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  • 1. Albertsson-Wikland, Kerstin
    et al.
    Aronson, A Stefan
    Gustafsson, Jan
    Hagenäs, Lars
    Ivarsson, Sten A
    Jonsson, Björn
    Kriström, Berit
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Marcus, Claude
    Nilsson, Karl Olof
    Ritzén, E Martin
    Tuvemo, Torsten
    Westphal, Otto
    Aman, Jan
    Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency.2008Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, nr 11, s. 4342-50Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: The effect of GH therapy in short non-GH-deficient children, especially those with idiopathic short stature (ISS), has not been clearly established owing to the lack of controlled trials continuing until final height (FH). OBJECTIVE: The aim of the study was to investigate the effect on growth to FH of two GH doses given to short children, mainly with ISS, compared with untreated controls. DESIGN AND SETTING: A randomized, controlled, long-term multicenter trial was conducted in Sweden. INTERVENTION: Two doses of GH (Genotropin) were administered, 33 or 67 microg/kg.d; control subjects were untreated. SUBJECTS: A total of 177 subjects with short stature were enrolled. Of these, 151 were included in the intent to treat (AllITT) population, and 108 in the per protocol (AllPP) population. Analysis of ISS subjects included 126 children in the ITT (ISSITT) population and 68 subjects in the PP (ISSPP) population. MAIN OUTCOME MEASURES: We measured FH sd score (SDS), difference in SDS to midparenteral height (diff MPHSDS), and gain in heightSDS. RESULTS: After 5.9+/-1.1 yr on GH therapy, the FHSDS in the AllPP population treated with GH vs. controls was -1.5+/-0.81 (33 microg/kg.d, -1.7+/-0.70; and 67 microg/kg.d, -1.4+/-0.86; P<0.032), vs. -2.4+/-0.85 (P<0.001); the diff MPHSDS was -0.2+/-1.0 vs. -1.0+/-0.74 (P<0.001); and the gain in heightSDS was 1.3+/-0.78 vs. 0.2+/-0.69 (P<0.001). GH therapy was safe and had no impact on time to onset of puberty. A dose-response relationship identified after 1 yr remained to FH for all growth outcome variables in all four populations. CONCLUSION: GH treatment significantly increased FH in ISS children in a dose-dependent manner, with a mean gain of 1.3 SDS (8 cm) and a broad range of response from no gain to 3 SDS compared to a mean gain of 0.2 SDS in the untreated controls.

  • 2. Albertsson-Wikland, Kerstin
    et al.
    Martensson, Anton
    Savendahl, Lars
    Niklasson, Aimon
    Bang, Peter
    Dahlgren, Jovanna
    Gustafsson, Jan
    Kriström, Berit
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Norgren, Svante
    Pehrsson, Nils-Gunnar
    Oden, Anders
    Mortality Is Not Increased in Recombinant Human Growth Hormone-treated Patients When Adjusting for Birth Characteristics2016Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, nr 5, s. 2149-2159Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: This study aimed to investigate whether reported high mortality in childhood recombinant human GH (rhGH)-treated patients was related to birth-characteristics and/or rhGH treatment.

    Design and Setting: We sought to develop a mortality model of the Swedish general population born between 1973 and 2010, using continuous-hazard functions adjusting for birth characteristics, sex, age intervals, and calendar year to estimate standardized mortality ratio (SMR) and to apply this model to assess expected deaths in Swedish rhGH-treated patients with idiopathic isolated GH deficiency (IGHD), idiopathic short stature (155) or born small for gestational age (SGA).

    Participants: The general population: Swedish Medical Birth Register (1973-2010: 1 880 668 males; 1 781 131 females) and Cause of Death Register (1985-2010).

    Intervention Population: Three thousand eight hundred forty-seven patients starting rhGH treatment between 1985 and 2010 and followed in the National GH Register and/or in rhGH trials diagnosed with IGHD (n = 1890), ISS (n = 975), or SGA (n=982).

    Main Outcome Measures: Death.

    Results: Using conventional models adjusting for age, sex, and calendar-year, the SMR was 1.43 (95% confidence interval, 0.89-2.19), P = .14, observed/expected deaths 21/14.68. The rhGH population differed (P < .001) from the general population regarding birth weight, birth length, and congenital malformations.

    Application of an Advanced Model: When applying the developed mortality model of the general population, the ratio of observed/expected deaths in rhGH-treated patients was 21/21.99; SMR = 0.955 (0.591-1.456)P = .95.

    Model Comparison: Expected number of deaths were 14.68 (14.35-14.96) using the conventional model, and 21.99 (21.24-22.81) using the advanced model, P < .001, which had at all ages a higher gradient of risk per SD of the model, 24% (range, 18-42%; P < .001).

    Conclusions: Compared with the general Swedish population, the ratio of observed/expected deaths (21/21.99) was not increased in childhood rhGH-treated IGHD, ISS, and SGA patients when applying an advanced sex-specific mortality model adjusting for birth characteristics.

  • 3. Beckmann, L
    et al.
    Hüsing, A
    Setiawan, VW
    Amiano, P
    Clavel-Chapelon, F
    Chanock, SJ
    Cox, DG
    Diver, R
    Dossus, L
    Feigelson, HS
    Haiman, C
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Hayes, RB
    Henderson, BE
    Hoover, RN
    Hunter, DJ
    Khaw, K
    Kolonel, LN
    Kraft, P
    Lund, E
    Le Marchand, L
    Peeters, PHM
    Riboli, E
    Stram, D
    Thomas, G
    Thun, MJ
    Tumino, R
    Trichopoulos, D
    Vogel, U
    Willett, WC
    Yeager, M
    Ziegler, R
    Hankinson, SE
    Kaaks, R
    Comprehensive analysis of hormone and genetic variation in 36 genes related to steroid hormone metabolism in pre- and postmenopausal women from the breast and prostate cancer cohort consortium (BPC3)2011Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 96, nr 2, s. E360-E367Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We confirmed associations between serum levels of SHBG and the SHBG gene and of E1 and E2 and the CYP19 and ESR1 genes. Novel associations were observed between FSHR and DHEAS, E1, and E2 and between AKR1C3 and DHEAS.

  • 4. Bengtsson, Daniel
    et al.
    Joost, Patrick
    Aravidis, Christos
    Stenmark, Marie Askmalm
    Backman, Ann-Sofie
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    von Salome, Jenny
    Zagoras, Theofanis
    Gebre-Medhin, Samuel
    Burman, Pia
    Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort2017Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, nr 11, s. 3928-3932Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported.

    Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patient’s germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS.

    Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected).

    Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.

  • 5.
    Bergman, Jonathan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Nordström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Nordström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Alendronate use and the risk of nonvertebral fracture during glucocorticoid therapy: a retrospective cohort study2018Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, nr 1, s. 306-313Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Glucocorticoids increase the risk of nonvertebral fracture, but no clinical trial has shown that nonvertebral fractures can be prevented by co-administration of an anti-osteoporotic drug.

    Objective: To estimate the effect of alendronate on the risk of nonvertebral fracture in older adults taking oral glucocorticoids.

    Design: Retrospective cohort study using national Swedish registers.

    Setting: Hospitalized care and ambulatory specialist care.

    Patients: Among adults aged 50 years or older (N=3,347,959), we identified those who initiated oral glucocorticoid therapy from 2006 through 2011 (≥2.5 mg/day of prednisone or equivalent for ≥91 days). The final analysis included 16,890 alendronate users and 16,890 nonusers, who were matched using time-dependent propensity scores.

    Main Outcome Measure: Nonvertebral fracture. This was not pre-specified.

    Results: Over a median follow-up of 14.5 months, the incidence rate of nonvertebral fracture was 2.0 cases per 100 person-years in alendronate users and 2.4 cases in nonusers. This difference corresponded to a 16% lower rate in users (hazard ratio 0.84, 95% confidence interval 0.75 to 0.94). For hip fractures specifically, the rate was 34% lower in alendronate users relative to nonusers (hazard ratio 0.66, 95% confidence interval 0.55 to 0.78). The association of alendronate use with a lower risk of nonvertebral fracture was strongest in patients who received high doses of glucocorticoid.

    Conclusion: Alendronate use was associated with a lower risk of nonvertebral fracture, including hip fracture. Similar, but not statistically significant, associations have been reported in meta-analyses of clinical trials.

  • 6. Bjarnason, R
    et al.
    Andersson, B
    Kim, H S
    Olsson, B
    Swolin-Eide, D
    Wickelgren, R
    Kriström, B
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Carlsson, B
    Albertsson-Wikland, K
    Carlsson, L M S
    Cartilage oligomeric matrix protein increases in serum after the start of growth hormone treatment in prepubertal children.2004Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 89, nr 10, s. 5156-60Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Both GH and IGF-I stimulate bone growth, but the molecular mechanisms mediating their effects on the growth plate are not fully understood. We measured gene expression by microarray analysis in primary cultured human chondrocytes treated with either GH or IGF-I. One of the genes found to be up-regulated by both GH and IGF-I was that encoding cartilage oligomeric matrix protein (COMP). This protein is predominantly found in the extracellular matrix of cartilage. Mutations in the COMP gene have been associated with syndromes of short stature. To verify that COMP is regulated by GH in vivo, we measured COMP levels in serum in short children treated with GH. The study included 113 short prepubertal children (14 girls and 99 boys) with a mean (+/- sd) age of 8.84 +/- 2.76 yr, height sd score of -2.74 +/- 0.67, and IGF-I sd score of -1.21 +/- 1.07 at the start of GH administration. Serum levels of COMP were 1.58 +/- 0.28, 1.83 +/- 0.28 (P < 0.0001), 1.91 +/- 0.28 (P < 0.0001), 1.78 +/- 0.28 (P < 0.001), and 1.70 +/- 0.24 (P < 0.05) microg/ml at baseline and after 1 wk and 1, 3, and 12 months, respectively. In conclusion, we have demonstrated that COMP expression is up-regulated by both GH and IGF-I in primary cultured human chondrocytes. Furthermore, serum levels of COMP increase after the start of GH treatment in short children.

  • 7.
    Björn, Inger
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Sundström-Poromaa, Inger
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Bixo, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Nyberg, Sigrid
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Bäckström, Gunnel
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Bäckström, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Increase of estrogen dose deteriorates mood during progestin phase in sequential hormonal therapy2003Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 88, nr 5, s. 2026-2030Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Previous studies have indicated that the addition of progestinsduring sequential hormonal replacement therapy (HRT)causes negative mood and physical symptoms. History of premenstrualsyndrome, type of progestin, and dose of progestinhave thus far been shown to influence the progestin-inducedadverse mood symptoms during HRT.

