Resting energy expenditure in women with polycystic ovary syndrome.

STUDY QUESTION: Is resting energy expenditure (REE) altered in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Women with PCOS have a reduction in REE, when corrected for fat-free mass, independent of PCOS clinical phenotypes and BMI categories. WHAT IS KNOWN ALREADY: Obesity is an important issue in women with PCOS, in terms of frequency and pathophysiological implications. It has been hypothesized that obesity may be favoured by alterations in REE, but the studies have been limited and conflicting. STUDY DESIGN, SIZE, DURATION: This case-control study was a comparison of 266 women with PCOS and 51 healthy controls, recruited in the Verona 3P study from 2010 to 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS diagnosed by the Rotterdam criteria, with normal thyroid function and no interfering medications, were referred to the outpatient clinic of a tertiary care centre of endocrinology and metabolism for a measurement of REE. Healthy controls were recruited in the same period and submitted to the same procedure. In all subjects, REE was measured by indirect calorimetry and serum androgens were measured by LC-MS/MS. In women with PCOS, insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp. MAIN RESULTS AND THE ROLE OF CHANCE: REE was similar in women with PCOS and controls. However, REE corrected for fat-free mass (REE/FFM) was significantly lower in women with PCOS than in controls (31.8 ± 4.0 vs 35.4 ± 3.9 kcal/kgFFM·day, P < 0.001). REE/FFM did not differ between normal-weight, overweight, or obese women with PCOS, and each of these subgroups showed lower REE/FFM values than controls. Reduced REE/FFM values were found in each phenotype of the syndrome. In multiple regression analysis, REE/FFM was independently associated with age and PCOS status, but not with fat mass. In PCOS women, REE/FFM was independently and directly associated with ovarian follicle number. LIMITATIONS, REASONS FOR CAUTION: Limitations of the study are the cross-sectional design, which limits the causal inference of the results, and the unavailability of precise information about lifestyle factors, which may be potential confounders. Further prospective studies are needed to establish the importance of this phenomenon in contributing to the weight excess of PCOS. WIDER IMPLICATIONS OF THE FINDINGS: A reduction of REE could potentially favour weight gain in women with PCOS and possibly contribute to the altered metabolic profile typical of this condition, even counteracting the therapeutic strategies aimed to reduce excess body fat in these women. Nevertheless, the presence of this abnormality in both obese/overweight and normal-weight patients suggests that other factors must play a role in this phenomenon. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by academic grants to PM from the University of Verona (FUR 2010-2022). All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Radiofrequency echographic multi spectrometry (REMS) in the diagnosis and management of osteoporosis: state of the art.

Radiofrequency Echographic Multi Spectrometry (REMS) is a radiation-free, portable technology, which can be used for the assessment and monitoring of osteoporosis at the lumbar spine and femoral neck and may facilitate wider access to axial BMD measurement compared with standard dual-energy x-ray absorptiometry (DXA).There is a growing literature demonstrating a strong correlation between DXA and REMS measures of BMD and further work supporting 5-year prediction of fracture using the REMS Fragility Score, which provides a measure of bone quality (in addition to the quantitative measure of BMD).The non-ionising radiation emitted by REMS allows it to be used in previously underserved populations including pregnant women and children and may facilitate more frequent measurement of BMD.The portability of the device means that it can be deployed to measure BMD for frail patients at the bedside (avoiding the complications in transfer and positioning which can occur with DXA), in primary care, the emergency department, low-resource settings and even at home.The current evidence base supports the technology as a useful tool in the management of osteoporosis as an alternative to DXA.

SHBG gene polymorphisms and their influence on serum SHBG, total and free testosterone concentrations in men.

