Amenorrhea and acne in the adolescent girl: is it polycystic ovary syndrome?

Amenorrhea and acne in the adolescent girl: is it polycystic ovary syndrome?

Contemporary Pediatrics, Oct, 2000, by Carole A. Stashwick

Hyperandrogenism, most notably polycystic ovary syndrome, is a common cause of acne and menstrual difficulties in teenage girls, yet many pediatricians fail to recognize the condition. Prompt diagnosis and treatment can relieve a significant source of distress for patients, while helping to prevent serious complications later in life.

Jessica, 15.8 years old, is concerned about her acne. It began when she was 11 and has worsened in the last year despite the use of prescription topical medications. Her menarche was at age 12, but she has never established regular; predictable menses. Jessica’s last period was four months ago. She denies sexual activity Jessica is also concerned about her weight, which is above the 95th percentile (height: 75th percentile). Upon questioning, she states that she has been bleaching dark hairs on her upper lip for the past year.

Androgen excess syndromes are frequent causes of acne and menstrual difficulties in adolescents, but they often go unrecognized by the pediatrician. [1] As many as 10% of all adolescent girls and women experience problems with androgen excess, which constitutes the most common endocrinopathy in females–even more common than thyroid dysfunction. [2]

By far the most frequent cause of excess androgen in females is a group of disorders known as polycystic ovary syndrome (PCOS). [2,3,4] PCOS (also called functional ovarian hyperandrogenism or hyperandrogenic chronic anovulation) and other androgen excess syndromes are apparent during adolescence, certainly by the late high school years or college, and the large majority of cases can be identified and managed by the primary care provider. Because polycystic ovary syndrome is associated with a range of complications–including infertility, type 2 diabetes, abnormal lipid metabolism, endometrial cancer, and cardiovascular disease–diagnosing the syndrome as early as possible can be critical to preventing health problems in adulthood. [2,5]

Common manifestations

Adolescent girls and women with androgen excess usually have one or more of three hallmark signs: menstrual irregularity, acne, and hirsutism (unusual male-pattern hair growth). Adolescents with PCOS typically experience menstrual irregularity and acne, while women in their 20s with the syndrome often present with acne and hirsutism.

Signs of virilism, on the other hand, indicate pronounced hyper-androgenism. They require vigorous and immediate investigation and should never be ignored or minimized. The most common sign of virilism is androgenetic alopecia, the female equivalent of male-pattern balding. Alopecia is most marked on the scalp vertex but is also apparent on the crown and in the temporal regions, sometimes with temporal recession. [6] Other signs of virilism in women include clitoromegaly, deepening of the voice, increased muscle mass, widening of the upper torso, and loss of breast tissue. Virilism may be associated with an androgen-secreting tumor of the ovary or adrenal gland or another very significant androgen endocrinopathy.

Menstrual irregularity. Ovarian androgen excess results in anovulation and the noncyclic production of estrogen and progesterone. Protracted, unopposed estrogen stimulation of the endometrium results in amenorrhea or oligomenorrhea. The latter is generally defined as irregular, infrequent menses occurring at intervals of more than about 45 days.

At least one third of adolescent and adult women with androgen excess experience abnormal menses. PCOS is the most common cause of menstrual irregularity in all females, and this irregularity begins perimenarchally. Many women in their 20s present with infertility as a result of chronic anovulation.

While it is common for adolescents with normal ovarian function to have irregular menstrual cycles in the first two years after menarche, a patient with irregular menses more than two years after menarche should be considered for androgen screening, especially if she has acne or hirsutism. [7]

Acne. Androgens are responsible for acne vulgaris in both boys and girls. In its mildest form, acne involves noninflammatory come-dones–open (blackheads) and closed (whiteheads)–around the nose and on the chin. Inflammatory acne, consisting of papules, pustules, and nodules, is often a source of significant distress for adolescents and a frequent reason they visit their pediatrician or dermatologist.

