Selective Estrogen Receptor Modulator Bazedoxifene Research Articles

Abstract 776: Change in background contrast enhancement category on abbreviated breast MRI with administration of 6 months of bazedoxifene and conjugated estrogen vs wait list control

Abstract Background MRI background contrast enhancement (BPE) has found to be a marker of breast cancer risk providing information beyond that provided by assessment of breast density. BPE is qualitatively classified into categories that correspond to BPE estimates as minimal, <25% BPE; mild, 25-50% BPE; moderate, 50-75% BPE; and marked, >75% BPE. We divided minimal into minimal and almost none (≤5%). We conducted a feasibility study of change in BPE after 6 months of the selective estrogen receptor modulator bazedoxifene (BZA) 20 mg + conjugated estrogen (CE) 0.45 mg marketed commercially as Duavee™ for relief of hot flashes and prevention of osteoporosis in postmenopausal women. Methods STUDY00145121 started 5-27-2020 with randomization to 6 months of Duavee™ vs waitlist control but was stopped after 11 entrants because participants were unable to receive follow-up breast MRIs due to COVID and Duavee™ became unavailable. STUDY0014761 was opened in early 2022 when a source of BZA was found. Doses of BZA and CE were the same as Duavee™ but given as two pills instead of one. 16 women have been randomized to 6 months of BZA/CE vs a wait list control between 2-14-2022 and 9-19-2023. Inclusion criteria are postmenopausal women ages 45-65 at increased risk for breast cancer, BMI < 36 kg/m2 and having current vasomotor symptoms. Participants had a blood draw, 3D mammogram, and abbreviated breast MRI at baseline and the studies were repeated at 6 months. Volumetric density was assessed by Volpara™ fully automated software. Research evaluation of abbreviated MRI background parenchymal contrast enhancement (BPE) was assessed by 5 categories as almost none, minimal, mild, moderate, and marked. BPE was evaluated by a single radiologist blinded to treatment assignment and compared to the 4-category clinical assessment. Results A total of 27 women have been entered in these studies. Six were not evaluable from STUDY00145121 because of the inability to perform 6-month MRI. Two women on STUDY0014761 are not endpoint evaluable due to early drop out and 3 have not yet completed study. A total of 16 women have completed the 6-month portion of the study and abbreviated MRI, with median age 55 (range 47-62) and median BMI 26 kg/m2 (20-33 kg/m2). At baseline, BPE were 3 almost none, 4 minimal, 8 mild, 1 moderate, and 0 marked. There was little correlation between absolute baseline mammographic fibroglandular volume and baseline BPE. A shift in BPE category using the 5-category assessment was noted in 6/11 women (all but one decreased) randomized to BZA +CE and 2/5 women (both decreased) on waitlist. The one increase and four categorical decreases would not have been detected without expansion of BPE to a 5-category system. Conclusion Using the 5-category classification, abbreviated MRI BPE may have promise as a response biomarker in prevention trials for postmenopausal high-risk women. Citation Format: Carol J. Fabian, Onilisa Winblad, Amy Kreutzjans, Krystal Pittman, Christy Altman, Kandy R. Powers, Mary McCarthy, Lauren Nye, Bruce F. Kimler. Change in background contrast enhancement category on abbreviated breast MRI with administration of 6 months of bazedoxifene and conjugated estrogen vs wait list control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 776.

Bazedoxifene does not share estrogens effects on IgG sialylation.

