Fracture is an under-recognized but common complication of diabetes mellitus, with an incidence approaching twofold in type 2 diabetes mellitus (T2DM) and up to sevenfold in type 1 diabetes mellitus (T1DM) compared with that in the general population. Both T1DM and T2DM induce chronic hyperglycaemia, leading to the accumulation of advanced glycosylation end products that affect osteoblast function, increased collagen crosslinking and a senescence phenotype promoting inflammation. Together with an increased incidence of microvascular disease and an increased risk of vitamin D deficiency, these factors reduce bone quality, thereby increasing bone fragility. In T1DM, reduced anabolic stimuli as well as the presence of autoimmune conditions might also contribute to reduced bone mass and increased fragility. Diabetes mellitus is the most common cause of kidney failure, and fracture risk is exacerbated when chronic kidney disease (CKD)-related mineral and bone disorders are superimposed on diabetic changes. Microvascular pathology, cortical thinning and trabecular deterioration are particularly prominent in patients with T1DM and CKD, who suffer more fragility fractures than do other patients with CKD. This Review explores the pathophysiology of bone fragility in patients with diabetes mellitus and CKD and discusses techniques to predict fracture and pharmacotherapy that might reduce fracture risk.

Sedentary behavior has emerged as a potential risk factor for various health issues, including hormonal imbalances like testosterone deficiency (TD). However, the relationship between sedentary time and TD remains underexplored, especially with respect to the complex biological mechanisms underlying this association. This study aimed to examine the association between sedentary time and TD in adult males.

This cross-sectional study analyzed data from the National Health and Nutrition Examination Survey 2011-2016. A total of 6057 male participants aged 20 years and older were included. Sedentary time was categorized into quartiles, and TD was defined as serum testosterone levels below 300 ng/dL. Logistic regression models were employed to assess the association between sedentary time and TD, adjusting for demographic, lifestyle, and health-related covariates. Restricted cubic spline (RCS) analysis and segmented regression were also conducted to explore potential non-linear relationships and thresholds. Subgroup analyses were performed to examine the consistency of associations across various groups.

The analysis revealed a significant positive association between sedentary time and TD. Prolonged sedentary behaviour was consistently associated with higher odds of TD across all models (all p < 0.001). RCS analysis showed a significant non-linear relationship, particularly as sedentary time exceeded 4.5 h per day, with a marked increase in the likelihood of TD (p-non-linear = 0.027). Subgroup analysis indicated that this association was most pronounced in Non-Hispanic Whites, current smokers, and drinkers, and was weaker in individuals with diabetes, where the association lost statistical significance after full adjustment.

This study identifies a significant association between prolonged sedentary behaviour and a higher risk of TD, suggesting that sedentary behavior may play a key role in the development of TD, particularly in specific high-risk populations.

In people with diabetes, the effect of sleeve gastrectomy on impaired sperm parameters, hormonal profile, and testis tissue remains controversial to some extent.

This study aimed to investigate the effects of sleeve gastrectomy on the hormonal profile, sperm parameters, and testis tissue in infertile rats with type II diabetes mellitus (TIIDM). This study included 32 rats with TIIDM with or without sleeve gastrectomy. All the rats underwent sperm, testis tissue, and serum hormone profile analyses before and 8 weeks after surgery.

There was a significant correlation between weight loss after sleeve gastrectomy and a decrease in glucose profile (p < 0.05). In the hormonal profile, testosterone improved significantly after 8 weeks following sleeve gastrectomy. There was a significant increase in sperm count (p < 0.05) and improved sperm morphology during the follow-up after sleeve gastrectomy. The analysis also showed significant changes in testis tissue after surgery.

Sleeve gastrectomy significantly improved testosterone deficiency, testis tissue, and sperm count in rats with TIIDM. Further prospective clinical studies are needed to show how bariatric surgery affects infertility in patients with TIIDM.

Type 2 diabetes mellitus (T2DM) is a well-established risk factor for erectile dysfunction (ED); the precise impact of glycemic control on male sexual function, including hormonal profiles, remains to be fully elucidated. This study aims to investigate the specific relationship between the degree of glycemic control in T2DM patients and the severity of both hormonal imbalances and ED.

A comparative study between two arms - relatively controlled and uncontrolled type 2 diabetic men. We considered a relatively controlled diabetes mellitus (DM), patient with glycated hemoglobin (HbA1c) of 7.9 mmol/L or less. Laboratory results for type 2 diabetic men presenting with ED were studied after stratifying them into the two groups - relatively controlled DM (HBA1c of 7.9 mmol/L or less) and uncontrolled DM (HBA1c equal to or more than 8 mmol/L). Retrieved data include patient's demographics, body mass index (BMI), hormonal profile, Complete Blood Count (CBC), lipid profile, prostate-specific antigen (PSA), urate, Vitamin D level, and the severity of ED as assessed by the International Index of Erectile Function (IIEF) scores. Statistical analysis was done to compare between the two groups using SPSS version 20. P < 0.05 was considered statistically significant.

This study found a significant association between poor glycemic control (HbA1c ≥8%) and ED in diabetic men (P < 0.0001). Longer diabetes duration correlated with both ED and poor glycemic control, suggesting a potential causal link. Well-controlled diabetics had lower BMI (P = 0.001), higher free testosterone (FT) (P = 0.0002), lower sex hormone-binding globulin (SHBG) (P = 0.0001), and higher IIEF scores (P < 0.0001) compared to the poorly controlled group, indicating better erectile function and potential benefits of weight management and improved testosterone availability. While follicle-stimulating hormone and luteinizing hormone levels were not significantly affected, Vitamin D levels were higher in the well-controlled group (P = 0.0002), suggesting a potential role for Vitamin D in ED, although further investigation is needed. Cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, PSA, thyroid-stimulating hormone, and T4 levels did not show significant differences but might warrant further exploration.

This study demonstrates an association between poor glycemic control and impaired erectile function in diabetic men. Lower FT levels, elevated SHBG, and increased BMI were observed in the poorly controlled group, potentially contributing to ED. Conversely, good glycemic control correlated with improved erectile function, potentially due to higher FT availability and Vitamin D levels.

Male hypogonadism, which is characterized by low testosterone levels, has a significant impact on male sexual function, overall health, and fertility. Testosterone replacement therapy (TRT) is the conventional treatment for this condition, but it has potential adverse effects and is not suitable for men seeking to conceive. Testosterone plays an essential role in male sexual function, metabolism, mood, and overall well-being. Clomiphene citrate, a drug originally developed for female infertility, has recently gained attention as an off-label treatment for male hypogonadism. By blocking the negative feedback of estrogen on the hypothalamus and pituitary glands, clomiphene stimulates gonadotropin secretion, leading to increased endogenous testosterone production, which, in turn, improves sperm parameters and fertility and alleviates the symptoms of hypogonadism. Regarding the safety profile of clomiphene compared with TRT, clomiphene appears to confer a lower risk than TRT, which is associated with adverse effects such as polycythemia. Furthermore, combination therapy with clomiphene and anastrozole or human chorionic gonadotropin has been investigated as a potential approach to enhancing the effectiveness of treatments for improving hypogonadism symptoms. In conclusion, clomiphene citrate may offer a promising alternative to TRT for men with hypogonadism, particularly those desiring fertility preservations. However, its long-term efficacy and safety remain inadequately understood. Future research should focus on exploring the benefits of combination therapies and personalized treatment strategies based on individual patient characteristics.

