The cyto-protective effects of LH on ovarian reserve and female fertility during exposure to gonadotoxic alkylating agents in an adult mouse model.
Ontology highlight
ABSTRACT:
SUBMITTER: Del Castillo LM
PROVIDER: S-EPMC8373474 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Mitochondria are dynamic organelles that continually adapt their structure through fusion and fission in response to changes in their bioenergetic environment. Targeted deletion of mitochondrial fusion protein mitofusin1 (MFN1) in oocytes resulted in female infertility associated with failure to achieve oocyte maturation. Oocyte-granulosa cell communication was impaired, and cadherins and connexins were downregulated, resulting in follicle developmental arrest at the secondary follicle stage. Deletion of MFN1 in oocytes resulted in mitochondrial dysfunction and altered mitochondrial dynamics, as well as accumulation of ceramide, which contributed to increased apoptosis and a reproductive phenotype that was partially rescued by treatment with ceramide synthesis inhibitor myriocin. Absence of MFN1 and resulting apoptotic cell loss also caused depletion of ovarian follicular reserve, and a phenotype consistent with accelerated female reproductive aging.
| S-EPMC6646343 | biostudies-literature
Project description:Calorie restriction (CR) (25-40%) is the most commonly studied strategy for curtailing age-related disease and has also been found to extend reproductive lifespan in female mice. However, the effects of mild CR (10%), which is sustainable, on ovarian aging has not yet been addressed. 17α-estradiol (17α-E2) is another intervention shown to positively modulate healthspan and lifespan in mice but its effects on female reproduction remain unclear. We evaluated the effects of mild CR (10%) and 17α-E2 treatment on ovarian reserve and female fertility over a 24-week period, and compared these effects with the more commonly employed 30% CR regimen. Both 10% and 30% CR elicited positive effects on the preservation of ovarian reserve, whereas 17α-E2 did not alter parameters associated with ovarian function. Following refeeding, both 10% and 30% increased fertility as evidenced by greater pregnancy rates. In aligned with the ovarian reserve data, 17α-E2 also failed to improve fertility. Collectively, these data indicate that 10% CR is effective in preserving ovarian function and fertility, while 17α-E2 does not appear to have therapeutic potential for delaying ovarian aging.
| S-EPMC8920046 | biostudies-literature
Project description:ObjectiveTo determine the association between ovarian reserve biomarkers and future fertility among late reproductive-age women.DesignCohort study of participants enrolled in Time to Conceive (TTC), a time-to-pregnancy cohort study of the ovarian reserve biomarkers.SettingCommunity.Patient(s)Women aged 30-44 years without a history of infertility who provided a blood sample at enrollment in TTC and who agreed to future follow-up.Intervention(s)Not applicable.Main outcome measure(s)The primary outcomes were probability of achieving a live birth >3 years after enrollment in TTC, diagnosis of infertility at any time, and time-to-pregnancy in future pregnancy attempts.Result(s)Women with diminished ovarian reserve, defined as those with an antimüllerian hormone (AMH) level <0.7 ng/mL or follicle-stimulating hormone (FSH) level ≥10 mIU/mL, did not have low risk of future live birth (relative risk [RR], 1.32; 95% confidence interval [CI], 0.95-1.83 and RR, 1.28; 95% CI, 0.97-1.70, respectively) compared with women with normal ovarian reserve after adjusting for age at blood draw, race, obesity, use of hormonal contraception, and year of enrollment in original study. Among women in the cohort that attempted to conceive, there was not a significant association between diminished ovarian reserve, as measured by AMH or FSH, and risk of future infertility (RR, 0.65; 95% CI, 0.21-2.07 and RR,1.69; 95% CI, 0.86-3.31, respectively). Similarly, there was no association between AMH and FSH levels and future fecundability (fecundability ratio, 0.97; 95% CI, 0.59, 1.60; and fecundability ration, 0.86; 95% CI, 0.55-1.36, respectively).ConclusionDiminished ovarian reserve is not associated with reduced future reproductive capacity. Given the lack of association, women should be cautioned regarding use biomarkers of ovarian reserve as predictors of their future reproductive capacity.
| S-EPMC10074834 | biostudies-literature
Project description:Premature ovarian failure and female infertility are frequent side effects of anticancer therapies, owing to the extreme sensitivity of the ovarian reserve oocytes to the damaging effects of irradiation and chemotherapy on DNA. We report here a robust protective effect of luteinizing hormone (LH) on the primordial follicle pool of prepubertal ovaries against the cisplatin (Cs)-induced apoptosis. In vitro LH treatment of prepubertal ovarian fragments generated anti-apoptotic signals by a subset of ovarian somatic cells expressing LH receptor (LHR) through cAMP/PKA and Akt pathways. Such signals, reducing the oocyte level of pro-apoptotic TAp63 protein and favoring the repair of the Cs-damaged DNA in the oocytes, prevented their apoptosis. Noteworthy, in vivo administration to prepubertal female mice of a single dose of LH together with Cs inhibited the depletion of the primordial follicle reserve caused by the drug and preserved their fertility in reproductive age, preventing significant alteration in the number of pregnancy and of delivered pups. In conclusion, these findings establish a novel ovoprotective role for LH and further support the very attracting prospective to use physiological 'fertoprotective' approaches for preventing premature infertility and risks linked to precocious menopause in young patients who survived cancer after chemotherapy.
