Polycystic Ovary Syndrome Ovaries Research Articles

Roles of HIF-1α/BNIP3 mediated mitophagy in mitochondrial dysfunction of letrozole-induced PCOS rats.

Mitochondrial dysfunction plays a crucial role in the pathological physiology of polycystic ovary syndrome (PCOS). Mitochondrial quality control system is vital to maintaining mitochondrial function, includes mitochondrial biosynthesis, dynamics and mitophagy. While mitophagy as a specific autophagy, plays an important role in the mitochondrial quality control system and is mediated by some signaling pathways to eliminate the excessive production of reactive oxygen species (ROS), such as hypoxia-inducible factor (HIF)-1α/B-cell lymphoma-2 adenovirus E1B 19kDa interacting protein 3 (BNIP3). Our previous studies have found that excessive production of ROS and the decreased expression of HIF-1α in the ovaries of PCOS rats. Thus, we hypothesized that excessive ROS leads to mitochondrial dysfunction, attenuates HIF-1α/BNIP3-mediated mitophagy in the ovaries of PCOS rats, and further reduces the mitophagic defense. Firstly, the oxidative stress status was detected and found excessive ROS damages ovarian tissue in PCOS rats. Secondly, the marker proteins of mitochondrial biosynthesis/dynamics and amount were examined and found that their expression levels were abnormal, which showed that the abnormal mitochondrial quality control system leads to accumulate the excess or damaged mitochondria in PCOS ovaries. Finally, we detected the HIF-1α/BNIP3 pathway and found HIF-1α-mediated mitophagy is impaired in the ovaries of PCOS rats. Together, these results clearly demonstrated excessive ROS causes mitochondrial dysfunction via the abnormal mitochondrial quality control system, and attenuates HIF-1α/BNIP3-mediated mitophagic defense in the granulosa cells of PCOS rats, which will provide a new direction for further understanding the role of HIF-1α in the molecular mechanism of mitochondrial dysfunction in PCOS ovaries.

A Mechanism for Ovulation Number Control.

Every menstrual cycle, many follicles begin to develop but only a specific number ovulate. This ovulation number determines how many offspring are produced per litter, and differs between species. The physiological mechanism that controls ovulation number is unknown; a class of mathematical models can explain it, but these models have no physiological basis. Here, we suggest a physiological mechanism for ovulation number control, which enables selection of a specific number of follicles out of many, and analyze it in a mathematical model of follicular growth. The mechanism is based on a signal, intra-follicular androgen concentration, that measures follicle size relative to the other follicles. This signal has a biphasic effect, suppressing follicles that are too large or too small compared to others. The ovulation number is determined by the androgen inhibitory thresholds. The model has a scaling symmetry that explains why the dominant follicles grow linearly with time, as observed in human ultrasound data. This approach also explains how chronic hyperandrogenism disrupts ovulation in polycystic ovary syndrome (PCOS), a leading cause of infertility. We propose specific experiments for testing the proposed mechanism.

Effects of N-acetylcysteine and metformin treatment on the stereopathological characteristics of uterus and ovary.

In this study, the stereo-pathological effect of metformin and N-acetyl cysteine is evaluated on the uterus and ovary of polycystic ovary syndrome (PCOS) mice. 96 mature females (8-weekold, weight of 20–30 gr) BALB/c mice were classified into 6 groups including the control group (n= 16), letrozole-induced PCOS group (n=16), PCOS + metformin (n=16), PCOS+NAC (n=16) and a separate control group for NAC (n=16). Another PCOS group was maintained for a month to make sure that features remain till the end of the study. Testosterone level, vaginal cytology and stereological evaluations were assessed. Vaginal cytology in letrozole-receiving mice showed a diestrus phase continuity. Testosterone level, body weight, uterine weight, endometrial volume, myometrial volume, gland volume, stromal volume, epithelial volume, vessel volume, daughter and conglomerate glands, endometrial thickness, and myometrial thickness exhibited an increasing trend in the uterus of PCOS mice. While normal gland and vessel length decreased in the PCOS group. Ovarian volume, corticomedullary volume, primary follicles, secondary follicles, and ovarian cysts were increased in PCOS ovaries. While corpus luteum, primordial, graafian, and atretic follicles showed a decline in the PCOS group. NAC and metformin, however, managed to restore the condition to normal. Given the prevalence of PCOS and its impact on fertility, the use of noninvasive methods is of crucial significance. NAC can control and treat pathological parameters and help as a harmless drug in the treatment of women with PCOS.

