in the neonatal period with virilization or adrenal insufficiency, with or without concurrent salt wasting. We report on a rare case of classic 21-hydroxylase deficiency diagnosed in late adulthood. A 39-year-old male patient presented for workup of infertility. Urologic investigation revealed small testes, bilateral testicular masses, and asthenozoospermia. The patient's steroid metabolism showed markedly increased levels of adrenal androgens, in particular of 17-hydroxyprogesterone amd 21-deoxycortisol. The gas chromatographic-mass spectrometric (GC-MS) urinary steroid profile was dominated by metabolites of 17-hydroxyprogesterone, while the endogenous glucocorticoid production was subnormally low. ACTH levels in plasma were elevated. These hormonal findings were consistent with 21-hydroxylase deficiency. Therapy with dexamethasone was initiated. The CTP21A2 gene analysis revealed the mutation I172N (ATC --> AAC) in exon 4 of allele 1 and a large gene deletion in allele 2. Cases of 21-hydroxylase deficiency diagnosed in late adulthood are rare; however, clinicians should be alert of this possibility.

Cortisol, aldosterone, cortisol precursor, androgen and endogenous ACTH concentrations in dogs with pituitary-dependant hyperadrenocorticism treated with trilostane.

Trilostane is thought to be a competitive inhibitor of the 3beta-hydroxysteroid dehydrogenase (3beta-HSD), an essential enzyme system for the synthesis of cortisol, aldosterone and androstenedione. Due to its reliable clinical efficacy, trilostane is increasingly used to treat dogs with pituitary-dependant hyperadrenocorticism (PDH). The objective of our study was to investigate the effect of trilostane on precursor concentrations located before (17alpha-OH-pregnenolone, dehydroepiandrostenedione) and after (17alpha-OH-progesterone, androstenedione, 11-deoxycortisol, 21-deoxycortisol) the proposed enzyme inhibition, on end products of steroid biosynthesis (cortisol and aldosterone) and on endogenous adrenocorticotrophic hormone (ACTH) concentrations in dogs with PDH. Hormones of the steroid biosynthesis pathway were evaluated in 15 dogs before and 1h after injection of synthetic ACTH prior to (t(0)), in weeks 1-2 (t(1)) and in weeks 3-7 (t(2)) of trilostane treatment. Endogenous ACTH concentrations were measured at the same time points before performing the ACTH stimulation test. During trilostane treatment baseline and post-stimulation cortisol concentrations decreased significantly. Baseline serum aldosterone levels showed a significant increase; post-stimulation values decreased. Baseline and post-stimulation 17alpha-OH-pregnenolone and dehydroepiandrostenedione concentrations increased significantly. 17alpha-OH-progesterone and androstenedione levels did not change. Post-stimulation 21-deoxycortisol concentrations decreased significantly, baseline 11-deoxycortisol concentrations increased significantly. Endogenous ACTH levels showed a significant increase. The significant increase in 17alpha-OH-pregnenolone and dehydroepiandrostenedione concentrations confirms an inhibitory effect of trilostane on the 3beta-HSD. Since 17alpha-OH-progesterone concentrations did not change, but cortisol concentrations markedly decreased, trilostane seems to influence additional enzymes of the hormone cascade, like the 11beta-hydroxylase and possibly the 11beta-hydroxysteroid dehydrogenase.

Adaptation of the hypothalamic-pituitary hormones during intensive endurance training.

OBJECTIVE: Physical activity leads to changes in the hypothalamic-pituitary hormonal system. However, acute and long-term adaptations have not yet been precisely characterized. In this study, the changes of the hormonal system as a result of marathon training and running a marathon were examined. In particular, we focused on adaptations of the hypothalamic-pituitary-adrenocortical (HPA) axis, regarding the activation or inactivation of cortisol to cortisone by the 11beta-hydroxysteroid-dehydrogenase system (11beta-HSD). DESIGN: Patient measurements: 8 healthy women and 11 healthy men volunteered for this study. Blood samples, 24-h urine and a dexamethasone suppression test were analysed for metabolic and hormonal parameters at five different dates 12 weeks around a marathon. RESULTS: Cortisol and ACTH values decreased significantly 2 days after the marathon, whereas the activity of the whole body 11beta-HSD-1 was up-regulated. An increased suppression of cortisol levels was observed in the dexamethasone suppression test after 6 weeks of reduced training levels. Ghrelin was elevated 2 days after the marathon. Only minor changes in the other hypothalamic-pituitary-hormonal axes could be observed. However, the free androgen index increased significantly after 6 weeks of reduced training. CONCLUSIONS: The HPA system appeared to become chronically activated by continuous physical training and therefore less sensitive to the dexamethasone suppression test. The acute stress of the marathon led to a central exhaustion of the HPA system with a paracrine counteraction by the activation of the 11beta-HSD system. Changes in the other hypothalamic-pituitary hormonal axes were the result of long-term differences in training levels and were not altered by the marathon.

