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A Calabrese, V Basile, S Puglisi, P Perotti, A Pia, L Saba, P Berchialla, F Porpiglia, A Veltri, M Volante, G Reimondo, A Berruti and M Terzolo

Objective

Many patients with adrenocortical carcinoma (ACC) suffer from tumor recurrence despite radical surgery. Evidence on the post-operative use of mitotane is controversial and no predictors of response are available. We aimed to assess whether adjuvant mitotane treatment may prolong survival in patients with non-metastatic ACC following complete resection and whether ACC patients at high risk of recurrence may benefit from treatment.

Design and methods

We retrospectively reviewed data from 152 non-metastatic ACC patients followed at the San Luigi Gonzaga Hospital: 100 patients were treated with adjuvant mitotane and 52 patients were left untreated following surgery. We assessed a number of potential predictive factors of recurrence and death. Mitotane effect was explored stratifying patients by staging (stage I–II vs stage III), hormone secretion (yes vs no) and Ki67 index.

Results

The non-treated group had a higher risk of recurrence (HR: 2.79, 95%CI: 1.58–4.91; P < 0.001) than mitotane-treated group, while overall survival was not significantly different between groups. Hormone secretion, elevated Weiss score and elevated Ki67 index confer a higher risk of both recurrence and death and stage III ACC of death. Adjuvant mitotane treatment reduced significantly the risk of death in patients with elevated Ki67 index (P = 0.005) and in patients with stage III ACC (P = 0.02).

Conclusions

Adjuvant mitotane may prolong recurrence-free survival in radically resected ACC patients with acceptable toxicity and may also prolong overall survival in a subgroup of ACC patients at high risk of recurrence.

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Laura Dauben, Marie-Christine Simon, Klaus Strassburger, Volker Burkart, Katharina S Weber, Sven Schinner, Michael Roden and Karsten Müssig

Objective

Insulinomas are rare pancreatic endocrine tumors characterized by hypoglycemia. Guidelines by the Endocrine Society (ES), the European (ENETS) and the North American (NANETS) Neuroendocrine Tumor Societies provide divergent diagnostic criteria. This study compared the diagnostic accuracy of these different criteria during the 72-h fasting test.

Design

Retrospective cohort study.

Methods

From 2000 to 2014, 64 patients with a suspected insulinoma underwent a 72-h fasting test and were included in the analysis. This study assessed the diagnostic sensitivity, specificity and accuracy based on venous blood glucose and corresponding insulin levels measured by electrochemiluminescence immunoassay (ECLIA).

Results

Based on 64 individuals (18 with, 46 without insulinoma), the ES criteria provided a diagnostic sensitivity of 0.94 (0.73–1.00), specificity of 0.89 (0.76–0.96) and accuracy of 0.91 (0.81–0.96). ENETS/NANETS criteria reached a diagnostic sensitivity of 0.78 (0.52–0.94), specificity of 1.00 (0.92–1.00) and accuracy of 0.94 (0.85–0.98).

Conclusions

These results point to a higher diagnostic sensitivity with less specificity for diagnosing insulinoma using ES criteria and a higher specificity at lower sensitivity by using ENETS/NANETS criteria. Before considering these results when applying the different criteria in clinical practice, the results should be confirmed in further studies comprising larger cohorts.

Free access

Cristina Eller-Vainicher, Alberto Falchetti, Luigi Gennari, Elisa Cairoli, Francesco Bertoldo, Fabio Vescini, Alfredo Scillitani and Iacopo Chiodini

An underlying disease affecting bone health is present in up to 40 and 60% of osteoporotic postmenopausal women and men respectively. Among the disorders leading to a secondary form of osteoporosis, the endocrine diseases are highly represented. A frequent finding in patients affected with an endocrine-related forms of bone disease is that the skeletal fragility is partially independent of the bone density, since the fracture risk in these patients is related more to a reduction of bone quality than to a decrease of bone mass. As a consequence, bone mineral density evaluation by dual-X-ray absorptiometry may be inadequate for establishing the risk of fracture in the setting of the endocrine-related forms of osteoporosis. In the recent years, several attempts to non-invasively estimating bone quality have been done. Nowadays, some new tools are available in the clinical practice for optimising the fracture risk estimation in patients with endocrine disorders. The aim of this review is to summarise the evidence regarding the role of the different imaging tools for evaluating bone density and bone quality in the most frequent forms of endocrine-related osteoporosis, such as obesity, diabetes, acromegaly, thyrotoxicosis, primary hyperparathyroidism, hypercortisolism and hypogonadism. For each of these disorders, data regarding both the current available tools and the future possible new techniques for assessing bone fragility in patients with endocrine diseases are reported.

