Relief Of Vasomotor Symptoms Research Articles

Potential benefits of hormone replacement therapy on cardiovascular and kidney outcomes in postmenopausal women with chronic kidney disease.

Hormone replacement therapy (HRT) is recommended for alleviating vasomotor symptoms or preventing bone loss in postmenopausal women. This study aimed to investigate the impact of hormone replacement therapy on major adverse cardiovascular events, kidney failure, and mortality in women with chronic kidney disease (CKD). This population-based cohort study analyzed data from the National Cancer Screening Program and the national health examination of South Korea. Data on postmenopausal women were extracted from the 2009 National Cancer Screening Program. Among these postmenopausal women, those with CKD without kidney replacement therapy were selected through a national health examination from 2009 to 2013. The study outcomes were the risks of major adverse cardiovascular events, kidney failure, and all-cause mortality according to hormone replacement therapy. A total of 768,279 postmenopausal women with CKD were enrolled in this study; of these women, 13.8% (N = 106,052) had a history of hormone replacement therapy. The user and non-user groups differed with respect to baseline characteristics, with the latter being older and having risk factors for cardiovascular disease. After adjustment for confounding factors, the group exposed tohormone replacement therapyshowed lower risks of major adverse cardiovascular events, kidney failure, and all-cause mortality. This study suggests the potential benefits of hormone replacement therapy in postmenopausal women with CKD and highlighted its potential advantages for cardiovascular and kidney outcomes.

Ultra-low dose estradiol and dydrogesterone for the treatment of menopausal symptoms in a pooled, multi-ethnic population

ObjectivesEvidence suggests ethnicity-specific differences in postmenopausal symptoms, highlighting the need for therapies that are efficacious across different ethnicities. We evaluated the efficacy of an ultra-low dose combination of 0.5 mg estradiol and 0.25 mg dydrogesterone (E 0.5 mg/D 2.5 mg) in alleviating vasomotor symptoms across a multi-ethnic population. Study designData from two controlled trials were pooled to form a dataset of 583 postmenopausal women from across Europe and China. Participants were randomized to receive treatment with E 0.5 mg/D 2.5 mg or placebo for 12 weeks. Main outcome measuresThe main efficacy variable was absolute change in the number of hot flushes from baseline to end of treatment. Health-related quality of life and safety were also assessed. ResultsChange in the number of hot flushes per day was greater with E 0.5 mg/D 2.5 mg versus placebo (mean difference − 1.5, 95 % confidence interval − 2.1, −1.0; p < 0.001). Participants treated with E 0.5 mg/D 2.5 mg reported improvement in health-related quality of life (including psychological symptoms, vaginal dryness), and high amenorrhea rates. Combined E 0.5 mg/D 2.5 mg was well tolerated: there were no differences between groups in the percentage of participants with at least one serious adverse event or treatment-emergent serious adverse events. Analysis of change in body weight indicated no differences between groups. ConclusionsThis pooled analysis demonstrates the consistent efficacy of E 0.5 mg/D 2.5 mg in the treatment of menopause-related symptoms across a multi-ethnic population of postmenopausal women.

Overcoming challenges in conducting early phase breast cancer prevention trials: Bazedoxifene and conjugated estrogens vs waitlist control

BackgroundThe combination of bazedoxifene 20 mg (BZA) and conjugated estrogens 0.45 mg (CE) marketed as Duavee® is approved for vasomotor symptom relief and osteoporosis prevention. Our pilot study suggested it had potential breast cancer risk reduction, and we proposed a multisite Phase IIB primary prevention trial assessing change in breast imaging and tissue risk biomarkers. By the time funding was acquired in February 2021, Duavee® was unavailable with an uncertain return date. A redesign was needed to salvage the study. MethodsThe basic trial design was minimally altered. Women age 45–64 at elevated risk for breast cancer with vasomotor symptoms and no menses for at least 2 months have mammography, phlebotomy, and benign breast tissue sampling before and after 6 months of intervention. However, instead of Duavee® (single pill) vs placebo, women are randomized to 6 months of BZA + CE vs Waitlist. Those initially randomized to Waitlist can receive BZA + CE after 6 months. The primary endpoint is between arm difference in change in a fully automated measure of mammographic density with blood and tissue-based secondary endpoints. OutcomesAccrual initiation was delayed due to contractual difficulties surrounding BZA importation during COVID-19 and deploying a fully automated method (Volpara®) to assess the primary endpoint. To accommodate this delay, a mid-grant no cost extension along with amended eligibility requirements were employed. 61/120 participants needed were entered in the initial 27 months of accrual and 37 months of funding. Despite a late start, accrual is likely to be completed within the funding period.

