Mechanism of action of steroid hormones

Abstract

These investigations will deal mainly with oestrogenic steroid hormones, except in SECTION II where work with adreno-corticosteroids is reported.

The mechanism of action of steroid hormones, in particular of oestrogens, has been investigated along two main lines.

(a) Attempts have been made to assess the physiological role of an oestrogen- sensitive transhydrogenase first demonstrated in the placenta of women. The original observations have been confirmed but it has not been possible to demonstrate the same enzyme activity in placentae from rat, guinea -pig, rabbit, golden- hamster or pig. Nor has the enzyme been found in such oestrogen "target" organs as human endometrium, rat and guinea -pig uterus, rat vagina, chicken oviduct or ox pituitary. Negative results are not due to destruction of substrates or coenzymes during the enzyme determinations, but may be due to the presence of endogeneous inhibitors.

The ratios of oxidised to reduced di- and triphosphopyridine nucleotides have been determined in the uteri of intact, ovariectomised and ovariectomised oestrogen treated rats. Changes in these ratios in response to oestrogenic steroids give no indication of transhydrogenase activity in vivo.

The inability of some 313- and 11ß-hydroxy steroids to act as coenzymes and promote transhydrogenation in the liver and adrenal has also been observed.

(b) Changes in levels of glucose -6- phosphate dehydrogenase (G6PDH), 6- phosphogluconic acid dehydrogenase (6PGDH), isocitric dehydrogenase (ICDH) and lactic dehydrogenase (LDH) and in concentrations of oxidised and reduced di- and triphosphopyridine nucleotides in the ovariectomised rat uterus in time in response to oestradiol- 17ß have been investigated. The concentrations of the oxidised pyridine nucleotides remain unchanged, but the reduced forms of the coenzymes decrease in concentration up to 6 hours after oestrogen administration and then show a steady increase until at 72 hours the concentrations are significantly higher than in the uteri from ovariectomised controls.

The levels of uterine G6PDH, 6PGDH and LDH are increased by oestrogen. That of ICDH shows no change.

It is suggested that there is an overall increase in reduced coenzyme concentration due to the increased levels of enzymes concerned but that the initial decrease in reduced coenzymes may be related to demands for energy and specific reductants for biosynthesis in response to oestrogen.

Some evidence is produced to support the view that the increases in levels of enzymes are due to synthesis of new enzyme protein rather than to activation of existing enzyme.

Changes in concentration of G6PDH and 6PGDH but not in ICDH suggested the possibility of an effect of oestrogen on glucose catabolism. This has been investigated using 4C- labelled glucose. In general oestrogen is found to stimulate glucose catabolism, the increase being mainly via the hexosemonophosphate 'shunt' pathway. Glycolysis is however the major pathway of glucose metabolism in the uteri of ovariectomised and oestrogen treated rats.

It has also been shown here that the use of the 'shunt' pathway is dependent on the rate of reoxidation of reduced triphosphopyridine nucleotide. Since this reoxidation may Troceed at a greater rate in vivo than under the in vitro conditions of the Present experiments, the 'shunt' pathway may in fact be of greater significance than it has been possible to demonstrate in this investigation.

The probable mechanisms of action of oestrogenic hormones are reviewed in the light of the results now obtained. It is concluded that the transhydrogenase theory of Villee & Talalay is of doubtful importance in explaining the action of oestrogens. It also seems likely that oestrogenic hormone is concerned with the induction of the biosynthesis of new enzyme protein and that this process in some way 'triggers' the whole anabolism of the 'target' tissue.