The Pathogenesis of Polycystic Ovarian Syndrome

#### **Chapter 1**

## Pathophysiology of Polycystic Ovarian Syndrome

*Manu, Thomson Soni, Victoria and Pranav Kumar Prabhakar*

#### **Abstract**

Polycystic ovarian syndrome (PCOS) is the most common endocrinopathy that affects 8–20% of the reproductive age females and adolescent girls every year worldwide and approximately 5 million cases reported in the USA annually. It is more prevalent in urban areas as compared to the rural areas because of the difference in the lifestyles of rural and urban ladies. Rarely PCOS is passed on by heredity in some cases. It mostly occurs due to a lack of awareness. Its symptoms become mild to severe like initially hirsutism, acne which further leads to irregular periods and infertility. The pathogenesis of PCOS is not known because it is a complex multigenetic disorder. Ovary and adrenal steroid genesis, the action of steroid hormone, action and regulation of gonadotropin, action, and secretion of insulin, obesity, and regulation of energy in PCOS involve genes. Its main clinical manifestations are insulin resistance and increased level of androgen. Metformin is used to sensitize the insulin because the risk of glucose intolerance also gets elevated with insulin resistance, type-2 diabetes, and lipid abnormalities. Likely, the outcome of different, deeply interrelated genetic abnormalities that influence each other and perpetuate the syndrome may be represented by PCOS.

**Keywords:** polycystic ovarian syndrome, insulin resistance, genetics of PCOS, metformin, gonadotropin

#### **1. Introduction**

Polycystic ovarian syndrome (PCOS), also known as hyperandrogenic anovulation (HA) or Stein-Leventhal Syndrome, is the most common endocrine disorder which affects reproductive age women [1, 2]. PCOS is a complex psychological, metabolic, and reproductive condition that is characterized by either hyperandrogenism or abnormal gonadotropin secretion and sometimes associated with insulin resistance [3, 4]. It refers to a disorder with a combination of reproductive [5], environmental and metabolic characteristics [6]. It also causes endometrial abnormalities such as fertility implication and cancer implication [7, 8]. It is most commonly found in the reproductive age group female [9, 10] but it can also affect males due to hormonal imbalances. The appearance of polycystic ovary under the transvaginal pelvic ultrasound look are like small cyst. These cysts are eggs or follicles rimming the ovaries, which starts increasing in size and then stops at a tiny follicle size of around 2–10 nm.

They described infertile women with shinny ovaries, which is having multiple cysts in the size of approx. 2–10 mm. According to many pieces of research, PCOS may affect 8–15% women of reproductive age but 35% premenopausal mothers and 40% of sisters were affected by this problem as compared to general rates [11–13]. These ranges of incidence may vary according to the diagnostic criterion of the PCOS. In the case of PCOS, there are multiple cysts present in the woman's ovaries which are not released on its actual time so as a result immature follicle keeps growing, and leads to the formation of multiple cysts. There are reports which say 65–95% of all the women have PCOS also have insulin resistance which might be due to perturbed receptor tyrosine kinase, or other protein of insulin signaling cascade, modified adipokine signaling, and its secretion when compared to normal women [14, 15]. Increased level of insulin induces the rise in male sex hormone androgens, like testosterone which plays an important role in the pathogenesis [16, 17]. The exact pathogenesis of PCOS is still not very clear [18, 19]. There are several clinical significances like hirsutism, infertility, irregular periods, alopecia and many more symptoms begin shortly after puberty [20] and they develop during late terms and into early adulthood [3]. There is no particular treatment done to cure this problem but it can be managed by controlling sugar level and regulating the menstrual cycle by taking forming drug i.e. first insulin-sensitizing drug and it can also be treated by gonadotropin as first step treatment agents in ovulation. Low level of progesterone leads to cause overstimulation of immune system that produces the more estrogen and it will further lead to the production of autoantibodies i.e. anti-thyroid, anti spermatic, antinuclear, anti-ovarian, etc. there is a study in which we come to know that there are many proteins involved in PCOS [21]. The cumulative effect of modified protein, which are the product of mutated genes, along with various other factors like genetic inheritance and environment leads to complications in the case of PCOS [11]. Many genes participated in etiology of this syndrome but this is not fully investigated yet but the study shows that abnormality of genes in case of PCOS mostly affects the pathways of signal transduction which controls the steroidogenesis (formation of steroids) [12], insulin action [22] and secretion, gonadotropin action and regulation [23, 24], steroid hormones action and many more [25, 26].

#### **2. Symptoms**

There are many symptoms which are contributed to PCOS such as hirsutism, acne, alopecia, acanthosis, seborrhea, infertility, insomnia, and irregular periods (**Figure 1**) [27, 28].

*Hirsutism:* It is excessive growth of hair on a woman's face and body. In this case, there is a condition of unwanted hair growth in women mainly on the face, chest, and back, just as males [29].

*Acne:* It is a chronic skin condition that causes the spots and pimples. It mainly occurs when oil and dead skin cells clog the hair follicles which leads to the formation of whiteheads, blackheads, pimples, cysts, etc. They mainly occur on the face, shoulders, back, neck, chest, upper arms. It may also occur due to the different peripheral sensitivity of the androgen receptors [30].

*Alopecia:* It is the condition in which there is sudden hair loss which leads to baldness and in this condition, there is also thinning of hair.

*Acanthosis:* It is skin condition when there are dark velvety patches in the body folds and body creases like underarms and neck. The affected skin can become thicken and blackened.

*Pathophysiology of Polycystic Ovarian Syndrome DOI: http://dx.doi.org/10.5772/intechopen.101921*

#### **Figure 1.**

*Common symptoms of polycystic ovary syndrome (PCOS).*

*Seborrhea:* It is a condition when there are patches and red skin mainly on the scalp. There may be yellow plaques on the scalp. It is also a chronic inflammatory disease.

*Striae:* This is also known as stretch marks. They appear as reddened streaks on the skin it is mainly due to rapid change in body weight or in case of pregnancy also.

*Acrochordons:* They also knew as skin tags. This is the common skin growth, which sticks out. They are small soft common benign.

*Infertility:* It is an inability to conceive after a long period with unprotected sex.

*Insomnia or sleeping disorder:* Women with PCOS reports for the poor sleep or insomnia. There are a number of factor which leads to poor sleep but the PCOS is associated with the sleep disorder called sleep apnea. In the case of sleep apnea person, stops breathing for some duration during sleep.

*Irregular periods:* It is a problem with menstrual cycles. It is a condition when there are delayed, missed, or more bleeding patterns [31]. It further leads to the problem in the reproductive system. With PCOS, there is a correlation to a low level of androgen with advancing age in women [32].

#### **3. Causes**

Exact etiology remains unknown but some of them are written below [33–35].

a.*High level of insulin:* Insulin is a polypeptide hormone, which is synthesized and released by pancreatic beta cells and its main function is to reduce the blood glucose sugar level in the body, which indicates that PCOS has metabolic and reproductive morbidity [36]. If there is no insulin production then there is a high level of sugar in the body. It will act as a driving force for hyperandrogenism [37]. There is insulin resistance also occurring in which insulin is produced by the pancreas but our body not able to use that insulin [38]. A high level of insulin induces the ovaries to produce more androgens such as testosterone which will prevent ovulation [39, 40]. In PCOS pregnancies, unable to prevent excess testosterone [41]. There are two possibilities in the case of hyperinsulinemia i.e. increased hyperandrogenemia [42, 43] and decreased the circulating level of sex hormone-binding globulin [44]. Peripheral insulin resistance is also related to uterine and ovarian problems [45].


#### **4. The difference in normal ovary and PCOS ovary**

In normal case ovaries, fallopian tubes, uterus, vagina are the main reproductive organs of females and they are having a lifetime supply of ovum and these ova are stored in sac-like fluid-filled structures called follicles. The sex hormones, which are helpful to act on the function of the ovaries, are produced by the pituitary gland located just below the hypothalamus at the base of the brain. So pituitary gland secretes follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the bloodstream. Through blood, these hormones reach the ovary where they start to get maturing the immature ovum and increases the size of follicles [62]. As the eggs get

*Pathophysiology of Polycystic Ovarian Syndrome DOI: http://dx.doi.org/10.5772/intechopen.101921*

#### **Figure 2.**

*Pathophysiology of polycystic ovary syndrome.*

matured the follicles start releasing estrogen, a female sex hormone. As soon as the estrogen level crosses threshold concentration, the pituitary gland senses the LH flow to ovaries and results in the rapturing of the mature follicles and releases its ovum/egg. This process is known as ovulation. The free ovum then passes through the fallopian tube where the fertilization process occurs and the remaining immature follicle gets dissolved. If ovum does not get fertilized then the egg and line of the uterus are shared to doing the next menstrual cycle. But in the case of PCOS, the Pituitary gland secretes a higher amount of LH due to biochemical destruction which disturbs the menstrual cycle. Then there are no mature follicles present so no ovulation occurs and it will lead to infertility. Some follicles do not dissolve, they remain there as such and formed as fluid-filled sac-like structures which are known as CYSTS (**Figure 2**). Increased level of insulin and LH will produce testosterone [62, 63] which causes hirsutism, acne, prevent ovulation which further leads to infertility [64].

#### **5. Genetics of PCOS**

PCOS is a complex genetic disease with several susceptibility genes. It has powerful genetic and environmental components [65]. Many pieces of research show that identical twins are more prone to get PCOS than fraternal twins or non-twin siblings. Women having a 50% chance to get PCOS if their mother or sibling also has this disease. Research also shows that the male siblings of women with PCOS are more susceptible to get insulin resistance than the male sibling of unaffected women. Genes that are linked with PCOS are responsible for the production and metabolism of sex hormones or linked with an impaired function of insulin. Genes involved in PCOS are

a.*DENND1A* gene which is linked to PCOS risk and this gene is responsible in the import of molecules into the cell which is responsible for the recycling of hormone receptors from the cell's surface and leads to PCOS,


#### **5.1 Genes which are responsible for Ovary and adrenal steroidogenesis**


### **6. Role of hormones in the PCOS**

#### **6.1 Steroid hormone actions**

PCOS is one of the most common endocrine disorders in females of reproductive age group with multiple manifestations. The reproductive physiology of female is highly affected by her body weight and the metabolic status of her body. PCOS is mainly linked with obesity with the deposition of fats in abdominal regions in almost 51% of women having PCOS. As it is associated with insulin resistance and hence results in hyperlipidemia, cardiovascular disorders, and also cancer of the endometrium. There are some important components of lipid metabolic pathways which play a significant role in the PCOS occurrence.


#### **6.2 Gonadotropin action and regulation**

Kisspeptin is a protein that is coded by the KISS1 gene. Initially, this protein was discovered as its role in the tumor suppression mainly for melanoma and breast cancers. Kisspeptins have recently emerged as essential upstream regulators of GnRH neurons with many roles in reproduction such as puberty onset [75, 76], brain sex differentiation [77], gonadotropin secretion [78], ovulation and metabolic regulation of fertility [79].


#### **6.3 Insulin action and secretion**

Many women having PCOS have shown glucose-induced hyperinsulinemia, insulin resistant, independent body mass index. The insulin-dependent glucose level decreases by 35–40% in the case of PCOS affected women when compared to normal women. More than 2% of women with PCOS moves from normal to type 2 diabetes mellitus and almost 16% of women move from impaired glucose tolerance to type 2 diabetes mellitus. The incidence of PCOS with obesity is very complex. Although PCOS occurs both in obese and lean women some recent studies and meta-analysis reveal that obesity more frequently occurs in women with PCOS. And it is a wellknown fact that obesity leads to insulin resistance and finally to diabetes mellitus type 2. To fulfill the body's requirement, the pancreas produces a high amount of insulin and a condition of hyperinsulinemia occurs. This condition mainly affects fibroblasts and adipocytes. One of the main effects of this hyperinsulinemia is the autophosphorylation of tyrosine in the insulin receptor decreases whereas the autophosphorylation of serine increases in both types of cells. In the fibroblast, the insulin-dependent glucose uptake, translocation of GLUT4 to the plasma membrane, and insulin-dependent glycogen synthesis decrease whereas in the case of adipocytes also glycogen synthesis decreases. Insulin influences the function of LH on to the ovary which increases the production of androgens. Insulin also inhibits sex hormone-binding globulin (SHBG) production by hepatocytes increases the free androgen fraction in blood circulation. An increase in adipocyte tissue also increases the severity of insulin resistance. Hence, it exacerbates the metabolic and endocrine derangements of PCOS (**Figure 3**).

i.*Insulin and IGF-I:* Growth of ovary is stimulated by insulin and IGF-I. The action of gonadotropins on ovary steroid synthesis is increased by them.

*Pathophysiology of Polycystic Ovarian Syndrome DOI: http://dx.doi.org/10.5772/intechopen.101921*

**Figure 3.** *Role of insulin in polycystic ovary syndrome.*

The concentration of IGF-I and androgens is augmented by Insulin. It does this by regulating the synthesis of IGFBP-1 and SHBG in the liver. One of the common symptoms of PCOS is resistance to insulin. The important reasons resulting in PCOS is increased in insulin level and IGFBP-1 activity.


#### **6.4 Obesity and energy regulation**


iii.*UCP2 + 3:* Androgen synthesis of granulosa cells of affected PCOS patients is controlled by UCP2 which is an uncoupling protein. Treatment with the T3 hormone increases the expression of ovary UCP2. It may also change the pregnenolone synthesis which further results in P450 sec expression. This will further affect testosterone production.

### **7. Diagnosis**

Diagnosis is the main purpose to detect or to identify the disease by seeing their symptoms, or by performing many tests. Like in the case of PCOS doctors may see the sign and symptoms and may also do to test for PCOS [82].

*Appearance:* Diagnosis of PCOS occurs by seeing the appearance of ovaries like in case of PCOS there are polycystic ovaries due to having more than 12 follicles present in it which cause enlargement of the ovary.

*Medical history:* To diagnose PCOS doctors may check a patient's medical history like is there any person already having the same problem in the patient family.

*Symptoms:* The doctor may check all the signs and symptoms of that disease, for example, hirsutism, acne, alopecia, acanthosis, seborrhea, striae, acrochordons, infertility, fatigue, pelvic pain, mood changes, sleeping problems, irregular periods. The person with PCOS is more prone to mental health problems like depression, anxiety because it is a chronic disease with increase male hormone i.e. testosterone causing problems and this hormone during pregnancy having reported increasing the risk of neurodevelopmental disorders. They may also have hypertension, high cholesterol, heart attack, sleep problem, diabetes, and breast cancer.

*The Rotterdam criteria for the diagnosis of PCOS:* A group of scientific experts, in 2003, elaborated the diagnostic criteria to include the ultrasound images of polycystic ovaries as another diagnostic marker and if two out of three diagnostic criteria will were met and the same endocrinopathies were excluded (**Figure 4**). This is known as

#### **Figure 4.**

*The Rotterdam criteria for polycystic ovary syndrome.*

*Pathophysiology of Polycystic Ovarian Syndrome DOI: http://dx.doi.org/10.5772/intechopen.101921*

Rotterdam criteria [83]. Slowly and steadily these criterions were accepted by various societies and commitees like European Society for Human Reproduction and Embryology (ESHRE), and the American Society for Reproductive Medicine (ASRM). Although this criteria is controversial and the Androgen Excess Society (AES) come up with a new set of diagnostic criteria in 2006 which are still the most commonly adopted criteria by different guidelines [84]. These guidelines are accepted and used by a wide group of obstetricians and gynecologists as well as other specialists. *Blood test:* There are many tests done to check or to access the PCOS:

	- Cholesterol
	- Blood pressure
	- Diabetes
	- Glucose tolerance test etc.

*Ultrasound:* It is a type of imaging that is used to look at organs and structures inside the body. To identify any cyst, which is present in ovaries, and to check the size of ovaries whether they are enlarged or small, ultrasound of uterus, ovaries, and pelvis is suggested. Transvaginal ultrasound is a painless test with no radiations, it is performed on sexually active women otherwise abdominal scan can be done to check where is the ovaries are viewed from the outside through the stomach walls. In this type of ultrasound, a pen-shaped probe with an ultrasound sensor on the tip of the probe is used. This is helpful to see the clearer picture than an abdominal ultrasound.

#### **8. Treatment**

Unfortunately, PCOS cannot be cured, it can only manage by controlling the symptoms by doing exercise or by taking a healthy diet. It can be managed best to regulate their menstrual cycle and lower blood glucose level [65]. High fiber food like broccoli, cauliflower, sprouts, green and red pepper, olive oil, almonds, spinach, walnuts, fruits, etc. may help to reduce the impact of sugar in the body. Women with PCOS are majorly suffering from infertility so fertility drugs are given to aid anovulation [85]. Women with PCOS having hirsutism and acne problems are recommended to complete the

course of anti-androgen and do exercise for 45 minutes daily. Metformin is prescribed to lower the insulin level and it also aids in the regulation of the menstrual cycle and improves ovulation and pregnancy rates [86]. Metformin which is used for the treatment of diabetes for a long time is only a remaining member of the biguanide family. It will also help by improving the sensitivity of peripheral tissue against insulin [87]. It also inhibits hepatic gluconeogenesis [88, 89]. It also helps to reduce fatty acid oxidation. The dose of metformin is 500 to 2500 per day, an increase of dose may lead to worsening of side effects. Spironolactone is a steroid that acts as an antiandrogen, is chemically related to mineralocorticoid aldosterone. It blocks the synthesis of androgen to a particular extent [89, 90]. So, it is being used for the treatment of anovulation [91] and hyperandrogenism mainly for hirsutism [91, 92]. This drug in PCOS is limited [93], it has a good impact if used in a limited amount [94, 95]. One of the major factors for PCOS is the reduction of antioxidants and a rise in oxidative stress. Diabetes mellitus also leads to oxidative stress due to hyperglycemia. The supplementation with antioxidants has shown a positive result in the severity of diabetes alone and also improved insulin sensitivity in the case of PCOS. The intake of antioxidant or antioxidant containing food can be a good strategy to manage PCOS [96].

