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  • 1.
    Bergthorsdottir, R
    et al.
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Nilsson, A G
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Gillberg, P
    Shire, Danderyd, Sweden.
    Ekman, Bertil
    Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Wahlberg, Jeanette
    Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Health-Related Quality of Life In Patients With Adrenal Insufficiency Receiving Plenadren Compared With Immediate-Release Hydrocortisone.2015In: Value in Health, ISSN 1098-3015, E-ISSN 1524-4733, Vol. 18, no 7, p. A616-Article in journal (Refereed)
    Abstract [en]

    Background

    Previous studies in patients with primary adrenal insufficiency (PAI) on conventional replacement therapy suggest decreased health-related quality of life (HRQoL), and that patients report more frequently fatigue, increased anxiety and inability to work compared to background population.

    Objectives

    To study self-reported health status with EQ-5D in patients with PAI. Patients treated with Plenadren (modified-release hydrocortisone) were compared with patients treated with immediate release hydrocortisone (IRHC) replacement therapy.

    Methods

    This was a cross-sectional, multi-centre, non-interventional survey of patients with PAI receiving Plenadren or immediate release hydrocortisone (IRHC) replacement.

    Subjects

    One hundred thirty-four adult patients with PAI of whom 36 (19 females [53%]) were treated with Plenadren and 98 (77 females [79%]) were treated with IRHC, were included.

    MAIN OUTCOME MEASURE

    HRQoL described by the EQ-5D, a generic preference-based measure of health.

    RESULTS

    Patients on Plenadren and on IRHC had a mean ± SD age of 53.1 ± 12.7 years and 48.0 ± 13.1 years, respectively (P=0.043). The majority of the patients were diagnosed more than 5 years ago (69%). The mean ± SD daily Plenadren and IRHC doses were 27.0 ± 6.8 mg and 26.6 ± 10.9 mg, respectively (P=0.807). 47% of the Plenadren patients had been receiving Plenadren and 82% of the IRHC patients had been receiving IRHC for more than 3 years. Patients receiving Plenadren had better HRQoL measured by the EQ-5D questionnaire compared to patients replaced with IRHC (0.76 ± 0.18 vs 0.68 ± 0.18, respectively [P=0.040]).

    CONCLUSIONS

    Replacement therapy with Plenadren in patients with PAI confers measurable benefit on HRQoL relative to IRHC as estimated by the EQ-5D questionnaire, and may therefore be advantageous when compared to IRHC substitution.

  • 2.
    Burman, P
    et al.
    Skånes University Hospital Malmö Lund, Sweden .
    Mattsson, A F
    Pfizer Health AB, Sweden .
    Johannsson, G
    University of Gothenburg, Sweden .
    Hoybye, C
    Karolinska University Hospital, Sweden .
    Holmer, H
    Central Hospital Kristianstad, Sweden .
    Dahlqvist, P
    Umeå University, Sweden .
    Berinder, K
    Karolinska University Hospital, Sweden .
    Engstrom, B E
    Uppsala University, Sweden .
    Ekman, Bertil
    Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Erfurth, E M.
    Skånes University Hospital Malmö Lund, Sweden .
    Svensson, J
    University of Gothenburg, Sweden .
    Wahlberg, J
    Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Karlsson, F A
    Uppsala University, Sweden .
    Deaths Among Adult Patients With Hypopituitarism: Hypocortisolism During Acute Stress, and De Novo Malignant Brain Tumors Contribute to an Increased Mortality2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 4, p. 1466-1475Article in journal (Refereed)
    Abstract [en]

    Context: Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified. less thanbrgreater than less thanbrgreater thanObjective: To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up. less thanbrgreater than less thanbrgreater thanDesign and Methods: All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed. less thanbrgreater than less thanbrgreater thanMain Outcome Measures: Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up. less thanbrgreater than less thanbrgreater thanResults: An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy. less thanbrgreater than less thanbrgreater thanConclusion: Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease. (J Clin Endocrinol Metab 98: 1466-1475, 2013)

  • 3.
    Burman, Pia
    et al.
    Lund University, Sweden.
    Eden-Engstrom, Britt
    Uppsala University, Sweden.
    Ekman, Bertil
    Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Anders Karlsson, F.
    Uppsala University, Sweden.
    Schwarcz, Erik
    University of Örebro, Sweden.
    Wahlberg Topp, Jeanette
    Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Limited value of cabergoline in Cushings disease: a prospective study of a 6-week treatment in 20 patients2016In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 174, no 1, p. 17-24Article in journal (Refereed)
    Abstract [en]

    Context and objective: The role of cabergoline in Cushings disease (CD) remains controversial. The experience is limited to case reports and few open studies that report the effects determined after >= 1 month of treatment. In prolactinomas and dopamine-responsive GH-secreting tumours, effects of cabergoline are seen within days or weeks. Here, we searched for short-term effects of cabergoline in CD. Design: Twenty patients (19 naive and one recurrent) were included in a prospective study. Cabergoline was administered in increasing doses of 0.5-5 mg/week over 6 weeks. Methods: Urinary free cortisol (UFC) 24 h, morning cortisol and ACTH, and salivary cortisol at 0800, 1600 and 2300 h were determined once weekly throughout. Diurnal curves (six samples) of serum cortisol were measured at start and end. Results: At study end, the median cabergoline dose was 5 mg, range 2.5-5 mg/week. The prolactin levels, markers of compliance, were suppressed in all patients. During the treatment, hypercortisolism varied, gradual and dose-dependent reductions were not seen. Five patients had a >50% decrease of UFC, three had a >50% rise of UFC. Salivary cortisol at 2300 h showed a congruent >50% change with UFC in two of the five cases with decreased UFC, and in one of the three cases with increased UFC. One patient with decreases in both UFC and 2300 h salivary cortisol also had a reduction in diurnal serum cortisol during the course of the study. Conclusions: Cabergoline seems to be of little value in the management of CD. Only one patient had a response-like pattern. Given the known variability of disease activity in CD, this might represent a chance finding.

  • 4.
    Ekman, Bertil
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    IGF-I in growth hormone deficiency and in type 1 diabetes2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Both GH-deficiency and type 1 diabetes are associated with low IGF-I levels. The aim with our studies was to develop a dose titration model to obtain physiological IGF-I levels in growth hormone deficiency and to evaluate the relationship between glycaemic control and IGF-I in diabetes. First we established reference values for insulin like growth factor-I (IGF-I) and insulin like growth factor bindingprotein-1 (IGFBP-1) from 101 women and 101 men randomly selected from the population registry. No gender differences in IGF-I levels were fmmd. IGF-1 decreases with advancing age in both sexes, whereas IGFBP-1 increases with age.

    Titrating the GH dose according to population based reference values of IGF-I might be a way to obtain a fairly physiological substitution dose of GH. We hypothesised that a safe and probably effective maintenance dose of GH should increase IGF-I to the mean or slightly below the mean according to age adjusted reference levels. Eighteen adult hypopituitary patients with severe GH deficiency were titrated in steps, according to age adjusted IGF-I levels, to an individual dose of recombinant GH. For comparison 17 untreated healthy control subjects were evaluated. Similar IGF-1 levels armmd the mean for corresponding age were obtained in both sexes, but the maintenance median GH dose was more than twice in the women compared to men. The :individual dose differed markedly and elderly patients needed lower GH doses due to unchanged GH-sensitivity. Six months on the maintenance GH dose induced changes in blood-glucose, lipids, and insulin sensitivity index, indicating increased insulin resistance, which compared with the controls, were a normalisation. No major changes were seen in the variables of the renin-angiotensin-system. A significant increase in atrial natriuretic peptide seems also to be a normalisation if compared with the controls. The patients had less muscle strength and endmance at baseline compared with the controls and increased the muscle strength and endmance about 10 % after GH-substitution, an effect associated with the increase in IGF-I.

    Paradoxically circulating IGF-I is decreased in type 1 diabetes despite increased GH levels. We studied 134 adult patients with type I diabetes (aged 20-60 years), without endogenous insulin secretion, and found that circulating IGF-I were decreased to about 70 % of the values in the reference population. No con·elation between glycaemic control and IGF-I levels was found.

    To conclude the GH dose obtained when normalising circulating IGF-I according to population-based IGF-I levels, depends on GH-sensitivity (gender) and the IGF-1 level aimed for (age). In comparison with matched controls several OR-dependent variables are improved. In type 1 diabetes, our results suggests that the low IGF-I levels are independent of glycaemic control, and can not be corrected with subcutaneous insulin substitution.

    List of papers
    1. Population-based reference values for IGF-I and IGF-binding protein-1: Relations with metabolic and anthropometric variables
    Open this publication in new window or tab >>Population-based reference values for IGF-I and IGF-binding protein-1: Relations with metabolic and anthropometric variables
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    1997 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 136, no 2, p. 165-172Article in journal (Refereed) Published
    Abstract [en]

    Population-based reference values for IGF-I and IGF-binding protein-1 (IGFBP-1) have been established. One hundred and one women and the same number of men, 20–70 years old, were randomly selected from the population registry in the community of Linköping. Participation rate was 67%. Venous blood was drawn in the fasting state. Serum IGF-I was measured by RIA after acid-ethanol extraction and IGFBP-1 was determined by ELISA. IGF-I levels did not differ between genders and the decline with age was similar in men and women (men: Y=366–3·28×age (years), r =−0·61, P<0·0001; women: Y=386–3·49×age, r =−0·57, P<0·0001, P=0·4 for difference in slope). There were negative correlations between IGF-I and plasma lipids and blood pressure in both genders, but none was independent of age. Serum angiotensin-converting enzyme activity correlated positively with IGF-I in men independently from age (r =0·21, P=0·01). The distribution of IGFBP-1 was positively skewed and it was higher in women than in men (5·9±4·8 μg/l and 4·0±3·3 μg/l respectively; Mann–Whitney, P=0·002). In men and in the women not taking oestrogen, IGFBP-1 correlated positively with age (Spearman rank correlation (Spearman): men: r=0·32, P=0·002; women: r=0·24, P=0·03). C-peptide correlated negatively (Spearman: men: r =−0·38, P=0·002; women: r =−0·49, P<0·000) and sex hormone binding globulin positively with IGFBP-1 (Spearman: men: r=0·50, P<0·0001; women: r =0·55, P<0·0001).

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-81631 (URN)10.1530/eje.0.1360165 (DOI)
    Available from: 2012-09-19 Created: 2012-09-19 Last updated: 2017-12-07Bibliographically approved
    2. A dose titration model for recombinant GH substitution aiming at normal plasma concentrations of IGF-I in hypopituitary adults
    Open this publication in new window or tab >>A dose titration model for recombinant GH substitution aiming at normal plasma concentrations of IGF-I in hypopituitary adults
    Show others...
    2002 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 147, no 1, p. 49-57Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: To evaluate a dose titration model for recombinant human GH substitution in adult patients with GH deficiency, aiming at normal plasma levels of IGF-I.

    DESIGN AND METHODS: Eighteen patients participated and a start dose of 0.17 mg GH/day was used except by two men who started with 0.33 mg/day. To demonstrate a clear GH effect the patients were first titrated, with steps of 0.17 mg GH/day every 6-8 weeks, to IGF-I levels in the upper range of age-adjusted reference values. The GH dose was then reduced 1 dose step and kept for a further 6 months. For comparison we investigated 17 healthy control subjects.

    RESULTS: Plasma IGF-I was increased after 2 weeks on the start dose and did not increase further for up to 8 weeks. Women had significantly lower GH sensitivity than men measured as net increment of IGF-I on the start dose of GH. GH sensitivity was not changed by age. The plasma IGF-I levels increased from 76.3+/-47.0 (s.d.) to 237+/-97 microg/l at the end of the study (P<0.001), and similar IGF-I levels were obtained in both sexes. The maintenance median GH dose was 0.33 mg/day in males and 0.83 mg/day in females (P=0.017). The GH dose correlated negatively with age in both sexes. Body weight, very low density triglycerides, lipoprotein(a) (Lp(a)), and fasting insulin increased, whereas insulin sensitivity index (QUICKI) decreased significantly. In comparison with the controls, the patients had lower fasting blood glucose, fasting insulin and Lp(a) levels at baseline, but these differences disappeared after GH substitution. The two groups had equal insulin sensitivity (QUICKI), but 2 h oral glucose tolerance test values of blood glucose and insulin were significantly higher in the patients at the end of the study.