    The aim of this study was to compare adverse mood effectsof two different doses of estradiol, in combination with a progestin,during postmenopausal HRT. Twenty-eight perimenopausalwomen were included in this randomized, doubleblind,crossover study comparing 2- or 3-mg continuousestradiol, with an addition of 10 mg medroxyprogesteroneacetate on d 17–28 during each treatment cycle. The mainoutcome measures were mood and physical symptoms kept ona daily rating scale. Together with the progestin, the higherdose of estrogen caused significantly more negative moodsymptoms than the lower dose. Tension, irritability, and depressedmood were all significantly augmented during theprogestin phase of cycles with 3mg estradiol (P<0.001). Physicalsymptoms also increased during the progestin phase of3-mg estradiol cycles (P<0.001), whereas positive mood symptomswere less affected. The only positive mood that changedwith estrogen dose was friendliness, which decreased duringthe progestin phase of high estradiol cycles compared withcycles with lower estradiol (P < 0.05).

    Our conclusion is that an increase of the estrogen doseaccentuates negativemoodand physical symptoms during theprogestin phase of sequential hormonal therapy.

  • 8. Burman, P.
    et al.
    Mattsson, A. F.
    Johannsson, G.
    Höybye, C.
    Holmer, H.
    Dahlqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Berinder, K.
    Engström, B. E.
    Ekman, B.
    Erfurth, E. M.
    Svensson, J
    Wahlberg, J.
    Karlsson, F. A.
    Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality2013Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, nr 4, s. 1466-1475Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified.

    Objective: To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up.

    Design 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.

    Main Outcome Measures: Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up.

    Results: 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.

    Conclusion: 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.

  • 9.
    Casar-Borota, Olivera
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Oslo University Hospital, University of Oslo and Uppsala University.
    Heck, Ansgar
    Schulz, Stefan
    Nesland, Jahn Marthin
    Ramm-Pettersen, Jon
    Lekva, Tove
    Alafuzoff, Irina
    Bollerslev, Jens
    Expression of SSTR2a, but not of SSTRs 1, 3, or 5 in Somatotroph Adenomas Assessed by Monoclonal Antibodies Was Reduced by Octreotide and Correlated With the Acute and Long-Term Effects of Octreotide2013Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, nr 11, s. E1730-E1739Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Reduced expression of somatostatin receptors (SSTRs) in somatotroph adenomas and their potential down-regulation after medical treatment may explain the unsatisfactory response to octreotide in particular acromegalic patients. The expression of SSTRs other than SSTR2a has not been studied in large, unselected cohorts using novel rabbit monoclonal antibodies. Objective: We aimed to determine the expression of SSTRs 1, 2a, 3, and 5 in somatotroph adenomas, to correlate expression with clinical characteristics and the response to octreotide, and to ascertain whether preoperative octreotide treatment affected SSTR expression. Design, Setting, Patients: The study included 78 adenomas from patients operated on consecutively during 2000 to 2010. After exclusion of 13 patients, immunohistochemical analysis with rabbit monoclonal antibodies against SSTRs 1, 2a, 3, and 5 (clones UMB-7, -1, -5, and -4) was performed on 65 adenomas. Intervention: Twenty-eight patients received preoperative octreotide, and 37 patients were operated on without pretreatment. Twenty-six patients were randomized to direct surgery (n = 13) or to octreotide pretreatment (n = 13). Main Outcome Measure: SSTR expression was evaluated using a 12-grade scoring system. The responses to the octreotide test dose (GH reduction) and to 6 months of octreotide (IGF-I reduction) were measured. Results: The majority of adenomas showed membranous expression of SSTRs 2a and 5. SSTR2a expression was reduced in the pretreated group and correlated with the acute octreotide test results and the effect of octreotide treatment. In a linear regression model with SSTR2 a expression as the determinant, the correlation with the acute test response improved after adjustment for medical pretreatment. Conclusion: Rabbit monoclonal antibodies are reliable markers of SSTRs in somatotroph adenomas. SSTR2a expression correlated with the response to octreotide and was reduced after octreotide treatment, indicating the need for adjustment when SSTR2a expression is correlated with baseline characteristics. Evaluation of SSTR subtypes may be an important aspect of improving the medical treatment for acromegaly.

  • 10. Dahlman, Ingrid
    et al.
    Kaaman, Maria
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Tan, Garry D
    Bickerton, Alex S T
    Wåhlén, Kerstin
    Andersson, Jonas
    Department of Medicine, Umeå University Hospital, Umeå, Sweden.
    Arvidsson Nordström, Elisabet
    Blomqvist, Lennart
    Sjögren, Annelie
    Forsgren, Margaretha
    Attersand, Anneli
    Arner, Peter
    A unique role of monocyte chemoattractant protein 1 among chemokines in adipose tissue of obese subjects2005Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 90, nr 10, s. 5834-5840Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Low-grade inflammation in adipose tissue may contribute to insulin resistance in obesity. However, the roles of individual inflammatory mediators in adipose tissue are poorly understood. Objectives: The objective of this study was to determine which inflammation markers are most overexpressed at the gene level in adipose tissue in human obesity and how this relates to corresponding protein secretion. Design: We examined gene expression profiles in 17 lean and 20 obese subjects. The secretory pattern of relevant corresponding proteins was examined in human sc adipose tissue or isolated fat cells in vitro and in vivo in several obese or lean cohorts. Results: In ranking gene expression, defined pathways associated with obesity and immune and defense responses scored high. Among seven markedly overexpressed chemokines, only monocyte chemoattractant protein 1 (MCP1) was released from adipose tissue and isolated fat cells in vitro. In obesity, the secretion and expression of MCP1 in adipose tissue pieces were more than 6- and 2-fold increased, respectively, but there was no change in circulating MCP1 levels. There was no net release of MCP1, but there was a net release of leptin, in vivo from adipose tissue into the circulation. Conclusions: Obesity is associated with the increased expression of several chemokine genes in adipose tissue. However, only MCP1 is secreted into the extracellular space, where it primarily acts as a local factor, because little or no spillover into the circulation occurs. MCP1 influences the function of adipocytes, is a recruitment factor for macrophages, and may be a crucial link among chemokines between adipose tissue inflammation and insulin resistance.

  • 11. Dalin, Frida
    et al.
    Nordling Eriksson, Gabriel
    Dahlqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Hallgren, Åsa
    Wahlberg, Jeanette
    Ekwall, Olov
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Rönnelid, Johan
    Olcén, Per
    Winqvist, Ola
    Catrina, Sergiu-Bogdan
    Kriström, Berit
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Laudius, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Isaksson, Magnus
    Halldin Stenlid, Maria
    Gustafsson, Jan
    Gebre-Medhin, Gennet
    Björnsdottir, Sigridur
    Janson, Annika
    Åkerman, Anna-Karin
    Åman, Jan
    Duchen, Karel
    Bergthorsdottir, Ragnhildur
    Johannsson, Gudmundur
    Lindskog, Emma
    Landin-Olsson, Mona
    Elfving, Maria
    Waldenström, Erik
    Hulting, Anna-Lena
    Kämpe, Olle
    Bensing, Sophie
    Clinical and immunological characteristics of Autoimmune Addison's disease: a nationwide Swedish multicenter study2017Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, nr 2, s. 379-389Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.

    OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.

    DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.

    MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.

    RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p<0.0001). AAD patients had lower BMI (p<0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).

    CONCLUSIONS: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.

  • 12. Decker, Ralph
    et al.
    Albertsson-Wikland, Kerstin
    Kriström, Berit
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Halldin, Maria
    Gustafsson, Jan
    Nilsson, Nils-Östen
    Dahlgren, Jovanna
    GH Dose Reduction Maintains Normal Prepubertal Height Velocity After Initial Catch-Up Growth in Short Children2019Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 104, nr 3, s. 835-844Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: GH responsiveness guides GH dosing during the catch-up growth (CUG) period; however, little is known regarding GH dosing during the prepubertal maintenance treatment period.

    Objective: To evaluate whether SD score (SDS) channel parallel growth with normal height velocity can be maintained after CUG by reducing the GH dose by 50% in children receiving doses individualized according to estimated GH responsiveness during the catch-up period.

    Design and Settings: Prepubertal children (n = 98; 72 boys) receiving GH during CUG (GH deficient, n = 33; non–GH deficient, n = 65), were randomized after 2 to 3 years to either a 50% reduced individualized dose (GHRID; n = 27; 20 boys) or unchanged individualized dose (GHUID; n = 38; 27 boys). Another 33 children (25 boys) continued a standard weight-based dose [43 µg/kg/d (GHFIX)].

    Main Outcome Measures: The primary endpoint was the proportion of children with ΔheightSDS within ±0.3 at 1 year after GH dose reduction compared with two control groups: GHUIDand GHFIX. The hypothesis was that heightSDS could be maintained within ±0.3 with a reduced individualized GH dose.

    Results: For the intention-to-treat population at 1 year, 85% of the GHRIDgroup maintained ΔheightSDS within ±0.3 vs 41% in the GHUIDgroup (P = 0.0055) and 48% in the GHFIXgroup (P = 0.0047). The ΔIGF-ISDS in the GHRID group was −0.75 ± 1.0 at 3 months (P = 0.003) and −0.72 ± 1.2 at 1 year compared with the GHUID group (0.15 ± 1.2; P = 0.005) and GHFIX group (0.05 ± 1.0; P = 0.02).

    Conclusions: Channel parallel growth (i.e., normal height velocity) and IGF-ISDS levels within ±2 were maintained after completed CUG using a 50% lower individualized dose than that used during the CUG period.

  • 13. Elgzyri, T
    et al.
    Parikh, H
    Zhou, Y
    Nitert, M Dekker
    Ronn, T
    Segerstrom, AB
    Ling, C
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Wollmer, P
    Eriksson, KF
    Groop, L
    Hansson, O
    First-degree relatives of type 2 diabetic patients have reduced expression of genes involved in fatty acid metabolism in skeletal muscle2012Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, nr 7, s. E1332-E1337Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: First-degree relatives of patients with type 2 diabetes (FH+) have been shown to have decreased energy expenditure and decreased expression of mitochondrial genes in skeletal muscle. In previous studies, it has been difficult to distinguish whether mitochondrial dysfunction and differential regulation of genes are primary (genetic) or due to reduced physical activity, obesity, or other correlated factors.

    Objective: The aim of this study was to investigate whether mitochondrial dysfunction is a primary defect or results from an altered metabolic state.

    Design: We compared gene expression in skeletal muscle from 24 male subjects with FH and 26 without FH matched for age, glucose tolerance, VO2peak (peak oxygen uptake), and body mass index using microarrays. Additionally, type fiber composition, mitochondrial DNA content, and citrate synthase activity were measured. The results were followed up in an additional cohort with measurements of in vivo metabolism. Results: FH+ vs. FH- subjects showed reduced expression of mitochondrial genes (P = 2.75 x 10(-6)), particularly genes involved in fatty acid metabolism (P = 4.08 x 10(-7)), despite similar mitochondrial DNA content. Strikingly, a 70% reduced expression of the monoamine oxidase A(MAOA) gene was found in FH+ vs. FH- individuals (P = 0.0009). Down-regulation of the genes involved in fat metabolism was associated with decreased in vivo fat oxidation and increased glucose oxidation examined in an additional cohort of elderly men.