It is estimated that 80% or more of adolescent girls experience acne. Acne in girls begins at the onset of puberty, often before menarche (which occurs at about 12.8 years of age in the United States) and peaks at midpuberty (about 14 years on average) [8] Androgen excess in girls usually results in moderate or severe acne, which may be difficult to differentiate clinically from the usual acne of adolescence. [8,9] However, some adolescents with androgen excess experience little or no acne until their 20s or later. [10]

Consider PCOS or another androgen excess problem when severe acne begins before 8 years of age, continues past the teen years, appears after adolescence, does not respond to usual therapies, is associated with amenorrhea or oligomenorrhea, or occurs in a young woman with hirsutism (Table 1). [8] If you are thinking of prescribing oral contraceptives or oral isotretinoin (13-cis-retinoic acid; Accutane) for severe acne in an adolescent girl, first do a workup for hyperandrogenism. [11]

Hirsutism. Excess androgens in adolescent or adult women can transform the vellus hairs of the pilosebaceous unit into “terminal,” or sexualized, hairs: darker, stiffer hairs appearing in male-pattern areas such as the upper lip, sides of the face, chin, neck, or chest. A male escutcheon may develop, and terminal hairs may appear on the upper inner thighs. [8,11] Transformation of vellus hairs to terminal hairs requires months or years of androgen exposure, which is why hirsutism is a more common marker for androgen excess in the college years or later, rather than in early adolescence.

Overall, skin changes (hirsutism, acne, or hair loss) are the number one reason women with androgen excess seek medical advice. Terminal facial hair is so distressing that many women remove virtually all such hair with depilatories, electrolysis, or shaving. To diagnose hirsutism, the physician must therefore ask the patient whether she is removing body hair from areas other than the axillae, lower legs, and bikini line.

The Ferriman-Gallwey scoring system can be helpful in documenting the amount of terminal hair (Figure 1). [12,13] A score of 0 to 4 is given for hairs on the upper lip, chin, chest, upper abdomen (linea alba), lower abdomen (including male escutcheon), inner upper arms, inner upper thighs, upper back, and sacral areas and buttocks. A total score of 8 to 15 indicates mild to moderate hirsutism.

About 5% or more of women are hirsute. [14] While PCOS or benign idiopathic hirsutism (normal androgen levels and other lab values; often racial or familial in origin) is the cause in 95% of hirsute women, hirsutism is so significant that it should always be thoroughly evaluated. Among the unusual causes of hirsutism–all of which should be considered in the hirsute adolescent–is congenital adrenal hyperplasia (CAH), especially nonclassical or “late-onset” CAH. Late-onset CAH results from an abnormality in a complex gene locus on chromosome 6, causing 21-hydroxylase deficiency. Other unusual causes of hirsutism include Cushing syndrome (excess adrenocorticoid production), adrenal tumor, and ovarian tumor. [11]

Hirsutism and androgen excess also may be side effects of medications, especially phenytoin, valproate, corticosteroids, danazol, diazoxide, minoxidil, cyclosporine, levonorgestrel (including Norplant), and anabolic steroids. Other causes of hirsutism include hyperprolactinemia, hyper- or hypothyrodism, and insulin resistance and hyperinsulinemia. [8,13]

Sources of androgen in women

Androgens in women are produced primarily in the ovary and the adrenal gland via the steroid biosynthetic pathways (Figure 2). In the ovary pituitary luteinizing hormone (LH) stimulates the theca cells to secrete androstenedione (A), which is metabolized to testosterone (T). Androstenedione is responsible for converting vellus hairs to terminal hairs in the pubic and axillary regions during normal puberty and for converting sweat glands and pilosebaceous units to active adult units. [8,15] Pituitary follicle stimulating hormone (FSH) prompts the ovarian follicle granulosa cells to convert androgens to the estrogens estrone (E1) and estradiol (E2).

In the adrenal gland, pituitary adrenocorticotropic hormone (ACTH) stimulates production of androstenedione, which is metabolized to testosterone. About 50% of circulating testosterone is contributed by the adrenal gland. Dehydroepiandrosterone sulfate (DHEAS) is almost exclusively an adrenal product and serves as an excellent marker for adrenal function. The skin metabolizes nonandrogenic precursors like dehydroepiandrosterone (DHEA) into A, T, and the highly androgenic dihydrotestosterone (DHT) [8]

Causes of androgen excess

Hyperandrogenism in women may be the result of either an ovarian disorder or an adrenal problem (Table 2).

