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Abstract

Vasomotor symptoms of menopause (VMS), otherwise known as hot flashes, can significantly impact women’s quality of life. Up to 87% of women report hot flashes during or after their menopause transition, and can last for a median duration of 7.4 years. The current mainstay of treatment and the most effective treatment for VMS is hormone therapy with estrogen. However, hormone therapy is not without risk, and the discovery of an effective nonhormonal treatment option with neurokinin B receptor antagonists for VMS provides an encouraging and potentially practice-changing treatment option for all women. This review will discuss the pathophysiology and mechanism of action, as well as review the current compounds in development targeting the neurokinin receptors.

Keywords

hot flashes KNDy neurons menopause neurokinin receptor vasomotor symptoms

Introduction

Menopause is the permanent cessation of menstruation that occurs after loss of ovarian activity, degeneration of ovarian follicles, and loss of ovarian estrogen secretion. It is a normal and expected transitional life occurrence. Clinical manifestations include genitourinary symptoms, sleep disturbances, mood changes, decreased libido, joint pain, and vasomotor symptoms (VMSs), otherwise known as hot flashes. Hot flashes are typically short, sudden sensations of heat in the upper body, often characterized by perspiration, flushing, chills, clamminess, anxiety, and heart palpitations. These symptoms can be disruptive and bothersome to women, as up to 87% of women report hot flashes during or after their menopause transition.¹ This review first addresses the impact of VMSs on women’s lives and traditional treatments and then focuses on the newest advances in pathophysiology that have led to targeting of the neurokinin-3 receptor (NK3R) for the alleviation of this cardinal symptom of menopause.

Search strategy for the review

Because the field is in its infancy, there are few published clinical trials and many agents in development. Our search strategy primarily utilized PubMed to identify publications that included human research and clinical trials as well as the keywords NK3R, hot flashes, and VMSs. Additional searches of clinicaltrials.gov using the keywords hot flashes and VMSs were performed to identify unpublished data, and abstracts from national and international menopause and other scientific meetings were searched for specific compounds.

The impact and pathophysiology of menopausal VMSs

Symptoms of menopause can significantly impact women’s quality of life. A large US population-based study by Williams et al. found that hot flashes cause a substantial burden on women’s lives. They found that VMSs interfered with work, social activities, leisure activities, and sexual activity. VMS also impacted sleep, mood, concentration, total energy level, and overall quality of life.² Lost productivity due to interference at work includes significantly increased time missed from work, as well as impairment at work.³ In addition, social factors and lifestyle choices contribute to the impact of menopausal symptoms on quality of life. Smoking was shown to increase the risk of hot flashes, while being younger at time of symptom onset, lack of physical activity and having a higher BMI resulted in poorer quality of life in relation to menopausal symptoms.² While it has been shown that VMS leads to significantly decreased quality of life, Avis et al.⁴ found the median total duration to be 7.4 years, with African-American women experiencing VMS for a medial duration of 10.1 years. They found the single most powerful predictor of total duration of VMS to be age at which women first experienced VMS. Together, these studies found that women who experienced onset of VMS at a younger age were shown to have significantly longer total duration, as well as decreased quality of life.^2,4

While the pathophysiology of VMS is not completely understood, their onset is thought to be related to the narrowing of the thermoregulatory system, which maintains the core body temperature within the thermoregulatory zone. The decline in estrogen can be due to the physiologic menopausal transition, anti-estrogenic medications or gonadectomy. Decreased estrogen results in an apparent narrowing of the comfortable temperature range for an individual, which causes the perception of excessive warmth to occur at temperatures at which the individual would have previously been comfortable or thermoneutral.⁵ Women undergoing the menopausal transition are more likely to experience symptoms, such as hot flashes, with changes in the core body temperature outside of the thermoregulatory zone as the thermoregulatory zone is narrowed in menopause.⁶ Autonomic thermoeffector pathways in the median pre-optic nucleus responds to fluctuations in body temperature outside of the thermoregulatory zone, which subsequently leads to cutaneous vasodilatation, which is the hallmark of VMS.⁷ Despite the association of VMS with the decline in estradiol associated with menopause, ambient estradiol levels during a hot flash, particularly in perimenopausal women, do not always predict VMS. There is likely some relationship to dynamic changes in estradiol during the menopause transition and early postmenopausal that precipitate VMS and some studies have associated VMS with more variable estradiol levels in perimenopausal women. The fact that most women restabilize at some time point after menopause and stop experiencing VMS indicates that low estradiol levels alone may not be sufficient to trigger VMS and that other mechanisms are at play. Estrogen plays an important role in body temperature regulation, as it has been clearly shown that treatment with estrogen improves VMS.

