Gender in Endocrine Diseases: Role of Sex Gonadal Hormones

Lauretta, R.; Sansone, M.; Sansone, A.; Romanelli, F.; Appetecchia, M.

doi:https://doi.org/10.1155/2018/4847376

International Journal of Endocrinology

On this page

Abstract Conclusions Conflicts of Interest References Copyright Related Articles

Review Article | Open Access

Volume 2018 | Article ID 4847376 | https://doi.org/10.1155/2018/4847376

Gender in Endocrine Diseases: Role of Sex Gonadal Hormones

R. Lauretta,¹M. Sansone,²A. Sansone,²F. Romanelli,²and M. Appetecchia¹

Academic Editor: Michael Horowitz

Received14 Jun 2018

Revised08 Sept 2018

Accepted03 Oct 2018

Published21 Oct 2018

Abstract

Gender- and sex- related differences represent a new frontier towards patient-tailored medicine, taking into account that theoretically every medical specialty can be influenced by both of them. Sex hormones define the differences between males and females, and the different endocrine environment promoted by estrogens, progesterone, testosterone, and their precursors might influence both human physiology and pathophysiology. With the term Gender we refer, instead, to behaviors, roles, expectations, and activities carried out by the individual in society. In other words, “gender” refers to a sociocultural sphere of the individual, whereas “sex” only defines the biological sex. In the last decade, increasing attention has been paid to understand the influence that gender can have on both the human physiology and pathogenesis of diseases. Even the clinical response to therapy may be influenced by sex hormones and gender, but further research is needed to investigate and clarify how they can affect the human pathophysiology. The path to a tailored medicine in which every patient is able to receive early diagnosis, risk assessments, and optimal treatments cannot exclude the importance of gender. In this review, we have focused our attention on the involvement of sex hormones and gender on different endocrine diseases.

1.1. Introduction

Sex and gender intersect with other biological and social variables to produce between- or within-group differences [1]. Those factors may reveal subgroup differences among women and among men that would have been obscured by using only gender or sex as a variable. Accounting for differences in socioeconomic status, for example, may reveal unexpected differences between women and men that cannot be explained by gender or socioeconomic status alone, such as women of high socioeconomic status having health outcomes similar to those of men of low socioeconomic status [2]. Understanding how factors interrelate with sex or gender is important in explaining or predicting differences in health outcomes and determining user needs [3]. Among the medical disciplines, endocrinology is probably the one that most falls in issues concerning gender medicine. The hormones, in fact, determine sex, male or female, but it is now clear that the epidemiology, the clinical manifestations, the natural history of diseases, and the response to therapy can be very different in both sexes as well as because of the differences closely linked to the hormonal structure to the influence of social, economic, and cultural factors, which contribute to ensuring that men and women have important differences in health [4].

The interactions between sex and gender characteristics are supposed to affect molecular and cellular processes and clinical characteristics as well as health and disease outcomes [5]. Nevertheless, evidence concerning how they interact is scarce and requires a multidisciplinary approach. In this manuscript, we focused our attention on the sex and gender differences in endocrine pathophysiology. What makes females different from males is essentially represented by sex hormones and, in fact, the attention of scientific literature has been, and continues to be, an understanding of the biological mechanisms activated by sex hormones that underlie their pathophysiological diversities [6, 7]. Our attention has focused on the effects that not only sex as hormones but also gender can have in explaining differences in the human endocrine system. Conditions such as thyroid disease, diabetes mellitus, osteoporosis, GH/IGF I axis diseases, obesity, and sarcopenia clearly present gender differences [8–15]. Energy metabolism is also gender-specific, being greatly influenced by estrogen, both at rest and during exercise [16–18]. These hormones have also a considerable effect on the pathogenesis of autoimmune endocrine diseases, as suggested by their different prevalence, often significantly higher in women than in men [19].

Finally, there are sex and gender differences which also affect response to therapies, in terms of dose response, efficacy, and appearance of adverse events, although these aspects need to be further explored [20–28].

1.2. Gender-Related Differences in the Endocrine System

Gender-specific medicine is a complex and intriguing challenge for the future of all medical specialties. Hormones represent what makes females different from males. Generally, females and males have the same hormones (i.e., estrogens, progesterone, and testosterone), but their production sites, their blood concentrations, and their interactions with different organs, systems, and apparatus are different [29]. Males produce predominantly testosterone from the testes in a relatively constant daily amount according to a circadian profile. Small amounts of estrogens and progesterone are produced by the testes and the adrenal glands or are produced in the peripheral tissues, such as adipose tissue or liver, by the conversion of other precursor hormones [30]. In contrast, females mainly produce estrogens and progesterone from the ovaries in a cyclical pattern, while a small amount of testosterone (T) is produced by the ovaries and adrenal glands. The levels of female sexual steroids follow a specific and oscillating profile, due to a complex interaction between the pituitary gland and the ovary [31–33]. Female and male sexual steroids modulate in a different way, for example, the distribution of body fat mass and fluids, the maintenance of muscle and bone mass, the hepatic synthesis of numerous enzymes (cytochrome P450 family enzymes), the synthesis of triglycerides and HDL, and glucose metabolism. As a consequence, in addition to the typical differences of sex directly induced by hormones, we also have to consider the drug peripheral distribution and transformation pathways, especially hepatic and renal, which may be responsible for their reduced or increased efficacy as well as of the appearance of adverse reactions, for example due to their inappropriate doses or ways of administration. Moreover, socioeconomic and cultural contexts may represent additional confounding factors being able to influence the epidemiological characteristics of diseases, the approach, and the response to specific therapeutic treatments [9, 10, 13, 15].

1.3. Gender-Related Differences in Thyroid Disease

Thyroid diseases are 5 to 8 times more common in females than in males [34, 35]. Such data can be considered not only for clinical and/or subclinical hypothyroidism and hyperthyroidism and for nodular thyroid diseases but also for autoimmune conditions, such as Hashimoto’s thyroiditis and Graves’ disease [36, 37]. It can be hypothesized that female sex hormones (i.e., estrogens and progesterone) and their particular patterns may be involved in explaining the higher prevalence of thyroid diseases in females [37–39]. Differentiated thyroid carcinoma (DTC), the most common endocrine neoplasm, is also more common in women than in men, but evidence regarding gender-related differences is scant [40]. According to recent data, the age-adjusted incidence ratio of thyroid cancer in 2013 was 21.61/100,000 women and 7.26/100,000 men, for a female-to-male ratio of almost 3 : 1. However, because of differences between sexes in thyroid cancer peak age incidence, the female-to-male ratio is higher during the reproductive period (4.1 : 1 at ages 20–49 years) and steadily decreases with advancing age (1.38 : 1 at ages ≥ 75 years). Furthermore, females have a better survival rate than age-matched males. Therefore, thyroid cancer is more common in females but is more aggressive in males [41, 42]. Pathophysiological reasons explaining this difference are unknown, but it has been proposed that estrogens may play a fundamental role. This hypothesis is supported by evidence that thyroid cancer has a higher incidence in fertile women [43]. A causal role for the number of children, age at first pregnancy, age at onset of menopause, and hysterectomy has also been suggested [44]. According to a recent meta-analysis, women with children have an increased risk of thyroid cancer compared to nulliparous women (Relative Risk 1.09, CI 1.03–1.15), but a linear relationship between the number of children and the increased risk has not been proven [40]. Nevertheless, the recent guidelines published by the American Association of Clinical Endocrinologists and the American College of Endocrinologists in 2015 suggest that clinical trials do not support the role of estrogens as a risk factor for the development of thyroid cancer at present [45]. Female sex, together with the absence of lymph node metastases, and the American Thyroid Association (ATA) pediatric risk stratification system remained factors related to better outcomes in pediatric DTC, even in longer periods of observation (i.e., 32 years). Furthermore, girls with no lymph node metastasis at diagnosis and those classified as low risk by the ATA pediatric risk stratification system were more likely to have no evidence of disease within the first year compared to boys [46]. Regarding the therapeutic aspects, gender does not affect the function of salivary glands in patients affected by thyroid cancer undergoing first attempt of radioactive iodine therapy [47].

