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    PCOS in adolescents: beyond the reproductive implications

     

    By Amy DiVasta, MD

    Dr. DiVasta is an assistant professor of pediatrics at Harvard Medical School, Boston, Massachusetts. 

     

     

    Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in adolescent and adult women, and importantly has both reproductive and metabolic consequences.1 However, PCOS is likely underdiagnosed, especially in adolescent patients.2,3 It is challenging to make a diagnosis during the 1–2 years following menarche because normal pubertal changes can mimic features of PCOS. These features include anovulatory menstrual cycles, transient multi-follicular ovarian morphology that may appear polycystic by ultrasound, increased androgen effects, and relative insulin resistance secondary to increased growth hormone levels.4

    Diagnostic practices vary widely even among specialists primarily because of lack of consensus criteria in diagnosing adolescents with PCOS.5 However, underdiagnosis is concerning because of the reproductive health consequences and associated cardiometabolic risks. Adolescents with PCOS have an increased risk of metabolic syndrome (metS) and factors associated with metS as compared to age- and body mass index [BMI]-matched controls.6,7 Thus, establishing a PCOS diagnosis has important implications for further screening, counseling, and treatment.

    In adolescents, the most common presenting clinical features of PCOS include menstrual irregularity (amenorrhea, oligomenorrhea, or polymenorrhea) and/or androgen excess (hirsutism, alopecia).7 These symptoms can be particularly distressing for adolescents and their families but are not usually the factors immediately associated with metabolic risk. A desire for immediate improvement of these presenting symptoms is often the focus of patients, families, and treating physicians. As such, the long-term cardiometabolic risks associated with PCOS may be overlooked.

    Although longitudinal studies evaluating the long-term cardiometabolic consequences of PCOS diagnosed during adolescence are lacking, available evidence suggests an elevated risk of premature cardiovascular dysfunction and cardiovascular disease.8,9 In fact, older adolescents with PCOS show abnormalities in surrogate markers of cardiovascular disease, independent of obesity, when compared to age-matched controls.10 Additionally, adults with clinical features of PCOS have an increased risk of cardiovascular events and death.11

    Phenotypic variation

    Because of differing diagnostic criteria, patients with PCOS may not have the same phenotypic features. The NIH guidelines offer the strictest criteria for diagnosis of PCOS, with patients needing to exhibit both hyperandrogenism and oligoovulation/anovulation.12 The Rotterdam criteria are looser, requiring just 2 of the following 3 characteristics to establish the diagnosis: 1) hyperandrogenism, 2) oligoovulation/anovulation, and 3) polycystic ovaries on ultrasound.13

    Why do the diagnostic criteria matter? Even in adolescent patients, different phenotypes are associated with varying metabolic risk profiles. Adolescents with phenotypes that have higher levels of circulating androgens are at greater risk of insulin resistance, metabolic syndrome, and type 2 diabetes, as compared to the other phenotypes. This finding is consistent with adults with PCOS.14-16 This phenotypic variation has led researchers at the most recent PCOS Consensus Workshop group to propose renaming the NIH phenotype to something more reflective of its metabolic consequences in addition to reproductive issues.1,16

    Cardiometabolic risk factor screening

    No formal recommendations currently exist for cardiometabolic risk factor screening in adolescents with PCOS. However, clinicians can use available data to guide their decision making.

    Body mass index

    Screening should begin with evaluation of BMI with weight being measured at every visit. Obesity is known to amplify the metabolic risk factors associated with PCOS and increases the risk of metS, even in adolescents.1,7,14,17,18 Furthermore, obesity can worsen undesirable cosmetic features of PCOS such as hirsutism and acne, which can decrease perceived quality of life in women with PCOS.19

    Blood pressure

    Adolescents with PCOS are at increased risk of hypertension as compared to age- and BMI-matched controls.6 Thus, blood pressure should also be measured at every visit. Special attention should be paid to overweight and obese adolescents, as BMI is the strongest predictor of hypertension in this age group. Hypertension in patients with PCOS confers an increased risk of cardiovascular disease, and an even greater risk in patients with metS or diabetes.

    Glucose metabolism

    Up to 1 in 4 adolescents with PCOS may have derangements in glucose metabolism, independent of their BMI.20,21 Simply measuring fasting levels of glucose and insulin may miss many of these patients, as the most common abnormality is impaired
    glucose tolerance (IGT).20 Thus, utilizing the oral glucose tolerance test as an initial metabolic screening method is preferred, even in normal-weight adolescents with PCOS.

