Polycystic Ovarian Syndrome: A Breakthrough Etiology, Symptoms and Therapy

The pathogenic mechanism

The principal reason for PCOD is still unclear; many studies are needed to understand its morphology, pathogenesis, and therapeutic approaches.^[9] Figure 2 gives a summary of the etiology, pathophysiology, and features of PCOD.^[10]

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Figure 2: The etiology, pathophysiology, and hallmarks. (GWAS: Genome-wide association study; HPAX: Hypothalamic -pituitary -adrenal axis; AMH: Anti-Müllerian hormone) (Adapted from Chang et al.)

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Many interrelated factors are involved in its incidence, such as individual traits, lifestyle choices, and genetics.^[11,12] The rise in the androgens in the body resulted in many symptoms, including acne, irregular menstruation, and obesity.^[13] The increase in the anti-Müllerian Hormone (AMH) concentration induced the production of a large number of primordial follicles.^[14] Figure 2 sketches the relationship between PCOD and related metabolic disorders.^[2]

Symptoms and complications of PCOD

The signs of PCOD include menstrual disturbance and many cysts in the ovary, causing abdominal pain and cramps during periods.^[1] Increase in ovarian size; capsules that are thicker than 100µm. An increase in the amount of subscapular follicular cysts.^[15] A decline in the number of corpora lutea or albicantia.^[15] Also, there are some physical features of PCOD such as hirsutism, acne, alopecia, and seborrhoea.^[1]

Hirsutism

A disorder that is associated with the growth of hair in regions that normally have sparse hair as a result of the increased androgen concentration.^[16] Androgens such as testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone sulphate (DHEAS), and androstenedione have been secreted from the female body at the fertility stage.^[17] When androgens and DHT bind to the androgen receptors, result in a change in the morphology and physiology of the hair follicles.^[18]

Acne and seborrhoea

The increased levels of androgens in PCOD resulted in the secretion of more sebum, which resulted in the formation of acne and seborrhea^[19,20] in the regions of the forehead, chin, and middle back.^[21]

Androgenic alopecia

A common dysfunction in cases with elevated testosterone resulted in continuous hair loss in a certain pattern.^[22] This dysfunction has resulted from the conversion of testosterone to dihydrotestosterone in hair follicles that binds to both the androgen receptor and the genes that induce gradual shrinkage of giant terminal hair follicles.^[23]

Onycholysis and onychorrhexis

A process by which an onychocorneal band causes the nail plate to be separated from the nail bed is termed onycholysis.^[24] Conversely, onychorrhexis describes the splitting of nails into lengthwise bridges^[25]. Many studies have discovered the relationship between the increased levels of androgen and the incidence of onycholysis and onychorrhexis in patients with PCOD.^[26]

The genetics of PCOD

The idea that PCOD can be inherited was accepted in 1968, as some studies assumed that PCOD is an X-linked or autosomal dominant condition. Less than 10% of its inheritance may now be explained by candidate genes proposed by genome-wide association studies (GWASs).^[27] The limitations of GWASs in PCOS research are further discussed in a study by Hiam et al.^[28] Consequently, GWAS which has yet to identify a single candidate gene, other techniques, including in utero programming, have been complemented.^[29] The phenome-wide association study (PheWAS), which examines many genetic changes that may be linked to different PCOS traits, is a supplementary strategy.^[16] Whole-exome sequencing (WES), which scans the complete exome and can manage massive parallel sequencing, may also estimate rare mutations.^[27]

Candidate genes associated with PCOS

According to recent studies, a change in the Differentially Expressed in Normal and Neoplastic Development isoform A1 (DENND1A) gene, which codes for the DENND1A protein found in theca cells, may be associated with PCOS due to its function in steroidogenesis. Other promising candidate genes include INRS, which is related to insulin resistance, follicle-stimulating hormone receptor (FSHR), which connects the ovarian response to follicle-stimulating hormone (FSH), and luteinizing hormone/choriogonadotropin receptor (LHCGR), which is related to luteinizing hormone (LH) levels and HA.^[17] Although the direct association between the Cytochrome P450 (CYP) family and the pathophysiology of PCOS has not yet been identified, genes associated with LH and FSH activity may have an indirect relation.

