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Only a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer, potentially explaining ∼40% of relapses. If other mechanisms underlie the evolution of hormone-dependent breast cancer under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CRE) to cancer evolution by focusing on 12 megabases of noncoding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies a limited set of noncoding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies trigger the emergence of transient features which could ultimately be exploited to hinder the adaptive process. Significance: This study shows that cells adapting to endocrine therapies undergo changes in the usage or regulatory regions. Dormant cells are less vulnerable to regulatory perturbation but gain transient dependencies which can be exploited to decrease the formation of dormant persisters.

Nearly all men with metastatic hormone-sensitive prostate cancer treated with intermittent androgen deprivation therapy (ADT) experience recurrence within 6 mo of testosterone recovery. We conducted a single-arm phase 2 trial to evaluate whether addition of dual androgen receptor pathway inhibitors (ARPIs) and metastasis-directed stereotactic body radiotherapy (SBRT) to intermittent ADT improves recurrence rates for men with between one and five nonvisceral, extrapelvic metastases on prostate-specific membrane antigen positron emission tomography/computed tomography after prior radical prostatectomy. Patients received 6 mo of androgen annihilation therapy (AAT; leuprolide, abiraterone acetate plus prednisone, and apalutamide) and metastasis-directed SBRT. The primary endpoint was the percentage of patients with prostate-specific antigen (PSA)

PURPOSE: Increased glucocorticoid receptor (GR) signaling is a proposed compensatory mechanism of resistance to androgen receptor (AR) inhibition in metastatic castration-resistant prostate cancer (mCRPC). ORIC-101 is a potent and selective orally-bioavailable GR antagonist. PATIENTS AND METHODS: Safety, pharmacokinetic/pharmacodynamic, and antitumor activity of ORIC-101 in combination with enzalutamide were studied in patients with mCRPC progressing on enzalutamide. ORIC-101 doses ranging from 80 to 240 mg once daily were tested in combination with enzalutamide 160 mg once daily. Pharmacokinetics/pharmacodynamics was assessed after a single dose and at steady state. Disease control rate (DCR) at 12 weeks was evaluated at the recommended phase 2 dose (RP2D). RESULTS: A total of 41 patients were enrolled. There were no dose-limiting toxicities and the RP2D was selected as 240 mg of ORIC-101 and 160 mg of enzalutamide daily. At the RP2D, the most common treatment-related adverse events were fatigue (38.7%), nausea (29.0%), decreased appetite (19.4%), and constipation (12.9%). Pharmacokinetic/pharmacodynamic data confirmed ORIC-101 achieved exposures necessary for GR target engagement. Overall, for 31 patients treated at the RP2D, there was insufficient clinical benefit based on DCR (25.8%; 80% confidence interval: 15.65-38.52) which did not meet the prespecified target rate, leading to termination of the study. Exploratory subgroup analyses based on baseline GR expression, presence of AR resistance variants, and molecular features of aggressive variant prostate cancer suggested possible benefit in patients with high GR expression and no other resistance markers, although this would require confirmation. CONCLUSIONS: Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.

Introduction: Preeclampsia is one of the causes of maternal death. The prevalence of preeclampsia cases in Indonesia is quite high, namely 34.1%. One of the risk factors for preeclampsia is a history of using hormonal contraception. For this reason, this study aims to know the influence of hormonal contraceptive risk factors on the incidence of preeclampsia. Materials and methods: This research was a case control analytical observational study. Samples were 24 cases and 24 controls. The independent variable was hormonal contraception, and the dependent variable was preeclampsia. Data was collected through medical records at the Pangkur Community Health Center, Ngawi Regency. Chi-square analysis test with a significance level of P<0.05. Results: The results of this study indicated that exposure to hormonal birth control for the incidence of preeclampsia was 66.6%, while exposure to hormonal Contraception for non-preeclampsia events was 25%. From the results of the analysis with the Chi-Square test, the significance value of P = 0.009. Conclusion: It can be concluded that there was an influence of hormonal contraceptive risk factors on the incidence of preeclampsia. It's recommended that potential acceptors undergo counseling before making a decision by looking at the short-term and long-term effects. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to investigate the associations between the early follicular (EF, i.e., menstruation), late follicular (LF), and middle luteal (ML) phases of the menstrual cycle and different factors that may influence football performance. Methods: To this end, 11 eumenorrheic sub-elite female football players underwent field tests to assess sprint speed, lower extremity power, repeated sprint ability, velocity on change of direction, and technical skills at each cycle phase. Results: Performance during the 15-m change of direction ability test, 15-m ball dribbling test, squat jump height, total sprint time [sum of 7 sprints] and decrement score [(mean sprint time/best sprint time × 100) − 100], maximum and mean heart rate, and perceived exertion did not significantly differ among menstrual cycle phases. Conversely, the linear sprint velocity over 10, 20, 30-m distances was decreased in EF vs LF (10-, 20- and 30-m) and in ML vs LF (10- and 20-m) (p < 0.05). The 40-m sprint velocity did not change in the different menstrual cycle phases. Conclusion: Overall, our study suggests that sex hormone fluctuations during the menstrual cycle are not associated with vertical jump, velocity on change of direction, and repeated sprint ability, but may influence linear sprint velocity over short distances (10, 20, and 30 m). [ABSTRACT FROM AUTHOR]

Geophytic plants synchronize growth and quiescence with the external environment to survive and thrive under changing seasons. Together with seasonal growth adaptation, dormancy and sprouting are critical factors determining crop yield and market supply, as various geophytes also serve as major food, floriculture, and ornamental crops. Dormancy in such crops determines crop availability in the market, as most of them are consumed during the dormant stage. On the other hand, uniform/maximal sprouting is crucial for maximum yield. Thus, dormancy and sprouting regulation have great economic importance. Dormancy–sprouting cycles in geophytes are regulated by genetic, exogenous (environmental), and endogenous (genetic, metabolic, hormonal, etc.) factors. Comparatively, the temperature is more dominant in regulating dormancy and sprouting in geophytes, unlike above-ground tissues, where both photoperiod and temperature control are involved. Despite huge economic importance, studies concerning the regulation of dormancy and sprouting are scarce in the majority of geophytes. To date, only a few molecular factors involved in the process have been suggested. Recently, omics studies on molecular and metabolic factors involved in dormancy and growth regulation of underground vegetative tissues have provided more insight into the mechanism. Here, we discuss current knowledge of the environmental and molecular regulation and control of dormancy and sprouting in geophytes, and discuss challenges/questions that need to be addressed in the future for crop improvement. [ABSTRACT FROM AUTHOR]

