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Original Studies |
Departments of Obstetrics and Gynecology and Medicine, University of Alabama (R.A.), Birmingham, Alabama 35249; Department of Medicine, University of Chicago Medical Center (D.E.), Chicago, Illinois 60637; Department of Obstetrics and Gynecology, Pennsylvania State University (R.S.L.), Hershey, Pennsylvania 17033; and Parke-Davis Pharmaceutical Research (R.W.W., R.H., A.G.F., M.O., M.N.G.), Ann Arbor, Michigan 48105
Address all correspondence and requests for reprints to: Mahmoud Ghazzi, M.D., Ph.D., Parke-Davis Pharmaceutical Research, 2800 Plymouth Road, Ann Arbor, Michigan 48105.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Of the 410 patients recruited, 305 (74.4%) met evaluability criteria and were included in the analyses. The patients’ baseline characteristics were similar across all treatment arms. Ovulatory rates were significantly greater for patients receiving TGZ-300 and TGZ-600 than for those receiving PBO (0.42 and 0.58 vs. 0.32; P < 0.05 and 0.0001, respectively). Of PCOS patients treated with TGZ-600, 57% ovulated over 50% of the time compared with 12% of placebo-treated patients. There was a significant decrease in the Ferriman-Gallwey score with TGZ-600 compared with PBO (0.22 ± 0.53 vs. -2.21 ± 0.49; P < 0.05, respectively). Free testosterone decreased and sex hormone-binding globulin increased in a dose-related fashion with troglitazone treatment, and all three troglitazone treatment groups were significantly different from placebo. Nearly all glycemic parameters showed dose-related decreases with troglitazone treatment. The total number and severity of adverse events (including elevations in liver enzymes) and the proportion of patients withdrawn from the study due to the development of adverse effects were similar between treatment groups.
Troglitazone improves the ovulatory dysfunction, hirsutism, hyperandrogenemia, and insulin resistance of PCOS in a dose-related fashion, with a minimum of adverse effects.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Existing therapies for PCOS have focused on suppressing androgen
production or effect or inducing ovulation. More recently, and
consistent with the premise that insulin resistance is an important
etiological cause of PCOS, several studies have demonstrated a
beneficial effect of insulin-lowering agents in this disorder
(11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24). However, reports examining the effect of these
drugs on ovulatory function in PCOS have generally been small (
30
subjects), brief (<3 months), and have not included dosing studies. In
addition, the effects of these drugs on other PCOS-related androgenic
features, such as hirsutism, has yet to be determined.
Troglitazone is an insulin-sensitizing agent of the thiazolidinedione class, with a postinsulin receptor mechanism of action. In preliminary studies troglitazone has demonstrated a dose-related decrease in circulating insulin and androgen levels in obese PCOS patients (12, 14). We hypothesized that the administration of troglitazone would demonstrate a dose-related improvement in ovulatory dysfunction and hirsutism of PCOS. To test our hypothesis we conducted a 44-week multicenter, double blind, placebo-controlled trial of PCOS patients using three different doses of troglitazone.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Of the 782 premenopausal women with suspected PCOS who were
screened for this study, 410 patients qualified and were randomized to
double blind treatment. Of these, 305 (74.4%) patients completed the
study sufficiently to meet evaluability criteria. For the purposes of
this study, PCOS was diagnosed by 1) the presence of chronic ovulatory
dysfunction, defined as intermenstrual intervals of 45 days or more or
a total of eight or fewer menses per yr; 2) hyperandrogenemia, defined
as a serum level of free testosterone (T) greater than the upper normal
limit used in the central laboratory for this study (i.e.
21.8 pmol/L); and 3) the exclusion of other disorders, such as
nonclassic adrenal hyperplasia (25), thyroid dysfunction,
and hyperprolactinemia. These diagnostic (i.e. inclusion)
criteria for PCOS are consistent with the suggestions arising from a
preliminary consensus conference sponsored by the NICHHD, NIH, in April
1990 (1).
