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Antonela S Fittipaldi, Julieta Hernández, Daniel Castrogiovanni, Daniela Lufrano, Pablo N De Francesco, Verónica Garrido, Patrick Vitaux, María Victoria Fasano, Jean-Alain Fehrentz, Adriana Fernández, María F Andreoli and Mario Perello

Objective

The octanoylated peptide hormone ghrelin regulates appetite and glycaemic control. Des-acyl ghrelin abolishes some effects of ghrelin, but does not bind to ghrelin receptor. LEAP2 is a novel ligand for ghrelin receptor that blocks the effects of ghrelin. Some evidences show that plasma levels of these peptides are altered in adults with obesity, but their levels in childhood obesity remain poorly studied. Therefore, the objective of this study was to assess fasting plasma levels of ghrelin, des-acyl ghrelin and LEAP2 in children with normoweight, overweight/obesity and their association with different anthropometric and metabolic variables.

Design

A total of 42 females and 40 males, ages 3–12 years old were enrolled as a cross-sectional cohort.

Results

Plasma levels of des-acyl ghrelin and LEAP2 (but not ghrelin) were lower and ghrelin/des-acyl ghrelin ratio was higher in children with overweight/obesity. Des-acyl ghrelin negatively correlated with age, BMI z-score, insulin and HOMA index, and the correlations were stronger in children with overweight/obesity. LEAP2 levels negatively correlated with BMI z-score. No gender differences were found.

Conclusions

Our findings suggest that ghrelin tone is increased in childhood obesity, due to a decrease on plasma levels of des-acyl ghrelin and LEAP2, and that des-acyl ghrelin is associated to insulin resistance, particularly in children with overweight/obesity.

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Daham Kim, Cheol Ryong Ku, Kyungwon Kim, Hyein Jung and Eun Jig Lee

Objective

The association between prolactin level variation and prolactinoma size reduction remains unclear. This study aimed to determine the prolactin level cut-off predictive of a tumor size reduction.

Design

Retrospective cohort study.

Methods

We reviewed medical records of patients with prolactinoma who received primary cabergoline therapy and for whom complete data on pituitary hormone assays and sellar MRI at baseline and 3 months post treatment were available. We tested whether the certain prolactin level after 3 months post treatment predicted better response.

Results

Prolactin levels normalized in 109 (88.6%) of 123 included macroprolactinoma patients. The mean tumor size reduction was 22.9%, and patients in the lowest prolactin tertile (≤0.7) had the highest frequency of tumor size reductions of ≥20% (73.7 vs 52.9% and 45.9% in tertiles 2 (>0.7 to 2.6) and 3 (>2.6 to 20), P = 0.015). Patients with prolactin levels ≤1 ng/mL exhibited larger tumor size reductions vs those with prolactin levels of 1–20 (27.2 ± 18.3% vs 19.5 ± 13.9%, P = 0.014), 1–10 (19.3 ± 13.7%, P = 0.017) and 1–5 ng/mL (19.2 ± 14.3%, P = 0.039). A multivariable logistic regression analysis revealed that a prolactin level ≤1 ng/mL at 3 months and high-dose cabergoline therapy were significantly associated with tumor size reductions of ≥20% (odds ratio (OR): 2.8, 95% confidence interval (CI): 1.2–6.7, P = 0.017; OR: 2.0, 95% CI: 1.0–3.9, P = 0.043).

Conclusions

A prolactin level ≤1 ng/mL at 3 months after cabergoline treatment was correlated with a significant tumor size reduction in patients with macroprolactinoma. This finding may help clinical decision making when treating macroprolactinoma patients.

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Gesine Meyer, Moritz Mayer, Antonia Mondorf, Anna Katharina Flügel, Eva Herrmann and Joerg Bojunga

Objective

Hormone treatment is an important part of gender reassignment therapy in gender dysphoria. Previous data about efficacy and safety are commonly based on small cohorts or they comprise former cohorts under meanwhile obsolete therapy regimes. Our objective was to investigate these topics in a large cohort of individuals under guideline-based treatment.

Design/methods

Cohort study of medical files of n = 155 male-to-female (transwomen) and n = 233 female-to-male transgender persons (transmen) of an Endocrine outpatient clinic between 2009 and 2017.

