Cellular senescence in the pathogenesis of ovarian dysfunction.

The follicular microenvironment is crucial for normal ovarian function, and intra-ovarian factors, in coordination with gonadotropins, contribute to its regulation. Recent research has revealed that the accumulation of senescent cells worsens the adverse environment of various tissues and plays critical roles in chronological aging and various pathological conditions. Cellular senescence involves cell-cycle arrest, a senescence-associated secretory phenotype (SASP), macromolecular damage, and dysmetabolism. In this review, I summarize the latest knowledge regarding the role of cellular senescence in pathological conditions in the ovary, in the context of reproduction. Specifically, cellular senescence is known to impair follicular and oocyte health in cisplatin- and cyclophosphamide-induced primary ovarian insufficiency and to contribute to the pathogenesis of polycystic ovary syndrome (PCOS). In addition, cellular senescence is induced during the decline in ovarian reserve that is associated with chronological aging, endometriosis, psychological stress, and obesity, but it remains unclear whether it plays a causative role in these conditions. Finally, I discuss the potential for use of cellular senescence as a novel therapeutic target. The modification of SASP using a senomorphic and/or the elimination of senescent cells using a senolytic represent promising therapeutic strategies. Further elucidation of the role of cellular senescence in the effects of various insults on ovarian reserve, including chronological aging, as well as in pathogenesis of ovarian pathologies, including PCOS, may facilitate a new era of reproductive medicine.

Laparoscopic guided minilaparotomy: a modified technique for management of benign large ovarian cysts.

BACKGROUND: The aim of the study is to evaluate the efficiency and safety of a novel technique to treat large benign ovarian cysts combining benefits of laparoscopic management along with mini-laparotomy without affection of the ovarian reserve. METHODS: The study included 112 women with large benign ovarian cyst candidate for ovarian cystectomy. The technique started with laparoscopy followed by guided cyst aspiration followed by exteriorization of the ovary through minilaprotomy and completion of cystectomy through microsurgical technique. The primary outcome was ipsilateral recurrence of the cyst. Other outcomes included ovarian reserve assessment and postoperative pain. RESULTS: The number of women with recurrence in the ipsilateral ovary after 12, 18 and 24 months were 5 (4.5%),16 (14.3%),20 (17.85%) respectively. Assessment of ovarian reserve revealed a significant decrease in the level of serum AMH (2.82 ± 0.44 vs. 2.50 ± 0.42) and a significant increase in AFC (3.5 ± 1.7 vs. 4.9 ± 1.3) after our novel technique in surgical treatment of ovarian cysts (P value < 0.001). The operative time was 50 ± 7 and 62 ± 7 min in unilateral and bilateral cysts respectively. CONCLUSIONS: Laparoscopic guided minilaparotomy is a safe and effective technique for the management of large benign ovarian cysts with minimal recurrence rate, ovarian reserve affection and adhesions. TRIAL REGISTRATION: clinical trial registry no. NCT03370952. Registered 13 December 2017, https://clinicaltrials.gov/ct2/show/NCT03370952.

MicroRNA-146 attenuates lipopolysaccharide induced ovarian dysfunction by inhibiting the TLR4/NF- κB signaling pathway.

Premature ovarian insufficiency (POI) is a disease that seriously affects women's reproductive function and even leads to lifelong infertility. Little is known about the mechanism of lipopolysaccharide (LPS)-induced ovarian dysfunction. Thus, we aimed to identify the role of the up-regulation of microRNA (miRNA)-146 expression offered protection against ovarian dysfunction by inhibiting the toll-like receptor (TLR) 4, TLR4/phosphorylated (p)-nuclear factor (NF)-κB signaling pathway and inflammatory cytokine tumor necrosis factor (TNF)-a and Interleukin (IL)-6. In an in vivo study, we established an LPS-induced ovarian dysfunction mouse model. The mouse ovarian granulosa cells were transfected with miR-146 mimic or negative controls or inhibitor and then treated with LPS. Therefore, cell viability, cells apoptosis, IL-6 and TNF-a, TLR4, NF- κB were assessed, respectively. These results demonstrated that the up-regulation of miRNA-146 expression may protect against LPS-induced ovarian dysfunction and markedly increased the cell viability, and significantly reduced the ovarian granulosa cells apoptotic rate, and down-regulated IL-6 and TNF-a expression. In addition, miRNA-146 exerted protective ovarian functions might be via inhibiting TLR4/NF-κB signaling pathway. In summary, we reveal the up-regulation of miRNA-146 expression mitigated ovarian dysfunction by negatively regulating expression of the IL-6 and TNF-a, which may shed light on the potential molecular mechanisms of overexpression of miRNA-146 may reversed the ovarian dysfunction by inhibiting the TLR4/ NF-κB signaling pathway.