    CONCLUSIONS: In conclusion our data suggest that the starting dose of GH substitution and the dose titration steps should be individualised according to GH sensitivity (gender) and the IGF-I level aimed for (age). The reduced insulin sensitivity induced by GH substitution could be viewed as a normalisation if compared with control subjects.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24897 (URN)10.1530/eje.0.1470049 (DOI)9300 (Local ID)9300 (Archive number)9300 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    3. Individualized growth hormone substitution with normalized IGF-I levels does not stimulate the renin–angiotensin–aldosterone system
    Open this publication in new window or tab >>Individualized growth hormone substitution with normalized IGF-I levels does not stimulate the renin–angiotensin–aldosterone system
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    2002 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 57, no 4, p. 473-479Article in journal (Refereed) Published
    Abstract [en]

    objective To study the effects of individualized recombinant GH substitution, aiming at normal circulating IGF-I levels, in GH-deficient adults on blood pressure, the renin–angiotensin–aldosterone system (RAAS), natriuretic peptides and urine free cortisol.

    study design Open study with control group. The patients were titrated in dose steps of 0·17 mg GH/day every 6–8 weeks until an IGF-I level around the mean + 1 SD was attained (Tmax). After another month the dose was reduced by 0·17 mg (minimum dose 0·17 mg/day) to produce IGF-I levels at or slightly below the age-related mean (Tend), and this maintenance dose was held constant for 6 months.

    subjects Eighteen patients (11 males and seven females) with GH deficiency participated. For comparison we also prospectively evaluated 17 matched control subjects.

    measurements Blood pressure and heart rate, circulating levels of IGF-I, plasma renin activity (PRA), immunoreactive active renin (IRR), angiotensin II, aldosterone, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and 24-h urine aldosterone and urine free cortisol levels.

    results Blood pressure was unchanged by GH substitution but heart rate increased significantly (P < 0·03). PRA was elevated on the highest GH dose (Tmax) compared to baseline (P < 0·01), but returned to baseline and levels of controls at Tend. Four patients developed transient oedema and tended to have higher PRA levels than the rest of the subjects (P = 0·09). The circulating levels of IRR, angiotensin II, aldosterone, BNP and 24-h urine aldosterone and urine free cortisol levels were unchanged by GH substitution, and did not differ from the levels in the control subjects. Baseline ANP levels in the patients were lower than in the controls (P < 0·01), but increased after GH substitution (P < 0·01) to levels found in with the controls.

    conclusions We found no major changes of the variables in the circulating renin–angiotensin–aldosterone system and a normalization of atrial natriuretic peptide when an individualized dose of GH was titrated to near-normal IGF-I levels.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-24919 (URN)10.1046/j.1365-2265.2002.01617.x (DOI)9323 (Local ID)9323 (Archive number)9323 (OAI)
    Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
    4. Improved muscle function in GH substituted adults is related to increase in circulating IGF-I
    Open this publication in new window or tab >>Improved muscle function in GH substituted adults is related to increase in circulating IGF-I
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    We studied the effects of individualized growth hormone substitution, aiming at normal IGF-I levels, on biomechanical output and EMG of isokinetic muscle strength and endurance performance in 18 hypopituitary adults compared with matched controls. The muscle function tests consisted of isokinetic contractions of the dght knee extensors, and torque and EMG were recorded. Plasma levels of IGF-I were normalized, and peak torque at 90° s-1, and peak torque endurance level increased after dose titration and 6 months constant GH-dose. The change in IGF-I correlated positively with the changes in biomechanical output and EMG variables and a negative correlation existed with the perception of fatigue. Despite improvement during GH-substitution the patients still had about 10-20 % less muscle strength and endurance compared with the controls at the study end. In summary we found that individualized GH substitution improves muscle function and that the net increase in IGF-I levels indicates generally increases in biomechanical output and EMG variables and a lower perception of fatigue.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-81632 (URN)
    Available from: 2012-09-19 Created: 2012-09-19 Last updated: 2012-09-19Bibliographically approved
    5. Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes
    Open this publication in new window or tab >>Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes
    2000 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 143, no 4, p. 505-510Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: To study plasma concentrations of insulin-like growth factor-I (IGF-I) in adults with type 1 diabetes (IDDM) in comparison with a reference population, and the influence of glycaemic control, dose of insulin, and sex on the concentration of circulating IGF-I in IDDM.

    DESIGN AND METHODS: Patients with type 1 diabetes were recruited consecutively from our outpatient diabetes unit. In all, 79 men and 55 women aged 20-60 years with a disease duration >/=6 years (range 6-51 years) took part in the study. A reference population of 80 men and 83 women aged 20-60 years was randomly obtained from the population registry. IGF-I was measured with radioimmunoassay after acid-ethanol extraction.

    RESULTS: Mean +/- s. d. values of IGF-I were lower in patients with diabetes (146+/-66 microg/l) than in controls (238+/-83 microg/l, P<0.001). Those with diabetes had lower IGF-I concentrations in all age groups and the differences were highly significant in all decades except in women aged 50-59 years. IGF-I was negatively correlated with age in patients and controls. No correlation was found between IGF-I and glycaemic control measured as haemoglobin A(1c) (HbA(1c)) in the patients. IGF-I was positively associated with the dose of insulin/kg body weight in male patients independently of age, HbA(1c) and body mass index (P<0.03), but not in female patients (P=0.14).

    CONCLUSIONS: Our data show that IGF-I concentrations are low in adult patients with type 1 diabetes with a disease duration >/=6 years, independently of glycaemic control. This suggests that subcutaneous insulin substitution is inadequate to normalize circulating IGF-I concentrations in patients without endogenous insulin secretion.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26789 (URN)10.1530/eje.0.1430505 (DOI)11394 (Local ID)11394 (Archive number)11394 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
  • 5.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Alstrand, N
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences. County Hospital, Kalmar .
    Bachrach-Lindström, Margareta
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Health Sciences.
    Jenmalm, Maria C
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Wahlberg, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Altered Chemokine Th1/Th2 Balance in Addison's Disease: Relationship with Hydrocortisone Dosing and Quality of Life2014In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 46, no 1, p. 48-53Article in journal (Refereed)
    Abstract [en]

    The adrenalitis found in autoimmune Addison’s disease (AAD) is considered having a Th1-driven pathogenesis. Circulating Th1- and Th2-associated chemokines responsible for the trafficking of leukocytes to inflammatory sites are markers for the Th1/Th2 balance. The aim of the study was to assess if the same daily hydrocortisone dose of 30 mg given in either 2 or 4 doses to patients with AAD could affect the Th1/Th2 balance of circulating chemokines.

    Fifteen patients (6 women) with AAD were included in this randomised, placebo controlled, double blind cross-over study. Samples for chemokines, Th1-associated (CXCL10, CXCL11) and Th2-associated (CCL17, CCL22), were drawn 5 times during a 24-h period at the end of each treatment period and analysed with Luminex. Seven control subjects did the same diurnal blood sampling once. Subjects with AAD had higher median diurnal levels of the Th1-associated chemokines than controls, CXCL10 [43 (33–56) pg/ml vs. 22 (19–34) pg/ml, p<0.01] and CXCL11 [37 (29–48) pg/ml vs. 16 (9–24) pg/ml, p<0.001], whereas no significant difference was found regarding the Th2-related chemokines. Similar chemokine levels were found when the same hydrocortisone dose of 30 mg was divided in 2 or 4 doses. Levels of CXCL11 correlated negatively with scores of SF-36 domains (high score indicate better health) of General Health (GH) and total score for Physical Component Summary (PCS), and these negative correlations were most pronounced at 04:00 h on the 2-dose regimen. Patients with AAD have a dominant Th1 chemokine profile that partially correlates to reduced quality of life.

  • 6.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Bachrach-Lindström, Margareta
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Wahlberg, Jeanette
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Blomgren, Johan
    Internal Medicine County Hospital, Eksjö.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    A randomised double blind crossover study comparing two and four dose hydrocortisone regimen with regard to quality for life, cortisol and ACTH profiles in patients with primary adrenal insufficiency2012In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 77, no 1, p. 18-25Article in journal (Refereed)
    Abstract [en]

    Context

    Current guidelines on how to divide the daily cortisol substitution dose in patients with primary adrenal insufficiency (PAI) are controversial and mainly based on empirical data.

    Objective

    To assess how an equal dose of hydrocortisone given either four times daily or twice daily influence diurnal profiles of cortisol and ACTH, patient preferences and health related quality of life (HRQoL).

    Design

    Double blind, crossover.

    Methods

    Fifteen patients with PAI (6 women) were included. Capsules of hydrocortisone or placebo were given at 07:00, 12:00, 16:00 and 22:00 h in 4-week treatment periods: either one period with four doses (10+10+5+5 mg) or one period with two doses (20+0+10+0 mg). Diurnal profiles of cortisol and ACTH were collected and area under the curve (AUC) was calculated. Questionnaires were used to evaluate patient preferences and HRQoL.

    Results

    The four-dose regimen gave a higher serum cortisol before tablet intake in the morning (P = 0.027) and a higher 24-h-cortisolAUC (P < 0.0001) compared with the two-dose period. In contrast a lower median plasma ACTH in the morning before tablet intake (P = 0.003) and a lower 24-h-ln(ACTHAUC) were found during the four-dose period. The patients preferred the four-dose regimen (P = 0.03), and the HRQoL scores tended to be higher (high score indicates better HRQoL) for the four-dose period.

    In summary a four-dose regimen gives increased availability of cortisol and an enhanced effect with a less elevated ACTH in the morning in comparison with a two-dose regimen but the effect on HRQoL remains inconclusive.

  • 7.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Blomgren, J.
    Internal Medicine County Hospital, Eksjö, Sweden.
    Andersson, P.-O.
    Internal Medicine County Hospital, Eksjö, Sweden.
    Carlsson, M.
    Internal Medicine County Hospital, Kalmar, Sweden.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Variable Sensitivity to the Glucocorticoid Activity of Cortisol in Patients with Primary Adrenal Insufficiency: Assessment with ACTH Profiles2010In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 42, no 13, p. 961-966Article in journal (Refereed)
    Abstract [en]

    Our aim was to investigate the usefulness of circulating levels of adrenocorticotropic hormone (ACTH) and also salivary cortisol to monitor cortisone substitution in patients with Addisons disease. 13 patients with primary adrenal insufficiency (8 women and 5 men, age 44 +/- 11 years) received 12.5 mg cortisone acetate orally at 16:00 h and 25 mg at 07:00 h. Blood samples for cortisol and ACTH analysis were drawn every hour for 24 h, and also every half hour between 07:00 and 12:00 h. Samples for salivary cortisol were collected in parallel. Total ACTH levels showed large inter-individual variations and a diurnal rhythm with a nadir in the early evening at 19:00 (median 19 ng/l, range 2-434 ng/l) and high levels in the early morning, with a peak around 07:30 (median 844 ng/l, range 45-2 249 ng/l). Plasma cortisol concentrations showed 2 peaks distinct in time, but variable in height, 1-2 h after intake of cortisone. Plasma cortisol correlated significantly with ln(ACTH) at 17:00 h (r = -0.56), at 10:00 h (r = -0.51), and at 10.30 h (r = -0.57). When tested at different time points, ln(ACTH) at 10:00 to 12:00 h was negatively correlated with plasma cortisol between 08:30 and 12:00 h. Plasma cortisol was highly correlated to ln(salivary cortisol) most of the time points measured, but 30-60 min after intake of cortisone acetate the correlation disappeared. In conclusion, the large interindividual variation in ACTH levels most likely indicates varying sensitivity to cortisol with a need for individualized dosing schemes. Furthermore ACTH-determinations may be useful for dose titration of cortisol.

  • 8.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Fitts, David
    ViroPharma Incorporated, Exton, Pennsylvania, USA .
    Marelli, Claudio
    ViroPharma SPRL, Maidenhead, UK .
    Murray, Robert D.
    St James’s University Hospital, Leeds, UK .
    Quinkler, Marcus
    Charité University of Medicine, Berlin, Germany .
    Zelissen, Pierre M. J.
    University Medical Center Utrecht, Netherlands .
    European Adrenal Insufficiency Registry (EU-AIR): a comparative observational study of glucocorticoid replacement therapy2014In: BMC Endocrine Disorders, ISSN 1472-6823, E-ISSN 1472-6823, Vol. 14, no 40Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Increased morbidity and mortality associated with conventional glucocorticoid replacement therapy for primary adrenal insufficiency (primary AI; estimated prevalence 93-140/million), secondary AI (estimated prevalence, 150-280/million, respectively) or congenital adrenal hyperplasia (estimated prevalence, approximately 65/million) may be due to the inability of typical glucocorticoid treatment regimens to reproduce the normal circadian profile of plasma cortisol. A once-daily modified-release formulation of hydrocortisone has been developed to provide a plasma cortisol profile that better mimics the daytime endogenous profile of cortisol. Here, we describe the protocol for the European Adrenal Insufficiency Registry (EU-AIR), an observational study to assess the long-term safety of modified-release hydrocortisone compared with conventional glucocorticoid replacement therapies in routine clinical practice (ClinicalTrials.gov identifier: NCT01661387).

