Current Updated Aspect Related to Pathogenesis, Diagnosis, Comorbidity and Management of Polycystic Ovary Syndrome—A Critical Review

1. Introduction

Polycystic ovary syndrome (PCOS) is an endocrine disorder having multiple etiologies that distresses between 8–13% among women of ovulatory age worldwide. Importantly, approximately 70% of diseased women remain undiagnosed, and their lives remain compromised [1]. PCOS has a complex origin involving genetic, environmental, and lifestyle factors, and many more are still debated. It is recognized as elevated levels of androgens, irregular menstrual cycles, resistance to insulin, and polycystic ovaries [2,3]. Numerous women with PCOS experience feature of the metabolic syndrome, together with insulin resistance (IR) and raised insulin levels. High androgen levels, a key feature of PCOS, have significant health impacts on the young female population.

Hirsutism, acne, and male pattern alopecia are some of the clinical signs of hyperandrogenism (HA). In around 20% of PCOS instances, chronic anovulation manifests as irregular menstrual bleeding, irregular menstrual periods, or infertility that occurs at the same time as similar to women with regular menstrual cycles [4,5]. Clinically, 50–80% of females with PCOS are obese, 30–35% have impaired glucose tolerance, and 8–10% have diabetes melitus [2,3,4].

PCOS has been found to be a major concern for women’s health, particularly impacting health-related quality of life (HRQOL). It is worth revealing that PCOS upsurges the odds, such as cardiovascular diseases (CVDs), type 2 diabetes mellitus (T2DM), and other metabolic syndromes concurrent to psychological distress, and puts women in serious life-threatening conditions [6,7,8]. The hormonal changes-based pathogenesis of PCOS involves elevated levels of the gonadotropin-releasing hormone (GnRH) from the hypothalamus that lead to excessively increased levels of the luteinizing hormone (LH) and lower levels of the follicle-stimulating hormone (FSH). This hyperstimulates the ovaries to secrete additional androgens and leads to ovulatory dysfunction. Another cause of PCOS is an endocrinological disturbance of the insulin axis, such as hyperinsulinemia and IR. Higher circulating levels of insulin diminish the secretion of sex hormone-binding globulin (SHBG) from the liver, which in turn elevates the free testosterone in body circulation and develops characteristics of hyperandrogenemia [9,10,11].

As the pathogenesis of PCOS is quite complex, the treatments must be individualized according to current signs and symptoms and require multiple drugs to manage the disease. Noteworthy, the United States Food and Drug Administration (USFDA) yet did not approve drugs explicitly for PCOS, and only off-label drugs are available for managing this condition. To manage PCOS, the most important step is to reduce at least 5% of the body weight. Thus, a healthy diet and regular exercise plan are well recommended for every woman with PCOS [12]. Moreover, all the management needed to revisit for improving the HRQOL among PCOS patients.

2. Pathogenesis and Clinical Manifestations in Polycystic Ovary Syndrome

There are a number of variables that are linked to the pathophysiology of PCOS, characterized by the interplay between endocrine secretions, genetic morphology, and ecological stressors (Figure 1).

Hyperandrogenism

Generally, HA develops due to decreased sex hormone-binding globulin (SHBG) levels and raises the free testosterone concentration in PCOS. Elevated amounts of testosterone in plasma can be transformed by adipose tissue into estrone. When the process of converting estrone to estradiol is interrupted, it affects follicular growth as well as changes the ratio of LH to FSH, leading to ovulatory failure [13,14]. Additionally, HA increases anti-mullerian hormone (AMH) levels, which suppresses follicle development and ovulation via various processes [15]. Moreover, HA is inversely correlated with IGF-II levels, which favorably influence follicle diameter and estradiol concentration in follicular fluid [16]. LH levels are indirectly raised by HA. Through negative feedback processes, progesterone and estradiol both regulate the secretion of GnRH and LH. This negative feedback loop gets disturbed by HA and raises LH levels [17]. Progesterone receptor transcription is hampered by androgen’s interaction with its receptor. Raised androgen levels are linked to changes in GABA-A receptors, activate GnRH neurons, and lessen the body’s reaction to the negative feedback mechanism of progesterone [18]. Furthermore, androgens can lower hepatocyte nuclear factor 4 (HNF-4) levels in the liver by blocking lipogenesis, and they also bind to the promoter of SHBG to increase its expression [9]. Other PCOS variables like inflammation, oxidative stress, and IR are facilitated in their advancement in HA [19]. It increases IR via a number of mechanisms, including lowering GLUT-4 expression, insulin sensitivity, and suppression of hepatocyte insulin degradation [20]. Adipocyte enlargement is mostly caused by HA, which also markedly reduces adipokine secretion [21]. These facts suggest that PCOS patients typically have high levels of circulating androgens; it is imperative to comprehend the involvement of hyperandrogenemia in the pathogenesis of PCOS-related abnormalities.

Neuroendocrine Implications

As evidenced, PCOS is reported as a disorder of neuroendocrine origin and mental health disorders, including mild to severe symptoms related to anxiety, depression, eating disorder, and even bipolar disorder [17,22]. Many studies suggested that changes in Gamma Amino Butyric Acid (GABA) activity and its level affect the hypothalamus-pituitary-gonadal (HPG) axis (stress axis) and cause development of PCOS [23,24,25]. When taken as a whole, these results highlight the possibility that the neuroendocrine axis plays a role in PCOS development. The data suggests neuronal involvement in the neuroendocrine trails contributing to PCOS. This will be highlighted by studying the involvement of GABAergic neurons.

GABAergic Neurons

GABA neurotransmitter acts primarily as inhibitory in nature stimulates GnRH neurons rather than inhibiting them because of their high intracellular chloride content. GABA-A receptor helps GABA to activate GnRH neurons. Evidence indicated that cerebral fluid of women with PCOS has greater than normal concentrations of GABA [26]. Thus, increased generation of GnRH in PCOS partially enlightened by the reported rise in GABA levels, but this is still conjectural [27,28]. Study suggests that GABA may have dual excitatory and inhibitory nature on different cell groups in the brain. A reduction in GABA levels may lead to an increase in the activity of afferent neurons that are responsible for activating GnRH neurons (Kisspeptin neurons). Kisspeptin functions as a strong inducer for the release of GnRH. High blood levels of LH and circulating kisspeptin are positively correlated among women with PCOS [29,30]. It has been suggested that PCOS may be influenced by kisspeptin neurons since kisspeptin normally stimulates GnRH neuron. Furthermore, the increased LH secretion and GnRH neuron activity are supported by increased Kiss1 mRNA expression in PCOS [31]. Ovulation and blood levels of testosterone or LH after therapy, however, were not assessed over the long term. In women with PCOS, metformin, OCP, dexamethasone, flutamide, and rosiglitazone reduced biochemical hyperandrogenemia, but their side effects may limit their use. [32]. Androgens, rather than decreasing negative feedback and encouraging higher GnRH/LH secretion, would be predicted to elicit more negative feedback, resulting in lower GnRH/LH release. In fact, androgen treatments further decrease the synthesis of GnRH by reducing Kisspeptin 1 (Kiss1) levels in addition to LH secretion in vivo [23,33]. The discrepancy related to the negative feedback process of androgen activities and future research that suggests androgens have a potential role in promoting the hypersecretion of GnRH in PCOS has to be addressed.

MicroRNA

Recently, much evidence about the pro-therapeutic benefits of microRNAs (miRNAs) has been demonstrated for various disorders, together with PCOS [35,36,37]. Gene expression is regulated after transcription by miRNAs, short non-coding RNAs attached with around 22 nucleotides. These miRNAs specifically target genes of the 3’ untranslated region (UTR) and impede their translation, concurrently developing instability [37]. miRNA interaction with target messenger RNA (mRNA) leads to mRNA splitting, obstructing translation, and mRNA degradation [38]. Several physiological processes, such as cell differentiation, proliferation, inflammation, and apoptosis involve various short RNA molecules [36]. Even individual miRNA has the ability to influence the diverse alterations in functioning of diverse target genes responsible for PCOS pathogenesis. The intensification or suppression of a miRNA-generated signal substantially alters the miRNA expression through regulatory feedback mechanisms. This change is an add-on in the initiation and progression of many diseases, like diabetes mellitus, cardiovascular disease, endometriosis, and ovarian cancer [39,40,41,42,43]. This aberrant miRNA expression is thought to have a pivotal role in the progression and development of the PCOS. It further regulates the production of steroidal hormones, impacts the growth and follicular maturation, adipocytes enlargement, and modulation of insulin signaling. In the context of PCOS, miRNAs play a pivotal role in inflammatory processesn, reduced ovarian insulin sensitivity, hyperinsulinemia, and compromised oocyte quality [36,40]. Gaining a comprehensive relationship between miRNAs, steroid hormone production and related metabolic abnormalities suggest the potential to assist in PCOS pathogenesis [44]. In addition, influencing the GLUT4-associated miRNA expression has potential role in controlling glucose metabolism, the insulin signaling system, and the development of IR in PCOS [45]. The impact of microRNAs on lipid metabolism is well discussed, and it seems that microRNAs such as miR-128-1, miR-148a, miR-185, and miR-375 is well associated with metabolism of LDL-C, adipogenesis, increased body mass index (BMI), and possesses aberrant expressions in PCOS conditions [46,47].

