Could menopause drug fezolinetant show promise for vasomotor symptoms associated with androgen deprivation therapy?
Letter to the Editor

Could menopause drug fezolinetant show promise for vasomotor symptoms associated with androgen deprivation therapy?

Kirby R. Qin1,2,3 ORCID logo, Eveline Mertens1, Jake A. Tempo4, Marlon Perera4, Janelle Brennan1,2

1Department of Urology, Bendigo Health, Bendigo, VIC, Australia; 2School of Rural Health, Monash University, Bendigo, VIC, Australia; 3Department of Paediatrics, Monash University, Melbourne, VIC, Australia; 4Department of Urology, Austin Health, Melbourne, VIC, Australia

Correspondence to: Kirby R. Qin, MBBS(Hons), BMedSc(Hons), GradDipSurgAnat. Department of Urology, Bendigo Health, 100 Barnard St., Bendigo, VIC 3550, Australia; School of Rural Health, Monash University, Bendigo, VIC, Australia; Department of Paediatrics, Monash University, Melbourne, VIC, Australia. Email:

Submitted Jan 06, 2024. Accepted for publication Mar 28, 2024. Published online May 15, 2024.

doi: 10.21037/tau-24-12

Vasomotor symptoms (VMS) affect up to 80% of females during the menopause transition, with hot flashes being one of the most common and troublesome symptoms. Hot flashes are defined as an uncomfortable, sudden feeling of warmth, flushing and diaphoresis that usually involve the upper body and face. Traditionally, the standard treatment for hot flashes has been hormone-based—with a focus on oestrogen replacement as the body’s natural production slows down. However, exogenous oestrogen is problematic and not suitable for all patients. This has led to the exploration of alternative therapies for this common and bothersome condition.

Globally, prostate cancer is the second most frequent cancer amongst males. Approximately one-third of males with prostate cancer are likely to receive some form of androgen deprivation therapy (ADT), either surgical (bilateral orchidectomy) or medical [gonadotropin-releasing hormone (GnRH) analogues] (1). Severe VMS are associated with ADT. Up to 80% of men on ADT experience hot flashes and 27% cite this as the most bothersome side-effect (2). VMS also occur in males with hypogonadism where the mechanism is similar. The clinical significance and impact of VMS in men is often overlooked. This is, however, an important consideration for oncological community, as the severity of hot flashes may not only impact quality-of-life but also lead to treatment cessation or treatment ‘holiday’ (1).

The exact mechanism of hot flashes in men on ADT has not been studied, although treatment evidence suggests that oestrogen depletion remains the primary mediator (3). In males, oestradiol is a GnRH-mediated steroid, produced in small amounts by Sertoli cells but mostly via peripheral aromatisation of androgens. Multiple trials have shown hormonal therapy to be efficacious for VMS of ADT (3). However, exogenous oestrogen administration in males is problematic. Side effects include breast enlargement, tenderness, mood changes and sexual dysfunction, in addition to poor patient uptake. Progesterone formulations have also shown efficacy in ADT-related VMS, but might be associated with prostate cancer progression (4).

Non-hormonal agents with trial evidence in ADT include neuroactive agents venlafaxine and gabapentin. Venlafaxine was significantly less effective than cyproterone and medroxyprogesterone (P<0.0001) (5). Gabapentin at 900 mg/day was associated with a moderate improvement in hot flash frequency (P<0.02) but not severity (P=0.1) (6). Venlafaxine and gabapentin, however, remain off-label for this indication. Despite a limited number of trials in men, the mechanisms for non-hormonal management of VMS of ADT should be similar to those in menopause. This provides the uro-oncologic community an option to investigate the role of a new first-in-class treatment for hot flashes.

Fezolinetant (VEOZAH™, Astellas Pharma Inc., Tokyo, Japan), at a dose of 45 mg daily, was approved by the U.S. Food and Drug Administration in May 2023 as a non-hormonal treatment for moderate-to-severe VMS of menopause (7). This came after efficacy and safety were shown in multiple phase III trials [SKYLIGHT 1 (8), 2 (9), and 4 (10); see Table 1]. Fezolinetant is a neurokinin-3 receptor antagonist, which treats VMS by targeting the neuronal mechanism behind this phenomenon. The thermoregulatory centre in the hypothalamus is innervated by kisspeptin/neurokinin B/dynorphin (KNDy) neurons. These KNDy neurons are stimulated by neuropeptide neurokinin B and inhibited by oestrogen. During menopause (and GnRH suppression by ADT), decline in oestrogen levels disrupts this balance, causing neurokinin-3 receptor-mediated hypertrophy of KNDy neurons, leading to unopposed activation of heat dissipation effectors. These, involuntary, mostly autonomic responses result in cutaneous vasodilatation and sweating, leading to hot flashes. Although the relationship between neurokinin, oestrogen and thermoregulation has yet to be studied in human males, experiments in hypogonadal men demonstrate oestradiol (as opposed to testosterone) deficiency as the primary regulator of VMS in men (11). Furthermore, mouse models have demonstrated KNDy neurons mediating systemic vasodilatation in both male and female mice (12).

