Dose Of Follicle-stimulating Hormone Research Articles

Exploring Independent Effects of Follicle-Stimulating Hormone In Vivo in a Mouse Model.

During the transition from a reproductive to a nonreproductive phase (menopause), many women experience significant physiological and pathological changes, including decreased bone mass, increased blood lipids, and increased visceral adiposity. Levels of follicle-stimulating hormone (FSH) rise during the menopausal transition. Many studies have shown that FSH in various extragonadal tissues and organs is associated with the pathogenesis of multiple diseases. Thus, building an animal model that can help study the independent effects of FSH in vivo is particularly important. In this study, C57BL/6 female mice were ovariectomized and supplemented with estradiol valerate (OVX + E2) to eliminate the effect of the hypothalamic-pituitary-gonadal axis. The OVX + E2 mice received solvent (N.S.) or different doses of recombinant FSH via intraperitoneal injection to create a mouse model (OVF) characterized by relatively stable estrogen and rising FSH levels. Thus, we successfully generated an experimental mouse model to mimic the early stage of menopause transition, characterized by elevated serum FSH levels. The OVF model has the advantages of being stable, low cost, and easy to operate, which is suitable for studies to explore the extragonadal actions of FSH. Here, we describe detailed protocols for the mouse OVF model.

Dose Nomogram of Individualization of the Initial Follicle-Stimulating Hormone Dosage for Patients with Polycystic Ovary Syndrome Undergoing IVF/ICSI with the GnRH-Ant Protocol: A Retrospective Cohort Study.

For high responders with polycystic ovary syndrome (PCOS), there is no clear recommendation for the initial follicle-stimulating hormone (FSH) dosage to ensure an optimal number of retrieved oocytes and avoid ovarian hyperstimulation syndrome (OHSS). The aim of this study was to determine the ideal initial FSH dosage of in patients with PCOS undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) using the gonadotropin-releasing hormone antagonist (GnRH-ant) protocol to obtain the optimal number of retrieved oocytes and minimize the risk of OHSS. The data of 1898 patients with PCOS aged 20-40years from January 2017 to December 2020 were retrospectively analyzed to explore the factors related to the number of retrieved oocytes. Statistically significant variables were used to construct a dose nomogram and it was then validated using an independent cohort of patients with PCOS from January 2021 to December 2021. Multivariate analyses demonstrated that body mass index (BMI) was the most significant factor to predict the number of retrieved oocytes compared to body weight (BW) and body surface area (BSA). Among patients with PCOS aged 20-40years undergoing their first IVF cycles with the GnRH-ant protocol, age was not a significant predictor of the initial FSH dosage. We developed a nomogram based on BMI, basal FSH, basal luteinizing hormone (bLH), anti-Müllerian hormone (AMH), and antral follicle count (AFC) to calculate the ideal initial FSH dosage for patients with PCOS undergoing IVF/ICSI using the GnRH-ant protocol. In addition, low BMI and high bLH and AMH levels and AFC appear to be risk factors for OHSS. We clearly demonstrated that the initial FSH dosage for patients with PCOS undergoing IVF/ICSI with the GnRH-ant protocol may be calculated on the basis of the woman's BMI and ovarian reserve markers. The nomogram will help guide clinicians in the selection of the most appropriate initial FSH dose in the future.

O-185 A clinically robust machine learning model for selecting the first FSH dose during controlled ovarian hyperstimulation: incorporating clinical knowledge to the learning process