Environmental Stressors, Epigenetic Mechanisms, and Xenobiotics

Multiple genetic and environmental variables contribute to the development of PCOS illness. An imbalance of free radical generation and antioxidant systems is also recognized as a possible factor contributing to PCOS initiation and progression [48,49]. Moreover, several studies indicate that prenatal exposure to androgens may have a role in the emergence of PCOS at the fetus stage itself [50,51]. According to the United States Environmental Protection Agency (USEPA), a range of chemicals called endocrine-disrupting chemicals (EDCs) hinder the synthesis, release, movement, attachment, or elimination of natural hormones responsible for metabolic homeostasis, growth, reproduction, and mental behavior. It is beyond a shadow of a doubt that even little disruptions in endocrine function, especially at some extremely sensitive periods of the lifecycle (for example, child growth, pregnancy, and breastfeeding), may result in significant and long-lasting repercussions [52,53]. Common EDCs like bisphenol A (BPA) are frequently used in plastic industries for manufacturing dental fillings, food and beverage packaging, infant bottles, and polyvinyl chloride. These substances disrupt metabolic processes via various mechanisms. BPA has a direct effect on the process of the formation of ovum by modulating estrogen receptors (ER), non-classical membrane ER, and G-protein-coupled receptor 30. In theca cells, it stimulates the production of androgens and prevents the breakdown of testosterone [54,55]. In addition, BPA has an effect on the adrenal cortex and gonad endoplasmic reticulum-resident enzyme CYP17, which is implicated in the production of glucocorticoids and sex hormones by mediating the 17a-hydroxylase and 17,20-lyase reactions of progesterone and pregnenolone [56,57]. BPA has the ability to decrease the expression of the aromatase enzyme and the generation of estrogen in granulose cells. This eventually leads to the disruption of the environment around the follicles and the halting of oocyte development as well as maturation [58]. BPA indirectly raised testosterone levels via diminishing the functioning of testosterone 2a-hydroxylase and testosterone 6b-hydroxylase enzymes in liver cells [59]. It further displaces testosterone from SHBG, leading to raised serum testosterone levels [60]. Due to PCOS’s clinical variability, it is now widely understood that environmental stressors such as EDCs seem to disrupt several neuroendocrine, hormonal, and metabolic signaling pathways, making them a potential environmental cause of PCOS.

Stress

Although the exact link between stress and PCOS is not well documented, it is established that PCOS may have negative impacts on self-esteem and mental well-being. Extended stress induces the excessive proliferation and expansion of fat cells, initiated by excessive release of glucocorticoids and their effect on the maturation of immature fat cells [61,62]. Stress may have detrimental consequences for the body, including the release of adipokines, the attraction of immune cells to adipose tissue, and their activation of these immune cells [63]. Stress-mediated raised glucocorticoids level triggers inflammation, as evidenced by raised cytokines such as IL-6 and TNF-α, and this interferes with the functioning of free radical scavanging enzymes [64]. Stress has a detrimental effect on the hypothalamic-pituitary-adrenal (HPA) axis, causing the release of cortisol. In turn, cortisol promotes the accumulation of fat in visceral organs as well as the processes of IR, gluconeogenesis, and lipolysis [65]. Importantly, stress is itself linked to the excessive release of insulin in the bloodstream. Additionally, stress-related variables include disruption of AMH and altered reproductive hormone in PCOS patients [66,67]. Stress-related PCOS includes metabolic, inflammatory, oxidative, and mental stress, and its pathophysiological core appears early in life. Metabolic stress causes long-term health problems that worsen the syndrome’s reproductive, metabolic, and psychological derangements, creating a cycle of chronic sickness.

Epigenetic Mechanism

Epigenetic alterations include the process of adding or removing chemical constituents from DNA or histone proteins. PCOS cases often display excessive activity of LH, associated to hirsutism and dysfunctions in the formation of ovarian follicles and hirsutism [68]. The production of steroids in theca cells is controlled by LH/choriogonadotropin receptor (LHCGR) [69]. Because of hypomethylation of LHCGR, there is an elevation in gene expression and an increase in LH sensitivity [68,69]. The hypomethylated sequences are linked to the increased expression of LHCGR on the surface of theca cells. Moreover, the enzyme Epoxide Hydrolase 1 (EPHX1) plays a vital role in breaking down aromatic chemicals [70,71]. Overproduction of EPHX1 hampers the conversion of testosterone to estradiol, hence playing a role in the development of PCOS. Peroxisome proliferator-activated receptor gamma (PPAR) plays a crucial role in maintaining normal ovarian function [72,73]. In PCOS women, hypermethylation of PPAR, hypomethylation of nuclear co-repressor 1, and changes in the acetylation of histone deacetylase 3 are well evidenced in the pathogenesis of PCOS [74].

Insulin Resistance

In women with PCOS, IR affects specific tissues such as skeletal muscles, adipocytes, and hepatocytes, which lose their sensitivity to insulin. However, the adrenal gland and ovaries maintain their sensitivity to insulin. Insulin has a direct influence on the generation of androgens and the formation of follicles in the ovaries [75]. On the other hand, an excess of insulin in the body decreases the levels of SHBG in the liver, which leads to a reduction in the synthesis of insulin-like growth factors (IGF-1)-binding proteins and raised androgen production in theca cells [76]. Reduced expression of IGF-1 makes the survival of granulosa cells difficult and thus the process of folliculogenesis, resulting in hindered development of follicles owing to both excessive androgen levels and high insulin levels [76,77]. Hyperinsulinemia due to IR has a negative impact on the pituitary gland by endorsing the release of LH and altering the production of GnRH (Tosi et al., 2012). Additionally, insulin is involved in the processes of adipogenesis, lipid synthesis, and fat storage [75]. IR increases the concentration of fatty acids in the bloodstream, which has a direct effect on the liver and adipocytes and triggers the building of masculine body features [78].

Inflammation

When it comes to ovulation and folliculogenesis, cytokines play a crucial role in regulating ovarian physiology by helping to establish conditions favorable to follicle selection and development. They control cell proliferation, differentiation, and maturation of oocytes [79,80]. Leukocytosis, raised levels of C-reactive protein (CRP), and other inflammatory mediators such as interleukins (ILs) in the stream remain associated with PCOS development [81,82,83]. Moreover, HA also significantly contributes to inflammatory processes [82]. TNF-α, a prominent pro-inflammatory cytokine, worsens IR by disrupting insulin signaling pathways, leading to a decrease in the expression of GLUT-4. IL-1 further hinders the manifestation of FSH and LH receptors, reducing the growth of follicles and the occurrence of ovulation [84,85]. TNF-α and IL-1 impede hepatic nuclear factor (HNF) activation in diverse ways. In addition, nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing proteins-3 (NLRP3) inflammasomes trigger pyroptosis in follicular cells, contribute to ovarian fibrosis, and interfere with the development of follicular cells [86]. The genetic polymorphism study also indicated the involvement of interleukins and other inflammatory mediators in the development of PCOS [87,88].

Oxidative Stress

Oxidative stress is characterized by an overproduction of highly reactive free radicals that is not neutralized by antioxidant systems [89]. Both reactive oxygen species (ROS) and reactive nitrogen species (RNS) are directly or indirectly involved in various signaling cascades (Lai et al., 2018), cellular growth, and differentiation [90,91]. Furthermore, ROS/RNS have an impact on the functional physiology of the ovaries, which includes the process of steroidogenesis and even change in eating behavior [92,93]. The overproduction of ROS/RNS, on the other hand, has been shown to be detrimental to essential molecules such as deoxyribonucleic acid (DNA), lipids, and proteins [89,94]. Nuclear factor-kappa B (NF-κB), which is connected with a number of different inflammatory pathways, is stimulated by increased oxidative stress, which alters the production of pro-inflammatory cytokines like TNF-α and ILs [95,96]. These free radicals further develop IR through suppressing the insulin signaling cascade via these inflammatory markers, leading to enlarged adipocytes and obesity. In turn, this furthermore initiates the physiological and psychological complexities related to PCOS [75]. Several evidences have shown that the etiology of PCOS is associated with elevated levels of oxidative stress [48,79,97].