In epidemiological studies, lowered serum testosterone concentrations are common in men with obesity, prediabetes, and established type 2 diabetes (T2D). In men with prediabetes, lowered serum testosterone also predicts a future risk of T2D in men. Administration of testosterone consistently reduces fat mass and increases skeletal muscle mass-body compositional changes expected to be metabolically favorable. In men with established T2D, the effects of testosterone treatment on glycemic measures are inconsistent. Irrespective of baseline serum testosterone concentration in men with prediabetes or newly diagnosed early-onset T2D, testosterone treatment prescribed in conjunction with a lifestyle program has been reported to reduce the risk of T2D by 40% after 2 years, suggesting that either a lifestyle program is required to facilitate the glycemic benefit of testosterone treatment and/or that testosterone treatment has more favorable effects on glycemia in men early in the evolution or onset of the disease. The durability of the benefit and longer-term safety of testosterone treatment have not been established. Therefore, more studies are required before testosterone treatment can be recommended for the prevention and/or treatment of men with or at elevated risk of T2D who do not have hypogonadism due to an established disease of the hypothalamic-pituitary-testicular axis.

Male obesity is one of the most associated factors with substandard testosterone levels. However, there is growing evidence linking low testosterone levels to insulin resistance and diabetic complications. We aimed to study the impact of diabetes mellitus on testosterone levels and to assess the correlation of various clinical and biochemical factors with hypogonadism.

This case-control study was conducted on 160 adult males categorized into four equal groups (40 each); Group A: lean men with T2DM, Group B: obese with T2DM, Group C: lean with normal glycemic profile, Group D: obese with normal glycemic profile. Serum total testosterone (TT), SHBG and HbA1c have been measured. Free testosterone (cFT) and HOMA-IR were calculated.

A significant negative correlation of serum TT and cFTwith BMI (r -0.16, p 0.04/ r -0.26, p < 0.001, respectively) and with waist circumference (WC) (r -0.23, p 0.003 and r -0.3, p < 0.001, respectively). A significant decrease in TT and cFT in the diabetes group versus the non-diabetes one (p < 0.001 for both). TT level was significantly lower in the diabetic lean group than in the non-diabetic lean (p < 0.001), and even significantly lower than in the non-diabetic obese (p < 0.001). TT level in the diabetic obese group was lower than in the non-diabetic obese (p < 0.001). The same for cFT level, lower in the diabetic lean group than in non-diabetic lean (p < 0.001) and lower in the diabetic obese than in the non-diabetic obese (p < 0.001). Concomitant significant reduction in SHBG in the diabetes group (p < 0.001). Linear regression analysis revealed that TT significantly correlated with HOMA-IR. HOMA-IR with WC, age and the duration of diabetes correlated significantly with cFT. In our model, HOMA-IR and HbA1c accounted for approximately 51.3% of TT variability (adjusted R-squared 0.513).

The impact of T2DM on serum testosterone levels was more significant than that of obesity. Our study showed a decrease in SHBG together with cFT among the diabetes group. Hypogonadism is significantly correlated to insulin resistance and poor glycemic control, which implies another perspective on the impact of suboptimal glycemic control on the development of hypogonadism.

Type 2 diabetes mellitus (T2DM) is a risk factor for male infertility, but the underlying molecular mechanisms remain unclear. Advanced glycation end products (AGEs) are pathogenic molecules for diabetic vascular complications. Here, we investigated the effects of the DNA aptamer raised against AGEs (AGE-Apt) on testicular and sperm abnormalities in a T2DM mouse model. KK-Ay (DM) and wild-type (non-DM) 4- and 7-week-old male mice were sacrificed to collect the testes and spermatozoa for immunofluorescence, RT-PCR, and histological analyses. DM and non-DM 7-week-old mice were subcutaneously infused with the AGE-Apt or control-aptamer for 6 weeks and were then sacrificed. Plasma glucose, testicular AGEs, and Rage gene expression in 4-week-old DM mice and plasma glucose, testicular AGEs, oxidative stress, and pro-inflammatory gene expressions in 7-week-old DM mice were higher than those in age-matched non-DM mice, the latter of which was associated with seminiferous tubular dilation. AGE-Apt did not affect glycemic parameters, but it inhibited seminiferous tubular dilation, reduced the number of testicular macrophages and apoptotic cells, and restored the decrease in sperm concentration, motility, and viability of 13-week-old DM mice. Our findings suggest that AGEs-Apt may improve sperm abnormality by suppressing AGE-RAGE-induced oxidative stress and inflammation in the testes of DM mice.

Diabetes has a significant global prevalence. Chronic hyperglycemia affects multiple organs and tissues, including bones. A large number of diabetic patients develop osteoporosis; however, the precise relationship between diabetes and osteoporosis remains incompletely elucidated. The activation of the AGE-RAGE signaling pathway hinders the differentiation of osteoblasts and weakens the process of bone formation due to the presence of advanced glycation end products. High glucose environment can induce ferroptosis of osteoblasts and then develop osteoporosis. Hyperglycemia also suppresses the secretion of sex hormones, and the reduction of testosterone is difficult to effectively maintain bone mineral density. As diabetes therapy, thiazolidinediones control blood glucose by activating PPAR-γ. Activated PPAR-γ can promote osteoclast differentiation and regulate osteoblast function, triggering osteoporosis. The effects of metformin and insulin on bone are currently controversial. Currently, there are no appropriate tools available for assessing the risk of fractures in diabetic patients, despite the fact that the occurrence of osteoporotic fractures is considerably greater in diabetic individuals compared to those without diabetes. Further improving the inclusion criteria of FRAX risk factors and clarifying the early occurrence of osteoporosis sites unique to diabetic patients may be an effective way to diagnose and treat diabetic osteoporosis and reduce the risk of fracture occurrence.

Insulin resistance (IR) is strongly correlated with the decreased deficiency of testosterone levels in males. The metabolic score for insulin resistance (METS-IR) index is regarded as an innovative measure for the assessment on IR. The research aims to explore the correlation between the METS-IR index and the testosterone levels in males.

In this study, a cross-sectional design was made through the data obtained from the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2020. Besides, the METS-IR index was derived from serum triglyceride levels, fasting plasma glucose, HDL-C and BMI.

A total of 2082 participants were included in the final analysis. After controlling for confounding variables, it was found that METS-IR was independently and negatively correlated with testosterone levels (β = -3.88, 95% CI = -4.49, -3.27, P < 0.001). As shown by the generalized smooth curve fitting, METS-IR had a linear correlation with testosterone levels without threshold or saturation effects, which was consistently observed across all subgroups through stratified analysis (all P > 0.05). As revealed by the analysis on the ROC curve, the area under the curve (AUC) for the METS-IR index (0.732, 95% CI = 0.705, 0.760) was significantly larger than that of homeostatic model assessment of insulin resistance (HOMA-IR), TG/HDL ratio, triglyceride-glucose index (TyG) and body mass index (BMI).

