CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a total of 36 AMA/PRA category 1 credit hours can be earned in 2006. Instructions for how CME credits can be earned appear on the last page of the Table of Contents.
Polycystic Ovary Syndrome and Its Differential Diagnosis
Danielle E. Lane, MD Director, Center for Reproductive Health, Kaiser Vacaville, Vacaville, California
Polycystic ovary syndrome (PCOS) is a common disorder of reproductive-aged women. It affects between 3.4-6.8% of this population. Common clinical symptoms of PCOS include menstrual irregularities, hirsutism, and often obesity. Long-term sequelae include anovulatory infertility, endometrial carcinoma, and an increased risk for cardiovascular disease due to type II diabetes mellitus, dyslipidemia, and systolic hypertension.
The diagnosis of PCOS is one of exclusion and is defined by the Rotterdam criteria which were established in 2004. However, several other endocrine disorders can closely resemble PCOS. It is important for practitioners to recognize and distinguish PCOS from other disorders in its differential.
Target Audience: Obstetricians & Gynecologists, Family Physicians
Learning Objectives: After completion of this article, the reader should be able to summarize the short-term reproductive and long-term metabolic consequences of polycystic ovary syndrome (PCOS), point out the importance of meeting the current criteria for diagnosis, and recall the recommended treatment related to the clinical presentation of the patient.
DEFINITION AND PREVALENCE OF POLYCYSTIC OVARY SYNDROME
In 1990, an National Institutes of Health/National Institute of Child Health and Human Development conference first defined standardized criteria for the diagnosis of polycystic ovary syndrome (PCOS). They defined PCOS as the presence of 1) chronic anovulation, 2) clinical hyperandrogenism (hirsut- ism, acne, androgenic alopecia) and/or hyperandro-
The author has disclosed that she has no financial relationships with or interests in any commercial companies pertaining to this educational activity.
The author has disclosed that combined oral contraceptives and the levonorgestrel-releasing intrauterine device have not been approved by the U.S. Food and Drug Administration for use in the treatment of menorrhagia. Please consult product labeling for the approved usage of this drug or device.
Wolters Kluwer Health has identified and resolved all faculty conflicts of interest regarding this educational activity.
Reprint requests to: Danielle E. Lane, MD, Director, Center for Reproductive Health, Kaiser Vacaville, 3700 Vaca Valley Parkway, Vacaville, CA 95688. E-mail: Danielle.lane@kp.org.
genemia, and 3) the exclusion of secondary causes such as hyperprolactinemia, thyroid dysfunction, and adrenal disorders (1). However, over the next decade, concerns developed regarding the marked heteroge- neity of this disease state (48) (Table 1). Thus, in 2003, another consensus workshop was held in Rot- terdam, and the criteria for PCOS were updated (2) (Table 2). The result was to include the ultrasono- graphic appearance of polycystic-appearing ovaries as part of the diagnostic criteria (Fig 1). The confer- ence further recognized that patients with PCOS were at increased risk for the development of insulin resistance, hyperinsulinemia, and type II diabetes mellitus in addition to other long-term sequelae, in- cluding obesity, infertility, cardiovascular risk (all components of the metabolic syndrome), and endo- metrial carcinoma.
Given the potential public health risk suggested by the long-term complications associated with PCOS, it is somewhat surprising that limited in- formation is available regarding its prevalence. In
| Characteristic | PCOS Women, % (n) | Control Women, % (n) | Odds Ratio | 95% Confidence Interval for Odds Ratio | P Value |
|---|---|---|---|---|---|
| Irregular menstrual cycles | 96 (44) | 0 (37) | Undefined | (0, 2, 0%) | <0.001 |
| Nulliparous | 84 (44) | 43 (79) | 7 | (3, 21) | <0.001 |
| Use of fertility medications in attempt to achieve pregnancy | 59 (39) | 6 (36) | 24 | (5, 228) | <0.001 |
| Hyperandrogenemia I (T >58 ng/dL) | 66 (35) | 11 (80) | 15 | (6, 40) | <0.001 |
| Hyperandrogenemia II (T >58 ng/dl and/or uT >16 ng/dL) | 74 (35) | 13 (80) | 20 | (7,63) | <0.001 |
By Fisher exact test, all P for individual characteristic comparisons of the 2 groups were <0.001.
the United States, a single prospective study at the University of Alabama defined the prevalence of PCOS in their community as 4.0%. In that study, 277 unselected women of reproductive age (18-45 year) seeking a preemployment physical were evaluated. The prevalence was 4.7% among white and 3.4% among black women (3). This study is unique not only in its assessment of prevalence in a general population, but also the heterogeneity of the study population.
