Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and is the main cause of anovulatory infertility. The prevalence is 5-10% among women of reproductive age. The clinical manifestations are highly diverse, such as irregular menstruation, hirsutism, obesity, hyperlipidemia, hyperandrogenization, cystic follicles, insulin resistance, and infertility, etc. Most patients have only a few of these manifestations, which are highly heterogeneous, and the diagnostic criteria are not uniform.
The pathogenesis of PCOS is still unclear. Most studies suggest that PCOS is a metabolic and endocrine disorder involving endocrine, metabolic, genetic and immune factors, and insulin resistance and hyperinsulinemia are closely related to the development of PCOS.
There are no uniform criteria for the diagnosis of PCOS. The diagnosis of PCOS is based on clinical symptoms, blood endocrine levels and ultrasonography, and the diagnostic indicators include: (1) irregular menstruation and ovulation disorders; (2) hyperandrogenemia: elevated total testosterone, free testosterone or androstenedione; (3) enlarged ovarian volume on ultrasound, enhanced interstitial echogenicity, and numerous small follicles (≥10, 4-10 mm in diameter) under the ovarian envelope; ( 4) increased LH/FSH in the blood. (4) Blood LH/FSH > 2-3, E2 level equal to mid follicular phase; (5) Other: hirsutism, acne, obesity. Hyperinsulinemia has not been included in the scope of diagnostic criteria, but in recent years, it has attracted widespread attention. 40% of patients with PCOS have hyperinsulinemia, therefore, some scholars advocate the presence of insulin resistance as a routine test index for PCOS. Most foreign scholars believe that the diagnosis of PCOS can be made by excluding adrenocortical hyperplasia, hyperprolactinemia, thyroid disease, hyperandrogenemia due to androgen-secreting tumors and ovulation disorders, regardless of ovarian morphology. Because the incidence of PCOS in the general population is 4-7%, while 16%-25% of the normal population can show polycystic ovarian changes on ultrasound, but do not show clinical symptoms such as endocrine disorders and ovulation disorders, this group of people is called polycystic ovarian changes (PCO), and is also a high-risk group for OHSS, which should be taken seriously when ovulation is performed. The role of LH and FSH in the diagnosis is still controversial, but it is believed that the elevation of LH is a secondary change, and that the elevation of LH does not affect the ovulation.
The role of LH and FSH in the diagnosis is still controversial.
The goals of PCOS treatment are to improve quality of life, restore normal weight, reduce androgen levels and the intensity of their biological effects on target organs, reduce insulin concentrations and improve insulin sensitivity in peripheral tissues, restore normal follicular development and ovulation, protect the endometrium under the continuous effect of estrogen, reduce the risk of cardiovascular disease, eliminate the adverse effects of hyperinsulinemia on the body, prevent It also reduces the risk of recurrent miscarriages and other obstetric complications.
Pregnancy support measures for PCOS include weight control, cycle modification, ovulation treatment, correction of insulin resistance, surgical treatment, and assisted reproduction techniques. Individualized selection of fertility support options is particularly important. Obesity, high LH levels, and insulin resistance in anovulatory women are negatively associated with pregnancy rates and increased miscarriage rates. Therefore, weight loss and increasing insulin sensitivity during the pre-ovulatory period are gaining more and more attention in clinical practice.
I. General treatment
1.Weight reduction
About 50% of PCOS patients are obese. For obese PCOS patients, weight reduction is the first treatment. Obesity can lead to menstrual disorders, infertility, miscarriage, poor response to ovulation drugs, low conception rate of both natural cycle and infertility treatment cycle, poor pregnancy outcome (high rate of spontaneous abortion and congenital malformation), poor fetal condition and diabetes, especially when the body mass index (BMI) is high and central obesity is obvious. Overweight increases androgen and insulin secretion and insulin resistance, and high levels of insulin and androgens further lead to abnormal fat distribution. Through low-calorie diet and energy-consuming exercise, obese infertile women after 6 months of treatment to lose 5% or more of body weight, can change or reduce menstrual disorders, hirsutism, acne and other symptoms, improve ovulation rate, pregnancy rate, pregnancy outcomes and endocrine indicators, and improve the patient’s self-esteem, which is also very important for infertile patients.
2.Lower LH and testosterone levels
A dual suppression regimen of oral contraceptives and GnRHa is used. Oral contraceptive pills (OC) can effectively inhibit the release of Gn from the pituitary gland, which decreases LH in the body and indirectly inhibits the production of androgens in the ovaries, while cyproterone acetate has a direct inhibitory effect on androgens, resulting in a more significant decrease in LH and androgens. The dual inhibition regimen of GnRHa is to start GnRHa on the last 5 days of OC to effectively inhibit the release of pituitary Gn, and to halve the dose of GnRHa until HCG is injected at the same time as ovulation with Gn from the third day of menstruation. The rapid and reversible inhibition of the pituitary gland by GnRH antagonists reduces the endogenous secretion of LH and FSH, causes partial follicular atresia in the early phase of administration, reduces the number of eggs obtained, and decreases egg quality and implantation rate due to early exposure of the follicles to high concentrations of LH and E2. Our animal studies have shown that the direct effect of GnRH antagonists on the endometrium, which impairs endometrial tolerance, may also reduce pregnancy rates. In order to correct the effect of high androgen levels in the early follicular phase of PCOS on egg quality, it was recently reported in the literature that the use of GnRH antagonists was started on the second day of menstruation, and then Gn treatment was started after LH suppression until follicular maturation and IUI was discontinued, resulting in a high pregnancy rate (44.4%). However, since this is a small sample (9 cases), its effectiveness and application value should be confirmed.
