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Insulin Resistance in Adolescents with Menstrual Irregularities
J Pediatr Adolesc Gynecol (2005) 18:269–274
Original Studies Insulin Resistance in Adolescents with Menstrual Irregularities Adriana Rodrigues Fernandes, MD, Ana Carolina Japur de Sa´ Rosa e Silva, MD, PhD, Gustavo Salata Roma˜o, MD, PhD, Maristela Carbol Pata, MD, PhD, and Rosana Maria dos Reis, MD, PhD Department of Obstetrics and Gynecology, Faculty of Medicine of Ribeira˜o Preto, University of Sa˜o Paulo, Ribeira˜o Preto, SP, Brazil
Abstract. Purpose: To assess the presence of insulin resistance as well as the incidence of polycystic ovary syndrome (PCOS) in adolescents with menstrual disorders. Methods: A case-control study was conducted with 34 adolescents during the period of 2 to 4 years after menarche. The patients were divided into two groups: group I (G I) with 22 patients with menstrual irregularity, and group II (G II) with 12 patients with regular menstrual cycles. Body mass index and Ferriman-Gallway index were calculated for all patients, who also received a pelvic ultrasound. We measured DHEA-S, 17 hydroxyprogesterone, testosterone, TSH, LH, FSH, and prolactin in serum sample and conducted the glucose tolerance test with 75 mg dextrose with measurement of glucose and insulin. Results: Mean ⫾ SD ovary volume was larger in G I (11.38 ⫾ 4.06 cm3) than in G II (7.72 ⫾ 5.59 cm3); P ⬍ 0.05. DHEA-S (G I ⫽ 47.23; G II ⫽ 38.38 µg/dl) and testosterone (G I ⫽ 54.19; G II ⫽ 32.53 ng/dl) levels were higher in patients with menstrual irregularity. In G I we detected two patients with diabetes mellitus and one patient with glucose intolerance. Sixteen patients in this group had clinical or hormonal characteristics of PCOS. The mean values of the area under the insulin curve (AUIC) were higher in patients with menstrual irregularities (8,556.52 µIU/mL/2 h) than in controls (5,743.38 µIU/mL/2 h); P ⬍ 0.05. Conclusions: The presence of PCOS was detected in 95% of the adolescents with menstrual irregularity. Patients with menstrual disorders presented higher AUIC values than controls.
Key Words. Adolescents—Insulin resistance— Polycystic ovary syndrome—Hyperandrogenism
Address correspondence to: Rosana Maria dos Reis, Department of Gynecology and Obstetrics, Faculty of Medicine of Ribeira˜o Preto, University of Sa˜o Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeira˜o Preto, Brazil; E-mail: [email protected]
쑖 2005 North American Society for Pediatric and Adolescent Gynecology Published by Elsevier Inc.
Introduction The onset of female puberty is marked by the appearance of breast buds and physical changes accompanied by accelerated growth and the beginning of adrenal steroidogenesis, followed by pubic hair growth and finally by menarche. After menarche, a positive feedback mechanism occurs in the action of estrogen on the hypothalamus-pituitary axis, with stimulation of the luteinizing hormone (LH) peak, followed afterwards by ovulation.1 The menstruations that follow menarche, especially during the first 2 years, are usually anovulatory, irregular, and occasionally abundant, a condition attributed to the immaturity of the hypothalamus-pituitary-ovary axis in young women.2 After this period, the hypothalamus-pituitary-ovary axis usually acquires normal functioning. The persistence of anovulatory cycles for more than 24 months after menarche, especially if associated with other characteristics of hormonal disorders, may suggest ovulatory dysfunction of pathologic origin,3 with hyperandrogenic anovulation being the condition most frequently detected. This kind of anovulation, also called polycystic ovary syndrome (PCOS), has been discussed in many publications, with difficulty in defining its characteristics. The 2003 Rotterdam consensus workshop4 concluded that PCOS is a syndrome of ovarian dysfunction, and that for its diagnosis two of three criteria might be present. The three criteria established at this consensus are: (1) chronic anovulation characterized by persistent menstrual irregularity for over six months; (2) clinical and/or laboratory hyperandrogenism; and (3) ultrasonographic appearance of the polycystic ovary. The ultrasonographic polycystic ovary characteristics are based on (1) ovarian volume (larger than 10 cm3 without functional cysts), (2) number of microcysts sized 2 to 9 millimeters in mean diameter on gonadal periphery, and (3) stroma echogenicity.5 PCOS remains a syndrome 1083-3188/05/$22.00 doi:10.1016/j.jpag.2005.05.006
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and, as such, no single diagnostic criterion is sufficient for clinical diagnosis.4 LH and FSH serum levels and high LH/FSH ratio is specific of PCOS, but if altered can be helpful. Even with these criteria satisfied, in adolescents the only manifestation may be menstrual irregularity,3 with an incidence of PCOS among adolescents ranging from 11 to 26%.5 The central pathogenesis of this type of anovulation seems to be insulin resistance,6 which is related to a post-insulin receptor defect that course with compensatory hyperinsulinemia7 in addition to other factors such as reduction of hepatic insulin clearance and increased pancreatic sensitivity leading to an abnormal biological response, with increased circulating insulin concentration.8 This hyperinsulinemia also seems to be responsible for the development of hyperandrogenism9 that induces anovulation.10 These patients, with hyperandrogenic chronic anovulation, also present a characteristic lipid profile that consists of elevation of very low density lipoproteins and triglycerides and a reduction of high density lipoproteins (HDL).11 The reduction in HDL and the increase in triglycerides are correlated with abdominal fat accumulation (abdominal wall and mesenteric viscera), known as android obesity, commonly observed in patients with insulin resistance and representing a high risk for cardiovascular disease.12 This risk is associated with hyperinsulinemia that leads to atherogenesis,13 but this effect is clinically demonstrable only during menopause.12 This is the major concern regarding the metabolic disorders secondary to hyperandrogenic anovulation, justified by the increasing incidence of type II diabetes mellitus among adolescents, especially those with a hyperandrogenic profile.14 The objective of the present study was to evaluate the presence of insulin resistance in adolescents with menstrual disorders at least 2 years after menarche and to determine the incidence of PCOS among these adolescents.
