Wil H.L. Hackeng

Bilateral occurrence of pheochromocytoma in patients with the multiple endocrine neoplasia syndrome type 2A (Sipple's syndrome)

Two kindreds with the multiple endocrine neoplasia type 2A syndrome were studied. Of one of these we examined 150 members, 20 of whom were treated with thyroidectomy for medullary carcinoma and nine with bilateral adrenalectomy for pheochromocytoma. Of the second kindred 50 members were examined, seven of whom were thyroidectomized and seven treated with bilateral adrenalectomy. Pheochromocytomas were invariably found on both sides, even in four cases in which the adrenals on one side appeared to be completely normal, not only at preoperative roentgenologic examination but also on inspection during the operation. The microscopic finding of micronodules and a cluster of abnormal medullary cells identical with those found in pheochromocytomas in one of the apparently normal adrenals represents a first stage in the development of diffuse medullary hyperplasia as well as nodular hyperplasia. This is in accordance with the fact that in the MEN type 2A syndrome pheochromocytomas are always multicentric and multiple in origin. On the basis of these findings we conclude that all patients with the MEN 2A syndrome who show symptoms and signs of active pheochromocytoma should be subjected to bilateral adrenalectomy, even when one or both of the adrenals appear to be normal at roentgenologic investigation.

Calcitonin gene-related peptide in human obesity

We studied plasma calcitonin gene-related peptide (CGRP) levels in obese women before (n = 24) and after (n = 13) weight loss, and in normal weight controls (n = 15). Furthermore, the influence of two isocaloric meals (high carbohydrate vs. high fat) on plasma CGRP concentrations was studied. The CGRP concentration in the obese group (32.26 +/- 2.01 pg/ml) was significantly (p less than 0.0001) higher than in the control group (21.64 +/- 0.15 pg/ml). After weight loss (14.3 +/- 0.72% of original weight) CGRP concentrations remained unchanged. Only the high-fat meal caused a significant (p less than 0.02) rise in CGRP levels. Our results indicate that elevated plasma CGRP levels may constitute a primary phenomenon in obese women, and that fat intake may be associated with increased CGRP secretion.

COMMON PRECURSOR MOLECULE AS ORIGIN FOR THE ECTOPIC-HORMONE-PRODUCING-TUMOUR SYNDROME

When messenger R.N.A. (m-R.N.A.) extracted from various hormone-secreting tumours was injected into Xenopus eggs, the translation products in all cases proved to be a protein of molecular weight 65 00. Analysis by polyacrylamide-gel electrophoresis and specific precipitation reactions with antibodies showed a striking similarity between the various proteins. When translation products of m-R.N.A. from calcitonin-secreting medullary thyroid carcinoma (M.T.C( and the non-secreting anaplastic form of M.T.C. were incubating with specific enzyme systems (the microsomal fraction) from both types of tumour, enzymes from anaplastic M.T.C. had no effect on the translation products, whereas enzymes from differentiated M.T.C. degraded the translation products from both differentiated and anaplastic M.T.C. The results support the hypothesis that the primary gene product of all the different types of carcinoma cell studied is a single large protein (a hormone precursor or prohormone) containing different specificities. The specific enzyme system in each carcinoma cell probably selects the specific hormone liberated from this primary protein.

Fat mobilization and plasma hormone levels in fasted dogs

Abstract The aim of this work was to study the regulation of ketone body metabolism in the dog during prolonged fasting. In nine nonobese dogs, which were starved for 2 wk, free fatty acids, triglycerides, glycerol, ketone bodies, and glucose were measured as well as insulin, glucagon, growth hormone, T 4 and T 3 , and reverse-T 3 . Free fatty acids and glycerol concentrations rose gradually during the whole period. Acetoacetate and β-hydroxybutyrate reached levels of 130 ± 50 and 350 ± 125 μmol/liter, respectively. Glucose levels remained constant initially but declined significantly by the end of the starvation period. Insulin levels declined moderately. Glucagon and growth hormone values were not influenced by fasting. T 4 concentrations remained in the normal range, T 3 levels declined significantly, but reverse-T 3 levels did not rise during starvation. The results are compared with data from the literature on human starvation. From the data on the lipid parameters it is concluded that fat mobilization progresses at a slower rate in the dog than in man. The absence of a pronounced hypoglycaemia results in a hormonal setting (unchanged glucagon and growth hormone concentrations, together with an only slightly decreased insulin concentration) which protects the dog from the development of severe ketosis.

