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The impact of GABA and GABAergic pathway in polycystic ovary syndrome: a systematic review

Article information

Obstet Gynecol Sci. 2025;68(2):93-108
Publication date (electronic) : 2025 February 11
doi : https://doi.org/10.5468/ogs.24255
Farzaneh Motafeghi, PhD1, Mina Amiri, PhD1,2, Mahsa Noroozzadeh, Msc1, Fahimeh Ramezani Tehrani, MD1,2
1Reproductive Endocrinology Research Center, Research Institute for Endocrine Molecular Biology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2Foundation for Research & Education Excellence, Vestavia Hills, AL, USA
Corresponding author: Fahimeh Ramezani Tehrani, MD, Reproductive Endocrinology Research Center, Research Institute for Endocrine Molecular Biology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran, E-mail: fah.tehrani@gmail.com
Received 2024 September 22; Revised 2025 January 3; Accepted 2025 February 3.

Abstract

Emerging evidence indicates that dysfunction of the gamma-aminobutyric acid (GABA)ergic pathway may contribute to the pathophysiology of polycystic ovary syndrome (PCOS), and GABA demonstrates potential in the management of PCOS symptoms. This systematic review aimed to determine the role of the GABAergic pathway in PCOS and evaluate the impact of GABA on improving the condition. Web of Science, Embase, Scopus, Cochrane, and PubMed databases were systematically searched for experimental studies, clinical trials, animal studies, and cellular investigations. The search was conducted for relevant English-language manuscripts, published up to February 2024, using keywords, such as “polycystic ovary syndrome”, PCOS, “gamma-aminobutyric acid” and GABA. Quality assessment of the included studies was performed using the Cochrane Collaboration’s tool and the Newcastle-Ottawa scale. The results indicate that GABAergic dysfunction adversely affects gonadotrophin-releasing hormone neuronal activity, leading to hormonal imbalances and reproductive issues. Prenatal androgen exposure and kisspeptin signaling influence GABAergic transmission to GnRH neurons, thereby linking GABA to the pathogenesis of PCOS. Additionally, GABAergic signaling affects peripheral tissues relevant to PCOS, including the immune system, gut-brain axis, and ovaries. GABA supplementation has demonstrated potential benefits in enhancing metabolic and reproductive health, such as reducing insulin resistance and modulating sex hormone levels, as supported by animal models and clinical studies involving females with PCOS. The GABAergic signaling pathway may represent a promising therapeutic target for the management of PCOS. Nevertheless, further studies are required to validate these findings and deepen our understanding of the role of GABA in the pathogenesis and treatment of PCOS.

Keywords: Polycystic ovary syndrome; Gamma-aminobutyric acid; Gonadotropin-releasing hormone

Introduction

Polycystic ovary syndrome (PCOS), a multifactorial disorder, is one of the most common endocrine disorders in reproductive- age females, with prevalences of 2.2% to 26.7% worldwide [1]. PCOS is characterized by hyperandrogenism (clinical and/or biochemical), oligo/anovulation, and polycystic ovaries [2]. PCOS can be associated with luteinizing hormone (LH) hypersecretion, a lower levels of follicles-stimulating hormone (FSH), infertility, elevated inflammatory markers, neurological and psychological issues, such as anxiety and depression, breast and endometrial cancers, obesity, insulin resistance, and dyslipidemia, which increase the risk of cardiovascular diseases (e.g., hypertension, an increased coronary artery calcium score, and increased carotid intimamedia thickness) and type 2 diabetes mellitus [3–5].

The hypothalamic-pituitary-ovarian (HPO) axis plays an important role in reproductive health in females. Disruptions in this axis, often caused by stress, a hormonal imbalance, or underlying conditions like PCOS, can lead to ovulation disorders and menstrual irregularities. Exposure to excess prenatal androgen can also negatively affect the HPO axis, leading to the development of PCOS later in life.

Gamma-aminobutyric acid (GABA), a crucial neurotransmitter, neurons that secrete GABA, and GABAergic signaling are implicated in the function of the reproductive system and influence the HPO axis by modulating gonadotrophin-releasing hormone (GnRH) release and hormonal secretion [6,7]. The roles of the GABAergic pathway and HPO axis have been reported in the pathophysiology of PCOS [8–10]. The relationship between a low level of GABA, hormonal imbalances, and metabolic disturbances in women with PCOS, underscores the potential role of GABA in the pathophysiology of PCOS. In addition, animal studies have shown the potential role of GABA in the pathophysiology of PCOS. GABA is also known to interact with GABAergic receptors in the ovaries, affecting progesterone secretion and corpus luteum formation, which are key elements of reproductive health [11].

Therefore, its influence on reproductive hormones, neuroendocrine regulation, and metabolic processes makes it a promising target for therapeutic interventions.

Despite the abundance of studies in this field, there is a notable lack of reviews that specifically focus on integrating findings from animal models and clinical studies to formulate a cohesive treatment approach. Accordingly, in the present study, we reviewed animal and human studies regarding the putative GABAergic pathway implicated in PCOS and assessed the impact of GABA on the improvement of this syndrome. This study may provide a potential area for further studies regarding the GABAergic pathway and GABA as a treatment of choice in patients with PCOS.

Methods

This systematic review was conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines [12]. A PRISMA flow diagram detailing the study selection process is presented in Fig. 1.

Fig. 1

Article flow diagram. ICTRP, international clinical trials registry platform.

