What is Polycystic Ovarian Syndrome (PCOS)?

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder commonly seen in women of reproductive age. Chronic anovulation (dysfunction or loss of ovulation) and hyperandrogenemia (excessive male hormone production in women) ), The main clinical manifestations of irregular menstrual cycle, infertility, hairy and / or acne, is the most common female endocrine disease.

Basic Information

nickname: Stein-Leventhal syndrome
English name: polycystic ovarian syndrome, PCOS
Visiting department: Obstetrics and Gynecology
Common locations: Ovary

Common causes: May be related to some genes that cause disease under the influence of specific environmental factors
Common symptoms: Amenorrhea, hairy, infertility, obesity
Contagious: no

Causes of polycystic ovary syndrome

There are currently two non-genetic theories and genetic theories for the etiology of PCOS.

1. PCOS non-genetic theory

Studies have suggested that the uterine hormone environment in pregnancy affects the endocrine status of adults in adulthood. Exposure to high concentrations of androgen during pregnancy, such as the mother's PCOS history, the mother's congenital adrenal hyperplasia, and poorly controlled high androgen, etc., ovulation is prone to occur after adolescence obstacle.

2. PCOS genetics theory

This theory is mainly based on the fact that PCOS presents a familial community phenomenon. Familial ovulation dysfunction and polycystic ovarian changes suggest a genetic basis for the disease. Hyperandrogenemia and / or hyperinsulinemia may be a genetic feature of the same disease in PCOS family members. The role of insulin in promoting ovarian androgen production is also affected by genetic factors or genetic susceptibility. Family members of rare ovulation, hyperandrogenemia, and polycystic ovarian changes have a higher prevalence of hyperinsulinemia in women and premature hair loss in men. The results of cytogenetics research indicate that PCOS may be X-linked recessive, autosomal dominant, or polygenic. Through genome-wide scanning, the largest number of PCOS-related genetic genes were found, such as candidate genes for steroid hormone synthesis and related functions, androgen synthesis-related regulatory genes, insulin synthesis-related genes, candidate genes for carbohydrate metabolism and energy balance, Candidate genes for gonadotropin function and regulation, genes related to adipose tissue, and genes related to chronic inflammation.

In short, PCOS etiology studies cannot confirm that the disease is caused by a certain gene locus or a certain gene mutation, and its pathogenesis may be related to the occurrence of diseases caused by the action of certain genes under the influence of specific environmental factors.

Classification of polycystic ovary syndrome

PCOS diagnosed according to the PCOS international diagnostic standards (see the diagnosis section for details) can be subtyped to facilitate individualized treatment options:

Type 1: Classic PCOS, ultrasound ovarian polycystic changes and clinical manifestations of hyperandrogens and / or hyperandrogenemia;

Type 2: Ultrasound-like polycystic changes in the ovary and thin ovulation or anovulation;

Type 3: NIH standard PCOS, clinical manifestations of high androgen and / or hyperandrogenemia and rare or anovulatory ovulation;

Type 4: It also has ultrasound polycystic ovarian changes, clinical manifestations of high androgen and / or hyperandrogenemia, and rare or anovulatory ovulation. This type is also called classic PCOS.

Clinical manifestations of polycystic ovary syndrome

Menstrual disorders

PCOS causes anovulation or rare ovulation in patients, about 70% of which are accompanied by menstrual disorders. The main clinical manifestations are amenorrhea, thin menstruation and dysfunction, accounting for 70% to 80% of women with abnormal menstruation and 30% of secondary amenorrhea. %, Accounting for 85% of anovulatory dysfunction. Due to ovulation dysfunction and lack of periodic progesterone secretion in PCOS patients, the endometrium has been under the stimulation of pure high estrogen for a long time. Continuous endometrial proliferation is prone to simple endometrial hyperplasia, abnormal proliferation, and even endometrial atypical hyperplasia And endometrial cancer.

2. High androgen-related clinical manifestations

(1) The amount and distribution of hairy hair vary according to gender and ethnicity. Hairy hair is one of the important manifestations of increased androgen. There are many clinical methods to evaluate hairy hair, and the evaluation method recommended by the World Health Organization is Ferriman-Gallway. Hair scoring criteria. The hairiness of PCOS patients in China is not serious. The large-scale community population flow analysis results show that mFG scores> 5 can diagnose hairiness, and excessive sexual hair is mainly distributed in the upper lip, lower abdomen and inner thigh.

