Adolescent Health Care: A Practical Guide
Hirsutism and Virilization
Catherine M. Gordon
Lawrence S. Neinstein
Hirsutism is defined as increased growth of terminal (long, coarse, and pigmented) hair in a young woman, more than is cosmetically acceptable in a certain culture. The condition commonly refers to an increase in length and coarseness of the hair, in a male pattern, including predominantly midline hair of the upper lip, chin, cheeks, inner thighs, lower back, and periareolar, sternal, abdominal, and intergluteal regions. Virilization implies the development of male secondary sexual characteristics in a woman, and may include a deepened voice, increased libido, increased muscle mass, clitoromegaly (>5-mm diameter), temporal balding, and acne. Decreased breast tissue, oligomenorrhea, or amenorrhea may also accompany these physical signs.
Hypertrichosis implies the predominance of excessive vellus hair on the body, particularly the forehead, forearms, and lower legs.
Androgen excess, or hyperandrogenism, results in appearance changes in a young woman and can be associated with abnormal menstrual patterns, infertility, and metabolic disturbances that include decreased high-density lipoprotein cholesterol level, insulin resistance, decreased sex hormone–binding globulin (SHBG), and alterations in the balance between thromboxane and α2-prostacyclin (Haseltine et al., 1994). Polycystic ovary syndrome (PCOS), a common cause of hyperandrogenism, can increase a patient's risks for developing obesity, type 2 diabetes mellitus, and cardiovascular disease (Gordon, 1999; Ehrmann, 2005; Pfeifer, 2005). These young women can also have increased levels of plasminogen-activator inhibitor-1, which inhibits fibrinolysis and is a risk factor for myocardial infarction (Ehrmann et al., 1997).
Androgen disorders must be evaluated, particularly in female adolescents, because appropriate interventions are now available. The evaluation does not require complicated, expensive procedures; and if untreated, the hyperandrogenism will persist and can lead to excess morbidity and psychosocial dysfunction (Trent et al., 2002). It is also important to delineate the etiology of the hyperandrogenism so that an appropriate management plan can be developed around a specific diagnosis (e.g., PCOS and late-onset congenital adrenal hyperplasia).
Hair grows from follicles that develop at 8 weeks of gestation. All hair follicles are developed in utero, and no new follicles develop during life. The concentration of hair follicles per unit area of skin is similar in males and females, but differs between races and ethnic groups. Whites have a greater concentration than Asians, and Mediterranean individuals have a greater concentration than those of Nordic descent. Hair grows in cycles according to the following phases:
- Anagen phase: Growing phase
- Catagen phase: Rapid involution phase
- Telogen phase: Resting phase
Hair length is determined by the duration of the growing phase. Factors influencing hair growth include the following:
- Androgens: Androgens initiate hair growth and increase hair diameter and pigmentation. These changes occur secondary to dihydrotestosterone (DHT) conversion of vellus hair to terminal hair. Once hair growth is established, the pattern may continue despite androgen withdrawal, albeit at a slower rate. Once the androgen level is reduced, there may be a lag time of 6 to 9 months before a significant change is noticed, as old terminal hairs fall out and are replaced by new vellus hairs.
- Estrogens: Estrogens retard initiation and the rate of hair growth, and may prolong the anagen phase.
The effects of sex hormones and other factors on hair development and distribution can be more easily understood by considering the pilosebaceous unit (Fig. 58.1). The clinical manifestations of androgen excess vary depending on endorgan sensitivity to androgens, as is shown. Hirsutism can result either from overproduction or increased sensitivity of hair follicles to androgens (Azziz, 2003). Terminal hair growth is stimulated by the increased conversion of testosterone to DHT from excess 5α-reductase within this unit or the presence of more numerous hair follicles.
Androgens are synthesized from the ovary or adrenals from steroidogenic pathways within each gland (Fig. 58.2).
