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Johan Verhelst and Roger Abs

Design

Data on lipids, body composition, and blood pressure (BP) from all published KIMS papers are summarized and compared with a literature review.

Results

KIMS data confirm and extend previous research showing that adults with GH deficiency (GHD) have an adverse cardiovascular risk profile. GHD patients have high levels of dyslipidemia, elevated body mass index, unfavorable waist-to-hip ratio and body composition, and a high risk of hypertension. These abnormalities are likely to explain the increased cardiovascular mortality observed in patients with hypopituitarism. When given GH replacement therapy, an improvement is seen in KIMS as well as earlier studies for lipid profile, body composition, and BP. The added value of the different KIMS papers over previous research is that KIMS involves a much larger number of patients, that lipid concentrations and IGF1 are measured in a single central laboratory, and that the effects of GH replacement therapy can be followed longer than the duration of earlier trials. By the large number of patients, KIMS gives insight into the effects of GH in different patients' subgroups such as elderly patients, patients with idiopathic GHD, patients with craniopharyngioma, patients after irradiation, and so on. In addition, KIMS has made it possible to calculate more exactly the influence of baseline parameters on these cardiovascular risk parameters and their response to GH.

Conclusions

Taken together, data from KIMS confirm earlier knowledge about the important benefits of GH replacement therapy, but also on the use of GH in specific subgroups such as isolated GHD, patients above 65 years, and patients after irradiation. No subgroup yet has been identified as not responding well to GH.

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Roger Abs, Achilles Stevenaert and Albert Beckers

Abs R, Stevenaert A, Beckers A. Autonomously functioning thyroid nodules in a patient with a thyrotropin-secreting pituitary adenoma: possible cause–effect relationship. Eur J Endocrinol 1994;131:355–8. ISSN 0804–4643

A 51-year-old female patient with long-standing hyperthyroidism due to a thyrotropin-secreting pituitary adenoma is reported, who became thyrotoxic again shortly after successful pituitary surgery. Functional testing and scintigraphy suggested the diagnosis of autonomous functioning thyroid nodules, which was confirmed by pathological examination of the resected thyroid tissue. This is the first report revealing the transition from a pituitary-dependent to a thyroid-dependent hyperthyroidism. Autonomous functioning thyroid nodules are, however, considered an intrinsic thyroid defect. In similarity with other disorders, in which trophic hormones may induce an autonomous secretion by the target gland, this report opens the possibility that a humoral factor may play a role in the development of autonomous functioning thyroid nodules.

A Beckers, CHU-B35, Department of Endocrinology, Sart-Tilman, B-4000 Liège, Belgium

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Etienne Delgrange, Tania Daems, Johan Verhelst, Roger Abs and Dominique Maiter

Context

Macroprolactinomas poorly responsive to dopamine-agonists are often more aggressive and are usually termed ‘resistant’ but this clinical concept has always been defined empirically.

Objective

To define resistance to cabergoline (CAB) on the basis of a dose–response relationship established in a large series of macroprolactinoma patients and to assess the influence of gender and tumor invasiveness on the response to treatment.

Design

Retrospective study.

Methods

One hundred and twenty-two patients (72 women and 50 men) primarily treated with CAB for at least 1 year were included. Main outcome measures were serum prolactin (PRL) and tumor size.

Results

Normalization of PRL was obtained in 115 out of the 122 patients (94%). The majority of patients (96/115, 83%) were controlled with a CAB dose ≤1.5 mg/week. Most of the other patients (19/26) had only a partial resistance, responding to a further increase of the CAB dose. Beyond the dose of 3.5 mg/week, there was no clear advantage in further increasing the dose instead of continuing the treatment at the same dose. Most tumors (98/119 assessable cases, 82%) showed a significant shrinkage during CAB treatment. It was more likely to occur in cases of PRL normalization. Both cavernous sinus invasion and male gender were significantly and independently associated with partial or complete resistance to treatment.

