The phenotypic spectrum associated with OTX2 mutations in humans.

Objective: The transcription factor OTX2 is implicated in ocular, craniofacial, and pituitary development. Design: We aimed to establish the contribution of OTX2 mutations in congenital hypopituitarism patients with/without eye abnormalities, study functional consequences, and establish OTX2 expression in the human brain, with a view to investigate the mechanism of action. Methods: We screened patients from the UK (n = 103), international centres (n = 24), and Brazil (n = 282); 145 were within the septo-optic dysplasia spectrum, and 264 had no eye phenotype. Transactivation ability of OTX2 variants was analysed in murine hypothalamic GT1-7 neurons. In situ hybridization was performed on human embryonic brain sections. Genetically engineered mice were generated with a series of C-terminal OTX2 variants. Results: Two chromosomal deletions and six haploinsufficient mutations were identified in individuals with eye abnormalities; an affected relative of one patient harboured the same mutation without an ocular phenotype. OTX2 truncations led to significant transactivation reduction. A missense variant was identified in another patient without eye abnormalities; however, studies revealed it was most likely not causative. In the mouse, truncations proximal to aa219 caused anophthalmia, while distal truncations and the missense variant were tolerated. During human embryogenesis, OTX2 was expressed in the posterior pituitary, retina, ear, thalamus, choroid plexus, and partially in the hypothalamus, but not in the anterior pituitary. Conclusions: OTX2 mutations are rarely associated with hypopituitarism in isolation without eye abnormalities, and may be variably penetrant, even within the same pedigree. Our data suggest that the endocrine phenotypes in patients with OTX2 mutations are of hypothalamic origin.

Síndrome de interrupción del tallo pituitario: Relaciones clínicas, bioquímicas y neurorradiológicas / Pituitary stalk interruption syndrome: Clinical, biochemical and neuroradiological relationships

El síndrome de interrupción del tallo pituitario (PSIS) se caracteriza por la demostración neurorradiológica de un tallo pituitario ausente, interrumpido o hipoplásico, adenohipófisis aplásica/hipoplásica o neurohipófisis ectópica. Este síndrome se ha relacionado con formas severas de hipopituitarismo congénito (HPC), asociado a múltiples deficiencias de hormonas pituitarias (MPHD). Evaluamos a pacientes con HPC y PSIS, analizando los signos y los síntomas neonatales al diagnóstico, relacionándolos con las deficiencias hormonales pituitarias y signos neurorradiológicos presentes. Estudiamos retrospectivamente a 80 pacientes asistidos en el Hospital de Niños de Córdoba, con diagnóstico de HPC, de los cuales 42 (52%) presentaron PSIS; 22 mujeres y 20 varones, EC: 5 días-9,5 años. El 62% presentó MPHD y el 38% insuficiencia somatotrófica aislada (IGHD). El análisis de las variables perinatales demostró antecedentes de parto natural en el 52% (11/21) de las MPHD vs. 13% (2/15) de las IGHD. Cuatro pacientes, 2 con MPHD y 2 con IGHD presentaban antecedentes obstétricos consistentes en presentación podálica y transversa respectivamente, todos ellos resueltos mediante operación cesárea. Los signos y los síntomas perinatales fueron hipo- glucemia: 61% en MPHD vs. 19% en IGHD, p: 0,0105; ictericia: 38% en MPHD vs. 25% en IGHD; micropene: 77% en MPHD y colestasis: 19% en MPHD. Convulsiones neonatales se presentaron en el 75% de los niños con MPHD e hipoglucemia. EC media de consulta: 2,1 años en MPHD (30% en el período neonatal, 70% antes de 2 años) y 3,6 años en IGHD (44% en menores de 2 años). Los pacientes con MPHD presentaban: tallo no visible 81% (n: 21/26) vs. tallo hipoplásico: 19% (n: 5/26), p: 0,0001; en IGHD 56% (n: 9/16) vs. 44% (n: 7/16), p: 0,5067, respectivamente. El 100% de los neonatos con HPC tenían tallo pituitario ausente. Concluimos que la demostración de PSIS en niños con HPC proporciona información valiosa como predictor de la severidad fenotípica, la presencia de MPHD y de la respuesta al tratamiento. La baja frecuencia de antecedentes obstétricos posicionales potencialmente distócicos, como parte de los mecanismos fisiopatogénicos responsables de PSIS, indicaría la necesidad de analizar la importancia de posibles factores genéticos y epigenéticos involucrados. El diagnóstico precoz de HPC debe sospecharse en presencia de signos y síntomas clínicos, tales como hipoglucemia, colestasis, micropene y defectos asociados en la línea media facial. La resonancia magnética cerebral debe formar parte de los estudios complementarios en pacientes con esta presunción diagnóstica, especialmente a edades tempranas. El reconocimiento tardío de esta entidad puede aumentar la morbilidad y la mortalidad con efectos potenciales deletéreos y permanentes.