(2) PCOS patients with high androgenic acne are mostly adult female acne, with rough skin and enlarged pores. Unlike adolescent acne, it has the characteristics of severe symptoms, long duration, stubbornness, and poor response to treatment.

(3) Female hair loss (FPA) PCOS begins to lose hair around 20 years of age. It mainly occurs at the top of the head, which can extend forward to the front of the head (but does not invade the hairline) and backwards to the back of the head (but does not invade the back of the occipital region), but the hair on the top of the head is diffuse and sparse and shedding. Neither violates the hairline, nor does baldness occur.

(4) Sebum overflow PCOS produces excessive androgen, hyperandrogenemia occurs, increasing sebum secretion, leading to excess oil on the head and face of the patient, enlarged pores, slightly reddish and oily skin on both sides of the nasolabial fold, and scalp scale , Scalp itching, chest and back oil secretion also increased.

(5) Masculine manifestations Mainly manifested by the distribution of masculine pubic hair, and generally there are no obvious masculine manifestations, such as clitoral hypertrophy, breast atrophy, low voice, and other abnormal development of external genitalia. In patients with PCOS, if there is a typical virilization, attention should be paid to identifying congenital adrenal hyperplasia, adrenal tumors, and tumors that secrete androgens.

3. Polycystic Ovary Changes (PCO)

Although a lot of research has been carried out on the diagnostic criteria of PCO ultrasound, there are still different opinions. In addition to the differences of races, it is more difficult to unify the diagnostic criteria of PCO. The PCO ultrasound standard for Rotterdam in 2003 was 12 unilateral or bilateral follicles in the ovary, with a diameter of 2-9mm, and / or ovarian volume (length × width × thickness / 2)> 10ml. At the same time can be manifested as medullary echo enhancement.

4. Other

(1) Obesity Obesity accounts for 30% to 60% of patients with PCOS, and its incidence varies according to race and diet. In the United States, 50% of women with PCOS are overweight or obese, while other countries have reported relatively few obese PCOS. PCOS obesity manifests as centripetal obesity (also known as abdominal obesity), and even non-obese patients with PCOS also exhibit an increased proportion of perivascular or omental fat distribution.

(2) Infertility Due to ovulation dysfunction, the pregnancy rate of PCOS patients is reduced, and the abortion rate is increased. However, it is unclear whether the abortion rate of PCOS patients is increased or whether the abortion is overweight.

(3) Obstructive sleep apnea This problem is common in patients with PCOS and cannot be explained by obesity alone. Insulin resistance is more predictive of dyspnea during sleep than age, BMI or circulating testosterone levels.

(4) Depression PCOS patients have an increased incidence of depression and are associated with high body mass index and insulin resistance, and patients' quality of life and sexual satisfaction have decreased significantly.

Diagnosis of polycystic ovary syndrome

In 1935, after Stein and Leventha first reported the disease, they were named Stein-Leventhal syndrome (SL sign). In 1960, because the patient was characterized by bilateral ovarian cystic enlargement, it was renamed polycystic ovary syndrome (PCOS). Due to the high clinical heterogeneity of PCOS, the etiology and pathogenesis are still unclear. By 2003, experts from the European Society for Human Reproduction and Embryo and the American Society for Reproductive Medicine (ESHRE / ASRM) convened an expert meeting of the PCOS International Collaboration Group to formulate the international The diagnostic criteria are as follows:

1. Thin ovulation or no ovulation;

2. Clinical manifestations of hyperandrogens and / or hyperandrogens;

3. Ultrasound manifestation is polycystic ovary (one or both ovaries have more than 12 follicles with a diameter of 2-9mm, and / or ovarian volume is greater than 10ml);

Of the above 3 items, 2 items are met, and other diseases such as congenital adrenal hyperplasia, Cushing syndrome, and tumors that secrete androgens are excluded.