In several European studies, a higher prevalence of PCOS has been reported. On the island of Lesbos, Greece, Diamanti-Kandarakis and colleagues (4) found a 6.8% prevalence of PCOS. They examined 192 women recruited through a free medical exami- nation and excluded any women receiving hormonal medications. Findings from a study conducted on 230 women aged 18-25 years from university and private practices in the United Kingdom indicated that the prevalence of PCOS was 6.8% (5). Finally, in a study by Asuncion and colleagues (6), 154 white women in Madrid, Spain, were identified prospec- tively after reporting spontaneously for blood dona- tion, and the prevalence of PCOS was 6.5%. These studies suggest that PCOS is likely the most common endocrinologic disorder of reproductive-age women.
TABLE 2 Revised diagnostic criteria of polycystic ovary syndrome
Revised 2003 criteria (patients should have 2 of criteria 1-3)
1 Oligo- or anovulation
2 Clinical and/or biochemical signs of hyperandrogenism
3 Polycystic ovaries
4 Exclusion of other etiologies (congenital adrenal hyperplasia, androgen-secreting tumors, Cushing syndrome)
Modified from The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (Group 2004) (2).
DIAGNOSIS OF POLYCYSTIC OVARY SYNDROME: CLINICAL EXAMINATION AND LABORATORY TESTING
The initial evaluation of patients suspected of hav- ing PCOS should include an evaluation of cycle regularity, androgen elevation, ultrasonographic ap- pearance of the ovaries, and the exclusion of any other endocrinologic abnormalities. Normal men- strual cycles range from 25 to 35 days in duration. Thus, women who report menstrual irregularity of greater than 35 days are likely have oligo- or anovu- lation and are at increased risk for PCOS.
Elevations in androgens can be determined by either clinical examination or laboratory testing. Clinical man- ifestations of hyperandrogenism include acne and/or hirsutism. Hirsutism should be evaluated after patients have had a hiatus from hormonal agents such as oral contraceptives or antiandrogenic agents. The severity of male-pattern hair growth should be quantitated using the Ferriman-Gallwey scale (49) (Fig. 2). Biochemical elevations in testosterone, free testosterone, andro- stenedione, or DHEAS are frequently seen in patients with PCOS. Unfortunately, assays for these tests are extremely inconsistent among individual laboratories, making the diagnosis of elevated androgen levels diffi- cult. It is unclear exactly how long patients should remain off of hormonal agents before clinical and bio- chemical assessment of androgen elevation. However, there are data showing that the average time to concep- tion after discontinuing oral contraceptives containing less than 50 µg estrogen averages 4.01 cycles. This would suggest that normalization of the hormonal mi- lieu has occurred by approximately 1 month before this (approximately 3 months without oral contraceptives) to achieve an ovulatory cycle (7).
In addition to the aforementioned clinical and bio- chemical evaluation, 2 groups of potential patients with
TABLE 3 Differential diagnosis of polycystic ovary syndrome
Hypogonadotropic hypogonadism Nutrition Excessive exercise Chronic disease Hyperprolactinemia Macroadenomas (>1 cm) Microadenomas (<1 cm) Idiopathic hyperprolactinemia (no visible lesion) Hypothyroidism Hyperadrenalism Cushing syndrome Cushing disease
Nonclassic congenital adrenal hyperplasia Androgen-secreting tumors Ovarian Adrenal
Androgenic alopecia
PCOS deserve further evaluation. Patients who are ei- ther obese or who have a family history of noninsulin- dependent diabetes mellitus should be evaluated for insulin resistance. Because nonobese women with PCOS also may have insulin resistance, some investi- gators advise assessing insulin resistance in all women with PCOS. There is controversy about the best manner of assessing insulin sensitivity, but the most practical evaluation involves a 2-hour glucose tolerance test with insulin levels measured after a 75-g glucose load. The test should be performed after an 8- to 12-hour fast and serum levels of insulin and glucose should be collected every 30 minutes from zero to 120 minutes.
Although PCOS remains the most common cause of anovulatory hyperandrogenism in the adolescent and reproductive-age woman, a variety of other con- ditions need to be excluded before this diagnosis is confirmed (Table 3). In general, the areas of focus in investigating the etiology of menstrual irregularities include the pituitary, thyroid, adrenal gland, and ovary.
DIFFERENTIAL DIAGNOSIS OF POLYCYSTIC OVARY SYNDROME: DISORDERS AND TREATMENT
Hypogonadotrophic Hypogonadism
Nutritional and metabolic disturbances are the most common causes of secondary hypogonado- trophic hypogonadism. Nutritional causes include anorexia nervosa and bulimia and are marked by decreased body weight over time. Other chronic causes of malnutrition include celiac disease with its associated gluten intolerance and chronic intestinal disorders such as Crohn disease.
Metabolic disturbances may arise from intensive physical training in athletes such as runners, swim- mers, skaters, and ballet dancers and result in the delay of sexual development. Fortunately, this met- abolic cause of anovulation has a better prognosis for recovery than nutritional disorders.