The effectiveness of desogestrel for endometrial protection in women with abnormal uterine bleeding-ovulatory dysfunction: a non-inferiority randomized controlled trial.

Women with chronic abnormal uterine bleeding-ovulatory dysfunction (AUB-O) are at increased risk of endometrial neoplasia. We conducted a non-inferiority randomized controlled trial to determine the effectiveness of two cyclic-progestin regimens orally administered 10 d/month for 6 months on endometrial protection and menstruation normalization in women with AUB-O. There were 104 premenopausal women with AUB-O randomized to desogestrel (DSG 150 µg/d, n = 50) or medroxyprogesterone acetate (MPA 10 mg/d, n = 54) group. Both groups were comparable in age (44.8 ± 5.7 vs. 42.5 ± 7.1 years), body mass index (24.8 ± 4.7 vs. 24.9 ± 4.7 kg/m2), and AUB characteristics (100% irregular periods). The primary outcome was endometrial response rate (the proportion of patients having complete pseudodecidualization in endometrial biopsies during treatment cycle-1). The secondary outcome was clinical response rate (the proportion of progestin withdrawal bleeding episodes with acceptable bleeding characteristics during treatment cycle-2 to cycle-6). DSG was not inferior to MPA regarding the endometrial protection (endometrial response rate of 78.0% vs. 70.4%, 95% CI of difference - 9.1-24.4%, non-inferiority limit of - 10%), but it was less effective regarding the menstruation normalization (acceptable bleeding rate of 90.0% vs 96.6%, P = 0.016).Clinical trial registration: ClinicalTrials.gov (NCT02103764, date of approval 18 Feb 2014).

Ovarian response to intraovarian platelet-rich plasma (PRP) administration: hypotheses and potential mechanisms of action.

PURPOSE: Platelet-rich plasma (PRP) therapy has been used as an adjunct to fertility treatments in women with very low ovarian reserve and premature ovarian insufficiency. Recent literature in both humans and animals suggest that intraovarian PRP administration in the setting of poor ovarian reserve may help ovarian function and increase the chances of pregnancy. METHODS: A comprehensive literature search through PubMed, MEDLINE databases, and recent abstracts published at relevant society meetings was performed and resulted in 25 articles and 2 abstracts published that studied effect of PRP on the ovaries for the purpose of reproduction. RESULTS: This review article presents all the data published to date pertaining to intraovarian PRP injection and pregnancy, both naturally and after in vitro fertilization. It also presents the most recent data on the use of ovarian PRP in in vitro and animal model studies highlighting the possible mechanisms by which PRP could impact ovarian function. CONCLUSIONS: Even though recent commentaries questioned the use of PRP as an "add-on" therapy in fertility treatment because it has not been thoroughly studied, the recent basic science studies presented here could increase awareness for considering more serious research into the efficacy of PRP as an adjunct for women with poor ovarian reserve, premature ovarian insufficiency, and even early menopause who are trying to conceive using their own oocytes. Given its low-risk profile, the hypothetical benefit of PRP treatment needs to be studied with larger randomized controlled trials.

TrkB agonist antibody ameliorates fertility deficits in aged and cyclophosphamide-induced premature ovarian failure model mice.

Premature ovarian failure (POF) is a leading cause of women's infertility without effective treatment. Here we show that intravenous injection of Ab4B19, an agonistic antibody for the BDNF receptor TrkB, penetrates into ovarian follicles, activates TrkB signaling, and promotes ovary development. In both natural aging and cyclophosphamide-induced POF models, treatment with Ab4B19 completely reverses the reduction of pre-antral and antral follicles, and normalizes gonadal hormone. Ab4B19 also attenuates gonadotoxicity and inhibits apoptosis in cyclophosphamide-induced POF ovaries. Further, treatment with Ab4B19, but not BDNF, restores the number and quality of oocytes and enhances fertility. In human, BDNF levels are high in granulosa cells and TrkB levels increase in oocytes as they mature. Moreover, BDNF expression is down-regulated in follicles of aged women, and Ab4B19 activates TrkB signaling in human ovary tissue ex vivo. These results identify TrkB as a potential target for POF with differentiated mechanisms, and confirms superiority of TrkB activating antibody over BDNF as therapeutic agents.

