Ovarian Failure Research Articles

MGA loss-of-function variants cause premature ovarian insufficiency.

Although premature ovarian insufficiency (POI), a common cause of female infertility and subfertility, has a well-established hereditary component, the genetic factors currently implicated in POI account for only a limited proportion of cases. Here, using an exome-wide, gene-based case-control analysis in a discovery cohort comprising 1,027 POI cases and 2,733 ethnically matched women controls from China, we found that heterozygous loss-of-function (LoF) variants of MAX dimerization protein (MGA) were significantly enriched in the discovery cohort, accounting for 2.6% of POI cases, while no MGA LoF variants were found in the matched control females. Further exome screening was conducted in 4 additional POI cohorts (2 from China and 2 from the United States) for replication studies, and we identified heterozygous MGA LoF variants in 1.0%, 1.4%, 1.0%, and 1.0% of POI cases, respectively. Overall, a total of 37 distinct heterozygous MGA LoF variants were discovered in 38 POI cases, accounting for approximately 2.0% of the total 1,910 POI cases analyzed in this study. Accordingly, Mga+/- female mice were subfertile, exhibiting shorter reproductive lifespan and decreased follicle number compared with WT, mimicking the observed phenotype in humans. Our findings highlight the essential role of MGA deficiency for impaired female reproductive ability.

Hormone replacement therapy in surgical menopause after gynecological malignancies

This review examines hormone replacement therapy (HRT) in cases of surgical menopause following gynecological malignancies. It aims to capture current knowledge, summarize recent findings, and provide recommendations for clinical settings. Unlike natural menopause, surgical menopause occurs abruptly, without an adjustment period, and is associated with a notably higher risk of fractures, arthritis, cognitive decline, dementia, Parkinson’s disease, and various metabolic disorders affecting glucose and lipid levels—all of which contribute to an increased risk of major cardiovascular events. In 2017, The North American Menopause Society recommended that, barring contraindications, HRT should be initiated in women who enter surgical menopause before age 45. If these women do not experience vasomotor symptoms or other issues, HRT should be maintained consistently at least until age 52. This guideline reflects contemporary knowledge and is the result of a multidisciplinary consensus, based on a review of existing literature and several randomized clinical trials focusing on women who have survived gynecological cancers and whose quality of life is significantly impacted by surgical or early menopause. Estrogen supplementation is particularly beneficial, as it is linked to marked improvements in quality of life, including delayed onset of chronic cardiovascular issues, reduced fracture risk, enhanced cognitive function, reduced inflammation, and improved self-esteem, as well as better social and work performance. Clinical implementation of HRT, however, requires a highly individualized approach. This approach must consider the type and stage of malignancy, histopathological characteristics, risk factors for recurrence (such as diet, concurrent medications, medical history, and genetic predispositions), and a thorough assessment of the potential benefits and risks of HRT, as well as the patient’s personal wishes and expectations.

Defects in meiosis I contribute to the genesis of androgenetic hydatidiform moles.

To identify novel genes responsible for recurrent hydatidiform moles (HMs), we performed exome sequencing on 75 unrelated patients who were negative for mutations in the known genes. We identified biallelic deleterious variants in 6 genes, FOXL2, MAJIN, KASH5, SYCP2, MEIOB, and HFM1, in patients with androgenetic HMs, including a familial case of 3 affected members. Five of these genes are essential for meiosis I, and their deficiencies lead to premature ovarian insufficiency. Advanced maternal age is the strongest risk factor for sporadic androgenetic HM, which affects 1 in every 600 pregnancies. We studied Hfm1-/- female mice and found that these mice lost all their oocytes before puberty but retained some at younger ages. Oocytes from Hfm1-/- mice initiated meiotic maturation and extruded the first polar bodies in culture; however, their meiotic spindles were often positioned parallel, instead of perpendicular, to the ooplasmic membrane at telophase I, and some oocytes extruded the entire spindle with all the chromosomes into the polar bodies at metaphase II, a mechanism we previously reported in Mei1-/- oocytes. The occurrence of a common mechanism in two mouse models argues in favor of its plausibility at the origin of androgenetic HM formation in humans.

Human umbilical cord mesenchymal stem cell-derived extracellular vesicles harboring IGF-1 improve ovarian function of mice with premature ovarian insufficiency through the Nrf2/HO-1 pathway.