CLINICO-PHARMACOLOGICAL ASPECTS OF OVARIAN-MENSTRUAL CYCLE SUPPORT. Review

Relevance. It is known that 12.5% of women suffer from infertility. Correction of menstrual disorders is an important way to maintain a woman's reproductive health.
 Objective is to consider current data on the physiology, etiopathogenesis and pharmacotherapy of women with ovarian-menstrual disorders.
 Methods. Analysis of the data presented in PubMed, by keywords "ovarian-menstrual cycle", "pharmacological support".
 Results. Modern data on physiology, humoral regulation of the ovarian-menstrual cycle are presented. The role of positive and negative feedback between estradiol and progesterone levels and the activity of anterior pituitary gonadotropic hormones and insulin regulatory pathways is emphasized. The main changes of the central nervous system and behavioral features depending on the phase of the menstrual cycle are described. The directions of pharmacological support and stimulation of ovulation are described. The mechanisms of action and indications for the use of oral hypoglycemic and gonadotropic drugs, the benefits and place of each in the maintenance and stimulation of the ovarian-menstrual cycle are presented. Metformin is effective in clomiphene-resistant women and may be combined with clomiphene, particularly in the treatment of polycystic ovary syndrome (PCOS). Sitagliptin improves ovulation in PCOS, is more effective in combination with metformin. Gonadotropins stimulate the ovaries, promoting the production and maturation of eggs, progesterone prepares the inner layer of the uterus to fix the embryo and helps to bear fruit. They are mainly used in women with PCOS in whom other drugs are ineffective.Some results of pharmacogenetic researches, efficiency, in particular, use of follicle-stimulating hormone depending on genetic polymorphisms of its receptor are noted.
 Conclusions. In modern conditions, the use of pharmacological agents is an important area of support and stimulation of the ovarian-menstrual cycle to improve female reproductive function.

Gut microbiota dysbiosis-derived macrophage pyroptosis causes polycystic ovary syndrome via steroidogenesis disturbance and apoptosis of granulosa cells

Gut microbiota dysbiosis is critical in the etiology of polycystic ovary syndrome (PCOS). However, the mechanisms of gut microbiota in PCOS pathogenesis have not been fully elucidated. We aimed to explore the role of gut microbiota-derived macrophage pyroptosis in PCOS. This study conducted dehydroepiandrosterone (DHEA) induced PCOS mice model, 16S rDNA sequencing, western blot, genetic knocking out, transcriptome and translatome profiling, et al. to evaluate the underlying mechanisms. 16S rDNA sequencing showed reduced gut Akkermansia and elevated gram-negative bacteria (Desulfovibrio and Burkholderia) abundances in DHEA induced PCOS mice, which was accompanied by increased serum lipopolysaccharide (LPS). LPS could induce macrophage pyroptosis in mice ovaries, also activated in PCOS. Gasdermin D (GSDMD) is the final executor of macrophage pyroptosis. We demonstrated that Gsdmd knockout in mice could dramatically ameliorate PCOS. Mechanistically, transcriptome and translatome profiling revealed that macrophage pyroptosis disrupted estrogen production and promoted apoptosis of granulosa cells. Interferon (IFN)-γ, which was elevated in PCOS mice serum and ovaries, enhanced macrophage pyroptosis and exacerbated its effect on estrogen receptor in granulosa cells. Inspiringly, we identified that disulfiram and metformin could augment gut Akkermansia abundance, reduce serum IFN-γ level, inhibit macrophage pyroptosis in ovaries, therefore ameliorating PCOS. Collectively, this study emphasizes that macrophage pyroptosis, which was induced by gut microbiota dysbiosis and enhanced by IFN-γ, plays a key role in PCOS pathogenesis through estrogen synthesis dysfunction and apoptosis of granulosa cells. Disulfiram and metformin, which enhanced gut Akkermansia abundance and suppressed macrophage pyroptosis, may be considered as potential therapeutic strategies for PCOS.

