Introduction
Polycystic ovary syndrome (PCOS), which was first described in 1935, is a common gynecologic endocrinopathy and affects 6%-8% of reproductive women [
1]. Since then, many researchers have initiated to pay close attention to this syndrome, and lots of related studies on its etiology, diagnosis, and management have been conducted. It is supposed that the pathogenesis of PCOS is associated with both heredity and environment; however, the exact pathogenesis remains uncertain. The diagnosis is also difficult because of its heterogeneity in phenotypes. The European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine sponsored in Rotterdam in 2003 issued that the diagnosis of PCOS should be made when two of the following characteristics are satisfied: (1) oligo-/anovulation; (2) the presence of hyperandrogenemia or clinical hyperandrogenism, and (3) polycystic ovarian morphology on ultrasound after excluding other related diseases that can induce ovarian dysfunction and hyperandrogenism [
2].
It has been demonstrated that PCOS can impact the women’s reproductive health, leading to 75% of anovulatory infertility and contributing to the increased rate of early pregnancy loss (EPL). PCOS has additional metabolic derangements, such as insulin resistance (IR), impaired glucose tolerance, and dyslipidemia. The risks of diabetes, cardiovascular disease, hypertension, metabolic syndrome, and endometrial cancer among PCOS patients are significantly increased as well. Therefore, PCOS is defined not only as a gynecologic endocrinopathy but also as a kind of metabolic disorder. Its impacts can emerge during puberty and last up to postmenopause, which makes it a nightmare persisting throughout a woman’s life.
Genetic studies
As concerned above, although the etiology of PCOS is not clear, genetics plays an important role in the pathogenesis of the syndrome. In recent decades, many researchers have focused on the virulence gene association studies, which are principally related to reproductive hormones, IR, and chronic inflammation.
We found that insulin receptor (INSR) was one of the susceptibility genes in patients with PCOS, especially in nonobese PCOS subjects [
3]. The single nucleotide polymorphism (SNP) rs2209972 was also evidenced to be associated with metabolic abnormalities in PCOS patients from Han Chinese population. The PCOS women with CC genotype had significantly higher fasting insulin level and homeostasis model assessment for insulin resistance (HOMA-IR) [
4].
Adiponectin is the most abundant adipocytokine and may play a role in the regulation of insulin sensitivity and IR in PCOS. It was reported that SNPs+45G15G(T/G) and+276(G/T) in the ADIPOQ gene were associated with PCOS in Han Chinese women. SNP+276(G/T) may contribute to an impact of insulin levels and IR [
5].
Calpain-10 gene (CAPN-10) is the first localized predisposing gene of diabetes. The pathophysiological characters of PCOS and diabetes are similar, which makes CAPN-10 an important candidate gene for PCOS. Chen
et al. found that CAPN-10 noticeably correlated to PCOS subjects who had family histories of diabetes or tumors [
6]. Lee
et al. also investigated the CAPN-10 polymorphisms in Korean PCOS patients and verified the association [
7].
The genes that can affect the synthesis and regulation of hormone, especially androgen, are also concerned as functional candidates for PCOS. CYP11alpha promoter pentannucleotide (tttta)n polymorphism was reported to be associated with PCOS patients who have metabolic abnormalities [
8]. Van
et al. found that PCOS patients with less number of CAG repeats in androgen receptor gene had more risk to be hyperandrogenism [
9]; however, it was not replicated, and some researchers held opposite opinion [
10].
Additionally, many other genes have been investigated, such as GDF9, IL-6, and PLA2G7, which were evidenced to be responsible for the susceptibilities of PCOS, while GHRL, MCF2L2, BMP15, AMH, AMHR2, CYP21, TNF-α, and IL-10 showed no association with the development of the syndrome [
11-
17].
As a complex disorder, the study in etiology of PCOS is difficult but very crucial. More efforts should be taken to get across the relationships among genetics, environment, and phenotypes.