Conclusions

Most macroprolactinomas primarily treated with CAB are adequately controlled with doses ≤1.5 mg/week. About 20% of patients, mainly men and/or those with invasive tumors will require a higher dose of CAB. We suggest defining such patients as resistant to CAB.

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Pascale Abrams, Orsalia Alexopoulou, Roger Abs, Dominique Maiter and Johan Verhelst

Abstract

Background

Lanreotide-Autogel is a depot formulation of the somatostatin analog lanreotide used in the treatment of acromegaly. We investigated whether prolonging or shortening the interval between injections would offer any benefit.

Subjects and methods

The interval was prolonged from once every 4 weeks to once every 6 weeks when patients (n=9) had normal IGF-I and GH concentrations. When patients (n=12) had still elevated IGF-I or GH on the maximal dose of 120 mg every 4 weeks, the interval was shortened to once every 3 weeks. Serum IGF-I and GH were measured after 12 and 24 weeks to allow for dose adaptation. Symptoms and tumor volume were evaluated at baseline and after 36 weeks.

Results

In seven of the nine subjects with normal IGF-I and GH, the interval could be extended to 6 weeks without loosing efficacy on IGF-I (195 vs 213 μg/l; not significant, NS) and GH concentrations (1.4 vs 1.3 μg/l; NS). The weekly dose could significantly be reduced (from 23.3 to 17.8 mg; P=0.002). In only 1 of the 12 not-controlled patients, reducing the interval to once every 3 weeks induced normalization of IGF-I and GH.

Conclusion

In subjects whose acromegaly is well controlled using lanreotide-Autogel, prolonging the time interval between injections can often be increased 4 to 6 weeks without loss of efficacy, thereby improving the subject's comfort and reducing the cost of treatment. On the other hand, in subjects whose acromegaly is not controlled on a dose of 120 mg every 4 weeks, reducing the interval to every 3 weeks is rarely beneficial.

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Roger Abs, Louis Verbist, Marleen Moeremans, Pierre Blockx, Ivo De Leeuw and Jozef Bekaert

Abstract

A selective glucagon deficiency was documented in a 36-year-old female patient suffering from severe hypoglycemic attacks. The extremely low fasting plasma glucagon levels could not be stimulated by hypoglycemia. The increase in plasma glucagon during stimulation with arginine did not prevent hypoglycemia provoked by the simultaneous insulin secretion. Treatment consisting of a continuous sc glucagon infusion system resulted in correction of both postabsorptive and postprandial hypoglycemia. Further lowering of the glucose level during an arginine test could be the hallmark of this hypoglycemic syndrome characterized by an inappropriate glucagon secretion. This case report would indicate that epinephrine cannot prevent hypoglycemia when glucagon release is completely deficient.

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Sophie Lefebvre, Lutgarde De Paepe, Roger Abs, Jacques Rahier, Philippe Selvais and Dominique Maiter

Lefebvre S, De Paepe L, Abs R, Rahier J, Selvais P, Maiter D. Subcutaneous octreotide treatment of a growth hormone-releasing hormone-secreting bronchial carcinoid: superiority of continuous versus intermittent administration to control hormonal secretion. Eur J Endocrinol 1995;133:320–4. ISSN 0804–4643

