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Relationship between insulin resistance and gonadotropin dissociation in obese and nonobese women with polycystic ovary syndrome
FERTILITY AND STERILITY威 VOL. 80, NO. 6, DECEMBER 2003 Copyright ©2003 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A.
Relationship between insulin resistance and gonadotropin dissociation in obese and nonobese women with polycystic ovary syndrome Carlos Moran, M.D., M.Sc., Edgardo Garcia-Hernandez, M.D., M.Sc., Edgar Barahona, B.S., Sandra Gonzalez, B.S., and Jose A. Bermudez, M.D. Health Research Council, Mexican Institute of Social Security, Mexico City, Mexico
Objective: To test the interdependence between insulin resistance (IR) and gonadotropin dissociation (GD) in polycystic ovary syndrome (PCOS). Design: Cross-sectional prospective study. Setting: Clinical research center. Patient(s): Thirty-two PCOS patients aged 19 –34 years; 16 obese (BMI ⱖ 27) and 16 nonobese (BMI ⬍ 27). Intervention(s): A 75-g oral glucose tolerance test (OGTT) and a 100-g i.v. GnRH test were performed on different days. Blood was taken at 0, 30, 60, 90, 120, and 180 minutes in each test. Serum glucose, insulin, LH, and FSH were measured. Main Outcome Measure(s): Area under the curve was calculated for glucose, insulin, and glucose-to-insulin ratio (GIR), and for LH, FSH, and LH-FSH ratio. Result(s): Glucose, insulin, and GIR were not modified significantly during the GnRH test, nor LH, FSH and LH-FSH ratio throughout the OGTT. There were no significant differences in GIR response of patients with and without GD, nor in LH-FSH ratio of patients with and without IR, after OGTT and GnRH test. However, obese patients with IR had a significantly larger (P⬍.04) area under the curve for LH-FSH ratio than those without IR after GnRH test, but not after OGTT test. Conclusion(s): Insulin resistance and GD do not appear to be related events in PCOS, suggesting that each one might be determined by different genetic disorders. However, IR can affect GD after chronic stimulation in obese patients. (Fertil Steril威 2003;80:1466 –72. ©2003 by American Society for Reproductive Medicine.) Key Words: Hyperandrogenism, insulin resistance, polycystic ovary syndrome Received September 24, 2002; revised and accepted May 5, 2003. Supported in part by a research grant (38371-M) from Consejo Nacional de Ciencia y Tecnologı´a (CONACyT), Mexico City, Mexico. Presented in part at the 10th International Congress of Endocrinology, San Francisco, California, June 12–15, 1996. Reprint requests: Carlos Moran, M.D., 413 Interamerica Blvd. WH1, PMB 67-139, Laredo, Texas 78045 (FAX: 52-555653-1903; E-mail: [email protected]). 0015-0282/03/$30.00 doi:10.1016/j.fertnstert.2003. 05.010
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The existence of gonadotropin dissociation (GD), characterized by an increase in LH levels with normal FSH levels, has been widely described in polycystic ovary syndrome (PCOS) (1). The GD appears as high LH levels producing an LH-FSH ratio of ⬎2; however, GD occurs in ⬍50%– 60% of cases (2, 3). Insulin resistance (IR) can be defined as a decrease in tissue sensitivity for the action of insulin on glucose transport, which results in a compensatory increase in insulin levels. A correlation between hyperandrogenism and hyperinsulinism has been observed (4). In addition, hyperinsulinism and IR may be related to the degree of hyperandrogenism in PCOS (5). PCOS is associated with an approximately
35% decrease in insulin action, independent of the effect of obesity, which produces close to 50% decrease in insulin action (6). However, it has been also mentioned that not all obese patients present IR and hyperandrogenism (7). The cellular mechanisms involved in the development of IR are not clear, but a decrease in the autophosphorylation of insulin receptors has been found in different tissues (8 –10). In vitro studies have demonstrated that insulin promotes basal and GnRH-stimulated LH and FSH secretion of anterior pituitary cells from adult ovariectomized rats (11). Furthermore, there is experimental evidence that insulin acts synergistically with LH to increase the secretion of androstenedione in the human
ovary (12). Alternatively, in vitro studies in ovarian stromal fragments from women indicate that ovarian insulin receptors are down-regulated by LH and FSH and not only by insulin (13). A previous report has suggested that exogenous hyperinsulinemia does not modify in vivo gonadotropin secretion in PCOS patients (14). However, the literature on PCOS lacks in vivo studies to clarify whether GnRH-stimulated LH/FSH levels can influence the glucose to insulin ratio (GIR), or whether glucose load–stimulated hyperinsulinemia can affect LH/FSH levels in PCOS patients. To test the hypothesis of interdependence of IR and GD in patients with PCOS, we studied the GIR response to high levels of endogenous gonadotropins released by GnRH test and tested the LH-FSH response to endogenous hyperinsulinemia induced by an oral glucose tolerance test (OGTT).