The incidence of rheumatoid arthritis (RA) increases at the same time as menopause when estrogen level decreases. Estrogen treatment is known to reduce the IgG pathogenicity by increasing the sialylation grade on the terminal glycan chain of the Fc domain, inhibiting the binding ability to the Fc gamma receptor. Therefore, treatment with estrogen may be beneficial in pre-RA patients who have autoantibodies and are prone to get an autoimmune disease. However, estrogen treatment is associated with negative side effects, therefore selective estrogen receptor modulators (SERMs) have been developed that have estrogenic protective effects with minimal side effects. In the present study, we investigated the impact of the SERM bazedoxifene on IgG sialylation as well as on total serum protein sialylation. C57BL6 mice were ovariectomized to simulate postmenopausal status, followed by ovalbumin immunization, and then treated with estrogen (estradiol), bazedoxifene, or vehicle. We found that estrogen treatment enhanced IgG levels and had a limited effect on IgG sialylation. Treatment with bazedoxifene increased the sialic acids in plasma cells in a similar manner to E2 but did not reach statistical significance. However, we did not detect any alteration in IgG-sialylation with bazedoxifene treatment. Neither estrogen nor bazedoxifene showed any significant alteration in serum protein sialylation but had a minor effect on mRNA expression of glycosyltransferase in the bone marrow, gonadal fat, and liver.

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.

88116 Effect of conjugated estrogens and bazedoxifene on glucose, energy and lipid metabolism in obese postmenopausal women

ABSTRACT IMPACT: A short treatment of 8 obese postmenopausal women with conjugated estrogens and bazedoxifene does not alter insulin sensitivity or ectopic fat but increases serum markers of hepatic de novo lipogenesis and production of triacylglycerides. OBJECTIVES/GOALS: Combining conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is a novel, orally-administered menopausal therapy. We investigated the effect of CE/BZA on insulin sensitivity, energy metabolism, and serum metabolome in postmenopausal women with obesity. METHODS/STUDY POPULATION: We conducted a randomized, double-blind, crossover pilot trial, testing the effect of CE/BZA on cardiometabolic health in postmenopausal women. Eight postmenopausal women (age 50-60 y, BMI 30-40 kg/m2) were randomization to an 8-week CE/BZA or placebo treatment separated by an 8-week washout period [NCT02274571]. The primary outcome was insulin sensitivity (hyperinsulinemic-euglycemic clamp), while secondary outcomes included body composition (DXA); resting metabolic rate (RMR); substrate oxidation (indirect calorimetry); ectopic lipids (1H-MRS); fat cell size, adipose and skeletal muscle gene expression (biopsies); inflammatory markers; and serum metabolome (LC/MS). RESULTS/ANTICIPATED RESULTS: CE/BZA had no effect on insulin sensitivity, body composition, ectopic fat, or substrate oxidation, but resulted in a non-significant increase in RMR (basal: p=0.06; high-dose clamp: p=0.08) compared to placebo. CE/BZA increased serum high-density lipoprotein cholesterol. CE/BZA also increased serum diacylglycerol (DAG) and triacylglycerol (TAG) species containing long-chain saturated, mono- and polyunsaturated fatty acids (FAs), and decreased long-chain acylcarnitines. These findings possibly reflect increased hepatic de novo FA synthesis and esterification into TAGs, and decreased FA oxidation, respectively (p<0.05). CE/BZA increased serum phosphatidylcholines, phosphatidylethanolamines, ceramides, and sphingomyelins, possibly reflecting the increase in lipoproteins (p<0.05). DISCUSSION/SIGNIFICANCE OF FINDINGS: A short treatment of postmenopausal women with CE/BZA did not alter insulin action or ectopic fat, but increased markers of hepatic de novo lipogenesis and TAG production. Study limitations include a small sample size and short treatment period. A larger, fully powered study is needed to validate the potential metabolic benefit of combining CE with BZA.

Effect of conjugated estrogens and bazedoxifene on glucose, energy and lipid metabolism in obese postmenopausal women.

