Abstract
Polycystic ovary syndrome (PCOS) is one of the most important gynecological disorders of women in the age of reproduction. Different hormonal and inflammatory cross-talks may play in the appearance of its eventual complications as a leading cause of infertility. Excessive production of reactive oxygen species over the power of the antioxidant system as oxidative stress is known to contribute to a variety of diseases like PCOS. Thus, the utilization of antioxidants can be efficient in preventing or assistant in treating these diseases. In this review, we describe the clinical trial studies that have examined the efficiency of antioxidant strategies against PCOS and the possible underlying mechanisms. The investigations presented here lead us to consider that targeting oxidative stress pathways is probably a powerful promising therapeutic approach towards PCOS. There is preparatory evidence of the effectiveness of antioxidant interventions in ameliorating some of the PCOS complications, including metabolic and hormonal disorders. Due to limited data and relatively few clinical trials, many of these interventions need further investigation before they can be considered effective agents for routine clinical use.
Keywords: Polycystic ovary syndrome, Hyperandrogenism, Reactive oxygen species, Oxidative stress, Antioxidant
Introduction
Hormonal and inflammatory mechanisms are involved in different female reproductive events such as ovulation, menstruation, embryo implantation, and pregnancy. Evidence denotes that hormonal defects and hyper-inflammatory states may deregulate the cross-talks between endometrium, myometrium, and cervix, also between decidua and trophoblast, leading to pregnancy abnormalities. PCOS is one of the most common and complex endocrine disorders in women of reproductive age, having a negative impact on their health by its important influences on many tissues and organs during their life span [1, 2].
PCOS, characterized by a failure in ovulation, hyperandrogenism (HA), and polycystic ovary, is a syndrome with a high heterogenicity and may be related to a wide range of endocrine and metabolic malfunctions, including hyperinsulinemia, hyperglycemia, and dyslipidemia, which also are considered as symptoms of a metabolic syndrome (MS) [3, 4]. The PCOS phenotypes are usually associated with disturbances in glucose and lipid metabolisms; thus, the prevalence of obesity, type 2 diabetes [T2D], depression, and cardiovascular diseases is higher in these patients, and also hyper-inflammatory state associated with an increased level of C-reactive protein (CRP) and oxidative stress (OS) is commonly observed in PCOS cases [5, 6]. Recent classification of PCOS based on the Rotterdam-wide criteria and syndrome heterogeneity has identified 4 different phenotypes (Table 1). Phenotypes-A (HA/OD/PCOM) and B (HA/OD) are often termed as “classic PCOS”. Women with classic PCOS seem to be more obese and hirsute, show a more irregular menstrual pattern, and are more likely to have IR, dyslipidemia, and increased risk of metabolic syndrome (MS). Phenotype-C (HA + PCOM, without OD) are so-called ovulatory PCOS. In phenotype-C patients, lipid and androgen levels, risk of MS, and hirsutism scores are between classic PCOS and phenotype-D. Phenotype-D (OD + PCOM, without HA) are so-called non-hyperandrogenic PCOS. These patients have normal androgen levels and the mildest degrees of endocrine dysfunctions such as IR and the lowest incidence of MS [7–9].
Table 1.
PCOS phenotypes [10]
Phenotype A | Phenotype B | Phenotype C | Phenotype D | |
---|---|---|---|---|
Clinical and/or biological HA | + | + | + | - |
Oligo/anovulation | + | + | - | + |
PCOM | + | - | + | + |
Related IR and/or MS | + + + | + + | + + | ± |
HA hyperandrogenism; PCOM polycystic ovary morphology; IR insulin resistance; MS metabolic syndrome.
According to this classification, phenotypes with HA may have higher metabolic risks and lower fertility outcomes [10].
Hyperandrogenism seen in PCOS is associated with lack of follicular development and hence a reduced chance of ovulation. This in turn leads to menstrual irregularities and infertility. In pregnancy, complications such a miscarriage, still-birth, pregnancy-induced hypertension, and gestational diabetes have been more commonly reported with PCOS [10–12].
Although the etiology of PCOS is not still fully clarified, PCOS is believed to be a multi-factorial disorder that can be caused by the interaction of different contributors including genetic and environmental factors and lifestyle in the appearance of the eventual phenotype. It seems that hyperandrogenism, hyperinsulinemia, and the increased level of oxidative stress can play important roles in the expression of the PCOS-related genes and amplification of the clinical symptoms. Considering the fact that several PCOS demonstrations such as a higher level of androgen, obesity, hyperlipidemia, insulin resistance, chronic inflammation, and defects in the antioxidant defense system of the body, that are common in PCOS, probably play pivotal roles in the development and progression of local and systemic oxidative stress and, in return, oxidative stress can worsen these metabolic abnormalities [1, 10, 13, 14], in this review, the role of oxidative stress in PCOS and the antioxidant agents used in the improvement of its symptoms have been concerned. We focused on clinical trial studies.
Oxidative stress
Oxygen is one of the essential elements for aerobic life, and oxidative metabolism is also the main source of energy. The reactive oxygen species (ROS) are produced during the natural oxygen metabolism as side products of the oxidative metabolism. It is necessary for the body to produce a particular amount of ROS for its physiological functions, including cell signaling, gene expression, and redox hemostasis. But, increasing the level of excessive ROS is deleterious for the body and damages the cells by receiving electrons from nucleoid acids, proteins, lipids, carbohydrates, or around molecules [15–17].
There are numerous defensive mechanisms in cells that neutralize the damaging effects of ROS. One of the important of these mechanisms is the antioxidant system. Antioxidants are molecules that decrease the damaging effects of free radicals by removing or scavenging them. In normal conditions, there are two kinds of antioxidants in the body: (1) enzymatic antioxidants, such as superoxide dismutase (SOD), catalase (CAT), glutathione reductase, and glutathione peroxidase, and (2) non-enzymatic antioxidants, such as glutathione (GSH) and vitamin E (a-tocopherol) that is the most important soluble antioxidant in all cell membranes and prevents the cells from lipid peroxidation, ascorbate, and β-carotene [16, 18, 19].
