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F. Roelfsema, A.J. Moolenaar and M. Frölich

Abstract. The urinary excretion of the androgen metabolites aetiocholanolone (E) and androsterone (A) as well as DHEA, 11-hydroxy-androsterone and the cortisol metabolites 11-oxo-aetiocholanolone and 11-hydroxy-aetiocholanolone in normoprolactinaemic and hyperprolactinaemic male and female acromegalics was studied and compared with that of appropriate control groups. In addition several plasma hormones were also measured. The growth hormone level in the patient group varied from 10–550 mU/l. The excretion of both 11-hydroxy-androsterone and DHEA was normal. The excretion of androsterone had decreased, while aetiocholanolone and cortisol metabolite excretion had increased. The ratio between aetiocholanolone and androsterone (E/A) excretion was significantly increased in all patient groups, but no correlation was found between the growth hormone level and the E/A ratio. Treatment with bromocriptine caused a decrease in the E/A ratio in patients with decreased growth hormone levels, but not in patients in whom the growth hormone level remained unchanged. After selective transsphenoidal removal of the pituitary adenoma the E/A ratio decreased significantly. The increased E/A ratio in untreated patients could not be attributed to eventual changes in plasma levels of cortisol, thyroxine, prolactin, testosterone or oestrogens. We therefore suggest that growth hormone is involved in androgen metabolism in acomegaly.

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J. van Doom, F. Roelfsema and D. van der Heide

Abstract.

The intracellular conversion of T4 to T3 was investigated in various tissues of hypothyroid rats after continuous iv infusion of radiolabelled T3 and T4. Two groups of 4 thyroidectomized rats were infused with carrier-free 125I-labelled T4 as well as 131I-labelled T3 until isotope equilibrium was achieved. Plasma, various tissue homogenates (liver, kidney, pituitary, thigh muscle, cerebral cortex and cerebellum) and subcellular fractions (nuclei, mitochondria, microsomes, cytoplasm) from liver, kidney and the pituitary gland were extracted for thin layer chromatography.

The [125I]T3/[131I]T3 ratios were determined and the extra contribution of [125I]T3 derived from local conversion of [125I]T4 to the total [125I]T3 was calculated in percent.

In addition to the [125I]T3 derived from plasma, [125I]T3 derived from locally converted [125I]T4 was present in all tissues investigated. There was substantially more, although in varying quantities, in the cerebral cortex (79 ± 2%), the cerebellum (68 ± 4%) and the pituitary gland (53 ± 1%) than in the liver (10 ± 6%), the kidney (11 ± 5%) and thigh muscle (17 ± 6%); in the latter tissues most of the 125I-labelled T3 is derived directly from plasma.

These results indicate that in the brain of severe hypothyroid rats there is pronounced conversion of T4 to T3 and effective binding of the T3 produced whereas the T3 in the liver, kidney, and muscle is predominantly derived from plasma. At the intracellular level, within the investigated tissues, the locally formed T3 was distributed equally over the subcellular fractions.

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YJ Janssen, M Frolich, P Deurenberg and F Roelfsema

OBJECTIVE: Recent studies suggest an involvement of the obese (OB) gene and its product leptin in the regulation of body fat. Since adults with growth hormone deficiency (GHD) have a high body fat mass which can be normalized with recombinant human (rh) GH therapy, we investigated whether GH influences serum leptin directly or indirectly via its lipolytic effect. DESIGN: Fourteen adults with GHD were treated with subcutaneous injections of rhGH given every evening for 52 weeks. Serum leptin, fat mass and body fat percentage were measured at baseline and after 4 and 52 weeks of treatment. METHODS: Serum leptin was measured with a commercially available RIA. Total body water was determined by dilution of deuterium. Fat free mass was estimated by assuming a hydration of 73%. Fat mass was estimated by subtracting fat free mass from weight. RESULTS: At baseline, serum leptin levels were exponentially related to body fat percentage (r = 0.88; P < 0.0005). rhGH treatment for 4 weeks did not significantly influence serum leptin levels, whereas treatment for 52 weeks significantly decreased serum leptin levels (15.6 +/- 2.9 to 10.8 +/- 2.1 micrograms/l; P = 0.020). Fat percentage was significantly decreased after 52 weeks of treatment (37.6 +/- 2.1 to 33.8 +/- 2.5%; P < 0.0005). The decrease in serum leptin could largely be explained by the decrease in body fat percentage, whereas the relation between leptin and body fat percentage did not change. CONCLUSIONS: The influence of GH on serum leptin in indirect, via its effect on body fat percentage.

