Hyperandrogenism and insulin resistance are co-pathologies of polycystic ovary syndrome (PCOS). Recent evidence has suggested that elevated local cortisol levels are associated with ovarian and endometrial insulin resistance in hyperandrogenic PCOS patients, but the molecular mechanisms underlying these clinical findings remain unclear. We and others have used chronic treatment with human chorionic gonadotropin (hCG) and insulin to create an in vivo rodent model for the onset and development of PCOS-like phenotypes. Here, we aimed to determine whether the molecular mechanisms of glucocorticoid receptor (GR) signaling, mitochondrial function, and local inflammation in the ovary and uterus are intrinsically different in PCOS-like rats compared to controls. In both the ovary and the uterus, decreased expression of two GR protein isoforms was concurrent with increased expression of Fkbp51 but not Fkbp52 mRNA in PCOS-like rats compared to controls. However, PCOS-like rats exhibited an opposite regulation of Hsd11b1 or Hsd11b2 mRNAs in the two tissues. Further, the expression of several oxidative phosphorylation-related protein components was decreased in the PCOS-like ovary and uterus, but surprisingly the expression of many genes involved in mitochondrial function and homeostasis was increased in the same tissues and animals. Additionally, PCOS-like rats showed the increased expression of ovarian and uterine NFκB signaling proteins and Tnfaip3 mRNA. In PCOS-like rats, while similar decreased expression of Il1b, Il6, and Mmp2 mRNAs was seen in the ovary and uterus, the opposite regulation of Tnfa, Ccl2, Ccl5, and Mmp3 mRNA expression was observed in the two tissues. Both ovaries and uteri from PCOS-like animals showed increased collagen deposition compared to controls. Collectively, our observations suggest that hyperandrogenism and insulin resistance disrupt ovarian and uterine GR activation and trigger compensatory or adaptive effects for mitochondrial homeostasis, allowing tissue-level maintenance of mitochondrial function in order to limit ovarian and uterine dysfunction. Our study also suggests that hyperandrogenism and insulin resistance-induced activation of NFκB signaling resulting in aberrant regulation of inflammation-related gene expression might be tissue specific in female reproductive tissues.

Ovarian lymphoma is an infrequent disease, accounting for less than 1% of all non-Hodgkin lymphoma diagnosis. Symptoms include abnormal vaginal bleeding or discharge, abdominal pain, and urinary obstruction due to the large mass. In our case, a 60-year-old woman, underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy, as she presented with low-grade follicular lymphoma (FL) in both the ovaries, and the left ovary was observed to be enlarged. The tumor is categorized as lymphoma based upon immunohistochemical markers. Computed tomography (CT) scan of the chest, abdomen, and pelvis and bone marrow biopsy are important for the staging of primary lymphoma of the ovary. The first-line chemotherapy regimen includes rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone (R-CHOP) for rapidly proliferative non-Hodgkin lymphoma (NHL). Lymphomas with slower growth patterns can be treated with Bendamustine-Rituximab and don’t need aggressive R-CHOP treatment.

Polycystic ovary syndrome (PCOS) is a prevalent condition characterized by manifestations that can influence self-image and potentially result in psychological distress; however, data from literature on sexual function (SF) in PCOS women are contradictory. We aimed to evaluate sexual dysfunction (SD) in PCOS women by carrying out a systematic review and meta-analysis, using the gold-standard assessment tool SD-diagnosis (Female Sexual Function Index:FSFI). Seven databases were analyzed until August-2023; study quality was assessed by risk of bias and Newcastle Ottawa Scale. Our analysis encompassed 25 case-control studies (9933 women). PCOS group presented significantly lower scores in arousal (MD= -0.36 CI95%-0.60;-0.11), lubrication (MD= -0.52 CI95%-0.75;-0.28), orgasm (MD= -0.39 CI95%-0.57;-0.20), satisfaction (MD= -0.32 CI95%-0.50;-0.14) and pain subdomains (MD= -0.46 CI95%-0.75;-0.16), as in overall FSFI score (MD= -2.27 CI95%-3.23;-1.31). Overweight/obese (OW/O) patients exhibited significantly higher overall FSFI than OW/O controls (MD=1.98 CI95%0.68;3.27), particularly in lubrication (MD= -0.34), orgasm (MD= -0.26) and satisfaction (MD= -0.25) subdomains. These findings offer insights regarding SD in PCOS women and emphasize the need to incorporate SF assessment into multidisciplinary care. By this way, PCOS can be also considered a gateway diagnosis to other long-term consequences. Further research should focus on controlling variables, as ethnicity, culture, religion and economic disparities.

Polycystic ovary syndrome (PCOS) is a complex, but relatively common endocrine disorder associated with chronic anovulation, hyperandrogenism, and micro-polycystic ovaries [1]. In addition to reduced fertility, people with PCOS have a higher risk of obesity, insulin resistance, and metabolic disease [1], all comorbidities that are associated with mitochondrial dysfunction. This review summarizes human and animal data that report mitochondrial dysfunction and metabolic dysregulation in PCOS to better understand how mitochondria impact reproductive organ pathophysiology. This in-depth review considers all the elements regulating mitochondrial quantity and quality, from mitochondrial biogenesis under transcriptional regulation of both the nuclear and the mitochondrial genome, to the ultrastructural and functional complexes that regulate cellular metabolism and reactive oxygen species production, to dynamics which regulate subcellular interactions that are key to mitochondrial quality control. When any of these mitochondrial functions are disrupted the energetic equilibrium within the cell changes, cell processes can fail, and cell death can occur. If this process is ongoing, it affects tissue and organ function to cause disease. The objective of this review is to consolidate and classify a broad number of PCOS studies to understand how various mitochondrial processes impact reproductive organs including the ovary (oocyte and granulosa cell), uterus, placenta, and circulation to cause reproductive pathophysiology. A secondary objective is to uncover the potential role of mitochondria in transgenerational transmission of PCOS and metabolic disorders.

The corpus luteum is a temporary endocrine gland formed in the ovary after ovulation, and it plays a critical role in reproductive processes. Tumors rely on the development of an adequate blood supply to ensure the delivery of nutrients and oxygen and the removal of waste products. While angiogenesis occurs in various physiological and pathological contexts, the corpus luteum and tumors share similarities in the signaling pathways that promote angiogenesis. In the corpus luteum and tumors, apoptosis plays a crucial role in controlling cell numbers and ensuring proper tissue development and function. Interestingly, there are similarities in the apoptotic-regulated signaling pathways involved in apoptosis between the corpus luteum and tumors. However, the regulation of apoptosis can differ due to their distinct physiological and pathological characteristics. Thus, we reviewed the biological events of the corpus luteum and tumors in similar microenvironments of angiogenesis and apoptosis for studying novel research methods.

Female gynecological organ dysfunction can cause infertility and psychological distress, decreasing quality of life of affected women. Incidence is constantly increasing due to growing rates of cancer and delaying of childbearing age in the developed world. Current treatments are often unable to restore organ function, and occasionally are the cause for female infertility. Alternative treatment options are currently being developed in order to face the inadequacy of current practices. In this review, pathologies and current treatments of gynecological organs (ovaries, uterus, and vagina) will be described. The state-of-the-art of tissue engineering alternatives to common practices are evaluated with a focus on in vivo models. Tissue engineering is an ever-expanding field, integrating various domains of modern science to create sophisticated tissue substitutes in the hopes of repairing or replacing dysfunctional organs using autologous cells. Application to gynecology has the potential of restoring female fertility and sexual wellbeing.

