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Basic Science

Sex Differences in Hippocampal Steroid Contents and the Expression of Their Receptors Following Neonatal Hypoxia-ischemia in Mice

Friday, September 19, 2025
10:30 AM - 10:45 AM CT
Location: Ann & Robert H. Lurie Children’s Hospital of Chicago, 11th Floor Conference Room 200 E. Superior
Disclosure(s):
Teresita de Jesus Valdes Arciniega, DVM, MS: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Background: Hypoxia-ischemia (HI) related brain injury impacts millions of neonates globally and is a leading cause of lifelong disability. Male neonates are more vulnerable to perinatal HI, and preclinical studies show greater long-term cognitive deficits in males. Research on sex differences in brain development suggests that perinatal hormonal environment—characterized by a testosterone (T) surge in males and its absence in females at birth—shapes neuronal circuits underlying sex-specific behaviors and functions in adulthood. Preclinical studies have shown that sex steroids modulate the GABAergic system and synaptic transmission, regulating the excitatory/inhibitory balance and thus memory and learning.

Objectives: We hypothesize that sex differences in HI outcomes are due to alterations in hippocampal steroid contents and their receptor profiles.

Design/Methods: To test that, HI was induced at postnatal (P) day 9 inC57BL/6J mice (adrenals and gonads intact) using Vannucci’s HI model. Sham mice underwent anesthesia and manipulation of the left common carotid artery. Hippocampi and blood were collected on days 1 (P10) and 3 (P12) post-HI. LC-MS/MS was used to determine estradiol (E2), T, progesterone (P4), and corticosterone (CORT) contents. Moderately injured hippocampal relative gene expression of Esr1, Esr2, Gper1, Nr3c1, Pgr, and Ar were quantified by qPCR and was normalized to Gapdh and Hprt1. Steroid contents (condition×day×sex; n=6-14) and gene expression (condition×sex; n=3-5) were analyzed by multifactorial ANOVA.

Results: Steroid contents were at least 10-fold higher in hippocampi than plasma, suggesting their in-situ synthesis. Males had higher hippocampal T (p=0.01) and E2 (p=0.03) content than females at 3 d post-HI. No sex differences were found in plasma and hippocampal P4 and CORT levels at 1- and 3- d post HI. In addition, HI induced upregulation of all steroid receptors in male hippocampi except Esr2 and Pgr. However, no HI effect was found in any female hippocampi receptor expression. Finally, only the expression of Gper1 was found to differ by sex post-HI, with higher values in males (p=0.04).

Conclusions: Our results suggest that steroids are synthesized in the developing sham and HI hippocampi at levels much higher than in plasma. Following HI, sex-specific profiles were identified, with males exhibiting higher T and E2 content, and upregulation of their corresponding receptors, suggesting that these pathways may be organized differently in males than in females.