Editorial: Androgen Receptors in Male and Female Reproduction

Federica Barbagallo¹Settimio D'Andrea^2*

• ¹Universita degli Studi di Catania, Catania, Italy
• ²Azienda Sanitaria Locale 1 Avezzano Sulmona L'Aquila, L'Aquila, Italy

deletion [amino acid variant-(NM 000044)] in the AR gene identified by whole-exome sequencing, leading to a diagnosis of CAIS. This case highlights the diagnostic challenge in patients with normal female external genitalia and expands the known mutation spectrum of CAIS (Exon 1 deletion of the androgen receptor gene causing complete androgen insensitivity syndrome in a newborn: a case report. Shengxia Wang,Ya-Ting Zhang, Fan Wang).Recent studies have shed new light on the broader implications of AR in male fertility. For instance, alterations in AR signaling can influence spermatogenesis, impacting both the quantity and quality of sperm production.Furthermore, emerging evidence points to the importance of AR in the regulation of male reproductive tract development, suggesting that the receptor may have more extensive roles than previously appreciated. These insights are essential for understanding male infertility, which often has underlying molecular defects in androgen receptor signaling [3].While much of the early research on AR focused on its role in males, it is increasingly clear that AR also exerts significant effects on female reproductive health. The presence of AR in ovarian granulosa cells, theca cells, and even the endometrial lining highlights the receptor's broad involvement in female fertility. In particular, AR is implicated in the regulation of folliculogenesis, ovulation, and the maturation of oocytes. Recent studies have demonstrated that disruptions in AR signaling can lead to ovarian dysfunction, a phenomenon observed in conditions such as PCOS [4]. PCOS, one of the most common endocrine disorders in women, is often characterized by hyperandrogenism (HA). Understanding how AR contributes to the pathophysiology of PCOS is crucial for developing new diagnostic and therapeutic strategies. Research on the interaction between androgens and AR in the ovaries has revealed a complex network of signaling pathways that regulate follicular development and steroidogenesis. Furthermore, these studies suggest that AR may be a potential target for therapeutic intervention, with the potential to alleviate symptoms of PCOS and improve fertility outcomes [5].to immune dysfunction and impaired fertility outcomes in PCOS. Through weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network construction, the study highlighted immune-related gene modules and inflammatory pathways associated with hyperandrogenic PCOS (HA PCOS). Key findings included the identification of DAPK2 (death-associated protein kinase 2), as a critical gene linked to granulosa cell apoptosis, immune dysregulation, and recurrent implantation failure (RIF) Moreover, different genes were identified as co-expressed in HA-PCOS and RIF, pointing to dysregulation in corticosteroid metabolism, bone maturation, and immune responses. These results suggest that androgen excess contributes to abnormal granulosa cell function, placental morphology, and endometrial receptivity, thereby increasing the risk of pregnancy complications and implantation failure. (Exploration of molecular features of PCOS with different androgen levels and immune-related prognostic biomarkers associated with implantation failure. Qinyu Gao, Cong Ma, Shuyu Meng, Guanxiong Wang, Qiong Xing, Yuping Xu, Xiaojin He, Tianjuan Wang, Yunxia Cao).While HA in PCOS is associated with impaired granulosa cell function and disrupted folliculogenesis, several studies, including that of Li et al., have reported a positive correlation between androgens levels and elevated levels of anti-Müllerian hormone (AMH), which is widely used as a biomarker for ovarian reserve (DivergentOvary Syndrome. Youran Li, Yanhong Zhai, Lin Li, Yifan Lu, Shaofei Su, Ying Liu, Zhengwen Xu, Mingwei Xin, Qiaoli Zhang, Zheng Cao). This underscores the need for further research into the molecular mechanisms that govern tissue-specific AR activation and its impact on fertility [6].Recent advances in genetic tools have allowed researchers to explore the function of AR in greater detail.Animal models, particularly those involving androgen receptor knockout (ARKO) mice, have been instrumental in elucidating the role of AR in both male and female reproductive physiology. Interestingly, female ARKO mice exhibit reproductive defects that challenge our understanding of AR's role in female fertility. These mice demonstrate impaired folliculogenesis and an early onset of ovarian failure, underscoring the importance of AR in maintaining ovarian function. Moreover, research on ARKO mice has revealed differences in the way androgens influence reproductive tissues in males and females, suggesting that the The identification of AR as a key player in reproductive health opens up exciting possibilities for the development of novel therapies. For example, selective modulators of AR could offer new treatment options for conditions such as PCOS, where the receptor's activity may be overactive. Conversely, AR antagonists could be used to mitigate the effects of excessive androgenic signaling in disorders like endometriosis or certain types of infertility. Therapeutic approaches targeting AR could also extend to male infertility, particularly in cases where AR mutations or dysfunction are involved. However, the challenge lies in the tissuespecific nature of AR signaling, as targeting the receptor without affecting other important systems could prove difficult. Therefore, future research will need to focus on the development of more refined AR modulators that can act selectively on specific tissues or organ. As previously mentioned, HA is a leading cause of dysfunction in ovarian granulosa cells of PCOS patients. Chen et al. reported that curcumin exerts protective effects against DHT-induced damage by enhancing estrogen synthesis and inhibiting AR activity, thereby restoring cell viability and correcting lipid metabolism disruptions caused by elevated androgen levels. (Transcriptomic analysis of the effects exerted by curcumin on dihydrotestosterone-induced ovarian granulosa cells. Dejian Chen, Qian Yu, Shuhao Sheng, Lingshi Cai, Jisuo Zheng, Yaling Zhang). This Research Topic underscores the complexity of AR signaling in both male and female reproductive function. The contributions collected here shed light on the multifaceted roles of AR in reproductive tissues, highlighting both shared features and differences across sexes. We truly hope that some of these studies will help address open questions in the field, stimulate further ad hoc research, and ultimately contribute to a more refined understanding of AR signaling. In turn, this could pave the way for future advances in diagnostic and therapeutic strategies for a wide range of reproductive disorders