Continuous versus cyclic progesterone exposure differentially regulates hippocampal gene expression and functional...

Area of Science:

• Neuroendocrinology
• Molecular Biology
• Genomics

Background:

• Ovarian hormonal depletion due to ovariectomy (OVX) significantly alters gene expression in the adult female rat hippocampus.
• Hormone therapy (HT) regimens, specifically continuous combined progesterone (CoP4) versus cyclic progesterone (CyP4) with 17β-estradiol (E2), differentially affect brain bioenergetics, metabolism, and inflammation.
• Understanding these molecular differences is crucial for optimizing HT strategies for menopausal women.

Purpose of the Study:

• To investigate the impact of chronic continuous (CoP4) versus cyclic (CyP4) progesterone, alone or with 17β-estradiol (E2), on hippocampal gene expression.
• To compare the effects of different HT regimens on genes related to bioenergetics, metabolism, and inflammation.
• To provide molecular insights into the potential neurological consequences of various HT strategies.

Main Methods:

• Adult female rats underwent ovariectomy (OVX) followed by chronic exposure to CoP4 or CyP4, with or without E2.
• High-throughput quantitative reverse transcription PCR (qRT-PCR) was used to analyze gene expression profiles.
• Bioinformatics analyses were employed to identify functional disparities between treatment groups.

Main Results:

• OVX induced significant gene expression alterations, largely reversed by E2 + CyP4 but not by E2 + CoP4.
• E2 + CoP4 induced a gene expression pattern similar to OVX, suggesting adverse effects.
• Specific genes involved in mitochondrial energy (Atp5a1), redox homeostasis (Prdx5), insulin signaling (Igf1), and cholesterol trafficking (Nr1h3) showed distinct regulation patterns between E2+CoP4 and E2+CyP4 groups. Genes in amyloid metabolism (Bace1) were downregulated by both, but with different efficacies. E2+CyP4 effects were linked to Pgrmc1.

Conclusions:

• Different hormone therapy (HT) regimens induce distinct gene expression profiles in the brain at the molecular level.
• Continuous combined HT (E2+CoP4) may have adverse consequences on hippocampal gene expression compared to OVX.
• Cyclic combined HT (E2+CyP4), being more physiological, could be a beneficial strategy for maintaining neurological health during menopausal aging.