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Claus H Gravholt and Philippe Backeljauw

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Jens J Christiansen, Jens M Bruun, Jens S Christiansen, Jens Otto Jørgensen and Claus H Gravholt

Context

Adrenal derived androgens are low in women with adrenal failure. The physiological consequences of substitution therapy are uncertain.

Objective

To investigate the effects of DHEA substitution in women with adrenal failure on body composition, fuel metabolism, and inflammatory markers.

Design, participants and intervention

In this study, ten female patients (median age 38.5 years, range 28–52) with adrenal failure were treated with DHEA 50 mg for 6 months in a double-blind, randomized, placebo-controlled, and crossover study. The participants underwent dual-energy X-ray absorptiometry (DXA) scan, computed tomography scan of abdominal fat, indirect calorimetry, bicycle ergometry, muscle and fat biopsies, and blood samples.

Results

Baseline androgens were normalized to fertile range during active treatment. Anthropometric data were unaffected, but lean body mass (LBM) slightly increased compared with placebo (delta LBM (kg) placebo versus DHEA: −0.48±6.1 vs 1.6±3.4, P=0.02) with no alterations in total or abdominal fat mass. PTH increased with DHEA, but no significant changes were observed in other bone markers or in bone mineral content. The mRNA levels of markers of tissue inflammation (adiponectin, interleukin 6 (IL6), IL10, monocyte chemoattractant protein 1, and tumor necrosis factor α) in fat and muscle tissue were unaffected by DHEA treatment, as was indirect calorimetry and maximal oxygen uptake. A high proportion of self-reported seborrheic side effects were recorded (60%).

Conclusion

In female adrenal failure, normalization of androgens with DHEA 50 mg for 6 months had no effects on muscle, fat, and bone tissue and on fuel metabolism in this small study. A small increase in LBM was observed. Treatment was associated with a high frequency of side effects.

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Lars C Gormsen, Christian Høst, Britta Eilersen Hjerrild, Claus H Gravholt and Søren Nielsen

Context

Long-term hormone replacement therapy (HRT) with estradiol (E2) is associated with an altered lipid profile including unfavorable increases in triglyceride (TG) concentrations and augmented hepatic very low-density lipoprotein (VLDL)–TG production. There are indications that this effect of estrogens may be immediate.

Objective

To study the in vivo effect of a single dose of E2 on VLDL–TG kinetics and oxidation in humans.

Methods

Eight healthy, postmenopausal women were given a single dose of either placebo or E2 (4 mg) orally. VLDL–TG kinetics was assessed by a 240-min primed-continuous infusion of ex vivo labeled [1-14C]triolein-labeled VLDL. Fractional and absolute VLDL–TG oxidation was determined by hyamin trapping of exhaled 14C label. Indirect calorimetry provided measurements of lipid oxidation.

Results

Administration of 4 mg of E2 orally rapidly increased plasma E2 concentrations from below detection threshold to premenopausal levels. Free fatty acids (FFA) and TG concentrations were unaltered. No immediate effect was observed on either VLDL–TG production (placebo versus E2): 20.0±12.4 vs 24.1±10.7 μmol/min, P=0.33; VLDL–TG oxidation: 12.3±10.9 vs 12.6±5.6 μmol/min, P=0.93); or VLDL–TG clearance rates: 51.4±16.8 vs 64.9±28.8 ml/min, P=0.34).

Conclusions

Short-term E2 elevation does not affect VLDL–TG production, oxidation, or clearance in humans. We therefore propose that HRT-associated dyslipidemia has a gradual rather than immediate onset.

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Line Cleemann, Britta E Hjerrild, Anna L Lauridsen, Lene Heickendorff, Jens S Christiansen, Leif Mosekilde and Claus H Gravholt

Context

Reduced bone mineral density (BMD) and increased risk of fractures are present in many women with Turner syndrome (TS).

Objective

Examine longitudinal changes in BMD in TS and relate changes to biochemical parameters.

Design

Prospective, pragmatic, and observational study. Examinations at baseline and follow-up (5.9±0.7 years).

Setting

Tertiary hospital.

Participants

Fifty-four women with TS (43.0±9.95 years).

Interventions

Hormone replacement therapy (HRT) and calcium and vitamin D supplementation.

Main outcome measures

BMD (g/cm2) measured at lumbar spine, hip, and the non-dominant forearm. Bone formation and resorption markers, sex hormones, IGF1, and maximal oxygen uptake.

Results

At follow-up, forearm BMD, radius ultradistal BMD, and hip BMD remained unchanged, radius 1/3 BMD declined (0.601±0.059 vs 0.592±0.059, P=0.03), while spine BMD increased (0.972±0.139 vs 1.010±0.144, P<0.0005). Bone formation markers did not change over time in TS. Bone resorption markers decreased over time in TS. Testosterone, IGF1, and maximal oxygen uptake was significantly reduced in TS.

Conclusion

Longitudinal changes in BMD in TS were slight. BMD can be maintained at most sites in well-informed women with TS, being encouraged to maintain a healthy lifestyle, including HRT and intake of calcium and vitamin D.