Materials and Methods Study Population A case-control study was conducted with 34 adolescents aged 12 to 18 years who were in the period of 2 to 4 years after menarche. The patients were seen at the Specialized Childhood-Pubertal Gynecology Outpatient Clinic of the University Hospital, Faculty of Medicine of Ribeira˜o Preto (HCFMRP-USP) and at the Adolescent Outpatient Clinic of the Vila Lobato Health Center, where these adolescents presented for routine examination and contraceptive follow-up, during the year of 2003. The patients were divided into two groups: G I, consisting of 22 adolescents presenting menstrual irregularities such as oligomenorrhea, amenorrhea, and polymenorrhea, and G II, a control
group of 12 adolescents with normal menstrual cycles. PCOS was defined when the patients presented menstrual disorders such as amenorrhea or oligomenorrhea (six or less menses per year) associated with clinical and/or laboratory signs of hyperandrogenism. Clinical hyperandrogenism was considered to be present when the Ferriman-Gallway index15 was 8 or more and when hair loss, acne, or oily skin was present. Laboratory hyperandrogenism was characterized by testosterone levels ⱖ80 ng/dl, 17 hydroxyprogesterone ⱖ 200ng/dl and DHEA-S (dehydroepiandrostenedione sulfate) levels ⱖ 300 µg/dl. Patients taking any type of medication or presenting any disease that might interfere with the hypothalamus-pituitary-ovary axis were excluded from the study. Each patient or guardian signed an informed consent form and the study was analyzed and approved by the Research Ethics Committee of the HCFMRP-USP. The body mass index (BMI ⫽ weight/height2) of each subject was calculated and classified according to the criteria of the World Health Organization.16 Blood glucose and insulin levels obtained after an 8- to 12-hour fast were used to diagnose disorders of glucose metabolism. An oral glucose tolerance test with 75 g dextrose was applied and glycemia and insulin were determined at 0, 30, 60, 90 and 120 minutes for the calculation of the area under the curve for insulin (AUIC) and glucose (AUGC). The criteria of normality for the interpretation of the glucose curve were established by considering patients with fasting glycemia higher than 126 mg/dl or 120-minute glycemia higher than 200 mg/dl to be diabetic and patients with 120-minute glycemia of 140–200 mg/dl to present impaired glucose tolerance, according to the recommendations of the Committee for the Diagnosis and Classification of Diabetes Mellitus (1997) and of the American Diabetes Association (2000).17 Prolactin (PRL), thyroid stimulating hormone (TSH) and thyroxine determinations were performed to exclude other causes of anovulation. Luteinizing hormone, follicle stimulating hormone (FSH), PRL, and TSH were determined by chemiluminescence; testosterone, DHEA-S, 17 hydroxyprogesterone (17-OHP) and insulin were determined by radioimmunoassay and plasma glucose was determined by the exokinase method. All patients received transabdominal pelvic ultrasound (no previous sexual activity) or to transvaginal ultrasound during the follicular phase for the evaluation of the morphological aspect of the ovaries. Data were analyzed statistically by the nonparametric Mann-Whitney test for comparison of the clinical and laboratory variables of the two groups, with the level of significance set at P ⱕ 0.05.
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Results Patient age was similar between the groups with median age of sixteen in both groups (P ⫽ 0.62). The two groups were also homogeneous regarding body mass index (G I ⫽ 22.68 ⫾ 6.11 and G II ⫽ 21.50 ⫾ 3.31, P ⫽ 0.91) and Ferriman-Gallway index score (median G I ⫽ 9.5 and G II ⫽ 7.5; P ⫽ 0.67). There was no difference in serum levels of 17- hydroxyprogesterone, PRL and TSH (P ⫽ 0.47, P ⫽ 0.69 and P ⫽ 0.72, respectively) between the two groups (Table 1). LH and FSH levels were also similar (LH ⫽ 4.73 ⫾ 3.10 and 3.35 ⫾ 1.95mIU/ml (P ⫽ 0.25) and FSH ⫽ 3.85 ⫾ 1.43 and 3.81 ⫾ 2.10mIU/ml (P ⫽ 0.93) in groups I and II respectively). See Table 1. Although the mean values of all androgen levels maintained normal ranges in both groups, DHEA-S was higher in adolescents with irregular menstrual cycles (with mean values of 47.23 ⫾ 28.12 mg/dl) than in patients with regular cycles (38.28 ⫾ 41.35 mg/dl; (P ⫽ 0.05)) and testosterone was also more elevated in G I than in G II, with mean values of 54.19 ⫾ 16.24 ng/dl and 32.53 ⫾ 10.37 ng/dl (P ⫽ 0.001), respectively (Table 1 and Fig. 1). A bilateral increase in ovarian volume was observed in the adolescents with menstrual irregularities (11.38 ⫾ 4.06 cm3) compared to those with regular menstrual cycles (7.72 ⫾ 5.59 cm3); P ⬍ 0.0001. Considering the right and left ovaries separately we found that the right ovary presented mean volumes of 12.10 ⫾ 4.70 in G I and 9.45 ⫾ 7.12 in G II (P ⫽ 0.04) and left ovary mean volumes were 10.66 ⫾ 3.25 in G I and 6.00 ⫾ 2.88 in G II (P ⫽ 0.0002); see Fig. 2. So, according to the 2003 Rotterdam consensus,4 21/22 patients with irregular cycles presented PCOS compared to 3/12 patients with regular cycles. In the analysis of carbohydrate metabolism (using the oral glucose tolerance test with 75 g dextrose
Fig. 1. Basal serum testosterone and dehydroepiandrosterone sulfate (DHEA-S) levels in adolescents with menstrual irregularity (G I) and with regular menstrual cycles (G II).
