Tissue Selective Estrogen Complex Research Articles

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.

225. The Effects of Tissue Selective Estrogen Complex (TSEC) Duavee on Mood Symptoms and Resting State Functional Connectivity in Perimenopausal Depression

225. The Effects of Tissue Selective Estrogen Complex (TSEC) Duavee on Mood Symptoms and Resting State Functional Connectivity in Perimenopausal Depression

Treatment options for postmenopausal osteoporosis

Osteoporosis is a systemic skeletal disease, characterized by a decrease of bone mass and bone quality, with a subsequent reduction of bone strenght and an increased risk of fracture. Hormone Therapy for menopausal women can significantly prevent osteopenia and osteoporosis, thus reducing the fracture risk. The use of HT, according to guidelines, is for postmenopausal women within 10 years since last menstruation or under the age of 60 years. Only HT at standard dose is able to reduce the fracture risk, while low-dose HT can prevent bone loss. Estrogens (with and without the addition of a progestin) and tibolone showed a fracture risk reduction effect. Also Tissue Selective Estrogen Complex (TSEC) can reduce the bone loss in postmenopause. For women without climacteric symptoms (as hot flushes and/or night sweats) the use of Selective Estrogen Receptor Modulators (SERMs) can be indicated, with a reduction of risk of vertebral fracture (for raloxifene and bazedoxifene), and non-vertebral fracture in high-risk women (for bazedoxifene). In more advence ages, antiresoptive agents as Bisphosphonates (Alendronate, Risedronate, Ibandronate and Zoledronate) can reduce the risk of vertebral, non-vertebral and hip fracture risk. Denosumab (DMAB), monoclonal antibobody against Rank-ligand (RANKL), providing an increased bone mass, significantly decreases risk of vertebral, non-vertebral and hip fracture. A drug holiday or treatment interruption is not recommended with DMAB, and DMAB dosing should not stopped without subsequent antiresorptive or other therapy to prevent a "rebound effect" with a possible increased risk of multiple vertebral fracture. Teriparatide (fraction 1-34 of recombinant PTH, administered daily 20 mcg sc) can stimulate osteoblast activity, with an important increase of bone mass and a significant reduction of risk of vertebral fracture, and of multiple vertebral fractures, but also of non-vertebral fragility fracture. Romosozumab (RMZ, adimnistered monlty 210 mg sc), is a bone-forming monoclonal antibody that binds to and inhibits sclerostin, with a dual effect of increasing bone formation and decreasing bone resorption. RMZ has showed to give marked increases in spine and hip bone density after 1 year of administration, also reducing fracture risk. The differences among the various treatments is the basis for the individualization of osteoporosis treatment, according to combination and/or sequential regimens of administration.

Epigenetic and transcriptome responsiveness to ER modulation by tissue selective estrogen complexes in breast epithelial and breast cancer cells.

Selective estrogen receptor modulators (SERMs), including the SERM/SERD bazedoxifene (BZA), are used to treat postmenopausal osteoporosis and may reduce breast cancer (BCa) risk. One of the most persistent unresolved questions regarding menopausal hormone therapy is compromised control of proliferation and phenotype because of short- or long-term administration of mixed-function estrogen receptor (ER) ligands. To gain insight into epigenetic effectors of the transcriptomes of hormone and BZA-treated BCa cells, we evaluated a panel of histone modifications. The impact of short-term hormone treatment and BZA on gene expression and genome-wide epigenetic profiles was examined in ERαneg mammary epithelial cells (MCF10A) and ERα+ luminal breast cancer cells (MCF7). We tested individual components and combinations of 17β-estradiol (E2), estrogen compounds (EC10) and BZA. RNA-seq for gene expression and ChIP-seq for active (H3K4me3, H3K4ac, H3K27ac) and repressive (H3K27me3) histone modifications were performed. Our results show that the combination of BZA with E2 or EC10 reduces estrogen-mediated patterns of histone modifications and gene expression in MCF-7ERα+ cells. In contrast, BZA has minimal effects on these parameters in MCF10A mammary epithelial cells. BZA-induced changes in histone modifications in MCF7 cells are characterized by altered H3K4ac patterns, with changes at distal enhancers of ERα-target genes and at promoters of non-ERα bound proliferation-related genes. Notably, the ERα target gene GREB1 is the most sensitive to BZA treatment. Our findings provide direct mechanistic-based evidence that BZA induces epigenetic changes in E2 and EC10 mediated control of ERα regulatory programs to target distinctive proliferation gene pathways that restrain the potential for breast cancer development.

