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Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92093
Address all correspondence and requests for reprints to: R. Jeffrey Chang, M.D., Department of Reproductive Medicine, University of California, San Diego, School of Medicine-0633, 9500 Gilman Drive, La Jolla, CA 92093-0633. E-mail: rjchang{at}ucsd.edu.
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Abstract |
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Introduction |
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Women with PCOS are known to be insulin resistant with compensatory hyperinsulinemia. That insulin resistance in this disorder may be linked to anovulation is suggested by the resumption of ovulation in individuals who have sustained a reduction in hyperinsulinemia by treatment with insulin-lowering drugs or dietary weight loss (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18). In studies that assessed granulosa cell function, measurement of serum E2 levels did not reveal any particular pattern of response in women who became ovulatory or remained anovulatory. Notably, administration of the thiazolidinedione, troglitazone, either alone or with concomitant clomiphene citrate, significantly increased ovulation rates in women with PCOS compared with those treated with placebo (5, 7). Similarly, an enhanced rate of ovulation was observed after treatment with a combination of metformin and clomiphene citrate compared with metformin alone in women with this disorder (19). In women undergoing weight reduction, initiation of regular menses was associated with improved insulin sensitivity as reflected by increased SHBG (9, 20). No changes were noted for serum FSH in any of the studies. Thus, in PCOS women, resumption of ovulatory function in response to medical or dietary therapy appeared to correlate with improved insulin sensitivity and reduced levels of circulating insulin, which suggests that insulin resistance and compensatory hyperinsulinemia may inhibit normal follicular function. However, the mechanism by which insulin resistance disrupts granulosa cell function remains unclear. Even less obvious is an explanation for recovery of granulosa cell responsiveness and normal follicle development after reduction of insulin resistance.
Recently, we demonstrated that women with PCOS exhibited dose-dependent granulosa cell hyperresponsiveness to FSH, the duration of which was transitory (21). These in vivo results were essentially identical with our previously published abnormal in vitro findings (3). In an extension of these studies, to determine the role of hyperinsulinemia on follicle function, we examined granulosa cell responsiveness to recombinant human FSH (r-hFSH) in women with PCOS before and during insulin infusion using the hyperinsulinemic-euglycemic clamp method. In addition, the effect of insulin resistance was investigated by administration of the insulin-lowering agent, pioglitazone, for 5 months during which r-hFSH stimulation and hyperinsulinemic-euglycemic clamp studies were repeated.
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Subjects and Methods |
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Seven women with PCOS and seven normal women with regular menstrual cycles were recruited for study. All PCOS subjects exhibited clinical and biochemical evidence of hyperandrogenism and were either oligomenorrheic or amenorrheic. In the PCOS and normal control groups, mean ages (±SE) were 29.0 ± 2.3 and 28.6 ± 1.5 yr, respectively, and not significantly different. The mean body mass index was significantly greater in PCOS subjects compared with that of normal women (40.1 ± 2.0 vs. 27.4 ± 1.9; P < 0.02) whereas the waist-to-hip ratios were similar in both groups. Each PCOS subject exhibited ultrasound evidence of bilateral polycystic ovaries (22). Late-onset congenital adrenal hyperplasia was excluded by a serum 17-hydroxyprogesterone (17-OHP4) level of less than 3 ng/ml (<9.1 nmol/liter). Circulating TSH and prolactin levels were normal and not significantly different between groups. The normal subjects were monitored by menstrual calendar for 3 months and by urinary LH testing for 1 month before study to establish the regularity of their cycles. None of the subjects in either group had received any hormone medication for at least 3 months before study. The study had been approved by the Institutional Review Board at the University of California, San Diego, and written informed consent was obtained from each participant before the study.
