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Research Question: Is thyroid autoimmunity (TAI) associated with the decline of ovarian reserve in euthyroid women?, Design: Case-control study. Data from 4302 euthyroid women with normal ovarian reserve (NOR) and low ovarian reserve (LOR), including biochemical premature ovarian insufficiency (POI) and overt POI, were retrospectively analysed. The prevalence and effect of TAI on ovarian reserve was evaluated between women with NOR and LOR. Status of ovarian insufficiency and TSH levels was further stratified for analysis. The correlation between anti-thyroid peroxidase antibody (TPOAb), anti-thyroglobulin antibody (TgAb) titres and ovarian reserve markers was also determined., Results: The prevalence of positive TAI and TgAb was equally distributed between women with NOR and LOR (P = 0.080, P = 0.172); the prevalence of TPOAb positivity was higher in the LOR group (P = 0.005). After stratifying ovarian reserve and TSH, positive TAI, TPOAb and TGAb were significantly associated with overt POI when TSH was >2.5 µIU/ml (all P < 0.001); no association was observed with biochemical POI or overt POI when TSH was ≤2.5 µIU/ml. No correlation was found between TPOAb, TGAb titres and AMH (P = 0.218, P = 0.368, respectively), and bilateral AFC (P = 0.184, P = 0.315, respectively) in patients with LOR; only TPOAb titre was positively correlated with FSH (P = 0.039)., Conclusions: Among the whole population of euthyroid women, TAI was not associated with low ovarian reserve but was significantly associated with overt POI in women with TSH>2.5 µIU/ml. Further basic studies on underlying mechanisms are needed., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Thyroid dysfunction is prevalent in reproductive-age women and has been identified as a risk factor for female infertility. However, it remains largely unclear whether subtle thyroid dysfunction, as estimated by moderately high thyrotropin (TSH) levels within the normal range, is associated with ovarian reserve in infertile women before assisted reproductive technology (ART) treatment. Methods: This cross-sectional study involved 3501 euthyroid infertile women, including 2189 women with TSH levels ≤2.5 μIU/mL and 1312 women with high-normal TSH levels (2.51-4.20 μIU/mL). Ovarian reserve markers were compared between women with low- and high-normal TSH levels. Correlation analysis and regression models were used to estimate the association of TSH levels with ovarian reserve. In addition, the association of subtle thyroid dysfunction with ovarian reserve was further evaluated after stratification for different infertility diagnoses and statuses of thyroid autoimmunity (TAI). Results: In the total population, women with high-normal TSH levels had significantly decreased anti-Müllerian hormone (AMH) concentrations ( p  < 0.001), a lower bilateral antral follicle count (AFC) ( p  < 0.001), and a higher prevalence of diminished ovarian reserve (DOR) ( p  = 0.018) than women with low-normal TSH levels. The TSH levels showed a negative association with both AMH levels ( r  = -0.050, p  = 0.003) and bilateral AFC ( r  = -0.071, p  < 0.001). Furthermore, the association of high-normal TSH levels with decreased AMH and AFC was more prominent in infertile women with ovulation dysfunction ( p  = 0.002, p  = 0.002), unexplained infertility ( p  = 0.020, p  = 0.028), or negative TAI (both p  < 0.001). Conclusions: These data suggested that subtle thyroid dysfunction was associated with DOR in infertile women before ART treatment, which will add evidence that strengthens the systematic screening of TSH levels/TAI in infertile women and will contribute to the discussion of specific TSH cutoff values in predicting ovarian reserve.