CONTEXT: Genetic variation in sex hormone-binding globulin (SHBG) structure may affect estimates of sex steroid exposure by altering the affinity of the protein for its ligand. Consequently, free hormone calculations assuming constant binding affinity may, for certain genetic variations, lead to incorrect diagnoses if genetic variation is not taken into consideration. OBJECTIVE: To investigate the effects of genetic variation in SHBG on calculated and measured serum free testosterone (T) in men. DESIGN, SETTING AND PARTICIPANTS: Population-based sibling-pair study in 999 healthy men aged 25 to 45 (mean: 34.5) years. MAIN OUTCOME MEASURES: Genotyping using microarray (Illumina®) for SNPs suggested to affect binding affinity and/or concentration of SHBG or T. SHBG concentrations were measured using immunoassay and in a subset (n = 32) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Total T was measured using LC-MS/MS. Free T was calculated and in a subset (n = 314) measured directly using LC-MS/MS after equilibrium dialysis. RESULTS: Allelic frequencies of analyzed SNPs ranged from 0.5% to 58.2%. Compared to wild-type, SHBG concentrations were lower in rs6258 heterozygotes (-24.7%; p < 0.05) and higher in rs6259 heterozygotes, rs727428 homozygotes, and carriers of rs1799941 (+10.8 to 23.1%; all p < 0.05). Total T was higher in rs727428 homozygotes and carriers of rs5934505, rs1799941and rs6259 (+3.9 to 21.4%; all p < 0.05). No clear effects on measured free T were found, except for a trend towards higher values in rs6259 homozygotes, significant for calculated free T (+18.7%; p < 0.05) in the larger global study population. CONCLUSION: In these men, analyzed SNPs were relatively prevalent and affected serum concentrations of total T and SHBG but not calculated or measured free T except for a higher trend in rs6259 homozygotes.

Evidence-Based Guideline for the management of osteoporosis in men.

Historically, osteoporosis has been viewed as a disease of women, with research, trials of interventions and guidelines predominantly focused as such. It is apparent, however, that this condition causes a substantial health burden in men also, and that its assessment and management must ultimately be addressed across both sexes. In this article, an international multidisciplinary working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases presents GRADE-assessed recommendations for the diagnosis, monitoring and treatment of osteoporosis in men. The recommendations are based on a comprehensive review of the latest research related to diagnostic and screening approaches for osteoporosis and its associated high fracture risk in men, covering disease burden, appropriate interpretation of bone densitometry (including the use of a female reference database for densitometric diagnosis in men) and absolute fracture risk, thresholds for treatment, and interventions that can be used therapeutically and their health economic evaluation. Future work should specifically address the efficacy of anti-osteoporosis medications, including denosumab and bone-forming therapies.

Physiological declines in sex steroid exposure in relation to changes in body composition in healthy men-a prospective cohort study.

OBJECTIVE: Androgen levels decline from early adulthood and decreases are steeper in men with increasing body mass index. It is, however, unclear to what extent changes in other indices of body composition and metabolism associate with changes in sex steroid levels in healthy men. Therefore, this study investigated longitudinal changes in body composition and metabolic health in relation to sex steroid levels in healthy adult men. DESIGN: This is a longitudinal, population-based study. A total of 676 healthy men aged 24-46 years were measured at baseline and after ±12 years. METHODS: Serum sex hormone-binding globulin (SHBG) was measured by immunoassay, testosterone (T), estradiol (E2), and dihydrotestosterone byliquid chromatography with tandem mass spectrometry (LC-MS/MS), calculated free T and calculated free E2 (cFE2), and homeostasis model assessment for insulin resistance (HOMA-IR) were calculated. Grip strength was measured by hand-grip dynamometry. Body composition was determined using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. RESULTS: Mean fat mass (FM), lean mass (LM), and HOMA-IR increased (all P < .001). Decreasing androgen and SHBG levels was associated with increasing FM, whereas decreasing (cF)E2 levels were associated with decreasing FM (all P < .005). Decreasing (cF)E2 levels and increasing SHBG levels associated with decreasing LM (all P < .002). Changes in sex steroid levels and HOMA-IR or grip strength were not interrelated. CONCLUSION: Aging leads to increases in FM indices and insulin resistance, whereas changes in parameters of LM are less unequivocal. In healthy adult men, physiological changes in sex steroid exposure clearly correlate with changes in adiposity but not so with lean mass, insulin resistance, or grip strength. CLINICAL TRIAL: The SIBEX study was registered on ClinicalTrials.gov (#NVT02997033).

Sex differences and sex steroids influence on the presentation and severity of cardiovascular autonomic neuropathy of patients with type 1 diabetes.

