A prospective study on the efficacy of oral estrogen in female patients with acromegaly.

PURPOSE: To evaluate the efficacy and safety of oral estrogen therapy in female patients of childbearing age with uncontrolled acromegaly and to verify the significance of the presence of estrogen receptor α (ER-α) in somatotropinomas. METHODS: Prospective study in which biochemical and radiological evaluations were performed at baseline and after six months of treatment with an oral formulation of ethinyl-estradiol 0.03 mg and levonorgestrel 0.15 mg. ER-α was assessed by immunohistochemistry and immunopositivity was considered when it was present in ≥ 1% of cells. RESULTS: Eight patients with uncontrolled acromegaly were selected. All patients underwent surgery. Four patients were on octreotide LAR 30 mg, two patients were on lanreotide autogel 120 mg, and two patients had active disease after surgery. At the end of follow-up, IGF-I normalized in 3/8 (37%), 2/8 (25%) patients presented with mean IGF-I reduction of 25% but without IGF-I normalization, and 2/8 (25%) did not respond-one had a 13% increase in IGF-I and IGF-I level remained unchanged after treatment in the other. In one patient, treatment was discontinued after 3 months due to side effects (headache), with an IGF-I reduction of 28% but without normalization. Tumor volume increase (41%) was observed in only one patient (the only tumor with positive ER-α expression). CONCLUSIONS: In uncontrolled patients with acromegaly, a trial with oral estrogen can be an option for young women. Oral estrogen was well tolerated, but the somatotropinoma that presented ER-α expression was the only somatotropinoma that presented growth during treatment.

Exon 3-deleted growth hormone receptor isoform is not related to worse bone mineral density or microarchitecture or to increased fracture risk in acromegaly.

PURPOSE: Acromegaly is a cause of secondary osteoporosis and is associated with increased risk of vertebral fractures (VFs). The influence of exon 3-deleted isoform of growth hormone receptor (d3-GHR) on bone microarchitecture has not been studied in acromegaly. AIM: The aim of this study was to analyze the associations between d3-GHR isoform and bone mineral density (BMD), bone microarchitecture, and VFs in acromegaly patients. METHODS: Consecutive acromegaly patients treated at a single reference center were included. BMD was analyzed using dual-energy X-ray absorptiometry (DXA) and bone microarchitecture was analyzed by high-resolution peripheral quantitative computed tomography (HR-pQCT). The presence of moderate to severe VFs was assessed by thoracic and lumbar X-ray. GHR genotyping was analyzed by PCR, and full-length isoform of GHR (fl-GHR) was represented by a 935-bp fragment and d3-GHR by a 532-bp fragment. RESULTS: Eighty-nine patients were included [56 females; median age at diagnosis: 43 years (17-78)]. Disease was uncontrolled in 63% of patients. At least one d3-GHR allele was present in 60% of patients. Frequency of active disease (p = 0.276) and hypogonadism (p = 1.000) was not different between patients with fl-GHR and those with at least one d3-GHR. There was no difference in any DXA or HR-pQCT parameters between patients with fl-GHR and those with d3-GHR. Significant VFs were observed in 14% of patients, but there was no difference in frequency between patients with fl-GHR and those with at least one d3-GHR allele (p = 0.578). CONCLUSIONS: Presence of d3-GHR was not associated with worse BMD or bone microarchitecture or with higher frequency of significant VFs.

A Brazilian multicentre study evaluating pregnancies induced by cabergoline in patients harboring prolactinomas.

