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Free access

Emanuel R Christ, Michael H Cummings, Michael Stolinski, Nicola Jackson, Peter J Lumb, Anthony S Wierzbicki, Peter H Sönksen, David L Russell-Jones, and A Margot Umpleby

Background: Epidemiological studies suggest that hypopituitary patients have an increased risk for cardiovascular mortality. The dyslipidaemia associated with this condition is often characterised by an increase in total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol (LDL-C) and may contribute to these findings. The underlying mechanisms are not fully elucidated.

Materials and Methods: LDL apolipoprotein B (apoB) production rate and metabolic clearance rate were measured in seven patients with hypopituitarism (including GH deficiency) under stable conventional replacement therapy (three males and four females; age 40–16.1 years; body mass index 29.0–6.1 kg/m2 (means ± s.d.)) and seven age-, gender- and body mass index-matched control subjects with an infusion of 1-13C-leucine. Fasting lipid profile and lipid composition of LDL were also measured.

Results: Fasting TC, triglycerides (TG), high-density lipoprotein-C, LDL-C and free fatty acid concentrations were not different between hypopituitary patients and control subjects. LDL-TG (P < 0.006) and LDL-TG/LDL apoB ratio (P < 0.02) were significantly increased in hypopituitary patients. LDL apoB pool size was not statistically different between patients and control subjects. In the hypopituitary patients, LDL apoB metabolic clearance rate (P < 0.05) and LDL apoB production rate (P < 0.02) were lower than in the control subjects.

Conclusions: The present results suggest that LDL apoB turnover and LDL composition is altered in hypopituitary patients. Whether these findings explain the increased risk for cardiovascular disease in hypopituitary patients remains to be established.

Free access

Harald J Schneider, Michael Buchfelder, Henri Wallaschofski, Anton Luger, Gudmundur Johannsson, Peter H Kann, and Anders Mattsson

Objective

There is no single clinical marker to reliably assess the clinical response to growth hormone replacement therapy (GHRT) in adults with growth hormone deficiency (GHD). The objective of this study was to propose a clinical response score to GHRT in adult GHD and to establish clinical factors that predict clinical response.

Design

This was a prospective observational cohort study from the international KIMS database (Pfizer International Metabolic Database).

Methods

We included 3612 adult patients with GHD for proposing the response score and 844 patients for assessing predictors of response. We propose a clinical response score based on changes in total cholesterol, waist circumference and QoL-AGHDA quality of life measurements after 2 years of GHRT. A score point was added for each quintile of change in each variable, resulting in a sum score ranging from 3 to 15. For clinical response at 2 years, we analysed predictors at baseline and after 6 months using logistic regression analyses.

Results

In a baseline prediction model, IGF1, QoL-AGHDA, total cholesterol and waist circumference predicted response, with worse baseline parameters being associated with a favourable response (AUC 0.736). In a combined baseline and 6-month prediction model, baseline QoL-AGHDA, total cholesterol and waist circumference, and 6-month change in waist circumference were significant predictors of response (AUC 0.815).

Conclusions

A simple clinical response score might be helpful in evaluating the success of GHRT. The baseline prediction model may aid in the decision to initiate GHRT and the combined prediction model may be helpful in the decision to continue GHRT.

Free access

Felix Schreiner, Magdalini Tozakidou, Rita Maslak, Ute Holtkamp, Michael Peter, Bettina Gohlke, and Joachim Woelfle

Objective

17-Hydroxyprogesterone (17-OHP) screening for classical congenital adrenal hyperplasia (CAH) is part of many newborn screening programs worldwide. Cut-off values are relatively high, and screening sensitivity does not reach 100%. Recently, the glucocorticoid receptor (GR) N363S-variant has been linked to relatively low degree of virilization and comparatively lower 17-OHP serum concentrations in clinically diagnosed female CAH patients. We sought to determine whether functional GR gene variants, either increasing (N363S, BclI) or decreasing GR sensitivity (R23K), underlie the variable 17-OHP screening levels in healthy newborns.

Design

GR genotypes were compared with 17-OHP screening values in 1000 random samples from routine screening. 17-OHP was measured by conventional immunoassay (TRFIA) and a liquid chromatography–tandem mass spectrometry method (LC–MS/MS), which has been shown to increase screening specificity by steroid profiling and avoiding cross-reactions of the 17-OHP-antibody.

