Recently Health Canada and the Food and Drug Administration warned about the cardiovascular risk of testosterone, making environmental drivers of testosterone potential prevention targets. Cotinine, a tobacco metabolite, inhibits testosterone breakdown. We assessed the association of smoking with testosterone in a systematic review and meta-analysis, searching PubMed and Web of Science through March 2015 using ("testosterone" or "androgen" or "sex hormone") and ("smoking" or "cigarette"). Two reviewers independently searched, selected, assessed quality and abstracted with differences resolved by consensus or reference to a third reviewer. The initial search yielded 2881 studies; 28 met the selection criteria. In 22 studies of 13,317 men, mean age 18-61years, smokers had higher mean testosterone than non-smokers (1.53nmol/L, 95% confidence interval (CI) 1.11 to 1.96) using a random effects model with inverse variance weighting. In 6 studies of 6089 women, mean age 28-62years, smoking was not clearly associated with testosterone (0.11nmol/L, 95% CI -0.08 to 0.30). Fixed effects models provided similar results, but suggested a positive association in women. Whether products which raise cotinine, such as e-cigarettes or nicotine replacement, also raise testosterone, should be investigated, to inform any regulatory action for e-cigarettes, which emit nicotine into the surrounding air, with relevance for both active and passive smokers.

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... Previous studies have shown gender-specific effect of smoking (Tsai et al., 2008;Allen et al., 2014;Minutillo et al., 2016;Weinberger et al., 2016;Zhao et al., 2016;Becker et al., 2017;Elmore et al., 2017;Nicolini et al., 2018;Sundberg et al., 2018;Lundberg et al., 2019). Men and women seem to differ in time and conditions of initiation (Elmore et al., 2017), smoking behavior (Tsai et al., 2008;Weinberger et al., 2016), dependence (Minutillo et al., 2016;Becker et al., 2017), and cessation (Weinberger et al., 2016). ...

... Men and women seem to differ in time and conditions of initiation (Elmore et al., 2017), smoking behavior (Tsai et al., 2008;Weinberger et al., 2016), dependence (Minutillo et al., 2016;Becker et al., 2017), and cessation (Weinberger et al., 2016). Additionally, there are smoking-related gender differences in body system responses and alterations (Zhao et al., 2016;Alomari et al., 2018b, c;Alomari et al., 2018a), diseases (Nicolini et al., 2018;Lundberg et al., 2019), morbidity, and mortality (Allen et al., 2014;Sundberg et al., 2018). These gender variations have been attributed to many factors, including physiological, behavioral, psychological, and social (Ostan et al., 2016). ...

... However, information about the effect of nicotine dependence on Wp smoking topography is a scarce. Understanding the contribution of gender and dependence to the variation in Wp smoking topography might, at least partially, explain the gender and dependence differences in physiological responses, diseases, morbidity, and mortality related to smoking (Tsai et al., 2008;Allen et al., 2014;Minutillo et al., 2016;Weinberger et al., 2016;Zhao et al., 2016;Becker et al., 2017;Elmore et al., 2017;Alomari et al., 2018b, c;Alomari et al., 2018a;Nicolini et al., 2018;Sundberg et al., 2018;Lundberg et al., 2019). Subsequently, smoking treatment strategies, including smoking cessation can be better determined. ...

Background Waterpipe smoking is spreading worldwide, and it is associated with many adverse effects. The aim of this study was to investigate the interaction of waterpipe smoking puffing topography, and related physiological measures, with both gender and level of dependence on waterpipe. Method Exclusive waterpipe smokers were asked to smoke a single waterpipe session in a specialized laboratory while their smoking topography, and in-breath CO level were recorded pre- and post- smoking. Waterpipe dependence was measured using the LWDS-11 scale. Results In the high dependence group, the total number of puffs, was greater in men than women. In addition, the average flow rate was greater in men with high compared to low dependence. For inter-puffing intervals, greater values were recorded in men and women with low versus high dependence. No other differences were found between the subgroups in total session time, average puff duration, average puff volume, and maximum flow rate. Pre-smoking CO content and CO boost were greater in men versus women in both dependence groups. Post-smoking CO content was greater in women with high versus low dependence, whereas it was lower in women versus men with low dependence. Conclusions The current results indicate several effects for waterpipe smoking dependence on smoking topography. Many of these differences were gender dependent with men having higher exposure than women in most aspects.

... Multiple studies reiterated a consistent effect of nicotine on testosterone level, independent to the route of administration (Schooling, 2015;Zhao, Leung, Lin, & Schooling, 2016). Both smoking and smokeless tobacco increases serum testosterone level in normal lean body weight individuals (Schooling, 2015). ...

... Both smoking and smokeless tobacco increases serum testosterone level in normal lean body weight individuals (Schooling, 2015). This effect was attributed either to nicotine or its metabolite cotinine and trans-30-hydroxycotinine (3HC) that competitively inhibits male sex androgen for clearance (Zhao et al., 2016). However, in obese individuals reverse testosterone behaviour was noticed due to conversion of testosterone to oestrogen in fatty tissues (Zhao et al., 2016). ...

... This effect was attributed either to nicotine or its metabolite cotinine and trans-30-hydroxycotinine (3HC) that competitively inhibits male sex androgen for clearance (Zhao et al., 2016). However, in obese individuals reverse testosterone behaviour was noticed due to conversion of testosterone to oestrogen in fatty tissues (Zhao et al., 2016). ...

Human infertility is a worldwide health issue and is the inability to conceive following twelve months of unprotected sexual intercourse. Consistent studies reiterated tobacco abuse to be an important risk factor which adversely effects male fertility. This study aims to determine the correlation of kisspeptin and total testosterone levels in smokeless tobacco, smoking tobacco users and healthy controls. A total of 180 subjects were selected using random sampling technique. Non‐fasting blood samples (5 ml) were drawn, and ELISA technique was used for the evaluation of plasma levels of kisspeptin and total testosterone. Total testosterone was found to be significantly high in smokers and smokeless tobacco users, while the level of kisspeptin was found to be significantly high in smokeless tobacco users only as compared to control group. Furthermore, the level of cholesterol was found to be significantly low, whereas HDL and triglycerides were found to be significantly high in smokeless tobacco users relative to control subjects. Findings of this study suggest that tobacco use has impact on HPG axis by affecting kisspeptin level. The increase in kisspeptin level can affect hypothalamic function leading to pituitary and gonadal dysfunction along with impairment of reproduction. The finding that smokeless tobacco significantly raises kisspeptin strengthens the idea that smokeless tobacco use has more potent effects centrally compared to smoking.

... A prior large-scale epidemiology study conducted using Chinese people aged 17 to 88 years suggested that smokers had significantly higher levels of TT (OR = 1.69, 95% CI: 1.34, 2.13) and free testosterone (FT) (OR = 1.27, 95% CI: 1.00, 1.61) [8]. Similarly, a metaanalysis study also reported that smokers had higher mean testosterone levels (1.53 nmol/L, 95% CI: 1.11, 1.96) than nonsmokers [27]. Furthermore, both TT and FT increased gradually as the number of cigarettes smoked increased [28]. ...

... Interestingly, the elevation of T could be partially explained by the role of nicotine in cigarettes. Cotinine, a metabolite of nicotine, may act as an aromatase inhibitor, leading to increased androgens [27]. Nicotine can cross the blood-brain barrier, and thus it may stimulate the secretion of LH levels in the central nervous system [27]. ...

... Cotinine, a metabolite of nicotine, may act as an aromatase inhibitor, leading to increased androgens [27]. Nicotine can cross the blood-brain barrier, and thus it may stimulate the secretion of LH levels in the central nervous system [27]. Additionally, the current study found that the interactive effects of smoking with drinking, physical activity, sleeping status, and diet were negatively associated with NSM. ...

Recently, the role of lifestyle factors in testicular function has developed into a growing area of interest. Based on cross-sectional data on 3283 Taiwanese men, we investigated whether interactive effects of unhealthy lifestyle behaviors were associated with testicular function. The men were recruited from a private screening institute between 2009 and 2015. Lifestyle behaviors (smoking, alcohol drinking, physical activity (PA), sleeping habits, and diet) were obtained by a validated self-reported questionnaire. The men provided a semen sample and had blood drawn for sex hormone measurement. Men who smoked and drank had higher testosterone (T) levels (β = 0.81, p < 0.001) than those who neither smoked nor drank. Men who smoked and had high Western dietary pattern scores had higher T levels by 0.38 ng/mL (p = 0.03). Those who drank and did not get enough sleep or had high Western dietary pattern scores had elevated T levels-by 0.60 ng/mL (p = 0.005) or 0.45 ng/mL (p = 0.02), respectively. Light PA and insomnia were associated with decreased T levels-by 0.64 ng/mL (p < 0.001). Those who smoked and drank or had light PA or had high Western dietary pattern scores had lower normal sperm morphologies (NSMs)-by 2.08%, 1.77%, and 2.29%, respectively. Moreover, drinkers who had high Western dietary pattern scores had higher sperm concentrations by 4.63 M/mL (p = 0.04). Awareness and recognition of the long-term impact of lifestyle behaviors and better lifestyle choices may help to optimize the chance of conception amongst couples.

... 17 Regarding testosterone, smoking is associated with higher testosterone levels; however, the specific association among women smokers remains unclear and is understudied. 18 Among the few studies that have examined the role of testosterone in female smoking behavior, 18 higher concentrations of testosterone have been found in premenopausal smokers relative to former female smokers and nonsmokers. 19 This pattern holds true for postmenopausal smokers, with higher levels of testosterone in current versus never smokers, which was associated with the number of cigarettes smoked per day. ...

... 17 Regarding testosterone, smoking is associated with higher testosterone levels; however, the specific association among women smokers remains unclear and is understudied. 18 Among the few studies that have examined the role of testosterone in female smoking behavior, 18 higher concentrations of testosterone have been found in premenopausal smokers relative to former female smokers and nonsmokers. 19 This pattern holds true for postmenopausal smokers, with higher levels of testosterone in current versus never smokers, which was associated with the number of cigarettes smoked per day. ...

... This supports previous literature that both male and female smokers, relative to nonsmokers or former smokers, have higher levels of testosterone. [18][19][20] Thus, it is likely that smoking increased testosterone levels among those smoking regularly, although future research should explore potential casual relationships and measure serum testosterone at multiple timepoints to capture potential dynamic changes in relation to smoking behavior. ...

Introduction: Current cigarette smoking rates among older women remain problematic, especially given that this population experiences increased smoking-related health consequences. Despite these increased health concerns, little research to date has explored smoking patterns across the menopausal transition (pre-, early peri-, late peri-, and postmenopausal) or the effect of unique factors such as sex hormones and depression during this transition. Methods: The present study used 10 yearly waves of data from the Study of Women's Health Across the Nation (SWAN), a longitudinal dataset. Data included 1,397 women endorsing ever smoking regularly at baseline. Random-effects logistic regression models were used to examine smoking transitions. Results: While there were not associations between menopausal transition stage and smoking behavior, increased estradiol was associated with an increased likelihood of quitting regular smoking (e.g., transitioning from regular smoking to non-regular/no smoking; Odds ratio [OR]=1.28), while increased testosterone was associated with an increased likelihood of relapsing to regular smoking (e.g., transitioning from former/non-regular smoking to regular smoking OR=2.56). Depression was associated with increased likelihood of continued smoking (OR=0.97) and relapse (OR=1.03). Conclusions: The results emphasize the need to develop interventions to target initiated or continued smoking among women across the menopausal transition and specifically highlight the importance of developing treatments that target depressive symptoms in this population. Additionally, while singular hormone measures were associated with smoking behavior, there is a need for future study of dynamic changes in hormones, as well as the impact of progesterone on smoking behaviors across the menopausal transition. Implications: To date, no studies have examined smoking behaviors across the menopausal transition. In the present study, while menopausal transition status was not significantly related to transitions in smoking behavior, important relationships between sex hormones and depression were observed. Increased estradiol was associated with an increased likelihood of quitting regular smoking, while increased testosterone was associated with an increased likelihood of relapsing to regular smoking behavior. Higher depression scores were related to continued smoking and relapse to regular smoking behavior. These results highlight the need to develop interventions to target smoking cessation among women across the menopausal transition.

... The concurrent increase in testosterone and LH levels was confirmed for current smokers of five or more cigarettes/day but not for smokers of less than five cigarettes/day [41]. Recently, a meta-analysis of 22 studies with a total of 13,317 men, confirmed that smokers show testosterone levels higher than non-smokers [43]. ...

... Another mechanism that could contribute to testosterone rise in smokers is the inhibition of testosterone breakdown by nicotine's metabolites. Indeed, the uridine 5′-diphospho (UDP)-glucuronosyltransferase (UGT) enzyme superfamily catalyzes the glucuronidation of both testosterone and nicotine's metabolites; so, cotinine and trans-3′-hydroxycotinine can compete with testosterone for binding to the catalytic site and prevent androgen inactivation [43]. ...

... Testicular damage is probably due to smoke-induced oxidative stress, but also a neuroendocrine mechanism of nicotine has been hypothesized [31]. Conversely, tobacco does not decrease testosterone levels in men; rather, it would seem to increase androgen concentrations with mechanisms not entirely clear [43]. ...

Progressive deterioration of male reproductive function is occurring in Western countries. Environmental factors and unhealthy lifestyles have been implicated in the decline of testosterone levels and sperm production observed in the last fifty years. Among unhealthy lifestyles, substance and drug abuse is a recognized cause of possible alterations of steroidogenesis and spermatogenesis. Alcohol, opioids and anabolic-androgenic steroids are capable to reduce testosterone production in male interfering with testicular and/or hypothalamic-pituitary function. Other substances such as nicotine, cannabis, and amphetamines alter spermatogenesis inducing oxidative stress and subsequent apoptosis in testicular tissue. Substance and drug abuse is a potentially reversible cause of hypogonadism, defined as the failure of the testis to produce physiological concentrations of testosterone and/or a normal number of spermatozoa. The identification of the abuse is important because the withdrawal of substance intake can reverse the clinical syndrome. This review summarizes the most important clinical and experimental evidence on the effect of substance abuse on testosterone and sperm production.

... Likewise, because both passive smoking and grip strength have been associated with kidney function, we adjusted our models for glomerular filtration rate [30,31]. Finally, since there is some evidence suggesting that cotinine may inhibit testosterone breakdown [32], and low testosterone levels are associated with decreased muscle strength [33,34], we run models that additionally adjusted for serum testosterone concentrations [32]. ...

... Likewise, because both passive smoking and grip strength have been associated with kidney function, we adjusted our models for glomerular filtration rate [30,31]. Finally, since there is some evidence suggesting that cotinine may inhibit testosterone breakdown [32], and low testosterone levels are associated with decreased muscle strength [33,34], we run models that additionally adjusted for serum testosterone concentrations [32]. ...

Secondhand tobacco smoke (SHS) exposure is a well-established risk factor for several diseases in adults. Despite the evidence that active tobacco smoke is harmful for the muscles, the association between SHS and muscle strength is still uncertain.We analyzed data from 5390 nonsmoking U.S. adults aged >30 years who participated in the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Exposure to SHS was assessed with serum cotinine concentrations. Grip strength was measured using a Takei digital handgrip dynamometer, and combined grip strength was calculated as the sum of the largest reading from each hand. Median (interquartile range) serum cotinine and grip strength were 0.015 ng/mL (IQR 0.011-0.36) and 65.5 kg (IQR 53.4-86.4), respectively. After adjusting for sociodemographic, anthropometric, health-related behavioral, and clinical risk factors, the highest (0.047-9.9 ng/mL) vs lowest (≤0.011 ng/mL) quartile of serum cotinine was associated with a reduction in combined grip strength of 1.41 kg (95%CI: -2.58, -0.24), p-trend=0.02. These results were consistent across socio-demographic and clinical subgroups. In the US nonsmoking adult population, even low levels of exposure to passive smoking were associated with decreased grip strength. Despite great achievements in tobacco control, extending public health interventions to reduce SHS exposure is still needed.

... The increased concentration of LH with diminished circulatory testosterone levels in experimental mice may suggest an intact pituitary-testicular axis (Souza et al., 2016). The literature on the effect of cigarette smoking on testosterone is at variance, as shown in a recent review article (Zhao et al., 2016). Most of the published papers found that smokers had higher mean testosterone than non-smokers in men, and no clear effect on women. ...

... Most of the published papers found that smokers had higher mean testosterone than non-smokers in men, and no clear effect on women. This has been explained by hypothesizing that nicotine and/or its metabolites have a common disposal pathway with androgenic hormones, and so can competitively inhibit androgen disposal (Zhao et al., 2016). However, in our work, the urinary excretion of nicotine metabolite was significantly enhanced, and we also found slight but significant decreases in both testosterone and estradiol concentrations in plasma, and no significant effect on LH. ...

There is a global increase in the popularity of water-pipe tobacco smoking including Europe and North America. Nevertheless, little is known about the male reproductive effects of water-pipe smoke (WPS), especially after long-term exposure. Here, we assessed effects of WPS exposure (30 min/day) in male mice for 6 months. Control mice were exposed to air-only for the same period of time. Twenty-four hours after the last exposure, testicular histopathology, and markers of inflammation and oxidative stress, and the tyrosine–protein kinase vascular endothelial growth factor receptor 1 (VEGFR1) were assessed in testicular homogenates. Moreover, plasma testosterone, estradiol, and luteinizing hormone (LH) concentrations were also measured. Chronic WPS exposure induced a significant decrease of testosterone and estradiol, and a slight but significant increase of LH. Glutathione reductase, catalase, and ascorbic acid were significantly decreased following WPS exposure. Plasma concentration of leptin was significantly decreased by WPS exposure, whereas that of tumor necrosis factor α and interleukin 6 was significantly increased. Histopathological analysis of the testes revealed the presence of a marked reduction in the diameter of the seminiferous tubules with reduced spermatogenesis. Transmission electron microscopy examination showed irregular thickening and wrinkling of the basement membranes with abnormal shapes and structures of the spermatozoa. VEGFR1 was overexpressed in the testis of the mice exposed to WPS and was not detected in the control. The urine concentration of cotinine, the predominant metabolite of nicotine, was significantly increased in the WPS-exposed group compared with the control group. We conclude that chronic exposure to WPS induces damaging effects to the reproductive system in male mice. If this can be confirmed in humans, it would be an additional concern to an already serious public health problem, especially with the increased use of WPS use all over the world, especially in young adults. Keywords: water-pipe smoke, mice, tobacco, testes, reproductive hormones

... The increased concentration of LH with diminished circulatory testosterone levels in experimental mice may suggest an intact pituitary-testicular axis (Souza et al., 2016). The literature on the effect of cigarette smoking on testosterone is at variance, as shown in a recent review article (Zhao et al., 2016). Most of the published papers found that smokers had higher mean testosterone than non-smokers in men, and no clear effect on women. ...