and the area under the curve of insulin and glucose levels) two G I patients had diabetes mellitus and one had glucose intolerance, whereas no glycemic alteration was detected in G II, even though the area under the glucose curve was similar (G I ⫽ 13,550 ⫾ 3,779 and G II ⫽ 11,710 ⫾ 2,108 mg/dl at 240 min; P ⫽ 0.32); see Fig. 3. Regarding the presence of insulin resistance, we observed that the area under the insulin curve values were higher in G I (mean of 8,556 ⫾ 3,775 µIU/ml at 240 min) than in G II (mean of 5,743 ⫾ 3,577 µIU/ml at 240min, P ⫽ 0.04; Fig. 4). Discussion There are major difficulties in the early diagnosis of PCOS during adolescence because of the clinical characteristics and endocrine changes that occur during the first years after menarche, which lead to a confusion of the clinical signs and symptoms of PCOS with the physiologic alterations during pubertal period.18 In a recent study by Van Hooff et al,19 the presence of
Table 1. Laboratory Values of Adolescents with Menstrual Irregularities (G I) and with Regular Menstrual Cycles (G II)
Variables
G-II N=22 (mean ⫾ SD)
FSH(mIU/mL) LH (mUI/ml) LH/FSH 17-OHP(ng/dl) PRL (ng/mL) TSH (µIU/mL) DHEA-S(mg/dl) Testosterone(ng/dl)
3.85 4,73 1.32 94.62 6.31 1.97 47.23 54.19
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
1.43 3,10 0.98 47.09 3.96 1.24 28.12 16.24
G-II N=12 (mean ⫾ SD)
P
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.93 0.25 0.53 0.47 0.69 0.72 0.05 0.001
3.81 3,35 0.97 84.00 5.68 1.68 38.28 32.53
2.10 1,95 0.38 55.12 1.72 0.91 41.35 10.37
FSH ⫽ follicle stimulating hormone; 17-OHP ⫽ 17 hydroxyprogesterone; PRL ⫽ prolactin; TSH ⫽ thyroid stimulating hormone; DHEA-S ⫽ dehydroepiandrosterone sulfate
Fig. 2. Mean ovarian volume (right and left) in adolescents with menstrual irregularity (G I) and with regular menstrual cycles (G II).
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Fig. 3. Mean Glucose levels at times zero, 30, 60, 90, and 120 minutes after ingestion of 75 g glucose in adolescents with menstrual irregularity (G I) and with regular menstrual cycles (G II). Area under the glucose curve: G I ⫽ 13,550 ⫾ 3,779; G II ⫽ 11,710 ⫾ 2,108 mg/dl at 240 min; P ⫽ 0.32).
oligomenorrhea at 15 years of age was found to be a better predictor of menstrual irregularity at 18 years, more than elevated levels of testosterone, androstenedione, LH, clinical manifestations of hyperandrogenism or an ultrasound image compatible with micropolycystic ovaries, regardless of patient BMI. According to Ehrmann et al20 menstrual irregularity may be considered to be physiological during the first years after menarche only if there are no associated signs of hyperandrogenism. In the present study, 14/22 patients with menstrual irregularity had associated clinical signs of hyperandrogenism (Ferriman-Gallway score ⱖ 8) suggesting a diagnosis of PCOS and 6/12 adolescents with regular menstrual cycles presented hirsutism, showing no difference between the two groups (P ⫽ 0.80). On the other hand, Avvad et al3 stated that the presence of hirsutism can be simply the expression of increased skin sensitivity to normal levels of circulating androgens and does not necessarily indicate an abnormal ovulatory mechanism in these patients.
Fig. 4. Mean insulin levels at times zero, 30, 60, 90 and 120 minutes after ingestion of 75 g glucose in adolescents with menstrual irregularity (G I) and with regular menstrual cycles (G II). Area under the insulin curve: G I ⫽ 8,525 ⫾ 3,861 and G II ⫽ 5,745 ⫾ 3,576 µIU/ml at 240 min; P ⫽ 0.04).
The literature shows that the levels of free testosterone, LH, and the LH/FSH ratio in adolescents with menstrual irregularity with no clinical signs of hyperandrogenism are similar to those of patients with PCOS and higher than those of adolescents with regular menstrual cycles.3 Some studies with a long-term followup of adolescents with irregular menstrual cycles have demonstrated that higher LH levels associated with hyperandrogenism tended to be persistent,21 suggesting a greater risk to develop the syndrome during adult age. In our study no difference was noticed between the two groups in relation to LH and FSH levels. However, the mean testosterone and DHEA-S levels in patients with menstrual irregularity were significantly higher than the control group, although only one patient presented with a serum testosterone level higher than normal limits, and all of them had values within normal ranges. We also observed that ovarian volume was larger in group I than in group II. The Rotterdam consensus4 included ovarian volume as a criterion for PCOS syndrome, and not only its volume is important but some of its characteristics such as number of peripheral follicles (between 2 and 9 mm), stroma echogenicity and its isolated volume. Perhaps because the evaluation was precocious, no clinical manifestations of hyperandrogenism were yet present, but there may be some primary changes in the ovarian development that are still unknown. Considering the criteria of PCOS based on the Rotterdam consensus4 we found that 21/22 patients of G I fulfilled the diagnostic criteria of the syndrome while only 3/12 patients in G II had two or more of the three criteria. These findings agree with other authors who point to menstrual irregularity as the most precocious marker of PCOS. The presence of early pubarche, the ethnic group (Hispanic or African descent), and a family history of PCOS are risk factors that should be considered in the diagnosis of this disease in adolescents, because the clinical signs cannot be very specific during this phase.5 A current speculation is that PCOS may be hereditary, with genetic predisposition and clinical expression related to environmental factors. Battaglia et al22 reported an increased incidence of polycystic ovaries detected by ultrasound in daughters of patients with PCOS, even of prepubertal age, with no increase in circulating androgens or LH, but with increased ovarian and uterine volume and a higher incidence of early pubarche in initial stages. Normal levels of 17OH progesterone, prolactin, and TSH described in these patients exclude the diagnosis of non-classic congenital adrenal hyperplasia, hyperprolactinemia and hypo or hyperthyroidism as a cause of menstrual disorders and clinical manifestations. A relation between PCOS and increased serum insulin levels have been described by many investigators.
