Associations of AMH in mid-reproductive years with bone mineral density and turnover markers in mid-life.

CONTEXT: Concentration of circulating anti-Müllerian hormone (AMH) predicts short-term (3-5 years) bone loss around menopause. Whether AMH during mid-reproductive years predicts bone health over a decade later is unknown. OBJECTIVE: To study the association of AMH levels in mid-reproductive years with bone density and turnover biomarkers measured after ∼14 years of follow-up. METHODS: We assessed plasma AMH in 2003-2006 (mean 37.0 years, SD 5.1) among 450 parous women (71% White) in a US longitudinal cohort, and bone mineral density (BMD; spine, hip, and femoral neck, measured by dual-energy X-ray absorptiometry) in 2017-2021 (mean 51.0 years, SD 5.1). Secondary outcomes were plasma levels of procollagen type I N-propeptide (PINP) and C-terminal telopeptide I (CTX-I). RESULTS: In linear regression models adjusted for demographics and lifestyle, compared to women with AMH >3.5 ng/mL, those with AMH <1.0 ng/mL had lower BMD (g/cm2) at follow-up (beta [95% CI]: spine: -0.06 [-0.10, -0.02]; hip: -0.05 [-0.08, -0.02]; femoral neck: -0.03 [-0.06, 0.00]) and higher bone turnover markers (beta [95% CI]: PINP: 0.36 SD [0.10, 0.63]; CTX-I: 0.34 SD [0.07, 0.60]). The association of AMH with spine BMD was more pronounced among post-menopausal women, in contrast to associations with bone turnover markers which were more pronounced among women who had not yet reached menopause. The associations between AMH and BMD were primarily mediated by menopausal status at follow-up. CONCLUSIONS: Lower AMH during mid-reproductive years is associated with lower BMD and higher bone turnover 14 years later. Ovarian reserve during mid-reproductive years may be a valuable predictor of long-term bone health.

Assessment of the efficacy of a gonadotropin releasing factor (GnRF) analog to suppress ovarian function in gilts under pre-clinical and clinical conditions.

BACKGROUND: The administration of a gonadotropin releasing factor (GnRF) analog to pigs has proven to induce antibodies against endogenous GnRF. In gilts (young female pigs), the subsequent blocking of GnRF activity by specific antibodies results in a temporary suppression of ovarian activity and sexual maturation. One pre-clinical and two clinical studies were conducted to assess the ability of the GnRF analog to produce immunologically suppression of the ovarian function, preventing gilts from reaching puberty before harvest, at 27 weeks of age. RESULTS: In the three studies, a significant reduction of size and weight of reproductive organs and gilts in oestrus was demonstrated in vaccinated gilts compared with intact gilts. A significant increase in anti-GnRF antibody levels in sera was observed after the 2nd dose, which lasted until the end of the study in each of the protocols used. Progesterone levels were significantly reduced from 6 to 8 weeks after 2nd vaccination in clinical studies 2 and 1 respectively, and from 6 weeks after 2nd vaccination in the pre-clinical study. Estradiol levels were below the limit of detection for clinical study 2 and significantly reduced in vaccinated gilts at the end of the pre-clinical study and the clinical study 1. CONCLUSIONS: Vaccination of gilts with a GnRF analog with two different protocols (1st dose from 10 to 14 weeks of age, and a 2nd dose 8 or 4 weeks later) was effective in reducing the development of puberty for at least 9 weeks post 2nd dose. These results confirm the flexibility of vaccination programs for veterinarians and producers which can be adapted to pig management practices in commercial farms.

Updates in Systemic Treatment of Hormone Receptor-Positive Early-Stage Breast Cancer.