Abstract Study question Can we improve the selection of the first dose of follicle stimulating hormone (FSH) for IVF patients by incorporating clinical evidence with machine learning? Summary answer A significant improvement in correct dose prescription is achieved when using a FSH dosing model that integrates a novel machine learning methodology with clinical knowledge. What is known already The appropriate selection of the initial FSH dose during controlled ovarian hyperstimulation (COH) is key for ART success. An optimal number of oocytes should be obtained for achieving pregnancy, while also avoiding complications for the patient. While clinical protocols achieve good results for the majority of patients, further refinements in individualized FSH dosing may improve safety while reducing the risk of poor response. Machine learning techniques have been applied to dose/response problems with promising results. However, the observational datasets used to train the models are often incomplete and biased, leading to less clinically robust predictions. Study design, size, duration We used a database of 2713 first cycles performed between January 2011 and December 2019, across five clinics to train the model. Predictors included age, body mass index (BMI), anti-Müllerian hormone (AMH) levels and antral follicle count (AFC). First FSH dose and number of mature oocytes retrieved were also recorded. Another 273 cycles performed between January 2020 and September 2021 were used for validation. Dosing was performed by 41 clinicians (mean 12 years of experience). Participants/materials, setting, methods The model was developed in Python and trained while incorporating available clinical evidence. The relationship between FSH dose and response (number of mature oocytes) was specified by assuming a positive linear function. Rules were incorporated to penalize dose changes that resulted in poorer outcomes compared to the clinician, and to discourage large dose modifications by the model. These same rules were applied during the validation phase. Comparisons were assessed by Chi-squared test with Bonferroni correction. Main results and the role of chance Mean maternal age was 37.1 ± 4.9 years. Patients had a mean BMI of 23.8 ± 4.2, AFC of 11.9 ± 7.7 and AMH of 2.4 ± 2.3. They were prescribed a first dose of 247.0 ± 59.0 IU of FSH and obtained 7.3 ± 5.3 mature oocytes after pick-up. An optimal outcome was defined as 10-15 mature oocytes retrieved, and 300 IU was the maximum FSH dose allowed. In the validation dataset, we observed that 22.9% patients could have received a higher FSH dose (<10 mature oocytes collected), 69.3% were correctly prescribed (10-15 mature oocytes or no change in dose was required), while 7.9% needed a decrease in FSH dose (>15 mature oocytes). In the machine learning model 9.4% of patients required a dose increase, 80.5% were correctly prescribed and 7.9% needed a decrease in dose. Accordingly, the model rescued 11.6% of patients that would have otherwise achieved suboptimal outcomes. Ultimately, when compared to the clinicians, the model significantly reduced the number of patients that required a dose increase, and significantly improved the number of patients that were prescribed a correct dose (p < 0.05). Limitations, reasons for caution The model assigned a non-conservative dose increase to 2.3% of patients, potentially leading to a risk of ovarian hyperstimulation syndrome. Moreover, hyper-responders were underrepresented in the database, resulting in no significant improvements in the dose/outcome relationship for this subgroup. Wider implications of the findings Coding clinical knowledge into the training of clinically relevant machine learning models ensured adherence to scientific evidence, and improved model performance while making conservative changes. This approach is critical for the safe and robust clinical implementation of interventional models. Trial registration number not applicable

Controlled ovarian hyperstimulation in breast cancer patients: Does oestrogen receptor status make a difference?

The presence of different breast cancer receptor status may impact ovarian stimulation outcomes. To study the association between oestrogen receptor (ER) status in breast cancer patients and fertility preservation outcomes in a major tertiary referral centre. Women who underwent fertility preservation following the diagnosis of breast cancer from 2008 to 2018 were included in the study. Patient age, ovarian stimulation parameters and laboratory outcomes were recorded and compared between the ER positive and negative groups. The primary outcome was total number of oocytes frozen. Secondary outcomes included total number of oocytes collected, mature oocytes, and embryos frozen. The women included in the study (n = 214) were analysed in the following groups based on their fertility preservation method: oocyte freezing (n = 131), embryo freezing (n = 70), and both embryo and oocyte freezing (n = 13). There was an increase in the mean (but not mature) number of oocytes frozen (12.4 and 9.2, P-value = 0.03) favouring the ER positive group, even though the women in this group were older (35.0 and 33.4, P-value of 0.03). There is no difference in the starting follicle-stimulating hormone dose, duration of stimulation, mature oocytes collected, and embryos frozen in both groups. Patients with ER positive breast cancer may have more positive ovarian stimulation outcomes.

Ovarian stimulation methods at a single-assisted reproductive technology institution: a retrospective study of successful outcomes

Aim : to examine an efficacy of various stimulation methods in a group of successful pregnancies. Materials and Methods . In a single center retrospective study 47 pregnancy cases were examined after performing embryo transfers at our institution from the years 2017 to 2021. Patients were divided into four groups: i) clomiphene hyperstimulation (CH), ii) stimulation with gonadotropin-releasing hormone (GnRH) agonist, iii) with GnRH antagonist, and iv) progestin-primed ovarian stimulation (PPOS). Age, anti-Mullerian hormone, presence of chronic disease, number of in-vitro fertilizations prior to conception, dosage of follicle stimulating hormone (FSH), presence of premature luteinizing hormone surge, number of egg retrievals, fertilization rate, and live birth rate were assessed. Results. The number of pregnancies obtained by CH, agonist, antagonist, and PPOS methods comprised 25, 12, 2, and 8 cases, respectively. No significant difference in parameters between CH group and non-CH groups, excepting FSH was observed. The FSH was used in CH group and non-CH group at dose of 1108 ± 468 IU and 1756 ± 394 IU, respectively (p < 0.0001). Conclusion. CH is not commonly used due to potential luteal phase defects, but it is thought to be cost-effective, requiring lower FSH doses, requiring no ovulation suppression antagonists, and exerting no effect on frozen embryos or fetuses. Hence, CH could be a suitable protocol for egg retrieval in Japan.

