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Infections and demanding endocrine care contribute to increased mortality in patients with APECED

Joonatan Borchers, Outi Mäkitie, and Saila Laakso

Objective

Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) has variable clinical course. Overall mortality is increased but reasons for this remain largely unknown. Our objective was to assess the causes of death and factors contributing to increased mortality.

Design

A follow-up study of the Finnish APECED cohort in 1970–2019.

Methods

In 33 deceased patients with APECED, causes of death and clinical course preceding the death were analyzed using national registry data, death certificates, autopsy reports, and patient records.

Results

Most common causes leading to death were infections (24%), oral and esophageal malignancies (15%; median age at death 36.7 years; median survival 1.5 years), and diseases of the circulatory system (18%). Adrenal crisis was an independent cause of death in two patients. In addition, in four patients, the adrenal crisis was a complicating factor during a fatal infection. Other APECED manifestations leading to death were hypoparathyroidism, diabetes, and hepatitis. Other causes of death included accidents (12%), alcohol-related causes, and amyotrophic lateral sclerosis. Challenges in overall, and especially in the endocrine, care contributed to deaths related to carcinomas and adrenal crisis. Age at death and year of death correlated (r = 0.345, P = 0.045), suggesting improved longevity.

Conclusions

Infections, malignancies, and diseases of the circulatory system are the most common primary causes of death in patients with APECED. Adrenal crisis is an independent cause of death but more often a contributing factor in fatal infections. Despite the high overall mortality and the demanding care, our results suggest improved patient survival in recent years.

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Insulin-like growth factor ternary complex components as biomarkers for the diagnosis of short stature

Aristeidis Giannakopoulos, Alexandra Efthymiadou, and Dionisios Chrysis

Objective

The diagnosis of growth hormone deficiency (GHD) in children is not always straightforward because insulin-like growth factor 1 (IGF-I) or GH stimulation tests may not be able to discriminate GHD from constitutional delay of growth and puberty (CDGP) or other causes of short stature.

Design

Boys and girls (n = 429, 0.7–16 years) who attended our department for short stature participated in this study. They were followed up for an average period of 9 years. At the end of follow-up after reaching the final height, a definitive diagnosis was assigned, and all the components of ternary complex (IGF-I, IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), and IGF-I/IGFBP-3 ratio) were evaluated as biomarkers for the respective diagnosis.

Results

All the components of the ternary complex were tightly correlated with each other and were positively related to age. IGF-I, IGFBP-3, ALS, and IGF-I/IGFBP-3 ratio differed significantly between GHD and normal groups. IGF-I and ALS levels were lower in GHD compared to children with familial short stature, while IGF-I and IGF-I/IGFBP-3 ratio was significantly lower in GHD compared to children with CDGP. IGF-I and IGF-I/IGFBP-3 receiver operating curve cutoff points were unable to discriminate between GHD and normal groups or between GHD and CDGP groups.

Conclusion

Despite the tight correlation among all the components of the ternary complex, each one shows a statistically significant diagnosis-dependent alteration. There is a superiority of IGF-I, ALS, and IGF-I/IGFBP-3 ratio in the distinction between GHD and CDGP or between GHD and normal groups but without usable discriminating power, making auxology as the primary criterion for establishing the diagnosis.

Free access

MECHANISMS IN ENDOCRINOLOGY: Local and systemic effects of glucocorticoids on metabolism: new lessons from animal models