OPINION STATEMENT: Hormone-receptor positive (HR +) and human epidermal growth factor receptor 2 (HER2) negative early breast cancer (eBC) is a heterogeneous disease with several contributing factors for increased risk of recurrence, including tumor features, individual biomarkers, and genomic risk. The current standard approach in the management of HR + /HER2neg eBC includes chemotherapy and endocrine therapy (ET), and additional therapies based on risk profile, menopausal status, and genetics are sometimes appropriate. The risk of recurrence is more pronounced in patients with high-risk eBC including large tumor size, nodal involvement, high proliferative index, and genetic predisposition. In premenopausal patients with high-risk eBC, ovarian function suppression in combination with adjuvant ET improves survival. In postmenopausal patients, extended aromatase inhibitor (AI) therapy can be considered. Recent trials have identified novel treatment approaches to reduce the risk of recurrence in high-risk HR + /HER2neg eBC including the addition of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to adjuvant ET. For patients with germline BRCA1/BRCA2 mutations, adjuvant poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have been shown to improve overall survival (OS). However, despite these recent advances, the risk of recurrence remains substantial, highlighting an area of unmet need. There are several ongoing clinical trials further investigating the role of CDK 4/6 inhibitors and immunotherapy in high-risk HR + /HER2neg eBC.

Proanthocyanidins protects 3-NPA-induced ovarian function decline by activating SESTRIN2-NRF2-mediated oxidative stress in mice.

Abnormal apoptosis of ovarian cells caused by oxidative stress is an important cause of premature ovarian failure (POF). Previous studies revealed that proanthocyanidins (PCs) are powerful natural antioxidants that can safely prevent oxidative damage in humans. However, the protective effect and mechanism of PCs on ovarian function during the course of POF remain unknown. In this study, female mice were injected with 3-nitropropionic acid (3-NPA) to establish an ovarian oxidative stress model; at the same time, the mice were treated with PC via gavage. Thereafter, the expression of various apoptosis genes, hormones, and related molecules was assessed. Compared with those in the control group, the ovarian index, follicle count at all levels, expression of MVH, PCNA and BCL2, and estradiol (E2) and progesterone (P) levels were significantly lower in the POF group, but significant recovery was observed in terms of MVH and PCNA expression and E2 and P levels in the POF + PCs group. The apoptosis marker genes BAX and ROS were significantly increased in the POF group but were notably restored in the POF + PCs group. In addition, the expression of Sestrin2, an antiapoptotic protein, was significantly increased in the PCs treatment group, as were the upstream and downstream regulatory factors NRF2 and SOD2, and the indices of the Sestrin2 overexpression group were similar to those of the PCs treatment group. In summary, these findings suggest that PCs have potential as innovative therapeutic agents for preventing and treating POF by activating the protective SESTRIN2-NRF2 pathway against oxidative stress.

Serum Cholesterol Level Changes during Gonadotropin-Releasing Hormone-Agonist Therapy in Premenopausal Female Patients with Breast Cancer.

OBJECTIVES: To investigate the changes in cholesterol levels during medical ovarian suppression. METHODS: We reviewed the medical records and blood test results of 187 female patients with breast cancer who underwent gonadotropin-releasing hormone (GnRH)-agonist therapy for > 24 weeks at our hospital between 1 January 2018 and 31 December 2020. The study excluded patients in this cohort who had previously been diagnosed with dyslipidemia, diabetes, or had recently received lipid-lowering agents, resulting in a final sample size of 152 participants. The age at diagnosis and preoperative body mass index (BMI) were included as baseline demographics. A generalized additive mixed model was applied to analyze the relationship between the duration of GnRH-agonist treatment and changes in cholesterol levels. RESULTS: The study participants had a mean age of 42.5 ± 5.2 years and a mean preoperative BMI of 23.0 ± 3.6 kg/m²; the mean GnRH-agonist therapy duration was 19.3 months (range: 5.6-37.7 months); and the total cholesterol level before GnRH-agonist treatment was 171 mg/dL that was significantly higher at 181 mg/dL (P = 0.03) during the most recent measurement. The total cholesterol level was unaffected by the GnRH-agonist therapy until 19.3 months after which it significantly increased by 1.28 mg/dL per month (P = 0.011). There was no significant effect of age, preoperative BMI, or the glomerular filtration rate on the total cholesterol levels. CONCLUSIONS: Long-term GnRH agonist therapy for > 19 months can cause a significant increase in the serum cholesterol levels. To prevent complications, patients receiving the treatment should be informed and monitored for the possible progression of dyslipidemia.