#### **9. Significance of metformin in PCOS management**

Metformin is a biguanide having the action for the reduction of glucose levels by increasing its utilization and also lowers down the androgen levels [97, 98]. The first insulin-sensitizing drug [99, 100] used to check the role of insulin resistance in PCOS is Metformin [101]. But according to research, Metformin alone is not a first-line treatment for the management of PCOS [102, 103]. Normal dosage for Metformin is 500–2500 mg/ day [104]. According to research, a particular period of metformin dose of 1500 mg/day leads to a huge decline in the levels of circulating androgens and BMI [33]. It will help to regulate and improve the menstrual and help in reduction in circulating androgens levels and it will also help in reduction in body weight [105]. Thiazolidinediones are also used in the management of PCOS [106, 107]. Because it may improve the menstrual cycle and also help to reduce the androgen levels but with the help of this, there is no change in body weight. Metformin affects ovarian steroidogenesis [108]. The addition of metformin to IVF will increase the pregnancy outcome and also help to decrease the risk of ovarian hyperstimulation syndrome. It improves the oocyte quality in PCOS patients undergoing IVF [109]. Metformin also used to reduce the BMI because taking metformin with a low-calorie diet will reduce the fat. Metformin reduces the hyperandrogenism by effecting on ovaries and adrenal gland [110], which further leads to, suppresses their androgen levels and reduce the LH and increase the sex hormone-binding globulin.

Metformin i.e. Fortamet, Glucophage, etc. by taking Spironolactone will lower the level of sex hormone but it can cause birth defects. So, do not take it during pregnancy or if any plan to get pregnant [111]. Orlistat stops the body from digesting some fat in your food so improve your cholesterol level that's why it may take to get weight loss. In the case of fertility, Clomiphene encourages steps in the process that triggers ovulation [86, 107]. Hypothalamus secretes a gonadotropin-releasing hormone [32], which binds its receptor on secretory cells of the adenohypophysis [112]. As a result of GnRH, gonadotroph produces LH and FSH, which help to regulate development growth menstruation and reproduction of the body [113].

#### **10. Infertility treatment**

To start treatment in a stepwise fashion from least aggressive to more aggressive treatment, the use of clomiphene citrate and IVF protocol [32, 82].

*Step one: Clomiphene treatment:* The main indication is irregular or absent ovulation. PCOS patient is an excellent candidate for the use of clomiphene but almost 50% of the patient experiences the failure of clomiphene. Clomiphene citrate is the effective method of inducing ovulation and improving fertility and its adverse effects are multiple pregnancies and ovarian cyst. This resistance and failure in ovulation induction with clomiphene citrate are also thought to be related to chronic low-grade inflammation [114].

*Step second: Gonadotropin treatment:* Gonadotropins are the natural next step for ovulation induction. One characteristic of ovulation induction in PCOS patients is the slow response and the risk for ovarian hyperstimulation syndrome and cyst formation. The most used current step up is characterized by a low starting dose, which is maintained for a longer period then increased only of the small amount per week. This protocol is associated with a low incidence of severe OHSS and multiple pregnancies.

*Step third: IVF:* The goal of induction of ovulation is the development of one or few ovulatory follicles and the goal of stimulation in In vitro fertilization (IVF) cycles is to obtain multiple follicles but without in occurring in ovarian hyperstimulation syndrome [112, 113].

#### **11. Conclusion**

The polycystic ovarian syndrome is a common endocrinopathy, which is characterized by hyperandrogenism, insulin resistance, and abnormal gonadotropin secretions. PCOS disturbs both reproductive and metabolic functions. Their symptom varies from mild to severe like hirsutism, acne, alopecia, striae, irregular periods, and ultimately leads to infertility. PCOS is a complex multi genetic disorder so its pathogenesis is unknown. Stein and Leventhal discover it in 1935. They described infertile women with shinny ovaries, which is having multiple cysts in the size of pigeon eggs. High insulin resistance, bad dietary choices, weakened the immune system and many more are main factors that promote the PCOS. It cannot be diagnosed only based on symptoms, so blood tests are done to measure hormonal levels, ultrasound also is done to check the reproductive organs, and personal and family history is also useful for diagnosis purposes. Some hormonal levels are measured when considered to PCOS i.e. LH, FSH, DHEAS, Prolactin, testosterone, Progesterone, Androstenedione. Many proteins are involved in PCOS. It is a familial condition so genes play a major role in PCOS. Genes who are linked with PCOS are responsible for the production and metabolism of sex hormones or linked with an impaired insulin function. Genes involved in PCOS are DENND1A, SHBG, THADA, FBN3, LHCGR, and INSR, etc. Oral contraceptives are used to reduce the androgen and LH levels with improvement in hirsutism, acne, body weight, and also help to regulate the menstrual cycle. Metformin is the most effective insulin-sensitizing drug. Treatment for infertility includes clomiphene, laparoscopic ovarian drilling, and gonadotropins.

### **Authors' contributions**

Manuscript concept and written content: Manu, T. Soni, P.K.Prabhakar; formatting and English correction: Victoria; critical revision of the manuscript and important intellectual content: Manu, T. Soni, P.K.Prabhakar.

### **Funding detail**

There is no funding received for this study.

### **Disclosure statement**

No potential conflict of interest was reported by the authors.

### **Author details**

Manu1† , Thomson Soni1† , Victoria<sup>2</sup> and Pranav Kumar Prabhakar1 \*

1 Department of Medical Laboratory Sciences, Lovely Professional University, Phagwara Punjab, India

2 Army College of Nursing, Jalandhar, Punjab, India

\*Address all correspondence to: prabhakar.iitm@gmail.com

† Shares the first authorship.

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Pathophysiology of Polycystic Ovarian Syndrome DOI: http://dx.doi.org/10.5772/intechopen.101921*

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#### **Chapter 2**

## Thyroid Dysfunction: In Connection with PCOS

*Mariya Anwaar and Qaiser Jabeen*

#### **Abstract**

As the prevalence of endocrine dysfunction is increasing and is associated with many complications including polycystic ovary syndrome (PCOS) which, itself is a risk factor of thyroid dysfunction. Although the causality of this association is uncertain, the two conditions share a bidirectional relationship. Both syndromes share certain common characteristics, risk factors and pathophysiological abnormalities, which can be managed by lifestyle changes as well as pharmacological treatment. Polycystic appearing ovaries are a clinical feature of hypothyroidism as well as hyperthyroidism in a few case studies. Adiposity, evidence of deranged autoimmunity, increased insulin resistance and disturbed leptin levels are present in both the disease states, seeming to play a complex role in connecting these two disorders. Major endocrine pathways including hypothalamic-pituitary-thyroid axis (HPTA) and HP-gonadal axis are involved in parallel relationship of PCOS and thyroid dysfunction. This chapter helps to explore all the dimensions of the relationship between PCOS and thyroid dysfunction.

**Keywords:** thyroid dysfunction, hypothyroidism, hyperthyroidism, PCOS, HPTA

#### **1. Introduction**

Thyroid dysfunction as well as polycystic ovary syndrome (PCOS) are very common endocrine disorders among the general population. Although, thyroid dysfunction and PCOS have completely different etiopathogenesis, but have various common features. In primary hypothyroidism, an increased ovarian volume and cystic changes in ovaries have been reported. It is also increasingly recognized that thyroid dysfunction is more common in females with PCOS as compared to the healthy individuals [1, 2]. This is may be due to some common considerations as well as pathophysiological connection between PCOS and thyroid disorders leading an individual towards both the disorders. Considering the high prevalence of Hashimoto's thyroiditis (HT) and the high prevalence of PCOS in women in the reproductive period, the emphasis will lie on the possible etiological and clinical connections between HT and PCOS.

#### **2. Endocrine system**

The endocrine system is a network of glands that produce and secrete hormones to regulate many physiological processes [3]. The endocrine system is comprised of

hypothalamus, pituitary gland, pancreas, adrenal gland, ovaries, testes, pineal gland, thyroid gland, parathyroid gland and thymus gland [4]. These glands communicate with each other through different pathways called axis. Major endocrine pathways include hypothalamic-pituitary-thyroid axis (HPTA), hypothalamic-pituitarygonadal axis, hypothalamic-pituitary-adrenal-axis, renin-angiotensin-aldosterone axis and hypothalamic-pituitary-adipose axis [5]. Endocrine glands are also closely linked with stress system, gut microbial flora and immune system [6].

#### **2.1 Endocrine feedback system**

Hormones are required for maintaining homeostasis and optimum body functions. Adequate secretion of hormones is ensured through biological feedback system that aims to provide hormones in a specific physiological range. Feedback system, is combination of several axis, that regulates endocrine and neural responses after any external or internal stimuli [7]. There are two types of feedback systems; positive feedback mechanism and negative feedback mechanism. Thyroid hormones exert both positive and negative feedback mechanism, which controls the release of both thyrotropin-releasing hormone (TRH) from hypothalamus and thyroid stimulating hormone (TSH) from anterior pituitary gland [8].

#### **2.2 Endocrine dysfunction**

Endocrine dysfunction is characterized by abnormal production and secretion of hormones from particular glands. Endocrine dysfunction can be categorized into following types; endocrine hyposecretion (deficiency of hormones), endocrine hypersecretion (excess of hormones), altered tissue response (hormone insensitivity irrespective of circulating hormone) and endocrine tumors [3, 9].

#### **3. Thyroid gland**

The thyroid gland is, morphologically, a butterfly-shaped organ, located anterior to the trachea, just inferior to the larynx. It is flanked by wing-shaped left and right lobes and the medial region called isthmus [3, 10]. The thyroid gland produces thyroid hormones, mainly triiodothyronine (T3) and thyroxine (T4). Multiple thyroid hormone receptor isoforms, derived from two distinct genes, mediate the action of thyroid hormones. The thyroid hormone receptors belong to a nuclear receptor superfamily. Thyroid hormone receptors bind to specific thyroid hormone-responsive sequences in promoters of target genes by regulating transcription. However, hypothalamic-pituitary-thyroid axis regulates thyroid hormones [7, 11].

#### **3.1 Hypothalamic-pituitary-thyroid (HPT) axis**

The hypothalamic-pituitary-thyroid axis is the part of neuroendocrine system consisting of hypothalamus, pituitary gland and thyroid gland. The hypothalamus is directly connected to the pituitary gland [12]. Hypothalamus secretes TRH which stimulates pituitary gland to produce and secrete TSH. TSH then acts on thyroid gland to produce and secrete thyroxine (T4) and triiodothyronine (T3). T4 is converted into T3 by deidonination controlled by various hormones like TSH, vasopressin and catecholamines in the peripheral organs (liver, adipose tissues, glia and skeletal muscles). T4 and T3 control the secretion of TRH and TSH by negative feedback mechanism to maintain normal levels of the hormones of HPT axis into the blood stream. Reduced levels of circulating TH result in increased TRH and TSH production and vice versa [13].

#### **3.2 Thyroid dysfunction**

Thyroid disease is very common worldwide affecting 5–15% of general population. Women are 3–4 times more susceptible to experience any type of thyroid disease. Thyroid dysfunction can be due to overproduction or under production of thyroid hormones. Thyroid disorders can lead to enlargement of thyroid gland as well as thyroid cancer. Abnormal production of thyroid hormones can lead to following pathological conditions; hypothyroidism (under production of thyroid hormones) and hyperthyroidism (overproduction of thyroid hormones) [3, 14]. There are a few drugs, classically associated with thyroid dysfunction, including lithium, amiodarone, interferon alfa, interleukin-2 and tyrosine kinase inhibitors [15].

#### *3.2.1 Hypothyroidism*

Hypothyroidism is described as the thyroid gland's inability to produce enough thyroid hormone to meet the body's metabolic demands. Hypertension, dyslipidemia, cognitive impairment, infertility and neuromuscular dysfunction are associated with untreated hypothyroidism. Hypothyroidism is more prevalent in women than men and increases with age. Primary thyroid gland failure or insufficient gland stimulation by the hypothalamus or pituitary gland may lead to hypothyroidism. Primary gland failure can be resulted from congenital abnormalities, iodine deficiency, autoimmune destruction (Hashimoto disease) and infiltrative diseases. Iatrogenic hypothyroidism occurs after radioiodine therapy, thyroid surgery and neck irradiation. Disorders generally associated with transient hypothyroidism include postpartum thyroiditis, silent thyroiditis, subacute thyroiditis and thyroiditis associated with thyroid stimulating hormone (TSH) and receptor-blocking antibodies. Basic causes of hypothyroidism are generally found with other manifestations of hypothalamic or pituitary dysfunction, and, are characterized by decreased levels of TSH relative to inadequate thyroid hormone.

#### *3.2.2 Hyperthyroidism*

Hyperthyroidism is defined as "the excessive production and secretion of thyroid hormones from the thyroid gland" and is characterized by weight loss, tachycardia, palpitation, arrhythmia, tremor, nervousness, irritability, anxiety, heat intolerance, sweating, increased thirst and appetite, fatigue, hyperdefecation, diffused goiter, warm and moist skin and disturbances in menstrual cycle [14, 16]. Hyperthyroidism can be caused by graves' disease, painless thyroiditis or postpartum thyroiditis, painful subacute thyroiditis, toxic multinodular goiter or toxic adenoma and exogenous thyroid hormone excess [3]. Menstrual disturbances are common in hyperthyroidism. Thyrotoxicosis may cause delay in sexual maturation and onset of menstrual cycle, oligomenorrhea, polymenorrhea and increased concentrations of sex hormone binding globulin (SHBG). Progesterone (P4) and follicle-stimulating hormone (FSH) significantly increase and, luteinizing hormone (LH) as well as estradiol (E2) significantly decrease in hyperthyroidism [17].

#### **4. Ovary**

Ovaries are the female pelvic reproductive organs that house the ova and are also responsible for the production of sex hormones. Ovaries are paired organs located on both sides of the uterus within the broad ligament beneath the uterine (fallopian) tubes. The ovary within the ovarian fossa is a space that is bound by the external iliac vessels, obliterated umbilical artery and the ureter. The ovaries house and release ova or eggs, needed for reproduction. A female has approximately 1–2 million eggs at the time of birth but only 300 of these eggs will become mature and released for fertilization [18].

#### **4.1 Polycystic ovary syndrome (PCOS)**

PCOS is the common endocrine disorder among females. It is estimated that 6–10% of women are affected by PCOS in reproductive years of their life. 1 out of 10 women experiences its symptoms in her fertile age. The multifaceted nature of PCOS makes it difficult to define. This clinically heterogenous endocrine syndrome is infertility to gynecologist, hirsutism to a dermatologist, menstrual irregularity to a physician and pseudo-Cushing's disease to an internist. Considering all the the symptoms collectively, it can be defined by hyperandrogenism, oligomenorrhea and multiple cystic follicles in ovaries. Disturbed pulsatile release of GnRH leads to excessive LH, contributing to hyperandrogenism and polycystic morphology. Genetic and epigenetic reasons of these changes have also been investigated [19, 20].

#### **4.2 Hypothalamic-pituitary-ovarian (HPO) axis**

Reproductive activity is regulated by the hypothalamic-pituitary-ovarian (HPO) axis which secretes hormones necessary for reproduction. HPO is comprised of three main components. Hypothalamus is located at the base of the brain, just above the brainstem. Along with homeostasis, the hypothalamus also secretes certain hormones, including gonadotropin-releasing hormone (GnRH). Pituitary gland is located below the hypothalamus, in the base of the skull. This gland secretes a variety of hormones, including luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in response to GnRH. Ovaries are located in the woman's pelvis, and secrete estrogen and progesterone [21].

### **5. PCOS and hypothalamic-pitutary-thyroid axis**

HPO axis and HPT axis are physiologically related. Thyroid receptors in ovaries control female reproductive functions and estrogen affects HPT axis. This link designates subclinical hypothyroidism as a determinant of PCOS. The high prevalence of hypothyroidism among PCOS patients also indicates a strong relation. Thyroid levels are more frequently disturbed in PCOS patients and are more commonly associated with anovulation. Insulin resistance is also a common feature of both the diseases. Incidence of subclinical hypothyroidism among PCOS women augments insulin resistance and hyperandrogenism [22, 23].

#### **6. Prevalence**

The autoimmune thyroid disease (AITD) is found more prevalent in females with PCOS than the females without PCOS. Many systematic prospective studies *Thyroid Dysfunction: In Connection with PCOS DOI: http://dx.doi.org/10.5772/intechopen.102492*

were carried out to observe the levels of thyroglobulin (Tg) antibodies and thyroid peroxidase (TPO), distinctive for hashimoto thyroiditis (HT) in females with PCOS. It was observed that TPO and Tg levels were elevated in PCOS patients than the healthy females. Moreover, in thyroid ultrasound, hypoechoic pattern which is typical of Hashimoto thyroiditis (HT) was also found more prevalent in PCOS patients. Increased level of thyroid antibodies and hypoechoic thyroid ultrasound pattern revealed the prevalence of HT in PCOS patients and found to be increased by threefold when compared with controls [24, 25]. In Asia, recently cross-sectional studies, revealed higher prevalence of TPO-positive autoimmune thyroiditis with increased mean TSH levels, increased prevalence of goiter and frequently a hypoechoic thyroid ultrasound pattern in patients with PCOS aged between 13 and 45 years, than in control [1, 26, 27]. Recent meta-analysis included most of the studies, which confirmed higher prevalence of AITD, higher TSH levels and positive TPO and TG antibodies in PCOS patients than in controls [28].

The possibility of having Graves' disease along with PCOS could be higher. In this regard, no broad epidemiological data was found as of recently with the exception of the case reports [1, 2, 29].

In girls of age 13–18 years with HT, a study showed highly significant prevalence of PCOS than in girls without HT, who were negative for TPO antibodies [30]. From the majority of studies, this can be concluded that HT and PCOS frequently occur together.

#### **7. Etiology and pathogenesis**

The etiology of HT is complicated and involves mainly genetic along with gender-associated and environmental factors like iodine supply, drugs, chemicals and infections [31]. Similarly, genetic, ovarian-related as well as other hormonal and metabolic factors such as hyperinsulinemia were supposed to involve in the etiology of PCOS [32].

Genetic susceptibility for HT has been confirmed by family and twin studies [33, 34]. Similarly, genetic susceptibility and familial aggregation were also found in PCOS patients [35, 36]. Various susceptibility genes have already been proposed for HT as well as PCOS [37, 38]. Although, a common genetic background still has not been established. Polymorphism of susceptibility genes in HT may influence the occurrence and characteristics of PCOS. Such possible connections will be discussed in more detail. Furthermore, HT is the most prevalent autoimmune disorder [37]. Possible role of autoimmune phenomena in the etiology of PCOS has been suggested [30, 39]. Therefore, supposed genetic and causal factors related to autoimmunity in both the disorders will be explained along with the role of polymorphism of susceptibility genes, alter growth factor beta (TGFβ), regulatory T cells (Tregs), the thymus and variations of sex hormones.

