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Hot flushes and night sweats (HFNS) affect 65–85% of women after breast cancer treatment; they are distressing, causing sleep problems and decreased quality of life. Hormone replacement therapy is often either undesirable or contraindicated. Safe, effective non-hormonal treatments are needed. We investigated whether cognitive behavioural therapy (CBT) can help breast cancer survivors to effectively manage HFNS. In this randomised controlled trial, we recruited women from breast clinics in London, UK, who had problematic HFNS (minimum ten problematic episodes a week) after breast-cancer treatment. Participants were randomly allocated to receive either usual care or usual care plus group CBT (1:1). Randomisation was done in blocks of 12–20 participants, stratifying by age (younger than 50 years, 50 years or older), and was done with a computer-generated sequence. The trial statistician and researchers collecting outcome measures were masked to group allocation. Group CBT comprised one 90 min session a week for 6 weeks, and included psycho-education, paced breathing, and cognitive and behavioural strategies to manage HFNS. Assessments were done at baseline, 9 weeks, and 26 weeks after randomisation. The primary outcome was the adjusted mean difference in HFNS problem rating (1–10) between CBT and usual care groups at 9 weeks after randomisation. Analysis of the primary endpoint was done by modified intention to treat. The trial is registered, ISRCTN13771934, and was closed March 15, 2011. Between May 5, 2009, and Aug 27, 2010, 96 women were randomly allocated to group CBT (n=47) or usual care (n=49). Group CBT significantly reduced HFNS problem rating at 9 weeks after randomisation compared with usual care (mean difference −1·67, 95% CI −2·43 to −0·91; p<0·0001) and improvements were maintained at 26 weeks (mean difference −1·76, −2·54 to −0·99; p<0·0001). We recorded no CBT-related adverse events. Group CBT seems to be a safe and effective treatment for women who have problematic HFNS after breast cancer treatment with additional benefits to mood, sleep, and quality of life. The treatment could be incorporated into breast cancer survivorship programmes and delivered by trained breast cancer nurses. Cancer Research UK.

In this trial involving women taking endocrine therapy for HR-positive breast cancer, elinzanetant (a neurokinin-targeted therapy) significantly reduced the frequency of moderate-to-severe vasomotor symptoms.

BackgroundAdherence to adjuvant tamoxifen therapy is suboptimal, and acceptance of tamoxifen for primary prevention is poor. Published results indicate effect of low-dose tamoxifen therapy. Using questionnaire data from a randomised controlled trial, we describe side effects of standard and low-dose tamoxifen in healthy women.MethodsIn the KARISMA trial, 1440 healthy women were randomised to 6 months of daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. Participants completed a 48-item, five-graded Likert score symptom questionnaire at baseline and follow-up. Linear regression models were used to identify significant changes in severity levels across doses and by menopausal status.ResultsOut of 48 predefined symptoms, five were associated with tamoxifen exposure (hot flashes, night sweats, cold sweats, vaginal discharge and muscle cramps). When comparing these side effects in premenopausal women randomised to low doses (2.5, 5 mg) versus high doses (10, 20 mg), the mean change was 34% lower in the low-dose group. No dose-dependent difference was seen in postmenopausal women.ConclusionsSymptoms related to tamoxifen therapy are influenced by menopausal status. Low-dose tamoxifen, in contrast to high-dose, was associated with less pronounced side effects, a finding restricted to premenopausal women. Our findings give new insights which may influence future dosing strategies of tamoxifen in both the adjuvant and preventive settings.Trial registrationClinicalTrials.gov ID: NCT03346200.

