bubble_chart Overview

Polycystic ovary syndrome (PCOS; Stein-Leventhal Syndrome; sclerocystic ovary disease) is a syndrome characterized by chronic anovulation, amenorrhea or oligomenorrhea, infertility, obesity, hirsutism, and polycystic ovarian enlargement. Polycystic ovary syndrome represents the final ovarian pathological changes caused by dysfunction of multiple endocrine axes. The initial neuroendocrine changes involve an increase in the frequency and pulse amplitude of GnRH-GnH release, leading to an elevated LH/FSH ratio.

bubble_chart Etiology

1. Genetic Factors PCOS is a disease caused by autosomal dominant inheritance, X-linked (sex-linked) inheritance, or gene mutations. Most patients have a karyotype of 46, XX, while some exhibit chromosomal aberrations or mosaicism such as 46, XX/45, XO; 46, XX/46, XXq, and 46, XXq.

2. Adrenal Initiation Hypothesis Chom (1973) proposed that PCOS originates from pre-pubertal adrenal disorders, where excessive androgen secretion from the zona reticularis under intense stress stimuli is converted to estrone outside the gonads. This feedback disrupts the GnRH-GnH release rhythm in the HP axis, leading to an elevated LH/FSH ratio, which in turn increases ovarian androgen production. Thus, both the adrenal glands and ovaries secrete more androgens, resulting in hyperandrogenemia. Hyperandrogenemia causes membrane fibrosis and thickening within the ovary, inhibits follicle development and ovulation, leading to cystic ovarian enlargement and chronic anovulation.

bubble_chart Pathological Changes

The typical polycystic ovary exhibits bilateral sclerotic polycystic changes. Grossly, the ovary appears fibrotic or collagenously thickened, tough, smooth, and exhibits an oyster shell color or grayish-white enhanced luminescence. The volume is increased by 2 to 5 times compared to normal.

On the ovarian section, numerous sub-membrane cystic follicles with diameters of 2 to 7 mm or larger retention follicular cysts are visible. Microscopic examination reveals sparse and scattered granulosa cells within the follicles, with hyperplasia of the follicular membrane cells. There is an increase in atretic follicles, and corpora lutea and corpora albicantia are extremely rare.

bubble_chart Clinical Manifestations

1. Menstrual disorders: Primary amenorrhea accounts for only 5%, while 51-77% of patients present with secondary amenorrhea, with normal or delayed menarche, followed by oligomenorrhea, hypomenorrhea, or amenorrhea. 12% still have regular menstruation, and 22-29% have dysfunctional uterine bleeding with unhealthy corpus luteum.

2. Infertility: 74% (35-94%) is due to chronic anovulation.

3. Hirsutism: 69% (17-83%), commonly seen on the lips, mandibular cheeks, lower abdomen, suprapubic area, inner thighs, and lateral calves, accompanied by acne, seborrhea, and alopecia areata. Hirsutism is not synchronous with hyperandrogenemia. (Lobo 1983).

4. Obesity: 41% (16-49%), often starting around puberty, progressive, due to the anabolic effects of hyperandrogenemia and extragonadal estrogen promoting cellular obesity.

5. Ovarian hyperplasia: 50-75%, bilateral symmetric polycystic enlargement 2-4 times, or one-third to one-fourth the size of the uterus in polycystic type, with 20-30% of ovaries not enlarged but sclerotic.

6. Complications: According to statistics, 19-25% of endometrial carcinoma patients under 40 years old are associated with PCOS. About 14% of PCOS cases progress to endometrial carcinoma within 14 years. {|105|}

bubble_chart Diagnosis

Diagnosis includes physical examination. The diagnosis of typical PCOS, also known as Stein-Leventhal syndrome, is not difficult. However, for the clinically common atypical cases, necessary experimental tests and ovarian pathology should be performed.

1. Hormone measurement

(1) Gonadotropins: About 75% of patients have elevated LH, with normal or decreased FSH, and LH/FSH ≥ 3.

(2) Steroid hormones

1. Androgens, including testosterone, dihydrotestosterone, androstenedione, and 17-ketosteroids, are elevated. Due to decreased SHBG, free androgens are increased.

2. Total estrogen can reach 140 pg/ml, estradiol is equivalent to early follicular phase levels of about 60 pg/ml, and increased extragonadal estrone production results in E₁/E₂ ≥ 1.