OBJECTIVE: To evaluate the maternal-fetal outcomes of CAB-induced pregnancies in patients with prolactinoma in a large cohort. METHODS: The prevalence of tumor growth, miscarriage, preterm, low birth weight, congenital malformations and impairment in neuropsychological development in children among women treated with CAB were assessed in a Brazilian multicentre retrospective observational study, RESULTS: We included 194 women with a mean age of 31 (17-45) years, 43.6% presenting microadenomas and 56.4% macroadenomas, at prolactinoma diagnosis. In 233 pregnancies, CAB was withdrawn in 89%, after pregnancy confirmation. Symptoms related to tumor growth occurred in 25 cases, more frequently in macroadenomas. The overall miscarriage rate was 11%, although higher in the subgroup of patients with CAB maintainance after pregnancy confirmation (38% vs. 7.5%). Amongst the live-birth deliveries, preterm occurred in 12%, low birth weight in 6% and congenital malformations in 4.3%. Neuropsychological development impairment was reported in 7% of cases. CONCLUSIONS: Our findings confirm previous results of safety in maternal and fetal outcomes in CAB-induced pregnancies; nevertheless, CAB maintenance after pregnancy confirmation was associated with higher miscarriage rate; result that must be further confirmed.

Frequency of familial pituitary adenoma syndromes among patients with functioning pituitary adenomas in a reference outpatient clinic.

INTRODUCTION: Pituitary adenomas (PA) occur mainly as sporadic disease, but familial syndromes are found in approximately 5% of cases. Identification of these syndromes is important in order to diagnose individuals at risk at an earlier stage. AIMS: To evaluate the frequency of familial PA in a reference outpatient clinic devoted to PA treatment and to identify family members suspected to have pituitary disease. METHODS: Patients with PA were interviewed with respect to the presence of family members with diagnosis of PA or with signs or symptoms suggestive of them. The family members who had a clinical picture suggestive of pituitary disease were further evaluated in an attempt to identify new PA cases. In families with familial disease, the AIP gene was sequenced. RESULTS: 262 patients were evaluated and familial syndrome was found in 13 (5%). Ten (3.8%) patients had familial isolated PA (FIPA) and three (1.2%) had multiple endocrine neoplasia type 1. After evaluation of family members' symptomatology, 110 were considered suspected of having pituitary disease, but only 24 participated in the study. Of these 24, 1 was diagnosed with a corticotropinoma. AIP mutations were found in 20% of FIPA families. CONCLUSION: We found a frequency of familial PA similar to that previously described, as well as a similar frequency of AIP mutations among FIPA families. An active search of the affected family members was able to identify one case of Cushing´s disease. Patients should be aware of pituitary disease's clinical picture to identify possibly affected family members.

Two-dimensional speckle tracking echocardiography demonstrates no effect of active acromegaly on left ventricular strain.

BACKGROUND: Speckle tracking echocardiography (STE) allows for the study of myocardial strain (ε), a marker of early and subclinical ventricular systolic dysfunction. Cardiac disease may be present in patients with acromegaly; however, STE has never been used to evaluate these patients. OBJECTIVE: To evaluate left ventricular (LV) global longitudinal strain in patients with active acromegaly with normal LV systolic function. DESIGN: Cross-sectional clinical study. METHODS: Patients with active acromegaly with no detectable heart disease and a control group were matched for age, gender, arterial hypertension and diabetes mellitus underwent STE. Global LV longitudinal ε (GLS), left ventricular mass index (LVMi), left ventricular ejection fraction (LVEF) and relative wall thickness (RWT) were obtained via two-dimensional (2D) echocardiography using STE. RESULTS: Thirty-seven patients with active acromegaly (mean age 45.6 ± 13.8; 48.6% were males) and 48 controls were included. The mean GLS was not significantly different between the acromegaly group and the control group (in %, -20.1 ± 3.1 vs. -19.4 ± 2.2, p = 0.256). Mean LVMi was increased in the acromegaly group (in g/m2, 101.6 ± 27.1 vs. 73.2 ± 18.6, p < 0.01). There was a negative correlation between LVMi and GLS (r = -0.39, p = 0.01). CONCLUSIONS: Acromegaly patients, despite presenting with a higher LVMi when analyzed by 2D echocardiography, did not present with impairment in the strain when compared to a control group; this finding indicates a low chance of evolution to systolic dysfunction and agrees with recent studies that show a lower frequency of cardiac disease in these patients.

Correlations between forced oscillation technique parameters and pulmonary densitovolumetry values in patients with acromegaly.