Abstract Context Menopause, the permanent cessation of menses, reflects oocyte depletion and loss of gonadal steroids. It is preceded by a transition state, the perimenopause, which is characterized by the gradual loss of oocytes, altered responsiveness to gonadal steroid feedback, wide hormonal fluctuations, and irregular menstrual patterns. The goal of this mini-review is to discuss the basic pathophysiology of the menopausal transition and the hormonal and nonhormonal management of clinicopathology attributed to it. Evidence Acquisition A Medline search of epidemiologic, population-based studies, and studies of reproductive physiology was conducted. A total of 758 publications were screened. Evidence Synthesis The reproductive hormonal milieu of the menopausal transition precipitates bothersome vasomotor symptoms, mood disruption, temporary cognitive dysfunction, genitourinary symptoms, and other disease processes that reduce the quality of life of affected women. The endocrine tumult of the menopause transition also exposes racial and socioeconomic disparities in the onset, severity, and frequency of symptoms. Hormone therapy (HT) treatment can be effective for perimenopausal symptoms but its use has been stymied by concerns about health risks observed in postmenopausal HT users who are older than 60 and/or women who have been postmenopausal for greater than 10 years. Conclusions The menopause transition is a disruptive process that can last for over a decade and causes symptoms in a majority of women. It is important for clinicians to recognize early signs and symptoms of the transition and be prepared to offer treatment to mitigate these symptoms. Many safe and effective options, including HT, are available.

Hot flushes affect 70% of menopausal women and often severely impact physical, psychosocial, sexual, and overall wellbeing. Hormone replacement therapy is effective but is not without risk. Neurokinin B signalling is increased in menopausal women, and has been implicated as an important mediator of hot flushes. This phase 2, randomised, double-blind, placebo-controlled, single-centre, crossover trial assessed the effectiveness of an oral neurokinin 3 receptor antagonist (MLE4901) on menopausal hot flushes. Eligible participants were healthy women aged 40–62 years, having seven or more hot flushes in every 24 h of which some were reported as being severe or bothersome, who had not had a menstrual period for at least 12 months, and who had not been taking any medication shown to improve menopausal flushes in the preceding 8 weeks. Participants received 4 weeks of MLE4901 (40 mg, orally, twice daily) and placebo (orally, twice daily) in random order separated by a 2 week washout period. Randomisation was completed by a central computer, and participants were allocated to treatment number in numerical order. The primary outcome was the total number of hot flushes during the final week of both treatment periods. Analyses were by intention to treat and per protocol using generalised linear mixed models and standard crossover analysis. All analyses were prespecified in the study protocol. The trial is registered at ClinicalTrials.gov, number NCT02668185. 68 women were screened between Feb 3 and Oct 10, 2016, of which 37 were randomly assigned and included in an intention-to-treat analysis. 28 participants completed the trial and were included in a per-protocol analysis. MLE4901 significantly reduced the total weekly number of hot flushes by 45 percentage points (95% CI 22–67) compared with the placebo (intention-to-treat adjusted means: placebo 49·01 [95% CI 40·81–58·56] vs MLE4901 19·35 [15·99–23·42]; adjusted estimate of difference 29·66 [17·39–42·87], p<0·0001). Treatment was well tolerated. Three participants developed a transaminase rise (alanine aminotransferase 4·5–5·9 times the upper limit of normal) with a normal bilirubin 28 days after starting MLE4901, which normalised within 90 days. Treatment with a neurokinin 3 receptor antagonist (MLE4901) could be practice changing as it safely and effectively relieves hot flush symptoms without the need for oestrogen exposure. Larger scale studies of longer duration are now indicated. UK Medical Research Council and National Institute for Health Research.