Simple Summary: Medroxyprogesterone acetate is a synthetic progesterone commonly used as a contraceptive in the United States, used by up to 25% of women aged 18–49 who have had intercourse. Progesterone is reported to be associated with the increased growth of meningiomas, a type of central nervous system tumor that can affect the meninges of the brain or spine, and recently an article utilizing a population of French women noted a significant association between medroxyprogesterone use and cerebral meningioma risk, particularly for patients using it for two years. The current study supported the findings of the prior published research, finding an increased chance of cerebral meningioma for those with use of medroxyprogesterone acetate; this association became stronger with longer duration of use. There were no associations observed for spinal meningiomas. Background/Objectives: Medroxyprogesterone acetate (MPA) is a synthetic progesterone that is most commonly used as a contraceptive. MPA acts by binding to the progesterone receptor of the hypothalamus, and this receptor has been found to be important in the pathophysiology of meningiomas. Recent research has reported an increased association between the use of MPA and intracranial meningioma, though the literature is mostly limited by low numbers of meningioma cases and low exposure to MPA. The objective of the current study is to build upon the previously published literature utilizing a large database from the United States. Methods: Utilizing a large commercial insurance database, the current matched case–control study identified meningioma cases using ICD-10 codes from hospital data and MPA exposure, as established from pharmaceutical claims data. Controls were matched 10:1 to cases based on age, year of enrollment, and duration of enrollment. A conditional logistic regression estimated odds ratios (ORs) for the association between MPA exposure and the odds of developing a meningioma. Results: Among 117,503 meningioma cases and 1,072,907 matched controls, oral MPA exposure was not associated with odds of meningioma; however, injection MPA exposure was associated with a 53% increased odds of being a case (OR 1.53, 95% CI 1.40–1.67). This association was specific to cerebral meningiomas (OR 1.68, 95% CI 1.50–1.87), an association that became stronger with a longer duration of use of injection MPA. Conclusions: The current results are consistent with the prior literature, which reports an association between injection exposures to MPA and a stronger association with increasing use of MPA. Women should be cautioned about the prolonged use of MPA, and future research should examine whether the extended use of MPA is associated with the meningioma grade. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovarian syndrome is affecting around 5-15% of females. Spexin hormone, identified as neuropeptide Q, has been newly recognized by bioinformatics methods. Objective: To evaluate the relationship concerning levels of spexin hormone with metabolic disruption in women with polycystic ovarian syndrome. Patients and Methods: A case-control study carried out in the department of Obstetrics and Gynecology in Al-Imamain Al-Khademain medical city/Baghdad, Iraq, from Jan 1, 2022, to the end of Dec 31, 2022. The study sample comprises, 192 participants aged 18-45 years were joined and allocated into a case group (96 women with PCOS) and a control group (96 women without PCOS). Results: Mean value of spexin hormone was (2.7±0.3 ng/mL) in the PCOS group, while it was (3.5±0.7 ng/mL) in the control group; fasting blood sugar shows significant association with a negative, weak correlation with Spexin in patients (P-value= 0.005), Insulin shows significant association with inverse correlation with Spexin in patients (P-value= 0.04), Homeostasis model valuation of insulin resistance (HOMA-IR) shows significant association with inverse correlation with Spexin in patients (P-value= 0.003). Spexin had a significant inverse correlation with LH, SHBG, testosterone, FAI, and Dehydroepiandrosterone. Conclusion: Serum level of spexin hormone was meaningfully decreased in patients with PCOS than that in healthy women. [ABSTRACT FROM AUTHOR]

Background: Studies concerning the negative effect of hormonal contraceptives is scarce and scanty. The main aim of this study the common health problems related to the intake of oral contraceptives (OCP) and injection contraceptives (INJ). Methods: This was a descriptive, cross-sectional study, The study was conducted in Omdurman Maternity Hospital. About 125 Sudanese women were participated in this study divided to test group which was consisted of 65 women used contraceptives, and 60 women were control group. The primary data was collected using questionnaire and laboratory investigations. Results: Sociodemographic characteristics of the two groups showed no association between residential areas and nutritional problems as it compared between control and test group (P ≤ 0.05). Level of blood pressure, cholesterol, triglycerides and Hb% among test and control group showed clear differences between the two groups (P ≤ 0.05). Conclusions: The most common side effects associated with consecutive use among test were headache, hair fall, weight increase, joint pain, fatigue, accelerated heart beats, unstable breathing and nausea. [ABSTRACT FROM AUTHOR]

Parturition is a complex physiological process that must occur in a reliable manner and at an appropriate gestation stage to ensure a healthy newborn and mother. To this end, hormones that affect the function of the gravid uterus, especially progesterone (P4), 17β-estradiol (E2), oxytocin (OT), and prostaglandins (PGs), play pivotal roles. P4 via the nuclear P4 receptor (PR) promotes uterine quiescence and for most of pregnancy exerts a dominant block to labor. Loss of the P4 block to parturition in association with a gain in prolabor actions of E2 are key transitions in the hormonal cascade leading to parturition. P4 withdrawal can occur through various mechanisms depending on species and physiological context. Parturition in most species involves inflammation within the uterine tissues and especially at the maternal-fetal interface. Local PGs and other inflammatory mediators may initiate parturition by inducing P4 withdrawal. Withdrawal of the P4 block is coordinated with increased E2 actions to enhance uterotonic signals mediated by OT and PGs to promote uterine contractions, cervix softening, and membrane rupture, i.e., labor. This review examines recent advances in research to understand the hormonal control of parturition, with focus on the roles of P4, E2, PGs, OT, inflammatory cytokines, and placental peptide hormones together with evolutionary biology of and implications for clinical management of human parturition. [ABSTRACT FROM AUTHOR]

Introduction: Night shift work disrupts circadian rhythms and has been associated with immune system alterations and various health conditions. However, there is limited data regarding its impact on psoriasis. The aim of our study was to compare psoriasis severity and the hormonal and immunological profile in patients with a night shift work to those with a daytime occupation. Methods: In this case-control study, we enrolled psoriatic patients aged >18 years engaged in night shift work and a control group of psoriatic patients with a daytime occupation. A further categorization was performed by the duration of night shift work: < or ≥7 days a month and < or ≥8 years. Disease severity was evaluated by PASI, BSA, and DLQI, and blood samples were taken to measure various hormonal and immunological markers. Univariable and multivariable analysis were performed to assess differences between the two groups. Results: A total of 40 night shift workers were included, along with 36 patients in the control group. Patients who worked night shifts at least 7 days a month had significantly higher PASI scores (11.2 ± 6.6 vs. 8.5 ± 6.6; p = 0.04) and higher IL-8 serum (115.33 ± 463.65 pg/mL vs. 19.98 ± 29.78 pg/mL; p = 0.006) compared to patients who did not. Night shifts workers for at least 8 years had higher BMI (28.65 ± 4.56 vs. 25.32 ± 5.50, p = 0.010), and females had higher testosterone levels (0.46 ± 0.53 ng/mL vs. 0.23 ± 0.13 ng/mL; p = 0.055). Conclusion: Night shift might increase psoriasis severity and have an impact on chronic inflammation, obesity, and hormonal imbalances. [ABSTRACT FROM AUTHOR]

Objective & methods: This study tested associations of genotype-predicted activity of CYP3A4, other pharmacogenes, SLC28A7 (rs11648166) and ALPPL2 (rs28845026) with systemic concentrations of the endocrine therapies anastrozole and fulvestrant in SWOG S0226 trial participants. Results: Participants in the anastrozole-only arm with low CYP3A4 activity (i.e. CYP3A4*22 carriers) had higher systemic anastrozole concentrations than patients with high CYP3A4 activity (β-coefficient = 10.03; 95% CI: 1.42, 18.6; p = 0.025). In an exploratory analysis, participants with low CYP2C9 activity had lower anastrozole concentrations and higher fulvestrant concentrations than participants with high CYP2C9 activity. Conclusion: Inherited genetic variation in CYP3A4 and CYP2C9 may affect concentrations of endocrine therapy and may be useful to personalize dosing and improve treatment outcomes.

