In this current randomized clinical trial, we set out to explore the potential impacts of Ziziphus jujuba on anthropometric parameters, biochemical factors, and pregnancy outcomes in infertile PCOS patients undergoing letrozole-induced ovulation. Furthermore, we undertook a comparative analysis involving Metformin and Myoinositol.
PCOS is a multifaceted condition characterized by diverse pathophysiological factors that contribute to the heterogeneity of its clinical manifestations. Among these factors, the overabundance of androgens is known to exert a direct and specific influence on the development of insulin resistance. While PCOS is undoubtedly multifactorial, the prominent roles played by insulin resistance and elevated androgen levels position them as major culprits in the etiology of the syndrome (28).
Obesity further compounds the PCOS phenotype, exacerbating issues such as infertility and impeding the effectiveness of fertility treatments (29). The intricate relationship between obesity and PCOS remains incompletely understood, but it undeniably constitutes a critical aspect of patient management, highlighting the urgent need to address weight loss in this context (30). Additionally, dyslipidemia is increasingly prevalent in women with PCOS, further complicating their clinical profile. Therefore, interventions capable of ameliorating these specific aspects of PCOS hold promise for improving the condition in infertile patients (31).
As the first line of treatment for PCOS, lifestyle modifications are crucial. Metformin and Myoinositol are considered secondary options. Metformin, a biguanide medication, operates by reducing hepatic glucose production and alleviating insulin resistance. Nevertheless, uncertainties surround its efficacy in improving clinical outcomes, with concerns about mild side effects (32). Moreover, its impact on birth outcomes, fasting glucose, serum lipids, and anthropometric parameters remains ambiguous (8).
Inositol, encompassing myo-inositol and di-chiro inositol, is a novel insulin-sensitizing agent that exhibits substantial efficiency in PCOS women. Acting as a second messenger, it plays a role in insulin signaling transduction. However, prior research has failed to identify significant effects on parameters such as BMI, triglycerides, fasting blood glucose, cholesterol, and ovulation when compared to a placebo (32). Moreover, concerns persist regarding the risk of hypoglycemia and suboptimal nutrient absorption, and it does not appear to influence pregnancy outcomes (8).
Ziziphus jujuba represents a promising natural source of nutraceutical and therapeutic agents (33). Recent investigations into the phytochemical and pharmacological properties of the jujube fruit have unveiled its diverse biological effects. These include impacts on anthropometric indices, immunomodulation, antioxidant activity, antitumor properties, hepatoprotection, hypoglycemic effects, gastrointestinal protection, anticancer potential, anti-inflammatory action, anti-hyperlipidemic influence, anti-hyperglycemic activity, neuroprotection, sedative properties, and antiviral function (20, 21, 34). Importantly, recent research has also shown that Ziziphus jujuba can decrease insulin resistance, lower triglyceride levels, and reduce fasting blood sugar, ultimately enhancing insulin sensitivity (21–23).
Numerous mechanisms have been postulated to elucidate the effects of Ziziphus jujuba on various health-related factors. Notably, the phenolic compounds present in Ziziphus jujuba, such as ferulic acid, catechin, and rutin, demonstrate the capacity to influence glucose metabolism. These compounds exert a hypoglycemic effect by inhibiting intestinal α-glycosidase activity, which, in turn, reduces glucose production in the liver and impacts glucose transporters. Furthermore, Ziziphus jujuba is theorized to play a pivotal role in regulating both glucose and lipid metabolism by activating the adiponectin signaling pathway. Adiponectin, in particular, exhibits a reverse correlation with glucose, triglyceride, very low-density lipoprotein (VLDL), and cholesterol levels, while demonstrating a positive association with high-density lipoprotein (HDL) cholesterol (22, 35, 36).