The intricate balance between ROS production and its scavenging by the antioxidant system is a key factor required for almost every metabolic function in mammals. When this balance is disrupted due to the production of excessive ROS over the power of the antioxidant system or a failure in this system, it causes an oxidative stress state. Therefore, the accumulated ROS in vivo can induce damages to the lipids and DNA of the cell. Various physiological processes can be affected by the OS, leading to negative effects on or even pathological situations in different systems of the body such as the reproductive system [16, 17, 20].
Several studies demonstrate that the pathological outcomes of the OS induction are involved in the development of many female reproductive diseases, including the PCOS, endometriosis, unexplained infertility, perturbation in oocyte quality, dysregulation of ovulation, and a decrease in the number of oocytes, as well as in the pregnancy complications, including recurrent miscarriage, pre-eclampsia, and IUGR (intrauterine growth restriction) [16, 17, 21].
Although there are over 100, 000 papers about the OS and reproduction, only a few of them (800) have discussed the relationship between the OS and the diseases related to the uterus and ovary. Since PCOS has high influences on female reproduction, it has attracted more attention in recent years [16].
OS and PCOS
Although an adequate level of ROS in the ovary plays an important role in signal transduction of folliculogenesis processes, maturation of oocyte and corpus luteum, and fetoplacental development, several studies have verified the association of the OS and PCOS that lead to the most prevalent endocrine disorder in the reproductive age [6]. According to a meta-analysis conducted by Murri et al., it has been clarified that circulating OS markers in women with the PCOS are not normal, indicating that OS may enroll in the pathophysiology of PCOS and its metabolic communications. Numerous features of PCOS, including an increase in androgens, abdominal obesity, insulin resistance, and an increase in inflammatory factors, may be involved in the development and progression of OS, which can, in return, promote these metabolic characteristics [22].
Although there is a wide variability in the estimates of obesity in women with PCOS across different countries and ethnicities, these women represent a high prevalence of overweight and obesity compared to healthy women with a typical central distribution of adipose tissue (up to 61%). Just as abdominal obesity, obesity is directly associated with OS and contributes to the increased levels of the OS in the PCOS patients. Obese patients are expected to have more serious OS levels, so that significant correlations between the OS markers and the obesity indexes have been discovered [4, 23].
The OS interferes with the glucose uptake from adipose and muscle tissues and decreases the insulin secretion from the pancreatic β-cell. On the other hand, ROS can play a critical role in the microvascular complications induced by hyperglycemia and endothelial failures in conditions with insulin resistance (IR) [22, 24]. IR, which is common in the PCOS patients, leads to a compensatory increase in insulin, which, through its own receptor or the IGF1 receptor, intensifies the stimulation of androgen production by the LH. IR has been regarded as one of the central mechanisms of PCOS, and its markers such as HOMA-IR (homeostatic model assessment of insulin resistance) significantly increase in women with the PCOS compared to healthy women, indicating a significant correlation with the increase in the OS markers. IR amplifies the OS because hyperglycemia and high level of free fatty acids augment the ROS production [4] (Fig. 1).
Fig. 1.
Relationship between oxidative stress and PCOS complications
Also, it has been demonstrated that PCOS patients are under the OS conditions and the level of this stress (OS) is high in infertile patients and patients with insulin resistance. On the other hand, several studies revealed that the level of antioxidants in the follicular fluid is also associated with successful fertilization [21]. Although the role of OS in the pathogenesis of PCOS is not still comprehensively understood, according to the results, it seems that OS is involved in the incidence of PCOS by changing the ovarian steroidogenesis that subsequently plays an important role in increasing androgens and interferes with the development of follicle and infertility [15]. Moreover, a decrease in the consumption of mitochondrial O2 and the glutathione (GSH) levels associated with fertilization has been reported in some studies, implying the mitochondrial dysfunctions in PCOS patients [16].
Treatment of PCOS
Treatment of PCOS is necessary not only for decreasing its clinical symptoms but also for preventing the incidence of long-term complications induced by this disease. The general goals for treatment of women with PCOS include the depletion of hyperandrogenic symptoms, oligo-/an ovulation, management of metabolic disorders, decreasing the risk factors related to type 2 diabetes and cardiovascular diseases, prevention of endometrial hyperplasia, programming and obtaining a safe pregnancy, and improvement of general good health and quality of life [25].
An important point that should be considered is that therapeutic strategies for PCOS are often highly complicated and there is no available universal specific treatment due to its multi-factorial pathogenesis and heterogeneity. Thus, clinicians should utilize the individualized treatment in accordance to the real requirements for an individual patient by considering the phenotypes and clinical symptoms closely. Hence, a multi-disciplinary approach accompanied by improving the lifestyle is regarded as the first line of treatment and management of this endocrinopathy [26–28].
In obese and overweight patients, losing weight by the utilizing a suitable diet and having physical activities results in the depletion of androgen and serum insulin and decreases the risk of developing glucose intolerance and type 2 diabetes [25]. Generally, clinical symptoms for hyperandrogenemia and menstrual irregularity are improved by antiandrogens and combined oral contraception pills (COCP) [28, 29]. Unfortunately, consumption of contraceptive pills is not a suitable treatment for women who tend to conceive, and also, the COCs do not specifically target at metabolic disorders in PCOS patients. Besides, consumption of the oral contraception pills (OCPs) for a long time can be associated with their side effects such as arterial thrombosis and increasing obesity, subsequently leading to an increase in the risks of hyperandrogenism, IR, and cardiovascular diseases [27].
