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W. E. de Lange, M. C. Snoep and H. Doorenbos

ABSTRACT

LH-RH injection and infusion studies were performed in advanced puberty, delayed puberty and hypogonadotrophic hypogonadism. No differential diagnosis could be made between delayed puberty and hypogonadotrophic hypogonadism using LH-RH injection. In the LH-RH infusion studies evidence was obtained that stimulation of the pituitary during 4 h results in continuously rising LH levels in advanced puberty and in delayed puberty while in hypogonadotrophic hypogonadism the secretory capacity of the pituitary is gradually exhausted. This phenomenon can be used in the differential diagnosis between delayed puberty and hypogonadotrophic hypogonadism. Though the FSH data point in the same direction they are not useful in this connection as the overlap between the different categories was considerable.

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W. E. de Lange, M. C. Snoep and H. Doorenbos

ABSTRACT

Eight boys with severely delayed puberty without pathological cause were treated for 6 months with testosterone. This resulted in acceleration of skeletal maturation and a marked increase in height and weight. No adverse effects were found on hypothalamic-pituitary and gonadal maturation. Basal LH, FSH and testosterone levels rose to nearly adult values at follow-up within a year and pituitary responsiveness to LH-RH increased markedly.

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M Lange, OL Svendsen, NE Skakkebaek, J Muller, A Juul, M Schmiegelow and U Feldt-Rasmussen

OBJECTIVE: The insulin-tolerance test (ITT) is currently considered to be the gold standard for evaluating adults suspected of GH deficiency (GHD). The aim of this study was to determine factors that may influence nadir blood glucose (BG) when using a mean insulin dose of 0.1 IU/kg body weight. Furthermore, we wanted to evaluate the safety and GH-related aspects of the ITT. DESIGN: ITT was performed in 277 patients, of whom 255 (129 females) were eligible for evaluation. RESULTS: Multiple regression analysis, including the whole population, showed that the major determining factors for nadir BG were basal BG and body mass index (BMI) (P<0.02). No serious adverse event was recorded. Sixty-three percent of all patients tested had severe GHD with peak GH response to hypoglycaemia below 7.8 mIU/l. The positive predictive value for IGF-I was 0.82 and the negative predictive value was 0.47, using a cut-off value corresponding to -2 s.d. GH peak response to hypoglycaemia decreased with increasing numbers of other pituitary hormone deficiencies. CONCLUSIONS: When determining the dose of insulin based on weight, factors like pre-test BG and BMI should also be considered. We propose an algorithm stating that the dose of insulin should be 0.1 IU insulin/kg body weight minus 2 IU if pre-test BG is <4.0 mmol/l and minus 2 IU if BMI is <20 kg/m(2) in order to take these factors into account. Our findings furthermore support the concept that the low-dose ITT is a safe test in adults, when performed in experienced hands. It was confirmed that IGF-I is not sufficient when diagnosing GHD in adults, and reliable stimulation tests like ITT are required in the diagnosis.

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T E de Lange, S Simsek, M H H Kramer and P W B Nanayakkara

Objective

To describe a patient with cocaine-induced panhypopituitarism associated with human neutrophil elastase-anti-neutrophil cytoplasmic antibodies (HNE-ANCA).

Case

A 41-year-old man presented with extreme fatigue, cold intolerance and anorexia with 20 kg weight loss in the last 6 months. His medical history was unremarkable. He snorted cocaine twice a week during the last 6 years. On examination, we saw a pale and skinny man, with a normal blood pressure. Because of the severity of symptoms central hypothyroidism was suspected and very low values of TSH, free thyroxine and free triiodothyronine were measured. His FSH, LH, ACTH, cortisol, prolactin and testosterone levels were also low.

Magnetic resonance imaging and computed tomography scan showed a normal-sized pituitary gland entirely embedded in a dense, oedematous, contrast-enhancing mass, and a total destruction of the nasal septum with the absence of conchae and severely impaired sinus walls. A transnasal biopsy showed an acute necrotising, non-specific and non-granulomatous inflammation. Although cocaine-induced panhypopituitarism was suspected, Wegener's granulomatosis could not be excluded. Serology on ANCA showed a strongly positive C-ANCA titre (320 U/l) with specificity for HNE. A cocaine-induced HNE-ANCA-associated panhypopituitarism was diagnosed.

Our patient was advised to quit using cocaine immediately and was initially treated with glucocorticoids and testosterone, followed by thyroxine. This led to a dramatic clinical response with an increase of appetite, weight gain and regained energy. After 2 years, the patient is well and his ANCA titre is no longer positive.