Pituitary stalk interruption syndrome (PSIS) is characterised by the combination of an interrupted or thin pituitary stalk, absent or ectopic posterior pituitary, and anterior pituitary hypoplasia. It is manifested as isolated (IGHD) or combined pituitary hormone deficiencies (CPHD) of variable degrees and timing of onset, with a wide spectrum of clinical phenotypes. PSIS may be an isolated morphological abnormality or be part of a syndrome. A retrospective evaluation is presented of clinical signs and symptoms present at early life stages, as well as an analysis of their relationship with hormone laboratory tests and diagnostic imaging in children with congenital hypopituitarism (CHP), and PSIS. This study was performed in a single centre on a sample of 42 children out of a total of 80 CHP patients, with a chronological age range between 5 days and 9.5 years from a database analysed over a period of 26 years. The study included 26/42 (62%) with CPHD and 16/42 (38%) with IGHD. The analysis of perinatal variables showed a natural delivery in 52% (11/21) of CPHD vs 13% (2/15) of IGHD. Four patients, two with CPHD and two IGHD had breech and transverse presentation respectively. All of them were resolved by caesarean section. The perinatal histories showed hypoglycaemia (61% CPHD vs 19% IGHD, P=.0105), jaundice (38% CPHDvs25% IGHD), micropenis (75%CPHD), hypoglycaemic seizures (75% CPHD), and cholestasis (19% CPHD). The mean CA of consulting for CPHD patients was 2.1 years, 30% in neonatal period and 70% before 2 years. The mean chronical age (CA) was 3.6 years in IGHD patients, with 44% of them less than 2 years. MRI showed that 81% of CPHD patients had absence of pituitary stalk vs 19% with thin pituitary stalk (P=.0001); Patients with IGHD presented 56% absence of pituitary stalk vs 44% with thin pituitary stalk (P=.5067). All (100%) of the patients diagnosed in the neonatal stage had absent pituitary stalk. The characterisation of GH deficient patients by presence and type of hypothalamic-pituitary imaging abnormality provides valuable information as a predictor of phenotypic severity, treatment response, and the potential to develop additional hormonal deficiencies. We conclude that demonstrating PSIS in children with HPC provides valuable information as a predictor of phenotypic severity, presence of MPHD, and response to treatment. The low frequency of potentially dysfunctional positional obstetric history, as part of the pathophysiological mechanisms responsible for PSIS, would indicate the need to analyse the importance of possible genetic and epigenetic factors involved. Early diagnosis of HPC should be suspected in the presence of clinical signs and symptoms, such as hypoglycaemia, cholestasis, micropenis, and associated facial midline defects. MRI should be part of complementary studies in patients with this diagnostic suspicion, especially at an early age. Late recognition of this entity may increase morbidity and mortality with potential permanent deleterious effects.

Maternal Exposure to Iodine Excess Throughout Pregnancy and Lactation Induces Hypothyroidism in Adult Male Rat Offspring.