Premature ovarian insufficiency (POI) is a disease with medical, psychological and reproductive implications, but its common therapies have limited efficacy and a likelihood of complications. This study delves into the therapeutic role of human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSCs-EVs) in POI mice through the insulin-like growth factor 1 (IGF-1)/nuclear factor E2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/autophagy pathway. hUC-MSCs were transfected with lentiviral short hairpin RNA of IGF-1 before EV extraction. Cyclophosphamide (CTX)-induced POI mouse models were administrated with hUC-MSCs-EVs. Mouse ovarian granulosa cells (GCs) were induced with CTX, then treated with hUC-MSCs-EVs and ML385. Ovarian histopathological changes were observed, changes in follicle number at all levels were counted and serum sex hormones were evaluated, as well as LC3II/I and Beclin-1 expression. GCs were subject to detection of proliferation, deaths, oxidative stress, and Nrf2 nuclear translocation. After CTX exposure, mice showed thinner GCs layer in the ovary, reduced number of GCs and follicles at all levels, disturbed serum sex hormones, enhanced oxidative stress and autophagy, and downregulated ovarian IGF-1; whereas, hUC-MSCs-EVs upregulated IGF-1 to improve the ovarian function. hUC-MSCs-EVs carrying IGF-1 activated Nrf2/HO-1 signaling to inhibit CTX-induced excessive autophagy of GCs, but this ameliorative effect was partially weakened by inhibiting Nrf2/HO-1 signaling. hUC-MSCs-EVs inhibited excessive autophagy of GCs and improved ovarian function of CTX-induced mice through IGF-1/Nrf2/HO-1 pathway. hUC-MSCs-EVs activate the Nrf2/HO-1 signaling by carrying IGF-1, which in turn inhibits excessive autophagy and damage of GCs, thus improving ovarian function in POI mice.

Examining suicidality in relation to the menopause: A systematic review

Suicide is one of the leading causes of deaths worldwide, with an estimated 1 in 100 deaths being attributable to suicide. Whilst rates of suicide are higher in men, evidence suggests that suicide attempts are more frequent in women. Suicidality data indicates that deaths by suicide in women are highest in those in midlife, warranting investigation into the relationship between the menopause and suicidality. The current study aimed to review the existing literature examining the relationship between suicidality and the menopause using a systematic review approach. A systematic literature search of MEDLINE, Cochrane Library, Scopus Web of Science, PsycINFO, and Embase databases was conducted in October 2023. Two authors independently screened the titles and abstracts of identified articles against the eligibility criteria. Any inconsistencies were discussed and resolved. This process was subsequently repeated with the articles’ full-text. Risk of bias was assessed using the Quality Assessment Tool for Studies with Diverse Designs (QATSDD). Relevant data were extracted and summarised in both a tabulated and narrative form. A total of 28 studies met the inclusion criteria, with the findings revealing a complex relationship between the menopause and suicidality. Several studies highlighted that the perimenopause period shows a higher prevalence of suicidal thoughts compared to pre-menopausal and post-menopausal stages. Conversely, some studies indicated increased suicidality during the post-menopausal phase, while others noted elevated suicidality in pre-menopausal individuals and those with primary ovarian insufficiency. Critically, several studies found no link between hormonal status and suicidality. The quality of the studies also varied, with a lack of involvement from individuals with relevant lived experience being a consistent methodological flaw across all the included studies. Overall, the current evidence on menopause and suicidality is mixed. Further research is needed to unravel the relationship between menopause and suicidality.

Evaluation of the macula, retinal nerve fiber layer and choroid thickness in premature ovarian failure using spectral-domain optical coherence tomography.

The aim of our study is to describe the basal findings at the first diagnosis of the disease in patients with premature ovarian failure (POF) and to draw attention to the early changes in the macula, optic nerve head and choroid. In a prospective case-control study, 90 patients with POF and 90 control patients were evaluated. All participants underwent the same ophthalmic examination, including visual acuity, intraocular preasure measurement, anterior and posterior segment evaluation, macular and coroidal thickening, and retinal nerve fiber layer (RNFL) measurements with the same device (Spectral Domain OCT, software version 5.6.3.0, Heidelberg, Germany). The median age was 30.00 (28.00-31.00) in the control group and 29.00 (27.00-31.00) in the POF group (p = 0.249). The median thickness of the temporal outer macular region was statistically significantly thinner in the POF group (295.00 (289.00-303.25)) compared to the control group (306.00 (290.75-328.00)) (p < 0.001). There was a statistically significant decrease in all choroidal regions (p < 0.001), including the central, nasal 500, nasal 1500, temporal 500, and temporal 1500 regions in the POF group according to the control group. An increase in intraocular pressure in the postmenopausal period has been reported, suggesting a link between the postmenopausal decline in sex hormones and glaucoma. Our study is the first to monitor changes in choroidal, retinal thickness and RNFL in POF images showing early menopausal symptoms.

