Chronic Estrus Disrupts Uterine Gland Development and Homeostasis.

Female mice homozygous for an engineered Gnrhr E90K mutation have reduced gonadotropin-releasing hormone signaling, leading to infertility. Their ovaries have numerous antral follicles but no corpora lutea, indicating a block to ovulation. These mutants have high levels of circulating estradiol and low progesterone, indicating a state of persistent estrus. This mouse model provided a unique opportunity to examine the lack of cyclic levels of ovarian hormones on uterine gland biology. Although uterine gland development appeared similar to controls during prepubertal development, it was compromised during adolescence in the mutants. By age 20 weeks, uterine gland development was comparable to controls, but pathologies, including cribriform glandular structures, were observed. Induction of ovulations by periodic human chorionic gonadotropin treatment did not rescue postpubertal uterine gland development. Interestingly, progesterone receptor knockout mice, which lack progesterone signaling, also have defects in postpubertal uterine gland development. However, progesterone treatment did not rescue postpubertal uterine gland development. These studies indicate that chronically elevated levels of estradiol with low progesterone and therefore an absence of cyclic ovarian hormone secretion disrupts postpubertal uterine gland development and homeostasis.

MicroRNA signatures in plasma and plasma exosome during window of implantation for implantation failure following in-vitro fertilization and embryo transfer.

BACKGROUND: MicroRNAs (miRNAs) are small, non-coding RNAs that are dysregulated in many diseases and can act as biomarkers. Although well-studied in cancer, the role of miRNAs in embryo implantation is poorly understood. Approximately 70% of embryos fail to implant following in-vitro fertilization and embryo transfer, 10% of patients experienced recurrent implantation failure. However, there are no well-established biomarkers that can predict implantation failure. Our purpose is to investigate distinct miRNA profiles in plasma and plasma exosomes during the window of implantation between patients with failed implantation and successful implantation. METHODS: We select a nested case-control population of 12 patients with implantation failure or successfully clinical pregnancy using propensity score matching. RNA was extracted from plasma and plasma exosomes collected during the window of implantation (WOI). MicroRNA expression in all samples was quantified using microRNA sequencing. The intersection of differently expressed miRNAs in plasma and exosomes were further validated in the GEO dataset. Significantly altered microRNAs in both plasma and plasma exosomes were then subjected to target prediction and KEGG pathway enrichment analyses to search for key signaling pathways. WGCNA analysis was performed to identify hub miRNAs associated with implantation. RESULTS: 13 miRNAs were differentially expressed in both plasma and plasma exosomes in patients with implantation failure. Among them, miR-150-5p, miR-150-3p, miR-149-5p, and miR-146b-3p had consistent direction changes in endometrium of patients with recurrent implantation failure (RIF), miR-342-3p had consistent direction changes in blood samples of patients with RIF. Pathway enrichment analysis showed that the target genes of differentially expressed miRNAs are enriched in pathways related to embryo implantation. WGCNA analysis indicated that miR-150-5p, miR-150-3p, miR-146b-3p, and miR-342-3p are hub miRNAs. CONCLUSIONS: Implantation failure is associated with distinct miRNA profiles in plasma and plasma exosomes during WOI.

Comparative effectiveness of recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa) versus highly purified urinary human menopausal gonadotropin (hMG HP) in assisted reproductive technology (ART) treatments: a non-interventional study in Germany.