Procedures
Each PCOS subject was admitted to the General Clinical Research Center (GCRC) at the University of California, San Diego (UCSD), on the evening before the day of testing on three separate occasions before treatment and three times during treatment. In PCOS subjects, each day of testing was separated by a minimum interval of at least 4 wk. During each admission, r-hFSH was administered as an iv bolus at a dose of 75 IU. Normal subjects were admitted to the UCSD GCRC on two separate occasions each during the midfollicular phase defined as d 5–8 and received r-hFSH at doses of 75 IU and 150 IU. The r-hFSH (Gonal-F) was kindly provided by Serono Laboratories, Inc. (Rockland, MA). Blood samples were drawn through an indwelling iv catheter at 0.5-h intervals for 2 h before and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 20, and 24 h after r-hFSH administration.
During the pretreatment phase, every PCOS subject was administered both a low-dose and a high-dose insulin infusion using the hyperinsulinemic-euglycemic clamp method in randomized fashion before r-hFSH stimulation. Subsequently, treatment with pioglitazone, 30 mg/d, for 5 months was initiated. At the end of 3, 4, and 5 months, each subject returned to the GCRC and received r-hFSH stimulation. At the end of the 4th and 5th month of treatment, low-dose and high-dose insulin infusions were repeated in a randomized fashion before FSH stimulation. None of the PCOS subjects experienced ovulation during the study as evidenced by changes in their menstrual patterns or scant bleeding episodes unaccompanied by premenstrual molimina. In addition, at the time of study in each PCOS woman, serum P4 levels were less than 1 ng/ml (<3.0 nmol/liter). None of the normal subjects received insulin infusions or were treated with pioglitazone. Serum E2 responses to r-hFSH, 75 IU and 150 IU, in normal women have been published previously and are cited as reference values as stated in the text (21).
Samples were allowed to clot, and sera were separated by centrifugation and stored at –20 C until assayed. Individual serum samples were analyzed in the same assay in duplicate.
Modified frequent sampling iv glucose tolerance test
Approximately 1 month before FSH stimulation tests, each subject was admitted to the UCSD GCRC early in the morning after an overnight fast. Two iv lines were inserted and kept open by slow saline infusion. Glucose was administered iv over 1 min at a dose of 0.3 g/kg, followed by administration of insulin (Humulin; Eli Lilly, Indianapolis, IN), 0.02 U/kg, 20 min later. Blood samples were obtained at -5, 0, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 19, 22, 24, 25, 27, 30, 40, 50, 60, 90, 120, and 180 min for glucose and insulin determinations. Insulin sensitivity was analyzed with the MINMOD computer program (23).
Hyperinsulinemic-euglycemic clamp
Studies were performed in the morning after a 12-h overnight fast. At 2100 h, an 18-gauge iv catheter was inserted into an antecubital vein and an infusion of normal saline was started. At 0700 h, another iv catheter was inserted in a retrograde fashion in a hand vein, with the hand placed in a hand warmer for sampling of arterialized blood. An iv infusion of insulin (Humulin; Eli Lilly) diluted in 0.15 mol/liter saline containing 1% wt/vol human albumin was then begun at a rate of either 30 mU/m2·min (low dose) or 200 mU/m2·min (high dose), which was started 2 h before r-hFSH administration and continued for 10 h. Potassium and phosphate were given iv to compensate for the intracellular movement of these ions and to maintain normal blood levels. A variable infusion of 20% glucose was delivered to maintain a plasma glucose concentration of 4.72 mol/liter (85 ng/dl). Blood samples were obtained every 5 min for measurement of plasma glucose with a glucose analyzer (YSI 2700 analyzer; Yellow Springs Instrument Co., Yellow Springs, OH). In addition, blood samples were obtained every 10 min for measurement of insulin. The mean glucose infusion rate (GIR) in each patient was calculated as the amount of glucose (in milligrams) infused per kilogram body weight during the last 6 h of the clamp, which reflected steady-state conditions.