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Mads Lillevang-Johansen, Bo Abrahamsen, Henrik Løvendahl Jørgensen, Thomas Heiberg Brix and Laszlo Hegedüs

Objective

To investigate the association between hypothyroidism and cardiovascular disease (CVD) in both treated and untreated hypothyroid patients, and the consequences of over- and under-treatment with respect to cardiovascular risk.

Design

A registry-based case–control study nested within a population-based cohort of 275 467 individuals with at least one serum thyroid stimulating hormone (TSH) measurement in the period of 1995–2011.

Methods

Incident cases of CVD were matched with controls according to gender, age and year of birth. Conditional logistic regression analyses were performed to calculate CVD risks associated with exposure to hypothyroidism, with adjustment for 19 pre-existing comorbidities, including cardiovascular disease and diabetes, using the Charlson Comorbidity Index.

Results

Overall, 20 487 individuals experienced CVD (9.4%, incidence rate 13.1 per 1000 person-years, 95% confidence interval (CI), 13.0–13.3). Risk of CVD was increased in untreated hypothyroidism compared to euthyroidism (odds ratio (OR): 1.83 (95% CI: 1.43–2.35; P < 0.001)). Cardiovascular risk was increased in both treated and untreated hypothyroid individuals per half year of elevated TSH (OR: 1.11 (95% CI: 1.06–1.16; P < 0.001) and OR: 1.15 (95% CI: 1.09–1.23; P = 0.001), respectively). In patients treated with levothyroxine, OR for CVD was 1.12 (95% CI: 1.06–1.18; P < 0.001) for each 6 months of decreased TSH.

Conclusion

Cardiovascular risk is increased in untreated, but not in treated hypothyroid patients. Among those with treated hypothyroidism, duration of decreased TSH (overtreatment) had a similar impact on cardiovascular risk as duration of elevated TSH (under-treatment), highlighting the importance of initiating treatment and maintaining biochemical euthyroidism in hypothyroid patients in order to reduce the risk of CVD and death.

Free access

Eberhard Nieschlag and Susan Nieschlag

As the most important male hormone, testosterone has an impact on almost all organs and body functions. The biological effects of testosterone and the testes have been known since antiquity, long before testosterone was identified as the active agent. Practical applications of this knowledge were castration of males to produce obedient servants, for punishment, for preservation of the prepubertal soprano voice and even for treatment of diseases. Testes were used in organotherapy and transplanted as treatment for symptoms of hypogonadism on a large scale, although these practices had only placebo effects. In reaction to such malpractice in the first half of the 20th century science and the young pharmaceutical industry initiated the search for the male hormone. After several detours together with their teams in 1935, Ernst Laqueur (Amsterdam) isolated and Adolf Butenandt (Gdansk) as well as Leopold Ruzicka (Zürich) synthesized testosterone. Since then testosterone has been available for clinical use. However, when given orally, testosterone is inactivated in the liver, so that parenteral forms of administration or modifications of the molecule had to be found. Over 85 years the testosterone preparations have been slowly improved so that now physiological serum levels can be achieved.

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Chin-Hsiao Tseng

Background

Whether metformin might affect the risk of benign nodular goiter in patients with type 2 diabetes mellitus has not been investigated.

Methods

Patients with new-onset type 2 diabetes mellitus during 1999–2005 were enrolled from Taiwan’s National Health Insurance database. Analyses were conducted in a propensity score matched-pairs of 20,048 ever users and 20,048 never users of metformin. The patients were followed until December 31, 2011, for the incidence of benign nodular goiter. Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using the propensity score.

Results

Among the never users and ever users of metformin, 392 and 221 cases were diagnosed of benign nodular goiter during follow-up, with incidence of 457.88 and 242.45 per 100,000 person-years, respectively. The overall hazard ratio for ever versus never users was 0.527 (95% confidence interval: 0.447–0.621). When cumulative duration of metformin therapy was divided into tertiles, the hazard ratios for the first (<25.3 months), second (25.3–57.3 months) and third (>57.3 months) tertiles were 0.815 (0.643–1.034), 0.648 (0.517–0.812) and 0.255 (0.187–0.348), respectively. Sensitivity analyses estimating the overall hazard ratios for patients enrolled in each specific year from 1999 to 2005 consistently showed a lower risk of benign nodular goiter among users of metformin.

Conclusion

Metformin use is associated with a lower risk of benign nodular goiter in patients with type 2 diabetes mellitus.

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Jordan Sibeoni, Emilie Manolios, Laurence Verneuil, Philipe Chanson and Anne Revah-Levy

Context

Acromegaly has a substantial diagnostic delay associated with an increased risk of comorbidities and psychosocial deterioration. Qualitative methods which focus on the ways that individuals understand and relate to what they are experiencing are the best methods for exploring patients’ perspectives. To the best of our knowledge, they have not been developed in the context of acromegaly.

