Biological bases of premature ovarian failure

1998 ◽  
Vol 10 (1) ◽  
pp. 73 ◽  
Author(s):  
Roger G. Gosden ◽  
Malcolm J. Faddy
Keyword(s):  
Mathematical Model ◽  
Causal Relationship ◽  
Premature Ovarian Failure ◽  
Ovarian Failure ◽  
Fixed Number ◽  
Human Ovary ◽  
Primordial Follicles

The ovary is endowed at birth with a fixed number of primordial follicles, which steadily dwindles throughout life as a result of atresia and recruitment towards ovulation. In addition to age, the number varies allometrically between species, larger and longer-lived animals tending to have more follicles initially and these disappear at a slower rate. A causal relationship between follicle depletion and menopause clearly exists, and there is a gradual acceleration of follicle wastage in the human ovary beginning more than a decade before the end of menstrual life. A mathematical model has provided confirmatory evidence of this relationship, and indicates that menopause is triggered by a threshold number of follicles which varies stochastically with a mean of 1100

scholarly journals Establishment of a Mouse Model of Premature Ovarian Failure Using Consecutive Superovulation

2018 ◽  
Vol 51 (5) ◽  
pp. 2341-2358 ◽  
Author(s):  
Xiaowei Nie ◽  
Youjin Dai ◽  
Yuan Zheng ◽  
Dan Bao ◽  
Qin Chen ◽  
...  
Keyword(s):  
Mouse Model ◽  
Premature Ovarian Failure ◽  
Cell Apoptosis ◽  
Quantitative Polymerase Chain Reaction ◽  
Oocyte Quality ◽  
Ovarian Failure ◽  
Control Group ◽  
Mrna Levels ◽  
Primordial Follicles ◽  
Ovarian Aging

Background/Aims: This study investigated the effect of consecutive superovulation on the ovaries and established a premature ovarian failure (POF) model in mice. Methods: The mouse POF model was induced by 5-15 consecutive superovulation treatments with pregnant mare serum gonadotropin (PMSG), human chorionic gonadotropin (HCG) and prostaglandin F2α (PGF2α). Normal adult mice were compared with mice displaying natural ovarian aging. The following serum biochemical parameters were measured: including follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P), estradiol (E2), inhibin B (INH B), malondialdehyde (MDA), total superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels. Follicles were counted using H&E staining. Levels of 8-hydroxyguanosine (8-OhdG), 4-hydroxynonenal (4-HNE), nitrotyrosine (NTY), anti-Mullerian hormone (AMH) and CDKN2A/ p16 (p16) were detected using immunohistochemical staining. Reactive oxygen species (ROS) levels were measured using dihydroethidium (DHE) staining. Cell apoptosis was detected using an in situ TUNEL fluorescence staining assay. Levels of proteins involved in ROS-related pathways and the p16 protein were detected using Western blotting. Sod1, Sod2 and Sod3 mRNA levels were detected using quantitative polymerase chain reaction (Q-PCR). Oocyte quality was evaluated using in vitro fertilization (IVF) and zygote culture. Results: Consecutive superovulation groups presented lower P, E2, SOD, GSH-Px and INH B levels, significantly higher FSH, LH, MDA and ROS levels, and significantly fewer primordial follicles compared with the control group. Consecutive superovulation groups presented significantly increased levels of Sod2, 8-OhdG, 4-HNE, NTY, significantly increased levels of the SIRT1 and FOXO1 proteins, significantly increased levels of the senescence-associated protein p16, as well as decreased AMH, Sod1 and Sod3 levels and increased granulosa cell apoptosis compared with the control group. Conclusion: Consecutive superovulation significantly decreased ovarian function and oocyte quality and increased oxidative stress and apoptosis in the ovary via a mechanism involving the p16 and SIRT1/FOXO1 signaling pathways. These findings suggest that consecutive superovulation may be used to establish a mouse model of ovarian aging.

scholarly journals Overactive Reproductive Axis Due to Fragile X Gene Mutation

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A547-A547
Author(s):  
Pedro Villa ◽  
Nancy Lainez ◽  
Iryna Ethell ◽  
Djurdjica Coss
Keyword(s):  
Mental Retardation ◽  
Premature Ovarian Failure ◽  
Fragile X ◽  
Reproductive Function ◽  
Ovarian Failure ◽  
Corpora Lutea ◽  
Primordial Follicles ◽  
Protein Levels ◽  
Fragile X Mental Retardation ◽  
Gnrh Neurons

