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    Diabetes and Sexuality. Kizilay Fuat,Gali Helena Elizabeth,Serefoglu Ege Can Sexual medicine reviews INTRODUCTION:Deterioration in sexual functioning is one of the major and serious complications of diabetes. This common metabolic disorder not only affects sexuality through microvascular and nerve damage but also has psychological aspects. In men, the primary complications are erectile dysfunction, ejaculatory dysfunction, and loss of libido. Women similarly experience sexual problems, including decreased libido and painful intercourse. AIM:To summarize the effects of diabetes on sexuality, evaluate the impact of diabetes on sexual function, and assess the conventional and novel treatment approaches based on recent studies. METHODS:A literature review of peer-reviewed journal articles and guidelines was performed. MAIN OUTCOME MEASURES:To assess the effects of diabetes on sexuality and to focus on treatment approaches. RESULTS:Male and female sexual dysfunctions are a significant complication of diabetes. Tight glycemic control seems to be beneficial in delaying the onset of sexual problems and ameliorating them when they are present. Erectile dysfunction occurs as one of the first problems. The current mainstay of treatment for erectile dysfunction is therapy with phosphodiesterase type 5 inhibitors and then a stepwise approach of management. Men also can experience ejaculation problems and loss of libido. Diabetes also can decrease testosterone levels, which further decreases libido. Hypogonadal men with diabetes might benefit from testosterone replacement therapy. Diabetic women also can have sexual problems. These problems mainly include loss of libido, decrease in arousal and lubrication resulting in painful intercourse, and loss of orgasm. All these challenges require a multidisciplinary approach. CONCLUSION:Diabetes has detrimental effects on the sexual function of patients. Diabetologists who primarily care for the patient should not only focus on the glycemic control of their patients but also address their sexual complaints, because these problems can significantly impair their quality of life. Urologists, gynecologists, endocrinologists, and psychiatrists should work in a multidisciplinary manner for the treatment of decreased sexual functioning as a result of diabetes. 10.1016/j.sxmr.2016.07.002
    The association of endogenous sex hormones, adiposity, and insulin resistance with incident diabetes in postmenopausal women. Kalyani Rita Rastogi,Franco Manuel,Dobs Adrian S,Ouyang Pamela,Vaidya Dhananjay,Bertoni Alain,Gapstur Susan M,Golden Sherita Hill The Journal of clinical endocrinology and metabolism CONTEXT:In postmenopausal women, endogenous bioavailable testosterone (T) and estradiol (E2) have been positively associated, and SHBG has been negatively associated, with incident type 2 diabetes (T2DM). Previous studies have not explored possible factors explaining these relationships. OBJECTIVE:Our objective was to examine the association of endogenous sex hormones with incident T2DM in postmenopausal women and possible explanatory factors. DESIGN, SETTING, AND PARTICIPANTS:The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective study that included 1612 postmenopausal women aged 45-84 yr, followed between the years 2000-2006, who were not taking hormone replacement therapy, had no prevalent cardiovascular disease or diabetes, and had complete ascertainment of sex hormones. MAIN OUTCOME MEASURES:T2DM was defined based on fasting glucose and/or treatment for diabetes. RESULTS:There were 116 incident cases of diabetes during follow-up. Across higher quartiles of bioavailable T and E2 and lower quartiles of SHBG, we found significantly greater hazards of developing incident T2DM (all P for trend <or=0.001). After adjustment for body mass index and insulin resistance estimated by homeostasis model assessment of insulin resistance, bioavailable T was no longer associated with incident T2DM. The associations of E2 and SHBG with incident T2DM were partially explained by body mass index and insulin resistance but persisted in fully adjusted models (both P for trend <0.02). Dehydroepiandrosterone had no relationship with incident T2DM. CONCLUSIONS:Adiposity and insulin resistance explained most of the association of bioavailable T but only partially explained the associations of E2 and SHBG with incident T2DM among postmenopausal women. 10.1210/jc.2009-0910
    Association of sex hormones with carotid artery distensibility in men and postmenopausal women: multi-ethnic study of atherosclerosis. Vaidya Dhananjay,Golden Sherita H,Haq Nowreen,Heckbert Susan R,Liu Kiang,Ouyang Pamela Hypertension (Dallas, Tex. : 1979) The decline in carotid distensibility with age is steeper in women than in men, however, the correlates of this sex difference are not known. We examined the association of bioavailable testosterone, estradiol, dehydroepiandrosterone, and sex hormone-binding globulin, in 2783 postmenopausal women and 2987 men aged 45 to 84 years at the Multi-Ethnic Study of Atherosclerosis baseline examination. Carotid artery lumen diameters by ultrasound and brachial artery blood pressures were measured at systole and diastole. Regression models to determine the association of