3.Insulin resistance reduction (IR)
Insulin resistance is common in PCOS, both obese and non-obese patients with PCOS have different degrees of hyperinsulinemia and insulin resistance. hyperinsulinemia in PCOS patients is involved in the occurrence of obesity, and obesity will aggravate the degree of insulin resistance; it also leads to impaired follicular development and promotes the development of PCOS. Congenital factors such as malnutrition during fetal life are also closely related to adipocyte hypertrophy, and insulin resistance in adipose tissue may occur before insulin resistance in skeletal muscle. Treatment to improve insulin sensitivity is a key measure in the treatment of PCOS. Metformin is currently the most commonly used. Metformin combined with diet and exercise is an effective and economical way to improve insulin sensitivity. It reduces insulin and testosterone levels by improving insulin sensitivity in the liver. Long-term metformin plus low-calorie diet can play a very important role in body shape and fat distribution in PCOS and non-PCOS patients with abdominal obesity. It also reduces the incidence of familial thrombophilia, familial hypofibrinolysis, recurrent IVF-ET failure and miscarriage. It plays an important role in the prevention of diabetes, dyslipidemia and cardiovascular diseases during pregnancy and postpartum. The addition of insulin sensitizer to in vitro fertilization significantly reduced the levels of HCG and estradiol, and reduced the incidence of OHSS during gonadotropin ovulation without affecting the rate of egg production. Metformin is necessary in the treatment of infertility in PCOS with insulin resistance and has a safe and reliable efficacy. Vindia selectively improves or partially mimics some functions of insulin, improves IR, lowers insulin levels, lowers androgen levels in the body, improves the success rate of natural ovulation and CC ovulation in PCOS patients, thus improving menstrual disorders, increasing the chance of pregnancy and reducing the rate of early spontaneous abortion, so it can be combined with metformin to treat insulin resistance in PCOS.
Ovulation promotion therapy for PCOS patients
The first choice of ovulation-promoting drug for infertile women with PCOS is CC, with an ovulation rate of >80% and a cumulative pregnancy rate of 30%-50% after 4-6 cycles of treatment. The most serious and common complications of Gn ovulation in PCOS patients are The most serious and common complications of Gn ovulation in PCOS patients are OHSS and multiple pregnancies, or ovarian hyporesponsiveness in PCOS due to complex endocrine disorders and possible FSH gene polymorphisms. (1) Uncontrollable Gn: the Gn required for follicular development varies greatly, whether this is due to polymorphic changes in the FSH receptor in PCOS patients, resulting in altered sensitivity to exogenous FSH stimulation remains to be confirmed; (2) Uncontrollable OHSS: since the threshold of individual follicular dominance and group follicular development are quite close, once follicular development is initiated, a large number of follicles often grow explosively and the E2 level rises sharply. (3) low response tendency: exogenous Gn does not reach the threshold of follicular growth, follicles stop growing, or even atresia, which may lead to endometrial breakthrough bleeding; (4) uncontrollable timing of egg retrieval and impaired egg quality. Due to the special nature of ovulation promotion in PCOS patients, ovulatory drugs may cause follicles to grow in batches, resulting in overmaturity and degeneration of some follicles and immaturity of some follicles that are difficult to retrieve, as well as decreased egg acquisition rate and impaired egg quality due to long-term exposure to high androgen environment, decreased fertilization rate and cycle pregnancy rate, and increased miscarriage rate.