... Most of the published papers found that smokers had higher mean testosterone than non-smokers in men, and no clear effect on women. This has been explained by hypothesizing that nicotine and/or its metabolites have a common disposal pathway with androgenic hormones, and so can competitively inhibit androgen disposal (Zhao et al., 2016). However, in our work, the urinary excretion of nicotine metabolite was significantly enhanced, and we also found slight but significant decreases in both testosterone and estradiol concentrations in plasma, and no significant effect on LH. ...

Front Physiol. 2017 Apr 4;8:158. doi: 10.3389/fphys.2017.00158. eCollection 2017. Chronic Water-Pipe Smoke Exposure Induces Injurious Effects to Reproductive System in Male Mice. Ali BH(1), Al Balushi KA(1), Ashique M(1), Shalaby A(2), Al Kindi MA(2), Adham SA(3), Karaca T(4), Beegam S(5), Yuvaraju P(5), Nemmar A(5). Author information: (1)Department of Pharmacology, College of Medicine and Health Sciences, Sultan Qaboos UniversityAl Khod, Oman. (2)Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos UniversityAl Khod, Oman. (3)Department of Biology, College of Science, Sultan Qaboos UniversityAl Khod, Oman. (4)Department of Histology-Embryology, Faculty of Medicine, University of TrakyaEdirne, Turkey. (5)Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates UniversityAl Ain, United Arab Emirates. There is a global increase in the popularity of water-pipe tobacco smoking including in Europe and North America. Nevertheless, little is known about the male reproductive effects of water-pipe smoke (WPS), especially after long-term exposure. Here, we assessed effects of WPS exposure (30 min/day) in male mice for 6 months. Control mice were exposed to air-only for the same period of time. Twenty-four hours after the last exposure, testicular histopathology, and markers of inflammation and oxidative stress, and the tyrosine-protein kinase vascular endothelial growth factor receptor 1 (VEGFR1) were assessed in testicular homogenates. Moreover, plasma testosterone, estradiol, and luteinizing hormone (LH) concentrations were also measured. Chronic WPS exposure induced a significant decrease of testosterone and estradiol, and a slight but significant increase of LH. Glutathione reductase, catalase, and ascorbic acid were significantly decreased following WPS exposure. Plasma concentration of leptin was significantly decreased by WPS exposure, whereas that of tumor necrosis factor α and interleukin 6 was significantly increased. Histopathological analysis of the testes revealed the presence of a marked reduction in the diameter of the seminiferous tubules with reduced spermatogenesis. Transmission electron microscopy examination showed irregular thickening and wrinkling of the basement membranes with abnormal shapes and structures of the spermatozoa. VEGFR1 was overexpressed in the testis of the mice exposed to WPS and was not detected in the control. The urine concentration of cotinine, the predominant metabolite of nicotine, was significantly increased in the WPS-exposed group compared with the control group. We conclude that chronic exposure to WPS induces damaging effects to the reproductive system in male mice. If this can be confirmed in humans, it would be an additional concern to an already serious public health problem, especially with the increased use of WPS use all over the world, especially in young adults. DOI: 10.3389/fphys.2017.00158 PMCID: PMC5378788 PMID: 28420996

... 33 accordingly, a recent metaanalysis, including 22 studies of 13,317 men (age 18-61years), has clearly showed that smokers have a higher mean testosterone than non-smokers [1.53 nmol/L, 95% CI 1.11 to 1.96)]. 41 Finally, the possibility of a lower prevalence, among tobacco abusers, of overweight/obesity, which further contribute to decreasing T and lH, should be taken in account. 42 Two studies, one performed in ed patients 8 and one in subjects with couple infertility, 36 documented that SHg was associated with an increased number of related morbidities. ...

... Furthermore, a number of lifestyle and environmental risk factors for hypertension have effects that are more potent in women. Smoking conveys a greater cardiovascular risk in women than men [20], which may be partially due to its effects on sex hormones [21,22]. Obesity is also an important modifier of cardiovascular risk in women: in combination with metabolic syndrome, cardioprotection is absent in pre-menopausal women [23,24]. ...

Abstract There has been intense interest in the role of the gut microbiome in human health and a broad range of diseases in recent years. In the context of cardiovascular disease, gut dysbiosis (defined as a change in the gut microbiome and the gut-epithelial barrier) has been linked to disturbances in blood pressure (BP) regulation. These findings build upon our understanding of the complex pathophysiology of essential hypertension. There are clear sex differences in the epidemiology of hypertension, with distinct trends in BP across the life-course in men and women. To date, a role for the gut microbiome in contributing to the sex differences in BP is yet to be clearly established. The purpose of this review is to summarise the current literature regarding how the gut microbiome differs between men and women and to investigate whether sex-determined differences in the gut microbiome influence the response to factors such as diet, obesity and inflammation. Finally, we will explore evidence for the possible interaction between sex-specific factors, including sex hormones and pregnancy, with the gut in the context of hypertension pathophysiology.

... Halmenschlager et al. found no relation between smoking and testosterone level 19 but the results of a meta-analysis showed that in a group of healthy men aged 18-61 years, smokers had a higher mean testosterone than non-smokers. 20 Moreover, the Tromsø Study showed differences between testosterone concentration in current, ex-and never-smokers. 21 Our study did not confirm these results. ...

Background: Testosterone has been recognized for its anabolic properties. It has been documented that in patients with chronic obstructive pulmonary disease (COPD), chronic hypoxia, disease severity, smoking, and corticosteroid treatment may contribute to low testosterone levels. Objectives: The aim of the study was to evaluate the incidence of decreased serum testosterone concentration in male COPD patients and its influence on their condition. Material and methods: The study group consisted of 90 male patients, aged 67.2 ±8.8 years in all stages of airflow limitation severity (mild n = 6, moderate n = 43, severe n = 28 and very severe n = 13) Serum testosterone concentration was evaluated using ELISA method (Testosterone ELISE LDN). Decreased serum testosterone level was defined as a value of less than 3 ng/mL. Testosterone levels were related clinical features of COPD. Results: Serum testosterone concentration did not differ in patients with different stages of airflow limitation severity (3.8 ±0.7 ng/mL for mild: 3.6 ±2.1 ng/mL for moderate; 3.4 ±1.2 ng/mL for severe and 3.7 ±1.7 ng/mL for very severe, respectively). Decreased serum testosterone was found in 30 patients (group A). There were no differences in age, the number of exacerbations or CRP concentration between patients with decreased and the normal serum testosterone group (group B). Group A was characterized by a lower FEV1, shorter 6-minute walking distance, longer smoking history and higher BMI, but no differences in body composition and densitometry results were found. Conclusions: Serum testosterone depression may occur in as much as 30% of male COPD patients in all COPD stages of severity. The relationship between serum testosterone and negative COPD prognostic factors indicates its influence on the natural history of the disease.

... In this context, the recommendation for lung cancer screening in Korea suggests that a low-dose chest computed tomography should be administered every year in high-risk patients aged 55 to 75 years who have a smoking history of 30 packs per year or more, and follow-up observations are suggested for 15 years after smoking cessation [12]. The incidence of erectile dysfunction, which is a men's health issue, is two times higher in smokers than in nonsmokers [13,14], although cigarette smoking may have a positive effect on testosterone levels [15]. It has been reported that the prevalence of erectile dysfunction is reduced after smoking cessation and becomes similar to that of nonsmokers. ...

  • Byoungjin Park
  • Yong-Jae Lee Yong-Jae Lee

Recent epidemiological research has indicated that men have increased health risks due to biological and social factors. Research in the area of men's health has been focused on disease events and subsequent disabilities. In future aging societies, more attention should be paid to the importance of men's health because a decreased quality of life and increased social burden are impending unless proper maneuvers are taken to slow the development and progression of morbidity through the use of preventive strategies. The adoption of a healthier lifestyle and the early identification and management of risk factors are very important and can be an initiative for prevention and for slowing the progression of morbidities with related quality of life issues. Males are rather vulnerable in terms of health, and conscious and active efforts are required to promote their health in an aging society. Here, we hope to shed light on the influence of lifestyle modifications and their clinical implications on men's health.

... Most plausible is adiposity, in high-income countries positively associated with socioeconomic disadvantage, and which lowers circulating testosterone (Gapstur et al., 2007;Cooper et al., 2015). Conversely, smoking is strongly linked to disadvantage but raises testosterone (Mohr et al., 2005;Zhao et al., 2016b), so could work against these effects or even produce a 'reverse gradient'. Meanwhile, experimental research shows circulating testosterone is sensitive to the social environment, in particular where an individual's status is threatened: testosterone changes in response to competition depending on outcome, rising in the winner compared to the loser (Archer, 2006;Mazur and Booth, 1998;Geniole et al., 2017). ...

  • Amanda Hughes Amanda Hughes
  • Meena Kumari

Lower testosterone levels in men are observationally associated with worse health, but it is unclear whether they contribute to well-established social gradients in health. Mendelian Randomization studies suggest positive testosterone-health associations may not be causal, with some intervention studies suggesting testosterone administration could be harmful. Since testosterone is rarely measured in general population studies, very little is known about how testosterone varies by social position. Differences by education and household income in British men aged 60-64y were recently reported, but it is unclear whether this reflects an influence of socioeconomic position (SEP) on testosterone, influence of testosterone on SEP, or confounding. In the UK Household Longitudinal Study, a nationally-representative survey of UK adults, we examine social differences in testosterone in 3663 men aged 16-97y in 2010–12. We consider diverse dimensions of SEP: education, employment status, equivalized household income and personal earnings. Multivariable regression is used to explore social differences in testosterone across the adult life-span (16-97y). Secondly, Mendelian Randomization (MR), an approach which uses gene variants as instrumental variables for endogenous exposures, is used to investigate causal directionality. We examine associations with risk-taking, a plausible mediator of testosterone-SEP associations. In observational models no social differences in testosterone are seen, but MR models suggest a positive influence of testosterone on earnings (increase in log-transformed monthly earnings (GBP) per standard deviation increase in testosterone: 0.51, 95%CI: 0.03,1.05, p = 0.07) and probability of being in work (probit coefficient:0.25, 95%CI: 0.01,0.51, p = 0.06). Though MR estimates are less precise, results are consistent with previous literature linking testosterone with labour market success. The discrepancy may reflect suppression of observational associations by factors positively correlated with testosterone and negatively correlated with SEP, or indicate an influence of typical lifetime testosterone, which may be better indexed by genetic variants than by single testosterone measurements subject to noise.

... At each session and in line with recommended guidelines for conducting hormone studies with humans ( van Anders, 2012), we excluded participants who reported the presence of medical conditions or current use of medications affecting cortisol, testosterone, or sexual drive/ functions from analyses. We also excluded nicotine users in line with these guidelines (van Anders, 2012); this choice is supported by a meta-analysis study showing that smoking cigarettes affects men's testosterone and may affect women's testosterone (Zhao, Leung, Lin, & Schooling, 2016) as well as women's and men's cortisol levels (Steptoe & Ussher, 2006). The number of participants who were excluded from analyses at each session varied depending on the participants' specific responses at each session. ...

Sexual desire and testosterone are widely assumed to be directly and positively linked to each other despite the lack of supporting empirical evidence. The literature that does exist is mixed, which may result from a conflation of solitary and dyadic desire, and the exclusion of contextual variables, like stress, known to be relevant. Here, we use the Steroid/Peptide Theory of Social Bonds as a framework for examining how testosterone, solitary and partnered desire, and stress are linked over time. To do so, we collected saliva samples (for testosterone and cortisol) and measured desire as well as other variables via questionnaires over nine monthly sessions in 78 women and 79 men. Linear mixed models showed that testosterone negatively predicted partnered desire in women but not men. Stress moderated associations between testosterone and solitary desire in both women and men, but differently: At lower levels of stress, higher average testosterone corresponded to higher average solitary desire for men, but lower solitary desire on average for women. Similarly, for partnered desire, higher perceived stress predicted lower desire for women, but higher desire for men. We conclude by discussing the ways that these results both counter presumptions about testosterone and desire but fit with the existing literature and theory, and highlight the empirical importance of stress and gender norms.

... The effect of smoking on T levels is not entirely clear, although Jeng et al. (2014) found diminished T in subjects with a history of 20 pack-years. A systematic review and a meta-analysis in 2016 (Zhao et al., 2016) on 22 studies of 13,317 men showed that smokers had higher mean testosterone than non-smokers using a random-effects model with inverse variance weighting. For sure, new compounds need to be evaluated, as in e-cigarettes, and more studies are needed. ...

Adult‐onset hypogonadism is a syndrome often underdiagnosed, undertreated, or incompletely explored. There are various reasons for this: firstly, undefined age range of men in whom testosterone levels should be investigated and then no definitive serum cutoff point for the diagnosis of hypogonadism; and finally, variable and non‐specific signs and symptoms; men and physicians do not pay adequate attention to sexual health. All these factors make the diagnostic criteria for hypogonadism controversial. The evaluation of the clinical features and causes of this syndrome, its link with age, the role of testosterone and other hormone levels, and the presence of any comorbidities are all useful factors in the investigation of this population. The purpose of this manuscript, after an accurate analysis of current literature, is to facilitate the diagnosis of hypogonadism in men through the use of the CATCH acronym and a checklist to offer a practical diagnostic tool for daily clinical practice. A narrative review of the relevant literature regarding the diagnosis of late‐onset hypogonadism or adult‐onset hypogonadism was performed. PubMed database was used to retrieve articles published on this topic. A useful new acronym CATCH (Clinical features [symptoms] and Causes, Age, Testosterone level, Comorbidities, and Hormones) and a practical checklist to facilitate the evaluation of hypogonadism in aging men were used. The evaluation of the clinical features and causes of hypogonadism, the link with age, the role of Testosterone and other hormones, and the evaluation of comorbidities are important in investigating adult‐onset hypogonadism. The CATCH checklist could be helpful for clinicians for an early diagnosis of both hypogonadism and associated comorbidities. We suggest the use of this acronym to advocate the investigation of declining testosterone in aging men.

... Cigarette smoking and alcohol use disorders A recent meta-analysis reports ORs of 2.05 for suicidal ideation, 2.36 for suicide plans, 2.84 for suicide attempts, and 1.83 for suicides in current smokers . We interpret the fact that smoking is associated with suicidal behaviors as further indirect evidence for the role of adult androgen activity because a meta-analysis reported higher testosterone levels in male smokers compared to male non-smokers (Zhao et al., 2016) and because several studies show that nicotine inhibits CYP19A1 activity (aromatization of androgens into estrogens) in the brain (Biegon et al., 2010), trophoblast (Barbieri et al., 1986), and breast tissues (Kadohama et al., 1993). ...

  • Bernd Lenz
  • Mareike Röther
  • Polyxeni Bouna-Pyrrou
  • Johannes Kornhuber Johannes Kornhuber

Suicide is a devastating public health issue that imposes severe psychological, social, and economic burdens not only for the individuals but also for their relatives, friends, clinicians, and the general public. Among the different suicidal behaviors, suicide completion is the worst and the most relevant outcome. The knowledge of biological etiopathological mechanisms involved in suicide completion is limited. Hitherto, no objective markers, either alone or in combination, can reliably predict who will complete a suicide. However, such parameters are strongly needed to establish and optimize prediction and prevention. We introduce here a novel ideation-to-completion framework in suicide research and discuss the problems of studies aiming at identifying and validating clinically useful markers. The male gender is a specific risk factor for suicide, which suggests that androgen effects are implicated in the transition from suicidal ideation to suicide completion. We present multiple lines of direct and indirect evidence showing that both an increased prenatal androgen load (with subsequent permanent neuroadaptations) and increased adult androgen activity are involved in suicide completion. We also review data arguing that modifiable maternal behavioral traits during pregnancy contribute to the offspring's prenatal androgen load and increase the risk for suicide completion later in life. We conclude that in utero androgen exposure and adult androgen levels facilitate suicide completion in an additive manner. The androgen model of suicide completion provides the basis for the development of novel predictive and preventive strategies in the future.

... Others have shown a direct adverse effect of smoking on skeletal remodeling, bone cell health, and decreased BMD [2,34]. These findings may partly relate to the influence of smoking on sex hormones, including estrogen and testosterone [35]. We postulate that this deleterious effect may be provoked by blood Pb, as smoking is a significant source of environmental Pb, demonstrating a dose-dependent relationship between tobacco and blood Pb [36]. ...

  • Ho-Sun Lee Ho-Sun Lee
  • Taesung Park

Osteoporosis has a complex etiology and is considered a multifactorial polygenic disease, in which genetic determinants are modulated by hormonal, lifestyle, environmental, and nutritional factors. Therefore, investigating these multiple factors, and the interactions between them, might lead to a better understanding of osteoporosis pathogenesis, and possible therapeutic interventions. The objective of this study was to identify the relationship between three blood metals (Pb, Cd, and Al), in smoking and nonsmoking patients' sera, and prevalence of osteoporosis. In particular, we focused on gene-environment interactions of metal exposure, including a dataset obtained through genome-wide association study (GWAS). Subsequently, we conducted a pathway-based analysis, using a GWAS dataset, to elucidate how metal exposure influences susceptibility to osteoporosis. In this study, we evaluated blood metal exposures for estimating the prevalence of osteoporosis in 443 participants (aged 53.24 ± 8.29), from the Republic of Korea. Those analyses revealed a negative association between lead blood levels and bone mineral density in current smokers (p trend <0.01). By further using GWAS-based pathway analysis, we found nuclear receptor (FDR<0.05) and VEGF pathways (FDR<0.05) to be significantly upregulated by blood lead burden, with regard to the prevalence of osteoporosis, in current smokers. These findings suggest that the intracellular pathways of angiogenesis and nuclear hormonal signaling can modulate interactions between lead exposure and genetic variation, with regard to susceptibility to diminished bone mineral density. Our findings may provide new leads for understanding the mechanisms underlying the development of osteoporosis, including possible interventions.

... Contributing factors leading to these effects in male smokers include the presence of nicotine and its metabolite, cotinine, benzo(a)pyrene, as well as cadmium levels [11]. For example, a meta-analysis of 13 317 men found that smoking was associated with higher mean testosterone levels, which could be attributed to the inhibition of testosterone breakdown by cotinine [18]. ...

