Hunter syndrome

Recent diagnostic and pharmacologic developments have focused renewed attention on polycystic ovary syndrome. Clinical features of the syndrome include anovulation, hyperandrogenism and menstrual dysfunction, but several other abnormalities, including hyperinsulinemia, luteinizing hormone hypersecretion, elevated testosterone levels and acyclic estrogen production, have been documented. Accompanying obesity and lipid abnormalities compound the risk of developing diabetes mellitus or cardiovascular disease, and chronic anovulation increases the risk for endometrial cancer. A careful history and physical examination should guide diagnostic testing. Slowly progressive hyperandrogenic symptoms with anovulation of peripubertal onset often represent polycystic ovary syndrome. Treatment goals include symptom management and the identification and prevention of potential cardiovascular risks. Treatment should take into account the patient's desire for fertility. Advances in transvaginal ultrasonography and infertility treatments, including newer medications, have facilitated assisted reproduction in patients with polycystic ovary syndrome. Ongoing pharmacologic research focusing on the treatment of insulin resistance appears promising in reversing the long-term complications of the syndrome. (Am Fam Physician 2000;62:1079-88,1090.)

Polycystic ovary syndrome, one of the most common endocrine disorders, affects approximately 6 percent of women of reproductive age.(1) The syndrome is the most frequent cause of anovulatory infertility, with its underlying etiology unknown. The classic description of the syndrome, which includes clinical findings of amenorrhea, hirsutism and bilaterally enlarged ovaries, is representative of more advanced cases.(2)

Polycystic ovary syndrome is now recognized as a heterogeneous syndrome. Affected women often have signs and symptoms of elevated androgen levels, menstrual irregularity and amenorrhea, without a well-defined cause of androgen excess.(3) The syndrome has an initial onset in the peripubertal years and is progressive.

Recent developments in pelvic ultrasonography have enabled more detailed descriptions of bilaterally enlarged cystic ovaries. Studies on the treatment of underlying metabolic disturbances associated with polycystic ovary syndrome are presently being conducted. Current treatment approaches are directed at preventing potential long-term consequences of the chronic anovulation and metabolic disturbances that are often associated with the syndrome.

Pathophysiology

The underlying defect in polycystic ovary syndrome remains unknown, but there is growing consensus that key features include insulin resistance, androgen excess and abnormal gonadotropin dynamics.(4) Recent evidence suggests that the principal underlying disorder is one of insulin resistance, with resulting hyperinsulinemia stimulating excess ovarian androgen production.(5,6)

Based on the two-cell two-gonadotropin theory of ovarian steroidogenesis, androgens produced by luteinizing hormone (LH)-stimulated theca cells normally undergo aromatization to estrogens by follicle-stimulating hormone (FSH)-stimulated granulosa aromatase.(7) This shift from an androgenic to an estrogenic environment follows an increase in aromatase activity within the developing follicle, and ovulation usually follows.

In patients with polycystic ovary syndrome, the ratio of follicular androstenedione to estradiol is high, suggesting an aromatization defect, and a recent P450 aromatase gene mutation has been found to cause a form of the syndrome.(8) This increase in intraovarian androgens is believed to play a significant role in the anovulatory process.(9)

When any anovulatory state exists for a period of time, the "polycystic ovary" emerges. As an end result, affected women develop bilaterally enlarged polycystic ovaries, defined by the presence of more than eight follicles per ovary, with the follicles less than 10 mm in diameter. These ultrasound findings are present in more than 90 percent of women with polycystic ovary syndrome,(10) but they are also present in up to 25 percent of normal women.(11,12)

Gonadotropin abnormalities in polycystic ovary syndrome include elevated levels of testosterone and LH or an elevated LH-to-FSH ratio, an increased LH pulse frequency and altered diurnal rhythm of LH secretion. Elevated serum LH levels are present in a significant proportion of women with the syndrome but are not necessary for its diagnosis.(13)

