Pediatric Annals

Diagnosis and Treatment of Polycystic Ovarian Syndrome and Insulin Resistance

Amy Fleischman, MD; Joan Mansfield, MD

Abstract

PCOSAND INSULIN RESISTANCE

Insulin resistance is a common component of PCOS.17 In fact, there is evidence suggesting hyperinsulinism may be a pathogenic factor in the development of PCOS. Women and girls with PCOS have hyperinsulinism at baseline and in response to a glucose challenge with elevated glucose values compared with other woman matched for age and body mass index. Insulin resistance is prevalent in both lean and obese women with PCOS18 and is seen in adolescents with hyperandrogenism8'19 and in prepubertal girls with early adrenarche.4,20 Therefore, the early manifestation of insulin resistance in the setting of early adrenarche and hyperandrogenism suggests that hyperinsulinism may be a primary etiologic component of PCOS.

In addition, obesity and PCOS contribute additively to impaired glucose tolerance and increased risk of type 2 diabetes.5 Therefore, women with PCOS may have intrinsic defects in insulin compensation, exacerbating the disease process in response to progressive insulin resistance, with or without obesity.

The specific mechanism for insulin resistance in PCOS has not been well elucidated. Attempts to associate the primary symptoms of hyperandrogenism and hyperinsulinism have yielded several hypotheses. Early investigation of incubation of human ovarian stroma and theca cells with insulin and insulinlike growth factor-1 (IGF-1) induced androgen production. In addition, in severe genetic forms of hyperinsulinism such as hyperandrogenism, insulin resistance and acanthosis nigricans (HAIR-AN) syndrome,21 there is an increased prevalence of hyperandrogenism.22

Studies of fibroblasts, ovarian cells, and other tissues have suggested tissue-specific defects that contribute to the increased incidence of insulin resistance and type 2 diabetes in women with PCOS. While myocytes are thought to have an extrinsic, acquired defect leading to insulin resistance, the adipocytes may have intrinsic defects in insulin signaling and lipolysis that contribute to the development of multisystem insulin resistance.23 Adipocytes from women with PCOS appear to have normal numbers of insulin receptors and receptor activity,24,25 but there appears to be a decrease in downstream insulin signaling activity. Adipocytes from women with PCOS also have been found to have decreased expression of glucose transporters, GLUT-4.26

There is some evidence that hyperinsulinism may result in the decrease in hepatic production of sex hormone binding globulin (SHBG) and result in an increase in the proportion of circulating free androgen levels.27 More recent in vitro data have implicated altered serine phosphorylation in the insulin-signaling cascade.23,28 In addition, alterations in the regulation of adipocyte lipolysis may contribute to tissue-specific and total-body insulin resistance.29,30 Therefore, adipocyte products such as tumor necrosis factor alpha, resistin, adiponectin, and free fatty acid levels may correlate with insulin resistance in this population, although this remains an area of some controversy.31-33

Hyperinsulinemia has been directly correlated with a decrease in hepatic production of insulin-like growth factor binding protein 1 (IGFBPl). The decrease in bound IGF-I results in an increase in free IGF-1. The increase in IGF-1 and the decrease in IGFBPl both have been found to correlate with increases in adrenal and ovarian androgens resulting in the clinical presentation of premature adrenarche and PCOS.20,34 Therefore, both high IGF-1 levels and low IGFBPl levels may correlate with early insulin resistance and be pathophysiologically and clinically linked to the progression to PCOS and insulin resistance.

Hyperandrogenism also may contribute to hyperinsulinism, making it difficult to differentiate the primary abnormality leading to this complex syndrome. In an experimental protocol in which healthy women were given androgens and evaluated for insulin sensitivity, the exogenous androgens contributed to the worsening of insulin sensitivity.35 In addition, in conditions associated with primary hyperandrogenism, such as adrenal tumors or congenital adrenal hyperplasia, there are reports of an increased prevalence of insulin resistance.36 Reduction in the level of insulin…

Polycystic ovarian syndrome (PCOS) is the most common cause of hyperandrogenism in women and adolescent girls.1 A 1990 consensus conference of the United States Institutes of Health2 identified key features for the diagnosis of PCOS: hyperandrogenism, menstrual dysfunction, clinical evidence of hyperandrogenism, and the exclusion of congenital adrenal hyperplasia. Probable criteria for PCOS included insulin resistance and perimenarchal onset.