An alternative mechanism through which Ziziphus may enhance lipid and glucose metabolism involves the preferential use of glucose as an energy source over lipids. This is coupled with the promotion of enhanced acetyl CoA synthesis resulting from pyruvic acid, facilitating entry into the Krebs cycle rather than triglyceride biosynthesis. Consequently, the reduction in triglycerides induced by Ziziphus extract leads to a noteworthy decrease in VLDL levels. Given that VLDL contributes indirectly to the generation of low-density lipoprotein (LDL) particles, a significant reduction in VLDL levels is expected to correspond with lowered LDL levels. Given that plasma HDL concentration displays an inverse relationship with plasma triglyceride levels and Ziziphus has demonstrated its capacity to reduce triglyceride levels, we anticipate an increase in HDL levels following triglyceride reduction. Furthermore, the enhancement of glucose metabolism is likely to promote the conversion of proteins into anabolism, resulting in increased protein synthesis. Apo-A1, a major constituent of HDL structure, accounts for 70% of its composition. This suggests that the increase in HDL levels can be attributed to the transformation of proteins into anabolism, potentially influenced by Ziziphus (37).
Notably, Ziziphus boasts substantial quantities of pectin, inulin, and unsaturated fatty acids, which could underlie its hypocholesterolemic effects. Additionally, the high saponin content in Ziziphus may exert a positive influence on plasma lipid levels. Furthermore, the presence of phytosterols in Ziziphus may inhibit the intestinal absorption of cholesterol, consequently leading to a reduction in both total cholesterol and low-density lipoprotein cholesterol (22).
Furthermore, Ziziphus jujuba exhibits substantial potential in mitigating inflammation. This fruit is notably rich in vitamin C, which plays a pivotal role in averting the production of free radicals. Additionally, ascorbic acid bears a structural resemblance to glucose, thus acting as a deterrent against non-enzymatic glycosylation of proteins. Noteworthy studies have indicated that Ziziphus might offer protection against both acute and chronic inflammatory responses, conceivably through the inhibition of nitric oxide synthase (NOS). The efficacy of Ziziphus in mitigating oxidative stress can be ascribed to its substantial content of natural antioxidant components, including flavonoids, tannins, carotenes, polysaccharide fractions, as well as vitamins (38).
Consequently, Ziziphus emerges as a prudent and herbal pre-treatment option for individuals with polycystic ovarian syndrome (PCOS) who are undergoing induction ovulation. It is imperative to highlight that this study stands as a singular endeavor employing the hydroalcoholic extract of Ziziphus jujuba as a pre-treatment for infertile PCOS patients undergoing induction ovulation. Furthermore, it is crucial to underline the unique aspect of this study as it represents the first comparative investigation encompassing the outcomes of metformin, myoinositol, and Ziziphus extract in patients of this demographic concerning their pregnancy outcomes. This pioneering approach demonstrates the potential benefits and distinctive attributes of Ziziphus jujuba in the context of PCOS management, particularly in the realm of fertility treatments.
Strengths and Limitations:
Our study exhibits several strengths that enhance its credibility and relevance. First, our selection criteria encompass not only PCOS patients with obesity but all PCOS individuals across the BMI spectrum. This non-biased approach mitigates the influence of weight loss motivation, a factor that commonly skews results in previous research. Second, the extended duration and intensity of this clinical trial set it apart, allowing for a more comprehensive assessment of the interventions. Furthermore, our study boasts a larger sample size compared to similar investigations, enhancing the statistical power and reliability of our findings. Additionally, our research benefits from a multidisciplinary team comprising nutritionists, pharmacologists, gynecologists, and methodologists, collectively contributing to the robustness and precision of our study.
Moreover, a distinguishing feature of our research is the utilization of the hydroalcoholic extract of Ziziphus jujuba as the primary intervention. This choice is underpinned by the significant flavonoid concentration in this product, maximizing its potential impact on our patients.
Despite these strengths, our study is not devoid of limitations. Variability in the use of products within each group and variations in dietary regimens among participants may introduce potential confounders that could influence the results. Nevertheless, our patient population's strong commitment to treatment, coupled with the implementation of a multidisciplinary team and regular weekly follow-up calls, aims to minimize these risks, thereby bolstering the study's internal validity.
Trial status:
The commencement of this clinical trial is scheduled for November 2023, with the hypothesis that data collection will extend through November 2024.
Protocol version number:
1