    Conclusions: These results suggest that genetically altered fatty acid metabolism predisposes to type 2 diabetes and propose a role for catecholamine-metabolizing enzymes like MAOA in the regulation of energy metabolism. (J Clin Endocrinol Metab 97: E1332-E1337, 2012)

  • 14. Eriksson, Daniel
    et al.
    Dalin, Frida
    Eriksson, Gabriel Nordling
    Landegren, Nils
    Bianchi, Matteo
    Hallgren, Asa
    Dahlqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Wahlberg, Jeanette
    Ekwall, Olov
    Winqvist, Ola
    Catrina, Sergiu-Bogdan
    Ronnelid, Johan
    Hulting, Anna-Lena
    Lindblad-Toh, Kerstin
    Alimohammadi, Mohammad
    Husebye, Eystein S.
    Knappskog, Per Morten
    Pielberg, Gerli Rosengren
    Bensing, Sophie
    Kampe, Olle
    Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS12018Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, nr 1, s. 179-186Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1.

    Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease.

    Design: We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE.

    Results: In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure.

    Conclusion: We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.

  • 15.
    Forsblad-d'Elia, Helena
    et al.
    Dept of Rheumatology and Inflammation Research, Sahlgrenska Academy, Göteborgs universitet.
    Carlsten, Hans
    Labrie, Fernand
    Konttinen, Yrjö T
    Ohlsson, Claes
    Low serum levels of sex steroids are associated with disease characteristics in primary Sjogren's syndrome; supplementation with dehydroepiandrosterone restores the concentrations.2009Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 94, nr 6, s. 2044-51Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: Serum levels of the sex steroid prohormones dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) decline upon aging and are reduced in primary Sjogren's syndrome.

    OBJECTIVE: Our aim was to investigate: 1) effects of 50 mg oral DHEA/day on changes in serum levels of DHEA and 12 of its metabolites; 2) relationships between steroid levels and disease characteristics; and 3) whether these parameters were influenced by DHEA.

    DESIGN: Twenty-three postmenopausal women with primary Sjogren's syndrome and subnormal levels of DHEA-S were included in a randomized, 9-month, controlled, double blind crossover study. Liquid chromatography/mass spectrometry (MS)/MS and gas chromatography/MS were used to measure the sex steroids. Anti-SS-A/Ro and/or anti-SS-B/La, salivary gland focus score, salivary flow rates, dry mouth and eye symptoms, and routine laboratory tests were assessed.

    RESULTS: Baseline erythrocyte sedimentation rate was inversely correlated with testosterone (Testo), dihydrotestosterone, and DHEA-S (rs = -0.42, -0.45, and -0.58, respectively). Dry mouth symptoms correlated with low Testo and androstenedione, whereas dry eyes correlated with low estrogens, most strongly estrone (rs = -0.63). Presence of anti-SS-A and/or anti-SS-B was independently associated with low estradiol (area under the receiver operating characteristic curve, 0.82). All metabolites increased during DHEA but not during placebo. The relative increases were less for estrogens and Testo compared to dihydrotestosterone and glucuronidated androgen metabolites. Dry mouth symptoms decreased during DHEA therapy.

    CONCLUSIONS: Disease manifestations in primary Sjogren's syndrome were associated with low sex hormone levels, dry mouth symptoms with low androgens, and dry eyes with low estrogens. Exogenous DHEA was preferentially transformed into androgens rather than into estrogens.

  • 16. Goedecke, Julia H
    et al.
    Evans, Juliet
    Keswell, Dheshnie
    Stimson, Roland H
    Livingstone, Dawn EW
    Hayes, Philip
    Adams, Kevin
    Dave, Joel A
    Victor, Hendriena
    Levitt, Naomi S
    Lambert, Estelle V
    Walker, Brian R
    Seckl, Jonathan R
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Kahn, Steven E
    Reduced gluteal expression of adipogenic and lipogenic genes in black south african women is associated with obesity-related insulin resistance2011Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 96, nr 12, s. E2029-E2033Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Black South African women are less insulin sensitive than their White counterparts, despite less central and greater peripheral fat deposition. We hypothesized that this paradox may be explained, in part, by differences in the adipogenic capacity of sc adipose tissue (SAT).

    Objective: Our objective was to measure adipogenic and lipogenic gene expression in abdominal and gluteal SAT depots and determine their relationships with insulin sensitivity (S(I)) in South African women.

    Participants and Design: Fourteen normal-weight [body mass index (BMI) <25 kg/m(2)] Black, 13 normal-weight White, 14 obese (BMI >30 kg/m(2)) Black, and 13 obese White premenopausal South African women participated in this cross-sectional study.Main outcomes:S(I) (frequently sampled iv glucose tolerance test) in relation to expression of adipogenic and lipogenic genes in abdominal and gluteal SAT depots.

    Results: With increasing BMI, Black women had less visceral fat (P = 0.03) and more abdominal (P = 0.017) and gynoid (P = 0.041) SAT but had lower S(I) (P < 0.01) than White women. The expression of adipogenic and lipogenic genes was proportionately lower with obesity in Black but not White women in the gluteal and deep SAT depots (P < 0.05 for ethnicity × BMI effect). In Black women only, the expression of these genes correlated positively with S(I) (all P < 0.05), independently of age and fat mass.

    Conclusions: Obese Black women have reduced SAT expression of adipogenic and lipogenic genes compared with White women, which associates with reduced S(I). These findings suggest that obesity in Black women impairs SAT adipogenesis and storage, potentially leading to insulin resistance and increased risk of type 2 diabetes.

  • 17. Gustafsson, Stefan
    et al.
    Lind, Lars
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Ingelsson, Erik
    Associations of circulating adiponectin with measures of vascular function and morphology2010Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, nr 6, s. 2927-2934Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Serum levels of adiponectin were positively associated with IM-GSM and plaque GSM (indicating lower fat content in the IM and plaques) and CCA distensibility (indicating higher wall elasticity), independent of potential confounders. Our results imply that adiponectin is associated with less arterial pathology.

  • 18. Johannsson, G
    et al.
    Nilsson, AG
    Bergthorsdottir, R
    Burman, P
    Dahlqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Ekman, B
    Engström, BE
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Ragnarsson, O
    Ryberg, Mats
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Wahlberg, J
    Biller, BMK
    Monson, JP
    Stewart, PM
    Lennernäs, H
    Skrtic, S
    Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation2012Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, nr 2, s. 473-481Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 19.
    Johansson, Mattias
    et al.
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap.
    McKay, James D
    Wiklund, Fredrik
    Rinaldi, Sabina
    Verheus, Martijn
    van Gils, Carla H
    Hallmans, Göran
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin. Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin, Näringsforskning.
    Bälter, Katarina
    Adami, Hans-Olov
    Grönberg, Henrik
    Stattin, Pär
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap.
    Kaaks, Rudolf
    Implications for prostate cancer of insulin-like growth factor-I (IGF-I) genetic variation and circulating IGF-I levels.2007Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, nr 12, s. 4820-4826Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Elevated levels of circulating IGF-I have consistently been associated with increased prostate cancer risk. We recently found a haplotype in the 3' region of the IGF-I gene associated with increased risk of prostate cancer, and we hypothesized that the observed association is mediated by circulating IGF-I. MATERIALS AND METHODS: We analyzed haplotypes and three haplotype-tagging single nucleotide polymorphisms (htSNPs) in the 3' region of the IGF-I gene in relation to circulating levels IGF-I in 698 control subjects from the CAncer Prostate in Sweden (CAPS) study and 575 cases and controls from the prospective Northern Sweden Health and Disease Cohort (NSHDC) study. We also performed a meta-analysis of these two and four other association studies on genetic variation in the 3' region of the IGF-I gene in relation to circulating IGF-I levels. RESULTS: The IGF-I haplotype previously associated with prostate cancer risk, labeled "TCC," was associated with elevated levels of IGF-I in the CAPS study (P = 0.02), but not in the NSHDC study. In contrast, two of the three IGF-I htSNPs tagging this haplotype, rs6220 and rs7136446, were associated with elevated levels of IGF-I in the NSHDC (P = 0.03 and P = 0.04, respectively), but not in the CAPS study. In the meta-analysis, the TCC haplotype and the rs6220 SNP were associated with elevated levels of circulating IGF-I (P = 0.001 and P < 0.0001, respectively). CONCLUSIONS: Genetic variation in the 3' region of the IGF-I gene seems to influence circulating levels of IGF-I. This observation is consistent with the hypothesis that variation in the IGF-I gene plays a role in prostate cancer susceptibility by influencing circulating levels of IGF-I.

  • 20.
    Kamel, Ashraf F
    et al.
    Department of Pediatrics, Huddinge University Hospital, Huddinge, Sweden.
    Norgren, Svante
    Department of Pediatrics, Huddinge University Hospital, Huddinge, Sweden.
    Strigård, Karin
    Department of Surgery, Huddinge University Hospital, Huddinge, Sweden.
    Thörne, Anders
    Endocrine Research Unit, Huddinge University Hospital, Huddinge, Sweden.
    Fakhrai-Rad, Hossein
    Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Galli, Joakim
    Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
    Marcus, Claude
    Department of Pediatrics, Huddinge University Hospital, Huddinge, Sweden.
    Age-dependent regulation of lipogenesis in human and rat adipocytes.2004Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 89, nr 9, s. 4601-4606Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The regulation of adipocyte metabolism is of importance for adipose tissue growth and therefore also for the development of obesity. This study was designed to investigate the regulation of basal and insulin-induced lipogenesis, glucose transport, and glucose transporter protein expression in human and rat adipocytes from different age groups. The study included 21 infants, 21 children, nine adults, and 80 male weaned and 20 male adult Fischer rats. The lipogenesis experiments were performed under conditions at which glucose transport is rate limiting. Basal lipogenesis was approximately three times higher in infants and children than in adults, whereas insulin-induced lipogenesis was two times higher in infants than in children and adults. In rats, basal lipogenesis, insulin-induced lipogenesis, and insulin sensitivity were two times higher in weaned than in adult animals. Moreover, basal and insulin-induced glucose transport were two times higher in weaned than in adult rats. No differences were detected in GLUT1 or GLUT4 content between any of the age groups in human or in rat adipocytes. In conclusion, basal and insulin-stimulated lipogenesis are increased in adipocytes early in life. This may promote adipose tissue growth in early age. The data indicate that age-dependent variation in basal and insulin-stimulated lipogenesis is differently regulated.

