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This report is written by MaltSci based on the latest literature and research findings

How do sex hormones influence disease risk? ​

Abstract ​

Sex hormones, including estrogens, androgens, and progesterone, are crucial regulators of various physiological processes and significantly impact disease susceptibility. This review examines how fluctuations in sex hormones influence health issues such as cardiovascular diseases, autoimmune disorders, and cancers, emphasizing the importance of gender differences in disease risk. Research highlights that estrogens can protect against cardiovascular diseases in premenopausal women, while androgens have a dual role in men, potentially increasing heart disease risk. Additionally, sex hormones modulate immune responses, with estrogens enhancing immune activity and androgens exhibiting immunosuppressive effects, which contribute to the higher prevalence of autoimmune diseases in women. In cancer, elevated levels of estrogens and androgens are associated with increased breast and prostate cancer risks, respectively. Hormonal therapies present both benefits and risks, necessitating a tailored approach based on individual patient profiles. Understanding the complex interactions between sex hormones and disease mechanisms is vital for developing effective, gender-specific prevention and treatment strategies. This review underscores the need for incorporating sex differences into biomedical research to improve health outcomes for diverse populations.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Overview of Sex Hormones
    • 2.1 Types of Sex Hormones
    • 2.2 Hormonal Regulation Mechanisms
  • 3 Sex Hormones and Cardiovascular Disease
    • 3.1 Estrogens and Cardiovascular Health
    • 3.2 Androgens and Heart Disease Risk
  • 4 Sex Hormones and Cancer Risk
    • 4.1 Hormonal Influence on Breast Cancer
    • 4.2 Role of Androgens in Prostate Cancer
  • 5 Sex Hormones and Autoimmune Diseases
    • 5.1 Gender Differences in Autoimmunity
    • 5.2 Hormonal Modulation of Immune Responses
  • 6 Implications for Hormonal Therapy
    • 6.1 Benefits and Risks of Hormonal Replacement Therapy
    • 6.2 Gender-Specific Treatment Approaches
  • 7 Summary

1 Introduction ​

Sex hormones, encompassing estrogens, androgens, and progesterone, are pivotal in regulating a multitude of physiological processes beyond their well-established roles in reproduction. These hormones significantly influence metabolic, cardiovascular, and immune systems, which are integral to disease susceptibility and overall health. The intricate interplay between sex hormones and various health conditions raises critical questions about their contributions to disease risk, particularly in the context of gender differences. This review seeks to elucidate how fluctuations and imbalances in sex hormones can predispose individuals to a range of health issues, including cardiovascular diseases, autoimmune disorders, and cancers. A comprehensive understanding of these relationships is essential for the development of gender-specific prevention strategies and therapeutic interventions.

Research in this area has gained momentum over the past few decades, revealing complex mechanisms by which sex hormones modulate disease pathways. For instance, estrogens have been shown to confer protective effects against cardiovascular diseases in premenopausal women, while androgens play a dual role in influencing heart disease risk in men [1][2]. Furthermore, the immune-modulating effects of sex hormones are well-documented, with estrogens generally enhancing immune responses and androgens exhibiting immunosuppressive properties [3][4]. These hormonal influences extend to various conditions, including autoimmune diseases, where sex differences in incidence and severity are evident [5][6].

Despite the growing body of evidence, significant gaps remain in our understanding of how sex hormones interact with disease mechanisms. Current literature highlights the need for more nuanced approaches to studying these relationships, particularly considering the varying effects of hormonal therapy across different populations [7][8]. As such, this review will systematically explore the following areas: (1) an overview of sex hormones, including their types and regulatory mechanisms; (2) the relationship between sex hormones and cardiovascular disease, focusing on estrogens and androgens; (3) the influence of sex hormones on cancer risk, particularly breast and prostate cancers; (4) the role of sex hormones in autoimmune diseases and the gender differences observed in these conditions; (5) the implications of hormonal therapy, including its benefits and risks, and the necessity for gender-specific treatment approaches; and (6) a summary of the key findings and their implications for future research and clinical practice.