  • Damayanthi Durairajanayagam Damayanthi Durairajanayagam

Objective: To examine the potential effects of lifestyle factors on male reproductive health. Evidence of a global decline in human sperm quality over recent decades has been accumulating. Environmental, occupational, and modifiable lifestyle factors may contribute to this decline. This review focuses on key lifestyle factors that are associated with male infertility such as smoking cigarettes, alcohol intake, use of illicit drugs, obesity, psychological stress, advanced paternal age, dietary practices, and coffee consumption. Other factors such as testicular heat stress, intense cycling training, lack of sleep and exposure to electromagnetic radiation from mobile phone use are briefly discussed. Materials and method: A comprehensive literature search was performed to identify and synthesise all relevant information, mainly from within the last decade, on the major lifestyle factors associated with male infertility and semen quality. Database searches were limited to reports published in English only. A manual search of bibliographies of the reports retrieved was conducted to identify additional relevant articles. Results: In all, 1012 articles were identified from the database search and after reviewing the titles and abstract of the reports, 104 articles met the inclusion criteria. Of these, 30 reports were excluded as the full-text could not be retrieved and the abstract did not have relevant data. The remaining 74 reports were reviewed for data on association between a particular lifestyle factor and male infertility and were included in the present review. Conclusion: The major lifestyle factors discussed in the present review are amongst the multiple potential risk factors that could impair male fertility. However, their negative impact may well be mostly overcome by behaviour modification and better lifestyle choices. Greater awareness and recognition of the possible impact of these lifestyle factors are important amongst couples seeking conception.

... A meta-analysis of 26 studies comprising 3,912,809 participants clearly demonstrated that smoking is associ ated with a greater risk of coronary heart disease in women than in men 220 , and another meta-analysis comprising 82 prospective cohort studies with 3,980,359 parti cipants demonstrated a greater risk of stroke in women than in men 221,222 . Interestingly, smoking has been associated with an increase in testosterone levels in men and women 223 and has been shown to cause oestro gen deficiency in women and to bring forward the onset of meno pause 224 . Therefore, alterations in sex hormone levels may be one mechanistic pathway by which smoking causes a greater risk of CVD in women. ...

  • Katrina M Mirabito Colafella Katrina M Mirabito Colafella
  • Kate M. Denton

Although intrinsic mechanisms that regulate arterial blood pressure (BP) are similar in men and women, marked variations exist at the molecular, cellular and tissue levels. These physiological disparities between the sexes likely contribute to differences in disease onset, susceptibility, prevalence and treatment responses. Key systems that are important in the development of hypertension and cardiovascular disease (CVD), including the sympathetic nervous system, the renin–angiotensin–aldosterone system and the immune system, are differentially activated in males and females. Biological age also contributes to sexual dimorphism, as premenopausal women experience a higher degree of cardioprotection than men of similar age. Furthermore, sex hormones such as oestrogen and testosterone as well as sex chromosome complement likely contribute to sex differences in BP and CVD. At the cellular level, differences in cell senescence pathways may contribute to increased longevity in women and may also limit organ damage caused by hypertension. In addition, many lifestyle and environmental factors — such as smoking, alcohol consumption and diet — may influence BP and CVD in a sex-specific manner. Evidence suggests that cardioprotection in women is lost under conditions of obesity and type 2 diabetes mellitus. Treatment strategies for hypertension and CVD that are tailored according to sex could lead to improved outcomes for affected patients.

... [28] Sigaranın eskiden beri bilinen, serum toplam testosteron seviyesini arttırdığı gösteren yazılara rağmen, son yıllardan yapılan araştırmalar yukarıdaki sonuçları göstermiştir. [29] Sigara, günümüzde sperm hücre hasarına en sık neden olan çevresel kirleticiler arasındadır. ...

... Furthermore, evidence has proved that PAHs can disturb the T production of Leydig Cells (Oh 2014). Additionally, the effect of cigarette smoking on serum T levels has been studied and has found that Cigarette smoking has positive effect on serum T level (Wei Wang et al. 2013;Zhao et al. 2016), we can only infer the relationship from the effects of cigarette smoking on serum T levels. However, the associations between PAHs and serum T levels have not been studied directly among people. ...

Effects of environmental chemicals on human reproductive health and sex hormone levels have been reported for several years, but compared to other environmental chemicals, such as heavy metals, PCBs, triclosan, Phthalate, the links between polycyclic aromatic hydrocarbons (PAHs) and sex hormone levels have not been studied widely. Therefore, our purpose of research was to study the associations between urinary PAH metabolites and serum total testosterone (T) levels among men. The data was obtained from the independent cross-section wave (2011–2012) of the National Health and Nutrition Examination Survey (NHANES), including demographic, socioeconomic, dietary, health-related questions, examinations and laboratory test. All analyses were performed by R software (version 3.2.3), including one-way analysis of variance, multivariable linear regression, stratified analysis and heterogeneity test. Of 1102 American adults aged 20 and above included in the statistical analysis, we found that urinary 3-hydroxyfluorene and 2-hydroxyfluorene were significantly positively associated with serum T levels (β = 40.62, 95%CI = 21.78–59.46, P = 2.56 × 10⁻⁵; β = 35.17, 95%CI = 13.18–57.15, P = 1.75 × 10⁻³, respectively). The associations between urinary PAH metabolites and serum T levels signified a major public health problem over the world. Prospective work is needed to investigate the potential long-term health consequences of these findings.

... nicotine following overnight abstinence, women in the luteal phase showed diminished subjective effects and increased cognitive performance compared with women during the follicular phase of the cycle (DeVito et al., 2014). Although the effect of androgens on smoking or nicotine preference is not apparent, a meta-analysis shows that the nicotine metabolite cotinine inhibits the breakdown of testosterone, and, subsequently, smoking (active or passive) increases testosterone levels in smoker men (Zhao et al., 2016). ...

Smoking is the major cause of preventable deaths worldwide, and although there is a decline in overall smoking prevalence in developed countries, the decline in women is less pronounced than in men. Women become dependent faster and experience greater difficulties in quitting. Similar trends have been observed in animal models of nicotine/tobacco addiction. Individual differences in vulnerability to drug abuse are also observed in nicotine/tobacco addiction and point to the importance of sex differences. This Review, summarizes findings from three experimental approaches used to depict nicotine preference in animal models, intravenous and oral nicotine self-administration and nicotine-induced conditioned place preference. Nicotine preference is considered to be reflected in the animal's motivation to administer the drug (intravenously or orally) or to prefer an environment paired with the presence of the drug (conditioned place preference). These approaches all point to the importance of sex and age of the subjects; the preference of females and adolescents appear to be more pronounced than that of males and adults, respectively. A closer look at these factors will help us understand the mechanisms that underlie nicotine addiction and develop strategies to cope. Ignoring sex differences and reaching conclusions based only on studies using male subjects has resulted in erroneous generalizations in the past. Sex differences in nicotine preference have been clearly documented, and awareness on this aspect of nicotine dependence will significantly impact our success in translational research.

... Smoking has already been reported to play a significant role in HNC carcinogenesis (5,19). The incidence of HNC was higher in men than in women (14)(15)(16), which reflects the larger number of men with a smoking habit than women, but also the higher impact of testosterone increase in men caused by cotinine (17), having in mind the significance of testosterone/oestrogen balance in carcinogenesis (18). ...

Objectives: The high incidence of head and neck cancer (HNC), significantly associated with living environment and behaviour, can be prevented more efficiently. The aim of this study was to evaluate the environmental and behavioural risk factors for HNC. Methods: Using a detailed questionnaire on social status, education, living and occupational environment exposures, family cancer and lifestyle, HNC patients (103 cases, 76.7% of men) were compared with control subjects (244 subjects, 73% of men) balanced by age: mean (standard deviation) 63.8 (9.3) and 63.8 (9.0) for cases and controls, respectively. Results: The results of this study showed that smoking and low education were significant risk factors for HNC regardless of sex. Family HNC and breast cancer were significant predictors of HNC risk. Conclusion: The study confirmed previous results that smoking and low education are significantly associated with HNC. Additionally, results pointed to significant HNC and breast cancer risk in HNC patient's families that may have originated from passive smoking or a smoking habit stemming from social environments that support it. Better dissemination programmes regarding smoking risks for children and adults are needed, targeting not only individuals but also families.

... Smoking has already been reported to play a significant role in HNC carcinogenesis (5). The incidence of HNC was higher in men than in women (14)(15)(16), which reflects the larger number of men with a smoking habit than women, but also the higher impact of testosterone increase in men caused by cotinine (17), having in mind the significance of testosterone/oestrogen balance in carcinogenesis (18). ...

Objectives: The high incidence of head and neck cancer (HNC), significantly associated with living environment and behaviour, can be prevented more efficiently. The aim of this study was to evaluate the environmental and behavioural risk factors for HNC. Methods: Using a detailed questionnaire on social status, education, living and occupational environment exposures, family cancer and lifestyle, HNC patients (103 cases, 76.7% of men) were compared with control subjects (244 subjects, 73% of men) balanced by age: mean (standard deviation) 63.8 (9.3) and 63.8 (9.0) for cases and controls, respectively. Results: The results of this study showed that smoking and low education were significant risk factors for HNC regardless of sex. Family HNC and breast cancer were significant predictors of HNC risk. Conclusion: The study confirmed previous results that smoking and low education are significantly associated with HNC. Additionally, results pointed to significant HNC and breast cancer risk in HNC patient's families that may have originated from passive smoking or a smoking habit stemming from social environments that support it. Better dissemination programmes regarding smoking risks for children and adults are needed, targeting not only individuals but also families.

... SEP could also influence testosterone via obesity, which, in men, lowers circulating testosterone (20), and is associated with disadvantage in high-income countries. Because smoking is more common in less-advantaged groups but may raise testosterone, smoking could reduce rather than contribute to social differences in testosterone in men (21). Socioeconomic influences on testosterone could also be mediated by self-perception of social status, a dimension of SEP whose influences on health may be distinct from income (22). ...

Men with more advantaged socioeconomic position (SEP) have been observed to have higher levels of testosterone. It is unclear whether these associations arise because testosterone has a causal impact on SEP. In 306,248 participants of UK Biobank, we performed sex-stratified genome-wide association analysis to identify genetic variants associated with testosterone. Using the identified variants, we performed Mendelian randomization analysis of the influence of testosterone on socioeconomic position, including income, employment status, neighborhood-level deprivation, and educational qualifications; on health, including self-rated health and body mass index; and on risk-taking behavior. We found little evidence that testosterone affected socioeconomic position, health, or risk-taking. Our results therefore suggest that it is unlikely that testosterone meaningfully affects these outcomes in men or women. Differences between Mendelian randomization and multivariable-adjusted estimates suggest that previously reported associations with socioeconomic position and health may be due to residual confounding or reverse causation.

... The explanation may lie in the effect of smoking on circulating testosterone levels. There is evidence that cigarette smoking leads to an acute increase in testosterone in men and women 45 . The effect may in part arise because cotinine, a tobacco metabolite, inhibits testosterone breakdown. ...

A prenatal sex steroid environment of high prenatal testosterone and low prenatal oestrogen inhibits lung development and may predispose individuals to be vulnerable to lung disease in later life. Therefore, the aim of this report was to investigate whether there is an association between right and left 2D:4D (biomarker of prenatal sex steroids exposure) and primary lung cancer in women and men. Also, we considered the relationship between right–left 2D:4D (Δ2D:4D, a negative correlate of high prenatal testosterone and low prenatal oestrogen) and the age of lung cancer diagnosis. The study included 109 patients (61 men) with lung cancer and 197 controls (78 men). In the study we found that: (i) women with lung cancer have lower 2D:4D compared to controls (the effect was independent of smoking), (ii) among women with cancer, age at diagnosis was positively related to 2D:4D, i.e. women with masculinized 2D:4D present earlier with the cancer than women with feminized 2D:4D, (iii) among men with lung cancer, those with the most aggressive form (small-cell lung cancer) had masculinized (low) Δ2D:4D compared to those with the less aggressive form (non-small cell lung cancer). The data suggests that masculinized right 2D:4D and Δ2D:4D are associated with a predisposition to lung cancer and/or the more aggressive forms of lung cancer.

... It recorded a highly significant decrease than the control group. Zhao et al.. (27) in a meta-analysis of 13 317 men, where it was found that smoking was associated with higher mean testosterone levels, and this was attributed to the inhibition of testosterone breakdown by cotinine. ...

... We further replicated the observed sex-specific discordance in sphingolipids by age (increasing in females and decreasing in males) from a recent longitudinal analysis of 1212 participants in the Wisconsin Registry of Alzheimer's Preven-tion [12]. The higher levels of androgenic, pregnenolone, and progestin steroids in men confirmed previous findings [29,30], as were the decreases in both men and women by age [12]. ...

Susceptibility and progression of lung disease, as well as response to treatment, often differ by sex, yet the metabolic mechanisms driving these sex-specific differences are still poorly understood. Women with chronic obstructive pulmonary disease (COPD) have less emphysema and more small airway disease on average than men, though these differences become less pronounced with more severe airflow limitation. While small studies of targeted metabolites have identified compounds differing by sex and COPD status, the sex-specific effect of COPD on systemic metabolism has yet to be interrogated. Significant sex differences were observed in 9 of the 11 modules identified in COPDGene. Sex-specific associations by COPD status and emphysema were observed in 3 modules for each phenotype. Sex stratified individual metabolite associations with COPD demonstrated male-specific associations in sphingomyelins and female-specific associations in acyl carnitines and phosphatidylethanolamines. There was high preservation of module assignments in SPIROMICS (SubPopulations and InteRmediate Outcome Measures In COPD Study) and similar female-specific shift in acyl carnitines. Several COPD associated metabolites differed by sex. Acyl carnitines and sphingomyelins demonstrate sex-specific abundances and may represent important metabolic signatures of sex differences in COPD. Accurately characterizing the sex-specific molecular differences in COPD is vital for personalized diagnostics and therapeutics.

... We also found that active smokers had higher total T and cFT, DHT, Adione, and SHBG levels at baseline than nonsmokers, which is in accordance with previous research (27). Longitudinal changes in sex steroid status, however, were not affected by baseline smoking behavior except for steeper increases in SHBG levels during follow-up in active smokers compared with nonsmokers. ...

Context Androgen levels have been shown to decline in aging men. However, there is no consensus on the effect of aging, (changes in) 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 24-46 years of whom 691 were re-evaluated after a mean period of 12 years. Main outcome measures Serum SHBG, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels measured using immuno-assays. Testosterone (T), estradiol (E2), dihydro-testosterone (DHT), androstenedione (Adione) measured using LC-MS/MS, free T calculated (cFT). Results Baseline age was 34±6 years. Mean BMI increased by 1.19kg/m², T levels decreased by 14.2%(20.8nmol/l vs. 17.8nmol/l), cFT by 19.1%(392pmol/l vs. 317pmol/l), DHT by 15.6%(1.5nmol/l vs.1.3nmol/l), and Adione by 10.7%(3.7nmol/l vs. 3.3nmol/l; all p<0.001). E2 did not change over time. SHBG increased by 3.0%(39.8nmol/l vs. 41.0nmol/l), LH by 5.8%(4.6U/l vs. 4.9U/l) and FSH by 14.7%(4.3U/l vs. 5.1U/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.

... SEP could also influence testosterone via obesity, which in men lowers circulating testosterone (19,20), and associates in high-income countries with disadvantage. Because smoking is more common in less advantaged groups but may raise testosterone, smoking could reduce rather than contribute to social differences in testosterone (21,22). Socioeconomic influences on testosterone could also be mediated by self-perception of social status, a dimension of SEP whose influences on health may be distinct from income (23). ...

Men with more advantaged socioeconomic position (SEP) and better health have been observed to have higher levels of testosterone. It is unclear whether these associations arise because testosterone has a causal impact on SEP and health. In 306,248 participants of UK Biobank, we performed sex- stratified genome-wide association analysis to identify genetic variants associated with testosterone. Using the identified variants, we performed Mendelian randomization analysis of the influence of testosterone on socioeconomic position, including income, employment status, area-level deprivation, and educational qualifications; on health, including self-rated health and BMI, and on risk-taking behaviour. We found little evidence that testosterone affected socioeconomic position, health, or risk-taking. Our results therefore suggest it is unlikely that testosterone meaningfully affects these outcomes in men or women. Differences between Mendelian randomization and multivariable-adjusted estimates suggest previously reported associations with socioeconomic position and health may be due to residual confounding or reverse causation.

... Since cigarette smoking was not associated with low T, we excluded it from the analysis. 19 A competitive electrochemiluminescence immunoassay on the 2010 Elecsys autoanalyzer (Roche Diagnostics, Indianapolis, IN) was used to quantify serum T, E 2 , and SHBG concentrations, which were archived in the NHANES database. ...

Introduction: Obese men can have testosterone deficiency (TD) but the etiology is uncertain. Leptin is a 16-kDa protein produced primarily by adipose tissue and, therefore, is positively associated with the amount of body fat and can affect testosterone (T) production. We hypothesized that increased leptin can be independently associated with low T. Materials and methods: We performed a cross-sectional analysis of men from National Health and Nutrition Examination III database to evaluate the association of leptin with serum T and calculated free testosterone (cFT). Linear regression was performed with leptin, age, waist circumference, hypertension, and diabetes as independent variables predicting cFT/T. Multiple linear regression was used to determine predictors for cFT and T using variables previously significant in the univariate analysis. Results: A total of 1193 men were analyzed. As expected, older and obese men were associated with having lower T. Interestingly, increasing leptin levels were an independent predictor of decreasing T and cFT on multivariable analysis. Increasing 1ng/mL in leptin resulted in a decrease of 5.13 and 0.11 ng/dL of T and cFT, respectively (p < 0.05). Also, every additional year of life led to a T and cFT reduction of 2.87 and 0.13 ng/dL, respectively, and increasing 1 cm in waist circumference corresponded to decrease of 4ng/dL in T (p < 0.05). Conclusions: We concluded that increasing leptin, age, and waist circumference were associated with decreasing of T and cFT. Elevated leptin levels could be one of the potential etiologies of TD.

... This relative increase in serum testosterone was found after controlling for BMI, tobacco smoking, and time of day of blood draw. However, they were not able to separate this finding from the effect of cigarette smoking [4], a variable known to elevate serum testosterone [20]. In a study of 1577 men from the 2011-2012 US National Health and Nutrition Examination Survey, time since the last regular use of cannabis was inversely correlated with serum testosterone (p < 0.02) [5]. ...

Cannabis and opioids are substances that affect reproductive health. Opioids suppress testosterone and studies have shown that cannabis may increase testosterone. However, there is minimal research describing the endocrine effects of concurrent cannabis and opioid use. We hypothesize that cannabis use improves opioid-induced testosterone suppression. To test this hypothesis, we used cross-sectional data from a prospective cohort study including 122 men enrolled in methadone maintenance treatment (MMT). We measured serum testosterone with an enzyme-linked immunosorbent assay at study enrolment. Urine drug screens were collected for 15 months and identified 52.5% of participants (n = 64) as cannabis users. The association between cannabis use and testosterone level was examined using regression models with serum testosterone as the dependent variable. In our multivariable regression, methadone dose was associated with lower serum testosterone (β = −0.003, 95% CI-0.005, −0.001, p = 0.003). However, neither cannabis use as a dichotomous variable nor the percentage of cannabis-positive urine drug screens were significantly associated with serum testosterone (β = 0.143, 95% CI −0.110, 0.396, p = 0.266, and β = 0.002, 95% CI > −0.001, 0.005, p = 0.116, respectively). Therefore, it does not appear that cannabis has an association with testosterone levels in men on MMT.