MATERIALS AND METHODS This project was carried out with prior authorization from the institutional research board of the Mexican Institute of Social Security, after informed written consent was obtained from all patients. The study included 32 women, 19 –35 years old, with PCOS diagnosed by the presence of oligoovulation (oligomenorrhea or amenorrhea) and clinical hyperandrogenism, as established by the consensus group for diagnosis of PCOS (15). Hirsutism was diagnosed by a modified Ferriman-Gallwey score (16). Although not included as a criterion for diagnosis, all patients had bilateral polycystic ovaries by abdominal ultrasound. Patients with hyperprolactinemia, nonclassical adrenal hyperplasia, hypothyroidism, and ovarian or adrenal tumors were excluded from the study by appropriate hormonal tests. None of the study subjects were taking hormonal medications, including oral contraceptives. Anthropometry was performed in all patients and consisted of weight and height measurement to calculate the body mass index (BMI). Patients were classified according to BMI into obese (BMI ⱖ 27 kg/m2, n ⫽ 16) and nonobese (BMI ⬍ 27 kg/m2, n ⫽ 16) (17). Waist and hip circumference were measured to evaluate body fat distribution by the waist-to-hip ratio (WHR), defining lower-segment obesity as WHR ⱕ 0.85 and upper-segment obesity as WHR ⬎ 0.85 (18). IR was defined as a GIR of ⬍0.035 nmol/pmol (⬍4.5 mg/dL over U/mL) in basal conditions (19). The GIR has been demonstrated to correlate with the measurement of insulin sensitivity determined by euglycemic clamp, the minimal model technique, and the OGTT (17, 19). To evaluate OGTT, the criteria of the Diabetes Data Group were used (20).
Dynamic Tests Two dynamic tests were performed on consecutive days, starting at 8 AM in fasting conditions, on days 3–5 of a spontaneous menstrual cycle or after a progestogen-induced bleeding. Initially, an OGTT with 75 g of glucose was given, FERTILITY & STERILITY威
TABLE 1 Clinical characteristics of obese and nonobese patients with PCOS. Characteristic Age (y) BMI (kg/m2) WHR Ferriman-Gallwey score
Obese PCOS patients (n ⫽ 16)
Nonobese PCOS patients (n ⫽ 16)
23 (20–32) 29.4 (27.0–39.2)* 0.89 (0.86–0.95)¶ 5 (2–18)
22 (19–34) 22.9 (19.1–26.6)* 0.81 (0.71–0.89)¶ 6 (3–14)
Note: The values express median and range in parentheses. The superscripts (*, ¶ ) indicate a statistically significant difference (P⬍.001) between pairs. BMI ⫽ body mass index; WHR ⫽ waist-to-hip ratio. Moran. Insulin resistance and LH-FSH in PCOS. Fertil Steril 2003.
and the following day, 100 g of GnRH was given i.v. An indwelling catheter was placed in an antecubital vein during the tests to obtain blood samples at 0, 30, 60, 90, 120, and 180 minutes for quantifying glucose, insulin, LH, and FSH. The catheter was flushed with normal saline solution at 1 mL/min to achieve permeability, and the first 3 mL of blood was discarded to avoid dilution of the sample. Each sample was allowed to coagulate at room temperature for later centrifugation, and the serum was separated and frozen at ⫺20°C until processed. Glucose level was determined immediately by the glucose oxidase technique (Stanbio Laboratory Inc., Boerne, TX) using a Gilford Express 550 (Ciba Corning Diagnostics, East Walpole, MA). A double-antibody RIA technique (Cis Bio International, Gif-sur-Yvette, France) was used to analyze LH, FSH, and insulin. The intraassay and interassay coefficients of variation were ⬍5% and ⬍9%, respectively.
Statistical Analysis All results are expressed as median and range. Area under the curve (AUC) for glucose, insulin, GIR, LH, FSH, and LH-FSH was calculated as previously reported (21). Chisquare and Mann-Whitney U tests were used to compare the groups, and Pearson (r) coefficient, for correlation. A P⬍.05 was considered as statistically significant.
RESULTS Clinical Characteristics Clinical characteristics, such as age, BMI, WHR, and the Ferriman-Gallwey score, of both obese and nonobese PCOS patients, are noted in Table 1. By design, obese and nonobese PCOS patients had a similar median age. As expected, median BMI and WHR of obese PCOS patients were significantly higher than those of nonobese PCOS patients. The Ferriman-Gallwey score of obese and nonobese PCOS patients were similar. 1467
TABLE 2
FIGURE 2
Basal determinations of glucose, insulin, LH, and FSH in obese and nonobese patients with PCOS. Analyte Glucose (mmol/L) Insulin (pmol/L) LH (IU/L) FSH (IU/L)
Obese PCOS patients (n ⫽ 16)
Nonobese PCOS patients (n ⫽ 16)
5.0 (3.8–7.0) 150.0 (101.9–382.4) 5.2 (0.6–10.5) 4.0 (1.0–10.1)
5.1 (3.3–7.6) 112.6 (54.5–342.2) 6.5 (1.8–12.7) 4.8 (2.9–7.4)
The relationship between WHR and GIR was observed in 32 patients with PCOS. A significantly negative correlation between body fat distribution and the GIR values was observed.
Note: The values express median and range in parentheses. Moran. Insulin resistance and LH-FSH in PCOS. Fertil Steril 2003.
Basal Glucose, Insulin, and GIR Basal levels for glucose and insulin are depicted in Table 2. There were no significant differences in glucose and insulin between obese and nonobese PCOS patients. Basal GIR was significantly lower (P⬍.03) in the obese than in nonobese patients (0.033 [0.013– 0.057] vs. 0.052 [0.015– 0.086]), indicating greater IR in the first group. A GIR of ⬍0.035 nmol/pmol was found in 10 of the 16 obese patients (62.5%) and in 5 of the 16 nonobese patients (31.3%; P⬍.01). A negative correlation was found between BMI and basal GIR (r⫽⫺0.38, P⫽.03; Fig. 1), and similarly, between WHR and basal GIR (r⫽⫺0.53, P⫽.002; Fig. 2). We performed the same analysis for data in Figure 1 and Figure 2 without the four points of higher basal GIR, but the coefficients of correlation decreased and did not become more statistically significant.
