The implications of microsurgical anatomy for surgical approaches to the sellar region

The knowledge of the normal anatomy and variations regarding the management of tumors of the sellar region is paramount to perform safe surgical procedures. The sellar region is located in the center of the middle cranial fossa; it contains complex anatomical structures, and is the site of various pathological processes: tumor, vascular, developmental, and neuroendocrine. We review the microsurgical anatomy (microscopic and endoscopic) of this region and discuss the surgical nuances regarding this topic, based on anatomical concepts.

Early onset of primary hypogonadism revealed by serum anti-Mullerian hormone determination during infancy and childhood in trisomy 21

Male patients with an extra sex chromosome or autosome are expected to present primary hypogonadism at puberty owing to meiotic germ-cell failure. Scarce information is available on trisomy 21, a frequent autosomal aneuploidy. Our objective was to assess whether trisomy 21 presents with pubertal-onset, germ-cell specific, primary hypogonadism in males, or whether the hypogonadism is established earlier and affects other testicular cell populations. We assessed the functional status of the pituitary-testicular axis, especially Sertoli cell function, in 117 boys with trisomy 21 (ages: 2 months-20 year). To compare with an adequate control population, we established reference levels for serum anti-Mullerian hormone (AMH) in 421 normal males, from birth to adulthood, using a recently developed ultrasensitive assay. In trisomy 21, AMH was lower than normal, indicating Sertoli cell dysfunction, from early infancy, independently of the existence of cryptorchidism. The overall prevalence rate of AMH below the 3rd percentile was 64.3% in infants with trisomy 21. Follicle-stimulating hormone was elevated in patients <6 months and after pubertal onset. Testosterone was within the normal range, but luteinizing hormone was elevated in most patients <6 months and after pubertal onset, indicating a mild Leydig cell dysfunction. We conclude that in trisomy 21, primary hypogonadism involves a combined dysfunction of Sertoli and Leydig cells, which can be observed independently of cryptorchidism soon after birth, thus prompting the search for new hypotheses to explain the pathophysiology of gonadal dysfunction in autosomal trisomy.

Expression profiles of the glucose-dependent insulinotropic peptide receptor and LHCGR in sporadic adrenocortical tumors

Glucose-dependent insulinotropic peptide receptor (GIPR) and LHCGR are G-protein-coupled receptors with a wide tissue expression pattern. Aberrant expression of these receptors has rarely been demonstrated in adult sporadic adrenocortical tumors with a lack of data on pediatric tumors. We quantified the GIPR and LHCGR expression in a large cohort of 55 patients (25 children and 30 adults) with functioning and non-functioning sporadic adrenocortical tumors. Thirty-eight tumors were classified as adenomas whereas 17 were carcinomas. GIPR, and LHCGR expression were analyzed by real-time PCR and normal human pancreatic and testicular tissue samples were used as positive controls. Mean expression values were determined by fold increase in comparison with a normal adrenal pool. GIPR mRNA levels were significantly higher in adrenocortical carcinomas than in adenomas from both pediatric and adult groups. LHCGR expression was similar in both carcinomas and adenomas from the pediatric group but significantly lower in carcinomas than in adenomas from the adult group (median 0.06 and 2.3 respectively, P<0.001). GIPR was detected by immunohistochemistry in both pediatric and adult tumors. Staining and real-time PCR results correlated positively only when GIPR in RN A levels were increased at least two-fold in comparison with normal adrenal expression levels. In Conclusion, GIPR overexpression was observed in pediatric and adult adrenocortical tumors and very low levels of LHCGR expression were found in all adult adrenocortical carcinomas.

Two cases of Kallmann syndrome associated with empty sella

Kallmann syndrome (KS) is a developmental disease characterized by the association of isolated hypogonadotropic hypogonadism and anosmia/hyposmia. We report an unusual presentation of two females with KS and empty sella. These females, aged at 20 and 29-year-old, presented primary amenorrhea with prepubertal estradiol and low gonadotropin levels. No other significant clinical signs were observed. Empty sella was observed on MRI in both cases. Sequencing of FGFR1 gene, recently implicated in autosomal form of KS, was performed and one splicing mutation (IVS14 + 1G > A) was identified in one patient.