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It seems that insulin-like growth factor (IGF-like) has the capacity of stimulating the follicular theca to produce ovarian androgens. The molecular structure similarity between insulin and IGF-like permits a cross match in the theca’s receptors, so high serum levels of insulin, which happen in cases of peripheral insulin resistance (receptor defect), leads to increased secretion of androgens by the ovary, more than its capacity to convert androgen in estrogen. The excess of androgen results from an inappropriate extraglandular contribution of estrogen (estrone), derived through the peripheral conversion. This hormone when elevated inhibits the pituitary secretion of dopamine and so it allows a higher secretion of gonadotrophins, especially LH, which also stimulates the theca to produce androgens. According to Reis et al23 and Morales et al,24 the effects of insulin resistance are potentiated in obese patients with PCOS. In the present study, obesity was not related to a greater incidence of PCOS; the weight of most of the anovulatory patients was within the normal range (19/22, 3 obese patients) and all control patients had normal BMI (P ⫽ 0.91). These findings agree with data obtained by Dunaif,25 who reported the presence of intense insulin resistance in adolescents with PCOS regardless of body composition or abdominal obesity. Hyperinsulinemia and insulin resistance are present in both obese and non-obese women with PCOS, who also frequently present dyslipidemia and an increased risk to develop diabetes mellitus26,27 and cardiovascular diseases.28–30 This risk is probably associated with the so-called “metabolic syndrome,” which is highly prevalent among these patients and which consists of the concomitant presence of dyslipidemia, central obesity, hypercoagulability, impaired fibrinolysis, and increased risk to develop arterial hypertension, type II diabetes, and coronary artery disease.31 During puberty, insulin sensitivity is usually decreased, causing increased secretion of this hormone.5 Some studies32,33 have assessed insulin resistance in adolescents with PCOS. The method considered to be the gold standard for the diagnosis of insulin resistance is the hyperinsulinemic euglycemic clamp,34 a venous glucose tolerance test frequently used in experimental and scientific investigations but still very difficult to perform in clinical practice. Although there still is no consensus about the best method for the detection of this disorder, the AUIC has been considered to be a good diagnostic parameter.35,36 In the present study we calculated the AUIC, which showed more elevated values in patients with menstrual irregularities than in controls (P ⫽ 0.04), probably demonstrating the lower insulin sensitivity of these patients. Avvad et al3 did not obtain the same result when they compared adolescents with menstrual irregularities and hyperandrogenism to normal adolescents, with the in-
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sulin levels detected being similar. We also calculated the AUGC and no difference was found between the groups (P ⫽ 0.32), probably because the elevation in the glucose levels begins only when even with high serum insulin levels the receptor resistance is such that the glucose levels cannot be controlled; in this stage the patient may present glucose intolerance, a step that leads to type II diabetes. Our results may perhaps be explained by the evaluation early in adolescence. The metabolic disorders to which PCOS patients are exposed is currently the major cause of concern from a medical point of view, more than its reproductive or esthetic importance, especially considering the early onset and the chronic nature of the alterations. Dietary orientation, physical exercise, and awareness of the importance of treatment become a priority in the treatment of this endocrine disorder, leading to a reduction of as much as 58% in the incidence of diabetes in this population.37 Specific controlled studies on the population of patients with PCOS are necessary in order to improve the control and prevention of metabolic repercussions. Based on these findings, we concluded that adolescents with persistent menstrual irregularities 2 years after menarche more frequently have the diagnosis of PCOS and also present a more elevated AUIC values than controls, indicating a great probability of the presence of insulin resistance.
References 1. Yen SSC: The polycystic ovary syndrome. Clin Endocrinol 1980; 12:177 2. Van Hooff MHA, Voorhorst FJ, Kaptein MBH: Relationship of menstrual cycle pattern in 14–17 year old adolescents with gynecological age, body mass index and historical parameters. Hum Reprod 1998; 13:2252 3. Avvad CK, Holeuwerger R, Silva VCG, et al: Menstrual irregularity in the first postmenarchal years: an early clinical sign of polycystic ovary syndrome in adolescence. Gynecol Endocrinol 2001; 15:170 4. ESHRE Rotterdam workshop group. Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19:41 5. Driscoll DA: Polycystic ovary syndrome in adolescence. Semin Reprod Med 2003; 21:301 6. Acie´n P, Quereda F, Matallı´n P, et al: Insulin, androgens, and obesity in women with and without polycystic ovary syndrome: a heterogeneous group of disorders. Fertil Steril 1999; 72:32 7. Ciaraldi TP, Roiey AE, Madar RZ, et al: Cellular mechanism of insulin resistance in polycystic ovarian syndrome. J Clin Endocrinol Metab 1992; 75:577 8. Poretsky L: On the paradox of insulin induced hyperandrogenism in insulin resistance states. Endocr Rev 1991; 12:3