BACKGROUND: Sex differences characterize cardiovascular outcomes in patients with type 1 diabetes. Cardioautonomic neuropathy is a common complication of type 1 diabetes that associates increased morbi-mortality. Data regarding the interplay between sex and cardiovascular autonomic neuropathy are scarce and controversial in these patients. We aimed to address sex-related differences in the prevalence of seemingly asymptomatic cardioautonomic neuropathy in type 1 diabetes, and their associations with sex steroids. METHODS: We conducted a cross-sectional study including 322 consecutively recruited patients with type 1 diabetes. Cardioautonomic neuropathy was diagnosed using Ewing's score and power spectral heart rate data. We assessed sex hormones by liquid chromatography/tandem mass spectrometry. RESULTS: When considering all subjects as a whole, asymptomatic cardioautonomic neuropathy prevalence was not significantly different between women and men. When age was taken into account, the prevalence of cardioautonomic neuropathy was similar among young men and those > 50 years. However, in women > 50 years, the prevalence of cardioautonomic neuropathy doubled that of young women [45.8% (32.6; 59.7) vs. 20.4% (13.7; 29.2), respectively]. The OR of having cardioautonomic neuropathy was 3.3 higher in women > 50 years than in their younger counterparts. Furthermore, women presented more severe cardioautonomic neuropathy than men. These differences were even more marked when women were classified according their menopausal status instead of age. Peri- and menopausal women had an OR 3.5 (1.7; 7.2) of having CAN compared with their reproductive-aged counterparts [CAN prevalence: 51% (37; 65) vs. 23% (16; 32), respectively]. A binary logistic regression model (R2: 0.161; P = 0.001) displayed age > 50 years as a significant determinant of cardioautonomic neuropathy only in women. Androgens were positively associated with heart rate variability in men, and negatively in women. Accordingly, cardioautonomic neuropathy was associated with increased testosterone/estradiol ratio in women but to decreased testosterone concentrations in men. CONCLUSIONS: Menopause in women with type 1 diabetes is accompanied by an increase in the prevalence of asymptomatic cardioautonomic neuropathy. This age-related excess risk of cardioautonomic neuropathy is not observed in men. Men and women with type 1 diabetes have opposite associations between circulating androgens and indexes of cardioautonomic function. Trial registration ClinicalTrials.gov Identifier: NCT04950634.

Diagnosis of hypogonadism in ageing men.

To make the diagnosis of hypogonadism in an ageing man, in absence of rare organic cause often referred to as functional or late onset hypogonadism (LOH), he should present with a clinical syndrome suggestive of androgen deficiency and have consistently low serum testosterone (T) levels. This does not differ from the diagnosis of any other form of hypogonadism. Particular to LOH diagnostic are uncertainties surrounding this entity: signs and symptoms of androgen deficiency (including sexual symptoms) are nonspecific in older men; clinical significance of only moderately low T levels is uncertain; comorbidity plays a substantial role with potential for reversibility; the place of T therapy in these men is debatable. This context demands for a pragmatic, but appropriately conservative approach to diagnosis. Evaluation should be stepwise with clinical evaluation, if suggestive for androgen deficiency, followed by measurement of a fasting morning serum T, if unequivocally low to be confirmed in a separate morning sample by a second low T or, if initial T borderline low or in presence of factors known to affect SHBG, by a low calculated free T level. All other (free) T results make hypogonadism an unlikely cause of the patient's symptoms. In the absence of consensus cut-off levels for total and free T in the published clinical guidelines for diagnosis of hypogonadism, it seems appropriate in the context of LOH to use stringent criteria indicating a convincingly low serum T. The approach to the diagnosis of LOH is not fundamentally different from that of other forms of hypogonadism but should put extra weight on prioritizing the shunning of overdiagnosis above the risk of underdiagnosis.

Novel formulations of oral bisphosphonates in the treatment of osteoporosis.

Oral bisphosphonates are a key intervention in the treatment of osteoporosis and in reducing the risk of fragility fractures. Their use is supported by over 3 decades of evidence; however, patient adherence to oral bisphosphonates remains poor in part due to complex dosing instructions and adverse events, including upper gastrointestinal symptoms. This problem has led to the development of novel oral bisphosphonate formulations. Buffered, effervescent alendronate is dissolved in water and so seeks to reduce upper gastro-intestinal adverse events, and gastro-resistant risedronate aims to reduce the complexity of dosing procedure (e.g. fasting prior to consumption) whilst still maintaining the efficacy of fracture risk reduction. Clinical trials and real-world data have been employed to demonstrate some benefits in terms of reduced upper gastro-intestinal adverse events, adherence, persistence and health economic outcomes. This report describes the result of an ESCEO (European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis) expert working group, which explores where oral bisphosphonates sit in current clinical practice guidelines, review their risk-benefit profile and the consequences of poor adherence before exploring novel oral bisphosphonate formulations and their potential clinical and health economic impact. Further research is required but there are signs that these novel, oral bisphosphonate formulations may lead to improved tolerance of oral bisphosphonates and thus, improved adherence and fracture outcomes.

