Polycystic ovary syndrome (PCOS), an inflammatory, systemic, lifestyle endocrinopathy

Highlights

• Polycystic ovary syndrome (PCOS) is an endocrinopathy causing infertility.

• Insulin resistance, obesity, cardiovascular problems, and psychological issues are its co-morbidities.

• It’s a polygenic, polyfactorial, systemic, inflammatory, autoimmune disease.

• Treatment option of PCOS include metformin, and hormone therapy.

• Avoidance of acidosis and inflammatory agents can prevent PCOS.

Abstract

Polycystic ovary syndrome (PCOS) is an endocrine disorder, afflicting females of reproductive age. This syndrome leads to infertility, insulin resistance, obesity, and cardiovascular problems, including a litany of other health issues. PCOS is a polygenic, polyfactorial, systemic, inflammatory, dysregulated steroid state, autoimmune disease, manifesting largely due to lifestyle errors. The advent of biochemical tests and ultrasound scanning has enabled the detection of PCOS in the affected females. Subsequently, a huge amount of insight on PCOS has been garnered in recent times. Interventions like oral contraceptive pills, metformin, and hormone therapy have been developed to bypass or reverse the ill effects of PCOS. However, lifestyle correction to prevent aberrant immune activation and to minimize the exposure to inflammatory agents, appears to be the sustainable therapy of PCOS. This holistic review with multiple hypotheses might facilitate to devise better PCOS management approaches.

Introduction

A number of ailments are gender-specific. Gynecological issues involve the impairment in reproductive or the estrogen-controlled organs in the females. While some of these feminine problems are curable, some are chronic, or fatal. Several of these disorders interfere with fertility. With the upsurge in the invasion of, and exposure to chemicals, which are to a large extent endocrine disruptors, the instances of hormonal disturbances are on the sharp rise.

Some of these commonly-encountered reproductive and hormonal anomalies include amenorrhea, endometriosis, polycystic ovary syndrome, fibroids, infertility, ovarian cancer, miscarriage, ectopic pregnancy, preterm delivery etc. [[1], [2], [3], [4], [5], [6]]. Polycystic ovary syndrome (PCOS), a constellation of symptoms, affecting women of child-bearing age is assuming epidemic proportions. This disease, a resultant of imbalance in female sex hormones, leads to cysts in the ovarian antral follicles. A cyst is a water-filled sac containing the egg, that should have been normally discharged for possible fertilization. The conversion of the egg into a cyst, termed as ‘functional cyst’, prevents ovulation. As ovulation is blocked, it results in the disruption of the menstrual cycle, causing ‘amenorrhea’. When multiple cysts are formed in the ovarian follicles due to the hormonal imbalance, it is characterized as PCOS. Because of the water-retained cysts, some of which can be as big as 10 mm wide, the size of ovary increases, up to 10 cm wide. Absence of ovulation and menstrual cycle prevents fertilization, and conception, thus pregnancy becomes difficult [5,7]. Even if implantation occurs, abortion and still birth risks increases. Eclampsia and the small-for-gestational-age babies can occur. PCOS can cause pregnancy-related complications such as gestational diabetes, pregnancy-induced hypertension [8].

Normally, ovarian theca cells provide support to the growing follicle, assisting in mature oocyte generation [9]. But, these cells in PCOS patients are hyper-responsive to the stimulatory effects of insulin, so they proliferate, causing ovarian hyperthecosis. Insulin resistance amplifies the androgenic potential in the theca cells, aggravating PCOS [10]. Also, the high sensitivity of theca cells to gonadal steroid gonadotropin stimulation aid to androgenism in PCOS.

Disrupted secretion of the pulsatile gonadotropin-releasing hormone (GnRH) from hypothalamus is a factor responsible for PCOS [11]. GnRH induces the pituitary gland to secrete follicle stimulating hormone (FSH) and luteinizing hormone (LH). These two hormones are essential for the two distinct phases of menstrual cycle. In PCOS, as these hormones are scanty, the egg is either not formed, or cannot be liberated from the follicle. So, the cycle is disrupted and amenorrhea occurs, which can be of two types, the primary or secondary amenorrhea. While primary amenorrhea is the inability to reach menarche due to chromosomal or anatomic issues, secondary amenorrhea, also called hypothalamic amenorrhea, is characterized by the absence of menstrual cycles for 3 or more consecutive months [12]. High level of prolactin, a peptide hormone, blocks the GnRH [13].

