What is the impact of serum and follicular fluid BMP-15 and AMH levels in ICSI-ET cycle outcomes?

Abstract BackgroundThis observational clinical study evaluated the expression levels and predictive values of some apoptosis-related genes in granulosa cells (GCs) and follicular fluid (FF) of women undergoing in vitro fertilization (IVF).Methods GCs and FF were obtained at oocyte retrieval from 31 consecutive patients with heterogeneous infertility diagnosis (age: 34.3±5.8 years, body mass index: 24.02±3.12 kg/m2, duration of infertility: 4.2±2.1 years). mRNA expression of pro-apoptotic (BAX, CASP3, CASP8) and anti-apoptotic (BCL2, AMH, AMHR, FSHR, LHR, CYP19A1) factors was determined by quantitative RT-PCR using ROCHE LightCycler 480. Results No significant difference in GC or FF mRNA expression of pro- and anti-apoptotic factors could be demonstrated between IVF patients with (9 patients) or without (22 patients) clinical pregnancy. Each transcript investigated was detected in FF, but their levels were markedly reduced and independent of those in GCs. The number of retrieved oocytes was positively associated with GC AMHR (r=0.393, p=0.029), but the day of embryo transfer was negatively associated with GC LHR (r=-0.414, p=0.020) and GC FSHR transcripts (r=-0.535, p=0.002). When pregnancy positive group was analysed separately the impact of apoptosis- related gene expressions on some selected measures of IVF success could be observed. Strong positive relationship was found between gene expression levels of pro- and anti-apoptotic factors in GCs.ConclusionOur study provides only marginal evidences for the apoptosis dependence of IVF outcome and suggests that the apoptosis process induces adaptive increases of the anti-apoptotic gene expression to attenuate apoptosis and to protect cell survival.

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Effect of Endometrioma cystectomy on cytokines of follicular fluid and IVF outcomes

Journal of Ovarian Research ◽

10.1186/s13048-019-0572-7 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Yu Liang ◽

Xiaokui Yang ◽

Yonglian Lan ◽

Lingling Lei ◽

Ying Li ◽

...

Keyword(s):

Growth Factors ◽

Inflammatory Cytokines ◽

Follicular Fluid ◽

Ovarian Function ◽

Ivf Outcomes ◽

Surgery Group ◽

The Impact ◽

Ivf Et

Abstract Background Endometriosis patients undergoing in vitro fertilization-embryo transfer (IVF-ET) treatment suffer from lower success rates. The success of IVF-ET is related to the receptivity of the uterus and the quality of embryos, and it is well known a patient’s endometriosis does not impair the receptivity. Whether endometrioma should be removed surgically before IVF remains controversial. Studies have shown that endometrioma removal decreases peritoneal inflammation, but little information is available regarding the alteration in the cytokines of follicular fluid. The objective of this study was to examine the impact of endometrioma cystectomy on the outcome of IVF and the levels of intrafollicular inflammatory cytokines and to investigate correlations between cytokine concentrations and IVF outcomes. Method A total of 41 women with endometriosis-associated infertility undergoing IVF were recruited; 13 patients (surgery group, S group) had surgery to remove the endometrioma before enrollment, and 28 patients (non-surgery group, NS group) were untreated before IVF. The follicular fluid from a dominant follicle was collected during oocyte retrieval, and the concentrations of sixteen soluble cytokines known to be involved in ovarian function were measured. Results Among the soluble molecules examined in this study, chemokines and growth factors and a few are inflammatory cytokines were found in the follicular fluid of patients with endometriosis. In addition, the expression levels of chemokines, growth factors, and most inflammatory cytokines did not differ between the S and NS groups, but interleukin (IL)-18 levels were significantly lower in the NS group. However, the levels of IL-18 in the FF did not correlate with IVF cycle parameters. The implantation and clinical pregnancy rates were similar between the two groups, but the anti-Müllerian hormone (AMH) level was lower in the S group than in the NS group. Conclusions These findings suggest that endometrioma surgery may potentially reduce the ovarian reserve and has little impact on the success rate of IVF. Ovarian endometriomas are not associated with cytokine profiles in FF from infertile women, and they are not likely to affect the quality of the oocyte and embryo as a result of an inflammatory mechanism.

