scholarly journals Impact of chemotherapy on the ovarian reserve: are all primordial follicles created equally?

Kutluk H. Oktay ◽  
Loris Marin ◽  
Shiny Titus
2021 ◽  
Vol 22 (12) ◽  
pp. 6570
Yue Lv ◽  
Rui-Can Cao ◽  
Hong-Bin Liu ◽  
Xian-Wei Su ◽  
Gang Lu ◽  

A better understanding of the mechanism of primordial follicle activation will help us better understand the causes of premature ovarian insufficiency (POI), and will help us identify new drugs that can be applied to the clinical treatment of infertility. In this study, single oocytes were isolated from primordial and primary follicles, and were used for gene profiling with TaqMan array cards. Bioinformatics analysis was performed on the gene expression data, and Ingenuity Pathway Analysis was used to analyze and predict drugs that affect follicle activation. An ovarian in vitro culture system was used to verify the function of the drug candidates, and we found that curcumin maintains the ovarian reserve. Long-term treatment with 100 mg/kg curcumin improved the ovarian reserve indicators of AMH, FSH, and estradiol in aging mice. Mechanistic studies show that curcumin can affect the translocation of FOXO3, thereby inhibiting the PTEN-AKT-FOXO3a pathway and protecting primordial follicles from overactivation. These results suggest that curcumin is a potential drug for the treatment of POI patients and for fertility preservation.

2021 ◽  
Vol 99 (Supplement_1) ◽  
pp. 20-20
Robert A Cushman ◽  
Alexandria Snider ◽  
Matthew S Crouse

Abstract While sequence variation can be informative to associate regions of the genome with specific traits and improve genetic selection, the epigenome may provide a more powerful tool to manage cattle. Identifying practices that are producer friendly and effectively control epigenetic function within animals is crucial to translating developmental programming to a production setting. Initial studies of developmental programming investigated how environmental or nutritional stresses during fetal and peri-natal development impacted performance of animals later in life. These studies demonstrated changes in methylation, alterations in transcript abundance, and negative impacts on physiology, but they also suggested that we may be able to beneficially impact the epigenome and developmentally program animals to excel in their niche in the production system. Maternal nutritional status during the third trimester influenced date of conception of female progeny in several studies but failed to do so in other studies. Transcriptomic analyses provided evidence that nutritional treatments alter mRNA abundance in brain, liver, muscle, and ovary, but does not conclusively demonstrate that this is due to functional changes in the epigenome. If developmental programming is to be applied in production systems, responses must be consistent and beneficial. Reducing nutrient intake in heifers during peri-pubertal development increased number of primordial follicles in the ovaries and reproductive longevity. While nutritional programming of the ovarian reserve in peri-pubertal heifers appears to occur consistently across locations and studies, it does not ensure that subsequent environmental stressors will not induce changes in the ovarian reserve that will negate beneficial effects. These studies demonstrate that it is possible to developmentally program the epigenome in cattle in ways that will improve production traits; however, there remains a need for studies to improve the consistency of response and to determine best practices that fit into production systems. USDA is an equal opportunity provider and employer.

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Fangui Zhao ◽  
Wenjun Wang

Diminished ovarian reserve (DOR) refers to a decrease in the number and quality of oocytes. Western treatment of DOR does not improve the ovarian reserve fundamentally, and the effect is limited. Gengnianchun recipe (GNC) is a traditional Chinese medicine formula originally applied to treat menopausal syndrome but is also found to be effective in treating clinical DOR patients. Here we aim to examine the effect of GNC in a DOR rat model induced by 4-vinylcyclohexene diepoxide (VCD), a chemical that selectively destroys ovarian small preantral follicles, and further investigate the possible mechanisms. Female SD rats were randomly divided into four groups: control group (C), model group (M), high-dose GNC group (H), and low-dose GNC group (L). Rats in M, H, and L were administered with VCD and normal saline, high-dose GNC, and low-dose GNC separately. Rat ovaries were harvested either to conduct HE staining for follicle count, immunohistochemistry, or western blot. We found that high dose of GNC significantly increased the ovarian index and sustained the number of primordial follicles and primary follicles in VCD treated rats. Moreover, high dose of GNC significantly increased the ovarian protein expression of mouse vasa homologue (MVH), anti-Müllerian hormone (AMH), follicle-stimulating hormone receptor (FSHR), and estrogen receptor β (ERβ) compared with that in the model group. Besides, high-dose GNC significantly increased ovarian AKT phosphorylation and the expression of downstream forkhead box O3 (FOXO3a). Proapoptosis proteins of Bax, cleaved caspase-3, and poly ADP-ribose polymerase (PARP) were significantly decreased after high-dose GNC treatment compared with those in the model group. Taken together, these findings suggest that high-dose GNC could protect ovarian reserve against VCD-induced toxicity via the activation of the AKT signaling pathway and reduced cell apoptosis in SD Rats. This effect could either be induced by the increased FSHR signaling or by the nontranscriptional activation of ERβ, which requires further investigation.