Correlation Between Circulating Adropin Levels and Patients with PCOS: An Updated Systematic Review and Meta-analysis.

An increasing number of young women suffer from polycystic ovary syndrome (PCOS). Reasonable diagnosis and monitoring are important steps in the treatment of PCOS. Therefore, we performed an updated meta-analysis between adropin levels and PCOS to identify their relationship. We searched 8 databases (Pubmed, EMBASE, Cochrane Library, CNKI, Wanfang, CBM, clinicaltrials.gov, OpenGrey) for relevant studies using the following search items: 'PCOS or polycystic ovary syndrome or Stein-Leventhal syndrome' AND 'adropin'. Standardized mean difference (SMD) and 95% confidence intervals(CIs) were used as the outcomes. Data were analyzed using Revman 5.3, Stata 16, and MetaXL. Nineteen articles were include in this meta-analysis. The PCOS group had significantly lower adropin levels than the healthy groups (SMD = -2.79ng/ml, 95%CI (-3.42, -2.16), p < 0.00001). Significant publication bias (p < 0.05) was observed; additionally, the results were robust based on metatrim and fail-safe number (Nfs). Meta-regression analysis showed that age, glucose ratio and luteinizing hormone (LH) may be sources of heterogeneity (univariate meta-regression analysis: P = 0.058 vs P = 0.026 vs P = 0.091). Furthermore, BMI, insulin, glucose, HOMA-IR, total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) may be closely related to adropin levels (p < 0.05) owing to meta-analysis of correlation coefficient. We found there was a correlation between adropin levels and PCOS: circulating adropin levels were significantly lower in patients with PCOS than healthy controls, which may be helpful for clinical diagnosis and detection of PCOS.

Comparison of Endometrial Receptivity Markers Between Women with Polycystic Ovary Syndrome, Endometrioma and Unexplained Subfertility: A Cross-Sectional Study

Objective: Uterine receptivity and implantation are complex processes that require the coordinated expression of molecules by the zygote and uterus. Some molecules have been identified at different stages of the luteal phase as receptivity markers that play roles in implantation. This cross-sectional prospective study aimed to compare the levels of insulin-like growth factor binding protein 1 (IGFBP 1), osteopontin (OPN) and prostaglandin E2 (PGE2) in endometrial flushing liquid during the midluteal phase between patients diagnosed with polycystic ovary syndrome (PCOS), endometrioma and unexplained subfertility, and ovulatory women. Material and Methods: The study groups were formed by women with ovulatory PCOS (n=24), endometrioma (n=17) and unexplained subfertility (n=25). The control group consisted of fertile women (n=18). During the implantation window, endometrial flushing samples were taken and IGFBP1, OPN and PGE2 levels were analyzed and compared among the groups. Results: There were no significant differences in the levels of IGFBP1, PGE2 and OPN among groups. PGE2 levels were 367.7±96.3 ng/mL and 239.2±106.9 ng/mL in women with PCOS and in healthy women, respectively. This difference was statistically significant (p=0.002). The present results show that PGE2 might be an indicator of unfavorable endometrial receptivity and might be responsible for the low pregnancy rates in patients with PCOS. Conclusion: We hypothesized that PGE2 downregulation may facilitate decidualization and improve the pregnancy rate in ovulatory PCOS. So, this can guide us about future treatment in the management of patients.