Tumors of the central nervous system such as craniopharyngiomas, germinomas (including pine- alomas, ectopic pinealomas, atypical teratomas, or dysgerminomas), or other extrasellar germ cell tu- mors may interfere with follicle-stimulating hormone (FSH) secretion and lead to the failure of ovulatory function. Patients who have very low levels of all pituitary hormones warrant radiologic evaluation.
In hypogonadotrophic hypogonadism, there is a de- ficiency of the pituitary gonadotropins, luteinizing hor- mone (LH), and FSH, leading to a relative estrogen deficiency. This may result from disturbances of ante- rior pituitary secretions or may be secondary to chronic disease or metabolic disturbance. In either case, mea- surement of serum LH and FSH will result in low to undetectable levels with an FSH predominance.
Treatment of this disorder in adolescent females should be limited to the use of sex steroids in cyclic fashion. The main objective of therapy in this group of patients is to protect bone mineral density. Use of injectable human menopausal gonadotropins and hu- man chorionic gonadotropins is typically avoided in this age range as a result of the need for close supervision. These agents are useful for induction of
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ovulation and fertility treatment for reproductive pur- poses (8). However, they will only induce ovulation in the cycle(s) in which they are administered. In addition to hormonal treatment, appropriate psycho- logic support and follow up must be added to hor- monal treatment.
Hyperprolactinemia
Elevations in prolactin affect the breast, the go- nads, and occasionally mood. Additionally, at least one study suggests an association of hyperprolactine- mia with insulin resistance in the patient with PCOS (9). Prolactin directly stimulates breast secretions, and as a result, approximately 90% of women with hyperprolactinemia develop galactorrhea. The im- pact of elevated prolactin on the gonads is hypothe- sized to be the result of the disruption of normal pulsatility of gonadotropin-releasing hormone (GnRH) and consequent alterations in the secretion of FSH and LH. Clinically, the end result is anovulation with either amenorrhea or oligomenorrhea in most women.
Hyperprolactinemia can be divided into pituitary and nonpituitary causes. Pituitary causes include prolactin-secreting microadenomas, nonsecreting pi- tuitary tumors, craniopharyngiomas, Rathke cleft cysts, altered forms of prolactin, and idiopathic hy- perprolactinemia. Any disruption of the pituitary stalk or macroadenomas can lead to failure of the
normal hypothalamic suppression of prolactin by dopamine. Nonpituitary causes are common and include pregnancy, hypothyroidism, and dopamine- antagonist drug therapy (phenothiazines and meto- clopramide). Some women with PCOS have mild hyperprolactinemia.
An elevated prolactin level should be repeated after counseling the patient to avoid any nipple stimula- tion. Once confirmed, the prolactin level may guide decisions regarding further evaluation. Hyperpro- lactinemia between 20 and 200 µg/L may be the result of various causes, including stress, hypothy- roidism, PCOS, microadenomas, and pituitary stalk disruption. Prolactin elevations >200 µg/L are usu- ally the result of macroadenomas; however, large nonprolactin-secreting tumors may be seen with only modest elevations of prolactin.
The initial evaluation of patients with hyperpro- lactinemia should include exclusion of nonpituitary causes by a careful history of medications, evaluation of the thyroid, pregnancy testing, and assessment of whether the patient has PCOS. After these potential causes have been excluded, the evaluation should focus on the pituitary. Clinical examination for all patients should include assessment of visual fields. Although direct confrontation testing is acceptable as a screening tool, any patients with a significant mass lesion should undergo formal ophthalmologic examination.
In patients with sustained hyperprolactinemia, the pituitary and hypothalamus must be evaluated for
structural pathology. Radiologic evaluation should be performed in any patient with sustained hyper- prolactinemia and no obvious secondary cause (10). Magnetic resonance imaging (MRI) or computed to- mography (CT) scanning are the preferred imaging modalities. Structural anomalies include pituitary microadenomas (<10 mm diameter), pituitary mac- roadenomas (>10 mm diameter), pituitary stalk lesions, hypothalamic tumors, and granulomas. MRI is quickly becoming the modality of choice as a result of its lack of radiation exposure, superior res- olution, and ability to distinguish structures such as the optic chiasm and carotid arteries. However, CT scanning is acceptable if thin slice images are used in conjunction with contrast material.
It is important to recognize that approximately 20% of the normal population has been found to have pituitary microadenomas at autopsy. Thus, as more small adenomas are being detected by imaging result- ing from increased sensitivity and resolution, the find- ing of a small pituitary adenoma may not explain an associated endocrinopathy. Conversely, some women with sustained hyperprolactinemia and no evident non- pituitary cause may not have a demonstrable lesion. These patients may have a lesion less than 2 mm in diameter, lactotroph hyperplasia, nonsecreting pituitary tumors, or nontumoral hyperprolactinemia.
