Effects of transdermal testosterone treatment on inflammatory markers in elderly males.

OBJECTIVE: During the male aging process, testosterone (T) levels progressively fall and inflammatory biomarkers increase. Although a relationship between these 2 phenomena has been tested in previous clinical trials, there is inconclusive evidence about the potential anti-inflammatory action of T. METHODS: A total of 108 healthy males >65 years with serum T concentration <475 ng/dL were recruited by direct mailings to alumni of the University of Pennsylvania and Temple University and randomized to 60-cm2 T or a placebo patch for 36 months. Ninety-six subjects completed the trial. Information and stored serum specimens from this trial were used to test the hypothesis of the inhibitory effect of T on inflammation. We evaluated 70 males (42 in the T group) who had banked specimens from multiple time points available for assays of T, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, soluble TNF-α receptor-1 (TNFR1), interleukin-6 (IL-6), and soluble IL-6 receptors (sIL6r and sgp130). RESULTS: The mean age ± SD at baseline was 71.8 ± 4.9 years. Testosterone replacement therapy for 36 months did not induce significant decreases in inflammatory markers. A trend toward a significant increase was observed in the placebo group for TNF-α (P = .03) and sgp130 (P = .01). Significant differences in estimated means of TNFR1 (but not other inflammatory markers), with lower levels in the T group, were observed at the 36-month time point. In T-treated subjects we found an almost significant treatment x time interaction term TNFR1 (P = .02) independent of total body fat content as assessed by dual energy X-ray absorptiometry (DXA). No serious adverse effect was observed. CONCLUSIONS: Transdermal T treatment of older males for 36 months is not associated with significant changes in inflammatory markers.

Mild thyroid hormone excess is associated with a decreased physical function in elderly men.

INTRODUCTION: In the adult, subclinical hyperthyroidism (Shyper) may alter skeletal muscle mass and strength. However, whether these effects are present in elderly subjects is not known. We explored the relationship between mild hyperthyroidism and physical function in a population-based sample of older persons. METHODS: In a cross-sectional analysis, calf muscle cross-sectional area (CMA), handgrip strength, nerve conduction velocity (NCV), and Short Physical Performance Battery (SPPB) scores were compared between 364 euthyroid (Eut) and 28 Shyper men as well as between 502 Eut and 39 Shyper women. In a longitudinal analysis, we evaluated the relationship between baseline plasma TSH, FT3 and FT4 and the 3-year change in SPPB score in 304 men and 409 women who were euthyroid at enrolment. RESULTS: At the cross-sectional analysis, Shyper men, but not women, had a significantly (p = 0.02) lower SPPB score than Eut controls, although with comparable CMA, grip strength and NCV, and were more likely to have poor physical performance (odds ratio = 2.97, p < 0.05). Longitudinal analysis showed that in Eut men higher baseline FT4 was significantly (p = 0.02) predictive of a lower SPPB score at the 3-year follow-up. CONCLUSION: Even a modest thyroid hormone excess is associated with a reduced physical function in elderly men.

Gonadal status and physical performance in older men.

OBJECTIVE: To test the relationship between gonadal status and objective measures and determinants of physical performance in older men and their determinants. METHODS: The study included 455 ≥ 65 year older men of InCHIANTI study, Italy, with complete data on testosterone levels, hand grip strength, cross-sectional muscle area (CSMA), short physical performance battery (SPPB). Linear models were used to test the relationship between gonadal status and determinants of physical performance. RESULTS: Three different groups of older men were created: (1) severely hypogonadal (N=23), total testosterone levels ≤ 230 ng /dl; (2) moderately hypogonadal (N=88), total testosterone >230 and < 350 ng/dl) and (3) eugonadal (N=344), testosterone levels ≥ 350 ng/dl. With increased severity of hypogonadal status, participants were significantly older while their BMI was substantially similar. In the age and BMI adjusted analysis, there was a significant difference in haemoglobin levels, hand grip strength and SPPB score (p for trend < 0.001) among three groups, with severely hypogonadal men having lower values of haemoglobin, muscle strength and physical performance. We found no association between testosterone group assignment and calf muscle mass and 4 m walking speed. In the multivariate analysis grip strength (p for trend = 0.004) and haemoglobin (p for trend < 0.0001) but not SPPB and other determinants of physical performance were significantly different between the three groups. CONCLUSIONS: In older men, gonadal status is independently associated with some determinants (haemoglobin and muscle strength) of physical performance.

