Molecular Imaging of Ovarian Follicles and Tumors With Near-Infrared II Bioconjugates.
Advanced materials (Deerfield Beach, Fla.)
Follicular tracking is typically conducted using ultrasound technology, but its effectiveness is constrained by limited resolution. High-resolution imaging of deep tissues can be accomplished using luminescence imaging in the near-infrared II window (NIR-II, 1000-1700 nm); however, the contrast agents that are used lack specificity. Here, it is reported that the FDA-approved indocyanine green (ICG)-conjugated recombinant human chorionic gonadotropin (hCG) protein can target early follicles with long-term effectiveness. A novel high-resolution NIR-II imaging approach is developed for monitoring follicular development as well as ovulation using multi-color imaging of ovarian vessels with a combination of non-overlapping downconversion nanoparticles (DCNPs). The results showed that the ability to monitor early follicles of around 50 µm in diameter exceeded the spatial and temporal resolution of ultrasound or MRI without the reproductive damage associated with computed tomography radiation, and this enabled the clinical identification of the follicular reserve in patients with infertility diseases such as polycystic ovary syndrome (PCOS). In addition, NIR-II imaging clearly targeted ovarian tumors and showed micro-metastatic lesions, thus providing a new tool for monitoring tumors in vivo and guiding surgical resection.
10.1002/adma.202414129
Reproductive risk factors across the female lifecourse and later metabolic health.
Cell metabolism
Metabolic health is characterized by optimal blood glucose, lipids, cholesterol, blood pressure, and adiposity. Alterations in these characteristics may lead to the development of type 2 diabetes mellitus or dyslipidemia. Recent evidence suggests that female reproductive characteristics may be overlooked as risk factors that contribute to later metabolic dysfunction. These reproductive traits include the age at menarche, menstrual irregularity, the development of polycystic ovary syndrome, gestational weight change, gestational dysglycemia and dyslipidemia, and the severity and timing of menopausal symptoms. These risk factors may themselves be markers of future dysfunction or may be explained by shared underlying etiologies that promote long-term disease development. Disentangling underlying relationships and identifying potentially modifiable characteristics have an important bearing on therapeutic lifestyle modifications that could ease long-term metabolic burden. Further research that better characterizes associations between reproductive characteristics and metabolic health, clarifies underlying etiologies, and identifies indicators for clinical application is warranted in the prevention and management of metabolic dysfunction.
10.1016/j.cmet.2024.01.002
Bromodomain-containing protein 4 activates androgen receptor transcription and promotes ovarian fibrosis in PCOS.
Cell reports
Polycystic ovary syndrome (PCOS) is an endocrine disorder and the main cause of anovulatory infertility, in which persistent activation of androgen receptor (AR) due to aberrant acetylation modifications of transcription is a potential trigger; however, the precise mechanisms of AR activation are poorly understood. In this study, AR activation in dehydroepiandrosterone- and letrozole-induced rat PCOS ovaries coincided with a marked increase of a chromatin acetylation "reader" BRD4. Further bioinformatic analysis showed that the AR promoter contained highly conserved binding motifs of BRD4 and HIF-1α. BRD4 and HIF-1α inducibly bound to the histone 3/4 acetylation-modified AR promoter, while administration of a BRD4-selective inhibitor JQ1 reduced the binding and AR transcription and improved the adverse expression of the core fibrotic mediators in PCOS ovaries and DHT-treated granulosa cells. Our data indicate that BRD4 upregulation and the resultant AR transcriptional activation constitute an important regulatory pathway that promotes ovarian fibrosis in PCOS.
10.1016/j.celrep.2023.113090
Mendelian randomization analyses for PCOS: evidence, opportunities, and challenges.
