Semaglutide and obesity: beyond the nutritional and lifestyle intervention?

Semaglutide is the second marketed glucagon-like peptide 1 receptor agonist that can be used safely and efficiently in non-diabetic people with excess weight, providing a new milestone in the pharmacological treatment of obesity. This narrative review aims to describe the clinical actions of this new drug in weight management in non-diabetic patients along with possible side-effects and dropout reasons. To accomplish this, the PubMed database was searched to retrieve the most relevant clinical studies published to date on this topic, using the following keywords "semaglutide and obesity". Currently, semaglutide is on the market in two formulations, the once-weekly subcutaneous (s.c.) semaglutide and once-daily oral semaglutide. Data in the literature on the anti-obesity action of semaglutide are available for both routes of administration of the drug, with a prevalence of studies using the s.c. one. However, given its dosage, oral semaglutide may provide greater attractiveness and better treatment adherence, but further research is needed in this field.

Global olfactory function correlates with global sexual functioning in men and women.

BACKGROUND: Olfaction is intimately involved in reproductive behaviors. However, there is limited evidence about the relationship between olfactory and sexual functioning, and whether this relationship is modulated by gender. This study aimed to investigate the correlates between olfactory and sexual functioning in a cohort of young healthy individuals; secondary outcomes were the possible correlates between disgust and perceived vulnerability to illness, with particular relation to sexual attitudes. METHODS: Between January 2019 and December 2022, we enrolled 125 participants (51 males and 74 females) without known sexual disorders. The mean age was 28.47±8.6, and the mean Body Mass Index (BMI) was 23.86±3.3 without major disease or concomitant drug assumption, except for nutraceutical use. Olfactory sensitivity was tested with the Sniffin' Sticks Test (SST). Body Odor Disgust Scale (BODS) and Perceived Vulnerability to Disease (PVD) questionnaires were administered for the evaluation of perceived susceptibility to illness along with the Sexual Attitude Scale (SAS) for the evaluation of sexual attitudes. Sexual function was evaluated by the Female Sexual Function Index (FSFI) and International Index of Erectile Function (IIEF) questionnaires, respectively. RESULTS: Overall, a close relationship between sexual function and olfaction in both sexes (P<0.05) was found. In the male sample, better olfactive scores were positively correlated to all IIEF sub-domains but negatively with BMI and age, respectively (P<0.05). Moreover, olfaction was negatively correlated with a restrictive attitude towards sexuality (SAS) (P<0.05). The latter was also positively correlated with PVD (P<0.01). In the female sample, all FSFI subscales but sexual desire was positively correlated with olfaction (P<0.05). CONCLUSIONS: We herein confirm that olfactory capacities positively correlate with sexual behavior in both sexes. In males, these findings were mostly dependent upon increasing age and BMI. In females all domains of sexual function but sexual desire correlated with olfactory capacity, thus suggesting independent neural pathway activation for sexual desire. Finally, better olfactory capacities seem to determine sexual attitudes and disease avoidance behaviors irrespective of gender.

NLRP3-inflammasome activation in male reproductive system diseases.

The nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome, a multiprotein complex belonging to the innate immune system, plays a key role in the chronic inflammatory response, through the production of proinflammatory cytokines, IL-1ß and IL-18, which can elicit their effects through receptor activation, both locally and systemically. Furthermore, it has been demonstrated the interaction of NLRP3 inflammasome components with redox signaling, endoplasmic reticulum stress, and mitochondrial function. A growing literature reported the involvement of NLRP3 platform dysregulation in the pathophysiology of different chronic diseases so it has been proposed that the inhibition of NLRP3 inflammasome could represent a new potential therapeutic target in the management of autoimmune and chronic inflammatory diseases, including cancer. In addition, it has been demonstrated that Sars-CoV2 preferentially activates NLRP3 inflammasome, strongly contributing to the hyperinflammatory state responsible for COVID-19. Recently, in vitro and animal models of both infectious and non-infectious male genital tract diseases affecting fertility, demonstrated the activation of the innate immune system, leading to increased levels of pro-inflammatory cytokines, as well as apoptosis and pyroptosis and that it was likely mediated by activation of the NLRP3 inflammasome. The objective of this review was to analyze the evidence on the role and the mechanisms by which NLRP3-inflammasome pathway activation may exert detrimental effects on the male reproductive system. Furthermore, although the literature data are still discordant, this review also highlighted the possible connection between SARS-CoV-2 infection/NLRP3 activation/oxidative stress and male infertility.

