Androgens are a Key Factor Affecting Immune Related Diseases.

INTRODUCTION
In 2021, Science released 125 new scientific questions to celebrate the 125th anniversary of the founding of Shanghai Jiao Tong University. One of the questions is 'How is immune homeostasis maintained and regulated?' Despite numerous studies, many challenges urgently need to be solved. In 2024, Chi et al [1] published a study in Science proposing that the androgen-type 2 innate lymphoid cells (ILC2s)-dendritic cell axis mediates gender differences in skin immunity. Androgens, vital sex steroid hormones for both sexes, may be important mediators of immune homeostasis and require more attention. Androgens bind to androgen receptors (AR) to form complexes, which are transported into the nucleus to regulate target gene expression or target plasma membrane receptors and proteins, stimulating kinase cascades to produce rapid responses and affecting cell proliferation and survival, and occupy a core position in maintaining male and female physiological health and in the development of diseases [23456].
Androgens affect the number and vitality of immune cells, having a significant impact on immune function [7]. The disorders of immune defense, immune homeostasis, and immune monitoring lead to external infections such as bacteria and viruses, allergic diseases, as well as malignant diseases such as tumors [89]. Androgens seem to regulate immune function and affect the occurrence and development of immune related diseases. Androgens bind to receptors to activate downstream pathways and gene expression, which can inhibit physiological processes such as proliferation, maturation, and cytokine secretion of neutrophils, natural killer (NK) cells, monocytes/macrophages, and lymphocytes [7]. Androgen has a two-way effect on the inhibition of immune cell function, such as promoting the growth of male bladder cancer, prostate cancer (PCa) and liver metastasis, but also preventing the susceptibility of male allergic diseases. However, because the androgen level and androgen signal pathway in women are far lower than those in men, the susceptibility to diseases is also opposite [7]. One of the characteristics of polycystic ovary syndrome (PCOS) is the increase of androgens in the female body, which leads to changes in immune cells. For example, Kwon et al [10] demonstrated that androgens activated transcription factor 7 (Tcf7)/TCF1 signaling, promoting the depletion of CD8+T cells within tumors, while the inhibition of androgen-AR promoted the differentiation of effector T cells and enhanced the efficacy of anti-programmed death receptor 1 (anti-PD-1) immune checkpoint blockade (ICB). Torstensson et al [11] demonstrated that hyperandrogenism can lead to a decrease in eosinophils, an increase in NK cells, and tissue-specific changes in macrophages in reproductive organs and visceral adipose tissue, which may result in reduced fertility in female mice and metabolic complications associated with PCOS. Another manifestation of androgen suppression of immune function is the promotion of the production and activity of inhibitory immune cells. Androgens increased the content of anti-inflammatory macrophages in mouse lungs and reduced lung inflammation [12]. AR knockout reduced the levels of regulatory T cells in mouse adipose tissue [13]. However, there are also some opposite situations. Inhibition of AR promotes the number and cytokine expression of anti-inflammatory macrophages in mouse with autoimmune myocarditis [14]. In addition, Hoffmann et al [7] also believe that diseases in turn affect androgen levels, thereby forming a bidirectional effect. Therefore, there are still many unresolved issues regarding the impact of androgens on immune function, the effects on immune related diseases, and the underlying mechanisms.
CiteSpace is developed by Professor Chaomei Chen from Drexel University in the United States, and can explore research hotspots and trends in a certain scientific field through the bibliometric methods [1516]. In this study, CiteSpace is applied to draw a bibliometric map of the intersection of androgens and immunity, explored the research hotspots in this field, and analyzed the regulatory effect of androgens on immune function based on the research hotspots. This may provide a better understanding of the application of androgens in the prevention and treatment of immune related diseases.

