INTRODUCTION:

The polycystic ovarian syndrome is a common endocrine disorder in females, generally seen in women of reproductive age. Besides reproductive abnormalities, PCOS is also strongly linked with many chronic diseases, such as hepatic steatosis, glucose intolerance, hypercholesterolemia, and diabetes mellitus type II, and high blood pressure^1,2. Polycystic ovary syndrome, also known as Stein Leventhal Syndrome, describes clinical manifestations related to the secretion of excess androgenic hormones (hyperandrogenism), Persistent anovulation (amenorrhea), and Ovaries containing many small subcapsular cysts³. Reproductive hormones like estrogen, testosterone, LH, FSH lead to irregular menstrual cycle⁴. Polycystic Ovarian Syndrome (PCOS) is characterized by infertility, acne, hirsutism, obesity, baldness, anxiety, and disordered sleep⁵.

According to World Health Organization (WHO), PCOS impacted 116 million women (3.4)% worldwide4. Depending on the population analysis and the criteria used for diagnosing POCS in India ranges from 3.7 – 22.5% 32. In PCOS, ovaries appear to be usually twice normal in size, are grey-white with smooth outer cortex, 0.5-1.5 cm in diameter⁶.

Signs and symptoms:

· Irregular menses (Oligomenrrohea)

· Anxiety

· Acne

· Mood swings

· Anovulation

· Baldness / Hair thinning

· Infertility

· Amenorrhea

· Depression

· Hyperpigmentation

· Irritation

· Excessive facial and bodily hair

· Enlarge ovaries with cyst

Pathophysiology:

Figure 1: Pathophysiology of Polycystic Ovarian Syndrome (PCOS)

Risk Factors:

a. Hyperandrogenism:

Normal androgen synthesis disturbs due to impaired folliculogenesis. Hyperandrogenism is a primary factor of PCOS⁷. Hyperandrogenism shows symptoms like hirsutism, acne, and androgenic alopecia⁸. Approximately 40% of diabetic women have clinical hyperandrogenism⁹. Pituitary release the gonadotropin hormone, which the GnRH activates secreted from the hypothalamus. For producing androgen in ovarian theca cells luteinizing hormone activates LH receptor and follicle growth occurs due to transformation of androgens to estrogens in ovarian granulosa cells when follicular stimulating hormone acts on FSH receptor simultaneously. Synthesis of androgen occurs firstly when LH concentration is more relative to that of FSH. It has been presumed that variance of the HPO axis (Hypothalamic Pituitary Ovarian Axis) is because of dysregulation in the neuroendocrine system, which causes the positive excess level of gonadotropin. Production of more LH than FSH takes place due to a rise in GnRH, resulting in a sharp hormonal rise in LH: FSH ratio in polycystic ovarian syndrome¹⁰.

b. Insulin Resistance:

PCOS is strongly linked with hyperinsulinemia and insulin resistance. Theca cells of the ovary get activated by insulin resistance or hyperinsulinemia and generate excess testosterone by acting synergistically with LH hormone, which is the cause of hyperandrogenism. According to several studies, insulin resistance is the critical pathophysiological element for the progress of the syndrome. Androgen production increases abnormally because of the synergistic action of insulin with the LH hormone¹¹. An abnormal serum lipid level occurs in approximately 70% of PCOS patients¹². Insulin reduces the level of sex hormones binding globulin (SHBG). For balancing the testosterone level, SHBG is an essential circulating protein. This reduces the level of SHBG results increasing the androgen level that generates clinical symptoms like abnormal hair growth on a woman’s face, acne, baldness. Insulin resistance is responsible for causing hypertension, hypercholesterolemia, and hyperglycemia and the risk or danger of these diseases is approximately threefold higher in PCOS women¹³. According to the several surveys, free fatty acids persuade insulin resistance and weaken the insulin action in obesity Type 2 DM and PCOS^13,14.

c. Obesity:

Over the last 40 years, the global prevalence of obesity in women has increased 2.5 fold from 6% to 15% suffering from PCOS. It has been revealed that between 38%-88% of women with PCOS. Obesity leads to insulin resistance, which increases insulin levels, resulting in increased abiogenesis. Obesity excites the thecal cells that stimulate luteinizing hormones, resulting in functional ovarian androgen excess¹⁵.

1. In PCOS, excess weight also worsens reproductive and psychological outcomes, which have been admitted in all researches & analyses.

2. Leptin, an adipokine that controls appetite, has a direct effect on the reproductive function and neuroendocrine function of obese PCOS women¹⁶.

d. Infertility:

Women with PCOS may suffer from reduced fertility due to ovulatory dysfunction and other endocrine abnormalities2. PCOS accounts for 75% of anovulatory infertility¹⁷.