    Further underscoring the importance of assessing glucose metabolism, PCOS is considered a nonmodifiable risk factor for the development of diabetes by the American Diabetic Association and the International Diabetes Federation. Insulin resistance, estimated to occur in at least 65% of patients with PCOS independent of BMI, is thought to be a primary contributor to the underlying pathophysiology of the condition and is typically the first metabolic derangement seen in adolescents who develop PCOS.6,22

    Lipid profile

    Assessing the fasting lipid profile may be an important part of cardiometabolic screening in adolescents with PCOS. In adults with PCOS, triglyceride, LDL, non-HDL, and HDL levels are often deranged, independent of BMI.1 These findings are not consistent in adolescents, for whom obesity is a better predictor of dyslipidemia.14 A fasting lipid panel should be performed on obese and overweight adolescents with PCOS at the time of diagnosis. Consideration can be given to screening lean adolescents with PCOS and a family history of dyslipidemia when oral contraceptive pills (OCPs) are prescribed, as this medication can worsen lipid profiles.23 However, changes in lipids resulting from OCP use are often not of a magnitude to be considered clinically significant; thus, screening all OCP users is not recommended.

    Fatty liver

    Due to the association with obesity, dyslipidemia, and insulin resistance, nonalcoholic fatty liver disease (NAFLD) and its precursor, fatty liver, are often seen in adults with PCOS.24 However, adolescents with PCOS do not seem to have an increased risk of fatty liver over the general adolescent population.25 Therefore, routine screening for NAFLD in all adolescents with PCOS is not recommended and instead should be based on presence of other risk factors for fatty liver such as obesity.

    Obstructive sleep apnea

    Obesity, insulin resistance, and hyperandrogenemia are all known to contribute to the high rates of obstructive sleep apnea (OSA) in adults with PCOS.18 Screening in this population has been proposed given that appropriate treatment of OSA can reduce cardiometabolic risk. It is unclear if asymptomatic adolescents with PCOS have an increased risk of OSA.18 This lack of knowledge and the typical cost of screening have precluded recommendations for universal screening for OSA in adolescents with PCOS.

    Management and risk reduction

    Initial management of PCOS in adolescents should target the presenting symptoms such as menstrual irregularity and signs of androgen excess, with lifestyle modification being the primary recommended strategy.26 However, strong consideration should be given to using OCPs with the goals of restoring menstrual cyclicity and improving signs of androgen excess in adolescents for whom the drugs are not contraindicated.26

    OCPs improve the signs of androgen excess by several mechanisms, including reduction of androgen production, increased production of sex hormone binding globulin (thus lowering biologically active testosterone), and inhibition of 5-α-reductase. OCPs should also be considered as a first-line therapy for adolescents who are sexually active, or who are contemplating initiating sexual activity, given the additional benefit of contraception.

    Concurrently, if the results of cardiometabolic screening are abnormal, risk reduction should be incorporated into the primary management strategy. For obese adolescents with PCOS, weight reduction, though often challenging, is the cornerstone of intervention for cardiometabolic risk reduction primarily through improvement in insulin resistance.17,27 A multidisciplinary approach to weight loss (including medical, nutritional, and emotional) seems to be a successful approach to at least short-term weight loss in these adolescents.28 Underscoring the importance of early diagnosis, the success of these lifestyle interventions is inversely related to age.29

    Pharmacologic agents, especially insulin sensitizers such as metformin, should be strongly considered in adolescents with IGT or diabetes.26 Use of these medications in patients without IGT is more controversial and opinion varies among specialty adolescent medicine providers.26,30 Because metformin helps to restore menstrual cyclicity and ovulation, sexually active adolescents need to be informed of this risk and counseled on birth control options if they do not desire pregnancy.1,26

    Other pharmacologic agents such as anti-hypertensives or lipid-lowering medications can be used when lifestyle modification is not sufficient or fails to modify risks.

    Summary

    Polycystic ovary syndrome is a common condition in adolescents. Physicians must take care to address all the associated sequelae of the disorder, both reproductive and metabolic. With increased awareness of the potential cardiometabolic consequences of PCOS, specialists can work in conjunction with primary care providers to improve long-term health outcomes for these patients.

     

    The North American Society for Pediatric and Adolescent Gynecology (NASPAG) is a nonprofit organization dedicated to educating healthcare professionals in pediatric and adolescent gynecology. For more information, visit www.naspag.org.

     

     
     
     
     

    References

    1. Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): The Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012;97:28–38.e25.

    2. March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010;25:544–551.

    3. Christensen SB, Black MH, Smith N, et al. Prevalence of polycystic ovary syndrome in adolescents. Fertil Steril. 2013;100:470–477.

    4. Rosenfield RL. Clinical review: Adolescent anovulation: maturational mechanisms and implications. J Clin Endocrinol Metab. Sep 2013;98(9):3572–3583.

    5. Bonny AE, Appelbaum H, Connor EL, et al. Clinical variability in approaches to polycystic ovary syndrome. J Pediatr Adolesc Gynecol. 2012;25:259–261.

    6. Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance. J Clin Endocrinol Metab. 2006;91(2):492–497.

    7. Roe AH, Prochaska E, Smith M, Sammel M, Dokras A. Using the androgen excess-PCOS society criteria to diagnose polycystic ovary syndrome and the risk of metabolic syndrome in adolescents. J Pediatr. 2013;162:937–941.

