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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.
    Almby, Kristina E.
    et al.
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Katsogiannos, Petros
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Pereira, Maria J.
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Anders Karlsson, F.
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Sundbom, Magnus
    Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Wiklund, Urban
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    Kamble, Prasad G.
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Eriksson, Jan W.
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Time course of metabolic, neuroendocrine, and adipose effects during 2 years of follow-up after gastric bypass in patients with type 2 diabetes2021Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 106, nr 10, s. E4049-E4061Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Roux-en-Y gastric bypass surgery (RYGB) markedly improves glycemia in patients with type 2 diabetes (T2D), but underlying mechanisms and changes over time are incompletely understood.

    Objective: Integrated assessment of neuroendocrine and metabolic changes over time inT2D patients undergoing RYGB.

    Design and Setting: Follow-up of single-center randomized study.

    Patients: Thirteen patients with obesity andT2D compared to 22 healthy subjects.

    Interventions: Blood chemistry, adipose biopsies, and heart rate variability were obtained before and 4, 24, and 104 weeks post-RYGB.

    Results: After RYGB, glucose-lowering drugs were discontinued and hemoglobin A1c fell from mean 55 to 41 mmol/mol by 104 weeks (P < 0.001). At 4 weeks, morning cortisol (P < 0.05) and adrenocorticotropin (P = 0.09) were reduced by 20%. Parasympathetic nerve activity (heart rate variability derived) increased at 4 weeks (P < 0.05) and peaked at 24 weeks (P < 0.01). C-reactive protein (CRP) and white blood cells were rapidly reduced (P < 0.01). At 104 weeks, basal and insulin-stimulated adipocyte glucose uptake increased by 3-fold vs baseline and expression of genes involved in glucose transport, fatty acid oxidation, and adipogenesis was upregulated (P < 0.01). Adipocyte volume was reduced by 4 weeks and more markedly at 104 weeks, by about 40% vs baseline (P < 0.01).

    Conclusions: We propose this order of events: (1) rapid glucose lowering (days); (2) attenuated cortisol axis activity and inflammation and increased parasympathetic tone (weeks); and (3) body fat and weight loss, increased adipose glucose uptake, and whole-body insulin sensitivity (months-years; similar to healthy controls).Thus, neuroendocrine pathways can partly mediate early glycemic improvement after RYGB, and adipose factors may promote long-term insulin sensitivity and normoglycemia.

    Fulltekst (pdf)
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  • 4. 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.

  • 5. 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.

  • 6. Bengtsson, Daniel
    et al.
    Ragnarsson, Oskar
    Berinder, Katarina
    Dahlqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Edén Engström, Britt
    Ekman, Bertil
    Höybye, Charlotte
    Burman, Pia
    Wahlberg, Jeanette
    Psychotropic drugs in patients with Cushing's disease before diagnosis and at long-term follow-up: a nationwide study2021Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 106, nr 6, s. 1750-1760Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: Psychiatric symptoms are common in Cushing's disease (CD) and seem only partly reversible following treatment.

    OBJECTIVE: To investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up.

    DESIGN: Nationwide longitudinal register-based study.

    SETTING: University Hospitals in Sweden.

    SUBJECTS: CD patients diagnosed between 1990 and 2018 (N=372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed.

    MAIN OUTCOME MEASURES: Data from the Swedish Prescribed Drug Register and the Patient Register.

    RESULTS: In the 5-year period before, and at diagnosis, use of antidepressants (OR 2.2[95%CI 1.3-3.7] and 2.3[1.6-3.5]), anxiolytics (2.9[1.6-5.3] and 3.9[2.3-6.6]) and sleeping pills (2.1[1.2-3.7] and 3.8[2.4-5.9]) was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants (2.4[1.5-3.9]) and sleeping pills (3.1[1.9-5.3]). Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (IQR 8.1-10.4) had higher use of antidepressants (OR 2.0[1.1-3.8]) and sleeping pills (2.4[1.3-4.7]), but not of drugs for hypertension.

    CONCLUSIONS: Increased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health.

    Fulltekst (pdf)
    fulltext
  • 7.
    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.

  • 8. 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.

  • 9.
    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.

  • 10. 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.

  • 11.
    Bäcklund, Nils
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Lundstedt, Staffan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Tornevi, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Wihlbäck, Anna-Carin
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Dahlqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Brattsand, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Salivary cortisol and cortisone can circumvent confounding effects of oral contraceptives in the short synacthen test2024Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Adrenal insufficiency (AI) is usually diagnosed by low plasma cortisol levels following a short Synacthen test (SST). Most plasma cortisol is bound to corticosteroid-binding globulin, which is increased by estrogen in combined estrogen-progestin oral contraceptives (COCs). Women with AI using COCs are therefore at risk of having an apparently normal plasma cortisol level during SST, which would not adequately reflect AI.