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9. Marcel HA, Van Hooff MD, Voorhorst FJ, et al: Polycystic ovaries in adolescents and the relationship with menstrual cycle patterns, luteinizing hormone, androgens, and insulin. Fertil Steril 2000; 74:49 10. Geffner ME, Kaplan SA, Bersch N, et al: Persistence of insulin resistance in polycystic ovary disease after inhibition of ovarian steroid secretion. Fertil Steril 1986; 45:327 11. Wild RA: Metabolic aspect of polycystic ovary syndrome. Semin Reprod Endocrinol 1997; 15:105 12. Pasquali R, Casimirri F, Vicennati V: Weight control and its beneficial effect on fertility in women with obesity and polycystic ovary syndrome. Hum Reprod 1997; 12:82 13. Kiren JM, Kwan F, Corenblum BFRC: Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity. Fertil Steril 2000; 73:150 14. Lewy VD, Danadian K, Witchel SF, et al: Early metabolic abnormalities in adolescent girls with polycystic ovarian syndrome. J Pediatr 2001; 138:38 15. Ferriman D, Gallway JD: Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961; 21:1440 16. Halpner A, Mancine MC: Obesidade. Rev Bras Med 2000; 57:77 17. Engelgau MM, Narayan KMV, Herman WH: Screening for type 2 diabetes. Diabetes Care 2000; 10:1563 18. Nobels F, Dewailly D: Puberty and polycystic ovarian syndrome: The insulin-like growth factor I hypothesis. Fertil Steril 1992; 58:655 19. Van Hooff MHA, Voorhorst FJ, Kaptein MBH, et al: Predictive value of menstrual cycle pattern, body mass index, hormone levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years. Hum Reprod 2004; 19:383 20. Ehrmann DA, Barnes RB, Rosenfield RL, et al: Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovarian syndrome. Diabetes Care 1999; 22:141 21. Apter D, Vihko R: Endocrine determinants of fertility: serum androgen concentrations during follow-up of adolescents into the third decade of life. J Clin Endocrinol Metab 1990; 71:970 22. Battaglia C, Regnani G, Mancini F, et al: Polycystic ovaries in childhood: a common finding in daughters of PCOS patients. A pilot study. Hum Reprod 2002; 17:771 23. Reis RM, Foss MC, Moura MD, et al: Insulin secretion in obese and non-obese women with polycystic ovary syndrome and its relationship with hyperandrogenism. Gynecol Endocrinol 1995; 64:45 24. Morales AJ, Laughlin GA, Butzom T, et al: Insulin somatotropic, and luteinizing hormone axes in lean and obese
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women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab 1996; 81:2854 Dunaif A: Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocrinol Rev 1997; 18:774 Legro RS, Kunselman AR, Dodson WC, 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 Ovalle F, Azziz R: Insulin resistance, polycystic ovary syndrome, and type 2 diabetes mellitus. Fertil Steril 2002; 77:1095 Dahlgren E, Janson PO: Polycystic ovary syndrome: long-term metabolic consequences. Int J Gynaecol Obstet 1994; 44:3 Mather KJ, Kwan F, Corenblum B: Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity. Fertil Steril 2000; 73:150 Talbott EO, Guzick DS, Sutton TK, et al: Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arterioscler Thromb Vasc Biol 2000; 20:2414 Goodarzi MO, Korenman SG: The importance of insulin resistance in polycystic ovary syndrome. Fertil Steril 2003; 80:255 Ibanez L, Potau N, Zampolli M: Hyper-insulinemia in post pubertal girls with a history of premature pubarche and functional ovarian hyperandrogenism. J Clin Endocrinol Metab 1996; 81:1237 Schiavon R, Altamirano BN, Jimenez C, et al: Fasting and postprandial serum insulin in Mexican adolescents with menstrual disorders. Rev Invest Clin 1996; 48:335 De Fronzo RA, Tobin JD, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237:E214 Apter D, Butzow T, Laughlin GA, et al: Metabolic features of polycystic ovary syndrome are found in adolescent girls with hyperandrogenism. Clin Endocrinol Metab 1995; 80:2966 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 Knowler WC, Barret-Connor E, Fowler SE, et al: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:293
Original Studies Insulin Resistance in Adolescents with Menstrual Irregularities Adriana Rodrigues Fernandes, MD, Ana Carolina Japur de Sa´ Rosa e Silva, MD, PhD, Gustavo Salata Roma˜o, MD, PhD, Maristela Carbol Pata, MD, PhD, and Rosana Maria dos Reis, MD, PhD Department of Obstetrics and Gynecology, Faculty of Medicine of Ribeira˜o Preto, University of Sa˜o Paulo, Ribeira˜o Preto, SP, Brazil
Abstract. Purpose: To assess the presence of insulin resistance as well as the incidence of polycystic ovary syndrome (PCOS) in adolescents with menstrual disorders. Methods: A case-control study was conducted with 34 adolescents during the period of 2 to 4 years after menarche. The patients were divided into two groups: group I (G I) with 22 patients with menstrual irregularity, and group II (G II) with 12 patients with regular menstrual cycles. Body mass index and Ferriman-Gallway index were calculated for all patients, who also received a pelvic ultrasound. We measured DHEA-S, 17 hydroxyprogesterone, testosterone, TSH, LH, FSH, and prolactin in serum sample and conducted the glucose tolerance test with 75 mg dextrose with measurement of glucose and insulin. Results: Mean ⫾ SD ovary volume was larger in G I (11.38 ⫾ 4.06 cm3) than in G II (7.72 ⫾ 5.59 cm3); P ⬍ 0.05. DHEA-S (G I ⫽ 47.23; G II ⫽ 38.38 µg/dl) and testosterone (G I ⫽ 54.19; G II ⫽ 32.53 ng/dl) levels were higher in patients with menstrual irregularity. In G I we detected two patients with diabetes mellitus and one patient with glucose intolerance. Sixteen patients in this group had clinical or hormonal characteristics of PCOS. The mean values of the area under the insulin curve (AUIC) were higher in patients with menstrual irregularities (8,556.52 µIU/mL/2 h) than in controls (5,743.38 µIU/mL/2 h); P ⬍ 0.05. Conclusions: The presence of PCOS was detected in 95% of the adolescents with menstrual irregularity. Patients with menstrual disorders presented higher AUIC values than controls.
Key Words. Adolescents—Insulin resistance— Polycystic ovary syndrome—Hyperandrogenism
Address correspondence to: Rosana Maria dos Reis, Department of Gynecology and Obstetrics, Faculty of Medicine of Ribeira˜o Preto, University of Sa˜o Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeira˜o Preto, Brazil; E-mail: [email protected]
쑖 2005 North American Society for Pediatric and Adolescent Gynecology Published by Elsevier Inc.