Clinical characteristics, pregnancy outcomes and ovarian function of pregnancy-associated breast cancer patients: a retrospective age-matched study.

BACKGROUND: Pregnancy-associated breast cancer (PABC) is a rare disease with increasing incidence. The prognosis, pregnancy outcomes and subsequent ovarian function of PABC patients are attracting attention. METHODS: Sixty-three PABC patients and 126 age-matched non-PABC patients were obtained in Tongji Hospital from January 2011 to September 2019. The clinical characteristics and ovarian function of PABC patients were compared with those of non-PABC patients. The pregnancy outcomes and neonatal outcomes of patients with breast cancer diagnosed during pregnancy (BCP) were described. Nonparametric tests, the χ2-test Kaplan-Meier, Cox regression and binomial logistic regression were used for analysis. RESULTS: PABC patients were diagnosed with a more advanced tumour stage (II: 47.6% vs. 45.2%, III: 33.3% vs. 19.8%, IV 3.2% vs. 0%, p = 0.003), which caused worse progression-free survival (PFS) (log-rank p = 0.0138) and breast cancer-specific survival (CSS) (log-rank p = 0.0076) than non-PABC patients. Tumour stage (III/IV vs. 0/I/II) (HR 16.017, 95% CI 5.830 ~ 44.006, p < 0.001) and endocrine therapy (HR 0.254, 95% CI 0.099 ~ 0.653, p = 0.004) were predictors of PFS. Tumour stage (III/IV vs. 0/I/II) (HR 30.875, 95% CI 7.232 ~ 131.820, p < 0.001), endocrine therapy (HR 0.200, 95% CI 0.049 ~ 0.818, p = 0.025) and targeted therapy (HR 0.143, 95% CI 0.028 ~ 0.743, p = 0.021) were predictors for breast CSS. Among the 15 BCP patients, 11 patients voluntarily continued their pregnancy, and the newborns had no obvious birth defects, either in 5 patients who received chemotherapy or in 6 patients who did not receive chemotherapy during pregnancy. Among the patients who received chemotherapy and did not receive endocrine therapy, 24 PABC patients and 48 non-PABC patients experienced chemotherapy-induced amenorrhea. There was no significant difference in resumption of menstruation between the two groups at 6 months and 12 months after the end of chemotherapy. No potential factors affecting resumption of menstruation were found. CONCLUSION: Pregnancy at diagnosis or within 1 year after delivery was not a risk factor for a worse prognosis in PABC patients. Compared with non-PABC patients, patients with PABC presented more aggressive tumour characteristics, which could mostly explain the worse prognosis observed in PABC patients. Receiving the appropriate regimen of chemotherapy in the second and third trimesters did not affect the maternal outcomes or neonatal outcomes of BCP patients. The special physiological state during pregnancy and lactation did not interfere with the damage of chemotherapy to ovarian function.

Maternal Perinatal Exposure to Dibutyl Phthalate Promotes Ovarian Dysfunction in Adult Female Offspring via Downregulation of TGF-ß2 and TGF-ß3.

Maternal exposure to dibutyl phthalate (DBP) may result in ovarian dysfunction in female offspring. However, the underlying mechanisms remain elusive. Pregnant Sprague-Dawley rats were intraperitoneally injected with different doses of DBP, estradiol, and corn oil from gestational day 7 until the end of lactation. The reproductive characteristics, mRNA, and protein expression of ovaries for the adult female offspring were compared. KGN cells were cultured in vitro with DBP, estrogen receptor antagonist, or ALK-5 inhibitor. Genes, proteins, estradiol, and progesterone expressed by KGN, cell proliferation, and apoptosis were measured respectively. Maternal perinatal exposure to DBP induced prolonged estrous period, increased secondary follicles, significant decreased mRNA, and protein levels of TGF-ß2, TGF-ß3, and TGF-ßRII in ovaries of the adult female offspring, but none difference for serum levels of sex hormones, ovarian TGF-ß1, and estrogen receptor. The mRNA levels of LHR, FSHR, and CYP19a in ovaries were also decreased. DBP might decrease the mRNA of TGF-ß2, TGF-ß3, and TGF-ßR II of KGN. DBP can inhibit the mRNA of CYP19 at 24 h, which might be blocked by the estrogen receptor antagonist, whose effects were attenuated at 48 h. DBP combined with FSH might time-dependently regulate the gene expression of TGF-ßR II, inhibitory at 24 h, but stimulative at 48 h, which could be blocked by the ALK5 inhibitor. However, the protein expressed by KGN was not influenced by DBP. DBP stimulated the proliferation of KGN at 24 h, which could be blocked by estrogen receptor antagonist, but attenuated at 48 h. The progesterone in culture medium secreted by KGN was decreased by DBP at 24 h. Maternal perinatal exposure to DBP induced decreased gene expression of TGF-ß signaling and functional proteins in ovaries of the adult female offspring. Molecular cross-talk between estrogen receptor and TGF-ß signaling pathway may play role in the mechanism of granulosa dysfunction induced by DBP.