Michael Swarbrick, Hong Zhou, and Markus Seibel

Glucocorticoids regulate a remarkable variety of essential functions, including development, immunomodulation, maintenance of circadian rhythm and the response to stress. Glucocorticoids acutely increase energy availability; this is accomplished not only by mobilizing energy stores but also by diverting energy away from anabolic processes in tissues such as skeletal muscle and bone. While this metabolic shift is advantageous in the short term, prolonged glucocorticoid exposure frequently results in central obesity, insulin resistance, hyperglycaemia, dyslipidaemia, muscle wasting and osteoporosis. Understanding how glucocorticoids affect nutrient partitioning is, therefore, critical for preventing the side effects of glucocorticoid treatment. Independently of circulating glucocorticoids, intracellular glucocorticoid activity is regulated by the 11β-hydroxysteroid dehydrogenases 1 and 2 (HSD11B1 and 2), which activate and inactivate glucocorticoids, respectively. Excessive HSD11B1 activity and amplification of local glucocorticoid activity in tissues such as adipose tissue and bone may contribute to visceral obesity, insulin resistance and ageing-related bone loss in humans. Several recent findings in animals have considerably expanded our understanding of how glucocorticoids exert their dysmetabolic effects. In mice, disrupting glucocorticoid signalling in either adipose tissue or bone produces marked effects on energy homeostasis. Glucocorticoids have also been shown to influence brown adipose tissue thermogenesis (acute activation, chronic suppression), in both rodents and humans. Lastly, recent studies in mice have demonstrated that many dysmetabolic effects of glucocorticoids are sexually dimorphic, although corresponding results in humans are lacking. Together, these studies have illuminated mechanisms by which glucocorticoids exert their metabolic effects and have guided us towards more targeted future treatments for metabolic diseases.

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Molecular diagnosis of polycystic ovary syndrome in obese and non-obese women by targeted plasma miRNA profiling

Antonio Romero-Ruiz, Beatriz Pineda, David Ovelleiro, Cecilia Perdices-Lopez, Encarnación Torres, María J Vazquez, Ipek Guler, Álvaro Jiménez, Rafael Pineda, Mariasara Persano, Cristina Romero-Baldonado, José E Arjona, Juan Lorente, Concepción Muñoz, Elier Paz, Fe-Isabel Garcia-Maceira, Álvaro Arjona-Sánchez, and Manuel Tena-Sempere

Objective

Polycystic ovary syndrome (PCOS) is diagnosed based on the clinical signs, but its presentation is heterogeneous and potentially confounded by concurrent conditions, such as obesity and insulin resistance. miRNA have recently emerged as putative pathophysiological and diagnostic factors in PCOS. However, no reliable miRNA-based method for molecular diagnosis of PCOS has been reported. The aim of this study was to develop a tool for accurate diagnosis of PCOS by targeted miRNA profiling of plasma samples, defined on the basis of unbiased biomarker-finding analyses and biostatistical tools.

Methods

A case–control PCOS cohort was cross-sectionally studied, including 170 women classified into four groups: non-PCOS/lean, non-PCOS/obese, PCOS/lean, and PCOS/obese women. High-throughput miRNA analyses were performed in plasma, using NanoString technology and a 800 human miRNA panel, followed by targeted quantitative real-timePCR validation. Statistics were applied to define optimal normalization methods, identify deregulated biomarker miRNAs, and build classification algorithms, considering PCOS and obesity as major categories.

Results

The geometric mean of circulating hsa-miR-103a-3p, hsa-miR-125a-5p, and hsa-miR-1976, selected among 125 unchanged miRNAs, was defined as optimal reference for internal normalization (named mR3-method). Ten miRNAs were identified and validated after mR3-normalization as differentially expressed across the groups. Multinomial least absolute shrinkage and selection operator regression and decision-tree models were built to reliably discriminate PCOS vs non-PCOS, either in obese or non-obese women, using subsets of these miRNAs as performers.

Conclusions

We define herein a robust method for molecular classification of PCOS based on unbiased identification of miRNA biomarkers and decision-tree protocols. This method allows not only reliable diagnosis of non-obese women with PCOS but also discrimination between PCOS and obesity.

Capsule

We define a novel protocol, based on plasma miRNA profiling, for molecular diagnosis of PCOS. This tool not only allows proper discrimination of the condition in non-obese women but also permits distinction between PCOS and obesity, which often display overlapping clinical presentations.

