Polycystic ovary syndrome (PCOS) is a complex and heterogeneous group of diseases whose etiology is still unknown.
I. Diagnostic criteria
Since 1990, three different diagnostic criteria have been developed internationally, including the diagnostic consensus developed by the National Institutes of Health (NIH) in Maryland in 1990, the diagnostic criteria developed by the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) in Amsterdam in 2003, and the diagnostic criteria developed by the Androgen Excess Society (AES) in 2006. (AES) in 2006.
Among these 3 diagnostic criteria, clinical and/or biochemical manifestations of hyperandrogenism are an accepted indicator. Since PCOS is a diagnosis of exclusion, it is also necessary to exclude thyroid disease, hyperprolactinemia, atypical congenital adrenocortical hyperplasia (CAH), androgen-secreting tumors, Cushing’s syndrome, hypothalamic amenorrhea, primary ovarian insufficiency, and other conditions that can lead to similar clinical manifestations.
Unlike the above criteria, in our current diagnostic criteria for PCOS, scanty menstruation or amenorrhea or irregular uterine bleeding are required for the diagnosis. In addition, PCOS can be diagnosed after meeting one of the following 2 criteria and excluding other diseases that may cause hyperandrogenism and diseases that cause abnormal ovulation: (1) clinical manifestations of hyperandrogenism or hyperandrogenemia; (2) ultrasound manifestations of polycystic ovaries.
This guideline follows the Rotterdam diagnostic criteria of 2003, i.e., PCOS is diagnosed when two of the following three criteria are met and similar clinical manifestations due to other diseases are excluded: (1) clinical and/or biochemical manifestations of hyperandrogenism, such as hirsutism, acne, androgenetic alopecia, elevated serum total or free testosterone; (2) sporadic ovulation or anovulation; (3) polycystic ovarian changes, i.e., unilateral (3) polycystic ovarian changes, i.e. unilateral ovarian enlargement of more than 10 ml (excluding cysts and dominant follicles) or more than 12 follicles of 2-9 mm in diameter in one ovary.
Serum androgen measurements may not be necessary for the diagnosis of hyperandrogenism if the patient has clinical signs of hyperandrogenism in combination with female masculinization. Similarly, if the patient has both signs of hyperandrogenism and ovulatory disturbances, then ovarian ultrasound findings may not be required for the diagnosis. For differential diagnosis, this guideline recommends screening for TSH, prolactin, and 17-hydroxyprogesterone in all patients to exclude some common conditions that may cause similar clinical presentations.
PCOS is more prevalent in women of childbearing age, but the guidelines specifically suggest a different diagnostic focus for non-childbearing women, such as adolescents, perimenopausal and postmenopausal women. In adolescent women, the diagnosis should be based on clinical and/or biochemical hyperandrogenic manifestations and persistent sporadic menstruation, with the exception of other causes of hyperandrogenic manifestations.
Adolescent acne can be transient and therefore cannot be used alone as a diagnostic basis for hyperandrogenic clinical manifestations. Adolescent hirsutism is slower and less severe than in adults, but can be a stronger indicator of hyperandrogenemia than acne. Androgenetic alopecia cannot be used as a clinical basis for hyperandrogenemia in adolescence at this time.
In the Rotterdam criteria, ovarian morphologic changes are based on transvaginal ultrasound and transabdominal ultrasound does not accurately reflect ovarian morphologic changes, but the former has ethical issues in its implementation in adolescent females, and because anovulation and ovarian polycystic changes can be natural stages of sexual maturation, the guidelines recommend against using ovarian polycystic changes as a basis for the diagnosis of adolescent PCOS.
In perimenopausal and postmenopausal women, new onset PCOS is unlikely, but persistent sporadic menstruation and hyperandrogenism since the onset of reproductive age can be used as a diagnostic basis. It has been reported that the decrease in androgen levels can shorten the menstrual interval in PCOS patients and improve the manifestation of sporadic menstruation, thus relieving most clinical symptoms. Therefore, in perimenopausal women, polycystic ovarian changes are more supportive of this diagnosis.
Awareness of related clinical issues
1. Skin lesions
Hypertrichosis, acne and androgenetic alopecia are typical skin manifestations of hyperandrogenemia, and acanthosis nigricans is also seen in PCOS patients with combined obesity. Due to ethnic and geographic differences, the prevalence of hirsutism ranges from 5% to 15% in the general population, but is as high as 65% to 75% in patients with PCOS and is more prominent in patients with comorbid abdominal obesity.
