Lasofoxifene as a potential treatment for aromatase inhibitor-resistant ER-positive breast cancer.

BACKGROUND: Breast cancers treated with aromatase inhibitors (AIs) can develop AI resistance, which is often driven by estrogen receptor-alpha (ERα/ESR1) activating mutations, as well as by ER-independent signaling pathways. The breast ER antagonist lasofoxifene, alone or combined with palbociclib, elicited antitumor activities in a xenograft model of ER + metastatic breast cancer (mBC) harboring ESR1 mutations. The current study investigated the activity of LAS in a letrozole-resistant breast tumor model that does not have ESR1 mutations. METHODS: Letrozole-resistant, MCF7 LTLT cells tagged with luciferase-GFP were injected into the mammary duct inguinal glands of NSG mice (MIND model; 6 mice/group). Mice were randomized to vehicle, lasofoxifene ± palbociclib, fulvestrant ± palbociclib, or palbociclib alone 2-3 weeks after cell injections. Tumor growth and metastases were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis. The experiment was repeated with the same design and 8-9 mice in each treatment group. RESULTS: Western blot analysis showed that the MCF7 LTLT cells had lower ERα and higher HER2 expressions compared with normal MCF7 cells. Lasofoxifene ± palbociclib, but not fulvestrant, significantly reduced primary tumor growth versus vehicle as assessed by in vivo imaging of tumors at study ends. Percent tumor area in excised mammary glands was significantly lower for lasofoxifene plus palbociclib versus vehicle. Ki67 staining showed decreased overall tumor cell proliferation with lasofoxifene ± palbociclib. The lasofoxifene + palbociclib combination was also associated with significantly fewer bone metastases compared with vehicle. Similar results were observed in the repeat experiment. CONCLUSIONS: In a mouse model of letrozole-resistant breast cancer with no ESR1 mutations, reduced levels of ERα, and overexpression of HER2, lasofoxifene alone or combined with palbociclib inhibited primary tumor growth more effectively than fulvestrant. Lasofoxifene plus palbociclib also reduced bone metastases. These results suggest that lasofoxifene alone or combined with a CDK4/6 inhibitor may offer benefits to patients who have ER-low and HER2-positive, AI-resistant breast cancer, independent of ESR1 mutations.

Efficacy and safety of endoxifen in bipolar disorder: A systematic review.

BACKGROUND: Endoxifen, a protein kinase C inhibitor and selective estrogen receptor modulator, primarily used in breast cancer treatment, has recently emerged as a potential therapeutic option for managing manic episodes associated with bipolar disorder (BD). This review aims to assess the existing evidence base for endoxifen in BD treatment and evaluate the strengths and limitations of current research findings. METHODS: A systematic search was conducted on Medline, Embase, and Web of Science databases. We included studies published in English that used endoxifen in BD, alongside any relevant studies identified through manual searching and conference papers with full-text availability. Information pertaining to dose, duration, clinical effects, and safety profiles was extracted from the included studies. The Cochrane Risk of Bias 2 tool was used to assess the risk of bias in clinical trials. RESULTS: The final review included seven case reports (including two conference presentations), two clinical trials, and one prospective study. Most studies administered endoxifen 8 mg and reported an improvement in manic symptoms. Several case reports included patients with comorbid substance use, and most patients received mood stabilizers concurrently. Few reports lacked any structured outcome measures. The clinical trials used divalproex 1000 mg as an active comparator, which was deemed sub-therapeutic. Despite being multicentric, the first trial lacked data on center-wise recruitment, and certain methodological concerns were observed across the included trials. There were no serious adverse effects noted, except for a significant elevation in lipid profile within a 3-week period. Limited data were available regarding endoxifen efficacy and safety in mixed episodes, depressive episodes, and maintenance treatment. CONCLUSION: There is a paucity of research on the efficacy and safety of endoxifen in BD. While existing evidence suggests short-term efficacy in manic episodes, significant limitations were identified in most of the included studies. Further research is imperative to establish the efficacy and safety of endoxifen in BD before considering its recommendation as a viable treatment option.