Abstract SS02-02: Hormone Replacement and Alternatives for Relief of Vasomotor Symptoms in Women at Increased Risk for Breast Cancer

Abstract 70% of women will experience vasomotor symptoms sufficient to impact their quality of life during menopause transition and the early menopause. These symptoms are thought result from neurotransmitter imbalances resulting from ovarian hormone reductions and hypersecretion of gonadotropins. Increases in gonadotropins result in neurotransmitter triggered stimulation of the neurokinin 3 (NK3) receptor and thermoregulatory imbalance. Estrogen deficiency also reduces serotonin which can also trigger increases in hot flashes, and sleep disturbances. Vasomotor symptoms last on the average for 7 years until acclimation to persistent low estrogen levels occurs. Estrogen +/- progestin replacement therapy is associated with the greatest likelihood of vasomotor symptom relief as it reduces gonadotropin and NK3 receptor signaling and increases serotonin. Progestins also increase the neuroinhibitory transmitter gamma-aminobutyric acid (GABA) which improves sleep quality. There continues to be confusion on the part of providers and patients regarding the excess risk of breast cancer and thromboembolic events as these risks are affected by type of agent, route of delivery, age, duration of treatment, and presence of obesity. The majority of placebo controlled randomized clinical trial data on hormone replacement with estrogen or estrogen + a progestin comes from the Women’s Health Initiative (WHI) for women 50-79 in which oral conjugated estrogen (CE) 0.625 mg was used as the estrogen for women without a uterus and medroxyprogesterone acetate (MPA) was added to CE for women with a uterus to protect against endometrial hyperplasia and cancer. The median age at entry to WHI that trial was 63 and a substantial proportion had previously taken hormones. Large longitudinal cohort studies have been helpful in assessing risks in women starting hormones at a more clinically relevant age (45-55) and with hormonal preparations other than oral CE and MPA. Five to seven years of estrogen alone results in minimal if any increased risk for breast cancer. However, combined estrogen+ progestin replacement for women over 50, necessary for women with a uterus, results in an ~ 30 % relative increased risk for breast cancer if taken for up to 5 years and a doubling of risk with 10 years of treatment. So called bioidentical hormones often compounded as oral troches of estradiol, progesterone, and testosterone, are also associated with increased breast cancer risk. Vaginal hormones have not been found to increase risk for breast cancer. Increased risk of thromboembolism is predominately observed in women over 50 using oral as opposed to transdermal preparations. Increased risk for stroke and dementia was observed in the WHI again with oral hormones in women over 65. In the WHI there was no increase in cancer related, cardiovascular or overall mortality with estrogen or estrogen and progestin. For high-risk peri and post-menopausal women with who would like to reduce/alleviate their vasomotor symptoms with no increase in risk for breast cancer there are several options: 1) the tissue selective estrogen complex bazedoxifene (BZA) combined with conjugated estrogen (CE) 2) the non-hormonal option of NK3 receptor antagonists such as fezolinetant ( 3) non-hormonal options of gabapentin, selective serotonin reuptake inhibitors (SSRI) and serotonin and norepinephrine uptake inhibitors (SNRI). BZA and CE and fezolinetant are reported to reduce hot flashes in 70% or more of individuals with paroxetine effectiveness reported as 50%. All three are FDA approved for reduction of vasomotor symptoms. The combination of BZA and CE is also being investigated for breast cancer risk reduction. These agents differ with respect to side effects with increased risk of blood clots for bazedoxifene and conjugated estrogen, increased risk of nausea, diarrhea, and liver dysfunction for fezolinetant and drowsiness and dry mouth for SSRIs. Drug costs may also dramatically affect insurance coverage and patient uptake of a particular strategy. A recent online perusal of a popular site for finding the lowest drug price suggested substantial differences in the cost of drugs for relief of vasomotor symptoms. The approximate cost for a 30- day supply of oral estradiol was $30, estradiol transdermal patches $35, oral progesterone $15, combined estradiol and levonorgestrel transdermal patches $240, oral CE $200, oral CE + medoxyprogesterone acetate $240, and for BZA+ CE $200. For non-hormonal therapies the cost of 30 days of gabapentin was $11, paroxetine $30 and fezolinetant $550. Crandall, Mehta, and Manson JAMA 2023 329:405-420 Collaborative Group on Hormonal Factors in Breast Cancer Lancet 2019 394: 1159-1168 Fabian et al Ca Prev Res 2019 10:711-720 Modi and Dhillo Neuroendocrinology 2019 109:242–248 Citation Format: C. Fabian. Hormone Replacement and Alternatives for Relief of Vasomotor Symptoms in Women at Increased Risk for Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr SS02-02.

