Dr M. Hermans, Department of Internal Medicine, Catharina Hospital Eindhoven, PO Box 1350, 5602 ZA Eindhoven, the Netherlands (fax: +31 402397229; e-mail: email@example.com).
Abstract. Hermans MMH, Lips CJM, Bravenboer B (Catharina Hospital Eindhoven, Eindhoven, and University Hospital Utrecht, Utrecht, the Netherlands). Growth hormone overproduction in a patient with multiple endocrine neoplasia type I (Case Report). J Intern Med 2000; 248: 527–532.
In a 69-year-old woman with a complicated history of multiple endocrine neoplasia type I (MEN 1), growth hormone overproduction was found without clinical features of acromegaly. Zollinger-Ellison syndrome was diagnosed at the age of 36 years. Total gastrectomy and partial pancreatectomy were performed. Two years later hypercalcaemia occurred, hyperparathyroidism was suspected and three hyperplastic parathyroid glands were removed. In 1994 the plasma gastrin level was elevated and a computertomography of the abdomen revealed a 1.5-cm large pancreatic tumour. Screening of the pituitary functions was unremarkable and a magnetic resonance scan of the pituitary gland showed no abnormalities. In 1995 type II diabetes mellitus was diagnosed. In 1997 basal plasma growth hormone levels were raised and plasma IGF-I levels were alternately high and normal. The patient had no clinical signs of acromegaly, but glucose tolerance testing resulted in a paradoxical rise in growth hormone concentration compatible with the diagnosis of growth hormone overproduction. Magnetic resonance imaging of the pituitary gland revealed a microadenoma.
Since its recognition by Erdheim in 1903 , the multiple endocrine neoplasia type I syndrome (MEN-I) has emerged as an array of endocrine tumours typically involving the parathyroid glands, islet cells of the pancreas and the pituitary gland. The thymus, lung, adrenal gland and thyroid are involved less frequently . (Table 1). Clinical manifestations of MEN-I include functional effects of hormone hypersecretion, mass effects secondary to tumour growth and malignant neoplasm . The gene responsible for this syndrome is located on chromosome-band 11q13 and has recently been identified [4, 5] The protein product has been termed menin . MEN-I is inherited as an autosomal dominant trait, often with high penetrance . Overproduction of growth hormone is a relatively rare finding in MEN-I. In most cases it is caused by a growth hormone-secreting pituitary tumour. However, a growth hormone-releasing hormone-releasing tumour in the pancreas is responsible for the growth hormone overproduction .
Table 1. Incidence of endocrine changes in MEN-I patients
Neuroendocrine pancreatic tumours
Neuroendocrine tumours (carcinoids) other locations
We report a patient with a complicated history of MEN I including growth hormone overproduction. We subsequently discuss whether and when it would be appropriate to screen patients with MEN-I for growth hormone overproduction. We believe that (subclinical) acromegaly may occur more frequently in MEN-I than is believed currently.
The patient initially presented in 1965 as a 36-year-old with a history of vomiting, weight loss and gastric complaints. She weighed 46 kg (body mass index: 18.9 kg m–2). These symptoms, combined with a very high degree of gastric acid production (2260 mL overnight), and the presence of a duodenal ulcer, eventually led to the diagnosis of Zollinger–Ellison syndrome. Measurement of serum gastrin levels was not possible at that time. The patient underwent a total gastrectomy and a partial resection of the pancreatic tail. Neither macroscopic inspection perioperatively, nor histological examination of the pancreas revealed any abnormalities.
Two years later, in 1967, the patient was evaluated because of persistent vomiting during pregnancy. The serum calcium level was 3.3 mmol L–1 and hyperparathyroidism was suspected. During pregnancy she underwent a neck exploration and three hyperplastic parathyroid glands were identified and removed, leaving only the right inferior macroscopic nonhyperplastic gland in situ. Multiple endocrine adenomatosis (Werner I) was diagnosed on the basis of the combination of Zollinger–Ellison syndrome and hyperparathyroidism. The course of her pregnancy was uncomplicated. Hereafter, the patient was examined periodically.