Bone histomorphometry and serum concentrations of intact parathyroid hormone (PTH(l–84)) in patients with primary hyperparathyroidism

The consequences of bone disease in primary hyperparathyroidism (PHPT) are still a matter of discussion. We studied transiliac bone biopsies of 24 patients (9 men and 15 women) with mild to moderate PHPT, proven by surgery. Histomorphometric data were compared with control values obtained from autopsy bone samples. The biopsies of the PHPT patients were characterized by increased trabecular bone volume (P < 0.01) and surface (P < 0.02), increased osteoid volume and increased osteoid and resorption surfaces (P < 0.001). Cortical porosity showed a non-significant increase in the PHPT patients. In the patients the fasting serum concentrations of parathyroid hormone (PTH(1-84)) correlated positively with cortical porosity (r = 0.50, P = 0.02), osteoid volume (r = 0.40, P = 0.05), osteoid surface (r = 0.50, P = 0.01), and eroded surface (r = 0.59, P < 0.01). It is concluded that moderate PHPT is associated with preservation of trabecular bone, whereas cortical bone may be lost in these patients. Cortical porosity and the parameters of bone turnover correlate well with the fasting serum PTH(1-84) concentration.

Evidence for the involvement of corticotropin-releasing factor in the inhibition of gonadotropin release induced by hyperprolactinemia.

The hypothesis was tested that corticotropin-releasing factor (CRF) is involved in the inhibition of gonadotropin secretion during chronic hyperprolactinemia. Two models of hyperprolactinemia were used, namely inoculation with the prolactin (PRL)-secreting tumor 7315b and implantation of isogenic pituitary glands. Gonadectomized, adrenalectomized male rats received a testosterone capsule and a corticosterone pellet and were inoculated subcutaneously with tumor 7315b. Similar rats without tumor served as controls. The rats were studied 3-4 weeks later while anesthetized with urethane. Plasma testosterone and corticosterone were similar in the two groups of rats. Compared to controls, the tumor-bearing rats had significantly higher plasma levels of PRL (100-fold increase) and adrenocorticotropin (ACTH; 3-fold increase), whereas plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) had significantly decreased to 15 and 40%, respectively. CRF release into hypophysial stalk plasma was higher in rats with tumor 7315b than in controls (298 +/- 23 vs. 197 +/- 28 pg/h), and hypothalamic CRF content had increased from 3.0 +/- 0.3 to 4.3 +/- 0.3 ng. Male rats received 3 pituitary glands under the kidney capsule. Sham-operated rats served as controls. They were studied 5-7 weeks later while anesthetized with urethane. Compared to controls, pituitary-grafted rats had larger adrenals (49 +/- 4 vs. 34 +/- 2 mg), higher plasma PRL (156 +/- 18 vs. 52 +/- 8 ng/ml), ACTH (0.46 +/- 0.05 vs. 0.22 +/- 0.02 ng/ml) and corticosterone (455 +/- 39 vs. 268 +/- 14 ng/ml), and lower plasma levels of LH (21 +/- 2 vs. 41 +/- 6 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence of multicentric origin of the multiple endocrine neoplasia syndrome type 2A (Sipple's syndrome) in a large family in the Netherlands: Diagnostic and therapeutic implications

