Puberty enables oestradiol‐induced progesterone synthesis in female mouse hypothalamic astrocytes

• Published in: Journal of neuroendocrinology 2022-06, Vol.34 (6), p.e13082-n/a
• Main Authors: Mohr, Margaret A., Keshishian, Tina, Falcy, Brennan A., Laham, Blake J., Wong, Angela M., Micevych, Paul E
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes; Astrocytes - metabolism; Calcium (intracellular); Caveolin; Estradiol - physiology; Estrogen Receptor alpha - metabolism; Estrogens - metabolism; Feedback; Female; Hypothalamus; Hypothalamus - metabolism; Luteinizing hormone; Mice; Phosphorylation; Progesterone; Progesterone - metabolism; Puberty; Rats; Sexual Maturation
• ISSN: 0953-8194; 1365-2826
• DOI: 10.1111/jne.13082

The development of oestrogen positive feedback is a hallmark of female puberty. Both oestrogen and progesterone signalling are required for the functioning of this neuroendocrine feedback loop but the physiological changes that underlie the emergence of positive feedback remain unknown. Only after puberty does oestradiol (E2) facilitate progesterone synthesis in the rat female hypothalamus (neuroP), an event critical for positive feedback and the LH surge. We hypothesize that prior to puberty, these astrocytes have low levels of membrane oestrogen receptor alpha (ERα), which is needed for facilitation of neuroP synthesis. Thus, we hypothesized that prepubertal astrocytes are unable to respond to E2 with increased neuroP synthesis due a lack of membrane ERα. To test this, hypothalamic tissues and enriched primary hypothalamic astrocyte cultures were acquired from prepubertal (postnatal week 3) and post‐pubertal (week 8) female mice. E2‐facilitated neuroP was measured in the hypothalamus pre‐ and post‐puberty, and hypothalamic astrocyte responses were measured after treatment with E2. Prior to puberty, E2‐facilitated neuroP synthesis did not occur in the hypothalamus, and mERα expression was low in hypothalamic astrocytes, but E2‐facilitated neuroP synthesis in the rostral hypothalamus and mERα expression increased post‐puberty. The increase in mERα expression in hypothalamic astrocytes corresponded with a post‐pubertal increase in caveolin‐1 protein, PKA phosphorylation, and a more rapid [Ca2+]i flux in response to E2. Together, results from the present study indicate that E2‐facilitated neuroP synthesis occurs in the rostral hypothalamus, develops during puberty, and corresponds to a post‐pubertal increase in mERα levels in hypothalamic astrocytes. Oestradiol facilitation of hypothalamic neuroprogesterone synthesis is necessary for the positive feedback of the LH surge. The present study localized the increase of neuroprogesterone to the rostral hypothalamus, a region that mediates oestrogen positive feedback. Across pubertal development, hypothalamic astrocytes increase levels of membrane ERα and the cell signalling responses needed to facilitate neuroprogesterone synthesis that triggers the LH surge demonstrating a mechanism for pubertal maturation resulting in reproductive competence.