Open access

An oral lipidic native testosterone formulation that is absorbed independent of food

John Newell-Price, Hiep Huatan, Jo Quirke, John Porter, Eleni Daniel, Enis Mumdzic, Bernard Voet, Brian Keevil, Martin J Whitaker, and Richard J Ross

Context

There is no licensed oral native testosterone (NT) because of challenges in the formulation. Licensed oral formulations of the ester, testosterone undecanoate (TU), require a meal for absorption and generate supraphysiological dihydrotestosterone (DHT) levels.

Objective

To develop an oral NT formulation.

Design and methods

A lipid-based formulation of native testosterone filled into soft-gelatin capsules at 40 mg per capsule was designed with 2 years of stability at ambient temperature. Pharmacokinetic comparison studies of this oral lipidic NT formulation to oral TU were conducted in dogs and hypogonadal men.

Results

In dogs, 40 mg NT was well absorbed under fasted conditions whereas 40 mg TU required a high-fat meal: for NT, the mean fed/fasted AUC ratio was 1.63 and for TU 7.05. In hypogonadal men, fed and fasted NT had similar pharmacokinetics: Cmax mean 26.5 vs 30.4 nmol/L (769 vs 882 ng/dL), AUC0–10 h 87 vs 88.6 h nmol/L. NT (fed state) showed a testosterone AUC increase of 45% between 120 and 200 mg, and NT 200 mg gave a similar mean AUC0–10 h to TU 80 mg: 87 vs 64.8 h nmol/L. Serum TU levels were variable and on a molar basis were ~ten-fold higher than serum testosterone levels after TU 80 mg fed. The DHT: testosterone AUC0–10 h ratio was more physiological for NT than TU being 0.19 vs 0.36. There were no emerging safety concerns with NT.

Conclusion

This novel oral lipidic native testosterone formulation has potential advantages over oral TU of dosing independently of food and a lower risk of supraphysiological DHT levels.

Significance statement

There is no licensed oral testosterone because of challenges in formulation, and the oral formulations of the ester, testosterone undecanoate, require a fatty meal for absorption and generate supraphysiological dihydrotestosterone levels. We have overcome the design challenges and formulated an oral native testosterone that can be taken with or without food and provides physiological levels of testosterone and dihydrotestosterone in hypogonadal men. This formulation, DITEST, has the potential advantage of being oral for patients who do not tolerate injections and less risk of adverse events that might theoretically be associated with elevated dihydrotestosterone levels. Future studies will need to define the dosing regimen for replacement in hypogonadal men.

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Plasma glycated CD59 predicts postpartum glucose intolerance after gestational diabetes

Katrien Benhalima, Diane D Ma, Annouschka Laenen, Chantal Mathieu, and Jose A Halperin

Aim

To assess whether in women with gestational diabetes mellitus (GDM), postpartum plasma glycated CD59 (pGCD59) levels predict conversion to glucose intolerance diagnosed with an oral glucose tolerance test (OGTT).

Methods

Blood levels of pGCD59 were measured in a case–control study of 105 women with GDM who underwent a 75 g OGTT 3 months postpartum. The 35 postpartum glucose intolerant cases were individually matched for age, BMI, ethnic origin, and parity with 70 women with GDM but normal postpartum OGTT (controls). The GDM cohort (105) was also matched with 105 normal glucose tolerant women during pregnancy. pGCD59 was measured by ELISA in standard peptide units (SPU).

Results

Mean pGCD59 postpartum was significantly higher in cases than in controls (1.5 ± 0.6 SPU vs 1.0 ± 0.6 SPU, P < 0.001). The area under the receiving operating characteristic curve (AUC) in cases vs controls was 0.72 (95% CI: 0.62–0.83) for postpartum pGCD59 and 0.50 (95% CI: 0.36–0.61) for postpartum HbA1c. A 0.5-unit increase in postpartum pGCD59 was associated with an odds ratio (OR) of 3.3 (95% CI: 1.82–6.16, P < 0.001) for glucose intolerance postpartum. A pGCD59 cut-off postpartum of 0.9 SPU had a sensitivity of 85.7% (95% CI: 69.7–95.2%), specificity of 47.8% (95% CI: 35.6–60.2%), positive predictive value of 45.4% (95% CI: 33.1–58.2%), and negative predictive value of 86.8% (95% CI: 71.9–95.6%). pGCD59 in pregnancy was a poor predictor for glucose intolerance postpartum (AUC of 0.61 (95% CI: 0.50–0.72)).