As the human body is a complex system and the metabolites are functionally-interlinked, disturbance in one can affect the others as well. Upset in the level of a number of hormones (prolactin, anti-Müllerian hormone (AMH), cortisol, androgen), neurotransmitters (dopamine), peptides, lipid, protein, and glucose are associated with PCOS manifestation. Hyperprolactinemia causes hypogonadotropic hypogonadism, characterized with amenorrhea, galactorrhea (abnormal milk production from the breasts), and osteoporosis [14]. Normally, after parturition, prolactin stimulates the production of milk by the alveolar cells in the breasts. Prolactinoma of the pituitary gland is one cause of high prolactin level. Roles of these components in PCOS have been discussed in later sections.

Anovulation or oligovulation is a common symptom of PCOS. Some of the cysts produce androgens, which result in the virilization or the expression of male-like characters in the females. So, PCOS leads to the appearance of a gamut of masculine symptoms or ‘hyperandrogenism’. Visible signs of hyperandrogenism include weight gain, abdominal and subcutaneous fat, hirsutism (facial and body hair), male-pattern alopecia (hair loss), clitoromegaly (enlargement of the clitoris), deep voice, seborrhea (oily skin), acne etc. [15]. Apart from these morphological features, alteration in metabolic profile occurs. Insulin resistance is a major symptom of PCOS. It results in hyperinsulinemia, and can lead to diabetes mellitus [5,16]. High insulin level is responsible for the deposition of fat around the abdomen or central adiposity. In a majority of females with PCOS, the body mass index (BMI) is 30 or higher. Other than that, hypertension, cardiovascular issues, dyslipidemia, etc. are co-morbidities of PCOS [5,16]. A healthy blood pressure for women is 120 over 80 or less. PCOS patients are at a high risk for the development of early-onset cardiovascular disease. The PCOS patients often display sugar cravings, frequent urination, delayed healing, fatigue, blurred vision, tingling sensation, mood swing, anxiety, and depression episodes. It is understandable, as these conditions are tied to diabetes as well. The patients often feel pelvic pain, fever, nausea, vomiting, urinary conditions, constipation etc. Pressing of the large cysts against the bladder or rectum is responsible for the anomalous urinary and bowl movement. Sleep apnea (sleep disorder in which breathing repeatedly stops and starts) is another symptom of PCOS, arising due to altered sex steroid level [17]. PCOS can put a female at the risk for uterine cancer, as the prevailing high estradiol level and the lack of progesterone due to ovarian malfunction increases the risk of endometrial hyperplasia [18]. Mucus-deficient endocervix, and smooth vagina is a feature of PCOS, which can be observed during a pelvic exam. Due to the hormonal imbalance in PCOS, skin develops light brown or black patches, a condition known as ‘acanthosis nigricans’. Skin of neck, armpits, thighs, and breasts are more prone to this skin pigmentation. Also, skin tags appear in those regions. In fact, the dark pigmentation is a cutaneous marker for insulin resistance [19]. The metabolic syndrome resultant of PCOS is vast. In fact, the pathologies are bilateral, as metabolic syndrome, and the constant inflammations, can lead to PCOS. Based on evidences, the link between non-alcoholic fatty liver disease (NAFLD), a chronic liver disease characterized by hepatic damage from fatty liver infiltration leading to end-stage liver disease, and PCOS has been traced, which has indicated a novel hepato-ovarian axis [20].

However, PCOS symptoms can be considered as a spectrum, as the manifestations vary among races, and individuals. Hirsutism is mild or absent in PCOS females of South Asian and Scandinavian origin, for the androgen sensitivity of pilo-sebaceous glands differ [21], but Middle Eastern and Mediterranean origin PCOS patients are more affected by hirsutism [22].

