https://orcid.org/0000-0002-6297-9184
Abstract
N-acetylcysteine (NAC), a compound known for its cysteine and glutathione precursor properties, has been used in therapeutic applications for many years. Recently, there has been increasing interest in exploring the potential benefits of NAC in addressing polycystic ovary syndrome (PCOS). However, the exact mechanisms underlying NAC’s therapeutic and clinical uses remain not fully understood. This review aims to specifically investigate how NAC offers protection against PCOS. This involved an extensive systematic review of the literature, and it made use of PubMed, Embase, and Web of Science databases. By analyzing key findings from over 100 research papers, the potential mechanisms through which NAC produces its effects were explored and summarized. Most studies suggest that NAC, whether used on its own or in combination with other medications, has the potential to counteract oxidative stress, utilize its anti-inflammatory and anti-apoptotic properties, and offer benefits in managing PCOS. Moreover, NAC might have the potential to influence specific signaling pathways in insulin target cells and β cells. Diverse biological effects of NAC indicate its potential usefulness as a supplementary or therapeutic approach for managing PCOS. As a result, additional research is required to explore its potential in addressing PCOS.
Introduction
Polycystic ovary syndrome (PCOS) is one of the common endocrine disorders that impact women in developed and developing countries, with a prevalence ranging from 8% to 13% [Citation1,Citation2]. The Rotterdam criteria are the most widely used guidelines for diagnosing PCOS [Citation3]. According to the criteria, a diagnosis is made if an individual meets at least two of the following three conditions: (1) irregular or absent ovulation (Oligoovulation or Anovulation, O); (2) clinical and/or biochemical signs of elevated androgen levels (Hyperandrogenemia, H); and (3) polycystic ovarian morphology detected via ultrasound (Polycystic Ovaries, P). PCOS is classified into four types based on the criteria: Type A (H + O+P), Type B (O + H), Type C (H + P), and Type D (O + P). The distribution of PCOS subtypes differs across various racial groups and study populations. People with PCOS often face metabolic and reproductive issues, including obesity, oxidative stress (OS), insulin resistance (IR), hirsutism, acne, irregular menstruation, infertility, and poor pregnancy outcomes. There is also a notable rise in long-term complications such as cardiovascular diseases and cancer [Citation3].
To date, the cause of PCOS remains unclear. Although various theories have been suggested to explain the pathogenic mechanisms of PCOS, OS, IR, hyperinsulinemia and hyperandrogenism play crucial roles [Citation4–7]. Studies also indicate that OS is linked to IR, hyperinsulinemia, hyperandrogenism, chronic inflammatory states, disturbances in glucose and lipid metabolism, ovarian dysfunction, and adverse pregnancy outcomes [Citation8–11]. Therefore, anti-oxidant therapy may be helpful in treating PCOS.
N-acetylcysteine (NAC) is a widely recognized antioxidant. NAC is recognized as a precursor to glutathione (GSH), which can serve as a co-participant in various enzyme reactions. NAC in its reduced form possesses an active sulfhydryl group capable of either creating disulfide bonds with free S-H groups or competing with and disassembling existing disulfide bonds, functioning as a reducing agent [Citation12]. NAC has exhibited a variety of biological effects, such as anti-apoptotic [Citation13], acting as an antioxidant [Citation14], safeguarding against localized ischemia [Citation15], and blocking processes like phospholipid metabolism, the release of proinflammatory cytokines, and protease activity [Citation16].
NAC action is extremely complicated in PCOS [Citation17–19]. Can NAC treat PCOS by reducing OS levels or through other mechanisms? This review aims to summarize, through the analysis of key findings from more than 100 research papers, the specific mechanisms through which NAC provides protection against PCOS.
The use of the antioxidant NAC in treatment PCOS
The effects of NAC, whether used alone or in combination with other medications, can vary significantly and may have both favorable and unfavorable outcomes for individuals with PCOS, as depicted in and .
Table 1. The use of antioxidant N-acetylcysteine in polycystic ovary syndrome.
Table 2. Systematic review and meta-analysis of antioxidant N-acetylcysteine in the treatment of polycystic ovary syndrome.
