Impact of Clomiphene Citrate on the Steroid Profile in Dysmetabolic Men with Low Testosterone Levels.

Clomiphene citrate (CC) in male hypogonadism increases testosterone (T) and estrogen levels by stimulating pituitary gonadotropin release. Our group confirmed these hormonal changes in a randomized, cross-over, double-blind trial of CC versus placebo in addition to metformin, conducted in 21 obese dysmetabolic men with low T levels. However, we hypothesize that based on its mechanism of action, CC may directly or indirectly affect adrenal steroidogenesis. The aim of this sub-study was to better understand the changes in steroid levels and metabolism induced by CC treatment. We assessed 17α-hydroxypregnelone (17αOH-P5), dehydroepiandrosterone (DHEA), progesterone (P4), 17α-hydroxyprogesterone (17αOH-P4), androstenedione (A), T, dihydrotestosterone (DHT), estrone (E1), 17ß-estradiol (E2), 11-deoxycortisol (11 S), cortisol (F), and cortisone (E) by LC-MS/MS, and corticosteroid binding globulin (CBG) by ELISA, before and after each treatment. In addition, free-F and steroid product/precursor ratios were calculated. We observed a significant change in serum levels induced by CC compared with placebo for 17αOH-P4, DHT, T, E2, E1, F, E, and CBG, but not free-F. In addition, compared to placebo, CC induced higher 17αOH-P4/P4, E2/E1, 17αOH-P4/17αOH-P5, A/17αOH-P4, T/A, E1/A, F/11 S, and F/E ratios. Therefore, besides the CC stimulating effect on testis steroidogenesis, our study showed increased F, E, but not free-F, levels, indicating changes in steroid metabolism rather than adrenal secretion stimulation. The steroid profiling also revealed the CC stimulation of the Δ5 rather than the Δ4 pathway, thus indicating considerable testicular involvement in the increased androgen secretion.

Signal Transduction of Mineralocorticoid and Angiotensin II Receptors in the Central Control of Sodium Appetite: A Narrative Review.

Sodium appetite is an innate behavior occurring in response to sodium depletion that induces homeostatic responses such as the secretion of the mineralocorticoid hormone aldosterone from the zona glomerulosa of the adrenal cortex and the stimulation of the peptide hormone angiotensin II (ANG II). The synergistic action of these hormones signals to the brain the sodium appetite that represents the increased palatability for salt intake. This narrative review summarizes the main data dealing with the role of mineralocorticoid and ANG II receptors in the central control of sodium appetite. Appropriate keywords and MeSH terms were identified and searched in PubMed. References to original articles and reviews were examined, selected, and discussed. Several brain areas control sodium appetite, including the nucleus of the solitary tract, which contains aldosterone-sensitive HSD2 neurons, and the organum vasculosum lamina terminalis (OVLT) that contains ANG II-sensitive neurons. Furthermore, sodium appetite is under the control of signaling proteins such as mitogen-activated protein kinase (MAPK) and inositol 1,4,5-thriphosphate (IP3). ANG II stimulates salt intake via MAPK, while combined ANG II and aldosterone action induce sodium intake via the IP3 signaling pathway. Finally, aldosterone and ANG II stimulate OVLT neurons and suppress oxytocin secretion inhibiting the neuronal activity of the paraventricular nucleus, thus disinhibiting the OVLT activity to aldosterone and ANG II stimulation.

Effect of clomiphene citrate treatment on the Sertoli cells of dysmetabolic obese men with low testosterone levels.

BACKGROUND: Clomiphene citrate (CC) has been shown to restore the hypothalamic-pituitary-gonadal (HPG) axis by increasing testosterone (T) levels to physiological levels in patients with dysmetabolic conditions such as obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM). However, the data are unclear regarding the effects on Sertoli cell (SC) function. AIM: To study SC function by assessing Inhibin B (IB) and anti-Mullerian hormone (AMH) levels at baseline and after 3 months of CC treatment. MATERIALS AND METHODS: This is an ancillary study of a cross-over, randomised, double-blind, placebo-controlled trial performed to evaluate androgen response to CC treatment in dysmetabolic obese subjects with low T levels treated with metformin. We evaluated SC function by assessing IB and AMH levels at baseline and after 3 months of each treatment in ten dysmetabolic obese subjects with low T levels. In all subjects, the influence of the clinical characteristics, metabolic and hormonal baseline parameters on SC and Leydig (LC) function, evaluated respectively with AMH, IB, follicle-stimulating hormone (FSH) and T levels, was tested. RESULTS: No significant changes were observed for IB and AMH concentrations after each treatment period. Whereas T and oestradiol (E2) levels were shown to be significantly higher in the CC plus metformin phase (CC/Met) only. No clinical, metabolic or hormonal parameters showed significant effects on serum AMH at baseline or after treatments. However, baseline T, dihydrotestosterone (DHT) and E2 positively affected IB levels during CC/Met therapy (P = .003, P = .038 and P = .049, respectively). Baseline leptin and FSH had a negative (P = 031) and positive (P = .048) respectively role on T levels during CC/Met, as they were statistically significant compared to the placebo period (Plac/Met). CONCLUSION: Unlike the LC activity, CC was unable to influence SC function, as shown by the lack of IB and AMH serum modifications, thus suggesting an intrinsic nonreversible defect of SC cells in patients with dysmetabolic conditions.

