Treatment Of Premenopausal Women Research Articles

The Role of lncRNAs in the Protective Action of Tamoxifen on the Ovaries of Tumor-Bearing Rats Receiving Cyclophosphamide.

Infertility due to ovarian toxicity is a common side effect of cancer treatment in premenopausal women. Tamoxifen (TAM) is a selective estrogen receptor modulator that prevented radiation- and chemotherapy-induced ovarian failure in preclinical studies. In the current study, we examined the potential regulatory role of long noncoding RNAs (lncRNAs) in the mechanism of action of TAM in the ovaries of tumor-bearing rats receiving cyclophosphamide (CPA) as cancer therapy. We identified 166 lncRNAs, among which 49 were demonstrated to be differentially expressed (DELs) in the ovaries of rats receiving TAM and CPA compared to those receiving only CPA. A total of 24 DELs were upregulated and 25 downregulated by tamoxifen. The identified DELs shared the characteristics of noncoding RNAs described in other reproductive tissues. Eleven of the identified DELs displayed divergent modes of action, regulating target transcripts via both cis- and trans-acting pathways. Functional enrichment analysis revealed that, among target genes ascribed to the identified DELs, the majority were involved in apoptosis, cell adhesion, immune response, and ovarian aging. The presented data suggest that the molecular mechanisms behind tamoxifen's protective effects in the ovaries may involve lncRNA-dependent regulation of critical signaling pathways related to inhibition of follicular transition and ovarian aging, along with the suppression of apoptosis and regulation of cell adhesion. Employing a tumor-bearing animal model undergoing chemotherapy, which accurately reflects the conditions of mammary cancer, reinforces the obtained results. Given that tamoxifen remains a key player in the management and prevention of breast cancer, understanding its ovarian-specific actions in cancer patients is crucial and requires detailed functional studies to clarify the underlying molecular mechanisms.

Ovarian microenvironment: challenges and opportunities in protecting against chemotherapy-associated ovarian damage.

Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating detailed data show that different chemotherapy regimens can lead to disturbance of ovarian hormone levels, reduced or lost fertility, and an increased risk of early menopause. Previous studies have often focused on the direct effects of chemotherapeutic drugs on ovarian follicles, such as direct DNA damage-mediated apoptotic death and primordial follicle burnout. Emerging evidence has revealed an imbalance in the ovarian microenvironment during chemotherapy. The ovarian microenvironment provides nutritional support and transportation of signals that stimulate the growth and development of follicles, ovulation, and corpus luteum formation. The close interaction between the ovarian microenvironment and follicles can determine ovarian function. Therefore, designing novel and precise strategies to manipulate the ovarian microenvironment may be a new strategy to protect ovarian function during chemotherapy. This review details the changes that occur in the ovarian microenvironment during chemotherapy and emphasizes the importance of developing new therapeutics that protect ovarian function by targeting the ovarian microenvironment during chemotherapy. A comprehensive review of the literature was performed by searching PubMed up to April 2024. Search terms included 'ovarian microenvironment' (ovarian extracellular matrix, ovarian stromal cells, ovarian interstitial, ovarian blood vessels, ovarian lymphatic vessels, ovarian macrophages, ovarian lymphocytes, ovarian immune cytokines, ovarian oxidative stress, ovarian reactive oxygen species, ovarian senescence cells, ovarian senescence-associated secretory phenotypes, ovarian oogonial stem cells, ovarian stem cells), terms related to ovarian function (reproductive health, fertility, infertility, fecundity, ovarian reserve, ovarian function, menopause, decreased ovarian reserve, premature ovarian insufficiency/failure), and terms related to chemotherapy (cyclophosphamide, lfosfamide, chlormethine, chlorambucil, busulfan, melphalan, procarbazine, cisplatin, doxorubicin, carboplatin, taxane, paclitaxel, docetaxel, 5-fluorouraci, vincristine, methotrexate, dactinomycin, bleomycin, mercaptopurine). The ovarian microenvironment shows great changes during chemotherapy, inducing extracellular matrix deposition and stromal fibrosis, angiogenesis disorders, immune microenvironment disturbance, oxidative stress imbalances, ovarian stem cell exhaustion, and cell senescence, thereby lowering the quantity and quality of ovarian follicles. Several methods targeting the ovarian microenvironment have been adopted to prevent and treat CAOD, such as stem cell therapy and the use of free radical scavengers, senolytherapies, immunomodulators, and proangiogenic factors. Ovarian function is determined by its 'seeds' (follicles) and 'soil' (ovarian microenvironment). The ovarian microenvironment has been reported to play a vital role in CAOD and targeting the ovarian microenvironment may present potential therapeutic approaches for CAOD. However, the relation between the ovarian microenvironment, its regulatory networks, and CAOD needs to be further studied. A better understanding of these issues could be helpful in explaining the pathogenesis of CAOD and creating innovative strategies for counteracting the effects exerted on ovarian function. Our aim is that this narrative review of CAOD will stimulate more research in this important field. Not applicable.