Mechanistic Effects of Estrogens on Breast Cancer.

Current concepts regarding estrogen and its mechanistic effects on breast cancer in women are evolving. This article reviews studies that address estrogen-mediated breast cancer development, the prevalence of occult tumors at autopsy, and the natural history of breast cancer as predicted by a newly developed tumor kinetic model. This article reviews previously published studies from the authors and articles pertinent to the data presented. We discuss the concepts of adaptive hypersensitivity that develops in response to long-term deprivation of estrogen and results in both increased cell proliferation and apoptosis. The effects of menopausal hormonal therapy on breast cancer in postmenopausal women are interpreted based on the tumor kinetic model. Studies of the administration of a tissue selective estrogen complex in vitro, in vivo, and in patients are described. We review the various clinical studies of breast cancer prevention with selective estrogen receptor modulators and aromatase inhibitors. Finally, the effects of the underlying risk of breast cancer on the effects of menopausal hormone therapy are outlined. The overall intent of this review is to present data supporting recent concepts, discuss pertinent literature, and critically examine areas of controversy.

A tissue-selective estrogen complex as treatment of osteoporosis in experimental lupus.

Osteoporosis is a common secondary complication in patients with systemic lupus erythematosus (SLE). Current osteoporosis treatment with bisphosphonates has some negative side effects and there is a lack of data regarding newer treatments options for SLE associated osteoporosis. The tissue-selective estrogen complex (TSEC) containing conjugated estrogens and the selective estrogen receptor modulator bazedoxifene (Bza) is approved for treatment of postmenopausal vasomotor symptoms and prevention of osteoporosis. However, it has not been evaluated for treatment of osteoporosis in postmenopausal SLE patients. Ovariectomized MRL/lpr mice constitute a model for postmenopausal lupus that can be used for osteoporosis studies. We used this model in a set of experiments where the mice were treated with different doses of 17β-estradiol-3-benzoate (E2), Bza, or TSEC (E2 plus Bza), administered in the early or late phases of disease development. The skeleton was analyzed by dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, and high-resolution microcomputed tomography. The lupus disease was assessed by determination of proteinuria, hematuria, and lupus disease markers in serum. Treatment with medium dose TSEC administered in early disease protected ovariectomized MRL/lpr mice from trabecular bone loss, while there were no differences in lupus disease parameters between treatments. This is the first experimental study to investigate TSEC as a potential new therapy for osteoporosis in postmenopausal SLE.

The Use of ERE-Luc Reporter Mice to Monitor Estrogen Receptor Transcriptional Activity in a Spatio-Temporal Dimension.

In spite of the fact that women spend 1/3 of their lives in postmenopause, the search for appropriate therapies able to counteract the derangements associated with the menopause still represents a sort of sought after the "Holy Grail."Nowadays, the combination of estrogens and selective estrogen receptor modulators (SERMs), a class of compounds with a mixed agonist/antagonistic activity on the estrogen receptor (ER) in various tissues, represents the most promising approach to improve postmenopausal women's health, by preserving the benefits while avoiding the side effects of estrogen-based therapy.Given their complex mechanisms of action, the evaluation of SERM activity in combination with conjugated estrogens (CE) requires a multifactorial analysis that takes into account the multifaceted and dynamic effects of these compounds in target tissues, even in relation to the physiological/pathological status.To accomplish such a goal, we took advantage of the ERE-Luc model, a reporter mouse that allows the monitoring of ER transcriptional activity in a spatio-temporal dimension. Cluster analyses performed on in vivo/ex vivo bioluminescence (BLI) data and ex vivo luciferase activity enabled to sustain the combination of CE plus bazedoxifene (TSEC, tissue-selective estrogen complex) as a valuable option for the pharmacological treatment of the postmenopause.

