Leonardo Guasti and James F H Pittaway
Laura Pekkarinen, Tatu Kantonen, Eleni Rebelos, Aino Latva-Rasku, Prince Dadson, Tomi Karjalainen, Marco Bucci, Kari Kalliokoski, Kirsi Laitinen, Noora Houttu, Anna K Kirjavainen, Johan Rajander, Tapani Rönnemaa, Lauri Nummenmaa, and Pirjo Nuutila
To investigate whether alterations in brain glucose uptake (BGU), insulin action in the brain–liver axis and whole-body insulin sensitivity occur in young adults in pre-obese state.
Healthy males with either high risk (HR; n = 19) or low risk (LR; n = 22) for developing obesity were studied with [18F]fluoro-d-glucose ([18F]FDG)–positron emission tomography during hyperinsulinemic–euglycemic clamp. Obesity risk was assessed according to BMI, physical activity and parental overweight/obesity and type 2 diabetes. Brain, skeletal muscle, brown adipose tissue (BAT), visceral adipose tissue (VAT) and abdominal and femoral s.c. adipose tissue (SAT) glucose uptake (GU) rates were measured. Endogenous glucose production (EGP) was calculated by subtracting the exogenous glucose infusion rate from the rate of disappearance of [18F]FDG. BGU was analyzed using statistical parametric mapping, and peripheral tissue activity was determined using Carimas Software imaging processing platform.
BGU was higher in the HR vs LR group and correlated inversely with whole-body insulin sensitivity (M value) in the HR group but not in the LR group. Insulin-suppressed EGP did not differ between the groups but correlated positively with BGU in the whole population, and the correlation was driven by the HR group. Skeletal muscle, BAT, VAT, abdominal and femoral SAT GU were lower in the HR group as compared to the LR group. Muscle GU correlated negatively with BGU in the HR group but not in the LR group.
Increased BGU, alterations in insulin action in the brain–liver axis and decreased whole-body insulin sensitivity occur early in pre-obese state.
Johanna Laru, Marja Ojaniemi, Stephen Franks, Marjo-Riitta Järvelin, Elisa Korhonen, Terhi T Piltonen, Sylvain Sebert, Juha S Tapanainen, and Laure Morin-Papunen
This study aimed to evaluate the association between birth weight (BW), childhood and adolescent BMI, with reproductive capacity in men.
A prospective, population-based cohort study (Northern Finland birth cohort 1966).
Around 6196 men born in 1966 were followed from birth to age 50 years. Weight and height were measured repeatedly by professionals. Reproductive capacity (infertility assessment, male factor infertility and infertility treatment by age 46 years) was evaluated by questionnaires at ages 31 and 46 years. The number of children by the age of 50 years was recovered from registers. After excluding the men who reported never having attempted to have children or not answering the question at age 31 or 46 years (n = 2041), 4128 men were included in the final study population. Results were adjusted for BW, BW for gestational age (GA), mother’s smoking status, marital status, educational level and smoking status.
Being small for GA (10.5% vs 8.2%, P = 0.012) or having a lower BW (3495 g vs 3548 g, P = 0.003) were associated with childlessness. The association was however no longer significant after adjusting for marital status. Being underweight in early childhood was associated with an increased risk of infertility assessment (adjusted, aOR: 2.04(1.07–3.81)) and childlessness (aOR: 1.47(1.01–2.17)) compared to the normal weight group. Conversely, overweight or obesity in early childhood was associated with a decreased risk of infertility assessment (aOR: 0.60 (0.41–0.87)), treatment (aOR: 0.42 (0.25–0.70)) and male factor infertility (aOR: 0.45 (0.21–0.97)). BMI in mid-childhood or puberty had no association with infertility or childlessness.
In boys, an optimal growth trajectory during pregnancy and early childhood seems to be very important for life-long fertility.
Daphné Karila, Bruno Donadille, Juliane Léger, Claire Bouvattier, Anne Bachelot, Veronique Kerlan, Sophie Catteau-Jonard, Sylvie Salenave, Frédérique Albarel, Claire Briet, Regis Coutant, Aude Brac De La Perriere, Alexander Valent, Jean-Pierre Siffroi, and Sophie Christin-Maitre
A gonadectomy is currently recommended in patients with Turner syndrome (TS) and a 45,X/46,XY karyotype, due to a potential risk of gonadoblastoma (GB). However, the quality of evidence behind this recommendation is low.
This study aimed to evaluate the prevalence of GB, its characteristics, as well as its risk factors, according to the type of Y chromosomal material in the karyotype.