Conclusion

We describe the first documented case of cocaine-induced panhypopituitarism associated with HNE-specific ANCA.

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A. WEINDL, J. UNGER, G. OCHS, M. SCHWARTZBERG, W. LANGE and A. STRUPPLER

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Geert Tjeerdsma, Wim J Sluiter, Joffre M Hew, Willemina M Molenaar, Willem E de Lange and Robin PF Dullaart

Tjeerdsma G, Sluiter WJ, Hew JM, Molenaar WM, de Lange WE, Dullaart RPF. Hyperprolactinaemia is associated with a higher prevalence of pituitary—adrenal dysfunction in non-functioning pituitary macroadenoma. Eur J Endocrinol 1996;135:299—308. ISSN 0804–4643

In non-functioning pituitary macroadenoma (NFMA), hyperprolactinaemia (hyperPRL) is considered to be a sign of hypothalamic—pituitary dysregulation, but it is unknown whether hyperPRL is associated with an increased frequency of pituitary hormone deficiencies. Forty consecutive patients with histology-proven NFMA were studied and hyperPRL was defined as serum prolactin (PRL) >200 mIU/l in men and >600 mIU/l in women. The pituitary—adrenal axis was evaluated by measurement of urinary free cortisol (N = 38), peak cortisol to insulin-induced hypoglycaemia (IIH, N = 36) and to human corticotrophin-releasing hormone (hCRF, N = 40) and by urinary tetrahydro11-deoxycortisol (H4S, N = 39), plasma androstenedione increment (N = 39) and serum 11-deoxycortisol (N = 1) after metyrapone. Central hypothyroidism, gonadotrophin deficiency and growth hormone (GH) reserve were also assessed. Twenty patients had hyperPRL (serum PRL 331 (2231120)mIU/l (median, range) in men and 932 (660–3927)mIU/l in women); urinary free cortisol excretion (p < 0.03) and peak serum cortisol in response to IIH (p < 0.02) were lower in hyperPRL than in normoPRL patients; peak serum cortisol after hCRF was not different between groups but occurred later in hyperPRL patients (at 60 vs 30 min, p < 0.03); urinary H4S excretion and androstenedione response after metyrapone were lower in hyperPRL than in normoPRL patients (p < 0.05 for both); 60% of hyperPRL patients and 15% of normoPRL patients had an abnormal H4S response (p < 0.025); central hypothyroidism (overt + subclinical) was present in 74% of hyperPRL and in 60% of normoPRL patients (NS); 78% of hyperPRL and 55% of normoPRL patients had gonadotrophin deficiency (NS); growth hormone (GH) deficiency was present in 83% of hyperPRL and in 89% of normoPRL patients (NS); 73.3% of 75 evaluable pituitary hormone axes were abnormal in hyperPRL patients compared to 5 3.8% of 78 hormone axes in normoPRL patients (by metyrapone test to examine adrenal function, p < 0.025); and no significant differences in tumour grade and stage distribution were found between hyperPRL and normoPRL patients. It is concluded that hyperprolactinaemia in NFMA is associated with a higher prevalence of pituitary–adrenal dysfunction, which is likely to be explained at least in part by functional hypothalamic–pituitary interruption.

RPF Dullaart. Department of Endocrinology, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands

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JO Thiele, P Lohrer, L Schaaf, M Feirer, W Stummer, M Losa, M Lange, M Tichomirowa, E Arzt, GK Stalla and U Renner

OBJECTIVE: Interleukin-6 (IL-6), a member of the gp130 cytokine family, is considered to be an important modulator of function and growth in endocrine anterior pituitary cells. In pituitary adenomas, where IL-6 is often produced by the tumour cells, it is thought to be involved in pituitary adenoma pathophysiology via autocrine/paracrine mechanisms. METHODS: We have studied in primary cell cultures of human somatotroph adenomas whether IL-6 stimulates growth hormone secretion and whether intratumoral IL-6 is affected by various IL-6-regulating factors. RESULTS: Interleukin-6 stimulated GH secretion in 10 out of 11 somatotroph adenoma cultures (1.4- to 6.5-fold above basal levels). In comparative studies the GH-stimulatory potency of IL-6 was identical, or even stronger, than that of GHRH. In eight out of 11 adenoma cell cultures, IL-6 production was observed. This suggests that GH production might be stimulated by IL-6 in an autocrine/paracrine manner in these tumours. Dexamethasone strongly inhibited basal IL-6 secretion in all IL-6-producing adenoma cell cultures, whereas the IL-6 inhibitory or stimulatory action of other factors (octreotide, transforming growth factor-beta1, insulin-like growth factor-I, pituitary adenylate cyclase-activating peptide and oestradiol) were heterogeneous in the different adenomas. Only transforming growth factor-alpha consistently stimulated IL-6 secretion in all of the adenomas studied. CONCLUSIONS: Intratumoral IL-6, which is differently regulated by various factors, might contribute to excessive GH production in the majority of somatotroph adenomas.

