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Gonadotrope Remodeling in Sustained Low Estrogen States: Single-Cell Transcriptomic Analysis Reveals Gonadotrope Subtypes and Activation of Stem Cell Populations.

ABSTRACT: The 4-vinylcyclohexene diepoxide (VCD)-induced ovarian failure model provides a physiologically relevant alternative to ovariectomy to gradually reduce serum estradiol (E2) for studying tissue responses to a menopause-like state. This study utilized single-cell sequencing transcriptomics analyses (scRNA-seq) to determine how reduced E2 levels influence pituitary gonadotrope gene expression and cell state, with a focus on potential transcriptomic contributions from stem cells to gonadotrope population growth. VCD-treated mice were acyclic and exhibited 8–15-fold increases in serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) gonadotropin levels. E2 levels were 2X lower than those of normally cycling proestrous females. scRNA-seq identified two gonadotrope clusters based upon distinct gene expression signatures (designated GON1 and GON2). The GON1 population increased in number significantly in VCD-treated mice, expressing markers of progenitor cells. Both gonadotrope clusters showed upregulated genes for canonical pathways supporting mRNA translation and secretion, which correlated well with the high serum gonadotropin levels. However, the LH beta subunit (Lhb) transcript was unchanged and FSH beta subunit (Fshb) was significantly reduced, suggesting that the high gonadotropin secretion may be supported by post-transcriptional regulators. The pituitary Sox2-positive (Sox2) stem cell cluster exhibited increased expression of Sox9, a marker for more mature transitional progenitors, and showed upregulation of pathways involved in stem cell development, mitotic activity, and mRNA translation. This model provides insight into the cellular and molecular adaptations of the gonadotropes and their progenitor cells to the low estrogen/menopausal state, with potential relevance for understanding human perimenopausal and menopausal physiology.

ORGANISM(S): Mus musculus

PROVIDER: GSE307613 | GEO | 2026/05/01

REPOSITORIES: GEO

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Project description:Gonadotrope or null cell pituitary tumors present clinically with signs of hypogonadism and hypopituitarism, together with visual disturbances due to mass effects. Since there are no medical therapies, surgery and/or radiation are the only therapeutic options. To identify dysregulated genes and/or pathways that may play a role in tumorigenesis and/ or progression, molecular profiling was performed on 14 gonadotrope tumors and 9 normal human pituitaries from autopsy samples. Principle component analysis (PCA) revealed clear discrimination between tumor and normal pituitary gene expression profiles. Bioinformatic analysis identified specific genes and pathways that were highly differentially regulated, including a cohort of putative downstream effectors of p53 were repressed in gonadotrope pituitary tumors, including GADD45Î², GADD45Î³ and Reprimo with concomitant downregulation of the upstream regulator, PLAGL1. PLAGL1 reexpression in gonadotrope cells did not directly modulate the downstream targets. Further functional analysis of GADD45Î² was performed. Overexpression of GADD45Î² in mouse gonadotrope cells blocked proliferation, increased rates of apoptosis in response to growth factor withdrawal and increased colony formation in soft agar. In contrast to prior studies with GADD45Î³, methylation interference assays showed no evidence of epigenetic modification of the GADD45Î² promoter in pituitary tumors. Thus, our data suggest that many components downstream of p53 are suppressed in gonadotrope pituitary tumors. A novel candidate, GADD45Î² is low in tumors and reexpression blocks proliferation, survival and tumorigenesis in gonadotrope cells. Unlike GADD45Î³, GADD45Î² is not methylated to block its expression. Together these studies identify new targets and mechanisms to explore concerning pituitary tumor initiation and progression. To elucidate mechanisms involved in pituitary tumorigenesis and progression, we performed individual gene expression microarray analysis using Affy U133 Plus 2.0 GeneChips comparing 14 gonadotrope tumors with 9 normal pituitary samples obtained at autopsy.

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Gonadotrope Remodeling in Sustained Low Estrogen States: Single-Cell Transcriptomic Analysis Reveals Gonadotrope Subtypes and Activation of Stem Cell Populations.

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