Assays
Serum LH and FSH concentrations were measured by RIA with intra- and interassay coefficients of variation (CV), respectively, of 5.4% and 8.0% for LH and 3.0% and 4.6% for FSH (Diagnostic Products Corp., Los Angeles, CA). Serum concentrations of estrone (E1), estradiol (E2), androstenedione (A4), and testosterone were measured by well-established RIA with intraassay CV less than 7%. Serum P4, 17-OHP4, and dehydroepiandrosterone sulfate were measured by RIA with intraassay CV less than 7% (Diagnostic Systems Laboratories, Webster, TX). Serum insulin levels were measured by a double-antibody RIA with an assay sensitivity of 2 µU/ml and intra- and interassay CV of 7% and 9%, respectively. Plasma glucose levels were determined by the glucose oxidase method (Yellow Springs Instrument Co.) with an intraassay CV less than 2% and an intraassay CV of 3%.
Statistical analysis
Baseline hormone values between PCOS and normal women were compared by independent Student’s group t tests. Within-group comparisons in PCOS were made using a one-factor ANOVA with repeated measures. Post hoc testing was performed using Student’s paired t tests with adjustment using a Bonferroni correction. Treatment effects of pioglitazone on glucose infusion rates during low-dose and high-dose insulin infusion were analyzed using Student’s paired t tests. E2 responses were analyzed as absolute maximal change from baseline, percentage maximal change from baseline, and area under the curve. Statistical analysis was performed using SPSS 11.0 software (SPSS Inc., Chicago, IL).
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Results |
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Baseline hormone values are shown in Table 1
. In PCOS women the mean (±SE) circulating levels of testosterone, androstenedione, E1, and fasting insulin were significantly greater than those of normal controls, as expected. Serum LH, FSH, dehydroepiandrosterone sulfate, 17-OHP4, P4, E2, and fasting glucose levels were similar in both groups.
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Insulin sensitivity in women with PCOS was 1.82 ± 0.62 (x10-4 min/µU·ml), which was significantly lower (P < 0.05) than that measured in normal women, 3.69 ± 0.91. Administration of hyperinsulinemic-euglycemic clamps to PCOS women before and after pioglitazone treatment resulted in mean steady-state serum insulin levels of 105 ± 1 µU/ml and 69 ± 2 µU/ml, respectively, during low-dose insulin infusion and 655 ± 19 µU/ml and 569 ± 10 µU/ml, respectively, during high-dose infusion. Steady-state serum glucose levels were maintained between 85 mg/dl and 90 mg/dl with all infusions.
Before treatment, the mean GIR during the low-dose clamp was 1.3 ± 0.5 mg/kg·min. With administration of pioglitazone, the GIR increased significantly (P < 0.03) to 2.6 ± 1.2 mg/kg·min during low-dose insulin infusion. The pretreatment GIR in PCOS women receiving high-dose insulin infusion was 4.2 ± 1.4 mg/kg·min, which increased significantly (P < 0.04) to 5.4 ± 1.6 mg/kg·min after pioglitazone treatment. At the high steady-state levels of insulin achieved during the high-dose clamp, hepatic glucose output is known to be suppressed. As a result, the GIR observed during high-dose insulin infusion was equivalent to the glucose disposal rate.
E2 responses to r-hFSH administration in normal and PCOS women
The mean basal serum E2 levels in normal women, 78 ± 7 pg/ml (289 ± 27 pmol/liter), was similar to that found in women with PCOS, 66 ± 2 pg/ml (243 ± 9 pmol/liter). After administration of r-hFSH, 75 IU, both groups exhibited similar progressive increases in circulating E2, achieving maximum serum concentrations at 8 h. Thereafter, in normal women serum, E2 levels were maintained up to 24 h, whereas in PCOS subjects, there was a steady decline of approximately 30% of maximal response.