BACKGROUND: This study compared the effectiveness of recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa; GONAL-f®) with urinary highly purified human menopausal gonadotropin (hMG HP; Menogon HP®), during assisted reproductive technology (ART) treatments in Germany. METHODS: Data were collected from 71 German fertility centres between 01 January 2007 and 31 December 2012, for women undergoing a first stimulation cycle of ART treatment with r-hFSH-alfa or hMG HP. Primary outcomes were live birth, ongoing pregnancy and clinical pregnancy, based on cumulative data (fresh and frozen-thawed embryo transfers), analysed per patient (pP), per complete cycle (pCC) and per first complete cycle (pFC). Secondary outcomes were pregnancy loss (analysed per clinical pregnancy), cancelled cycles (analysed pCC), total drug usage per oocyte retrieved and time-to-live birth (TTLB; per calendar week and per cycle). RESULTS: Twenty-eight thousand six hundred forty-one women initiated a first treatment cycle (r-hFSH-alfa: 17,725 [61.9%]; hMG HP: 10,916 [38.1%]). After adjustment for confounding variables, treatment with r-hFSH-alfa versus hMG HP was associated with a significantly higher probability of live birth (hazard ratio [HR]-pP [95% confidence interval (CI)]: 1.10 [1.04, 1.16]; HR-pCC [95% CI]: 1.13 [1.08, 1.19]; relative risk [RR]-pFC [95% CI]: 1.09 [1.05, 1.15], ongoing pregnancy (HR-pP [95% CI]: 1.10 [1.04, 1.16]; HR-pCC [95% CI]: 1.13 [1.08, 1.19]; RR-pFC [95% CI]: 1.10 [1.05, 1.15]) and clinical pregnancy (HR-pP [95% CI]: 1.10 [1.05, 1.14]; HR-pCC [95% CI]: 1.14 [1.10, 1.19]; RR-pFC [95% CI]: 1.10 [1.06, 1.14]). Women treated with r-hFSH-alfa versus hMG HP had no statistically significant difference in pregnancy loss (HR [95% CI]: 1.07 [0.98, 1.17], were less likely to have a cycle cancellation (HR [95% CI]: 0.91 [0.84, 0.99]) and had no statistically significant difference in TTLB when measured in weeks (HR [95% CI]: 1.02 [0.97, 1.07]; p = 0.548); however, r-hFSH-alfa was associated with a significantly shorter TTLB when measured in cycles versus hMG HP (HR [95% CI]: 1.07 [1.02, 1.13]; p = 0.003). There was an average of 47% less drug used per oocyte retrieved with r-hFSH-alfa versus hMG HP. CONCLUSIONS: This large (> 28,000 women), real-world study demonstrated significantly higher rates of cumulative live birth, cumulative ongoing pregnancy and cumulative clinical pregnancy with r-hFSH-alfa versus hMG HP.

Serum Progesterone Profile Across the Mid and Late Luteal Phase in Artificial Cycles Is Associated With Pregnancy Outcome.

Introduction: Recent studies have shown that low serum progesterone levels on the day of embryo transfer (ET) are associated with poorer pregnancy outcome in hormonal replacement therapy cycles. It is of interest to know if serum progesterone levels during late luteal phase (following days after ET) are also related with the chances of ongoing pregnancy. Objective: To evaluate the luteal phase endocrine profile through measurements of serum progesterone and estradiol on days ET+4, ET+7 and ET+11, to test their predictive value in relation to pregnancy outcome. Setting: Private infertility center, Valencia, Spain. Materials and Methods: Prospective cohort study performed between June 2017 and August 2018. Eligible patients were aged between 18-42 years, with a normal uterus, and being transferred 1-2 good quality blastocysts in a frozen ET cycle after an artificial endometrial preparation with estradiol valerate and vaginal micronized progesterone (400 mg/12 hours). Results: A total of 127 patients were included. Mean age = 38.0 ± 3.9 years; BMI = 23.6 ± 3.6 kg/m2; endometrial thickness = 9.1 ± 1.6mm. Overall ongoing pregnancy rate = 47.2% (95%CI:38.3-56.3). Significantly higher levels of serum progesterone were observed on ET+4 (13.6 ± 6.0 vs. 11.1 ± 4.6ng/ml, p = 0.03) and ET+11 (15.7 ± 1.2 vs. 10.3 ± 0.6ng/ml, respectively; p = 0.000) in ongoing pregnancies versus negative ß-hCG (ß-human chorionic gonadotrophin) cases. On ET+7, ongoing pregnancies also had higher serum progesterone levels (14.2 ± 0.9 vs. 11.7 ± 0.8ng/ml, but did not reach statistical significance (p = 0.07). Serum estradiol levels were not related with pregnancy outcome at any moment of the luteal phase (p > 0.05). On days ET+4, +7 and +11, the ROC analysis showed that serum progesterone levels were predictive of ongoing pregnancy, and Pearson's coefficient showed a significant association (p<0.05) of serum ß-hCG levels with serum progesterone. Conclusions: In hormonal replacement therapy cycles, serum progesterone levels across luteal phase days are associated with pregnancy outcome. Ongoing pregnancies were associated with a higher exposure to progesterone in comparison with pregnancy losses or negative ß-hCG. Therefore, serum progesterone might be playing an important role not only during implantation, but also in pregnancy maintenance. It remains unknown if the variability in serum progesterone levels among patients, after receiving the exact same progesterone dose for luteal phase support, is the cause or just a consequence of pregnancy results.

Elevated peritoneal soluble endoglin and GDF-15 in infertile women with severe endometriosis and pelvic adhesion.