Objective: To characterize the status of ovarian reserve and ART outcomes in BPES women and provide informative reference for clinical diagnosis and treatment., Methods: Twenty-one women with BPES were screened for mutations in the FOXL2 gene and underwent assisted reproductive technology (ART) treatment. Indicators for ovarian reserve and ART outcomes were compared between patients with and without FOXL2 mutations. Additionally, ART outcomes were compared among patients with different subtypes of FOXL2 mutations., Results: A total of 13 distinct heterozygous variants in the FOXL2 gene were identified in 80.95% of BPES women, including 4 novel mutations with plausible pathogenicity (c.173&#95;175dup, c.481C>T, c.576del and c.675&#95;714del). Compared to non-mutation group, patients with FOXL2 mutations had elevated levels of FSH (P=0.007), decreased AMH levels (P=0.012) and less AFC (P=0.015). They also had worse ART outcomes with large amount of Gn dosage (P=0.008), fewer oocytes (P=0.001), Day3 good quality embryos (P=0.001) and good quality blastocysts (P=0.037), and a higher cancellation rate (P=0.272). High heterogeneity of ART outcomes existed in BPES patients with different FOXL2 mutation types., Conclusions: BPES patients with FOXL2 mutations had diminished ovarian reserve and adverse ART outcomes. The genotype-reproductive phenotype correlations were highly heterogeneous and cannot be generalized. Genetic counseling for fertility planning and preimplantation or prenatal genetic diagnosis to reduce offspring inheritance are recommended., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Meng, Zhang, Zhang, Li, Gao, Qin and Jiao.)

Objective: To characterize the ovarian reserve indicators for premature ovarian insufficiency (POI) at different disease stages and with various etiologies., Methods: According to different FSH levels and menstrual conditions, patients with normal ovarian reserve (NOR with 5 IU/L40 IU/L, n=454) were retrospectively screened and their records were abstracted from Reproductive Hospital Affiliated to Shandong University between 2014 and 2019. Based on the known etiologies, POI patients were subdivided into genetic, iatrogenic, autoimmune and idiopathic subsets according to the known etiologies. The phenotypic features were compared within different subgroups, and the predictive value of ovarian reserve markers was analyzed., Results: The ovarian reserve indicators consecutively deteriorated with the progress of ovarian insufficiency, indicated as an increase of FSH and LH but decrease of AMH, inhibin B, AFC, E 2 and T (P<0.01). Most of them changed significantly from NOR to pre-POI while remained relatively stable at a low level or even undetectable at early POI and POF stage. AMH showed the highest predictive value for pre-POI (AUC 0.932, 95% CI 0.918-0.945) and POI (AUC 0.944, 95% CI 0.933-0.954), and the combination of AMH and AFC was highly promising for early prediction. Additionally, significant differences existed in AMH, inhibin B and AFC among women with different etiologies of POI (P<0.05), and the genetic POI presented the worst hormone status., Conclusions: Our study indicated a high heterogeneity of POI in both endocrine hormones and etiological phenotypes. The quantitative changes and cutoff values of AMH and AFC could provide new insights in the prediction and early diagnosis of POI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jiao, Meng, Zhai, Zhao, Luo, Liu and Qin.)

Background: Thyroid autoimmunity (TAI) is the most frequent autoimmune disease among reproductive-aged women. It has been related to premature ovarian insufficiency, but the mechanisms remain elusive, and its association with ovarian reserve in euthyroid women is debatable. Moreover, the impact of TAI on assisted reproduction is controversial: especially for women with diminished ovarian reserve (DOR), few studies are available. Therefore, the present study was aimed to look for an association between TAI and DOR, and to evaluate the effect of TAI on pregnancy outcomes and offspring health following assisted reproductive technology stratified by ovarian reserve. Methods: A total of 6213 euthyroid women from the Reproductive Hospital Affiliated to Shandong University between 2012 and 2017 were retrospectively included. The prevalence of DOR in women with negative or positive TAI was calculated, and pregnancy and neonatal outcomes after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles were compared between the TAI-positive and TAI-negative groups both in women with DOR and in those with normal ovarian reserve (NOR). Longitudinal growth parameters and temperament type of the offspring were also observed in the TAI-positive and TAI-negative groups. Results: The prevalence of DOR in women with positive TAI and those with negative TAI was not significantly different (4.09% vs. 2.96%, p  = 0.053), even after stratifying patients by age. In women with DOR, the live birth rate, pregnancy loss rate, neonatal complication rate, and offspring outcomes between the TAI-positive and TAI-negative groups were comparable ( p  > 0.05). In women with NOR, a higher rate of live births (44.94% vs. 40.34%, p  = 0.027) and a higher prevalence of congenital anomalies (4.68% vs. 2.14%, p  = 0.005) were observed in the TAI-positive group. Conclusions: TAI had no impact on ovarian reserve in euthyroid women and had no association with IVF/ICSI outcomes in women with DOR. Although an increased incidence of congenital anomalies in the TAI-positive group was observed in women with NOR, an association between neonatal anomalies and TAI cannot be demonstrated. Large cohort studies to evaluate the effects of TAI on offspring health are warranted, and further experimental studies are required to explore the underlying mechanisms.