Effectiveness and safety of fezolinetant in alleviating vasomotor symptoms linked to Menopause.: A systematic review and Meta-Analysis

Background & ObjectiveVasomotor symptoms (VMS) are the most common symptoms during menopause including hot flushes and night sweats. They are highly disruptive to the quality of life. Fezolinetant is an FDA-approved non-hormonal selective neurokinin3 receptor antagonist for the treatment of VMS. In this study, we aim to assess the efficacy and safety of fezolinetant for VMS associated with menopause. MethodsDatabases were searched until September 2023 for relevant studies comparing fezolinetant against placebo. Data was extracted into an online form and analyzed using RevMan (Version 5.4.1). The GRADE approach was conducted to evaluate the quality of evidence regarding efficacy outcomes. We included randomized controlled trials (RCTs) comparing fezolinetant to placebo in postmenopausal women experiencing VMS. Exclusion criteria comprised studies involving participants with contraindications to fezolinetant or those evaluating its efficacy for indications other than VMS associated with menopause. ResultsSix studies were included in this study involving 3301 patients. Compared to placebo, fezolinetant reduced the frequency of VMS episodes from baseline (SMD = -0.64, 95 % CI [-0.77, −0.5]) and (SMD = -0.63, 95 % CI [-0.72, −0.53] at weeks 4 and 12 respectively. Additionally, fezolinetant reduced VMS severity score (SMD = -0.59, 95 %CI [-0.77, −0.42]) and (SMD = -0.4, 95 % CI [-0.54, −0.27]) at weeks 4 at 12 respectively. These reductions were positively reflected on Menopause specific quality of life score (SMD = -0.46, 95 %CI [-57, −0.34]), (SMD = -0.37, 95 %CI [-0.48, −0.25]) at weeks 4 and 12 respectively. Regarding safety analysis, fezolinetant showed increased risk for drug-related TEAEs (RR = 1.47, 95 %CI [1.06,2.04]), serious TEAEs (RR = 1.67, 95 %CI [1.09,2.55]), fatigue (RR = 4.05, 95 %CI [1.27,12.88]), arthralgia (RR = 2.83, 95 %CI [1.02,7.8]) and ALT or AST > 3 times (RR = 2, 95 %CI [1.12,3.57]), with no other statistically significant difference regarding other safety terms. ConclusionFezolinetant has demonstrated efficacy in reducing the frequency and severity of VMS in postmenopausal women, leading to an improvement in their quality of life. These findings suggest that Fezolinetant may serve as a viable alternative to hormonal therapy for managing VMS.

Low thrombin generation in postmenopausal women using estetrol

Objective Estetrol (E4) represents a novel estrogen of interest to relieve vasomotor symptoms. E4 activates the nuclear estrogen receptor α (ERα) but antagonizes the estradiol ERα-dependent membrane-initiated steroid signaling pathway. The distinct pharmacological properties of E4 could explain its low impact on hemostasis. This study aimed to assess the effect of E4 on coagulation in postmenopausal women, using the thrombin generation assay (TGA). Methods Data were collected from a multicenter, randomized, placebo-controlled, dose-finding study in postmenopausal women (NCT02834312). Oral E4 (2.5 mg, n = 42; 5 mg, n = 29; 10 mg, n = 34; or 15 mg, n = 32) or placebo (n = 31) was administered daily for 12 weeks. Thrombograms and TGA parameters were extracted for each subject at baseline and after 12 weeks of treatment. Results After 12 weeks of treatment, all treatment groups showed a mean thrombogram (±95% confidence interval [CI] of the mean) within the reference ranges, that is, the 2.5th–97.5th percentile of all baseline thrombograms (n = 168), as well as for TGA parameters. Conclusions The intake of E4 15 mg for 12 weeks led to significant but not clinically relevant changes compared to baseline as the mean values (±95% CI of the mean) remained within reference ranges, demonstrating a neutral profile of this estrogen on hemostasis.

