Editorial for "The Role of Ketogenic Diet in Human Health and Diseases": The Multifaceted Impact of Ketogenic Diets on Health and Disease.

The ketogenic diet (KD), characterized by a very low carbohydrate intake and variable protein, fat and calorie intake, has long been in the spotlight for its potential therapeutic applications [...].

Predictors of weight loss in patients with obesity treated with a Very Low-Calorie Ketogenic Diet.

Introduction: The Very Low-Calorie Ketogenic Diet (VLCKD) has emerged as a safe and effective intervention for the management of metabolic disease. Studies examining weight loss predictors are scarce and none has investigated such factors upon VLCKD treatment. Among the molecules involved in energy homeostasis and, more specifically, in metabolic changes induced by ketogenic diets, Fibroblast Growth Factor 21 (FGF21) is a hepatokine with physiology that is still unclear. Methods: We evaluated the impact of a VLCKD on weight loss and metabolic parameters and assessed weight loss predictors, including FGF21. VLCKD is a severely restricted diet (<800 Kcal/die), characterized by a very low carbohydrate intake (<50 g/day), 1.2-1.5 g protein/kg of ideal body weight and 15-30 g of fat/day. We treated 34 patients with obesity with a VLCKD for 45 days. Anthropometric parameters, body composition, and blood and urine chemistry were measured before and after treatment. Results: We found a significant improvement in body weight and composition and most metabolic parameters. Circulating FGF21 decreased significantly after the VLCKD [194.0 (137.6-284.6) to 167.8 (90.9-281.5) p < 0.001] and greater weight loss was predicted by lower baseline FGF21 (Beta = -0.410; p = 0.012), male sex (Beta = 0.472; p = 0.011), and central obesity (Beta = 0.481; p = 0.005). Discussion: VLCKD is a safe and effective treatment for obesity and obesity related metabolic derangements. Men with central obesity and lower circulating FGF21 may benefit more than others in terms of weight loss obtained following this diet. Further studies investigating whether this is specific to this diet or to any caloric restriction are warranted.

The Influence of Ketone Bodies on Circadian Processes Regarding Appetite, Sleep and Hormone Release: A Systematic Review of the Literature.

Chrononutrition is an emerging branch of chronobiology focusing on the profound interactions between biological rhythms and metabolism. This framework suggests that, just like all biological processes, even nutrition follows a circadian pattern. Recent findings elucidated the metabolic roles of circadian clocks in the regulation of both hormone release and the daily feeding-fasting cycle. Apart from serving as energy fuel, ketone bodies play pivotal roles as signaling mediators and drivers of gene transcription, promoting food anticipation and loss of appetite. Herein we provide a comprehensive review of the literature on the effects of the ketogenic diets on biological processes that follow circadian rhythms, among them appetite, sleep, and endocrine function.

Applications of Ketogenic Diets in Patients with Headache: Clinical Recommendations.

Headaches are among the most prevalent and disabling neurologic disorders and there are several unmet needs as current pharmacological options are inadequate in treating patients with chronic headache, and a growing interest focuses on nutritional approaches as non-pharmacological treatments. Among these, the largest body of evidence supports the use of the ketogenic diet (KD). Exactly 100 years ago, KD was first used to treat drug-resistant epilepsy, but subsequent applications of this diet also involved other neurological disorders. Evidence of KD effectiveness in migraine emerged in 1928, but in the last several year's different groups of researchers and clinicians began utilizing this therapeutic option to treat patients with drug-resistant migraine, cluster headache, and/or headache comorbid with metabolic syndrome. Here we describe the existing evidence supporting the potential benefits of KDs in the management of headaches, explore the potential mechanisms of action involved in the efficacy in-depth, and synthesize results of working meetings of an Italian panel of experts on this topic. The aim of the working group was to create a clinical recommendation on indications and optimal clinical practice to treat patients with headaches using KDs. The results we present here are designed to advance the knowledge and application of KDs in the treatment of headaches.