Objective: To explore the potential damaging effect of chronic pelvic inflammation on ovarian reserve., Design: Case-control study., Patients: A total of 122 women with bilateral tubal occlusion, diagnosed by hysterosalipingography (HSG) and 217 women with normal fallopians were recruited., Measurements: Serum anti-Mullerian hormone (AMH), basic follicle-stimulating hormone (FSH), luteining hormone (LH), estradiol (E2), and testosterone (T) were measured; and antral follicle counts (AFCs) were recorded., Results: Significantly lower level of AMH was observed in women with bilateral tubal occlusion compared to control group [2.62 (2.95) ng/ml vs. 3.37 (3.11) ng/ml, P = 0.03], and the difference remained after adjustment of BMI (Padjust = 0.04). However, no statistical difference was found in the levels of FSH [7.00 (2.16) IU/L vs. 6.74 (2.30) IU/L], LH [4.18 (1.52) IU/L vs. 4.63 (2.52) IU/L], E2 [35.95 (20.40) pg/ml vs. 34.90 (17.85) pg/ml], T [25.07±11.46 ng/dl vs. 24.84±12.75 ng/dl], and AFC [6.00 (4.00) vs. 7.00 (4.00)] between two groups (p>0.05)., Conclusions: Women with bilateral tubal occlusion showed decreased AMH level, suggesting that chronic pelvic inflammation may diminish ovarian reserve. More caution should be paid when evaluating the detriment of PID on female fertility.

Background: Several studies on pregnancy complications of poor ovarian response (POR) patients did not draw a consistent conclusion. The POSEIDON criteria introduces the concept of "low prognosis" and divides POR patients into four groups based on age, AFC and AMH for individualized management. We analyzed low-prognosis population and patients with regular ovarian response, compared maternal and neonatal complications and discussed the relevant risk factors. Methods: A retrospective cohort study was conducted of females who achieved a singleton clinical pregnancy after IVF / ICSI—fresh embryo transfer in a single center from January 2014 to March 2019. Participants with low prognosis, as defined by the POSEIDON criteria, were enrolled in the study groups. The controls were defined as AFC ≥ five and number of retrieved oocytes > nine. Maternal and neonatal complications were compared among those groups. Results: There were 2554 cycles in POSEIDON group 1, 971 in POSEIDON group 2, 141 in POSEIDON group 3, 142 in POSEIDON group 4, and 3820 in Control. Univariate analysis roughly showed that Groups 2 and 4 had an increased tendency of pregnancy complications. Multi-variable generalized estimating equations (GEE) analysis showed that the risks of GDM, total pregnancy loss, and first-trimester pregnancy loss in Groups 2 and 4 were significantly higher than in Control. The risk of hypertensive disorders of pregnancy (HDP) in Groups 2 and 3 increased, and Group 4 had an increased tendency without statistical significance. After classification by age, GEE analysis showed no significant difference in risks of all complications among groups ≥ 35 years. In patients < 35 years, the risk of HDP in POSEIDON group 3 was significantly higher than in controls (< 35 years), and there was no significant increase in the risk of other complications. Conclusion: Compared to patients with regular ovarian response, low-prognosis population have increased tendency of maternal and neonatal complications. In low-prognosis patients, advanced age (≥ 35 years) might be the predominant risk factor for pregnancy complications. In those < 35 years, poor ovarian reserve could contribute to HDP. [ABSTRACT FROM AUTHOR]