The pathogenic role of the immune system in erectile dysfunction and Peyronie's disease: focusing on immunopathophysiology and potential therapeutic strategies.

INTRODUCTION: Erectile dysfunction (ED) represents the major cause of male sexual dysfunction, which is often associated with obesity, diabetes mellitus, atherosclerotic cardiovascular disease, and cigarette smoking. Peyronie's disease is a chronic disorder associated with irreversible fibrotic damage of the tunica albuginea leading to ED, painful erection, coital disturbance, and physical and social complaints. Both conditions are characterized by chronic inflammation, oxidative stress, and significant changes in intracavernous hydrodynamics. In this scenario, oxidized lipoproteins, M1-polarized macrophages, proinflammatory cytokines (such as the tumor necrosis factor α), endothelial nitric oxide synthase, penile smooth muscle cells, and toll-like receptors represent the main triggers of the inflammatory process in ED. Phosphodiesterase-5 inhibitors are the most common treatment for ED. This treatment is used intermittently, as it is conceived as a symptomatic and not curative therapy. Moreover, not all patients respond to phosphodiesterase-5 inhibitors (35%-85%), particularly those with dysmetabolic phenotypes. Additional or alternative treatments are therefore desirable, mostly in refractory cases. OBJECTIVES: In this review, we describe the immune-mediated pathogenesis of ED and Peyronie's disease (PD). In our literature search we placed particular emphasis on potentially practical therapeutic approaches, including natural products (such as polyphenols), due to their anti-inflammatory and antioxidant activities, stem cell therapy, and platelet-derived preparations. METHODS: We searched PubMed/MEDLINE, Web of Science, Scopus, Cochrane Library, Google Scholar, and institutional websites. Original studies, narrative reviews, systematic reviews, and meta-analyses written in English were searched, screened, and selected. RESULTS: In animal models of ED and PD, therapeutic approaches, including anti-inflammatory and antioxidant agents, stem cell therapy, and platelet-derived preparations, have provided positive results, including improved penile function, reduced inflammation and oxidative stress, and promotion of tissue repair. However, clinical evidence of improvement in human patients is still insufficient. CONCLUSION: Promising results for treating ED and PD have been shown in preclinical and pilot clinical studies, but specific clinical trials are needed to validate the efficacy of these therapeutic approaches in men with ED.

Long-acting glucagon-like peptide 1 receptor agonists boost erectile function in men with type 2 diabetes mellitus complaining of erectile dysfunction: A retrospective cohort study.