Other exclusionary criteria included unresolved medical conditions; hysterectomy and/or oophorectomy, type 1 or type 2 diabetes mellitus, significant cardiovascular disease, active cancer within the past 5 yr, and participation in another investigational study within the past 30 days. The use of medications known or suspected to affect reproductive or metabolic functions within 60 days of study entry was prohibited. This study was approved by, and conducted according to, the guidelines of the institutional review boards of each of the participating centers. All subjects provided written informed consent.
Study protocol
After a 2-week baseline evaluation, eligible patients were randomized in a double blind fashion to one of the following treatment groups: placebo (PBO), or troglitazone [150 mg/day (TGZ-150), 300 mg/day (TGZ-300), or 600 mg/day (TGZ-600)]. Parke-Davis Pharmaceutical Research, Inc. (the sponsor) provided the medication. Patients were asked to follow a weight maintenance diet throughout the study to minimize the effect of weight changes on the disease state.
Patients returned for assessment 4 weeks after the start of the double blind, randomized phase and every 8 weeks thereafter (weeks 4–44). At each visit vital signs and body measures were obtained and recorded, and blood and urine specimens were obtained to monitor safety (see below). Laboratory efficacy parameters were assessed, and an oral glucose tolerance test (OGTT) was performed at weeks 0, 20 and study completion. For the OGTT, blood samples were obtained at -10, 0, 30, 60, 90, and 120 min after the oral ingestion of 75 g glucose.
Patients collected daily morning (first void) urine samples in specially designated containers. The samples were frozen and transported to the study site at the appropriate clinic visit. In addition, patients were instructed to record in a daily diary menstrual bleeding and spotting and urine collection information.
The presence and extent of hirsutism were determined at the randomization visit (week 0), week 20, and at study completion using a modification of the Ferriman-Gallwey (F-G) scoring method (26). Patients in the study were requested not to use electrolysis, waxing, or plucking for removal of unwanted hair, except for treatment of lower legs and forearms.
Safety assessment
Safety evaluation included vital signs, blood tests (liver function tests, chemistry panel, complete blood counts), and urinalysis. Initially these were evaluated at entry into the protocol, after 4 weeks, and every 8 weeks thereafter. However, after approximately half of the patients were recruited, the sponsor issued new safety and prescribing guidelines for the use of troglitazone, and all patients remaining underwent additional study visits to ensure that liver function tests were monitored every 2 weeks during the first 6 months of the double blind phase and monthly thereafter until the end of the trial. The presence of a large ovarian cyst (>30 mm) mandated periodic transvaginal ultrasound evaluations until resolution. In addition, measurements of endometrial thickness were performed by transvaginal ultrasound. If the single wall thickness was more than 14 mm an endometrial biopsy was performed to exclude endometrial hyperplasia or carcinoma, if deemed appropriate by the investigator.
Patients, either during the initial screening or throughout the study, who demonstrated elevations in the hepatic enzymes aspartate aminotransferase (AST) or alanine aminotransferase (ALT) of 1.5 times or more than the upper normal limits were retested within 7 days. If the ALT or AST level rose to greater than 3 times the upper normal limit, the patient was immediately withdrawn from the study and followed periodically until her laboratory values returned either to normal or to prestudy levels.
All nonsterilized patients were asked to use a barrier method of contraception (condom or diaphragm) during intercourse. Those patients conceiving during the study were immediately withdrawn from the study, and periodic follow-up information was obtained.
Laboratory analysis
Blood samples were analyzed for total and free T, androstenedione (A4), SHBG, FSH, LH, PRL, estradiol, TSH, and 17-hydroxyprogesterone (17-HP). The safety profile consisted of blood samples analyzed for electrolytes, glucose, blood urea nitrogen, creatinine, uric acid, total protein, albumin, liver function tests (AST, ALT, lactate dehydrogenase, and total, direct and indirect bilirubin), lipids (total, low density lipoprotein, and high density lipoprotein cholesterol, and triglycerides), complete hematological profile, serum pregnancy test, and urinalysis. Blood samples for efficacy determination were analyzed for total and free T, A4, SHBG, FSH, and LH. Glucose and insulin were measured at all time points during the OGTT.