OBJECTIVES: Chronic inflammation and pelvic adhesion play a critical role in endometriosis-related infertility. Research studies suggest that TGF-ß superfamily members, such as soluble endoglin (sEng), growth differentiation factor 15 (GDF-15) and tumor growth factor-beta (TGF-ß1) contribute to the regulation of inflammation, angiogenesis and cell adhesion. The objective of this study is to investigate the association between the concentrations of these TGF-ß-related members and the clinical parameters of infertile women with endometriosis. MATERIALS AND METHODS: Sixty-five infertile women who underwent laparoscopy were divided into two groups in this study: those who had endometriosis (n = 33) and control subjects with benign gynecologic disorders (n = 32). The levels of TGF-ß- related members in peritoneal fluid and serum were evaluated by the enzyme-linked immunosorbent assay (ELISA). Clinical and hematological parameters were documented and analyzed. RESULTS: Endometriosis cases had significantly higher levels of sEng, GDF-15 and TGF-ß1 in peritoneal fluid (p<0.0005) compared to control subjects, but not in serum. Moreover, serum GDF-15 level was significantly elevated in the late-stage endometriosis compared to the early-stage group. The levels of three TGF-ß related molecules in peritoneal fluid showed positive correlations with rASRM score. Blood neutrophil counts have correlation with the peritoneal sEng concentration. CONCLUSION: Our novel evidence on the elevated concentration of peritoneal sEng and GDF-15 in endometriosis, specifically in the late-stage, may indicate the essential role of TGF-ß-dependent signaling in endometriosis. Serum GDF-15 might serve as a candidate biomarker for endometriosis severity. Further studies are warranted to investigate the role and regulation of these molecules in endometriosis.

Decline in anti-Müllerian hormone concentrations following radioactive iodine treatment in women with differentiated thyroid cancer: A systematic review and meta-analysis.

AIM: Radioactive iodine (RAI) is frequently used as adjuvant therapy in patients with differentiated thyroid cancer (DTC). However, its effect on ovarian reserve has not been fully elucidated, with studies yielding inconsistent results. The aim of this study was to systematically review and meta-analyze the best available evidence regarding the effect of RAI on ovarian reserve in premenopausal women with DTC. METHODS: A comprehensive literature search was conducted in PubMed, Cochrane and Scopus, through to December 6th, 2020. Data were expressed as weighted mean difference (WMD) with a 95% confidence interval (CI). The I2 index was used to assess heterogeneity. RESULTS: Four prospective studies were included in the qualitative and quantitative analysis. Anti-Müllerian hormone (AMH) concentrations decreased at three (WMD -1.66 ng/ml, 95% CI -2.42 to -0.91, p<0.0001; I2 0%), six (WMD -1.58, 95% CI -2.63 to -0.52, p=0.003; I2 54.7%) and 12 months (WMD -1.62 ng/ml, 95% CI -2.02 to -1.22, p<0.0001; I2 15.5%) following a single RAI dose compared with baseline (three studies; n=104). With respect to follicle-stimulating hormone (FSH) concentrations, no difference was observed at six (WMD +3.29 IU/l, 95% CI -1.12 to 7.70, p=0.14; I2 96.8%) and 12 months (WMD +0.13 IU/l, 95% CI -1.06 to 1.32, p=0.83; I2 55.2%) post-RAI compared with baseline (two studies; n=83). No data were available for antral follicle count. CONCLUSIONS: AMH concentrations are decreased at three months and remain low at 6 and 12 months following RAI treatment in women with DTC. No difference in FSH concentrations post-RAI is observed.

Anti-Müllerian hormone level may predict successful pregnancy after adenomyomectomy in patients with infertility due to adenomyosis.

ABSTRACT: We aimed to determine clinical factors predicting successful pregnancy by comparing pregnancy failure and success groups after adenomyomectomy. Additionally, we analyzed fertility outcomes after adenomyomectomy.The medical records of 43 patients who had undergone adenomyomectomy and received in vitro fertilization treatment from 2017 to 2020 were retrospectively reviewed. Patients were divided into pregnancy failure (n = 28) and pregnancy success (n = 15) groups. Patients' demographic factors were evaluated and compared between the groups.The age of patients was higher (39.0 [32.0-45.0] vs. 37.0 [33.0-42.0] years, P = .006) whereas the level of anti-Müllerian hormone (anti-Müllerian hormone [AMH]; 0.54 [0.01-8.54] vs. 2.91 [0.34-7.92] ng/mL, P = .002) lower in the pregnancy failure group compared to the pregnancy success group. The operative time was longer (220.0 [68.0-440.0] vs. 175.0 [65.0-305.0] min, P = .048) while the estimated blood loss higher (750 [100-2500] vs. 500 [50-2000] mL, P = .016) in the pregnancy failure group compared to the pregnancy success group. No significant difference was observed in body mass index, symptoms, cancer antigen 125, preoperative uterine volume, or type of adenomyosis. In the multivariate analysis, age and AMH were significant predictive factors for successful pregnancy.Ovarian reserve (age and AMH) and disease severity might be predictive factors for successful pregnancy in patients who have undergone adenomyomectomy. Adenomyomectomy should be considered for women desiring pregnancy and having appropriate ovarian reserve. Our results would be beneficial for patients and clinicians before deciding on adenomyomectomy. Larger prospective studies are required to confirm our findings.

