Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, covering almost all of their lives.
I. Clinical features: hyperandrogenism and persistent anovulation?
Epidemiology: It accounts for 5-10% of women of reproductive age and 30-60% of anovulatory infertility, with some reports reaching 75%. The prevalence of PCOS in women of childbearing age in Jinan and Yantai is 6.46% and 7.2%, respectively; there is a lack of national, large sample and multicenter studies in China.
Third, the etiology of PCOS: including genetic factors: candidate gene studies involving insulin action-related genes, hyperandrogenism-related genes and chronic inflammatory factors; environmental factors: geographical, nutritional and lifestyle factors. The exact etiology is unclear and may be the result of the interaction between genetic genes and the environment.?
The clinical manifestations of PCOS: scanty menstruation or amenorrhea, anovulation; hirsutism, seborrhea, acne, hair loss; infertility; male-pattern obesity.
Fifth, PCOS endocrine disorder features: androgen elevation; SHBG level is reduced; estrone is elevated, estradiol is low, E1 to E2 ratio is elevated; insulin resistance and/or gonadotropin separation. Most obese patients have insulin resistance and hyperinsulinemia, some patients have insignificant LH elevation, non-obese patients have predominant LH/ FSH separation; elevated prolactin.?
VI. Long-term effects of PCOS: hyperlipidemia, hypertension, type II diabetes mellitus, myocardial infarction, gestational diabetes mellitus, gestational hypertensive disorders, some malignant lesions, such as endometrial cancer, etc. ?
Seven, the pathology of PCOS?
1, changes in the ovaries: Gross view: ovaries are 2 to 3 times larger than normal. Oyster-colored or gray-white luminescence is enhanced. ?
Ovarian section: multiple cystic follicles of 2-7 mm in diameter or large retained follicular cysts are seen under the peritoneum.?
2. Endometrial changes: mainly manifested as anovulatory endometrium. Follicular dysplasia-proliferative endometrium; follicular persistent estrogen secretion-hyperplastic endometrium; long-term effect-endometrial cancer.
Eight, the pathophysiology of PCOS: PCOS pathophysiological changes are extensive, involving abnormalities in neuroendocrine, sugar, fat, protein metabolism and ovarian local regulatory factors. The causes of these changes are not yet fully understood. The main cause I: H-P-O axis feedback malfunction; the main cause II: ovarian P450c17/17-20 cleavage enzyme hyperactivity.?
IX. Diagnosis of PCOS:?
1, the 2003 Rotterdam Conference revised diagnostic criteria:?
It is emphasized that elevated LH, or elevated LH/FSH ratio is not a diagnostic criterion for PCOS. Gonadotropins vary during each phase of the menstrual cycle and are released into the circulation in a pulsatile manner; therefore, a single measurement of LH/ FSH has little diagnostic sensitivity. It is possible that insulin and IGF/IGFBP play an important role in the hyperandrogenemia of obese PCOS patients with insignificant or no elevation of LH.?
It is emphasized that the diagnosis of PCOS does not necessarily require the presence of PCO, and the presence of PCO alone does not confirm the diagnosis of PCOS.?
2, PCOS diagnostic criteria Chongqing consensus: recommended at this stage to use the 2003 Rotterdam criteria. Sporadic ovulation or anovulation; clinical manifestations of hyperandrogenism and/or hyperandrogenemia; polycystic ovarian changes: ≥12 follicles of 2-9 mm in diameter in one or both ovaries and/or ovarian volume ≥10 ml. 2 of the above 3, and exclude other hyperandrogenic causes: congenital adrenocortical hyperplasia, Cushing’s syndrome, androgen-secreting tumors, etc.?
(1) Sporadic ovulation or anovulation: two years after menarche without regular menstruation; amenorrhea (menopause for more than 3 previous menstrual cycles or menstrual cycle ≥ 6 months); sporadic menstruation (≥ 35 days and ≥ 3 months per year without ovulation). Regular menstruation cannot be used as evidence to determine the presence of ovulation. BBT, ultrasound monitoring of ovulation and progesterone measurement in the second half of menstruation clarify whether ovulation is occurring. normal FSH and E2 levels exclude hypogonadotropic hypogonadism and premature ovarian failure.?
2) Clinical manifestations of hyperandrogenism: ?
Hyperandrogenic acne: Recurrent acne, often located on the forehead, cheeks, nose and jaw?
Hyperandrogenic hirsutism: coarse and stiff hairs on the upper lip, jaw, around the areola, and in the midline of the lower abdomen?
Hyperandrogenemia: Total testosterone, free testosterone: higher than the normal laboratory reference value.