The specifics of the laboratory methods are detailed as follows. Serum free T was determined using equilibrium dialysis against a buffer containing tritium-labeled T. Total serum T was measured by RIA after extraction with hexane-ethyl acetate and column chromatography. The binding capacity of SHBG was directly measured in serum using a displacement technique that uses ammonium sulfate precipitation of free and protein bound steroid in place of equilibrium dialysis or gel filtration. A4 was measured by a direct RIA. These assays were performed by Endocrine Sciences, Inc. (Calabasas Hills, CA). All other analyses, including chemistry, hematology, lipids, and urinalysis, were performed by Medical Research Laboratories, Inc. (Highland Heights, KY). Glucose levels were measured by the hexokinase procedure 747–200(747–200, Hitachi, Hialeah, FL), hemoglobin A1c (HbA1c) levels by high performance liquid chromatography (Variant, Bio-Rad Laboratories, Inc., Richmond, CA), and insulin levels by RIA. Triglyceride levels were measured using the standard lipase, glycerokinase, glycerol-3-phosphate oxidase, and peroxidase method, and high density lipoprotein cholesterol was determined by the precipitation and enzymatic method of lipoprotein (Hitachi 747). Low density lipoprotein cholesterol levels were calculated using the Friedewald formula. Routine hematology and clinical chemistry analyses were performed by standard methodology using Coulter STKS and Hitachi 747 instrumentation. The level of pregnanediol-3-glucuronide was determined by an enzyme immunoassay competitive assay.
Test (efficacy) parameters
The efficacy of troglitazone at modifying the following parameters was compared between all four study groups.
Ovulation. Ovulatory frequency was assessed for each patient by monitoring the daily urinary levels of the progesterone metabolite pregnanediol-3-glucuronide, as described previously (27). The ovulation rate was calculated for each patient as the number of ovulatory events observed divided by the number of events that could have occurred during the time period studied (i.e. number of actual ovulatory events/number of potential ovulatory events). The ovulation rates were averaged across patients within each treatment group.
Hirsutism. The change in hirsutism score was assessed only in those patients exhibiting an F-G score of 6 or more at baseline.
Androgen and gonadotropin levels. The mean changes from baseline in serum total and free T, A4, SHBG, LH, FSH, and LH/FSH ratio were compared among groups.
Markers of glucose and insulin homeostasis. The mean change from baseline in the fasting levels of glucose, insulin and HbA1c, and the glucose and insulin areas under the curve (AUC) during the OGTT were evaluated.
Statistical analysis
Primary treatment comparisons were those between each
troglitazone treatment and placebo. Tests were two-sided
and conducted at 
= 0.05. In general, the methods used for the
analyses were analysis of covariance with treatment and center in the
model and baseline as the covariate, for all parameters except
incidence of ovulation. For ovulation, ANOVA with treatment and center
in the model was performed. All P values reported from the
analyses of covariance and ANOVAs are from stepdown trend tests via
contrast statements. The P values reported for comparison of
ovulation responder rates are from the Cochran-Mantel-Haenszel test of
general association. The comparison of time to ovulation was performed
using the log-rank test. Unless otherwise indicated values represent
the mean ± SE.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As noted, 305 (74%) patients met the evaluability criteria and
were included in the analyses. The clinical characteristics of these
patients are depicted in Table 1
, and
their hormonal and metabolic profiles are shown in Table 2. Overall, there were no significant
differences in baseline features between treatment groups. The
percentage of patients not completing the entire study and the reasons
for termination were similar among all treatment groups
(i.e. those completing 40 weeks of study were 40.8%,
42.3%, 34.3%, and 39.6% for the PBO, TGZ-150, TGZ-300, and TGZ-600
treatment groups, respectively). The principal reasons for patients not
completing the study were early termination of the study by the sponsor
(range, 11.5–19.8%) and lack of compliance (range,
5.0–13.6%). The percentage of patients withdrawing from the study due
to adverse events ranged from 4–7%; this was not different between
treatment arms.
