An overview: Menopause and LYNKUET for the treatment of vasomotor symptoms

Author: Tiffany Peters

Editor: Joe Krzeski

Menopause and its associated symptoms

The definition of menopause has evolved over the past 20 years. Menopause has been defined as the moment one year after menstrual flow has stopped [1]. It can also be defined as the point of a woman’s very last period [2,3], but the actual event of a final period can be hard to predict and/or recognize for a number of reasons. Perimenopause is a years-long process characterized by anovulatory and irregular cycles, and vaginal bleeding during this time is not exclusively a symptom of menstruation [3].

Menopause generally occurs in a woman’s 50’s with a perimenopausal period of up to 7.5 years on average [1-3]. Associated symptoms typically include genito-urinary syndrome (GSM: vaginal dryness, burning, itching, and pain), sleep and mood dysregulation, changes in sexual behaviour,  and very commonly, vasomotor symptoms, which manifest as hot flashes and/or night sweats. Predictably, at least half of the global population will at some point in their lives experience menopause, though not all symptoms will occur and not all with equal severity. Treatment for menopause symptoms is considered a highly individual decision and should be decided on with substantial input from the patient regarding the level of stress menopause causes [1].

Cognitive symptoms have also been observed during perimenopause and menopause [3], though there should be a distinction noted between subjective reports from patients and objective data from standardized tests of cognitive function, with subjective reports marked by increased severity. Reduced memory, attention, and concentration have been reported, while subtle reductions in learning and processing speeds have been gleaned from testing during perimenopause, though it must be noted that these can be conflated with the common symptoms of aging regardless of sex. Sometimes, cognitive reductions are actually corrected without intervention once a patient transitions beyond perimenopause into postmenopause.

State-of-the-art therapy for menopause treatment 

On average, the most prevalent and ‘bothersome’ [1-3] of all the symptoms mentioned above are vasomotor symptoms which affect, by some estimates, up to 80% [4-6] of perimenopausal women. As menopause is the result of a natural decline over time in ovarian function and consequently in oestrogen and progesterone production, a typical course of treatment is hormone therapy (HT) [1-5] which typically includes oestrogen (and sometimes progestin) in the form of oestradiol with a dose in concordance to the intensity of the hot flashes. If needed, testosterone is administered in parallel when sexual dysfunction is a major concern for the patient. HT is associated with risks of breast, endometrial, and other cancers with tumors that express oestrogen receptors, blood clots, and cardiovascular indications; the inclusion of testosterone carries additional risks of alopecia, acne, and weight gain [2].

The overwhelming majority of current treatments for menopause associated with VMS is hormonal, with over twenty brand name treatments with oestradiol as the active ingredient existing in a multitude of forms, including pills, patches, and topical creams [7]. Non-hormonal treatments for VMS, prior to 2023 [8], consisted of repurposed drugs such as SSRIs (antidepressants such as Paroxetine [9], which in 2013 received FDA approval for treatment of VMS) or anticonvulsants [10] that were less effective and higher risk than HT. Further nonhormonal treatments for the symptoms of menopause have maintained pharmaceutical R&D interest as many patients have contra-indications that preclude the use of HT. 

Novel treatments

In 2023, Veozah (generic name fezolinetant) was introduced by Astellas Pharma as the first successful, non-hormonal, de novo drug development effort for menopause associated vasomotor symptoms. Since then, in October of 2025, Bayer Health Care Pharmaceuticals similarly enjoyed the success of an FDA stamp of approval on Lynkuet (generic name elizanetant). Through dual inhibition of neurokinin NK1 and NK3 receptors, Lynkuet blocks neurokinin B (NKB) binding, resulting in decreased stimulation of thermoregulatory warm sensitive and GnRH (gonadotropin releasing hormone) neurons (Figure 1) [8]. Veozah, in contrast, is a selective inhibitor of NK1 only. NKB, which is overexpressed in menopausal women [11] , increases activation of NK receptors on thermoregulatory neurons triggering heat defense mechanisms [12]. These mechanisms include vasodilation and sweating, which give rise to hot flashes. 

FDA approval of Lynkuet was given on the basis of three Phase III clinical trials: two twenty-six week long trials to determine efficacy with placebo control only in the first twelve weeks, and a fifty-two week long study focused on safety was conducted on 628 patients, randomized to placebo and treatment groups for the entire duration [12, 13]. Just over 1400 participants were involved across all three studies. The primary endpoints were a reduction in frequency of hot flashes for the treatment group as compared to placebo, with sleep disturbance and menopause related quality of life as secondary and exploratory endpoints. Lynkuet was found to significantly reduce VMS frequency as well as increase quality of life. Side effects included headache, fatigue, and drowsiness, with headache only observed in the Lynkuet trials. The dual inhibitory nature of Lynkuet as compared to Veozah may be responsible for Lynkuet’s more potent effect in improving sleep quality in menopausal women [14]. 

Concluding remarks

Over the past 9 years, significant progress has been made since the first in vivo human study showing that NK3 inhibition reduces hot flashes [15]. Menopause is an inevitability for 50% of the global population and results in uncomfortable symptoms for which hormonal intervention is not suitable for a sizable fraction of patients. The advent of FDA approved NK3 inhibitory drugs, first with fezolinetant, an NK3 inhibitor, in 2023 and now elinzanetant, dual NK3 and NK1 inhibitor,  in 2025 ushers in a more comfortable and approachable era of late-stage life for women.

References

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