Discovery of the role of the NK3R in VMS pathophysiology

The hypothalamic-pituitary ovarian axis is responsible for reproductive function in women. Gonadotropin releasing hormone (GnRH) is released in a pulsatile fashion from the hypothalamus, which in turn triggers the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. Elevated FSH and LH trigger the release of estrogen from the ovaries, which then leads to a negative feedback effect on the secretion of GnRH. Postmortem studies performed by Rance et al.⁸ found hypertrophy of a subpopulation of neurons in the arcuate nucleus, called the “KNDy neurons,” in postmenopausal women. These estrogen-responsive neurons express kisspeptin, neurokinin B (NKB), and dynorphin, which have been found to be implicated in the secretion of GnRH.⁹ The NKB and dynorphin neurons act on the kisspeptin neurons to stimulate the secretion of kisspeptin. In turn, the kisspeptin drives the secretion of GnRH in a pulsatile fashion. Elevated circulating levels of estrogen suppress kisspeptin and the expression of the KNDy neurons, which in turn leads to reduced secretion of GnRH and LH.¹⁰ In addition, these neurons have projection pathways to the warmth-sensing neurons in the medial preoptic area of the brain, so it is thought that NKB signaling could additionally influence heat-defense effectors and cutaneous vasodilatation.⁸ In summary, estrogen deficiency in menopause leads to the upregulation of NKB and its receptor (NK3R) via the median preoptic nucleus, which receives input and projects to the autonomic thermoregulatory pathway leading to the hallmark symptom of cutaneous vasodilatation, VMS.¹¹

In 2017, Crandall et al. performed a genome-wide association study to evaluate the relationship of genetic variation and VMSs of menopause. In this study, they found that the tachykinin receptor 3 gene on chromosome 14 was associated with VMSs.¹² The tachykinin receptor 3 (TAC3R) gene encodes for NKB receptor, thus supporting a biological pathway involved in VMSs. Mittleman-Smith et al. ablated the KNDy neurons in ovariectomized rats with a selective toxin and compared skin-tail vasodilation to ovariectomized rats with intact KNDy neurons. They found that the average core temperature of the ovariectomized control rats was significantly elevated compared to the ovariectomized rats with ablated KNDy neurons, suggesting that blocking the KNDy neuroendocrine pathway is associated with improved VMSs.⁷

Other molecular targets currently being studied for nonhormonal treatments of menopause discussed in this review include the transient receptor potential melastatin 8 channel (TRPM8) channel, chemokine receptor type 4 (CXCR4) receptor, and granulocyte colony-stimulating factor. TRPM8 plays a role in the sensation of cold temperature, and it is hypothesized that a TRPM8 antagonist would reduce VMSs by using the body’s natural cooling to prevent increases in core body temperature leading to improvement in VMSs.¹³ CXCR4 interacts with the KNDy neurons as described above and could be utilized as a target for treatment options.

Traditional treatments for VMSs

The current mainstay of treatment for VMSs of menopause is hormone therapy and it remains the most effective treatment. Systemic hormone therapy with estrogen alone or in combination with progestin is the most effective treatment for VMS.¹ In users of oral estrogen or oral estrogen plus progestin compared to placebo showed a 75% reduction in weekly hot flush frequency.¹ Estrogen can be administered orally or transdermally via patches, gels or sprays. However, hormone therapy is not without risk. The Women’s Health Initiative study found that hormonal therapy with estrogen plus progestin was associated with an increased risk of breast cancer and cardiovascular disease, including coronary heart disease, stroke, and thromboembolic disease.¹⁴ The effect of hormone therapy on the risk of coronary heart disease was found to be associated with age. A meta-analysis in 2006, including the WHI study and 22 smaller studies, found that hormone therapy reduced coronary heart disease events in younger postmenopausal women, those aged less than 60 years of age, and those less than 10 years from menopause onset.¹⁵ For women who had had a hysterectomy, hormone therapy with estrogen only was associated with fewer risks—importantly, breast cancer risk was not increased with this treatment—but did not have sufficient long-term benefit to justify its use in the absence of symptoms. Thus, the American College of Obstetricians and Gynecologists recommends individualizing hormone treatment based on each woman’s risk–benefit ratio and their clinical symptoms.¹