#### **7.1 Susceptibility and candidate genes**

In HT, family and twin studies recognized strong genetic susceptibility. The risk of developing HT is increased by 32 and 21 fold in children and siblings of patients with HT respectively, where females were more prone to be affected than males [33]. Various genes are said to be associated with the disease occurrence, progression and severity such as human leukocyte antigen (HLA-DR), cytotoxic

T-lymphocyte-associated protein 4 (CTLA4), CD40, interleukin 2 receptor, protein tyrosine phosphatase 22 (PTPN22), alpha (IL2RA), vitamin D receptor (VDR) and thyroid-specific gene thyroglobulin (Tg) [31, 40, 41].

Familial clustering is well established in PCOS. An increased prevalence of PCOS has been documented in first-degree relatives of females with PCOS [38, 42, 43]. Several candidate genes have been studied for PCOS, such as those coding for fibrillin 3 (FBN3), insulin (INS), INS receptor substrate 1, transcription factor 7-like 2, calpain 10, the fat mass and obesity associated protein [44, 45], sex hormone binding globulin (SHBG) [38] and VDR [46]. Recently, in an Asian as well as European population, the DENND1A gene, which encodes a protein participating in the endosomal membrane transport, was recognized by genome-wide association studies (GWAS) as a true PCOS susceptibility gene [47, 48]. However, the found results of a large number of candidate gene studies were mostly inconclusive.

#### **7.2 Genetic polymorphism**

FBN3 gene polymorphisms may play a role in the etiology of PCOS and HT by influencing the activity of TGF, which is regulated by FBNs. The FBN3 gene, like FBN1 and FBN2, is likely to encode FBNs, which are microfibril networks in the extracellular matrix that provide binding opportunities for TGF sequestration [49, 50]. Polymorphisms in the FBN3 gene, which impact the activity of TGF, which is regulated by FBNs, may play a role in the etiology of PCOS and HT. FBN3 is likely to encode FBNs, which are a component of extracellular matrix microfibril networks that provide binding opportunities for TGF sequestration, similar to FBN1 and FBN2 [47, 50–52]. Activins, inhibins, and anti-Mullerian hormone, all members of the TGF superfamily, are thought to play a role in the etiology of PCOS. However, genome wide association studies (GWAS) have found no members of the TGF signaling pathway to be among the top signals for PCOS. Changes in TGF have been linked to the etiology of PCOS in terms of prenatal origins, metabolic abnormalities, and reproductive abnormalities [50]. FBN3 is abundant in fetal organs, including the ovaries [53, 54]. FBN3 expression in the stromal compartments of fetal ovaries disappears after the first trimester. As a result, FBN3 has an effect on the activity of TGF, which is involved in the regulation of stromal formation and function throughout fetal development, confirming notions about PCOS having a fetal origin [54]. Recent genetic studies have also reported that polymorphism of the FBN3 gene has been shown to be associated with the levels of TGFβ. Allele 8 (A8) of D19S884, a dinucleotide repeat polymorphism in intron 55 of the fibrillin-3 gene, is linked to polycystic ovary syndrome [55]. Similarly, in HT, lower levels of serum TGFβ1 were found when compared with healthy controls. Moreover, levels of serum TGFβ1 did not increase after treatment with levothyroxine (l-T4), indicating the interrelation between TGFβ1 and HT [56]. TGF stimulates the production of the transcription factor forkhead box P3 (FOXP3) and the creation of Tregs in the establishment of immunological tolerance, and it works as a fundamental regulator of immune tolerance by promoting suppressive Tregs and blocking T cell differentiation [31, 57].

As a result, TGF could play a role in the development of autoimmune diseases like HT. Given this context, it's possible that PCOS women with allele 8 of the D19S884 gene in the FBN3 gene, and hence lower TGF1 levels, are more likely to develop HT than PCOS women without allele 8, but this has yet to be researched.

There has recently been evidence of a link between the three prime untranslated region (3′-UTR) mutation rs1038426 of the gonadotropin-releasing hormone receptor *Thyroid Dysfunction: In Connection with PCOS DOI: http://dx.doi.org/10.5772/intechopen.102492*

(GnRHR) and INS production in PCOS, as well as a link between serum TSH, serum INS levels, and INS sensitivity. This could point to a significant role for GnRHR genetic variants in INS secretion and INS resistance in PCOS, as well as a link to thyroid function [58].

Finally, the CYP1B1 gene, which codes for an enzyme that converts E2 to 4-hydroxyestradiol, is linked to PCOS. The CYP1B1 L432V (rs1056836) polymorphism was linked to serum thyroxine (T4), free T3 (fT3), and free T4 (fT4) levels [59]. This discovery could point to a third genetic relationship between thyroid function and PCOS.

#### **7.3 Thymus**

The importance of the thymus gland in immune system modulation and autoimmune development is well understood. Two processes permit the maintenance of self-tolerance and prevention of autoimmunity; the central immunological tolerance, which is enabled by the thymic deletion of autoreactive T cells during fetal development, and peripheral immune tolerance, in which Tregs play the key role [37, 60]. These cells are attained from the thymus as well as peripheral T cells. Tregs suppress the immune system and prevent an overabundance of immunological responses [61]. As previously established, lower TGF1 levels in the blood have been linked to HT [56].

In animal models, estrogen-induced immunological disruption has been demonstrated to play a role in the development of PCOS. Anovulation and follicular cysts were generated in female mice when estrogen was given before 10 days of age, when the thymus was in the latter stages of development [62]. The effect of estrogen on the thymus was investigated in estrogen-injected female mice with intact thymus, had follicular cysts in their ovaries; however, no cysts were found in mice who were thymectomized before estrogen injections and then reconstituted with adult thymocytes. Ovulation occurred and follicular cysts did not arise when estrogen was unable to exert influence upon the thymus during its development when adult thymic cells were given later. In addition, estrogen-injected animals with an intact thymus had a lower number of thymocytes than controls. The absence of Tregs due to an estrogenaffected thymus was thought to be a needed for the production of estrogen-induced cysts, supporting the autoimmune etiology of PCOS [63]. Similarly, the highest prevalence of infertility was seen in women prenatally exposed to diethylstilbestrol (DES), a strong synthetic estrogen that was given in the United States from 1940 to 1971, when they were exposed to DES from 9 to 12 gestational weeks [64]. This is also the period during which the thymus develops at its most rapidly [65]. A higher frequency of autoimmune disorders has been found in DES-exposed women [66]. Phytoestrogens, which are found in flax seeds and soy bean products, may expose modern pregnant women to higher doses of estrogen. In addition to estrogens, adrenal steroids like corticosterone have been demonstrated to reduce thymic weight and number, resulting in anovulation and the production of ovarian cysts in mice [67].

To summarize, different variables such as excessive estrogen levels or severe stress with increased adrenal hormones may be responsible for changes in the fetal thymus, resulting in changes in immunological tolerance and the occurrence of HT and PCOS in predisposed individuals in adulthood.

#### **7.4 Sex hormones**

The sex hormones play an important role as females are significantly more often affected by autoimmune disorders than males. Autoimmune disease autoimmune

affects 5% of the world's population and 78% of those affects women [68]. A doubled chromosome X and a low androgen-to-estrogen ratio were thought to play a role in the etiology of autoimmune disorders even in Klinefelter's syndrome [69]. The onset of autoimmune disorders in women is earlier than in males, and it frequently correlates with elevated levels of the female hormone progesterone [68]. As a result, when comparing pre-pubertal children with chronic autoimmune thyroiditis to pubertal adolescents or adults, the female-to-male ratio was shown to be considerably lower in pre-pubertal children with chronic autoimmune thyroiditis [70]. Similarly, estrogen usage was linked negatively with the presence of TPO antibodies [71]. During the menstrual cycle, higher levels of estrogens during the follicular phase and lower levels of estrogens during menstruation and luteal phase, lead to a shift from Th1 to Th2 mediated immunity, respectively [72]. As a result, throughout the typical menstrual cycle, levels of the Th2 cytokine interleukin 6 (IL6) were adversely linked with progesterone levels in young women. IL6 levels were lowest during the luteal phase and highest during the follicular phase [73]. The activation of FOXP3 and the generation of Tregs was inhibited by IL6 [62]. On the other hand estrogens have been shown to promote Treg development [72].

As a result, it was observed that the number of Tregs decreases during the luteal phase and increases during the late follicular phase [74]. Pregnancy causes several changes in the immune system in order to tolerate the fetus, the most notable of which is a shift from Th1 to Th2 cytokine profile [75, 76]. This is most likely due to Treg expansion generated by estrogen, which suppresses both Th1 and Th2 immune responses, while the latter are less vulnerable to Tregs and thus prevail. After delivery, a decrease in Tregs alters the cytokine profile from Th2 to Th1, causing autoimmunity to exacerbate or worsen [76]. A connection between the number of deliveries and the risk of AITD was found in a few retrospective studies [77, 78].

Sex hormones regulate in vitro and in vivo immune system [79]. Estrogens have been linked to a hyperactivity of T cells and a hypoactivity of B cells in animal studies [80]. The generation of autoantibodies was higher in female mice than in male mice [81]. Estrogens have been shown to decrease T suppressor cell function, enhance B cell activity, boost the release of the Th2 cytokine IL6, and shift the immune response to Th2 and antibody generation [38, 68]. In comparison to men, women have a greater CD4+/CD8+ ratio, higher CD4+ levels, and more antibodies [75]. Androgens suppress most immune system components, increase the activity of T suppressor cells, and increase the Th1 response and CD8+ cell activation [74, 82]. Progesterone inhibits macrophage growth, IL6 generation, and peripheral antibody production [82]. Oscillations in progesterone levels during pregnancy and the ovulatory cycle are thought to be linked to reversible immune system alterations [83].

Women with PCOS have lower progesterone and higher testosterone levels than women without PCOS [2]. Menstrual irregularity in women suffering from PCOS and several anovulatory cycles may have no or very low progesterone, resulting in an elevated estrogen-to-progesterone ratio for long duration. As a result, their vulnerability to autoimmune diseases may increases because of a stimulating effect of estrogens on the immune system [39, 49]. On the other hand, autoimmune disease could be prevented by androgens. However, their impact on the immune system and levels in PCOS are unlikely to be sufficient to avoid autoimmunity. As a result, an imbalance in progesterone, estrogen, and androgens may contribute to the development of HT. Taking this idea into account, as well as the three PCOS phenotypes that have been postulated [84], the increased prevalence of HT would be expected in women with

*Thyroid Dysfunction: In Connection with PCOS DOI: http://dx.doi.org/10.5772/intechopen.102492*

PCOS and chronic anovulation as well as without hyperandrogenism, followed by classic PCOS with hyperandrogenism and anovulation, while the decreased incidence would be supposed to expect in ovulatory PCOS with hyperandrogenism. However, this hypothesis is yet to be confirmed.

#### **8. Conclusions**

Almost unanimously, prevalence studies report on a frequent joint appearance of PCOS and HT in women within the reproductive age. Therefore, the above discussion, may conclude that thyroid disorders and PCOS are undoubtedly associated with each other, with respect to their etiology, pathogenesis and clinical consequences. However, this chapter provides scientific ground to further investigate the connection between thyroid dysfunction and PCOS.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Acronyms and abbreviations**



### **Author details**

Mariya Anwaar\* and Qaiser Jabeen Faculty of Pharmacy, Department of Pharmacology, The Islamia University of Bahawalpur, Pakistan

\*Address all correspondence to: pharmacistmariyaanwaar@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Thyroid Dysfunction: In Connection with PCOS DOI: http://dx.doi.org/10.5772/intechopen.102492*

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#### **Chapter 3**

## Polycystic Ovary Syndrome: It's Not Just Infertility

*Naheed Akhter, Sadia Sana, Naila Iftikhar, Muhammad Adnan Ahsan, Abu Huraira and Zafaar Siddique*

#### **Abstract**

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine issue described by unpredictable menses, hyperandrogenism, and polycystic ovaries (PCO). The commonness of PCOS changes relying upon which measures are utilized to conclude yet is just about as high as **15–20%** when the European culture for human propagation and embryology/American culture for regenerative medication rules are utilized. Clinical signs incorporated grown-ups incorporate sort 1 diabetes, type 2 diabetes, and gestational diabetes. Insulin opposition influences half **70%** of ladies with PCOS prompting a few comorbidities including metabolic condition, hypertension, dyslipidemia, glucose narrow-mindedness, and diabetes. Studies show that ladies with PCOS are bound to have expanded coronary corridor calcium scores and expanded carotid intima-media thickness. Psychological wellness problems including despondency, uneasiness, bipolar turmoil, and voraciously consuming food issues additionally happen all the more habitually in ladies with PCOS. Weight reduction works on feminine abnormalities, indications of androgen abundance, and barrenness the board of clinical appearances of PCOS incorporates oral contraceptives for feminine inconsistencies and hirsutism. Spironolactone and finasteride are utilized to treat indications of androgen overabundance.

**Keywords:** infertility, PCOS, subfertility, endometrial malignancy, hirsutism

#### **1. Introduction**

In 1935, scientists depicted a few ladies giving oligo/amenorrhea joined with the presence of reciprocal polycystic ovaries (PCO) set up during the medical procedure. Three of these seven ladies likewise gave weight, while five gave indications of hirsutism [1–5]. Just a single lady was both fat and showed hirsutism [6]. These discoveries infer that on the off chance that PCO is determined by morphology in ladies to have oligo/anovulation, not every one of the elements which are accepted to be related to PCOS should be present [5, 7]. Moreover, with the utilization of transvaginal ultrasonography, it has become obvious that ladies with oligo/amenorrhea, weight, and hirsutism do not all have the common PCO morphology. The event of significant heterogeneity in clinical indications and endocrine provisions related to polycystic ovary disorder (PCOS) infers that a few ladies with PCO on ultrasound output might even show none of the different elements of PCOS.

Since there is at present no general meaning of PCOS, distinctive master bunches utilize various measures to analyze the condition. In any case, every one of the gatherings searches for the accompanying three components [8, 9].


#### **2. Causes of polycystic ovary syndrome**

Doctors do not know what causes PCOS. They admit that a high amount of male hormones prevent the ovaries from producing hormones and eggs normally. Genes, insulin resistance, and inflammation have all been associated with excess androgen production [10].

#### **2.1 Genes**

Research shows that polycystic ovary syndrome runs in families. Almost certainly, numerous qualities—not only one—add to the conditions [11].

#### **2.2 Insulin resistance**

More than 70% of ladies with polycystic ovary syndrome have insulin opposition, implying that their body cells cannot utilize insulin appropriately. The chemical produces by the pancreas to help the body use sugar from food sources for energy is insulin [12].

At the point when cells cannot utilize insulin appropriately, the interest of the body in insulin increments. The pancreas produces more insulin to redress. Additional insulin activates the ovaries to create more androgen.

The significant reason for insulin obstruction is weight. Corpulence and insulin opposition can expand your danger for type 2 diabetes [13].

#### **2.3 Inflammation**

Ladies with polycystic ovary syndrome frequently have expanded degrees of irritation in their bodies. Being overweight can in like manner add to aggravations. Research has connected overabundance irritation to higher androgen levels [14].

#### **3. PCOS dangers**

If you have been determined to have polycystic ovary disorder (PCOS), comprehend the drawn-out well-being hazards related to the sickness, which include the following:

*Polycystic Ovary Syndrome: It's Not Just Infertility DOI: http://dx.doi.org/10.5772/intechopen.101923*


Not all ladies with PCOS will foster these conditions, however, having PCOS expands your danger. Accordingly, have your well-being checked routinely by a doctor who has experience treating ladies with PCOS. Normal doctor visits ought to be booked through your conceptive years and proceed after menopause, even though you will presently do not have sporadic periods and other PCOS manifestations might diminish after the feminine cycle closes [8, 10].

The globally regarded doctors at the middle for polycystic ovary condition supervise the consideration of thousands of ladies with PCOS consistently. UChicago medication is additionally home to specialists in malignancy, coronary illness, and other medical issues who can analyze and treat these conditions if they create [3].

#### **3.1 Fruitlessness or subfertility**

Numerous ladies do not understand that they have PCOS until they see a specialist decide why they cannot get pregnant. Fruitlessness or subfertility (diminished richness) is a typical issue for ladies with PCOS.

This might be because of the lopsidedness of chemicals brought about by an overproduction of the male chemical testosterone. The ovaries may inconsistently deliver ova (eggs). Because of the accessibility of ovulation-inciting medications and advances in helped conceptive advances, numerous ladies with PCOS would now be able to imagine [15].

Even though PCOS might diminish a lady's opportunities to become pregnant, the illness is certifiably not a substitute for anti-conception medication. Numerous ladies with PCOS do become pregnant, without clinical help. Ladies who are physically dynamic and do not wish to imagine ought to think about utilizing a prophylactic [16].

#### **3.2 Endometrial malignancy (endometrial carcinoma)**

Ladies with PCOS have all the earmarks of being at expanded danger for creating malignant growth of the endometrium (coating of the uterus) further down the road. From your teenagers through menopause, all ladies experience a month-to-month development of the endometrial covering in the uterus, as the body sets itself up for the capability of a treated egg. On the off chance that you do not become pregnant, the coating regularly is shed through the period [17].

Ladies with PCOS likewise experience the month-to-month development of the endometrial covering. Notwithstanding, the covering is not adequately shed since she has rare or nonexistent feminine periods. In this way, the covering proceeds to assemble and can build the danger of endometrial malignant growth [18].

#### **3.3 Diabetes**

Insulin assists the body with using or interaction (glucose). Insulin obstruction or weakened glucose resistance have been connected to PCOS. Moreover, significant degrees of insulin invigorate the creation of testosterone, which bothers PCOS [17, 19].

By age 40, up to 40% of ladies with PCOS have some degree of unusual glucose resilience, as one or other diabetes or weakened glucose resistance. Our doctors at UChicago Medication's Middle for Polycystic Ovary Disorder direct continuous exploration on the job of insulin opposition and insulin activity in ladies with PCOS. A lot of this exploration has been distributed in clinical diaries, such as New Britain Diary of Medication and Diary of Clinical Endocrinology and Digestion [20].

#### **3.4 Lipid irregularities**

Hyperandrogenism (expanded testosterone) can prompt a troublesome lipid profile in ladies with PCOS. This implies that a lady with PCOS might have an undeniable degree of fat substances in her circulatory system. In certain ladies, the blood lipid profile might show a lower pace of high-thickness lipoproteins (HDL the "Great" cholesterol) and a higher pace of low-thickness lipoproteins (LDL the "Awful" cholesterol). This irregularity builds the danger of cardiovascular sickness [21].

