Cyto-Histological Profile of MicroRNAs as Diagnostic Biomarkers in Differentiated Thyroid Carcinomas.

INTRODUCTION: The repertoire of microRNAs (miRNAs) in thyroid carcinomas starts to be elucidated. Among differentiated thyroid carcinomas (DTCs), papillary thyroid carcinoma (PTC) is the most frequent. The assessment of miRNAs expression may contribute to refine the pre-surgical diagnosis in order to obtain a personalized and more effective treatment for patients. AIMS: This study aims to evaluate (1) the miRNAs in a series of DTCs, and their association with the presence of selected genetic mutations in order to improve diagnosis and predict the biologic behavior of DTC/PTC. (2) The reliability of molecular tests in Ultrasound-guided Fine Needle Aspiration Cytology (US-FNAC) for a more precise preoperative diagnosis. MATERIAL AND METHODS: This series includes 176 samples (98 cytology and 78 histology samples) obtained from 106 patients submitted to surgery, including 13 benign lesions (controls) and 93 DTCs (cases). The microRNA expression was assessed for miR-146b, miR-221, miR-222, and miR-15a through quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). The results were analyzed by the 2-ΔΔCT method, using miR16 as an endogenous control. Regarding PTC diagnosis, the discriminative ability of miRNAs expression was assessed by the area under the Receiver Operating Characteristic Curve (AUC). In PTCs, the association of miRNAs expression, clinicopathological features, and genetic mutations (BRAF, RAS, and TERTp) was evaluated. RESULTS/DISCUSSION: All the analyzed miRNAs presented a tendency to be overexpressed in DTCs/PTCs when compared with benign lesions, both in cytology and histology samples. In cytology, miRNAs expression levels were higher in malignant tumors than in benign tumors. In histology, the discriminative abilities regarding PTC diagnosis were as follows: miR-146b (AUC 0.94, 95% CI 0.87-1), miR-221 (AUC 0.79, 95% CI 0.68-0.9), miR-222 (AUC 0.76, 95% CI 0.63-0.89), and miR-15a (AUC 0.85, 95% CI 0.74-0.97). miR-146b showed 89% sensitivity (se) and 87% specificity (sp); miR-221 se = 68.4, sp = 90; miR-222 se = 73, sp = 70; and mi-R15a se = 72, sp = 80. MicroRNAs were associated with worst-prognosis clinicopathological characteristics in PTCs (p < 0.05), particularly for miR-222. Our data reveal a significant association between higher expression levels of miR-146b, miR-221, and miR-222 in the presence of the BRAF mutation (p < 0.001) and miR-146b (p = 0.016) and miR-221 (p = 0.010) with the RAS mutation, suggesting an interplay of these mutations with miRNAs expression. Despite this study having a relatively small sample size, overexpression of miRNAs in cytology may contribute to a more precise preoperative diagnosis. The miRNAs presented a good discriminative ability in PTC diagnosis. The association between the miRNAs expression profile and genetic alterations can be advantageous for an accurate diagnosis of DTCs/PTCs in FNAC.

Comparative Cyto-Histological Genetic Profile in a Series of Differentiated Thyroid Carcinomas.