1.4. Gender-Related Differences and Diabetes Mellitus

Recently, it has been observed that diabetes mellitus may also have some gender-specific peculiarities; some data highlight that women have longer-term illness and higher body mass index (BMI) compared to men [14]. In women, diabetes mellitus appears to be less controlled considering each metabolic parameter. Italian data from annals published by Associazione Medici Diabetologi (AMD), the Italian association of diabetologists, showed that diabetic women had 14% higher chance of having HbA1c > 9% regardless of insulin therapy, 42% more likely to have low-density lipoprotein (LDL) cholesterol > 130 mg/dL irrespective of statin therapy, and 50% greater chance of having BMI > 30 kg/m² [48, 49]. These data seem to be partially confirmed in type 1 diabetic patients, in whom women showed worse metabolic control and men had higher blood pressure [13]. Furthermore, diabetic women, regardless of menopausal state, present significantly higher risk of ischemic cardiomyopathy than diabetic men. Diabetic women also have a worse prognosis after myocardial infarction and a higher mortality rate from cardiovascular disease than diabetic men [50, 51]. A Canadian study showed that long-term statin therapy reduces total and cardiovascular mortality after myocardial infarction, and this effect is pronounced over time in both sexes. However, this risk reduction is lower in women than in men, suggesting a gender-specific model of therapy response [25]. Regarding the metabolic aspect, women show a different behavior in their insulin response compared to men. In fact, the susceptibility to develop insulin resistance and the insulin response to stimuli that physiologically improve or compromise insulin sensitivity are different in the two sexes [52]. Women show a tendency to have lower insulin sensitivity than their male counterpart but increase their insulin response to maintain normoglycemia (Table 1) [53, 54]. It can suggest that these differences in insulin action may explain that in prediabetic state women are more prone to develop impaired glucose tolerance whereas their male counterparts are more susceptible to develop impaired fasting glycemia [55, 56]. This gender-related physiology may underline the different effects showed by a combined therapy with exenatide and metformin which induced better therapeutic results in women compared with men [57]. Interestingly, the difference in sex affects the prevalence of diabetes that is reversed according to the stage of reproductive life. There are more diabetic men before the age of puberty, while there are more diabetic women after the age of menopause and in old age [55]. Recent evidence confirms higher prevalence of T2DM in adolescent females than males associated with a greater insulin resistance in girls than in boys during puberty. Beyond puberty, T2DM is more common in middle aged men; different patterns of fat accumulation providing with a greater subcutaneous fat presence in women along with better insulin sensitivity may represent possible reasons [58]. The role of menopausal estrogen deficiency in the increased risk of type 2 diabetes mellitus in menopausal women has been extensively studied. It should be considered that estrogens affect positively glucose homeostasis within a physiological window and any change outside the physiological range, such as menopause or oral contraceptives, represents a risk factor for insulin resistance [55, 56]. In diabetes mellitus, women are at higher risk of experiencing hypoglycemia using insulin and for urinary tract and genital infection using gliflozin drugs. As a result of the use of thiazolidinediones, the risk of bone fractures in postmenopausal women increases [15]. Finally, recent studies have observed a marked influence of socioeconomic and psychosocial aspects on glycemic health control and a significant association between sociodemographic profile and absolute control of T1DM risk factors [59, 60]. Furthermore, T2DM women and men with lower income and education level show poor food choice revealing higher carbohydrate and lower fat intake. Considering the sex-related difference in insulin sensitivity, it is clear how sociodemographic aspects may interact with biology [61]. This association has been observed also in pregnant woman [62]. Even in the prevention and management of gestational diabetes mellitus, maternal income and education may have a strong impact [63]. Keeping in mind that the term “gender” refers to social and psychological differences between men and women, further studies are warranted to clarify the influence of gender on glycemic health and the interactions with biological distinctions [4].

1.5. Gender-Related Differences and Osteoporosis

A large part of clinical evidence is based on trials on male subjects, creating the so-called male-bias evidence-based medicine. Nevertheless, scientific studies on osteoporosis represent an exception to male-bias evidence-based medicine. In fact, osteoporosis has always been considered a typical female disease, although it is also common in males. As a consequence, osteoporosis is most commonly investigated in women, especially after menopause, and it is rarely considered in men, who also present significant risk factors [64]. Indeed, a lower proportion of men at high risk of fracture are treated than women at high risk [65]. Men also tend to have worse outcomes after fracture than women; they are twice as likely to die after hip fracture as women [66].

Interestingly, the Epidemiologic Study on the Prevalence of Osteoporosis (ESOPO), the main Italian epidemiologic study on osteoporosis, was conducted on 11,011 females and 4981 males and showed that in females the prevalence of osteoporosis was about 18.5%, while in males it was about 10%. Similarly, the prevalence of osteopenia was 44.7% and 36%, respectively. The presence of bone fracture was confirmed in 17.6% of females and in 17.5% of males. Thereafter, mortality was 2–3 times higher in males suffering with femur fracture than in females. These data suggest that bone health and status should be carefully evaluated even in elderly males [67]. The physiopathology of osteoporosis is clearly sex-specific. Males tend to have higher bone mineral density and bone content and reach it at an older age than females, while females tend to lose bone density at a younger age and at a faster rate than males and also have higher bone reabsorption markers [68]. Later in life, the production of sex hormones decreases earlier and more markedly in females. This aspect can be the basis of the presence of fractures about 5–10 years earlier in females than in males [69]. Indeed, estrogens play a crucial role in bone health in both sexes, and their deficiency is supposed to be the main cause of bone loss in postmenopausal females and in elderly males, in particular for cortical bone [70]. Estrogens inhibit generation and activity of osteoclasts through an upregulation of osteoprotegerin, decrease T-cell activation and consequently also interferon-γ release by T-cells, and increase intestinal calcium absorption [71, 72]. In females, estrogen decline is abrupt at the beginning of the menopausal period, while in males the decline in T and, consequently, in estrogen, is low and constant with aging, so it is clear how sex differences in osteoporosis exist. An increase in both bone formation markers and bone reabsorption markers have been observed in postmenopausal females, suggesting an increase in the rate of bone remodeling as confirmed by histomorphometry. In elderly males, biochemical markers of bone degradation seem to increase but bone formation markers appear to be stable or decreased, therefore suggesting a low bone remodeling rate (Table 1) [8]. Furthermore, an alteration of the inflammatory state of the bone has been demonstrated to be more pronounced in postmenopausal females than in older males, thus negatively affecting bone health [73, 74].

According to the underlying causes, osteoporosis may be primary or secondary. Prevalence of secondary osteoporosis in females reaches up to 20–40% of cases, while this value rises to 65% in males [75]. Scientific studies on osteoporosis therapy have mostly focused their attention on females, then considering their results applicable to males. However, it seems that females are more prone to suffer from side effects associated with bisphosphonates. The higher relative cases of atypical bone fractures in women than in men are not entirely related to an increased use of bisphosphonates but also to sex per se, which should be considered a risk factor for atypical fracture [76]. Some oncological diseases (breast and prostate cancer) can induce modification of the bone metabolism, also aggravated by the use of anticancer therapies both in women and in men. Hormone therapy (aromatase inhibitors such as anastrozole, letrozole and exemestane, LHRH analogs, bicalutamide, and abiraterone) and chemotherapies can induce a greater bone resorption compared to its synthesis, creating a net effect of loss of bone mass, a reduction of resistance and a consequent increase in bone fractures in both women and men, even in the absence of trauma. Global bone health can also be compromised by high doses of cortisone associated with certain treatments and pathological changes related to oncology in itself (early menopause in women and hypogonadism in men).

1.6. Gender-Related Differences and the Growth Hormone/Insulin Growth Factor 1 Axis

The clinical evidence supports the effects of estrogens on the growth hormone (GH)/insulin growth factor 1 (IGF-1) axis [77]. In fact, several studies have shown that estrogens inhibit GH-stimulated liver production of IGF-1 [77, 78]. In turn, GH levels rise to overcome the inhibitory effects of estrogen. It has been observed that the levels of GH are higher in females than in males, and they fluctuate according to the phase of the menstrual cycle and depending on the menopausal state [79]. Moreover, during the first trimester of pregnancy, estrogen levels increase and consequently IGF-1 levels decrease in the absence of any change in GH levels. IGF-1 levels increase from the beginning of the second quarter due to the gradual increase in placental GH [80]. The effect of estrogens on the GH/IGF-1 axis is also noteworthy even in pathologies characterized by deficiency or excess of GH.

