Epidemiology of polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is the most common gynecologic endocrine disorder with variable clinical manifestations, usually including sporadic ovulation or anovulation, hyperandrogenemia (clinical or biochemical), and ovarian polycystic lesions, often accompanied by metabolic disorders.PCOS patients account for 5-12% of women of reproductive age. The epidemiological survey of the Han population in southern Guangdong showed that the prevalence of PCOS was 6.7% in women of childbearing age and 3.86% in adolescence; the prevalence of PCOS in women of childbearing age in Jinan and Yantai was 6.46% and 7.2%, respectively. 30-60% of patients with anovulatory infertility have PCOS, and the rate has even been reported to be as high as 75%.
Three consensus symposia on PCOS have been held, sponsored by the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine (ESHRE/ASRM). The first, held in Rotterdam, the Netherlands, in 2003, focused on diagnostic criteria for PCOS; the second, held in Thessaloniki, Greece, in 2007, focused on infertility treatment in patients with PCOS; and the third, held in Amsterdam, the Netherlands, in October 2010, clarified the differences in perceptions of various female health aspects of PCOS, emphasizing multiple aspects of health care during and after reproduction Multifaceted health issues, including pubertal problems, hirsutism and acne, contraception, menstrual cycle abnormalities, quality of life and sexual health issues, ethnicity, pregnancy complications, long-term (metabolic) cardiovascular health, and cancer risk.
Pathogenesis of Polycystic Ovary Syndrome
Genetic factors PCOS is currently considered to be a genetic and environmental disorder with an unclear etiology and a variable phenotype. A number of genome-wide association studies targeting PCOS alone are underway in the United States, Europe and Asia, and some interesting or puzzling new candidate genes have been identified. Genome-wide association analysis of a large multicenter sample of PCOS and control women led by our Professor T.J. Chen showed that PCOS may be associated with genes related to insulin signaling pathway, sex hormone function and type 2 diabetes, in addition to genes related to calcium signaling pathway and endocytosis, which provides a new vision and direction to discover the biological mechanisms of PCOS.
Mechanisms of hyperandrogenemia Approximately 25% of androstenedione and testosterone originate from the ovaries, 25% from the adrenal glands, and 50% from peripheral tissues. Many of the factors associated with PCOS are also associated with increased sympathetic activity. The increased density of catecholamine nerve fibers in polycystic ovaries supports the involvement of the sympathetic nervous system in PCOS patients in shaping their pathology, and increased sympathetic activity in the ovaries may contribute to the development of PCOS by stimulating androgen production.
Nerve growth factor (NGF) is a clear marker of sympathetic activity, and recent studies have shown that ovarian NGF is significantly elevated in PCOS patients. In a transgenic mouse model, NGF was overexpressed in the ovaries, and their plasma levels of luteinizing hormone were consistently elevated as a necessary condition for the appearance of typical morphological abnormalities, i.e., experimental data suggest that ovarian NGF overproduction is a cause of morphological changes in polycystic ovaries. Furthermore, a randomized controlled clinical trial showed that low frequency electrical stimulation and exercise, both of which have been shown to modulate sympathetic nerve activity, reduced circulating high levels of sex hormone precursors, estradiol, androgens and androgen-binding globulin metabolism, improved menstrual regularity and broke the vicious cycle of androgen excess in PCOS patients. Moreover, in a subset of patients, low-frequency electrical stimulation and exercise were shown to reduce the already increased sympathetic nerve activity. This finding may at least partially explain the benefit of low-frequency electrical stimulation and exercise in women with PCOS, and may also raise the hypothesis that ovarian wedging or laparoscopic ovarian perforation therapy in PCOS patients may improve ovarian function and decrease androgen synthesis by temporarily disrupting ovarian sympathetic innervation.
