A double-blind, randomized, placebo-controlled trial of suvorexant for the treatment of vasomotor symptom-associated insomnia disorder in midlife women

Study Objectives The neuropeptide orexin promotes wakefulness, modulates thermoregulation, increases after menopause, and is normalized in women receiving estrogen therapy, suggesting a role for orexin antagonism as a treatment for vasomotor symptom (VMS)-associated insomnia disorder. We tested the efficacy of the dual orexin receptor antagonist suvorexant for chronic insomnia related to nighttime VMS. Methods In a double-blind, placebo-controlled trial, 56 women with chronic insomnia associated with nighttime VMS, Insomnia Severity Index (ISI) scores ≥15, and >30 minutes of diary-rated wake after sleep-onset (WASO) were randomized to receive oral suvorexant 10-20 mg (n=27) or placebo (n=29) nightly for 4 weeks. Analysis of within-person change in ISI was adjusted for baseline ISI and race. Results Mean baseline ISI scores were 18.1 (95% CI, 16.8-19.4) and 18.3 (95% CI, 17.2-19.5) in the suvorexant and placebo groups, respectively (p=0.81). The average 4-week ISI within-person decrease from baseline was greater on suvorexant [-8.1 (95% CI, -10.2 to -6.0)] compared to placebo [-5.6 (95% CI, -7.4 to -3.9), p=0.04]. Compared to placebo, nighttime diary-rated VMS frequency was significantly reduced with suvorexant (p<0.01). While diary-rated WASO and total sleep time trended toward improvement on suvorexant, findings were not significant after adjustment for multiple comparison. Daytime VMS and other sleep-related outcomes did not differ between groups. Suvorexant was well tolerated. Conclusion These results suggest that suvorexant is likely a well-tolerated and efficacious treatment for VMS-associated insomnia disorder and reduces nighttime VMS. Antagonism of orexin receptors could provide a novel therapeutic option for midlife women with VMS-associated chronic insomnia.

Vulvovaginal atrophy in postmenopausal women: diagnosis and modern-day treatments

Статья посвящена изучению современных методов диагностики и лечения доброкачественных заболеваний вульвы и влагалища у женщин постменопаузального возраста. Проведен анализ этиологии, клинической картины, методов диагностики и лечения вульвовагинальной атрофии как наиболее часто встречающегося доброкачественного заболевания вульвы и влагалища в постменопаузе. Установлено, что основной фактор, приводящий к вульвовагинальной атрофии, — климактерический гормональный дисбаланс с постепенно нарастающим дефицитом эстрогенов. Женщины в постменопаузе отмечают такие признаки вульвовагинальной атрофии, как сухость влагалища, жжение и зуд, диспареуния, повышенная чувствительность к инфекционным болезням органов малого таза, что существенно усугубляет плохое самочувствие и отрицательное влияние на общее и сексуальное качество жизни. Диагностика вульвовагинальной атрофии основывается на данных осмотра, лабораторных и инструментальных исследованиях. Основная терапевтическая цель при лечении вульвовагинальной атрофии – облегчение симптомов и восстановление среды влагалища до здорового пременопаузального состояния. Золотым стандартом лечения вульвовагинальной атрофии является местная и системная терапия эстрогенами. Препараты заместительной гормональной терапии содействуют увеличению пролиферативных процессов, улучшению кровоснабжения, стремительной нормализации микрофлоры влагалища и могут назначаться с лечебной и профилактической целью. Для лечения вульвовагинальной атрофии у женщин, которым противопоказаны препараты эстрогена, используют селективные модуляторы рецепторов эстрогена. Препараты этой группы – оспемифеном и ласофоксифен способствуют облегчению симптомов атрофии влагалища и диспареунии, улучшению вагинального эпителия и pH влагалища. Также при маловыраженных симптомах улучшение состояния наступает при использовании негормональных вагинальных лубрикантов. Кроме того, существуют экспериментальные варианты вульвовагинального омоложения у женщин с симптомами, которым не подходят или которые не переносят местной или системной терапии эстрогенами: инъекции богатой тромбоцитами плазмы, гиалуроновая кислота или жировые имплантаты, фракционный лазер на диоксиде углерода, диодный лазер и монополярные радиочастотные устройства, вагинопластика. The article is devoted to the study of modern methods of diagnosis and treatment of benign diseases of the vulva and vagina in postmenopausal women. The analysis of the etiology, clinical picture, methods of diagnosis and treatment of vulvovaginal atrophy, as the most common benign disease of the vulva and vagina in postmenopausal women, has been carried out. It has been established that the main factor leading to vulvovaginal atrophy in postmenopausal women is climacteric hormonal imbalance with a gradually increasing estrogen deficiency. Postmenopausal women note such signs of vulvovaginal atrophy as vaginal dryness, burning and itching, dyspareunia, hypersensitivity to infectious diseases of the pelvic organs, which significantly aggravates the state of health, a negative effect on the general and sexual quality of life. Diagnosis of vulvovaginal atrophy is based on examination data, laboratory and instrumental studies. The main therapeutic goal in the treatment of vulvovaginal atrophy is to relieve symptoms and restore the vaginal environment to a healthy premenopausal state. The «gold standard» for the treatment of vulvovaginal atrophy is local and systemic estrogen therapy. HRT drugs contribute to an increase in proliferative processes, an improvement in blood supply, a rapid normalization of the vaginal microflora and can be prescribed for therapeutic and prophylactic purposes. For the treatment of vulvovaginal atrophy in women for whom estrogen preparations are contraindicated, selective estrogen receptor modulators are used. The drugs in this group, ospemifen and lasofoxifene, help to alleviate the symptoms of vaginal atrophy and dyspareunia, improve vaginal epithelium and vaginal pH. Also, with mild symptoms, an improvement in the condition occurs with the use of non-hormonal vaginal lubricants. In addition, there are experimental options for vulvovaginal rejuvenation in women with symptoms that do not fit or tolerate local or systemic estrogen therapy: platelet-rich plasma injections, hyaluronic acid or fat implants, fractional carbon dioxide laser, diode laser and monopolar radiofrequency devices, vaginoplasty.