Clinical Signs and Symptoms

Although anovulation, obesity, hirsutism and bilateral polycystic ovaries are considered classic manifestations, polycystic ovary syndrome is perhaps best viewed as a spectrum of symptoms, pathologic findings and laboratory abnormalities. In 1990, the National Institutes of Health (NIH) proposed new diagnostic criteria for this disorder--hyperandrogenism and chronic anovulation--excluding other causes such as adult-onset congenital adrenal hyperplasia, hyperprolactinemia and androgen-secreting neoplasms.(14)

Women with polycystic ovary syndrome may display a wide range of clinical symptoms (Table 1),(15) but they usually present for three primary reasons: menstrual irregularities, infertility and symptoms associated with androgen excess (e.g., hirsutism and acne). In one study,(15 70) percent of affected women reported menstrual dysfunction. A smaller percentage of women with polycystic ovary syndrome actually have normal cycles. Most women with the syndrome experience menarche at a normal age but have irregular menstrual periods that gradually become more abnormal, often leading to amenorrhea.

Clinical signs include those associated with a hyperandrogenic anovulatory state. Hirsutism and acne are common. Approximately 70 percent of affected women manifest growth of coarse hair in androgen-dependent body regions (e.g., sideburn area, chin, upper lip, periareolar area, chest, lower abdominal midline and thigh), as well as upper-body obesity with a waist-to-hip ratio of greater than 0.85.(16) Patients usually retain normal secondary sexual characteristics and rarely exhibit virilizing signs such as clitorimegaly, deepening of the voice, temporal balding or masculinization of body habitus. Obesity is present in up to 70 percent of patients. Ovarian enlargement may be unilateral or absent.(4)

In recent years, it has become apparent that polycystic ovary syndrome is also associated with insulin resistance and an increased risk for the development of glucose intolerance or type 2 diabetes mellitus.(1,4,17,18) Although not always recognized in the early stages, hyperinsulinemia and insulin resistance occur at higher rates in women with the syndrome than in weight-matched control subjects.(19,20) Hyperinsulinemia is also believed to be a key factor leading to hyperproduction of ovarian androgens. Acanthosis nigricans, which commonly occurs in persons with high states of insulin resistance, may also be present.

Complications

Untreated polycystic ovary syndrome may be regarded as a disorder that progresses until the time of menopause. Ongoing studies lend support to the hypothesis that women with the syndrome are at increased risk for the development of cardiovascular disease.(21) Because the syndrome is also associated with lipid abnormalities, affected women could benefit from measures to prevent cardiovascular disease and the other sequelae of long-standing hypertension and diabetes mellitus that are associated with the syndrome.

Other long-term effects of polycystic ovary syndrome are related to the clinical consequences of persistent anovulation. These effects include infertility, menstrual irregularities ranging from amenorrhea to dysfunctional uterine bleeding, hirsutism and acne.

More important, the long-term effects of unopposed estrogen place women with the syndrome at considerable risk for endometrial cancer, endometrial hyperplasia and, perhaps, breast cancer.(22,23) The risk of endometrial cancer is three times higher in women with polycystic ovary syndrome than in normal women. In addition, small observational studies have suggested that chronic anovulation during the reproductive years is associated with a three to four times increased risk of breast cancer in the postmenopausal years. Other studies have failed to find an association with increased rates of breast cancer. Although no evidence shows that outcomes are improved, mammography and endometrial sampling to search for underlying estrogen-stimulated cancer should be considered in high-risk women with dysfunctional uterine bleeding.(24)

Differential Diagnosis

Polycystic ovary syndrome is one of the most common endocrine disorders in women of reproductive age. However, anovulation in the reproductive years may also be due to rapid fluctuations in weight or extreme physical exertion (normal FSH and LH levels), eating disorders (low FSH and LH levels), premature ovarian failure (high FSH and LH levels), use of certain medications (i.e., progestational agents), pituitary adenoma with elevated prolactin levels, or hyperthyroidism or hypothyroidism (Table 2). Other potential causes of androgen excess and menstrual irregularities include conditions unique to pregnancy, such as luteoma and a hyperactive luteal body.

