POLYCYSTIC OVARY SYNDROME (PCOS)

Zeng LH, Rana S, Hussain L, Asif M, Mehmood MH, Imran I, Younas A, Mahdy
A, Al-Joufi FA, Abed SN. Polycystic Ovary Syndrome: A Disorder of Reproductive
Age, Its Pathogenesis, and a Discussion on the Emerging Role of Herbal
Remedies. Front Pharmacol. 2022 Jul 18;13:874914. doi:
10.3389/fphar.2022.874914. PMID: 35924049; PMCID: PMC9340349.

INTRODUCTION

Polycystic Ovary Syndrome (PCOS) is a highly prevalent disorder representing the most
common heterogeneous condition which is related to an endocrine reproductive disorder in
females of reproductive age (Ajmal et al., 2019). It involves the persistent hormonal
disbalance that is an imbalance in the ratio of luteinizing hormone (LH) to follicle-
stimulating hormone (FSH), which leads to complexities such as numerous cysts in ovaries,
hyperandrogenism, insulin resistance, infertility and irregular menstrual cycles (Reem et al.,
2022). PCOS was named as Stein-Leventhal Syndrome by an American Gynecologist Irving
F. Stein and Michael L. Leventhal which are regarded to have been the first investigators of

PCOS in 1935 (Zeng et al., 2022). The global prevalence of PCOS is estimated between 4%
and 20% (Jabeen et al., 2022). The World Health Organization (WHO) data suggests that
approximately 116 million women (3.4%) are affected by PCOS globally (Singh et al., 2023).
Elevated levels of androgen beyond its normal range causes hyperandrogenism whereas
insulin resistance leads to obesity in females affected with PCOS (Ajmal et al., 2021).
Treatment initially includes lifestyle changes, folic acid therapy and halting the consumption
of tobacco and alcohol. An appropriate knowledge of personal and family history, lifestyle
and dietary habits of PCOS women has a great importance to early identify and manage this
syndrome (Bruni et al., 2022).

DIAGNOSIS OF PCOS

There is no certain test for PCOS diagnosis. Although considering past medical history,
weight changes, and symptoms of insulin resistance might be helpful, pelvic examination, a
transvaginal ultra-sound, and measuring the level of hormones are among the most frequently
recommended investigations. According to the National Health Service (NHS), irregular or
infrequent periods, high levels of androgenic hormones or symptoms, and scans showing
polycystic ovaries are the specified criteria for PCOS. In addition, Rotterdam PCOS
diagnostic criteria in adults are the most commonly used method. In an ultrasound, the
presence of two clinical or biochemical hyperandrogenism, ovulatory dysfunction, or
polycystic ovaries would finalize a PCOS diagnosis (Sadhegi et al., 2022).

ETIOLOGY AND RISK FACTORS

The exact etiology of PCOS have not been well known. Both genetic and environmental
factors are responsible for etiology of PCOS.

Genetic FactorsKhan MJ, Ullah A, Basit S. Genetic Basis of Polycystic Ovary

Syndrome (PCOS): Current Perspectives. Appl Clin Genet. 2019 Dec 24;12:249-
260. doi: 10.2147/TACG.S200341. PMID: 31920361; PMCID: PMC6935309.

Genetic factors play a role in the development of the syndrome although PCOS cases do not
exhibit a clear pattern of Mendelian inheritance (Unluturk et al., 2007). Mothers of PCOS
women are more likely to have cardiovascular disease and the high risk of hypertension as
compared to mothers of females who exhibits the risk twice as compared to mothers of
females without PCOS, while fathers of women with PCOS are twice as likely to have heart
disease and 4 times to have experienced cerebral stroke (Davies et al., 2017). The level of
hormones that is Gonadotrophin releasing hormone (GnRH), follicle stimulating hormone
(FSH), Luteinizing hormone (LH) and prolactin is disturbed in females affected with PCOS.
(Ajmal et al., 2019).

Nutritional and Environmental Factors

Unhealthy diet is a lead cause of PCOS. Saturated fatty acids (SFAs) intake plays a role in
PCOS by producing inflammatory status and reducing insulin sensitivity. Vitamin D
deficiency may exacerbate PCOS. Furthermore, Vitamin D downregulates AMH promoter.
On the other hand, environmental factors include agents like endocrine-disrupting chemical
(EDC) that maintains homeostasis, reproduction, development and/or behaviour. EDCs are
almost parts of everything we use in our daily life. There are higher serum concentration of
EDCs in PCOS suffering women. Prolonged and continuous exposure to EDCs from prenatal
to adolescence can cause susceptibility to PCOS. Advanced glycation end products (AGEs),
also called glycotoxins, are another chemical group affect body health. High concentration of
AGEs in serum has been detected in PCOS patients (Sadheghi et al., 2022).