1. Search strategy

Web of Science, Embase, Scopus, Cochrane, and PubMed databases were systematically searched for relevant studies published in English, between January 2000 and February 2024, without any time limitation to retrieve experimental, clinical trials, animal studies, and cell studies that examined the GABAergic pathway implicated in PCOS, and assessed the impact of GABA on this syndrome.

The search strategies used were consistent across all databases and were performed using MeSH terms, focusing on titles, abstracts, and keywords: (PCOS OR “Polycystic Ovary Syndrome” OR “Ovary Syndrome, Polycystic” OR “Syndrome, Polycystic Ovary” OR “Stein-Leventhal Syndrome” OR “Stein Leventhal Syndrome” OR “Syndrome, Stein-Leventhal” OR “Sclerocystic Ovarian Degeneration” OR “Ovarian Degeneration, Sclerocystic” OR “Sclerocystic Ovary Syndrome” OR “Polycystic Ovarian Syndrome” OR “Ovarian Syndrome, Polycystic” OR “Polycystic Ovary Syndrome” OR “Sclerocystic Ovaries” OR “Ovary, Sclerocystic” OR “Sclerocystic Ovary”) AND (“γ-Aminobutyric acid” OR GABA OR “gamma Aminobutyric Acid” OR “Aminalon” OR “Aminalone” OR “4-Aminobutanoic Acid” OR “4 Aminobutanoic Acid” OR “4-Aminobutyric Acid” OR “4 Aminobutyric Acid” OR “gamma-Aminobutyric Acid”, Hydrochloride OR “Acid, Hydrochloride gamma- Aminobutyric” OR “Hydrochloride gamma-Aminobutyric Acid” OR “gamma Aminobutyric Acid”, Hydrochloride OR Gammalon OR “gamma-Aminobutyric Acid”, “Monosodium Salt” OR “gamma Aminobutyric Acid”, “Monosodium Salt” OR “gamma-Aminobutyric Acid”, “Zinc Salt” OR “gamma- Aminobutyric Acid”, “Calcium Salt” OR “gamma-Aminobutyric Acid”, “Monolithium Salt” OR “gamma Aminobutyric Acid”, “Monolithium Salt” OR “Lithium GABA” OR “GABA, Lithium”).

The searches were conducted based on titles, abstracts, and keywords. Based on the ‘pearl growing’ strategy, after obtaining the full-text articles, the reference list of all included studies was reviewed for any additional publications that could be used in this review. Studies with other designs, such as reviews, case reports, case series, guidelines, commentary, abstracts and articles with unreliable and incomplete results, and studies that did not assess both outcomes of interest were excluded.

2. Study selection and quality assessment

Two reviewers independently screened the titles and abstracts, followed by a full-text review to determine study eligibility. All searches were conducted by two reviewers (F.M and F.RT). The search results were screened based on predefined eligibility criteria. All references were entered into EndNote software. The initial selection was based on the title. Duplicates were deleted, and all remaining abstracts were reviewed. The full texts of all selected articles were obtained for data processing. Disagreements were resolved through discussion and, if necessary, consultation with a third reviewer.

The methodological quality of the included studies was assessed using the Cochrane Collaboration’s tool to assess the risk of bias and the Newcastle-Ottawa scale (NOS). The Cochrane Collaboration’s tool examines various domains of potential bias, including selection bias, performance bias, detection bias, attrition bias, reporting bias, and other sources of bias. Each included study was independently assessed by two reviewers, who evaluated the risk of bias as “low”, “high”, or “unclear” for each domain. Discrepancies between the reviewers’ assessments were resolved through discussion. The risk of bias was categorized as low, moderate, or high based on specific criteria. For the NOS, three domains were scored for selection and comparability of study groups, and to determine the outcome of interest. If a study obtained ≥70% of the highest level of the NOS, it was considered as high quality, those with 40–70% as moderate, those with 20–40% as low, and those with <20% as very low quality.

Result

1. GABAergic pathway implicated in a prenatal androgen exposure (PAE) animal model of PCOS

Prenatal exposure to dihydrotestosterone (DHT), a potent androgen, disrupts the GABA-GnRH network in the developing fetal brain via androgen receptors, resulting in an abnormal estrous cycle, obesity, and anovulation in adulthood [13–15]. GABAergic neurons in the arcuate nucleus of the hypothalamus modulate LH secretion [16–18], indicating their involvement in regulation of the reproductive cycle [19]. Morphological evidence suggests that microglia play a role in the excessive GABAergic connectivity that leads to PCOS-like features in the prenatal androgenized brain. These findings suggest that microglia may contribute to the development or progression of PCOS-like conditions by influencing brain structure and function [20]. In a mouse model of PAE-induced PCOS, the expression of progesterone receptor protein was decreased in the arcuate nucleus of GABAergic neurons [15]. Furthermore, alterations in the neuropeptide Y/agouti-related peptide/GABA circuit that interacts with GnRH neurons suggest impairments in the regulation of reproductive hormones and the hypothalamic- pituitary-gonadal (HPG) axis [21]. PAE mice exhibit reduced GnRH neuron activity during prepuberty, leading to an increased firing rate of these neurons in adulthood [22]. GABAergic neurons in the anteroventral periventricular nucleus can activate the HPG axis and induce PCOS-like reproductive deficits in healthy females [17,23]. Anti mullerian hormone affects GnRH neuronal electrical activity and hormone release. Chronic inhibition of androgen receptor signaling from early adulthood restores normal GABAergic innervation of GnRH neurons, improves ovarian morphology, and rescues the reproductive cycle in PAE mice. Enhanced numbers of excitatory GABAergic inputs to the medial basal hypothalamic GnRH and kisspeptin/neurokinin B/dynorphin neurons following prenatal testosterone exposure may contribute to disturbances in steroid feedback mechanisms and elevated GnRH/LH plasticity [24–28] (Table 1).