Ovarian hyperstimulation syndrome (OHSS) is a condition of fluid collection in the abdomen and chest (ascites and pleural effusion), resulting due to complications in ovulation induction. This shift of fluids into the third space i.e. abdominal and pleural cavity is due to vascular hyperpermeability [23]. OHSS is graded based on the symptoms. It can be mild, leading to weight gain, abdominal pain, nausea and vomiting, bloated abdomen due to ovarian distension (from 5 to 12 cm), low urinary sodium excretion, oliguria etc. But sometimes, the condition is severe, manifesting in difficulty with breathing; ionic imbalance; deep vein thrombosis; hypovolemia, rupture of a cyst in an ovary leading to serious bleeding; ovarian torsion; pregnancy loss from miscarriage, or termination because of complications; pulmonary embolism, kidney failure etc. Ovarian torsion is a medical emergency, and it can cut off blood to the ovaries, causing intense pain and bleeding. In serious cases, death can occur due to hypovolemia, hypercoagulation, respiratory, and circulatory collapse [23]. It means the sodium, and potassium pump functionality is affected. The hormone HCG (human chorionic gonadotrophin) causes the ovary to undergo extensive luteinization, causing the release of excess estrogens, progesterone, and local cytokines. Vascular endothelial growth factor (VEGF) is a substance that induces vascular hyperpermeability. VEGF induces HCG to increase capillary permeability in OHSS. PCOS makes the female susceptible to OHSS [24].

Apart from the physical effects, PCOS can affect the psychiatric aspects of a patient’s life. Anxiety, depression, binge eating disorder, and bipolar disorder have been observed as PCOS co-morbidities [25,26]. In postmenopausal women with PCOS, cerebral white matter develops lesions. The neural pathology is likely to be due to neural damages.

The factors causing PCOS are multiple. Genetic, or lifestyle mistakes, and their combinations can cause PCOS. Thyroid dysfunction, hyperprolactinemia, androgen-secreting tumors, Cushing’s syndrome (a syndrome associated with excess cortisol levels), and congenital adrenal hyperplasia can drive PCOS pathogenesis. Chemical exposure has been held responsible for the development of PCOS. The exposure to a number of chemicals, by accidental (pesticide, vehicle exhausts, industrial pollutants etc.) or deliberate (cosmetics, household cleaning agents, chemotherapeutics etc.), means are common in current times. Personal care products such as perfume, sunscreen, deodorant, hair dye etc., which have become the quintessential grooming ingredients, are major culprits behind the rising instances of PCOS. A majority of consumers are unaware of the fact that these innocuous-seeming hygiene substances are endocrine disruptors. These chemical products contain phthalates, parabens, isopropanol, glutaraldehyde, benzophenones, oil of turpentine, metals (nickel sulfate, cobalt chloride), benzophenones etc. [[27], [28], [29]]. Chemicals such as bisphenol A (BPA), present in packaged and canned foods, which when exposed to for a long period, can lead to reproductive issues, including PCOS [[30], [31], [32]]. These and other chemicals are included in consumer products in the form of fragrance, emulsifier, preservative, color, fixatives etc. The strong role of fragrance compounds in perturbing hormonal homeostasis and paving the path for conditions like PCOS has been reviewed [33].

Genetic predisposition is one risk factor of PCOS. A number of genes and pathways, mediating PCOS, have been recognized. Variations in these genes such as single nucleotide polymorphisms (SNPs), deletions, additions, inversions, translocations etc. are likely reasons for PCOS development. Several of such causative genes have been genotyped by polymerase chain reaction (PCR) and next generation sequencing (NGS).

Some of the well-studied genes include SIRT1 (NAD-dependent deacetylase sirtuin-1). The SIRT1 gene product regulates DNA damage [34]. SNP-63 and indel-19 variant in the calpain-10 gene is being studied. The protein domain calpain_III has been previously detected in Ebola virus, which indicates its pathologic role [35]. Cytokine gene polymorphisms has been observed in PCOS patients. Association of TLR2 S450S and ICAM1 K469E polymorphisms with PCOS and obesity has come forth. A study based on Korean women revealed that the TGF-β1 gene is linked to PCOS development [36].