Role of vitamin D supplementation in the management of musculoskeletal diseases: update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group.

Vitamin D is a key component for optimal growth and for calcium-phosphate homeostasis. Skin photosynthesis is the main source of vitamin D. Limited sun exposure and insufficient dietary vitamin D supply justify vitamin D supplementation in certain age groups. In older adults, recommended doses for vitamin D supplementation vary between 200 and 2000 IU/day, to achieve a goal of circulating 25-hydroxyvitamin D (calcifediol) of at least 50 nmol/L. The target level depends on the population being supplemented, the assessed system, and the outcome. Several recent large randomized trials with oral vitamin D regimens varying between 2000 and 100,000 IU/month and mostly conducted in vitamin D-replete and healthy individuals have failed to detect any efficacy of these approaches for the prevention of fracture and falls. Considering the well-recognized major musculoskeletal disorders associated with severe vitamin D deficiency and taking into account a possible biphasic effects of vitamin D on fracture and fall risks, an European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group convened, carefully reviewed, and analyzed the meta-analyses of randomized controlled trials on the effects of vitamin D on fracture risk, falls or osteoarthritis, and came to the conclusion that 1000 IU daily should be recommended in patients at increased risk of vitamin D deficiency. The group also addressed the identification of patients possibly benefitting from a vitamin D loading dose to achieve early 25-hydroxyvitamin D therapeutic level or from calcifediol administration.

Modest Changes in Sex Hormones During Early and Middle Adulthood Affect Bone Mass and Size in Healthy Men: A Prospective Cohort Study.

Bone metabolism in men is in part determined by sex steroid exposure. This is especially clear during puberty and senescence but it remains to be established whether declines in sex steroid levels during young and middle adulthood are associated with changes in bone mass and size. This study investigated changes in bone mineral content (BMC), areal bone mineral density (aBMD), volumetric BMD (vBMD), and bone size in relation to sex steroid levels in 999 young adult men (age 24-46 years) of whom 676 were re-evaluated after a mean period of 12 years. Sex hormone-binding globulin (SHBG) levels were measured using immunoassay, testosterone (T) and estradiol (E2) using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and free fractions were calculated (cFT and cFE2, respectively). Areal bone parameters and BMC were measured at the hip and lumbar spine using dual-energy X-ray absorptiometry (DXA). Radial and tibial vBMD and bone size were determined using peripheral quantitative computed tomography (pQCT). Linear mixed models were used for statistical analyses. With aging, we observed decreases in almost all bone mass and density indices, whereas changes in bone geometry resulted in larger bones with thinner cortices. These changes in bone mass and size appeared related to sex steroid levels. Specifically, decreases in cFT (but not total T) levels were associated with larger decreases in lumbar spine BMC and especially with geometric changes in cortical bone at the tibia. Similarly, decreases in total E2 and cFE2 were associated with larger decreases in bone mass (all sites) and also with some geometric changes. Also increases in SHBG were independently associated with aging-related changes in bone mass and size in these men. In summary, even small changes in T, E2, and SHBG levels during young and middle adulthood in healthy men are associated with changes in bone mass and size. © 2022 American Society for Bone and Mineral Research (ASBMR).

Management of patients at very high risk of osteoporotic fractures through sequential treatments.

Osteoporosis care has evolved markedly over the last 50 years, such that there are now an established clinical definition, validated methods of fracture risk assessment and a range of effective pharmacological agents. Currently, bone-forming (anabolic) agents, in many countries, are used in those patients who have continued to lose bone mineral density (BMD), patients with multiple subsequent fractures or those who have fractured despite treatment with antiresorptive agents. However, head-to-head data suggest that anabolic agents have greater rapidity and efficacy for fracture risk reduction than do antiresorptive therapies. The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) convened an expert working group to discuss the tools available to identify patients at high risk of fracture, review the evidence for the use of anabolic agents as the initial intervention in patients at highest risk of fracture and consider the sequence of therapy following their use. This position paper sets out the findings of the group and the consequent recommendations. The key conclusion is that the current evidence base supports an "anabolic first" approach in patients found to be at very high risk of fracture, followed by maintenance therapy using an antiresorptive agent, and with the subsequent need for antiosteoporosis therapy addressed over a lifetime horizon.