Physical and Emotional Stress

Stress is an invisible factor affecting modern day living and is strongly associated with many
disease pathogenesis including polycystic ovarian syndrome (PCOS) in women. PCOS
possesses adverse effects on self-esteem and mental health. Salivary amylase and cortisol are
major stress mediators that have been implicated in PCOS (Basu et al., 2018). Chronic stress
results in hypertrophy and hyperplasia of adipocytes. This happens as a result of
glucocorticoids’ effect on pre-adipocytes maturation. Chronic stress is also associated with
adipokine secretion, attraction, and activation of stromal fat immune cells. Stress triggers the
hypothalamic-pituitary-adrenal (HPA) axis to release cortisol. Cortisol leads to IR by
stimulating visceral fat accumulation, gluconeogenesis, and lipolysis. Moreover, cortisol
arouses glucose production in the liver. Stress is also involved in enhancing insulin levels
(Sadheghi et al., 2022).

Hyperandrogenism

Hyperandrogenism is the defining cause of PCOS which is a hormonal disbalance

characterised by elevation of male hormones that is androgens (Ajmal et al., 2022). High
levels of androgens are observed in 75–90% of PCOS patients with oligomenorrhea, and their
concentrations frequently increase with the severity of the phenotype. Excessive androgen
synthesis by the ovaries as well as the adrenals contributes to hyperandrogenism (Singh et al.,
2023). HA reduces the SHBG level, leading to a higher concentration of free testosterone. It
was observed that PCOS women have higher concentrations of testosterone in plasma which
can convert to estrone in adipose tissue. Increased alteration of estrone to estradiol affect
follicle growth and increases the LH to FSH ratio causing ovulatory dysfunction. In addition,
HA is a cause of adipocyte hypertrophy and consequential damages to adipokine

secretion. An altered cortisol metabolism is another proposed mechanism that contributes to

excess androgens in PCOS patients (Singh et al., 2023).

Inflammation

Inflammation is the body's natural response to threats, such as injuries and viruses. It is a vital
cause of oocyte growth and ovulation. Inflammation is also a cause of HA. Moreover, high
levels of white blood cell, C-reactive protein (CRP), and other inflammatory biomarkers in
peripheral blood are associated with PCOS (Sadheghi et al., 2022). The discovery of TNF-α
elevations in PCOS served as the initial clue that PCOS is a pro inflammatory state. TNF-α is
a pro-inflammatory chemical that can worsen IR by the interference of pro-inflammatory
molecules with insulin signaling pathway and reduction of GLUT-4 expression. Circulating
levels of the pro inflammatory cytokine tumor necrosis factor-α (TNF-α) are elevated in
PCOS (Gonzalez et al., 2012).

Insulin resistance

Insulin resistance (IR) is tissue-specific in PCOS. It is a common feature of PCOS affecting

50-70% of women with the disorder (González et al., 2012). IR means less cell response to
insulin. Insulin interferes with the production of androgens in ovarian theca cells. Insulin
effectively stimulates ovarian follicle growth and hormone secretion by stimulating its
receptors in the follicle membrane cells. PCOS progression and severity increases with the
increase in insulin level as well as an androgen. Hyperinsulinemia affects ovarian theca cells
and raise androgen level. This condition reduces the hepatic biosynthesis of SHBG and
IGFBP-1. Elevated androgen level, stimulates visceral adipose tissue (VAT) that generates
free fatty acids (FFA’s) which contributes in insulin resistance. Insulin stimulates
adipogenesis and lipogenesis and inhibits lipolysis, resulting in fat accumulation. IR leads to
enhanced plasma levels of free fatty acids (FFAs), affecting the liver and adipose tissue
(Sadheghi et al., 2022).

ROLE OF FSHR IN PCOS

Follicle-stimulating hormone (FSH) is a glycoprotein playing a central role in mammalian

reproduction and development. In the ovary, FSH regulates folliculogenesis, oocyte selection,
and the synthesis of sex steroid hormones, thus preparing the reproductive tract for

fertilization, implantation, and pregnancy (Casarini et al., 2019). Cytogentic location of

FSHR is at chromosome 2p16.3 and it has total of 14 exons. This gene encodes a protein
named as G coupled receptors and plays an important role in gonad development (Laven et
al., 2019). The glycoprotein follicle-stimulating hormone (FSH) acts on gonadal target cells,
hence regulating gametogenesis. The transduction of the hormone-induced signal is mediated
by the FSH-specific G protein-coupled receptor (FSHR), of which the action relies on the
interaction with a number of intracellular effectors (Casarini et al., 2019). FSHR
polymorphisms do alter the phenotype of PCOS. The disturbed hormonal levels effects
endocrine reproductive system. Apart from other hormones, the imbalance level of FSH also
responsible for PCOS severity. Up till now around 1,800 SNPs of the FSHR gene have been
reported in the National Centre for Biotechnology Information (NCBI) SNP database (Ajmal
et al., 2019).

Tang, R., & Zhu, J. (2019). Kisspeptin and polycystic ovary syndrome. Frontiers in endocrinology, 10,
450717.

OBJECTIVE OF THE STUDY

To study and analyse the genetic association of Follicle-stimulating Hormone Receptor

(FSHR) with Polycystic Ovary Syndrome (PCOS)