The 2003 Rotterdam consensus workshop3 defined PCOS more broadly, recognizing ovarian dysfunction as the primary component, without mandatory anovulation. The revised definition included two of three criteria: oligo or anovulation, clinical or biochemical signs of hyperandrogenism, and polycystic ovaries by ultrasonography, with the exclusion of other etiologies of hyperandrogenism.

These consensus definitions are broad, allowing for a clinical and biochemical diagnosis of a wide spectrum of phenotypes. Recent data have contributed to the theory that PCOS is a heritable, developmental abnormality, manifesting in the peripubertal period.4

In adult females, PCOS is a common endocrinopathy, affecting 5% to 10% of premenopausal women. It is associated with infertility, obesity, type 2 diabetes, hyperlipidemia, hypertension, and cardiovascular disease. In adult women with this syndrome, 30% to 40% have evidence of impaired glucose tolerance or type 2 diabetes based on oral glucose challenge testing.5,6 In addition, irregular menstrual cycles in adult women appear to confer an increased risk of developing type 2 diabetes.7 Impaired glucose tolerance also is present early in the progression of disease, as 30% of adolescents with PCOS already have evidence of impaired glucose metabolism.8

Adolescents with PCOS typically present to health care providers with complaints of acne, hirsutism, irregular menses, and obesity. The diagnosis of PCOS can be complicated by the increased incidence of anovulatory cycles in the initial postmenarchal years and therefore needs to be considered carefully in a young adolescent with consistent complaints.

PCOS confers significant morbidity in the adolescent period, with the increased risk of insulin resistance, poor selfesteem, and concern about future fertility.9 Therefore, the adolescent patient with PCOS presents a diagnostic and therapeutic challenge to the pediatric practitioner but presents an important opportunity to diagnose and manage a lifelong disease process.

SCREENING

The evaluation of an adolescent with irregular menstrual cycles is beyond the scope of this review but includes the exclusion of pregnancy, chronic or acute illness, nutritional disorders, medication use, and endocrinopathies such as hypothyroidism, hyperthyroidism, and hyperprolactinemia.10 Irregular menstrual cycles in the setting of clinical signs of hyperandrogenism, such as increased acne, hirsuitism, or virilization, can be evaluated by a more focused investigation for the source of excess androgen production. In addition, a basic evaluation of glucose metabolism and insulin sensitivity can be initiated simultaneously and can assist in both diagnosis and prognosis for the adolescent female.

The initial physical examination for PCOS should focus on signs of hyperandrogenism and hyperinsulinism. This would include an assessment of growth, nutritional status, pubertal development, acne, hirsuitism, acanthosis nigricans, hair distribution, and clitoral size. Acanthosis nigricans, thickening and hyperpigmentation of the skin found in intertrigenous areas, is a clinical finding often consistent with the presence of insulin resistance.

The history should focus on a family history of female hyperandrogenism, hirsuitism, irregular menses, or problems with fertility in female relatives. PCOS appears to aggregate in families, although the degree of genetic and environmental influences is difficult to differentiate. More than onethird of mothers and 40% of sisters of young women with PCOS also have the syndrome.11

The patient's birth weight and pubertal pattern are important because children who are bom small for gestational age have an increased risk for insulin resistance, premature adrenarche (secondary sexual hair development before age 8), and the development of PCOS.412

Because there is no diagnostic laboratory marker for PCOS, the screening evaluation focuses on ruling out other etiologies of androgen excess. Toward this end, a normal 17-hydroxyprogesterone blood level taken in an early morning (7 to 8 a.m.) can be used essentially to eliminate the possibility of the diagnosis of late-onset congenital adrenal hyperplasia. Rare androgen-secreting adrenal or ovarian tumors also can present with rapid virilization, including vocal changes, clitoromegaly, and abrupt menstrual changes. Most tumors produce a markedly elevated blood level of dehydroepiandrosterone-sulfate, testosterone, or dehydroepiandrosterone.