The aims of this study were to evaluate the forced oscillation technique (FOT) and pulmonary densitovolumetry in acromegalic patients and to examine the correlations between these findings. In this cross-sectional study, 29 non-smoking acromegalic patients and 17 paired controls were subjected to the FOT and quantification of lung volume using multidetector computed tomography (Q-MDCT). Compared with the controls, the acromegalic patients had a higher value for resonance frequency [15.3 (10.9-19.7) vs 11.4 (9.05-17.6) Hz, P=0.023] and a lower value for mean reactance [0.32 (0.21-0.64) vs 0.49 (0.34-0.96) cm H2O/L/s2, P=0.005]. In inspiratory Q-MDCT, the acromegalic patients had higher percentages of total lung volume (TLV) for nonaerated and poorly aerated areas [0.42% (0.30-0.51%) vs 0.25% (0.20-0.32%), P=0.039 and 3.25% (2.48-3.46%) vs 1.70% (1.45-2.15%), P=0.001, respectively]. Furthermore, the acromegalic patients had higher values for total lung mass in both inspiratory and expiratory Q-MDCT [821 (635-923) vs 696 (599-769) g, P=0.021 and 844 (650-945) vs 637 (536-736) g, P=0.009, respectively]. In inspiratory Q-MDCT, TLV showed significant correlations with all FOT parameters. The TLV of hyperaerated areas showed significant correlations with intercept resistance (rs=-0.602, P<0.001) and mean resistance (rs=-0.580, P<0.001). These data showed that acromegalic patients have increased amounts of lung tissue as well as nonaerated and poorly aerated areas. Functionally, there was a loss of homogeneity of the respiratory system. Moreover, there were correlations between the structural and functional findings of the respiratory system, consistent with the pathophysiology of the disease.

Correlations between forced oscillation technique parameters and pulmonary densitovolumetry values in patients with acromegaly

The aims of this study were to evaluate the forced oscillation technique (FOT) and pulmonary densitovolumetry in acromegalic patients and to examine the correlations between these findings. In this cross-sectional study, 29 non-smoking acromegalic patients and 17 paired controls were subjected to the FOT and quantification of lung volume using multidetector computed tomography (Q-MDCT). Compared with the controls, the acromegalic patients had a higher value for resonance frequency [15.3 (10.9-19.7) vs 11.4 (9.05-17.6) Hz, P=0.023] and a lower value for mean reactance [0.32 (0.21-0.64) vs 0.49 (0.34-0.96) cm H2O/L/s2, P=0.005]. In inspiratory Q-MDCT, the acromegalic patients had higher percentages of total lung volume (TLV) for nonaerated and poorly aerated areas [0.42% (0.30-0.51%) vs 0.25% (0.20-0.32%), P=0.039 and 3.25% (2.48-3.46%) vs 1.70% (1.45-2.15%), P=0.001, respectively]. Furthermore, the acromegalic patients had higher values for total lung mass in both inspiratory and expiratory Q-MDCT [821 (635-923) vs 696 (599-769) g, P=0.021 and 844 (650-945) vs 637 (536-736) g, P=0.009, respectively]. In inspiratory Q-MDCT, TLV showed significant correlations with all FOT parameters. The TLV of hyperaerated areas showed significant correlations with intercept resistance (rs=−0.602, P<0.001) and mean resistance (rs=−0.580, P<0.001). These data showed that acromegalic patients have increased amounts of lung tissue as well as nonaerated and poorly aerated areas. Functionally, there was a loss of homogeneity of the respiratory system. Moreover, there were correlations between the structural and functional findings of the respiratory system, consistent with the pathophysiology of the disease.

Low risk of coronary artery disease in patients with acromegaly.