Obesity

Obesity is a significant cause for developing chronic inflammation [98,99]. Subsequent necrosis is caused by the overdeposition of adipocytes and lipids in visceral organs, which in turn triggers the further release of inflammatory cytokines [100]. Adipose cell hypertrophy and abdominal fat accumulation relate to the onset of an inflammatory condition [100,101]. In addition, obesity has a role in the development of both IR and HA. Elevated levels of non-esterified fatty acids (NEFAs) in the body’s circulation cause visceral adeposity and thus obesity [102,103]. Skeletal muscles preferentially use NEFAs as an energy source rather than utilizing glucose. This hyperglycemic condition triggers the pancreas, resulting in hyperinsulinemia. In addition, visceral fat and catecholamines stimulate the breakdown of fats, leading to lipotoxicity and hindering the removal and effectiveness of insulin [104,105]. Higher levels of free fatty acids (FFAs) lead to a reduction in glucose sensitivity and insulin absorption inside muscle cells, resulting in lower intramyocellular lipid levels [75,106,107]. Research has shown that women with a genetic predisposition to developing PCOS commonly undergo these many clinical and biochemical changes as a result of gaining weight and becoming obese, suggesting a strong link between obesity and the development of PCOS [108,109,110].

Diet

While there is a lack of definitive information addressing the involvement of diet in PCOS, earlier research has shown a correlation between diet intake and diagnostic markers of PCOS [111,112,113]. Saturated fatty acid (SFA) intake has been associated with the development of PCOS via overproduction of inflammatory cytokines, decreasing insulin sensitivity, and increasing IR [114,115]. Saturated fatty acids generate inflammatory markers like TNF-α in the blood and activating genes that repress production of certain cytokines [116]. Importantly, vitamin D deficiency worsens PCOS and its associated health conditions [117,118,119]. Calcitriol increases the expression of insulin receptors at both the mRNA and protein levels. This leads to a direct and indirect improvement in insulin sensitivity. The indirect impact refers to the activation of PPAR-γ, metabolism of fatty acids in adipocytes, and skeletal muscles. On the other hand, a lack of vitamin D is linked to IR mediated by the generation of inflammatory markers. Furthermore, there have been reports indicating that deficiency in vitamin D might decrease the activity of the anti-müllerian hormone (AMH) promoter [117,118,119].

3. Clinical Features Related to Polycystic Ovary Syndrome

Clinically, PCOS-related features have been categorized into three groups: reproductive, psychological, and metabolic features (Figure 2). Reproductive features include hirsutism, HA, menstrual and ovulation dysfunction, pregnancy difficulties, infertility, gestational diabetes, chances of miscarriage, preeclampsia, endometrial hyperplasia, as well as neonatal morbidity. Psychological features include anxiety, poor self-esteem, depression, and compromised HRQOL. Metabolic features include IR, dyslipidemia, T2DM, impaired GTT, and risk of CVDs [120].

4. Major Co-Morbidities Related to Polycystic Ovary Syndrome

Many eminent institutions, like the Endocrine Society, the Androgen Excess and PCOS Society, and the American College of Obstetricians and Gynecologists, have concluded that clinicians should be recommended to evaluate patients’ blood pressure, OGTT, obstructive sleep apnea, depression, and mood disorders at the time of diagnosis and at every subsequent visit [120,121]. PCOS is often associated with multiple alterations, primarily metabolic syndrome, which has been reported to have major associated co-morbidities (Figure 3).

The study suggests that once a woman gets diagnosed with PCOS, the risk for her developing T2DM also increases by up to four times [122,123]. Additionally, an elevated risk of mood disorders among the patients diagnosed with PCOS is well evidenced [124,125,126]. All the important risk factors related to PCOS has been depicted in Figure 4.

Cardiovascular Disease and Dyslipidemia

As reported, the leading cause of death for women is CVDs among those suffering from PCOS [127]. The core risk factors associated with increased CVDs include central obesity, IR, and dyslipidemia [123,128,129]. Women with polycystic ovaries (PCOs) have higher chances of developing CVDs than normal women [127,129]. Existence research reports a greater preponderance of developing atherosclerotic conditions in women suffering from hirsutism, and evidence of substantial intima-media thickness has been recorded among affected patients [130,131]. Independent of facts like age, BMI, T2DM, and dyslipidemia, the study suggests that women with PCOS had 40% higher chances of getting hypertension than the non-PCOS women [132]. Evidence further indicated that the occurrence of pregnancy-associated hypertension (pre-eclampsia) was significantly greater in PCOS-affected patients [133,134].

Diabetes Mellitus and Gestational Diabetes

Along with obesity and T2DM, gestational diabetes mellitus (GDM) is on the rise, impacting an estimated 14% of births worldwide [135]. The disease’s incidence varies according to variations in risk factors and screening and diagnostic procedures [136]. Furthermore, data indicated that from 2016 to 2021, there was a shift from 6.0% to 8.3% in the proportion of mothers who were diagnosed with GDM [135]. This condition arises from an imbalance in β-cell thresholds and their inability to meet insulin needs due to decreased sensitivity during pregnancy [136,137]. PCOS-affected patients often share the same metabolic abnormalities with women suffering from GDM [138,139]. GDM cases have witnessed high incidences of polycystic ovaries, irregular menstruation, and hirsutism, as compared to patients who have had uncomplicated pregnancies [140,141]. Both retrospective and prospective data exist to support the higher chances of GDM in PCOS patients [142,143], particularly if there is a history of hyperinsulinemia from premature conception [144].

Cancer

Extensive research has been conducted to provide evidence in favor of the hypothesis that obesity makes significant contributions to the evolution of cancer in endometrial cells [145,146]. T2DM has been shown to raise the incidence of endometrial cancer by as much as threefold, according to meta-analysis evidence [147,148]. There is a direct correlation between the elevated levels of estrogen that are linked with PCOS and the undeniable risk of developing endometrial cancer [149,150]. This is also reported from a meta-analysis that increased BMI is directly related to the risk of cancer [151]. Furthermore, evidence suggests that hormonal irregularities, particularly estrogens, may contribute to the initiation and progression of ovarian cancer [152]. A population-based study reported a high risk of ovarian cancer among PCOS patients having irregular menstrual cycles for long periods of time [153].

5. Criteria for Diagnosis

The National Institute of Child Health and Human Development endorsed the below-mentioned criteria based on three physical/physiological conditions. 1. Absence/irregular ovulation, resulting in menstrual irregularities such as light or missed periods. 2. High levels of androgens not due to other conditions or augmented body or facial hair. 3. Undergrowth of one or both of the ovaries, clumps of ovarian follicles as detected by ultrasound. A diagnostic approach requires either only features 1 and 2, or any two of the three for a PCOS diagnosis [154]. Then, “Rotterdam Criteria” expanded the PCOS phenotype to encompass any two of the three essential characteristics: oligo-amenorrhea, hyperandrogenism, and polycystic-appearing ovarian morphology on ultrasonography. With passing time and based on evidence, Androgen Excess Society (AES) declared hirsutism, biochemical hyperandrogenism, oligo-anovulation, and polycystic-appearing ovarian morphology (PCOM) to diagnose PCOS [121]. The major three diagnostic criteria have been depicted in Figure 5.

In 2012, the NIH held an evidence-based methodology workshop on PCOS, and experts further recommended broader use of 2003 modified Rotterdam criteria: (1) androgen excess and ovulatory dysfunction, (2) androgen excess and polycystic appearing ovarian morphology (PCOM), (3) ovulatory dysfunction and PCOM, and (4) androgen excess, ovulatory dysfunction, and PCOM [155]. The Rotterdam criteria (developed by the European Society for Human Reproduction and Embryology-ESHRE and the American Society for Reproductive Medicine-ASRM) are still the most extensively used as in the 2018, International Evidence-Based Guideline for the Assessment and Management of PCOS unanimously endorsed them [156]. Currently, It is recommended to use the modified Rotterdam criteria (discussed above) Focusing the PCOM, In 2014, the Androgen Excess and Polycystic Ovary Syndrome Society conducted a meta-analysis that supported raising the bar for polycystic ovarian morphology to at least 25 follicles, and they discovered that reproductive-aged women typically have a median FNPO ranging from 13 to 16 follicles [157].

6. Management of PCOS

PCOS management needs to address the conditions of hyperinsulinemia and hyperandrogenemia, both of which constitute the characteristic markers of PCOS disorder and are extensively addressed in the majority of the treatment strategies. Treatment strategies include changes in lifestyle to intervening pharmacological therapy. A decision support system for early diagnosis can significantly help in preventing or delaying the occurrence of PCOS [158]. The evidences for the management of PCOS has been summarized in Table 1.