| S-EPMC5260508 | biostudies-literature
Project description:Ovarian reserve (OR) and fertility are critical in women's healthcare. Clinical methods for encoding OR and fertility rely on the combination of tests, which cannot serve as a multi-functional platform with limited information from specific biofluids. Herein, metabolic fingerprinting of follicular fluid (MFFF) from follicles is performed, using particle-assisted laser desorption/ionization mass spectrometry (PALDI-MS) to encode OR and fertility. PALDI-MS allows efficient MFFF, showing fast speed (≈30 s), high sensitivity (≈60 fmol), and desirable reproducibility (coefficients of variation <15%). Further, machine learning of MFFF is applied to diagnose diminished OR (area under the curve of 0.929) and identify high-quality oocytes/embryos (p < 0.05) by a single PALDI-MS test. Meanwhile, metabolic biomarkers from MFFF are identified, which also determine oocyte/embryo quality (p < 0.05) from the sampling follicles toward fertility prediction in clinics. This approach offers a powerful platform in women's healthcare, not limited to OR and fertility.
| S-EPMC10427401 | biostudies-literature
Project description:ObjectiveTo examine the association between dietary folate intake and antral follicle count (AFC) among women seeing treatment for infertility.DesignCohort study.SettingAcademic fertility center.PatientsA total of 552 women attending the Massachusetts General Hospital Fertility Center (2007-2019) who participated in the Environment and Reproductive Health Study.InterventionsNone. Folate intake was measured with a validated food frequency questionnaire at study entry. Multivariable Poisson regression models with robust standard errors were used to estimate the association of folate intake with AFC adjusting for calorie intake, age, body mass index, physical activity, education, smoking status, year of AFC, and intakes of vitamin B12, iron, and vitamin D. Nonlinearity was assessed with restricted cubic splines.Main outcome measureAFC as measured by transvaginal ultrasonography as part of routine care.ResultsAmong the 552 women (median age, 35.0 years; median folate intake, 1,005 μg/d), total and supplemental folate intake had a significant nonlinear relationship with AFC. There was a positive linear association with AFC up to approximately 1,200 μg/d for total folate intake and up to 800 μg/d for supplemental folate intake; however, there was no additional benefit of higher folate intakes. The magnitude of the association was modest; for example, the predicted adjusted difference in AFC between a woman consuming 400 vs. 800 μg/d of supplemental folate was approximately 1.5 follicles.ConclusionHigher intake of folate, particularly from supplements, was associated with modestly higher ovarian reserve as measured by AFC among women attending a fertility center.Clinical trial registration numberThis trial was registered at clinicaltrials.gov as NCT00011713.
| S-EPMC8714696 | biostudies-literature
Project description:ObjectiveTo evaluate the associations of caffeinated, alcoholic, and sweetened beverage intakes with antral follicle count (AFC), a well-accepted biomarker of ovarian reserve.DesignObservational prospective cohort study.SettingFertility center at an academic hospital.PatientsThis study includes 567 women seeking fertility care at the Massachusetts General Hospital who participated in the Environment and Reproductive Health Study.InterventionNone. Women self-reported consumption of caffeinated (coffee, tea, soda), alcoholic (wine, beer, liquor), sugar-sweetened, and artificially sweetened beverages using a validated food-frequency questionnaire.Main outcome measureAntral follicle count was assessed using a transvaginal ultrasound performed on the 3rd day of an unstimulated menstrual cycle or on the 3rd day of a progesterone withdrawal bleed.ResultsMedian (interquartile range) age and AFC were 35.0 (32.0-38.0) years and 13.0 (9.0-18.0), respectively. Median (range) intake of caffeinated, alcoholic, sugar-sweetened, and artificially sweetened beverages in servings/day were 1.08 (0-7.08), 0.35 (0-3.84), 0.04 (0-4.80), and 0.04 (0-7.50), respectively. All examined beverages were unrelated to AFC. The multivariable adjusted mean AFC (95% confidence interval) for women in the top and bottom quartiles of intake were 13.8 (13.0-14.7) and 13.8 (12.9-14.7) for caffeinated beverages; 13.8 (13.0-14.7) and 13.8 (13.0-14.6) for alcoholic beverages; 13.5 (12.6-14.4) and 13.3 (12.4-14.2) for sugar-sweetened beverages; and 13.2 (12.4-14.1) and 13.4 (12.6-14.3) for artificially sweetened beverages.ConclusionLow-to-moderate intakes of caffeinated, alcoholic, sugar-sweetened, and artificially sweetened beverages were unrelated to ovarian reserve, as measured by AFC, in a cohort of women seeking fertility care.