Free testosterone index (FAI) = total testosterone/SHBG concentration × 100 ?
(3) PCO measurement: vaginal ultrasound is more accurate, early follicular phase (in those with regular menstruation) or ultrasound in the absence of dominant follicles. Ovarian volume calculation: 0.5 × length × width × thickness (ml). Follicle number measurement: transverse and longitudinal scans should be included. Follicle diameter <10 mm: average of transverse and longitudinal diameters.?
(3) Exclusion criteria for the diagnosis of PCOS: Exclusion criteria are mandatory for the diagnosis of PCOS. Congenital adrenocortical hyperplasia, Cushing’s syndrome, androgen-secreting tumors, thyroid dysfunction, hypogonadotropic hypogonadism and premature ovarian failure, and hyperprolactinemia need to be excluded.?
3. comorbidities of PCOS: obesity, insulin resistance, metabolic syndrome.?
1) Diagnostic criteria for obesity:?
① Classification of weight according to BMI in Asian adults ?
[BG(!]
[BHDFG1*2,WK10. 2, WK15W] Classification BMI (kg/m?2) Risk of associated diseases*
[BHD] Underweight <18.5 Low (but increased risk of other diseases)
[BHDW] Normal range 18.5-22.9 Average
[BH]Overweight ≥23
[BH]Pre-obese 23-24.9 Increased
[BH]I degree obesity 25-29.9 Moderate increase
[BH]degree II obesity ≥30 Severe increase
[BG)F]
② Diagnostic criteria of central obesity: Waist-to-hip ratio (WHR): the cut point of central obesity was expressed as waist cm / hip cm. Men ≥ 0.9, women ≥ 0.8 (results of a sample survey of more than 40,000 people in urban and rural areas in 11 provinces and cities by the Chinese Academy of Preventive Medicine and others). China Obesity Working Group: Waist circumference indicates the cut point of central obesity. Men ≥ 85cm, women ≥ 80cm.?
2）Insulin resistance?
Concept: a state in which normal doses of insulin produce less than normal biological effects. That is, the physiological function of insulin (such as the ability of insulin to lower blood glucose) is decreasing and cannot play its proper role. That is, a pathophysiological state in which the insulin effector organ or site is insensitive to the physiological effect of insulin. Insensitivity to insulin action is not only limited to the range of glucose metabolism, but also has a tendency to disorders of lipid metabolism and vascular pathology, which affects the reproductive function of female patients of reproductive age. Obesity, especially male-pattern obesity, is the most common risk factor for insulin resistance.?
When insulin resistance occurs, in order to ensure that the blood glucose in the body reaches normal levels, the normal pancreatic beta cells of the body tend to secrete more insulin to compensate for the lack of glucose-lowering capacity per unit amount of insulin, thus ensuring normal blood glucose levels. When IR occurs, the sensitivity of insulin effector organs or sites to the physiological effects of insulin is reduced, and peripheral tissues such as muscle and fat become resistant to insulin’s role in promoting glucose uptake. Elevated blood glucose leads to postprandial hyperglycemia, which stimulates increased insulin secretion to normalize blood glucose, and the body shows hyperinsulinemia but normal blood glucose. Long-term stimulation leads to defective B-cell function resulting in fasting hyperglycemia and hyperinsulinemia, and the number of insulin receptors decreases and the affinity decreases, resulting in increased insulin resistance and inability to lower blood glucose as clinical diabetes.
Measurement of insulin resistance by.
[BG(!]
[BHDFG1*2, WK14ZQ, WK17ZQ, WK10ZQW] Experimental method Measurement significance
[BHDG3] High insulin clamp test M/I (mean glucose utilization/mean blood insulin concentration) The test is complicated and not used as a routine test
[BHDW] Homeostasis model of insulin resistance (HOMA-IR) Fasting insulin (U/ml) × fasting glucose (mmol/L)/22.5 For population-based statistical investigation
[BH] Quantitative insulin sensitivity index (QUICKI) 1/[log fasting insulin (U/ml) + log fasting glucose (mg/dL)] for population-based statistical investigations
[BH] fasting insulin Each hospital uses its own testing equipment and local population as the standard to develop its own normal reference value Related to the measurement method
[BG)F]?
Methods with more clinical applications.