In the case of a tendency for fertility, treatment of infertility in these people is conducted by correcting of their lifestyle and induction of ovulation using clomiphene citrate (CC), letrozole, and gonadotropins. Although induction of ovulation is usually successful, the pregnancy rate is unexplainably low, and about 30% of the obese women with PCOS cannot respond to the treatment with clomiphene. In other words, they have drug resistance, and so assisted reproductive techniques (ART) are recommended for these cases [28].
The most commonly used drug for metabolic control in PCOS patients is metformin. The therapeutic effects of metformin, an agent that increases insulin sensitivity and reduces the glucose level, have been well-demonstrated in women with PCOS. But, in contrary to the public belief, there is not any convincing evidence that shows the role of metformin in decreasing the BMI, waist circumference, and triglyceride level in these patients [27]. On the other hand, the consumption of metformin is associated with a high incidence of the side effects, including gastrointestinal disturbances, vomiting, and nausea that potentially worsen the quality of life in these women and can lead to stopping the drug consumption. Therefore, the current drug treatment has been restricted due to the contraindications in women with PCOS, low efficiency, the prevalence of the side effects and their related infertility, and patients’ preferences for alternative items [29, 30]. Nowadays, a large number of PCOS patients’ attention has been attracted towards the complementary medicines (CM) and newer adjunctive agents for the improvement of fertility and health because of their knowledge about the possible side effects of the pharmaceutical methods and the lack of satisfaction with the drug management [27, 30, 31].
In an investigation on women with PCOS, 99% of these patients expressed that they were tended to receive alternatives for replacing birth control pills and fertility drugs and even it has been identified that 70% of these women used adjunct agents, such as complementary drugs and herbal medicines. Since the level of oxidative stress in the women with PCOS is higher than its level in normal people, antioxidants, such as vitamin E, are among the CM options for improving the PCOS complications, which have attracted more attention from numerous researchers in recent years [27, 30–32].
The most common antioxidants used in PCOS treatment
Vitamin E
Vitamin E, also known as α-tocopherol, is an exogenous molecule soluble in lipid that was first discovered by Evans and Bishop (1922). Several studies have demonstrated that vitamin E has a high capability for ROS scavenging in cell membranes, pointing out that it is a powerful non-enzymatic antioxidant. It seems that vitamin E acts as a direct free radical scavenger through activation of the intracellular antioxidant enzymes and preserving cell membranes from lipid peroxidation [33–35]. The role of vitamin E as a peroxyl scavenger has been also fully validated in the treatment of cancer progression, infertility, and high-risk pregnancies. Vitamin E has great importance during the whole process of reproduction, and in order to maintain the membrane integrity, modulating the normal physiological function of the reproductive system, this molecule is able to attenuate the oxidative stress induced by oxygen free radicals and disturbances in antioxidant balance via inhibiting the activation of phospholipase A and lipoxygenase [36].
Probably, the antioxidant property of vitamin E can also decrease the reaction of aging-related oxidative stress that can have deleterious effects on the number and quality of ovules. On the other hand, vitamin E deficiency can be associated with female infertility, IUGR, abortion, preterm delivery, and other pregnancy-related disorders, and even abnormal quality of semen [37, 38]. In contrary to the possible effects of this vitamin on the physiology of the reproductive system, there is no evident data to confirm that only the consumption of vitamin E as an adjuvant can be effective in the treatment of PCOS patients. In most related studies, the impact of vitamin E has been evaluated in combination with other agents.
More recently, by conducting a prospective cohort clinical trial study, Chen et al. has assessed the effects of short-term consumption of vitamin E (100 mg/day) in 321 PCOS patients who were candidates for IVF and were divided into 3 experimental groups (group A did not receive vitamin E, and groups B and C received vitamin E in follicular and luteal phases, respectively). Although no significant differences were observed in the ovulation rate, clinical pregnancy rates, and ongoing live pregnancy rates, the required HMG dose was reduced, and the thickness of endometrium and estradiol level was increased before the day of the HMG injection in group B compared to the two other groups. The antioxidant status was improved in group B as well. Moreover, no significant difference in the ovulation rate was observed between the obese and non-obese individuals in each group [36]. It should be noted that in this study, obesity was surveyed without considering other important phenotypes, including hyperinsulinemia and HA. It is necessary to consider this point when designing PCOS trials.
In an effort by Fatemi et al., vitamins E (400 mg/day) and D3 (50,000 IU/week) were administered for the intracytoplasmic sperm injection (ICSI) in PCOS candidates, starting from 2 weeks before the COCP. They found that the pregnancy, clinical pregnancy, and implantation rates in the treatment group were higher than in the placebo group, whereas malondialdehyde (MDA) and total antioxidant capacity (TAC) levels in serum and follicular fluid were not associated with the ICSI results, suggesting that there was no significant relationship between the use of vitamins E and D3 and the success rate of the IVF through antioxidant mechanism [39].
Another study investigated the effects of vitamin E and magnesium (Mg) co-supplementation on the metabolic status of PCOS patients. In this study, the people in the treatment group received vitamin E (400 mg/day) and Mg oxide (250 mg/day) for 12 weeks. The co-supplementation resulted in a significant decrease in hirsutism and serum hs-CRP (high sensitivity CRP) and an increase in serum NO and TAC, without affecting the serum level of testosterone, sex hormone-binding globulin (SHBG), GSH, and MDA. Meanwhile, co-supplementation of vitamin E (400 IU) and fatty acid omega 3 in women with PCOS for 12 weeks was significantly related to the improved insulin resistance index, free and total testosterone levels, decreased LP(a) (lipoprotein A) and ox-LDL expression and improved lipid profile and oxidative stress markers [40]. In other studies, the influence of co-supplementation of vitamin E and Q10 has been evaluated and discussed in the following.
