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Ferdinand Roelfsema, Marijke Frölich, Hans de Boer and Alan G. Harris

Abstract.

The effect of a schedule of three daily injections of 100 μg octreotide (pen treatment) compared with that of a continuous sc infusion of 300 μg/24 h on GH and IGF-I suppression, and other GH-dependent parameters was studied in 10 acromegalic patients in a cross-over study. Treatment was administered via a specially designed pen or a pump for 4 weeks. Following a washout period of a further 4 weeks, patients were switched to the other mode of delivery. Mean GH levels decreased from 26.2±4.7 to 9.9±3.1 mU/l (p=0.007) during pen therapy and to 7.7±2.4 mU/l (p=0.003) during pump treatment. IGF-I levels decreased from 75.6±9.5 to 42.0±9.3 nmol/l (p=0.003) during pen treatment and to 32.5±2.5 nmol/l (p=0.001) during pump treatment. There was a significant difference in IGF-I levels between pen and pump treatments (p=0.03). In 7 patients the IGF-I levels normalized during pump treatment compared with 3 patients in the pen treatment group. There was no change in the free T4 index levels, but the free T3 index significantly decreased during therapy, without changes in plasma TSH. This study demonstrates that continuous infusion with octreotide results in a better control of GH oversecretion than the intermittent mode of delivery.

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Jaap van Doom, Ferdinand Roelfsema and Daan van der Heide

Abstract. The local conversion of thyroxine (T4) to 3,5,3'-triiodothyronine (T3) has been recognized as a source of T3 at various sites in euthyroid rats. The present study was designed to evaluate the effect of hypothyroidism on the source and quantity of T3 at several of these sites (liver, cerebral cortex (Cx), thymus, testis, brown adipose tissue). For this purpose intact euthyroid rats and radiothyroidectomized (RTx) rats received a continuous iv infusion of [125I]T4 and [131I]T3 until isotopic equilibrium was attained. In addition to the labelled iodothyronines, RTx rats received a continuous iv infusion of 0.75 μg T4/day, in order to maintain a defined hypothyroid state. At the end of the infusion period the animals were bled and perfused, and homogenates of the various organs were prepared. The mean plasma T4 and T3 levels in T4-maintained RTx rats, as measured by RIA, were 1.5 μg/dl and 15 ng/dl (euthyroid values: 5.2 μg/dl and 48 μg/dl, respectively). The plasma and tissue homogenates were processed for thin layer chromatography and the [125I]T4, [125I]T3 and [131I]T3 levels determined. From these data the concentrations of T4, total T3 and T3 derived from local T4 to T3 conversion (LcT3(T4)) in tissue could be calculated. The relative mean contribution of LcT3(T4) to the total T3 in Cx (75%), thymus (31%), testis (43%) and brown adipose tissue (65%) from hypothyroid rats was higher than that determined for euthyroid animals (66%, 19%, 29% and 27%, respectively). The reverse was found for the liver (15% vs 39%). As a consequence, hypothyroidism led to a substantial loss of intracellular T3 in the liver (about 80%), whereas in all other tissues investigated the decrease in total T3 was less. In spite of the low intracellular T4 levels in hypothyroid rats, the quantity of LcT3(T4) in brown adipose tissue had increased significantly. This was not the case in the other tissues investigated. However, as found for brown adipose tissue, the ratio between LcT3(T4) and T4 found for Cx, thymus and (although not statistically significant) testis was higher in hypothyroid rats than in euthyroid animals, again suggesting a higher degree of in vivo T4 to T3 conversion in the hypothyroid state. These results strongly suggest that local factors play an important role in the regulation of intracellular T3 levels.

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Ferdinand Roelfsema, Hanno Pijl, Daniel M Keenan and Johannes D Veldhuis

Background

The ACTH–cortisol axis in women is activated and associated with decreased ACTH potency, estimated by relating ACTH and cortisol pulse masses. Recently, a new accurate method for constructing the endogenous dose–response relationship was introduced, which is based on the relation between ACTH concentrations and associated cortisol secretion rates within cortisol bursts.

Hypothesis

The endogenous dose–response relation between ACTH and cortisol in obesity is changed, leading to diminished responsiveness.

Subjects

Twenty-five obese premenopausal women and 16 normal weight premenopausal women were studied by 10-min blood sampling for 24 h.

Outcomes

ACTH and cortisol secretion rates, analytical dose–response estimates of endogenous ACTH efficacy (maximal cortisol secretion), dynamic ACTH potency, and adrenal sensitivity (slope term) from 24-h ACTH–cortisol profiles were quantified.

