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Adolescent GynEcology

Hyperandrogenism in the Adolescent Girl

Shawn J. Smith, MD; Amit M. Deokar, MD, MPH; Hatim A. Omar, MD

Hyperandrogenism can cause acute psychological distress in the teen years, as well as having potentially serious metabolic and reproductive consequences. Early recognition of polycystic ovary syndrome and its subtypes—the most common cause of hyper- androgenism—enables prompt initiation of therapy, minimizing the risk of adverse sequelae.

Hyperandrogenism in the adolescent female population can be difficult to recognize, and is often a component of other clinical entities—eg, idiopathic hyperandrogenism, polycystic ovary syndrome (PCOS), congenital adrenal hyperplasia, Cushing syndrome, and androgen-secreting tumors. Of these conditions, PCOS is the most common endocrinologic disorder in reproductive-age women,1 and the most frequent cause of hyperandrogenism.

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DEFINITION

The wide spectrum of clinical presentations of PCOS and its still-elusive etiology remain subject to debate. It was first described by Stein and Leventhal in 1935, when they correlated amenorrhea, polycystic ovaries, and the occurrence of “masculinizing changes.”2 One controversy concerning this syndrome is the inability to reach a consensus on diagnostic standards. In 1990, the US National Institutes of Health recommended the following criteria for PCOS: clinical or biochemical evidence of hyperandrogenism, chronic anovulation, and exclusion of other known disorders.3 Most recently, in 2003, an international consensus conference suggested expanding the criteria to include ultrasonographic evidence of polycystic ovaries, such that diagnosis would require two of the following: oligomenorrhea and/or anovulation, clinical and/or biochemical signs of hyperandrogenism, and visual evidence of polycystic ovaries.4

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CLINICAL PRESENTATION

The adolescent girl has a very unique clinical PCOS presentation compared with adult women, and applying these diagnostic criteria is difficult in this younger population. During puberty, normal endocrinologic changes often resemble the pathologic hormonal profile seen in PCOS—ie, physiologic anovulation, an increase in insulin resistance, and rising luteinizing hormone (LH) levels—phenomena that also characterize PCOS. In addition, the male-pattern hirsutism of PCOS and other clinical signs of androgen excess (eg, acne, oily skin) may be mistaken for physiologic pubertal changes. Diagnosis may also be complicated because transvaginal ultrasonography to assess ovarian morphology is not always appropriate in the virginal girl.

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HAIR-AN SYNDROME

A subphenotype of PCOS may be more applicable to the adolescent population—ie, an entity comprising hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN syndrome). This condition is similar to PCOS because it includes hyperandrogenism, but patients also have insulin resistance and consequent acanthosis nigricans. Many patients with HAIR-AN syndrome have menstrual dysfunction and polycystic ovaries, as do women with PCOS, but these features are not included in the diagnostic criteria for the HAIR-AN subtype.5 A retrospective study at a university clinic showed that 40% of patients presenting with menstrual irregularity were diagnosed with HAIR-AN syndrome as defined strictly by hyperandrogenism, insulin resistance, and acanthosis nigricans.6

Early recognition is important not only because treatment options exist and can reduce morbidity, but also because the long-term sequelae of the HAIR-AN triad are significant.7 Due to insulin resistance, obesity, and menstrual dysfunction, patients have a significantly increased risk of type 2 diabetes mellitus and infertility.8 In women with PCOS, 40% will have type 2 diabetes or insulin resistance by the time they reach 40 years of age.9 Furthermore, they have a higher risk of gynecologic cancer.10 Finally, one of the most important reasons to recognize and treat PCOS and HAIR-AN syndrome early is the psychological impact it can have on the adolescent girl, which can have both sociologic and hormonal components. For example, 24% of a sample of adolescents with HAIR-AN syndrome also reported depression.11

Adolescent Hyperandrogenism at a Glance

Hyperandrogenism is extremely common in the adolescent girl, but can be difficult to diagnose because symptoms may resemble normal pubertal changes. The HAIR-AN syndrome is associated with an increased risk of type 2 diabetes mellitus and infertility. Early recognition and treatment of PCOS is vital to reduce future morbidity and improve quality of life. The mainstay of treatment is a combination of OCs and metformin.