Abstract The occurrence of simultaneous tumors in different organs and the multicentric localization of the tumors in each of these organs are discussed on the basis of the findings in six patients belonging to a large kindred with Sipples syndrome and in patients with Sipples syndrome not belonging to this kindred, as well as the data in the literature. The high number of accessory pheochromocytomas in this family and in the other patients with Sipples syndrome was striking. Both the pheochromocytomas and the accessories were found in the form of both cortical nodules and complete adrenal glands with hyperplastic medullary tissue. The invariable occurrence of pheochromocytoma changes in accessory adrenal tissue in this family and in other cases supports and demonstrates the multicentricity of tumor development in Sipples syndrome. The aim of surgical treatment should be to remove all the pheochromocytoma tissue identified in the adrenal glands, the celiac plexus and side chain regions, thereby reducing the chance of recurrence of the symptoms in these patients and the need for repeated surgical intervention. However, more extensive exploration of the chest, cervical area, etc., to attempt curative surgery, is too destructive to be justifiable. The medullary thyroid carcinoma, which is also multicentric in origin, is, on the contrary, a dangerous tumor for which total thyroidectomy with extensive neck exploration is obligatory, preferably in an early phase. A modified short calcium test which is especially sensitive in this early phase, is described for screening for medullary thyroid carcinoma.

Total Deficiency of Growth Hormone and Prolactin, and Partial Deficiency of Thyroid Stimulating Hormone in Two Dutch Families: a New Variant of Hereditary Pituitary Deficiency

Four out of 10 children in two unrelated families presented with a total pituitary growth hormone (GH) and prolactin deficiency and a partial thyrotropin (TSH) deficiency. The GH gene was intact in family I. The pituitaries, visualized by magnetic resonance imaging, were normal. All children responded well to GH and L-thyroxine therapy. Baseline plasma somatostatin and its peak response to arginine infusion were elevated in family I and they had a milder TSH deficiency than family II. Plasma insulin showed a poor response to arginine infusion. This hereditary combination of pituitary deficiencies suggests a deficiency of a common positive transcription factor.

Primary somatomedin deficiency: Case report

A child presenting with the clinical features of hyposomatotropism but with high immunoreactive plasma growth hormone is described. During short-term administration of human growth hormone (HGH) his response with regard to fasting blood-glucose and free fatty acids, plasma-somatomedin, urinary excretion of calcium, nitrogen, and hydroxyproline was minimal or absent. 6 months of treatment with HGH did not reduce the endogenous HGH secretion. Insulin secretion had not increased and plasma somatomedin levels remained extremely low. Over a period of 2 years of treatment, growth response and loss of subcutaneous fat were minimal. On serial dilution in radioimmunoassay, his growth hormone (GH) molecule yielded a parallel line with the HGH standard. In electrofocusing experiments the GH molecule was in the same pH range as growth hormone in acromegalic plasma and the major peak of clinical grade HGH (5·03 against 5·01 and 4·98). It is concluded that an overall and specific diminished responsiveness to HGH is present in this patient. This includes a lack of generation of somatomedin, which is thought to be the cause of his short stature. There was no evidence of abnormality of the GH molecule.

A close correlation between the amount of met-enkephalin-immunoreactivity and epinephrine in adrenal pheochromocytoma tissue from patients with sipple's syndrome

The concentration of epinephrine, norepinephrine, dopamine, met-enkephalin-, ACTH-, calcitonin- and somatostatin-like immunoreactivity (IR) were determined in the extracts of 9 adrenal pheochromocytomas from 7 patients. Six of these patients had Sipples syndrome. There was a close correlation between the amounts of met-enkephalin-IR and of epinephrine present in the tumor tissue (p less than 0.01). Such a correlation was not found between catecholamines and the other polypeptide hormones investigated. The relevance of the close parallel in the occurrence of met-enkephalin-IR and epinephrine in human adrenal pheochromocytoma tissue is unknown, but it underlines earlier observations in the normal bovine and rat adrenal medulla on a co-storage and co-release of these substances in normal circumstances.