... Smoking has repeatedly been shown to be associated with increased T concentrations ( [62,71]; see [74], for a meta-analytic review). Therefore, we differentiated between smokers (n = 11) and non-smokers (n = 71). ...

Two main hypotheses have been formulated to explain short-term testosterone responses to competitions. The challenge hypothesis and the biosocial model of status make different predictions concerning the point of time, direction, and meaning of hormonal changes. This field study investigated whether testosterone reacts to experiences of challenge during the early stages of a competition or to experiences of status change as a consequence of the competition's outcome. Over a period of 28 days, approximately 2000 salivary testosterone samples were collected from 82 football fans (53% men), while they were watching the matches of their favorite national team during the 2014 World Cup. Conducting repeated measurements across seven competitive events (i.e., matches) and over the course of each match allowed us to split vicarious experiences during each competition into phases of challenge and phases of status change. For both sexes, the results revealed discriminable testosterone trajectories depending on whether the fans experienced highly competitive matches or quick victories. By use of a discontinuous change model, maximal testosterone increases were detected during experiences of challenge. In contrast, a return to pre-contest baseline testosterone levels was initiated as soon as a status gain became certain. Testosterone responsiveness was partly moderated by the subjective importance of the competitive event. Thus, this study provides evidence in favor of the challenge hypothesis and emphasizes the value of conducting high-resolution within-subject designs to further explain the adaptive meaning of androgen responses.

... 33 accordingly, a recent metaanalysis, including 22 studies of 13,317 men (age 18-61years), has clearly showed that smokers have a higher mean testosterone than non-smokers [1.53 nmol/L, 95% CI 1.11 to 1.96)]. 41 Finally, the possibility of a lower prevalence, among tobacco abusers, of overweight/obesity, which further contribute to decreasing T and lH, should be taken in account. 42 Two studies, one performed in ed patients 8 and one in subjects with couple infertility, 36 documented that SHg was associated with an increased number of related morbidities. ...

Introduction: The concept of subclinical or compensated male hypogonadism (SHG), characterized by increased gonadotropins and normal testosterone levels is emerging. However, its real clinical significance is still conflicting. The aim of the present study is to summarize and discuss the available evidence related to the possible definition of SHG and the possible advantages of testosterone replacement therapy (TRT). Evidence acquisition: A comprehensive systematic Medline, Embase and Cochrane search was performed. Publications from January 1, 1969 up to February 29th, 2020 were included. The search was restricted to English-language articles and studies of human participants. Evidence synthesis: Two main clinical forms of SHG can be described. The first identifies young patients who have a positive medical history for testis damage occurring before puberty onset. The second form can occur as a consequence of an age-dependent decline of T. Whereas the former can be the consequence of several congenital or acquired diseases, also possible causes of primary hypogonadism, the real significance of the latter is still debatable. Available evidence indicates that age-related SHG is quite a common phenomenon, occurring in 9.4% of aging men from the general population. Cross-sectional and longitudinal data have documented that it is associated with poor health and can be a sign of forthcoming increased cardiovascular mortality and morbidity. Conclusions: Although available evidence suggests that in aging populations SHG can be considered a particular condition associated with an increased CV risk, it is still unknown if treatment with T can improve any outcomes in these subjects. Hence, further interventional studies are advisable in order to better understand the characteristics of SHG and the possible advantages of an early TRT.

... This suggests that the 2D:4D, even if related with prenatal testosterone level, should not be used as a proxy of the adult testosterone level. The adult testosterone level is related with many aspects of a man's lifestyle, such as, for instance, smoking 54 , body weight 55 , diet 56 , that may act on various stages of ontogenesis and impact the relationship between the 2D:4D and the adult testosterone level. ...

The digit ratio (2D:4D) is said to be a potential marker of exposure to prenatal sex steroids. Some studies suggest that the 2D:4D is also linked with the testosterone response to challenging situations due to organizational effect of prenatal hormonal milieu on adult endocrine functioning. However, up to date, there were only four studies (conducted on small samples) that examined the 2D:4D and the testosterone response to a challenging situation (i.e. physical exertion or aggressive context). Here, we examined the relationship between the 2D:4D and the testosterone change under an acute exercise among 97 men. We found that the digit ratios (the right 2D:4D, the left 2D:4D, and the right minus left 2D:4D) were neither predictors of pre-exercise testosterone, nor the change in testosterone level after a cycling task. Our results add a contradictory to previous studies evidence in a discussion on the links of the 2D:4D and the testosterone change.

... [41][42][43][44] However, there is also some research suggesting that both nicotine use and recent marijuana use can increase physiological testosterone levels in cisgender men, so it is conceivable that other factors may be at play. 45,46 Further research is needed to understand the association between prescribed testosterone and use of these substances, as well as how marijuana use affects physiological and social risks (e.g., attention deficits and injury risk) 47 around the time of surgery. ...

Purpose: We evaluated behavioral health histories and eligibility factors for patients seeking chest reconstruction. Methods: One hundred and fifty-eight consecutive transgender patients were seen for initial masculinizing top surgery consults between May 2017 and July 2019. Chart review was used to assess behavioral health and demographic factors, and eligibility factors related to the World Professional Association for Transgender Health (WPATH) Standards of Care. Univariate and age-adjusted regression models were used to examine the relationship between demographic and behavioral health factors and WPATH criteria. Results: The average age of patients at the time of their first consult was 18 (standard deviation = 3.3, range = 14-33). Eighty-five percent had at least one behavioral health diagnosis; 27% had three or more. Sixty-four percent endorsed a history of self-harm or suicidal ideation, 13% within the last 6 months. Thirty-two percent reported a history of marijuana use and 19% a history of nicotine use. For those prescribed testosterone, additional months on testosterone were significantly associated with male (vs. nonbinary) gender (β = 4.64, 95% confidence interval [CI] 0.37-8.90, p = 0.033), age (β = 0.87, 95% CI 0.41-1.34, p < 0.001), living as one's affirmed gender for over 1 year (β = 6.37, 95% CI 1.37-11.37, p = 0.013), history of marijuana use (β = 4.54, 95% CI 1.10-7.98, p = 0.010), and history of nicotine use (β = 6.23, 95% CI 2.22-10.26, p = 0.003). Conclusion: Patients seeking gender-affirming masculinizing top surgery are behaviorally complex, in ways not necessarily associated with surgical eligibility. Involving a behavioral health provider in perioperative assessment can help identify and address potential risks to recovery and outcomes.

... There are more than 4,000 volatile chemicals other than nicotine present in cigarette smoke, many of which have not been evaluated in terms of effects on steroidogenesis (13). There have been conflicting reports of the effects of tobacco on serum testosterone levels (14)(15)(16). These conflicting results may be attributable to variability in laboratory methods, time of specimen collection, or other factors. ...

Background: While epidemiological studies have clearly documented that smoking cessation significantly enhances sexual health, the underlying mechanism remains largely unknown. Thus, we wished to explore possible mechanisms by using a rat model of smoking-associated erectile dysfunction (ED). Methods: Forty 8-week old male Sprague-Dawley rats were divided into 4 groups. Ten rats were exposed only to room air (N group). The remaining 30 rats were passively exposed to cigarette smoke over a 12-week period. At the end of 12 weeks, the smoking (S, n=10) group underwent immediate erectile function testing and were sacrificed. The remaining 20 rats were exposed to room air only for 4 (Q4W, n=10) or 8 (Q8W, n=10) weeks and then underwent erectile function testing and sacrifice. Erectile function was evaluated by measuring intracavernous pressure (ICP) and mean arterial pressure (MAP). After blood collection for serum testosterone determination, rats were sacrificed to obtain corporal tissue for immunohistochemistry. Results: Mean ICP/MAP ratio was significantly lower in the S group compared to the N and Q8W groups (0.52±0.11, 0.94±0.05, and 0.94±0.12, respectively, P=0.0189). Smooth muscle/collagen ratio was also significantly lower in the S group compared to the N and Q8W groups (11.8±0.94, 17.5±1.82, and 16.4±0.60, respectively, P=0.0008). Oxidative stress and apoptotic indices were significantly higher in the S group compared to the N and Q8W groups. Neuronal and endothelial nitric oxide synthases were significantly less expressed in the S group compared to the N and Q8W groups. Conclusions: Smoking cessation is associated with partial recovery of penile hemodynamics in a rat model of smoking associated ED.

... However, it is also worth noting that randomized, controlled trials in which testosterone therapy was compared to a placebo have not shown consistent results on the link between personality or psychological well-being and testosterone treatment (Huo et al., 2016). Also, the effect of cigarette smoking on testosterone levels in men is debated (Tweed et al., 2012;Zhao et al., 2016). The data on the levels of total, free, and bioavailable testosterone and sex-hormone-binding globulin in male smokers and never-smokers have been contradictory (English et al., 2001;Svartberg & Jorde, 2007;Wu et al., 2008;Halmenschlager et al., 2009). ...

  • Krzysztof Czaderny Krzysztof Czaderny

Background: Social identity theory proposes that people define themselves in terms of the social groups they belong to or aspire to belong to. Tobacco smoking and alcohol use in men have been hypothesized to be symbolic of adult male status. The current study examines whether adolescent personality characteristics linked to masculinity and nonconformity are associated with tobacco smoking and alcohol misuse in men. Methods: The analysis is based on the results of a cross-sectional study conducted in 2018 on a stratified, random sample of 703 adult male residents of Warsaw, Poland, with elementary- and secondary-school education. All survey data were collected through a paper-and-pencil questionnaire. A path model is employed to examine the direct and indirect effects of adolescent characteristics on tobacco smoking and alcohol consumption. Results: According to the path model, retrospective perceptions of self-reported character strength, rebellion against unjustified prohibitions and rules, ease in making decisions, willingness to differ from others, and interest in the opposite gender in adolescence had a significant direct effect on tobacco smoking in adolescence and a significant indirect effect on tobacco smoking in adulthood. The variables representing character strength, rebellion against unjustified prohibitions and rules, ease in making decisions, and interest in the opposite gender in adolescence also showed a significant direct effect on alcohol use in adolescence. Conclusion: Masculinity and nonconformity were related to addictive behaviors in men, which might have health policy implications. In this paper, associating traditional masculinity with health orientation in society is proposed as a possible preventive intervention.

... Observational studies highlighted that smokers are characterized by lower estrogens and progesterone [71,72], and higher androgens [73][74][75] levels in the circulating blood, as well as lower estrogens levels and an increased androgens/estrogens ratio in the follicular fluids [76]; these evidences are suggestive of impaired steroidogenesis, or steroid hormones metabolism, occurring at both extra-ovarian and ovarian level. A large body of evidences from observational studies suggest that smoking exerts multiple anti-estrogenic actions, by interfering with estrogen biosynthesis, bioavailability, catabolism, and clearance; the potential mechanisms underlying these actions include: the increase of sex hormone binding globulin (SHBG) levels resulting in lower levels of biologically active free estrogens [77]; the increase in production of estrogen metabolites with minimal estrogenic activity [78] which shifts away from the more estrogenically potent 16a-hydroxylation towards the 2hydroxylation pathway, with production of metabolites which are rapidly cleared from the circulation [79]; and the potential increased estrogen hepatic metabolism [80], the latter being hypothesized by reduced estrogens levels in a cohort of post-menopausal women under hormone-replacement therapy. ...

  • Cristina de Angelis Cristina de Angelis
  • Antonio Nardone
  • Francesco Garifalos
  • Rosario Pivonello

Background: Considerable interest has been gathered on the relevant impact of preventable factors, including incorrect lifestyle and unhealthy habits, on female fertility. Smoking, alcohol and addictive drugs consumption represent a major concern, given the broad range of diseases which might be favored or exacerbated by these dependable attitudes. Despite the well-characterized effects of prenatal exposure on pregnancy outcomes and fetus health, a substantial proportion of women of reproductive age is still concerned with these habits. At present, the impact of smoke, alcohol and addictive drugs on women fertility, and, particularly, the specific targets and underlying mechanisms, are still poorly understood or debated, mainly due to the scarcity of well-designed studies, and to numerous biases. Objective: The current review will provide a comprehensive overview of clinical and experimental studies in humans and animals addressing the impact of smoke, alcohol and addictive drugs on female fertility, by also embracing effects on ovary, oviduct, and uterus, with particular reference to primary endpoints such as ovarian reserve, steroidogenesis, ovulation and menstrual cycle, oviduct function and uterus receptivity and implantation. A brief focus on polycystic ovary syndrome and endometriosis will be also included. Methods: A Pubmed literature search was performed with selected keywords; articles were individually retrieved by each author. No limitation was set for publication date. Articles in languages other than English were excluded. Additional articles were retrieved from references list of selected manuscripts. Results and conclusions: Currently, the most consistent evidences of a detrimental effect of smoke, alcohol and addictive drugs on specific domains of the female reproductive function are provided by experimental studies in animals. Overall, clinical studies suggest that smoking is associated to decreased fertility, although causal inference should be further demonstrated. Studies addressing the effect of alcohol consumption on female fertility provide conflicting results, although the majority reported lack of a correlation. Extremely scarce studies investigated the effects of addictive drugs on female fertility, and the specific actions of selected drugs have been difficult to address, due to multidrug consumption.

... In lung cancer, we found evidence that expression of PDE4D could be regulated by male hormones using TCGA data ( Supplementary Fig. 2). Thus, as smoking is associated with both higher testosterone levels and PDE4D expression [52,53], our data suggest that PDE4D responsiveness to hormone stimulation could be one mechanism that explains the epidemiological dimorphism seen in our study. Of note, Hispanic patients with a high percentage of Native American ancestry were more likely to carry a variant of PDE4B, a close relative of PDE4D, that was strongly associated with leukemia relapse [54]. ...

Purpose African Americans, especially men, have a higher incidence of lung cancer compared with all other racial and ethnic groups in the US. Self-reported race is frequently used in genomic research studies to capture an individual's race or ethnicity. However, it is clear from studies of genetic admixture that human genetic variation does not segregate into the same biologically discrete categories as socially defined categories of race. Previous studies have suggested that the degree of West African ancestry among African Americans can contribute to cancer risk in this population, though few studies have addressed this question in lung cancer. Methods Using a genetic ancestry panel of 100 SNPs, we estimated West African, European, and Native American ancestry in 1,407 self-described African Americans and 2,413 European Americans. Results We found that increasing West African ancestry was associated with increased risk of lung cancer among African American men (ORQ5 vs Q1 = 2.55 (1.45–4.48), p = 0.001), while no association was observed in African American women (ORQ5 vs Q1 = 0.90 (0.51–1.59), p = 0.56). This relationship diminished following adjustment for income and education. Conclusions Genetic ancestry is not a major contributor to lung cancer risk or survival disparities.

... In nonsmoking men a general pattern of higher hormone levels were associated with a lower risk of IHD and to a less degree with stroke, whereas in smokers higher hormone levels were in most cases associated with an increased risk of the two outcomes. It is well known that smoking men have higher total T, free T, and SHBG levels compared with nonsmokers; whereas the mechanism of this association remains unclear (37), it seems evident that smoking is a causal factor for higher hormone levels because T levels in former smokers are in the same range as seen in men who never smoked (4). At the same time, smoking is a well-described risk factor for T2D and cardiovascular disease (38). ...

Context: Low serum testosterone (T) levels have been associated with type 2 diabetes (T2D) and cardiovascular disease (CVD). However, it is unresolved whether low T is a risk factor or rather a risk marker for these conditions. Objective: To investigate serum levels of total T, SHBG, free T, estradiol, LH and FSH, and subsequent risk of T2D and/or CVD. Design, setting and participants: A prospective cohort study consisting of 5,350 men from the general population aged 30 to 70 years at baseline, examined between 1982 and 2001 and followed with complete registry follow-up until December 2011; i.e. up to 29 years of follow-up. Main outcome measures: T2D outcomes defined as the first diagnosis of T2D and cardiovascular outcomes defined as first diagnosis of either ischemic heart disease (IHD) or stroke (ischemic and hemorrhagic stroke). Results: In Cox proportional hazards models, a significantly negative association between T quartile and risk of T2D was seen. Similarly, men with SHBG in the highest quartile had a decreased risk of developing T2D (non-smokers: HR=0.30, 95%CI: 0.14-0.63, smokers: HR=0.40, 95%CI: 0.20-0.78). Similar trends were seen for free T, however, insignificant in the fully adjusted analysis. No associations were seen for estradiol, LH, and FSH. A less consistent pattern was seen for the hormones in relation to CVD outcomes; non-smoking men showed a pattern of higher levels of total T, SHBG, and LH being negatively associated with IHD and less pronounced for stroke whereas in smokers higher levels of total T, free T, and LH were positively associated with the two CVD outcomes. Conclusions: The observed negative associations of T and SHBG with T2D, but no association to LH and free T, indicates that low T in men who develop T2D is a marker of the disease rather than primary hypogonadism being a causal risk factor.

Cigarette smoking is suggested to influence androgen milieu, which is closely associated with pathogenesis and prognosis of prostate cancer. In this study, we investigated the association between serum testosterone level before or during androgen‐deprivation therapy (ADT) as well as prognoses and cigarette smoking status among men with metastatic prostate cancer. Serum testosterone level before ADT in current smokers (n = 6, median [interquartile range, IQR]; 454 ng/ml [426–478 ng/ml]) was significantly higher than that in nonsmokers (n = 26, median [IQR]; 397 ng/ml [312–435 ng/ml]). Serum testosterone level during ADT in current smokers (n = 7, median [IQR]; 7 ng/ml [3–11 ng/ml]) was comparable with that in nonsmokers (n = 55, median [IQR]; 9 ng/ml [3–20 ng/ml]). Progression‐free survival and overall survival were comparable between current smokers and nonsmokers when adjusted with serum testosterone level before ADT or during ADT. These results suggest adequate pharmacological effect of ADT, even in current smokers. However, serum testosterone level before ADT was higher in current smokers. Thus, we need to interpret serum testosterone level in current smokers with caution.