The AMH gene may also be a good indication. Additionally, the AMH gene might be a reliable predictor. Other possible FTO, PCOS 1, SRD5A1, SRD5A2, etc., are examples of possible genes. Nevertheless, none of these potential genes could account for more than 10% of the PCOS linkage.

Diagnosis of PCOS

The diagnosis of PCOS depends on the presence of at least two of three clinical features: clinical or biochemical HA, ovulatory disorders (oligo-amenorrhea), or polycystic ovarian morphology (>20 follicles and/or ovarian volume >10 mL), based on the latest recommendations for the assessment and management of polycystic ovarian dysfunction, which support the earlier Rotterdam criteria and the Androgen Excess Society guidelines.^[10,30] The main change to the 2023 diagnostic recommendations is the focus on individual diagnostic criteria related to lifestyle, education, emotional health, and quality of life.^[7]

The Rotterdam criteria have been used to detect several syndrome phenotypes. Phenotype A has been identified by polycystic ovarian ultrasound morphology, elevated levels of androgens, and ovulatory failure. Phenotype B has been estimated by ovulatory malfunction and elevated levels of androgens. Women with phenotypes A and B are also more likely to experience menstrual irregularities, dyslipidemia, hepatic steatosis, obesity, and metabolic syndrome (increased insulin secretion and insulin resistance). Ovulatory PCOS with HA and polycystic ovarian ultrasound morphology is characterized by high hirsutism scores and moderately high serum insulin, atherogenic lipid, and androgen levels (Phenotype C).

It’s amazing to note that females from higher socioeconomic backgrounds are more likely to have it, probably as a result of their lifestyle and food choices. On the other hand, phenotype D has the lowest risk of metabolic diseases when androgen levels fall within the referral range.^[31,32]

Despite their inability to fully capture the differences in metabolic dysfunction between lean and obese PCOD patients, the Rotterdam criteria are crucial for identifying phenotypes A–D and making the diagnosis.^[31,32]

Molecular basis of PCOD

Although the underlying pathophysiology of PCOD is yet to be understood, it is thought to follow a “two-hit” pattern in which the inherited predispositions become clinically apparent following postnatal triggers.^[33] Functional ovarian hyperandrogenism (FOH), the main sign of PCOD, is due to an imbalance in androgen production. The synthesis of steroidogenic enzymes in this gonadotropin-dependent dysfunction demands LH stimulation. Typical FOH has been characterized by ovarian 17-hydroxyprogesterone (17-OH-Pg) hyper-responsivity to gonadotropin stimulation and unregulated steroidogenesis, particularly at the level of cytochrome P450c17, the main enzyme in the process of androgen production in the ovaries and adrenal glands. In a comparison with healthy women, it was found that women with PCOD have 20 times more androstenedione in their theca cells.^[1] Additionally, their levels of 17-OH-Pg and progesterone are greater. The granulosa and theca cells are divided as a result of the ovary’s enhanced androgen production, leading to the development of many small follicles.

The polycystic ovary disease has three times as many antral follicles as a normal ovary, although having the same number of primordial follicles.^[34,35] Androgen-induced follicular atresia is thought to be caused by excessive AMH, which inhibits ovulation, progesterone synthesis, dominant follicle selection, and follicular extension. Low progesterone levels have been associated with increased pulsatile gonadotropin-releasing hormone (GnRH) activity, which further increases LH and androgen output, while inhibiting FSH, which worsens the follicular arrest and hormonal imbalance Figure 3.^[34,35]

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Figure 3: Role of different hormones in the development of polycystic ovary disease. (LH: Luteinizing hormone; FSH: Follicle-stimulating hormone; AMH: Anti-Müllerian hormone) (Adapted from Malik et al.)

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Estrogen, inhibin B, and regional paracrine hormones, including follistatin, and additionally, tumor necrosis factor, reduce FSH activity, changing the FSH/LH ratio.^[36,37] Dexamethasone-induced suppression of adrenal androgen production can identify atypical FOH, a rare condition characterized by elevated testosterone. The tiny follicles produced by FOH seldom reach the pre-ovulatory stage. This leads to polycystic ovarian morphology and oligo-ovulation, both of which are frequently linked with high levels of AMH.