Disrupted GABAergic pathway in animals

2. Improvement of the GABAergic pathway in animal models of PCOS

In the PCOS animal model, dysregulation of the expression of hypothalamic neuropeptides has been well-documented. GnRH, the primary regulator of the HPG axis, plays a crucial role in reproductive functions. Kisspeptin and RF-amide related peptide-3 (RFRP-3) are important modulators of GnRH secretion, whereas ghrelin is implicated in the regulation of energy homeostasis and metabolic processes [29,30].

Various experimental studies on the GABAergic pathway have been conducted to restore the altered expression patterns of key hypothalamic neuropeptides in animal models [31,32].

These studies suggest that the targeted modulation of gene expression profiles within the hypothalamus may represent a potential therapeutic approach for addressing the complex hormonal and metabolic disturbances associated with PCOS.

Baclofen reversed alterations in gene expression of GnRH, kisspeptin, RFRP-3, and ghrelin in the hypothalamus of female rats with PCOS. It restores the equilibrium between the excitatory and inhibitory factors that control GnRH and LH secretion [6]. Troxerutin attenuated body weight gain and ovarian damage induced by DHT. It lowered the elevated levels of GnRH, LH, FSH, and testosterone in PCOS rats. Troxerutin normalized the expression of kisspeptin and neurokinin B in GnRH-positive neurons in the median eminence. It regulated the levels of GABA and glutamate in the hypothalamus, which influence GnRH release [33]. GABA ameliorated metabolic and reproductive disturbances in letrozole-induced PCOS rats. GABA significantly decreased body weight, body mass index, and testosterone level. GABA increased the levels of catalase, superoxide dismutase, peroxidase, and estradiol. GABA improved the lipid profile, glucose tolerance, and oral glucose tolerance test. GABA reduced the number of cystic follicles and adipocytes in the ovaries, enhancing ovarian morphology and function. GABA treatment may have therapeutic potential for treating PCOS in humans [34]. Allopregnanolone enhanced the amplitude and duration of GABAergic inhibition in GnRH neurons. Sullivan and Moenter [35] investigated the specific effects of dehydroepiandrosterone sulfate (DHEAS) on the electrophysiological properties of GABA receptor-mediated chloride currents. The results demonstrated that DHEAS reduced the amplitude of GABA receptor-mediated currents, but did not significantly affect the decay time of these currents. Importantly, the observed effects of DHEAS on GABA receptor currents were dose dependent, with modulation occurring within a physiologically relevant concentration range of 0.1 to 10 micromoles. This dose-dependent relationship suggests that the neurosteroid DHEAS can exert differential and concentration-specific effects on the function of GABA receptors [35] (Table 2).

Improvement of GABAergic pathway in animal models of PCOS

3. Disruption of GABAergic signaling in females with PCOS

GABA is a ubiquitous neurotransmitter in the central nervous system that plays a crucial role in the regulation of various physiological functions, including mood, anxiety, sleep, and hormone regulation. Several studies have investigated the potential links between GABA and PCOS, exploring the role of the GABAergic pathway in females with PCOS. These studies can be broadly categorized into two subgroups: 1) studies reporting GABA dysfunction as a consequence of PCOS and 2) studies proposing that PCOS-related features may arise as a result of primary GABA dysfunction. This categorization was based on the directionality of the proposed relationship between GABAergic signaling and the development of PCOS-associated characteristics. The first subgroup encompasses studies that have identified alterations in GABA neurotransmission as a secondary consequence of the hormonal imbalances and metabolic disturbances that are characteristic of PCOS. The second subgroup included investigations that hypothesized that primary disruptions in GABAergic pathways may contribute to the manifestation of PCOS-related features, such as reproductive dysfunction and metabolic abnormalities.

4. GABA dysfunction as a consequence of PCOS

Several studies have reported alterations in GABA neurotransmission secondary to the hormonal and metabolic disturbances associated with PCOS. Liang et al. [36] showed that GABA-producing species (Parabacteroides distasonis, Bacteroides fragilis, and Escherichia coli) were increased in females with PCOS, and their levels were positively correlated with the serum concentration of LH and the LH: FSH ratio. Several studies have examined the potential relationship between PCOS and various psychiatric disorders that may result from GABA dysfunction. A recent study by Jin et al. [37] investigating this association in European populations reported that PCOS may be a causal factor in the development of obsessive-compulsive disorder, but not anxiety disorder, bipolar disorder, major depression disorder, or schizophrenia.