This study aimed to investigate the consequences of maternal exposure to iodine excess (IE; 0.6 mg NaI/L) throughout pregnancy and lactation on the hypothalamus-pituitary-thyroid axis of the male offspring in adulthood. Maternal IE exposure increased hypothalamic Trh mRNA expression and pituitary Tsh expression and secretion in the adult male offspring. Moreover, the IE-exposed offspring rats presented reduced thyroid hormones levels, morphological alterations in the thyroid follicles, increased thyroid oxidative stress and decreased expression of thyroid differentiation markers (Tshr, Nis, Tg, Tpo, Mct8) and thyroid transcription factors (Nkx2.1, Pax8). Finally, the data presented here strongly suggest that epigenetic mechanisms, as increased DNA methylation, augmented DNA methyltransferases expression, hypermethylation of histone H3, hypoaceylation of histones H3 and H4, increased expression/activity of histone deacetylases and decreased expression/activity of histone acetyltransferases are involved in the repression of thyroid gene expression in the adult male offspring. In conclusion, our results indicate that rat dams' exposure to IE during pregnancy and lactation induces primary hypothyroidism and triggers several epigenetic changes in the thyroid gland of their male offspring in adulthood.

The Mexican Acromegaly Registry: Clinical and Biochemical Characteristics at Diagnosis and Therapeutic Outcomes.

CONTEXT: Acromegaly is a systemic disorder caused by a GH-secreting pituitary adenoma. As with other rare diseases, acromegaly registries developed in various European countries have provided us with important information. OBJECTIVE: The objective of the study was to analyze the epidemiological, clinical, biochemical, and therapeutic data from the Mexican Acromegaly Registry (MAR). SETTING: The setting of the study was a nationwide patient registry. DESIGN AND METHODOLOGY: The MAR was created in 2009. It gathers data from 24 participating centers belonging to three different institutions using a specifically designed on-line platform. Only patients diagnosed after 1990 were included in the program. RESULTS: A total of 2057 patients (51% female, mean age at diagnosis 41.1 ± 24.5 y) have been registered for an estimated prevalence of 18 cases per 1 million inhabitants. Hypertension, glucose intolerance, diabetes, and dyslipidemia were present in 27%, 18.4%, 30%, and 24% of the patients, respectively. The IGF-1 level at diagnosis and the concomitant presence of hypertension were significantly associated with the development of diabetes. Transsphenoidal surgery was the primary treatment in 72% of the patients. Pharmacological treatment, mostly with somatostatin analogs, was administered primarily and adjunctively in 26% and 54% of the patients, respectively. Treatment choice varied among the three participating institutions, with the predominance of pharmacological therapy in two of them and of radiation therapy in the third. Therapeutic outcomes were similar to those reported in the European registries. CONCLUSIONS: The MAR is the largest and first non-European registry of the disease. Our findings highlight important within-country differences in treatment choice due to variations in the availability of resources.

Underlying Mechanisms of Pituitary-Thyroid Axis Function Disruption by Chronic Iodine Excess in Rats.

BACKGROUND: Iodine is essential for thyroid hormone synthesis and is an important regulator of thyroid function. Chronic iodine deficiency leads to hypothyroidism, but iodine excess also impairs thyroid function causing hyperthyroidism, hypothyroidism, and/or thyroiditis. This study aimed to investigate the underlying mechanisms by which exposure to chronic iodine excess impairs pituitary-thyroid axis function. METHODS: Male Wistar rats were treated for two months with NaI (0.05% and 0.005%) or NaI+NaClO4 (0.05%) dissolved in drinking water. Hormone levels, gene expression, and thyroid morphology were analyzed later. RESULTS: NaI-treated rats presented high levels of iodine in urine, increased serum thyrotropin levels, slightly decreased serum thyroxine/triiodothyronine levels, and a decreased expression of the sodium-iodide symporter, thyrotropin receptor, and thyroperoxidase mRNA and protein, suggesting a primary thyroid dysfunction. In contrast, thyroglobulin and pendrin mRNA and protein content were increased. Kidney and liver deiodinase type 1 mRNA expression was decreased in iodine-treated rats. Morphological studies showed larger thyroid follicles with higher amounts of colloid and increased amounts of connective tissue in the thyroid of iodine-treated animals. All these effects were prevented when perchlorate treatment was combined with iodine excess. CONCLUSIONS: The present data reinforce and add novel findings about the disruption of thyroid gland function and the compensatory action of increased thyrotropin levels in iodine-exposed animals. Moreover, they draw attention to the fact that iodine intake should be carefully monitored, since both deficient and excessive ingestion of this trace element may induce pituitary-thyroid axis dysfunction.