INTRODUCTION: The pharmacological management of erectile dysfunction (ED) in type 2 diabetes (T2D) is challenging as ED has a multifactorial etiology. The therapeutic potential of certain antihyperglycemic medications, such as glucagon-like peptide 1 receptor agonists (GLP-1RAs), has yet to be entirely studied in this setting. MATERIAL AND METHODS: A retrospective cohort study was conducted on 108 outpatients (median age 60 [56, 65] years) with T2D complaining of ED. Data were extracted from a database referring to patients with a 1-year follow-up on stable treatment with metformin alone (n = 45) and GLP-1RAs as an add-on to metformin (n = 63). Erectile function was assessed by the 5-item International Index of Erectile Function (IIEF5) at baseline and after 1 year of stable treatment . Values were compared between baseline (T0) and after 12 months of treatment (T12). RESULTS: ED was confirmed in all at baseline, with an IIEF5 score range between 13 and 19 points. After 12 months of treatment, glucose management was better in patients treated with GLP-1RAs plus metformin (HbA1c T0: 8.3 ± 0.2 vs. HbA1c T12: 7% ± 0.3%, p < 0.0001) than in those on metformin alone (HbA1c T0: 7 ± 0.5 vs. HbA1c T12: 7.3 ± 0.4, p = 0.0007). GLP-1RAs plus metformin over metformin alone resulted in a significant weight loss (-5.82 ± 0.69 kg, p < 0.0001), reduction in waist circumference (-4.99 ± 0.6 cm, p < 0.0001), improvement in HbA1c (-0.56% ± 0.13%, p < 0.0001), and fasting plasma glucose (-25.54 ± 3.09 mg/dL, p < 0.0001), increase in total (+41.41 ± 6.11 ng/dL, p < 0.0001) and free (0.44 ± 0.09 ng/dL, p < 0.0001) testosterone levels, and gain in self-reported erectile function (IIEF5 score: +2.26 ± 0.26, p < 0.0001). The gain in the IIEF5 score was more relevant in patients with higher baseline IIEF5 score (estimated coefficient: 0.16 ± 0.08, p = 0.045), those having carotid stenosis (0.50 ± 0.24, p = 0.045), and showing weight loss from baseline (-0.08 ± 0.03, p = 0.013). The leading determinant of the final IIEF5 score was a 1-year treatment with GLP-1RAs plus metformin over metformin alone (2.74 ± 0.53, p < 0.0001). DISCUSSION: GLP-1RAs plus metformin over metformin alone improved ED regardless of different background characteristics of patients and partially irrespective of therapeutic targets achieved after 12 months of treatment. GLP-1RAs may have induced positive vasculature effects, resulting in improved erectile function in T2D. CONCLUSION: Due to the retrospective nature of the study, a potential cause-effect relationship between the use of GLP-1RAs plus metformin over metformin alone in improving ED cannot be verified and confirmed. Randomized clinical trials are needed to provide evidence supporting the use of GLP-1RAs for treating ED in T2D.

The neurohypophyseal hormone oxytocin and eating behaviors: a narrative review.

BACKGROUND: The neuropeptide oxytocin (OT) is crucial in several conditions, such as lactation, parturition, mother-infant interaction, and psychosocial function. Moreover, OT may be involved in the regulation of eating behaviors. METHODS: This review briefly summarizes data concerning the role of OT in eating behaviors. Appropriate keywords and medical subject headings were identified and searched for in PubMed/MEDLINE. References of original articles and reviews were screened, examined, and selected. RESULTS: Hypothalamic OT-secreting neurons project to different cerebral areas controlling eating behaviors, such as the amygdala, area postrema, nucleus of the solitary tract, and dorsal motor nucleus of the vagus nerve. Intracerebral/ventricular OT administration decreases food intake and body weight in wild and genetically obese rats. OT may alter food intake and the quality of meals, especially carbohydrates and sweets, in humans. DISCUSSION: OT may play a role in the pathophysiology of eating disorders with potential therapeutic perspectives. In obese patients and those with certain eating disorders, such as bulimia nervosa or binge/compulsive eating, OT may reduce appetite and caloric consumption. Conversely, OT administered to patients with anorexia nervosa may paradoxically stimulate appetite, possibly by lowering anxiety which usually complicates the management of these patients. Nevertheless, OT administration (e.g., intranasal route) is not always associated with clinical benefit, probably because intranasally administered OT fails to achieve therapeutic intracerebral levels of the hormone. CONCLUSION: OT administration could play a therapeutic role in managing eating disorders and disordered eating. However, specific studies are needed to clarify this issue with regard to dose-finding and route and administration time.

Predicting Factors of Worse Prognosis in COVID-19: Results from a Cross-sectional Study on 52 Inpatients Admitted to the Internal Medicine Department.