    Objective: To test whether salivary cortisol or cortisone during SST is more robust against the COC effect and to calculate the lower reference limits (LRLs) for these to be used as tentative diagnostic cutoffs to exclude AI.

    Methods: Forty-one healthy women on COCs and 46 healthy women without exogenous estrogens performed an SST with collection of plasma and salivary samples at 0, 30, and 60 min after Synacthen injection. The groups were compared using regression analysis with age as covariate and the LRLs were calculated parametrically.

    Results: SST-stimulated plasma cortisol levels were significantly higher in the COC group versus controls, while mean salivary cortisol and cortisone levels were slightly lower in the COC group. Importantly, COC use did not significantly alter LRLs for salivary cortisol or cortisone. The smallest LRL difference between groups was seen for salivary cortisone.

    Conclusion: Salivary cortisol and especially salivary cortisone are considerably less affected by COC use than plasma cortisol during SST. Due to similar LRLs, a common cutoff for salivary cortisol and cortisone during SST can be used to exclude AI in premenopausal women irrespective of COC use.

    Fulltekst (pdf)
    fulltext
  • 12.
    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.

  • 13.
    Clendenen, Tess V.
    et al.
    Department of Population Health, New York University School of Medicine, NY, New York, United States.
    Ge, Wenzhen
    Department of Population Health, New York University School of Medicine, NY, New York, United States.
    Koenig, Karen L.
    Department of Population Health, New York University School of Medicine, NY, New York, United States.
    Afanasyeva, Yelena
    Department of Population Health, New York University School of Medicine, NY, New York, United States.
    Agnoli, Claudia
    Epidemiology and Prevention Unit, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy.
    Bertone-Johnson, Elizabeth
    Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts, MA, Amherst, United States.
    Brinton, Louise A.
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Darvishian, Farbod
    Pathology, New York University School of Medicine, NY, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, NY, New York, United States.
    Dorgan, Joanne F.
    Department of Epidemiology and Public Health, University of Maryland School of Medicine, MD, Baltimore, United States.
    Eliassen, A. Heather
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, MA, Boston, United States.
    Falk, Roni T.
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Hankinson, Susan E.
    Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts, MA, Amherst, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, MA, Boston, United States.
    Hoffman-Bolton, Judith
    Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, MD, Baltimore, United States.
    Key, Timothy J.
    Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
    Krogh, Vittorio
    Epidemiology and Prevention Unit, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy.
    Nichols, Hazel B.
    Department of Epidemiology, University of North Carolina, NC, Chapel Hill, United States.
    Sandler, Dale P.
    Epidemiology Branch, National Institute of Environmental Health Sciences, NC, Research Triangle Park, United States.
    Schoemaker, Minouk J.
    Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
    Sluss, Patrick M.
    Department of Pathology, Harvard Medical School, MA, Boston, United States.
    Sund, Malin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi. Department of Surgery, Umeå University Hospital, Umeå, Sweden.
    Swerdlow, Anthony J.
    Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom; Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom.
    Visvanathan, Kala
    Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, MD, Baltimore, United States; Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, MD, Baltimore, United States.
    Liu, Mengling
    Department of Population Health, New York University School of Medicine, NY, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, NY, New York, United States.
    Zeleniuch-Jacquotte, Anne
    Department of Population Health, New York University School of Medicine, NY, New York, United States; Perlmutter Cancer Center, New York University School of Medicine, NY, New York, United States.
    Breast Cancer Risk Factors and Circulating Anti-Müllerian Hormone Concentration in Healthy Premenopausal Women2021Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 106, nr 11, s. E4542-E4553Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: We previously reported that anti-Müllerian hormone (AMH), a marker of ovarian reserve, is positively associated with breast cancer risk, consistent with other studies.

    Objective: This study assessed whether risk factors for breast cancer are correlates of AMH concentration.

    Methods: This cross-sectional study included 3831 healthy premenopausal women (aged 21-57, 87% aged 35-49) from 10 cohort studies among the general population.

    Results: Adjusting for age and cohort, AMH positively associated with age at menarche (P < 0.0001) and parity (P = 0.0008) and inversely associated with hysterectomy/partial oophorectomy (P = 0.0008). Compared with women of normal weight, AMH was lower (relative geometric mean difference 27%, P < 0.0001) among women who were obese. Current oral contraceptive (OC) use and current/former smoking were associated with lower AMH concentration than never use (40% and 12% lower, respectively, P < 0.0001). We observed higher AMH concentrations among women who had had a benign breast biopsy (15% higher, P = 0.03), a surrogate for benign breast disease, an association that has not been reported. In analyses stratified by age (<40 vs ≥40), associations of AMH with body mass index and OCs were similar in younger and older women, while associations with the other factors (menarche, parity, hysterectomy/partial oophorectomy, smoking, and benign breast biopsy) were limited to women ≥40 (P-interaction < 0.05).