Maternal immune activation and estrogen receptor modulation induce sex-specific dopamine-related behavioural and molecular alterations in adult rat offspring.

Dopamine dysregulation contributes to psychosis and cognitive deficits in schizophrenia that can be modelled in rodents by inducing maternal immune activation (MIA). The selective estrogen receptor (ER) modulator, raloxifene, can improve psychosis and cognition in men and women with schizophrenia. However, few studies have examined how raloxifene may exert its therapeutic effects in mammalian brain in both sexes during young adulthood (age relevant to most prevalent age at diagnosis). Here, we tested the extent to which raloxifene alters dopamine-related behaviours and brain transcripts in young adult rats, both control and MIA-exposed females and males. We found that raloxifene increased amphetamine (AMPH)-induced locomotor activity in female controls, and in contrast, raloxifene reduced AMPH-induced locomotor activity in male MIA offspring. We did not detect overt prepulse inhibition (PPI) deficits in female or male MIA offspring, yet raloxifene enhanced PPI in male MIA offspring. Whereas, raloxifene ameliorated increased startle responsivity in female MIA offspring. In the substantia nigra (SN), we found reduced Drd2s mRNA in raloxifene-treated female offspring with or without MIA, and increased Comt mRNA in placebo-treated male MIA offspring relative to placebo-treated controls. These data demonstrate an underlying dopamine dysregulation in MIA animals that can become more apparent with raloxifene treatment, and may involve selective alterations in dopamine receptor levels and dopamine breakdown processes in the SN. Our findings support sex-specific, differential behavioural responses to ER modulation in MIA compared to control offspring, with beneficial effects of raloxifene treatment on dopamine-related behaviours relevant to schizophrenia found in male MIA offspring only.

Effects of novel raloxifene analogs alone or in combination with mechanical loading in the Col1a2G610c/+ murine model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a hereditary bone disease in which gene mutations affect collagen formation, leading to a weak, brittle bone phenotype that can cause severe skeletal deformity and increased fracture risk. OI interventions typically repurpose osteoporosis medications to increase bone mass, but this approach does not address compromised tissue-level material properties. Raloxifene (RAL) is a mild anti-resorptive used to treat osteoporosis that has also been shown to increase bone strength by a-cellularly increasing bone bound water content, but RAL cannot be administered to children due to its hormonal activity. The goal of this study was to test a RAL analog with no estrogen receptor (ER) signaling but maintained ability to reduce fracture risk. The best performing analog from a previous analog characterization project, named RAL-ADM, was tested in an in vivo study. Female wildtype (WT) and Col1a2G610C/+ (G610C) mice were randomly assigned to treated or untreated groups, for a total of 4 groups (n = 15). Starting at 10 weeks of age, all mice underwent compressive tibial loading 3×/week to induce an anabolic bone formation response in conjunction with RAL-ADM treatment (0.5 mg/kg; 5×/week) for 6 weeks. Tibiae were scanned via microcomputed tomography then tested to failure in four-point bending. RAL-ADM had reduced ER affinity, and increased post-yield properties, but did not improve bone strength in OI animals, suggesting some properties can be improved by RAL analogs but further development is needed to create an analog with decidedly positive impacts to OI bone.

Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2- breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2.