Co-enzyme Q
Co-enzyme Q (Q10), also known as ubiquinone, is a lipid-soluble benzoquinone, which is structurally similar to vitamin K, has 10 isopern units in its side chain, and exists in most aerobic organisms, from bacteria to mammals. The most important dietary sources containing Q10 are oily fishes (e.g., salmon and tuna), organ meat, and all grains [41]. Q10 is a key element in electron transport chain of the redox reactions involved in the ATP synthesis. Thus, this co-enzyme is found in all cellular membranes, especially in mitochondria. Q10 is highly concentrated in the body organs with elevated metabolic activity such as the heart, lung, liver, kidney, spleen, and pancreas. In addition to its involvement in mitochondrial bioenergetic events, co-enzyme Q is an intracellular lipid antioxidant that protects mitochondrial phospholipids and proteins from oxidative damages through avoiding production of free radicals. Furthermore, recent data have shown that Q10 in human affects the genes involved in cell signaling, transport, and metabolism and its critical role as an antiapoptotic factor has been fully established [42, 43]. Ubiquinone is also able to re-constitute vitamin E from its oxidized form. It seems that this interaction with vitamin E is of great importance in protecting low-density lipoproteins and other lipoproteins from oxidative damages. Q10, by itself and in combination with Vitamin E, acts as a very powerful antioxidant. This dietary supplement has been widely used for treatment of abnormalities like cardiovascular diseases, cholesterolemia, diabetes, and several female disorders and improvement of immune system in HIV patients and also as an anticancer agent against breast cancer [41, 42, 44]. Since the oocyte has the highest number of mitochondria per cell (about 2 × 105 copy), the functional status of mitochondria impacts the quality of oocytes and has a pivotal role in fertilization process and embryonic development. Therefore, a deficiency in mitochondrial Q10 of the oocyte can result in the production of a poor embryo. Moreover, given the fact that the apoptosis is the main mechanism involved in atresia of the follicular cohort, Q10 as an antiapoptotic factor can play a role in the follicular survival [45, 46].
In a clinical trial study performed by El Refaeey et al., it was demonstrated that the combined Q10/clomiphene therapy significantly leads to an increase in the rate of ovulation and clinical pregnancy in PCOS patients who are resistant to clomiphene, and the thickness of endometrium in Q10-receiving patients dramatically increased, which is more likely related to the elevated concentration of estradiol and better ovulation results [44]. In another work, Samimi et al. have treated 60 PCOS patients by the use of Q10 (100 mg/day). After a 12-week intervention, they observed that supplementation of Q10 had a positive effect on the glucose metabolism, serum total cholesterol, and LDL; however, no effect was observed in other lipid profiles [47].
Studies have shown that Ox-LDL and Lp(a) are the risk factors of atherosclerotic diseases. Rahmani et al. found that taking CoQ10 (100 mg/day) for 12 weeks by subjects with PCOS down-regulated Ox-LDL receptor 1 (LDLR1) expression, but did not affect Lp(a) expression. Also this research showed that CoQ10 supplementation up-regulated PPAR-c expression, but had no effect on glucose transporter 1 (GLUT-1) expression. Peroxisome proliferator-activated receptor-C (PPAR-c) is primarily present in adipocytes and plays an important role in glucose and insulin metabolisms. In addition, they found that taking CoQ10 down-regulated gene expression of interleukin-1 (IL-1), IL-8, and tumor necrosis factor (TNF-a) compared to the placebo, it did not affect gene expression of Transforming growth factor-beta (TGF.β). As increased inflammatory cytokines would result in the development of insulin resistance via the inhibition of insulin signaling, and inflammation in the PCOS patients would expose them to an increased risk for the development of atherosclerosis and infertility, CoQ10 can be effective in preventing the PCOS complications [48].
Moreover, Izadi et al. showed that taking vitamin E (400 IU/day) and Q10 (200 mg/day), separately or in combination with each other, for 8 weeks had a beneficial effect on serum insulin and fasting blood sugar (FBS) levels and HOMA-IR and also decreased total testosterone in PCOS patients; however, the changes observed in the glucose homeostasis parameters after vitamin E supplementation did not reach any statistical significance. This study also showed a decrease in luteinizing hormone (LH) levels in the patients who received supplements as compared with the placebo group, whereas the follicle-stimulating hormone (FSH) levels did not change significantly and the concentration of SHBG was improved only under the co-supplementation treatment [49]. Also, lipid profiling of the PCOS patients under vitamin E/Q10 treatment has revealed that consumption of vitamin E (400 IU/day) and Q10 (200 mg/day) or co-supplementation of these two antioxidants for 8 weeks decreased serum triglyceride in these patients significantly, particularly in the women who received the both supplements. But a significant improvement in LDL-C and HDL–C and a significant depletion in total cholesterol were only observed in the combined vitamin E-Q10 treatment group. In other words, these two supplements can have beneficial effects on cardiometabolic outcomes in women with PCOS [50].
In general, these investigations provide evidence that administration of Q10 and vitamin E or co-supplementation of these antioxidants improve the quality of oocyte and metabolic and endocrinal characteristics of PCOS patients, but little is known about these impacts. Thus, further attempts are needed to clarify this issue.
Vitamin D
Vitamin D (also referred to as “calciferol”) is a pleiotropic steroid hormone, and a multi-functional micronutrition is involved in many intracellular genomic activities through biochemical and enzymatic reactions. Physiological concentrations of vitamin D are essential for overcoming the inflammatory response, minimizing the oxidative stress, modulating the plasma levels of calcium and phosphate, vessel dilation, neuro-transmission, and secretion of hormones [51–53]. Wismane showed for the first time in 1993 that vitamin D is an antioxidant that can prevent iron-dependent lipid peroxidation in the cell membranes [54]. Also, the existing data suggest that just as vitamin E, this vitamin can decrease lipid peroxidation and induce ROS-scavenging enzymes such as SOD [55]. Vitamin D and its cognate receptor (VDR) modulate calcium and ROS-dependent signaling pathways particularly. Moreover, it has been shown that vitamin D exerts its antioxidative activity via deregulation of Nox2, the main isoform of NADPH oxidase, and up-regulation of nuclear related factor 2 (NRF-2), the major inducer of antioxidative response. Thus, the deficiency of vitamin D can result in abnormal changes in these pathways and trigger oxidative stress-related pathological circumstances. However, the oxidative stress related to hypovitaminose D is commonly observed in women with PCOS. Also, a decrease in vitamin D level can be associated with metabolic disorders in this syndrome such as hyper-insulinemia and interference with glucose tolerance [53, 55, 56]. Hence, the effects of this supplement attract many researchers’ attention.