Background: Polycystic ovary syndrome (PCOS) is a common reproductive and endocrinological disease characterized by ovulatory dysfunction, polycystic ovaries, and hyperandrogenism. Adipokines are believed to contribute to developing PCOS and its accompanying metabolic complications such as dyslipidemia, insulin resistance, and cardiovascular diseases. Oncostatin M (OSM), a novel adipokine, plays a role in oogenesis, lipogenesis, and inflammation and may contribute to PCOS pathogenesis and its related metabolic problems. Methods: In this case-control study, the patients were grouped in a 1:1 ratio into either the PCOS (n = 32) or the control group (n = 32). Blood samples were obtained between the 3rd and 5th days of the menstrual cycle. Serum levels of fasting glucose, insulin, C-reactive protein (CRP), low-density lipoprotein, high-density lipoprotein, triglyceride, white blood cell count, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, total testosterone, prolactin estradiol, and OSM were analyzed. Results: OSM levels were significantly lower, but CRP levels were substantially higher in the PCOS group than in the control group (p = .002, p = .001, respectively). OSM was inversely correlated with total cholesterol, non-high-density lipoprotein cholesterol, fasting glucose, and the luteinizing hormone/follicle-stimulating hormone ratio (ρ = .329, p = .017; ρ = .386, p = .005; ρ = .440, p = .001; ρ = .316, p = .023, respectively). Conversely, there was no correlation between OSM and total testosterone level (ρ = .220; p = .118). In the context of inflammation and metabolic parameters, OSM was inversely correlated with CRP, Homeostatic Model Assessment for Insulin Resistance score (HOMA-IR), and low-density lipoprotein cholesterol (LDL) (ρ = .353, p = .019; ρ = .275, p = .048; ρ = .470, p < .001, respectively). The performance of Oncostatin M for diagnosing PCOS showed 50% sensitivity, 75% specificity, and 63% accuracy (p = .009) in ROC curve analysis. Conclusions: Plasma OSM levels were considerably lower in patients with PCOS than in the control group, and this was inversely correlated with the hormonal and metabolic parameters of PCOS. Thus, OSM may be a novel therapeutic target for PCOS and metabolic complications.

Although effective in term of chance of future live birth, the current methods for fertility preservation such as oocytes, embryo or ovarian tissue cryopreservation cannot be offered to all cancer patients and in all clinical contexts. Expanding options for fertility preservation is crucial to address the need to encompass all situations. One emerging strategy is pharmacoprotection, which is non-invasive and has the potential to fill existing gaps in fertility preservation. Besides the identification of the most efficient therapeutic agent itself, the potential off-target effect re-mains one of the main limitation of this strategy for clinical application, particularly when healthy ovarian tissue is targeted. This review focuses on the advances in pharmacoprotective approaches and the challenge of targeting the ovaries to deliver these agents. The unique properties of gold nanoparticles (AuNPs) make them an attractive candidate for this purpose. We discuss how AuNPs meet many of the requirements for an ideal drug delivery system, as well as the existing limitations that have hindering the progression of AuNPs research into more clinical trials. Additionally, the review highlights microRNA (miRNA) therapy as a next-generation approach to address the issues of fertility preservation and discusses the obstacles that currently impede its clinical availability.

On a bleak therapeutic landscape unchanged since the 1980’s, IVF with egg donation still stand as the lone medical answer to diminished reserve and premature ovarian insufficiency. Intraovarian platelet-rich plasma (PRP) crossed the horizon in 2016 as hopeful answer to these intertwined problems. The once remote mirage of platelet cytokine effects on gene regulation or telomere stabilization is now in sharper focus, and current work is clarifying how PRP corrects oxidative stress, rectifies tissue hypoxia, downregulates apoptosis, and enhances cellular metabolism. Not yet ready for routine use, this investigational treatment does offer one point of general agreement: How intraovarian PRP results should be classified—Patients are either responders or non-responders. From this, it is intriguing that no published PRP protocol has reported a supranormal ovarian rebound or hyperstimulation effect. This could be explained by baseline age-related ovarian conditions prevalent among poor responders, but since dysregulated or malignant transformations are also absent in other tissue contexts following autologous PRP treatment, the contribution of some platelet product which intrinsically delimits regenerative action cannot be discounted. Here we summarize results with recent experimental and clinical platelet research, framing those most likely to help advance reproductive endocrinology practice.

Understanding the reproductive patterns and strategies of a species is an important step in establishing the species’ life history. Campostoma oligolepis, the Largescale Stoneroller, is a species that has received little attention in the 90 years since it was first identified, and the work that has been done has been localized in the American Midwest. Collections of C. oligolepis were made monthly from the Flint River in Madison County in northern Alabama, USA, from March, 2014, to September, 2015. A total of 768 fish were collected over the collection period including 492 adults, 268 females and 224 males. We found strong evidence that the peak spawning time for C. oligolepis in the Flint River is March and April. Ovarian maturation, gonadosomatic index for both sexes, and monthly clutch size all support this conclusion. Two unexpected features were found. The first is how few females of mature size were found to carry either oocytes or a clutch except in the peak observed reproductive month of April, 2014. The second unusual feature is the prevalence of asymmetric ovaries, with the left the larger if a difference exists. Campostoma oligolepis may have unusually strong inter-annual responses to abiotic factors such as water temperature and river discharge.

Mycotoxins are produced by more than one hundred fungi and produce secondary metabolites that contaminate various agricultural commodities, especially rice and corn. Their presence in the food chain is considered a serious problem worldwide. In recent years, a link between exposure to mycotoxins and impaired fertility has been suggested. Consequently, it has become vital to investigate the interactive effects of these mycotoxins on ovarian function. In this study, we investigated the intergenerational effects of mycotoxin fumonisin B1 (FB1) on ovarian structure and function. Virgin Wistar albino female rats were separated into control and FB1 treatment groups and examined from day 6 of pregnancy until delivery (20 and 50 mg/kg/day). The obtained females of the first (F1) and second generations (F2) were euthanized at 4 weeks of age, and ovary samples were collected. We found that the ovary weight index increased with the high dose of treatment (50 mg/kg/day) among both F1 and F2, similar to that observed in polycystic ovary syndrome. As expected, FB1 at a high dose (50 mg/kg) reduced the number of primordial follicles in F1 and F2, leading to an accelerated age-related decline in reproductive capacity. Moreover, it reduced the fertility rate among F1 females by affecting follicle growth and development, as the number of secondary and tertiary follicles was decreased. Histopathological changes were evidenced by the altered structures of most of the growing follicle oocytes, as revealed by a thinning irregular zona pellucida and pyknosis in granulosa cells. These findings are concomitant with steroidogenesis- and folliculogenesis-related gene expression, as evidenced by the decrease in CYP19 activity and estrogen receptor beta (ESR2) gene expression. Additionally, GDF-9 mRNA levels significantly decreased, and IGF-1 mRNA levels significantly increased. However, the results from the ovaries of the F2 treatment groups were different and unexpected. While there was no significant variation in CYP19 compared to the control, ESR2 significantly increased, leading to stereological and histopathological changes similar to those of the control, except for some altered follicles. The hallmark histological feature was the appearance of vacuolar structures within the oocyte and between granulosa cell layers. Interestingly, the autophagic marker LC3 significantly increased in F2 offspring, whereas this protein significantly decreased in F1 offspring. Therefore, we suggest that the promotion of autophagy among the ovaries of F2 offspring may be considered a recovery mechanism from the effect of prenatal FB1 exposure. Thus, autophagy corrected the effect of FB1 during the early life of F1 females, leading to F2 offspring with ovarian structure and function similar to those of the control. However, the offspring treated females may have early ovarian aging because their ovarian pool was affected.