Ovarian causes. PCOS is the most common cause of androgen excess in adolescent girls and adult women. [11,16] The disorders that make up PCOS are characterized by dysfunctional overproduction of ovarian androgens (A,T, DHEA), which leads to chronic anovulation, acne, and hirsutism.

PCOS occurs in at least 3% to 5%, and as many as 10%, of female adolescents and adults and appears to have a dominant mode of inheritance. [17,18] It is twice as common in Caribbean Hispanic females as in Caucasians.

The “classic” form of PCOS, first described by Stein and Leventhal in 1935, includes bilateral polycystic ovaries, amenorrhea, anovulation, hirsutism, obesity (50% to 80% of adult women with PCOS are obese), moderate hyperandrogenemia (total T: 85 to 150 ng/dL; normal in women is 50 to 70 ng/dL), and an elevated LH level or LH:FSH ratio. The primary care pediatrician must recognize, however, that PCOS is heterogeneous both clinically and biochemically and is often not “classic.” You’re unlikely to find all abnormalities associated with the syndrome in one patient. Irregular menses and moderate or severe acne, especially in early adolescence, may be the only signs.

Indeed, experts at a 1990 National Institutes of Health conference on PCOS were unable to agree on specific laboratory or clinical criteria for diagnosing this group of disorders. [2,13,19,20] They did, however, identify hyperandrogenism and oligomenorrhea or amenorrhea as being included in the diagnostic criteria, as well as the absence of adrenal hyperplasia.

Another sign of PCOS, besides the “classic” ones, may be insulin resistance. In addition, an excellent marker for PCOS is acanthosis nigricans (AN)–hyperpigmented, hypertrophic, velvety skin usually located at the back of the neck and in the axillae. While AN can be a sign of malignancy in adults, it is usually associated with obesity or PCOS in adolescents. The HAIR-AN syndrome (HyperAndrogen production, Insulin Resistance, and Acanthosis Nigricans) is strongly associated with polycystic ovary syndrome. [7,8,10]

Ovarian causes of androgen excess other than PCOS include unusual syndromes of abnormal gonadal development and very rare androgen-producing ovarian tumors. Some believe that ovarian stromal hyperthecosis, which is often associated with HAIR-AN, may be a severe variant of PCOS.

Adrenal causes. Adrenal hypersecretion of androgens is a relatively uncommon cause of androgen excess in adolescents, occurring in just 1% of cases. Nonclassical CAH, the most common autosomal recessive defect in humans, may present as premature pubarche (pubic hair developing before 8.5 years of age), or as PCOS with acne, menstrual irregularity, or peri- or postpubertal hirsutism. [21] While CAH appears in about one in 1,000 adults, it is present in 1% to 5% of adult women with longstanding hirsutism and amenorrhea, and in 3% of Ashkenazi Jews. Girls with nonclassical CAH have elevated blood levels of androgens, 17-hydroxyprogesterone, and DHEAS. They do not have signs of insulin resistance. [7]

Considerable clinical overlap exists between PCOS and nonclassical CAH. The latter is best revealed by an early morning elevated level of 17-hydroxyprogesterone (or by an increase in 17-hydroxyprogesterone in a rapid ACTH stimulation test, usually done by an endocrinologist). The diagnosis of nonclassical CAH can be verified by DNA analysis. [7,21,22]

Other forms of CAH that can result in androgen excess are the very rare 11-[beta]-hydroxylase deficiency and 3-[beta]-hydroxysteroid dehydrogenase deficiency Consider the former when virilization occurs with hypertension. Experts disagree on clinical criteria for 11-[beta]-hydroxylase deficiency, and no molecular defect has yet been demonstrated. The 3-[beta]-enzyme deficiency can be diagnosed by the endocrinologist, with some difficulty, by response to ACTH. [21,22]

Patient evaluation

Adolescents presenting with symptoms suggestive of androgen excess or PCOS require a comprehensive workup (Figure 3), beginning with a history and physical exam.

History. Focus on pubertal landmarks (pubarche, the first appearance of sexual hair, menarche) and on the menstrual history, especially oligomenorrhea or amenorrhea. Also take a detailed acne history. In many girls with PCOS or another hyperandrogen syndrome, acne begins well before menarche, progressing instead of clearing after age 14 or 15. Many older adolescents with PCOS report that their acne significantly worsened in college, coincident with the development of irregular menses.