Glucocorticoid supplementation improves reproductive outcomes in infertile women with antithyroid autoimmunity undergoing ART: A meta-analysis.

BACKGROUND: Thyroid autoimmune disease (TAI) has been verified to be related to multiple adverse pregnancy outcomes. A growing number of evidences highlight the protective roles of glucocorticoid on the treatments of TAI. This meta-analysis aimed to study whether it is beneficial to add glucocorticoid treatment in infertile women with TAI when they are undergoing assisted reproductive technology (ART). METHODS: We conducted a systematic search in PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), WanFang database, Weipu China Science and Technology Journal Databases (VIP database) up to September 10, 2020. The Revman 5.3 software was utilized for data statistics. We used a random-effects model to analyze data and the odds ratio (OR) combining with 95% confidence interval (95% CI) were employed to reveal the results. RESULTS: Three publications with 237 antithyroid antibody (ATA)-positive and 384 ATA-negative women were included in the final analysis. Overall, glucocorticoid therapy showed satisfying effects on improving clinical pregnancy rate (OR = 4.63, 95% CI [2.23, 9.58], I2 = 0.0%, P < .0001) and live birth rate (OR = 3.19, 95% CI [1.13, 9.04], I2 = 0.0%, P = .03) of ATA-positive women compared with control group. However, it seems that glucocorticoid showed no significant difference in the abortion rate (OR = 0.62, 95% CI [0.09, 4.32], I2 = 35%, P = .64) and oocyte recovery (OR = 2.26, 95% CI [-1.46, 5.99], I2 = 79%, P < .0001) between the 2 groups. CONCLUSIONS: Glucocorticoid may improve the pregnancy outcomes of ART women with ATA positive, but there is no significant reduction in the risk of miscarriage. Due to the limited enrolled references, glucocorticoid adjuvant therapy should be applied after more randomized controlled trials.

The status and comparison of ovarian reserve between fertile and infertile healthy Chinese women of reproductive age.

ABSTRACT: We aimed to investigate ovarian reserve status, and explore differences in ovarian reserve between fertile and infertile healthy Chinese women of reproductive age.We recruited 442 fertile women aged 23 to 49 years (mean: 35.22 ±â€Š4.91 years) as subjects, and 196 infertile women aged 23 to 46 years (mean: 32.34 ±â€Š4.34 years) as controls. For all participants, a number of parameters were tested on days 2 to 4 of a spontaneous cycle, including basal serum follicle-stimulating hormone (FSH), estradiol (E2), luteinizing hormone (LH), total testosterone, anti-Müllerian hormone (AMH), ovarian response prediction index (ORPI), and antral follicle count (AFC).There were significant differences in terms of AFC, serum AMH levels, and ORPI among subject subgroups (10.58 ±â€Š5.80; 2.533 ±â€Š2.146 ng/mL; 1.28 ±â€Š1.87; respectively), and among control subgroups (12.44 ±â€Š5.69; 3.189 ±â€Š2.551 ng/mL; 1.88 ±â€Š2.68; respectively) (P < .01 for all). For both subjects and controls, AFC, AMH levels, and ORPI decreased gradually with increasing age, and presented with similar age-related trends; there were positive correlations between AMH and AFC (P < .001), and negative correlations between age and AFC, AMH, ORPI (P < .05 for all). There was a significant difference in age (P < .001), serum E2 (P < .01), and AMH (P < .01) levels between subjects and controls; however, when controlling for confounding factors (age, body mass index, total testosterone, and LH), we found no differences between the 2 groups with regards to the serum levels of AMH, FSH, E2, and AFC (P > .05 for all). Moreover, receiver operating characteristic curve analysis indicated that the significant variables of subjects and controls for evaluating ovarian reserve included age, AMH and ORPI, and ORPI was more valuable than other variables.A diminished ovarian reserve was one of the manifestations caused by female aging. When confounding factors were controlled for, we found no differences in ovarian reserve when compared between fertile and infertile women, and no correlation with infertility.

Diagnosis and treatment of luteal phase deficiency: a committee opinion.