Combining conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is a novel, orally administered menopausal therapy. We investigated the effect of CE/BZA on insulin sensitivity, energy metabolism, and serum metabolome in postmenopausal women with obesity. Randomized, double-blind, crossover pilot trial with washout was conducted at Pennington Biomedical Research Center. Eight postmenopausal women (age 50-60 years, BMI 30-40 kg/m2) were randomized to 8 weeks CE/BZA or placebo. Primary outcome was insulin sensitivity (hyperinsulinemic-euglycemic clamp). Secondary outcomes included body composition (DXA); resting metabolic rate (RMR); substrate oxidation (indirect calorimetry); ectopic lipids (1H-MRS); fat cell size, adipose and skeletal muscle gene expression (biopsies); serum inflammatory markers; and serum metabolome (LC/MS). CE/BZA treatment produced no detectable effect on insulin sensitivity, body composition, ectopic fat, fat cell size, or substrate oxidation, but resulted in a non-significant increase in RMR (basal: P = 0.06; high-dose clamp: P = 0.08) compared to placebo. CE/BZA increased serum high-density lipoprotein (HDL)-cholesterol. CE/BZA also increased serum diacylglycerol (DAG) and triacylglycerol (TAG) species containing long-chain saturated, mono- and polyunsaturated fatty acids (FAs) and decreased long-chain acylcarnitines, possibly reflecting increased hepatic de novo FA synthesis and esterification into TAGs for export into very low-density lipoproteins, as well as decreased FA oxidation, respectively (P < 0.05). CE/BZA increased serum phosphatidylcholines, phosphatidylethanolamines, ceramides, and sphingomyelins, possibly reflecting the increase in serum lipoproteins (P < 0.05). A short treatment of obese postmenopausal women with CE/BZA does not alter insulin action or ectopic fat but increases serum markers of hepatic de novo lipogenesis and TAG production.

Bazedoxifene – a promising brain active SERM that crosses the blood brain barrier and enhances spatial memory

Over 20 years of accumulated evidence has shown that the major female sex hormone 17β-estradiol can enhance cognitive functioning. However, the utility of estradiol as a therapeutic cognitive enhancer is hindered by its unwanted peripheral effects (carcinogenic). Selective estrogen receptor modulators (SERMs) avoid the unwanted effects of estradiol by acting as estrogen receptor antagonists in some tissues such as breast and uterus, but as agonists in others such as bone, and are currently used for the treatment of osteoporosis. However, understanding of their actions in the brain are limited. The third generation SERM bazedoxifene has recently been FDA approved for clinical use with an improved biosafety profile. However, whether bazedoxifene can enter the brain and enhance cognition is unknown. Using mice, the current study aimed to explore if bazedoxifene can 1) cross the blood-brain barrier, 2) rescue ovariectomy-induced hippocampal-dependent spatial memory deficit, and 3) activate neural estrogen response element (ERE)-dependent gene transcription. Using liquid chromatography-mass spectrometry (LC-MS), we firstly demonstrate that a peripheral injection of bazedoxifene can enter the brain. Secondly, we show that an acute intraperitoneal injection of bazedoxifene can rescue ovariectomy-induced spatial memory deficits. And finally, using the ERE-luciferase reporter mouse, we show in vivo that bazedoxifene can activate the ERE in the brain. The evidence shown here suggest bazedoxifene could be a viable cognitive enhancer with promising clinical applicability.

Abstract 4962: Repurposing bazedoxifene to suppress gastrointestinal cancer growth

Abstract The interleukin (IL)6 family of inflammatory cytokines, characterized by the shared use of the gp130 receptor, supports the progression of solid cancers. Specifically, gp130 signaling becomes rate limiting for the growth of gastrointestinal tumors arising from oncogenic driver mutations in Apc, but remains dispensable for the homeostatic renewal of the gastrointestinal mucosa. In the present study we investigate the effects of the selective estrogen receptor modulator bazedoxifene, clinically approved for the treatment of osteoporosis, as a putative small molecule inhibitor of gp130 receptor oligomerization and activation. We assessed the effects of bazedoxifene on IL6 and IL11-dependent STAT3 activation and cell proliferation in gastric and colon cancer cell lines. In patient-derived colon cancer organoid cultures, we assessed bazedoxifene effects on IL11-dependent growth. The gp130Y757F, Lgr5CreERT2- or Cdx2CreERT2-driven Apc flox mouse models of gastrointestinal cancer, were used to examine the effects of bazedoxifene on tumour growth. In silico modeling suggests that the inhibitory activity of bazedoxifene is due to its ability to mimic the interaction between the Site III interface of gp130 receptor and the tryptophan-157 in IL6, or tryptophan-168 in IL11 cytokine. We show that bazedoxifene interferes with IL6 and IL11-dependent proliferation of BAF/03 cells. Bazedoxifene suppresses gastric tumor growth in gp130Y757F mice irrespective of their gender, in which tumors arise through excessive IL11-dependent STAT3 signaling. Strikingly, in sporadic colon cancer models based on aberrant activation of the β-catenin/canonical WNT pathway, bazedoxifene treatment also reduces tumor burden in mice following conditional ablation of the Apc suppressor gene using the Lgr5CreERT2- or Cdx2CreERT2-driver alleles. Consistent with our observation that nuclear accumulation of β-catenin remains unaffected in colonic tumors of bazedoxifene-treated mice, bazedoxifenetreatment of human SW480 colon cancer cells harboring mutant APC did not affect canonical WNT signaling, but suppressed IL11-dependent STAT3 signaling. Our findings provide compelling proof-of-concept for the repurposing of bazedoxifene for the treatment of gastrointestinal cancers that arise from bona fide oncogenic driver mutations. Note: This abstract was not presented at the meeting. Citation Format: Pathum Thilakasiri, Tracy Nero, Michael W. Parker, Matthias Ernst, Ashwini L. Chand. Repurposing bazedoxifene to suppress gastrointestinal cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4962.