The Trend in the Sales of Menopausal Hormone and Other Osteoporosis Medications in South Korea from 2016 to 2019.

BackgroundIncreasing geriatric population, osteoporosis prevalence, and interest in bone health are key contributing factors for the growth of osteoporosis medication markets. Thus, this study evaluated changes in the menopausal hormone and other osteoporosis medication markets from 2016 to 2019.MethodsThis study’s dataset was obtained from the International Marketing Services of IQVIA Inc. in South Korea. The sales of medications for osteoporosis treatment with menopausal hormones were evaluated for drug sales for osteoporosis treatment from 2016 to 2019.ResultsThe results showed that the tissue-selective estrogen complex (TSEC) sales had increased annually while the estrogen-progesterone therapy (EPT) sales had decreased. Excluding menopausal hormones, bisphosphonates were the most widely sold medications for osteoporosis treatment. Among the bisphosphonate medications, sales of ibandronate and zoledronate increased annually, while alendronate and risedronate decreased. Teriparatide also showed increasing sales. A rapid rise was noted in the sales of denosumab.ConclusionsWhile the sales of TSEC, injectable bisphosphonates, and denosumab have increased annually, the sales of EPT, estrogen therapy, oral bisphosphonates have not increased, as reflected in hormone therapy and osteoporosis medication market trends. This study showed the recent trends in hormone therapy and the osteoporosis medication market from 2016 to 2019 in South Korea.

Hormone therapy in the postmenopausal years: considering benefits and risks in clinical practice.

Menopausal symptoms can be very distressing and considerably affect a woman's personal and social life. It is becoming more and more evident that leaving bothersome symptoms untreated in midlife may lead to altered quality of life, reduced work productivity and, possibly, overall impaired health. Hormone therapy (HT) for the relief of menopausal symptoms has been the object of much controversy over the past two decades. At the beginning of the century, a shadow was cast on the use of HT owing to the concern for cardiovascular and cerebrovascular risks, and breast cancer, arising following publication of a large randomized placebo-controlled trial. Findings of a subanalysis of the trial data and extended follow-up studies, along with other more modern clinical trials and observational studies, have provided new evidence on the effects of HT. The goal of the following paper is to appraise the most significant clinical literature on the effects of hormones in postmenopausal women, and to report the benefits and risks of HT for the relief of menopausal symptoms. A Pubmed search of clinical trials was performed using the following terms: estrogens, progestogens, bazedoxifene, tibolone, selective estrogen receptor modulators, tissue-selective estrogen complex, androgens, and menopause. HT is an effective treatment for bothersome menopausal vasomotor symptoms, genitourinary syndrome, and prevention of osteoporotic fractures. Women should be made aware that there is a small increased risk of stroke that tends to persist over the years as well as breast cancer risk with long-term estrogen-progestin use. However, healthy women who begin HT soon after menopause will probably earn more benefit than harm from the treatment. HT can improve bothersome symptoms, all the while conferring offset benefits such as cardiovascular risk reduction, an increase in bone mineral density and a reduction in bone fracture risk. Moreover, a decrease in colorectal cancer risk is obtainable in women treated with estrogen-progestin therapy, and an overall but nonsignificant reduction in mortality has been observed in women treated with conjugated equine estrogens alone or combined with estrogen-progestin therapy. Where possible, transdermal routes of HT administration should be preferred as they have the least impact on coagulation. With combined treatment, natural progesterone should be favored as it is devoid of the antiapoptotic properties of other progestogens on breast cells. When beginning HT, low doses should be used and increased gradually until effective control of symptoms is achieved. Unless contraindications develop, patients may choose to continue HT as long as the benefits outweigh the risks. Regular reassessment of the woman's health status is mandatory. Women with premature menopause who begin HT before 50 years of age seem to have the most significant advantage in terms of longevity. In women with bothersome menopausal symptoms, HT should be considered one of the mainstays of treatment. Clinical practitioners should tailor HT based on patient history, physical characteristics, and current health status so that benefits outweigh the risks.