Our study within French rare disease centers included patients with TS and a 45,X/46,XY karyotype, without ambiguity of external genitalia. Clinical characteristics of the patients, their age at gonadectomy, and gonadal histology were recorded. The regions of the Y chromosome, the presence of TSPY regions, and the percentage of 45,X/46,XY mosaicism were evaluated.
A total of 70 patients were recruited, with a median age of 29.5 years (21.0–36.0) at the end of follow-up. Fifty-eight patients had a gonadectomy, at a mean age of 15 ± 8 years. GB was present in nine cases. Two were malignant, which were discovered at the age of 14 and 32 years, without metastases. Neither the percentage of XY cells within the 45,X/46,XY mosaicism nor the number of TSPY copies was statistically different in patients with or without GB (P = 0.37). However, the entire Y chromosome was frequent in patients with GB (6/9).
In our study, including a large number of patients with 45,X/46,XY TS, the prevalence of gonadoblastoma is 12.8%. An entire Y chromosome appears as the main risk factor of GB and should favor early gonadectomy.
About 10% of patients with TS have a karyotype containing Y chromosomal material: 45,X/46,XY. Its presence is related to the risk of GB. Therefore, a prophylactic gonadectomy is currently recommended in such patients. However, the quality of evidence is low. Our objective was to evaluate the prevalence of GB according to the type of Y-chromosomal material. We found a prevalence of GB of 12.8% in a cohort of 70 TS patients. No sign of hyperandrogenism was observed. The entire Y chromosome was the most frequent type of Y-material in patients with GB. As the prognosis of these tumors was good, a delay of surgery might be discussed.
Nicolas Sahakian, Romain Appay, Noémie Resseguier, Thomas Graillon, Cécilia Piazzola, Cécilia Laure, Dominique Figarella-Branger, Jean Régis, Frédéric Castinetti, Thierry Brue, Henry Dufour, and Thomas Cuny
Usually benign, pituitary tumors (PT) can be invasive and aggressive with a propensity to progress and/or recur. Trouillas’s clinicopathological classification attempts to predict the evolutionary risk of a PT. In this study, we assessed the prognostic value of this classification in an independent patient cohort and analyzed its impact on treatment strategies.
Patients and methods
In this study, 607 patients operated on between 2008 and 2018 for a PT were included. Grading was established based on invasion, proliferative activity (Ki-67, mitotic index) and p53 positivity. The therapeutic management following surgery was analyzed. Progression-free survival (PFS) of the graded tumors was estimated (Kaplan–Meier method and log-rank test) and a multivariate analysis was performed (Cox regression model).
Grading identified non-invasive PT without (grade 1a: 303 cases) or with proliferative activity (grade 1b: 53 cases) and invasive PT without (grade 2a: 202 cases) or with proliferative activity (grade 2b: 49 cases). The mean follow-up was 47 ± 30 months (median: 38 months). Progression/recurrence occurred in 127 cases. Grades were significant and independent predictors of PFS (P < 0.001) with a 4.8-fold higher risk of progression/recurrence in grade 2b as compared to grade 1a. As second-line therapy, gamma knife or conventional radiotherapy controlled tumor growth in 91.6 and 100% of cases, respectively, irrespective of the grade. Proliferative tumors exposed the patient to a 9.5-fold higher risk of having ≥3 adjuvant therapeutic lines as compared to non-proliferative tumors.
Grading of a PT according to Trouillas’s classification predicts its risk of progression and should advocate for a personalized therapeutic approach in invasive and proliferative tumors.
This is the first study to assess, on a cohort of 607 well-characterized patients, the real-life therapeutic impact of the five-tiered clinicopathological classification of pituitary tumors. First, we validate that pituitary tumor grades predict the evolutionary risk of the tumor, with a significant higher risk of progression/recurrence in invasive and/or proliferative tumors (mean follow-up: 47 ± 30 months, median: 38 months). Moreover, our study provides evidence that patients with proliferative tumors have a higher risk to be retreated after primary surgery and point toward the fact that radiotherapy can successfully control tumor growth in case of progression or recurrence. Our findings advocate for a personalized therapeutic approach in clinically aggressive pituitary tumors.
Shun-Cheong Ho, Gloria Hoi-Yee Li, Anskar Yu-Hung Leung, Kathryn C B Tan, and Ching-Lung Cheung
Haematopoiesis was shown to regulate bone metabolism in in vivo studies. However, whether haematopoiesis has causal effects on bone health has never been investigated in humans. We aimed to evaluate the causal relationships of blood traits with bone mineral density (BMD) and fracture.