Effect of insulin infusion on E2 responses to r-hFSH administration in PCOS
Baseline serum E2 levels and mean maximal E2 responses (increment) to r-hFSH administration in normal women and women with PCOS before and during insulin infusions are shown in Table 2. The mean baseline concentrations of serum E2 in PCOS women were unaltered by either low-dose or high-dose hyperinsulinemic clamps initiated 2 h before r-hFSH administration. During low-dose and high-dose insulin infusions, mean maximal increases of serum E2 in response to r-hFSH were not significantly different from that observed in the absence of insulin administration. The 24-h time course of serum E2 release, after r-hFSH stimulation before and during the hyperinsulinemic-euglycemic clamp studies, revealed similar response patterns (Fig. 1). Initial E2 responses were detected only after 2 h after r-hFSH, irrespective of insulin infusion, which is consistent with our previous observation (21) suggesting the length of time required for induction of detectable aromatase enzyme activity in granulosa cells. Peak concentrations of E2 were reached at 6–8 h after administration of r-hFSH. Subsequently, there were progressive decreases in serum E2 levels similar to the pattern of decline observed in these PCOS women when tested without insulin infusions. This was most pronounced during the high-dose infusion as serum E2 decreased by 46% of the mean peak value. By comparison, in normal subjects, residual circulating E2 levels after maximal stimulation failed to exhibit a significant decline.
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Administration of pioglitazone for 3 months was not associated with alterations of either baseline or stimulated E2 release in response to r-hFSH at a dose of 75 IU. In addition, the time-course response of E2 remained unchanged.
During the low-dose hyperinsulinemic clamp, the mean maximal serum E2 level after r-hFSH was similar to that observed in the absence of insulin administration (Table 2
). In contrast, high-dose insulin infusion was associated with a distinct and significant (P < 0.02) increase of peak E2 responsiveness after r-hFSH stimulation compared with responses observed in the absence of insulin or during low-dose infusion. In addition, this response was significantly greater than that found before pioglitazone treatment (P < 0.04) (Fig. 2). Moreover, the 24-h pattern of E2 release revealed a uniformly larger integrated response compared with those found without insulin or low-dose infusion, which was reflected by the significantly increased (P < 0.01) area under the curve (Table 2 and Fig. 3). Administration of insulin did not appear to alter the interval required to achieve peak concentrations of E2, although the incremental portion of the serum E2 response curve during high-dose insulin infusion was more rapid and of greater magnitude (Fig. 4) than that observed for PCOS women not undergoing the hyperinsulinemic clamp. In the absence of insulin infusion, the maximum E2 response in PCOS women occurred at 6 h and was 120 ± 7 pg/ml (444 ± 26 pmol/liter), whereas during the high-dose clamp, a comparable stimulated value was achieved in less than 4 h after r-hFSH. In addition, women receiving high-dose insulin at 6 h had a significantly (P < 0.0001) higher mean maximal E2 level, 177 ± 20 pg/ml (655 ± 74 pmol/liter). This rate of insulin infusion also appeared to prolong the duration of maximally stimulated E2 in PCOS women treated with pioglitazone as peak values were maintained up to 16 h after which substantial decreases were noted, which was not dissimilar to the residual pattern of response reported for normal women after r-hFSH administration at a dose of 150 IU (Fig. 5). Collectively, these findings indicate that PCOS women treated with pioglitazone exhibit greater E2 responsiveness to r-hFSH compared with responses found before treatment.
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None of the PCOS subjects ovulated as judged by changes in their menstrual patterns, nor did they experience any uterine bleeding after r-hFSH administration alone or in combination with insulin infusion indicating the lack of any functional effects. Normal ovulatory women did not experience any alteration in their menstrual patterns.