3. Adrenal DHEAS production increases, with plasma concentrations ≥ 3.3 μg/ml, and 17-hydroxyprogesterone is also elevated (normal <200ng/dL），然若≧800ng/dl應考慮為遲發型先天性腎上腺皮質增生症，21羥化酶或11β羥化酶缺陷。若處200～800ng/dl者，應作ACTH試驗（Cotrosyn0.25mg iv）注藥後60分鐘17羥孕酮升高者為先天性腎上腺皮質增生。

(3) Prolactin (PRL): About 25-40% of patients have levels ≥ 25 ng/ml.

(4) Insulin: Fasting insulin is elevated ≥ 14 mu/L, IGF-I is elevated (normal 120 mmol/L), and plasma IGF-I binding proteins are decreased (normal <300ng/mL）。

(5) Proopiomelanocortin (POMC) and its derivatives: β-lipotropin, β-endorphin, and β-MSH are elevated, ACTH is normal or elevated. TSH and GH are normal.

2. Ultrasound examination

Bilateral ovaries are polycystic and enlarged, with thickened membrane and strong echo. Numerous follicles with diameters of 2-7 mm can be seen under the membrane. The ovarian stroma shows uneven echoes, and the uterine membrane is thickened. Uterine and ovarian tumors and adrenal lesions should be excluded.

3. Retroperitoneal pneumography and hysterosalpingography

The purpose is to observe the morphology and size of the ovaries and adrenal glands to identify the cause of hyperandrogenemia.

4. Diagnostic curettage and endometrial biopsy

For patients aged ≥ 35 years, routine diagnostic curettage and endometrial biopsy should be performed to understand histological changes (cystic/adenomatous/atypical hyperplasia) and to exclude endometrial cancer.

5. Endoscopy

Including culdoscopy and laparoscopy, to directly observe ovarian morphology or perform biopsy, puncture, wedge resection, and electrocautery.

6. CT and MRI

To identify and exclude pelvic tumors.

7. Exploratory laparotomy

Performed when ovarian tumors are suspected or when ovarian wedge resection is planned.

bubble_chart Treatment Measures

1. Infertility Treatment

refers to ovulation induction therapy, which includes reasonable dietary management to improve insulin resistance, drug-induced ovulation, laparoscopic surgery, and assisted reproductive technology.

(1) Dietary Management: The focus is on reducing the carbohydrate/fat intake ratio to curb insulin resistance and lose weight to suppress abnormal gonadotropin and androgen secretion (Pasquali 1986).

(2) Drug-induced Ovulation: Mainly using Clomiphene Citrate (CC), and appropriately combining other ovulation-inducing drugs.

1. Clomiphene Citrate (CC): The first-choice ovulation-inducing drug, simple, safe, and effective to use. As an anti-estrogen, it competes with endogenous estrogen at the hypothalamic-pituitary level for receptors, inhibits estrogen feedback, causes GnRH-GnH release, increases ovulation induction, and directly promotes ovarian steroid hormone production (Kerin 1985).

Method: Start taking CC 50-200mg orally daily from the fifth day of the menstrual cycle (or progesterone withdrawal bleeding) for 5 days, with a maximum daily dose not exceeding 250mg to avoid causing ovarian hyperstimulation syndrome (OHSS). The above treatment is used for 3-6 cycles and monitors ovulation and pregnancy rates.

2. Tamoxifen: Suitable for those who are ineffective with CC treatment. Tamoxifen is also an anti-estrogen, and small-dose short-term treatment can promote ovulation, with the same mechanism as CC.

Method: Take 20-40mg/d from the second day (or fifth day) of the menstrual cycle (or progesterone withdrawal bleeding) for 5 days. The treatment effect is similar to CC.

3. CC-hCC: Suitable for those who cannot induce ovulation with CC alone or have combined luteal phase defects. That is, after completing CC 50-200mg/d×5 treatment, inject hCG 5000-10000 units intramuscularly once on the 15th day of the menstrual cycle, or inject hCG the next day when the follicle diameter is ≥18mm and serum E2 ≥300-500pg/ml under ultrasound monitoring of follicle development. ₂ ≥300-500pg/ml the next day.