Design and methods
Using two-sample Mendelian randomization, causal relationship of 29 blood traits with estimated BMD (eBMD), total body BMD (TBBMD), lumbar spine BMD (LSBMD), femoral neck BMD (FNBMD) and fracture were evaluated by inverse-variance weighted (IVW) method and multiple sensitivity analyses. Relevant genetic data were obtained from the largest possible publicly available genome-wide association studies.
Eight genetically determined red blood cell traits showed positive causal effects on eBMD, with beta estimates ranging from 0.009 (mean corpuscular haemoglobin) to 0.057 (haemoglobin concentration), while three white blood cell traits, including lymphocyte count (beta: −0.020; 95% CI: −0.033 to −0.007), neutrophil count (beta: −0.020; 95% CI: −0.035 to −0.006) and white blood cell count (beta: −0.027; 95% CI: −0.039 to −0.014), were inversely associated with eBMD. Causal effects for six of these blood traits were validated on TBBMD, LSBMD, FNBMD and/or fracture. The association of reticulocyte count (beta: 0.040; 95% CI: 0.016 to 0.063), haemoglobin (beta: 0.058; 95% CI: 0.021 to 0.094) and mean corpuscular haemoglobin concentration (beta: 0.030; 95% CI: 0.007 to 0.054) with eBMD remained significant in multivariable IVW analyses adjusted for other blood traits.
This study provided evidence that haematopoietic system might regulate the skeletal system in humans and suggested the possible pathophysiology of bone diseases among people with haematological diseases.
We conducted a novel Mendelian randomization study investigating the causal relationship of blood cells with bone mineral density. Red and white blood cell traits have positive and inverse causal relationship with bone mineral density, respectively, suggesting a potential link of haematopoietic system with the skeletal system in humans. Current findings suggest individuals with related haematological diseases, such as anaemia and leukocytosis, may have a lifelong increased risk of osteoporosis and/or fracture. Given that complete blood count is commonly performed in clinical setting, whether complete blood count can be used to predict fracture risk warrants further investigation.
Hanna F Nowotny, Leah Braun, Frederick Vogel, Martin Bidlingmaier, Martin Reincke, Lea Tschaidse, Matthias K Auer, Christian Lottspeich, Stefan A Wudy, Michaela F Hartmann, James Hawley, Joanne E Adaway, Brian Keevil, Katharina Schilbach, and Nicole Reisch
Symptoms of hyperandrogenism are common in patients with Cushing’s disease (CD), yet they are not sufficiently explained by androgen concentrations. In this study, we analyzed the contribution of 11-oxygenated C19 steroids (11oxC19) to hyperandrogenemia in female patients with CD.
We assessed saliva day profiles in females with CD pre (n = 23) and post (n = 13) successful transsphenoidal surgery, 26 female controls, 5 females with CD treated with metyrapone and 5 treated with osilodrostat for cortisol, cortisone, androstenedione (A4), 11-hydroxyandrostenedione (11OHA4), testosterone (TS), 11-ketotestosterone (11KT), as well as metabolites of classic and 11-oxygenated androgens in 24-h urine. In addition, morning baseline levels of gonadotropins and estradiol, sex hormone-binding globulin, cortisol and dehydroepiandrosterone sulfate (DHEAS) in serum and adrenocorticotrophic hormone in plasma in patients and controls were investigated.
Treatment-naïve females with CD showed a significantly elevated area under the curve of 11OHA4 and 11KT in saliva throughout the day compared to controls (11OHA4 mean rank difference (mrd) 18.13, P = 0.0002; 11KT mrd 17.42; P = 0.0005), whereas A4, TS and DHEAS were comparable to controls. Gonadotropin concentrations were normal in all patients with CD. After transsphenoidal surgery, 11oxC19 and their metabolites dropped significantly in saliva (11OHA4 P < 0.0001; 11KT P = 0.0010) and urine (11-oxo-androsterone P = 0.0011; 11-hydroxy-androsterone P < 0.0001), treatment with osilodrostat and metyrapone efficaciously blocked 11oxC19 synthesis.
Hyperandrogenemia in CD is predominantly caused by excess of 11oxC19 steroids.