Local Regulatory Changes of HSD11B1 and NR3C1 in the Follicular and Luteal Tissue During Experimentally Induced Ovulation in the Cow.

The objective of the study was to characterise the expression patterns of the two key components of cortisol action namely HSD11B1 (11-beta-hydroxysteroid dehydrogenase type 1) and NR3C1 (nuclear receptor subfamily 3, group C, member 1, also known as the glucocorticoid receptor) in superovulation induced bovine follicles during the periovulation and subsequent corpus luteum (CL) formation. Bovine ovaries containing preovulatory follicles or CL were timely defined during induced ovulation as follows: 0 h before GnRH (Gonadotropin-releasing hormone) application, and 4, 10, 20, 25 (follicles) and 60 h (early CL) after GnRH. The low mRNA expression of HSD11B1 and NR3C1 in the follicle group before the GnRH application increased significantly in the follicle group 20 h after GnRH and remained high afterward also in the early CL group. In contrast, the high NR3C1 mRNA decreased in follicles 25 h after GnRH (close to ovulation) and significantly increased again after ovulation (early CL). Our results indicated the involvement of HSD11B1 and NR3C1 as the two key components of cortisol action in the local mechanisms coordinating final follicle maturation, ovulation, follicular-luteal transition and CL development in the cow.

Premature ovarian insufficiency in pediatric cancer patients: a 10 year Rady Children's hospital experience.

OBJECTIVES: To highlight the occurrence of premature ovarian insufficiency in pediatric cancer patients and determine which patient characteristics or treatment modalities are associated with ovarian failure and recovery. METHODS: Between August 2011-August 2021, 36 of 2,661 patients with cancer were identified to have subsequent ovarian failure. Data collected included cancer type, diagnosis age, types of chemotherapy, bone marrow transplant or radiation treatment, peak FSH, peak AMH, GnRHa treatment, type of hormone replacement therapy, and if ovarian function recovery occurred. RESULTS: The most common cancer type identified was ALL. The mean age of diagnosis was 8.5±4.3 years and mean age of peak FSH value was 12.6±2.8 years. Most patients (97.2 %) were treated with alkylating agents and 72.2 % received radiation. Most patients (72.2 %) received hormone therapy, and 15.8 % of patients received GnRHa Lupron. Ten patients (27.8 %) had ovarian function recovery. Diagnosis age and treatment type were recovery predictors in multivariate regression modeling. Each year older in age was associated with a 30 % decrease in odds of recovery (OR: 0.7, CI: 0.5-0.95, p=0.035), and alkylating agent treatment without transplant was associated with a 3-fold increase in odds of recovery (OR: 3, CI: 2.7-564, p=0.007). CONCLUSIONS: This retrospective review demonstrates that POI can occur in pediatric cancer survivors, emphasizing the importance of educating patients on potential long-term effects of cancer treatment and importance of routine surveillance. This study confirmed that recovery of ovarian function is possible, especially when diagnosed at a younger age, making continued monitoring essential.

Systemic low-dose anti-fibrotic treatment attenuates ovarian aging in the mouse.

The female reproductive system is one of the first to age in humans, resulting in infertility and endocrine disruptions. The aging ovary assumes a fibro-inflammatory milieu which negatively impacts gamete quantity and quality as well as ovulation. Here, we tested whether the systemic delivery of anti-inflammatory (Etanercept) or anti-fibrotic (Pirfenidone) drugs attenuates ovarian aging in mice. We first evaluated the ability of these drugs to decrease the expression of fibro-inflammatory genes in primary ovarian stromal cells treated with a pro-fibrotic or a pro-inflammatory stimulus. Whereas Etanercept did not block Tnf expression in ovarian stromal cells, Pirfenidone significantly reduced Col1a1 expression. We then tested Pirfenidone in vivo where the drug was delivered systemically via mini-osmotic pumps for 6 weeks. Pirfenidone mitigated the age-dependent increase in ovarian fibrosis without impacting overall health parameters. Ovarian function was improved in Pirfenidone-treated mice as evidenced by increased follicle and corpora lutea number, AMH levels, and improved estrous cyclicity. Transcriptomic analysis revealed that Pirfenidone treatment resulted in an upregulation of reproductive function-related genes at 8.5 months and a downregulation of inflammatory genes at 12 months of age. These findings demonstrate that reducing the fibroinflammatory ovarian microenvironment improves ovarian function, thereby supporting modulating the ovarian environment as a therapeutic avenue to extend reproductive longevity.