- Circulating androgenic steroids in females
- 17-Ketosteroids (17-KSs)
- Dehydroepiandrosterone sulfate (DHEAS)
- Dehydroepiandrosterone (DHEA)
FIGURE 58.1 Effect of ovarian androgens on the pilosebaceous unit. Within the ovarian theca cell, insulin and luteinizing hormone (LH) may stimulate cytochrome P-450c17α activity, resulting in increased 17α-hydroxylase and 17,20-lyase activity, as denoted by asterisks above. These two enzymes comprise the P-450c17α complex. Ovarian testosterone, along with dihydrotestosterone (DHT) from 5α-reductase within the pilosebaceous unit, stimulates the androgen receptors at the hair follicle and sebaceous glands. Hirsutism and acne can result. (From Gordon CM. Menstrual disorders in adolescents: excess androgens and the polycystic ovary syndrome. Pediatr Clin North Am 1999;46:519–543, with permission.)
- Metabolism: Androgens originate in the adrenal gland and ovaries, either through direct secretion or peripheral conversion of precursors (Fig. 58.2). DHEAS, DHEA, and androstenedione, which are mainly produced in the adrenal gland, exert their androgenic activity after peripheral conversion to testosterone or its metabolites.
FIGURE 58.2 Sources of androgens in women. DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate. (From Emans SJ. Androgen abnormalities in the adolescent girl. In: Pediatric and adolescent gynecology, 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:301, with permission.)
- Adrenal: Androgens are by-products of cortisol synthesis (Fig. 58.3).
- 17-KSs: Most of the 17-KSs are generated from adrenal sources. This includes a daily secretion of 7 mg of DHEAS (90% of total daily secretion), 5.5 mg of DHEA, and 1.8 mg of androstenedione (50% of total daily secretion). All of these compounds have low androgenic activity because they are precursors of testosterone.
- Testosterone: Twenty-five percent is derived from adrenal secretion, or a total of 0.06 mg/day is secreted from the adrenal gland. Testosterone is a potent androgen, although the most potent androgen is DHT, formed after conversion by 5α-reductase.
- Ovarian: Androgens from the ovary are metabolized as intermediates in the production of estrogen and progesterone. Androgenic hormones secreted by the ovary include the following (Fig. 58.2):
- Testosterone: Approximately 25% of total daily secretion (0.06 mg/day)
- Androstenedione: Approximately 50% of total daily secretion (1.7 mg/day)
- Peripheral conversion: Approximately 50% of testosterone is derived from peripheral conversion of androstenedione in liver, fat, and skin cells.
- Testosterone is 95.5% bound to SHBG in females; only the free portion is active. During pregnancy, approximately 99% is bound. In healthy males, 92.8% of testosterone is bound.
FIGURE 58.3 Major pathways of steroid biosynthesis. 21-OH, 21-hydroxylase; 11β-OH, 11β-hydroxylase; 18-OH, 18-hydroxylase; 3β-HSD, 3β-hydroxysteroid dehydrogenase; 17β-HSD, 17β-hydroxysteroid dehydrogenase (17-ketosteroid reductase); 17β-OH, 17-β hydroxylase; C-17,20 lyase also termed 17,20 desmolase. (From: Emans SJ. Androgen abnormalities in the adolescent girl. In: Pediatric and adolescent gynecology, 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:312, with permission.)
The relative prevalence of hirsutism is presented in Table 58.1 (Curran et al., 2005), with data obtained from an original sample of more than 1,000 women (Azziz et al., 2004). Note that PCOS is the most common cause of androgen excess and one of the most common endocrine abnormalities in female adolescents and young women.
- Idiopathic hirsutism: As the pathophysiology behind specific causes of hyperandrogenism is better delineated, the percentage of hirsute women with idiopathic hirsutism has continued to fall. This diagnosis represents between 4% and 15% of hirsute women (Azziz, 2003; Curran et al., 2005).