Mechanisms of follicular atresia Studies have found that androgens may promote follicular atresia and arrest development, leading to anovulation and the development of polycystic ovaries; in turn, premature acquisition of LH receptors due to insulin may cause premature luteinization of follicles. Studies have found that anti-mullerian hormone (AMH) levels are elevated in patients with PCOS and are more pronounced in anovulatory PCOS patients than in ovulatory PCOS patients, and recent data show that those with decreased AMH levels respond best to ovulation induction. These studies suggest that excessive AMH may have a role in inhibiting follicular development. Kit ligand (KL) is an intra-ovarian cytokine that has been shown to promote follicular development in animal models in a number of ways, including abnormal oocyte development, increased follicularity and mesenchymal density, follicular membrane thickening, and increased androgen synthesis in endometrial cells in polycystic ovaries (PCO), biological processes that are more likely to be disrupted in PCOS patients with hyperandrogenemia, especially in anovulation. Therefore, KL may play an important role in the formation of polycystic ovaries. Androgen regulation of KL has been reported, but the role of the KL signaling pathway, its regulation in the human ovary, and its relevance to PCOS are not known.
Influence of gonadotropins, determinants of ovarian morphology There is a loss of selection process from increased follicular pool to dominant follicles in PCO, which may be associated with increased steroid hormone synthesis, androgen excess, hyperinsulinemia and growth differentiation factor 9 (GDF9) deficiency, but follicle-stimulating hormone (FSH) nonavailability may be critical. After laparoscopic ovarian perforation, patients who respond experience a rapid increase in FSH level reactivity. Thus, the 2- to 5-mm-sized follicular pool appears to have an independent but important role in promoting follicular atresia. In patients with PCOS, possible factors influencing FSH nonresponsiveness include transforming growth factor alpha, epidermal growth factor, follicle inhibitors, and especially high levels of AMH in PCOS. in PCO granulosa cells, overexpression of LH receptors can lead to terminal differentiation and premature atresia of growing follicles, and deficiency of circulating progesterone leads to high LH levels, thus exacerbating androgen excess, small follicular multiplication and the consequences thereof. Thus, proper gonadotropin activity in the ovary has a role in restoring follicular development and ovulation in women and in PCOS patients, and inappropriate gonadotropin secretion in PCOS patients is a major determinant of the altered ovarian morphology, although this claim is still controversial.
Developmental origin theory Models of fetal testosterone excess in PCOS show that adult female or male rhesus monkeys can have metabolic defects. Treatment of female monkeys with testosterone leads to mild to moderate glucose tolerance abnormalities, i.e., intrauterine exposure to excess androgens may lead to metabolic disturbances after birth, which could be used to explain the metabolic defects that occur in adult offspring of both females and males exposed to excess intrauterine androgens. Female offspring exposed to excessive intrauterine testosterone also show fetal head circumference growth and slight postnatal weight gain, as well as some fetal hyperglycemia and postnatal hyperinsulinism. In female neonates exposed to excess androgens, hyperinsulinemia may act synergistically with hyperandrogenemia in increasing adipose synthesis and muscle protein synthesis, resulting in an increase in their insulin-sensitive tissue mass and thus participating in the mechanisms of their adulthood fat accumulation and insulin resistance. The finding of insulin resistance in prepubertal girls whose mothers had PCOS or metabolic abnormalities during pregnancy also provides evidence for an important developmental theory of the PCOS phenotype.
The hyperpuberty theory Some scholars have compared the relationship between the pathophysiology of PCOS and the physiological changes of puberty and found that there are many similarities and overlaps between the two. Therefore, it is believed that PCOS may be a continuation and expansion of puberty, which develops due to abnormal initiation and hyperdevelopment during puberty, called the phenomenon of hyperdevelopment during puberty. More studies have suggested that metabolic abnormalities may originate in the peri-pubertal period, and several studies in recent years have shown that in some populations, early onset of adrenocortical function is associated with insulin resistance and can lead to an increased risk of high ovarian androgens after the first menstrual period, an association that is particularly pronounced in girls born prematurely. Elevated gonadotropin levels, increased growth hormone (GH), insulin-like growth factor 1 (IGF-1), and insulin activity during the second period of ovarian growth, near menarche and during puberty, all act on the ovaries. It has been suggested that some girls with PCOS may originate from altered PCO due to high insulin and IGF-I during puberty, a condition that persists into puberty and then develops into PCOS.
