Novel Non-Hormonal Therapies for VMS: Mechanisms and Clinical Evidence

In "Novel Non-Hormonal Therapies for VMS: Mechanisms and Clinical Evidence," our panel explores the neurophysiology underlying vasomotor symptoms and the clinical significance of two FDA-approved neurokinin receptor antagonists that represent a meaningful advance in non-hormonal VMS treatment.

Dr. Kristi DeSapri opens by identifying three key patient populations for whom non-hormonal options are particularly relevant: women with contraindications to menopausal hormone therapy due to cardiovascular or breast cancer risk or personal preference; women well beyond the menopause transition — including so-called "super flashers," approximately 10% of women who continue experiencing hot flashes for more than 15 years, even into their 70s; and women living with breast cancer who are on aromatase inhibitors or other adjuvant therapies that induce VMS while precluding hormone therapy use.

The physiological mechanism driving VMS is explained in accessible terms. When estrogen levels decline, KNDy neurons in the hypothalamus become hyperactivated and enlarged, overstimulating the thermoregulatory center and triggering frequent, persistent hot flashes and night sweats — described as a "broken thermostat." Neurokinin receptor antagonists work by calming this neuronal activity and interrupting the signaling cascade responsible for VMS.

The two agents are then distinguished: fezolinetant, approved in 2023, is a selective NK3 receptor antagonist, while elinzanetant, approved in 2025, is a dual NK1/NK3 receptor antagonist that may additionally influence neurokinin and substance P activity, with potential benefits for sleep. Clinical trial data across thousands of women demonstrate that both medications reduce hot flash frequency and severity by approximately 40–50%, offering a clinically meaningful and well-tolerated option for women across a wide range of VMS presentations.

Our next episode, "Safety and Cardiovascular Considerations of Novel Non-Hormonal VMS Therapies," examines the safety profiles, monitoring requirements, and cardiovascular implications of fezolinetant and elinzanetant, offering clinicians practical guidance on patient selection, contraindications, and what to watch for when initiating these novel agents. to use menopausal hormone therapy.