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Impact of Exogenous Gonadotropin Stimulation on Circulatory and Follicular Fluid Cytokine Profiles

International Journal of Reproductive Medicine ◽

10.1155/2014/218769 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

N. Ellissa Baskind ◽

Nicolas M. Orsi ◽

Vinay Sharma

Keyword(s):

Follicular Fluid ◽

Fluid Phase ◽

Controlled Ovarian Hyperstimulation ◽

Developmental Competence ◽

Leukaemia Inhibitory Factor ◽

Natural Cycle ◽

Cytokine Profiles ◽

Cytokine Levels ◽

The Impact

Background. The natural cycle is the prototype to which we aspire to emulate in assisted reproduction techniques. Increasing evidence is emerging that controlled ovarian hyperstimulation (COH) with exogenous gonadotropins may be detrimental to oogenesis, embryo quality, and endometrial receptivity. This research aimed at assessing the impact of COH on the intrafollicular milieu by comparing follicular fluid (FF) cytokine profiles during stimulatedin vitrofertilization (IVF) and modified natural cycle (MNC) IVF.Methods. Ten women undergoing COH IVF and 10 matched women undergoing MNC IVF were recruited for this pilot study. 40 FF cytokine concentrations from individual follicles and plasma were measured by fluid-phase multiplex immunoassay. Demographic/cycle/cytokine data were compared and correlations between cytokines were computed.Results. No significant differences were found between COH and MNC groups for patient and cycle demographics, including outcome. Overall mean FF cytokine levels were higher in the MNC group for 29/40 cytokines, significantly so for leukaemia inhibitory factor and stromal cell-derived factor-1α. Furthermore, FF MNC cytokine correlations were significantly stronger than for COH data.Conclusions. These findings suggest that COH perturbs intrafollicular cytokine networks, in terms of both cytokine levels and their interrelationships. This may impact oocyte maturation/fertilization and embryo developmental competence.

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175 METABOLIC STRESS IMPAIRS FOLLICULAR GROWTH IN SUPEROVULATED HEIFERS

Reproduction Fertility and Development ◽

10.1071/rdv23n1ab175 ◽

2011 ◽

Vol 23 (1) ◽

pp. 189 ◽

Cited By ~ 1

Author(s):

H. Aardema ◽

B. A. J. Roelen ◽

B. M. Gadella ◽

P. L. A. M. Vos

Keyword(s):