Abstract Context Vasomotor symptoms (VMS) are common, bothersome, and can persist for years before and after menopause. Objective We aimed to assess efficacy/safety of fezolinetant for treatment of moderate to severe VMS associated with menopause. Methods In this double-blind, placebo-controlled, 12-week phase 3 trial with a 40-week active treatment extension (NCT04003142; SKYLIGHT 2), women aged 40 to 65 years with minimum average 7 moderate to severe VMS/day were randomized to 12 weeks of once-daily placebo, fezolinetant 30 mg, or fezolinetant 45 mg. Completers were rerandomized to fezolinetant 30/45 mg for 40 additional weeks. Coprimary efficacy endpoints were mean daily change from baseline to week 4 (W4) and W12 in VMS frequency and severity. Safety was also assessed. Results Both fezolinetant doses statistically significantly reduced VMS frequency/severity at W4 and W12 vs placebo. For VMS frequency, W4 least squares mean (SE) reduction vs placebo: fezolinetant 30 mg, –1.82 (0.46; P < .001); 45 mg, –2.55 (0.46; P < .001); W12: 30 mg, –1.86 (0.55; P < .001); 45 mg, −2.53 (0.55; P < .001). For VMS severity, W4: 30 mg, −0.15 (0.06; P < .05); 45 mg, −0.29 (0.06; P < .001); W12: 30 mg, −0.16 (0.08; P < .05); 45 mg, −0.29 (0.08; P < .001). Improvement in VMS frequency and severity was observed by W1 and maintained through W52. Serious treatment-emergent adverse events were infrequent, reported by 2%, 1%, and 0% of those receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo, respectively. Conclusion Daily fezolinetant 30 and 45 mg were efficacious and well tolerated for treating moderate to severe VMS associated with menopause.

Study Objectives. To study the relationship between perimenopausal insomnia (PI) and intestinal flora and the potential mechanism of Tianwang Buxin granules (TWBXG) in exerting its clinical efficacy. Methods. The subjects included 13 PI patients from the Hubei Provincial Hospital of TCM, Hubei University of TCM, and Wuhan Traditional Chinese Medicine Hospital, and the corresponding noninsomniac spouses of the patients were selected as controls. TWBXG was continuously administered for 4 weeks. The feces of PI patients and their noninsomniac spouses before and after treatment with TWBXG were collected. The intestinal flora composition of each group was detected by metagenomic sequencing, and the efficacy of TWBXG was evaluated by the PSQI scale. Results. Compared with the control group, the model group showed an increase in the abundance of Roseburia faecis, Ruminococcus, Prevotella copri, Fusicatenibacter saccharivorans, and Blautia obeum, while those of Bacteroides, fecal Bacteroidetes, and Faecalibacterium prausnitzii were decreased. Compared with pretreatment, the PSQI score was significantly reduced (P<0.05), the abundance of Bacteroides, fecal Bacteroidetes, and Faecalibacterium prausnitzii increased, and that of Roseburia faecis, Ruminococcus, Prevotella copri, Fusicatenibacter saccharivorans, and Blautia obeum decreased after treatment. However, there was still a certain gap in the abundance of related flora in the treatment group compared with the control. Conclusion. PI is associated with disturbances in the intestinal flora and is mainly related to the disorders of Roseburia faecis, Ruminococcus, Prevotella copri, Fusicatenibacter saccharivorans, Blautia obeum, Bacteroides, fecal Bacteroidetes, and Faecalibacterium prausnitzii. TWBXG can effectively treat PI, and its effect may be achieved by regulating the disordered intestinal flora. Clinical Trials. The study was registered in the Chinese clinical trial registry and approved by the World Health Organization clinical trial registration platform (Effects of the modified Tianwang Buxin granule and modified Tianwang Buxin decoction pieces on insomnia: a randomized, controlled trial, ChiCTR-IPR-17011549).

Menopause is the time of life when menstrual cycles cease, and is caused by reduced secretion of the ovarian hormones oestrogen and progesterone. Although menopause is a normal event for women, individual experiences vary, and some women seek medical advice for the management of symptoms. Many symptoms have been attributed to menopause, but only vasomotor dysfunction and vaginal dryness are consistently associated with this time of life in epidemiological studies. Other common symptoms such as mood changes, sleep disturbances, urinary incontinence, cognitive changes, somatic complaints, sexual dysfunction, and reduced quality of life may be secondary to other symptoms, or related to other causes. Trials of therapies for vasomotor dysfunction have shown improvements with oestrogen, gabapentin, paroxetine, and clonidine, but little or no benefit with other agents; adverse effects of these treatments must also be considered. Many questions about menopausal transition and its effects on health have not been adequately addressed.

