Endocrine disorders Polycystic ovary

The occurrence of polycystic ovary is closely related to endocrine disorders. Once the patient is ill, he or she may experience four typical symptoms: amenorrhea, hirsutism, obesity and infertility. Among them, infertility may be the most harmful. It is best to treat endocrine disorders such as polycystic ovary in a timely manner. There are many methods, and the specific treatment should be determined according to the condition. Let’s take a look at the treatment of endocrine disorder polycystic ovary.

treat

1. Medication

Currently, drug treatment for PCOS has replaced surgical treatment as the first-line treatment method, and the purpose of treatment is mainly related to the patient's fertility requirements.

(1) Drug treatment to reduce hyperandrogenism

1) Oral contraceptive pills (OCPs) have been used as a traditional long-term treatment for women with PCOS. They are mainly used to protect the endometrium, regulate the menstrual cycle, and improve hirsutism and/or acne by reducing androgen production in the ovaries. OCP can reduce hyperandrogenism in PCOS patients. Among them, the most commonly used OCP for reducing hyperandrogenemia is cyproterone acetate, which has progestin activity and can combine with ethinyl estradiol to exert an anti-androgenic effect. It can also bind to the dihydrotestosterone receptor in the cytoplasm of hair follicles, blocking the conduction of androgen effects to the cell nucleus. By inhibiting the activity of this receptor, it inhibits the activity of 5α-reductase, reduces DHT production and gonadotropin synthesis, and reduces gonadotropin levels, which reduces steroid synthesis, increases SHBG levels and reduces gonadotropin levels. Therefore, cyproterone acetate has been used as the first choice for the treatment of PCOS hirsutism in the past 20 years. Continuous treatment for more than 6 cycles is effective for 60% to 80% of hirsutism patients. OCP is a simple and economical treatment for PCOS patients who do not desire fertility. However, recent studies have shown that it may reduce insulin sensitivity and glucose tolerance in women with PCOS. Other common side effects include headache, weight gain, mood changes, decreased libido, gastrointestinal reactions and breast pain, which should be paid attention to.

2) Glucocorticoids are used to treat hyperandrogenism caused by excessive adrenal androgen synthesis. Dexamethasone and prednisone are more effective because they have a greater affinity for receptors and can inhibit pituitary ACTH secretion, thereby reducing ACTH-dependent adrenal androgen secretion. With long-term use, be aware of the possibility of hypothalamic-pituitary-adrenal axis suppression.

3) Spironolactone is an aldosterone analogue, and its effectiveness in enzyme inhibition is similar to that of cyproterone acetate, so the two treatment effects are also similar. At the same time, it has an anti-androgen effect. Its mechanism of action for treating hyperandrogenism is to competitively bind to androgen receptors, and to competitively bind to receptors with dihydrotestosterone (DHT) in peripheral tissues, inhibiting 17α hydroxylase and reducing T and A.

4) Flutamide is a steroid compound that is a potent and highly specific non-steroidal antiandrogen. It has no intrinsic hormone or anti-gonadotropin effect and cannot reduce steroid synthesis, but it inhibits the androgen effect through receptor binding. Compared with cyproterone acetate, serum androgen levels (including total testosterone and free testosterone) increased after treatment, but because the androgen target organ effects were antagonized, clinical manifestations did not worsen despite the increase in serum androgen levels. Long-term and excessive use of the drug may cause liver damage. It is also unclear whether it will cause fetal malformations, so contraception should be used while taking the drug.

(2) Ovulation-inducing drug treatment

PCOS patients who want to have children often need ovulation induction treatment to become pregnant. The drug-induced ovulation treatment of PCOS has made great progress in the past 50 years, but some patients have poor efficacy with conventional methods. Therefore, choosing the right plan is the key to ovulation induction treatment.

