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  • Author: Fabrice Bonnet x
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Free access

Liver iron overload is associated with elevated SHBG concentration and moderate hypogonadotrophic hypogonadism in dysmetabolic men without genetic haemochromatosis

Alain Gautier, Fabrice Lainé, Catherine Massart, Laure Sandret, Xavier Piguel, Pierre Brissot, Beverley Balkau, Yves Deugnier, and Fabrice Bonnet

Aims

To assess the relation between moderate iron overload on sex hormone binding globulin (SHBG) levels and gonadotroph function in men with dysmetabolic iron overload syndrome and the effects of phlebotomy.

Methods

The relationship between magnetic resonance imaging assessed liver iron concentration (LIC) and plasma ferritin levels with total testosterone, bioavailable testosterone (BT), SHBG and LH levels, were studied in 50 men with moderate dysmetabolic iron excess, in the absence of genetic haemochromatosis, who were randomised to phlebotomy therapy or to normal care.

Results

Four patients (8%) had low total testosterone (<10.4 nmol/l) and 13 patients (26%) had low BT (<2.5 nmol/l). In the entire population, those with LIC above the median (90 μmol/l) had a higher mean SHBG (P=0.028), lower LH (P=0.039) than those with LIC below the median. In multivariable analysis (adjusted for age, and fasting insulin) LIC was significantly associated with SHBG (positively) and LH (negatively). Patients in the highest quartile of SHBG had higher LIC (P=0.010) and higher ferritinaemia (P=0.012) than those in the three other quartiles. Iron depletion by venesection did not significantly improve any hormonal levels.

Conclusions

Hypogonadism is not infrequent in men with dysmetabolic iron overload syndrome. Liver iron excess is associated with increased plasma SHBG and moderate hypogonadotrophic hypogonadism. Phlebotomy therapy needs further investigation in symptomatic hypogonadal men with dysmetabolic iron excess.

Free access

Elevated heart rate predicts β cell function in non-diabetic individuals: the RISC cohort

Fabrice Bonnet, Jean-Philippe Empana, Andrea Natali, Lucilla Monti, Alain Golay, Katarina Lalic, Jacqueline Dekker, Andrea Mari, Beverley Balkau, and on behalf of the RISC Study Group

Context

Elevated heart rate has been associated with insulin resistance and incident type 2 diabetes but its relationship with β-cell function is not known. Our aim was to investigate whether baseline heart rate is associated with β-cell function and hyperglycaemia.

Methods

We used the prospective RISC cohort with 1005 non-diabetic individuals who had an oral glucose tolerance test (OGTT) at baseline and after 3 years. Impaired glucose regulation was defined as a fasting plasma glucose ≥6.1 mmol/l or a 2-h plasma glucose ≥7.8 mmol/l. Insulin sensitivity was assessed by the OGIS index and insulin secretion and β-cell glucose sensitivity at both baseline and 3 years.

Results

Baseline heart rate was positively related to both fasting (P<0.0001) and 2 h glucose levels (P=0.02) at year 3 and predicted the presence of impaired glucose regulation at year 3 in a logistic regression model adjusting for insulin sensitivity at inclusion (OR/10 beats per min: 1.31; 95% CI (1.07–1.61); P=0.01). Baseline heart rate was associated with lower insulin sensitivity (β=−0.11; P<.0001), a decrease in both β-cell glucose sensitivity (β=−0.11; P=0.003) and basal insulin secretion rate (β=−0.11; P=0.002) at 3 years in an adjusted multivariable regression model. Baseline heart rate predicted the 3-year decrease in β-cell glucose sensitivity (β=−0.10; P=0.007) and basal insulin secretion (β=−0.12; P=0.007).

Conclusions

Heart rate predicts β-cell function and impaired glucose regulation at 3 years in non-diabetic individuals, independently of the level of insulin sensitivity. These findings suggest a possible effect of the sympathetic nervous system on β-cell dysfunction, which deserves further investigation.

Free access

Mentally tiring work and type 2 diabetes in women: a 22-year follow-up study

Guy Fagherazzi, Gaelle Gusto, Douae El Fatouhi, Francesca Romana Mancini, Beverley Balkau, Marie-Christine Boutron-Ruault, and Fabrice Bonnet

Hypothesis

Previous work suggested no or inconsistent associations between components of work-related stress and type 2 diabetes risk, but suggested sex-specific differences should be further investigated, as women potentially had higher risks.

Methods

We analyzed data from 73 517 women, mostly teachers, from the E3N cohort study followed for 22 years (1992–2014), to study the association between mentally tiring work, used as a proxy of job demands, and type 2 diabetes risk. Univariate and multivariable Cox regression models were used to estimate hazard ratios and 95% confidence intervals.