Migraine in perimenopausal women

Sex hormones have a significant influence on the course of migraine in women. Perimenopause is accompanied by unstable cycle length, vasomotor, urogenital and other symptoms, while the course of migraine usually worsens. In postmenopause ovarian follicular function decreases, and the course of migraine improves in most cases. However, a number of studies have shown that the course of migraine does not change or even worsen after menopause. Perimenopausal and postmenopausal migraine patients are also more likely to suffer from vasomotor symptoms. Hormone replacement therapy is prescribed to relieve vasomotor symptoms, which may worsen the course of migraine. In this review, the influence of perimenopause and postmenopause on the course of migraine, the use of hormone replacement therapy, and methods to relieve and prevent attacks in patients with migraine are examined in detail.

Efficacy and safety of non-hormonal agents for vasomotor symptoms of menopause: A prospective, double-blind, placebo-controlled study

Aim. To assess the safety and efficacy of non-hormonal agents for mild vasomotor symptoms of menopause.&#x0D; Materials and methods. The study included 173 females aged 4855 with mild vasomotor symptoms during the early postmenopausal period. Patients in the study cohort were stratified into two groups by the double-blind method. In group 1 (study), the patients took the homeopathic agent Neoclimsal 1 tablet 4 times a day sublingually until completely dissolved for 4 weeks (n=86). In group 2 (n=87), the patient received a placebo (30 mg of microcrystalline cellulose) in a regimen mimicking the study treatment. Twenty-three patients withdrew from the study due to protocol violation or revoked their consents for reasons not related to medication. At the end of the study, 75 patients remained in both groups. The therapeutic efficacy was assessed based on the Greene and MENQOL scores change. The SF-36 questionnaire was used to evaluate patients' quality of life, and the average rate of falling asleep was calculated to assess the change in sleep disturbance. The change of M-echo and mammography results were reviewed using the BI-RADS scale 12 months after the start of the treatment to assess the agent's safety. Study design: A prospective, double-blind, placebo-controlled study.&#x0D; Results. The course of Neoclimsal, sublingual tablets, reduced the severity of vasomotor symptoms by 2.3 times, the severity of depression by half (p0.001), and at the end of treatment after 12 weeks of observation, the therapeutic effect not only persisted but tended to increase (p0.001). Improvement in the quality of life of patients treated with Neoclimsal was confirmed by an improvement in the MENQOL score by 1.4 times a month after the start of therapy while maintaining the achieved result after 12 weeks of observation (p0.001). The drug's safety is confirmed by the absence of adverse side effects and allergic reactions, the absence of endometrial thickness change within 3 months after the start of treatment, and mammography results using the BI-RADS scale at 12 months.&#x0D; Conclusion. The results indicate the effectiveness of non-hormonal therapy in relieving vasomotor symptoms of mild postmenopause with a high safety profile. The drug has a beneficial effect on sleep disorders, reducing the severity of mental distress and improving the general quality of life.

Effects of flaxseed (Linum usitatissimum) on climacteric symptoms and clinical parameters in post-menopausal women

Menopause is the irreversible and permanent cessation of menstruation after one year of amenorrhea. Common symptoms include vaginal dryness, hot flashes, night sweating, and bone pain. Traditionally Linum usitatissimum (Flaxseeds) has been used for the treatment of postmenopausal symptoms. However, the effect of this medicinal herb on the satiety hormone; leptin and body weight in menopausal women has not been elucidated well. This study was designed to evaluate the effect of flaxseeds on serum estrogen, progesterone, leptin, and malondialdehyde, body mass index, blood pressure in menopausal women. Moreover, the flaxseed effect on climacteric symptoms was also investigated.&#x0D; The study was carried out as an interventional pre-post design. The study was a six-week oral administration of 1000 mg flaxseed powder twice daily by menopausal women. The duration of the study was eight months. Serum levels of estrogen, progesterone, and leptin hormones as well as total plasma malondialdehyde were determined pre-and-post flaxseed intervention. Clinical symptoms and bothersome complaints of postmenopausal women such as hot flashes, vaginal dryness, bone pain, and night sweating were also evaluated. Furthermore, blood pressure elements and body mass index were also measured. The results showed that Linum usitatissimum seed powder significantly reduced vaginal dryness, hot flashes, bone pain, and night sweating in menopausal women. The same dose of flaxseed had no significant effects on serum estrogen and progesterone. However, it significantly decreased serum malondialdehyde and increased serum leptin. Flaxseed had a non-significant effect on body mass index and blood pressure. In conclusion Linum usitatissimum seed had significant efficacy in relieving vasomotor symptoms, decreasing oxidative stress, and increasing serum levels of leptin in menopausal women.&#x0D; Keywords: climacteric, estrogen, progesterone, leptin, malondialdehyde.