, Hiroshi Arima, Timothy Cheetham, Mirjam Christ-Crain, Deborah Cooper, Mark Gurnell, Juliana B Drummond, Miles Levy, Ann I McCormack, Joseph Verbalis, John Newell-Price, and John A H Wass
‘What’s in a name? That which we call a rose/By any other name would smell as sweet.’ (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare’s implication is that a name is nothing but a word and it therefore represents a convention with no intrinsic meaning. Whilst this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rationale for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology, nephrology and pediatric societies now proposes changing the name of ‘diabetes insipidus’ to ‘arginine vasopressin deficiency (AVP-D)’ for central etiologies and ‘arginine vasopressin resistance (AVP-R)’ for nephrogenic etiologies. This editorial provides both the historical context and the rationale for this proposed name change.
Melanie S Haines, Allison Kimball, Erinne Meenaghan, Kate Santoso, Caitlin Colling, Vibha Singhal, Seda Ebrahimi, Suzanne Gleysteen, Marcie Schneider, Lori Ciotti, Perry Belfer, Kamryn T Eddy, Madhusmita Misra, and Karen K Miller
Anorexia nervosa is complicated by high bone resorption, low bone mineral density (BMD), and increased fracture risk. We investigated whether off-label antiresorptive therapy with denosumab increases BMD in women with anorexia nervosa.
Twelve-month, randomized, double-blind, placebo-controlled study.
Thirty ambulatory women with anorexia nervosa and areal BMD (aBMD) T-score <−1.0 at ≥1 sites were randomized to 12 months of denosumab (60 mg subcutaneously q6 months)(n = 20) or placebo (n = 10). Primary end point was postero-anterior (PA) lumbar spine aBMD by dual-energy x-ray absorptiometry. Secondary end points included femoral neck aBMD, tibia and radius volumetric BMD and bone microarchitecture by high-resolution peripheral quantitative CT, tibia and radius failure load by finite element analysis (FEA), and markers of bone turnover.
Baseline mean (±s.d.) age (29 ± 8 (denosumab) vs 29 ± 7 years (placebo)), BMI (19.0 ± 1.7 vs 18.0 ± 2.0 kg/m2), and aBMD (PA spine Z-score −1.6±1.1 vs −1.7±1.4) were similar between groups. PA lumbar spine aBMD increased in the denosumab vs placebo group over 12 months (P = 0.009). The mean (95% CI) increase in PA lumbar spine aBMD was 5.5 (3.8–7.2)% in the denosumab group and 2.2 (−0.3–4.7)% in the placebo group. The change in femoral neck aBMD was similar between groups. Radial trabecular number increased, radial trabecular separation decreased, and tibial cortical porosity decreased in the denosumab vs placebo group (P ≤ 0.006). Serum C-terminal telopeptide of type I collagen and procollagen type I N-terminal propeptide decreased in the denosumab vs placebo group (P < 0.0001). Denosumab was well tolerated.
Twelve months of antiresorptive therapy with denosumab reduced bone turnover and increased spine aBMD, the skeletal site most severely affected in women with anorexia nervosa.
Lin Gan, Nanfang Li, Mulalibieke Heizati, Mengyue Lin, Qing Zhu, Jing Hong, Ting Wu, Ling Tong, Zuhere Xiamili, and Yue Lin
The hypothalamic–pituitary–adrenal (HPA) axis may be associated with cardiovascular disease (CVD) and the effects of diurnal cortisol features on future CVD remain unclear among patients with hypertension. This study aimed to evaluate the association between diurnal cortisol features and CVD in patients with hypertension.
Design and methods
Participants with cortisol rhythm test at baseline in Urumqi Research on Sleep Apnea and Hypertension (UROSAH) in 2011–2013 were enrolled and followed up till 2021. Incident events included coronary heart disease, stroke, and heart failure. Cox proportional hazards model was used to evaluate the relationship between diurnal cortisol features and incident CVD. Sex-specific and sensitivity analyses were also performed.
In total, 2305 hypertensive participants comprised the current analytical sample. During a median follow-up of 7.2 years and 16374.9 person-years, there were 242 incident CVD cases. Multivariable Cox regression showed that steep diurnal cortisol slope (DCS) was significantly associated with decreased CVD risk (per s.d., hazard ratio (HR) = 0.86, 95% CI: 0.77–0.96, P = 0.011). Midnight cortisol was positively associated with an increased CVD risk (per s.d., HR = 1.24, 95% CI: 1.08–1.42, P = 0.002). Comparable results were observed in the sensitivity analyses. Neither midnight cortisol nor DCS was associated with incident CVD in the female subgroup.
Flatter DCS and higher midnight cortisol levels are associated with an increased risk of CVD in patients with hypertension, especially in men. The detection of diurnal cortisol rhythm may help identify patients with hypertension at high risk of CVD.