However, its presence does not predict ovulatory disturbances and, as in previous guidelines, this guideline still recommends the use of the Ferriman-Gallwey score to assess the degree of hirsutism. Acne is more common in adolescent patients, with a prevalence of 14% to 25%, and androgenetic alopecia is seen less frequently and later, and has been shown to be associated with metabolic syndrome and insulin resistance. Guidelines call for a thorough evaluation of skin lesions in patients with PCOS, but because of the subjective nature of the evaluation, dermatologists should be consulted for acne and alopecia that do not respond to hormonal contraceptive therapy.
2. Infertility
In a large sample of women with PCOS, half of the women had primary infertility and another quarter had secondary infertility, making infertility a prominent clinical problem in patients with PCOS. However, this does not mean that PCOS patients cannot ovulate spontaneously; in a randomized controlled study, 32% of PCOS patients were able to ovulate spontaneously. A Swedish study also showed that three quarters of patients with PCOS eventually conceived spontaneously.
Therefore, this guideline recommends checking ovulation in PCOS patients who are interested in becoming pregnant. For some patients with PCOS who have normal menstrual cycles, they may also face ovulation disorders. The guideline recommends additional mid-luteal progesterone testing to clarify ovulation and to screen for other causes of infertility other than abnormal ovulation.
3. Obstetric complications
PCOS patients, especially those with combined obesity, are at risk for many obstetric complications, including gestational diabetes mellitus (GDM), preterm labor, and pre-eclampsia. Obesity has been clearly demonstrated to increase the risk of GDM, and early miscarriage is considered to be an adverse pregnancy outcome associated with PCOS. However, to minimize the risk of pregnancy, the guidelines strongly recommend screening for body mass index, blood pressure and oral glucose tolerance tests in this population to better guide pregnancy care.
4. Offspring status
Studies in animal models suggest that embryos exposed to a high androgenic environment increase the risk of PCOS in adulthood. Serum testosterone levels are elevated during human gestation, but there are limited studies on the increased incidence of PCOS in the offspring, and the results are not consistent. The current popular study on “adult diseases of embryonic origin” shows that female infants with low birth weight have increased incidence of early adrenal gland development, insulin resistance and PCOS later in life, and that a surge in birth weight may also promote the occurrence of metabolic abnormalities and PCOS, so it is important to pay attention to their adolescent development and be alert to the occurrence of metabolic disorders in such newborns.
5. Endometrial cancer
PCOS patients may have multiple risk factors for endometrial cancer, such as obesity, hyperinsulinemia, diabetes mellitus and abnormal uterine bleeding, and their risk of endometrial cancer is three times higher than that of normal women. The majority of young endometrial cancer patients are nulliparous or infertile and have a high rate of hirsutism and sporadic menstruation. However, there is no evidence that PCOS is an independent risk factor for endometrial cancer, and the American Cancer Society does not recommend routine screening for endometrial cancer in patients with PCOS, except for Lynch syndrome, and prompt consultation for unintended spotting vaginal bleeding.
6. Obesity, type 2 diabetes and cardiovascular disease
The incidence of obesity reported by different countries varies greatly, ranging from 30% to 70%. Since obesity, especially abdominal obesity, is associated with hyperandrogenemia, it can also increase the risk of metabolic abnormalities. The incidence of nonalcoholic fatty liver disease (NAFLD) due to abnormal lipid accumulation is increased in obese patients with PCOS, but guidelines do not recommend routine screening for NAFLD in patients with normal liver function.
Menstrual disturbances and sporadic ovulation are more common in obese patients than in normal weight PCOS patients, and are less effective with ovulatory medications; the guidelines strongly recommend measurement of BMI, body fat content, and waist circumference in PCOS patients.
Since PCOS patients are 5-10 times more likely to develop type 2 diabetes than the normal population, the overall prevalence of impaired glucose tolerance (IGT) in PCOS patients in the United States is 30%-35%, and the prevalence of type 2 diabetes is 3%-10%, and glycated hemoglobin is less sensitive in screening for glucose metabolism disorders in this population, the guidelines strongly recommend the use of the oral glucose tolerance test (OGTT) The guidelines strongly recommend the use of the oral glucose tolerance test (OGTT) as a valid indicator for screening IGT and type 2 diabetes.
The guidelines consider the following cardiovascular risk factors for patients with PCOS: obesity (especially abdominal obesity), smoking, hypertension, hyperlipidemia (especially elevated LDL cholesterol), subclinical vascular disease, IGT, and familial early onset (before age 55 for men and 65 for women) cardiovascular disease.