Effectiveness of letrozole in pituitary downregulated normogonadotrophic young women with an initial poor response.

It has been reported that 10 to 15% of young normogonadotrophic women show suboptimal response to standard long protocols. Letrozole (LE), an aromatase inhibitor, was shown to improve ovarian sensitivity to follicle stimulating hormone (FSH) and follicular response to gonadotrophin treatment in poor ovarian response patients. We reasoned that it might be possible to utilize LE in young normogonadotrophic patients with unexpected hypo-response in standard gonadotropin-releasing hormone agonist long protocol. A total of 652 patients defined as normogonadotrophic patients with unexpected hypo-response were divided into 2 groups, the +LE group and the +Gn group. +LE group: A fixed daily dose of 2.5 mg of LE was added on day 8 of stimulation. +Gn group: A fixed daily dose of 75 U of human menopausal gonadotrophin was added on day 8 of stimulation. The primary outcome measures were the number of oocytes obtained, fertilization rate, days of stimulation, and total FSH dosage. The secondary outcome measures were the implantation rate and ongoing pregnancy rate. There were no significant differences in the clinical and hormonal characteristics between the 2 groups. A shorter duration of stimulation and a lower dosage of recombinant FSH consumption on the day of human chorionic gonadotropin administration were all observed in the +LE group. Patients who received LE therapy showed a higher number of oocytes obtained and significantly higher fertilization rates. The implantation rate and ongoing pregnancy rate were comparable in both groups. LE significantly improves the number of oocytes obtained in patients with suboptimal response to standard gonadotropin-releasing hormone agonist long protocol.

Identification of common genetic polymorphisms associated with down-regulated gonadotropin levels in an exome-wide association study

To investigate whether common genetic polymorphisms are associated with gonadotropin levels after down-regulation with daily gonadotropin-releasing hormone agonist and whether the polymorphisms of candidate variants influence the ovarian response to exogenous gonadotropins. Genetic association study. University-affiliated invitro fertilization center. Subjects enrolled in an exploratory exome-wide association study (n = 862), a replication exome-wide association study (n= 86), and a classifier validation study (n = 148) were recruited from September 2016 to October 2018, September 2019 to September 2020, and January 2021 to December 2021, respectively. The included patients were aged ≤40 years and had a basal follicle-stimulating hormone (FSH) ≤12 IU/L. All participants received a luteal phase down-regulation long protocol. Genome DNA was extracted from the peripheral blood leukocytes. For the exploratory and replication cohorts, exome sequencing was conducted on a HiSeq 2500 sequencing platform. The multiplex polymerase chain reaction amplification technique and next-generation sequencing also were performed in the exploratory and replication cohorts. For the samples of the validation cohort, Sanger sequencing was performed. The primary endpoint was the gonadotropin levels after down-regulation, and the secondary endpoints were hormone levels and follicle diameters during stimulation, the total dose of FSH, duration of FSH stimulation, number of oocytes retrieved, and clinical pregnancy rate. In the exploratory cohort, we identified that FSHB rs6169 (P=2.71 × 10-24) and its single-nucleotide polymorphisms in high linkage disequilibrium were associated with the down-regulated FSH level. The same locus was confirmed in the replication cohort. Women carrying the C allele of FSHB rs6169 exhibited higher average estradiol level during stimulation (P=6.82 × 10-5), shorter duration of stimulation, and less amount of exogenous FSH (Pduration=0.0002; Pdose=0.0024). In the independent validation set, adding rs6169 genotypes into the prediction model for FSH level after down-regulation enhanced the area under the curve from 0.560 to 0.712 in a logistic regression model, and increased prediction accuracy by 41.05% when a support vector machine classifier was applied. The C allele of FSHB rs6169 is a susceptibility site for the relatively high level of FSH after down-regulation, which may be associated with increased ovarian FSH sensitivity.