Thickened pituitary stalk associated with a mass in the sphenoidal sinus: an alarm to suspect hypophysitis by immunoglobulin g4?

Introduction Hypophysitis is a chronic inflammation of the pituitary gland of complex and still incompletely defined pathogenesis. It belongs to the group of non-hormonesecreting sellar masses, sharing with them comparable clinical presentation and radiographic appearance. Objectives Describe the case of immunoglobulin G4 (IgG4)-related hypophysitis presenting as a mass in the sphenoid sinus. Resumed Report A 40-year-old Brazilian man had a diagnosis of central diabetes insipidus since 2001 associated with pituitary insufficiency. Pituitary magnetic resonance imaging revealed a centered pituitary stalk with focal nodular thickening and the presence of heterogeneous materials inside the sphenoid sinus. The patient was treated with testosterone replacement therapy. Laboratory results revealed increased IgG4 serum. Conclusion IgG4-related hypophysitis should be considered in patients with pituitary insufficiency associated with sellar mass and/or thickened pituitary stalk. IgG4 serum measurement for early diagnosis of IgG4-related hypophysitis should be performed.

Successful treatment of pituitary abscess with intravenous antibiotics: a case report and literature review.

Pituitary abscess is a rare intrasellar infectious disease. It is usually treated with a combination of surgical drainage and intravenous antibiotics. We describe the case of a 38-year-old man with headache, fever, left earache, subsequent diabetes insipidus, and anterior pituitary insufficiency due to pituitary abscess, which was confirmed on the basis of clinical symptoms, laboratory examination results, and magnetic resonance imaging features. He was treated nonsurgically with intravenous antibiotics, with complete resolution of the pituitary abscess and recovery of pituitary function. Nonsurgical treatment may be an option for pituitary abscess.

Pituitary deficiency after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage puts patients at high risk for the development of pituitary insufficiency. We evaluated the incidence of pituitary dysfunction in these patients and its correlation with clinical outcome. METHODS: Pituitary function was tested in 66 consecutive patients in the first 15 days after aneurysmal subarachnoid hemorrhage. The following were measured in all patients: thyroid-stimulating hormone, free thyroxine, triiodothyronine, luteinizing hormone, follicle-stimulating hormone, total testosterone (in males), estradiol (in females), prolactin, serum cortisol, plasma adrenocorticotropic hormone, growth hormone and insulin growth factor. RESULTS: The endocrine assessment was made at a mean of 7.4 days (standard deviation ±6.6) after subarachnoid hemorrhage. Forty-four (66.7%) female and 22 (33.3%) male patients were evaluated. Thirty-nine patients (59.1%) had some type of pituitary dysfunction. Follicle-stimulating hormone/luteinizing hormone deficiency was the most frequent disorder (34.8%), followed by growth hormone/insulin growth factor (28.7%), adrenocorticotropic hormone (18.1%) and thyroid-stimulating hormone (9%). Seventeen (25.7%) patients showed deficiencies in more than one axis. A greater incidence of hormone deficiency was observed in patients with a Glasgow Coma Scale score ≤13 (t test, p=0.008), Hunt-Hess grade ≥4 (t test, p<0.001), or Fisher grade 4 (t test, p=0.039). Hormone deficiency was not significantly associated (p>0.05) with increased hospitalization or clinical outcome. CONCLUSION: Pituitary dysfunction was identified in a substantial portion of patients with previous aneurysmal subarachnoid hemorrhage, but no association was found between this dysfunction and poor clinical outcome.