Effect of Tissue-Selective Estrogen Complex on Hip Structural Geometry in Postmenopausal Women: A 12-Month Study

BackgroundHip structural analysis (HSA) is a method for evaluating bone geometry reflecting bone structural and biomechanical properties. However, tissue-selective estrogen complex (TSEC) treatment effects on HSA have not been investigated.ObjectiveThis study was performed to evaluate the effect of TSEC treatment on hip geometry in postmenopausal Korean women. The treatment was given for 12 months, and hip geometry was measured by HSA.Materials and MethodsA total of 40 postmenopausal women who received TSEC containing conjugated estrogen 0.45 mg and bazedoxifene 20 mg for treating vasomotor symptoms were included in this retrospective cohort study. The changes in bone mineral density and parameters of HSA including the outer diameter, cross-sectional area, cross-sectional moment of inertia, cortical thickness, section modulus, and buckling ratio as determined by dual-energy X-ray absorptiometry were compared before and after 12 months of TSEC treatment.ResultsMean age and years since menopause were 55.1 and 4.5 years, respectively. Total hip bone mineral density significantly increased by 0.74% after treatment (P=0.011). The changes in HSA were mainly demonstrated in the narrow femoral neck: cross-sectional area (P=0.003) and cortical thickness (P<0.001) increased significantly. For the shaft region, only SM decreased significantly after treatment (P=0.009). However, most parameters did not change significantly with TSEC treatment in the intertrochanteric and shaft regions.ConclusionsOur findings demonstrate that 12 months of TSEC treatment could improve bone geometry as measured by HSA. The findings suggest that TSEC might be an interesting option for the prevention of fracture as well as osteoporosis in postmenopausal women.

Role of estrogen in the management of COVID – 19 in females

With the increase, the spread of COVID-19 its effect can be seen on health care systems seek innovative treatment ways as the need of the hour. The suspected leading cause of COVID-19 is due to the response to inflammations and the cytokine storm, which majorly damages the lung tissue. The difference in response to the vaccine can be seen due to different sex. Moreover, age-related decrease in sex steroid hormones like Estrogen as well as testosterone can promote pro-inflammatory raise in older individuals which in turn increases the risk of COVID-19 related adverse outcomes. Such sex hormones have the capacity of mitigating inflammatory response and can also provide promising therapeutic benefits for patients suffering from COVID-19. Moreover, over above the effects of on any ERS, these drugs showed useful ancillary properties. Most showed to highlight broader roles in mitigating viral replication by the ER-independent mechanisms as mentioned. Data simplifies ER modulation an apt pharmacological approach for restricting storm and thus prevents the inflammation due to COVID-19. Mainly the application of or tissue-selective estrogen complex can provide a pharmacological response. Such treatment options can be fruitful for both sexes in the early phase of such disease condition to prevent further progression of the disease to severe forms.

Selective estrogen receptor modulator with estrogen does not affect the proliferation and apoptosis of uterine leiomyoma cells.