carotid distensibility coefficient and lumen diameter with sex-specific quartiles of sex hormones were adjusted for age, race, height, weight, diabetes mellitus, current smoking, antihypertensive medication use, total and high-density lipoprotein cholesterol levels, and hormone replacement therapy in women. A higher DC indicates a more distensible vessel. In women, higher dehydroepiandrosterone (P=0.008) and lower sex hormone-binding globulin (P=0.039) were associated with lower distensibility; higher dehydroepiandrosterone and lower estradiol were associated with smaller carotid diameters. In men, higher Bio-T (P=0.009) and lower estradiol (P=0.007) were associated with greater distensibility and also with smaller diameters (P=0.012 and 0.002, respectively). An androgenic internal milieu is associated with lesser carotid distensibility and diameter remodeling in women, but the opposite is true for men. Higher levels of estradiol are associated with smaller carotid diameters in both the sexes. Future longitudinal and experimental studies are needed to reveal the mechanism and clinical consequences of these associations. 10.1161/HYPERTENSIONAHA.114.04826
    Reproductive Hormones and Subclinical Cardiovascular Disease in Midlife Women. Thurston Rebecca C,Bhasin Shalender,Chang Yuefang,Barinas-Mitchell Emma,Matthews Karen A,Jasuja Ravi,Santoro Nanette The Journal of clinical endocrinology and metabolism Context:Reproductive hormones are important to the pathophysiology of cardiovascular disease (CVD) in women. However, standard estradiol (E2) and testosterone (T) assays lack sensitivity at the levels of postmenopausal women. Objective:Investigate relations of mass spectrometry-assessed estrone (E1), E2, and T and SHBG and subclinical CVD in women. Design, Setting, and Participants:Three hundred and four perimenopausal and postmenopausal women aged 40 to 60 years underwent subclinical CVD measurements. E1, E2, and T were assayed using liquid chromatography-tandem mass spectrometry; free T (FT) was estimated using ensemble allostery models. Regression models were adjusted for CVD risk factors. Main Outcome Measures:Carotid artery intima media thickness, interadventitial diameter (IAD), and plaque; brachial flow mediated dilation (FMD). Results:Higher E1 was related to higher FMD [β(SE) = 0.77 (0.37), P = 0.04], indicating better endothelial function. Higher E2 was related to lower IAD [β(SE) = -0.07 (0.02), P = 0.004], indicating less carotid remodeling. Higher SHBG was related to higher FMD [β(SE) = 1.31 (0.40), P = 0.001], yet higher IAD [β(SE) = 0.15 (0.06), P = 0.02] and plaque [OR (95% CI) = 1.84 (1.16 to 2.91), P = 0.009]; FT showed a similar yet inverse pattern of relations as SHBG. Thus, higher SHBG and lower FT were associated with better endothelial function, yet greater carotid remodeling and plaque. Conclusions:Endogenous E1 levels were related to endothelial function and E2 to vascular remodeling, suggesting distinct roles of these estrogens. SHBG and FT have complex roles depending on the vessel under study. 10.1210/jc.2018-00579
    High Androgens in Postmenopausal Women and the Risk for Atherosclerosis and Cardiovascular Disease: The Rotterdam Study. Meun Cindy,Franco Oscar H,Dhana Klodian,Jaspers Loes,Muka Taulant,Louwers Yvonne,Ikram M Arfan,Fauser Bart C J M,Kavousi Maryam,Laven Joop S E The Journal of clinical endocrinology and metabolism Context:Polycystic ovary syndrome (PCOS) is closely linked to hyperandrogenism (HA). In PCOS, HA has been associated with metabolic disturbances that increase the risk for cardiovascular disease (CVD). Objective:To assess the association of high serum androgen levels, as a postmenopausal remnant of PCOS, with the prevalence of atherosclerosis and incidence of CVD in postmenopausal women. Design:The Rotterdam Study, a prospective population-based cohort study. Median follow-up was 11.36 years. Setting:General community. Participants:A total of 2578 women aged >55 years. Exclusion criteria were missing informed consent or follow-up data, perimenopausal status, and menopause by surgical intervention or at an unnatural age (age <40 or >62). Intervention:None. Main Outcomes and Measures:Linear, logistic, and Cox regression models assessed the association of top quartiles (P75) of serum testosterone, free androgen index (FAI), dehydroepiandrosterone, and androstenedione and sex hormone-binding globulin with coronary artery calcium, carotid intima-media thickness (IMT), pulse wave velocity, peripheral artery disease, and incidence of coronary heart disease (CHD), stroke, and CVD. Results:Mean age (standard deviation) was 70.19 (8.71) years, and average time since menopause was 19.85 (9.94) years. Highest quartile FAI was associated with higher pulse wave velocity (β [95% confidence interval (CI)], 0.009 [0.000 to 0.018]). Highest quartile dehydroepiandrosterone [β (95% CI), -0.008 (-0.015 to -0.001)] and androstenedione [β (95% CI), -0.010 (-0.017 to -0.003)] levels were associated with a lower IMT. We found no association between high androgen levels and incident stroke, CHD, or CVD. Conclusion:Postmenopausal high androgen levels were not associated with an elevated risk for CVD. Cardiovascular health in women with PCOS might be better than was anticipated. 10.1210/jc.2017-02421