Research question: Is deficiency of IL‐22 associated with premature ovarian insufficiency (POI)? Design: Levels of IL‐22 and IL‐22BP, IL‐22‐producing T cells, and IL22RA1/IL10R2 expression were measured and compared among 29 patients with POI, 42 with precursor stage of POI (pre‐POI) and 46 control women. Correlation of serum IL‐22 and IL‐22+CD4+T subsets with ovarian reserve markers were further analyzed. Results: IL‐22 levels in serum significantly differed among control women and patients with pre‐POI and POI, with the lowest concentrations in POI group (p =.019). Significant reduction of peripheral CD4+IL‐22+T cells was observed in patients with POI (p =.010), which mainly contributed by decrease of CD4+IL‐22+IL‐17− TH22 cells (p =.012) but not TH17 cells (p =.125). Levels of serum IL‐22 and IL‐22‐producing CD4+T subsets were significantly correlated with ovarian reserve markers, including AMH, bilateral AFC, follicle‐stimulating hormone (FSH), and E2 (p <.05). The specific receptor IL22RA1 expression was marginally reduced in granulosa cells from patients with pre‐POI (p =.051). No difference of IL‐22BP was observed either in serum (p =.216) or follicular fluid (p =.856) among groups. Conclusions: Our study first demonstrated the significant association between TH22‐mediated IL‐22 deficiency and ovarian insufficiency, which provide new insights into the autoimmune disturbance and opens new avenues for exogenous IL‐22 administration as potential intervention of POI. [ABSTRACT FROM AUTHOR]

Background: Declining ovarian function in advance-aged women and in premature ovarian insufficiency (POI) patients seriously affects quality of life, and there is currently no effective treatment to rescue ovarian function in clinic. Stem cell transplantation is a promising therapeutic strategy for ovarian aging, but its clinical application is limited due to the low efficiency and unclear mechanism. Here, a novel combination of umbilical cord-mesenchymal stem cells (UC-MSCs) and autocrosslinked hyaluronic acid (HA) gel is explored to rescue ovarian reserve and fecundity in POI and naturally aging mice. Methods: To investigate HA prolonged the survival after UC-MSCs transplantation, PCR and immunofluorescence were performed to track the cells on day 1, 3, 7 and 14 after transplantation. The effects of HA on UC-MSCs were analyzed by CCK8 assay, RNA-sequencing and 440 cytokine array. In vivo experiments were conducted to evaluate the therapeutic effects of UC-MSCs combined with HA transplantation in 4-vinylcyclohexene diepoxide (VCD)-induced POI mice and naturally aging mice model. Ovarian function was analyzed by ovarian morphology, follicle counts, estrous cycle, hormone levels and fertility ability. To investigate the mechanisms of stem cell therapy, conditioned medium was collected from UC-MSCs and fibroblast. Both in vitro ovarian culture model and 440 cytokine array were applied to assess the paracrine effect and determine the underlying mechanism. Hepatocyte growth factor (HGF) was identified as an effective factor and verified by HGF cytokine/neutralization antibody supplementation into ovarian culture system. Results: HA not only prolongs the retention of UC-MSCs in the ovary, but also boosts their secretory function, and UC-MSCs promote follicular survival by activating the PI3K-AKT pathway through a paracrine mechanism both in vitro and in vivo. More importantly, HGF is identified as the key functional cytokine secreted by MSCs. Conclusions: The results show that HA is an excellent cell scaffold to improve the treatment efficiency of UC-MSCs for ovarian aging under both physiological and pathological conditions, and the therapeutic mechanism is through activation of the PI3K-AKT pathway via HGF. These findings will facilitate the clinical application of MSCs transplantation for ovarian disorders. [ABSTRACT FROM AUTHOR]