Lifestyle Modifications

High BMI makes PCOS cases undergo different clinical and biochemical changes that even worse by exacerbating the reproductive and metabolic implications among PCOS patients [109,110]. Furthermore, it has a significant impact on the patient’s outcome undergoing management of infertility, metabolic abnormalities, and menstrual dysfunction [112,159]. A decrease in body mass of up to just 5–10% is able to considerably improve the function of the ovaries and normalize the concentration of androgen in individuals who are afflicted by PCOS [159,160,161]. For the purpose of weight loss treatment, dietitians suggested incorporating a diet including a low carbohydrate content, more fiber content, and a low fat content into the consumption plan [12]. Diets rich in polyunsaturated fatty acids (PUFA), Vitamin D3, Vitamin E, and omega-3 fatty acids have been shown to modify the amount of glucose in the blood as well as sex hormones [162,163,164].

Pharmacological Interventions

Current management and drug therapy have been considered comparatively operative in PCOS, and still some cases go untreated despite different available interventions. A combination therapy of estrogen-progestin or individual progestin is opted as a primary option for treating oligomenorrhea or amenorrhea in case infertility is not the primary concern. Oral contraceptives (OCs) function by regulating menstruation, thus lowering the chances of developing hyperplasia in the endometrial tissue. Drugs that increase sensitivity to insulin still have a controversial contribution to the therapy to aid in ovulation. Moreover, surgery of the ovary and gonadotropin therapy are the available alternatives in the event of the failure of pharmacological therapy [165,166].

Antiandrogens

HA are routinely reported in the PCOS population owing to the accentuated concentrations of unbound testosterone. Oral contraceptives (OCs) are commonly considered the primary option in the pharmacological management of hirsutism and acne and not suitable for targeted PCOS treatment [167,168]. Moreover, there is a correlation between prescribing the anti-androgen medication at an earlier stage and an improved spontaneous fertility rate [169]. The efficacy of other OCPs for hirsutism was comparable to or hardly different from that of OCPs containing levonorgestrel, cyproterone acetate, or drospirenone. Finasteride and spironolactone are the drugs employed in the treatment of hirsutsmic conditions [170]. Eflornithine is the topical application used for managing hirsutism that affects the face and visible body parts [171,172]. Electrolysis or laser treatments along with eflornithine are favorably used to treat hirsute women, as waxing or shavings are means of temporary relief from the problem [173].

Antidiabetic Agents

Metformin and thiazolidinediones (TZDs) are frequently prescribed for the treatment of hyperinsulinemia; however, TZDs have little additional benefit [174,175,176]. Metformin is used to improve ovulation rates, normalize the BMI, and diminish the levels of testosterone as well as fasting insulin [176,177]. It is a well-established fact that altered glucose metabolism and hyperinsulinemia due to IR are much greater in PCOS patients. This evidence favors the metformin intervention to manifest improvement in the condition of polycystic ovaries, induce regularity in menstruation, and potentiate ovulation in all patients exhibiting anovulation, irrespective of their resistance to clomiphene citrate treatment [174,175,176,177]). Apart from certain undesirable outcomes like gastrointestinal symptoms, metformin, when administered in combination with a hypocaloric diet, showed more beneficial than weight management therapy [174]. Finally, it was concluded by yet another study that therapy with this agent could be concluded as an economical, safer, and easy alternative when compared to others even during in vitro fertilization [178,179]. Collective data on conception rate showed significant improvements in the combined group rather than the individual therapy. However, numerous meta-analyses showed that metformin and clomiphene citrate together were mainly relevant for clomiphene-resistant women with polycystic ovaries. [180,181]. Furthermore, during rFSH therapy, metformin has no discernible impact on ovarian response; however, it may restore ovulation in clomiphene citrate-resistant polycystic ovary syndrome patients with normal glucose tolerance, even if it does not improve insulin resistance. [180,182]. TZDs, namely rosiglitazone and pioglitazone, are employed to treat T2DM and possess an unbeatable impact on the ovaries by diminishing the secretion of estradiol and testosterone [138,176,177,183]. Some changes to the lifestyle must be inculcated, along with the administration of insulin sensitizers, for weight loss and improved BMI along with managing endocrine and metabolic abnormalities. This definitely ameliorates the fertility and ovulation among PCOS patients [159,161,179]. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two examples of incretin hormones that are well-known stimulators of glucose-dependent insulin release. GLP-1 agonists including liraglutide, semaglutide, dulaglutide, and exenatide, offer enhanced insulin sensitivity via reducing inflammation, free radical generation, and fatty acid metabolism. It also acts through increased expression and translation of GLUT-4, ameliorating endoplasmic reticulum (ER), and insulin signaling as evidenced [184,185]. The data from systematic review and meta-analysis reported that both GLP-1 and GIP receptor agonists are promising novel medicines that have the potential for managing PCOS conditions through various aspects [186,187,188]. Therefore, if they are shown to be useful in clinical research, they have the potential to be innovative therapy choices for women who have PCOS in order to improve metabolic risk.

Oral Contraceptives

Ovulation inducers, particularly tamoxifen, bromocriptine, clomiphene, gonadotropins, and GnRH, are drugs commonly employed to induce ovulation [189]. Aromatase inhibitors may yield an additional option of hormone therapy to treat PCOS patients [190]. Meantime, egg quality and egg quantity should be taken into consideration for evaluation by an endocrinologist before prescribing the patient with ovulation induction therapy. The age of the patient also plays a role in estimating the quality and quantity of eggs; for instance, both get compromised with age [191,192].

Clomiphene Citrate

Clomiphene citrate (CC) has been widely employed for potentiating ovulation in women suffering from anovulation accompanied by infertility issues [193,194]. Its treatment in affected patients has claimed to achieve a 60–85% rate of ovulation and 30–40% chances of conception [195,196]. However, a 13-25% rate of abortion has also been reported [197]. It centrally potentiates the agonistic impact on the binding site, dampening their inhibitory effect, and accentuates the recurrence of pulsating gonadotropins, leading to ovulation [198]. CC is preferred because it is economical, has higher patient acceptability, seldom has fewer side effects, and aids in the spontaneous induction of growth in the follicles. Evidence suggests efficacy of CC in encouraging ovulation in PCOS subjects [199]. Approximately 50% of individuals who ovulate do so at a dose of 50 milligrams, another 20%–25% at a dose of 100 milligrams, and 10% at a dose of 150 milligrams. The absence of the ovulation process for up to three or four cycles of the treatment phase, even after administering the highest dose, is an indicator of drug resistance that can be treated with combination therapy.

Gonadotropins

Normal maturation, libido, and procreation depend on the gonadotropins, a family of peptide hormones that control ovarian and testicular function. FSH, LH, and human chorionic gonadotropin (HCG) are all human gonadotropins. The pituitary gland produces FSH and LH, whereas the placenta synthesizes the HCG. The majority of women who suffer from PCOS have abnormal gonadotropin production, particularly an elevated level of mean LH. Once the patient has been determined to be “clomiphene citrate-resistant,” gonadotropins are traditionally prescribed in these cases [166,200]. Evidence for ovarian hyperstimulation and chances of multiple pregnancies, specifically in women already suffering from PCOS, is contraindicated in its use [200]. Moreover, for PCOS women who have tried and failed with CC, then FSH is a good alternative therapeutic option. To achieve optimum follicular development with fewer injections, molecular engineering has made possible to alter FSH preparations to extend their half-lives and therapeutic effects [201]. In women with PCOS who have not yet tried gonadotropin treatment, evidence indicates that it may be more beneficial than CC. Human menopausal gonadotropin (HMG), urinary FSH (uFSH), highly purified uFSH, recombinant FSH (rFSH), follitropin alpha, and follitropin beta are the gonadotropins used for ovulation induction in PCOS patients [200]. These analogues have already shown promise in assisted reproductive therapy.

Aromatase Inhibitors

Aromatase is an estrogen synthetase that potentiates production of estradiol and estrone by facilitating the conversion of testosterone and androstenedione. The disparity in ovulation and pregnancy rates caused by CC due to antiestrogenic action on the endometrium and cervical mucus has suggested use of aromatase inhibitors (AIs) as a possible substitute for CC in inducing ovulation [202]. Letrozole, the most frequently utilized aromatase inhibitor for ovulation induction, is given in doses ranging from 2.5 to 7.5 mg per day for a duration of 5 days, commencing on days 3 to 7 of the menstrual cycle [203]. In the past ten years, numerous studies have been published regarding the use of Letrozole for inducing ovulation in women with PCOS. It is clearly demonstrated that letrozole is equally effective as CC in terms of ovulation rate, pregnancy rate, live birth rate, and rates of multiple pregnancies [190,204]. In summary, letrozole is not advisable as the primary pharmacological treatment for ovulation induction in patients with PCOS; however, it may serve as a more suitable option for specific individuals, particularly those who are obese or resistant to CC [205,206].