Conjugated Estrogens and Bazedoxifene Improve β Cell Function in Obese Menopausal Women.

ContextStudies suggest that menopausal hormone therapy (MHT) prevents type 2 diabetes (T2D). The combination of conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is an MHT that improves obesity and T2D in preclinical models of menopausal metabolic syndrome. The effect of CE/BZA on adiposity and glucose homeostasis in obese postmenopausal women is unknown.ObjectiveTo investigate the effect of CE/BZA on body composition, glucose homeostasis, and markers of inflammation in obese postmenopausal women.Research Design, Intervention, and ParticipantsRandomized, double-blind, placebo-controlled pilot trial of 12 obese menopausal women assigned to 12-week treatment with CE 0.45 mg/BZA 20 mg (n = 7) or placebo (n = 5). At baseline and after 12 weeks, we assessed body composition (dual-energy X-ray absorptiometry), glucose homeostasis (IV glucose tolerance test), and inflammation biomarkers.ResultsWomen treated with CE/BZA exhibited increased β cell function using homeostatic model assessment-B [median (interquartile range) CE/BZA vs placebo: 18.5 (−0.9 to 320.6) μU/mM vs −25.5 (−39.9 to −0.1) μU/mM; P = 0.045], and decreased basal glucose concentrations (Gb) [−5.2 (−9.2 to −1.7) mg/dL vs 2.7 (0.9 to 4.9) mg/dL; P = 0.029]. Insulin sensitivity was higher in the placebo arm [1.35 (1.12 to 1.82) (μU/mL) min−1 vs −0.24 (−1.50 to 0.19) (μU/mL) min−1; P = 0.029]. No changes between treatment groups were observed for the acute insulin response to glucose (AIRg), the disposition index (DI), body composition, and inflammatory biomarkers.ConclusionsA 12-week treatment of obese postmenopausal women with CEs/BZA improves fasting β cell function and glucose concentrations without change in AIRg, HOMA-IR, DI, body composition, or markers of inflammation.

Bazedoxifene-induced vasodilation and inhibition of vasoconstriction is significantly greater than estradiol

