Jayme Goldman

ACANTHOSIS NIGRICANS, HIRSUTISM, INSULIN RESISTANCE AND INSULIN RECEPTOR DEFECT

A 24‐year‐old negress with the triad of acanthosis nigricans, hirsutism associated with polycystic ovaries and insulin resistance is reported. Metabolic studies were done 3 years after a bilateral ovarian wedge resection. Partial remission of the hirsutism and return of menstrual cycles occurred after surgery. Extreme resistance to endogenous and exogenous insulin was observed. Three studies of insulin receptors on circulating red blood cells (RBC) showed abnormal inhibition‐competition curves, characterized by increased percentage insulin binding at higher unlabelled insulin levels. Scatchard plots suggested an apparent increase in the number of low affinity receptors. Despite the changes in receptor‐insulin interaction, the defect does not seem to explain the insulin resistance since binding of insulin to a target tissue (RBC) appeared to be quantitatively normal at physiological insulin levels, suggesting a simultaneous post receptor defect.

Apoplexia subclínica em tumores pituitários

Acute pituitary apoplexy is a rare event, even in patients with pituitary macroadenomas. On the other hand, the presence of necrotic/hemorrhagic areas, especially in macroadenomas, seems to be more common than earlier reported in the CT period. After the introduction of MR in the presurgical workup of these patients, these apopleptic areas have been more easily diagnosed preoperatively. Forty consecutive patients with pituitary macroadenomas were studied with high-resolution 1.5 T T1 coronal, sagittal and axial slices over the sellar region. Special attention was paid in the detection of necrotic, cystic and hemorrhagic areas within these tumors. Ten patients had hemorrhagic/necrotic areas within their tumors, without any sign or symptom of acute apoplexy. These areas varied from small (2 mm) to very large (30 mm) ones. Seven patients had non-secreting tumors, 2 GH and 1 prolactin secreting tumors, which is the same profile of secretory pattern for the whole series (40 patients). The clinical picture included (other than that caused by endocrine secretion) slowly progressive (but not acute) visual loss (n = 8) and headache (n = 3). After surgical decompression of the surrounding structures and visual apparatus, which was facilitated by the presence of the necrotic areas, there was visual improvement in 6 patients and headache resolution in 2. The presence of asymptomatic apopletic areas in these macroadenomas and their absence in microadenomas as can be seen in the literature suggest that they are related more to the size of the tumor than to its endocrine secretion pattern. This is in agreement with a vascular insufficiency hypothesis in the pathogenesis of these lesions.Acute pituitary apoplexy is a rare event, even in patients with pituitary macroadenomas. On the other hand, the presence of necrotic/hemorrhagic areas, especially in macroadenomas, seems to be more common than earlier reported in the CT period. After the introduction of MR in the presurgical workup of these patients, these apopleptic areas have been more easily diagnosed preoperatively. Forty consecutive patients with pituitary macroadenomas were studied with high-resolution 1.5 T T1 coronal, sagittal and axial slices over the sellar region. Special attention was paid in the detection of necrotic, cystic and hemorrhagic areas within these tumors. Ten patients had hemorrhagic/necrotic areas within their tumors, without any sign or symptom of acute apoplexy. These areas varied from small (2 mm) to very large (30 mm) ones. Seven patients had non-secreting tumors, 2 GH and 1 prolactin secreting tumors, which is the same profile of secretory pattern for the whole series (40 patients). The clinical picture included (other than that caused by endocrine secretion) slowly progressive (but not acute) visual loss (n=8) and headache (n=3). After surgical decompression of the surrounding structures and visual apparatus, which was facilitated by the presence of the necrotic areas, there was visual improvement in 6 patients and headache resolution in 2. The presence of asymptomatic apopleptic areas in these macroadenomas and their absence in microadenomas as can be seen in the literature suggest that they are related more to the size of the tumor than to its endocrine secretion pattern. This is in agreement with a vascular insufficiency hypothesis in the pathogenesis of these lesions.