Abstract 4138306: Impact of Early Menopause and Hormonal Replacement Therapy on Aortic Stenosis Progressio

Background: Early menopause is associated with an increased risk of cardiovascular disease and mortality in women. The present study aimed to examine the impact of early menopause and hormonal replacement therapy (HRT) on the progression of aortic stenosis (AS). Methods: Thirty-three postmenopausal women (mean age 65 ± 10 years) with mild or moderate AS prospectively recruited in the PROGRESSA study (NCT01679431) were included in this sub-analysis. All patients underwent multidetector computed tomography and Doppler-echocardiography at least twice during follow-up to assess both anatomic and hemodynamic AS severity, based on aortic valve calcification (AVC), mean pressure gradient (MG), and aortic valve area indexed to body surface area (AVA). Annualized changes in AVC, MG and AVAi were calculated between baseline and the last follow-up. Results: Over a median follow-up of 2 [1-4] years, early menopausal women had a faster progression rate of AVC, MG, and AVAi compared to other women: (100[58-130] vs. 23[2-71] AU/year, p=0.03); (2.37[0.82-3.61] vs. 0.31[0.01-1.78] mmHg/year, p=0.04); and (-0.12[-0.23-0.002] vs. -0.004[-0.07-0.08] cm 2 /m 2 /year, p=0.08) respectively. In multivariate analysis adjusted for age, AS severity at baseline, and comorbidities, early menopause remained significantly associated with faster AVC progression (p=0.003). Moreover, after comprehensive adjustment, women who received HRT (45%) had a slower progression rate of AVC (20[10-42] AU/year vs. 62[2-100], adjusted p=0.04). Conclusion: Early menopause is associated with faster progression of AS, both anatomically and hemodynamically. However, the use of HRT is associated with slower progression of AS. Integrating female-specific risk factors, particularly menopausal history and hormonal therapy status, into the clinical management of AS could enhance patient care.

Reproductive and Metabolic Health Following Exposure to Environmental Chemicals: Mechanistic Insights from Mammalian Models.

The decline in human reproductive and metabolic health over the past 50years is associated with exposure to complex mixtures of anthropogenic environmental chemicals (ECs). Real-life EC exposure has varied over time and differs across geographical locations. Health-related issues include declining sperm quality, advanced puberty onset, premature ovarian insufficiency, cancer, obesity, and metabolic syndrome. Prospective animal studies with individual and limited EC mixtures support these observations and provide a means to investigate underlying physiological and molecular mechanisms. The greatest impacts of EC exposure are through programming of the developing embryo and/or fetus, with additional placental effects reported in eutherian mammals. Single-chemical effects and mechanistic studies, including transgenerational epigenetic inheritance, have been undertaken in rodents. Important translational models of human exposure are provided by companion animals, due to a shared environment, and sheep exposed to anthropogenic chemical mixtures present in pastures treated with sewage sludge (biosolids). Future animal research should prioritize EC mixtures that extend beyond a single developmental stage and/or generation. This would provide a more representative platform to investigate genetic and underlying mechanisms that explain sexually dimorphic and individual effects that could facilitate mitigation strategies.

MSCs-derived EVs protect against chemotherapy-induced ovarian toxicity: role of PI3K/AKT/mTOR axis.