The investigation of sex hormones in the context of disease risk is not merely an academic exercise; it holds profound implications for public health and clinical outcomes. By synthesizing current research findings, this report aims to underscore the necessity of incorporating sex differences into biomedical research and clinical practice, ultimately contributing to improved health outcomes for diverse populations. As we navigate through the complexities of hormonal influences on health, it becomes increasingly clear that a gendered lens is essential for advancing our understanding of disease mechanisms and enhancing therapeutic strategies.

2 Overview of Sex Hormones ​

2.1 Types of Sex Hormones ​

Sex hormones, including estrogens, progesterone, and androgens, play a critical role in influencing disease risk through their complex interactions with the immune system, metabolic pathways, and susceptibility to various diseases. These hormones are synthesized primarily in the gonads and exhibit significant effects on health and disease processes, often resulting in sex-specific disease prevalence and outcomes.

Estrogens, which are primarily female sex hormones, have been shown to enhance immune responses. For instance, they stimulate both antibody production and cellular immune responses, leading to a generally more vigorous immune reaction in females compared to males. This increased immune responsiveness is associated with a higher incidence of autoimmune diseases in women, as estrogens can promote B cell activation and autoantibody production, potentially contributing to conditions like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) [9][10]. Additionally, estrogen's influence varies with the reproductive status of women, suggesting that hormonal fluctuations can impact disease risk at different life stages [5].

On the other hand, androgens, which include testosterone, typically exert immunosuppressive effects. They are associated with reduced immune responses and a lower incidence of autoimmune diseases in males compared to females. Androgens can suppress T cell and B cell activities, which may explain the lower prevalence of autoimmune conditions among men [3][4]. The balance between androgens and estrogens can significantly affect disease expression, with the interplay of these hormones influencing susceptibility to various conditions.

Progesterone, another key hormone, also has immunomodulatory effects, particularly in the context of pregnancy, where it helps to maintain a tolerant immune environment. Its role in autoimmunity is complex, as it may counteract some of the effects of estrogens, potentially reducing the risk of autoimmune diseases in certain contexts [10].

The relationship between sex hormones and metabolic syndrome (MetS) further illustrates their influence on disease risk. High levels of testosterone and low levels of estrogen have been linked to increased risks of MetS and type 2 diabetes in women. Conditions such as polycystic ovary syndrome, which is characterized by hormonal imbalances, are also associated with higher insulin resistance and increased risk for MetS [11].

In infectious diseases, sex hormones can modulate susceptibility and severity. For example, during viral infections like COVID-19, sex hormones have been implicated in the regulation of viral receptors and immune responses, leading to observed gender differences in disease severity and outcomes [12][13]. Hormonal levels can also influence the response to vaccinations, with females often demonstrating stronger humoral responses compared to males [14].

In summary, sex hormones are pivotal in determining disease risk through their diverse effects on the immune system, metabolic health, and susceptibility to infections. The complex interplay between these hormones, alongside genetic and environmental factors, contributes to the observed sexual dimorphism in various diseases. Understanding these mechanisms is crucial for developing targeted therapies and preventive strategies that consider sex differences in health and disease.

2.2 Hormonal Regulation Mechanisms ​

Sex hormones play a critical role in influencing disease risk through various hormonal regulation mechanisms, significantly impacting immune responses, metabolic processes, and the development of certain diseases. The interplay between sex hormones and the immune system results in notable differences in disease susceptibility and progression between genders.

Studies indicate that sex hormones, such as estrogens and androgens, exert profound effects on immune function. For instance, females typically exhibit higher immunoglobulin levels and stronger immune responses following immunization or infection compared to males. This heightened immune responsiveness is associated with a greater susceptibility to autoimmune diseases in females, which may be attributed to the effects of estrogen that induce polyclonal B cell activation and increase the expression of autoantibodies [9].

