Effect of Salidroside on Pregnancy Outcomes in High Childbearing Age Patients in Viro Fertilization

With the continuous decline in China's birth rate and number of births in recent years, the population issue has become a long-term and strategic issue in China. In addition to the impact of the decrease in the number of women of childbearing age and the non-marriage, the increase in the incidence of reproductive disorders and the postponement of the age of marriage and childbearing are also important factors leading to the continuous decline in the number of births in China. Among them, ovarian aging is a key factor causing fertility difficulties in women. Therefore, it is of great significance to establish an effective ovarian aging prevention and treatment strategy to improve women's reproductive health and serve the national population strategy. Recently, studies have found that a variety of supplements can promote follicular genesis and improve oocyte quality. However, to date, there are no approved effective treatments for ovarian aging. Therefore, it is urgent to develop effective strategies for the prevention and treatment of ovarian aging. Salidroside is the most active ingredient of Rhodiola rosea in traditional Chinese medicine, and has the highest content in the root of Rhodiola rosea, which is also the main medicinal site. The main effects of salidroside in traditional Chinese medicine are to invigorate qi and blood, and to relieve asthma. At the same time, in basic research, more and more experiments have shown that salidroside has a variety of pharmacological properties, including anti-hypoxia, anti-fatigue and anti-aging effects, anti-cancer effects, anti-inflammatory effects, antioxidant effects, antiviral effects, etc. These pharmacological effects suggest that salidroside may be an effective drug for the prevention and treatment of atherosclerosis, Parkinson's disease, Alzheimer's disease, pneumonia and other diseases. In terms of aging, it has been confirmed that supplementation of salidroside can prolong the life of Pseudogill medaka and save the premature aging of human skin fibroblasts, which further confirms the anti-aging effect and potential application value of salidroside. In the process of clinical assisted reproduction, the proportion of elderly women has been increasing in recent years; Due to the significant decline of female ovarian function in middle age, the success rate of assisted reproduction in elderly women has always been at a low level. However, whether in animal model studies or in human tissue sections, it is generally believed that there are still a large number of follicles in the ovaries of middle-aged females or females that are sufficient to support reproductive activities, but because the physiological reasons for the decline of ovarian function in middle-aged women are unknown, the contradiction of abundant follicles but declining ovarian function in middle-aged women cannot be overcome.Recently, Zhang Hua's team in China used high-resolution ovarian organ imaging technology combined with genetically modified animal models, single-cell omics and drug screening to reveal that the ovaries have specific vascular degeneration in middle age, which leads to a decrease in ovarian blood supply, stunted follicle development, and ultimately a decline in fertility. Mechanistic studies have confirmed that ovarian vascular endothelial aging is the cause of ovarian vascular degeneration in middle age. Based on the above findings, through the screening of a large number of natural products, it was found that in vitro treatment of salidroside can improve the regeneration ability of follicular blood vessels without affecting the development of follicles. Continuous injection of salidroside in vivo can significantly improve the ability of ovarian angiogenesis in elderly mice, improve ovarian blood supply, and then promote follicle development, increase the quantity and quality of ovulation in advanced mice, and increase the number of births in elderly mice. The safety evaluation proved that salidroside treatment had no effect on the blood vessels of heart, kidney, liver and other organs, and long-term (12 months) monitoring showed that there was no abnormal organ development and tumor production in mice after salidroside treatment. Other teams, using different in vitro and in vivo models, have also found that salidroside supplementation can improve oocyte quality in mice or pigs. On the one hand, the addition of salidroside to oocytes cultured in vitro can improve the maturation, fertilization and development ability of oocytes of childbearing age by maintaining normal spindle/chromosome structure and mitochondrial function, including improving oocyte spindle/chromosome arrangement, mitochondrial and cortical particle distribution, mitochondrial membrane potential, and reducing reactive oxygen species. On the other hand, it can also improve the oocyte quality of reproductive elderly mice by enhancing mitophagy, including improving their oocyte genesis, maturation, fertilization and embryonic development potential. The above studies provide a solid theoretical basis for salidroside to improve the quality of female oocytes. In summary, salidroside can improve oocyte quality and fertility through a variety of mechanisms. However, current research is still limited to animal experiments, and in-depth clinical evidence is lacking. Therefore, it is necessary to further explore the effect of salidroside on ovarian function, promote the clinical transformation of basic research, and serve the national population strategy.

Inclusion criteria

• Age ≥35 and < 40 years old
• For the first or second cycle of IVF, ICSI or IVF with donor sperm
• According to the 2016 Poseton criteria for poor prognosis: the number of oocytes obtained in the previous routine ovulation induction protocol was 1-9, or AFC < 5 or AMH < 1.2ng/ml (measured within the past half year) in both ovaries.

Exclusion criteria

• Patients with coagulation disorders
• Patients with previous abnormal uterine bleeding
• Combined with hydrosalpinx confirmed by B-ultrasound and HSG
• Uterine malformation (unicornuate uterus, septate uterus) or history of intrauterine adhesions
• Patients with previous spontaneous abortion ≥3 times
• Patients with contraindications to assisted reproductive technology or pregnancy
• Previous or current oral medication containing salidroside
• The controlled ovarian stimulation protocol included PPOS protocol, luteal phase ovulation induction protocol, and continuous stimulation protocol