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M Lange, J Thulesen, U Feldt-Rasmussen, NE Skakkebaek, N Vahl, JO Jorgensen, JS Christiansen, SS Poulsen, SB Sneppen and A Juul

OBJECTIVE: To evaluate the histomorphology of skin and its appendages, especially eccrine sweat glands, in patients with GH disorders, because reduced sweating ability in patients with growth hormone deficiency (GHD) is associated with increased risk of hyperthermia under stressed conditions. DESIGN AND METHODS: A skin biopsy was obtained from 17 patients with GHD treated with GH, five patients with untreated GHD, 10 patients with active acromegaly and 13 healthy controls. RESULTS: The sweat secretion rate (SSR) was significantly decreased in both the untreated (median 41 mg/30 min, range 9-79 mg/30 min) and the GH-treated (median 98 mg/30 min, range 28-147 mg/30 min) patients with GHD compared with that in controls (median 119 mg/30 min, range 90-189 mg/30 min; P=0.001 and 0.01 respectively). Epidermal thickness was significantly decreased in both untreated (median 39 microm, range 28-55 microm) and GH-treated patients with GHD (median 53 microm, range 37-100 microm), compared with that in controls (median 66 microm, range 40-111 microm; P<0.02). A statistically non-significant tendency towards thinner epidermis (median 59 microm, range 33-83 microm) was recorded in acromegalic patients (P=0.08) compared with controls. There was no significant difference in the area of the sebaceous glands in the biopsies between the three groups and the controls. The area of eccrine sweat gland glomeruli was significantly decreased in the untreated patients with GHD (median 16407 microm2, range 12758-43976 microm2) compared with that in controls (median 29446 microm2, range 13511-128661 microm2; P=0.03), but there was no significant difference between the GH-treated patients with GHD and controls. CONCLUSIONS: We conclude that GH, either directly or via IGF-I, may have both a structural and a functional effect on human skin and its appendages, and that patients with GHD have histomorphological changes in skin compared with controls. Importantly, these changes are not fully reversed despite long-term and adequate GH treatment in patients with childhood onset GHD.

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F Bonnet, B Balkau, J M Malécot, P Picard, C Lange, F Fumeron, R Aubert, V Raverot, H Déchaud, J Tichet, P Lecomte, M Pugeat and for the DESIR Study Group

Objective

Previous evidence has suggested that a low sex hormone-binding globulin (SHBG) concentration is associated with insulin-resistance and a low adiponectin concentration. We investigated the association between SHBG and the risk of hyperglycemia in each sex and we determined potential interactions between SHBG and adiponectin levels in the development of dysglycemia.

Design

We used a nested case–control design in the large prospective study, Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR). We studied 227 men and women who were normoglycemic at baseline but hyperglycemic at 3 years (glycemia≥6.1 mmol/l or type 2 diabetes). They were matched for sex, age, and body mass index with 227 subjects who remained normoglycemic at 3 years.

Results

At baseline, the concentration of SHBG was significantly lower in women who subsequently developed hyperglycemia than in those who remained normoglycemic, with no difference for men. In multiple regression, SHBG at baseline was as an independent determinant of plasma adiponectin levels, in both women (P<0.0001) and men (P=0.002). In multivariate conditional logistic regression taking into account physical activity and changes in waist circumference over the follow-up, plasma SHBG remained significantly associated with the development of hyperglycemia in women but not in men. These associations persisted after adjustment for fasting insulinemia, high fasting glucose, and adiponectin levels.

Conclusions

These findings suggest that a low SHBG level is a strong risk marker for dysglycemia in women, independently of both adiponectinemia and insulinemia. SHBG may therefore improve the identification of women at risk of diabetes.

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A C Gore, J Balthazart, D Bikle, D O Carpenter, D Crews, P Czernichow, E Diamanti-Kandarakis, R M Dores, D Grattan, P R Hof, A N Hollenberg, C Lange, A V Lee, J E Levine, R P Millar, R J Nelson, M Porta, M Poth, D M Power, G S Prins, E C Ridgway, E F Rissman, J A Romijn, P E Sawchenko, P D Sly, O Söder, H S Taylor, M Tena-Sempere, H Vaudry, K Wallen, Z Wang, L Wartofsky and C S Watson