BACKGROUND: The initial phases of the COVID-19 pandemic posed a real need for clinicians to identify patients at risk of poor prognosis as soon as possible after hospital admission. AIM: The study aimed to assess the role of baseline anamnestic information, clinical parameters, instrumental examination, and serum biomarkers in predicting adverse outcomes of COVID-19 in a hospital setting of Internal Medicine. METHODS: Fifty-two inpatients consecutively admitted to the Unit of Internal Medicine "Baccelli," Azienda Ospedaliero - Universitaria Policlinico of Bari (February 1 - May 31, 2021) due to confirmed COVID-19 were grouped into two categories based on the specific outcome: good prognosis (n=44), patients discharged at home after the acute phase of the infection; poor prognosis, a composite outcome of deaths and intensive care requirements (n=8). Data were extracted from medical records of patients who provided written informed consent to participate. RESULTS: The two study groups had similar demographic, anthropometric, clinical, and radiological characteristics. Higher interleukin 6 (IL-6) levels and leucocyte count, and lower free triiodothyronine (fT3) levels were found in patients with poor than those with good prognosis. Higher IL-6 levels and leucocyte count, lower fT3 concentration, and pre-existing hypercholesterolemia were independent risk factors of poor outcomes in our study population. A predicting risk score, built by assigning one point if fT3 < 2 pg/mL, IL-6 >25 pg/mL, and leucocyte count >7,000 n/mm3, revealed that patients totalizing at least 2 points by applying the predicting score had a considerably higher risk of poor prognosis than those with scoring <2 points [OR 24.35 (1.32; 448), p = 0.03]. The weight of pre-existing hypercholesterolemia did not change the risk estimation. CONCLUSION: Four specific baseline variables, one anamnestic (pre-existing hypercholesterolemia) and three laboratory parameters (leucocyte count, IL-6, and fT3), were significantly associated with poor prognosis as independent risk factors. To prevent adverse outcomes, the updated 4-point score could be useful in identifying at-risk patients, highlighting the need for specific trials to estimate the safety and efficacy of targeted treatments.

Is Testosterone the "Fountain of Youth" for Aging Men?

BACKGROUND: Late-Onset Hypogonadism (LOH) is defined as a clinical and biochemical syndrome associated with advancing age. It is characterized by specific symptoms and less specific manifestations due to deficiency of serum testosterone (T) levels. OBJECTIVE: This review aims to summarize the evidence related to LOH definition, diagnostic approach, and treatment to answer a clinical question: "Is Testosterone the fountain of youth for aging men?". METHODOLOGY: MEDLINE/PubMed and institutional websites were searched for original papers, guidelines, and position statements published in the last ten years. RESULTS: Observational and randomized controlled studies on T replacement therapy in older men have been reported. DISCUSSION AND CONCLUSION: Despite some heterogeneities regarding diagnostic definition, therapeutic target, and testosterone prescription, all guidelines agreed that male hypogonadism should be diagnosed and managed in aged men as in adulthood. However, trials assessing the efficacy of T therapy conducted for male rejuvenating are lacking; thus, T prescription for this purpose is not recommended.

Pancreatic Macrophages and their Diabetogenic Effects: Highlight on Several Metabolic Scenarios and Dietary Approach.

BACKGROUND: Evidence shows that a low-grade inflammation sustains type 2 diabetes (T2D). Pancreatic macrophages release cytokines and chemokines that play a fundamental role in the pathophysiology of islet damage and destruction of beta-cells. METHODS: The authors discuss the main mechanism by which resident (pancreatic) and circulating macrophages regulate beta-cell development and survival in several scenarios, including T2D, type 1 diabetes mellitus, obesity, and insulin resistance. Data are mostly related to in vitro and animal studies. RESULTS: Lastly, an overview of the role of the Mediterranean diet components (i.e., polyphenols, polyunsaturated fatty acids, prebiotics, probiotics, and vitamins) will be illustrated as potential agents for reducing inflammation and oxidative stress in patients with T2D when used along with antihyperglycemic treatments.

Dopamine in the Regulation of Glucose Homeostasis, Pathogenesis of Type 2 Diabetes, and Chronic Conditions of Impaired Dopamine Activity/Metabolism: Implication for Pathophysiological and Therapeutic Purposes.

Dopamine regulates several functions, such as voluntary movements, spatial memory, motivation, sleep, arousal, feeding, immune function, maternal behaviors, and lactation. Less clear is the role of dopamine in the pathophysiology of type 2 diabetes mellitus (T2D) and chronic complications and conditions frequently associated with it. This review summarizes recent evidence on the role of dopamine in regulating insular metabolism and activity, the pathophysiology of traditional chronic complications associated with T2D, the pathophysiological interconnection between T2D and chronic neurological and psychiatric disorders characterized by impaired dopamine activity/metabolism, and therapeutic implications. Reinforcing dopamine signaling is therapeutic in T2D, especially in patients with dopamine-related disorders, such as Parkinson's and Huntington's diseases, addictions, and attention-deficit/hyperactivity disorder. On the other hand, although specific trials are probably needed, certain medications approved for T2D (e.g., metformin, pioglitazone, incretin-based therapy, and gliflozins) may have a therapeutic role in such dopamine-related disorders due to anti-inflammatory and anti-oxidative effects, improvement in insulin signaling, neuroinflammation, mitochondrial dysfunction, autophagy, and apoptosis, restoration of striatal dopamine synthesis, and modulation of dopamine signaling associated with reward and hedonic eating. Last, targeting dopamine metabolism could have the potential for diagnostic and therapeutic purposes in chronic diabetes-related complications, such as diabetic retinopathy.