    METHODS:

    Patients enrolled in EU-AIR have primary or secondary AI and are receiving either modified-release or conventional glucocorticoid replacement therapy. The primary endpoints of EU-AIR are the incidence of intercurrent illness, adrenal crisis and serious adverse events (SAEs), as well as the duration of SAEs and dose changes related to SAEs. Data relating to morbidity, mortality, adverse drug reactions, dosing and concomitant therapies will be collected. Patient diaries will record illness-related dose changes between visits. All decisions concerning medical care are made by the registry physician and patient. Enrolment is targeted at achieving 3600 patient-years of treatment (1800 patient-years per group) for the primary analysis, which is focused on determining the non-inferiority of once-daily modified-release replacement therapy compared with conventional glucocorticoid therapy.

    RESULTS:

    Recruitment began in August 2012 and, as of March 2014, 801 patients have been enrolled. Fifteen centres are participating in Germany, the UK and Sweden, with recruitment soon to be initiated in the Netherlands.

    CONCLUSIONS:

    EU-AIR will provide a unique opportunity not only to collect long-term safety data on a modified-release preparation of glucocorticoid but also to evaluate baseline data on conventional glucocorticoid replacement. Such data should help to improve the treatment of AI.

  • 9.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Gerdle, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Rehabilitation Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Improved muscle function in GH substituted adults is related to increase in circulating IGF-IManuscript (preprint) (Other academic)
    Abstract [en]

    We studied the effects of individualized growth hormone substitution, aiming at normal IGF-I levels, on biomechanical output and EMG of isokinetic muscle strength and endurance performance in 18 hypopituitary adults compared with matched controls. The muscle function tests consisted of isokinetic contractions of the dght knee extensors, and torque and EMG were recorded. Plasma levels of IGF-I were normalized, and peak torque at 90° s-1, and peak torque endurance level increased after dose titration and 6 months constant GH-dose. The change in IGF-I correlated positively with the changes in biomechanical output and EMG variables and a negative correlation existed with the perception of fatigue. Despite improvement during GH-substitution the patients still had about 10-20 % less muscle strength and endurance compared with the controls at the study end. In summary we found that individualized GH substitution improves muscle function and that the net increase in IGF-I levels indicates generally increases in biomechanical output and EMG variables and a lower perception of fatigue.

  • 10.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Nyström, Fredrik
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Olsson, Anders
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Toss, Göran
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    A dose titration model for recombinant GH substitution aiming at normal plasma concentrations of IGF-I in hypopituitary adults2002In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 147, no 1, p. 49-57Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate a dose titration model for recombinant human GH substitution in adult patients with GH deficiency, aiming at normal plasma levels of IGF-I.

    DESIGN AND METHODS: Eighteen patients participated and a start dose of 0.17 mg GH/day was used except by two men who started with 0.33 mg/day. To demonstrate a clear GH effect the patients were first titrated, with steps of 0.17 mg GH/day every 6-8 weeks, to IGF-I levels in the upper range of age-adjusted reference values. The GH dose was then reduced 1 dose step and kept for a further 6 months. For comparison we investigated 17 healthy control subjects.

    RESULTS: Plasma IGF-I was increased after 2 weeks on the start dose and did not increase further for up to 8 weeks. Women had significantly lower GH sensitivity than men measured as net increment of IGF-I on the start dose of GH. GH sensitivity was not changed by age. The plasma IGF-I levels increased from 76.3+/-47.0 (s.d.) to 237+/-97 microg/l at the end of the study (P<0.001), and similar IGF-I levels were obtained in both sexes. The maintenance median GH dose was 0.33 mg/day in males and 0.83 mg/day in females (P=0.017). The GH dose correlated negatively with age in both sexes. Body weight, very low density triglycerides, lipoprotein(a) (Lp(a)), and fasting insulin increased, whereas insulin sensitivity index (QUICKI) decreased significantly. In comparison with the controls, the patients had lower fasting blood glucose, fasting insulin and Lp(a) levels at baseline, but these differences disappeared after GH substitution. The two groups had equal insulin sensitivity (QUICKI), but 2 h oral glucose tolerance test values of blood glucose and insulin were significantly higher in the patients at the end of the study.

    CONCLUSIONS: In conclusion our data suggest that the starting dose of GH substitution and the dose titration steps should be individualised according to GH sensitivity (gender) and the IGF-I level aimed for (age). The reduced insulin sensitivity induced by GH substitution could be viewed as a normalisation if compared with control subjects.

  • 11.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Nyström, Fredrik
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Circulating IGF-I concentrations are low and not correlated to glycaemic control in adults with type 1 diabetes2000In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 143, no 4, p. 505-510Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study plasma concentrations of insulin-like growth factor-I (IGF-I) in adults with type 1 diabetes (IDDM) in comparison with a reference population, and the influence of glycaemic control, dose of insulin, and sex on the concentration of circulating IGF-I in IDDM.

    DESIGN AND METHODS: Patients with type 1 diabetes were recruited consecutively from our outpatient diabetes unit. In all, 79 men and 55 women aged 20-60 years with a disease duration >/=6 years (range 6-51 years) took part in the study. A reference population of 80 men and 83 women aged 20-60 years was randomly obtained from the population registry. IGF-I was measured with radioimmunoassay after acid-ethanol extraction.

    RESULTS: Mean +/- s. d. values of IGF-I were lower in patients with diabetes (146+/-66 microg/l) than in controls (238+/-83 microg/l, P<0.001). Those with diabetes had lower IGF-I concentrations in all age groups and the differences were highly significant in all decades except in women aged 50-59 years. IGF-I was negatively correlated with age in patients and controls. No correlation was found between IGF-I and glycaemic control measured as haemoglobin A(1c) (HbA(1c)) in the patients. IGF-I was positively associated with the dose of insulin/kg body weight in male patients independently of age, HbA(1c) and body mass index (P<0.03), but not in female patients (P=0.14).

    CONCLUSIONS: Our data show that IGF-I concentrations are low in adult patients with type 1 diabetes with a disease duration >/=6 years, independently of glycaemic control. This suggests that subcutaneous insulin substitution is inadequate to normalize circulating IGF-I concentrations in patients without endogenous insulin secretion.

  • 12.
    Ekman, Bertil
    et al.
    Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Wahlberg Topp, Jeanette
    Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Landberg, Eva
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences.
    Urine oligosaccharide pattern in patients with hyperprolactinaemia2015In: Glycoconjugate Journal, ISSN 0282-0080, E-ISSN 1573-4986, Vol. 32, no 8, p. 635-641Article in journal (Refereed)
    Abstract [en]

    Free milk-type oligosaccharides are produced during pregnancy and lactation and may have an impact on several cells in the immune system. Our aim was to investigate if patients with isolated hyperprolactinaemia, not related to pregnancy, also have increased synthesis and urinary excretion of milk-type oligosaccharides and to compare the excretion pattern with that found during pregnancy. Urine samples were collected as morning sample from 18 patients with hyperprolactinaemia, 13 healthy controls with normal prolactin levels and four pregnant women. After purification, lactose and free oligosaccharides were analysed and quantified by high-performance anion-exchange chromatography with pulsed amperometric detection. The identity of peaks was confirmed by exoglycosidase treatment and comparison with oligosaccharide standards. Prolactin was measured in serum collected between 09 and 11 a.m. by a standardized immunochemical method. Patients with hyperprolactinaemia had higher urinary excretion of lactose than normoprolactinemic controls and urinary lactose correlated positively to prolactin levels (r = 0.51, p less than 0.05). Increased levels of the fucosylated oligosaccharides 2-fucosyl lactose and lacto-di-fucotetraose were found in urine from three and two patients, respectively. The acidic oligosaccharide 3-sialyl lactose was found in high amount in urine from two patients with prolactin of greater than 10,000 mU/l. However, pregnant women in their third trimester had the highest concentration of all these oligosaccharides and excretion increased during pregnancy. This study is first to show that both lactose and certain fucosylated and sialylated milk-type oligosaccharides are increased in some patients with hyperprolactinaemia. It remains to elucidate the functional importance of these findings.

  • 13.
    Ekman, Bertil
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Öhman, Peter K
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Nyström, Fredrik
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Individualized growth hormone substitution with normalized IGF-I levels does not stimulate the renin–angiotensin–aldosterone system2002In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 57, no 4, p. 473-479Article in journal (Refereed)
    Abstract [en]

    objective To study the effects of individualized recombinant GH substitution, aiming at normal circulating IGF-I levels, in GH-deficient adults on blood pressure, the renin–angiotensin–aldosterone system (RAAS), natriuretic peptides and urine free cortisol.

    study design Open study with control group. The patients were titrated in dose steps of 0·17 mg GH/day every 6–8 weeks until an IGF-I level around the mean + 1 SD was attained (Tmax). After another month the dose was reduced by 0·17 mg (minimum dose 0·17 mg/day) to produce IGF-I levels at or slightly below the age-related mean (Tend), and this maintenance dose was held constant for 6 months.

    subjects Eighteen patients (11 males and seven females) with GH deficiency participated. For comparison we also prospectively evaluated 17 matched control subjects.

    measurements Blood pressure and heart rate, circulating levels of IGF-I, plasma renin activity (PRA), immunoreactive active renin (IRR), angiotensin II, aldosterone, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and 24-h urine aldosterone and urine free cortisol levels.

    results Blood pressure was unchanged by GH substitution but heart rate increased significantly (P < 0·03). PRA was elevated on the highest GH dose (Tmax) compared to baseline (P < 0·01), but returned to baseline and levels of controls at Tend. Four patients developed transient oedema and tended to have higher PRA levels than the rest of the subjects (P = 0·09). The circulating levels of IRR, angiotensin II, aldosterone, BNP and 24-h urine aldosterone and urine free cortisol levels were unchanged by GH substitution, and did not differ from the levels in the control subjects. Baseline ANP levels in the patients were lower than in the controls (P < 0·01), but increased after GH substitution (P < 0·01) to levels found in with the controls.

    conclusions We found no major changes of the variables in the circulating renin–angiotensin–aldosterone system and a normalization of atrial natriuretic peptide when an individualized dose of GH was titrated to near-normal IGF-I levels.

  • 14.
    Fjalldal, S.
    et al.
    Skane Univ Hosp, Sweden.
    Follin, C.
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Svärd, Daniel
    Lund University, Lund, Sweden.
    Rylander, L.
    Lund Univ, Sweden.
    Gabery, S.
    Lund Univ, Sweden.
    Petersen, A.
    Lund Univ, Sweden.
    van Westen, D.
    Lund Univ, Sweden.
    Sundgren, P. C.
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Bjorkman-Burtscher, I. M.
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Latt, J.
    Skane Univ Hosp, Sweden.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Johanson, A.
    Skane Univ Hosp, Sweden.
    Erfurth, E. M.
    Skane Univ Hosp, Sweden.
    Microstructural white matter alterations and hippocampal volumes are associated with cognitive deficits in craniopharyngioma2018In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 178, no 6, p. 577-587Article in journal (Refereed)
    Abstract [en]

    Context: Patients with craniopharyngioma (CP) and hypothalamic lesions (HL) have cognitive deficits. Which neural pathways are affected is unknown. Objective: To determine whether there is a relationship between microstructural white matter (WM) alterations detected with diffusion tensor imaging (DTI) and cognition in adults with childhood-onset CP. Design: A cross-sectional study with a median follow-up time of 22 (6-49) years after operation. Setting: The South Medical Region of Sweden (2.5 million inhabitants). Participants: Included were 41 patients (24 women, amp;gt;= 17 years) surgically treated for childhood-onset CP between 1958-2010 and 32 controls with similar age and gender distributions. HI was found in 23 patients. Main outcome measures: Subjects performed cognitive tests and magnetic resonance imaging, and images were analyzed using DTI of uncinate fasciculus, fornix, cingulum, hippocampus and hypothalamus as well as hippocampal volumetry. Results: Right uncinate fasciculus was significantly altered (P amp;lt;= 0.01) Microstructural WM alterations in left ventral cingulum were significantly associated with worse performance in visual episodic memory, explaining approximately 50% of the variation. Alterations in dorsal cingulum were associated with worse performance in immediate, delayed recall and recognition, explaining 26-38% of the variation, and with visuospatial ability and executive function, explaining 19-29%. Patients who had smaller hippocampal volume had worse general knowledge (P = 0.028), and microstructural WM alterations in hippocampus were associated with a decline in general knowledge and episodic visual memory. Conclusions: A structure to function relationship is suggested between microstructural WM alterations in cingulum and in hippocampus with cognitive deficits in CP.