Evidence-based hormonal, mutational, and endocrine-disrupting chemical-induced zebrafish as an alternative model to study PCOS condition similar to mammalian PCOS model.

Polycystic ovarian syndrome (PCOS) causes swollen ovaries in women at reproductive age due to hormonal disorder with small cysts on the outer edges. The cause of the disorder is still yet to be found. Multiple factors have increased PCOS prevalence, hyperandrogenism, oxidative stress, inflammation, and insulin resistance. Various animal PCOS models have been developed to imitate the pathophysiology of PCOS in humans. Zebrafish is one of the most versatile animal experimental models because of the transparency of the embryos, small size, and rapid growth. The zebrafish similarity to higher vertebrates made it a useful non-mammalian model for PCOS drug testing and screening. This review provides an insight into the usage of zebrafish, a non-mammalian model for PCOS, as an opportunity for evaluating future initiatives in such a research domain.

Prenatal and pubertal exposure to 17α-ethinylestradiol disrupts folliculogenesis and promotes morphophysiological changes in ovaries of old gerbils (Meriones unguiculatus).

17α-Ethinylestradiol is an endocrine-disrupting chemical that make up most contraceptive pills and can be found in the environment. Exposure to ethinylestradiol in different development periods may promote changes in morphophysiological parameters of reproductive and endocrine organs. Considering that the effects of low doses (15 µg/kg/day) of ethinylestradiol in ovaries from 12-month-old female gerbils (Meriones unguiculatus) were investigated. Four experimental groups used were control (without treatment), EE/PRE (treated from the 18th to the 22nd gestational day), EE/PUB (treated from the 42nd to the 49th day of life), and EE/PRE-PUB (treated in the both periods). The animals were euthanized at 12 months. Testosterone and 17ß-estradiol levels were measured. The ovaries were stained with Hematoxylin and Eosin, Periodic Acid Schiff, and Gomori's Trichome. The follicles, corpus luteum, interstitial gland, lipofuscin, ovarian epithelium, and tunica albuginea were analyzed. Estradiol was higher in EE/PRE and EE/PUB groups, while testosterone was higher only in EE/PUB group. The main changes in follicle count occurred in EE/PUB and EE/PRE-PUB groups, with higher primordial follicle count and lower maturation of follicles. The corpus luteum was more evident in EE/PRE group. No differences were found in atretic follicles count. A higher area occupied by interstitial gland cells and lipofuscin deposit in these cells was noted in EE/PUB and EE/PRE-PUB groups. Higher epithelium height and thicker tunic albuginea were showed in treated groups. These results suggest that exposure to doses of EE2 in prenatal and pubertal periods of the development leads to morphological changes in senile ovaries.

Zika Virus Infection in the Ovary Induces a Continuously Elevated Progesterone Level and Compromises Conception in Interferon Alpha/Beta Receptor-Deficient Mice.