COCs with estradiol valerate/dienogest vs 17β-estradiol/nomegestrol acetate: effects on metabolism and body composition in menopausal transition women

Context: Women during the menopausal transition (MT) have reduced fertility, and yet frequency of pregnancy in the absence of contraception is about 30%. Late reproductive age women are at a higher risk of adverse pregnancy outcome, and thus require effective contraceptive methods if pregnancy is to be avoided. The use of combined oral contraceptives (COCs), in addition to highly effective pregnancy prevention, is associated with important non-contraceptive benefits for perimenopausal women, such as an improved bleeding pattern, particularly in the setting of irregular or heavy menses, alleviation of vasomotor symptoms. The main requirements in choosing СOCs for women during the MT are their safety, metabolic neutrality, and no weight gain, because during the MT occurs adverse changes in metabolic profile and body composition.

Use of dietary supplements to alleviate vasomotor symptoms among menopausal women

Given that menopausal women experiencing vasomotor symptoms may prefer complementary and integrative health approaches such as dietary supplements, this article provides current information on their efficacy and safety and examines the implications for clinical practice.

Dietary advanced glycation end-products and postmenopausal hot flashes: A post-hoc analysis of a 12-week randomized clinical trial

ObjectivePostmenopausal hot flashes are associated with an increased risk of cardiovascular disease and diabetes. Because dietary advanced glycation end-products (AGEs) may act as endocrine disruptors, this study examined the potential association of modifications to the intake of dietary AGEs with the frequency and severity of postmenopausal hot flashes. MethodsPostmenopausal women (n = 84) reporting ≥2 moderate-to-severe hot flashes daily were randomly assigned to either the intervention group or the control group. The former were asked to follow a low-fat, vegan diet, including cooked soybeans (1/2 cup [86 g]/day) for 12 weeks, and the latter continued their usual diets for 12 weeks. Frequency and severity of hot flashes were recorded with a mobile application. Three-day diet records were analyzed using the Nutrition Data System for Research software and dietary AGEs were estimated, using a database. Seventy-one participants completed the whole study and 63 provided complete hot flash and dietary data for the AGEs analysis (n = 31 in the intervention and n = 24 in the control group). Pearson correlations were used to assess the association between changes in hot flashes and dietary AGEs. ResultsDietary AGEs decreased in the intervention group by 73 %, that is by 5509 ku/day on average (95 % −7009 to −4009; p < 0.001), compared with the control group (+458; 95 % CI −835 to +1751; p = 0.47; treatment effect −5968 ku/day [95 % CI −7945 to −3991]; Gxt, p < 0.001). Severe hot flashes decreased by 92 % (p < 0.001) and moderate-to-severe hot flashes decreased by 88 % in the intervention group (p < 0.001). Changes in dietary AGEs correlated with changes in severe (r = +0.39; p = 0.002) and moderate hot flashes (r = +0.34; p = 0.009) and remained significant after adjustment for changes in energy intake (r = +0.45; p < 0.001; and r = +0.37; p = 0.004, respectively) and changes in body mass index (r = +0.37; p = 0.004; and r = +0.27; p = 0.04, respectively). The reduction in dietary AGEs required to achieve a predicted reduction in hot flashes by 1/day was 6933 ku/day for severe and 4366 ku/day for moderate-to-severe hot flashes. ConclusionsThe reduction in dietary AGEs with a low-fat plant-based diet was associated with a significant reduction in the frequency of severe and moderate-to-severe postmenopausal hot flashes, independent of changes in energy intake and weight loss. Plant-based diets could be used not only to alleviate vasomotor symptoms in postmenopausal women, but also to reduce other health risks associated with AGEs. Trial registrationClinicalTrials.gov, NCT04587154.

The Utilization of Dehydroepiandrosterone as a Sexual Hormone Precursor in Premenopausal and Postmenopausal Women: An Overview.