The corpus luteum is a temporary reproductive endocrine structure established from a ruptured follicle wall after ovulation. In the ovarian cycle of ruminant species, the corpus luteum organ undergoes a repeated pattern of specific cellular proliferation, differentiation, and transformation. The corpus luteum encounters several physiological events, including growth, function, and regression throughout its life span. Also, the corpus luteum comprises granulosa and theca cells and endothelial cells, such as luteal steroidogenic cells and luteal endothelial cells. These cells play an important role in the physiology of the corpus luteum and the maintenance and degeneration of the corpus luteum. Furthermore, the role of reproductive hormones in the ovaries is important. Representative hormones include estrogen, progesterone, prostaglandin F2α, and oxytocin. Understanding their functions is important in studying the physiological phenomena and various mechanisms of the corpus luteum in the ovary. Therefore, the following review will discuss the role of reproductive hormones and luteal cell types in the microenvironment of the corpus luteum in the bovine ovary.

Cancer treatment with specific chemotherapeutic agents has been well documented to have an adverse impact on female fertility leading to premature ovarian failure (POF). The objective of this study was to investigate if chemotherapeutic induced POF can be reversed with an infusion of autologous nucleated peripheral blood cells (PBMC). To reach our goal, mice were treated with a single intraperitoneal injections of busulfan and cyclophosphamide to induce POF. This was followed by transfusion of PBMC. The ovarian morphology and functional parameters were monitored by radioimmunoassay, real-time PCR, immunofluorescence and immunohistochemistry analysis. Our study showed that chemotherapy (CTX) protracted estrous cycle period and repressed E2 production. CTX decreased the expressions of steroidogenesis markers- CYP-17 synthesis, StAR and Connexin-43 protein expression from the ovarian follicles. We also observed reduced numbers and sizes of the primordial and primary follicles in CTX-treated mice compared to untreated controls (P < 0.05). When both CTX and untreated –control groups were stimulated with gonadotrophin, the control group produced ten times more ova than the CTX group. Finally, the treatment of premature ovarian failure induced by CTX with autologous PBMC transfusion resulted in over-expression and a statistically significant increase in several stem cell markers and restoration of fertility. Infusion with PBMC in CTX further decreased the estrous cycle length by 2.5 times (P < 0.01). We found that transfusion of autologous PBMC to mice with chemotherapy induced POF was very effective at restoring fertility. These results are similar to other studies using bone marrow derived mesenchymal stem cells.

Pomegranate extract has potential benefits for women's reproductive health, including fertility enhancement, menstrual cycle regulation, pregnancy support, and polycystic ovary syndrome (PCOS) treatment. It possesses antioxidant properties, reducing oxidative stress and improving fertility. Phytoestrogens in pomegranate extract may help regulate hormonal imbalances and promote regular menstrual cycles. The extract's rich nutrient profile supports placental development and fetal growth and may reduce the risk of preterm birth. Additionally, pomegranate extract shows promise in improving insulin sensitivity and reducing inflammation and oxidative damage in PCOS. Some studies suggest its potential anticancer properties, particularly against breast cancer. However, further research, including human clinical trials, is necessary to establish its effectiveness and safety. The current evidence is limited and primarily based on in vitro studies, animal studies, and clinical trials. This review provides a comprehensive summary of the benefits of pomegranate extract for women's reproductive health and breast cancer, serving as a reference for future research.

Polycystic Ovary Syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder in women of reproductive age. Diagnosis of this syndrome relies on criteria established by the Rotterdam Consensus, with PCOS phenotypes being crucial for distinguishing potential complications, treatment approaches, and timing. The aim of this study is to characterize the biodemographic, clinical, metabolic, and reproductive variables and their association with PCOS phenotypes in a population from the Ecuadorian Andes. Methodology: A cross-sectional study was conducted with a non-random consecutive sample of 92 women attending the gynecology and endocrinology outpatient clinic at the Technical University of Loja Hospital (UTPL)-Santa Inés, Loja, Ecuador, between January 2022 and July 2023.Results: The average age was 22±3.4 years, predominantly mestizo, urban, single, with higher education and a medium-high socioeconomic status. Oligo-amenorrhea and acne appear strongly associated with phenotypes A and B, while hirsutism and polycystic ovaries on ultrasound show a weaker association with these phenotypes. Alopecia is more prevalent in phenotypes C and D. Triglyceride levels and BMI have a strong association with phenotypes A and B. Total testosterone levels, 17 OH progesterone, LH, and free androgen index show a moderate association with phenotypes A and B, while other reproductive variables exhibit weak associations. Conclusions: Classical phenotypes A and B of PCOS are most common in Andean Ecuadorian women, carrying higher risks of insulin resistance, anovulation, metabolic disorders, and elevated triglycerides compared to phenotypes C and D. Ethnic diversity and sociocultural habits influence the prevalence and clinical manifestations of phenotypes.

Emerging evidence has indicated the involvement of extra-hypothalamic kisspeptin and GnRHR in reproductive function. In this study, we evaluate if maternal exposure to the pesticide chlorpyrifos (CPF) and/or a high-fat diet (HFD) have an impact on the expression of kisspeptin and GnRHR in reproductive organ of offspring’s rats. 16 Pregnant rats are divided into 4 groups, control group (n=4), CPF group (4 rats exposed daily to 1/mg/kg/day), HFD group (4 rats randomly fed a 5,25 kcal/g HFD), co-exposed group (4 rats exposed to CPF and HDF). At postnatal development PND60, males and female offspring were sacrificed. The reproductive organs (ovary and testis) were removed and histological, immunohistological analysis and in silico quantification (software Tissuefax, HistoQuest) was assessed to investigate the impact of different treatment on kisspeptin and GnRHR expression in reproductive organs. The main outcomes of the study showed a significant decrease in rat offspring’s body weight in CPF group from PND30 andPND60 (p&lt;0.05 and p&lt;0.01, respectively). Histological analysis shows a significant increase in atretic follicle and abnormal testis structure with germ cell desquamation at CPF exposed group. The immunodetection quantification of protein shows a significant decrease in GnRHR and kisspeptin in HFD and CPF exposed group, respectively in testis rat offspring. Perinatal exposure to CPF and HFD exposure affect the reproduction function of rat offspring.