BACKGROUND: Acquired ESR1 mutations in estrogen receptor-positive (ER+) metastatic breast cancer (mBC) drive treatment resistance and tumor progression; new treatment strategies are needed. Lasofoxifene, a next-generation, oral, endocrine therapy and tissue-specific ER antagonist, provided preclinical antitumor activity, alone or combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in ESR1-mutated mBC. PATIENTS AND METHODS: In the open-label, phase II, ELAINE 2 trial (NCT04432454), women with ESR1-mutated, ER+/human epidermal growth factor receptor 2-negative (HER2-) mBC who progressed on prior therapies (including CDK4/6i) received lasofoxifene 5 mg/day and abemaciclib 150 mg b.i.d until disease progression/toxicity. The primary endpoint was safety/tolerability. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and objective response rate (ORR). RESULTS: Twenty-nine women (median age 60 years) participated; all but one were previously treated with a CDK4/6i (median duration 2 years). The lasofoxifene-abemaciclib combination was well tolerated with primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, and vomiting. One patient (with no prior CDK4/6i) discontinued treatment due to grade 2 diarrhea. No deaths occurred during the study. Median PFS was 56.0 weeks [95% confidence interval (CI) 31.9 weeks-not estimable; ∼13 months]; PFS rates at 6, 12, and 18 months were 76.1%, 56.1%, and 38.8%, respectively. CBR at 24 weeks was 65.5% (95% CI 47.3% to 80.1%). In 18 patients with measurable lesions, ORR was 55.6% (95% CI 33.7% to 75.4%). ESR1-mutant circulating tumor DNA (ctDNA) allele fraction decreased from baseline to week 4 in 21/26 (80.8%) patients. CONCLUSIONS: Lasofoxifene plus abemaciclib had an acceptable safety profile, was well tolerated, and exhibited meaningful antitumor activity in women with ESR1-mutated, ER+/HER2- mBC after disease progression on prior CDK4/6i. Observed decreases in ESR1-mutant ctDNA with lasofoxifene concordant with clinical response suggest target engagement. If the ELAINE 2 findings are confirmed in the initiated, phase III, ELAINE 3 trial, these data could be practice-changing and help address a critical unmet need.

Lasofoxifene versus fulvestrant for ER+/HER2- metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial.

BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts. PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. RESULTS: A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (∼5.6 months) versus 16.2 weeks (∼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. CONCLUSIONS: Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.

Sex Steroid Modulators and the Development of Buschke-Lowenstein Tumor: A Case Report of an Immunocompetent Patient.

Buschke-Lowenstein tumors (BLTs) are benign dermatologic manifestations of human papillomavirus (HPV). They originate from longstanding condylomata in individuals with compromised immune systems. In this case report, we present a 68-year-old immunocompetent female with HPV condylomata that had transitioned to a large, fungated BLT in her right groin. The patient's immunocompetency was determined by the absence of diabetes, corticosteroid therapy, organ transplant, cytotoxic therapy, or any known primary or other secondary immunodeficiencies. Notably, the patient had a history of breast cancer, managed through lumpectomy, local radiation, and two years of combined aromatase inhibitor and selective estrogen receptor modulator (SERM) therapy, followed by three years of further SERM therapy. We propose that the effect of her previously received SERM therapy shifted the T helper (Th)1 immune response to a Th2 response. This may have compromised the patient's HPV-specific cell-mediated immunity, favoring a non-protective Th2-dominant effect. Thus, it potentially enabled immune evasion, transitioning to a BLT phenotype. Additionally, the immune skewing of the SERM may have been initially opposed by the known ability of aromatase inhibitors to potentiate Th1 responses. Indeed, the patient first noticed the appearance of HPV condylomata progressing to the BLT phenotype with the cessation of the aromatase inhibitor therapy under the unopposed influence of the SERM. The resultant cytokine milieu may have contributed to the unusual progression to the BLT phenotype in this otherwise immunocompetent patient.

The potential renoprotective effect of Raloxifene in renal ischemia-reperfusion injury in a male rat model.