Immunosuppressive Traits of the Hybrid Epithelial/Mesenchymal Phenotype

Recent preclinical and clinical data suggests enhanced metastatic fitness of hybrid epithelial/mesenchymal (E/M) phenotypes, but mechanistic details regarding their survival strategies during metastasis remain unclear. Here, we investigate immune-evasive strategies of hybrid E/M states. We construct and simulate the dynamics of a minimalistic regulatory network encompassing the known associations among regulators of EMT (epithelial-mesenchymal transition) and PD-L1, an established immune-suppressor. Our simulations for the network consisting of SLUG, ZEB1, miR-200, CDH1 and PD-L1, integrated with single-cell and bulk RNA-seq data analysis, elucidate that hybrid E/M cells can have high levels of PD-L1, similar to those seen in cells with a full EMT phenotype, thus obviating the need for cancer cells to undergo a full EMT to be immune-evasive. Specifically, in breast cancer, we show the co-existence of hybrid E/M phenotypes, enhanced resistance to anti-estrogen therapy and increased PD-L1 levels. Our results underscore how the emergent dynamics of interconnected regulatory networks can coordinate different axes of cellular fitness during metastasis.

Cost-Effectiveness of perioperative Vaginally Administered estrogen in postmenopausal women undergoing prolapse surgery (EVA trial): study protocol for a multicenter double-blind randomized placebo-controlled trial

Background Surgery for pelvic organ prolapse (POP) is associated with high recurrence rates. The costs associated with the treatment of recurrent POP are huge, and the burden from women who encounter recurrent POP, negatively impacts their quality of life. Estrogen therapy might improve surgical outcome for POP due to its potential beneficial effects. It is thought that vaginal estrogen therapy improves healing and long-term maintenance of connective tissue integrity. Hence, this study aims to evaluate the cost-effectiveness of perioperative vaginal estrogen therapy in postmenopausal women undergoing POP surgery. Methods The EVA trial is a multi-center double-blind randomized placebo-controlled trial conducted in the Netherlands comparing the effectiveness and costs-effectiveness of vaginal estrogen therapy. This will be studied in 300 postmenopausal women undergoing primary POP surgery, with a POP-Q stage of ≥ 2. After randomization, participants administer vaginal estrogen cream or placebo cream from 4 to 6 weeks preoperative until 12 months postoperative. The primary outcome is subjective improvement of POP symptoms at 1 year follow-up, measured with the Patient Global Impression of Improvement (PGI-I) scale. Secondary outcomes are POP-Q anatomy in all compartments, re-interventions, surgery related complications, general and disease specific quality of life, sexual function, signs and complaints of vaginal atrophy, vaginal pH, adverse events, costs, and adherence to treatment. Follow up is scheduled at 6 weeks, 6 months and 12 months postoperative. Data will be collected using validated questionnaires and out-patient visits including gynecological examination performed by an independent gynecologist. Discussion This study investigates whether perioperative vaginal estrogen will be cost-effective in the surgical treatment of POP in postmenopausal women. It is hypothesized that estrogen therapy will show a reduction in recurrent POP symptoms and a reduction in reoperations for POP, with subsequent improved quality of life among women and cost savings. Trial registrationNetherlands Trial Registry: NL6853; registered 19-02-2018, https://www.trialregister.nl/trial/6853. EudraCT: 2017-003144-21; registered: 24-07-2017.