Although as many as 20 percent of healthy eumenorrheic patients have morphologic features consistent with polycystic ovary syndrome, only a fraction of these women have the accompanying endocrinologic abnormalities of menstrual irregularity and hyperandrogenism.(11,25)

Laboratory and Imaging Studies

In the absence of pregnancy and when amenorrhea or oligomenorrhea has persisted for six months or more without a diagnosis, a careful history and physical examination should be undertaken, with particular attention to patterns of hair distribution and a search for acanthosis nigricans.

Like the clinical symptoms, the laboratory biochemical findings in polycystic ovary syndrome lack uniformity, and some controversy exists concerning the diagnostic criteria that should be used to identify the disorder (Table 3).(14) Polycystic ovary syndrome is primarily a clinical diagnosis, and the evaluation should be tailored to the clinical presentation. Compared with healthy control subjects, many women with this syndrome have elevated levels of testosterone, androstenedione, LH, estradiol, estrone and fasting insulin, an elevated LH-to-FSH ratio, and reduced levels of sex hormone-binding globulin.(26,27)

With respect to hyperandrogenism, some debate exists about whether the diagnosis should be based on assays of circulating androgens or on the clinical signs and symptoms of hirsutism and/or acne. Use of clinical assays of elevated testosterone has been advocated because a substantial number of women with polycystic ovary syndrome have no overt clinical signs of androgen excess.(15)

Attention has also been given to ovarian morphology as a primary distinguishing characteristic.(28) With this approach, the diagnosis of polycystic ovary syndrome is based on the finding of more than eight discrete follicles in the ovary, with the follicles less than 10 mm in diameter and usually peripherally arrayed around an enlarged hyperechogenic ovarian stroma. Typically, the multiple follicles resemble a "pearl necklace" on ultrasound examination. Improvements in ultrasound assessment using a transvaginal approach have allowed better delineation of multiple follicular cysts.

Inappropriate gonadotropin secretion has been used to diagnose polycystic ovary syndrome. LH and FSH levels and the LH-to-FSH ratio are used to facilitate diagnosis, and many researchers consider an LH-to-FSH ratio of 3:1 diagnostic of the syndrome.(29)

The suggested laboratory and radiologic evaluation of women with chronic hyperandrogenic anovulation is presented in Table 4.(15) The urine human chorionic gonadotropin (hCG) level should be measured to exclude pregnancy in any woman of reproductive age who has menstrual irregularities or amenorrhea. In the absence of pregnancy-related conditions, hCG is low or absent in patients with polycystic ovary syndrome.

Although serum testosterone levels may be mildly to moderately elevated in women with polycystic ovary syndrome, testosterone levels are generally measured to rule out virilizing tumors. In particular, a virilizing tumor should be suspected when hirsutism is rapidly progressive. The presence of a virilizing tumor is strongly suggested when the mean of three separate serum testosterone measurements is greater than 150 to 200 ng per dL.

Consideration should also be given to measuring dehydroepiandrosterone sulfate (DHEAS) levels to screen for a virilizing adrenal tumor in women with rapidly progressive hirsutism. DHEAS levels above 700 [micro]g per dL in premenopausal women are suggestive of such a tumor.

In women with androgen excess, the prolactin level should also be measured to exclude a possible prolactinoma. Although up to 22 percent of women with polycystic ovary syndrome may have mildly elevated prolactin levels,30 profound prolactinemia should be investigated further.

