| 1. |
- Nordenström, Anna, et al.
(författare)
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Are carriers of CYP21A2 mutations less vulnerable to psychological stress? A population-based national cohort study
- 2016
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Ingår i: Clinical Endocrinology. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0300-0664 .- 1365-2265.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Congenital adrenal hyperplasia (CAH) is one of the most common monogenic autosomal recessive disorders with an incidence of one in 15 000. About one in 70 individuals in the general population are carriers of a severe CYP21A2 mutation. It has been suggested that this confers a survival advantage, perhaps as a result of increased activity in the hypothalamic–pituitary–adrenal axis. We investigated vulnerability to psychological stress in obligate carriers. Method: The Swedish CAH Registry encompasses more than 600 patients. Parents, that is obligate carriers of the CYP21A2 mutation, were identified through the Multigeneration Register. The diagnosis of the child was used as the psychological stressor. Psychiatric diagnoses before and after the birth of a child with CAH were compared to those of controls derived from (i) the general population, (ii) parents of children with hypospadias and (iii) parents of children with diabetes mellitus type 1 (T1DM). Results: Parents of children with CAH had less risk of being diagnosed with any psychiatric disorder (OR, 0 6), an affective disorder (OR, 0 5) or substance misuse (OR, 0 5) after the diagnosis of the child, compared to the general population. Their risk was also decreased compared to parents of a child with hypospadias (OR, 0 6, 0 4 and 0 2, respectively) and parents of a child with T1DM (OR 0 7, 0 6 and 0 2, respectively). The CYP21A2 carriers had a lower risk of developing mood and stress-related disorders after the diagnosis of the child. Conclusion: Obligate CYP21A2 carriers had a reduced risk of a psychiatric diagnosis and were less vulnerable to a psychologically stressful situation, at least with respect to receiving a psychiatric diagnosis. This indicates a better ability to cope with psychological stress among heterozygous carriers of severe CYP21A2 mutations, which may contribute to the apparent survival advantage
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| 2. |
- Ahern, Tomás, et al.
(författare)
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Natural history, risk factors and clinical features of primary hypogonadism in ageing men : Longitudinal Data from the European Male Ageing Study
- 2016
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Ingår i: Clinical Endocrinology. - : Wiley. - 0300-0664. ; 85:6, s. 891-901
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Tidskriftsartikel (refereegranskat)abstract
- Objective: In ageing men, the incidence and clinical significance of testosterone (T) decline accompanied by elevated luteinizing hormone (LH) are unclear. We describe the natural history, risk factors and clinical features associated with the development of biochemical primary hypogonadism (PHG, T < 10·5 nmol/l and LH>9·4U/l) in ageing men. Design, Patients and Measurements: A prospective observational cohort survey of 3,369 community-dwelling men aged 40-79 years, followed up for 4·3 years. Men were classified as incident (i) PHG (eugonadal [EUG, T ≥ 10·5 nmol/l] at baseline, PHG at follow-up), persistent (p) PHG (PHG at baseline and follow-up), pEUG (EUG at baseline and follow-up) and reversed (r) PHG (PHG at baseline, EUG at follow-up). Predictors and changes in clinical features associated with the development of PHG were analysed by regression models. Results: Of 1,991 men comprising the analytical sample, 97·5% had pEUG, 1·1% iPHG, 1·1% pPHG and 0·3% rPHG. The incidence of PHG was 0·2%/year. Higher age (>70 years) [OR 12·48 (1·27-122·13), P = 0·030] and chronic illnesses [OR 4·24 (1·08-16·56); P = 0·038] predicted iPHG. Upon transition from EUG to PHG, erectile function, physical vigour and haemoglobin worsened significantly. Men with pPHG had decreased morning erections, sexual thoughts and haemoglobin with increased insulin resistance. Conclusions: Primary testicular failure in men is uncommon and predicted by old age and chronic illness. Some clinical features attributable to androgen deficiency, but not others, accompanied the T decline in men who developed biochemical PHG. Whether androgen replacement can improve sexual and/or physical function in elderly men with PHG merits further study.
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| 3. |
- Andersson, Björn, 1939, et al.