The aims of this study are to determine the prevalence of coronary atherosclerosis in acromegalic patients and to investigate the relationship between the coronary artery calcium score (CS) and acromegaly status and clinical parameters [Framingham risk score (FRS)]. Fifty-six acromegalic patients and paired non-acromegalic volunteers were stratified according to the FRS into low-, intermediate-, and high-risk groups. CS was assessed using multidetector computed tomography. The patients were considered to have controlled or active acromegaly at the time they were submitted to evaluation. Sixty-six percent of acromegalic patients exhibited arterial hypertension, 36 % had diabetes mellitus, and 34 % had hypercholesterolemia. The median FRS and the median risk for cardiovascular event within the next 10 years were similar in the acromegalics and the controls. The median total CS and CS >75th percentile didn't differ significantly between these groups. In patients with controlled acromegaly, a low, intermediate, or high FRS risk was observed in 86, 14, and 0 %, respectively. In patients with active disease, a low, intermediate, or high FRS risk was verified in 94, 3, and 3 %, respectively, and differences between the controlled and active groups were not significant. Seventy-two percent of the patients had total CS = 0, and there were no differences between the controlled and active groups. The risk of coronary artery disease in acromegalic patients, determined according to FRS and CS, is low despite the high prevalence of metabolic abnormalities.

Ipilimumab-induced hypophysitis: review of the literature.

PURPOSE: Ipilimumab is a human monoclonal antibody against cytotoxic T-lymphocyte antigen 4 available as an immunotherapy mainly for advanced melanoma. It induces an activation of T cells, resulting in an immune-mediated anti-tumor response and also immune-related adverse events, including hypophysitis. The aim of this review is to identify and discuss features concerning ipilimumab-induced hypophysitis (IIH). DESIGN: A MEDLINE research of all years of publication of IIH was conducted. We gathered information regarding clinical, radiologic and laboratory features of 71 cases recorded in the literature. RESULTS: In our review, IIH was more frequent among older and male patients. Fatigue and headache were the most frequent initial clinical manifestations of IIH and enlargement of the pituitary gland at MRI was present in the majority of patients. Those who received more than 3 cycles of ipilimumab had more fatigue (p = 0.04) and arthritis (p = 0.04). Adrenal insufficiency was more prevalent in men (p = 0.007). Glucocorticoid therapy and hormone replacement were required in most patients and pituitary function recovery was uncommon. Low prolactin at diagnosis tended to predict permanent pituitary dysfunction (p = 0.07). CONCLUSION: Hypopituitarism as a consequence of IIH, if not promptly recognized, can lead to potentially fatal events, such as adrenal insufficiency. IIH can be easily managed with glucocorticoids and hormonal replacement; therefore, physicians should be familiar with the key aspects of this condition. More studies to develop screening protocols and therapeutic intervention algorithms should be performed to decrease morbidity related to IIH.

MicroRNAs: Suggested role in pituitary adenoma pathogenesis.

MicroRNAs (miRNAs) are small non-coding RNA molecules that represent a major class of molecular regulators. miRNAs have been implicated in the pathogenesis of several human tumors, including pituitary adenomas. Altered expression of miRNAs has been described in pituitary adenomas, and specific miRNA signatures are related to clinical and therapeutic characteristics of the tumors. The data suggest that miRNAs influence various genes known to be associated with the pathogenesis of pituitary adenomas and in this review we summarize these currently available studies focusing on miRNAs in pituitary adenomas.

Low somatostatin receptor subtype 2, but not dopamine receptor subtype 2 expression predicts the lack of biochemical response of somatotropinomas to treatment with somatostatin analogs.

OBJECTIVES: To evaluate somatostatin receptor 2A (SSTR2A) and dopamine receptor 2 (DR2) protein expression in somatotropinomas and to relate it to response to somatostatin analogues (SA). DESIGN AND PATIENTS: SSTR2A and DR2 expression was analyzed by immunohistochemistry in 88 somatotropinomas from patients submitted to either pre-surgical or adjuvant SA treatment. Tumors were scored according to percentage of immunostained cells: 0 (< 25%), 1 (25-50%), and 2 (> 50%). Relation between protein expression and response to SA was performed in 66 patients. Response to SA was assessed by percent IGF-I reduction, being considered as an IGF-I per cent reduction higher than 50%. Disease control was also assessed (GH < 1.0 ng/ml and normal IGF-I). RESULTS: SSTR2A and DR2 were expressed in 100% and 98% of tumors, respectively. Biochemical response and disease control rates were 48% and 32%, respectively. Median IGF-I percent reduction after 3 months of SA treatment was lower in the SSTR2A score 0 than in the scores 1 and 2 (p < 0.001, both), and after 6 months in the score 0 than in the score 1 (p = 0.001) and 2 (p < 0.001). Biochemical response and disease control were associated with SSTR2 expression (p < 0.001 and p = 0.004, respectively). A negative predictive value for biochemical response of 100% was found when a SSTR2A expression < 25%of immunostained cells cut-off point was considered. No relation was found between DR2 expression and biochemical response and disease control. CONCLUSION: SSTR2A and DR2 are highly expressed in somatotropinomas. Low SSTR2A, but not DR2, expression is a negative predictive factor to response to SA.