In order to formulate the diagnosis and treatment norms of PCOS in China, the Endocrinology Group of the Chinese Medical Association's Obstetrics and Gynecology Branch discussed and initially formulated the consensus of experts on PCOS diagnosis and treatment in China in Chongqing in 2006. In 2007, the consensus of experts on the diagnosis and treatment of PCOS in China was introduced. Experts recommend that the 2003 Rotterdam PCOS international diagnostic standard be recommended at this stage. That is, thin ovulation or anovulation; clinical manifestations of hyperandrogen and / or hyperandrogenemia; polycystic ovarian changes: 12 follicles with diameter of 2-9mm on one or both ovaries, and / or ovarian volume 10ml ; 2 of the above 3 items are met, and other causes of high androgen are excluded: congenital adrenal hyperplasia, Cushing syndrome, androgen-producing tumors, etc.

Differential diagnosis of polycystic ovary syndrome

Cushing syndrome

Various causes lead to hyperadrenal function. Typical manifestations are full moon face, buffalo back, centripetal obesity, purple skin, hairy, acne, hypertension, and osteoporosis, impaired glucose tolerance, skin pigmentation, and more with virilization. Laboratory tests showed that the normal circadian rhythm of plasma cortisol disappeared and that free cortisol in urine increased. The overnight low-dose dexamethasone inhibition test is a simple method to screen for this disease. If Cortisol drops by 50% (L) after administration, Cushing's syndrome can be ruled out, such as Cortisol> 390nmol / L, and there are no factors causing false positives. If it exists, it may be Cushing's syndrome.

2. Congenital adrenal hyperplasia (CAH)

It is an autosomal recessive disease. The most common are congenital 21-hydroxylase and 11-hydroxylase deficiency. Such patients cannot synthesize glucocorticoids, the pituitary ACTH loses its inhibition, and the adrenal cortex proliferates, leading to the accumulation of pre-enzyme metabolites-17-hydroxyprogesterone, 17-hydroxypregnenolone and its metabolites gestinol, androgen secretion. increase. Patients had chromosomes 46, XX, the gonads were ovaries, the internal genitals had uterus and fallopian tubes, but the external genitals and secondary sexual characteristics had different degrees of virilization under the action of excessive androgens, because the fetus had been affected by excessive androgens Therefore, abnormal genital development has occurred at birth. A small number of patients have delayed adrenal hyperplasia, and clinical manifestations are delayed until after puberty, which can be manifested as slow progressive hairy, thin menstruation, and no obvious genital deformities. Laboratory tests showed elevated serum T and A levels (T> 2.8nmol / L, A> 9.5nmol / L), serum cortisol levels were mostly normal, and 17-hydroxyprogesterone increased (> 9.1nmol / L), but The basal level of 17-hydroxyprogesterone in late-onset patients can be within the normal range, but its level is significantly higher than normal after the ACTH excitation test, which has the most diagnostic value.

3. Ovarian virilization tumor

Such tumors include testicular blastoma, portal cell tumor, lipocytoma, granulosa cell tumor, and follicular membrane cell tumor. Occurs between the ages of 30 to 50 years. Menstruation and fertility were normal before the onset of the disease, and obvious virilization, amenorrhea, and infertility occurred after the onset of the disease. Laboratory tests show elevated androgen levels, mainly elevated T and A (T> 7nmol / L, A> 21nmol / L), and most tumors secrete androgens that are neither regulated by ACTH nor gonadotropins Adjustment. B-mode ultrasound is a better way to check for this disease, and CT or MRI can also assist in diagnosis.

4. Adrenal tumor

Both benign and malignant tumors of the adrenal cortex can lead to increased androgens, tumor growth and secretory functions are autonomous, not controlled by the pituitary ACTH, and not inhibited by exogenous glucocorticoids. Adrenal cancer generally does not respond to exogenous ACTH stimulation, and adenomas sometimes respond. The patient's hirsutism and virilization developed rapidly, accompanied by abnormal metabolism of the whole body caused by excessive secretion of glucocorticoid or mineralocorticoid. CT or MRI is very sensitive to adrenal tumors, and can locate and show contralateral adrenal atrophy.

5. Follicular membrane cell hyperplasia sign

This lesion is similar to PCOS but differs. In the ovarian stroma, there are diffuse islands of luteinized follicular membrane cells that secrete too much androgen. There are fewer ovarian follicles, and the original follicles are degraded due to fatty changes, so the number is less than PCOS. Significant interstitial hyperplasia and more solid ovaries.