1) Clomiphene (CC) In 1961, Greenblatt reported the use of clomiphene for ovulation induction treatment. CC has become the drug of choice for ovulation induction treatment of PCOS. CC can bind to the hypothalamic estrogen receptors, blocking the central nervous system's response to circulating estrogen levels, increasing the secretion of pulsatile GnRH and gonadotropin, and further causing follicle growth and development. In addition, CC can also directly affect the pituitary gland and ovary, respectively increasing the secretion of gonadotropin and synergistically enhancing FSH-induced aromatase activity. CC can also exhibit antiestrogenic properties in other parts of the female reproductive tract, particularly the endometrium and cervix (making cervical mucus thicker). These anti-estrogenic effects can have a negative impact on pregnancy. Treatment often starts after the natural menstrual cycle or after the withdrawal of progesterone bleeding, that is, from the 2nd to 5th day of the cycle, and the medication is taken for 5 days. The starting time has no significant effect on the ovulation rate, pregnancy rate and endometrium. Starting in the early follicular stage can ensure sufficient follicle recruitment. The starting dose of clomiphene is usually 50 mg, but 100 mg is more appropriate for obese women. If there is no ovulation response to the above methods, the next dose can be increased by 50 mg until ovulation occurs. Although the FDA recommends a maximum daily dose of 250 mg, the highest dose commonly used in clinical practice is 150 mg. The lowest dose possible should be used, as higher doses do not improve pregnancy outcomes and may theoretically have a negative impact on endometrial thickness and implantation. If B-ultrasound is used to monitor the maturation of follicles, the dominant follicle is considered a mature follicle when it reaches an average diameter of 18 to 20 mm. For those whose B-ultrasound shows enlarged follicles but who cannot ovulate, human chorionic gonadotropin (hCG) can be used to induce ovulation and guide the timing of sexual intercourse. The ovulation rate of PCOS patients can reach over 80% after using CC, and the pregnancy rate can reach 30% to 60% when used alone. The two most significant side effects of clomiphene are mild ovarian enlargement (13.6%) and multiple pregnancy. Other side effects include hot flashes (10.4%), abdominal distension (5.5%), and rarely visual disturbances (1.5%). Some patients are ineffective with CC treatment, which is called clomiphene resistance. However, the current definition of clomiphene resistance is different. The maximum dose ranges from 150 to 250 mg. After three consecutive cycles of application, there is no ovulation response.

2) Gonadotropin (Gn) For patients with CC resistance, gonadotropin (Gn) is a commonly used ovulation-inducing drug, including FSH and HMG. Currently, there are various preparations of Gn, such as hMG, urinary FSH and recombinant FSH, but there are problems of high price, multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) risks when used. The conventional method starts 3 to 5 days after menstruation, with 1 tube of HMG per day or 75 IU of pure FSH per day. The ovulation rate and pregnancy rate are higher, but the incidence of ovarian overstimulation syndrome (OHSS) and the multiple birth rate are high. Currently, a small-dose slow-increase regimen is mostly used. This method has an ovulation rate of 70% to 90%, a single follicle development rate of 50% to 70%, a cycle pregnancy rate of 10% to 20%, and a low OHSS incidence of 0% to 5%. However, the treatment cycle is long and the patient cost is relatively high.

3) Letrozole ovulation induction therapy is a new indication for aromatase inhibitors (AIs), which were previously mainly used to treat breast cancer. They can be used alone or in combination with FSH. The main side effects include gastrointestinal effects, fatigue, hot flashes, and headache and back pain. The aromatase inhibitor commonly used in clinical practice is letrozole, which is mainly used for patients who are resistant to clomiphene. The ovulation rate is 80%. It is usually applied on the 3rd to 7th day of menstruation (5 days in total) after the start of the menstrual cycle or after progesterone withdrawal bleeding. The subsequent monitoring process is the same as clomiphene.

