POLYCYSTIC OVARY SYNDROME (PCOS)

Polycystic ovarian syndrome (PCOS) was originally described in 1905 by Stein and Leventhal as a syndrome consisting of amenorrhea, hirsutism, and obesity in association with enlarged polycystic ovaries. It is now realized that this relatively common syndrome is an extremely heterogenous clinical syndrome that begins soon after menarche and some authors prefer to refer to it as a syndrome of hyperandrogenic chronic anovulation. In fact, earlier studies of PCOS have focused on ovarian morphological findings and were considered to be an important diagnostic criteria. However, it was found that polycystic changes of the ovaries were observed in some normally cycling women. Furthermore, polycystic changes of the ovaries were shown to be associated with other well-defined diseases such as Cushing's syndrome, and an ovarian or adrenal tumor capable of producing androgen.

In addition, recent studies have demonstrated that some women with characteristic clinical features of PCOS have normal-sized ovaries. Indeed, nothing inherently abnormal has thus far been found in the ovaries of PCOS. Therefore, the focus on ovarian morphology was shifted towards the hormonal characteristics of the syndrome.

The incidence of PCOS is about 3% in both adolescents and adults. It is the most common cause of hyperandrogenisim of prepubertal onset. However, it appears that there is some variabilities of PCOS clinical manifestations among races. Obesity and hirsutism are not pronounced in Japanese women with PCOS. In the United States, 70% of patients have hirsutism compared to 10-20% in Japan and the Orient. Obesity, although thought to be common in PCOS is usually noted in 40% of cases. There is no particular pattern with respect to fat distribution. However, obesity is an important feature with regard to hirsutism because it is associated with decreased sex hormone binding globulin (SHBG), which results in an increased fraction of unbound testosterone.

In addition, obesity contributes to chronic estrogen stimulation because there is increased peripheral conversion of androgen to estrogens in these patients. Among women with resistant acne, not responding to conventional treatments, the polycystic ovary syndrome is very common. The primary affected areas are the facial (angle of the jaw, upper lip, and chin) and suprapubic region of the body. Other common sites include the chest, inner thigh, and perineum. Another clinical sign in hyperandrogenic syndromes is acanthosis nigricans. It is characterized by symmetric, velvet-like, grey-brown hyperpigmentation of the skin. It commonly affects the nape of the neck, axillae and groin.

The most common features of PCOS are chronic anovulation and infertility in addition to the hyperandrogenism. The clinical manifestation of chronic anovulation include irregular menstrual cycles, oligo or amenorrhea interspersed with heavy vaginal bleeding. The menstrual dysfunction usually presents from menarche. In the absence of ovulation, the usual premenstrual molimina does not occur. In addition, because there is unopposed estrogen stimulation of the endometrium, endometrial hyperplasia and in some instances, adenocarcinoma may develop.

Fortunately, adrenocarcinomas associated with PCOS is usually of low histologic grade and presents at an early stage. In PCOS, chronic anovulation reflects abnormal folliculogenesis. As a result, these patients suffer from infertility. Occasionally, spontaneous ovulation and pregnancy may occur in this syndrome. A family history may be present in a subset of patients. However, so far, efforts to elucidate a particular mode of genetic inheritance have been unsuccessful. PCOS is an endocrinologic disorder of undetermined etiology characterized by inappropriate gonadotropin-releasing hormone (GnRH) pulse amplitude and tonically elevated levels of luteinizing hormone (LH), but not of follicle-stimulating hormone (FSH).

In addition, there are increased circulatory levels of androgens produced by both the ovaries and the adrenal glands. If they are elevated, serum testosterone levels are usually between 70-120ng/dl, and androstenedione levels are usually between 3 and 5ng/ml. Also, about half the women with this syndrome have elevated DHEA-S. The presence or absence of hirsutism depends on whether these androgens are converted peripherally by 5 alpha reductase to the more potent androgen DHT dihydrotestosterone and 3 alpha diol-G as reflected by increased levels of 3 alpha-diol-G. Therefore, it is skin 5-alpha reductase activity that largely determine the presence or absence of hirsutism. The chronically elevated LH are usually above 20 mIU/ml. Because FSH levels in PCOS patients are normal or low, it has been found that an LH/FSH ratio greater than 3, provided the LH level is not lower than 8mIU/ml, may be used to suggest the diagnosis in women with clinical features of PCOS. About 20% of women with PCOS also have mildly elevated levels of prolactin (20-30ng/ml), possibly related to increased pulsatility of GnRH or to a relative dopamine deficiency or to both. In addition, many women with this syndrome have mild degrees of hyperinsulinism and insulin resistance.