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Discussion |
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We have previously shown in vitro that PCOS granulosa cells are minimally responsive to insulin administration in the presence or absence of FSH stimulation (3). In that study, granulosa cells were obtained from a single patient with PCOS, and FSH-stimulated E2 production was detectable only after incubation with insulin at a dose of 1 µg/ml, whereas E2 release was not observed at lower concentrations. In the current in vivo study, raised levels of circulating insulin during hyperinsulinemic clamps were not associated with significant increases in E2 responsiveness to r-hFSH in PCOS women compared with responses obtained without insulin infusion or those observed in normal women, which is consistent with our earlier in vitro findings. However, with pioglitazone treatment and resultant increased insulin sensitivity, enhanced granulosa cell responsiveness to r-hFSH during insulin infusion was readily apparent. Remarkably, the stimulated E2 response with high-dose insulin administration was characterized by a more rapid rate and greater increment of change as well as a more sustained rise compared with that noted before treatment. In particular, with treatment, the accelerated rise of serum E2 in response to 75 IU of r-hFSH during high-dose insulin infusion bore a striking resemblance to the rapid E2 increment displayed by normal women administered r-hFSH at a dose of 150 IU, as reported previously (21). In addition, the persistence of simulated E2 concentrations once maximal values had been achieved was clearly distinct from the uniform decline of serum E2 observed in absence of pioglitazone therapy. These results indicate that in women with PCOS, granulosa cell responsiveness to FSH during insulin infusion may be restored and, perhaps, enhanced by increasing insulin sensitivity. Moreover, the data are compatible with the notion that in women with PCOS, insulin resistance within granulosa cells may, in part, account for abnormal E2 release.
A role for insulin in granulosa cell function has been suggested from the results of previous in vitro studies (4). It was demonstrated that granulosa cells removed from PCOS ovaries exhibited substantial E2 release after incubation with insulin at doses well below 1 µg/ml, which simulated physiological concentrations. In vivo, this facilitative effect of insulin on PCOS granulosa cells has, as yet, not been observed as initial clinical responses to FSH are characterized by reduced E2 increments after FSH stimulation in PCOS women compared with those observed in normal women (24, 25). The results of the current study suggest that insulin resistance in the granulosa cell may be, at least in part, responsible for decreased E2 responsiveness to FSH. In PCOS women, reduced follicle responsiveness may be overcome with progressive increases in the dose or duration of FSH. Low-dose administration of FSH has been particularly useful because the risk of ovarian hyperstimulation syndrome is considerably diminished with this method of ovulation induction (26). However, the duration of treatment, which is dictated by the follicular response, may be protracted, resulting in an overall increased total dose of gonadotropin. The gradual accumulation of constant low-dose FSH over time is preferred to an escalation of the daily dose because of an apparent FSH threshold beyond which the risk of ovarian hyperstimulation syndrome increases (27). Consistent with this concept, our previous studies have demonstrated that PCOS women displayed significantly greater E2 responses to FSH at a dose of 150 IU compared with that observed in normal women, whereas responses to 75 IU were equivalent between groups (21). Collectively, these results suggest that in women with PCOS, initial suboptimal ovarian responsiveness to FSH stimulation during ovulation induction may be, in part, due to insulin resistance within the granulosa cell. However, eventual stimulation of follicle growth may be accomplished with daily, low-dose FSH, which may require prolonged administration compared with progressive increments in the daily dose that may exceed the FSH threshold and increase the risk of ovarian hyperstimulation syndrome.