Twelve years after the first operation, in 1979, a raised serum calcium level of 2.95 mmol L–1 was measured. Physical examination was unremarkable. X-ray of hands and skull showed no signs of hyperparathyroidism. Venous sampling of the venae thyroideae showed a rise in parathyroid hormone (PTH) level at the position of the residual right inferior parathyroid gland. A second neck exploration was performed and a parathyroid adenoma as well as the right thyroid lobe were removed. Serum calcium normalized after this intervention.
Serum calcium levels remained normal for a number of years but hypercalcaemia reoccurred in December 1982; the patient presented with complaints of acute vertigo, vomiting and signs of dehydration. These symptoms disappeared spontaneously after 2 weeks and in the absence of symptoms an expectative policy was thought reasonable.
In 1994, a sestamibi scan was performed because of a persistent hypercalcaemia with high PTH levels. Increased uptake was demonstrated 5 cm inferior to the thyroid gland (Fig. 1). After further localization with computer tomography a fifth, retrosternal-situated, parathyroid gland was surgically excised and partly autotransplantated to the right forearm. Serum calcium levels then normalized. At this time the routinely measured gastrin level was 8500 ng L–1 (n < 75 ng L–1) and a computertomography of the abdomen revealed a 1.5-cm large density (Fig. 2), which was interpreted as the gastrinoma already suspected in 1965. Surgical intervention was not undertaken. Screening of the pituitary functions was unremarkable and an magnetic resonance imaging-scan of the pituitary gland showed no abnormalities.
One year later, in 1995, type 2 diabetes mellitus was diagnosed. (fasting glucose: 8.0 mmol L–1, HbA1c: 7.6%). She was not overweight (body mass index: 21 kg m–2) and the family history for this type of diabetes was negative. There was no evidence of a glucagonoma or hypercortisism (plasma 8 AM cotisol: 490 nmol L–1), and plasma growth hormone and insulin-like growth factor 1 levels were normal. Since then, basal growth hormone and insulin-like growth factor 1 levels were measured regularly. Insulin-like growth factor 1 was measured by a radioimmunoassay . The diabetes was treated with gliclazide 80mg bid and the HbA1c dropped from 7.6% to 6.7%.
In March 1997, basal growth hormone levels were raised and insulin-like growth factor 1 levels were alternately high and normal. The patient showed no symptoms or signs of acromegaly. A magnetic resonance imaging scan of the pituitary gland revealed a microadenoma of 5 mm (Fig. 3). The octreotide test showed suppression of growth hormone production (Fig. 4). Glucose tolerance testing showed a paradoxical rise in growth hormone concentration compatible with the diagnosis of growth hormone-overproduction (Fig. 5). Surgical intervention was considered not necessary because of a lack of symptoms, the patient’s age and wish, and the alternately high and normal insulin-like growth factor 1 levels.
This case entails the remarkable history of a patient with MEN-I. There is clear evidence of growth hormone overproduction but without the classical features of acromegaly, such as acral enlargement or facial changes. No other pituitary axes were affected. Most MEN-I patients with a pituitary adenoma have overproduction of a single hormone of the pituitary gland. Hyperprolactinaemia is the most frequently encountered abnormality, followed by growth hormone and adrenocorticotropic hormone (ACTH) overproduction. The prevalence rates of growth hormone overproduction in MEN-I kindreds depend on the studied population [9, 10, 11]. According to Burgess et al., secondary genetic factors may be required for the phenotypic expression of growth hormone-secreting adenomas . Perhaps our kindred belongs to a ‘growth hormone-overproducing MEN-I family’ and screening for growth hormone overproduction is indicated in view of the potential harms of acromegaly such as cardiovascular complications, diabetes mellitus and colon cancer .
In MEN-I there is no clear correlation between the genotype–phenotype of the disease. In our patient the MEN-I gene was analysed for a germline mutation by sequencing the exons using intron primers. This mutation analysis revealed an intron mutation: int7(+ 5)G(r)A. Although an effect of this intron mutation is not yet known, it is not likely to be a common nucleotide sequence polymorphism since it could not be detected in 100 alleles from 50 unrelated individuals. In addition, this mutation has not been described previously as a polymorphism and no other MEN-I gene abnormalities were found in this patient. The effect of this intron mutation will be further investigated at the RNA level.
