Targeting estrogen receptors in PCOS: A receptor-specific framework for neuropsychiatric dysfunction and therapeutic...

Area of Science:

• Endocrinology
• Neuroendocrinology
• Reproductive Medicine

Background:

• Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with reproductive, metabolic, and neuropsychiatric features.
• Current treatments focus on androgen suppression or ovulation induction, often overlooking underlying molecular mechanisms.
• Estrogen receptor (ER) signaling dysregulation is proposed as a central factor in PCOS pathophysiology.

Purpose of the Study:

• To investigate the role of dysregulated estrogen receptor (ER) signaling, specifically ER-β and GPER1, in the multisystem manifestations of PCOS.
• To explore the potential of receptor-specific estradiol-based interventions for PCOS treatment.
• To propose a framework for a receptor-informed, personalized treatment model for PCOS.

Main Methods:

• Synthesis of genomic, transcriptomic, and neuroendocrine data.
• Analysis of ER-β and GPER1 activity in relation to ER-α dominance.
• Evaluation of receptor-specific estradiol-based interventions, including SERMs and brain-selective estrogens.
• Review of ER-related polymorphisms for patient stratification.

Main Results:

• Reduced ER-β activity impairs hypothalamic-pituitary-ovarian (HPO) feedback and neuroplasticity pathways.
• GPER1 hypoactivity contributes to inflammation and insulin resistance in PCOS.
• Estradiol-based interventions targeting ER-β and GPER1 show therapeutic promise, avoiding ER-α risks.

Conclusions:

• Dysregulated ER signaling, particularly ER-β and GPER1 hypoactivity, is a core mechanism in PCOS.
• Receptor-informed, personalized treatment strategies using specific estradiol-based therapies are a promising avenue for PCOS management.
• Addressing translational barriers and incorporating genotypic/symptomatic stratification is crucial for advancing PCOS research and treatment.