2021 ◽  
Vol 36 (Supplement_1) ◽  
A Volodarsky-Perel ◽  
M Zajicek ◽  
D Shai ◽  
H Raanani ◽  
N Gruber ◽  

Abstract Study question What is the predictive value of ovarian reserve evaluation in patients with non-iatrogenic primary ovarian insufficiency (NIPOI) for follicle detection in ovarian tissue harvested for cryopreservation? Summary answer Ovarian tissue cryopreservation (OTCP) should be considered if patients present at least one of the following parameters: detectable AMH, FSH≤20mIU/ml, detection of ≥ 1 antral follicle. What is known already In pre-pubertal girls suffering from NIPOI, which majorly has a genetic etiology, fertility preservation using OTCP is commonly practiced. When OTCP was performed in an unselected group of children and adolescents with NIPOI, only 26% of them had follicles in ovarian tissue while 74% did not benefit from the surgery. The role of preoperative evaluation of anti-müllerian hormone (AMH) serum level, follicular stimulating hormone (FSH) serum level, and trans-abdominal ultrasound for the antral follicle count to predict the detection of primordial follicles in the harvested ovarian tissue is unclear. Study design, size, duration We conducted a retrospective analysis of all patients ≤ 18 years old who were referred for fertility preservation counseling due to NIPOI at a single tertiary hospital between 2010 and 2020. If initial evaluation suggested a diminished ovarian reserve and at least one positive parameter indicating a follicular activity (AMH > 0.16ng/ml, FSH ≤ 20mIU/ml, detection of ≥ 1 antral follicle by transabdominal sonography), OTCP was offered. Patients with 46XY gonadal dysgenesis were excluded. Participants/materials, setting, methods OTCP was performed laparoscopically in all cases. A fresh sample of cortical tissue was fixed in buffered formaldehyde for histological analysis. The rest of the ovarian tissue was cut into small cuboidal slices 1–2 mm in thickness and cryopreserved. After the serial sections, the histological slides were evaluated for the presence of follicles by a certified pathologist. Follicles were counted and categorized as primordial, primary, and secondary. Main results and the role of chance During the study period, 39 patients with suspected NIPOI were referred to the fertility preservation center. Thirty-seven patients included in the study were diagnosed with Turner’s syndrome (n = 28), Galactosemia (n = 3), Blepharophimosis-Ptosis-Epicanthus Inversus syndrome (n = 1), and idiopathic NIPOI (n = 6). Of 28 patients with Turner’s syndrome, 6 had 45X monosomy, 15 had mosaicism and 7 had structural anomalies in X-chromosome. One patient with gonadal dysgenesis and one with the presence of Y-chromosome in 20% of somatic cells were excluded from the study. OTCP was conducted in 14 patients with at least one positive parameter suggesting ovarian function. No complications of the surgical procedure or the anesthesia were observed. Primordial follicles were found in all patients with two or three positive parameters (100%) and in three of six cases with one positive parameter (50%). In total, of the 14 patients who underwent OTCP with at least one positive parameter, 11 (79%) had primordial follicles at biopsy (mean 23.9, range 2–47). This study demonstrates a positive predictive value of 79% for the detection of primordial follicles in patients who had at least one positive parameter of ovarian reserve evaluation. If two or three parameters were positive, the positive predictive value increased to 100%. Limitations, reasons for caution This study did not examine the negative predictive value of our protocol as OTCP was not recommended in the absence of positive parameters. The future fertility potential of cryopreserved tissue in the population with NIPOI is unclear and should be discovered in further studies. Wider implications of the findings: We suggest the evaluation of ovarian reserve by antral follicles count, AMH, and FSH serum levels prior to OTCP in patients with NIPOI. By recommendation of OTCP only if ≥ 1 parameter suggesting the ovarian function is positive, unnecessary procedures can be avoided. Trial registration number Not applicable

2012 ◽  
Vol 3 (4) ◽  
pp. 276-286 ◽  
V. Padmanabhan ◽  
P. Smith ◽  
A. Veiga-Lopez