    Endogenous sex hormones are not associated with subclinical atherosclerosis in menopausal women. Celestino Catão Da Silva D,Nogueira De Almeida Vasconcelos A,Cleto Maria Cerqueira J,De Oliveira Cipriano Torres D,Oliveira Dos Santos A C,De Lima Ferreira Fernandes Costa H,Bregieiro Fernandes Costa L O Minerva ginecologica AIM:The aim of this paper was to compare the carotid intima-media thickness (IMT) in pre- and postmenopausal women and to evaluate the association between endogenous sex hormones, body fat distribution, and insulin resistance and the IMT. METHODS:This cross-sectional study included 145 women aged 45-65 yr, comprising 56 premenopausal (FSH<20IU/mL and regular menstrual cycles) and 89 postmenopausal (FSH>40IU/ml and amenorrheic). All patients were evaluated for lipid profile, estradiol and testosterone, insulin ratio (G/I), HOMA-IR, and ultrasound measurement of IMT. Each variable was assessed for correlation with IMT using the univariate model. RESULTS:No difference was observed in IMT between pre- and postmenopausal women. A positive and statistically significant correlation was found between IMT and FSH levels (rs=0.21, P<0.009) and HOMA (rs=0.16, P<0.04). A positive and statistically significant correlation was observed between testosterone and waist (rs=0.3, P<0.04). No correlation was found between IMT and time of menopause (r=0.02, P=0.19). CONCLUSION:Estradiol and testosterone are not associated with subclinical atherosclerosis in menopausal women. A positive correlation between IMT and FSH may reflect an association between low estrogen and IMT. Abdominal fat can be an important link between androgenic levels and cardiovascular risk.
    Subclinical atherosclerosis and hyperandrogenemia are independent risk factors for increased epicardial fat thickness in patients with PCOS and idiopathic hirsutism. Cakir Evrim,Doğan Mehmet,Topaloglu Oya,Ozbek Mustafa,Cakal Erman,Vural Mustafa Gokhan,Yeter Ekrem,Delibasi Tuncay Atherosclerosis OBJECTIVE:Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting reproductive-age women and is reported to be associated with an increased risk of cardiovascular disease and early atherosclerosis. Epicardial fat thickness (EF) is clinically related to subclinical atherosclerosis and visceral fat changes. Therefore, the objective of this study is to compare the carotid artery intima-media thickness (CIMT), EF and cardiometabolic risk factors in patients with PCOS, patients with idiopathic hirsutism (IH) and healthy controls. METHODS:This cross-sectional controlled study was conducted in a training and research hospital. The study population consisted of 50 reproductive-age PCOS women, 34 women with IH and 39 control subjects. We evaluated anthropometric, hormonal and metabolic parameters as well as CIMT and EF measurements in PCOS patients, IH patients and controls. RESULTS:The mean fasting insulin, HOMA-IR, hsCRP, GGT, CIMT, and EF levels were significantly higher in patients with PCOS and IH (p < 0.05). A significant positive correlation was found between EF and age, BMI, WHR, Ferriman Gallwey score (FG), fasting insulin, HOMA-IR, triglyceride, total cholesterol, LDL-C, 17 OH progesterone, free testosterone, CIMT, hsCRP, and GGT, whereas a significant negative correlation was observed between EF and HDL-C (p < 0.05). In the multiple linear regression analyses, EF was found to be associated with the FG (β coefficient: 0.389, p < 0.001), CIMT (β coefficient: 0.376, p < 0.001) and free testosterone levels (β coefficient: 0.173, p < 0.038). CONCLUSION:EF appears to be a marker that will enable the detection of the cardiometabolic response in patients with PCOS and IH, even at an early stage. 10.1016/j.atherosclerosis.2012.11.004
    Androgen excess is associated with the increased carotid intima-media thickness observed in young women with polycystic ovary syndrome. Luque-Ramírez Manuel,Mendieta-Azcona Covadonga,Alvarez-Blasco Francisco,Escobar-Morreale Héctor F Human reproduction (Oxford, England) BACKGROUND:We evaluated carotid intima-media thickness (CIMT) as an early marker of atherosclerosis, as well as its main determinants among androgen excess, obesity and insulin resistance, in patients with polycystic ovary syndrome (PCOS). METHODS:We selected 40 PCOS patients and 20 non-hyperandrogenic women who were similar in terms of age and grade of obesity. Complete clinical, metabolic and hormonal profiles and left common CIMT measurements were obtained. RESULTS:Patients with PCOS presented with increased mean CIMT values when compared with controls (F = 8.575; P = 0.005), and this was independent of obesity. Five PCOS patients but no controls had increased CIMT values. CIMT correlated directly with serum total and free testosterone, androstenedione and dehydroepiandrosterone-sulfate levels and mean 24-h heart rate (HR), and inversely with the insulin sensitivity index (ISI), but no correlation was observed with the body mass index (BMI). Multiple stepwise linear regression models showed that in PCOS patients, the main determinants of CIMT were serum total testosterone or androstenedione concentrations, with no influence of ISI or the mean 24-h HR. CONCLUSIONS:Compared with control women, PCOS patients present with an increased CIMT, independent of obesity and related directly to androgen excess; this suggests that hyperandrogenism is associated with atherosclerosis and cardiovascular risk in these women. 10.1093/humrep/dem324