Females suffering from GH deficiency require a much higher dose of recombinant GH (rhGH) than males. Women taking oral estrogens need a higher dose of rhGH than those taking transdermal estrogens [81, 82]. It can be hypothesized that the inhibitory action of oral estrogens on the metabolic effect of GH is mediated by stimulation of cytokine 2 suppressor expression (SOCS-2), which in turn inhibits the phosphorylation of Janus kinase 2 (JAK2), a key passage in the signaling path JAK2/signal transducer and activator of transcription 5 (STAT5) activated by GH. The inhibition of enzymatic function of JAK prevents GH from exerting its metabolic effects, including the hepatic synthesis of IGF-1 [83]. Indeed, stimulated JAK2 adds a phosphate group to specific tyrosine residues on the cytoplasmic domain of the GH receptor. Therefore, using its Src homology 2 (SH2) domain, STAT5 binds to these phosphorylated tyrosine residues [84]. The bound STAT5 is phosphorylated by JAK2 to specific tyrosine residues and is ready to form homodimers or heterodimers to act as a transcription factor (Table 1) [11]. Females suffering from acromegaly show lower IGF-1 levels than males who suffer from the same condition. It is interesting to highlight that in some specific acromegalic females, IGF-1 levels decrease during the first trimester of pregnancy [85]. A possible explanation could be the physiological increase in estrogen levels and their subsequent inhibition of IGF-1 production in the liver [84]. This mechanism can be considered as a possible reason for the improvement of the clinical conditions of acromegalic females during this period [84]. Acromegaly has also shown some clinical differences between the sexes, as specific metabolic alterations of the acromegaly are sex-specific. Acromegalic females are more prone to suffer from insulin resistance and metabolic syndrome than males, even in the absence of significant differences in blood glucose and/or glycated hemoglobin (HbA1c). In addition, a higher prevalence of metabolic syndrome, visceral obesity, and diabetes mellitus was observed in postmenopausal females compared to premenopausal females and males [12]. It is interesting to note that the administration of rhGH often leads to hypothyroidism through both central and peripheral mechanisms; in particular, rhGH appears to decrease the TSH level by increasing IGF-1 [86]. In fact, IGF-1 seems to be involved in the direct stimulation of somatostatin mRNA synthesis and, in turn, somatostatin inhibits TSH secretion [87]. This process has not always been observed in females, and it seems that gonadal hormones play a fundamental role due to their inhibition of IGF-1 secretion, as mentioned above, and their downregulation of the thyroid somatostatin receptor (SSTR) by estrogen. SSTRs 1, 3, 4, and 5 are highly expressed in normal thyroid tissue, and estrogen has a differential effect on distinct SSTs, subregulating the expression of SSTRs 1 and 5 (Table 1) [11].

1.7. Gender-Related Differences and Obesity

Females and males showed marked differences in the prevalence of obesity, in fat deposition patterns, and in fat metabolism. Females generally have a higher percentage of fat mass and are more likely to deposit fat subcutaneously and on their lower extremities while men are more likely to deposit visceral fat in the abdominal region [88]. Adipose tissue increases with puberty and early pregnancy, suggesting that gonadal steroids can influence body fat. Following menopause-induced estrogen loss, a shift towards visceral adiposity occurs, which is sensitive to estrogen therapy [89]. These facts highlight the importance of estrogens in subcutaneous fat accumulation. At cellular level, estrogen function is mediated by alpha (ERα) and beta (ERβ) receptors although recent research observed nongenomic and rapid effects of steroid hormones throughout cytosolic or plasma membrane-associated receptors. Both ERα and ERβ are expressed in subcutaneous and visceral adipose tissue; however, it seems that ERα plays a pivotal role in sexual dimorphism of fat distribution. Female and male mice that lack ERα have visceral obesity with severe insulin resistance. Furthermore, estrogens seem to promote and maintain the typical female type of fat distribution by affecting lipolysis, which is controlled in humans primarily by the action of β-adrenergic receptors (lipolytic) and α2A-adrenergic receptors (antilipolytic). Estrogens increase the number of antilipolytic α2A-adrenergic receptors in subcutaneous adipocytes; in contrast, no effect of estrogens on α2A-adrenergic receptor mRNA expression was observed in adipocytes from the intra-abdominal fat depot where a high α2A/β ratio is present [90]. In premenopausal women, α2A to β1–2-adrenergic receptor ratio is increased in subcutaneous fat tissue compared to men and to postmenopausal women thus decreasing the lipolytic response to adrenergic and noradrenergic stimuli. This balance of adrenergic receptors is reversed in the visceral depot of premenopausal women, favoring lipolysis of visceral fat and it accounts for deposition of fat in subcutaneous adipocytes in premenopausal women. In postmenopausal females, adrenergic receptor ratio is reversed thus potentially explaining the preferential accumulation of fat in the visceral depot. Therefore, at the adipocyte levels, estrogens and their receptors may have the capacity to increase the accumulation of fat cells in the subcutaneous deposit and to inhibit it in the visceral deposit [91].

This pattern of fat accrual affords protection from the negative consequences associated with obesity and the metabolic syndrome in premenopausal females. However, after menopause, the decrease of estrogen secretion leads to fat deposition and accrual shift in favor of the visceral depot. This shift is accompanied by a parallel increase in metabolic risk similar to that seen in males. Estrogen appears to protect against obesity also through the suppression of appetite, as observed during the periovulatory phase of the menstrual cycle, and by increasing energy expenditure [91]. T exerts its antiobesity effect by activation of the androgen receptor (AR) pathway on mesenchymal stem cells, suppressing the adipogenic line cells and favoring the myogenic line. Furthermore, T increases lipolysis and the number of β-adrenergic receptors on the membranes of adipocytes and inhibits triglyceride uptake and lipoprotein lipase activity. Nevertheless, in females, hyperandrogenism positively correlated with visceral fat, waist circumferences, and insulin resistance. Androgen excess may induce these effects through both central and peripheral mechanisms. Failure to activate leptin with consequent blockage of brown adipose tissue thermogenesis and reduced expression of hypothalamic proopiomelanocortin may represent important central control mechanisms. Peripherally, the interaction with estradiol may explain the different effects of T on women metabolism [92]. Additionally, cross-sex hormonal therapy of male-to-female transsexuals increases the amount of subcutaneous adipose tissue accrual relative to intra-abdominal adipose tissue whereas more masculine body fat distribution with a lower hip circumference has been observed in trans males [93].

Finally, a sex-specific fat deposition pattern represents a physiological condition in which sex hormones play a pivotal role. Nevertheless, in both sexes, the presence of normal sex hormone levels is protective against obesity, and a tendency to increase central obesity is observed with a decrease in sex steroid hormones, as it happens with old age or gonadectomy [94].

Estrogens also affect fuel metabolism by reducing postprandial fatty acid oxidation, leading to an increase in body fat which may account for the increased fat mass observed in women compared to men and the increased fat early in pregnancy (Table 1) [95]. Interestingly, O'Sullivan et al. showed that basal lipid oxidation was reduced in pregnant and nonpregnant women compared to postmenopausal women, and postprandial lipid oxidation was reduced in pregnancy compared to nonpregnant healthy women, who in turn have lower postprandial lipid oxidation than postmenopausal women (Table 1) [96]. A possible explanation for this efficient fat storage of energy in female puberty and in early pregnancy is the obvious biological advantage in preparation for fertility, fetal development, and lactation [95]. Otherwise, women show a greater reliance on fat oxidation than men during submaximal exercise, showing a higher maximum fat oxidation rate and a fat oxidation curve which tends to be shifted toward higher exercise intensities [97]. It seems likely that both genomic and nongenomic actions of estrogens may play a role in explaining these observations. In particular, estrogens mainly act through estrogen receptor-alpha in the skeletal muscle to stimulate the genomic expression of proteins to increase the availability of long chain fatty acids (LCFA) improving adipocyte lipolysis and increasing intramyocellular lipid storage. Following on, estrogens affect fuel metabolism during exercise by nongenomic means to increase the activation of 5 adenosine monophosphate-activated protein kinase (AMPK) [16, 98].

1.8. Gender-Related Differences in Sarcopenia

Sarcopenia is an age-related syndrome defined by the loss of muscle mass and strength and/or performance, often associated with chronic diseases, obesity, and prolonged immobilization. However, it also represents a physiological condition of aging [99, 100]. The etiology of sarcopenia is multifactorial but still poorly understood. A decrease of anabolic hormones plays a role in the development and in the maintenance of sarcopenia [101]. In particular, the decrease in T appears to be crucial in elderly males, and the administration of T in hypogonadal subjects may be extremely helpful in limiting the loss of muscle mass and strength (Table 2). Indeed, T administration is able to significantly increase muscle mass and decrease fat mass also in eugonadal males, even in total absence of any training stimulus [102–104]. T is also of paramount importance in supporting adaptation to strength training. Indeed, in evaluating sarcopenia, three aspects should be carefully evaluated: physical exercise, nutrition, and hormonal homeostasis [101]. In particular, strength training represents the form of physical exercise which has the greater positive impact in limiting loss of muscle mass. However, it has been observed that the adaptive process to strength training requires adequate serum level of T [105]. Therefore, in the presence of overt hypogonadism, strength training results to be almost useless and ineffective in the therapy of sarcopenia (Table 2). Aside these effects, the positive effects of T on erythropoiesis and on mood should be also considered as they may support elderly men to follow a consistent training schedule [106–108].