Chemotherapy detrimentally impacts fertility via depletion of follicular reserves in the ovaries leading to ovarian failure (OF) and development of estrogen deficiency-related complications. The currently proposed options to preserve fertility such as Oocyte or ovarian cortex cryopreservation are faced with many technical obstacles that limit their effective implementation. Therefore, developing new modalities to protect ovarian function remains a pending target. Exosomes are nano-sized cell-derived extracellular vesicles (EVs) with documented efficacy in the field of regenerative medicine. The current study sought to determine the potential beneficial effects of mesenchymal stem cells (MSCs)-derived EVs in experimentally induced OF. Female albino rats were randomly allocated to four groups: control, OF group, OF + MSCs-EVs group, OF + Rapamycin (mTOR inhibitor) group, and OF + Quercetin (PI3K/AKT inhibitor) group. Follicular development was assessed via histopathological and immunohistochemical examination, and ovarian function was evaluated by hormonal assay. PI3K/Akt/mTOR signaling pathway as a key modulator of ovarian follicular activation was also assessed. MSCs-EVs administration to OF rats resulted in restored serum hormonal levels, preserved primordial follicles and oocytes, suppressed ovarian PI3K/AKT axis and downstream effectors (mTOR and FOXO3), modulated miRNA that target this axis, decreased expression of ovarian apoptotic markers (BAX, BCl2) and increased expression of proliferation marker Ki67. The present study validated the effectiveness of MSCs-EVs therapy in preventing ovarian insufficiency induced by chemotherapy. Concomitant MSCs-EVs treatment during chemotherapy could significantly preserve ovarian function and fertility by suppressing the PI3K/Akt axis, preventing follicular overactivation, maintaining normal ovarian cellular proliferation, and inhibiting granulosa cell apoptosis.

Single-cell RNA sequencing reveals common interactions between follicle immune cells and granulosa cells in premature ovarian insufficiency patients.

To investigate the follicle microenvironment of individuals with premature ovarian insufficiency (POI), normal ovarian reserve (normal) and advanced maternal age (AMA), and identify potential therapeutic targets. A total of 9 women, including 3 POI, 3 normal and 3 AMA women, underwent in vitro fertilization or intracytoplasmic sperm injection were included in this study. For each participant, the first punctured follicle not containing cumulus cells were submitted to single-cell RNA sequencing to explore the characteristics of the follicle microenvironment of POI, normal and AMA individuals. A total of 87,323 cells were isolated and grouped into six clusters: T cells, B cells, neutrophils, basophils, mononuclear phagocytes, and granulosa cells. Further analysis demonstrated that the population of granulosa cells in cluster 6 was increased in AMA and POI patients, whereas the population of gamma delta T (GDT)-cells was decreased. We also found that the genes that were differentially expressed between GDT cells and monocytes were enriched in ribosome- and endoplasmic reticulum (ER)-related pathways. In addition, it showed that VEGFA-FLT1 interaction between the monocytes and granulosa cells may be lost in the AMA and POI patients as compared with the normal group. Loss of the VEGFA-FLT1 interaction in monocytes and granulosa cells, along with enriched ER- and ribosome-related pathways, may drive excess inflammation, accelerating granulosa cell senility and contributing to infertility. This study provides new insights into the pathogenesis of POI and aging and highlights the VEGFA/FLT1 interaction may be a potential therapeutic target for reducing inflammation and treating POI.