Renal ischemia-reperfusion injury is caused by a temporary reduction in oxygen-carrying blood flow to the kidney, followed by reperfusion. During ischemia, kidney tissue damage induces overproduction of reactive oxygen species, which produces oxidative stress. The blood flow restoration during the reperfusion period causes further production of reactive oxygen species that ends with apoptosis and cell death. This study aimed to investigate the potential renoprotective effects of Raloxifene on bilateral renal ischemia-reperfusion injury in rats by looking into kidney function biomarkers, urea and creatinine, inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß). Additionally, antioxidant markers such as total antioxidant capacity (TAC) and the pro-apoptotic marker caspase-3 were assessed. Histopathological scores were also employed for evaluation. Our experimental design involved 20 rats divided into four groups: the sham group underwent median laparotomy without ischemia induction, the control group experienced bilateral renal ischemia for 30 minutes followed by 2 hours of reperfusion, the vehicle group received pretreatment with a mixture of corn oil and dimethyl sulfoxide (DMSO) before ischemia induction, and the Raloxifene-treated group was administered Raloxifene at a dose of 10 mg/kg before ischemia induction, followed by ischemia-reperfusion. Urea and creatinine, TNF-α, IL-1ß, and caspase-3 in the Raloxifene group were significantly lower compared to the control and vehicle groups. On the other hand, TAC levels in the Raloxifene group were significantly higher than in the control and vehicle groups. This study concluded that Raloxifene had a renoprotective impact via multiple actions as an anti-inflammatory, anti-apoptotic, and antioxidant agent.

Modest Effects of Osteoclast-Specific ERα Deletion after Skeletal Maturity.

Estrogen regulates bone mass in women and men, but the underlying cellular mechanisms of estrogen action on bone remain unclear. Although both estrogen receptor (ER)α and ERß are expressed in bone cells, ERα is the dominant receptor for skeletal estrogen action. Previous studies using either global or cell-specific ERα deletion provided important insights, but each of these approaches had limitations. Specifically, either high circulating sex steroid levels in global ERα knockout mice or the effects of deletion of ERα during growth and development in constitutive cell-specific knockout mice have made it difficult to clearly define the role of ERα in specific cell types in the adult skeleton. We recently generated and characterized mice with tamoxifen-inducible ERα deletion in osteocytes driven by the 8-kb Dmp1 promoter (ERαΔOcy mice), revealing detrimental effects of osteocyte-specific ERα deletion on trabecular bone volume (-20.1%) and bone formation rate (-18.9%) in female, but not male, mice. Here, we developed and characterized analogous mice with inducible ERα deletion in osteoclasts using the Cathepsin K promoter (ERαΔOcl mice). In a study design identical to that with the previously described ERαΔOcy mice, adult female, but not male, ERαΔOcl mice showed a borderline (-10.2%, p = 0.084) reduction in trabecular bone volume, no change in osteoclast numbers, but a significant increase in serum CTx levels, consistent with increased osteoclast activity. These findings in ERαΔOcl mice differ from previous studies of constitutive osteoclast-specific ERα deletion, which led to clear deficits in trabecular bone and increased osteoclast numbers. Collectively, these data indicate that in adult mice, estrogen action in the osteocyte is likely more important than via the osteoclast and that ERα deletion in osteoclasts from conception onward has more dramatic skeletal effects than inducible osteoclastic ERα deletion in adult mice. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Re-WRAP (Remyelination for women at risk of axonal loss and progression): A phase II randomized placebo-controlled delayed-start trial of bazedoxifene for myelin repair in multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a major cause of disability in young and middle-aged people, and myelin repair therapies are needed to slow or potentially reverse this damage. Bazedoxifene (BZA) is a selective estrogen receptor modulator identified in a novel high-throughput unbiased screen for its remyelinating potential, and its remyelinating effects were demonstrated in pre-clinical models. METHODS: This is a single-center, double blind, randomized, controlled, delayed-start Phase 2 clinical trial (NCT04002934) investigating the remyelinating effects of BZA relative to placebo. Female patients with relapsing-remitting MS, aged 45-60 years (or > 40 if post-menopausal), and ambulatory status (EDSS 0-6 inclusive), will be recruited into a clinical trial with 2 arms of identical design, except that the "Chronic Optic Neuropathy" arm requires additional inclusion criteria of electrophysiological evidence of prior visual pathway demyelination. Clinical, electrophysiological, and imaging evaluations will occur at baseline, 3 months, and 6 months. The primary outcome is change in Myelin Water Fraction (MWF) on MRI within the corpus callosum. Secondary outcomes are: visual evoked potential (VEP) P100 latency, novel digital measures of cognition and activity, and patient reported outcomes. Tertiary outcomes are: safety and tolerability. DISCUSSION: BZA has strong preclinical effects on myelin repair, and in the general population demonstrated benefits in treating postmenopausal osteoporosis. Together, these findings support the rationale for an RCT testing BZA in women with MS, evaluating established neuroimaging and neurovisual measures of myelin repair. Additionally, validating novel digital tools could increase sensitivity to change and inform the duration and design of future clinical trials.