Background: Ovarian mesonephric-like adenocarcinoma (MLA) is a newly described histological type known for its aggressive behavior. This study aims to determine the frequency of ovarian MLA, review existing literature, and elucidate its clinicopathological characteristics, including potential therapeutic targets. Methods: We retrospectively reviewed the pathological diagnoses of 516 primary ovarian cancer surgical cases at our institution from 2010 to 2023. MLAs exhibiting typical morphological and immunohistochemical features were included. The frequency and clinicopathological characteristics of these cases were summarized. Additionally, we conducted a literature search using PubMed to collect and summarize previously reported cases of ovarian MLA. Results: Among the 516 primary ovarian cancer cases, we identified 3 cases (0.6%) of MLA. The patients were 52-76 years old, and the initial FIGO stages were IC1 (2 cases) and IIIB (1 case). All cases exhibited HRP, pMMR, PD-L1 negativity (CPS&lt;1), and HER2-low expression. Two cases experienced metastatic recurrence. A literature review identified 97 cases of MLA. MLA frequently exhibited KRAS mutations (90%, 38/42), with a recurrence rate of 39% (26/67). Conclusion: MLA accounted for 0.6% of malignant ovarian tumors at our institution, all of which were advanced or recurrent cases. These cases showed HRP, pMMR, and PD-L1 negativity, indicating a lack of current therapeutic targets. Literature also reports a high incidence of advanced and recurrent cases, highlighting the need for accurate diagnosis and the development of new treatments. The frequent KRAS mutations suggest a potential therapeutic target for recurrent or metastatic MLA.

Ozonated sunflower oil (OSO) is renowned for its diverse therapeutic benefits. Nonetheless, the consequences of extended dietary intake of OSO have yet to be thoroughly investigated. Herein, the effect of 2-year dietary supplementation of OSO was examined on the zebrafish survivability, obesity, skeletal deformities, swimming behavior, and liver, kidney, ovary, and testis function. Results showed that the zebrafish feed supplemented with 20% (wt/wt) OSO for 2 years emerged with higher survivability and body weight management compared to sunflower oil (SO) and normal diet (ND) supplemented zebrafish. Radio imaging (X-ray) based analysis revealed 2.6o and 15.2o lower spinal curvature in the OSO-supplemented groups than in SO and ND-supplemented groups; consistently, OSO-supplemented zebrafish showed better swimming behavior. The histology analysis of the liver revealed a least fatty liver change and interleukin 6 (IL-6) generation in the OSO-supplemented group. Additionally, a significantly lower level of reactive oxygen species (ROS), apoptotic, and senescent cells were observed in the liver of the OSO-supplemented zebrafish. Also, no adverse effect on the kidney, testis, and ovary morphology was detected during 2 years of OSO consumption. Moreover, lower senescence with diminished ROS and apoptosis was noticed in the kidney and ovary in response to OSO consumption. The OSO supplementation was found to be effective in countering age-associated dyslipidemia by alleviating total cholesterol (TC), triglycerides (TG), low-density lipoproteins (LDL-C) and elevating high-density lipoproteins (HDL-C)/TC levels. Conclusively, prolonged OSO consumption showed no adverse effect on the morphology and functionality of vital organs; in fact, OSO supplementation displayed a protective effect against age-associated detrimental effects on spinal deformities, vital organ functionality, cell senescence, and survivability of zebrafish.

Background: Polycystic ovary syndrome is a common reproductive and endocrinological disease characterized by ovulatory dysfunction, polycystic ovaries, and hyperandrogenism. Adipokines are believed to contribute to developing polycystic ovary syndrome and its accompanying metabolic complications such as dyslipidemia, insulin resistance, and cardiovascular diseases. Oncostatin M, a novel adipokine, plays a role in oogenesis, lipogenesis, and inflammation and may contribute to polycystic ovary syndrome pathogenesis and its related metabolic problems. Methods: In this case-control study, the patients were grouped in a 1:1 ratio into either the polycystic ovary syndrome (n = 32) or the control group (n = 32). Blood samples were obtained between the third and fifth days of the menstrual cycle. Serum levels of fasting glucose, insulin, C-reactive protein, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, white blood cell count, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, total testosterone, prolactin, estradiol, homeostasis model assessment of insulin resistance and oncostatin M were analyzed. Results: Oncostatin M levels were significantly lower, but C-reactive protein levels were substantially higher in the polycystic ovary syndrome group than in the control group (p = 0.002, p = 0.001, respectively). Oncostatin M was inversely correlated with total cholesterol, non-high-density lipoprotein cholesterol, fasting glucose, and the luteinizing hormone/follicle-stimulating hormone ratio (ρ = -0.329, p =0 .017; ρ = -0.386, p = 0.005; ρ = -0.440, p = 0.001; ρ = -0.316, p = 0.023, respectively). Conversely, there was no correlation between oncostatin M and total testosterone level (ρ = 0.220; p = 0.118). In the context of inflammation and metabolic parameters, oncostatin M was inversely correlated with C-reactive protein, homeostatic model assessment for insulin resistance score, and low-density lipoprotein cholesterol (ρ = -0.353, p = 0.019; ρ = -0.275, p = 0.048; ρ = -0.470, p &lt; 0.001, respectively). The diagnostic performance of oncostatin M, C-reactive protein, homeostasis model assessment of insulin resistance, and non-high-density lipoprotein cholesterol for polycystic ovary syndrome is as follows: Oncostatin M, sensitivity: 50%, specificity: 75%, Accuracy: 63%, p = 0.009; C-reactive protein, sensitivity: 84%, specificity: 61%, Accuracy: 74%, p = 0.004; homeostasis model assessment of insulin resistance, sensitivity: 72%, specificity: 81%, Accuracy: 77%, p &lt; 0.001; and non-high-density lipoprotein cholesterol; sensitivity: 72%, specificity: 75%, accuracy: 73%, p &lt; 0.001. Conclusions: Plasma oncostatin M levels were considerably lower in patients with polycystic ovary syndrome than in the control group, and this was inversely correlated with the hormonal and metabolic parameters of polycystic ovary syndrome. Thus, oncostatin M may be a novel therapeutic target for polycystic ovary syndrome and its metabolic complications.

The aim of this study was to examine whether H2O2, generated in such beverages as tea and coffee, is formed also in infusions of medicinal herbs and propose the possible mechanism of its formation. Infusions of sixteen herbs were studied and the presence of H2O2 was found in all cases. The highest concentrations of H2O2, exceeding 50 µM, were found in the infusions of leaves of Betula and Polygonum, and of the inflorescence of Tilia. These low amounts of H2O2 should not have a harmful effect and may even exert beneficial action, perhaps contributing to the health effects of the herbs. Generation of semiquinone and superoxide radicals was detected in herbal infusions, indicating that oxidation of phenolic compounds is the main source of H2O2 in these infusions. Herbal infusions were cytotoxic to human ovary cancer SKOV-3 and PEO1 cells; this cytotoxicity was compromised by catalase added to the growth medium, demonstrating the contribution of hydrogen peroxide to the cytotoxic action of herbal extracts.