Dehydroepiandrosterone (DHEA), and its metabolite, dehydroepiandrosterone sulfate ester (DHEAS), are the most abundant circulating steroid hormones, and are synthesized in the zona reticularis of the adrenal cortex, in the gonads, and in the brain. The precise physiological role of DHEA and DHEAS is not yet fully understood, but these steroid hormones can act as androgens, estrogens, and neurosteroids, and perform many roles in the human body. Since both levels decline with age, use of DHEA supplements have gained more attention due to being advertised as an antidote to aging in postmenopausal women, who may have concerns on age-related diseases and overall well-being. However, current research has not reached an overall consensus on the effects of DHEA on postmenopausal women. This overview is a summary of the current literature, addressing the metabolic pathway for DHEA synthesis and utilization, as well as the effects of DHEA on premenopausal and postmenopausal women with disease states and other factors. As for the therapeutic effects on menopausal syndrome and other age-related diseases, several studies have found that DHEA supplementations can alleviate vasomotor symptoms, preserve the integrity of the immune system, reduce bone loss, and increase muscle mass. Intravaginal DHEA has shown significant beneficial effects in menopausal women with severe vulvovaginal symptoms. On the other hand, DHEA supplements have not shown definitive effects in cardiovascular disease, adrenal insufficiency, insulin sensitivity, and cognition. Due to inadequate sample sizes and treatment durations of current studies, it is difficult to assess the safety and efficacy of DHEA and draw reliable conclusions for the physiological role, the optimal dosage, and the effects on premenopausal and postmenopausal women; therefore, the study of DHEA warrants future investigation. Further research into the roles of these steroid hormones may bring us closer to a therapeutic option in the future.

Effects of estetrol on vaginal cytology, genitourinary syndrome of menopause and health-related wuality of life: results from the E4Relief Phase 2b Study

Introduction: Estetrol (E4), a native estrogen with selective action in tissues, is in development for the treatment of menopausal symptoms. A dose of E4 15 mg was considered to be the minimal effective dose for alleviating vasomotor symptoms (VMS)*. Here we present the data for vaginal cytology, genitourinary syndrome of menopause (GSM) and health-related quality of life (HR-QoL).

Selective Inhibition of JAK1 Primes STAT5-Driven Human Leukemia Cells for ATRA-Induced Differentiation.

All-trans retinoic acid (ATRA), a derivate of vitamin A, has been successfully used as a therapy to induce differentiation in M3 acute promyelocytic leukemia (APML), and has led to marked improvement in outcomes. Previously, attempts to use ATRA in non-APML in the clinic, however, have been underwhelming, likely due to persistent signaling through other oncogenic drivers. Dysregulated JAK/STAT signaling is known to drive several hematologic malignancies, and targeting JAK1 and JAK2 with the JAK1/JAK2 inhibitor ruxolitinib has led to improvement in survival in primary myelofibrosis and alleviation of vasomotor symptoms and splenomegaly in polycythemia vera and myelofibrosis. While dose-dependent anemia and thrombocytopenia limit the use of JAK2 inhibition, selectively targeting JAK1 has been explored as a means to suppress inflammation and STAT-associated pathologies related to neoplastogenesis. The objective of this study is to employ JAK1 inhibition (JAK1i) in the presence of ATRA as a potential therapy in non-M3 acute myeloid leukemia (AML). Efficacy of JAK1i using INCB52793 was assessed by changes in cell cycle and apoptosis in treated AML cell lines. Transcriptomic and proteomic analysis evaluated effects of JAK1i. Synergy between JAK1i+ ATRA was assessed in cell lines in vitro while efficacy in vivo was assessed by tumor reduction in MV-4-11 cell line-derived xenografts. Here we describe novel synergistic activity between JAK1i inhibition and ATRA in non-M3 leukemia. Transcriptomic and proteomic analysis confirmed structural and functional changes related to maturation while in vivo combinatory studies revealed significant decreases in leukemic expansion. JAK1i+ ATRA lead to decreases in cell cycle followed by myeloid differentiation and cell death in human leukemias. These findings highlight potential uses of ATRA-based differentiation therapy of non-M3 human leukemia.

Selective Estrogen Receptor Modulators in Gynecology Practice.

Selective estrogen receptor (ER) modulators have variable tissue specific estrogen agonist and antagonist activities. Tamoxifen is approved for treatment and prevention of breast cancer; acts as an endometrial estrogen agonist. Raloxifene is approved for prevention and treatment of osteoporosis and prevention of breast cancer. The selective ER modulators bazedoxifene paired with conjugated estrogens relieves vasomotor symptoms and prevents bone loss with neutral effects on breast and amenorrhea similar to placebo. Ospemifene is approved to treat dyspareunia. Lasofoxifene is in development for resistant ER positive breast cancer. Estetrol (E4), synthesized by human fetal liver, has dual weak-estrogenic/antiestrogenic features, now approved as a contraceptive.