Laproscopic Ovarian Drilling

The emerging advances in techniques of laproscopy velocified this evolving surgical approach to address the problem of PCOS [207,208]. Laparoscopic ovarian drilling (LOD) involves 3–6 incisions made with an insulated needle positioned at a 45-degree angle to the ovarian surface, using unipolar current. This results in a local and systemic decrease in androgen and inhibin levels, thus elevating FSH levels, which facilitates follicular development and ovulation [201,209]. Recent research indicated that obesity, prolonged infertility over three years, low baseline LH levels below 10 IU/l, testosterone levels above 4.5 nmol/l, and elevated basal AMH levels above 7.7 ng/ml may correlate with a suboptimal response to LOD [211]. Despite its benefits, LOD is not the primary treatment for PCOS nor the preferred option for CC-resistant PCOS due to the emergence of various safe and effective oral alternatives and the broader acceptance of a relatively safe low-dose step-up regimen of gonadotropin therapy [212]. Indeed, LOD, both with and without medical ovulation induction, may reduce the live birth rate in women with anovulatory PCOS and CC resistance as compared to medical ovulation induction alone [213]. It is also obvious that letrozole and LOD both provide comparable efficacy in attaining live birth rates in individuals with CC-resistant PCOS. Consequently, knowing determinants of LOD success is crucial for enhancing outcomes and preventing needless surgery [211].

7. Other Pharmacological Interventions

Inositols

Inositol is a natural compound, and its related two compounds, myoinositol and d-chiro-inositol, are the most available isomers among their nine isomeric forms. This phosphatidyl-myoinositol precedes the synthesis of inositol triphosphate (InsP3) that functions as an intracellular signaling molecule and controls the activity of many endocrine secretions such as TSH, FSH, and insulin [214]. Activation of myoinositol-based secondary messengers enhances glucose uptake by upregulating glucose transport mechanisms. However, activation of d-chiro-inositol secondary messengers promotes glycogen synthesis. The alterations in the insulin signaling system may lead to insulin resistance by hindering insulin signaling cascades. Importantly, epimerase is an enzyme that transforms myoinositol into d-chiro-inositol while preserving a natural ratio of 40:1 for most tissues [215]. Myoinositol consumption has been shown to enhance ovulation and increase the effectiveness of reproductive therapies in PCOS women who are unable to conceive naturally [215,216]. Moreover, its treatment significantly decreased both the time required for ovulation induction and the amount of recombinant FSH needed [217]. Concurrent to increased insulin sensitivity, myoinositol treatment significantly reduces the levels of androstenedione, LH, LH/FSH ratio, prolactin, and insulin [218]. These improvements have substantial impacts on endocrine, metabolic, and reproductive parameters. However, both clinicians and patients should be engaged in shared decision-making about inositol for PCOS. It is important to take into account both the ambiguity of the evidence and individual beliefs and preferences. [219,220].

MicroRNA Therapy

The significant association among miRNAs, obesity, and dyslipidemia highlights the therapeutic possibility of targeting PCOS-related metabolic alterations [221]. Evidence suggests that miRNAs might serve as valuable clinical indicators for diagnosing PCOS and as a target for therapeutic interventions in the treatment of PCOS [222,223,224]. Based on miRNA profiling, it might enhance the provision of individualized medical treatment for PCOS. High-throughput sequencing and profiling of microRNAs may improve clinical management and help patients by choosing the most effective treatment for infertility. Through the use of cutting-edge technology and easily available databases, this instrument offers accurate diagnosis, prevention, and treatment of reproductive issues related to PCOS [35,225] Deswal and Dang, 2020). The main objective is to conduct comprehensive replication tests in order to identify particular miRNAs that have substantial modulatory effects on PCOS, and this will provide innovative possibilities and convincing alternatives for PCOS-associated metabolic problems. Therapeutics, including small interfering RNA (siRNA), anti-miRNA oligonucleotides, and miRNA mimics, are the current areas of scientific interest [44,226]. The miRNAs that have a role in PCOS are not yet the focus of any therapy. However, investigating miRNAs that are associated with PCOS may provide new opportunities for future research on PCOS [44,227,228].

Interleukin-22 Therapy

Interleukin-22 (IL-22) is a central mediator secreted by immune cells and reported to be responsible for inflammation, mucous production, microbial infection, tissue regeneration, and facilitating the body’s defensive mechanisms. It does this by restraining cellular necrosis and tissue damage either due to inflammation or different infections, thus maintaining homeostasis for body immunity [229,230]. Metabolic abnormalities and immunological challenges associated with persistent low-grade inflammation are prevalent in persons with PCOS. Recent studies indicate that IL-22 is therapeutically helpful in addressing immunological dysfunction and metabolic disorders, implying its potential relevance in the treatment of PCOS. [231,232,233]. Another study showed that IL-22-associated browning of white adipose tissue plays a major role in regulating tissue sensitivity to insulin and ovarian functions in PCOS. This endorses the potential therapeutic application for treating PCOS with HA phenotype [234]. Exogenous IL-22 treatment has been shown to have therapeutic advantages, as evidenced by experimental studies. Decreased IL-22 may play a role in the onset of PCOS. IL-22 stimulates cell proliferation, prevents apoptosis, and controls steroidogenic human granulosa-like tumor cell line (KGN) cell steroidogenesis when exposed to lipopolysaccharide [235]. Concurrently, Geng and coworkers (2023) have reported that IL-22 could potentially serve as a viable therapeutic agent for PCOS patients in the future. Given the circumstances, the IL-22 pathway might open another door for intervention in diseases related to metabolic alterations like PCOS [232].

Restoration of the Gut Microbiome

The development of PCOS-related symptoms might be significantly influenced by an imbalance in the gut flora [236]. With enhanced comprehension and pathological involvements of gut microbiota, substantial efforts have been made to develop innovative approaches for managing PCOS [237,238]. Treatment options related to PCOS include probiotics (living microorganisms), prebiotics (sources of food for good gut bacteria), synbiotics, and more modern treatments such as fecal microbiota transplants [239,240]. In nature, probiotic bacteria grow in food post-fermentation and possess antioxidant, antimicrobial, and anti-inflammatory effects [241,242,243]. They also have the capacity to ameliorate metabolic parameters like IR and dyslipidemia, maintaining dysbiosis, and modifying the immune system [244]. The most important bacterial families related to probiotics include the Lactobacillus, Bifidobacterium, Lactococcus, Carnobacterium, Enterococcus, Streptococcus, Pediococcus, Propionibacterium, Leuconostoc, and Bacillus species, Saccharomyces yeasts, and Aspergillus molds [245]. Multiple mechanisms contribute to the development and worsening of PCOS, including dysbiosis in the gut microbiota, which significantly regulates HA, IR, chronic inflammation, and metabolic abnormalities [246]. Probiotics significantly impact the regulation of hormonal and inflammatory indicators, according to a new meta-analysis. The study indicated a major decrease in the HA and malondialdehyde, as well as an increase in SHBG and nitric oxide. Additionally, probiotics have been shown to improve weight, BMI, HOMA-IR, insulin levels, dyslipidemia, hirsutism, as well as total testosterone [246,247,248]. Prebiotics exert their effects in several ways, such as selectively stimulating the activity of beneficial bacteria in the intestines, undergoing fermentation by the gut microbiota, and inhibiting the colonization of pathogens by interacting with them. According to some research, prebiotics promote the proliferation of gut microbiota and indirectly promote the therapeutic benefits of probiotics [236,246,247,248]. Further research is necessary to clarify the efficacy of various prebiotics and probiotic strains and doses, establish the optimal treatment regimen, and demonstrate its beneficial impact on clinical outcomes in PCOS.

Fecal microbiota transplants (FMTs) are a cutting-edge biotherapy that entails transferring the fecal fluid from healthy individuals who have undergone intestinal treatment. The purpose is to rebuild the intestinal flora and effectively cure the ailments in question [249]. FMTs have emerged as an effective approach in the treatment of metabolic diseases [250,251]. FMTs can decrease intestine permeability by increasing short-chain fatty acid synthesis, promoting the intestinal adaptive immune response, and controlling gut microflora. They can also modulate blood sugar levels and insulin sensitivity and may influence inflammatory cytokine production [250,252]. In vivo research shows FMTs decrease testosterone levels, increase estrogen levels, and support menstrual cycle maintenance [253]. A new theory suggests altered gut microbiota in PCOS conditions and FMTs could be effective in treatment, reducing the remission rates in PCOS [248,254]. An analysis of publicly available data revealed that the microbial characteristics of PCOS patients, especially those with varying testosterone levels, establish a basis for further research into the pathogenesis of PCOS and the formulation of effective diagnostic, treatment, and intervention strategies [255].