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DIAGNOSIS

Establishing the diagnosis of PCOS versus HAIR-AN syndrome in these patients depends on an accumulation of data, including medical history, family history, careful physical examination, and laboratory studies. Obtaining a pubertal history is helpful, as there is an association between premature pubarche and PCOS.12 Due to the wide spectrum of symptoms and hormone profiles, there is no single diagnostic test. Whenever an adolescent presents with signs of hyperandrogenism (acne, hirsutism), insulin resistance (central adiposity, acanthosis nigricans), and/or menstrual irregularity, it is essential to consider PCOS—and especially HAIR-AN syndrome—early in the diagnostic process. Laboratory tests that may be helpful include fasting insulin levels, fasting glucose-to-insulin ratio, and a glucose challenge (Table).

TABLE. Laboratory Tests for the Hyperandrogenic Adolescent

Fasting insulin levels Fasting glucose-to-insulin ratio Glucose challenge test Testosterone levels Dehydroepiandrosterone sulfate (DHEAS) levels

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MANAGEMENT

Treatment for this condition is multifactorial, and largely depends on the severity of symptoms. Because of the cosmetic effects of hyperandrogenism, addressing and treating hirsutism and acne is extremely important. Managing the obesity component may require a multidisciplinary approach; these patients often benefit from frequent clinic visits to monitor and reinforce their progress.

Medication also plays a role in treatment. The use of oral contraceptives (OCs) is the standard therapy, improving menstrual regularity, decreasing hyperandrogenism, and reducing ovarian steroid/androgen production.13 Treating the insulin resistance with medications is somewhat controversial in the pediatric population; studies have shown that treatment with metformin reduces the body mass index (BMI), promotes menstrual regularity, and decreases the risk of type 2 diabetes.14

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CONCLUSION

Hyperandrogenism in the young female patient has a wide spectrum of clinical presentations, and can be caused by many disorders. Polycystic ovary syndrome is the leading etiology, along with its subphenotype HAIR-AN syndrome, and requires early recognition and treatment in the adolescent patient to prevent serious sequelae. Comorbidities—which include psychological disorders—must also be considered and addressed. Although much remains to be learned about hyperandrogenism, establishing the diagnosis while the patient is still quite young can help to minimize both physical and psychological consequences.

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Shawn J. Smith, MD, and Amit M. Deokar, MD, MPH, are Assistant Professors, Department of Pediatrics, and Hatim A. Omar, MD, is Professor of Pediatrics and Obstetrics/Gynecology and Division Chief, Adolescent Medicine and Young Parent Programs; all in the Division of Adolescent Medicine, University of Kentucky, Lexington.

References

1. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab. 1998;83(9):3078-3082.
2. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 1935;29:181-191.
3. Zawadzki J, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Duanif A, Givens JR, Haseltine F, eds. Polycystic Ovary Syndrome. Boston, MA: Blackwell Scientific; 1992: 377-384.
4. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004; 19(1):41-47.
5. Rager K, Omar H. Androgen excess disorders in women: the severe insulin-resistant hyperandrogenic syndrome, HAIR-AN. ScientificWorldJournal. 2006;6:116-121.
6. Omar HA, Logsdon S, Richards J. Clinical profiles, occurrence and management of adolescent patients with HAIR-AN syndrome. ScientificWorldJournal. 2004;4:507-511.
7. Tan S, Hahn S, Benson S, et al. Metformin improves polycystic ovary syndrome symptoms irrespective of pre-treatment insulin resistance. Eur J Endocrinol. 2007;157(5):669-676.
8. Sheehan MT. Polycystic ovary syndrome: diagnosis and management. Clin Med Res. 2004; 2(1):13-27.
9. Kidson W. Polycystic ovary syndrome: a new direction in treatment. Med J Aust. 1998; 169(10):537-540.
10. Meirow D, Schenker JG. The link between female infertility and cancer: epidemiology and possible aetiologies. Hum Reprod Update. 1996;2(1): 63-75.
11. McClanahan KK, Omar HA. Navigating adolescence with a chronic health condition: a perspective on the psychological effects of HAIR-AN syndrome on adolescent girls. ScientificWorldJournal. 2006;6:1350-1358.
12. Siklar Z, Ocal G, Adiyaman P, Ergur A, Berberoglu M. Functional ovarian hyperandrogenism and polycystic ovary syndrome in prepubertal girls with obesity and/or premature pubarche. J Pediatr Endocrinol Metab. 2007; 20(4):473-474.
13. Jensen JT, Speroff L. health benefits of oral contraceptives. Obstet Gynecol Clin North Am. 2000;27(4):705-707.
14. Haas DA, Carr BR, Attia GR. Effects of metformin on body mass index, menstrual cyclicity, and ovulation induction in women with polycystic ovary syndrome. Fertil Steril. 2003;79(3): 469-481.

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