BackgroundThe complex relationship between insulin-like growth factor 1 (IGF-1) levels and heart failure (HF) is not fully understood, particularly across different populations and conditions. This meta-analysis aims to elucidate the dual perspectives of IGF-1 levels in the general population, HF patients, and individuals with treatment-naïve acromegaly, highlighting IGF-1 as a biomarker and potential therapeutic target in HF management.MethodsStudies were searched across multiple electronic databases up to January 2024 and independently identified by reviewers. The outcomes were analyzed using RevMan 5.4 and STATA 15.ResultsA total of 25 articles were ultimately included in the analysis. Six studies compared IGF-1 levels between HF patients and non-HF controls, revealing significantly lower IGF-1 levels in HF patients (mean difference −20.93; 95% CI −37.88 to −3.97; p = 0.02). This reduction was consistent across various HF subtypes and severities. In addition, individuals with intermediate IGF-1 levels had a lower risk of developing HF [risk ratio (RR) 0.78; 95% CI 0.74–0.83; p

Bioluminescence is the ability of organisms to emit their own light which can be self-produced in light organs by photogenic cells (photocytes) or symbiotically by bearing cultures of luminous bacteria. Luminous animals are mainly comprised in the ocean, nocturnal coastal shallow-water species or, as the majority of species, inhabiting deep-sea where dim light conditions are optimal for communication by luminous signals. Due to difficult access to species, fisheries of bioluminescent fishes worldwide are rare, mostly for traditional cuisine and fishing bait. Fishes are the only bioluminescent vertebrates and thus their light organs present an astonishing level of complexity for light modulation to adequate light signals for specific ecological roles. Fishes control the output of light intensity using different mechanisms which can be categorized as being under control of hormonal or neuronal pathways. Usually, neural control allows fast and direct response to the photocytes while endocrinal systems allow to control the light produced by bacteria, via manipulation of individual melanophores. In some species, mechanical movement of melanophore-filled tissues by muscular action is under neuronal or hormonal control. Sexual dimorphism of light organs, driven by hormonal regulation during ontogeny, takes a crucial role in communication and reproductive success of these species.

Biomarkers relating to player "stress balance," immunological (ie, immunoglobulin-A), and hormonal (ie, testosterone and cortisol [T:C]) status are now commonly used in football. This article is our critical review of the scientific literature relating to the response of these measures to player load and their relationships with player health. The commonly reported relationship between immunoglobulin-A and training or match load highlights its sensitivity to changes in psychophysiological stress and the increased risk of compromised mucosal immunity. This is supported by its close relationship with symptoms of upper respiratory tract infection and its association with perceived fatigue in football players. Testosterone and cortisol concentrations and the testosterone–cortisol ratio are sensitive to changes in player load, but the direction of their response is often inconsistent and is likely influenced by player training status and non-sport-related stressors. Some evidence indicates that sustained periods of high training volume can increase resting testosterone and that sustained periods of low and high training intensity can increase resting cortisol, compromising the testosterone–cortisol ratio. These findings are noteworthy, as recent findings indicate interrelationships between testosterone, cortisol, and testosterone:cortisol and perceived measures of fatigue, sleep quality, and muscle soreness in football players. Variability in individual responses suggests the need for a multivariate and individualized approach to player monitoring. Overall, we consider that there is sufficient evidence to support the use of salivary immunoglobulin-A, testosterone, cortisol, and testosterone:cortisol measures as part of a multivariate, individualized player monitoring system in professional football. [ABSTRACT FROM AUTHOR]

ObjectivesExogenous estrogen is associated with growth of hepatocellular adenomas (HCAs), although the influence of progestin-only agents is unknown. We therefore evaluated the association of progestin-only agents on HCA progression compared to no hormone exposure and compared to estrogen exposure in female patients.Study designIn this single-center, retrospective cohort study of reproductive-aged female patients (ages 16-45) with diagnosed HCAs between 2003 and 2021, we evaluated radiographic HCA growth during discrete periods of well-defined exogenous hormone exposures.ResultsA total of 34 patients were included. Nineteen (55.9%) had follow-up scans during periods without hormone exposure, 7 (20.6%) during estrogen exposure, and 8 (23.5%) during progestin-only exposure. Over a median follow-up of 11 months, percent change in sum of adenoma diameters from baseline to last available scan was -15.0% with progestin-only agents versus 29.4% with estrogen exposure (p = 0.04), and -7.4% with no hormonal exposure (p = 0.52 compared to progestin-only). Greater than 10% growth was observed in two individuals (25.0%) with progestin-only agent use (one patient on high-dose progestin for menorrhagia) versus five individuals (71.4%) with estrogen use (p = 0.13), and 7 (36.8%) with no exogenous hormone use (p = 0.68 vs progestin-only).ConclusionsDuring discrete periods of progestin-only use, HCA growth overall declined, similar to declining growth during periods without exogenous hormonal exposure. This differed from discrete periods of exogenous estrogen exposure, during which time HCAs demonstrated overall increased growth. Though larger studies are needed, these findings support recent guidance supporting progestin-only agents for female patients with HCAs seeking non-estrogen alternatives for contraception.ImplicationsIn this small retrospective study, we observed overall decrease in HCA size during discrete periods of progestin-only contraception use, similar to that observed during periods without exogenous hormone exposure, supporting their use as a safe alternative to estrogen-containing contraceptives in this patient population.

The objective of this study was to determine the effects of heat stress (HS) on physiological, blood biochemical, and energy metabolism in Dazu black goats. Six wether adult Dazu black goats were subjected to 3 experimental periods: high HS (group H, temperature-humidity index [THI] > 88) for 15 d, moderate HS (group M, THI was 79-88) for 15 d, and no HS (group L, THI < 72) for 15 d. Rectal temperature (RT) and respiratory rate (RR) were determined on d 7 and 15 of each period, and blood samples were collected on d 15 of each period. All goats received glucose (GLU) tolerance test (GTT) and insulin (INS) tolerance test on d 7 and d 10 of each period. The results showed that HS decreased dry matter intake (DMI) and INS concentrations (p < 0.05), and increased RT, RR, non-esterified fatty acid (NEFA), cortisol (COR), and total protein (TP) concentrations (p < 0.05). Compared to group L, the urea nitrogen (BUN) concentration increased and GLU concentration decreased in group H (p < 0.05).During the GTT, the area under the curve (AUC) of GLU concentrations increased by 12.26% (p > 0.05) and 40.78% (p < 0.05), and AUC of INS concentrations decreased by 26.04% and 14.41% (p < 0.05) in groups H and M compared to group L, respectively. The INS concentrations were not significant among the three groups (p > 0.05) during the ITT. A total of 60 differentially expressed metabolites were identified in response to groups H and M. In HS, changes in metabolites related to carbohydrate metabolism and glycolysis were identified (p < 0.05). The metabolites related to fatty acid βoxidation accumulated, glycogenic and ketogenic amino acids were significantly increased, while glycerophospholipid metabolites were decreased in HS (p < 0.05). HS significantly increased 1-methylhistidine, creatinine, betaine, taurine, taurolithocholic acid, inosine, and hypoxanthine, while decreasing vitamin E in blood metabolites (p < 0.05). In summary, HS changed the metabolism of fat, protein, and energy, impaired GLU tolerance, and mainly increased amino acid metabolism to provide energy in Dazu black goats. [ABSTRACT FROM AUTHOR]