Abstract Women carrying a pre-mutation or mutation of the Fragile X mental retardation gene (FMR1) comprise the largest portion of premature ovarian failure (POF) cases due to known genetic factors. FMR1 mutation causes Fragile X syndrome, the most common cause of inherited mental impairment. The mutation inhibits the expression of the fragile X mental retardation protein (FMRP), a ubiquitously expressed mRNA binding protein. The specific molecular mechanism(s) leading to premature ovarian failure in Fragile X carriers are not known. Here, we utilize the complete KO mouse model, to mimic the lack of FMRP in Fragile X mutations and analyze the hypothalamic-pituitary-gonadal axis to uncover causes of POF due to FMR1 mutation. Consistent with mutations in human population, KO females experience early cessation of reproductive function and stop having litters at 150 days of age, compared to controls that stop reproducing at 250 days of age. Since POF can be caused by either insufficient pool of primordial follicles or by increased recruitment in each cycle and early depletion, we analyzed ovaries at 3 weeks of age and determined that the FMR1 KO mice had the same number of primordial follicles when compared to the controls, suggesting that POF is not due to a deficit in primordial follicles. However, at 8 weeks of age, FMR1 KO ovaries had higher number of corpora lutea, and KO females had larger litters, indicating that FMR1 KO mice have more follicles recruited in each estrous cycle. FMR1 KO mice have higher FSH, which corresponds to the high FSH in women. Serum estradiol levels and inhibin b expression levels were unaffected by FMR1 mutation suggesting normally functioning negative feedback signals from the ovaries. Analyses of hypothalamic gene expression demonstrated elevated GnRH mRNA in KO mice. To further investigate alterations is hypothalamic protein levels, western blot analyses determined that FMR1 KO mice have higher levels of NMDAR1 and higher levels of GABAA receptor G2 subunit. Dual label immunofluorescence analyses revealed higher number of NMDAR1 and GABAA receptors specifically in GnRH neurons of FMR1 KO mice when compared to control, suggesting that GnRH neurons themselves are affected by FMR1 mutation. Given that both glutamate and GABA can activate GnRH neurons, alterations in the number of these receptors can potentially cause hyperactivity in the HPG axis at the hypothalamic level leading to elevated FSH and the subsequent POF. In summary, our results reveal a potential mechanism of premature ovarian failure in Fragile X mutation carriers.

Effects of quercetin and rosuvastatin each alone or in combination on cyclophosphamide-induced premature ovarian failure in female albino mice

2019 ◽  
Vol 38 (11) ◽  
pp. 1283-1295 ◽  
Author(s):  
MA Elkady ◽  
S Shalaby ◽  
F Fathi ◽  
S El-Mandouh
Keyword(s):  
Premature Ovarian Failure ◽  
Ovarian Function ◽  
Ovarian Tissue ◽  
Ovarian Failure ◽  
Control Group ◽  
Primordial Follicles ◽  
Ovarian Toxicity ◽  
Versus Group ◽  
Group 3 ◽  
Dose Dependent

Background: Cyclophosphamide (CP) causes premature ovarian failure (POF) due to ovarian toxicity. The toxicity mechanism is attributed to oxidative stress, inflammation, and apoptosis. We assessed whether quercetin and rosuvastatin could promote ovarian protection against CP ovotoxicity. Methods: A total of 80 female BALB/c mice were randomly assigned; 10 mice into each of eight groups. Group 1 (control), group 2 (EH), group 3 (CP), group 4 (QH), group 5 (QL), group 6 (RH), group 7 (RL), and group 8 (COM). Results: Quercetin and rosuvastatin groups (4:8) showed signs of restored ovarian function in the form of a significant, dose-dependent increase in primordial follicles number, serum anti-Mullerian hormone level, and ovarian tissue glutathione level ( p < 0.05) versus group 3, and a significant, dose-dependent decrease in atretic follicles number and ovarian tissue level of malondialdehyde ( p < 0.05) versus group 3. Immunohistochemistry analysis demonstrated a lower expression of caspase and nuclear factor-kappa B of groups (4:8) versus group 3, although quercetin and rosuvastatin showed a nonsignificant reduction in tumor volume. Conclusions: We demonstrated the protective effect of quercetin and rosuvastatin against ovarian toxicity and POF induced by CP without compromising its antitumor effect.

scholarly journals Premature ovarian failure

2012 ◽  
Vol 140 (11-12) ◽  
pp. 806-811 ◽  
Author(s):  
Svetlana Vujovic ◽  
Miomira Ivovic ◽  
Milina Tancic-Gajic ◽  
Ljiljana Marina ◽  
Marija Barac ◽  
...  
Keyword(s):  
T Cell ◽  
Premature Ovarian Failure ◽  
Gene Dosage ◽  
Oocyte Donation ◽  
Ovarian Failure ◽  
T Cell Subsets ◽  
Bilateral Oophorectomy ◽  
Cytotoxic Lymphocyte ◽  
Primordial Follicles ◽  
First Line Therapy