Current management practices for acromegaly: an international survey

To determine whether peer-reviewed consensus statements have changed clinical practice, we surveyed acromegaly care in specialist centers across the globe, and determined the degree of adherence to published consensus guidelines on acromegaly management. Sixty-five acromegaly experts who participated in the 7th Acromegaly Consensus Workshop in March 2009 responded. Results indicated that the most common referring sources for acromegaly patients were other endocrinologists (in 26% of centers), neurosurgeons (25%) and primary care physicians (21%). In sixty-nine percent of patients, biochemical diagnoses were made by evaluating results of a combination of growth hormone (GH) nadir/basal GH and elevated insulin like growth factor-I (IGF-I) levels. In both Europe and the USA, neurosurgery was the treatment of choice for GH-secreting microadenomas and for macroadenomas with compromised visual function. The most widely used criteria for neurosurgical outcome assessment were combined measurements of IGF-I and GH levels after oral glucose tolerance test (OGTT) 3 months after surgery. Ninety-eight percent of respondents stated that primary treatment with somatostatin receptor ligands (SRLs) was indicated at least sometime during the management of acromegaly patients. In nearly all centers (96%), the use of pegvisomant monotherapy was restricted to patients who had failed to achieve biochemical control with SRL therapy. The observation that most centers followed consensus statement recommendations encourages the future utility of these workshops aimed to create uniform management standards for acromegaly.

Immunoendocrinology of the Thymus in Chagas Disease

During immune response to infectious agents, the host develops an inflammatory response which could fail to eliminate the pathogen or may become dysregulated. In this case, the ongoing response acquires a new status and turns out to be detrimental. The same elements taking part in the establishment and regulation of the inflammatory response (cytokines, chemokines, regulatory T cells and counteracting compounds like glucocorticoids) may also mediate harmful effects. Thymic disturbances seen during Trypanosoma cruzi (T. cruzi) infection fit well with this conceptual framework. After infection, this organ suffers a severe atrophy due to apoptosis-induced thymocyte exhaustion, mainly affecting the immature double-positive (DP) CD4+CD8+ population. Thymus cellularity depletion, which occurs in the absence of main immunological mediators involved in anti-T. cruzi defense, seems to be linked to a systemic cytokine/hormonal imbalance, involving a dysregulated increase in Tumor Necrosis Factor alpha (TNF-alpha) and corticosterone hormone levels. Additionally, we have found an anomalous exit of potentially autoimmune DP cells to the periphery, in parallel to a shrinkage in the compartment of natural regulatory T cells. In this context, our data clearly point to the view that the thymus is a target organ of T. cruzi infection. Preserved thymus may be essential for the development of an effective immune response against T. cruzi, but this organ is severely affected by a dysregulated circuit of proinflammatory cytokines and glucocorticoids. Also, the alterations observed in the DP population might have potential implications for the autoimmune component of human Chagas disease. Copyright (C) 2011 S. Karger AG, Basel

Localization of myosin-Va in subpopulations of cells in rat endocrine organs

Myosin-Va is a Ca2+/calmodulin-regulated unconventional myosin involved in the transport of vesicles, membranous organelles, and macromolecular complexes composed of proteins and mRNA. The cellular localization of myosin-Va has been described in great detail in several vertebrate cell types, including neurons, melanocytes, lymphocytes, auditory tissues, and a number of cultured cells. Here, we provide an immunohistochemical view of the tissue distribution of myosin-Va in the major endocrine organs. Myosin-Va is highly expressed in the pineal and pituitary glands and in specific cell populations of other endocrine glands, especially the parafollicular cells of the thyroid, the principal cells of the parathyroid, the islets of Langerhans of the pancreas, the chromaffin cells of the adrenal medulla, and a subpopulation of interstitial testicular cells. Weak to moderate staining has been detected in steroidogenic cells of the adrenal cortex, ovary, and Leydig cells. Myosin-Va has also been localized to non-endocrine cells, such as the germ cells of the seminiferous epithelium and maturing oocytes and in the intercalated ducts of the exocrine pancreas. These data provide the first systematic description of myosin-Va localization in the major endocrine organs of rat.

