A Deep Dive into Polycystic Ovary Syndrome: A Multidisciplinary Approach

Abstract

Introduction:

Polycystic ovary syndrome (PCOS) is a common disorder found in women of reproductive age in India. It has multigenic etiology, including genetic, lifestyle, stress, diet, exercise, and obesity.

Methods:

We have searched various databases such as PubMed and Google Scholar including the relevant literature on “PCOS.”

Results:

Some of the most common clinical features observed are oligomenorrhea/amenorrhea, hyperandrogenemia, hyperinsulinemia, polycystic ovaries in ultrasonography, hirsutism, alopecia, acne, and acanthosis nigricans. Several studies have shown an association between PCOS and heart disease because of varied causes, including altered lipid/glucose metabolism, hypertension, systemic inflammatory conditions, vascular injuries, obesity, and hyperandrogenism. PCOS and hyperprolactinemia are the two most common etiologies of anovulation in women, although evidence linking them suggests independent origins of these conditions. Hence, PCOS influences the quality of life as its clinical manifestations may lead to fear of sexual unattractiveness, poor self-esteem, discontent with one's physical appearance, social anxiety, emotional changes, and mood swings, causing huge psychological distress.

Conclusion:

Keywords

Amenorrhea infertility lifestyle polycystic ovary syndrome women

Introduction

Polycystic ovary syndrome (PCOS), previously known as Stein–Leventhal syndrome, is a common disorder among women of reproductive age in India. The main consequence of PCOS is infertility. It is characterized by irregular menstrual cycles, lack of ovulation, infertility, excessive hair growth, and obesity in young women whose ovaries are enlarged and cystic. The primary biochemical abnormalities in most patients are excessive androgen production and low levels of pituitary follicle-stimulating hormone (FSH), which affect reproductive, endocrine, and metabolic functions. Previously, these abnormalities were thought to be due to dysfunction of the ovaries, which was demonstrated by the successful outcome of ovarian wedge resection.^[1]

Epidemiology and Pathogenesis

At present, the prevalence of PCOS in India is not entirely clear. However, previous research studies suggest that the incidence of PCOS in Indian women can range between 3.7% and 22.5%.^[2] PCOS has a complex, multigenic etiology that includes various factors such as genetics, lifestyle, stress, diet, exercise, and obesity. The precise pathogenesis of PCOS is still the subject of ongoing research. The current understanding of the pathogenesis of PCOS is that it results from an imbalance in the release of FSH and luteinizing hormone (LH) by the pituitary gland. Testosterone inhibits the release of FSH, while the level of LH is sufficient to induce luteinization of ovarian theca and granulosa cells, leading to inappropriate androgen secretion and an abnormal state of anovulation.^[2] Excessive insulin production and insulin resistance also play a role in anovulation, decreased SHBG, insulin growth factor 1 (IGF-1), blood pressure (BP), and androgen excess, leading to metabolic syndrome and abdominal obesity.

Clinical Features and Diagnostic Criteria

PCOS is characterized by oligomenorrhea/amenorrhea, hyperandrogenemia, hyperinsulinemia, polycystic ovaries in ultrasonography (USG), hirsutism, alopecia, acne, and acanthosis nigricans. The flowsheet describing the PCOS symptoms can be seen in [Figure 1]. The long-term risks include cardiovascular diseases (CVDs), endometrial cancer, breast cancer, dyslipidemia, recurrent pregnancy loss, and ovarian failure after surgery.^[2]

Figure 1

The flow sheet describing the PCOS symptoms. PCOS: Polycystic ovary syndrome

Rotterdam consensus criteria are most commonly used to diagnose PCOS, which requires two of the following observations-hyperandrogenism (HA), polycystic ovaries, and ovulatory dysfunction (OD). National Institutes of Health (NIH)-1990 report, the androgen excess and PCOS Society (PCOS) 2006 position statement are also used to diagnose PCOS.^[2] USG can be used to diagnose PCOS and is a noninvasive method for evaluating the ovaries. The sonographic criteria for PCOS diagnosis are based on the presence of multiple small follicles (also known as antral follicles) in the ovaries. The following are the sonographic criteria for PCOS diagnosis:

Presence of at least 12 follicles measuring 2–9 mm in diameter in each ovary, or

Ovarian volume >10 cm≥, or

Both criteria 1 and 2 are above.