Follicular Fluid ◽

Ovarian Tissue ◽

Control Diet ◽

Animal Health ◽

Metabolic Stress ◽

Negative Influence ◽

Follicular Growth ◽

Size Category ◽

Lh Surge ◽

The Impact

Metabolic stress during the early postpartum period has been postulated to be one of the major causes of prolonged calving intervals. To study the impact of metabolic stress on ovarian follicular function via hormonal analysis of follicular fluid and follicular growth, 12 cycling heifers were randomly allocated to a group (n = 6) that received a control diet (ad libitum grass silage) or to an experimental group (n = 6) that was fasted during the superovulation (SO) treatment for 4 days until ovariectomy (Jorritsma et al. 2003 Theriogenology 60, 151–161). Heifers were synchronized with a CIDR® intravaginal device (Pfizer AH) during 7 days, and a prostaglandin injection (5 mL Enzaprost® CEVA AH) was administered 1 day before CIDR® removal. On day 9 of the synchronized cycle, the dominant follicle of the first follicular wave was removed and the standard SO protocol was started 2 days later (twice daily decreasing doses for 4 days, total 200 mg of Folltropin-V®, Bioniche AH). Cows received a CIDR® device during SO to suppress a spontaneous LH surge. To collect ovarian tissue at 22 h after the LH peak by ovariectomy, a controlled LH surge was induced by a GnRH injection (1 mg of Fertagyl® Intervet SP AH) at the time of CIDR® removal (Vos et al. 1994 J. Reprod. Fertil. 100, 387–393). Ovaries were transported to the laboratory at 37°C directly after ovariectomy. For each animal, follicular growth was determined by counting the number of follicles >8 mm in diameter (defined as presumptive follicles). The size category of follicles was based on the volume collected after puncturing (8 to 10 mm, 10 to 12 mm, >12 mm). To determine the quality of the follicle, follicular fluid of each individual follicle was analyzed for estradiol (E2) and progesterone (P4) concentrations. Healthy follicles at 22 h after the LH peak were defined as follicles showing low E2 and high P4 >0.5 μmol L–1 (E2/P4<1; Dieleman et al. 1983 J. Endocrinol. 97, 31–42). Statistical analysis was performed by logistic regression for grouped data (P < 0.05; mean ± SEM). The total number of follicles per animal (follicles >8 mm in diameter) did not differ between the control (18 ± 2.8) and fasted group (19.8 ± 2.9). However, the number of large follicles (>12mm) that developed in the fasted heifers was significantly lower (2.7 ± 0.9) compared with that in the control heifers (6.0 ± 1.7). No difference was observed for the percentage of healthy follicles per animal between fasted (32 ± 9.2%) and control (56 ± 13%) heifers. These data show that follicular growth was impaired during SO treatment in fasted heifers. Although not significantly different, a numerically lower number of healthy follicles was observed in the fasted group of heifers, possibly indicating a negative influence of metabolic stress on follicular function. Whether metabolic stress affects the metabolic composition of the follicular fluid and as a consequence influences oocyte and embryo quality is under current investigation. Project is sponsored by Pfizer Animal Health.

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Follicular fluid metabolome and cytokinome profiles in poor ovarian responders and the impact of dehydroepiandrosterone supplementation

10.1101/2020.11.03.366047 ◽

2020 ◽

Author(s):

Veronique Viardot-Foucault ◽

Jieliang Zhou ◽

Dexi Bi ◽

Yoshihiko Takinami ◽

Heng Hao Tan ◽

...

Keyword(s):

Clinical Trial ◽

Amino Acids ◽

Follicular Fluid ◽

Lower Number ◽

Vitro Fertilization ◽

Future Studies ◽

Poor Ovarian Responders ◽

The Impact

AbstractPoor ovarian responders (POR) are women undergoing in-vitro fertilization who respond poorly to ovarian stimulation, resulting in the retrieval of lower number of oocytes, and subsequently lower pregnancy rates. The follicular fluid (FF) provides a crucial microenvironment for the proper development of follicles and oocytes. Conversely, dysregulated FF metabolome and cytokinome could have detrimental effects on oocytes in POR. Androgens such as dehydroepiandrosterone (DHEA) have been proposed to alter the POR follicular microenvironment but its effects on the FF metabolome and cytokine profiles is unknown. In this study, untargeted LC-MS/MS metabolomics was performed on FF of POR patients with DHEA supplementation (DHEA+) and without (DHEA-) in a randomized clinical trial (N=52). Untargeted metabolomics identified 118 FF metabolites of diverse chemistries, which included lipids, steroids, amino acids, hormones, among others. FF metabolomes were different between DHEA+ and DHEA- groups. Specifically, glycerophosphocholine, linoleic acid, progesterone, and valine were significantly lower in DHEA+ relative to DHEA-. Among cytokines, MCP1, IFNγ, LIF and VEGF-D were significantly lower in DHEA+ relative to DHEA. Collectively, our data suggest a role of DHEA on these metabolic and cytokines pathways, and these FF metabolites could be used to guide future studies in DHEA supplementation regimen.

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1 CUMULUS CELLS PROTECT OOCYTES AGAINST POTENTIAL LIPOTOXICITY FROM ELEVATED FREE FATTY ACID CONCENTRATIONS IN FOLLICULAR FLUID

Reproduction Fertility and Development ◽

10.1071/rdv25n1ab1 ◽

2013 ◽

Vol 25 (1) ◽

pp. 148

Author(s):

H. Aardema ◽

F. Lolicato ◽

B. A. J. Roelen ◽

P. L. A. M. Vos ◽

J. B. Helms ◽

...