Patients are considered at high risk for cardiovascular disease if any of the following 4 conditions are present: metabolic syndrome, type 2 diabetes, clinical vascular disease, renal or cardiovascular disease, and obstructive sleep apnea syndrome (OSA). Guidelines recommend screening for the presence of risk factors for cardiovascular disease in patients with PCOS to allow for timely intervention.
7. Depression
Several observational studies and questionnaires have shown that patients with PCOS have an increased incidence of depression and are 7 times more likely to be suicidal than the normal population. The guidelines recommend that patients with PCOS be given a detailed history to detect depression or anxiety in a timely manner, and that they be referred and treated accordingly once the diagnosis is confirmed.
8. Obstructive sleep apnea syndrome (OSA)
The combined effect of high androgens and obesity, the incidence of OSA in PCOS patients is not lower than that of men, and even higher than that of men. Studies have confirmed that even after correcting for the effects of BMI, the incidence of sleep disordered breathing and daytime sleepiness in PCOS patients is 30 times and 9 times higher than in the normal population. The guidelines recommend that patients with OSA diagnosed by polysomnography should receive prompt treatment.
Treatment strategies
Due to the clinical diversity of PCOS, it is easy to combine the following conditions: obesity, infertility, preterm birth, pre-eclampsia, endometrial cancer, depression, obstructive sleep apnea syndrome, non-alcoholic fatty liver disease, abnormal glucose tolerance, gestational diabetes, type 2 diabetes, and cardiovascular disease. Therefore, it is important to screen for the combination of these diseases and adjust the treatment plan accordingly.
1. Hormonal contraceptives (HCs)
As in previous guidelines, this guideline recommends HCs as the first choice for PCOS patients with menstrual disorders and acne vulgaris, using progestin to suppress LH levels and ovarian secretion of androgens, and estrogen to increase sex hormone-binding globulin levels, thereby reducing free testosterone levels.
There are no clear criteria for the duration of HCs, but spironolactone therapy is an option for hirsutism that does not improve with HCs.
HCs have been shown to improve insulin sensitivity but do not yet affect glucose metabolic status. HCs do not increase the risk of developing type 2 diabetes nor do they increase body weight in women with normal glucose tolerance or a history of HCsGDM. In terms of lipid metabolism, HCs with high estrogen content can increase HDL cholesterol levels while decreasing LDL cholesterol.
For the treatment of adolescent PCOS, this guideline recommends HCs as the first choice for girls who have not yet had their first menstrual period, but who have clinical or biochemical hyperandrogenemia and significant secondary sex characteristics development (e.g., mammary gland development at or above the Tanner IV level).
2. Lifestyle modification
For overweight and obese patients with PCOS, the guidelines recommend lifestyle modifications, including dietary control and increased exercise, to reduce weight and thereby reduce the risk of cardiovascular disease and diabetes. If necessary, pharmacological or surgical weight loss options are available to reduce hyperandrogenemia and normalize the menstrual cycle, but there is no evidence that weight loss is associated with improved conception rates and pregnancy outcomes.
3. Metformin
In 2010, ESHRE/ASRM proposed that metformin should only be used in PCOS combined with IGT, but now the understanding of metformin in the treatment of PCOS has been greatly expanded. androgenemia, menstrual cycle and ovulation function.
This guideline positions metformin as an adjunctive agent for the prevention of ovarian hyperstimulation syndrome (OHSS) in patients with PCOS undergoing in vitro fertilization therapy. The addition of metformin is recommended for patients with PCOS who have a combination of IGT or metabolic syndrome and for whom lifestyle modification alone is not effective. If patients are unable to take HCs or are intolerant to them, metformin may be considered as a second-line agent for menstrual cycle adjustment.
4.Other drugs
Commonly used insulin sensitizers include inositol and thiazolidinedione, which are pregnancy class C drugs and are not recommended in this guideline given their insignificant benefits, lack of large randomized controlled studies, and safety concerns (hepatotoxicity, cardiovascular events, and bladder cancer). Lipid-lowering drugs can lower LDL cholesterol levels, reduce precursors for the synthesis of sex hormones, and inhibit follicular membrane cell growth, but clinical studies related to PCOS are lacking.
Statins are not recommended in this guideline for the treatment of hyperandrogenemic and anovulatory PCOS patients, but are recommended for women with PCOS who meet the indications for statin use while being alert to the adverse effects of myopathy and renal impairment. There is a lack of evidence on the benefit of other hypoglycemic agents such as GLP-1 analogs and DPP4 inhibitors for PCOS.