The relationship between circulating hormone levels, bone turnover markers and skeletal development in healthy boys differs according to maturation stage.

INTRODUCTION: This study investigates peri-pubertal changes in bone turnover markers, Wnt-signalling markers, insulin-like growth factor-1 (IGF-1) and sex steroid levels, and how they reflect skeletal development in peri-pubertal boys. MATERIALS AND METHODS: Population-based study in 118 peri-pubertal boys from the NINIOS cohort (age range at baseline 5.1-17.3 years) with repeated measurements at baseline and after two years. Serum levels of the classical bone turnover markers (BTM) procollagen type 1 N-terminal propeptide and carboxy-terminal collagen crosslinks, as well as sex-hormone binding globulin, IGF-1, osteoprotegerin, sclerostin and dickkopf-1 were measured using immunoassays. Sex steroids (estradiol, testosterone, and androstenedione) were measured using mass spectrometry and free fractions calculated. Dual energy x-ray absorptiometry was used for bone measurements at the lumbar spine and whole body. Volumetric bone parameters and bone geometry at the proximal and distal radius were assessed by peripheral QCT. Pubertal development was categorized based on Tanner staging. RESULTS: During puberty, sex steroid and IGF-1-levels along with most parameters of bone mass and bone size increased every next Tanner stage. In contrast, classical bone turnover markers and sclerostin peaked around mid-puberty, with subsequent declines towards adult values in late puberty. Especially classical BTM and sex steroid levels showed consistent associations with areal and volumetric bone parameters and bone geometry. However, observed associations differed markedly according to pubertal stage and skeletal site. CONCLUSION: Serum levels of sex steroids, IGF-1 and bone metabolism markers reflect skeletal development in peri-pubertal boys. However, skeletal development during puberty is nonlinear, and the relations between skeletal indices and hormonal parameters are nonlinear as well, and dependent on the respective maturation stage and skeletal site.

Clinical Value of Serum Levels of 11-Oxygenated Metabolites of Testosterone in Women With Polycystic Ovary Syndrome.

CONTEXT: Recent data suggested that 11-oxygenated androgens may be the preponderant circulating androgens in women with PCOS. However, the pathophysiological significance of these hormones remains unclear. OBJECTIVE: The aim of this study was to evaluate the relationships between serum 11-OH testosterone (11-OHT) and 11-keto testosterone (11-KetoT) and clinical and biochemical hyperandrogenism, as well as the metabolic parameters, in women with PCOS. METHODS: The main classic and 11-oxygenated androgens were measured by LC-MS/MS and direct equilibrium dialysis in 123 women with PCOS, diagnosed according to the Rotterdam criteria, and 38 healthy controls. Insulin sensitivity was assessed by hyperinsulinemic euglycemic clamp. RESULTS: Serum 11-oxygenated androgens were higher in women with PCOS than in controls. Elevated levels of 11-OHT and 11-KetoT were found in 28.5% and 30.1% of PCOS women, respectively, whereas free testosterone (FT) was increased in 61.0% of them. Serum 11-oxygenated androgens showed a limited performance in recognizing women with classically defined hyperandrogenism. Unlike FT, 11-oxygenated androgens did not show significant relationships with anthropometric and metabolic parameters, except for a direct association with insulin sensitivity. In multivariable analysis, 11-OHT and 11-KetoT, directly, and FT, inversely, remained significant independent predictors of insulin sensitivity. CONCLUSIONS: Serum levels of 11-oxygenated androgens are higher in women with PCOS than in controls. However, these hormones show a poor performance in recognizing women with hyperandrogenism, as currently defined. The relationships of these androgens with insulin sensitivity strongly differ from that of FT, suggesting a different role of classic and 11-oxygenated androgens in the pathophysiology of PCOS.

Insulin-Mediated Substrate Use in Women With Different Phenotypes of PCOS: the Role of Androgens.