Simple Summary: Historically, birth control has been geared toward targeting and subsequently reducing female fertility. The cost of unplanned pregnancies is significant, both in human and veterinary medicine. The development of an effective male contraceptive drug could provide an inclusive approach to the responsible use of contraception. The characteristics of an ideal contraceptive drug include reversibility, high efficacy, minimal adverse side effects, and easy administration. Although this seems like an uphill task, there are a few male contraceptive methods that are currently available, along with substantial interest and research being focused on novel targets. This review uses a comparative medicine approach to succinctly identify and discuss the different types of male contraceptives currently available, while also highlighting newer methods and potential targets for the future development of novel male contraceptives. The last few decades have brought contraception to the forefront of research, with great strides made in effectively targeting and optimizing the physiology, pharmacology, and delivery processes that prevent pregnancy. However, these advances still predominantly target female contraceptives for the prevention of contraception, whereas targeting the male sex has lagged far behind. This has led to a marked deficiency in safe and effective male contraceptive agents, resulting in a heavy dependence on female contraceptives to prevent unwanted and unplanned pregnancies. Current research in the veterinary field and in rodents highlights several promising avenues whereby novel, safe, and effective male contraceptive alternatives are being developed—with an emphasis on reduced side effects and reversibility potential. This review aims to discuss current and novel male contraceptives (both human and veterinary formulations) while highlighting their efficacy, advantages, and disadvantages. [ABSTRACT FROM AUTHOR]

Bioluminescence is the ability of organisms to emit their own light which can be self-produced in light organs by photogenic cells (photocytes) or symbiotically by bearing cultures of luminous bacteria. Luminous animals are mainly comprised in the ocean, nocturnal coastal shallow-water species or, as the majority of species, inhabiting deep-sea where dim light conditions are optimal for communication by luminous signals. Due to difficult access to species, fisheries of bioluminescent fishes worldwide are rare, mostly for traditional cuisine and fishing bait. Fishes are the only bioluminescent vertebrates and thus their light organs present an astonishing level of complexity for light modulation to adequate light signals for specific ecological roles. Fishes control the output of light intensity using different mechanisms which can be categorized as being under control of hormonal or neuronal pathways. Usually, neural control allows fast and direct response to the photocytes while endocrinal systems allow to control the light produced by bacteria, via manipulation of individual melanophores. In some species, mechanical movement of melanophore-filled tissues by muscular action is under neuronal or hormonal control. Sexual dimorphism of light organs, driven by hormonal regulation during ontogeny, takes a crucial role in communication and reproductive success of these species. [ABSTRACT FROM AUTHOR]

PURPOSE: Oral anti-cancer medications are increasingly common and endocrine therapies represent the most common oral anti-cancer medications in breast cancer. Adjuvant endocrine therapies reduce the likelihood of recurrence and mortality in the approximately 80% of women diagnosed with hormone-receptor-positive breast cancer, thus rendering adherence essential. Real-time medication adherence monitors, such as the Wisepill electronic pillbox, transmit adherence data remotely, allowing for early intervention for non-adherence. However, their feasibility and acceptability have yet to be examined among breast cancer survivors taking endocrine therapies. METHODS: This study presents quantitative patient-report and technical support data and qualitative patient acceptability data on Wisepill, a common real-time adherence monitor, among 88 breast cancer survivors prescribed adjuvant endocrine therapy. RESULTS: This mixed-methods study of a common real-time adherence monitor, among the first in breast cancer survivors taking adjuvant endocrine therapy, demonstrates its technical feasibility and patient acceptability. CONCLUSION: The use of wireless medication monitors that transmit real-time adherence data is uniquely promising for maximizing the benefits of adjuvant endocrine therapy by allowing for continuous tracking, ongoing communication with oncologic or research teams, and early intervention. This study demonstrates the feasibility and patient acceptability of one such real-time adherence monitor.

According to the locus coeruleus–norepinephrine (LC–NE) theory, activity of the LC, the major releaser of NE in the brain, regulates inhibitory control. As there is reciprocal communication between circulating epinephrine and the LC, plasma epinephrine is used as the index of LC–NE activity. The aim of this crossover randomized controlled trial is to expand on previous findings by investigating the effects of free‐weight, multiple‐joint, and structural barbell resistance exercises. Previous studies have had some methodological limitations, such as failure to report the process of randomization, absence of resistance exercise familiarization before the maximal strength testing, and lack of protocol publication. To address these issues, this study incorporates resistance exercise familiarization, transparent reporting of randomization, and submission as a registered report. The results suggest that a single session of resistance exercise (barbell squat, press, and deadlift) with an intensity of 65%–78% 1RM for five repetitions (70%–90% relative intensity) and three sets with 3‐min rest intervals improved Stroop congruent reaction time (RT) only (t(27) = −2.663, mean reduction = −15 ms, p =.013, 95% CI [−26, −3]). No significant enhancements were observed in Stroop incongruent RT, inhibitory control as indexed by Stroop effect, or inhibitory control as indexed by the RT difference between the Stroop task and the simple reaction task. Moreover, the alterations in plasma epinephrine levels did not significantly associate with changes in any measure of cognitive performance. By addressing previous methodological limitations and employing a registered report format, this study provides more reliable findings on the effects of acute resistance exercise on cognitive performance. We found that, although acute resistance exercise enhances a certain cognitive outcome measured by the Stroop task, the improvement does not appear to be associated with changes in plasma epinephrine. [ABSTRACT FROM AUTHOR]

Background: As the accessibility and usage of contraception continue to rise, it becomes crucial to thoroughly investigate how contraception affects the restoration of fertility after discontinuation. Aim of the study: To evaluate any potential connections between the usage of hormonal contraceptives and intrauterine devices and secondary infertility. Subjects and method: In Salah Al-Deen General Hospital, between January 1 and June 30, 2023, crosssectional research was conducted to enrol 100 women, a nonprobability practical sampling technique was adopted, who presented after one year after intrauterine contraceptive devices removal (including hormonal and non-hormonal), removal of contraceptive implants, and stopping the use of oral contraceptive pills and contraceptive injections. Results: About 86% got pregnant within one year after the discontinuation of contraception. Secondary infertility and the prevalence of contraceptive complications were significantly associated (P-value = 0.042). Among those who got pregnancy, a significant positive correlation was obtained between the duration of contraception use and the time to get pregnant (Pvalue =0.023). Conclusion: The incidence of secondary infertility was 14%. There was a significant correlation between the existence of complications and the frequency of secondary infertility. The type and duration of the contraception did not significantly impact the incidence of secondary infertility but among those who got pregnant within one year, the length of contraceptive use and the time it took to become pregnant were significantly correlated. [ABSTRACT FROM AUTHOR]

PURPOSE: Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor-positive breast cancer has not been confirmed. PATIENTS AND METHODS: In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer-free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival. RESULTS: Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial. CONCLUSION: At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor-positive breast cancer.

Genomic analysis has recently identified multiple ESR1 gene translocations in estrogen receptor alpha-positive (ERα+) metastatic breast cancer (MBC) that encode chimeric proteins whereby the ESR1 ligand binding domain (LBD) is replaced by C-terminal sequences from many different gene partners. Here we functionally screened 15 ESR1 fusions and identified 10 that promoted estradiol-independent cell growth, motility, invasion, epithelial-to-mesenchymal transition, and resistance to fulvestrant. RNA sequencing identified a gene expression pattern specific to functionally active ESR1 gene fusions that was subsequently reduced to a diagnostic 24-gene signature. This signature was further examined in 20 ERα+ patient-derived xenografts and in 55 ERα+ MBC samples. The 24-gene signature successfully identified cases harboring ESR1 gene fusions and also accurately diagnosed the presence of activating ESR1 LBD point mutations. Therefore, the 24-gene signature represents an efficient approach to screening samples for the presence of diverse somatic ESR1 mutations and translocations that drive endocrine treatment failure in MBC. SIGNIFICANCE: This study identifies a gene signature diagnostic for functional ESR1 fusions that drive poor outcome in advanced breast cancer, which could also help guide precision medicine approaches in patients harboring ESR1 mutations.