NAC alone in treatment PCOS
As shown in and , dozens of studies (both basic and clinical research as well as meta-analyses) have investigated the effects of using NAC alone to treat PCOS on parameters such as blood glucose, lipid/hormone levels, and pregnancy outcomes. Considering the different control groups, dosages, treatment durations, and the diversity of PCOS subjects/locations across these studies, the majority indicate that NAC is inferior to or slightly inferior to metformin but significantly improves PCOS-related symptoms compared to placebo. Due to the potential side effects of metformin, NAC, with a wide safety range and minimal side effects, can be considered as an alternative or supplementary treatment.
NAC treatment improves insulin sensitivity in women with PCOS [Citation17]. NAC is more effective than metformin in enhancing clinical symptoms, IR markers, hormone levels, and ovulation in women with PCOS. Moreover, because of its minimal side effects, NAC can be considered a suitable alternative to insulin-lowering drugs in the treatment of PCOS patients, ultimately benefiting their long-term health [Citation20]. Similarly, another study proved that NAC outperforms metformin in enhancing the lipid profile, fasting blood sugar, and fasting blood insulin levels [Citation21]. On the contrary, in metformin treatment groups and NAC treatment groups, there was a notable reduction in body mass index (BMI), hirsutism score, fasting insulin, homeostatic model assessment of insulin resistance index, free testosterone, and menstrual irregularity compared to the initial values. Both treatments demonstrated similar effectiveness [Citation22]. A meta-analysis has indicated that NAC could be a valuable supplement for addressing female infertility linked to PCOS and unexplained factors. Its influence may be more pronounced in women with higher BMI, IR, and OS. However, it’s essential to validate these findings through well-structured randomized controlled trials that assess clinical outcomes, such as the live birth rate, over extended follow-up durations [Citation23]. A separate meta-analysis investigated both the benefits and potential limitations of utilizing NAC in the treatment of PCOS in women [Citation24]. In comparison to a placebo, women using NAC had a higher probability of achieving a live birth, pregnancy, and ovulation. However, when compared to metformin, women taking NAC were less likely to experience pregnancy or ovulation. There were no significant differences in the occurrence of miscarriage, menstrual regulation, acne, hirsutism, adverse events, or changes in BMI, testosterone, and insulin levels between the NAC group and the placebo group. Furthermore, the meta-analysis suggests that there was no substantial difference in clinical pregnancy rates between individuals treated with NAC and those treated with metformin. Nonetheless, in comparison to metformin, NAC did lead to a notable decrease in BMI and total testosterone levels. While metformin is widely used in the management of PCOS, NAC, with its antioxidant, anti-apoptotic, and lipid peroxidation-reducing characteristics, could offer an alternative treatment for individuals with IR or obesity in the context of PCOS who may not tolerate or respond effectively to metformin therapy [Citation25]. Metformin on its own effectively stimulates ovulation in PCOS cases when clomiphene citrate (CC) is ineffective. In contrast, NAC alone does not achieve this. While NAC has the potential to augment the effects of CC, it cannot serve as a substitute for it [Citation26]. In a rat model with PCOS exposed to 5α-dihydrotestosterone (DHT) and insulin (INS), NAC has been observed to restrain ferroptosis in uterine and placental tissues [Citation27]. In individuals with PCOS, NAC reduces oxidative harm, apoptosis, and the entry of calcium through TRPV1 channels in neutrophils [Citation19].
The efficacy of NAC seems to be closely tied to the dosage, which may explain the inconsistent results observed in clinical trials regarding its impact on blood glucose regulation. This emphasizes the need to identify the optimal NAC dosage for human use in order to fully harness its benefits. Additionally, it’s worth mentioning that the NAC dosage affecting body weight was higher than the minimum amount required to enhance glucose tolerance and decrease liver fat accumulation. This implies that NAC may influence distinct pathways to achieve these varied effects, underlining the complexity of NAC’s mechanisms of action. At the same time, maintaining a balanced state in redox reactions is of utmost importance in the regulation of insulin signaling [Citation28,Citation29]. The differing effects of NAC highlight a level of specificity in the secondary signaling role of reactive oxygen species (ROS) that remains not fully comprehended.