Abnormal adipokine secretion Some studies have shown that adipose tissue is not only a passive energy store, but also has an endocrine role in regulating the body’s endocrine and energy metabolism and inflammation. It has become a hot topic to study the relationship between adipokine abnormalities and obesity, insulin resistance (IR), metabolic syndrome (MBS) and PCOS. Adipocytes secrete a variety of cytokines that are involved in the formation and development of insulin resistance, and insulin resistance is significantly associated with obesity in PCOS, and the vicious circle of adipocytokines and insulin resistance promoting each other may be one of the main mechanisms for the development of PCOS. The interaction between the immune system and germ cells is complex, and various secreted factors are regulated by other hormones and cytokines while interacting with each other to form a complex regulatory network. An in-depth study of adipokines may provide new perspectives on the development of visceral obesity and systemic hypo-inflammatory response, IR, PCOS and diabetes, cardiovascular diseases, and may understand these endocrine disorders as a unified whole with continuous changes.
Diagnosis of PCOS
The diagnostic criteria for PCOS developed by the National Institutes of Health (NIH) in 1990 include
1. abnormal menstruation and anovulation.
2. clinical or biochemical demonstration of hyperandrogenemia.
3, except for other diseases causing hyperandrogenemia, congenital adrenocortical hyperplasia, Cushing’s syndrome, hyperprolactinemia, severe insulin resistance syndrome, tumors, and abnormal thyroid function.
The criteria recommended by the 2003 ESHRE and ASRM Rotterdam expert meeting (and the current global diagnostic criteria for PCOS) consider that PCOS can be diagnosed by meeting two of the following three criteria.
1. sporadic ovulation or anovulation
2. clinical manifestations of hyperandrogenism and/or hyperandrogenemia.
3. ultrasound demonstration of polycystic ovaries [12 or more follicles of 2-9 mm diameter in one or both ovaries and/or ovarian volume greater than 10 ml]; and polycystic changes in the ovaries as the main symptom for diagnosis.
In 2006, the Androgen Excess Society (AES) suggested that the diagnosis of PCOS should be based on hyperandrogenemia as the primary condition, and that PCOS can be diagnosed in the presence of clinical or hyperandrogenemia with sporadic ovulation or anovulation, or with polycystic ovarian manifestations on ultrasound. The diagnosis of PCOS is an exclusive diagnosis, and other diseases related to androgen excess must be excluded.
In June 2011, the Endocrinology Group of the Obstetrics and Gynecology Branch of the Chinese Medical Association also developed diagnostic and treatment criteria for PCOS suitable for Chinese people, and the Ministry of Health issued diagnostic criteria first, considering that patients with symptoms of menorrhagia or amenorrhea or irregular uterine bleeding can be diagnosed as suspected PCOS. Excluded diseases include late-onset congenital adrenocortical hyperplasia, Cushing’s syndrome, androgen-secreting tumors of the ovaries or adrenal glands, thyroid abnormalities, and hyperprolactinemia.
Treatment of polycystic ovary syndrome
The goal of treatment for patients with fertility requirements is to promote ovulation and normal pregnancy in anovulatory patients.
Patients with PCOS often have hyperandrogenemia and hyperinsulinemia. It has been reported in the literature that in the presence of hyperandrogenemia and insulin resistance, the use of ethinylestradiol cyproterone and metformin to correct the endocrine disorder can improve the ovulation effect of ovulation-promoting drugs. However, the application process must be decided individually according to the patient’s specific situation.
Lifestyle modification Obese patients should control or reduce their weight through low-calorie diet and energy-consuming exercise.
Treatment of hyperandrogenemia The first choice is oral short-acting contraceptive treatment, in which ethinyl estradiol can increase sex hormone binding globulin (SHBG) and reduce free testosterone levels; the progestin component inhibits cytochrome P45017α-hydroxylase (P450c17)/17,20 lyase activity, reducing androgen synthesis, and can compete with androgens for binding receptors in target organs, blocking androgen peripheral effects. Inhibits hyperandrogen production in follicular membrane cells by inhibiting hypothalamic-pituitary LH secretion.