PurposeTo update recommendations of the ASCO systemic therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC) guideline.MethodsAn Expert Panel conducted a systematic review to identify new, potentially practice-changing data.ResultsFifty-one articles met eligibility criteria and form the evidentiary basis for the recommendations.RecommendationsAlpelisib in combination with endocrine therapy (ET) should be offered to postmenopausal patients, and to male patients, with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, ABC, or MBC following prior endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor. Clinicians should use next-generation sequencing in tumor tissue or cell-free DNA in plasma to detect PIK3CA mutations. If no mutation is found in cell-free DNA, testing in tumor tissue, if available, should be used as this will detect a small number of additional patients with PIK3CA mutations. There are insufficient data at present to recommend routine testing for ESR1 mutations to guide therapy for HR-positive, HER2-negative MBC. For BRCA1 or BRCA2 mutation carriers with metastatic HER2-negative breast cancer, olaparib or talazoparib should be offered in the 1st-line through 3rd-line setting. A nonsteroidal aromatase inhibitor (AI) and a CDK4/6 inhibitor should be offered to postmenopausal women with treatment-naïve HR-positive MBC. Fulvestrant and a CDK4/6 inhibitor should be offered to patients with progressive disease during treatment with AIs (or who develop a recurrence within 1 year of adjuvant AI therapy) with or without one line of prior chemotherapy for metastatic disease, or as first-line therapy. Treatment should be limited to those without prior exposure to CDK4/6 inhibitors in the metastatic setting.Additional information can be found at www.asco.org/breast-cancer-guidelines.

PurposeThe US National Cancer Institute Moonshot initiative calls for improving analysis and reporting of toxicity to inform treatment tolerability. We used existing clinician-reported adverse event (AE) and patient-reported outcome (PRO) questionnaire data from the randomized, double-blind NSABP B-35 clinical trial to explore reasons for anastrozole and tamoxifen discontinuation.MethodsPostmenopausal women with ductal carcinoma in situ treated with breast-conserving therapy were randomly assigned to anastrozole or tamoxifen for 5 years. The primary outcome for this analysis was time to treatment discontinuation. AEs were collected every 6 months post-random assignment from all 3,104 participants and summarized using the Toxicity Index (TI). PRO data were collected at baseline and every 6 months from 1,194 participants. Univariate and multivariable analyses of time to treatment discontinuation were performed using Cox regression models with TIs and PROs as time-dependent covariates.ResultsOf 3,046 analyzed participants, 869 (28.5%) discontinued treatment prematurely. In multivariable analysis, when both baseline PROs and on-treatment AEs were considered, thrombosis and arthralgia AEs were associated with discontinuation of both tamoxifen and anastrozole; additional AEs associated with discontinuation varied by drug. In addition, baseline pain interference, hot flashes, and unhappiness were associated with tamoxifen discontinuation (n = 589; overall Harrell's C-statistic 0.686 [95% CI, 0.640 to 0.732]); no baseline PROs were associated with anastrozole discontinuation (n = 589; overall Harrell's C-statistic 0.656 [95% CI, 0.630 to 0.681]). When only baseline PROs were examined, pain interference, hot flashes, and unhappiness were associated with shorter time to discontinuation of tamoxifen; only hot flashes were associated with discontinuation of anastrozole.ConclusionAnalysis of AEs using the TI yielded important insights into reasons for discontinuation of endocrine therapy that was enhanced by the addition of PRO baseline and treatment-emergent symptoms.

PurposeSerum thymidine kinase 1 (sTK1) activity is associated with poor prognosis in metastatic breast cancer (MBC). We assessed the prognostic effect of sTK1 in patients with hormone receptor-positive MBC treated on a prospective randomized trial of anastrozole (A) versus A plus fulvestrant (A + F).Patients and methodssTK1 was assessed in 1,726 serums [baseline (BL), cycles 2, 3, 4, and 7] using the DiviTum assay. A prespecified cutoff of ≥200 Du/L was considered high. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier, log-rank tests, and Cox regression.ResultsBL sTK1 was elevated in 171 (40%) of 432 patients. Patients with high versus low BL sTK1 had significantly worse PFS [median 11.2 vs. 17.3 months, HR = 1.76; 95% confidence interval (CI; 1.43-2.16); P < 0.0001] and OS [median 30 vs. 58 months, HR = 2.38; 95% CI (1.91-2.98); P < 0.0001]. OS was significantly better for patients with high sTK1 who did not have prior adjuvant tamoxifen and who received A + F versus A alone [median 46 vs. 21 months, HR = 0.58; 95% CI (0.38-0.87); P = 0.0087]. Patients with low sTK1 had no difference in outcomes by therapy (P = 0.44). At serial timepoints, high versus low sTK1 had significantly worse subsequent PFS and OS [at cycle 2: PFS HR = 1.70, 95% CI (1.34-2.17); P < 0.0001, OS HR = 2.51, 95% CI (1.93-3.26); P < 0.0001].ConclusionsHigh sTK1 at BL and subsequent timepoints is associated with worse prognosis in patients with MBC starting first-line endocrine therapy (ET). Patients with low sTK1 at BL have comparable outcomes on single-agent or combination ET.

PurposeThis analysis evaluated the genomic landscape of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer and the association of genetic alterations with response to ribociclib in the phase III MONALEESA-7 trial.MethodsPremenopausal patients were randomly assigned 1:1 to receive endocrine therapy plus ribociclib or placebo. Plasma collected at baseline was sequenced using targeted next-generation sequencing for approximately 600 relevant cancer genes. The association of circulating tumor DNA alterations with progression-free survival (PFS) was evaluated to identify biomarkers of response and resistance to ribociclib.ResultsBaseline circulating tumor DNA was sequenced in 565 patients; 489 had evidence of ≥ 1 alteration. The most frequent alterations included PIK3CA (28%), TP53 (19%), CCND1 (10%), MYC (8%), GATA3 (8%), receptor tyrosine kinases (17%), and the Chr8p11.23 locus (12%). A treatment benefit of ribociclib was seen with wild-type (hazard ratio [HR] 0.45 [95% CI, 0.33 to 0.62]) and altered (HR 0.57 [95% CI, 0.36 to 0.9]) PIK3CA. Overall, patients with altered CCND1 had shorter PFS regardless of treatment, suggesting CCND1 as a potential prognostic biomarker. Benefit with ribociclib was seen in patients with altered (HR 0.21 [95% CI, 0.08 to 0.54]) or wild-type (HR 0.52 [95% CI, 0.39 to 0.68]) CCND1, but greater benefit was observed with altered, suggesting predictive potential of CCND1. Alterations in TP53, MYC, Chr8p11.23 locus, and receptor tyrosine kinases were associated with worse PFS, but ribociclib benefit was independent of alteration status.ConclusionIn this study-to our knowledge, the first large study of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer-multiple genomic alterations were associated with poor outcome. A PFS benefit of ribociclib was observed regardless of gene alteration status, although in this exploratory analysis, a magnitude of benefits varied by alteration.