CONTEXT: Few studies have explored in vivo insulin action on substrate use in women with PCOS. In particular, no data are available in women with different PCOS phenotypes. OBJECTIVE: The aim of the study was to evaluate insulin action on glucose (Gox) and lipid (Lox) oxidation, nonoxidative glucose metabolism (Gnonox), and serum free fatty acids (FFAs) in different PCOS phenotypes. METHODS: Participants included 187 nondiabetic women with PCOS diagnosed according to the Rotterdam criteria. Data from a historical sample of 20 healthy women were used as reference values. Whole-body substrate use data were obtained by the hyperinsulinemic euglycemic clamp associated with indirect calorimetry. Serum androgens were assessed by liquid chromatography-mass spectrometry and equilibrium dialysis. RESULTS: During hyperinsulinemia, the increase of Gox (ΔGox), Gnonox, as well as the suppression of Lox (ΔLox) and serum FFA (Δ% FFA) were altered in each PCOS phenotype. Moreover, Gnonox and Δ% FFA were lower in women with the classic phenotype than in those with the ovulatory or the normoandrogenic phenotypes, and ΔGox was lower in women with the classic than in those with the ovulatory phenotype. In multivariable analysis fat mass and free testosterone were independent predictors of ΔGox, Gnonox, and Δ% FFA, whereas only fat mass predicted ΔLox. CONCLUSION: In women with PCOS, regardless of phenotype, insulin-mediated substrate use is impaired. This phenomenon is greater in individuals with the classic phenotype. Free testosterone plays an independent role in insulin action abnormalities in glucose and lipid metabolism.

Management of osteoporosis in older men.

As many as one out of three fragility fractures occur in older men and the outcome of major osteoporotic fractures, in particular hip fractures, is worse in men than in women. Osteoporosis in older men is thus an important threat to the quality of life of individual patients and a considerable burden for society. However, only a small minority of older men with high or very high fracture risk are receiving therapy. This does not need to be so as tools for fracture risk assessment are available and several drugs have been approved for treatment. Nevertheless, the evidence base for the management of osteoporosis in older men remains limited. This narrative review summarises the evidence for older men on the burden of osteoporosis, the pathophysiology of fragility fractures, the clinical presentation, diagnosis and risk assessment, the patient evaluation, and the non-pharmacological and pharmacological management.

2019 revised algorithm for the management of knee osteoarthritis: the Southeast Asian viewpoint.

BACKGROUND: Since 2014, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) algorithm for the management of knee osteoarthritis (OA) is available worldwide. AIM: Based on this document, a Southeast Asia Working Group (SEAWG) wished to see how the new ESCEO algorithm developed in 2019 was perceived by Southeast Asian experts and how it was integrated into their clinical practice. METHODS: A SEAWG was set up between members of the international ESCEO task force and a group of Southeast Asian experts. RESULTS: Non-pharmacological management should always be combined with pharmacological management. In step 1, symptomatic slow-acting drugs for osteoarthritis are the main background therapy, for which high-quality evidence is available only for the formulations of patented crystalline glucosamine sulfate and chondroitin sulfate. In step 2, oral NSAIDs are a useful option, considering the cardiovascular/renal/gastrointestinal profiles of the individual patient. Intra-articular hyaluronic acid and corticosteroids are a possible alternative to oral NSAIDs, but limited evidence is available. If steps 1 and 2 do not give adequate relief of symptoms, tramadol can be used, but its safety is debated. In general, the indications of the ESCEO algorithm are important in Southeast Asian countries, but the reimbursement criteria of local health systems are an important aspect for adherence to the ESCEO algorithm. CONCLUSION: This guidance provides evidence-based and easy-to-follow advice on how to establish a treatment algorithm in knee OA, for practical implementation in clinical practice in Southeast Asian countries.

Metabolism of testosterone during weight loss in men with obesity.

OBJECTIVE: Men with obesity often have low total and, with increasing adiposity, also low free testosterone (T) levels, which can partially restore during weight loss. Although this is partly explained by lower sex hormone binding globulin (SHBG) production and hypothalamic-pituitary downregulation, it is still not unravelled whether changes in androgen metabolism contribute to this phenomenon. Therefore, early changes in urinary excretion of T and its metabolites, during weight loss, in men with obesity are investigated. DESIGN: Longitudinal study. METHODS: Fourteen men with obesity (age 52(45-60)years, BMI 42.6(41.8-44.8)kg/m²) underwent gastric bypass surgery (GBS). Before surgery and 3 weeks, 6 weeks, 6 months and 1 year thereafter, 24 h urine and fasting serum samples were collected. Serum T and estradiol (E2) levels were analyzed using LC-MS/MS and urinary metabolites of T with GC-MS/MS. RESULTS: Already three weeks after GBS, serum SHBG and total T levels increased and remained increased as compared to baseline (all,p < 0.0125). Gonadotropins and (free) E2 levels were unchanged, serum E2/T ratio decreased (p < 0.0125). Total amount of urinary T increased non-significantly with mean increases of 53 % one year after GBS (p = 0.026). Urinary E2/T, estrone/T, 3α-androstanediol/T and androsterone/T ratios decreased after GBS (p < 0.0125). CONCLUSIONS: Restoration of circulating T levels during weight loss in this population is not only brought about by normalization of circulating SHBG levels, but increased production of and alterations in T metabolism also contribute. More specifically, relative decreases in aromatization and lower 5α-reductase activity might also be involved in restoring T levels in men with obesity.

