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Irregular Menses in an Adolescent: When to Consider Polycystic Ovary Syndrome

Educational Objectives

 

After reading this article and answering the review questions, the reader will:

  • Recognize the clinical features and workup recommended for diagnosing polycystic ovary syndrome
  • Explain the underlying pathophysiology of polycystic ovary syndrome
  • Describe the appropriate metabolic workup in adolescents and young women presenting with polycystic ovary syndrome

Case

 

Jessica is a 15-year-old female who presents to your office with the concern of lack of menstrual periods. She had her first menstrual period at 12 years of age. Periods initially occurred every month up until 1 year ago, when they became less frequent and now occur every 2-4 months. Her last menstrual period was 3 months ago. She also complains of worsening acne since menarche, increasing dark hair growth on her chin and abdomen, and escalating weight gain over the past several years. She is worried because she does not look like her other girlfriends and wants to know what to do.

 

Birth history is notable for a birth weight of 5 pounds 8 ounces; otherwise Jessica was a healthy infant and child. Family history is positive for a father with type 2 diabetes diagnosed at the age of 38 years and a mother who is obese and has a history of irregular periods.

 

Physical exam is notable for a BMI of 34kg/m2 (>99th percentile) and BP 138/82mmHg. General: obese adolescent girl who appears sullen. HEENT: acne noted on forehead, terminal dark hairs noted on chin and sideburn regions, acanthosis nigricans on back of neck (Figure 1). Abdomen: obese, pink-colored striae appreciated, hair growth noted near umbilicus and along lower abdomen. Extremities: darkening of skin on knuckles. There are no Cushingnoid features.

 

Figure 1

 

 

 

In summary, this patient is presenting with ovulatory dysfunction, clinical hyperandrogenism, and obesity with evidence of insulin resistance on exam, features characteristic of polycystic ovary syndrome (PCOS).

 

Introduction to PCOS

 

Polycystic ovarian syndrome affects 5% to 10% of adult women and is increasingly recognized in the adolescent population.1 Considerable debate has surrounded how to diagnose this syndrome in both adult women and adolescents. In 2003, the Rotterdam Criteria defined women with PCOS as demonstrating two of the following three criteria: 1) chronic anovulation, 2) clinical or biochemical evidence of androgen excess, and 3) polycystic ovaries on ultrasound2 in the absence of other causes. With this definition, a heterogeneous group, including women without evidence of hyperandrogenemia, meets the diagnostic criteria of PCOS. Experts from the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society believe the role of hyperandrogenemia is crucial in defining PCOS and its long-term associated health risks, and defines PCOS based on the presence of hyperandrogenism and ovulatory dysfunction, with other causes ruled out with appropriate testing.3

 

Adolescents with PCOS are an intriguing subgroup to define, as features that define PCOS often overlap with normal puberty. For example, several months of anovulatory irregular menses may follow menarche and findings suggesting androgen excess (e.g., acne) are common. What distinguishes adolescents with PCOS is the persistence of ovulatory dysfunction beyond two years and the onset or worsening of hyperandrogenism around menarche.

 

Etiology of PCOS

 

The precise etiology of PCOS remains unknown and is likely multifactorial. The hypothalamic secretion of gonadotropin releasing hormone (GnRH) is disrupted in women with PCOS.4  The increased frequency of GnRH promotes a predominant release of luteinizing hormone (LH) compared to follicle stimulating hormone (FSH) by the pituitary. LH acts on the theca cells and leads to increased steroidogenesis and testosterone production. High testosterone levels feed back to the pituitary and hypothalamus, suppressing the rise in LH mid-cycle and thereby disrupting ovulation.5  In spite of an absent LH surge mid cycle, LH levels remain chronically elevated relative to the FSH levels.

 

The ovary also plays a role in the pathogenesis of PCOS. In vitro studies of theca cells from women with PCOS demonstrate a higher expression of steroidogenic enzymes than normal, which promotes testosterone production.6  This expression is further augmented by not only the chronically elevated LH levels but by insulin as well. Theca cells from women with PCOS secrete higher androgen levels than women without PCOS when stimulated with insulin in vitro, supporting the direct role of insulin in ovarian androgen production.7

 

Insulin also acts indirectly in women with PCOS to promote a hyperandrogenic state by decreasing sex hormone binding globulin (SHBG) in the liver.8  SHBG acts as a carrier protein and determines the amount of free or bioavailable hormone; thus, lower SHBG levels can increase the bioavailable androgen. Interestingly, the role of insulin in the pathogenesis of PCOS is one of insulin action, whereas some metabolic consequences of PCOS are secondary to insulin resistance or lack of insulin action. This selective insulin resistance found in the PCOS population is an enigma for researchers.9,10