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RG Veldman, M Frolich, SM Pincus, JD Veldhuis and F Roelfsema

The episodicity of 24 h leptin release was studied in seven women (mean age 39 years, range 22-56 years) with pituitary-dependent hypercortisolism and in seven age- and body mass index (BMI)-matched female controls. Pulsatile leptin release was quantified by model-free cluster analysis and deconvolution, the orderliness of leptin patterns by the approximate entropy statistic (ApEn), and nyctohemeral leptin rhythmicity by cosinor analysis. Blood samples were taken at 10 min intervals for 24 h. Both cluster and deconvolution analysis revealed 2.4-fold increased leptin secretion in patients, caused by combined and equal amplification of basal and pulsatile secretion. Cluster analysis identified 7.1+/-1.5 peaks per 24 h in patients and 6.0+/-0.5 in controls (not significant). The statistical distribution of the individual sample secretory rates was similarly skewed in patients and controls (0.55+/-0.12 vs 0.52+/-0.07). The acrophase (timing of the nyctohemeral leptin peak) in patients occurred at 2314 h (+/-76 min) and at 0058 h (+/-18 min) in controls (not significant). The approximate entropy of leptin release was equivalent in patients and controls (1.67+/-0.03 vs 1.61+/-0.05). The approximate entropy (ApEn) for cortisol in patients was 1.53+/-0.09 and in controls was 0.93+/-0.07 (P<0.0005). Cross-ApEn showed significant pattern synchrony between leptin and cortisol release, which (unexpectedly) was not disrupted by the cortisol excess (patients, 2.02+/-0.04; controls, 1.88+/-0.09; P=0.233). Insulin levels in fasting patients ('fasting insulin') were 27+/-5.7 mU/l vs 14+/-1.6 mU/l in controls (P=0.035). Leptin secretion correlated with fasting insulin levels (R(2)=0.34, P=0.028) and with the cortisol production rate (R(2)=0.33, P=0.033) when patients and controls were combined. In summary, Cushing's disease in women increases leptin production about twofold in an amplitude-specific way. The pulse-generating, nyctohemeral phase-determining, and entropy-control mechanisms that govern the 24 h leptin release are not altered. The increased secretion is not explained by BMI and is probably only partly explained by increased insulin production, suggesting a cortisol-dependent change in adipose leptin secretion.

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J. van Doom, F. Roelfsema and D. van der Heide

Abstract. The effect of prolonged oral administration of PTU and MMI on the local conversion of T4 to T3 was studied in T4-maintained athyreotic rats. For this purpose the rats were equilibrated with [125I]T4 and [131I]T3 by means of continuous iv infusions.

PTU treatment reduced the MCR of both T4 and T3, as well as the T3 levels in plasma, muscle, liver, kidney and cerebellum. In the cerebral cortex the total intracellular T3 concentration was not affected, while in the pituitary it even increased. The amount of T3 derived from local conversion of T4 to T3 (LcT3(T4)) was reduced in the liver. PTU treatment did not influence Lc T3(T4) in the cerebellum, but did cause an increase in the amount of T3 derived from this source in the cerebral cortex and the pituitary gland (both the homogenate and the nuclear fraction). The results indicate that in contrast to that in liver, local T3 production in the brain and pituitary must occur predominantly via a pathway which is not inhibited by PTU.

In MMI-treated rats the total T3 concentration in the cerebral cortex and cerebellum was not altered, whereas both the MCR of T3 and the T3 levels in plasma and various other tissues were elevated. The relative contribution of Lc T3(T4) increased in liver and was reduced in the cerebral cortex, cerebellum and pituitary gland.

In all experiments in liver the contribution of Lc T3(T4) to nuclear T3 was negligible, whereas this was not the case for the other hepatic subcellular fractions. As in liver, virtually all renal nuclear T3 was derived from plasma. The present findings suggest that the production of T3 in liver and kidney, and its subsequent release into the blood, may provide a mechanism for the regulation of plasma T3 levels but is not a direct source of their nuclear T3.

In the pituitary gland and the brain local T4 to T3 conversion functions as a source of T3 for the control of local utilization. In this respect the maintainance of constant T3 levels in the brain might be important.

These differences among tissues suggest that different mechanisms are involved in T4 5'-deiodination.

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J. W. F. Elte, J. K. Bussemaker, W. Termorshuizen, B. M. Goslings and F. Roelfsema

Abstract. In order to investigate whether patients with euthyroid multinodular goitre (EMG) lose more iodine through urinary excretion than is to be expected due to an elevated renal clearance of iodine and/or whether the iodine is handled differently in the thyroid of these patients than in that of normal subjects, the following data were obtained for 33 patients with EMG and 30 normal subjects: thyroid clearance (TC), absolute iodine uptake (AIU), renal 123I clearance (RC) and plasma inorganic iodine (PII).