Background: Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is highly prevalent in women of Indian ethnicity. Clinical practice guidelines do not adequately consider ethnic-cultural differences in the care of women with PCOS. This study aimed to explore ethnic Indian women’s experiences with PCOS diagnosis and management, their concerns and it’s impact on their quality of life (QoL). Methods: Global online survey of ethnic Indian women of reproductive age living with PCOS. Results: Respondents (n=4409) had a mean age of 26.8 (SD 5.5) years and the majority were diagnosed with one or more co-morbidities (anxiety/depression being the most common). Women waited one year on average before seeking treatment following symptom onset. Irregular periods, cysts on the ovaries and excess unwanted facial hair growth were their three major concerns. Weight and emotional concerns had the greatest impact on QoL. One-third did not receive information on long-term complications, appropriate behavioral advice to improve diet or exercise, or emotional support following diagnosis. Among those who received information at diagnosis, the majority were dissatisfied. Conclusions: Ethnic Indian women wait for a considerable time before seeking medical help for PCOS, have poor QoL relating to weight and mental health and are dissatisfied with the information and support provided at diagnosis. These gaps in care should be addressed in clinical practice and future research.

Polycystic Ovarian Syndrome (PCOS) is a common endocrine condition that affects 8–13% of women of reproductive age and is one of the leading causes of anovulation and infertility. In Kazakhstan, the prevalence of this syndrome is particularly high compared to other countries and the global average. Currently, the diagnosis of polycystic ovarian syndrome is based on internationally established Rotterdam criteria, using hyperandrogenism, i.e. high testosterone levels, as a key parameter. These criteria are applied to diagnose PCOS in all female patients, although obese patients may have excess testosterone produced by adipose tissue. To avoid possible false PCOS diagnoses, an additional criterion could be considered to diagnose PCOS among obese women. Anti-Müllerian hormone (AMH) is promising as a more effective diagnostic criterion, since its level represents the state of the ovarian reserve and adipose tissue does not produce AMH. Therefore, the use of AMH instead of hyperandrogenism as a diagnostic criterion for PCOS among obese women might improve diagnostic precision and patient treatment. In this study, data on the levels of various hormonal indicators such as estrogen, progesterone, and others were analyzed for a large cohort of female patients with and without PCOS to explore possible correlations between these indicators, AMH, and testosterone. The findings suggest that the absence of a negative correlation between AMH and follicle-stimulating hormone (FSH), and a positive correlation of AMH with testosterone could support the use of AMH as a reliable additional criterion for PCOS diagnosis among obese women.

Background: Endocrine conditions that impact women define polycystic ovary syndrome. Previous studies have demonstrated a connection between PCOS and insulin intolerance, oxidative stress, and immune system dysfunction. Additionally, some reports have indicated that propolis has antioxidant properties and that chitosan nanoparticles have beneficial effects on the reproductive system. The goal of the present study is to compare metformin (Met) to chitosan-propolis nanoparticles and explain how they protect against a rat PCOS model caused by estradiol valerate (EV). (as a control treatment). Methods: In order to cause PCOS in rodents, a single subcutaneous injection of estradiol valerate was used, followed by a 42-day oral administration of 500 mg/kg of chitosan-propolis nanoparticles. Four sets of rats were created: the control, PCOS, metformin (PCOS and 150 mg/kg metformin), and chitosan-propolis nanoparticle (PCOS and 500 mg/kg chitosan-propolis nanoparticle) groups. The histopathological examination of the ovaries and measurement of serum ferctors were performed on all of the animals. Estradiol valerate caused PCOS, but chitosan-propolis nanoparticle therapy reversed it. Results: After chitosan-propolis nanoparticle intervention, the body weight and ovarian morphology had improved, and the serum biochemical parameters, including esretogen, progestron, vitamin D, calcium, and the insulin resistance index, had been corrected. These EV-induced changes include decreased SOD activity, elevated MDA levels, and evidence that oxidative stress was increased by EV when chitosan-propolis nanoparticle/Met were administered for 42 straight days. Additionally, certain relative mRNA transcripts, including those for the MCP, IL18, and CRP genes, were markedly upregulated in EV-treated animals. These findings unequivocally demonstrate the beneficial effects of chitosan-propolis nanoparticles/Met in inflammatory disorders. Conclustion: Together, the study's end findings, which are presented here, are consistent with the hypothesis that chitosan-propolis nanoparticle/Met offered protective activity against the harmful effects of EV. Although ameliorative effects may have been implicated, the primary pathway or pathways still need to be clarified.

We identified a novel heterozygous hypofibrinogenemia, γY278H (Hiroshima). To demonstrate the cause of reduced plasma fibrinogen levels (functional level: 1.12 g/L and antigenic level: 1.16 g/L), we established γY278H fibrinogen-producing Chinese hamster ovary (CHO) cells. An enzyme-linked immunosorbent assay demonstrated that synthesis of γY278H fibrinogen inside CHO cells and secretion into the culture media were not reduced. Then, we established an additional five variant fibrinogen-producing CHO cell lines (γL276P, γT277P, γT277R, γA279D, and γY280C) and performed further investigations. We have already established 33 γ-module variant fibrinogen-producing CHO cell lines including 6 cell lines in this study, but only the γY278H and γT277R cell lines showed disagreement, namely recombinant fibrinogen production was not reduced but the patients’ plasma fibrinogen level was reduced. Finally, we performed fibrinogen degradation assays and demonstrated that the γY278H and γT277R fibrinogens were easily cleaved by plasmin whereas their polymerization in the presence of Ca2+ and “D:D” interaction was normal. In conclusion, our investigation suggested that patient γY278H showed hypofibrinogenemia because γY278H fibrinogen is secreted normally from the patient’s hepatocytes but had accelerated degradation by plasmin in the circulation.

Exosome-based therapy has emerged as a promising strategy for addressing diverse disorders, indicating the need for further exploration of the potential therapeutic effects of the exosome cargos. This study introduces "enhanced exosomes," a novel type of exosomes developed through a novel cell culture system. These specific exosomes may become potent therapeutic agents for treating ovarian disorders. In this study, we conducted a comparative analysis of the protein and miRNA cargo compositions of enhanced exosomes and naïve exosomes. Our findings revealed distinct cargo compositions in enhanced exosomes, featuring upregulated proteins such as EFEMP1, HTRA1, PAM, RSU1, and SDF4, suggesting their potential for treating ovarian disorders. MicroRNA profiling revealed that miR-1-3p, miR-103a-3p, miR-122-5p, miR-1271-5p, miR-133a-3p, miR-184, miR-203a-3p, and miR-206 are key players in regulating ovarian cancer and chemosensitivity by affecting cell cycle progression, cell proliferation, and cell development. We examined polycystic ovary syndrome and premature ovarian insufficiency and identified altered expression of various miRNAs, such as miR-106a-5p, miR-130b-5p, and miR-130b-3p, for diagnostic insights. This study highlights the potential of enhanced exosomes as new therapeutic agents for women's reproductive health, offering a detailed understanding of the impact of their cargo on ovarian disorders.