MATERIALS AND METHODS
The database selected is the Web of Science Core Collection (WoSCC). The search query (TS=(androgens OR testosterone OR dihydrotestosterone) AND TS=(immune OR immunity)) is used to gain 2,789 papers of articles and reviews, dating from January 1, 2015 to December 31, 2024. Two main analyses, co-words analysis and co-citation analysis, were conducted using CiteSpace 6.1.R6. All 2,789 articles were included in the analysis. In co-words analysis, select Pathfinder and Pruning the merged network to make the network clearer. The g-index is set to 25 by default, and all other parameters are set to default. In co-citation analysis, do not select Pathfinder and Pruning the merged network, other parameters are the same as above.
Before viewing the graphical results, let's briefly understand how to interpret them. (1) In co-words analysis, each point represents a vocabulary, and we conducted clustering and keyword burst analysis. When several keywords appear together in a certain article, it indicates that these words have a close relationship and are therefore classified as one thematic category. When a keyword appears frequently during a certain period of time, it indicates that it is a current hot topic in keyword burst analysis. Dark colors represent distant time, while light colors represent closer time. (2) In co-citation analysis, in addition to clustering and burst analysis, we plotted a timeline graph. In the graph, each point represents an article. The meaning of color is the same as above. That is to say, the areas where light colored dots gather indicate current research hotspots and trends. Some spots are red, which is the result of burst analysis, indicating that this article has been cited multiple times during a certain period of time. Some spots have purple circles around themselves, indicating that they are key literature that connects two or several research topics. And it may lead to new research directions. Timeline chart can better display the period of attention for each research topic, which can be viewed together with colors. In addition, whether it is a word graph or a literature graph, the lines connecting points represent their intimate relationship.

RESULTS

1. Co-words analysis
Firstly, we display vocabulary with a co-occurrence frequency of over 90 occurrences (Fig. 1). A total of 510 nodes and 760 connections were obtained. “Androgen receptor” has the maximum count (499) and “regulatory T cell” has the minimum count (91). Part of vocabulary with relatively high co-occurrence frequency can be found in Supplement Material 1. Burstness analysis sets the minimum duration to 2 and extracts 90 words and there are obvious red circles with these spots (Fig. 1). The red bar represents the time period when their co-occurrence frequency suddenly increases, indicating that they are hot words during that period (Supplement Material 2). We further presented the top 10 keywords with co-occurrence frequency rankings in the past 3 years (Table 1). Through high-frequency and hot terms such as AR, immune cell, trial, deprivation, and combination, we can see that immunotherapy for malignant tumors and the effect of androgens on immune cells may be current research hotspots.

2. Co-citation analysis
Co-citation analysis of literature can effectively identify important and hot topics, and then analyze popular research directions. We presented literature that has been co cited 30 times or more, with four papers featuring purple outer rings (center value ≥0.1), indicating that these four papers have played a pivotal or bridging role in the development of this field (Fig. 2A).
We briefly introduced the research in these four articles. (1) In the article, the author focuses on the role of androgens in PCa, arguing that androgens suppress immunity and promote tumor progression, while anti-androgen therapy can enhance the efficacy of immunotherapy [17]. Androgens mainly suppress immune cell function by increasing the expression of anti-inflammatory factors and reducing the expression of pro-inflammatory factors, which may also be one of the reasons why the activation of AR pathways leads to high incidence and mortality rates of cancers such as PCa in male [17]. Two years before this, in 2018, it was pointed out that androgen mediated immune reactivity and inflammation suppression increase the threshold for women's autoimmune development, but may lower the threshold for male cancer [18]. Combining two articles seems to provide a more comprehensive understanding of the effects of androgens on immune cells and immune related diseases. (2) In the randomized open phase III clinical trial, Robson et al [19] proved that olabanib significantly prolonged the progression free survival (PFS) of metastatic breast cancer patients with human epidermal growth factor receptor type 2 (HER2)-negative and germline breast cancer susceptibility gene (BRCA) mutation compared with standard single chemotherapy drugs (7.0 months vs. 4.2 months; hazard ratio for disease progress or death, 0.58; 95% confidence interval, 0.43 to 0.80; p<0.001). (3) Rastrelli et al [20] conducted cohort study indicating that lower baseline levels of total testosterone and calculate free testosterone (cFT) predict poorer prognosis and mortality in men with severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2) infection admitted to respiratory intensive care unit. (4) Zhu et al [21] demonstrated that androgens can upregulate the expression of thymic autoimmune regulator (Aire) to inhibit the proliferation of T cells that recognize self-antigens and protect males from multiple sclerosis (MS). This suggests that androgen suppression of immune function affects the occurrence and development of autoimmune diseases, pulmonary viral infections, and cancer.