Management of hyperprolactinemia depends on the identified etiology. The goal of treatment is to restore ovulatory function, to promote estrogen production, and to prevent lactation. In patients with prolactino- mas, tumor shrinkage may also be of significance. With hyperprolactinemia of even 6 months duration, patients are at significant risk for bone mineral den- sity reduction. Thus, prevention of osteoporosis is of paramount importance.
Pituitary adenomas can be approached surgically, medically, or radiologically. Surgery plays a rela- tively small role in the treatment of prolactinomas currently. Although surgical treatment has the poten- tial to yield a long-term cure and obviate the need for medication, in reality, long-term remission of the hyperprolactinemia in larger tumors (macroadeno- mas) is uncommon.
Currently, medical management has become the primary treatment of both pituitary prolactinomas and “idiopathic” hyperprolactinemia. Dopamine ago- nists are the primary medications used in the treat- ment of hyperprolactinemia. D2 receptor agonists have demonstrated prolactin suppression and even tumor shrinkage in 80% to 90% of patients. Approx- imately 90% of women demonstrate restoration of ovarian function. Furthermore, 80% of patients dem-
onstrate up to 25% tumor shrinkage in timeframes as short as 48 hour. Bromocriptine was the initial med- ication used in the dopamine receptor agonist group. Although it is still widely used in practice, it has a side effect profile that includes nausea, postural hy- potension, dizziness, headache, and constipation. Ad- ditionally, less common side effects include mild depression and, on occasion, psychosis. Newer agents with fewer side effects have been developed in place of bromocriptine. These include cabergoline and quinagolide, specific D2 receptor ligands. Both agents have a longer half-life, with cabergoline being administered one to 2 times per week and quniagol- ide given once each day. Although side effects such as nausea and postural hypotension still exist with these agents, they are significantly less common. All 3 agents require low initial doses with gradual in- creases to minimize side effects. Restoration of ovu- lation and normal menstrual cycles is generally within weeks.
Given the impressive success rates with dopamine agonists, the question of how long to continue therapy has arisen. Historically, discontinuance of bromocrip- tine has been found to result in return of symptoms, including headache, oligomenorrhea or amenorrhea, in- fertility, galactorrhea, and visual changes. The prolacti- nomas typically return to pretreatment size and the prolactin levels again increase. However, a recent study by Colao and colleagues evaluated the withdrawal of cabergoline in patients treated for micro- or macropro- lactinomas. That study indicates that 2 to 5 years after withdrawal, recurrences occurred in 24% of pa- tients with nontumoral hyperprolactinemia, 31% of pa- tients with microprolactinomas, and 36% of patients with macroprolactinomas. Renewed tumor growth was not seen in any patients, and only 22% of women with recurrent hyperprolactinemia demonstrated gonadal dysfunction. Additionally, prolactin levels at the time of recurrence were significantly lower in all groups. Thus, it seems that some patients taking cabergoline can have the medication safely withdrawn in patients with nor- malized prolactin levels and no evidence of tumor, providing that they continue close follow up (11).
An additional alternative for patients with microad- enomas or nontumoral hyperprolactinemia is to treat them with estrogen replacement or oral contraceptive pills. If there is no symptomatic galactorrhea, the main concern for patients not actively trying to con- ceive is protection of bone density. Therefore, estro- gen treatment may be considered a less expensive and effective treatment to regulate cycles and protect the patient from bone loss. Only rarely will tumor growth be noted.
Hypothyroidism
In reproductive-age women, hypothyroidism results in changes in cycle length and amount of bleeding. Therefore, menstrual disorders can include oligomen- orrhea and amenorrhea, polymenorrhea, and menorrha- gia (12). The excessive bleeding disorders may result from estrogen breakthrough bleeding secondary to anovulation. Additionally, defects in hemostasis such as decreased levels of factors VII, VIII, IX, and XI may be present in hypothyroidism and contribute to the polymenorrhea and menorrhagia seen in these patients (13).
Hypothyroidism should be excluded in all cases of menstrual irregularity. On physical examination, the clinician may see a delay in the onset of puberty with respect to chronologic age or paradoxically preco- cious puberty and galactorrhea in juvenile hypo- thyroidism (14). Although overt hypothyroidism is easily detected by measuring the level of serum thy- roid stimulating hormone (TSH), subclinical disease may require performance of a prolactin stimulation test with metoclopramide. This becomes particularly important as reproductive age is reached because subclinical hypothyroidism is of greater clinical im- portance in infertile women with menstrual disorders (15).
Adequate thyroid supplementation should resolve the reproductive symptoms associated with hypothy- roidism, including oligo- or amenorrhea, and allow progression of delayed puberty. Additionally, in cases of severe hypothyroidism with associated hy- perprolactinemia, prolactin levels should return to normal as the hypothalamic thyrotropin-releasing hormone (TRH) level, which stimulates prolactin as well as TSH, normalizes (14).