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As the onset of metabolic effects of troglitazone is gradual, we initially did not consider the first 12 weeks of therapy when calculating ovulatory rates. Hence, when analyzing ovulatory function we considered all evaluable patients, i.e. those completing at least 84 days (12 weeks) in the study. Approximately 85% of patients remained in the study long enough to be eligible for analysis of ovulation and menses data.
The ovulatory event rates observed from week 12 onward was
significantly greater for patients receiving TGZ-300 and TGZ-600 than
for those given PBO (Fig. 1). The
dose-related positive effect of troglitazone on ovulation
remained even when ovulatory events observed within the first 12 weeks
of the study were included in the analysis (0.32 ± 0.04,
0.39 ± 0.04, 0.42 ± 0.04, and 0.58 ± 0.04 for PBO,
TGZ-150, TGZ-300, and TGZ-600, respectively; P < 0.05
and P < 0.0001 for TGZ-300 and TGZ-600 vs.
PBO, respectively). In all, 57% of PCOS patients treated with TGZ-600
ovulated over 50% of the time, respectively, compared with 12% of the
PBO-treated patients. Finally, the time to first ovulation was
significantly less for PCOS patients treated with TGZ-300 or TGZ-600
compared with women treated with either PBO or TGZ-150 (Fig. 2). The improvement in menstrual cycle
regularity mirrored that of ovulation (data not shown).
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In-study pregnancies
Fourteen patients were withdrawn from the study due to pregnancy: 2 in the PBO-treated and 12 in the troglitazone-treated arms. Two additional patients were found to be pregnant at their last visit: 1 a PBO-treated patient and the other a patient who was taking TGZ-300. Thus, there were a total of 3 pregnancies on PBO and 13 on troglitazone during the study. Overall, the number of unexpected pregnancies among patients treated with either TGZ-300 or TGZ-600 was greater than that among women treated with either TGZ-150 or PBO (5.9% vs. 1.4%, respectively; P < 0.02).
Effect of troglitazone on hirsutism in PCOS
Approximately 50% of randomized patients had a baseline F-G score
of 6 or more and at least one follow-up observation and were thus
evaluable for analysis of the hirsutism scores. At baseline, there was
no difference in the number of hirsute patients (n = 57, 56, 55,
or 62) or in the mean basal F-G scores (14.23 ± 0.94, 14.77
± 0.84, 14.27 ± 0.95, and 14.42 ± 0.84) among the PBO,
TGZ-150, TGZ-300, or TGZ-600 treatment groups, respectively. Overall,
there appeared to be a dose-related decrease in F-G scores with
troglitazone treatment (0.22 ± 0.53, -0.51 ±
0.53, -0.80 ± 0.53, and -2.21 ± 0.49 for PBO, or TGZ-150,
TGZ-300, or TGZ-600, respectively), a difference that became
significant from PBO at the TGZ-600 dose (P < 0.0003;
Fig. 3). The effect of therapy on excess
hair growth was not evaluated in patients whose initial F-G score was
less than 6.
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For these analyses all patients who had a baseline and at least
one follow-up observation were considered evaluable. Free T decreased
in a dose-related fashion with troglitazone treatment, and
all three troglitazone treatment groups were significantly
different from PBO (Table 3). Consistent
with this finding, SHBG levels increased in a dose-related fashion, and
the changes observed in the TGZ-300 and TGZ-600 treatment groups were
significantly different from PBO. Although total T and
A4 levels appeared to decrease with therapy, this
difference did not reach significance. Finally, neither basal
gonadotropin levels nor the LH/FSH ratio changed with therapy.
