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Gender, smoking during pregnancy and gestational age influence cord leptin concentrations in newborn infants

Simon Kayemba-Kay's, Michael P P Geary, Jane Pringle, Charles H Rodeck, John C P Kingdom, and Peter C Hindmarsh

Background

Low birth weight (BW), small head circumference, reduced length, increased preterm births and neuro-endocrine dysfunctions are among known consequences of smoking during pregnancy. Few studies have linked leptin to clinical features of growth restriction associated with maternal smoking and explored interaction with other determinants of size at birth, such as gender.

Methods

Cord serum leptin concentrations were measured in 1215 term infants born to Caucasian mothers at completion of uneventful pregnancy. Serum concentrations were related to BW, gestational length, gender and maternal smoking and interaction with other determinants of size at birth evaluated.

Results

Smoking was more frequent in younger (P<0.001) and shorter mothers (P=0.03) from lower socio-economic groups (SEGPs) (P<0.001). Infants born to smokers were lighter (190 g less), shorter and with smaller head circumference. Cord serum leptin concentrations were higher in girls (9.8 s.d. 7.6 ng/ml) than in boys (7.05 s.d. 5.8 ng/ml) (P<0.001). Boys were heavier (BW 3.52 s.d. 0.49 kg) than girls (3.39 s.d. 0.44 kg) (P<0.001), but girls had greater skinfold thickness measurements (sub-scapular and quadriceps skinfold thicknesses 5.5 s.d. 1.6 mm and 7.6 s.d. 1.9 mm respectively; boys 5.3 s.d. 1.6 vs 7.24±1.90 mm, P<0.001 respectively). Multivariate analyses showed gender (P<0.001), BW SDS (P<0.001), gestational length (P<0.001) and maternal smoking (P<0.042) as factors that influenced umbilical cord serum leptin concentrations in newborns.

Conclusion

Maternal smoking restrains foetal growth through placental vascular effects, and likely also via associated effects on leptin metabolism. More studies are needed to determine the influence that maternal smoking may have on placental syncytiotrophoblast and foetal adipose tissue.

Open access

Mitotane treatment in patients with metastatic testicular Leydig cell tumor associated with severe androgen excess

Vasileios Chortis, Nicholas J Johal, Irina Bancos, Matthew Evans, Kassiani Skordilis, Peter Guest, Michael H Cullen, Emilio Porfiri, and Wiebke Arlt

Mitotane (o,p′DDD) is established in the adjuvant and advanced-stage treatment of adrenocortical carcinoma and counteracts both tumor growth and tumor-related steroid production. Both the adrenal glands and the gonads are steroidogenically active organs and share a common embryogenic origin. Here, we describe the effects of mitotane in two patients with metastatic Leydig cell tumor (LCT) of the testes and associated severe androgen excess (serum testosterone 93 and 88 nmol/L, respectively; male reference range 7–27 nmol/L). Both men suffered from severe restlessness, insomnia and irritability, which they described as intolerable and disrupting normal life activities. Urinary steroid profiling by gas chromatography–mass spectrometry (GC–MS) confirmed excess androgen production and revealed concurrent overproduction of glucocorticoids and glucocorticoid precursors, which under physiological conditions are produced only by the adrenal glands but not by the gonads. In a palliative approach, they were commenced on mitotane, which achieved swift control of the hormone excess and the debilitating clinical symptoms, restoring normal quality of life. GC–MS demonstrated normalization of steroid production and decreased 5α-reductase activity, resulting in decreased androgen activation, and imaging demonstrated disease stabilization for 4–10 months. In conclusion, mitotane can be highly effective in controlling steroid excess in metastatic LCTs, with anti-tumor activity in some cases.

Open access

Measurement of immunofunctional leptin to detect and monitor patients with functional leptin deficiency

Martin Wabitsch, Lutz Pridzun, Michael Ranke, Julia von Schnurbein, Anja Moss, Stephanie Brandt, Katja Kohlsdorf, Barbara Moepps, Michael Schaab, Jan-Bernd Funcke, Peter Gierschik, Pamela Fischer-Posovszky, Bertram Flehmig, and Jürgen Kratzsch

Context and aims

Functional leptin deficiency is characterized by high levels of circulating immunoreactive leptin (irLep), but a reduced bioactivity of the hormone due to defective receptor binding. As a result of the fact that affected patients can be successfully treated with metreleptin, it was aimed to develop and validate a diagnostic tool to detect functional leptin deficiency.