#### **3.5 Cardiovascular dangers**

Proof proposes that ladies with PCOS are at expanded danger for coronary illness and other cardiovascular sicknesses. Moreover, the inclination for ladies with PCOS to be overweight expands the danger of cardiovascular sickness, similarly as heftiness increments cardiovascular danger among ladies and men who do not have PCOS [20].

#### **3.6 Obstructive rest apnea**

Studies led at the College of Chicago have affirmed the outstandingly high danger of obstructive rest apnea among ladies with PCOS. While expanded body weight adds to this danger, ladies with PCOS appear to be at high danger as an outcome of different elements notwithstanding weight. For instance, the high testosterone levels in PCOS additionally appear to assume a part in the improvement of rest apnea [22].

#### **4. Sign and symptoms**

Polycystic ovary condition (PCOS) is a hormonal issue normal among ladies of conceptive age. PCOS indications might start soon after pubescence, yet can likewise create during the later high scholar years and early adulthood. Since indications might be ascribed to different causes or go unrecognized, PCOS might go undiscovered for quite a while. Generally, an analysis of PCOS can be made when you experience two of these **three signs** [23].

#### **4.1 Unpredictable periods**

Individuals with PCOS regularly have sporadic or missed periods because of not ovulating. Rare periods are a typical indication of PCOS. For instance, you may have less than nine periods every year with over 35 days between periods. Different ladies experience the ill effects of strangely weighty periods [24].

#### **4.2 Polycystic ovaries**

Albeit certain individuals might foster blisters on their ovaries, many individuals do not. Your ovaries may be developed and contain follicles that encompass the eggs. Accordingly, the ovaries may neglect to work routinely [18, 25].

#### **4.3 Overabundance androgen**

Raised degrees of male chemicals might bring about actual signs, such as overabundance of facial and body hair (hirsutism), and sometimes extreme skin inflammation and male-design hairlessness [25, 26].

### **5. Symptoms**


### **6. Indications of polycystic ovary syndrome**

#### **6.1 Weight gain**

About a portion of individuals with polycystic ovary syndrome will have weight gain and stoutness that is hard to oversee [28].

#### **6.2 Exhaustion**

Many individuals with polycystic ovary syndrome report expanded exhaustion and low energy. Related issues, for example, helpless rest might add to the sensation of weariness [29].

#### **6.3 Undesirable hair development (hirsutism)**

Regions influenced by overabundance hair development might incorporate the face, arms, back, chest, thumbs, toes, and mid-region. Hirsutism identified with PCOS is because of hormonal changes in androgens [30].

#### **6.4 Diminishing hair on the head**

Going bald identified with polycystic ovary syndrome might increment in middle age.

#### **6.5 Fruitlessness**

PCOS is the main source of female fruitlessness. Notwithstanding, only one out of every odd lady with PCOS is something very similar. Albeit certain individuals might require the help of fruitfulness medicines, others can imagine normally [31].

#### **6.6 Skin inflammation**

Hormonal changes identified with androgens can prompt skin inflammation issues. Male chemicals can make the skin oilier than expected and cause breakouts in regions, such as the face, chest, and upper back [31].

#### **6.7 Obscuring of skin**

You might see thick, dull, smooth patches of skin under your arms or bosoms, or on the rear of your neck [32].

#### **6.8 State of mind change**

Having polycystic ovary syndrome can improve the chances of emotional episodes, sorrow, and uneasiness [11, 33].

#### **6.9 Pelvic agony**

Pelvic agony might happen with periods, alongside weighty dying. It might likewise happen when a lady is not dying [11, 32].

#### **7. How PCOS affects fertility**

Polycystic ovarian disorder is the main source of ovulatory fruitlessness. Up to 80% of females who have polycystic ovary syndrome experience related fruitfulness challenges. In case you are experiencing issues getting pregnant, you have an assortment of treatment choices. A certain way of life alterations is the best option to further develop fruitfulness, trailed by prescriptions, hormonal medicines, and helped regenerative strategies [34].

A trademark indication of polycystic ovary syndrome is sporadic or missing feminine periods. Certain individuals with PCOS may not get a period for months, even a

#### *Polycystic Ovary Syndrome: It's Not Just Infertility DOI: http://dx.doi.org/10.5772/intechopen.101923*

long time, while others will encounter draining for quite some time. A little level of those with polycystic ovary syndrome will encounter month-to-month cycles [35].

Sporadic or missing feminine cycles in polycystic ovary syndrome are because of a fundamental hormonal awkwardness [36].


Minuscule follicles show up as a string of pearl on an ultrasound, sometimes encompassing the ovary. These follicles are called cysts/pimples because of their appearance, despite the fact that they vary from the ovarian sores that can develop and crack. Unsuccessful labors are likewise normal with polycystic ovary syndrome and might be because of the imbalance of sex chemicals and more elevated levels of insulin [35, 37].

#### **8. Diagnoses**

Medical care suppliers search for three trademark elements of polycystic ovary disorder (PCOS)—nonattendance of ovulation, significant degrees of androgens, and blisters on the ovaries. Having at least one of these components could prompt a finding of PCOS. If your clinical history proposes that you may have PCOS, your medical care supplier will preclude different conditions that might cause comparable manifestations [37, 38].

#### **8.1 Before making a finding of PCOS**

#### *8.1.1 Take a full family history*

Your medical care supplier will get some information about your feminine cycle and any set of experiences of fruitlessness. The person likewise will find out if you have a mother or sister with PCOS or with manifestations like yours, as PCOS will in general spat families [39].

#### *8.1.2 Conduct a complete physical exam*

Your medical care supplier will do an actual test and search for additional hair development, skin break out, and different indications of undeniable levels of the chemical androgen. The individual additionally will take your pulse, measure your abdomen, and work out your weight list, a proportion of your muscle versus fat dependent on your stature and weight [40].

#### *8.1.3 Take blood tests*

Your medical care supplier will look at the degrees of androgens, cholesterol, and sugar in your blood [41].

#### *8.1.4 Do a pelvic test or ultrasound to look at your ovaries*

During the pelvic test, your medical care supplier will embed two fingers into your vagina and push on your midsection to feel for blisters on your ovaries. To assist with seeing growths in your ovaries, the individual in question may suggest an ultrasound, a test that utilizes sound waves to snap a photo of your pelvic region. Your medical care supplier likewise will check how thick the coating of your uterus is; if your periods are unpredictable, the covering of your uterus could be thicker than typical.

#### **9. How is polycystic ovary syndrome treated?**

Treatment for polycystic ovary syndrome depends on several aspects. These might incorporate your age, how serious your indications are, and your general well-being. The kind of treatment may likewise rely upon whether you need to become pregnant later on [42, 43].

• If you do plan to become pregnant, your treatment may include:

A change in diet and activity

A sound eating routine and more active work can assist you with getting in shape and lessen your indications. They can likewise help your body to use insulin all the more productively, lower blood glucose levels, and may assist you with ovulating [44].

Medications to cause ovulation

Medicine can assist the ovaries with delivering eggs normally. These drugs additionally have specific dangers. They can expand the chances of multiple births (twins or more). What's more, they can cause ovarian hyperstimulation. This is the point at which the ovaries discharge and excessive hormones. It can cause manifestations, for example, stomach bulging and pelvic agony [45].

• If you do not plan to become pregnant, your treatment may include:

#### Birth control pills

These assist to control periods, lowering androgen levels, and diminishing skin inflammation [44].

Diabetes medication

This is frequently used to bring down insulin opposition in PCOS. It might likewise assist with diminishing androgen levels, slow hair development, and assist you with ovulating all the more routinely [46, 47].

A change in diet and activity

*Polycystic Ovary Syndrome: It's Not Just Infertility DOI: http://dx.doi.org/10.5772/intechopen.101923*

A healthy diet and more exercise can help you to reduce weight and your indication. They can also assist your body to utilize insulin more efficiently, diminish blood glucose levels, and may help in ovulating [48].

Medications to treat other symptoms

A few drugs can assist with lessening hair development or skin inflammation [47].

#### **Author details**

Naheed Akhter1 , Sadia Sana1 \*, Naila Iftikhar1 , Muhammad Adnan Ahsan1 , Abu Huraira1 and Zafaar Siddique2

1 College of Allied Health Professionals, Government College University, Faisalabad, Pakistan

2 Faculty of Allied Health Sciences, University Institute of Radiological Sciences and Medical Imaging Technology, The University of Lahore, Pakistan

\*Address all correspondence to: sadiasana203@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 4**

## Rare and Underappreciated Causes of Polycystic Ovarian Syndrome

*Alan Sacerdote*

#### **Abstract**

While hyperinsulinemia is a common contributing mechanism in the pathogenesis of polycystic ovarian syndrome (PCOS), other mechanisms may give rise to or add to the effects of hyperinsulinemia, as well as other causes of hyperandrogenism, in the pathogenesis of PCOS. Such underappreciated causes may include autoimmune, insulin receptor mutations, mutations of post-receptor insulin signaling response elements, polymorphisms of LH, androgen, and estrogen signaling pathways, epigenetic alterations in hormonal signaling cascade response elements, infestations and infections with organisms capable of endocrine disruption by various mechanisms, as well as drugs and other chemicals which may be endocrine disruptors. In addition, alterations in the gut, oral, or vaginal biome may be associated with PCOS and insulin resistance and may, in some instances, have a role to play in its pathogenesis. In this chapter I plan to review what is known about these lesser-known causes of PCOS, in the hopes of alerting clinicians to consider them and stimulating investigators to better understand PCOS pathogenesis in general and, hopefully, develop more individualized, precision treatment and prevention strategies for the people in our care.

**Keywords:** PCOS, insulin resistance, biome, polymorphisms, epigenetic, endocrine disruptors, autoimmune, vitamin D

#### **1. Introduction**

Polycystic ovarian syndrome (PCOS) is believed to be the most common cause of infertility in reproductive age women [1]. Although men lack ovaries, there is also a syndrome called male PCOS featuring a similar set of cardiometabolic indicators and risks to that seen in female PCOS as well as early balding [2]. Most people with PCOS are insulin resistant/hyperinsulinemic [3]. When overweight or obesity is present in people with PCOS (as is the case in most people with this disorder) insulin resistance/hyperinsulinemia is exacerbated [3]. Several mutations are associated with an increased risk of PCOS [4]. Gene methylation and histone acetylation abnormalities as well as certain non-coding RNAs may also contribute to the expression of PCOS [5].

Autoimmune disease has been shown to play a role in some people with PCOS, severely insulin resistant diabetes, acanthosis nigricans, and systemic lupus

erythematosus with nephritis [6]. Besides these rare and dramatic examples of the Type B syndrome, there is some evidence that an autoimmune process triggered by low progesterone levels may be a trigger for PCOS in many women [7]. A similar phenotype without lupus or anti-insulin receptor antibodies, but with insulin receptor mutations or abnormal post-receptor signaling has also been described [6].

Parasitoses, which are especially common in the tropical and subtropical parts of the world (and becoming more common as a result of the climate crisis), can induce PCOS by virtue of their ability to synthesize steroid hormones, e.g., estradiol and 1,25-OH2-vitamin D3 from its precursor, 25-OH-vitamin D [8].

Alterations in the microbiome have been reported in people with PCOS which may play a causative role [9–11].

Endocrine disruptor chemicals (EDCs), which are ubiquitous and increasing in our environment, including certain drugs, may also contribute to the pathogenesis of PCOS [12, 13].

Epilepsy has been cited as a cause of PCOS, however, there is controversy as to whether the disorder itself, treatment with valproate, or both are responsible [14].

Many drugs are associated with an increase in insulin resistance (IR) which may be an initial step in PCOS pathogenesis. In addition, EDCs in our environment may initially cause IR or bind as agonists to estrogen or androgen receptors, eventually contributing to PCOS [15].

In the remainder of this chapter, I shall review what is known about these diverse contributing causes of PCOS in the hope that in so doing clinicians might explore these often-reversible factors in their patients. I further hope that such a review may point to common pathogenic pathways in many, if not all, people with PCOS. Finally, I hope that appreciation of the various causes of PCOS can lead to improved preventive strategies and individualized, precision treatment of people with PCOS.

#### **2. Genetic predisposition to PCOS**

The marked tendency of PCOS for familial clustering (made even more remarkable by the hypo-fertility of people with PCOS) has long supported the notion that PCOS has a genetic component. However, since families often share similar diets, lifestyles, and EDC exposures, twin studies using monozygotic twins raised in very different environments would be helpful in separating genetic and environmental effects. Although it was shown that the tetrachoric correlation for PCOS in monozygotic twin sisters is higher than for dizygotic twins or for non-twin sisters, each set of twins or sisters in this large study was brought up in the same family. Despite efforts of most parents to raise monozygotic twins as distinct individuals, they are apt to, nonetheless, share a more similar environment and set of experiences than less closely related siblings, leaving open the possibility that shared environment/experience contributes significantly to the correlation [16]. In addition to tetrachoric correlation, both univariate analysis and a trivariate genetic analysis of major findings occurring in women with PCOS suggested a strong genetic component of PCOS in this Dutch twin study by Vink and colleagues [16]. Other twin studies in people with PCOS have reached similar conclusions [17–20].

Genome-wide association studies (GWAS) have been helpful in identifying polymorphisms that are associated with an increased risk of PCOS development [21–24]. Nevertheless, only about 10% of the apparent heritability of PCOS to date can be explained by these associations, leading to speculation that various phenotypes are associated with rare polymorphisms. Newer technologies e.g., gene and whole exome sequencing may clarify the contribution of rare polymorphisms to different phenotypes in the future [21].

Among the GWAS-identified candidate loci are DENND1A, LHCGR, INSR, FSHR, ZNF217, YAP1, INSR, RAB5B, and C9orf3 [22]. Polymorphisms found in DENND1A (P = .0002), THADA (P = .035), FSHR (P = .007), and INSR (P = .046) in Chinese women with PCOS were also strongly associated with PCOS in European women [24].

GWAS often fails to identify candidate loci in the mitochondrial portion of the genome [25]. Recent publications suggest that the mitochondria may play a pivotal role in PCOS pathogenesis, both genetically and epigenetically, given the essential mitochondrial role in cellular metabolism and IR. Recently Ye and colleagues reported that a 4977 base pair deletion in mitochondrial DNA detected in peripheral blood using multiplex probe-based qPCR was highly associated with PCOS in a logistic regression analysis [26]. In a study by Saeed and colleagues it was reported that most of the mitochondrial DNA mutations (80%) were limited to a 3157–3275 base region which is evolutionarily conserved and would be expected to change the secondary structure of mitochondrial transfer RNAs. As suspected, 6 mutations (A to G and/or T to C) altered the expected base pairing. Mitochondrial DNA copy numbers were also diminished in women with PCOS compared with controls [27]. Zeng et al. have reviewed the role of oxidative stress (OS) in people with PCOS [28]. They summarized much of what is currently known about the role of mitochondrial dysfunction in PCOS. Reduction of mitochondrial DNA copy number and mitochondrial mutations contribute to IR, metabolic syndrome, and disordered development of ovarian follicles through increased production of reactive oxygen species (ROS). Obesity plays a pivotal role in the pathogenesis of PCOS in most people, however, mitochondrial genome alterations related to PCOS with obesity are not yet well understood, underlining the need to investigate changes in the mitochondrial genome that are associated with obesity. External environmental factors may also disrupt mitochondrial function. Recent attention has focused on the effect of environmental factors e.g., cigarette smoke and bisphenol A on reproduction. Cigarette smoke has been reported to disrupt ovarian development; 1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal (NNA), contained in third-hand smoke, reduced ovarian weight and follicle number in rats exposed to NNA for 30 days compared with controls and even had a serious negative effect on development of the offspring of NNA-exposed rats. These adverse reproductive effects of cigarette smoke seem to be due to mitochondrial dysfunction. NNA exposure causes ROS buildup by increasing superoxide dismutase (SOD) mRNA levels, inducing apoptosis. Benzo(a)pyrene (BaP), another component of cigarette smoke, causes massive mitochondrial ROS leakage/dysfunction, resulting in significant plasma membrane lipid peroxidation and disrupted ovum fertilization. Cigarette smoke also adversely effects the development of granulosa cells, which have an essential role in providing optimal amounts of the hormones and nutrients needed for follicular development.

#### **3. Epigenetic contributions to PCOS**

These include abnormalities of DNA methylation, histone acetylation, and downstream signal transduction abnormalities.

#### **3.1 Abnormalities of DNA methylation and histone acetylation**

Epigenome-wide association studies (EWASs) are helping in the discovery of environmentally mediated molecular changes in PCOS from disease pathogenesis to the discovery of epigenetic markers. Recent epigenetic studies offer persuasive evidence linking epigenetic regulation with PCOS etiology, presentation, clinical phenotypes, and comorbidities, which could potentially lead to improved disease prevention and management via precisely targeted strategies. Several pivotal biological pathways have been repeatedly reported by independent groups, supporting functional regulation by endocrine abnormalities and metabolic dysfunction in PCOS, while also suggesting an autoimmune component in the syndrome [29]. Increasing application of high-throughput sequencing technologies for epigenome analysis combined with evidence-based causal inference should facilitate precision PCOS prevention/treatment in the future.

Vázquez-Martínez et al. recently reviewed the topic of DNA methylation in women with PCOS [5]. Alterations in DNA methylation, histone acetylation and noncoding RNAs have been found in diverse tissues of women with PCOS. DNA methylation abnormalities appear in peripheral and umbilical cord blood, and in ovarian and fat tissue of women with PCOS, suggesting a pivotal role for these epigenetic modifications in the pathogenesis of this disorder. Possibly, these derangements in DNA methylation facilitate deregulation of gene expression involving inflammation, hormone biosynthesis and signaling, as well as glucose and lipid metabolism. The authors have compiled an extensive table of the tissues in which methylation abnormalities are encountered in women with PCOS indicating whether the involved DNA is hypo- or hypermethylated, the changes in gene expression, if any, related to the methylation variants, and any documented clinical/phenotypic expression resulting from these changes. Interestingly, both hypomethylation of some genes and hypermethylation of others may predispose to PCOS.

