If vasomotor symptoms (VMS) like hot flashes and night sweats disrupt your days and nights, know you’re not alone. These symptoms affect up to 80% of menopausal women. For many, hormone replacement therapy (HRT) offers meaningful relief. However, for those who can’t take HRT, fezolinetant can offer similar relief without hormones.

Which of these medications might be right for you? Read on as we compare HRT versus fezolinetant, including how they work, what symptoms they treat, and which side effects and risks they present.

‍

What causes VMS in menopause?

During menopause, estrogen and progesterone levels naturally decline. This drop in estrogen is the primary driver of VMS like hot flashes and night sweats. 

Your brain’s temperature control center (hypothalamus) is full of KNDy neurons. These neurons contain estrogen receptors that keep nerve signaling stable. When estrogen levels drop, these receptors lose their primary input (estrogen), causing nerve signaling to destabilize. This overstimulates KNDy neurons, causing them to flood the area with a signaling protein called neurokinin B (NKB).

Excess NKB then binds neurokinin 3 (NK3) receptors, specialized docking sites on nearby nerve cells in the hypothalamus. Normally, these receptors help regulate body temperature by turning temperature signals on and off. But the flood of NKB keeps those temperature signals stuck on.

Because of this chemical disruption, your brain misinterprets small external or internal temperature changes as dangerous overheating events. Your hypothalamus then triggers emergency measures, like sudden blood vessel widening (vasodilation) and sweating, to cool your body back down.

‍

Understanding fezolinetant and HRT

Your doctor may consider HRT or fezolinetant to relieve VMS like hot flashes and night sweats. These medications each work differently in your body.

How does fezolinetant relieve VMS?

Fezolinetant (brand name Veozah®) is a nonhormonal hot flash treatment that works by plugging NK3 receptors so the excess NKB flooding the area can’t dock. This effectively blocks overheating signals.

How does HRT relieve VMS?

HRT is a broader treatment for symptoms of menopause. While fezolinetant blocks a specific receptor downstream, HRT addresses the problem at the root by directly supplementing the hormones your body has lost. 

When replacement estrogen binds to the estrogen receptors in your hypothalamus, it acts like a natural brake. It calms the KNDy neuron, causing it to stop overproducing and releasing NKB. When there’s no excess NKB to bind to NK3 receptors, the NK3 receptors naturally calm down. 

Your doctor may prescribe estrogen-only therapy or combined HRT with both estrogen and progesterone (or a progestin). For people with an intact uterus, doctors often recommend combination HRT, which pairs estrogen with progesterone. This supports hormonal balance, provides comprehensive menopause symptom relief, and protects the uterine lining to reduce endometrial cancer risk.

‍

HRT vs. fezolinetant at a glance

The main differences between HRT and fezolinetant is the range of symptoms they treat. By supplementing declining hormones, HRT can address a wider range of menopause symptoms than just VMS, including sleep disturbances, low mood, and vaginal dryness. Fezolinetant’s role is narrower; doctors prescribe it to treat VMS specifically. There are a few other factors that set these medications apart, too, which we’ll cover below:

‍

Which is more effective in relieving VMS?

According to The Menopause Society, HRT is the most effective treatment for VMS. However, there aren’t any studies directly comparing HRT and fezolinetant. Instead, we can look at separate studies to understand their effectiveness in this area.

HRT

One study, published in the Cochrane Database of Systematic Reviews, pooled data from 24 trials involving 3,329 menopausal women. Researchers compared oral HRT against placebo, and here’s what they found: 

• VMS Frequency: Participants on oral HRT experienced 17.92 fewer hot flashes per week than those on placebo, a 75% reduction in frequency. 
• VMS Severity: Compared with placebo, participants taking oral HRT also experienced a meaningful reduction in symptom severity. 

Fezolinetant

The SKYLIGHT 1 trial, published in The Lancet, included 527 menopausal women who experienced seven or more moderate-to-severe hot flashes per day. Researchers assigned participants to receive either fezolinetant (30 mg or 45 mg) or placebo. 

At week 12 of the study, the 45 mg group experienced 2.55 fewer episodes per day than placebo, on average. The 30 mg group experienced 2.39 fewer. Severity meaningfully dropped across both groups, too.

HRT vs. fezolinetant: Side effects and risk considerations

HRT and fezolinetant have distinctive side effects and risk profiles. Your doctor will work with you to determine which treatment is right for you.

Common side effects

HRT side effects tend to be broad and system-wide, while fezolinetant’s side effects are concentrated in the nervous system. This means they share some side effects, but each medication also has a few unique ones. For both, side effects tend to ease as your body adjusts to treatment. Here are some of the most common, though this isn’t an exhaustive list:

Rare but serious side effects

Both medications have more serious side effects, though they’re less common. Oral HRT carries additional systemic risks like blood clots and stroke due to body-wide circulation. Local HRT largely minimizes those additional risks because very little of the hormone enters the bloodstream. Synthetic progesterone also slightly increases the risk of breast cancer. 

Fezolinetant carries a rare but serious risk of liver injury. Liver numbers must be checked at baseline and months one, two, three, six, and nine of treatment. 

Risk considerations

HRT and fezolinetant both have conditions or circumstances that make treatment unsafe (contraindications). If you have one, your doctor will walk you through alternative treatment options.

Fezolinetant’s contraindications include known late-stage liver scarring (cirrhosis) and severe renal impairment or end-stage kidney disease. If you’re taking CYP1A2 liver inhibitors, you also shouldn’t take this medication. These inhibitors can increase the level of fezolinetant in your system, leading to increased side effects.

Because HRT involves introducing external hormones into the body, certain contraindications apply across both oral and local treatments, including:

• A history of estrogen-sensitive cancers, such as certain types of endometrial or breast cancer, as hormones can stimulate the growth of these cells
• Unexplained vaginal bleeding, as it can be a sign of abnormal thickening (endometrial hyperplasia) or endometrial cancer.
• Active liver disease because the liver metabolizes hormones.

‍

Who should take HRT or fezolinetant?

Choosing the right treatment depends on your personal symptom goals, health history, and preferences. Your doctor will review your full health picture to help you decide between the two:

• HRT is typically a fitting choice for broader symptom relief beyond just hot flashes and night sweats.
• Fezolinetant may make more sense if you can’t take estrogen due to a personal history of estrogen-sensitive cancers, blood clots, or other hormone-related risks.

Your comfort level with using a hormonal versus a nonhormonal path also plays an important role. Bring your preferences up with your doctor so you can weigh the benefits together. 

‍

A whole-person approach to menopause care

Because no two experiences of menopause are alike, navigating treatment options requires weighing your symptom goals, health history, and personal preferences. At Maven Clinic, our specialists work with you to identify the right treatment option using a whole-person approach.

As one of our patients, Dara, expressed: "The holistic view and approach for managing perimenopause and menopause have been life-changing! Nearing 50, I am in the best physical shape with support from the physical support and nutrition coaches."

Discover our approach to hormone care.