Trends in genetics : TIG
Identifying etiological risk factors is significant for preventing and treating patients with polycystic ovary syndrome (PCOS). Through genetic variation, Mendelian randomization (MR) assesses causal associations between PCOS risk and related exposure factors. This emerging technology has provided evidence of causal associations of anti-Müllerian hormone (AMH) levels, sex hormone-binding globulin (SHBG) levels, menopause age, adiposity, insulin resistance (IR), depression, breast cancer, ovarian cancer, obsessive-compulsive disorder (OCD), and forced vital capacity (FVC) with PCOS, while lacking associations of type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), stroke, anxiety disorder (AD), schizophrenia (SCZ), bipolar disorder (BIP), and offspring birth weight with PCOS. In this review, we briefly introduce the concept and methodology of MR in terms of the opportunities and challenges in this field based on recent results obtained from MR analyses involving PCOS.
10.1016/j.tig.2022.01.005
Polycystic ovary syndrome.
Nature reviews. Disease primers
Despite affecting ~11-13% of women globally, polycystic ovary syndrome (PCOS) is a substantially understudied condition. PCOS, possibly extending to men's health, imposes a considerable health and economic burden worldwide. Diagnosis in adults follows the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome, requiring two out of three criteria - clinical or biochemical hyperandrogenism, ovulatory dysfunction, and/or specific ovarian morphological characteristics or elevated anti-Müllerian hormone. However, diagnosing adolescents omits ovarian morphology and anti-Müllerian hormone considerations. PCOS, marked by insulin resistance and hyperandrogenism, strongly contributes to early-onset type 2 diabetes, with increased odds for cardiovascular diseases. Reproduction-related implications include irregular menstrual cycles, anovulatory infertility, heightened risks of pregnancy complications and endometrial cancer. Beyond physiological manifestations, PCOS is associated with anxiety, depression, eating disorders, psychosexual dysfunction and negative body image, collectively contributing to diminished health-related quality of life in patients. Despite its high prevalence persisting into menopause, diagnosing PCOS often involves extended timelines and multiple health-care visits. Treatment remains ad hoc owing to limited understanding of underlying mechanisms, highlighting the need for research delineating the aetiology and pathophysiology of the syndrome. Identifying factors contributing to PCOS will pave the way for personalized medicine approaches. Additionally, exploring novel biomarkers, refining diagnostic criteria and advancing treatment modalities will be crucial in enhancing the precision and efficacy of interventions that will positively impact the lives of patients.
10.1038/s41572-024-00511-3
Polycystic ovary syndrome.
The lancet. Diabetes & endocrinology
Polycystic ovary syndrome (PCOS) affects 5-18% of women, and is a reproductive, metabolic, and psychological condition with impacts across the lifespan. The cause is complex, and includes genetic and epigenetic susceptibility, hypothalamic and ovarian dysfunction, excess androgen exposure, insulin resistance, and adiposity-related mechanisms. Diagnosis is recommended based on the 2003 Rotterdam criteria and confirmed with two of three criteria: hyperandrogenism (clinical or biochemical), irregular cycles, and polycystic ovary morphology. In adolescents, both the criteria of hyperandrogenism and irregular cycles are needed, and ovarian morphology is not included due to poor specificity. The diagnostic criteria generates four phenotypes, and clinical features are heterogeneous, with manifestations typically arising in childhood and then evolving across adolescent and adult life. Treatment involves a combination of lifestyle alterations and medical management. Lifestyle optimisation includes a healthy balanced diet and regular exercise to prevent excess weight gain, limit PCOS complications and target weight reduction when needed. Medical management options include metformin to improve insulin resistance and metabolic features, combined oral contraceptive pill for menstrual cycle regulation and hyperandrogenism, and if needed, anti-androgens for refractory hyperandrogenism. In this Review, we provide an update on the pathophysiology, diagnosis, and clinical features of PCOS, and discuss the needs and priorities of those with PCOS, including lifestyle, and medical and infertility treatment. Further we discuss the status of international evidence-based guidelines (EBG) and translation, to support patient self management, healthcare provision, and to set research priorities.
10.1016/S2213-8587(22)00163-2
Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction.
Science (New York, N.Y.)
Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.
10.1126/science.adk5382