Erectile Dysfunction in Patients with Multiple Chronic Conditions: A Cross- Sectional Study.

BACKGROUND: The prevalence of erectile dysfunction (ED) rises with the number and severity of chronic diseases. AIMS: This cross-sectional study assessed the frequency and severity of ED in patients with multiple chronic conditions. METHODS: The 5-item International Index of Erectile Function questionnaire (IIEF-5) was used to diagnose and classify ED. The Charlson Comorbidity Index (CCI) was used to assess the burden of chronic comorbidity. The primary outcome was to assess the ED frequency according to CCI severity. The secondary outcomes included the assessment of the correlation between 1) IIEF-5 and total testosterone (TT), 2) CCI and TT, and 3) IIEF-5 and CCI. Lastly, the CCI and modified CCI (mCCI) performances were compared with each other. RESULTS: The overall frequency of ED increased along with the CCI score severity: 45% for CCI=0; 95% for CCI=1; 91% for CCI=2; 99% for CCI≥3 (p<.0001). CCI correlated negatively with TT levels and IIEF-5 score (r=-0.34 and -0.44; p<.0001). Compared to the CCI, a novel proposed mCCI performs well. DISCUSSION: The frequency and severity of ED are relevant in outpatients with sexual complaints and those with chronic comorbidities. Despite limitations, mCCI may be considered a reliable tool to assess the overall burden of multiple chronic conditions in patients with comorbidities. CONCLUSION: ED is a reliable proxy of overall male health. Further studies are needed to confirm this potential application.

Iodine Deficiency and Iodine Prophylaxis: An Overview and Update.

The thyroid gland requires iodine to synthesize thyroid hormones, and iodine deficiency results in the inadequate production of thyroxine and related thyroid, metabolic, developmental, and reproductive disorders. Iodine requirements are higher in infants, children, and during pregnancy and lactation than in adult men and non-pregnant women. Iodine is available in a wide range of foods and water and is susceptible to almost complete gastric and duodenal absorption as an iodide ion. A healthy diet usually provides a daily iodine consumption not exceeding 50% of the recommended intake. Iodine supplementation is usually necessary to prevent iodine deficiency disorders (IDDs), especially in endemic areas. The community-based strategy of iodine fortification in salt has eradicated IDDs, such as endemic goiter and cretinism, in countries providing adequate measures of iodine prophylaxis over several decades in the 20th century. Iodized salt is the cornerstone of iodine prophylaxis in endemic areas, and the continuous monitoring of community iodine intake and its related clinical outcomes is essential. Despite the relevant improvement in clinical outcomes, subclinical iodine deficiency persists even in Western Europe, especially among girls and women, being an issue in certain physiological conditions, such as pregnancy and lactation, and in people consuming unbalanced vegetable-based or salt-restricted diets. Detailed strategies to implement iodine intake (supplementation) could be considered for specific population groups when iodized salt alone is insufficient to provide adequate requirements.

Hypothyroidism in older adults: A narrative review.

INTRODUCTION: The prevalence of hypothyroidism increases along with aging, resulting in one of the most common comorbidities among patients over 75 years. The leading causes of hypothyroidism in older adults are iatrogenic, Hashimoto's thyroiditis, and medications. AIMS: The narrative review aimed to discuss the clinical characteristics of hypothyroidism in older adults and the impact of hormonal replacement therapy on survival rates. RESULTS: Thyroid function declines over time due to physiological changes in the thyroid stimulating hormone signaling, iodine absorption and metabolism, thyroid hormone metabolism, and activity at peripheral sites. A serum TSH value over the upper limit of the normal reference range is not necessarily attributable to hypothyroidism. However, an appropriate diagnostic work-up is required to rule out true hypothyroidism and discriminate the etiology (i.e., thyroid autoimmune diseases, iodine deficiency, drug-induced hypothyroidism). Levothyroxine treatment should be considered in cases of overt hypothyroidism. A complete risk-to-benefit assessment, particularly considering the overall health status, life expectancy, cognitive function, mood, and cardiovascular and neurological background, should be considered before treating subclinical hypothyroidism with more potential benefits in patients under 75 years old. Levothyroxine formulations facilitating hormone absorption and increasing compliance to long-term treatment should be preferred. TSH target should usually be set over 3 mIU/ml. CONCLUSION: Defining optimal diagnostic approaches and targeted therapeutic strategies should be considered in the personalized management of aged patients with hypothyroidism.