Validation of immunohistochemistry for somatostatin receptor subtype 2A in human somatotropinomas: comparison between quantitative real time RT-PCR and immunohistochemistry.

Somatostatin receptors subtype 2 (SSTR2) expression in somatotropinomas is recognized as a predictor of response to the currently available somatostatin analogs and may be analyzed, mainly, by quantitative RT-PCR or immunohistochemistry (IHC). The former has the advantages of a higher sensitivity and of being quantitative, while the latter, although semi-quantitative, evaluates protein expression and is routinely used in the evaluation of pituitary adenomas. We aimed to evaluate the SSTR2A protein expression in somatotropinomas and to compare it to our previous data regarding mRNA expression, assessed by quantitative real time RTPCR. Thirteen somatotropinomas were analyzed by IHC and the tumors were scored according to percent of immunostained cells: 0 (<25%), 1 (25-50%) and 2 (>50%). SSTR2A immunostaining was present in all but one somatotropinoma, 4 (31%) tumors were classified as score 0, 4 (31%) as score 1, and 5 (38%) as score 2. Median SSTR2 mRNA content was significantly different among the three IHC scores (p=0.036) and was lower in the score 0 than in the score 2 (p=0.016). The finding that there is a positive correlation between RT-PCR and IHC indicates that IHC can be applied in order to assess the SSTR2A content in somatotropinomas.

Effects of GH-IGF-I excess and gonadal status on bone mineral density and body composition in patients with acromegaly.

SUMMARY: Studies on body composition and bone mineral density in acromegaly have conflicting results. Our data point to an increase in lean mass, a decrease in adipose tissue, and that the anabolic effect of GH on bone is partially dependent on modifications in body composition. INTRODUCTION: The effects of growth hormone (GH) and insulin-like growth factor I (IGF-I) excess and gonadal status on bone mineral density (BMD) and body composition (BC) in acromegalic patients are uncertain. METHODS: Bone mineral density and BC were evaluated by dual-energy X-ray absorptiometry (Prodigy-GE) in 75 patients (22 men and 53 women) with acromegaly, mean age 48.9 ± 14.5 years. Acromegaly was considered "controlled" when serum IGF-I was within the specific age-adjusted reference range, and serum GH was lower than 2.5 ng/mL. Comparisons between groups were performed using unpaired t test or Mann-Whitney U test. Categorical variables were analyzed by chi-square (x (2)) test. In order to compare data of different subgroups stratified by disease activity and gonadal status, one-way analysis of variance (ANOVA) and Bonferroni post hoc analysis were performed. To evaluate the correlation between GH and IGF-I and densitometric parameters, Pearson and Spearman rank order correlation were performed, as appropriate. RESULTS: There were no differences in BMD when considering disease activity and gonadal status. Active disease and eugonadism were positively correlated to an increase in lean mass and a decrease in fat mass. After multiple linear regression, there were positive correlations between GH and Z-score at lumbar spine and between lean mass and BMD at proximal femur. CONCLUSION: Our data support that GH-IGF-I excess and eugonadism have great influence on BC modifications and that the anabolic effects of GH-IGF-I on bone are, at least in part, dependent on these alterations in body composition.

Diagnosis and management of hyperprolactinemia: results of a Brazilian multicenter study with 1234 patients.