The CROWN study: Cardiac outcomes with near-complete estrogen deprivation.

TPS12146 Background: Treatment for premenopausal women with high/intermediate risk hormone receptor (HR)-positive breast cancer (BC) includes the concurrent use of ovarian function suppression (OFS) and an aromatase inhibitor (AI) to induce near-complete estrogen deprivation (NCED). The long-term cardiovascular (CV) sequela for women treated with NCED is unknown. Premature menopause in non-cancer populations is associated with CV morbidity. Given the overall CV injury associated with BC treatment and the future life-years of these women, the CV impact of NCED warrants further study. The CROWN study uses sophisticated imaging assessments of cardiac dysfunction and biomarker and demographic correlates to understand the evolution of CV injury with the goal of developing tools to assess and mitigate CV risk. Methods: This is an NIH funded prospective cohort study conducted at 3 regional NCI-supported Cancer Centers (Duke University, Wake Forest University and Virginia Commonwealth University) that includes premenopausal women, age ≤ 55, with Stage I-III BC following completion of planned chemotherapy, surgery and radiation with an ECOG 0-2. HR-positive BC patients are receiving an AI and OFS. Women with HR-negative BC are included as comparators. CV imaging and biomarkers will be obtained at baseline, 1 year and 2 years (Table). These assessments include serial cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) imaging as well as laboratory measurements, including exploratory biomarkers. The primary objective is to determine the 24-month difference in stress myocardial blood flow as measured by adenosine CMR imaging in both groups. Correlation of CMR imaging with CCTA detail of coronary plaque changes is planned. The relevance of pre-existing risk factors on study outcomes, including an emphasis on race and dynamic change in modifiable and treatment related risk factors will also be assessed. We plan to enroll 90 women,65 in the NCED group and 25 in the HR-negative group, allowing for a 10% drop out rate. The first primary statistical analyses will include testing hypotheses between group (NCED vs HR-negative) and within group (longitudinal changes within the NCED group). Secondary analyses involve developing predictive equations to determine if patient demographics, clinical parameters and serum biomarkers are associated with CV changes over time. We have currently enrolled 34 women (31 NCED and 3 HR-negative). 2 out of 3 patients entering the 2nd year of the study have returned for their year 1 imaging. Retention will be a key component of this study as analysis of the primary and secondary endpoints are dependent on completion of imaging. Clinical trial information: NCT05309655 . [Table: see text]

Abstract PO3-19-04: The CROWN STUDY: A multicenter prospective cohort study of cardiovascular outcomes in premenopausal women with hormone receptor positive breast cancer treated with ovarian suppression and an aromatase inhibitor

Abstract Background: Treatment for premenopausal women with high or intermediate risk hormone receptor (HR)+ breast cancer (BC) includes the concurrent use of ovarian function suppression (OFS) and an aromatase inhibitor (AI) to induce near complete estrogen deprivation (NCED). The long-term cardiovascular (CV) sequela for women treated with NCED is unknown. Premature menopause in non-cancer populations is associated with CV disease. The CROWN study (CaRdiac Outcomes With Near complete estrogen deprivation) will use sophisticated imaging assessments of cardiac dysfunction to understand the evolution of CV injury, as well as biomarker and demographic correlates, with the goal of developing tools to assess and mitigate CV risk. Methods: This is a NIH funded prospective cohort study conducted at 3 regional NCI-supported Cancer Centers (Atrium Health Wake Forest Baptist, Virginia Commonwealth and Duke) that will include premenopausal women, age ≤ 55, with Stage I-III BC following completion of planned chemotherapy, surgery and radiation with an ECOG 0-1. HR+ BC patients will receive an AI and OFS. Women with HR- BC are included as comparators. CV imaging and biomarkers will be obtained at baseline, 1 year and 2 years (Table 1). These assessments will include serial cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) imaging as well as laboratory measurements, including exploratory biomarkers. The primary objective is to determine the 24-month difference in stress myocardial blood flow as measured by adenosine CMR imaging in both groups. We will correlate CMR imaging with CCTA to provide complementary detail of coronary plaque changes. The study will also assess the relevance of pre-existing risk factors on study outcomes, including an emphasis on racial disparities, and dynamic change in modifiable and treatment related risk factors. We plan to enroll 90 women, 67 in the NCED group and 23 in the HR-group, allowing for a 10% drop out rate. There are two primary types of statistical analyses. The first includes testing hypotheses between group (NCED vs HR-) and within group (longitudinal changes within the NCED group). The second analyses, involve developing predictive equations utilizing a stepwise linear regression approach to determine if patient demographics, clinical parameters and serum biomarkers are associated with cardiovascular changes over time. A total of 17 patients are enrolled as of 07/2023. NCT05309655 Study Procedures XX- XX Citation Format: Susan Dent, Emily Douglas, Sarah Hatcher, Katherine Ansley, Carolyn Park, Nathaniel O'Connell, Mary Hackney, Ralph D'Agostino, Rani Bansal, Renee Avecilla, Monica Brown, Kacey Clayton-Stiglbauer, Igor Klem, Jennifer Jordan, Alexandra Thomas. The CROWN STUDY: A multicenter prospective cohort study of cardiovascular outcomes in premenopausal women with hormone receptor positive breast cancer treated with ovarian suppression and an aromatase inhibitor [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 PO3-19-04.

