Mechanisms subserving the bipotential actions of estrogen on ovarian cells: Studies with a selective anti-estrogen, LY156758, and the sparingly metabolizable estrogen agonist, moxestrol

Johannes D Veldhuis, Paula Azimi, Diana Juchter, James Garmey

Research output: Contribution to journalArticle

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Abstract

Estrogen exerts biphasic effects on progesterone biosynthesis by swine granulosa cells, such that initial transient inhibition is followed by delayed but sustained stimulation. We have tested the functional role of the estradiol receptor in these biphasic responses by utilizing the highly selective estrogen-receptor antagonist, LY156758, and the synthetic estrogen agonist, moxestrol. The acute inhibitory action of estradiol was mimicked in a dose-dependent action by moxestrol (half-maximally inhibitory dose: 54.3 ± 25 ng/ml), but was not antagonized by LY156758. Rather, the antiestrogen alone significantly suppressed basal progesterone synthesis, and accentuated the suppressive effect of submaximally inhibitory doses of estradiol. Inhibition was accompanied by increased pregnenolone accumulation, with a consequently augmented ratio of pregnenolone to progesterone. Moreover, in cell-free sonieates of granulosa cells, LY156758 directly inhibited 3β-hydroxysteroid dehydrogenase activity in a dose-dependent fashion, with half-maximal inhibition expressed at a drug concentration of 2.44 ± 0.31 μg/ml compared with 85 ± 19 ng/ml for estradiol. In addition, the combination of LY156758 and submaximally inhibitory doses of estradiol resulted in further suppression of 3β-hydroxysteroid dehydrogenase activity. The sustained stimulatory phase of estrogen action was also mimicked by moxestrol in a dose-dependent fashion. However, in contrast to its acute inhibitory effects, longer-term treatment with LY156758 slightly enhanced basal progesterone accumulation, and effectively antagonized estradiol's stimulatory actions. In summary, our results with moxestrol demonstrate that both the inhibitory and the stimulatory actions of estradiol are effectively mimicked by this synthetic estrogen agonist. Results with the selective anti-estrogen LY156758 indicate a small degree of intrinsic estrogen agonist activity (approx 4% that of estradiol), which is reflected by its acute and direct inhibition of 3β-hydroxysteroid dehydrogenase activity. However, under longer-term conditions in which estradiol's stimulation of progesterone production is expressed, LY156758 significantly antagonizes estradiol's trophic actions. Accordingly, we suggest that the acute suppressive effects of estradiol on progesterone production are mediated predominantly by direct inhibition of 3β-hydroxysteroid dehydrogenase activity, while delayed stimulatory effects are transduced via estrogen-receptor mechanisms. We conclude that the disparate effects of estrogen on granulosa-cell progesterone biosynthesis are dissociable under in vitro conditions and expressed via distinct and separable mechanisms.

Original languageEnglish (US)
Pages (from-to)977-982
Number of pages6
JournalJournal of Steroid Biochemistry
Volume24
Issue number5
DOIs
StatePublished - 1986
Externally publishedYes

Fingerprint

moxestrol
Estradiol
Estrogens
Progesterone
3-Hydroxysteroid Dehydrogenases
Granulosa Cells
Estradiol Congeners
Pregnenolone
Biosynthesis
Raloxifene Hydrochloride
Estradiol Receptors
Estrogen Receptor Modulators

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Cite this

Mechanisms subserving the bipotential actions of estrogen on ovarian cells : Studies with a selective anti-estrogen, LY156758, and the sparingly metabolizable estrogen agonist, moxestrol. / Veldhuis, Johannes D; Azimi, Paula; Juchter, Diana; Garmey, James.

In: Journal of Steroid Biochemistry, Vol. 24, No. 5, 1986, p. 977-982.