Baseline HOMA IR and Circulating FGF21 Levels Predict NAFLD Improvement in Patients Undergoing a Low Carbohydrate Dietary Intervention for Weight Loss: A Prospective Observational Pilot Study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease. Very low-calorie ketogenic diets (VLCKD) represent a feasible treatment as they induce profound weight loss and insulin resistance (IR) improvement. Despite the recognized benefits on NAFLD deriving from pharmacological administration of fibroblast growth factor 21 (FGF21), whose endogenous counterpart is a marker of liver injury, little is known about its physiology in humans. AIM: To identify predictors of NAFLD improvement as reflected by the reduction of the non-invasive screening tool hepatic steatosis index (HSI) in obese patients undergoing a weight loss program. METHODS: Sixty-five obese patients underwent a 90-day dietary program consisting of a VLCKD followed by a hypocaloric low carbohydrate diet (LCD). Anthropometric parameters, body composition, and blood and urine chemistry were assessed. RESULTS: Unlike most parameters improving mainly during the VLCKD, the deepest HSI change was observed after the LCD (p = 0.02 and p < 0.0001, respectively). Baseline HOMA-IR and serum FGF21 were found to be positive (R = 0.414, p = 0009) and negative (R = 0.364, p = 0.04) independent predictors of HSI reduction, respectively. CONCLUSIONS: We suggest that patients with IR and NAFLD derive greater benefit from a VLCKD, and we propose a possible role of human FGF21 in mediating NAFLD amelioration following nutritional manipulation.

Very-Low-Calorie Ketogenic Diets With Whey, Vegetable, or Animal Protein in Patients With Obesity: A Randomized Pilot Study.

CONTEXT: We compared the efficacy, safety, and effect of 45-day isocaloric very-low-calorie ketogenic diets (VLCKDs) incorporating whey, vegetable, or animal protein on the microbiota in patients with obesity and insulin resistance to test the hypothesis that protein source may modulate the response to VLCKD interventions. SUBJECTS AND METHODS: Forty-eight patients with obesity (19 males and 29 females, homeostatic model assessment (HOMA) index ≥ 2.5, aged 56.2 ± 6.1 years, body mass index [BMI] 35.9 ± 4.1 kg/m2) were randomly assigned to three 45-day isocaloric VLCKD regimens (≤800 kcal/day) containing whey, plant, or animal protein. Anthropometric indexes; blood and urine chemistry, including parameters of kidney, liver, glucose, and lipid metabolism; body composition; muscle strength; and taxonomic composition of the gut microbiome were assessed. Adverse events were also recorded. RESULTS: Body weight, BMI, blood pressure, waist circumference, HOMA index, insulin, and total and low-density lipoprotein cholesterol decreased in all patients. Patients who consumed whey protein had a more pronounced improvement in muscle strength. The markers of renal function worsened slightly in the animal protein group. A decrease in the relative abundance of Firmicutes and an increase in Bacteroidetes were observed after the consumption of VLCKDs. This pattern was less pronounced in patients consuming animal protein. CONCLUSIONS: VLCKDs led to significant weight loss and a striking improvement in metabolic parameters over a 45-day period. VLCKDs based on whey or vegetable protein have a safer profile and result in a healthier microbiota composition than those containing animal proteins. VLCKDs incorporating whey protein are more effective in maintaining muscle performance.

Beneficial effects of the ketogenic diet on nonalcoholic fatty liver disease: A comprehensive review of the literature.

Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease, characterized by hepatic fat accumulation and possible development of inflammation, fibrosis, and cancer. The ketogenic diet (KD), with its drastic carbohydrate reduction, is a now popular weight loss intervention, despite safety concerns on a possible association with fatty liver. However, KDs were also reported to be beneficial on hepatic pathology, with ketone bodies recently proposed as effective modulators of inflammation and fibrosis. If the beneficial impact of weight loss on NAFLD is established, less is known on the effect of macronutrient distribution on such outcome. In a hypocaloric regimen, the latter seems not to be crucial, whereas at higher calorie intake, macronutrient ratio and, theoretically, ketosis, may become important. KDs could positively impact NAFLD for their very low carbohydrate content, and whether ketosis plays an additional role is unknown. Indeed, several mechanisms may directly link ketosis and NAFLD improvement, and elucidating these aspects would pave the way for new therapeutic strategies. We herein aimed at providing an accurate revision of current literature on KDs and NAFLD, focusing on clinical evidence, metabolic pathways involved, and strict categorization of dietary interventions.

Very Low-Calorie Ketogenic Diet: A Safe and Effective Tool for Weight Loss in Patients With Obesity and Mild Kidney Failure.