FIGURE 1 The relationship between BMI and GIR in 32 patients with PCOS. There is a negative correlation between BMI and GIR, indicating greater insulin resistance as BMI increases.
Moran. Insulin resistance and LH-FSH in PCOS. Fertil Steril 2003.
Basal LH, FSH, and LH-FSH Ratio Basal levels of LH and FSH are depicted in Table 2. There were no significant differences between obese and nonobese PCOS patients. The basal LH-FSH ratios for the obese and nonobese group were not significantly different (1.1 [0.2–2.5] vs. 1.5 [0.3–2.4], respectively). An LH-FSH ratio of ⬎2 was observed in 3 of the 16 obese PCOS patients (18.8%) and in 4 of the 16 nonobese patients (25.0%). No correlation was found between LH-FSH ratio and BMI or WHR.
Glucose, Insulin, and GIR Response to Dynamic Tests The maximum rise in glucose levels occurred at 30 minutes during OGTT. Impaired glucose tolerance was observed in 6 of the 16 (37.5%) obese and 4 of the 16 (25%) nonobese patients, but the difference did not reach statistical significance. A clear decrease in GIR was observed at 30 minutes after the glucose load and lasted until the end of the test. During the GnRH test, glucose, insulin, and GIR did not show significant changes (Fig. 3). The AUC of glucose and insulin of the obese and nonobese PCOS patients in response to OGTT and the GnRH test are shown in Table 3. Only insulin demonstrated greater values (P⬍.05) in obese than in nonobese PCOS patients, both in the OGTT and GnRH test. Furthermore, the AUC of GIR was significantly lower in obese than in nonobese PCOS patients (P⬍.03) during the two tests (Fig. 3).
Moran. Insulin resistance and LH-FSH in PCOS. Fertil Steril 2003.
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Considering PCOS patients with GD (n ⫽ 7) and PCOS patients without GD (n ⫽ 25), we did not find any statistical difference in GIR response to either OGTT or GnRH test. We did not find any other differences in the response to these tests comparing obese PCOS patients with GD (n ⫽ 3) or Vol. 80, No. 6, December 2003
FIGURE 3 Analysis of GIR in obese and nonobese PCOS patients during OGTT and GnRH test. The AUC for GIR was significantly lower (P⬍.03) in obese women than in nonobese women, both during OGTT and GnRH test. Symbols in left panel: filled triangle, nonobese GnRH; filled diamond, obese GnRH; open square, nonobese OGTT; filled square, obese OGTT. Right panel: open bars for AUC after GnRH and filled bars for AUC after OGTT.
Moran. Insulin resistance and LH-FSH in PCOS. Fertil Steril 2003.
without GD (n ⫽ 13), nor between nonobese patients with GD (n ⫽ 4) or without GD (n ⫽ 12). However, we had very few patients in some groups for this analysis, and so it did not have the statistical power to demonstrate differences among groups.
Luteinizing Hormone, FSH, and LH-FSH Ratio Response to the Dynamic Tests During the GnRH test a rapid increase in LH levels was noted at 30 minutes, followed by a gradual decrease that did not reach basal levels by 180 minutes. FSH responded similarly, but with a smaller magnitude, with the highest increase at 60 minutes. After GnRH, LH-FSH ratio increased at 60 minutes because of the greater secretion of LH (Fig. 4).
Levels of LH, FSH, and LH-FSH ratio remained without significant changes during the OGTT in both groups. The AUC of LH and FSH of the obese and nonobese PCOS patients in response to OGTT and the GnRH tests are shown in Table 3. There were no statistical differences between the two groups. Also, the AUC of LH-FSH ratio did not demonstrate significant differences between obese and nonobese PCOS patients in the OGTT and the GnRH test (Fig. 4). Considering PCOS patients with IR (n ⫽ 15) and without IR (n ⫽ 17), there were no significant differences in the AUC of LH-FSH ratio after either GnRH or OGTT test. However, among obese patients only, we found that those
TABLE 3 Area under the curves for glucose, insulin, LH, and FSH of obese and nonobese patients with PCOS during OGTT and GnRH test. Obese PCOS patients (n ⫽ 16) Analyte Glucose (mmol/L ⫻ min) Insulin (pmol/L ⫻ min) LH (IU/L ⫻ min) FSH (IU/L ⫻ min)
Nonobese PCOS patients (n ⫽ 16)
OGTT
GnRH test
OGTT
GnRH test
7.1 (5.6–10.1) 958.9 (410.6–4140.1)* 824.9 (120.4–1633.6) 799.9 (497.7–1034.6)
5.0 (4.3–7.6) 143.1 (107.3–306.7)¶ 2567.2 (383.7–6576.4) 1185.2 (847.2–1578.7)
7.3 (3.9–11.2) 677.9 (232.3–1647.9)* 1091.8 (268.2–3090.9) 838.0 (478.0–1118.4)
5.3 (4.3–7.3) 119.1 (37.4–264.8)¶ 3443.4 (715.9–14663.4) 1314.5 (885.0–2173.5)
Note: The values express median (range). The superscripts (*, ¶ ) indicate a statistically significant difference (P⬍.05) between pairs. Moran. Insulin resistance and LH-FSH in PCOS. Fertil Steril 2003.