PCOS clinical characteristics
There are various phenotypes of PCOS, such as oligomenorrhea, amenorrhea, obese, acne, and hirsutism. Three of them are concerned as the main clinical characteristics because of the high prevalence and are suggested as the criteria of the syndrome. They are oligo-/anovulation, hyperandrogenism, and polycystic ovaries. According to our study of 3313 patients satisfying the Rotterdam criteria, the prevalence of menstrual dysfunction, hyperandrogenism, and polycystic ovaries was 97.2%, 94.3%, and 70.0%, respectively. 16.5% of the PCOS patients complained of hirsutism, and 18.1% worried about their acne. Although the most prevalent feature is ovulatory dysfunction, hyperandrogenism is suggested as “the root of all evil.”
Hyperandrogenism is represented as hyperandrogenemia and clinical manifestations (e.g., hirsutism). According to the complete task force by Androgen Excess and PCOS Society in 2009, 70% of patients with PCOS demonstrate supernormal levels of free testosterone (T), and 65%-75% of patients with PCOS present hirsutism, the prevalence of which is likely to be less among East Asian cases compared with affected women who are white and black [
18]. Hyperandrogenism will accelerate the atresia of preantral follicles and result in the absence of dominant follicle. The androgen excess will additionally bring about the thickened ovarian matrix, which is one of the characteristics in PCOS ovaries [
19]. The increased androgen can convert into estrogen in periphery. The latter will feedback and suppress the follicle stimulating hormone (FSH) secretion and consequently disrupt the normal modus for follicle election and dominant follicles development [
20]. In contrast, the elevated estrogen level will increase the sensibility of pituitary and lead to hypersecretion of luteinizing hormone (LH), which will affect the follicle development and ovulation. On the other hand, high LH level is a pathological stimulus for androgen synthesis in ovarian theca cells and plays an important role in maintaining hyperandrogenemia. This vicious cycle promotes further adverse impacts on the reproductive system.
PCOS and early pregnancy loss
Many researches demonstrated that PCOS was associated with EPL. It is believed that the poor quality of oocytes and disturbed internal environment threaten the pregnancy maintenance. According to several studies, the rate of spontaneous EPL in PCOS is about 30%-50%, which is two-fold higher than normal controls. The habitual EPL rate in patients is also as high as 36%-82% [
21]. However, a meta-analysis result showed no significance of the miscarriage rate between PCOS patients and other infertility women undergoing
in vitro fertilization (IVF) [
22]. Hence, there should be more studies to confirm the association between PCOS and abortion.
PCOS also has negative effects on the process and outcomes of pregnancy, including high risk of gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), prematurity, etc. In a meta-analysis of 15 articles on PCOS and pregnancy outcomes, Boomsma concluded that the increasing rate of premature delivery was related to PCOS, whereas there was no statistically significant difference after excluding the effect of gestational weeks. Additionally, PCOS patients were at higher risk of developing PIH, pre-eclamptic toxaemia, GDM, as well as adverse pregnancy outcomes. Their babies were more likely to suffer neonatal complications, and they had higher rates of their children’s admission to neonatal intensive care units and a higher perinatal mortality of their babies [
23]. Therefore, measures should be taken for PCOS patients, such as dieting, losing weight, use of metformin, and decreasing the level of LH, to facilitate the prevention of pregnancy and neonatal complications.
PCOS metabolic disturbance and long-term consequences
Metabolic disturbance, including obesity, IR, dyslipidemia, and hypertension, is prevalent among PCOS patients and makes an adverse impact on their long-term health consequences in both metabolic and reproductive aspects.
Obesity is one of the major complaints of PCOS patients. 30%-50% of patients are affected by being obese or overweight [
18]. This prevalence varies among different countries because of the varieties of ethnicities and life habits. In general, black and white patients with PCOS in Europe and America are more affected than eastern Asian women [
24]. Obesity is known as the independent risk factor of type 2 diabetes and contributes to the occurrence of cardiovascular morbidity and mortality. Cupisti
et al. reported that the obese PCOS had higher levels of HOMA-IR, free androgen index, fasting glucose, and fasting insulin than nonobese patients; nevertheless, their glucose/insulin ratio, insulin-sensitivity index, sex hormone binding globulin, and high density lipoprotein were lower than in lean PCOS [
25]. Wagenknecht
et al. found that the increased waist-to-hip ratio was associated with IR and raised the risk of diabetes [
26].