Sleep Deprivation Triggers the Excessive Activation of Ovarian Primordial Follicles via ß2 Adrenergic Receptor Signaling.

Sleep deprivation (SD) is observed to adversely affect the reproductive health of women. However, its precise physiological mechanisms remain largely elusive. In this study, using a mouse model of SD, it is demonstrated that SD induces the depletion of ovarian primordial follicles, a phenomenon not attributed to immune-mediated attacks or sympathetic nervous system activation. Rather, the excessive secretion of stress hormones, namely norepinephrine (NE) and epinephrine (E), by overactive adrenal glands, has emerged as a key mediator. The communication pathway mediated by the KIT ligand (KITL)-KIT between granulosa cells and oocytes plays a pivotal role in primordial follicle activation. SD heightened the levels of NE/E that stimulates the activation of the KITL-KIT/PI3K and mTOR signaling cascade in an ß2 adrenergic receptor (ADRB2)-dependent manner, thereby promoting primordial follicle activation and consequent primordial follicle loss in vivo. In vitro experiments further corroborate these observations, revealing that ADRB2 upregulates KITL expression in granulosa cells via the activation of the downstream cAMP/PKA pathway. Together, these results reveal the significant involvement of ADRB2 signaling in the depletion of ovarian primordial follicles under sleep-deprived conditions. Additionally, ADRB2 antagonists are proposed for the treatment or prevention of excessive activation of primordial follicles induced by SD.

Mechanism of Zuogui pill enhancing ovarian function and skin elastic repair in premature aging rats based on artificial intelligence medical image analysis.

BACKGROUND: AI medical image analysis shows potential applications in research on premature aging and skin. The purpose of this study was to explore the mechanism of the Zuogui pill based on artificial intelligence medical image analysis on ovarian function enhancement and skin elasticity repair in rats with premature aging. MATERIALS AND METHODS: The premature aging rat model was established by using an experimental animal model. Then Zuogui pills were injected into the rats with premature aging, and the images were detected by an optical microscope. Then, through the analysis of artificial intelligence medical images, the image data is analyzed to evaluate the indicators of ovarian function. RESULTS: Through optical microscope image detection, we observed that the Zuogui pill played an active role in repairing ovarian tissue structure and increasing the number of follicles in mice, and Zuogui pill also significantly increased the level of progesterone in the blood of mice. CONCLUSION: Most of the ZGP-induced outcomes are significantly dose-dependent.

Monitoring of estradiol levels in premenopausal women receiving adjuvant abemaciclib and ovarian function suppression.