Analysis of the benefit of gonadotropin-releasing hormone agonist treatment in premenopausal women undergoing hematopoietic cell transplantation

Gonadotropin-releasing hormone agonist (GnRHa) appears to exhibit ovarian protection during chemotherapy for malignant tumors. The purpose of this study was to analyze the benefits of GnRHa in premenopausal women undergoing hematopoietic cell transplantation (HSCT). Candidates for myeloablative chemotherapy HSCT requiring fertility preservation in the Gynecological Endocrinology Clinic of Peking University People’s Hospital from December 2011 to December 2021 were retrospectively analyzed. Patients who chose to receive GnRHa treatment were given at least 2 courses of a 3.75-mg dose of a GnRHa before myeloablative chemotherapy, and patients who chose not to receive GnRHa treatment were included in the control group. All patients were monitored for menstruation return and menopause-related symptoms, and ovarian function tests [follicle-stimulating hormone (FSH), luteinizing hormone, and estradiol] were performed 6–12 months after HSCT. In addition, we assessed the vaginal bleeding of patients in the laminar air-flow room (LAFR). A total of 234 cases were included in this study: 77 cases in the treatment group and 157 cases in the control group. The incidence of vaginal bleeding in the LAFR in the treatment group was significantly lower than that in the control group (24.68% vs. 79.62%, P < 0.001). The menopausal symptoms of the patients in the treatment group were reduced after transplantation (46.75% vs. 19.75%, P < 0.001). There was no difference in visible follicles by follow-up ultrasound in the two groups after HSCT (16.88% vs. 13.38%, P = 0.474). The level of FSH at 6–12 months after transplantation was lower (98.00 mIU/ml vs. 117.53 mIU/ml, P = 0.001). The proportion of patients with FSH < 40 mIU/ml did not differ between the two groups. One patient in the treatment group recovered spontaneous menstruation, while none recovered spontaneous menstruation in the control group (1.30% vs. 0%, P = 0.329). The use of GnRHa may relieve menopause-related symptoms and reduce vaginal bleeding in the LAFR and breakthrough bleeding after transplantation. GnRHa treatment can reduce the level of FSH after myeloablative chemotherapy, but it cannot reduce the incidence of premature ovarian failure in women of reproductive age following myeloablative HSCT.

The CROWN study (CaRdiac outcomes with near complete estrogen deprivation): A multicenter, prospective cohort study of cardiovascular outcomes in premenopausal women with hormone receptor positive breast cancer treated with ovarian suppression and an aromatase inhibitor.

TPS12142 Background: Treatment for premenopausal women with high or intermediate risk hormone receptor (HR)+ breast cancer (BC) now includes the concurrent use of ovarian function suppression (OFS) and an aromatase inhibitor (AI) to induce near complete estrogen deprivation (NCED). The long-term cardiovascular (CV) sequela for women treated with NCED is unknown. Premature menopause in non-cancer populations is associated with CV disease. Taken together with the CV morbidity associated with other aspects of BC treatment and the future life-years of these women, the CV impact of NCED warrants further study. The CROWN study will use sophisticated imaging assessments of cardiac dysfunction to understand the evolution of CV injury, as well as biomarker and demographic correlates, with the goal of developing tools to assess and mitigate CV risk. Methods: This is a NIH funded prospective cohort study conducted at 3 regional NCI-supported Cancer Centers (Atrium Health Wake Forest Baptist, Virginia Commonwealth and Duke) that will include premenopausal women, age ≤ 55, with Stage I-III BC following completion of planned chemotherapy, surgery and radiation with an ECOG 0-1. HR+ BC patients will receive an AI and OFS. Women with HR- BC are included as comparators. CV imaging and biomarkers will be obtained at baseline, 1 year and 2 years (Table 1). These assessments will include serial cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) imaging as well as laboratory measurements, including exploratory biomarkers. The primary objective is to determine the 24-month difference in stress myocardial blood flow as measured by adenosine CMR imaging in both groups. We will correlate CMR imaging with CCTA to provide complementary detail of coronary plaque changes. The study will also assess the relevance of pre-existing risk factors on study outcomes, including an emphasis on racial disparities, and dynamic change in modifiable and treatment related risk factors. We plan to enroll 90 women, 67 in the NCED group and 23 in the HR-group, allowing for a 10% drop out rate. There are two primary types of statistical analyses. The first includes testing hypotheses between group (NCED vs HR-) and within group (longitudinal changes within the NCED group). The second analyses, involve developing predictive equations utilizing a stepwise linear regression approach to determine if patient demographics, clinical parameters and serum biomarkers are associated with cardiovascular changes over time. Present accrual is 4. Clinical trial information: NCT05309655 . [Table: see text]