6. Hyperprolactinemia

Studies have found that there are prolactin receptors on the adrenal cell membrane. Prolactin can stimulate the secretion of adrenal androgens. Prolactin levels are usually accompanied by elevated serum DHEA and DHEA-S. Obesity in patients with this disease is usually diffuse obesity. Obesity is more obvious. About 20% of women with pituitary prolactin adenoma have hirsutism and acne.

7. Drug factors

Mainly androgens, followed by long-term or large-scale use of glucocorticoids or progestins. Hairiness can occur, manifested as female beards, increased body hair, and even other masculine manifestations. Non-hormonal drugs, such as phenytoin sodium, dalentin, diazole, synthetic steroids, danazol, etc. can also be induced, which is characterized by the symptoms gradually disappearing after withdrawal, and the history of medication is the main basis for diagnosis.

8. Central nervous factors

Certain diseases such as encephalitis, cranial trauma, multiple cerebrospinal sclerosis, or pineal tumors can promote increased androgen secretion and hairiness, usually without other virilization manifestations.

9. Stress factors

Under stress, the hypothalamic gonadotropin-releasing hormone (CRH) increases, causing ACTH secretion from the pituitary gland to increase, which can overstimulate the adrenal cortex and increase androgen.

10. High androgen performance during pregnancy

A large number of chorionic gonadotropins during pregnancy can cause extreme luteinization of the ovaries or stimulate portal cells, increase androgen production, and cause hairiness.

11. Ectopic ACTH tumor

Rarely clinically, because cancers other than the adrenal gland produce biologically active ACTH, which stimulates adrenal hyperplasia. The most common are lung oat cell carcinoma (approximately 50%), followed by thymoma and pancreatic tumor (approximately 10% each), and other tumors originating from neurospine tissue and medullary thyroid carcinoma.

Polycystic Ovary Syndrome Treatment

Drug treatment

At present, the medical treatment of PCOS has replaced surgical treatment as a first-line treatment method, and the purpose of treatment is mainly related to the fertility requirements of patients.

(1) Drug treatment to reduce hyperandrogenemia

1) Oral contraceptives (OCP) have been used as a traditional long-term treatment for women with PCOS. They are mainly used to protect the endometrium, adjust the menstrual cycle, and improve hairiness and / or acne by reducing androgens produced by the ovaries. OCP can reduce hyperandrogenemia in patients with PCOS. The most commonly used OCP to reduce hyperandrogenemia is cycloprogesterone acetate, which has progestin activity and can combine with ethinyl estradiol to exert antiandrogenic effects. Body binding, blocking the transmission of the androgen effect to the nucleus, inhibiting the activity of this receptor and inhibiting 5 reductase activity, reducing DHT production, reducing gonadotropin synthesis, reducing gonadotropin levels reducing steroid synthesis, increasing SHBG levels and Reduce gonadotropin levels. Therefore, cyproterone acetate has been used as the first choice for hairy treatment of PCOS in the past 20 years. Treatment for more than 6 consecutive cycles is effective for 60% to 80% of hairy patients. OCP is a simple and economical treatment for patients with PCOS without fertility requirements, but recent studies have shown that it may reduce insulin sensitivity and glucose tolerance in women with PCOS. Common side effects include headaches, weight gain, mood changes, and decreased libido. Gastrointestinal reactions and breast pain should be given attention.

2) Glucocorticoids For the treatment of hyperandrogenemia with excessive androgen synthesis by the adrenal glands, dexamethasone and prednisone are more effective because they have a greater affinity with the receptor and can inhibit the secretion of pituitary ACTH and make Reduced ACTH-dependent adrenal androgen secretion. Pay attention to the possibility of hypothalamic-pituitary-adrenal axis inhibition for long-term application.

3) Spironolactone is an aldosterone analogue. Its effectiveness in inhibiting enzymes is similar to cycloprogesterone acetate, so the two treatment effects are similar. At the same time, it has an anti-androgen effect, and its mechanism of action for treating androgenemia is to competitively bind to androgen receptors, and to compete with dihydrotestosterone (DHT) in peripheral tissues to bind to receptors, inhibiting 17 hydroxylase, and T and A decrease.