Keyword(s):

Fatty Acids ◽

Oleic Acid ◽

Fatty Acid ◽

Free Fatty Acid ◽

Free Fatty Acids ◽

Follicular Fluid ◽

Animal Health ◽

Cumulus Cells ◽

The Impact

Metabolic conditions characterized by elevated free fatty acid levels in the blood are often associated with reduced fertility performance. Increased concentrations of saturated free fatty acids can induce lipotoxicity in cumulus–oocyte-complexes in vitro, while unsaturated fatty acids like oleic acid are mostly harmless and able to counteract the impact of saturated fatty acids (Aardema et al. 2011 Biol. Reprod. 85, 62–69). This study investigates the impact of elevated free fatty acids in the blood on the follicular fluid and the lipid of cumulus and oocytes derived from these follicles. Furthermore, in vitro maturing oocytes were exposed to free fatty acid concentrations measured in follicles of control and metabolically stressed animals from this study to determine the impact on oocyte developmental competence. Cyclic heifers (n = 12) were synchronized (7 days CIDR®) and superstimulated from Day 10 of the synchronized cycle [4 days of Folltropin-V® (Bioniche Animal Health Inc., Belleville, ON, Canada) in decreasing doses; in total 200 mg]. Heifers received ad libitum grass silage, apart from the experimental group (n = 6), which was metabolically stressed during the period of superstimulation. Ovaries were collected by ovariectomy at final maturation, 22 h after the induced LH peak. Follicular fluids and cumulus–oocyte complexes (COC) were collected from follicles of ≥8 mm. To determine the free fatty acid and lipid composition, blood, follicular fluid, cumulus cells, and oocytes were analyzed with mass spectrometry. The COC (4 runs, 400 per group) derived from slaughterhouse ovaries were in vitro matured in a standard medium without or with the dominating free fatty acids, saturated palmitic and stearic and unsaturated oleic acid, in concentrations measured in follicular fluid of control (80, 70, and 100 µM) and experimental heifers (150, 100, and 200 µM) and fertilized and cultured until the blastocyst stage. Culture data were analyzed by one-way ANOVA and lipid data by two-sample t-test (P ≤ 0.05 considered significant). Procedures were approved by the Institutional Animal Care and Use Committee. Metabolic stress resulted in elevated free fatty acid levels in blood (from 430 ± 70 to 1048 ± 190 µM) and follicular fluid (from 357 ± 72 to 670 ± 133 µM), with relatively high oleic acid concentrations in follicular fluid (+10%). The increased levels of free fatty acids in follicular fluid resulted in a massive increase of fatty acids in the cumulus cells, but oocytes did only show marginal changes. In line with this, maturation in the presence of elevated palmitic, stearic, and oleic acid did not impair oocyte developmental competence and resulted in comparable blastocyst rates for the standard medium and the free fatty acid control and metabolic stress medium (31 ± 8.7, 34 ± 7.8, and 28 ± 1.7%). Thus, cumulus cells appear to protect oocytes against potential lipotoxicity from elevated free fatty acid concentrations by the accumulation of these fatty acids. This work was funded by Pfizer Animal Health.

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Expression of mRNAs for pro-and anti-apoptotic factors in granulosa cells and follicular fluid of women undergoing in vitro fertilization. A pilot study

BMC Pregnancy and Childbirth ◽

10.1186/s12884-021-03834-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

József Bódis ◽

Endre Sulyok ◽

Ákos Várnagy ◽

Viktória Prémusz ◽

Krisztina Gödöny ◽

...