Endocrine, Metabolic, and Immune Pathogenesis of Postmenopausal Osteoporosis. Is there a Therapeutic Role in Natural Products?

BACKGROUND: Bone health relies on the equilibrium between resorption and new bone generation. Postmenopausal osteoporosis depends on estrogen deficiency which favorite bone resorption and elevated risk of fractures. Moreover, osteoporosis is characterized by a high release of proinflammatory cytokines suggesting the role of the immune system in the pathogenesis of this complex disease (immunoporosis). AIMS: To review the pathophysiology of osteoporosis from an endocrinological and immunological viewpoint and treatments with a specific focus on nutraceuticals. METHODS: PubMed/MEDLINE, Scopus, Google Scholar, and institutional web site were searched. Original articles and reviews were screened and selected by September 2022. RESULTS: The activation of the Gut Microbiota-Bone Axis contributes to bone health by releasing several metabolites, including short-chain fatty acids (SCFAs), that facilitate bone mineralization directly and indirectly by the induction of T regulatory cells, triggering anti-inflammatory pathways. CONCLUSION: Treatments of postmenopausal osteoporosis are based on lifestyle changes, calcium and vitamin D supplementation, and anti-resorptive and anabolic agents, such as bisphosphonates, Denosumab, Teriparatide, Romosozumab. However, phytoestrogens, polyphenols, probiotics, and polyunsaturated fatty acids may improve bone health by several mechanisms, including anti-inflammatory properties. Specific clinical trials are needed to assess the efficacy/effectiveness of the possible anti-osteoporotic activity of natural products as add on to background treatment.

The role of male hypogonadism, aging, and chronic diseases in characterizing adult and elderly men with erectile dysfunction: a cross-sectional study.

BACKGROUND: Erectile function depends on a complex interaction between demographic, metabolic, vascular, hormonal, and psychological factors that trigger erectile dysfunction (ED). In the present study we carried out a cross-sectional study assessing the impact of non-communicable chronic diseases (NCDs), male hypogonadism, and demographic factors in characterizing men with ED. Four hundred thirty-three consecutive outpatients with ED were extracted from the electronic database from January 2017 to December 2019. The International Index of Erectile Function (IIEF) 5 score was used to diagnose ED and stratify its severity, standardized values of serum testosterone (10.5 nM/L) and luteinizing hormone (LH 9.4 IU/L) to diagnose and classify male hypogonadism and the Charlson Comorbidity Index (CCI) to weigh the role of each NCD on ED. RESULTS: Forty-six percent of participants were eugonadal (EuG), 13% had organic hypogonadism (OrH), and the remaining 41% had functional hypogonadism (FuH). Hypogonadal men had a significantly lower IIEF 5 score (p < .0001) than EuG. FuH had a higher CCI than OrH and EuG (all p < .0001). In a multivariable model, only free T (FT) and Sex Hormone Binding Globulin (SHBG) showed a direct correlation with the IIEF 5 score (all p < .0001). Age and CCI had an inverse correlation with IIEF 5 score (all p < .0001). CONCLUSION: Serum FT, SHBG, and CCI are the leading determinants of ED severity. Besides overt hypogonadism, a relevant burden of severe NTCDs in middle-aged or older adults features the patient's characteristics who will suffer from severe ED. Appropriate clinical approaches and, when necessary, treatments are required in these clusters of patients.