Gut-microbiome-expressed 3β-hydroxysteroid dehydrogenase degrades estradiol and is linked to depression in premenopausal females

Estradiol decline can result in depressive disorders in females; nevertheless, the causes of this decline are unclear. In this study, we isolated estradiol-degrading Klebsiella aerogenes from the feces of premenopausal females with depression. In mice, gavaging with this strain led to estradiol decline and depression-like behaviors. The gene encoding the estradiol-degrading enzyme in K.aerogenes was identified as 3β-hydroxysteroid dehydrogenase (3β-HSD). Heterologously expressing 3β-HSD resulted in Escherichia coli obtaining the ability to degrade estradiol. Gavaging mice with 3β-HSD-expressing E.coli decreased their serum estradiol levels, causing depression-like behaviors. The prevalence of K.aerogene and 3β-HSD was higher in premenopausal women with depression than in those without depression. These results suggest that the estradiol-degrading bacteria and 3β-HSD enzymes are potential intervention targets for depression treatment in premenopausal women.

Abstract P1-02-06: Improved survival with ovarian function suppression in premenopausal hormone receptor-positive breast cancer: a propensity score matching of ASTRRA-trial participants with single-center postmenopausal patients

Abstract Background: Poor survival outcome in young women with hormone-sensitive breast cancer was reported. And previous studies have demonstrated that the addition of ovarian function suppression (OFS) significantly improved disease-free survival (DFS) in patients with premenopausal hormone receptor–positive breast cancer. In this study, we examined whether ovarian function suppression treatment in premenopausal women is effective in survival comparable to postmenopausal status. Methods: We evaluated 1,298 breast cancer patients included in the post-trial follow-up of the Addition of Ovarian Suppression to Tamoxifen in Young Women With Hormone-Sensitive Breast Cancer Who Remain Premenopausal or Regain Vaginal Bleeding After Chemotherapy (ASTRRA) trial who received either tamoxifen (TAM) only (n=647) or TAM + OFS (n=635), randomly assigned in a 1:1 ratio and postmenopausal patients in AMC (Asan Medical Center; Seoul, Korea) treated with aromatase inhibitor (AI) (n=603). All patients analyzed in this study underwent surgery between March 2009 and November 2011. The primary endpoint was disease-free survival (DFS) and the secondary endpoint was overall survival (OS). We use propensity-score matching by lymph node status, tumor size, tumor grade, histologic type of cancer, human epidermal growth factor receptor-2 (HER2) status, chemotherapy regimen, surgical modality, and radiotherapy in the overall cohort and in separate subgroups according to anti-hormonal therapy regimens. Results: In the overall matched cohort, there was a significant difference between the postmenopausal AI group and premenopausal Tam only group in DFS (hazard ratio for the postmenopausal AI group, 0.654; 95% CI, 0.432 to 0.991) and OS was not significantly different between the premenopausal Tam only group and postmenopausal AI group (p=0.061). On the other hand, there was no significant difference between the postmenopausal AI group and premenopausal Tam+OFS group in disease free survival (hazard ratio for the postmenopausal AI group, 1.156; 95% confidence interval [CI], 0.735 to 1.820) or the overall survival (hazard ratio for the postmenopausal AI group, 1.04; 95% CI, 0.553 to 1.956). Conclusion: This study’s findings suggest that the poor prognosis of young women with hormone-sensitive breast cancer is improved by adding OFS to Tam and the effect is not inferior to that of using AI in post-menopausal women. Outcomes in a Cohort of Patients Matched for Propensity Scores postmeno AI, postmenopausal patients who treated with aromatase inhibior in Asan Medical Center; premeno Tam+OFS, premenopausal ASTRRA participants who treated with tamoxifen and ovarian function suppression; premeno Tam, premenopausal ASTRRA participants who treated with tamoxifen only Citation Format: Young-jin Lee, Tae-Kyung Yoo, Sae Byul Lee, Jisun Kim, Il-Yong Chung, Beom Seok Ko, Jong Won Lee, Byung Ho Son, Sei Hyun Ahn, Seonok Kim, Hee Jeong Kim. Improved survival with ovarian function suppression in premenopausal hormone receptor-positive breast cancer: a propensity score matching of ASTRRA-trial participants with single-center postmenopausal patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-02-06.

