What is the mechanism of action of Veozah (fezolinetant) in a 40-year-old white female with surgical menopause?

Mechanism of Action of Veozah (Fezolinetant)

Veozah (fezolinetant) is a selective neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B (NKB) binding on kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the hypothalamic thermoregulatory center, thereby preventing the neuronal activation that triggers vasomotor symptoms. 1

How Fezolinetant Works at the Molecular Level

Receptor Selectivity and Binding:

• Fezolinetant demonstrates high affinity for the NK3 receptor with a Ki value of 19.9 to 22.1 nmol/L, which is more than 450-fold higher than its binding affinity to NK1 or NK2 receptors 1
• This selective antagonism specifically targets the pathophysiology of vasomotor symptoms at the hypothalamic level 2

Central Nervous System Action:

• The drug crosses the blood-brain barrier to reach its site of action in the thermoregulatory center 3
• By blocking NKB binding on KNDy neurons, fezolinetant modulates neuronal activity in the median preoptic nucleus (MnPO) of the hypothalamus 1, 4
• This inhibition of neuronal activity in the MnPO prevents the cascade that leads to hot flashes and night sweats 4

Physiological Effects

Hormonal Profile:

• Fezolinetant does not significantly alter sex hormone levels—it shows no clear trends in follicle-stimulating hormone, testosterone, estrogen, or dehydroepiandrosterone sulfate in menopausal women 1
• A transient decrease in luteinizing hormone (LH) levels occurs at peak drug concentrations, but this is temporary 1
• This non-hormonal mechanism distinguishes fezolinetant from traditional hormone therapy, making it suitable for women who cannot or prefer not to use estrogen-based treatments 2, 5

Clinical Relevance for Your Patient

For a 40-year-old woman with surgical menopause:

• The mechanism is particularly relevant because surgical menopause causes abrupt estrogen withdrawal, leading to overexpression of neurokinin B in the hypothalamus 2
• Fezolinetant's NK3 receptor antagonism directly addresses this pathophysiological change without introducing exogenous hormones 5
• This makes it an appropriate option when hormone therapy is contraindicated or undesired, as outlined in the 2024 AHA/ASA stroke prevention guidelines for women with specific cardiovascular risk factors 6

Important Caveat:

• While fezolinetant effectively treats vasomotor symptoms through this central mechanism, it does not address other consequences of estrogen deficiency such as bone loss or genitourinary symptoms, which may require separate management 7, 8