RéSUMé: CONTEXTE: La fonction érectile dépend d'une interaction complexe entre les facteurs démographiques, métaboliques, vasculaires, hormonaux et psychologiques qui déclenchent la dysfonction érectile (DE). Dans la présente étude, nous avons mené ici une étude transversale évaluant l'impact des maladies chroniques non transmissibles (MNT), de l'hypogonadisme masculin et des facteurs démographiques dans la caractérisation des hommes atteints de dysfonction érectile. Quatre cent trente-trois patients externes consécutifs présentant une dysfonction érectile ont été extraits de la base de données électronique de janvier 2017 à décembre 2019. Le score de l'indice international de la fonction érectile (IIEF) 5 a été utilisé pour diagnostiquer la dysfonction érectile et stratifier sa gravité, les valeurs normalisées de la testostérone sérique (10,5 nM/L) et de l'hormone lutéinisante (LH 9,4 UI/L) pour diagnostiquer et classer l'hypogonadisme masculin, et l'indice de comorbidité de Charlson (ICC) pour évaluer le rôle de chaque MNT sur la DE. RéSULTATS: Quarante-six pour cent des participants étaient eugonadiques (EuG), 13% avaient un hypogonadisme organique (OrH) et les 41% restants avaient un hypogonadisme fonctionnel (FuH). Les hommes hypogonadiques avaient un score IIEF 5 significativement plus faible (p < 0,0001) que EuG. Les hommes FuH avait un ICC plus élevé que les hommes OrH et EuG (tous p < .0001). Dans un modèle multivariable, seules la T libre (TL) et la globuline liant les hormones sexuelles (SHBG) ont montré une corrélation directe avec le score IIEF 5 (tous p <,0001). L'âge et l'ICC avaient une corrélation inverse avec le score IIEF 5 (tous p < 0,0001). CONCLUSION: La TL sérique, la SHBG et le CCI sont les principaux déterminants de la gravité de la DE. Outre l'hypogonadisme manifeste, une charge significative de MNT sévères chez les adultes d'âge moyen ou plus âgés dessine les caractéristiques du patient qui souffrira de DE sévère. Des approches cliniques appropriées et, si nécessaire, des traitements sont requis chez ces patients. MOTS-CLéS : Dysfonction érectile, Testostérone, Indice de Comorbidité de Charlson, Maladies chroniques non transmissibles, Hypogonadisme masculin.

Sarcopenia and Diabetes: A Detrimental Liaison of Advancing Age.

Sarcopenia is an age-related clinical complaint characterized by the progressive deterioration of skeletal muscle mass and strength over time. Type 2 diabetes (T2D) is associated with faster and more relevant skeletal muscle impairment. Both conditions influence each other, leading to negative consequences on glycemic control, cardiovascular risk, general health status, risk of falls, frailty, overall quality of life, and mortality. PubMed/Medline, Scopus, Web of Science, and Google Scholar were searched for research articles, scientific reports, observational studies, clinical trials, narrative and systematic reviews, and meta-analyses to review the evidence on the pathophysiology of di-abetes-induced sarcopenia, its relevance in terms of glucose control and diabetes-related outcomes, and diagnostic and therapeutic challenges. The review comprehensively addresses key elements for the clinical definition and diagnostic criteria of sarcopenia, the pathophysiological correlation be-tween T2D, sarcopenia, and related outcomes, a critical review of the role of antihyperglycemic treatment on skeletal muscle health, and perspectives on the role of specific treatment targeting myokine signaling pathways involved in glucose control and the regulation of skeletal muscle metabolism and trophism. Prompt diagnosis and adequate management, including lifestyle inter-vention, health diet programs, micronutrient supplementation, physical exercise, and pharmaco-logical treatment, are needed to prevent or delay skeletal muscle deterioration in T2D.

The Pathogenic Role of Foam Cells in Atherogenesis: Do They Represent Novel Therapeutic Targets?

BACKGROUND: Foam cells, mainly derived from monocytes-macrophages, contain lipid droplets essentially composed of cholesterol in their cytoplasm. They infiltrate the intima of arteries, contributing to the formation of atherosclerotic plaques. PATHOGENESIS: Foam cells damage the arterial cell wall via the release of proinflammatory cytokines, free radicals, and matrix metalloproteinases, enhancing the plaque size up to its rupture. THERAPY: A correct dietary regimen seems to be the most appropriate therapeutic approach to minimize obesity, which is associated with the formation of foam cells. At the same time, different types of antioxidants have been evaluated to arrest the formation of foam cells, even if the results are still contradictory. In any case, a combination of antioxidants seems to be more efficient in the prevention of atherosclerosis.

Endocrine-Disrupting Chemicals: Introduction to the Theme.

BACKGROUND: Endocrine-disrupting chemicals (EDCs) are natural or synthetic compounds deriving from different human activities and are widely spread into the environment, contributing to indoor and outdoor pollution. EDCs may be conveyed by food and water consumption and skin, airways, placental, and breastfeeding. Upon entering the circulation, they can interfere with endocrine system homeostasis by several mechanisms. AIM: In this narrative review, the authors overviewed the leading mechanisms by which EDCs interact and disrupt the endocrine system, leading to possible human health concerns. RESULTS: The leading mechanisms of EDCs-related toxicity have been illustrated in in vitro studies and animal models and may be summarized as follows: receptor agonism and antagonism; modulation of hormone receptor expression; interference with signal transduction in hormone-responsive cells; epigenetic modifications in hormone-producing or hormone-responsive cells; interference with hormone synthesis; interference with hormone transport across cell membranes; interference with hormone metabolism or clearance; interference with the destiny of hormone-producing or hormone- responsive cells. DISCUSSION: Despite these well-defined mechanisms, some limitations do not allow for conclusive assumptions. Indeed, epidemiological and ecological studies are currently lacking and usually refer to a specific cluster of patients (occupational exposure). Methodological aspects could further complicate the issue since these studies could require a long time to provide useful information. The lack of a real unexposed group in environmental conditions, possible interference of EDCs mixture on biological results, and unpredictable dose-response curves for some EDCs should also be considered significant limitations. CONCLUSION: Given these limitations, specific observational and long-term studies are needed to identify at-risk populations for adequate treatment of exposed patients and effective prevention plans against excessive exposure to EDCs.

