The effects of the aromatase inhibitor Δ1-testolactone on gonadotropin release and steroid metabolism in polycystic ovarian disease

Andrea Dunaif*, Christopher Longcope, Jacob Canick, Thomas Badger, William F. Crowley

*Corresponding author for this work

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

This study was designed to examine the importance of aromatization in the gonadotropin secretory dynamics of polycystic ovarian disease (PCOt)) by using the aromatase inhibitor Δ1 testolactone (TL) as a probe and to determine the effects of TL on steroid metabolism in vivo and in vitro. The pulsatile patterns of gonadotropin secretion and peripheral steroid levels were studied in eight women with PCOD before and during TL administration. There was a significant fall in peripheral estrone (E1) levels, a rise in peripheral androstenedione levels, and an increase in the androstenedione/E1 ratio during TL administration in these women. Isotopic determinations of androgen and estrogen production and metabolism before and during TL administration in two women confirmed a 90-95% decrease in the overall rate of aromatization. One patient also had an increase in the production and clearance rates of estradiol and Ei during TL administration, suggesting resistance to TL of the ovarian aromatase enzyme system. There were significant increases in both mean LH pulse amplitude [1.2 ± 0.3 (SE) mlU/ ml LER-907 before vs. 1.7 ± 0.3 mlU/ml LER-907 during TL, P < 0.05, paired t test] and frequency per 6 h (median: 3 before vs. 4 during TL, P < 0.05, Wilcoxon signed rank test). Mean levels of LH and FSH did not, however, change significantly during TL administration. TL maximally inhibited neonatal rat hypothalamic aromatase in vitro at concentrations of 200 μM, a level theoretically obtainable during pharmacological therapy. These data suggest that: 1) in humans TL is a potent inhibitor of peripheral but not ovarian aromatase, and of hypothalamic aromatase in rats; 2) TL administration increases LH pulse amplitude and frequency in PCOD,. either directly via hypothalamic aromatase inhibition, or indirectly by alterations in gonadal steroid metabolism; and 3) because of the multiple potential actions of TL, its usefulness as a probe in studies of gonadotropin secretion in PCOD is limited.

Original languageEnglish (US)
Pages (from-to)773-780
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume60
Issue number4
DOIs
StatePublished - Apr 1985

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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