INTRODUCTION: Molecular tests can contribute to improve the preoperative diagnosis of thyroid nodules. Tests available are expensive and not adapted to different populations. AIM: This study aimed to compare the cyto-histological genetic profile and to evaluate the reliability of molecular tests using ultrasound-guided fine needle aspiration cytology (US-FNAC) in accurately diagnosing differentiated thyroid carcinomas (DTCs) and predicting biologic behavior of papillary thyroid carcinomas (PTCs). MATERIALS AND METHODS: The series included 259 patients with paired cyto-histological samples totaling 518 samples. The genetic alterations were analyzed via PCR/Sanger sequencing. The association with clinicopathologic features was evaluated in PTCs. RESULTS/DISCUSSION: From the 259 patients included, histologies were 50 (19.3%) benign controls and 209 (80.7%) DTC cases, from which 182 were PTCs; cytologies were 5.8% non-diagnostic, 18.2% benign, 39% indeterminate, and 37.1% malignant. In histology, indeterminate nodules (n = 101) were 22.8% benign and 77.2% malignant. Mutation frequencies in cytology and histology specimens were, respectively, TERTp: 3.7% vs. 7.9%; BRAF: 19.5% vs. 25.1%; and RAS: 11% vs. 17.5%. The overall cyto-histological agreement of the genetic mutations was 94.9%, with Cohen's k = 0.67, and in indeterminate nodules agreement was 95.7%, k = 0.64. The identified mutations exhibited a discriminative ability in diagnosing DTC with a specificity of 100% for TERTp and BRAF, and of 94% for RAS, albeit with low sensitivity. TERTp and BRAF mutations were associated with aggressive clinicopathological features and tumor progression in PTCs (p < 0.001). The obtained good cyto-histological agreement suggests that molecular analysis via US-FNAC may anticipate the genetic profile and the behavior of thyroid tumors, confirming malignancy and contributing to referring patients to surgery.

Newly Diagnosed Type 1 Diabetes in an Elderly Patient.

Type 1 diabetes (T1D) is typically diagnosed in young people; however, it can appear at any age. Its incidence in adulthood is not as well-known as in childhood, particularly if it is diagnosed in geriatric age. T1D diagnosed in adulthood can be explained by the development of antibodies in adulthood or also by the existence of slow-disease progressors. A 71-year-old normal-weight woman presented to the Emergency Department complaining of polyuria, polydipsia, and tiredness. She was identified with hyperglycemia (450mg/dL) and high blood and urine ketone bodies. Her arterial gasometry revealed mild metabolic ketoacidosis. Further laboratory work-up was remarkable for positive anti-GAD and anti-ICA antibodies and her HbA1c was 14.1%. The diagnosis of T1D was established. A urinary infection was also identified. The patient's symptoms in association with metabolic ketoacidosis, in the presence of high titers of more than one positive T1D-related antibody, have helped us to diagnose T1D in this elderly woman. A prompt diagnosis enabled us to establish adequate diabetes treatment. The urinary infection was probably a trigger to the symptomatic phase of diabetes.  T1D can be diagnosed at any age, even in elderly patients. A prompt T1D diagnosis can avoid the misdiagnosis of type 2 diabetes (T2D), enabling the beginning of correct medication earlier.

Factors for second non-diagnostic ultrasound-guided fine-needle aspiration cytology in thyroid nodules.

INTRODUCTION: Results in fine-needle aspiration cytology (FNAC) of thyroid nodules may be non-diagnostic (ND). In these cases, it is recommended to repeat the FNAC. The aim of our study was to evaluate the influence of demographic, clinical and ultrasound (US) characteristics in the recurrence of an ND result in thyroid nodule FNAC. METHODS: A retrospective study of ND thyroid nodule FNAC was performed for the period 2017-2020. Demographic and clinical data (age, gender, cervical radiotherapy, presence of Hashimoto's thyroiditis, and TSH value) and US characteristics (nodule size, echogenicity, composition and microcalcifications) were collected at first ND FNAC. RESULTS: Out of 230 nodules with first ND FNAC (83% women; mean age 60.2±14.1 years), 195 (84.8%) underwent a second FNAC: 121 benign, 63 non-diagnostic, 9 indeterminate and 2 malignant. Nine (3.9%) underwent surgery, only 1 of which showed malignant histology and 26 (11.3%) remained under US monitoring. Demographically, patients with second ND FNAC were older (63.4±14 vs. 59±14 years; P=0.032). Females had lower risk of second ND FNAC (OR, 0.4, 0.2-0.9; P=0.016); risk of second ND FNAC was higher in patients treated with anticoagulant/antiplatelet drugs (OR, 2.2, 1.1-4.7; P=0.03). Previous cervical radiotherapy, family history of thyroid cancer, Hashimoto's thyroiditis and TSH value did not influence the risk of second ND FNAC. On US, nodule echogenicity differed significantly between the ND and diagnostic FNAC, with greater risk of an ND result in hypoechogenic nodules. Microcalcification increased the risk of ND FNAC (OR 2.2, 1.1-4.5; P=0.03). Nodule composition and size did not significantly differ according to ND or diagnostic second FNAC. CONCLUSION: Male gender, advanced age, anticoagulant/antiplatelet drug therapy, hypoechogenic nodules and microcalcified nodules are likely factors for second ND FNAC. Nodules with two ND FNACs were rarely malignant, and a more conservative approach in these cases is not unsafe.