- Ovarian causes
- PCOS or functional ovarian hyperandrogenism (see Chapter 52), with or without insulin resistance
- Tumor: Sertoli-Leydig cell tumor, lipoid cell tumor, hilar cell tumor
- Pregnancy: Luteoma
- Adrenal causes
- Congenital adrenal hyperplasia: 21-hydroxylase or 11-hydroxylase deficiency, classic or nonclassic, late onset
- Tumors: Adenomas and carcinomas
- Cushing syndrome
- Nonandrogenic causes of hirsutism
- Genetic: Racial, familial
- Physiological: Pregnancy, puberty, postmenopausal
- Endocrine: Hypothyroidism, acromegaly
- Drug-induced: Drugs that cause hirsutism by increasing androgenic activity include testosterone, DHEAS, danazol, corticotropin, high-dose corticosteroids, metyrapone, phenothiazine derivatives, anabolic steroids, androgenic progestin, and acetazolamide. Nonandrogenic drugs that can cause hirsutism include cyclosporine, phenytoin, diazoxide, triamterene-hydrochlorothiazide, minoxidil, hexachlorobenzene, penicillamine and psoralens, and minoxidil. Valproate is also associated with menstrual disturbances and hyperandrogenism (Isojarvi et al., 1993).
- Central nervous system lesions: Multiple sclerosis, encephalitis
- Congenital lesions: Hurler syndrome, de Lange syndrome
Indications for Evaluation
- Rapid onset of signs and symptoms
- Onset of hirsutism or virilism that is not peripubertal
- Symptoms suggesting Cushing syndrome (e.g., weight gain, weakness, or hypertension)
Consider hyperandrogenism in any female with premature pubarche, severe acne, hirsutism, or androgenetic alopecia. Girls with premature pubarche are at higher risk to develop PCOS and metabolic syndrome during adolescence (Ibanez et al., 2000). Insulin resistance can accompany the clinical picture with the potential to alter lipid profiles and glucose.
- Menstrual history, evaluating for amenorrhea or oligomenorrhea
- Drug history
- Ethnic background and family history of hirsutism, irregular menses, infertility, miscarriages, type 2 diabetes mellitus
- Rapidity of androgenizing or virilizing symptoms and signs: Most women with an androgen-producing ovarian or adrenal tumor have rapid onset of virilization.
- Extent of hirsutism: Grading systems are available that enable a clinician to quantitate the degree of hirsutism in a patient. One method is illustrated and discussed by Hatch et al. (1981), based on grading the nine areas of the body from 1 to 4. The Ferriman-Gallwey hirsutism scoring system (Ferriman and Gallwey, 1961) is another frequently used system that enables clinicians to quantify the extent of hirsutism by circling an individual's appearance on a flow sheet and recording the total score on the patient's chart. These scores can be helpful for making comparative assessments between visits and for appraising the efficacy of a particular therapy. Some terminal hair on the lower abdomen, face, and around the areola is normal, but hair on the upper back, shoulders, sternum, and upper abdomen suggests more marked androgen activity.
- Stigmata of Cushing syndrome (e.g., truncal obesity, striae, posterior fat pad)
- Signs of virilization: Check clitoral diameter or index. A clitoral diameter >5 mm is abnormal and is a measurement that can be easily followed up. The clitoral index is the product of the vertical and horizontal dimensions of the glans. The normal range is 9 to 35 mm2; a clitoral index >100 mm2suggests a serious underlying disorder.
- Presence of ovarian or adrenal masses.
- Evidence of insulin resistance (e.g., acanthosis nigricans, as is seen in patients with PCOS).
The goals of the laboratory evaluation include demonstrating androgen excess and locating the source of the excess.
- Measuring androgen excess
- Plasma testosterone is the most important measurement, although this is a subject of debate in the diagnostic work-up of these patients. Levels >150 to 200 ng/dL suggest significant hyperandrogenism and potentially, severe disease.
- Other important indicators
- DHEAS: Levels >700 µg/dL suggest significant adrenal androgen production. An adrenal tumor must be ruled out. Rarely, PCOS, congenital adrenal hyperplasia, or an ovarian tumor will result in levels this high.
- 17-Hydroxyprogesterone (17-OHP): This hormone should only be measured in the morning (ideally between 7 and 9 a.m.). This is characteristically elevated in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. One can also measure 11-deoxycortisol in the morning to rule out 11-hydroxylase deficiency.