  • 21.
    Kriström, Berit
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Aronson, A Stefan
    Dahlgren, Jovanna
    Gustafsson, Jan
    Halldin, Maria
    Ivarsson, Sten A
    Nilsson, Nils-Osten
    Svensson, Johan
    Tuvemo, Torsten
    Albertsson-Wikland, Kerstin
    Growth hormone (GH) dosing during catch-up growth guided by individual responsiveness decreases growth response variability in prepubertal children with GH deficiency or idiopathic short stature.2009Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 94, nr 2, s. 483-90Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: Weight-based GH dosing results in a wide variation in growth response in children with GH deficiency (GHD) or idiopathic short stature (ISS). OBJECTIVE: The hypothesis tested was whether individualized GH doses, based on variation in GH responsiveness estimated by a prediction model, reduced variability in growth response around a set height target compared with a standardized weight-based dose. SETTING: A total of 153 short prepubertal children diagnosed with isolated GHD or ISS (n = 43) and at least 1 SD score (SDS) below midparental height SDS (MPH(SDS)) were included in this 2-yr multicenter study. INTERVENTION: The children were randomized to either a standard (43 microg/kg.d) or individualized (17-100 microg/kg.d) GH dose. MAIN OUTCOME MEASURE: We measured the deviation of height(SDS) from individual MPH(SDS) (diffMPH(SDS)). The primary endpoint was the difference in the range of diffMPH(SDS) between the two groups. RESULTS: The diffMPH(SDS) range was reduced by 32% in the individualized-dose group relative to the standard-dose group (P < 0.003), whereas the mean diffMPH(SDS) was equal: -0.42 +/- 0.46 and -0.48 +/- 0.67, respectively. Gain in height(SDS) 0-2 yr was equal for the GH-deficient and ISS groups: 1.31 +/- 0.47 and 1.36 +/- 0.47, respectively, when ISS was classified on the basis of maximum GH peak on the arginine-insulin tolerance test or 24-h profile. CONCLUSION: Individualized GH doses during catch-up growth significantly reduce the proportion of unexpectedly good and poor responders around a predefined individual growth target and result in equal growth responses in children with GHD and ISS.

  • 22.
    Kriström, Berit
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Carlsson, B
    Rosberg, S
    Carlsson, L M
    Albertsson-Wikland, K
    Short-term changes in serum leptin levels provide a strong metabolic marker for the growth response to growth hormone treatment in children. Swedish Study Group for Growth Hormone Treatment.1998Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 83, nr 8, s. 2735-41Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The growth response to GH treatment varies between children. Besides regulating longitudinal growth, GH exerts important metabolic effects, including lipolysis. In this study we examined whether GH-induced changes in serum levels of the adipose tissue-derived hormone leptin can be used as a marker for the long term growth response to GH treatment in short prepubertal children. The study group consisted of 150 children (21 girls and 129 boys), who were 3-15 yr of age at the start of GH treatment and had a maximum GH secretory capacity ranging from very low to high. They were treated with GH (0.1 IU/kg x day) and followed for at least 1 yr. The first year mean increase in height SD score was 0.79 (SD, 0.34), with a broad range (0.08-2.27). Serum leptin concentrations were significantly reduced after 1, 3, and 12 months of GH treatment compared with levels at the start of treatment. The growth response correlated with the serum leptin concentration at the start of treatment (r = 0.49; P < 0.0001) and with the change in serum leptin concentration after both 1 month (r = -0.41; P < 0.01) and 3 months (r = -0.60; P < 0.0001) of treatment. When multiple stepwise regression analysis was applied to the auxological and biochemical variables that correlated (P < 0.10) with the first year growth response to GH treatment, the 3-month change in serum leptin concentration was the single most important variable for explaining the variance in individual growth responses. We conclude that leptin levels at the start of GH treatment as well as short term changes in leptin levels in response to GH treatment are valuable markers of the long term growth response.

  • 23.
    Kriström, Berit
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Jansson, C
    Rosberg, S
    Albertsson-Wikland, K
    Growth response to growth hormone (GH) treatment relates to serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 in short children with various GH secretion capacities. Swedish Study Group for Growth Hormone Treatment.1997Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 82, nr 9, s. 2889-98Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The purpose of the study was to evaluate the relationship between the 1-yr (n = 193) and 2-yr (n = 128) growth response and the individual serum concentrations of insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) before and during GH treatment. Our study group of prepubertal short children had from very low to high GH secretory capacity, estimated during an arginine-insulin tolerance test, and the ages ranged from 3-15 yr at the start of treatment. Their serum levels of IGF-I and IGFBP-3 were low before treatment compared to those in an age-related reference group of prepubertal children and increased significantly from the start to 1 month of GH treatment. The mean increase in height SD score was 0.80 SD score after 1 yr of GH treatment and 1.26 SD score after 2 yr, with a wide range. In univariate analyses the highest correlation coefficients to the 2-yr growth response were found to be vs. the following variables from the start of treatment: IGF-I SD score (r = -0.49), log maximum GH concentration (log GHmax) during the arginine-insulin tolerance test (r = -0.47), difference between the height SD score of the individual child and the midparental height SD score (diffSD score; r = -0.45), IGFBP-3 SD score (r = -0.39), age (r = -0.30), short term change in IGFBP-3 SD score (r = 0.37), and IGF-I SD score (r = 0.34). In multivariate stepwise regression analysis, 41% of the variation in the 2-yr growth response could be explained by IGF-I SD score or log GHmax together with age at the start of treatment, weight SD score at 1 yr of age, and diffSD score. When both IGF-I SD score and GHmax were included and when the short term changes in IGF-I SD score were added, 46% and 58% of the variation, respectively, could be explained. The regression algorithms using different combinations of variables and their corresponding prediction intervals are also presented.

  • 24.
    Kriström, Berit
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Lundberg, Elena
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Jonsson, Björn
    Albertsson-Wikland, Kerstin
    IGF-1 and growth response to adult height in a randomized GH treatment trial in short non-GH-deficient children2014Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, nr 8, s. 2917-2924Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: GH treatment significantly increased adult height (AH) in a dose-dependent manner in short non-GH-deficient children in a randomized, controlled, clinical trial; the mean gain in height SD score (height(SDS)) was 1.3 (range 0-3), compared with 0.2 in the untreated group. Objective: The objective of the study was to analyze the relationship between IGF-1(SDS), IGF binding protein-3 SDS (IGFBP3(SDS)), and their ratio(SDS) with a gain in the height(SDS) until AH in non-GH-deficient short children. Design and Setting: This was a randomized, controlled, multicenter clinical trial. Intervention: The intervention included GH treatment: 33 or 67 mu g/kg.d plus untreated controls. Subjects: One hundred fifty-one non-GH-deficient short children were included in the intent-to-treat (ITT) population and 108 in the per-protocol (PP) population; 112 children in the ITT and 68 children in the PP populations had idiopathic short stature (ISS). Main Outcome Measures: Increments from baseline to on-treatment study mean IGF-1(SDS) (Delta IGF-1(SDS)), IGFBP3(SDS), and IGF-1 to IGFBP3 ratio(SDS) were assessed in relationship to the gain in height(SDS). Results: Sixty-two percent of the variance in the gain in height(SDS) in children on GH treatment could be explained by four variables: Delta IGF-1(SDS) (explaining 28%), bone age delay, birth length (the taller the better), and GH dose (the higher the better). The lower IGF-1(SDS) was at baseline, the higher was its increment during treatment. For both the All(PP)- and the ISSPP-treated groups, the attained IGF-1(SDS) study level did not correlate with height gain. Conclusion: In short non-GH-deficient children, the GH dose-related increment in IGF-1(SDS) from baseline to mean study level was the most important explanatory variable for long-term growth response from the peripubertal period until AH, when IGF-1(SDS), IGFBP3(SDS), and their ratio(SDS) were compared concurrently.

  • 25.
    Kriström, Berit
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Löfqvist, C
    Rosberg, S
    Albertsson Wikland, K
    Effect of spontaneous GH secretion and the GH sampling period on the accuracy of models for predicting growth responses to GH treatment.2001Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 86, nr 10, s. 4963-4Artikkel i tidsskrift (Fagfellevurdert)
  • 26.
    Kriström, Berit
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Zdunek, Anna-Maija
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi.
    Rydh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi.
    Jonsson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Sehlin, Petra
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Andersson Escher, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    A novel mutation in the LIM homeobox 3 gene is responsible for combined pituitary hormone deficiency, hearing impairment, and vertebral malformations.2009Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 94, nr 4, s. 1154-1161Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: The LIM homeobox 3 (LHX3) LIM-homeodomain transcription factor gene, found in both man and mouse, is required for development of the pituitary and motor neurons, and is also expressed in the auditory system. OBJECTIVE: The objective of this study was to determine the cause of, and further explore, the phenotype in six patients (aged 6 months to 22 yr) with combined pituitary hormone deficiency (CPHD), restricted neck rotation, scoliosis, and congenital hearing impairment. Three of the patients also have mild autistic-like behavior. DESIGN: Because patients with CPHD and restricted neck rotation have previously been shown to have mutations in the LHX3 gene, a candidate gene approach was applied, and the gene was sequenced. Neck anatomy was explored by computed tomography and magnetic resonance imaging, including three-dimensional reformatting. RESULTS: A novel, recessive, splice-acceptor site mutation was found. The predicted protein encoded by the mutated gene lacks the homeodomain and carboxyl terminus of the normal, functional protein. Genealogical studies revealed a common gene source for all six families dating back to the 17th century. Anatomical abnormalities in the occipito-atlantoaxial joints in combination with a basilar impression of the dens axis were found in all patients assessed. CONCLUSIONS: This study extends both the mutations known to be responsible for LHX3-associated syndromes and their possible phenotypical consequences. Previously reported traits include CPHD and restricted neck rotation; patients examined in the present study also show a severe hearing defect. In addition, the existence of cervical vertebral malformations are revealed, responsible for the rigid neck and the development of scoliosis.

  • 27. Lindström, Sara
    et al.
    Ma, Jing
    Altshuler, David
    Giovannucci, Edward
    Riboli, Elio
    Albanes, Demetrius
    Allen, Naomi E
    Berndt, Sonja I
    Boeing, Heiner
    Bueno-de-Mesquita, H Bas
    Chanock, Stephen J
    Dunning, Alison M
    Feigelson, Heather Spencer
    Gaziano, J Michael
    Haiman, Christopher A
    Hayes, Richard B
    Henderson, Brian E
    Hunter, David J
    Kaaks, Rudolf
    Kolonel, Laurence N
    Le Marchand, Loic
    Martínez, Carmen
    Overvad, Kim
    Siddiq, Afshan
    Stampfer, Meir
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Stram, Daniel O
    Thun, Michael J
    Trichopoulos, Dimitrios
    Tumino, Rosario
    Virtamo, Jarmo
    Weinstein, Stephanie J
    Yeager, Meredith
    Kraft, Peter
    Freedman, Matthew L
    A large study of androgen receptor germline variants and their relation to sex hormone levels and prostate cancer risk: Results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium2010Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, nr 9, s. E121-E127Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Androgens are key regulators of prostate gland maintenance and prostate cancer growth, and androgen deprivation therapy has been the mainstay of treatment for advanced prostate cancer for many years. A long-standing hypothesis has been that inherited variation in the androgen receptor (AR) gene plays a role in prostate cancer initiation. However, studies to date have been inconclusive and often suffered from small sample sizes.

