Marker Of Ovarian Reserve Research Articles

P-521 Inter-individual variation in gonadotoxicity in female childhood cancer survivors – a genome-wide association study: results from the PanCareLIFE study

Abstract Study question To identify new variants associated with alkylating agent (AA) induced gonadotoxicity among adult female childhood cancer survivors (CCS) using a genome-wide association study approach (GWAS). Summary answer Upon meta-analysis of two independent cohorts, the variant rs78861946 was associated with lower AMH levels in CCS, but not separately in the smaller replication cohort. What is known already Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the inter-individual variability in gonadotoxicity may be explained by genetic polymorphisms. Study design, size, duration A genome-wide association study (GWAS) approach was used to discover new variants associated with AA-induced gonadotoxicity among adult female CCS. The discovery cohort included adult female CCS from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, CNS, total body irradiation, or stem cell transplantation. Results were replicated in the USA-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years) and combined in a meta-analysis. Participants/materials, setting, methods Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in both the discovery and replication cohort. A GWAS was performed using a linear regression model adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study. Main results and the role of chance Three genome-wide significant (<5.0x10E-8 ) and 16 genome-wide suggestive (<5.0x10E-6 ) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. Based on effect allele frequency (EAF) (>0.01 if not genome-wide significant), p-value (<5.0 × 10E−6 ), and biological relevance, 15 SNPs were selected for replication in the independent replication cohort of the St. Jude Lifetime Cohort. None of the SNPs were statistically significantly associated with AMH levels in this smaller cohort. A meta-analysis indicated thatrs78861946 was associated at borderline genome-wide statistical significance (reference/effect allele: C/T;EAF: 0.04, Beta (SE): −0.484 (0.091), p-value= 9.39 × 10E−8). While the sample size of both the discovery and replication cohorts are large for CCS cohorts, they are very small compared to GWASs in the general population. The limited power is likely one of the reasons the identified SNPs were not statistically significant in our replication cohort of SJLIFE. Limitations, reasons for caution While AMH is a valuable surrogate marker for ovarian reserve, it remains a proxy for ovarian reserve and low AMH levels may still coincide with fertility potential and pregnancy. Wider implications of the findings Identification of risk-contributing variants such as rs78861946 may prove useful to better identify patients who are specifically susceptible for alkylating agent-induced gonadal toxicity. Future polygenic risk scores may aid individualized counselling regarding the treatment-related risk of gonadotoxicity and fertility preservation options for female childhood cancer survivors. Trial registration number not applicable

O-301 Progesterone Primed Ovarian Stimulation (PPOS) for DuoStim combined with PGT-A in poor prognosis patients: a valuable strategy