Prenatal testosterone (T) excess leads to reproductive dysfunctions in sheep with obesity exaggerating such defects. Developmental studies found ovarian reserve is similar in control and prenatal T sheep at fetal day 140, with prenatal T females showing increased follicular recruitment and persistence at 10 months of age (postpubertal). This study tested whether prenatal T sheep show accelerated depletion prepubertally and whether depletion of ovarian reserve would explain loss of cyclicity in prenatal T females and its amplification by postnatal obesity. Stereological examinations were performed at 5 (prepubertal, control and prenatal T) and 21 months of age (control, prenatal T and prenatal T obese, following estrus synchronization). Obesity was induced by overfeeding from weaning. At 5 months, prenatal T females had 46% less primordial follicles than controls (P < 0.01), supportive of increased follicular depletion. Depletion rate was slower and a higher percentage of growing follicles was present in 21-month compared with 5-month-old prenatal T females (P < 0.01). Postnatal obesity did not exaggerate the impact of prenatal T on follicular recruitment indicating that compounding effects of obesity on loss of cyclicity females is not due to depletion of ovarian reserve. Assessment of follicular dynamics across several time points during the reproductive lifespan (this and earlier study combined) provides evidence supportive of a shift in follicular dynamics in prenatal T females from one of accelerated follicular depletion initiated before puberty to stockpiling of growing follicles after puberty, a time point critical in the development of the polycystic ovary syndrome phenotype.

2021 ◽  
Vol 3 ◽  
Kim Cat Tuyen Vo ◽  
Kazuhiro Kawamura

Since the first baby was born after in vitro fertilization, the female infertility treatment has been well-developed, yielding successful outcomes. However, successful pregnancies for patients with premature ovarian insufficiency and diminished ovarian reserve are still difficult and diverse therapies have been suggested to improve the chances to have their genetically linked offspring. Recent studies demonstrated that the activation Akt pathway by using a phosphatase and tensin homolog enzyme inhibitor and a phosphatidylinositol-3 kinase stimulator can activate dormant primordial follicles in both mice and human ovaries. Subsequent researches suggested that the disruption of Hippo signaling pathway by ovarian fragmentation increased the expression of downstream growth factors and secondary follicle growth. Based on the combination of ovarian fragmentation and Akt stimulation, the in vitro activation (IVA) approach has resulted in successful follicle growth and live births in premature ovarian insufficiency patients. The approach with disruption of Hippo signaling only was also shown to be effective for treating poor ovarian responders with diminishing ovarian reserve, including advanced age women and cancer patients undergoing sterilizing treatments. This review aims to summarize the effectiveness of ovarian fragmentation and Akt stimulation on follicle growth and the potential of IVA in extending female fertile lifespan.

Reproduction ◽  
2018 ◽  
Amy L Winship ◽  
Sarah E Gazzard ◽  
Luise A Cullen McEwen ◽  
John F Bertram ◽  
Karla J Hutt

The ovarian reserve of primordial follicle oocytes is formed during in utero development and represents the entire supply of oocytes available to sustain female fertility. Maternal undernutrition during pregnancy and lactation diminishes offspring ovarian reserve in rats. In mice, maternal oocyte maturation is also susceptible to undernutrition, causing impaired offspring cardiovascular function. We aimed to determine whether programming of the ovarian reserve is impacted in offspring when maternal undernutrition extends from preconception oocyte development through to weaning. C57BL6/J female mice were fed normal protein (20%) or low protein (8%) diet during preconception, pregnancy and lactation periods. Maternal ovaries were harvested at weaning and offspring ovaries collected at postnatal day (PN)21 and 24 weeks of age. Total follicle estimates were obtained by histologically sampling one ovary per animal (n=5/group). There was no impact of diet on maternal follicle numbers. However, in offspring, maternal protein restriction significantly depleted primordial follicles by 37% at PN21 and 51% at 24 weeks (p<0.05). There were no effects of diet on other follicle classes. Histological analysis showed no differences in the proportion of proliferative follicles (pH3-positive), but increased atresia (cleaved caspase-3-positive, or TUNEL-positive) was detected in ovaries of protein-restricted offspring at both ages (p<0.05). Our data show that maternal diet during the preconception period, in utero development and early life has significant impacts on follicle endowment and markers of follicle health later in life. This highlights the need for further investigation into the importance of maternal preconception diet for offspring reproductive development and health.