Abstract Background Globally, hormonal contraceptives have proved to be effective in the prevention of unwanted pregnancies. However, despite evidence of the many benefits associated with the use of hormonal contraceptives, concerns related to their safety and side effects have been reported. We conducted a study to explore the perspectives on the side effects of hormonal contraceptives among women of reproductive age in Kitwe district of Zambia. Methods An explorative qualitative study was done among 32 women of reproductive age (18–45 years). Participants were selected conveniently as they accessed family planning services at a designated reproductive, maternal, and child health facility. Data collection was done through in-depth interviews (IDIs). Recruitment of participants and data collection continued until the saturation point was reached. The interviews were recorded, translated, and transcribed verbatim. Data were imported into NVivo.x64 for coding and node generation after which categories and themes were developed manually. Results Overall, participants demonstrated a considerable amount of knowledge of family planning, recounting the economic and health benefits as well as demerits of family planning use. The main reasons for discontinuing and switching hormonal contraceptive methods were the desire to get pregnant and the fear of unpleasant side effects, including excessive bleeding or prolonged menstruation, headache, dizziness, lower abdominal/back pain, and weight gain. Most importantly, participants cited concerns about the delay in the resumption of fertility after the termination of contraception and how the side effects disrupted their daily activities at home. Conclusion There is a need for family planning providers to offer family planning services that address the side effects of hormonal contraceptives during counselling and how women can manage them. Family planning services should adopt a patient-centred approach that takes into consideration the concerns regarding side effects and how this affects the quality of life among women. Also, there is a need to extend family planning services to include scheduled follow-ups and clinical management of contraceptive side effects among women.

Background: In recent years, new combined oral contraceptives (COCs) have become available, representing an advance in terms of individualization and compliance by users. Objective: To provide recommendations regarding COCs: formulations, use, efficacy, benefits and safety. Method: For these recommendations, we have used the modified Delphi methodology and carried out a systematic review of studies found in the literature and reviews performed in humans, published in English and Spanish in Pubmed, Medline and advanced medicine and computer networks until the year 2021, using the combination of terms: 'oral contraceptives', 'estroprogestins' and 'combined oral contraceptives'. Results: Regarding the estrogen component, initially switching from mestranol (the pro-drug of ethinylestradiol) to ethinylestradiol (EE) and then reducing the EE dose helped reduce side effects and associated adverse events. Natural estradiol and estradiol valerate are already available and represent a valid alternative to EE. The use of more potent 19-nortestosterone-derived progestins, in order to lower the dose and then the appearance of non-androgenic progestins with different endocrine and metabolic characteristics, has made it possible to individualize the prescription of COC according to the profile of each woman. Conclusion: Advances in the provision of new COCs have improved the risk/benefit ratio by increasing benefits and reducing risks. Currently, the challenge is to tailor contraceptives to individual needs in terms of safety, efficacy, and protection of female reproductive health. [ABSTRACT FROM AUTHOR]

Objective: Polycystic Ovary Syndrome is the most prevalent hormonal disorder in females. Over the years, metformin (MET) has become the first-line choice of treatment; however, due to its gastrointestinal side effects, a more recent drug, myo-inositol (MI), has been introduced. We aim to conduct a systematic review and meta-analysis to compare the effects of MET and MI on hormonal and metabolic parameters. Materials and methods: Authors extensively searched PubMed, Scopus, Cochrane Library, Google Scholar, and Web of Science for randomized clinical trials (RCTs) until August 2021. Eight (n = 8) articles were included, with a total sample size of 1088, of which 460 patients received MET, 436 received MI, and 192 received a combination of both. Standard mean differences (SMDs) and Confidence Intervals (CIs) were used for data synthesis, and forest plots were made using Review Manager 5.4 for Statistical Analysis using the random-effect model. Results: The meta-analysis indicates that there is no significant difference between MET and MI in terms of their effects on BMI (SMD = 0.16, 95% CI: − 0.11 to 0.43, p = 0.24), fasting insulin (SMD = 0.00, 95% CI: − 0.26 to 0.27, p = 0.97), fasting blood sugar (SMD = 0.11, 95% CI: − 0.31to 0.53, p = 0.60), HOMA index (SMD = 0.09, 95% CI: − 0.20 to 0.39, p = 0.50), and LH/FSH (SMD = 0.20, 95% CI: − 0.24 to 0.64, p = 0.37). BMI, fasting blood sugar, and LH/FSH ratio reported moderate heterogeneity because of the varying number of study participants. Conclusion: Our meta-analysis comparing hormonal and metabolic parameters between MET and MI did not show much significant difference, indicating both drugs are equally beneficial in improving metabolic and hormonal parameters in patients with PCOS. [ABSTRACT FROM AUTHOR]

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Tamoxifen has been used for years for treating estrogen receptor-positive breast cancer; drug resistance, however, constitutes one of the main challenges for this therapy. We found that the protein expression level of ATF3 is significantly higher in tamoxifen-resistant (TamR) MCF-7 cells than the corresponding parental cancer cells. In addition, ATF3 protein expression is positively correlated with the resistance of TamR MCF-7 cells to 4-hydroxytamoxifen (4-OHT). Mechanistically, elevated ATF3 protein expression in TamR MCF-7 cells results from a lower level of expression of YTHDF2, an m6A reader protein, and the ensuing stabilization and increased translational efficiency of ATF3 mRNA. Additionally, TamR MCF-7 cells exhibited decreased methylation at A131, a consensus motif site for m6A, in the 5-untranslated region (5-UTR) of ATF3 mRNA. Moreover, augmented ATF3 stimulates the expression of ABCB1, an efflux pump that confers drug resistance in breast cancer cells, and ATF3 itself is also positively regulated by adenylate kinase 4. Together, our results uncovered a novel molecular target for m6A modification (i.e., ATF3 mRNA) and the epitranscriptomic regulator for this target (i.e., YTHDF2). We also illustrated the role of ATF3 in drug resistance, revealed its downstream target (i.e., ABCB1), and suggested ATF3 as a candidate therapeutic target for overcoming drug resistance in cancer cells.

Lessons learnedFulvestrant is a selective estrogen receptor (ER)-downregulating antiestrogen that blocks ER transcriptional activity and is approved for ER-positive breast cancer. Fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models.BackgroundFulvestrant is a selective estrogen receptor (ER)-downregulating antiestrogen that blocks ER transcriptional activity and is approved for ER-positive (+) breast cancer. Fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models.MethodsThis is a single-center phase Ib study with a 3+3 design of fulvestrant and the proteasome inhibitor ixazomib (MLN9708) in patients with advanced ER+ breast cancer that was progressing on fulvestrant. A dose-escalation design allowed establishment of the ixazomib maximum tolerated dose (MTD). Secondary objectives included progression-free survival, pharmacokinetics, and tumor molecular analyses.ResultsAmong nine evaluable subjects, treatment was well-tolerated without dose-limiting toxicities The MTD of ixazomib was 4 mg in combination with fulvestrant. Plasma concentrations of the active form of ixazomib (MLN2238) in the 4-mg dose cohort had a median (range) maximal concentration (Cmax ) of 155 (122-171) ng/mL, time of maximal concentration (Tmax ) of 1 (1-1.5) hour, terminal elimination half-life of 66.6 (57.3-102.6) hour after initial dose, and area under the curve (AUC) of 5,025 (4,160-5,345) ng*h/mL. One partial response was observed, and median progression-free survival was 51 days (range, 47-137).ConclusionThis drug combination has a favorable safety profile and antitumor activity in patients with fulvestrant-resistant advanced ER+ breast cancer that justifies future testing.