Very low-calorie ketogenic diets (VLCKD) are an effective and increasingly used tool for weight loss. Traditionally considered high protein, ketogenic diets are often looked at with concern by clinicians due to the potential harm they pose to kidney function. We herein evaluated the efficacy and safety of a VLCKD in patients with obesity and mild kidney failure. A prospective observational real-life study was conducted on ninety-two patients following a VLCKD for approximately 3 months. Thirty-eight had mild kidney failure and fifty-four had no renal condition and were therefore designated as control. Anthropometric parameters, bioelectrical impedance and biochemistry data were collected before and at the end of the dietary intervention. The average weight loss was nearly 20% of initial weight, with a significant reduction in fat mass. We report an improvement of metabolic parameters and no clinically relevant variation regarding liver and kidney function. Upon stratification based on kidney function, no differences in the efficacy and safety outcomes were found. Interestingly, 27.7% of patients with mild renal failure reported normalization of glomerular filtrate after dietary intervention. We conclude that, when conducted under the supervision of healthcare professionals, a VLCKD is an effective and safe treatment for weight loss in patients with obesity, including those affected by mild kidney failure.

Mangosteen Extract Shows a Potent Insulin Sensitizing Effect in Obese Female Patients: A Prospective Randomized Controlled Pilot Study.

There is a widely acknowledged association between insulin resistance and obesity/type 2 diabetes (T2DM), and insulin sensitizing treatments have proved effective in preventing diabetes and inducing weight loss. Obesity and T2DM are also associated with increased inflammation. Mangosteen is a tropical tree, whose fruits—known for their antioxidant properties—have been recently suggested having a possible further role in the treatment of obesity and T2DM. The objective of this pilot study has been to evaluate safety and efficacy of treatment with mangosteen extract on insulin resistance, weight management, and inflammatory status in obese female patients with insulin resistance. Twenty-two patients were randomized 1:1 to behavioral therapy alone or behavioral therapy and mangosteen and 20 completed the 26-week study. The mangosteen group reported a significant improvement in insulin sensitivity (homeostatic model assessment-insulin resistance, HOMA-IR −53.22% vs. −15.23%, p = 0.004), and no side effect attributable to treatment was reported. Given the positive preliminary results we report and the excellent safety profile, we suggest a possible supplementary role of mangosteen extracts in the treatment of obesity, insulin resistance, and inflammation.

Safety and efficacy of a multiphase dietetic protocol with meal replacements including a step with very low calorie diet.

To investigate safety, compliance, and efficacy, on weight loss and cardiovascular risk factors of a multiphasic dietary intervention based on meal replacements, including a period of very low calorie diet (VLCD) in a population of obese patients. Anthropometric parameters, blood tests (including insulin), dual-energy-X-ray absorptiometry (DXA), and questionnaires for the assessment of safety and compliance before and after (phase I) a 30-day VLCD, 700 kcal/day, normoproteic, 50 g/day carbohydrate, four meal replacements; (phase II) a 30-day low calorie diet (LCD), 820 kcal/day, three meal replacements plus a protein plate; (phase III) 60-day LCD, 1,100 kcal/day, two meal replacements plus two protein plates and reintroduction of small amounts of carbohydrates; (phase IV) 60-day hypocaloric balanced diet (HBD), 1,200 kcal/day, one meal replacement, two protein plates and the reintroduction of carbohydrates. 24 patients (17 females, 7 males, mean BMI 33.8±3.2 kg/m2, mean age 35.1±10.2 years) completed the study. The average weight loss was 15.4±6.7%, with a significant reduction of fat mass (from 32.8±4.7 to 26.1±6.3% p<0.05) and a relative increase of lean mass (from 61.9±4.8 to 67.1±5.9% p<0.05). An improvement of metabolic parameters and no variations of the liver and kidney functions were found. A high safety profile and an excellent dietary compliance were seen. The VLCD dietary program and the replacement dietary system described here is an effective, safe, and well-tolerated treatment for weight control.

Obstructive sleep apnea and bone mineral density in obese patients.