Table 1

Phase III trials of fezolinetant in female menopause

Trial Setting Results
Skylight 1 (8) 2019–2021; North America, Europe Reduced VMS frequency by 51% at 4 weeks, and 61% at 12 weeks from baseline, effect maintained at 52 weeks
Skylight 2 (9) 2019–2021; North America, Europe Reduced VMS frequency by 55% at 4 weeks, and 64% at 12 weeks from baseline, effect maintained at 52 weeks
Moonlight 3 2020–2023; China Yet to report
Skylight 4 (10) 2019–2022; North America, Europe Similar incidence of all treatment-emergent adverse events to placebo at 52 weeks

VMS, vasomotor symptoms.

Fezolinetant signals a paradigm shift in the treatment of bothersome VMS and represents the first available treatment which directly targets the control mechanism behind thermoregulation. If the VMS of ADT is related to oestrogen depletion, then neurokinin B is also predicted to stimulate heat dissipation in males, and therefore, its blockade may be of clinical benefit. Whilst fezolinetant is currently only approved for menopause, its potential utility in prostate cancer and male hypogonadism is promising. Appropriate trials exploring its safety and efficacy in males will determine its suitability for regulatory approval. We hope that pharmaceutical manufacturers will be willing to explore this market, as it may greatly improve the quality-of-life and quality-of-care in men with advanced prostate cancer.


Funding: None.


Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

Peer Review File: Available at

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See:


  1. Liede A, Hallett DC, Hope K, et al. International survey of androgen deprivation therapy (ADT) for non-metastatic prostate cancer in 19 countries. ESMO Open 2016;1:e000040. [Crossref] [PubMed]
  2. Shore ND, Antonarakis ES, Cookson MS, et al. Optimizing the role of androgen deprivation therapy in advanced prostate cancer: Challenges beyond the guidelines. Prostate 2020;80:527-44. [Crossref] [PubMed]
  3. Russell N, Hoermann R, Cheung AS, et al. Effects of oestradiol treatment on hot flushes in men undergoing androgen deprivation therapy for prostate cancer: a randomised placebo-controlled trial. Eur J Endocrinol 2022;187:617-27. [Crossref] [PubMed]
  4. Grindstad T, Richardsen E, Andersen S, et al. Progesterone Receptors in Prostate Cancer: Progesterone receptor B is the isoform associated with disease progression. Sci Rep 2018;8:11358. [Crossref] [PubMed]
  5. Irani J, Salomon L, Oba R, et al. Efficacy of venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for the treatment of vasomotor hot flushes in men taking gonadotropin-releasing hormone analogues for prostate cancer: a double-blind, randomised trial. Lancet Oncol 2010;11:147-54. [Crossref] [PubMed]
  6. Loprinzi CL, Dueck AC, Khoyratty BS, et al. A phase III randomized, double-blind, placebo-controlled trial of gabapentin in the management of hot flashes in men (N00CB). Ann Oncol 2009;20:542-9. [Crossref] [PubMed]
  7. United States Food and Drug Administration. FDA Approves Novel Drug to Treat Moderate to Severe Hot Flashes Caused by Menopause. 2023. Accessed May 12, 2023. Available online:
  8. 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;401:1091-102. [Crossref] [PubMed]
  9. Johnson KA, Martin N, Nappi RE, et al. Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT. J Clin Endocrinol Metab 2023;108:1981-97. [Crossref] [PubMed]
  10. Neal-Perry G, Cano A, Lederman S, et al. Safety of Fezolinetant for Vasomotor Symptoms Associated With Menopause: A Randomized Controlled Trial. Obstet Gynecol 2023;141:737-47. [Crossref] [PubMed]
  11. Taylor AP, Lee H, Webb ML, et al. Effects of Testosterone and Estradiol Deficiency on Vasomotor Symptoms in Hypogonadal Men. J Clin Endocrinol Metab 2016;101:3479-86. [Crossref] [PubMed]
  12. Padilla SL, Johnson CW, Barker FD, et al. A Neural Circuit Underlying the Generation of Hot Flushes. Cell Rep 2018;24:271-7. [Crossref] [PubMed]
Cite this article as: Qin KR, Mertens E, Tempo JA, Perera M, Brennan J. Could menopause drug fezolinetant show promise for vasomotor symptoms associated with androgen deprivation therapy? Transl Androl Urol 2024;13(5):920-922. doi: 10.21037/tau-24-12

Download Citation