Methylenetetrahydrofolate reductase (MTHFR) plays a vital role in folate metabolism, DNA methylation, and RNA synthesis. The association between MTHFR C677T and A1298C variations and the risk of PCOS has been traced [37]. Polymorphism at the chromosome 11-located insulin gene INS-VNTR has been linked to insulin resistance. LH action is enhanced in PCOS, and genetic variants of the LH β-subunit have been reported in these patients [38].

A study found that the daughters of women with PCOS are highly likely to develop the disease as well. The factor for this predisposition is AMH level, which is high in PCOS mothers [39]. So, AMH-coding gene is likely to be involved as well. The gene HSD3B2 (3beta-hydroxysteroid dehydrogenase/delta (5)-delta (4) isomerase type II) is involved in PCOS. SREBP1 (Sterol regulatory element binding protein-1) gene expression is increased in PCOS and endometrial cancer. SNP in rs10830963 in the MTNR1B (melatonin receptor 1B) gene is not only associated with the susceptibility to PCOS, but also contributes to the PCOS phenotype [40]. In a study, the effect of copy-number variations (CNVs) on metabolic phenotypes in PCOS was examined. The intragenic rs1244979, rs2815752 in NEGR1 gene, and rs780094 in GCKR gene was studied. It was found that SNPs are not associated with the pathogenesis of PCOS, but affect metabolic phenotypes. Not only genetic variants, but also CNVs in metabolically-relevant genes, have an effect on metabolic phenotypes in PCOS patients [41]. Association of glucocorticoid receptor polymorphisms with clinical and metabolic profiles in PCOS has emerged. Association of the LH/HCG receptor gene polymorphism with PCOS has been traced. The link of vitamin D receptor gene FokI, BsmI, ApaI, and TaqI polymorphisms with PCOS development has come forth. Critical enzymes such as serine protease and aromatase, mediate estrogen imbalance [42,43], so they are linked to PCOS as well. Genes coding for these enzymes, and other enzymes in their pathway, are likely to be involved in PCOS. Immunomodulatory effects of estrogen are mediated by serine proteases. A mice model study found that estrogen increased the expression and IL-12-induced activity of a serine protease Granzyme A [44]. Serine protease PRSS23, a tumor progression marker, is co-expressed with estrogen receptor $\mathrm{\alpha }$ (ER$\mathrm{\alpha }$), a marker of human breast cancer. A breast cancer microarray dataset analysis showed the correlation between ER$\mathrm{\alpha }$ and PRSS23 [45]. Despite the obvious and assumed link between serine proteases and estrogen, published reports are sparse. Few decades back, an article had reported that the ligand binding site of human uterine estrogen receptor, and the substrate binding site of the serine protease chymotrypsin have structural similarity and some functional overlapping [46]. So, it is worthy of investigation if estrogen might be acting as a ligand for serine proteases. The genetic basis of PCOS has been listed in Table 1.

Epigenetic factors responsible for PCOS development are being investigated. Post-translational modifications of proteins are important for protein functions, which act as the ‘on’ or ‘off’ switch. Methylation, acetylation, glycosylation etc. of proteins can change their functionalities. A study using Rhesus monkey model revealed that prenatal androgenization modified DNA methylation patterns in both infant as well as adult visceral adipose tissue. Such alteration of the epigenome might be a predisposing factor for PCOS [47]. A study conducted with 64 PCOS females and 30 controls found that PCOS patients have several transcriptional and epigenetic changes in the adipose tissues [48].

Evolutionary significance of PCOS has been studied, and the multiple follicles has been attributed as a ‘fertility storage condition’. Inflammation is perceived as stress, and to tide it over, or sensing that the inflammatory female body is not fit to conceive, the eggs are not lost but saved as cysts, for future release, when favorable condition will return. It is a reason that multiple pregnancies are often observed in PCOS patients.