    Higher endogenous estrogen levels in 70-year-old women and men: an endogenous response to counteract developing atherosclerosis? Naessen Tord,Bergquist Jonas,Lind Lars,Kushnir Mark M Menopause (New York, N.Y.) OBJECTIVE:Reported associations between endogenous steroid hormone levels and cardiovascular disease in the older population have been contradictory. We evaluated plasma steroid concentrations in terms of the dimensions of the common carotid artery wall layers as a measure of the extent of atherosclerosis. METHODS:A subgroup of 70-year-old participants (32 women and 50 men) from the Prospective Investigation of the Vasculature in Uppsala Seniors study was investigated. All participants had assessments of common carotid artery wall layer parameters (intima thickness, media thickness, and intima-media thickness [IMT] ratio; measured by high-frequency ultrasound at 22 MHz) and endogenous steroid hormone concentrations (measured by liquid chromatography-tandem mass spectrometry). RESULTS:Low androgen levels, high aromatase enzyme activity (estrone [E1]/androstenedione and estradiol [E2]/testosterone), high E2/E1 ratio, and high estrogen levels (E1, E2, estriol, and E2/sex hormone-binding globulin) were consistently associated (often significantly) with a more unhealthy artery wall (thick intima, thin media, and high IMT ratio) in both sexes. Consistently strong associations were found between the aromatase index E2/testosterone and intima, media, and the IMT ratio. For IMT ratio, in both men (rs = 0.52) and women (rs = 0.58), P was <0.001 for both and remained significant after adjustment for cardiovascular disease risk factors and the Framingham risk score (both P < 0.01). CONCLUSIONS:Low androgens, high aromatase enzyme activity, and high estrogen levels are often significantly associated with an unhealthy artery wall on ultrasound. We suggest that the steroid hormone profile of older individuals with higher estrogens most probably reflects an endogenous response to developing atherosclerosis, rather than a cause-and-effect relationship. However, the reverse causality cannot be excluded. 10.1097/gme.0b013e31825ea8c1
    [Low testosterone levels are inversely correlated with carotid artery plaque formation in elderly women]. Ma Qiang,Cheng Qing-Li,Ma Jian,Ao Qiang-Guo,Tan Guo-Juan,Zhi Guang Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology OBJECTIVE:To study the relationship between serum testosterone levels and the plaque formation of the carotid artery in a population-based cohort of independently living healthy women above 60 years of age. METHODS:Analysis of the healthy elders from a population-based cohort study in 9 communities of Beijing. Carotid intima-media thickness and atherosclerotic plaques were determined ultrasonographically. Serum testosterone levels were measured by immunoassay. The data were analyzed with ANOVA and logistic regression analysis. RESULTS:There was an inverse correlation between testosterone and plaque formation in old females (P < 0.01), while no association was found in males. Female with testosterone levels in the lowest quartile (< 0.49 nmol/L) had more risk of plaque formation (OR = 3.805, P < 0.01) after adjusted with age and other traditional factors of atherosclerosis. CONCLUSION:Testosterone concentrations are negatively associated with carotid artery atherosclerosis in old women in Beijing, experimental and prospective studies are needed to determine the possible therapeutic role of testosterone in atherosclerosis.
    Gender determinants of cardiovascular risk factors and diseases. Mercuro Giuseppe,Deidda Martino,Piras Alessandra,Dessalvi Christian Cadeddu,Maffei Silvia,Rosano Giuseppe M C Journal of cardiovascular medicine (Hagerstown, Md.) This article addresses the various aspects concerning gender dissimilarities in the cardiovascular system. It examines sex differences in the genetic susceptibility to cardiovascular disease (CVD) development or outcome: with the presence of either XX or XY chromosomes, every cell is sexually differentiated and there exist postpuberal differences between male and female cardiovascular systems. The main action mechanisms of sex steroid hormones are discussed, mainly as to testosterone (Te) in men and 17beta-estradiol (E2) and progesterone (Pro) in women. In women, susceptibility to CVD is known to increase in the postmenopausal period, when the ovarian hormone function expires. Some concepts of the sex-based differences in anatomy and physiology are also explained. Although they have the same structural elements, women and men use them in a different way to guarantee cardiovascular system homeostasis. Some examples of differences between men and women in pathological cardiovascular function are given. A further important issue regards the prevalence and role of cardiovascular risk factors in the two genders. Compared to boys of the same age, adolescent girls and premenopausal women have a more favorable risk profile: lower blood pressure (BP), less atherogenic lipid profile, and lower prevalence of cardiovascular risk factors. Women develop CVD later than men and diabetic women have a considerably higher mortality rate compared to men of the same age. Finally, there exist several clinically significant differences between men and women as to prevalence, presentation, management and outcome of CVD. Clinical peculiarities related to gender in presentation of some CVDs, such as coronary heart disease (CHD), stroke and heart failure, are described. We are absolutely convinced that only an accurate knowledge of the sex-specific pathophysiology may allow determination of the appropriate diagnostic instruments and to implement tailored treatments of CVD in men and women. 10.2459/JCM.0b013e32833178ed