PURPOSE: To develop guideline recommendations concerning optimal neoadjuvant therapy for breast cancer. METHODS: ASCO convened an Expert Panel to conduct a systematic review of the literature on neoadjuvant therapy for breast cancer and provide recommended care options. RESULTS: A total of 41 articles met eligibility criteria and form the evidentiary basis for the guideline recommendations. RECOMMENDATIONS: Patients undergoing neoadjuvant therapy should be managed by a multidisciplinary care team. Appropriate candidates for neoadjuvant therapy include patients with inflammatory breast cancer and those in whom residual disease may prompt a change in therapy. Neoadjuvant therapy can also be used to reduce the extent of local therapy or reduce delays in initiating therapy. Although tumor histology, grade, stage, and estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) expression should routinely be used to guide clinical decisions, there is insufficient evidence to support the use of other markers or genomic profiles. Patients with triple-negative breast cancer (TNBC) who have clinically node-positive and/or at least T1c disease should be offered an anthracycline- and taxane-containing regimen; those with cT1a or cT1bN0 TNBC should not routinely be offered neoadjuvant therapy. Carboplatin may be offered to patients with TNBC to increase pathologic complete response. There is currently insufficient evidence to support adding immune checkpoint inhibitors to standard chemotherapy. In patients with hormone receptor (HR)-positive (HR-positive), HER2-negative tumors, neoadjuvant chemotherapy can be used when a treatment decision can be made without surgical information. Among postmenopausal patients with HR-positive, HER2-negative disease, hormone therapy can be used to downstage disease. Patients with node-positive or high-risk node-negative, HER2-positive disease should be offered neoadjuvant therapy in combination with anti-HER2-positive therapy. Patients with T1aN0 and T1bN0, HER2-positive disease should not be routinely offered neoadjuvant therapy.Additional information is available at www.asco.org/breast-cancer-guidelines.

To our knowledge, no study has evaluated the quality of control groups in randomised controlled trials of multiple myeloma. We aimed to do a systematic review of randomised controlled trials of multiple myeloma to ascertain the quality of the control groups used. PubMed (MEDLINE), Embase, Cochrane Controlled Register of Trials, and CinicalTrials.gov were searched for articles of randomised controlled trials of multiple myeloma based in the USA that initiated participant enrolment between Jan 1, 2010, and June 30, 2020. A control group regimen was considered to be inferior if a previous randomised controlled trial had shown an improved progression-free survival versus the control group before enrolment. Of 49 identified randomised controlled trials, seven (14%) began enrolling patients into inferior control groups after an existing superior regimen to the control had already been published. Nine (18%) of the 49 trials continued enrolment on substandard control groups after data emerged during the study enrolment period. The median time that newer data emerged regarding inferiority of the control group from the time a trial first enrolled a patient was 13 months (IQR 8-29 months). 12 (75%) of these 16 randomised controlled trials are published, and nine (75%) of the 12 published trials had overlapping investigators with trials that had previously shown the inferiority of the control group being used. Greater scrutiny on the quality of control groups in randomised controlled trials of multiple myeloma is needed.

Background. The most frequent female reproductive system tumors are uterine leiomyoma (UL). They are benign monoclonal tumors of uterine smooth muscle. They affect reproductive-age women with a lifetime prevalence of 3070%. UL is a disease with complex etiology determined by many genetic and environmental factors. Despite the frequency of UL, there is no long-term, cost-effective or fertility-preserving therapy option for it. Aim. To summarize the available literature data on the etiopathogenesis of uterine fibroids as well as the risk factors for the development of this disease. Materials and methods. The PubMed, Scopus, and Web of science literature databases were searched for relevant articles using such keywords as uterine fibroids, UL, association, genetic and hormonal factors, gene, etiology in various combinations. Results. Genetic disorders and hormonal and growth factors all have a part in the etiology of UL, and studies have resulted to the use of hormone therapy for fibroids, with varying results. Recent findings on the etiopathogenesis of UL, as well as the introduction of relevant genetically modified mouse models of UL, have rekindled interest in the disease. In this review, the basic features of fibroids are discussed, as well as the primary contributors to UL etiopathogenesis, including as genetic, hormonal, and growth causes. Besides the risk factors that contribute to the development of UL. Conclusion. Many questions about the causes and mechanisms of development factors that predispose remain unanswered, necessitating the continuation of these studies in order to obtain new information. Prospective studies are needed to better understand the biology and epidemiological associations, both to better understand modifiable risk factors and to shed light on the etiopathogenesis of this disease.

BACKGROUND: The 2015 American Society of Clinical Oncology guidelines recommend first-line treatment of hormone receptor (HR)-positive breast cancer with endocrine therapy plus or minus palbociclib, a selective cyclin-dependent kinase (CDK)4/6 inhibitor. In 2018, the U.S. Food and Drug Administration approved ribociclib, a new orally available selective CDK4/6 inhibitor. While gains in progression-free survival (PFS) and overall survival (OS) from ribociclib are important for clinical and treatment outcomes, trade-offs in adverse events (AEs) and additional costs necessitate cost-effectiveness analysis (CEA) to assist consideration by third-party payer systems, physicians, and patients. OBJECTIVES: To (a) develop a Markov model and (b) determine the cost-effectiveness of ribociclib plus endocrine therapy versus endocrine therapy alone as treatment for premenopausal and perimenopausal patients with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS: A lifetime 3-state Markov model (stable, progressed, and dead health states) was developed using a U.S. payer perspective. Transition probabilities were calculated based on OS and PFS outcomes from the randomized controlled phase 3 trial MONALEESA-7. These Kaplan-Meier curves were extended to lifetime by estimating best-fit distributions using loglogistic distribution for ribociclib curves and Weibull distribution for placebo curves. Costs were obtained from national data sources using 2019 U.S. dollars (USD) and discounted by 3%. Utilities were obtained via published breast cancer literature and were included for each health state and for time spent with each AE. Results were expressed as an incremental cost-effectiveness ratio (ICER) expressed as USD per quality-adjusted life-year (QALY) saved. Treatments were assumed to be cost-effective based on a willingness-to-pay (WTP) threshold of $150,000 per QALY gained. Base-case, 1-way sensitivity tornado diagrams and probabilistic sensitivity analyses demonstrated changes in the ICER and were driven by the cost of ribociclib and the utility of remaining in the stable health state. RESULTS: Ribociclib plus endocrine therapy was cost-effective at an ICER of $124,513 per QALY when compared with endocrine therapy alone at a WTP threshold of $150,000. The ribociclib plus endocrine therapy arm had an effectiveness of 5.28 QALYs and a total cost of $385,112, while placebo plus endocrine therapy provided only 2.46 QALYs at a lower total cost of $67.246. The model was sensitive to the cost of ribociclib and the utility of time spent in the stable health state. Probabilistic sensitivity analysis demonstrated that endocrine therapy alone was cost-effective until a WTP of $125,000 and was cost-effective 72% of the time at the WTP threshold. CONCLUSIONS: Ribociclib plus endocrine therapy is more cost-effective than endocrine therapy alone. Professionals in managed care settings should consider the pharmacoeconomic benefits of ribociclib for the treatment of HR-positive, HER2-negative breast cancer as they make value-based formulary decisions. Further CEAs should be considered as direct treatment comparison trials between CDK4/6 inhibitors are completed in the future. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose.