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FIGURE 4 Analysis of LH-FSH ratio in obese and nonobese patients during oral glucose tolerance test (OGTT) and GnRH test. The AUC for LH-FSH ratio was similar in both groups during both OGTT and GnRH test. Symbols in the left panel: filled triangle, nonobese GnRH; filled diamond, obese GnRH; open square, nonobese OGTT; filled square, obese OGTT. Right panel: open bars for AUC after GnRH and filled bars for AUC after OGTT.
Moran. Insulin resistance and LH-FSH in PCOS. Fertil Steril 2003.
with IR (n ⫽ 10) had a significantly higher AUC of LH-FSH ratio after the GnRH test than obese patients without IR (n ⫽ 6; P⬍.04), but not after the OGTT test. Nonobese patients with IR (n ⫽ 5) and without IR (n ⫽ 11) did not show any significant difference in LH-FSH ratio, after either test.
DISCUSSION Polycystic ovary syndrome is a heterogeneous clinical disorder; IR and GD play an important role in its pathophysiology (3, 22). In this study, both obese and nonobese patients with PCOS were studied in response to two dynamic tests (OGTT and GnRH) to determine the relationship between IR and GD, on the basis of glucose, insulin, GIR, LH, FSH, and LH-FSH ratio. The two groups were compared to establish probable differences in the metabolic and endocrine behavior, as determined by the presence or absence of obesity. This study demonstrates that IR and GD appear to be independent events in PCOS. However, it is interesting that obese patients with IR had a significantly higher response of LH-FSH ratio than those without IR after the GnRH test, suggesting that chronic stimulation of IR in obese patients can affect GD. Glucose to insulin ratio had a negative correlation with the BMI and the WHR, which demonstrates that as body weight increases and adipose tissue is deposited in the upper segment, GIR decreases, indicating greater IR. Other studies have found glucose and insulin levels to be significantly higher in those with predominantly upper-segment obesity rather than with lower-segment obesity (23). In this study, it 1470 Moran et al.
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was possible to confirm that IR was greater in the obese group but that IR also occurred in the nonobese group, demonstrating that IR in PCOS is independent of body weight (6, 24). Impaired glucose tolerance was observed in both groups. It is interesting to note that all obese patients included in this study had upper-segment obesity, and it has been suggested that androgens, mainly DHEAS, promote deposition of adipose tissue in the upper-body segment (25). We have demonstrated previously that upper-body obesity is associated with hyperinsulinemia and anovulation (18). According to results obtained, IR and GD are different pathophysiological events. Classification of patients with PCOS into those who are obese with IR, hyperinsulinemia, and normal LH and patients who are nonobese with high LH and without IR (26, 27) is too narrow. There are nonobese subjects who have IR, as established elsewhere (6, 24), and there is also a group of obese PCOS patients who do not have alterations in insulin secretion (22). Luteinizing hormone levels found in this study were similar in both groups in the basal state and after GnRH stimulation test. One previous study evaluated the roles of LH and IR in PCOS, finding a clear reduction in insulin sensitivity in patients with low LH in comparison to patients with high LH (3). Also, a positive correlation was found between insulin sensitivity and LH levels, both in lean and obese PCOS patients. Our results do not agree with this study, because we found that obese patients with IR had a significantly higher response of LHFSH ratio to GnRH test than did patients without IR. Vol. 80, No. 6, December 2003
The insulin resistance and GD relationship is controversial. It has been found in vitro that insulin promotes pituitary LH and FSH (11); however, this has not been demonstrated in vivo (14). On the other hand, the influence of LH or GnRH on insulin secretion has not been investigated. In this work, no modification of LH-FSH ratio by OGTT, nor GIR after GnRH test, was seen, demonstrating that these events are independent of each other. However, it appears that chronic IR can affect GD, at least in obese patients. Our study findings agree with those of Fulghesu et al. (22), who found that hyperinsulinemia and hypersecretion of LH seem to be present in an independent way in PCOS patients. However, in a study in which a long-acting opioid antagonist (naltrexone, 50 mg/d for 4 – 6 weeks, p.o.) was administered, insulin secretion during the OGTT and LH release after GnRH injection decreased 20%–30% after treatment in PCOS patients with hyperinsulinemia (28). These data support the partial involvement of opioids in the regulation of insulin and LH secretion in a specific group of PCOS patients with hyperinsulinemia. Poretsky and Piper (29) have proposed the dual-defect hypothesis in PCOS in which neither GD nor IR appears to explain totally the pathophysiology of PCOS. Apparently, they are two primary coexistent defects determined genetically, as the genes for LH -subunit and insulin receptor are mapped to chromosome 19 (30, 31). However, there are many candidate genes proposed for PCOS involved in the following: [1] steroid hormone biosynthesis or metabolism, [2] gonadotropin action and regulation, [3] obesity and energy regulation, and [4] insulin action (32). Some reported candidate genes have functional impact on the IR component of PCOS, such as polymorphic alleles of both insulin receptor substrate (IRS)-1 and IRS-2 (33) or the variant of peroxisome proliferator–activated receptor-␥2 (PPAR␥2) (34). Other candidate genes may have functional impact on the gonadotropic component of PCOS, such as the allelic variant of follistatin gene (32) or the polymorphic variants of the FSH gene (35). As has been indicated, the complex characteristics of PCOS make it difficult to define a model to explain the pathophysiology of the syndrome. The data obtained in this study give information on the relationship between GD and IR, allowing these defects to be identified as independent of each other but with a final synergic effect on the ovary; however, there remain many doubts about the mechanisms involved in PCOS pathogenesis that require more research in this field.