 

Finally, in recent years researchers have uncovered a relationship between intrauterine growth retardation (IUGR) and premature adrenarche and the subsequent development of PCOS and its metabolic consequences.11,12 The IUGR state reflects a nutritionally restricted state in utero. According to the Barker's hypothesis, the prenatal undernutritional state leads to reprogramming of the endocrine metabolic status, resulting in increased insulin resistance.13  This energy-sparing state may be beneficial in an in utero environment of limited caloric supply, but not in an energy surplus environment. Studies suggest that the development of insulin resistance may be secondary to up-regulation of the hypothalamus-pituitary-adrenal axis.14  Chronically elevated cortisol levels, coupled with the nutrient-deficient state, during critical times in utero may reduce beta cell mass and secretion, and increase gluconeogenesis and lipolysis.15  The compromised beta cell mass is vulnerable to future insulin-resistant states (puberty, PCOS obesity, aging) which may lead to type 2 diabetes.

 

Clinical Features of PCOS

 

Adolescents with PCOS present in a variety of ways. Patients most commonly seek care for menstrual abnormalities. Although oligomenorrhea predominates, these patients may experience frequent menses, prolonged menses, secondary amenorrhea, and even primary amenorrhea. In a study evaluating the characteristics of adolescents presenting to a multidisciplinary clinic for PCOS, 7% experienced primary amenorrhea (and all but one had a BMI above the 97%).16 

 

Another common reason for seeking medical attention is worsening acne, intractable to over-the-counter therapy, or hirsutism, each of which can have a significant psychological as well as cosmetic impact on an adolescent. Hirsutism is defined as terminal hair growing in an androgen-dependent pattern and is graded by the Ferriman-Gallway score (Figure 2). A score greater than 8 indicates mild to moderate hirsutism. This must be distinguished from hypertrichosis, which is an overall excess of body hair and can be hereditary. The development or acceleration of acne or hirsutism near the time of menarche or after is consistent with possible PCOS. Other clinical signs of hyperandrogenism include 1) seborrhea, 2) alopecia (particularly in temporal regions), and 3) hyperhidrosis.

 

Figure 2

 

Buggs and Rosenfield. "Polycystic Ovary Syndrome in Adolescence" Endocrin Metal Clinic N Am 2005 34:677

 

 

 

Obesity is a common cormobidity of PCOS and affects over 50% of adults with this disorder.17  In an adolescent PCOS multidisciplinary clinic, over 80% of patients presented with a BMI above the 85% and over 70% with a BMI above the 95%.11   Women with PCOS often also have an increased waist circumference (defined as > 88 cm in adult Caucasian women). This truncal adiposity is a marker of metabolic risk, including insulin resistance.

 

Evaluation for PCOS

 

The evaluation of an adolescent with signs and symptoms suggestive of PCOS is aimed at demonstrating the presence of key diagnostic criteria (e.g., menstrual irregularity and hyperandrogenism) and excluding disorders that mimic PCOS (e.g., CAH, ovarian/adrenal tumors). To evaluate menstrual irregularities the following blood tests should be ordered: TSH, prolactin, LH, and FSH (to rule out primary ovarian failure). Although an increased LH to FSH ratio (reflecting the chronic LH secretion with lack of LH surge) is often seen in PCOS, it is not diagnostic. Pregnancy must always be considered when evaluating a teen with either primary or secondary amenorrhea.

 

Both the ovary and adrenal gland are sources of normal androgen production in the female. With hyperandrogenism, excess production secondary to a tumor must be considered and screened for by measuring serum androgen levels. Testosterone levels primarily reflect androgen production from the ovary; however, these levels need to be interpreted with caution. SHBG, a carrier protein for testosterone, is often lowered due to the inhibition on hepatic production by both androgens and insulin.18,19  This can lead to a lower total testosterone lab value. Therefore, a free testosterone level is more specific in identifying elevated bioactive testosterone levels. Total testosterone levels suggesting a malignancy are generally above 150 ng/dl.19  Comparable levels of free testosterone are unclear; thus, both may be useful.