In the context of autoimmune diseases, sex hormones can modulate disease expression through their immunomodulatory effects. Estrogens are known to enhance antibody production and aggravate B cell-dependent diseases, while androgens generally suppress both T-cell and B-cell immune responses, resulting in a reduced expression of autoimmune diseases [3]. The differential responses observed in males and females can be partly explained by the influence of sex hormones on cytokine secretion and immune cell activity, where altered levels of sex hormones in autoimmune patients may contribute to a skewed cytokine milieu [4].

Moreover, the interaction between sex hormones and epigenetic mechanisms also plays a significant role in disease manifestation. Sex hormones can induce epigenetic modifications that influence gene expression in immune cells, thereby shaping the immune response and contributing to sex-specific disease risks [15]. For example, the presence of sex-specific hormones can affect the expression of immune-related genes encoded on sex chromosomes, leading to differences in disease incidence and severity [16].

In addition to autoimmune diseases, sex hormones are implicated in the risk and progression of cardiovascular diseases. Estrogens and androgens have been shown to influence blood pressure regulation, vascular function, and the development of atherosclerosis [17]. The modulation of cardiovascular health by sex hormones can vary across the lifespan, with hormonal changes influencing the risk factors associated with cardiovascular diseases [18].

The hormonal regulation mechanisms also extend to metabolic processes, where sex hormones can influence body composition and fat distribution, contributing to conditions such as obesity, which is a known risk factor for various diseases [12]. In particular, androgens are associated with the development of visceral obesity, which can lead to severe complications, including thrombosis [12].

Overall, the influence of sex hormones on disease risk is multifaceted, involving direct immunological effects, epigenetic regulation, and metabolic alterations. Understanding these mechanisms is crucial for developing targeted therapeutic strategies and improving disease management across genders.

3 Sex Hormones and Cardiovascular Disease ​

3.1 Estrogens and Cardiovascular Health ​

Sex hormones, particularly estrogens, play a significant role in influencing cardiovascular health and disease risk. The relationship between sex hormones and cardiovascular disease (CVD) is complex and involves multiple mechanisms that vary between men and women.

Estrogens have been shown to have cardioprotective effects. In women, the incidence of cardiovascular disease is generally lower than in men until menopause, after which the risk increases significantly. This increase is thought to be related to the decline in estrogen levels, which have been linked to beneficial effects on lipid metabolism, vascular function, and inflammation [2].

The protective role of estrogens is evidenced by their influence on the development of atherosclerosis, which is a major contributor to CVD. Estrogens are believed to improve endothelial function, reduce oxidative stress, and inhibit the inflammatory processes that lead to atherosclerosis [19]. Moreover, hormone replacement therapy in postmenopausal women has shown mixed results, with some studies suggesting potential cardiovascular benefits when initiated at an appropriate time [19].

Conversely, higher levels of testosterone in men have been associated with an increased risk of cardiovascular disease. Testosterone may promote cardiovascular calcification and atherosclerosis, potentially due to its effects on lipid profiles and vascular health [20]. Furthermore, a study indicated that a higher testosterone to estradiol ratio in post-menopausal women is linked to an elevated risk of cardiovascular events, suggesting that the balance of these hormones is crucial for cardiovascular health [21].

The influence of sex hormones extends beyond direct effects on cardiovascular tissues; they also interact with other risk factors such as insulin sensitivity and body fat distribution. For instance, lower levels of sex hormone-binding globulin (SHBG) in postmenopausal women have been associated with adverse lipid profiles and increased insulin resistance, further elevating cardiovascular risk [22].

Moreover, the gender differences in cardiovascular disease susceptibility may also be attributed to genetic and environmental factors that interact with sex hormone levels. For example, the impact of sex chromosomes and gonadal hormones on cardiovascular risk factors and disease progression has been highlighted, indicating that both biological sex and gender play critical roles in cardiovascular health [23].

In summary, estrogens contribute positively to cardiovascular health, particularly in premenopausal women, while higher testosterone levels in men may be detrimental. The balance and interaction of these hormones are essential in understanding the risk of cardiovascular disease, and further research is needed to elucidate the underlying mechanisms and to develop effective interventions targeting these hormonal pathways.