Association of LH/FSH ratio with menstrual cycle regularity and clinical features of patients with polycystic ovary syndrome

BackgroundUnderstanding the global prevalence and phenotypic features of polycystic ovary syndrome (PCOS) is important as geographic factors and ethnic variations can significantly alter the clinical syndrome. The aim of this study was to determine and evaluate the luteinizing hormone/follicle-stimulating hormone ratio (LH/FSH) in women with PCOS during therapy on selected endocrine and biochemical parameters.ResultsWomen with PCOS were included in the study and were classified into two groups: women without therapy (de novo) and women with therapy for PCOS. ESHERE/ASRM criteria that require the presence of two out of three criteria: ovulatory dysfunction, hyperandrogenism, and morphological PCOS detected by ultrasound diagnostics. Electrochemiluminescence immunoassay (ECLIA) was used for FSH and insulin analysis. The enzymatic method was used to analyze the biochemical profile. There was a significant difference between the two groups in terms of the LH/FSH ratio (2.56 vs. 2.41, P=0.043), glucose (6.23 vs. 5.12, P=0.003), insulin (19.21 vs. 7.35, P=0.000), IR (3.22 vs. 1.42, P=0.000), cholesterol (5.97 vs. 4.92, P=0.002), and LDL (3.56 vs. 2.56, P=0.001). The data suggest that patients with PCOS therapy have reduced hyperinsulinemia and insulin resistance. There was a significant correlation between the LH and FSH in the de novo group, as well as the correlation between hormone levels and LH/FSH ratio in both groups. Patients with PCOS therapy have a tendency for normal body weight and reduction of severe obesity compared to patients without therapy. Clinical features such as regular menstrual cycle and the prevalence of acne and hirsutism are not significantly different between groups.ConclusionPCOS cause irregularities of the menstrual cycle, the appearance of clinical manifestations, especially changes of LH/FSH ratio. Therapy for PCOS contributes to better regulation of endocrine and biochemical parameters, especially in the reduction of hyperinsulinemia, insulin resistance, and reduced LH/FSH ratio.

Impaired Sexual Function in Young Women With PCOS: The Detrimental Effect of Anovulation

BackgroundEven though polycystic ovary syndrome (PCOS) is a common reproductive disorder affecting young women, its impact on their sexual health is not well known. AimTo examine the different aspects of female sexuality in young women with PCOS and attempt to associate hormonal changes and ovulatory status with their sexual function. MethodsAnthropometric characteristics, hormonal levels and sexual function based on the Female Sexual Function Index (FSFI) questionnaire were assessed in 76 young women with PCOS and 133 matched controls. OutcomesSexual function is significantly impaired in young women with PCOS. ResultsWomen with PCOS demonstrated lower scores than controls in arousal (5.04 ± 1.19 vs 4.48 ± 1.44, P < .001), lubrication (5.29 ± 1.17 vs 4.69 ± 1.54, P < .001), orgasm (4.78 ± 1.40 vs 4.11 ± 1.61, P = .001), satisfaction (5.22 ± 1.10 vs 4.78 ± 1.31, P = .016), and total score of the FSFI (29.51 ± 5.83 vs 26.76 ± 6.81, P < .001), even after correction for BMI. When corrected for total testosterone, the domains of lubrication, satisfaction, and total score of FSFI remained significantly impaired in women with PCOS (P values .037, .024, & .044 respectively). In multivariate logistic regression analysis, after adjusting for the effect of BMI and hormone levels, dysfunction in orgasm, satisfaction and the total FSFI score were still 3–4 times more common in PCOS (adjusted OR [95% CI]: 3.54, P = .020; 2.96, P = .050; 3.87, P = .027). Even though no statistically significant differences were observed between women with ovulatory PCOS and controls, we detected statistically significant differences in all domains of sexual function apart from pain between controls and PCOS women with anovulation (desire P value .04, arousal P value <.001, lubrication P value <.001, orgasm P value .001, satisfaction P value .001 and FSFI total score P value <.001). Clinical ImplicationsWomen with PCOS have compromised sexual function, which is independent of their BMI and highly dependent on their ovulatory status. Strengths and LimitationsThis is the first study in women with PCOS that implicates anovulation as a risk factor for sexual impairment in PCOS. Further studies are needed to elucidate the mechanisms implicated and to examine the effect of PCOS therapy on the patients’ sexual function. ConclusionThe adverse effect of PCOS status on the female sexual function is independent of BMI and only partially dependent on hormonal changes characterizing the syndrome. Anovulation appears to be the major determinant of sexual impairment among women with PCOS.Mantzou D, Stamou MI, Armeni AK, et al. Impaired Sexual Function in Young Women With PCOS: The Detrimental Effect of Anovulation. J Sex Med 2021;18:1872–1879.