We further conducted burstness analysis and cluster analysis (Fig. 2B). A total of 788 nodes and 3,437 connections were obtained. Modularity (Q) value >0.3 indicates significant clustering structure, Weighted Mean Silhouette (S) value >0.7 indicates reasonable and reliable cluster with good internal homogeneity, indicating that our results are excellent. The image shows these high Strength Value hot topic literature, which also have red circles or entire spots turning red. Table 2 shows the hot literature from 2022 to 2024 (extracted from burst analysis), where Counts represents co-citation frequency and Citations represents citation frequency of literature in WoSCC (as of January 10, 2025). The recent popular literature can provide guidance for our research direction and ideas. It can be inferred from the article focus in Table 2 of the that advanced PCa, triple-negative breast cancer (TNBC), and gender gene and molecular phenotype differences are the current focus of attention in this field. Additionally, hot literature from other periods can be found in Supplement Material 3.
Afterwards, we drew a timeline chart (Fig. 2C). By combining the overall color flow (Fig. 2B) and timeline (Fig. 2C), we have analyzed and extracted several recent popular research topics, cluster 1, 4, 5, 6, and 14, respectively. Meanwhile, these clusters have a certain number of hot literatures that confirms this inference. Naming based on the most frequently cooccurrence keywords in each cluster, the names of the five clusters are #1 immunotherapy, #4 sex hormones, #5 genomics, #6 TNBC, and #14 androgen-induced cellular senescence. Furthermore, these five clusters were named based on the information databases of title and abstract (Table 3). It can be speculated that the relationship between androgen and immunity is a recent research hotspot in the research of PCa and TNBC. Sex differences in immunity caused by androgens are also an important area of concern for researchers.

DISCUSSION
Based on our analysis results, including keyword cooccurrence analysis, literature co-citation and cluster analysis, highlighting analysis, etc., We have preliminarily identified three hot and key research topics in the intersection of androgens and immunity, involving PCa, TNBC, and sex differences in immunity. The effect of androgens on individual immune cells is not within the scope of our discussion and can be found in the literature Hoffmann et al, Immunity (2023) [7]; Ben-Batalla et al, Front Immunol (2020) [17]; and Gubbels Bupp and Jorgensen, Front Immunol (2018) [18]. We mainly focus on the relationship between androgens affecting immune cells and disease progression, as well as the gender differences in immunity caused by androgens.

1. Prostate cancer
The development of PCa is closely related to androgens and is suitable for studying the relationship between androgens, immune interactions, and cancer. The inevitable progression of PCa to metastatic castration-resistant prostate cancer (mCRPC) is currently the focus of research. The results of our literature analysis also confirm this viewpoint, with a large amount of research in this area.

1) Androgens regulate the immune microenvironment of PCa
AR plays a crucial role in PCa, particularly in the progression towards mCRPC [22]. Androgen deprivation therapy (ADT) targeting androgen and AR seems to have both positive and negative regulatory effects, inhibiting the progression of PCa and inducing an immunosuppressive environment to promote the progression towards advanced PCa [23]. The tumor immune microenvironment (IME) is mainly composed of tumor cells and the surrounding immune and inflammatory cells, fibroblasts, stromal tissue, microvessels, and various cytokines. The changes in IME may be the root cause of contradictions in ADT applications.