    Conclusion: This is the largest study of AMH and breast cancer risk factors among women from the general population (not presenting with infertility), and it suggests that most associations are limited to women over 40, who are approaching menopause and whose AMH concentration is declining.

  • 14. 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.

  • 15. 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.

  • 16.
    Dam, Veerle
    et al.
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Netherlands Heart Institute, Utrecht, Netherlands.
    Onland-Moret, N. Charlotte
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
    Burgess, Stephen
    MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom; MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Homerton College, Cambridge, United Kingdom.
    Chirlaque, Maria-Dolores
    Department of Epidemiology, Regional Health Authority, IMIB-Arrixaca, Murcia University, Murcia, Spain.
    Peters, Sanne A. E
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; The George Institute for Global Health, Imperial College London, London, United Kingdom.
    Schuit, Ewoud
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
    Tikk, Kaja
    Division of Clinical Epidemiology and Aging Research, German Cancer Research Centre (DKFZ), Heidelberg, Germany; German Cancer Consortium, DKFZ, Heidelberg, Germany.
    Weiderpass, Elisabete
    International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Oliver-Williams, Clare
    MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Homerton College, Cambridge, United Kingdom.
    Wood, Angela M
    MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Tjønneland, Anne
    Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Dahm, Christina C
    Department of Public Health, Aarhus University, Aarhus, Denmark.
    Overvad, Kim
    Department of Public Health, Aarhus University, Aarhus, Denmark; Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.
    Boutron-Ruault, Marie-Christine
    INSERM, Centre for Research in Epidemiology and Population Health, U1018, Nutrition, Hormones, and Women's Health Team, Institut Gustave Roussy, Villejuif, France.
    Schulze, Matthias B
    Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
    Trichopoulou, Antonia
    Hellenic Health Foundation, Athens, Greece; WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
    Ferrari, Pietro
    International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Masala, Giovanna
    Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
    Krogh, Vittorio
    Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
    Tumino, Rosario
    Cancer Registry and Histopathology Department, "Civic - M.P. Arezzo" hospital, ASP Ragusa, Ragusa, Italy.
    Matullo, Giuseppe
    Department of Medical Sciences, University of Torino, Torino, Italy; Italian Institute for Genomic Medicine–IIGM/HuGeF, Torino, Italy.
    Panico, Salvatore
    Dipartimento di medicina clinica e chirurgia, Federico II University, Naples, Italy.
    Boer, Jolanda M. A
    National Institute for Public Health and the Environment, Bilthoven, Netherlands.
    Verschuren, W. M. Monique
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; National Institute for Public Health and the Environment, Bilthoven, Netherlands.
    Waaseth, Marit
    Department of Pharmacy, Faculty of Health Sciences, UiT the Arctic University of Norway, Tromsø, Norway.
    PCrossed D sign©rez, Maria JosCrossed D sign© Sánchez
    Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA, Universidad de Granada, Granada, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
    Amiano, Pilar
    CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Public Health Division of Gipuzkoa, Biodonostia Research Institute, San Sebastian, Spain.
    Imaz, Liher
    CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Public Health Division of Gipuzkoa, Biodonostia Research Institute, San Sebastian, Spain.
    Moreno-Iribas, Conchi
    Instituto de Salud Pública de Navarra, IdiSNA, Navarre Institute for Health Research, REDISSEC, Pamplona, Spain.
    Melander, Olle
    Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Harlid, Sophia
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nordendahl, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Wennberg, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Key, Timothy J
    Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
    Riboli, Elio
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
    Santiuste, Carmen
    CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Epidemiology, Murcia Regional Health Authority, IMIB-Arrixaca, Murcia, Spain.
    Kaaks, Rudolf
    Division of Cancer Epidemiology, DKFZ, Foundation under Public Law, Heidelberg, Germany.
    Katzke, Verena
    Division of Cancer Epidemiology, DKFZ, Foundation under Public Law, Heidelberg, Germany.
    Langenberg, Claudia
    MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
    Wareham, Nicholas J
    MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
    Schunkert, Heribert
    Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
    Erdmann, Jeanette
    Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.
    Willenborg, Christina
    Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.
    Hengstenberg, Christian
    Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.
    Kleber, Marcus E
    Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
    Delgado, Graciela
    Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
    März, Winfried
    Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
    Kanoni, Stavroula
    William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
    Dedoussis, George
    Department of Nutrition-Dietetics/Harokopio University, Athens, Greece.
    Deloukas, Panos
    William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Centre for Genomic Health, Queen Mary University of London, London, United Kingdom; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.
    Nikpay, Majid
    Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, ON, Ottawa, Canada.
    Mcpherson, Ruth
    Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, ON, Ottawa, Canada.
    Scholz, Markus
    Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany; LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
    Teren, Andrej
    LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany; Heart Center Leipzig, Leipzig, Germany.
    Butterworth, Adam S
    MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Van Der Schouw, Yvonne T
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
    Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-sample Mendelian Randomization2022Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 107, nr 7, s. E2952-E2961Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause. Objectives: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men. Design: Two-sample MR, using both cohort data as well as summary statistics, with 4 methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression. Participants: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available genome-wide association studies were pooled for the different analyses. Main Outcome Measures: CHD, CHD risk factors, and ANM. Results: Across different methods of MR, no association was found between genetically determined reproductive aging and CHD risk in women (relative risk estimateIVW = 0.99; 95% confidence interval (CI), 0.97-1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging. Conclusion: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men.