Recently, Jamilian et al. have observed that the high dose of vitamin D (4000 IU/day) compared to its low dose (1000 IU/day) and the placebo in PCOS patients has positive effects on total testosterone, SHBG, hs-CRP, and TAC, without changing NO, GSH, and MDA levels [57]. In another work by this research group, co-supplementation of vitamin D (50,000 IU every 2 weeks) and Omega 3 (2000 mg/day) increased TAC level and decreased inflammation and symptoms of stress and depression in women with PCOS. Also, this co-supplementation to some extent elevated the expression of vascular endothelial growth factor (VEGF), providing the oxygen supply and amplifying the immune system in these women [58]. Additionally, it has been shown that co-supplementation of vitamin D (50,000 IU every 2 weeks) and probiotics (8 × 109 CFU/day) for 12 weeks in PCOS patients is helpful in the improvement of their mental health, total testosterone, hirsutism, hs-CRP, and parameters of oxidative stress, including TAC, GSH, and serum MDA; however, no change in SHGB and serum NO and acne and alopecia have been observed in the women under this treatment [59].
TGF.β is a key factor that modulates angiogenesis, proliferation of fibroblast cells, and fibrosis of tissues. The ovary of PCOS women also exhibited all the characteristics of over-activity of TGF.β, including high-vascularization and increased deposition of collagen in the stroma of this organ. Interestingly, administration of vitamin D (50,000 Iu/week) for 8 weeks in PCOS women with vitamin D deficiency is associated with decreased bioavailability of TGF.β1, triglycerides (TG), and total cholesterol and clinical symptoms, including acne, hirsutism, and menstrual interval [60]. However, based on the frequency of the previous intervention studies related to the effects of vitamin D supplement in the improvement of metabolic biomarkers in PCOS women, several meta-analyses have been conducted to evaluate the obtained results. Although these studies have provided useful evidence, conflicting results have been observed presumably due to considering diverse interventions in different meta-analysis studies. Fang et al. (2017) conducted a meta-analysis including vitamin D or metformin interventions in PCOS patients. They found that vitamin D supplement is not effective in metabolic and lipid parameters in PCOS women [61]. In a meta-analysis conducted by Izadi et al. in 2017, it was shown that vitamin D can efficiently affect total testosterone without changing the other androgenic profile parameters in PCOS women [62]. Moreover, Akbari et al. (2018) performed a meta-analysis to investigate the effects of vitamin D on oxidative stress and inflammatory factors in PCOS women. They found that supplementation of this vitamin can affect the levels of TAC and MDA, but not of GSH. This controversy in the impacts of vitamin D on the oxidative stress markers in these women may be due to the differences in the experimental design, population properties of the studied people, the dose of vitamin D, and time periods of the interventions included in their meta-analysis [63]. According to a meta-analysis on different interventions in PCOS patients conducted by Miao et al. in 2020, consumption of vitamin D as a potent remedy for this syndrome can effectively improve IR, HA, and several other metabolic and lipid parameters in a short-term intervention in PCOS women [64]. Interestingly, in a recent meta-analysis on different RCTs, Guo et al. demonstrated that consumption of vitamin D without any co-supplementation can improve IR and decrease the serum levels of fasting glucose and insulin in PCOS women [65]. In contrast, Fang et al. did not find any positive effect of this vitamin on glucose metabolism in these women. Also, in contrary to the meta-analysis conducted by Miao et al., no improvement in serum levels of testosterone, dehydroepiandrosterone sulfate (DHEAS), and SHGB in the PCOS patients was observed in the meta-analysis conducted by Guo et al. [64, 65]. Although, in a meta-analysis on co-supplementation of vitamin D and other nutrients, Akbari et al. showed that supplementation of this vitamin improves hs-CRP in PCOS patients, Guo et al. revealed that serum hs-CRP in these women cannot be affected after consumption of vitamin D alone [63, 65]. Therefore, to address these controversies, more investigations with bigger sample sizes and longer periods of interventions and population-based studies especially in geographic areas with a lower sunlight exposure are essentially needed.
Carnitine
L-Carnitine (LC) or β-hydroxy-γ-trimethyl-aminobutyric acid is a water-soluble molecule catalyzed from the essential amino acids, methionine, and lysine. LC plays an important role in mammalian metabolic processes, principally for natural mitochondrial oxidative events of long-chain fatty acids; it also has pivotal cellular performances during metabolic activities in mitochondria and peroxisome. Metabolism of cell energy is generally maintained by way of β oxidation of fatty acids in mitochondria. Thus, any insufficiency in the accessibility of carnitine and/or carnitine-related transport system in mitochondria leads to limited fatty acid oxidation. In addition, LC improves coenzyme A (CoA) recovery by binding short acyl groups from within the mitochondria to the cytosol, leading to an increase in mitochondrial CoA levels. As a result, a decrease in carnitine availability increases the acetate CoA/CoASH ratio, resulting in an interference with other means of mediating metabolic activities, predominantly amino acid catabolism, glycolysis, gluconeogenesis, and production of ketone body [66–68].
