Hepatic estrogen responsiveness. Possible mechanisms for sexual dimorphism

C Thompson and GW Lucier

In addition to estrogen receptors, liver contains a second class of estrogen-binding proteins referred to as higher-capacity, lower- affinity (HCLA) binding sites which are distinct from estrogen receptors. HCLA sites comprise two classes of proteins: moderate- affinity (KD = 0.45 microM and 0.24 microM) estrogen-binding sites unique to male cytosol and a low-affinity, nonsaturable estrogen- binding site present in both sexes. The sex differences observed in HCLA sites are apparently a consequence of imprinting by testicular androgen during a critical neonatal period. Neonatal castration causes a reduction in the concentration of HCLA sites in the subsequent adult male. Furthermore, the moderate-affinity sites detected by Scatchard analysis in adult male liver are not observed in neonatal castrates. Cell-free nuclear translocation assays demonstrate that nuclear uptake of cytosolic receptor-ligand complexes is more efficient in females than in males. This sex difference in nuclear uptake can be minimized when the concentration of the ligand is increased to a level necessary to saturate the estrogen receptor in the presence of HCLA sites. Nuclear uptake of receptor-ligand complexes in neonatally castrated males (deficient in HCLA sites) is similar to that seen in adult females. Elevations of serum triglyceride following estradiol exposure have been monitored as an indicator of hepatic responses to estrogen. Our studies have shown that female liver appears more responsive to estrogen exposure than does male liver. While a dose of 20-30 micrograms of estradiol per kilogram of body weight per day was sufficient to produce a 3- to 4-fold increase in the concentration of triglyceride associated with the very low-density lipoprotein fraction in females, a dose of 100 micrograms of estradiol per kilogram of body weight per day was needed to obtain a similar response in males. However, following neonatal castration, estrogen responsiveness in the subsequent adult male rat was similar to that in females, suggesting a role for neonatal androgens in regulating sex differences in the action of hepatic estrogen.

Volume 24, Issue 1, pp. 69-76, 07/01/1983
Copyright © 1983 by American Society for Pharmacology and Experimental Therapeutics