APOPLEXIA PITUITARIA SEGUIDA DE REMISSAO ENDOCRINA : RELATO DE DOIS CASOS

Pituitary apoplexy is rare and endocrine remission in patients with apopletic secreting pituitary adenomas is even rarer. This study reports on two patients with pituitary macroadenomas (one with Cushings disease and the other with acromegaly) in whom endocrine remission occurred after apoplexy. The first patient had Cushings disease and had an ictus of headache and vomiting after which she started a progressive remission of hypercortisolism. A post-apoplexy MRI disclosed persistence of a sellar and supra-sellar mass. She was submitted to transesphenoidal surgery. An hypertensive hemorhagic cyst was found with no tumor. The second patient had acromegaly. While performing a LHRH-stimulation test he had an ictus of headache, vomiting, no visual loss and appearance of diabetes insipidus. A CT scan disclosed an intrasellar hematoma. Despite the size of the tumor and since there was no visual impairment, this patient was followed up without surgery. Imaging follow-up showed a progressive shrinkage and disappearance of the mass, which was corroborated by endocrine remission. A high rate of recurrence is reported in such patients in the literature. Both patients are being currently followed-up on a long-term basis.

A case of congenital generalized lipodystrophy: metabolic effects of four dietary regimens. Lack of association of CGL with polymorphism in the lamin A/C Gene

Sirs, Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder, characterized by severe metabolic derangement associated with the absence of subcutaneous adipose tissue. The exact genetic defect is unknown, and systematic studies of optimal dietary and pharmacological therapy for CGL have not been performed. We report a case of CGL, in which the patients dietary/pharmacological management was optimized with the help of metabolic testing. In addition, DNA from this patient was screened for mutations in several candidate genes. A 36-year-old female presented for treatment of diabetes mellitus uncontrolled with 0·8 units per kg of insulin per day. The diabetes was diagnosed 10 years earlier and was complicated by macroalbuminuria (533 µg/minutes), retinopathy, neuropathy, and peripheral vascular disease. Her parents were first cousins. She had generalized fat loss, prominent musculature, hepatomegaly, clitoromegaly, mild hirsutism and no acanthosis nigricans. Her height was 151 cm and weight was 49·2 kg (body mass index 21 kg/m2). Tetrapolar bioelectric impedance revealed a fat mass of 3% (1·5 kg). CT demonstrated no subcutaneous fat in the abdominal area, and visceral abdominal fat was approximately one third of that in age, height and body weight matched females. Her blood chemistry profile, pituitary, gonadal, adrenal and thyroid tests were normal. Serum leptin was 0·8 µg/l (10·8–16·6 µg/l is normal for females with BMI 21 ± 5 kg/m2). All research procedures were approved by the Institutional Review Board of the Hospital das Clinicas at the University, Sao Paulo, Brazil. After the patient was hospitalized, baseline studies were performed, and four dietary regimens (Reg. 1–4, see Table 1) varying in energy and fat content, and with the addition of dL-fenfluramine with intensive insulin therapy were Instituted under carefully controlled conditions with a goal to maintain body weight and optimize glycaemic control. After each intervention, energy substrate metabolism was tested with a euglycaemic hyperinsulinaemic clamp (insulin infusion rate 10 mU × m−2 × minutes−1) and indirect calorimetry using a flow-through canopy gas analyser system in the resting state and after a glucose load (Felber et al., 1987). The respiratory exchange ratios (RER) indicate (Table 1) that in all but the hypercaloric moderate-fat diet (Reg. 2), glucose was the primary fuel source after an overnight fast. This finding was supported by the low fasting free fatty acid availability in all regimens except for the hypercaloric moderate-fat regimen. The thermic effect of glucose did not change with any of the interventions, including dL-fenfluramine (Table 1). As measured by euglycaemic hyperinsulinaemic clamp exogenous glucose disposal did not correlate with energy content in the diet. According to the clamp data (Table 1), treatment with a hypercaloric very low-fat diet (Reg. 3) and hypercaloric low-fat diet (Reg. 4) resulted in markedly greater exogenous glucose disposal than treatment with a hypercaloric moderate-fat diet (Reg. 2). However, the total glucose disposal determined by indirect calorimetry was not considerably different in the four regimens, suggesting that the disposal of glucose produced endogenously accounts for the difference between glucose disposal measured by the clamp vs. indirect calorimetry. Indeed, basal plasma glucose was higher after treatment with a moderate-fat diet (Reg. 2 vs. 3). Interestingly, with slightly higher basal plasma glucose levels, basal plasma insulin and C-peptide levels after an overnight fast (Table 1) were almost twice as low in Reg. 2 compared to Reg. 3. The lower endogenous insulin levels in Reg. 2 may be due to suppression by free fatty acids, which were at higher levels in Reg. 2. Table 1 Effects of dietary modifications, insulin therapy and addition of dL-fenfluramine in a patient with CGL Energy restriction in the diet has limitations in patients with CGL because of undesirable weight loss and persistent hunger (Reg. 1). However, as in our patients case, modestly hypercaloric diets (Reg. 2 and 3, see Table 1) add a risk of hyperglycaemia that responds poorly to insulin. The exogenous glucose disposal rate was the highest and basal plasma glucose after an overnight fast normalized after the addition of dL-fenfluramine to a hypercaloric low-fat diet (Reg. 4). In addition, this drug in sharp contrast to dietary treatments alone, seems to be responsible for increased lipid oxidation after an oral glucose load, apparently at the expense of suprabasal glucose oxidation. However, even this decrease in suprabasal glucose oxidation may be a positive phenomenon in a patient with CGL if it reflects an overall decrease in glucose recycling and hepatic glucose production. Our findings are supported by data from Andersen et al. (1993), who have shown that lipid oxidation is increased and glucose oxidation is decreased during dL-fenfluramine treatment in obese nondiabetic patients. We suggest that the improvement in insulin sensitivity, despite no change in total energy intake and virtually the same nutrient composition after transition from dietary Reg. 3–4, is related to a dL-fenfluramine induced augmentation in fat oxidation and diminished cycling of the nutritional substrates. Clinically this positive effect was reflected by achievement of euglycaemia with just 1·1 U/kg of insulin per day. We performed single-stranded conformational polymorphism (SSCP) and DNA analysis to search for mutations in the coding regions, exon-intron junctions and proximal promoter regions of the β3-adrenergic receptor (β3AR) and the peroxisome proliferator-activated receptor-gamma (PPARγ) genes. We did not detected mutations in the β3-AR gene in this patient, similar to studies by Silver et al. (1997) and Vigouroux et al. (1997) in other patients with CGL. The only polymorphism in the PPARγ gene in this patient was a silent nucleotide substitution at the position 1431 (CACHis→CATHis). This variant was also present in several nonlipodystrophic controls. Similarly, we (unpublished) and colleagues (Vigouroux et al., 1998) did not find unique mutations in the PPARγ gene in other patients with CGL. Heterozygosity for several missense mutations in the lamin A/C gene on chromosome 1 has been associated with familial partial lipodystrophy (Cao & Hegele 2000). DNA sequence analysis of the lamin A/C gene revealed that our patient was heterozygous for the previously reported polymorphism at codon 583 [GCCAla→GACAla] (Speckman et al. 2000). The patient was also heterozygous for a C2737T polymorphism in intron 8, which introduces a potential new splice donor site (GC→GT). However, this novel intron variant was also present in three of nine normal controls. In conclusion, we show that a low-fat diet with supplemental dL-fenfluramine and insulin therapy may be an effective method to manage hyperglycaemia in a patient with CGL. Studies of the genes for lamin A/C, PPARγ and β3-AR in our patient failed to detect pathogenic alterations. Uncovering the genetic defect of CGL will allow a better understanding of the pathogenesis of this disease and provide insights into adipocyte development and function, as well as potential treatments for CGL and perhaps other metabolic disorders such as obesity and type 2 diabetes.