Abstract Study question Is PPOS rather than conventional GnRH-antagonist a valid strategy in DuoStim protocols? Summary answer PPOS-DuoStim and conventional-DuoStim showed similar mean euploid blastocyst rate (EBR) per inseminated metaphase-II (MII) oocytes. What is known already DuoStim (double stimulation in the same ovarian cycle) is an efficient strategy to increase the number of oocytes retrieved and embryos obtained in the shortest possible timeframe. PPOS is based on the use of exogenous oral progesterone to prevent LH surge during ovarian stimulation (OS). The effectiveness and safety of PPOS have been consistently reported across the last years, supporting it as a clinically-valuable OS protocol. To date, no evidence exists about PPOS application in DuoStim protocols and its association with oocyte competence, defined as EBR per MII-oocytes. Study design, size, duration Retrospective study involving 138 PPOS-DuoStim and 138 matched conventional-DuoStim patients treated at a single clinic between 2021 and 2022 and collecting ≥1 MII-oocyte after both stimulations. Matching was based on maternal age (40.3±2.7 years), number of oocytes collected after the I-stimulation (5.8±3.6 years), and sperm quality (66% normozoospermic). The primary outcome was the EBR per MII-oocytes. All intermediate embryological and clinical outcomes were also compared. Sub-analyses among I- and II-Stimulations were also conducted. Participants/materials, setting, methods DuoStim entailed the same protocol in I- and II-Stimulations with FSH 300IU/day+LH 150IU/day, 5 days spanning the two stimulations and GnRH-agonist to trigger ovulation. The only difference between PPOS-DuoStim and conventional-DuoStim was the administration of medrossiprogesterone acetate10mg/day orally from the first day of stimulation versus flexible GnRH-antagonist from the day the follicles reached a diameter of 13-14 mm. The same laboratory procedures were applied: ICSI, trophectoderm biopsy, comprehensive-chromosome-testing to report uniform aneuploidies and vitrified-warmed single-embryo-transfers. Main results and the role of chance The patients in the two groups were comparable for ovarian reserve markers, BMI, and duration of infertility. All data were comparable in conventional-DuoStim and PPOS-DuoStim (Mann-Whitney U tests were conducted): (i) overall fertilization rate per inseminated MII-oocytes were 73.1±23.2% versus 76.8±17.8% (p = 0.143), (ii) overall blastulation rate per 2PN-zygotes were 46.6±30.4% versus 45.7±25.1%(p = 0.797), (iii) overall euploidy rates per biopsied blastocysts were 24.1±30.9% versus 25.4±31.3%(p = 0.956), (iv) EBR per inseminated MII-oocytes were 9.6±17% versus 9.2±12.7% (p = 0.735). The data among only I- and II-stimulations were also similar. When comparing I- versus II-stimulations, paired t-tests highlighted longer II-stimulations (11±1.9 vs11.6±1.9 days, p = 0.001), resulting in larger cohorts of MII-oocytes (4.3±2.8 vs 5.2±3.3, p < 0.001) with comparable EBR per MII-oocytes (9.7±20.2% vs 11.6±16.2%, p = 0.233), thereby eliciting larger cohorts of euploid blastocysts (0.5±0.07 vs 0.7±0.09, p = 0.005). These data were confirmed also among conventional-DuoStim and PPOS-DuoStim study arms only. From a cycle perspective, among the 138 conventional-DuoStim couples, 31 (22%), 44 (32%) and 59 (43%) obtained ≥1 euploid blastocyst after I-stimulation, II-stimulation and overall, respectively. The same figures among the 138 PPOS-DuoStim were 36 (26%), 44 (32%) and 63 (46%), respectively. No statistical difference was reported (Fisher’s exact test=0.716). Limitations, reasons for caution Retrospective single center design. The current sample size should be doubled in order to reach a 80%-power with a 5%-α to exclude a 5% two-sided difference in the primary outcome. Patients’ compliance and discomfort, as well as clinical, gestational, and perinatal outcomes and cost-effectiveness analyses are needed. Wider implications of the findings PPOS is valuable in unconventional-OS protocols entailing freeze-all, like DuoStim with PGT-A. Future studies should assess if PPOS-DuoStim, by decreasing the number of injections and scans, may improve patient compliance and decrease OS discomfort. Any putative impact on follicular recruitment and oocyte yield should also be determined. Trial registration number not applicable

P-556 Genetic variation in genes related to folliculogenesis and steroidogenesis in Caucasian and Asian women: Baby steps towards a pharmacogenetic approach in assisted reproductive techniques

Abstract Study question What is the impact of single nucleotide polymorphisms (SNPs) in genes related to the folliculogenesis and steroidogenesis on ovarian response to stimulation? Summary answer SMAD2 rs13381619 and COMT rs4680 variants are associated with the follicular output rate (FORT). What is known already The prediction of ovarian response (OR) is crucial for an optimal and individualized management. Despite the good accuracy of ovarian reserve markers in the prediction of OR, a proportion of patients are unexpected hypo-responders. Therefore, a link between OR and individual genotype has been suggested. However, the available evidence is limited by small sample sizes and heterogeneous study designs, including patients with different profiles and allowing for dose adjustments during treatment. Our aim was to analyze the association between SNPs in genes related to folliculogenesis and steroidogenesis and OR in an ethnic diverse population treated with the same fixed-dose protocol. Study design, size, duration This is a secondary analysis of a multicenter multinational prospective study, including 368 patients from Vietnam, Belgium, and Spain (168 from Europe and 200 from Asia) recruited from 11/2016-06/2019. The study included predicted normal responders <38 years old undergoing their first or second ovarian stimulation (OS) cycle. All patients underwent OS in an antagonist protocol with a fixed daily dose of 150 IU rFSH until triggering. Participants/materials, setting, methods First, an interactome was developed using “FSHR” and “LHCGR” as keyword imputed in the Homo sapiens STRING database for protein network analysis. Genetic information from sixty-eight final SNPs involved in the folliculogenesis and steroidogenesis was obtained and used for clustering analysis. Secondly, genotype-phenotype analysis was performed. The prevalence of hypo-responders (<10 oocytes retrieved), number of oocytes retrieved, FORT and follicle to oocyte index (FOI) were compared between different SNPs genotypes. Main results and the role of chance Clustering analysis revealed four distinct genetic clusters according to the selected SNPs related to folliculogenesis and steroidogenesis. Principal component analysis (PCA) was used to display individuals’ distribution according to the fertility centre, resulting in an obvious distribution according to ethnicity. However, PCA failed to demonstrate a clinically significant association between our interactome and the outcomes of interest. We further refined our SNP panel by categorizing SNPs according to their physiological pathway and analyzed their individual impact on OR. Following multivariable linear regression adjusting for patient’s age, Anti-Mullerian hormone (AMH), duration of stimulation and ethnicity, SMAD2 rs13381619 genotype GC (estimated mean difference (EMD) 11.57, 95% Confidence interval (CI) 2.66-20.49), and COMT rs4680 genotype AA (EMD 18.31, 95% CI 4.91-31.72) were associated with improved FORT. No impact of the studied polymorphisms was found on the prevalence of hypo-response, number of oocytes retrieved nor FOI. Limitations, reasons for caution The study was performed in young women with a normal ovarian reserve to eliminate biases related to age-related fertility decline, precluding the extrapolation of the results to other populations. Moreover, the low prevalence of some genotypes might have limited the analysis of some of the included variants. Wider implications of the findings Our findings confirm the variation of SNPs prevalence according to ethnic diversity, highlighting the importance of the intercontinental design of our study. Moreover, a novel association between SMAD2 and COMT variants and OR was reported, opening new opportunities for further pharmacogenetics studies and paving the way towards personalized medicine. Trial registration number Not applicable