Association Between Follicle-Stimulating Hormone Receptor (FSHR) rs6166 and Estrogen Receptor 1 (ESR1) rs2234693 Polymorphisms and Polycystic Ovary Syndrome Risk, Phenotype, and Reproductive Outcomes in an Infertile Portuguese Population.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder often leading to anovulatory infertility. PCOS pathophysiology is still unclear and several potential genetic susceptibility factors have been proposed. The effect of polymorphisms in two genesrelated to follicular recruitment and development, the follicle-stimulating hormone receptor (FSHR) and the estrogen receptor 1 (ESR1), have been studied in different populations with contradictory results. To evaluate the influence of FSHR rs6166 (c.2039A>G) and of ESR1 rs2234693 (Pvull c.453-397 T > C) polymorphisms on PCOS risk, phenotype, and response to controlled ovarian stimulation (COS). Genotyping of the FSHR rs6166 andthe ESR1 rs2234693 polymorphisms was performed inPCOS women and a control group undergoing in vitro fertilization (IVF). Demographic, clinical, and biochemical data, genotype frequency, and IVF outcomes were compared between groups. We evaluated 88 PCOS women and 80 controls. There was no significant difference in the genotype distribution of FSHR rs6166 polymorphism between PCOS women and controls (AA 31.8%/AS 48.9%/SS 19.3% in PCOS women vsAA 37.5%/AS 40.0%/SS 22.5%in controls; p = 0.522). The same was true for the ESR1 rs2234693 (CC 24.1%/CT 46.0%/TT 29.9% in PCOS women vsCC 18.8%/CT 48.8%/TT 32.5%in controls; p = 0.697).In PCOS women, we found higher follicle-stimulating hormone (FSH) levels on the third day of the menstrual cycle associated with the SS variant of the FSHR polymorphism (9.2 vs6.2 ± 1.6 and 5.6 ± 1.6 mUI/mL; p = 0.011). We did not find other associations between the baseline hormonal parameters, antral follicle count, and response measures to COS with FSHR or ESR1 genotypes. We found, however, a need for higher cumulative doses of FSH for COS in patients with the SS variant of the FSHR rs6166 polymorphism (1860.5 ± 627.8 IU for SSvs1498.1 ± 359.3 for AA and 1425.4 ± 474.8 for SA; p = 0.046 and p = 0.046). Our data suggest thatin the population,FSHR rs6166and ESR1 rs2234693 polymorphisms do not influence the risk of developing PCOS nor do they influence the patient's phenotype and IVF success. However, the SS variant of the FSHR rs6166 polymorphism may beassociated with FSH resistance requiring higher FSH doses for COS.

POvaStim: An online tool for directing individualized FSH doses in ovarian stimulation

POvaStim: An online tool for directing individualized FSH doses in ovarian stimulation

Retrospective study of ovarian reaction and fertility in women with discordant antimullerian hormone and follicle-stimulating hormone/luteinizing hormone ratios during in vitro fertilization.

The objective of this study was to examine the predictive ability of follicle-stimulating hormone (FSH)/luteinizing hormone (LH) ratio and antimullerian hormone (AMH) levels in the same cohort when both are inconsistent and to identify which has an excellent ability to predict live birth and ovarian response to in vitro fertilization (IVF). A retrospective cohort study was performed within 6096 IVF cycles executed between January 2016 and August 2019 at the Center for Assisted Reproduction, The Third Affiliated Hospital of Zhengzhou University, and Jiaozuo Maternity and Child Health Care Hospital. Initially, IVF cycles were classified according to basal FSH/LH ratio and AMH values, and the primary outcome was a comparison of live birth rate per cohort. Secondary outcomes included characteristics of the study individuals such as body mass index (BMI), age, antral follicle count, ovarian sensitivity index, cycle cancellation rate, and cycle outcome data. Women with FSH/LHhigh ratio and AMHnormal levels had a meaningly higher live birth rate compared with those with FSH/LHnormal ratio and AMHlow levels (46.59% vs. 21.21%, p < 0.001). In addition, women with FSH/LHnormal ratio and AMHlow levels were found to have a higher cancellation rate in their IVF cycles (80.98%). In women with FSH/LHnormal ratio, further multivariate analysis revealed that AMH level, age, number of retrieved oocytes, and FSH dosage were relevant risk factors for live birth. The relative risk of live birth was 0.11 (95% [CI] 0.06-0.20, p < 0.001) in patients with AMHlow compared with patients with AMHnormal . It also suggested that the probability of AMHlow level may be higher as the women's age (≥35 years, odd ratio [OR] 1.94, 95% [CI] 1.44-2.61; p < 0.001) and increasing BMI (≥28 kg/m2 , OR 2.38, 95% [CI] 1.33-4.27; p=0.004). Receiver operating characteristic curve analysis indicated that AMH had higher sensitivity and specificity to predict live birth compared with FSH/LH (AUC 0.627 vs. 0.539). AMH levels can be an excellent predictor of the discrepancy between FSH/LH ratio and AMH levels regarding living birth rates in women undergoing IVF.

