How gender influence the health state ? A cross sectional study in an endocrine setting 2


 Background: Gender medicine focuses on how gender differences affect health status and diseases development and how they influence health services access and attitude to screening programmes. Endocrine diseases are influenced by many gender-related issues, some of which have not been sufficiently investigated. The aim of this study was to evaluate gender difference in determinants of health (as lifestyle, level of education, area of origin, distance from hospital) and how these elements could influence diseases prevalence in an endocrine outpatients setting, with a special focus on oncological disease. Methods: We performed a cross-sectional study enrolling patients referring for the first time to our Oncological Endocrinology Unit, between January 2019 to December 2019. Results: We enrolled 1107 consecutive patients. Mean age was 56.8 ± 15.0 years (77% females). The main reasons for referral were thyroid and bone diseases. We found a gender difference in some disease prevalences: malignant endocrine diseases and iatrogenic thyroid diseases were more frequent in males, while other thyroid disorders, adrenal and metabolic diseases and cancer treatment induced bone loss were higher in females. The frequency of oncological comorbidities was higher in females. No difference was found in the propensity to travel long distances to reach the hospital. In our population, women had a higher socio-cultural level and followed healthier lifestyle. In fact, alcohol and tobacco consumption was lower in females and women had lower BMI. The percentage of smokers or ex-smokers was higher in patients with any malignancy compared to patients with benign endocrine diseases. Conclusions: the study showed the importance of considering gender as a determinant of health, able to influence also lifestyle and habits, and as an element to keep in consideration to promote a healthier lifestyle and a targeted endocrine screening especially in oncological setting.


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Background 39 Gender medicine deals with biological, psychological and socio-cultural differences between 40 men and women, which can affect health status and disease development (1). The term "gender" 41 goes beyond the simple biological differences between male and female, classically defined as 42 "sex", taking into account also environmental, social, cultural and relational factors(2).Gender 43 medicine is therefore a complex study of how these gender differences affect the state of health, the 44 onset and progression of diseases, the access to health services, the attitude towards prevention 45 interventions and to therapeutic strategies(3). In fact, men and women, despite being susceptible to 46 almost the same pathologies, could present different symptoms, disease progression and response 47 to treatments. In addition, women have a higher propensity to consult health care providers, 48 generally they take more medication and usually manage family health problems (4). 49 In 2019, Italian Ministry of Health arranged a plan for the application and the diffusion of gender 50 medicine in the country, testifying its importance in the wider field of precision medicine(5). 51 Gender medicine therefore aims to achieve a "health" condition by paying attention not only to the 52 disease itself, but also to the "determinants of health" starting from lifestyles such as alcohol, 53 smoking, physical activity, nutrition and body weight(6). These, in fact, contribute to determining 54 the health of women and men and have an impact on the incidence of many chronic diseases, such 55 as cardiovascular and respiratory diseases, diabetes mellitus, and cancer diseases. Exposure to the 56 aforementioned risk factors depends on individual choices, but it is strongly influenced by the 57 socio-cultural and environmental context and therefore by gender(7). 58 In modern society, gender medicine appears essential to achieve the best diagnostic and 59 therapeutic work-up for both men and women and to optimize health services planning(8). 60 Endocrinology is one of the medical disciplines most influenced by issues related to gender, as the 61 most widespread endocrine diseases (e.g. thyroid diseases, osteoporosis and diabetes mellitus) 62 have marked gender differences in term of prevalence. This is certainly due to hormonal 63 differences between males and females, while the impact of gender-related determinants of health 64 have not yet been sufficiently investigated(9 Legend and abbreviations: *=statistically significant differences between groups; # = chi-square 116 test. Values are expressed as mean± standard deviation if not otherwise statedare cited. 117

Reason for referral 118
Patients of both genders referred to our center mainly for thyroid diseases. The secondary most 119 frequent reason was bone disease. Among patients referring for benign endocrine diseases, there 120 was a high prevalence of oncological comorbidity. In fact, at list one malignancy was present in 121 56.1% of patients with benign endocrine disease compared to only 14.5% of patients with 122 endocrine malignancies, with a statistically significant difference (p<0.001). Considering gender, 123 malignant endocrine diseases were more frequent in males than in females (11.5% vs 5.3%, 124 p<0.001). All reasons for referral are summarized in Table 2. 125 Values are expressed as number of patients (percentage). NA= not applicable. 127