Results

Median time to reach amenorrhoea in transmen under testosterone monotherapy was 3 months, regardless of whether testosterone undecanoat or gel was used. Transmen with higher levels of hemoglobin 3–4 months after onset of GAHT had a greater chance to reach amenorrhea early, whereas testosterone levels showed no significant correlation (hemoglobin: HR: 1.639; 95% CI: 1.036–2.591, P = 0.035; testosterone: HR: 0.999; 95% CI: 0.998–1.001, P = 0.490). Estradiol levels (ρ −0.117; P = 0.316) had no significant influence on breast development in transwomen. Testosterone levels (ρ −0.398; P < 0.001) and FAI (ρ 0.346; P = 0.004) were significantly negatively correlated with reached Tanner stage. Liver values and blood lipids showed an alignment to reference range of the required sex in both groups. Relevant elevations of liver values were rare (2.44% in transmen, 4.23% in transwomen) and transient in most cases. Most relevant side effects were acne (44.8%), respectively erythrocytosis (up to 5.6%) in transmen and venous thrombembolism (1.9%) in transwomen.

Conclusions

Gender-affirming hormone therapy in accordance with current clinical practice guidelines is efficient and safe.

Open access

Angel Elenkov, Yahia Al-jebari, Yvonne Lunberg Giwercman and Aleksander Giwercman

Male hypogonadism is associated with higher risk of co-morbidity and premature mortality. It is therefore of utmost importance to identify young men, who are at highest risk of testosterone deficiency and who may benefit from preventive measures. In this context, infertile men constitute a high-risk group. The extent of testosterone replacement therapy (TRT) among infertile men, defined as men who have to undergo assisted reproduction for fatherhood, is currently unknown. Therefore, we evaluated the pattern of prescription of TRT in the years following child conception among men who have fathered children with the help of intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF).

By sourcing data from national population registries, hazard ratio (HR) for subsequent TRT was assessed for IVF and ICSI treated men and compared to those who conceived spontaneously with age Cox regression analysis adjusted for age, educational level and previous intake of medicines for metabolic diseases.

ICSI and IVF fathers had increased incidence of newly prescribed TRT compared to fathers conceiving spontaneously (ICSI: HR=3.81, 95% CI=3.09-4.69, p<0.001; IVF: HR=1.54, 95% CI=1.15-2.05, p=0.003). After adjustment for prescription of medication for one or more components of the MetS prior to TRT the risk estimates attenuated but remained robust both for ICSI treated (HR = 3.17 (95% CI:2.56 – 3.9) and IVF treated men (HR = 1.06 (95%CI: 1.05 – 1.07).

Men who have to utilise powerful techniques, such as ICSI for fathering children, may be at risk for testosterone deficiency. Routine endocrine evaluation of men seeking fertility treatment is hence warranted.

Open access

John Newell-Price, Rosario Pivonello, Antoine Tabarin, Maria Fleseriu, Przemysław Witek, Mônica R Gadelha, Stephan Petersenn, Libuse Tauchmanova, Shoba Ravichandran, Pritam Gupta, André Lacroix and Beverly M K Biller

Objective

Monitoring of patients with Cushing’s disease on cortisol-lowering drugs is usually performed with urinary free cortisol (UFC). Late-night salivary cortisol (LNSC) has an established role in screening for hypercortisolism and can help to detect the loss of cortisol circadian rhythm. Less evidence exists regarding the usefulness of LNSC in monitoring pharmacological response in Cushing’s disease.

Design

Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushing’s disease (clinicaltrials.gov: NCT01374906).

Methods

Mean LNSC (mLNSC) was calculated from two samples, collected on the same days as the first two of three 24-h urine samples (used to calculate mean UFC [mUFC]). Clinical signs of hypercortisolism were evaluated over time.

Results

At baseline, 137 patients had evaluable mLNSC measurements; 91.2% had mLNSC exceeding the upper limit of normal (ULN; 3.2 nmol/L). Of patients with evaluable assessments at month 12 (n = 92), 17.4% had both mLNSC ≤ULN and mUFC ≤ULN; 22.8% had mLNSC ≤ULN, and 45.7% had mUFC ≤ULN. There was high variability in LNSC (intra-patient coefficient of variation (CV): 49.4%) and UFC (intra-patient CV: 39.2%). mLNSC levels decreased over 12 months of treatment and paralleled changes in mUFC. Moderate correlation was seen between mLNSC and mUFC (Spearman’s correlation: ρ = 0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC ≤ULN and mUFC ≤ULN.

