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.

Overview of PROTACs targeting the estrogen receptor: Achievements for biological and drug discovery

: Estrogen receptors (ERs) are steroid hormone receptors, which belong to a large nuclear receptor family. Endocrine diseases correlate strongly with dysregulated ER signaling. Traditional therapies continue to rely on small molecule inhibitors, including aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs), all of which permit acquired resistance to endocrine therapy. Proteolytic targeting chimeras (PROTACs) offer unprecedented potential for solving acquired endocrine resistance. ARV-471, an ER-targeting PROTAC developed by Arvinas, entered clinical trials in 2019 to treat patients suffering from locally advanced or metastatic ER-positive/HER2-negative breast cancer and has since been approved by the US FDA. In this review, we will focus on progress in developing ER-targeting PROTACs from publications and patents aimed at the treatment of endocrine diseases.

99mTc labeled genistein kits: development methods and quality control for breast cancer radiotracer applications

Objective. Selective estrogen receptor modulators (SERMs) have been widely used to treat breast cancer, osteoporosis, and postmenopausal symptoms. SERMs have an affinity for estrogen receptors (ER) in target tissues and resist stimulation of the breast, bone, and endometrium. Genistein as an isoflavone compound that has a high affinity for ERβ targets makes it a potential target or prognostic marker for breast cancer. This study was carried out to develop 99mTc-genistein kit that can be used to detect breast cancer. Methods. The synthesis process and quality control were investigated to obtain the optimal formula for the ratio of a substance, reducing agent, optimal conditions of the synthesis reaction, physicochemical properties of the kit, and its stability to meet the requirements of radiochemical purity. Results. The radiochemical purity in the development of the radiopharmaceutical kit was 93.25% ± 0.30%. The physicochemical properties of the kit preparations showed hydrophilic properties, good plasma protein binding, no electrical charge, and were stable at storage temperatures. Conclusions. The radiochemical purity of the radiopharmaceutical kits meets the requirements of the United State Pharmacopeia and has good physicochemical properties to be developed into kits.

Clinical aspect, pathogenesis and therapy options of alopecia induced by hormonal therapy for breast cancer

Adjuvant hormonal therapy is one of the most important treatments of hormone-receptor-positive breast cancer and includes selective estrogen receptor modulators, aromatase inhibitors, and luteinizing hormone-releasing hormone analogs. In patients receiving these drugs, a progressive recession of frontal-temporal hairlines is often observed, such as a certain grade of hair miniaturization in the same areas and the central scalp area, producing a pseudo-female androgenic alopecia, which has to be considered oncotherapy-induced alopecia. The aim of this work, is to describe the clinical aspects and pathogenesis of this type of alopecia and to analyze the different drugs which have been proposed until now. The authors concude that topical hormones should not be considered as a therapeutic approach because of their direct or indirect oncogenic potential. A therapeutic approach that could be both safe and effective is proposed.

Lnc-DC promotes estrogen independent growth and tamoxifen resistance in breast cancer

Selective estrogen receptor modulators (SERMs) such as tamoxifen have proven to be effective in the treatment of estrogen receptor (ER) positive breast cancer. However, a major obstacle for such endocrine therapy is estrogen independent growth, leading to resistance, and the underlying mechanism is not fully understood. The purpose of this study was to determine whether long non-coding RNAs (lncRNAs) are involved in regulation of estrogen independent growth and tamoxifen resistance in ER positive breast cancer. Using a CRISPR/Cas9-based SAM (synergistic activation mediator) library against a focus group of lncRNAs, we identify Lnc-DC as a candidate lncRNA. Further analysis suggests that Lnc-DC is able to reduce tamoxifen-induced apoptosis by upregulation of anti-apoptotic genes such as Bcl2 and Bcl-xL. Furthermore, Lnc-DC activates STAT3 by phosphorylation (pSTAT3Y705), and the activated STAT3 subsequently induces expression of cytokines which in turn activate STAT3, forming an autocrine loop. Clinically, upregulation of Lnc-DC is associated with poor prognosis. In particular, analysis of a tamoxifen-treated patient cohort indicates that Lnc-DC expression can predict the response to tamoxifen. Together, this study demonstrates a previously uncharacterized function of Lnc-DC/STAT3/cytokine axis in estrogen independent growth and tamoxifen resistance, and Lnc-DC may serve as a potential predictor for tamoxifen response.

Incident Type 2 Diabetes Risk of Selective Estrogen Receptor Modulators in Female Patients with Breast Cancer

Accumulating evidence indicates a link between diabetes and cancer. Selective estrogen receptor modulators (SERMs) may increase diabetes risk via antiestrogen effects. This study investigated incident diabetes risk of SERM treatment and its effects on metastatic cancer and death prevention in breast cancer survivors. This retrospective cohort study included female patients with early-stage breast cancer, treated with or without SERMs, between 2008 and 2020 in a tertiary care hospital in Korea. Four propensity score-matched comparison pairs were designed: SERM use versus non-use, long-term use (≥1500 days) versus non-use, tamoxifen use versus non-use, and toremifene use versus non-use; then, logistic regression analysis was performed for risk analysis. SERMs in general were not associated with an elevated risk of diabetes; however, when used for ≥1500 days, SERMs—especially toremifene—substantially increased diabetes risk in breast cancer patients (OR 1.63, p = 0.048). Meanwhile, long-term SERM treatment was effective at preventing metastatic cancer (OR 0.20, p < 0.001) and death (OR 0.13, p < 0.001). SERM treatment, albeit generally safe and effective, may increase diabetes risk with its long-term use in women with breast cancer. Further studies are required to verify the association between toremifene treatment and incident diabetes.

Selective Estrogen Receptor Modulators (SERMs) Synergize with Cisplatin, induce apoptosis and Suppress Cellular Migration and Colony Formation of Lung Cancer Cells

Background: Lung cancer remains the leading cause of cancer-related deaths worldwide. Hence, novel therapeutic approaches targeting crucial pathways are needed to improve its treatment. Previous studies have verified the involvement of the estrogen pathway, mediated through estrogen receptor β (ERβ), in the development and progression of lung carcinogenesis. Selective estrogen receptor modulators (SERMs) are a group of estrogen receptor agonists/antagonists that have tissue selective effects. Many of the available SERMs are used for the management of breast cancer. However, their role in lung cancer is still under investigation. Objectives: The aim of this research is to investigate the anti-tumorigenic activity of the selective estrogen receptor modulators, tamoxifen, raloxifene, and toremifene, against different lung cancer cell lines. Methods: The anti-proliferative and combined effects of SERMs with standard chemotherapy were evaluated by MTT assay. Cell migration was assessed using a wound-healing assay. The mechanism of cell death was determined using the Annexin V-FITC/ propidium iodide staining flow cytometry method. Cells’ capability to form colonies was evaluated by soft agar colony formation assay. Estrogen receptors expression was determined using real-time PCR. Results: Our results have demonstrated the presence of ERβ in A549, H1299, and H661 lung cancer cells. Cellular proliferation assay suggested that SERMs have significantly reduced lung cancer cells proliferation in a time and concentration-dependent manner. Additionally, SERMs exhibited a synergistic effect against A549 cells when combined with cisplatin. SERMs treatment have increased cell apoptosis and resulted in concentration-dependent inhibition of cell migration and colony formation of A549 cells. Conclusion: Selective estrogen receptor modulators may possess potential therapeutic utility for the treatment of lung cancer as monotherapy or in combination with standard chemotherapy.