Ask about signs of virilism: marked hirsutism, male-pattern alopecia, change in voice pitch, and change in muscle mass or breast size. A medication history is essential, as is a family history, which should include ethnic background and possible consanguinity. Ask about relatives with hirsutism, type 2 diabetes mellitus, or symptoms suggestive of PCOS or CAH.

Physical examination. Perform a thorough exam, including a pelvic exam when appropriate. Document height and weight percentiles on growth charts, and calculate BMI (BMI = wt in kg/[[ht in meters].sup.2]) as a measure of obesity. Elevated blood pressure may indicate CAR (11-[beta]-hydroxylase deficiency). Document terminal hair in androgen-sensitive areas, including the pubic area, using the Ferriman-Gallwey system, and look for hair thinning or alopecia in the temporal areas or on the crown of the head.

The presence of acanthosis nigricans strongly supports the diagnosis of PCOS. Galactorrhea may indicate excess prolactin from a pituitary prolactinoma as the cause of the hyperandrogenism. Search for such signs of adrenal overproduction as plethora, a prominent interscapular fat pad (“buffalo hump”), and purple truncal striae.

A pelvic exam is helpful in ruling out an ovarian mass or an abnormality of sexual development. Examine the external genitalia for clitoral size (breadth greater than 5 mm may indicate virilism). [13]

Laboratory evaluation. No absolute guidelines exist to suggest when a young woman should have an endocrinologic evaluation for androgen excess. [9] Some believe that the presence of acne in the situations listed in Table 1 should prompt an evaluation.

The basic screen for a possible hyperandrogen syndrome in a girl or young woman with acne, amenorrhea or oligomenorrhea, or mild hirsutism without evidence of virilism, should include serum LH and FSH and an LH:FSH ratio (normally about 1), a serum DHEAS level to rule out adrenal tumor, and a total and free testosterone level. [13,14] Additional tests, especially when hirsutism is present, can include a measurement of 17-OH-progesterone after an overnight fast (to screen for late-onset 21-hydroxylase deficiency CAH) and a serum cortisol (to screen for Cushing syndrome). [14] Some endocrinologists also recommend a dexamethasone suppression test if free T, DHEAS, cortisol, or 17-OH-progesterone is increased. If dexamethasone suppresses the serum level of androgens, referral to an endocrinologist for ACTH testing is indicated.

While no consensus exists on which lab tests to order, Table 3 lists those that are often performed to rule out uncommon endocrinopathies and other conditions and to rule in PCOS. A urine or blood test to rule out pregnancy is always indicated in a postmenarchal adolescent with oligomenorrhea. Many clinicians order thyroid function tests (thyroxine [[T.sub.4]], triidothyronine [[T.sub.3]], thyroid stimulating hormone [TSH], and others) to rule out hypo- or hyperthyroidism.

Serum FSH and LH are strongly recommended. FSH, which is normal in PCOS, is helpful in ruling out other causes of oligomenorrhea, such as ovarian failure or hypothalamic amenorrhea. LH is usually elevated in PCOS, but it may be in the normal range. Similarly the LH:FSH ratio, normally 1 in adolescents, is often 2:1, 3:1, or higher in PCOS. [7] A normal prolactin level (2 to 10 ng/mL) rules out a pituitary adenoma as the cause of oligomenorrhea and hyperandrogenism. Prolactin is modestly elevated in about 20% of patients with PCOS. [3]

Testosterone levels (total and free) are very helpful. In adolescent girls, total T is normally 15 to 70 ng/dL (depending on pubertal stage), but a normal level does not, unfortunately, rule out androgen excess. A very high total T level (greater than 150 to 200 ng/dL) may indicate an androgen-producing tumor of the adrenal gland, ovary, or other organ.