The impact of FSH stimulation and age on the ovarian and uterine traits and histomorphometry of prepubertal gilts

This study investigated the effect of age and follicle stimulating hormone (FSH) treatment on the estradiol (E2) plasma concentration, ovarian follicle development, endometrial histomorphometry, and ultrasonographic parameters of the ovaries and uterus in prepubertal gilts. Thirty-five prepubertal gilts were grouped according to age (140 or 160 d), and within each age, gilts were allotted to receive 100 mg of FSH (treated; G140 + FSH [n = 10] and G160 + FSH [n = 7]) or saline solution (control; G140 + control [n = 10] and G160 + control [n = 8]). The total dose of FSH was divided into 6 similar doses administered every 8 h (days 0–2). Before and after FSH treatment, blood sample was collected, and transabdominal scanning of the ovaries and uterus was performed. Twenty-four hours after the last FSH injection, the gilts were slaughtered and their ovaries and uterus were processed for histological and histomorphometric analysis. The histomorphometric parameters of the uterus differed (P < 0.05) between prepubertal gilts at 160 d and 140 d of age. Moreover, changes (P < 0.05) in uterine and ovarian ultrasound images occurred between 140 and 160 d of age. Age and FSH treatment did not affect (P > 0.05) E2 plasma concentrations. Follicle stimulating hormone treatment did not affect (P > 0.05) the early stage of folliculogenesis in the prepubertal gilts; however, the number of early atretic follicles decreased (P < 0.05) after the FSH treatment. Follicle stimulating hormone administration increased (P < 0.05) the number of medium follicles and decreased (P < 0.05) the number of small follicles in 140 and 160 d old gilts. In the endometrium, luminal/glandular epithelium height and glandular diameter increased (P < 0.05) after FSH treatment. Thus, injections of 100 mg of FSH stimulate the endometrium epithelium and induce follicular growth to a medium follicle size without affecting the preantral stages in prepubertal gilts; also, the uterine macroscopic morphometry does not change from 140 to 160 d of age.

The Ala307Thr polymorphism of the follicle-stimulating hormone receptor (FSHR) gene is associated with the dose of recombinant FSH received during IVF/ICSI treatment.

Follicle-stimulating hormone (FSH) is essential for folliculogenesis, acting through the follicle-stimulating hormone receptor (FSHR) that is present on the membrane of granulosa cells. Polymorphisms in the FSHR gene may lead to an altered pattern of receptor expression on the cell surface or to changes in affinity for FSH. The aim of this prospective study was to detect any association between the follicle-stimulating hormone receptor (FSHR) gene Ala307Thr polymorphism (rs6165) and ovarian reserve, ovarian response or clinical results in IVF/ICSI treatment. This prospective cohort study included 450 women who underwent IVF/ICSI cycles. DNA was extracted from peripheral blood, and the Ala307Thr FSHR polymorphism (rs6165) was genotyped using the TaqMan SNP genotyping assay. Participants were divided into three groups according to their Ala307Thr FSHR genotype: Thr/Thr (n:141), Thr/Ala (n=213) and Ala/Ala (n=96). The results were tested for associations with age, anti-Mullerian hormone (AMH) levels, antral follicle count (AFC), total dose of r-FSH, follicle size, number of retrieved oocytes, and clinical outcome of IVF/ICSI cycles. The statistical analyses were performed using Fisher's exact test and the Kruskal‒Wallis test. An association between the genotype of the FSHR (Ala307Thr) polymorphism and the dose of r-FSH was observed. Patients with the Ala/Ala genotype received a higher r-FSH dose than patients with the Ala/Thr (p=0.0002) and Thr/Thr (p=0.02) genotypes. No other correlation was observed. The Ala/Ala genotype was associated with the use of higher doses of recombinant FSH (r-FSH), suggesting that homozygosis of this allelic variant (Ala) provides lower sensitivity to r-FSH.

Follicle-Stimulating Hormone Promotes the Development of Endometrial Cancer In Vitro and In Vivo.

Endocrine disruptors as risk factors for endometrial cancer (EC) are positively correlated with serum follicle-stimulating hormone (FSH) levels. Additionally, increased FSH is associated with EC. However, its exact mechanism is not yet clear. Therefore, this study investigated how FSH affects the occurrence of EC. Using immunohistochemistry (IHC), immunofluorescence (IF), and Western blot (WB), we found that FSH receptor (FSHR) was expressed in both EC tissues and cell lines. To explore the effect of FSH on EC in vitro, Ishikawa (ISK) cells were cultured in different doses of FSH, and it was found that FSH could promote the proliferation and migration of ISK cells. Furthermore, the detection of key molecules of migration and apoptosis by WB showed that FSH promoted cell migration and inhibited apoptosis. Additionally, FSH decreased AMPK activation. To clarify the effect of FSH on EC in vivo, we subcutaneously planted ISK cells into ovariectomized mice and then gave two of the groups oestradiol (E2). In comparison with the OE (ovariectomy plus E2) and sham groups, the growth rates and weights of the tumors in the OE plus FSH group were significantly higher. The findings above suggest that FSH promotes the proliferation and metastasis of EC, providing a new strategy for the treatment of EC.