The findings suggest a negative relationship between the METS-IR index and the testosterone levels in male adults. Furthermore, the METS-IR index demonstrates superior predictive ability for testosterone deficiency in comparison to HOMA-IR, TG/HDL ratio, TyG and BMI.

It is known that many diabetic patients experience testicular atrophy. This study sought to investigate the effect of 4-hexylresorcinol (4HR) on testicular function in rats with streptozotocin (STZ)-induced diabetes, focusing on testicular weight, sperm motility, histological alterations, and serum testosterone levels to understand the efficacy of 4HR on testes. Our findings reveal that 4HR treatment significantly improves testicular health in diabetic rats. Notably, the STZ group exhibited a testicular weight of 1.22 ± 0.48 g, whereas the STZ/4HR group showed a significantly enhanced weight of 1.91 ± 0.26 g (p < 0.001), aligning closely with the control group's weight of 1.99 ± 0.17 g and the 4HR group's weight of 2.05 ± 0.24 g, indicating no significant difference between control and 4HR groups (p > 0.05). Furthermore, the STZ/4HR group demonstrated significantly improved sperm motility compared to the STZ group, with apoptotic indicators notably reduced in the STZ/4HR group relative to the STZ group (p < 0.05). These results underscore the therapeutic potential of 4HR for maintaining testicular function under diabetic conditions.

Sexual dysfunction is a common but underestimated disorder of diabetic patients of both genders, entailing specific and complex pathogenesis and severely affecting reproductive health and quality of life. Hyperglycemia, dyslipidemia, hypertension, obesity, aging, and psychological factors underlie its pathogenesis. A large body of evidence indicates that advanced glycation end products and oxidative stress have a distinct impact on the pathogenesis of diabetes and its complications, including hypogonadism, which is closely related to sexual dysfunction. Advanced glycation end products seem to affect sexual function either directly by accumulation in various regions of the reproductive system and/or correlation or indirectly through oxidative stress induction via several mechanisms. They are also involved in the pathogenesis of diabetic complications, which are related to sexual dysfunction. Herein, we review the issue of sexual dysfunction in diabetic males and females, with special emphasis on the impact of advanced glycation end products in the pathogenesis of sexual dysfunction, the relationship of advanced glycation end products with low testosterone levels in diabetic subjects, which account for the proportion of disorder and the available therapeutic interventions.

Type 2 diabetes mellitus (T2DM) is an endocrine-related disease with an increasing incidence worldwide. Male sexual dysfunction is common in diabetic patients. Therefore, we designed a Mendelian randomization (MR) study to investigate the association of type 2 diabetes and 3 glycemic traits with testosterone levels.

Uncorrelated single nucleotide polymorphisms (SNPs) associated with T2DM (N = 228), fasting insulin (N = 38), fasting glucose (N = 71), and HbA1c (N = 75) at the genome-wide significance were selected as instrument variables. Genetic associations with testosterone levels (total testosterone, TT, bioavailable testosterone, BT, and sex hormone-binding globulin, SHBG) were obtained from the UK Biobank studies and other large consortia. Two-sample MR analysis was used to minimize the bias caused by confounding factors and response causality. Multivariable MR analysis was performed using Body mass index (BMI), Triglycerides (TG), LDL cholesterol (LDL), and adiponectin to adjust for the effects of potential confounders.

Type 2 diabetes mellitus was associated with the decrease of total testosterone (β: -0.021,95%CI: -0.032, -0.010, p<0.001) and sex hormone binding globulin (β: -0.048,95%CI: -0.065, -0.031, p<0.001). In males, total testosterone (β: 0.058, 95% CI: 0.088, 0.028, p < 0.001) decreased. In females, it was associated with an increase in bioavailable testosterone (β: 0.077,95%CI: 0.058,0.096, p<0.001). Each unit (pmol/L) increase in fasting insulin was associated with 0.283nmol/L decrease in sex hormone-binding globulin (95%CI: -0.464, -0.102, p=0.002) and 0.260nmol/L increase in bioavailable testosterone (95%CI: -0.464, -0.102, p= 0.002). In males, sex hormone binding globulin decreased by 0.507nmol/L (95%CI: -0.960, -0.054, p= 0.028) and bioavailable testosterone increased by 0.216nmol/L (95%CI: 0.087,0.344, p= 0.001). In females, sex hormone binding globulin decreased by 0.714 nmol/L (95%CI: -1.093, -0.335, p<0.001) and bioavailable testosterone increased by 0.467nmol/L (95%CI: 0.286,0.648, p<0.001). Each unit (%) increase in HbA1c was associated with 0.060nmol/L decrease in sex hormone-binding globulin (95%CI: -0.113, -0.007, p= 0.026). In males, total testosterone decreased by 0.171nmol/L (95%CI: -0.288, -0.053, p=0.005) and sex hormone binding globulin decreased by 0.206nmol/L (95%CI: -0.340, -0.072, p=0.003). Total testosterone increased by 0.122nmol/L (95%CI: 0.012,0.233, p=0.029) and bioavailable testosterone increased by 0.163nmol/L (95%CI: 0.042,0.285, p=0.008) in females.

Using MR Analysis, we found independent effects of type 2 diabetes, fasting insulin, and HbA1c on total testosterone and sex hormone-binding globulin after maximum exclusion of the effects of obesity, BMI, TG, LDL and Adiponectin.

The prevalence of 'low bone mineral density (BMD)' in Type 2 diabetes (T2DM), especially stratified by body mass index, is seldom reported. The relation of the euthyroid range and low BMD in T2DM remains to be further elucidated.

We aim to investigate the thyroid hormones' impact on BMD among euthyroid patients with T2DM.

A total of 1452 hospitalized T2DM patients with normal thyroid function (43.6% males aged over 50 and 56.4% postmenopausal females) were enrolled in this cross-sectional study. BMD was measured at lumbar spine by GE lunar dual-energy X-ray absorptiometry system, and 'low BMD' was defined as T-score <-1.0 SD. The prevalence of 'low BMD' was compared between obese and nonobese (body mass index < 25 kg/m2) groups for both sexes, and the relation of low BMD and free T4 quartiles was explored by multiple logistic regression.

The general prevalence of 'low BMD' was 12.3% for male patients aged over 50 (15.5% in the nonobese group and 8.0% in the obese group) and 49.8% for postmenopausal females (56.7% in the nonobese group and 48.9% in the obese group). After adjustment in multiple linear regression, free T4 level remained significantly related to decreased BMD in nonobese male subgroup. Multiple logistic regression revealed that BMD of the highest free T4 quartile (1.12-1.48 ng/dL) decreased significantly than other three quartiles after adjusting for confounding factors including age, body mass index, serum calcium and creatinine level, fasting glucose, alkaline phosphatase, glycosylated hemoglobin, total cholesterol, and smoking history (OR = 2.724, 95% CI = 1.085-6.840, p = 0.033). No significant relation was found in obese male or postmenopausal female groups.

High-normal free T4 is a potential independent risk factor for 'low BMD' in nonobese male T2DM patients aged over 50. Close attention should be paid to thyroid function profile, even within normal range, in nonobese men with underlying higher fracture risks on diabetes status.