Telomerase activity, telomere length, and the euploidy rate of human embryos

Background Telomeres maintain chromosome stability, while telomerase counteracts their progressive shortening. Telomere length varies between cell types, with leukocyte telomere length (LTL) decreasing with age. Reduced telomerase activity has been linked to reproductive issues in females, such as low pregnancy rates and premature ovarian failure, with recent studies indicating correlations between telomere length in granulosa cells and IVF outcomes. Objectives The study aims to explore the relationship between telomere length, telomerase activity, and euploid blastocyst rate in infertile women undergoing IVF/ICSI PGT-A cycles. Methods This prospective study involves 108 patients undergoing controlled ovarian stimulation and PGT-A. Telomere length and telomerase activity were measured in peripheral mononuclear cells and granulosa cells (GC), respectively. Results The telomere repeat copy number to single gene copy number ratio (T/S) results respectively 0.6 ± 0.8 in leukocytes and 0.7 ± 0.9 in GC. An inverse relationship was found between LTL and the patient’s age (p < .01). A higher aneuploid rate was noticed in patients with short LTL, with no differences in ovarian reserve markers (p = .15), number of oocytes retrieved (p = .33), and number of MII (p = 0.42). No significant association was noticed between telomere length in GC and patients’ age (p = 0.95), in ovarian reserve markers (p = 0.32), number of oocytes retrieved (p = .58), number of MII (p = .74) and aneuploidy rate (p = .65). Conclusion LTL shows a significant inverse correlation with patient age and higher aneuploidy rates. Telomere length in GCs does not correlate with patient age or reproductive outcomes, indicating differential telomere dynamics between leukocytes and granulosa cells.

Anti-Müllerian hormone a surrogate of follicular fluid oxidative stress in polycystic ovary syndrome?

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women at childbearing age. Anti-Müllerian hormone (AMH) is a widely accepted sensitive marker of ovarian reserve, which has been suggested that could also act as biomarker of ovarian morphology for PCOS diagnosis. Oxidative stress (OS) is known to be associated and have a negative impact factor in several reproductive conditions, including PCOS. However, the relationship between circulating AMH and OS within the follicular fluid (FF), and its potential impact on in vitro fertilization (IVF) outcomes of women with PCOS, remains largely unexplored. A total of 84 women, with PCOS (n = 30) or ovulatory controls (n = 54), were enrolled in this study. Women underwent individualized controlled ovarian stimulation for oocyte retrieval. Blood and FF obtained from mature follicles were collected at the time of oocyte retrieval, for measuring total testosterone, ∆4-androstenedione, progesterone, sex hormone binding globulin (SHBG) and AMH. OS in the FF was assessed by measuring total antioxidant capacity (TAC) through the ferric reducing antioxidant power (FRAP) and lipid peroxidation (LPO) by quantification of malondialdehyde (MDA) levels. Our results demonstrated that women with PCOS had significantly higher plasma levels of AMH, ∆4-androstenedione, total testosterone and a free androgen index (FAI) than observed in non-PCOS controls. In women with PCOS, total testosterone and AMH levels in the FF were also higher, while TAC was lower compared to non-PCOS. Furthermore, circulating AMH levels were positively correlated with ∆4-androstenedione, albeit negatively correlated with TAC. In this study we demonstrated that the susceptibility to OS, as assessed by the total antioxidant capacity in the FF, is higher in women with PCOS and inversely related to AMH levels. This study results lead us to forge the reasonable hypothesis that the greater susceptibility to OS within the follicle microenvironment is potentially at the end of a roadway that starts with elevated ∆4-androstenedione and AMH within the FF, which in turn are mirrored by circulating AMH and androgen levels. Thus, suggesting that circulating AMH levels could act as a surrogate biomarker of follicular fluid oxidative stress in women with PCOS.

