Effect of estradiol withdrawal on luteal hormone responsive adenylyl cyclase and luteal function in the pseudopregnant rabbit.

Abstract

We showed previously that continued administration of high levels of estradiol (E) to pseudopregnant (PSP) rabbits from Day 8 through Day 11 does not affect their serum progesterone levels, but leads to a 75% decrease in the ability of LH to stimulate the adenylyl cyclase enzyme in their corpora lutes (CL). To determine if the deleterious effect of estrogen is readily reversible, we now explored the effect of a 2-day withdrawal or a switch to low levels of E following the 3-day treatment with high E. From 2200 h of Day 8 through 2200 h of Day 11, PS? rabbits were injected at 12 h intervals with 0.1 ml sesame oil alone (control), or with oil containing either 1.5 pg E (E-1.5) or 15 pg E (E-15). Several animals from each group were killed between 1000-1100 h the following morning (Day 12). The remaining animals were either switched from E-15 or E-1.5 to oil (E-withdrawal), were switched from E-15 to E-1.5, or were maintained on their original E regiments. The final injections were at 0800 h on Day 14 and the animals were killed 2-3 h later. Adenylyl cyclase activities and serum and luteal progesterone levels were determined. We found that: 1) Withdrawal of E-15 did not reverse the E-15-induced inactivation of the LHresponsive adenylyl cyclase, nor did it alter the isoproterenol-responsive adenylyl cyclase. 2) Withdrawal of E-1.5 had no effect on the degree of hormonal responsiveness of the adenylyl cyclase when compared with control values. 3) E-15 withdrawal but not E-1.5 withdrawal, resulted in a significant decrease in serum and luteal progesterone content, but 4) did not result in a decrease in the weight of the CL within the 48-h time period tested. 5) Switching from E-15 to E-1.5 treatment did not cause a drop in serum progesterone concentrations, but 6) resulted in LIIstimulated cyclase activity, which although somewhat elevated over that found in animals treated with E-1 5 throughout, was still markedly decreased compared with controls or rabbits treated with E-1 -5. These results suggest that 1) a high dose of estradiol is required to establish a “dependency” on exogenous E in CL of PSP in rabbits; 2) low levels of exogenous E are sufficient to fulfill the requirements imposed by this E “dependent” state; and 3) the establishment of “dependency” on E is associated with the decrease in the LU-responsive adenylyl cyclase. an unphysiological situation. These data provide evidence that while a partial reversal of the suppression of cyclase activity by high levels of estradiol is possible, it proceeds only slowly taking several days to become effective.