A new strategy for menopausal hormone therapy replaces medroxyprogesterone with the selective estrogen receptor modulator bazedoxifene. While the agonist or antagonist activity of bazedoxifene has been examined in other tissues, the current study explored the impact of bazedoxifene on resistance artery reactivity. We hypothesized that bazedoxifene may induce greater vasoprotective effects than estradiol due to enhanced activation of the G-protein-coupled estrogen receptor. We measured the vasodilation of mesenteric resistance arteries from adult male and female wild-type and G-protein-coupled estrogen receptor knockout mice (n = 58) in response to increasing concentrations of bazedoxifene, medroxyprogesterone, and estradiol, and also the impact of these compounds on the responses to phenylephrine and sodium nitroprusside. Bazedoxifene-induced vasorelaxation was greater than estradiol and blunted phenylephrine-induced contraction-an effect not observed with estradiol. Neither estradiol nor bazedoxifene altered relaxation to sodium nitroprusside. The combination of bazedoxifene + estradiol promoted greater vasodilation than medroxyprogesterone + estradiol, and opposed phenylephrine-induced contraction, whereas medroxyprogesterone + estradiol failed to attenuate this response. Both bazedoxifene + estradiol and medroxyprogesterone + estradiol enhanced sodium nitroprusside-induced relaxation in females. Vascular responses were similar in both sexes in wild-type and G-protein-coupled estrogen receptor knockout mice. Bazedoxifene and bazedoxifene + estradiol relaxed mesenteric arteries and opposed vasoconstriction to a greater degree than estradiol or medroxyprogesterone + estradiol. These effects were independent of sex and G-protein-coupled estrogen receptor expression. We conclude that bazedoxifene may provide vascular benefits over estrogen alone or estrogen plus progestogen combinations in postmenopausal women.

Differential utilization of nuclear and extranuclear receptor signaling pathways in the actions of estrogens, SERMs, and a tissue-selective estrogen complex (TSEC)

Estrogens act through nuclear and extranuclear initiated pathways involving estrogen receptors (ERs) to regulate gene expression and activate protein kinases. We investigated the involvement of extracellular signal-regulated kinase2 (ERK2) and ERα in the activities of estradiol (E2), conjugated estrogens (CEs), selective estrogen receptor modulators (SERMs), and a Tissue-Selective Estrogen Complex (TSEC), a combination of a SERM and CE that has a blended activity. We found that CE and individual CE components were generally less effective than E2 in ERK2 recruitment to chromatin binding sites of E2-regulated genes. Likewise, CE was much less agonistic than E2 in stimulation of proliferation of ERα-positive breast cancer cells. The SERM bazedoxifene (BZA) fully suppressed proliferation stimulated by E2 or CE and reversed gene stimulation by CE or E2, as did the antiestrogen Faslodex. Thus, the balance of biological activities mediated through nuclear ERα vs. ERK2-mediated activities is different for CE vs. E2, with CE showing lower stimulation of kinase activity. Furthermore, at the BZA to CE concentrations in TSEC, BZA antagonized CE stimulation of gene expression and proliferation programs in ERα-positive breast cancer cells. The studies provide molecular underpinnings of the different ways in which SERMs and estrogens support or antagonize one another in regulating the chromatin binding of ERα and ERK2, and modulating gene and cell activities. They illuminate how the combined actions of two classes of ER ligands (SERM and CE, present in TSEC) can achieve unique modes of regulation and efficacy.

Selective estrogen receptor modulators and the combination therapy conjugated estrogens/bazedoxifene: A review of effects on the breast.

Traditional menopausal hormone therapy containing estrogens/progestin has been associated with an increased risk of breast cancer, and estrogen exposure is known to promote growth and proliferation of a majority of breast cancers. Therefore, it is important for clinicians to consider the breast safety profile of any hormone-based therapy used in postmenopausal women. This review provides an overview of the breast safety and tolerability profiles of currently marketed selective estrogen receptor modulators, antiestrogens, and the first tissue selective estrogen complex combining conjugated estrogens with the selective estrogen receptor modulator bazedoxifene in postmenopausal women. Selective estrogen receptor modulators and antiestrogens act as estrogen receptor antagonists in the breast. Tamoxifen, toremifene, and the selective estrogen receptor degrader fulvestrant are used to treat breast cancer, and tamoxifen and raloxifene protect against breast cancer in high-risk women. Postmenopausal women using selective estrogen receptor modulators for prevention or treatment of osteoporosis (raloxifene, bazedoxifene) can be reassured that these hormonal treatments do not adversely affect their risk of breast cancer and may, in the case of raloxifene, even be protective. There are limited data on breast cancer in women who use ospemifene for dyspareunia. Conjugated estrogens/bazedoxifene use for up to two years did not increase mammographic breast density or breast pain/tenderness, and there was no evidence of an increased risk of breast cancer, suggesting that conjugated estrogens/bazedoxifene has an improved breast safety profile compared with traditional menopausal hormone therapies. Future research will continue to focus on development of selective estrogen receptor modulators and selective estrogen receptor modulator combinations capable of achieving the ideal balance of estrogen receptor agonist and antagonist effects.