In vivo activity of 11beta-hydroxysteroid dehydrogenase type 1 and free fatty acid-induced insulin resistance.

INTRODUCTION: Free fatty acids (FFAs) induce hepatic insulin resistance and enhance hepatic gluconeogenesis. Glucocorticoids (GCs) also stimulate hepatic gluconeogenesis. The aim of this study was to investigate whether the FFA-induced hepatic insulin resistance is mediated by increased activity of hepatic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), accompanied by elevated hepatic cortisol levels. METHODS: Following a 10-h overnight fast, six healthy male volunteers were investigated. A euglycaemic hyperinsulinaemic clamp was performed during lipid or saline infusion. To assess hepatic 11beta-HSD1 activity, plasma cortisol levels were measured after oral administration of cortisone acetate during lipid or saline infusion. In addition, 11beta-HSD activities were determined in vivo by calculating the urinary ratios of GC metabolites. RESULTS: Lipid infusion increased FFAs (5.41 +/- 1.00 vs. 0.48 +/- 0.20 mmol/l; P < 0.005) and significantly increased insulin resistance [glucose infusion rate (GIR) 6.02 +/- 2.60 vs. 4.08 +/- 2.15 mg/kg/min; P < 0.005]. After lipid and saline infusions no changes in 11beta-HSD1 activity were found, neither by changes in cortisone acetate to cortisol conversion nor by differences in urinary free cortisol (UFF) or cortisone (UFE), 5beta-tetrahydrocortisol (THF), 5alpha-THF, cortisone (THE), UFF/UFE and (5alpha-THF + THF)/THE ratios. CONCLUSIONS: We found no change in hepatic and whole-body 11beta-HSD1 activity during acute FFA-induced insulin resistance. Further studies are necessary to clarify whether 11beta-HSD1 in muscle and adipose tissue is influenced by FFAs and whether 11beta-HSD1 is involved in other conditions of insulin resistance.

Steroid profile in an adrenocortical carcinoma producing aldosterone.

We report a rare case of primary aldosteronism due to an adrenocortical carcinoma. A 61-year-old woman with a history of hypertension and hypokalemia was referred for evaluation of a 4.2 cm measuring adrenal mass without secondary signs of malignancy. Endocrinological testing was consistent with primary aldosteronism. The patient underwent surgical resection of the adrenal mass; histology revealed an adrenocortical carcinoma. Postoperatively blood pressure, serum potassium, and aldosterone returned to normal. Four months after adrenalectomy, the patient presented again with hypokalemic hypertension and was found to have metastatic disease. Endocrinological investigation revealed primary aldosteronism and subclinical autonomous glucocorticoid hypersecretion. Careful hormonal investigation should be obtained in patients with adrenal masses causing excessive aldosterone secretion. In uncertain cases of primary aldosteronism, we would suggest to measure 18-hydroxycortisol levels, as excessive amounts may indicate adrenocortical carcinoma.

Adrenocortical carcinoma producing 11-deoxycorticosterone: a rare cause of mineralocorticoid hypertension.

A 37-yr-old man presented with the classic signs of mineralocorticoid excess hypertension and hypokalemia. The cause was not aldosterone excess, but elevation of plasma 11-deoxycorticosterone (DOC). Computed tomography (CT) scans showed a large right adrenal mass without signs of metastatic disease. The tumor was removed by open laparotomy, and histology revealed an adrenocortical carcinoma. Two yr after diagnosis, the patient is in good general condition and there is no sign of recurrence or metastatic disease, despite the large tumor size. DOC producing adrenocortical carcinomas causing mineralocorticoid hypertension are very rare, so far only 10 cases have been described in the literature.

Loss of Gq/11 family G proteins in the nervous system causes pituitary somatotroph hypoplasia and dwarfism in mice.