High initial FSH dosage reduces the number of available cleavage-stage embryos in a GnRH-antagonist protocol: Real-world data of 8,772 IVF cycles from China.

To evaluate the relationship between the initial follicle stimulating hormone (FSH) dose and the number of available cleavage-stage embryos in in vitro fertilization (IVF) cycles.We included 8772 fresh IVF cycles using a GnRH antagonist protocol at the Genetic and Reproductive Institution of Chongqing, P. R. China, from January 2016 to June 2021.Univariate linear regression was used to evaluate the associations between the initial FSH dosage (≤ 150, 187.5-200, 225, 250, or 300 IU) with the number of available cleavage-stage embryos on day 3.A two-factor linear regression model was applied to calculate the threshold effect of the initial FSH dosage on the number of available cleavage-stage embryos based on a smoothing plot. The initial FSH dose was negatively correlated with the number of available cleavage-stage embryos, independent of female age, body mass index, infertility factors, duration of infertility, anti-Müllerian hormone and basal FSH levels, antral follicle count and the proportions of patients with poor ovarian response or polycystic ovarian syndrome. Using a two-factor linear regression model, we calculated the inflection point to be 200 IU of FSH. The relationship between the initial FSH dose and the number of available cleavage-stage embryos was nonlinear. The initial FSH dose was negatively associated with the number of available cleavage-stage embryos when the initial FSH dose was > 200 IU. Therefore, clinicians should try to avoid unnecessarily increasing the initial FSH dose.

Ovarian stimulation with a low dose of follicle stimulating hormone improved recovery rates and developmental competence of goat oocytes

Ovarian stimulation with a low dose of follicle stimulating hormone improved recovery rates and developmental competence of goat oocytes

Follicular Hyperstimulation Dysgenesis: New Explanation for Adverse Effects of Excessive FSH in Ovarian Stimulation.

High follicle-stimulating hormone (FSH) doses during ovarian stimulation protocols for assisted reproductive technologies (ART) are detrimental to ovulatory follicle function and oocyte quality. However, the mechanisms are unclear. In a small ovarian reserve heifer model, excessive FSH doses lead to phenotypic heterogeneity of ovulatory size follicles, with most follicles displaying signs of premature luteinization and a range in severity of abnormalities. By performing whole transcriptome analyses of granulosa cells, cumulus cells, and oocytes from individual follicles of animals given standard or excessive FSH doses, we identified progressive changes in the transcriptomes of the 3 cell types, with increasing severity of follicular abnormality with the excessive doses. The granulosa and cumulus cells each diverged progressively from their normal phenotypes and became highly similar to each other in the more severely affected follicles. Pathway analysis indicates a possible dysregulation of the final stages of folliculogenesis, with processes characteristic of ovulation and luteinization occurring concurrently rather than sequentially in the most severely affected follicles. These changes were associated with disruptions in key pathways in granulosa and cumulus cells, which may account for previously reported reduced estradiol production, enhanced progesterone and oxytocin production and diminished ovulation rates. Predicted deficiencies in oocyte survival, stress response, and fertilization suggest likely reductions in oocyte health, which could further compromise oocyte quality and ART outcomes.

P-613 Association between basal androgen concentrations and number of follicles on the day of triggering final oocyte maturation in poor responders undergoing IVF; A prospective study