It is important to note that the sonographic criteria alone are not sufficient to diagnose PCOS, and other clinical and laboratory tests may be needed to confirm the diagnosis. In addition, the presence of these criteria does not necessarily mean a woman has PCOS, as some women may have similar findings on ultrasound without any other signs or symptoms of the disorder. Various guidelines proposed to date depicting the criteria for diagnosing PCOS can be seen in [Table 1].

Table 1

Various guidelines proposed till date depicting the criteria for diagnosing polycystic ovary syndrome

Dermatological Manifestations of Polycystic Ovary Syndrome

SAHA syndrome is associated with PCOS comprising a tetrad of seborrhea, acne, hirsutism, and alopecia.^[3] Other dermatological manifestations associated with PCOS are acanthosis nigricans, pyoderma gangrenosum, acrochordons, xanthoma, and psoriasis.^[3] Acanthosis nigricans, hirsutism, and acne are considered the most common cutaneous manifestations.^[4] The pathogenic process leading to acne lesions is considerably higher in hyper-androgenic diseases such as PCOS and women undergoing hormonal therapy.^[5] Acanthosis nigricans is considered a marker for metabolic derangement, having associations with elevated free testosterone, body mass index (BMI), glucose intolerance, and insulin resistance.^[4]

A combination of axillary acanthosis nigricans and reduced levels of high-density lipoprotein cholesterol can differentiate women with a higher risk of PCOS in a racially diverse population and aid in their diagnostic evaluation.^[4] Some studies have shown elevated levels of bone morphogenetic protein in females expressing cutaneous manifestations of PCOS. Hormonal studies have shown elevated 5α reductase activity, which further aids in the development of insulin resistance, acne, and hirsutism. Emphasizing early dermatological changes can be beneficial in preventing long-term complications.^[3]

Environmental Determinants of Polycystic Ovary Syndrome

Polycystic ovary syndrome phenotypes

The first attempt to classify PCOS was made in April 1990 at the US NIH Conference by the National Institute of Child Health and Human Development. They classified PCOS based on the presence of either clinical or biochemical HA and chronic oligo-anovulation. A revised definition was provided in May 2003 by the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine in the Netherlands. This directive required the presence of at least two of the following three criteria: (1) evidence of clinical and biochemical HA; (2) Chronic OD; (3) polycystic ovarian morphology (PCOM), after excluding other secondary causes. In 2012, the NIH proposed four PCOS phenotypes: (1) Phenotype A: Presence of HA (clinical or biochemical), OD, and PCOM; (2) Phenotype B: Presence of HA and OD; (3) Phenotype C: Presence of HA and PCOM; (4) Phenotype D: Presence of OD and PCOM. Women falling under phenotypes A and B are considered to have “classic PCOS,” where they have more severe menstrual irregularities, insulin resistance, and predominant obesity.^[6]

Environmental toxins

Endocrine-disrupting chemicals such as human byproducts, potent pharmaceutical phytosterols such as estrogen, beta-blockers, and antiepileptic drugs have significantly impacted reproductive health, including PCOS. Limited studies have found a higher level of perfluorinated compounds (specifically perfluorooctanoate and perfluorooctanoate), polychlorinated biphenyls and polycyclic aromatic hydrocarbons in the serum of women suffering from PCOS.^[7] Common plastic contains a synthetic compound, bisphenol A, whose prolonged exposure can augment androgen levels leading to its inefficient metabolism.