BackgroundThe administration of menopausal hormone therapy (MHT) in women with uterine leiomyomas is still debated. The purpose of this article is to study the proliferation and apoptosis of uterine leiomyoma cells under the impact of selective estrogen receptor modulator (SERM) combined with estrogen.MethodsPrimary cultured uterine leiomyoma cells in the perimenopausal period were treated with estrogen (17-beta estradiol) + SERM (raloxifene) as the tissue selective estrogen complex (TSEC) group, while both estrogen + medroxyprogesterone acetate (E+P) and estrogen (E) alone as were used as control groups. The expression of proliferating cell nuclear antigen (PCNA) and B-cell lymphoma-2 (Bcl-2) proteins was assessed by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay and western-blot analysis, respectively.ResultsThe proliferation in the TSEC group was weaker than the control groups (P<0.001). There was no statistical difference between the TSEC and blank control group on cell proliferation at 72 h (P=0.13). However, there was a significant difference between the other groups (P<0.001). PCNA expression of TSEC was lower than that of the E + P and E groups (P<0.05). There was no statistical difference in the expression of PCNA between the TSEC and blank control groups (P=0.63). Bcl-2 expression of TSEC was lower than that of the E + P and E groups (P<0.05). There was no statistical difference in the expression of Bcl-2 between the TSEC group and the blank control group (P=0.60).ConclusionsSERM combined with estrogen may have a better safety for perimenopausal women with uterine leiomyoma in MHT.

Postmenopausal hormone therapy in BRCA gene mutation carriers: to whom and which?

ABSTRACT Introduction Risk-reducing-salpingo-oophorectomy (RRSO) inevitably leads BRCA mutation carriers to premature menopause. Areas covered To evaluate the existing evidence for use of postmenopausal hormone therapy (HT) in BRCAmc, after RRSO or menopause occurring naturally, for both breast cancer (BC) survivors and those without BC. Expert opinion All BC survivors are excluded from any HT treatment: in other BRCAmc, before 51 years of age the benefits of HT overcome the risks after RRSO and/or premature ovarian insufficiency (POF). After 51 years of age, it is important to treat only women with important vasomotor symptoms, after the failure of alternative therapies. Estrogens-only therapy plays a key role in hysterectomized women (HW). In the case of an intact uterus (UW), associations with the lowest dose of progestins/natural progesterone derivatives have to be preferred, as progestins has been shown to play an important role in BC transformation, especially in BRCA1mc. No studies have been performed in BRCAmc with regard to ‘progestin-free’ HT, in particular the old tibolone (both in HW and UW) and the new tissue-selective estrogen complex (in UW). However, preliminary data obtained from the general population are reassuring about the use of these ‘progestin-free’ preparations and BC safety.

Abstract OT3-09-02: A large-scale multicenter phase II study evaluating the protective effect of a tissue selective estrogen complex (TSEC) in women with newly diagnosed ductal carcinoma in situ (DCIS)