Analyzing the biochemical, clinical, and hormonal characteristics of patients with polycystic ovary syndrome

To analyze the biochemical, clinical, and hormonal characteristics of patients with four phenotypes of Polycystic ovary syndrome (PCOS). A total of 225 patients admitted to Medistate Kavacık Hospital Gynecology and Obstetrics outpatient clinic and Giresun University Faculty of Medicine Gynecology and Obstetrics clinic between January 2019 and January 2020 diagnosed as PCOS and healthy controls were included in the study. The revised Rotterdam criteria were applied to diagnose PCOS. The patients with PCOS were divided into Type I classic, Type II classic, Ovulatory and Normoandrogenic PCOS. Biochemical, clinical, and hormonal values were compared. The mean age of the participants is 28 (±5.7) and the mean body mass index (BMI) is 26.15 (±5.36). The mean Ferriman Gallwey Score (FGS) is 7.4(±5.4), which is normal. There is a statistically significant difference between the four PCOS groups and control group in terms of age (p-value=0.000), BMI (p- value=0.000), Luteinizing hormone / Follicle stimulating hormone (LH/FSH) (p-value=0.000), and fasting blood sugar (p-value=0.01). There is a statistically significant difference among the four phenotypes in terms of BMI (p-value =0.002), LH/FSH (p-value =0.000), LH (p-value =0.000), free T4 (p-value =0.01), fasting insulin (p-value =0.001), total testosterone (p-value =0.000), FGS (p-value =0.000), etc. Age, BMI, LH/FSH, FSH, LH, fasting blood sugar, and hirsutism are good predictors of PCOS.

A comprehensive evaluation of progestin-primed ovarian stimulation protocol in patients with or without PCOS undergoing in vitro fertilization

Progestin-primed ovarian stimulation (PPOS) regimen was established for assisted reproduction. However, its feasibility and outcomes in polycystic ovary syndrome (PCOS) patients need further evaluation. The outcomes of infertile patients with PCOS (study group) and normal ovaries (control group with unexplained infertility and tubal factor infertility) who underwent PPOS and IVF/ICSI protocol were retrospectively studied. The baseline information, primary, and secondary outcomes of patients were collected. The dynamic changes of hormones were closely monitored. 198 PCOS patients and 374 controls were included in this study. After controlled ovarian hyperstimulation (COH), 15 oocytes were retrieved from PCOS patients on average, which was more than those from the controls (p < 0.001). The oocytes and embryos obtained from the PCOS patients exhibited better developmental potential as the number of fertilized oocytes, cleaved embryos, top-quality embryos, viable embryos, cryopreserved embryos, the rate of fertilization, and viable embryo per oocyte retrieved in PCOS patients were significantly higher than those in the controls (all p < 0.001). No significant difference between the two groups was identified regarding the primary outcome, ongoing pregnancy, and other secondary outcomes. No moderate to severe ovarian hyperstimulation syndrome (OHSS) was diagnosed in either group. With the proposed PPOS protocol, the quantity, quality, developmental potential of oocytes, and embryos obtained from PCOS patients were superior to those from controls. The protocol was efficient and safe in terms of pregnancy, obstetric, and perinatal outcomes. OHSS was effectively mitigated in the patients, with or without PCOS, who underwent COH.