  • 15.
    Fjalldal, Sigridur
    et al.
    Skåne University Hospital, Sweden .
    Holmer, Helene
    Central Hospital Kristianstad, Sweden .
    Rylander, Lars
    Lund University, Sweden .
    Elfving, Maria
    Skåne University Hospital, Sweden .
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Osterberg, Kai
    Lund University, Sweden .
    Erfurth, Eva Marie
    Skåne University Hospital, Sweden .
    Hypothalamic Involvement Predicts Cognitive Performance and Psychosocial Health in Long-term Survivors of Childhood Craniopharyngioma2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 8, p. 3253-3262Article in journal (Refereed)
    Abstract [en]

    Context: Hypothalamic damage caused by craniopharyngioma (CP) is associated with poor functional outcome. less thanbrgreater than less thanbrgreater thanObjective: To assess cognitive function and quality of life in childhood-onset CP on hormonal replacement, including GH treatment. less thanbrgreater than less thanbrgreater thanDesign: A cross-sectional study with a median follow-up time of 20 years (1-40). less thanbrgreater than less thanbrgreater thanSetting: Patients were recruited from the South Medical Region of Sweden. less thanbrgreater than less thanbrgreater thanParticipants: The study included 42 patients (20 women) surgically treated for a childhood-onset CP between 1958 and 2000. Patients were aged andgt;= 17 years. Equally many controls, matched for age, sex, residence, and smoking habits, were included. Tumor growth into the third ventricle was found in 25 patients. less thanbrgreater than less thanbrgreater thanMain Outcome Measures: All subjects were examined with a battery of cognitive tests and the following questionnaires: Symptom Checklist-90, the Interview Schedule for Social Interaction, and the Social Network concept. less thanbrgreater than less thanbrgreater thanResults: The CP patients had lower cognitive performance, reaching statistical significance in 12 of 20 test variables, including executive function and memory. Comparison of patients with tumor growth into the third ventricle to controls revealed a significant lower mean total score (P = .006). A significant negative correlation was recorded between mean z-score of cognitive performance and years since operation (r = -0.407; P = .014). No statistically significant group differences were observed across any of the 9 Symptom Checklist-90 subscales. less thanbrgreater than less thanbrgreater thanConclusions: Adults with childhood-onset CP, on hormone replacement, including GH treatment, have memory defects, disturbed attention, and impaired processing speed. Patients with hypothalamic involvement are more affected. Patients rated their quality of life as good as their matched controls.

  • 16.
    Fjälldal, S.
    et al.
    Skåne Univ Hosp, Sweden.
    Follin, C.
    Skane Univ Hosp, Sweden.
    Gabery, S.
    Lund Univ, Sweden.
    Sundgren, P. C.
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Bjorkman-Burtscher, I. M.
    Skane Univ Hosp, Sweden; Lund Univ, Sweden; Lund Univ, Sweden.
    Latt, J.
    Skane Univ Hosp, Sweden.
    Mannfolk, P.
    Skane Univ Hosp, Sweden.
    Nordstrom, C. H.
    Skane Univ Hosp, Sweden.
    Rylander, L.
    Lund Univ, Sweden.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Cheong, R.
    Lund Univ, Sweden.
    Palsson, A.
    Skane Univ Hosp, Sweden.
    Petersen, A.
    Lund Univ, Sweden.
    Erfurth, E. M.
    Skane Univ Hosp, Sweden.
    Detailed assessment of hypothalamic damage in craniopharyngioma patients with obesity2019In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 43, no 3, p. 533-544Article in journal (Refereed)
    Abstract [en]

    Background/objectives Hypothalamic obesity (HO) occurs in 50% of patients with the pituitary tumor craniopharyngioma (CP). Attempts have been made to predict the risk of HO based on hypothalamic (HT) damage on magnetic resonance imaging (MRI), but none have included volumetry. We performed qualitative and quantitative volumetric analyses of HT damage. The results were explored in relation to feeding related peptides and body fat. Subjects/methods A cross-sectional study of childhood onset CPs involving 3 Tesla MRI, was performed at median 22 years after first operation; 41 CPs, median age 35 (range: 17-56), of whom 23 had HT damage, were compared to 32 controls. After exclusions, 35 patients and 31 controls remained in the MRI study. Main outcome measures were the relation of metabolic parameters to HT volume and qualitative analyses of HT damage. Results Metabolic parameters scored persistently very high in vascular risk particularly among HT damaged patients. Patients had smaller HT volumes compared to controls 769 (35-1168) mm(3) vs. 879 (775-1086) mm(3); P amp;lt; 0.001. HT volume correlated negatively with fat mass and leptin among CP patients (r(s) = -0.67; P amp;lt; .001; r(s) = -0.53; P = 0.001), and explained 39% of the variation in fat mass. For every 100 mm(3) increase in HT volume fat mass decreased by 2.7 kg (95% CI: 1.5-3.9; P amp;lt; 0.001). Qualitative assessments revealed HT damage in three out of six patients with normal volumetry, but HT damage according to operation records. Conclusions A decrease in HT volume was associated with an increase in fat mass and leptin. We present a method with a high inter-rater reliability (0.94) that can be applied by nonradiologists for the assessment of HT damage. The method may be valuable in the risk assessment of diseases involving the HT.

  • 17.
    Holmer, Helene
    et al.
    Centralsjukhuset, Kristianstad.
    Ekman, Bertil
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Björk, Jonas
    Lund University Hospital.
    Nordström, Carl-Henrik
    Lund University Hospital.
    Popovic, Vera
    Centralsjukhuset, Kristianstad.
    Siversson, AnnBritt
    Centralsjukhuset, Kristianstad.
    Hypothalamic involvement predicts cardiovascular risk in adults with childhood onset craniopharyngioma on long-term GH therapy.2009In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 16, p. 671-679Article in journal (Refereed)
    Abstract [en]

    Context: Craniopharyngioma patients without GH therapy are at an increased cardiovascular disease (CVD) risk and particularly concerning women. No previous study on long-term GH therapy in adults with childhood onset (CO) craniopharyngioma was identified.

    Objective: To investigate CVD risk in adults with CO craniopharyngioma on complete hormone replacement, including long-term GH therapy, and to investigate the impact of disease-related factors on CVD risk.

    Design and participants: In a cross-sectional study of operated CO craniopharyngiomas (1958–2000) from a defined area of Sweden (2.5 million), we enrolled 42 patients (20 women) with a median age of 28 years (range 17–57) and assessed CVD risk of 20 (4–40) years after first operation. Comparisons were made with matched controls and between patients with tumor growth into the third ventricle (TGTV) versus non-TGTV. GH therapy was 10–12 years in women and men.

    Results: In comparison with controls, both male and female patients had increased body mass index, fat mass, insulin, and leptin levels. Overall, while not significantly increased in male patients, 55–60% of female patients had a medium–high CVD risk, compared with 10–20% in controls. An increased CVD risk (all P<0.05) and higher levels of fat mass and insulin were recorded in the TGTV group versus the non-TGTV group. Late puberty induction and lack of androgens were shown in female patients.

    Conclusions: Adult patients with CO craniopharyngioma, especially those with TGTV, have persistently increased CVD risk. Conventional hormone substitution, including GH, is insufficient to normalize CVD risk, suggesting an important role for irreversible hypothalamic dysfunction.

  • 18.
    Holmer, Helene
    et al.
    Lund University Hospital.
    Popovic, Vera
    University Clin Centre, Belgrade.
    Ekman, Bertil
    Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL. Linköping University, Department of Medical and Health Sciences, Endocrinology.
    Follin, Cecilia
    Lund University Hospital.
    Siversson, Ann Britt
    Lund University Hospital.
    Erfurth, Eva Marie
    Lund University Hospital.
    Hypothalamic involvement and insufficient sex steroid supplementation are associated with low bone mineral density in women with childhood onset craniopharyngioma2011In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 165, no 1, p. 25-31Article in journal (Refereed)
    Abstract [en]

    Context: Data on bone mineral density (BMD) are lacking in adults with childhood onset (CO)-craniopharyngioma (CP) with hypothalamic damage from the tumor. In patients with CO GH deficiency, BMD increases during GH treatment. Objective: The aims were to evaluate BMD in adults with CO-CPs on complete hormone replacement, including long-term GH and to evaluate the impact of hypothalamic damage on these measures. Design and participants: BMD (dual-energy X-ray absorptiometry), markers of bone turn over, physical activity and calcium intake were assessed in 39 CO-CP adults (20 women), with a median age of 28 (17-57) years, in comparison with matched population controls. Results: Late puberty induction was recorded in both genders, but reduced androgen levels in females only. Only CP women had lower BMD (PZ0.03) at L2-L4, and reduced Z-scores at femoral neck (P=0.004) and L2-L4 (P=0.004). Both genders had increased serum leptin levels (P=0.001), which significantly correlated negatively with BMD at L2-L4 (P=0.003; r=-0.5) and 45% of CP women had Z-score levels less than= -2.0 S.D. Furthermore, 75% of those with a Z-score less than= -2.0 S.D. had hypothalamic involvement by the tumor. Calcium intake (P=0.008) and physical activity (P=0.007) levels were reduced in CP men only. Levels of ostecalcin and crossLaps were increased in CP men only. Conclusions: Despite continuous GH therapy, low BMD was recorded in CO-CP females. Insufficient estrogen and androgen supplementation during adolescence was the main cause, but hypothalamic involvement with consequent leptin resistance was also strongly associated with low BMD in both genders.

  • 19.
    Holmer, Helene
    et al.
    Central Hospital, Kristianstad, Sweden.
    Pozarek, Gabriella
    Lund-Malmö University Hospital, Lund, Sweden.
    Wirfält, Elisabet
    Lund University, Sweden.
    Popovic, Vera
    University Clinical Center, Belgrade, Serbia.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Björk, Jonas
    Lund University Hospital, Sweden.
    Erfurth, Eva-Marie
    Lund-Malmö University Hospital, Lund, Sweden.
    Reduced Energy Expenditure and Impaired Feeding-Related Signals But Not High Energy Intake Reinforces Hypothalamic Obesity in Adults with Childhood Onset Craniopharyngioma2010In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, no 12, p. 5395-5402Article in journal (Refereed)
    Abstract [en]

    Context: Obesity is a frequent manifestation of hypothalamic damage from a craniopharyngioma (CP). It is not yet clarified whether the obesity is due to alterations in energy expenditure, i.e. basal metabolic rate (BMR) and physical activity, or to increased energy intake (EI). Objective: The aim was to investigate whether energy expenditure and EI differed between childhood onset CP patients and matched population controls and whether these measures were related to hypothalamic damage, as tumor growth into the third ventricle (TGTV). Design and Methods: Forty-two CP patients (20 women) aged 28 yr (range, 17-57 yr) operated between 1958 and 2000 in the South Medical Region of Sweden (population, 2.5 million) were studied. Body composition, satiety hormones, BMR (indirect calorimetry), physical activity, EI, and attitudes toward eating were assessed. Comparisons were made with matched controls and between patients with (n = 25) and without (n = 17) TGTV. Results: After adjustment, patients had lower BMR compared to controls (-90 kcal/24 h; P = 0.02) and also had lower EI (1778 vs. 2094 kcal/24h; P = 0.008), and the EI/BMR ratio was significantly lower in TGTV patients. Similar dietary macronutrient composition was found, and only significantly higher scales in restricting food intake were recorded in patients. Ghrelin levels were significantly lower in patients, whereas serum insulin and leptin levels were higher (P less than 0.001), and both ghrelin and insulin correlated significantly to tumor growth. Lower levels of physical activity (P less than 0.01) were recorded in patients. Conclusions: The major mechanisms that reinforced obesity were hypothalamic damage causing disrupted or impaired sensitivity to feeding-related signals for leptin, insulin, and ghrelin, and reductions in both BMR and physical activity.

  • 20.
    Holmer, Helene
    et al.
    Department Internal Med, Sweden .
    Svensson, Johan
    Sahlgrens University Hospital, Sweden .
    Rylander, Lars
    Lund University, Sweden .
    Johannsson, Gudmundur
    Sahlgrens University Hospital, Sweden .
    Rosen, Thord
    Sahlgrens University Hospital, Sweden .
    Bengtsson, Bengt-Ake
    Sahlgrens University Hospital, Sweden .
    Thoren, Marja
    Karolinska University Hospital Solna, Sweden .
    Hoybye, Charlotte
    Karolinska University Hospital Solna, Sweden .
    Degerblad, Marie
    Karolinska University Hospital Solna, Sweden .
    Bramnert, Margareta
    Skånes University Hospital, Sweden .
    Hagg, Erik
    University Hospital, Sweden .
    Eden Engstrom, Britt
    University of Uppsala Hospital, Sweden .
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Erfurth, Eva-Marie
    Skånes University Hospital, Sweden .
    Psychosocial health and levels of employment in 851 hypopituitary Swedish patients on long-term GH therapy2013In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 38, no 6, p. 842-852Article in journal (Refereed)
    Abstract [en]

    Context: The psychosocial health and working capacity in hypopituitary patients receiving long-term growth hormone (GH) therapy are unknown. less thanbrgreater than less thanbrgreater thanObjective: Psychosocial health and levels of employment were compared between GH deficient (GHD) patients on long-term replacement and the general population. less thanbrgreater than less thanbrgreater thanDesign and participants: In a Swedish nationwide study, 851 GHD patients [101 childhood onset (CO) and 750 adult onset (AO)] and 2622 population controls answered a questionnaire regarding current living, employment and educational level, alcohol consumption and smoking habits. The median time on GH therapy for both men and women with CO GHD was 9 years and for AO GHD 6 years, respectively. less thanbrgreater than less thanbrgreater thanResults: As compared to the controls, the GHD patients were less often working full time, more often on sick leave/disability pension, and to a larger extent alcohol abstainers and never smokers (all; P andlt; 0.05). Predominantly CO GHD women and men, but to some extent also AO GHD women and men, lived less frequently with a partner and more often with their parents. Particularly AO GHD craniopharyngioma women used more antidepressants, while AO GHD men with a craniopharyngioma used more analgesics. less thanbrgreater than less thanbrgreater thanConclusions: A working capacity to the level of the general population was not achieved among hypopituitary patients, although receiving long-term GH therapy. Patients were less likely to use alcohol and tobacco. The CO GHD population lived a less independent life.