Diagnosis of ectopic acromegaly was made in a 21-year-old female patient who 3 years before had undergone a right pneumectomy for a disseminated bronchial carcinoid. Plasma growth hormonereleasing hormone (GHRH) concentrations were markedly elevated (6440 ng/l; normal value <100 ng/l), as were serum GH (187 μg/l; normal <5 μg/l) and plasma insulin-like growth factor I (IGF-I) levels (6.7 U/ml; normal <2 U/ml). Retrospective immunohistochemical examination of the carcinoid tumor was positive for GHRH and the tumoral content of GHRH was 2130 ng/g wet weight. Subcutaneous treatment with octreotide was begun and first resulted in a profound inhibition of GH hypersecretion, normalization of plasma IGF-I and only partial reduction of GHRH concentrations. However, the initial dose of 3 × 100 μg had to be increased gradually to 4 × 750 μg because of a progressive deterioration of the hormonal control. After 15 months of intermittent therapy, octreotide was administered by continuous sc infusion. This treatment improved compliance, allowed the daily dose of octreotide to be reduced to 1500 μg and normalized serum GH levels. A near-normalization of the plasma IGF-I concentrations was also obtained, whereas the suppression of plasma GHRH concentrations remained incomplete. Despite favorable evolution of the endocrine parameters, intramedullar metastases were diagnosed and required radiation therapy. This observation emphasizes the superiority of continuous over intermittent administration of octreotide in the treatment of ectopic acromegaly. It also shows that the somatostatin analog acts more at the pituitary level to inhibit GH secretion than at the site of the neuroendocrine tumor.

S Lefebvre, Division of Rheumatology, Clinique du Refuge, Rue du Couvent 39, B-7700 Mouscron, Belgium

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Guy T’Sjoen, Marie Bex, Dominique Maiter, Brigitte Velkeniers and Roger Abs

Objective: To assess the impairment of quality of life (QoL), evaluated by the acromegaly QoL (AcroQoL) questionnaire, in patients with controlled and uncontrolled acromegaly.

Design: Cross-sectional evaluation of AcroBel, a national observational registry of acromegalic patients newly diagnosed or in follow-up.

Methods: Disease perception by the patients was evaluated by the disease-specific signs and symptoms score (SSS) and QoL was assessed by the AcroQoL questionnaire. Hormonal status was determined by central measurements of GH and IGF-I.

Results: Patients (n = 291) had a median GH of 1.43 μg/l (0.65–3.03; IQR), a median IGF-I of 231 μg/l (150–367), and a mean IGF-I z-score of +1.91 (s.d. 2.21). The AcroQoL total score in the whole group was 67.1 (51.1–78.4), with a score of 65.6 (43.8–78.1) for the physical dimension, 67.9 (53.6–80.4) for the psychological dimension, 78.6 (64.3–89.3) for personal relations and 57.1 (39.3–75) for appearance. The median SSS was 3 (15). There was a negative correlation between both questionnaires (r = −0.478; P < 0.001). There was no correlation between AcroQoL score and biochemical markers of disease activity. When subdividing patients into groups of biochemical control according to GH and IGF-I levels, no difference could be established for either SSS or AcroQoL scores.

Conclusions: The AcroQoL results from the AcroBel registry confirm the marked impairment of the patients’ QoL, especially in relation with appearance. A negative correlation between AcroQoL and SSS was confirmed. There was, however, no correlation between AcroQoL and biochemical markers of disease activity.

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Roger Abs, Ludo Van Breusegem, Griet Verhaert, Helena Smet and Paul M Parizel

Abs R, Van Breusegem L, Verhaert G, Smet H, Parizel PM. Intrasellar bony spine, a possible cause of hypopituitarism. Eur J Endocrinol 1995;132:82–5. ISSN 0804–4643

A 39-year-old male patient with long-standing pituitary deficiency is reported. The onset of hypopituitarism was probably at about the age of 12 years, but diagnosis was not made until 6 years later. Since then he has received substitutive hormonal treatment and was referred with complaints suggestive of growth hormone deficiency. Retrospective study of a skull radiography performed at the age of 18 years revealed a calcified lesion in the sellar region. Additional radiological examinations showed the presence of a 9-mm intrasellar bony spine. Magnetic resonance examination showed a ventrally extending arrow-shaped bone deformation in continuity with the dorsum sellae, consisting of a hyperintense structure comparable with the intensity of the bone marrow of the dorsum and clivus. Computed tomography scanning confirmed in detail the morphology of the bony spine. This deformity probably represents the non-regressed cephalic segment of the notochord. Only in four reports has the existence of this congenital abnormality been described, but this is the first one in which hypopituitarism can be regarded as a complication of the intrasellar spine.