HA and IR are the most significant characteristics of PCOS that are related to declined serum carnitine levels [69, 70]. Diseases of glycemic situation are the most prevalent complications following IR in PCOS. In the cases with these disorders, there is a reverse correlation among their LC levels and insulin, FBS, HOMA-IR, and HbA1c [69, 71]. Also, LC administration with doses of 0.25 and 3 g/day demonstrated a dramatic reduction in glucose, insulin, HOMA-IR [71–73], and HbA1c [71]. Quantitative analyses have surveyed the relationship between lipid profile and carnitine levels in PCOS patients. And only two studies [70, 73] displayed a noteworthy correlation between fat profile and carnitine levels. In the studies conducted by Ismail et al. and El Sharkwy et al., the dose of 3 g of carnitine for 3 months enhanced the fat profile significantly [71, 73]. But the dose of 0.25 g for the similar period in Samimi et al.’s study showed no significant effect [72].
The conclusions from the experimental investigations reviewed showed that the association between the serum carnitine level and anthropometric condition is not consistent [69, 70]. Conversely, clinical trials studies utilizing 0.25 g and 3 g of carnitine complements discovered a substantial decline in body mass index (BMI), weight, and waist circumstance [71–74]. Whereas studies in this area are limited, further studies are required to investigate the exact effects of carnitine on anthropometric indices.
The antioxidant properties of carnitine are somewhat associated with scavenging of free radical and inhibition of radical generation, retaining the veracity of mitochondrial electron-transport system in which results in a decrease in the exudation of ROS under stress circumstances, and influencing redox-signal transduction through blockage of NF-kB which results in the extra production of antioxidant molecules [75]. In a study conducted by Jamilian et al., 12 weeks of supplementation with 0.025 g of carnitine in PCOS women led to a major advancement in MAD, TAC, and MDA/TAC proportion. But no momentous change was observed in the levels of GSH [74].
Latifian et al. presented that carnitine administration in infertile PCOS patients leads to the development of dominant follicles, an increase in the average thickness of the ondometer, and indoctrinated positive dissimilarities in the magnitude of the left ovarian follicles [76]. Moreover in another report, it was found that there was a considerable and negative relevance between LC and free androgen index, and a notable positive correlation between the levels of LC and SHBG, owing to HA and/or IR in PCOS [70]. While in El Sharkawy et al.’s study, a significant improvement in the levels of sex hormones (FSH, LH, free testosterone) was observed [73]; in a clinical trial, the free testosterone levels proportion to the levels in the control people was not significantly altered by supplementation with 0.25 g of LC [72]. More investigations with different amounts and periods are needed to improve the knowledge about the impacts of this antioxidant on sex hormones in patients with PCOS.
In El Sharkawy et al.’s study, clomiphene citrate-, L-carnitine- (3 g/day for 3 months), and metformin-treated group exhibited meaningful amelioration in the ovulation rate, menstrual regularity, and pregnancy rate in comparison to placebo, clomiphene citrate, and metformin group. There was no statistically meaningful change in the abortion rates and the reductions in BMI between the two groups [73]. Contradictory to the El Sharkawy et al.’s study, Ismail et al. appended LC only as an adjuvant treatment for clomiphene-resistant PCOS patients. A considerable amelioration in the rates of ovulation and the pregnancy was found [71]. In another work, Gharib assessed the effects of adding LC to letrozole during the induction of ovulation among PCOS patients (2 g of L-carnitine daily). The results showed that the cumulative ovulation, chemical, and clinical pregnancy rates were remarkably greater in the LC-treated group compared to rates in the control group [77].
Resveratrol
Phytoestrogens are phytochemicals that include several bioactive molecules with different biological properties. Amongst, stilbenes, especially trans-resveratrol, have interesting biological impacts on human health. Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a phytoalexin synthesized during the response to mechanical damage, UV-radiation, and fungal infections in plants. This natural polyphenol characterized in more than 70 plant species is highly abundant in grapes possibly due to the defense against Vitis vinifera as a fungal infection. Resveratrol has a wide range of biological functions, and one of the most important activities of this molecule is its high antioxidant potency. Resveratrol is able to promote the activity of antioxidant enzymes, keeping the concentration of intracellular antioxidants in biological systems. Also, the ability of this resveratrol to scavenge both O2° and OH° radicals has been proved; it has been suggested that this bioactive molecule has cardioprotective, neuroprotective, anti-inflammatory, and cancer-preventive properties [78, 79]. Given the fact that the inflammatory suppressive and antioxidant roles of resveratrol have been shown in numerous investigations and its useful impact on ovary and reduction of female hormones has been confirmed in vitro, this potent agent can be a promising alternative for the treatment of PCOS and the improvement of its clinical symptoms [80, 81].
According to the first clinical trial study conducted by Banaszewska et al. on the effects of resveratrol on PCOS, a 3-month co-supplementation of resveratrol and metformin declined the serum testosterone and DHEAS evidently, and the magnitude of the observed improvement of hyperandrogenism was higher than that of the observations from the consumption of OCP or metformin alone. On the other hand, since a decrease in the testosterone can be gradually achieved by pharmacological interventions for several months, a significant decrease in HA only after a 3-month consumption of resveratrol will be promising. However, resveratrol can contribute to the reduced serum DHEAS and testosterone in PCOS women, without affecting their BMI, lipid profile, and inflammatory markers or endothelial function [82].