Introduction The onset of female puberty is marked by the appearance of breast buds and physical changes accompanied by accelerated growth and the beginning of adrenal steroidogenesis, followed by pubic hair growth and finally by menarche. After menarche, a positive feedback mechanism occurs in the action of estrogen on the hypothalamus-pituitary axis, with stimulation of the luteinizing hormone (LH) peak, followed afterwards by ovulation.1 The menstruations that follow menarche, especially during the first 2 years, are usually anovulatory, irregular, and occasionally abundant, a condition attributed to the immaturity of the hypothalamus-pituitary-ovary axis in young women.2 After this period, the hypothalamus-pituitary-ovary axis usually acquires normal functioning. The persistence of anovulatory cycles for more than 24 months after menarche, especially if associated with other characteristics of hormonal disorders, may suggest ovulatory dysfunction of pathologic origin,3 with hyperandrogenic anovulation being the condition most frequently detected. This kind of anovulation, also called polycystic ovary syndrome (PCOS), has been discussed in many publications, with difficulty in defining its characteristics. The 2003 Rotterdam consensus workshop4 concluded that PCOS is a syndrome of ovarian dysfunction, and that for its diagnosis two of three criteria might be present. The three criteria established at this consensus are: (1) chronic anovulation characterized by persistent menstrual irregularity for over six months; (2) clinical and/or laboratory hyperandrogenism; and (3) ultrasonographic appearance of the polycystic ovary. The ultrasonographic polycystic ovary characteristics are based on (1) ovarian volume (larger than 10 cm3 without functional cysts), (2) number of microcysts sized 2 to 9 millimeters in mean diameter on gonadal periphery, and (3) stroma echogenicity.5 PCOS remains a syndrome 1083-3188/05/$22.00 doi:10.1016/j.jpag.2005.05.006
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and, as such, no single diagnostic criterion is sufficient for clinical diagnosis.4 LH and FSH serum levels and high LH/FSH ratio is specific of PCOS, but if altered can be helpful. Even with these criteria satisfied, in adolescents the only manifestation may be menstrual irregularity,3 with an incidence of PCOS among adolescents ranging from 11 to 26%.5 The central pathogenesis of this type of anovulation seems to be insulin resistance,6 which is related to a post-insulin receptor defect that course with compensatory hyperinsulinemia7 in addition to other factors such as reduction of hepatic insulin clearance and increased pancreatic sensitivity leading to an abnormal biological response, with increased circulating insulin concentration.8 This hyperinsulinemia also seems to be responsible for the development of hyperandrogenism9 that induces anovulation.10 These patients, with hyperandrogenic chronic anovulation, also present a characteristic lipid profile that consists of elevation of very low density lipoproteins and triglycerides and a reduction of high density lipoproteins (HDL).11 The reduction in HDL and the increase in triglycerides are correlated with abdominal fat accumulation (abdominal wall and mesenteric viscera), known as android obesity, commonly observed in patients with insulin resistance and representing a high risk for cardiovascular disease.12 This risk is associated with hyperinsulinemia that leads to atherogenesis,13 but this effect is clinically demonstrable only during menopause.12 This is the major concern regarding the metabolic disorders secondary to hyperandrogenic anovulation, justified by the increasing incidence of type II diabetes mellitus among adolescents, especially those with a hyperandrogenic profile.14 The objective of the present study was to evaluate the presence of insulin resistance in adolescents with menstrual disorders at least 2 years after menarche and to determine the incidence of PCOS among these adolescents.
Materials and Methods Study Population A case-control study was conducted with 34 adolescents aged 12 to 18 years who were in the period of 2 to 4 years after menarche. The patients were seen at the Specialized Childhood-Pubertal Gynecology Outpatient Clinic of the University Hospital, Faculty of Medicine of Ribeira˜o Preto (HCFMRP-USP) and at the Adolescent Outpatient Clinic of the Vila Lobato Health Center, where these adolescents presented for routine examination and contraceptive follow-up, during the year of 2003. The patients were divided into two groups: G I, consisting of 22 adolescents presenting menstrual irregularities such as oligomenorrhea, amenorrhea, and polymenorrhea, and G II, a control
group of 12 adolescents with normal menstrual cycles. PCOS was defined when the patients presented menstrual disorders such as amenorrhea or oligomenorrhea (six or less menses per year) associated with clinical and/or laboratory signs of hyperandrogenism. Clinical hyperandrogenism was considered to be present when the Ferriman-Gallway index15 was 8 or more and when hair loss, acne, or oily skin was present. Laboratory hyperandrogenism was characterized by testosterone levels ⱖ80 ng/dl, 17 hydroxyprogesterone ⱖ 200ng/dl and DHEA-S (dehydroepiandrostenedione sulfate) levels ⱖ 300 µg/dl. Patients taking any type of medication or presenting any disease that might interfere with the hypothalamus-pituitary-ovary axis were excluded from the study. Each patient or guardian signed an informed consent form and the study was analyzed and approved by the Research Ethics Committee of the HCFMRP-USP. The body mass index (BMI ⫽ weight/height2) of each subject was calculated and classified according to the criteria of the World Health Organization.16 Blood glucose and insulin levels obtained after an 8- to 12-hour fast were used to diagnose disorders of glucose metabolism. An oral glucose tolerance test with 75 g dextrose was applied and glycemia and insulin were determined at 0, 30, 60, 90 and 120 minutes for the calculation of the area under the curve for insulin (AUIC) and glucose (AUGC). The criteria of normality for the interpretation of the glucose curve were established by considering patients with fasting glycemia higher than 126 mg/dl or 120-minute glycemia higher than 200 mg/dl to be diabetic and patients with 120-minute glycemia of 140–200 mg/dl to present impaired glucose tolerance, according to the recommendations of the Committee for the Diagnosis and Classification of Diabetes Mellitus (1997) and of the American Diabetes Association (2000).17 Prolactin (PRL), thyroid stimulating hormone (TSH) and thyroxine determinations were performed to exclude other causes of anovulation. Luteinizing hormone, follicle stimulating hormone (FSH), PRL, and TSH were determined by chemiluminescence; testosterone, DHEA-S, 17 hydroxyprogesterone (17-OHP) and insulin were determined by radioimmunoassay and plasma glucose was determined by the exokinase method. All patients received transabdominal pelvic ultrasound (no previous sexual activity) or to transvaginal ultrasound during the follicular phase for the evaluation of the morphological aspect of the ovaries. Data were analyzed statistically by the nonparametric Mann-Whitney test for comparison of the clinical and laboratory variables of the two groups, with the level of significance set at P ⱕ 0.05.