Pituitary deficiency after aneurysmal subarachnoid hemorrhage

OBJECTIVE: Aneurysmal subarachnoid hemorrhage puts patients at high risk for the development of pituitary insufficiency. We evaluated the incidence of pituitary dysfunction in these patients and its correlation with clinical outcome. METHODS: Pituitary function was tested in 66 consecutive patients in the first 15 days after aneurysmal subarachnoid hemorrhage. The following were measured in all patients: thyroid-stimulating hormone, free thyroxine, triiodothyronine, luteinizing hormone, follicle-stimulating hormone, total testosterone (in males), estradiol (in females), prolactin, serum cortisol, plasma adrenocorticotropic hormone, growth hormone and insulin growth factor. RESULTS: The endocrine assessment was made at a mean of 7.4 days (standard deviation ±6.6) after subarachnoid hemorrhage. Forty-four (66.7%) female and 22 (33.3%) male patients were evaluated. Thirty-nine patients (59.1%) had some type of pituitary dysfunction. Follicle-stimulating hormone/luteinizing hormone deficiency was the most frequent disorder (34.8%), followed by growth hormone/insulin growth factor (28.7%), adrenocorticotropic hormone (18.1%) and thyroid-stimulating hormone (9%). Seventeen (25.7%) patients showed deficiencies in more than one axis. A greater incidence of hormone deficiency was observed in patients with a Glasgow Coma Scale score ≤13 (t test, p = 0.008), Hunt-Hess grade ≥4 (t test, p<0.001), or Fisher grade 4 (t test, p = 0.039). Hormone deficiency was not significantly associated (p>0.05) with increased hospitalization or clinical outcome. CONCLUSION: Pituitary dysfunction was identified in a substantial portion of patients with previous aneurysmal subarachnoid hemorrhage, but no association was found between this dysfunction and poor clinical outcome. .

Diagnosis of adrenal failure in critically ill patients.

In the last two decades there was important evolution on the knowledge of the function of the hypothalamic-pituitary-adrenal axis. In the last decade, the expression "relative adrenal insufficiency" (RAI) was created, and more recently "critical illness-related corticosteroid insufficiency" (CIRCI) was used to designate those patients in which cortisol production was not sufficiently increased in stress situations. Patients with CIRCI have elevated hospital morbidity and mortality. Currently, there is a wide discussion about diagnostic criteria for this dysfunction. Besides basal cortisol, some publications now study the role of other tests, such as cortrosyn test - either in low (1 µg) or high doses (250 µg); free cortisol, salivary cortisol, metyrapone test and others. With this review, we aimed at summarizing the results of the most influent papers that intended to define diagnostic criteria for CIRCI. We also suggest an approach for CIRCI diagnosis and make it clear that the decision about steroid therapy in septic shock patients is matter apart from RAI.

Diagnosis of adrenal failure in critically ill patients / Diagnóstico de insuficiência adrenal em pacientes críticos

In the last two decades there was important evolution on the knowledge of the function of the hypothalamic-pituitary-adrenal axis. In the last decade, the expression "relative adrenal insufficiency" (RAI) was created, and more recently "critical illness-related corticosteroid insufficiency" (CIRCI) was used to designate those patients in which cortisol production was not sufficiently increased in stress situations. Patients with CIRCI have elevated hospital morbidity and mortality. Currently, there is a wide discussion about diagnostic criteria for this dysfunction. Besides basal cortisol, some publications now study the role of other tests, such as cortrosyn test - either in low (1 μg) or high doses (250 μg); free cortisol, salivary cortisol, metyrapone test and others. With this review, we aimed at summarizing the results of the most influent papers that intended to define diagnostic criteria for CIRCI. We also suggest an approach for CIRCI diagnosis and make it clear that the decision about steroid therapy in septic shock patients is matter apart from RAI.