    Objective and Methods: We investigated the association of AR sequence variants with circulating sex hormone levels and prostate cancer risk in 6058 prostate cancer cases and 6725 controls of Caucasian origin within the Breast and Prostate Cancer Cohort Consortium. We genotyped a highly polymorphic CAG microsatellite in exon 1 and six haplotype tagging single nucleotide polymorphisms and tested each genetic variant for association with prostate cancer risk and with sex steroid levels.

    Results: We observed no association between AR genetic variants and prostate cancer risk. However, there was a strong association between longer CAG repeats and higher levels of testosterone (P = 4.73 × 10−5) and estradiol (P = 0.0002), although the amount of variance explained was small (0.4 and 0.7%, respectively).

    Conclusions: This study is the largest to date investigating AR sequence variants, sex steroid levels, and prostate cancer risk. Although we observed no association between AR sequence variants and prostate cancer risk, our results support earlier findings of a relation between the number of CAG repeats and circulating levels of testosterone and estradiol.

  • 28. Lubin, Jay H.
    et al.
    Adams, M. Jacob
    Shore, Roy
    Holmberg, Erik
    Schneider, Arthur B.
    Hawkins, Michael M.
    Robison, Leslie L.
    Inskip, Peter D.
    Lundell, Marie
    Johansson, Robert
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Kleinerman, Ruth A.
    de Vathaire, Florent
    Damber, Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Sadetzki, Siegal
    Tucker, Margaret
    Sakata, Ritsu
    Veiga, Lene H. S.
    Thyroid Cancer Following Childhood Low-Dose Radiation Exposure: A Pooled Analysis of Nine Cohorts2017Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, nr 7, s. 2575-2583Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: The increased use of diagnostic and therapeutic procedures that involve radiation raises concerns about radiation effects, particularly in children and the radiosensitive thyroid gland.

    Objectives: Evaluation of relative risk (RR) trends for thyroid radiation doses <0.2 gray (Gy); evidence of a threshold dose; and possible modifiers of the dose-response, e.g., sex, age at exposure, time since exposure.

    Design and Setting: Pooled data from nine cohort studies of childhood external radiation exposure and thyroid cancer with individualized dose estimates, ≥1000 irradiated subjects or ≥10 thyroid cancer cases, with data limited to individuals receiving doses <0.2 Gy.

    Participants: Cohorts included the following: childhood cancer survivors (n = 2); children treated for benign diseases (n = 6); and children who survived the atomic bombings in Japan (n = 1). There were 252 cases and 2,588,559 person-years in irradiated individuals and 142 cases and 1,865,957 person-years in nonirradiated individuals.

    Intervention: There were no interventions.

    Main Outcome Measure: Incident thyroid cancers.

    Results: For both <0.2 and <0.1 Gy, RRs increased with thyroid dose (P < 0.01), without significant departure from linearity (P = 0.77 and P = 0.66, respectively). Estimates of threshold dose ranged from 0.0 to 0.03 Gy, with an upper 95% confidence bound of 0.04 Gy. The increasing dose–response trend persisted >45 years after exposure, was greater at younger age at exposure and younger attained age, and was similar by sex and number of treatments.

    Conclusions: Our analyses reaffirmed linearity of the dose response as the most plausible relationship for “as low as reasonably achievable” assessments for pediatric low-dose radiation-associated thyroid cancer risk.

  • 29.
    Lundgren, Magdalena
    et al.
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin, Medicin.
    Buren, Jonas
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin, Medicin.
    Ruge, Toralph
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Kirurgi.
    Myrnäs, Torbjörn
    Umeå universitet, Medicinsk fakultet, Kirurgisk och perioperativ vetenskap, Kirurgi.
    Eriksson, Jan
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin, Medicin.
    Glucocorticoids down-regulate glucose uptake capacity and insulin-signaling proteins in omental but not subcutaneous human adipocytes.2004Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 89, nr 6, s. 2989-2997Artikkel i tidsskrift (Fagfellevurdert)
  • 30. Ma, Lijun
    et al.
    Hanson, Robert L
    Que, Lorem N
    Mack, Janel L
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Infante, Aniello M
    Kobes, Sayuko
    Bogardus, Clifton
    Baier, Leslie J
    Association analysis of Krüppel-like factor 11 variants with type 2 diabetes in Pima Indians2008Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, nr 9, s. 3644-3649Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: Krüppel-like factor 11 (KLF11) is a transcription factor of the zinc finger domain family that has been shown to regulate expression of the insulin gene. An initial study reported that a KLF11 variant predicting a Q62R was associated with type 2 diabetes (T2D) in French Caucasians; however, subsequent studies have failed to identify an association between this variant and T2D in subjects from a similar Northern-European ancestry. OBJECTIVE: We sought to determine whether the Q62R or other variants within KLF11 were associated with T2D in Pima Indians, a population with an extremely high prevalence of this disease.

    DESIGN, SETTING, AND SUBJECTS: KLF11 was sequenced in 24 Pima Indians to identify potentially novel variants. There were 18 variants genotyped in a family-based sample of 1337 Pima Indians to analyze the linkage disequilibrium pattern of this gene and identify representative variants. Four representative variants were further genotyped in a population-based sample of 3501 full-heritage Pima Indians for association analyses. Among these subjects, 413 had undergone metabolic studies when they were nondiabetic to measure traits that predict T2D.

    RESULTS: Neither the Q62R nor any other common variant in KLF11 was associated with T2D in the Pima population. In addition, no variant was associated with insulin secretion or insulin-stimulated glucose disposal rate.

    CONCLUSIONS: Common variation in KLF11 variation does not appear to influence the population-based risk for developing T2D among full-heritage Pima Indians. Thus, KLF11 is unlikely to play a major role in the etiology of T2D among this Native American population.

  • 31. Mannerås-Holm, Louise
    et al.
    Leonhardt, Henrik
    Kullberg, Joel
    Jennische, Eva
    Odén, Anders
    Holm, Göran
    Hellström, Mikael
    Lönn, Lars
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Stener-Victorin, Elisabet
    Lönn, Malin
    Adipose tissue has aberrant morphology and function in PCOS: enlarged adipocytes and low serum adiponectin, but not circulating sex steroids, are strongly associated with insulin resistance2011Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 96, nr 2, s. E304-E311Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In PCOS, adipose tissue has aberrant morphology/function. Increased waist-to-hip ratio indicates abdominal/visceral fat accumulation, but this is not supported by MRI. Enlarged adipocytes and reduced serum adiponectin, together with a large waistline, rather than androgen excess, may be central factors in the pathogenesis/maintenance of insulin resistance in PCOS.

  • 32.
    Mattsson, Cecilia
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Reynolds, Rebecca M
    Simonyte, Kotryna
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Walker, Brian R
    Combined receptor antagonist stimulation of the HPA axis test identifies impaired negative feedback sensitivity to cortisol in obese men2009Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 94, nr 4, s. 1347-1352Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation may underlie disorders including obesity, depression, cognitive decline and the metabolic syndrome. Conventional tests of HPA axis negative feedback rely on glucocorticoid receptor (GR) agonists such as dexamethasone, but do not test feedback by endogenous cortisol, potentially mediated by both GR and mineralocorticoid receptors (MR).

    Objective: To use a combination of GR (RU38486, mifepristone) and MR (spironolactone) antagonists to explore the poorly understood activation of the HPA axis that occurs in obesity.

    Design: Double blind, placebo-controlled randomized cross-over study.

    Setting: Clinical research facility.

    Participants: 15 lean (BMI 22.0+/-1.6 kg/m(2)) and 16 overweight/obese (BMI 30.1+/-3.5 kg/m(2)) men.

    Intervention: Subjects attended on four occasions for blood and saliva sampling every 30 minutes between 1800h and 2200h. At 1100h and 1600h before visits subjects took either 200mg spironolactone, 400mg RU38486, 200mg spironolactone + 400mg RU38486, or placebo orally.

    Main outcome measures: serum cortisol levels following drug or placebo.

    Results: Cortisol levels did not differ between lean and obese following placebo. Spironolactone and RU38486 alone had modest effects, increasing cortisol by <50% in both groups. However, combined spironolactone plus RU38486 elevated cortisol concentrations substantially, moreso in lean than obese men (2.9(0.3) vs 2.2(0.3) fold elevation, p=0.002).

    Conclusions: Combined receptor antagonist stimulation of the HPA axis reveals redundancy of MR and GR in negative feedback in humans. Obese men have impaired responses to combined receptor antagonist stimulation, suggesting impaired negative feedback by endogenous cortisol. Such an approach may be useful to dissect abnormal HPA axis control in neuropsychiatric and other disorders.

  • 33. Meyer, Barbara J.
    et al.
    Stewart, Frances M.
    Brown, Elizabeth A.
    Cooney, Josephine
    Nilsson, Solveig
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Ramsay, Jane E.
    Griffin, Bruce A.
    Caslake, Muriel J.
    Freeman, Dilys J.
    Maternal Obesity Is Associated With the Formation of Small Dense LDL and Hypoadiponectinemia in the Third Trimester2013Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, nr 2, s. 643-652Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Maternal obesity is associated with high plasma triglyceride, poor vascular function, and an increased risk for pregnancy complications. In normal-weight pregnant women, higher triglyceride is associated with increased small, dense low-density lipoprotein (LDL). Hypothesis: In obese pregnancy, increased plasma triglyceride concentrations result in triglyceride enrichment of very low-density lipoprotein-1 particles and formation of small dense LDL via lipoprotein lipase. Design: Women (n = 55) of body mass index of 18-46 kg/m(2) were sampled longitudinally at 12, 26, and 35 weeks' gestation and 4 months postnatally. Setting: Women were recruited at hospital antenatal appointments, and study visits were in a clinical research suite. Outcome Measures: Plasma concentrations of lipids, triglyceride-rich lipoproteins, lipoprotein lipase mass, estradiol, steroid hormone binding globulin, insulin, glucose, leptin, and adiponectin were determined. Results: Obese women commenced pregnancy with higher plasma triglyceride, reached the same maximum, and then returned to higher postnatal levels than normal-weight women. Estradiol response to pregnancy (trimester 1-3 incremental area under the curve) was positively associated with plasma triglyceride response (r(2) adjusted 25%, P < .001). In the third trimester, the proportion of small, dense LDL was 2-fold higher in obese women than normal-weight women[mean (SD) 40.7 (18.8) vs 21.9 (10.9)%, P = .014], and 35% of obese, 14% of overweight, and none of the normal-weight women displayed an atherogenic LDL subfraction phenotype. The small, dense LDL mass response to pregnancy was inversely associated with adiponectin response (17%, P = .013). Conclusions: Maternal obesity is associated with an atherogenic LDL subfraction phenotype and may provide a mechanistic link to poor vascular function and adverse pregnancy outcome.

