Can the menopause transition raise LDL and non-HDL cholesterol?

The menopause transition marks a critical metabolic turning point, characterized by profound changes in circulating lipids that elevate cardiovascular risk.

Clinical lipid changes

• The decline in ovarian follicular activity leads to a sharp reduction in circulating 17β-estradiol.
• This hormonal shift directly corresponds to a clinical shift toward an atherogenic lipid profile, specifically manifesting as significant elevations in circulating low-density lipoprotein (LDL) cholesterol and non-HDL cholesterol.

Mechanistic pathways

• Receptor downregulation: In estrogen-replete states, estrogen stimulates genomic LDLR gene transcription via estrogen receptor-alpha (ERα) in hepatocytes. The loss of estrogen during menopause directly reduces this transcription.
• PCSK9-mediated degradation: Estrogen normally acts through ERα and G-protein estrogen receptor (GPER) to suppress the transcription and activity of PCSK9. Depleted estrogen levels allow PCSK9 expression to rise. PCSK9 binds to hepatic LDL receptors (LDLR), targeting them for lysosomal degradation and preventing their recycling to the cell surface.
• Lipogenesis and VLDL secretion: Diminished ERα activation accelerates hepatic de novo lipogenesis, alters ApoB-100 and VLDL secretion, and blunts reverse cholesterol transport.
• Impaired clearance: The combined reduction in LDLR transcription and accelerated PCSK9-mediated LDLR degradation significantly lowers functional hepatic LDLR density, directly impairing the uptake and clearance of circulating apolipoprotein B-containing particles.

Bottom line

• Bottom line: The menopause transition elevates circulating LDL and non-HDL cholesterol through an estrogen-depletion pathway that upregulates PCSK9, accelerates hepatic LDLR degradation, and decreases LDLR transcription, ultimately impairing the liver's ability to clear atherogenic lipoproteins.