IR is the key pathophysiology of PCOS and contributes largely to its changing aspects throughout the lifespan. It is well known as an independent risk factor of diabetes. Glueck
et al. found that PCOS patients had increased morbidity of metabolic syndrome, cardiovascular disease, and dyslipidemia, which was associated with IR [
27]. IR has additional important reproductive impacts including androgen excess and oligo-anovulation. The elevated insulin can stimulate the secretion of androgen directly and indirectly by increasing the secretion of LH, which will affect the biosynthesis of the theca cells. Thus, IR also increases the risk of EPL of PCOS patients. Treatments by antidiabetic agents improving insulin sensitivity have been examined in a number of randomized studies, which have shown benefits to both the endocrine and metabolic abnormalities in the syndrome [
28].
IR is more pronounced among obese subjects but cannot totally be attributed to obesity. Several studies assessing insulin action among PCOS patients have suggested that such pathological state was associated with both obese and lean patients independent of the effect of body mass index (BMI) [
29]. In the study of Dunaif, the lean patients were documented to be more IR than their counterparts being matched for BMI after euglycemic insulin clamps (the gold standard for measuring IR) [
30]. Therefore, we cannot ignore the pathophysiological changes in lean patients.
PCOS patients are also at increased risk of suffering from other metabolic dysfunctions. The metabolic syndrome defined by the National Cholesterol Education Program Third Consensus Report (NCEPATP III) includes central obesity, hypertension, dyslipidemia, and hyperglycaemia. Apridonidze
et al. documented that the prevalence of metabolic syndrome in PCOS was 43%, which was two-fold higher than that identified among age-matched general population in their study [
31]. Several other studies also demonstrated the same results and reminded us to notice the increased risk of diabetes mellitus, hypertension, and cardiovascular disease, the largest threats to the long-term health consequences of women with PCOS [
32].
Dyslipidemia, a well-known risk factor for cardiovascular disease, is prevalent in PCOS patients. Levels of high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglyceride are recognized as predictors of cardiovascular mortality. It was demonstrated that PCOS patients had higher LDL-cholesterol and lower HDL [
18]. Rocha
et al. found that the cholesteryl ester fractional clearance rate was reduced in both obese and nonobese PCOS groups as compared with the controls, meaning the risk of cardiovascular events was increased among PCOS independent of BMI [
33]. In the study of Soare
et al., the decreased HDL-C level was also mentioned as the most prevalent individual component among the measurements of metabolic syndrome in Brazilian patients with PCOS [
34]. Although the reason of dyslipidemia among PCOS patients remains unknown, it is evident that women with obesity and/or IR exhibit more pronounced dyslipidemia. More attention should be paid to this group of patients.
PCOS has been found to be an independent risk factor for the development of diabetes, dyslipidemia, obesity, and hypertension [
35]. Also, the patients with obesity, lipid dysfunction, cigarette smoking, hypertension, impaired glucose tolerance, and subclinical vascular disease are at risk for cardiovascular diseases. Those with metabolic syndrome and/or type 2 diabetes mellitus are at even higher risk. Lifestyle management is the fundamental and primary prevention for this population.
Endometrial carcinoma is another threat to PCOS patients. Chronic anovulation bringing about unopposed estrogen exposure to endometrium is noted as the main cause. In addition, diabetes is also well recognized as a risk factor, which may be due to obesity and insulin excess, because the concentrations of plasma insulin are increased in patients with endometrial cancer.
In conclusion, PCOS has adverse impacts on female endocrine, reproduction, and metabolism. It will lead to anovulation, infertility, endocrine and metabolic dysfunctions and further contribute to pregnancy complications including miscarriage, preterm labor, GDM, and PIH. Therefore, we should not only focus on the complaints of PCOS patients but also pay more attention to their long-term health consequences, especially for the ones with obesity and/or IR. To prevent against the adverse consequences, early effective interventions are crucial for PCOS patients.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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