Figure 2: Risk Factors Polycystic Ovarian Syndrome (PCOS)

Diagnostic Criteria for PCOS:

Table No 1. Criteria for diagnosis of PCOS¹⁸

Organization

Criteria for diagnosis

1. NIH

2. ESHRE /ASRM

· Excess androgen

· Chronic anovulation

(menstrual disturbance)

· Morphology of polycystic ovary on

ultrasound scan

· Characteristic of excess of androgen

· Irregular menses

NIH- National Institute of Health

ESHRE – European society for Human reproduction and Embryology

ASRM- American Society for Reproductive Medicines

SIGNS AND SYMPTOMS:

a. Irregular Menses:

Unpredictable menses commonly indicate ovulatory dysfunction; they occur between less than 21 days or more than 35 days interval because of the lack of thyroid, adrenal or other pituitary dysfunction¹⁹. Generally, over regular lifetime ovulation varies. The survey of the androgen excess/PCOS society task force reveals that 85% of the PCOS patients have clinical evidence of menstrual irregularies. According to Van Hoff and colleagues, a group of teenagers from the general population reported oligomenorrhea, and according to them, age 15 was the best age for estimation of oligomenorrhea. Meanwhile, the irregular menstrual cycle is not the sole criteria for predicting PCOS²⁰.

b. Screening criteria for polycystic ovary syndrome:

Polycystic ovary syndrome can be diagnosed in women with hirsuteness, irregular menses, or obesity. The history and physical examination should be directed towards ascertaining disorders that mimic PCOS²¹. In women with polycystic ovary syndrome, screening should be done for cigarette smoking, obstructive sleep asphyxia, depression, and anxiety, with further checking and treatment needed²¹.

c. Ultrasound methods:

Based on transabdominal ultrasound by the clinicians, polycystic ovarian morphology is explained by “the existence of 12 or more follicles in each ovary measuring 2-9 mm in diameter. Twelve or more follicles can detect polycystic ovarian syndrome in each ovary which measures 2-9 mm in diameter; Rotterdam gave this definition on 2004. After evaluation of sonographic reports of women suffering from PCOS, it is found that some women can have irregular menses with signs of hyperandrogenism.

e. Determination of androgen excess:

By determining the androgen excess, a diagnosis of PCOS can be made. Direct free testosterone assay may not be done, but from total testosterone, SHBG (Sex Hormone Binding Globulin) and free testosterone can be calculated. Hirsutism is the cause of hyperandrogenism, and this is the present benchmark for identifying PCOS. Screening of hyperandrogenism can be done by an androgen profile test that contains free testosterone, plasma total testosterone, and another androgen such as dehydroepiandrosterone sulfate (DHEA sulfate). If more than 90ng/dL total testosterone level is confirmed, then it is considered that it contains excess androgen. By plasma-free testosterone, androgen excess can be determined. In hirsute women, total testosterone level is high because they have proportionally low SHGB (sex hormone-binding globulin) levels. The binding protein is suppressed by androgen excess and hyperinsulinemia of insulin resistance. It finds outs the portion of plasma testosterone free or tied to albumin²².

Treatment of PCOS:

Table No. 2: Therapeutic options for PCOS^22-25

DRUG

Mechanism

1. Oral contraceptives

a) Combine pills containing both estrogen and progesterone

2. Antiandrogen

a) Cyproteron acetate

b) Flutamide

3. Insulin sensitizer

a) Metformin

c) Thiazolidinediones

4. Ovulation inducing agent

a) Clomiphene citrate

· Endometrial changes

· Decrease gonadotropin releasing hormone

· Decreases LH and FSH

· Increases SHBG

· Decreases androgen

· It inhibits the binding of testosterone and 5a-dihydrotestosteron to androgen receptor.

· It act as competitive antagonist at androgen receptor

· Increases SHBG and reduce free testosterone. It also increases insulin sensitivity.

· It block PPARy (peroxisome proliferator- activated receptor- gamma) thereby decrease insulin resistance.

· Estrogen antagonist, interfere with negative feedback of estrogen signaling pathway. Increase FSH.

Antiandrogen:

Androgen mainly acts as an antagonist, which inhibits 5-alpha-reductase enzyme, reducing androgen production. The antiandrogen category comprises flutamide, cyproterone acetate, and spironolactone, which reduce androgen secretion and are preferred as first-line to treat hirsutism. Spironolactone leads to a more frequent menstrual cycle. Flutamide is a potent competitive antagonist at androgen receptors. It is used with GnRH /leuprolide in the treatment of carcinoma²⁵. Cyproteron acetate is a progestationalantiandrogen. It is usually recommended for hirsutism. The binding of testosterone and its more potent conversion product 5a-dihydrotestosterone to androgen receptor is prohibited by cyproterone²⁴. Because of the increased risk of teratogenicity to male fetuses, contraception is recommended when patients use antiandrogens to treat PCOS. Finasteride is also an antiandrogen [15-alpha reductase inhibitor, but less potent as compared to other antiandrogens for treating hirsutism.