Distinct microRNA (miRNA) profiles have been reported in premature ovarian insufficiency (POI), but their functional relevance in POI is not yet clearly stated. In this study, aberrant expressions of miR‐127‐5p and high mobility group box 2 (HMGB2) were observed by microarrays in granulosa cells (GCs) from biochemical POI (bPOI) women and further confirmed by a quantitative reverse‐transcription polymerase chain reaction. Immortalized human granulosa cell line and mouse primary ovarian GCs were used for functional validation. Orthotopic mouse model was established to examine the role of miR‐127‐5p in vivo. Finally, the expression of miR‐127‐5p was measured in the plasma of bPOI women. The receiver operating characteristic curve analysis was performed to determine the indicative role of miR‐127‐5p for ovarian reserve. Results showed the upregulation of miR‐127‐5p was identified in GCs from bPOI patients. It inhibited GCs proliferation and impaired DNA damage repair capacity through targeting HMGB2, which was significantly downregulated in GCs from the same cohort of cases. miR‐127‐5p was confirmed to attenuate DNA repair capability via HMGB2 in mouse ovary in vivo. Intriguingly, the upexpression of miR‐127‐5p was also detected in plasma of bPOI individuals, suggesting that miR‐127‐5p could be a promising indicator for bPOI. Taken together, our results discovered the deleterious effects of miR‐127‐5p on GCs function and its predictive value in POI process. The target gene HMGB2 could be considered as a new candidate for POI. This study highlights the importance of DNA repair capacity for ovarian function and sheds light on the epigenetic mechanism in the pathogenicity of POI. [ABSTRACT FROM AUTHOR]

Problem: Premature ovarian insufficiency (POI) imposes great challenge on female reproduction. Whether immune disturbance in ovarian environment was implicated in POI remains unclear. We aimed to characterize the cytokine profile in follicular fluid (FF) and paired serum in patients with biochemical POI (bPOI). Method of study: Multiplex immunoassay containing 45 cytokines was performed for individual FF and paired serum samples from 35 bPOI patients and 37 matched controls. Cytokine profiles were compared between the two groups and cytokines correlated to ovarian reserve, and the rates of day‐3 good‐quality embryos were further analyzed. Results: In FF, significantly elevated level of chemokines MIP‐1α (P =.043), CXCL8 (P =.024), IP‐10 (P =.041), and eotaxin‐1 (P =.015) as well as growth factors VEGF‐D (P =.047), BDNF (P =.043), LIF (P =.002), and bFGF (P =.046) was found in bPOI patients compared to controls. Yet RANTES manifested an opposite trend with reduced levels among bPOI patients (P =.006). All these chemokines and growth factors in FF were significantly correlated with ovarian reserve (P <.05). In paired serum, cytokine signature was not likely accordant with that in FF between two groups, except for increased IP‐10 (P =.032) in bPOI patients and its significant correlation to FSH and AFC (P <.05). Among all differentially expressed cytokines, RANTES in FF was correlated with the rate of day‐3 good‐quality embryos (P =.035). Conclusion: Altered cytokine profile characterized by increased chemokines and growth factors was associated with early stage of POI, which may fuel the progression of the disease or even play a crucial role in the development of ovarian insufficiency. [ABSTRACT FROM AUTHOR]