Acknowledgments: The authors thank Jacky Stafford, B.S., for language reviewing in the preparation of the manuscript.
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Vol. 80, No. 6, December 2003
Relationship between insulin resistance and gonadotropin dissociation in obese and nonobese women with polycystic ovary syndrome Carlos Moran, M.D., M.Sc., Edgardo Garcia-Hernandez, M.D., M.Sc., Edgar Barahona, B.S., Sandra Gonzalez, B.S., and Jose A. Bermudez, M.D. Health Research Council, Mexican Institute of Social Security, Mexico City, Mexico
Objective: To test the interdependence between insulin resistance (IR) and gonadotropin dissociation (GD) in polycystic ovary syndrome (PCOS). Design: Cross-sectional prospective study. Setting: Clinical research center. Patient(s): Thirty-two PCOS patients aged 19 –34 years; 16 obese (BMI ⱖ 27) and 16 nonobese (BMI ⬍ 27). Intervention(s): A 75-g oral glucose tolerance test (OGTT) and a 100-g i.v. GnRH test were performed on different days. Blood was taken at 0, 30, 60, 90, 120, and 180 minutes in each test. Serum glucose, insulin, LH, and FSH were measured. Main Outcome Measure(s): Area under the curve was calculated for glucose, insulin, and glucose-to-insulin ratio (GIR), and for LH, FSH, and LH-FSH ratio. Result(s): Glucose, insulin, and GIR were not modified significantly during the GnRH test, nor LH, FSH and LH-FSH ratio throughout the OGTT. There were no significant differences in GIR response of patients with and without GD, nor in LH-FSH ratio of patients with and without IR, after OGTT and GnRH test. However, obese patients with IR had a significantly larger (P⬍.04) area under the curve for LH-FSH ratio than those without IR after GnRH test, but not after OGTT test. Conclusion(s): Insulin resistance and GD do not appear to be related events in PCOS, suggesting that each one might be determined by different genetic disorders. However, IR can affect GD after chronic stimulation in obese patients. (Fertil Steril威 2003;80:1466 –72. ©2003 by American Society for Reproductive Medicine.) Key Words: Hyperandrogenism, insulin resistance, polycystic ovary syndrome Received September 24, 2002; revised and accepted May 5, 2003. Supported in part by a research grant (38371-M) from Consejo Nacional de Ciencia y Tecnologı´a (CONACyT), Mexico City, Mexico. Presented in part at the 10th International Congress of Endocrinology, San Francisco, California, June 12–15, 1996. Reprint requests: Carlos Moran, M.D., 413 Interamerica Blvd. WH1, PMB 67-139, Laredo, Texas 78045 (FAX: 52-555653-1903; E-mail: [email protected]). 0015-0282/03/$30.00 doi:10.1016/j.fertnstert.2003. 05.010
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The existence of gonadotropin dissociation (GD), characterized by an increase in LH levels with normal FSH levels, has been widely described in polycystic ovary syndrome (PCOS) (1). The GD appears as high LH levels producing an LH-FSH ratio of ⬎2; however, GD occurs in ⬍50%– 60% of cases (2, 3). Insulin resistance (IR) can be defined as a decrease in tissue sensitivity for the action of insulin on glucose transport, which results in a compensatory increase in insulin levels. A correlation between hyperandrogenism and hyperinsulinism has been observed (4). In addition, hyperinsulinism and IR may be related to the degree of hyperandrogenism in PCOS (5). PCOS is associated with an approximately
35% decrease in insulin action, independent of the effect of obesity, which produces close to 50% decrease in insulin action (6). However, it has been also mentioned that not all obese patients present IR and hyperandrogenism (7). The cellular mechanisms involved in the development of IR are not clear, but a decrease in the autophosphorylation of insulin receptors has been found in different tissues (8 –10). In vitro studies have demonstrated that insulin promotes basal and GnRH-stimulated LH and FSH secretion of anterior pituitary cells from adult ovariectomized rats (11). Furthermore, there is experimental evidence that insulin acts synergistically with LH to increase the secretion of androstenedione in the human
ovary (12). Alternatively, in vitro studies in ovarian stromal fragments from women indicate that ovarian insulin receptors are down-regulated by LH and FSH and not only by insulin (13). A previous report has suggested that exogenous hyperinsulinemia does not modify in vivo gonadotropin secretion in PCOS patients (14). However, the literature on PCOS lacks in vivo studies to clarify whether GnRH-stimulated LH/FSH levels can influence the glucose to insulin ratio (GIR), or whether glucose load–stimulated hyperinsulinemia can affect LH/FSH levels in PCOS patients. To test the hypothesis of interdependence of IR and GD in patients with PCOS, we studied the GIR response to high levels of endogenous gonadotropins released by GnRH test and tested the LH-FSH response to endogenous hyperinsulinemia induced by an oral glucose tolerance test (OGTT).