Nas últimas décadas, houve uma importante evolução no conhecimento sobre a função do eixo hipotálamo-pituitária-adrenal. Na última década, foi cunhada a expressão "insuficiência adrenal relativa" (IAR) e, mais recentemente, a expressão "insuficiência adrenal relacionada à doença grave" (CIRCI) foi utilizada para designar aqueles pacientes nos quais a produção de cortisol não era suficientemente elevada em situações de estresse. Pacientes com CIRCI apresentam elevada morbidade e mortalidade em hospitais. Atualmente, há uma ampla discussão sobre os critérios de diagnóstico para essa desordem. Além do cortisol basal, algumas publicações analisaram o papel de outros testes, tais como o teste de estímulo com ACTH (cortrosina), com doses baixas (1 mg) ou altas (250 mg), cortisol livre, cortisol salivar, teste da metirapona e outros. O objetivo desta revisão foi resumir os resultados dos artigos mais importantes que buscaram definir os critérios de diagnóstico para a CIRCI. Também sugerimos uma abordagem para o diagnóstico da CIRCI e deixamos claro que a decisão sobre a terapia com esteroides em pacientes em choque séptico é uma questão separada da IAR.

A comparative study by age and gender of the pituitary adenoma and ACTH and alpha-MSH secretion in dogs with pituitary-dependent hyperadrenocorticism.

Pituitary-dependent hyperadrenocorticism (PDH) is frequent in dogs. Little is known about its presentation in different age groups and its characteristics. Dividing the population under study (n=107) into three age groups we observed that 11.2% were young, 51.4% adults and 37.4% aged. Using magnetic resonance, pituitary tumours were intra-sellar (IS) in 30.8% and extra-sellar (ES) in 62.6% and the pars intermedia (PI) was affected in 6.5%. ES are predominant in females and IS in males (p<0.0001). In the adult-aged population, the ES and PI are predominant, while in the young, the IS predominate (p<0.0001). ACTH concentration was greater in the ES vs. IS (p<0.05). alpha-MSH did not present significant differences according to tumour size, showing a negative correlation (r=-0.47; p<0.01) vs. ACTH. Differences in adenoma size according to gender and their age-related frequency of apparition could be because of different origins of the corticotrophinoma.

Hypogonadism after traumatic brain injury: [review] / Hipogonadismo após traumatismo craniano encefálico: [revisão]

Traumatic brain injury (TBI) is the most common cause of death and disability in young adults. Post-TBI neuroendocrine disorders have been increasingly acknowledged in recent years due to their potential contribution to morbidity and, probably, to mortality after trauma. Marked alterations of the hypothalamic-pituitary axis during the post-TBI acute and chronic phases have been reported. Prospective and longitudinal studies have shown that some abnormalities are transitory. On the other hand, there is a high frequency (15 percent to 68 percent) of pituitary hormone deficiency among TBI survivors in a long term setting. Post-TBI hypogonadism is a common finding after cranial trauma, and it is predicted to develop in 16 percent of the survivors in the long term. Post-TBI hypogonadism has been associated with adverse results in the acute and chronic phases after injury. These data reinforce the need for identification of hormonal deficiencies and their proper treatment, in order to optimize patient recovery, improve their life quality, and avoid the negative consequences of non-treated hypogonadism in the long term.

O traumatismo cranioencefálico (TCE) é a causa mais comum de morte e incapacidade em adultos jovens. Desordens neuroendócrinas pós-TCE vêm sendo reconhecidas cada vez mais nos últimos anos devido à sua potencial contribuição para a morbidade e, possivelmente, mortalidade após trauma. Alterações acentuadas do eixo hipotálamo-hipófise foram documentadas nas fases aguda e crônica pós-TCE. Estudos prospectivos e longitudinais têm mostrado que algumas anormalidades são transitórias. Por outro lado, existe uma elevada frequência de deficiências hormonais hipofisárias a longo prazo entre os sobreviventes de TCE, que varia de 15 por cento a 68 por cento. Hipogonadismo pós-TCE é um achado comum a longo prazo e estima-se que, em média, 16 por cento dos sobreviventes sejam afetados. Hipogonadismo pós-TCE tem sido associado a resultados adversos tanto na fase aguda quanto na fase crônica após a lesão. Esses dados reforçam a necessidade da identificação e adequado tratamento das deficiências hormonais, para otimizar a recuperação do paciente, melhorar a qualidade de vida e evitar as consequências negativas a longo prazo do hipogonadismo não tratado.