- Free testosterone: Free testosterone may be elevated in the presence of normal total testosterone. However, free testosterone will be elevated in the presence of hirsutism, so it is not a specific test. Total testosterone tests are less expensive and may be sufficient to point the diagnosis toward an ovarian cause.
- 17-KS: This is a nonspecific test, because some 17-KSs are nonandrogenic and the potent 17β-hydroxysteroids are not measured.
- If the teen has either amenorrhea or oligomenorrhea, prolactin and thyroid-stimulating hormone should be measured and a pregnancy test performed.
Overall, in most individuals minimal laboratory testing is necessary because of the complete response to combination oral contraceptives, with or without spironolactone. This includes a total testosterone determination to eliminate the rare individual with a testosterone-secreting tumor. A baseline early morning level of 17-OHP is useful. DHEAS is also usually measured, but in many instances, a moderate increase is found in women with anovulation who have no adrenal disease.
- Locating the source of androgen excess
- If male levels of testosterone are obtained or a mass is felt on examination, perform an ultrasonography or computed tomography (CT) scan of adrenal glands and ovaries. Markedly elevated serum testosterone and DHEAS levels suggest an adrenal tumor and the need for a CT scan, whereas markedly elevated serum testosterone and normal DHEAS levels suggest an ovarian source and the need for ultrasonography of the ovaries.
- If any of the androgens' levels are elevated or signs suggest hypercortisolism, perform a dexamethasone suppression test.
- An ovarian source is suggested by cortisol suppression, but a lack of androgen suppression. An ultrasonography of the ovaries is helpful in this instance.
- Both adrenogenital syndrome and idiopathic hirsutism are suggested by suppression of cortisol and androgens after dexamethasone administration.
- Cushing syndrome or an adrenal tumor is suggested by lack of cortisol suppression.
Indicators of suppression after dexamethasone (0.5 mg q.i.d. for 5 to 7 days)
- –Free testosterone level <8 pg/mL
- –Total testosterone level <58 ng/dL
- –Free plasma 17β-hydroxysteroid level <42 pg/mL
- –Decrease in DHEAS level of at least 50%
- If 17-OHP level is elevated, perform an adrenocorticotropic hormone (ACTH) stimulation test. This is helpful in differentiating normal and idiopathic hirsute females from those with late-onset congenital adrenal hyperplasia due to incomplete 21-hydroxylase deficiency.
To perform the test measure a baseline 17-OHP and repeat a serum level 60 minutes after 0.25 mg of ACTH is administered intravenously. In a positive result, there is an increase in the serum level to >30 ng/mL, whereas in normal or idiopathic hirsute females, the levels are usually <5 ng/m This test can also be used to rule out less common forms of late-onset congenital adrenal hyperplasia due to 11-hydroxylase or 3β-hydroxysteroid dehydrogenase deficiency.
- Specific diagnoses
- Idiopathic hirsutism: These women generally ovulate regularly and have normal levels of androgens. 5α-reductase activity in the skin and follicle appears to be overactive in these young women, leading to hirsutism in the face of normal androgen (Azziz, 2003). The definitive underlying mechanism remains to be identified, with the following other possible causes of androgen excess:
- Altered gonadotropin secretory patterns
- Exaggerated adrenal androgen secretion
- Increased prolactin levels, augmenting adrenal androgen secretion
- Alteration of SHBG (decreased SHBG level, resulting in mild elevation of free testosterone level)
- Ovarian tumors
- Palpable adnexal mass
- Testosterone level >200 ng/mL
- Nonsuppression of androgens after dexamethasone
- PCOS or functional ovarian hyperandrogenism (see Chapter 52)
- Hirsutism, infertility, menstrual irregularities, obesity
- Elevations in androgen levels (free and/or total testosterone; 50% or more may also have an elevated DHEAS level)
- Increase in luteinizing hormone (LH) level and LH: follicle stimulating hormone (FSH) ratio. LH and FSH have been suggested as markers for PCOS
with a high LH and low-normal FSH level (ratio >3:1), but this test is neither sensitive nor specific, because only approximately 50% of patients with PCOS exhibit these abnormalities.