Objective: To examine whether higher T and/or antimüllerian hormone (AMH) was associated with anovulation, time to pregnancy (TTP), or pregnancy loss risk among healthy, fecund women without diagnosed polycystic ovary syndrome. Design: Prospective cohort study conducted as a secondary analysis from the Effects of Aspirin in Gestation and Reproduction randomized trial. Setting: University medical centers. Patient(s): A total of 1,198 healthy, eumenorrheic women aged 18-40 years attempting spontaneous pregnancy with one to two prior pregnancy losses were included. Women were categorized by baseline antimüllerian hormone (AMH), as a surrogate marker of antral follicle count, and T concentrations; the highest quartile for each was "high," and below the top quartile (i.e., lower 75% of values) was "norm," forming four groups: norm T/norm AMH (n = 742), norm T/high AMH (n = 156), high T/norm AMH (n = 157), and high T/high AMH (n = 143). Intervention(s): Not applicable. Main outcome measure(s): Anovulation, pregnancy incidence, TTP, and pregnancy loss incidence. Result(s): Women with high T/high AMH had a greater anovulation risk (risk ratio 1.58, 95% confidence interval 1.13-2.22) compared with women with norm T/norm AMH, but with imprecise differences in incidence of pregnancy, TTP, or pregnancy loss. Conclusion(s): Women with higher T and AMH had more frequent anovulatory cycles but with marginal impacts on TTP or pregnancy loss. A continuum of mild inefficiency in reproductive function may be related to higher T and AMH, including in fecund women with normal menstrual cycles and no clinical diagnosis of polycystic ovary syndrome, but with unclear effects on fecundability and pregnancy loss. Clinical trial registration number: NCT00467363.

We analyzed the association between smoking and oncological outcome after radical prostatectomy with neoadjuvant hormonal therapy. This study included men who had undergone radical prostatectomy with neoadjuvant hormonal therapy between 2003 and 2016. We evaluated the association between clinicopathological factors and smoking status as well as the prognostic significance of smoking status in biochemical recurrence. The patients' backgrounds were comparable between smokers and nonsmokers. Smoking status were identified as significant risk factors of biochemical recurrence. Smoking was a risk factor of biochemical recurrence, suggesting that smoking may promote cancer recurrence after surgical treatment combined with hormonal therapy.

This narrative review presents an overview of present knowledge on fertility and reproductive hormones changes in aging men, the factors driving and modulating these changes, their clinical consequences, and benefits and risks of testosterone (T) therapy. Aging is accompanied by moderate decline of gamete quality and fertility. Population mean levels show mild total T decline, SHBG increase, steeper free T decline, and moderate LH increase with important contribution of comorbidities (e.g. obesity) to these changes. Sexual symptoms and lower hematocrit are associated with low T and partly responsive to T therapy. Relationship of serum T with body composition and metabolic health is bidirectional; limited beneficial effects of T therapy on body composition have only marginal effects on metabolic health and physical function. Skeletal changes are associated primarily with estradiol and SHBG. Cognitive decline is not consistently linked to low T and not improved by T therapy. Although limited evidence links moderate androgen decline with depressive symptoms, T therapy has small beneficial effects on mood, depressive symptoms and vitality in elderly with low T. Not optimal T (and/or DHT) has been associated with increased risk of stroke, but not of ischemic heart disease, whereas association with mortality probably reflects that low T is a marker of poor health. Globally, neither severity of clinical consequences attributable to low T, nor nature and magnitude of beneficial treatment effects justify the concept of some broadly applied 'T replacement therapy' in older men with low T. Moreover, long-term safety of T therapy is not established.

  • Haihui Wang
  • Yuehua Li
  • Xinlu Wang
  • Danfei Lou Danfei Lou

Background: Low testosterone levels have been associated with coronary heart disease (CHD) morbidity and mortality in men, but the influence of hormones in postmenopausal women is unclear. This meta-analysis aimed to examine whether there is an association between endogenous sex hormones and CHD risk in postmenopausal women. Methods: A systematic search of the PubMed and EMBASE databases from 1966 to 30 November 2016 was performed for prospective studies that reported an association between endogenous sex hormones and CHD in postmenopausal women. Summary relative risks (RRs) and 95% confidence intervals (CIs) were combined by using a random-effects model. Results: A total of 13 publications (12 studies, including six prospective cohort and six nested case-control studies) were included. The summary RRs for CHD were 1.01 (95% CI 0.77-1.31) comparing the highest versus lowest tertile of total testosterone, with evidence of high heterogeneity (I2=80.7%). In subgroup and meta-regression analyses, none of the variables were identified as contributing to significant heterogeneity. Based on a comparison of the highest versus lowest tertile models, the summary RRs (95% CIs) for CHD were 0.88 (0.63-1.23, I2=48.7%) for free testosterone, 1.16 (0.82-1.63, I2=47.8%) for estradiol, 0.98 (0.90-1.07, I2=3.2%) for sex hormone-binding globulin and 1.19 (0.89-1.58, I2=0) for dehydroepiandrosterone. Conclusion: There is limited evidence to suggest that endogenous levels of sex hormones are not significantly associated with CHD risk in postmenopausal women.

  • Yi X. Chan
  • Helman S Alfonso Helman S Alfonso
  • S A Paul Chubb
  • Bu B Yeap

Advancing age is associated with increased cancer incidence, but the role of sex hormones as risk predictors for common cancers in older men remains uncertain. This study was performed to assess associations of testosterone (T), dihydrotestosterone (DHT) and estradiol (E2), with incident prostate, lung and colorectal cancer in community-dwelling older men. Plasma T, DHT and E2 were assayed using liquid chromatography-mass spectrometry between 2001 and 2004 in 3690 men. Cancer outcomes until 20 June 2013 were ascertained using data linkage. Analyses were performed using proportional hazards competing-risks models, and adjustments were made for potential confounding factors including smoking status. Results are expressed as subhazard ratios (SHR). There were 348, 107 and 137 cases of prostate, lung and colorectal cancers respectively during a median of 9.1-year follow-up. Mean T was comparable in current and non-smokers, whilst mean DHT was lower in ex- and current smokers compared to non-smokers. After adjusting for confounders including smoking, higher T or DHT was associated with an increased incidence of lung cancer (SHR = 1.30, 95% CI 1.06–1.60; p = 0.012 per 1 SD increase in T and SHR = 1.29, 95% CI 1.08–1.54; p = 0.004 for DHT). Sex hormones were not associated with prostate or colorectal cancer. In older men, higher T or DHT predict increased incidence of lung cancer over the next decade. Sex hormones are not associated with incident prostate or colorectal cancer. Further studies are warranted to determine if similar associations of sex hormones with lung cancer are present in other populations and to investigate potential underlying mechanisms.

The use of electronic cigarettes increases as a supposedly healthier form of nicotine consumption, but safety of vaping remains uncertain. In this study, we assessed whether the use of electronic cigarettes increases the risk of infertility in male rats. Malformations of sperm morphology were more frequent in nicotine-exposed groups than in the control group. Vacuolization of seminiferous epithelium, reduction of spermatogenesis, increased apoptosis of spermatogonia and spermatocytes, and acceleration of degeneration of testes were observed. The male reproductive organs are slightly less affected by vaping than by smoking. Nevertheless, in consequence both may lead to the reduction of fertility.

Mortality among current smokers is 2 to 3 times as high as that among persons who never smoked. Most of this excess mortality is believed to be explained by 21 common diseases that have been formally established as caused by cigarette smoking and are included in official estimates of smoking-attributable mortality in the United States. However, if smoking causes additional diseases, these official estimates may significantly underestimate the number of deaths attributable to smoking. We pooled data from five contemporary U.S. cohort studies including 421,378 men and 532,651 women 55 years of age or older. Participants were followed from 2000 through 2011, and relative risks and 95% confidence intervals were estimated with the use of Cox proportional-hazards models adjusted for age, race, educational level, daily alcohol consumption, and cohort. During the follow-up period, there were 181,377 deaths, including 16,475 among current smokers. Overall, approximately 17% of the excess mortality among current smokers was due to associations with causes that are not currently established as attributable to smoking. These included associations between current smoking and deaths from renal failure (relative risk, 2.0; 95% confidence interval [CI], 1.7 to 2.3), intestinal ischemia (relative risk, 6.0; 95% CI, 4.5 to 8.1), hypertensive heart disease (relative risk, 2.4; 95% CI, 1.9 to 3.0), infections (relative risk, 2.3; 95% CI, 2.0 to 2.7), various respiratory diseases (relative risk, 2.0; 95% CI, 1.6 to 2.4), breast cancer (relative risk, 1.3; 95% CI, 1.2 to 1.5), and prostate cancer (relative risk, 1.4; 95% CI, 1.2 to 1.7). Among former smokers, the relative risk for each of these outcomes declined as the number of years since quitting increased. A substantial portion of the excess mortality among current smokers between 2000 and 2011 was due to associations with diseases that have not been formally established as caused by smoking. These associations should be investigated further and, when appropriate, taken into account when the mortality burden of smoking is investigated. (Funded by the American Cancer Society.).

  • Amy L Fairchild Amy L Fairchild
  • Ronald Bayer

In advance of a critical Framework Convention on Tobacco Control (FCTC) held in October 2014, two groups of scientists and public health experts launched a global battle royal over electronic cigarettes—devices that heat liquid nicotine but involve no tobacco.

A significant proportion of patients with type 2 diabetes mellitus have a low testosterone level relative to reference ranges based on healthy young men. Only a small number of these patients suffer from classical hypogonadism as a result of recognizable hypothalamic–pituitary–gonadal axis pathology. The cut-off value of the serum testosterone level in men without obvious hypothalamic–pituitary–gonadal axis pathology is controversial. It is unclear to what extent a low serum testosterone level causally leads to type 2 diabetes and/or the metabolic syndrome. From a theoretical standpoint, there can be complex interactions among the hypothalamic–pituitary–gonadal axis, body composition and insulin resistance, which can be further influenced by intrinsic and extrinsic factors to give rise to metabolic syndrome, glucose intolerance, and low-grade inflammation to increase the risk of cardiovascular disease. Although a low serum testosterone level frequently coexists with cardiometabolic risk factors and might serve as a biomarker, more studies are required to clarify the causal, mediating or modifying roles of low serum testosterone level in the development of adverse clinical outcomes. Currently, there are insufficient randomized clinical trial data to evaluate the effects of testosterone replacement therapy on meaningful clinical outcomes. The risk-to-benefit ratio of testosterone therapy in high-risk subjects, such as those with type 2 diabetes, also requires elucidation. The present article aims to review the current evidence on low serum testosterone levels in patients with type 2 diabetes, and its implications on cardiovascular risk factors, metabolic syndrome and adverse clinical outcomes.

STUDY QUESTION Do women with polycystic ovary syndrome (PCOS) seeking fertility treatment report smoking accurately and does participation in infertility treatment alter smoking? SUMMARY ANSWER Self-report of smoking in infertile women with PCOS is accurate (based on serum cotinine levels) and smoking is unlikely to change over time with infertility treatment. WHAT IS KNOWN ALREADY Women with PCOS have high rates of smoking and it is associated with worse insulin resistance and metabolic dysfunction. STUDY DESIGN, SIZE, DURATION Secondary study of smoking history from a large randomized controlled trial of infertility treatments in women with PCOS (N = 626) including a nested case–control study (N = 148) of serum cotinine levels within this cohort to validate self-report of smoking. PARTICIPANTS/MATERIALS, SETTING, METHODS Women with PCOS, age 18–40, seeking fertility who participated in a multi-center clinical trial testing first-line ovulation induction agents conducted at academic health centers in the USA. MAIN RESULT(S) AND THE ROLE OF CHANCE Overall, self-report of smoking in the nested case–control study agreed well with smoking status as determined by measure of serum cotinine levels, at 90% or better for each of the groups at baseline (98% of never smokers had cotinine levels

Previous studies have suggested that testosterone levels are linked to a variety of diseases, such as cardiovascular disease, type-2 diabetes, the metabolic syndrome, erectile dysfunction, depression, stroke and osteoporosis. Since cigarette smoking is a major health problem and highly prevalent among men, several groups have studied the effects of cigarette smoking on testosterone levels in men. However, the results have been conflicting. Our objectives were to examine the association of cigarette smoking and serum levels of sex hormone-binding globulin (SHBG), total testosterone (TT) and free testosterone (FT) in a large male population. Data from 2,021 men (989 nonsmokers and 1,032 smokers), aged 20-69, were collected from the Fangchenggang Area Male Health and Examination survey using an in-person interview and self-administered questionnaires from September to December, 2009. We have found the following: (a) smokers had significantly higher TT and FT levels compared to nonsmokers, even after stratification as per age, BMI, triglycerides and alcohol consumption. (b) Both TT (r = -0.083, P <0.001) and FT (r = -0.271, P <0.001) levels were negatively correlated to the amount of tobacco exposure. (c) Smoking was an independent influencing factor for the levels of both TT (unadjusted OR = 1.64, 95% CI: 1.33-2.01, P <0.001; adjusted OR = 1.69, 95% CI: 1.34-2.13, P <0.001) and FT (unadjusted OR = 1.32, 95% CI: 1.08-1.61, P = 0.007; adjusted OR = 1.27, 95% CI: 1-1.61, P = 0.050) levels in multivariate logistic regression models before and after adjusting for age, BMI, fasting blood glucose, triglycerides, alcohol consumption and estradiol. (d) Smoking was not found to be an independent predictor of SHBG level after adjustment for confounders in multivariate regression model (P >0.05), although a positive association between increasing pack-years and SHBG level was observed (r = 0.174, P <0.001). More research is needed to elucidate the biological mechanisms and clinical significance of these associations.

Background Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease. Methods A systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using "("testosterone" or "androgen") and trial and ("random*")" with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting. Results Of 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180 cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60). Conclusions The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy.

Drugs are two-sided swords and statins are no exception. Schooling et al. demonstrate that, on average, statins produce small, but statistically significant, decreases in testosterone. They appropriately emphasize that the clinical significance of their observations is unclear but suggest that changes in testosterone might be related to the benefits of therapy as well as the risks, such as the increased chance of diabetes mellitus. Their findings and hypotheses are noteworthy. However, we believe this represents another example of the limitations in the published summaries of drug effects. How do we know all changes induced by drugs are normally distributed? Some may be affected much more than others. Moreover, the confidence intervals of a meta-analysis describe the variance of the mean effect, not the range of effects, and while the mean change characterizes the impact of a drug on a group of patients, the range more fully characterizes its effects on individuals. We treat individuals not groups. Averages do not disclose enough about the risks and benefits of drugs. See related research article here http://www.biomedcentral.com/1741-7015/11/57

Background: Reliable and timely information on the leading causes of death in populations, and how these are changing, is a crucial input into health policy debates. In the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010), we aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex. Methods: We attempted to identify all available data on causes of death for 187 countries from 1980 to 2010 from vital registration, verbal autopsy, mortality surveillance, censuses, surveys, hospitals, police records, and mortuaries. We assessed data quality for completeness, diagnostic accuracy, missing data, stochastic variations, and probable causes of death. We applied six different modelling strategies to estimate cause-specific mortality trends depending on the strength of the data. For 133 causes and three special aggregates we used the Cause of Death Ensemble model (CODEm) approach, which uses four families of statistical models testing a large set of different models using different permutations of covariates. Model ensembles were developed from these component models. We assessed model performance with rigorous out-of-sample testing of prediction error and the validity of 95% UIs. For 13 causes with low observed numbers of deaths, we developed negative binomial models with plausible covariates. For 27 causes for which death is rare, we modelled the higher level cause in the cause hierarchy of the GBD 2010 and then allocated deaths across component causes proportionately, estimated from all available data in the database. For selected causes (African trypanosomiasis, congenital syphilis, whooping cough, measles, typhoid and parathyroid, leishmaniasis, acute hepatitis E, and HIV/AIDS), we used natural history models based on information on incidence, prevalence, and case-fatality. We separately estimated cause fractions by aetiology for diarrhoea, lower respiratory infections, and meningitis, as well as disaggregations by subcause for chronic kidney disease, maternal disorders, cirrhosis, and liver cancer. For deaths due to collective violence and natural disasters, we used mortality shock regressions. For every cause, we estimated 95% UIs that captured both parameter estimation uncertainty and uncertainty due to model specification where CODEm was used. We constrained cause-specific fractions within every age-sex group to sum to total mortality based on draws from the uncertainty distributions. Findings: In 2010, there were 52·8 million deaths globally. At the most aggregate level, communicable, maternal, neonatal, and nutritional causes were 24·9% of deaths worldwide in 2010, down from 15·9 million (34·1%) of 46·5 million in 1990. This decrease was largely due to decreases in mortality from diarrhoeal disease (from 2·5 to 1·4 million), lower respiratory infections (from 3·4 to 2·8 million), neonatal disorders (from 3·1 to 2·2 million), measles (from 0·63 to 0·13 million), and tetanus (from 0·27 to 0·06 million). Deaths from HIV/AIDS increased from 0·30 million in 1990 to 1·5 million in 2010, reaching a peak of 1·7 million in 2006. Malaria mortality also rose by an estimated 19·9% since 1990 to 1·17 million deaths in 2010. Tuberculosis killed 1·2 million people in 2010. Deaths from non-communicable diseases rose by just under 8 million between 1990 and 2010, accounting for two of every three deaths (34·5 million) worldwide by 2010. 8 million people died from cancer in 2010, 38% more than two decades ago; of these, 1·5 million (19%) were from trachea, bronchus, and lung cancer. Ischaemic heart disease and stroke collectively killed 12·9 million people in 2010, or one in four deaths worldwide, compared with one in five in 1990; 1·3 million deaths were due to diabetes, twice as many as in 1990. The fraction of global deaths due to injuries (5·1 million deaths) was marginally higher in 2010 (9·6%) compared with two decades earlier (8·8%). This was driven by a 46% rise in deaths worldwide due to road traffic accidents (1·3 million in 2010) and a rise in deaths from falls. Ischaemic heart disease, stroke, chronic obstructive pulmonary disease (COPD), lower respiratory infections, lung cancer, and HIV/AIDS were the leading causes of death in 2010. Ischaemic heart disease, lower respiratory infections, stroke, diarrhoeal disease, malaria, and HIV/AIDS were the leading causes of years of life lost due to premature mortality (YLLs) in 2010, similar to what was estimated for 1990, except for HIV/AIDS and preterm birth complications. YLLs from lower respiratory infections and diarrhoea decreased by 45-54% since 1990; ischaemic heart disease and stroke YLLs increased by 17-28%. Regional variations in leading causes of death were substantial. Communicable, maternal, neonatal, and nutritional causes still accounted for 76% of premature mortality in sub-Saharan Africa in 2010. Age standardised death rates from some key disorders rose (HIV/AIDS, Alzheimer's disease, diabetes mellitus, and chronic kidney disease in particular), but for most diseases, death rates fell in the past two decades; including major vascular diseases, COPD, most forms of cancer, liver cirrhosis, and maternal disorders. For other conditions, notably malaria, prostate cancer, and injuries, little change was noted. Conclusions: Population growth, increased average age of the world's population, and largely decreasing age-specific, sex-specific, and cause-specific death rates combine to drive a broad shift from communicable, maternal, neonatal, and nutritional causes towards non-communicable diseases. Nevertheless, communicable, maternal, neonatal, and nutritional causes remain the dominant causes of YLLs in sub-Saharan Africa. Overlaid on this general pattern of the epidemiological transition, marked regional variation exists in many causes, such as interpersonal violence, suicide, liver cancer, diabetes, cirrhosis, Chagas disease, African trypanosomiasis, melanoma, and others. Regional heterogeneity highlights the importance of sound epidemiological assessments of the causes of death on a regular basis. Funding: Bill & Melinda Gates Foundation.