Vitamin D in older population: new roles for this 'classic actor'?

Vitamin D is a group of lipophilic hormones with pleiotropic actions. It has been traditionally related to bone metabolism, although several studies in the last decade have suggested its role in muscle strength and falls, cardiovascular and neurological diseases, insulin-resistance and diabetes, malignancies, autoimmune diseases and infections. Vitamin D appears to be a hormone with several actions and is fundamental for many biological systems including bone, skeletal muscle, brain and heart. The estimated worldwide prevalence of vitamin D deficiency of 50% in elderly subjects underlines the importance of vitamin D deficiency for public health. In this review, we will describe changes in vitamin D levels with age in both sexes, cut off values to define Vitamin D status, the impact of vitamin D deficiency in age-related disease and finally different therapeutic options available to treat Vitamin D deficiency in older populations.

Aging as an allostasis condition of hormones secretion: summing up the endocrine data from the inChianti study.

Aging phenomena can be seen as a breakdown of the intercellular organisation mechanisms like those represented by endocrine secretions. Such hypothesis is decidedly supported by the analysis of endocrine data coming out from the epidemiological inChianti study. Among the age related endocrine changes a leading role is played by the decline of hormones capable of anabolic effect like Testosterone, IGF-1, DHEAS on the one hand and on the other hand by the even slight increase of the hormones capable of catabolic activity like Cortisol and thyroid hormones. The derangement of this endocrine equilibrium that can be defined with the term of "allostasis", when chronically protracted, might be seen as responsible for many aging phenomena. Consequently specific hormone supplementations might be suggested as a proper strategy to counteract the functional declines occurring in the last decades of life. Nevertheless clinical intervention trials are mandatory in order to validate the hypothesis and to properly verify the risk/benefit ratio.

The concept of multiple hormonal dysregulation.

Aging process is accompanied by hormonal changes characterized by an imbalance between catabolic hormones that remain stable and anabolic hormones (testosterone, insulin like growth factor-1 (IGF-1) and dehydroepiandrosterone sulphate (DHEAS), that decrease with age. Despite the multiple hormonal dysregulation occurring with age, the prevalent line of research in the last decades has tried to explain many age-related phenomena as consequence of one single hormonal derangement with disappointing results. In this review we will list the relationship between hormonal anabolic deficiency and frailty and mortality in older population, providing evidence to the notion that multiple hormonal dysregulation rather than change in single anabolic hormone is a powerful marker of poor health status and mortality.

Subclinical thyroid disease in elderly subjects.

Subclinical thyroid disease (STD) is defined as circulating concentrations of free T4 and free T3 within their respective reference ranges in the presence of abnormal circulating concentrations of TSH. SCD is being diagnosed more frequently in clinical practice and is reported to be more prevalent in elderly as compared to young or adult subjects. The clinical impact of subclinical thyroid dysfunction is still a matter of debate, although it has been associated with various negative clinical outcomes, such as increased cardiovascular risk, reduction in bone density, decline in cognitive function, and increased risk of overt thyroid dysfunction. The treatment of STD is controversial and there is no consensus on the TSH cutoff values which can be used as indicators for treatment, especially in elderly subjects. In the present review, we report data on the prevalence of STD and on the potential clinical consequences of these disorders. Also, data of the Literature regarding the issue of the treatment of STD in relation to the age of the patient are reported.

Update on new therapeutic options for the somatopause.

During the last decade, a significant body of evidence has accumulated, indicating that the declining activity of the GH-IGF-I axis with aging might play a role in the development of frailty and in several pathological conditions commonly seen during aging, such as atherosclerosis, cardiovascular disease, and cognitive decline. GH therapy has become widely popular as antiaging therapy in order to counteract the age-related decline in muscle mass and strength and the increase in fat mass. However there are only few proven beneficial effects of GH therapy in healthy elderly subjects and its use remains highly controversial in the scientific community. In this paper we will review the current evidence related to the use of GH and/or GH-secretagogues in normal and pathological aging.

[Dehydroepiandrosterone [DHEA(S)]: anabolic hormone?]. / Deidroepiandrosterone [DHEA(S)]: ormone anabolico?