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For this analysis all patients who had a baseline and at least one
follow-up observation (i.e. intent to treat) were
considered. Because the first postrandomization efficacy laboratory
measurements were not taken until week 20, about 70% of the randomized
patients are included in these analyses. Nearly all glycemic parameters
showed dose-related decreases with troglitazone treatment
(Table 3
). TGZ-600 reduced circulating insulin by 53%, fasting glucose
by 5.7%, HbA1c by 2.7%, the AUC for glucose by
12.2%, and the AUC for insulin by 44.9%. Patients receiving
troglitazone had small increases in body weight (-0.77,
+0.51, +0.78, and +1.01 kg for PBO, TGZ-150, TGZ-300, and TGZ-600,
respectively.) Only TGZ-300 and TGZ-600 were statistically significant
(P = 0.03 and 0.02, respectively).
Adverse events
Overall, there was no significant difference between treatment groups in the proportion of all or only associated adverse events, and none of the patients died during the study. The proportion of patients withdrawn from the study due to the development of potentially associated adverse effects was not different among treatment groups (1.9%, 2.9%, 2.9%, and 5.9% for PBO, TGZ-150, TGZ-300, and TGZ-600, respectively). There was no difference in the proportion of patients treated with PBO, or TGZ-150, TGZ-300, and TGZ-600 who experienced either a mild (1.5–3 times the upper normal limit) or a severe (>3 times the upper normal limit) increase in ALT (5.2%, 7.1%, 6.1%, and 3.0% and 2.0%, 1.0%, 4.0%, and 3.0%, respectively) or AST (5.2%, 6.2%, 5.1%, and 4.1% and 2.1%, 0%, 2.0%, and 1.0%, respectively). Across treatment groups (PBO, TGZ-150, TGZ-300, and TGZ-600) 1.0%, 1.9%, 2.9%, and 2.0% of patients, respectively, were withdrawn from the study due to the development of an abnormal liver function test. Of note, at screening 46 (5.8%) patients seen had elevations in serum ALT (n = 43) and/or AST (n = 23). Two (0.2% of the total screened) of these patients had an ALT value greater than 3 times the upper normal limit.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The present study clearly demonstrates the therapeutic effect of troglitazone on the ovulatory dysfunction of PCOS. About 60% of cycles were ovulatory among patients receiving TGZ-600, and 57% of these patients ovulated at least 50% of the time. This ovulatory rate is similar to that reported by other investigators for ovulation induction with clomiphene citrate in PCOS (28, 29, 30). Although TGZ-300 was moderately successful in stimulating ovulation, TGZ-150 was ineffectual in improving ovulatory function. The importance of including a placebo-treated control group is highlighted by the fact that 32% of untreated cycles in our PCOS patients were apparently ovulatory, consistent with the findings of other investigators (19, 31). Overall 75% of our placebo-treated patients ovulated in less than 50% of the cycles.
Few other investigators have examined the effect of insulin-lowering or insulin-sensitizing agents administered alone on ovulatory function. Ovulation rates of 28% and 43% were reported when troglitazone (400 mg/day) was administered for 4 and 12 weeks, respectively, in uncontrolled studies of small numbers (<20) of subjects (21, 22). Nestler and colleagues treated 61 obese PCOS patients with either metformin (1500 mg/day) or placebo for 35 days (17). These investigators noted that 34% of patients treated with metformin alone ovulated compared with 4% of controls, similar to the ovulatory response noted by other investigators in a smaller uncontrolled study (18). Nestler and colleagues also treated 44 women with PCOS with either placebo or the insulin sensitizer D-chiro-inositol (1200 mg/day) for 6–8 weeks and observed that 86% of treated patients ovulated (19). However, these latter studies primarily addressed the ovulatory response during 1 treatment cycle and not the restoration of ovulatory function over time.