The diagnosis of PCOS is strongly suggested by the clinical history and physical examination. In particular, a pattern of infrequent and irregular menstruation commencing at time of puberty is highly suggestive. Evidence of concomitant excessive hair is almost pathognomonic. The most worrisome consideration in the hirsute woman is the presence of an androgen-producing neoplasm. It is for this reason that a measurement of total testosterone and DHEA-S is recommended. A level greater than 200ng/dl, as determined by radioimmunoassay with chromatographic separation should raise suspicion of an androgen-producing tumor of ovarian or adrenal origin. Serum DHEA-S is the marker of adrenal androgen and a level greater than 700ng/dl implies a possible neoplasm. Mild to moderate hirsutism may reflect the presence of CAH, 21 hydroxylase deficiency, although severe hirsutism is frequently the case.

Other characteristic clinical findings associated with hirsutism in this disorder include regular menstrual cycles, virilization such as clitoromegaly, family history, and short stature. Although 17-OH progesterone is elevated in both PCOS and CAH, 21 hydroxylase deficiency, levels rarely exceed 300ng/dl in PCOS. Therefore, concentration above 300ng/dl suggest CAH, 21 hydroxylase deficiency and ACTH stimulation should be performed. Other enzyme defects of CAH that give rise to hirsutism are deficiencies of 11-beta hydroxylase deficiency and 3-beta hydroxylase deficiency. Diagnosis of the former is suggested by the presence of coexistent hypertension and salt retention, whereas the latter condition is associated with a marked elevation of serum DHEA-S.

The treatment of PCOS is directed primarily at the problems of hirsutism, menstrual irregularity and infertility. Treatment modalities for hirsutism include ovarian and adrenal suppression, anti- androgen therapy and local depilatory measures. Oral contraceptives are simple and relatively safe method of ovarian suppression, in addition the estrogen component increases the sex hormone binding globulin SHBG with a resultant decrease in free testosterone. A direct target organ effect of the progestins is inhibition of 5 alpha reductase enzyme and competition for androgen receptors. When DHEA-S levels are elevated, the addition of dexamethasone may be helpful. Spironolactone is the preferred anti- androgenic compound. It competitively inhibits intracellular dihydrotestosterone receptors within the hair follicles. Both cimetidine and cyproheptadine (a serotonin and histamine antagonist) have weak anti- androgenic effects.

The drug commonly used to induce ovulation is clomiphene citrate and in patients who do not respond to an optimal dose, the addition of human chorionic gonadotropin may be beneficial. In patients with increased circulating DHEA-S and in patients who fail to ovulate on clomiphene citrate alone, the concomitant use of dexamethasone (0.25-0.5mg/day) has been shown to increase both ovulation and pregnancy rates. Also, human menopausal gonadotrophin (HMG) may be tried in clomiphene citrate resistant patients. Laparoscopy electrocauterization or laser cauterization of all visible subcapsular follicles of the polycystic ovaries in patients who failed medical therapy remain experimental. Wedge resection is now rarely performed because it can result in pelvic adhesion and many effective hormonal regimens are available.

REFERENCES

Cheung PA et al. Polycystic ovary syndrome. Clin Obst & Gyne 33: 655-667; 1990.

Droegemueller W, Herbert AL, Mishell DR and Stenchaver MA. Hyperandrogenism. In Comprehensive Gynecology. Second ed. 1992.

Lobo RA. Hirsutism in polycystic ovary syndrome: current concepts. Clin Obst & gyne 34: 817-826; 1991.

Rosenfeld RL. Hyperandrogenism in prepubertal girls. Current Issues in Pedia & Adolescent Endocrinology 37: 1333-1358; 1990.

Taketani Y. Pathophysiology of polycystic ovary syndrome. Horm Res 33: 3-4; 1990.