Methods

An immunoassay capable of recognizing the functionally relevant receptor-binding complex with leptin was developed (bioLep). The analytical quality of bioLep was validated and compared to a conventional assay for immune-reactive leptin (irLep). Its clinical relevance was evaluated in a cohort of lean and obese children and adults as well as in children diagnosed with functional leptin deficiency and their parents.

Results

In the clinical cohort, a bioLep/irLep ratio of 1.07 (range: 0.80–1.41) was observed. Serum of patients with non-functional leptin due to homozygous amino acid exchanges (D100Y or N103K) revealed high irLep but non-detectable bioLep levels. Upon treatment of these patients with metreleptin, irLep levels decreased, whereas levels of bioLep increased continuously. In patient relatives with heterozygous amino acid exchanges, a bioLep/irLep ratio of 0.52 (range: 0.48–0.55) being distinct from normal was observed.

Conclusions

The new bioLep assay is able to diagnose impaired leptin bioactivity in severely obese patients with a homozygous gene defect and in heterozygous carriers of such mutations. The assay serves as a diagnostic tool to monitor leptin bioactivity during treatment of these patients.

Open access

Patient-reported outcomes of parenteral somatostatin analogue injections in 195 patients with acromegaly

Christian J Strasburger, Niki Karavitaki, Sylvère Störmann, Peter J Trainer, Ilonka Kreitschmann-Andermahr, Michael Droste, Márta Korbonits, Berit Feldmann, Kathrin Zopf, Violet Fazal Sanderson, David Schwicker, Dana Gelbaum, Asi Haviv, Martin Bidlingmaier, and Nienke R Biermasz

Background

Long-acting somatostatin analogues delivered parenterally are the most widely used medical treatment in acromegaly. This patient-reported outcomes survey was designed to assess the impact of chronic injections on subjects with acromegaly.

Methods

The survey was conducted in nine pituitary centres in Germany, UK and The Netherlands. The questionnaire was developed by endocrinologists and covered aspects of acromegaly symptoms, injection-related manifestations, emotional and daily life impact, treatment satisfaction and unmet medical needs.

Results

In total, 195 patients participated, of which 112 (57%) were on octreotide (Sandostatin LAR) and 83 (43%) on lanreotide (Somatuline Depot). The majority (>70%) of patients reported acromegaly symptoms despite treatment. A total of 52% of patients reported that their symptoms worsen towards the end of the dosing interval. Administration site pain lasting up to a week following injection was the most frequently reported injection-related symptom (70% of patients). Other injection site reactions included nodules (38%), swelling (28%), bruising (16%), scar tissue (8%) and inflammation (7%). Injection burden was similar between octreotide and lanreotide. Only a minority of patients received injections at home (17%) and 5% were self-injecting. Over a third of patients indicated a feeling of loss of independence due to the injections, and 16% reported repeated work loss days. Despite the physical, emotional and daily life impact of injections, patients were satisfied with their treatment, yet reported that modifications that would offer major improvement over current care would be ‘avoiding injections’ and ‘better symptom control’.

Conclusion

Lifelong injections of long-acting somatostatin analogues have significant burden on the functioning, well-being and daily lives of patients with acromegaly.

Open access

European expert consensus on practical management of specific aspects of parathyroid disorders in adults and in pregnancy: recommendations of the ESE Educational Program of Parathyroid Disorders (PARAT 2021)

Jens Bollerslev, Lars Rejnmark, Alexandra Zahn, Ansgar Heck, Natasha M Appelman-Dijkstra, Luis Cardoso, Fadil M Hannan, Filomena Cetani, Tanja Sikjaer, Anna Maria Formenti, Sigridur Björnsdottir, Camilla Schalin-Jäntti, Zhanna Belaya, Fraser Gibb, Bruno Lapauw, Karin Amrein, Corinna Wicke, Corinna Grasemann, Michael Krebs, Eeva Ryhänen, Özer Makay, Salvatore Minisola, Sébastien Gaujoux, Jean-Philippe Bertocchio, Zaki Hassan-Smith, Agnès Linglart, Elizabeth M Winter, Martina Kollmann, Hans-Georg Zmierczak, Elena Tsourdi, Stefan Pilz, Heide Siggelkow, Neil Gittoes, Claudio Marcocci, Peter Kamenický, and the 2021 PARAT Working Group

This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders in 2019 were discussed during two virtual workshops in 2021 and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosis of familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represents areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborn children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed at a broader clinical audience and were developed with the focus on endocrinologists in training.