  • 21.
    Holmer, Helene
    et al.
    Centralsjukhuset, Kristianstad, Sweden.
    Svensson, Johan
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Rylander, Lars
    Lund University, Sweden.
    Johansson, Gudmundur
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Rosén, Thord
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Bengtsson, Bengt Åke
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Thorén, Marja
    Karolinska University Hospital Solna, Stockholm, Sweden .
    Höybye, Charlotte
    Karolinska University Hospital Solna, Stockholm, Sweden.
    Degerblad, Marie
    Karolinska University Hospital Solna, Stockholm, Sweden.
    Bramnert, Margareta
    University Hospital, Malmö, Sweden.
    Hägg, Erik
    University Hospital, Umeå, Sweden.
    Edén Engström, Britt
    Uppsala University Hospital, Sweden.
    Ekman, Bertil
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Norrving, Bo
    Lund University Hospital, Sweden.
    Hagmar, Lars
    Lund University, Sweden.
    Erfurth, Eva-Marie
    Lund University Hospital, Sweden.
    Nonfatal stroke, cardiac disease, and diabetes mellitus in hypopituitary patients on hormone replacement including growth hormone2007In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, no 9, p. 3560-3567Article in journal (Refereed)
    Abstract [en]

    Context: The impact of long-term GH replacement on cerebrovascular and cardiovascular diseases and diabetes mellitus in hypopituitary patients is unknown. Objective: The incidence of nonfatal stroke and cardiac events, and prevalence of type 2 diabetes mellitus (T2D) and cardioprotective medication were compared between cohorts of GH-deficient (GHD) patients and population controls. Design and Participants: The incidence of nonfatal stroke and cardiac events was estimated retrospectively from questionnaires in 750 GHD patients and 2314 matched population controls. A prevalence of T2D and cardioprotective medication was recorded at the distribution of questionnaires. Time since first pituitary deficiency to start of GH therapy was 4 and 2 yr, and time on GH therapy was 6 yr for GHD women and men, respectively. Results: Lifelong incidence of nonfatal stroke was tripled in GHD women and doubled in GHD men, but a decline was seen in both genders during periods after first pituitary hormone deficiency and GHD, during which most patients had GH therapy. The lifelong incidence of nonfatal cardiac events declined in GHD men during first pituitary hormone deficiency and GHD periods. GHD women had a higher prevalence of T2D and lipid-lowering medication, whereas GHD men had a higher prevalence of antihypertensive medication. Conclusions: The declined risks of nonfatal stroke in both genders and of nonfatal cardiac events in GHD men during periods on GH replacement may be caused by prescription of cardioprotective drugs and 6-yr GH replacement. GHD women had an increased prevalence of T2D, partly attributed to higher body mass index and lower physical activity. Copyright © 2007 by The Endocrine Society.

  • 22.
    Holmer, Helene
    et al.
    Centralsjukhuset, Kristianstad, Sweden.
    Svensson, Johan
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Rylander, Lars
    Lund University, Sweden.
    Johansson, Gudmundur
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Rosén, Thord
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Bengtsson, Bengt-Åke
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Thorén, Marja
    Karolinska University Hospital Solna, Stockholm, Sweden .
    Höybye, Charlotte
    Karolinska University Hospital Solna, Stockholm, Sweden .
    Degerblad, Marie
    Karolinska University Hospital Solna, Stockholm, Sweden .
    Bramnert, Margareta
    University Hospital, Malmö, Sweden.
    Hägg, Erik
    University Hospital, Umeå, Sweden.
    Engström, Britt Edén
    Uppsala University Hospital, Sweden.
    Ekman, Bertil
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Thorngren, Karl-Göran
    University Hospital, Lund, Sweden.
    Hagmar, Lars
    Lund University, Sweden.
    Erfurth, Eva-Marie
    Lund University Hospital, Sweden.
    Fracture incidence in GH-deficient patients on complete hormone replacement including GH2007In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 22, no 12, p. 1842-1850Article in journal (Refereed)
    Abstract [en]

    Fracture risk in GHD patients is not definitely established. Studying fracture incidence in 832 patients on GH therapy and 2581 matched population controls, we recorded a doubled fracture risk in CO GHD women, but a significantly lower fracture risk in AO GHD men. Introduction: The objective of this study was to evaluate fracture incidence in patients wilh confirmed growth hormone deficiency (GHD) on replacement therapy (including growth hormone [GH]) compared with population controls, while also taking potential confounders and effect modifiers into account. Materials and Methods: Eight hundred thirty-two patients with GHD and 2581 matched population controls answered a questionnaire about fractures and other background information. Incidence rate ratio (IRR) and 95% CI for first fracture were estimated. The median time on GH therapy for childhood onset (CO) GHD men and women was 15 and 12 yr, respectively, and 6 and 5 yr for adult onset (AO) GHD men and women, respectively. Results: A more than doubled risk (IRR, 2.29, 95% CI, 1.23-4.28) for nonosteoporotic fractures was recorded in women with CO GHD, whereas no risk increase was observed among CO GHD men (IRR. 0.61) and AO GHD women (IRR, 1.08). A significantly decreased incidence of fractures (IRR, 0.54, 95% CI 0.34-0.86) was recorded in AO GHD men. Conclusions: Increased fracture risk in CO GHD women can most likely be explained by interaction between oral estrogen and the GH-IGF-I axis. The adequate substitution rate of testosterone (90%) and GH (94%) may have resulted in significantly lower fracture risk in AO GHD men.

  • 23.
    Johannsson, G
    et al.
    Sahlgrens University Hospital.
    Nilsson, A G
    Sahlgrens University Hospital.
    Bergthorsdottir, R
    Sahlgrens University Hospital.
    Burman, P A
    Malmo University Hospital.
    Eden Engstrom, B
    Uppsala University Hospital.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Dahlqvist, P
    Umea University Hospital.
    Ryberg, M
    Umea University Hospital.
    Ragnarsson, O
    Sahlgrens University Hospital.
    Wahlberg Topp, Jeanette
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Lennernas, H
    Uppsala University.
    Skrtic, S
    Sahlgrens University Hospital.
    Improved Quality of Life in Patients with Primary Adrenal Insufficiency by Using a Novel Once-Daily Dual Release Hydrocortisone Tablet: A Randomised Controlled, Cross-Over Trial. in ENDOCRINE REVIEWS, vol 31, issue 3, pp2010In: ENDOCRINE REVIEWS, Endocrine Society , 2010, Vol. 31, no 3Conference paper (Refereed)
    Abstract [en]

    n/a

  • 24.
    Johansson, G.
    et al.
    Sahlgrenska Academy, University of Gothenburg.
    Nilsson, A. G.
    Sahlgrenska Academy, University of Gothenburg.
    Bergthorsdottir, R.
    Sahlgrenska Academy, University of Gothenburg.
    Burman, P.
    Skånes University Hospital, Malmö.
    Dahlqvist, P.
    Umeå University.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Engström, B. E
    Uppsala University.
    Olsson, T.
    Umeå University.
    Ragnarsson, O.
    Sahlgrenska Academy, University of Gothenburg.
    Ryberg, M.
    Umeå University.
    Wahlberg, Jeanette
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Biller, B. M. K.
    Massachusetts General Hospital, Harvard Medical School, Boston.
    Monson, J. P.
    St. Bartholomew's Hospital, Queen Mary University of London.
    Stewart, P. M.
    University of Birmingham.
    Lennernäs, H.
    Uppsala University.
    Skrtic, S.
    Sahlgrenska Academy, University of Gothenburg.
    Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomised trial of a novel hydrocortisone dual-release formulation2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 2, p. 473-481Article in journal (Refereed)
    Abstract [en]

    Context: Patients with treated adrenal insufficiency (AI) have increased morbidity and mortality rate. Our goal was to improve outcome by developing a once-daily (OD) oral hydrocortisone dual-release tablet with a more physiological exposure-time cortisol profile.

    Objective: The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily (TID) dose of conventional hydrocortisone tablets.

    Design and Setting: We conducted an open, randomized, two-period, 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers.

    Patients: The trial enrolled 64 adults with primary AI; 11 had concomitant diabetes mellitus (DM).

    Intervention: The same daily dose of hydrocortisone was administered as OD dual-release or TID.

    Main Outcome Measure: We evaluated cortisol pharmacokinetics.

    Results: Compared with conventional TID, OD provided a sustained serum cortisol profile 0-4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure. The mean weight (difference = -0.7 kg, P = 0.005), systolic blood pressure (difference = -5.5 mm Hg, P = 0.0001) and diastolic blood pressure (difference: -2.3 mm Hg; P = 0.03), and glycated hemoglobin (absolute difference = -0.1%, P = 0.0006) were all reduced after OD compared with TID at 12 wk. Compared with TID, a reduction in glycated hemoglobin by 0.6% was observed in patients with concomitant DM during OD (P = 0.004).

    Conclusion: The OD dual-release tablet provided a more circadian-based serum cortisol profile. Reduced body weight, reduced blood pressure, and improved glucose metabolism were observed during OD treatment. In particular, glucose metabolism improved in patients with concomitant DM.

  • 25.
    Jonsson, Anna K.
    et al.
    National Board Forens Med, Department Forens Genet and Forens Toxicol, S-58758 Linkoping, Sweden.
    Lövborg, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Lohr, Wolfgang
    Umeå University, Sweden.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Rocklov, Joacim
    Umeå University, Sweden; Heidelberg University, Germany.
    Increased Risk of Drug-Induced Hyponatremia during High Temperatures2017In: International Journal of Environmental Research and Public Health, ISSN 1661-7827, E-ISSN 1660-4601, Vol. 14, no 7, article id 827Article in journal (Refereed)
    Abstract [en]

    Purpose: To investigate the relationship between outdoor temperature in Sweden and the reporting of drug-induced hyponatremia to the Medical Products Agency (MPA). Methods: All individual adverse drug reactions (ADR) reported to MPA from 1 January 2010 to 31 October 2013 of suspected drug-induced hyponatremia and random controls were identified. Reports where the ADR had been assessed as having at least a possible relation to the suspected drug were included. Information on administered drugs, onset date, causality assessment, sodium levels, and the geographical origin of the reports was extracted. A case-crossover design was used to ascertain the association between heat exposure and drug-induced hyponatremia at the individual level, while linear regression was used to study its relationship to sodium concentration in blood. Temperature exposure data were obtained from the nearest observation station to the reported cases. Results: During the study period, 280 reports of hyponatremia were identified. More cases of drug-induced hyponatremia were reported in the warmer season, with a peak in June, while other ADRs showed an opposite annual pattern. The distributed lag non-linear model indicated an increasing odds ratio (OR) with increasing temperature in the warm season with a highest odds ratio, with delays of 1-5 days after heat exposure. A cumulative OR for a lag time of 1 to 3 days was estimated at 2.21 at an average daily temperature of 20 degrees C. The change in sodium per 1 degrees C increase in temperature was estimated to be -0.37 mmol/L (95% CI: -0.02, -0.72). Conclusions: Warm weather appears to increase the risk of drug-induced hyponatremia.

  • 26.
    Landberg, Eva
    et al.
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Wahlberg Topp, Jeanette
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Rydén, Ingvar
    Division of Clinical Chemistry, Kalmar County Hospital, Kalmar, Sweden.
    Arvidsson, Britt-Marie
    Division of Clinical Chemistry, Kalmar County Hospital, Kalmar, Sweden.
    Ekman, Bertil
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Detection of molecular variants of prolactin in human serum, evaluation of a method based on ultrafiltration2007In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 376, no 1-2, p. 220-225Article in journal (Refereed)
    Abstract [en]

    Background

    In human blood, there are several molecular variants of prolactin with different biological effects. There is a need for new methods to detect and quantify these variants in order to fully understand the pathophysiological role of prolactin.

    Methods

    A method based on ultrafiltration was optimized, validated and compared to PEG precipitation. Serum samples from 84 patients were analyzed before and after pre treatment on two immunoassays, Elecsys (Roche) and Access (Beckman). Protein G precipitation was used to confirm presence of macroprolactin.

    Results

    The recovery of prolactin after ultrafiltration was lower than after PEG precipitation. A limit of 40% recovery after PEG precipitation corresponded to 27% recovery after ultrafiltration. Using these limits there were total agreement regarding detection of macroprolactin (rs = 0.96). In contrast, recovery of prolactin in samples without macroprolactin showed a considerable disagreement between ultrafiltration and PEG precipitation (rs = 0.48). Within-run CV was 4% for the ultrafiltration method. The correlation coefficient (r) between the immunoassays was 0.96 after ultrafiltration.