Conclusion

mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushing’s disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled.

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Saskia le Cessie, Jelle J Goeman and Olaf M Dekkers

When statistically comparing outcomes between two groups, researchers have to decide whether to use parametric methods, such as the t-test, or non-parametric methods, like the Mann–Whitney test. In endocrinology, for example, many studies compare hormone levels between groups, or at different points in time. Many papers apply non-parametric tests to compare groups. We will explain that non-parametric tests have clear drawbacks in medical research, and, that’s the good news, they are often not necessary.

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Kyeong Jin Kim, Sujung Jang, Kyoung Jin Kim, Jee Hyun An, Nam Hoon Kim, Dong Yeob Shin, Hye Jin Yoo, Hee Young Kim, Ji A Seo, Nan Hee Kim, Juneyoung Lee, Kyung Mook Choi, Sei Hyun Baik and Sin Gon Kim

Objective

Thyroid cancer (TC) incidence has increased robustly in Korea. However, the actual cause of death, overall mortality risk, and cause-specific mortality risk in TC patients have not been clearly elucidated.

Design

Retrospective cohort study.

Methods

We analyzed 4082 TC patients from the Korean National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS, 2002–2013) with a median of 48-month follow-up. We compared these patients with 12 246 controls matched for age, sex, and histories of major cardiovascular disease (CVD) to investigate the cause of death and risks of overall and cause-specific mortality.

Results

Overall, 61 deaths (1.5%) occurred in the TC group. The most common cause of death was TC-specific mortality (32.8%), followed by other malignancy-related mortality (31.1%) and CVD mortality (13.1%). The overall mortality risk was comparable between the TC and control groups (unadjusted hazard ratio (HR): 1.17; 95% confidence interval (CI): 0.87–1.58); the adjusted HR remained at 1.25 (95% CI: 0.90–1.74) after multivariate adjustment for body mass index (BMI), socioeconomic status (SES), smoking, alcohol consumption, and histories of hypertension, diabetes mellitus, and dyslipidemia. In addition, there was not enough evidence against the surmise that the CVD mortality risk was similar between the TC and control groups, with an HR of 0.50 (95% CI: 0.22–1.16) after adjustment for CVD risk factors.

Conclusions

Excellent overall survival was observed in TC patients. The most common cause of death was TC-specific mortality, suggesting the importance of thyroid cancer treatment. The overall and cause-specific mortality risks, particularly CVD mortality risk, did not differ between TC patients and the general population.

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Bu B Yeap, Jennie Hui, Matthew W Knuiman, Chubb S A Paul, Ho Ken K Y, Leon Flicker, Mark L Divitini, Gillian M Arscott, Stephen M Twigg, Osvaldo P Almeida, Graeme J Hankey, Jonathan Golledge and John P Beilby

Objective

Effects of insulin-like growth factor 1 (IGF1) and its binding proteins (IGFBPs) on ageing, and their interaction with sex hormones, remain uncertain. We examined associations of plasma IGF1, IGFBP1, IGFBP3, estradiol and testosterone, with leucocyte telomere length (LTL), a marker of biological age, in 2999 community-dwelling men aged 70–84 years.

Methods

Plasma IGF1, IGFBP1 and IGFBP3 measured using immunoassay, sex hormones using mass spectrometry. LTL measured by PCR, expressed as ratio of telomeric to single-copy control gene DNA (T/S ratio). Linear regression models adjusted for age and cardio-metabolic risk factors, median splits defined low/high groups.