Given the risks of hormone treatment for VMS, other treatment options include selective serotonin-reuptake inhibitors (SSRI) and serotonin and norepinephrine reuptake inhibitors (SNRI), gabapentin, oxybutynin, and other complementary or alternative medicine approaches.⁶ However, these treatment modalities are less efficacious as compared to hormone therapy.⁶ Currently, paroxetine is the only nonhormonal treatment option to be FDA-approved for the indication of hot flashes. Other complementary or alternative medicine approaches include mind-body interventions (such as hypnosis, cognitive behavioral therapy, relaxation, meditation and aromatherapy), natural products (e.g., herbs, vitamins, minerals and dietary supplements), and whole-system approaches (including traditional Chinese medicine, reflexology, acupuncture, homeopathy).¹⁶ Complementary approaches are not regulated by the FDA and data thus far is mixed for use of herbal supplements and lifestyle modifications for the treatment of VMS.¹ The Menopause Strategies: Finding Lasting Answers for Symptoms and Health clinical trials network evaluated the effect of various complementary methods, including yoga, aerobic exercise, omega-3 fatty acids, and cognitive behavioral therapy, on menopausal symptoms. These trials found that cognitive behavioral therapy was effective in reducing insomnia symptoms for menopausal women with hot flashes, while there was no benefit on VMSs with yoga, exercise, or omega-3 supplementation.^17,18 However, the CBT-Meno randomized controlled trial found that cognitive behavioral therapy for menopausal symptoms showed significantly greater improvements in VMS interference, “bothersomeness,” sexual concerns, sleep difficulties, and depressive symptoms.¹⁹

Menown and Tello and colleagues performed a systematic qualitative review directly comparing NK3R antagonists with SNRIs for the treatment of VMSs. They found that NK3R antagonist administration resulted in a larger reduction from baseline in hot flash frequency, severity, and night sweats as compared to SNRIs. In addition, they found that NK3R antagonist trials showed good tolerability of the oral medication, while SNRI trials reported increased nausea and overall poor tolerability.²⁰

Additionally, hormone therapy is contraindicated in patients who have a history of certain cancers, most notably breast cancer. Women may be experiencing VMS due to oophorectomy or chemotoxic effects on the ovaries. Hormone therapy is also contraindicated in women who have had venous thromboembolism or who have active liver disease or other hepatic impairment. Finally, many women simply do not wish to take hormones for a variety of reasons, even though they are not contraindicated. Thus, the discovery of an effective nonhormonal treatment option, such as an NKB3 receptor antagonist, for VMS provides an encouraging and potentially practice-changing treatment option for all women.

Clinical data to date on NK3R antagonists

Current compounds that target the NK3R include fezolinetant, MLE4901, MT-8554, and Q-122. Fezolinetant is the most studied compound to date. Studies performed by Santoro et al., Fraser et al., and Depypere et al., have shown promising results for fezolinetant and improvement of VMSs.^21–23 Given these compounds are not yet to market, the clinical data are limited and are summarized below. However, studies to date have shown that fezolinetant is generally well-tolerated and safe. Fraser et al.²² reported the most common side effects experienced with fezolinetant to include nausea, diarrhea, fatigue, urinary tract infections, upper respiratory tract infections, sinusitis, headaches, and cough.²² They reported treatment-related adverse events to include cholelithiasis and drug-induced liver injury. Transient elevations of liver enzymes were followed and rapidly returned to baseline after discontinuation of therapy or trend toward normalization in patients that remained on the study drug.

Targeting of the neurokinin receptors as clinical treatments for VMSs appears to be a highly specific intervention and has led to some promising initial findings. Some basic clinical findings are summarized in the Table 1. No agent is yet available on the market, and thus there is little widespread clinical experience at this point. However, in standardized clinical trials that conform to the FDA guidance for studies of VMS treatment (which includes criteria that participants should have a minimum average of 7 hot flashes a day or 49 per week and the test agent must be compared to a concurrent placebo group), the NK3R antagonist compounds compare favorably to estrogen. This is remarkable, given that none of the nonhormonal alternatives currently available for treating VMS have such efficacy. This class of compounds is, therefore, of great potential interest to menopausal women and the clinicians who care for them.

Table 1.

Summary Table of VMS Frequency Reduction Achieved With Novel Nonhormonal Agents.