Premature ovarian failure (POF) is the occurrence of hypergonadotropic hypoestrogenic amenorrhea in women under the age of forty years. It is idiopathic in 74-90% patients. Known cases can be divided into primary and secondary POF. In primary POF genetic aberrations can involve the X chromosome (monosomy, trisomy, translocations, deletions) or autosomes. Genetic mechanisms include reduced gene dosage and non-specific chromosome effects impairing meiosis, decreasing the pool of primordial follicles and increasing atresia due to apoptosis or failure of follicle maturation. Autoimmune ovarian damage is caused by alteration of T-cell subsets and T-cell mediated injury, increase of autoantibody producing B-cells, a low number of effector/cytotoxic lymphocyte, which decreases the number and activity of natural killer cells. Bilateral oophorectomy, chemotherapy, radiotherapy and infections cause the secondary POF. Symptoms of POF include irritability, nervousness, loss of libido, depression, lack of concentration, hot flushes, weight gaining, dry skin, vaginal dryness, frequent infections etc. The diagnosis is confirmed by the level of FSH of over 40 IU/L and estradiol below 50 pmol/L in women aged below 40 years. Biochemical and other hormonal analysis (free thyroxin, TSH, prolactin, testosterone), karyotype (<30 years of age), ultrasound of the breasts and pelvis are advisable. Optimal therapy is combined estrogen progestagen therapy given in a sequential rhythm, after excluding absolute contraindications. Testosterone can be added to adnexectomized women and those with a low libido. Sequential estrogen progestagen replacement therapy is the first line therapy for ovulation induction in those looking for pregnancy and after that oocyte donation will be advised. Appropriate estro-progestagen therapy improves the quality of life and prevents complications such as cardiovascular diseases, osteoporosis, stroke etc.

scholarly journals Premature ovarian failure: morphological and ultrastructural aspects

1994 ◽  
Vol 112 (2) ◽  
pp. 534-538 ◽  
Author(s):  
Mauro Abi Haidar ◽  
Edmund Chada Baracat ◽  
Manuel de Jesus Simões ◽  
Gustavo Rubino de Azevedo Focchi ◽  
Joaquim Evêncio Neto ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Connective Tissue ◽  
Corpus Luteum ◽  
Premature Ovarian Failure ◽  
Ovarian Follicles ◽  
Ovarian Failure ◽  
Primordial Follicles ◽  
Dense Connective Tissue ◽  
Transmission Electron

The authors documented by means of light and transmission electron microscopy that the ovaries of women with premature ovarian failure (POF) displayed dense connective tissue and rare corpora albicantia. Eight of the ten studied cases did not present ovarian follicles; in two cases, it was verified the presence of ovarian follicles, atypical primordial follicles and in one case, a corpus luteum was identified (after stimulation with exogenous gonadotrophin). Regarding the ultrastructural analysis, it was noted that the fibroblasts were united one to each other by cellular prolongations that formed a woof, constituting a cellular syncicius.

scholarly journals Chemoprotective effects of plasma derived from mice of different ages and genders on ovarian failure after cyclophosphamide treatment

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Soghra Bahmanpour ◽  
Eisa Moradiyan ◽  
Farzaneh Dehghani ◽  
Nehleh Zarei-fard
Keyword(s):  
Blood Plasma ◽  
Premature Ovarian Failure ◽  
Ovarian Tissue ◽  
Young Female ◽  
Ovarian Failure ◽  
Control Group ◽  
Protective Effects ◽  
Primordial Follicles ◽  
Chemotherapy Drugs ◽  
Different Ages

Abstract Background Premature ovarian failure is one of the major side effects of chemotherapy drugs. Blood plasma contains several factors that might lead to the repair of different tissues. Objective The chemoprotective effects of plasma derived from mice with different ages and genders were assessed on ovarian tissue in cyclophosphamide-treated mice. Methods Forty-two adult female mice were divided into six groups as follows: (A) control; (B) 0.9% sodium chloride as vehicle; (C) cyclophosphamide; (D) cyclophosphamide + young male blood plasma; (E) cyclophosphamide + old male blood plasma; (F) cyclophosphamide + young female blood plasma. Ovarian failure was induced by injecting cyclophosphamide. On the 1st day, three groups received simultaneous injections of 150 μL intraperitoneal and 70 μL intravenous plasma derived from mice of different ages and genders. Each plasma type (150 μL) was then injected intraperitoneally every other 3 days for 19 days. On day 21, the dissected ovaries were stained for stereological analysis. Also, estrogen and progesterone levels were measured. Results Cyclophosphamide had damaging effects on ovarian parameters and led to reduced hormone levels in comparison with the control group. However, treating with young female and, old male blood plasma, to a lesser degree, showed beneficial effects on the number of primordial follicles, pre-antral follicles, and granulosa cells. Also, these two treatments had protective effects on the volume of ovarian parameters as well as estrogen and progesterone levels in comparison with the cyclophosphamide group (P < 0.05). Conclusion Plasma derived from mice of different ages and genders can ameliorate premature ovarian failure against the adverse effects of cyclophosphamide.