Results

A total of 4187 incident cases of type 2 diabetes cases were observed. There was a higher type 2 diabetes risk for women with a ‘Very mentally tiring work’ when compared to women with ‘Little or not mentally tiring work’ (HR = 1.21 (1.09–1.35)). This association was independent of unhealthy lifestyle and traditional metabolic factors. An interaction between mentally tiring work and BMI was detected (P < 0.0001), with a stronger association being observed in non-overweight women, HR = 1.26 (1.08–1.47) vs HR = 1.14 (0.98, 1.32), in overweight women.

Conclusions

We observed an increased risk of type 2 diabetes associated with mentally tiring work, used as a proxy of job demands. These observational results suggest the importance of taking into consideration the potential long-term metabolic impact of work-related stress for women working in a demanding environment. Increased support for such women should be investigated in intervention studies.

Free access

Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas

Hélène Lasolle, Christine Cortet, Fréderic Castinetti, Lucie Cloix, Philippe Caron, Brigitte Delemer, Rachel Desailloud, Christel Jublanc, Christine Lebrun-Frenay, Jean-Louis Sadoul, Luc Taillandier, Marie Batisse-Lignier, Fabrice Bonnet, Nathalie Bourcigaux, Damien Bresson, Olivier Chabre, Philippe Chanson, Cyril Garcia, Magalie Haissaguerre, Yves Reznik, Sophie Borot, Chiara Villa, Alexandre Vasiljevic, Stephan Gaillard, Emmanuel Jouanneau, Guillaume Assié, and Gérald Raverot

Objectives

Only few retrospective studies have reported an efficacy rate of temozolomide (TMZ) in pituitary tumors (PT), all around 50%. However, the long-term survival of treated patients is rarely evaluated. We therefore aimed to describe the use of TMZ on PT in clinical practice and evaluate the long-term survival.

Design

Multicenter retrospective study by members of the French Society of Endocrinology.

Methods

Forty-three patients (14 women) treated with TMZ between 2006 and 2016 were included. Most tumors were corticotroph (n = 23) or lactotroph (n = 13), and 14 were carcinomas. Clinical/pathological characteristics of PT, as well as data from treatment evaluation and from the last follow-up were recorded. A partial response was considered as a decrease in the maximal tumor diameter by more than 30% and/or in the hormonal rate by more than 50% at the end of treatment.

Results

The median treatment duration was 6.5 cycles (range 2–24), using a standard regimen for most and combined radiotherapy for six. Twenty-two patients (51.2%) were considered as responders. Silent tumor at diagnosis was associated with a poor response. The median follow-up after the end of treatment was 16 months (0–72). Overall survival was significantly higher among responders (P = 0.002); however, ten patients relapsed 5 months (0–57) after the end of TMZ treatment, five in whom TMZ was reinitiated without success.

Discussion

Patients in our series showed a 51.2% response rate to TMZ, with an improved survival among responders despite frequent relapses. Our study highlights the high variability and lack of standardization of treatment protocols.

Free access

Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016

Ann McCormack, Olaf M Dekkers, Stephan Petersenn, Vera Popovic, Jacqueline Trouillas, Gerald Raverot, Pia Burman, and ESE survey collaborators

Objective

To collect outcome data in a large cohort of patients with aggressive pituitary tumours (APT)/carcinomas (PC) and specifically report effects of temozolomide (TMZ) treatment.

Design

Electronic survey to ESE members Dec 2015–Nov 2016.

Results

Reports on 166 patients (40 PC, 125 APT, 1 unclassified) were obtained. Median age at diagnosis was 43 (range 4–79) years. 69% of the tumours were clinically functioning, and the most frequent immunohistochemical subtype were corticotroph tumours (45%). Ki-67 index did not distinguish APT from PC, median 7% and 10% respectively. TMZ was first-line chemotherapy in 157 patients. At the end of the treatment (median 9 cycles), radiological evaluation showed complete response (CR) in 6%, partial response (PR) in 31%, stable disease (SD) in 33% and progressive disease in 30%. Response was more frequent in patients receiving concomitant radiotherapy and TMZ. CR was seen only in patients with low MGMT expression. Clinically functioning tumours were more likely to respond than non-functioning tumours, independent of MGMT status. Of patients with CR, PR and SD, 25, 40 and 48% respectively progressed after a median of 12-month follow-up. Other oncological drugs given as primary treatment and to TMZ failures resulted in PR in 20%.

Conclusion

This survey confirms that TMZ is established as first-line chemotherapeutic treatment of APT/PC. Clinically functioning tumours, low MGMT and concurrent radiotherapy were associated with a better response. The limited long-term effect of TMZ and the poor efficacy of other drugs highlight the need to identify additional effective therapies.