The effect of DHEA on apoptosis and cohesin levels in oocytes in aged mice.

Female fertility declines with age as the number of ovarian follicles decreases and aneuploidy increases. Degradation of the cohesin complex might be responsible for age-related aneuploidy. Dehydroepiandrosterone (DHEA) can improve the ovarian reserve and reduce the rate of aneuploidy, but the relationship between DHEA and cohesin levels in oocytes is still unknown. The aim of the current study was to evaluate the effect of the supplement DHEA on ovarian function, including the number of follicles and cohesin levels in oocytes. C57BL/6J mice at 3 weeks, 6 weeks, 12 weeks, 6 months, and 10 months of age were used to obtain a systematic view into follicle apoptosis and cohesin levels in oocytes. Nine-month-old C57BL/6J mice were administered saline (n = 5), 17ß-estradiol (100 µg/kg per day, n = 5), or DHEA (5mg/Kg per day, n = 5). After 4 weeks, aged mice were weighed and sacrificed, and ovarian tissue samples were prepared. Anti-VASA staining and HE staining were used to count the number of follicles. Anti-γH2AX staining and TUNEL were used to measure follicle apoptosis and immunofluorescent staining was used to detect the levels of three oocyte cohesin subunits: REC8, SMC1ß, and SMC3. Administration of the supplements 17ß-estradiol and DHEA to aged mice increased the number of primordial and primary follicles and decreased the age-related apoptosis of follicles. Levels of the cohesin subunits REC8 and SMC1ß declined with age, but DHEA and 17ß-estradiol tended to delay that decline. The supplement DHEA increased the number of primordial and primary follicles in aged mice by inhibiting follicle apoptosis and tended to delay the decrease in cohesin levels in oocytes.

Exposure Duration-Dependent Ovarian Recovery in Methoxychlor-Treated Mice.

The pesticide methoxychlor (MXC) is known to target ovarian antral follicles in the mouse. In previous in vivo studies, MXC administration for 20 days increased atresia, but did not affect female fertility immediately after dosing. Thus, we hypothesized that perhaps not enough time had elapsed between the onset of MXC-induced atresia and actual follicle loss to result in reduced fertility. The current study was undertaken to determine whether MXC treatment for 20 days results in reduced antral follicle numbers and fertility at 30 and 60 days after dosing. To test this hypothesis, adult CD-1 female mice were dosed with vehicle control or MXC (64 mg/kg/day) for 20 days. At 30 and 60 days postdosing, the mice were either subjected to fertility tests or their ovaries were collected and subjected to histological evaluation of follicle numbers and atresia. The results indicate that at 30 days after the completion of dosing, MXC significantly increased atresia and reduced primordial and total follicle numbers, but did not affect fertility compared to controls. At 60 days after completion of dosing, MXC did not significantly affect fertility, follicle numbers, or atresia compared to controls. Collectively, these data indicate that the ovary may be able to recover from MXC treatment for 20 days.

Effect of duration of dosing on onset of ovarian failure in a chemical-induced mouse model of perimenopause.

OBJECTIVE: Repeated daily dosing with 4-vinylcyclohexene diepoxide (VCD) causes gradual ovarian failure in mice. As a result, the animal undergoes ovarian failure, but retains residual ovarian tissue. The purpose of this study was to use a mouse model to regulate the induction of a period analogous to perimenopause in women. DESIGN: Female B6C3F1 mice (28 days old; n = 8) were dosed daily for 10 or 20 days with VCD (160 mg/kg/d) or sesame oil. The animals were evaluated for reproductive function on days 10, 20, 35 after the onset of dosing, and on the day of follicle depletion. Each animal was killed at the specified time points, and ovaries, uteri, and plasma were collected. RESULTS: VCD reduced (P < 0.05) the number of primordial (by 93.2%) and primary (by 85.1%) follicles after 10 days of dosing, whereas essentially all primordial and primary follicles were lost (P < 0.05) after 20 days of dosing. The average time to ovarian failure was on day 135 for 10-day-dosed mice and on day 52 for 20-day-dosed mice. Follicle-depleted mice in both groups had decreased (P < 0.05) ovarian and uterine weights. Circulating follicle-stimulating hormone levels were increased (P < 0.05) on day 44 after the onset of dosing in 10-day-dosed mice and on day 35 in 20-day-dosed mice. CONCLUSION: These results demonstrate that ovarian failure can be caused by VCD more rapidly if repeated daily dosing occurs for a longer period. Thus, the length of time leading up to ovarian failure (model for perimenopause) can be adjusted by varying the length of exposure.

[Role of IGF system in the ovary]. / Rôle du système IGF dans l'ovaire.

The stimulating effect of Insulin-like Growth Factors (IGFs) on ovarian folliculogenesis is modulated by binding proteins (IGFBPs). During follicular growth, levels of IGFBP-2, -4 and -5 decrease in follicular fluid. These changes are a consequence of a decrease in synthesis and of a degradation by gonadotropin-stimulated specific proteases. They lead to an increase in the bioavailability of IGFs and their action on granulosa cells. By contrast, follicular atresia is characterized by a high increase in the synthesis and levels of IGFBPs < 40kDa, and by a dramatic decrease in IGFs bioavailability. Finally, at least part of intrafollicular IGFs and IGFBP-3 may be derived from the circulatory pool. Their levels only change slightly during follicular growth and atresia.