Abstract OT2-01-05: The CROWN Study (CaRdiac Outcomes With Near complete estrogen deprivation): A multicenter, prospective cohort study of cardiovascular outcomes in premenopausal women treated with ovarian suppression and an aromatase inhibitor

Abstract Background: Treatment for premenopausal women with high or intermediate risk hormone receptor (HR)+ breast cancer (BC) now includes the concurrent use of ovarian function suppression (OFS) and an aromatase inhibitor (AI) therapy to induce near complete estrogen deprivation (NCED). The long-term cardiovascular (CV) sequela for women treated with NCED is unknown. Premature menopause in the non-cancer population is associated with CV disease, including atherosclerosis and coronary artery disease, which can be detected pre-clinically by myocardial perfusion imaging and coronary artery plaques. This, together with the CV morbidity associated with other aspects of BC treatment and future life-years of these women, warrants further investigation with the goal of identifying pre-clinical markers of myocardial compromise. We seek to do this with the following specific aims: 1. Characterize and quantify the extent of coronary microvascular injury and perfusion changes experienced during early NCED therapy. 2. Characterize and quantify the extent of structural and functional alterations to the aorta and left ventricle while on NCED therapy. 3. Identify potential biomarkers and additional risk factors for CV morbidity in patients receiving NCEDTrial Design: This is a federally funded (NHLBI) prospective cohort study conducted at 3 regional NCI-supported Cancer Centers (Atrium Health Wake Forest Baptist, Virginia Commonwealth and Duke) that will include premenopausal women, age ≤ 55, with Stage I-III BC following completion of planned chemotherapy, surgery and radiation with an ECOG 0-1. HR+ BC patients will receive an AI and OFS. Women with HR- BC are included as comparators. CV imaging and biomarkers will be obtained at baseline, 1 year and 2 years (Table 1). These assessments will include serial cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) imaging as well as laboratory measurements, including exploratory biomarkers. The primary outcome is myocardial perfusion reserve (MPR) as measured by CMR imaging stress studies. We will correlate CMR imaging with CCTA to provide complementary detail of coronary plaque changes. The study will also assess the relevance of pre-existing risk factors, including an emphasis on racial disparities, on study outcomes, and dynamic change in modifiable and treatment related risk factors. Statistical Methods: We plan to enroll 90 women, 67 in the NCED group and 23 in the HR-group, allowing for a 10% drop out rate. There are two primary types of statistical analyses. The first includes testing hypotheses between group (NCED vs HR-) and within group (longitudinal changes within the NCED group) for Aims 1 and 2. Comparisons will be made using longitudinal mixed models to examine effects on outcomes measured. The second analyses, for Aim 3, involve developing predictive equations utilizing a stepwise linear regression approach to determine if patient demographics, clinical parameters and serum biomarkers are associated with MPR. The sample size allows 80% power to address specific aims for between and within group comparisons, including a between group difference of 2.8% in our primary outcome, MPR. Present Accrual: 0 Target Accrual: 90 Contact information: Emily Douglas, MD; edouglas@wakehealth.edu Table 1: Study Procedures Citation Format: Emily Douglas, Nathaniel O’Connell, Mary Hackney, Wendy Bottinor, John Grizzard, Igor Klem, Carolyn Park, Sujethra Vasu, Karl Richardson, Susan Dent, Ralph D’Agostino, Gregory Hundley, Jennifer Jordan, Alexandra Thomas. The CROWN Study (CaRdiac Outcomes With Near complete estrogen deprivation): A multicenter, prospective cohort study of cardiovascular outcomes in premenopausal women treated with ovarian suppression and an aromatase inhibitor [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-05.

Risk of Endometrial Polyps, Hyperplasia, Carcinoma, and Uterine Cancer After Tamoxifen Treatment in Premenopausal Women With Breast Cancer