    8. Meyer C, McGrath BP, Cameron J, Kotsopoulos D, Teede HJ. Vascular dysfunction and metabolic parameters in polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:4630–4635.

    9. Moran LJ, Hutchison SK, Meyer C, Zoungas S, Teede HJ. A comprehensive assessment of endothelial function in overweight women with and without polycystic ovary syndrome. Clin Sci. 2009;116:761–770.

    10. Jovanovic VP, Carmina E, Lobo RA. Not all women diagnosed with PCOS share the same cardiovascular risk profiles. Fertil Steril. 2010;94:826–832.

    11. Shaw LJ, Bairey Merz CN, Azziz R, et al. Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health—National Heart, Lung, and Blood Institute sponsored W. J Clin Endocrinol Metab. 2008;93:1276–1284.

    12. Zawadzki JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine F, Merriam G, editors. Polycystic ovary syndrome. Boston: Blackwell Scientific Publications; 1992;377–384.

    13. Group RE-SP consensus workshop. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19:41–47.

    14. Hart R, Doherty DA, Mori T, et al. Extent of metabolic risk in adolescent girls with features of polycystic ovary syndrome. Fertil Steril. 2011;95:2347–2353, 2353.e1.

    15. Pinola P, Lashen H, Bloigu A, et al. Menstrual disorders in adolescence: a marker for hyperandrogenaemia and increased metabolic risks in later life? Finnish general population-based birth cohort study. Hum Reprod. 2012;27:3279–3286.

    16. Dunaif A, Fauser B. Renaming PCOS: a two state solution. J Clin Endocrinol Metab. 2013;98(11):4325-4328.

    17. Moran LJ, Pasquali R, Teede HJ, Hoeger KM, Norman RJ. Treatment of obesity in polycystic ovary syndrome: a position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil Steril. 2009;92:1966–1982.

    18. Nandalike K, Agarwal C, Strauss T, et al. Sleep and cardiometabolic function in obese adolescent girls with polycystic ovary syndrome. Sleep Med. 2012;13:1307–1312.

    19. Barnard L, Ferriday D, Guenther N, Strauss B, Balen AH, Dye L. Quality of life and psychological well being in polycystic ovary syndrome. Hum Reprod. 2007;22:2279–2286.

    20. Flannery CA, Rackow B, Cong X, Duran E, Selen DJ, Burgert TS. Polycystic ovary syndrome in adolescence: impaired glucose tolerance occurs across the spectrum of BMI. Pediatr Diabetes. 2013;14:42–49.

    21. Palmert MR, Gordon CM, Kartashov AI, Legro RS, Emans SJ, Dunaif A. Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87:1017–1023.

    22. DeUgarte CM, Bartolucci AA, Azziz R. Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment. Fertil Steril. 2005;83:1454–1460.

    23. Creatsas G, Koliopoulos C, Mastorakos G. Combined oral contraceptive treatment of adolescent girls with polycystic ovary syndrome. Lipid profile. Ann N Y Acad Sci. 2000;900:245–252.

    24. Gambarin-Gelwan M, Kinkhabwala S V, Schiano TD, Bodian C, Yeh HC, Futterweit W. Prevalence of nonalcoholic fatty liver disease in women with polycystic ovary syndrome. Clin Gastroenterol Hepatol. 2007;5:496–501.

    25. Michaliszyn SF, Lee S, Tfayli H, Arslanian S. Polycystic ovary syndrome and nonalcoholic fatty liver in obese adolescents: association with metabolic risk profile. Fertil Steril. 2013 [ePub ahead of print]

    26. Geller DH, Pacaud D, Gordon CM, Misra M, Society of the D and TC of the PE. State of the art review: emerging therapies: the use of insulin sensitizers in the treatment of adolescents with polycystic ovary syndrome (PCOS). Int J Pediatr Endocrinol. 2011;2011:9.

    27. Reinehr T, Widhalm K, l’Allemand D, et al. Two-year follow-up in 21,784 overweight children and adolescents with lifestyle intervention. Obes. 2009;17:1196–1199.

    28. Geier LM, Bekx MT, Connor EL. Factors contributing to initial weight loss among adolescents with polycystic ovary syndrome. J Pediatr Adolesc Gynecol. 2012;25:367–370.

    29. Lass N, Kleber M, Winkel K, Wunsch R, Reinehr T. Effect of lifestyle intervention on features of polycystic ovarian syndrome, metabolic syndrome, and intima-media thickness in obese adolescent girls. J Clin Endocrinol Metab. 2011;96:3533–3540.

    30. Auble B, Elder D, Gross A, Hillman JB. Differences in the management of adolescents with polycystic ovary syndrome across pediatric specialties. J Pediatr Adolesc Gynecol. 2013;26:234–238.

    Amy DiVasta, MD
    Dr. DiVasta is an assistant professor of pediatrics at Harvard Medical School, Boston, Massachusetts.

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