Key Takeaways

• HCPs should initiate conversations on menopause-related symptoms, beginning when individuals are approximately 40 years of age, because patients may not recognize that their symptoms are related to the menopause transition.
• Most patients with menopause-related symptoms like VMS can be managed in the primary care setting, and referrals to specialists should be reserved for cases in which standard therapies are contraindicated.
• The FDA recently removed boxed warnings from hormone replacement therapy products, making these treatments more widely available for individuals experiencing the menopause transition.
• Neurokinin receptor antagonists are novel nonhormonal therapies that are approved by the FDA to treat moderate to severe VMS. Evidence suggests that they may also provide sleep benefits.
• HCPs should be prepared to offer hormonal and nonhormonal therapies as treatment options for individualized care of menopause-related VMS.

In this commentary, Hugh S. Taylor, MD, answers questions posed by healthcare professionals (HCPs) during a live symposium titled, “Missed Opportunities in Menopause Management: Advancing Relief for VMS and Sleep.” Learn about having conversations on menopause-related symptoms with patients, considerations for using hormonal and nonhormonal therapies, and individualizing care to help patients manage menopausal symptoms, particularly vasomotor symptoms (VMS) and sleep disturbances, to improve their overall well-being and quality of life. 

When should HCPs talk with patients about menopause-related symptoms?
It is important for HCPs to understand that many patients who are approaching or are in menopause will not bring up menopause-related symptoms, in part because they may not recognize that the symptoms they are experiencing are associated with menopause. Therefore, we should provide anticipatory guidance to those who are in the age range for transitioning into perimenopause, beginning at approximately 40 years of age, so patients know what to expect as they approach the average age at which menopause occurs, which is 52 years of age in the United States.

The most obvious signs and symptoms of menopause are VMS (ie, hot flashes and night sweats), and sleep disturbance is also common. Other key symptoms include trouble concentrating, joint pain, and vaginal atrophy and dryness, which can translate to sexual dysfunction. Our job is to ensure that patients are aware that these symptoms can be menopause-related symptoms. This is especially true for sleep disturbances because these issues are often underrecognized as being menopause-related symptoms, and they can significantly affect patients’ quality of life. In addition, some might dismiss their symptoms as a natural result of aging or stress. I often see this among patients who do not experience the classic signs of VMS. For example, a little joint pain might trigger some patients to think that they are developing arthritis, but it may be a result of a lack of estrogen because of menopause.

If any of these symptoms are troublesome enough to interfere with patients’ lives or bother them, there is no reason not to treat them. Because symptoms can come on slowly, individuals might not consider them to be related to the transition to menopause and menopause, so patients should be made aware of the full scope of menopause-related symptoms and understand that there are options available to manage them.

How do you initiate conversations with patients about menopausal symptoms and determine if a referral to a specialist is needed?
I start by getting a menstrual history from my patients. If they have not had a period for a while, I am usually confident that their symptoms are related to menopause. I then introduce the concept of perimenopause to them, ensuring they understand that menopause is not just the ovaries suddenly turning off one day. Rather, there often is waxing and waning of ovarian function over a year or longer. Educating patients about menopause, its gradual progression, and the signs and symptoms they can look for ultimately helps HCPs provide treatments, in a timely manner, to improve symptoms and quality of life. For most patients, VMS and other menopause-related symptoms can be easily managed in the primary care setting. However, if there is a contraindication present for conventional therapies for menopause-related symptoms, particularly hormone replacement therapy, that might be the right time to refer patients to a specialist.

What contraindications should HCPs keep in mind when considering hormonal therapy?
There are a few absolute contraindications for hormone replacement therapy. Presence of estrogen-sensitive cancer is one absolute contraindication because estrogen can make those cancers cells grow quickly. So those with currently active or a history of estrogen-sensitive cancer, most commonly breast cancer but also uterine or endometrial cancers, should not receive this treatment option. In addition, HCPs should ensure that patients do not have an estrogen-sensitive breast, uterine, or endometrial cancer before prescribing hormonal therapy. These cancers must be ruled out before offering hormonal therapy as a treatment for menopause-related symptoms. Unexplained vaginal bleeding is also an absolute contraindication for hormonal therapy.