- Adolescent girls with severe acne: High incidence of PCOS
- Congenital adrenal hyperplasia: Elevated 17-OHP, with large increase after ACTH administration is diagnostic of incomplete 21-hydroxylase deficiency. This condition is often recognized during adolescence with presentation similar to PCOS syndrome. Elevated 11-deoxycortisol or DHEAS and 17-hydroxypregnenolone levels are found in 11-hydroxylase and 3β-hydroxysteroid dehydrogenase deficiencies.
- Adrenal tumors
- Androgen-secreting tumors: Rare and associated with rapid defeminization
- Adrenal mass: Palpable in many individuals
- Elevated 17-KS, DHEAS, and DHEA levels
- Subnormal suppression with dexamethasone administration
- Mass on ultrasonography, intravenous pyelogram, or CT scan
- Drug-induced hirsutism: The cause of nonandrogen drug-induced hirsutism is not well understood. The pattern is not restricted to androgen-dependent areas, and the hair is usually vellus in nature.
- Anabolic steroid abuse
- Hyperandrogenic insulin-resistant acanthosis nigricans (HAIR-AN) syndrome: This includes the following characteristic features: hyper androgenism, insulin resistance, andacanthosis nigricans. This syndrome may lead to the clinical and metabolic features of PCOS, as well as myocardial hypertrophy. Insulin receptor mutations, circulating antibodies to the insulin receptor, and postreceptor signaling defects have been described in variants of this syndrome. These individuals have fasting basal insulin levels of >80 µU/mL compared with reference-range levels of approximately 7 to 8 µU/mL, as well as peaks of >1,000 µU/mL compared with approximately 60 µU/mL in healthy individuals.
- Tumor: Remove the androgen source
- Drug-induced: Stop medication
- Congenital adrenal hyperplasia: Replace cortisol and suppressive adrenal androgen precursors with oral hydrocortisone or prednisone. In rare instances, use low-dose dexamethasone (0.25 mg q.d.). Oral contraceptives may also be used to regulate menstrual bleeding and provide contraception.
- Functional ovarian hyperandrogenism (e.g., PCOS): Multi-faceted treatment directed at individual problems (e.g., hirsutism, menstrual irregularity, insulin resistance, hyperlipidemia, obesity)
- Specific therapies (hyperandrogenism)
- Cosmetic approaches: Standard treatments include camouflaging with heavy make-up, bleaching, and removal with physical methods such as rubbing, cutting, shaving, plucking, or waxing. Chemical depilatories are designed to use on specific body locations. Most of these methods last from hours to days. Electrolysis or thermodestruction of the hair follicle retards regrowth for days to weeks and can permanently remove hair. Electrolysis can be expensive, time-consuming, and uncomfortable. Photothermodestruction with a laser is a new hair-removal technique. It is expensive but can offer long periods between regrowth and can lead to permanent hair loss. All of these methods can cause skin irritation, folliculitis, and pigment abnormalities.
- Topical therapy: Eflornithine hydrochloride 13.9% cream has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of unwanted facial hair. The agent is an irreversible inhibitor of L-ornithine decarboxylase, an enzyme that is important in controlling hair growth and proliferation. The agent slows and miniaturizes hairs that are present. Side effects are mild, including rash and stinging, and occur in <10% of patients (Balfour and McClellan, 2001).
- Weight loss: Weight loss in obese girls with PCOS and hirsutism can reduce hirsutism. Weight loss reduces insulin resistance and therefore insulin levels, thereby reducing testosterone secretion.
- Estrogen/progestins: Oral contraceptives work in 60% to 100% of hirsute girls. Medical therapy is slow and requires 6 to 12 months before physical changes are evident. Lag time occurs because of the delay before terminal hair falls out and is replaced by thinner less-pigmented hair. Combination pills that contain low androgenic progestins, such as norethindrone or norgestimate, are optimally used. Oral contraceptives also provide contraception for women who are on other antiandrogenic medications that may be teratogenic. Combinations of oral contraceptives and antiandrogenic medications may enhance therapeutic effectiveness and prolong remission. A new estroprogestinic preparation is available containing the antimineralocorticoid progestin drospirenone and 30-µg ethinyl estradiol. In one study, hirsutism improved from the 6th cycle onward (Guido, 2004). All oral contraceptives decrease androgen production in the following ways:
- –Lowering LH levels, thus decreasing androgen production
- –Increasing SHBG, thereby lowering free androgens
- –Decreasing adrenal androgen production
- –Decreasing 5α-reductase activity
The above is an off-label use of oral contraceptives.