Levels of prolactin and thyroid-stimulating hormone also should be considered in the initial evaluation to rule out other primary endocrinologie etiologies of irregular menstrual cycles. Chshing's syndrome, although also extremely uncommon in this population, can present with obesity, clinical hyperandrogenism, and irregular menses. This can be evaluated with a 24-hour urine collection for free Cortisol if suspected clinically. Elevated total and free testosterone levels, reduced sex hormone binding globulin, and an elevated luteinizing hormone (LH) to follicle stimulating hormone (FSH) ratio are suggestive, although not diagnostic, of PCOS.

The utility of a pelvic ultrasound for ovarian morphology is controversial. There are data indicating that ultrasound is not necessary in the initial evaluation for PCOS, as the finding of normal ovarian structure does not rule out the diagnosis of PCOS, and cystic ovaries may be found without the clinical features of PCOS.13 However, there also are data to suggest that, in adult females, structural assessment may assist in prognosis and fertility treatment planning.14

The screening evaluation for abnormal glucose metabolism is an area of continued debate. The current American Diabetes Association recommendations for pediatric diabetes screening include the evaluation of a fasting blood sugar every 2 years, beginning at age 10 or puberty, in all children who are overweight 1 9 "Overweight," in this case, is defined by a body mass index of greater than the 85th percentile for age and sex, weight for height greater than the 85th percentile, or weight greater than 120% of ideal for height, in addition to any two of the designated risk factors: family history of type 2 diabetes in a first- or second-degree relative; high-risk race or ethnicity (eg, American Indian, black, Hispanic, Asian/Pacific Islander); signs of insulin resistance; or conditions associated with insulin resistance (eg, acanthosis nigricans, hypertension, dyslipidemia, PCOS).15

PCOS is listed as a condition associated with insulin resistance; therefore, the obese adolescent diagnosed with PCOS who has a family history of diabetes or high-risk ethnicity meets the criteria for fasting blood glucose screening. However, there is growing evidence that lean adolescents with PCOS may also be at risk for insulin resistance and that both lean and obese girls with PCOS may benefit from oral glucose tolerance testing (oral glucose challenge of 1.75 g/kg, up to a maximum of 75 grams).8

The absence of obesity and acanthosis nigricans does not rule out insulin resistance in the presence of clinical hyperandrogenism. The oral glucose tolerance test, with the use of a 75-gram glucose load with measurements at baseline and 2 hours, can detect impaired glucose tolerance (2-hour post-load glucose value of greater than 140 mg/dL and less than 200 mg/dL)16 before abnormalities in fasting parameters. This may lead to the targeting of insulin resistance in the treatment of PCOS. Therefore, the initial evaluation for suspected PCOS includes a thorough history and physical examination, hormonal laboratory evaluation, and consideration of investigation for evidence of insulin resistance.

Figure. Relationship between polycystic ovarian syndrome and metabolic syndrome.

Figure. Relationship between polycystic ovarian syndrome and metabolic syndrome.

PCOSAND INSULIN RESISTANCE

Insulin resistance is a common component of PCOS.17 In fact, there is evidence suggesting hyperinsulinism may be a pathogenic factor in the development of PCOS. Women and girls with PCOS have hyperinsulinism at baseline and in response to a glucose challenge with elevated glucose values compared with other woman matched for age and body mass index. Insulin resistance is prevalent in both lean and obese women with PCOS18 and is seen in adolescents with hyperandrogenism8'19 and in prepubertal girls with early adrenarche.4,20 Therefore, the early manifestation of insulin resistance in the setting of early adrenarche and hyperandrogenism suggests that hyperinsulinism may be a primary etiologic component of PCOS.

In addition, obesity and PCOS contribute additively to impaired glucose tolerance and increased risk of type 2 diabetes.5 Therefore, women with PCOS may have intrinsic defects in insulin compensation, exacerbating the disease process in response to progressive insulin resistance, with or without obesity.