Early diagnosis can help avoid the aggravation of PCOS. Gynecologist can tell PCOS from the symptom description by the patients (such as the history of oligomenorrhea), and morphological features (hirsutism). However, PCOS diagnosis is based on some pre-defined criteria. In 1990, a conference convened by National Institutes of Health (NIH) defined the signs and symptoms of PCOS, which served as the original diagnostic criteria [49]. Rotterdam consensus workshop held in 2003 characterized hyperandrogenism, menstrual irregularities and insulin resistance as the key features of PCOS [50]. Anthromorphometric (blood pressure, cycle duration), and ultrasound (follicle count, mean ovarian volume) parameters, endocrine (SHBG, testosterone, free androgen index (FAI), FSH, AMH, thyroid function tests), and lipid profiles can indicate PCOS. Glucose tolerance test (GTT), and prolactin test can also indicate PCOS conditions. Normal prolactin levels are less than 500 mIU/L for women. Ultrasound is a imaging technique which can detect PCOS. Transabdominal as well as vaginal ultrasound can show the cysts.

A large number of discriminating biomarkers can be identified in PCOS patients. These parameters are at hypo or hyper level in the patient, as compared to healthy female, free of PCOS.

In PCOS patients, the intercellular adhesion molecule (ICAM)-1, tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein (MCP)-1 have been detected in higher concentration. These parameters indicate an inflammatory condition in the body. The mean platelet volume (MPV) and neutrophil to lymphocyte ratio in PCOS patient is higher than healthy women. Leukocytosis, neutrophilia, and platelet aggregation have been frequently detected in PCOS patient blood profile [51]. High platelet reactivity has been recognized as a major cause of morbidities. In a clinical study, MPV level was found increased in PCOS patients with higher than normal prolactin level [52]. Serum IL-6 levels were also found to be elevated in women with PCOS as compared to controls [53].

Along with androgens, the level of estradiol is high in PCOS patients, whereas the level of progesterone is low [54]. AMH, the glycoprotein hormone from the transforming growth factor beta (TGF-β) superfamily, is coded by the AMH gene [55]. This hormone is expressed by the granulosa cells of the ovarian follicles. In females with PCOS, AMH expression is high (>10 ng/mL) which inhibits folliculogenesis, leading to anovulation [55,56]. AMH level can indicate the presence of PCOS. Some studies report that PCOS is linked to endogenous opioid system, and plasma β-endorphin level increases pain in PCOS group [57].

Adipocytokines are known to alter normal metabolic profile, leading to PCOS. In this regard, the functions of adipocytokines such as chemerin, omentin-1, leptin and adiponectin have been studied. Increased concentrations of serum chemerin, a chemoattractant protein, that acts as a ligand for the G protein-coupled receptor CMKLR1 (chemokine-like receptor-1) in PCOS patients have been observed [58]. Chemerin is correlated to adiposity and insulin resistance [59]. Chemerin is activated by serine proteases. Significant association between chemerin gene rs17173608 polymorphism and PCOS has emerged [60]. Leptin, a 16-kDa peptide, an adipokine and a satiety hormone, derived from white adipocytes, is crucial for the regulation of energy balance [61]. Leptin quenches hunger, and is opposed by the hunger hormone ghrelin, a 28-amino acid octanoylated peptide. Both hormones act upon the receptors in the hypothalamus, regulating appetite. Elevated leptin levels are detected in women with PCOS compared with non-PCOS controls. Higher leptin levels may be correlated with insulin resistance, metabolic disorder, infertility, and even cardiovascular disease risk in PCOS, which may contribute to the etiology and the development of PCOS. Ghrelin is independently associated with AMH levels in obese PCOS patients. Ghrelin acts as a neuropeptide in the central nervous system. It can reduce enlarged prostate (benign prostatic hyperplasia) by regulating inflammation, cell proliferation, apoptosis, and angiogenesis, by its ability to bind to growth hormone secretagogue receptor (GHSR) [62]. Omentin-1 is produced by visceral adipose tissue and its plasma level is decreased in obesity and other insulin-resistant states.

Nicotinamide phosphoribosyltransferase (NAMPT), also known as pre-B-cell colony-enhancing factor 1 (PBEF1), or visfatin, is an enzyme encoded by the PBEF1 gene. This protein is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway, that converts nicotinamide to nicotinamide mononucleotide in mammals, to enable NAD + biosynthesis. NAMPT has also been reported to be a cytokine pre-B cell colony enhancing factor (PBEF) that promotes B cell maturation and inhibits neutrophil apoptosis. Visfatin is elevated in cardiovascular disease, independent of insulin resistance. The role of this enzyme in PCOS is suspected. Phosphatidylinositide-3 kinase is a molecular target in metabolic and hormonal pathway of PCOS.