Statins

Statins have been added as newer treatment options as they decrease the production of sex steroid and ovarian androgen by preventing androgen production in thecal cells [156,157,158]. New research lends credence to the idea that the mevalonate pathway is crucial to thecal interstitial cell function and that statin-induced alterations in this system may have a positive impact on PCOS and CVDs [258]. In another study, clinical and biochemical abnormalities, such as ovulation dysfunction, in women with PCOS have been shown to improve with long-term statin treatment [259]. Moreover, atorvastatin may induce a decrease in the levels of testosterone and other androgens by decreasing the level of cholesterol, which is the precursor of the steroidogenesis pathway. Testosterone and other androgens are essential for the proper functioning of the reproductive physiology. There is a possibility that atorvastatin may result in adverse effects in the majority of situations due to the potential reduction in androgen levels. Conversely, in the context of polycystic ovary syndrome (PCOS), the administration of atorvastatin may be advantageous for the reduction of excessive androgen levels [260]. The evidence also suggests the use of statins and adjunct therapy with first line drugs used in PCOS management, particularly those associated with dyslipedimia [81,261].

Vitamin D and Calcium Supplements

Evidence suggests that follicle maturation, HA, and menstrual regularity are all improved with vitamin D and calcium supplementation for PCOS [118,262]. Vitamin D modulates AMH signaling, FSH sensitivity, and progesterone levels in human granulosa cells, all of which are important for ovarian follicular growth [119]. Women who suffer from PCOS have aberrant ovarian folliculogenesis due to elevated AMH levels. An improvement in folliculogenesis may be directly connected to vitamin D treatment via a decrease in blood AMH levels [117]. For PCOS individuals who are vitamin D insufficient, taking the supplement improves insulin sensitivity as well. The systematic review and meta-analysis overviewed the impact of vitamin D supplementation on biomarkers of inflammation and oxidative stress in women with PCOS [263]. Numerous studies have shown that IR in PCOS is associated with vitamin D insufficiency and reported to have beneficial effects on insulin metabolism and the lipid profile of infertile women with PCOS who are candidates for IVF in particular [263,264].

Table 1. Management of polycystic ovary syndrome.

Category	Mechanism of action	Efficacy	Side effects		Dose/Duration	Reference
Lifestyle modifications	Lifestyle treatment (diet, exercise, behavioral or combined treatments)	Improved free androgen index, Weight reduction, Reduced body mass index, Improved OGTT	Not available		2-3sessions of 40 to 60 minutes per week of an aerobic training programme	[111,112,159,179]
OCs
Levonorgestrel	Binds to progesterone and androgen receptors and decreases the GnRH release from the hypothalamus	Menstrual cyclicity by inhibiting ovulation, Hirsutism, Acne	Nausea, Breast tenderness, Bleeding, weight gain, dark pigmentation of facial skin		30 µg/day	[161,167,175,265]
Ethinyl estradiol	Estrogen receptor (Erα or Erβ) agonist	Inhibiting the release of gonadotropins to prevent ovulation, altering the endometrial lining to prevent implantation, and modifying cervical mucus to inhibit sperm penetration	Headache or migraine, menstrual irregularities, nausea and vomiting, breast pain or tenderness, mood changes, fatigue, irritability, decreased libido, increased weight		20-30 µg/day for 28 days	[161,167,175,265,266,267,268]
Estradiol valerate			Headaches, irregular uterine bleeding, breast tenderness, nausea and vomiting, acne, and increased weight		5 mg per day for 5 days	[161,167,175,269]
Cyproterone acetate	Blocking androgen receptors	Suppresses LH Reduces testosterone level Inhibits ovulation	Dysmenorrhea, breast tenderness, change in libido, headache, depression, nervousness, chloasma, varicosity, edema, dizziness		2 mg per day	[161,167,175,265,267,268]
Drospirenone	Aldosterone receptors antagonist	High antigonadotropic activity Blockade of ovulation Prevention of follicular growth	PMS, headache or migraine, breast discomfort/tenderness, nausea and vomiting, abdominal discomfort, mood changes		3 mg per day for 28 days	[161,167,175,265,268,270]
Dienogest	Progesterone receptor (PR) agonist	Progestogenic effect on the endometrium and inhibits the increase in the estradiol level through the inhibition of the growth of ovarian follicles. Inhibits ovulation	Headaches, irregular uterine bleeding, breast tenderness, nausea and vomiting, acne, and increased weight		2-4mg/day	[161,167,175,269,271]
Chlormadinone acetate			Breast pain or tension, depressed state, loss of libido, migraine or headache		2 mg per day	[161,167,175,269, 270,272]
Progestins
Medroxyprogesterone acetate	Activates the progesterone receptor	Inhibits the production of gonadotropin, preventing follicular maturation and ovulation	Amenorrhea, change in menstrual flow, hot flash, weight gain or weight loss, menstrual disease, abdominal pain, headache, nervousness		8-10 mg per day	[161,167,175,273]
Antiandrogens
Finasteride	Inhibitor of type II 5-alpha-reductase	Blocking androgens in the hair follicles, it lessens the PCOS-related hair loss	Risk for teratogenicity in male fetuses		0.5 to 55 mg per day. depending on patient condition (3-4 months)	[168,170,274]
Spironolactone	Competitive antagonistic activity against aldosterone receptors	Synergism with COCs	Nausea and menstrual irregularities Inhibition of adrenal and ovarian steroidogenesis		50 mg bid on days 5–25 of menstrual cycle (09 months)	[275,276]
Antiestrogens
Clomiphene citrate	Blocks ERs, Inhibiting normal estrogen negative feedback, which results in increased pulsatile GnRH secretion from the hypothalamus and pituitary gonadotropin release	Increased pulsatile GnRH secretion from the hypothalamus. Secretion of FSH and LH. Follicle growth and maturations Ovulation induction	Ovarian enlargement, flush, pelvic discomfort, breast discomfort, blurred vision, photophobia, diplopia, abnormal uterine bleeding intermenstrual spotting, menorrhagia		50-100 mg per day for 5 days	[180,194,198,204]
Tamoxifen			Increased bone or tumor pain, or reddening around the tumor site. Hot flashes, nausea. Excessive tiredness, dizziness, depression, headache		60 mg/day PO 5 days	[277,278]
Aromatase inhibitors
Letrozole	Competitive inhibitor of the aromatase enzyme.	Prevents conversion of androgens to estrogens Ovulation induction	Hot flashes, arthralgia, flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, bone pain		2.5 to 7.5 mg for 5 days	[190,203,279]
Laparoscopic ovarian drilling	Surgical intervention	Ameliorating disturbances of the ovarian-pituitary feedback mechanism Promote follicular recruitment, maturation and subsequent ovulation.	Bleeding, Infection, Adhesions or scarring of ovary		None	[190,208,211,213]
Gonadotrophins
Human menopausal gonadotropins (HMG)	Stimulate LH and FSH activity	promotes follicle maturation, stimulate ovulation and corpus luteum development.	Pain at the injection site, skin erythema, muscle pain		75-150 U per day for 2 weeks	[280,281]
Urinary FSH (uFSH)	FSH specific activity LH activity-- (<2%-5%)	Stimulates ovary Follicle growth and maturations Ovulation induction	Pain at injection sites Enlarged ovaries Abdominal swelling and discomfort Nausea or even vomiting		35-40 IU per day	[282,283,284]
recombinant FSH (rFSH) -99% purity	FSH specific activity LH activity-None				75-225 IU per day	[182,282,283]
Follitropin alpha (Human FSH rDNA preparation)	Similar to FSH activity				Initial dose of first cycle: 75 IU SC qDay; Dose can be increased based on response	[280,281,285]
Follitropin beta (Human FSH rDNA preparation)					150-225 units SC/IM for at least 4 days Dose can be increased based on response	[280,281,286]
Antidiabetic agents
Metformin	Decreased glucose production (hepatic) and its intestinal absorption, Improved insulin sensitivity	Antidiabetic agent for type II diabetes weight loss and has a lesser effect on lowering Testosterone levels. It improves ovulation and decreases androgen levels. Reduces insulin level increases insulin sensitivity.	Diarrhea, nausea and vomiting, flatulence, asthenia, indigestion, abdominal discomfort, headache		1500–2550 mg/day (500 1500–2550 mg/day03 months	[138,174,175,179]
Rosiglitazone	PPARγ-Agonist	Reduces BG level Increased insulin sensitivity Balances plasma lipid levels	Allergic reactions, Headache Chest pain (angina)		4 mg/day 06 months	[287,288,289]
Pioglitazones	PPARγ-Agonist	Reduces BG level Increased insulin sensitivity	URTIs, Headache, Myalgia,		15-30 mg PO with meal qDay	[183,290]
Troglitazones	PPARγ-Agonist	Reduces BG level Increased insulin sensitivity Greater effects on testosterone levels	URTIs, Headache. UTIs. Diarrhea, Malaise Inflammation in extremities		200-400 mg OD	[289,291]
Empagliflozin	SGLT-2 inhibitor	Glucose reabsorption from the PCT Lowers renal glucose threshold Reduces PCOS related comorbidities	Urinary tract infections Female genital mycotic infections		10 mg OD	[292,293,294]
Dapagliflozin			Thrush, Back pain, Urinary tract infections female genital mycotic infections		5 mg OD	[295]
Sitagliptin	DPP-4 inhibitor	Improves Incretin levels, Increases insulin synthesis	Upper respiratory tract infection, nasopharyngitis, headache		100 mg OD	[296,297,298]
Liraglutide	GLP-1 receptor agonist	Improved glucose-dependent insulin secretion and maintains glucagon secretion Reduces gastric emptying and food intake	Tachycardia, Hypoglycemia, GI disturbances		0.6 mg to 3 mg OD	[299,300]
Semaglutide			GI disturbances		Oral dose: 7 to 14 mg orally OD. S.C. dose: 0.25 mg once a week for 4 weeks, then 0.5 mg once a week	[301]
Exenatide			Hypoglycemia, GI disturbances		5-10 mcg S.C. twice daily	[184,185]
Statins
Rosuvastatin	3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase) inhibitor	Reduces HMG-CoA And cholesterol biosynthesis	Nasopharyngitis, arthralgia Diarrhea, pain in extremity		20 mg OD	[256,258,302]
Atorvastatin					20 mg OD	[258,303]
Simvastatin			Upper respiratory infections headache abdominal pain constipation nausea		20 mg OD	[81,258,260,261]
Others
Inositol	Second messengers of the insulin-signaling pathway synthesis.	Insulin-sensitizing and mimetic effects, lowering blood glucose and promoting hepatic glycogen	Not well-evidenced		1000-4000 mg per day 12-24 weeks	[214,218,219,220]
miRNA therapy (small interfering RNA (siRNA), anti-miRNA oligonucleotides, miRNA mimics	Downstream target of AR - miRNA	Downstream target of AR miR-200b, which is required for HPO axis-mediated ovulation. MiR-29c acts through the downstream pathways that affect androgen receptor localization.	Inefficient delivery Immune mediated toxicities		Not applicable	[36,44,229]
Interleukin-22 (IL-22) therapy	Binds to IL-22 receptor complex (IL-22R) Activating the IL-22R downstream signalling pathway	Stimulates cell proliferation, prevents apoptosis, and controls steroidogenic human granulosa-like tumor cell line (KGN) cell steroidogenesis when exposed to lipopolysaccharide	Body inflammation, osteoporosis, diabetes, and vulnerability to infection		Variable	[87,231,232,234,304,305]
Gut microbiota (Probiotics, prebiotics, and synbiotics FMTs	Maintenance of metabolic homeostasis	Antioxidant, antimicrobial, and anti-inflammatory effects Modifying the immune system Regulates HA	Not available		Variable	[237,238,248]
Vitamin D	Modulation of AMH signaling, FSH sensitivity, and progesterone levels	Follicle maturation, HA, and menstrual regularity	Not reported at normal dose supplement		50,000 IU of Vitamin D every other week for 8 weeks	[117,118,119,262]