  • 34. Michaëlsson, Karl
    et al.
    Lind, Lars
    Frystyk, Jan
    Flyvbjerg, Allan
    Gedeborg, Rolf
    Berne, Christian
    Zethelius, Björn
    Mallmin, Hans
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Melhus, Håkan
    Serum adiponectin in elderly men does not correlate with fracture risk.2008Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, nr 10, s. 4041-7Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: Recent evidence suggests that adiponectin may play a role in bone metabolism, but studies of the correlation between serum adiponectin and bone mineral density (BMD) have given conflicting results, and the impact on fracture risk is unknown. OBJECTIVE: Our objective was to investigate the association between serum adiponectin levels and BMD and fracture risk. DESIGN, SETTING, PARTICIPANTS, MAIN OUTCOME MEASURES: We used regression analyses to estimate the relationship between adiponectin and BMD in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort of 441 men and 457 women aged 70 yr. The association was thereafter analyzed in the Uppsala Longitudinal Study of Adult Men (ULSAM), in which adiponectin was analyzed at age 70 yr and BMD at 82 yr in 507 men. Fractures in the ULSAM were documented in 314 men during 15 yr follow-up. Cox regression analysis was used to determine the risk of fracture according to serum adiponectin levels. RESULTS: In multivariable analysis a negative association between adiponectin and BMD was found in both cohorts. When individuals in the highest quintile of adiponectin were compared with those in the lowest quintile, adjusted BMD was 9.7% lower at the lumbar spine, 7.1% lower at the proximal femur, and 5.2% lower for total body in the Prospective Investigation of the Vasculature in Uppsala Seniors (P < 0.001 for all three), and 8.1, 5.1, and 4.1% (P < 0.003 for all three), respectively, in the ULSAM. However, the hazard ratio for fracture per 1 sd of serum adiponectin was 0.99 (95% confidence interval 0.89-1.11). CONCLUSION: Although adiponectin was a negative determinant of BMD in two independent cohorts, it was not associated with fracture risk in men.

  • 35. Nilsson, K O
    et al.
    Albertsson-Wikland, K
    Alm, J
    Aronson, S
    Gustafsson, J
    Hagenäs, L
    Häger, A
    Ivarsson, S A
    Karlberg, J
    Kriström, Berit
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Marcus, C
    Moell, C
    Ritzen, M
    Tuvemo, T
    Wattsgård, C
    Westgren, U
    Westphal, O
    Aman, J
    Improved final height in girls with Turner's syndrome treated with growth hormone and oxandrolone.1996Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 81, nr 2, s. 635-40Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The spontaneous growth process in Turner's syndrome is characterized by a progressive decline in height velocity during childhood and no pubertal growth spurt. Therefore, therapy aimed at improving height during childhood as well as increasing final height is desirable for most girls with Turner's syndrome. Forty-five girls with Turner's syndrome, 9-16 yr of age (mean age, 12.2 yr), were allocated to three study groups. Group 1 (n = 13) was initially treated with oxandrolone alone; after 1 yr of treatment, GH without (group 1a; n = 6) or with (group 1b; n = 7) ethinyl estradiol was added. Group 2 (n = 17) was treated with GH plus oxandrolone. Group 3 (n = 15) was treated with GH, oxandrolone, and ethinyl estradiol. The dosage were: GH, 0.1 IU/kg.day; oxandrolone, 0.05 mg/kg.day; and ethinyl estradiol, 100 ng/kg.day. A height of 150 cm or more was achieved in 61%, 75%, and 60% of the girls in groups 1, 2, and 3, respectively. The most impressive increase in height was seen in group 2. In this group the mean final height was 154.2 cm (SD = 6.6), which is equivalent to a mean net gain of 8.5 cm (SD = 4.6) over the projected final height. In group 3, in which ethinyl estradiol was included from the start of therapy, the initially good height velocity decelerated after 1-2 yr of treatment. Their mean final height was 151.1 (SD = 4.6) cm, equivalent to a mean net gain of 3.0 cm (SD = 3.8). A similar growth-decelerating effect of ethinyl estradiol was seen in group 1b. We conclude that in girls with Turner's syndrome who are older than 9 yr of age, treatment with GH in combination with oxandrolone results in significant growth acceleration, imitating that in normal puberty, leading to a more favorable height during childhood. This mode of treatment also results in a significantly increased final height, permitting a great number of the girls to attain a final height of more than 150 cm. However, early addition of estrogen decelerates the height velocity and reduces the gain in height.

  • 36.
    Nordström, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Hadrévi, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Idrottsmedicin.
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115.
    Nordström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik. Lunds Universitet.
    The Higher Prevalence of Type 2 Diabetes in Men Than in Women is Associated with Differences in Visceral Fat Mass2016Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, nr 10, s. 3740-3746Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: We have previously found that visceral fat is a stronger predictor for cardiovascular risk factors than body mass index (BMI). Objective: To investigate the prevalence of diabetes in elderly men and women in relation to objectively assessed visceral fat volume. Design and settings: The cohort consisted of a population-based sample of 705 men and 688 women, all aged 70 years at the time of examination. Main outcome measures: Associations between body fat estimates, plasma glucose level and diabetes prevalence were investigated using multivariable-adjusted statistical models.Results:Theprevalence of type2 diabetes was 14.6% in men and 9.1% inwomen (p0.001). Mean BMI was slightly higher in men than in women (27. 3 vs. 26.6 kg/m2, p 0.01), with a greater difference in mean visceral fat mass (1987 vs. 1087 g, p 0.001). After adjustment for physical activity and smoking, men had about twice the odds of having type 2 diabetes compared with women (OR, 1.95; 95% CI, 1.38–2.76). The inclusion of BMI in this model did not change the risk associated with male sex (OR, 1.93; 95% CI, 1.34–2.77). However, when visceral fat was included as a covariate, male sex was not associated with increased risk of type 2 diabetes (OR, 0.77; 95% CI, 0.51–1.18).Conclusions: The higher prevalence of type 2 diabetes in older men than in older women was associated with larger amount of visceral fat in men. In contrast, differences in BMI was not associated with this difference.

  • 37.
    Nordström, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Nordström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Sustained benefits from previous physical activity on bone mineral density in males.2006Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 91, nr 7, s. 2600-2604Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: The effect of physical activity on bone mineral density (BMD) is not well investigated longitudinally after puberty in men.

    Objective: Our objective was to evaluate the effect of exercise and reduced exercise on BMD after puberty in men.

    Design: We conducted a longitudinal study.

    Participants: Sixty-three healthy young athletes and 27 male controls, both with a mean age of 17 yr at baseline, participated. Also, 136 of the participants’ parents were investigated to evaluate heritable influences.

    Main Outcome Measures: Total body, total hip, femoral neck, and humerus BMD (grams per square centimeter) were measured at baseline and after mean periods of 27, 68, and 94 months in the young cohort.

    Results: BMDs of control parents and athlete parents were equal, suggesting absence of selection bias. The 23 athletes that remained active throughout the study increased BMD at all sites when compared with controls (mean difference, 0.04–0.12 g/cm2; P < 0.05) during the study period. After an average of 3 yr, 27 athletes ended their active careers. Although this group initially lost BMD at the hip compared with active athletes, the former athletes still had higher BMD than controls at the femoral neck (0.12 g/cm2; P = 0.007), total hip (0.11 g/cm2; P = 0.02), and humerus (0.10 g/cm2; P = 0.02) at the final follow-up.

    Conclusions: High sensitivity to physical loading persists after puberty in men. Reduced physical activity is associated with BMD loss in the first 3 yr in weight-bearing bone. Sustained benefits in BMD are preserved 5 yr after intensive training ends.

  • 38. Onnestam, Lisa
    et al.
    Berinder, Katarina
    Burman, Pia
    Dahlqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Engström, Britt Edén
    Wahlberg, Jeanette
    Nyström, Helena Filipsson
    National Incidence and Prevalence of TSH-Secreting Pituitary Adenomas in Sweden2013Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, nr 2, s. 626-635Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: TSH-secreting pituitary adenomas (TSHomas) are rare. Epidemiological data are scant and there are no reports on national incidence. Objective: The objective of the study was to estimate the national Swedish incidence and prevalence of TSHomas. Design: This was an observational study. Setting: The study was conducted at tertiary referral centers. Patients: The Swedish Pituitary Registry and World Health Organization International Statistical Classification of Diseases and Related Health Problems coding at all university hospitals were used to identify patients diagnosed with TSHomas 1990-2010. The identified patients' medical records were studied until the latest follow-up [median 5.0 years (range < 1-20 years)]. Main Outcome Measurements: Incidence, prevalence, demographics, tumor characteristics, treatment outcome, and thyroid hormone level at diagnosis were measured. Results: The age-standardized national incidence of 28 TSHoma patients was 0.15 per 1 million inhabitants per year, with an increasing incidence over time (0.05 per 1 million per year in 1990-1994 to 0.26 per 1 million per year in 2005-2009). The national prevalence in 2010 was 2.8 per 1 million inhabitants, in which 0.85 per 1 million had active disease. Most patients (n = 22) underwent pituitary surgery, 5 had radiotherapy, and 6 had somatostatin analogues. Eighteen patients were considered cured at the latest follow-up; 25% remained uncontrolled. Subjects treated for putative primary hyperthyroidism prior to diagnosis had TSH levels more than double those with intact thyroid at diagnosis (P = .013). The median time to diagnosis was longer for women than men (4 vs < 1 year, P = .026). More women than men were treated surgically (94.1% vs 54.5%, P = .022). Conclusion: This is the first estimate of a national incidence of TSHoma. Additional epidemiological studies are needed to compare these results with other geographical areas. This study suggests an increased incidence of TSHomas, in agreement with reports on other pituitary adenomas.