    Low free testosterone levels are associated with all-cause and cardiovascular mortality in postmenopausal diabetic women. Wehr Elisabeth,Pilz Stefan,Boehm Bernhard O,Grammer Tanja B,März Winfried,Obermayer-Pietsch Barbara Diabetes care OBJECTIVE:Hyperandrogenemia is associated with cardiovascular risk factors in women but evidence about the relationship of testosterone levels with mortality is sparse. We aimed to evaluate whether total testosterone (TT), free testosterone (FT), and sex hormone-binding globulin (SHBG) are associated with all-cause and cardiovascular mortality in a cohort of postmenopausal women. RESEARCH DESIGN AND METHODS:We measured TT and SHBG levels in 875 postmenopausal women who were referred for coronary angiography (during 1997-2000). FT was calculated according to the Vermeulen method. The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes and from cardiovascular causes. RESULTS:After a median follow-up time of 7.7 years, 179 women (20.5%) had died. There were 101 deaths due to cardiovascular disease (56.4% of all deaths). We found no association of FT, TT, and SHBG levels with mortality in all postmenopausal women. In postmenopausal diabetic women, multivariable-adjusted HRs (with 95% CIs) in the fourth compared with the first FT quartile for all-cause and cardiovascular mortality were 0.38 (0.08-0.90), P = 0.025, and 0.28 (0.08-0.90), P = 0.032, respectively. We found no association of TT and SHBG with mortality in diabetic postmenopausal women. CONCLUSIONS:In postmenopausal diabetic women referred for coronary angiography, low FT levels are independently associated with increased all-cause and cardiovascular mortality. 10.2337/dc11-0596
    Vascular effects of estrogen in type II diabetic postmenopausal women. Koh K K,Kang M H,Jin D K,Lee S K,Ahn J Y,Hwang H Y,Yang S H,Kim D S,Ahn T H,Shin E K Journal of the American College of Cardiology OBJECTIVES:We assessed the effects of estrogen on vascular dilatory and other homeostatic functions potentially affected by nitric oxide (NO)-potentiating properties in type II diabetic postmenopausal women. BACKGROUND:There is a higher cardiovascular risk in diabetic women than in nondiabetic women. This would suggest that women with diabetes do not have the cardioprotection associated with estrogen. METHODS:We administered placebo or conjugated equine estrogen, 0.625 mg/day for 8 weeks, to 20 type II diabetic postmenopausal women in a randomized, double-blinded, placebo-controlled, cross-over design. RESULTS:Compared with placebo, estrogen tended to lower low-density lipoprotein (LDL) cholesterol levels by 15 +/- 23% (p = 0.007) and increase high-density lipoprotein (HDL) cholesterol levels by 8 +/- 16% (p = 0.034). Thus, the ratio of LDL to HDL cholesterol levels significantly decreased with estrogen, by 20 +/- 24%, as compared with placebo (p = 0.001). Compared with placebo, estrogen tended to increase triglyceride levels by 16 +/- 48% and lower glycosylated hemoglobin levels by 3 +/- 13% (p = 0.295 and p = 0.199, respectively). However, estrogen did not significantly improve the percent flow-mediated dilatory response to hyperemia (17 +/- 75% vs. placebo; p = 0.501). The statistical power to accept our observation was 81.5%. Compared with placebo, estrogen did not significantly change E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1 or matrix metalloproteinase-9 levels. Compared with placebo, estrogen tended to decrease tissue factor antigen and increase tissue factor activity levels by 7 +/- 46% and 5 +/- 34%, respectively (p = 0.321 and p = 0.117, respectively) and lower plasminogen activator inhibitor-1 levels by 16 +/- 31% (p = 0.043). CONCLUSIONS:The effects of estrogen on endothelial, vascular dilatory and other homeostatic functions were less apparent in type II diabetic postmenopausal women, despite the beneficial effects of estrogen on lipoprotein levels. 10.1016/s0735-1097(01)01566-2
    Effect of hormone replacement therapy on cardiovascular risk factors in postmenopausal women with diabetes. Scott A R,Dhindsa P,Forsyth J,Mansell P, Diabetes, obesity & metabolism BACKGROUND:Hormone replacement therapy (HRT) in postmenopausal women improves menopausal symptoms, decreases the incidence of osteoporotic fracture, but the effects on cardiovascular risk factors remain controversial. AIM:To test the hypothesis that HRT may have beneficial effects on the cardiovascular risk profile in postmenopausal women with diabetes. METHODS:One hundred and fifty postmenopausal patients with type 1 (T1DM) and type 2 diabetes (T2DM) were randomized to receive HRT (Kliofem) or placebo for 12 months. We monitored the effects on cardiovascular risk factors, including lipid profile, glycaemic control, blood