Polycystic ovarian syndrome (PCOS) is a prevalent disorder, affecting 15-20% of reproductive-aged women.[1,2] Its clinical presentation is a heterogeneous mix of physical, hormonal, metabolic and psychological signs and symptoms that can vary significantly both between, and within, individuals over a lifetime.[3,4]
Such variability highlights the complexity associated with ascertaining the specific aetiology of different the PCOS phenotypes, though interactions between environmental and genetic antecedents is considered to be a common factor.[2,3,6]
Increased research into the role of genetics in disease pathogenesis in recent years has included PCOS. This article discusses some of these genetic factors and how they are thought to influence the clinical presentation of the disorder.
Hormonal regulation of the menstrual cycle
The female menstrual cycle is regulated by hormones produced by the hypothalamus, pituitary gland and ovaries. The hypothalamic-regulated pulsatile secretion of gonadotropin-releasing hormone (GnRH) stimulates the synthesis of the gonadotropins, follicle stimulating hormone (FSH) and luteinising hormone (LH) by the pituitary gland.
During the menstrual cycle, FSH and LH work together to promote follicular growth and maturation, steroidogenesis (the synthesis of the steroid hormones oestrogen, progesterone and androgens [androstenedione, testosterone]) and a healthy endometrial lining. A large proportion of testosterone and oestrogen are bound to sex-hormone binding globulin (SHBG), rendering them inactive.[8,9]
Within ovarian follicular tissue before ovulation, LH promotes the synthesis of pregnenolone in granulosa cells. This is subsequently converted to dehydroepiandrosterone (DHEA) in ovarian theca cells, and then androstenedione and testosterone in granulosa cells. The conversion of androstenedione and testosterone from pregnenolone also occurs in the follicle just before ovulation and in the corpus luteum after ovulation.
FSH also influences the conversion of these androgens to oestradiol by regulating the production of aromatase and, in a balanced menstrual cycle, the majority of androstenedione and testosterone is converted into oestradiol.[2,5,7,10]
On a genetic level, the functionality of LH and FSH requires them to bind to the luteinising hormone choriogonadotropin receptor (LHCGR) and follicle stimulating hormone receptor (FSHR), respectively.[5,7]
Clinical features of PCOS
The heterogeneous clinical presentation of PCOS means that the amount, type and severity of physical, hormonal, metabolic and psychological characteristics that occur can range from significant to negligible, and this varies between the four recognised PCOS phenotypes.[5,11,12]
Hormonal characteristics of PCOS can include hyperandrogenism, low SHBG, elevated pulse frequency and levels of GnRH, variable levels of LH, FSH and oestradiol (i.e. high or low), and reduced progesterone.[5,6,9,11,13,14]
The impact of such hormone imbalances can be: physical (e.g. polycystic ovaries, irregular menstruation, hirsutism, acne, infertility); metabolic (e.g. insulin resistance, hyperinsulinaemia, metabolic syndrome, cardiovascular disease); or psychological (e.g. anxiety, depression), and varies between the PCOS phenotypes.[5,6,14,15]
Common characteristics exhibited by type A and B phenotypes are the ‘classic’ clinical features of PCOS, including polycystic ovarian morphology, significant menstrual dysfunction, hyperandrogenism, higher body mass index (BMI) and insulin resistance.[11,12,16]
Type C is often referred to as ‘ovulatory PCOS’, presenting with no polycystic ovarian morphology, milder ovarian dysfunction, more regular menstrual cycles and moderately high androgen and insulin levels.[11,12,16]
Characteristics frequently observed in the type D phenotype includes ovulatory dysfunction, alternating regular and irregular menstrual cycles, low-normal androgen levels and mild metabolic imbalances.[11,12,16]
However, while the type and severity of such characteristics observed within each of these phenotypes varies, there is a commonality in the underlying physiology driving them.