Results

There was no significant association of 17-OHP with GR genotypes, even after inclusion of gestational and postnatal age as covariates. However, among LC–MS/MS steroid measurements, we observed some unexpected trends, including lower 11-deoxycortisol concentrations in both 363S- and 23K-carriers. For carriers of the frequent BclI variant, linear regression analysis revealed a significant increase of 4-androstenedione levels with every mutant allele inherited.

Conclusions

Functional GR variants do not underlie the variation of 17-OHP values observed in healthy individuals. However, whether and to which extent genetically determined differences in individual GR sensitivity influence 17-OHP screening levels in conditions of a pathological hypothalamus-pituitary-adrenal gland-axis stimulation and thus may explain false-negative screening results in those affected by CAH remains to be investigated.

Free access

Mette L Nielsen, Manan Pareek, Margrét Leósdóttir, Karl-Fredrik Eriksson, Peter M Nilsson, and Michael H Olsen

Objective

To examine the predictive capability of a 1-h vs 2-h postload glucose value for cardiovascular morbidity and mortality.

Design

Prospective, population-based cohort study (Malmö Preventive Project) with subject inclusion 1974–1992.

Methods

4934 men without known diabetes and cardiovascular disease, who had blood glucose (BG) measured at 0, 20, 40, 60, 90 and 120 min during an OGTT (30 g glucose per m2 body surface area), were followed for 27 years. Data on cardiovascular events and death were obtained through national and local registries. Predictive capabilities of fasting BG (FBG) and glucose values obtained during OGTT alone and added to a clinical prediction model comprising traditional cardiovascular risk factors were assessed using Harrell’s concordance index (C-index) and integrated discrimination improvement (IDI).

Results

Median age was 48 (25th–75th percentile: 48–49) years and mean FBG 4.6 ± 0.6 mmol/L. FBG and 2-h postload BG did not independently predict cardiovascular events or death. Conversely, 1-h postload BG predicted cardiovascular morbidity and mortality and remained an independent predictor of cardiovascular death (HR: 1.09, 95% CI: 1.01–1.17, P = 0.02) and all-cause mortality (HR: 1.10, 95% CI: 1.05–1.16, P < 0.0001) after adjusting for various traditional risk factors. Clinical risk factors with added 1-h postload BG performed better than clinical risk factors alone, in predicting cardiovascular death (likelihood-ratio test, P = 0.02) and all-cause mortality (likelihood-ratio test, P = 0.0001; significant IDI, P = 0.0003).

Conclusion

Among men without known diabetes, addition of 1-h BG, but not FBG or 2-h BG, to clinical risk factors provided incremental prognostic yield for prediction of cardiovascular death and all-cause mortality.

Free access

Camilo Jimenez, Pia Burman, Roger Abs, David R Clemmons, William M Drake, Kent R Hutson, Michael Messig, Michael O Thorner, Peter J Trainer, and Robert F Gagel

Objective

We examined pituitary tumor volumes in patients treated with pegvisomant for 18 months or longer, and in whom the tumors were monitored for at least 3 years. We present details on 9 of 304 patients in clinical trials with pegvisomant who experienced tumor growth within the first year of treatment.

Method

Magnetic resonance images prior to start of pegvisomant and at last follow-up were examined in 43 patients (14% of participating patients). Twenty-nine had received prior radiation therapy (18% of irradiated patients) and all but five received somatostatin analogs between periods of pegvisomant treatment.

Results

At follow-up, the median tumor volume was 0.6 cc (range 0.0–19.7 cc), in comparison with 1.6 cc (0.0–19.7 cc) at baseline (P<0.001). Twenty-five patients, of which 23 received radiation therapy, had tumor volume reduction. Seventeen patients had no significant change. One patient, who had not received radiation therapy, had an increase in tumor volume from 1.61 to 1.93 cc. Of the nine patients with tumor growth, six had progressive growth before initiating pegvisomant. Two patients with stable tumors while on octreotide experienced enlargement after octreotide discontinuation but remained stable on long-term pegvisomant therapy.

Conclusion

The present data indicate that pegvisomant does not promote tumor growth and suggest that the nine observed cases of tumor progression, which occurred within 8 months after commencing pegvisomant, are likely rebound expansions after discontinuation of somatostatin analogs and/or the natural history of aggressively growing pituitary tumors. Continued long-term surveillance of tumor volume, particularly in non-irradiated patients, is recommended.

