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Infertility due to Gonadotropin-Resistant Ovary Syndrome (GROS) is a rare type of hypergonadotropic hypogonadism. Here, we report an original case of GROS, associated with compound heterozygous follicle-stimulating hormone receptor (FSHR) variants, in a woman who achieved a live birth by in vitro maturation (IVM) of her oocytes. This 31-year-old woman consulted our assisted reproduction center for a second opinion after having been advised, because of pervasive high serum follicle-stimulating hormone (FSH) levels, to pursue in vitro fertilization (IVF) with donor oocytes. She presented with primary infertility and progressively prolonged menstrual cycles. Her serum FSH levels were indeed found to be high, but in discordance with a normal anti-Müllerian hormone (AMH) level and antral follicle count. Genetic investigation found the patient to be compound heterozygous for two FSHR variants: I160T, a known pathologic variant, and N558H, which has never been previously reported. As there was no ovarian response to high daily doses of exogenous gonadotropins, IVM was proposed to the patient with success and she finally delivered at term a healthy boy. Effects of the receptor variants were analyzed in heterologous cells. Whereas the I160T mutation blocked FSHR membrane trafficking and FSH-stimulated cAMP-dependent signaling in transfected CHO cells, the novel variant, N558H, functioned equivalently to wild-type FSHR in the assays employed. In conclusion, IVM should always be offered as a first-line therapy to infertile women presenting with GROS. The N558H variant discovered in FSHR is novel, but its functional significance, if any, is unresolved and merits further investigation as it may be associated with a recessive FSHR-related disorder.

Analysis of mitochondrial replacement therapy shows, even with efficient mutant mitochondrial DNA replacement and maintenance in embryonic stem cells, a gradual loss of donor mitochondrial DNA in some lines owing to a polymorphism in the D-loop, potentially causing preferential replication of specific mitochondrial DNA haplotypes. A new mitochondrial replacement technique Mitochondrial replacement techniques (MRT) could potentially be used to avoid mother-to-child transmission of mitochondria carrying disease-causing mutations. Shoukhrat Mitalipov and colleagues have investigated the outcome of MRT using oocytes from women from families with common mtDNA-associated syndromes and by transferring meiotic spindle from patient oocytes to healthy donor oocytes. Although donor mtDNA replaced the patient mtDNA efficiently and was stably maintained in embryonic stem cells (ES cells) derived from most embryos, some ES cell lines lost donor mtDNA. The authors' analysis suggests that polymorphisms in mtDNA could be associated with preferential replication and could be cause the amplification of specific maternal haplotype. Maternally inherited mitochondrial (mt)DNA mutations can cause fatal or severely debilitating syndromes in children 1 , 2 , 3 , with disease severity dependent on the specific gene mutation and the ratio of mutant to wild-type mtDNA (heteroplasmy) in each cell and tissue 4 . Pathogenic mtDNA mutations are relatively common, with an estimated 778 affected children born each year in the United States 5 . Mitochondrial replacement therapies or techniques (MRT) circumventing mother–to–child mtDNA disease transmission involve replacement of oocyte maternal mtDNA 6 , 7 , 8 . Here we report MRT outcomes in several families with common mtDNA syndromes. The mother’s oocytes were of normal quality and mutation levels correlated with those in existing children. Efficient replacement of oocyte mutant mtDNA was performed by spindle transfer 8 , resulting in embryos containing >99% donor mtDNA. Donor mtDNA was stably maintained in embryonic stem cells (ES cells) derived from most embryos. However, some ES cell lines demonstrated gradual loss of donor mtDNA and reversal to the maternal haplotype. In evaluating donor–to–maternal mtDNA interactions, it seems that compatibility relates to mtDNA replication efficiency rather than to mismatch or oxidative phosphorylation dysfunction. We identify a polymorphism within the conserved sequence box II region of the D-loop as a plausible cause of preferential replication of specific mtDNA haplotypes. In addition, some haplotypes confer proliferative and growth advantages to cells. Hence, we propose a matching paradigm for selecting compatible donor mtDNA for MRT.

Maternal obesity is associated with poor outcomes across the reproductive spectrum including infertility, increased time to pregnancy, early pregnancy loss, fetal loss, congenital abnormalities and neonatal conditions. Furthermore, the proportion of reproductive-aged woman that are obese in the population is increasing sharply. From current studies it is not clear if the origin of the reproductive complications is attributable to problems that arise in the oocyte or the uterine environment. We examined the developmental basis of the reproductive phenotypes in obese animals by employing a high fat diet mouse model of obesity. We analyzed very early embryonic and fetal phenotypes, which can be parsed into three abnormal developmental processes that occur in obese mothers. The first is oocyte meiotic aneuploidy that then leads to early embryonic loss. The second is an abnormal process distinct from meiotic aneuploidy that also leads to early embryonic loss. The third is fetal growth retardation and brain developmental abnormalities, which based on embryo transfer experiments are not due to the obese uterine environment but instead must be from a defect that arises prior to the blastocyst stage. Our results suggest that reproductive complications in obese females are, at least in part, from oocyte maternal effects. This conclusion is consistent with IVF studies where the increased pregnancy failure rate in obese women returns to the normal rate if donor oocytes are used instead of autologous oocytes. We postulate that preconceptional weight gain adversely affects pregnancy outcomes and fetal development. In light of our findings, preconceptional counseling may be indicated as the preferable, earlier target for intervention in obese women desiring pregnancy and healthy outcomes.