3.2 Androgens and Heart Disease Risk ​

Sex hormones, particularly androgens and estrogens, significantly influence cardiovascular disease (CVD) risk through various mechanisms that are often gender-specific. Research indicates that the incidence of cardiovascular disease is sexually dimorphic, with men generally exhibiting higher rates of CVD compared to women until post-menopause, when women's risk increases markedly. This pattern suggests that sex hormones play a critical role in mediating cardiovascular health.

Androgens, which are male sex hormones such as testosterone, have been shown to exert various biological effects on cardiovascular function. They are involved in the transcriptional regulation of genes in multiple target organs, including the cardiovascular system. However, the exact influence of androgens on cardiovascular health is complex and not fully elucidated. Some studies indicate that androgens may have a cardioprotective effect, particularly in men, where lower levels of testosterone are associated with increased rates of cardiovascular disease [24]. This correlation raises the hypothesis that testosterone could potentially serve as a protective factor against CVD.

In women, the effects of androgens are also notable, especially in conditions such as polycystic ovary syndrome (PCOS), where excess androgens are linked to increased cardiovascular risk factors, including hypertension and dyslipidemia [25]. The impact of testosterone on female vascular health remains an emerging area of study, indicating that androgens may contribute to cardiovascular pathology independently of other risk factors [25].

Estrogens, on the other hand, are well-recognized for their protective effects against cardiovascular disease in premenopausal women. They influence vascular function, promote endothelial health, and help maintain a favorable lipid profile [2]. However, the protective effects of estrogens may diminish after menopause, leading to increased cardiovascular risk [2]. The timing of hormone replacement therapy in postmenopausal women is critical, as initiating therapy later may paradoxically increase cardiovascular risk [19].

The interaction between androgens and estrogens is also significant in understanding cardiovascular disease risk. Studies suggest that the relative levels and ratios of these hormones may be more critical than their absolute levels alone. For instance, both high and low levels of endogenous androgens in women have been associated with cardiovascular disease, underscoring the need to consider hormonal balance [24].

Furthermore, androgens have been linked to both acute and chronic effects on the cardiovascular system. While they may promote vasodilation and improve vascular reactivity acutely, chronic exposure to high androgen levels can lead to adverse outcomes, including increased blood pressure [26]. This duality of effect necessitates a nuanced understanding of how androgens are administered and their potential long-term implications on cardiovascular health.

In summary, sex hormones significantly influence cardiovascular disease risk through a variety of mechanisms, including direct effects on vascular function, modulation of risk factors, and the interplay between different hormones. Understanding these relationships is crucial for developing targeted therapies and preventive strategies in both men and women, especially considering the distinct physiological roles that androgens and estrogens play in cardiovascular health. Further research is warranted to clarify these complex interactions and to guide clinical practices regarding hormone therapies and cardiovascular disease management.

4 Sex Hormones and Cancer Risk ​

4.1 Hormonal Influence on Breast Cancer ​

Sex hormones, particularly estrogens and androgens, have been extensively studied for their roles in influencing breast cancer risk, especially in postmenopausal women. The relationship between circulating levels of these hormones and breast cancer has been established through various epidemiological studies, indicating a significant positive association.

In a nested case-control study involving 265 postmenopausal women diagnosed with breast cancer and 541 controls, it was found that women in the top quintile of individual estrogen or androgen levels had approximately a doubling of breast cancer risk compared to those in the bottom quintile. Specifically, having seven or eight hormones above the age- and batch-adjusted geometric mean was associated with a relative risk (RR) of 2.7 for total breast cancer and 3.4 for estrogen receptor (ER)-positive breast cancer (Tworoger et al., 2011) [27]. This highlights that elevated levels of multiple hormones significantly increase the risk of breast cancer, particularly ER-positive types.

Another study within the Multiethnic Cohort examined the association of sex hormones with breast cancer risk across diverse ethnicities. This study reported that elevated levels of estradiol (E2) and testosterone were positively associated with breast cancer risk, with an odds ratio (OR) of 2.26 for a doubling of E2 levels (Woolcott et al., 2010) [28]. The findings were consistent across different ethnic groups, suggesting that the association is generalizable beyond specific populations.