In postmenopausal women, evidence regarding the effect of abrupt decrease of estrogens on muscle mass and strength and eventually the impact of hormonal replacement therapy (HRT) is scarce. During menopause, females show a marked decrease in muscle mass and strength, while in males this loss is constant and takes place more slowly. However, this is not shown in women undergoing HRT [109]. A meta-analysis showed that strength was significantly greater in women on HRT. The effect sizes (ESs) were calculated as the standardized mean difference and amounted to 0.23, equating to women on HRT being ∼5% stronger. Nevertheless, effect sizes tended to be greater (∼0.45) when only randomized; controlled trials were considered or when strength was normalized for muscle size, indicating that estrogens affect positively muscle strength and contractile properties of muscle tissue [110]. Estrogens appear to act via several mechanisms, such as increased levels of proanabolic factors, reduced systemic and muscle inflammation, decreased muscle damage, and augmented postexercise muscle satellite cell activation and proliferation. Furthermore, estrogens also seem to improve intrinsic contractile muscle function altering myosin functions, as reported by increased strength normalized to muscle size (Table 1) [109, 111]. A recent study with monozygotic twin pairs showed that thigh muscle cross-sectional area tended to be larger, relative muscle area greater, and relative fat area smaller in HRT users than in their sisters. In particular, tibolone administration, a tissue-specific compound with estrogenic, progestogenic, and weak androgenic activities [112], increased muscle cross-sectional area [113]. Tibolone showed promising effects, increasing significantly handgrip strength compared to placebo in postmenopausal women and improving markedly isometric knee extension strength, adjusted for BMI [114]. In a cross-sectional study, mean knee extensor strength was higher in women taking tibolone or estrogen compared to no HRT [115]. Following on, tibolone seems to affect body composition, increasing lean mass and decreasing total body fat mass [112, 116–118]. Thus, the lower rate of falling in the tibolone group observed by Cummings et al. might reflect an androgenic effect on muscular function [119].

1.9. Gender-Related Differences in Drug Response

Most scientific studies on drug response have been performed on male subjects and the results have been considered valid also for females, assuming that sex did not affect the outcome (Yentl syndrome) [120, 121]. However, it should be noted that in 2005 eight out of ten prescription drugs were withdrawn from the US market because of women’s health issues [122]. Recently, the NHS and Medical Research Council have evaluated the causes and effects of women’s sociodemographic exclusions from clinical trials. Therefore, the use of statins and nonsteroidal anti-inflammatory drugs (NSAIDs) has been investigated. These drugs demonstrated a marked difference in the sex of subjects included in the trials. Studies on NSAIDs have reflected the population in which they were used, while those for statins did not and only 16% of women were included in trials compared with 45% who were using statins [123]. The therapeutic response may be different between genders, and even if evidence is far from being conclusive, the existing data have to be considered and evaluated [124]. Indeed, it is well known that cytochrome expression may be a gender-specific mechanism involved in difference in drug metabolism [125, 126]. Concerning lipid-lowering drugs, it has been observed that women on atorvastatin had more side effects (i.e., increased liver enzymes and myalgia) than men. However, atorvastatin and rosuvastatin seemed to have similar efficacy in both sexes [26]. On the contrary, fenofibrate improved lipid profile more in women than in men and reduced cardiovascular events by 30% in women and 13% in men [27, 127]. In evaluating gender differences, it should be considered that patients with lower income are more likely to use generic drugs. The presence of different excipients may affect drug response therapy according to sex [128].

2. Conclusions

Sex- and gender-specific differences can be observed in several endocrine diseases, but the majority of these aspects have not been carefully assessed so far. However, evidence in the scientific literature holds that sex and gender should always be considered in every element of the disease, from the causes to the treatment.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