Agent	Target	N	Country(ies)/Continent(s)^a	Age range	Race/Ethnicity	Max %VMS reduction	Citation	Length of study	Type of study
MLE4901	NK3R	37	UK	40–62	N/A	72	Prague et al.²⁴	4 weeks crossover	RCT
Fezolinetant	NK3R	352	USA	40–65	18–33% Black21–40% Hispanic	87	Fraser et al.²²	12 weeks	RCT
NT-814	NK1/NK3	76	USA	40–65	21% Black	84	Trower et al.²⁵	2 weeks	RCT
NT-814	NK1/NK3	152	North America, UK	40–65	21% Black	60	Simon et al.²⁶	12 weeks
MT-8554 (Elismetrep)	TRPM8	375	North America, Europe, Asia	⩾18	20–31% Black	44	Kingsberg et al.¹³	12 weeks	RCT
Q-122	CXCR4, KNDy neurons	21	N/A	30–70	90% Black	59	Painter et al.²⁷	28 days	Dose escalation
G-CSF	Unknown, multiple anti-inflammatory actions	29	USA	50–65	44% Black	35	Guiahi et al.²⁸	12 weeks	RCT

Race/ethnicity of study samples are not available for abstract derived data. When available the % of participants who self-identified as Black/African-American or Hispanic/Latino are indicated.

CXCR, chemokine receptor, G-CSF, Granulocyte colony-stimulating factor, KNDy, kisspeptin, neurokinin (NKB), and dynorphin, NK3R, neurokinin-3 receptor, RCT, randomized clinical trial, TRPM8, transient receptor potential melastatin 8 channel, VMS, vasomotor symptom.

Initial studies of MLE4901 indicated immediate, highly significant and sustained relief from VMS.²⁴ A total of 37 women were randomized to MLE4901 or to placebo. Active drug reduced hot flash frequency by 72% by day 3, compared to 20% in the placebo group, and this effect persisted throughout the 4 weeks of initial dosing. After crossover, similar findings were observed. Notably, a significant reduction in VMS frequency was observed (38%) by the third day of dosing, indicating a very rapid onset of effect. Daytime and night-time VMS were analyzed separately, with similar relief during both time periods. An examination of menopausal symptoms using the Menopause-specific Quality of Life Questionnaire and the Hot Flash Related Daily Interference Scale (HFRDIS) indicated rapid and significant improvement.^29,30 Further examination of the domains of these two questionnaires implied that sleep quality was improved by MLE4901 along with the rapid and dramatic reduction in VMS. Further development of MLE4901 was halted due to liver enzyme elevations in some participants.

Fezolinetant has been the most extensively investigated and reported NK3R antagonist to date. In a 12-week, multicenter randomized clinical trial of 87 Belgian women, participants were randomized to 90 mg fezolinetant bid or to placebo. In addition to noting near-immediate improvement in VMS score (a combination of frequency and severity), 12-week results indicated that women randomized to fezolinetant experienced 5.7 hot flashes per week compared to 39 per week in the placebo group.³¹ Additional improvements were observed in sleep quality, hot flash daily interference, and overall climacteric symptoms. Adverse events were rare and evenly distributed between active drug and placebo groups.

A subsequent dose-ranging study of fezolinetant included 7 dosing regimens with daily doses of 30–100 mg. Of 352 women who took at least one dose of study medication or placebo, a reduction of VMS of at least 50% was experienced by 81.4–94.7% of women randomized to fezolinetant compared to 58.5% of women randomized to placebo.²² Per cent reduction in moderate-to-severe hot flash frequency ranged from 74–87% with fezolinetant versus 55% with placebo by week 12. Adverse effects were noted again to be rare and evenly distributed across all doses and placebo groups. Endometrial thickness was also monitored in this study, with no evidence of changes related to fezolinetant administration. In a follow-up study (the VESTA trial) addressing patient-reported outcomes, dose-related improvements in the HFRDIS and the Greene Climacteric Scale (GCS) demonstrated treatment-associated responses for active drug greater than placebo throughout the 12-week study.^21,32

Subsequent studies include the Skylight and Moonlight trials (NCT04003155, NCT04003142, NCT04003389 and NCT04234204), which are currently undergoing preparation for publication. Initial findings in the form of abstracts indicate similar efficacy and safety of fezolinetant in US, Canadian, and European women but not in Chinese women.^33,34 The Moonlight trial, which tested 30 mg daily of fezolinetant compared to placebo in 302 women from China, Japan, and Korea, did not meet its primary efficacy end points at 12 weeks. Based on the overall lower frequency and duration of VMSs and less overall severity seen in Chinese-American women in the Study of Women’s Health Across the Nation (SWAN),³⁵ it is possible that the women recruited for the Moonlight trial had overall less severe symptoms, making it more difficult to measure differences between the placebo and active treatment groups.