  • 17. 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.

  • 18. Deshmukh, Harshal A.
    et al.
    Madsen, Anne Lundager
    Vinuela, Ana
    Have, Christian Theil
    Grarup, Niels
    Tura, Andrea
    Mahajan, Anubha
    Heggie, Alison J.
    Koivula, Robert W.
    De Masi, Federico
    Tsirigos, Konstantinos K.
    Linneberg, Allan
    Drivsholm, Thomas
    Pedersen, Oluf
    Sorensen, Thorkild I. A.
    Astrup, Arne
    Gjesing, Anette A. P.
    Pavo, Imre
    Wood, Andrew R.
    Ruetten, Hartmut
    Jones, Angus G.
    Koopman, Anitra D. M.
    Cederberg, Henna
    Rutters, Femke
    Ridderstrale, Martin
    Laakso, Markku
    McCarthy, Mark, I
    Frayling, Tim M.
    Ferrannini, Ele
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, UK; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Lund University, Sweden; Department of Nutrition, Harvard TH Chan School of Public Health, Boston, Massachusetts.
    Pearson, Ewan R.
    Mari, Andrea
    Hansen, Torben
    Walker, Mark
    Genome-Wide Association Analysis of Pancreatic Beta-Cell Glucose Sensitivity2021Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 106, nr 1, s. 80-90Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Pancreatic beta-cell glucose sensitivity is the slope of the plasma glucose-insulin secretion relationship and is a key predictor of deteriorating glucose tolerance and development of type 2 diabetes. However, there are no large-scale studies looking at the genetic determinants of beta-cell glucose sensitivity.

    Objective: To understand the genetic determinants of pancreatic beta-cell glucose sensitivity using genome-wide meta-analysis and candidate gene studies.

    Design: We performed a genome-wide meta-analysis for beta-cell glucose sensitivity in subjects with type 2 diabetes and nondiabetic subjects from 6 independent cohorts (n = 5706). Beta-cell glucose sensitivity was calculated from mixed meal and oral glucose tolerance tests, and its associations between known glycemia-related single nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) SNPs were estimated using linear regression models.

    Results: Beta-cell glucose sensitivity was moderately heritable (h2 ranged from 34% to 55%) using SNP and family-based analyses. GWAS meta-analysis identified multiple correlated SNPs in the CDKAL1 gene and GIPR-QPCTL gene loci that reached genome-wide significance, with SNP rs2238691 in GIPR-QPCTL (P value = 2.64 × 10−9) and rs9368219 in the CDKAL1 (P value = 3.15 × 10−9) showing the strongest association with beta-cell glucose sensitivity. These loci surpassed genome-wide significance when the GWAS meta-analysis was repeated after exclusion of the diabetic subjects. After correction for multiple testing, glycemia-associated SNPs in or near the HHEX and IGF2B2 loci were also associated with beta-cell glucose sensitivity.

    Conclusion: We show that, variation at the GIPR-QPCTL and CDKAL1 loci are key determinants of pancreatic beta-cell glucose sensitivity.

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  • 19. 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)

  • 20. 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.

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  • 21. Espiard, Stéphanie
    et al.
    McQueen, Johanna
    Sherlock, Mark
    Ragnarsson, Oskar
    Bergthorsdottir, Ragnhildur
    Burman, Pia
    Dahlqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Ekman, Bertil
    Engström, Britt Edén
    Skrtic, Stanko
    Wahlberg, Jeanette
    Stewart, Paul M
    Johannsson, Gudmundur
    Improved Urinary Cortisol Metabolome in Addison's disease: a Prospective Trial of Dual-Release Hydrocortisone2021Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 106, nr 3, s. 814-825Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy has demonstrated an improved metabolic profile compared to conventional 3-times-daily (TID-HC) therapy among patients with primary adrenal insufficiency. This effect might be related to a more physiological cortisol profile, but also to a modified pattern of cortisol metabolism.