Osteoporosis Associated with Breast Cancer Treatments Based on Types of Hormonal Therapy: A Cross-Sectional Study Using Korean National Sample Data.

Background and Objectives: This study aimed to investigate osteoporosis-related treatments and the overall anticancer drug treatment tendencies, with a focus on selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs), in Korean patients with breast cancer from 2010 to 2019. Materials and Methods: Data were obtained from the Health Insurance Review and Assessment Service. Patients with breast cancer (International Classification of Diseases, 10th Revision code: C50) as a principal diagnosis at least once from 2010 to 2019 were included. Those with osteoporosis (M80, M81, or M82) as a principal or sub-diagnosis or those who received osteoporosis treatment at least once were categorized as the osteoporosis-related treatment group, and others as the non-osteoporosis-related treatment group. The trends of drug prescriptions and treatment costs in patient groups were evaluated using descriptive statistics. Results: Among all included patients, those aged 45-54 years (40.20%) without osteoporosis treatment and those aged 55-64 years (34.11%) with osteoporosis treatment were the most common. SERM was the most commonly prescribed anticancer drug (29.20%) in the entire patient group, followed by AIs (20.83%). Patients without osteoporosis treatment had the highest prescription rate of SERM (31.48%), and those with osteoporosis treatment had a higher prescription rate of AIs (34.28%). Additionally, SERM and AIs were prescribed most frequently before and after the age of 55 years, respectively, regardless of the presence of treatment. Conclusions: This study found that osteoporosis-related treatment and patient age were associated with anticancer drug prescriptions. The present findings would help clinicians and researchers in the clinical diagnosis and treatment of breast cancer.

Urolithin A: A promising selective estrogen receptor modulator and 27-hydroxycholesterol attenuator in breast cancer.

27-hydroxycholesterol (27-HC) is an oxysterol that acts as an endogenous selective estrogen receptor modulator (SERM), and its adverse effects on breast cancer via the estrogen receptor (ER) have provided new insights into the pathology of cholesterol-linked breast cancer. Our earlier in vitro experiments showed that the methanolic extract of pomegranate could exhibit SERM properties and compete with 27-HC. The major constituents of pomegranate are ellagitannins and ellagic acid, which are converted into urolithins by the colonic microbiota. In recent years, urolithins, especially urolithin A (UA) and urolithin B (UB), have been reported to have a plethora of advantageous effects, including antiproliferative and estrogenic activities. In this study, we attempted to determine the potential of urolithins in antagonizing and counteracting the adverse effects of 27-HC in breast cancer cells. Our findings suggested that UA had an antiproliferative capacity and attenuated the proliferative effects of 27-HC, resulting in subsequent loss of membrane potential and apoptosis in breast cancer cells. Further, UA induced estrogen response element (ERE) transcriptional activity and modulated estrogen-responsive genes, exhibiting a SERM-like response concerning receptor binding. Our in vivo hollow fiber assay results showed a loss of cell viability in breast cancer cells upon UA consumption, as well as a reduction in 27-HC-induced proliferative activity. Additionally, it was shown that UA did not induce uterine proliferation or alter blood biochemical parameters. Based on these findings, we can conclude that UA has the potential to act as a potent estrogen receptor alpha (ERα) modulator and 27-HC antagonist. UA is safe to consume and is very well tolerated. This study further opens up the potential of UA as ER modulator and its benefits in estrogen-dependent tissues.

Complete Regression of an 8-cm Desmoid Fibromatosis After Treatment With Tamoxifen.