Although testosterone replacement in men with classic hypogonadism due to an identified pathology of the hypothalamic-pituitary-testicular axis is uncontroversial, the role of testosterone treatment for men with age-related declines in circulating testosterone is unclear. This is due to the lack of large, long-term testosterone therapy trials assessing definitive clinical endpoints. However, men ≥50 years of age, particularly those who have a body mass index >25 kg/m2 and multiple comorbidities, commonly present with clinical features of androgen deficiency and low serum testosterone concentrations. Clinicians are faced with the question whether to initiate testosterone therapy, a difficult dilemma that entails a benefit-risk analysis with limited evidence from clinical trials. Using a case scenario, we present a practical approach to the clinical assessment and management of such men.

Follicle-stimulating hormone (FSH) was negatively associated with nonalcoholic fatty liver disease (NAFLD) in women older than 55 years old. People with obesity and diabetes had higher prevalence of NAFLD. Thus, we aimed to explore the association between FSH and NAFLD in postmenopausal women with type 2 diabetes mellitus (T2DM).

A total of 583 postmenopausal women with T2DM with an average age of 60.22 ± 6.49 were recruited in this cross-sectional study through January 2017 to May 2021. Anthropological data, biochemical indexes, and abdominal ultrasound results were retrospectively collected. Abdominal ultrasound was used to diagnose NAFLD. FSH was measured by enzymatic immunochemiluminescence and divided into tertiles for further analysis. The logistic regression was used to assess the association of FSH with prevalent NAFLD. Likelihood ratio tests were used to assess the interactions between groups.

A total of 332 (56.94%) postmenopausal women had NAFLD. Compared with postmenopausal women in the lowest tertile of FSH, postmenopausal women in the highest tertile of FSH had lower prevalence of NAFLD (p < .01). After adjusting for age, diabetes duration, metabolism-related indicators, and other sex-related hormones, FSH was inversely associated with NAFLD (odds ratio: 0.411, 95% confidence intervals: 0.260-0.651, p < .001). In subgroup analysis, there were no significant interactions of FSH with strata of metabolic factors on the association of NAFLD.

FSH was negatively and independently associated with NAFLD in postmenopausal women with type 2 diabetes mellitus. It might be a potential index for screening and identifying individuals with high risk of NAFLD in postmenopausal women.

This review explores the challenges in the diagnosis of hypogonadotropic hypogonadism, the transition of care from paediatric to adult care and the considerable health implications of this condition. The role gynaecologists and general practitioners have in managing hormone replacement therapy and reproductive potential is also highlighted. The fertility treatment options, which include ovulation induction with gonadotrophins and in-vitro fertilisation, are discussed in detail along with highlighting the fact that anovulation and markers of low ovarian reserve prior to priming treatment may not be reflective of poor reproductive potential. The holistic management of women with hypogonadotropic hypogonadism is still not standardised and evidence for subfertility management is scarce. This review aims to highlight this concern and provide guidance by evaluating current evidence.

The impact of utilizing both symptoms as well as biochemically confirmed androgen deficiency in diagnosis of hypogonadism among type 2 diabetic men is relatively less studied. Furthermore, various determinants of hypogonadism in these men especially the role of insulin resistance and hypogonadism were studied.

This is a cross sectional study of 353 T2DM men aged 20-70 years of age. Hypogonadism was defined by taking both symptoms as well as calculated testosterone levels. Symptoms were defined using androgen deficiency in ageing male (ADAM) criteria. Various metabolic and clinical parameters were assessed and evaluated with regards to presence or absence of hypogonadism.

Among 353 patients, 60 had both symptoms as well as biochemical evidence of hypogonadism. Assessment of calculated free testosterone but not total testosterone identified all such patients. Body mass index, HbA1c, fasting triglyceride level and HOMA IR inversely correlated with calculated free testosterone. We found that insulin resistance (HOMA IR) was independently associated with hypogonadism (odds ratio=1.108).

Assessment of both symptoms of hypogonadism and calculated free testosterone represents a better way for correct identification of hypogonadal diabetic men. Insulin resistance has a strong association with hypogonadism independent of obesity and complication status of diabetes.

This study aimed to explore the proportion of andropause in male patients with type 2 diabetes using an aging male symptoms scale and assess the clinical outcome of testosterone supplementation in patients with deficient testosterone levels at a tertiary care hospital.

Male patients with diabetes and total serum testosterone levels (≤12 nmol/L) were included in the study. Patients with testosterone supplementation, the standard of care among testosterone-deficient male patients, were included in the study (n = 35). Those not exposed to testosterone supplementation were considered controls (n = 35) and reassessed over 14 weeks for aging male symptom scores (AMS).

The prevalence of andropause among the participants was 11% (117/1057). Data was analyzed as per protocol analysis. Exposure group had a frequency of 25.80%, and 19.35% in moderate and severe symptoms of AMS scores. Non-exposure group had frequency of 26.66% and 23.34% in moderate and severe symptoms of AMS scores. A significant mean difference (t = -2.93, P-value <0.05) was noted between exposure and non-exposure to testosterone supplementation.

Results concluded that andropause is prevalent in patients with type 2 diabetes and low testosterone levels. Testosterone therapy affects aging andropausal symptoms such as the feeling of general well-being, joint pain and muscular ache, sleep problems, anxiety, and libido among patients with type 2 diabetes.

Erectile dysfunction is associated with diabetes mellitus with an estimated prevalence of 52.5% in the diabetic population. The first-line therapy for erectile dysfunction is phosphodiesterase type 5 inhibitors, but data suggest that diabetic men may be less responsive than non-diabetic men. Thus, other treatments, including intracavernosal injections, intraurethral prostaglandin, vacuum erection devices and penile prosthetic surgery, should be considered in management of diabetic men with erectile dysfunction refractory to phosphodiesterase type 5 inhibitors. Furthermore, combination therapy of phosphodiesterase type 5 inhibitors and other oral treatments such as arginine or l-carnitine may have synergistic effects resulting in better outcomes. In addition, there are novel therapies such as low-intensity shockwave therapy and stem-cell therapy, which may also be effective in targeted treatment modalities. Furthermore, studies suggest that erectile dysfunction can be improved by targeting concurrent comorbidities or metabolic diseases such as depression, hypertension, hypogonadism, and dyslipidaemia. We present an evidence-based narrative review focusing on the management of erectile dysfunction in diabetic men who have not responded to phosphodiesterase type 5 inhibitors.

Both clinicians and patients should be aware of the different management options in diabetic patients who have not responded to phosphodiesterase type 5 inhibitors.

There has been little recognition within the medical community of the health impact of testosterone (T) deficiency (TD), also known as hypogonadism, and the substantial benefits of testosterone therapy (TTh) on health and quality of life despite high-level clinical evidence. In a roundtable symposium, investigators summarized the contemporary evidence in several key clinical areas. TD negatively impacts human health and quality of life and is associated with increased mortality. Several studies have demonstrated that TTh in men with TD reduced all-cause and cardiovascular mortality. The longstanding belief that TTh is associated with increased prostate cancer (PCa) risk is contradicted by recent evidence, including multiple studies showing that TTh is associated with reduced PCa risk. Similarly, the weight of current evidence indicates the purported concern that TTh is associated with increased cardiovascular risk is incorrect. Normalization of physiological T reduces myocardial infarction, stroke, and deaths compared with men whose testosterone levels failed to normalize. In diabetic men TTh improves insulin resistance, and a large 2-year controlled study in men with abnormal glucose tolerance showed a substantially reduced rate of diabetes among men treated with TTh compared with untreated controls. Long-term TTh in diabetic men resulted in progressive improvements in obesity and insulin requirements, including a substantial number who experienced complete remission of diabetes. Finally, TTh has been shown to reduce severe outcomes with Covid-19 infection. These lines of evidence argue strongly for the need for greater awareness in the medical community of the impact of TD on health, and of the health benefits of TTh.