Abstract Background: TSECs were developed to treat menopausal symptoms after progesterone containing hormone replacement therapy was found to significantly increase the risk of invasive breast cancer (IBC). The first of this class of agents combines conjugated estrogens (CE), a collection of steroidal estrogens that collectively have both estrogen receptor (ERα) agonistic and antagonistic activity, and bazedoxifene (BZA), a third generation selective estrogen receptor modulator that does not stimulate the mammary gland or endometrium. The FDA approved CE/BZA for treatment of menopausal symptoms and osteoporosis after five randomized placebo controlled trials demonstrated the safety, efficacy and tolerability of CE/BZA in healthy postmenopausal women. Since then, a substantial body of evidence has emerged suggesting that CE/BZA may have additional therapeutic benefits in women. It is widely accepted that progression to IBC occurs through both epithelial and stromal mechanisms. Recent in vitro and in vivo data provide support that CE/BZA prevents progression to IBC through its effects on both epithelium and stroma. In epithelial cells, CE/BZA antagonizes estrogen-induced proliferation and expression of markers of ERα activity and also degrades ERα protein. In the stroma, CE/BZA increases expression of the scavenger receptor CD36 and consequently, reduces expression of extracellular matrix proteins (ECM) and pro-inflammatory cytokines that have been shown to contribute to the development of pro-tumorigenic microenvironment. Based on these preliminary data, we hypothesized that CE/BZA will have an anti-tumorigenic effect in the breast. Our ultimate objective is to provide postmenopausal women diagnosed with DCIS a novel and safe therapeutic option to prevent progression to IBC. Specific Aims: Aim 1: To assess epithelial contributions by determining if a short intervention of CE/BZA will have antagonistic activity in breast epithelium of postmenopausal women with ER + DCIS. Aim 2: To assess stromal contributions by determining if a short intervention of CE/BZA will alter expression of stromal markers of progression in breast tissue of postmenopausal women with ER + DCIS. Aim 3: To determine if a short intervention of CE/BZA is well tolerated and safe in postmenopausal women with ER + DCIS. Trial Design: We are currently conducting a multicenter randomized placebo controlled window of opportunity trial with CE/BZA in post-menopausal women with DCIS, a non-obligate precursor to IBC. The duration of intervention is 28 ± 7 days prior to surgical resection to enable comparison of CE/BZA on the breast using the diagnostic core biopsy and surgical sample. To date 33/166 women have enrolled in the trial. Eligibility Criteria: Post-menopausal women between 18-79 years of age diagnosed with ER (+) DCIS (&amp;gt;1cm on imaging) undergoing surgery are eligible. Women must not be on current hormonal therapy, have a current or past diagnosis of IBC, other ER sensitive tumors or have recurrent DCIS. Statistics: Results will be compared between diagnostic biopsy and surgical resection specimens and contrasted between the CE/BZA intervention group and placebo group using Fisher’s exact test for categorical variables and independent sample t-tests, or rank sum tests for continuous data. For RNAseq data, transcripts that have &amp;gt;1.5-fold expression change (at 20% FDR) between control and experimental samples will be used for downstream analysis, such as to plot heat maps, pathway and gene ontology analysis. Summary: At the conclusion of this study, we will have the first direct evidence of the potential benefits of CE/BZA therapy on DCIS lesions in the human breast, along with an initial assessment of symptoms and pharmacogenomics that will inform the design of future studies. Citation Format: Swati A. Kulkarni, Geoffrey Greene, Thea Tlsty, Luis Blanco, Judy Garber, Al George, Fred Rademaker, Seema A Khan, Nora Hansen, Kevin Bethke, Rebecca Aft, Julia Tchou. A large-scale multicenter phase II study evaluating the protective effect of a tissue selective estrogen complex (TSEC) in women with newly diagnosed ductal carcinoma in situ (DCIS) [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 OT3-09-02.

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.

Tissue-Selective Estrogen Complex and Breast.

Although estrogen-progestin therapy has traditionally been standard care for postmenopausal women with an intact uterus experiencing bothersome menopausal symptoms, concerns about side effects related to menopausal hormone therapy (MHT) have led to a dramatic decrease in MHT use over recent decades. As many MHT side effects are now believed to be associated with the progestin component of MHT, efforts have been made to develop a progestin-free alternative to conventional MHT. Recently, a tissue-selective estrogen complex (TSEC), a combination of conjugated estrogen and bazedoxifene, was developed as a progestin-free MHT and is now approved and used worldwide for the relief of vasomotor symptoms and the prevention of bone loss in postmenopausal women. Replacement of synthetic progestin with bazedoxifene could allow more favorable safety profiles, such as those for pain or tenderness, mammographic density, and cancer incidence, for the breast. This review examined the effects of the TSEC on breasts and demonstrated evidence from preclinical and clinical studies supporting TSEC use in clinical practice.

Effects of conjugated estrogen and bazedoxifene on hemostasis and thrombosis in mice.