The specific mechanism for insulin resistance in PCOS has not been well elucidated. Attempts to associate the primary symptoms of hyperandrogenism and hyperinsulinism have yielded several hypotheses. Early investigation of incubation of human ovarian stroma and theca cells with insulin and insulinlike growth factor-1 (IGF-1) induced androgen production. In addition, in severe genetic forms of hyperinsulinism such as hyperandrogenism, insulin resistance and acanthosis nigricans (HAIR-AN) syndrome,21 there is an increased prevalence of hyperandrogenism.22

Studies of fibroblasts, ovarian cells, and other tissues have suggested tissue-specific defects that contribute to the increased incidence of insulin resistance and type 2 diabetes in women with PCOS. While myocytes are thought to have an extrinsic, acquired defect leading to insulin resistance, the adipocytes may have intrinsic defects in insulin signaling and lipolysis that contribute to the development of multisystem insulin resistance.23 Adipocytes from women with PCOS appear to have normal numbers of insulin receptors and receptor activity,24,25 but there appears to be a decrease in downstream insulin signaling activity. Adipocytes from women with PCOS also have been found to have decreased expression of glucose transporters, GLUT-4.26

There is some evidence that hyperinsulinism may result in the decrease in hepatic production of sex hormone binding globulin (SHBG) and result in an increase in the proportion of circulating free androgen levels.27 More recent in vitro data have implicated altered serine phosphorylation in the insulin-signaling cascade.23,28 In addition, alterations in the regulation of adipocyte lipolysis may contribute to tissue-specific and total-body insulin resistance.29,30 Therefore, adipocyte products such as tumor necrosis factor alpha, resistin, adiponectin, and free fatty acid levels may correlate with insulin resistance in this population, although this remains an area of some controversy.31-33

Hyperinsulinemia has been directly correlated with a decrease in hepatic production of insulin-like growth factor binding protein 1 (IGFBPl). The decrease in bound IGF-I results in an increase in free IGF-1. The increase in IGF-1 and the decrease in IGFBPl both have been found to correlate with increases in adrenal and ovarian androgens resulting in the clinical presentation of premature adrenarche and PCOS.20,34 Therefore, both high IGF-1 levels and low IGFBPl levels may correlate with early insulin resistance and be pathophysiologically and clinically linked to the progression to PCOS and insulin resistance.

Hyperandrogenism also may contribute to hyperinsulinism, making it difficult to differentiate the primary abnormality leading to this complex syndrome. In an experimental protocol in which healthy women were given androgens and evaluated for insulin sensitivity, the exogenous androgens contributed to the worsening of insulin sensitivity.35 In addition, in conditions associated with primary hyperandrogenism, such as adrenal tumors or congenital adrenal hyperplasia, there are reports of an increased prevalence of insulin resistance.36 Reduction in the level of insulin through the use of insulin-sensitizing agents, even in women with normal insulin sensitivity, has been shown to reduce the level of androgens and clinical evidence of hyperandrogenism.37 Therefore, both hyperandrogenism and hyperinsulinism appear to contribute to the pathologic mechanism that initiates and propagates the clinical manifestations of PCOS and insulin resistance.

METABOLIC SYNDROME AND PCOS

Insulin resistance is a primary component of metabolic syndrome, a combination of factors that increases the risk of developing type 2 diabetes and cardiovascular disease. Metabolic syndrome, as defined in adults by the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III), includes three or more of the following: waist circumference in females greater than 88 cm, fasting serum glucose equal to 110 mg/dL, fasting serum triglycerides equal to 150 mg/dL, serum HDL cholesterol less than 50 mg/dL, and blood pressure equal to 130/85 mmHg.38 The Expert Committee on Diagnosis and Classification of Diabetes Mellitus of the American Diabetes Association recently changed the definition of impaired fasting glucose to greater than 100 mg/dL.39

Pediatric literature has modified these criteria to take into account the alterations in body proportions and cardiovascular risk factors during growth and pubertal development.40 The modified criteria include a body mass index (BMI = kg/m2 ) above the 97th percentile, z score of 2 or greater, adjusted for age and sex; systolic or diastolic blood pressure greater than the 95th percentile for age and sex; ageadjusted elevations in lipids (triglyceride level above the 95th percentile, HDL cholesterol level below the 5th percentile); and impaired glucose tolerance.

The baseline prevalence of metabolic syndrome in young women is approximately 6% to 15%, depending on age of evaluation.41 Obese children have a high prevalence of metabolic syndrome, up to 50% in the most severely obese, by the modified pediatric criteria.40 Insulin resistance also contributes to an increased risk of metabolic syndrome in obese children and adolescents.40 Multiple studies have found a significantly increased prevalence of metabolic syndrome in women with PCOS, at close to 50% in some populations.42,43 Therefore, the increased prevalence of metabolic syndrome in PCOS is associated with additional risk of future cardiovascular disease and diabetes in young women with PCOS and insulin resistance (Figure, see page 735).