Conclusion

pGCD59 might identify women at low risk for glucose intolerance postpartum and could help to avoid an OGTT.

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Quantification of androgens and their precursors in full-term human placenta

Tomoko Yoshida, Kenji Matsumoto, Mami Miyado, Yoshimichi Miyashiro, Haruhiko Sago, Reiko Horikawa, and Maki Fukami

Introduction

The two major androgens in humans are testosterone (T) and dihydrotestosterone (DHT). DHT is produced via the classical, backdoor, and alternative steroidogenic pathways. In addition, recent studies have identified C11-oxy C19 steroids as novel human androgens. Although the placenta is known to be involved in steroid metabolism, androgen levels in full-term placentas have poorly been investigated.

Subjects and methods

Ten placentas of healthy full-term neonates (five males and five females) were examined. We quantified progesterone, androstenedione (A4), T, allopregnanolone, androsterone, and estradiol, as well as four C11-oxy androgens (11β-hydroxyandrostenedione, 11β-hydroxytestosterone, 11-ketoandrostenedione (11KA4), and 11-ketotestosterone (11KT)), using liquid chromatography-tandem mass spectrometry.

Results

In all samples, levels of the ten steroids were above the detection limit. Progesterone was by far most abundant, while levels of T and androsterone were relatively low. Levels of 11KT and 11KA4 were higher than those of T and A4, respectively. There were no differences in steroid levels between male and female samples.

Discussion

This study demonstrates that full-term placentas contain several steroids in the classical, backdoor, and alternative pathways. Placentas are likely to function as the supplier of progesterone to other steroidogenic tissues. More importantly, we found that placentas comprise relatively large amounts of 11KA4 and 11KT, which may be produced through steroid transfer from the adrenal gland or from the maternal circulation. These results indicate that the placenta participates in a feto-maternal multi-organ network for androgen biosynthesis.

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Renin, a marker for left ventricular hypertrophy, in primary aldosteronism: a cohort study

Anton Köhler, Anna-Lina Sarkis, Daniel Alexander Heinrich, Lisa Müller, Laura Handgriff, Sinan Deniz, Holger Schneider, Heike Künzel, Roland Ladurner, Martin Reincke, and Christian Adolf

Context

Primary aldosteronism (PA) causes left ventricular hypertrophy (LVH) via hemodynamic factors and directly by aldosterone effects. Specific treatment by mineralocorticoid receptor antagonists (MRA) or adrenalectomy (ADX) has been reported to improve LVH. However, the cardiovascular benefit could depend on plasma renin concentration (PRC) in patients on MRA.

Patients and objective

We analyzed data from 184 patients from the Munich center of the German Conn’s Registry, who underwent echocardiography at the time of diagnosis and 1 year after treatment. To assess the effect of PRC on cardiac recovery, we stratified patients on MRA according to suppression (n = 46) or non-suppression of PRC (n = 59) at follow-up and compared them to PA patients after ADX (n = 79).

Results

At baseline, patients treated by ADX or MRA had comparable left ventricular mass index (LVMI, 61.7 vs 58.9 g/m2.7, P  = 0.591). Likewise, patients on MRA had similar LVMI at baseline, when stratified into treatment groups with suppressed and unsuppressed PRC during follow-up (60.0 vs 58.1 g/m2.7, P  = 0.576). In all three groups, we observed a significant reduction in LVMI following treatment (P  < 0.001). However, patients with suppressed PRC had no decrease in pro-BNP levels, and the reduction of LVMI was less intense than in patients with unsuppressed PRC (4.1 vs 8.2 g/m2.7, P  = 0.033) or after ADX (9.3 g/m2.7, P  = 0.019). Similarly, in multivariate analysis, higher PRC was correlated with the regression of LVH.