The association of tamoxifen use with the risk of uterine diseases, such as endometrial cancer, in premenopausal women with breast cancer remains controversial. However, many studies have reported an increased risk of uterine disease among postmenopausal tamoxifen users. To investigate the association of tamoxifen use with the risk of endometrial cancer and other uterine diseases in premenopausal women with breast cancer. A nationwide, population-based, retrospective longitudinal cohort study with an 18-year study period was conducted using data obtained from the Korean National Health Insurance Service. Participants included premenopausal women aged 20 to 50 years with breast cancer diagnoses between January 2003 and December 2018. Data were analyzed from April to December 2021. Tamoxifen treatment. The incidence of uterine diseases, including endometrial cancer, hyperplasia, polyps, and other uterine cancers, was identified in the study cohort using insurance claim codes. The incidence of uterine diseases per 1000 person-years was compared between women receiving tamoxifen and those not treated with adjuvant hormone therapy. Multivariable Cox proportional hazard regression analysis was performed to determine the risk of each uterine disease. Among 78 320 female participants with a mean (SD) age of 42.1 (6.1) years, 34 637 (44.2%) were categorized into the tamoxifen group and 43 683 (55.8%) were categorized into the control group. Among tamoxifen users, during the mean (SD) follow-up duration of 6.13 (4.15) years, the incidence of newly diagnosed endometrial polyps was 20.13 cases per 1000 person-years, that of endometrial hyperplasia was 13.49 cases per 1000 person-years, that of endometrial cancer was 2.01 cases per 1000 person-years, and that of other uterine cancers was 0.45 cases per 1000 person-years. The risk of endometrial cancer was higher in the tamoxifen group than in the control group (hazard ratio, 3.77; 95% CI, 3.04-4.66) after adjusting for age, body mass index, history of diabetes, hypertension, dyslipidemia, polycystic ovary syndrome, gonadotropin-releasing hormone agonist treatment, and trastuzumab treatment. In this longitudinal cohort study, premenopausal Korean women with breast cancer who received tamoxifen as adjuvant hormone therapy had a significantly increased risk of endometrial hyperplasia, polyps, carcinoma, and other uterine cancers compared with those who were not treated with adjuvant hormone therapy. These findings suggest that clinicians should consider the risk of uterine disease among tamoxifen users, including premenopausal women.

Extended adjuvant endocrine treatment for premenopausal women: A Delphi approach to guide clinical practice.

The use of an aromatase inhibitor (AI) in combination with ovarian function suppression (OFS) has become the mainstay of adjuvant endocrine therapy in high-risk premenopausal patients with hormone receptor-positive breast cancer. Although five years of such therapy effectively reduces recurrence rates, a substantial risk of late recurrence remains in this setting. Multiple trials have shown that extending AI treatment beyond five years could offer further protection. However, as these studies comprised only postmenopausal patients, no direct evidence currently exists to inform about the potential benefits and/or side effects of extended AI + OFS therapies in premenopausal women. Given these grey areas, we conducted a Delphi survey to report on the opinion of experts in breast cancer treatment and summarize a consensus on the discussed topics. A total of 44 items were identified, all centred around two main themes: 1) defining reliable prognostic factors to pinpoint premenopausal patients eligible for endocrine therapy extension; 2) designing how such therapy should optimally be administered in terms of treatment combinations and duration based on patients' menopausal status. Each item was separately discussed and anonymously voted by 12 experts representing oncological institutes spread across Italy. The consensus threshold was reached in 36 out of 44 items (82%). Herein, we discuss the levels of agreement/disagreement achieved by each item in relation to the current body of literature. In the absence of randomized trials to guide the tailoring of extended AI treatment in premenopausal women, conclusions from our study provide a framework to assist routine clinical practice.

Intermediate results of the prospective randomized controlled trial VOG-01: "Evaluation of the efficacy of neoadjuvant combination hormone therapy in premenopausal patients with ER+ HER2- breast cancer"

To date, the standard of care for neoadjuvant treatment of HER2-negative breast cancer remains chemotherapy with the inclusion of anthracyclines and taxanes in both luminal and triple-negative tumor subtypes. The purpose of this article was to scientifically substantiate the use of combined hormone therapy at the preoperative treatment of premenopausal patients with ER+ HER2- breast cancer. After analyzing the scientific data presented in scientific databases (PubMed, MEDLINE, BMS), as well as studying active clinical trials on the ClinicalTrials.gov, we concluded that most of the studies where hormone therapy was used in the preoperative regimen were conducted in the postmenopausal patient. In this regard, a randomized controlled clinical trial was initiated to study the efficacy and safety of a new method of preoperative treatment in premenopausal women with ER+ HER2- breast cancer, the preliminary results of which will be reported in this article. Currently, the study included 28 patients, of which 13 patients were analyzed who received the neoadjuvant and surgical stages of complex treatment. The research is ongoing.

Drug flibanserin–in hypoactive sexual desire disorder

Hypoactive sexual desire disorder (HSDD) is a widely known type of female sexual dysfunction that could also cause emotional distress and relationship problems. Flibanserin, a benzimidazole, was being studied as a treatment for premenopausal women with hypoactive sexual desire disorder because there was no accurate drug therapy available at the time (HSDD). The US Food and Drug Administration (FDA) approved Flibanserin in 2015 for the treatment of generalised acquired HSDD in premenopausal women. It has a high affinity for postsynaptic 5-HT-1A receptors (agonist) and 5-HT-2A receptors (antagonist), and it tends to work by increasing dopamine and noradrenaline levels in the brain while decreasing serotonin levels. This review was to assess Flibanserin efficacy and safety and it is found the drug Flibanserin benefits did not outweigh the risks in premenopausal and postmenopausal women.