| S-EPMC9219250 | biostudies-literature
Project description:The hypothalamic-pituitary-ovarian (HPO) axis is a tightly regulated system controlling female reproduction. HPO axis dysfunction leading to ovulation disorders can be classified into three categories defined by the World Health Organization (WHO). Group I ovulation disorders involve hypothalamic failure characterized as hypogonadotropic hypogonadism. Group II disorders display a eugonadal state commonly associated with a wide range of endocrinopathies. Finally, group III constitutes hypergonadotropic hypogonadism secondary to depleted ovarian function. Optimal evaluation and management of these disorders is based on a careful analysis tailored to each patient. This article reviews ovulation disorders based on pathophysiologic mechanisms, evaluation principles, and currently available management options.
| S-EPMC6466056 | biostudies-literature
Project description:IntroductionThis study examined the association of smoking with ovarian reserve in a cross-sectional study of 207 women enrolled in the Louisville Tobacco Smoke Exposure, Genetic Susceptibility, and Infertility (LOUSSI) Study and assessed effect modification by NAT2 acetylator phenotype.MethodsInformation on current smoking status was collected using a structured questionnaire and confirmed by cotinine assay. Serum anti-Müllerian hormone (AMH) levels were used to assess ovarian reserve. Diminished ovarian reserve (DOR) was defined as AMH <1ng/mL. Single nucleotide polymorphisms in the NAT2 gene, which metabolizes toxins found in cigarette smoke, were analyzed to determine NAT2 acetylator status. Linear and logistic regression were used to determine the effects of smoking on ovarian reserve and evaluate effect modification by NAT2. Regression analyses were stratified by polycystic ovary syndrome (PCOS) status and adjusted for age.ResultsCurrent smoking status, either passive or active as measured by urinary cotinine assay, was not significantly associated with DOR. For dose-response assessed using self-report, the odds of DOR increased significantly for every additional cigarette currently smoked (Odds ratio, OR:1.08; 95% confidence interval, 95%CI:1.01-1.15); additionally, every 1 pack-year increase in lifetime exposure was associated with an increased odds of DOR among women without PCOS (OR: 1.08 95%CI: 0.99-1.18). These trends appear to be driven by the heavy or long-term smokers. Effect modification by NAT2 genotype was not established.ConclusionA history of heavy smoking may indicate increased risk of diminished ovarian reserve.
| S-EPMC9746951 | biostudies-literature
Project description:BackgroundChemical agents such as alkylating agents (AAs) that are commonly used for the treatment of cancer cause great damage to the ovaries, thereby significantly increasing the risk of premature ovarian insufficiency (POI). However, the exact molecules underlying AA-induced POI remain largely obscure. Upregulation of the p16 gene may contribute to the progression of POI. As yet, no in vivo data from p16-deficient (KO) mice are available to demonstrate a critical role of p16 in POI. In the present study, we employed p16 KO mice to investigate whether loss of p16 could protect against POI caused by AAs.MethodsWT mice and their p16 KO littermates received a single dose of BUL + CTX to establish an AA-induced POI mouse model. One month later, oestrous cycles were monitored. Three months later, some of the mice were sacrificed to collect sera for measurements of hormone levels and ovaries for measurements of follicle counts, the proliferation and apoptosis of granulosa cells, ovarian stromal fibrosis and vessels. The remaining mice were mated with fertile males for the fertility test.ResultsOur results showed that treatment with BUL + CTX significantly disrupted the oestrous cycles, increased the levels of FSH and LH while decreasing the levels of E2 and AMH, decreased the counts of primordial follicles and growing follicles while increasing the counts of atretic follicles, reduced the vascularized area in the ovarian stroma, and decreased fertility. All of these results were comparable between WT and p16 KO mice treated with BUL + CTX. In addition, ovarian fibrosis was not increased significantly in WT and p16 KO mice treated with BUL + CTX. Growing follicles with normal appearance had normally proliferating granulosa cells (without apparent apoptosis).ConclusionWe concluded that genetic ablation of the p16 gene did not attenuate ovarian damage or help preserve the fertility of mice challenged by AAs. This study demonstrated for the first time that p16 is dispensable for AA-induced POI. Our preliminary findings suggest that targeting p16 alone may not preserve the ovarian reserve and fertility of females treated with AAs.
| S-EPMC9993597 | biostudies-literature