PCOS: Polycystic ovary syndrome, OGTT: Oral glucose tolerance test, LH: Luteinizing hormone; COCs: Combined oral contraceptive pill, GnRH: Gonadotropin-releasing hormone, FSH: Follicle stimulating hormone, IU: international unit, S.C.: Subcutaneous injection, I.M.: Intramuscular Injection, BG: Blood glucose, PCT: Proximal convoluted tubule, OD: Once a day, HA: Hyperandrogenism, FMTs: Faecal microbiota transplantation, AMH: Anti-mullerian hormone, HPO: Hypothalamic-pituitary-ovarian, miR/miRNA: Micro ribonucleic acid, AR: androgen receptor.

Table 1. Management of polycystic ovary syndrome.

Category	Mechanism of action	Efficacy	Side effects		Dose/Duration	Reference
Lifestyle modifications	Lifestyle treatment (diet, exercise, behavioral or combined treatments)	Improved free androgen index, Weight reduction, Reduced body mass index, Improved OGTT	Not available		2-3sessions of 40 to 60 minutes per week of an aerobic training programme	[111,112,159,179]
OCs
Levonorgestrel	Binds to progesterone and androgen receptors and decreases the GnRH release from the hypothalamus	Menstrual cyclicity by inhibiting ovulation, Hirsutism, Acne	Nausea, Breast tenderness, Bleeding, weight gain, dark pigmentation of facial skin		30 µg/day	[161,167,175,265]
Ethinyl estradiol	Estrogen receptor (Erα or Erβ) agonist	Inhibiting the release of gonadotropins to prevent ovulation, altering the endometrial lining to prevent implantation, and modifying cervical mucus to inhibit sperm penetration	Headache or migraine, menstrual irregularities, nausea and vomiting, breast pain or tenderness, mood changes, fatigue, irritability, decreased libido, increased weight		20-30 µg/day for 28 days	[161,167,175,265,266,267,268]
Estradiol valerate			Headaches, irregular uterine bleeding, breast tenderness, nausea and vomiting, acne, and increased weight		5 mg per day for 5 days	[161,167,175,269]
Cyproterone acetate	Blocking androgen receptors	Suppresses LH Reduces testosterone level Inhibits ovulation	Dysmenorrhea, breast tenderness, change in libido, headache, depression, nervousness, chloasma, varicosity, edema, dizziness		2 mg per day	[161,167,175,265,267,268]
Drospirenone	Aldosterone receptors antagonist	High antigonadotropic activity Blockade of ovulation Prevention of follicular growth	PMS, headache or migraine, breast discomfort/tenderness, nausea and vomiting, abdominal discomfort, mood changes		3 mg per day for 28 days	[161,167,175,265,268,270]
Dienogest	Progesterone receptor (PR) agonist	Progestogenic effect on the endometrium and inhibits the increase in the estradiol level through the inhibition of the growth of ovarian follicles. Inhibits ovulation	Headaches, irregular uterine bleeding, breast tenderness, nausea and vomiting, acne, and increased weight		2-4mg/day	[161,167,175,269,271]
Chlormadinone acetate			Breast pain or tension, depressed state, loss of libido, migraine or headache		2 mg per day	[161,167,175,269, 270,272]
Progestins
Medroxyprogesterone acetate	Activates the progesterone receptor	Inhibits the production of gonadotropin, preventing follicular maturation and ovulation	Amenorrhea, change in menstrual flow, hot flash, weight gain or weight loss, menstrual disease, abdominal pain, headache, nervousness		8-10 mg per day	[161,167,175,273]
Antiandrogens
Finasteride	Inhibitor of type II 5-alpha-reductase	Blocking androgens in the hair follicles, it lessens the PCOS-related hair loss	Risk for teratogenicity in male fetuses		0.5 to 55 mg per day. depending on patient condition (3-4 months)	[168,170,274]
Spironolactone	Competitive antagonistic activity against aldosterone receptors	Synergism with COCs	Nausea and menstrual irregularities Inhibition of adrenal and ovarian steroidogenesis		50 mg bid on days 5–25 of menstrual cycle (09 months)	[275,276]
Antiestrogens
Clomiphene citrate	Blocks ERs, Inhibiting normal estrogen negative feedback, which results in increased pulsatile GnRH secretion from the hypothalamus and pituitary gonadotropin release	Increased pulsatile GnRH secretion from the hypothalamus. Secretion of FSH and LH. Follicle growth and maturations Ovulation induction	Ovarian enlargement, flush, pelvic discomfort, breast discomfort, blurred vision, photophobia, diplopia, abnormal uterine bleeding intermenstrual spotting, menorrhagia		50-100 mg per day for 5 days	[180,194,198,204]
Tamoxifen			Increased bone or tumor pain, or reddening around the tumor site. Hot flashes, nausea. Excessive tiredness, dizziness, depression, headache		60 mg/day PO 5 days	[277,278]
Aromatase inhibitors
Letrozole	Competitive inhibitor of the aromatase enzyme.	Prevents conversion of androgens to estrogens Ovulation induction	Hot flashes, arthralgia, flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, bone pain		2.5 to 7.5 mg for 5 days	[190,203,279]
Laparoscopic ovarian drilling	Surgical intervention	Ameliorating disturbances of the ovarian-pituitary feedback mechanism Promote follicular recruitment, maturation and subsequent ovulation.	Bleeding, Infection, Adhesions or scarring of ovary		None	[190,208,211,213]
Gonadotrophins
Human menopausal gonadotropins (HMG)	Stimulate LH and FSH activity	promotes follicle maturation, stimulate ovulation and corpus luteum development.	Pain at the injection site, skin erythema, muscle pain		75-150 U per day for 2 weeks	[280,281]
Urinary FSH (uFSH)	FSH specific activity LH activity-- (<2%-5%)	Stimulates ovary Follicle growth and maturations Ovulation induction	Pain at injection sites Enlarged ovaries Abdominal swelling and discomfort Nausea or even vomiting		35-40 IU per day	[282,283,284]
recombinant FSH (rFSH) -99% purity	FSH specific activity LH activity-None				75-225 IU per day	[182,282,283]
Follitropin alpha (Human FSH rDNA preparation)	Similar to FSH activity				Initial dose of first cycle: 75 IU SC qDay; Dose can be increased based on response	[280,281,285]
Follitropin beta (Human FSH rDNA preparation)					150-225 units SC/IM for at least 4 days Dose can be increased based on response	[280,281,286]
Antidiabetic agents
Metformin	Decreased glucose production (hepatic) and its intestinal absorption, Improved insulin sensitivity	Antidiabetic agent for type II diabetes weight loss and has a lesser effect on lowering Testosterone levels. It improves ovulation and decreases androgen levels. Reduces insulin level increases insulin sensitivity.	Diarrhea, nausea and vomiting, flatulence, asthenia, indigestion, abdominal discomfort, headache		1500–2550 mg/day (500 1500–2550 mg/day03 months	[138,174,175,179]
Rosiglitazone	PPARγ-Agonist	Reduces BG level Increased insulin sensitivity Balances plasma lipid levels	Allergic reactions, Headache Chest pain (angina)		4 mg/day 06 months	[287,288,289]
Pioglitazones	PPARγ-Agonist	Reduces BG level Increased insulin sensitivity	URTIs, Headache, Myalgia,		15-30 mg PO with meal qDay	[183,290]