References

K. L. Whittle and M. C. Inhorn, “Rethinking difference: a feminist reframing of gender/race/class for the improvement of women’s health research,” International Journal of Health Services, vol. 31, no. 1, pp. 147–165, 2001.
View at: Publisher Site | Google Scholar
G. Sen, A. Iyer, and C. Mukherjee, “A methodology to analyse the intersections of social inequalities in health,” Journal of Human Development and Capabilities, vol. 10, no. 3, pp. 397–415, 2009.
View at: Publisher Site | Google Scholar
G. Gonzales and K. Ortiz, “Health insurance disparities among racial/ethnic minorities in same-sex relationships: an intersectional approach,” American Journal of Public Health, vol. 105, no. 6, pp. 1106–1113, 2015.
View at: Publisher Site | Google Scholar
S. E. Short, Y. C. Yang, and T. M. Jenkins, “Sex, gender, genetics, and health,” American Journal of Public Health, vol. 103, Suppl 1, pp. S93–101, 2013.
View at: Publisher Site | Google Scholar
É. Rásky, A. Waxenegger, S. Groth, E. Stolz, M. Schenouda, and A. Berzlanovich, “Sex and gender matters: a sex-specific analysis of original articles published in the Wiener klinische Wochenschrift between 2013 and 2015,” Wiener Klinische Wochenschrift, vol. 129, no. 21-22, pp. 781–785, 2017.
View at: Publisher Site | Google Scholar
I. W. Craig, E. Harper, and C. S. Loat, “The genetic basis for sex differences in human behaviour: role of the sex chromosomes,” Annals of Human Genetics, vol. 68, no. 3, pp. 269–284, 2004.
View at: Publisher Site | Google Scholar
G. Baggio, A. Corsini, A. Floreani, S. Giannini, and V. Zagonel, “Gender medicine: a task for the third millennium,” Clinical Chemistry and Laboratory Medicine, vol. 51, no. 4, pp. 713–727, 2013.
View at: Publisher Site | Google Scholar
P. Pietschmann, M. Rauner, W. Sipos, and K. Kerschan-Schindl, “Osteoporosis: an age-related and gender-specific disease – a mini-review,” Gerontology, vol. 55, no. 1, pp. 3–12, 2009.
View at: Publisher Site | Google Scholar
M. I. Maiorino, G. Bellastella, O. Casciano et al., “Gender-differences in glycemic control and diabetes related factors in young adults with type 1 diabetes: results from the METRO study,” Endocrine, vol. 61, no. 2, pp. 240–247, 2018.
View at: Publisher Site | Google Scholar
D. Zhang, J. Tang, D. Kong et al., “Impact of gender and age on the prognosis of differentiated thyroid carcinoma: a retrospective analysis based on SEER,” Hormones and Cancer, vol. 9, no. 5, pp. 361–370, 2018.
View at: Publisher Site | Google Scholar
P. Sgrò, M. Sansone, A. Parisi et al., “Supra-physiological rhGH administration induces gender-related differences in the hypothalamus-pituitary-thyroid (HPT) axis in healthy individuals,” Journal of Endocrinological Investigation, vol. 39, no. 12, pp. 1383–1390, 2016.
View at: Publisher Site | Google Scholar
A. Ciresi, M. C. Amato, R. Pivonello et al., “The metabolic profile in active acromegaly is gender-specific,” The Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 1, pp. E51–E59, 2013.
View at: Publisher Site | Google Scholar
V. Manicardi, G. Russo, A. Napoli et al., “Gender-disparities in adults with type 1 diabetes: more than a quality of care issue. A cross-sectional observational study from the AMD Annals initiative,” PLoS One, vol. 11, no. 10, article e0162960, 2016.
View at: Publisher Site | Google Scholar
A. Kautzky-Willer, J. Harreiter, and G. Pacini, “Sex and gender differences in risk, pathophysiology and complications of type 2 diabetes mellitus,” Endocrine Reviews, vol. 37, no. 3, pp. 278–316, 2016.
View at: Publisher Site | Google Scholar
A. Kautzky-Willer and J. Harreiter, “Sex and gender differences in therapy of type 2 diabetes,” Diabetes Research and Clinical Practice, vol. 131, pp. 230–241, 2017.
View at: Publisher Site | Google Scholar
T. Oosthuyse and A. N. Bosch, “Oestrogen’s regulation of fat metabolism during exercise and gender specific effects,” Current Opinion in Pharmacology, vol. 12, no. 3, pp. 363–371, 2012.
View at: Publisher Site | Google Scholar
M. J. Hamadeh, M. C. Devries, and M. A. Tarnopolsky, “Estrogen supplementation reduces whole body leucine and carbohydrate oxidation and increases lipid oxidation in men during endurance exercise,” The Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 6, pp. 3592–3599, 2005.
View at: Publisher Site | Google Scholar
A. C. Maher, M. Akhtar, J. Vockley, and M. A. Tarnopolsky, “Women have higher protein content of beta-oxidation enzymes in skeletal muscle than men,” PLoS One, vol. 5, no. 8, article e12025, 2010.
View at: Publisher Site | Google Scholar
O. L. Quintero, M. J. Amador-Patarroyo, G. Montoya-Ortiz, A. Rojas-Villarraga, and J. M. Anaya, “Autoimmune disease and gender: plausible mechanisms for the female predominance of autoimmunity,” Journal of Autoimmunity, vol. 38, no. 2-3, pp. J109–J119, 2012.
View at: Publisher Site | Google Scholar
P. Cirillo, L. di Serafino, G. Patti et al., “Gender-related differences in antiplatelet therapy and impact on 1-year clinical outcome in patients presenting with ACS: the START ANTIPLATELET registry,” Angiology, no. article 3319718783866, 2018.
View at: Publisher Site | Google Scholar
L. K. Lind, M. von Euler, S. Korkmaz, and K. Schenck-Gustafsson, “Correction to: sex differences in drugs: the development of a comprehensive knowledge base to improve gender awareness prescribing,” Biology of Sex Differences, vol. 9, no. 1, p. 5, 2018.
View at: Publisher Site | Google Scholar
J. H. A. van der Heyden, L. Gisle, E. Hesse, S. Demarest, S. Drieskens, and J. Tafforeau, “Gender differences in the use of anxiolytics and antidepressants: a population based study,” Pharmacoepidemiology and Drug Safety, vol. 18, no. 11, pp. 1101–1110, 2009.
View at: Publisher Site | Google Scholar
N. Kokras, C. Dalla, and Z. Papadopoulou-Daifoti, “Sex differences in pharmacokinetics of antidepressants,” Expert Opinion on Drug Metabolism & Toxicology, vol. 7, no. 2, pp. 213–226, 2011.
View at: Publisher Site | Google Scholar
E. M. Rodenburg, B. H. Stricker, and L. E. Visser, “Sex differences in cardiovascular drug-induced adverse reactions causing hospital admissions,” British Journal of Clinical Pharmacology, vol. 74, no. 6, pp. 1045–1052, 2012.
View at: Publisher Site | Google Scholar
I. Karp, S. F. Chen, and L. Pilote, “Sex differences in the effectiveness of statins after myocardial infarction,” CMAJ, vol. 176, no. 3, pp. 333–338, 2007.
View at: Publisher Site | Google Scholar
L. B. Goldstein, P. Amarenco, M. Lamonte et al., “Relative effects of statin therapy on stroke and cardiovascular events in men and women: secondary analysis of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) study,” Stroke, vol. 39, no. 9, pp. 2444–2448, 2008.
View at: Publisher Site | Google Scholar
M. C. d'Emden, A. J. Jenkins, L. Li et al., “Favourable effects of fenofibrate on lipids and cardiovascular disease in women with type 2 diabetes: results from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study,” Diabetologia, vol. 57, no. 11, pp. 2296–2303, 2014.
View at: Publisher Site | Google Scholar
U. Seeland and V. Regitz-Zagrosek, “Sex and gender differences in cardiovascular drug therapy,” in Sex and Gender Differences in Pharmacology. Handbook of Experimental Pharmacology, vol 214, V. Regitz-Zagrosek, Ed., pp. 211–236, Springer, Berlin, Heidelberg.
View at: Publisher Site | Google Scholar
K. Svechnikov and O. Soder, “Ontogeny of gonadal sex steroids,” Best Practice & Research. Clinical Endocrinology & Metabolism, vol. 22, no. 1, pp. 95–106, 2008.
View at: Publisher Site | Google Scholar
V. Tyagi, M. Scordo, R. S. Yoon, F. A. Liporace, and L. W. Greene, “Revisiting the role of testosterone: are we missing something?” Revista de Urología, vol. 19, no. 1, pp. 16–24, 2017.
View at: Publisher Site | Google Scholar
E. R. Simpson, “Sources of estrogen and their importance,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 86, no. 3–5, pp. 225–230, 2003.
View at: Publisher Site | Google Scholar
K. L. Britt and J. K. Findlay, “Estrogen actions in the ovary revisited,” The Journal of Endocrinology, vol. 175, no. 2, pp. 269–276, 2002.
View at: Publisher Site | Google Scholar
L. R. Nelson and S. E. Bulun, “Estrogen production and action,” Journal of the American Academy of Dermatology, vol. 45, no. 3, pp. S116–S124, 2001.
View at: Publisher Site | Google Scholar
S. J. Merrill and Y. Mu, “Thyroid autoimmunity as a window to autoimmunity: an explanation for sex differences in the prevalence of thyroid autoimmunity,” Journal of Theoretical Biology, vol. 375, pp. 95–100, 2015.
View at: Publisher Site | Google Scholar