Hyperglycemia-Induced Immune System Disorders in Diabetes Mellitus and the Concept of Hyperglycemic Memory of Innate Immune Cells: A Perspective.

A wealth of information suggests that hyperglycemia plays a paramount role in diabetes- related chronic complications. Notably, in Type 2 Diabetes Mellitus (T2DM), a persistent condition of hyperglycemia and altered insulin signaling seems to account for a status of chronic low-grade inflammation. This systemic inflammatory condition, in turn, depends on the profound impairment of the immune machinery, especially in some corporeal districts such as the adipose tissue, pancreatic islets, endothelia, and circulating leukocytes. Interestingly, poor glycemic control has been associated with cardiac autoimmunity in patients with Type 1 Diabetes (T1DM), and cardiac autoantibody positivity is associated with an increased risk of Cardiovascular Diseases (CVD) decades later. This condition also suggests a role for autoimmune mechanisms in CVD development in patients with T1DM, possibly through inflammatory pathways. Evidence has been provided for an elevated release of cytokines, such as interleukin (IL)-1 beta and IL-6, as well as chemokines (C-C motif Ligand 2 and IL-8). Of note, these mediators are responsible for abnormal leukocyte trafficking into many tissues, contributing to insulin resistance, reduced insulin secretion, and vascular complications. In fact, hyperglycemia in individuals with diabetes mellitus is associated with higher circulating E-selectin, soluble Cell Adhesion Molecule (sCAM)-1, and vascular CAM-1 compared to normoglycemic healthy volunteers. Therefore, patients with diabetes mellitus exhibit an exaggerated adhesion of leukocytes to endothelia, and this phenomenon is related to hyperglycemia. The increased production of advanced glycosylation end products or AGEs activates a further cascade of noxious events with a massive generation of Reactive Oxygen Radicals (ROS) and enhanced expression of CAMs.

Overall Sexual Function in Dysmetabolic Obese Men with Low Testosterone Levels Treated with Clomiphene Citrate.

BACKGROUND: Sexual disorders are the most common clinical manifestations of hypogonadism. Functional hypogonadism is the most frequent form, and clomiphene citrate (CC) has been recently introduced as a possible off-label therapeutic option for these patients. OBJECTIVES: This study aimed to evaluate the effects of CC on the overall sexual function in dysmetabolic obese men with low testosterone (T) levels. METHODS: This was a sub-study of a randomized, double-blind, cross-over, placebo-controlled trial that included twenty-four obese or overweight subjects with impaired glucose tolerance or type 2 diabetes and confirmed low total T (≤10.4 nmol/l) levels. Subjects were treated with CC or placebo (Plac) for 12 weeks, with an interval wash-out period of 6 weeks between treatments. All subjects were on metformin 2gr/day and a low-calorie diet. The between-treatment difference in the overall sexual function was assessed by IIEF-15 and a qADAM questionnaire. RESULTS: IIEF-15 and qADAM questionnaire data were available for 18 individuals. In unadjusted analyses, CC was associated with lower IIEF-15 total, erectile function, and intercourse satisfaction domain scores than Plac. After adjustments for multiple variables, CC was associated with a higher IIEF-15 sexual desire domain score (+0.9 ± 0.8; p<.001) despite a lower qADAM score (-2.1 ± 0.9; p=.008) with respect to Plac. No differences were found for the other domains between groups. DISCUSSION: The clinical significance of the absolute changes in IIEF-15 and qADAM scores during CC versus Plac is limited. However, CC has a reliable effect on sexual desire and is also as safe as Plac. According to the sample size, duration of follow-up, and inclusion criteria defined for the main study, further studies are therefore needed to assess the long-term efficacy of CC. CONCLUSION: Compared to Plac, CC was found to be associated with a neutral effect on overall sexual function.