R Abs University of Antwerp, Department of Endocrinology, Universiteitsplein 1, B-2610 Wilrijk, Belgium

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Charlotte Hoybye, Peter Jönsson, John P Monson, Maria Kołtowska-Häggström, Václav Hána, Mitchell Geffner and Roger Abs

Abstract

Objective

The impact of the aetiology of childhood-onset GH deficiency (CO-GHD) on the clinical presentation during adulthood and the response to GH replacement has been poorly defined. Our study aims to characterize CO-GHD in adults due to different aetiologies and evaluate the effect of 2 years of GH replacement therapy.

Design and methods

Data from 353 adults with CO-GHD from Pfizer International Metabolic Database KIMS were retrospectively grouped according to GHD aetiology: non-organic disorder (n=147), organic pituitary disease (n=159), and brain tumour (n=47). Extent of pituitary dysfunction, IGF-I concentration, lipid concentrations and quality-of-life (QoL) were assessed at baseline and after 2 years of GH replacement.

Results

GHD was diagnosed at a later age in the organic pituitary group than in the other groups, resulting in a shorter duration of GH treatment during childhood. However, the final height was greater in the organic pituitary group. Panhypopituitarism was most common in the non-organic disorder and in the organic pituitary groups, while isolated GHD was more prominent in the brain tumour group. Serum IGF-I levels were the lowest in the non-organic group. QoL was the poorest in the brain tumour group. Lipid profile and QoL improved significantly during GH replacement.

Conclusion

The adverse consequences of CO-GHD in adulthood vary between aetiologies, but improve similarly with GH treatment. It is, therefore, important to consider retesting all patients with CO-GHD in early adulthood and, if persistent severe GHD is confirmed, recommence GH replacement.

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Roger Abs, Frank Nobels, Johan Verhelst, Philippe Chanson, Charles Mahler, Bob Corthouts, Pierre Blockx and Albert Beckers

We aimed to investigate the dynamics of adrenocorticotropin (ACTH) and cortisol secretion in pituitary-dependent Cushing's syndrome with bilateral macronodular adrenal hyperplasia presenting as a single adrenal macronodule, and to determine the imaging characteristics of this syndrome. Three female patients were studied. Plasma ACTH and serum cortisol secretion were studied by determining their rhythmicity and pulsatility and their responses to the administration of ovine corticotropin-releasing factor, thyrotropin-releasing hormone, metyrapone, tetracosactrin, insulin and dexamethasone. Techniques used to localize the anatomical lesion were bilateral simultaneous inferior petrosal sinus sampling, magnetic resonance examination of the pituitary, computed tomography (CT) scanning and [75Se]cholesterol scintigraphy of the adrenal glands. Plasma ACTH and serum cortisol levels were measured using a commercial radioimmunoassay and an immunoradiometric assay. The ACTH and cortisol pulse number and amplitude were calculated using established computer software. In all three patients ACTH and cortisol secretory dynamics fulfilled the requirements for diagnosis of pituitary-dependent Cushing's syndrome. A close relationship between ACTH and cortisol pulses also favored a pituitary dependency. Study of the amplitude of cortisol pulses classified two patients in the group of hypopulsatile Cushing's disease. Adrenal CT scanning demonstrated the presence of a large single nodule. [75Se]Cholesterol scintigraphy showed bilateral radionuclide uptake, although mostly localized over the adrenal nodule. All patients underwent successful trans-sphenoidal hypophysectomy. Over a period of 1 year, a slow shrinkage of the adrenal nodule was observed in two patients, while no change in volume was observed in one patient. Demonstration of an adrenal macronodule on CT scanning in patients with Cushing's syndrome is in itself insufficient to allow the diagnosis of hypercorticism due to a unilateral adrenal adenoma. Additional dynamic endocrine testing, inferior petrosal sinus sampling and imaging techniques such as [75Se]cholesterol scintigraphy remain necessary to reach a correct diagnosis.