    Conclusions

    Ultrafiltration can be used to compare different prolactin immunoassays and to detect macroprolactin in assays with interference from PEG. For samples without macroprolactin ultrafiltration may give additional information reflecting individual variations of other molecular variants of prolactin.

  • 27.
    Lood, Yvonne
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Artillerigatan 12, S-58758 Linkoping, Sweden.
    Aardal-Eriksson, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Webe, C.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Artillerigatan 12, S-58758 Linkoping, Sweden.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Wahlberg, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Relationship between testosterone in serum, saliva and urine during treatment with intramuscular testosterone undecanoate in gender dysphoria and male hypogonadism2018In: Andrology, ISSN 2047-2919, E-ISSN 2047-2927, Vol. 6, no 1, p. 86-93Article in journal (Refereed)
    Abstract [en]

    Long-term testosterone replacement therapy is mainly monitored by trough levels of serum testosterone (S-T), while urinary testosterone (U-T) is used by forensic toxicology to evaluate testosterone doping. Testosterone in saliva (Sal-T) may provide additional information and simplify the sample collection. We aimed to investigate the relationships between testosterone measured in saliva, serum and urine during standard treatment with 1,000mg testosterone undecanoate (TU) every 12th week during 1year. This was an observational study. Males with primary and secondary hypogonadism (HG; n=23), subjects with gender dysphoria (GD FtM; n=15) and a healthy control group of men (n=32) were investigated. Sal-T, S-T and U-T were measured before and after TU injections. Sal-T was determined with Salimetrics((R)) enzyme immunoassay, S-T with Roche Elecsys((R)) testosterone II assay and U-T by gas chromatography-mass spectrometry. Sal-T correlated significantly with S-T and calculated free testosterone in both controls and patients (HG men and GD FtM), while Sal-T to U-T showed weaker correlations. Trough values of Sal-T after 12months were significantly higher in the GD FtM group (0.77 +/- 0.35nmol/L) compared to HG men (0.53 +/- 0.22nmol/L) and controls (0.46 +/- 0.15nmol/L), while no differences between S-T and U-T trough values were found. Markedly elevated concentrations of salivary testosterone, 7-14days after injection, were observed, especially in the GD FtM group. This study demonstrates that Sal-T might be a useful clinical tool to monitor long-term testosterone replacement therapy and might give additional information in forensic cases.

  • 28.
    Murray, Robert D.
    et al.
    Leeds Teaching Hospital NHS Trust, England.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Uddin, Sharif
    Shire, MA USA.
    Marelli, Claudio
    Shire, Switzerland.
    Quinkler, Marcus
    Endocrinol Charlottenburg, Germany.
    Zelissen, Pierre M. J.
    University of Medical Centre Utrecht, Netherlands.
    Management of glucocorticoid replacement in adrenal insufficiency shows notable heterogeneity - data from the EU-AIR2017In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 86, no 3, p. 340-346Article in journal (Refereed)
    Abstract [en]

    Context and objectiveTreatment for adrenal insufficiency (AI) remains suboptimal. Despite glucocorticoid replacement, patients with AI have reduced life expectancy and quality of life. This study aimed to describe the spectrum of management of glucocorticoid replacement in patients with AI enrolled in the European Adrenal Insufficiency Registry (EU-AIR). Design, setting and patientsEU-AIR is a prospective, multinational, multicentre, observational study initiated in August 2012 to monitor the long-term safety of glucocorticoid replacement in routine clinical practice in Germany, the Netherlands, Sweden and the UK (ClinicalTrials.gov identifier: NCT01661387). This analysis included 1166 patients with primary and secondary AI (mean disease duration 16amp;lt;boldamp;gt;amp;lt;/boldamp;gt;1 11amp;lt;boldamp;gt;amp;lt;/boldamp;gt;6 years) receiving long-term glucocorticoid replacement therapy. Main outcome measureGlucocorticoid type, dose, frequency and treatment regimen were examined. ResultsMost patients (87amp;lt;boldamp;gt;amp;lt;/boldamp;gt;4%) were receiving hydrocortisone. The most common dose range, taken by 42amp;lt;boldamp;gt;amp;lt;/boldamp;gt;2% of patients, was 20 to amp;lt;25 mg/day; however, 12amp;lt;boldamp;gt;amp;lt;/boldamp;gt;6% were receiving doses of 30 mg/day. Hydrocortisone was being taken once daily by 5amp;lt;boldamp;gt;amp;lt;/boldamp;gt;5%, twice daily by 48amp;lt;boldamp;gt;amp;lt;/boldamp;gt;7%, three times daily by 43amp;lt;boldamp;gt;amp;lt;/boldamp;gt;6% and four times daily by 2amp;lt;boldamp;gt;amp;lt;/boldamp;gt;1%. Patients with primary AI received higher replacement doses than those with secondary AI (23amp;lt;boldamp;gt;amp;lt;/boldamp;gt;4 +/- 8amp;lt;boldamp;gt;amp;lt;/boldamp;gt;9 and 19amp;lt;boldamp;gt;amp;lt;/boldamp;gt;6 +/- 5amp;lt;boldamp;gt;amp;lt;/boldamp;gt;9 mg/day, respectively). Twenty-five different regimens were being used to deliver a daily hydrocortisone dose of 20 mg. ConclusionsWe have shown significant heterogeneity in the type, dose, frequency and timing of glucocorticoid replacement in real-world clinical practice. This reflects dose individualization based on patient symptoms and lifestyle in the absence of data supporting the optimal regimen.

  • 29.
    Nilsson, A. G.
    et al.
    University of Gothenburg, Sweden.
    Marelli, C.
    ViroPharma SPRL, England.
    Fitts, D.
    ViroPharma Inc, Sweden.
    Bergthorsdottir, R.
    University of Gothenburg, Sweden.
    Burman, P.
    Skånes University Hospital, Sweden.
    Dahlqvist, P.
    Umeå University, Sweden.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Eden Engstrom, B.
    University of Uppsala Hospital, Sweden.
    Olsson, T.
    Umeå University, Sweden.
    Ragnarsson, O.
    University of Gothenburg, Sweden.
    Ryberg, M.
    Umeå University, Sweden.
    Wahlberg Topp, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Lennernas, H.
    Uppsala University, Sweden.
    Skrtic, S.
    University of Gothenburg, Sweden; AstraZeneca RandD, Sweden.
    Johannsson, G.
    University of Gothenburg, Sweden.
    Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency2014In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 171, no 3, p. 369-377Article in journal (Refereed)
    Abstract [en]

    Objective: The objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI). Design: Randomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden. Methods: Sixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20-40 mg once daily and hydrocortisone 20-40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness). Results: In stage 1, patients had a median 1.5 (range, 1-9) intercurrent illness events with DR-HC and 1.0 (1-8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1-3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure. Conclusions: This long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy.

  • 30.
    Nilsson, Anna G.
    et al.
    University of Gothenburg, Sweden.
    Bergthorsdottir, Ragnhildur
    University of Gothenburg, Sweden.
    Burman, Pia
    Lund University, Sweden.
    Dahlqvist, Per
    Umeå University, Sweden.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Eden Engstrom, Britt
    University Hospital, Sweden.
    Ragnarsson, Oskar
    University of Gothenburg, Sweden.
    Skrtic, Stanko
    University of Gothenburg, Sweden; AstraZeneca RandD, Sweden.
    Wahlberg Topp, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Achenbach, Heinrich
    Shire Int GmbH, Switzerland.
    Uddin, Sharif
    Shire, MA USA.
    Marelli, Claudio
    Shire Int GmbH, Switzerland.
    Johannsson, Gudmundur
    University of Gothenburg, Sweden.
    Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study2017In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 176, no 6, p. 715-725Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI). Design: Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden. Methods: Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires. Results: Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n = 2), gastritis (n = 1) and syncope (n = 1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6-5.4 episodes per patient per year), fasting plasma glucose (0.7 mmol/L; P amp;lt; 0.0001) and HDL cholesterol (0.2 mmol/L; P amp;lt; 0.0001) increased and patient-/investigator-assessed tolerability improved. QoL total scores were unchanged but worsening physical functioning was recorded (P = 0.008). Conclusions: In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment.

  • 31.
    Nyström, Fredrik H.
    et al.
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Öhmar, Peter K.
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences.
    Ekman, Bertil Å.
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences.
    Österlund, Maria K.
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences.
    Karlberg, Bengt E.
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences.
    Arnqvist, Hans J.
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences.
    Population-based reference values for IGF-I and IGF-binding protein-1: Relations with metabolic and anthropometric variables1997In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 136, no 2, p. 165-172Article in journal (Refereed)
    Abstract [en]

    Population-based reference values for IGF-I and IGF-binding protein-1 (IGFBP-1) have been established. One hundred and one women and the same number of men, 20–70 years old, were randomly selected from the population registry in the community of Linköping. Participation rate was 67%. Venous blood was drawn in the fasting state. Serum IGF-I was measured by RIA after acid-ethanol extraction and IGFBP-1 was determined by ELISA. IGF-I levels did not differ between genders and the decline with age was similar in men and women (men: Y=366–3·28×age (years), r =−0·61, P<0·0001; women: Y=386–3·49×age, r =−0·57, P<0·0001, P=0·4 for difference in slope). There were negative correlations between IGF-I and plasma lipids and blood pressure in both genders, but none was independent of age. Serum angiotensin-converting enzyme activity correlated positively with IGF-I in men independently from age (r =0·21, P=0·01). The distribution of IGFBP-1 was positively skewed and it was higher in women than in men (5·9±4·8 μg/l and 4·0±3·3 μg/l respectively; Mann–Whitney, P=0·002). In men and in the women not taking oestrogen, IGFBP-1 correlated positively with age (Spearman rank correlation (Spearman): men: r=0·32, P=0·002; women: r=0·24, P=0·03). C-peptide correlated negatively (Spearman: men: r =−0·38, P=0·002; women: r =−0·49, P<0·000) and sex hormone binding globulin positively with IGFBP-1 (Spearman: men: r=0·50, P<0·0001; women: r =0·55, P<0·0001).

  • 32.
    Quinkler, Marcus
    et al.
    Endocrinol Charlottenburg, Germany.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Marelli, Claudio
    Shire Int GmbH, Switzerland.
    Uddin, Sharif
    Shire, MA USA.
    Zelissen, Pierre
    University of Medical Centre Utrecht, Netherlands.
    Murray, Robert D.
    Leeds Teaching Hospital NHS Trust, England.
    Prednisolone is associated with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency2017In: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 6, no 1Article in journal (Refereed)
    Abstract [en]

    Objective: Prednisolone is used as glucocorticoid replacement therapy for adrenal insufficiency (AI). Recent data indicate that its use in AI is associated with low bone mineral density. Data on risk factors for cardiovascular disease in patients with AI treated with prednisolone are scarce, despite this condition being the predominant cause of excess mortality. We aimed to address this question using real-world data from the European Adrenal Insufficiency Registry (EU-AIR). Design/methods: EU-AIR, comprising of 19 centres across Germany, the Netherlands, Sweden and the UK, commenced enrolling patients with AI in August 2012. Patients receiving prednisolone (3-6 mg/day, n = 50) or hydrocortisone (15-30 mg/day, n = 909) were identified and grouped at a ratio of 1: 3 (prednisolone: hydrocortisone) by matching for gender, age, duration and type of disease. Data from baseline and follow-up visits were analysed. Data from patients with congenital adrenal hyperplasia were excluded. Results: Significantly higher mean +/- s. d. total (6.3 +/- 1.6 vs 5.4 +/- 1.1 mmol/L; P = 0.003) and low-density lipoprotein (LDL) cholesterol levels (3.9 +/- 1.4 vs 3.2 +/- 1.0 mmol/L; P = 0.013) were identified in 47 patients on prednisolone vs 141 receiving hydrocortisone at baseline and at follow-up (P = 0.005 and P = 0.006, respectively). HbA1c, high-density lipoprotein and triglyceride levels, body mass index, systolic and diastolic blood pressure and waist circumference were not significantly different. Conclusions: This is the first matched analysis of its kind. Significantly higher LDL levels in patients receiving prednisolone relative to hydrocortisone could predict a higher relative risk of cardiovascular disease in the former group.