Characteristics of markers of ovarian reserve in women with transfusion-dependent beta thalassaemia major with a successful pregnancy outcome

Objective: Spontaneous fertility and successful pregnancies have been reported in well-chelated and transfused women with beta thalassaemia major (BTM) however majority of women are sub fertile due to hypogonadotropic hypogonadism (HH) and lack of ovulation. Little is known about the effect of iron overload on ovarian follicles and whether ovarian reserve is affected by the condition or treatment. The predictive value of markers of ovarian reserve in relation to live birth in this group of women remains unclear. The aim of this study was to characterize the markers of ovarian reserve in women with transfusion-dependent beta thalassaemia major who had at least one successful live birth. Study design: This is a retrospective study in which we collected data from 12 women with transfusion-dependent BTM and at least one successful live birth from our thalassaemia clinic between July 2007 to June 2022. Patient demographics, medical history, menstrual history, hormonal parameters (serum levels of FSH, oestradiol, TSH and AMH) and antral follicle count were recorded. Serum levels of ferritin, cardiac T2*, liver iron concentration and thyroid function results were recorded from clinic visit prior to either natural conception or assisted conception treatments. Results: There was a wide variation in serum levels of AMH and antral follicle counts amongst women with BTM who had a successful live birth. Low serum AMH levels were noted in 4 women with HH with a background of BTM (33.3%) as compared to the established normal ranges for women of similar age. Also, low AFC counts were noted in 7 women (out of which 6 had HH) with BTM (58.3%) as compared to the established normal ranges for women of similar age. Conclusion: Levels of serum AMH and antral follicle counts appeared lower in up to half the women with BTM and hypogonadotropic hypogonadism with a successful live birth as compared to established normal ranges for women of similar age suggesting that these markers may not accurately reflect the ovarian reserve for all in this group of women. There are limited data about the predictive value of contemporary markers ovarian reserve such as serum AMH and AFC levels in predicting successful fertility or pregnancy outcomes in women with transfusion dependent BTM and larger studies are needed.

Associations between a normal-range free thyroxine concentration and ovarian reserve in infertile women undergoing treatment via assisted reproductive technology

BackgroundSome recent studies have shown that female subclinical hypothyroidism (SCH) is associated with diminished ovarian reserve (DOR). In this study, we aimed to investigate whether serum-free thyroxine (fT4) concentrations within the reference range are associated with ovarian reserve in women.MethodsThis cross-sectional study included 4933 infertile women with normal-range fT4 concentrations who received assisted reproductive technology treatment in our clinic. The data of women in different fT4 concentration tertiles (namely 12–15.33, 15.34–18.67, and 18.68–22 pmol/L) were compared with ovarian reserve markers, namely the anti-Müllerian hormone (AMH) concentration, the antral follicle count (AFC), and the number of aspirated oocytes. The primary outcomes were the AMH concentration and the risk of DOR, diagnosed as an AMH concentration < 1.1 ng/mL.ResultsThe average ages of women in the low-normal, middle-normal, and high-normal fT4 tertiles were 33.20 (standard deviation [SD]: 5.11), 32.33 (SD: 5.13), and 31.61 (SD: 5.10) years, respectively (p < 0.0001). AMH concentrations (adjusted mean: 3.32 [95% confidence interval {CI}: 3.16 to 3.50] vs. 3.51 [3.40 to 3.62] vs. 3.64 [3.50 to 3.80] ng/mL, p = 0.022) were significantly different between the fT4 concentration tertiles. The risk of DOR was significantly increased in the low-normal (adjusted odds ratio: 1.61 [95% CI: 1.01 to 2.58]) and middle-normal (1.47 [95% CI: 1.00 to 2.16]) tertiles compared with the high-normal tertile. Subgroup analysis showed that AMH concentrations were significantly different among the fT4 concentration tertiles in women aged < 35 years (adjusted mean: 3.94 [95% CI: 3.70 to 4.20] vs. 4.25 [4.11 to 4.39] vs. 4.38 [4.18 to 4.58], p = 0.028), whereas this difference was not significant in women aged ≥ 35 years (p = 0.534). The general additive models using fT4 as a continuous variable indicated that a lower fT4 concentration within the normal range was significantly associated with a lower AMH concentration (p = 0.027), a lower AFC (p = 0.018), a lower number of aspirated oocytes (p = 0.001), and a higher risk of DOR (p = 0.007).ConclusionLow-normal fT4 concentrations are associated with lower ovarian reserve in infertile women.