Functional adrenal hyperandrogenism (FAH), which is linked to congenital adrenal hyperplasia in approximately 5% of instances, affects less than 10% of women with PCOD. The remaining PCOD cases are mild, lack steroidogenic abnormalities, and are often associated with normal body mass index (BMI); they can also occur in obese women.^[38] The negative effects of obesity appear to be directly responsible for endocrine and ovulatory dysfunctions.

Obesity and PCOD share comparable pathophysiological processes. Hyperaldosteronism, insulin resistance, compensatory hyperinsulinemia, and hyperandrogenism all trigger the renin-angiotensin system. Additionally, there is an increase in serum levels of apelin, polygenic predisposition, and 20-hydroxyeicosatetraenoic acid. Recent studies have shown that insulin receptor (IR) and hyperandrogenism, which are fundamental causes of PCOD irrespective of obesity, play a major role in the pathogenesis of the disorder.^[1]

The role of insulin resistance, obesity, and PCOD

Recent research, reported that IR is an intrinsic cause of PCOD that is unrelated to obesity and hyperandrogenism.^[29,31] Normal-weight PCOD patients typically have a significantly lower degree of IR than obese PCOD patients.

75% of lean PCOD patients and 95% of obese people had IR. While lean women with PCOD have intrinsic IR [Figure 4], patients with obesity have both intrinsic resistance as a component of the disease and extrinsic resistance because of obesity.^[29,39,40]

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Figure 4: The prospective mechanism of PCOD and obesity pathogenesis. (DHES: Dehydroepiandrosterone sulfate; BMI: Body mass index; IR: Insulin receptor; DM: Diabetes mellitus) (Adapted from Bila et al.)

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These results are corroborated by the observation that PCOS typically manifests in slim individuals during adolescence, when growth hormone (GH), insulin-like growth factor-1 (IGF-1), and consequent insulin levels and IR experience a brief surge. Clinical signs of hyperandrogenism, including irregular menstruation, acne, excessive hair growth, thinning hair, and darker skin patches, are brought on by the steroidogenic ovaries and adrenal glands continued sufficient sensitivity to the effects of insulin. Reduced sex hormones binding globulins (SHBG) production in the liver is another consequence of insulin that also raises free androgen levels.^[41-43] Follicular dysplasia results from granulosa cell activity being affected by hyperandrogenism. A particular ovarian morphology, ineffective follicle selection, and anovulation were the outcomes of follicular dysplasia, which also led to aberrant folliculogenesis and failed follicles.^[43]

Unlike PCOD in lean people, IR in obese patients is usually caused by obesity and decreased tissue sensitivity to insulin. Overweight, obesity, and PCOD are closely related, as evidenced by recent studies that showed moderate weight loss frequently resulted in a clinically significant improvement in the reproductive, hyperandrogenic, and metabolic features of PCOD.^[10,40,42] Insulin resistance is made worse by obesity, especially visceral adiposity, which is prevalent in obese PCOD patients. This leads to hyperinsulinemia, which increases adipogenesis and lowers lipolysis. Furthermore, there is a malfunction in the post-receptor phosphatidylinositol 3-kinase (PI3-K) insulin pathway, which interferes with insulin’s metabolic actions and makes cells resistant to it.^[1]

According to ^[44], patients with PCOD continue to experience the dysmetabolic and steroidogenic effects of the mitogen-activated protein kinase (MAPK) pathway. All PCOD patients who are overweight or obese have worse metabolic and reproductive traits, greater levels of testosterone and androstenedione, a higher free androgen index, and lower levels of SHBG, according to earlier research. Obesity has been related to restricted ovulation and higher LH serum levels, which affect thecal cells and enhance FOH by increasing ovarian androgen production.^[45-47]

Obese PCOD individuals are more likely to have diabetes mellitus, metabolic syndrome, IR, HOMA-IR, irregular menstruation, and impaired glucose tolerance. Additionally, endometrial hyperplasia was significantly more prevalent in obese patients with PCOD than in non-obese women.^[10,45,48] Because of their excess androgen, women with PCOD are more likely to have visceral fat hypertrophy, which is associated with insulin resistance. Conversely, IR expression is elevated and linked to persistent low-grade inflammation when there is a decrease in the production of certain adipocyte-derived chemicals (adipokines).