NAC combined with other drugs treatment PCOS
As shown in , numerous studies (basic or clinical research) have explored the effects of combination therapy for PCOS based on NAC on parameters such as blood glucose, lipid/hormone levels, and pregnancy outcomes. Similarly, considering the different control groups, dosages, treatment durations, and the diversity of PCOS subjects/locations across these studies, the majority indicate that combination therapy based on NAC significantly improves PCOS-related symptoms compared to the respective control groups, suggesting that NAC can serve as a beneficial adjunct.
NAC and metformin have proven to be effective complementary treatments when used in combination with CC. They notably improve IR, enhance ovulation, and increase pregnancy rates in PCOS patients who do not respond to CC alone. Both drugs can lead to positive outcomes with long-term use. Moreover, NAC provides added advantages by reducing PCOS-related indicators and addressing anovulatory infertility after extended treatment. It can be a viable alternative or supplement for managing conditions characterized by elevated insulin levels, increased androgens, raised homocysteine levels, OS, and particularly PCOS, especially when dealing with CC-resistant cases of polycystic ovaries [Citation30]. A study by Rizk et al. demonstrated that the combination of NAC (1.2 g/d) with CC (100 mg/d) for a short duration of five days significantly improved ovulation and pregnancy rates in obese women with CC-resistant PCOS (49.3% vs. 1.3% and 21.3% vs. 0, respectively). However, it’s important to note that these results have not been consistently replicated by other studies. The limited duration of NAC administration (only five days) might not be sufficient to fully realize the metabolic and hormonal benefits of NAC [Citation18]. Metformin’s treatment of the human granulosa-like tumor cell line (KGN) resulted in reduced expression of miR-670-3p, NOX2, NLRP3, ASC, cleaved caspase-1, and GSDMD-N when exposed to Lipopolysaccharide (LPS). Additionally, cellular caspase-1 activity, ROS production, OS, and the release of pro-inflammatory cytokines (IL-1β, IL-6, IL-18, and TNF-α) were all decreased. These positive effects were further enhanced by the addition of NAC [Citation31]. NAC improves oocyte and embryo quality and could be administered as an alternative to metformin [Citation32]. On the contrary, the simultaneous application of metformin and NAC did not lead to an amelioration of clinical symptoms in individuals with PCOS undergoing Intracytoplasmic Sperm Injection (ICSI) [Citation33].
A combination therapy involving insulin-sensitizing agents (myo-inositol, D-chiro-inositol, and chromium picolinate), antioxidants (NAC and lycopene), and vitamins (vitamin D, biotin, and folic acid) was administered to women with PCOS. After 12 weeks of supplementation, significant improvements in menstrual regularity and reductions in acne and hirsutism were observed in both obese and non-obese PCOS patients. Notably, obese individuals experienced a substantial decrease in body weight and BMI, while these parameters remained unchanged in lean subjects. This suggests that a comprehensive approach utilizing insulin-sensitizing agents, antioxidants, and vitamins could be an effective strategy for managing PCOS [Citation34]. Research findings suggest that a combination of antioxidants (including lipoic acid, NAC, vitamin B6, and S-adenosyl-l-methionine) could be a viable treatment option for PCOS patients, especially when the use of oral contraceptives is not indicated [Citation35]. Preliminary findings from an open study suggest that prolonged administration of NAC and L-arginine (ARG) may have the potential to restore reproductive function and improve glucose metabolism in individuals with PCOS [Citation36]. Inositol and NAC improve ovarian function in PCOS patients, regardless of their IR status, indicating that these substances may have beneficial effects through pathways not directly related to insulin, even in individuals with a negative IR [Citation37].
In a general sense, the use of the antioxidant NAC and other drugs as combination treatment for PCOS may lead to improvements in clinical symptoms, IR, hormone levels, and ovulation. However, the outcomes may vary based on the underlying pathological conditions.
The potential therapeutic mechanisms of NAC
The response to NAC treatment for PCOS varies, which may be attributed to the ethnic diversity of PCOS patients and differences in epigenetic and environmental factors [Citation38]. NAC treatment for PCOS mainly focuses on classical features of PCOS, including reducing insulin/blood glucose levels to improve IR; as an adjunct, inducing ovulation, improving ovarian function, and pregnancy outcomes; regulating hormone levels (reducing testosterone), lowering BMI, and partially restoring menstrual cycles.