Low and High-Normal FMR1 Triplet Cytosine, Guanine Guanine Repeats Affect Ovarian Reserve and Fertility in Women Who Underwent In Vitro Fertilization Treatment? Results from a Cross-Sectional Study.

Dynamic mutations in the 5' untranslated region of FMR1 are associated with infertility. Premutation alleles interfere with prenatal development and increase infertility risks. The number of CGG repeats that causes the highest decrease in ovarian reserves remains unclear. We evaluated the effect of FMR1 CGG repeat lengths on ovarian reserves and in vitro fertilization (IVF) treatment outcomes in 272 women with alleles within the normal range. FMR1 CGG repeat length was investigated via PCR and capillary electrophoresis. Alleles were classified as low-normal, normal, and high-normal. Serum levels of follicle-stimulating hormone and anti-Mullerian hormone (AMH) in the follicular phase of the menstrual cycle were measured, and antral follicles (AFC) were counted. IVF outcomes were collected from medical records. Regarding FMR1 CGG repeat length alleles, 63.2% of women presented at least one low-normal allele. Those carrying low-normal alleles had significantly lower AMH levels than women carrying normal or high-normal alleles. Low-normal/low-normal genotype was the most frequent, followed by low-normal/normal and normal/normal. A comparison of ovarian reserve markers and reproductive outcomes of the three most frequent genotypes revealed that AFC in the low-normal/normal genotype was significantly lower than the low-normal/low-normal genotype. The low number of FMR1 CGG repeats affected AMH levels and AFC but not IVF outcomes per cycle of treatment.

Serum anti-Müllerian hormone is an indirect predictor of ovarian reserve in domestic cats

Anti-Müllerian hormone (AMH) serves as an indirect marker for predicting primordial follicles that are representative of ovarian reserve. In this study the possibility of using AMH and age to predict the ovarian reserve in domestic cats. Ovaries and blood were collected from 30 cats undergoing routine ovariohysterectomy. The animals were divided into three age groups: prepubertal (<4 mo, n = 10), adult (1–5 y, n = 10), and senior (>5 y, n = 10). Blood was collected at surgery for serum AMH measurements using the AMH Gen II ELISA kit. The intra-assay coefficient of variation (CV) and inter-assay CV were 3.56 % and 7.68 %, respectively. One side of the ovary was processed to determine AMH localization using immunohistochemistry and for a histological count of follicles, which is the gold standard. The expression of AMH protein was quantified from the contralateral ovary by Western blot analysis. Primordial follicles exhibited the most pronounced inverse relationship with age (rho = −0.779, P < 0.05), followed by a positive association with serum AMH concentration (rho = 0.490, P < 0.05), indicating that both age and AMH are potential markers indicative of primordial follicles. Furthermore, secondary (rho = 0.651, P < 0.05) and small antral follicles (rho = 0.648, P < 0.05) were identified as the major sources of circulating AMH, as indicated by the stronger correlation with serum AMH concentrations compared with primary follicles. However, there was no significant correlation between the expression of AMH protein and other factors, including age, primordial follicles, primary follicles, secondary follicles, small antral follicles, and serum AMH concentration. A model for predicting primordial follicle number using serum AMH concentration (AIC = 672.66, P < 0.05) and age (AIC = 668.93, P < 0.05) was established. In conclusion, both serum AMH concentration and age may serve as comparable markers of ovarian reserve in domestic cats. Moreover, AMH is particularly useful in situations where age information is not available.

Dietary acid load and risk of diminished ovarian reserve: a case-control study

BackgroundThe epidemiologic evidence on the association between acid load potential of diet and the risk of diminished ovarian reserve (DOR) is scarce. We aim to explore the possible relationship between dietary acid load (DAL), markers of ovarian reserve and DOR risk in a case-control study.Methods370 women (120 women with DOR and 250 women with normal ovarian reserve as controls), matched by age and BMI, were recruited. Dietary intake was obtained using a validated 80-item semi-quantitative food frequency questionnaire (FFQ). The DAL scores including the potential renal acid load (PRAL) and net endogenous acid production (NEAP) were calculated based on nutrients intake. NEAP and PRAL scores were categorized by quartiles based on the distribution of controls. Antral follicle count (AFC), serum antimullerian hormone (AMH) and anthropometric indices were measured. Logistic regression models were used to estimate multivariable odds ratio (OR) of DOR across quartiles of NEAP and PRAL scores.ResultsFollowing increase in PRAL and NEAP scores, serum AMH significantly decreased in women with DOR. Also, AFC count had a significant decrease following increase in PRAL score (P = 0.045). After adjustment for multiple confounding variables, participants in the top quartile of PRAL had increased OR for DOR (OR: 1.26; 95%CI: 1.08–1.42, P = 0.254).ConclusionDiets with high acid-forming potential may negatively affect ovarian reserve in women with DOR. Also, high DAL may increase the risk of DOR. The association between DAL and markers of ovarian reserve should be explored in prospective studies and clinical trials.