Free access

Mette Lundgren Nielsen, Manan Pareek, Margrét Leósdóttir, Kurt Højlund, Karl-Fredrik Eriksson, Peter M Nilsson, and Michael Hecht Olsen

Abstract

Objective

To examine the impact of follow-up duration on the incremental prognostic yield of a baseline oral glucose tolerance test (OGTT) for predicting type 2 diabetes and to assess the discrimination ability of blood glucose (BG) obtained at different time points during OGTT.

Design

A prospective, population-based cohort study (Malmö Preventive Project) with inclusion of subjects from 1974 to 1992.

Methods

A total of 5256 men without diabetes, who had BG measured at 0, 20, 40, 60, 90, and 120 min during OGTT (30 g/m2 glucose), were followed for 30 years. Incident type 2 diabetes was recorded using registries. The performance of OGTT added to a clinical prediction model (age, body mass index (BMI), diastolic blood pressure, fasting BG, triglycerides, and family history of diabetes) was assessed using Harrell’s concordance index (C-index) and integrated discrimination improvement (IDI).

Results

Median age was 48 years, mean BMI 24.9 kg/m2, and mean fasting BG 4.7 mmol/L. Models with added post-load BG performed better than the clinical model (C-index: P = 0.08 for BG at 120 min at 5 years, otherwise P ≤ 0.045; IDI: P ≥ 0.06 for BG at 60 and 90 min at 5 years, otherwise P ≤ 0.01). With a longer follow-up duration, C-index decreased, and the C-index increase associated with OGTT was attenuated. Models including BG at 60 or 90 min performed significantly better than the model with BG at 120 min, evident beyond follow-up of 10 and 5 years, respectively.

Conclusions

OGTT provided incremental prognostic yield for type 2 diabetes prediction. BG measured at 60 or 90 min provided better discrimination than BG at 120 min.

Open access

Simon Kayemba-Kay's, Michael P P Geary, Jane Pringle, Charles H Rodeck, John C P Kingdom, and Peter C Hindmarsh

Background

Low birth weight (BW), small head circumference, reduced length, increased preterm births and neuro-endocrine dysfunctions are among known consequences of smoking during pregnancy. Few studies have linked leptin to clinical features of growth restriction associated with maternal smoking and explored interaction with other determinants of size at birth, such as gender.

Methods

Cord serum leptin concentrations were measured in 1215 term infants born to Caucasian mothers at completion of uneventful pregnancy. Serum concentrations were related to BW, gestational length, gender and maternal smoking and interaction with other determinants of size at birth evaluated.

Results

Smoking was more frequent in younger (P<0.001) and shorter mothers (P=0.03) from lower socio-economic groups (SEGPs) (P<0.001). Infants born to smokers were lighter (190 g less), shorter and with smaller head circumference. Cord serum leptin concentrations were higher in girls (9.8 s.d. 7.6 ng/ml) than in boys (7.05 s.d. 5.8 ng/ml) (P<0.001). Boys were heavier (BW 3.52 s.d. 0.49 kg) than girls (3.39 s.d. 0.44 kg) (P<0.001), but girls had greater skinfold thickness measurements (sub-scapular and quadriceps skinfold thicknesses 5.5 s.d. 1.6 mm and 7.6 s.d. 1.9 mm respectively; boys 5.3 s.d. 1.6 vs 7.24±1.90 mm, P<0.001 respectively). Multivariate analyses showed gender (P<0.001), BW SDS (P<0.001), gestational length (P<0.001) and maternal smoking (P<0.042) as factors that influenced umbilical cord serum leptin concentrations in newborns.

Conclusion

Maternal smoking restrains foetal growth through placental vascular effects, and likely also via associated effects on leptin metabolism. More studies are needed to determine the influence that maternal smoking may have on placental syncytiotrophoblast and foetal adipose tissue.

Free access

Andreas Oberbach, Stefanie Lehmann, Katharina Kirsch, Joanna Krist, Melanie Sonnabend, Axel Linke, Anke Tönjes, Michael Stumvoll, Matthias Blüher, and Peter Kovacs

Objective

Exercise training has been shown to have anti-inflammatory effects in patients with type 2 diabetes. Changes in interleukin-6 (IL-6) serum concentrations in response to training could contribute to these beneficial effects. However, there are heterogeneous data on whether circulating IL-6 is altered by exercise training. We therefore hypothesize that genetic factors modify the individual changes in IL-6 levels after long-term training.

