Identification of the estrogen product of extraglandular aromatization of plasma androstenedione

The purpose of these studies was (1) to determine the duration of urine collection needed for complete excretion of radiolabeled metabolites of estrone following the infusion of (³H)-estrone and (¹⁴C)-androstenedione; (2) to compare the transfer constant of conversion of plasma androstenedione to plasma estrone measured from the ³H:¹⁴C ratio of plasma estrone [ρ{variant}]_BU^AE1 after four hours of tracer infusion to the [ρ{variant}]_BU^AE1 computed from the ³H:¹⁴C ratio of urinary estrone; and (3) to determine the duration of tracer infusion required to achieve steady-state conditions in the ³H:¹⁴C ratio of plasma estrone when (³H)-estrone and (¹⁴C)-androstenedione are infused into obese and nonobese women. We found that the ³H:¹⁴C ratios of urinary estrone, estradiol, and estriol are very similar when urine collections are complete and obtained for a sufficient time to allow complete excretion of both (³H)-estrone metabolites and (¹⁴C)-estrone metabolites. The rate of urinary excretion of the estrone metabolites is slower in obese subjects than in nonobese subjects. Four-hour infusions of (³H)-estrone and (¹⁴C)-androstenedione are insufficient to obtain steady-state conditions in the concentrations of plasma (³H)-estrone and plasma (¹⁴C)-estrone derived from infused (¹⁴C)-androstenedione. The time required to reach steady-state conditions varies directly with body weight. In thin individuals, seven hours of tracer infusion may be sufficient to reach steady-state conditions when (³H)-estrone and (¹⁴C)-androstenedione are infused; whereas, 48 hours of infusion may be necessary to achieve these same conditions in morbidly obese individuals. When the time of infusion required to reach an equilibrium between (¹⁴C)-estrone derived from infused (¹⁴C)-androstenedione and (³H)-estrone in plasma is analyzed as a function of body weight, a highly significant correlation (p < 0.001) is found. From these studies, we conclude that estrone is the near-exclusive estrogen produced by extraglandular aromatization of plasma androstenedione and that extraglandularly formed estrone enters blood unaltered. Thus, little or no irreversible metabolism of estrone occurs in the tissue site(s) of aromatization.