Enhancement of estradiol potency by the 17 beta-hydroxysteroid dehydrogenase inhibitor, 16-methylene E2 in vivo.
The ability of 16-methylene E2, a 17 beta-hydroxysteroid dehydrogenase inhibitor, to enhance estradiol 17 beta (E2) potency was assayed by 24-hr weight gain in the immature rat uterus. Initial studies demonstrated that 16-methylene E2 (1-100 micrograms s.c.) did not produce significant uterine weight gain 24 hr after administration, whereas E2 (0.1-10 micrograms s.c.) produced a significant uterine weight gain under the same experimental conditions. A subthreshold dose of E2 (0.01 microgram s.c.) when administered in combination with 100 micrograms (s.c.) of 16-methylene E2 produced a significant uterine weight gain. When rats were predosed with 16-methylene E2 at 72, 48, 24, 6 or 0 hr before the administration of 0.01 microgram of E2, the magnitude of the 24-hr uterine weight gain increased and attained maximal values for the 6-hr pretreatment time point. A subsequent dose-response study of 16-methylene E2 (1-100 micrograms s.c.) administered 6 hr before 0.01 microgram of E2 revealed that the 10, 50 and 100 microgram 16-methylene E2 dose significantly increased uterine weight gain in a dose-dependent manner. These results indicate that 16-methylene E2 is not a direct acting estrogen but acts synergistically with E2 to produce an enhanced uterine response. In a separate set of monkey experiments: 1) A trace dose of [3H]E2 was perfused through the in situ, term rhesus monkey placenta via the umbilical arteries and samples were collected from the umbilical vein of this open system.(ABSTRACT TRUNCATED AT 250 WORDS)
McDonald
Z A
ZA
Division of Reproductive and Developmental Toxicology, National Center for Toxicological Research, Jefferson, Arkansas.
Slikker
W
W
Fu
P P
PP
Bailey
J R
JR
Lipe
G W
GW
Unruh
L E
LE
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D008253:Macaca mulatta; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D014599:Uterus / Q000187:drug effects
D004958:Estradiol; C039437:16-methylene estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C032690:3-alpha-(17-beta)-hydroxysteroid dehydrogenase (NAD(+))