Treatment of insulin resistance (metformin) Indicated for patients who are obese or have insulin resistance to enhance glucose uptake by peripheral tissues, inhibit hepatic glucose production, enhance insulin sensitivity, reduce postprandial insulin secretion, and improve insulin resistance to increase sensitivity to CC.
Ovulation promotion therapy Ovulation promotion therapy is used to achieve pregnancy. Commonly used drugs include clomiphene (first-line treatment), gonadotropins [e.g. human menopausal gonadotropin (HMG), high purity FSH (HP-FSH) and recombinant FSH (r-FSH)] (second-line treatment), as well as laparoscopic perforation of polycystic ovaries and in vitro fertilization-embryo transfer (IVF-ET) treatment .
The goals of treatment for patients without fertility requirements include both immediate and long-term goals, with the immediate goal of menstrual cycle adjustment, treatment of hirsutism and acne, and weight control, and the long-term goal of preventing diabetes, endometrial cancer, and cardiovascular disease.
Treatment measures also include lifestyle modification and oral contraceptive treatment to correct hyperandrogenemia, improve the clinical manifestations of hyperandrogenism, effective contraception, establish regular menstruation, and prevent the development of endometrial cancer. For anovulatory patients without significant hyperandrogenic clinical and laboratory manifestations and without significant insulin resistance, regular progestin therapy alone can be used to restore menstruation. In patients with concomitant metabolic abnormalities, concomitant symptomatic treatment (e.g., improvement of insulin resistance and lipid-lowering therapy) is required.
Although there is a broad consensus that PCOS is a female endocrine disorder with metabolic disorders, long-term medication is required. Since androgen levels in women decrease with age and the symptoms of hyperandrogenism in women with PCOS may apparently improve, it is thought that PCOS can be cured or that the infertility problem can be resolved without further treatment. In fact, the metabolic abnormalities of PCOS may worsen with age and may be more prominent in women with perimenopause with clinical manifestations of geriatric disease and concurrent hormone-dependent tumors, so PCOS deserves long-term attention and intervention.
Relationship between polycystic ovary syndrome and other diseases
PCOS and reproductive health
The clinical manifestations of PCOS can be summarized in 3 aspects.
1. endocrine abnormalities, including menstrual disorders, scanty or amenorrhea, anovulation, recurrent miscarriages, hirsutism, acne and baldness.
2. metabolic abnormalities, including insulin resistance, impaired glucose tolerance (IGT) or type 2 diabetes, overweight or obesity, dyslipidemia and increased risk of cardiovascular disease.
3. biochemical abnormalities, including increased levels of plasma androgens, luteinizing hormone (LH), estrogen and prolactin (PRL).
Patients with PCOS have abnormalities in female reproductive health mainly in the form of sporadic ovulation, irregular menstruation, infertility, recurrent miscarriage and gestational diabetes. In recent years, health education, insulin sensitizers and various ovulation promotion measures have shown good results in promoting the restoration of menstruation, ovulation and conception. Meanwhile, with the rapid development of assisted reproductive technology, more and more PCOS patients have successfully conceived through ovulation promotion and in vitro fertilization embryo transfer, but due to the special pathophysiological characteristics of PCOS patients, pregnancy may still be complicated by miscarriage, preterm delivery, gestational diabetes mellitus (GDM), gestational hypertension and other complications.
Studies have shown that the incidence of early spontaneous abortion in PCOS patients ranges from 20% to 41%, which is significantly higher than that in the general population, and the increased rate of spontaneous abortion in PCOS patients may be related to hyperandrogenemia, insulin resistance, high levels of LH in the follicular phase, and decreased endometrial tolerance, but the exact mechanism is not well understood. Although studies have shown that the application of metformin in early pregnancy significantly reduces the rate of spontaneous abortion, and metformin treatment before pregnancy and early pregnancy does not increase the rate of fetal malformation, so some scholars believe that treatment to improve insulin sensitivity is a key measure to prevent pregnancy loss in patients with PCOS, but metformin can pass through the placenta, and the potential effect of this drug on offspring growth and development remains to be confirmed in large samples and long-term clinical randomized controlled studies are still pending.