A study showed the level of serum soluble CD163 (Cluster of Differentiation 163), a monocyte/macrophage specific marker, elevated in females with PCOS [63]. Higher than normal fecal calprotectin level indicates the migration of neutrophils to the intestinal mucosa, which occurs during intestinal inflammation [64]. The levels of CRP (C-reactive protein), a metric of inflammation, are elevated in PCOS patients. The link between high CRP and other inflammatory diseases such as diabetes, atherosclerosis, cardiovascular illnesses [65], cystic fibrosis [66], Crohn’s disease [67] is well-substantiated. CRP is pivotal to oxygen radical generation, increased generation of adhesion molecules and plasminogen activator inhibitor-1, clotting.

A dietary medium-chain fatty acid (MCFA) decanoic acid inhibits the recruitment of Nur77, also, known as the nerve growth factor IB (NGFIB), and NR4A1. Nur77 is a protein in humans encoded by the NR4A1 gene. Androgen signaling through androgen receptors are regulated by Nur77. The efficacy of decanoic acid in reversing the endocrine and metabolic abnormalities of PCOS in rat model has been validated [68].

Fasting insulin, fasting plasma glucose, glycated hemoglobin A1c (HbA1_c), and c-peptide levels can determine the status of PCOS. HbA1_c level can indicate plasma glucose concentration. High glucose level indicates insulin resistance, which is a hallmark of PCOS [[69], [70], [71]]. In PCOS, the level of LDL cholesterol increases, whereas that of HDL cholesterol decreases. This condition of dyslipidemia poses the risk of plaque generation in coronary vessels, and thus, the risk of heart attack.

The role of miRNA (microRNAs) in androgen metabolism and subsequent PCOS development has come forth. Circulatory miRNA 23a and miRNA 23b in PCOS have been studied. The miR-483-5p and miR-486-5p are down-regulated in cumulus cells (cells surrounding the oocyte) of metaphase II oocytes from women with PCOS [72]. As miRNA can modulate gene expression pattern, the role of epigenetics in PCOS manifestation is understandable.

Each metabolite has functions beyond their known roles. Profiling the serum and plasma components and tracing their role in the immune-neural-endocrine axis can offer robust insights regarding PCOS. The functions of AMH, and inhibin B (a glycoprotein produced by ovarian granulosa cells which suppresses FSH level) in PCOS etiology should be probed. Creatinine is a waste product of the muscles, and is removed by the kidneys. High creatinine level in the blood indicates suboptimal GFR (glomerular filtration rate), which can be linked to PCOS as well, like cystatin C [73]. Serum cystatin C is a biomarker of renal function in acute kidney injury. Elevated GFR in PCOS patients is correlated with elevated serum CRP and uric acid [74]. Serum ferritin level is elevated in PCOS women, especially in obese PCOS patients. High ferritin level in the serum indicates insulin resistance and hyperglyceridemia [75]. Serum metabolomics study can help profile the levels of these biomarkers and can detect novel prognostic markers. Fig. 1 illustrates the perturbed metabolites in PCOS, and how they affect hypothalamus, pituitary gland, and ovary.

Therapeutic options of PCOS range from pharmacological to surgical. The PCOS cysts are functional cysts that can resolve on their own. But, some cysts can burst and bleed, leading to sudden severe pain in the lower abdomen.