Endometriosis is an estrogen-dependent chronic inflammatory condition that affects women in their reproductive period causing infertility and pelvic pain. The disease, especially at the ovarian site has been shown to have a detrimental impact on ovarian physiology. Indeed, sonographic and histologic data tend to support the idea that ovarian follicles of endometriosis patients are decreased in number and more atretic. Moreover, the local intrafollicular environment of patients affected is characterized by alterations of the granulosa cell compartment including reduced P450 aromatase expression and increased intracellular reactive oxygen species generation. However, no comprehensive evaluation of the literature addressing the effect of endometriosis on oocyte quality from both a clinical and a biological perspective has so far been conducted. Based on this systematic review of the literature, oocytes retrieved from women affected by endometriosis are more likely to fail in vitro maturation and to show altered morphology and lower cytoplasmic mitochondrial content compared to women with other causes of infertility. Results from meta-analyses addressing IVF outcomes in women affected would indicate that a reduction in the number of mature oocytes retrieved is associated with endometriosis while a reduction in fertilization rates is more likely to be associated with minimal/mild rather than with moderate/severe disease. However, evidence in this field is still far to be conclusive, especially with regards to the effects of different stages of the disease and to the impact of patients’ previous medical/surgical treatment(s).

Stress is an important factor that affects physical and mental status of a healthy person disturbing homeostasis of the body. Changes in the lifestyle are one of the major causes that lead to psychological stress. Psychological stress could impact the biology of female reproduction by targeting at the level of ovary, follicle and oocyte. The increased level of stress hormone such as cortisol reduces estradiol production possibly by affecting the granulosa cell functions within the follicle, which results deterioration in oocyte quality. Adaptation of lifestyle behaviours may generate reactive oxygen species (ROS) in the ovary, which further affects female reproduction. Balance between level of ROS and antioxidants within the ovary are important for maintenance of female reproductive health. Physiological level of ROS modulates oocyte functions, while its accumulation leads to oxidative stress (OS). OS triggers apoptosis in majority of germ cells within the ovary and even in ovulated oocytes. Although both mitochondria- as well as death-receptor pathways are involved in oocyte apoptosis, OS-induced mitochondria-mediated pathway plays a major role in the elimination of majority of germ cells from ovary. OS in the follicular fluid deteriorates oocyte quality and reduces reproductive outcome. On the other hand, antioxidants reduce ROS levels and protect against OS-mediated germ cell apoptosis and thereby depletion of germ cells from the ovary. Indeed, OS is one of the major factors that has a direct negative impact on oocyte quality and limits female reproductive outcome in several mammalian species including human.

Advanced maternal age has been reported to impair oocyte quality; however, the underlying mechanisms remain to be explored. In the present study, we identified the lowered NAD+ content and decreased expression of NMNAT2 protein in oocytes from old mice. Specific depletion of NMNAT2 in mouse oocytes disturbs the meiotic apparatus assembly and metabolic activity. Of note, nicotinic acid supplementation during in vitro culture or forced expression of NMNAT2 in aged oocytes was capable of reducing the reactive oxygen species (ROS) production and incidence of spindle/chromosome defects. Moreover, we revealed that activation or overexpression of SIRT1 not only partly prevents the deficient phenotypes of aged oocytes but also ameliorates the meiotic anomalies and oxidative stress in NMNAT2‐depleted oocytes. To sum up, our data indicate a role for NMNAT2 in controlling redox homeostasis during oocyte maturation and uncover that NMNAT2‐ NAD+‐SIRT1 is an important pathway mediating the effects of maternal age on oocyte developmental competence. Loss of NAD+ content and NMNAT2 protein results in the meiotic abnormalities and metabolic dysfunction in oocytes from old mouse. NA supplement and SIRT1 overexpression/activation could partly rescue the defective phenotype of these aged oocytes.