Free testosterone (normal: 2 to 12 pg/mL) is a more sensitive measurement than total testosterone. Free T is often modestly increased in PCOS; because levels of sex hormone binding globulin (SHBG) are lower, less of the T is bound. [20]

In PCOS, serum DHEAS (normal 50 to 500 [micro]g/dL) is often normal or modestly elevated in the 300 to 600 [micro]g/dL) range. A serum DHEAS level of more than 500 to 700 [micro]g/dL) strongly suggests an adrenal tumor. Measurement of blood 17-OH-progesterone, done in the early morning after an overnight fast, should be normal in PCOS (60 to 300 ng/dL) but elevated in late-onset CAM (21-hydroxylase deficiency). Table 4 lists age-specific values for androgens in adolescent girls and women. [23]

To ascertain whether a patient with a possible androgen excess syndrome has associated metabolic abnormalities, many endocrinologists recommend a fasting glucose and fasting insulin level, especially in the presence of acanthosis nigricans, which may indicate HAIR-AN syndrome. A glucose tolerance test should be performed if either glucose or insulin is elevated. Because patients with androgen excess have increased triglycerides and reduced high-density lipoprotein (HDL) cholesterol, which predisposes them to cardiovascular problems later in life, a fasting lipid profile should be considered as well. [13] Some endocrinologists also include a serum androstenedione measurement in the workup to rule out an androgen-producing tumor, particularly if virilization is present. [7] If there are reasons to suspect a chromosomal abnormality or genital ambiguity, a karyotype should be obtained. [13]

Pelvic ultrasound is an insensitive test for androgen excess and is therefore not recommended as part of the routine workup. [7,13,20] Despite the traditional name “polycystic ovary syndrome,” only about one third of PCOS patients have ultrasound evidence of ovarian cysts. What’s more, other syndromes, such as obesity, CAH, virilizing adrenal adenomas, and hyperprolactin states, are also associated with polycystic ovaries. Measurement of 24-hour urine 17-ketosteroids has been replaced by serum DHEAS values, which are much more reliable.

Treatment strategies

The aims of treatment, outlined in Table 5, are twofold: to address the immediate concerns of the patient–usually menstrual irregularity, acne, and hirsutism–and to prevent or minimize complications that could develop in adulthood, including infertility. Women who experience continuous estrogen stimulation of the endometrium without regular menses are also at increased risk for endometrial cancer and perhaps breast cancer. And the insulin resistance that may occur with PCOS, along with obesity and adverse lipid changes, dramatically increases the incidence of type 2 diabetes mellitus and the risk of myocardial infarction, especially in the fourth and fifth decades of life. [7]

When laboratory tests and physical examination make the diagnosis of PCOS very likely and exclude more ominous and unusual conditions, management of the androgen syndrome by the primary care pediatrician is in order. The most effective strategy is a combination of estrogen and progestin to interrupt the pituitary-ovarian axis.[7,8,24] Oral contraceptive pills (OCPs), which may also be indicated for contraception in the sexually active adolescent, suppress FSH and LH secretion from the pituitary and turn off ovarian stimulation. In so doing, they lower free testosterone levels from both the ovary and the adrenal gland, reduce DHEAS levels, increase SHBG and hence lower free T, increase HDL-cholesterol, and provide protection from endometrial cancer by regulating menses and promoting regular withdrawal bleeds. [7,25]

Do not begin OCPs in the oligomenorrheic patient until after the next menses, to avoid annoying spotting and to insure contraceptive efficacy You may choose to induce a withdrawal bleed using a course of medroxyprogesterone (Provera) 10 mg daily for seven to 10 days to prime the endometrium. The bleed will occur within a few days of ending the medroxyprogesterone. An oral contraceptive can be started within five to seven days of the beginning of the withdrawal bleed.

Most young women with androgen excess do well on a combination low-dose estrogen-progestin pill, especially one that has very low androgenic potential. Low-androgenic progestins also are very beneficial in young women with problematic acne. They can be very effective for hirsutism, too, although somewhat less so than for acne. [7,13]

OCP preparations that contain a low-androgenic progestin (Table 6) include norgestimate (in Ortho-Cyclen and Ortho Tri-Cyclen), ethynodiol diacetate (in Demulen and Ovulen), desogestrel (in Desogen and OrthoCept), or gestodene (available in Canada and the United Kingdom but not in the US). The progestin norethindrone, which is norethinyl testosterone, is intermediate in androgenicity, but pill preparations with the lowest dose of norethindrone can still be helpful (OrthoNovum 1/35, Norinyl 1/35, TriNorinyl). While all these preparations are reasonably effective for acne, Ortho Tri-Cyclen is currently the only OCP formally approved by the FDA for adolescent acne.