H. Li and J. Li, “Thyroid disorders in women,” Minerva Medica, vol. 106, no. 2, pp. 109–114, 2015.
View at: Google Scholar
D. S. A. McLeod and D. S. Cooper, “The incidence and prevalence of thyroid autoimmunity,” Endocrine, vol. 42, no. 2, pp. 252–265, 2012.
View at: Publisher Site | Google Scholar
Y. Lu, J. Li, and J. Li, “Estrogen and thyroid diseases: an update,” Minerva Medica, vol. 107, no. 4, pp. 239–244, 2016.
View at: Google Scholar
R. S. Fortunato, A. C. F. Ferreira, F. Hecht, C. Dupuy, and D. P. Carvalho, “Sexual dimorphism and thyroid dysfunction: a matter of oxidative stress?” The Journal of Endocrinology, vol. 221, no. 2, pp. R31–R40, 2014.
View at: Publisher Site | Google Scholar
S. Xu, G. Chen, W. Peng, K. Renko, and M. Derwahl, “Oestrogen action on thyroid progenitor cells: relevant for the pathogenesis of thyroid nodules?” The Journal of Endocrinology, vol. 218, no. 1, pp. 125–133, 2013.
View at: Publisher Site | Google Scholar
J. Zhu, X. Zhu, C. Tu et al., “Parity and thyroid cancer risk: a meta-analysis of epidemiological studies,” Cancer Medicine, vol. 5, no. 4, pp. 739–752, 2016.
View at: Publisher Site | Google Scholar
R. Rahbari, L. Zhang, and E. Kebebew, “Thyroid cancer gender disparity,” Future Oncology, vol. 6, no. 11, pp. 1771–1779, 2010.
View at: Publisher Site | Google Scholar
M. Moleti, G. Sturniolo, M. di Mauro, M. Russo, and F. Vermiglio, “Female reproductive factors and differentiated thyroid cancer,” Frontiers in Endocrinology, vol. 8, p. 111, 2017.
View at: Publisher Site | Google Scholar
M. Derwahl and D. Nicula, “Estrogen and its role in thyroid cancer,” Endocrine-Related Cancer, vol. 21, no. 5, pp. T273–T283, 2014.
View at: Publisher Site | Google Scholar
S. Caini, B. Gibelli, D. Palli, C. Saieva, M. Ruscica, and S. Gandini, “Menstrual and reproductive history and use of exogenous sex hormones and risk of thyroid cancer among women: a meta-analysis of prospective studies,” Cancer Causes & Control, vol. 26, no. 4, pp. 511–518, 2015.
View at: Publisher Site | Google Scholar
L. Davies, L. G. T. Morris, M. Haymart et al., “American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: the increasing incidence of thyroid cancer,” Endocrine Practice, vol. 21, no. 6, pp. 686–696, 2015.
View at: Publisher Site | Google Scholar
B. P. Pires, P. A. G. Alves Jr, M. A. Bordallo et al., “Prognostic factors for early and long-term remission in pediatric differentiated thyroid carcinoma: the role of sex, age, clinical presentation, and the newly proposed American Thyroid Association risk stratification system,” Thyroid, vol. 26, no. 10, pp. 1480–1487, 2016.
View at: Publisher Site | Google Scholar
A. Upadhyaya, Z. Meng, P. Wang et al., “Effects of first radioiodine ablation on functions of salivary glands in patients with differentiated thyroid cancer,” Medicine, vol. 96, no. 25, p. e7164, 2017.
View at: Publisher Site | Google Scholar
E. Guastamacchia, V. Triggiani, A. Aglialoro et al., “Italian Association of Clinical Endocrinologists (AME) & Italian Association of Clinical Diabetologists (AMD) position statement : diabetes mellitus and thyroid disorders: recommendations for clinical practice,” Endocrine, vol. 49, no. 2, pp. 339–352, 2015.
View at: Publisher Site | Google Scholar
G. Russo, B. Pintaudi, C. Giorda et al., “Age- and gender-related differences in LDL-cholesterol management in outpatients with type 2 diabetes mellitus,” International Journal of Endocrinology, vol. 2015, Article ID 957105, 8 pages, 2015.
View at: Publisher Site | Google Scholar
M. C. Rossi, M. R. Cristofaro, S. Gentile et al., “Sex disparities in the quality of diabetes care: biological and cultural factors may play a different role for different outcomes: a cross-sectional observational study from the AMD Annals initiative,” Diabetes Care, vol. 36, no. 10, pp. 3162–3168, 2013.
View at: Publisher Site | Google Scholar
V. Manicardi, M. C. Rossi, E. L. Romeo et al., “Gender differences in type 2 diabetes (Italy),” Italian Journal of Gender-Specific Medicine, vol. 2, no. 2, pp. 60–68, 2016.
View at: Publisher Site | Google Scholar
B. Mittendorfer, “Insulin resistance: sex matters,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 8, no. 4, pp. 367–372, 2005.
View at: Publisher Site | Google Scholar
J. H. Goedecke, C. George, K. Veras et al., “Sex differences in insulin sensitivity and insulin response with increasing age in black South African men and women,” Diabetes Research and Clinical Practice, vol. 122, pp. 207–214, 2016.
View at: Publisher Site | Google Scholar
A. Basu, S. Dube, and R. Basu, “Men are from Mars, women are from Venus: sex differences in insulin action and secretion,” Advances in Experimental Medicine and Biology, vol. 1043, pp. 53–64, 2017.
View at: Publisher Site | Google Scholar
F. Mauvais-Jarvis, “Gender differences in glucose homeostasis and diabetes,” Physiology & Behavior, vol. 187, pp. 20–23, 2018.
View at: Publisher Site | Google Scholar
O. Varlamov, C. L. Bethea, and C. T. Roberts Jr, “Sex-specific differences in lipid and glucose metabolism,” Frontiers in Endocrinology, vol. 5, p. 241, 2015.
View at: Publisher Site | Google Scholar
H. Quan, H. Zhang, W. Wei, and T. Fang, “Gender-related different effects of a combined therapy of exenatide and metformin on overweight or obesity patients with type 2 diabetes mellitus,” Journal of Diabetes and its Complications, vol. 30, no. 4, pp. 686–692, 2016.
View at: Publisher Site | Google Scholar
N. Sattar, “Gender aspects in type 2 diabetes mellitus and cardiometabolic risk,” Best Practice & Research. Clinical Endocrinology & Metabolism, vol. 27, no. 4, pp. 501–507, 2013.
View at: Publisher Site | Google Scholar
E. Lowry, N. Rautio, V. Karhunen et al., “Understanding the complexity of glycaemic health: systematic bio-psychosocial modelling of fasting glucose in middle-age adults; a DynaHEALTH study,” International Journal of Obesity, 2018.
View at: Publisher Site | Google Scholar
C. Willers, H. Iderberg, M. Axelsen et al., “Sociodemographic determinants and health outcome variation in individuals with type 1 diabetes mellitus: a register-based study,” PLoS One, vol. 13, no. 6, article e0199170, 2018.
View at: Publisher Site | Google Scholar
S. H. Kim, S. Y. Lee, C. W. Kim et al., “Impact of socioeconomic status on health behaviors, metabolic control, and chronic complications in type 2 diabetes mellitus,” Diabetes & Metabolism Journal, vol. 42, 2018.
View at: Publisher Site | Google Scholar
J. A. Teixeira, T. G. Castro, C. C. Grant et al., “Dietary patterns are influenced by socio-demographic conditions of women in childbearing age: a cohort study of pregnant women,” BMC Public Health, vol. 18, no. 1, p. 301, 2018.
View at: Publisher Site | Google Scholar
M. L. Burks, G. D. Cozzi, L. Wang, S. M. Jagasia, and R. J. Chakkalakal, “Socioeconomic status and care metrics for women diagnosed with gestational diabetes mellitus,” Clinical Diabetes, vol. 35, no. 4, pp. 217–226, 2017.
View at: Publisher Site | Google Scholar
P. D'Amelio and G. C. Isaia, “Male osteoporosis in the elderly,” International Journal of Endocrinology, vol. 2015, Article ID 907689, 8 pages, 2015.
View at: Publisher Site | Google Scholar
G. M. Kiebzak, G. A. Beinart, K. Perser, C. G. Ambrose, S. J. Siff, and M. H. Heggeness, “Undertreatment of osteoporosis in men with hip fracture,” Archives of Internal Medicine, vol. 162, no. 19, pp. 2217–2222, 2002.
View at: Publisher Site | Google Scholar
P. Haentjens, J. Magaziner, C. S. Colón-Emeric et al., “Meta-analysis: excess mortality after hip fracture among older women and men,” Annals of Internal Medicine, vol. 152, no. 6, pp. 380–390, 2010.
View at: Publisher Site | Google Scholar
S. Maggi, M. Noale, S. Giannini et al., “Quantitative heel ultrasound in a population-based study in Italy and its relationship with fracture history: the ESOPO study,” Osteoporosis International, vol. 17, no. 2, pp. 237–244, 2006.
View at: Publisher Site | Google Scholar
B. L. Clarke and S. Khosla, “Physiology of bone loss,” Radiologic Clinics of North America, vol. 48, no. 3, pp. 483–495, 2010.
View at: Publisher Site | Google Scholar
K. A. Alswat, “Gender disparities in osteoporosis,” Journal of Clinical Medical Research, vol. 9, no. 5, pp. 382–387, 2017.
View at: Publisher Site | Google Scholar
S. Khosla, L. J. Melton III, and B. L. Riggs, “The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed?” Journal of Bone and Mineral Research, vol. 26, no. 3, pp. 441–451, 2011.
View at: Publisher Site | Google Scholar
C. Schiller, R. Gruber, K. Redlich et al., “17β-estradiol antagonizes effects of 1α,25-dihydroxyvitamin D3 on interleukin-6 production and osteoclast-like cell formation in mouse bone marrow primary cultures,” Endocrinology, vol. 138, no. 11, pp. 4567–4571, 1997.