Disease prevalence according to gender 128
Most patients referred to our Unit for just one endocrine disease (corresponding to the reason 129 for referral), while a lower but significant percentage of patients had more than one disease: in 130 particular, 227 patients had two endocrine diseases and 23 patients had 3 endocrine 131 diseases.Global diseases prevalence is summarized in No difference was found in physical activities between males and females (p=0.854), and this 157 data was confirmed also dividing patients in two age groups (under and over 45 years). 158 Men had a statistically significant higher BMI compared to women (27.8 ± 5.0 vs 26.1 ± 5.5 kg/m 2 , 159 p<0.001). A higher proportion of males was smokers or ex-smokers compared to females 160 (p<0.001); accordingly, 58% of women had never smoked in their life compared to only 42% of 161 males. Dividing the study population in two groups according to age, in younger people there was 162 no statistically significant difference in smoking habits regarding to sex, while in people older than 163 45 years there was a statistically significant gender difference in the proportion of smokers 164 (p<0.001). Also alcohol consumption was higher in males than in females (49.2 vs 33.0%, 165 p<0.001). As smoking habits, there was a difference in alcohol habits only in older 166 patients(p<0.001). 167 No difference was found in smoking status, physical activity and alcohol consumption regarding 168 nationality (comparing Italian and foreign patients), neither between patients referring for benign 169 and malignant endocrine diseases. However, gathering together people with any malignancies, 170 both endocrine or non-endocrine, the percentage of smokers or ex-smokers was higher compared 171 to the group without malignancies (p=0.041), while no difference in proportion was found 172 regarding physical activity and alcohol consumption. 173 In our study population, women had a higher level of education compared to men (p=0.024), as 174 well as not Italian people had more frequently a degree or upper title compared to Italian patients 175 (39.1% vs 23%, p= 0.02). 176 Only 22% of patients lived nearby the hospital (<10 km). The prevalence of malignant endocrine 177 disease was 7.7% in the group of patients who lived far from the hospital (>10 km) versus 3.8% in 178 patients who lived closer (p= 0.031). No significant difference was found in the distance from the 179 hospital according to gender, nationality or non-endocrine oncological comorbidities. 180 Gender-related determinants of health are summarized in Table 1. 181