    OBJECTIVE: To study cortisol metabolism during DR-HC and TID-HC.

    DESIGN: Randomized, 12-week, crossover study.

    INTERVENTION AND PARTICIPANTS: DC-HC and same daily dose of TID-HC in patients with primary adrenal insufficiency (n=50) versus healthy subjects (n=124) as control.

    MAIN OUTCOME MEASURES: Urinary corticosteroid metabolites measured by gas chromatography/mass spectrometry on 24-hour urinary collections.

    RESULTS: Total cortisol metabolites decreased during DR-HC compared to TID-HC (P < 0.001) and reached control values (P = 0.089). During DR-HC, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity measured by tetrahydrocortisol+5α-tetrahydrocortisol/tetrahydrocortisone ratio was reduced compared to TID-HC (P < 0.05), but remained increased versus controls (P < 0.001). 11β-HSD2 activity measured by urinary free cortisone/free cortisol ratio was decreased with TID-HC versus controls (P < 0.01) but normalized with DR-HC (P = 0.358). 5α- and 5β-reduced metabolites were decreased with DR-HC compared to TID-HC. Tetrahydrocortisol/5α-tetrahydrocortisol ratio was increased during both treatments, suggesting increased 5β-reductase activity.

    CONCLUSIONS: The urinary cortisol metabolome shows striking abnormalities in patients receiving conventional TID-HC replacement therapy with increased 11β-HSD1 activity that may account for the unfavorable metabolic phenotype in primary adrenal insufficiency. Its change towards normalization with DR-HC may mediate beneficial metabolic effects. The urinary cortisol metabolome may serve as a tool to assess optimal cortisol replacement therapy.

    Fulltekst (pdf)
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  • 22.
    Flanagan, John
    et al.
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Chatzittofis, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Medical School, University of Cyprus, Nicosia, Cyprus.
    Boström, Adrian Desai E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Neuropaediatric Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Hallberg, Jonas
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Öberg, Katarina Görts
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Arver, Stefan
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Stockholm, Sweden.
    High plasma oxytocin levels in men with hypersexual disorder2022Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 107, nr 5, s. e1816-e1822Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Hypersexual disorder (HD) involves excessive, persistent sexual behaviors related to various mood states and the diagnosis compulsive sexual behavior disorder is included as an impulse control disorder in the 11th revision of the International Classification of Diseases. Although the neurobiology behind the disorder is not clear, some studies suggest dysregulated hypothalamic-pituitary-adrenal axis. Oxytocin acts as counterregulatory neuroendocrine hormone to cortisol and is also involved in sexual behavior.

    Objective: We hypothesized that oxytocin may play a role in the pathophysiology of HD with compensatory actions to cortisol.

    Design: Longitudinal.

    Setting: ANOVA clinic (Karolinska University Hospital).

    Patients or other participants: 64 males with HD and 38 age-matched healthy volunteers.

    Main Outcome Measures: Plasma oxytocin levels, measured with radioimmunoassay; Hypersexual Disorder Screening Inventory; and Hypersexual Disorder: Current Assessment Scale for assessing hypersexual symptoms.

    Interventions: A patient subgroup (n=30) completed the manual-based group-administered cognitive-behavioral therapy (CBT) program for HD, and posttreatment oxytocin levels were measured.

    Results: Hypersexual men (n=64) exhibited significantly higher oxytocin plasma levels (mean±SD: 31.0±9.9 pM) compared with healthy volunteers (16.9±3.9 pM; P<0.001). There were significant positive correlations between oxytocin levels and the rating scales measuring hypersexual behavior. Patients who completed CBT treatment (n=30) had a significant reduction of oxytocin plasma levels from pretreatment (30.5±10.1 pM) to posttreatment (20.2±8.0 pM; P<0.001).

    Conclusions: The results suggest that the hyperactive oxytocinergic system in hypersexual men may be a compensatory mechanism to attenuate hyperactive stress.

    Fulltekst (pdf)
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  • 23.
    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.

  • 24. Goedecke, Julia H.
    et al.
    Chorell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    van Jaarsveld, Paul J.
    Risérus, Ulf
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Fatty Acid Metabolism and Associations with Insulin Sensitivity Differs Between Black and White South African Women2021Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 106, nr 1, s. E140-E151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Genetic differences in desaturase genes and consequently fatty acid metabolism have been reported. The aims were to examine ethnic differences in serum fatty acid composition and desaturase indices, and assess the ethnic-specific associations with insulin sensitivity (IS) and liver fat in black and white South African (SA) women.