Adipokines, which are called adipocytokines, are cell-signaling molecules (cytokines) that are secreted by adipose tissue and maintain the body’s energy and metabolic status, inflammation, obesity, etc. Leptin, adiponectin, resistin, interleukin-6, and tissue necrosis factor are notable instances of adipokines.^[49] They also play an important role in the etiopathogenesis of PCOD, and their exact part remains unclear and requires further research. The relationship between adipokines and PCOD, as seen in Figure 5,^[49] Ovarian and adrenal androgen synthesis is stimulated by abdominal obesity and insulin resistance, which may result in further abdominal obesity and inflammation, creating a vicious cycle.^[47,50]

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Figure 5: Adipokines in adolescent girls. (PCOS: Polycystic ovarian syndrome) (Adapted from Orszulak et al.)

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About 50-90% of women with PCOS suffer from insulin resistance. Hyperinsulinemia arises as a compensatory response to insulin resistance, and within ovarian theca cells, it acts in concert with LH as a co-gonadotrophin. The production and release of androgens are subsequently increased by the activation of CYP17, which codes for P450c17α, a crucial enzyme in ovarian androgen biosynthesis. Insulin also encourages the arrest of pre-antral follicle development in the ovary.

Hyperinsulinemia also has other extra-ovarian pleiotropic effects, including enhancement of LH production, stimulation of adrenal P450c17α activity, and suppression of hepatic sex hormone binding globulin production.^[42] An overview of peripheral insulin resistance and its role in the pathogenesis of PCOS is shown in Figure 6.^[51]

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Figure 6: Overview of luteinizing hormone. (PCOS: Polycystic ovarian syndrome; SHBG: Sex hormone binding globulin; T2DM: Type 2 diabetes mellitus; DHEA: Dehydroepiandrosterone; LH: Luteinizing hormone) (Adapted from Barber et al.)

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In contrast, women who are genetically predisposed to the incidence of PCOS frequently reveal clinical signs of the disorder as a result of weight increase. Given that both insulin resistance and hyperinsulinemia are critical for the development of PCOS, there is a difficulty in trying to harmonize insulin resistance with the harmful effects of hyperinsulinemia.^[1] When the molecular pathways involved are taken into consideration, this seeming contradiction has been resolved. After interacting with its receptor, insulin primarily affects two intracellular processes: mitogen-activated protein kinase (MAP kinase) and phosphatidylinositol 3-kinase (PI3-kinase).^[1,42]

Role of visceral fat as a contributor to insulin resistance in PCOS

Unfortunately, many initial investigations on fat distribution in PCOS have employed technology like lipometers and ultrasounds, which have disadvantages such as operator dependency and low picture quality. To analyze and evaluate the distribution of fat among obese BMI- and fat mass-matched pairs of PCOD cases and controls.

A study by Barber et al.^[52] quantified and compared the cross-sectional areas of fat depots from axial MRI images obtained at anatomically predetermined sites.^[52] The groups of women with PCOS and BMI-matched control women did not significantly differ in fat depots, particularly visceral fat, despite differences in insulin sensitivity.

In conclusion, obesity is a symptom of PCOS in women worldwide. Based on research by Barber et al.^[52] and a large dual-energy X-ray absorptiometry-based investigation on PCOS and weight-matched control women, women’s abdominal fat mass is proportionate to their total fat mass independent of PCOS status. This makes sense as to why women’s insulin resistance deteriorates as they gain weight.