Low testosterone, with or without symptoms, reported in diabetic men in some studies. We investigated the prevalence of hypogonadism in Iranian type 2 diabetic men. Total testosterone (TT) and sex hormone binding globulin (SHBG) concentrations were measured in 247 diabetic men >30 years who had symptoms of androgen deficiency, according to ADAMs questionnaire. The correlation between some parameters and total, free and bioavailable testosterone levels was determined using Pearson correlation coefficient. Free and bioavailable testosterone were calculated by electronic calculator. Four patients were excluded because of high testosterone level, due to unreported androgen use. Overt hypogonadism was defined as total testosterone ≤8 nmol/l or calculated bioavailable testosterone (cBT)≤2.5 nmol/l and borderline hypogonadism was considered as TT 8-12 nmol/l or cBT 2.5-4nmol/l. The mean and SD of age was 59 (9.3) years. The mean TT, calculated free testosterone (cFT), and cBT and SHBG levels were 4.81 (1.7) nmol/l, 0.11 (0.06) nmol/l, 2.42 (1.17) nmol/l and 36.15 (18.3) nmol/l, respectively. According to TT and cBT, overt hypogonadism observed in 7.4% and 61.6% of men, respectively, and the prevalence of borderline hypogonadism was 9.9% and 36%, respectively. cFT ≤0.16 nmol/l found in 227 diabetic men (96%). Hypogonadism (TT ≤12 nmol/l) was not correlated with obesity, smoking, age,duration of diabetes, blood pressure, and HbA1c. Hypogonadism is highly prevalent in type 2 diabetes men.

Objective: To evaluate the association between lifestyle and dietary factors and serum concentrations of androgens in middle-aged healthy men. Methods: We conducted a cross-sectional analysis of the association of lifestyle factors with circulating concentrations of androstenedione (A-dione), 3-alpha-androstanediol glucuronide (A-diol-g), testosterone (T), SHBG (sex hormone-binding globulin), and free testosterone (FT) among 636 men in the European Prospective Investigation into Cancer and Nutrition. Results: Compared with the youngest age group (40-49 years), the oldest (70-79 years) had a higher mean concentration of SHBG (by 44%) and lower mean concentrations of A-diol-g (by 29%) FT (19%). Men in the highest BMI group (> or =29.83 kg/m(2)) had a higher mean A-diol-g concentration (by 38%) and lower mean concentration of T (by 20%) SHBG (29%) compared with the lowest (<24.16 kg/m(2)). Current smokers had higher mean concentrations of T (by 13%), SHBG (14%), and A-dione (15%) compared with never smokers. Physical activity and dietary factors were not associated with androgen concentrations, although men in the highest fifth of alcohol intake had higher mean concentrations of A-dione (by 9%), FT (11%) compared with the lowest. Conclusion: Our results suggest that age, body weight, smoking, and alcohol intake are associated with circulating androgen concentrations in men.

  • T J Key
  • Paul N Appleby
  • Gillian Reeves
  • Howard Strickler Howard Strickler

Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Despite worldwide anti-smoking campaigns, cigarette smoking prevalence is increasing in the third-world countries. It is now regarded as the most important public health issue. Here, we study the current smoking situation and investigate the impact of cigarette smoking on semen quality and hormonal levels among adult people. Furthermore, we suggest various strategies to reduce smoking consumption among young individuals. Across-sectional data from 804 adult smoker subjects (male n = 530 and female n = 274) aged between 15 and 45 years were analyzed. One hundred and eleven males were agreed for further evaluation of their semen quality and hormones compared with 93 age-matched non-smoking males. This study showed that the majorfactors initiating smoking among women were friends' influence (49%), life pressures (16%) and parental imitation (14%). The major reasons in men was friends' influence (65%). Furthermore, 61% ofwomen and 89% of men smoke in public implying social acceptance oreven encouragement of this habit. This study also found that low-income Jordanians consume more tobacco materials than those in the middle- and higher income. Furthermore, smokers had significantly lower (p < 0.001) sperm concentration and motility values and higher (p < 0.001) serum testosterone and luteinizing hormone (LH) levels than non-smokers.

Glucuronidation is an important pathway in the metabolism of nicotine, with previous studies suggesting that ∼22% of urinary nicotine metabolites are in the form of glucuronidated compounds. Recent in vitro studies have suggested that the UDP-glucuronosyltransferases (UGT) 2B10 and 2B17 play major roles in nicotine glucuronidation with polymorphisms in both enzymes shown to significantly alter the levels of nicotine-glucuronide, cotinine-glucuronide, and trans-3'-hydroxycotinine (3HC)-glucuronide in human liver microsomes in vitro. In the present study, the relationship between the levels of urinary nicotine metabolites and functional polymorphisms in UGTs 2B10 and 2B17 was analyzed in urine specimens from 104 Caucasian smokers. Based on their percentage of total urinary nicotine metabolites, the levels of nicotine-glucuronide and cotinine-glucuronide were 42% (P < 0.0005) and 48% (P < 0.0001), respectively, lower in the urine from smokers exhibiting the UGT2B10 (*1/*2) genotype and 95% (P < 0.05) and 98% (P < 0.05), respectively, lower in the urine from smokers with the UGT2B10 (*2/*2) genotype compared with the urinary levels in smokers having the wild-type UGT2B10 (*1/*1) genotype. The level of 3HC-glucuronide was 42% (P < 0.001) lower in the urine from smokers exhibiting the homozygous UGT2B17 (*2/*2) deletion genotype compared with the levels in urine from wild-type UGT2B17 subjects. These data suggest that UGTs 2B10 and 2B17 play important roles in the glucuronidation of nicotine, cotinine, and 3HC and suggest that the UGT2B10 codon 67 SNP and the UGT2B17 gene deletion significantly reduce overall glucuronidation rates of nicotine and its major metabolites in smokers.

UDP-glucuronosyltransferases (UGTs) are enzymes involved in the metabolism of steroid hormones, carcinogens, cancer chemotherapy agents, and addictive agents from cigarettes. Because the UGT2B family of genes has been linked to hormonal regulation in human cell lines in vitro, we hypothesized that there may be sex-related differences in the expression and activity of these genes in human tissues. To evaluate whether there are sex differences in UGT2B expression and activity, we examined 103 normal human liver specimens for UGT2B expression by real-time polymerase chain reaction and in vitro glucuronidation activities in human liver microsomes (HLM). Men exhibited an approximately 4-fold higher level of expression of UGT2B17 than women (p = 0.007). Consistent with the increased expression of UGT2B17 in men, HLM from men also had a higher level of glucuronidation activity than HLM from women against three UGT2B17 substrates: 3-fold higher for 17-dihydroexemestane (p = 0.002); 3-fold higher for 3-hydroxycotinine (p < 0.001); and 1.5-fold higher for suberoylanilide hydroxamic acid (p = 0.014). When we stratified by UGT2B17 gene deletion genotype, similar patterns were observed for all three substrates, with HLM from men with the UGT2B17 (+/+) or (+/0) genotypes exhibiting significantly higher levels of glucuronidation activity against all three substrates compared with HLM from women. These data suggest that men have a higher amount of UGT2B17 glucuronidation activity then women. This sex difference in UGT2B17 gene expression and corresponding protein activity could potentially result in different levels of carcinogen detoxification or drug elimination in men versus women.

The risks of testosterone therapy in men remain poorly understood. The aim of this study was to conduct a systematic review and meta-analyses of testosterone trials to evaluate the adverse effects of testosterone treatment in men. We searched MEDLINE, EMBASE, and Cochrane CENTRAL from 2003 through August 2008. Review of reference lists and contact with experts further identified candidate studies. Eligible studies were comparative, randomized, and nonrandomized and reported the effects of testosterone on outcomes of interest (death, cardiovascular events and risk factors, prostate outcomes, and erythrocytosis). Reviewers, working independently and in duplicate, determined study eligibility. Reviewers working independently and in duplicate determined the methodological quality of studies and collected descriptive, quality, and outcome data. The methodological quality of the 51 included studies varied from low to medium, and follow-up duration ranged from 3 months to 3 yr. Testosterone treatment was associated with a significant increase in hemoglobin [weighted mean difference (WMD), 0.80 g/dl; 95% confidence interval (CI), 0.45 to 1.14] and hematocrit (WMD, 3.18%; 95% CI, 1.35 to 5.01), and a decrease in high-density lipoprotein cholesterol (WMD, -0.49 mg/dl; 95% CI, -0.85 to -0.13). There was no significant effect on mortality, prostate, or cardiovascular outcomes. The adverse effects of testosterone therapy include an increase in hemoglobin and hematocrit and a small decrease in high-density lipoprotein cholesterol. These findings are of unknown clinical significance. Current evidence about the safety of testosterone treatment in men in terms of patient-important outcomes is of low quality and is hampered by the brief study follow-up.

Interest is rising in smokeless tobacco as a safer alternative to smoking, but published reviews on smokeless tobacco and cancer are limited. We review North American and European studies and compare effects of smokeless tobacco and smoking. We obtained papers from MEDLINE searches, published reviews and secondary references describing epidemiological cohort and case-control studies relating any form of cancer to smokeless tobacco use. For each study, details were abstracted on design, smokeless tobacco exposure, cancers studied, analysis methods and adjustment for smoking and other factors. For each cancer, relative risks or odds ratios with 95% confidence intervals were tabulated. Overall, and also for USA and Scandinavia separately, meta-analyses were conducted using all available estimates, smoking-adjusted estimates, or estimates for never smokers. For seven cancers, smoking-attributable deaths in US men in 2005 were compared with deaths attributable to introducing smokeless tobacco into a population of never-smoking men. Eighty-nine studies were identified; 62 US and 18 Scandinavian. Forty-six (52%) controlled for smoking. Random-effects meta-analysis estimates for most sites showed little association. Smoking-adjusted estimates were only significant for oropharyngeal cancer (1.36, CI 1.04-1.77, n = 19) and prostate cancer (1.29, 1.07-1.55, n = 4). The oropharyngeal association disappeared for estimates published since 1990 (1.00, 0.83-1.20, n = 14), for Scandinavia (0.97, 0.68-1.37, n = 7), and for alcohol-adjusted estimates (1.07, 0.84-1.37, n = 10). Any effect of current US products or Scandinavian snuff seems very limited. The prostate cancer data are inadequate for a clear conclusion.Some meta-analyses suggest a possible effect for oesophagus, pancreas, larynx and kidney cancer, but other cancers show no effect of smokeless tobacco. Any possible effects are not evident in Scandinavia. Of 142,205 smoking-related male US cancer deaths in 2005, 104,737 are smoking-attributable. Smokeless tobacco-attributable deaths would be 1,102 (1.1%) if as many used smokeless tobacco as had smoked, and 2,081 (2.0%) if everyone used smokeless tobacco. An increased risk of oropharyngeal cancer is evident most clearly for past smokeless tobacco use in the USA, but not for Scandinavian snuff. Effects of smokeless tobacco use on other cancers are not clearly demonstrated. Risk from modern products is much less than for smoking.

We evaluated the associations of smoking, alcohol consumption, and physical activity with sex steroid hormone concentrations among 1,275 men > or =20 years old who participated in the Third National Health and Nutrition Examination Survey (NHANES III). Serum concentrations of testosterone, estradiol, and sex hormone-binding globulin (SHBG) were measured. We compared geometric mean concentrations across levels of smoking, alcohol, and physical activity using multiple linear regression. Current smokers had higher total testosterone (5.42, 5.10, and 5.26 ng/ml in current, former, and never smokers), free testosterone (0.110, 0.102, and 0.104 ng/ml), total estradiol (40.0, 34.5, and 33.5 pg/ml), and free estradiol (1.05, 0.88, and 0.84 pg/ml) compared with former and never smokers (all p < or = 0.05). Men who consumed > or =1 drink/day had lower SHBG than men who drank less frequently (31.5 vs. 34.8 nmol/l, p = 0.01); total (p-trend = 0.08) and free testosterone (p-trend = 0.06) increased with number of drinks per day. Physical activity was positively associated with total (p-trend = 0.01) and free testosterone (p-trend = 0.05). In this nationally representative sample of men, smoking, alcohol, and physical activity were associated with hormones and SHBG, thus these factors should be considered as possible confounders or upstream variables in studies of hormones and men's health, including prostate cancer.

  • Julian P T Higgins
  • Ian R White
  • Judith Anzures Judith Anzures

When literature-based meta-analyses involve outcomes with skewed distributions, the best available data can sometimes be a mixture of results presented on the raw scale and results presented on the logarithmic scale. We review and develop methods for transforming between these results for two-group studies, such as clinical trials and prospective or cross-sectional epidemiological studies. These allow meta-analyses to be conducted using all studies and on a common scale. The methods can also be used to produce a meta-analysis of ratios of geometric means when skewed data are reported on the raw scale for every study. We compare three methods, two of which have alternative standard error formulae, in an application and in a series of simulation studies. We conclude that an approach based on a log-normal assumption for the raw data is reasonably robust to different true distributions; and we provide new standard error approximations for this method. An assumption can be made that the standard deviations in the two groups are equal. This increases precision of the estimates, but if incorrect can lead to very misleading results.

  • Catherine Mary Schooling Catherine Mary Schooling

Jahangir et al1 provided a fascinating analysis showing, among older people, a higher risk of abdominal aortic aneurysm (AAA) in those with normal body mass index (BMI), those who smoke and in men. Although AAA is relatively rare, ruptured AAA has a high mortality rate, so prevention, based on reversible risk factors, is important. The observed association of normal BMI with AAA may be an artefact of weight loss due to ill-health in older people. Men often have higher rates than women of cardiovascular disease, for reasons … [Full text of this article]

  • Catherine A. Wassenaar
  • David V. Conti
  • Soma Das
  • Rachel F Tyndale Rachel F Tyndale

Background: Identifying sources of variation in the nicotine and nitrosamine metabolic inactivation pathways is important to understanding the relationship between smoking and cancer risk. Numerous UGT1A and UGT2B enzymes are implicated in nicotine and nitrosamine metabolism in vitro; however, little is known about their roles in vivo. Methods: Within UGT1A1, UGT1A4, UGT1A9, UGT2B7, UGT2B10, and UGT2B17, 47 variants were genotyped, including UGT2B10*2 and UGT2B17*2. The association between variation in these UGTs and glucuronidation activity within European and African American current smokers (n=128), quantified as urinary ratios of the glucuronide over unconjugated compound for nicotine, cotinine, trans-3'-hydroxycotinine, and NNAL, was investigated in regression models assuming a dominant effect of variant alleles. Results: Correcting for multiple testing, three UGT2B10 variants were associated with cotinine glucuronidation, rs2331559 and rs11726322 in European Americans and rs835309 in African Americans (P≤.0002). Additional variants predominantly in UGT2B10 were nominally associated with nicotine (P=.008-.04) and cotinine (P=<.001-.02) glucuronidation in both ethnicities in addition to UGT2B10*2 in European Americans (P=.01, P<.001). UGT2B17*2 (P=.03) in European Americans and UGT2B7 variants (P=.02-.04) in African Americans were nominally associated with 3HC glucuronidation. UGT1A (P=.007-.01), UGT2B10 (P=.02) and UGT2B7 (P=.02-03) variants in African Americans were nominally associated with NNAL glucuronidation. Conclusions: Findings from this initial in vivo study support a role for multiple UGTs in the glucuronidation of tobacco-related compounds in vivo, in particular UGT2B10 and cotinine glucuronidation. Impact: Findings also provide insight into ethnic differences in glucuronidation activity, which could be contributing to ethnic disparities in the risk for smoking-related cancers.

  • Wasim Maziak Wasim Maziak

The recent popularity of electronic (e)-cigarettes and their rapid uptake by youth has ignited the debate about their role as a harm-reduction strategy. Harm reduction in the context of tobacco control contends that in societies that have achieved considerable success in curbing smoking, leaving the remaining hard-to-quit smokers with an abstinence-only option is unfair, especially when less-harmful choices are available. On one side of the debate are those who call for caution in endorsing such products until critical pieces of evidence about their safety and potential become available, whereas the other side argues that waiting until all questions about e-cigarettes are answered is dogma driven. In this piece, I try to discuss the unresolvable contention between harm-reduction goals of offering safer options to smokers, and those of e-cigarette makers of being commercially viable and profitable.

Factors suspected of causing certain chronic diseases and death are often associated with lower mortality among those with disease. For end-stage renal disease, examples include high cholesterol and homocysteine. Here, we consider obesity, thought to cause both end-stage renal disease and premature mortality, but which is associated with lower mortality among end-stage renal disease patients. Such seeming paradoxes could reflect collider (index event) bias due to selection of a diseased population for study. However, previous descriptions are incomplete, as they posit an uncontrolled factor causing both end-stage renal disease (the index event) and death. Here, we explicitly note that death can precede end-stage renal disease onset. The target population is obese persons with end-stage renal disease, effects of interest are seemingly controlled direct effects, the usual estimator is a conditional risk ratio, and remaining at risk until the onset of end-stage renal disease is a collider. Collider bias is then expected if any mortality risk factor is uncontrolled, even if no factor also affects end-stage renal disease. The bias is similar to, but differs from, that associated with competing risks. Because control of every mortality risk factor is implausible, bias of the standard estimator is practically unavoidable. Better awareness of these issues by clinicians and researchers is needed if observational research is to usefully guide care of this vulnerable patient population.

Electronic cigarettes (e-cigarettes) are products that deliver a nicotine-containing aerosol (commonly called vapor) to users by heating a solution typically made up of propylene glycol or glycerol (glycerin), nicotine, and flavoring agents (Figure 1) invented in their current form by Chinese pharmacist Hon Lik in the early 2000s.1 The US patent application describes the e-cigarette device as "an electronic atomization cigarette that functions as substitutes [sic] for quitting smoking and cigarette substitutes" (patent No. 8,490,628 B2). By 2013, the major multinational tobacco companies had entered the e-cigarette market. E-cigarettes are marketed via television, the Internet, and print advertisements (that often feature celebrities)2 as healthier alternatives to tobacco smoking, as useful for quitting smoking and reducing cigarette consumption, and as a way to circumvent smoke-free laws by enabling users to "smoke anywhere."3

Stopping smoking is associated with many important improvements in health and quality of life. Use of cessation medications is recommended to increase the likelihood of quitting. However, there is historical and renewed concern that smoking cessation therapies may increase the risk of cardiovascular disease (CVD) events associated within the quitting period. We aimed to examine whether the three licensed smoking cessation therapies: nicotine replacement therapy (NRT); bupropion, and; varenicline and were associated with an increased risk of CVD events using a network meta-analysis. We searched ten electronic databases, and made communication with authors of published randomized clinical trials (RCT), and accessed internal US Food and Drug Administration (FDA) reports. We included any RCT of the 3 treatments that reported on CVD outcomes. Among 63 eligible RCTs involving 21 NRT RCTs, 28 bupropion RCTs and 18 varenicline RCTs, we found no increase in the risk of all-CVD events with bupropion (RR 0.98, 95% Confidence Intervals [CIs], 0.54-1.73) or varenicline (RR 1.30, 95% CI, 0.79-2.23). There was an elevated risk associated with NRT that was predominantly driven by less serious events (2.29, 95% CI, 1.39-3.82). When we examined major adverse cardiovascular events (MACE) events, we found a protective effect with bupropion (RR 0.45, 95% CI, 0.21-0.85) and no clear evidence of harm with varenicline (RR 1.34, 95% CI, 0.66-2.66) or NRT (RR 1.95, 95% CI, 0.26-4.30). Smoking cessation therapies do not appear to raise the risk of serious CVD events.