MATERIALS AND METHODS This project was carried out with prior authorization from the institutional research board of the Mexican Institute of Social Security, after informed written consent was obtained from all patients. The study included 32 women, 19 –35 years old, with PCOS diagnosed by the presence of oligoovulation (oligomenorrhea or amenorrhea) and clinical hyperandrogenism, as established by the consensus group for diagnosis of PCOS (15). Hirsutism was diagnosed by a modified Ferriman-Gallwey score (16). Although not included as a criterion for diagnosis, all patients had bilateral polycystic ovaries by abdominal ultrasound. Patients with hyperprolactinemia, nonclassical adrenal hyperplasia, hypothyroidism, and ovarian or adrenal tumors were excluded from the study by appropriate hormonal tests. None of the study subjects were taking hormonal medications, including oral contraceptives. Anthropometry was performed in all patients and consisted of weight and height measurement to calculate the body mass index (BMI). Patients were classified according to BMI into obese (BMI ⱖ 27 kg/m2, n ⫽ 16) and nonobese (BMI ⬍ 27 kg/m2, n ⫽ 16) (17). Waist and hip circumference were measured to evaluate body fat distribution by the waist-to-hip ratio (WHR), defining lower-segment obesity as WHR ⱕ 0.85 and upper-segment obesity as WHR ⬎ 0.85 (18). IR was defined as a GIR of ⬍0.035 nmol/pmol (⬍4.5 mg/dL over U/mL) in basal conditions (19). The GIR has been demonstrated to correlate with the measurement of insulin sensitivity determined by euglycemic clamp, the minimal model technique, and the OGTT (17, 19). To evaluate OGTT, the criteria of the Diabetes Data Group were used (20).
Dynamic Tests Two dynamic tests were performed on consecutive days, starting at 8 AM in fasting conditions, on days 3–5 of a spontaneous menstrual cycle or after a progestogen-induced bleeding. Initially, an OGTT with 75 g of glucose was given, FERTILITY & STERILITY威
TABLE 1 Clinical characteristics of obese and nonobese patients with PCOS. Characteristic Age (y) BMI (kg/m2) WHR Ferriman-Gallwey score
Obese PCOS patients (n ⫽ 16)
Nonobese PCOS patients (n ⫽ 16)
23 (20–32) 29.4 (27.0–39.2)* 0.89 (0.86–0.95)¶ 5 (2–18)
22 (19–34) 22.9 (19.1–26.6)* 0.81 (0.71–0.89)¶ 6 (3–14)
Note: The values express median and range in parentheses. The superscripts (*, ¶ ) indicate a statistically significant difference (P⬍.001) between pairs. BMI ⫽ body mass index; WHR ⫽ waist-to-hip ratio. Moran. Insulin resistance and LH-FSH in PCOS. Fertil Steril 2003.
and the following day, 100 g of GnRH was given i.v. An indwelling catheter was placed in an antecubital vein during the tests to obtain blood samples at 0, 30, 60, 90, 120, and 180 minutes for quantifying glucose, insulin, LH, and FSH. The catheter was flushed with normal saline solution at 1 mL/min to achieve permeability, and the first 3 mL of blood was discarded to avoid dilution of the sample. Each sample was allowed to coagulate at room temperature for later centrifugation, and the serum was separated and frozen at ⫺20°C until processed. Glucose level was determined immediately by the glucose oxidase technique (Stanbio Laboratory Inc., Boerne, TX) using a Gilford Express 550 (Ciba Corning Diagnostics, East Walpole, MA). A double-antibody RIA technique (Cis Bio International, Gif-sur-Yvette, France) was used to analyze LH, FSH, and insulin. The intraassay and interassay coefficients of variation were ⬍5% and ⬍9%, respectively.
Statistical Analysis All results are expressed as median and range. Area under the curve (AUC) for glucose, insulin, GIR, LH, FSH, and LH-FSH was calculated as previously reported (21). Chisquare and Mann-Whitney U tests were used to compare the groups, and Pearson (r) coefficient, for correlation. A P⬍.05 was considered as statistically significant.
RESULTS Clinical Characteristics Clinical characteristics, such as age, BMI, WHR, and the Ferriman-Gallwey score, of both obese and nonobese PCOS patients, are noted in Table 1. By design, obese and nonobese PCOS patients had a similar median age. As expected, median BMI and WHR of obese PCOS patients were significantly higher than those of nonobese PCOS patients. The Ferriman-Gallwey score of obese and nonobese PCOS patients were similar. 1467
TABLE 2
FIGURE 2
Basal determinations of glucose, insulin, LH, and FSH in obese and nonobese patients with PCOS. Analyte Glucose (mmol/L) Insulin (pmol/L) LH (IU/L) FSH (IU/L)
Obese PCOS patients (n ⫽ 16)
Nonobese PCOS patients (n ⫽ 16)
5.0 (3.8–7.0) 150.0 (101.9–382.4) 5.2 (0.6–10.5) 4.0 (1.0–10.1)
5.1 (3.3–7.6) 112.6 (54.5–342.2) 6.5 (1.8–12.7) 4.8 (2.9–7.4)
The relationship between WHR and GIR was observed in 32 patients with PCOS. A significantly negative correlation between body fat distribution and the GIR values was observed.
Note: The values express median and range in parentheses. Moran. Insulin resistance and LH-FSH in PCOS. Fertil Steril 2003.
Basal Glucose, Insulin, and GIR Basal levels for glucose and insulin are depicted in Table 2. There were no significant differences in glucose and insulin between obese and nonobese PCOS patients. Basal GIR was significantly lower (P⬍.03) in the obese than in nonobese patients (0.033 [0.013– 0.057] vs. 0.052 [0.015– 0.086]), indicating greater IR in the first group. A GIR of ⬍0.035 nmol/pmol was found in 10 of the 16 obese patients (62.5%) and in 5 of the 16 nonobese patients (31.3%; P⬍.01). A negative correlation was found between BMI and basal GIR (r⫽⫺0.38, P⫽.03; Fig. 1), and similarly, between WHR and basal GIR (r⫽⫺0.53, P⫽.002; Fig. 2). We performed the same analysis for data in Figure 1 and Figure 2 without the four points of higher basal GIR, but the coefficients of correlation decreased and did not become more statistically significant.