View at: Publisher Site | Google Scholar
G. Eghbali-Fatourechi, S. Khosla, A. Sanyal, W. J. Boyle, D. L. Lacey, and B. L. Riggs, “Role of RANK ligand in mediating increased bone resorption in early postmenopausal women,” The Journal of Clinical Investigation, vol. 111, no. 8, pp. 1221–1230, 2003.
View at: Publisher Site | Google Scholar
P. Pietschmann, E. Gollob, S. Brosch et al., “The effect of age and gender on cytokine production by human peripheral blood mononuclear cells and markers of bone metabolism,” Experimental Gerontology, vol. 38, no. 10, pp. 1119–1127, 2003.
View at: Publisher Site | Google Scholar
T. Fulop, A. Larbi, G. Dupuis et al., “Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes?” Frontiers in Immunology, vol. 8, article 1960, 2018.
View at: Publisher Site | Google Scholar
J. E. South-Paul, “Osteoporosis: part I. Evaluation and assessment,” American Family Physician, vol. 63, no. 5, pp. 897–904, 908, 2001, 8.
View at: Google Scholar
M. Kharazmi, P. Hallberg, and K. Michaelsson, “Gender related difference in the risk of bisphosphonate associated atypical femoral fracture and osteonecrosis of the jaw,” Annals of the Rheumatic Diseases, vol. 73, no. 8, p. 1594, 2014.
View at: Publisher Site | Google Scholar
T. Münzer, C. J. Rosen, S. M. Harman et al., “Effects of GH and/or sex steroids on circulating IGF-I and IGFBPs in healthy, aged women and men,” American Journal of Physiology. Endocrinology and Metabolism, vol. 290, no. 5, pp. E1006–E1013, 2006.
View at: Publisher Site | Google Scholar
C. Norman, N. L. Rollene, D. Erickson, J. M. Miles, C. Y. Bowers, and J. D. Veldhuis, “Estradiol regulates GH-releasing peptide’s interactions with GH-releasing hormone and somatostatin in postmenopausal women,” European Journal of Endocrinology, vol. 170, no. 1, pp. 121–129, 2014.
View at: Publisher Site | Google Scholar
N. Glynn and A. Agha, “Diagnosing growth hormone deficiency in adults,” International Journal of Endocrinology, vol. 2012, Article ID 972617, 7 pages, 2012.
View at: Publisher Site | Google Scholar
M. L. Persechini, I. Gennero, S. Grunenwald, D. Vezzosi, A. Bennet, and P. Caron, “Decreased IGF-1 concentration during the first trimester of pregnancy in women with normal somatotroph function,” Pituitary, vol. 18, no. 4, pp. 461–464, 2015.
View at: Publisher Site | Google Scholar
J. P. T. Span, G. F. F. M. Pieters, C. G. J. Sweep, A. R. M. M. Hermus, and A. G. H. Smals, “Gender difference in insulin-like growth factor I response to growth hormone (GH) treatment in GH-deficient adults: role of sex hormone replacement,” The Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 3, pp. 1121–1125, 2000.
View at: Publisher Site | Google Scholar
A. A. van der Klaauw, N. R. Biermasz, P. M. J. Zelissen et al., “Administration route-dependent effects of estrogens on IGF-I levels during fixed GH replacement in women with hypopituitarism,” European Journal of Endocrinology, vol. 157, no. 6, pp. 709–716, 2007.
View at: Publisher Site | Google Scholar
K. C. Leung, N. Doyle, M. Ballesteros et al., “Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 3, pp. 1016–1021, 2003.
View at: Publisher Site | Google Scholar
K. C. Leung, G. Johannsson, G. M. Leong, and K. K. Y. Ho, “Estrogen regulation of growth hormone action,” Endocrine Reviews, vol. 25, no. 5, pp. 693–721, 2004.
View at: Publisher Site | Google Scholar
B. A. Laway, “Pregnancy in acromegaly,” Therapeutic Advances in Endocrinology and Metabolism, vol. 6, no. 6, pp. 267–272, 2015.
View at: Publisher Site | Google Scholar
P. Sgrò, L. Guidetti, C. Crescioli et al., “Effect of supra-physiological dose administration of rhGH on pituitary-thyroid axis in healthy male athletes,” Regulatory Peptides, vol. 165, no. 2-3, pp. 163–167, 2010.
View at: Publisher Site | Google Scholar
K. Horiguchi, M. Yamada, R. Umezawa et al., “Somatostatin receptor subtypes mRNA in TSH-secreting pituitary adenomas: a case showing a dramatic reduction in tumor size during short octreotide treatment,” Endocrine Journal, vol. 54, no. 3, pp. 371–378, 2007.
View at: Publisher Site | Google Scholar
M. L. Power and J. Schulkin, “Sex differences in fat storage, fat metabolism, and the health risks from obesity: possible evolutionary origins,” The British Journal of Nutrition, vol. 99, no. 5, pp. 931–940, 2008.
View at: Publisher Site | Google Scholar
M. R. Meyer, D. J. Clegg, E. R. Prossnitz, and M. Barton, “Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors,” Acta Physiologica, vol. 203, no. 1, pp. 259–269, 2011.
View at: Publisher Site | Google Scholar
F. Lizcano and G. Guzmán, “Estrogen deficiency and the origin of obesity during menopause,” BioMed Research International, vol. 2014, Article ID 757461, 11 pages, 2014.
View at: Publisher Site | Google Scholar
B. F. Palmer and D. J. Clegg, “The sexual dimorphism of obesity,” Molecular and Cellular Endocrinology, vol. 402, pp. 113–119, 2015.
View at: Publisher Site | Google Scholar
V. E. Bianchi and V. Locatelli, “Testosterone a key factor in gender related metabolic syndrome,” Obesity Reviews, vol. 19, no. 4, pp. 557–575, 2018.
View at: Publisher Site | Google Scholar
M. Klaver, C. J. M. de Blok, C. M. Wiepjes et al., “Changes in regional body fat, lean body mass and body shape in trans persons using cross-sex hormonal therapy: results from a multicenter prospective study,” European Journal of Endocrinology, vol. 178, no. 2, pp. 165–173, 2018.
View at: Publisher Site | Google Scholar
J. S. Mayes and G. H. Watson, “Direct effects of sex steroid hormones on adipose tissues and obesity,” Obesity Reviews, vol. 5, no. 4, pp. 197–216, 2004.
View at: Publisher Site | Google Scholar
A. J. O'Sullivan, “Does oestrogen allow women to store fat more efficiently? A biological advantage for fertility and gestation,” Obesity Reviews, vol. 10, no. 2, pp. 168–177, 2009.
View at: Publisher Site | Google Scholar
A. J. O'Sullivan, A. Martin, and M. A. Brown, “Efficient fat storage in premenopausal women and in early pregnancy: a role for estrogen,” The Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 10, pp. 4951–4956, 2001.
View at: Publisher Site | Google Scholar
X. Chenevière, F. Borrani, D. Sangsue, B. Gojanovic, and D. Malatesta, “Gender differences in whole-body fat oxidation kinetics during exercise,” Applied Physiology, Nutrition, and Metabolism, vol. 36, no. 1, pp. 88–95, 2011.
View at: Publisher Site | Google Scholar
D. Sarafian, Y. Schutz, J. P. Montani, A. G. Dulloo, and J. L. Miles-Chan, “Sex difference in substrate oxidation during low-intensity isometric exercise in young adults,” Applied Physiology, Nutrition, and Metabolism, vol. 41, no. 9, pp. 977–984, 2016.
View at: Publisher Site | Google Scholar
A. J. Cruz-Jentoft, J. P. Baeyens, J. M. Bauer et al., “Sarcopenia: European consensus on definition and diagnosis: report of the European working group on sarcopenia in older people,” Age and Ageing, vol. 39, no. 4, pp. 412–423, 2010.
View at: Publisher Site | Google Scholar
A. J. Cruz-Jentoft, F. Landi, S. M. Schneider et al., “Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS),” Age and Ageing, vol. 43, no. 6, pp. 748–759, 2014.
View at: Publisher Site | Google Scholar
P. Sgrò, M. Sansone, A. Sansone et al., “Physical exercise, nutrition and hormones: three pillars to fight sarcopenia,” The Aging Male, pp. 1–14, 2018.
View at: Publisher Site | Google Scholar
T. W. Storer, L. Woodhouse, L. Magliano et al., “Changes in muscle mass, muscle strength, and power but not physical function are related to testosterone dose in healthy older men,” Journal of the American Geriatrics Society, vol. 56, no. 11, pp. 1991–1999, 2008.
View at: Publisher Site | Google Scholar
S. Bhasin, T. W. Storer, N. Berman et al., “The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men,” The New England Journal of Medicine, vol. 335, no. 1, pp. 1–7, 1996.
View at: Publisher Site | Google Scholar
S. Bhasin, L. Woodhouse, R. Casaburi et al., “Testosterone dose-response relationships in healthy young men,” American Journal of Physiology. Endocrinology and Metabolism, vol. 281, no. 6, pp. E1172–E1181, 2001.
View at: Publisher Site | Google Scholar
T. Kvorning, M. Andersen, K. Brixen, and K. Madsen, “Suppression of endogenous testosterone production attenuates the response to strength training: a randomized, placebo-controlled, and blinded intervention study,” American Journal of Physiology. Endocrinology and Metabolism, vol. 291, no. 6, pp. E1325–E1332, 2006.
View at: Publisher Site | Google Scholar