A higher occurrence of VEGF in serum and follicular fluid is repeatedly observed in the PCOS women, and it seems that induction of androgens is the leading cause of this up-regulation. However, any therapeutic agent that down-regulates the key angiogenesis-related genes, like VEGF, in PCOS patients can be directly effective in the expression of ovarian hyperstimulation syndrome (OHSS) during the ovulation induction process. Bahramrezaei et al. revealed that administration of resveratrol (800 mg/day) as a natural supplement in PCOS patients who were candidates for IVF for 40 days can reform the molecular pathways related to angiogenesis in granulosa cells through down-regulation of VEGF and hypoxia-inducible factor 1 (HIF-1), as a key factor for modulation of VEGF and other angiogenic factors. Also, resveratrol can increase high-quality oocytes and embryos [83]. In another 40-day intervention for PCOS patients who were candidates for IVF with resveratrol (800 mg/day), it was shown that this biomolecule can decrease the serum pro-inflammatory factors such as IL-6, IL-18, IL-1b, TNF-a, and CRP. Moreover, the anti-inflammatory action of resveratrol is probably mediated by the inhibition of nuclear factor-κB (NF-κB) and its associated genes. Alternatively, resveratrol can suppress the endoplasmic reticulum (ER) stress in granulosa cells via modulating the genes involved in the unfolding protein response (UPR) process, as a signaling pathway activated in response to the ER stress. However, the ER stress and UPR in granulosa cells are the main regulatory axes in physiological and pathological circumstances; thus, the ER stress can be a putative therapeutic target in PCOS patients [84]. On the other hand, despite the reported advantageous effects of resveratrol on protecting and improving ovarian function, recent scientific evidence has shown its anti-decidualization effects on the uterine endometrium in the luteal phase and a decrease in clinical pregnancy rate compared to controlling by the ART practices. According to Ochiai and Kuroda’s study, resveratrol seems to prevent the expression of cellular retinoic acid-binding protein 2 (CRABP2-RAR), evading the decidualization procedure and decidual senescence. Since the teratogenicity of resveratrol is still debatable, it has been suggested that this biomolecule is not suitable to be used during the luteal phase and pregnancy [85–89].
Although all reports identified the efficacy of resveratrol in the improvement of different manifestations of PCOS, due to the low sample sizes and analyzed non-concentrated parameters in previous researches, further attempts are needed to focus on particular features in order to verify the exact influence of this powerful antioxidant on PCOS.
Systematic pharmacology approach can discover molecular and pharmacological mechanisms by the “multi-target, multi-drug, multi-directional, and multi-pathway” way. This method is broadly used in drug detection, mechanism research, and target prediction. Recently, a study has shown that the combined use of resveratrol and quercetin can pool their effects and become a new drug option, which can be a good target for laboratory and clinical research. Also, these types of research are proper options for predicting efficiency and negative effects of desired pharmacological agents and their combination before performing clinical studies [90].
Quercetin
Quercetin (3-, 5-, 7-, 3′-, 4′-pentahydroxyflavone) is the most prevalent flavonoid with a strong antioxidative activity present in fruits and vegetables such as berry, onion, tea, and apple. It has been demonstrated that this flavonoid has diverse biological and pharmacological functions that are mostly related to its capability to decline the ROS levels through different mechanisms [91, 92]. In other words, quercetin can be regarded as an effective antioxidant, due to its ability in preventing xanthine oxidase by reducing the production of free radicals, reforming cellular antioxidants, and inhibiting lipid peroxidation. In recent years, numerous researchers have reported the useful effects of this supplement in controlling the redox status, suppression of inflammatory response, protection of cardiovascular system (through inhibition of platelet aggregation), and prevention of cancer and diabetes [93, 94]. Interestingly, quercetin is able to improve the glucose and lipid metabolisms and increase insulin sensitivity. This molecule has a helpful impact on the protection of human granulosa cells as well [93, 95]. Therefore, quercetin can be assumed as a suitable option to improve the metabolic parameters in PCOS patients.
Resistin, an adipocytokine usually secreted from macrophages in adipose tissues, is involved in the induction of inflammatory pathways and metabolic abnormalities such as insulin resistance. Furthermore, the plasma level of resistin in PCOS patients is higher than in healthy people, contributing to the emergence of insulin resistance and hyperinsulinemia in these patients. Khorshidi et al. showed that quercetin supplementation (1000 mg/day) for 12 weeks resulted in a significant decrease in the plasma level and gene expressions of resistin, which is associated with a considerable reduction of sexual hormones, such as LH and testosterone, in obese or overweight PCOS patients. On the other hand, although they found that consumption of this supplement also improves the fasting insulin, FBS, and insulin resistance (HOMA-IR) in PCOS patients, these changes are not statistically significant compared to the changes in the placebo group [96].
Adiponectin, another important factor derived from adipose tissue, is involved in the improvement of insulin sensitivity and has anti-inflammatory and anti-atherogenic effects. However, there is convincing evidence that the reduction of adiponectin is associated with IR and obesity. In contrary to resistin, the adiponectin level in PCOS patients is lower than in healthy people. In a recent clinical trial study, Rezvan et al. showed the promising effects of quercetin on the improvement of adiponectin-mediated IR and sexual hormones in women with PCOS [97]. Additionally, this oral supplement elevates the adiponectin signaling pathways and improves the metabolic features in PCOS patients through up-regulation of the adiponectin receptors and AMP-activated protein kinase (AMPK) in the adipose tissue. AMPK is a key sensor for the regulation of GLUT4, promotes energy, and increases glucose uptake [98]. Totally, although recent data imply that quercetin can suppress the PCOS manifestations via the improvement of IR and hyperandrogenemia, there is no definitive evidences yet to judge it.
Curcumin
Curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-hepta-1,6-diene-3,5-dione) is a bioactive lipophilic polyphenol, and the yellow component of turmeric is a spicy derived from rhizome of Curcuma longa [99, 100]. Several clinical studies suggest that curcumin can exert its biological activities in human health, resulting in suppression of inflammation, oxidative stress, cancer, diabetes, and neurodegeneration by affecting different molecular targets and controlling biochemical pathways. It is believed that the biological functions of curcumin are related to its unique biochemical structure. The most important function of curcumin is its strong antioxidant feature. The reactive functional groups of curcumin can undergo oxidation to remove the most deleterious ROS through the process of electron transfer and hydrogen attraction. This feature enables curcumin to protect lipids and proteins from peroxidation in oxidative stress. Moreover, the antioxidative action of this molecule is mediated by its ability to activate the NRF-2 pathway. This transcription factor can modulate the antioxidative and anti-inflammatory response genes, thereby playing a critical role in keeping the cellular redox status. Curcumin also induces the activity of antioxidant enzymes such as SOD and glutathione peroxidase (GPx)[99–101]. A recent systematic review on clinical trials suggests that curcumin decreases the concentration of circulating MDA and increases the activity of SOD in human serum [102]. According to clinical and pre-clinical studies, via affecting the AMPK signaling pathway and preventing liver gluconeogenesis, this efficient anti-inflammatory and antioxidative supplement can cut down the production of glycogen. Thus, it can be applied as an adjuvant to conventional antidiabetic agents for the treatment of severe diabetes and its complications [101]. However, curcumin can be assumed as a therapeutic adjuvant for the treatment of PCOS according to the pathophysiology of this disease.