    Methods: In this cross-sectional study including 92 premenopausal black (n = 46) and white (n = 46) SA women, serum fatty acid composition was measured in cholesteryl ester (CE) and nonesterified fatty acid (NEFA) fractions. Desaturase activities were estimated as product-to-precursor ratios: stearoyl-CoA desaturase-1 (SCD1-16, 16:1n-7/16:0); d-5 desaturase (D5D, 20:4n-6/20:3n-6), and d-6 desaturase (D6D, 18:3n-6/18:2n-6). Whole-body IS was estimated from an oral glucose tolerance test using the Matsuda index. In a subsample (n = 30), liver fat and hepatic IS were measured by 1H-magnetic resonance spectroscopy and hyperinsulinemic euglycemic clamp, respectively.

    Results: Despite lower whole-body IS (P = .006), black women had higher CE D5D and lower D6D and SCD1-16 indices than white women (P < .01). CE D6D index was associated with lower IS in white women only (r = -0.31, P = .045), whereas D5D index was associated with higher IS in black women only (r = 0.31, P = .041). In the subsample, D6D and SCD1-16 indices were positively and D5D was negatively associated with liver fat (P < .05). Conversely, CE SCD1-16 was negatively associated with hepatic IS (P < .05), but not independently of liver fat. Conclusions: Ethnic differences in fatty acid-derived desaturation indices were observed, with insulin-resistant black SA women paradoxically showing a fatty acid pattern typical for higher insulin sensitivity in European populations.

  • 25. 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.

  • 26.
    Grahnemo, Louise
    et al.
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Eriksson, Anna L.
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Drug Treatment, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
    Nethander, Maria
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; Sahlgrenska Academy, Bioinformatics and Data Centre, University of Gothenburg, Gothenburg, Sweden.
    Johansson, Robert
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Lorentzon, Mattias
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg and Geriatric Medicine, Sahlgrenska University Hospital, Sweden; Mary McKillop Institute for Health Research, Australian Catholic University, 3000 VIC, Melbourne, Australia.
    Mellström, Dan
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg and Geriatric Medicine, Sahlgrenska University Hospital, Sweden.
    Pettersson-Kymmer, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Ohlsson, Claes
    Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Drug Treatment, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
    Low circulating valine associate with high risk of hip fractures2023Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 108, nr 11, s. e1384-e1393Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: Hip fractures constitute a major health concern. An adequate supply of amino acids is crucial to ensure optimal acquisition and remodeling of bone. Circulating amino acid levels have been proposed as markers of bone mineral density, but data on their ability to predict incident fractures are scarce.

    OBJECTIVES: To investigate the associations between circulating amino acids and incident fractures.

    METHODS: We used UK Biobank (n = 111 257; 901 hip fracture cases) as a discovery cohort and the Umeå Fracture and Osteoporosis (UFO) hip fracture study (hip fracture cases n = 2225; controls n = 2225) for replication. Associations with bone microstructure parameters were tested in a subsample of Osteoporotic Fractures in Men Sweden (n = 449).

    RESULTS: Circulating valine was robustly associated with hip fractures in the UK Biobank (HR per SD increase 0.79, 95% CI 0.73-0.84), and this finding was replicated in the UFO study (combined meta-analysis including 3126 incident hip fracture cases, odds ratio per SD increase 0.84, 95% CI 0.80-0.88). Detailed bone microstructure analyses showed that high circulating valine was associated with high cortical bone area and trabecular thickness.

    CONCLUSION: Low circulating valine is a robust predictor of incident hip fractures. We propose that circulating valine may add information for hip fracture prediction. Future studies are warranted to determine whether low valine is causally associated with hip fractures.

    Fulltekst (pdf)
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  • 27. 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.

  • 28.
    Himonakos, Christos
    et al.
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Department of Internal Medicine, Center for Endocrinology and Diabetes, Karlstad Central Hospital, Karlstad, Sweden.
    Burman, Pia
    Department of Endocrinology, Lund University, Skåne University Hospital, Malmö, Sweden.
    Borg, Henrik
    Department of Endocrinology, Lund University, Skåne University Hospital, Lund, Sweden.
    Dahlqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Engström, Britt Edén
    Department of Medical Sciences, Endocrinology and Mineral Metabolism, Uppsala University and Uppsala University Hospital, Uppsala, Sweden.
    Ekman, Bertil
    Department of Endocrinology and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
    Emilsson, Louise
    Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway; Nysäter Health Care Center and Center for Clinical Research, County Council of Värmland, Karlstad, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Olsson, Daniel S.
    Department of Endocrinology at Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Ragnarsson, Oskar
    Department of Endocrinology at Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Wahlberg, Jeanette
    Department of Medicine, Örebro University Hospital, Sweden; School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Sweden.
    Åkerman, Anna-Karin
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Department of Medicine, Örebro University Hospital, Sweden.
    Hoybye, Charlotte
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden.
    Berinder, Katarina
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden.
    Long-term follow-up of 84 patients with giant prolactinomas: a swedish nationwide study2023Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 108, nr 12, s. e1506-e1514Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To describe the clinical presentation and treatment outcomes in a nationwide cohort of patients with giant prolactinomas.