A significantly lower PII and a higher TC was found in the goitre patients. In the control group PII appeared to be higher and TC and RC lower in the older age group (> 50 years). The difference in PII and TC is most easily explained by a higher iodine uptake in the subgroup of normal subjects over 50 years of age. AIU did not differ in any of the groups.

Thus, it may be concluded that an endogenous iodine deficiency due to elevated renal clearance of 123I is not a factor in sporadic goitre, at least in our patients. At the observed plasma iodine levels a significantly higher AIU was not found for goitrous patients.

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P. H. L. M. Geelhoed-Duijvestijn, J. K. Bussemaker and F. Roelfsema

Abstract.

T4 and T3 levels, TSH response to TRH and somatomedin-C levels in 63 patients with acromegaly, were measured before transsphenoidal surgery and during a 4-year follow-up period. Criteria for cure were: mean GH level <5 mU/l, suppression of GH by oral glucose tolerance test below 2.5 mU/l and normalization of paradoxical GH reaction to TRH. Nine patients underwent radioiodine studies to assess the renal and thyroid clearance of iodide, plasma inorganic iodine level and absolute iodine uptake. Among the patients 40% had goitre, with a male preponderance. T4 and T3 levels were in the normal range both before and after surgery. A transient decrease in T3 levels was found in the immediate postoperative period. Before treatment a diminished or absent TSH response to TRH was exhibited by 64% of the goitre patients and 34% of the non-goitre groups (p < 0.05). Despite normalization of GH and somatomedin-C levels and normal T4 and T3 levels no improvement of the TSH response was found during followup. No correlation between the incremental response of TSH to TRH and circulating T4 or T3 levels, basal TSH, GH or tumour size was found. There was, however, a negative correlation (r = −0.765, p < 0.05) between the incremental TSH response to TRH and somatomedin-C levels for females with goitre. Somatomedin-C levels were higher in patients with goitre than in those without goitre (95 ± 26 vs 75 ± 30 nmol/l; mean ± sd, p = 0.05). Radioiodine studies showed an increased renal clearance of iodide which was related to the increase in creatinine clearance. The absolute iodine uptake was significantly higher for male acromegalic patients than for controls (7.2 ± 2.2 vs 3.9 ± 2.3, p < 0.05) and decreased significantly postoperatively. From this study we conclude that the increased incidence of goitre in acromegaly is not caused by iodine deficiency, but is probably related to a stimulatory effect of GH or somatomedin-C on thyroid growth and function. In contrast to patients with other pituitary tumours, the impaired TSH response in acromegalic patients is not associated with hypothyroidism, and the TSH response to TRH does not normalize postoperatively, despite normalization of GH levels.

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R Groote Veldman, G van den Berg, SM Pincus, M Frolich, JD Veldhuis and F Roelfsema

To quantify prolactin (PRL) secretion patterns, ten untreated (female) microprolactinoma patients and six (male) macroprolactinoma patients underwent repetitive blood sampling every 10 min over 24 h. PRL release activity was analyzed from plasma PRL concentration (immunofluorimetric assay) profiles via a model-independent discrete peak detection program (Cluster) and a waveform-independent deconvolution technique (Pulse). Diurnal variations were analyzed by cosinor analysis. The number of distinct PRL pulses (mean +/- S.E.M.) was increased in patients: microprolactinoma 18.6 +/- 0.6/24 h versus female controls 12.4 +/- 0.6 (P = 6.7 x 10-s), and macroprolactinoma 18.0 +/- 0.9 versus male controls 13.5 +/- 0.8/24 h (P = 0.003). In patients, PRL pulse height, amplitude, pulse area and interpeak nadir concentrations were each greatly elevated compared with gender-matched controls. By 2-component deconvolution analysis, the mean nadir PRL secretion rate in microprolactinoma patients was augmented 20-fold at 0.408 +/- 0.089 microgram/l per min versus in female controls 0.019 +/- 0.009 microgram/l per min (P < 0.001); and in macroprolactinoma by 130-fold at 2.067 +/- 0.693 micrograms/l per min versus male controls 0.016 +/- 0.001 microgram/l per min (P = 0.001). Corresponding 24 h mean PRL secretion rates were in women, 0.658 +/- 0.147 and 0.044 +/- 0.018 (P < 0.001), and in men, 3.309 +/- 1.156 and 0.035 +/- 0.010 micrograms/l per min (P = 0.001), being respectively 15- and 94-fold increased in tumors. The estimated PRL production per day was 160 +/- 15 and 187 +/- 20 micrograms in male and female controls respectively. PRL production was 2860 +/- 640 micrograms in female patients with microadenomas (P < 0.001), and 37,800 +/- 5900 micrograms in male macroadenoma patients (P = 0.001). Cosinor analysis of the plasma concentrations revealed a significant rhythm in nine of ten, patients with a microadenoma, and in five of six with a macroadenoma. The same method applied to pulse height and amplitude disclosed a significant rhythm for PRL pulse height, but not for pulse amplitude, suggesting preserved rhythmicity of baseline interpulse nadir PRL concentrations. Approximate entropy (ApEn), a scale- and model-independent regularity statistic, averaged 1.6559 +/- 0.028 in microprolactinoma patients versus 0.8128 +/- 0.079 in female controls (P = 1.7 x 10(-8)); ApEn in macroadenomas was 1.5674 +/- 0.054 versus male controls 0.8773 +/- 0.076 (P = 1.7 x 10(-5), signifying greater secretory irregularity in the patients. Compared with microadenomas, macroadenomas exhibited a higher mean plasma concentration, overall mean PRL secretion rate, nadir secretion rate and pulse area, but similar peak frequency. We conclude that PRL secretion by prolactinomas is characterized by increased plasma PRL episodicity of release, increased total (15- to 100-fold) and basal (20- to 130-fold) secretion rates, and increased disorderlines of minute-to-minute secretion. These abnormalities of secretory control are very similar to those for GH and ACTH identified earlier in acromegaly and Cushing's disease respectively, thus suggesting mechanistic generality of pituitary tumor secretory derangements, independent of the particular hormone.