PURPOSE: Approximately 15% of women who receive ovarian function suppression (OFS) as adjuvant treatment for high-risk, localized hormone receptor-positive (HR+) breast cancer may have inadequate estradiol suppression which can require therapeutic modification when used in combination with an aromatase inhibitor (AI). We previously reported that abemaciclib may interfere with the estradiol Abbott Alinity chemiluminescent microparticle immunoassay (CMIA) commonly used to monitor estradiol levels and suggested liquid chromatography-mass spectrometry (LC-MS/MS) is preferred in this setting. The aim of this study was to determine discrepancies in estradiol levels using CMIA compared to LC-MS/MS and subsequent treatment changes in a larger patient population. METHODS: We conducted a retrospective review of premenopausal women with early-stage HR+ breast cancer at our institution who received adjuvant OFS and abemaciclib with at least 1 CMIA estradiol level drawn during abemaciclib therapy from October 2021 to April 2023. RESULTS: Of the 22 women who met criteria for review, 20 (90.9%) had CMIA estradiol levels in the premenopausal range, of whom 9 also had estradiol measured by LC-MS/MS. All 9 women receiving OFS and abemaciclib with estradiol measurements by both methods had premenopausal range CMIA estradiol levels and postmenopausal range LC-MS/MS estradiol levels. Of the 20 patients with premenopausal estradiol levels by CMIA estradiol, treatment changes included increased OFS dosage or preparation (n = 7), change from AI to tamoxifen (n = 3), and surgical oophorectomy (n = 7). CONCLUSION: Our findings suggest the likely interference of abemaciclib with the Abbott Alinity immunoassay which may lead to unnecessary treatment changes. It is recommended that the LC-MS/MS assay be used when monitoring estradiol levels in patients receiving abemaciclib concurrently with OFS.

Meta-analysis highlight the therapeutic potential of stem cells for premature ovarian failure.

Stem cell (SC) transplantation has shown potential as a therapeutic approach for premature ovarian failure (POF). Despite this, no quantitative analysis has been conducted on the efficacy of SC therapy for POF in humans. To address this gap, the present study conducted a meta-analysis to evaluate the effectiveness of the transplantation of SC in improving ovarian function among POF patients. A systematic review in this regard by searching PubMed, ScienceDirect, clinicalTrial.gov, and Cochrane's library databases was conducted to identify relevant studies, while associated reviews were also considered. The extracted data included parameters such as estradiol (E2), follicle-stimulating hormone (FSH), follicle count (FC), ovarian weight (OW), number of pregnancies, and live birth. As per the combined effect taking the last follow-up time, the level of FSH and AMH for the SC group was lower than these were at the baseline as (SMD: 1.58, 95% CI: 0.76 to 3.92, P-value: 0.185 > 0.05, I2: 94.03%) and (SMD: 1.34, 95% CI: 0.77 to 1.92, P-value: 0.001 < 0.05, I2: 0%) respectively. While the means of E2 and OW for the SC group was higher than these were at the baseline as (SMD: -0.47, 95% CI: -0.73 to -0.21, P-value: 0.001 < 0.01, I2: 38.23%) and (SMD: -1.18, 95% CI: -2.62 to 0.26, P-value: 0.108 > 0.05, I2: 76.68%) respectively. The overall effect size measured with proportion of pregnancy and live birth at a 5% level of significance expected SC transplantation results were as (combined proportion: 0.09, 95% CI: 0.03 to 0.15, P-value: 0.002 < 0.05, I2: 46.29%) and (SMD: 0.09, 95% CI: 0.03 to 0.15, P-value: 0.003 < 0.05, I2: 1.76%) respectively. Based on the fixed-effects model, the estimated average log odds ratio of Follicles count was 1.0234 (95% CI: 0.1252 to 1.9216). Therefore, the average outcome differed significantly from zero (P-value: 0.0255 < 0.05) due to SC transplantation. These results suggest that using SCs to restore ovarian function may be viable for treating POF. However, larger and better-quality investigations would need to be conducted in the future due to the heterogeneity of the examined studies.

An Overview of Long-Acting GnRH Agonists in Premenopausal Breast Cancer Patients: Survivorship Challenges and Management.

