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

Date Published: May 22, 2018

Publisher: Impact Journals

Author(s): Jinjin Zhang, Zhiwen Lai, Liangyan Shi, Yong Tian, Aiyue Luo, Zheyuan Xu, Xiangyi Ma, Shixuan Wang.

http://doi.org/10.18632/aging.101449

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.

Partial Text

More than 15% of couples will likely face infertility problems during their reproductive life, and by 2025, the number of women with this problem will be approximately seven million worldwide [1]. Superovulation procedures and assisted reproductive technologies (ART) have been widely used to treat couples who have infertility problems. Although generally safe, superovulation procedures can lead to serious complications, which include ovarian hyper-stimulation syndrome (OHSS), thromboembolism, and adnexal torsion [2]. In addition, a series of studies have suggested that repeated superovulation (RS) may influence the structure and function of the ovary. In mice, repeated ovarian stimulation can induce oxidative damage and mitochondrial DNA mutations in ovaries, increase the incidence of oocyte spindle defects, and decrease the quality of oocytes [3–5]. Clinical studies have found that ovulation induction cycles can impair the ovarian response and/or alter the quality of oocytes [6]. However, there is no consensus regarding the adverse effects of repeated ovulation stimulation. Some large-scale retrospective studies have shown that the number of oocytes retrieved over five repeated in vitro fertilization (IVF) cycles remained the same and that there was no difference in oocyte quality [7]. Therefore, although an increasing number of studies have focused on the effects of repeated ovulation on ovaries or oocytes, studies conducted to date have failed to reach a definitive conclusion as a result of numerous shortcomings, such as inconsistent drug exposure and use and relatively short follow-up periods [8]. Furthermore, ovarian damage often causes a decline in follicular quantity and quality, which is a complex process associated with ovarian aging. Changes in hormone production caused by ovarian aging may affect various health consequences including vasomotor symptoms, cardiovascular diseases (CVDs), osteoporosis, cognition, depression, mood disorders, sexual function, and vaginal atrophy [9]. Until now, few studies have focused on long-term effects of RS on health outcomes, specifically ovarian aging and aging-associated disorders such as osteoporosis and CVD in mouse models, which is of vital importance.

Ovarian stimulation with exogenous gonadotropins and ovulation induction using hCG could cause OHSS, which is a potentially life-threatening iatrogenic complication. The clinical manifestations of OHSS are ascites and edema [29]. Our data showed that the body weights of the RS group did not significantly increase, and no evidence of ascites or edema was shown. The ovarian weight and size of the RS mice increased, which may be due to the increased number of recruited follicles. An exhaustive swimming exercise was used to test physical strength, and we found that physical strength was markedly decreased in the repeatedly super-ovulated mice.

 

Source:

http://doi.org/10.18632/aging.101449

 

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