Testosterone as a Biomarker of Adverse Clinical Outcomes in SARS-CoV-2 Pneumonia.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may affect testicles. Lower testosterone levels have been associated with worse clinical outcomes and higher mortality. Our objective was to evaluate the hypothalamic−pituitary−gonadal axis of men admitted with SARS-CoV-2 pneumonia and its link with the pneumonia-treatment intensification. Short-term changes in hormonal parameters were also assessed. Methods: Men admitted with SARS-CoV-2 pneumonia were recruited in two different hospitals in Piedmont, Italy. In all patients, the assessment of total testosterone (TT), calculated free testosterone (cFT), gonadotropins, inhibin B (InhB), and other biochemical evaluations were performed at admission (T0) and before discharge (T1). Through a review of medical records, clinical history was recorded, including data on pneumonia severity. Results: Thirty-five men (median age 64 [58−74] years) were recruited. Lower TT and cFT levels at T0 were associated with CPAP therapy (p = 0.045 and 0.028, respectively), even after adjusting for age and PaO2/FIO2 ratio in a multivariable analysis. In those discharged alive, lower TT and cFT levels were associated with longer hospital stay (p < 0.01). TT, cFT, and InhB were below the normal range at T0 and significantly increased at T1 (TT 1.98 [1.30−2.72] vs. 2.53 [1.28−3.37] ng/mL, p = 0.038; cFT (0.0441 [0.0256−0.0742] vs. 0.0702 [0.0314−0.0778] ng/mL, p = 0.046; InhB 60.75 [25.35−88.02] vs. 77.05 [51.15−134.50], p < 0.01). Conclusions: Both TT and cFT levels are associated with adverse clinical outcomes in men admitted with SARS-CoV-2 pneumonia. As TT, cFT and InhB levels increase before discharge, short-term functional recovery of steroidogenesis and an indirect improvement of spermatozoa functional status could be hypothesized.

Aging and comorbidities influence the risk of hospitalization and mortality in diabetic patients experiencing severe hypoglycemia.

BACKGROUND AND AIMS: To assess the risk of hospitalization and mortality within 1 year of severe hypoglycaemia and theirs clinical predictors. METHODS AND RESULTS: We retrospectively examined 399 admissions for severe hypoglycemia in adults with DM at the Emergency Department (ED) of the University Hospital of Novara (Italy) between 2012-2017, and we compared the clinical differences between older (aged ≥65 years) and younger individuals (aged 18-64 years). A logistic regression model was used to explore predictors of hospitalization following ED access and 1-year later, according to cardiovascular (CV) or not (no-CV) reasons; 1-year all-cause mortality was also detected. The study cohort comprised 302 patients (median [IQR] age 75 [17] years, 50.3% females, 93.4% white, HbA1c level 7.6% [1.0%]). Hospitalization following ED access occurred in 16.2% of patients and kidney failure (OR 0.50 [95% CI 1.29-5.03]) was the only predictor of no-CV specific hospitalization; 1-year hospitalization occurred in 24.5% of patients and obesity (OR 3.17 [95% CI 1.20-8.12]) and pre-existing heart disease (OR 3.20 [95% 1.20-9.39]) were associated with CV specific hospitalization; 1-year all-cause mortality occurred in 14.9% of patients and was associated with older age (OR 1.12 [95% CI 1.07-1.18]) and pre-existing heart disease (OR 2.63 [95% CI 1.19-6.14]) CONCLUSIONS: Severe hypoglycemia is associated with risk of hospitalization and mortality mainly in elderly patients and it may be predictive of future cardiovascular events in diabetic patients with pre-existing heart disease and obesity.

A Long Contiguous Stretch of Homozygosity Disclosed a Novel STAG3 Biallelic Pathogenic Variant Causing Primary Ovarian Insufficiency: A Case Report and Review of the Literature.

Primary ovarian insufficiency (POI) refers to an etiologically heterogeneous disorder characterized by hypergonadotropic hypogonadism that represents a major cause of infertility in women under 40 years of age. Most cases are apparently sporadic, but about 10-15% have an affected first-degree relative, indicating a genetic etiology. Pathogenic variations in genes involved in development, meiosis and hormonal signaling have been detected in the hereditary form of the disorder. However, most cases of POI remain unsolved even after exhaustive investigation. A 19-year-old Senegalese female affected by non-syndromic POI presented with primary amenorrhoea and answered well to the hormonal induction of puberty. In order to investigate the presence of a genetic defect, aCGH-SNP analysis was performed. A 13.5 Mb long contiguous stretch of homozygosity (LCSH) was identified on chromosome 7q21.13-q22.1 where the exome sequencing revealed a novel homozygous 4-bp deletion (c.3381_3384delAGAA) in STAG3. Pathogenic variants in this gene, encoding for a meiosis-specific protein, have been previously reported as the cause of POI in only eight families and recently as the cause of infertility in a male. The here-identified mutation leads to the truncation of the last 55 amino acids, confirming the important role in meiosis of the STAG3 C-terminal domain.