2020 ◽  
S. Titus ◽  
K.J. Szymanska ◽  
B. Musul ◽  
V. Turan ◽  
E. Taylan ◽  

AbstractGonadotoxic chemotherapeutics, such as cyclophosphamide, cause early menopause and infertility in women. Earlier histological studies showed ovarian reserve depletion via severe DNA damage and apoptosis, but others suggested activation of PI3K/PTEN/Akt pathway and follicle ‘burn-out’ as a cause. Using a human ovarian xenograft model, we performed single-cell RNA-sequencing on laser-captured individual primordial follicle oocytes 12h after a single cyclophosphamide injection to determine the mechanisms of acute follicle loss after gonadotoxic chemotherapy. RNA-sequencing showed 190 differentially expressed genes between the cyclophosphamide- and vehicle-exposed oocytes. Ingenuity Pathway Analysis predicted a significant decrease in the expression of anti-apoptotic pro-Akt PECAM1 (p=2.13E-09), IKBKE (p=0.0001), and ANGPT1 (p=0.003), and reduced activation of PI3K/PTEN/Akt after cyclophosphamide. The qRT-PCR and immunostaining confirmed that in primordial follicle oocytes, cyclophosphamide did not change the expressions of Akt (p=0.9), rpS6 (p=0.3), Foxo3a (p=0.12) and anti-apoptotic Bcl2 (p=0.17), nor affect their phosphorylation status. There was significantly increased DNA damage by γH2AX (p=0.0002) and apoptosis by active-caspase-3 (p=0.0001) staining in the primordial follicles and no change in the growing follicles 12h after chemotherapy. These data suggest that the mechanism of acute follicle loss by cyclophosphamide is via apoptosis, rather than growth activation of primordial follicle oocytes in the human ovary.One Sentence SummarySingle-cell transcriptomic interrogation of primordial follicles in human ovarian xenografts reveals that chemotherapy causes acute ovarian reserve depletion by inducing a pro-apoptotic state rather than activating pathways that result in follicle growth initiation.

2005 ◽  
Vol 17 (2) ◽  
pp. 252
R. De Roover ◽  
C. Hanzen

The pool of primordial follicles in the ovary or ovarian reserve is a major factor in human fertility potential. In bovine medicine as well, this ovarian reserve has been linked to the results of superovulation procedures (Cushman et al. 1999 Biol. Reprod. 60, 349–354). These authors suggested a biopsy to assess the level of this reserve. Whether the biopsy(ies) is(are) a true reflection of the follicular distribution in the ovarian cortex, is (to the best of our knowledge) a factor never investigated until now in bovine medicine. In human medicine, this procedure has been critically examined for that particular use and found not to be suited (Lass et al. 2004 Hum. Reprod. 19, 467–469). Indeed, randomized or “blind” sampling of one biopsy is adequate only if follicles are evenly spread in the ovarian cortex; in any case they are not deeper than a few mm from the surface. Moreover, the quantitative counting of follicles does not provide any information about the quality of the oocytes embedded in them. Taking a biopsy of a bovine ovary in a minimally invasive way is technically feasible (Aerts 2004 Reprod. Fertil. Dev. 16, 229–230). Therefore, the aim of this study was to examine the natural distribution of primordial follicles in the ovarian cortex of bovine ovaries. Slaugtherhouse ovaries were collected at random. The volume (mL) was measured and the macroscopically visible follicles were counted. Then the ovaries were cut in slices of 5Âμm, and every 8th (8 × 5 = 40 μm interval) slice was subjected to fixation in formalin and hematoxylin-eosin staining. Before counting of the primordial follicles, the ovarian cortex was subdivided into 8 equal parts. These “parts” were supposed to mimick a (single) ovarian biopsy. The 8 parts of a slice represent here multiple biopsies. For each of these parts, the number of primordial follicles was counted; only follicles with a visible oocyte were included. The results of the parts containing the ligament of the ovary were excluded. Results are shown in Table 1. The results show that the distribution of primordial follicles between small parts of the bovine ovarian tissue was extremely uneven. A large variation was observed between samples obtained from the same ovary. Moreover, an extrapolation of follicle numbers found in biopsies to entire ovaries were hampered by the uneven size and morphology of these ovaries. Therefore, we conclude that the use of single biopsies of ovarian cortex for a quantitative evaluation of the ovarian reserve has limited value; an empty cortex or a cortex with very few follicles might be just incidental and meaningless. Even the use of multiple biopsies, although less variable, does not solve the problem of extrapolation of these data to entire ovaries. Table 1. Macroscopically visible follicles on 4 ovaries and primordial (“microscopical”) follicles on 4 slices of each of these ovaries

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