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Antonio Sitges-Serra, Leyre Lorente, Germán Mateu, and Juan J Sancho

Since its introduction in the '70s and '80s, CND for papillary cancer is here to stay. Compartment VI should always be explored during surgery for papillary thyroid carcinoma (PTC) for obvious lymph node metastases. These can be easily spotted by an experienced surgeon or, eventually, by frozen section. No doubt, obvious nodal disease in the Delphian, paratracheal and subithsmic areas should be dissected in a comprehensive manner (therapeutic central neck dissection), avoiding the selective removal of suspicious nodes. Available evidence for routine prophylactic CND is not completely satisfactory. Our group's opinion, however, is that it reduces or even eliminates the need for repeat surgery in the central neck, better defines the extent (and stage) of the disease and provides a further argument against routine radioiodine ablation. Thus, PTC is becoming more and more a surgical disease that can be cured by optimized surgery alone in the majority of cases. Prophylactic CND, however, involves a higher risk for the parathyroid function and should be skilfully performed, preferably only on the same side as the primary tumour and preserving the cervical portion of the thymus.

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John Eden

Managing the symptoms of menopause after a diagnosis of breast cancer offers some unique clinical challenges. For some women, vasomotor symptoms can be severe and debilitating, and hormone therapy is at least relatively contraindicated. Non-oestrogen therapies for hot flushes include SSRIs, clonidine, gabapentin and perhaps black cohosh extracts. Vulvovaginal atrophy can usually be alleviated by simple moisturizers, although some may need specialized physiotherapy such as vaginal dilators. In a small number, topical oestrogens may be the only treatment that works. The CO2 laser may be a novel, non-oestrogen therapy to alleviate this unpleasant symptom. Bone loss can be accelerated in some patients on AIs or those who had early menopause induced by chemotherapy.

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Frederic Castinetti, Rachel Reynaud, Alexandru Saveanu, Nicolas Jullien, Marie Helene Quentien, Claire Rochette, Anne Barlier, Alain Enjalbert, and Thierry Brue

Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations of POU1F1 or PROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge.

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Laurence Amar, Aurélien Lorthioir, Michel Azizi, and Pierre-Francois Plouin

Mineralocorticoid receptor antagonists have been used in patients with aldosterone-producing adenomas (APAs) as a test designed to predict the blood pressure (BP) outcome of surgery. They are commonly used in patients undergoing adrenalectomy to reduce BP and increase plasma potassium levels during the preoperative period. A small number of studies have compared the effects of surgery and mineralocorticoid antagonists either on BP, on serum potassium levels, or on the incidence of cardiovascular and renal outcomes in patients with primary aldosteronism with or without an APA; these studies found no difference between the two therapeutic options. Mineralocorticoid receptor antagonists can be used as a maintenance treatment for patients with APAs, who are judged to be poor operative risks or who do not want to undergo surgery.

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Mohsen Khosravi-Maharlooei, Ensiyeh Hajizadeh-Saffar, Yaser Tahamtani, Mohsen Basiri, Leila Montazeri, Keynoosh Khalooghi, Mohammad Kazemi Ashtiani, Ali Farrokhi, Nasser Aghdami, Anavasadat Sadr Hashemi Nejad, Mohammad-Bagher Larijani, Nico De Leu, Harry Heimberg, Xunrong Luo, and Hossein Baharvand

Over the past decades, tremendous efforts have been made to establish pancreatic islet transplantation as a standard therapy for type 1 diabetes. Recent advances in islet transplantation have resulted in steady improvements in the 5-year insulin independence rates for diabetic patients. Here we review the key challenges encountered in the islet transplantation field which include islet source limitation, sub-optimal engraftment of islets, lack of oxygen and blood supply for transplanted islets, and immune rejection of islets. Additionally, we discuss possible solutions for these challenges.

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Andromachi Vryonidou, Stavroula A Paschou, Giovanna Muscogiuri, Francesco Orio, and Dimitrios G Goulis

The normal function of the female reproductive system is closely linked to energy homeostasis with the ultimate scope of fertility and human race perpetuation through the centuries. During a woman's lifetime there are normal events such as puberty, pregnancy and menopause which are related to alterations in energy homeostasis and gonadal steroids levels followed by increase of body fat and insulin resistance, important components of metabolic syndrome (MetS). Pathological conditions such as premature adrenarche, polycystic ovary syndrome and gestational diabetes also present with shifts in gonadal steroid levels and reduced insulin sensitivity. The aim of this review is to discuss these conditions, both normal and pathological, analyzing the changes or abnormalities in ovarian function that coexist with metabolic abnormalities which resemble MetS in relationship with environmental, genetic and epigenetic factors.