Keyword(s):

Gene Expression ◽

In Vitro Fertilization ◽

Mrna Expression ◽

Granulosa Cells ◽

Follicular Fluid ◽

Vitro Fertilization ◽

Expression Levels ◽

The Impact ◽

Apoptotic Factors

Abstract Background This observational clinical study evaluated the expression levels and predictive values of some apoptosis-related genes in granulosa cells (GCs) and follicular fluid (FF) of women undergoing in vitro fertilization (IVF). Methods GCs and FF were obtained at oocyte retrieval from 31 consecutive patients with heterogeneous infertility diagnosis (age: 34.3 ± 5.8 years, body mass index: 24.02 ± 3.12 kg/m2, duration of infertility: 4.2 ± 2.1 years). mRNA expression of pro-apoptotic (BAX, CASP3, CASP8) and anti-apoptotic (BCL2, AMH, AMHR, FSHR, LHR, CYP19A1) factors was determined by quantitative RT-PCR using ROCHE LightCycler 480. Results No significant difference in GC or FF mRNA expression of pro- and anti-apoptotic factors could be demonstrated between IVF patients with (9 patients) or without (22 patients) clinical pregnancy. Each transcript investigated was detected in FF, but their levels were markedly reduced and independent of those in GCs. The number of retrieved oocytes was positively associated with GC AMHR (r = 0.393, p = 0.029), but the day of embryo transfer was negatively associated with GC LHR (r = − 0.414, p = 0.020) and GC FSHR transcripts (r = − 0.535, p = 0.002). When pregnancy positive group was analysed separately the impact of apoptosis- related gene expressions on some selected measures of IVF success could be observed. Strong positive relationship was found between gene expression levels of pro- and anti-apoptotic factors in GCs. Conclusion Our study provides only marginal evidences for the apoptosis dependence of IVF outcome and suggests that the apoptosis process induces adaptive increases of the anti-apoptotic gene expression to attenuate apoptosis and to protect cell survival.

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Ovarian follicular function is not altered by SARS-Cov-2 infection or BNT162b2 mRNA Covid-19 vaccination

10.1101/2021.04.09.21255195 ◽

2021 ◽

Author(s):

Yaakov Bentov ◽

Ofer Beharier ◽

Arbel Moav-Zafrir ◽

Maor Kabessa ◽

Miri Godin ◽

...

Keyword(s):

Follicular Fluid ◽

Ovarian Function ◽

Ovarian Follicle ◽

Oocyte Retrieval ◽

Study Groups ◽

Oocyte Quality ◽

University Hospital ◽

Recent Infection ◽

Quality Reporting ◽

The Impact

AbstractImportanceThis is the first study to examine the impact of SARS-Cov-2 infection and COVID-19 vaccination on ovarian function.ObjectiveTo characterize anti-COVID-19 antibodies in follicular fluid and compare ovarian follicle function in women following confirmed SARS-CoV-2 infection, COVID-19 vaccination, and non-infected, unvaccinated controls.DesignThis is a cohort study conducted between February 1 and March 10, 2021.SettingA single university hospital-based IVF clinic.ParticipantsConsecutive sample of female patients undergoing oocyte retrieval.InterventionsConsenting patients were recruited and assigned to one of three study groups: recovering from confirmed COVID 19 (n=9); vaccinated (n=9); and uninfected, non-vaccinated controls (n=14). Serum and follicular fluid samples were taken and analyzed for anti-COVID IgG as well as estrogen, progesterone and HSPG2 concentration, as well as the number and maturity of aspirated oocytes and previous estrogen and progesterone measurements.Main outcome measuresFollicular function, including steroidogenesis, follicular response to the LH/hCG trigger, and oocyte quality biomarkers.ResultsBoth natural and vaccine elicited anti-COVID IgG antibodies were detected in the follicular fluid in levels proportional to the IgG serum concentration. No differences were detected in any of the surrogate ovarian follicle quality reporting parameters.Conclusions and relevanceBoth SARS-COV-2 infection and vaccination with the BNT162b2 mRNA vaccine mediate IgG immunity that crosses into the follicular fluid. No detrimental effect on follicular function was detected.Trial RegistrationCinicalTrials.gov registry number NCT04822012Key PointCOVID 19 disease and BNT162b2 mRNA vaccine induce anti-COVID IgG in follicular fluid; neither recent infection nor vaccination appear to negatively effect follicular function.