Usefulness of a clinicopathological classification in predicting treatment-related outcomes and multimodal therapeutic approaches in pituitary adenoma patients: retrospective analysis on a Portuguese cohort of 129 patients from a tertiary pituitary center.

PURPOSE: A clinicopathological classification has been designed to predict recurrence/progression in patients with pituitary adenomas (PAs). We aimed to study its usefulness in predicting PAs that will have a challenging disease course and may require more often complex multimodal and multiple therapeutic approaches. METHODS: Retrospective analysis of 129 patients with PAs operated in our institution between 2001 and 2020 (84 non-clinically functioning PAs, 32 acromegaly, 9 Cushing's disease, 2 prolactinomas and 2 thyrotropinomas). Grading was based on invasion and proliferation: 1a (non-invasive, non-proliferative; n = 59), 1b (non-invasive, proliferative; n = 17), 2a (invasive, non-proliferative; n = 38), and 2b (invasive, proliferative; n = 15). RESULTS: Of the 129 patients, 68 (52.7%) were females, and the mean age at diagnosis was 53.7 ± 15.4 years. The mean follow-up duration was 93.1 ± 61.8 months. Grade 2b PAs when compared to other grades (2b-2a-1b-1a) had significantly higher rates of persistent tumor remnant within 1-year after operation (93-78-18-30%; p < 0.001), active disease at last follow-up (40-27-12-10%; p = 0.004), re-operation (27-16-0-5%; p = 0.023), irradiation (53-38-12-7%; p < 0.001), multimodal treatment (67-49-18-25%; p = 0.003), multiple treatment (33-27-6-9%; p = 0.017). Patients with grade 2b PAs also required a higher mean number of treatments (2.6-2.1-1.2-1.4; p < 0.001). CONCLUSIONS: This clinicopathological classification appears to be a useful grading system to identify PAs that may be more refractory and more often require complex multimodal and multiple therapeutic approaches. Invasive PAs, especially grade 2b tumors, may be more likely to need complex treatment approach, including radiotherapy, and may display higher rates of active disease at last follow-up, despite receiving higher number of treatments.

In Search of the Hyperglycemic Threshold Required to Induce Growth Hormone (GH) Suppression.

Introduction According to the 2014 Endocrine Society Clinical Practice Guideline on acromegaly, the confirmation of acromegaly diagnosis is established by finding a lack of suppression of growth hormone (GH) to < 1 ug/L following documented hyperglycemia during an oral glucose tolerance test. However, in this setting, the concept of hyperglycemia has never been clearly defined. Objective This study aimed to define the hyperglycemic threshold required to induce GH suppression. Methods We retrieved the glycemia profile of 44 individuals after a standard 2-h 75g oral glucose tolerance test prescribed to assess GH suppression and performed a comprehensive analysis of two subgroups of individuals (28 reaching GH suppression and 16 in whom GH suppression was not observed). All of the data were analyzed with the program Graph Pad Prism. Differences between means were assessed by Student's unpaired t-test or Mann-Whitney U test as deemed appropriate. Fisher's exact test was used for categorical variables. Results Individuals in G1 and G2 were different only for the median basal GH and median IGF-1. No significant differences in terms of the prevalence of diabetes and prediabetes were found. The glucose peak was achieved earlier in the group that reached GH suppression. The median of the highest glucose values of both subgroups was not different. A correlation between peak and baseline glucose value was found only among those in whom GH suppression was reached. Among these, the median glucose peak (P50) was 177 mg/dl, whereas the 75th percentile (P75) and 25th percentile (P25) were 199 mg/dl and 120 mg/dl, respectively. Conclusion Considering that 75% of those in whom GH suppression was observed after an oral glucose overload test reached blood glucose values above 120 mg/dl, we propose to use this value as the blood glucose threshold for inducing GH suppression. In light of our results, whenever GH suppression is not observed; and the highest glycemic value is below 120 mg/dl, it might be useful to repeat the test prior to any conclusion.