Managing breast cancer in premenopausal women poses unique challenges due to its considerable effect on both morbidity and mortality. Goserelin, a gonadotropin-releasing hormone agonist, has emerged among the various modalities as a preferred option for ovarian function suppression, owing to its efficacy in reducing ovarian estrogen production in premenopausal women with hormone receptor-positive breast cancer. Recent studies have affirmed the efficacy and safety of long-acting (LA) goserelin 10.8 mg every 12 weeks, offering comparable outcomes to monthly injections. This flexibility enables personalized treatment approaches, potentially enhancing patient satisfaction. Off-label utilization of goserelin LA surged during the coronavirus disease pandemic, prompting initiatives to broaden its use for breast cancer treatment. Switching to goserelin LA can streamline treatment, boost adherence, and optimize resource utilization. With the recent approval of goserelin 10.8 mg LA by Health Canada on 6 May 2024, for use in breast cancer, Canada is the latest to join over 60 countries worldwide to expand the accepted indications for goserelin LA and ensure its availability to potentially enhance healthcare delivery, patient care, and breast cancer outcomes. Goserelin LA offers premenopausal patients a means to more effectively manage the constraints imposed by breast cancer treatment and its impact on survivorship.

Effects of cyclophosphamide administration on ovarian dysfunction in pediatric patients with connective tissue diseases: A systematic scoping review.

OBJECTIVE: This systematic scoping review assess the effect of cyclophosphamide (CY) administration during childhood on ovarian function in patients with juvenile-onset connective tissue diseases. METHODS: A MEDLINE database search was conducted using terms related to CY, juvenile-onset connective tissue diseases, and ovarian function. Studies were included if they met specific criteria. RESULTS: The search, conducted on 28 November 2023, yielded 3328 references. After a two-stage screening process, six observational studies on systemic lupus erythematosus patients were included. All studies had a high risk of confounding bias, as none adjusted for confounding variables. Two studies assessing clinical ovarian dysfunction found no clear difference between CY and non-CY groups. However, statistical differences were observed in hormonal profiles. Decreased ovarian reserve was more frequent in CY-exposed patients. Two studies showed significantly higher follicle-stimulating hormone (FSH) levels in the CY group, while one showed a trend towards higher FSH levels without statistical significance. CONCLUSION: This review suggested that CY use in childhood may not conclusively have clinically significant effects on ovarian function. Further investigation needed on CY's effect on hormonal levels, fertility, and pregnancy outcomes.

Effect of dietary with Zhibai dihuang pills and gonadotropin-releasing-hormone-analogue on girls with precocious and rapidly progressive puberty.

BACKGROUND: At present, the clinical mechanisms underlying precocious puberty remain unclear, making effective intervention for children experiencing this condition and rapidly progressive puberty essential. AIM: To explore the effects of Zhibai dihuang pills and gonadotropin-releasing hormone analogue (GnRHa) on growth and ovarian function in girls with precocious puberty. METHODS: The clinical data of 84 adolescent girls with precocious puberty and rapidly progressive puberty from February 2017 to August 2023 were retrospectively analyzed. Girls were divided into a control group and an observation group, with 42 cases in each group. The control group received diet intervention combined with GnRHa treatment, while the observation group received diet intervention combined with Zhibai dihuang pills + GnRHa treatment. Outcomes such as clinical efficacy, growth indicators, ovarian function, and adverse reactions were compared between the two groups. RESULTS: The observation group showed superior clinical efficacy compared to the control group (P < 0.05). Prior to the intervention, no significant differences were found in growth or ovarian function between the groups (P > 0.05). Post-intervention, the observation group exhibited significantly lower rates in growth, height, and bone age, along with reduced levels of progesterone, testosterone, estradiol, prolactin, luteinizing hormone, and follicle-stimulating hormone compared to the control group (P < 0.05). The incidence of adverse reactions was similar across both groups (P > 0.05). CONCLUSION: Combining Zhibai dihuang pills with GnRHa and dietary intervention effectively improves growth, enhances ovarian function, and minimizes adverse reactions in adolescent girls with precocious and rapidly progressive puberty.

Systemic low-dose anti-fibrotic treatment attenuates ovarian aging in the mouse.

