ReviewMolecular insights into hormone regulation via signaling pathways in Sertoli cells: With discussion on infertility and testicular tumor
Introduction
Cell differentiation happens when a cell changes into another specific cell type. It is a progressive and coordinated process which is regulated by signaling pathways (Sun et al., 2015a, Sun et al., 2015b). Spermatogenesis is an essential differentiation process for male reproduction in vertebrates (Wong and Cheng, 2005). Once spermatogenesis is disturbed, male infertility and even tumor will develop which will interfere with male health.
Spermatogenesis in higher vertebrates requires hormone regulation along the hypothalamic-pituitary–gonadal (HPG) axis, and disruption of HPG axis will impair sperm quality (Ilgin, 2020). Gonadotropin-releasing hormone (GnRH) is synthesized in the preoptic area of the hypothalamus and released to the anterior pituitary, which can stimulate the synthesis of follicle-stimulating hormone (FSH) and luteinising hormone (LH) (Abreu and Kaiser, 2016). FSH and LH regulate spermatogenesis and steroidogenesis in testis at puberty (for reviews, see Bhattacharya et al., 2019a, Bhattacharya et al., 2019b, Coss, 2020), and also participate in the feedback regulation along the HPG axis (Kanda, 2018). In the context of the HPG axis, Sertoli cells (SCs) serve as protectors, supporters, and nourishers of spermatogenesis (Mäkelä et al., 2019). We’d like to pointed out that hormones play critical roles in this process, including androgen, estradiol, FSH, leptin, LH, Müllerian-inhibiting substance (MIS), ouabain, prostaglandin D2 (PGD2), thyroid hormone, etc. (Fig. 1).
As the only somatic cells in the seminiferous epithelium in the testis, SCs are entwined with spermatogenic cells via cell junctions. SCs secret hormone, lactate and cytokines to promote mitosis, meiosis, and maturation of germ cells (GCs) (Morohoshi et al., 2019). Between SCs, there are cell junctions forming the blood–testis barrier (BTB), which is a physical protective barrier between the basal and the adluminal compartments of the seminiferous epithelium. Generally, only the preleptotene and leptotene spermatocytes are allowed to cross the BTB into the adluminal compartment to continue spermatogenesis (Ahmed et al., 2018). Disturbing any function of SCs can contribute to the inability of spermatogenesis. The failure organization of cell junction or inadequate supply of growth factors by SCs are recognized as the primary causes of Sertoli cell only syndrome (SCOS) (Paduch et al., 2019). In patients with non-obstructive azoospermia (NOA), disruption of BTB and adherens junction (AJ) between SCs and GCs are also observed (Zhu et al., 2019).
Owe to their precise regulation, the signaling pathways in SCs are vital for spermatogenesis (Wang et al., 2019a, Wang et al., 2019b). We had reviewed the mitogen-activated protein kinase (MAPK), adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK), and transforming growth factor-β/Sma- and Mad-related protein (TGF-β/Smad) signaling pathways in spermatogenesis. Those three pathways regulate spermatogenesis via SCs proliferation, cell junction dynamics, lactate supply, self-renewal of spermatogonial stem cells (SSCs), and apoptosis of GCs as well (Ni et al., 2019, Pradhan et al., 2019). However, the spermatogenesis supporting functions of SCs are not restricted in their determination by the intracellular signaling pathways, but also regulated by hormones. Meroni et al. had reviewed that endogenic hormones including FSH can participate in the proliferation of SCs via the cyclic adenosine monophosphate/cAMP-dependent protein kinase (cAMP/PKA), extracellular regulated protein kinase 1/2 (ERK1/2), phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), and mechanistic target of rapamycin kinase complex 1 (mTORC1) signaling pathways (Meroni et al., 2019). We surveyed articles from 1982 to 2020 in the Pubmed database with following search terms: signaling pathway*, Sertoli cell*, spermatogenesis, hormone*, AR, androgen receptor, cAMP, PKA, PI3k, Akt, testosterone, androgen, ouabain, MIS, estradiol, LH, FSH, thyroid hormone, prostaglandin, leptin, male infertility, testicular cancer*, SCOS, NOA. We choose the findings which study how signaling pathways in SCs regulate spermatogenesis upon hormone regulation. Relevant articles about certain genes are also included as an extension or supplement. According to our investigation, hormones along the HPG axis and other endogenous hormones can be critical for spermatogenesis of higher vertebrates via their regulation of signaling pathways in SCs. The androgen receptor (AR), cAMP/PKA and PI3k/Akt signaling pathways are significant in this physiological regulation process (Table 1). In our review, we try to clarify this issue from the organ/system perspective. For contradictory outcomes of clinical trials, we put forward our analyses and suggestions to improve further studies. Based on the abnormal activity of signaling pathways and levels of hormone in clinical specimens, we also discuss possible clinical applications and productive approaches to clarify pathogenesis mechanisms, and develop therapies for testicular cancer and male infertility.