PurposeMany patients with hormone receptor-positive (HR+) breast cancer do not adhere to endocrine therapy (ET), and treatment-related side effects are often discussed by participants in online breast cancer forums. Our aim was to survey this unique group of patients about their ET-related experiences.MethodsWe partnered with patients active in breast cancer social media communities to develop a survey assessing ET-related side effects and medical team communication. Patients with a history of HR+ breast cancer who had received a recommendation to take ET were eligible to participate in the anonymous, online survey.ResultsRespondents included 2353 women and 54 men. Aromatase inhibitors were the most commonly used medication. Side effects were reported by 91.2%, were more often experienced by women than men (p

Although hormonal therapy (HT) inhibits the growth of hormone receptor-positive (HR+) breast and prostate cancers, HT resistance frequently develops within the complex metastatic microenvironment of the host organ (often the bone), a setting poorly recapitulated in 2D culture systems. To address this limitation, we cultured HR+ breast cancer and prostate cancer spheroids and patient-derived organoids in 3D extracellular matrices (ECM) alone or together with bone marrow stromal cells (BMSC). In 3D monocultures, antiestrogens and antiandrogens induced anoikis by abrogating anchorage-independent growth of HR+ cancer cells but exhibited only modest effects against tumor cells residing in the ECM niche. In contrast, BMSC induced hormone-independent growth of breast cancer and prostate cancer spheroids and restored lumen filling in the presence of HR-targeting agents. Molecular and functional characterization of BMSC-induced hormone independence and HT resistance in anchorage-independent cells revealed distinct context-dependent mechanisms. Cocultures of ZR75-1 and LNCaP with BMSCs exhibited paracrine IL6-induced HT resistance via attenuation of HR protein expression, which was reversed by inhibition of IL6 or JAK signaling. Paracrine IL6/JAK/STAT3-mediated HT resistance was confirmed in patient-derived organoids cocultured with BMSCs. Distinctly, MCF7 and T47D spheroids retained ER protein expression in cocultures but acquired redundant compensatory signals enabling anchorage independence via ERK and PI3K bypass cascades activated in a non-IL6-dependent manner. Collectively, these data characterize the pleiotropic hormone-independent mechanisms underlying acquisition and restoration of anchorage-independent growth in HR+ tumors. Combined analysis of tumor and microenvironmental biomarkers in metastatic biopsies of HT-resistant patients can help refine treatment approaches. SIGNIFICANCE: This study uncovers a previously underappreciated dependency of tumor cells on HR signaling for anchorage-independent growth and highlights how the metastatic microenvironment restores this malignant property of cancer cells during hormone therapy.

Adjuvant tamoxifen therapy improves survival in breast cancer patients. Unfortunately, long-term treatment comes with side effects that impact health and quality of life, including hot flashes, changes in bone density, and fatigue. Partly due to a lack of proven animal models, the tissues and cells that mediate these negative side effects are unclear. Here, we show that mice undergoing tamoxifen treatment experience changes in temperature, bone, and movement. Single-cell RNA sequencing reveals that tamoxifen treatment induces widespread gene expression changes in the hypothalamus and preoptic area (hypothalamus-POA). These expression changes are dependent on estrogen receptor alpha (ERα), as conditional knockout of ERα in the hypothalamus-POA ablates or reverses tamoxifen-induced gene expression. Accordingly, ERα-deficient mice do not exhibit tamoxifen-induced changes in temperature, bone, or movement. These findings provide mechanistic insight into the effects of tamoxifen on the hypothalamus-POA and indicate that ERα mediates several physiological effects of tamoxifen treatment in mice.

The last few decades have brought contraception to the forefront of research, with great strides made in effectively targeting and optimizing the physiology, pharmacology, and delivery processes that prevent pregnancy. However, these advances still predominantly target female contraceptives for the prevention of contraception, whereas targeting the male sex has lagged far behind. This has led to a marked deficiency in safe and effective male contraceptive agents, resulting in a heavy dependence on female contraceptives to prevent unwanted and unplanned pregnancies. Current research in the veterinary field and in rodents highlights several promising avenues whereby novel, safe, and effective male contraceptive alternatives are being developed—with an emphasis on reduced side effects and reversibility potential. This review aims to discuss current and novel male contraceptives (both human and veterinary formulations) while highlighting their efficacy, advantages, and disadvantages.

Background: In recent years, new combined oral contraceptives (COCs) have become available, representing an advance in terms of individualization and compliance by users.Objective: To provide recommendations regarding COCs: formulations, use, efficacy, benefits and safety.Method: For these recommendations, we have used the modified Delphi methodology and carried out a systematic review of studies found in the literature and reviews performed in humans, published in English and Spanish in Pubmed, Medline and advanced medicine and computer networks until the year 2021, using the combination of terms: ‘oral contraceptives’, ‘estroprogestins’ and ‘combined oral contraceptives’.Results: Regarding the estrogen component, initially switching from mestranol (the pro-drug of ethinylestradiol) to ethinylestradiol (EE) and then reducing the EE dose helped reduce side effects and associated adverse events. Natural estradiol and estradiol valerate are already available and represent a valid alternative to EE. The use of more potent 19-nortestosterone-derived progestins, in order to lower the dose and then the appearance of non-androgenic progestins with different endocrine and metabolic characteristics, has made it possible to individualize the prescription of COC according to the profile of each woman.Conclusion: Advances in the provision of new COCs have improved the risk/benefit ratio by increasing benefits and reducing risks. Currently, the challenge is to tailor contraceptives to individual needs in terms of safety, efficacy, and protection of female reproductive health.

Sleep is a fundamental biological behavior that affects various aspects of health and wellbeing. However, there are some differences in respect of sleep between men and women. Notably, there are sex differences in relation to sleep problems and the potential comorbidities, such as diabetes and cardiovascular diseases, that are associated with these problems, with some evidence suggesting that women may have a greater predisposition to sleep disturbances. This narrative review provides a comprehensive analysis of the literature in respect of sex differences in the sleep, with the main focus being on women. Basic research has investigated sex-specific distinctions in sleep architecture, sleep quality, and circadian rhythms, while clinical studies have examined sex differences in sleep disorders, such as insomnia, sleep apnea, and restless leg syndrome. This narrative review also highlights the impact of the periods of hormonal fluctuations that occur across a woman's lifespan - such as during the menstrual cycle, pregnancy, and menopause phase - and examines their effects on sleep. It also explores the influence of social and cultural factors on sleep patterns in women. Taken together, the evidence suggests that women may be more susceptible to sleep disturbance, and that gender-specific factors should be considered when evaluating sleep in clinical practice. Further research is warranted to elucidate the mechanisms that underlie this and help guide the development of sex-specific interventions to improve sleep quality and promote holistic health in women.

ABSTRACT Objective To describe the epidemiological aspects of COVID-19 in patients with prostate cancer who received androgen deprivation therapy and those who did not. Methods We retrospectively analyzed the medical records of patients with prostate cancer undergoing androgen deprivation therapy and those who did not undergo androgen deprivation therapy. These patients were treated at the A.C.Camargo Cancer Center between March 2020 and March 2021. Results Of the 78 patients with prostate cancer and positive RT-PCR test results, 50% were undergoing androgen deprivation therapy, and 49% were experiencing a non-metastatic biochemical relapse. Of these, 80.6% were symptomatic on the day of examination compared to 97.2% in the Control Group. A total of 82.1% of the patients receiving androgen deprivation therapy required hospitalization, with 30.8% admitted to the intensive care unit compared to 21.6% in the Control Group. There was no statistically significant difference in the use of a high-flow oxygen cannula, the need for orotracheal intubation and mechanical ventilation, the need for dialysis, multiple organ failure, or death. A significant difference was found between the groups in terms of the average length of stay in the intensive care unit. Conclusion Androgen deprivation therapy was not associated with protective factors or potential treatments in patients with prostate cancer and COVID-19. Although the number of patients analyzed was limited, and there may have been a selection bias, this is a unique study that cannot be expanded or replicated in similar (unvaccinated) populations.