 

Late-onset congenital adrenal hyperplasia (CAH) shares similar characteristics with PCOS. The evaluation for CAH includes measurements of 17 hydroxyprogesterone and DHEA-S levels, preferably drawn prior to 9:00 a.m. A 17 hydroxyprogesterone level above 2ng/ml warrants further workup with ACTH stimulation testing.20  When symptoms progress rapidly or are accompanied by severe hypertension, purple striae, or truncal obesity with extremity muscle wasting, Cushing's disease as well as adrenal tumor should be considered. These are evaluated with a 24-hour urine free cortisol or salivary cortisol measurement obtained at 11:00 p.m. and an adrenal androgen profile.

 

The Rotterdam Criteria includes cystic ovaries in its definition of PCOS. As cystic ovaries occur in 20% of the normal population,21 the Rotterdam definition in PCOS is the presence of 12 or more follicles measuring 2-9 millimeters in diameter, and/or an increase in ovarian volume > 10 ml in at least one ovary.2  As multi-follicular ovaries are normal in adolescence, applying this criteria to this age group can be a challenge.18  In addition, obtaining an informative transabdominal pelvic ultrasound in an obese patient may be difficult and a transvaginal approach can be traumatic for a young woman. Therefore, it is reasonable to weigh the pros and cons of this imaging study in the younger PCOS patients, particularly if the diagnosis of PCOS is well defined by the clinical presentation or laboratory evaluation. Patients with significant pelvic pain or elevated testosterone levels not consistent with PCOS should always undergo ovarian imaging studies.

 

Table 1: Laboratory Evaluation when Considering PCOS 

 

  • TSH
  • Prolactin
  • LH and FSH
  • Total and Free Testosterone (SHBG)
  • 17 OH Progesterone
  • DHEA-S

Case by case: beta-HCG, pelvic ultrasound, salivary cortisol

 

 

Metabolic Consequences of PCOS

 

Women with PCOS are intrinsically insulin resistant. Guzick et al demonstrated this eloquently in measuring insulin sensitivity in normal weight and obese women compared to normal weight and obese PCOS subjects. Interestingly, the normalweight PCOS subjects had diminished insulin sensitivity compared to weight-matched controls; however, these same patients had similar values to the obese control patients. The obese PCOS patients were the least insulin sensitive.22 Thus the insulin-resistant state demonstrated in PCOS is intrinsic and further compounded by obesity. Mechanisms for this intrinsic insulin resistant state are not completely understood, but differences in post-receptor activity account for decreased insulin action in select organs.23  Furthermore, chronic insulin resistance challenges the beta cells in the pancreas, which respond with increased insulin secretion and compensated hyperinsulinemia. This leads to the clinical finding of acanthosis nigricans, which is a dark, velvety, thickened area of skin prominently found around along the neck, the axilla, and knuckles (Figure 1). Defining the degree of insulin resistance biochemically and quantitatively is challenging, and is often debated in the literature. Using comparative euglycemic clamp studies in adult women with PCOS, a fasting glucose to insulin ratio less than 4.5 was defined as significant insulin resistance.24  Similar diagnostic ratios have not been established in the adolescent PCOS population. Using measures that are clinically available, insulin resistance and compensated hyperinsulinemia are found in 50%-70% of adolescent and adult women with PCOS. 3, 11

 

With the chronic insulin resistant state and challenges to the beta cell, natural progression in PCOS can be development of type 2 diabetes mellitus. Over ten percent of adult women with PCOS have type 2 diabetes by the age of 40 years, with an overall 10-fold increased lifetime risk.25, 26, 27  Numbers of cases of type 2 diabetes in adolescents are less well-defined, but are areas of investigation and intervention.28

 

Dyslipidemia is common in women with PCOS, seen in almost 70% of the patients. Although elevated triglyceride with low HDL levels are the most frequent abnormalities and reflect insulin resistance, LDL levels may also be increased. In adolescents, a low HDL is particularly common (greater than 50% in one study).11  This is clinically significant, because low HDL alone is independently a strong marker of cardiac risk.

 

Metabolic syndrome (increased blood pressure, dyslipidemia, increased waist circumference, and impaired fasting glucose) occurs more commonly in women with PCOS. Its prevalence approaches 47%, twice that of a control population matched for BMI.29,30  In the younger population, the prevalence is lower, at 20%, which may simply reflect the stage of disease.31

 

Women with PCOS have an increased prevalence of nonalcoholic fatty liver disease (NAFLD), which can progress to the more serious nonalcoholic steatohepatitis (NASH). The risk for NAFLD is increased by obesity and hyperinsulinemia. In a study using ultrasound to identify NAFLD, 41% of young women with PCOS had evidence of liver disease vs. 19% in the control group.32  Further research is ongoing on how best to identify those with NAFLD and interventions to prevent progression to more serious liver disease.