#### **3.2 Epigenetic effects of hyperandrogenism**

Qu and colleagues studied the effects of hyperandrogenism on the expression of histone deacetylase 3 (HDAC3), peroxisome proliferator-activated receptor gamma 1 (PPARG1), and nuclear corepressor 1 (NCOR1) genes in the granulosa cells of women with a hyperandrogenic form of PCOS, compared with women with non-hyperandrogenic PCOS, women without PCOS who had tubal infertility, and a rodent model of PCOS [30]. NCOR1 and HDAC3 mRNA expression was higher in the hyperandrogenic women than in normo-androgenemic women with PCOS and controls (P < 0.05). When all women were divided into successful and failed pregnancy subgroups, they found lower PPARG1 mRNA levels and higher NCOR1 and HDAC3 mRNA levels in the failed subgroup with hyperandrogenic PCOS (P < 0.05). Two hypermethylated CpG loci in the PPARG1 promoter and 5 hypomethylated CpG loci in the NCOR1 promoter were encountered only in the hyperandrogenic women with PCOS (P < 0.01–P < 0.0005). The acetylation levels of histone H3 at lysine 9 and p21 mRNA expression were low in human granulosa cells cultured with dihydrotestosterone in vitro (P < 0.05). A PCOS rodent model also displayed abnormal PPARG1, NCOR1, and HDAC3 mRNA expression and methylation alterations of PPARG1 and NCOR1, consistent with those found in women with hyperandrogenic PCOS. A strength of this study is the consistent effect of hyperandrogenism in the induction of epigenetic changes in PPARG1, NCOR1, and HDAC3 in granulosa cells in hyperandrogenic

women and rodents with PCOS as well as in vitro, which have a role in the ovarian dysfunction encountered in women with a hyperandrogenic PCOS phenotype.

#### **4. Parasitosis as a cause of PCOS**

When considering our genome and our epigenome we often lose sight of the fact that the organisms that live within us and on us, though having a different number of chromosomes than the cells we think of as human with somewhat different gene sequences, contribute to our total genome and epigenome. In sheer number, the cells of our biome far exceed the number of cells we think of as human. The character and density of their gene products profoundly influence our hormonal, metabolic, and immune milieu, and even our mood and personality. In the case of parasites, they are in turn hosts to biomes of their own.

As mentioned in the Introduction, we have published the case history of a woman who had PCOS associated with extensive neurocysticercosis [8]. She had refused standard treatment with albendazole for her parasitosis (which she presumably acquired in her native Mexico) because of fear of drug side effects that some of her affected friends had experienced. She had been referred to our clinic because of complaints of worsening hirsutism and amenorrhea x 2 years. She was 32 years old G1P1001. Diagnostic work-up fulfilled Rotterdam criteria for PCOS with amenorrhea, hirsutism, low sex hormone binding globulin, and an elevated LH/FSH ratio. Non-classic adrenal hyperplasia, pregnancy, and virilizing tumors were excluded by appropriate tests. Hypovitaminosis D was excluded by measurement of vitamin D metabolites, however, her serum 1,25(OH)2-vitamin D3 level was elevated. Treatment with lifestyle modification (weight loss diet, prescribed exercise), and gradually uptitrated doses of metformin to 2000 mg/day was associated with a gradual reduction in hirsutism and a return of menses, although still with oligomenorrhea. SHBG rose slightly and there was normalization of the LH/FSH ratio.

We wanted to know whether her extensive burden of neurocysticercosis was playing a role in the etiopathogenesis of her PCOS, perhaps by pressing on the GnRH cells of the hypothalamus, however, the neuroradiologist could find no evidence of anatomic hypothalamic involvement by the encysted parasites. We also considered the possibility that her elevated serum 1,25-(OH)2-vitamin D3 elevation was due to the formation of granuloma-like lesions around the encysted parasites with either the encysted parasites or the surrounding mononuclear cells synthesizing 1,25(OH)2-vitamin D3 in excess, as occurs in other granulomatous disorders like pulmonary sarcoidosis and tuberculosis. We also performed a literature search for associations between cysticercosis and PCOS. While we did not find any reports of such an association, we did learn that Taenia sp. prefer female to male hosts, and pregnant to non-gravid hosts [31–33]. It was later learned that Taenia sp. have steroidogenic enzymes and can synthesize steroid hormones e.g., estradiol [34–39]. As the cysticercosis burden increases, the host, whether female or male, will be further estrogenized, rendering the host milieu more favorable to the parasites. While PCOS is correctly considered a hyperandrogenic condition in most women, it is also important to remember that it is also a state of unopposed estrogen effect in anovulatory or oligo-ovulatory women. The sustained estrogen effect would be conducive to Taenia parasitization and increasing cysticercosis burden. In addition, Taenia sp. can metabolize the relatively weak androgen, androstenedione, to the more potent androgen, testosterone [34].

In searching further, we learned that the selective estrogen receptor modulator (SERM), tamoxifen, had successfully reduced cysticercosis burden in a murine model [40]. Since our patient continued to decline standard treatment for cysticercosis we offered her a trial of treatment with another SERM, raloxifene, which did not carry the risk of estrogenic endometrial stimulation reported with tamoxifen [41]. We thoroughly reviewed the article by Vargas-Villavicencio et al. with our patient and carefully explained that raloxifene was an approved and generally safe drug in the US for the treatment of post-menopausal osteoporosis/osteopenia, but not for neurocysticercosis. We explained that it was similar to, but distinct from and safer than the tamoxifen used in that article. We emphasized the importance of avoiding conception during the trial using abstinence or reliable barrier contraception as this was an FDA Category X drug (should not be used in pregnancy). We obtained her informed consent and initiated treatment with raloxifene at the standard dose for osteoporosis/ osteopenia of 60 mg/day. When she returned to clinic, about 7 weeks after starting raloxifene, she related that she thought she might be pregnant and that, despite being forewarned, she had had unprotected intercourse on a few occasions. Pregnancy was confirmed by physical examination and serum HCG level, and she was counseled on her options. She elected to terminate her pregnancy. Following termination, a repeat brain MRI was performed. It was read by the same neuroradiologist who had read her baseline study. He was blinded regarding her treatment between the 2 studies. On the repeat study the total number of encysted lesions fell from 37 to 33, 10 lesions shrunk, 5 disappeared, 18 were unchanged, 4 enlarged and 1 new lesion appeared. Subsequently, after the patient belatedly agreed to and underwent standard treatment with albendazole and dexamethasone, serum 1,25-(OH)2-vitamin D3 fell from 81 to 41 pg/ml while 25-OH-vitamin D level only fell from 34 to 30 ng/ml. This reduction in calcitriol level occurred even though dexamethasone has been reported to increase the serum concentration of this metabolite [42].

This was the first case to be reported of human neurocysticercosis wherein modification of the hormonal milieu was associated with a reduction of cestode burden. The pregnancy on raloxifene, though unfortunate, supported the concept that neurocysticercosis contributed to the pathogenesis of her PCOS. Serum 1,25-(OH)2-vitamin D3 may ultimately prove to be a useful biomarker for assessing disease activity in neurocysticercosis, as it is in several other granulomatous disorders [43]. This report and the preclinical reports preceding it conceptually opened the field of biome contribution to endocrine disorders.

#### **5. The Biome in the pathogenesis and maintenance of PCOS**

Yurtdaş and Akdevelioğlu recently reviewed the literature on the gut biome and PCOS [44]. While genetic, neuroendocrine, epigenetic and metabolic factors are reported to contribute to the pathogenesis of PCOS, knowledge of the etiologies of the syndrome(s) remains incomplete. Recently, studies in humans and preclinical models have found associations between alterations in the gut microbiome and the metabolic/ clinical features of PCOS.

It is theorized that gut dysbiosis could be a pathogenetic factor in PCOS. Accordingly, changing the gut microbiome using probiotics, prebiotics, and synbiotics as well as diet may serve as a new therapeutic modality for PCOS. Specific changes of the gut microbiome in women with PCOS are apparently associated with distinct PCOS phenotypes. Several recent studies indicate that IR, sex steroid concentrations,

#### *Rare and Underappreciated Causes of Polycystic Ovarian Syndrome DOI: http://dx.doi.org/10.5772/intechopen.101946*

and obesity alter the quantity, diversity and species composition of gut bacteria in women with PCOS (and vice versa).

Liang and colleagues studied gut biome dysbiosis in PCOS in association with obesity [45]. They recruited 8 obese women with PCOS, 9 lean women with PCOS, and 9 lean control women. Gut bacterial composition was assessed by PCR. Obese women with PCOS were found to have lower observed bacterial structural variants (SVs) and alpha diversity (a composite of different measurements that estimate diversity in a single sample) than the control group, higher beta diversity (a measure of the similarity/dissimilarity of 2 communities) than the lean PCOS group (P < 0.05), and lower abundances of genera (particularly butyrate producers). Regression analysis demonstrated that decreased abundances of several bacterial genera correlated with higher serum testosterone and impaired glucose tolerance. PCOS was associated with alterations in the gut microbiome population. Obesity appears to have a critical role in the development of a dysbiotic gut microbiome in women with PCOS.

Lindheim et al. studied associations between changes in the gut microbiome composition and gut barrier function and metabolic and reproductive abnormalities in women with PCOS [46]. Gut microbiome composition was assessed in stool samples from women with PCOS (n = 24) and healthy control women (n = 19) using 16S rRNA gene amplicon sequencing. Processing of data and microbiome analysis were performed in mothur and QIIME utilizing differing relative abundance cut-off points. Integrity of gut barrier function, inflammation, and endotoxemia were assessed using serum and stool indicators. Correlations with anthropometric, metabolic, and reproductive measures were then calculated. The stool microbiome of women with PCOS demonstrated lower bacterial species diversity and an altered phylogenetic mix compared with controls. The authors did not find significant differences in any bacterial taxa with a relative abundance>1%. Among rare bacterial taxa the relative abundance of those from the order ML615J-28 (phylum Tenericutes) and from the family S24-7 (phylum Bacteroidetes) was significantly lower and was associated with unfavorable reproductive parameters in women with PCOS. Women with PCOS showed alterations in some, but not all markers of gut barrier function and endotoxemia.

Women with PCOS had less species diversity and an altered phylogenetic mix in their stool microbiome, which was associated with certain adverse clinical parameters. Gut barrier malfunction and endotoxemia were not pivotal factors in these women, however, they may contribute to the particular phenotype seen in some people with PCOS.

Given the accumulating data that the gut biome population contributes to the etiopathogenesis of PCOS it seems intuitive that "normalizing" the gut biome in the most rapid way possible, fecal transplant from a "healthy" woman to a woman with PCOS, might effect the most rapid amelioration of the syndrome with the least risk. Such an approach has been dramatically successful in treating pseudomembranous colitis [47]. Although there are no human studies to date, a small study assessing fecal transplant to treat PCOS in a rodent model has been reported with encouraging results [48]. This same study also found amelioration of PCOS in the model with isolated Lactobacillus transplantation.

While a relatively short term improvement in the gut biome is usually sufficient to treat antibiotic dysbiosis-related conditions like pseudomembranous colitis, more chronic conditions, like PCOS, metabolic syndrome, Type 2 diabetes, and inflammatory bowel disease seem to require long term lifestyle changes e.g. shifting from a Westernstyle diet high in sucrose, animal fat, and animal protein to a prebiotic/probiotic rich,

lower calorie, phytonutrient-rich, mostly plant-based diet and an increased amount of regular exercise in order to sustain the improved gut biome and remission of the disorder being treated [49, 50]. Plant-based diets of this type are accompanied by reduced inflammation, less gut permeability, reduced generation of reactive oxygen species (ROS), and improved insulin sensitivity.

#### **5.1 Drugs which alter the gut biome**

Certain drugs, chiefly those used to treat obesity, prediabetes, and T2DM are known to alter the gut biome favorably, while others, the best known of which are antibiotics, may cause dysbiosis with unfavorable metabolic consequences [51–53]. Among the drugs with beneficial gut biome effects which explain at least part of their clinical actions are metformin, the alpha-glucosidase inhibitors, the GLP-1 receptor agonists, and the dual GLP-1/GLP-2 receptor agonist, tirzepatide.

#### **5.2 Bariatric surgery and the gut biome**

In addition to diet and drugs, bariatric (metabolic) surgery may affect the gut biome [54]. The taxonomic make-up of the gut bacterial microbiome is significantly affected by metabolic surgery. The most frequent alteration reported in most preclinical and human studies is a relative decline in abundance of Firmicutes with an increase in Bacteroidetes, Proteobacteria, and its class Gammaproteobacteria (order Enterobacteriales, family Enterobacteriaceae, genus Escherichia). Interestingly, the gut microbiome population differs substantially in rodents and humans. Proteobacteria increase after metabolic surgery due to a higher gut lumen pH and higher levels of dissolved oxygen that favor growth of facultative aerobic bacteria and inhibit growth of anaerobic bacteria. Reduction in stomach volume after bariatric surgery increases luminal gastric and distal gut pH, resulting in altered bacterial populations and overgrowth. More alkaline gut pH favors growth of *Akkermansia muciniphila*, *Escherichia coli*, and Bacteroides spp. which are species more typical of the oral microbiome. The greater bacterial diversity postoperatively includes increases in the phyla Verrucomicrobia and Fusobacteria, and a lower proportion of Actinobacteria. It is interesting that the use of metformin is also associated with an increased growth of Akkermansia [55].

#### **5.3 Alterations in the vaginal biome are also associated with PCOS**

While far more research has been reported on the contributions of the gut biome to the pathogenesis and maintenance of PCOS, recently the possible role of the vaginal biome in PCOS has come under scrutiny [10]. Hong and associates obtained vaginal swabs from 39 women with recently diagnosed PCOS and 40 women without PCOS and compared them using 16S rRNA gene sequencing in a case control study. Screening values for possible bacterial biomarkers of PCOS were analyzed by receiver operating characteristic (ROC) curve methodology. There were significant differences in the vaginal biome bacterial populations between the 2 groups. The vaginal bacterial species in the PCOS group were more diversified than those in the control group (Simpson index of the PCOS group vs. the control group: median 0.49 vs. 0.80, P = .008; Shannon index: median 1.07 vs. 0.44, P = .003; Chao1 index: median 85.12 vs. 66.13, P < .001). This is in marked contrast to what has been reported for the gut biome, which is less diverse in women with PCOS, obesity, and T2DM than in healthy

control women. Relative abundance of *Lactobacillus crispatus* in the stool samples of the women with PCOS was significantly lower than in healthy controls (P = .001), and relative abundance of Mycoplasma and Prevotella was higher than in healthy control women (P < .001, P = .002, respectively). Adjustments for BMI and vaginal cleanliness grade did not change these associations. Genus Mycoplasma may be a biomarker for PCOS screening, since ROC analysis showed that the area under the curve (AUC) for relative abundance of Mycoplasma was 0.958 (95% CI, 0.901–0.999).

#### **5.4 The oral cavity biome and PCOS**

The oral cavity biome has also been explored in terms of PCOS [11]. This study was designed to investigate the hypothesis that the concentrations of suspected periodontal pathogens in saliva and the host serum antibody response is elevated in women with PCOS, compared with healthy controls. In total, 125 women in 4 groups were studied: 45 with PCOS+healthy periodontium, 35 with PCOS+gingivitis, 25 systemically and periodontally healthy women, and 20 systemically healthy women with gingivitis.

Salivary concentrations of 7 suspected periodontal pathogens were analyzed by quantitative real-time PCR, while serum antibody titres were measured by ELISA. In women who had PCOS, salivary populations of *Porphyromonas gingivalis*, *Fusobacterium nucleatum*, *Streptococcus oralis* and *Tannerella forsythia* levels were higher than in matched systemically healthy women, especially when gingivitis was also present. PCOS was also associated with increased *P. gingivalis*, *Prevotella intermedia*, and *S. oralis* serum antibody titres if gingivitis was present. The most consistent effect appeared to be the increased population of and antibody response to *P. gingivalis*.

In my search I could not find any reports of associations of the skin, aural, or nasal/sinus biomes with PCOS.

Although newer technologies e.g., 16S rRNA are a giant step forward in our understanding of biome/systemic disorder interactions, it is important to understand that the study of biomes is still in its infancy. Our microbiomes include viruses, fungi, prions, protozoa, and sometimes parasites, and algae. Future research will doubtless uncover important associations between these organisms/pre-organisms and systemic disorders like PCOS.

#### **6. Endocrine disrupting chemicals and PCOS**

Endocrine disrupting chemicals (EDCs), both environmental and drug, appear to contribute to the etiopathogenesis of PCOS. This may occur via binding to sex hormone receptors or by causing IR/hyperinsulinemia; additional mechanisms are also possible.

Environmental EDCs-In our species increased serum bisphenol A (BPA) concentrations have been reported in teenagers and women with PCOS compared with reproductively healthy controls and these are positively correlated with androgen levels, suggesting a role for this chemical in the etiopathogenesis of PCOS, although causality is yet be established [56–60]. It is possible that embryonic/fetal exposure to certain EDCs permanently changes reproductive, neuro-endocrine, and metabolic regulation favoring PCOS development, in genetically predisposed people, or hastening and/or exacerbating the natural course of the disorder via lifelong exposure.

In pre-clinical studies, exposure of mothers to BPA changes postnatal development and sexual maturation in the offspring. Exposure to dibutyl phthalate and

di(2-ethylhexyl)phthalate during pregnancy results in polycystic ovaries and a hormonal profile similar to that seen in human PCOS. Androgenic EDCs, nicotine, and 3,4,4′-trichlorocarbanilide, all contribute to the creation of a concerning hyperandrogenic embryonic/fetal milieu. Prenatal EDC exposure may contribute to abnormal embryonic/fetal developmental programming and partially explain the wide variability in PCOS phenotype.

Research has mostly focused on the possible roles of the most widely distributed and studied environmental agents suspected of contributing to the etiopathogenesis of PCOS. Plasticizers, including BPA and phthalates, which are known EDCs, and advanced glycation end products (AGEs) are ubiquitous in our milieu; therefore, our attention should be focused on reducing such exposure. The timing of EDC exposure is critical for understanding the diversity and severity of adverse health consequences. Embryos/fetuses, infants, and young children are the most vulnerable groups. Prenatal EDC exposure that imitates some actions of endogenous hormones may contribute to abnormal fetal programming and, ultimately, result in PCOS and other adverse health consequences, possibly even trans-generationally. Acute or more protracted EDC exposure and dietary (mostly from Western type diets), as well as endogenously formed AGE exposure in different stages of the life cycle can alter the hormonal milieu and result in disruption of reproductive function. AGEs are proinflammatory molecules capable of interacting with cell membrane receptors and mediate triggering of proinflammatory signaling pathways and oxidative stress. These agents may also contribute to metabolic changes, e.g., obesity, IR, and the compensatory hyperinsulinemia that can create or worsen the PCOS phenotype and contribute to its complications, e.g., Type 2 diabetes and cardiovascular disease. Prediabetes and T2DM both result in hyperglycemia, leading to the formation of even more AGEs in a vicious cycle [61, 62].