Dietary supplements

Fat-soluble Vitamin A metabolites such as retinol, retinoic acid, and retinoids expressing retinol-binding protein 4 are associated with obesity and irregular glucose metabolism. Vitamin B6, B12, and folic acid play a significant role in aggravating homocysteine (Hcy), an essential amino acid in PCOS. Studies have shown dependency between insulin resistance and Hcy, which were related to low serum insulin B12 concentration.^[8] Inositol and its metabolites have an additive effect as a supplement by playing a key role in insulin sensitivity and oocyte maturation. For optimum effect, Myo-inositol and D-chiro inositol are given at a certain plasma physiologic ratio (MI/DCI = 40/1).^[8],[9] Limited research has shown that PCOS patients undergoing Vitamin D3 replacement therapy have better folliculogenesis, menstrual frequency, and androgen profile. Studies suggest that the anticoagulant and antioxidant properties of Vitamin E can improve endometrial thickness in PCOS patients. Alpha-lipoic acid, an antioxidant and naturally occurring fatty acid found in many foods, including yeast, spinach, broccoli and organ meat, has shown significant improvement in progesterone levels, insulin resistance and decreasing the number of ovarian cysts.^[8] Mineral supplements such as calcium, chromium, zinc, magnesium, and selenium have been proven to boost menstrual cyclicity, ovulation, and mental health.^[7],[8] Omega 3 fatty acids may improve follicular differentiation and oocyte maturation by expressing gene IGF-1 and cyclooxygenase 2, but they do not aid in weight loss.^[7],[9]

Type-2 Diabetes in Women with Polycystic Ovary Syndrome

PCOS necessitates an increased risk for prediabetic and types 2 diabetes by incorporating insulin resistance. Increasing age worsens insulin resistance in patients suffering from PCOS as it is associated with loss of beta-cell function.^[10],[11] There is no clear data, but it is deduced that BMI, consecutive pregnancies, and oral contraceptives play a vital role in impairing glucose metabolism.

According to studies, many pregnancies are indirectly proportional to type 2 diabetes among women suffering from PCOS.^[11] Other factors that increment insulin resistance include body composition, muscle mitochondrial dysfunction, gut microbiome, and HA. Genetic factors, including positive family history of type 2 diabetes, especially a mono-zygotic twin suffering from the same, increase the chances of glucose intolerance.^[10] Although normal pregnancy has a physiologic insulin-resistant state in the third trimester, women suffering from PCOS have an additive foregoing case of insulin resistance. According to various meta-analysis studies available, patients suffering from PCOS are 2.8 to 4.3 times at risk for suffering from gestational diabetes compared with an average healthy woman of the same age.^[12] Fasting glucose level and glycated hemoglobin have restricted sensitivity in recognizing PCOS patients as prediabetic as well. Lifestyle changes, including changes in diet like having low-calorie meals comprising mono-saturated and poly-saturated fats and vegetables, and reduced carbohydrate consumption in meals, have proven to decrease abdominal fat in patients suffering from PCOS.

In addition, exercise and behavioral management are also considered primary treatments. Consumption of metformin is advised to patients who show no recovery despite lifestyle changes. Other anti-diabetic agents such as sulfonylureas, meglitinides, glucagon-like-peptide 1 agonists, and dipeptidyl peptidase 4 (DPP)-4 inhibitors can be consumed by patients with high glycemic index.^[7]

Polycystic Ovary Syndrome and Bone Metabolism and Vitamin-D

Vitamin D plays a vital physiological role in regulating phosphorus and calcium homeostasis and promoting bone health. However, the relationship between endocrine changes in women with PCOS and their impact on bone health requires further research.^[13] Many women with PCOS have low levels of 25 (OH) D, and 67%–85% having a serum concentration of <20 ng/mL. Low levels of Vitamin D are associated with features like insulin resistance, menstrual irregularities, hirsutism, reduced pregnancy rates, obesity, and an increased risk of CVD, which are commonly seen in PCOS.^[14] The action of parathyroid hormone and calcitonin on osteoblasts and osteoclasts respectively plays an important role in calcium metabolism.^[15] In PCOS women, compared to ovulatory women without hyperandrogenemia, the concentration of parathyroid hormone is significantly higher.^[16] Similarly, plasma levels of calcitonin gene-related peptides are also elevated in PCOS patients.^[17]