Studies from cells and animals have shown that ADT includes inhibiting androgen levels and antagonizing AR, activating immune cells to block PCa progression (Table 4). Androgens may inhibit lymphocyte immune activity by promoting the secretion of cytokines by cancer cells, ultimately promoting cancer progression [24]. Enzalutamide or AR knockdown (ARKD) increases tumor cell major histocompatibility complex class I (MHC I) expression and CD8+T cell cytotoxicity, killing tumor cells and inhibiting tumor growth [25]. The vaccine that inhibits AR RNA splice variant 7 (AR-V7) promotes CD4+ and CD8+T cell infiltration, improve inhibitory IME, and inhibit tumor growth compared to the use of enzalutamide and anti-PD-1 alone [26]. In addition, inhibiting AR (flutamide) enhances the inhibitory effect of chimeric antigen receptor T cells (CAR-T) on LNCaP cells [27]. Inhibition of androgen levels can enhance the efficacy of AR inhibitors and anti-programmed death-ligand 1 (anti-PD-L1). ADT combined with enzalutamide and anti-PD-L1 can enhance CD8 T cell function and interferon-γ (IFN-γ) secretion, inhibit the growth of orthotopic PPSM tumor, and prolong the overall survival (OS) of mice [28]. Degarelix has also been shown to prolong the progression of mice from castration-sensitive prostate cancer (CSPC) to CRPC, while depletion of T cells reversed this effect [29]. This indicates that anti-androgen therapy can indeed promote the cytotoxicity of immune cells such as CD8+T cells, promote cancer cell apoptosis, and inhibit tumor growth.
Almost all primary PCa inevitably develop into mCRPC after ADT, which may be related to mutations in cancer tissue cell AR and related genes, as well as the subsequent formation of an inhibitory IME. Immune related signals such as IFN-α/γ response, inflammatory response, and cell chemotaxis are inhibited in human CRPC cells in PCa cells tolerant to enzalutamide, while PD-L1 expression is increased [30]. Enzalutamide also promoted PD-L1 expression, myeloid-derived suppressor cells (MDSCs) infiltration, and reduced CD8+T cell count in mouse Myc-CaP cancer cells [30]. This change mainly comes from two aspects, one is the mutation of cancer cell genes, and the other is the change of immune cells, stromal cells and other components. The membrane AR, 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid receptor (OSER1), mediates the mutual attraction between cancer cells and macrophages, thereby promoting macrophage infiltration and chronic inflammation, such as secretion of interleukin-1β (IL-1β), inducing MDSCs accumulation that inhibits the activation of cytotoxic T cells, ultimately leading to changes in the actin cytoskeleton of cancer cells and increasing their migration [3132]. Compared with benign prostatic hyperplasia and CSPC, CRPC cells highly express Yes-associated protein 1 (YAP1), while CD4+/8+T cells, APC infiltration, and inflammatory factors increase in CRPC. This may be due to the pro-inflammatory variation of cancer cells leading to castration resistance [33]. CRPC cells have also been shown to express the transcription factor enhancer of zeste homolog 2 (EZH2), which exerts resistance to enzalutamide. Inhibiting EZH2 expression can restore enzalutamide sensitivity, promote CD8+T cell cytotoxicity and inflammatory cytokine secretion, and inhibit tumor growth [34]. In addition to the changes in molecular expression of cancer cells mentioned above, changes in the expression of other cellular components in tumor IME also promote the development of PCa. Inhibition of androgen synthesis synergistically suppresses the growth of Myc-CaP tumors in mice through immunotherapy, while flutamide inhibits CD8+T cell function through a non-AR dependent pathway, possibly γ-aminobutyric acid type A (GABA-A) receptors, impairing the efficacy of immunotherapy and leading to tumor growth [35]. ADT induces activation of the leukemia inhibitory factor (LIF)/LIFR receptor (LIFR) pathway in PCa cells and stromal cells, promoting the expression of brain-derived neurotrophic factor and PD-L1, leading to immunosuppressive IME, and promoting the transformation of neuronal differentiation [36]. Inhibition of LIF/LIFR weakens these effects, indicating the role of the interaction between stromal cells and cancer cells in cancer progression [36]. Cancer associated fibroblasts secrete CC motif chemokine ligand 5 (CCL5) to promote PCa cell resistance to enzalutamide, while maraviroc inhibits the CCL5 receptor/Protein Kinase B (AKT) signaling pathway to restore cancer cell sensitivity to enzalutamide, reduce AR and PD-L1 expression, promote cell apoptosis and inhibit tumor growth [37]. In addition, in the tissue of PCa bone metastasis, enzalutamide promoted the expression of TβRI in neutrophils while inhibiting its cytotoxicity. Inhibiting or knocking out transforming growth factor-β receptor type 1 (TβRI) restores its sensitivity and inhibits the growth of bone tumor [38]. Overall, current research supports the view that androgens suppress immunity and promote PCa immune escape. As for why the progression after ADT is closely related to changes in tumor IME caused by various mechanisms, including gene mutations in tumor cells, activation of cancer cells by stromal cells and fibroblasts, loss of function of aggressive immune cells, infiltration of inhibitory immune cells, etc.