OESTROGEN DYNAMICS IN ADRENAL VENOUS EFFLUENTS IN CONGENITAL VIRILIZING ADRENAL HYPERPLASIA

Four patients with untreated congenital virilizing adrenal hyper‐plasia (partial 21‐hydroxylase deficiency) were studied by bilateral adrenal vein catheterization. Simultaneous right and left adrenal and peripheral blood samples were collected for determination of oestrone (E1) and oestradiol (E2. The concentrations of both were higher in the adrenal effluents than in the peripheral blood samples, indicating their secretion by the adrenals. All patients were also studied during a sequential test of suppression (0.5 h after i.v. administration of 4 mg dexamethasone) and stimulation (5 min after i.v. administration of 250 μg ACTH 1–24; Synacthen). Mean peripheral E2 concentrations did not change significantly whereas E1 increased above control levels after stimulation. In contrast, suppression of adrenal venous blood concentrations with dexamethasone, and stimulation with ACTH, was demonstrated for every patient. The results indicate that in congenital adrenal hyperplasia the adrenal glands secrete significant amounts of E1 and E2.

Failure of partial hypophysectomy as definitive treatment in cushing’s disease owing to nodular corticotrope hyperpiasia; report of four cases

Nodular corticotrope hyperpiasia is a rare pathology causing Cushing’s syndrome owing to a primary pituitary disease or ectopic CRH production. In this study, we evaluated the laboratory and pathological findings and results of transsphenoidal pituitary surgery in four patients with Cushing’s disease. Dynamic tests of pituitary-adrenal function (dexamethasone suppression, metyrapone, CRH, and DDAVP tests) were done before and after transsphenoidal pituitary surgery. Plasma and total urinary cortisol, serum 11-deoxycortisol, and plasma ACTH were determined by RIA. Hormonal dynamic tests and radiologic studies were compatible with a pituitary ACTH source. The transsphenoidal surgery revealed the presence of corticotrope hyperpiasia confirmed by immunoperoxidase stain and a preserved reticulum framework in the removed pituitary tissue of these four patients. The pituitary surgery led to a short period of improvement in two of the patients (1 and 4), a 3-yr remission in one patient (patient 2), and no improvement in one (patient 3). We conclude that although our patients appear to have inadequate suppression with high-dose dexamethasone, there is no way to diagnose this pathology presurgically, and that total hypophysectomy, bilateral adrenalectomy, and irradiation are the only alternatives for definitive treatment. A CRH-secreting ectopic tumor could not be found in our patients either before or after surgery in the follow-up period.

Gêmeas idênticas discordantes para a doença de Cushing: relato de caso

Cushings disease is rare in children and its ocurrence in identical twins is extremely rare. This paper reports on identical twins discordant for Cushings disease. One of them first presented with a cushingoid phenotype by the age of 10. Her evaluation showed an increased urinary free-cortisol and serum ACTH. Her pattern in the dexametazone supression tests was compatible with Cushings disease. MRI disclosed a pituitary macroadenoma which was removed by the transesphenoidal approach. Immunohistochemical studies of the tumor showed the presence of ACTH-producing cells. The patient went into clinical and laboratorial remission after surgery. She re-started to grow after the disappearance of the Cushings phenotype but she is still shorter than her healthy sister. The latter remains disease-free 4 years after her sisters diagnosis. This represents the third such case reported in the literature. Our findings suggest that acquired factors may be responsible for the genesis of Cushings disease.

Hypothalamic - Pituitary Function in Patients with Idiopathic Growth Hormone Deficiency

The combined insulin (0.05 or 0.1 U/Kg), GnRH (100 Mg) and TRH (200 stimulation test was used to study hypothalamic-pituitary-target gland function in 58 patients with idiopathic GH deficiency and 34 children with short-stature unrelated to endocrine disorders. 79.3% of the patients with GH deficiency had abnormal secretion patterns of one or more other pituitary hormones. Altered TSH secretion was the most frequently observed abnormality occurring in 65.5% of the growth-hormone deficient patients. Failure of TSH to respond to TRH, indicating pituitary disease, was observed in four (6.9%) patients. 28 (48.2%) patients had normal basal TSH levels, but showed an exaggerated or prolonged response to TRH. Elevated basal TSH levels associated with an exaggerated response to TRH were observed in 6 (10.3%) patients, one of whom had primary hypothyroidism. Abnormalities of prolactin (PRL) secretion were present in 39.6% of the patients. Basal PRL levels were increased in 29.3% of GH deficient patients, 10.3% had a low PRL response following the combined stimulation test and In 3.4% of the patients the subnormal PRL response was associated with TSH deficiency. Abnormal Cortisol secretion was present in 37.9%. GH deficiency was associated with a single additional hormone defect in 24.1% (TSH), 8.6% (PRL), and

Evaluation of the gonadotropic responsiveness of the pituitary to acute and prolonged administration of LH/FSH-releasing hormone (lhrh) in untreated patients with congenital adrenal hyperplasia.

The pituitary gonadotropic responsiveness to acute and prolonged administration of LH/FSH-releasing hormone (LHRH) were assessed in 6 patients with untreated congenital virilizing adrenal hyperplasia (partial 21-hydroxylase deficiency). The oldest subjects had normal response in comparison to females at the midfollicular phase, to the acute infusion of 25 ug LHRH regarding both gonadotropins whereas LH secretory area was decreased during the prolonged (100 ug LHRH in 8 hours) infusion with normal FSH secretion. The two youngest subjects, with higher steroid levels in our series, were either unresponsive on both ways of testing or presented pre-pubertal response.