Objectives

This study aimed to explore the experience of the diagnostic pathway of patients with acromegaly.

Design

We conducted a qualitative study, based on 20 face-to-face unstructured interviews in a third referral Endocrinology center. Participants, purposively selected until data saturation, were patients with acromegaly with diverse disease durations, types of treatment or associated comorbidities. The data were examined by thematic analysis.

Results

Our analysis found four themes: (i) what happened for patients before the diagnosis; (ii) what happened after; (iii) the style or type of doctor involved and (iv) patients’ suggestions for limiting diagnostic delay. Our findings underlined the direct associations between diagnostic delay and the doctor–patient encounter, and the truly catastrophic experience of this disease, both before and after the diagnosis.

Conclusions

Diagnosis of acromegaly requires active medical involvement and awareness. Intervention of patient-experts in medical schools may help to be more aware of this disease. Endocrinologists caring for patients with acromegaly should also address the catastrophic dimension of the patient’s experience and initiate the narrative to help them to put it into words for preventing harmful consequences such as social isolation and QoL impairment, but also anxiety or depression.

Open access

Julia Otten, Mats Ryberg, Caroline Mellberg, Tomas Andersson, Elin Chorell, Bernt Lindahl, Christel Larsson, Jens Juul Holst and Tommy Olsson

Objective

To investigate how weight loss by different diets impacts postprandial levels of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon.

Methods

In this single-centre, parallel group 2-year trial, 70 healthy postmenopausal obese women were randomised to the Paleolithic diet or a healthy control diet based on Nordic Nutrition Recommendations. Both diets were without calorie restriction. The primary outcome was the change in fat mass. Here, secondary analyses on GLP-1, GIP and glucagon measured during an OGTT are described.

Results

In the Paleolithic diet group, mean weight loss compared to baseline was 11% at 6 months and 10% at 24 months. In the control diet group, mean weight loss was 6% after 6 and 24 months (P = 0.0001 and P = 0.049 for the comparison between groups at 6 and 24 months respectively). Compared to baseline, the mean incremental area under the curve (iAUC) for GLP-1 increased by 34 and 45% after 6 and 24 months in the Paleolithic diet group and increased by 59% after 24 months in the control diet group. The mean iAUC for GIP increased only in the Paleolithic diet group. The area under the curve (AUC) for glucagon increased during the first 6 months in both groups. The fasting glucagon increase correlated with the β-hydroxybutyrate increase.

Conclusions

Weight loss caused an increase in postprandial GLP-1 levels and a further rise occurred during weight maintenance. Postprandial GIP levels increased only after the Paleolithic diet. Reduced postprandial glucagon suppression may be caused by a catabolic state.

Open access

Irina Bancos, Jon Hazeldine, Vasileios Chortis, Peter Hampson, Angela E Taylor, Janet M Lord and Wiebke Arlt

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Maria Othelie Underdal, Øyvind Salvesen, Anne Schmedes, Marianne Skovsager Andersen and Eszter Vanky

Objective

To explore whether gestational prolactin and breast increase are markers of metabolic health in pregnancy and on long-term, in PCOS.

Design

Follow-up study. Women with PCOS, according to the Rotterdam criteria (n = 239), former participants of the randomized controlled trial (RCT) PregMet were invited, 131 participated in the current follow-up study, at mean 8 years after pregnancy.

Methods

Metformin 2000 mg/day or placebo from first trimester to delivery in the original RCT. No intervention in the current study.

Prolactin was analyzed in the first trimester and at gestational week 32 and metabolic characteristics which are part of the metabolic syndrome and measures of glucose homeostasis were examined. Metabolic health was also evaluated according to breast increase versus lack of breast increase during pregnancy.

Results

Prolactin increase in pregnancy was negatively correlated to BMI (P = 0.007) and systolic blood pressure (P ≤ 0.001) in gestational week 32. Prolactin at gestational week 32 was negatively correlated to BMI (P = 0.044) and visceral fat area (P = 0.028) at 8-year follow-up in an unadjusted model. Prolactin at gestational week 32 showed no associations to metabolic health at follow-up when baseline BMI was adjusted for. Women who reported lack of breast increase during pregnancy, had higher BMI (P = 0.034), waist-hip ratio (P = 0.004), visceral fat area (P = 0.050), total cholesterol (P = 0.022), systolic (P = 0.027) and diastolic blood pressure (P = 0.011) at 8-year follow-up.

Conclusion

High prolactin levels and breast increase in pregnancy were associated with a more favorable long-term metabolic health in women with PCOS. Both prolactin and breast increase may be mediated by gestational BMI.