Furthermore, a reanalysis of nine prospective studies indicated that increasing concentrations of endogenous sex hormones, including total estradiol and testosterone, were significantly associated with an increased risk of breast cancer in postmenopausal women. For instance, the relative risks for women with increasing quintiles of estradiol were found to be statistically significant, with the highest quintile showing an RR of 2.00 (Key et al., 2002) [29].

In addition to estrogens, androgens also play a role in breast cancer risk. A case-control study indicated that testosterone levels were associated with an increased risk of breast cancer, although the association diminished when adjusted for estrogen levels, suggesting that androgens may influence breast cancer risk primarily through their conversion to estrogens (Zeleniuch-Jacquotte et al., 2004) [30].

The hormonal environment, influenced by factors such as body mass index, lifestyle, and genetic predispositions, is critical in modulating breast cancer risk. For example, higher levels of sex hormone-binding globulin (SHBG) were inversely associated with breast cancer risk, further complicating the relationship between sex hormones and cancer (Hankinson & Eliassen, 2010) [31].

In conclusion, sex hormones significantly influence breast cancer risk, with elevated levels of estrogens and androgens correlating with increased incidence, particularly in postmenopausal women. The evidence suggests that multiple hormones interact in complex ways to modulate cancer risk, underscoring the need for further research to explore these relationships and develop risk prediction models that incorporate hormonal levels.

4.2 Role of Androgens in Prostate Cancer ​

Sex hormones, particularly androgens, play a significant role in the pathogenesis of prostate cancer. Numerous studies have explored the complex relationship between circulating sex hormone levels and the risk of developing prostate cancer, yielding varying and sometimes contradictory results.

A nested case-control study conducted by Sawada et al. (2010) examined the association between plasma concentrations of testosterone and sex hormone-binding globulin (SHBG) with prostate cancer risk among Japanese men. The study found no overall association between the plasma levels of total testosterone, free testosterone, or SHBG and the risk of total prostate cancer. Specifically, the odds ratios for the highest versus lowest groups were 0.71 (95% CI = 0.36-1.41, Ptrend = 0.43) for total testosterone, 0.70 (95% CI = 0.39-1.27, Ptrend = 0.08) for free testosterone, and 1.38 (95% CI = 0.69-2.77, Ptrend = 0.23) for SHBG. However, when stratified by factors such as cancer stage, age, body mass index (BMI), and plasma isoflavone levels, free testosterone was inversely associated with localized cancers and equol producers, while SHBG was linked to an increased risk of prostate cancer in younger men [32].

Further investigations, such as the study by Travis et al. (2009), analyzed genetic variations in the CYP19A1 gene concerning prostate cancer risk and circulating sex hormone concentrations. The study found that while several haplotype-tagging single nucleotide polymorphisms (htSNPs) in the CYP19A1 locus were associated with measurable differences in estradiol concentrations, they did not significantly influence the risk of prostate cancer [33].

Gann et al. (1996) conducted a prospective nested case-control study within the Physicians' Health Study, which reported that high levels of circulating testosterone and low levels of SHBG were associated with increased risks of prostate cancer. Specifically, the odds ratios by quartile for testosterone were 1.00, 1.41, 1.98, and 2.60 (95% CI = 1.34-5.02; P for trend = .004), indicating a strong trend of increasing prostate cancer risk with higher testosterone levels. Conversely, a non-linear inverse association was found with increasing levels of estradiol [34].

In a more recent study by Black et al. (2014), the balance between estrogen and androgen levels was emphasized as a crucial factor in the development of aggressive prostate cancer. The study found that a strong inverse association existed between the estradiol:testosterone ratio and the risk of aggressive prostate cancer, indicating that a higher estrogen-to-androgen ratio might be protective against the disease [35].