Avaliação tardia do eixo hipofisário-gonadal em pacientes adultos que sofreram traumatismo cranioencefálico grave / Late evaluation of the pituitary-gonadal axis in survivors of severe traumatic brain injury

OBJETIVO: Avaliar a função hipofisária-gonadal nos pacientes vítimas de TCE graves ocorridos na Grande Florianópolis, entre 2000 e 2004. MÉTODOS: Foram estudados 30 pacientes, sendo 22 homens e 8 mulheres, submetidos à avaliação clínica e laboratorial em seguimento médio de 4 anos após a data do traumatismo. RESULTADOS: Os homens possuíam em média 38 anos no ano da avaliação, enquanto as mulheres, 42 anos. A maioria dos traumatismos está relacionada aos acidentes de trânsito (63,3 por cento). Três pacientes (10 por cento) estavam com valores de FSH abaixo do normal e apenas 1 paciente (3,3 por cento) apresentou LH alterado. Nas mulheres avaliadas, os níveis de estradiol foram normais. Na população masculina, foi evidenciado nível de testosterona baixo em 2 pacientes (9,1 por cento). Todos os pacientes apresentavam normoprolactinemia. CONCLUSÃO: Dois casos de hipogonadismo masculino (9,1 por cento) foram diagnosticados neste estudo. Isso indica a necessidade de atenção aos pacientes sobreviventes de TCE grave para realizar diagnóstico precoce de hipogonadismo.

OBJECTIVE: The purpose of this study is to evaluate pituitary function impairment in order to verify the prevalence of sex hormone deficiency and to analyze the profile of TBI population. METHODS: Thirty patients were studied, 22 were male and 8 were female. All patients had their gonadal function assessed and they were evaluated at a median of 4 years post-trauma. RESULTS: The average age of the men was 38 years at the time of the evaluation, while the mean age of women was 42 years. The majority of TBI was related to traffic accidents (63.3 percent). Three patients (10 percent) had low FSH and only 1 patient (3.3 percent) had low LH. There was no biochemical evidence of hypogonadism in women. Two male patients presented low testosterone (9.1 percent) and were diagnosed with hypogonadism. Prolactin levels were normal in all patients. CONCLUSION: Two cases of hypogonadism (9.1 percent) were diagnosed among men in this study. It is therefore necessary that medical professionals involved in the management of TBI patients are aware of hypogonadism as a complication of TBI, in order to diagnose it early.

Pituitary-testicular axis function, biological to immunological ratio and charge isoform distribution of pituitary LH in male rats with experimental diabetes.

Men with insulinopenic diabetes mellitus frequently present hypogonadism and exhibit circulating luteinizing hormone (LH) molecules with increased biological activity. To further study this latter issue, we analyzed the pattern of isoform distribution and the impact of changes in terminal glycosylation of pituitary LH on the bioactivity of this gonadotropin in experimental diabetes. Adult male rats were treated with streptozotocin or vehicle and euthanized on days 30, 60, or 90 posttreatment. All diabetic groups exhibited a significant decrease in serum insulin and testosterone levels as well as in sperm count; serum gonadotropins and 17beta-estradiol decreased only after 90 days of insulinopenia. Both the immunoreactive concentrations and the biological to immunological ratio of intrapituitary LH significantly increased in all experimental groups, as assessed by an in vitro homologous bioassay in HEK-293 cells expressing a recombinant LH receptor. Chromatofocusing of pituitary extracts revealed the presence of multiple LH charge isoforms; the pH distribution profile of LH in diabetic and control rats was indistinguishable on days 30 and 60 posttreatment. By contrast, the abundance of more basic isoforms (pH 9.99-9.0) decreased and that of isoforms with pH values 8.99-8.0 increased in rats with long-standing diabetes compared to controls. It is concluded that experimental diabetes alters the function of the pituitary-testicular axis, resulting in reduced sex steroids levels and hypogonadotropism. Long-standing insulinopenia leads to a paradoxical accumulation of intrapituitary LH molecules enriched in bioactivity with altered terminal glycosylation, which are apparently subserved by distinct mechanisms involving altered hypothalamic and/or gonadal inputs on the gonadotrope.

