Trehalose Suppresses Lysosomal Anomalies in Supporting Cells of Oocytes and Maintains Female Fertility.

Supporting cells of oocytes, i.e., cumulus cells, control oocyte quality, which determines fertilization success. Therefore, the transformation of mature and immature cumulus cells (MCCs and ICCs, respectively) into dysmature cumulus cells (DCCs) with dead characteristics deteriorates oocyte quality. However, the molecular basis for this transformation remains unclear. Here, we explored the link between autophagic decline and cumulus transformation using cumulus cells from patients with infertility, female mice, and human granulosa cell-derived KGN cell lines. When human cumulus cells were labeled with LysoTracker probes, fluorescence corresponding to lysosomes was enhanced in DCCs compared to that in MCCs and ICCs. Similarly, treatment with the autophagy inhibitor chloroquine elevated LysoTracker fluorescence in both mouse cumulus cells and KGN cells, subsequently suppressing ovulation in female mice. Electron microscopy analysis revealed the proliferation of abnormal lysosomes in chloroquine-treated KGN cells. Conversely, the addition of an autophagy inducer, trehalose, suppressed chloroquine-driven problematic lysosomal anomalies and ameliorated ovulation problems. Our results suggest that autophagy maintains the healthy state of the supporting cells of human oocytes by suppressing the formation of lysosomes. Thus, our results provide insights into the therapeutic effects of trehalose on female fertility.

Glutathione S-transferase theta 1 expressed in granulosa cells as a biomarker for oocyte quality in age-related infertility.

OBJECTIVE: The goal of this study was to identify a reliable biomarker for age-related infertility. DESIGN: Laboratory study. SETTING: ART laboratory. PATIENT(S): Patients undergoing intracytoplasmic sperm injection or IVF cycles. INTERVENTION(S): Expression of Glutathione S-transferase (GST) mRNA and protein in mural and cumulus granulosa cells obtained from infertile patients were examined by reverse transcriptase-polymerase chain reaction and immunofluorescence. MAIN OUTCOME MEASURE(S): Correlation between the expression of GST theta 1 (GSTT1) in granulosa cells and oocyte quality was a main outcome measure. RESULT(S): Expression of GSTT1 in granulosa cells from male factor patients was positively correlated with age and negatively with cumulus-oocyte complex maturity. When samples with high and low GSTT1 in granulosa cells were extracted from the other infertility factors, cumulus-oocyte complex maturity in the high GSTT1 group was significantly lower than that in the low GSTT1 group (high: 27.2% vs. low: 51.3%). The developmental capacity of oocytes in the high GSTT1 group was likely to be lower (high: 26.4% vs. low: 43.9%). Up-regulation of GSTT1 during aging may be promoted by FSH and H(2)O(2), determined by an in vitro model. CONCLUSION(S): GSTT1 is a good indicator for age-related infertility.

Successful pregnancy, achieved by ovulation induction using a human menopausal gonadotropin low-dose step-up protocol in an infertile patient with Kallmann's syndrome.

A 25-year-old woman, diagnosed with Kallmann's syndrome and wanting to become pregnant, visited our hospital. Because her serum gonadotropin levels indicated hypogonadotropic hypogonadism, a main symptom of Kallmann's syndrome, we attempted to induce ovulation using a low-dose human menopausal gonadotropin (hMG) step-up protocol. In this protocol, 75 IU of hMG was used as an initial dose and this was continued for the first 14 days because adequate follicular development was not achieved. The dose of hMG was subsequently increased to 150 IU for the next 7 days. After 22 days from the start of stimulation, two follicles had developed, and were ovulated using an injection of human chorionic gonadotropin. She became pregnant, and her pregnancy was uneventful during the first trimester; however, in the second trimester both uterine contractions and blood pressure could not be controlled, and at 27 weeks' gestation she delivered a male infant weighing 830 g by cesarean section.