Challenges in the diagnosis and management of glucocorticoid‐induced osteoporosis in younger and older adults

Glucocorticoids constitute a considerable risk for developing osteoporosis in both younger and older adults. However, currently available bone imaging modalities and fracture-risk assessment tools do not adequately capture the dramatic changes in bone microarchitecture, heterogeneity of glucocorticoid exposure, the impact of chronic disease and other osteoporosis risk factors on the assessment of osteoporosis in these individuals. A narrative review is presented, following a systematic search of the literature from 2000 to 2021. Our current appreciation of glucocorticoid-induced osteoporosis (GIO) is focused on older populations, with limited evidence to guide the investigation, risk assessment and treatment in premenopausal women and men less than 50 years. The impact of the underlying chronic disease on secondary osteoporosis in these younger adults is also poorly understood. Through this narrative review, we provide a comprehensive overview of and recommendations for optimising the management of this common cause of secondary osteoporosis younger and older adults.

Treatment of Premenopausal Women: Finding the Right-Sized Endocrine Therapy.

Right-sized endocrine therapy should be driven by both evidence and risk-benefit discussions with patients, likely evolving over time. Against the backdrop of Sella et al's recent pragmatic approac...

Bone Mineral Density Changes Associated With Pregnancy, Lactation, and Medical Treatments in Premenopausal Women and Effects Later in Life.

Bone mineral density (BMD) changes during the life span, increasing rapidly during adolescence, plateauing in the third decade of life, and subsequently entering a phase of age-related decline. In women, menopause leads to accelerated bone loss and an increase in fracture risk. Between peak bone mass attainment and menopause, BMD is generally stable and the risk of fracture is typically low. This time period is marked by life events such as pregnancy and lactation, which transiently decrease BMD, yet their long-term effects on fracture risk are less certain. BMD may also be altered by exposure to medications that affect bone metabolism (e.g., contraceptives, glucocorticoids, antidiabetic medications, antiepileptic drugs). Although oral contraceptives are often believed to be neutral with regard to bone health, depot medroxyprogesterone acetate (DMPA) and gonadotropin-releasing hormone (GnRH) agonists have been associated with decreases in BMD. Development of newer medical therapies, principally GnRH antagonists (e.g., ASP1707, elagolix, linzagolix, relugolix), for treatment of endometriosis-associated pelvic pain and heavy menstrual bleeding due to uterine fibroids has renewed interest in the short- and long-term impacts of changes in BMD experienced by premenopausal women. It is important to understand how these drugs influence BMD and put the findings into context with regard to measurement variability and naturally occurring factors that influence bone health. This review summarizes what is known about the effects on bone health pregnancy, lactation, and use of DMPA, GnRH agonists, and GnRH antagonists in premenopausal women and potential consequences later in life. ClinicalTrials.gov identifier: NCT03213457.

O-173 Decline in anti-Müllerian hormone (AMH) concentrations following radioactive iodine (RAI) treatment in women with differentiated thyroid cancer (DTC): a systematic review and meta-analysis

Abstract Study question Does radioactive iodine (RAI) treatment in premenopausal women with differentiated thyroid cancer (DTC) affects ovarian reserve, as evaluated by anti-Müllerian hormone (AMH), antral follicle count (AFC) and follicle-stimulating hormone (FSH)? Summary answer AMH concentrations decreased at three, six and 12 months following RAI treatment in women with DTC, whereas no difference was observed regarding FSH. What is known already Thyroid cancer is the third most common type of female malignancy and DTC is the most common histopathological type. Thyroidectomy constitutes the mainstay of treatment for DTC, followed by administration of RAI, which acts as an adjuvant therapy to destroy residual cancerous thyroid tissue. However, the effect of RAI on ovarian reserve of these women, as assessed by AMH, AFC and FSH, remains controversial. Study design, size, duration A systematic review and meta-analysis was performed aiming to identify studies evaluating the effect of RAI treatment on ovarian reserve in women with DTC. For this purpose, a literature search in the electronic databases PubMed, Scopus and CENTRAL was carried out until 06/12/2020. The primary outcome measure was the effect of RAI on ovarian reserve, as evaluated by AMH, AFC and FSH. Participants/materials, setting, methods Studies were eligible if they included premenopausal women with DTC, treated with a single RAI dose and assessed for at least one marker of ovarian reserve repeatedly within 12 months post-RAI.Meta-analysis of weighted data was performed using random effects model. Results were reported as weighted mean difference (WMD) with 95% confidence interval (CI). Main results and the role of chance Four prospective eligible studies, published between 2005 and 2020, were eligible for the meta-analysis, evaluating a total of 154 women. The number of participants ranged from 24 to 50. The single dose of RAI used to treat DTC ranged from 50 to 150 mCi. AMH concentrations decreased at three (WMD -1.66 ng/ml, 95% CI -2.42 to -0.91, p &amp;lt; 0.0001; I2 0%), six (WMD -1.58 ng/ml, 95% CI -2.63 to -0.52, p = 0.003; I2 54.7%) and 12 months (WMD -1.62 ng/ml, 95% CI -2.02 to -1.22, p &amp;lt; 0.0001; I2 15.5%) following a single RAI dose compared with baseline (three studies; n = 104). With respect to FSH concentrations, no difference was observed at six (WMD +3.29 IU/l, 95% CI -1.12 to + 7.70, p = 0.14; I2 96.8%) and 12 months (WMD +0.13 IU/l, 95% CI -1.06 to + 1.32, p = 0.83; I2 55.2%) post-RAI compared with baseline (two studies; n = 83). No data on AFC was available. Limitations, reasons for caution The small number of studies and patients included, as well as the lack of data on AFC may have compromised the validity of the conclusions drawn. Moreover, subgroup analysis according to female age was not feasible, due to the lack of relevant data. Wider implications of the findings The negative effect of RAI on ovarian reserve in premenopausal women with DTC, as indicated by the decreased AMH, should be confirmed by data on AFC, which are currently not available. These findings necessitate close monitoring of ovarian reserve in such women, counselling them regarding the need for fertility preservation. Trial registration number N/A