The role of dehydroepiandrosterone (DHEA) and its sulphated form (DHEAS) as anabolic hormones is still debated in the literature. In this review we describe the fundamental steps of DHEA physiological secretion and its peripheral metabolism. Moreover we will list all the observational and intervention studies conducted in humans. Many observational studies have tested the relationship between low DHEA levels and age-related changes in skeletal muscle and bone, while intervention studies underline the positive and significant effects of DHEA treatment on several parameters of body composition. Surprisingly, observational studies are not consistent with different effects in men and women. There is recent evidence of a significant role of DHEA in frailty syndrome and as predictor of mortality. However a more complete approach of the problem suggests the opportunity to not focus only on one single hormonal derangement but to analyze the parallel dysregulation of anabolic hormones including sex steroids, GH-IGF-1 system and other catabolic hormones.

Estradiol and inflammatory markers in older men.

BACKGROUND: Aging is characterized by a mild proinflammatory state. In older men, low testosterone levels have been associated with increasing levels of proinflammatory cytokines. It is still unclear whether estradiol (E2), which generally has biological activities complementary to testosterone, affects inflammation. METHODS: We analyzed data obtained from 399 men aged 65-95 yr enrolled in the Invecchiare in Chianti study with complete data on body mass index (BMI), serum E2, testosterone, IL-6, soluble IL-6 receptor, TNF-alpha, IL-1 receptor antagonist, and C-reactive protein. The relationship between E2 and inflammatory markers was examined using multivariate linear models adjusted for age, BMI, smoking, physical activity, chronic disease, and total testosterone. RESULTS: In age-adjusted analysis, log (E2) was positively associated with log (IL-6) (r = 0.19; P = 0.047), and the relationship was statistically significant (P = 0.032) after adjustments for age, BMI, smoking, physical activity, chronic disease, and serum testosterone levels. Log (E2) was not significantly associated with log (C-reactive protein), log (soluble IL-6 receptor), or log (TNF-alpha) in both age-adjusted and fully adjusted analyses. CONCLUSIONS: In older men, E2 is weakly positively associated with IL-6, independent of testosterone and other confounders including BMI.

Effect of estrogen therapy for 1 year on thyroid volume and thyroid nodules in postmenopausal women.

OBJECTIVE: Estrogen receptors are present in thyroid follicular cells in normal and neoplastic tissue. We evaluated changes in total thyroid volume and volume of thyroid nodules in postmenopausal women given either hormone therapy (HT) or no treatment in a 1-year observational follow-up. DESIGN: We studied 33 women receiving HT and 76 women receiving no treatment, comparing total thyroid volume, thyroid nodule volume, and serum concentrations of thyroid-stimulating hormone and estradiol at baseline and 1 year of follow-up. RESULTS: Serum thyroid-stimulating hormone concentrations were not different between groups either at baseline or at 1 year. Estradiol rose significantly in the HT group. The final percent changes in total thyroid volume were comparable between groups (HT, 1.59 +/- 2.56%; no treatment, 1.20 +/- 2.28%). At baseline, nodules were detected in 17 (51.5%) and 33 (43.4%) of women in the HT and no treatment groups, respectively, with no statistically significant difference between groups. The final number of nodules was unchanged or reduced in 88.2% and 81.1% and increased in 11.8% and 18.9% of women in the HT and no treatment groups, respectively, with no differences between groups. Baseline volumes of thyroid nodules were 0.8 +/- 0.4 and 1.4 +/- 0.4 mL in women in the HT and no treatment groups, respectively (P = 0.4). After 1 year the volume of thyroid nodules was unchanged or reduced in 47.1% and 52.8% and increased in 52.9% and 47.2% of women in the HT and no treatment groups, respectively, with no differences between groups. CONCLUSIONS: Estrogen administration for 1 year did not affect thyroid volume or the number and volume of thyroid nodules in postmenopausal women.

Inverse relationship between scores on the quality of life questionnaire SF-12 and on the Aging Males' Symptoms scale in Italian men.