scholarly journals Curcumin exerts a protective effect against premature ovarian failure in mice

2018 ◽  
Vol 60 (3) ◽  
pp. 261-271 ◽  
Author(s):  
Zhengjie Yan ◽  
Youjin Dai ◽  
Heling Fu ◽  
Yuan Zheng ◽  
Dan Bao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Expression ◽  
Protective Effect ◽  
Premature Ovarian Failure ◽  
Ovarian Function ◽  
Ovarian Failure ◽  
Protective Agent ◽  
Primordial Follicles ◽  
Expression Levels ◽  
P16 Expression

This study was designed to investigate the protective effect of curcumin against d-galactose (d-gal)-induced premature ovarian failure (POF) in mice. A mouse POF model was induced by subcutaneous injection of d-gal (200 mg/kg/day) daily for 42 days. Mice in the curcumin group received both d-gal treatment and intraperitoneal injection of curcumin (100 mg/kg/day) for 42 days. Ovarian function, oxidative stress and apoptosis were evaluated. The P, E2 and SOD levels were higher, and the FSH, LH and MDA levels were significantly lower in the curcumin group than those in the d-gal group. The proportion of primordial follicles was also significantly higher in the curcumin group than that in the d-gal group. In addition, curcumin treatment after d-gal administration resulted in significantly lower Sod2, Cat, 8-OhdG, 4-HNE, NTY and senescence-associated protein P16 expression levels, higher Amh expression levels and less apoptosis in granulosa cells than was observed in the d-gal group. Moreover, the p-Akt, Nrf2 and HO-1 protein expression levels were significantly higher and the apoptosis-related cleaved caspase-3 and -9 protein expression levels were markedly lower in the curcumin group than in the d-gal group. In conclusion, curcumin effectively inhibited d-gal-induced oxidative stress, apoptosis and ovarian injury via a mechanism involving the Nrf2/HO-1 and PI3K/Akt signaling pathways, suggesting that curcumin is a potential protective agent against POF.

EPIGENETIC ALTERATIONS ASSOCIATED WITH PREMATURE OVARIAN FAILURE

2008 ◽  
Vol 31 (4) ◽  
pp. 11
Author(s):  
Manda Ghahremani ◽  
Courtney W Hannah ◽  
Maria Peneherrera ◽  
Karla L Bretherick ◽  
Margo R Fluker ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Premature Ovarian Failure ◽  
Promoter Region ◽  
Gene Promoter ◽  
Ovarian Failure ◽  
P Value ◽  
Epigenetic Alterations ◽  
Methylation Array ◽  
Cpg Sites ◽  
Deficient Mice

Background/Purpose: Premature ovarian failure (POF) affects 1% of women with a largely idiopathic and poorly understood etiology. The objective of this study was to identify specific epigenetic alterations by measuring DNA methylation of gene regulatory regions in women with POF vs. controls. Methods: Blood samples were collected from idiopathic POFpatients (Amenorrhea for at least 3 months and 2 serum FSH levels of > 40mIU/ml obtained > 1 month apart prior to age 40) and control women (CW) (healthy pregnancy after age 37 with out a pregnancy loss). Genomic DNA was extracted from EDTA anticoagulated blood and bisulfite converted for analysis using the Illumina Golden Gate Methylation Panel which measures DNA methylation at 1506 CpG sites in the promoter regions of 807 genes in 10 POF and 12 CW. Candidate genes with altered epigenetic marks between POF and CW at a nominal P-value < 0.05 were identified using a t-testcomparison within the Illumina bead studio software. Genes of interest were further analyzed for quantitative methylation at specific CpG sites using pyrosequencing in 30 POF and 30 CW. Results: Comparison of DNA methylation profiles of our initial POF and CW groups identified several genes with statistically significanthyper- or hypo- methylation in the POF group (P < 0.05), including the Androgen Receptor (AR)promoter region, which was significantly hypermethylated. To further validate these results, DNA methylation of the AR gene promoter was quantified bypryosequencing in a larger group of POF and CW. Pyrosequencing further confirmed a significantly higher DNA methylation of the AR promoter region inPOF vs. CW (P=0.007). Conclusions: This is a novel study identifying epigenetic alterations in POF. The hypermethylation of the AR gene in POF patients may cause decreased level of the AR in these women. This is especially interesting given a recent report of induced POF in AR deficient mice^1. Specific epigenetic markers, as identified by DNA methylation array profiling in blood, may serve as useful biomarkers for POF and other fertility disorders. However, it will need to be determined if these methylation changes are present prior to diagnosis, or are a consequence of menopause itself. Reference: 1.Hiroko S. et al. Premature ovarian failure in androgenreceptor deficient mice. PNAS;103:224-9

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