Comparison of Clomiphene Citrate Plus N-Acetyl Cysteine and Clomiphene Citrate Alone for Induction of Ovulation in Polycystic Ovary Syndrome

Aim: To compare the frequency of ovulation with clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate alone in married females presenting with polycystic ovarian syndrome. Study design: Randomized clinical trial Place and duration of study: Department of Obstetrics and Gynaecology, Unit-3 Jinnah Hospital, Lahore from 1st September 2018 to 28th February 2019. Methodology: A total of 60 patients (30 in each group) were enrolled. In group A, females were prescribed clomiphene citrate 50-mg tablets twice daily with N-acetyl cysteine 1200 mg/day orally for 5 days starting on day 3 of the menstrual cycle and in group B, females were prescribed clomiphene citrate 50-mg tablets twice daily. Results: Patients ranged between 18-35 years of age. Mean age of the patients was 28.5±3.3 and 28.1±3.1 years in group A and B, respectively. Mean duration of marriage in group A was 3.4±0.9 and in group B 3.5±0.9 year. Mean BMI in group-A was 3.4±0.9 while in group-B 3.5±0.9 (kg/m2). Ovulation was observed at 1st month in group A was 12 (40%) and in group B 9 (30%). Ovulation was observed at 2nd month in group A was 16 (53.3%) and in group B 13 (43.3%). In 3rd months ovulation was seen in 19 patients (63.3%) of group A and 18 patients (60%) of group B. Stratification for age and BMI was also carried out. Conclusion: This study could not find any clinical superiority for clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate alone in term of ovulation rate. Keywords: N-acetyl cysteine, Polycystic ovary syndrome, Ovulation induction

Are Dietary Indices Associated with Polycystic Ovary Syndrome and Its Phenotypes? A Preliminary Study.

Polycystic ovary syndrome (PCOS) is a complex hormonal disorder which impairs ovarian function. The adherence to healthy dietary patterns and physical exercise are the first line of recommended treatment for PCOS patients, but it is yet unclear what type of diet is more adequate. In this case-control study, we explored associations between adherence to five dietary quality indices and the presence of PCOS. We enrolled 126 cases of PCOS and 159 controls living in 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 of 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 Hyperandrogenism + Oligoanovulation PCOS phenotype (ORQ3 vs. Q1 = 0.1; 95% CI: (0.0; 0.9); Pfor trend = 0.02). We did not find any statistical significant association between dietary indices and total anovulatory or ovulatory PCOS. However, further studies with higher sample sizes exploring these associations among the diverse phenotypes of PCOS are highly warranted.

Extended Use of Clomiphene Citrate in Induction of Ovulation in Polycystic Ovary Syndrome with Clomiphene Citrate Resistance

Background: Clomiphene citrate (CC) is still holding its place as the first-line treatment for induction of ovulation in polycystic ovary syndrome (PCOS) patients. Objective: to assess the effect of extended clomiphene citrate on pregnancy outcomes of clomiphene resistant PCOS. Patients and methods: this study was conducted on 48 PCO patients with CC resistance attended to the Obstetrics and Gynecology Outpatient Clinic at Menoufia University and Al-Bajour General Hospitals, from April 2018 to February 2020. Patients were treated with an extended CC administration (150 mg for 10 days) to overcome anovulation. Result: There was highly significant change in follicle-stimulating hormone (FSH), luteinizing hormone (LH) and FSH/LH after extended CC treatment (p < 0.001). Also, serum progesterone and number of follicles were significantly increased after treatment compared to before treatment. Conclusion: CC extended is a safe, effective with minimal side effect, but low pregnancy rate was observed. Therefore, further studies with large number of PCO patients with CC resistant with addition of other drugs are required to investigate the improvement of the pregnancy rate.

Extended Use of Clomiphene Citrate in Induction of Ovulation in Polycystic Ovary Syndrome with Clomiphene Citrate Resistance

Background: Clomiphene citrate (CC) is still holding its place as the first-line treatment for induction of ovulation in polycystic ovary syndrome (PCOS) patients. Objective: to assess the effect of extended clomiphene citrate on pregnancy outcomes of clomiphene resistant PCOS. Patients and methods: this study was conducted on 48 PCO patients with CC resistance attended to the Obstetrics and Gynecology Outpatient Clinic at Menoufia University and Al-Bajour General Hospitals, from April 2018 to February 2020. Patients were treated with an extended CC administration (150 mg for 10 days) to overcome anovulation. Result: There was highly significant change in follicle-stimulating hormone (FSH), luteinizing hormone (LH) and FSH/LH after extended CC treatment (p < 0.001). Also, serum progesterone and number of follicles were significantly increased after treatment compared to before treatment. Conclusion: CC extended is a safe, effective with minimal side effect, but low pregnancy rate was observed. Therefore, further studies with large number of PCO patients with CC resistant with addition of other drugs are required to investigate the improvement of the pregnancy rate.