Hyperadrenalism
Cushing syndrome refers to chronic glucocorticoid excess irrespective of the cause. It should be in the differential diagnosis of PCOS, obesity, diabetes, hirsutism, and menstrual disorders. The most com- mon time for presentation is during the reproductive years (ages 20-40), and the disease occurs in women more often than men in a ratio of 10:1. Furthermore, of adults with Cushing syndrome, 70% have Cushing disease.
Cushing disease refers to the presence of an ACTH-hypersecreting pituitary adenoma that dem- onstrates partial resistance to the normal suppressive effect of glucocorticoids. As a result of systemic hypercortisolism, peripheral tissues manifest the
classic features of Cushing syndrome. The classic symptom complex includes obesity, amenorrhea, hy- pertension, glucose intolerance or diabetes, hirsut- ism, striae, weakness, osteoporosis, purpura and easy bruisability, and psychiatric disorders. The distribu- tion of adipose tissue in Cushing disease tends to be facial and truncal with apparent sparing of the limbs resulting from muscle wasting. There is elevation of both the systolic and diastolic blood pressures, and 70% to 80% of patients have evidence of decreased glucose tolerance. Menstrual irregularities are com- mon and may even develop into complete amenor- rhea. Excessive hair growth may be noted in the sideburn region, the forehead, the limbs, and the trunk. There can also be temporal hairline recession and a deepening of the voice when androgen excess is present. Purple striae are present in the hip and abdominal regions, as well as the shoulders and the breast regions. Muscle weakness is extremely com- mon, affecting the upper legs and arms and occurring secondary to a reduction in muscle mass. Finally, 40% to 80% of patients are affected by osteoporosis. In the setting of hypercortisolism, there is both a decrease in bone formation as well as an increase in bone resorption.
Treatment of Cushing disease resulting from an ACTH-producing tumor with bilateral adrenal hyper- plasia has varied with time. Historically, bilateral adrenalectomy was performed, which corrected the hypercortisolism but produced adrenal insufficiency. This secondary endocrinopathy requires lifetime glu- cocorticoid and mineralocorticoid replacement and may result in the development of a pituitary tumor. Current management options of the pituitary tumor include primarily transsphenoidal surgery, followed by radiation and medical therapy in the cases of incomplete surgical removal or recurrent tumor. In the case of persistent disease, surgical bilateral adre- nalectomy can be life-saving.
Several medications have been used in the treat- ment of Cushing disease. Cyproheptadine, a seroto- nin antagonist, can be useful in suppressing ACTH. However, its use is short-term and it does not result in normal serum cortisol levels. Bromocriptine, a dopamine agonist, although useful for the treatment of prolactin- and sometimes growth-hormone secret- ing tumors, is of little use in ACTH-secreting pitu- itary tumors.
Treatment of ectopic ACTH syndrome requires localization and removal of the ACTH-secreting tu- mor. In cases of iatrogenic Cushing syndrome, ces- sation of excess exogenous glucocorticoid treatment should be sufficient.
Adrenal adenomas and carcinomas are infrequent findings in the female. When present, they generally produce large amounts of 17-ketosteroids such as DHEA and androstenedione as well as cortisol (16). The majority of these tumors are not responsive to dexamethasone suppression, and systemically low but persistent levels of ACTH are found.
A variety of tests may be useful in assessing adreno- cortical function. It is common to begin preliminary investigation with an 8:00 AM plasma cortisol concen- tration. The timing of this test is critical as a result of the diurnal variation in the secretion of cortisol normally. Nonetheless, this single value is only of limited signif- icance. Urinary 17-hydroxycorticosteroids (17-OHCS) and urinary-free cortisol may be useful, particularly in combination to rule out Cushing disease. Finally, the CRH test is used to assess the source of a cortisol excess. It involves the intravenous administration of CRH (100 µg/dose) and leads to an exaggerated in- crease in both plasma cortisol and ACTH in Cushing disease, but no change in ectopic ACTH syndrome. Using a combination of these tests, it should be possible to determine the presence and cause of hyperadrenalism.
Nonclassic (cryptic, peripubertal, adult-onset) ad- renal hyperplasia (CAH) results in a spectrum of clinical manifestations of postnatal androgen excess (17). The disorders are autosomal-recessive in inher- itance pattern and reflect problems in the adrenal steroid synthesis pathway. Approximately 95% of pa- tients with CAH have disorders of 21-hydroxylation as a result of a deficiency of the 21-hydroxylase enzyme (21BOH, P450c21). Other enzyme deficiencies that present a similar clinical picture include the much less common 11ß hydroxylase (11BOH, P450c11) and 3ß- hydroxysteroid dehydrogenase-isomerase deficiency (3ßHSD).
The prevalence of nonclassic CAH varies accord- ing to the population in question. The frequency of 21BOH deficiency in women with suspected PCOS has been reported to be anywhere from 1% to 19% (18,19). Another study by Sahin et al (20) found that 8.4% of women with PCOS in Turkey had 11-ß OH deficiency. Thus, this is clearly an important consid- eration when evaluating reproductive-age women for PCOS.