A new proctoscope for transanal endoscopic operations

Transanal access is one of many currently used procedures for rectal cancer treatment. The techniques used for local excision include conventional transanal excision, posterior access, therapeutic colonoscopy and transanal endoscopic approaches. The aim of the present study was to present a new surgical proctoscope for the endoscopic transanal excision of rectal lesions. A cylindrical proctoscope with a diameter of 4 cm was devised and built. The end inserted into the anus has a bevelled aspect and rounded borders, allowing correct exposure of the anal lesion. The rectoscope is fixed to the anal border with surgical thread through perforations in the external end. A base screw holds a fibre-light which illuminates the operative field. Part of the equipment is a guide which is positioned inside the rectoscope on insertion into the anus. In operations utilizing this proctoscope, 17 adenomas, 25 adenocarcinomas, 1 carcinoid and 1 endometrioma were excised. The diameter of the lesions varied from 1 to 6 cm. The range of procedures that are possible with this new proctoscope are similar to those achieved with conventional techniques which, however, require more expensive equipment. Hence, the present study demonstrates that this newly devised low-cost proctoscope is an efficient tool for the transanal endoscopic excision of rectal lesions.

TAC3/TACR3 Mutations Reveal Preferential Activation of Gonadotropin-Releasing Hormone Release by Neurokinin B in Neonatal Life Followed by Reversal in Adulthood

Context: Mutations in TAC3 and TACR3 (encoding neurokinin B and its receptor) have been identified in Turkish patients with idiopathic hypogonadotropic hypogonadism (IHH), but broader populations have not yet been tested and genotype-phenotype correlations have not been established. Objective: A broad cohort of normosmic IHH probands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships. Design and Setting: The study consisted of sequencing of TAC3/TACR3, in vitro functional assays, and neuroendocrine phenotyping conducted in tertiary care centers worldwide. Patients or Other Participants: 345 probands, 18 family members, and 292 controls were studied. Intervention: Reproductive phenotypes throughout reproductive life and before and after therapy were examined. Main Outcome Measure: Rare sequence variants in TAC3/TACR3 were detected. Results: In TACR3, 19 probands harbored 13 distinct coding sequence rare nucleotide variants [three nonsense mutations, six nonsynonymous, four synonymous (one predicted to affect splicing)]. In TAC3, one homozygous single base pair deletion was identified, resulting in complete loss of the neurokinin B decapeptide. Phenotypic information was available on 16 males and seven females with coding sequence variants in TACR3/TAC3. Of the 16 males, 15 had microphallus; none of the females had spontaneous thelarche. Seven of the 16 males and five of the seven females were assessed after discontinuation of therapy; six of the seven males and four of the five females demonstrated evidence for reversibility of their hypogonadotropism. Conclusions: Mutations in the neurokinin B pathway are relatively common as causes of hypogonadism. Although the neurokinin B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time. (J Clin Endocrinol Metab 95: 2857-2867, 2010)

Role of N-Methyl-D-Aspartate and Non-N-Methyl-D-Aspartate Receptors in the Cardiovascular Effects of L-Glutamate Microinjection Into the Hypothalamic Paraventricular Nucleus of Unanesthetized Rats

We report on the cardiovascular effects of L-glutamate (L-glu) microinjection into the hypothalamic paraventricular nucleus (PVN) as well as the mechanisms involved in their mediation. L-glu microinjection into the PVN caused dose-related pressor and tachycardiac responses in unanesthetized rats. These responses were blocked by intravenous (i.v.) pretreatment with the ganglion blocker pentolinium (PE; 5 mg/kg), suggesting sympathetic mediation. Responses to L-glu were not affected by local microinjection of the selective non-NMDA receptor antagonist NBQX (2 nmol) or by local microinjection of the selective NMDA receptor antagonist LY235959 (LY; 2 nmol). However, the tachycardiac response was changed to a bradycardiac response after treatment with LY235959, suggesting that NMDA receptors are involved in the L-glu heart rate response. Local pretreatment with LY235959 associated with systemic PE or dTyr(CH(2))(5)(Me)AVP (50 mu g/kg) respectively potentiated or blocked the response to L-glu, suggesting that L-glu responses observed after LY235959 are vasopressin mediated. The increased pressor and bradycardiac responses observed after LY + PE was blocked by subsequent i.v. treatment with the V(1)-vasopressin receptor antagonist dTyr(CH(2))(5)(Me)AVP, suggesting vasopressin mediation. The pressor and bradycardiac response to L-glu microinjection into the PVN observed in animals pretreated with LY + PE was progressively inhibited and even blocked by additional pretreatment with increasing doses of NBQX (2, 10, and 20 nmol) microinjected into the PVN, suggesting its mediation by local non-NMDA receptors. In conclusion, results suggest the existence of two glutamatergic pressor pathways in the PVN: one sympathetic pathway that is mediated by NMDA receptors and a vasopressinergic pathway that is mediated by non-NMDA receptors. (C) 2009 Wiley-Liss, Inc.

