Detection of FSH receptors in mouse and human penile tissue

1. Introduction

Follicle-stimulating hormone (FSH) is a heterodimeric glycoprotein hormone that consists of two distinct subunits: alpha (α) and beta (β) and has a crucial role in the regulation of reproductive physiology. The α-subunit is common among pituitary and placental glycoprotein hormones, including chorionic gonadotropin (CG) and thyroid-stimulating hormone (TSH) [1], while the β-subunit is hormone-specific. Luteinizing hormone (LH) and hCG activate the same receptor, i.e., luteinizing hormone/choriogonadotropin receptor (LHCGR), but TSH and FSH have their receptors [2].

FSH is crucial for reproductive functions in both men and women. In males, it interacts with Sertoli cells in the male gonads, prompting the synthesis of proteins essential for spermatogenesis [3]. In females, FSH is involved in the development of preantral follicles, and follicular growth, as well as in the selection of the dominant follicle and oocyte maturation [4]. FSH binds to the follicle-stimulating hormone receptor (FSHR), a seven-transmembrane G protein-coupled receptor located on the plasma membrane of granulosa cells, activating G proteins that initiate various intracellular signaling pathways [5]. The FSHR gene is located on chromosome 2 p21-p16 and consists of 10 exons and 9 introns [6]. Human FSHR is a G protein-coupled receptor with a molecular weight of approximately 75 kDa. It features a long extracellular domain, 7 transmembrane domains, 3 extra loops, 3 short intracellular loops, and an intracellular tail [7].

In addition to its well-known roles in reproductive physiology, FSHR has been demonstrated to exert biological effects in various extragonadal tissues. Detailed investigations have confirmed the expression of FSHR in the human female reproductive tract and placenta [8], appendix neuroendocrine neoplasm [9], and selectively in blood vessels across other human tumors [10]. Additionally, FSHR expression is observed in human monocytes [11], bones [12], adipose tissues [13, 14], the nervous system [15] and pancreatic islet β-cells [16]. Notably, it is also expressed in endothelial cells, M1-macrophages, M1-derived foam cells, osteoclasts associated with human atherosclerotic plaques, and giant multinucleated macrophages [17].

Despite the well-documented presence of the luteinizing hormone receptor within the same glycoprotein hormone receptor family in mouse [18] and human [19] penile tissues, no evidence yet confirms the presence of FSH receptors in the penis. This study aims to investigate the expression of the FSH receptor in both mouse and human penile tissues to explore its potential role in penile tissue function.

2. Materials and methods

3. Results

3.1 Human penis tissue

Positive staining for FSH receptors was observed in all examined tissue samples from patients. Concisely, staining was evident in the sebaceous gland cells, throughout all layers of the epithelium, and in the fibroblasts of the subepithelial connective tissue of the penis (Fig. 1A). Additionally, FSH receptors were detected in the corpus cavernosum (Fig. 1B), the connective tissue fibroblasts, the walls of small blood vessels (Fig. 1B,C), and in the plasma cells of the penis (Fig. 1C). Human penis tissue was used for negative controls, where no positive staining was observed (Fig. 1D).

Fig. 1.Immunohistochemistry results. Localization of FSH receptors in human penile tissue. (A) FSH receptors are visible in cells of the sebaceous gland (SG), throughout all layers of the epithelium (E), and in the fibroblasts of subepithelial connective tissue (FB). (B) FSH receptors are detected in the corpus cavernosum (CC), fibroblasts of connective tissue (FB), and in the intima of small blood vessels (BV). (C) The presence of FSH receptors is noted in fibroblasts of connective tissue (FB), walls of small blood vessels (BV), and plasma cells (PC). (D) Negative controls showed no detectable positive cells.

3.2 Mouse penis tissue

The positive immunoreaction was absent in most of the tissue samples of the mouse penis tissue. However, negligible positive immunoreaction was observed in fibrocytes (FC) and mast cells (MC) of the mouse penis (Fig. 2A). For detecting FSH receptors in target cells, testicular tissue served as positive control. Positive immunoreaction was found in the Sertoli cells (SC) of seminiferous tubules (Fig. 2B).

Fig. 2.Immunohistochemistry results. Presence of FSH receptors in mouse penile tissue. (A) Minimal positive staining is detected in fibrocytes (FC) and mast cells (MC) of the mouse penis. (B) Prominent positive immunoreaction was observed in the Sertoli cells (SC) of seminiferous tubules.

4. Discussion

The current findings confirm the presence of FSH receptors in human penile tissue but reveal only negligible staining in mouse penile tissue, suggesting species-specific differences in receptor expression.

Although FSHR and its possible role have already been identified in several extragonadal tissues, its expression in penile tissue has not been previously documented. In contrast, luteinizing hormone/choriogonadotropin receptor (LHCGR) has been established in both mouse [18] and human penile tissues [19]. In the testes, FSH is known to target Sertoli cells to support spermatogenesis, whereas LH influences Leydig cells to stimulate androgen production [20]. The roles of these two gonadotropins in the penis remain unclear, however, it is possible that elevated levels of FSH and LH may affect the function of the corpus spongiosum and cavernosum in aging men, potentially influencing erectile function or other penile tissue functionalities. Recent studies have proposed several potential roles for FSH, including its involvement in extragonadal tissues, such as eliciting signaling that may lead to compromising the endothelial membrane [21], regulation of pancreatic islet insulin secretion [16], stimulating bone resorption [11] and upregulating FSHR in adipocytes, which may promote increased fat accumulation [13].

5. Conclusions

FSH receptors have been identified in several extragonadal tissues, indicating that the role of FSH may extend beyond traditional gonadal functions. Given these findings, further research is imperative to elucidate whether FSH receptors play a specific role in penile tissue and, if so, to define this role. The study faced significant limitations, primarily due to the small sample size and reliance on archived human penile tissue samples. The use of human penile tissue in research is highly restricted, constrained by limited availability and stringent legal and ethical considerations.

Availability of data and materials

Data used in this study can be accessed upon reasonable request to the corresponding author.

Author contributions

KK and PP—designed the research study. LS and AK—collected tissue samples. SS, TT and SR—performed the research. HZ, KK and SS—analyzed the data. HZ—wrote the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Ethical approval was obtained from the Research Ethics Committee of the University of Tartu to perform study on human tissue (No. 391/T-10). Informed consent was waived by the ethics committee. All human data used in this study were anonymized prior to analysis to ensure compliance with applicable data protection regulations. According to the national guidelines, no permission was required by authorities to collect tissue specimens from sacrificed mice.

Acknowledgment

We would like to thank Agu Raudheiding and Liina Pärnsalu for technical assistance.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.