The female reproductive system is one of the first to age in humans, resulting in infertility and endocrine disruptions. The aging ovary assumes a fibro-inflammatory milieu which negatively impacts gamete quantity and quality as well as ovulation. Here we tested whether the systemic delivery of anti-inflammatory (Etanercept) or anti-fibrotic (Pirfenidone) drugs attenuates ovarian aging in mice. We first evaluated the ability of these drugs to decrease the expression of fibro-inflammatory genes in primary ovarian stromal cells. Whereas Etanercept did not block Tnf expression in ovarian stromal cells, Pirfenidone significantly reduced Col1a1 expression. We then tested Pirfenidone in vivo where the drug was delivered systemically via mini-osmotic pumps for 6-weeks. Pirfenidone mitigated the age-dependent increase in ovarian fibrosis without impacting overall health parameters. Ovarian function was improved in Pirfenidone-treated mice as evidenced by increased follicle and corpora lutea number, AMH levels, and improved estrous cyclicity. Transcriptomic analysis revealed that Pirfenidone treatment resulted in an upregulation of reproductive function-related genes at 8.5 months and a downregulation of inflammatory genes at 12 months of age. These findings demonstrate that reducing the fibroinflammatory ovarian microenvironment improves ovarian function, thereby supporting modulating the ovarian environment as a therapeutic avenue to extend reproductive longevity.

Adjuvant endocrine therapy choices in premenopausal patients with hormone receptor-positive early breast cancer: Insights from the prospective GIM23-POSTER study.

BACKGROUND: Most premenopausal patients with early breast cancer (eBC) are diagnosed with hormone receptor-positive disease and therefore candidate for adjuvant endocrine therapy (ET). PATIENTS AND METHODS: The Gruppo Italiano Mammella (GIM) 23-POSTER (GIM23) is a multicenter, prospective, observational study conducted in 26 Italian institutions, aiming to evaluate ET choices for premenopausal patients affected by hormone receptor-positive eBC in a real-world setting. Here we report also the results in terms of type of ET prescribed according to the definition of high-risk patients by monarchE and NATALEE trials. RESULTS: Between October 2019 and June 2022, 600 premenopausal patients were included, with a median age of 46 years. Almost half (271, 45.2 %) of the patients had stage I disease, while 254 (42.3 %) and 60 (10.0 %) patients had stage II and III, respectively. Overall, 149 (25.1 %) patients received tamoxifen alone, 83 (14.0 %) tamoxifen with ovarian function suppression (OFS), while 361 (60.9 %) received aromatase inhibitor (AI) with OFS. Patients treated with AI and OFS had higher number of metastatic axillary nodes, higher grade and more often received chemotherapy (all p < 0.001). According to the inclusion criteria of the monarchE and NATALEE trials, 81 patients (15.6 %) were considered high-risk for the monarchE and received AI with OFS in 88.9 % of the cases, while 231 patients (44.4 %) were considered high-risk for the NATALEE trial and received AI with OFS in 74.5 % of cases. CONCLUSIONS: AI with OFS is the most prescribed adjuvant ET among premenopausal patients, especially in the presence of high-risk features.

Fermented Aronia melanocarpa pomace improves the nutritive value of eggs, enhances ovarian function, and reshapes microbiota abundance in aged laying hens.

Introduction: There is a decline in the quality and nutritive value of eggs in aged laying hens. Fruit pomaces with high nutritional and functional values have gained interest in poultry production to improve the performance. Methods: The performance, egg nutritive value, lipid metabolism, ovarian health, and cecal microbiota abundance were evaluated in aged laying hens (320 laying hens, 345-day-old) fed on a basal diet (control), and a basal diet inclusion of 0.25%, 0.5%, or 1.0% fermented Aronia melanocarpa pomace (FAMP) for eight weeks. Results: The results show that 0.5% FAMP reduced the saturated fatty acids (such as C16:0) and improved the healthy lipid indices in egg yolks by decreasing the atherogenicity index, thrombogenic index, and hypocholesterolemia/hypercholesterolemia ratio and increasing health promotion index and desirable fatty acids (P < 0.05). Additionally, FAMP supplementation (0.25%-1.0%) increased (P < 0.05) the ovarian follicle-stimulating hormone, luteinizing hormone, and estrogen 2 levels, while 1.0% FAMP upregulated the HSD3B1 expression. The expression of VTG II and ApoVLDL II in the 0.25% and 0.5% FAMP groups, APOB in the 0.5% FAMP group, and ESR2 in the 1% FAMP group were upregulated (P < 0.05) in the liver. The ovarian total antioxidant capacity was increased (P < 0.05) by supplementation with 0.25%-1.0% FAMP. Dietary 0.5% and 1.0% FAMP downregulated (P < 0.05) the Keap1 expression, while 1.0% FAMP upregulated (P < 0.05) the Nrf2 expression in the ovary. Furthermore, 1.0% FAMP increased cecal acetate, butyrate, and valerate concentrations and Firmicutes while decreasing Proteobacteria (P < 0.05). Conclusion: Overall, FAMP improved the nutritive value of eggs in aged laying hens by improving the liver-blood-ovary function and cecal microbial and metabolite composition, which might help to enhance economic benefits.