Data is inconsistent and, for the most part, not sufficient to demonstrate the association between serum Prolactin (PRL) concentration within the physiologic range and the incidence rate of type 2 Diabetes Mellitus (DM) among men. Moreover, since both PRL and type 2 DM are associated with reproductive hormones, investigating these hormones might improve our understanding of how PRL might impose its effect on the incidence rate of type 2 DM.

For the present study, 652 eligible men aged 29-70 with a normal baseline PRL concentration were selected from the Tehran Lipid and Glucose Study (TLGS). Participants were sub-classified into three groups (tertiles) according to the serum concentration of PRL and were followed for 15.8 years. The incidence of type 2 DM and PRL, LH, FSH, testosterone, and AMH concentrations were measured. The effect of hormonal variables on the incidence of type 2 DM was estimated using the log-binomial model, adjusted for major confounding factors. The correlations between PRL and the indicators of glucose and lipid metabolism and other hormonal variables were also explored.

In the unadjusted model, PRL was not significantly associated with the incidence rate of type 2 DM (RR = 0.98, 95% CI: 0.94 - 1.03). After adjusting for potential confounders, the inverse effect of AMH on the incidence rate of type 2 DM was the only significant association. The analyses also indicated a significant positive association between PRL and LH/FSH ratio (r = 0.1, P = 0.01).

No significant association was found between serum PRL concentrations within the physiologic range and the incidence rate of type 2 diabetes mellitus among middle-aged men. Men with higher concentrations of PRL within the physiologic range tended to show higher levels of LH and LH/FSH. AMH was the only variable significantly linked to the incidence rate of type 2 DM in men.

In the absence of obesity, adverse lifestyle behaviours, and use of medication such as opioids serum testosterone concentrations decrease by only a minimal amount at least until very advanced age in most men. Obesity is heterogeneous in its phenotype, and it is the accumulation of excess adipose tissue viscerally associated with insulin resistance, dyslipidaemia, inflammation, hypothalamic leptin resistance and gliosis that underpins the functional hypogonadism of obesity. Both central (hypothalamic) and peripheral mechanisms are involved resulting in a low serum total testosterone concentration, while LH and FSH are typically in the normal range. Peripherally a decrease in serum sex hormone binding globulin (SHBG) concentration only partially explains the decrease in testosterone and there is increasing evidence for direct effects in the testis. Men with obesity associated functional hypogonadism and serum testosterone concentrations below 16 nmol/L are at increased risk of incident type 2 diabetes (T2D); high testosterone concentrations are protective. The magnitude of weight loss is linearly associated with an increase in serum testosterone concentration and with the likelihood of preventing T2D or reverting newly diagnosed disease; treatment with testosterone for 2 years increases the probability of a positive outcome from a lifestyle intervention alone by approximately 40%. Whether the additional favourable benefits of testosterone treatment on muscle mass and strength and bone density and quality in the long-term remains to be determined.

Diabetes mellitus (DM) is rarely sought among infertile patients due to a lack of studies and inconsistency regarding its impact on semen quality. This cross-sectional study aimed to determine the influence of T2DM on the pituitary gland hormones (FSH and LH) in males. A total of 60 participants participated in this study, of which 35 were diagnosed with diabetes mellitus, and 25 were without diabetes. Fasting blood sugar, HbA1c, LH, FSH, TT, E2, and prolactin were tested. Diabetic men had lower serum LH, FSH, and TT levels than non-diabetics and higher prolactin and E2 levels. According to the semen examination, including sperm count, PH, motility, and morphology, diabetic patients had considerably lower sperm counts, motility, and morphology than non-diabetic patients. In conclusion, the decrease in the concentration of reproductive hormones in diabetic patients leads to sexual weakness, resulting in abnormal seminal fluid parameters, which are below the normal levels than in apparently healthy persons.

Sexual dysfunction, which is defined as 'difficulty during any stage of the sexual encounter that prevents or impairs the individual or couple from enjoying sexual activity', is globally prevalent in males with prediabetes and diabetes. It is an early harbinger of cardiovascular diseases and has a profound impact on one's physical, mental, and social health. Among patients with either prediabetes or diabetes, the most common male sexual dysfunctions are hypogonadism, erectile dysfunction, and premature ejaculation. In Asia, although sexual health is an important factor of men's health, it is rarely discussed freely in real-life practice. Addressing sexual health in Asian males has always been challenging with multiple barriers at the levels of patients and health care providers. Therefore, the assessment and management of sexual dysfunction in routine clinical practice should involve a holistic approach with effective patient-provider communication. In this review, we discuss the epidemiology, pathophysiology, and the management of hypogonadism, erectile dysfunction, and premature ejaculation among males with either prediabetes or diabetes (type 1 and type 2), as well as the evidence gaps across Asia.

Purpose: COVID-19, a novel infection, presented with several complications, including socioeconomical and reproductive health challenges such as erectile dysfunction (ED). The present review summarizes the available shreds of evidence on the impact of COVID-19 on ED.Materials and methods: All published peer-reviewed articles from the onset of the COVID-19 outbreak to date, relating to ED, were reviewed. Results: Available pieces of evidence that ED is a consequence of COVID-19 are convincing. COVID-19 and ED share common risk factors such as disruption of vascular integrity, cardiovascular disease (CVD), cytokine storm, diabetes, obesity, and chronic kidney disease (CKD). COVID-19 also induces impaired pulmonary haemodynamics, increased ang II, testicular damage and low serum testosterone, and reduced arginine-dependent NO bioavailability that promotes reactive oxygen species (ROS) generation and endothelial dysfunction, resulting in ED. In addition, COVID-19 triggers psychological/mental stress and suppresses testosterone-dependent dopamine concentration, which contributes to incident ED.Conclusions: In conclusion, COVID-19 exerts a detrimental effect on male reproductive function, including erectile function. This involves a cascade of events from multiple pathways. As the pandemic dwindles, identifying the long-term effects of COVID-19-induced ED, and proffering adequate and effective measures in militating against COVID-19-induced ED remains pertinent.

To study the effect of testosterone undecanoate on sexual functions, glycaemic parameters, and cardiovascular (CV) risk factors in hypogonadal men with type 2 diabetes mellitus (T2DM).

It was an open label, single-arm interventional study where testosterone undecanoate (TU) was used in 105 T2DM males aged 30-60 years with hypogonadism. The effect of TU on sexual functions was assessed using the Aging Male Symptoms (AMS) Scale and the International Index of Erectile Function-5 (IIEF-5) Questionnaire. The effect on glycaemic parameters, cardiovascular risk factors (lipids, high-sensitivity C-reactive protein [hsCRP] and carotid intima media thickness [CIMT]) were assessed over a period of 54 weeks of TU therapy.