Early Decline of Androgen Levels in Healthy Adult Men: An Effect of Aging Per Se? A Prospective Cohort Study.

CONTEXT: Androgen levels have been shown to decline in aging men. However, there is no consensus on the effect of aging, (changes in) body mass index (BMI), lifestyle factors, and intercurrent disease. OBJECTIVE: Investigating longitudinal changes in serum androgen levels in healthy men in relation to body composition, lifestyle factors, and intercurrent disease. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal, population-based sibling pair study at a university research center. 999 healthy men aged 24 to 46 years of whom 691 were reevaluated after a mean period of 12 years. MAIN OUTCOME MEASURES: Serum SHBG, LH, and FSH levels measured using immuno-assays. Testosterone (T), estradiol (E2), dihydro-testosterone (DHT), and androstenedione (Adione) measured using liquid chromatography-tandem mass spectometry, free T calculated (cFT). RESULTS: Baseline age was 34 ±â€…6 years. Mean BMI increased by 1.19 kg/m2, T levels decreased by 14.2% (20.8 nmol/L vs. 17.8 nmol/L), cFT by 19.1% (392 pmol/L vs. 317 pmol/L), DHT by 15.6% (1.5 nmol/L vs.1.3 nmol/L), and Adione by 10.7% (3.7 nmol/L vs. 3.3 nmol/L; all P < 0.001). E2 did not change over time. SHBG increased by 3.0% (39.8 nmol/L vs. 41.0 nmol/L), LH by 5.8% (4.6 U/L vs. 4.9 U/L) and FSH by 14.7% (4.3 U/L vs. 5.1 U/L) (all P < 0.001). For T, cFT, DHT, Adione, and SHBG, these longitudinal changes persisted after adjustment for confounders (all P < 0.001). CONCLUSION: Serum androgen levels start declining early during adult life and independently from changes in BMI and other lifestyle factors, suggesting that aging per se leads to an altered sex steroid status. Given the concurrent rise in gonadotropin levels, the decline in androgen status most likely arises from primary decrease in testicular function.

MANAGEMENT OF ENDOCRINE DISEASE: Rationale and current evidence for testosterone therapy in the management of obesity and its complications.

Overt hypogonadism in men adversely affects body composition and metabolic health, which generally improve upon testosterone (TS) therapy. As obese men often display lower serum TS levels, in particular when they present with the metabolic syndrome (MetS) or type 2 diabetes (T2DM), there have been claims that androgen therapy prevents or reverses obesity and improves metabolic health. This has contributed to the increase in TS prescriptions during the past two decades. In this narrative review, based on findings from larger observational studies and randomized controlled intervention trials, we evaluate whether low TS predicts or predisposes to obesity and its metabolic consequences, and whether obese men with low TS are truly hypogonadal. We further describe the mechanisms underlying the bi-directional relationships of TS levels with obesity and metabolic health, and finally assess the evidence for TS therapy in men with obesity, MetS and/or T2DM, considering efficacy, safety concerns and possible alternative approaches. It is concluded that low serum sex hormone-binding globulin and total TS levels are highly prevalent in obese men, but that only those with low free TS levels and signs or symptoms of hypogonadism should be considered androgen deficient. These alterations are reversible upon weight loss. Whether low TS is a biomarker rather than a true risk factor for metabolic disturbances remains unclear. Considering the limited number of sound TS therapy trials have shown beneficial effects, the modest amplitude of these effects, and unresolved safety issues, one cannot in the present state-of-the-art advocate TS therapy to prevent or reverse obesity-associated metabolic disturbances. Instead, the focus should remain on lifestyle measures and management of obesity-related consequences.