Aydogan Kirmizi et al. [38] investigated the relationship between PCOS and depression and reported that individuals with PCOS had significantly higher levels of inflammatory markers compared to healthy controls. Patients with PCOS also presented with elevated levels of depression-related biomarkers relative to the control group. Moreover, the severity of depressive symptoms in patients was found to be associated with lower concentrations of GABA and the neurotrophin brain-derived neurotrophic factor. Conversely, the severity of depression in PCOS was linked to a higher level of the excitatory neurotransmitter glutamate and increased inflammation markers [38]. Another study by Radwan et al. [10] suggested that a disrupted GABA level in the peripheral circulation is an additional contributing factor to the manifestation of PCOS. They found that GABA deficiency correlated with 25-hydroxyvitamin D3 vitamin D deficiency, dyslipidemia, and total testosterone [39]. Higher cerebrospinal fluid levels of GABA and estradiol, and possibly T, than eumenorrheic, ovulatory women were also observed in women with PCOS [40].

5. PCOS as a consequence of GABA dysfunction

Several studies have proposed that GABA dysfunction contributes to the manifestation of PCOS-related features, directly or indirectly. Ye et al. [41] investigated amino acid metabolism in females with PCOS and reported that these patietns had severe dysregulation of amino acid metabolism compared with healthy controls. They found that a combination of specific amino acids (AAs), including alanine, valine, leucine, tyrosine, glutamic acid, cysteine, and glycine, demonstrated potential predictive value for assessing the risk of metabolic syndrome in females with PCOS. Moreover, elevated levels of branched-chain AAs, tyrosine, alanine, and lysine were positively correlated with insulin resistance in the PCOS cohort. Alterations in the concentrations of tyrosine, lysine, methionine, hydroxyarginine, 3-methylhistidine, GABA, methyl histidine, and glycine were associated with obesity in females with PCOS [41]. Abnormal central GABA signaling has been identified in patients and in preclinical models as a possible link between androgen excess and elevated GnRH/LH secretion [42]. Females with PCOS had an elevated baseline allopregnanolone concentration compared with follicular-phase controls; however, the mediating effect of obesity on this association is not clear; obese females, regardless of PCOS status, were less sensitive to allopregnanolone than normal-weight controls [43] (Table 3).

Disrupted GABAergic pathway in woman with PCOS

Conclusion

The present review proposes a significant association between GABA pathway dysfunction and PCOS; however, the causal direction of this association has not yet been fully elucidated. It is unclear whether the observed GABA dysfunction is a primary driver of PCOS pathogenesis, or whether it arises as a consequence of the hormonal and metabolic disturbances characteristic of this syndrome.

The GABAergic pathway plays a crucial role in the regulation of reproduction by influencing the activity of GnRH neurons, the central regulators of the HPG axis [16,44]. In PCOS, dysregulation of the GnRH/LH pulse frequency leads to ovarian dysfunction and hyperandrogenism. The GABAergic regulation of GnRH neurons is influenced by a variety of factors, including PAE, kisspeptin, and sex steroids [21,45].

PAE alters the development and function of GnRH neurons and their GABAergic inputs. This PAE-induced alteration results in increased firing activity and excitatory GABAergic transmission onto GnRH neurons in adulthood. This dysregulation of the GABAergic system is believed to contribute to increased GnRH and LH secretion as well as hyperandrogenism, as observed in animal models of PAE [21,45]. However, the precise mechanisms by which PAE affects the GABAergic control of GnRH neurons remain an active area of investigation [18,46,47].

Kisspeptin can modulate GABAergic transmission in a concentration-dependent manner. Low doses of kisspeptin suppress GABAergic transmission, whereas high doses stimulate it, reflecting its diverse roles in regulating GnRH secretion throughout the reproductive cycle [18,46,47].

In addition to the aforementioned factors, the activity of GnRH neurons is modulated by neurotransmission mediated by GABAA and kainate receptors. Both receptor types are expressed by GnRH neurons as well as their afferent input [18,48,49]. Activation of either GABA-A or kainate receptors expressed by GnRH neurons can increase the GnRH neuronal firing rate and stimulate GnRH and LH secretion. Alterations in these neurotransmission pathways have been reported in animal models and females diagnosed with PCOS. Elucidating the specific alterations in GABA-A and kainate receptor-mediated neurotransmission in PCOS is an important area of ongoing research, as it may lead to the identification of novel therapeutic targets for the treatment of this common endocrine disorder affecting females of reproductive age [6,45,50,51].

In addition to its direct effects on GnRH neurons, GABAergic signaling may also indirectly influence their function through the immune system [19]. GABA signaling can influence the gut-brain axis and contribute to the pathogenesis of PCOS [52]. Additionally, GABA plays a crucial role in regulating ovarian function, which is impaired in PCOS. These peripheral GABA sources and targets may influence central GnRH neuron regulation and contribute to the pathogenesis of PCOS [53].

Emerging evidence suggests that GABA supplementation may offer therapeutic potential for the management of PCOS. Numerous animal model studies have demonstrated that GABA supplementation can ameliorate metabolic disturbances, improve ovarian function, and modulate neuroendocrine parameters in PCOS animal models [34]. Furthermore, several clinical trials have shown that GABA administration may improve insulin sensitivity, reduce androgen levels, enhance ovulation rates, and improve sleep quality in females with PCOS [54]. Although these results are promising, further large-scale well-designed clinical trials are warranted to conclusively establish the efficacy and safety of GABA supplementation as a therapeutic approach for PCOS.