As is observed with the use of clomiphene (28, 32, 33, 34, 35, 36), patients who were more affected (i.e. greater degree of obesity or higher free T or basal insulin levels) were also less likely to ovulate in response to troglitazone. Furthermore, there was no difference in the insulin response to an OGTT between patients with high and low ovulatory rates after TGZ-600 treatment, suggesting that this drug was effective in inducing ovulation in PCOS patients even in the absence of marked hyperinsulinemia. Similarly, Nestler and Jakubowicz reported that lean women with PCOS and with a relatively normal insulin response to an oral glucose challenge experienced a reduction in hyperandrogenism with the use of metformin (1500 mg/day) (37). Hence, troglitazone appears to be effective for improving ovulatory function in patients with PCOS regardless of the degree of clinically evident hyperinsulinemia. However, and as with other therapeutic agents, the degree of therapeutic response tends to be less the more severe the disorder.
Despite extensive contraceptive counseling, 16 patients became pregnant during the study: 3 in the placebo-treated and 13 in the troglitazone-treated arms. Although not an objective of the study, the number of pregnancies occurring was 4-fold higher among those patients treated with either TGZ-300 or TGZ-600 than in those given PBO or TGZ-150. There is no reason to believe that the proportion of patients not using adequate contraception would have been varied among the treatment groups. A number of other pregnancies have been reported with the use of troglitazone in hyperandrogenic patients (22, 38), although outcome data are not yet available. Troglitazone is categorized as a pregnancy class B drug, with no ill effects demonstrated in animal models. Nonetheless, additional studies documenting the impact of troglitazone on the fetus and pregnancy outcome are required.
Consistent with the improvement in androgen levels, we observed a dose-related decrease in hirsutism with troglitazone treatment. When treated with TGZ-600, hirsute PCOS patients experienced a 15% decrease in F-G score by 20 weeks of therapy. As most previous studies using insulin sensitizers in PCOS have been relatively short, it is not surprising that the impact of this therapy on hirsutism has not been systematically studied. In 2 studies in which this clinical feature was assessed, no difference in F-G score could be documented after the administration of metformin (1500 mg/day) for at least 4 months (15, 24). However, it is probable that these studies were of insufficient power to detect a difference, because they included less than 25 patients each, and not all were hirsute.
Various investigators have observed improvements in hyperinsulinemia and hyperandrogenemia when treating small numbers of PCOS patients with up to 400 mg/day troglitazone (12, 14, 21, 39). In the present study we observed a clear dose response, with TGZ-600 providing the greatest degree of improvement in insulin and androgen levels. TGZ-600 reduced circulating insulin by 53% and the insulin response to an oral glucose challenge by 45%. Similarly, this dose of drug reduced mean circulating free T levels by 38%, primarily due to a 71% rise in mean SHBG levels. Nonetheless, it is interesting to note that the mean free T levels after TGZ therapy remained above the upper normal limit of our laboratory (21.8 pmol/L).
We observed a mean increase in body weight of about 1 kg for the highest dose of TGZ used that represents only a 1% change in body weight for this population. Hence, the overall improvement in PCOS symptoms cannot be explained by an indirect action of the drug on body weight.
Rare, but serious, acute hepatic failure associated with troglitazone use in patients with type 2 diabetes has been reported (40, 41, 42, 43). The majority appears to be related to idiosyncratic drug-related hepatocellular damage, and there does not appear to be any association with gender, age, daily dose, or the use of concomitant medication (42). Although the overall frequency of this adverse event is rare, strict prescribing guidelines and frequent monitoring of liver function tests have been instituted for type 2 diabetes. Recently, the manufacturer has withdrawn the marketing of troglitazone for type 2 diabetes. In our population of over 300 reproductive-aged PCOS patients the administration of troglitazone, regardless of dose, was not associated with an increased frequency (±2%) or withdrawals (±2%) due to liver function abnormalities.