Estrogen–progestin therapy was previously considered as the standard of care for managing bothersome symptoms associated with menopause, but it increases risks of breast cancer and of thromboembolism. The combination of conjugated estrogen (CE) with bazedoxifene (BZA) named tissue-selective estrogen complex (TSEC) was designed to minimize or even abrogate the undesirable effects on breast, while maintaining the beneficial effects such as prevention of osteoporosis and suppression of climacteric symptoms. The risk on thromboembolism associated with TSEC is unknown, although the clinical available data are reassuring. The aim of this study was to define the impact of a chronic administration of CE, BZA or CE + BZA on hemostasis and thrombosis in ovariectomized mice. As expected, CE, but not BZA neither CE + BZA, induced uterine and vagina hypertrophy. As previously demonstrated for 17β-estradiol (E2), we found that CE (i) increased tail-bleeding time, (ii) prevented occlusive thrombus formation in injured carotid artery and (iii) protected against collagen/epinephrine-induced thromboembolism. Thus, whereas BZA antagonized CE action on reproductive tissues, it had no impact on the effect of CE on hemostasis, thromboembolism and arterial thrombosis in mice. CE + BZA shared the anti-thrombotic actions of CE in these mouse models. If a similar process is at work in women, CE combined with BZA could contribute to minimize the risk of thrombosis associated with hormone replacement therapy.

Tissue-selective estrogen complex for women who experience breast discomfort or vaginal bleeding when on hormone therapy

The objective of this study was to evaluate the effects of switching from hormone therapy to tissue-selective estrogen complex (TSEC) in women who experience vaginal bleeding or breast discomfort. This retrospective cohort study included 82 postmenopausal women who received TSEC after switching from another hormone therapy due to adverse events. Changes in symptoms and imaging after switching to TSEC were evaluated. The mean age was 56.9 years. The women were switched to TSEC due to vaginal bleeding in 56.1% and breast discomfort in 47.6% (multiple choices were allowed). After the switch, almost all women (97.6%) experienced an improvement in adverse events. However, 27% of the women had worsening of vasomotor symptoms, which was more common when hormone therapy was changed from 2 mg of estradiol (41.7%) compared with 1 mg of estradiol (16.7%), 0.625 mg of conjugated estrogen (30%), or tibolone (12.5%). Images of breast lesions and fibroids before the switch were assessed, showing no change in most women. This study suggests that TSEC is a good option for women who have breast discomfort or persistent bleeding during other hormone therapy when taking into account the differences in estrogen dose.

Menopausia y Terapia Hormonal de la Menopausia Las recomendaciones 2018 de la Unidad de Endocrinología Ginecológica de Clínica Alemana de Santiago -Sociedad Italiana de la Menopausia y la Sociedad Chilena de Endocrinología Ginecológica

ABSTRACT In the last decade, the risk benefits ratio of MHT has been evaluated mainly in terms of cardiovascular risk. Present Consensus Statement is largely inspired by the Global Consensus on Menopausal Hormone Therapy in 2013 and 2016 by leading global menopause societies (The American Society for Reproductive Medicine, The Asia Pacific Menopause Federation, The Endocrine Society, The European Menopause and Andropause Society, The International Menopause Society, The International Osteoporosis Foundation and The North American Menopause Society). The aim of these Recommendations is to provide a simple and updated reference on postmenopausal MHT. The term MHT typically includes estrogen replacement therapy (ERT) and estrogen-progestogen therapy (EPT). EPT can be sequential (Seq) when progestogen is added to ERT for 10-14 days a month, or continuous combined (CC) when progestogen is administered continuously every day along with a fixed amount of estrogen. MHT also includes Tibolone and the Tissue Selective Estrogen Complex (TSEC).

Tissue-selective Estrogen Complex for Menopausal Hormone Therapy.

The first approved tissue-selective estrogen complex is a pairing of conjugated estrogen combined with the selective estrogen-receptor modulator, bazedoxifene. Advantages include relief of menopausal symptoms without the increased chance of bleeding or breast tenderness unlike with traditional estrogen-progestin therapy, which is associated with both bleeding and breast tenderness. Tissue-selective estrogen complex effects on relief of vasomotor symptoms, prevention of bone loss, improvement in vaginal symptoms, lack of significant cardiovascular effects beyond the expected 2-fold increase in venous thrombosis, neutral effect on breast, and protective effects on the endometrium are discussed.