A common clinical presentation of the reproductive- age woman with nonclassic CAH is hirsutism, men- strual irregularity, and infertility (21). Furthermore, studies have suggested that polycystic-appearing ovaries are not uncommon in patients with nonclassic CAH resulting from 21BOH, 11BOH, or 3BHSD (22-25). This profile is difficult to distinguish clini-
cally from PCOS. Most patients with either PCOS or nonclassic CAH as their diagnosis will demonstrate elevations of DHEAS, androstenedione, and testos- terone levels on baseline laboratory evaluations.
In general, a basal 17-hydroxyprogesterone (17- OHP) measurement should be obtained as a screen- ing test in women suspected of having PCOS. Levels <200 ng/dL (6.0 nmol/L) effectively rule out pa- tients with 21-OH-deficient nonclassic CAH. Addi- tionally, a study by Dewailly et al (26) suggested that in patients with a basal 17-OHP level >500 ng/dL (15.1 nmol/L), the diagnosis of nonclassic CAH is certain and there is no reason for further adrenal testing. For patients with basal 17-OHP levels be- tween 200 and 500 ng/dL (6.0-15.1 nmol/L), an ACTH stimulation test should be performed to con- firm the diagnosis of 21-OH-deficient nonclassic CAH. After the administration of ACTH (25 USP units) or @-corticotropin (250 µg), levels of 17-OH P, 11-DOC, and DHEAS are measured to determine the presence of 21-OH, 11-B OH, or 3-6 HSD deficiencies (27). In a recent study in which the prevalence of nonclassic 21-OH CAH in a Turkish population was determined, a 17-OHP cutoff of 13.4 ng/ml (1340 ng/dL) after ACTH stimulation was used as the diagnostic criterion, because this value was greater than the 95th percentile (17). Other au- thors have suggested that a poststimulation 17-OHP level exceeding 1000 ng/dL (30 nmol/L) is consistent with at least a carrier status for CAH (28).
Treatment of nonclassic CAH in females involves replacement of cortisol and in patients who are also salt-wasters, the mineralocorticoid 9& fluorohy- drocortisone (29). This results in normalization of adrenal progestin and androgen secretion, renin, and electrolyte imbalance. In adolescent or reproductive- age females, who have essentially completed growth, a long-acting glucocorticoid such as prednisone, prednisolone, or dexamethasone is preferred. The maintenance dose of prednisone is 10 mg per day in divided doses in classic 21-hydroxylase-deficient pa- tients or 5 to 7.5 mg per day in nonclassic patients in 2 divided doses. Treatment should be titrated accord- ing to the patients’ clinical signs (hirsutism score, menstrual history, weight changes, blood pressure, and cushingoid features) (29) Additionally, periodic review of biochemical findings (progesterone, 17- OHP, androstenedione, testosterone, and renin levels) is important. Of note, use of spironolactone for the treat- ment of hirsutism in women with 21-hydroxylase defi- ciency CAH is not recommended as a result of the potentially salt-wasting complication of the drug even in the nonclassic form of CAH (30,31). Of note, earlier
work by Azziz and colleagues has suggested that very low doses of 0.25 to 0.5 mg dexamethasone nightly or every other night are adequate for the management of nonclassic CAH (28). The goal of treatment using this regimen is to reduce adrenal hyperandrogenism without any attempt to normalize 17-OHP levels. No study has compared the effective- ness of these 2 approaches.
Androgenic Alopecia
Androgenic alopecia (AGA) is the most common cause of hair loss in women, affecting up to 40% by the end of the reproductive years (32). In women, the hair loss resulting from AGA typically involves the central portions of the scalp, but not the frontotemporal hairline. Rarely is the hair loss complete. However, after the menopausal transi- tion, women may develop a male hair pattern. The development of AGA is a function of both genetic and hormonal factors with androgens playing a significant role. Dihydrotestosterone (DHT), a po- tent metabolite of testosterone, is thought to be the dominant androgen in the development of AGA. From puberty onward, androgens interact with an- drogen-sensitive hair follicles triggering a series of events that include the gradual miniaturization of the follicles, alteration of the hair growth cycle and, ultimately, progressive thinning and loss of hair. Hair follicle responses to androgens are a genetically predetermined event. Clinical presen- tation of AGA in women is less prominent, likely as a result of lower levels of 5a- reductase (which converts testosterone to DHT) and higher levels of aromatase (which converts testosterone to estra- diol). Additionally, the distribution of androgen- sensitive hair follicles differs in women compared with men resulting in a different balding pattern. In addition, premenopausal women benefit from the anti- androgenic effect of estradiol that occurs because estra- diol increases sex hormone-binding globulin (SHBG).