The mechanism by which FSH and insulin may interact within the granulosa cell has not been extensively studied. Previous histochemical analysis of human ovaries have demonstrated that insulin receptor mRNA and protein expression in granulosa cells of PCOS follicles was similar to that found in antral follicles from normal ovaries (28, 29). Insulin binding to the heterotetrameric insulin receptor tyrosine kinase causes phosphorylation of insulin receptor substrate, resulting in the activation of extracellular receptor kinase and phosphatidylinositol 3-kinase signaling pathways. In preliminary studies, we have demonstrated that insulin activates phosphorylation of several intracellular signaling proteins in ovarian tissue obtained from a woman with PCOS (30). Activation appeared to be cell specific and variable with respect to individual proteins. Increased activation of MAPK by gonadotropins also has been demonstrated in ovarian granulosa cells of animals (31, 32). The recognition that multiple splicing variants of FSH receptor mRNA exist in animals as well as humans has led to studies that have demonstrated that activation of extracellular receptor kinase signaling may occur in addition to the cAMP pathway (33). Thus, whereas both FSH and insulin signaling may converge at the level of MAPK activation, cross-talk between these pathways may exist at other levels to coregulate granulosa cell function. Alternatively, it has been previously demonstrated that G protein-coupled receptors, of which the FSH receptor is one, may undergo desensitization and internalization after G protein-coupled receptor kinase-activated serine and threonine phosphorylation. This is followed by binding to ß-arrestin-1, a regulatory protein that prevents further G protein coupling. Insulin appears to be involved in this process by down-regulating ß-arrestin-1 through ubiquitin-mediated proteasomal degradation (34, 35, 36). This relationship may pertain to the observed increased granulosa cell responsiveness in pioglitazone-treated PCOS women during insulin infusion. Improvement of insulin sensitivity in association with high-dose insulin administration may have reduced ß-arrestin-1 and precluded desensitization, thereby allowing accumulation of the FSH receptor. This notion is supported by studies that have demonstrated increased [125I]FSH binding on granulosa cells of ovaries from women with PCOS compared with that found on normal granulosa cells (37). Currently, studies are underway to examine the cellular interaction between FSH and insulin signaling in granulosa cells of PCOS ovaries.
As to whether pioglitazone may have exerted a direct effect on the ovary to enhance E2 responsiveness in our study is not clear. Recent in vitro studies of porcine granulosa cells have demonstrated that pioglitazone, as well as other thiazolidinediones, inhibited progesterone production by decreasing the expression of 3ß-hydroxysteroid dehydrogenase (DHEA-S) (38). Subsequently, these investigators showed a similar effect of these compounds in human granulosa cells (39). Notably, the inhibitory action of pioglitazone was less than that of the related drug, troglitazone. Comparable findings have been detected in yeast because pioglitazone and rosiglitazone were shown to exhibit a direct, albeit weak, inhibitory effect on DHEA-S activity compared with that found for troglitazone (40). Moreover, the relative effectiveness of these thiazolidinediones was evident in decreasing the enzymatic activity of 17
-hydroxylase and 17,20-lyase. Incubation of porcine granulosa cells with troglitazone failed to significantly alter aromatase activity compared with that of control cells (38). In contrast, inhibition of aromatase activity by troglitazone was demonstrated in luteinized granulosa cells obtained from women undergoing in vitro fertilization (41). An effect of pioglitazone on aromatase expression in nonstimulated human granulosa cells has not been reported. Thus, it remains to be determined whether pioglitazone may exert a direct effect on ovarian steroidogenesis to enhance estrogen production in PCOS.
In contrast to our in vivo findings, earlier studies by other investigators performed on ovaries from 19 women with PCOS demonstrated that E2 release from granulosa cells could be induced by doses of insulin at physiological concentrations well below 1 µg/ml, which indicated that these cells were extremely sensitive to insulin (4). These in vitro results are not necessarily inconsistent with those of the current study, in that granulosa cells were removed from the intact follicular environment. That extracellular events may be responsible for regulating insulin action on granulosa cell function must be considered.
An effect of insulin administration on basal E2 secretion before r-hFSH stimulation was not found in our study. This is in contrast with previous results obtained in PCOS women undergoing a 6-h hyperinsulinemic clamp at a comparable dose of insulin infusion (42). In that study, postinfusion serum E2 levels were significantly increased compared with values measured before the clamp despite the absence of changes in circulating gonadotropin concentrations. In the current study, initiation of the insulin infusion preceded administration of r-hFSH by 2 h, which may have been insufficient time to observe a change in serum E2 as a result of insulin action. However, in preliminary results, we have found that during a 12-h hyperinsulinemic clamp, which achieved a mean steady-state serum insulin level of 235 ± 25 µU/ml, neither serum E1 nor E2 levels were altered (43). Alternatively, the mean serum insulin level achieved during the 6-h clamp was 2-fold greater than that attained in the current study, which suggests that an effect of insulin on ovarian steroidogenesis may be dose-dependent.