Results

The initial potency (negative logarithm) was −7.83±0.75 (mean±s.e.m.) in obese women and −10.14±1.08 in lean women (P=0.10), and the corresponding values for the recovery phase were −26.62±2.21 and −36.67±1.66 (P=0.004). The sensitivity (curve slope) amounted to 0.468±0.05 in obese women and 0.784±0.09 in normal weight women (P=0.004). The efficacy (maximal value) was 17.6±4.9 nmol/l per min in obese women and 26.3±3.8 nmol/l per min in normal weight women (P=0.009). Basal secretion rate, inflection point, and EC50 values were not different. Bromocriptine or acipimox did not change the dose–response curve.

Conclusion

The ACTH–cortisol relation in obesity in women is characterized by decreased sensitivity and efficacy, thus explaining non-elevated serum cortisol concentrations despite increased plasma ACTH levels.

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Marleen Kars, Ferdinand Roelfsema, Johannes A Romijn and Alberto M Pereira

Pituitary carcinomas are extremely rare. In general, the initial clinical, biochemical, and histological characteristics are of minimal utility in distinguishing benign adenomas from pituitary carcinomas. We describe a 63-year-old woman with a macroprolactinoma, who presented with diplopia and blurred vision. This unusual initial presentation and the subsequent aggressive clinical course, with diffuse local and distant intramedulary metastases, prompted us in retrospect to make a detailed analysis of the therapeutic interventions and histology. In addition, we reviewed all available literature on published cases of malignant prolactinoma and detailed their epidemiological, clinical, and histopathological characteristics. In brief, it is postulated that pituitary carcinomas arise from the transformation of initially large, but benign, adenomas. Unusual and/or atypical clinical manifestations appear to occur more frequently. In vivo, the development of dopamine agonist resistance in invasive macroprolactinoma is indicative of malignancy and should prompt the clinician to perform a biopsy of the tumor. For pituitary tumors that exhibit high mitotic activity, increased Ki-67 and/or p53 immunoreactivity, it may be useful to denote these tumors as ‘atypical’ prolactinomas to raise the possibility of future malignant development.

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Nienke R Biermasz, Neveen A T Hamdy, Alberto M Pereira, Johannes A Romijn and Ferdinand Roelfsema

Introduction: The anabolic actions of growth hormone (GH) are well documented. In acromegaly, the skeletal effects of chronic GH excess have been mainly addressed by evaluating bone mineral density (BMD). Most data were obtained in patients with active acromegaly, and apparently high or normal BMD was observed in the absence of hypogonadism. Data on BMD are not available after successful treatment of acromegaly. Whether the positive effect of GH excess on bone mass is maintained in the long term after clinical and biochemical cure of acromegaly remains to be established.

Patients and methods: In a cross-sectional study design, lumbar spine and femoral neck BMD was measured in 79 acromegalic patients cured or well controlled on octreotide treatment (45 male and 34 female patients; mean age 57±1 years). Successful treatment (by surgery, radiotherapy and/or use of octreotide) was defined as normal age-adjusted IGF-I. Mean time after biochemical remission was 10.2±7 years.

Results: Normal or increased BMD was observed at the femoral neck and lumbar spine in both men and women in remission after treatment for acromegaly. Similar results were obtained in patients in remission for 5 years or longer. Osteoporosis was present in 15% of the patients, with similar prevalence in men and women. There was no relationship between BMD and duration or severity of GH excess before treatment, gonadal status and presence of pituitary hormone deficiencies. Pituitary irradiation was a strong negative predictor of bone mass at the femoral neck. Long-term bone loss was observed only at the femoral neck.

Conclusion: Our data suggest that the anabolic effect of GH on trabecular and cortical bone remains demonstrable after remission of acromegaly, although it may not be maintained at cortical sites in the long term. In the present study, the lack of effect of gonadal status on BMD may be explained by the presence of only mild hypogonadism and by our policy of prompt hormonal replacement therapy for severe hypogonadism. The negative effect of pituitary irradiation on femoral neck BMD remains intriguing, although it is probably related to some degree of the diminished GH secretion frequently observed after this form of treatment.

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Gerrit van den Berg, Steven M Pincus, Johannes D Veldhuis, Marijke Frölich and Ferdinand Roelfsema

Abstract

We investigated the episodicity of 24-h ACTH and cortisol secretory profiles in 16 patients with Cushing's disease and 25 healthy matched controls, with a recently introduced scale- and modelindependent regularity statistic, approximate entropy (ApEn). The mean (± s.e.m.) ApEn value for plasma ACTH concentrations in Cushing's disease was 1·3817 ± 0·033, and in controls 0·8394 ± 0·049 (P< 10−10); for plasma cortisol concentrations the values were 1·4575 ± 0·052 and 0·8637 ± 0·020 respectively (P<10−10), implying greater irregularity of release for both hormones in Cushing's subjects. The calculated sensitivity and specificity of ApEn for ACTH profiles were 94% and 100% respectively. For cortisol the sensitivity and specificity were both 100%. ApEn was not correlated with sex, age, or the total 24-h secretion rate of ACTH and cortisol in patients and controls. The increased ApEn in patients with Cushing's disease points to an increased disorderliness of ACTH and cortisol secretion compared with healthy controls. In conjunction with the available literature, we hypothesize more generally that autonomous endocrine tumors may be typified by reduced regularity, orderliness, or synchrony of the time structure of hormone release.

