Blockade of estrogen synthesis with an aromatase inhibitor affects luteal function of the pseudopregnant rat

Abstract

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 μg/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-17β (E₂) levels. The serum and intraovarian progesterone (P₄) levels as analyzed on day 4 of pseudopregnancy were also reduced by ≥ 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 μg/day could completely reverse the AI induced reduction in P₄ secretion. The luteal cells of experimental rats depleted of Ein vivo showed a significantly reduced response upon incubation with hCG or dbcAMPin vitro (P <0.05 and 0.001, respectively). Addition of E₂ (500 pg/tube) at the time ofin 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 treatmentin vivo. Both esterified and total cholesterol content of luteal cells of rats treated with AIin 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.