 

Table 2: Screening for Metabolic Complications of PCOS

 

  • Oral glucose tolerance test with fasting glucose, insulin, and 2-hour glucose and insulin levels
  • Hemoglobin A1c
  • Fasting lipid panel
  • Liver tests - AST, ALT, GGT
  • Waist circumference measurement
  • Blood pressure measurement
  • BMI calculation

 

Treatment of PCOS

 

Management options for PCOS aim at treating individual symptoms while preventing the long-term metabolic sequelae. In adolescent girls with PCOS, treatment is primarily focused on management of irregular menses and reduction of symptoms related to hyperandrogenism. Most commonly this intervention is in the form of an oral contraceptive pill (OCP). OCPs regulate menses and reduce ovarian testosterone production by suppressing LH secretion. Another option to address menstrual irregularities is hydroxyprogesterone. Given at a minimum of once every 3 months, this progestin derivative induces withdrawal bleeding and prevents endometrial hyperplasia, a precursor to endometrial malignancy. Hydroxyprogesterone will not, however, inhibit ovarian testosterone production and thus has little impact on the clinical effects of hyperandrogenism.

 

Hirsutism may improve with suppression of ovarian testosterone secretion by OCP therapy, but may need more aggressive intervention. Spironolactone, a weak diuretic, acts to block the action of androgen at the hair follicle and inhibit future hair growth. This therapy may take several months to see noticeable results, usually recognized as a decrease in frequency of cosmetic treatments. As this medication is teratogenic for male fetuses, patients must be counseled on contraceptive therapy. Finally, patients on this medication are advised to avoid a high-potassium diet and may need to increase fluid intake given spironolactone's weak potassium-sparing properties.

 

Treating the underlying insulin resistance and metabolic consequences is a challenge, but should always begin with efforts to alter lifestyle. The Diabetes Prevention Program (DPP) demonstrated that diet and exercise decreased the incidence of type 2 diabetes in adults with prediabetes by 60%.33  It is logical to apply this diet and exercise recommendation to the high-risk insulin-resistant PCOS patient population, although formal studies have not been performed. Weight loss, which decreases insulin resistance and improves insulin levels, can affect ovulation and fertility in women with PCOS, as well as have a positive impact on lipids, blood pressure, and fatty liver.34, 35, 36 Therefore, lifestyle modification is a core element in treating women with PCOS.

 

Metformin, a biguanide that acts to inhibit hepatic glucose production and decrease peripheral insulin resistance, has been studied extensively in the PCOS population. Metformin diminishes insulin levels, and may improve ovulation, fertility, and hyperandrogenemia, and possibly prevent diabetes.37  An uncontrolled retrospective review of the impact of metformin on diabetes prevention in the adult PCOS population revealed evidence for effective diabetes prevention. Fifty women with PCOS treated with metformin for 43 months showed no progression to type 2 diabetes. In addition, the annual conversion rate of normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) was decreased to 1.4%, compared to the expected rate of 16%-19%.38  Despite this research, there is no consensus on the use of metformin in patients with PCOS, and it is not approved for use in children less than 10 years of age. Young women at higher risk of developing diabetes mellitus (high risk ethnicity, obesity, strong family history, presence of acanthosis nigricans, elevated fasting, and 2-hour insulin levels) are most likely to benefit from metformin. Guidelines from the AE-PCOS recommend healthcare providers consider metformin in the prevention of type 2 diabetes mellitus in the PCOS patient, but emphasize that further studies are needed.39 

 

Multidisciplinary Approach to PCOS

 

There are many aspects to evaluating and treating the adolescent with PCOS, including 1) regulating menses, 2) addressing future concerns (e.g., infertility, endometrial cancer), 3) screening for metabolic consequences (i.e., insulin resistance, dyslipidemia), 4) normalizing nutrition, and 5) behavioral counseling and modification(depression, anxiety, poor self image).40  With this in mind, a multidisciplinary adolescent PCOS Clinic was established at the American Family Children's Hospital at the University of Wisconsin in 2005. This team consists of two pediatric endocrinologists, a pediatric gynecologist, a nutritionist, and a health psychologist. Since 2005, over 225 patients have been evaluated and their health concerns addressed in this multidisciplinary clinic. An analysis of patient follow-up from 2005 to 2008 showed that 79 (72%) of 110 patients diagnosed with PCOS returned to clinic after the initial consultation visit. Of these, 57% percent demonstrated weight loss and 70% demonstrated no weight gain.41 Halting the weight acceleration seen commonly in this population is a positive step.