Luteal phase deficiency (LPD) is a clinical diagnosis associated with an abnormal luteal phase length of ≤10 days. Potential etiologies of LPD include inadequate progesterone duration, inadequate progesterone levels, or endometrial progesterone resistance. LPD has not only been described in association with medical conditions but also in fertile, normally menstruating women. Although progesterone is important for the process of implantation and early embryonic development, LPD has not been proven to be an independent entity causing infertility or recurrent pregnancy loss. Controversy exists regarding the multiple proposed measures for diagnosing LPD and, assuming it can be diagnosed accurately, whether treatment improves outcomes. This document replaces the document entitled "Current clinical irrelevance of luteal phase deficiency: a committee opinion," last published in 2015 (Fertil Steril 2015;103:e27-e32).

4D ultrasound as a method to assess uterine peristalsis.

OBJECTIVE: To study uterine peristalsis using step-by-step 4-dimensional (4D) ultrasound assessment video, explore its relationship with progesterone levels in a select in vitro fertilization population, and assess the reproducibility of the technique. DESIGN: Four-dimensional uterine ultrasound and a retrospective analysis of outcomes in relation with progesterone levels. The videos were also analyzed by a senior doctor, junior doctor, and a nurse for their reproducibility. SETTING: Instituto Bernabeu of Alicante is a private clinic. PATIENT(S): The study included 197 consecutive patients undergoing in vitro fertilization (from 2018 to 2019) with a history of recurrent implantation failure (defined as unsuccessful implantation of a total number of ≥3 blastocysts originated from oocyte donation cycles). Because it is known that most failures are attributed to the quality of the embryo, we deemed it important to explore the potential uterine factors explaining the failures in oocyte donation cycles, the use of which decreases the probability of embryo-related factors influencing it. INTERVENTION(S): The participants were evaluated for uterine contractions and serum progesterone levels (10-30 minutes before the embryo transfer procedure). Uterine contractility (UC) was assessed by recording a 6-minute-long video using a 4D mode (Voluson E10; General Electric, Boston, MA), which was performed by a single operator (B.M.). MAIN OUTCOMES MEASURE(S): The contractions were seen like waves going through the endometrial cavity. They were counted on a ×15 accelerated recording video. To define high-frequency UC, we separated uterine peristalsis (contractions per minute [cpm]) into quartiles. The highest quartile defined the hypercontractility group (>1.51 cpm; n = 41), considering the remaining quartiles as the normal contractility group (≤1.51 cpm; n = 156). The Mann-Whitney U test was performed. The intraclass correlation coefficient was used to validate variability. P <.05 was considered significant. SPSS version 21.0 was used for the statistical analysis. The institutional review board's approval was obtained. RESULT(S): Overall, an average of 1.1 cpm was found in the study population. There were no differences between the groups (hypercontractility vs. normal contractility) in terms of patient age and the presence of any uterine factor (adenomyosis, myomas, adhesions, or polyps). An inverse association was observed between UC and progesterone levels. Low progesterone levels (15.9 vs. 19.5 ng/mL; P = .027) were observed in the HUP and NUP group, respectively. The intraclass correlation coefficient to evaluate the interobserver variability was 0.75 (0.63-0.85; P = .000). CONCLUSION(S): Four-dimensional ultrasound assessment provides a dynamic view of uterine contractions, including their directionality and frequency. Even though recurrent implantation failure is yet a title of obscure definition and probably associated with multiple factors, a subgroup of patients with elevated UC associated with "low" progesterone levels may have a potential effect on their outcomes. Four-dimensional scan evaluation of UC constitutes a promising diagnostic tool in clinical practice; however, larger studies confirming our initial results are still pending.

Serum testosterone levels are positively associated with serum anti-mullerian hormone levels in infertile women.

Anti-Mullerian hormone (AMH) and testosterone (T) both play distinct roles in the early stages of folliculogenesis. However, the relationship between serum T and AMH levels is poorly understood. This study aimed to investigate the association between serum T and AMH levels in infertile women. A total of 1935 infertile women aged 20-46 years were included in the cross-sectional study and divided into four quartile groups (Q1 to Q4) based on serum T levels. Compared to the subjects in the highest T quartile (Q4), those in the lowest T quartile (Q1) showed significantly lower AMH levels. After adjustment for age, body weight, body mass index and FSH, increasing T quartile categories were associated with higher AMH levels. Binary logistic regression analyses revealed that the odds for the risk of diminished ovarian reserve (DOR) were 11.44-fold higher in Q1 than in Q4 and the odds for the risk of excess ovarian reserve (EOR) were 10.41-fold higher in Q4 than in Q1. Our data show that serum T levels are positively associated with serum AMH levels and suggest that androgen insufficiency may be a potential risk factor for DOR; androgen excess may lead to EOR in infertile women.