Role of the bed nucleus of the stria terminalis in the cardiovascular responses to acute restraint stress in rats

The aim of this work was to test the hypothesis that the bed nucleus of the stria terminalis (BST) and noradrenergic neurotransmission therein mediate cardiovascular responses to acute restraint stress in rats. Bilateral microinjection of the non-specific synaptic blocker CoCl2 (0.1nmol/100nl) into the BST enhanced the heart rate (HR) increase associated with acute restraint without affecting the blood pressure increase, indicating that synapses within the BST influence restraint-evoked HR changes. BST pretreatment with the selective 1-adrenoceptor antagonist WB4101 (15nmol/100nl) caused similar effects to cobalt, indicating that local noradrenergic neurotransmission mediates the BST inhibitory influence on restraint-related HR responses. BST treatment with equimolar doses of the 2-adrenoceptor antagonist RX821002 or the -adrenoceptor antagonist propranolol did not affect restraint-related cardiovascular responses, reinforcing the inference that 1-adrenoceptors mediate the BST-related inhibitory influence on HR responses. Microinjection of WB4101 into the BST of rats pretreated intravenously with the anticholinergic drug homatropine methyl bromide (0.2mg/kg) did not affect restraint-related cardiovascular responses, indicating that the inhibitory influence of the BST on the restraint-evoked HR increase could be related to an increase in parasympathetic activity. Thus, our results suggest an inhibitory influence of the BST on the HR increase evoked by restraint stress, and that this is mediated by local 1-adrenoceptors. The results also indicate that such an inhibitory influence is a result of parasympathetic activation.

Both alpha 1 and alpha 2-adrenoceptors mediate the cardiovascular responses to noradrenaline microinjected into the bed nucleus of the stria terminal of rats

Background and purpose: We have previously shown that noradrenaline microinjected into the bed nucleus of stria terminalis (BST) elicited pressor and bradycardiac responses in unanaesthetized rats. In the present study, we investigated the subtype of adrenoceptors that mediates the cardiovascular response to noradrenaline microinjection into the BST. Experimental approach: Cardiovascular responses following noradrenaline microinjection into the BST of male Wistar rats were studied before and after BST pretreatment with different doses of the selective alpha(1)-adrenoceptor antagonist WB4101, the alpha(2)-adrenoceptor antagonist RX821002, the combination of WB4101 and RX821002, the non-selective beta-adrenoceptor antagonist propranolol, the selective beta(1)-adrenoceptor antagonist CGP20712 or the selective beta(2)-adrenoceptor antagonist ICI118,551. Key results: Noradrenaline microinjected into the BST of unanaesthetized rats caused pressor and bradycardiac responses. Pretreatment of the BST with different doses of either WB4101 or RX821002 only partially reduced the response to noradrenaline. However, the response to noradrenaline was blocked when WB4101 and RX821002 were combined. Pretreatment with this combination also shifted the resulting dose-effect curve to the left, clearly showing a potentiating effect of this antagonist combination. Pretreatment with different doses of either propranolol or CGP20712 increased the cardiovascular responses to noradrenaline microinjected into the BST. Pretreatment with ICI118,551 did not affect cardiovascular responses to noradrenaline. Conclusion and implications: The present results indicate that alpha(1) and alpha(2)-adrenoceptors mediate the cardiovascular responses to noradrenaline microinjected into the BST. In addition, they point to an inhibitory role played by the activation of local beta(1)-adrenoceptors in the cardiovascular response to noradrenaline microinjected into the BST.

