A role for the androgen receptor in the endometrial antiproliferative effects of progesterone antagonists.
In women and nonhuman primates, treatment with progesterone antagonists suppresses estrogen-dependent mitotic activity in the endometrial glands. This antiproliferative effect is paradoxical, because progesterone antagonists do not bind to the estrogen receptor (ER). While this phenomenon has been termed a "functional noncompetitive antiestrogenic effect," it does not occur in all species or in all regions of the primate reproductive tract, so is best referred to as an "endometrial antiproliferative effect." Recent studies of ours in both women and macaques revealed that the endometrial androgen receptor (AR) was increased by progesterone antagonist treatment. Because androgens are known to suppress estrogen-dependent endometrial proliferation, we hypothesized that the AR was involved in the antiproliferative effects induced by progesterone antagonists. In a test of this hypothesis, we administered the antiandrogen, flutamide, along with progesterone antagonists to ovariectomized, estrogen-treated macaques. Flutamide counteracted the suppressive effects of the progesterone antagonists on endometrial wet weight, thickness, stromal compaction, and mitotic index. Hyaline degeneration of the spiral arteries was also blocked by flutamide. These data implicate the AR as a functional component of the mechanism through which progesterone antagonists induce endometrial antiproliferative effects in the presence of estrogens.
Brenner
Robert M
RM
Oregon National Primate Research Center, 505 N.W. 185th Avenue, Beaverton, OR 97006, USA. brennerr@ohsu.edu
Slayden
Ov D
OD
Nayak
Nihar R
NR
Baird
David T
DT
Critchley
Hilary O D
HO
D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D002455:Cell Division; D004717:Endometrium / Q000378:metabolism*; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D006801:Humans; D017403:In Situ Hybridization; D008251:Macaca; D011374:Progesterone / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism / Q000502:physiology*
D000726:Androgen Antagonists; D012333:RNA, Messenger; D011944:Receptors, Androgen; D011374:Progesterone; D005485:Flutamide