Zika virus (ZIKV) belongs to mosquito-borne flaviviruses. Unlike other members in the family, ZIKV can be sexually transmitted, and the female genital tracts are susceptible to ZIKV. However, the impact of ZIKV infection on nonpregnant female reproductive health is not understood. In this study, we investigated the effects of ZIKV infection on the ovary by using nonpregnant female interferon α/ß receptor-deficient (Ifnar1-/-) mice. The results showed that the ovary supported ZIKV replication, and the granulosa and theca cells of antral follicles were susceptible. ZIKV replication in situ significantly reduced the numbers of antral follicles, aggravated follicular atresia, and disrupted folliculogenesis. Notably, ZIKV replication in the ovary caused disordered ovarian steroidogenesis manifested by decreased expression of key enzymes linked to sex hormone synthesis, including the cytochrome P450 17A1 (CYP17A1) and aromatase (CYP19A1). Further, we observed that ZIKV infection disrupted the estrous cycle and thus prolonged the time to conceive. More importantly, although ZIKV RNA could not be detected at 3 months postinfection, damaged ovarian structure and dysfunction were also observed. Taken together, our study demonstrates that ZIKV infection in nonpregnant female mice cause ovarian damage and dysfunction, even long after ZIKV clearance. These data provide important information to understand the effects of ZIKV infection in female reproductive tissues and basic evidence for further studies. IMPORTANCE Zika virus (ZIKV), a flavivirus, is primarily transmitted by mosquito bites. But it can also be transmitted vertically and sexually. Although ZIKV-associated Guillain-Barré syndrome and microcephaly have drawn great attention, there have been few studies on the potential effects of ZIKV on the genital tract of nonpregnant females. This study investigated the effects of ZIKV on the ovaries in mice. We found that ZIKV replicated in the ovary and the granulosa and theca cells of antral follicles were susceptible. ZIKV replication in situ significantly damaged ovarian structure and function and disrupted folliculogenesis. Notably, ZIKV infection further disrupted the estrous cycle and prolonged the time to conceive in mice by causing disordered ovarian steroidogenesis. These effects were observed in both the acute phase and the recovery phase after viral elimination. Overall, the new findings provide important additions to make out the potential adverse impacts of ZIKV on reproductive health in females.

Ovariectomy Reduces Vasocontractile Responses of Rat Middle Cerebral Arteries After Focal Cerebral Ischemia.

ABSTRACT: Effects of sex hormones on stroke outcome are not fully understood. A deleterious consequence of cerebral ischemia is upregulation of vasoconstrictor receptors in cerebral arteries that exacerbate stroke injury. Here, we tested the hypothesis that female sex hormones alter vasocontractile responses after experimental stroke in vivo or after organ culture in vitro, a model of vasocontractile receptor upregulation. Female rats with intact ovaries and ovariectomized (OVX) females treated with 17ß-estradiol, progesterone, or placebo were subjected to transient, unilateral middle cerebral artery occlusion followed by reperfusion (I/R). The maximum contractile response, measured my wire myography, in response to the endothelin B receptor agonist sarafotoxin 6c was increased in female arteries after I/R, but the maximum response was significantly lower in arteries from OVX females. Maximum contraction mediated by the serotonin agonist 5-carboxamidotryptamine was diminished after I/R, with arteries from OVX females showing a greater decrease in maximum contractile response. Contraction elicited by angiotensin II was similar in all arteries. Neither estrogen nor progesterone treatment of OVX females affected I/R-induced changes in endothelin B- and 5-carboxamidotryptamine-induced vasocontraction. These findings suggest that sex hormones do not directly influence vasocontractile alterations that occur after ischemic stroke; however, loss of ovarian function does impact this process.

Gestational exposure to acrylamide suppresses luteal endocrine function through dysregulation of ovarian angiogenesis, oxidative stress and apoptosis in mice.

The discovery of acrylamide in various carbohydrate-rich foods cooked at high temperatures has attracted public health concerns. This study aimed to elucidate the effects and mechanisms additional with acrylamide exposure on the luteal function in vivo during early- and mid-pregnancy. Mice were fed with different dosages of acrylamide (0, 10 and 50 mg/kg/day) by gavage from gestational days (GD) 3 to GD 8 or GD 13. The results indicated that acrylamide exposure significantly decreased levels of serum progesterone and estradiol, and the numbers and relative areas of ovarian corpora lutea. The expression levels of Hsd3b1, Cyp11a1 and Star mRNA markedly reduced in acrylamide-treated ovaries. Furthermore, acrylamide exposure obviously suppressed the activities of catalase and superoxide dismutase, but increased the levels of H2O2 and malondialdehyde. Additionally, acrylamide treatment significantly inhibited luteal angiogenesis and induced the apoptosis of ovarian cells by up-regulation of P53 and Bax protein and down-regulation of Bcl-2 protein. Thus, our results showed that gestational exposure to acrylamide significantly inhibited luteal endocrine function via dysregulation of ovarian angiogenesis, oxidative stress and apoptosis in vivo.