In women with PCOS and a BMI of <27 kg/m², osteocalcin levels are reduced, and there is a decrease in bone mass density in the spine and femur, along with reduced bone formation. However, no significant differences were found between PCOS and controls in women with a BMI of ≥27 kg/m².^[18] Vitamin D may have a possible physiological role in ovarian follicular development and luteinization by altering anti-Mullerian hormone (AMH) signaling, FSH sensitivity, and progesterone production and release.^[19] Vitamin D supplementation has been observed to lower elevated serum AMH levels, indicating that it may improve folliculogenesis in women with PCOS and Vitamin D deficiency.^[20],[21]

Among the four phenotypes of PCOS, there were no significant differences in serum Vitamin D levels.^[17] Vitamin D supplementation was found to increase 25 (OH) D significantly but had no significant effect on area under the curve glucose or endocrine and metabolic parameters. However, it did result in reduced plasma glucose during the oral glucose tolerance test.^[21]

Breastfeeding and Polycystic Ovary Syndrome

PCOS is a common condition among reproductive women, affecting 18% of them, and leading to psychological, reproductive, and metabolic dysfunctions. Breastfeeding is crucial for maternal and infant health, and lactational support is particularly important for obese and overweight women, with or without PCOS, due to various factors such as impaired lactogenesis, mechanical difficulties, and psychological considerations. Obese women with PCOS tend to have reduced breastfeeding duration and initiation.^[22]

Breastfeeding rates were not found to be associated with maternal gestational levels of androstenedione, sex hormone-binding globulin, testosterone, or free testosterone index. However, women with PCOS in the early postpartum period appeared to have a reduced breastfeeding rate due to gestational dehydroepiandrosterone-sulfate, which could negatively influence it.^[23] The synchronicity of LH and leptin pulses suggests that leptin may modulate the episodic secretion of LH in healthy women and patients with PCOS.^[24] LH concentrations tend to increase between the 4^th and 8^th weeks postpartum in both groups, but serum leptin concentrations are not affected. Compared to controls, women with PCOS have lower rates of breastfeeding at one month postpartum.^[25] The ability to breastfeed depends on the endocrine stimulation of the mammary glands, which prepares them for milk production and initiates milk secretion postpartum.^[25],[26]

Polycystic Ovary Syndrome and Hyperprolactinemia

PCOS and hyperprolactinemia are the two most common causes of anovulation in women. Current research suggests that these conditions have independent origins, despite hyperprolactinemia (HPRL) often being found in PCOS patients. The high levels of prolactin found in PCOS patients are likely due to nonpermanent increases in prolactin levels caused by macroprolactinemia or other factors, rather than a direct link between PCOS and HPRL. Recent studies have conducted thorough investigations into the etiology of these conditions and have shown that they are less frequently associated than previously believed.^[27],[28]

Hypothalamic pituitary abnormality is a common hypothesis explaining the link between PCOS and HPRL, as it can cause both conditions.^[28] Some studies suggest that dopamine may play a role in regulating LH secretion, but there are conflicting results regarding its effects on LH levels in PCOS patients.^{[29],[30],[31]} Another hypothesis proposes that hyperprolactinemia induces relative hyperestrogenemia, which can explain the presence of HPRL in PCOS patients.^[32] However, it is important to confirm the presence of HPRL by performing a second independent sample to rule out excess macroprolactin.^[33] When treating PCOS and HPRL, it is necessary to consider each condition separately, as their origins and treatments may differ.

If HPRL is confirmed in a patient, it is important to conduct a thorough investigation to rule out the classical etiologies of HPRL before diagnosing it as secondary to PCOS. Patients with high PRL levels and a clinical history similar to PCOS must be investigated further for other causes of HPRL, such as a pituitary tumor, medications, or macroprolactinemia. HPRL is not a typical laboratory finding in PCOS, so it is essential to rule out other potential causes before making a diagnosis. Additionally, some studies have demonstrated that macroprolactin, which is linked to prolactin elevation, is not uncommon in women with PCOS and should be screened for.^[34] Future discoveries and studies on the relationship between PCOS and HPRL will require a better understanding of the regulation of LH and prolactin secretion by the hypothalamus and pituitary gland.^[35] At present, there is still insufficient data to draw conclusive findings on this subject, and a larger, more rigorous cohort of PCOS women will be necessary to confirm any findings.