Abstract Study question Are basal androgen concentrations associated with the number of follicles on the day of triggering final oocyte maturation in poor responders undergoing in vitro fertilization (IVF)? Summary answer A significant negative association is present between (dehydroepiandrosterone sulfate) DHEAS concentrations and the number of follicles on the day of triggering final oocyte maturation. What is known already Studies in animals have shown that androgens promote early follicular development and granulosa cell proliferation, by augmenting follicle-stimulating hormone (FSH) receptor expression in granulosa cells. Several retrospective studies have evaluated the association between basal androgen concentrations and follicular development in normal and poor responders undergoing ovarian stimulation for IVF with conflicting results. Study design, size, duration This prospective study was performed between 02/2020 and 01/2022 in 103 poor responders according to the Bologna criteria. Androgens, including total testosterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), Δ4-androstenedione and 17-OH progesterone (17-OHP), were measured at the initiation of ovarian stimulation, using the automated Elecsys immunoanalyser (Roche Diagnostics, Mannheim, Germany). Ovarian stimulation was performed using a fixed dose of 300 IU of recombinant gonadotrophins and gonadotrophin-releasing hormone (GnRH) analogues. Participants/materials, setting, methods Triggering of final oocyte maturation was performed in the presence of three follicles of ≥ 17mm. The primary outcome measure was the number of follicles ≥11mm on the day of triggering final oocyte maturation. The association between androgen concentrations and the number of follicles ≥11mm on the day of triggering was evaluated using generalized estimating equations, accounting for female age and body mass index (BMI). Values were expressed as coefficient (coef) or mean (95% confidence interval). Main results and the role of chance Female age was 41.9 (41.2-42.6) years, while BMI was 26.1 (24.9-27.3) kg/m2. The duration of ovarian stimulation was 10.3 (9.7-10.8) days and the total dose of gonadotrophins required was 3058 (2903-3213) IU. The number of follicles ≥11 mm on the day of triggering final oocyte maturation was 6.1 (5.3-7.0). The number of COCs retrieved was 3.9 (3.2-4.6), the number of MII oocytes was 3.4 (2.8-3.9) and the number of 2pn oocytes was 2.5 (2.1-2.8). No significant association was found between basal testosterone (coef: -0.008, -0.019 to + 0.003, p = 0.17), 17-OHP (coef: -0.044, -0.391 to + 0.303, p = 0.80), SHBG (coef: -0.002, -0.007 to + 0.002, p = 0.25) Δ4-androstenedione (coef: -0.101, -0.306 to + 0.104, p = 0.33) concentrations and the number of follicles ≥11mm on the day of triggering final oocyte maturation. In contrast, a significant negative association was found between basal DHEAS (coef: -0.011, -0.019 to -0.003, p = 0.007) concentrations and the number of follicles ≥11 mm on the day of triggering final oocyte maturation. Higher DHEAS concentrations were associated with the development of fewer follicles ≥11 mm. Limitations, reasons for caution This prospective study evaluated the association between basal androgen concentrations and the number of follicles on the day of triggering final oocyte maturation in poor responders stimulated with a fixed dose of recombinant FSH. However, the precision of the estimates could be increased by analyzing a larger study population. Wider implications of the findings DHEA supplementation in poor responders undergoing IVF has not been shown to improve ovarian response. Given the significant negative association between DHEAS concentrations and the number of follicles on the day of triggering final oocyte maturation, future studies on DHEA supplementation should consider basal DHEAS concentrations. Trial registration number N/A

Prior salpingectomy impairs the retrieved oocyte number in in vitro fertilization cycles of women under 35 years old without optimal ovarian reserve.

The impairment of the ovarian response in in vitro fertilization (IVF) cycles after salpingectomy remains contentious. Therefore, we investigated whether a history of salpingectomy affects the number of oocytes retrieved in women undergoing IVF in comparison with the number in women without underlying tubal disease. Case-control study (Canadian Task Force Classification II-2). A tertiary hospital-affiliated fertility center. Fifty-four women aged <35 years with a history of salpingectomy and 59 age-matched women without tubal disease. Gonadotropin-releasing hormone antagonist protocol for controlled ovarian stimulation and transvaginal oocyte retrieval. The antral follicle count (AFC), anti-Müllerian hormone (AMH) levels, and the number of retrieved oocytes were significantly lower in women with prior salpingectomy than in women without tubal disease. Day-3 follicle-stimulating hormone (FSH) levels, total gonadotropin dosage, and stimulation days did not significantly differ between the groups. The indications of salpingectomy (i.e., hydrosalpinx and ectopic pregnancy) did not differ significantly in terms of ovarian response or reserve among women with salpingectomy history. A history of salpingectomy and other factors related to ovarian response in IVF, such as age, AMH, AFC, day-3 FSH, and total gonadotropin dose, were significantly correlated with the number of oocytes retrieved by univariate regression analysis. In the multivariate-adjusted model after controlling all the above-mentioned variables, only AFC and AMH levels continued to exhibit significant associations with the number of retrieved oocytes. In a subgroup analysis, the negative impact of prior salpingectomy on the number of retrieved oocytes was especially significant in women with suboptimal ovarian reserves (defined as AMH < 4 ng/mL), regardless of the indication of salpingectomy or whether salpingectomy was bilateral or unilateral. A negative effect on the number of retrieved oocytes in the subsequent IVF cycle after salpingectomy is more likely in women aged <35 years with suboptimal ovarian reserve. Nevertheless, postsurgical AMH and AFC levels still possess a more direct predictive value on ovarian response than the history of salpingectomy.

The relationship between serum FSH level and ovarian response during controlled ovarian stimulation.

