Blockade of estrogen synthesis with an aromatase inhibitor affects luteal function of the pseudopregnant rat.
The luteotropic action of estrogen (E) was investigated using immature pseudopregnant rat as the model and CGS 16949A (Fadrozole hydrochloride), a potent aromatase inhibitor (AI), to block E synthesis. Aromatase activity could be inhibited by administering CGS 16949A (50 micrograms/day/rat) via a mini osmotic Alzet pump (model 2002) for 3 days during pseudopregnancy. This resulted in significant reduction of serum (40%, P < 0.05) and intraovarian 70.6%, P < 0.001) estradiol-17 beta (E2) levels. The serum and intraovarian progesterone (P4) levels as analyzed on day 4 of pseudopregnancy were also reduced by > or = 50% (for both, P < 0.01). Simultaneous administration of estradiol-3-benzoate (E2B) via an Alzet pump during the AI treatment period at a dose of 1 microgram/day could completely reverse the AI induced reduction in P4 secretion. The luteal cells of experimental rats depleted of E in vivo showed a significantly reduced response upon incubation with hCG or dbcAMP in vitro (P < 0.05 and 0.001, respectively). Addition of E2 (500 pg/tube) at the time of in vitro incubation was able to partially increase the responsiveness to hCG. The luteal cell LH/hCG receptor content and the affinity of hCG binding to the receptor remained unchanged following AI treatment in vivo. Both esterified and total cholesterol content of luteal cells of rats treated with AI in vivo was significantly high (P < 0.05) suggesting that E lack results in an impairment in cholesterol utilization for steroidogenesis. The results clearly show that E regulates luteal function in the pseudopregnant rat by acting at a non-cAMP mediated event and this perhaps involves facilitation of cholesterol utilization at the mitochondrial level for P4 synthesis.
Center for Reproductive Biology and Molecular Endocrinology, Indian Institute of Science, Bangalore, India.
G
G
Shetty
A S
AS
Bhatnagar
N R
NR
Moudgal
D000818:Animals; D047072:Aromatase Inhibitors; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D002784:Cholesterol / Q000032:analysis; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D003338:Corpus Luteum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004958:Estradiol / Q000096:biosynthesis / Q000097:blood / Q000737:chemistry; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000096:biosynthesis*; D017316:Fadrozole / Q000494:pharmacology*; D005260:Female; D010053:Ovary / Q000737:chemistry / Q000187:drug effects; D011247:Pregnancy; D011374:Progesterone / Q000096:biosynthesis / Q000097:blood / Q000737:chemistry; D011555:Pseudopregnancy / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D047072:Aromatase Inhibitors; D006063:Chorionic Gonadotropin; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D004967:Estrogens; D011374:Progesterone; D004958:Estradiol; D003994:Bucladesine; D002784:Cholesterol; D017316:Fadrozole