Breast-related effects of selective estrogen receptor modulators and tissue-selective estrogen complexes.

A number of available treatments provide relief of menopausal symptoms and prevention of postmenopausal osteoporosis. However, as breast safety is a major concern, new options are needed, particularly agents with an improved mammary safety profile. Results from several large randomized and observational studies have shown an association between hormone therapy, particularly combined estrogen-progestin therapy, and a small increased risk of breast cancer and breast pain or tenderness. In addition, progestin-containing hormone therapy has been shown to increase mammographic breast density, which is an important risk factor for breast cancer. Selective estrogen receptor modulators (SERMs) provide bone protection, are generally well tolerated, and have demonstrated reductions in breast cancer risk, but do not relieve menopausal symptoms (that is, vasomotor symptoms). Tissue-selective estrogen complexes (TSECs) pair a SERM with one or more estrogens and aim to blend the positive effects of the components to provide relief of menopausal symptoms and prevention of postmenopausal osteoporosis without stimulating the breast or endometrium. One TSEC combination pairing conjugated estrogens (CEs) with the SERM bazedoxifene (BZA) has completed clinical development and is now available as an alternative option for menopausal therapy. Preclinical evidence suggests that CE/BZA induces inhibitory effects on breast tissue, and phase 3 clinical studies suggest breast neutrality, with no increases seen in breast tenderness, breast density, or cancer. In non-hysterectomized postmenopausal women, CE/BZA was associated with increased bone mineral density and relief of menopausal symptoms, along with endometrial safety. Taken together, these results support the potential of CE/BZA for the relief of menopausal symptoms and prevention of postmenopausal osteoporosis combined with breast and endometrial safety.

Endometriosis impairs bone marrow-derived stem cell recruitment to the uterus whereas bazedoxifene treatment leads to endometriosis regression and improved uterine stem cell engraftment.

Endometriosis is a disease defined by the ectopic growth of uterine endometrium. Stem cells contribute to the generation of endometriosis as well as to repair and regeneration of normal endometrium. Here we demonstrate that the selective estrogen receptor modulator bazedoxifene (BZA), administered with conjugated estrogens (CEs), leads to regression of endometriosis lesions as well as reduction in stem cell recruitment to the lesions. Female mice underwent transplantation of male bone marrow. Endometrium was transplanted in the peritoneal cavity of half to create experimental endometriosis. Mice with or without experimental endometriosis were randomized to BZA/CE or vehicle treatment. Endometriosis lesions, bone marrow-derived mesenchymal stem cell engraftment of the lesions, and eutopic endometrium as well as ovarian stimulation were assessed. BZA treatment significantly reduced lesion size, gland number, and expression of proliferation marker proliferating cell nuclear antigen. Ovarian weight was not affected. Stem cells were recruited to the endometriosis lesions, and this recruitment was dramatically reduced by BZA/CE treatment. Stem cell engraftment was reduced in the uterus of animals with endometriosis; however the number of stem cells engrafting the uterus was completely restored by treatment with BZA/CE. Competition between endometriosis and the eutopic endometrium for a limited supply of stem cells and depletion of normal stem cells flux to the uterus is a novel mechanism by which endometriosis interferes with endometrial function and fertility. BZA/CE not only treats lesions of endometriosis, it also dramatically reduces stem cell recruitment to the lesions and restores stem cell engraftment of the uterine endometrium.

Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice

Pairing the selective estrogen receptor modulator bazedoxifene (BZA) with estrogen as a tissue-selective estrogen complex (TSEC) is a novel menopausal therapy. We investigated estrogen, BZA and TSEC effects in preventing diabetisity in ovariectomized mice during high-fat feeding. Estrogen, BZA or TSEC prevented fat accumulation in adipose tissue, liver and skeletal muscle, and improved insulin resistance and glucose intolerance without stimulating uterine growth. Estrogen, BZA and TSEC improved energy homeostasis by increasing lipid oxidation and energy expenditure, and promoted insulin action by enhancing insulin-stimulated glucose disposal and suppressing hepatic glucose production. While estrogen improved metabolic homeostasis, at least partially, by increasing hepatic production of FGF21, BZA increased hepatic expression of Sirtuin1, PPARα and AMPK activity. The metabolic benefits of BZA were lost in estrogen receptor-α deficient mice. Thus, BZA alone or in TSEC produces metabolic signals of fasting and caloric restriction and improves energy and glucose homeostasis in female mice.

Osteoporosis: Current review

Although hormone therapy using estrogens plus progestogens (EPT) is effective for the management of menopausal symptoms (e.g., vasomotor symptoms and vulvar/vaginal atrophy) and prevention/treatment of postmenopausal osteoporosis, EPT is associated with safety and tolerability concerns. A new alternative to EPT is the tissue selective estrogen complex (TSEC), which partners a selective estrogen receptor modulator (SERM) with one or more estrogens and is designed to treat menopausal symptoms and prevent postmenopausal osteoporosis without the tolerability concerns associated with EPT. The first TSEC to reach advanced clinical development is a combination of the SERM bazedoxifene (BZA) with conjugated estrogens (CE). BZA has been shown to inhibit the stimulatory activity of CE on uterine tissue and breast in vitro and in vivo. In clinical studies, BZA/CE treatment has been associated with significant improvements in menopausal symptoms including hot flushes and vulvar/vaginal atrophy and significant increases in bone mineral density, coupled with reductions in bone turnover marker levels and improvements in sleep and health-related quality of life. Additionally, BZA/CE has been shown to have a neutral effect on endometrial and breast tissue because BZA inhibits the stimulatory effects of estrogens in selective tissue fashion in these two organs. Taken together, results of these preclinical and clinical studies indicate that the benefits of estrogens for treating menopausal symptoms are maintained with BZA/CE without endometrial or breast stimulation, resulting in a safe and effective treatment for symptomatic postmenopausal women.

CB2 cannabinoid receptor is a novel target for third-generation selective estrogen receptor modulators bazedoxifene and lasofoxifene

The purpose of the current study was to investigate the ability of the third-generation selective estrogen receptor modulators (SERMs) bazedoxifene and lasofoxifene to bind and act on CB2 cannabinoid receptor. We have identified, for the first time, that CB2 is a novel target for bazedoxifene and lasofoxifene. Our results showed that bazedoxifene and lasofoxifene were able to compete for specific [3H]CP-55,940 binding to CB2 in a concentration-dependent manner. Our data also demonstrated that by acting on CB2, bazedoxifene and lasofoxifene concentration-dependently enhanced forskolin-stimulated cAMP accumulation. Furthermore, bazedoxifene and lasofoxifene caused parallel, rightward shifts of the CP-55,940, HU-210, and WIN55,212-2 concentration–response curves without altering the efficacy of these cannabinoid agonists on CB2, which indicates that bazedoxifene- and lasofoxifene-induced CB2 antagonism is most likely competitive in nature. Our discovery that CB2 is a novel target for bazedoxifene and lasofoxifene suggests that these third-generation SERMs can potentially be repurposed for novel therapeutic indications for which CB2 is a target. In addition, identifying bazedoxifene and lasofoxifene as CB2 inverse agonists also provides important novel mechanisms of actions to explain the known therapeutic effects of these SERMs.