Heshmati et al. showed that administration of curcumin (1500 mg/day) for 3 months in PCOS women elevated the expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha and the activity of serum GPX. To some extent, this consumption increased the expression of Sirt1, a NAD + dependent histone deacetylase in the pathway of insulin secretion, and the activity of SOD in PCOS patients; however, this increase was not statistically significant compared to the placebo group [103]. Biomarkers related to oxidative stress and inflammation can be considered as prognostic factors for an abnormal metabolic profile in PCOS patients due to the increased incidence of metabolic disorders and chronic inflammatory responses in these women. In another study, investigating the effects of curcumin on the metabolic and inflammatory parameters of PCOS showed that administration of this biomolecule for 6 weeks (1 g/day) did not affect the hyperglycemic status and lipid profile in these women, but only the amounts of insulin and quantitative insulin-sensitivity check index (QUICKI) were improved in the curcumin-treated group compared to the placebo group. Also, this administration could not decrease hs-CRP – an indicator of slight inflammation and an important mediator of IR – in these patients [104]. In contrary to the above-mentioned studies, another RCT has recently demonstrated that consumption of curcumin (500 mg/day) for 12 weeks decreased the fasting glucose, serum insulin, IR, and BMI in PCOS patients and increased the sensitivity to insulin in them. This supplementation also improved the lipid profile, decreased total cholesterol and LDL, and increased HDL and expressions of PPARL-8 – the gene involved in regulating fatty acid storage and glucose metabolism – and LDLR in PCOS patients [105]. Due to the small number of studies and conflicting results, further investigations with a larger sample size are needed to verify the effects of curcumin on the hormonal and metabolic profiles and the improvement of other symptoms of PCOS (Fig. 2).
Fig. 2.
Natural antioxidants may improve PCOS patients’ fertility by reducing oxidative stress, angiogenesis inflammation, and enhancing sex hormone profile, metabolic profile, and anthropometric indices
Concluding remarks
Since the PCOS strongly affects the function of the reproductive system and is one of the major causes of infertility in women, it has attracted more attention in recent years. Currently, treatment management of PCOS is usually concentrated on (i) treatment of clinical symptoms, including ovulation, hirsutism, and menstrual irregularity and (ii) controlling the sexual hormones and insulin levels. The first line of treatment is metformin and combined oral contraceptives [106]. Although the effectiveness of these agents in the relative improvement of the mentioned impacts of this disease has been established, more studies are needed to investigate the different pathways involved in the pathogenesis of PCOS using combinational strategies, while eliminating the main clinical symptoms of PCOS and addressing other syndrome-associated complications.
The efficacies of a wide range of antioxidants in controlling the PCOS symptoms have been confirmed in vitro and in vivo. Therefore, the antioxidants can be considered as the most promising pharmacological agents against PCOS probably because the therapeutic perspective of these biomolecules is bigger than that of other strategies. In other words, antioxidants can be effective in different clinical symptoms of PCOS such as IR, hyperlipidemia, inflammation, and its long-lasting effects via affecting diverse molecular pathways. Also according to the etiology and different deleterious mechanisms involved in PCOS, the antioxidants, individually and/or in combination with other therapeutic strategies, can be efficient in the PCOS treatment. Alternatively, antioxidant supplementation can reduce the dose of the current undesirable drugs in PCOS women who were candidates for IVF and attenuate the severity of the side effects, such as OHSS. The present review discusses the existing RCTs relevant to the treatment of PCOS by the established natural antioxidants. But, in addition to the limited data, these studies were methodologically patchworked and are very hard to derive a correct deduction from these results. Despite the limited data and relatively few RCTs of antioxidant interventions for PCOS patients, there is preliminary evidence suggesting that some of these modalities can be effective adjuncts in the PCOS treatment. For example, Q10 as an antioxidant can improve the clinical appearance of PCOS, including insulin sensitivity, the level of sexual hormones, and lipid profile, although there are conflicting results [44, 47]. Also, despite the fact that several studies have obtained the positive effects of curcumin on PCOS, further studies are needed to verify these trends due to the small sample size and similarity of the results between the treatment and placebo groups in previous RCTs.
Furthermore, recent scientific evidence suggests that PCOS patients with different phenotypes represent different responses to treatment processes and ART outcomes. In addition, the NIH 2012 evidence-based methodology PCOS workshop recommends that diverse PCOS phenotypes should be considered in research studies and clinical care. However, this issue has not been considered in studies on the efficiency of antioxidants, and only in some studies, ancillary criteria such as obesity have been used in the classification of groups.
Therefore, a major problem for investigating the effects of antioxidants in the PCOS treatment is the deficiency of RCTs. Also the low quality of the evidence generated by the existing RCTs makes it difficult to draw clear conclusions about the efficacy of antioxidants in PCOS management. Moreover, the range of antioxidants studied and the use of different doses make it difficult to identify the preferred antioxidants and their optimal doses and durations. Therefore, more and larger well-designed RCTs are needed to evaluate and confirm the positive effects of antioxidants as part of the treatment for clinical symptoms and infertility or preventing future chronic diseases in PCOS women.
Declarations
Competing interests
The authors declare no competing interest.
Footnotes
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