To provide the best antiandrogen effect, it is preferable to avoid pill preparations with the greatest androgenic activity, especially those that contain levonorgestrel, norgestrel, or norethindrone acetate. Similarly, levonorgestrel subdermal implants (Norplant) are not a good contraceptive choice for young women with signs of androgen excess. [7,9]

In addition to the use of low-androgenic progestin OCPs, acne should be managed as usual by the pediatrician or dermatologist (Table 7), with products such as topical benzoyl peroxide 5% or 10%, topical or oral antibiotics, and topical tretinoin cream (Retin A) or adapalene (Differin). [8,9,13,26] Adolescent or young adult women with androgen excess syndromes may have such severe, scarring acne that oral isotretinoin is indicated. Isotretinoin should be used with very effective contraception–such as that provided by the compliant use of oral contraceptives–to avoid birth defects in fetuses conceived while on cis-retinoic acid and to provide synergistic acne intervention. If you are considering prescribing Accutane for an adolescent girl or young woman with severe acne, do an androgen workup first, especially before prescribing OCPs. Otherwise, using the pill may obscure endocrine abnormalities. Remember too that the use of OCPs alone will result in significant improvement in acne, so that Accutane may not b e necessary.

Other management strategies include encouraging weight management, increased exercise, and a diet lower in saturated fats, in order to improve glucose tolerance, increase HDL-cholesterol, and decrease hypertension if present. Weight loss alone has been shown to reverse many of the abnormalities associated with PCOS. [4,18]

The combination of estrogen-progestin pills may reduce hirsutism significantly. An antiandrogen such as spironolactone (or cyproterone acetate, available in Europe but not in the US at this time) can be very helpful in blocking further conversion of hair follicles into terminal hairs at the level of the skin receptors for androgens. [10,24] Spironolactone can be given in a dose of 50 to 100 mg bid for several months, in addition to OCPs. [4,27] Let your patient know that hairs that have already been androgenized may become a bit softer but will not disappear. Encourage cosmetic management of the unwanted hair by bleaching, waxing, shaving, or electrolysis. [7]

When to refer

The pediatrician can work cooperatively with the dermatologist to manage severe acne or hirsutism. For patients with androgenetic alopecia, the dermatologist may order spironolactone and topical minoxidil, to be used in addition to oral contraceptives prescribed by the pediatrician. [6] If isotretinoin is prescribed, the patient needs frequent follow-up by the dermatologist or pediatrician to monitor lipid levels, liver functions, and oral contraceptive compliance.

Referral to a pediatric or adult reproductive endocrinologist is indicated in the circumstances listed in Table 8. These include situations where there is evidence of the following: insulin resistance; late-onset CAH; high levels of prolactin; very high levels of DHEAS, which may indicate adrenal carcinoma; male-level testosterone of 200 to 350 ng/dL, which may indicate an androgen-producing tumor of the adrenal or ovary; very high levels of androstenedione (greater than 500 ng/dL), which may indicate a tumor; signs of virilism; hypertension plus virilization; or infertility or concerns about fertility. [7,21,22]

Patient follow-up

Monitor young women on OCPs as usual for compliance, changes in blood pressure, and other medication side effects. Patients diagnosed with PCOS who have increased free testosterone and elevated DHEAS should be retested within three months of starting OCPs. [7] Measure free T and DHEAS during the second or third week of the third OCP packet (not during the week of placebo pills), ideally in the early morning fasting state. Free T and DHEAS should be suppressed, usually to a normal range. FSH and LH should also be in the normal range, with an LH:FSH ratio of about 1. The failure of OCP use to suppress free T and DHEAS should prompt a referral to an endocrinologist for further evaluation.

See the young woman with androgen excess often enough (every three to six months initially, then every six months) to encourage compliance, to monitor for overall improvement in health and antiandrogenic effect, and to support her in adjusting to this chronic illness. Encourage exercise and weight reduction, and check for changes in glucose metabolism, lipid metabolism, and hypertension. [10] Advise young women to continue OCPs indefinitely, at least until their care is transferred to a reproductive endocrinologist or gynecologist experienced in the management of androgen excess syndromes and associated infertility.