Troglitazones	PPARγ-Agonist	Reduces BG level Increased insulin sensitivity Greater effects on testosterone levels	URTIs, Headache. UTIs. Diarrhea, Malaise Inflammation in extremities		200-400 mg OD	[289,291]
Empagliflozin	SGLT-2 inhibitor	Glucose reabsorption from the PCT Lowers renal glucose threshold Reduces PCOS related comorbidities	Urinary tract infections Female genital mycotic infections		10 mg OD	[292,293,294]
Dapagliflozin			Thrush, Back pain, Urinary tract infections female genital mycotic infections		5 mg OD	[295]
Sitagliptin	DPP-4 inhibitor	Improves Incretin levels, Increases insulin synthesis	Upper respiratory tract infection, nasopharyngitis, headache		100 mg OD	[296,297,298]
Liraglutide	GLP-1 receptor agonist	Improved glucose-dependent insulin secretion and maintains glucagon secretion Reduces gastric emptying and food intake	Tachycardia, Hypoglycemia, GI disturbances		0.6 mg to 3 mg OD	[299,300]
Semaglutide			GI disturbances		Oral dose: 7 to 14 mg orally OD. S.C. dose: 0.25 mg once a week for 4 weeks, then 0.5 mg once a week	[301]
Exenatide			Hypoglycemia, GI disturbances		5-10 mcg S.C. twice daily	[184,185]
Statins
Rosuvastatin	3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase) inhibitor	Reduces HMG-CoA And cholesterol biosynthesis	Nasopharyngitis, arthralgia Diarrhea, pain in extremity		20 mg OD	[256,258,302]
Atorvastatin					20 mg OD	[258,303]
Simvastatin			Upper respiratory infections headache abdominal pain constipation nausea		20 mg OD	[81,258,260,261]
Others
Inositol	Second messengers of the insulin-signaling pathway synthesis.	Insulin-sensitizing and mimetic effects, lowering blood glucose and promoting hepatic glycogen	Not well-evidenced		1000-4000 mg per day 12-24 weeks	[214,218,219,220]
miRNA therapy (small interfering RNA (siRNA), anti-miRNA oligonucleotides, miRNA mimics	Downstream target of AR - miRNA	Downstream target of AR miR-200b, which is required for HPO axis-mediated ovulation. MiR-29c acts through the downstream pathways that affect androgen receptor localization.	Inefficient delivery Immune mediated toxicities		Not applicable	[36,44,229]
Interleukin-22 (IL-22) therapy	Binds to IL-22 receptor complex (IL-22R) Activating the IL-22R downstream signalling pathway	Stimulates cell proliferation, prevents apoptosis, and controls steroidogenic human granulosa-like tumor cell line (KGN) cell steroidogenesis when exposed to lipopolysaccharide	Body inflammation, osteoporosis, diabetes, and vulnerability to infection		Variable	[87,231,232,234,304,305]
Gut microbiota (Probiotics, prebiotics, and synbiotics FMTs	Maintenance of metabolic homeostasis	Antioxidant, antimicrobial, and anti-inflammatory effects Modifying the immune system Regulates HA	Not available		Variable	[237,238,248]
Vitamin D	Modulation of AMH signaling, FSH sensitivity, and progesterone levels	Follicle maturation, HA, and menstrual regularity	Not reported at normal dose supplement		50,000 IU of Vitamin D every other week for 8 weeks	[117,118,119,262]

PCOS: Polycystic ovary syndrome, OGTT: Oral glucose tolerance test, LH: Luteinizing hormone; COCs: Combined oral contraceptive pill, GnRH: Gonadotropin-releasing hormone, FSH: Follicle stimulating hormone, IU: international unit, S.C.: Subcutaneous injection, I.M.: Intramuscular Injection, BG: Blood glucose, PCT: Proximal convoluted tubule, OD: Once a day, HA: Hyperandrogenism, FMTs: Faecal microbiota transplantation, AMH: Anti-mullerian hormone, HPO: Hypothalamic-pituitary-ovarian, miR/miRNA: Micro ribonucleic acid, AR: androgen receptor.

9. Future Perspectives

Clinically speaking, PCOS is a complicated ailment that may cause issues throughout a woman’s lifetime. Furthermore, it is becoming an increasingly common feminine disorder among the reproductive age group population. This disease presents a number of challenges, in particular inaccurate diagnostic criteria and the tremendous variations and complications of its characteristic features. Realtime deployment of tailored therapeutic techniques will improve the overall PCOS and thus comorbidities and better HRQOL. Early identification and treatment are vital in order to enhance the prognosis among females who may encounter infertility throughout their reproductive years. There is a possibility that key gene polymorphisms for screening of PCOS subtypes might be supportive in the early PCOS identification. For the purpose of determining effective preventative methods as well as treatment approaches, it will be important to explore more research on PCOS-associated genetic alterations. As supplementation with prebiotics, probiotics, and synbiotics in women who have PCOS seems to enhance a number of biochemical results and have positive benefits, it is necessary to do more studies in order to determine whether or not the composition of intestinal bacteria changes PCOS conditions. Thorough and practical research in the future will pave the way for the gut microbiota to be used as a PCOS biomarker. Additionally, the targeted and individualized alteration of the gut microbiota will contribute to the advancement of this study. There is a need for more study to evaluate the importance of the above-discussed drugs in the management of PCOS, or maybe in the prevention of its characteristic features. Therapies, up to this point, focused on alleviating symptoms rather than treating the sickness itself, and there is no cure for the condition. It is imperative that extensive efforts be made to conduct a comprehensive investigation of the illness in order to enhance treatment and postpone the severe long-term effects that the sickness has on the PCOS patients. There are a number of new chemical entities under study for managing T2DM that can be explored for implications in managing metabolic complications of PCOS. However, clinical trials are required to assess the clinical effectiveness and safety of these therapies in women who have PCOS. In order to show that novel medicines, such as miRNA therapy, IL-22 therapy, and others, have the ability to successfully treat PCOS, it will be important to do more study.

10. Conclusion

PCOS patients continue to struggle with a significant issue that has a negative impact on their HRQOL. It has been stated that several clinical elements may be used to correct the principal clinical and biochemical indications of PCOS, despite the fact that there are variations in the clinical presentation of PCOS among young women. When considering the possibility of becoming pregnant, it is necessary to implement appropriate lifestyle management and therapeutic intervention, the specifics of which are determined by the severity of the comorbid disease and the clinical signs. Furthermore, a strategy that is founded on research needs to be adapted to the specific needs of each individual woman.