Repression of HDAC5 by acetate restores hypothalamic-pituitary-ovarian function in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) accounts for 90-95 % of worldwide diabetes cases and is primarily characterized by insulin resistance. Its progression as a chronic metabolic disease has been largely associated with female reproductive abnormalities, including ovarian dysfunction with consequent infertility. Epigenetic modifications have been suggested as a possible link to metabolic comorbidities. We therefore hypothesized that short chain fatty acids, acetate (ACA), a potential histone deacetylase inhibitor (HDAC) ameliorates hypothalamic-pituitary-ovarian (HPO) dysfunction in T2DM. Female Wistar rats weighing 160-190 g were allotted into three groups (n = 6/group): Control (vehicle; po), T2D and T2D + ACA (200 mg/kg; po). T2DM was induced by fructose administration (10 %; w/v) for 6 weeks and single dose of streptozotocin (35 mg/kg; ip). The present data showed that in addition to insulin resistance, increased fasting blood glucose and insulin, T2DM induced elevated plasma, hypothalamic and ovarian triglyceride, lipid peroxidation, TNF-α and glutathione depletion. Aside, T2DM also led to increased plasma lactate production and γ-Glutamyl transferase as well as decreased gonadotropins/17ß-estradiol. Histologically, hypothalamus, pituitary and ovaries revealed disrupted neuronal cells/moderate hemorrhage, altered morphology/vascular congestions, and degenerated antral follicle/graafian follicle with mild fibrosis and infiltrated inflammatory cells respectively in T2D animals. Interestingly, these alterations were accompanied by elevated plasma/hypothalamic HDAC5 and attenuated when treated with acetate. The present results demonstrate that T2DM induces HPO dysfunction, which is accompanied by elevated circulating/hypothalamic HDAC5. The results in addition suggest that acetate restores HPO function in T2DM by suppression of HDAC5 and enhancement of insulin sensitivity.

Fertility evaluation of infertile women: a committee opinion.

Diagnostic evaluation for infertility in women should be conducted in a systematic, expeditious, and cost-effective manner to identify all the relevant factors with an initial emphasis on the least invasive methods for detecting the most common causes of infertility. The purpose of this committee opinion is to provide a critical review of the current methods and procedures for the evaluation of in fertile women, and it replaces the document of the same name, last published in 2015 (Fertil Steril 2015;103:e44-50). This guidance is intended for any provider evaluating women for infertility.

Roles of melatonin in the field of reproductive medicine.

Melatonin, mostly released by the pineal gland, is a circadian rhythm-regulated and multifunctional hormone. Great advances in melatonin research have been made, including its role in rhythms of the sleep-wake cycle, retardation of ageing processes, as well as antioxidant or anti-inflammatory functions. Melatonin can scavenge free radicals such as reactive oxygen species (ROS), a key factor in reproductive functions. Melatonin plays an important role in oocyte maturation, fertilization and embryonic development as well. The concurrent use of melatonin increases the number of mature oocytes, the fertilization rate, and number of high-quality embryos, which improves the clinical outcome of assisted reproductive technology (ART). This review discusses the relationship between melatonin and human reproductive function, and potential clinical applications of melatonin in the field of reproductive medicine.

Development and Validation of a Clinical Pregnancy Failure Prediction Model for Poor Ovarian Responders During IVF/ICSI.

Backgrounds: Despite the great advances in assisted reproductive technology (ART), poor ovarian response (POR) is still one of the most challenging tasks in reproductive medicine. This predictive model we developed aims to predict the individual probability of clinical pregnancy failure for poor ovarian responders (PORs) under in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). Methods: The nomogram was developed in 281 patients with POR according to the Bologna criteria from January 2016 to December 2019, with 179 in the training group and 102 in the validation group. Univariate and multivariate logistic regression analyses were used to identify characteristics that were associated with clinical pregnancy failure. The nomogram was constructed based on regression coefficients. Performance was evaluated using both calibration and discrimination. Results: Age >35 years, body mass index (BMI) >24 kg/m2, basic follicle-stimulating hormone (FSH) >10 mIU/ml, basic E2 >60 pg/ml, type B or C of endometrium on human chorionic gonadotropin (hCG) day, and the number of high-quality embryos <2 were associated with pregnancy failure of POR patients. The area under the receiver operating characteristic curve (AUC) of the training set is 0.786 (95% confidence interval (CI): 0.710-0.861), and AUC in the validation set is 0.748 (95% CI: 0.668-0.827), showing a satisfactory goodness of fit and discrimination ability in this nomogram. Conclusion: Our nomogram can predict the probability of clinical pregnancy failure in PORs before embryo transfer in IVF/ICSI procedure, to help practitioners make appropriate clinical decisions and to help infertile couples manage their expectations.