Conclusion

PA patients with suppressed PRC on MRA show impaired regression of LVH. Therefore, dosing of MRA according to PRC could improve their cardiovascular benefit.

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Risk of over- and under- treatment with levothyroxine in primary care in Copenhagen, Denmark

Jeppe Lerche la Cour, Bjarke Røssner Medici, Mia Klinten Grand, Dagny Ros Nicolaisdottir, Bent Lind, Jens Faber, Christen Lykkegaard Andersen, and Birte Nygaard

Objective

A decrease over time in thyroid stimulating hormone (TSH) levels when initiating levothyroxine (L-T4) therapy for hypothyroidism has been reported, where treatment most often is initiated with TSH levels below 10 mIU/L. The primary objective of this study was to investigate whether this lower TSH threshold resulted in an increased number of overtreated patients.

Design and method

Retrospective cohort study comprising inhabitants in Copenhagen had TSH measurements requested by general practitioners which led to a new prescription of L-T4 between 2001 and 2012. Over- and under- treatment were defined as TSH <0.1 mIU/L or above 10 mIU/mL, respectively, in three consecutive measurements. Data were analyzed by Aalen–Johansen estimators and Cox proportional hazards models.

Results

In total, 14 533 initiations of L-T4 were included in the study. The cumulative risk of being over- or undertreated was 4.7 and 7.4% after 10 years. The hazard of overtreatment was higher among women, younger adults, and with lower initial TSH levels. The hazard of overtreatment decreased over the time period from 2001 to 2012. Among overtreated individuals, the chance of returning to a normal TSH was about 55% after 10 years. In 18% of the cases, L-T4 therapy was initiated on TSH levels less than 5 mIU/L.

Conclusion

Although a still decreasing threshold for initiating L-T4 therapy is known, the risk of overtreatment (and undertreatment) was low and lessened in the period 2001–2012 among Danish primary care patients. Nevertheless, as many as 18% were started on L-T4 with normal TSH levels.

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Serum anti-Müllerian hormone as a marker of ovarian reserve after cancer treatment and/or hematopoietic stem cell transplantation in childhood: proposal for a systematic approach to gonadal assessment

Silvia Molinari, Francesca Parissone, Veronica Evasi, Paola De Lorenzo, Maria Grazia Valsecchi, Simone Cesaro, Donatella Fraschini, Roberta Sangalli, Gianluca Cacace, Andrea Biondi, Adriana Balduzzi, and Alessandro Cattoni

Objective

Female patients treated with alkylating agents in childhood are at risk for ovarian impairment. We aimed at describing the pattern of residual ovarian function in a cohort of survivors of hematological malignancies and/or hematopoietic stem cell transplantation (HSCT) and assessing the relationship between cyclophosphamide equivalent dose (CED) and anti-Müllerian hormone (AMH).

Design and methods

Gonadal health was clinically and biochemically assessed in 124 post-menarchal survivors who underwent treatment for pediatric hematological malignancies and/or HSCT between 1992 and 2019.

Results

Overt 'premature ovarian insufficiency' (POI) was detected in 72.1 and 3.7% of transplanted and non-transplanted patients, respectively; milder 'diminished ovarian reserve' (DOR) in 16.3 and 22.2%. In non-transplanted patients, increasing CED values were associated with lower AMH-SDS (P = 0.04), with the threshold of 7200 g/m2 being the best discriminator between DOR/POI and normal ovarian function (AUC: 0.75 on ROC analysis) and with an observed decrease of 0.14 AMH-SDS for each CED increase of 1 g/m2. In addition, age at diagnosis ≥10 years played a detrimental role on ovarian reserve (P = 0.003). In the HSCT group, irradiation was associated with a statistically significant reduction in AMH-SDS (P = 0.04).

Conclusions

In non-transplanted patients, CED ≥ 7200 mg/m2 was associated with a DOR, while younger age at diagnosis played a protective role on ovarian reserve. As a result of the data collected, we propose a systematic algorithm to assess iatrogenic gonadal impairment in young female patients exposed to chemo-radiotherapy in childhood for hematological disorders.