Service evaluation: HRT regimens prescribed for complex menopausal patient cases

Abstract Introduction With government and NHS drivers, there has been an increase in menopause awareness and management. The NHS Business Services Authority reported a 29% increase in hormone replacement therapy (HRT) prescribing between 2022-2023, with expectation that this would rise further with introduction of the new HRT prepayment certificate in April 20231. Partly due to celebrity sway and supported by national guidance2,3 there is patient expectation towards transdermal oestrogen with natural progesterone HRT. Older women, some years since undergoing natural menopause, are also seeking advice on HRT use (3) with referrals accepted by specialist menopause clinics. Aims This service evaluation project was undertaken to evaluate the prescribing of HRT regimens in complex patient cases seen within a specialist menopause clinic and included assessment of those advised to use natural progesterone as part of their HRT regimen, for endometrial protection2,3. Method 366 specialist menopause clinic appointments over 6 months (05.01.23-22.06.23) were retrospectively evaluated, with patients seen by a multidisciplinary team within an outpatient secondary care setting. Exclusion criteria included appointments not attended, those that were incorrectly booked or patients with inaccessible records. Data was collected using electronic patient records with results analysed using Microsoft Excel. Results Of 327 (89%) appointments evaluated, the patient age ranged between 30-84 years (median age 53). HRT was recommended for 288 (88%) patients. HRT was not recommended in cases such as antiphospholipid syndrome, breast cancer without genitourinary symptoms, in those of advanced age or in line with patient choice with patient decision not to take HRT after an individualised risk benefit evaluation. For 26 (9%) patients, only topical oestrogen treatment for localised genitourinary syndrome symptoms was advised. 171 (52%) patients were postmenopausal, 61 (19%) perimenopausal, 46 (14%) with premature ovarian insufficiency and 20 (6%) with surgical menopause. For 22 patients (7%) with Mirena intra-uterine system in situ, their menopause phase could not be accurately defined. 243 (88%) of those recommended HRT were advised a combined regime; 154 (53%) continuous combined; 67 (23%) sequential combined and 22 (9%) oestrogen with Mirena coil. For patients accepting combined HRT, one third (81) were recommended natural progesterone, with the other patients using progestogens for endometrial protection. Of these 81 patients, 77 (95%) were recommended transdermal oestrogen in combination with natural progesterone. For patients recommended natural progesterone, 68 (84%) were for doses in line with licensing and current British Menopause Society guidance. For 10 patients the off-label recommendation involved doubled doses of natural progesterone to help with control of unfavourable bleeding. Discussion For prescribing of natural progesterone, we assumed that our recommendations to the GP were enacted. With retrospective evaluation of patient letters as a limitation, this project identified that within our specialist clinic complex patient population, a recommendation for natural progesterone was made for one third of patients suitable for combined HRT use. When not prescribed in line with licensing, this was due to issues with vaginal bleeding. Acknowledgments Biranavi Kirupakaran, Sahil Misri, Hernani Almeida, Medical Students, Imperial College London for data collection.

Anti-Müllerian Hormone Can Help With Predicting Ovarian Failure for Premenopausal Women Who Have Undergone Ablative Radioiodine Treatment for Thyroid Cancer

Differentiated thyroid carcinoma is the most common endocrinological malignancy with an increasing incidence over the last 30 years, with women being more frequently affected. In indicated cases, total thyroidectomy followed by adjuvant radioiodine administration is performed, despite current trends towards less aggressive treatment. We would like to investigate the possible adverse effects of radioiodine (RAI) on ovarian function using a simple serum biomarker. Anti-Müllerian hormone (AMH) appears to be the best endocrine marker for assessing physiological age-related oocyte loss for healthy women. The aim of our ongoing prospective study is to determine serum AMH to estimate ovarian reserve for premenopausal women treated with RAI. Over the course of one year, 33 serum samples from women with thyroid cancer and 3 serum samples from healthy women were examined. AMH levels were compared before radioiodine treatment and at regular intervals after treatment. Mean of the AMH level was 5.4 ng/ml (n=33) prior to RAI. The average level of AMH decreased to 1.8 ng/ml in 4-6 months after treatment. In 22.2 % of patients AMH dropped to 0 ng/ml from a non-zero value. Thereafter, we observed an increase in AMH, the average value was 2.7 ng/ml in 8-12 months. We demonstrated a significant decrease in AMH shortly after radioiodine treatment and a subsequent trend of increase at one year after treatment. Consequently, predicting the adverse effects of radioiodine by assessing a serum biomarker could help to select an appropriate treatment strategy for young women planning pregnancy.

Human umbilical cord mesenchymal stem cells restore chemotherapy-induced premature ovarian failure by inhibiting ferroptosis in vitro ovarian culture system