We report a case of a relatively large desmoid fibromatosis that responded completely to tamoxifen as a single drug therapy. A 47-year-old Japanese man underwent laparoscopy-assisted endoscopic submucosal dissection for a duodenal polyp. He developed postoperative generalized peritonitis and underwent an emergency laparotomy. Sixteen months after the surgery, a subcutaneous mass was found on the abdominal wall. Biopsy of the mass revealed estrogen receptor alpha-negative desmoid fibromatosis. The patient underwent total tumor resection. Two years after the initial surgery, he was found to have multiple intra-abdominal masses, with the largest mass measuring 8 cm in diameter. Biopsy revealed fibromatosis, as in the case of the subcutaneous mass. Complete resection was impossible due to the proximity of the duodenum and superior mesenteric artery. Tamoxifen was administered for three years, resulting in complete regression of the masses. No recurrence was observed for the following three years. This case indicates that relatively large desmoid fibromatosis can be successfully treated with a selective estrogen receptor modulator alone and that its effect is not dependent on the estrogen receptor alpha status of the tumor.

Effects of ospemifene on overactive bladder in postmenopausal women with vulvovaginal atrophy.

OBJECTIVE: Overactive bladder (OAB) is a complex and multifactorial syndrome associated with urinary frequency, urgency and incontinence. The menopause-associated hormonal changes play a role in the development of this condition. Vaginal estrogens are effective in improving OAB in postmenopausal women (PMW) with vulvovaginal atrophy (VVA). Ospemifene is a selective estrogen receptor modulator licensed for the treatment of VVA. This study aimed to evaluate the effects of ospemifene on OAB symptoms in PMW with VVA. METHODS: Forty PMW suffering from OAB and VVA received oral ospemifene (60 mg/day) for 12 weeks. All patients were assessed with a urodynamic study, a 3-day bladder diary and validated questionnaires (International Consultation on Incontinence Questionnaire - Urinary Incontinence Short Form [ICIQ-UI SF] and International Consultation on Incontinence Questionnaire - Overactive Bladder [ICIQ-OAB]) at enrollment and at the end of the study. RESULTS: Cytometric capacity, bladder compliance and verbal sensory threshold responses during bladder filling were improved after treatment. The voiding diary showed a significant reduction of daily voids, urge urinary incontinence episodes and nocturnal events. The median overall scores of the ICIQ-UI and ICIQ-OAB were also significantly improved. CONCLUSIONS: Our study suggest that treatment with ospemifene in PMW suffering from OAB is associated with a reduction of OAB symptoms due to a decreased bladder sensitivity and with an improvement in quality of life.

Clomiphene citrate for male infertility: A systematic review and meta-analysis.

BACKGROUND: Male infertility is a prevalent and worldwide problem with various difficulties in treatment. Clomiphene citrate is a selective estrogen receptor modulator and may improve semen quality by stimulating hormone synthesis and spermatogenesis. There is lack of evidence on the efficacy of clomiphene citrate as therapy for male infertility. OBJECTIVES: Therefore, a systematic review and meta-analysis was performed to assess the efficacy of clomiphene citrate on sperm quality in infertile men. METHODS: A search was conducted in the PubMed, EMBASE and Cochrane databases for effectiveness in infertile males treated with clomiphene citrate. Both intervention and observational studies were included. Primary outcome measures were semen parameters (concentration, motility and morphology). Secondary outcomes included hormonal evaluation, pregnancy rate and side effects. Studies were included for meta-analysis if they provided absolute numbers for outcomes before and during treatment with appropriate SD or SE. RESULTS: Total 1799 studies were identified during the search, 18 studies remained for qualitative analysis (n = 731) and 15 studies for meta-analysis (n = 566). Study populations ranged between 11 and 140 participants. Sperm concentration was higher during treatment, with a mean difference 8.38 × 106 /ml (95% confidence interval: 5.17-11.59; p < 0.00001; I2  = 87%). Total sperm motility was higher during treatment, with a mean difference of 8.14% (95% confidence interval: 3.83-12.45; p < 0.00001; I2  = 76%). There was no difference in sperm morphology before and during treatment. Total testosterone, follicle-stimulating hormone, luteinizing hormone and estradiol were higher during clomiphene citrate treatment. During follow-up, no serious adverse effects occurred. In 10 studies, pregnancy rate was reported and yielded a mean of 17% during clomiphene citrate treatment (range: 0%-40%). CONCLUSIONS: Clomiphene citrate increased sperm concentration and motility and could be considered as a safe therapy for improving sperm parameters in infertile males.