Prevalence of hypogonadism in T2DM patients was 19.1%, of which 74.1% had functional hypogonadism. AMS and IIEF-5 scores showed negative and positive correlation, respectively, with baseline serum testosterone levels. The AMS score showed a significant reduction of 5.8% and IIEF-5 score improved by 31.5% at 54 weeks of TU therapy. Glycosylated hemoglobin (HbA1c), homeostatic model assessment for insulin resistance (HOMA-IR), and lipids such as total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides (TG) were significantly reduced by 0.6%, 10.9%, 6.28%, 9.04%, and 6.77%, respectively, at 54 weeks. CIMT was significantly reduced by 2.57% at 54 weeks, whereas no significant change observed with hsCRP.

TU is an effective treatment modality for hypogonadal men with T2DM, and it has beneficial effects on sexual functions, glycaemic parameters, and CV risk factors.

Testosterone deficiency, defined as low total testosterone combined with physical, cognitive, and sexual signs and/or symptoms, is a common finding in adult men. Functional hypogonadism (FH) is defined as borderline low testosterone (T) secondary to aging and/or comorbid conditions such as diabetes, obesity, and/or metabolic syndrome. The relationship between FH and metabolic disorders is multifactorial and bidirectional, and associated with a disruption of the hypothalamic-pituitary-gonadal axis. Resolution of FH requires the correct diagnosis and treatment of the underlying condition(s) with lifestyle modifications considered first-line therapy. Normalization of T levels through dietary modifications such as caloric restriction and restructuring of macronutrients have recently been explored. Exercise and sleep quality have been associated with T levels, and patients should be encouraged to practice resistance training and sleep seven to nine hours per night. Supplementation with vitamin D and Trigonella foenum-graecum may also be considered when optimizing T levels. Ultimately, treatment of FH requires a multidisciplinary approach and personalized patient care.

To identify presurgical and surgical factors associated with the development of hypopituitarism and its recovery after endoscopic endonasal transsphenoidal (EET) resection of pituitary adenomas (PAs).

Retrospective study of patients with PAs operated by the same neurosurgeon through an EET approach in two Spanish tertiary hospitals in ten years.

242 pituitary surgeries performed in 231 patients were analyzed. In the 154 surgeries performed in 146 patients with non-functioning PAs (NFPAs), 46.8% (n=72) presented presurgical hypopituitarism. After PAs resection, 41 of these (56.9%) normalized pituitary function and 11 of 82 patients with preoperative normal function (13.4%) developed new pituitary deficits. Patients with preoperative visual impairment (OR=3.9, p=0.046) and operated in the first four years of the neurosurgeon's learning curve (OR=5.7, p=0.016) presented a higher risk of developing postoperative hypopituitarism. Of the 88 surgeries in 85 patients with functioning PAs (FPAs), 23.9% presented presurgical hypopituitarism, and 47.6% of those recovered after surgery. 9% of the cases with preoperative normal function developed new pituitary deficit/s. Diabetic patients presented a higher risk of persistence of hypopituitarism (OR=10.5, p=0.024). Patients with presurgical visual impairment (OR=30.0, p=0.010) and PAs>3cm (OR=14.0, p=0.027) had higher risk of developing new pituitary deficits.

Approximately 50% of patients with PAs and preoperative hypopituitarism recover pituitary function after EET surgery. 10% of patients with normal function develop new deficits. Patients with NFPAs with visual involvement and operated in the first four years of neurosurgeon's learning curve, and FPAs patients with presurgical visual impairment and tumor size>3cm have a higher risk of postoperative hypopituitarism.

Androgens are an important and diverse group of steroid hormone molecular species. They play varied functional roles, such as the control of metabolic energy fate and partition, the maintenance of skeletal and body protein and integrity and the development of brain capabilities and behavioral setup (including those factors defining maleness). In addition, androgens are the precursors of estrogens, with which they share an extensive control of the reproductive mechanisms (in both sexes). In this review, the types of androgens, their functions and signaling are tabulated and described, including some less-known functions. The close interrelationship between corticosteroids and androgens is also analyzed, centered in the adrenal cortex, together with the main feedback control systems of the hypothalamic-hypophysis-gonads axis, and its modulation by the metabolic environment, sex, age and health. Testosterone (T) is singled out because of its high synthesis rate and turnover, but also because age-related hypogonadism is a key signal for the biologically planned early obsolescence of men, and the delayed onset of a faster rate of functional losses in women after menopause. The close collaboration of T with estradiol (E2) active in the maintenance of body metabolic systems is also presented Their parallel insufficiency has been directly related to the ravages of senescence and the metabolic syndrome constellation of disorders. The clinical use of T to correct hypoandrogenism helps maintain the functionality of core metabolism, limiting excess fat deposition, sarcopenia and cognoscitive frailty (part of these effects are due to the E2 generated from T). The effectiveness of using lipophilic T esters for T replacement treatments is analyzed in depth, and the main problems derived from their application are discussed.

Type 2 diabetes (T2D) and obesity are common and associated with increased morbidity and mortality. Cross-sectional and longitudinal studies have demonstrated a clear association between T2D, obesity and reduced total testosterone concentration. This relationship becomes less significant or absent with correction for changes in body composition, supporting the notion that changes in body composition are mediating these effects. Moreover, this mediating effect of body composition changes is bi-directional, as evidenced by interventional studies of weight loss and testosterone treatment. On the one hand, in obese men, serum testosterone increases markedly with weight loss. On the other hand, testosterone improves body composition. This relationship is driven by multiple complex interaction between obesity and insulin resistance and the hypothalamic-pituitary-testicular axis, at all levels. Data from randomised control trials have demonstrated that intervention with testosterone therapy increases muscle mass and reduces adiposity. Most recently it has been shown that treatment with testosterone prevents progression of impaired glucose tolerance to T2D, or reverses newly diagnosed T2D beyond lifestyle intervention alone. At present there are insufficient safety data to support the use of testosterone for prevention of type 2 diabetes.

In this narrative review we provide an overview of the current literature on male hypogonadism and related comorbidities, also depicting the role of testosterone therapy (TTh) in the various settings. Male hypogonadism has been associated with major comorbidities such as type 2 diabetes mellitus, obesity and cardiovascular diseases, promoting a vicious cycle that may lead to further hypogonadism. The biological underpinnings of this association are currently under investigations, but clearly emerges the relevance of the hypothalamic-pituitary-gonadal axis. Hypogonadism has also been associated with increased risk of mortality. As such, TTh has the potential to oppose these patterns and improve cardiovascular and metabolic health in hypogonadal men. Clinical and observational data suggest that in males with hypogonadism, TTh, together with lifestyle changes and diabetes medications, may improve glycemia, reduce risk of progression to diabetes and provides positive effects on cardiovascular risk. Conversely, available data does not fully support any increased risk of prostate cancer in men under TTh. Of clinical relevance, a possible harmful role of hypogonadal status in men with COVID-19 eventually emerged.

The previous studies showed that hypogonadotropic hypogonadism (HH) occurred commonly in men with type 2 diabetes. However, since all the cohorts tested were from American and European studies, the occurrence of HH/nongonadal illness (NGI) in Chinese populations is unclear.

The study aimed to explore the occurrence of HH/NGI in Chinese men with type 2 diabetes. Furthermore, the correlative factors and predictors of hypogonadism were investigated.