A COMPARATIVE EVALUATION OF STATIN AND FENOFIBRATE (LIPID LOWERING DRUGS) ON THE INTERACTION OF PRO¬-INFLAMMATORY CYTOKINES AND VASOMOTOR INSTABILITY IN WOMEN WITH NATURALAND SURGICAL MENOPAUSE.

Introduction:Evidence suggests that the decline in ovarian function with menopause is associated with spontaneous increase in proinammatory cytokines, especially IL-1, IL-6 and TNF-α. Objective:To evaluate the possible relationship of pro-inammatory cytokines and vasomotor symptoms in menopausal women on lipid lowering drugs- statin and fenobrate.Materials &amp;Method: A prospective randomized clinical trial was carried out in the Dept. of Obstetrics and Gynaecology, I.P.G.M.E.R., Kolkata enrolling 100 women and dividing them into six groups. They were given either atorvastatin or fenobrate or no drug. The main outcome measures were to estimate changes in cytokine levels and vasomotor symptoms and their correlation. Results: Although the cytokine levels (except TGF-β) &amp; incidence of vasomotor symptoms increased with menopause, there was only some positive correlation between TNF-α with increasing symptom at three month postoperative period. With atorvastatin therapy, moderate positive correlation (r &gt;0.5) exists between decreasing levels of IL-1, IL-6 and TNF-α and decreasing vasomotor symptoms &amp; strong negative correlation [r = -0.79] PB PB in case of TGF-β in natural menopausal women. In surgical menopausal women treated with atorvastatin correlation exists between TNF-α and TGF-β levels and vasomotor symptoms.There was no correlation found between any of the cytokine level and vasomotor symptom in women given fenobrate in natural menopausal group.but correlation found between TNF-α and TGF-β levels and vasomotor symptoms in the other group of subjects (for TNF-α r =+0.35 and for TGF-β r =−0.49 ). The levels of inammatory cytokines IL-1, IL-6, TNF-α increased within PB PB Conclusion: three months of surgical menopause while the level of anti-inammatory cytokine TGF-β decreased. Atorvastatin and fenobrate- both are effective in alleviating vasomotor symptoms, though statistically insignicant. The levels of inammatory cytokines, TNF-α and TGF-β are best correlated with vasomotor symptoms in menopausal women.

From menarche to menopause

On September 11–12, 2020, in Kyiv hosted the International Women's Health Summit “From Menarche to Menopause” with the participation of leading foreign and domestic experts in the field of obstetrics and gynecology. The event was devoted to such topical topics as miscarriage, infertility, menstrual irregularities, menopausal hormone therapy (MHT).The current concern in clinical practice is not overuse of MHT, but it underutilization, and the fact that only a small number of women with impaired quality of life through menopausal symptoms receive treatment, despite that they perfectly fit the patient's profile for such therapy.All types of MHT are characterized by following effects: a positive effect on the cardiovascular system if MHT was start before 60 ages or in the first 10 years after menopause onset; the mortality rate from all causes is not increased in patients on MHT. The “ideal” MHT should relieve vasomotor symptoms, influence urogenital symptoms, prevent fractures and bone loss, protect the cardiovascular system and endometrium, and should not increase the risks of breast cancer, deep vein thrombosis and pulmonary embolism. Estradiol + dydrogesterone (Femoston®) scheme fits perfectly into these criteria. Femoston® is an oral MHT preparation that is effective in relieving symptoms of estrogen deficiency with a proven safety profile on the cardiovascular system and breast. This drug helps to reduce the manifestations of symptoms of estrogen deficiency, increase bone mineral density, and has a positive effect on metabolic processes. Numerous studies have shown that combination of estradiol + dydrogesterone is not only highly effective against menopausal symptoms, but also extremely important features, in particular, a proven safety profile for breast cancer.

Efficacy of a novel extract of fenugreek seeds in alleviating vasomotor symptoms and depression in perimenopausal women: A randomized, double-blinded, placebo-controlled study.