H. R. Amanatkar, J. T. Chibnall, B. W. Seo, J. N. Manepalli, and G. T. Grossberg, “Impact of exogenous testosterone on mood: a systematic review and meta-analysis of randomized placebo-controlled trials,” Annals of Clinical Psychiatry, vol. 26, no. 1, pp. 19–32, 2014.
View at: Google Scholar
F. A. Zarrouf, S. Artz, J. Griffith, C. Sirbu, and M. Kommor, “Testosterone and depression: systematic review and meta-analysis,” Journal of Psychiatric Practice, vol. 15, no. 4, pp. 289–305, 2009.
View at: Publisher Site | Google Scholar
D. P. Delev, D. P. Davcheva, I. D. Kostadinov, and I. I. Kostadinova, “Effect of testosterone propionate on erythropoiesis after experimental orchiectomy,” Folia Medica, vol. 55, no. 2, pp. 51–57, 2013.
View at: Publisher Site | Google Scholar
P. M. Tiidus, D. A. Lowe, and M. Brown, “Estrogen replacement and skeletal muscle: mechanisms and population health,” Journal of Applied Physiology, vol. 115, no. 5, pp. 569–578, 2013.
View at: Publisher Site | Google Scholar
S. M. Greising, K. A. Baltgalvis, D. A. Lowe, and G. L. Warren, “Hormone therapy and skeletal muscle strength: a meta-analysis,” The Journals of Gerontology Series A, Biological Sciences and Medical Sciences, vol. 64, no. 10, pp. 1071–1081, 2009.
View at: Publisher Site | Google Scholar
D. A. Lowe, K. A. Baltgalvis, and S. M. Greising, “Mechanisms behind estrogen's beneficial effect on muscle strength in females,” Exercise and Sport Sciences Reviews, vol. 38, no. 2, pp. 61–67, 2010.
View at: Publisher Site | Google Scholar
D. E. Jacobsen, M. M. Samson, S. Kezic, and H. J. J. Verhaar, “Postmenopausal HRT and tibolone in relation to muscle strength and body composition,” Maturitas, vol. 58, no. 1, pp. 7–18, 2007.
View at: Publisher Site | Google Scholar
P. H. A. Ronkainen, V. Kovanen, M. Alén et al., “Postmenopausal hormone replacement therapy modifies skeletal muscle composition and function: a study with monozygotic twin pairs,” Journal of Applied Physiology, vol. 107, no. 1, pp. 25–33, 2009.
View at: Publisher Site | Google Scholar
I. B. A. E. Meeuwsen, M. M. Samson, S. A. Duursma, and H. J. J. Verhaar, “Muscle strength and tibolone: a randomised, double-blind, placebo-controlled trial,” BJOG, vol. 109, no. 1, pp. 77–84, 2002.
View at: Publisher Site | Google Scholar
K. Brooke-Wavell, G. M. Prelevic, C. Bakridan, and J. Ginsburg, “Effects of physical activity and menopausal hormone replacement therapy on postural stability in postmenopausal women — a cross-sectional study,” Maturitas, vol. 37, no. 3, pp. 167–172, 2001.
View at: Publisher Site | Google Scholar
M. A. Boyanov and A. D. Shinkov, “Effects of tibolone on body composition in postmenopausal women: a 1-year follow up study,” Maturitas, vol. 51, no. 4, pp. 363–369, 2005.
View at: Publisher Site | Google Scholar
I. B. Meeuwsen, M. M. Samson, S. A. Duursma, and H. J. Verhaar, “The effect of tibolone on fat mass, fat-free mass, and total body water in postmenopausal women,” Endocrinology, vol. 142, no. 11, pp. 4813–4817, 2001.
View at: Publisher Site | Google Scholar
A. Arabi, P. Garnero, R. Porcher, C. Pelissier, C. L. Benhamou, and C. Roux, “Changes in body composition during post-menopausal hormone therapy: a 2 year prospective study,” Human Reproduction, vol. 18, no. 8, pp. 1747–1752, 2003.
View at: Publisher Site | Google Scholar
S. R. Cummings, B. Ettinger, P. D. Delmas et al., “The effects of tibolone in older postmenopausal women,” The New England Journal of Medicine, vol. 359, no. 7, pp. 697–708, 2008.
View at: Publisher Site | Google Scholar
S. Vaina, A. Milkas, C. Crysohoou, and C. Stefanadis, “Coronary artery disease in women: from the yentl syndrome to contemporary treatment,” World Journal of Cardiology, vol. 7, no. 1, pp. 10–18, 2015.
View at: Publisher Site | Google Scholar
C. N. B. Merz, “The Yentl syndrome is alive and well,” European Heart Journal, vol. 32, no. 11, pp. 1313–1315, 2011.
View at: Publisher Site | Google Scholar
A. Holdcroft, “Gender bias in research: how does it affect evidence based medicine?” Journal of the Royal Society of Medicine, vol. 100, no. 1, pp. 2-3, 2007.
View at: Publisher Site | Google Scholar
C. Bartlett, L. Doyal, S. Ebrahim et al., “The causes and effects of socio-demographic exclusions from clinical trials,” Health Technol Assess, vol. 9, no. 38, 2005.
View at: Publisher Site | Google Scholar
I. Beierle, B. Meibohm, and H. Derendorf, “Gender differences in pharmacokinetics and pharmacodynamics,” International Journal of Clinical Pharmacology and Therapeutics, vol. 37, no. 11, pp. 529–547, 1999.
View at: Google Scholar
O. P. Soldin and D. R. Mattison, “Sex differences in pharmacokinetics and pharmacodynamics,” Clinical Pharmacokinetics, vol. 48, no. 3, pp. 143–157, 2009.
View at: Publisher Site | Google Scholar
B. Meibohm, I. Beierle, and H. Derendorf, “How important are gender differences in pharmacokinetics?” Clinical Pharmacokinetics, vol. 41, no. 5, pp. 329–342, 2002.
View at: Publisher Site | Google Scholar
V. Benz, U. Kintscher, and A. Foryst-Ludwig, “Sex-specific differences in type 2 diabetes mellitus and dyslipidemia therapy: PPAR agonists,” in Sex and Gender Differences in Pharmacology. Handbook of Experimental Pharmacology, vol 214, V. Regitz-Zagrosek, Ed., Springer, Berlin, Heidelberg.
View at: Publisher Site | Google Scholar
A. U. Mishuk, J. Qian, J. N. Howard et al., “The association between patient sociodemographic characteristics and generic drug use: a systematic review and meta-analysis,” Journal of Managed Care & Specialty Pharmacy, vol. 24, no. 3, pp. 252–264, 2018.
View at: Publisher Site | Google Scholar
N. A. Mazer, “Interaction of estrogen therapy and thyroid hormone replacement in postmenopausal women,” Thyroid, vol. 14, Supplement 1, pp. 27–34, 2004.
View at: Publisher Site | Google Scholar
F. Mauvais-Jarvis, D. J. Clegg, and A. L. Hevener, “The role of estrogens in control of energy balance and glucose homeostasis,” Endocrine Reviews, vol. 34, no. 3, pp. 309–338, 2013.
View at: Publisher Site | Google Scholar
B. Lunenfeld, G. Mskhalaya, M. Zitzmann et al., “Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men,” The Aging Male, vol. 18, no. 1, pp. 5–15, 2015.
View at: Publisher Site | Google Scholar
E. P. Praveen, M. L. Khurana, B. Kulshreshtha et al., “Plasma testosterone in adult normoglycaemic men: impact of hyperinsulinaemia,” Andrologia, vol. 44, no. 5, pp. 293–298, 2012.
View at: Publisher Site | Google Scholar
X. Cai, Y. Tian, T. Wu, C. X. Cao, H. Li, and K. J. Wang, “Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials,” Asian Journal of Andrology, vol. 16, no. 1, pp. 146–152, 2014.
View at: Publisher Site | Google Scholar
G. Tirabassi, N. delli Muti, A. Gioia, A. Biagioli, A. Lenzi, and G. Balercia, “Effects of testosterone replacement therapy on bone metabolism in male post-surgical hypogonadotropic hypogonadism: focus on the role of androgen receptor CAG polymorphism,” Journal of Endocrinological Investigation, vol. 37, no. 4, pp. 393–400, 2014.
View at: Publisher Site | Google Scholar
F. Oury, “A crosstalk between bone and gonads,” Annals of the New York Academy of Sciences, vol. 1260, no. 1, pp. 1–7, 2012.
View at: Publisher Site | Google Scholar
A. Aversa, R. Bruzziches, D. Francomano et al., “Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study,” The Aging Male, vol. 15, no. 2, pp. 96–102, 2012.
View at: Publisher Site | Google Scholar
P. Sgrò, M. Sansone, A. Sansone, F. Romanelli, and L. di Luigi, “Effects of erythropoietin abuse on exercise performance,” The Physician and Sportsmedicine, vol. 46, no. 1, pp. 105–115, 2018.
View at: Publisher Site | Google Scholar
S. H. Ballal, D. T. Dornoto, D. C. Polack, P. Marciulonis, and K. J. Martin, “Androgens potentiate the effects of erythropoietin in the treatment of anemia of end-stage renal disease,” American Journal of Kidney Diseases, vol. 17, no. 1, pp. 29–33, 1991.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2018 R. Lauretta et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

15581

Downloads

1840

Citations

International Journal of Endocrinology

Gender in Endocrine Diseases: Role of Sex Gonadal Hormones

Abstract

1. Sex Hormones in Endocrine Gender-Related Differences

1.1. Introduction

1.2. Gender-Related Differences in the Endocrine System

1.3. Gender-Related Differences in Thyroid Disease

1.4. Gender-Related Differences and Diabetes Mellitus

1.5. Gender-Related Differences and Osteoporosis

1.6. Gender-Related Differences and the Growth Hormone/Insulin Growth Factor 1 Axis

1.7. Gender-Related Differences and Obesity

1.8. Gender-Related Differences in Sarcopenia

1.9. Gender-Related Differences in Drug Response

2. Conclusions

Conflicts of Interest

References

Copyright