Contradictory to clinical findings, immunocytochemical studies on surgically resected pituitary tumours from MEN-I patients revealed that approximately 40% of the adenomas were immunoreactive for more than one hormone [11, 13]. O’Brien et al.  reported increased serum levels of more than one pituitary gland hormone in 15% of their cases. In our case, there was no evidence, at least clinically, of a plurihormonal pituitary adenoma.
A magnetic resonance imaging scan of the pituitary gland of our patient revealed a microadenoma with a size of 5 mm. We believe this adenoma to be the source of the growth hormone overproduction. However, in some cases acromegaly is caused by ectopic growth hormone releasing hormone production, resulting in pituitary gland hyperplasia [13–15]. These extra-pituitary growth hormone-releasing hormone-producing tumours can be localized in the pancreas and are a part of the MEN–I syndrome, just like other pancreatic islet cell tumours such as insulinoma, glucagonoma or gastrinoma. Other sites of extrapituitary growth hormone-releasing hormone secretions are hypothalamic gangliocytomas, carcinoid tumours of the bronchus, foregut and the adrenal gland . Ectopic growth hormone-releasing hormone production is generally associated with high growth hormone-releasing hormone levels (growth hormone-releasing hormone > 300 ng L–1) [16, 17]. Serum samples were sent for determination of the growth hormone-releasing hormone level (radioimmunoassay, Department of Clinical Biochemistry, St Bartholomew’s Hospital, London) ; the laboratory analysis revealed a growth hormone-releasing hormone level of < 10 ng L–1 (N : 10–60 ng L–1). An ectopic growth hormone-releasing hormone production was therefore ruled out.
Pituitary adenomas often occur in the general population with a prevalence of 11–23% at autopsy, although only 0.02–0.025% become clinically important . As in our case, pituitary adenomas are clinically often without symptoms in MEN-I. In comparison to sporadic disease, pituitary adenomas, and in particular prolactinomas behave more aggressively . A majority of untreated prolactinoma patients developed micro or macroadenomas  with a risk of mass-lesion effects such as headache and visual field deficits. In view of this, and of the high prevalence of pituitary adenomas, screening for pituitary disease in MEN I is mandatory. A screening protocol could consist of an annual assessment of serum PRL, α-subunits, IGF-I and assessment of adrenal, thyroid and gonadal axes. Regular magnetic resonance imaging or CT-scanning of the pituitary gland is also advised .
There are some controversial issues in the management of patients with the MEN–I syndrome. In hyperparathyroidism there is consensus about three and a half or four gland parathyroidectomy . In the past, successful subtotal parathyroidectomy was often followed by recurrent hyperparathyroidism, characteristically within 15 years . The need for an aggressive approach is illustrated by the recurrent hypercalcaemia in our case.
More controversy exists in the treatment of gastrinomas and pituitary adenomas. In gastrinomas, as in our case, proton pump inhibitors are the drugs of choice to treat gastric acid hypersecretion . Hypergastrinaemia will continue and may eventually lead to the development of fundic neuroendocrine tumours . Moreover, proton pump inhibitors do not stop the development of malignant gastrinomas. Therefore, surgery is often performed when a gastrinoma is larger than 2.5 cm. However, it remains unproven that this approach will prolong survival .
Selective trans-sphenoidal surgical resection is the indicated treatment for well-circumscribed somatotroph cell adenomas . The somatostatin analogue octreotide could be an alternative by inhibiting growth hormone secretion and improving many of the signs and symptoms of acromegaly [24–26]. Recently, an antiproliferative effect of octreotide was shown on growth hormone-producing pituitary tumours .
In our case we have a patient with MEN–I syndrome with symptomless growth hormone overproduction caused by a pituitary microadenoma and a Zollinger–Ellison syndrome treated with total gastrectomy. One can discuss whether her diabetes is related to the growth hormone overproduction. In view of the low growth hormone and insulin-like growth factor 1 levels during the initial presentation of her diabetes, we do not think this is the case. Because of the patient’s age, her own wish and the relatively symptom-free situation, surgery for her gastrinoma and pituitary adenoma has not been undertaken. We think that a somatostatin analogue could be a useful addition in the therapy of this patient, if she becomes symptomatic.
Received 10 April 2000; accepted 20 September 2000.