PurposeTo determine how clinical, demographic, and laboratory characteristics influence ovarian tissue oocyte quality.MethodsImmature cumulus-oocyte complexes were isolated from removed ovaries and cultured for 48–52 h in either monophasic standard or biphasic CAPA media for fertility preservation. A total of 355 MII oocytes from 53 patients were described for intracytoplasmic and extracytoplasmic anomalies. Multiple clinical, laboratory, and demographic characteristics were analyzed. Statistically significant differences between independent groups in qualitative variables were identified using Pearson’s χ2 and Fisher’s exact tests. The diagnostic value of quantitative variables was assessed using the ROC curve analysis. Factors associated with the development of dysmorphism, taking patient age into account, were identified using the binary logistic regression analysis.ResultsDysmorphisms were observed in 245 oocytes (69.0%), with a median number of dysmorphisms of 2. Oocyte dysmorphisms were found to be 2.211 times more likely to be detected in patients with ovarian cancer, while the presence of dark-colored cytoplasm was associated with gynecologic surgery in the anamnesis (p = 0.002; OR 16.652; 95% CI, 1.977–140.237; Cramer’s V 0.187). Small polar bodies developed 2.717 times more often (95% CI, 1.195–6.18) in patients older than 35. In the case of ovarian transportation on ice at 4 ℃, the chances of development of cytoplasmic granularity increased 2.569 times (95% CI, 1.301–5.179). The use of biphasic CAPA IVM media contributed to a decrease in the probability of large polar body formation (p = 0.034) compared to the standard monophasic IVM media.ConclusionsBoth patients’ characteristics and laboratory parameters have an impact on the quality of IVM ovarian tissue oocytes.

Maternal obesity can impair embryo development and offspring health, yet the mechanisms responsible remain poorly understood. In a high-fat diet (HFD)-based female mouse model of obesity, we identified a marked reduction of Stella (also known as DPPA3 or PGC7) protein in oocytes. Starting with this clue, we found that the establishment of pronuclear epigenetic asymmetry in zygotes from obese mice was severely disrupted, inducing the accumulation of maternal 5-hydroxymethylcytosine modifications and DNA lesions. Furthermore, methylome-wide sequencing analysis detected global hypomethylation across the zygote genome in HFD-fed mice, with a specific enrichment in transposon elements and unique regions. Notably, overexpression of Stella in the oocytes of HFD-fed mice not only restored the epigenetic remodeling in zygotes but also partly ameliorated the maternal-obesity-associated developmental defects in early embryos and fetal growth. Thus, Stella insufficiency in oocytes may represent a critical mechanism that mediates the phenotypic effects of maternal obesity in embryos and offspring. The authors find that, in a high-fat diet (HFD) mouse model, levels of Stella protein are reduced in oocytes, leading to abnormal epigenetic patterning during development and to embryonic growth defects. Overexpression of Stella in oocytes from HFD-fed mice partially ameliorates developmental defects.

ContextRecent clinical and laboratory studies suggested that women with BRCA mutations have lower ovarian reserve and their primordial follicle oocytes may be more prone to DNA damage; however, direct proof is lacking.ObjectiveTo determine whether women with germline BRCA mutations have reduced primordial follicle reserve and increased oocyte DNA damage.DesignA comparative laboratory study of ovarian tissue obtained from unaffected BRCA mutation carriers (BMCs) vs age-matched organ donor cadavers.SettingTwo academic centers.Patients or Other ParticipantsOf the 230 ovarian specimens from BMCs, 18 met the study inclusion criteria. Healthy ovaries from 12 organ donor cadavers served as controls.InterventionHistology and immunohistochemical analysis on paraffin-embedded ovarian sections.Main Outcome Measure(s)Primordial follicle density and the percentage of DNA double-strand break (DSB)−positive primordial follicle oocytes.ResultsOvaries from BMCs had significantly lower primordial follicle densities than those of controls (11.2 ± 2.0 vs 44.2 ± 6.2 follicles/mm3; P = 0.0002). BRCA mutations were associated with increased DNA DSBs in primordial follicle oocytes (62% ± 5.2% vs 36% ± 3.4%; P = 0.0005). In subgroup analyses, both BRCA1 and BRCA2 mutations were associated with lower primordial follicle density (P = 0.0001 and 0.0030, respectively), and BRCA1 mutations were associated with higher DNA DSBs (P = 0.0003) than controls. The rates of follicle decline (R2 = 0.74; P = 0.0001) and DNA DSB accumulation (R2 = 0.70; P = 0.0001) appeared to be accelerated, particularly in primordial follicle oocytes of BMCs over age 30 years.ConclusionsWe provide direct evidence of diminished ovarian reserve as well as accelerated primordial follicle loss and oocyte DNA damage in women with BRCA mutations. These findings may further our understanding of ovarian aging, and be useful when counseling BMCs.Comparison of BRCA mutation carrier ovaries with controls showed that BRCA mutations were associated with accelerated loss of primordial follicle reserve and increased oocyte DNA damage with age.

Endometriosis, a highly prevalent gynecological disease, is often associated with infertility, even in its milder forms (minimal and mild endometriosis). However, no consensus has been established with regard to this relationship and the possible mechanisms involved have not been completely elucidated. The oocyte is believed to have an important role in the infertility presented by these patients. Hence, oxidative stress events associated with alterations in the peritoneal, serum and/or follicular microenvironments might result in poor oocyte quality and compromise the reproductive potential of these women. Here, we review possible mechanisms involved in oocyte quality impairment that might lead to infertility in patients with early endometriosis.