NAC and IR/hyperinsulinemia
While IR is not explicitly listed in the diagnostic criteria for PCOS, it is highly prevalent among women with PCOS, with approximately 95% of obese women with PCOS exhibiting IR [Citation3,Citation39]. As we know, IR leads to the occurrence of hyperinsulinemia, resulting in the coexistence of IR and hyperinsulinemia. IR is a main reason in the etiology of PCOS [Citation40]. OS impairs glucose uptake in tissue and reduces insulin secretion from pancreatic β-cells [Citation41]. The mechanism through which NAC hinders the development of IR seems to be attributed to its antioxidative characteristics [Citation42,Citation43]. However, NAC supplies cysteine and encourages the production of GSH [Citation43]. GSH has been discovered to play roles within cells that go beyond its antioxidant properties, including its function as a co-factor in the metabolic breakdown of methylglyoxal catalyzed by glyoxalase [Citation44]. Interestingly, NAC has been observed to safeguard cells both in laboratory cultures and in living organisms from the harmful effects of excessive glucose, thereby preserving insulin production and release [Citation45,Citation46]. A prior study indicated that antioxidants with high concentrations of -SH groups, like NAC and lipoic acid, might lead to a reduction in immunoreactive insulin levels [Citation47].
NAC and HA
There is a lack of basic research on the improvement of HA in PCOS patients by NAC. As shown in and , clinical studies indicate that NAC can significantly reduce HA in PCOS patients in both short-term and long-term treatments. Furthermore, the relationship between OS and HA is relatively well-documented. Compared to the non-HA-PCOS phenotype (OA + PCO), the HA-PCOS phenotype has higher levels of serum total oxidant status (TOS), oxidative stress index (OSI), and malondialdehyde (MDA), as well as more severe impairment in the antioxidant function of high-density lipoprotein (HDL) [Citation48,Citation49]. Studies also showed that elevating circulating androgens can sensitize leukocytes, increase the expression of glucose-induced NADPH oxidase, and enhance the production of ROS, thereby promoting OS [Citation50]. OS can decrease the production and secretion of hepatic sex hormone-binding globulin (SHBG), promote the proliferation of T-I cells, increase the expression of key enzymes involved in ovarian testosterone synthesis, and enhance testosterone production [Citation51]. Besides, OS is positively correlated with hirsutism score and androgen levels [Citation48,Citation52]. Based on the above studies, we can hypothesize that the reduction of HA by NAC is likely primarily through the improvement of OS.
NAC and reproduction
OS is critically important for oocyte and embryo quality. NAC can improve reproduction in women with PCOS, which may mainly be related to its antioxidant effect. Firstly, NAC serves as a source of sulfhydryl groups, which are crucial for neutralizing free radicals such as H2O2, OH*, and O2−* [Citation53]. Additionally, NAC supplementation has been shown to elevate GSH levels in individuals with low GSH levels, leading to improved redox balance [Citation54]. Furthermore, NAC has the ability to inhibit the activation of mitogen-activated protein kinase induced by ROS [Citation55]. Therefore, by reducing lipid peroxidation, NAC may exert beneficial effects on reproductive biomarkers. Besides, previous studies have demonstrated the antioxidant effects of NAC and its protective properties against focal ischemia, which might explain NAC’s positive impact on endometrial thickness [Citation15].
NAC and metabolic parameters
NAC can improve metabolic parameters in women with PCOS, which may be related to its antioxidant effect. Additionally, NAC supplementation can improve the levels of interleukin-6, malondialdehyde, and homocysteine, which may have a positive effect on metabolism [Citation52].
In summary, PCOS is a highly heterogeneous disorder, hence it may have complex etiology and pathogenic mechanisms. Further research is needed to elucidate the role played by NAC.