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Line Cleemann, Kirsten Holm, Hanne Kobbernagel, Bent Kristensen, Sven Oluf Skouby, Andreas Kryger Jensen and Claus H Gravholt

Objective

Reduced bone mineral density (BMD) is seen in Turner syndrome (TS) with an increased risk of fractures, and body composition is characterized by increased body fat and decreased lean body mass. To evaluate the effect of two different doses of oral 17B-estradiol in young TS women on bone mineral density (BMD), biochemical markers of bone turnover and body composition with the hypothesis of a positive effect of the higher dose.

Design

A double-blind 5-year randomized controlled clinical trial. 20 young TS women participated. Inclusion criteria were diagnosis of TS, age 15–25 years and current treatment with 2 mg oral estradiol daily.

Methods

The low-dose (LD) group was administered 2 mg 17B-estradiol/day orally and placebo, the high-dose (HD) group was administered 2 + 2 mg 17B-estradiol/day orally. Main outcome measures were whole body and regional bone mineral density (BMD), lean body mass (LBM), fat mass (FM) measured yearly by DXA scan and resorptive and formative bone markers in serum.

Results

BMD, whole body and regional, increased over time with an attenuation toward the end of the study, and bone turnover markers decreased over time, both with no differences between the treatment groups (P = 0.2–0.9). LBM increased significantly more in the HD group (P = 0.02). FM remained stable in both groups.

Conclusions

A steady increase in BMD over time in TS was found similar to healthy young women. The higher estrogen dose did not differentially affect BMD or bone markers. The positive effect on body composition may have long-ranging health benefits in TS.

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Kirstine Stochholm, Claus H Gravholt, Torben Laursen, Jens O Jørgensen, Peter Laurberg, Marianne Andersen, Lars Ø Kristensen, Ulla Feldt-Rasmussen, Jens S Christiansen, Morten Frydenberg and Anders Green

Objective: Data on incidence rates are scarce in GH deficiency (GHD). Here, we estimate the incidence rate in childhood onset (CO) and adult onset (AO) GHD in Denmark.

Design: We used three national registries to identify 9131 cases with an increased risk of GHD. Date of entry was defined using the date when a registration had taken place and when a date of sufficient information could be defined from a thorough examination of a record of a GHD patient, which ever came last. We considered date of entry as the incident date.

Methods: Sex-specific incidence rates of GHD in children and adults using the background population as reference.

Results: During 1980–1999, 1823 patients were incident. Three-hundred and three males and 191 females had CO, 744 males and 585 females had AO GHD. The incidence rate over time was stable for females with AO GHD and increasing for the other three subgroups. Average incidence rate for CO males, 2.58 (95% confidence interval (CI), 2.30–2.88), CO females, 1.70 (95% CI, 1.48–1.96), AO males, 1.90 (95% CI, 1.77–2.04), and AO females, 1.42 (95% CI, 1.31–1.54) all per 100 000. The incidence rate was significantly higher in males compared to females in the CO GHD group (P < 0.001) and in the AO GHD group in the age ranges of 45–64 and 65+years (P < 0.001). There was no significant difference in the 18–44 years age group.

Conclusions: In conclusion, we have identified the incidence rates of GHD in a nationwide study of Denmark. In this population-based study, we have identified in CO GHD and in the two oldest age groups of AO GHD, a statistically significant higher incidence rate in males when compared with females.

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Claus H Gravholt, Niels H Andersen, Gerard S Conway, Olaf M Dekkers, Mitchell E Geffner, Karen O Klein, Angela E Lin, Nelly Mauras, Charmian A Quigley, Karen Rubin, David E Sandberg, Theo C J Sas, Michael Silberbach, Viveca Söderström-Anttila, Kirstine Stochholm, Janielle A van Alfen-van derVelden, Joachim Woelfle, Philippe F Backeljauw and On behalf of the International Turner Syndrome Consensus Group

Turner syndrome affects 25–50 per 100,000 females and can involve multiple organs through all stages of life, necessitating multidisciplinary approach to care. Previous guidelines have highlighted this, but numerous important advances have been noted recently. These advances cover all specialty fields involved in the care of girls and women with TS. This paper is based on an international effort that started with exploratory meetings in 2014 in both Europe and the USA, and culminated with a Consensus Meeting held in Cincinnati, Ohio, USA in July 2016. Prior to this meeting, five groups each addressed important areas in TS care: 1) diagnostic and genetic issues, 2) growth and development during childhood and adolescence, 3) congenital and acquired cardiovascular disease, 4) transition and adult care, and 5) other comorbidities and neurocognitive issues. These groups produced proposals for the present guidelines. Additionally, four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with a separate systematic review of the literature. These four questions related to the efficacy and most optimal treatment of short stature, infertility, hypertension, and hormonal replacement therapy. The guidelines project was initiated by the European Society of Endocrinology and the Pediatric Endocrine Society, in collaboration with the European Society for Paediatric Endocrinology, the Endocrine Society, the European Society of Human Reproduction and Embryology, the American Heart Association, the Society for Endocrinology, and the European Society of Cardiology. The guideline has been formally endorsed by the European Society of Endocrinology, the Pediatric Endocrine Society, the European Society for Paediatric Endocrinology, the European Society of Human Reproduction and Embryology and the Endocrine Society. Advocacy groups appointed representatives who participated in pre-meeting discussions and in the consensus meeting.