Other compounds under investigation for VMS treatment include NT-814, a dual NK1 and three antagonists. In a 2-week US-based Phase 2b randomized trial of 76 postmenopausal women with moderate-to-severe VMS, the two maximal doses of NT-814, 150 mg and 300 mg, caused an 84% and 66% reduction in hot flashes, respectively. Hot flash reduction in the placebo group was 37%.²⁵

Other compounds that are in clinical trials include MT-8554 (NCT03291067), which has just completed a 12 weeks, Phase 2 randomized clinical trial with 375 participants.¹³ Three doses of elismetrep (1, 5, and 10 mg) were administered to 58, 59 and 58 women, respectively. A total of 54 women were randomized to placebo. By week 12, the 5 mg elismetrep dose resulted in a 42% reduction in VMS frequency compared to a 15% reduction in the placebo group. Safety and tolerability appeared acceptable for women receiving the 5 mg dose.

Q-122 is another related compound under investigation for its usefulness in treating VMS in women with breast cancer. It does not target the NK3R, but it does inhibit the firing of the kisspeptin–neurokinin–dynorphin (KNDy) neurons in the brain. It is a CXCR4 modulator. In Phase 1b study of Q-122, 21 women with breast cancer who were taking tamoxifen or an aromatase inhibitor were administered Q-122 for 28 days with potential dose escalation (from 100 to 200 mg a day) for a second 28 days period.²⁷ A 59% reduction in VMS frequency was observed, along with improvements in the GCS. No adverse side effects were reported. A Phase 2 clinical trial is currently underway (NCT03518138).

Granulocyte colony-stimulating factor (G-CSF) has also been investigated as a possible nonhormonal treatment for VMS.²⁸ In a 12 week pilot trial of a single dose, G-CSF was given to 19 women and 10 received placebo. A statistically significant 35% reduction in hot flashes was observed at 2 weeks in the treated group versus 5% in the placebo group. G-CSF does not have a verified mechanism of action but has overall anti-inflammatory effects. Further trials are currently underway (NCT03640754).

Taken together, the newer NK targeting compounds appear to have high efficacy against VMS and reduce both frequency and severity. When additional measures have been sought, there appears to be an improvement in sleep, particularly for the NK3R antagonists. Whether these promising early findings will carry over into the clinic remains to be seen, but enthusiasm is overall high for agents that have comparable efficacy to hormone therapy but can be used in women who cannot or will not take hormones.

Summary and conclusions

VMS is a hallmark symptom of menopause and constitutes a substantial burden to many women due to their ability to disrupt daily activities, negatively impact sleep and mood, and overall decrease quality of life. Despite decades of research, the anatomical source of VMS has only recently been localized to the KNDy neurons in the hypothalamus. Prior to this discovery, estrogen was the mainstay for the treatment of VMS and, for many years, was the only FDA-approved treatment for VMS. Women in whom estrogen was contraindicated were, therefore, often without recourse.

The subsequent discovery of nonhormonal agents that were effective for the treatment of VMS relied upon serendipity—women would present to their clinician noting that their VMS improved with the introduction of a new medication for an entirely different purpose. In this manner, nonhormone treatments such as the SSRI/SNRI class of drugs, used for depression, gabapentin, used for neuropathic pain and sleep, and oxybutynin, used for irritable bladder, were eventually systematically tested in randomized clinical trials. These latter agents are backed by substantial medical evidence for efficacy. Despite these additional clinical trials, however, only one other agent, paroxetine mesylate, went through the arduous process of FDA approval for the treatment of VMS.

Targeting the NK3R on the KNDy neuron has proven to be a successful strategy for reducing or eliminating the bothersome VMS associated with menopause. Early trials have been hampered by adverse events for some agents, but others in development appear well on their way to FDA approval. Agents that target other neurokinin receptors, combinations of neurokinin receptors, the entire KNDy neuron, or other immune and inflammatory pathways are also under investigation. Hopefully, a new era in the treatment of VMS will be opened up by these exciting scientific advances.

Footnotes

Acknowledgements

Not applicable.

Declarations

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Neurokinin receptor antagonists as potential non-hormonal treatments for vasomotor symptoms of menopause

Abstract

Keywords

Introduction

Search strategy for the review

The impact and pathophysiology of menopausal VMSs

Discovery of the role of the NK3R in VMS pathophysiology

Traditional treatments for VMSs

Clinical data to date on NK3R antagonists

Summary and conclusions

Footnotes

Acknowledgements

Declarations

References