Porth's Essentials of Pathophysiology, 4e

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Genitourinary and Reproductive Function

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Chronic anovulation, causing amenorrhea or irregu- lar menses, is now thought to be the underlying cause of the bilaterally enlarged “polycystic” ovaries. Hence, the polycystic ovary is a sign of the disease, not the cause of the disease. There is increasing evidence that the disor- der may begin before adolescence and that many of the manifestations of PCOS begin to make their appearance at that time. Because many of the symptoms common to PCOS, such as hirsutism, acne, and obesity, can be detrimental to a teenage girl’s health and self-esteem, early detection and treatment of PCOS in adolescents are essential. 40 The underlying etiology of the disorder is unknown, although most women have altered gonadotropin lev- els. 4,40 This is manifested by increased release of LH in relation to FSH release, with a resultant increase in production of androstenedione and testosterone by the theca cells of the ovary. Androstenedione, in turn, is con- verted to estrone within adipocytes. Although estrone is a weak estrogen, it stimulates LH release and suppresses FSH release. The resultant decrease in FSH levels allows for new follicular development, but full maturation is not attained and ovulation does not occur. The elevated LH levels result in increased androgen production, which in turn, prevents normal follicular development and contributes to a vicious cycle of anovulation and multiple cyst formation. Increased androgen levels also lead to the development of acne and hirsutism. The typical woman with PCOS has hyperinsulinemia and many of the signs of the metabolic syndrome (see Chapter 33). 4 It has been shown that the cause of hyper- insulinemia is insulin resistance. The frequency and degree of hyperinsulinemia in women with PCOS is often amplified by the presence of obesity. In addition to its clinical manifestations, long-term health problems linked to PCOS include cardiovascular disease and type 2 diabetes. Classic lipid abnormalities include elevated triglyceride levels, low HDL levels, and elevated LDL levels. Hypertension is also common in women with PCOS. There is also concern that women with PCOS who are anovulatory do not produce progesterone. This, in turn, may subject the endometrium to an unop- posed estrogen environment, which is a significant risk factor for development of endometrial cancer. 4,40 The diagnosis of PCOS can be suspected from the clinical presentation. Although there is no consensus as to which tests should be used, laboratory evaluation to exclude hyperprolactinemia, late-onset adrenal hyper- plasia, and androgen-secreting tumors of the ovary and adrenal gland are commonly done. Because of the high risk of insulin resistance, a fasting blood glucose, 2-hour oral glucose tolerance test, and insulin levels may be done to evaluate for hyperinsulinemia. Confirmation with ultrasonography or laparoscopic visualization of the ovaries is often done, but not required. 38 The overall goal of treatment of PCOS should be directed toward symptom relief, prevention of potential malignant endometrial sequelae, and reduction in risk for development of diabetes and cardiovascular disease. The preferred and most effective treatment for PCOS is lifestyle modification. Weight loss may be beneficial

in restoring normal ovulation when obesity is present. Combined oral contraceptive agents ameliorate men- strual irregularities and improve hirsutism and acne. The addition of spironolactone, a mineralocorticoid antagonist that inhibits the production of androgens by the adrenal gland, may be beneficial to women with severe hirsutism. 4 Insulin-sensitizing agents (e.g., metformin) alone or with ovulation-inducing medications are emerging as an important component of PCOS treatment. 40 In addition to expected improvements in insulin sensitivity and glu- cose metabolism, they have been associated with reduc- tions in androgen and LH levels and are highly effective in restoring normal menstrual regularity and ovulatory cycles. Ovarian Cancer Ovarian cancer is the second most frequent gyneco- logic malignancy after endometrial cancer in the United States, and it carries the highest mortality rate of all gen- ital cancers combined. 6 The incidence of ovarian cancer and mortality rate increases with age, with most cases occurring in women older than 50 years of age. 41 Malignant ovarian tumors are categorized accord- ing to cell type of origin—epithelial cell tumors, germ cell tumors, and gonadal stromal cell tumors (see Fig. 40-16). Approximately 90% of ovarian can- cers are of epithelial cell origin. 6,7 These tumors tend to occur in older women, are usually discovered late in the disease, and have a high mortality rate. The nonepithe- lial ovarian cancers, which include germ cell tumors and stromal cell tumors, tend to occur in a younger popula- tion of women. They typically present with earlier signs of disease and excellent survival potential when detected early. The most significant risk factor for ovarian cancer appears to be ovulatory age—the length of time during a woman’s life when her ovarian cycle is not suppressed by pregnancy, lactation, or oral contraceptive use. 41–43 The incidence of ovarian cancer is much lower in coun- tries where women bear numerous children. Epithelial cancer of the ovaries derives from malignant transfor- mation of the epithelium of the ovarian surface. When these epithelial cells are situated over developing folli- cles, they undergo metaplastic transformation whenever ovulation occurs. It follows that repeated stimulation of the epithelium of the ovarian surface, which occurs with uninterrupted ovulation, may predispose the epi- thelium to malignant transformation. Family history also is a significant risk factor for ovarian cancer. The breast cancer susceptibility genes, BRCA1 and BRCA2 mutations, which are tumor-suppressor genes, increase the susceptibility to ovarian cancer 6,7,41–43 (see Chapter 7). The estimated lifetime risk of ovarian cancer in women bearing the BRCA1 and BRCA2 mutations is 23% to 54%. A high-fat Western diet and use of pow- ders containing talc in the genital area are other factors that have been linked to the development of ovarian cancer.