Androgen Receptors in the Anterior Pituitary and Central Nervous System of the Androgen “Insensitive” (Tfm) Rat: Correlation Between Receptor Binding and Effects of Androgens on Gonadotropin Secretion

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Abstract
The cytosol fractions of the anterior pituitary, hypothalamus, preoptic area and brain cortex of androgen insensitive (Tfm) rats possess androgen receptors. In the Tfm rats the androgen binding per milligram protein was only 10-15% of that in the corresponding normal littermates (Nl). The physicochemical properties of the androgen receptors in the anterior pituitary of the Tfm rat were indistinguishable from those of the normal rat. No distinctive differences were observed with regard to electrophoretic mobility in 3.25% polyacrylamide gels, isoelectric point (pI = 5.8), binding affinity (Kd = 1.5 .times. 10-9 M), temperature stability, sulfhydryl dependence and steroid specificity. It is likely that the very low androgen binding capacity by the anterior pituitary and the CNS is due to an extreme reduction in the receptor number rather than to the presence of abnormal receptors. Since in the Tfm animals the androgen receptor number is reduced by 85-90%, very high doses of androgens would be required to achieve hormonal effects. In fact, low doses of 5.alpha.-dihydrotestosterone propionate (50 .mu.g/100 g body wt) given s.c. daily for 12 days had no effect on serum levels of LH [luteinizing hormone] and FSH [follicle stimulating hormone]. Very high doses (2 mg/100 g body wt) of testosterone propionate and 5.alpha.-dihydrotestosterone propionate, which maintained circulating androgen levels above 20 ng/ml, significantly reduced serum gonadotropin levels in castrated Tfm rats. In Nl both low and high doses of the androgens suppressed gonadotropin secretion to low levels. Androgen receptors are essential to androgen action on the anterior pituitary and CNS in the rat. The serum levels of testosterone (7.7 .+-. 0.15 (SE) ng/ml) and 5.alpha.-dihydrotestosterone (0.37 .+-. 0.06 ng/ml) were significantly higher in intact Tfm rats than in Nl (2.6 .+-. 0.03 and < 0.1 ng/ml, respectively). The failure of the elevated concentrations of serum androgens to reduce the high serum levels of LH and FSH in intact Tfm rats is most likely due to the extreme reduction of the androgen receptor number and the consequent insufficient hypothalamic and/or pituitary response to androgens.