Overall, while androgens, particularly testosterone, have been implicated in prostate cancer progression, the evidence regarding their role is complex. Some studies suggest that high testosterone levels may increase risk, particularly in younger men or in cases of aggressive disease, while others indicate a potential protective effect or no significant association at all. The role of SHBG also complicates the relationship, as its levels appear to inversely correlate with prostate cancer risk in certain contexts. As research continues, understanding the nuanced interactions between androgens, estrogens, and their binding proteins will be essential for elucidating their roles in prostate cancer risk and for developing targeted therapeutic strategies.

5 Sex Hormones and Autoimmune Diseases ​

5.1 Gender Differences in Autoimmunity ​

Sex hormones significantly influence the risk and manifestation of autoimmune diseases, with notable gender differences observed in prevalence, clinical presentation, and outcomes. A clear female predominance is documented in many autoimmune conditions, which is believed to be influenced by various factors, including sex hormones and genetic predispositions.

Autoimmunity is affected by sex hormones, with females exhibiting higher levels of immunoglobulins and stronger immune responses compared to males. This enhanced immune responsiveness in females is associated with a greater susceptibility to autoimmune diseases, as highlighted by Nussinovitch and Shoenfeld (2012), who noted that sex hormones might affect the vulnerability of target organs to autoimmune responses and influence the clinical presentation and progression of diseases such as multiple sclerosis and Crohn's disease[36].

Androgens, such as testosterone, have been shown to exert immunosuppressive effects, dampening immune responses and thereby potentially reducing the incidence and severity of autoimmune diseases. For instance, Gubbels Bupp and Jorgensen (2018) discussed how androgens modulate immune cell activities and affect the expression of functional androgen receptors, which may alter immune responses and disease progression in systemic autoimmune disorders[4]. Conversely, estrogens tend to enhance humoral immunity and have been implicated in the exacerbation of certain autoimmune diseases, as seen in systemic lupus erythematosus (SLE) and rheumatoid arthritis[10].

The interaction between sex hormones and the immune system is complex. Estrogens have been found to increase the risk of autoimmune diseases by influencing key immune pathways, including the type 1 interferon response and the differentiation of T helper cells[10]. Moreover, variations in hormone levels throughout different life stages, such as during pregnancy or menopause, can further impact the immune response and disease risk. For example, changes in estrogen levels during pregnancy have been associated with alterations in the clinical phenotypes of autoimmune diseases[37].

In addition to hormonal influences, genetic factors, such as skewed X chromosome inactivation and sex-biased microRNAs, also play a critical role in shaping immune responses and disease susceptibility. Kim et al. (2025) emphasized the importance of understanding these genetic and hormonal interactions, which contribute to the heightened risk and distinct clinical features of autoimmune diseases in females[38].

Overall, the interplay between sex hormones and the immune system not only elucidates the mechanisms underlying gender differences in autoimmunity but also highlights potential therapeutic avenues. Understanding how these hormones modulate immune function could lead to the development of sex-specific diagnostic and treatment strategies for autoimmune diseases. Further research is necessary to clarify the intricate relationships between sex hormones, immune regulation, and autoimmune disease pathogenesis.

5.2 Hormonal Modulation of Immune Responses ​

Sex hormones play a critical role in modulating immune responses and influencing the risk of autoimmune diseases. The influence of these hormones is characterized by a clear gender dimorphism, with significant implications for disease susceptibility, clinical manifestations, and disease progression.

In autoimmune diseases, a notable female predominance is observed, which is believed to be associated with the effects of sex hormones. For instance, estrogen has been shown to enhance humoral immunity and increase antibody production, which may exacerbate autoimmune conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) (Hughes & Choubey, 2014). Estrogen affects key immune pathways, including the type 1 interferon response and the differentiation and survival of autoreactive B cells, thereby increasing disease risk in genetically predisposed women (Hughes & Choubey, 2014). Conversely, progesterone appears to have a protective role, counteracting some of the effects of estrogen and potentially reducing the risk of SLE (Hughes & Choubey, 2014).