Role of Age as a Major Determinant of Assisted Reproductive Technologies Outcome

The aim of the present study was to determine the influence of age on the prediction of the outcome of assisted reproductive technologies. The study included data of 1992 women who had performed ovarian stimulation according to a protocol with a gonadoliberin antagonist or a long protocol and underwent a follicular puncture. Patients were divided into four age groups, where numbers of oocytes collected, number of atretic oocytes and percentage of clinical pregnancies were evaluated. We found significantly reduced average number of oocytes collected with increase of age. In patients with poor ovarian reserve the average age is higher than in patients with good response, i.e. normal ovarian reserve. We have found clear tendency of decreased clinical pregnancy rate with the increase of women's age. In conclusion, our data show convincingly that age is a strong prognostic marker of ovarian reserve in both quantitative and qualitative terms, estimated by the clinical pregnancies achieved.

Correlation of FMR4 expression levels to ovarian reserve markers in FMR1 premutation carriers.

Fragile X-associated primary ovarian insufficiency (FXPOI), characterized by amenorrhea before age 40 years, occurs in 20% of female FMR1 premutation carriers. Presently, there are no molecular or biomarkers that can help predicting which FMR1 premutation women will develop FXPOI. We previously demonstrated that high FMR4 levels can discriminate between FMR1 premutation carriers with and without FXPOI. In the present study the relationship between the expression levels of FMR4 and the ovarian reserve markers was assessed in female FMR1 premutation carriers under age of 35 years. We examined the association between FMR4 transcript levels and the measures of total antral follicle count (AFC) and serum anti-müllerian hormone (AMH) levels as markers of ovarian follicle reserve. Results revealed a negative association between FMR4 levels and AMH (r = 0.45) and AFC (r = 0.64). Statistically significant higher FMR4 transcript levels were found among those FMR1 premutation women with both, low AFCs and AMH levels. These findings reinforce previous studies supporting the association between high levels of FMR4 and the risk of developing FXPOI in FMR1 premutation carriers.

Ovarian reserve in obese patients: where do the eggs disappear?

Currently, the issue of obesity and its impact on various aspects of human health is actively being discussed. The role of obesity in the development of metabolic syndrome is well known. Within the study of the obesity pandemic, the modern medical community is conducting research in the field of reproductive health. In women, markers of ovarian reserve are considered, with the main one being the level of anti-Mullerian hormone (AMH). It is known that with age, the number of AMH and antral follicles in a woman's body decreases. However, there is data in the modern literature indicating a decrease in ovarian reserve parameters in conditions of weight gain. Weight gain is accompanied by a imbalance of adipokines - biologically active substances produced mainly by adipose tissue and other tissues of the body that affect metabolic processes. It can be assumed that a deep study of the relationship between decreased reproductive potential and obesity, timely prevention of metabolic disorders will improve fertility indicators.

The Effect of Bilateral Uterine Artery Ligation after Intrapartum or Postpartum Hemorrhage on Ovarian Reserve Markers and Pregnancy Outcome

The Effect of Bilateral Uterine Artery Ligation after Intrapartum or Postpartum Hemorrhage on Ovarian Reserve Markers and Pregnancy Outcome

Effect of breast cancer prognostic factors on ovarian reserve and response in fertility preservation

Research questionDo breast cancer prognostic factors influence ovarian reserve and response to ovarian stimulation in the context of fertility preservation? DesignObservational, bicentric retrospective study of 352 women with breast cancer who underwent ovarian stimulation using a random start gonadotrophin releasing hormone antagonist protocol and vitrified oocytes between November 2015 and August 2022. Serum anti-Müllerian hormone (AMH) levels and antral follicle count (AFC) were measured. The number of oocytes recovered, maturation rate and follicular output rate (FORT) were analysed according to patients’ characteristics and breast cancer prognostic factors. ResultsMedian age was 34 years (31.1–37.1). Median AFC and serum AMH level were 17 (12–26) follicles and 2 (1.2–3.4) ng/ml, respectively. After ovarian stimulation, 10.5 (6.0–16.0) oocytes were recovered, with eight (4–13) being mature. Mean oocyte maturation rate was 79% (62–92). Antral follicle count (>12) significantly affected the risk of recovering fewer than eight mature oocytes (P < 0.0001, multivariate analysis). Follicular responsiveness to FSH, assessed by the follicular output rate (FORT index) and number of oocytes recovered, were 31% (21–50) and 10.5% (6.0–16.0), respectively. FORT index and ovarian stimulation outcomes were not influenced by breast cancer prognostic factors. ConclusionBreast cancer prognostic factors do not influence ovarian reserve markers or response to ovarian stimulation in fertility preservation. Therefore, tumour grade, triple-negative status, HER2 overexpression and high Ki67 should not alter the fertility-preservation strategy when considering ovarian stimulation for oocyte vitrification.