Temporal Changes of Clomiphene on Testosterone Levels and Semen Parameters in Subfertile Men.

PURPOSE: Clomiphene citrate (CC) is prescribed off-label in men to improve testosterone and sperm parameters, but the duration of treatment needed to reach maximal benefit remains unclear. Our objective was to examine temporal effects of CC on total testosterone (TT) and semen analysis (SA) using longitudinal follow-up data in treated men. MATERIALS AND METHODS: We analyzed an IRB-approved database of men treated with CC (25 mg q.d. or 50 mg q.o.d.) from January 2016 through May 2021. We identified patients with 3, 6, 9, and 12 month follow-up data for TT and 3, 6, and 9 month follow-up SA. Mean absolute changes in TT and sperm concentration compared to baseline were calculated, along with 95% confidence intervals. Men with prior genitourinary procedures or hormone therapy were excluded. Paired t-tests were used to compare TT and sperm concentration at each time point to baseline (alpha=0.05). RESULTS: One hundered thirty-four men received CC, mean age 37.7 years (SD 6.7, range 24-52). TT at all follow-ups (3, 6, 9, and 12 months) were available for 25 men, and SA at 3, 6, and 9 months for 26 men. Baseline TT was 358±145 ng/dL and sperm concentration was 13±17.2 M/mL. Significant improvement in TT was identified at 3 months (62.7 ng/dL, 95% CI: 0.49-125.0, p=0.048), additional benefit at 6 months (181.8 ng/dL, 95% CI: 114.1-249.5, p<0.01), and plateau at 9 and 12 months. Improvement in sperm concentration was first observed at 9 months (20.7 M/mL, 95% CI: 10.2-31.2, p<0.01). Semen volume and sperm motility did not change. CONCLUSIONS: Duration of treatment with clomiphene may impact testosterone and sperm concentration, and the historical 3 month milestone may be insufficient for clinical and research evaluation. Men taking CC may experience plateau in TT at 6 months and first benefit in sperm concentration at 9 months.

Estrogen Receptor Signaling in the Immune System.

The immune system functions in a sexually dimorphic manner, with females exhibiting more robust immune responses than males. However, how female sex hormones affect immune function in normal homeostasis and in autoimmunity is poorly understood. In this review, we discuss how estrogens affect innate and adaptive immune cell activity and how dysregulation of estrogen signaling underlies the pathobiology of some autoimmune diseases and cancers. The potential roles of the major circulating estrogens, and each of the 3 estrogen receptors (ERα, ERß, and G-protein coupled receptor) in the regulation of the activity of different immune cells are considered. This provides the framework for a discussion of the impact of ER modulators (aromatase inhibitors, selective estrogen receptor modulators, and selective estrogen receptor downregulators) on immunity. Synthesis of this information is timely given the considerable interest of late in defining the mechanistic basis of sex-biased responses/outcomes in patients with different cancers treated with immune checkpoint blockade. It will also be instructive with respect to the further development of ER modulators that modulate immunity in a therapeutically useful manner.

Raloxifene potentiates the effect of gefitinib in triple-negative breast cancer cell lines.