The serum 17-hydroxyprogesterone (17-OHP) measurement is a screening test for adult-onset congenital adrenal hyperplasia. This test should be considered when the initial evaluation for polycystic ovary syndrome is nondiagnostic in hyperandrogenic anovulatory women. Common signs of hyperandrogenism in postadolescent women with adult-onset congenital adrenal hyperplasia are hirsutism, acne and menstrual irregularity. As many as 25 percent of women with adult onset of this disorder also exhibit LH hypersecretion. Serum levels of 17-OHP should be drawn at 8 a.m. in the morning. Basal follicular-phase serum 17-OHP levels above 5 ng per mL suggest adult-onset congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. In contrast, serum 17-OHP levels are normal in women with polycystic ovary syndrome.(31)

An overnight dexamethasone suppression test should be performed in women with physical features of cortisol excess, such as hypertension, central obesity, facial plethora, easy bruising, striae, proximal muscle weakness and/or increased cervicodorsal-supraclavicular fat. For this test, 1 mg of dexamethasone is administered orally at 11 p.m., and serum cortisol measurements are taken at 8 a.m. the following morning. Serum cortisol levels below 5 [micro]g per dL (140 nmol per L) make the diagnosis of Cushing's syndrome unlikely but are routinely present in women with polycystic ovary syndrome.

All obese hyperandrogenic anovulatory women should be screened for abnormal glucose metabolism because of the association of glucose intolerance with polycystic ovary syndrome. A fasting glucose measurement is a reasonable screening test for diabetes mellitus. If the fasting glucose level is less than 110 mg per dL (6.1 mmol per L), the patient probably has normal glucose metabolism, whereas a finding of fasting glucose values greater than 126 mg per dL (7.0 mmol per L) on two separate occasions is diagnostic of diabetes mellitus. Fasting glucose levels between 110 and 126 mg per dL indicate some degree of glucose intolerance.

To aid in the possible prevention of cardiovascular disease, consideration should be given to screening for lipid abnormalities and monitoring blood pressure annually. Identified abnormalities should be treated appropriately with dietary and pharmacologic interventions.

Treatment

Because the primary cause of polycystic ovary syndrome is unknown, treatment is presently directed at the symptoms of the disorder. Few treatment approaches improve all aspects of the syndrome, and the patient's desire for fertility may preclude treatment despite the presence of symptoms.

Treatment goals should include maintaining a normal endometrium, antagonizing the actions of androgens on target tissues, reducing insulin resistance (when present) and correcting anovulation. The patient's desire for fertility is an important consideration, because the available treatments, particularly those used to induce ovulation, have their own complications. Note that spontaneous resumption of menses, along with improved pregnancy rates, has occurred.(32)

BEHAVIOR MODIFICATIONS

Behavior modifications, including weight reduction, diet and exercise, are recommended for all women with polycystic ovary syndrome. These measures remain important even when pharmacologic therapy is used. Weight reduction decreases serum androgen (testosterone), insulin and LH levels. Frequently, weight reduction also improves lipid abnormalities.

PHARMACOLOGIC TREATMENT

Medroxyprogesterone (Provera), in a dosage of 5 to 10 mg per day for 10 to 14 days each month, or norethindrone (Norlutin), in a dosage of 5 to 20 mg per day for 10 to 14 days each month, can be used in women who do not wish to conceive and are not at risk for pregnancy. Monthly progestin therapy avoids abnormal endometrial proliferation but does not suppress ovarian androgen production.

Low-dose oral contraceptive pills are another option in patients who do not desire pregnancy. Advantages of this approach include contraception, prevention of endometrial hyperplasia and cancer, normalization of menstrual cycles and treatment of hirsutism and acne. Women with hirsutism usually notice clinical improvement after approximately six months of treatment with oral contraceptive pills, although additional electrolysis or depilatory therapy may be necessary.

Antiandrogens may be combined with oral contraceptive pills for the treatment of hirsutism. Up to 75 percent of women report clinical improvement with this combination therapy.(31) If used alone, antiandrogens may produce irregular uterine bleeding. The most commonly used antiandrogens are spironolactone (Aldactone), flutamide (Eulexin) and cyproterone (Cyprostat). These agents should not be used in pregnant women. Spironolactone, in a dosage of 25 to 100 mg administered twice daily, is the most commonly used antiandrogen because of its safety, availability and low cost. Flutamide is usually given in a dosage of 250 mg twice daily, and cyproterone is given in a dosage of 25 to 50 mg per day for 10 days each month.