Observationally lower testosterone is associated with an unhealthier cardiovascular (CVD) risk profile, but this association is open to confounding and reverse causality. The authors examined the association of testosterone with well-established cardiovascular disease (CVD) risk factors (blood pressure, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL)cholesterol and fasting glucose) and the Framingham score using a Mendelian randomization analysis with a separate-sample instrumental variable estimator. To minimize reverse causality, a genetic score predicting testosterone was developed in 289 young Chinese men from Hong Kong, based on three selected testosterone-related single nucleotide polymorphisms (rs10046, rs1008805 and rs1256031). Multivariable censored and linear regressions were used to examine the association of genetically predicted testosterone levels with CVD risk factors and Framingham score among 4212 older Chinese men from the Guangzhou Biobank Cohort Study. Predicted testosterone was unrelated to systolic blood pressure [-0.11 mmHg, 95% confidence interval (CI) -0.70 to 0.48], diastolic blood pressure (0.04 mmHg, 95% CI -0.27 to 0.36), fasting glucose (0.02 mmol/l, 95% CI -0.02 to 0.06) or Framingham score (0.02, 95% CI -0.0001 to 0.03) but associated with higher LDL-cholesterol (0.02 mmol/l, 95% CI 0.01 to 0.04) and lower HDL-cholesterol (-0.01 mmol/l, 95% CI -0.02 to -0.001), after adjustment for potential confounders (age, education, smoking status, use of alcohol and body mass index). Our findings did not corroborate observed protective effects of testosterone on cardiovascular risk factors or risk of ischaemic heart disease among men, but raises the possibility that higher testosterone may be associated with an unhealthier lipid profile.

  • Catherine Mary Schooling Catherine Mary Schooling

Observationally, low serum testosterone among men is associated with cardiovascular diseases and its risk factors, but it is unclear whether raising endogenous androgens would be protective. To clarify the role of androgens, the association of two different androgen biomarkers (serum testosterone and androstanediol glucuronide) with cardiovascular disease risk factors and mortality was examined in a nationally representative sample of US men. Multivariable linear and proportion hazards regression were used to examine the adjusted associations of serum testosterone and androstanediol glucuronide with cardiovascular disease risk factors and death from major cardiovascular diseases in 1460 men from NHANES III phase 1 (1988-1991) followed-up through 2006. Serum testosterone and androstanediol glucuronide were weakly correlated (0·13). Serum testosterone was associated with healthier values of most cardiovascular disease risk factors but not with death from ischaemic heart disease or stroke, adjusted for age, education, race/ethnicity, smoking and alcohol use. Similarly adjusted, androstanediol glucuronide was associated with unhealthier values of some cardiovascular risk factors and death from ischaemic heart disease (hazard ratio 1·16, 95% confidence interval 1·003-1·33 per standard deviation). Androgen biomarkers had inconsistent associations with cardiovascular disease risk factors and ischaemic heart disease. Androstanediol glucuronide, rather than serum testosterone, had associations with cardiovascular disease risk factors more similar to those seen in randomized controlled trials of testosterone therapy, with corresponding implications for raising androgens.

  • Catherine Mary Schooling Catherine Mary Schooling

Inflammation contributes to chronic diseases. Lower serum testosterone among men is associated with less inflammation, yet immune defense is thought to trade-off against reproduction with androgens adversely affecting immune function. Anti-androgens are effective at castrate levels of serum testosterone, suggesting serum testosterone may not capture all androgen activity. The association of two androgen biomarkers with key markers of inflammation was examined. The adjusted association of serum testosterone and androstanediol glucuronide with C-reactive protein, white blood cell, granulocyte and lymphocyte count, fibrinogen, and hemoglobin, as a control outcome because testosterone administration raises hemoglobin, were examined in a nationally representative sample of 1,490 US men from the National Health and Nutrition Examination Survey III phase 1 (1988-1991) using multivariable linear regression. Serum testosterone and androstanediol glucuronide were weakly correlated (0.13). Serum testosterone was associated with lower white blood cell count [-0.26 × 10(-9) per standard deviation, 95% confidence interval (CI) -0.37 to -0.14] and granulocyte count (-0.21 × 10(-9) , 95% CI -0.29 to -0.13) but not with hemoglobin (0.02 g/l, 95% CI -0.89 to 0.92), adjusted for age, education, race/ethnicity, smoking, and alcohol. Similarly adjusted, androstanediol glucuronide was not associated with white blood cell count (0.10 × 10(-9) , 95% CI -0.05 to -0.25), granulocyte count (0.12 × 10(-9) , 95% CI -0.02 to 0.25), or fibrinogen (0.05 g/l, 95% CI -0.004 to 0.11), but was with hemoglobin (0.70 g/l, 95% CI 0.07 to 1.32). Different androgen biomarkers had different associations with inflammatory markers, highlighting the need to consider several androgen biomarkers. The possibility remains that androgens may generate inflammatory processes with implications for chronic diseases. Am. J. Hum. Biol., 2013. © 2013 Wiley Periodicals, Inc.

The androgen receptor (AR) is expressed in many cell types and the androgen/AR signaling has been found to have important roles in modulating tumorigenesis and metastasis in several cancers including prostate, bladder, kidney, lung, breast and liver. However, whether AR has differential roles in the individual cells within these tumors that contain a variety of cell types remains unclear. Generation of AR knockout (ARKO) mouse models with deletion of AR in selective cells within tumors indeed have uncovered many unique AR roles in the individual cell types during cancer development and progression. This review will discuss the results obtained from various ARKO mice and different human cell lines with special attention to the cell type- and tissue-specific ARKO models. The understanding of various results showing the AR indeed has distinct and contrasting roles in each cell type within many hormone-related tumors (as stimulator in bladder, kidney and lung metastases vs as suppressor in prostate and liver metastases) may eventually help us to develop better therapeutic approaches by targeting the AR or its downstream signaling in individual cell types to better battle these hormone-related tumors in different stages.Oncogene advance online publication, 22 July 2013; doi:10.1038/onc.2013.274.

ContextThere are few population-based studies reporting longitudinal changes in total testosterone (T), luteinizing hormone (LH), follicle stimulating hormone (FSH), and sex hormone binding globulin (SHBG) levels, and limited information on risk factors for their change.Objective The objective of the study was to examined 5-year changes in serum T, LH, FSH, and SHBG levels among Australian men.DesignA randomly selected, community based cohort of 1,588 men age 35 or older at recruitment (mean age 54±11y), with available data at two visits. Men on medications known to affect, or with established pathology of, the hypothalamo-pituitary gonadal axis were excluded, leaving 1,382 for analysis.ResultsMean baseline and follow-up T levels were 16.2±1.4nmol/L and 15.6±1.4nmol/L; a change of -0.13nmol/L/y. Annualized T changes were associated with being unmarried, obesity, and smoking at baseline, but not diabetes, hypertension, or cardiovascular disease. T declined in men with persistent depression, or who developed chronic disease, and increased in men who were married, as compared to unmarried, at both time points. In the multivariate analysis, smoking cessation, development of central (waist ≥100cm) or generalised (BMI ≥ 30) obesity resulted in T decreases of 0.36, 0.25, and 0.20nmol/L/y respectively. Quitting smoking, developing obesity, and having persisting depression were inversely related to SHBG change.Conclusions An age-related decline in T levels is not inevitable but largely explained by smoking behaviour and intercurrent changes in health status, particularly obesity and depression.

  • Rajat S Barua
  • John A Ambrose John A Ambrose

Acute rupture or erosion of a coronary atheromatous plaque and subsequent coronary artery thrombosis cause the majority of sudden cardiac deaths and myocardial infarctions. Cigarette smoking is a major risk factor for acute coronary thrombosis. Indeed, a majority of sudden cardiac deaths attributable to acute thrombosis are in cigarette smokers. Both active and passive cigarette smoke exposure seem to increase the risk of coronary thrombosis and myocardial infarctions. Cigarette smoke exposure seems to alter the hemostatic process via multiple mechanisms, which include alteration of the function of endothelial cells, platelets, fibrinogen, and coagulation factors. This creates an imbalance of antithrombotic/prothrombotic factors and profibrinolytic/antifibrinolytic factors that support the initiation and propagation of thrombosis.

  • James D Neaton
  • Deborah Wentworth

To assess the combined influence of blood pressure (BP), serum cholesterol level, and cigarette smoking on death from coronary heart disease (CHD) and to describe how these associations vary with age, data on those factors and on mortality for 316 099 men screened for the Multiple Risk Factor Intervention Trial (MRFIT) were examined. Vital sta tus of participants has been determined after an average follow-up of 12 years; 6327 deaths from CHD have been identified. Strong graded relationships between serum cho lesterol levels above 4.65 mmol/L (180 mg/dL), systolic BP above 110 mm Hg, and diastolic BP above 70 mm Hg and mortality due to CHD were evident. Smokers with serum cholesterol and systolic BP levels in the highest quintiles had CHD death rates that were approximately 20 times greater than nonsmoking men with systolic BP and cholesterol lev els in the lowest quintile. Systolic and diastolic BP, serum cholesterol level, and cigarettes per day were significant predictors of death due to CHD in all age groups. Systolic BP was a stronger predictor than diastolic BP. These results, together with the findings of clinical trials, offer strong support for intensified preventive efforts in all age groups. (Arch Intern Med. 1992;152:56-64)

  • Liang Xu
  • Yan Wang
  • Yuanyuan Xu
  • LW Liu LW Liu

MicroRNAs (miRNAs) are endogenous, non-coding, small RNAs that play significant regulatory roles in plant growth, development, and biotic and abiotic stress responses. To date, a great number of conserved and species-specific miRNAs have been identified in many important plant species such as Arabidopsis, rice and poplar. However, little is known about identification of miRNAs and their target genes in radish (Raphanus sativus L.). In the present study, a small RNA library from radish root was constructed and sequenced using the high-throughput Solexa sequencing. Through sequence alignment and secondary structure prediction, a total of 545 conserved miRNA families as well as 15 novel (with their miRNA* strand) and 64 potentially novel miRNAs were identified. Quantitative real-time PCR (qRT-PCR) analysis confirmed that both conserved and novel miRNAs were expressed in radish, and some of them were preferentially expressed in certain tissues. A total of 196 potential target genes were predicted for 42 novel radish miRNAs. Gene ontology (GO) analysis showed that most of the targets were involved in plant growth, development, metabolism and stress responses. This study represents a first large-scale identification and characterization of radish miRNAs and their potential target genes. These results could lead to the further identification of radish miRNAs and enhance our understanding of radish miRNA regulatory mechanisms in diverse biological and metabolic processes.

Prospective studies showed that low serum testosterone concentrations are associated with various cardiometabolic risk factors and mortality. However, the causal nature of these associations is controversial. We studied 1 882 men aged 20-79 years with serum testosterone concentrations and genotyping data from the longitudinal population-based Study of Health in Pomerania. Testosterone concentrations were cross-sectionally associated with cardiometabolic risk factors, including anthropometric, lipid, blood pressure and glycaemic parameters; and prospectively with all-cause mortality (277 deaths, 14.7%) during the 10-year follow-up. To overcome problems of residual confounding, reverse causation, or regression dilution bias in the investigated testosterone-outcome associations, we used two-stage least square regression models with previously identified polymorphisms at the SHBG gene (rs12150660) and X chromosome (rs5934505) as multiple genetic instruments in an instrumental variable (IV) approach, also known as Mendelian randomization. In standard regression analyses, testosterone was robustly associated with a wide range of cardiometabolic risk factors. In subsequent IV analyses, no such significant associations were observed. Similarly, prospective analyses showed a consistent association of low testosterone concentrations with increased all-cause mortality risk, which was not apparent in subsequent IV analyses. The present Mendelian randomization analyses did not detect any evidence for causal associations of testosterone concentrations with cardiometabolic risk factors and mortality, suggesting that previously reported associations might largely result from residual confounding or reverse causation. Although testosterone assessment might improve risk prediction, implementation of testosterone replacement therapy requires further evidence of a direct effect on cardiometabolic outcomes from double-blinded randomized controlled trials and large-scale Mendelian randomization meta-analyses.

Background: The presence of cardiovascular risk factors during the menopausal transition could be critical in the development of atherosclerosis. In the present study, we evaluated whether the menopausal transition has impact on traditional and newly discussed risk factors. Methods: Six hundred ninety nine women from population-based study underwent ultrasound measurement of the intima-media thickness of the common carotid arteries (CIMT) - Prague Pre and Postmenopausal Females study (3PMFs). In addition, 40 women selected according to reproductive and smoking status were examined with regard to number of circulating endothelial progenitor cells, markers of reverse cholesterol transport and sex hormones, including their fluctuation - Hormone Variability study (HVs). Results: Age, smoking, body mass index, systolic blood pressure and HDL cholesterol were independently associated with the CIMT in 3PMFs group. The increase in the CIMT with age was markedly steeper in current/past smokers than in non-smokers among perimenopausal women (p for equality of slopes=0.005). This difference was not observed in premenopausal and menopausal women. In the HVs group, endothelial progenitor cells and reverse cholesterol transport were substantially higher while triglycerides and fluctuation of free testosterone were lower in non-smokers than in smokers in menopausal transition. In contrast, in menopausal women, the fluctuation of free testosterone was higher in non-smokers; no other differences between smokers and non-smokers were detected. Conclusions: These results suggest that atherogenic effect of smoking may be enhanced during menopausal transition. The mechanism could be impaired reparative vascular processes, impaired reverse cholesterol transport and rapidly changing status of sex hormones.

  • Teresa Sicinska-Werner
  • M MedraÅ›

Background. Tobacco addiction undoubtedly plays a major role in coronary atherosclerosis formation in men. An age-related decrease in androgenic hormones is probably also involved. Since the coexistence of diabetes dramatically increases cardiovascular risk and mortality from these causes, it is important to study this issue in men without diabetes in assessing the impact of hormonal changes and tobacco consumption on atherogenesis. Objectives. Assessment of impact of hormonal changes and tobacco consumption on artheriosclerosis in the coronary arteries in non-diabetic men aged 40-60. Material and Methods. One hundred two men, including 62 smokers, aged 40-60 years without diabetes in whom angiography due to cardiac indications was performed were involved in the study. From this group, subgroups of patients, 42 with coronary atherosclerosis and 20 without changes in coronary angiography, were established. A control group of 40 healthy men with a negative medical history and normal physical examination and exercise test included 20 smokers and 20 nonsmokers. The concentrations of total and free testosterone, calculated free and bioavailable testosterone, SHBG, DHEAS, E(2), IGF-1, GH, and the free androgen index (FAI) were studied in the men. Hormonal status and tobacco addiction parameters were compared with atherogenesis development in the coronary arteries. Results. The presence of atherosclerosis in the coronary arteries correlated with increased tobacco consumption, reduced concentration of free testosterone (assessed by an RIA test), and increased SHBG compared with the men without atherosclerosis. Smokers with atherosclerosis of the coronary arteries also showed lower levels of DHEAS than the healthy smokers and higher LH than the healthy nonsmokers. There were no differences in the mean concentrations of total testosterone, FAI, free and calculated bioavailable testosterone, estradiol, growth hormone, and IGF-1 in the studied groups. No relationship was observed between hormone levels tested with the parameters characterizing tobacco addiction and the degree of coronary occlusion assessed with the number of significantly stenosed vessels and the Gensini score. Conclusions. Coronary atherosclerosis in men is associated with smoking and lower concentrations of free testosterone and DHEAS. Lack of correlation of the other hormone levels with the parameters of tobacco addiction and the degree of vascular occlusion confirmed that the etiology of coronary heart disease is multifactorial (Adv Clin Exp Med 2010, 19, 2, 211-218).

Introduction. Cigarette smoking is highly prevalent among men. Many studies have evaluated the effect of cigarette smoking on levels of male reproductive hormones; however, the findings still remain controversial. Aim. To evaluate the influence of cigarette smoking on serum levels of total testosterone (TT), free testosterone (FT), bioavailable testosterone (BT), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Methods. A total of 255 men (90 smokers and 165 nonsmokers), aged 30 to 70 years, were investigated. Weight and height were obtained and body mass index (BMI) was calculated. Also, waist circumference and hip circumference were measured and waist-to-hip ratio was obtained. Fasting blood samples were drawn for determination of plasmatic glucose levels and serum levels of total cholesterol, high-density lipoprotein cholesterol (HDL-c), triglycerides, albumin, prolactin, TT, SHBG, LH, and FSH. The values of low-density lipoprotein cholesterol (LDL-c) were determined by Friedwald equation and the values of FT and BT were calculated from TT, SHBG, and albumin. Statistical significance was set at P ≤ 0.05. Main Outcome Measures. The influence of smoking on levels of TT, FT, and BT. Results. No significant difference was observed in the mean values of TT (P = 0.580), FT (P = 0.869), BT (P = 0.933), SHBG (P = 0.279), LH (P = 0.573), and FSH (P = 0.693) in the different levels of pack-years when compared to nonsmokers. Moreover, after multivariate logistic regression, no association between increased pack-years of smoking and increased odds ratio for occurrence of low hormones and SHBG levels was observed. Conclusion. In this study, smokers and nonsmokers had similar mean values of androgens, gonadotropins and SHBG. However, it is necessary to standardize pack-years of smoking in order to elucidate the influence of cigarette smoking on sex hormone levels, as well as to minimize differences among studies and to confirm our results. Halmenschlager G, Rossetto S, Lara GM, and Rhoden EL. Evaluation of the effects of cigarette smoking on testosterone levels in adult men. J Sex Med 2009;6:1763–1772.