Androgens, on the other hand, are associated with immunosuppressive effects. They generally suppress both T-cell and B-cell immune responses, leading to a reduced expression of autoimmune diseases (Da Silva, 1999). The interaction between androgens and immune cells suggests that these hormones can temper inflammatory responses, thereby altering the incidence and progression of autoimmune diseases (Gubbels Bupp & Jorgensen, 2018).

The modulation of immune responses by sex hormones also involves alterations in cytokine production. For example, sex hormones influence the secretion of cytokines and the activity of cytokine-secreting cells, which can contribute to the skewed cytokine milieu often observed in autoimmune patients (Verthelyi, 2001). Furthermore, hormonal fluctuations, such as those occurring during pregnancy or menopause, can lead to changes in immune function and disease activity, emphasizing the dynamic nature of hormonal influence on autoimmunity (Selmi & Gershwin, 2019).

Additionally, sex chromosome factors, such as skewed X chromosome inactivation and the presence of a single X chromosome in females, have been implicated in the heightened susceptibility to autoimmune diseases (Kim et al., 2025). These genetic factors, combined with the immunomodulatory effects of sex hormones, create a complex interplay that shapes the immune landscape in both sexes.

In summary, sex hormones significantly influence disease risk and the immune response through their effects on immune cell activity, cytokine production, and the modulation of specific immune pathways. The differential effects of estrogens, progesterone, and androgens highlight the importance of understanding hormonal influences in the context of autoimmune diseases, which may lead to novel therapeutic strategies tailored to the unique needs of different patient populations.

6 Implications for Hormonal Therapy ​

6.1 Benefits and Risks of Hormonal Replacement Therapy ​

Sex hormones significantly influence disease risk, particularly in the context of menopausal hormone replacement therapy (HRT). The assessment of risks and benefits associated with HRT is complex, as highlighted by multiple studies.

HRT, which includes both estrogen plus progestin therapy (OPT) and estrogen-only therapy (OT), is linked to various health outcomes. One of the primary concerns regarding HRT is its association with breast cancer and cardiovascular health. Research indicates that there is a slight increase in breast cancer incidence among women using HRT compared to those receiving placebo [39]. Furthermore, HRT has been shown to influence cardiovascular health, with evidence suggesting an increase in stroke and venous thromboembolism (VTE), although some studies also point to a potential cardioprotective effect [39].

In terms of benefits, HRT provides significant relief from menopausal symptoms, including vasomotor instability, sexual dysfunction, mood disturbances, fatigue, and skin issues. Additionally, HRT has been associated with a decrease in fracture risk [39]. Decision analyses indicate that HRT can increase life expectancy for most postmenopausal women, particularly those with risk factors for coronary heart disease (CHD) [40]. Specifically, for women with at least one risk factor for CHD, the benefits of HRT in reducing the likelihood of developing CHD may outweigh the associated risks of breast cancer [40].

However, the decision to initiate HRT should be personalized, considering individual risk profiles. For instance, women without risk factors for CHD or hip fractures but with a family history of breast cancer may not benefit from HRT [40]. The risks associated with HRT, including thrombotic events and certain cancers, necessitate careful consideration and a tailored approach [41].

Furthermore, the role of sex hormones in chronic respiratory diseases has also garnered attention. Limited research suggests that hormonal changes during the menopausal transition may impact pulmonary function and the severity of respiratory diseases [42]. The need for personalized HRT based on individual hormone levels is emphasized, potentially facilitated by artificial intelligence-driven platforms for accurate monitoring [42].

In conclusion, the influence of sex hormones on disease risk is multifaceted, with HRT presenting both significant benefits and risks. Ongoing research and a nuanced understanding of individual health profiles are crucial for optimizing HRT use in postmenopausal women, balancing the alleviation of menopausal symptoms and the potential long-term health implications.

6.2 Gender-Specific Treatment Approaches ​

Sex hormones play a critical role in modulating disease risk across various conditions, particularly autoimmune diseases, cardiovascular diseases, and cancer. Their influence is not only determined by hormonal levels but also by the biological sex of the individual, leading to gender-specific treatment approaches.