Correlation of Anti-Mullerian Hormone with Antral Follicle Count among South Indian Infertile Women in a Tertiary Care Center

Abstract Context: Diminished ovarian reserve (DOR) is one of the important causes of infertility and its incidence is increasing even in younger age groups with no risk factors. Ovarian reserve needs to be evaluated in an infertile couple as the fecundity or response to ovarian stimulation is less in women with DOR. Anti-Mullerian hormone (AMH) and antral follicle count (AFC) are markers of ovarian reserve with the highest sensitivity. Aims: The aim of this study was to assess the ovarian reserve among infertile women through AMH and AFC, to find if there is a correlation between AMH and AFC, and to see if there is a correlation between AMH and AFC with age. Settings and Design: This study was conducted at the Department of OBG, JSS Hospital, JSS AHER, Mysore. This was a cross-sectional study. Materials and Methods: The study included 141 infertile women aged 19–45 years. Serum AMH was measured using chemiluminescent immunoassay irrespective of the day of the menstrual cycle and AFC was measured on 2nd or 3rd day of the menstrual cycle by transvaginal ultrasound. Statistical Analysis Used: Student’s-t-test, Chi-square test, and Pearson’s correlation were used for analysis. Results: Mean AMH and AFC of the subjects were 4.52 ± 4.16 ng/ml and 17.08 ± 12.54, respectively. A significant positive correlation was noted between AMH and AFC (r = 0.663, P &lt; 0.01) and there was a significant negative correlation between age as compared with AFC (r = −0.349, P &lt; 0.01) and AMH (r = −0.244, P &lt; 0.01). Conclusion: AFC and AMH showed a significant negative correlation with age. AFC had a strong positive correlation with serum AMH.

Prevalence of FSH-R Asn680Ser and Ala307Thr receptor polymorphism and their correlation with ART outcomes among infertile Indian-Asian women-a prospective cohort study.

The present prospective cohort study evaluated the prevalence of FSH-R receptor Asn680Ser and Ala307Thr among infertile Indian women and the correlation of these polymorphisms with ART outcomes. Total 804 infertile and 209 fertile controls were enrolled for FSH-R analysis. Correlation of different genotypes with ovarian reserve markers, IVF parameters, and cumulative live birth rates (CLBR) was done among women undergoing IVF. In fertile controls, at 680 position GG (Ser/Ser) was the most common genotype; but among infertile women, all the genotypes were equally distributed. There was no significant difference in ovarian response parameters, oocyte yield, and CLBR among the three genotype groups. Empty follicle syndrome (EFS) was highest in women with AA or AG type at both positions. On categorisation of unexpected poor responders according to POSEIDON stratification; GG genotype at both positions had the lowest risk ratio of low-oocyte yield in ART cycles, but these differences were not statistically significant. This is the largest study from Indian ethnicity showing GG (Ser/Ser) genotype is most common among fertile women. The effect of FSH-R genotypes is very marginal on IVF parameters and is not reflected in CLBR. More prospective data may be required on the correlation of these genotypes with genuine EFS, thus stratifying the next cycles with self or donor oocytes. Routine genetic testing of FSH-R polymorphism should not be done except in a research setting. As both 680 and 307 positions are in linkage disequilibrium, only 680 position analysis may be done in a research setting.