Several studies have suggested that GABAergic dysfunction plays a dual role in neurological and reproductive disorders. Specifically, it may contribute to cognitive impairment and neuronal degeneration in Alzheimer’s disease (AD) while also playing a role in the regulation of ovarian function and the pathophysiology of PCOS [55–57]. Epidemiological studies have reported an increased risk of cognitive impairment and dementia in females diagnosed with PCOS compared with their counterparts without the condition [58]. However, the potential mechanistic links between PCOS and AD require further investigation. It is proposed that the neuroendocrine dysfunction observed in PCOS, characterized by a low level of GABA, may contribute to neuroinflammation and other disruptions within the central nervous system. Studies have shown a decrease in the GABA level and glutamic acid decarboxylase enzyme activity in brain regions affected by AD, such as the cingulate cortex and medial parietal lobe [59–61]. This GABAergic dysfunction is believed to lead to an imbalance between excitatory and inhibitory neurotransmission, resulting in neural network hyperactivity and subsequent episodic memory impairment, cognitive decline, and neurodegeneration [62,63]. The GABAergic system has emerged as a promising therapeutic target for restoring the excitation/inhibition (E/I) balance and improving cognitive function in AD [64,65].

The association between PCOS and AD may also be partially attributed to the shared pathways of neuroinflammation and metabolic dysfunction that characterize both conditions. PCOS and AD are associated with increased systemic inflammation and oxidative damage, which lead to synaptic dysfunction, neuronal death, and ultimately cognitive impairment [66]. Chronic hyperinsulinemia and impaired insulin signaling, as metabolic features of PCOS, may result in neuroinflammation, oxidative damage, and disruption of glucose and lipid metabolism in the brain. These factors are believed to contribute to the cognitive decline and neurodegeneration observed in AD [67,68]. Alterations in the lipid profile, including elevated triglycerides, a low high-density lipoproteincholesterol level, and the presence of small dense low-density lipoprotein particles, are commonly observed in females with PCOS. These lipid abnormalities may also promote the accumulation of amyloid-beta peptides and formation of amyloid plaques, which are considered hallmarks of AD pathology [69,70].

The potential mechanistic links between PCOS and AD warrant further investigation as elucidating these connections could lead to the identification of shared therapeutic targets and the development of more effective strategies for the prevention and management of both disorders. Several GABAergic drugs, including GABA receptor modulators, have been investigated as potential therapeutic agents for the treatment of AD in preclinical and clinical studies. Targeting specific GABA receptor subtypes, such as the α5 subunit-containing GABA-A receptors, has shown promise in restoring the E/I balance and improving cognitive function in AD models [62,71]. Further studies are required to fully elucidate the precise mechanisms by which GABAergic dysfunction results in AD and also to optimize GABAergic drugs to treat the cognitive and neuropsychiatric symptoms of this disease [52,72,73]. Further investigations are essential to explore potential therapeutic interventions aimed at modulating the GABA level with the goal of improving the reproductive and the neurodegenerative aspects associated with PCOS and AD. Given the emerging evidence linking GABAergic dysfunction to the pathophysiology of both conditions, targeted therapies that enhance GABA signaling may offer a promising avenue for mitigating the cognitive decline and reproductive disturbances observed in affected individuals.

This review underscores the pivotal role of the GABAergic signaling pathway as a potential shared mechanistic link underlying the pathogenesis of PCOS. This observation may open new avenues for the exploration of potential therapeutic interventions targeting GABAergic modulation in PCOS. However, the exact causal relationship between GABAergic dysfunction and the development of PCOS remains unclear. Further studies are required to elucidate the precise molecular and cellular mechanisms underlying dysregulation of the GABAergic system and its contribution to the pathogenesis of these conditions. Furthermore, comprehensive evaluations are required to assess the efficacy, safety, and optimal dosing strategies of GABA-based pharmacological interventions for the management of PCOS and associated conditions.

1. Limited future recommendations

To advance our understanding of the GABAergic pathway in PCOS, future studies should prioritize well-designed randomized controlled trials with larger sample sizes to evaluate the efficacy and safety of GABA supplementation across diverse PCOS phenotypes, utilizing standardized GABA formulations and dosages. These trials should incorporate placebo controls, blinding, and comprehensive monitoring of endocrine, metabolic, reproductive, and quality of life outcomes. Additionally, longitudinal studies are essential to assess the long-term impact of GABA on the progression of PCOS and associated health risks. Mechanistic studies should further explore the interaction between GABA and other neuroendocrine pathways. Standardizing diagnostic criteria, employing validated outcome measures, and utilizing rigorous study designs, with adequate sample sizes and control groups, will be crucial for all future research endeavors.

Notes

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

The study proposal received approval from the ethics review board of the Research Institute for Endocrine Sciences (approval number: IR.SBMU.ENDOCRINE.REC.1402.028).

Patient consent

Not applicable.

Funding information

Research Ethics Committees of Research Institute for Endocrine Sciences-Shahid Beheshti University of Medical Sciences (IR.SBMU.ENDOCRINE.REC.1402.028).

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Fig. 1

Article flow diagram. ICTRP, international clinical trials registry platform.