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Georg Brabant, Robin P Peeters, Shiao Y Chan, Juan Bernal, Philippe Bouchard, Domenico Salvatore, Kristien Boelaert, and Peter Laurberg

Guideline advice of many societies on the management of subclinical hypothyroidism in pregnancy suggests treatment when TSH serum levels exceed 2.5 mU/l. Justification of this procedure is based on limited experience, mainly from studies carried out in patients with positive thyroid-specific antibodies and higher TSH levels that classically define the condition in the non-pregnant state. Taking into account a lack of clear understanding of the regulation of thyroid hormone transport through the utero-placental unit and in the absence of foetal markers to monitor the adequacy of thyroxine treatment, this review attempts to discuss currently available data and suggests a more cautious approach.

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Jonàs Juan-Mateu, Olatz Villate, and Décio L Eizirik

Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic β cells are killed by infiltrating immune cells and by cytokines released by these cells. This takes place in the context of a dysregulated dialogue between invading immune cells and target β cells, but the intracellular signals that decide β cell fate remain to be clarified. Alternative splicing (AS) is a complex post-transcriptional regulatory mechanism affecting gene expression. It regulates the inclusion/exclusion of exons into mature mRNAs, allowing individual genes to produce multiple protein isoforms that expand the proteome diversity. Functionally related transcript populations are co-ordinately spliced by master splicing factors, defining regulatory networks that allow cells to rapidly adapt their transcriptome in response to intra and extracellular cues. There is a growing interest in the role of AS in autoimmune diseases, but little is known regarding its role in T1D. In this review, we discuss recent findings suggesting that splicing events occurring in both immune and pancreatic β cells contribute to the pathogenesis of T1D. Splicing switches in T cells and in lymph node stromal cells are involved in the modulation of the immune response against β cells, while β cells exposed to pro-inflammatory cytokines activate complex splicing networks that modulate β cell viability, expression of neoantigens and susceptibility to immune-induced stress. Unveiling the role of AS in β cell functional loss and death will increase our understanding of T1D pathogenesis and may open new avenues for disease prevention and therapy.

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Irene Campi, Guia Vannucchi, and Mario Salvi

Management of Graves’ orbitopathy (GO) must be based on the correct assessment of activity and severity of the disease. Activity is usually assessed with the Clinical Activity Score, whereas severity is classified according to a European Group On Graves' Orbitopathy (EUGOGO) consensus statement as mild, moderate-to-severe, and sight-threatening. Myopathic and chronic congestive forms are uncommon clinical presentations of GO. Restoration and maintenance of stable euthyroidism are recommended in the presence of GO.

In moderate-to-severe disease, steroids have been widely employed and have shown to possess an anti-inflammatory activity, but about 20–30% of patients are not responsive and present recurrence. Some novel immunosuppressors have already been employed in clinical studies and have shown interesting results, although the lack of randomized and controlled trials suggests caution for their use in clinical practice. Potential targets for therapy in GO are the thyroid-stimulating hormone and the insulin-like growth factor 1 receptor on the fibroblasts, inflammatory cytokines, B and T cells, and the PIK3/mTORC1 signaling cascades for adipogenesis. A recent open study has shown that tocilizumab, an anti-sIL-6R antibody, inactivates GO. Consistent reports on the efficacy of rituximab have recently been challenged by randomized controlled trials.

As the main goal of treatment is the well-being of the patient, the therapeutic strategy should be addressed to better suit the patient needs, more than improving one or more biological parameters. The increasing availability of new therapies will expand the therapeutic options for GO patients and allow the clinician to really personalize the treatment to better suit the patients’ personal needs.

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Garcilaso Riesco-Eizaguirre and Pilar Santisteban

Thyroid cancer is the most common endocrine malignancy giving rise to one of the most indolent solid cancers, but also one of the most lethal. In recent years, systematic studies of the cancer genome, most importantly those derived from The Cancer Genome Altas (TCGA), have catalogued aberrations in the DNA, chromatin, and RNA of the genomes of thousands of tumors relative to matched normal cellular genomes and have analyzed their epigenetic and protein consequences. Cancer genomics is therefore providing new information on cancer development and behavior, as well as new insights into genetic alterations and molecular pathways. From this genomic perspective, we will review the main advances concerning some essential aspects of the molecular pathogenesis of thyroid cancer such as mutational mechanisms, new cancer genes implicated in tumor initiation and progression, the role of non-coding RNA, and the advent of new susceptibility genes in thyroid cancer predisposition. This look across these genomic and cellular alterations results in the reshaping of the multistep development of thyroid tumors and offers new tools and opportunities for further research and clinical development of novel treatment strategies.