Quality of Life in Women with Polycystic Ovary Syndrome

PCOS is an endocrine disorder with reproductive, metabolic, and mental disturbances. Its manifestations include HA (hirsutism, thinning of hair, acne), diabetes mellitus, menstrual dysfunction, obesity, infertility which leads to fear of sexual unattractiveness, poor self-esteem, discontent with one's physical appearance, social anxiety, emotional changes, and mood swings causing huge psychological distress.^[36] Hormonal disturbances affecting the quality of life (QOL) in women suffering from PCOS were described in [Figure 2]. In addition, socio-economic situation, BMI, age, and profession are seen to be influencing the QOL in women with PCOS.^[37] It has been reported that an increase in emotional changes in adolescent and middle-aged women with PCOS is mainly due to infertility and problems in the relationship, cosmetic issues, and discontent with one's physical appearance.^[38] It seems that weight loss through regular exercise and healthy diet habits, usage of oral contraceptive pills, improvement in clinical HA (acne and hirsutism) helps in the physical and mental domains of QOL.^[39] Stress affecting gonadotrophins in the body was described in [Figure 3]. Further studies are required in this context to ensure that women suffering from PCOS a better happy life as it is a life-long syndrome.

Figure 2

Hormonal disturbances affecting the quality of life in women suffering from PCOS. PCOS: Polycystic ovary syndrome

Figure 3

Stress affecting gonadotrophins in the body. FSH: Follicle-stimulating hormone, LH: Luteinizing hormone

Risk of Cardiovascular Disease in Women with Polycystic Ovary Syndrome

Research suggests that women with PCOS are at a higher risk of developing CVD, with an estimated 19% greater risk compared to those without PCOS.^[40] Multiple studies have established a link between PCOS and heart disease, primarily due to altered lipid and glucose metabolism, which leads to dyslipidemia and diabetes. Additionally, hypertension, systemic inflammatory conditions, vascular injuries, obesity, and HA are also factors that increase the risk of CVD in women with PCOS.^[41] There is evidence that CVD risk in women with PCOS is nonuniform, i.e., women with a certain phenotype of PCOS are prone to getting CVD (mainly women with classic PCOS).^[42] Women with PCOS are likely to have metabolic syndrome, which has severe consequences on the cardiovascular system.^[41] Insulin resistance is said to be the main underlying mechanism for all components of metabolic syndrome. Some observations suggested that irrespective of BMI, Adipose tissue distribution, systemic inflammation, and various metabolic markers, PCOS affects atherosclerosis.^[41],[42] According to Oliver-Williams et al. and their recent meta-analytical study (2020), women with PCOS in their 30s and 40s have a higher probability of getting heart disease than their peers, as per postmenopausal women, no much data and evidence are limited.^[40] The treatment of PCOS in women should be tailored to individual needs and based on the specific symptoms present. The primary focus should be on controlling the risk factors associated with CVD, which should be regularly evaluated in women with PCOS, as the development of CVD cannot always be predicted, even in young individuals. Individuals with CVD risk factors should undergo regular screening, including oral glucose testing, lipid profile evaluation, BP monitoring, and yearly weight checks. For women aged over 40, a CAC score is a useful tool for assessing CVD risk, indicating subclinical atherosclerosis if the score is >0. In such cases, statin therapy should be initiated. However, in younger women, CAC scores may not be as helpful in assessing CVD risk.^[42]

Metformin and Polycystic Ovary Syndrome

Metformin helps in lowering blood glucose levels and increases insulin sensitivity by its action on the tissues of several organs, namely the liver, skeletal muscle, ovary and adipose tissue.^[43],[44]