Humanin regulates oxidative stress in the ovaries of polycystic ovary syndrome patients via the Keap1/Nrf2 pathway.

Polycystic ovary syndrome (PCOS) is the most common endocrinological pathology among women of reproductive age, whereas the pathogenesis is still not fully understood. Systemic and ovarian oxidative stress (OS) imbalance is a pivotal feature of PCOS. Humanin, a mitochondria-derived peptide, has been reported to function as an antioxidant in cardiomyocytes, pancreatic beta cells and other cells, but how this function is regulated remains unclear. In this study, we investigated whether humanin expression differs in the granulosa cells (GCs) of PCOS patients versus controls, and whether humanin alleviates OS in PCOS ovaries. Sixteen PCOS patients and 28 age- and BMI-matched controls undergoing IVF were recruited, and their serum, follicular fluid and GCs were collected for humanin analysis. Dehydroepiandrosterone-induced rat PCOS models, and vitamin K3-induced OS COV434 cell lines were applied to investigate the mechanism. Humanin expression was significantly down-regulated in the ovaries of PCOS patients relative to those of non-PCOS patients. Exogenous humanin supplementation significantly attenuated body weight gain, ovarian morphological abnormalities, endocrinological disorders and ovarian and systemic OS in PCOS rat models. Our study further demonstrated that this attenuation effect was involved in the modulation of the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor-erythroid 2-related factor 2 (Nrf2) signalling pathway. In summary, this study reported for the first time that decreased expression of humanin in the GCs was associated with oxidative imbalance in PCOS. Humanin alleviates OS in ovarian GCs of PCOS patients via modulation of the Keap1/Nrf2 signalling pathway.

The impact of adding a nitric oxide donor as adjuvant therapy to clomiphene citrate to improve pregnancy rate in polycystic ovarian syndrome, a randomized controlled trial

Aim: This study aimed to compare the effect of adding a nitric oxide donor to clomiphene citrate in women with polycystic ovarian syndrome for induction of ovulation to attempt and reverse the anti-estrogenic effect and thus improve the clinical pregnancy rate.Material and Methods: This is an open labelled randomized controlled trial in a University Hospital infertility out-patient clinic. Eighty participants, fulfilling the inclusion criteria were enrolled in the study from January 2019 till December 2019. They were divided into 2 groups, group A received clomiphene citrate (CC) and Isosorbide mononitrate (ISMN), while group B received CC only. The primary outcome was the clinical pregnancy rate.Results: The clinical pregnancy rate was higher in the ISMN group but did not show statistical significance. Although, the addition of ISMN had a favorable outcome on the number of follicles, endometrial volume, cervical mucus score, uterine artery RI.Conclusion: The addition of nitric oxide donors to CC in the induction of ovulation in polycystic ovarian syndrome improved cycle parameters but did not significantly increase clinical pregnancy rates and thus should be cautiously used for such purpose.

Differential regulation of osteopontin and CD44 correlates with infertility status in PCOS patients