OBJECTIVE: The aim of the study was to evaluate clinical and laboratorial features of 1234 patients with different etiologies of hyperprolactinemia, as well as the response of 388 patients with prolactinomas to dopamine agonists. DESIGN, SETTING, AND PATIENTS: A total of 1234 hyperprolactinemic patients from 10 Brazilian endocrine centers were enrolled in this retrospective study. MAIN OUTCOME MEASURE: PRL measurement, thyroid function tests, and screening for macroprolactin were conducted. RESULTS: Patients were subdivided as follows: 56.2% had prolactinomas, 14.5% drug-induced hyperprolactinemia, 9.3% macroprolactinemia, 6.6% non-functioning pituitary adenomas, 6.3% primary hypothyroidism, 3.6% idiopathic hyperprolactinemia, and 3.2% acromegaly. Clinical manifestations were similar irrespective of the etiology of the hyperprolactinemia. The highest PRL levels were observed in patients with prolactinomas but there was a great overlap in PRL values between all groups. However, PRL>500 ng/ml allowed a clear distinction between prolactinomas and the other etiologies. Cabergoline (CAB) was more effective than bromocriptine (BCR) in normalizing PRL levels (81.9% vs 67.1%, p<0.0001) and in inducing significant tumor shrinkage and complete disappearance of tumor mass. Drug resistance was observed in 10% of patients treated with CAB and in 18.4% of those that used BCR (p=0.0006). Side-effects and intolerance were also more common in BCR treated patients. CONCLUSION: Prolactinomas, drug induced hyperprolactinemia, and macroprolactinemia were the 3 most common causes of hyperprolactinemia. Although PRL levels could not reliably define the etiology of hyperprolactinemia, PRL values >500 ng/ml were exclusively seen in patients with prolactinomas. CAB was significantly more effective than BCR in terms of prolactin normalization, tumor shrinkage, and tolerability.

Acromegaly secondary to growth hormone-releasing hormone secreted by an incidentally discovered pheochromocytoma.

Ectopic growth hormone-releasing hormone (GHRH)-secreting tumors are rare and cause acromegaly with somatotroph hyperplasia. We report a case of acromegaly secondary to GHRH secretion by an incidentally discovered pheochromocytoma in a normotensive patient. A 23-year-old man presented with signs and symptoms of acromegaly. Laboratory evaluation confirmed the diagnosis and magnetic resonance imaging (MRI) revealed a sellar mass which was thought to be a macroadenoma and surgically resected. The patient was not cured and medical treatment was indicated. An abdominal ultrasound performed before initiation of medical treatment showed a solid/cystic lesion superiorly to the right kidney. An abdominal MRI confirmed an adrenal tumor. Hormonal workup of the adrenal incidentaloma revealed elevated urinary catecholamine and total metanephrines findings strongly suggestive of a pheochromocytoma. Acromegaly was then suspected to be due to ectopic secretion of GHRH by the tumor. Patient underwent surgical resection and histopathologic examination confirmed a pheochromocytoma which stained positively for GHRH. Also, review of the pituitary specimen confirmed somatotrophic hyperplasia. Genetic analysis of the ret proto-oncogene showed no mutation. Pituitary MRI was repeated 10 months after pheochromocytoma resection and revealed a slightly enlarged pituitary and partial empty sella. The diagnosis of acromegaly caused by ectopic production of GHRH is a challenging task. A careful histopathological examination of the surgically excised pituitary tissue has a key role to arouse the suspicion and guide the investigation of a secondary cause of acromegaly.

Novel vasopressin type 2 (AVPR2) gene mutations in Brazilian nephrogenic diabetes insipidus patients.

Nephrogenic diabetes insipidus (NDI) is an inherited disorder characterized by renal resistance to the antidiuretic effect of arginine vasopressin (AVP), resulting in polyuria, polydipsia, and hypoosmolar urine. In the vast majority of cases, NDI is associated with germ-line mutations in the vasopressin receptor type 2 gene (AVPR2) and in about 8% of the cases with the water channel aquaporin-2 gene (AQP-2) mutations. To date, approximately 277 families with 185 germ-line mutations in the AVPR2 gene have been described worldwide. In the present study, the AVPR2 gene was genotyped in eight unrelated Brazilian kindred with NDI. In five of these NDI families, novel mutations were noted (S54R, I130L, S187R, 219delT, and R230P), whereas three seemingly unrelated probands were found to harbor previously described AVPR2 gene mutations (R106C, R137H, R337X). Additionally a novel polymorphism (V281V) was detected. In conclusion, although NDI is a rare disease, the findings of mutations scattered over the entire coding region of the AVPR2 gene are a valuable model to determine structure function relationship in G-protein-coupled receptor related diseases. Furthermore, our data indicate that in Brazil the spectrum of AVPR2 gene mutations is "family specific".