OBJECTIVES: To analyse the relation between results of the Aging Males' Symptoms (AMS) questionnaire for aging males, and of quality of life (QOL) questionnaire SF-12 and cardiovascular risk factors. METHODS: 1,927 men aged 55-85 years were interviewed by 56 general practitioners. During the interview the men were asked to fill in the AMS scale and the QOL questionnaire SF-12. RESULTS: Of 1,927 men 1,806 men filled correctly the AMS questionnaire. The mean SF-12 mental index was respectively 55.9 in men with a total AMS score indicating no impairment, 50.9 mild, 42.8 moderate, and 32.8 severe impairment. The corresponding values for the physical index were 51.2, 46.7, 40.8 and 32.3. A history of diabetes was associated with an increased risk of reporting moderate/severe impairment: in relation to the total AMS score the odds ratio, (OR), of moderate/severe impairment in comparison with no impairment was 1.6 (95%CI 1.2-2.1). A history of myocardial infarction and hypertension increased the risk (respectively OR 1.4 (95%CI 1.1-18) and 1.7 (95%CI 1.2-2.4)). CONCLUSIONS: This study shows that higher AMS scores are associated with lower SF-12 indices and suggests that elevated values of the AMS score are associated with cardiovascular risk factors or diseases.

Relationship between low levels of anabolic hormones and 6-year mortality in older men: the aging in the Chianti Area (InCHIANTI) study.

BACKGROUND: Aging in men is characterized by a progressive decline in levels of anabolic hormones, such as testosterone, insulinlike growth factor 1 (IGF-1), and dehydroepiandrosterone sulfate (DHEA-S). We hypothesized that in older men a parallel age-associated decline in bioavailable testosterone, IGF-1, and DHEA-S secretion is associated with higher mortality independent of potential confounders. METHODS: Testosterone, IGF-1, DHEA-S, and demographic features were evaluated in a representative sample of 410 men 65 years and older enrolled in the Aging in the Chianti Area (InCHIANTI) study. A total of 126 men died during the 6-year follow-up. Thresholds for lowest-quartile definitions were 70 ng/dL (to convert to nanomoles per liter, multiply by 0.0347) for bioavailable testosterone, 63.9 ng/mL (to convert to nanomoles per liter, multiply by 0.131) for total IGF-1, and 50 microg/dL (to convert to micromoles per liter, multiply by 0.027) for DHEA-S. Men were divided into 4 groups: no hormone in the lowest quartile (reference) and 1, 2, and 3 hormones in the lowest quartiles. Kaplan-Meier survival and Cox proportional hazards models adjusted for confounders were used in the analysis. RESULTS: Compared with men with levels of all 3 hormones above the lowest quartiles, having 1, 2, and 3 dysregulated hormones was associated with hazard ratios for mortality of 1.47 (95% confidence interval [CI], 0.88-2.44), 1.85 (95% CI, 1.04-3.30), and 2.29 (95% CI, 1.12-4.68), respectively (test for trend, P <.001). In the fully adjusted analysis, only men with 3 anabolic hormone deficiencies had a significant increase in mortality (hazard ratio, 2.44; 95% CI, 1.09-5.46 (test for trend, P <.001). CONCLUSIONS: Age-associated decline in anabolic hormone levels is a strong independent predictor of mortality in older men. Having multiple hormonal deficiencies rather than a deficiency in a single anabolic hormone is a robust biomarker of health status in older persons.

Low testosterone levels and the risk of anemia in older men and women.

BACKGROUND: Anemia is a frequent feature of male hypogonadism and anti-androgenic treatment. We hypothesized that the presence of low testosterone levels in older persons is a risk factor for anemia. METHODS: Testosterone and hemoglobin levels were measured in a representative sample of 905 persons 65 years or older without cancer, renal insufficiency, or anti-androgenic treatments. Hemoglobin levels were reassessed after 3 years. RESULTS: At baseline, 31 men and 57 women had anemia. Adjusting for confounders, we found that total and bioavailable testosterone levels were associated with hemoglobin levels in women (P = .001 and P = .02, respectively) and in men (P<.001 and P = .03, respectively). Men and women in the lowest quartile of total and bioavailable testosterone were more likely than those in the highest to have anemia (men, 14/99 vs 3/100; odds ratio [OR], 5.4; 95% confidence interval [CI], 1.4-21.8 for total and 16/99 vs 1/99; OR, 13.1; 95% CI, 1.5-116.9 for bioavailable testosterone; women, 21/129 vs 12/127; OR, 2.1; 95% CI, 0.9-5.0 for total and 24/127 vs 6/127; OR, 3.4; 95% CI, 1.2-9.4 for bioavailable testosterone). Among nonanemic participants and independent of confounders, men and women with low vs normal total and bioavailable testosterone levels had a significantly higher risk of developing anemia at 3-year follow-up (21/167 vs 28/444; relative risk, 2.1; 95% CI, 1.1-4.1 for total and 26/143 vs 23/468; relative risk, 3.9; 95% CI, 1.9-7.8 for bioavailable testosterone). CONCLUSION: Older men and women with low testosterone levels have a higher risk of anemia.