  • 39. Ragnarsson, Oskar
    et al.
    Olsson, Daniel S.
    Papakokkinou, Eleni
    Chantzichristos, Dimitrios
    Dahlqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Segerstedt, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Petersson, Maria
    Berinder, Katarina
    Bensing, Sophie
    Höybye, Charlotte
    Edén-Engstrom, Britt
    Burman, Pia
    Bonelli, Lorenza
    Follin, Cecilia
    Petranek, David
    Erfurth, Eva Marie
    Wahlberg, Jeanette
    Ekman, Bertil
    Åkerman, Anna-Karin
    Schwarcz, Erik
    Bryngelsson, Ing-Liss
    Johannsson, Gudmundur
    Overall and Disease-Specific Mortality in Patients With Cushing Disease: A Swedish Nationwide Study2019Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 104, nr 6, s. 2375-2384Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 40. Rask, Eva
    et al.
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Andrew, R
    Livingstone, D E
    Johnson, O
    Walker, B R
    Tissue-specific dysregulation of cortisol metabolism in human obesity.2001Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 86, nr 3, s. 1418-1421Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cortisol has been implicated as a pathophysiological mediator in idiopathic obesity, but circulating cortisol concentrations are not consistently elevated. The tissue-specific responses to cortisol may be influenced as much by local prereceptor metabolism as by circulating concentrations. For example, in liver and adipose tissue cortisol is regenerated from inactive cortisone by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). In obese Zucker rats 11beta-HSD1 activity is reduced in liver but enhanced in adipose tissue. This study addressed whether the same tissue-specific disruption of cortisol metabolism occurs in human obesity. 34 men were recruited from the MONICA population study in Northern Sweden to represent a wide range of body composition and insulin insensitivity. Plasma cortisol was measured at 0830h and 1230h, after overnight low-dose dexamethasone suppression, after intravenous corticotropin releasing hormone (CRH), and after oral cortisone administration. Urinary cortisol metabolites were measured in a 24 h sample. A subcutaneous fat biopsy was obtained from 16 participants to measure cortisol metabolism in vitro. Higher body mass index was associated with increased total cortisol metabolite excretion (r = 0.47, p < 0.01), but lower plasma cortisol at 1230 h and after dexamethasone, and no difference in response to CRH. Obese men excreted a greater proportion of glucocorticoid as metabolites of cortisone rather than cortisol (r = 0.43, p < 0.02), and converted less cortisone to cortisol after oral administration (r = 0.49, p < 0.01), suggesting impaired hepatic 11beta-HSD1 activity. By contrast, in vitro 11beta-HSD1 activity in subcutaneous adipose tissue was markedly enhanced in obese men (r = 0.66, p < 0.01). We conclude that in obesity, reactivation of cortisone to cortisol by 11beta-HSD1 in liver is impaired, so that plasma cortisol levels tend to fall, and there may be a compensatory increase in cortisol secretion mediated by a normally functioning hypothalamic-pituitary-adrenal axis. However, changes in 11beta-HSD1 are tissue-specific: strikingly enhanced reactivation of cortisone to cortisol in subcutaneous adipose tissue may exacerbate obesity; and it may be beneficial to inhibit this enzyme in adipose tissue in obese patients.

  • 41. Rask, Eva
    et al.
    Walker, Brian R
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Livingstone, Dawn E W
    Eliasson, Mats
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Johnson, Owe
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Andrew, Ruth
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity.2002Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 87, nr 7, s. 3330-3336Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cushing's syndrome and the metabolic syndrome share clinical similarities. Reports of alterations in the hypothalamic-pituitary-adrenal (HPA) axis are inconsistent, however, in the metabolic syndrome. Recent data highlight the importance of adipose 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regenerates cortisol from cortisone and, when overexpressed in fat, produces central obesity and glucose intolerance. Here we assessed the HPA axis and 11beta-HSD1 activity in women with moderate obesity and insulin resistance. Forty women were divided into tertiles according to body mass index (BMI; median, 22.0, 27.5, and 31.4, respectively). Serum cortisol levels were measured after iv CRH, low dose dexamethasone suppression, and oral cortisone administration. Urinary cortisol metabolites were measured in a 24-h sample. A sc abdominal fat biopsy was obtained in 14 participants for determination of 11beta-HSD type 1 activity in vitro. Higher BMI was associated with higher total cortisol metabolite excretion (r = 0.49; P < 0.01), mainly due to increased 5alpha- and, to a lesser extent, 5beta-tetrahydrocortisol excretion, but no difference in plasma cortisol basally, after dexamethasone, or after CRH, and only a small increase in the ACTH response to CRH. Hepatic 11beta-HSD1 conversion of oral cortisone to cortisol was impaired in obese women (area under the curve, 147,736 +/- 28,528, 115,903 +/- 26,032, and 90,460 +/- 18,590 nmol/liter.min; P < 0.001). However, 11beta-HSD activity in adipose tissue was positively correlated with BMI (r = 0.55; P < 0.05). In obese females increased reactivation of glucocorticoids in fat may contribute to the characteristics of the metabolic syndrome. Increased inactivation of cortisol in liver may be responsible for compensatory activation of the HPA axis. These alterations in cortisol metabolism may be a basis for novel therapeutic strategies to reduce obesity-related complications.

  • 42. Schill, Fredrika
    et al.
    Nilsson, Margareta
    Olsson, Daniel S.
    Ragnarsson, Oskar
    Berinder, Katarina
    Engström, Britt Eden
    Dahlqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Wahlberg, Jeanette
    Englund, Elisabet
    Burman, Pia
    Pituitary Metastases: A Nationwide Study on Current Characteristics With Special Reference to Breast Cancer2019Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 104, nr 8, s. 3379-3388Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To investigate the contemporary presentation of pituitary metastases. Patients: Thirty-eight patients diagnosed with pituitary metastases from 1996 to 2018 in Sweden.

    Methods: Pituitary metastases were confirmed by histopathology (n = 27) or considered highly likely according to radiological findings, including rapid tumor progression (n = 11). Medical records were reviewed and cellar images reexamined centrally.

    Results: Breast and lung cancers were the most common primary tumors, in 45% and 21% of patients, respectively. Sixty-seven percent of breast cancers overexpressed human epidermal growth factor receptor 2 (HER2); 53% of pituitary metastases from breast cancers appeared >= 10 years after diagnosis of the primary tumor. At presentation, 71% appeared to have ACTH deficiency, 65% had TSH deficiency, and 26% had diabetes insipidus. Fatigue, nausea/vomiting, loss of appetite, weight loss, myalgia, and/or arthralgia were reported in 47% of patients with morning cortisol <100 nmol/L vs 23% with cortisol >= 200 nmol/L. Sixteen patients had visual field defects, and eight had diplopia. Intrasellar and suprasellar tumor growth was the most frequent finding. Initially, a pituitary adenoma was considered the etiology in 18% of patients. Radiotherapy, pituitary surgery, and chemotherapy were used in 68%, 68%, and 11% of patients, respectively. One and 2 years after diagnosis of pituitary metastases, 50% and 26% of patients were alive.

    Conclusion: Pituitary metastases may be mistaken for pituitary adenomas and can appear late, especially in breast cancer. Breast cancers overexpressing HER2 seem prone to metastasize to the pituitary. Hypocortisolism may be misdiagnosed as cancer-related malaise. An increased awareness of pituitary metastases and undiagnosed pituitary failure can improve management in these patients.

  • 43.
    Simonyte, Kotryna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Näslund, Ingmar
    Angelhed, Jan-Erik
    Lönn, Lars
    Mattsson, Cecilia
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Rask, Eva
    Weight loss after gastric bypass surgery in women is followed by a metabolically favorable decrease in 11beta-hydroxysteroid dehydrogenase 1 expression in subcutaneous adipose tissue2010Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, nr 7, s. 3527-3531Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Weight loss after gastric bypass surgery was followed by metabolically favorable changes in insulin sensitivity, circulating leptin and adiponectin, and peripheral glucocorticoid metabolism. A significant reduction in 11beta-HSD1 expression was observed in sc adipose tissue after weight loss. This suggests that up-regulation of 11beta-HSD1 is a consequence, rather than a cause, of obesity.

  • 44. Stattin, P
    et al.
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Hallmans, G
    Bylund, A
    Kaaks, R
    Stenman, U H
    Bergh, A
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Leptin is associated with increased prostate cancer risk: a nested case-referent study.2001Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 86, nr 3, s. 1341-1345Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A Western lifestyle has been implicated in the pathogenesis of prostate cancer. However, no clear association between obesity and prostate cancer has been shown. Leptin may stimulate prostate growth and angiogenesis, and receptors for leptin are present in the prostate. Leptin may, thus, be associated with increased risk of prostate cancer. One hundred forty-nine men with prostate cancer were identified (together with 298 matched referents) who, before diagnosis, had participated in population-based health surveys in Northern Sweden. Blood pressure, body mass index, and use of tobacco were recorded. Leptin, insulin, insulin-like growth factor I (IGF-I), IGF-I-binding proteins 1-3, testosterone, and sex hormone-binding globulin were analyzed in stored samples. Their influences on prostate cancer were estimated by conditional logistic regression analysis. Prostate cancer specimens were investigated for immunoreactivity for the leptin receptor. Relative risk (95% confidence intervals) estimates of prostate cancer over the quintiles of leptin were 1.0, 2.1 (1.1-4.1), 2.6 (1.4-4.8), 1.4 (0.7-2.7), and 1.6 (0.8-3.2). Adjustments for metabolic variables, testosterone, and IGF-I and its binding proteins did not attenuate this increased risk. Immunoreactivity for the leptin receptor was detected in normal, high-grade prostatic intraepithelial neoplasia lesions and malignant prostatic epithelium. Moderately elevated plasma leptin concentrations are associated with later development of prostate cancer. This may be due to direct effects of leptin on prostatic intraepithelial neoplasia lesions, or to indirect actions through other mechanisms. A critical fat mass related to an interior milieu favorable for prostate cancer development seems to exist, because intermediate but not high leptin levels are related to prostate cancer risk.

  • 45.
    Tervo, Taru
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Nordström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Neovius, Martin
    Nordström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Rehabiliteringsmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Constant adaptation of bone to current physical activity level in men: a 12-year longitudinal study2008Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, nr 12, s. 4873-4879Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: A high peak bone mineral density (BMD; grams per square centimeter) could reduce the risk of osteoporosis related fractures later in life. OBJECTIVE: This 12-yr longitudinal study investigated whether a high BMD from previous high physical activity is maintained with reduced activity later in life. DESIGN: This was a longitudinal study. PARTICIPANTS: Three groups were investigated with a mean age of 17 yr at baseline; 51 athletes who stopped their active careers during follow-up (former athletes), 16 who were active throughout follow-up (active athletes), and 25 controls. Main Outcome Measures: BMD of the femoral neck, total body, and lumbar spine were examined five times during the 12-yr follow-up period. RESULTS: After adjustment for age, weight, and height, the former athletes were found to have higher BMD at all sites at every follow-up visit except the last one, when compared with controls (P < 0.05). The active athletes were found to have significantly higher BMD at all measured locations when compared with controls throughout the entire study (P < 0.05). From the first to the final follow-up visit, the former athletes were found to have lost more femoral neck BMD than both the active athletes (mean difference, 0.12 g/cm(2); P = 0.003) and controls (mean difference 0.08 g/cm(2); P = 0.02). CONCLUSION: This study suggests that BMD constantly adapts to the present physical activity levels in young men. Thus, increased BMD due to previous high physical activity may not prevent osteoporosis in later years.