2) Human study on androgen related therapy for PCa
Multiple clinical studies have shown that androgen inhibition and AR antagonism can regulate PCa tumor IME (Table 5). ADT was shown to induce infiltration of CD4+T cells CD8+T cells, Foxp3+Tregs, CD204+macrophages, and CD20+B cells in PCa biopsy specimen [39]. However, the results can only provide a certain degree of reference, as the nature of the cancer is not specified. In mCRPC, ADT (degarelix) induces an increase in bone marrow cells and a decrease in CD4+Tconv in bone metastases, and ADT induces the expansion of CD4+non Tregs in lymph node metastases [40]. ADT also rapidly converted the primary PCa IME into an inflammatory environment within a few days prior to surgery, leading to an increase in activated CD8 T cells, regulatory T cells (Tregs), M1 macrophages, upregulation of MHC I and II antigens, and a decrease of CD47 in cancer cells [41]. The authors emphasized the crucial role of ADT application time and disease background in optimizing the therapeutic effect of immune modulators combined with androgen ablation [41]. A mouse-based study showed that treatment mode, ADT prior to radioactive nuclide 90Y-NM600, increased CD4+and CD8+T cells with an activated and memory phenotype, reduced MDSCs infiltration levels, and prolonged mouse OS [42]. Therefore, the order of application of ADT with other drugs or surgeries is a question worth exploring. High level infiltration of CD163+M2 type M Φ in the tumor surrounding area is associated with late-stage adverse clinical outcomes [43]. This may be related to macrophages promoting cholesterol transport, intratumoral androgen synthesis, and AR activation [44]. Of course, this requires more clinical data to support it. In addition, ADT (bicalutamide) also induces infiltration of anti-tumor/suppressive immune cells in primary advanced PCa, suggesting that early or short-term ADT treatment can significantly activate the IME of PCa. As ADT continues to enter the CRPC stage, the activation of the IME caused by ADT treatment is limited [45]. Therefore, the changes in IME caused by ADT may have an early inhibitory effect on tumor growth. Over time, complex reasons led to changes within IME that were favorable for cancer cell survival, ultimately resulting in the emergence of mCRPC. For example, overexpression of ubiquitin-specific proteinase 13 (USP13) may promote PCa progression by participating in AR signaling pathways, DNA damage repair (DDR), and immunosuppressive IME [46].