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Serum and follicular fluid testosterone concentrations do not correlate, questioning the impact of androgen supplementation on the follicular endocrine milieu

Reproductive BioMedicine Online ◽

10.1016/j.rbmo.2017.07.012 ◽

2017 ◽

Vol 35 (5) ◽

pp. 616-623 ◽

Cited By ~ 7

Author(s):

Michael von Wolff ◽

Petra Stute ◽

Markus Eisenhut ◽

Ulrich Marti ◽

Norman Bitterlich ◽

...

Keyword(s):

Follicular Fluid ◽

The Impact ◽

Androgen Supplementation

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P–565 Does length really matter? The impact of lifestyle on granulosa cell telomeres length and IVF outcome

Human Reproduction ◽

10.1093/humrep/deab130.564 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

O Limonad ◽

S Hantisteanu ◽

S Meise. Sharon ◽

N Haggiag ◽

D Estrada ◽

...

Keyword(s):

Treatment Outcome ◽

Telomere Length ◽

Pregnancy Rate ◽

Quantitative Pcr ◽

Granulosa Cells ◽

Follicular Fluid ◽

Relative Length ◽

Oocyte Retrieval ◽

Relative Telomere Length ◽

The Impact

Abstract Study question Is the relative telomere length in granulosa cells associated with an abnormal metabolic profile of IVF patients and treatment outcome? Summary answer Longer telomeres and higher pregnancy rates have been observed in women with higher follicular fluid glucose levels. What is known already Telomeres may serve as a biomarker of cell senescence; their length varies depending on two factors: genetic predisposition and shortening processes related to cell division. In several studies, telomere shortening in granulosa cells has been shown to be correlated with ovarian aging. However, these findings are still limited in applicability, and more research is required to define the factors involved. Study design, size, duration Women undergoing IVF participated in a prospective cohort study between 2018 and 2019. Peripheral blood was obtained on the day of oocyte retrieval. Pooled samples of follicular fluid were collected for a comprehensive telomere length analysis in granulosa and cumulus cells by quantitative PCR (qPCR). Participants/materials, setting, methods DNA was extracted from granulosa cells and assessed for relative telomere length by monochrome multiplex quantitative PCR (qPCR). Telomere length was then analyzed relative to a single copy gene (36B4) to evaluate possible metabolic profile’s impact on telomere length and treatment outcome. Hormonal profile, chemistry, and inflammation factors were analyzed in the follicular fluid and serum. Main results and the role of chance Out of forty-nine women recruited for the study, forty-one cases were eligible for a comprehensive analysis. Follicular fluid CRP and triglyceride levels in BMI-based analysis were significantly lower in women with BMI <25 compared to those with BMI >30 (0.5 (0.2–1.5) vs. 6.6 (3.6–10.6); p < 0.0001 and 21.04 ± 8.04 vs. 28.18 ± 8.97; p = 0.011, respectively). Interestingly, a significant correlation between the relative lengths of telomeres and pregnancy rate was observed (p < 0.001), with a higher pregnancy rate in women with longer telomeres (88%) than in women with shorter telomeres (38%). Relatively longer telomeres (0.96 (0.94–0.99) vs. 0.91 (0.82–0.95), p = 0.02) and higher levels of follicular fluid glucose (63±11.12 vs. 50.67±15.69, p = 0.006) were observed in those who conceived. No statistically significant differences were detected in the levels of the other hormones measured in the blood or follicular fluid on the day of oocyte retrieval or other clinical parameters, including follicle size and number, embryo quality, and the number of OHSS cases. Limitations, reasons for caution As a preliminary study, there were few participants. Further implications can be reached by increasing the sample size, but telomerase activity evaluation is required to confirm telomere length measurements without question. Whether short telomeres associate with infertility as a cause or consequence of BMI warrant more research. Wider implications of the findings: The relative length of telomeres in granulosa cells at the time of oocyte retrieval may serve as a predictive biomarker for oocyte competence and subsequent pregnancy. Moreover, healthy lifestyle behavior is recommended. Trial registration number Not applicable

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