Estrogen-Receptor-Positive Breast Cancer in Postmenopausal Women: The Role of Body Composition and Physical Exercise.

Breast cancer (BC) is the most commonly diagnosed cancer among women worldwide and the most common cause of cancer-related death. To date, it is still a challenge to estimate the magnitude of the clinical impact of physical activity (PA) on those parameters producing significative changes in future BC risk and disease progression. However, studies conducted in recent years highlight the role of PA not only as a protective factor for the development of ER+ breast cancer but, more generally, as a useful tool in the management of BC treatment as an adjuvant to traditional therapies. In this review, we focused our attention on data obtained from human studies analyzing, at each level of disease prevention (i.e., primary, secondary, tertiary and quaternary), the positive impact of PA/exercise in ER+ BC, a subtype representing approximately 70% of all BC diagnoses. Moreover, given the importance of estrogen receptors and body composition (i.e., adipose tissue) in this subtype of BC, an overview of their role will also be made throughout this review.

Epigenetic Modifications Induced by Nutrients in Early Life Phases: Gender Differences in Metabolic Alteration in Adulthood.

Metabolic chronic diseases, also named noncommunicable diseases (NCDs), are considered multifactorial pathologies, which are dramatically increased during the last decades. Noncommunicable diseases such as cardiovascular diseases, obesity, diabetes mellitus, cancers, and chronic respiratory diseases markedly increase morbidity, mortality, and socioeconomic costs. Moreover, NCDs induce several and complex clinical manifestations that lead to a gradual deterioration of health status and quality of life of affected individuals. Multiple factors are involved in the development and progression of these diseases such as sedentary behavior, smoking, pollution, and unhealthy diet. Indeed, nutrition has a pivotal role in maintaining health, and dietary imbalances represent major determinants favoring chronic diseases through metabolic homeostasis alterations. In particular, it appears that specific nutrients and adequate nutrition are important in all periods of life, but they are essential during specific times in early life such as prenatal and postnatal phases. Indeed, epidemiologic and experimental studies report the deleterious effects of an incorrect nutrition on health status several decades later in life. During the last decade, a growing interest on the possible role of epigenetic mechanisms as link between nutritional imbalances and NCDs development has been observed. Finally, because of the pivotal role of the hormones in fat, carbohydrate, and protein metabolism regulation throughout life, it is expected that any hormonal modification of these processes can imbalance metabolism and fat storage. Therefore, a particular interest to several chemicals able to act as endocrine disruptors has been recently developed. In this review, we will provide an overview and discuss the epigenetic role of some specific nutrients and chemicals in the modulation of physiological and pathological mechanisms.

Redundant modulatory effects of proinflammatory cytokines in human osteoblastic cells in vitro.

OBJECTIVES: The aim of our study was to investigate possible interaction of IL-17, TRAIL, and TNF-α in the modulation of osteoblast homeostasis in vitro, using human differentiated osteoblastic Saos-2 cells as in vitro model. METHODS: The effects of these cytokines on osteoblastic cell viability were assessed, by MTT assay, alone or in combination, at different times and concentrations. The effects of IL-17 and TNF-α on the regulatory system of osteoclast activity RANK/RANKL/ OPG were evaluated by Western blot and ELISA techniques in cell culture media. Quantitative expression of RANKL, OPG and pro-inflammatory factors were analysed at the mRNA level by quantitative real time RT-PCR. RESULTS: Effects of IL-17, TNF-α and TRAIL on osteoblastic cell viability indicated that IL-17 alone, or in combination with TNF-α did not alter Saos-2 cell viability. On the other hand, TRAIL, as expected, exhibited time- and concentration-dependent cytotoxicity. The expression both RANKL and OPG were increased at the mRNA level and protein release by IL-17 and TNF-α, either alone or in combination. The analysis of IL-17 and TNF-α on pro-inflammatory molecules mRNA expression, such as CXC family chemokines CXCL-1 and CXCL-5, COX-2 and IL-6 demonstrated an increase in these pro-inflammatory cytokines with cooperative effects of the combination. CONCLUSIONS: Overall, these results suggest that IL-17, TRAIL and TNF-α sustain bone tissue inflammation associated with decrease of calcified component. To do so, they act redundantly each other, to amplify the inflammatory response in the bone. In conclusion, unravelling novel molecular targets within the bone-cytokine network represents a platform for innovative treatment of bone diseases due to immunological diseases such as psoriatic arthritis.