DDR is one of the markers of cancer and may promote the progression of PCa. Mismatch repair deficiency (dMMR) is a type of DDR, which accounts for about 2% to 5% of PCa patients and has a good response to ICB treatment. For instance, Karzai et al demonstrated that durvalumab and olaparib promote dendritic cell maturation, enhance CD4 T cell activity, and reactivate CD8 T cell anti-tumor immunity, improving clinical presentation in mCRPC patients, particularly those with dMMR [47]. However, its relationship with androgen or anti-androgen therapy is still unclear. Antonarakis et al [48] indicated that DMMR patients responded well to ADT, with a PFS of 67 months for initial ADT and 26 months for abiraterone/enzalutamide. But Ye et al [49] found that compared to wild-type MMR patients, dMMR patients receiving abiraterone had a shorter median PFS, which may be related to AR copy number or AR ligand binding domain mutation amplification. However, among patients receiving standard ADT treatment, there was no difference in PFS between dMMR patients and wild-type MMR patients [49]. A study based on the Chinese population also showed that dMMR patients had poorer responses to ADT and abiraterone than non-MMR patients [50]. In addition, studies have shown that dMMR patients have more CD8+T cell infiltration in their tumor tissues [50]. The contradictions in the results of these retrospective studies may be related to differences in sample size or selection bias, and larger sample sizes and more rigorously designed studies are still needed to the role of the relationship between ADT and immunity in dMMR PCa. Moreover, 27-hydroxycholesterol, as a precursor to androgens, induces DNA damage in PCa cells and increase sensitivity to olaparib in vitro, providing a reference for androgen regulation of DDR [51]. But another study suggests that androgens can promote DDR and ultimately promote PCa progression [52]. At present, there is limited research on the relationship between androgen regulation of DDR and immunity, which deserves further investigation to provide reference for selecting precision treatments such as ADT, immunotherapy, or treatment targeting DDR.

2. Preclinical and clinical evidence of androgen inhibition of AR+ TNBC
The second research hotspot identified through bibliometric analysis focuses on TNBC, referring to breast cancer with negative estrogen receptor, progesterone receptor and proto-oncogene HER2 in immunohistochemical examination of cancer tissue. TNBC has a subtype with high expression of AR, which is attracting increasing attention. In TNBC, androgens appear to initiate the second messenger signaling cascade leading to tumor progression [53]. But there is also increasing evidence that AR expression is associated with well prognosis, so androgen/AR as controversial targets deserve further exploration [5354].
Activation of androgen/AR pathway promotes proliferation, invasion, and tumor growth of TNBC cells. AR inhibition can exert anti-tumor effects. For example, androgens promote TNBC cell invasion through the AR/Src/phosphatidylinositol 3-kinase pathway [55] and increasing the expression of the anti-apoptosis genes myeloid cell leukemia-1 and B-cell lymphoma-2 (BCL-2) in the TNBC cells [56]. Flutamide and enzalutamide reduced the cell growth, migration, and invasion of AR positive (AR+) TNBC cells in vitro [57]. AR inhibition significantly reduced baseline proliferation, growth, migration, and invasion of four TNBC lines (SUM159PT, HCC1806, BT549, and MDA-MB-231), increased apoptosis, representing three non-luminal AR (LAR) TNBC molecular subtypes (mesenchymal like, mesenchymal stem cell like, and basal like). In vivo, enzalutamide significantly reduced the survival rate of SUM159PT and HCC1806 xenografts [58]. In addition, Inhibiting the expression of AR and its targeted gene DLGAP5 can promote TNBC cell apoptosis, promote CD8+T cell infiltration and inhibit Tregs, and suppress tumor growth [59]. AR stimulated the expression of glutathione peroxidase 4 (GPX4) and promoted ferroptosis in LAR TNBC cells. However, considering the dual positive and negative role of AR, researchers believe that targeted inhibition of GPX4 is a better treatment option. At the same time, GPX4 inhibitor increased CD4+T, CD8+T, M1 macrophage infiltration and decreased M2 macrophage infiltration in mouse tumors, indicating that the development of LAR TNBC is related to changes in the immune environment [60]. Therefore, current preclinical studies have shown that anti-androgen therapy can effectively inhibit the progression of AR+ TNBC, and some of its effects may be achieved by regulating tumor IME.
