Repeated superovulation increases the risk of osteoporosis and cardiovascular diseases by accelerating ovarian aging in mice

Abstract

Superovulation procedures and assisted reproductive technologies have been widely used to treat couples who have infertility problems. Although generally safe, the superovulation procedures are associated with a series of complications, such as ovarian hyper-stimulation syndrome, thromboembolism, and adnexal torsion. The role of long-term repeated superovulation in ovarian aging and especially in associated disorders such as osteoporosis and cardiovascular diseases is still unclear. In this study, we sought to determine if repeated superovulation by ten cycles of treatment with pregnant mare serum gonadotropin/human chorionic gonadotropin could affect ovarian reserve, ovarian function, bone density and heart function. Ovarian reserve and function were reflected by the size of the primordial follicle pool, anti-Mullerian hormone expressions, hormone levels and fertility status. Furthermore, we examined bone density and heart function by microCT and cardiovascular ultrasonography, respectively. After repeated superovulation, the size of the primordial follicle pool and the expression of anti-mullerian hormone decreased, along with the concentrations of estrogen and progesterone. Mice exposed to repeated superovulation showed an obvious decrease in fertility and fecundity. Furthermore, both bone density and heart ejection fraction significantly decreased. These results suggest that repeated superovulation may increase the risk of osteoporosis and cardiovascular diseases by accelerating ovarian aging.

Macrophage‐derived extracellular vesicles regulate follicular activation and improve ovarian function in old mice by modulating local environment

“… 36 One recent study reported that mice exposed to repeated superovulation showed an obvious decrease in the primordial follicle pool and poor oocyte quality. 37 Another study reported ovulation suppression protected against egg aneuploidy in aged female mice. 38 Although the effects of repeated assisted reproduction techniques on ovarian response in humans remain controversial, 39 our findings suggest that the increased risk of repetitive ovarian stimulation on ovarian reserve should be considered in the clinic.…”

Cumulative probabilities of live birth across multiple complete IVF/ICSI cycles: a call for attention

“…It is important to mention that literature supports the notion that the "hazard" or the individual LB probability of each woman within a particular cohort does not remain constant over different treatment cycles. In fact, in mice, repeated superovulation cycles may induce over-expression and over-activation of proteins controlling cell cycle progression in fallopian tubes [22]; alter mitochondrial functions of cumulus cells [23], impair oocyte spindle [23]; and affect ovarian function and decrease the ovarian reserve, fertility, and fecundity [24]. In humans, repeated ovarian stimulation in oocyte donation cycles does not seem to have any adverse effect on number of oocytes collected, oocyte quality, fertilization, preimplantation embryo qualities, and embryo implantation in oocyte recipients [25].…”

The role of oxidative stress in ovarian aging: a review

“…Repeated ovulation promotion increased the number of abnormal mitochondria in mouse oocytes, reduced the volume of the primordial follicular pool, decreased serum AMH levels and significantly inhibited embryo development [ 137 ]. This process also significantly increases the risk of long-term complications such as osteoporosis and cardiovascular disease [ 138 ]. In contrast, oral contraceptives have been shown to alleviate age-related ovarian aging and fertility decline by suppressing ovulation [ 139 ].…”