(3) Insulin sensitizer (ISD) therapy

A cardinal feature of PCOS is insulin resistance, which results in compensatory hyperinsulinemia in order to maintain normal glucose tolerance (normal insulin response to glucose ingestion). In young women with PCOS, hyperinsulinemia is a major risk factor for impaired glucose tolerance and later heart disease. In addition, hyperinsulinemia can also cause increased ovarian androgen synthesis, leading to anovulation, amenorrhea and infertility. Many PCOS women are obese, and their insulin resistance is more obvious due to weight gain; non-obese PCOS women (accounting for 20% to 50% of PCOS) often have an increased waist/hip ratio and a more obvious tendency to insulin resistance than the normal group. The main insulin sensitizing drugs are metformin, troglitazone, rosiglitazone, ioglitazone and D-Chiro-Inosito. Their main indications are PCOS women with insulin resistance, impaired glucose tolerance or type 2 diabetes.

2. Surgery

The treatment of PCOS patients has always been a difficult problem in clinical treatment. The earliest effective treatment was bilateral ovarian wedge resection (BOWR) reported by Stein and Leventhal in 1935, which ushered in the era of surgical treatment of infertility. Surgical treatment can reduce some granulosa cells in the ovaries, reduce the production of androgens by the ovarian stroma, and thus reduce the level of circulating androgens, and then reduce GnRH, causing a further decrease in serum androgen concentrations. This also shows that the ovarian stroma is also regulated by the pituitary-ovarian axis. Due to the decrease in androgen levels, most patients can resume spontaneous ovulation and menstruation after surgery, and some may become pregnant naturally, but most pregnancies occur about 6 months after surgery. Surgical treatments are divided into the following categories according to different methods:

(1) Bilateral ovarian wedge resection (BOWR) is the earliest and most effective method for treating anovulatory PCOS. The surgery requires the removal of 1/3 of the ovarian tissue. Stein et al. reported that 95% of patients were able to resume normal menstruation after surgery, and the pregnancy rate could reach 85%. Subsequent reports confirmed the effectiveness of this method, but the success rate varied greatly. However, this method has a variety of adverse reactions, including adhesion formation after surgery leading to tubal infertility. There are also reports of premature ovarian failure after surgery. Because this method causes great damage, it is rarely used nowadays.

(2) Laparoscopic ovarian electrocautery or laser drilling (LOD) Currently, the preferred surgical treatment method is laparoscopic ovarian drilling using thermal penetration or laser. The response to postoperative ovarian induction treatment is improved, the multiple pregnancy rate is reduced due to medical intervention, and the incidence of postoperative adhesions is significantly reduced compared with ovarian wedge resection. It is mainly suitable for second-line treatment of patients with clomiphene resistance. It has a high rate of single follicles and avoids multiple births and OHSS problems. Especially for those with BMI less than 29 and free androgen index less than 4, the treatment effect is good, with an ovulation rate of 80% to 90% and a pregnancy rate of 60% to 70%.

(3) Transvaginal hydrolaparoscopy (THL) is mainly used to examine the fallopian tube and ovarian structure in patients with infertility without obvious pelvic causes. The cumulative pregnancy rate of 6 months after ovarian drilling treatment of clomiphene-resistant PCOS patients reached 71%.

3. Assisted reproductive technology

For PCOS patients who have ovulated but have not become pregnant after more than 6 months of standard ovulation induction cycle treatment, or patients who have not ovulated after multiple drug ovulation induction treatments and auxiliary treatments and are in urgent need of pregnancy, assisted reproductive technology such as embryo transfer can be chosen.

(1) In vitro fertilization (IIVF) IVF-ET is an effective treatment for patients with refractory PCOS.

(2) In vitro oocyte maturation (IVM) is a technology that simulates the maturation environment of oocytes in vivo, allowing immature oocytes collected from the ovaries to reach final maturation in vitro. The high androgen level in PCOS patients makes it easy for them to have too many follicles recruited but maturation disorders during ovulation induction. Therefore, IVM technology provides a new way to treat infertility in PCOS patients.