Table 1

Disrupted GABAergic pathway in animals

Study Title Type of animal, method for inducing animal model of PCOS Results Cochrane collaboration’s tool (total)
Watanabe et al. [13] (2023) Defining potential targets of prenatal androgen excess: expression analysis of androgen receptor on hypothalamic neurons in the fetal female mouse brain

  • -Mouse, C57BL/6 female or_vGaT-ires-Cre/tdTomato

  • -On days 16–18 of pregnancy, mice were injected s.c. with 250 μg/day dihydrotestosteron

 Dihydrotestosterone (DHT) indirectly modulates the release of GnRH release in the fetal brain by acting on kisspeptin neurons, rather than on GABA neurons, within the GABA-GnRH pathway Low risk of bias in all domains
Bhattarai et al. [14] (2023) Suppression of neurotransmission on gonadotropin-releasing hormone neurons in letrozole-induced polycystic ovary syndrome: a mouse model

  • -Mouse, GnRH-GFP; strain: C57BL/6 and ICR mice

  • -Letrozole was administered orally in drinking water at 1 mg/kg/day for 5 weeks to induce PCOS in adult female mice (8–10 weeks old)

 Letrozole inhibits GABAA, kainate, and kisspeptin neurotransmission in GnRH neurons, thereby associating these disruptions with reproductive abnormalities and pathogenesis of PCOS High risk of bias in the blinding domains, and an unclear risk of bias in the random sequence generation and allocation concealment domains
Coyle et al. [18] (2022) Chronic androgen excess in female mice does not impact luteinizing hormone pulse frequency or putative GABAergic inputs to GnRH neurons Mouse, DHT was administered via s.c capsules (0.5 mg of DHT per day) that were implanted at postnatal day 21 and remained in place for 90 days Chronic exposure to DHT results in an increase in neurons expressing androgen receptors; however, it does not exhibit the effects of prenatal androgen excess effects on the GnRH network or LH secretion Low risk of bias in all domains
Watanabe et al. [15] (2021) Prenatal androgenization causes expression changes of progesterone and androgen receptor mRNAs in the arcuate nucleus of female mice across development Mouse injected TP into pregnant female mice from day 12 of gestation until birth Prenatal exposure to androgen diminishes the expression of progesterone receptor in GABA neurons within the arcuate nucleus, indicating a potential mechanism underlying hormonal imbalances associated with PCOS Low risk of bias in all domains
Sati et al. [20] (2021) Morphological evidence indicates a role for microglia in shaping the PCOS-like brain Mouse pregnant mice were s.c with 100 μL DHT; 250 μg on days 16–18 of gestational period Microglia contribute to the heightened GABAergic connectivity that results in features analogous to PCOS in the brain affected by prenatal androgen exposure Low risk of bias in all domains
Marshall et al. [21] (2020) Investigating the NPY/AgRP/GABA to GnRH neuron circuit in prenatally androgenized PCOS-like mice Mouse pregnant mice were s.c injected with 100 μL DHT; 250 μg on days 16–18 of gestational period Excessive prenatal androgen exposure remodels GABA-to-GnRH circuits within a non-NPY/AgRP subpopulation of GABA ARN neurons Low risk of bias in all domains
Dulka et al. [22] (2020) Chemogenetic suppression of gnrh neurons during pubertal development can alter adult gnrh neuron firing rate and reproductive parameters in female mice Mouse pregnant mice were s.c injected with 100 μL DHT; 250 μg on days 16–18 of gestational period PAE-induced suppression of GnRH during prepubertal period results in increased firing rates in adulthood, with androgen exposure being essential for reproductive neuroendocrine programming in the context of PAE and potentially PCOS Low risk of bias in all domains
Silva et al. [17] (2019) Activation of arcuate nucleus GABA neurons promotes luteinizing hormone secretion and reproductive dysfunction: implications for polycystic ovary syndrome Mouse pregnant mice were s.c injected with 100 μL DHT; 250 μg on days 16–18 of gestational period Chronic activation of GABA neurons in the arcuate nucleus can replicate the reproductive deficits associated with PCOS, while attenuated HPG responses in mice subjected to PAE may be attributable to frequent GnRH/LH secretion as well as depleted LH reserves Low risk of bias in all domains
Silva et al. [28] (2018) Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS Mouse pregnant mice were s.c injected with 100 μl DHT; 250 μg on days 16–18 of gestational period Neurological circuit abnormalities manifest prior to the onset of symptoms associated with PCOS; however, inhibiting androgen signaling in adults has the potential to rectify these abnormalities and restore normal reproductive function. Furthermore, excess androgen appears to perpetuate the neurological and ovarian complications related to PCOS Low risk of bias in all domains
Berg et al. [19] (2018) Prepubertal development of GABAergic transmission to GnRH neurons and postsynaptic response are altered by prenatal androgenization Mouse pregnant mice were s.c injected with 225 μg DHT on days 16–18 of gestational period PAE disrupts the prepubertal development of the GABAergic network associated with GnRH neurons, resulting in alterations to presynaptic organization and postsynaptic response, which may contribute to reproductive dysfunction in adulthood Low risk of bias in all domains
Dai et al. [74] (2016) Different transcriptional levels of GABAA receptor subunits in mouse cumulus cells around oocytes at different mature stage Mouse transcriptional levels of GABAA receptor subunits in germinal vesicle and metaphase II mouse CCs, and explored the role of GABA-A receptor subunits during ovarian follicular development and oocyte maturation Various stages of oocyte development exhibit differing levels of GABAA receptor subunits, indicating that these receptors may play a role in the maturation of oocytes An unclear risk of bias in the random sequence generation, allocation concealment, and blinding domains, and a low risk of bias in the other domains
Cimino et al. [26] (2016) Novel role for anti-Müllerian hormone (AMH) in the regulation of GnRH neuron excitability and hormone secretion