Large population surveys find countless chemicals in our serum and tissues that did not even exist in our grandparents' generation [60] Sadly, regulatory agencies are losing the race to evaluate these compounds for safety before they are released into our environment.

#### **7. Drugs which may contribute to the pathogenesis of PCOS**

In addition to the EDCs which accidentally find their way into our bodies, many prescription drugs may also contribute to the etiopathogenesis and maintenance of PCOS [61]. Most of the drugs which contribute to causing PCOS do so by causing IR/ hyperinsulinemia. In so doing they often contribute to causing other disorders associated with IR, including metabolic syndrome, T2DM, hypertension, gout, dyslipidemia, and congenital adrenal hyperplasia [62, 63]. Among these drugs are some of the beta-blockers, thiazides and related diuretics, like indapamide, some of the inhibitors of the renin-angiotensin system, nicotinic acid, the fluoroquinolones (which may also contribute by causing bacterial dysbiosis), protease inhibitors, nucleoside reverse transcriptase inhibitors, antipsychotic drugs, especially atypical antipsychotic drugs, divalproex, and high estrogen oral contraceptives.

#### **8. Role of vitamin D in PCOS**

The role of vitamin D and polymorphisms in its receptor have been the subject of considerable research, given that vitamin D deficiency has been associated with

#### *Rare and Underappreciated Causes of Polycystic Ovarian Syndrome DOI: http://dx.doi.org/10.5772/intechopen.101946*

IR [63–68]. Vitamin D has a physiologic role in female reproduction, which includes ovarian follicle development and luteinization, by regulating anti-Mullerian hormone (AMH) signaling, follicle-stimulating hormone (FSH) sensitivity, and progesterone biosynthesis in granulosa cells. Vitamin D also affects glucose homeostasis via diverse routes. The evidence for an important role for vitamin D on glucose metabolism includes: the presence of vitamin D receptors in pancreatic β-cells and skeletal muscle, the expression of 1-α-hydroxylase enzyme in these tissues which catalyzes the 1-α-hydroxylation of 25-hydroxy vitamin D (25(OH)D) to 1,25-dihydroxyvitamin D, as well as the presence of a vitamin D response element in the human insulin gene promoter region. About 67–85% of women with PCOS have vitamin D deficiency. While there is no significant difference in serum 25(OH) D concentrations between women with PCOS and controls, a high prevalence of vitamin D deficiency is reported to be associated with metabolic syndrome.

Hypovitaminosis D may worsen the signs and symptoms of PCOS, such as IR, ovulatory and menstrual perturbations, infertility, androgen excess, obesity and increased risk of cardiovascular disease. Many observational reports support a role for vitamin D in an inverse association between women's vitamin D status and metabolic disturbances in PCOS, however, it is difficult to reach a conclusion regarding causality because of contradictory findings from various individual studies and from a recent meta-analysis.

Supplementation of vitamin D reduces abnormally elevated serum AMH concentrations and raises serum anti-inflammatory soluble receptor for AGEs in women with both vitamin D-deficiency women and PCOS. Notably, vitamin D and calcium added to metformin in women with PCOS and vitamin D deficiency improves menstrual regularity and ovulatory rate.

Low serum 25(OH)D concentrations are significantly associated with IR in women with PCOS, leading to suggestions that genes regulating vitamin D metabolism could be candidate genes for PCOS susceptibility. Certain polymorphisms in the vitamin D receptor (VDR) gene including: Cdx2, Taq1, Bsm1, Apa1, and Fok1, have been reported to play an important regulatory role on insulin secretion and sensitivity in women with PCOS. The VDR Fok1 polymorphism was found to have a protective effect against the risk of Type 2 diabetes mellitus, while the Bsm1 polymorphism augmented the risk of Type 2 diabetes. The Apa1 polymorphism has been reported to reduce the risk of vitamin D deficiency [65].

A study was carried out in India, to investigate the association pattern of 4 VDR polymorphisms (Cdx2, Fok1, Apa1 and Taq1) with PCOS among Indian women. They reported a significant difference in genotype and allele frequency distributions of the Cdx2 polymorphism between women with PCOS and controls. A significantly higher frequency of the heterozygous GA genotype and the A allele of Cdx2 was encountered in control women when compared to those with PCOS (P < 0.001), suggesting that this single nucleotide polymorphism (SNP) affords some protection against PCOS development. Following adjustment for the covariates of BMI and age, the carriers of the GA genotype and the A allele remained relatively protected against PCOS development. No other significant associations were encountered between the remaining 3 VDR polymorphisms (Fok1, Apa1 and Taq1) and PCOS. They also investigated associations between VDR genotypes and some PCOS clinical/biochemical characteristics and reported that the Cdx2 genotypes were significantly associated with serum testosterone levels while the Fok1 polymorphism showed a significant association with infertility. In addition, the 2 haplotypes made up of 4 polymorphisms, ACCA and ACTA, were also significantly associated with PCOS risk [64].

In a group of Austrian women with PCOS, the VDR Cdx2 polymorphism was found to be associated with higher insulin sensitivity, and the Apa1 polymorphism was associated with lower serum testosterone concentrations. Nevertheless, other investigators did not report any significant differences in the VDR gene polymorphism frequencies between women with PCOS and controls [65].

In a study from Taiwan, it was found that the VDR 1a promoter polymorphisms were not associated with the risk of PCOS but were associated with serum 25(OH)D levels. This study also found that significantly lower serum 25(OH)D levels were seen in women who carried the heterozygous 1521CG/1012GA haplotype of the VDR 1a promoter polymorphisms in both women with PCOS and controls. However, metformin was only able to increase serum 25(OH)D concentrations in women with PCOS who carried the homozygous 1521G/1012A haplotype [65].

Even though several polymorphisms in the VDR gene have been implicated in the etiopathogenesis and presenting phenotype of PCOS, there is considerable heterogeneity in reports from both individual investigators and meta-analyses. Therefore, the role of these VDR gene polymorphisms in the pathogenesis of IR and PCOS remains controversial [65].

Future research with large, independent cohorts and with diverse ethnic populations may clarify whether the associations between vitamin D and PCOS are ethnicity-specific or have differing thresholds depending upon the influence of other individual genotypes in women with PCOS.

A recent reanalysis of data from the D2d trial by the original study authors, using a Cox proportional hazards model, concluded that daily vitamin D intake, sufficient to achieve and maintain a serum 25-(OHD) level ≥ 100 nmol/l, is a promising approach to reduce the risk of T2DM in adults with prediabetes, in contrast with their original conclusion, that vitamin D administration was not effective in the prevention of T2DM in those with prediabetes [67, 68].

#### **9. Autoimmunity contributing to the etiopathogenesis of PCOS**

In addition to the Type B syndrome of severe insulin resistance, acanthosis, SLE with nephritis, & PCOS discussed in the Introduction, several other autoimmune disorders are associated with PCOS [69, 70]. These include vitiligo, alopecia areata, and the autoimmune polyglandular syndrome. Autoimmune thyroid disease, especially autoimmune (Hashimoto's) thyroiditis, is about 3x more common in women with PCOS compared with controls [70]. Among the reasons cited for these associations are the sustained high estrogen/progesterone ratios in women with PCOS, which prenatally derail embryonic/fetal thymic development and disrupt thymic function as regards preservation of immune self-tolerance, vitamin D deficiency/ insufficiency and VDR gene polymorphisms, as well as similarities in the gut biome in people with PCOS and autoimmune disorders, such as increase in those species causing more gut permeability and a reduction of overall bacterial species diversity. These biomic changes are also seen in obesity, metabolic syndrome, and T2DM. In addition, 3 genetic polymorphisms have been reported as predisposing to both PCOS and Hashimoto's thyroiditis. They are polymorphisms of the genes for gonadotropin releasing hormone receptor, fibrillin 3, regulating the activity of transforming growth factor-β and regulatory T cell levels, and CYP1B1 affecting estradiol hydroxylation.

#### **10. PCOS resulting from insulinoma or nesidioblastosis**

Murray and colleagues reported PCOS in association with an insulinoma, which resolved following successful removal of the tumor [71]. My literature search did not find any reports of nesidioblastosis-associated PCOS, however, it is predictable, given their chronic hyperinsulinemia, that such individuals will eventually be found.

#### **11. Insulin resistance is not global in PCOS**

While there is evident insulin resistance in people with PCOS in terms of carbohydrate, lipid, and uric acid metabolism, there is also evidence of normal or even increased insulin action in features such as hyperandrogenism, acanthosis nigricans, acrochordons, organomegaly, and visceral obesity.

There are 2 major signaling pathways through which insulin's actions are expressed: one signaling cascade is used to regulate intermediary metabolism while the other modulates growth and cell division as well as the hypothalamic/ pituitary, gonadal and adrenocortical axes. Regulation of these 2 distinct cascades may be dissociated and data suggest that the activity of the signaling pathway which governs intermediary metabolism is decreased in people with PCOS, T2DM, metabolic syndrome, gout, and congenital adrenal hyperplasia, while the pathways modulating growth processes and mitoses is normal or even enhanced [72]. Most of the intermediary metabolism pathway is activated by insulin binding to its own receptor followed by phosphorylation of IRS-1 and IRS-2. Some of the pathway regulating growth and cell division is initiated by insulin binding to IGF-1 receptors. Even though insulin has greater affinity for its own receptor, when insulin levels are high its receptor is downregulated, limiting available binding sites, so that "excess" insulin will bind to the IGF-1 receptor as an agonist, mimicking the effects of growth hormone. When activation of the IGF-1 cascade is extreme it is sometimes referred to as pseudo acromegaly [73]. Studies show that insulin's signaling pathways normally regulate cell growth, metabolism and survival via activation of mitogen-activated protein kinases (MAPKs) and phosphotidylinositide-3-kinase (PI3K). Activation of PI-3K-associated with insulin receptor substrates-1 and -2 (IRS1, 2) and the subsequent Akt → Foxo1 phosphorylation cascade plays a pivotal role in regulating nutrient homeostasis and organ survival. Several mechanisms have been suggested as causes contributing to the development of IR and metabolic syndrome. These include genetic polymorphisms of proteins in the insulin signaling cascade, suboptimal fetal nutrition, and increased intra-abdominal fat. IR develops as the key player in a cluster of cardiovascular/metabolic dysfunctions we now recognize as metabolic syndrome, which may result in T2DM, a distinctive (Type IV, Fredrickson) dyslipidemia with high VLDL, low HDL, and normal-moderately elevated LDL, accelerated atherosclerosis, hypertension, or congenital adrenal hyperplasia depending on the genetic/epigenetic background of the person with IR including the genetic/epigenetic characteristics of our relevant biomes, vitamin D status, and the influence of drugs and environmental chemicals with endocrine disruptor effects. Inactivation of Akt and activation of Foxo1, via suppression of IRS1 and IRS2 in different tissues following hyperinsulinemia, metabolic inflammation, and overnutrition could be the mechanisms leading to metabolic syndrome in our species [74].

IR in women with PCOS seems to be associated with exaggerated serine residue phosphorylation of insulin receptor substrates. An enzyme extrinsic to the insulin receptors, quite possibly a serine/threonine kinase, causes this aberration and exemplifies a key mechanism for induction of human IR related to extrinsic factors regulating insulin receptor signaling. Serine phosphorylation seems to regulate the activity of P450c16, the pivotal regulatory enzyme in androgen biosynthesis. It is very possible that a single defect results in both IR and hyperandrogenism in some women with PCOS. This IR is selective, affecting glucose/lipid metabolism, but not cell division or growth [75].

#### **12. Sleep disorders and PCOS**

It has been reported that women with PCOS have significantly higher risk of obstructive sleep apnea (OSA). OSA severity is significantly correlated with plasma glucose and insulin levels and homeostasis model assessment for insulin resistance (HOMA-IR)-index in women with PCOS. It appears that the progressive worsening of PCOS results in OSA which, in turn, exacerbates the metabolic disturbances, such as IR, associated with this syndrome [76].

Clinic-based studies report that sleep disturbance and disorders such as OSA and excessive daytime sleepiness are more frequently encountered among women with PCOS. Data from the few published population-based studies is substantially concordant. Women with PCOS are mostly overweight/obese, however, this fact only partially explains their sleep problems as significant associations persist after adjusting for body mass index; sleep issues also occur in lean women with PCOS. There are several, likely bidirectional, pathways through which PCOS and sleep disturbances are associated. PCOS pathophysiology includes hyperandrogenemia, a unique form of IR, and possible changes in cortisol and melatonin secretion, plausibly reflecting hypothalamic-pituitary-adrenal dysfunction. Psychological/behavioral factors probably also play a role, such as anxiety and depression, tobacco use, alcohol use, and insufficient exercise which are also frequent among women with PCOS, likely in response to their symptoms. The effects of sleep disturbances on the health of women with PCOS is not completely understood, however, both PCOS and disordered sleep are associated with worsening long term cardiometabolic health and augmented T2DM risk. Immediate quality of life and long-term health status of women with PCOS will likely improve from timely diagnosis and comprehensive management of sleep disorders [77].

#### **13. Light pollution as a contributing cause of PCOS**

Several investigators have reported that exposure of rats to continuous light can induce PCOS; however, hyperandrogenism, a key feature of human PCOS, has not been reported previously. In Kang et al.'s article they reported that (a) body weight declined in female rats in continuous light conditions with both ovarian and uterine augmentation; (b) the estrous cycle in rats living in continuous light was disordered, and PCOS-like changes were noted accompanied by hair loss and lethargy; and (c) serum testosterone levels rose significantly in rats living in continuous light. Their results suggest that continuous light can lead to PCOS in female rats without the need for drugs. Poor sleep habits, faulty sleep hygiene, and light pollution may be important contributors to the pathogenesis of PCOS [78].

Dominoni and colleagues as well as others have described reproductive hardships in free-living wildlife associated with light pollution [79].

#### **14. Noise pollution and reproduction**

In addition, human-generated noise pollution has been implicated in reduced reproductive success in wildlife, although the mechanisms involved are not clear [80].

#### **15. Undiagnosed non-classic adrenal hyperplasia (NCAH)**

Based on my years in clinical practice and academia, I hope readers will indulge me in a personal gripe. When applying the Rotterdam criteria for the diagnosis of PCOS many clinicians ignore or only pay lip service to the exclusions which must be considered an essential part of these criteria. These include thyroid disease, Cushing's syndrome, androgen-secreting neoplasia, hyperprolactinemia, and nonclassical congenital adrenal hyperplasia. In my referral practice I found, in reviewing the referral or the written or electronic medical records of patients referred to me for PCOS treatment, that these conditions, especially NCAH had very seldom been excluded by the referring colleague. In the PCOS research literature many investigators do not mention exclusion of these disorders in their PCOS cohorts. In many other articles a single morning unstimulated serum 17-OH-progesterone is proffered as excluding NCAH. The best articles offer a cosyntropin-stimulated 17-OH-progesterone to exclude this diagnosis. In my readings I have not yet encountered a study where NCAH was thoroughly excluded with genetic testing for 21-hydroxylase deficiency as well as cosyntropin stimulation of 17-OH-progesterone, 17-OH-pregnenolone, 11-deoxycortisol, deoxycorticosterone, corticosterone, and 18-OH-corticosterone. Thus, without fully testing for NCAH, most of us have the impression that PCOS is very common and NCAH, except in high-risk ethnic groups is very rare. This is concerning because NCAH and PCOS are often phenotypically identical. However, since therapies aimed at decreasing IR, normalizing the menstrual cycle, reducing androgen secretion or expression, and inducing ovulation are often able to ameliorate both conditions the real-world consequences of misdiagnosis of PCOS may not be as grave as we might expect [63]. Carbunaru and colleagues have reported that the common, non-classic or phenotypic form of 3-beta-ol dehydrogenase deficiency (3-beta-HSD) controlling the adrenal/ovarian synthesis of this enzyme is not associated with an exonic polymorphism, but is associated with IR, hyperandrogenism, and a PCOS phenotype, which in severe forms is called Hyperandrogenism, Insulin Resistance-Acanthosis Nigricans (HAIR-AN) syndrome [81]. It is possible, that a polymorphism may exist in the promoter region of the gene, as has been reported in a group of Brazilian women with non-classic 21-hydroxylase deficiency [82]. Alternatively, several epigenetic modifications could be downregulating the expression of the gene.

#### **16. Lipodystrophies as a cause of PCOS**

Lipodystrophies are associated with PCOS due to insulin resistance, which is intrinsic to the lipodystrophies [83, 84].

#### **17. Conclusions**

In this chapter I have tried to highlight truly rare contributing causes of PCOS, like insulinomas, as well as showcasing causes that are not particularly rare, but are very rarely considered in clinical practice. The latter include: biomic alterations, epigenetic disturbances such as disordered DNA methylation and/or histone acetylation, and EDCs, including many drugs which contribute to IR. In addition, I have described some very rarely reported causes, like cysticercosis, which, given its extensive global endemicity, will likely turn out to be much more common causes of PCOS than is currently recognized. In exploring this topic, I hope that I have shed some light on common pathways by which these diverse agents might contribute to the etiopathogenesis and maintenance of PCOS, mostly by causing IR/hyperinsulinemia, hyperandrogenism, chronic inflammation, or unopposed estrogenic effects. It is hoped that clinicians will consider these causes more often when evaluating their patients and considering treatments. In so doing, it is likely that better treatment results can be achieved. It is already possible for individual clinicians and their patients to achieve much with interventions such as lower calorie, plant-based diets, supplementation with pre- and probiotics, exercise, ensuring adequate vitamin D status, and choosing drugs with favorable effects on the biome. In addition, patients once educated, may be able to improve their therapeutic outcomes by minimizing their exposure to EDCs in plastics, self-care products, and household products. Major improvements in outcomes may result from efforts at the community, regional, national, and international levels to improve diets, increase exercise, and reduce our exposure to EDCs, light and noise pollution. Attention to sleep hygiene by patients and providers may further reduce the burden of PCOS, metabolic syndrome, resistant hypertension, and T2DM. Fecal transplantation may jump start amelioration of PCOS, provided it is followed with sustained lifestyle changes including plant-based diets, exercise, and possibly pre- and probiotic supplementation. Looking toward the future, the experience we have gained in developing mRNA vaccines against COVID-19 might be applied to develop mRNA "vaccines" against gene products whose overabundance is contributing to PCOS. A fragment of the mRNA could be used to synthesize a fragment of the peptide different enough from the native protein to provoke an adaptive immune response.