We conducted a cross-sectional study of 637 Chinese men with type 2 diabetes aged 20-75 years in our clinic. The prevalence of HH/NGI was investigated by measuring serum total testosterone (TT), sex hormone-binding globulin (SHBG), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the enrolled subjects. Free testosterone (FT) was calculated by using SHBG and TT levels and hypogonadism was defined as TT lower than 10.4 nmol/L and calculated FT (cFT) lower than 0.225 nmol/L. The LH cut-off value for defining HH/NGI was 9.4 mIU/ml.

The results suggested that 31.9% of male Chinese type 2 diabetes patients had hypogonadism and 26.5% of subjects in our cohort were determined as HH/NGI. The occurrence of hypogonadism was markedly correlated with body mass index (BMI). There was a significant association between TT, cFT and SHBG levels with BMI. TT levels are inversely correlated with BMI and homeostasis model assessment-estimated insulin resistance (HOMA-IR) while positively related with SHBG. The cFT levels were inversely correlated with age, LH, FSH, BMI and HOMA-IR. Multiple regression analysis suggested that SHBG, BMI and HOMA-IR were significant predictors of TT and cFT.

Our present study offered the first evidence that the occurrence of HH/NGI in Chinese male type 2 diabetes was 26.5%. TT and cFT were significantly correlated with BMI, SHBG and HOMA-IR in Chinese men with type 2 diabetes.

Testosterone deficiency (TD), also known as male hypogonadism, is a complex syndrome encompassing physical, biochemical, and social aspects that increasingly affects the aging population. TD has been analyzed over recent decades, with an enhanced focus on etiologies relating to aging males. There is debate whether testosterone decline leading to hypogonadism is directly and primarily related to age-specific processes or if it is the subsequent result of accumulating comorbidities throughout a lifetime. Several studies have been done to further characterize this distinction. Chronic comorbidities that have commonly been associated with TD include hypertension (HTN), cardiovascular disease (CVD), diabetes mellitus (DM), obesity, metabolic syndrome (MetS), chronic kidney disease (CKD), and tobacco use. Although clear associations between hypogonadism and aging have been biochemically demonstrated, many large studies have illustrated the concomitant effects of highly prevalent chronic diseases and social behaviors in aging men. Given the significant impact of hypogonadism on the physical and mental health of men, this paper aims to delve into these studies and further define the complex relationship of testosterone deficiency in the aging male.

The adverse effects of short-term opioid analgesics are well known and acknowledged; however, the spectrum of the sequelae of long-term use seems less clear. Some effects may remain undetected but still have the potential to cause harm and reduce patients' quality of life.

To review the literature on the adverse effects of long-term opioid therapy.

We performed a quasi-systematic search, analyzing articles published in the MEDLINE database between January 2000 and March 2021 that identified adverse effects of opioids used for chronic pain treatment.

Growing evidence indicates that there are multiple serious adverse effects of opioid treatment. Long-term opioid use may have significant effects on the endocrine, immune, cardiovascular, respiratory, gastrointestinal, and neural systems. Studies show that long-term opioid treatment increases the risk of fractures, infections, cardiovascular complications, sleep-disordered breathing, bowel dysfunction, overdose, and mortality. Opioids may potentially affect cancer development. Most consequences of the long-term use of opioids have been identified in studies of patients with non-malignant pain.

Studies indicate that long-term use of opioids increases the risk of drug-related events in a significant number of patients. Clinicians should be aware of these complications associated with prescribing opioids, discuss them with patients, prevent complications, if possible, and diagnose them early and manage adequately. More human studies are needed to assess the risk, including trials with individual opioids, because they have different adverse effect profiles.

We aimed to evaluate the effects of hypogonadism on metabolic and chronic complications in type 2 diabetic males. 261 nonobese males with type 2 diabetes aged 18-70 were involved in the study. Hypononadal males were divided into 2 groups as overt hypogonadism (total testosterone≤230 ng/dl) and borderline hypogonadism (230-345 ng/dl). The control group involved eugonadal diabetic males. Micro-macrovascular complications were recorded. 101 patients had hypogonadism (38.7%), and 160 patients were eugonadal (61.3%). Microvascular complication rate was not different, but macrovascular complication rate was significantly higher in hypogonadal males (42.6%/31.3%, p = 0.042). Optimal glycosylated haemoglobin (HbA1c) achievement(<7%) was significantly lower in hypogonadal patients (20.8%/31.3%, p = 0.043). Poor glycaemic control (HbA1c≥7%), presence of microvascular complication and increased triglyceride levels were independent risk factors for hypogonadism (OR: 1.5, p = 0.044;OR:3.89,p = 0.025 and OR: 1.0, p = 0.016 respectively). Overt hypogonadism, hypertension, hypercholesterolaemia and severe hypoglycaemia were independent risk factors for macrovascular complications (OR: 1.0, p = 0.027; OR:2.6, p = 0.002; OR: 1.8, p = 0.047 and OR: 1.0, p = 0.007 respectively), diabetes duration (≥5 years) and poor glycaemic control for microvascular complication (OR: 1.0, p = 0.031 and OR:2.0, p = 0.028). As a result, hypogonadism is frequent among diabetic males and poor glycaemic control may be an important contributing factor. Furthermore overt hypogonadism is an important cardiovascular risk marker. Therefore, ensuring eugonadism in diabetic patients may positively affect both glycaemic control and complications.

Sex as a physiologic factor has a strong association with the features of metabolic syndrome. Our previous study showed that loss of the voltage-gated proton channel Hv1 inhibits insulin secretion and leads to hyperglycemia and glucose intolerance in male mice. However, there are significant differences in blood glucose between male and female Hv1-knockout (KO) mice. Here, we investigated the differences in glucose metabolism and insulin sensitivity between male and female KO mice and how sex steroids contribute to these differences. We found that the fasting blood glucose in female KO mice was visibly lower than that in male KO mice, which was accompanied by hypotestosteronemia. KO mice in both sexes exhibited higher expression of gluconeogenesis-related genes in liver compared with WT mice. Also, the livers from KO males displayed a decrease in glycolysis-related gene expression and an increase in gluconeogenesis-related gene expression compared with KO females. Furthermore, exogenous testosterone supplementation decreased blood glucose levels in male KO mice, as well as enhancing insulin signaling. Taken together, our data demonstrate that knockout of Hv1 results in higher blood glucose levels in male than female mice, despite a decreased insulin secretion in both sexes. This sex-related difference in glucose homeostasis is associated with the glucose metabolism in liver tissue, likely due to the physiological levels of testosterone in KO male mice.