Evaluation of paternal lymphocyte immunotherapy and potential biomarker mixed lymphocyte reaction-blocking factor in an Argentinian cohort of women with unexplained recurrent spontaneous abortion and unexplained infertility.

PROBLEM: Analyze the effect of paternal immunotherapy treatment (PIT) in primary and secondary unexplained recurrent spontaneous abortion (URSA) and unexplained infertility (UI). METHODS OF STUDY: A retrospective study analyzed a two-year follow-up between the generation of MLR-Bfs after PIT treatment (or controls first consultation) and a live birth. Recruited patients included primary URSA with two or more miscarriages at <12 weeks gestation, secondary URSA with previous live birth before two or more miscarriages, and UI with inability to conceive after 2 years of regular unprotected intercourse or in vitro fertilizations (IVF). PIT treated were compared with untreated controls. RESULTS: Primary URSA: live birth was 241/416 (58%) versus 64/282 (23%) controls (p < .0001). Up to age 35, success was 158/217 (73%) and 37/144 (26%) controls (p < .0001). With 3 or more previous URSA, success was 90/135 (67%) versus 17/79 (22%) controls (p < .0001). Between ages 36 and 40, success was 69/147(47%) versus 22/98 (22%) controls (p < .0003), with 3 or more previous URSA live birth was 45/95 (47%) versus 6/46 (13%) controls (p < .0001). In UI, live birth was 99/298 (33%) versus 54/263 (21%) in controls (p < .0009) that increased under age 35 to 53/116 (46%) in treated versus 26/101 (26%) controls (p < .0056). In PIT treated, IVF success required a median of 1 (1.37 ± 0.67) versus a median of 3 IVF procedures (2.75 ± 0.84) in controls. CONCLUSION: PIT is a successful treatment for primary and secondary URSA, and UI. PIT reduced the number of IVF required for achieving pregnancy.

Androgens and Anti-Müllerian Hormone in Infertile Patients.

To investigate whether there is an association between androgens and ovarian reserve, expressed through anti-Mullerian hormone. This is a retrospective cross-sectional analysis of all consecutive women attending a tertiary fertility center, who presented with regular menstrual cycles. Patients had their AMH values measured with the same AMH assay (Immunotech (IOT) Beckmann Coulter assay), the same day in which androgens sampling was performed. Women with PCOS or other forms of androgen excess or untreated endocrine or metabolic disorders were excluded. A total of 942 women were included. Significant correlation was observed between total testosterone/free androgens index (FAI)/DHEAS and AMH (Spearman's r = 0.20/0.14/0.13, P value < 0.001, P value < 0.001, and P value < 0.001, respectively). After multiple linear regression analysis adjusting for confounders (age, BMI, cause of infertility, day of the menstrual cycle when the blood sample was performed), the regression slope in all participants for total testosterone predicting logAMH was 0.20 (P value < 0.001). Similarly, FAI was significantly associated with logAMH (regression coefficient = 0.04, P value = 0.04). In contrast, DHEAS was not significantly associated with logAMH. There was a significant, but weak relation between testosterone and AMH, while no significant association was observed between DHEAS and AMH. Future research is needed to elucidate whether testosterone supplementation may have any effect on ovarian function.

[Clinical characteristics of 21 infertile women with non-classic 21-hydroxylase deficiency].

Objective: To investigate the clinical features of infertile women with non-classic 21-hydroxylase deficiency (21-OHD). Methods: The study enrolled 21 infertile women with non-classic 21-OHD in Sun Yat-sen Memorial Hospital of Sun Yat-sen University from January 2009 to December 2018. The clinical presentation, endocrine hormone, glucolipid metabolism and treatment outcome were retrospectively analyzed. The diagnosis of non-classic 21-OHD was comprehensively based on clinical and hormonal characteristics. Results: Among 21 cases, the age was (29.9±2.9) years, the mean age at menarche was (13.6±2.0) years, body mass index was (22.1±2.9) kg/m2, and 38% (8/21) had oligomenorrhea. Hirsutism was diagnosed in 3 cases (14%, 3/21). Clitoromegaly was seen in 14% (3/21) and polycystic ovarian morphology was found in 33% (7/21) of the patients. The mean serum level of basal progesterone was (11.3±21.0) nmol/L, with 48% (10/21) having high basal progesterone level; after therapy by glucocorticoid, the level of progesterone was (1.9±2.0) nmol/L. Serum 17-hydroxyprogesterone concentration was (66.4±123.6) nmol/L; after therapy by glucocorticoid, it was (2.4±1.8) nmol/L. In the study increased testosterone, androstenedione and dehydroepiandrosterone sulfate were present in 62% (13/21), 52% (11/21) and 43% (9/21), respectively; and 52% (11/21) of patients manifested androgen excess and basal progesterone elevation; androgen levels decreased after therapy by glucocorticoid. The pregnancy rate was 76% (16/21). Out of 19 pregnancies, 6/19 ended in spontaneous miscarriages. Conclusions: Infertile women with non-classic 21-OHD are characterized by hyperandrogenism and basal progesterone elevation, whereas gonad axis disorder is not apparent. After no response to conventional therapy, adult infertile women with non-classic 21-OHD could achieve a desirable pregnancy outcome with proper treatment of glucocorticoid.