Obesity and reproduction: a committee opinion.

The purpose of this American Society for Reproductive Medicine Practice Committee report is to provide clinicians with principles and strategies for the evaluation and treatment of couples with infertility associated with obesity. This revised document replaces the Practice Committee document titled "Obesity and reproduction: an educational bulletin" last published in 2015 (Fertil Steril 2015;104:1116-26).

Down regulatory response of reproductive potentials in stress-induced rats supplemented with clomifene citrate: The fate of infertility.

This study was designed to physiologically investigate the fate of stress related infertility conditions to focus on the regulatory response of reproductive potentials in stress-induced female Wistar rats supplemented with clomifene citrate. 42 apparently healthy female Wistar rats weighing about 120-160 g were used in the study. The animals were randomly distributed into 3 groups after acclimatization for 2 weeks. Group 1 served as the control pregnant rats not induced by restraint, mirrored and intruder stressors, group 2 consisted of rats treated with 0.013 mg/g of clomifene citrate drug and exposed to three different stressors while group 3 represented pregnant rats exposed to different stressors but not treated with clomifene citrate. At the end of 3weeks, the rats were euthanized via cervical dislocation. The uterus and ovary organs were carefully isolated, weighed and examined for histological changes. The reproductive capacities studied were gestation period, mean pup weight, litter size and survival rate respectively. Data collected is expressed in Mean±SEM and one way ANOVA statistics was used for comparison of means while Fisher's LSD was employed for post hoc test and the level of significance is determined at p-value < 0.05. Results from our study revealed that restraint and intruder stressors following supplementation with clomifene citrate produced similar stress response in the gestation length, pub-weights, litter size and percentage of survival. Stress of different nature altered the histoarchitecture of the ovary and the uteri of rats exposed to restraint or intruder stressor. Meanwhile, Clomifene citrate administration produced effect on ovulation and pregnancy outcome of stressed pregnant rats and the survival ratio of the offspring.

Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Improve Ovarian Function and Proliferation of Premature Ovarian Insufficiency by Regulating the Hippo Signaling Pathway.

Background: Premature ovarian insufficiency (POI) is associated with severe physical damage and psychological burden on women. Transplantation of exosomes is an encouraging regenerative medicine method, which has the potential for restoring ovarian functions on POI with high efficiency. This study aims at evaluating the therapeutic efficacy of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) on ovarian dysfunction of POI and the role of Hippo pathway in this exosome-mediated treatment. Methods: POI mice models were established through intraperitoneal injection of cyclophosphamide. Subsequently, transplantation of hUCMSC-Exos was conducted to administer POI mice. Ovaries and plasma of these mice models were harvested after two weeks of treatment. Ovarian morphology and follicle number were assessed by hematoxylin and eosin staining. Moreover, ELISA was used to detect hormone levels, which are related to ovarian function in serum. To assess the recovery of reproductive ability, we recorded the rate of pregnancy, the amount of offspring, and the time of birth in different groups. To explore the underlying mechanisms of exosome-mediated treatment for ovarian function recovery, the proliferation of ovarian cells in vivo was detected by immunohistochemistry and immunofluorescence staining. Additionally, we conducted EdU and CCK-8 assays to assess the proliferative ability of ovarian granulosa cells (GCs) that were cultured in vitro. Western blot analysis was conducted to estimate the proteins levels of Hippo- and proliferation-associated molecules in vivo and in vitro. Results: After transplantation of hUCMSC-Exos, the ovarian function-related hormone levels and the number of ovarian follicles returned to nearly normal degrees. Meanwhile, there was a significant improvement in reproductive outcomes after exosomal treatment. Furthermore, the improvement of ovarian function and proliferation was associated with the regulation of Hippo pathway. In vitro, co-culture with exosomes significantly elevated the proliferation of ovarian GCs by regulating Hippo pathway. However, the positive effects on the proliferation of GCs were significantly depressed when key Hippo pathway molecule was inhibited. Conclusion: This study suggested that hUCMSC-Exos promoted ovarian functions and proliferation by regulating the Hippo pathway. Therefore, exosomal transplantation could be a promising and efficient clinical therapy for POI in the near future.