The Rational Use of Hormone Replacement Therapy in Older Adults

Multiple hormone levels are lower in older compared to younger adults, but the clinical implications are controversial. Lower thyroid hormone, testosterone, estrogen and vitamin D are variously associated with metabolic syndrome, sarcopenia, low bone density and cognitive decline, for which treatment has been recommended in the past. However, evidence from the T Trials of testosterone therapy failed to show benefit for endpoints other than sexual function. In the Women’s Health Initiative, a large RCT of estrogen replacement in older women, found evidence of an interaction between estrogen therapy and metabolic risk factors such as diabetes that actually exacerbates risk of cognitive decline. Longitudinal observation of thyroid hormone and thyrotropin patterns in the Baltimore Longitudinal Study of Aging demonstrate heterogeneity that might account for a lack of benefit in studies of treatment for subclinical hypothyroidism in older adults. At the same time, new data suggest the need for a more aggressive threshold for vitamin D in older adults, with a lower threshold associated with a drop in physical function compared to younger adults. Complexity in the regulation of hormonal pathways and the downstream effects on target tissues means multiple individuals with similar hormone levels may have different underlying physiology, with divergent clinical needs. Changes in activity and diet common during aging, and exacerbated by the pandemic, lead to physical and mood changes associated with hormonal dysfunction in popular culture and patient requests for evaluation. The ultimate goal should be personalized treatment decisions based on comprehensive evaluation and pathophysiology.

Metabolomics Analysis Discovers Estrogen Altering Cell Proliferation via the Pentose Phosphate Pathway in Infertility Patient Endometria

Estrogen therapy is widely used as a supplementary treatment after hysteroscopy for female infertility patients owing to its protective function that improves endometrial regeneration and menstruation, inhibits recurrent adhesions, and improves subsequent conception rate. The endometrial protective function of such estrogen administration pre-surgery is still controversial. In the current study, 12 infertility patients were enrolled, who were treated with estrogen before hysteroscopy surgery. Using cutting-edge metabolomic analysis, we observed alterations in the pentose phosphate pathway (PPP) intermediates of the patient’s endometrial tissues. Furthermore, using Ishikawa endometrial cells, we validated our clinical discovery and identified estrogen–ESR–G6PD–PPP axial function, which promotes estrogen-induced cell proliferation.

Risk of Venous Thromboembolism in Transgender People Undergoing Hormone Feminizing Therapy: A Prevalence Meta-Analysis and Meta-Regression Study

BackgroundAlthough venous thromboembolism (VTE) is a recognized side effect of some formulations of estrogen therapy, its impact in transgender people remains uncertain. The aim of this study was to define pooled prevalence estimate and correlates of VTE in Assigned Males at Birth (AMAB) trans people undergoing gender affirming hormone therapy.MethodsA thorough search of MEDLINE, COCHRANE LIBRARY, SCOPUS and WEB OF SCIENCE databases was carried out to identify suitable studies. Quality of the articles was scored using the Assessment Tool for Prevalence Studies. Data were combined using random effects models and the between-study heterogeneity was assessed by the Cochrane’s Q and I2.ResultsThe eighteen studies included gave information about 11,542 AMAB undergoing gender affirming hormone therapy. The pooled prevalence of VTE was 2% (95%CI:1-3%), with a large heterogeneity (I2 = 89.18%, P<0.0001). Trim-and-fill adjustment for publication bias produced a negligible effect on the pooled estimate. At the meta-regression analysis, a higher prevalence of VTE was significantly associated with an older age (S=0.0063; 95%CI:0.0022,0.0104, P=0.0027) and a longer length of estrogen therapy (S=0.0011; 95%CI:0.0006,0.0016, P<0.0001). When, according to the meta-regression results, the analysis was restricted to series with a mean age ≥37.5 years, the prevalence estimate for VTE increased up to 3% (95%CI:0-5%), but with persistence of a large heterogeneity (I2 = 88,2%, P<0.0001); studies on younger participants (<37.5 years) collectively produced a pooled VTE prevalence estimate of 0% (95%CI:0-2%) with no heterogeneity (I2 = 0%, P=0.97). Prevalence estimate for VTE in series with a mean length of estrogen therapy ≥53 months was 1% (95%CI:0-3%), with persistent significant heterogeneity (I2 = 84,8%, P=0.0006); studies on participants subjected to a shorter length of estrogen therapy (<53 months), collectively produced a pooled VTE prevalence estimate of 0% (95%CI:0-3%) with no heterogeneity (I2 = 0%, P=0.76).ConclusionsThe overall rate of VTE in AMAB trans people undergoing gender affirming hormone therapy was 2%. In AMAB population with <37.5 years undergoing estrogen therapy for less than 53 months, the risk of VTE appears to be negligible. Further studies are warranted to assess whether different types and administration routes of estrogen therapy could decrease the VTE risk in AMAB trans people over 37.5 years subjected to long-term therapy.Systematic Review Registration[https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021229916].