BackgroundMesenchymal stem cells (MSCs) have shown potential in repairing chemotherapy-induced premature ovarian failure (POF). However, challenges such as stem cell loss and immune phagocytosis post-transplantation hinder their application. Due to easy and safe handling, in vitro ovarian culture is widely available for drug screening, pathophysiological research, and in vitro fertilization. MSCs could exhibit therapeutic capacity for ovarian injury, and avoid stem cell loss and immune phagocytosis in vitro tissue culture system. Therefore, this study utilizes an in vitro ovarian culture system to investigate the reparative potential of human umbilical cord mesenchymal stem cells (hUCMSCs) and their mechanism.MethodsIn this study, a chemotherapy-induced POF model was established by introducing cisplatin in vitro ovarian culture system. The reparative effects of hUCMSCs on damaged ovarian tissue were validated through Transwell chambers. Tissue histology examination, immunohistochemical staining, Western blotting, and RT-PCR were employed to evaluate the expression effects of hUCMSCs on ferroptosis and fibrosis-related genes during the process of repairing cisplatin-induced POF.ResultsCisplatin was found to activate ovarian follicles in vitro POF model. Transcriptomic sequencing analysis revealed that cisplatin could activate genes associated with ferroptosis. hUCMSCs alleviated cisplatin-induced POF by suppressing the expression of ferroptosis. Moreover, inhibiting ferroptosis by hUCMSCs also ameliorated ovarian hormone levels and reduced the expression of fibrosis-related factors α-SMA and COL-I in the ovaries.ConclusionsThis study confirms that cisplatin-induced ovarian damage via ferroptosis in vitro POF model, and hUCMSCs repair ovarian injury by inhibiting the ferroptosis pathway and suppressing fibrosis. This research contributes to evaluating the effectiveness of hUCMSCs in treating chemotherapy-induced POF by inhibiting ferroptosis in an in vitro ovarian culture system and provides a potential therapeutic strategy for chemotherapy-induced POF.

P300 Maintains Primordial Follicle Activation by Repressing VEGFA Transcription.

During the reproductive life, most primordial follicles remain dormant for years or decades, while some are progressively activated for development. Misactivation of primordial follicles can cause ovarian diseases, for example, premature ovarian insufficiency (POI). Our results show that p300 expression increased with primordial follicle activation. Using a p300 inhibitor resulted in premature activation of primordial follicles in cultured mouse ovaries. Conversely, the ratio of primordial follicle activation was markedly decreased upon culturing with the p300 agonist. Furthermore, p300 regulated primordial follicle activation by inhibiting Vegfa transcription in granulosa cells. Additionally, this study was extended to potential clinical applications, showing that short-term treatment with a p300 inhibitor in vitro significantly increased primordial follicle activation in newborn mouse ovaries after dorsal kidney membrane transplantation in female NSG mice. Our results revealed that p300 controls the activation of primordial follicles in mammalian ovaries.

The association between age of menopause and type 2 diabetes: a systematic review and meta-analysis

BackgroundType-2 diabetes mellitus (T2DM) is considered one of the chronic diseases that can have a relationship with age of menopause onset. Several studies have revealed that early menopause or late menopause can have a correlation with type-2 diabetes. This systematic review and meta-analysis aimed to investigate the association between the age of menopause onset and type-2 diabetes.Methods and materialsPubMed, Web of Science, Scopus, Science Direct, Google Scholar, and Cochrane were searched for studies that have evaluated the relationship between T2DM and age of menopause onset. We pooled the effect sizes of the included studies using both adjusted odds ratios (OR) and hazard ratios (HR) of interest outcomes with their 95% confidence interval (CI).ResultsNineteen papers were included in this study, 8 studies were cohorts, and 11 were cross sectional. Studies revealed a statistically significant association between early menopause age and increased odds of T2DM (OR = 1.24, 95% CI: 1.09–1.40; I2 = 67%; p = 0.001). Late menopause age was also associated with an increased odds of T2DM (OR = 1.14, 95% CI: 1.03–1.26; I2 = 56%; p = 0.01) compared to the reference group with normal menopausal age. As our secondary outcome, the hazard of developing T2DM in individuals with early or late menopausal age was assessed. Pooled analysis demonstrated a significantly higher hazard of T2DM among women with early menopause age (HR = 1.31, 95% CI: 1.05–1.64; I2 = 72%; p = 0.02). Late menopause age did not show a significant association (HR = 0.96, 95% CI: 0.84–1.10; I2 = 68%; p = 0.56).ConclusionEarly and late menopause can both increase the risk of T2DM. Future research is needed to warrant the certainty of our findings.