  • 33.
    Quinkler, Marcus
    et al.
    Endocrinol Charlottenburg, Germany.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Zhang, Pinggao
    Shire, MA USA.
    Isidori, Andrea M.
    Sapienza Univ Rome, Italy.
    Murray, Robert D.
    Leeds Teaching Hosp NHS Trust, England.
    Mortality data from the European Adrenal Insufficiency RegistryPatient characterization and associations2018In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 89, no 1, p. 30-35Article in journal (Refereed)
    Abstract [en]

    ObjectiveMortality from primary and secondary adrenal insufficiency (AI; PAI and SAI, respectively) is 2-3-fold higher than in the general population. Mortality relates to cardiovascular disease, acute adrenal crisis (AC), cancer and infections; however, there has been little further characterization of patients who have died. Design/MethodsWe analysed real-world data from 2034 patients (801 PAI, 1233 SAI) in the European Adrenal Insufficiency Registry (EU-AIR; NCT01661387). Baseline clinical and biochemical data of patients who subsequently died were compared with those who remained alive. ResultsFrom August 2012 to June 2017, 26 deaths occurred (8 PAI, 18 SAI) from cardiovascular disease (n=9), infection (n=4), suicide (n=2), drug-induced hepatitis (n=2), and renal failure, brain tumour, cachexia and AC (each n=1); cause of death was unclear in 5 patients. Patients who died were significantly older at baseline than alive patients. Causes of AI were representative of patients with SAI; however, 3-quarters of deceased patients with PAI had undergone bilateral adrenalectomy (3 with uncontrolled Cushings disease, 3 with metastatic renal cell cancer). There were no significant differences in body mass index, blood pressure, low-density lipoprotein cholesterol, total cholesterol or electrolytes between deceased and alive patients. Deceased patients with SAI were more frequently male individuals, were receiving higher daily doses of hydrocortisone (24.07.6 vs 19.3 +/- 5.7mg, P=.0016) and experienced more frequent ACs (11.1 vs 2.49/100 patient-years, P=.0389) than alive patients. ConclusionsThis is the first study to provide detailed characteristics of deceased patients with AI. Older, male patients with SAI and frequent AC had a high mortality risk.

  • 34.
    Ragnarsson, Oskar
    et al.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Olsson, Daniel S.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Chantzichristos, Dimitrios
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Papakokkinou, Eleni
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Dahlqvist, Per
    Umea Univ, Sweden.
    Segerstedt, Elin
    Umea Univ, Sweden.
    Olsson, Tommy
    Umea Univ, Sweden.
    Petersson, Maria
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Berinder, Katarina
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Bensing, Sophie
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Hoybye, Charlotte
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Engstrom, Britt Eden
    Uppsala Univ Hosp, Sweden.
    Burman, Pia
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Bonelli, Lorenza
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Follin, Cecilia
    Skane Univ Hosp, Sweden.
    Petranek, David
    Skane Univ Hosp, Sweden.
    Erfurth, Eva Marie
    Skane Univ Hosp, Sweden.
    Wahlberg, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Akerman, Anna-Karin
    Orebro Univ, Sweden.
    Schwarcz, Erik
    Orebro Univ, Sweden.
    Bryngelsson, Ing-Liss
    Orebro Univ Hosp, Sweden.
    Johannsson, Gudmundur
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    The incidence of Cushings disease: a nationwide Swedish study2019In: Pituitary, ISSN 1386-341X, E-ISSN 1573-7403, Vol. 22, no 2, p. 179-186Article in journal (Refereed)
    Abstract [en]

    BackgroundStudies on the incidence of Cushings disease (CD) are few and usually limited by a small number of patients. The aim of this study was to assess the annual incidence in a nationwide cohort of patients with presumed CD in Sweden.MethodsPatients registered with a diagnostic code for Cushings syndrome (CS) or CD, between 1987 and 2013 were identified in the Swedish National Patient Registry. The CD diagnosis was validated by reviewing clinical, biochemical, imaging, and histopathological data.ResultsOf 1317 patients identified, 534 (41%) had confirmed CD. One-hundred-and-fifty-six (12%) patients had other forms of CS, 41 (3%) had probable but unconfirmed CD, and 334 (25%) had diagnoses unrelated to CS. The mean (95% confidence interval) annual incidence between 1987 and 2013 of confirmed CD was 1.6 (1.4-1.8) cases per million. 1987-1995, 1996-2004, and 2005-2013, the mean annual incidence was 1.5 (1.1-1.8), 1.4 (1.0-1.7) and 2.0 (1.7-2.3) cases per million, respectively. During the last time period the incidence was higher than during the first and second time periods (Pamp;lt;0.05).ConclusionThe incidence of CD in Sweden (1.6 cases per million) is in agreement with most previous reports. A higher incidence between 2005 and 2013 compared to 1987-2004 was noticed. Whether this reflects a truly increased incidence of the disease, or simply an increased awareness, earlier recognition, and earlier diagnosis can, however, not be answered. This study also illustrates the importance of validation of the diagnosis of CD in epidemiological research.

  • 35.
    Ragnarsson, Oskar
    et al.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Olsson, Daniel S.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Papakokkinou, Eleni
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Chantzichristos, Dimitrios
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Dahlqvist, Per
    Umea Univ, Sweden.
    Segerstedt, Elin
    Umea Univ, Sweden.
    Olsson, Tommy
    Umea Univ, Sweden.
    Petersson, Maria
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Berinder, Katarina
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Bensing, Sophie
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Hoybye, Charlotte
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Eden-Engstrom, Britt
    Uppsala Univ Hosp, Sweden.
    Burman, Pia
    Lund Univ, Sweden.
    Bonelli, Lorenza
    Lund Univ, Sweden.
    Follin, Cecilia
    Skane Univ Hosp, Sweden.
    Petranek, David
    Skane Univ Hosp, Sweden.
    Erfurth, Eva Marie
    Skane Univ Hosp, Sweden.
    Wahlberg, Jeanette
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Akerman, Anna-Karin
    Orebro Univ, Sweden.
    Schwarcz, Erik
    Orebro Univ, Sweden.
    Bryngelsson, Ing-Liss
    Orebro Univ Hosp, Sweden.
    Johannsson, Gudmundur
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Overall and Disease-Specific Mortality in Patients With Cushing Disease: A Swedish Nationwide Study2019In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 104, no 6, p. 2375-2384Article in journal (Refereed)
    Abstract [en]

    Context: Whether patients with Cushing disease (CD) in remission have increased mortality is still debatable. Objective: To study overall and disease-specific mortality and predictive factors in an unselected nationwide cohort of patients with CD. Design, Patients, and Methods: A retrospective study of patients diagnosed with CD, identified in the Swedish National Patient Registry between 1987 and 2013. Medical records were systematically reviewed to verify the diagnosis. Standardized mortality ratios (SMRs) with 95% CIs were calculated and Cox regression models were used to identify predictors of mortality. Results: Of 502 identified patients with CD (n = 387 women; 77%), 419 (83%) were confirmed to be in remission. Mean age at diagnosis was 43 (SD, 16) years and median follow-up was 13 (interquartile range, 6 to 23) years. The observed number of deaths was 133 vs 54 expected, resulting in an overall SMR of 2.5 (95% CI, 2.1 to 2.9). The commonest cause of death was cardiovascular diseases (SMR, 3.3; 95% CI, 2.6 to 4.3). Excess mortality was also found associated with infections and suicide. For patients in remission, the SMR was 1.9 (95% CI, 1.5 to 2.3); bilateral adrenalectomy and glucocorticoid replacement therapy were independently associated with increased mortality, whereas GH replacement was associated with improved outcome. Conclusion: Findings from this large nationwide study indicate that patients with CD have excess mortality. The findings illustrate the importance of achieving remission and continued active surveillance, along with adequate hormone replacement and evaluation of cardiovascular risk and mental health.

  • 36.
    Rosén, Thord
    et al.
    Sahlgrenska universitetssjukhuset, Göteborg .
    Burman, Pia
    Skånes universitetssjukhus, Malmö.
    Dahlqvist, Per
    Norrlands universitetssjukhus, Umeå.
    Dahm, Peter
    Sahlgrenska universitetssjukhuset, Göteborg .
    Edén-Engström, Britt
    Akademiska sjukhuset, Uppsala.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology.
    Höybye, Charlotte
    Karolinska universitetssjukhuset, Stockholm.
    Jakobsson, Karl-Erik
    Sahlgrenska universitetssjukhuset, Göteborg.
    Koskinen, Lars-Owe
    Norrlands universitetssjukhus, Umeå.
    Tölli, Anna
    Danderyds sjukhus, Stockholm.
    Valdemarsson, Stig
    Skånes universitetssjukhus, Lund.
    Ulfarsson, Traudur
    Högsbo sjukhus, Göteborg.
    Traumatisk hjärnskada kan ge hypofyssvikt2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 12, p. 629-632Article in journal (Refereed)
    Abstract [sv]

    Traumatisk hjärnskada (traumatic brain injury, TBI) är en av de vanligaste orsakerna till död och nedsatt funktion hos människor i arbetsför ålder.

    Patienter som överlever svåra skallskador utgör en växande patientkategori inom dagens sjukvård.

    På senare år har det aktualiserats att allvarligt skalltrauma kan ge skador i hypofys–hypotalamusregionen.

    Det är angeläget att dessa patienter utreds för eventuell hypofyssvikt så att hormonell substitutionsterapi kan inledas om endokrin insufficiens fastställs. Detta kan förhoppningsvis underlätta efterföljande rehabilitering och därmed förbättra pro­gnosen.

    Vi presenterar här ett förslag till riktlinjer för utvärdering av hypofysfunktionen hos TBI-patienter. Samtidigt vill  vi informera en bredare läsekrets om TBI-begreppet.

  • 37.
    Svanberg, Christina
    et al.
    Region Östergötland, Public Dental Health Care. County Council Jamtland, Sweden.
    Norevall, Lars-Inge
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ekman, Bertil
    Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Wahlberg Topp, Jeanette
    Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Bågesund, Mats
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Public Dental Health Care.
    Cephalometric analysis of adults with Turner syndrome2016In: Swedish Dental Journal, ISSN 0347-9994, Vol. 40, no 1, p. 33-41Article in journal (Refereed)
    Abstract [en]

    Turner syndrome (TS) is a genetic disorder of females with a prevalence of 1/2000-3000 live female births. The aim of this study was to compare cephalometric variables from adult women diagnosed with TS to a standardized reference group of 31-year old healthy women, and to evaluate the possible effects of human growth hormone (hGH) therapy in women with TS. Registered TS subjects in the Southeast region of Sweden were invited to take part in the study. Twenty-one women aged 36 +/- 13(18-57) years accepted participation. Lateral radiographs of the head were analyzed using standard cephalometric methods (Hasund analysis) and with the commercially available soft-ware program FACAD. Comparisons were made with roentgen-cephalometric standards from a reference group of nineteen 31-year old Swedish women. Analysis of the cephalometric radiographs from the TS subjects showed a more retrognathic maxilla (SNA 80.3 +/- 5.4) (p=0.0460) and mandible (SNB 77.0 +/- 5.2) (p=0.0014), and a correspondingly backward position of the chin (SN/Pg 78.9 +/- 5.5) (p=0.0046) as compared to the reference values of 31-year old women (SNA 83.2 +/- 3.0, SNB 81.5 +/- 2.3 and SNPg 83.0 +/- 2.3, respectively). In addition there was an increased posterior inclination of the maxilla (SN/NL 8.6 +/- 4.1), as compared to the reference values (SN/NL 5,3 +/- 2.7) (p=0.0048). There were no significant differences regarding sagittal or vertical jaw relations, mandibular inclination or cranial base angle between the TS-group and the 31-year olds with the reference values. No significant difference was seen in jaw relationship, as measured by the ANB value, however the Wits(index) (3.3 +/- 3.5) was higher (p=0.0001) than the reference values (-0.1 +/- 1.8). Subjects with or without previous hGH administration did not show any significant differences in cephalometric values. In conclusion, women with TS had a significantly more retrognathic maxilla (SNA) and mandible (SNB) and a correspondingly significantly posterior position of the chin (SN/Pg), a significantly increased posterior inclination of the maxilla (SN/NL) and a significantly increased Witsindex as compared to the reference group of 31-year old women. No craniofacial variables differed significantly between previously hGH-treated and not hGH-treated women with TS.

