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SW Lamberts, JA Romijn and WM Wiersinga

In recent years the future position of clinical endocrinology has been extensively discussed by Western European endocrine societies. Clinical endocrinology seems to suffer from being too intellectual, generating too little income, and lacking too few spectacular interventions. In this manuscript we describe 'the endocrine patient' of the past, the present, and the future. Complete therapeutic breakthroughs resulting in 'cure' are compared with 'halfway technologies' which help in creating the (life-long) chronic endocrine patient. The potential use of molecular diagnostics in optimalizing hormone replacement therapy is discussed. Clinical endocrinology is at risk of developing into a subspecialty where life-style drugs created for new diseases or conditions are offered, but also actively pursued by otherwise healthy individuals (e.g. in normal short stature, regulation of appetite, body composition, sexuality, reproduction and aging). The potential opportunities and risks for clinical endocrinology in creating 'the endocrine patient' of the future are discussed.

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JA Romijn, JW Smit and SW Lamberts

Hormonal substitution therapy has been extremely successful, with respect to morbidity and mortality, in the treatment of the major syndromes of endocrine insufficiency. However, many patients treated for endocrine insufficiencies still suffer from more or less vague complaints and a decreased quality of life. It is likely that these complaints are, at least in part, caused by intrinsic imperfections of hormone replacement strategies in mimicking normal hormone secretion. Unfortunately, these complaints are often difficult to assess by clinicometric or biochemical tests, because the effects of hormones in general, and thus of hormone replacement strategies in particular, are difficult to quantify at the tIssue level. Therefore, in clinical practice we rely mostly on plasma variables - 'plasma endocrinology' - which are a poor reflection of hormone action at the tIssue level. Appreciation of these intrinsic shortcomings of endocrine therapy is of utmost importance to prevent incorrect labelling of the complaints of many endocrine patients and to achieve further improvement in endocrine replacement strategies.

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EP Corssmit, E Endert, HP Sauerwein and JA Romijn

OBJECTIVE: Recombinant human interferon alpha (rhIFN-alpha) is used therapeutically in malignant disorders and chronic hepatitis. The present study was assessed to study the effects of rhIFN-alpha on the hypothalamic-pituitary-testicular (HPT) axis. DESIGN AND METHODS: We performed a saline-controlled cross-over study in six healthy men, sequentially measuring the serum concentrations of gonadotropins, testosterone, the free androgen index (FAI) and sex hormone-binding globulin (SHBG) after a bolus subcutaneous injection of rhIFN-alpha. RESULTS: rhIFN-alpha induced a sustained decrease of both testosterone (from 19.5+/-1.88 to a nadir of 5.49+/-0.51nmol/l at the end of the study) and FAI (from 98.7+/-14.7 to a nadir of 32. 1+/-5.3 at the end of the study), whereas concentrations of LH, FSH and SHBG were not different between the two studies. CONCLUSIONS: Our results suggest that rhIFN-alpha affects the HPT axis at the testicular level, either directly or indirectly, and changes feedback relationships between the pituitary and the testis.

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JP Schroder-van der Elst, D van der Heide, JA Romijn and JW Smit

OBJECTIVE: Natural flavonoids (plant pigments) have been shown to inhibit thyroid peroxidase (TPO) in vitro and the growth of thyroid cancer cell lines. We have studied the role of flavonoids on the iodide transport and the growth of the human follicular thyroid cancer cell line (FTC133) which was stably transfected with the human Na(+)/I(-) symporter (hNIS). DESIGN AND METHODS: Cells were treated with flavonoids (0.5-50 microM) for 0, 2, 4 and 6 days; (125)I content and (125)I efflux of the cells and DNA content were measured. RESULTS: Cell growth was inhibited significantly at day 6 by most flavonoids. Eight out of ten flavonoids decreased the (125)I content of the cells at day 4. Morin did not influence the (125)I content of the cells and, surprisingly, myricetin increased the (125)I content of the cells. Kaempferol, apigenin, luteolin and F21388 decreased NIS mRNA expression after 15, 29 and 48 h; after 96 h NIS mRNA returned to normal. CONCLUSION: As TPO is not present in this cell line, the effects of the flavonoids on the iodide uptake are not related to organification. Myricetin was the only flavonoid studied that increased the influx and decreased the efflux of iodide. The effect of myricetin (decreased growth and increased retention of iodide) can be of therapeutic value in the radioiodide treatment of thyroid carcinoma.

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SW van Thiel, JA Romijn, NR Biermasz, BE Ballieux, M Frolich, JW Smit, EP Corssmit, F Roelfsema and AM Pereira

OBJECTIVE: Recently a new depot preparation of the long-acting somatostatin analogue, lanreotide Autogel was introduced for the treatment of acromegaly. Like octreotide long-acting repeatable (LAR), it has high binding affinity for the somatostatin receptor subtype SSTR 2 and less binding affinity for SSTR 5. We hypothesized that the ability to suppress growth hormone (GH) secretion in patients with acromegaly would be similar for these depot preparations. PATIENTS AND STUDY DESIGN: Seven patients (mean age+/-S.E.M. 48.4+/-7 years) on long-term octreotide LAR treatment at a monthly injection interval for a mean of 2.8 years were enrolled in the study. They underwent a GH secretory profile study with 10 min sampling for 24 h, 28 days after an injection. At 2, 4 and 6 weeks after the next injection fasting GH profiles (every 30 min for 3.5 h) and serum IGF-I measurements were measured. These investigations were repeated 12 months later, when the patients were on an individually titrated stable dose of lanreotide Autogel. RESULTS: Secretory characteristics and total 24 h GH secretion, estimated by deconvolution analysis of the 10 min 24 h plasma GH concentrations, did not show differences between these two long-acting somatostatin analogues. Both drugs were equally effective in GH and IGF-I suppression as measured at 2, 4 and also at 6 weeks following an injection. CONCLUSION: The efficacy of lanreotide Autogel and octreotide LAR was equal, notwithstanding that these drugs are administered in a different way and have different pharmacokinetics.

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EJ Van Someren, J Swart-Heikens, E Endert, PH Bisschop, DF Swaab, PJ Bakker, JA Romijn and E Fliers

BACKGROUND: Cranial radiation therapy (CRT) is required for successful treatment of a variety of brain tumours in childhood. OBJECTIVE: To investigate whether childhood CRT leads to altered sleep-wakefulness organization in adulthood, and to identify the determinants of such alterations. SUBJECTS AND METHODS: Subjective (questionnaires) and objective (actigraphy) measures of circadian rhythmicity and sleep were assessed in 25 individuals, 8-29 years after CRT for medulloblastoma (n=17) or other intracranial tumours (n=8), and in a group of 34 age-matched healthy individuals. Serum GH peak during insulin-induced hypoglycaemia and serum concentrations of prolactin and leptin (expressed per fat mass) were determined in the CRT group. RESULTS: The CRT group showed a markedly increased sleep duration (8.66 h, compared with 7.66 h in controls). In addition, the sleep-wake rhythm showed greater amplitude and less fragmentation, and less tolerance for alterations in the timing of sleep. Regression analysis showed both radiation dosage and neuroendocrine status to be determinants of sleep changes, suggesting that some of the alterations may be normalized with hormone supplementation. CONCLUSION: The present study shows that high-dose cranial radiation therapy in childhood is associated with objective and subjective changes in the sleep-wake rhythm in adulthood.