Adolescents and young women with PCOS should be reassured that infertility can be addressed by using ovulation-inducing medications such as clomiphene citrate, so that future childbearing will be possible.

Pediatricians who identify and treat PCOS and other androgen excess problems in adolescent patients gain not only their patients’ gratitude for the improvement in their appearance and menstrual cycles. They also gain the satisfaction of helping to prevent the significant adult morbidity associated with undiagnosed androgen excess.

THE AUTHOR is Director of the Adolescent Program, Department of Pediatrics, Dartmouth-Hitchcock Medical Center, Lebanon, NH.

REFERENCES

(1.) Wild IRA: Hyperandrogenism in the adolescent. Obstet Gynecol Clin North Am 1992;19:71

(2.) Carmina E, Lobo RA: Polycystic ovary syndrome (PCOS): Arguably the most common endocrinopathy is associated with significant morbidity in women. J Clin Endocrinol Metab 1999:84:1897

(3.) Hagon P, Knott P: Diagnosiog and treating polycystic ovary syndrome. Practitioner 1998;242:98

(4.) Derman RJ. Androgen excess in women. Int J Fertil 1996;41:172

(5.) Solomon CG: The epidemiology of polycystic ovary syndrome: Prevalence and associated disease risks. Endocrinol Metab Clin North Am 1999;84:1897

(6.) Bergfeld WF: Androgenetic alopecia: An autosomol dominant disorder. Am J Med 1995;98(1A):95S

(7.) Emans SJ, Laufer MR, Goldstein DP (eds): Pediatric and Adolescent Gynecology, ed 4. Philadelphia, Lippincott-Raven, 1998

(8.) Rosenfield RL, Lucky AW: Acne, hirsutism, and alopecia in adolescent girls: Clinical expressions of androgen excess. Endocrinol Metab Clin North Am 1993;22:507

(9.) Lucky AW: Hormonal correlates of acne and hirsutism. Am J Med 1995;98(1A):89S

(10.) Redmond GP: Androgenic disorders of women: Diagnostic and therapeutic decision making. Am J Med 1995;98(1A):120S

(11.) Rosenfield RL: Hyperandrogenism in peripubertal girls. Pediatr Clin North Am 1990;37:1333

(12.) Ferriman D, Gollwey JD: Clinical assessment of body hair growth is women. J Clin Endocrinol Metab 1961;21:1440

(13.) Gordon CM: Menstrual disorders in adolescents: Excess androgens and the polycystic ovary syndrome. Pediatr Clin North Am 1999;46:519

(14.) McKenna TJ: Screening for sinister causes of hirsutism. N Engl J Med 1994;331:1015

(15.) Rosenfield RL, Deplewski D: Role of androgens in the developmental biology of the pilosebaceous unit. Am J Med 1995;98(1A):80S

(16.) Rosenfield RL: Ovarian and adrenal function in polycystic ovary syndrome. Endocrinol Metab Clin North Am 1999;28:265

(17.) Legro RS: The genetics of polycystic ovary syndrome Am J Med 1995:98(1A):9S

(18.) Franks S: Polycystic ovary syndrome. N Engl J Med 1995;333:853

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

(20.) Taylor AE: Polycystic ovary syndrome. Endocrinol Metab Clin North Am 1998;27:877

(21.) Pang S: Congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 1997;26:853

(22.) Miller WL: Pathophysiology, genetics, and treatment of hyperandrogenism. Pediatr Clin North Am 1997;44:375

(23.) Moll GW Jr: Plasma free testosterone in the diagnosis of adolescent polycystic ovary syndrome. J Pediatr 1983;102:462

(24.) Burkman R: The role of oral contraceptives in the treatment of hyperandrogenic disorders. Am J Med 1995;98(1A):130S

(25.) Derman RJ: Effects of sex steroids on women’s health: Implications for practitioners. Am J Med 1995;98(1A):137S