    Methods: Register-based study of patients with giant prolactinomas [serum prolactin (PRL) > 1000 & mu;g/L, tumor diameter & GE;40 mm] identified in the Swedish Pituitary Register 1991-2018.

    Results: Eighty-four patients [mean age 47 (SD & PLUSMN;16) years, 89% men] were included in the study. At diagnosis, the median PRL was 6305 & mu;g/L (range 1450-253 000), the median tumor diameter was 47 mm (range 40-85), 84% of the patients had hypogonadotropic hypogonadism, and 71% visual field defects. All patients were treated with a dopamine agonist (DA) at some point. Twenty-three (27%) received 1 or more additional therapies, including surgery (n = 19), radiotherapy (n = 6), other medical treatments (n = 4), and chemotherapy (n = 2). Ki-67 was & GE;10% in 4/14 tumors. At the last follow-up [median 9 years (interquartile range (IQR) 4-15)], the median PRL was 12 & mu;g/L (IQR 4-126), and the median tumor diameter was 22 mm (IQR 3-40). Normalized PRL was achieved in 55%, significant tumor reduction in 69%, and combined response (normalized PRL and significant tumor reduction) in 43%. In the primary DA-treated patients (n = 79), the reduction in PRL or tumor size after the first year predicted the combined response at the last follow-up (P < .001 and P = .012, respectively).

    Conclusion: DAs effectively reduced PRL and tumor size, but approximately 1 patient out of 4 needed multimodal treatment. Our results suggest that the response to DA after 1 year is useful for identifying patients who need more careful monitoring and, in some cases, additional treatment.

    Fulltekst (pdf)
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  • 29. Holmer, Helene
    et al.
    Svensson, Johan
    Rylander, Lars
    Johannsson, Gudmundur
    Rosén, Thord
    Bengtsson, Bengt-Åke
    Thorén, Marja
    Höybye, Charlotte
    Degerblad, Marie
    Bramnert, Margareta
    Hägg, Erik
    Umeå University Hospital.
    Edén Engström, Britt
    Ekman, Bertil
    Norrving, Bo
    Hagmar, Lars
    Erfurth, Eva-Marie
    Nonfatal stroke, cardiac disease, and diabetes mellitus in hypopituitary patients on hormone replacement including growth hormone2007Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, nr 9, s. 3560-3567Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: The impact of long-term GH replacement on cerebrovascular and cardiovascular diseases and diabetes mellitus in hypopituitary patients is unknown.

    Objective: The incidence of nonfatal stroke and cardiac events, and prevalence of type 2 diabetes mellitus ( T2D) and cardioprotective medication were compared between cohorts of GH-deficient (GHD) patients and population controls.

    Design and Participants: The incidence of nonfatal stroke and cardiac events was estimated retrospectively from questionnaires in 750 GHD patients and 2314 matched population controls. A prevalence of T2D and cardioprotective medication was recorded at the distribution of questionnaires. Time since first pituitary deficiency to start of GH therapy was 4 and 2 yr, and time on GH therapy was 6 yr for GHD women and men, respectively.

    Results: Lifelong incidence of nonfatal stroke was tripled in GHD women and doubled in GHD men, but a decline was seen in both genders during periods after first pituitary hormone deficiency and GHD, during which most patients had GH therapy. The lifelong incidence of nonfatal cardiac events declined in GHD men during first pituitary hormone deficiency and GHD periods. GHD women had a higher prevalence of T2D and lipid-lowering medication, whereas GHD men had a higher prevalence of antihypertensive medication.

    Conclusions: The declined risks of nonfatal stroke in both genders and of nonfatal cardiac events in GHD men during periods on GH replacement may be caused by prescription of cardioprotective drugs and 6-yr GH replacement. GHD women had an increased prevalence of T2D, partly attributed to higher body mass index and lower physical activity.