  • -Mouse and rat C57BL/6J mouse and sprague dawley rat

  • -Pregnant mice were s.c injected with 100 μL DHT; 250 μg on days 16–18 of gestational period

 AMH may contribute to the heightened pulsatility of LH pulsatility observed in PCOS, thereby presenting a potential new therapeutic target for this prevalent cause of infertility Low risk of bias in all domains
Moore et al. [32] (2015) Enhancement of a robust arcuate GABAergic input to GnRH neurons in a model of polycystic ovarian syndrome

  • -Mouse adult female C57BL/6J (B6)

  • -Pregnant mice were s.c injected with 100 μL DHT; 250 μg on days 16–18 of gestational period

 A robust GABAergic circuit originating from the ARN is augmented in a model of PCOS. This intensified circuit may contribute the neuroendocrine abnormalities observed in PCOS Low risk of bias in all domains
Sullivan and Moenter [23] (2004) Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder Mouse pregnant mice were s.c injected with 100 μL DHT; 250 μg on days 16–18 of gestational period Prenatal exposure to steroids modifies GnRH inputs, thereby affecting reproduction and contributing to fertility disorders Low risk of bias in all domains
Chaudhari et al. [75] (2018) GnRH dysregulation in PCOS is a manifestation of an altered neurotransmitter profile Rat oral administration of letrozole (aromatase inhibitor) 0.5 mg/kg B.W of letrozole In PCOS, the levels of inhibitory neurotransmitters associated with GnRH and LH are reduced, while stimulatory glutamate levels increase, accompanied by alterations in metabolizing enzymes and receptors Low risk of bias in all domains
Chaudhari and Nampoothiri [76] (2017) Neurotransmitter alteration in a testosterone propionate-induced polycystic ovarian syndrome rat model Rat 21-day-old rats were s.c. injected with 10 mg/kg weight B.W of TP for 35 days TP-induced PCOS in rats, is characterized by elevated testosterone, the presence of ovarian cysts, deficits in neurotransmitter (NE, DA, serotonin, and GABA), increased brain acetylcholinesterase activity, and mood disorders associated with disruptions in GnRH and ovarian dysfunction Low risk of bias in all domains
Sotomayor-Zárate et al. [77] (2011) Neonatal exposure to single doses of estradiol or testosterone programs ovarian follicular development-modified hypothalamic neurotransmitters and causes polycystic ovary during adulthood in the rat Rat neonatal rats were s.c. injected with a single dose of 0.1 mg EV, 1.0 mg TP, or 1.0 mg DHT Exposure to EV resulted in increased levels of 5-HT, DA, NA, and Glu, while simultaneously decreasing GABA in the VMH-AN. In contrast, TP exposure led to an increase in Glu, a decrease in 5-HT, and alteration in follicular dynamics, without inducing ovarian changes associated with DHT Low risk of bias in all domains
Porter et al. [24] (2019) Prenatal testosterone exposure alters GABAergic synaptic inputs to GnRH and KNDy neurons in a sheep model of polycystic ovarian syndrome Sheep pregnant suffolk sheep were injected with 100 mg per injection of T propionate twice weekly from 30 to 90 days of gestational period Prenatal exposure to testosterone enhances stimulatory signals to critical reproductive neurons in the brain. This may disrupt hormone balance and elevate LH pulsatility, resembling the patterns observed in PCOS Low risk of bias in all domains

GABA, gamma-aminobutyric acid; PCOS, polycystic ovary syndrome; s.c., subcutaneous; GnRH, gonadotrophin-releasing hormone; GFP, green fluorescent protein; ICR, institute of cancer research; GABAA, γ-aminobutyric acid type A; TP, testosterone propionate; NPY, neuropeptide Y; AgRP, agouti-related protein; ARN, arcuate nucleus; PAE, prenatal androgen exposure; HPG, hypothalamic-pituitary-gonadal; LH, luteinizing hormone; CCs, cumulus cells; B.W, body weight; NE, norepinephrine; DA, dopamine; EV, estradiol valerate; 5-HT, 5-hydroxytryptamine; NA, noradrenaline; VMH-AN, ventromedial hypothalamus-arcuate nucleus; KNDy, kisspeptin/neurokinin B/dynorphin.

Table 2

Improvement of GABAergic pathway in animal models of PCOS

Study Title Type of animal and treatment Result Cochrane collaboration’s tool (total)
Sullivan and Moenter [35] (2003) Neurosteroids alter gamma-aminobutyric acid postsynaptic currents in gonadotropin-releasing hormone neurons: a possible mechanism for direct steroidal control Mouse allopregnanolone (0.1, 0.5, 1, 2, 5, and 10 μm) Allopregnanolone enhances the responsiveness of GnRH neuron responsiveness to GABAA receptor activation, while DHEAS diminishes this responsiveness. These effects modulate modulating chloride channel currents and mediate steroid feedback mechanisms Low risk of bias in all domains
Rahimi Rick et al. [6] (2021) A role for GABA agonist in controlling the reproduction of female rats via hypothalamic ghrelin, kisspeptin, and RFRP-3 gene expression Rat rats were i.p. injected with 5 or 10 mg/kg B.W of baclofen for 2 weeks In the context of PCOS, the GABAergic signaling pathway may modulate GnRH neural activity through the downregulation or upregulation of intra-hypothalamic neuropeptides that act upstream of GnRH neurons Low risk of bias in all domains
Gao et al. [33] (2020) Troxerutin protects against DHT-induced polycystic ovary syndrome in rats Rats were i.p. injected with 150 or 300 mg/kg B.W of troxerutin for up to 4 weeks Troxerutin mitigates the symptoms of PCOS in rats by regulating reproductive hormones and neuropeptides, while normalizing levels of GABA and glutamate to modulate the release of GnRH Low risk of bias in all domains
Ullah et al. [34] (2017) Protective effects of GABA against metabolic and reproductive disturbances in letrozole induced polycystic ovarian syndrome in rats Rat or GABA (100, 500 mg/kg/day) along with letrozole GABA significantly reduced body weight, BMI, and testosterone levels, while increasing the levels of CAT, SOD, POD, and estradiol. These changes resulted in improvements in lipid profile, glucose tolerance, and ovarian function, with effects comparable to those observed with metformin Low risk of bias in all domains