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Results Patient age was similar between the groups with median age of sixteen in both groups (P ⫽ 0.62). The two groups were also homogeneous regarding body mass index (G I ⫽ 22.68 ⫾ 6.11 and G II ⫽ 21.50 ⫾ 3.31, P ⫽ 0.91) and Ferriman-Gallway index score (median G I ⫽ 9.5 and G II ⫽ 7.5; P ⫽ 0.67). There was no difference in serum levels of 17- hydroxyprogesterone, PRL and TSH (P ⫽ 0.47, P ⫽ 0.69 and P ⫽ 0.72, respectively) between the two groups (Table 1). LH and FSH levels were also similar (LH ⫽ 4.73 ⫾ 3.10 and 3.35 ⫾ 1.95mIU/ml (P ⫽ 0.25) and FSH ⫽ 3.85 ⫾ 1.43 and 3.81 ⫾ 2.10mIU/ml (P ⫽ 0.93) in groups I and II respectively). See Table 1. Although the mean values of all androgen levels maintained normal ranges in both groups, DHEA-S was higher in adolescents with irregular menstrual cycles (with mean values of 47.23 ⫾ 28.12 mg/dl) than in patients with regular cycles (38.28 ⫾ 41.35 mg/dl; (P ⫽ 0.05)) and testosterone was also more elevated in G I than in G II, with mean values of 54.19 ⫾ 16.24 ng/dl and 32.53 ⫾ 10.37 ng/dl (P ⫽ 0.001), respectively (Table 1 and Fig. 1). A bilateral increase in ovarian volume was observed in the adolescents with menstrual irregularities (11.38 ⫾ 4.06 cm3) compared to those with regular menstrual cycles (7.72 ⫾ 5.59 cm3); P ⬍ 0.0001. Considering the right and left ovaries separately we found that the right ovary presented mean volumes of 12.10 ⫾ 4.70 in G I and 9.45 ⫾ 7.12 in G II (P ⫽ 0.04) and left ovary mean volumes were 10.66 ⫾ 3.25 in G I and 6.00 ⫾ 2.88 in G II (P ⫽ 0.0002); see Fig. 2. So, according to the 2003 Rotterdam consensus,4 21/22 patients with irregular cycles presented PCOS compared to 3/12 patients with regular cycles. In the analysis of carbohydrate metabolism (using the oral glucose tolerance test with 75 g dextrose
Fig. 1. Basal serum testosterone and dehydroepiandrosterone sulfate (DHEA-S) levels in adolescents with menstrual irregularity (G I) and with regular menstrual cycles (G II).
and the area under the curve of insulin and glucose levels) two G I patients had diabetes mellitus and one had glucose intolerance, whereas no glycemic alteration was detected in G II, even though the area under the glucose curve was similar (G I ⫽ 13,550 ⫾ 3,779 and G II ⫽ 11,710 ⫾ 2,108 mg/dl at 240 min; P ⫽ 0.32); see Fig. 3. Regarding the presence of insulin resistance, we observed that the area under the insulin curve values were higher in G I (mean of 8,556 ⫾ 3,775 µIU/ml at 240 min) than in G II (mean of 5,743 ⫾ 3,577 µIU/ml at 240min, P ⫽ 0.04; Fig. 4). Discussion There are major difficulties in the early diagnosis of PCOS during adolescence because of the clinical characteristics and endocrine changes that occur during the first years after menarche, which lead to a confusion of the clinical signs and symptoms of PCOS with the physiologic alterations during pubertal period.18 In a recent study by Van Hooff et al,19 the presence of
Table 1. Laboratory Values of Adolescents with Menstrual Irregularities (G I) and with Regular Menstrual Cycles (G II)
Variables
G-II N=22 (mean ⫾ SD)
FSH(mIU/mL) LH (mUI/ml) LH/FSH 17-OHP(ng/dl) PRL (ng/mL) TSH (µIU/mL) DHEA-S(mg/dl) Testosterone(ng/dl)
3.85 4,73 1.32 94.62 6.31 1.97 47.23 54.19
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
1.43 3,10 0.98 47.09 3.96 1.24 28.12 16.24
G-II N=12 (mean ⫾ SD)
P
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.93 0.25 0.53 0.47 0.69 0.72 0.05 0.001
3.81 3,35 0.97 84.00 5.68 1.68 38.28 32.53
2.10 1,95 0.38 55.12 1.72 0.91 41.35 10.37
FSH ⫽ follicle stimulating hormone; 17-OHP ⫽ 17 hydroxyprogesterone; PRL ⫽ prolactin; TSH ⫽ thyroid stimulating hormone; DHEA-S ⫽ dehydroepiandrosterone sulfate
Fig. 2. Mean ovarian volume (right and left) in adolescents with menstrual irregularity (G I) and with regular menstrual cycles (G II).
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Fig. 3. Mean Glucose levels at times zero, 30, 60, 90, and 120 minutes after ingestion of 75 g glucose in adolescents with menstrual irregularity (G I) and with regular menstrual cycles (G II). Area under the glucose curve: G I ⫽ 13,550 ⫾ 3,779; G II ⫽ 11,710 ⫾ 2,108 mg/dl at 240 min; P ⫽ 0.32).
oligomenorrhea at 15 years of age was found to be a better predictor of menstrual irregularity at 18 years, more than elevated levels of testosterone, androstenedione, LH, clinical manifestations of hyperandrogenism or an ultrasound image compatible with micropolycystic ovaries, regardless of patient BMI. According to Ehrmann et al20 menstrual irregularity may be considered to be physiological during the first years after menarche only if there are no associated signs of hyperandrogenism. In the present study, 14/22 patients with menstrual irregularity had associated clinical signs of hyperandrogenism (Ferriman-Gallway score ⱖ 8) suggesting a diagnosis of PCOS and 6/12 adolescents with regular menstrual cycles presented hirsutism, showing no difference between the two groups (P ⫽ 0.80). On the other hand, Avvad et al3 stated that the presence of hirsutism can be simply the expression of increased skin sensitivity to normal levels of circulating androgens and does not necessarily indicate an abnormal ovulatory mechanism in these patients.