Our understanding of the biome and of epigenetics is still in its infancy. As more is learned the opportunities for precision prevention and treatment will increase.

#### **Conflict of interest**

The author declares no conflict of interest.

*Rare and Underappreciated Causes of Polycystic Ovarian Syndrome DOI: http://dx.doi.org/10.5772/intechopen.101946*

#### **Author details**

Alan Sacerdote1,2,3,4

1 SUNY Downstate Medical Center, Brooklyn, NY, USA

2 NYU Grossman School of Medicine, New York, NY, USA

3 NYC Health + Hospitals/Woodhull, Brooklyn, NY, USA

4 St. George's University School of Medicine, Grenada, West Indies

\*Address all correspondence to: walrusa@netscape.net

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[79] Dominoni DM, Borniger JC, Nelson RJ. Light at night, clocks and health: From humans to wild organisms. Biology Letters. 2016;**12**(2):20160015. DOI: 10.1098/rsbl.2016.0015

[80] Bernat-Ponce E, Gil-Delgado JA, López-Iborra GM. Recreational noise pollution of traditional festivals reduces the juvenile productivity of an avian urban bioindicator. Environmental Pollution. 2021;**286**:117247. DOI: 10.1016/j.envpol.2021.117247. Epub 2021 May 3

[81] Carbunaru G, Prasad P, Scoccia B, Shea P, Hopwood N, Ziai F, et al. The hormonal phenotype of nonclassic 3 beta-hydroxysteroid dehydrogenase (HSD3B) deficiency in hyperandrogenic females is associated with insulinresistant polycystic ovary syndrome and is not a variant of inherited HSD3B2 deficiency. The Journal of Clinical Endocrinology and Metabolism. 2004;**89**(2):783-794. DOI: 10.1210/ jc.2003-030934

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[83] Gambineri A, Zanotti L. Polycystic ovary syndrome in familial partial lipodystrophy type 2 (FPLD2): Basic and clinical aspects. Nucleus. 2018;**9**(1):392- 397. DOI: 10.1080/19491034.2018.1509659

[84] Lungu AO, Zadeh ES, Goodling A, Cochran E, Gorden P. Insulin resistance is a sufficient basis for hyperandrogenism in lipodystrophic women with polycystic ovarian syndrome. The Journal of Clinical Endocrinology and Metabolism. 2012;**97**(2):563-567. DOI: 10.1210/ jc.2011-1896. Epub 2011 Nov 16

#### **Chapter 5**

## Special Considerations on Hyperandrogenism and Insulin Resistance in Nonobese Polycystic Ovaries Syndrome

*Tatyana Tatarchuk, Tetiana Tutchenko and Olga Burka*

#### **Abstract**

PCOS is a widespread phenotypically inhomogeneous endocrinopathy with significant health consequences and incompletely elucidated pathogenesis. Though visceral adiposity and insulin resistance (IR) is a well-proved pathogenic set of factors of PCOS, not all women with obesity and IR have PCOS and not all PCOS women are obese and have IR, which is explained by certain genetic backgrounds. The reported prevalence of nonobese PCOS (NonObPCOS) is about 20–30%, but it may be higher because especially in lean women with nonclassical phenotypes PCOS diagnosis is often delayed or unrecognized. Unlike obese PCOS, NonObPCOS management is less clear and is limited to symptomatic treatment. This chapter presents in structured fashion the existing results on the prevalence of NonObPCOS, as well as on special aspects of body composition, IR, and hyperandrogenism pathogenesis, including adrenal contribution in NonObPCOS.

**Keywords:** hyperandrogenism, adrenal androgen precursors, insulin resistance, adipokines, hepatokines, steatohepatosis, visceral adiposity, body composition

#### **1. Introduction**

Today with the use of Rotterdam diagnostic criteria (at least two of three are present—oligo-anovulation, clinical/biochemical hyperandrogenism (HA), polycystic ovarian morphology (POM) on ultrasound when other causes of these conditions are excluded) polycystic ovary syndrome (PCOS) is the most widespread endocrine disorder in women affecting their reproductive and cardio-metabolic health lifelong [1–5]. PCOS prevalence among reproductive-aged women is from 8 to13% depending on the population ethnicity and diagnostic criteria used [3]. A meta-analysis published in 2017 showed such proportions of PCOS prevalence (95% CI) according to the diagnostic criteria of the National Institute of Health (NIH), Rotterdam criteria, and Androgen Access PCOS Society (AE-PCOS)—6%, 10%, and 10%, respectively. When only unselected population studies were included, the given rates were 6%, 9%, and 10% [6]. Same year meta-analysis of PCOS prevalence in different ethnic groups showed the lowest prevalence in Chinese women (Rotterdam criteria: 5.6%), Caucasians

(NIH: 5.5%), Middle Eastern (NIH 6.1%; Rotterdam 16.0%; AE-PCOS 12.6%), and Black women (NIH: 6.1%) [7]. Despite intensive investigations PCOS etiology remains unclear, relations between its known pathogenic mechanisms are contradictory and consequently the effectiveness of overall management is suboptimal leading to patient dissatisfaction [8]. The reason for this is the high heterogenicity of PCOS in terms of complex genetic background, involvement of developmental origins, and consequently various combinations of pathogenetic mechanisms and clinical features [9, 10].

Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome 2018 confirmed the idea of the 2012 international working group on the need of defining PCOS phenotypic forms based on combinations of diagnostic criteria in research and clinical practice. Thus, there are four phenotypic forms of PCOS—classic (A) involving all three diagnostic criteria, incomplete classic (B), ovulatory (HA and POM only) (C), and normoandrogenic (anovulation and POM only) (D). Back in 2012, much hope was relied on studying PCOS pathogenesis in different phenotypes, but to date, this approach resulted in no definitive answers on details of pathogenesis in different phenotypic forms. It was shown by numerous studies that classic phenotypes are more often associated with obesity, significant visceral adiposity, metabolic syndrome (MS), lifetime risks of type 2 diabetes mellitus (TDM), and cardiovascular disease (CVD) [11–13]. At the same time, ovulatory and normoandrogenic phenotypes seem to be more metabolically safe primarily because of a lower incidence of obesity [12–14]. Though this observation is not universal. Moreover, recent studies showed that while obesity in PCOS universally leads to metabolic complications, hyperandrogenic non-obese women with PCOS (nonObPCOS) also have serious metabolic disturbances, such as nonalchocholic fatty liver disease (NAFLD), dyslipidemia, hyperinsulinemia, and age-related complications like TDM and CVD, in spite of the absence of obvious risk factors [15].

Apart from androgen excess and hypothalamic-pituitary-gonadal axis disfunction, there are two other gross pathogenetic factors of PCOS not included in diagnostic criteria—insulin resistance (IR) with compensatory hyperinsulinemia and ectopic fat distribution with adiposopathy [16, 17]. All these factors are very much interconnected and the question of which of them is primary is still unclear. This can be explained by the fact that the primary factors of encircled pathogenic mechanisms are different in different subgroups of PCOS patients and probably change with time.

The role of overall and especially visceral adiposity is well established in overweight and obese PCOS women [18–21]. Weight reduction is an effective therapeutic approach both for fertility and menstrual function improvement and metabolic risks reduction in overweight/obese women with PCOS [22–25]. But this is not the case with NonObPCOS women. In the scientific aspect, the absence of the main driver of glucose and fat metabolism disruption (obesity) makes NonObPCOS a different pathogenetic subtype of the syndrome.

Reviews summarizing data on NonObPCOS were published in 2017 [26, 27]. In this chapter, we analyze older and recent data on epidemiology, body composition, pathogenesis of insulin resistance, and hyperandrogenism in NonObPCOS.

#### **2. Definition, epidemiology of nonobese PCOS and clinical issues of this population**

NonObPCOS gained more researchers' attention after the introduction of Rotterdam criteria. This term emerged spontaneously and there is still no clear-cut

#### *Special Considerations on Hyperandrogenism and Insulin Resistance in Nonobese Polycystic… DOI: http://dx.doi.org/10.5772/intechopen.103808*

definition of professional societies, guidelines, or consensus statements. Most authors use the criteria of BMI under 25 kg/m<sup>2</sup> and address it as "normal weight PCOS" or "lean PCOS" or "nonobese PCOS" (NonObPCOS) [28]. In some sources, NonObPCOS is addressed as women with PCOS having BMI under 30 kg/m2 [29]. In this case, it includes both the category of overweight women (BMI 25–29) and normal weight (BMI 18–24). There is data on rare cases of underweight PCOS (BMI < 18), which has to be carefully differentiated with hypothalamic amenorrhea [30, 31]. In this chapter, NonObPCOS will be addressed as any PCOS phenotypic form with BMI < 25 kg/m2 . Lack of a clear-cut definition of NonObPCOS using BMI criteria leads to inconsistent results on its prevalence in different populations. We did not observe studies focused specifically on the prevalence of NonObPCOS. Most available data on the prevalence of nonObPCOS comes from studies on the prevalence of PCOS in different populations or studies targeting metabolic derangements of PCOS and having BMI stratification in their design (**Table 1**). As follows from **Table 1**, the portion of NonObPCOS even with the use of NIH criteria in older studies varies from 20 to 76% [39, 44]. With the use of Rotterdam criteria, the percentage of NonObPCOS varies from 41 to 75% [29, 32–36, 38, 40–43]. Heterogeneity in studies' methodology, participants age, and other factors certainly influence the accuracy of these figures, but still depicts the fact that NonObPCOS is not a minority in this syndrome. Of note is that a greater proportion of NonObPCOS cases is observed in nonselective studies compared to clinical ones when (cohorts of women seeking medical help for hirsutism, menstrual irregularity, etc.).

Data from a meta-analysis by Lizneva et al. [45] supports the notion of the underestimated prevalence of NonObPCOS, probably more often associated with nonclassic phenotypes. The aim of this paper was to evaluate the prevalence of PCOS phenotypes and obesity among patients detected in referral versus unselected populations. The prevalence of more complete phenotypes in PCOS and mean BMI was higher in subjects identified in referral versus unselected populations, suggesting the presence of significant referral bias. The authors analyzed 41 eligible studies. Pooled estimates of detected PCOS phenotype prevalence were consequently documented in referral versus unselected populations, as phenotype A, 50% (95% confidence interval [CI], 46–54) versus 19% (95% CI, 13–27); phenotype B, 13% (95% CI, 11–17) versus 25% (95% CI, 15–37); phenotype C, 14% (95% CI, 12–16) versus 34% (95% CI, 25–46); and phenotype D, 17% (95% CI, 13–22) versus 19% (95% CI, 14–25). Differences between referral and unselected populations were statistically significant for phenotypes A, B, and C. Referral PCOS subjects had a greater mean BMI than local controls, a difference that was not apparent in unselected PCOS [45].

In the setting of the Endocrine gynecology department, Kyiv, Ukraine preliminary patients' database analysis from 2012 to 2021 shows the prevalence of 64% NonObPCOS among all referral PCOS patients (including primary visits of symptomatic patients and referrals from primary care gynecologists because of difficulties in making the diagnosis). We suggest that such prevalence of NonObPCOS in our fourth level institution is caused by uncertainties primary care doctors face in diagnosing PCOS in lean patients especially with mild HA or nonclassical phenotypes as well doubts of patients in the correctness of the diagnosis. With these patients, we often observe interesting phenomena of "not being prone to gaining extra weight" and "having no need to control their calorie intake", which might be a presentation of a "specific type of metabolism worth deeper investigation in terms of metabolic consequences." Thus, available data on NonObPCOS prevalence shows, that this condition is not rare, but likely to be underdiagnosed or diagnosed with delay.


*\* Figure obtained by subtraction of the percentage of BMI > 25.*

*\*\*Non-obese (<30 kg/m2 ) NIH -75.0%; Rotterdam 84.6% AE-PCOS 85.0%. Obese (*≥*30 kg/m2 ) NIH -25.0%; Rotterdam 15.4% AE-PCOS 15.0%.*

*\*\*\*Criterion of* ≥*27 kg/m2 was used for obesity and < 23 kg/m2 for normal weight.*

**Table 1.**

*Prevalence of NonObPCOS.*

#### *Special Considerations on Hyperandrogenism and Insulin Resistance in Nonobese Polycystic… DOI: http://dx.doi.org/10.5772/intechopen.103808*

Today it is obvious that BMI is not an accurate marker of metabolic health since not only adipose tissue excess but more its distribution plays role in metabolic complications, giving the basis for A. De Lorenzo classification—normal weight obese; metabolically obese normal weight; metabolically healthy obese; and metabolically unhealthy obese or "at risk" obese [46, 47]. Thus, while the presence of elevated BMI has a significant positive predictive value for metabolic risks normal BMI does not guarantee their absence since they can be caused by the predominance of ectopic fat distribution and adiposopathy. This fact is considered by most studies of PCOS metabolic aspects discussed below. Studies considering body composition and fat distribution are also inhomogeneous in methodology as will be shown below. In addition, the more accurate methods of body composition evaluation are used the smaller the groups are.

#### **3. Body composition in NonObPCOS, specifics of adipose, and muscle tissue function**

In the case of NonObPCOS, we think it is reasonable to analyze body composition data in the first place, as it may have the key to a paradox—of keeping normal BMI despite the presence of predisposing factors, such as HA and IR, and at the same time developing metabolic consequences. Recent studies on bidirectional Mendelian randomization analyses state that increased BMI is causal for PCOS while PCOS is not predictive of obesity [48, 49]. This finding puts even more questions on obese and nonobese PCOS pathogenesis. One of the interpretations can be that high BMI in PCOS is a factor exacerbating epigenetically determined features of the syndrome, such as HA, OD, and IR. This notion is supported by studies demonstrating the presence of IR in most PCOS women irrespective of BMI, though it is positively correlated with BMI. The similar association can be observed for HA—more mild forms of HA are observed in NonObPCOS compared to PCOS with obesity [11, 16, 34]. Taken together these facts shifted research focus from fat mass to the role of the functional state of muscles and different adipose tissue compartments in PCOS pathogenesis. Today adipose tissue (AT) is a recognized player of endocrine, paracrine, and even neurocrine cross-talks, being a target tissue of pancreatic and steroid hormones, source of numerous adipokines, and a place of sex steroids conversion [50]. Visceral AT (VAT) demonstrates more endocrine/paracrine actions [17, 51]. Skeletal muscles are also among the key target organs of pancreatic hormones and sex steroids as well as an important player in metabolism [13]. Thus, studies on body composition's role in and tissue-specific effects of insulin action, androgen synthesis, and lipid turnover seem to be most perspective, especially in the case of NonObPCOS.

Most studies on the body composition of PCOS women were done using anthropometric characteristics that lack accuracy compared to imaging methods (MRI, CT). This led to the formation of the dogma of visceral adiposity in PCOS, which is being debunked by 2019 meta-analysis that using golden standards MRI or CT found no significant difference in accumulations of visceral fat, abdominal subcutaneous fat, total body fat, trunk fat, and android fat in PCOS compared to BMI matched controls. At the same time, meta-regression and subgroup analyses showed that young and non-obese patients were more likely to accumulate android fat [52]. The authors of the paper note the problem of small sample size in studies using gold standard methods for body composition assessment.

Studies on body composition in NonObPCOS in relation to endocrine dysfunctions are limited. In a cross-sectional study of Indian nonobese and obese PCOS women assessed by DXA-scan, higher total body fat, truncal fat, and estimated VAT compared to their age- and BMI-matched controls were reported. Corrected estimated VAT difference was not significant between obese and nonobese PCOS women suggesting that nonobese PCOS women had a similar amount of VAT as that of obese PCOS women when adjusted for their body weight. Also, this study reports that NonObPCOS (overweight and normal weight) were less insulin resistant when compared to the obese PCOS group and postulate that there may be factors other than IR that make the nonobese PCOS women have more VAT, such as postprandial dysglycemia caused by intracrine intestinal factors [53].

Earlier studies of SAT topography in PCOS women using optical devices demonstrated significantly lower total SAT development with a slightly lowered amount of body fat in the upper region and a highly significant leg SAT reduction [54, 55].

In a prospective cohort study of six normal-weight PCOS women and 14 age- and BMI-matched normoandrogenic ovulatory controls, an association of HA with preferential intra-abdominal fat deposition and an increased population of small subcutaneous (SC) abdominal adipocytes was shown. Authors hypothesize that such distribution could constrain SC adipose storage and promote metabolic dysfunction [56]. *In vitro* studies showed that cultured subcutaneous abdominal adipocytes from women with PCOS have diminished insulin-induced glucose transport, reduced insulin receptors content, and decreased insulin-stimulated serine phosphorylation of glycogen synthase kinase (GSK)-3*β* [57, 58]*.* Further investigations of SAT-specific features in NonObPCOS by the Dumesic group discovered more details of these compartments' role in PCOS-related dysmetabolism. A prospective cohort study including ten normal-weight women with PCOS and 18 control subjects matched for age and BMI demonstrated that NonObPCOS women have increased adipose-IR and altered adipose stem cell gene expression related to HA and IR [59]. The fact that the number of small adipocytes is stable from early childhood suggests the possibility that SC abdominal adipose expandability through the generation of new small adipocytes is programmed in early life and subsequently becomes insufficient to meet the metabolic demands of most normal-weight women with PCOS. We did not find studies on birthweight, prematurity, and puberty details focusing specifically on NonObPCOS but they might be of great interest. Results of prospective cohort study show accelerated SAT abdominal adipose stem cell differentiation into adipocytes *in vitro* favors sensitivity to insulin *in vivo*, suggesting a role for HA in the evolution of metabolic thrift to enhance fat storage through increased cellular glucose uptake [60].

The role of local androgen conversion in the regulation of abdominal SAT morphology and function is not yet clear in NonObPCOS. Overexpression of aldo-keto reductase 1C3 (AKR1C3)-mediated testosterone (T) generation from androstenedione (A4) promotes local triglyceride (TG) storage in SAT, potentially protecting against lipotoxicity and IR. One study showed that elevated serum T to A4 ratio was a biomarker of subcutaneous abdominal AKR1C3 activity that improved metabolic function in NonObPCOS [61].