Section snippets
The AR signaling pathway
LH from pituitary can stimulate the Leydig cells in the seminiferous tubules to produce androgens. After androgens diffuse to SCs and bind to AR, the AR signaling pathway is initiated (Smith and Walker, 2014). Testosterone is the androgen in the testis, whose receptor expresses in SCs (Walker, 2011), so the AR signaling pathway in SCs are crucial for androgen mediated spermatogenesis (Soffientini et al., 2017) (Fig. 2).
The AR signaling pathway includes classical and non-classical testosterone
The cAMP/PKA signaling pathway
The de novo activation of the cAMP/PKA signaling pathway is tightly and directly connected to FSH (Eto et al., 2012). During the first spermatogenic wave in mice from 8 dpp onward, increasing FSH binds to its receptor, which is then coupled to stimulatory G-proteins complex (Gs)-coupled seven-transmembrane receptor (Simoni et al., 1997){Simoni, 1997 #61}. Gsα dissociates from FSH receptor and activates adenylyl cyclase (AC). Then the intracellular cAMP level is increased upon the catalysis of
The PI3k/Akt signaling pathway
FSH, insulin and insulin-like growth factor (IGF) highly participate in the PI3k/Akt signaling pathway (Cannarella et al., 2018) (Fig. 4). When IGF and insulin bind to IGF receptor (IGFR), firstly insulin receptor substrate 1 (IRS1) and then PI3K are phosphorylated (Mok et al., 2014). The phosphorylated PI3k converts phosphatidylinositol-4,5-bisphosphate (PIP2) lipids to phosphatidylinositol-3,4,5-trisphosphate (PIP3). Then PIP3 activates a subsequent phosphorylation cascade of
The abnormal spermatogenesis: Infertility
Infertility is a worldwide health issue, disturbing individuals, families, society and countries for a long history. Among them, 15% of the infertile men were diagnosed as azoospermia, whose ejaculate lack sperm according to the clinical manifestation (Wosnitzer and Goldstein, 2016). Azoospermia is classified into obstructive azoospermia and NOA, and SCOS is diagnosed in 26.3%-57.8% of azoospermic patients (Abofoul-Azab et al., 2019). Benefiting from the progression in microsurgical vasal
Abnormal spermatogenesis: Testicular tumor
Testicular cancer is the most common type of cancer in men aged 15–34 years old. In 2016, 8700 cases of testicular cancer and 380 deaths were estimated in the United States (Smith et al., 2018). While in 2017, the corresponding indexes turn into 8850 and 410 (Baird et al., 2018). Sertoli cell tumor (SCT) is a kind of sex-cord stromal tumor, and only accounts for 0.4%-1.5% of testicular malignancies (Coleman et al., 2014, Ishida et al., 2013). Existing cases indicate the relevance between the
Conclusions and perspectives
Currently, studies are rarely focusing on the relationship of hormone determined signaling pathways in SCs, spermatogenesis, and clinical cases. However, the signaling pathways, especially the AR signaling pathway, promise a great future in diagnosis and therapy of male diseases, as well as drug development. Mutation in the AR exon and expression level of AR in SCs, as well as downstream genes of the AR signaling pathway can serve as markers of diseases to screen potential therapies and agents
Funding Information
This work was supported in part by National Natural Science Foundation of China (No 41776144) and Zhejiang Province Public Welfare Technology Application Research Project (including Natural Science Foundation) (No. LGF20C120001).
Author Contribution
F.-D.N, S.-L.H., and W.-X.Y. conceived of and authored the paper.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors are grateful to all members of the Sperm Laboratory at Zhejiang University for valuable discussions.
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Authors contributed equally to this work.