Surgical treatment of PCOS
(i) Ovarian wedge resection and laparoscopic perforation
Surgical treatment of polycystic ovary syndrome began in 1935 when ovulation was found after biopsy of the ovaries, and wedge resection of the ovaries was the only treatment for anovulatory polycystic ovary syndrome until the advent of clomiphene in 1961. After the advent of ovulation-promoting drugs, the use of wedge resection has decreased and is now being replaced by laparoscopic surgery. The latter is mainly laparoscopic electrocautery, multi-point perforation or laser perforation. Under laparoscopy, the ovary is fixed appropriately, and 4-20 holes of 2-4 mm in diameter and 3-5 mm in cortical penetration are made on the ovarian surface with a monopolar electrocoagulation needle perpendicular to the ovarian surface or with a laser aimed at the ovarian surface, depending on the size of the ovary, with the power and working time adjusted. During the operation, the ovaries are flushed and care is taken to avoid damaging the structures near the ovarian hilum and, more importantly, to avoid damaging the blood vessels of the ovarian tract, which may affect the blood supply to the ovaries. Measures to prevent adhesions can be used as appropriate. Postoperative monitoring of ovulation. The mechanism of surgical treatment of polycystic ovary syndrome is complex and not yet clear. It may be related to a reduction in the size of the enlarged ovary, a reduction in the secretion of abnormal hormones such as androgens, a reduction in the secretion of inhibitory hormones such as inhibin, an increase in sensitivity to gonadotropins, a trauma-induced release of growth factors that amplify the effect of FSH or the destruction of old follicles to allow the growth of new ones. In addition, surgery also affects the feedback regulation between the ovary and the pituitary gland: surgery on one ovary can restore ovulation to the opposite ovary, often before the operated side. There is a wide variation in effectiveness reported. Ovulation resumes after surgery in 50% to 90% of patients. Postoperative pregnancy rates of 40% and even 70% have been reported. The duration of surgical efficacy is controversial, with some data suggesting that ovulation resumes only a few months to six months after laparoscopic surgery. Surgical treatment is more suitable for patients with high LH levels and is not recommended as a priority for obese, insulin-resistant PCOS. Studies have shown that surgical treatment does not change insulin resistance. Some data suggest that in patients with clomiphene-resistant PCOS, surgical treatment has similar efficacy to gonadotropin, and the choice between the two approaches is still open to discussion. Certainly, the reduced incidence of OHSS compared to gonadotropins, the absence of frequent ultrasound monitoring, the benefit to patients in remote areas, and the lower rate of multiple births, thus reducing maternal and infant problems in obstetrics, are certainly favorable aspects of surgical management. The side effects of the surgical approach include the general surgical and anesthetic risks as well as the risks of laparoscopic surgery. In addition, ovarian and pelvic adhesions can occur and cases of premature ovarian failure have been reported. Of further concern is whether damage to the ovarian epithelium can lead to an increased incidence of ovarian epithelial neoplasia, which needs to be observed in a large sample over time. Therefore, surgical treatment of anovulatory polycystic ovary syndrome should be considered in cases where pharmacological treatment is not effective.
(B) Clinical study of immature follicle aspiration under ultrasound in the treatment of PCOS infertility
Gn can easily lead to OHSS. surgical wedge resection of ovaries may not only cause pelvic adhesions and refractory infertility, but also may cause irreversible damage to ovarian function. In vitro fertilization can solve most of the problems of PCOS fertility, but the cost is high. Therefore, the clinical management strategies and measures for patients with PCOS have received increasing attention in the field of reproductive endocrinology. In recent years, we have tried ultrasound transvaginal immature follicular aspiration for the treatment of patients with moderate to severe PCOS infertility. The aim was to reduce the number of sinus follicles in the ovaries of patients with PCOS, to improve the endocrine status and response to ovulatory drugs, to reduce the risk of OHSS, and to investigate the effectiveness and feasibility of transvaginal immature follicular aspiration in clinical treatment. Compared with laparoscopic surgery, transvaginal immature follicular puncture technique is transvaginal, which is less traumatic and less risky.
The role of assisted reproductive technology in the treatment of infertility in PCOS patients
(i) IVF/ ICSI-ET
For patients with PCOS who have ovulation but no pregnancy after more than 6 months of standard ovulatory cycles, or patients who have no ovulation with multiple drugs and adjuvant therapy and are urgently waiting for pregnancy, embryo transfer assisted reproductive technology can be chosen. For patients with refractory PCOS, IVF2ET is an effective treatment option. However, the hyperandrogenemia and insulin resistance in PCOS cause multiple dysfunctions of the reproductive and endocrine systems, making PCOS patients prone to high Gn response during IVF treatment, resulting in excessive follicle count and high blood E2, which increases the incidence of OHSS, and high LH level decreases oocyte quality and fertilization rate. These make PCOS patients a relative difficulty in IVF treatment.
PCOS patients are extremely sensitive to exogenous gonadotropin stimulation and have a high incidence of OHSS during assisted reproduction. In vitro maturation of immature oocytes (IVM) was first used in 1994 to achieve pregnancy in patients with PCOS.
(ii) In vitro culture of immature eggs (IVM)
A number of studies have confirmed that the follicles in PCOS patients are not completely apoptotic and atretic, but are at a stagnant stage of growth and can continue to grow after removal from the abnormal local environment and the addition of gonadotropins. In 1994, Trounson et al. first reported a case of successful pregnancy in a PCOS patient using IVM, and in the following decade, a number of centers in China and abroad have conducted this study with good results. The IVM technique itself has the advantages of being inexpensive, avoiding the side effects associated with the use of large amounts of superovulatory drugs, and preventing the occurrence of OHSS.
In the future, PCOS will remain a hot clinical issue for quite some time, and many practical problems need to be solved, such as the development of suitable diagnostic criteria for national population, related population epidemiological studies, and the exploration of new assisted reproduction techniques for PCOS.