Summarizing the existing limited data on AT distribution and function in NonObPCOS, it can be concluded that these women have a predominance of dysfunctional VAT and specific features of SAT limiting its lipid storage capacity. This puts NonObPCOS in the category of normal weight obese or metabolically obese. Metabolic significance of VAT is explained by the following facts—its location in the mesentery and omentum causes drainage directly through the portal circulation to

#### *Special Considerations on Hyperandrogenism and Insulin Resistance in Nonobese Polycystic… DOI: http://dx.doi.org/10.5772/intechopen.103808*

the liver; the dominance of large or hypertrophic adipocytes and infiltration with immune cells; intensive vascularization and innervation; high density of androgen and glucocorticoid receptors; higher sensitivity to lipolysis and adrenergic stimulation and lower sensitivity to insulin; greater capacity to generate free fatty acids and to uptake glucose, circulating free fatty acids (FFA), and TG [62]. The impaired ability of SAT to store abundant lipids as well as SAT excess leads to accumulation of lipids in atypical sites (liver, skeletal muscles, and even pancreas), known as lipotoxicity phenomena. Lipotoxicity has detrimental effects on a molecular level—endoplasmatic reticulum and mitochondria damage with reactive lipid peroxides (endoplasmatic reticulum stress). The latter can eventually lead to cell apoptosis. At the same time, high levels of circulating FFA leads to a vicious circle of deepening glucose dysmetabolism by limiting blood glucose uptake in AT and muscles [63, 64]. Another effect of AT dysfunctional state in PCOS is altered synthesis of adipokines. Upregulated levels of mRNA levels of the proinflammatory cytokine tumor necrosis factor (TNF) in PCOS reflecting a state of chronic low-grade inflammation in SAT that could lead to low adiponectin were reported [65]. Later independent of BMI and IR decrease in high molecular weight adiponectin in PCOS was demonstrated [66].

The etiology of the described specifics of body composition and AT dysfunction most likely takes roots in genetics and epigenetics. In 2016, Kokosar et al. reported a number of genes and pathways that are affected in adipose tissue from women with PCOS as well as some specific DNA methylation pathways that may affect mRNA expression [67].

Though skeletal muscles also belong to insulin-sensitive organs and normally can utilize up to 70–80% of blood glucose, there are far less studies on specific features of their function in PCOS. There are a lot of debatable aspects to this topic. While osteosarcopenia was reported in obese PCOS no such studies are available for NonObPCOS [68]. On one hand, studies from sports medicine report a positive effect of higher physiological androgen levels on muscle performance as well as superior performance of mildly hyperandrogenic women in sports [69]. On the other hand, peripheral IR documented by euglycemic hyperinsulinemic clamp test in the majority of obese and NonObPCOS suggests the presence of some insulin signaling defect similar to that of TDM [70, 71]. Recent studies by N. Stepto and Hansen suggest that this defect is located in the distal part of the insulin signaling pathway but there may also be additional mechanisms [71, 72]. Hansen suggests that reduced expression and activation of AMP-activated protein kinase (key regulator of glucose uptake in muscle) is due to low levels of adiponectin [72]. Infiltration of muscle tissue with lipids both in lean and obese PCOS either due to lipodystrophy or due to fat excess may be one of the accidental causes of IR [73]. Transforming growth factor-beta (TGFβ) signaling contributes to the remodeling of reproductive and hepatic tissues in women with PCOS. It is possible that these adverse effects including profibrotic changes of extracellular matrix influence insulin signaling in skeletal muscles [74, 75]**.** The most recent study by Stepto et al. tested the hypothesis that TGFβ superfamily ligands signaling pathways and tissue fibrosis are involved in PCOS-specific insulin resistance. These signaling defects are probably involved in PCOS ovulatory dysfunction too [76]. The results of this study showed reduced signaling in PCOS of the mechanistic target of rapamycin (mTOR). Notably, exercise augmented but did not completely rescue this signaling defect. Molecular tests showed that genes in the TGFβ signaling network were upregulated in skeletal muscle in the overweight women with PCOS but were unresponsive to exercise except for genes encoding lipid oxidation, collagen 1 and 3 [77]. Authors admit a limited number of patients and inability to

rule out the influence of other factors, such as HA, cardiometabolic fitness, and body composition. In *in vitro* study of TGFβ effects on myotubules suggest its indirect role in peripheral IR in PCOS [78]. Another study with *in vivo* and *in vitro* arms state that altered mitochondrial-associated gene expression in skeletal muscle in PCOS is not preserved in cultured myotubes, indicating that the *in vivo* extracellular milieu, rather than genetic factors, may drive this alteration [79]. Thus, molecular dysfunctions underlying peripheral resistance in women with PCOS in combination with the hormonal milieu need further investigation as they are likely to be the main cause of intrinsic IR and a perspective therapy target.

#### **4. Specifics of androgen excess in NonObPCOS**

HA is one of PCOS diagnostic criteria both by NIH, Rotterdam, and AE-PCOS criteria. Clinical HA implies mainly the presence of hirsutism. Biochemical HA is a stable elevation of circulating androgens over gender, age, and population-specific reference range. Free testosterone was traditionally considered the best maker of active androgen excess, but as its assessment with available indirect methods is not enough, an accurate estimated value of free androgen index (FAI) is recommended for clinical routine [1, 80]. In 2018, active androgens' precursors (dehydroepiandrosterone sulfate (DHEA-s) and A4) were recognized as useful markers of mild HA present in about 30% of PCOS and recommended for lab assessment in some cases [1]. Recent studies have demonstrated that 11-oxygenated androgens can be regarded as a marker of HA in PCOS [81]. Multiple bidirectional effects of HA with IR, OD, and adiposopathy in PCOS as well as their biological effects were consistently described in many reviews [16, 50, 82].

In this chapter, we address the proportional contribution and specific effects of androgens from different sources in NonObPCOS. HA in PCOS has complex nature involving ovarian, adrenal sources, peripheral tissue androgen synthesis, and conversion; elevated free T due to low sex-steroid binding globulin (SHBG). All these components are highly interconnected with IR, ovarian hormones, adipose tissue distribution, and function [3, 82]. The role of peripheral androgen convention is the least investigated aspect of HA in PCOS. But this specific aspect is important in terms of the disproportionate severity of clinical and biochemical HA often observed both in NonObPCOS and obese PCOS. In NonObPCOS, HA symptoms and biochemical HA are sometimes disproportionate to IR and OD that demands differentiation with secondary polycystic changes of ovarian morphology or investigating other than ovarian dominating androgen excess sources. Moreover, HA may have different metabolic sequelae depending on its origination. Contemporary methods of steroid metabolome assessment may open a new page in understanding the wholesome picture of androgen excess in PCOS.

The dominance of adrenal androgen excess was reported in older studies [83, 84]. In 2015, Moran et al. paper A4 and DHEA-s levels were significantly higher in nonobese than in obese PCOS patients. A significant correlation between luteinizing hormone (LH) and A4 in nonobese PCOS patients was observed. The frequency of hyperandrogenism by increased A4, and DHEA along with DHEAs was significantly higher in NonObPCOS compared with high-BMI PCOS patients [85]. In a 2015 review paper by M. Goodarzi, E. Carmina and R. Azziz analyzing the issue of adrenal androgen precursors' elevation etiology and role in PCOS conclude that inherited defects of steroidogenesis may be one of the causes and have to be further investigated; also there

*Special Considerations on Hyperandrogenism and Insulin Resistance in Nonobese Polycystic… DOI: http://dx.doi.org/10.5772/intechopen.103808*

is the intrinsic exaggerated activity of hypothalamic-pituitary-adrenal axis, while extraadrenal factors, such as IR, play a limited role in the adrenal androgen precursors excess of PCOS [86].

A new study addressed specifically the issue of androgen excess sources in obese and NonObPCOS using liquid chromatography-tandem mass spectrometry and genetic tests. Its results showed increased DHEA-s, 17-hydroxyprogesterone(17- OHP), 17-hydroxypregnenolone, and estrone (E1) levels in NonObPCOS compared with both the lean controls and the obese PCOS patients, while lower FAI was found in the lean PCOS patients compared with the obese PCOS patients. The correlation analysis showed that FAI was positively correlated with BMI and HOMA-IR, which is in line with previous studies [34, 53, 87]. Enzyme activity evaluation showed that NonObPCOS had increased activity of cytochromes P450c17, P450aro, 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2) and decreased activity of P450c21. Higher frequencies of CYP21A2- (encoding P450c21) c.552 C > G (p. D184E) in NonObPCOS were found compared with obese patients. The limitation of this study was that the gene sequencing was performed only for those with HA [88].

Active androgens and androgen precursors seem to have different effects on metabolism [89]. This is clearly demonstrated in a new cross-sectional study of 823 women with PCOS 76.2% with biochemical HA and 23.8% with normal androgen levels. Anthropometric indexes were used to assess metabolic risk characteristics. In normoandrogenemic PCOS, FAI predicted significant abnormality in the visceral adipose index (VAI) and dehydroepiandrosterone (DHEA) predicted against alteration in β-cell function. In HA PCOS, FAI predicted derangements in waist TG index and lipid accumulation products. DHEA weakly predicted against VAI, DHEA-s tended to predict against the abdominal obesity index [90].

Thus, existing studies show that NonObPCOS women have different profiles of androgen excess sources. Evaluation of the prevailing source of androgen excess might be a valuable component of metabolic risk estimation since some types of androgens seem to have a protective role. Also, more studies on steroidogenic enzymes function and alternative steroidogenic adrenal and peripheral tissue pathways are needed to have the whole picture of NonObPCOS pathogenesis.

#### **5. Specifics of glucose and lipid metabolism in NonObPCOS**

Inconsistencies in data on IR incidence in NonObPCOS can be explained by prevalent usage of indirect and not enough accurate methods of IR assessment. Indexes, such as HOMA-IR and others, have a good positive predictive value, but a poor negative predictive value [34, 91]. First studies proving the presence of hyperinsulinemia and IR in NonObPCOS with the use of gold standard method hyperinsulinemic euglycemic clamp were published in the nineties [92, 93]. The presence of unique disorder of insulin action was hypothesized. More recent studies with larger groups and more sophisticated methods supported these findings [94]. A study by Stepto et al. showed that the prevalence of IR in PCOS is 75% in NonObPCOS, 62% in overweight controls, and 95% in overweight PCOS [95]. In 2016, meta-analysis of premenopausal women diagnosed with PCOS compared with a control group for insulin sensitivity, measured by euglycaemic–hyperinsulinaemic clamp, NonObPCOS, and overweight PCOS compared with their respective controls had lower insulin sensitivity with large and very large magnitudes [96]. In a recent study by Tosi, evaluation of insulin action on glucose and lipid oxidation, nonoxidative glucose metabolism, and serum

FFA in different PCOS phenotypes was performed. Results of this study showed that irrespective of phenotype, PCOS women had impaired insulin-mediated substrate use influenced by T levels [97].

Thus, studies using the gold standard method of insulin sensitivity assessment demonstrate the presence of hyperinsulinemia and IR in NonObPCOS while estimated indexes are often not enough sensitive to detect mild IR in fasting state. At the same time, it is necessary to take into account some limitations of clamp tests apart from the technical complexity and high price. In the case of intravenous glucose administration, intestinal factors (glucagon-like peptide (GLP1), glucose-dependent insulinotropic peptide (GIP)) are not involved. Thus, being a gold standard for IR evaluation clamp tests detects glucose uptake in specific conditions that are quite different from physiological. At the same time, recent investigations in TDM pay much attention to the role of postprandial dysmetabolism including postprandial dysglycemia and dyslipidemia [98]. Studies on postprandial dysglycemia in NonObPCOS are very limited. One study with obese PCOS women showed that area under curve (AUC) for TG, insulin, and glucose were higher compared to obese controls while AUC for high-density lipoproteins (HDL) was lower after meal after adjustment for BMI and HOMA-IR [99]. In a study including also NonObPCOS HOMA-IR and AUC for glucose, TG, very low-density lipoproteins, and total cholesterol were higher in PCOS compared to BMI-matched controls [100]. Thus, clinical assessment of postprandial dysglycemia could be a valuable tool for glucose metabolism impairments early detection in NonObPCOS. Well known tool for this purpose is the oral glucose tolerance test with 75 g of glucose hardly can be done often. For this reason, emerging methods like self-monitoring blood glucose and continuous glucose monitoring as well as biomarkers are very much awaited to be approved for routine use in PCOS. Standardized methods of postprandial dyslipidemia are not yet available. In terms of postprandial dysglycemia data on patients eating habits are of great importance, especially on the frequency of food intake.

Described above altered body composition as well as AT and skeletal muscles physiology combined with HA results not only in IR but in high rates of dyslipidemia in NonObPCOS. In meta-analysis elevated prevalence of high-TG and low-HDL were shown NonObPCOS (for high-TG: OR 10.46; 95% CI 1.39–78.56; for low-HDL: OR 4.03; 95% CI 1.26–12.9) [15]. Thus, laboratory monitoring for dyslipidemia which by some authors is regarded as an IR marker is warranted for all NonObPCOS patients [101].

Liver is an active participant in glucose, lipid, steroid, and protein metabolism. NAFLD is a clinical disease characterized by the histologic finding of ≥5% macrovesicular steatosis of the hepatocytes in individuals with nonsignificant alcohol consumption or other known cause of chronic liver disease [102]. Traditionally NAFLD was attributed to overt diabetes and obesity. Studies on metabolic obesity in general and specifically on NonObPCOS changed this view. 2018 meta-analysis shows that compared to the control group, the risk of NAFLD in the PCOS group was higher (OR = 2.25, 95% CI = 1.95–2.60). When stratified by BMI frequency of NAFLD risk was significantly higher in both obese subjects (OR = 3.01, 95% CI = 1.88–4.82) and non-obese subjects (OR = 2.07, 95% CI = 1.12–3.85). In addition, PCOS patients with HA had a significantly higher risk of NAFLD, compared with controls (OR = 3.31, 95% CI = 2.58–4.24) [103]. Some studies do not demonstrate such a strong association with HA [104].

Overall pathogenesis of NAFLD includes not only IR but a complex of factors: altered energy balance, adipose tissue excess, hormonal changes, genetic factors

*Special Considerations on Hyperandrogenism and Insulin Resistance in Nonobese Polycystic… DOI: http://dx.doi.org/10.5772/intechopen.103808*

[105]. As the liver secretes proteins, metabolites, and hepatokines to influence metabolism in other tissues presence of NAFLD in PCOS exacerbates all major and minor pathological circuits of the syndrome. Most vivid example is low SSBG secreted by the liver leading to higher levels of free T and HA symptoms. Thus, it is logical to detect NAFLD in NonObPCOS regarding epidemiological data and close pathophysiological associations of NonObPCOS features and NAFLD. Though screening for NAFLD is very restricted by currant guidelines on this pathology [102]. Liver biopsy remains a gold standard for diagnosis of NAFLD, but diagnostics ultrasound and transient elastography proved to be effective for noninvasive diagnosis [106].

Thus, there are many unsolved clinical issues of detection crucial alterations in NonObPCOS like mild IR, postprandial dysglycemia, and NAFLD. But still regarding existing scientific data search of solutions of these issues are among primary goals on the way to more effective NonObPCOS management.

#### **6. Management of NonObPCOS**

There is not enough evidence to make specific prevention recommendations for NonObPCOS women since most of the studies on lifestyle modification included either overweight/obese or mixed populations. Taking into account all the abovementioned data on specifics of NonObPCOS physiology it is reasonable to educate patients on the risks of early dyslipidemia, NAFLD, and metabolic syndrome. It is reasonable to monitor these conditions on a regular basis and to raise patient's awareness of the importance of healthy lifestyle especially eating behavior including food frequency, respect of circadian rhythms as well as food characteristics [107]. These recommendations remain actual for NonObPCOS women taking combined hormonal contraceptives. Until evidence-based specific dietary recommendations become available women with NonObPCOS can be recommended to keep Mediterranean diet principles as it proved to be protective from cardiometabolic risks in different populations including PCOS [108]. Also, control of fructose intake is highly recommended in view of NAFLD risks [109]. In the absence of definitive data on types of exercise favorable for muscle metabolism of NonObPCOS general recommendations from 2018 guidelines should be translated to every patient [1]. The arrival of new diagnostic methods for steroid metabolome, different metabolites (ceramides, bile acids, fatty acids, etc.), and gut microbiota assessment are promising in reaching targeted approaches for symptoms relief and MS prevention in NonObPCOS [110]. A number of pharmacological agents are promising for affecting main pathogenic mechanisms of NonObPCOS (insulin signaling defects, mitochondrial dysfunction, oxidative stress) and their consequences (IR, hyperinsulinemia, postprandial dysglycemia, ovarian dysfunction, dyslipidemia, NAFLD) including nutritional products and complex synthetic molecules. Among them are vitamin D, inositols, quercetin, resveratrol, L-carnitine, thiazolidinediones, GLP-1 receptor agonists, antihyperlipidemic drugs [111–119]. But all these groups of medications need an evaluation of their efficacy in properly designed clinical trials.

#### **7. Conclusion**

The prevalence of NonObPCOS is probably underscored**.** In the absence of high BMI unrecognized metabolic risks lead to their delayed diagnosis and interventions in NonObPCOS. Existing data on NonObPCOS suggests that intrinsic alterations in adipose and muscle tissue function might be the starting point of key pathogenic factor – IR and consequent hormonal and metabolic derangements. There is a need for deeper investigation and improvement of diagnostic approaches to mild IR, steatohepatosis, and androgen excess sources for better management of NonObPCOS.

### **Acknowledgements**

We would like to express our sincere gratitude to organizations, that housed our research and practical work on hyperandrogenism and supported us in writing and publishing this chapter: Ukrainian Association of Endocrine Gynecology, National Academy of Medical Sciences, Institute of Pediatrics, Obstetrics and Gynecology and Centre of Innovative Medical Technologies. Taking into account historical conditions in which completion of this text took place we express deepest gratitude to Ukrainian government and all people who have been heroically opposing Russian war attack.

### **Author details**

Tatyana Tatarchuk1 , Tetiana Tutchenko1 \* and Olga Burka2

1 Institute of Pediatrics, Obstetrics and Gynecology National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine

2 National Medical University, Kyiv, Ukraine

\*Address all correspondence to: ttutchenko@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Special Considerations on Hyperandrogenism and Insulin Resistance in Nonobese Polycystic… DOI: http://dx.doi.org/10.5772/intechopen.103808*

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### Section 2