Frailty as a dysruption of steroid "syncrinology" in elderly man.

In the background of the endocrinological hypothesis of aging, frailty in man can be seen as a dysruption of syncrinology, a term with which we could define the harmonized activity of steroid hormones (DHEAS, cortisol, testosterone). Such endocrine age-related modifications might promote the activation of sarcopenia, which exerts a core position in the progression of frailty in the elderly. Consequently, the use of replacement treatment in order to delay the beginning of such steroid derangement might be a suitable strategy to improve the quality of life of man, whose life length has been significantly extended.

Correlation between testosterone and the inflammatory marker soluble interleukin-6 receptor in older men.

CONTEXT: An age-associated decline in testosterone (T) levels and an increase in proinflammatory cytokines contribute to chronic diseases in older men. Whether and how these changes are related is unclear. OBJECTIVE: We hypothesized that T and inflammatory markers are negatively correlated in older men. DESIGN: This was a cross-sectional study. SETTING: A population-based sample of older men was studied. PARTICIPANTS AND MEASURES: After excluding participants taking glucocorticoids or antibiotics or those with recent hospitalization, 467 men, aged 65 yr or older, had complete determinations of total T, bioavailable T, SHBG, albumin, IL-6, soluble IL-6 receptor (sIL-6r), TNF-alpha, IL-1beta, and C-reactive protein. RESULTS: After adjusting for potential confounders, sIL-6r was significantly and inversely correlated with total T (r = -0.20; P < 0.001) and bioavailable T (r = -0.12; P < 0.05). T was not correlated with any other inflammatory marker. CONCLUSIONS: These preliminary findings suggest an inverse relationship between T and sIL-6r. Longitudinal studies are needed to establish the causality of this association.

Relation of angiotensin-converting enzyme inhibitor treatment to insulin-like growth factor-1 serum levels in subjects >65 years of age (the InCHIANTI study).

Observational studies have shown that the use of angiotensin-converting enzyme (ACE) inhibitors is associated with the maintenance of greater muscle strength and physical performance in older subjects. However, the mechanism that underlies these beneficial effects remains poorly understood. Because ACE inhibitors block the production of angiotensin II, which is a potent inhibitor of insulin-like growth factor-1 (IGF-1) production, it was hypothesized that treatment with ACE inhibitors is associated with higher levels of IGF-1. This hypothesis was tested in 745 subjects (417 women, 328 men) enrolled in the Invecchiare in Chianti study. Of these, 160 were receiving ACE inhibitors. The association between ACE inhibitor use and serum IGF-1 was tested by linear regression models. After adjusting for multiple potential confounders, serum levels of total IGF-1 were significantly higher in participants receiving ACE inhibitors (mean +/- SD 129.0 +/- 56.1 ng/ml) compared with the rest of the study population (mean +/- SD 116.5 +/- 54.8 ng/ml) (p <0.001). Participants with short (<3 years) and long (3 to 9 years) treatment durations had higher serum IGF-1 levels than participants who were not receiving ACE inhibitor treatment, but the difference was statistically significant only for the short-duration group (p <0.05). In conclusion, in older subjects, treatment with ACE inhibitors for <3 years is associated with significantly higher levels of IGF-1. This may be 1 of the mechanisms by which ACE inhibitors might slow the decreases in muscle strength and physical function that are often observed in older subjects.

Association between hormones and metabolic syndrome in older Italian men.