4. CC-Dexamethasone: Suitable for PCOS combined with hyperandrogenemia, that is, those with elevated plasma testosterone and DHEAS. The method is to take dexamethasone 0.5mg/d before bedtime, with an ovulation rate of 50% in this group.

5. hMG-Dexamethasone: Suitable for those who are ineffective with CC treatment, hypogonadotropic hypogonadism, and hyperandrogenemia. The ovulation rate is 81%, and the pregnancy rate is 75%.

6. hMG-hCC: Suitable for those who are ineffective with CC treatment and hypogonadotropic hypogonadism. hMG 75-150 ^u /d intramuscular injection starts from the fifth day of the menstrual cycle, and hCG is injected intramuscularly at the right time after the follicle matures under ultrasound monitoring of follicle development and serum E2. ₂ under ultrasound monitoring of follicle development and serum E2.

7. Pure FSH (pFSH)-hCG: The purpose of using pFSH is to reduce the adverse effects of high LH and hyperandrogenemia during follicle development and oocyte maturation, and to improve the LH/FSH ratio. Recent clinical data show that replacing hMG with pFSH after GnRHa desensitization in PCOS does not significantly improve the success rate of IVF, so this group of treatments still needs further observation.

8. GnRHa-hMg-hCG: The purpose of GnRHa application is to promote pituitary desensitization, prevent premature menstruation intermediate stage [second stage] LH surge and premature luteinization of follicles, and suppress hyperandrogenemia. After 4 weeks of GnRHa treatment in PCOS patients, plasma androgen levels can be reduced to post-castration levels, without affecting adrenal-derived androgen secretion. The pregnancy rate in this group after 3 treatment cycles reached 77%, which is higher than that of the groups treated with hMG or HCG alone.

9. Pulsatile GnRHa Therapy: Suitable for individuals with hypogonadotropic hypogonadism, but shows no significant efficacy for PCOS patients. After this group treatment, an increase in LH and testosterone can be observed, with an ovulation rate of 38% and a pregnancy rate of 8%.

(3) Assisted Reproductive Technology: Only two groups have reported the use of IVF/ET for treating PCOS infertility. DaLe (1991) observed 44 cases treated with GnRHa-hMG for superovulation, with an average of 18.8±9 to 19.3±6.1 oocytes retrieved per cycle, and a pregnancy rate of 33% after embryo transfer. However, due to a canceled cycle rate of 24.13% (14/58) caused by OHSS, the value of assisted reproductive technology in PCOS treatment still requires further research.

II. Surgical Treatment

Includes ovarian wedge resection and laparoscopic microsurgery.

(1) Ovarian Wedge Resection (OWR): The exact mechanism of OWR in treating PCOS is not yet fully understood. Two literature reports indicate that serum To, Adione, E₁, and E₂ significantly decrease 3-4 days after OWR, followed by a decrease in LH while FSH remains unchanged. Two weeks post-operation, the LH/FSH ratio returns to normal, followed by follicular development and ovulation. The ovulation rate after OWR is 80%, with a pregnancy rate of 50%, and a postoperative adhesion rate of 41% (Buttram 1975). The application of new microsurgical techniques and new adhesive barrier methods can effectively prevent postoperative adhesions.

(2) Laparoscopic Ovarian Treatment: This is a new technique. It involves performing multiple punch biopsy resection (MPBR), ovarian cauterization, and multiple ovarian vaporization with laser and laser wedge resection using laparoscopy.

III. Treatment of Hirsutism and Hyperandrogenemia

In PCOS, the incidence of hirsutism is 20-80%, and its severity is not synchronized with hyperandrogenemia but is related to 5a-reductase activity. Treatment depends on the source of hyperandrogenemia (ovarian or adrenal) and the degree of hirsutism (mild, moderate, severe) to choose different drug treatments.

(1) Ovarian Hyperandrogenemia: Oral contraceptives (OC), GnRHa, and Ketoconazole (a competitive α-receptor blocker imidazole derivative) are selected.

OC negatively feedback inhibits the release of GnRH-GnH to reduce ovarian androgen production, promotes SHBG synthesis to lower free testosterone concentration, and inhibits endometrial hyperplasia to treat mild to moderate hirsutism.