Objective: To study the age-specific distribution of antimüllerian hormone (AMH) and describe the association of AMH with androgenic and metabolic profiles at different ages.Design: Cross-sectional study.Setting: University hospital.Patient(s): A total of 6,763 Chinese women from birth to menopause.Intervention(s): None.Main Outcome Measure(s): Anthropometric parameters (height, weight, and blood pressure), and levels of AMH and testosterone, glucose metabolism, and lipid profiles.Result(s): According to the level of AMH, four age phases were established: childhood (0-10 years), adolescence (11-18 years), reproductive age (19-50 years), and advanced age (≥51 years). During childhood and adolescence, AMH levels increased, reaching a peak at 18 years. A decline occurred thereafter during the reproductive-age period until the age of 50 years, and it remained at a low level above 0 onward. We found that AMH was negatively correlated with testosterone in childhood (r = -0.25), but was positively correlated with testosterone and the free androgen index in adolescence (r = 0.30; r = 0.26, respectively) as well as during the reproductive phases (r = 0.28; r = 0.31, respectively). No correlation was observed between AMH and body mass index, fasting blood glucose, fasting insulin, the homeostasis model assessment, total cholesterol, triglycerides, low-density lipoprotein, or high-density lipoprotein at any phase.Conclusion(s): From birth to 18 years, AMH increases, then it declines thereafter, indicating changes of ovarian maintenance. A positive relationship between androgenic profiles and AMH during adolescence and reproductive years implies a synchronism between androgens and ovarian reserve. [ABSTRACT FROM AUTHOR]

Do embryo euploidy rates differ in the four groups of women with low prognosis as stratified by the POSEIDON criteria? This was a retrospective cohort study of low-prognosis patients who met the POSEIDON criteria and underwent preimplantation genetic testing for aneuploidies (PGT-A) from January 2013 to June 2020 at the Center for Reproductive Medicine, Shandong University, China. A total of 3016 blastocysts from 1269 PGT-A cycles were included in the study. The primary outcome was the euploidy rate of the blastocysts. For each group, regression analyses were performed to quantitatively describe the relationship between maternal age and embryo euploidy rate. The euploidy rate of embryos in women with poor ovarian response (POR) was 39.1% in total. There were 727, 1052, 275 and 962 blastocysts in groups 1, 2, 3 and 4, respectively, with corresponding embryo euploidy rates of 57.2%, 34.9%, 52.4% and 26.2% (P < 0.001). Within each group, the euploidy rate decreased with age, especially in women aged 35 years or older (i.e. groups 2 and 4). Euploidy rates were more favourable in groups 1 and 3, of a young age, re-emphasizing that oocyte quality is the primary factor determining embryo euploidy rate. The study's findings demonstrated the reasonability of categorizing women with POR by the POSEIDON criteria depending on female age and ovarian reserve biomarkers. These results also provide information for women with POR in different subgroups so they can receive proper counselling on the possible prognosis. [ABSTRACT FROM AUTHOR]

Objective: To characterize circulating insulin-like factor 3 (INSL3) in different stages of ovarian insufficiency and its role in the evaluation of premature ovarian insufficiency (POI).Design: Retrospective cohort study.Setting: University-based center for reproductive medicine.Patient(s): A total of 145 women, including 48 patients with POI (25 IU/L < follicle-stimulating hormone [FSH] ≤40 IU/L), 49 with biochemical POI (bPOI) (10 IU/L < FSH ≤25 IU/L) and 48 age-matched control women with normal ovarian reserve (FSH <10 IU/L), retrospectively included from the reproductive hospital affiliated with Shandong University between 2017 and 2019.Intervention(s): Levels of INSL3 in the serum and follicular fluid assayed with a commercial radioimmunoassay.Main Outcome Measure(s): Level of INSL3 in serum and follicular fluid among control women and patients with bPOI and POI, its association with different ovarian reserve markers, and its predictive value for bPOI and POI.Result(s): The serum INSL3 level continuously declined with the progress of ovarian insufficiency. It showed strong negative association with FSH (-0.655) and luteinizing hormone (-0.433), but positively correlated with antimüllerian hormone (0.617), inhibin B (0.400), antral follicle count (0.630), and testosterone (0.180). Additionally, the circulating INSL3 served as a good predictor for bPOI and POI. No statistically significant difference of INSL3 levels in follicular fluid was observed between bPOI patients and control women.Conclusion(s): For the first time our study has revealed an INSL3 deficiency in women with POI, indicating that circulating INSL3 could serve as a promising theca-cell specific marker for POI. Future research on the role of INSL3 in modulating follicular development, steroidogenesis, and POI pathogenesis is warranted. [ABSTRACT FROM AUTHOR]