There has been an increase in the use of non-hormonal options to treat hot flashes among many menopausal women, basically due to the potential risks of long-term systemic estrogen therapy. Physiologic studies have shown that nitric oxide is pivotal in mediating vasodilation related to hot flash. Hence, it can be suggested that non-hormonal medications that induce nitrate tolerance in the vasculature may offer therapeutic benefit for vasomotor symptoms. Bearing this in mind, recently, Huang et al.  carried out a randomized, double-blinded, placebo-controlled clinical trial that included peri- or postmenopausal women that reported 7 or more hot flashes per day, in order to determine if the uninterrupted administration of transdermal nitroglycerin (NTG, aimed to induce nitrate cross-tolerance) would decrease the frequency or severity of menopause-related hot flashes.
Women used daily NTG patches (dose titrated from 0.2-0.6 mg/h; n=65) or identical placebo patches (n=69), registering daily frequency and severity of their hot flashes for 12 weeks. At baseline women reported a daily mean of 10.8 ± 3.5 hot flashes and 8.4 ± 3.6 were moderate-to-severe. Over 5 weeks, the estimated change in any hot flash frequency associated with NTG vs placebo was -0.9 (95% CI, -2.1 to 0.3) episodes per day (P = .10), and change in moderate-to-severe hot flash frequency with NTG vs placebo was -1.1 (95% CI, -2.2 to 0) episodes per day (P = .05). At 12 weeks, treatment with NTG did not significantly decrease the frequency of any hot flashes or moderate-to-severe hot flashes relative to placebo. Even upon combining 5-week and 12-week data analysis, no significant differences in change in the frequency of any hot flashes or moderate-to-severe hot flashes were detected with NTG vs placebo. The authors conclude that the continuous use of NTG did not result in sustained improvements in hot flash frequency or severity relative to placebo and was associated with more early but not persistent headache.
Estrogen is still considered the best option for the management of hot flashes and other bothersome menopausal symptoms, as well as an effective treatment for osteoporosis. However, because of its potential adverse effects, a lot of effort has been invested by research centers and pharmaceutical companies to find non-estrogenic molecules that might be effective in the treatment of menopausal symptoms . Years ago, drugs that were indicated for unrelated clinical situations showed benefit also for menopausal symptoms. These include selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, clonidine, and gabapentin . Dehydroepiandrosterone (DHEA) in various forms is a very good example of another successful, popular alternative especially for vulvo-vaginal indications . Recently, fezolinetant, a neurokinin 3 receptor antagonist – a non-steroidal product was approved by the FDA for the indication of vasomotor symptoms in the menopause .
Clinical trials with NTG may seem a strange pick for the purpose of reducing hot flashes. NTG is a well-known pharmacologic agent with direct and potent effects on NO mediated vasodilation, an organic nitrate widely used to treat chest pain in patients with coronary disease by promoting coronary vasodilation . While intermittent use of NTG triggers release of NO, promotes vascular smooth muscle relaxation and vasodilation, sustained NTG use rapidly leads to tolerance to the drug’s vasodilatory effects within only 24 hours, as well as cross-tolerance to endogenous nitrates because of enhanced NO degradation . This phenomenon, widely known as nitrate tolerance, offers a potential approach to decreasing vasomotor symptoms by suppressing NO-mediated peripheral vasodilation. Unfortunately, the study of Huang et al.  was unsuccessful and despite the well-established basal scientific assumption, in real life NTG was not effective in reducing frequency or severity of hot flashes. Nevertheless, efforts will continue to identify alternative therapies for hot flashes and menopause symptoms in order to enlarge the spectrum of available treatment options.
Amos Pines, MD
Sackler Faculty of Medicine, Tel-Aviv University, Israel
- Huang AJ, Cummings SR, Ganz P, et al. Efficacy of Continuous Transdermal Nitroglycerin for Treating Hot Flashes by Inducing Nitrate Cross-tolerance in Perimenopausal and Postmenopausal Women: A Randomized Clinical Trial. JAMA Intern Med. 2023:e231977.
- The 2023 nonhormone therapy position statement of The North American Menopause Society. Menopause. 2023;30(6):573-590.
- Szabo RA, Marino JL, Hickey M. Managing menopausal symptoms after cancer. Climacteric. 2019;22(6):572-578.
- Wierman ME, Kiseljak-Vassiliades K. Should Dehydroepiandrosterone Be Administered to Women? J Clin Endocrinol Metab. 2022;107(6):1679-1685.
- Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet. 2023;401(10382):1091-1102.
- Twiner MJ, Hennessy J, Wein R, Levy PD. Nitroglycerin Use in the Emergency Department: Current Perspectives. Open Access Emerg Med. 2022;14:327-333.
- Thadani U. Challenges with nitrate therapy and nitrate tolerance: prevalence, prevention, and clinical relevance. Am J Cardiovasc Drugs. 2014;14(4):287-301.
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