Research output: Contribution to journalArticle

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title = "Mechanisms subserving the bipotential actions of estrogen on ovarian cells: Studies with a selective anti-estrogen, LY156758, and the sparingly metabolizable estrogen agonist, moxestrol",
abstract = "Estrogen exerts biphasic effects on progesterone biosynthesis by swine granulosa cells, such that initial transient inhibition is followed by delayed but sustained stimulation. We have tested the functional role of the estradiol receptor in these biphasic responses by utilizing the highly selective estrogen-receptor antagonist, LY156758, and the synthetic estrogen agonist, moxestrol. The acute inhibitory action of estradiol was mimicked in a dose-dependent action by moxestrol (half-maximally inhibitory dose: 54.3 ± 25 ng/ml), but was not antagonized by LY156758. Rather, the antiestrogen alone significantly suppressed basal progesterone synthesis, and accentuated the suppressive effect of submaximally inhibitory doses of estradiol. Inhibition was accompanied by increased pregnenolone accumulation, with a consequently augmented ratio of pregnenolone to progesterone. Moreover, in cell-free sonieates of granulosa cells, LY156758 directly inhibited 3β-hydroxysteroid dehydrogenase activity in a dose-dependent fashion, with half-maximal inhibition expressed at a drug concentration of 2.44 ± 0.31 μg/ml compared with 85 ± 19 ng/ml for estradiol. In addition, the combination of LY156758 and submaximally inhibitory doses of estradiol resulted in further suppression of 3β-hydroxysteroid dehydrogenase activity. The sustained stimulatory phase of estrogen action was also mimicked by moxestrol in a dose-dependent fashion. However, in contrast to its acute inhibitory effects, longer-term treatment with LY156758 slightly enhanced basal progesterone accumulation, and effectively antagonized estradiol's stimulatory actions. In summary, our results with moxestrol demonstrate that both the inhibitory and the stimulatory actions of estradiol are effectively mimicked by this synthetic estrogen agonist. Results with the selective anti-estrogen LY156758 indicate a small degree of intrinsic estrogen agonist activity (approx 4{\%} that of estradiol), which is reflected by its acute and direct inhibition of 3β-hydroxysteroid dehydrogenase activity. However, under longer-term conditions in which estradiol's stimulation of progesterone production is expressed, LY156758 significantly antagonizes estradiol's trophic actions. Accordingly, we suggest that the acute suppressive effects of estradiol on progesterone production are mediated predominantly by direct inhibition of 3β-hydroxysteroid dehydrogenase activity, while delayed stimulatory effects are transduced via estrogen-receptor mechanisms. We conclude that the disparate effects of estrogen on granulosa-cell progesterone biosynthesis are dissociable under in vitro conditions and expressed via distinct and separable mechanisms.",
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T1 - Mechanisms subserving the bipotential actions of estrogen on ovarian cells

T2 - Studies with a selective anti-estrogen, LY156758, and the sparingly metabolizable estrogen agonist, moxestrol

AU - Veldhuis, Johannes D

AU - Azimi, Paula

AU - Juchter, Diana

AU - Garmey, James

PY - 1986

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N2 - Estrogen exerts biphasic effects on progesterone biosynthesis by swine granulosa cells, such that initial transient inhibition is followed by delayed but sustained stimulation. We have tested the functional role of the estradiol receptor in these biphasic responses by utilizing the highly selective estrogen-receptor antagonist, LY156758, and the synthetic estrogen agonist, moxestrol. The acute inhibitory action of estradiol was mimicked in a dose-dependent action by moxestrol (half-maximally inhibitory dose: 54.3 ± 25 ng/ml), but was not antagonized by LY156758. Rather, the antiestrogen alone significantly suppressed basal progesterone synthesis, and accentuated the suppressive effect of submaximally inhibitory doses of estradiol. Inhibition was accompanied by increased pregnenolone accumulation, with a consequently augmented ratio of pregnenolone to progesterone. Moreover, in cell-free sonieates of granulosa cells, LY156758 directly inhibited 3β-hydroxysteroid dehydrogenase activity in a dose-dependent fashion, with half-maximal inhibition expressed at a drug concentration of 2.44 ± 0.31 μg/ml compared with 85 ± 19 ng/ml for estradiol. In addition, the combination of LY156758 and submaximally inhibitory doses of estradiol resulted in further suppression of 3β-hydroxysteroid dehydrogenase activity. The sustained stimulatory phase of estrogen action was also mimicked by moxestrol in a dose-dependent fashion. However, in contrast to its acute inhibitory effects, longer-term treatment with LY156758 slightly enhanced basal progesterone accumulation, and effectively antagonized estradiol's stimulatory actions. In summary, our results with moxestrol demonstrate that both the inhibitory and the stimulatory actions of estradiol are effectively mimicked by this synthetic estrogen agonist. Results with the selective anti-estrogen LY156758 indicate a small degree of intrinsic estrogen agonist activity (approx 4% that of estradiol), which is reflected by its acute and direct inhibition of 3β-hydroxysteroid dehydrogenase activity. However, under longer-term conditions in which estradiol's stimulation of progesterone production is expressed, LY156758 significantly antagonizes estradiol's trophic actions. Accordingly, we suggest that the acute suppressive effects of estradiol on progesterone production are mediated predominantly by direct inhibition of 3β-hydroxysteroid dehydrogenase activity, while delayed stimulatory effects are transduced via estrogen-receptor mechanisms. We conclude that the disparate effects of estrogen on granulosa-cell progesterone biosynthesis are dissociable under in vitro conditions and expressed via distinct and separable mechanisms.

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