Oral contraceptive pill (OCP) taken for 6 months, ameliorate hyperandrogenism and regularize menstrual cycles, by suppressing ovulation, and preventing cyst formation. However, it poses the risk of venous thrombosis [76]. Also, it reduces serum 25-hydroxy vitamin D levels, which can affect bone health. This therapy increases plasma ICAM-1, MCP-1, and TNF-α levels in the PCOS patients. Though these cytokines are inflammatory, they normalize the metabolic parameters, including plasma glucose, lipids, and insulin [77]. Metformin, an insulin sensitizer, improves the quality of life in females afflicted with PCOS, by lowering the elevated parameters as insulin, androgens, circulating free T levels, while increasing SHBG (sex hormone-binding globulin) and IGFBP (insulin-like growth factor-binding protein) levels [78]. SHBG and androgen level has an inverse relation. Metformin treatment before and during in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) in women with PCOS prevented the risk of OHSS [79]. Metformin acts on the adipocytokines such as IL-6, IL-8, angiogenic proteins (VEGF), and metabolic regulators (such as adiponectin, leptin). Also, this drug reduces the hyper-reactivity of platelets in PCOS patients, by improving mitochondrial integrity. Exenatide and liraglutide (glucagon-like peptide-1 (GLP-1) receptor agonists), either as monotherapy or in combination with metformin, can reduce PCOS patient weight [80]. Combination therapy with exenatide and metformin improved menstrual cyclicity, hormonal parameters, metabolic profiles, and inflammatory markers in overweight, insulin-resistant oligoovulatory females with PCOS. However, the side effects of metformin include lactic acidosis, tiredness, dizziness, severe drowsiness, cold skin, muscle pain, labored breathing, slow/irregular heartbeat, stomach pain, nausea, vomiting, and diarrhea [81].

Steroid hormonal interventions are another way to resolve PCOS. For ovulation induction, aromatase inhibitor like letrozole are being studied [82]. Antiandrogens such as spironolactone, cyproterone acetate, flutamide, and finasteride are administered to treat androgenism. N-Acetyl-cysteine and other insulin sensitizers are administered to tackle insulin resistance. The anti-estrogen medication clomiphene citrate is administered to help with anovulatory infertility [83]. Metformin plus clomiphene citrate was effective in clomiphene-resistant PCOS cases. Gonadotrophins stimulation is also recruited to treat clomiphene resistance.

So, all of the above-mentioned therapies are effective to certain extent, but not entirely. Also, these therapeutic modalities are not side-effect free. The relevance and the risk of therapy depends on the host factors. Long term usage of these hormone manipulators can cause obesity, cancer, psychiatric issues, among a range of other problems.

If the cysts do not go away after few months, and they pose the risk of ovary torsion, they need to be removed by surgical intervention. This can be achieved by laparoscopy and laparotomy. Laparoscopic ovarian cautery (drilling) has been found effective for PCOS treatment [84]. Using a laparoscope, the cyst is removed through incisions made at the pubic hair line. For big cysts, laparotomy is used. In severe cases, both ovaries, the uterus, omentum (a fold of fatty tissue), and some lymph nodes are removed.

Hyperprolactinemia and PCOS, both cause female infertility, and share several clinical features, so they are considered to be linked. However, a study reports that the coexistence of these two conditions do not prove their pathologic dependence [85]. Given its complexity and risks, hyperprolactinemia is treated with dopamine agonist (dopamine receptor activator), which reduces prolactin secretion and often causes prolactinoma shrinkage [86]. Dopamine agonist approved for the treatment of hyperprolactinemia is L-DOPA. This dopamine precursor, L-DOPA, along with monoamine oxidase-B (MAO-B), and ergot alkaloid derivatives, are among the therapeutic options to delay neural pathologies driven by estrogen deficiency. These agonists activate signaling pathways through trimeric G-proteins and β-arrestins, ultimately leading to changes in gene transcription. Cabergoline, an ergot derivative, is a potent dopamine receptor agonist on D2 receptors. But, it has been associated with an increased risk for the development of heart valve defects in patients using it as a treatment for Parkinson’s disease. Much lower doses of the drug (0.5 mg twice a week) are needed in the treatment of hyperprolactinemia. Excess dopamine causes schizophrenia, so dopamine antagonists are used to resolve the psychiatric disease [87]. But then, these antagonists cause hyperprolactinemia. Another study reports that prolactin tends to stimulate the production of dopamine, inhibiting its own secretion [88]. So, the adverse effects of dopamine manipulation are major risks for PCOS.