Discussion 182
Gender medicine has recently received increasing attention(10). In this perspective, we 183 decided to design this cross-sectional study in order to provide an overview of our patients, 184 focusing on the role of gender on endocrine diseases, risks factors and other important aspects 185 related to health care, always in a gender perspective. Many studies in the literature have focused 186 on the impact of gender on lifestyle(11). Men seem more prone to consume alcohol and to develop 187 alcohol-related diseases compared to women(12). Conversely, women who physiologically 188 tolerate lower amount of alcohol (due to the sex differences in gastric absorption and metabolism), 189 usually drink less alcohol also for cultural reason, as society's disapproval of drinking or increased 190 risk of physical and sexual assault(12, 13). 191 In our population, we confirmed a gender difference in alcohol consumption, which was lower in 192 females. Interestingly, this difference was not statistically significant in younger people, testifying 193 as younger women have a more similar lifestyle to males, perhaps due to female emancipation, 194 while in older people traditional gender differences are yet more preserved. Likewise, a higher 195 proportion of men was smokers than women. In Italy, data from two recent tobacco use surveys 196 show a smoking prevalence of 26% in men compared to 17.2% in women.This gender difference is 197 reduced in young adults: in Italian adolescents (15-24 years), 21.9% of boys are smokers against 198 18.2% of girls(14). Therefore, these studies underline that the use of tobacco in young women is a 199 behavior to be monitored carefully. Scientific research has also shown differences in food intake and the practice of physical activity in 211 both sexes(19, 20). For example, in modern Western societies, the male gender seems to prefer red 212 meat, high protein foods and sugar-sweetened beverages, while healthier foods such as vegetables, 213 fruit, fish and dairy products are mostly eaten by women(20-22). These differences may depend on 214 a different awareness of the relationship between food behavior and health and on a different 215 attention to weight control or good physical shape, in line with modern society stereotypes(23). 216 This attitude is reflected in the nutritional pattern and body mass index. Unfortunately, we did not 217 collect information on dietary habits of our patients, but males had a higher BMI compared to 218 women, testifying to probably less healthy dietary habits. In our population, there were no 219 differences in physical activity level between males and females, unlike other studies published in 220 literature which have shown, especially in younger people, a greater propensity to physical 221 activities in males than in females(24, 25). 222 Taking all these aspects together, in our study population, women seem to follow a healthier 223 lifestyle. This data could dependon the influence of multiple factors. First, women pay greater 224 attention to their health condition compared to men(4); secondary, it is the conditioning of society 225 that leads women to maintain a good body shape in order to achieve beauty stereotypes; finally, the 226 level of education of patients. Indeed, in our population, women had a higher level of education 227 compared to men and this could have affected the lifestyle of our patients. It is demonstrated that 228 better educated people follow a healthier lifestyle, probably due to the increased awareness of the 229 correlation between lifestyle and health(26). 230 National habits also seem to influence the state ofhealth; in fact, in our study, foreign people 231 (mainly women from European Union States) did not follow a healthier lifestyle than Italian 232 patients, despite their higher education level. 233 During a year, the percentage of women referring for a first endocrine visit was significantly higher 234 than men. This fact could be explained by the more common prevalence of endocrine diseases in 235 females(27), but also by the higher attention paid to personal health status typical of women and 236 their higher propensity to refer to health care centers (1). 237 One of the aims of our study was to ascertain if women were more willing than men to travel long 238 distances for obtaining medical care. The willingness to move from own home area to reach 239 tertiary center health care was the same in both sexes and did not change according to nationality; 240 in fact, most patients decided to go to a qualified cancer endocrinology center, even if it was not 241 close to their residences. This was particularly true for patients with endocrine tumors who showed 242 a higher propensity to travel long distances. It is important to consider that a relevant part of the 243 first access to our center was allowed regardless of the reported disease, considering that the 244 booking service of the Italian public health system does not indicate to the patients the most 245 suitable hospital. According to this, the reason for referral to our center was only partially biased 246 by the type of center (Oncological Endocrine Unit). 247 The most common reason for referral to our center was an endocrine malignancy or a benign 248 endocrine disease associated to other oncological comorbidities, probably because our center is a 249 national reference hospital for neoplastic diseases. In our population, women had a higher 250 prevalence of oncological comorbidities: a high percentage of these patients referred to the 251 Endocrine Unit for prevention and treatment of cancer induced bone loss, mainly due to the intake 252 of aromatase inhibitors or gonadotropin-releasing hormone analogs for breast cancers. 253 Benign thyroid diseases were the most common endocrine disorders in both sexes; this finding 254 could be explained by the high prevalence of thyroid nodules. The increased prevalence in our 255 population could be caused by the fact that oncological patients undergo multiple and deepened 256 whole body radiological examinations (such as computed tomography and magnetic resonance 257 imaging) and functional procedures (such as positron emission tomography), therefore thyroid 258 nodules can be an accidental finding(28), and patients have been referred to our Unit for 259 subsequent tests, such as the fine needle aspiration diagnostic biopsy of the thyroid nodule. 260 Furthermore, there was no gender difference in the prevalence of benign thyroid disease, although 261 some disorders, such as Hashimoto's thyroiditis or thyroid nodules, are known to be more frequent 262 in females(27). However, this finding could be explained considering that in our population this 263 group of diseases also contains drug related thyroid dysfunction (e.g. due to TKI or amiodarone 264 intake) or subclinical thyroid disease due to age or chronic diseases, which usually do not showed 265 significant gender differences(29, 30). 266 Probably, the high incidence of adrenal incidentalomas could be explained by the high number of 267 radiological and functional tests performed in our Hospital for the cancer diagnosis and for 268 patients' follow-up. 269 In our study, thyroid malignancies were more frequent in males than females.The risk of 270 malignancy of the thyroid nodules is known to be greater in males(31, 32), and that male gender is 271 an independent prognostic factors in papillary thyroid carcinoma, which influences staging and 272 risk of recurrence(33, 34). These factors together could explain the propensity to refer to a national 273 cancer center in male patients. 274 We therefore sought to evaluate the impact of common gender-influenced risk factors in the higher 275 prevalence of endocrine malignancies found in males. 276 In patients with at least one tumor (endocrine or non-endocrine), the percentage of smokers and 277 ex-smokers was higher compared to patients without neoplasms. 278 This finding has not been confirmed considering only patients with endocrine malignancies, 279 probably due to the low number of patients affected and also considering that for some of these 280 malignancies (for example thyroid cancer) other risk factors are of considerable importance, such 281 as family history or previous radiation exposure(32, 35). 282 In a gender medicine perspective, it should be also interesting to evaluate possible differences 283 between men and women in terms of inclination in carrying out periodic follow-up visits and 284 adherence to the treatment proposed by physician, with possible impact on progression and 285 outcomes of the endocrine disorders. Unfortunately, we do not have data on these aspects in our 286 population, as only one visit per patient has been analysed, but this topic is of a great interest for 287 further studies. 288

Conclusions 289
Biological and sociocultural aspects are known to influence lifestyle, patient health, disease 290 development and treatment adherence. The study highlights and confirms the importance of 291 considering gender and gender-related health determinants as key factors for health, even in 292 patients affected by endocrine diseases, in which this approach has not been widely used. 293 Our study demonstrated that smoking and alcohol consumption are more common in males and 294 younger women. Therefore, in the approach to the patient, doctors should pay special attention to 295 female and male lifestyle, in order to discourage voluptuous habits and to encourage physical 296 activity and healthy eating habits.This is particularly important mainly in subjects who, nowadays, 297 seem to be less careful to these aspects, as men, younger women or patients with lower 298 socio-cultural level. 299 Our study confirmed, as already known in the literature, that women were more affected by 300 endocrine disorders but, in our cohort, the proportion of endocrine malignancies was higher in 301 men. Therefore, from a precision medicine perspective, all efforts must be made to raise 302 awareness, in oncological patients and health care providers, on the risk of endocrine diseases 303 development in order to promote targeted screening in both genders. 304