Pediatric growth hormone and prolactin-secreting tumor associated with an AIP mutation and a MEN1 variant of uncertain significance.

OBJECTIVES: Pituitary gigantism is a rare condition and it often has an identifiable genetic cause. In this article we report a case of a young girl with pituitary gigantism and two genetic changes. CASE PRESENTATION: A 15-year-old girl with primary amenorrhea was diagnosed with a growth hormone (GH) and prolactin (PRL)-producing tumor, needing surgery and medical treatment with octreotide in order to achieve disease control. The co-occurrence of an AIP mutation and a MEN1 variant of uncertain significance was demonstrated in this patient. The germline mutation involving AIP was inherited from her father who at the age of 55 was unaffected and the MEN1 variant was a de novo duplication of the region 11q13.1. The latter variant, not previously reported, is unlikely to be pathogenic. Nonetheless, screening for other components of multiple endocrine neoplasia type 1 (MEN1) was performed and proved negative. CONCLUSIONS: The rare co-occurrence of an AIP mutation and a MEN 1 variant of uncertain significance was demonstrated in this patient.

Adherens Junction Integrity Is a Critical Determinant of Sodium Iodide Symporter Residency at the Plasma Membrane of Thyroid Cells.

While most cases of differentiated thyroid carcinoma (DTC) are associated with a good prognosis, a significant number progress to advanced disease exhibiting aggressive clinical characteristics and often becoming refractory to radioactive iodine (RAI) treatment, the current gold-standard therapeutic option for metastatic disease. RAI-refractoriness is caused by defective functional expression of the sodium-iodide symporter (NIS), which is responsible for the active transport of iodide across the plasma membrane (PM) into thyroid follicles. NIS deficiency in these tumors often reflects a transcriptional impairment, but also its defective targeting and retention at the cells' PM. Using proteomics, we previously characterized an intracellular signaling pathway derived from SRC kinase that acts through the small GTPase RAC1 to recruit and bind the actin-anchoring adaptor EZRIN to NIS, regulating its retention at the PM of both non-transformed and cancer thyroid cells. Here, we describe how by reanalyzing the proteomics data, we identified cell-cell adhesion as the molecular event upstream the pathway involved in the anchoring and retention at the PM. We show that by interacting with NIS at the PM, adherens junction (AJ)-associated P120-catenin recruits and is phosphorylated by SRC, allowing it to recruit RAC1 to the complex. This enables SRC-phosphorylated VAV2 exchange factor to activate RAC1 GTPase, inducing NIS retention at the PM, thus increasing its abundance and function at the surface of thyroid cells. Our findings indicate that the loss of epithelial cell-cell adhesion may contribute to RAI refractoriness, indicating that in addition to stimulating NIS expression, successful resensitization therapies might require the employment of agents that improve cell-cell adhesion and NIS PM retention in refractory TC cells.

Different antibody-associated autoimmune diseases have distinct patterns of T follicular cell dysregulation.