Gonadotropin-releasing hormone (GnRH) analogs such as luprolide (Lupron) should be reserved for use in women who do not respond to combination hormonal therapy or cannot tolerate oral contraceptive pills. The GnRH analogs should be used cautiously, with particular attention given to long-term consequences (e.g., hot flushes, bone demineralization, atrophic vaginitis) that can occur secondary to hypoestrogenemia induced by these agents.(31)

Ovulation-inducing agents are usually employed in patients who desire pregnancy. These patients are often best managed by a reproductive endocrinologist or a primary care physician who is familiar with ovulation induction. Clomiphene citrate (Clomid) is a mainstay of treatment. Ovulation is successful in approximately 75 percent of women treated with clomiphene, but subsequent pregnancy rates are only 30 to 40 percent.(33)

Women who do not respond to clomiphene or are unable to conceive with clomiphene therapy may be treated with human menopausal gonadotropins such as follitropin alpha (Gonal-F). This therapy has achieved pregnancy rates of 58 to 82 percent, but the risks from ovarian hyperstimulation and multiple pregnancies remain of concern.(33)

Treatment with an insulin-sensitizing agent such as metformin (Glucophage), in a dosage of 500 mg two to three times daily, has been shown to improve insulin sensitivity and decrease serum LH and free testosterone levels. Studies have found that metformin restores menstrual cyclicity in 68 to 95 percent of patients treated for as short a time as four to six months.(34,35) Although insulin-sensitizing agents show promise in the treatment of polycystic ovary syndrome, there are no studies of adequate power or design to allow them to be recommended as standard therapy, especially in women with normal glucose function.

Specific details about selected pharmacologic options are presented in Table 5.

SURGERY

Recent successes with ovulation-inducing agents has decreased the use of ovarian wedge resection surgery. Newer surgical techniques such as ovarian drilling often provide temporary results and do not address the underlying metabolic disturbances in patients with polycystic ovary syndrome. A significant percentage of women who undergo ovarian cautery or laser vaporization via laparoscopic techniques have spontaneous restoration of ovulation with subsequent pregnancy, but postoperative complications, including adhesion formation, tend to overshadow the potential benefits of these surgical interventions.(31,36)

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(30.) Carmina E, Rosato F, Maggiore M, Gagliano AM, Indovina D, Janni A. Prolactin secretion in polycystic ovary syndrome (PCO): correlation with the steroid pattern. Acta Endocrinol [Copenh] 1984; 105:99-104.

(31.) Goudas VT, Dumesic DA. Polycystic ovary syndrome. Endocrinol Metab Clin North Am 1997; 26:893-12.

(32.) Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol [Oxf] 1992;36:105-11.

(33.) Yen SS. Chronic anovulation caused by peripheral endocrine disorders. In: Yen SS, Jaffe RB, eds. Reproductive endocrinology: physiology, pathophysiology, and clinical management. 3d ed. Philadelphia: Saunders, 1991:576-630.

(34.) Velazquez E, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol 1997;90:392-5.

(35.) Morin-Papunen LC, Koivunen RM, Ruokonen A, Martikainen HK. Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil Steril 1998;69:691-6.

(36.) Azziz R, Zacur HA. Polycystic ovary syndrome. In: Wallach EE, Zacur HA, eds. Reproductive medicine and surgery. St. Louis: Mosby, 1995:209.

MELISSA H. HUNTER, M.D., is assistant professor in the Department of Family Medicine at the Medical University of South Carolina College of Medicine, Charleston, where she earned her medical degree. Dr. Hunter completed a family medicine residency at McLeod Regional Medical Center, Florence, S.C.

JAMES J. STERRETT, PHARM.D., is assistant professor in the Department of Pharmacy Practice at the Medical University of South Carolina. Dr. Sterrett completed pharmacy school at the University of South Carolina in Columbia and received a doctorate of pharmacy degree from the Medical University of South Carolina.

Address correspondence to Melissa H. Hunter, M.D., University Family Medicine, 9298 Medicine Plaza Dr., Charleston, SC 29406. Reprints are not available from the authors.

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