Comorbidity problems in patients with osteoporosis

BACKGROUND: Osteoporosis is a metabolic skeletal disease characterized by decreased bone mass, impaired microarchitecture of bone tissue and, as a consequence, fractures with minimal trauma. The social significance of osteoporosis is determined by its consequences — fractures of the vertebral bodies and bones of the peripheral skeleton, leading to high medical costs and causing a high level of disability, including disability and mortality. Osteoporosis is most often combined with cardiovascular diseases caused by atherosclerosis, which are widespread and are the leading cause of disability and mortality. A small number of studies have been devoted to the study of the features of clinical manifestations of cardiovascular diseases in the combination of coronary heart disease and osteoporosis. AIM: To identify the frequency and severity of comorbid diseases and their risk factors in postmenopausal osteoporosis. MATERIALS AND METHODS: A retrospective and prospective cohort study was conducted from 2013 to 2023. 8250 women with postmenopausal osteoporosis were examined and the data from the medical records of these patients who applied to the Osteoporosis Center of the North-Western State Medical University named after I.I. Mechnikov of the Ministry of Health of the Russian Federation from 2013 to 2020 were analyzed. At the prospective stage, two comparison groups of 100 patients with and without postmenopausal osteoporosis were formed from 500 patients with comorbid diseases (coronary heart disease, hypertension, type 2 diabetes, stroke, transient ischemic attack). Bone mineral density was assessed based on the Hologic Discoveri Wi dual-energy X-ray absorptiometry at 2 points in the lumbar spine (L1–L4) and the femoral neck. Along with traditional laboratory examination methods, bone metabolism markers (total calcium, phosphorus, vitamin D, urine analysis for deoxypyridinoline, C-terminal telopeptide of type 1 collagen, osteocalcin, alkaline phosphatase, parathyroid hormone) were assessed dynamically. In all the patients, along with a general clinical examination, an assessment of risk factors for cardiovascular disease and osteoporosis was performed. RESULTS: Body mass index was higher in the group of patients with osteoporosis — 28.4 (26.9–32.4) kg/m2 (p 0.001), versus 27.64 (25.8–30.0) kg/m2 (p 0.05). Bone mineral density in the group of patients with osteoporosis was statistically lower than in the group without osteoporosis. In the group of patients with osteoporosis, the risk of fractures was high and amounted to 37 (95% confidence interval 15.0–38.50) %, p 0.001), versus in the control group 9.55 (95% confidence interval 7.67–15.0) % (p 0.001) according to the FRAX questionnaire for the Russian Federation. In the group of patients with osteoporosis, the Charlson index values were 5.1 (95% confidence interval 4.7–5.6) points. As a result of the correlation analysis, a reliable positive relationship was revealed between low bone mineral density L1–L4 and hip with bone metabolism: alkaline phosphatase, C-terminal telopeptide of type 1 collagen, vitamin D, osteocalcin, urinary deoxypyridinoline. We found a negative relationship between bone mineral density and the Charlson index, absolute ten-year risk of hip fracture and the duration of early menopause, and the level of hypertension. To assess the dependence of QRISK3-2018 on osteoporosis risk factors in the group of patients with osteoporosis, multiple linear regression was performed. This model was characterized by a statistically significant correlation between the factors and the dependent variable of high tightness. The coefficient of determination was 0.608, indicating a 60.8% contribution of the factors taken into account in the model to the variance of QRISK3-2018. CONCLUSIONS: In women with postmenopausal osteoporosis, comorbid pathology is more common, aggravating the course of the disease. Knowledge of the prevalence of concomitant pathology and joint risk factors will make it possible to simultaneously form groups at increased risk of development, which will ensure prevention of both diseases with the same non-medical means and drugs.

Genetic Landscape of a Cohort of 120 Patients with Diminished Ovarian Reserve: Correlation with Infertility

Diminished ovarian reserve (DOR) and primary ovarian insufficiency (POI) are major causes of female infertility. We recently found a monogenic etiology in 29.3% of POI, leading to personalized medicine. The genetic landscape of DOR is unknown. A prospective study (2018–2023) of an international cohort of 120 patients with unexplained DOR was performed using a large custom targeted next-generation sequencing panel including all known POI-causing genes. The diagnostic yield, based on the American College of Medical Genetics, was 24, 2%. Genes belong to different pathways: metabolism and mitochondria (29.7%), follicular growth (24.3%), DNA repair/meiosis (18.9%), aging (16.2%), ovarian development (8.1%), and autophagy (2.7%). Five genes were recurrently found: LMNA, ERCC6, SOX8, POLG, and BMPR1B. Six genes identified in single families with POI were involved in DOR, GNAS, TGFBR3, XPNPEP2, EXO1, BNC1, ATG, highlighting their role in maintaining ovarian reserve. In our cohort, 26 pregnancies were recorded, but no pregnancy was observed when meiosis/DNA repair genes were involved, suggesting severely impaired oocyte quality. Additional studies should confirm these preliminary results. This study with a large NGS panel defines the genetic landscape of a large cohort of DOR. It supports routine genetic diagnosis. Genetics could be a biomarker predicting infertility and progression to POI.