pressure and body weight. RESULTS:Mean low-density lipoprotein (LDL) cholesterol was associated with a nonsignificant decrease [-0.14 mmol/l (CI=-0.44, 0.17) (p=0.37)] in the Kliofem-treated group. Total cholesterol fell by 0.42 mmol/l (CI=-0.78, -0.05) (p=0.027). High-density lipoprotein (HDL) cholesterol was reduced by a mean of 0.07 mmol/l compared to a mean rise of 0.12 mmol/l on placebo. There were apparent differences in the treatment effects between T1DM and T2DM. There was no change in triglycerides or apoprotein B and no effect on glycaemic control, blood pressure or menopausal symptom scores. In the Kliofem group, BMI fell by 0.66 kg/m2 compared to an increase of 0.14 kg/m2 for placebo patients (p=0.046). CONCLUSIONS:Although the long-term effects of HRT in women with or without diabetes appear to suggest that some types of HRT either confer no cardiovascular protection or may increase risk, the impact of Kliofem diabetic women on cardiovascular risk factors is probably neutral. 10.1111/j.1463-1326.2004.00294.x
    Effects of hormone replacement therapy on cardiovascular responses in postmenopausal women with and without type 2 diabetes. Manwaring Paul,Phoon Stephen,Diamond Terence,Howes Laurence Guy Maturitas OBJECTIVE:To determine whether blood pressure (BP) responses to pressor stimuli during hormone replacement therapy are reduced by oral conjugated equine estrogens 0.625 mg/day (ERT) and ERT in combination with 5 mg/day continuous medroxyprogesterone (HRT) in women with and without type 2 diabetes. METHODS:Twenty type 2 diabetic and 20 non-diabetic women completed a three period, randomised, double bind crossover studying the effects of 1 month of therapy of ERT, HRT and placebo on BP responses to mental arithmetic and isometric stress and to intravenous infusions of noradrenaline and angiotensin II. RESULTS:Significant differences were found between the effects of ERT, HRT and placebo therapy on BP responses to mental arithmetic in the women with type 2 diabetes apparently due to a smaller response during ERT therapy. BP responses to mental arithmetic were not affected in non-diabetic women. BP responses to isometric exercise and to intravenous infusions of noradrenaline and angiotensin II were similar in the type 2 diabetic and non-diabetic women and were not affected by ERT or HRT therapy. Plasma renin activity differed significantly between ERT, HRT and placebo therapies in type 2 diabetic women, apparently because of lower levels during ERT and HRT therapy. CONCLUSIONS:ERT and HRT may produce beneficial effects on BP responses to psychological stress and on plasma renin activity in women with type 2 diabetes. BP responses to isometric exercise and to intravenous infusions of noradrenaline and angiotensin II are not altered by ERT or HRT in type 2 diabetic or non-diabetic women.
    The effects of transdermal estradiol alone or with cyclical dydrogesterone on markers of cardiovascular disease risk in postmenopausal women with type 2 diabetes: a pilot study. Stojanovic N D,Kwong P,Byrne D J,Arnold A,Jagroop I A,Nair D,Press M,Hurel S,Mikhailidis D P,Prelevic G M Angiology The objective of this open, longitudinal, controlled study was to assess the effect of transdermal estradiol alone or combined with cyclical dydrogesterone on the markers of cardiovascular disease (CVD) risk in postmenopausal women with type 2 diabetes. The control group consisted of postmenopausal diabetic women who declined menopausal hormone replacement therapy (HRT). Twenty-eight postmenopausal women (19 on HRT and 9 controls) with type 2 diabetes were followed up for 12 months. From the active treatment group 14 women with a uterus in situ had 80 microg/24 hr transdermal estradiol (Fematrix 80; Solvay Healthcare Ltd, Southampton, UK) and oral dydrogesterone 10 mg daily for the first 12 days of the calendar month, whereas 5 women with previous hysterectomy had 80 microg/24 hr transdermal estradiol (Fematrix 80) alone. CVD risk markers were measured before and at regular intervals after starting HRT. The main outcome measures were weight, systolic and diastolic blood pressure, fasting plasma glucose, glycated hemoglobin (HbA1c), glucose/insulin ratio, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein (a), high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and endothelin-1. Transdermal estradiol with or without dydrogesterone in women with type 2 diabetes did not adversely affect any of the measured markers of cardiovascular risk. There was a significant decrease in HbA1c, total cholesterol, and LDL cholesterol at 6 months in women receiving HRT. Some of the cardiovascular disease risk markers may improve in postmenopausal women with type 2 diabetes with transdermal estradiol. This effect may have important clinical implications and it deserves further investigation in appropriately designed trials. 10.1177/000331970305400402