Abstract SP114: Body Image and Sexual Health

Abstract Attention to body image and sexual health after breast cancer are important components of treatment decisions, support through treatment and survivorship care. A high proportion of breast cancer survivors report dissatisfaction with their physical appearance. Body image issues are particularly common among women who undergo mastectomy with or without reconstructive surgery and those who experience weight gain, hair loss from chemotherapy, and other psychosocial issues. Scalp cooling, proactive counseling about potential effects of treatment on weight and physical activity, and psychosocial support through treatment may help to prevent some of these negative effects. Weight loss and subsequent weight maintenance are notoriously difficult to achieve through diet alone, and exercise plays an important role in energy balance through and after treatment. Sexual health is frequently a concern for breast cancer survivors as well, with up to 40% of women reporting issues with sexual interest and 60% with physical sexual function. Issues may arise in the short term following both surgery and chemotherapy, due to factors including lower perceived attractiveness and vaginal dryness. Endocrine therapy with tamoxifen, aromatase inhibitors, and treatment-related amenorrhea or ovarian suppression treatment in premenopausal women are associated with sexual dysfunction. However, a multi-prong approach has been shown to improve such problems. Providers should actively monitor for and manage the consequences of diagnosis and treatment on body image and sexual health in survivors, using psychosocial, behavioral, and pharmacologic tools as needed. Citation Format: A Partridge. Body Image and Sexual Health [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP114.

Ablation/Resection Vs Levonorgestrel Intrauterine System (LNG-IUS) for Heavy Menstrual Bleeding : A Systematic Review and Meta-Analysis

Study Objective To compare the efficacy and safety of endometrial ablation/resection with the LNG-IUS in the treatment of premenopausal women with heavy menstrual bleeding and to investigate sources of heterogeneity between studies. Design A systematic review with meta-analysis. Setting We searched the databases MEDLINE, EMBASE, CENTRAL, Web of Science, Biosis and Google Scholar as well as citations and reference lists published up to August 2019. Patients or Participants We included randomized controlled trials published in any language, comparing endometrial ablation/resection to the LNG-IUS in the treatment of premenopausal women with heavy menstrual bleeding and a normal uterine cavity. Thirteen studies were eligible (n=884 women). Interventions Endometrial ablation/resection versus LNG-IUS. Measurements and Main Results No significant differences were observed between endometrial ablation/resection and the LNG-IUS in terms of subsequent hysterectomy (primary outcome, risk ratio (RR)=1.13,95% CI 0.60 to 2.11, p=0.71, I2=14%, 12 studies), satisfaction, quality of life, amenorrhea and treatment failure. Side effects were less common in women treated with endometrial ablation/resection (p 42 years old), although the reduction did not reach statistical significance (RR= 0.51, 95% CI 0.21 to 1.24, p =0.14, I2 =0%, 5 studies).Sensitivity analysis taking into account methodological quality of included studies and type of surgical devices (first and second generation) did not modify the results. Conclusion Endometrial ablation/resection and the LNG-IUS are two excellent treatment options for heavy menstrual bleeding, although younger women probably have a higher risk of eventually requiring hysterectomy following endometrial ablation.

Treatment of Premenopausal Women with Osteoporosis.

Treatment of Premenopausal Women with Osteoporosis.