Its usage in women with PCOS is mainly based on its ability to increase insulin sensitivity in the body, as insulin resistance plays a major role in the pathophysiology of PCOS.^[43] It also helps in reducing testosterone levels in women with PCOS by 20% to 25% (more prominent in nonobese women with PCOS) through its direct and indirect actions on the androgen production from the ovaries.^[44] Usage of metformin in the women with PCOS with a gradual increase in the dosage over a particular period helps in the improvement of the menstrual cycle (increase in frequency), decrease in the BMI, decrease in the testosterone and the LH levels in both obese and nonobese woman with PCOS.^[45] Weight reduction is seen in obese women with PCOS with the prolonged usage of metformin.^[46] Furthermore, in clomiphene-resistant women with PCOS, metformin alone or Clomiphene citrate is used for ovulation induction therapy.^[47] It was observed that the usage of standard metformin (500 mgtds) along with the Clomiphene citrate increased in the live birth and the decrease in miscarriage rates.^[48] According to a study, its use during pregnancy can help in maintaining androgen levels as well as insulin levels in the normal range. The female children born to such women have reduced AMH levels, whereas male children have reduced androgen levels and are heavier.^[49],[50] Constant differences in the studies concerning the topics conjoining metformin, PCOS, pregnancy are seen, and there is a huge requirement for further studies for the rational usage of metformin in PCOS.

Recommendations

A multidisciplinary team approach is recommended for the management of PCOS, as this condition affects multiple systems and can have wide-ranging implications for a woman's health.^[51],[52] The following healthcare professionals may be involved in a multidisciplinary team approach to the management of PCOS:

Gynecologist: These specialists can help diagnose PCOS and manage its effects on reproductive health, including infertility

Endocrinologist: An endocrinologist can help manage the hormonal imbalances associated with PCOS, such as insulin resistance and HA

Dietitian: A dietitian can provide guidance on nutrition and lifestyle changes that can help manage PCOS, such as weight loss and the adoption of a low-glycemic index diet

Psychiatrist or Psychologist: PCOS is associated with a higher risk of depression and anxiety, so a mental health professional can help manage these aspects of the condition

Dermatologist: PCOS can cause acne and hirsutism, so a dermatologist can help manage these skin-related symptoms.

Lifestyle changes, including counseling for diet and psychotherapy, can play an important role in the management of PCOS, especially for patients with low self-esteem and depression.^[53] Dietary counseling can be useful for patients with PCOS, as it can help them adopt healthy eating habits and manage their weight. A low-glycemic index diet may be recommended, as it can help improve insulin sensitivity and reduce the risk of diabetes. Counseling for diet can also help patients with PCOS adopt a healthy and sustainable lifestyle that can help manage the condition over the long term. Psychotherapy can also be beneficial for patients with PCOS, especially those with low self-esteem and depression. PCOS can affect a woman's self-esteem, body image, and emotional well-being, leading to feelings of anxiety and depression. Psychotherapy can help patients develop coping strategies and improve their self-esteem, as well as manage the emotional and psychological aspects of the condition. A multidisciplinary approach that includes counseling for diet and psychotherapy can provide patients with PCOS with a comprehensive treatment plan that addresses both the physical and emotional aspects of the condition. This can help improve their overall health and well-being and lead to better management of the condition over the long term. As the multidisciplinary approach is perceived to be beneficial at some centers globally, hence furthermore research is required to assess and validate additional and existing multidisciplinary approaches and outcomes for determining the prognosis of the treatment and patient satisfaction compared to routine treatment strategies (i.e., treatment from a single healthcare provider).^[52] Additional research can guarantee a greater understanding and exploration of evidence-based protocols and strategies toward PCOS treatment.

Conclusion

It is essential to focus on managing the patients' primary needs and reducing the impact of long-term risk factors when treating a patient with PCOS. The symptoms of a PCOS patient could be well managed when a variety of specialists work together, catering to a multidisciplinary approach. The risk of missed PCOS diagnosis will be far reduced when the patients are referred to multiple healthcare providers of varying specialties. Therefore, the screening and diagnosis will be made earlier, and treatment could be initiated sooner, thereby improving the prognosis of the patient's condition and QOL. The observed favorable outcomes of the multidisciplinary approach worldwide include significant weight loss, enhanced satisfaction, patient well-being, enhanced body image, and improved PCOS management from a comprehensive point of view.

Footnotes

Acknowledgements

Sincere thanks to Squad Medicine and Research (SMR) for their support and guidance.

Conflicts of interest

There are no conflicts of interest.

Funding

Nil.

Author's contribution

All authors contributed equally to the manuscript.

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