Treatment of PCOS patients with insulin-sensitizing agents has various potential advantages over traditional therapies, including 1) correcting both the metabolic and the endocrinological aberrations of the disorder; 2) permitting the resumption of normal endogenous ovulatory function, with little or no risk of ovarian hyperstimulation and multiple gestation; and 3) possibly decreasing their long-term risk of type 2 diabetes mellitus (44, 45, 46). We conclude that troglitazone, primarily in a dose of 600 mg/day, improves the ovulatory dysfunction, hirsutism, hyperandrogenemia, and hyperinsulinemia of patients with PCOS, with a minimum of adverse effects.
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Acknowledgments |
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Footnotes |
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2 In addition to the authors, the following investigators
participated in the PCOS/Troglitazone Study Group: Stephen
Aronoff, Dallas, TX; Richard Bernstein, Greenbrae, CA; Donald Bodenner,
Rochester, NY; Susan Braithwaite, Chicago, IL; Joshua Cohen,
Washington, D.C.; David DePaolo, Boulder, CO; Daniel Einhorn, San
Diego, CA; Jennifer Hone, Arvada, CO; Anne Kenshole, Toronto, Canada;
Charles Kilo, St. Louis, MO; Siri Linda Kjos, Los Angeles, CA; Mary
Korytkowski, Pittsburgh, PA; Diane Koster, Albuquerque, NM; Rebecca
Lau, Indianapolis, IN; Rogerio Lobo, New York, NY; Jean Lucas, Atlanta,
GA; Kathryn Martin, Boston, MA; William Meyer, Chapel Hill, NC; Sumer
Pek, Ann Arbor, MI; Samantha Pfeifer, Philadelphia, PA; Robert Rebar,
Cincinnati, OH; Geoffrey Redmond, Cleveland, OH; Roger Rittmaster,
Halifax, Canada; Peter Ross, Fairfax, VA; Sherwyn Schwartz, San
Antonio, TX; Robert Wild, Oklahoma City, OK; and Samuel S. C. Yen,
La Jolla, CA.
Received August 31, 2000.
Revised December 5, 2000.
Accepted January 4, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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activity and serum androgens. J Clin
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
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|
|
|
|
 |
|
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 |
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 R. PASQUALI and A. GAMBINERI Polycystic Ovary Syndrome: A Multifaceted Disease from Adolescence to Adult Age Ann. N.Y. Acad. Sci., December 1, 2006; 1092(1): 158 - 174. [Abstract] [Full Text] [PDF]
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A. Gambineri, L. Patton, A. Vaccina, M. Cacciari, A. M. Morselli-Labate, C. Cavazza, U. Pagotto, and R. Pasquali Treatment with Flutamide, Metformin, and Their Combination Added to a Hypocaloric Diet in Overweight-Obese Women with Polycystic Ovary Syndrome: A Randomized, 12-Month, Placebo-Controlled Study J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3970 - 3980. [Abstract] [Full Text] [PDF]
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A. V. Schwartz, D. E. Sellmeyer, E. Vittinghoff, L. Palermo, B. Lecka-Czernik, K. R. Feingold, E. S. Strotmeyer, H. E. Resnick, L. Carbone, B. A. Beamer, et al. Thiazolidinedione Use and Bone Loss in Older Diabetic Adults J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3349 - 3354. [Abstract] [Full Text] [PDF]
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 S.K. Blank, C.R. McCartney, and J.C. Marshall The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome Hum. Reprod. Update, July 1, 2006; 12(4): 351 - 361. [Abstract] [Full Text] [PDF]
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R. Pasquali and A. Gambineri Insulin-sensitizing agents in polycystic ovary syndrome. Eur. J. Endocrinol., June 1, 2006; 154(6): 763 - 775. [Abstract] [Full Text] [PDF]
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K. Rautio, J.S. Tapanainen, A. Ruokonen, and L.C. Morin-Papunen Endocrine and metabolic effects of rosiglitazone in overweight women with PCOS: a randomized placebo-controlled study Hum. Reprod., June 1, 2006; 21(6): 1400 - 1407. |