Current research suggests that polycystic ovary syndrome (PCOS) might originate in utero and implicates the placenta in its pathogenesis. Kisspeptin (KISS1) and neurokinin B (NKB) are produced by the placenta in high amounts, and they have been implicated in several pregnancy complications associated with placental dysfunction. However, their placental expression has not been studied in PCOS. We isolated mRNA after delivery from the placentae of 31 PCOS and 37 control women with term, uncomplicated, singleton pregnancies. The expression of KISS1, NKB, and neurokinin receptors 1, 2, and 3 was analyzed with real-time polymerase chain reaction, using β-actin as the reference gene. Maternal serum and umbilical cord levels of total testosterone, sex hormone binding globulin (SHBG), free androgen index (FAI), androstenedione, dehydroepiandrosterone sulfate (DHEAS), Anti-Mullerian hormone (AMH), and estradiol were also assessed. NKB placental mRNA expression was higher in PCOS versus controls in pregnancies with female offspring. NKB expression depended on fetal gender, being higher in pregnancies with male fetuses. NKB was positively correlated with umbilical cord FAI and AMH, and KISS1 with cord testosterone and FAI; there was also a strong positive correlation between NKB and KISS1 expression. Women with PCOS had higher serum AMH and FAI and lower SHBG than controls. Our findings indicate that NKB might be involved in PCOS-related placental dysfunction, and warrant further investigation. Studies assessing the placental expression of NKB should take fetal gender into consideration.

Polycystic ovary syndrome (PCOS) is increasingly being viewed as an evolutionary mismatch disorder that manifests in women after exposure to a range of lifestyle and environmental factors. Although there is ongoing debate regarding the pathogenesis, international guidelines recommend lifestyle treatment, with diet and exercise, as the first line of management in all women with PCOS. In addition, accumulating evidence suggests that environmental factors such as endocrine disrupting chemicals (EDC) may be involved in the pathogenesis of PCOS due to their known hormonal and metabolic effects. As a result, international professional bodies have recommended that all pregnant women be advised of the risks of EDC and that education programs be developed to inform health professionals. Microparticulate air pollution (MAP) is also a significant environmental exposure that has been associated with a variety of chronic diseases, including PCOS. We performed a systematic review of studies examining the relationship between MAP and PCOS using the PRISMA methodology. The review identified 214 records from PubMed, Cochrane, and Scopus databases, and 4 studies that met the inclusion criteria for qualitative assessment. Preliminary data suggest that MAP may contribute to the pathogenesis of PCOS via a number of mechanisms. This review highlights the need for greater awareness and further research on the effects of MAP in women with PCOS.

A critical quality attribute of therapeutic monoclonal antibodies (mAbs) is the terminal sugar molecules of the N-linked glycan attached to the fragment crystalizable (Fc) region. There exists naturally-occurring heterogeneity in the N-linked glycan structure of mAbs, and such heterogeneity has a significant influence on the clinical safety and efficacy of mAb drugs. We previously proposed a constraint-based modeling method called glycosylation flux analysis (GFA) to characterize the rates (fluxes) of intracellular glycosylation reactions and applied the method to examine the N-linked glycosylation of immunoglobulin G (IgG) in fed-batch Chinese hamster ovary (CHO) fed-batch cultivations. In this work, we significantly improved the computational efficiency of the GFA, and employed the method to analyze the glycosylation of IgG in continuous perfusion CHO cultivations. Perfusion cell cultures have several advantages over the traditional (fed-)batch operation, including higher productivity per unit volume of reactor and more consistent product quality. The GFA showed that as in the fed-batch cultivation, the dynamical changes of IgG glycan heterogeneity in the perfusion culture are mainly attributed to alterations in the galactosylation flux activity. Furthermore, a regression analysis of the galactosylation flux activity using random forest regression linked the dynamics of galactosylation activity with the cell-specific productivity of IgG and the extracellular ammonia concentration.

Polycystic ovary syndrome (PCOS) usually comes along with metabolic disturbances attributed to androgen excess and obesity, but the contribution of each has not been defined, and the occurrence of metabolic disturbances is frequently not investigated. We evaluated 99 PCOS and 41 non-PCOS women. Clinical biomarkers of glucose-, liver-, and endothelial-related metabolic alterations were measured; participants were categorized into four groups according with obesity (OB) and hyperandrogenemia (HA) statuses: Healthy (no-HA, lean), HA (HA, lean), OB (no-HA, OB), and HAOB (HA, OB). Metabolic disturbances were highly frequent in PCOS women (70%). BMI correlated with all biomarkers, while free testosterone (FT) only with glucose- and hepatic-related indicators. Despite insulin sensitivity and liver enzymes were associated with FT, women with obesity exhibited lower M [coeff = 8.56 – 0.080(FT) –3.71(Ob); p &lt;0.001)] and higher aspartate aminotransferase (coeff = 26.27 + 0.532(FT) + 8.08(Ob); p = 0.015)] than lean at the same level of FT. Women with obesity exhibited greater risk of metabolic disorders than lean, independently of hyperandrogenemia. Clinicians are compelled to search for metabolic alterations in PCOS women; obesity must be handled in all cases, but hyperandrogenemia needs to be managed also in those with glucose- or liver-related disturbances.

Resveratrol is one of the most investigated natural polyphenolic compounds and is contained in more than 70 types of plants and in red wine. The widespread interest in this polyphenol derives from its antioxidant, anti-inflammatory and anti-aging properties. Several studies have established that resveratrol regulates animal reproduction. However, the mechanisms of action and the potential therapeutic effects are still unclear. This review aims to clarify the role of resveratrol in the male and female reproductive functions, with a focus on animals of veterinary interest. In the female, resveratrol has been considered a phytoestrogen due to its capacity to modulate ovarian function and steroidogenesis via sirtuins, SIRT1, in particular. Resveratrol has also been used to enhance aged oocyte quality, and as a gametes cryo-protectant with mainly antioxidant, and anti-apoptotic effects. In the male, resveratrol enhanced testes function and spermatogenesis through activation of AMPK pathway. Furthermore, resveratrol has been supplemented to semen extenders improving the preservation of sperm quality. In conclusion, resveratrol has potentially beneficial effects for ameliorating ovarian and testes function. However, due to unclear data, further studies are necessary to consolidate these findings.

Polycystic ovary syndrome (PCOS) is a complex disorder that impacts both the endocrine and metabolic systems. The gut microbiota plays a crucial role in in metabolism regulation and immune responses through its interaction with the external environment. This article explores the intricate interplay between intestinal flora and the pathogenesis of PCOS, focusing on the pivotal role of microbial metabolites, specifically short-chain fatty acids (SCFAs). SCFA levels in fecal and blood samples from women with PCOS (n=69) and healthy controls (n=18) were analyzed using Gas Chromatography-Mass Spectrometry (GC/MS) for precise measurement. The results revealed that women with PCOS exhibited a significant reduction in beneficial bacteria alongside a notable overgrowth of opportunistic microorganisms. An overproduction of acetic acid (AA) and valeric acid (VA) in fecal samples suggests a link between elevated SCFAs and the development of obesity and PCOS. Interestingly, AA in the bloodstream might offer a protective effect against PCOS by ameliorating key symptoms such as high body mass index (BMI), insulin resistance (IR), and chronic inflammation. This finding points to the potential therapeutic value of maintaining optimal AA levels in the blood. Although serum SCFA levels showed non-significant changes following metformin treatment, the normalization of AA in the gut underscores that metformin exerts a more pronounced effect locally within the gastrointestinal tract. This treatment also led to an increase in beneficial gut bacteria and a reduction in opportunistic pathogens, suggesting a restoration of gut microbial balance. Furthermore, the study identified the most effective model for predicting the success of metformin therapy, based on serum concentrations of butyric acid (BA) and VA, achieving a 91% accuracy rate, 100% sensitivity, and 80% specificity. These promising findings highlight the potential for developing targeted interventions and personalized treatments, ultimately improving clinical outcomes for women with PCOS.