Research design and methods

The −174G/C variant in the IL-6 gene was genotyped in 60 subjects with impaired glucose tolerance. For a 12-month interventional study, patients were randomized into three groups: a control group (n=16) was compared with one group, which underwent a standardized training program (n=24) and another group, which was treated with 4 mg rosiglitazone once daily (n=20). At baseline, after 1, 6, and 12 months, we measured anthropometric parameters and serum concentration of IL-6 and, at baseline and after 12 months, we determined glucose tolerance and fitness level.

Results

Only in subjects carrying the SNP −174C allele did long-term exercise training result in significantly reduced IL-6 serum concentrations. Multivariate linear regression analysis identified the IL-6 genotype as a significant predictor of changes in IL-6 serum concentrations independent of age, gender and improvement in body mass index, hemoglobin (Hb)A1c, and fitness level in response to training.

Conclusions

Genetic variants in the IL-6 gene significantly modify changes in IL-6 serum concentrations in response to long-term exercise training programs. Our data suggest that genetic factors are important determinants for the individual response to anti-inflammatory effects of exercise training.

Free access

Simon Kayemba-Kay's, Catherine Peters, Michael P P Geary, Nathan R Hill, David R Mathews, and Peter C Hindmarsh

Objective

To evaluate the relationships across a range of glucose and insulin measures at 12 weeks of gestation with the development of pregnancy-induced hypertension (PIH), gestational diabetes mellitus (GDM) and birth size.

Materials and methods

Prospective study of pregnant women booking before 15th week of gestation. At the first antenatal visit, standard measures of height, weight, blood pressure (BP) and social status were recorded, and blood sample was drawn for measurements of fasting glucose and plasma insulin. Oral glucose tolerance test with 75 g glucose load was performed after overnight fast. Odds ratios (ORs) with 95% CI were calculated to determine the risk of developing PIH or GDM depending on quartiles of blood glucose or tertiles of plasma insulin levels.

Results

One thousand six hundred and fifty pregnant women were included in the study. Of them, 1484 delivered a live infant of whom 70 were preterm, 166 did not complete the study, 155 mothers developed PIH (10.4%), 18 were diagnosed with GDM (1.2%) and four had both PIH and GDM. At 12 weeks of gestation, women who became hypertensive were heavier (P<0.001), with higher BMI (P<0.001) than controls. Both systolic (P<0.001) and diastolic BPs (P<0.001) were already higher in women who developed PIH. Fasting insulin concentrations were higher in PIH group (P<0.002). Fasting glucose level >6.8 mmol/l was associated with the likelihood of delivering a macrosomic baby (OR 3.1 (95% CI: 1.21–8.0); P=0.02); the effect was heightened in multiparous mothers (OR 4.0 (95% CI: 1.4–11.1); P=0.01). Fasting plasma insulin had, however, no effect on size at birth in this study.

Conclusions

Our data suggest that women who develop PIH may be metabolically challenged at early stages of pregnancy with hyperinsulinism, insulin insensitivity and slightly higher BP.

Open access

Vasileios Chortis, Nicholas J Johal, Irina Bancos, Matthew Evans, Kassiani Skordilis, Peter Guest, Michael H Cullen, Emilio Porfiri, and Wiebke Arlt

Mitotane (o,p′DDD) is established in the adjuvant and advanced-stage treatment of adrenocortical carcinoma and counteracts both tumor growth and tumor-related steroid production. Both the adrenal glands and the gonads are steroidogenically active organs and share a common embryogenic origin. Here, we describe the effects of mitotane in two patients with metastatic Leydig cell tumor (LCT) of the testes and associated severe androgen excess (serum testosterone 93 and 88 nmol/L, respectively; male reference range 7–27 nmol/L). Both men suffered from severe restlessness, insomnia and irritability, which they described as intolerable and disrupting normal life activities. Urinary steroid profiling by gas chromatography–mass spectrometry (GC–MS) confirmed excess androgen production and revealed concurrent overproduction of glucocorticoids and glucocorticoid precursors, which under physiological conditions are produced only by the adrenal glands but not by the gonads. In a palliative approach, they were commenced on mitotane, which achieved swift control of the hormone excess and the debilitating clinical symptoms, restoring normal quality of life. GC–MS demonstrated normalization of steroid production and decreased 5α-reductase activity, resulting in decreased androgen activation, and imaging demonstrated disease stabilization for 4–10 months. In conclusion, mitotane can be highly effective in controlling steroid excess in metastatic LCTs, with anti-tumor activity in some cases.