Carbohydrate complexity and proportion of serum FSH isoforms reflect pituitary-ovarian activity in perimenopausal women and depot medroxyprogesterone acetate users.

BACKGROUND: FSH is synthesized and secreted in multiple glycosylation variants with different oligosaccharide structures; the endocrine milieu regulates the composition of FSH carbohydrate moiety. OBJECTIVES: To characterize serum FSH isoforms according to their sialic acid content and oligosaccharide complexity in regularly menstruating women and in depot medroxyprogesterone acetate (DMPA) users during the menopausal transition. Subjects and methods Ten regularly menstruating perimenopausal women aged 45-52, with mid-follicular phase FSH levels < or =10 IU/l and 10 regularly menstruating women, aged 20-39, were included. Blood samples were collected on the ninth day of the menstrual cycle. Twenty DMPA users were divided into two groups (n = 10) according to age: DMPA(1), age range 20-39 and DMPA(2), age range 45-52. Blood samples were collected 90 +/- 5 days after the last injection of DMPA. Oestradiol (E(2)), inhibin B (Inh B), Pro-alphaC levels and the relative abundance of FSH isoforms on the basis of charge (preparative isoelectric focusing) and carbohydrate complexity (Concanavalin A chromatography) were determined. RESULTS: Decreased Inh B and moderately elevated E(2) levels were observed in perimenopausal women associated with an increase in FSH sialylation and a decrease in its oligosaccharide complexity. DMPA induced changes in the hormonal profile and FSH molecular microheterogeneity; the secreted hormone was more heterogeneous and its oligosaccharides were less complex under this condition. CONCLUSION: Serum FSH glycoforms with increased sialylation and decreased oligosaccharide complexity reflect the decline of the gonadal activity induced either by age or by the use of a DMPA as a contraceptive.

Modulation of growth hormone and prolactin secretion in Trypanosoma cruzi-infected mammosomatotrophic cells.

OBJECTIVE: In a previous study, we reported an imbalance in the hypothalamus-pituitary-adrenal axis of mice acutely infected with the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. METHODS: Possible effects of this parasitic infection on the endocrine function of other pituitary cell types were studied, in particular regarding the production of prolactin (PRL) and growth hormone (GH). RESULTS: In the mammosomatotrophic cell line GH3, both GH and PRL secretion were decreased, reflecting the diminished PRL concentrations in the pituitary glands of infected mice. Additionally, expression of extracellular matrix proteins, e.g. laminin, was increased in T. cruzi-infected GH3 cells, which may be related to the diminished secretory function of these cells. Lastly, the expression of Pit-1, a major transcription factor for the PRL and GH genes, is also decreased in T. cruzi-infected cultures. CONCLUSION: T. cruzi infection downregulates PRL and GH production. Combined with our previous data showing increased glucocorticoid levels following T. cruzi infection, the immunosuppression induced by T. cruzi infection may be partially related to multiple endocrine changes involving the hypothalamus-pituitary axis and corresponding target endocrine glands.

Hypogonadism after traumatic brain injury.

Traumatic brain injury (TBI) is the most common cause of death and disability in young adults. Post-TBI neuroendocrine disorders have been increasingly acknowledged in recent years due to their potential contribution to morbidity and, probably, to mortality after trauma. Marked alterations of the hypothalamic-pituitary axis during the post-TBI acute and chronic phases have been reported. Prospective and longitudinal studies have shown that some abnormalities are transitory. On the other hand, there is a high frequency (15% to 68%) of pituitary hormone deficiency among TBI survivors in a long term setting. Post-TBI hypogonadism is a common finding after cranial trauma, and it is predicted to develop in 16% of the survivors in the long term. Post-TBI hypogonadism has been associated with adverse results in the acute and chronic phases after injury. These data reinforce the need for identification of hormonal deficiencies and their proper treatment, in order to optimize patient recovery, improve their life quality, and avoid the negative consequences of non-treated hypogonadism in the long term.