Osteosarcoma and acromegaly: a case report and review of the literature.

A 72-yr-old acromegalic man, who presented with pain in the left femur, was found to have a metastatic osteosarcoma. Only three cases describing the coexistence of acromegaly and osteosarcoma have been reported by the literature. As the patient didn't have other risk factors for osteosarcoma, the hypothesis that accelerated rate of bone turnover caused by long-term exposure to high GH and IGF-I could act as a predisposing factor in the development of this malignant bone tumor is discussed.

[Hormonal dysfunction of nonpituitary lesions from midline and perisellar area]. / Disfunção hormonal em lesões não hipofisárias das regiões selar e periselar.

OBJECTIVE: To analyse clinical and/or laboratorial preoperative hormonal dysfunction, of the nonpituitary intracranial lesions from midline and parasellar area. METHOD: Forty-four patients were evaluated with nonpituitary intracranial lesions, who had images studies (computed tomography or magnetic resonance) and preoperative basal hormonal level; 16 had preoperative hypothalamus-hypophysial function tests (megatests). These patients were divided in two groups. Group I - 34 lesions from midline: 11 craniopharyngiomas, 8 meningiomas, 3 germinomas, 3 tumors of sphenoid sinus, 2 empty sella syndrome, 2 pylocitic astrocytomas, 1 giant aneurysm, 2 mucoceles, 1 III ventricle diverticulum and 1 Rathke's cleft cyst; Group II - 10 lesions from parasellar area: 9 meningiomas and 1 giant aneurysm. RESULTS: In group I, 25/34 (73.5%) patients showed laboratorial hormonal deficit (14 without clinical manifestations) 18/34 (52.9%) hyperprolactinemia (5 with galactorreia) and 8 (53.3%) showed growth hormone deficiency in 15 megatests available in this group; 3 (8.8 %) patients presented central diabetes insipidus (CDI). In group II, 6/10 (60%) patients showed laboratorial hormonal deficit (5 without clinical manifestations), 1 (10%) hyperprolactinemia and 1 growth hormone deficiency (single megatest realized in this group); no patient had preoperative CID. CONCLUSIONS: The presence of nonspecific or poorly valorized clinical manifestations, does not indicate absence of hormonal dysfunction; in this present serie, 19/38 (50%) patients with laboratorial abnormalities, didn't show clinical manifestations. Hormonal dysfunction is frequent in sellar and perisellar nonpituitary lesions, specially involving midline.

The growth hormone (GH)-axis of GH receptor/binding protein gene-disrupted and metallothionein-human GH-releasing hormone transgenic mice: hypothalamic neuropeptide and pituitary receptor expression in the absence and presence of GH feedback.