1. Calculation of insulin resistance index (HOMA-IR) using the accepted steady-state model HOMA formula.
HOMA-IR = fasting blood glucose x fasting insulin / 22,5. greater than 2,8 is insulin resistance
2. Fasting blood glucose / fasting insulin.
The normal reference value of the hospital is set based on the hospital testing equipment and the local population
Fasting blood glucose / fasting insulin <6 indicates the presence of IR
3. Oral glucose tolerance – insulin release test.
Fasting insulin in normal people is 5~25μu/ml. 30~60 minutes after taking sugar is about 5~10 times of the basal value, and 180 minutes to return to normal level. If fasting insulin is elevated; if it is more than 5~10 times the basal value 30~60 minutes after taking sugar; if it does not return to the normal level 180 minutes after taking sugar, it is indicative of IR.
It is not difficult to roughly assess IR in clinical work.
Elevated insulin level + normoglycemia, or elevated insulin level + hyperglycemia, are suggestive of IR.
X. Treatment strategies for PCOS
Treatment strategy: pathological link/patient needs. Regulation of menstrual cycle, anti-kaohsiung, promotion of fertility, control of insulin resistance, prevention of distant diseases (type II diabetes, CHD, endometrial cancer).
(i) Treatment of PCOS patients without fertility requirements
1. Treatment objectives: the immediate goal is to regulate menstrual cycle, treat hirsutism and acne, and control body weight; the long-term goal is to prevent diabetes, protect endometrium, prevent endometrial cancer, and prevent cardiovascular disease.
2. Treatment methods.
① Lifestyle adjustment: low-calorie diet, exercise, energy-consuming exercise, lifestyle changes, smoking cessation, alcohol cessation, and weight reduction through behavioral modifications can improve insulin resistance. Reducing body weight by 5% or more in obese patients can change or reduce symptoms such as menstrual disorders, hirsutism and acne and facilitate the treatment of infertility. Reducing body weight to the normal range can stop the long-term development of PCOS with adverse consequences such as diabetes, hypertension, hyperlipidemia, and cardiovascular disease and other metabolic syndromes.
② Treatment of hyperandrogenism: Various short-acting oral contraceptives are available, with Daing-35 being the first choice.
Indications: hyperandrogenemia or hyperandrogenic clinical manifestations.
Pathophysiology of female hyperandrogenism: increased total testosterone, decreased concentration of plasma SHBG, increased free testosterone, increased dihydrotestosterone, and increased androgen receptor sensitivity.
Pathways for the treatment of hyperandrogenism in women: reduction of androgen production (adrenal and/or ovarian secretion); reduction of peripheral conversion of androgens (weight loss); increase in plasma SHBG concentrations (stimulation of synthesis); blockade of androgen receptors in target organs.
Currently, Daimon-35 (2 mg CPA and 35 g EE) is preferred.
Dosage: Take 1 tablet daily for 21 days on days 1 to 5 of natural menstruation or withdrawal bleeding. Withdrawal bleeding begins about 5 days after discontinuation of the drug, and the drug is restarted on the 5th day of withdrawal bleeding or repeatedly activated after 7 days of discontinuation. It can be repeated for at least 3 to 6 months of application.
Comparison of CPA with other progestins’ anti-androgenic activity: Daing-35 has a multi-linked anti-oxalant effect, such as inhibition of gonadotropin overproduction; inhibition of ovarian and adrenal sources of androgen overproduction; increase in SHBG concentration and decrease in androgenic activity; inhibition of IGF-1 action; competition for androgen receptors on target organs and inhibition of androgenic activity.
Therapeutic effects of Da-ying-35 on PCOS: improve hyperandrogenic signs, provide regular menstrual cycles, stop endometrial hyperplasia, assist fertility in combination with ovulation-promoting drugs, and treat obese patients with hyperinsulinemia in combination with insulin sensitizers.
Precautions: PCOS patients are a special group of people who often have disorders of glucose and lipid metabolism. Contraindications to oral contraceptives should be excluded before using OC, and changes in blood glucose and lipids should be monitored during OC. Adolescent girls should give full informed consent before applying OC.
③ Progestin therapy.
Indications: Anovulatory patients without significant hyperandrogenic clinical and laboratory manifestations and without significant insulin resistance can be treated with regular progestin therapy alone to restore menstruation.
Advantages: restoration of regular menstruation, protection of the endometrium and may reduce the occurrence of endometrial cancer; may reduce androgen levels to some extent by slowing down the frequency of GnRH-LH pulse secretion.
Disadvantages: no change in endocrine status; no improvement in polycystic ovaries; weak androgen-lowering effect, cannot improve the symptoms and metabolic disorder condition in Kaohsiung.
