These 2 experiments will enroll 24 women. Eight will be midreproductive aged and there will be 16 perimenopausal women. Women in these studies will undergo intravenous infusion of estradiol to mimic a normal ovulatory rise in estradiol (physiologic infusion protocol) and an excessive rise in estradiol (supraphysiologic infusion). The target levels will be 250-300 pg/ml and 700-900 pg/ml, respectively. Once the target levels are achieved and maintained for 48 hours, participants will be admitted to the GCRC for a 36 hour admission and will undergo hourly blood sampling to characterize the LH surge. Our hypothesis is that chronic exposure to supranormal estrogen, as happens in the early stages of the perimenopausal transition, will cause a failure of positive feedback response. A second, follow-up study will test pituitary sensitivity to exogenous GnRH after infusion and attainment of target levels of physiologic and supraphysiologic estradiol. This protocol is currently undergoing preliminary evaluation. An infusion pump has been purchased and the hospital pharmacy has prepared estradiol for infusion twice. In the first experiment, ideal, target levels were achieved within 48 hours in a participant. In a second experiment, target levels were not achieved and were unexpectedly low. Measurement of the exit volume from the tubing revealed procedural losses of almost half of the measured estradiol. Even so, the low concentration of circulating estradiol achieved in the participant was not consistent with even half of the infused estradiol being absorbed appropriately. We will continue to pilot this experiment with more frequent monitoring of estradiol, perhaps twice a day, and rapid adjustment of the pump volume to achieve the desired levels of circulating steroid. The techniques of IV maintenance, infusion preparation and convenience have all been addressed, as the pump is easy to use.
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