Polycystic ovary syndrome (PCOS) is a common condition in reproductive-age women. Women with PCOS are at higher risk of pregnancy complications including gestational diabetes (GDM). The prevalence of PCOS and GDM varies according to the diagnostic criteria used. The mechanism for the occurrence of GDM in women with PCOS is still unclear. Materials &amp; Methods- A systematic search of the electronic database was done using keywords like PCOS, and GDM to include studies between April 2008 and March 2023 where uniform diagnostic criteria were used. Studies were excluded with high-risk of bias after the assessment of bias, and meta-analysis was done with relative risks and confidence intervals. Results &amp; Discussion-Out of 1896 search results, 95 were selected for full-text. The quality of the studies was scrutinized and a total of 28 studies were included as they fulfilled the inclusion criteria. The incidence of GDM in women with PCOS was found to be 10.55 % (2.9- 54.9%) from pooled data involving 1,280,245. The prevalence of PCOS in women diagnosed with GDM was found from pooled data of 36,351 women in retrospective studies to be 2.47% (1.5- 50.1%). Selection predominantly included cohort studies, most commonly from China. The meta-analysis reported the risk of GDM is higher in women with PCOS than in those without PCOS (HR: 1.59, 95% CI: 1.27–1.91, p &lt; 0.001). Family history of diabetes, ethnicity, pre-pregnancy BMI, insulin resistance, gestational weight gain, use of assisted reproductive techniques, and multifetal gestation were the risk factors for GDM in women with PCOS. Conclusion- The prevalence of GDM in patients with PCOS is high, but the causality is complex. The newer predictive models are promising in clarifying the causative relationships, yet use various parameters at different cut-offs. There is a need for the development of universally acceptable parameters for the early prediction of GDM in women with PCOS.

Keywords: pelvic ultrasound, follicle number per ovary, FNPO, ovarian volume, PCOM, upper normal limits, referral population

Although many policosanols from different sources, such as sugar cane, rice bran, and insects, have been marketed worldwide, there has been no comparative study of the in vivo efficacy using a hyperlipidemic animal model. This study compared the efficacy of treating dyslipidemia with four different policosanols, including one sugar cane wax alcohol from Cuba (Raydel®) and three policosanols from China (Xi’an Natural sugar cane, Xi’an Realin sugar cane, and Shaanxi rice bran) in hyperlipidemic zebrafish. After 12 weeks of consumption of each policosanol (final 0.1% in diet, wt/wt) and high cholesterol diet (HCD, final 4%, wt/wt) in a tetrabit, the Raydel policosanol group and Xi’an Natural policosanol group showed the highest survivability of approximately 81%, whereas the Xi’an Realin policosanol group and Shaanxi policosanol group showed 57% and 67% survivability, respectively. Among five HCD groups, the Raydel policosanol group showed the lowest serum total cholesterol (TC, p<0.001 versus HCD control) and triglyceride (TG, p<0.001 versus HCD control) with the highest percentage of high-density lipoproteins (HDL)-C in TC. The Raydel policosanol group also showed the lowest serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels with the least infiltration of inflammatory cells and interleukin-6 production in hepatocytes. In the ovary, the Raydel policosanol group also showed the highest contents of mature vitellogenic oocytes with the lowest production of reactive oxygen species and cellular apoptosis in ovarian cells. In the testis, the Raydel policosanol group also showed the healthiest morphology for spermatogenesis with the least interstitial area and reactive oxygen species (ROS) production in testicular cells. In conclusion, 12 weeks of Raydel policosanol consumption resulted in remarkable improvement of the blood lipid profile, amelioration of inflammation in the liver, and enhancement of the cell morphology in the ovary and testis with the highest survivability under the HCD.

Polycystic ovary syndrome (PCOS) is increasingly recognized as a complex metabolic disorder that manifests in genetically susceptible women following a range of negative exposures to nutritional and environmental factors related to contemporary lifestyle. The hypothesis that PCOS phenotypes are derived from a mismatch between ancient genetic survival mechanisms and modern lifestyle practices is supported by a diversity of research findings. The proposed evolutionary model of the pathogenesis of PCOS incorporates evidence related to evolutionary theory, genetic studies, in-utero developmental epigenetic programming, transgenerational inheritance, metabolic features including insulin resistance, obesity and the apparent paradox of lean phenotypes, reproductive effects and subfertility, the impact of the microbiome and dysbiosis, endocrine disrupting chemical exposure, and the influence of lifestyle factors such as poor quality diet and physical inactivity. Based on these premises, the diverse lines of research are synthesized into a composite evolutionary model of the pathogenesis of PCOS. It is hoped that this model will assist clinicians and patients to understand the importance of lifestyle interventions in the prevention and management of PCOS and provide a conceptual framework for future research. It is appreciated that this theory represents a synthesis of the current evidence and that it is expected to evolve and change over time.

Cadherins are a group of membrane proteins responsible for cell adhesion. They are crucial for cell sorting and recognition during the morphogenesis, but also play many other roles such as assuring tissue integrity and resistance to stretching, mechanotransduction, cell signaling, regulation of cell proliferation, apoptosis, survival, carcinogenesis, etc. Within the cadherin superfamily, the E- and N-cadherin have been especially well studied. They are involved in many aspects of sexual development and reproduction, such as germline development and gametogenesis, gonad development and functioning, and fertilization. E-cadherin is expressed in the primordial germ cells, (PGCs) and also participates in PGC migration to the developing gonads where they become enclosed by the N-cadherin-expressing somatic cells. The differential expression of cadherins is also responsible for the establishment of the testis or ovary structure. In the adult testes, the N-cadherin is responsible for the integrity of the seminiferous epithelium, regulation of sperm production, and the establishment of the blood-testis barrier. Sex hormones regulate the expression and turnover of N-cadherin influencing the course of spermatogenesis. In the adult ovaries, E- and N-cadherin assure the integrity of ovarian follicles and the formation of corpora lutea. Cadherins are expressed in the mature gametes, and facilitate the capacitation of sperm in the female reproductive tract, and gamete contact during fertilization. The germ cells and accompanying somatic cells express a series of different cadherins, however, their role in gonads and reproduction is still unknown. In this review, we show what is known and unknown about the role of cadherins in the germline and gonad development, and suggest the topics for future research.