FIGURE 1 The relationship between BMI and GIR in 32 patients with PCOS. There is a negative correlation between BMI and GIR, indicating greater insulin resistance as BMI increases.
Moran. Insulin resistance and LH-FSH in PCOS. Fertil Steril 2003.
Basal LH, FSH, and LH-FSH Ratio Basal levels of LH and FSH are depicted in Table 2. There were no significant differences between obese and nonobese PCOS patients. The basal LH-FSH ratios for the obese and nonobese group were not significantly different (1.1 [0.2–2.5] vs. 1.5 [0.3–2.4], respectively). An LH-FSH ratio of ⬎2 was observed in 3 of the 16 obese PCOS patients (18.8%) and in 4 of the 16 nonobese patients (25.0%). No correlation was found between LH-FSH ratio and BMI or WHR.
Glucose, Insulin, and GIR Response to Dynamic Tests The maximum rise in glucose levels occurred at 30 minutes during OGTT. Impaired glucose tolerance was observed in 6 of the 16 (37.5%) obese and 4 of the 16 (25%) nonobese patients, but the difference did not reach statistical significance. A clear decrease in GIR was observed at 30 minutes after the glucose load and lasted until the end of the test. During the GnRH test, glucose, insulin, and GIR did not show significant changes (Fig. 3). The AUC of glucose and insulin of the obese and nonobese PCOS patients in response to OGTT and the GnRH test are shown in Table 3. Only insulin demonstrated greater values (P⬍.05) in obese than in nonobese PCOS patients, both in the OGTT and GnRH test. Furthermore, the AUC of GIR was significantly lower in obese than in nonobese PCOS patients (P⬍.03) during the two tests (Fig. 3).
Moran. Insulin resistance and LH-FSH in PCOS. Fertil Steril 2003.
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Considering PCOS patients with GD (n ⫽ 7) and PCOS patients without GD (n ⫽ 25), we did not find any statistical difference in GIR response to either OGTT or GnRH test. We did not find any other differences in the response to these tests comparing obese PCOS patients with GD (n ⫽ 3) or Vol. 80, No. 6, December 2003
FIGURE 3 Analysis of GIR in obese and nonobese PCOS patients during OGTT and GnRH test. The AUC for GIR was significantly lower (P⬍.03) in obese women than in nonobese women, both during OGTT and GnRH test. Symbols in left panel: filled triangle, nonobese GnRH; filled diamond, obese GnRH; open square, nonobese OGTT; filled square, obese OGTT. Right panel: open bars for AUC after GnRH and filled bars for AUC after OGTT.
Moran. Insulin resistance and LH-FSH in PCOS. Fertil Steril 2003.
without GD (n ⫽ 13), nor between nonobese patients with GD (n ⫽ 4) or without GD (n ⫽ 12). However, we had very few patients in some groups for this analysis, and so it did not have the statistical power to demonstrate differences among groups.
Luteinizing Hormone, FSH, and LH-FSH Ratio Response to the Dynamic Tests During the GnRH test a rapid increase in LH levels was noted at 30 minutes, followed by a gradual decrease that did not reach basal levels by 180 minutes. FSH responded similarly, but with a smaller magnitude, with the highest increase at 60 minutes. After GnRH, LH-FSH ratio increased at 60 minutes because of the greater secretion of LH (Fig. 4).
Levels of LH, FSH, and LH-FSH ratio remained without significant changes during the OGTT in both groups. The AUC of LH and FSH of the obese and nonobese PCOS patients in response to OGTT and the GnRH tests are shown in Table 3. There were no statistical differences between the two groups. Also, the AUC of LH-FSH ratio did not demonstrate significant differences between obese and nonobese PCOS patients in the OGTT and the GnRH test (Fig. 4). Considering PCOS patients with IR (n ⫽ 15) and without IR (n ⫽ 17), there were no significant differences in the AUC of LH-FSH ratio after either GnRH or OGTT test. However, among obese patients only, we found that those
TABLE 3 Area under the curves for glucose, insulin, LH, and FSH of obese and nonobese patients with PCOS during OGTT and GnRH test. Obese PCOS patients (n ⫽ 16) Analyte Glucose (mmol/L ⫻ min) Insulin (pmol/L ⫻ min) LH (IU/L ⫻ min) FSH (IU/L ⫻ min)
Nonobese PCOS patients (n ⫽ 16)
OGTT
GnRH test
OGTT
GnRH test
7.1 (5.6–10.1) 958.9 (410.6–4140.1)* 824.9 (120.4–1633.6) 799.9 (497.7–1034.6)
5.0 (4.3–7.6) 143.1 (107.3–306.7)¶ 2567.2 (383.7–6576.4) 1185.2 (847.2–1578.7)
7.3 (3.9–11.2) 677.9 (232.3–1647.9)* 1091.8 (268.2–3090.9) 838.0 (478.0–1118.4)
5.3 (4.3–7.3) 119.1 (37.4–264.8)¶ 3443.4 (715.9–14663.4) 1314.5 (885.0–2173.5)
Note: The values express median (range). The superscripts (*, ¶ ) indicate a statistically significant difference (P⬍.05) between pairs. Moran. Insulin resistance and LH-FSH in PCOS. Fertil Steril 2003.