Fig. 4. Mean insulin levels at times zero, 30, 60, 90 and 120 minutes after ingestion of 75 g glucose in adolescents with menstrual irregularity (G I) and with regular menstrual cycles (G II). Area under the insulin curve: G I ⫽ 8,525 ⫾ 3,861 and G II ⫽ 5,745 ⫾ 3,576 µIU/ml at 240 min; P ⫽ 0.04).
The literature shows that the levels of free testosterone, LH, and the LH/FSH ratio in adolescents with menstrual irregularity with no clinical signs of hyperandrogenism are similar to those of patients with PCOS and higher than those of adolescents with regular menstrual cycles.3 Some studies with a long-term followup of adolescents with irregular menstrual cycles have demonstrated that higher LH levels associated with hyperandrogenism tended to be persistent,21 suggesting a greater risk to develop the syndrome during adult age. In our study no difference was noticed between the two groups in relation to LH and FSH levels. However, the mean testosterone and DHEA-S levels in patients with menstrual irregularity were significantly higher than the control group, although only one patient presented with a serum testosterone level higher than normal limits, and all of them had values within normal ranges. We also observed that ovarian volume was larger in group I than in group II. The Rotterdam consensus4 included ovarian volume as a criterion for PCOS syndrome, and not only its volume is important but some of its characteristics such as number of peripheral follicles (between 2 and 9 mm), stroma echogenicity and its isolated volume. Perhaps because the evaluation was precocious, no clinical manifestations of hyperandrogenism were yet present, but there may be some primary changes in the ovarian development that are still unknown. Considering the criteria of PCOS based on the Rotterdam consensus4 we found that 21/22 patients of G I fulfilled the diagnostic criteria of the syndrome while only 3/12 patients in G II had two or more of the three criteria. These findings agree with other authors who point to menstrual irregularity as the most precocious marker of PCOS. The presence of early pubarche, the ethnic group (Hispanic or African descent), and a family history of PCOS are risk factors that should be considered in the diagnosis of this disease in adolescents, because the clinical signs cannot be very specific during this phase.5 A current speculation is that PCOS may be hereditary, with genetic predisposition and clinical expression related to environmental factors. Battaglia et al22 reported an increased incidence of polycystic ovaries detected by ultrasound in daughters of patients with PCOS, even of prepubertal age, with no increase in circulating androgens or LH, but with increased ovarian and uterine volume and a higher incidence of early pubarche in initial stages. Normal levels of 17OH progesterone, prolactin, and TSH described in these patients exclude the diagnosis of non-classic congenital adrenal hyperplasia, hyperprolactinemia and hypo or hyperthyroidism as a cause of menstrual disorders and clinical manifestations. A relation between PCOS and increased serum insulin levels have been described by many investigators.
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It seems that insulin-like growth factor (IGF-like) has the capacity of stimulating the follicular theca to produce ovarian androgens. The molecular structure similarity between insulin and IGF-like permits a cross match in the theca’s receptors, so high serum levels of insulin, which happen in cases of peripheral insulin resistance (receptor defect), leads to increased secretion of androgens by the ovary, more than its capacity to convert androgen in estrogen. The excess of androgen results from an inappropriate extraglandular contribution of estrogen (estrone), derived through the peripheral conversion. This hormone when elevated inhibits the pituitary secretion of dopamine and so it allows a higher secretion of gonadotrophins, especially LH, which also stimulates the theca to produce androgens. According to Reis et al23 and Morales et al,24 the effects of insulin resistance are potentiated in obese patients with PCOS. In the present study, obesity was not related to a greater incidence of PCOS; the weight of most of the anovulatory patients was within the normal range (19/22, 3 obese patients) and all control patients had normal BMI (P ⫽ 0.91). These findings agree with data obtained by Dunaif,25 who reported the presence of intense insulin resistance in adolescents with PCOS regardless of body composition or abdominal obesity. Hyperinsulinemia and insulin resistance are present in both obese and non-obese women with PCOS, who also frequently present dyslipidemia and an increased risk to develop diabetes mellitus26,27 and cardiovascular diseases.28–30 This risk is probably associated with the so-called “metabolic syndrome,” which is highly prevalent among these patients and which consists of the concomitant presence of dyslipidemia, central obesity, hypercoagulability, impaired fibrinolysis, and increased risk to develop arterial hypertension, type II diabetes, and coronary artery disease.31 During puberty, insulin sensitivity is usually decreased, causing increased secretion of this hormone.5 Some studies32,33 have assessed insulin resistance in adolescents with PCOS. The method considered to be the gold standard for the diagnosis of insulin resistance is the hyperinsulinemic euglycemic clamp,34 a venous glucose tolerance test frequently used in experimental and scientific investigations but still very difficult to perform in clinical practice. Although there still is no consensus about the best method for the detection of this disorder, the AUIC has been considered to be a good diagnostic parameter.35,36 In the present study we calculated the AUIC, which showed more elevated values in patients with menstrual irregularities than in controls (P ⫽ 0.04), probably demonstrating the lower insulin sensitivity of these patients. Avvad et al3 did not obtain the same result when they compared adolescents with menstrual irregularities and hyperandrogenism to normal adolescents, with the in-
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sulin levels detected being similar. We also calculated the AUGC and no difference was found between the groups (P ⫽ 0.32), probably because the elevation in the glucose levels begins only when even with high serum insulin levels the receptor resistance is such that the glucose levels cannot be controlled; in this stage the patient may present glucose intolerance, a step that leads to type II diabetes. Our results may perhaps be explained by the evaluation early in adolescence. The metabolic disorders to which PCOS patients are exposed is currently the major cause of concern from a medical point of view, more than its reproductive or esthetic importance, especially considering the early onset and the chronic nature of the alterations. Dietary orientation, physical exercise, and awareness of the importance of treatment become a priority in the treatment of this endocrine disorder, leading to a reduction of as much as 58% in the incidence of diabetes in this population.37 Specific controlled studies on the population of patients with PCOS are necessary in order to improve the control and prevention of metabolic repercussions. Based on these findings, we concluded that adolescents with persistent menstrual irregularities 2 years after menarche more frequently have the diagnosis of PCOS and also present a more elevated AUIC values than controls, indicating a great probability of the presence of insulin resistance.
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