Life Style Intervention:

Lifestyle modification is essential, and hence it is given first preference in treatment. Weight loss decreases hyperinsulinemia which reduces hyperandrogenism. Hence, it is essential to consult a dietician for weight management in women with PCOS. A diet low in fat and calories is suggested for obese PCOS women with less carbohydrate intake. Physical exercise is also suggested for PCOS, and it is necessary²⁶.

Insulin Sensitizers:

As a therapy, insulin-sensitizing agents have recently been proposed to treat PCOS. Insulin sensitizers act by reduction of insulin levels and increasing insulin sensitivity. As insulin level decreases, it reduces androgen level and induces menstrual cyclicity and ovulatory cycle. Most females with PCOS had reduced sensitivity to insulin, which means insulin resistance, and present with stimulated hyperinsulinemia; the use of insulin sensitizers could therefore be preferred in most patients with PCOS²⁷.

Metformin:

Metformin is used for the treatment of type 2 DM. Metformin is an insulin-sensitizing agent and directly reduces ovarian gluconeogenesis. This drug is used to decrease insulin resistance. It also improves fertility and reduces androgen levels. Metformin acts by increasing glucose absorption and its usage in patients with insulin resistance. Metformin works indirectly by reducing the insulin level. When the insulin level is reduced, there is also a reduction in CYP17 cytochrome activity, which involves androgens information. It also raises sex hormone-binding globulin (SHBG) and reduces the free testosterone. During the pregnancy, metformin use does not cause any abnormality or defect. It decreases complications related to pregnancy and also decreases inflammation. In infertile PCOS patients, the ovulation and fertility rate were elevated when metformin combined with clomiphene citrate. Antiandrogen like flutamide combined with metformin shows co-operative effect in overweighted PCOS women. Metformin has an inhibitory role in chronic diseases related to PCOS women, such as endometrial cancer, hypertension, and type 2 diabetes.

Thiazolidinediones:

Glitazones is another named for the class thiazolidinediones, it comprises rosiglitazone, pioglitazone. Glitazones convert the cortical by decreasing 11alpha- HSD enzyme activity. Thiazolidinediones are the second-line choice of drugs. Thiazolidinediones increase insulin sensitivity in adipose tissue by blocking PPARy (peroxisome proliferator-activated receptor-gamma). Thiazolidinediones elevate the SHGB level by reducing the excess of androgen.

Oral Contraceptives:

Oral contraceptives are categorized into progesterone-only pills and estrogen (Estradiol) and progesterone (norethisterone, desogestrel) containing combined pills. Oral contraceptives are the first-line treatment in women facing irregularity in the menstrual cycle. OCS is also used for women who do not want to be pregnant. OCS is also a first-line treatment for hyperandrogenism. OCS is combined with antiandrogens for synergy. OCS pills reduce free testosterone that is not bound to any protein by decreasing LH and FSH by increasing sex-hormone-binding globulins (SHBG). OCS is readily used to regulate PCOS symptoms in particular hirsutism, acne, and irregular menstruation. Researchers suggest that the OCS reduced the risk of ovarian cancer and breast cancer²⁸.

Ovulation Inducing Agent:

The goal of therapy is ovulation induction and finally to facilitate healthy and full-term gestation.

· Clomiphene citrate is the first preference in treatment for infertility and anovulation. If this fails, the second preference is laparoscopic ovarian surgery²⁹. Clomiphene citrate acts as an antagonist of estrogen, which blocks or disturbs the negative feedback of the estrogen signaling pathway, so that is why FSH is increased. Follicular growth occurs due to the increased level of FSH followed by LH surge and ovulation. The dose suggested of clomiphene is 50 mg every day for five days. The clomiphene should be taken on the second to fifth days of menstruation.

· However, clomiphene should not be used for more than six cycles because of the risk of ovarian cancer.

· Tamoxifen is another drug that is intended through oral route, which is the same as clomiphene citrate in its mechanism, but it has a lack of antiestrogenic property on the endometrium cervix and cervical mucus, and they both increases pregnancy rate.

· Aromatase inhibitors like letrozole are approved for breast cancer, but they effectively induce ovulation in PCOS.

· Insulin sensitizing agents have been used in the treatment of infertile PCOS patient10. By decreasing insulin resistance, metformin effectively improves ovulation induction in PCOS patients. Androgen production in the ovary is finally decreased by directly inhibiting gluconeogenesis³⁰.

CONCLUSION:

PCOS is a complex disease linked with endocrine, environmental, and behavioral factors giving rise to metabolic, reproductive, and psychological characteristics, and it acts on women's health. The quality of life of females is also affected. PCOS patients should be aware of the risk factors associated with this disorder. Screening and diagnosis should be made, and proper treatment should be taken as early as possible.

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Received on 02.06.2022 Modified on 28.06.2022

Asian J. Res. Pharm. Sci. 2022; 12(4):309-313.

DOI: 10.52711/2231-5659.2022.00053