(författare)
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Short-term changes in bone formation markers following growth hormone (GH) treatment in short prepubertal children with a broad range of GH secretion
- 2015
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Ingår i: Clinical Endocrinology. - : Wiley: 12 months. - 0300-0664 .- 1365-2265. ; 82:1, s. 91-99
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesGrowth hormone (GH) promotes longitudinal growth and bone modelling/remodelling. This study investigated the relationship between levels of bone formation markers and growth during GH treatment in prepubertal children with widely ranging GH secretion levels. MethodsThe study group comprised 113 short prepubertal children (mean ageSD, 937213years; 99 boys) on GH treatment (330 +/- 006g/kg/day) for 1year. Blood samples were taken at baseline and 1 and 2weeks, 1 and 3months, and 1year after treatment start. Intact amino-terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (BALP) and osteocalcin were measured using an automated IDS-iSYS immunoassay system. ResultsIntact amino-terminal propeptide of type I procollagen (PINP), BALP and osteocalcin, increased in the short-term during GH treatment. PINP after 1week (P=000077), and BALP and osteocalcin after 1month (Pless than00001 and P=00043, respectively). PINP levels at 1 and 3months correlated positively, and osteocalcin levels at 1week and percentage change after 1month correlated negatively, with first year growth response. No significant correlations were found between BALP and first year growth. Multiple regression analysis showed that bone marker levels together with auxological data and insulin-like growth factor binding protein-3 explained the variation in first year growth response to 36% at start, 32% after 2weeks and 48% at 3months. ConclusionShort-term increases in levels of the bone formation markers PINP, BALP and osteocalcin showed different temporal patterns, but all correlated with first year growth response during GH treatment. These markers may be a useful addition to existing prediction models for growth response.
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| 4. |
- Atiomo, William, et al.
(författare)
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Expression of NAD(P)H quinone dehydrogenase 1 (NQO1) is increased in the endometrium of women with endometrial cancer and women with polycystic ovary syndrome
- 2017
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Ingår i: Clinical Endocrinology. - : John Wiley & Sons. - 0300-0664 .- 1365-2265. ; 87:5, s. 557-565
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Women with a prior history of polycystic ovary syndrome (PCOS) have an increased risk of endometrial cancer (EC). Aim: To investigate whether the endometrium of women with PCOS possesses gene expression changes similar to those found in EC. Design and Methods: Patients with EC, PCOS and control women unaffected by either PCOS or EC were recruited into a cross-sectional study at the Nottingham University Hospital, UK. For RNA sequencing, representative individual endometrial biopsies were obtained from women with EC, PCOS and a woman unaffected by PCOS or EC. Expression of a subset of differentially expressed genes identified by RNA sequencing, including NAD(P)H quinone dehydrogenase 1 (NQO1), was validated by quantitative reverse transcriptase PCR validation (n = 76) and in the cancer genome atlas UCEC (uterine corpus endometrioid carcinoma) RNA sequencing data set (n = 381). The expression of NQO1 was validated by immunohistochemistry in EC samples from a separate cohort (n = 91) comprised of consecutive patients who underwent hysterectomy at St Mary's Hospital, Manchester, between 2011 and 2013. A further 6 postmenopausal women with histologically normal endometrium who underwent hysterectomy for genital prolapse were also included. Informed consent and local ethics approval were obtained for the study. Results: We show for the first that NQO1 expression is significantly increased in the endometrium of women with PCOS and EC. Immunohistochemistry confirms significantly increased NQO1 protein expression in EC relative to nonmalignant endometrial tissue (P < .0001). Conclusions: The results obtained here support a previously unrecognized molecular link between PCOS and EC involving NQO1.
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| 5. |
- Barbaro, Michela, et al.