Autoantibodies are produced within germinal centers (GC), in a process regulated by interactions between B, T follicular helper (Tfh), and T follicular regulatory (Tfr) cells. The GC dysregulation in human autoimmunity has been inferred from circulating cells, albeit with conflicting results due to diverse experimental approaches. We applied a consistent approach to compare circulating Tfr and Tfh subsets in patients with different autoimmune diseases. We recruited 97 participants, including 72 patients with Hashimoto's thyroiditis (HT, n = 18), rheumatoid arthritis (RA, n = 16), or systemic lupus erythematosus (SLE, n = 32), and 31 matched healthy donors (HD). We found that the frequency of circulating T follicular subsets differed across diseases. Patients with HT had an increased frequency of blood Tfh cells (p = 0.0215) and a reduced Tfr/Tfh ratio (p = 0.0338) when compared with HD. This was not observed in patients with systemic autoimmune rheumatic diseases (RA, SLE), who had a reduction in both Tfh (p = 0.0494 and p = 0.0392, respectively) and Tfr (p = 0.0003 and p = 0.0001, respectively) cells, resulting in an unchanged Tfr/Tfh ratio. Activated PD-1+ICOS+Tfh and CD4+PD-1+CXCR5-Tph cells were raised only in patients with SLE (p = 0.0022 and p = 0.0054), without association with disease activity. Our data suggest that GC dysregulation, assessed by T follicular subsets, is not uniform in human autoimmunity. Specific patterns of dysregulation may become potential biomarkers for disease and patient stratification.

PGL4 syndrome in a patient with synchronous paraganglioma-pheochromocytoma.

Pheochromocytoma and paraganglioma (PGL) are rare neuroendocrine tumours, frequently associated with genetic syndromes. We report the case of a man in his 40s with a left anterior neck mass and a history of hypertensive crisis, heavy sweating and constipation. Biochemical tests showed increased plasma and urine normetanephrines. Neck ultrasound suggested left carotid body PGL, but it was mandatory to search for other lesions. Whole-body MIBG failed to show abnormal uptake. Abdominal MRI was suggestive of another PGL, anterior to the right adrenal gland. Abdominal surgery was performed uneventfully under alpha and beta blockers. This intervention proved to be effective, as normetanephrines levels became completely normal after 1 month. Carotid body PGL was successfully excised 4-months later. Genetic study identified a large deletion in exon 1 of the SDHB gene allowing the diagnosis of paraganglioma syndrome type 4 (PGL4). After 19 months of follow-up, he is still on clinical and biochemical remission and will continue life-long surveillance.

The microenvironment of pituitary adenomas: biological, clinical and therapeutical implications.

The microenvironment of pituitary adenomas (PAs) includes a range of non-tumoral cells, such as immune and stromal cells, as well as cell signaling molecules such as cytokines, chemokines and growth factors, which surround pituitary tumor cells and may modulate tumor initiation, progression, invasion, angiogenesis and other tumorigenic processes. The microenvironment of PAs has been actively investigated over the last years, with several immune and stromal cell populations, as well as different cytokines, chemokines and growth factors being recently characterized in PAs. Moreover, key microenvironment-related genes as well as immune-related molecules and pathways have been investigated, with immune check point regulators emerging as promising targets for immunotherapy. Understanding the microenvironment of PAs will contribute to a deeper knowledge of the complex biology of PAs, as well as will provide developments in terms of diagnosis, clinical management and ultimately treatment of patients with aggressive and/or refractory PAs.

MAPK Inhibition Requires Active RAC1 Signaling to Effectively Improve Iodide Uptake by Thyroid Follicular Cells.

The Sodium/Iodide Symporter (NIS) is responsible for the active transport of iodide into thyroid follicular cells. Differentiated thyroid carcinomas (DTCs) usually preserve the functional expression of NIS, allowing the use of radioactive iodine (RAI) as the treatment of choice for metastatic disease. However, a significant proportion of patients with advanced forms of TC become refractory to RAI therapy and no effective therapeutic alternatives are available. Impaired iodide uptake is mainly caused by the defective functional expression of NIS, and this has been associated with several pathways linked to malignant transformation. MAPK signaling has emerged as one of the main pathways implicated in thyroid tumorigenesis, and its overactivation has been associated with the downregulation of NIS expression. Thus, several strategies have been developed to target the MAPK pathway attempting to increase iodide uptake in refractory DTC. However, MAPK inhibitors have had only partial success in restoring NIS expression and, in most cases, it remained insufficient to allow effective treatment with RAI. In a previous work, we have shown that the activity of the small GTPase RAC1 has a positive impact on TSH-induced NIS expression and iodide uptake in thyroid cells. RAC1 is a downstream effector of NRAS, but not of BRAF. Therefore, we hypothesized that the positive regulation induced by RAC1 on NIS could be a relevant signaling cue in the mechanism underlying the differential response to MEK inhibitors, observed between NRAS- and BRAF-mutant tumors. In the present study, we found that the recovery of NIS expression induced through MAPK pathway inhibition can be enhanced by potentiating RAC1 activity in thyroid cell systems. The negative impact on NIS expression induced by the MAPK-activating alterations, NRAS Q61R and BRAF V600E, was partially reversed by the presence of the MEK 1/2 inhibitors AZD6244 and CH5126766. Notably, the inhibition of RAC1 signaling partially blocked the positive impact of MEK inhibition on NIS expression in NRAS Q61R cells. Conversely, the presence of active RAC1 considerably improved the rescue of NIS expression in BRAF V600E thyroid cells treated with MEK inhibitors. Overall, our data support an important role for RAC1 signaling in enhancing MAPK inhibition in the context of RAI therapy in DTC, opening new opportunities for therapeutic intervention.