CONTEXT: Obesity and its co-morbidities may adversely affect bone mineral density (BMD). Obstructive sleep apnea (OSA) is a major complication of obesity. To date, the effects of OSA on BMD in obese patients have been poorly studied. OBJECTIVE: To examine whether the severity of OSA independently correlates with BMD in obese patients. METHODS: One hundred and fifteen obese subjects with OSA (Apnea/Hypopnea Index [AHI] ≥5 events per hour) were included in the study. BMD was measured at lumbar spine, total hip, and femoral neck by dual energy X-ray absorptiometry. Body mass index, lean mass, and representative measures of metabolic syndrome (waist circumference, fasting plasma glucose, blood pressure, HDL-cholesterol, triglycerides) and inflammation (ESR, CRP, fibrinogen) were also evaluated. RESULTS: BMD did not differ among obese individuals regardless of OSA severity. Correlation coefficient analysis for all the covariates showed a lack of association between AHI and BMD that was strongly influenced by age and weight. CONCLUSION: Our study does not support an independent association between AHI and BMD in obese patients. Controlled studies involving a greater number of patients are warranted.

Assessing disability in morbidly obese individuals: the Italian Society of Obesity test for obesity-related disabilities.

PURPOSE: To validate a new obesity-specific disability assessment test: the Obesity-related Disability test (Test SIO Disabilità Obesità Correlata, TSD-OC). METHODS: Adult obese individuals were assessed with the TSD-OC, 36-Item Short-Form Health Survey (SF-36), 6-min walking test (6MWT) and grip strength. The TSD-OC is composed of 36 items divided into seven sections (pain, stiffness, activities of daily living and indoor mobility, housework, outdoor activities, occupational activities and social life). Statistical correlations between the TSD-OC, functional assessment (6MWT and grip strength) and quality of life parameters (SF-36) were analysed. Internal consistency was assessed with Cronbach's α test. Test-retest reliability was evaluated in a subgroup of 30 individuals. A linking exercise between TSD-OC items and categories of the International Classification of Functioning, Disability and Health was performed. RESULTS: Test-retest showed excellent stability (r = 0.90) and excellent internal consistency was reported (Cronbach's α > 0.90). Significant low to moderate correlations between TSD-OC, SF-36 scores, 6MWT and grip strength were observed. A total of 26 ICF categories were linked, mostly related to the area of mobility. CONCLUSIONS: The TSD-OC is a reliable and valid instrument for measuring self-reported disability in obese subjects. It may represent an important tool for establishing rehabilitation needs in individuals with obesity-related disability, for planning appropriate rehabilitation programmes and for evaluating their effectiveness.

Erectile dysfunction of sclerodermic patients correlates with digital vascular damage.

BACKGROUND: The prevalence of erectile dysfunction (ED) in men with systemic sclerosis (SSc) can be considered a manifestation of endothelium damage. Aim of the study is to investigate ED in SSc patients by color Doppler ultrasound examination and to correlate it with disease severity and digital vascular damage. METHODS: In 20 males SSc patients blood flow velocity in the cavernous artery was determined with Duplex ultrasonography. Naifold videocapillaroscopy, Sexual Health Inventory for Men (SHIM) and Medsger Disease Severity Scale (DSS) were performed. Arteriogenic ED was defined by the presence of a reduced peak systolic velocity (PSVs), while diastolic velocity (EDV) and the resistive index (RI) were estimated to evaluate venocclusive dysfunction. SSc patients are classified by capillaroscopic pattern and vascular domain of DSS into two groups: low vascular damage (early or active capillaroscopic pattern and score of vascular domain of DSS≤2) and high vascular damage (late capillaroscopic pattern and score of vascular domain of DSS≥3). RESULTS: In all SSc patients a reduction of SHIM is present (mean 13.5±6.3). Patients with less vascular damage have a significantly (p<0.001) higher score of SHIM than patients with greater vascular damage (19.2±2.4 vs 7.9±2.7). No significant difference (p>0.5) between the two groups of vascular damage was found in PSVs. Venocclusive dysfunction was present only (p<0.001) in the group with high vascular damage. CONCLUSION: We can assert that there is a relationship between SSc vascular digital damage and ED.

Severe oligozoospermia in a young man with chronic myeloid leukemia on long-term treatment with imatinib started before puberty.