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FIGURE 4 Analysis of LH-FSH ratio in obese and nonobese patients during oral glucose tolerance test (OGTT) and GnRH test. The AUC for LH-FSH ratio was similar in both groups during both OGTT and GnRH test. Symbols in the left panel: filled triangle, nonobese GnRH; filled diamond, obese GnRH; open square, nonobese OGTT; filled square, obese OGTT. Right panel: open bars for AUC after GnRH and filled bars for AUC after OGTT.
Moran. Insulin resistance and LH-FSH in PCOS. Fertil Steril 2003.
with IR (n ⫽ 10) had a significantly higher AUC of LH-FSH ratio after the GnRH test than obese patients without IR (n ⫽ 6; P⬍.04), but not after the OGTT test. Nonobese patients with IR (n ⫽ 5) and without IR (n ⫽ 11) did not show any significant difference in LH-FSH ratio, after either test.
DISCUSSION Polycystic ovary syndrome is a heterogeneous clinical disorder; IR and GD play an important role in its pathophysiology (3, 22). In this study, both obese and nonobese patients with PCOS were studied in response to two dynamic tests (OGTT and GnRH) to determine the relationship between IR and GD, on the basis of glucose, insulin, GIR, LH, FSH, and LH-FSH ratio. The two groups were compared to establish probable differences in the metabolic and endocrine behavior, as determined by the presence or absence of obesity. This study demonstrates that IR and GD appear to be independent events in PCOS. However, it is interesting that obese patients with IR had a significantly higher response of LH-FSH ratio than those without IR after the GnRH test, suggesting that chronic stimulation of IR in obese patients can affect GD. Glucose to insulin ratio had a negative correlation with the BMI and the WHR, which demonstrates that as body weight increases and adipose tissue is deposited in the upper segment, GIR decreases, indicating greater IR. Other studies have found glucose and insulin levels to be significantly higher in those with predominantly upper-segment obesity rather than with lower-segment obesity (23). In this study, it 1470 Moran et al.
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was possible to confirm that IR was greater in the obese group but that IR also occurred in the nonobese group, demonstrating that IR in PCOS is independent of body weight (6, 24). Impaired glucose tolerance was observed in both groups. It is interesting to note that all obese patients included in this study had upper-segment obesity, and it has been suggested that androgens, mainly DHEAS, promote deposition of adipose tissue in the upper-body segment (25). We have demonstrated previously that upper-body obesity is associated with hyperinsulinemia and anovulation (18). According to results obtained, IR and GD are different pathophysiological events. Classification of patients with PCOS into those who are obese with IR, hyperinsulinemia, and normal LH and patients who are nonobese with high LH and without IR (26, 27) is too narrow. There are nonobese subjects who have IR, as established elsewhere (6, 24), and there is also a group of obese PCOS patients who do not have alterations in insulin secretion (22). Luteinizing hormone levels found in this study were similar in both groups in the basal state and after GnRH stimulation test. One previous study evaluated the roles of LH and IR in PCOS, finding a clear reduction in insulin sensitivity in patients with low LH in comparison to patients with high LH (3). Also, a positive correlation was found between insulin sensitivity and LH levels, both in lean and obese PCOS patients. Our results do not agree with this study, because we found that obese patients with IR had a significantly higher response of LHFSH ratio to GnRH test than did patients without IR. Vol. 80, No. 6, December 2003
The insulin resistance and GD relationship is controversial. It has been found in vitro that insulin promotes pituitary LH and FSH (11); however, this has not been demonstrated in vivo (14). On the other hand, the influence of LH or GnRH on insulin secretion has not been investigated. In this work, no modification of LH-FSH ratio by OGTT, nor GIR after GnRH test, was seen, demonstrating that these events are independent of each other. However, it appears that chronic IR can affect GD, at least in obese patients. Our study findings agree with those of Fulghesu et al. (22), who found that hyperinsulinemia and hypersecretion of LH seem to be present in an independent way in PCOS patients. However, in a study in which a long-acting opioid antagonist (naltrexone, 50 mg/d for 4 – 6 weeks, p.o.) was administered, insulin secretion during the OGTT and LH release after GnRH injection decreased 20%–30% after treatment in PCOS patients with hyperinsulinemia (28). These data support the partial involvement of opioids in the regulation of insulin and LH secretion in a specific group of PCOS patients with hyperinsulinemia. Poretsky and Piper (29) have proposed the dual-defect hypothesis in PCOS in which neither GD nor IR appears to explain totally the pathophysiology of PCOS. Apparently, they are two primary coexistent defects determined genetically, as the genes for LH -subunit and insulin receptor are mapped to chromosome 19 (30, 31). However, there are many candidate genes proposed for PCOS involved in the following: [1] steroid hormone biosynthesis or metabolism, [2] gonadotropin action and regulation, [3] obesity and energy regulation, and [4] insulin action (32). Some reported candidate genes have functional impact on the IR component of PCOS, such as polymorphic alleles of both insulin receptor substrate (IRS)-1 and IRS-2 (33) or the variant of peroxisome proliferator–activated receptor-␥2 (PPAR␥2) (34). Other candidate genes may have functional impact on the gonadotropic component of PCOS, such as the allelic variant of follistatin gene (32) or the polymorphic variants of the FSH gene (35). As has been indicated, the complex characteristics of PCOS make it difficult to define a model to explain the pathophysiology of the syndrome. The data obtained in this study give information on the relationship between GD and IR, allowing these defects to be identified as independent of each other but with a final synergic effect on the ovary; however, there remain many doubts about the mechanisms involved in PCOS pathogenesis that require more research in this field.
Acknowledgments: The authors thank Jacky Stafford, B.S., for language reviewing in the preparation of the manuscript.
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