Currently, AR as a therapeutic target has received increasing attention from researchers. Partial clinical evidence suggests that anti androgen therapy, combined or not combined with immunotherapy or targeted therapy, has achieved clinical benefits and demonstrated good safety (Table 6) [61626364]. However, due to the limited sample size or low-level scheme design, these results need to be carefully considered. Overall, anti-androgen therapy is a promising treatment option for AR+ TNBC. In Yuan et al, Oncologist (2021) [65], the authors' research showed that enobosarm (GTx-024), an AR agonist, also has clinical benefits, hypothesized that enobosarm could enhance pembrolizumab induced immune response while targeting AR. The current researches have not conducted in-depth exploration on the immune infiltration results of anti-androgen therapy for TNBC. Therefore, the conclusion that androgens regulate immunity to improve TNBC is not yet sufficient, and may be a direction worthy of further research in the future.

3. Androgen regulates the immune microenvironment of respiratory tract
From the analysis of keywords and literature, we also discovered another important point, which is the sex difference in the immune regulation of androgens, mainly focusing on respiratory diseases such as allergic asthma and 2019 Coronavirus Disease (COVID-19).
Androgens are gradually being recognized to affect lung development [66]. Dehydroepiandrosterone (DHEA) inhibits epithelial mesenchymal transition induced airway remodeling [67]. Dihydrotestosterone can induce bronchial smooth muscle relaxation by inhibiting calcium ion influx, and testosterone inhibit the release of inflammatory cytokines from lung epithelial cells [6869]. Undoubtedly, airway remodeling, bronchial constriction, and the release of inflammatory factors are all important links in the onset of asthma. A survey conducted among the population aged 40 to 69 years in the UK showed that higher levels of testosterone are associated with lower asthma, wheezing, asthma hospitalizations, and better lung function [70]. Two other studies yielded similar results [7172]. High expression of AR genes and high levels of androgens in bronchial epithelial cells are associated with better lung function and lower asthma symptoms, suggesting that androgens/AR affect lung function [73]. Therefore, when considering asthma or respiratory infections, we have to pay attention to the interaction between lung tissue cells and immune cells.
The incidence rate of asthma in men is significantly lower than that in women. This is inseparable from the high levels of male testosterone and female estrogen. Androgens affect the expression of IL-33 in bronchial epithelial cells and promote the inhibitory function of Tregs, jointly reducing the occurrence of allergic inflammation [74]. The number of ILC2s of male asthma patients is lower than that in females [75]. Moreover, the number of ILC2s in the lungs of male asthmatic mice was significantly lower than that of females, and DHT reduced the expression of IL-13 and IL-5 in ILC2s. Testosterone reduced the number of ILC2s and eosinophils in the lungs, indicating that androgens also regulate ILC2s mediated airway allergic inflammation [75]. And it is indicated a decrease in the number of ILC2 progenitor cells and mature ILC2s in the peripheral tissues of male mice, and androgens and AR signaling inhibited the secretion of IL-33 by ILC2s in the lungs to alleviate inflammation [76]. The number of M2 macrophages is related to airway allergic inflammation, and male asthma patients have a lower number than females. Experiments have shown that DHT restored increased inflammation in the lungs of castrated rats, strengthened M2 polarization of macrophages, and further experiments have shown that knocking out AR in macrophages reduces chemokines and IL-5 levels in alveolar macrophages of rats, inhibiting recruitment of eosinophils in the lungs [11]. Androgens can also reduce the number of Th2 and Th17 cells in the airway, inhibit cytokine secretion, and reduce the occurrence of asthma [7778].