    Association of hyperandrogenemia and hyperestrogenemia with type 2 diabetes in Hispanic postmenopausal women. Phillips G B,Tuck C H,Jing T Y,Boden-Albala B,Lin I F,Dahodwala N,Sacco R L Diabetes care OBJECTIVE:Accumulating evidence suggests that hyperandrogenemia may be a risk factor for coronary heart disease (CHD) in women. The present study was carried out to test the hypothesis that hyperandrogenemia is associated with type 2 diabetes in women and thus may contribute to the increased risk of CHD in women with type 2 diabetes. RESEARCH DESIGN AND METHODS:Sex hormones, sex hormone-binding globulin (SHBG), and risk factors for CHD were measured in 20 postmenopausal women with type 2 diabetes and in 29 control subjects. All of the diabetic and control subjects were Hispanic women aged >55 years who were not taking hormone replacement therapy lipid-lowering drugs, or insulin and who were otherwise randomly chosen from a cohort of stroke-free subjects from the Northern Manhattan Stroke Study RESULTS:Mean age, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, blood pressure, and smoking were not significantly different between cases and control subjects, but waist-to-hip ratio (WHR) was significantly higher in the diabetic subjects (P = 0.01). The mean levels of free testosterone (FT) (P = 0.01), dehydroepiandrosterone sulfate (P<0.04), and estradiol (P = 0.01) (controlled for WHR) were significantly higher in the diabetic subjects; with the statistical outliers removed, the testosterone (P = 0.05) and androstenedione (P = 0.002) levels (controlled for WHR) were also significantly higher in the diabetic subjects. The mean levels of estrone, cortisol, and SHBG were not significantly different. The results were similar in the 10 diabetic subjects treated with diet only Significant positive correlations (controlled for age and BMI) were observed between FT or testosterone and cholesterol, LDL cholesterol, and blood pressure. CONCLUSIONS:Postmenopausal Hispanic women with type 2 diabetes had both hyperandrogenemia and hyperestrogenemia, and testosterone or FT correlated positively with risk factors for CHD. Hyperandrogenemia may be a link between diabetes and CHD in women. 10.2337/diacare.23.1.74
    Using human genetics to understand the disease impacts of testosterone in men and women. Ruth Katherine S,Day Felix R,Tyrrell Jessica,Thompson Deborah J,Wood Andrew R,Mahajan Anubha,Beaumont Robin N,Wittemans Laura,Martin Susan,Busch Alexander S,Erzurumluoglu A Mesut,Hollis Benjamin,O'Mara Tracy A, ,McCarthy Mark I,Langenberg Claudia,Easton Douglas F,Wareham Nicholas J,Burgess Stephen,Murray Anna,Ong Ken K,Frayling Timothy M,Perry John R B Nature medicine Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses. 10.1038/s41591-020-0751-5
    Comprehensive Evaluation of Type 2 Diabetes and Cardiovascular Disease Risk Profiles in Reproductive-Age Women with Polycystic Ovary Syndrome: A Large Canadian Cohort. Kazemi Maryam,Pierson Roger A,Lujan Marla E,Chilibeck Philip D,McBreairty Laura E,Gordon Julianne J,Serrao Shani B,Zello Gordon A,Chizen Donna R Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC OBJECTIVE:This study compared the prevalence of metabolic syndrome (MetS) and characterized type 2 diabetes (DM2) and cardiovascular disease (CVD) risk profiles between Canadian women with polycystic ovary syndrome (PCOS) and healthy women recruited from the general population. Furthermore, within the PCOS cohort, the study contrasted the CVD and DM2 risk profiles of women with or without MetS. METHODS:Measures of MetS (International Diabetes Federation; National Heart, Lung, and Blood Institute; and the American Heart Association definition), DM2 (Diabetes Canada Clinical Guidelines), and CVD risk factors (Androgen Excess and Polycystic Ovary Syndrome Society statement) were evaluated for 237 women with PCOS (Androgen Excess and PCOS Society definitions) and 42 controls (aged 18-36) in a prospective observational study (Canadian Task Force Classification II-2). RESULTS:The prevalence of MetS was 29.5% in the PCOS group, which was approximately six-fold higher than age-matched controls (P < 0.001). Women with PCOS exhibited higher glucose abnormality, acanthosis nigricans, total cholesterol to high-density lipoprotein cholesterol ratio (TC/HDL-C), and lower sex hormone-binding globulin concentrations when compared with controls after accounting for differences in the BMI (P < 0.01). Further, women with PCOS and MetS exhibited exacerbated insulin and glucose responses to a 75-g oral glucose tolerance test and greater acanthosis nigricans, hirsutism, TC/HDL-C, TC, and sex hormone-binding globulin concentrations compared with their BMI-adjusted counterparts without MetS (P < 0.05). CONCLUSION:Canadian reproductive-age women with PCOS have a high prevalence of MetS and exhibit adverse cardiometabolic risk factors that warrant early screening and regular monitoring across their reproductive lifespan. 10.1016/j.jogc.2018.11.026