Insulin growth factor-1 correlates with higher bone mineral density and lower inflammation status in obese adult subjects.

PURPOSE: Obesity is a severe public health problem worldwide, leading to an insulin-resistant state in liver, adipose, and muscle tissue, representing a risk factor for type 2 diabetes mellitus, cardiovascular diseases, and cancer. We have shown that abdominal obesity is associated with homeostasis derangement, linked to several hormonal and paracrine factors. Data regarding potential link between GH/IGF1 axis, bone mineral density, and inflammation in obesity are lacking. Thus, aim of this study was to evaluate correlation among IGF-1, BMD, and inflammation in obese individuals. METHODS: The study included 426 obese subjects, mean age 44.8 ± 14 years; BMI 34.9 ± 6.1. Exclusion criteria were chronic medical conditions, use of medications affecting bone metabolism, hormonal and nutritional status, recent weight loss, and prior bariatric surgery. Patients underwent measurements of BMD and body composition by DEXA and were evaluated for hormonal, metabolic profile, and inflammatory markers. RESULTS: In this population, IGF-1 was inversely correlated with abdominal FM% (p < 0.001, r 2 = 0.12) and directly correlated with osteocalcin (OSCA) (p < 0.002, r 2 = 0.14). A negative correlation was demonstrated between IGF-1 levels and nonspecific inflammatory index, such as fibrinogen (p < 0.01, r 2 = 0.04) and erythrocyte sedimentation rate (p < 0.0001, r 2 = 0.03). IGF-1 was directly correlated with higher BMD, at both lumbar (p < 0.02, r 2 = 0.03) and femoral site (p < 0.04, r 2 = 0.03). CONCLUSIONS: In conclusion, our results show that higher levels of serum IGF-1 in obese patients correlate with lower inflammatory pattern and better skeletal health, as demonstrated by higher BMD and osteocalcin levels. These results lead to speculate the existence of a bone-adipose-muscle interplay modulating energy homeostasis, glucose, bone metabolism, and chronic inflammation in individuals affected by abdominal obesity.

Tadalafil improves lean mass and endothelial function in nonobese men with mild ED/LUTS: in vivo and in vitro characterization.

PURPOSE: Phosphodiesterase type-5 inhibitor administration in diabetic men with erectile dysfunction (ED) is associated with reduced waist circumference. We evaluated potential effects of daily tadalafil administration on body composition and investigated its possible mechanism(s) of action in C2C12 skeletal muscle cells in vitro. METHODS: Forty-three men on stable caloric intake (mean age 48.5 ± 7; BMI 25.5 ± 0.9 kg/m2) complaining mild ED and/or low urinary tract symptoms (LUTS) were randomly assigned to receive tadalafil (TAD) 5 mg/daily (once-a-day=OAD-TAD; n = 23) or 20 mg on-demand (on-demand=OD-TAD; n = 20) for 2 months. Primary outcomes were variations of body composition measured by Dual-energy X-ray absorptiometry; secondary outcomes were ED/LUTS questionnaire scores along with hormone (testosterone, estradiol, insulin) and endothelial function (Endopat2000) variations. RESULTS: OAD-TAD increased abdominal lean mass (p < 0.01) that returned to baseline after 2 months withdrawal. LUTS scores improved (p<0.01) in OD-TAD while ED scores improved (p < 0.01) in both groups. We found significant improvements in endothelial function (p < 0.05) that directly correlated with serum insulin (p < 0.01; r = 0.3641) and inversely correlated with estradiol levels (p < 0.01; r = 0.3655) even when corrected for potential confounders. Exposure of C2C12 cells upon increasing tadalafil concentrations (10-7 to 10-6 M) increased total androgen receptor mRNA and protein expression as well as myogenin protein expression after 24 and 72 h (2.8 ± 0.4-fold and 1.4 ± 0.02-fold vs. control, respectively, p < 0.05). CONCLUSIONS: Daily tadalafil improved lean mass content in non-obese men probably via enhanced insulin secretion, estradiol reduction, and improvement of endothelial function in vivo. The in vitro increased myogenin and androgen receptor protein expression in skeletal muscle cells suggests a translational action of phosphodiesterase type-5 on this receptor.