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G van den Berg, SM Pincus, M Frolich, JD Veldhuis and F Roelfsema

The episodicity of 24 h GH release was studied in 18 patients with active acromegaly, 12 patients 7-10 days after pituitary surgery, 14 patients long after operation (3-17 years), and 21 healthy gender- and age-matched control subjects, using a recently introduced scale- and model-independent regularity statistic, approximate entropy (ApEn). Blood samples were taken at 10-min intervals for 24 h, and plasma GH concentrations were measured by immunofluorometric assay (detection limit 11.5 ng/l). For this study we selected operated patients who were biochemically in remission, defined by normal circulating IGF-I and insulin-like growth factor-binding protein-3 (IGFBP-3) concentrations, normal glucose-suppressed plasma GH concentration (<0.38 microg/l), and the normalization of the paradoxical rise of GH to TRH or GnRH. In patients with active acromegaly ApEn was 1.23+/-0.04, with no overlap with the control subjects (P = 1.2 x 10[-16]), who had an ApEn of 0.40+/-0.04. ApEn in patients shortly after surgery was 0.71+/-0.09 (P < 0.001 vs controls), and long after surgery 0.56+/-0.05 (P < 0.011 vs controls). ApEn values in treated and untreated patients correlated significantly with the plasma concentration of IGF-I (r=0.531) and IGFBP-3 (r=0.598), and the log-transformed 24h GH secretion rate (r=0.749). Shortly after surgery only one-third of the patients had a normal ApEn value, whereas long after surgery about 70% of the patients had a normal ApEn value. Although ApEn eventually normalized in about 70% of the operated patients, the cause of the persistence of abnormal GH release in the remainder of the subjects is not known, and might reflect permanent hypothalamic-pituitary dysfunction or a very early recurrence of the somatotroph adenoma.

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Solrun Vidarsdottir, Ferdinand Roelfsema, Trea Streefland, Jens J Holst, Jens F Rehfeld and Hanno Pijl

Background

Treatment with olanzapine (atypical antipsychotic drug) is frequently associated with various metabolic anomalies, including obesity, dyslipidemia, and diabetes mellitus. Recent data suggest that olanzapine orally disintegrating tablets (ODT), which dissolve instantaneously in the mouth, might cause less weight gain than olanzapine standard oral tablets (OST).

Design and methods

Ten healthy men received olanzapine ODT (10 mg o.d., 8 days), olanzapine OST (10 mg o.d., 8 days), or no intervention in a randomized crossover design. At breakfast and dinner, blood samples were taken for measurement of pancreatic polypeptide, peptide YY, glucagon-like peptide-1, total glucagon, total ghrelin, and cholecystokinin (CCK) concentrations.

Results

With the exception of pre- and postprandial concentration of ghrelin at dinner and preprandial CCK concentrations at breakfast, which were all slightly increased (respectively P=0.048, P=0.034 and P=0.042), olanzapine did not affect gut hormone concentrations. Thus, olanzapine ODT and OST had similar effects on gut hormone secretion.

Conclusion

Short-term treatment with olanzapine does not have major impact on the plasma concentration of gut hormones we measured in healthy men. Moreover, despite pharmacological difference, gut hormone concentrations are similar during treatment with olanzapine ODT and OST. The capacity of olanzapine to induce weight gain and diabetes is unlikely to be caused by modulation of the secretion of gut hormones measured here. We cannot exclude the possibility that olanzapine's impact on other gut hormones, to impair insulin sensitivity and stimulate weight gain, exists.