The present randomized, double-blinded, placebo-controlled study investigated the effect of a standardized fenugreek extract (FHE) on perimenopausal discomforts and its influence on hormonal balance and safety. Healthy women characterized with perimenopausal symptoms (n=48), as assessed by MRS questionnaire, were randomized either to FHE (n=24) or placebo (n=24) and supplemented with 250mg×2/day for 42days. Both inter and intra-group comparison revealed a significant improvement in somatic, psychological, and urogenital scores in FHE group, especially for hot flashes (25.9%), night sweats (26.5%), depression (31.8%), and insomnia (21.6%). Further hormone analysis revealed an enhancement in serum estradiol (18.9%), free testosterone (38.2%), and progesterone (19.9%) concentrations and a significant decrease in FSH (38.2%) and SHBG (21.1%) concentrations toward establishing a hormonal balance among FHE-group; without significant changes in other clinical safety parameters. Thus, FHE supplementation offered a significant reduction in vasomotor effects and depression in perimenopausal women, without any adverse effects PRACTICAL APPLICATIONS: Fenugreek is a popular kitchen spice and Ayurvedic medicine for a variety of health conditions including diabetes, hypercholesterolemia, hepatotoxicity, gastritis, and also for a variety of hormone-related health conditions such as sexual functions, lactation, osteoporosis, PCOS, and post/perimenopausal discomforts. Fenugreek is rich in alkaloids, steroidal saponins, flavonoids and 4-hydroxyisoleucine. The present randomized-controlled study investigated the plausible application of a standardized hydro-ethanolic extract of fenugreek seeds (FHE) having a unique 3:1 ratio for protodioscin to trigonelline in the management of perimenopausal discomforts. It was observed that FHE at a dosage of 250mg×2/day for 42days significantly reduced the discomforts, especially vasomotor symptoms and depression, and helped to attain a hormonal balance without any adverse effects or deviations in clinical safety parameters. Thus, FHE could be a potential natural agent for the management of post and perimenopausal discomforts and has to be explored in future studies.

Abstract PD3-06: Biomarker modulation by bazedoxifene and conjugated estrogen (Duavee®) in women at high risk for development of breast cancer

Abstract Agents which both reduce risk for development of breast cancer and relieve vasomotor symptoms are likely to have good uptake and adherence. We conducted a pilot study with 6 months of the tissue selective estrogen complex bazedoxifene (20 mg) and conjugated estrogen (0.45 mg) (Duavee®) to assess feasibility and effects on biomarkers. Risk biomarkers for postmenopausal breast cancer included fully automated mammographic volumetric density (Volpara®), benign breast tissue Ki-67, and serum levels of progesterone, IGF-1 and IGFBP3, bioavailable estradiol and testosterone. Exploratory biomarkers included selected estrogen and progesterone responsive gene expression in benign breast tissue. 28 peri- and post-menopausal women at increased risk for breast cancer were enrolled; 13 in Cohort A with baseline Ki-67 &amp;lt; 1% and 15 in Cohort B with baseline Ki-67 of 1-4%. All completed the study with &amp;gt; 85% drug adherence. An improvement in median hot flash score from 15 at baseline to 0 at 6 months, and menopause specific quality of life total, vasomotor and sexual domain scores were also observed (p&amp;lt; 0.001). Significant changes in risk biomarkers, uncorrected for multiple comparisons, were a decrease in mammographic fibroglandular volume (p=0.043); decreases in serum progesterone, bioavailable testosterone, and IGF-1 (p&amp;lt;0.01); and for women from Cohort B, a reduction in Ki-67 (p=0.017) despite an increase in serum bioavailable estradiol. Unsupervised cluster analysis of RT-qPCR results indicated two clusters with differences in change in early estrogen response genes including ERS1, TFF1, GREB1a, PGR and AREG. The 10 women in one cluster tended to have increased expression of two or more of early estrogen response genes, but not increased expression of CCND1 (cyclin D1) or genes downstream of activated progesterone receptor such as STAT5a, PdK4, and STK. A trend towards decrease in several genes with predominant stromal expression implicated in breast cancer development including FASN, LEP, CXCL12, SDF1a and B, and CYP19A1 was observed. The 17 women in cluster 2 by contrast exhibited predominately decreased expression of early estrogen response genes. Given the favorable effects on vasomotor symptoms and risk biomarkers, a placebo-controlled Phase IIB trial is warranted. This study was supported in part by grants from the Breast Cancer Research Foundation (BCRF-16-049, BCRF-17-049, BCRF-18-049); and an NIH Clinical and Translational Science Award grant (UL1 TR000001, formerly UL1RR033179) awarded to the University of Kansas Medical Center, and an internal clinical pilot grant program of the KUMC Research Institute. Citation Format: Carol J Fabian, Lauren Nye, Teresa A Phillips, Onalisa Winblad, Carola M Zalles, Christy R Hagan, Merit L Goodman, Byron J Gajewski, Devin C Koestler, Prabhakar Chalise, Bruce F Kimler. Biomarker modulation by bazedoxifene and conjugated estrogen (Duavee®) in women at high risk for development of breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-06.