Cholecystokinin and hypothalamic corticotrophin-releasing factor participate in endotoxin-induced hypophagia

Cholecystokinin (CCK) provides a meal-related signal that activates brainstem neurons, which have reciprocal interconnections with the hypothalamic paraventricular nucleus. Neurons that express corticotrophin-releasing factor (CRF) in the hypothalamus possess anorexigenic effects and are activated during endotoxaemia. This study investigated the effects of CCK(1) receptor blockade on lipopolysaccharide (LPS)-induced hypophagia and hypothalamic CRF neuronal activation. Male Wistar rats were pretreated with a specific CCK(1) receptor antagonist (devazepide; 1 mg kg(-1); I.P.) or vehicle; 30 min later they received LPS (100 mu g kg(-1); I.P.) or saline injection. Food intake, corticosterone responses and Fos-CRF and Fos-alpha-melanocyte-stimulating hormone (alpha-MSH) immunoreactivity in the hypothalamus and Fos-tyrosine hydroxylase immunoreactivity in the nucleus of the solitary tract (NTS) were evaluated. In comparison with saline treatment, LPS administration decreased food intake and increased plasma corticosterone levels, as well as the number of Fos-CRF and Fos-tyrosine hydroxylase double-labelled neurons in vehicle-pretreated rats; no change in Fos-alpha-MSH immunoreactivity was observed after LPS injection. In saline-treated animals, devazepide pretreatment increased food intake, but it did not modify other parameters compared with vehicle-pretreated rats. Devazepide pretreatment partly reversed LPS-induced hypophagia and Fos-CRF and brainstem neuronal activation. Devazepide did not modify the corticosterone and Fos-alpha-MSH responses in rats treated with LPS. In conclusion, the present data suggest that LPS-induced hypophagia is mediated at least in part by CCK effects, via CCK(1) receptor, on NTS and hypothalamic CRF neurons.

Corticotrophin-releasing factor mediates hypophagia after adrenalectomy, increasing meal-related satiety responses

Adrenalectomy-induced hypophagia is associated with increased satiety-related responses, which involve neuronal activation of the nucleus of the solitary tract (NTS). Besides its effects on the pituitary-adrenal axis, corticotrophin-releasing factor (CRF) has been shown to play an important role in feeding behaviour, as it possesses anorexigenic effects. We evaluated feeding-induced CRF mRNA expression in the paraventricular nucleus (PVN) and the effects of pretreatment with CRF(2) receptor antagonist (Antisauvagine-30, AS30) on food intake and activation of NTS neurons in response to feeding in adrenalectomised (ADX) rats. Compared to the sham group, ADX increased CRF mRNA levels in the PVN of fasted animals, which was further augmented by refeeding. AS30 treatment did not affect food intake in the sham and ADX + corticosterone (B) groups; however, it reversed hypophagia in the ADX group. In vehicle-pretreated animals, refeeding increased the number of Fos and Fos/TH-immunoreactive neurons in the NTS in the sham, ADX and ADX + B groups, with the highest number of neurons in the ADX animals. Similarly to its effect on food intake, pretreatment with AS30 in the ADX group also reversed the increased activation of NTS neurons induced by refeeding while having no effect in the sham and ADX + B animals. The present results show that adrenalectomy induces an increase in CRF mRNA expression in the PVN potentiated by feeding and that CRF(2) receptor antagonist abolishes the anorexigenic effect and the increased activation of NTS induced by feeding in the ADX animals. These data indicate that increased activity of PVN CRF neurons modulates brainstem satiety-related responses, contributing to hypophagia after adrenalectomy. (C) 2010 Elsevier Inc. All rights reserved.

Carbon monoxide and nitric oxide modulate hyperosmolality-induced oxytocin secretion by the hypothalamus in vitro

OT (oxytocin) is secreted from the posterior pituitary gland, and its secretion has been shown to be modulated by NO (nitric oxide). In rats, OT secretion is also stimulated by hyperosmolarity of the extracellular fluid. Furthermore, NOS (nitric oxide synthase) is located in hypothalamic areas involved in fluid balance control. In the present study, we evaluated the role of the NOS/NO and HO (haem oxygenase)/CO (carbon monoxide) systems in the osmotic regulation of OT release from rat hypothalamus in vitro. We conducted experiments on hypothalamic fragments to determine the following: (i) whether NO donors and NOS inhibitors modulate OT release and (ii) whether the changes in OT response occur concurrently with changes in NOS or HO activity in the hypothalamus. Hyperosmotic stimulation induced a significant increase in OT release that was associated with a reduction in nitrite production. Osmotic stimulation of OT release was inhibited by NO donors. NOS inhibitors did not affect either basal or osmotically stimulated OT release. Blockade of HO inhibited both basal and osmotically stimulated OT release, and induced a marked increase in NOS activity. These results indicate the involvement of CO in the regulation of NOS activity. The present data demonstrate that hypothalamic OT release induced by osmotic stimuli is modulated, at least in part, by interactions between NO and CO.