Menopause part I: Vasomotor symptoms (I)

Area of Science:

• Reproductive Endocrinology
• Neuroscience
• Pharmacology

Background:

• Menopause, characterized by estrogen decline, significantly impacts women's health, with vasomotor symptoms (VMS) affecting up to 80% of individuals.
• VMS negatively impacts physical, psychological, and social well-being, persisting for over seven years.
• Traditional hormone therapy for VMS faces benefit-risk debates, driving interest in non-hormonal treatments targeting VMS pathophysiology.

Purpose of the Study:

• To review the recent advancements in managing moderate-to-severe VMS in menopausal women.
• To focus on the efficacy and safety of fezolinetant, a novel neurokinin 3 receptor (NK3R) antagonist, as a non-hormonal treatment for VMS.
• To discuss the role of the KNDy neuron pathway in VMS and the therapeutic potential of NK3R antagonists.

Main Methods:

• Review of recent randomized clinical trials (RCTs), including SKYLIGHT 1, 2, and 4, evaluating fezolinetant for VMS.
• Analysis of the MONGLIGHT RCTs assessing fezolinetant in East Asian populations.
• Exploration of the neurobiological mechanisms involving Kisspeptin (Kp), neurokinin B (NKB), and dynorphin (DYN) neurons (KNDy neurons) in thermoregulation and VMS.

Main Results:

• Three major RCTs (SKYLIGHT 1, 2, 4) demonstrated the safety and efficacy of fezolinetant in treating moderate-to-severe VMS.
• The MONGLIGHT RCTs indicated a potentially controversial therapeutic effect in East Asian populations, but confirmed safety.
• Fezolinetant represents a significant breakthrough in non-hormonal VMS management by targeting the central thermoregulatory circuitry.

Conclusions:

• Fezolinetant is a promising non-hormonal therapeutic agent for moderate-to-severe VMS in menopausal women.
• While generally safe and effective, further RCTs are warranted to validate efficacy across diverse populations.
• Targeting the KNDy neuron pathway via NK3R antagonism offers a novel approach to managing menopausal vasomotor symptoms.