GnRHa inhibits ovarian androgen production through pituitary desensitization and down-regulation to treat moderate to severe hirsutism, requiring long-term treatment.

Ketoconazole inhibits ovarian and adrenal androgen production by blocking cytochrome P450-dependent enzyme activity, with a dose of 500-600mg/d for at least 6 months. Side effects include liver and kidney damage.

(2) Adrenal Hyperandrogenemia: Mainly treated with glucocorticoids and Ketoconazole. Glucocorticoids negatively feedback inhibit ACTH release to suppress adrenal androgen production, with an efficacy rate of 26%.

(3) Anti-androgen drugs: including spironolactone, cyproterone acetate (CPA), and flutamide.

Spironolactone is an aldosterone antagonist and has various anti-androgenic activities, such as inhibiting testosterone production, increasing the conversion of testosterone to E₁, antagonizing 5a-reductase activity and androgen receptors (1986). Its dose range is 75～200mg/d. The effective rate is 72%. With large-scale long-term treatment, side effects include hypermenorrhea 65% and intermenstrual bleeding 33%.

CPA is a derivative of 17-hydroxyprogesterone, an androgen receptor antagonist, which inhibits GnH release and ovarian androgen production and increases testosterone MCR. Due to its long half-life, it is often combined with ethinyl estradiol (EE₂) as an OC (CPA2mg+EE₂35～50μg, Dianette/Diane), or combined with natural estrogen (sequential) application, such as CPA50～100μg/d taken from the fifth to the fourteenth day of the menstrual cycle, along with EE₂35～50μg or 17β-E₂100μg/d, taken from the fifth to the twenty-fourth day. Long-acting injection type 300mg/month (Marcondes 1990). High dose (>100mg/d) acts quickly, while low dose (2～20mg/d) acts slowly.

Flutamide is only an androgen receptor antagonist and does not affect serum androgen concentrations (To, FTo, △⁴dione, DHEAS and E₂, SHBG). Dose 250mg two to three times daily should be combined with OC to avoid accidental pregnancy and feminization of male fetuses.

(4) Drug selection for hirsutism treatment: ① Mild cases: OC; ② Moderate/severe cases: Spironolactone + OC; CPA + OC; Flutamide + OC. In addition to drug treatment, local cosmetic treatment is also necessary.

bubble_chart Differentiation

PCOS should be differentiated from other diseases that cause amenorrhea, hirsutism, and ovarian enlargement:

1. Ovarian androgen-secreting tumors

including Sertoli-Leydig cell tumor, hilus cell tumor, lipid cell tumor, gonadoblastoma, adrenal rest tumor, luteoma, teratoma, and metastatic carcinoma. Except for gonadoblastoma, most of these tumors are unilateral, solid tumors with autonomous androgen secretion, obvious virilization, and often accompanied by ascites and metastases.

2. Adrenal diseases

including congenital adrenal hyperplasia, adenoma, and carcinoma. The latter two mainly secrete androstenedione and DHEA, which are also autonomously secreted and not promoted by ACTH or suppressed by dexamethasone. In congenital adrenal hyperplasia with 21-hydroxylase deficiency, there is a typical urogenital sinus malformation with genital dysplasia.

3. Thyroid diseases

including hyperthyroidism and hypothyroidism. In hyperthyroidism, T₃, T₄, and SHBG are increased, and the metabolic clearance rate of androgens is reduced, leading to elevated plasma testosterone, causing virilization and menstrual disorders. In hypothyroidism, the conversion of androgens to estrogens increases, leading to anovulation.

4. Hereditary hirsutism

has a family history, with only simple hirsutism without PCOS symptoms and signs. Fertility is normal.

5. Ovarian hyperthecosis

In this condition, gonadotropin secretion is normal, the ovaries are not enlarged, but the theca cells show nest-like (island) hyperplasia, with significantly elevated plasma androgens and severe virilization. It is not sensitive to clomiphene treatment.

6. Insulin resistance syndrome and acanthosis nigricans

This is a disease of insulin receptor defects (type A/B), which can present with symptoms and signs similar to PCOS. Its significant features are hyperinsulinemia and acanthosis nigricans on the neck and armpits.

7. Hyperprolactinemia

amenorrhea, galactorrhea, infertility, elevated PRL and DHEAS, with no obvious virilization and normal ovaries.