Erectile Dysfunction in Men with Chronic Obstructive Pulmonary Disease.

Erectile dysfunction (ED) seems to be a widespread sexual issue in men affected by chronic obstructive pulmonary disease (COPD). Multiple causes appear to be involved such as hormonal imbalance, smoking habit, chronic inflammation, endothelial dysfunction, chronic hypoxia, psychiatric disorders (depression and anxiety), and medications. ED can have a significant impact on COPD men and consequently on their quality of life, which is usually already compromised. Given this situation, however, pneumologists usually do not properly care for the sexuality of COPD patients especially because men can be reluctant to talk about their intimate issues. The aim of this narrative review is to briefly summarize the evidence emerging from literature and to provide a wide point of view about sexual dysfunction in COPD men.

Gonadal Failure and Infertility in Cancer Survivors: Clinical Management and Strategies for Prevention.

Modern advances in oncological treatments determined a significant improvement in survival rates for several malignancies. Nevertheless, survivorship and quality of life of cancer survivors may be negatively impaired by metabolic and endocrine side effects related to anticancer treatments, including alterations of pituitary-gonadal axis function. In fact, both medical (chemo- and radiotherapy) and surgical approaches may negatively impact on gonadal function, leading to transient or permanent hypogonadism and infertility. In view of these considerations, fertility preservation (FP) should be a primary concern in all oncological patients who may potentially achieve parenthood, irrespectively from their sex and pubertal status at treatment, and adequate counselling should be provided before undergoing gonadotoxic therapy or gonadectomy. Cryopreservation of gametes, when feasible, represents the mainstay for FP in postpubertal age, while procedures involving storage of tissue specimens or stem cells should still be considered as experimental. Given the complexity of both hormonal and psychological implications in this clinical setting, a multidisciplinary approach is advisable for optimal FP and for early diagnosis and treatment of hypogonadism.

Impact of Allogeneic Stem Cell Transplantation on Testicular and Sexual Function.

High-dose chemotherapy and radiotherapy, administered as a conditioning regimen before stem cell transplantation, are known to negatively impact testicular function and sexuality. However, to date, only a few studies have simultaneously analyzed the real prevalence of these complications in this clinical setting. Therefore, this study aimed to assess the prevalence of testicular dysfunction and sexual impairment in a cohort of males who underwent allogeneic stem cell transplantation in adulthood. This observational, cross-sectional, single-center study consecutively enrolled 105 subjects on outpatient follow-up. Testicular function and sexuality were evaluated through a hormonal profile (testosterone, follicle-stimulating hormone, luteinizing hormone, and inhibin B) and the IIEF-15 questionnaire, respectively. We found a higher prevalence of hypogonadism (21%), impaired spermatogenesis (87%), and erectile dysfunction (72%) compared with the general population. Chronic graft-versus-host disease, especially of moderate/severe grade, was associated with an increased risk of developing erectile dysfunction (odds ratio, 6.338). Moreover, a high proportion of patients presented with alterations in all domains of sexual function, even after complete clinical remission of hematologic disease. Our data confirm both testicular function and sexuality alterations as frequent complications after allogeneic stem cell transplantation. A multidisciplinary approach is advisable for early diagnosis and adequate treatment.

Neuroinflammation and Hypothalamo-Pituitary Dysfunction: Focus of Traumatic Brain Injury.

The incidence of traumatic brain injury (TBI) has increased over the last years with an important impact on public health. Many preclinical and clinical studies identified multiple and heterogeneous TBI-related pathophysiological mechanisms that are responsible for functional, cognitive, and behavioral alterations. Recent evidence has suggested that post-TBI neuroinflammation is responsible for several long-term clinical consequences, including hypopituitarism. This review aims to summarize current evidence on TBI-induced neuroinflammation and its potential role in determining hypothalamic-pituitary dysfunctions.

Immunomodulatory Effects of Vitamin D in Thyroid Diseases.

Vitamin D is a secosteroid with a pleiotropic role in multiple physiological processes. Besides the well-known activity on bone homeostasis, recent studies suggested a peculiar role of vitamin D in different non-skeletal pathways, including a key role in the modulation of immune responses. Recent evidences demonstrated that vitamin D acts on innate and adaptative immunity and seems to exert an immunomodulating action on autoimmune diseases and cancers. Several studies demonstrated a relationship between vitamin D deficiency, autoimmune thyroid disorders, and thyroid cancer. This review aims to summarize the evidences on the immunomodulatory effect of vitamin D on thyroid diseases.