4) Flutamide is a steroid complex. It has strong and highly specific non-steroidal antiandrogens, has no intrinsic hormone or anti-gonadotropin effect, cannot reduce steroid synthesis, but is inhibited by receptor binding. Androgenic effect. Compared with cycloprogesterone acetate, serum androgen (including total testosterone and free testosterone) levels increased after treatment, but because of the androgen target organ effects were antagonized, despite the increase in serum androgen levels, clinical manifestations did not worsen. Long-term use of large amounts may cause liver damage, and it is inconclusive whether fetal malformations are caused. Therefore, contraception should be taken during medication.

(2) Ovulation-promoting drug treatment

Most patients with PCOS who have fertility requirements need to use ovulation-promoting therapy to get pregnant. PCOS's drug-ovulation-promoting therapy has made great progress in the past 50 years, but some patients have poor efficacy with conventional methods, so the appropriate method is ovulation-promoting. The key to treatment.

1) Clomiphene (CC) In 1961, Greenblatt reported the use of clomiphene to promote ovulation. CC has become the drug of choice for PCOS ovulation therapy. CC can bind to the hypothalamic estrogen receptor, which can block the central nervous system's response to circulating estrogen levels, and increase the pulsed GnRH and gonadotropin secretion. Causes follicle growth and development. In addition, CC can also directly affect the pituitary and ovaries, increase gonadotropin secretion, and synergistically enhance the aromatase activity induced by FSH. CC can also show anti-estrogen characteristics in other parts of the female reproductive tract, especially the endometrium and cervix (thickening cervical mucus). These anti-estrogen effects have a negative impact on pregnancy. Treatment often begins after the menstrual cycle of the natural cycle or after the withdrawal of progesterone from the blood, that is, from the 2nd to the 5th day of the cycle, and the medication is used for 5 days. The start time does not significantly affect the ovulation rate, pregnancy rate, and endometrium. Beginning can ensure adequate follicular recruitment. The starting dose of clomiphene is usually 50 mg, while 100 mg is more suitable for obese women. If there is no ovulation response in the above method, the next dose can be increased by 50mg until ovulation. Although the maximum daily dose recommended by the FDA is 250mg, the highest clinically used dose is 150mg. The smallest dose should be used as much as possible because high doses do not improve pregnancy outcomes and theoretically have a negative impact on endometrial thickness and implantation. If the ultrasound is used to monitor the maturation of follicles, the dominant follicle is considered to be mature when the average diameter of the follicle is 18-20mm. For those who show an increase in follicles but cannot ovulate, they can use human chorionic gonadotropin (hCG) to stimulate ovulation. Same room time. The ovulation rate of patients with PCOS after applying CC can reach more than 80%, and the pregnancy rate of 30% to 60% when used alone. The two most obvious side effects with clomiphene are mild ovarian enlargement (13.6%) and multiple pregnancies. Other side effects include hot flashes (10.4%), abdominal distension (5.5%), and minimal visual impairment (1.5%). . In some patients, the treatment with CC is not effective, which is called clomiphene resistance. However, the current definition of clomiphene resistance is different. The maximum dose ranges from 150 to 250 mg. There are no ovulation reactions for 3 consecutive cycles.

2) Gonadotropin (Gn) For patients with CC resistance, gonadotropin (Gn) is a commonly used ovulation-promoting drug, including FSH and HMG. At present, there are various preparations of Gn, such as hMG, urine FSH, and recombinant FSH. Both have high prices, multiple pregnancies and the risk of ovarian hyperstimulation syndrome (OHSS). The conventional method starts from 3 to 5 days of menstruation, with 1 HMG / d or pure FSH75IU / d per day. The ovulation rate is higher and the pregnancy rate is higher. However, the incidence of ovarian transition stimulation syndrome (OHSS) is high and the rate of multiple births is high. At present, a small-dose slow-increasing program is mostly used. This method has an ovulation rate of 70 to 90%, a single follicular development rate of 50 to 70%, a periodic pregnancy rate of 10 to 20%, and a lower incidence of OHSS of 0 to 5%. The cycle is long and the patient cost is relatively high.

3) Letrozole Ovulation - promoting therapy is a new indication for aromatase inhibitors (AIs). These drugs have been used mainly in the treatment of breast cancer in the past. They can be used alone or in combination with FSH. Major side effects include gastrointestinal reactions, fatigue, hot flashes, and head and back pain. Letrozole, an aromatase inhibitor commonly used in clinical practice, is mainly used in patients with clomiphene resistance, with an ovulation rate of 80%, more than after the menstrual cycle begins or after progesterone withdrawal bleeding. 7 days (total of 5 days) was applied. The subsequent monitoring process was the same as that of clomiphene.

