Ovarian reserve reflects the reproductive potential and ART outcomes in women [30, 31]. DOR is frequently encountered during infertility treatment . However, no unified definition of DOR is available . AMH and age are considered to be the most valuable factors that affect ovarian response during IVF cycles. Therefore, all the patients engaged with the present study were aged less than 40, with a serum AMH level of < 0.5–1.1 ng/mL. Numerous solutions are available for promoting the ovarian response and increasing the pregnancy outcome among the patients receiving IVF . GH significantly increases the ovarian response among patients with POR who are about to receive IVF . Dehydroepiandrosterone (DHEA) supplementation improves the serum AMH level and increases the embryo score for patients with DOR . However, studies regarding ZYP efficacy in patients with DOR are rare. ZYP is considered gentle and safe.
In traditional Chinese medicine theory, the kidney stores the essence and is vital for reproduction; thus, the fundamental physiological processes of women have some connections with the kidney, and sufficient kidney essence is vital for a successful pregnancy. Under conventional Chinese medicine theory, POR belongs to the category of ʻinfertilityʼ, ʻhypomenorrheaʼ, ʻamenorrheaʼ, and ʻmenopausal syndromeʼ. Additionally, POR is considered to have a close relation with the spleen and deficiency of kidney energy . Therefore, improved physical conditions in the kidney and spleen can lead to improved POR. ZYP (ʻzishenʼ means ʻtonifying the kidneyʼ) comprises 15 herbs in combination with other natural substances, and such compound has been considered conducive for tonifying the kidney and invigorating the spleen. Thus, ZYP might have a positive effect on patients with DOR.
Research has verified ZYP’s effect on infertility and miscarriage treatment [37, 39]. However, only few studies have used ZYP to treat patients with POR. A randomised controlled trial investigated the mechanism of ZYP supplementation during POR treatment. Liang et al. reported that the use of ZYP and ear-point pressing with coxherb seeds for the treatment of patients with reduced ovarian reserve greatly reduced FSH, FSH/LH, and estradiol levels during menstruation compared with the artificial cycle group. Additionally, both life quality (traditional Chinese medicine syndrome scores) and clinical pregnancy rate rose considerably (P < 0.05) . Another randomised controlled trial by Liu et al. reported that co-treatment using ZYP during controlled ovarian stimulation cycles might promote estradiol levels, clinical pregnancy, and implantation rates, whereas they observed no significant difference between the experimental and control groups concerning freeze-thaw embryo transfer of clinical pregnancy and implantation rates .
All transplanted embryos in present study were high quality embryos (cleavage embryos or a blastocyst), so pregnancy outcomes including clinical pregnancy rate, implantation rate and live birth rate between two groups were similar. However, the number of gathered oocytes and transferred embryos was greater among patients receiving IVF cycles along with ZYP treatment than those directly undergoing IVF cycles. And the expression of BMP-15 and GDF-9 in the ZYP treatment group were significantly higher than those in the control group.Thus, a combination of ZYP and Gn treatment is capable of improving the ovarian response to superovulation drugs in ART and also in DOR populations. Most importantly, Zishen Yutai Pills significantly increased the number of oocytes and high-quality embryos produced by patients. Therefore, ZYP is beneficial to follicle development. This finding is concurrent with those of several animal studies, which suggest that ZYP can increase the blood supply to the gonads and sexual organs of rabbits . Kidney jing plays a crucial role in female reproduction. Several preliminary reports have suggested the efficacy of kidney-tonifying medicines in improvement of reproductive function. Li et al. verified the role of a kidney-tonifying medicine in increasing the number of ovarian follicles in the mouse model, which is in agreement with our experimental results . Some studies have suggested that spleen-strengthening and kidney-reinforcing traditional Chinese medicines can slow down DOR progression and improve the ovarian reserve . Hu et al. reported that kidney-tonifying medicines can recover oestrogen receptor expression in menopause . Therefore, this medicine could be used as a therapy as a substitute of hormonal treatment.
Studies have reported the antioxidant potential of ZYP in removing free radicals . However, the detailed molecular mechanisms through which ZYP effects the oocytes, cumulus cells, and granulosa cells are unknown. This is due to the oocyte-secreting factor that controls ovarian function during female reproduction. It not only modulates fate for somatic granulosa cells but also improves the quality and developmental competence for eggs. BMP15 and GDF9 are oocyte-secreted factors that play a leading role in controlling ovarian function in female reproduction, regulating the apoptosis of somatic granulosa cells and the quality and developmental competence of the oocyte. BMP15 and GDF9 can also enhance the effect of FSH aon GCs and provide more E2 for oocyte[47, 48]. Super-GDP9 is able to improve the rate of blastocysts in vitro maturation (IVM). The expression of the BMP15 and GDF9 genes was declined among patients with DOR[50, 51].The decline expression BMP15 and GDF9 may lead to abnormal folliculogenesis and poor oocyte quality.Gong et al also proved that such decline was associated with increased age,especially for those over 40. BMP15 and GDF9 may provide more earlier biomarkers for fertility in DOR. In this study, ZYP could improve the expression of BMP15 and GDP9, and also increased the number of blastocysts. Therefore, ZYP improves the quality both oocyte and embryo by increasing the expression of BMP15 and GDF9.However, the underlying molecular mechanism of ZYP actions in oocyte demands further research.
The present study has certain limitations. The sample was from single center, and most patients belonged to the same geographical area, which may have affected the results. More interventional trials are warranted to verify ZYP-related clinical relevance in promoting reproductive outcomes of the subpopulations. Additionally, the study on the security of the long-terms outcomes of ZYP on both mother and child was overlooked.
In conclusion, we determined the major effects of ZYP on recruiting dominant follicles from associated cohorts, leading to high-quality blastocysts by upregulating the expression of BMP15 and GDF9. Therefore, the administration of ZYP in an IVF cycle could considerably intensify the ovarian response in patients with DOR.