Chronic insulin resistance and hypercortisolemia, common in FS patients with metabolic syndrome, may further inhibit estrogen action through: (i) Nuclear receptor crosstalk, where glucocorticoid receptor activation suppresses ER-mediated transcription [145]; (ii) Histone deacetylase activation, which closes chromatin at ER target sites [146]; (iii) Direct inhibition of aromatase, reducing local estrogen synthesis in tissues such as fat and muscle [147]. Here, ESR1 is linked to adrenal gland hyperfunction.