Decreased Frequency of CD8+HLA-G+ T Cell in the Peripheral Blood of Primary Unexplained Infertile Females.

Most of the findings have focused on the importance of CD4+HLA-G+ and CD8+HLA-G+ regulatory T cells (Treg) during pregnancy. It has been demonstrated that these HLA-G+ T cell subsets could induce maternal immune tolerance against semi-allogenic conceptus during pregnancy. There are only a few experiments regarding the Treg cells in the context of unexplained infertility (UI). Thirty-five participants including 18 primary unexplained infertile and 17 fertile females were enrolled in this study. A total of 3-5 ml blood samples were taken, and peripheral blood mononuclear cells (PBMCs) were separated by using Ficoll. Using a flow cytometer, the frequency of CD4+HLA-G+ and CD8+ HLA-G+ T cells was assessed in the peripheral blood samples of primary unexplained infertile and fertile females. Our results showed that the frequency of CD8+HLA-G+ Treg cells was significantly lower in primary unexplained infertile females than fertile females (P = 0.048). Although the frequency of CD4+HLA-G+ Treg cells in the primary unexplained infertile females was lower than fertile females, the difference was not statistically significant (P = 0.25). Regarding the important role of CD8+HLA-G+ Treg cells during pregnancy and its decrease in females with primary UI, it seems that reduced CD8+ HLA-G+ Treg cells could be a leading immunological factor in the context of infertility. Nevertheless, more researches are needed in this field.

Associations Between Sex Hormone Levels and Autistic Traits in Infertile Patients With Polycystic Ovary Syndrome and Their Offspring.

Objectives: 1) To explore the associations between autistic traits and sex hormone changes in patients with polycystic ovary syndrome (PCOS); 2) To explore the influence of PCOS parental autistic traits and related sex hormone changes on autistic traits in their offspring. Method: This is a case-control study that recruited two groups: polycystic ovarian syndrome-induced infertile subjects as the observation group and fallopian tube factor-induced infertility subjects as the control group. Both cohorts were patients undergoing infertility treatment in the Productive Medicine Center, Peking University People's Hospital. Two types of questionnaires were completed by patients between May 1st, 2015, and May 1st, 2016: 1. The autism-spectrum quotient (AQ) 2. Repetitive behavior scale-revised (RBS-r). Levels of sex hormones in serum were measured in patients. The correlations between the levels of these biochemical factors and scores of the autistic traits were analysed. From July 1st, 2020 to September 1st, 2021, these patients were followed up by telephone and asked to fill out a questionnaire online. The questionnaire included date of delivery, complications, medicine used and negative events during pregnancy (e.g., death of relatives, divorce, etc.), delivery condition, breastfeeding, AQ scale and Autism Behavior Checklist (ABC) of their children. Results: The patients in the PCOS group had significantly higher AQ scores than those in the control group. Levels of luteinizing hormone and testosterone were also higher in the PCOS group. No significant differences were found between the two groups in RBS-r levels, follicle-stimulating hormone, estradiol or progesterone. In the two combined groups, there were significantly positive correlations between the AQ scores and the luteinizing hormone concentration, as well as between scores of RBS-r and testosterone concentration. Moreover, there was a significantly negative correlation between the level of progesterone and the RBS-r score. According to the follow-up data, the AQ scores of offspring were positively correlated with the RBS-r scores of their mothers. The ABC scores of offspring were positively correlated with the RBS-r scores and the childbearing age of their mothers. No significant difference was found between the two groups in age of delivery, complications, special medication used, negative events during pregnancy, delivery situation, postpartum breastfeeding, age of children, or AQ scores or ABC scores of children. There were no significant correlations between the scale scores of children and the related sex hormone levels of mothers. This could indicate that the higher levels of luteinizing hormone and testosterone and the lower level of progesterone accompanied more pronounced autistic traits in PCOS. Furthermore, the higher delivery age and RBS-r score in mothers accompanied the higher AQ and ABC scores in children. Conclusion: Compared with the control group, PCOS patients had more autistic traits (especially social dysfunction). The autistic traits in PCOS patients might be related to the elevation in testosterone concentration and luteinizing hormone levels and the decline in progesterone level. Moreover, the autistic traits in the offspring of PCOS patients might be related to the parental high delivery age and high tendency to autism traits.