- Antiandrogenic agents: Antiandrogenic agents include drugs that block androgen cytochrome P-450 receptors, resulting in decreased testosterone, DHT, and DHEAS levels; and drugs that inhibit 5α-reductase, reducing conversion of testosterone to DHT. Spironolactone and cyproterone acetate (investigational) have been used. Spironolactone works primarily by competing at the androgen receptor peripherally, and also inhibits 5α-reductase. The starting dose is usually 50 mg/day and is typically effective between approximately 75 and 200 mg/day. The medication can be increased by 25 mg every 1 to 2 weeks. However, the maximal response is not seen for 6 months to 1 year. Side effects are minimal but can include dry mouth,
diuresis, fatigue, and menstrual spotting, and hyperkalemia on laboratory evaluation. The drug is contraindicated during pregnancy, because it can lead to feminization of the male fetus. Therefore, an oral contraceptive should be prescribed simultaneously. In Europe, flutamide (a nonsteroidal antiandrogen) and 5α-reductase inhibitors (such as finasteride) have been used, but reports of severe hepatotoxicity prohibit its use in teenagers.
- Combination therapy: The combination of low-dose oral contraceptives and spironolactone is very effective.
- Future directions: Therapies will probably include more widespread use of insulin-sensitizing agents, inhibitors of the enzyme 5α-reductase, and long-acting gonadotropin-releasing hormone (GnRH) agonists. The efficacy of insulin-sensitizing agents (e.g., metformin) in patients with PCOS is an area of intensive research, and efficacy and safety data from adolescent studies to date have been encouraging (Arslanian et al., 2002). One study of women showed effective treatment of moderate to severe hirsutism after 12 months of metformin (Harborne, et al., 2003). GnRH agonists are alternative agents for patients with PCOS, but should be reserved for severe cases of hyperandrogenism, because they are fraught with adverse side effects. Carr et al. (1995) compared the use of oral contraceptives alone, GnRH agonists alone, or the two in combination. They found that by 6 months, measurements of hirsutism were not different between the groups. GnRH agonists alone had a negative impact on bone density. For this reason, GnRH agonists are used only rarely in young women with PCOS.
- Menstrual abnormality
- Cyclic progestin
- Combined oral contraceptives
- Infertility (referral to infertility specialist)
- Clomiphene citrate
- Human chorionic gonadotropin
- Insulin-sensitizing agents plus/minus clomiphene citrate (their use in adolescents is currently experimental
For Teenagers and Parents
http://www.obgyn.net/pcos/articles/hairissue_article.htm. OB-GYN net handout on hirsutism.
http://www.pcosupport.org. PCOS Association Web site includes facts and figures on PCOS, as well as on-line support.
http://www.obgyn.net/pcos/pcos.asp. PCOS Pavilion.
http://www.pcosupport.org/proteen. PCO Teenlist home page is dedicated to teenagers with PCOS. Includes a chat room and bulletin board so teens can share their thoughts on the disease.
http://www.noah-health.org/en/endocrine/endocrine/hirsutism.html. New York On-line Access to Health list of resources for hirsutism information.
http://www.hormone.org/Public/polycystic.cfm. A helpful overview of PCOS, including treatment options. Developed by the professional organization, The Endocrine Society.
http://www.youngwomenshealth.org/pcosinfo.html. A teen-friendly Web site developed at Children's Hospital Boston that is written using terminology that adolescents can easily understand.
For Health Professionals
http://www.postgradmed.com/issues/2000/06_00/bergfeld.htm. Postgraduate Medicine symposium on hirsutism.
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