    Sex differences in micro- and macro-vascular complications of diabetes mellitus. Maric-Bilkan Christine Clinical science (London, England : 1979) Vascular complications are a leading cause of morbidity and mortality in both men and women with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus, however the prevalence, progression and pathophysiology of both microvascular (nephropathy, neuropathy and retinopathy) and macrovascular [coronary heart disease (CHD), myocardial infarction, peripheral arterial disease (PAD) and stroke] disease are different in the two sexes. In general, men appear to be at a higher risk for diabetic microvascular complications, while the consequences of macrovascular complications may be greater in women. Interestingly, in the absence of diabetes, women have a far lower risk of either micro- or macro-vascular disease compared with men for much of their lifespan. Thus, the presence of diabetes confers greater risk for vascular complications in women compared with men and some of the potential reasons, including contribution of sex hormones and sex-specific risk factors are discussed in this review. There is a growing body of evidence that sex hormones play an important role in the regulation of cardiovascular function. While estrogens are generally considered to be cardioprotective and androgens detrimental to cardiovascular health, recent findings challenge these assumptions and demonstrate diversity and complexity of sex hormone action on target tissues, especially in the setting of diabetes. While some progress has been made toward understanding the underlying mechanisms of sex differences in the pathophysiology of diabetic vascular complications, many questions and controversies remain. Future research leading to understanding of these mechanisms may contribute to personalized- and sex-specific treatment for diabetic micro- and macro-vascular disease. 10.1042/CS20160998
    Clinical correlates of sex hormones in women: The study of health in Pomerania. Kische Hanna,Gross Stefan,Wallaschofski Henri,Völzke Henry,Dörr Marcus,Nauck Matthias,Haring Robin Metabolism: clinical and experimental BACKGROUND:Despite associations of sex hormones in women with increased cardiometabolic risk and mortality, the clinical correlates of altered sex hormone concentrations in women are less clearly understood. We investigated a broad range of clinical correlates of sex hormones in women from a large population-based sample. METHODS:Data from 2560 women from two cohorts of the Study of Health in Pomerania were used. Stepwise multivariable regression models were implemented to investigate a broad range of behavioral, socio-demographic, and cardiometabolic clinical correlates related to total testosterone (TT), free testosterone (fT), androstenedione (ASD), dehydroepiandrosterone-sulfate (DHEAS), estrone (E1), estradiol (E2), and sex hormone-binding globulin (SHBG). RESULTS:Waist circumference and BMI (β-coefficient: -0.03; 95% CI: -0.04; 0.03) were inversely related to SHBG, and BMI was positively related to TT (β-coefficient: 0.005; 95% CI: 0.001; 0.009), fT, E1, and E2. Smoking was positively related to TT (β-coefficient: 0.04; 95% CI: 0.01; 0.06), ASD, and fT. Systolic blood pressure (TT: β-coefficient: 0.002; 95% CI: 0.001; 0.003), hypertension (TT: β-coefficient: 0.05; 95% CI: 0.003; 0.11), low-density lipoprotein (LDL) cholesterol (TT: β-coefficient: 0.02; 95% CI: 0.01; 0.05), and total cholesterol (TT: β-coefficient: -0.03; 95% CI: 0.01; 0.05) were positively related to TT and ASD. Finally, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MetS) were positively related to fT, but inversely related to SHBG. CONCLUSIONS:Our population-based study, with sex hormone concentrations measured by liquid chromatography tandem mass spectrometry, revealed associations between clinical correlates including waist circumference, smoking, cohabitation, systolic blood pressure, cholesterol, and MetS with sex hormones. Thus, sex hormones and SHBG may play a role in the cardiovascular risk profile of women. 10.1016/j.metabol.2016.05.011
    Low concentrations of serum testosterone predict acute myocardial infarction in men with type 2 diabetes mellitus. Daka Bledar,Langer Robert D,Larsson Charlotte A,Rosén Thord,Jansson Per Anders,Råstam Lennart,Lindblad Ulf BMC endocrine disorders BACKGROUND:The aim of the present study was to investigate the associations between endogenous testosterone concentrations and the incidence of acute myocardial infarction (AMI) in men and women with and without type 2 diabetes. METHODS:The study comprised 1109 subjects ≥40 years of age (mean age 62 ± 12 years) participating in a baseline survey in Sweden in 1993-94. Information about smoking habits and physical activity was obtained using validated questionnaires. Serum concentrations of testosterone and sex hormone-binding globulin (SHBG) were obtained using radioimmunoassay. Diagnosis of type 2 diabetes was based on WHO's 1985 criteria. Individual patient information on incident AMI was ascertained by record linkage with national inpatient and mortality registers from baseline through 2011. RESULTS:The prevalence of type 2 diabetes at baseline was 10.0% in men and 7.5% in women. During a mean follow-up of 14.1 years (±5.3), there were 74 events of AMI in men and 58 in women. In age-adjusted Cox models, a significant inverse association between concentrations of testosterone and AMI-morbidity was found in men with type 2 diabetes (HR = 0.86 CI (0.75-0.98)). In a final model also including waist-to-hip ratio, systolic blood pressure, total cholesterol and active smoking, the association still remained statistically significant (HR = 0.754 CI (0.61-0.92)). CONCLUSION:Low concentrations of testosterone predicted AMI in men with type 2 diabetes independent of other risk factors. Trials with testosterone investigating the effect regarding cardiovascular outcome are still lacking. Future trials in this field should take into account a modification effect of diabetes. 10.1186/s12902-015-0034-1