What are the factors affecting IVF success in women with hypogonadotropic hypogonadism?

OBJECTIVE: This study aimed to investigate in vitro fertilization (IVF) outcomes in women with hypogonadotropic hypogonadism (HH) and unexplained infertility and investigate factors affecting the pregnancy rate among HH patients. MATERIALS AND METHODS: This retrospective cohort study was conducted at Zeynep Kamil Maternity and Children's Diseases Training and Research Hospital, Turkey, a tertiary care referral center. The medical records of 143 women who underwent IVF treatment at this hospital between 2015 and 2020 were reviewed. Sixty-three had hypogonadotropic hypogonadism (HH) and 74 had unexplained infertility. Demographics, hormonal profile, IVF cycle characteristics, and pregnancy rates were recorded. The factors affecting the ongoing pregnancy rates were evaluated among HH patients. RESULTS: Anti-Mullerian hormone (AMH) levels were lower among women with HH compared to those with unexplained infertility (1.64±1.2 vs. 3.0±2.13). IVF cycle characteristics and ongoing pregnancy outcome (20.28% vs. 22.97%) were similar between the groups; however, the total dose of human menopausal gonadotrophin (HMG) used (5127.74±1845.8 vs. 2035.71±1387.45) was higher in the HH group. Increased estradiol level (2596.35±1085 vs. 1869.9±1203.4), endometrial thickness (10.82±1.74 vs. 8.43±2.33), higher number of total oocytes retrieved (12.14±4.34 vs. 8.43±5.44) were correlated with higher ongoing pregnancy rates among the HH group. CONCLUSIONS: IVF success rates were similar between the HH and unexplained infertility groups. Although AMH level was not a prognostic factor for IVF success, higher doses of HMG were needed to achieve pregnancy in the HH group. The factors affecting the ongoing pregnancy rates in the HH group were higher estradiol level, increased endometrial thickness, and a higher number of oocytes retrieved.

Live Birth Rate in Patients With Premature Ovarian Insufficiency During Long-Term Follow-Up Under Hormone Replacement With or Without Ovarian Stimulation.

We analyzed data from 466 patients with premature ovarian insufficiency (POI) who wished to have a biological child and were followed up while undergoing hormone replacement (HR) therapy with or without ovarian stimulation (OS) between April 2014 and December 2020. OS was conducted in 6891 cycles in 429 patients (Group OS), whereas only HR (Group HR) was conducted in 1117 cycles in 37 patients. The follicle growth rate was 48.3% (207/429) per patient in Group OS and 5.4% (2/37) in Group HR (p<0.01). There were 51 live births (LBs) in 50 patients during follow-up. In Group OS, the LB rate was 5.8% (47/807) in cycles where in vitro fertilization (IVF) and embryo transfer were attempted (Group IVF), and 1.3% (3/236) in cycles where intrauterine insemination/timed intercourse was attempted (p<0.01). No pregnancies occurred in Group HR. Among the patients in Group IVF, the LB rate was significantly higher in patients aged <35 years at the initiation of follow-up than in patients who started at later ages (p<0.01). Among the cases who achieved an LB, 39 were patients with idiopathic POI (Group IVF-1, n=297) and seven were patients who had undergone surgical treatment for benign ovarian tumors (Group IVF-2, n=50); however, no LBs occurred in patients who had undergone treatment for malignancy (n=17), and only one in patients with chromosomal abnormalities (n=22). The LB rate per case in the patients in Group IVF-1 and those aged <35 years at the start of follow-up (Group IVF-1-a) was 24.1% (26/108), which was higher than those of the other age groups. The LB rate per case in the patients in Group IVF-1-a with <4 years of amenorrhea was 37.3% (19/51), and that in the patients in Group IVF-2 with <4 years of amenorrhea was 21.2% (7/33). These results suggest that infertility treatment is possible in some patients with POI, especially those that can be classified in Group IVF-1-a and Group IVF-2 with <4 years of amenorrhea. Therefore, OS combined with HR therapy should be considered for such patients before attempts at oocyte donation.