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Cited by 461Ovarian function and disordersDiabetes, Cardiovascular Risks, and LipoproteinsGenetic and Kidney Cyst Diseases

Troglitazone Improves Defects in Insulin Action, Insulin Secretion, Ovarian Steroidogenesis, and Fibrinolysis in Women with Polycystic Ovary Syndrome1

Ehrmann, David A., Schneider, David J., Sobel, Burton E., Cavaghan, Melissa K., Imperial, Jacqueline, Rosenfield, Robert L., Polonsky, Kenneth S.·1997·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jcem.82.7.4069
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Abstract

Women with polycystic ovary syndrome (PCOS) are characterized by defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis. We administered the insulin-sensitizing agent troglitazone to 13 obese women with PCOS and impaired glucose tolerance to determine whether attenuation of hyperinsulinemia ameliorates these defects. All subjects had oligomenorrhea, hirsutism, polycystic ovaries, and hyperandrogenemia. Before and after treatment with troglitazone (400 mg daily for 12 weeks), all had 1) a GnRH agonist (leuprolide) test, 2) a 75-g oral glucose tolerance test, 3) a frequently sampled iv glucose tolerance test to determine the insulin sensitivity index and the acute insulin response to glucose, 4) an oscillatory glucose infusion to assess the ability of the beta-cell to entrain to glucose as quantitated by the normalized spectral power for the insulin secretion rate, and 5) measures of fibrinolytic capacity [plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator]. There was no change in body mass index (39.9 +/- 1.4 vs. 40.2 +/- 1.4 kg/m2) or body fat distribution after treatment. Both the fasting (91 +/- 3 vs. 103 +/- 3 mg/dL; P < 0.001) and 2 h (146 +/- 8 vs. 171 +/- 6 mg/dL; P < 0.02) plasma glucose concentrations during the oral glucose tolerance test declined significantly. There was a concordant reduction in glycosylated hemoglobin to 5.7 +/- 0.1 from a pretreatment level of 6.1 +/- 0.1% (P < 0.03). Insulin sensitivity increased from 0.58 +/- 0.14 to 0.95 +/- 0.26 10(-5) min-1/pmol.L (P < 0.01) after treatment as did the disposition index (745 +/- 135 vs. 381 +/- 96; P < 0.05). The ability of the beta-cell to appropriately detect and respond to an oscillatory glucose infusion improved significantly after troglitazone treatment; the normalized spectral power for the insulin secretion rate increased to 5.9 +/- 1.1 from 4.3 +/- 0.8 (P < 0.05). Basal levels of total testosterone (109.3 +/- 15.2 vs. 79.4 +/- 9.8 ng/dL; P < 0.05) and free testosterone (33.3 +/- 4.0 vs. 21.2 +/- 2.6 pg/mL; P < 0.01) declined significantly after troglitazone treatment. Leuprolide-stimulated levels of 17-hydroxyprogesterone, androstenedione, and total testosterone were significantly lower posttreatment compared to pretreatment. The reduction in androgen levels occurred independently of any changes in gonadotropin levels. A decreased functional activity of PAI-1 in blood (from 12.7 +/- 2.8 to 6.3 +/- 1.4 AU/mL P < 0.05) was associated with a decreased concentration of PAI-1 protein (from 64.9 +/- 9.1 to 44.8 +/- 6.1 ng/mL; P < 0.05). No change in the functional activity of tissue plasminogen activator (from 5.3 +/- 0.4 to 5.1 +/- 0.5 IU/mL) was observed despite a decrease in its concentration (from 9.6 +/- 0.9 to 8.2 +/- 0.7 ng/mL; P < 0.05). The marked reduction in PAI-1 could be expected to improve the fibrinolytic response to thrombosis in these subjects. We conclude that administration of troglitazone to women with PCOS and impaired glucose tolerance ameliorates the metabolic and hormonal derangements characteristic of the syndrome. Troglitazone holds potential as a useful primary or adjunctive treatment for women with PCOS.

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Authors
Ehrmann, D. A., Schneider, D. J., Sobel, B. E., Cavaghan, M. K., Imperial, J., Rosenfield, R. L., & Polonsky, K. S.
Affiliations
  • University of Chicago (US)
  • University of Vermont (US)
Corresponding author
Ehrmann, David A.
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
1997-07
Volume
82
Issue
7
Pages
2108-2116
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jcem.82.7.4069
OpenAlex
W2073637312
Cited by
461
References
7
Citations by year
2025: 2 · 2024: 3 · 2022: 6 · 2021: 2 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 7 · 2015: 2 · 2014: 5 · 2013: 10 · 2012: 11
FWCI
36.83
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5k08dk002315-02)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-31842, DK 20595, DK-02315)
  • NIH Clinical Center
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
Keywords
troglitazone, polycystic ovary syndrome, insulin resistance, insulin secretion, beta-cell function, ovarian steroidogenesis, fibrinolysis, plasminogen activator inhibitor-1, tissue plasminogen activator, hyperinsulinemia, impaired glucose tolerance, insulin sensitizers, hyperandrogenemia, obese women, leuprolide
MeSH terms
Troglitazone, Adult, Androgens, Chromans, Female, Fibrinolysis, Glucose, Glucose Tolerance Test, Gonadotropins, Humans, Insulin, Insulin Resistance, Polycystic Ovary Syndrome, Thiazoles, Leuprolide, Plasminogen Activator Inhibitor 1, Thiazolidinediones

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