Sex hormones (including androgen and estrogen) and their receptors play a role in the development of COVID-19 [7980]. The symptoms of men infected with SARS-CoV-2 infection are more serious than those of women. Angiotensin converting enzyme 2 (ACE2) is the cellular entry point for SARS-CoV-2. Androgens promoted the expression of ACE2 in respiratory smooth muscle cells of both sexes in vitro [81]. ACE2 seems to promote viral infection, while ARs antagonist enzalutamide can inhibit ACE2 expression in lung tissue [82]. Transmembrane protease serine 2 (TMPRSS2) is another factor that promotes infection. However, in vitro experiments showed that methyltrienolone (R1881) or estradiol seemed to promote its expression and virus transfection in cells, but had no effect on ACE2 [83]. PT150 is a glucocorticoid receptor and AR antagonist that has been certificated to inhibit the expression of TMPRSS and ACE2 in mouse lungs, as well as macrophage and CD4+T cell infiltration, alleviate tissue damage, and reduce IL-6 expression [84]. But studies have also shown that ACE2 inhibits viral invasion and protects the lungs [85]. This contradiction requires rigorous experiments to further verify. Additionally, androgens/AR affect the prognosis of influenza virus infection in the lungs. Older mice vaccinated with influenza A virus showed more severe lung inflammation and clinical symptoms compared to younger mice, as well as prolonged virus clearance. Young mice undergoing gonadectomy also showed clinical symptoms and worsening lung pathology, while testosterone treatment alleviated these symptoms [86]. Androgens exert their effects by inhibiting the number and function of monocytes and CD8+T cells, as well as the influx of eosinophils in the lungs, and the AR antagonist flutamide group breaks the protective effect of testosterone [87]. This points out that androgens increase the tolerance to infection rather than resistance through the AR pathway to alleviate lung inflammation and improve prognosis in both male and female [87]. For lung inflammation caused by viral infection, androgens may alleviate the degree of inflammation in both sexes during the acute phase by inhibiting pro-inflammatory and stimulating anti-inflammatory effects.
Overall, the difference in sex hormones is an important factor leading to sexual dimorphism in diseases. Androgens are the main sex hormones in men, which typically suppress immune function, making them more susceptible to infections and tumor invasion, but less susceptible to autoimmune diseases. This is a research field that cannot be ignored in life sciences and medicine. In order to better understand the development direction of this field and assist in future scientific research, we used bibliometric research methods to analyze the literature in this field in the WoSCC database over the past decade. The results indicate that androgen/AR does indeed affect the occurrence and development of immune and immune related diseases, and several key diseases worthy of attention have been identified, such as PCa, TNBC, respiratory virus infection, allergic asthma, etc. There are still many urgent issues that need to be addressed in current research. (1) It is unclear what changes and bipolar androgen therapy IME where PCa progresses to mCRPC after ADT treatment. The important bipolar androgen therapy has an inhibitory effect on late PCa. What is the impact of bipolar androgen therapy on IME and is it contradictory to ADT? Is there any interaction between the numerous immune cells in IME under the influence of androgen related therapy, and what effect does it have on cancer cells? (2) The research on androgens and androgen related treatments mainly focuses on AR+ TNBC. However, the research is not in-depth enough, and the relevant mechanisms and clinical evidence are not clear enough, requiring further and extensive research. (3) The sex differences in androgen mediated immunity are a larger topic, and in this article, we discuss respiratory diseases based on bibliometric results. Androgens can inhibit the function of respiratory pro-inflammatory immune cells and promote anti-inflammatory immune cells, alleviate lung inflammation, reduce the occurrence of male allergic asthma, and increase susceptibility to lung infections. However, many diseases such as MS [21], type 1 diabetes [88], Alzheimer's disease [89], etc. have gender differences and are related to the regulation of immunity by sex hormones. Sex hormones may be an important influencing factor of immune related diseases with sexual dimorphism, and require more attention.
The androgen and AR signaling pathways affect the homeostasis of IME in tissue physiology and pathology, inhibiting reactive immune cells and promoting inhibitory immune cell function, resulting in immune function suppression effects. The differences in this effect between males and females lead to differences in disease incidence. This article only explores the cross-over of androgens on immunity, forming a potential "androgen-immune axis" pattern. Androgens are mainly produced by the male testes and female ovaries, highlighting the significant impact of reproduction on immunity and potentially providing a reproductive perspective for the treatment of immune related diseases.