When obesity is a factor, it contributes to elevated GnRH pulse frequency and subsequent high LH levels, resulting in hyperandrogenism and increased conversion (aromatisation) of such androgens to oestrogen, which perpetuates the cycle.[5,13]
Hyperinsulinaemia leads to hyperandrogenism via several mechanisms involving the liver and ovaries, specifically: increased ovarian theca cell androgen production and responsiveness to LH; dysfunction of the liver enzyme involved in androgen production and inhibition of hepatic SHBG synthesis. These mechanisms result in increased levels of circulating free (active) androgens.[5,13,17,18]
Along with hyperandrogenism and hyperinsulinaemia, low FSH levels adversely influence follicular growth, causing growth arrest which results in both polycystic ovarian morphology and ovulatory issues (i.e. sporadic or absent ovulation).[13,19,20] A consequence of such ovulatory dysfunction and hyperinsulinaemia is reduced production of progesterone.
Aetiology of PCOS
Variability in the clinical presentation and underlying physiology of PCOS emphasises the complexity associated with establishing its aetiology. However, what is generally accepted is that an interaction between environmental and genetic influences is a key factor.[2,3,5,6]
Environmental factors correlated with PCOS are classified as prenatal or postnatal. Prenatal influences that increase the risk of PCOS in offspring include the presence of hyperandrogenism, obesity, type 2 diabetes, insulin resistance or excessive weight gain during pregnancy. Postnatal risk factors include diet, obesity, inactivity, stress, environmental toxins and medications (e.g. oral contraceptive pill). Such environmental factors have the capacity to imitate the effects of endogenous hormones and stimulate pre-existing metabolic issues in individuals with a genetic predisposition to PCOS.[5,21]
However, not all women with PCOS have had exposure to these environmental prenatal or postnatal factors, demonstrating the requirement for genetic predisposition to be present for environmental factors to influence the disorders development.
Also, PCOS has been observed to cluster in families, with 20-40% of individuals with PCOS having a first degree relative with the condition. Taken together, this points to genetics being an important factor in PCOS aetiology.[5,22-26]
The complexity of PCOS aetiology extends to what is currently understood about these genetic factors. Evidence looking into the genetics of disease pathogenesis involves either linkage (genome-wide) or association study methodologies.
The association methodology is where non-genetically related subjects are used to explore the potential correlation between candidate genes and a disorder, providing evidence of numerous variants (polymorphisms or SNPs) with small effects; conversely the linkage approach uses genetically-related subjects to explore genetic polymorphisms that may cause a disease in that family cluster, providing evidence of rare mutations with significant effects.
Genetic studies involving PCOS subjects have used both methodologies. Evidence from linkage studies have demonstrated that, on a population level, the heritability of PCOS, or the amount that genetic variation contributes to PCOS pathogenesis and characteristics, is approximately 65-70%.[5,6,27,28]
PCOS association studies have discovered 16 genetic variants in different PCOS ethnic population groups, including luteinising choriogonadotropin receptor (LHCGR), follicle stimulating hormone receptor (FSHR), the insulin receptor gene (INSR), thyroid adenoma gene (THAD A) and DENND1A.[5,6,15]
PCOS-associated genetic variants
The LHCGR gene is required for normal gonadal and reproductive processes involving LH and human chorionic gonadotropin (hCG) functionality, including steroidogenesis, ovulation (including pre-ovulatory follicular response to LH), corpus luteum activity and pregnancy maintenance.[3,10,29]
LHCGR receptors are present on ovarian thecal and granulosa cells, reproductive organs (uterus, fallopian tubes, placenta, breast tissue), adipose and muscle tissues, the brain and immune cells (lymphocytes and macrophages).
More than 300 polymorphisms in the LHCGR gene have been discovered, with evidence demonstrating varying levels of associations between some of these SNPs and PCOS in different ethnic populations.
These LHCGR polymorphisms influence PCOS by altering the structure, function and bioactivity of LHCGR and LH. Consequently, the reproductive processes they are involved in, potentially contribute to anovulation, oligomenorrhoea, amenorrhoea and enlarged ovaries.[3,5]
A study investigated the association between SNPs in the adipose tissue of PCOS and non-PCOS obese and lean subjects and gene activity (methylation and expression).