  • 38.
    Touraine, Philippe A
    et al.
    GH Pitie Salpetriere, Paris, France .
    DSouza, Gwyn
    Pfizer, New York, NY 10017 USA .
    Kourides, Ione
    Pfizer, New York, NY 10017 USA .
    Abs, Roger
    University Antwerp, Antwerp, Belgium .
    Barclay, Paul
    Pfizer, New York, NY 10017 USA .
    Torres, Elena
    Hospital University San Cecilio Granada, Granada, South Africa .
    Ekman, Bertil
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Lipoatrophy in growth hormone deficient patients treated with a long-acting pegylated growth hormone in HORMONE RESEARCH, vol 72, issue , pp 199-2002009In: HORMONE RESEARCH, 2009, Vol. 72, p. 199-200Conference paper (Refereed)
    Abstract [en]

    n/a

  • 39.
    Touraine, Philippe
    et al.
    Department of Endocrinology and Reproductive Medicine, GH Pitié Salpêtrière, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Université Paris VI Pierre et Marie Curie.
    D'Souza, Gwyn A
    Department of Endocrinology and Reproductive Medicine, GH Pitié Salpêtrière, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Université Paris VI Pierre et Marie Curie.
    Kourides, Ione
    Pfizer Limited, Sandwich, Kent, UK.
    Abs, Roger
    Pfizer, New York, New York, USA.
    Barclay, Paul
    Pfizer Limited, Sandwich, Kent, UK.
    Xie, Rujia
    Department of Endocrinology and Reproductive Medicine, GH Pitié Salpêtrière, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Université Paris VI Pierre et Marie Curie.
    Pico, Antonio
    University of Antwerp.
    Torres-Vela, Elena
    Hospital General Universitario de Alicante.
    Ekman, Bertil
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL. Linköping University, Faculty of Health Sciences.
    Lipoatrophy in GH deficient patients treated with a long-acting pegylated GH2009In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 161, p. 533-540Article in journal (Refereed)
    Abstract [en]

    Objective: Changes observed during adult GH deficiency (GHD) are most often reversed with the administration of recombinant human GH (rhGH). To avoid daily injections, a long-acting GH molecule has been obtained by covalent binding of polyethylene glycol (PEG) with rhGH (PEG–GH), allowing weekly s.c. injections. This study was designed to assess its efficacy and safety, in adult GHD subjects.

    Design and methods: This was a randomized, double-blind, placebo-controlled, multiple-dose, parallel group study. Subjects were recruited from 34 centers. A total of 105 subjects with GHD were assigned a treatment. They received 6 weekly injections of either PEG–GH or placebo. Subjects were randomized into one out of four treatment groups (Groups A–D) or placebo (Group E). Groups A, B, and C received 1, 3, and 4 mg PEG–GH respectively, for the first 3 weeks followed by 2, 6, and 8 mg PEG–GH respectively, for the remaining 3 weeks. Group D received 4 mg PEG–GH for 6 weeks. Group E received placebo. The study was suspended because of the development of lipoatrophy in certain subjects and restarted with an injection rotation plan, before being terminated due to further subjects developing lipoatrophy.

    Results: A total of 13 cases of injection-site lipoatrophy were reported, of which ten were in females and three occurred after the first injection; all cases were independent of PEG–GH dose or IGF1 levels, either basal or under treatment.

    Conclusion: The unpredictable occurrence of injection-site lipoatrophy with weekly long-acting pegylated GH molecules may be a limiting factor for their development.

  • 40.
    Wahlberg, J
    et al.
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Bachrach-Lindström, Margareta
    Linköping University, Department of Medicine and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ekman, Bertil
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Alterations in the Chemokine Th1/Th2 Balance and Not the Mode of Dosing Hydrocortisone May Explain the Increased Fatigue in Addisons Disease. in ENDOCRINE REVIEWS, vol 31, issue 3, pp2010In: ENDOCRINE REVIEWS, Endocrine Society , 2010, Vol. 31, no 3Conference paper (Refereed)
    Abstract [en]

    n/a

  • 41.
    Wahlberg, Jeanette
    et al.
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Endocrinology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Atypical or typical adrenocorticotropic hormone-producing pulmonary carcinoids and the usefulness of 11C-5-hydroxytryptophan positron emission tomography: two case reports2013In: Journal of Medical Case Reports, ISSN 1752-1947, E-ISSN 1752-1947, Vol. 7, p. 80-Article in journal (Refereed)
    Abstract [en]

    Introduction

    Pulmonary carcinoids associated with ectopic adrenocorticotropic hormone secretion have a good prognosis if histological examination shows typical pulmonary carcinoid and low proliferation, whereas a poor outcome is linked to atypical pulmonary carcinoid and high proliferation. Here we describe the diagnostic challenges to find the tumor in Cushing’s syndrome secondary to ectopic adrenocorticotropic hormone secretion in two cases with an atypical and a typical pulmonary carcinoid, respectively.     

    Case presentation

    A 63-year-old Caucasian woman presented with aggressive clinical features related to Cushing’s syndrome, having very high levels of urinary cortisol and circulating adrenocorticotropic hormone and cortisol. Magnetic resonance imaging showed no pituitary tumor, and bilateral inferior petrosal sinus sampling revealed no central peripheral ratio of adrenocorticotropic hormone. Computed tomography and 111Indium-pentetreoide somatostatin receptor scintigraphy could not visualize any ectopic tumor. The patient was referred for an 11C-5-hydroxytryptophan positron emission tomography, and a small 8mm nodule in her left lung was found. The tumor was removed via a lateral thoracic incision and wedge excision. The histological examination showed an atypical carcinoid with Ki-67 index of 9 to 10%, and an additional lobectomy was performed.     

    The second patient, a 22-year-old Caucasian man, also presented with aggressive Cushing’s syndrome, with very high urinary cortisol levels and increased circulating cortisol as well as adrenocorticotropic hormone levels. A magnetic resonance imaging scan of the pituitary showed no tumor, whereas a 12×9×14mm tumor was detected in the right lung on the primary computed tomography scan and no further investigation was performed. The tumor was removed via a lateral thoracic incision and wedge excision. A typical carcinoid with Ki-67 index of 1 to 2% was found and no further surgery was performed.     

    After surgical removal, the biochemical disturbances resolved and significant clinical improvement were achieved in both patients after 24 months of follow up.     

    Conclusions

    Diagnostic evaluation time is limited due to the aggressive course in ectopic adrenocorticotropic hormone-dependent Cushing’s syndrome. We suggest that 11C-5-hydroxytryptophan positron emission tomography could be considered early as a secondary diagnostic tool when primary computed tomography and/or magnetic resonance imaging scans fail to show any tumor.

  • 42.
    Wahlberg, Jeanette
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Department of Clinical and Experimental Medicine.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Most Women with Previous Gestational Diabetes Mellitus Have Impaired Glucose Metabolism after a Decade2018In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 19, no 12, article id 3724Article in journal (Refereed)
    Abstract [en]

    Of 1324 women diagnosed with gestational diabetes mellitus (GDM) in Sweden, 25% reported amp;gt;10 years after the delivery that they had developed diabetes mellitus. We assessed the long-term risk of all glucose metabolic abnormalities in a subgroup of these women. Women (n = 51) previously diagnosed with GDM by capillary blood glucose amp;gt;= 9.0 mmol/L (approximate to plasma glucose amp;gt;= 10.0 mmol/L) after a 2 h 75 g oral glucose tolerance test (OGTT) were included. All underwent a clinical and biochemical evaluation, including a second 2 h 75 g OGTT. Individuals with known type 1 diabetes were excluded. At the follow-up, 12/51 (24%) reported previously diagnosed type 2 diabetes. Another four cases were diagnosed after the second OGTT, increasing the prevalence to 16/51 cases (31%). Impaired fasting plasma glucose (IFG) was diagnosed in 13/51 women and impaired glucose tolerance (IGT) in 10/51 women, leaving only 12 women (24%) with normal glucose tolerance. In addition, 2/51 women had high levels of glutamic acid decarboxylase (GAD) antibodies; of these, one woman classified as type 2 diabetes was reclassified as type 1 diabetes, and the second GAD-positive woman was diagnosed with IGT. Of the women diagnosed with GDM by a 2 h 75 g OGTT, a large proportion had impaired glucose metabolism a decade later, including type 1 and type 2 diabetes.

  • 43.
    Wahlberg, Jeanette
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Sydsjö, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Ledin, Torbjön
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Bågesund, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Public Dental Health Care, Centre for Orthodontics and Paediatric Dentistry.
    Ekman, Bertil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Impaired Postural Balance in Turner Syndrom2013In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 45, no 7, p. 537-540Article in journal (Refereed)
    Abstract [en]

    An impaired body balance has been found in Turner syndrome (TS) in clinical tests like Rombergs’s test and walking on a balance beam. The aim of the study was to assess postural balance in TS subjects with specific balance testing using dynamic posturography and relate to body composition. Nineteen TS subjects (20–57 years) were included. Balance was measured with dynamic posturography (Equitest) and compared with 19 sex and age-matched controls (22–59 years). Equitest, visual, vestibular, and somatosensory systems were provoked with increasing difficulty (6 tests, SO1–SO6) and body sway was measured with a dual forceplate. Body composition was measured with DXA. No difference was found between the TS subjects and the controls on fixed platform with open eyes (SO1), with closed eyes (SO2), with stable platform and visual disorientation (SO3), or on unstable platform with open eyes (SO4). In the difficult tests on unstable platform the TS subjects did worse compared with controls both in the test with eyes closed (SO5), p<0.01, and in the test with visual disorientation (SO6), p<0.05. Composite (a merge of all six recordings) was significantly lower in the TS-group, p<0.05. In the TS group high total body weight was related to worse outcome on tests SO5, SO6, and composite, while total bone mass, age, height, or waist showed no significant association with balance scores. Our findings indicate that TS could have an increased risk for falling due to impaired ability to manage complex coordination tasks.

  • 44.
    Wahlberg Topp, Jeanette
    et al.
    Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Ekman, Bertil
    Region Östergötland, Heart and Medicine Center, Department of Endocrinology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Nystrom, Lennarth
    Umeå University, Sweden.
    Hanson, Ulf
    Uppsala University, Sweden.
    Persson, Bengt
    Karolinska Institute, Sweden.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Gestational diabetes: Glycaemic predictors for fetal macrosomia and maternal risk of future diabetes2016In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 114, p. 99-105Article in journal (Refereed)
    Abstract [en]

    Aims: To investigate how glucose levels at diagnosis of gestational diabetes (GDM) are associated with infant birth weight and long-term risk of manifest diabetes mellitus in the mother. Methods: In a case control study GDM pregnancies (n = 2085) were compared with non-GDM pregnancies matched for day of delivery and obstetric unit (n = 3792). GDM was defined as capillary blood glucose (cB-glucose) &gt;9.0 mmol/l (plasma glucose &gt;10.0 mmol/l) after a 75 g oral glucose tolerance test (OGTT). The GDM cohort were followed up 8.5-13.5 yrs after initial diagnosis with a questionnaire, answered by 1324 GDM women (65%). Results: GDM women had higher mean infant birth-weight compared with controls (3682 g vs. 3541 g, P &lt; 0.001). In multiple linear regression analysis, birth weight was positively correlated to fasting cB-glucose at GDM diagnosis (P &lt; 0.001), increased week of gestation (P &lt; 0.001) and BMI before pregnancy (P &lt; 0.003), while 2 h OGTT cB-glucose values &gt;= 9.0 mmol/l were not related. Infants born to mothers with fasting cB-glucose &gt;= 4.5 mmol/l had no increased mean birth-weight or macrosomia (&gt;= 4500 g) compared to controls. In the follow up 334/1324 women (25%) of the GDM women had developed diabetes, 215 type 2 diabetes, 46 type 1 diabetes and 72 unclassified diabetes. In logistic regression fasting cB-glucose and 2 h OGTT cB-glucose at diagnosis of GDM as well as BMI &gt;25 and origin outside Europe were risk factors for manifest diabetes. Conclusions: Fasting blood glucose at diagnosis of GDM gives important information besides 2 h OGTT glucose about pregnancy outcome and future risk for maternal diabetes. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

  • 45.
    Wahlberg Topp, Jeanette
    et al.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Tillmar, Linda
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ekman, Bertil
    Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Landberg, Eva
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Effects of prolactin on platelet activation and blood clotting2013In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 73, no 3, p. 221-228Article in journal (Refereed)
    Abstract [en]

    Increased levels of prolactin often coincide with an increased risk for thromboembolic events, but it is unclear whether a direct causal relation exists. Our aim was to examine the effect of prolactin on platelet function. In addition to using recombinant prolactin for experiments in vitro, we analyzed platelet function by flow cytometry in a group of 13 females with hyperprolactinaemia and 18 healthy female controls. Platelet activation was measured by P-selectin expression and by the amount of platelet-bound fibrinogen after stimulation with adenosine diphosphate (ADP), collagen-related peptide and the protease activated receptor (thrombin receptor) (PAR)-activating peptides PAR4-AP and PAR1-AP. Free oscillation rheometry was used to measure clotting time in whole blood. No significant effect on platelet activation or clotting time could be seen in in vitro experiments by adding recombinant prolactin. However, significantly lower P-selectin expression was found in the hyperprolactinemic group when platelets were activated by ADP (5 and 10 mu M) or PAR4-AP. The expression of fibrinogen did not differ between the two groups for any of the activators used. For all samples, inverse significant correlations between P-selectin expression and prolactin concentration were found for both 5 mu M ADP (r = 0.61, p andlt; 0.01), 10 mu M ADP (r = -0.62, p andlt; 0.001) and PAR4-AP (r = -0.69, p andlt; 0.001). Thrombin cleavage of recombinant prolactin resulting in a 16 kDa C-terminal fragment did not alter the P-selectin expression upon activation. We found an indirect inhibitory effect of prolactin on platelets in hyperprolactinemic patients, suggesting that prolactin might have a protective role in thromboembolic disease.

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