European Journal of Endocrinology 136 394–400

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Bert-Jan Looij, Ferdinand Roelfsema, Marijke Frölich and Arie C. Nieuwenhuijzen Kruseman

Abstract.

In a single-blind placebo-controlled study, the effect of an iv bolus injection of 100 μg GHRH(1–29)NH2 on the response to 200 μg TRH was assessed in 10 untreated patients with acromegaly to determine whether GHRH interacts with TRH in acromegaly, as previously described in healthy subjects. The combination of GHRH(1–29)NH2 with TRH resulted in a larger increment of peak and of integrated plasma TSH and PRL levels than after TRH alone. GHRH alone had no effect on TSH secretion and only a modest effect on PRL secretion. These findings suggest that in acromegaly, like in healthy individuals, GHRH potentiates the TSH response to TRH and that the effects of GHRH and TRH on PRL secretion are additive.

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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.

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Nieke E Kokshoorn, Nienke R Biermasz, Ferdinand Roelfsema, Johannes W A Smit, Alberto M Pereira and Johannes A Romijn

Context

Recombinant human GH (rhGH) is prescribed for the treatment of adults with GH deficiency (GHD). However, conflicting data are available on the efficacy of rhGH treatment in elderly GHD patients.

Objective

To assess the efficacy of rhGH treatment in elderly GHD subjects.

Methods

We searched the available literature in PubMed, Cochrane Library, Web of Science and EMBASE.

Study selection

Studies on GHD patients, aged >60 years, treated with rhGH were eligible for inclusion. Data extraction was performed by two reviewers independently.

Results

We found 11 eligible studies with a total of 534 patients. Only two studies had prospective, randomized, placebo-controlled study designs of rhGH treatment with a duration of 6 (n=15) and 12 months (n=62), respectively. Treatment with rhGH decreased total and low density lipoprotein (LDL) cholesterol levels by 4–8 and 11–16%, respectively, but did not alter high density lipoprotein or triglyceride levels. RhGH did not affect body mass index, but decreased waist circumference (by ∼3 cm) and waist/hip ratio. RhGh did not consistently affect blood pressure or bone mineral density. RhGH increased lean body mass by 2–5% and decreased total fat mass by 7–10% in four studies, but did not affect body composition in two other studies. RhGH consistently improved quality of life (QoL) parameters reflected in AGHDA-scores. There were no explicit data on elderly GHD patients aged >80 years.

Conclusion

RhGH replacement in elderly subjects with GHD decreases LDL cholesterol levels and improves QoL, but the effects on other parameters are not unequivocal. There were no data on the efficacy and safety of rhGH treatment in octogenarians with GHD.

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Claire E H M Donjacour, N Ahmad Aziz, Marijke Frölich, Ferdinand Roelfsema, Sebastiaan Overeem, Gert Jan Lammers and Hanno Pijl

Objective

Hypocretin deficiency causes narcolepsy and may affect neuroendocrine systems, including TSH, ACTH and LH secretion. Symptoms can be treated effectively with sodium oxybate (SXB) in many patients. This study was performed to compare prolactin (PRL) secretion in patients and matched controls and establish the effect of SXB administration on PRL and sleep in both the groups.

Design

Open label intervention. Blood was sampled before and after 5 days of SXB treatment. The study was performed at the Leiden University Medical Centre, Leiden, The Netherlands.

Methods

Subjects were admitted to the clinical research centre on both occasions.

Patients or participants

Eight male hypocretin-deficient narcolepsy with cataplexy patients and eight controls matched for sex, age, body mass index, waist-to-hip ratio and fat percentage were enrolled.

Interventions

SXB two times 3 g per night for five consecutive nights.

Results

Patients and controls underwent 24 h blood sampling at 10 min intervals for measurement of PRL concentrations. The PRL concentration time series was analysed with a new deconvolution programme, approximate entropy (ApEn) and Cosinor analysis. Sleep was polygraphically recorded. Basal and pulsatile PRL secretion, as well as pulse regularity and frequency, ApEn and diurnal parameters were similar in patients and controls. SXB treatment caused similar nocturnal increase in PRL secretion, advance of the acrophase and decrease in ApEn in patients and controls. Slow wave sleep was increased to a similar extent in patients and controls.

Conclusion

This detailed study did not demonstrate altered PRL secretion in hypocretin-deficient narcolepsy patients during the basal state or during SXB administration. Therefore, hypocretin signalling is unlikely to be a regulator of the lactotrophic system.