GABA, gamma-aminobutyric acid; PCOS, polycystic ovary syndrome; GnRH, gonadotropin-releasing hormone; DHEAS, dehydroepiandrosterone sulfate; RFRP-3, RF-amide related peptide-3; i.p., intraperitoneal injection; B.W, body weight; DHT, dihydrotestosterone; BMI, body mass index; CAT, catalase; SOD, superoxide dismutase; POD, peroxidase.

Table 3

Disrupted GABAergic pathway in woman with PCOS

Study Title Study design and population Result Newcastle-Ottawa case control scale (NOS) tool total
Ye et al. [41] (2022) Amino acid signatures in relation to polycystic ovary syndrome and increased risk of different metabolic disturbances

  • -Case control (Chinese Han women)

  • -Chinese Han women (n=380; 190 with PCOS and 190 controls)

 Women with PCOS suffered from severe dysfunction of amino acid metabolism

  • -A combination of alanine, valine, leucine, tyrosine, glutamic acid, cysteine and glycine indicated the predictive potential of metabolic syndrome risk in women with PCOS

  • -Enhanced levels of branched-chain amino acids, tyrosine, alanine and lysine were correlated to insulin resistance in the PCOS group

  • -Alterations of tyrosine, lysine, methionine, hydroxy arginine, 3-methyhistidine, GABA, methyl histidine, and glycine were related to obesity in women with PCOS

 7
Liang et al. [36] (2021) Gut microbiota alterations reveal potential gut-brain axis changes in polycystic ovary syndrome Case control (Han nationality women) aged from 18 to 40 years (n=40; 20 with PCOS and 20 control) Dietary analysis showed that the intake of dietary fiber, and vitamin D significantly decreased in PCOS. For the first time, our study found an increase of GABA-producing species in PCOS, including parabacteroides distasonis, bacteroides fragilis, and escherichia coli, which significantly positively correlated with serum LH levels and LH: FSH ratios 9
Jin et al. [37] (2021) Polycystic ovary syndrome and risk of five common psychiatric disorders among European women: a two-sample mendelian randomization study Case control the genetic variants were from summary data of genome-wide association studies in European populations In European populations, PCOS may be a causal factor in obsessive-compulsive disorder, but not anxiety disorder, bipolar disorder, major depression disorder, or schizophrenia 8
Aydogan Kirmizi et al. [38] (2020) Sexual function and depression in polycystic ovary syndrome: is it associated with inflammation and neuromodulators? Case control n=80; 20 fertile and 30 infertile patients diagnosed with PCOS and 30 healthy volunteers The study found that PCOS patients had higher levels of inflammation and depression markers than healthy controls. Depression severity was linked to lower levels of GABA and BDNF and higher levels of glutamate and inflammation markers. Obesity and high waist-to-hip ratio were risk factors for sexual dysfunction, but no link was found between sexual function and inflammation or depression markers 5
Radwan et al. [39] (2019) Decreased serum level of gamma-amino butyric acid in egyptian infertile females with polycystic ovary syndrome is correlated with dyslipidemia, total testosterone and 25(OH) vitamin D levels Case control 18 PCOS patients and 18 age-matched healthy females The findings of this study suggest that disrupted GABA level in the peripheral circulation is an additional contributing factor to PCOS manifestations. GABA deficiency was correlated with 25(OH) vitamin D deficiency, dyslipidemia, and total testosterone 5
Kawwass et al. [40] (2017) Increased cerebrospinal fluid levels of GABA, testosterone and estradiol in women with polycystic ovary syndrome Case control women with PCOS as compared to EW Women with PCOS displayed higher CSF levels of GABA and E2, and possibly T, than EW 5
Hedström et al. [43] (2015) Women with polycystic ovary syndrome have elevated serum concentrations of and altered GABA(A) receptor sensitivity to allopregnanolone Case control nine women with PCOS and 24 age-matched eumenorrheic controls Women with PCOS exhibited elevated baseline concentrations of allopregnanolone compared to follicular-phase controls. Furthermore, all overweight women including those with PCOS and controls, demonstrated reduced sensitive to allopregnanolone in comparison to normal-weight controls 9

GABA, gamma-aminobutyric acid; PCOS, polycystic ovary syndrome; LH, luteinizing hormone; FSH, follicle stimulating hormone; BDNF, brain-derived neurotrophic factor; 25(OH), 25-hydroxyvitamin D3; EW, eumenorrheic, ovulatory women; CSF, cerebrospinal fluid; E2, estradiol; T, testosteron.