Triple-negative breast cancers (TNBCs) are characterized by a lack of approved targeted therapies and remain a challenge in the clinic. Several overexpressed proteins, including epidermal growth factor receptor (EGFR), have been associated with TNBCs and are considered potential therapeutic targets. However, EGFR inhibitors alone failed to demonstrate a cutting-edge advantage for treating TNBCs over conventional chemotherapies. Studies have shown that selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene also affect TNBC cell viability. The combination of gefitinib and raloxifene was assessed against TNBC cell lines in vitro. Two TNBC cell lines, MDA-MB-231 and MDA-MB-468, were used to investigate the combination of gefitinib and raloxifene on cell viability, DNA synthesis, and apoptosis. The combination was assessed on intracellular signaling pathways, colony formation, migration, and angiogenesis. In the present study, raloxifene, in combination with gefitinib, decreased cell viability. The combination potentiates apoptosis and affects the expression and phosphorylation pattern of proteins involved in cell proliferation, such as NFκB, ß-catenin, and EGFR. Furthermore, evidence of apoptosis activation was also observed, along with a decreased cell migration and tumorigenicity of TNBC cells. Moreover, the combined treatment decreased the ability of neovascularization as assessed by tube formation of endothelial cells. These results suggested the potential of the combination of raloxifene and gefitinib for the prevention of TNBC growth and the appearance of metastatic events. Our findings provide the basis for future studies on the mechanism involved in raloxifene-gefitinib inhibition of ER-negative tumor growth.

Risk of venous thromboembolism among women receiving ospemifene: a comparative observational study.

Introduction: The primary aim of this study was to compare the incidence of venous thromboembolism (VTE) among women initiating ospemifene vs other selective estrogen receptor modulator (SERM) therapies for estrogen-deficiency conditions or breast cancer prevention, and vs women with untreated vulvar and vaginal atrophy (VVA). The secondary objective examined numerous additional safety outcomes. Methods: This was a retrospective cohort study using the IBM Watson MarketScan claims database. Women receiving ospemifene, another SERM, or with a new diagnosis of VVA with no treatment from 1 May 2013 to 2 October 2018 were followed through the claims for incident adverse outcomes. The primary outcome was the first occurrence of VTE following cohort entry; secondary outcomes included cerebrovascular events and other adverse events potentially associated with SERM use. Cox models compared the risk of VTE between ospemifene and comparators, using a variety of approaches to control for confounding. Results: The incidence of VTE during the first continuous treatment episode was 3.39 (95% confidence interval [CI]: 1.55-6.43) events per 1,000 person-years (PY) for ospemifene (N = 8977), 11.30 (95% CI: 8.81-14.28) events per 1,000 PY for comparator SERM (N = 12,621), and 10.92 (95% CI: 10.49-11.37) events per 1,000 PY for untreated VVA (N = 242,488). Cox models indicated no increase in risk of VTE for ospemifene vs other SERMs (hazard ratio [HR]: 0.40, 95% CI: 0.19-0.82), and vs untreated VVA (HR: 0.47, 95% CI: 0.24-0.91). Conclusion: This real-world safety analysis found no increase in risk of VTE or other adverse events with use of ospemifene in postmenopausal women. Plain Language Summary: Introduction: This study assessed the risk of venous thromboembolism (VTE) among women treated with ospemifene or another selective estrogen receptor modulator (SERM) therapy and women with untreated vulvar and vaginal atrophy (VVA). Numerous additional safety outcomes were examined.Methods: This study was conducted in the IBM Watson MarketScan claims database. Women receiving ospemifene, another SERM, or with a new diagnosis of VVA with no treatment from 1 May 2013 to 2 October 2018 were followed through the claims for adverse outcomes, including VTE, cerebrovascular events (such as stroke), and other outcomes that might occur with use of a SERM. The analyses compared the risk of VTE between ospemifene and the other two groups, using methods that accounted for differences in patient characteristics between the groups. Because few women over 72 years old used ospemifene, the main analyses examined women aged 54-72 years.Results: The analyses included 8,977 ospemifene users, 12,621 other SERM users, and 242,488 women with untreated VVA. Among women aged 54-72 years, only 9 experienced a VTE during ospemifene treatment, while 55 other SERM users and 1,788 women with untreated VVA had a VTE. The analyses that accounted for differences between the groups confirmed that the risk of VTE was no higher in ospemifene users than in either comparison group.Conclusion: This real-world safety analysis found no increase in risk of VTE or other adverse events with use of ospemifene in postmenopausal women.