Heterotrimeric G proteins of the Gq/11 family transduce signals from a variety of neurotransmitter and hormone receptors and have therefore been implicated in various functions of the nervous system. Using the Cre/loxP system, we generated mice which lack the genes coding for the alpha subunits of the two main members of the Gq/11 family, gnaq and gna11, selectively in neuronal and glial precursor cells. Mice with defective gnaq and gna11 genes were morphologically normal, but they died shortly after birth. Mice carrying a single gna11 allele survived the early postnatal period but died within 3 to 6 weeks as anorectic dwarfs. In these mice, postnatal proliferation of pituitary somatotroph cells was strongly impaired, and plasma growth hormone (GH) levels were reduced to 15%. Hypothalamic levels of GH-releasing hormone (GHRH), an important stimulator of somatotroph proliferation, were strongly decreased, and exogenous administration of GHRH restored normal proliferation. The hypothalamic effects of ghrelin, a regulator of GHRH production and food intake, were reduced in these mice, suggesting that an impairment of ghrelin receptor signaling might contribute to GHRH deficiency and abnormal eating behavior. Taken together, our findings show that Gq/11 signaling is required for normal hypothalamic function and that impairment of this signaling pathway causes somatotroph hypoplasia, dwarfism, and anorexia.

Neuroendocrine changes in patients with acute space occupying ischaemic stroke.

OBJECTIVE: To evaluate neuroendocrine changes in critical care patients with acute space occupying hemispheric stroke. METHODS: 22 patients with acute space occupying hemispheric stroke were studied (mean age 57.7 years; five women, 17 men). Plasma levels of prolactin, thyrotropin (TSH), total thyroxine (T4), free thyroxine (FT4), and total triiodothyronine (T3) were measured on admission and thereafter on days 3, 5, 7, and 9. Cortisol and ACTH levels were analysed at 8.00, 16.00, and 24.00 hours each day. A TRH stimulation test with measurements of TSH and prolactin was done on day 3. RESULTS: Nine patients underwent decompressive craniectomy and nine were treated with moderate hypothermia. All patients received vasopressor drugs because of arterial hypotension. Plasma ACTH and cortisol values were abnormally low despite systemic hypotension and acute systemic illness, and remained low throughout the observation period. The diurnal rhythm of cortisol was not preserved. Prolactin levels increased during the observation period, and were well above normal on day 9. Thyroid function was slightly suppressed until day 7. TRH stimulation of plasma TSH and prolactin was low. CONCLUSIONS: Patients with an acute space occupying cerebral infarct show profound neuroendocrine changes. The central regulation of adrenal and thyroid function and prolactin release is impaired, which may compromise the clinical course of affected patients and have implications for therapeutic management.

Enhanced 11beta-hydroxysteroid dehydrogenase type 1 activity in stress adaptation in the guinea pig.

The 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) convert cortisol to its inactive metabolite cortisone and vice versa. 11beta-HSD type 1 (11beta-HSD-1) functions as a reductase in vivo, regulating intracellular cortisol levels and its access to the glucocorticoid receptor. In contrast, 11beta-HSD-2 only mediates oxidation of natural glucocorticoids, and protects the mineralocorticoid receptor from high cortisol concentrations. We investigated the in vivo and in vitro effects of ACTH on the recently characterized 11beta-HSDs in guinea pig liver and kidney. Tissue slices of untreated guinea pigs were incubated with (3)H-labelled cortisol or cortisone and ACTH(1-24) (10(-10) and 10(-9) mol/l). The 11beta-HSD activities in liver and kidney slices were not influenced by in vitro incubation with ACTH(1-24). In addition, guinea pigs were treated with ACTH(1-24) or saline injections s.c. for 3 days. Liver and kidney tissue slices of these animals were incubated with (3)H-labelled cortisol or cortisone. In vivo ACTH treatment significantly increased reductase and decreased oxidase activity in liver and kidney. Furthermore, 11beta-HSD-1 activity assessed by measurement of the urinary ratio of (tetrahydrocortisol (THF)+5alphaTHF)/(tetrahydrocortisone) was significantly increased after ACTH treatment compared with the control group. Plasma levels of cortisol, cortisone, progesterone, 17-hydroxyprogesterone and androstenedione increased significantly following in vivo ACTH treatment. The enhanced reductase activity of the hepatic and renal 11beta-HSD-1 is apparently caused by cortisol or other ACTH-dependent steroids rather than by ACTH itself. This may be an important fine regulation of the glucocorticoid tonus for stress adaptation in every organ, e.g. enhanced gluconeogenesis in liver.