Analysis of the potential regulatory mechanisms of female and latent genital tuberculosis affecting ovarian reserve function using untargeted metabolomics

Female and latent genital tuberculosis (FGTB and LGTB) in young women may lead to infertility by damaging ovarian reserve function, but the regulatory mechanisms remain unclear. In this study, we investigated the effects of FGTB and LGTB on ovarian reserve function and potential regulatory mechanisms by untargeted metabolomics of follicular fluid, aiming to provide insights for the clinical management and treatment approaches for afflicted women. We recruited 19 patients with FGTB, 16 patients with LGTB, and 16 healthy women as a control group. Clinical data analysis revealed that both the FGTB and LGTB groups had significantly lower ovarian reserve marker levels compared to the control group, including lower anti-Müllerian hormone levels (FGTB: 0.82 [0.6, 1.1] μg/L; LGTB: 1.57 [1.3, 1.8] μg/L vs. control: 3.29 [2.9, 3.5] μg/L), reduced antral follicular counts (FGTB: 6 [5.5, 9.5]; LGTB: 10.5 [7, 12.3] vs. control: 17 [14.5, 18]), and fewer retrieved oocytes (FGTB: 3 [2, 5]; LGTB: 8 [4, 8.3] vs. control: 14.5 [11.5, 15.3]). Conversely, these groups exhibited higher ovarian response marker levels, such as longer gonadotropin treatment days (FGTB: 12 [10.5, 12.5]; LGTB: 11 [10.8, 11.3] vs. control: 10 [8.8, 10]) and increased gonadotropin dosage requirements (FGTB: 3300 [3075, 3637.5] U; LGTB: 3037.5 [2700, 3225] U vs. control: 2531.25 [2337.5, 2943.8] U). All comparisons were statistically significant at P < 0.05. The results suggested that FGTB and LGTB have adverse effects on ovarian reserve and response. Untargeted metabolomic analysis identified 92 and 80 differential metabolites in the control vs. FGTB and control vs. LGTB groups, respectively. Pathway enrichment analysis revealed significant alterations in metabolic pathways in the FGTB and LGTB groups compared to the control group (P < 0.05), with specific changes noted in galactose metabolism, biotin metabolism, steroid hormone biosynthesis, and nicotinate and nicotinamide metabolism in the FGTB group, and caffeine metabolism, primary bile acid biosynthesis, steroid hormone biosynthesis, and glycerophospholipid metabolism in the LGTB group. The analysis of metabolic levels has revealed the potential mechanisms by which FGTB and LGTB affect ovarian reserve function, namely through alterations in metabolic pathways. The study emphasizes the importance of comprehending the metabolic alterations associated with FGTB and LGTB, which is of considerable relevance for the clinical management and therapeutic approaches in afflicted women.

Exposure to heavy metallic and trace essential elements and risk of diminished ovarian reserve in reproductive age women: A case-control study

The associations between metallic elements and ovarian reserve function have remained uncertain yet. In this case-control study, we involved 149 women with diminished ovarian reserve (DOR) and 151 women with normal ovarian reserve, and assessed the levels of six heavy metallic (Cr, Cd, As, Hg, Pb, and Mn) and seven trace essential (Se, Fe, Zn, Co, Mo, Cu, I) elements in their follicular fluid with inductively coupled plasma mass spectrometry. Associations were examined with logistic regressions and Bayesian kernel machine regression (BKMR). As a result, we found that the medium and the highest tertiles of Pb were significantly associated with an increased likelihood of DOR compared to the lowest tertile, while the medium or/an the highest tertiles of Cu, I, and Fe showed significantly lower likelihoods of DOR compared to the lowest tertiles. Cu and Pb showed significantly non-linear associations with ovarian reserve markers such as follicle-stimulating, anti-mullerian hormone levels, and antral follicle count. With the rising overall concentrations of heavy metals, the likelihood of DOR increased although not significant. There was a trend of a "U-shaped" association across the whole concentration range of trace essential elements and the likelihood of DOR. Our study revealed that avoiding heavy metallic elements and properly supplementing trace essential elements are conducive to ovarian function.

Poor ovarian response classification systems in the clinical setting - time for an update?

Poor ovarian response (POR) remains a key challenge to the success of assisted reproductive technology. Here, we offer a comprehensive review of the two main classification systems for POR, discussing their promises and pitfalls, evaluating their performance, and exploring potential avenues for improving upon these definitions of POR. The Bologna criteria represented the first meaningful attempt to create a universal POR definition. Subsequently, the POSEIDON classification system was published to provide a more nuanced view of POR, classifying patients into four groups based on age and ovarian reserve markers. A recent study evaluated the likelihood of achieving at least one euploid embryo for transfer and found that, indeed, these classification systems are effective predictors of this outcome.While these criteria provide an effective counseling tool, several limitations - not considering underlying conditions, selecting somewhat arbitrary cutoffs, and evaluating the number of oocytes retrieved regardless of maturity - highlight the importance of improving upon these systems to create a more useful tool to more accurately predict ovarian response for clinical and research purposes. In the era of personalized medicine, it is time to reconsider whether diagnostic criteria for a continuous metric such as ovarian response should be based on meeting all-or-nothing thresholds for specific parameters.