To evaluate whether serum follicle stimulating hormone (FSH) level during the early controlled ovarian stimulation can be used as a predictor of the ovarian response in the in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles. The participants of this retrospective study were chosen from Reproductive Medicine Center, Weifang People's Hospital between January 2015 and December 2020.The participants of this study met the age of 20~43 years old, anti-Müllerian hormone (AMH) ≥ 1.2 ng/mL, antral follicle count (AFC) ≥ 5, and the data was complete and no cancellation cycle. Each participant was given GnRH agonist protocol and given a fixed dose of recombinant FSH in the first four days during the controlled ovarian stimulation (COS). According to the number of oocytes retrieved, the participants were divided into two different ovarian response groups. Serum FSH level after the fourth recombinant follicle stimulating hormone (rFSH) injection were compared during the different ovarian responders. The number of participants who met both the inclusion criteria and exclusion criteria was 235. Serum sFSH levels (mean: 11.76 ± 3.10 IU/L) in the inappropriate responders was significantly higher than serum sFSH levels (mean: 10.79 ± 2.52 IU/L) in the superior responders(p = 0.029). There was a weak correlation between serum sFSH levels and the number of oocytes retrieved (r = -0.134, p = 0.041). Serum sFSH levels had significant clinical valuable (p = 0.0346) in predicting the number of oocytes retrieved. Serum sFSH levels may be a potential marker to predict the ovarian response during the early COS in the IVF/ICSI cycles, which can guide the adjustment of the exogenous rFSH dose.

Ефективність ембріологічного етапу екстракорпорального запліднення в пацієнток із прогнозованою слабкою відповіддю яєчників

Purpose - to show the efficacy of the embryological stage of in vitro fertilisation (IVF) in women with infertility and predicted poor ovarian response to stimulation with various gonadotropins. Materials and methods. This article analyzes the embryological stage of IVF in 140 women with infertility and predicted poor ovarian response. The main clinical group included 75 women who underwent controlled ovarian superstimulation with urinary gonadotropins in the protocol along with gonadotropin-releasing hormone antagonist. Group II (comparison) included 65 women who underwent stimulation of superovulation as per the similar scheme with recombinant gonadotropins. Oocyte pickups, fertilization, cultivation, and embryo transfer were carried out as per standard techniques. Confirmation or exclusion of biochemical pregnancy was carried out by determining the level of total chorionic gonadotropin in the blood serum 14 days after embryo transfer. When calculating the results, the analysis applied methods that were adopted in medical and biological statistics and described in the Glantz Manual. Data were processed by means of StatSoft Statistica 8.0 software package. Results. Among female patients of Groups I and II - where duration of ovarian stimulation did not exceed 10 days - the average duration of using gonadotropins estimated 8.4±1.3 and 9.5±1.2 days respectively (p&lt;0.05). In patients with a longer administration of drugs compared, the average duration of gonadotropin stimulation was definitely higher when using recombinant gonadotropins, i.e. 12.8±2.0 days versus 10.4±1.4 days (p&lt;0.05). When evaluating the follicle-stimulating hormone (FSH) dose used as part of gonadotropin products compared, it was found that in female patients of Groups I and II - where duration of gonadotropin stimulation did not exceed 10 days - the FSH course dose averaged 2,700±300 IU respectively. With the gonadotropin stimulation lasting for more than 10 days, the FSH dose in Group I increased on average up to 3,000±300 IU; in Group II, it increased on average up to 3,300±300 IU (p&lt;0.05). The number of viable embryos on Day 5-6 of cultivation - in the groups compared - averaged to 5.4±2.1, whereas 4.3±2.3 (p=0.014), and their percentage of the number of obtained zygotes reached 91.2±4.1% and 90.0±5.6% (p=0.041). On Day 5, the process of cultivating viable embryos in the groups decreased down to 4.2±1.5 and 3.6±1.7 (p=0.005), whereas their percentage of the number of obtained zygotes decreased down to 77.2±3.5% and 76.0±4.8% (p=0.012). When conducting the cytomorphological examination of embryos under cultivation, it was found that percentage of good quality embryos in the total pool of embryos aged 5 days was 60.4±13.6% and 54.6±14.2% (p=0.011) respectively, whereas in the total pool of embryos aged 6 days, the percentage was 72.6±14.7% and 68.7±16.4% (p=0.013). Conclusions. The conducted comparative study of the effects of human menopausal gonadotropin and the combination of recombinant FSF + recombinant luteinizing hormone at the pre-transfer stage in all examined female patients with expected poor response to gonadotropins showed that the administration of these drugs was accompanied by definitive differences within a number of parameters of stimulated cycles; in terms of statistics, significant are the conclusions as follows: reducing the stimulation period in women who had duration of gonadotropin for less than 10 days; decreasing the average dose of FSH if the gonadotropin stimulation period lasted less than and more than 10 days; improving the survival rate of embryos aged 5 and 6 days; increasing the percentage of good quality embryos among embryos aged 5 and 6 days. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local ethics committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the author. Key words: infertility, assisted reproductive technologies, controlled ovarian stimulation, urinary gonadotropins, recombinant gonadotropins.