 

With the ever-rising tide of childhood obesity, identification and treatment of adolescents with PCOS is of prime importance. Early intervention and counseling for patients with PCOS may prevent the emergence of co-morbid medical conditions. Educating the adolescent about PCOS and its associated metabolic risks, as well as providing emotional support, empowers the patient to make informed choices in regard to establishing and maintaining a healthy lifestyle.

 

CME Questions

 

Go to CME Quiz page

 

References

 

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6. Jakimiuk AJ et al. Luteinizing hormone receptor, steroidogenesis acute regulatory protein, and steroidogenic enzyme messenger ribonucleic acids are overexpressed in thecal and granulosa cells from polycystic ovaries. J Clin Endocrinol Metab. 2001;86:1318

 

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11. Goodarzi MO, Azziz R. Diagnosis, epidemiology, and genetics of the polycystic ovary syndrome. Best Pract Res Clin Endocrinol Metab. 2006;20:19  

 

12. Warren-Ulanch J and Arslanian S. Treatment of PCOS in adolescence. Best Pract Res Clin Endocrinol Metab. 2006;20:311 

 

13. Barker DJ et al. Fetal nutrition and cardiovascular disease in adult life. Lancet. 1993;341:938

 

14. Kapoor A et al. Fetal programming of the hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids. J Physiol. 2006;572:31

 

15. Kanaka-Gantenbein C. Fetal origins of adult diabetes. Ann N Y Acad Sci. 2010;1205:99  

 

16. Bekx MT et al. Characteristics of adolescents presenting to a multidisciplinary clinic for polycystic ovarian syndrome. J Pediatr Adolesc Gynecol. 2009; 23(1):7-10

 

17. Azziz R et al. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab. 2001;86:1626

 

18. Buggs C, Rosenfield RL. Polycystic ovary syndrome in Adolescence. Endocrinol Metal Clin N Am 2005;34:677

 

19.  O'Driscoll JB et al. A prospective study of the prevalence of clear-cut endocrine disorders and polycystic ovaries in 350 patients presenting with hirsutism or androgenic alopecia. Clin Endocrinol (Oxf). 1994;41(2):231-6

 

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24. Legro RS, Finegood D, Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1998;83:2694

 

25. Ehrmann DA et al. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22:141

 

26. Legro RS et al. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84:165 

 

27. Nestler JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med. 2008;358:47

 

28. Nur MM et al. Glucose metabolism in overweight Hispanic adolescents with and without polycystic ovary syndrome. Pediatrics. 2009;124(3):e496-502

 

29. Wild RA et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: A consensus atatement by the androgen excess and polycystic ovary syndrome (AE-PCOS) society. J Clin Enocronol Metab. 2010;95:2038   

 

30. Moran LJ et al. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: A systematic meta-analysis. Human Reprod Update. 2010;16 (4):347

 

31. Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab . 2005;90:1929-35 

 

32. Cerda C et al. Nonalcoholic fatty liver disease in women with polycystic ovary syndrome. J Hepatol. 2007;47:412

 

33. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393

 

34.  Vause TD et al. Ovulation induction in polycystic ovary syndrome. J Obstet Gyn. 2010;32(5):495-502

 

35. Shephard RJ, Balady GJ. Exercise as cardiovascular therapy. Circ. 1999;99:963-72

 

36.  Haus JM et al. Free fatty acid-induced hepatic insulin resistance is attenuated following lifestyle intervention in obese individuals with impaired glucose tolerance. J Clin Endocrinol Meta. 2010;95(1):323-7

 

37. Nesgler JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med. 2008;358:47

 

38. Sharma ST, Wickham EP III, Nestler JE. Changes in glucose tolerance with metformin treatment in polycystic ovary syndrome: a retrospective analysis. Endocr Pract. 2007;13:373

 

39. Salley KE et al. Glucose intolerance in polycystic ovary syndrome: a position statement of the Androgen Excess Society. J Clin Endocrinol Metab. 2007;92:4546-56

 

40. Rofey DL et al. Cognitive-behavioral therapy for physical and emotional disturbances in adolescents with polycystic ovary syndrome: a pilot study. J Pediatr Psychol. 2008;1:1

 

41. Geier L et al. The role of a multidisciplinary clinic in achieving weight loss among adolescent girls with polycystic ovarian syndrome. Pediatric Academic Society National Meeting, Vancouver, Canada, May 2010; abstract 

 

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