Estrogen Receptor (ER)α and ERβ Are Both Expressed in Human Ejaculated Spermatozoa: Evidence of Their Direct Interaction with Phosphatidylinositol-3-OH Kinase/Akt Pathway
Abstract
Human and animal models have evidenced how estrogen insufficiency is associated with abnormal spermatogenesis and male infertility. We previously demonstrated that estradiol is able to influence both capacitation and acrosome reaction in human ejaculated spermatozoa. It remains to be elucidated whether the biochemical changes induced by estradiol, in a rapid nongenomic way, are mediated by a single estrogen receptor (ER) or by the two ER subtypes, ER alpha and ER beta. In the present study, we have first demonstrated the concomitant expression of ER beta and ER alpha in human ejaculated spermatozoa. By RT-PCR and Southern blot, transcripts of both ERs were detected. Western blot analysis showed ER alpha and ER beta proteins at the same size as the "classical" ERs. The localization of ER alpha and ER beta with the immunocytochemistry shows a differential distribution of the two ER subtypes, the former being prevalently located in the midpiece, but the latter being in the tail. Estradiol has been associated with sperm longevity; however, the mechanism through which estradiol acts in sperm survival was never investigated. Upon estradiol exposure, we observed an enhanced phosphorylation of the proteins involved in the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway like PDK1, Akt, GSK-3, Bcl-2, together with ERK1/2, which was also involved in cell survival signals. Moreover, such phosphorylations were reduced in the presence of ICI 182, 780, addressing the role of estradiol and ERs in sperm survival. For instance we have provided, for the first time, a different interaction of the two ERs with the PI3K/Akt pathway, because ER alpha interacts with the p55 regulatory subunit of PI3K, whereas ER beta interacts with Akt1. However, it still remains to be elucidated whether the functional role of each of the ER subtypes in sperm survival signaling is redundant or distinct.
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Pregnenolone regulates gene expression via a nuclear receptor-mediated genomic pathway and via a TRP cation channel-mediated nongenomic pathway.
“Pregnenolone, the precursor of androgens, estrogens, progesterone, mineralocorticoids, and glucocorticoids [15], regulates gene expression via a nuclear receptor-mediated genomic pathway and via a transient receptor potential (TRP) cation channels-mediated nongenomic pathway [16].”
From G protein-coupled receptors function as cell membrane receptors for the steroid hormone 20-hydroxyecdysone (2020) · cites this paper as [16]
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Cytochrome P450arom, androgen and estrogen receptors in pig sperm
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Steroid receptors and their ligands: Effects on male gamete functions
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Self-citationOestrogens as apoptosis regulators in mammalian testis: angels or devils?
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Receptors in Spermatozoa: Are They Real?
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Potential Involvement of Several Signaling Pathways in Initiation of the Chicken Acrosome Reaction1
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Identification of G protein‐coupled estrogen receptor in human and pig spermatozoa
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Aromatase and oestrogens in human male germ cells
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The association of aromatase (CYP19) gene variants with sperm concentration and motility
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- Authors
- Aquila, S., Sisci, D., Gentile, M., Middea, E., Catalano, S., Carpino, A., Rago, V., & Andò, S.
- Affiliations
- University of Calabria (IT)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2004-03
- Volume
- 89
- Issue
- 3
- Pages
- 1443-1451
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W1979238526
- Cited by
- 184
- References
- 41
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 9 · 2016: 9 · 2015: 8 · 2014: 12 · 2013: 5 · 2012: 18
- FWCI
- 13.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Archive of Doctoral Theses and Digital Collections (University of Calabria) (submittedVersion)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Università della Calabria
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Reproductive biology and impacts on aquatic species
- Keywords
- estrogen receptor alpha, estrogen receptor beta, estradiol, sperm survival, PI3K/Akt signaling, non-genomic estrogen signaling, sperm capacitation, acrosome reaction, fulvestrant, AKT1, PDK1, glycogen synthase kinase-3, ERK1/2, Bcl-2
- MeSH terms
- Cell Survival, Ejaculation, Estradiol, Humans, Male, Proto-Oncogene Proteins, Receptors, Estrogen, Spermatozoa, Blotting, Southern, Blotting, Western, Gene Expression, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins c-bcl-2, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinase 1, Reverse Transcriptase Polymerase Chain Reaction, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Estrogen Receptor alpha, Estrogen Receptor beta, Mitogen-Activated Protein Kinase 3, Proto-Oncogene Proteins c-akt
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