  • 46. Ueland, Grethe Å.
    et al.
    Methlie, Paal
    Øksnes, Marianne
    Thordarson, Hrafnkell B.
    Sagen, Jørn
    Kellmann, Ralf
    Mellgren, Gunnar
    Ræder, Maria
    Dahlqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Dahl, Sandra R.
    Thorsby, Per M.
    Løvås, Kristian
    Husebye, Eystein S.
    The Short Cosyntropin Test Revisited: New Normal Reference Range Using LC-MS/MS2018Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, nr 4, s. 1696-1703Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The cosyntropin test is used to diagnose adrenal insufficiency (AI) and nonclassical congenital adrenal hyperplasia (NCCAH). Current cutoffs for cortisol and 17-hydroxyprogesterone (17-OHP) are derived from nonstandardized immunoassays. Liquid chromatography tandem mass spectrometry (LC-MS/MS) offers direct measurement of steroids, prompting the need to re-establish normal ranges. Objective: The goal of this study was to define cutoff values for cortisol and 17-OHP in serum by LC-MS/MS 30 and 60 minutes after intravenous administration of 250 µg tetracosactide acetate to healthy volunteers and to compare the results with LC-MS/MS with routine immunoassays. Methods: Cosyntropin testing was performed in healthy subjects (n = 138) and in patients referred for evaluation of adrenocortical function (n = 94). Steroids were assayed by LC-MS/MS and compared with two immunoassays used in routine diagnostics (Immulite and Roche platforms). The cutoff level for cortisol was defined as the 2.5% percentile in healthy subjects not using oral estrogens (n = 121) and for 17-OHP as the 97.5% percentile. Results: Cortisol cutoff levels for LC-MS/MS were 412 and 485 nmol/L at 30 and 60 minutes, respectively. Applying the new cutoffs, 13 of 60 (22%) subjects who had AI according to conventional criteria now had a normal test result. For 17-OHP, the cutoff levels were 8.9 and 9.0 nmol/L at 30 and 60 minutes, respectively. Conclusions: LC-MS/MS provides cutoff levels for cortisol and 17-OHP after cosyntropin stimulation that are lower than those based on immunoassays, possibly because cross-reactivity between steroid intermediates and cortisol is eliminated. This reduces the number of false-positive tests for AI and false-negative tests for NCCAH.

  • 47.
    Virtanen, Ismo
    et al.
    University of Helsinki.
    Korhonen, Matti
    Petäjäniemi, Noora
    Karhunen, Tuula
    Thornell, Lars-Eric
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Sorokin, Lydia M
    Konttinen, Yrjö T
    Laminin isoforms in fetal and adult human adrenal cortex2003Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 88, nr 10, s. 4960-4966Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Laminin has been proposed to influence the function of human adrenal cortex. We have studied the distribution of laminin (Ln) chains using immunofluorescence in human fetal and adult adrenal cortex. In the fetal gland Ln alpha2- and alpha5-chains were weakly expressed in the definitive zone, whereas Ln alpha4-, beta1-, and gamma1-chains occurred around vessels. In the adult gland, Ln alpha2-, alpha5-, and gamma1-chains were found in epithelial basement membranes (BM) in all cortical zones, Ln alpha4-chain in vessels, Ln beta1-chain in outer zone, and Ln beta2-chain in the two inner zones of the cortex, respectively. Among the integrins in adult gland, integrin alpha(3)-subunit was confined to basal surfaces of cortical cells, alpha(6) to vessels, alpha(1) to the stroma, and alpha(2) diffusely to epithelial cells. Lutheran glycoprotein and dystroglycan occurred in the fetal gland diffusely in the definitive zone and throughout the epithelium in the adult. The isoform composition of BM of the adult adrenal gland is distinct, with Ln-2 and -10 in BM of the outer zone and Ln-4 and -11 in BM of the two inner zones. The results suggest that integrin alpha(3)beta(1) and Lutheran are candidate receptors for Ln-10 and -11, whereas dystroglycan probably binds Ln-2 and -4.

  • 48. Wake, Deborah J
    et al.
    Rask, Eva
    Livingstone, Dawn E W
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Walker, Brian R
    Local and systemic impact of transcriptional up-regulation of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue in human obesity.2003Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 88, nr 8, s. 3983-3988Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In idiopathic obesity circulating cortisol levels are not elevated, but high intraadipose cortisol concentrations have been implicated. 11beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyzes the conversion of inactive cortisone to active cortisol, thus amplifying glucocorticoid receptor (GR) activation. In cohorts of men and women, we have shown increased ex vivo 11HSD1 activity in sc adipose tissue associated with in vivo obesity and insulin resistance. Using these biopsies, we have now validated this observation by measuring 11HSD1 and GR mRNA and examined the impact on intraadipose cortisol concentrations, putative glucocorticoid regulated adipose target gene expression (angiotensinogen and leptin), and systemic measurements of cortisol metabolism. From aliquots of sc adipose biopsies from 16 men and 16 women we extracted RNA for real-time PCR and steroids for immunoassays. Adipose 11HSD1 mRNA was closely related to 11HSD1 activity [standardized beta coefficient (SBC) = 0.58; P < 0.01], and both were positively correlated with parameters of obesity (e.g. for BMI, SBC = 0.48; P < 0.05 for activity, and SBC = 0.63; P < 0.01 for mRNA) and insulin sensitivity (log fasting plasma insulin; SBC = 0.44; P < 0.05 for activity, and SBC = 0.33; P = 0.09 for mRNA), but neither correlated with urinary cortisol/cortisone metabolite ratios. Adipose GR-alpha and angiotensinogen mRNA levels were not associated with obesity or insulin resistance, but leptin mRNA was positively related to 11HSD1 activity (SBC = 0.59; P < 0.05) and tended to be associated with parameters of obesity (BMI: SBC = 0.40; P = 0.09), fasting insulin (SBC = 0.65; P < 0.05), and 11HSD1 mRNA (SBC = 0.40; P = 0.15). Intraadipose cortisol (142 +/- 30 nmol/kg) was not related to 11HSD1 activity or expression, but was positively correlated with plasma cortisol. These data confirm that idiopathic obesity is associated with transcriptional up-regulation of 11HSD1 in adipose, which is not detected by conventional in vivo measurements of urinary cortisol metabolites and is not accompanied by dysregulation of GR. Although this may drive a compensatory increase in leptin synthesis, whether it has an adverse effect on intraadipose cortisol concentrations and GR-dependent gene regulation remains to be established.

  • 49.
    Wiklund, Peder
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik. Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Rehabiliteringsmedicin.
    Toss, Fredrik
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Rehabiliteringsmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Weinehall, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och folkhälsovetenskap.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Nordström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Rehabiliteringsmedicin.
    Nordström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Abdominal and gynoid fat mass are associated with cardiovascular risk factors in men and women2008Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, nr 11, s. 4360-4366Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: Abdominal obesity is an established risk factor for cardiovascular disease (CVD). However, the correlation of dual-energy x-ray absorptiometry (DEXA) measurements of regional fat mass with CVD risk factors has not been completely investigated.

    OBJECTIVE: The aim of this study was to investigate the association of estimated regional fat mass, measured with DEXA and CVD risk factors.

    DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study of 175 men and 417 women. DEXA measurements of regional fat mass were performed on all subjects, who subsequently participated in a community intervention program.

    MAIN OUTCOME MEASURES: Outcome measures included impaired glucose tolerance, hypercholesterolemia, hypertriglyceridemia, and hypertension. RESULTS: We began by assessing the associations of the adipose measures with the cardiovascular outcomes. After adjustment for confounders, a sd unit increase in abdominal fat mass was the strongest predictor of most cardiovascular variables in men [odds ratio (OR)=2.63-3.37; P<0.05], whereas the ratio of abdominal to gynoid fat mass was the strongest predictor in women (OR=1.48-2.19; P<0.05). Gynoid fat mass was positively associated with impaired glucose tolerance, hypertriglyceridemia, and hypertension in men (OR=2.07-2.15; P<0.05), whereas the ratio of gynoid to total fat mass showed a negative association with hypertriglyceridemia and hypertension (OR=0.42-0.62; P<0.005).

    CONCLUSIONS: Abdominal fat mass is strongly independently associated with CVD risk factors in the present study. In contrast, gynoid fat mass was positively associated, whereas the ratio of gynoid to total fat mass was negatively associated with risk factors for CVD.

  • 50.
    Zhang, Lei
    et al.
    Department of Public Health, University of Helsinki, FIN-00014 Helsinki, Finland.
    Qiao, Qing
    Department of Public Health, University of Helsinki, FIN-00014 Helsinki, Finland.
    Tuomilehto, Jaakko
    Department of Public Health, University of Helsinki, FIN-00014 Helsinki, Finland.
    Janus, Edward D
    Department of Medicine, University of Melbourne, Western Hospital, Footscray, VIC 3011, Australia.
    Lam, Tai Hing
    Department of Community Medicine, School of Public Health, University of Hong Kong, Hong Kong, China.
    Ramachandran, Ambady
    India Diabetes Research Foundation and Dr. A. Ramachandran’s Diabetes Hospitals, Egmore, Chennai 600 008, India.
    Mohan, Viswanathan
    Madras Diabetes Research Foundation and Dr. Mohan’s Diabetes Specialities Centre, Chennai 600 086, India.
    Stehouwer, Coen D A
    Department of Internal Medicine and Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, 6202 AZ Maastricht, The Netherlands.
    Dong, Yanhu
    Qingdao Endocrinology and Diabetes Hospital and Institute, 266071 Qingdao, China.
    Nakagami, Tomoko
    Diabetes Center, Tokyo Women’s Medical University School of Medicine, 162-8666 Tokyo, Japan.
    Onat, Altan
    Turkish Society of Cardiology, Istanbul University, Istanbul 34452, Turkey.
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Distinct ethnic differences in lipid profiles across glucose categories2010Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, nr 4, s. 1793-1801Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Dyslipidemia coexists with hyperglycemia. However, little is known about the ethnic differences in lipid profiles at comparable glucose tolerance status.

    Objective: The aim was to study ethnic differences in lipid profiles stratified by glucose levels.

    Design and Setting: Data from 31 study cohorts of 12 countries, consisting of 24,760 men and 27,595 women aged 25–74 yr, were compared. The odds ratio for having dyslipidemia was estimated for each ethnic group stratified by glucose categories.

    Results: Compared with central and northern Europeans, multivariable adjusted odds ratios (95% confidence intervals) for having lower high-density lipoprotein-cholesterol were 4.74 (4.19–5.37), 5.05 (3.88–6.56), 3.07 (2.15–4.40), and 2.37 (1.67–3.35) in Asian Indian men, but 0.12 (0.09–0.16), 0.07 (0.04–0.13), 0.11 (0.07–0.20), and 0.16 (0.08–0.32) in Chinese men who had normoglycemia, prediabetes, and undiagnosed and diagnosed diabetes, respectively. Similar results were obtained for women. The prevalence of low high-density lipoprotein-cholesterol remained higher in Asian Indians (62.8% of the nondiabetic and 67.4% of the diabetic) than in central and northern Europeans (20.3 and 37.3%), Japanese (25.7 and 34.1%), or Qingdao Chinese (15.7 and 17.0%), even in individuals with low-density lipoprotein-cholesterol of less than 3 mmol/liter.

    Conclusion: There are distinct patterns of lipid profiles associated with ethnicity regardless of the glucose levels, suggesting that ethnic-specific strategies and guidelines on risk assessment and prevention of cardiovascular disease are required.

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