Commonly used drugs: [ZK (] progesterone: 6mg/day, 10-14 days per month
Imazine: 200mg/day for 10-14 days per month [ZK)]
Darvon: [ZK (] 20mg/day for 10-14 days per month
Withdrawal of bleeding at least once every two months [ZK)
④ Treatment of insulin resistance (IR): – Metformin
Indications: Patients who are obese or have insulin resistance
Mechanism: Enhance glucose uptake by peripheral tissues, inhibit hepatic glucose production and enhance insulin sensitivity at the post-receptor level, reduce postprandial insulin secretion, and improve insulin resistance can increase sensitivity to CC.
Dosage: 500mg, 2 or 3 times daily, 1000-1500mg/day, 3-6 months treatment
Class B drug, the drug description does not include post-pregnancy women as an indication group, whether to continue the application after pregnancy should be decided carefully according to the patient’s specific situation and the endocrinologist’s recommendation.
Side effects: Gastrointestinal reactions are the most common and are dose-dependent, with symptoms reduced when taken during meals. The dose can be gradually increased, usually to the full dose in 2 to 3 weeks. Serious side effects are renal impairment and lactic acidosis.
(B) the treatment of patients with PCOS with fertility requirements
1, the purpose of treatment: to promote ovulation and obtain a normal pregnancy.
2. Treatment method: basic treatment + ovulation treatment
1）Basic treatment
① Lifestyle modification.
② Treatment of hyperandrogenemia: – currently TAIE-35 is preferred
③ Treatment of insulin resistance: – Metformin basic treatment
2) PCOS – Ovulation promotion therapy.
① First-line ovulation treatment – Clomiphene: 50mg/day for 5 days starting from the 5th day of natural menstruation or withdrawal bleeding and increasing by 50mg/day until 150mg/day per cycle if there is no ovulation. It is not necessary to increase the dose if there is satisfactory ovulation. If the follicular phase is long or the luteal phase is short, it means the dose is insufficient and the dose can be increased appropriately.
Basal body temperature should be tested and recorded during the cycle of clomiphene to determine the efficacy of the treatment. If the basal body temperature does not rise, transvaginal ultrasonography can be performed 7-10 days after stopping the drug. If the ovaries have near mature follicles, intramuscular HCG injection can be chosen to induce ovulation.
Clomiphene resistance: from day 5 of natural menstruation or withdrawal bleeding.
Cycle 1: CC50mg/day for 5 days
Cycle 2: CC100mg/day for 5 days
Cycle 3: CC150mg/day for 5 days. All without ovulation, for CC resistance
Side effects of clomiphene: weak anti-estrogenic effect, affects cervical mucus, sperm should not survive and penetrate; affects tubal peristalsis and endometrial development, unfavorable for embryo implantation, can add natural estrogens such as estradiol valerate in appropriate amount near ovulation. Symptoms of hot flashes with vasodilation; abdominal swelling or discomfort, chest pain, nausea and vomiting; headache, visual symptoms. Occasionally, patients cannot tolerate this drug
② Second-line ovulation treatment – gonadotropin therapy or laparoscopic ovarian perforation
Types of gonadotropins: human menopausal gonadotropin (hMG), pure FSH drug, high purity FSH (HP-FSH), genetically recombinant FSH (r-FSH) (almost no LH amount, especially for PCOS patients).
Indications: CC-resistant patients with anovulatory infertility, other causes of infertility have been excluded
Contraindications: elevated blood FSH levels suggestive of ovarian anovulation; no technical conditions for monitoring follicular development and ovulation.
Usage: low-dose, small incremental FSH regimen and tapered regimen.
Complications: multiple pregnancy, ovarian hyperstimulation syndrome (OHSS).
Dosing monitoring: repeated ultrasound and estrogen monitoring is required. The literature reports that with 4 or more follicles >16 mm in diameter, the likelihood of OHSS is greatly increased and the cycle should be cancelled. Gonadotropin therapy can only be performed in hospitals with pelvic ultrasound and estrogen monitoring and with techniques for the treatment of OHSS and fetal reduction. Relevant infertility tests must be performed prior to drug administration to exclude other infertility factors.
Laparoscopic Ovarian Perforation.
Indications: CC resistance, need for laparoscopic examination of the pelvis due to other diseases, poor follow-up conditions, inability to monitor gonadotropin therapy. BM I <34, LH >10mIu/ml, and high free testosterone are selected for treatment.
Ovulation-promoting mechanism: destruction of the androgen-producing ovarian mesenchyme, indirect regulation of the pituitary-ovarian axis, resulting in decreased serum LH concentrations; decreased LH and testosterone levels increase the chance of pregnancy and may reduce the risk of miscarriage.
Disadvantages: short duration of maintenance effect; risk of premature ovarian failure.
(iii) In vitro fertilization-embryo transfer (IVF-ET)
Indications: Patients who have failed to be treated by the above methods are recommended to be treated by IVF.