In autoimmune diseases, such as multiple sclerosis (MS), there is a well-documented female predominance, with women exhibiting a higher prevalence and generally better prognosis compared to men. This disparity may be attributed to the effects of sex hormones on the immune system, blood-brain barrier, and central nervous system cells. For instance, both clinical and experimental studies suggest that sex steroid supplementation could be beneficial for MS, potentially due to anti-inflammatory actions on the immune system and direct neuroprotective properties (Nicot 2009) [43]. Furthermore, the dynamics of sex hormones, such as estrogen and progesterone, can significantly influence disease activity and progression, particularly during reproductive phases such as pregnancy and menopause (Murgia et al. 2022) [44].

The modulation of the immune response by sex hormones is also evident in other autoimmune conditions. For example, estrogen appears to increase the risk of diseases like systemic lupus erythematosus (SLE) by enhancing immune responses, while progesterone may mitigate these effects (Hughes & Choubey 2014) [10]. This interplay highlights the importance of understanding hormonal influences in disease management and the potential therapeutic applications of hormone-based treatments.

In cardiovascular health, gender differences are prominent, with men typically experiencing a higher incidence of cardiovascular diseases compared to women, particularly before menopause. After menopause, women's cardiovascular risk increases, which has been linked to the decline in estrogen levels (Vitale et al. 2009) [19]. Hormone replacement therapy (HRT) has been explored as a preventive strategy; however, its effects can vary significantly depending on the timing of initiation and the specific hormonal regimens used. Evidence suggests that estrogens may have protective cardiovascular effects when administered early post-menopause, while late initiation could increase risks (Vitale et al. 2009) [19].

In the context of cancer, sex hormones influence the progression and treatment outcomes of hormone-sensitive cancers such as breast and prostate cancer. Estrogens, for instance, play a pivotal role in breast cancer development, and the response to therapies like tamoxifen can differ based on hormonal status (Bakhshi et al. 2024) [45]. Gender-affirming hormone therapy in transgender individuals also presents unique considerations; for example, transgender women receiving estrogen therapy may have altered breast cancer risk profiles, necessitating careful monitoring and individualized treatment plans (Berliere et al. 2022) [46].

Given these complexities, there is a pressing need for gender-specific treatment approaches that consider the differential effects of sex hormones on disease risk and progression. Future research should aim to include gender-diverse populations to enhance our understanding of these interactions and improve therapeutic strategies. This will facilitate the development of personalized medicine approaches that optimize treatment efficacy while minimizing risks associated with hormonal therapies across different genders and conditions (Nesbitt et al. 2025) [47].

In conclusion, the influence of sex hormones on disease risk underscores the necessity for tailored treatment strategies that account for gender-specific biological differences. Continued research into the interplay between sex hormones and disease processes is essential for advancing healthcare outcomes for all individuals.

7 Conclusion ​

The exploration of sex hormones and their influence on disease risk has revealed significant findings that underscore the complexity of hormonal interactions with various health conditions. Notably, sex hormones such as estrogens and androgens play crucial roles in modulating immune responses, cardiovascular health, cancer susceptibility, and autoimmune disease prevalence. The observed gender differences in disease incidence and progression highlight the need for a gender-specific approach in both research and clinical practice. Current research indicates that while estrogens generally confer protective effects against cardiovascular diseases in premenopausal women, androgens may increase cardiovascular risks in men. Additionally, the relationship between sex hormones and cancer risk is intricate, with elevated hormone levels linked to increased incidence of hormone-sensitive cancers like breast and prostate cancer. The impact of hormonal therapy further complicates these dynamics, necessitating personalized treatment strategies that consider individual hormonal profiles and health risks. Future research should focus on elucidating the mechanisms underlying these relationships and developing targeted interventions that incorporate gender differences to improve health outcomes across diverse populations. By advancing our understanding of sex hormones in the context of disease, we can foster more effective prevention and treatment strategies tailored to the unique needs of men and women.

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