There has been an exponential rise in diabetes mellitus (DM) cases on a global scale. Diabetes affects almost every system of the body, and the nervous system is no exception. Although the brain is dependent on glucose, providing it with the energy required for optimal functionality, glucose also plays a key role in the regulation of oxidative stress, cell death, among others, which furthermore contribute to the pathophysiology of neurological disorders. The variety of biochemical processes engaged in this process is only matched by the multitude of clinical consequences resulting from it. The wide-ranging effects on the central and peripheral nervous system include, but are not limited to axonopathies, neurodegenerative diseases, neurovascular diseases, and general cognitive impairment. All language search was conducted on MEDLINE, COCHRANE, EMBASE, and GOOGLE SCHOLAR till September 2021. The following search strings and Medical Subject Headings (MeSH terms) were used: "Diabetes Mellitus," "CNS," "Diabetic Neuropathy," and "Insulin." We explored the literature on diabetic neuropathy, covering its epidemiology, pathophysiology with the respective molecular pathways, clinical consequences with a special focus on the central nervous system and finally, measures to prevent and treat neuronal changes. Diabetes is slowly becoming an epidemic, rapidly increasing the clinical burden on account of its wide-ranging complications. This review focuses on the neuronal changes occurring in diabetes such as the impact of hyperglycemia on brain function and structure, its association with various neurological disorders, and a few diabetes-induced peripheral neuropathic changes. It is an attempt to summarize the relevant literature about neuronal consequences of DM as treatment options available today are mostly focused on achieving better glycemic control; further research on novel treatment options to prevent or delay the progression of neuronal changes is still needed.

Metabolic syndrome (MetS) is a complex pathological state consisting of metabolic risk factors such as hypertension, insulin resistance, and obesity. The interconnectivity of cellular pathways within various biological systems suggests that each individual component of MetS may share common pathological sources. Additionally, MetS is closely associated with vasculopathy, including a reduction in microvessel density (MVD) (rarefaction) and elevated risk for various cardiovascular diseases. Microvascular impairments may contribute to perfusion-demand mismatch, where local metabolic needs are insufficiently met due to the lack of nutrient and oxygen supply, thus creating pathological positive-feedback loops and furthering the progression of disease. Sexual dimorphism is evident in these underlying cellular mechanisms, which places males and females at different levels of risk for cardiovascular disease and acute ischemic events. Estrogen exhibits protective effects on the endothelium of pre-menopausal women, while androgens may be antagonistic to cardiovascular health. This review examines MetS and its influences on MVD, as well as sex differences relating to the components of MetS and cardiovascular risk profiles. Finally, translational relevance and interventions are discussed in the context of these sex-based differences.

Obesity (OBS) has been established as a link to male hypogonadism with consequent infertility. Previous studies have shown that melatonin (MEL) modulates hypothalamic-pituitary-gonadal function. The present study therefore investigated the hypothesis that MEL supplementation would attenuate spermatogenic and steroidogenic dysfunctions associated with obesity induced by high-fat diet (HFD). Twenty-four adult male Wistar rats (n = 6/group) were used: control group received vehicle (normal saline), obese group received 40% high-fat diet and distilled water, MEL-treated group received MEL (4 mg/kg), and OBS + MEL group received MEL and 40% HFD and the treatment lasted for 12 weeks. HFD caused increased body weight, glucose intolerance, plasma triglyceride and low-density lipoprotein cholesterol/ very low-density lipoprotein cholesterol and malondialdehyde, as well as decreased antioxidant capacity, high-density lipoprotein cholesterol, gonadotrophin-releasing hormone, follicle-stimulating hormone and testosterone and altered sperm parameters. However, all these alterations were attenuated when supplemented with MEL. Taken together, these results indicate that HFD exposure causes endocrine dysfunction and disrupted sperm parameters in obese animals, which are accompanied by lipid peroxidation/defective antioxidant capacity. In addition, the present results suggest that melatonin supplementation restores endocrine function and sperm integrity in obese rat model by suppression of oxidative stress-dependent mechanism.

Diabetes mellitus (DM), as a multiorgan syndrome, is an endocrine and metabolic disorder that is associated with male reproductive system dysfunction and infertility. Safflower (Carthamus tinctorius L.) as an herbal remedy improves DM and infertility-related disorders. The anti-hypercholesterolemic, anti-inflammatory, and antioxidative properties of this herb have been well documented, but its role in testosterone production, male reproductive system and zinc homeostasis has not been fully illustrated.

This study aimed to investigate the preventive and therapeutic properties of different doses of safflower seed oil against reproductive damage caused by type II DM by investigating zinc element homeostasis, inflammation and oxidative damage in testis tissue and their relationship with testosterone production and sperm parameters.

Eighty adult male Sprague-Dawley rats were randomly divided into eight groups and treated daily for 12 and 24 weeks in protective and therapeutic studies, respectively. Type II DM was induced by a High Fat Diet (HFD) in normoglycemic rats for three months. At the end of each study, serum level of glucose, testosterone, gonadotropins, TNF-α, insulin, and leptin were measured. Moreover, antioxidant enzymes activity, lipid peroxidation, zinc and testosterone along with the expression of Nrf-2, NF-κB, TNF-α, StAR, P450scc, and 17βHSD3 genes in the testis were detected.

After the intervention, the activity of antioxidant enzymes and the level of testosterone and gonadotropins significantly decreased in the rats with DM in comparison to the others. However, lipid peroxidation and serum level of insulin, leptin and TNF-α increased and the testicular level of zinc significantly changed in the rats with DM compared to the control groups (p < 0.05). The gene expression of NF-κB and TNF-α were also significantly increased and the gene expression of Nrf2, StAR, P450scc and 17βHSD3 were decreased in the testis of diabetic rats (p < 0.05). The results showed that pretreatment and treatment with safflower seed oil could improve these parameters in diabetic rats compared with untreated diabetic rats (p < 0.05).

HFD could impair the production of testosterone and sperm, and reduce gonadotropin by increasing the serum level of leptin and inducing insulin resistance, oxidative stress and inflammation. However, safflower oil in a dose-dependent manner could improve testosterone level and sperm parameters by improving the level of leptin, zinc and insulin resistance, and the genes expression involved in testosterone synthesis, inflammation and oxidative stress.

Male hypogonadism is associated with low bone mineral density (BMD) and increased fragility fracture risk. Patients with type 2 diabetes (T2D) have relatively higher BMD, but greater fracture risk.

Evaluate the skeletal response to testosterone therapy in hypogonadal men with T2D compared with hypogonadal men without T2D.

Single arm, open-label clinical trial (NCT01378299) involving 105 men (40-74 years old), with average morning testosterone <300 ng/dL. Subjects were injected intramuscularly with testosterone cypionate (200 mg) every 2 weeks for 18 months. Testosterone and estradiol were assessed by liquid chromatography/mass spectrometry; serum C-terminal telopeptide of type I collagen (CTX), osteocalcin and sclerostin by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) by high-performance liquid chromatography, areal BMD (aBMD) and body composition by dual-energy x-ray absorptiometry; tibial volumetric BMD (vBMD) and bone geometry by peripheral quantitative computed tomography.

Among our population of hypogonadal men, 49 had T2D and 56 were non-T2D. After 18 months of testosterone therapy, there were no differences in circulating testosterone and estradiol between the groups. Hypogonadal men with T2D had increased osteocalcin, reflecting increased osteoblast activity, compared with non-T2D men (P < .01). T2D men increased lumbar spine aBMD (P < .05), total area at 38% tibia (P < .01) and periosteal and endosteal circumferences at the same site (P < .01 for both). T2D men had reduced tibial vBMD (P < .01), but preserved bone mineral content (P = .01). Changes in HbA1c or body composition were similar between the 2 groups.

Testosterone therapy results in greater improvements in the skeletal health of hypogonadal men with T2D than their nondiabetic counterparts.