Vasomotor symptoms (hot flushes and night sweats) are experienced by more than two-thirds of women with breast cancer taking oral adjuvant endocrine therapy. Safe and effective treatments are lacking. Q-122 is a novel, non-hormonal compound that has shown promise for reducing vasomotor symptoms by modulation of oestrogen-responsive neurons in the hypothalamus. We aimed to assess the efficacy and safety of Q-122 in women with breast cancer taking oral adjuvant endocrine therapy and experiencing vasomotor symptoms. We conducted a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial at 18 sites in Australia, New Zealand, and the USA. Eligible participants were women, aged 18–70 years, taking a stable dose of tamoxifen or an aromatase inhibitor following breast cancer and experiencing at least 50 self-reported moderate to severe vasomotor symptoms per week. Participants were randomly assigned (1:1) using an interactive web response system to oral Q-122 100 mg or identical placebo, twice daily for 28 days. Randomisation was stratified by BMI (≤30 kg/m2 or >30 kg/m2) and use of any of a selective serotonin reuptake inhibitor, selective norepinephrine reuptake inhibitor, gabapentin, or pregabalin. Q-122 and placebo capsules were identical in appearance and containers identically labelled. During the double-blind treatment and analysis phases, the participants, investigators, clinical research organisation staff, and sponsor were masked to treatment allocation. The primary outcome was the difference in the mean percentage change from baseline in the Vasomotor Symptom Severity Score of moderate and severe hot flushes and night sweats (msVMS-SS) between Q-122 and placebo after 28 days of treatment. Primary analysis was by modified intention-to-treat and safety was assessed in all participants receiving at least one dose of study drug. This study is registered at ClinicalTrials.gov, NCT03518138. Between Oct 24, 2018, and Sept 9, 2020, 243 patients were screened, 131 of whom were randomly assigned and received treatment (Q-122 n=65 and placebo n=66). Q-122 resulted in a significantly greater mean percentage change in msVMS-SS from baseline over 28 days of treatment compared with placebo (least squares mean: Q-122 –39% [95% CI –46 to –31] vs placebo –26% [–33 to –18]; p=0·018). Treatment-emergent adverse events were generally mild to moderate and similar between the two groups (treatment-related treatment-emergent adverse events in 11 [17%] of 65 patients in the Q-122 group vs nine [14%] of 66 in the placebo group); zero patients in the Q-122 group and two (3%) patients in the placebo group had serious adverse events. Q-122 is an effective and well tolerated non-hormonal oral treatment for vasomotor symptoms in women taking oral adjuvant endocrine therapy after breast cancer. Our results support the conduct of larger and longer studies of Q-122, with potential use extending to postmenopausal women who require an alternative to menopausal hormone therapy. QUE Oncology.

Abstract Many cancer treatments can lead to reduced levels of sex hormones, which in turn may cause vasomotor symptoms (VMS) such as hot flashes. These symptoms are associated with impaired quality of life, as well as suboptimal tolerability of and adherence to cancer treatment. Hormone therapy, performed by increasing estradiol or testosterone levels, is the gold standard for treatment of VMS. However, this approach is generally contraindicated in patients with hormone-sensitive cancers. Nonhormone agents with low to moderate efficacy in controlling VMS are available, but their use may be limited by side effects and tolerability. In this narrative review, the approach to VMS in cancer patients will be discussed. The evidence for various treatment options, including novel agents such as fezolinetant that target the hypothalamic thermoregulatory pathway, will be evaluated. Finally, special considerations in different patient populations based on cancer types (eg, breast, prostate) and age groups (eg, older adults) will be explored.