None of the seven PCOS women studied had evidence of ovulation as indicated by scant bleeding without premenstrual symptoms as well as concomitant low serum progesterone levels. Previous studies involving larger numbers of women have shown an approximate 30% ovulation rate in PCOS subjects treated with either troglitazone or metformin (5, 7, 10, 11, 14, 15, 16, 17, 18). The failure of ovulation in our subjects may have been due to the comparatively few numbers of women treated, a relatively low dose of pioglitazone (30 mg/d), the presence of significant obesity as reflected in the mean body mass index of 40, or a combination of all. In addition, the mean fasting insulin levels in our subjects was more than 3-fold greater than the control group. In the recent report of the PCOS/Troglitazone Study Group involving 305 subjects, ovulation rates were significantly lower in women with obesity and markedly increased basal insulin levels, which is consistent with our findings (5).
In summary, this study has demonstrated that administration of pioglitazone to women with PCOS is associated with increased granulosa cell responsiveness to FSH stimulation during insulin infusion compared with that observed without pioglitazone therapy. These findings are consistent with the possibility that PCOS granulosa cells may be insulin resistant. Reversal of insulin resistance by pioglitazone was accompanied by a uniformly robust response to r-hFSH, characterized by an E2 increment that was more rapid, of greater magnitude, and of longer duration than that of the response observed without treatment. These findings underscore the synergistic relationship between insulin and FSH relative to E2 release from the granulosa cell in PCOS, which may have clinical implications regarding ovulation induction and the risk of ovarian hyperstimulation.
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Footnotes |
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Abbreviations: CV, Coefficient(s) of variation; DHEA-S, 3ß-hydroxysteroid dehydrogenase; E1, estrone; E2, estradiol; E3, estriol; GCRC, General Clinical Research Center; GIR, glucose infusion rate; P4, progesterone; PCOS, polycystic ovary syndrome; r-hFSH, recombinant human FSH; UCSD, University of California, San Diego.
Received April 28, 2003.
Accepted September 8, 2003.
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activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 335:617–622 activity and serum androgens. J Clin Endocrinol Metab 82:4075–4079s signaling in 3T3–L1 adipocytes. Proc Natl Acad Sci USA 100:161–166This article has been cited by other articles:
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  D. Seto-Young, M. Paliou, J. Schlosser, D. Avtanski, A. Park, P. Patel, K. Holcomb, P. Chang, and L. Poretsky Direct Thiazolidinedione Action in the Human Ovary: Insulin-Independent and Insulin-Sensitizing Effects on Steroidogenesis and Insulin-Like Growth Factor Binding Protein-1 Production J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6099 - 6105. [Abstract] [Full Text] [PDF]
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D. Glintborg, R. K. Stoving, C. Hagen, A. P. Hermann, J. Frystyk, J. D. Veldhuis, A. Flyvbjerg, and M. Andersen Pioglitazone Treatment Increases Spontaneous Growth Hormone (GH) Secretion and Stimulated GH Levels in Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5605 - 5612. [Abstract] [Full Text] [PDF]
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 E. J P van Santbrink, F. P Hohmann, M. J C Eijkemans, J. S E Laven, and B. C J M Fauser Does metformin modify ovarian responsiveness during exogenous FSH ovulation induction in normogonadotrophic anovulation? A placebo-controlled double-blind assessment Eur. J. Endocrinol., April 1, 2005; 152(4): 611 - 617. [Abstract] [Full Text] [PDF]
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 V. L. Nelson-Degrave, J. K. Wickenheisser, K. L. Hendricks, T. Asano, M. Fujishiro, R. S. Legro, S. R. Kimball, J. F. Strauss III, and J. M. McAllister Alterations in Mitogen-Activated Protein Kinase Kinase and Extracellular Regulated Kinase Signaling in Theca Cells Contribute to Excessive Androgen Production in Polycystic Ovary Syndrome Mol. Endocrinol., February 1, 2005; 19(2): 379 - 390. [Abstract] [Full Text] [PDF]
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