OBJECTIVE: To report the effect of long-term treatment with the tyrosine kinase inhibitor imatinib started before the onset of puberty on semen parameters, bone mineral density, and hormone values. DESIGN: Case report. SETTING: University hospital. PATIENT(S): An 18-year-old man given treatment with imatinib for chronic myeloid leukemia. INTERVENTION(S): Clinical, biochemical and dual-energy X-ray absorptiometry evaluations. MAIN OUTCOME MEASURE(S): Semen analysis, serum levels of gonadotropins, inhibin-B, and testosterone, bone mineral density, markers of skeletal homeostasis. RESULT(S): Semen analyses showed severe oligozoospermia after long-term administration of imatinib started before puberty. The inhibin-B/FSH ratio was reduced. A low bone mineral density for chronologic age was observed. CONCLUSION(S): This case study documents the potential risk of an impairment of semen parameters in patients undergoing a treatment with tyrosine kinase inhibitors before the complete maturation of the testis.

Exposure to phosphodiesterase type 5 inhibitors stimulates aromatase expression in human adipocytes in vitro.

INTRODUCTION: Prolonged tadalafil administration in men with erectile dysfunction is associated with increased testosterone (T): estradiol (E(2)) ratio mainly related to reduction of E(2) levels. AIM: To investigate the presence of phosphodiesterase type 5 (PDE5) isoenzyme in primary human visceral adipocytes and whether different PDE5 inhibitors (PDE5i) could directly modulate aromatase (ARO) expression in differentiated human visceral adipocytes in culture. MAIN OUTCOME MEASURES: PDE5 mRNA and protein expression in primary human visceral adipocytes as well as mRNA and protein expression of ARO, with functional activity after selective PDE5 blockade by tadalafil and sildenafil. METHODS: Purified primary human visceral pre-adipocytes were differentiated ex vivo and were exposed to tadalafil or sildenafil (1 µM) for different intervals of time (6-12-24-96 hours). ARO mRNA content and expression were measured by Western Blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), respectively. T and E(2) in supernatants were measured by ELISA also in the presence of letrozole. RESULTS: Differentiated adipocytes were found to express detectable levels of PDE5 transcripts. Acute exposure (6 hours) to both PDE5i tadalafil and sildenafil increased ARO mRNA expression by 4.7- and 2.8-fold, respectively (P < 0.001). ARO mRNA and protein levels were increased by the treatment with PDE5i in a time- and dose-dependent manner. Such effect was mimicked by 8-bromo-cGMP but was lost after 24 and 96 hours; differently, the PDE3B specific inhibitor milrinone (1 µM), displayed no effect. Accordingly, long-term exposure (24 and 96 hours) to PDE5i caused a significant increase in E(2) concentrations in the supernatant (1.7 and 2 fold, respectively; P < 0.001), with a parallel reduction of T (15% and 30%, respectively; P < 0.001). Such effect was reversed by the co-incubation with the specific ARO-inhibitor letrozole. CONCLUSIONS: Our results demonstrate that PDE5 is expressed in human visceral adipocytes and that acute exposure to PDE5i selectively stimulates ARO expression, which is related to a specific PDE5 blockade. We speculate that modulation of ARO activity by PDE5i could be one of the mechanisms responsible, at least in part, for the beneficial effects of PDE5i on endothelial and metabolic functions.

Penile involvement in Systemic Sclerosis: New Diagnostic and Therapeutic Aspects.

Systemic Sclerosis (SSc) is a connective tissue disorder featuring vascular alterations and an immunological activation leading to a progressive and widespread fibrosis of several organs such as the skin, lung, gastrointestinal tract, heart, and kidney. Men with SSc are at increased risk of developing erectile dysfunction (ED) because of the evolution of early microvascular tissutal damage into corporeal fibrosis. The entity of penile vascular damage in SSc patients has been demonstrated by using Duplex ultrasonography and functional infra-red imaging and it is now clear that this is a true clinical entity invariably occurring irrespective of age and disease duration and constituting the ''sclerodermic penis". Once-daily phosphodiesterase type-5 (PDE5) inhibitors improve both sexual function and vascular measures of cavernous arteries by improving surrogate markers of endothelial dysfunction, that is, plasma endothelin-1 and adrenomedullin levels, which may play a potential role in preventing progression of penile fibrosis and ED. Also, the beneficial effect of long-term PDE5i add-on therapy to SSc therapy in the treatment of Raynaud's phenomenon is described.

Role of platelet-derived growth factors in the testis.