Severe active liver disease and history of cardiovascular disease are additional important contraindications. Since estrogen promotes clot formation, patients with an active clot because of stroke, myocardial infarction, or venous thromboembolism (VTE) should not receive hormonal therapy. But a history of VTE, especially if related to a trauma or surgery, is only an absolute contraindication for oral hormonal therapy. It is generally safe for these patients to take transdermal estrogen therapy, but caution is still warranted. Regarding atherosclerotic cardiovascular disease (ASCVD), this is generally a contraindication for those with established ASCVD or higher ASCVD risk (eg, 10% or higher 10-year risk). Of note, caution is warranted in patients with dyslipidemia, diabetes, or hypertension who are in their 50s and have a family history of cardiovascular disease, regardless of their ASCVD risk. If premature cardiovascular disease is suspected in any patients, HCPs should use a little more caution when prescribing hormonal therapy.

There are also patients who wish to avoid hormonal therapy altogether, even though they have no medical contraindications. This is important to consider in the context of shared decision-making. Thankfully, we now have nonhormonal alternatives that are available for managing symptoms like VMS and, potentially, sleep disturbances.

How do you determine which formulation and administration route for hormonal therapy is best for each patient?
This is where shared decision-making comes into play. HCPs should discuss all options with patients and consider their preferences when determining the ideal regimen. If the only complaint is vaginal atrophy or dryness or pain during intercourse, then low-dose vaginal estrogen therapy is a good option. In turn, systemic therapy with transdermal or oral administration (ie, patches or pills, respectively) is more appropriate for those with moderate to severe VMS and other symptoms.

There is some evidence that shows a decreased risk of blood clots with transdermal hormonal therapy. But for most patients who are starting the menopause transition, that is not necessarily a significant concern, and I would not let this be a determining factor. If patients are more comfortable with an oral option, I would prescribe that. The same is true for those who are more comfortable with using patches and wish to avoid oral medications. Both transdermal and oral hormonal therapy options serve a purpose, and certain comorbidities may further inform which option is best for each patient. For example, patients may see better sexual function with transdermal application vs increased diabetes control with oral administration of hormonal therapy.

Systemic hormone therapy is necessary for addressing symptoms like VMS, joint pain, and sleep disturbances. In these cases, HCPs must remember that, in patients with a uterus, they need to use a therapy that will counteract the estrogen in the uterus to prevent endometrial hyperplasia—either estrogen in combination with progestin or conjugated estrogen plus bazedoxifene. In the latter option, bazedoxifene, which is a selective estrogen receptor modulator (SERM), counteracts estrogen in both the uterus and breasts.

In general, I avoid compounded hormonal therapies. That is because there is less reliability when it is compounded, especially since there are well-controlled pharmaceutical estradiol and progesterone options that are approved by the FDA. These pharmaceutical options are less expensive, considering generic forms are available, and they can be easily administered in traditional formulations that allow for flexibility in dosing. Furthermore, the American College of Obstetrics & Gynecology recommends against the routine use of compounded bioidentical hormonal therapy for menopause-related symptoms.

The other thing I have not mentioned yet is bone health, which is particularly sensitive to hormonal therapy. Of course, I do not suggest using hormonal therapy specifically for bone disease, as there are FDA-approved therapies with relevant and specific indications. However, it is an additional benefit of treating menopause-related symptoms because osteoporosis is a major complication of menopause.

What are the common pitfalls HCPs should avoid when prescribing hormonal therapy?
It is not as hard as people think. There was so much publicity over the exaggerated results of the Women’s Health Initiative that ingrained fears and concerns in women’s heads for decades. But for a typical 50-year-old patient starting the menopause transition, there is little risk with using hormonal therapy. The only thing to be cautious of is making sure HCPs use estrogen combined with a progestin or bazedoxifene in those with a uterus to prevent endometrial hyperplasia.

We also have novel nonhormonal therapies, specifically the neurokinin (NK) receptor antagonists that directly improve VMS and may also help with sleep disturbances. But they do not directly address sexual dysfunction, joint pain, or bone health. Therefore, if moderate to severe VMS is the only complaint patients have and they are hesitant to use or have an absolute contraindication to hormonal therapy, NK receptor antagonists are effective and safe for this population.

Finally, the one mistake I see HCPs make is ignoring patients’ menopause-related symptoms and not helping them feel better. We have so many different treatment options available now, including for those who do not want to or cannot take hormonal therapy, that there is no reason HCPs should refrain from offering their patients treatments for menopause-related symptoms.

How do you address patients’ concerns about hormonal therapy?
I think HCPs should review the current data with patients. In doing so, I like to discuss the risks presented in the Women’s Health Initiative and today’s interpretation of the results. Then with combination estrogen–progestin therapy, patients should know that there is a modest increase in their risk for breast cancer. I also make it clear that those who initiate hormonal therapy within 10 years of menopause onset see a reduction in all-cause mortality and fracture risks, which shows my patients that people are not dying but seeing benefit from hormonal therapy.