OBJECTIVES: To determine whether low levels of testosterone, sex hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), and dehydroepiandrosterone sulfate (DHEAS) and high levels of cortisol and leptin would be associated with metabolic syndrome (MS). DESIGN: Cross-sectional. SETTING: Population-based sample of older Italian men. PARTICIPANTS: Four hundred fifty-two men aged 65 and older enrolled in the Invecchiare in Chianti (InCHIANTI) study. MEASUREMENTS: Complete data on testosterone, cortisol, DHEAS, SHBG, fasting insulin, IGF-1 and leptin. MS was defined according to Adult Treatment Panel III criteria. RESULTS: MS was present in 73 men (15.8% of the sample). After adjusting for confounders, total testosterone (P < .05) and log (SHBG) (P < .001) were inversely associated, whereas log (leptin) was positively associated with MS (P < .001). Independent of age, log (SHBG) was positively associated with high-density lipoprotein cholesterol (P < .05) and negatively associated with abdominal obesity (P < .001) and triglycerides (P < .001). Log (leptin) was significantly associated with each component of MS. Cortisol, DHEAS, free and bioavailable testosterone, and IGF-1 were not associated with MS. Having three or more hormones in the lower (for hormones lower in MS) or the upper (for hormones higher in MS) quartile was associated with three times the risk of being affected by MS (odds ratio = 2.8, 95% confidence interval = 1.3-6.9) (P = .005), compared with not having this condition. CONCLUSION: Total testosterone and SHBG are negatively and leptin is positively associated with MS in older men. Whether specific patterns of hormonal dysregulation predict the development of MS should be tested in longitudinal studies.

Estrogen receptor (ER)-beta, but not ER-alpha, is present in thyroid vessels: immunohistochemical evaluations in multinodular goiter and papillary thyroid carcinoma.

OBJECTIVE: Estrogen receptors (ERs) have been demostrated in the vessel structures of several systems. Little is known on the presence of ERs in the thyroid vessels. DESIGN: We immunohistochemically evaluated both ER-alpha and ER-beta immunoreactivity (IR) in both vascular and follicular thyroid cells in tissue samples from 17 cases of multinodular goiter (MNG) and 17 cases of papillary thyroid carcinoma (PTC). MAIN OUTCOME: ER-alpha IR was undetectable in either tissue examined. In 100% of MNG samples, nuclear ER-beta IR was detected in both endothelial and follicular cells. In PTC samples, endothelial nuclear ER-beta IR was found in 100% of cases, whereas the nuclear staining of follicular cells was found in 83% of cases. The intensity of staining of the endothelial ER-beta IR was comparable between MNG and PTC. However, when follicular cells were considered, a tendency toward a decrease in nuclear staining and a significant increase in cytoplasmic staining were found in PTC lesions as compared to MNG. CONCLUSIONS: This study demonstrated that ER-beta, but not ER-alpha, IR is present in the endothelium of thyroid vessels. Furthermore, although data need to be confirmed in larger observations, these results suggest the lack of differences in the pattern of vascular ER-beta IR between MNG and PTC.

Insulin resistance and muscle strength in older persons.

BACKGROUND: The functional consequences of an age-related insulin resistance (IR) state on muscle functioning are unknown. Because insulin is needed for adequate muscle function, an age-related insulin-resistant state may also be a determining factor. We evaluated the relationship between IR and handgrip muscle strength in men and women from a large population-based study (n = 968). METHODS: The degree of IR was evaluated by the homeostasis model assessment (HOMA) and muscle strength was assessed using handgrip. RESULTS: Simple sex-stratified correlations demonstrated that, in men, body mass index-adjusted handgrip strength correlated positively with physical activity (r = 0.321; p < .001), muscle area (r = 0.420; p < .001), muscle density (r = 0.263; p = .001), plasma albumin (r = 0.156; p = .001), insulin-like growth factor-1 (r = 0.258; p < .001), calcium (r = 0.140; p = .006), and testosterone (r = 0.325; p < .001) concentrations, whereas a negative association was found for age (r = -0.659; p < .001) and myoglobin plasma levels (r = -0.164; p =.001). In women, body mass index-adjusted handgrip strength correlated positively with physical activity (r = 0.280; p < .001), muscle area (r = 0.306; p < .001), muscle density (r = 0.341; p = .001), plasma albumin (r = 0.140; p =.001), and insulin-like growth factor-1 (r = 0.300; p < .001), whereas a negative association was found for age (r = -0.563; p < .001), myoglobin levels (r = -0.164; p = .001), and IR (r = -0.130; p = .04). CONCLUSIONS: Sex-stratified analyses adjusted for multiple confounders showed that the relationship between IR and handgrip strength was found significant in women, whereas it was negligible and not significant in men.