  • Adetunji T. Toriola
  • Marja Vääräsmäki Marja Vääräsmäki
  • Matti Lehtinen
  • Annekatrin Lukanova

To examine the associations of maternal and child characteristics with early pregnancy maternal concentrations of testosterone, androstenedione, progesterone, 17-hydroxyprogesterone, and estradiol (E2). We analyzed these hormones among 1,343 women with singleton pregnancies who donated serum samples to the Finnish Maternity Cohort from 1986 to 2006 during the first half of pregnancy (median 11 weeks). The associations of maternal and child characteristics with hormone concentrations were investigated by correlation and multivariable regression. Women older than age 30 years had lower androgen and E2 but higher progesterone concentrations than women younger than that age. Multiparous women had 14% lower testosterone, 11% lower androstenedione and 17-hydroxyprogesterone, 9% lower progesterone, and 16% lower E2 concentrations compared with nulliparous women (all P<.05). Smoking mothers had 11%, 18%, and 8% higher testosterone, androstenedione, and 17-hydroxyprogesterone levels, respectively, but 10% lower progesterone compared with nonsmoking women (all P<.05). E2 concentrations were 9% higher (P<.05) among women with a female fetus compared with those with a male fetus. Parity, smoking, and, to a lesser extent, maternal age and child sex are associated with sex steroid levels during the first half of a singleton pregnancy. The effects of smoking on the maternal hormonal environment and the possible long-term deleterious consequences on the fetus deserve further evaluation.

  • Judith S Brand Judith S Brand
  • Mei-Fen Chan
  • Mitch Dowsett
  • Kay-Tee Khaw

Sex hormones play a key role in women's health, but little is known about lifestyle factors that influence their levels. The objective of the study was to investigate the relationship between cigarette smoking habits and endogenous sex hormone levels in postmenopausal women. This was a cross-sectional study among 2030 postmenopausal women aged 55-81 yr from the Norfolk population of the European Prospective Investigation into Cancer. All women were at least 1 yr postmenopausal and not currently using hormone replacement therapy. General linear models were used to examine the relationship between smoking habits and sex hormone levels. Among current smokers, the daily number of cigarettes smoked was associated with increased levels of testosterone (19-37%), free testosterone (19-34%), 17-hydroxprogesterone (17-22%), androstenedione (2-23%), SHBG (6-10%), and estradiol (-2 to 15%). Stratified analysis for body mass index revealed an interaction such that the association with SHBG was restricted to lean women, whereas a smoking-related increase in free estradiol was found only in overweight women. No clear dose-response relationship was observed for estrone, although its levels were highest in heavy smokers. Current smoking habit was associated with a larger difference in sex hormone levels than lifetime cigarette exposure as measured by pack-years. Among former smokers, sex hormones were at levels of never smokers within 1-2 yr of smoking cessation. Cigarette smoking is associated with higher circulating levels of androgens, estrogens, 17-hydroxprogesterone, and SHBG in postmenopausal women. The almost immediate lower levels with smoking cessation may indicate that hormone related disease risks could potentially be modified by changing smoking habits.

  • Mostafa Saadat Mostafa Saadat

It is reported that parental exposure to toxicants can influence offspring sex ratio at birth. Studies have reported that several chemicals found in cigarette smoke are substrates of glutathione S-transferase T1 (GSTT1, a member of GSTtheta). To determine the effect of cigarette smoke on serum levels of testosterone and gonadotrophins of smokers and possible association of these hormones levels with GSTT1 polymorphism, the present study was done. Our study was conducted on 181 (40 smokers, 141 non-smokers) male subjects. Genomic DNA was extracted from peripheral blood. The GSTT1 genotyping was performed using PCR-based method. All measurements for testosterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) were done in one laboratory. In smoker subjects the mean +/- sd of serum testosterone, FSH, and LH were 4.64 +/- 1.63 ng/ml, 2.72 +/- 1.17 IU/l, and 3.03 +/- 1.04 IU/l, respectively. In non-smoker subjects the mean +/- sd of serum testosterone, FSH, and LH were 4.49 +/- 1.24 ng/ml, 2.89 +/- 1.26 IU/l, and 3.07 +/- 1.28 IU/l, respectively. There was no significant difference between smokers and non-smokers for serum testosterone (t = 0.622, df = 179, P = 0.535), FSH (t = -0.757, df = 179, P = 0.450), and LH (t = -0.179, df = 179, P = 0.858). Also there was no significant difference between smokers and non-smokers in either GSTT1 null or positive genotypes for levels of testosterone, FSH, and LH. Based on present data, it might be concluded that serum levels of testosterone and gonadotrophins were not significantly different between smoker and non-smoker males in both null and present GSTT1 genotypes.

In men, hypoandrogenism is associated with features of the metabolic syndrome. It is not known whether men with the metabolic syndrome are at a higher risk of developing hypogonadism. We therefore assessed whether the metabolic syndrome predicts development of hypogonadism 11 yr later in 651 middle-aged Finnish men participating in a population-based cohort study. Men with the metabolic syndrome at baseline as defined by the World Health Organization (n = 114, 20%) had a 2.6-fold increased risk of developing hypogonadism as defined by total testosterone levels less than 11 nmol/liter at the 11-yr follow-up independent of age, smoking, and other potential confounders. Further adjustment for body mass index (OR, 2.0; 95% CI, 1.1-3.8) or baseline total testosterone levels (OR, 1.9; 95% CI, 1.0-3.4) attenuated the association. The association of the metabolic syndrome with hypogonadism as defined by calculated free testosterone levels less than 225 pmol/liter was similar, but weaker. The adjusted decrease in testosterone concentrations during the 11-yr follow-up was also greater in men with than without the metabolic syndrome. Smokers had a nonsignificantly lower risk of developing hypogonadism during follow-up, whereas a decrease in smoking increased the risk of hypogonadism. The metabolic syndrome predisposes to development of hypogonadism in middle-aged men. Prevention of abdominal obesity and the accompanying metabolic syndrome in middle age may decrease the risk of hypogonadism in men, especially in those who quit smoking.

  • Shalender Bhasin Shalender Bhasin
  • Michael Pencina
  • Guneet K Jasuja
  • Ramachandran S Vasan

Reference ranges are essential for partitioning testosterone levels into low or normal and making the diagnosis of androgen deficiency. We established reference ranges for total testosterone (TT) and free testosterone (FT) in a community-based sample of men. TT was measured using liquid chromatography tandem mass spectrometry in nonobese healthy men, 19-40 yr old, in the Framingham Heart Study Generation 3; FT was calculated. Values below the 2.5th percentile of reference sample were deemed low. We determined the association of low TT and FT with physical dysfunction, sexual symptoms [European Male Aging Study (EMAS) only], and diabetes mellitus in three cohorts: Framingham Heart Study generations 2 and 3, EMAS, and the Osteoporotic Fractures in Men Study. In a reference sample of 456 men, mean (sd), median (quartile), and 2.5th percentile values were 723.8 (221.1), 698.7 (296.5), and 348.3 ng/dl for TT and 141. 8 (45.0), 134.0 (60.0), and 70.0 pg/ml for FT, respectively. In all three samples, men with low TT and FT were more likely to have slow walking speed, difficulty climbing stairs, or frailty and diabetes than those with normal levels. In EMAS, men with low TT and FT were more likely to report sexual symptoms than men with normal levels. Men with low TT and FT were more likely to have at least one of the following: sexual symptoms (EMAS only), physical dysfunction, or diabetes. Reference ranges generated in a community-based sample of men provide a rational basis for categorizing testosterone levels as low or normal. Men with low TT or FT by these criteria had higher prevalence of physical dysfunction, sexual dysfunction, and diabetes. These reference limits should be validated prospectively in relation to incident outcomes and in randomized trials.

Cigarette tobacco smoke is a potent environmental contaminant known to adversely affect health including fertility and pregnancy. To examine the associations between second-hand cigarette tobacco-smoke exposure, or active smoking and serum concentrations of steroid hormones using tandem mass spectrometry. Healthy women (18-45 y) from the general community in the Metropolitan Washington, DC were recruited at the follicular stage of their menstrual cycle. Participants were assigned to one of three study groups: active smokers (N=107), passive smokers (N=86), or non-smokers (N=100). Classifications were based on a combination of self-reporting and serum cotinine concentrations. Serum androgens, estrogens, progestins, androstenedione, aldosterone, cortisol, corticosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), 11-deoxycortisol and 25-hydroxy-vitamin D3 (25-OHVitD3) and cotinine were measured by isotope dilution tandem mass spectrometry (LC/MS/MS) (API-5000). Kruskal-Wallis tests were used to assess median differences among the three groups, with Dunn's multiple comparison test for post hoc analysis. Serum estrone, estradiol, and estriol concentrations were lower in active and passive smokers than in non-smokers. The three study groups differed significantly in serum concentrations of 16-OHE1, aldosterone and 25-OHVitD3, as well as in the ratios of many of the steroids. Pair-wise comparison of the groups demonstrated significant differences in hormone concentrations between (i) smokers and non-smokers for aldosterone: (ii) passive smokers and non-smokers for aldosterone, progesterone and estriol. Moreover, for smokers and passive smokers, there were no significant differences in these hormone concentrations. Smoke exposure was associated with lower than normal median steroid hormone concentrations. These processes may be instrumental in explaining some adverse effects of tobacco smoke on female health and fertility.

  • Johannes Ruige
  • Ahmed Mahmoud Ahmed Mahmoud
  • Dirk De Bacquer
  • Jean-Marc Kaufman

The literature provides no clear answer as to whether low endogenous testosterone increases risk of cardiovascular disease (CVD) in healthy men. Our purpose was to estimate the predictive value of testosterone for CVD and to identify study features explaining conflicting results. Articles were identified by a Medline and Embase search and citation tracking. Eligible were prospective population-based cohort and nested case-control studies of testosterone and atherosclerosis, stroke, myocardial infarction, ischaemic heart disease, death from coronary heart disease or mortality. Two independent researchers re-expressed associations of testosterone and CVD in a uniform manner to be used in meta-regression analyses for identification of study features explaining conflicting results, and to estimate the predictive value of testosterone for CVD. 19 potentially eligible articles were identified. Overall, a weak independent association was found with an estimated summary RR of 0.89 for a change of one standard deviation in total testosterone level (95% CI 0.83 to 0.96). Age of study population and year of publication modified the relationship between testosterone and CVD. The estimated summary RR was 1.01 (0.95 to 1.08) for studies of men younger than 70 years of age, and 0.84 (0.76 to 0.92) for studies including men over 70 years of age. The latter studies showed a particular pronounced association if published after 1 January 2007. Results were largely confirmed by separate analyses of free- and bioavailable testosterone. The systematic review displayed no association between endogenous testosterone and risk for CVD in middle-aged men. In elderly men, testosterone may weakly protect against CVD. Alternatively, low testosterone may indicate a poor general health.

The effects of weight loss on erectile function and hormones have not been well studied. The aim of this study was to measure the degree to which sexual function and in particular erectile function and hormonal environment change after substantial weight loss, surgically and non-surgically induced in the morbidly obese male in a prospective randomized long-term controlled trial. Furthermore, how surgery makes a difference when treating morbidly obese men was envisaged in this context. We prospectively studied 20 morbidly obese men for 24 months, divided into two groups: group A included 10 patients who underwent life style modifications (exercise and diet) for 4 months and subsequently gastric bypass, and another 10 patients in group B were kept on weekly follow-up. None of the men were taking phosphodiesterase type-5 inhibitors. All patients underwent International Index of Erectile Function (IIEF)-5 questionnaire, serum oestradiol, prolactin (PRL), luteinizing (LH) and follicle-stimulating (FSH) hormones, free and total testosterone (FT and TT) at baseline (time 0), surgery - 4 months latter baseline (time 1) and final evaluation - 24 months (time 2). From times 0 to 1, group A presented a mean body mass index (BMI) reduction of 12.6 (p < 0.0001), whereas group B, 2.1 (p > 0.05). The BMI reductions between times 0 and 2 were 24.7 (p < 0.0001) and 0.7 (p > 0.05) for groups A and B respectively. BMI average between the two groups was similar at time 0 (p = 0.2142), and different at times 1 (p = 0.0033) and 2 (p < 0.0006). Increase in IIEF-5 score (p = 0.0469), TT (p = 0.0349) and FSH levels (p = 0.0025), and reduction in PRL level (p < 0.0001) were observed in group A from times 0 to 2 and 1 to 2. There were no changes from times 0 to 1. Comparing groups A and B at time 2, IIEF-5, TT and FT increased significantly in group A (p = 0.0224, 0.0043 and 0.0149 respectively). Surgery-induced weight loss increased erectile function quality measured by IIEF-5 questionnaire, increased TT, FT and FSH and reduced PRL levels. The hormonal impact verified could justify the improvement in erectile function. Lifestyle modifications impacted BMI without hormonal or sexual impact in morbidly obese. New studies are warranted in the field to support our data.

The objective of this study was comparison of circulating androgens and their metabolites as well as estrogens measured for the first time by a validated mass spectrometry technology in 60-80-year-old men and women of comparable age. Castration in men (n=34) reduces the total androgen pool by only about 60% as indicated by the decrease in the serum levels of the glucuronide metabolites of androgens compared to intact men (n=1302). Such data are in agreement with the 50 to 75% decrease in intraprostatic dihydrotestosterone (DHT) concentration after castration. Most interestingly, the same amounts of androgens and estrogens are found in postmenopausal women (n=369) and castrated men of comparable age. The most significant therapeutic implication of these findings is the absolute need to add a pure (nonsteroidal) antiandrogen to castration in men with prostate cancer in order to block the action of the 25 to 50% DHT left in the prostate after castration. Not adding an antiandrogen to castration in men treated for prostate cancer is equivalent to not prescribing a blocker of estrogens in women suffering from breast cancer because they are postmenopausal and have low circulating estradiol.

  • Chrissy J Cochran
  • Lisa Gallicchio
  • Susan R Miller Susan R Miller
  • Jodi A Flaws

To test the hypothesis that cigarette smoking is associated with hot flushes through a mechanism involving androgen levels, progesterone levels, sex hormone-binding globulin levels, or the ratio of androgens to estrogens. Women with and without hot flushes were recruited from Baltimore, Maryland, and the surrounding counties. Women were between 45 and 54 years of age, with at least three menstrual periods in the previous 12 months, and were not postmenopausal. Study participants completed a questionnaire and gave a blood sample for hormone measurements. Current smokers had significantly higher androstenedione levels and a higher androgen-to-estrogen ratio than never smokers. Current smokers had significantly lower progesterone levels compared with never smokers. Former and current cigarette smokers had increased odds of experiencing hot flushes compared with never smokers (former: odds ratio [OR] 1.41, 95% confidence interval [CI] 0.99-2.01; current: OR 2.43, 95% CI 1.28-4.62). This association, however, was not attenuated by the addition of hormones to the smoking and hot-flush model. Cigarette smoking is associated with hot flushes through a mechanism that may not involve alterations in hormone levels or their ratios. II.

  • Mawunyo Daniel Mawunyo Daniel
  • A D Martin
  • C Faiman

Androgen dominance is associated with android (abdominal) adiposity and increased health risk. Cigarette smoking has an anti-estrogenic effect in women and recent evidence has linked cigarette smoking with abdominally-localized adipose tissue. The relationship between cigarette smoking, endogenous sex steroid levels and adipose tissue distribution in women has not been examined. We assessed anthropometric indicators of fat distribution and serum levels of estradiol, testosterone and sex hormone-binding globulin (SHBG) in 56 women aged 20-35 years (27 cigarette smokers and 29 non-smokers). Free estradiol and testosterone were estimated. Endocrine and anthropometric variables were adjusted for overall fatness. Cigarette smokers had significantly higher mean serum levels of SHBG than non-smokers (63.38 nmol/l and 57.85 nmol/l, respectively; P less than 0.01); there were no differences in serum estradiol, testosterone or estimated free levels of these sex steroids. Cigarette smokers had a more android distribution of adipose tissue: significantly greater waist-to-hip ratio (WHR) (P less than 0.01), greater waist-to-thigh ratio (WTR) (P less than 0.02) and smaller thigh girth (P less than 0.05). Waist and umbilical girths were greater in cigarette smokers (P less than 0.0002), but there was no difference in the sum of central skinfold thicknesses (abdominal, iliac crest and supra-spinale). A significant interaction (P less than 0.05) of cigarette smoking with serum testosterone levels was observed in effects on WHR; the relative impact of serum testosterone upon abdominal adiposity was greater in cigarette smokers than in non-smokers. The results suggest that in premenopausal women, cigarette smoking promotes android adiposity by increasing abdominal fat deposition and decreasing femoral fat deposition via interactive effects with sex steroids. The results also suggest an effect of cigarette smoking on serum SHBG, independent of effects on androgen/estrogen balance.

Serum total testosterone (T), free testosterone (fT) sex hormone binding globulin (SHBG), androstenedione (A) and 3 alpha androstanediol glucuronide (3 alpha-diol G) levels as well as serum free androgen index (FAI), fT/T and 3 alpha-diol G/T ratios were measured in premenopausal and cyclic women, grouped according to sexual status and smoking status. Our results showed that serum T, fT, SHBG, A and 3 alpha-diol G levels were lower in cyclic women in the follicular than in the luteal phase of the ovarian cycle, although the differences between these values were not significant. Postmenopausal women had significantly lower values of T, fT, A 3 alpha-diol G, FAI and 3 alpha diolG/T but not SHBG and fT/T than cyclic women. When we compared women smokers and nonsmokers, women smokers had serum levels of T, fT, SHBG, 3 alpha-diol G, and values of FAI, fT/T and 3 alpha-diol G/T, similar to those in nonsmokers. Serum A levels were higher in women smokers than in nonsmokers, although the difference was significant only in postmenopausal women.

Previous studies have revealed effects of prenatal nicotine treatment on fetal plasma testosterone and perinatal sexual brain differentiation in the rat. In an attempt to further elucidate the processes underlying this action of nicotine, we studied the effect of the drug on brain steroid aromatase which converts androgens to estrogens and is known to be important in sexual brain differentiation. Aromatase activity (AA) was measured by the conversion of [1 beta-3H]-androstenedione to estrone in a brain region comprising preoptic, hypothalamic and amygdaloid areas. In untreated animals, the development of AA between gestational day (GD) 18 and postnatal day (PN) 15 was similar in both sexes, except for a significant drop of AA in female brain at PN6, i.e., during the later part of the critical period for sexual brain differentiation. When time-pregnant rats were treated with nicotine delivered by an osmotic minipump for either one week (2 mg/kg/d or 6 mg/kg/d from GD12) or two weeks (6 mg/kg/d from GD8), their male offspring showed a decrease of AA to female levels at PN6, the sex difference existing at this stage thus being abolished. AA of offspring from dams bearing tartaric acid-containing minipumps or sham-operated at GD8 or GD12 was identical to that of untreated controls. No drug effect was seen in female fetuses and offspring. Sex differences in the developmental effect of nicotine may thus involve brain aromatase. An additional sex-dependent effect of nicotine was observed in the male fetal adrenal axis at GD18. Whether the drug effects on the two steroid hormone systems are interrelated, remains to be elucidated.