The idea that PCOS is a high-risk factor for gestational diabetes is widely accepted. Insulin resistance is a common feature of patients with PCOS and gestational diabetes mellitus. About 50%-70% of PCOS patients have insulin resistance, and anti-insulin-like substances increase in women in mid- to late-pregnancy, while placental lactogen, estrogen, progesterone, placental insulinase and cortisol all have insulin antagonistic functions, and the superposition of the two effects can lead to islet β-cell failure and the development of GDM. GDM can cause maternal and child complications such as hyperhydramnios, preterm delivery, macrosomia, and neonatal pulmonary hyaline membrane disease. Prevention of GDM and reduction of the risk to mother and child are of great significance not only for improving pregnancy outcome, but also for protecting maternal β-cell function, delaying the onset of diabetes, and reducing metabolic diseases of fetal origin in offspring, but the details of when to start screening and diagnosis and how to perform maternal and child monitoring and management remain to be determined by further research.
Preterm delivery is a common pregnancy complication in patients with PCOS, and the incidence of late miscarriage and preterm delivery are significantly higher in patients with PCOS, which may be related to ovulation promotion leading to multiple pregnancies in PCOS patients, resulting in an excessive increase in uterine tone.
It has been suggested that insulin resistance is one of the pathogenic mechanisms of hypertensive disorders in pregnancy. Patients with PCOS, especially those with combined insulin resistance, have an increased incidence of hypertensive disorders in pregnancy. However, information on the correlation between PCOS and hypertension in pregnancy is still very limited, and how to carry out preventive treatment needs to be explored and studied in depth.
In conclusion, pregnancy can exacerbate the endocrine and metabolic complexity of PCOS patients due to various factors, which can lead to poor pregnancy outcomes in PCOS patients. To fully study the metabolic characteristics of PCOS patients after pregnancy and the relationship with various pregnancy complications, and to take early targeted preventive measures to improve pregnancy outcomes is a major project to benefit PCOS patients and their offspring, and is of great significance to protect maternal and infant health.
PCOS and insulin resistance, metabolic syndrome and type 2 diabetes
About 50% of patients with PCOS are overweight or obese, and most of them are centrally obese. Insulin resistance is present in most of the obese population and is most prevalent and severe in women with PCOS, especially in patients with classic NIH PCOS with hyperandrogenemia and prolonged menopause. Regular cyclic assessment of women with PCOS using the Rotterdam criteria revealed that patients tend to have progressive metabolic abnormalities. Insulin resistance is a prominent feature of PCOS, and epidemiological data show a strong association with low glucose tolerance, GDM and T2D.
Biochemical screening in the form of an oral glucose tolerance test (OGTT) is required in patients with PCOS who are obese and have excess visceral fat (as measured by waist circumference). The risk of IGT or diabetes mellitus is highest in patients with PCOS with sporadic ovulation or anovulation and hyperandrogenemia, and obesity further increases these risks. Indications for glucose tolerance screening include hyperandrogenemia with cessation of ovulation, acanthosis nigricans, obesity (BMI >30 kg/m2 or >25 kg/m2 in Asian populations), and a family history of T2DM or GDM in women.
The molecular cytological mechanisms of insulin resistance phenomenon in PCOS patients are different from those in obese and T2D patients. In patients with PCOS, insulin action on skeletal muscle cells is extremely low due to defective signaling, while insulin resistance in hepatocytes is only seen in obese women with PCOS, so obesity and PCOS play a synergistic negative role on the insulin metabolic activity of the patient’s organism. In addition, β-cell dysfunction is also present in the pancreas of patients with PCOS, but this disorder is more likely to be associated with T2DM, as the most severe β-cell dysfunction is found in some women with first-degree relatives with T2DM. There is substantial evidence that hyperinsulinemia has a direct effect on reduced fertility in patients with PCOS, and the incidence of metabolic syndrome is significantly higher in women with typical NIH PCOS than in normal women of the same age and weight class.
For female patients at risk of developing T2D, first-line treatment should include dietary management and lifestyle improvement, while for patients who present with IGT but do not perform well on first-line treatments such as dietary control and lifestyle changes, metformin therapy may be used; for patients with mild diabetes, metformin is considered a safe and effective therapeutic agent, and for women of childbearing age, thiazolidinediones and glucagon-like Peptide-1 drugs for treatment, there are still some clinical concerns.
