Research Paper Volume 12, Issue 7 pp 6089—6108

Estradiol-induced senescence of hypothalamic astrocytes contributes to aging-related reproductive function declines in female mice

Xiaoman Dai1, *, , Luyan Hong1,3, *, , Hui Shen1, *, , Qiang Du2, , Qinyong Ye1, , Xiaochun Chen1, , Jing Zhang1, ,

  • 1 Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350001, Fujian, China
  • 2 Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, China
  • 3 Department of Biochemistry and Molecular Biology, Gannan Medical University, Ganzhou 341000, Jiangxi, China
* Equal contribution

Received: November 25, 2019       Accepted: January 27, 2020       Published: April 7, 2020
How to Cite

Copyright © 2020 Dai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Hypothalamic astrocytes are important contributors that activate gonadotropin-releasing hormone (GnRH) neurons and promote GnRH/LH (luteinizing hormone) surge. However, the potential roles and mechanisms of astrocytes during the early reproductive decline remain obscure. The current study reported that, in intact middle-aged female mice, astrocytes within the hypothalamic RP3V accumulated senescence-related markers with increasing age. It employed an ovariectomized animal model and a cell model receiving estrogen intervention to confirm the estrogen-induced senescence of hypothalamic astrocytes. It found that estrogen metabolites may be an important factor for the estrogen-induced astrocyte senescence. In vitro molecular analysis revealed that ovarian estradiol activated PKA and up-regulated CYPs expression, metabolizing estradiol into 2-OHE2 and 4-OHE2. Of note, in middle-aged mice, the progesterone synthesis and the ability to promote GnRH release were significantly reduced. Besides, the expression of growth factors decreased and the mRNA levels of proinflammatory cytokines significantly increased in the aging astrocytes. The findings confirm that ovarian estradiol induces the senescence of hypothalamic astrocytes and that the senescent astrocytes compromise the regulation of progesterone synthesis and GnRH secretion, which may contribute to the aging-related declines in female reproductive function.


HPO: hypothalamic-pituitary-ovarian axis; LH: luteinizing hormone; GnRH: gonadotropin-releasing hormone; E2: estradiol; ERα: estradiol receptor-alpha; PKA: protein kinase A; P450scc: cholesterol-side-chain cleavage enzyme; 3β-HSD: 3β-hydroxysteroid dehydrogenase; TGF: Transforming growth factor; OVX: ovariectomy; RP3V: rostral periventricular area of the third ventricle; SA-β-Gal: senescence associated β-galactosidase; 2-OHE2: 2-hydroxyestradiol; 4-OHE2: 4-hydroxyestradiol.