Efficacy of acupuncture in animal models of various ovarian dysfunctions: a systematic review and meta-analysis.

Objective: This study aims to assess the comprehensive and integrated modulatory effects of acupuncture and electroacupuncture on various ovarian dysfunctions. Methods: We systematically searched for articles on animal experiments related to polycystic ovary syndrome (PCOS), premature ovarian failure (POF), premature ovarian insufficiency (POI), and perimenopausal syndrome (PMS) across multiple databases, including PubMed, Web of Science, Cochrane Library, Embase, and four Chinese language databases. The search covered the period from inception to November 2023. We conducted a comparative analysis between the acupuncture group and the model group (untreated) based on eligible literature. Our primary outcomes encompassed serum sex hormones (Luteinizing hormone, Follicle-stimulating hormone, Testosterone, Estradiol, Progesterone, and Anti-Müllerian hormone) and ovarian weight. Dichotomous data were synthesized to establish the relative risk (RR) of notable post-treatment improvement, while continuous data were pooled to determine the standardized mean difference (SMD) in post-treatment scores between the groups. Statistical analyses, including sensitivity analysis, Egger's test, and the trim-and-fill method, were executed using Stata 15.0 software. Results: The meta-analysis encompassed 29 articles involving a total of 623 rats. In comparison to rat models of PCOS, the experimental group exhibited a reduction in serum levels of LH, T and LH/FSH ratio. However, no statistically significant differences were observed in AMH, FSH, E2 levels, and ovarian weight between the two groups. In the ovarian hypoplasia model rats, both acupuncture and electroacupuncture interventions were associated with an increase in E2 levels. However, the levels of LH and FSH did not exhibit a significant difference between the two groups. Conclusions: Acupuncture or electroacupuncture facilitates the restoration of ovarian function primarily through the modulation of serum sex hormones, exerting regulatory effects across various types of ovarian dysfunction disorders. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022316279.

Adipose-derived Mesenchymal Stem Cell Transplantation Improves Ovarian Function and Oocyte Quality in Aged Mice.

BACKGROUND/AIM: Age-related decline in the number of ovulations and ovum quality are major causes of female infertility, and stem cells have been reported to be effective in tissue regeneration. However, current therapeutic modalities are inadequate. This study investigated the effects of adipose-derived mesenchymal stem cells (ASCs) on ovarian functions in aged mice. MATERIALS AND METHODS: Following the characterization of ASCs using flow cytometry, the effects of ASCs on the number of ovulations, fertilization rate, and blastocyst-formation rate were investigated. In addition, the number of ovarian follicles and serum anti-Müllerian hormone (AMH) levels were examined. ASCs marked with Kusabira Orange were used to examine the location after cell administration. The quality of ovulated oocytes was analyzed using next-generation RNA sequencing. RESULTS: ASCs showed characteristics of mesenchymal stem cells and were distributed to various organs, including the ovarian stroma. The transplantation resulted in increased number of oocytes and ovulation in the ovaries and increased AMH values. Genetic analysis revealed improved oocyte quality and increased fertilization and blastocyst-formation rates. CONCLUSION: ASC therapy may be effective in improving fertility in older women.