Analysis of NIS Plasma Membrane Interactors Discloses Key Regulation by a SRC/RAC1/PAK1/PIP5K/EZRIN Pathway with Potential Implications for Radioiodine Re-Sensitization Therapy in Thyroid Cancer.

The functional expression of the sodium-iodide symporter (NIS) at the membrane of differentiated thyroid cancer (DTC) cells is the cornerstone for the use of radioiodine (RAI) therapy in these malignancies. However, NIS gene expression is frequently downregulated in malignant thyroid tissue, and 30% to 50% of metastatic DTCs become refractory to RAI treatment, which dramatically decreases patient survival. Several strategies have been attempted to increase the NIS mRNA levels in refractory DTC cells, so as to re-sensitize refractory tumors to RAI. However, there are many RAI-refractory DTCs in which the NIS mRNA and protein levels are relatively abundant but only reduced levels of iodide uptake are detected, suggesting a posttranslational failure in the delivery of NIS to the plasma membrane (PM), or an impaired residency at the PM. Because little is known about the molecules and pathways regulating NIS delivery to, and residency at, the PM of thyroid cells, we here employed an intact-cell labeling/immunoprecipitation methodology to selectively purify NIS-containing macromolecular complexes from the PM. Using mass spectrometry, we characterized and compared the composition of NIS PM complexes to that of NIS complexes isolated from whole cell (WC) lysates. Applying gene ontology analysis to the obtained MS data, we found that while both the PM-NIS and WC-NIS datasets had in common a considerable number of proteins involved in vesicle transport and protein trafficking, the NIS PM complexes were particularly enriched in proteins associated with the regulation of the actin cytoskeleton. Through a systematic validation of the detected interactions by co-immunoprecipitation and Western blot, followed by the biochemical and functional characterization of the contribution of each interactor to NIS PM residency and iodide uptake, we were able to identify a pathway by which the PM localization and function of NIS depends on its binding to SRC kinase, which leads to the recruitment and activation of the small GTPase RAC1. RAC1 signals through PAK1 and PIP5K to promote ARP2/3-mediated actin polymerization, and the recruitment and binding of the actin anchoring protein EZRIN to NIS, promoting its residency and function at the PM of normal and TC cells. Besides providing novel insights into the regulation of NIS localization and function at the PM of TC cells, our results open new venues for therapeutic intervention in TC, namely the possibility of modulating abnormal SRC signaling in refractory TC from a proliferative/invasive effect to the re-sensitization of these tumors to RAI therapy by inducing NIS retention at the PM.