Ovotesticular Disorder of Sex Development: A Rare Case of Lateral Subtype 45X/46XY kariotype Diagnosed in Adulthood.

A 53-year-old male referred to our centre because of hypergonadotropic hypogonadism detected during urological follow-up for urethral lithiasis. Physical examination showed short stature, micropenis, ambiguous external genitalia, and normal secondary sexual characteristics. Karyotype: 45 × 0/46XY. Abdominal MRI revealed the presence of uterus-like structure, right annex, and left testes without prostate. He underwent laparoscopic removal of dysgenetic tissues; histologic examination confirmed the presence of little uterus, fallopian tubes, little atrophic ovary, and vaginal tract; left testes was atrophic with sclero-jalinosis of seminal tubes and Leydig's cells hyperplasia. Testosterone replacement therapy was started after surgery and prostate became MRI visible after 2 years.

Risk of Erythrocytosis During Concomitant Testosterone and SGLT2-Inhibitor Treatment: A Warning From Two Clinical Cases.

Context: Erythrocytosis is one of the most common side effects occurring during testosterone replacement therapy (TRT) in male hypogonadism. It is well known that all testosterone formulations may cause Hb and hematocrit increase, especially with short-acting injectable formulations. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a new class of glucose-lowering agents that reduce hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by inhibition of renal glucose reabsorption, leading to increased urinary glucose excretion. The co-occurrence of T2DM and hypogonadism is known to be increasingly frequent. However, to date, no adverse events with the concomitant use of TRT and SGLT2is are reported. Case Description: We report two cases of erythrocytosis during testosterone treatment and SGLT2i in patients with hypogonadism and T2DM. Conclusion: Considering that hypogonadism and T2DM are frequently associated, clinicians should carefully monitor the risk of occurrence of erythrocytosis when prescribing TRT and SGLT2i together.

Thyroid cancer phenotypes in relation to inflammation and autoimmunity.

Thyroid cancer represents the most frequent endocrine neoplasm and is epidemiologically linked to a growing incidence worldwide, which is only in part explained by the increased detection of small cancers in a preclinical stage. Understanding the molecular pathogenesis of well-differentiated thyroid cancers and poorly-differentiated thyroid cancers has prompted interest into the identification of crucial signaling pathways and molecular derangements related to genetic and epigenetic alterations. Increasing attention has been recently focused on inflammation and immunity as major culprit mechanisms involved in thyroid tumourigenesis, through the detection of activated immune cells, pro-inflammatory cytokines, as well as signal integrations between inflammatory and proliferative pathways within the thyroid tumour micro-environment. In addition to playing important roles in tumour surveillance and rejection, the presence of tumour-associated macrophages and the activation of NF-κB signaling pathway are now reckoned as hallmarks and crucial mediator of inflammation-induced growth and progression of thyroid cancer. Thorough understanding of this immunological link and identification of novel molecular targets could provide unprecedented opportunities for research and development of diagnostic, prognostic and treatment strategies for thyroid cancer.

Baseline glucose homeostasis predicts the new onset of diabetes during statin therapy: A retrospective study in real life.

OBJECTIVE: We evaluated the risk of altered glucose levels and new-onset diabetes (NOD) associated with statins according to glucose levels at baseline in a population treated for dyslipidemia on primary prevention for >5 years. DESIGN: The retrospective study included 308 subjects (265 on statins and 43 controls on diet) with a follow-up of 5-15 years. The cohort was classified according to glucose tolerance at both baseline and follow-up. RESULTS: The cumulative incidence of NOD was 13.6% (9.3% in controls and 13.5% in treated patients). NOD was diagnosed after 3.4±1.8 years. In the group with normal glucose levels at baseline, a family history of diabetes (OR: 3.4, 95% CI 1.3-8.9), BMI >30 kg/m2 (OR: 8.5, 95% CI 2.0-35.8), treatment with thiazide (OR: 21.9, 95% CI 1.2-384.2) and no alcohol consumption (OR: 0.3, 95% CI 0.1-0.8) reduced the risk of developing altered glucose levels or NOD. No effects of statins were seen. In the group with altered glucose levels at baseline, hypertension (OR: 5.0, 95% CI 1.0-25.3) and hypertriglyceridemia (OR: 3.5, 95% CI 1.0-11.8) increased the risk of remaining with altered glucose levels or developing NOD. Treatment with statins (OR: 7.5, 95% CI 1.5-37.4), in particular atorvastatin, was associated with an increased risk. In the whole population, statin therapy (OR: 4.0, 95% CI 1.1-14.1, p<0.020), and in particular simvastatin and atorvastatin, was associated with increased risk of altered glucose levels or NOD. Patients who developed or maintained altered glucose levels or NOD had a poor metabolic phenotype at baseline. CONCLUSIONS: Statins were associated with an increased risk of NOD or altered glucose levels, mainly in subjects with altered glucose levels before the beginning of therapy. Poor metabolic phenotype and unhealthy behaviors or family history of diabetes contributed to that risk.