Endometrial receptivity is mediated by adhesion molecules at the endometrium-trophoblast interface where osteopontin (OPN) and CD44 form a protein complex that plays an important role in embryo recognition. Here, we undertook a prospective study investigating the expression and regulation of OPN and CD44 in 50 fertile and 31 infertile ovulatory polycystic ovarian syndrome (PCOS) patients in the proliferative and secretory phases of the natural menstrual cycle and in 12 infertile anovulatory PCOS patients. Endometrial biopsies and blood samples were evaluated for expression of OPN and CD44 using RT-PCR, immunohistochemistry and ELISA analysis to determine circulating levels of OPN, CD44, TNF-α, IFN-γ and OPN and CD44 levels in biopsy media. Our findings highlighted an increased level of circulating OPN and CD44 in serum from infertile patients that inversely correlated with expression levels in endometrial tissue and positively correlated with levels secreted into biopsy media. OPN and CD44 levels positively correlated to each other in serum and media from fertile and PCOS patients, as well as to circulating TNF-α and IFN-γ. In vitro analysis revealed that hormone treatment induced recruitment of ERα to the OPN and CD44 promoters with a concomitant increase in the expression of these genes. In infertile patients, inflammatory cytokines led to recruitment of NF-κB and STAT1 proteins to the OPN and CD44 promoters, resulting in their overexpression. These observations suggest that the endometrial epithelial OPN-CD44 adhesion complex is deficient in ovulatory PCOS patients and displays an altered stoichiometry in anovulatory patients, which in both cases may perturb apposition. This, together with elevated circulating and local secreted levels of these proteins, may hinder endometrium-trophoblast interactions by saturating OPN and CD44 receptors on the surface of the blastocyst, thereby contributing to the infertility associated with ovulating PCOS patients.Key messages• Endometrial epithelial OPN-CD44 adhesion complex levels are deficient in ovulatory PCOS patients contributing to the endometrial infertility associated with ovulating PCOS patients.• Circulating levels of OPN, CD44 and inflammatory cytokines TNF-α and IFN-γ are altered in infertile PCOS patients.• Increased levels of both OPN and CD44 in biopsy media and serum inversely correlate with endometrial expression of these markers in endometrial tissue.• In infertile PCOS patients, high levels of oestrogens and inflammatory cytokines stimulate the recruitment of transcription factors to the OPN and CD44 promoters to enhance gene transcription.• Our study identifies a novel crosstalk between the CD44-OPN adhesion complex, ERα, STAT1 and NF-κB pathways modulating endometrial receptivity.

Sitagliptin/Metformin: A New Medical Treatment in Polycystic Ovary Syndrome

Metformin has long been used in the treatment of polycystic ovarian syndrome (PCOS). Recently, sitagliptin has been reported to improve ovarian cycles and ovulation in PCOS. We suggest that a combination of sitagliptin and metformin can be more effective than either treatment alone in improving different aspects of PCOS.

Assessing and validating housekeeping genes in normal, cancerous, and polycystic human ovaries.

Housekeeping genes (HKGs), reference or endogenous control genes, are vital to normalize mRNA levels between different samples. Since using inappropriate HKGs can lead to unreliable results, selecting the proper ones is critical for gene expression studies. To this end, normal human ovaries, as well as those from patients diagnosed with ovarian endometrioid adenocarcinoma (OEA), ovarian mucinous adenocarcinoma (OMA), ovarian serous papillary carcinoma (OSPC), and polycystic ovary syndrome (PCOS), were used to identify the most suitable housekeeping genes. RNA was isolated from 5 normal human ovaries (52-79years of age), 9 cancerous ovaries (3 OEA, 3 OMA, 3 OSPC; 49-75years of age), and 4 PCOS ovaries (18-35years of age) in women undergoing hysterectomy. cDNA was synthesized using a whole transcriptome kit, and quantitative real-time PCR was performed using TaqMan array 96-well plates containing 32 human endogenous controls in triplicate. Among 32 HKGs studied, RPS17, RPL37A, PPIA, 18srRNA, B2M, RPLP0, RPLP30, HPRT1, POP4, CDKN1B, and ELF1 were selected as the best reference genes. This study confirms recent investigations demonstrating that conventional HKGs, such as GAPDH and beta-actin, are not suitable reference genes for specific pathological conditions, emphasizing the importance of determining the best HKGs on a case-by-case basis and according to tissue type. Our results have identified reliable HKGs for studies of normal human ovaries and those affected by OEA, OMA, OSPC, or PCOS, as well as combined studies of control subjects vs. each cancer or PCOS group.