Physical activity and hypocaloric diet recovers osteoblasts homeostasis in women affected by abdominal obesity.

Obesity is a multifactorial disease linked to metabolic chronic disorders such as diabetes, and hypertension. Also, it has recently been associated with skeletal alterations and low bone mineral density. We previously demonstrated that exposure of osteoblasts to sera of sedentary subjects affected by obesity alters cell homeostasis in vitro, leading to disruption of intracellular differentiation pathways and cellular activity. Thus, the purpose of the present study has been to evaluate whether sera of sedentary obese women, subjected to physical activity and hypocaloric diet, could recover osteoblast homeostasis in vitro as compared to the sera of same patients before intervention protocol. To this aim, obese women were evaluated at time 0 and after 4, 6, and 12 months of individualized prescribed physical activity and hypocaloric diet. Dual-energy-X-ray absorptiometry measurements were performed at each time point, as well as blood was collected at the same points. Cells were incubated with sera of subjects before and after physical activity as described: obese at baseline and after for 4, 6, and 12 months of physical activity and nutritional protocol intervention. Osteoblasts exposed to sera of patients, who displayed increased lean and decreased fat mass (from 55.5 ± 6.5 to 57.1 ± 5.6% p ≤ 0.05; from 44.5 ± 1.1 to 40.9 ± 2.6% p ≤ 0.01 respectively), showed a time-dependent increase of Wnt/ß-catenin signaling, versus cells exposed to sera of obese patients before intervention protocol, suggesting recovery of osteoblast homeostasis upon improvement of body composition. An increase in ß-catenin nuclear accumulation and nuclear translocation was also observed, accompanied by an increase in Adiponectin receptor 1 protein expression, suggesting positive effect on cell differentiation program. Furthermore, a decrease in sclerostin amount and an increase of type 1 procollagen amino-terminal-propeptide were depicted as compared to baseline, proportionally to the time of physical activity, suggesting a recovery of bone remodeling modulation and an increase of osteoblast activity induced by improvement of body composition. In conclusion, our results show for the first time that sera of obese sedentary women who increased lean mass and decreased fat mass, by physical activity and hypocaloric diet, rescue osteoblasts differentiation and activity likely due to a reactivation of Wnt/ß-catenin-pathway, suggesting that a correct life style can improve skeletal metabolic alteration induced by obesity.

CAG repeat testing of androgen receptor polymorphism: is this necessary for the best clinical management of hypogonadism?

INTRODUCTION: It is controversial whether or not testing the length of the androgen receptor polymorphism in clinical practice is useful for correct diagnosis and treatment of hypogonadism. AIM: To describe the molecular and clinical implications of testing the length of the androgen receptor polymorphism for treatment of hypogonadism in both male and female subjects. METHODS: A systematic Medline search was conducted using several terms related to and including the terms "androgen receptor," "CAG-repeat polymorphism," "male hypogonadism," "female hypogonadism," and "neurodegenerative disease." MAIN OUTCOME MEASURES: Clinical evidence that demonstrates the importance of CAG repeat number investigation in male and female hypogonadism. RESULTS: A thorough review of the clinical utility of CAG repeat polymorphism investigation in men and women with hypogonadism is presented. CONCLUSIONS: The role of AR CAG repeat number investigation in hypogonadism (male and female) is not yet established in the clinical practice. In both sexes, a role during clinical management of hormonal replacement therapies may be hypothesized, but the CAG repeat number's relationship with the presence or absence of hypogonadal symptoms remains unclear. Pharmacogenomic investigations of the AR polymorphism may be a future option to tailor testosterone titration individually and to better identify subjects as potentially more or less responsive to treatments; also, investigation may be important to individually predict beneficial and side effects in special subpopulations, specifically, obese men and postmenopausal women.

Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study.

We evaluated the effects of long-term testosterone replacement therapy (TRT) on the bone mineral density (BMD) in obese patients with metabolic syndrome (MS) and late-onset hypogonadism (LOH). Sixty men (mean age 57 ± 10) with low serum testosterone (T < 320 ng/dL) and MS regardless the presence of osteoporosis were enrolled. Forty men received intramuscular T-undecanoate (TU) four times/year for 36 months and 20 age-matched hypogonadal men with MS in whom T treatment was contraindicated were used as controls. Hormonal, biochemical markers, vertebral and femoral BMD by dual-energy x-ray absorptiometry were measured. At baseline, overall patients had mild osteopenia (lumbar BMD= 0.891 ± 0.097 g/cm(2); femoral BMD= 0.847 ± 0.117 g/cm(2)). TU induced a significant improvement of bone mass after 36 months (lumbar BMD=1.053 ± 0.145 g/cm(2); p < 0.002; femoral BMD=0.989 ± 0.109; p < 0.003 g/cm(2)) with a 5%/year increase and a significant reduction in hs-CRP without changes in body mass index. A direct relationship between serum T and BMD increments at the lumbar (r(2) = 0.66, p < 0.0001) and femoral (r(2) =0.52, p < 0.0001) sites was demonstrated. Study adherence was 50% without serious side effects. Long-term TRT in middle-aged men with LOH and MS determines a significant increase in both vertebral and femoral BMD related to increased serum T levels, probably independently from estradiol modifications.

Testosterone:estradiol ratio changes associated with long-term tadalafil administration: a pilot study.

INTRODUCTION: It has been reported that lack of sexual activity due to erectile dysfunction (ED) may be associated with testosterone (T) decline. AIM: To investigate whether the known changes in sex hormones associated with resumption of sexual activity are sustained in the long term. MAIN OUTCOME MEASURES: Primary endpoints were variations from baseline of steroid hormones: total T, free T (f T), and estradiol (E). Secondary endpoints were variations of erectile function domain scores at International Index of Erectile Function-5 (IIEF-5). METHODS: In an open-label fashion, 20 patients (mean age 54.8 +/- 8.4 years) received tadalafil 10-20 mg on demand for 12 months. Exclusion criteria were those reported for phosphodiesterase inhibitors, including hypogonadism and hyperprolactinemia. RESULTS: Tadalafil assumption was safe and well tolerated (overall adverse effects in 15% of patients) and none discontinued medication. A significant decrease in E levels occurred at the end of the study (from 19.9 +/- 9.6 to 16.6 +/- 8.1 ng/dL, P = 0.042 vs. baseline), with parallel increase in the T:E ratio (26.3 +/- 15.3 to 32.6 +/- 17.7, P = 0.05), whereas no changes in T and f T serum levels were observed, respectively (411.4 +/- 131.4 to 434.2 +/- 177.1 ng/dL and 47.7 +/- 15.3 to 49.9 +/- 19.1 pmol/L, not significant). Interestingly, nonparametric subgroup analysis for related samples revealed that E decrease was detectable only in lean (N = 14) but not in obese (N = 6, body mass index > 27.5 kg/m2) subjects (17.8 +/- 10.1 vs. 13.5 +/- 6.8, P < 0.05). A net increase in IIEF-5 scores was observed at the endpoint (13.7 +/- 5.9 vs. 25.7 +/- 2.9, P < 0.0001). CONCLUSIONS: Sustained improvement in sexual function after 12 months of tadalafil administration is associated with increased T:E ratio mainly related to reduction of E levels. We hypothesize that androgen-estrogen cross-talk and possible inhibition of aromatase activity during chronic exposure to tadalafil might have a role in the regulation of erectile function.