Advanced Adrenocortical Carcinoma: Current Perspectives on Medical Treatment.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. For stage I and II tumors, surgery is a curative option, but even in these cases recurrence is frequent. Practical guidelines advocate a combination of mitotane with etoposide, doxorubicin, and cisplatin as first-line therapy for metastatic adrenocortical carcinoma. However, this scheme presents limited efficacy and high toxicity. The use of Immune Checkpoint Inhibitors (ICI) and multi-Tyrosine Kinase Inhibitors (mTKI) has modified the approach of multiple malignancies. The expectation of their applicability on advanced adrenocortical carcinoma is high but the role of these new therapies persists unclear. This article provides a short summary of last years' findings targeting outcomes, limitations, and adverse effects of these new therapeutic approaches. The results of recent trials and case series pointed pembrolizumab as the most promising drug among these new therapies. It is the most often used ICI and the one presenting the best results with less related adverse effects when in comparison to the standard treatment with mitotane. Hereafter, the identification of specific molecular biomarkers or immune profiles associated with ICI or mTKI good response will facilitate the selection of candidates for these therapies. So far, microsatellite instability and Lynch Syndrome related germline mutations are suggested as predictive biomarkers of good response. Contrarywise, cortisol secretion has been associated with more aggressive ACC tumors and potentially poor responses to immunotherapy.

Multifactorial diabetes insipidus during pregnancy: a challenging diagnosis.

Diabetes insipidus (DI) is characterised by thirst and polydipsia with hypotonic polyuria. Several forms exist, namely, central or pituitary, nephrogenic and gestational and must be differentiated for adequate treatment. We describe the case of a 41-year-old woman chronically infected with HIV who had been recently medicated with a tenofovir-based antiretroviral treatment and who, at 22 weeks of pregnancy, presented with transient gestational DI. Obstetric ultrasound revealed oligohydramnios and foetal growth restriction that did not improve despite serum sodium correction. The severity of the case suggested the presence of an underlying disorder and elevated copeptin levels indicated that an underlying subclinical form of nephrogenic DI, possibly induced by HIV-related nephropathy or tenofovir use, was present and rendered clinically overt during pregnancy.

A benign cause of hyperandrogenism in a postmenopausal woman.

SUMMARY: Menopause is a relative hyperandrogenic state but the development of hirsutism or virilizing features should not be regarded as normal. We report the case of a 62-year-old woman with a 9-month history of progressive frontotemporal hair loss and hirsutism, particularly on her back, arms and forearms. Blood tests showed increased total testosterone of 5.20 nmol/L that remained elevated after an overnight dexamethasone suppression test. Free Androgen Index was 13.1 and DHEAS was repeatedly normal. Imaging examinations to study adrenals and ovaries were negative. The biochemical profile and the absence of imaging in favor of an adrenal tumor made us consider the ovarian origin as the most likely hypothesis. After informed consent, bilateral salpingectomy-oophorectomy and total hysterectomy were performed. Gross pathology revealed ovaries of increased volume and histology showed bilateral ovarian stromal hyperplasia. Testosterone levels normalized after surgery and hirsutism had completely subsided 8 months later. LEARNING POINTS: Menopause is a relative hyperandrogenic state Hirsutism and/or virilizing features, in a postmenopausal woman, should raise the hypothesis of a malignant cause In the absence of an identifiable ovarian or adrenal tumor, the ovarian origin remains the most likely Peripheral aromatization of excess androgen may conduct to high levels of estrogen increasing the risk of endometrial cancer Bilateral oophorectomy results in significant clinical improvement.

Thyroid tuberculosis: an unexpected diagnosis.

Mycobacterium tuberculosis (MTB) is an aerobic bacillus responsible for tuberculous infection. The the thyroid gland being affected by MTB is a rare condition. A 71-year-old woman had 6 months of slight cervical discomfort. Her neck ultrasound showed, at the right lobe of the thyroid, a dominant heterogeneous nodule of 18 mm and homolateral lymph nodes with suspicious ultrasonographic features. The patient underwent fine-needle aspiration, the results of which were non-diagnostic (thyroid nodule) and reactive pattern (lymph node). A total thyroidectomy was performed and a lymph node was sampled for extemporaneous examination. Surprisingly, necrotising granulomas were documented. The diagnosis was definitely established by a positive culture of the lymph node tissue and molecular detection of MTB. Pulmonary involvement was excluded and she was started on antituberculous agents. In the absence of systemic, specific complaints or history of exposition, histopathology and culture of MTB remain a key step for the diagnosis.