Results

Mean age was 76.7 ± 3.2 years. IGF1 and IGFBP3 showed age-adjusted correlations with LTL (coefficient 0.59, P = 0.001 and 0.45, P = 0.013 respectively), IGFBP1 did not. In multivariable-adjusted models IGF1 and IGFBP3 (but not IGFBP1) were associated with LTL (T/S ratio 0.015 higher per 1 s.d. increase in IGF1, P = 0.007, and 0.011 per 1 s.d. IGFBP3, P = 0.049). IGF1 and estradiol were independently associated with longer telomeres (T/S ratio 0.012 higher per 1 s.d. increase in estradiol, P = 0.027, when included in model with IGF1). Testosterone was not associated with LTL. Men with both high IGF1 (>133 µg/L) and high estradiol (>70 pmol/L) had longer LTL compared to men with lower values (multivariable-adjusted T/S ratio 1.20 vs 1.16, P = 0.018).

Conclusions

Higher IGF1 and IGFBP3 are independently associated with longer telomeres in older men. Additive associations of higher IGF1 and higher estradiol with telomere length are present. Further studies are needed to determine whether these hormonal exposures cooperate to slow biological aging.

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Oluwatoyosi Bello, Meera Ladwa, Olah Hakim, Chinmay Marathe, Fariba Shojaee-Moradie, Geoff Charles-Edwards, Janet L Peacock, A Margot Umpleby, Stephanie A Amiel and Louise M Goff

Objectives

In men of black west African (BAM) and white European (WEM) ethnicity, we aimed to (1) compare adipose tissue, peripheral and hepatic insulin sensitivity and (2) investigate associations between ectopic fat and insulin sensitivity by ethnicity.

Design and methods

In overweight BAM (n = 21) and WEM (n = 23) with normal glucose tolerance, we performed a two-step hyperinsulinaemic–euglycaemic clamp with infusion of [6,6 2H2]-glucose and [2H5]-glycerol to measure whole body, peripheral, hepatic and adipose tissue insulin sensitivity (lipolysis). Visceral adipose tissue (VAT), intrahepatic lipids (IHL) and intramyocellular (IMCL) lipids were measured using MRI and spectroscopy. Associations between insulin sensitivity and ectopic fat were assessed using Pearson’s correlation coefficient by ethnicity and regression analysis.

Results

There were no ethnic differences in whole body or tissue-specific insulin sensitivity (all P  > 0.05). Suppression of lipolysis was inversely associated with VAT and IHL in WEM but not BAM (VAT: WEM r = −0.68, P < 0.01; BAM r = 0.07, P = 0.79. IHL: WEM r = −0.52, P = 0.01; BAM r = −0.12, P = 0.63). IMCL was inversely associated with skeletal muscle insulin sensitivity in WEM but not BAM (WEM r = −0.56, P < 0.01; BAM r = −0.09, P = 0.75) and IHL was inversely associated with hepatic insulin sensitivity in WEM but not BAM (WEM r = −0.53, P = 0.02; BAM r = −0.13, P = 0.62).

Conclusions

Ectopic fat deposition may play a lesser role in reducing insulin sensitivity in men of black African ethnicity and may not be driven by lipolysis. Resistance to storing VAT, IHL and IMCL may enable men of black African ethnicity to maintain comparable insulin sensitivity to white Europeans.

Free access

R Pasquali, F Casanueva, M Haluzik, L van Hulsteijn, S Ledoux, M P Monteiro, J Salvador, F Santini, H Toplak and O M Dekkers

Obesity is an emerging condition, with a prevalence of ~20%. Although the simple measurement of BMI is likely a simplistic approach to obesity, BMI is easily calculated, and there are currently no data showing that more sophisticated methods are more useful to guide the endocrine work-up in obesity. An increased BMI leads to a number of hormonal changes. Additionally, concomitant hormonal diseases can be present in obesity and have to be properly diagnosed – which in turn might be more difficult due to alterations caused by body fatness itself. The present European Society of Endocrinology Clinical Guideline on the Endocrine Work-up in Obesity acknowledges the increased prevalence of many endocrine conditions in obesity. It is recommended to test all patients with obesity for thyroid function, given the high prevalence of hypothyroidism in obesity. For hypercortisolism, male hypogonadism and female gonadal dysfunction, hormonal testing is only recommended if case of clinical suspicion of an underlying endocrine disorder. The guideline underlines that weight loss in obesity should be emphasized as key to restoration of hormonal imbalances and that treatment and that the effect of treating endocrine disorders on weight loss is only modest.