The diagnosis of AGA is a clinical one based predominantly on history and physical examina- tion. The classic pattern is one of diffuse thinning that is greatest over the central scalp without ob- vious recession of the frontal hairline. The pres- ence of a central parting often appears both wider and more prominent as a result of the overall sparseness of the hair. Further criteria for diagno- sis include the onset of hair loss after puberty, the aforementioned pattern of hair loss, visible minia- turization of hairs, and a family history of hair loss or thinning in first- or second-degree relatives.
Treatments for mild to moderate AGA include topical agents, antiandrogens, and estrogens. Mi- noxidil (2%) is a topical agent that is more effec- tive in women than in men. Stronger preparations (5%) are not advised as a result of resultant local- ized or diffuse hypertrichosis in a large proportion of patients.
Antiandrogens such as cyproterone acetate and spironolactone have been used for the treatment of AGA for many years. Their use in the reproduc- tive-age population requires concomitant contra- ceptive use because of the risk of feminization of the developing male fetus. As a result, antiandro- gens such as finasteride are not U.S. Food and Drug Administration-approved for use in women with AGA. No studies have been conducted in premenopausal women, and in a double-blind, placebo-controlled trial of AGA in postmeno- pausal women, finasteride was not found to be effective. Nonetheless, these agents are widely used in treating women with a variety of hyperan- drogenic conditions, including hirsutism, acne, and AGA.
Cyproterone acetate (CPA) is an androgen receptor antagonist. Recommended dosages for the treatment of hirsutism, acne, and AGA in women range from 25 to 100 mg per day for 10 days during the follicular phase of the menstrual cycle. In addition, estrogen is used in combination with CPA, and therefore combination drugs such as Diane/Dianette (2 mg CPA and 35 µg ethinyl estradiol) plus 50 mg CPA are used for the first 10 days. Although the contraceptive alone is insuffi- cient to provide efficacy for hirsutism or acne, it is often prescribed as the sole antiandrogen. Hepatotoxicity has been demonstrated at doses of 100 mg and above. It is not approved for use in the United States.
Spironolactone is another antiandrogen that is available in the United States. It prevents the inter- action between androgens and their receptor. In addition, it decreases enzymes necessary for the syn- thesis of androgens. Spironolactone administered in doses of 200 mg per day for women with AGA has been shown to retard hair loss (33).
Androgen-Producing Tumors
These tumors can be either ovarian or adrenal in origin. In the presence of ovarian androgen-secreting tumors, autonomous androgen production may result in chronic anovulation and virilization. The tumor types include hilus cell tumors, arrhenoblastomas (Sertoli- Leydig cell tumors), benign cystic teratomas, luteinized
thecomas, gynandroblastomas (Leydig and granulosa cell elements), and ovarian sex cord tumors (granulosa and Sertoli cells). Tumor markers may be helpful in differentiating the various tumors. Inhibin and mullerian-inhibiting substance are markers for sex cord tumors, germ cell tumors in XY individuals, and occa- sionally in granulosa and Leydig cell tumors. Isolated androgen secreting tumors are possible.
The workup for ovarian or adrenal androgen- producing tumors in suspected cases should in- clude MRI, CT, or ultrasonography. Further local- ization may necessitate the use of retrograde ve- nous catheterization to clarify both location (ovary vs adrenal) and site (left vs right) of the excess hormone production (16).
MANAGEMENT OF POLYCYSTIC OVARY SYNDROME
Lifestyle Modification
Currently, the best recommendation for the man- agement of PCOS is lifestyle modification. Much of the support for this recommendation comes from the Diabetes Prevention Program (DPP) Research Group, which conducted a large National Institutes of Health-sponsored trial. In the DPP, over 3000 nondiabetic, insulin-resistant subjects greater than 25 years of age were followed for an average of 2.8 years. They were randomized to placebo, lifestyle modification, or metformin use. At the end of the trial, the incidence of new-onset diabetes was 11.0 cases per 100-person years in the placebo group, 7.8 cases per 100 person-years in the metformin group and only 4.8 cases per 100 person-years in the life- style modification group (34). Although the study population does not completely replicate the PCOS population, the overlap is likely close enough that the recommendations should be the same.
With this in mind, goals of modification should be to decrease weight by approximately 7% and to per- form an average of 150 minutes of physical activity per week. Although this should certainly be the goal for all patients with PCOS, there are cases when more directed therapy may be required.
Menstrual Irregularities
Chronic anovulation is a prevalent symptom of PCOS and results in menstrual irregularities as well as an increased risk of endometrial hyperplasia and carcinoma. Menstrual irregularities can be addressed with the addition of a progestin either alone or in
combination oral contraceptives. The recommended interval of use is no less than every 3 months. Me- droxyprogesterone acetate may be dosed at 10 mg per day for 7 to 10 days duration. If this does not result in control of the dysfunctional uterine bleeding often associated with PCOS, then use of the combi- nation estrogen-progestin preparation may be used on a cyclic schedule.