THERAPY

The pathophysiologic explanation for the hyperandrogenism and hyperinsulinism seen in PCOS remains an area of intense study. Therefore, targeting of the etiologic factor is not yet possible, and treatment focuses on clinical improvement based on the goals of patient and clinician.

The goals of therapy for adolescents with PCOS are similar to the goals for adult women, with some important differences. Central therapeutic goals in adolescents include improvements in body image and self-esteem, improvements in acne and hirsuitism, and regulation of menstrual cycling.9 In most women and girls with PCOS, therapeutic aims also include weight reduction for obese or overweight patients, improved insulin sensitivity, and prevention of impaired glucose tolerance, diabetes, and cardiovascular disease. In addition, in adult women, fertility often is a major aim of therapy, so interventions often focus on induction of ovulation. Therefore, the direct extrapolation of therapy recommendations from adults to adolescents is not always appropriate.

Lifestyle modifications are an important component of therapy for obesity, insulin resistance, and related disorders such as PCOS. In large-scale diabetes prevention trials, it has been shown that weight loss through lifestyle changes in diet and activity improves insulin sensitivity and prevents the progression to type 2 diabetes.44 In PCOS, weight loss has been shown to reduce androgen levels and improve menstrual function.45

Because lifestyle modifications are difficult and often time-limited in efficacy, however, pharmacologic therapies have been used in adults to improve insulin sensitivity, assist in weight reduction, and promote pregnancy. Pediatric practitioners have focused on the adolescents' concerns of hirsuitism, acne, and menstrual irregularity as primary treatment goals, with reduction of diabetes risk, cardiovascular disease, and future infertility as additional long-term goals.

First-line pharmacologic therapy for PCOS in adolescents is hormonal suppression of ovarian androgens with daily combination estrogen/progestin therapy in the form of contraceptive pills or patches. This therapy increases SHBG and reduces the level of free androgens available to produce clinical hyperandrogenism, manifested as hirsuitism and acne. Oral contraceptive formulations with nonandrogenic progestins (eg, norgestimate, norethindrone, drospirenone) and moderate doses of ethinyl estradiol (30 to 35 meg) are the medications of choice. In addition, cyclical hormone therapy induces regular estrogen withdrawal bleeding, reducing the risk of long-term complications of amenorrhea such as uterine cancer.

The expectations of combination estrogen and progesterone therapy are improvement of acne, stabilization or moderate improvement of hirsuitism, and regulation of menses. However, this therapy does not treat the accompanying insulin resistance or reduce cardiovascular risk status.46 Importantly, this therapy also provides contraception for sexually active adolescents. Any other therapy for PCOS may induce ovulation in an adolescent and therefore must also include discussion about the need for contraceptive options if the patient is sexually active.

The use of insulin-sensitizing medications in the treatment of PCOS recently has become an area of great interest. Many clinicians and scientists favor the treatment of insulin resistance in women with PCOS because these women are at increased risk for the development of type 2 diabetes and cardiovascular disease. In addition, the reduction of hyperandrogenism by hormonal therapy does not correct hyperinsulinism.47 The use of insulin-sensitizing agents such as metformin may reduce the risk of hyperinsulinism, type 2 diabetes, and metabolic syndrome.44 Reduction in hyperinsulinism also has been shown to induce ovulation and regulation of menstrual cycling.48,49 Studies have shown that the use of metformin in young adolescents with PCOS may regulate menstrual cycling and reduce clinical hyperandrogenic effects. Metformin also may be able to prevent the development of the PCOS phenotype in young girls with premature adrenarche.50"51

Studies by Glueck and Ibanez50,51 found improvement in ovarian function with meformin treatment in a cohort with varying degrees of insulin resistance. Therefore, metformin may be an effective therapy in young women with PCOS with or without evidence of insulin resistance by standard screening measures.

Metformin is approved by the Food and Drug Adminstration for use in patients 10 and older with type 2 diabetes. However, metformin can cause gastrointestinal side effects, which may limit its use in some adolescents. This side effect often is temporary and can be mitigated by a slow escalation in dose to maximal tolerated dosage. Patients with impaired renal function, hepatic dysfunction, and possibly excessive binge drinking have an increased risk of lactic acidosis with the use of metformin and thus are not appropriate candidates for this therapy. However, lactic acidosis is a very rare side effect and has not been reported in the pediatric age range.