(författare)
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In vitro functional studies of rare CYP21A2 mutations and establishment of an activity gradient for nonclassic mutations improve phenotype predictions in congenital adrenal hyperplasia
- 2015
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Ingår i: Clinical Endocrinology. - : Wiley. - 0300-0664 .- 1365-2265. ; 82:1, s. 37-44
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundA detailed genotype-phenotype evaluation is presented by studying the enzyme activities of five rare amino acid substitutions (Arg233Gly, Ala265Ser, Arg341Trp, Arg366Cys and Met473Ile) identified in the CYP21A2 gene in patients investigated for Congenital adrenal hyperplasia (CAH). ObjectiveTo investigate whether the mutations identified in the CYP21A2 gene are disease causing and to establish a gradient for the degree of enzyme impairment to improve prediction of patient phenotype. Design and patientsThe CYP21A2 genes of seven patients investigated for CAH were sequenced and five mutations were identified. The mutant proteins were expressed in vitro in COS-1 cells, and the enzyme activities towards the two natural substrates were determined to verify the disease-causing state of the mutations. The in vitro activities of these rare mutations were also compared with the activities of four mutations known to cause nonclassic CAH (Pro30Leu, Val281Leu, Pro453Ser and Pro482Ser) in addition to an in silico structural evaluation of the novel mutants. Main outcome measureTo verify the disease-causing state of novel mutations. ResultsFive CYP21A2 mutations were identified (Arg233Gly, Ala265Ser, Arg341Trp, Arg366Cys and Met473Ile). All mutant proteins exhibited enzyme activities above 5%, and four mutations were classified as nonclassic and one as a normal variant. By comparing the investigated protein changes with four common mutations causing nonclassic CAH, a gradient for the degree of enzyme impairment could be established. Studying rare mutations in CAH increases our knowledge regarding the molecular mechanisms that render a mutation pathogenic. It also improves phenotype predictions and genetic counselling for future generations.
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| 8. |
- Bjornsdottir, Sigridur, et al.
(författare)
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Circadian hormone profiles and insulin sensitivity in patients with Addison's disease : a comparison of continuous subcutaneous hydrocortisone infusion with conventional glucocorticoid replacement therapy
- 2015
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Ingår i: Clinical Endocrinology. - : Wiley. - 0300-0664 .- 1365-2265. ; 83:1, s. 28-35
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Tidskriftsartikel (refereegranskat)abstract
- ContextConventional glucocorticoid replacement therapy in patients with Addison's disease (AD) is unphysiological with possible adverse effects on mortality, morbidity and quality of life. The diurnal cortisol profile can likely be restored by continuous subcutaneous hydrocortisone infusion (CSHI). ObjectiveThe aim of this study was to compare circadian hormone rhythms and insulin sensitivity in conventional thrice-daily regimen of glucocorticoid replacement therapy with CSHI treatment in patients with AD. Design and settingAn open, randomized, two-period, 12-week crossover multicentre trial in Norway and Sweden. PatientsTen Norwegian patients were admitted for 24-h sampling of hormone profiles. Fifteen Swedish patients underwent euglycaemic-hyperinsulinaemic clamp. InterventionThrice-daily regimen of oral hydrocortisone (OHC) and CSHI treatment. Main outcome measureWe measured the circadian rhythm of cortisol, adrenocorticotropic hormone (ACTH), growth hormone (GH), insulin-like growth factor-1, (IGF-1), IGF-binding protein-3 (IGFBP-3), glucose, insulin and triglycerides during OHC and CSHI treatment. Euglycaemic-hyperinsulinaemic clamp was used to assess insulin sensitivity. ResultsContinuous subcutaneous hydrocortisone infusion provided a more physiological circadian cortisol curve including a late-night cortisol surge. ACTH levels showed a near normal circadian variation for CSHI. CSHI prevented a continuous decrease in glucose during the night. No difference in insulin sensitivity was observed between the two treatment arms. ConclusionContinuous subcutaneous hydrocortisone infusion replacement re-established a circadian cortisol rhythm and normalized the ACTH levels. Patients with CSHI replacement had a more stable night-time glucose level compared with OHC without compromising insulin sensitivity. Thus, restoring night-time cortisol levels might be advantageous for patients with AD.
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| 9. |
- Bobjer, Johannes, et al.
(författare)
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High Prevalence of Hypogonadism and Associated Impaired Metabolic and Bone Mineral Status in Subfertile Men.
- 2016
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Ingår i: Clinical Endocrinology. - : Wiley. - 1365-2265 .- 0300-0664. ; 85:2, s. 189-195
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Tidskriftsartikel (refereegranskat)abstract
- It is yet unknown to which degree young subfertile men present with signs of hypogonadism and whether low testosterone concentration, like in older men, is associated with risk of osteoporosis and metabolic derangements in those subjects. The objective was, therefore, to investigate the prevalence of hypogonadism and its association with metabolic and bone parameters in young subfertile men.
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| 10. |
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