(3) Insulin sensitizer (ISD) treatment

A major feature of PCOS is insulin resistance, which leads to compensatory hyperinsulinemia in order to maintain normal glucose tolerance (the normal response of insulin after glucose intake). In young women with PCOS, hyperinsulinemia is a major risk factor for impaired glucose tolerance and late-stage heart disease. In addition, hyperinsulinemia can cause increased ovarian androgen synthesis, which in turn can lead to anovulation, amenorrhea, and infertility. Many women with PCOS are obese, and insulin resistance is more pronounced due to weight gain. Non-obese women with PCOS (20% to 50% of PCOS) have increased waist / hip ratio, and have more significant insulin resistance than the normal group. tendency. The main insulin-sensitizing drugs are metformin, troglitazone, rosiglitazone, ioglitazone, and D-Chiro-Inosito. Their main indications are insulin resistance and impaired glucose tolerance. Or PCOS women with type 2 diabetes.

2. Surgical treatment

The treatment of PCOS patients has always been a difficult problem in clinical treatment. The earliest effective treatment was the bilateral ovarian wedge resection (BOWR) reported by Stein and Leventhal in 1935, which pioneered the era of surgical treatment of infertility. Surgical treatment can reduce some granulosa cells in the ovary, and the production of androgens in the ovarian stroma is reduced, thereby reducing the circulating androgen level, and then GnRH is reduced, causing the serum androgen concentration to be further reduced, which also indicates that the ovarian stroma is also affected by the pituitary gland- Ovarian axis regulation. Due to the decrease in androgen levels, most patients can resume spontaneous ovulation and menstruation after surgery, and some of them may become pregnant naturally, but most pregnancy occurs about 6 months after surgery. Surgical treatment is divided into the following types according to different methods:

(1) Bilateral ovary wedge resection (BOWR) is the earliest and effective method for the treatment of anovulatory PCOS. Surgery requires the removal of 1/3 of ovarian tissue. Stein et al reported that 95% of patients can recover to normal menstruation and pregnancy. The rate can reach 85%. Subsequent reports confirm the effectiveness of this method, but the success rate varies widely. However, this method has a variety of adverse reactions, including tubal infertility caused by adhesion formation after surgery. After the occurrence of premature ovarian failure. Because of this method's great damage, it is rarely used now.

(2) Laparoscopic electrocautery or laser perforation (LOD). The currently preferred surgical treatment method is laparoscopic ovarian perforation using thermal penetration or laser. The response to ovulation promotion is improved after surgery. Due to medical intervention The multiple pregnancy rate was reduced, and the incidence of postoperative adhesions was significantly reduced compared with wedge resection. It is mainly used for second-line treatment of patients with clomiphene resistance. It has a high single follicular rate and avoids multiple births and OHSS. It is especially effective for patients with a BMI of less than 29 and a free androgen index of less than 4. The ovulation rate is 80% 90%, pregnancy rate of 60% to 70%.

(3) Transvaginal water laparoscopy (THL) is mainly used for the examination of fallopian tubes and ovarian structures in infertile patients without obvious pelvic causes. Patients with PCOS resistant to clomiphene by THL were treated with ovarian perforation, and the cumulative pregnancy rate at 6 months after operation reached 71%.

3. Assisted Fertility Technology

For patients with PCOS who have ovulated but have not been pregnant after applying the standard ovulation-promoting cycle for more than 6 months, or patients with ovulation-promoting therapy and adjuvant treatment for anovulation-free patients who are anxious for pregnancy, you can choose assisted reproduction technology of embryo transfer .

(1) IVF-ET is an effective treatment method for patients with refractory PCOS.

(2) In vitro maturation of oocytes (IVM) is a technique that mimics the mature environment of oocytes in vivo and enables immature oocytes collected from the ovary to reach the final maturity in vitro. PCOS patients' high androgen levels make them prone to excessive follicle recruitment but maturation disorders during ovulation promotion. Therefore, IVM technology provides a new approach for the treatment of infertility in PCOS patients.