Background: Metabolic flux analysis (MFA) is an indispensable tool in metabolic engineering. The simplest variant of MFA relies on an overdetermined stoichiometric model of the cell’s metabolism under the pseudo-steady state assumption, to evaluate the intracellular flux distribution. Despite its long history, the issue of model error in the overdetermined MFA, particularly misspecifications of the stoichiometric matrix, has not received much attention. Method: We evaluated the performance of statistical tests from linear least square regressions, namely Ramsey RESET test, F-test and Lagrange multiplier test, in detecting model misspecifications in the overdetermined MFA, particularly missing reactions. We further proposed an iterative procedure using the F-test to correct such an issue. Result: Using Chinese hamster ovary and random metabolic networks, we demonstrated that: (1) a statistically significant regression does not guarantee high accuracy of the flux estimates, (2) the removal of a reaction with a low flux magnitude can cause disproportionately large biases in the flux estimates, (3) the F-test could efficiently detect missing reactions, and (4) the proposed iterative procedure could robustly resolve the omission of reactions. Conclusion: Our work demonstrated that statistical analysis and tests could be used to systematically assess, detect and resolve model misspecifications in the overdetermined MFA.

Polycystic ovary syndrome (PCOS) is an insulin resistant state, compensated by hyperinsulinemia. More than 50% of the women with PCOS are obese, and/or have metabolic syndrome. Weight loss improves both metabolic and reproductive outcomes. Not only the energy content, but also the nutrient composition of a diet may be important. This article will present a series of studies from our research comparing effects of dietary protein vs. simple-carbohydrates (CHO). Results of the acute challenge studies demonstrate that simple-CHO intake causes reactive hypoglycemia in one third of the women with PCOS, especially among obese and insulin resistant individuals. Symptoms of hypoglycemia are associated with secretion of cortisol and adrenal androgens. Simple-CHO suppresses the hunger signal ghrelin for a shorter period. During weight loss, women who receive protein supplementation achieve larger amounts of weight- and fat-mass losses. Amino acid compositions of the protein supplements do not affect the improvements in weight and insulin resistance. It is plausible that simple-CHO intake leads to weight gain, or interferes with weight-loss, by causing reactive hypoglycemia, triggering adrenal steroid secretion, and leading to snacking. Since obese women with PCOS are more susceptible to reactive hypoglycemia, a vicious cycle establishes. Restriction of simple-CHO may break this cycle.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy of reproductive-aged women characterized by hyperandrogenism, oligo-anovulation and insulin resistance closely linked with preferential abdominal fat accumulation. As an ancestral primate trait, PCOS was likely further selected in humans when scarcity of food in hunter-gatherers of the late Pleistocene additionally programmed for enhanced fat storage to meet the metabolic demands of reproduction in later life. As an evolutional model for PCOS, healthy normal-weight women with hyperandrogenic PCOS have subcutaneous (SC) abdominal adipose stem cells that favor fat storage through exaggerated lipid accumulation during development to adipocytes in vitro. In turn, fat storage is counterbalanced by reduced insulin sensitivity and preferential accumulation of highly-lipolytic intra-abdominal fat in vivo. This metabolic adaptation in PCOS balances energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction; its accompanying oligo-anovulation allowed PCOS women from antiquity sufficient time and strength for childrearing of fewer offspring with a greater likelihood of childhood survival. Heritable PCOS characteristics are now affected by today’s contemporary environment through epigenetic events that predispose to lipotoxicity with excess weight gain and pregnancy complications, calling for an emphasis on preventive healthcare to optimize the long-term, endocrine-metabolic health of PCOS women in today’s obesogenic environment.

Polycystic ovary syndrome (PCOS) is increasingly being characterized as an evolutionary mismatch disorder that presents with a complex mixture of metabolic and endocrine symptoms. The Evolutionary Model proposes that PCOS arises from a collection of inherited polymorphisms that have been consistently demonstrated in a variety of ethnic groups and races. In-utero developmental programming of susceptible genomic variants are thought to predispose the offspring to develop PCOS. Postnatal exposure to lifestyle and environmental risk factors results in epigenetic activation of developmentally programmed genes and disturbance of the hallmarks of health. The resulting pathophysiological changes represent the consequences of poor-quality diet, sedentary behaviour, endocrine disrupting chemicals, stress, circadian disruption, and other lifestyle factors. Emerging evidence suggests that lifestyle-induced gastrointestinal dysbiosis plays a central role in the pathogenesis of PCOS. Lifestyle and environmental exposures initiate changes that result in disturbance of the gastrointestinal microbiome (dysbiosis), immune dysregulation (chronic inflammation), altered metabolism (insulin resistance), endocrine and reproductive imbalance (hyperandrogenism), and central nervous system dysfunction (neuroendocrine, autonomic nervous system). PCOS can be a progressive metabolic condition that leads to obesity, gestational diabetes, type 2 diabetes, metabolic-associated fatty liver disease, metabolic syndrome, cardiovascular disease, and cancer. This review explores the mechanisms that underpin the evolutionary mismatch between ancient survival pathways and contemporary lifestyle factors involved in the pathogenesis and pathophysiology of PCOS.

Gene electrotransfer is one of the main non-viral methods for intracellular delivery of plasmid DNA, wherein pulsed electric fields are used to transiently permeabilize the cell membrane allowing enhanced transmembrane transport. By localizing the electric field over small portions of the cell membrane using nanostructured substrates, it is possible to increase considerably the gene electrotransfer efficiency while preserving cell viability. In this study, we design an electrotransfer approach based on commercially available cell culture inserts with polyethylene-terephthalate (PET) porous substrate. We first use multiscale numerical modelling to determine the pulse parameters, substrate pore size, and other factors that are expected to result in successful gene electrotransfer. Based on numerical results we design a simple device combining an insert with substrates containing pores with 0.4 um and 1.0 um diameter, a multiwell plate, and a pair of wire electrodes. We test the device in three mammalian cell lines and obtain transfection efficiencies similar to those achieved with bulk electroporation, but with low-voltage pulses that do not require the use of expensive electroporators. Our combined theoretical and experimental analysis calls for further systematic studies that will investigate the influence of substrate pore size and porosity on gene electrotransfer efficiency and cell viability.

Polycystic ovary syndrome (PCOS) is a complex hormonal disorder which impair ovarian function. The adherence to healthy dietary patterns and physical exercise are the first line of recommended treatment for PCOS patients, but it is no clear what type of diet is more adequate. In this case-control study, we explore the association between the adherence to five dietary quality indices widely used and PCOS. We enrolled 126 cases of PCOS and 159 controls (Murcia, Spain). Diagnostic of PCOS and its phenotypes were established following the Rotterdam criteria [hyperandrogenism (H), oligoanovulation (O), polycystic ovaries morphology (POM)]. We used a validated food frequency questionnaires to calculate the scores for five dietary indices: alternate Healthy Eating index (AHEI), AHEI-2010, relative Mediterranean Dietary Score (rMED), alternate Mediterranean Dietary Score (aMED) and Dietary Approaches to Stop Hypertension (DASH). We used multivariable logistic regression to estimate adjusted odds ratios and confidence intervals. In the multivariable analysis, AHEI-2010 index was inversely associated with “H+O” PCOS’ phenotype (ORQ3 VS Q1= 0.1; 95% CI :(0.0; 0.9); P for trend= 0.02). In conclusion, we did not find any statistical significative association between dietary indices and total, anovulatory and ovulatory PCOS, but it seems interesting explore these association among the diverse phenotypes of PCOS in studies with higher sample size.