  • 30. Jarvie, Eleanor M.
    et al.
    Stewart, Frances M.
    Ramsay, Jane E.
    Brown, E. Ann
    Meyer, Barbara J.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Griffin, Bruce A.
    Freeman, Dilys J.
    Maternal Adipose Tissue Expansion, A Missing Link in the Prediction of Birth Weight Centile2020Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 105, nr 3, s. E814-E825Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Maternal body mass index (BMI) is associated with increased birth weight but does not explain all the variance in fetal adiposity.

    Objective: To assess the contribution of maternal body fat distribution to offspring birth weight and adiposity.

    Design: Longitudinal study throughout gestation and at delivery.

    Setting: Women recruited at 12 weeks of gestation and followed up at 26 and 36 weeks. Cord blood was collected at delivery.

    Patients: Pregnant women (n = 45) with BMI 18.0 to 46.3 kg/m(2) and healthy pregnancy outcome.

    Methods: Maternal first trimester abdominal subcutaneous and visceral adipose tissue thickness (SAT and VAT) was assessed by ultrasound.

    Main Outcome Measures: Maternal body fat distribution, maternal and cord plasma glucose and lipid concentrations, placental weight, birth weight, and fetal adiposity assessed by cord blood leptin.

    Results: VAT was the only anthropometric measure independently associated with birth weight centile (r(2) adjusted 15.8%, P=.002). BMI was associated with trimester 2 and trimesters 1 through 3 area under the curve (AUC) glucose and insulin resistance (Homeostatic Model Assessment). SAT alone predicted trimester 2 lipoprotein lipase (LPL) mass (a marker of adipocyte insulin sensitivity) (11.3%, P=.017). VAT was associated with fetal triglyceride (9.3%, P=.047). Placental weight was the only independent predictor of fetal adiposity (48%, P<.001). Maternal trimester 2 and AUC LPL were inversely associated with fetal adiposity (r = -0.69, P=.001 and r = -0.58, P=.006, respectively).

    Conclusions: Maternal VAT provides additional information to BMI for prediction of birth weight. VAT may be a marker of reduced SAT expansion and increased availability of maternal fatty acids for placental transport.

  • 31. 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.

  • 32.
    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.

  • 33.
    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.

  • 34.
    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.

  • 35.
    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.

  • 36.
    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.

  • 37.
    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.

  • 38.
    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)
  • 39.
    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.

  • 40. 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.

  • 41. 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.

  • 42.
    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)
  • 43. 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.

  • 44. 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.

  • 45.
    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.

  • 46. 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.

  • 47. 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.

  • 48. Nethander, Maria
    et al.
    Pettersson-Kymmer, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Vandenput, Liesbeth
    Lorentzon, Mattias
    Karlsson, Magnus
    Mellström, Dan
    Ohlsson, Claes
    BMD-Related Genetic Risk Scores Predict Site-Specific Fractures as Well as Trabecular and Cortical Bone Microstructure2020Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 105, nr 4, s. e1344-e1357Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: It is important to identify patients at highest risk of fractures.

    OBJECTIVE: To compare the separate and combined performances of bone-related genetic risk scores (GRSs) for prediction of forearm, hip and vertebral fractures separately, as well as of trabecular and cortical bone microstructure parameters separately.

    DESIGN, SETTING, AND PARTICIPANTS: Using 1103 single nucleotide polymorphisms (SNPs) independently associated with estimated bone mineral density of the heel (eBMD), we developed a weighted GRS for eBMD and determined its contribution to fracture prediction beyond 2 previously developed GRSs for femur neck BMD (49 SNPs) and lumbar spine BMD (48 SNPs). Associations between these GRSs and forearm (ncases = 1020; ncontrols = 2838), hip (ncases = 1123; ncontrols = 2630) and vertebral (ncases = 288; ncontrols = 1187) fractures were evaluated in 3 Swedish cohorts. Associations between the GRSs and trabecular and cortical bone microstructure parameters (n = 426) were evaluated in the MrOS Sweden cohort.

    RESULTS: We found that eBMDGRS was the only significant independent predictor of forearm and vertebral fractures while both FN-BMDGRS and eBMDGRS were significant independent predictors of hip fractures. The eBMDGRS was the major GRS contributing to prediction of trabecular bone microstructure parameters while both FN-BMDGRS and eBMDGRS contributed information for prediction of cortical bone microstructure parameters.

    CONCLUSIONS: The eBMDGRS independently predicts forearm and vertebral fractures while both FN-BMDGRS and eBMDGRS contribute independent information for prediction of hip fractures. We propose that eBMDGRS captures unique information about trabecular bone microstructure useful for prediction of forearm and vertebral fractures. These findings may facilitate personalized medicine to predict site-specific fractures as well as cortical and trabecular bone microstructure separately.

    Fulltekst (pdf)
    fulltext
  • 49. 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.

  • 50.
    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.

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