PCOS and cardiovascular disease
Patients with PCOS have metabolic disturbances that increase their risk of cardiovascular disease (CVD) with age. In addition, altered cardiovascular function may not occur with obesity, but can be amplified by obesity. Currently, an increasing number of non-obese PCOS patients exhibit centripetal obesity, and the severity of insulin resistance is associated with abdominal obesity, even in some women with normal body mass index (BMI), and this correlation is likely to be responsible for the abnormal traditional markers associated with CVD risk. the risk of CVD in PCOS patients is approximately 3 times higher than in non-PCOS patients, and in BMI-matched studies have found that the risk of CVD in PCOS patients is about twice that of non-PCOS patients. Furthermore, this increased risk of CVD showed different epidemiological characteristics in different regions. In a study of obese and non-obese women with PCOS, it was found that the more severe the clinical presentation of PCOS patients, the greater the risk of developing CVD.
PCOS patients had significantly higher concentrations of triglycerides, low-density lipoprotein (LDL), and non-high-density lipoprotein (HDL) cholesterol than non-PCOS patients, reflecting the higher apolipoprotein B (ApoB)/ApoA ratio that can lead to atherosclerosis in PCOS patients as well. Furthermore, this difference between PCOS patients and non-PCOS patients was more pronounced when diagnosed using the NIH criteria compared to diagnosis using the Rotterdam diagnostic criteria. Assessment of a patient’s waist circumference and non-HDL cholesterol is arguably the most useful means of diagnosing metabolic dysfunction in the clinical setting today.
Systemic inflammation associated with vascular endothelial tissue dysfunction and metabolic disorders is commonly seen in patients with PCOS. In patients with PCOS, many biochemical inflammatory and thrombogenic factors are overexpressed in the circulating blood stream, and some of these factors can also be found in association with insulin resistance. However, it is not clear whether the use of these inflammatory and thrombogenic factor levels to assess a patient’s risk of concurrent CVD provides more useful information for individual CVD assessment than traditional CVD risk factors. The specific age at which dyslipidemia treatment measures are initiated remains controversial, as these treatments and medications can lead to a slightly elevated risk of some serious side effects, such as statins, which can lead to rhabdomyolysis, symptoms that are not seen in younger women with PCOS. In addition, there are currently clinical concerns about the reproductive implications of these drug treatments, including concerns that they may lead to an increased risk of unintended ovulation and potential fetal abortion. Many lipid therapy drugs have been clearly shown to have teratogenic effects because they interfere with cholesterol synthesis and metabolism, and LDL cholesterol is a precursor to placental synthesis of sex hormones.
PCOS patients with insulin resistance are more likely to have vascular dysfunction, so these patients may have more subclinical vascular disease than normal women. It has been shown that carotid intima-media thickening, coronary artery calcification and to a lesser extent aortic calcification are more prominent in patients with PCOS (according to NIH criteria), but this severity is independent of age and BMI. However, the evidence of increased CVD prevalence and mortality in PCOS patients obtained from studies based on Rotterdam and/or NIH criteria alone does not allow conclusions to be drawn.
Numerous clinical studies have also found that patients with PCOS have a higher prevalence of classical and non-classical CVD causative factors, associated with insulin resistance, excess adiposity and low inflammation, in addition to PCOS status itself. However, the comprehensive analysis of risk factors in the reports published so far has not been able to demonstrate a uniform association between PCOS and CVD, with possible reasons including inaccurate description of PCOS symptoms, inappropriate diagnosis of CVD, insufficient observation time or indeed no association between the two.
A recent US study showed that a higher proportion of patients with PCOS were found to have coronary angiographic manifestations and CVD symptoms in an accurately matched population of postmenopausal women. This study confirms that PCOS may increase the angiographic manifestations of coronary heart disease and reduce survival to CVD; and that accurate diagnosis of postmenopausal women with clinical manifestations of PCOS may facilitate interventions for risk factors to prevent coronary artery disease (CAD) and CVD. However, this remains to be done in more targeted studies or longitudinal prospective studies.