Bazedoxifene Exhibits Antiestrogenic Activity in Animal Models of Tamoxifen-Resistant Breast Cancer: Implications for Treatment of Advanced Disease

There is compelling evidence to suggest that drugs that function as pure estrogen receptor (ER-α) antagonists, or that downregulate the expression of ER-α, would have clinical use in the treatment of advanced tamoxifen- and aromatase-resistant breast cancer. Although such compounds are currently in development, we reasoned, based on our understanding of ER-α pharmacology, that there may already exist among the most recently developed selective estrogen receptor modulators (SERM) compounds that would have usage as breast cancer therapeutics. Thus, our objective was to identify among available SERMs those with unique pharmacologic activities and to evaluate their potential clinical use with predictive models of advanced breast cancer. A validated molecular profiling technology was used to classify clinically relevant SERMs based on their impact on ER-α conformation. The functional consequences of these observed mechanistic differences on (i) gene expression, (ii) receptor stability, and (iii) activity in cellular and animal models of advanced endocrine-resistant breast cancer were assessed. The high-affinity SERM bazedoxifene was shown to function as a pure ER-α antagonist in cellular models of breast cancer and effectively inhibited the growth of both tamoxifen-sensitive and -resistant breast tumor xenografts. Interestingly, bazedoxifene induced a unique conformational change in ER-α that resulted in its proteasomal degradation, although the latter activity was dispensable for its antagonist efficacy. Bazedoxifene was recently approved for use in the European Union for the treatment of osteoporosis and thus may represent a near-term therapeutic option for patients with advanced breast cancer.

Atrophic Vaginitis: Diagnosis and Treatment

ABSTRACT Atrophic vaginitis is an inflammation of the vagina which develops when there is a significant decrease in estrogen levels after menopause. The initial and most common symptom is often lack of lubrication during intercourse. Eventually, persistent vaginal dryness may occur leading to dyspareunia. The onset of symptoms may not be immediate and may occur 3 to 4 years after menopause. Nonhormonal treatment includes vaginal moisturizers for atrophy symptoms, lubricants for dyspareunia, hyaluronic acid vaginal tablets and phtoestrogens. Estrogens are known to increase vascularity, secretions and thickness of vagina and decrease vaginal pH. They can be given both systemically or vaginally. Local therapy has been found to be more efficacious than systemic therapy and has the advantage of not having systemic adverse effects. They can be given as pessaries, creams or rings. Delivery system used should be convenient to patient so that therapy is consistent, as that is critical for effect. Improvement in vaginal atrophy symptoms starts within a few weeks of starting vaginal estrogen but, some may need to use it for 4 to 6 weeks before adequate improvement is observed. Selective estrogen receptor modulator bazedoxifene may be combined with estrogens. Postmenopausal vaginal atrophy is a common cause of easily treatable distressing symptoms which severely affect quality of life. How to cite this article Ghumman S. Atrophic Vaginitis: Diagnosis and Treatment. J South Asian Feder Menopause Soc 2013;1(1):4-12.

Advances in menopausal therapy: The tissue‐selective estrogen complex

Most menopausal women experience vasomotor symptoms, vulvar-vaginal atrophy, and/or bone loss. Although available estrogen and progestin therapies are effective in treating menopausal symptoms and preventing bone loss, some women may seek a therapy that provides symptom relief and has an improved tolerability profile. One option is a tissue-selective estrogen complex (TSEC), or the pairing of estrogen(s) with a selective estrogen receptor modulator (SERM) to achieve the benefits of each component with fewer side effects. The first TSEC in clinical development combines the SERM bazedoxifene (BZA) with conjugated estrogens (CEs). The purpose of this article is to review published data for BZA/CE. Data were obtained from phase 3 BZA/CE clinical trial study articles. Daily BZA 20 mg/CE 0.625 mg or 0.45 mg effectively relieved hot flushes, maintained or increased bone mineral density, treated vulvar-vaginal atrophy, and improved quality of life. Further, BZA prevented stimulation of the endometrium by CE, and resulted in rates of amenorrhea and breast pain similar to placebo. These results support the use of a TSEC consisting of BZA/CE as a promising therapy for managing the signs and symptoms from reduced estrogen levels associated with menopause.

In search of the perfect SERM—a 5-year study of bazedoxifene

Selective estrogen receptor modulators (SERMs) hold the promise of an ideal estrogenic compound. Moderate efficacy for the prevention of osteoporotic vertebral fractures has now been found after 5 years of treatment with the SERM bazedoxifene; however, expectations for one SERM to provide multiple benefits for postmenopausal women might be a pipe dream.