It was found that the LHCGR gene was over-expressed in adipose tissue from non-obese PCOS subjects compared with obese PCOS, obese non-PCOS and lean non-PCOS subjects, with corresponding decreases in methylation. This suggests that the increased ovarian tissue responsiveness to LH in PCOS subjects may be partly caused by an increased number and expression of LHCGR receptors, leading to elevated thecal cell androgen production.
A separate study assessed the correlation between LHCGR gene polymorphisms and PCOS susceptibility and clinical characteristics in Egyptian women.3 A significant association between some of these polymorphisms and PCOS risk was observed, particularly in obese subjects. Clinical characteristics correlating with various SNPs included increasing fasting blood glucose, total and free testosterone and LH/FSH compared with subjects without such variants, indicating that such variants influence LH levels and functionality.
Another study observed an association between certain LHCGR polymorphisms and increased BMI levels, waist-to-hip ratio, insulin resistance, LH and LH/FSH levels in PCOS vs non-PCOS subjects, and was associated with a 3.36 times higher risk of PCOS compared to other genotypes.
As the gene for FSH, the FSHR gene is required for normal gonadal development and follicular growth and maturation by influencing ovarian tissue response to FSH.[10,15,32]
As with LHCGR polymorphisms, different FSHR variants have been observed in some ethnic population groups but not others.15 Some of these variants have been associated with follicular arrest, primary amenorrhoea and elevated FSH levels, however further research is required to confirm the role of specific FSHR polymorphisms and FSH levels in PCOS subjects.[10,15]
In a study assessing the impact of FSHR and LHCGR variants in European and non- European women with and without PCOS, there were several findings. This included: a significantly higher level of some LHCGR variants in PCOS vs non-PCOS subjects, particularly in obese individuals; significant associations between LHCGR variants (and to a lesser extent FSHR variants) and altered FSH sensitivity; and a link between some LHCGR variants and hyperandrogenism.
The potential link between INSR gene variants and PCOS is related to the influence of hyperinsulinaemia on PCOS pathogenesis, with this gene being involved in insulin metabolism and receptor activity.
Associations between INSR polymorphisms and insulin resistance, elevated insulin and LH, hyperandrogenism, endometrial thickness, ovarian volume and hirsutism in some PCOS population groups have been observed.[10,31]
Polymorphisms in the THAD A gene have been associated with insulin resistance in PCOS and in some PCOS groups such variants have been associated with abnormal glucose metabolism, elevated LH, hyperandrogenism and polycystic ovarian morphology.[5,6]
The DENND1A gene is found in ovarian thecal tissue, with the number of receptors and gene activity being observed to be over expressed in such cells in PCOS subjects. Being involved in GnRH-stimulated synthesis of LH, clinical characteristics associated with DENND1A variants include hyperandrogenism, irregular menses, tissue responsiveness to insulin, type 2 diabetes and obesity.[10,34]
A study using Chinese women looked at the relationship between DENND1A, THAD A and LHCGR polymorphisms and clinical and biochemical parameters in PCOS vs non-PCOS subjects.2 PCOS subjects had significantly higher levels of THAD A and LHCGR variants compared with the non-PCOS group, and these variants were associated with elevated levels of testosterone.
Overall, the current evidence regarding the role of genetics in the pathogenesis and clinical presentation of PCOS is indicative of shared genetic susceptibility, or put another way, the combination of the effect of multiple genetic polymorphisms as opposed to an individual gene variant.[6,34]
Further evidence is required pertaining to many aspects of PCOS aetiology and clinical management, including the role of both individual and multiple gene polymorphisms in different ethnic populations on its clinical presentation and the effective use of genetic assessments to determine PCOS phenotypes. Such information will allow more individualised management and treatment of the disorder, resulting in effective clinical patient outcomes.
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