(26.) Leyden JJ: Therapy for acne vulgaris. N Engl J Med 1997;336:1156

(27.) Sokiyama R. Approach to patients with hirsutism. West J Med 1996;165:386

When acne in females may indicate androgen excess

Appears before age 8

Persists past teen years

Develops in late teens or early 20s

Responds poorly to usual acne therapies

Occurs in the presence of oligomenorrthea or amenorrhea

Occurs in the presence of hirsutism

Causes of androgen excess

Ovarian

Polycystic ovary syndromes

Abnormal gonadal or sexual development (for example, harmaphroditism)

Androgen-producing ovarian tumor

Ovarian stromal hyperthecosis

Adrenal

Congenital adrenal hyperplasia, nonclassical or “late onset”

21- hydroxylase deficiency

11- [beta]-hydroxylase deficiency

3-[beta]-hydroxysteroid dehydrogenase deficiency

Cushing disease or syndrome

Androgen-producing adrenal tumor

Hyperprolactinemia

Benign premature adrenarche

Common lab tests for an androgen-excess workup

Pregnancy test

Thyroid function tests

Serum FSH

Serum LH

LH:FSH ratio

Prolactin

Testosterone, total and free

DHEAS

Early morning fasting 17-OH-progesterone

Fasting glucose

Fasting insulin level

Fasting lipid profile

Androstenedione (should be considered)

Karyotype (should be considered)

Aims of treatment in hyperandrogen syndromes

Manage irregular menses

Manage acne

Prevent further hirsutism

Optimize fertility

Prevent endometrial carcinoma

Monitor long-term for:

Type 2 diabetes mellitus Increased risk of cardiovascular disease

Choosing an OCP

Use OCPs with low-androgenic progestins

Norgestimate (Ortho-Cyclen, Ortho Tri-Cyclen)

Ethynodiol diacetate (Demulen, Ovulen)

Desogestrel (Desogen, OrthoCept)

Gestodene (not available in US)

Norethindrone (intermediate in androgenicity, so choose lowest doses, such as Norinyl 1/35, OrthoNovum. [ON] 1/35, ON 777, TriNorinyl)

Avoid OCPs with the greatest androgenic activity

Levonorgestrel (Alesse, Levien, Nordette, Norplant, TriLevlen, TriPhasil)

Norgestrel (Lo-Ovral, Ovral, Ovrette)

Norethindrone acetate (Loestrin)

Management of acne

Topigal benzoyl peroxide, 5%, 10%

Topical antibiotics, such as:

Clindamycin

Erythromycin

Tetracycline

Meclocycline

Oral antibiotics, such as:

Tetracycline

Erythromycin

Minocycline

Doxycycline

TMP/SMX

Ampicillin

Cephalexin

Topical tretinoin cream (Retin A)

Topical adapalene (Differin)

Consider 13-cis-retinoic acid (isotretinoin; Accutane) with OCPs, especially for severe, scarring acne

When to refer to a subspecialist

Refer when there is evidence of any of the following

Significant hirsutism or alopecia

Insulin resistance or abnormal glucose tolerance test

Nonclassical CAH

Hyperprolactinemia

Very elevated DHEAS levels

Male level testosterone: 200-350+ ng/dL

Elevated androstenedione: [greater than]500 ng/dL

Increased FSH

Abnormal karyotype

Virilism:

Clitoromegaly

Deepening of voice

Increase muscle mass

Loss of female body contour, breast tissue

Hypertension plus virilization

Infertility

Failure to suppress free testosterone within 3 mo of OCPs

Failure to suppress DHEAS within 3 mo of OCPs

LEARNING OBJECTIVES

After reviewing this article the physician should be able to:

* Recognize the common presentations of androgen excess syndromes in adolescence.

* Summarize polycystic ovary syndrome and other less common ovarian and adrenal causes of androgen excess.

* Use history, physical examination, and laboratory evaluation to diagnose polycystic ovary syndrome and to rule out other causes of androgen excess.

* Manage adolescents with polycystic ovary syndrome, following a clinical algorithm.

* Recognize when consultation with a subspecialist in endocrinology or dermatology is indicated.

COPYRIGHT 2000 A Thomson Healthcare Company in association with The Gale Group and LookSmart.
COPYRIGHT 2001 Gale Group