Association of Changes in Relevant Indicators With Cardiovascular Disease and Osteoporosis in Perimenopausal and Postmenopausal Women

ABSTRACTThe essence of menopause is ovarian failure, decreased estrogen volatility, and deficiency leading to multiple related symptoms and an increased risk of metabolic disease in women, such as cardiovascular disease and osteoporosis. This study screened 773 eligible postmenopausal and perimenopausal women from an initial pool of 1187 participants, and various physiological and biochemical indices were measured and analyzed to assess differences across three age groups (40–44 years, 45–49 years, 50–54). We found no significant difference in the rate of cardiovascular disease between postmenopausal and perimenopausal women, while the rate of osteoporosis was higher in postmenopausal women compared to perimenopausal women. The disease of osteoporosis in postmenopausal women was associated with age (p &lt; 0.05). We also found that postmenopausal women and perimenopausal women had significant effects on follicle‐stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), total cholesterol (TC), lumbar spine BMD (T1), femoral neck BMD, The bone density (T2) of the right femur was significantly affected. There are significant differences in FSH, LH, E2, TC, low‐density lipoprotein (LDL), L2–L4, T1, Neck of femur decrease, and T2 in women of different ages. Furthermore, the correlation analysis between age and E2 and metabolic indicators showed that age has a greater impact on the risk of postmenopausal and perimenopausal females. This study can help further understand the mechanisms of cardiovascular disease and osteoporosis in perimenopausal and menopausal women.

Cardio-metabolic Disorders Affected by Genetic Polymorphisms Related to Premature Menopause.

Premature menopause (PM) is defined as the end of ovulation before the age of 40 years, a condition commonly referred to as primary ovarian insufficiency. It has been shown there is an association between early menopause and a high risk of cardiovascular disease. This study aimed to evaluate the effect of genetic polymorphisms related to premature menopause on cardio-metabolic disorders Objective: We aimed to investigate the single nucleotide polymorphisms associated with PM and the risk of cardio-metabolic disorders in the MASHAD cohort study. In this cross-sectional study, a total of 117 women with PM were recruited and compared with 183 healthy women. All participants were assessed for anthropometric indices and genotyped for eight selected polymorphisms within seven different genes. A significant difference was observed in physical activity level (PAL) between the groups. Individuals with rs4806660 CC genotype had a 3.63-fold increased risk of metabolic syndrome. Moreover, individuals with a TT genotype of the rs2303369 polymorphism had a 3.11-- fold increased risk of obesity. Our findings showed that genetic variations are risk factors related to cardio- metabolic disorders in women with premature menopause.

Uptake of gonadotrophin-releasing hormone agonists for prevention of premature ovarian insufficiency in women undergoing chemotherapy: an Australian single-centre study.

Treatment-related premature ovarian insufficiency (POI) can result in early-onset menopause and infertility. To assess the prevalence of goserelin use for POI prevention in women with cancer since it was listed by the Australian Pharmaceutical Benefits Scheme in 2018 for this indication. This retrospective study included women aged 18-45 years who received curative-intent alkylating chemotherapy for a malignancy between August 2020 and December 2022 at the Peter MacCallum Cancer Centre. The co-primary end-points were (i) documentation of a discussion with the patient regarding goserelin for POI prevention and (ii) prescription of goserelin for POI prevention prior to chemotherapy commencement. Sixty-six patients were eligible. Fifty patients (76%) had a documented discussion regarding goserelin for POI prevention and 53 patients (80%) were prescribed goserelin for POI prevention. Nulliparous women were more likely to have a discussion regarding goserelin (P = 0.004). Younger women, nulliparous women and those referred to a fertility service were more likely to have been prescribed goserelin for POI prevention (P = 0.003, P = 0.001 and P = 0.002 respectively). Twenty-one of 53 patients (40%) who received goserelin had the first dose administered ≥7 days before chemotherapy commencement. One-quarter of eligible patients did not have a documented discussion regarding goserelin, despite the negative consequences of POI. Efforts are needed to increase the discussion and use of goserelin in all premenopausal women regardless of their fertility interests and to ensure timely administration in those who choose to receive it.