Elevation of circulating GH acts to feed back at the level of the hypothalamus to decrease GH-releasing hormone (GHRH) and increase somatostatin (SRIF) production. In the rat, GH-induced changes in GHRH and SRIF expression are associated with changes in pituitary GHRH receptor (GHRH-R), GH secretagogue receptor (GHS-R), and SRIF receptor subtype messenger RNA (mRNA) levels. These observations suggest that GH regulates its own synthesis and release not only by altering expression of key hypothalamic neuropeptides but also by modulating the sensitivity of the pituitary to hypothalamic input, by regulating pituitary receptor synthesis. To further explore this possibility, we examined the relationship between the expression of hypothalamic neuropeptides [GHRH, SRIF, and neuropeptide Y (NPY)] and pituitary receptors [GHRH-R, GHS-R, and SRIF receptor subtypes (sst2 and sst5)] in two mouse strains with alterations in the GH-axis; the GH receptor/binding protein gene-disrupted mouse (GHR/BP-/-) and the metallothionein promoter driven human GHRH (MT-hGHRH) transgenic mouse. In GHR/BP-/- mice, serum insulin-like growth factor I levels are low, and circulating GH is elevated because of the lack of GH negative feedback. Hypothalamic GHRH mRNA levels in GHR/BP-/- mice were 232 +/- 20% of GHR/BP+/+ littermates (P < 0.01), whereas SRIF and NPY mRNA levels were reduced to 86 +/- 2% and 52 +/- 3% of controls, respectively (P < 0.05; ribonuclease protection assay). Pituitary GHRH-R and GHS-R mRNA levels of GHR/BP-/- mice were elevated to 275 +/- 55% and 319 +/- 68% of GHR/BP+/+ values (P < 0.05, respectively), whereas the sst2 and sst5 mRNA levels did not differ from GHR/BP intact controls as determined by multiplex RT-PCR. Therefore, in the absence of GH negative feedback, both hypothalamic and pituitary expression is altered to favor stimulation of GH synthesis and release. In MT-hGHRH mice, ectopic hGHRH transgene expression elevates circulating GH and insulin-like growth factor I. In this model of GH excess, endogenous (mouse) hypothalamic GHRH mRNA levels were reduced to 69 +/- 6% of nontransgenic controls, whereas SRIF mRNA levels were increased to 128 +/- 6% (P < 0.01). NPY mRNA levels were not significantly affected by hGHRH transgene expression. Also, MT-hGHRH pituitary GHRH-R and GHS-R mRNA levels did not differ from controls. However, sst2 and sst5 mRNA levels in MT-hGHRH mice were increased to 147 +/- 18% and 143 +/- 16% of normal values, respectively (P < 0.05). Therefore, in the presence of GH negative feedback, both hypothalamic and pituitary expression is altered to favor suppression of GH synthesis and release.

Isolated familial somatotropinomas: establishment of linkage to chromosome 11q13.1-11q13.3 and evidence for a potential second locus at chromosome 2p16-12.

The majority of somatotropinomas are sporadic, although a small number occur with a familial aggregation, either as a component of an endocrine neoplasia complex that includes multiple endocrine neoplasia type 1 (MEN-1) and Carney complex (CNC) or as isolated familial somatotropinomas (IFS). IFS is defined as the occurrence of at least two cases of acromegaly or gigantism in a family that does not exhibit MEN-1 or CNC. This rare disease is associated with loss of heterozygosity (LOH) on chromosome 11q13, the locus of the MEN-1 gene, although the MEN-1 sequence and expression appear normal. These data suggest the presence of another tumor suppressor gene located at 11q13 that is important in the control of somatotrope proliferation. To establish linkage of IFS to 11q13 and to define the candidate interval of the IFS gene, we performed haplotype and allelotype analyses on two families with IFS. Collectively, allelic retention in one tumor and a recombinant haplotype in an affected individual mapped the tumor suppressor gene involved in the pathogenesis of IFS to a region of 8.6 cM between polymorphic microsatellite markers D11S1335 and INT-2 located at chromosome 11q13.1-13.3. Maximum two-point LOD scores for five markers within this region were 3.0 or more at theta = 0.0. As somatotropinomas are the predominant pituitary tumor subtype associated with CNC and arise before 30 yr of age, which is strikingly similar to the age at diagnosis for IFS, we explored the possibility that the putative CNC genes might also contribute to the pathogenesis of IFS. Although the genetic defect responsible for the complex is unknown, CNC has been mapped by linkage analysis to chromosomes 2p15-16 and 17q23-24 in different kindreds. Two-point LOD scores less than -2.0 were obtained using marker D17S949 from chromosome 17q23-24, excluding linkage. However, LOD scores of 2.5 were obtained for markers within 2p16-12; therefore, linkage of IFS to chromosome 2p cannot be excluded. This report establishes linkage of the tumor suppressor gene involved in the pathogenesis of IFS to chromosome 11q13.1-13.3 and identifies a potential second locus at chromosome 2p16-12.