Hyperandrogenism and Hirsutism
Similar to the treatment of androgenic alopecia (discussed previously), the goal of treatment in hy- perandrogenism and hirsutism is to interrupt the steps leading to increased androgen expression. Although mechanical hair removal methods such as shaving, electrolysis, tweezing, waxing, and depilatory creams can provide some improvement in hirsutism, a com- bination of medical treatments and mechanical meth- ods provides the best prospect for improvement.
Suppression of circulating ovarian androgens with low-dose oral contraceptives has resulted in moder- ate improvement in hirsutism (35,36). Combination oral contraceptives continue to represent the first-line approach to the treatment of hirsutism and acne. The mechanism of action is thought to be a combination of suppression of gonadotropin secretion, thereby reducing ovarian androgen secretion, increasing SHBG synthesis, inhibiting DHT receptor binding, and en- hancing antiandrogen effectiveness (35-37).
Gonadotropin-releasing hormone (GnRH) agonist therapy such as with leuprolide acetate has also been successful in improving hirsutism. However, long- term use with this therapy requires the addition of estrogen and progestin to prevent the associated hy- poestrogenism seen with this therapy (38-40). The need for an injection and additional medication make this a challenging option, particularly for adolescents.
In addition to these options, a more direct approach is the use of agents to block the effects of androgens at their receptors. A variety of antiandrogenic agents, including cyproterone acetate (not available in the United States), spironolactone, flutamide, and finas- teride, have been used in the treatment of PCOS-related hirsutism and acne. The use of these medications is discussed previously in the treatment of androgenic alopecia.
Insulin Resistance and Hyperinsulinemia
Although adolescent patients with PCOS typically present for cosmetic reasons relating to hirsutism and acne or as a result of menstrual irregularities, meta-
bolic abnormalities represent the most serious long- term risk factors for patients with PCOS. Legro and colleagues (41) have demonstrated that by their fourth decade of life, as many as 40% of patients with PCOS have impaired glucose tolerance and up to 10% go on to develop type II diabetes mellitus. Given these risks, the attenuation of hyperinsulinemia may have a beneficial effect on the long-term sequelae thought to develop in patients with PCOS. Currently, the use of metformin, an insulin-sensitizing agent, provides the opportunity to treat hyperinsulinemic patients with PCOS with the goals of improving insulin resistance and lowering insulin levels, thereby improving asso- ciated metabolic sequelae, including dyslipidemia, glucose intolerance, and hyperandrogenism.
A study by Palmert and colleagues (42) concluded that adolescents with PCOS are at increased risk for both impaired glucose tolerance and diabetes melli- tus. Additionally, they found that a 2-hour glucose tolerance test after a 75-g oral load was the most sensitive test to screen for insulin resistance in this population.
Metformin (dimethylbiguanide) is an oral agent used in the treatment of noninsulin-dependent dia- betes mellitus (NIDDM). It maintains glucose ho- meostasis through suppression of hepatic glucose output. Additionally, it improves insulin sensitivity and decreases insulin levels. Overall, the use of met- formin leads to a decrease in serum insulin and androgen levels, as well as an improvement in ovu- latory function (43). Metformin should be given to reach maximum combined doses of 1500 to 2000 mg per day divided over 2 to 3 daily doses. The goal of treatment should be to improve insulin resistance and hyperinsulinemia while encouraging the use of diet and exercise for long-term therapy. Assessment of insulin sensitivity should occur at no less than yearly intervals. Treatment with metformin requires that renal and liver function be assessed on an annual basis.
In addition to metformin, thiazolidinediones con- tinue to be under investigation for use in the man- agement of PCOS-related metabolic abnormalities. Early work with troglitazone before its withdrawal from the market indicated that daily treatment with 400 mg for 12 weeks resulted in a decrease in insulin and androgen levels in patients with PCOS (44). As a family of compounds, thiazolidinediones are selec- tive ligands for PPARy, a nuclear receptor that reg- ulates the transcription of multiple insulin-responsive genes crucial to the control of glucose and lipid metabolism and plays a central role in the regulation of adipocyte gene expression and regulation (45-47).
Although troglitazone is no longer available for use, several other compounds in the thiazolidindione fam- ily, including pioglitazone, have been suggested for use in the treatment of PCOS. Definitive studies have not yet been performed.
SUMMARY
PCOS is a common but heterogeneous disorder. The goal of management in adolescence should focus on addressing the concerns of the patient while pro- viding education regarding the long-term sequelae of the syndrome. Further studies are needed to clarify the extent of excess cardiovascular disease in patients with PCOS and to determine the best course of short-term and long-term management. Current stud- ies suggest that diet and exercise, perhaps with use of insulin-sensitizing agents, provide the best opportu- nity for long-term improvement of dyslipidemia, im- paired glucose tolerance, and hyperandrogenemia in adolescents with PCOS.
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