Metformin is becoming a first-line therapy in adults with PCOS, particularly those with documented insulin resistance. This therapy should be considered for appropriate adolescents with PCOS to reduce the risk of development of diabetes, improve menstrual functioning, and perhaps improve clinical and biochemical hyperandrogenism. Data remain limited regarding metformin's effects on hirsuitism and acne,52,53 two primary concerns in the adolescent population, and long-term studies of metfornin use in adolescents are lacking. The addition of oral contraceptive hormones or anti-androgen medications often is used in this population.

The use of other insulin sensitizers, such as the thiozoladinediones, pioglitazone, and rosiglitazone, has not yet been studied adequately in adolescents. An ongoing multicenter clinical trial in the treatment of type 2 diabetes in this population (the TOD2AY study) will determine the safety and efficacy of these medications in this age range in the coming years (information available at http://www.todaystudy.org).

Anti-androgen therapies have been used as primary and secondary therapeutics in the treatment of PCOS, with conflicting results regarding their contribution to improving insulin resistance.54,55 Anti-androgens include spironolactone and cyproterone acetate, which interfere with steroidogenesis. These medications are most often used in combination with estrogen or combined estrogen-progestin therapy. Although both medications have some effect in ameliorating the clinical effects of hyperandrogenism, when used without additional hormonal therapy, spironolactone commonly causes irregular menstrual bleeding. Cyproterone acetate, not currently available in the US, has progestin effects and therefore must be used in association with estrogen.56

Gonadotropin-releasing hormone agonists also have been used in adults to suppress the hypothalamic-pituitary activation and subsequent androgen production in the context of fertility treatment However, this is not an appropriate therapy in a young adolescent who is progressing through pubertal development

Other anti-androgen medications, currently used only in research settings, include flutamide and finasteride. Flutarnide acts at the androgen receptor site and has significant direct and indirect anti-androgenic effects,57 but liver toxicity is a rare, yet serious, side effect of this medication, limiting its utility as a therapy for clinical hyperandrogenism.58 Finasteride is a 5-a-reductase inhibitor, reducing the conversion of testosterone to the active metabolite dihydrotestosterone and approved by the FDA for the treatment of prostate cancer. Data have indicated this drug may prove to be a useful medication in the treatment of hyperandrogenism and subsequent hirsuitism, but it is not currently approved for use in PCOS.59

Thus, spironolactone currently represents the only clinically useful antiandrogenic therapy and can be used in combination with oral contraceptive therapy. The initial starting doses usually is 25 mg twice daily, with a treatment goal of 100 to 200 mg daily. Electrolytes, particularly potassium, should be monitored when treating with this potassium-sparing diuretic agent. Young women should be counseled about the risks of anti-androgenic therapy on a developing fetus, and contraception should be recommended when appropriate.

Several combination therapies have been investigated for the treatment of adolescents with PCOS. For example, a recent study by Ibanez et al.60 examined the use of flutannde-metformin and a combination oral contraceptive pill. This study, among others, suggests the combination of therapies for adolescents with PCOS may be the most appropriate therapeutic option and may directly target the undesirable clinical sequelae while minimizing long-term risk factors. Recommended combinations would include metformin plus oral contraceptive therapy, spironolactone plus oral contraceptive therapy, metformin plus spironolactone, or the use of all three medications. Until the development of diagnostic modalities to identify the specific etiology of PCOS in a given individual, it remains prudent to use clinical judgment in determining an individualized treatment plan.

SUMMARY

PCOS is a complex syndrome that includes clinical and biochemical evidence of hyperandrogenism and hyperinsulinism. Adolescents with PCOS are affected by the diagnosis with both short-term and long-term consequences. Adolescents with PCOS report lower self-esteem and quality of life, based on standard assessments, when compared with age matched peers.9 These young women also are concerned about future fertility, which may affect psychological well being and health behaviors.61 In addition, patients with PCOS are at an increased risk for development of insulin resistance, type 2 diabetes, metabolic syndrome, and cardiovascular disease. Therefore, this identified at-risk group requires rigorous evaluation, treatment and long-term counseling and management by healthcare providers.

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