Clinical and diagnostic approach to patients with hypopituitarism due to traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), and ischemic stroke (IS).

The hypothalamic-pituitary dysfunction attributable to traumatic brain injury (TBI), aneurysmal subarachnoid hemorrhage (SAH), and ischemic stroke (IS) has been lately highlighted. The diagnosis of TBI-induced-hypopituitarism, defined as a deficient secretion of one or more pituitary hormones, is made similarly to the diagnosis of classical hypopituitarism because of hypothalamic/pituitary diseases. Hypopituitarism is believed to contribute to TBI-associated morbidity and to functional and cognitive final outcome, and quality-of-life impairment. Each pituitary hormone must be tested separately, since there is a variable pattern of hormone deficiency among patients with TBI-induced-hypopituitarism. Similarly, the SAH and IS may lead to pituitary dysfunction although the literature in this field is limited. The drive to diagnose hypopituitarism is the suspect that the secretion of one/more pituitary hormone may be subnormal. This suspicion can be based upon the knowledge that the patient has an appropriate clinical context in which hypopituitarism can be present, or a symptom known as caused by hypopituitarism. Hypopituitarism should be diagnosed as a combination of low peripheral and inappropriately normal/low pituitary hormones although their basal evaluation may be not distinctive due to pulsatile, circadian, or situational secretion of some hormones. Evaluation of the somatotroph and corticotroph axes require dynamic stimulation test (ITT for both axes, GHRH + arginine test for somatotroph axis) in order to clearly separate normal from deficient responses.

One-year treatment with liraglutide improved renal function in patients with type 2 diabetes: a pilot prospective study.

Unlike GLP-1, liraglutide is not cleared by the glomerulus and its pharmacokinetic is not altered in patients with mild renal impairment. The aim of our study was to analyze the effects of liraglutide on renal function in patients with type 2 diabetes. A twelve-month longitudinal prospective post-marketing study was performed. According to eGFR (estimated glomerular filtration rate) calculated with CKD-EPI equation, 84 consecutive patients were divided in Group A (eGFR > 90 ml/min) and Group B (eGFR < 90 ml/min). BMI, glucose, HbA1c, serum creatinine, microalbuminuria, and eGFR were evaluated at baseline and after 12 months of treatment. A reduction in fasting plasma glucose (p < 0.01), HbA1c (p < 0.003), BMI (p < 0.01), and systolic (p < 0.01) and diastolic blood pressure (p < 0.006) was recorded irrespective of eGFR category. Concerning renal function, creatinine levels had a trend to decrease in both groups. eGFR did not change in Group A, while it increased in Group B (p < 0.05) independently from the concomitant changes of other parameters. Moreover, seven out of 41 patients of Group B had increased eGFR levels which reached the normal values (>90 ml/min). At baseline, five patients had pathological microalbuminuria, but at 12 months three of them returned to normal albuminuria (p < 0.006). Total microalbuminuria levels improved in both groups (p < 0.02). According to preliminary data in animals, our study shows that liraglutide is effective in preserving eGFR in diabetic patients, increasing it in those with reduced renal function. This was associated with a decrease of frequency of patients positive to microalbuminuria. Further studies are needed to confirm these data.

Unusual metastases from tall cell variant of papillary thyroid cancer.

BACKGROUND: Tall cell variant (TCV) cancer is considered more aggressive than the classic variant of papillary thyroid cancer (PTC). Distant metastases are more common among this variant and affect survival. Little is known about the molecular pattern of this histotype. METHODS: This is a report of 2 cases of unusual metastases from TCV, BRAF V600E-positive. RESULTS: A 38-year-old woman developed subcutaneous metastases during short-term follow-up; at medium-term follow-up, the patient showed detectable stimulated serum thyroglobulin without disease evidence at imaging. A 33-year-old man presented incidental thymic metastases at time of surgical treatment; this is the first case of not ectopic thymic metastases from PTC. CONCLUSION: TCV may present with unusual metastases already during early follow-up. The more aggressive behavior could be linked to the higher prevalence of BRAF point mutations, but only a long-term follow-up might clarify if this association could worsen the prognosis. Moreover, skin metastases have been predictive factors of worse outcome in our patients, but not thymic metastases.