Treatment for PCOS-related symptoms

The control of PCOS can be achieved by changing lifestyle, such as keeping a healthy strategy for weight loss, increasing physical activity, and following dietary adjustments.^[26] Although its availability and relative expense prevent it from being widely used, bariatric surgery can help treat PCOS.^[11]

It is important to develop effective weight-loss strategies to improve outcomes in PCOS and other weight-related problems. One possible target for such a novel therapy is brown adipose tissue (BAT). Recent observations of active BAT in adult humans have transformed this field.^[53] BAT uncouples oxidative phosphorylation and, in the process, releases stored caloric energy as heat.^[53] Calculations show that a sugar-cube volume of active BAT over the course of a year would burn up between 3 and 4 kg of white adipose tissue, demonstrating the therapeutic capacity of BAT as an anti-glycemic, lipid-lowering agent, and weight loss-inducing “metabolic panacea.”^[54]

It was mentioned by Abdelrahman et al,^[55] that the most widely used drugs to be the first line of defense against hirsutism include eflornithine, metformin, and spirolactone. It was reported in 2020 that their minimal androgenic effect, progestins, norgestimate, desogestrel, or drospirenone are the common contraceptive pills used to treat hirsutism Figure 7. The four most regularly utilized medications are rosiglitazone, acarbose, spironolactone, and contraceptives.^[56]

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Figure 7: Pathophysiology and management of PCOS. (PCOS: Polycystic ovarian syndrome) (Adapted from Malik et al.)

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A study in 2018^[44] reported the effective role of metformin in the control of PCOS, as it decreases the level of androgens. Insulin, testosterone, and the free androgen index (FAI), while raising SHBG, control appetite, increase sensitivity to insulin, change circadian rhythm, maintaining fat oxidation and storage in the liver and skeletal muscles. It was reported that metformin enhances glucose absorption and decreases hepatic synthesis by activating AMP-activated protein kinase (AMPK).

Metformin has been observed to downregulate the FSH receptors in human granulose cells and diminish the FSH-induced phosphorylation of the cyclic adenosine monophosphate response. Additionally, metformin may help PCOS sufferers lose weight and lower their risk of type 2 diabetes and cardiovascular disease.

Metformin suppresses appetite through lactate-mediated metabolic acidosis, gut-brain axis modulation, increased production of the anorectic hormone peptide YY and glucagon-like peptide 1 (GLP-1), suppression of hypothalamic AMPK, and reduction of leptin resistance in the hypothalamus.^[57-59] Consequently, studies have shown that metformin drastically lowers waist circumference and boosts BMI.

It was recorded that patients with PCOS who received metformin repressed TLR4/IRF-7/NFκB signaling pathway in the endometrium, the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), and progesterone receptor (PR) was decreased. Another study in 2022 recorded that few numbers of oocytes & fertilized oocytes have been retrieved as a result of metformin treatment.^[58]

One of the drugs that has a good reputation in controlling PCOS by improving the expression of glucose transporters in insulin-dependent tissues, decreasing oxidative stress, decreasing inflammation, and altering lipid metabolism.^[60,61] As insulin synthesis has been promoted and glucagon secretion has been suppressed, the intestinal hormone GLP-1 plays important physiological roles in the control of glucose homeostasis.^[60] The theory that GLP-1 integrates reproductive processes, the metabolic system, nutrition, and energy balance mechanisms has been accepted due to the distribution of GLP-1 receptors across the gastrointestinal, neurological, and reproductive systems.^[62]

Administration of GLP-1 agonists was shown to reduce the ovarian granulosa cells’ apoptosis caused by PCOS in a concentration-dependent manner. Additionally, these effects are linked to changes in the phosphorylation sites of forkhead box protein O1 (FOXO1) and a negative regulation of cell viability.^[30] By inhibiting progestogenic factors and enzymes, GLP-1 also reduced the production of progesterone generated by FSH.^[30]

In animal models, the GLP-1 agonist therapy can reduce the degree of fibrosis and inflammation in the endometrium and ovary. This was a significant discovery because inflammation is one of the most common metabolic problems associated with obesity in PCOS patients.

It was recorded by many researchers that treatment with myoinositols induced the enhancement of ovarian function and fertility, decreased intensity of hyperandrogenism and its accompanying signs like acne and hirsutism, positively affecting metabolic aspects and modulating a range of hormonal parameters incorporated in the reproductive axis functioning, including ovulation.^[45] Myoinositols can improve insulin sensitivity; modulate the activity of steroidogenic enzymes, which decrease androgen levels; have an anti-inflammatory effect; improve mitochondrial function; and promote follicular maturation and ovulation are just a few possible explanations for the positive effects of inositol.^[46,63]