The clinical application setbacks and countermeasures of NAC
The clinical application setbacks of antioxidants, particularly NAC, can be attributed to three main factors. First, there’s a lack of comprehensive understanding regarding the physiological functions of oxidative-reductive stress. This form of stress response is integral to cellular and organismal well-being, as it selectively modulates the functioning of biomolecules, signal transmission, and physiological functions through oxidative-reductive modifications. It’s crucial to understand that OS is not the same as oxidative damage. Excessive antioxidant action can induce reductive stress, causing unintended effects. Secondly, NAC, being a thiol-containing compound, has the capacity to directly diminish disulfide bonds or disrupt their formation [Citation56], influencing the configuration of proteins, their functionality, and their ability to bind to ligands [Citation57,Citation58]. Therefore, besides its antioxidant properties, NAC may participate in thiol post-translational modifications and influence protein functionality. Thirdly, a lack of specificity in antioxidant approaches is the most fundamental and widespread issue. Determining the ideal NAC dosage is challenging, and inappropriate NAC concentrations can render interventions ineffective. It’s increasingly clear that precisely controlled levels of ROS are not always detrimental byproducts and are integral to numerous essential physiological processes. ROS and reactive nitrogen species serve as vital components in insulin, MAPK, and JNK signaling pathways, playing roles in regulating gene expression, cell growth, differentiation, and survival [Citation28,Citation59].
To tackle the three points discussed earlier, upcoming strategies for managing redox balance should focus on leveraging the physiological functions governed by oxidative-reductive stress. They should also strive to prevent excessive antioxidant actions and reductive stress that might result in oxidative-reductive harm, all while considering the preciseness required for redox control. Precision redox regulation appears to be the prospective avenue for advancement, and precision redox medicine research is presently in progress [Citation60]. Moreover, addressing PCOS with NAC may serve as a supplementary method. The optimal approach is to enhance physiological functioning and reestablish normalcy through physical activity, dietary management, and non-pharmacological interventions [Citation61,Citation62].
Discussion
NAC, whether used alone or in combination with other medications, may offer some benefits in the treatment of PCOS. However, it’s important to recognize that the therapeutic effects of NAC in the context of PCOS treatment are quite intricate and not fully understood. A personalized supplementation strategy, involving tailored dosage based on individual patient needs, is necessary. Accurate biomarkers should be identified to monitor the patient’s OS levels, assess the requirement for NAC supplementation, determine the appropriate dosage, and evaluate the effectiveness of the pharmacological intervention. The most effective approach is to adopt a holistic healthy lifestyle, including a balanced diet, moderate exercise, and consistent habits, to effectively manage PCOS. Additionally, further evaluation is required to understand the role of NAC in women with PCOS, especially in basic research.
This review certainly has some limitations. Firstly, the combination of NAC with other compounds (such as insulin-sensitizing agents, antioxidants, and vitamins) complicates attributing the observed benefits solely to NAC treatment. Many studies involve multi-compound interventions, making it difficult to clearly state that NAC alone is responsible for treating PCOS. Secondly, the physiological role of OS presents a major challenge in alleviating the pathological effects of oxidants using antioxidant agents. This paradox is likely one of the reasons behind the somewhat discouraging outcomes observed in antioxidant intervention trials thus far. Thirdly, according to the Rotterdam diagnostic criteria, PCOS presents with different phenotypes, and currently, there is no additional evidence available regarding the effects of NAC on these different phenotypes. It would be very meaningful to compare the effects of NAC on different PCOS phenotypes (A/B/C/D types) to elucidate the potential benefits of NAC for various PCOS patients.
Several priorities for future research have been identified through this review: (1) Investigating the efficacy of NAC on psychological outcomes in women with PCOS. (2) Determining the therapeutic doses of NAC needed to elicit clinically beneficial effects on PCOS features and understanding the mechanisms underlying these effects. (3) Conducting robust systematic reviews and meta-analyses of existing studies, particularly focusing on the effects of NAC on PCOS features where higher levels of evidence are scarce. (4) Utilizing and reporting on standardized PCOS diagnostic criteria in future studies, consistent with the most recent 2023 International Guideline for the assessment and management of PCOS. (5) Establishing further standardized criteria (e.g. dosage and duration) with appropriate inclusion criteria (age range, BMI groups, and specific phenotypes of PCOS) to facilitate the comparison of reliable results. (6) Adopting a more rigorous approach to monitoring and recording adverse effects. (7) Ensuring that future studies are adequately powered and representative of the population to improve external validity and facilitate translation into clinical practice.
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