Protective effects of melatonin against metabolic and reproductive disturbances in PCOS have been observed in rat models. In a cohort study, 6-month melatonin treatment could restore menstrual cyclicity in PCOS patients [89]. Sleep disturbances in women with PCOS is frequently-reported. As melatonin assists in sleep, its beneficial effect in PCOS is understandable. This pineal gland-secreted hormone and neurotransmitter, protects the skin against oxidative stress as well [90]. This correlation indicates - be that ovary, or skin, or brain, their malfunctions arise from oxidative stress and inflammations.

Relevance of acupuncture in PCOS has got some credence. Circulating GnRH and adiponectin system are stimulated by acupuncture. In a RCT (randomized controlled trial), electroacupuncture increased menstrual frequency compared to the no intervention group [91]. In this regard, additional RCTs should be carried out to assess the relevance of acupuncture for treatment of ovulation disorders in PCOS patients [91]. Transcutaneous acupoint electrostimulation on serum sex hormone level in PCOS condition was studied. The application lowered endocrine and reproductive dysfunction in PCOS women, most likely by modulating sympathetic nerve activity, or sex steroid synthesis [92].

BMI, glycemic index, lipid accumulation product (LAP), and visceral adiposity index (VAI) are markers of insulin disturbance and metabolic syndrome. So, these parameters need to be observed periodically. Long-term follow-up studies are needed to optimize PCOS therapeutic options.

Obesity (characterized by abdominal fat mass, high waist circumference, and high BMI (>25)) is one of the key cause that aggravates PCOS [71]. Loss of abdominal fat lowers inflammation, thus reducing androgen level, inducing ovulation, and restoring metabolic functions. Weight loss can be achieved by glucagon-like peptide-1 receptor agonists (GLP-1RA), though the latter has side effects like nausea [80]. So, it is better to engage in physical activity, and to adhere to healthy food habits, to lower BMI in overweight patients with PCOS [93]. Weight reduction has been observed to resolve a majority of adverse symptoms of PCOS. Exercise training can improve the cardiometabolic profile in PCOS females. However, acute, strenuous exercise can lead to platelet activation and resultant cardiovascular issues. Also, human body is very sensitive to energy fluctuations, so rigorous exercise, and heavy dieting is perceived as a threat to survival, and hormones can go awry again. Instead, regular, moderate physical activity is recommended for PCOS mitigation.

A number of phytochemicals belonging to diverse classes have shown ameliorative effects in animal models of PCOS, some of which have been mentioned below. The flavonoid rutin has restorative effects against the metabolic, biochemical and hormonal disturbances in rat models of PCOS [94]. Rutin conferred metformin-like effect and decreased the number of cystic follicles. The therapeutic mechanism was by the improvement of antioxidant and lipid profiles in PCOS patients. Rutin has been shown to lower the level of CRP. A rat model study has shown that quercetin decreases insulin resistance in PCOS by resolving inflammatory microenvironment [95]. Soy isoflavones exert beneficial effects on letrozole-induced rat PCOS model through anti-androgenic mechanism [96]. Resveratrol, at 10 mg/kg/d dose is effective in the treatment of PCOS in rats due to its antioxidant properties [97]. Resveratrol lowered AMH hormone level and increased glutathione content [97]. Colchicine, a secondary metabolite from plants of genus Colchicum, improved histopathological parameters in PCOS animal models. Noscapine, a benzylisoquinoline alkaloid from plants of the poppy family, has the potential to mitigate PCOS [98]. Potent therapeutic effects of shouwu jiangqi (prepared from the root of Polygonum multiflorum) decoction on PCOS rat models was observed, which was attributed to the manipulation of insulin signal transduction pathway [99]. The claims of efficacy by intervention with herbal products motivate PCOS patients to seek those drugs. Among others, Vitex agnus-castus, Cimicifuga racemosa, Tribulus terrestris, Glycyrrhiza spp., Paeonia lactiflora and Cinnamomum cassia have been reported to be effective against PCOS [100]. But, herbal drugs are generally not standardized. They can aggravate the condition, by inducing further hormone dysregulation. Also, their plant origin does not exempt them from their adverse side effects. They can tamper with ion channels, neural receptors, or thrombocytes, leading to grave consequences.