I put all this information into perspective and balance it, too. For example, that increased breast cancer risk is not seen with estrogen alone or combined conjugated estrogen plus a SERM. In addition, we have done a lot to alleviate that risk by using natural forms of progestin or lowering the dosing or frequency of it. This helps patients understand that we do not want to increase their risk and can always use those other combinations that avoid progestin altogether as needed.

I also will share the many benefits reported in current studies. Part of that addresses cardiovascular risk, which was overstated for so many years after the Women’s Health Initiative. I ensure my patients understand that during the time when most people go through menopause and need relief, they are not at increased cardiovascular risk with hormonal therapy. If patients are 75 years of age, that is a different and more difficult conversation. As I mentioned before, most patients do not go through menopause at 75 years of age, so this is not representative of our reality. But it is something that, unfortunately, got integrated into the public health discussion about hormonal therapy that HCPs must address.

Do you have any tips for helping patients discontinue hormonal therapy?
There is no set time for when patients must stop hormonal therapy. They should use it as long as it is needed, and HCPs should reevaluate the risks and benefits with patients annually. For those in their 50s to 60s, I do not encourage my patients to stop it. If they miss doses for a few days and their symptoms return, I actually encourage them to continue their hormonal therapy

As patients age (ie, into their 70s) or if they develop underlying cardiovascular disease, then this becomes a more difficult risk vs benefit discussion. I generally taper patients down and get them off their hormonal therapy later in their lives. But again, not everyone has relevant risk factors. Some might have very few risk factors and experience severe VMS until much later in their lives. Therefore, the timing of discontinuation must be individualized based on patient factors and through shared decision-making.

How do nonhormonal therapies, particularly the newer NK receptor antagonists, fit into the treatment algorithm for menopause?
The nonhormonal NK receptor antagonists include elinzanetant (an NK1/3 receptor antagonist) and fezolinetant (an NK3 receptor antagonist). Both are effective at reducing the frequency and severity of VMS and are approved by the FDA for the treatment of moderate to severe VMS. In addition, elinzanetant has been shown to significantly improve sleep quality. I tend to prescribe these options for patients with a contraindication to or who do not want to use hormonal therapy.

As a reminder, VMS are not restricted to hot flashes. In reality, patients also experience a racing heart, palpitations, sweating, and anxiety. It can be quite disturbing. Having these 2 nonhormonal agents as well as hormonal therapy available is great because all are incredibly effective at addressing VMS and allow patients the ability to choose which option best fits their needs.

If patients also have issues related to their bone health, joint pain, or vaginal atrophy or dryness, why not use estrogen therapy? If they do not have a contraindication, hormonal therapy will take care of all their symptoms, including VMS, simultaneously. In these cases, I would lean in that direction. But if their only concern is VMS and/or sleep, HCPs can rely on an NK receptor antagonist as well. Ultimately, the decision should be made via shared decision-making with patients.

Regarding the concomitant use of both nonhormonal and hormonal therapy, I do not suggest using both options for VMS alone. Some patients might not want to use systemic estrogen therapy but are experiencing VMS and vaginal atrophy or dryness. In these cases, you can use an NK receptor antagonist for the VMS and vaginal estrogen therapy to restore the vagina. This allows patients to only use local estrogen when and where they need it while relying on the nonhormonal option to alleviate any hot flashes or night sweats. This is a nice combination. In general, however, I do not use both hormonal and nonhormonal therapies for the same indication (eg, VMS); I will pick one or the other.

Is there any specific information HCPs should know when integrating NK receptor antagonists into their practice?
One thing is exacerbation of liver toxicity with fezolinetant. It is recommended that HCPs measure patients’ liver function at baseline and throughout the first few months of treatment. This was not commonly reported in clinical trials—only 2.3% of patients receiving fezolinetant in 3 clinical trials saw elevations in their liver enzymes. But it is a significant concern that must be monitored.

Your Thoughts
Menopausal symptoms are almost universal and can be quite severe and debilitating for some patients. These symptoms can be devastating and interrupt someone’s life. The surge of adrenaline, sweating, and anxiety with VMS can interfere with patients’ jobs and relationships. This is why relieving menopause-related symptoms must be taken seriously. They can have a major impact on patients’ quality of life despite being relatively easy to address with the many great therapies that are now available.

How often do you prescribe a therapy that is indicated to relieve menopause-related symptoms for your patients who experience them? You can get involved in the discussion by answering the poll question and posting a comment below.