Normal development and function of the testis are controlled by endocrine and paracrine signaling pathways. Platelet-derived growth factors (PDGFs) are growth factors that mediate epithelial-mesenchymal interactions in various tissues during normal and abnormal processes such as embryo development, wound healing, tissue fibrosis, vascular disorders, and cancer. PDGFs and their receptors (PDGFRs) have emerged as key players in the regulation of embryonic and postnatal development of the male gonad. Cells that express PDGFs and PDGFRs are found in the testis of mammals, birds, and reptiles, and their distribution, regulation, and function vary across species. Testicular PDGFs and PDGFRs appear after the process of sex determination in animals that use either genetic sex determination or environmental sex determination. Sertoli cells are the main PDGF-producing cells during the entire period of prenatal and postnatal testis development. Fetal Leydig cells and their precursors, adult Leydig cells and their stem cell precursors, peritubular myoid cells, cells of the blood vessels, and gonocytes are the testicular cell types expressing PDGFRs. Genetically targeted deletions of PDGFs, PDGFRs, PDGFR target genes or pharmacological silencing of PDGF signaling produce profound damage on the target cells that, depending on the developmental period, are under direct or indirect control of PDGF. PDGF signaling may also serve diverse functions outside of the realm of testis development, including testicular tumors. In this review, we provide a framework of the current knowledge to clarify the useful information regarding how PDGFs function in individual cells of the testis.

Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.

INTRODUCTION: Longitudinal studies have demonstrated that male hypogonadism could be considered a surrogate marker of incident cardiovascular disease. AIM: To evaluate the effects of parenteral testosterone undecanoate (TU) in outclinic patients with metabolic syndrome (MS) and late-onset hypogonadism (total testosterone (T) at or below 11nmol/L or free T at or below 250pmol/L). METHODS: This is a randomized, double-blind, double-dummy, placebo-controlled, parallel group, single-center study. Fifty patients (mean age 57±8) were randomized (4:1) to receive TU 1,000mg (every 12 weeks) or placebo (PLB) gel (3-6 g/daily) for 24 months. MAIN OUTCOME MEASURES: Homeostasis model assessment index of insulin resistance (HOMA-IR), carotid intima media thickness (CIMT), and high-sensitivity C-reactive protein (hsCRP). RESULTS: At baseline, all patients fulfilled the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII) and International Diabetes Federation (IDF) criteria for the definition of MS. An interim analysis conducted at 12 months showed that TU markedly improved HOMA-IR (P < 0.001), CIMT (P < 0.0001), and hsCRP (P<0.001) compared with PLB; thus, all patients were shifted to TU treatment. After 24 months, 35% (P < 0.0001) and 58% (P < 0.001) of patients still presented MS as defined by NCEP-ATPIII and IDF criteria, respectively. Main determinants of changes were reduction in waist circumference (P<0.0001), visceral fat mass (P<0.0001), and improvement in HOMA-IR without changes in body mass index (BMI). CONCLUSIONS: TU reduced fasting glucose, waist circumference, and improved surrogate markers of atherosclerosis in hypogonadal men with MS. Resumption and maintenance of T levels in the normal range of young adults determines a remarkable reduction in cardiovascular risk factors clustered in MS without significant hematological and prostate adverse events.

Cardiovascular effect of testosterone replacement therapy in aging male.

Cardiovascular diseases (CVD) are the most important causes of morbidity and mortality in the developed and developing world. Particularly, coronary heart disease is the commonest cause of death worldwide. Testosterone (T) is an anabolic hormone with putative beneficial effects on men's health and restoration of normal T levels in deficient men represents an important key-point of male well-being. In the lasts years it has emerged a possible linkage between androgen deficiency and CVD. Many studies noted that T deficiency might contribute to increased risk of CVD. Furthermore, androgen deficiency is frequently associated with increased levels of glucose, total cholesterol, low-density lipoprotein, increased production of pro-inflammatory cytokines, and increased thickness of the arterial wall that all contribute to worsen endothelial function. The clinical and epidemiological studies discussed in this section give an update on the interplay between late onset hypogonadism (LOH) and CVD. The linkage between androgen deficiency and men's vascular health has a great impact in the modern approach to the ageing male, and should be further investigated to determine the therapeutic potential of androgens in men with vascular disease.