The progesterone-like action of testosterone and certain related compounds

Abstract

[Plate 26]The isolation of naturally occurring forms of oestrogenic and male hormones was soon followed by the demonstration that similar activity might be possessed, to a greater or lesser degree, by related compounds made artificially. When progesterone was isolated from the corpus luteum it was assumed that there would be an analogous lack of specificity, and investigation was immediately begun on the effect of slight changes in chemical constitution on the power to evoke progestational prolifera tion. In the course of this work, Butenandt and his co-workers {see the review by Westphal, 1935) examined a large number of compounds closely related to progesterone (pregnene-3: 20-dione), but failed to find progesterone-like activity in any. Among the more interesting of these inactive compounds were " dihydroprogesterone " (pregnen-20-ol-3-one), inactive in a 2 • 7 mg. dose; pregnenolone (3-ol-20-one), inactive in 25 mg.; pregnanedione, inactive in 50 m g.; pregnanediol, inactive in 50 mg.; pregnan-20-ol-3-one, inactive in 9 mg.; and androstenedione, inactive in 30 mg. With the possible exception of dihydroprogesterone, which was tested in only a small dose, this work seemed to establish the in activity of these very closely related compounds, and by implication indicated the absolute specificity of progesterone.A general investigation of the biological properties of compounds of the androsterone-testosterone series carried out in this laboratory during 1935-36 led to the examination of certain of the compounds, especially those methylated or ethylated in position 17, for progesterone-like activity {see Ruzicka, 1936, for discussion of the chemical relationships). To our surprise, in view of Butenandt's results, certain of these compounds proved to be active (Klein and Parkes, 1936), and fuller investigation has shown that seven of them exert the specific activity previously thought to be restricted to progesterone.

The response of the rabbit's endometrium to uterine implants of progesterone and other steroids

“…The last column indicates whether or not the substance in question has been shown to have progesterone-like activity on the rabbit's endometrium when given by systemic injection. This information is based on the findings of Selye & Masson (1943) and Klein & Parkes (1937). A number of the findings call for discussion.…”

“…The table shows that even in large doses (40 mg.) testosterone has no local progestational effect. On the other hand, Klein & Parkes (1937) sterone does have a local progestational action. Hence, the change, as a result of which testosterone acquires progestational activity need be no more than the acquisition of a methyl group at 0-17.…”

The effect of steroids on the maintenance of pregnancy in the spayed rat*

“…Methyl testosterone, in a quantity which is ten times the effective dose of progesterone, also failed to maintain pregnancy, and yet this substance has been said to have progesterone actions of the order of 1/20 of progesterone (Klein & Parkes, 1937). Higher doses of methyl testosterone were not used because of the very large volumes of solvent which would be needed.…”

Factors influencing the effectiveness of administered hormones

“…Capon plumage test-This test for oestrogenic activity, depending on the production of the female coloration on the normally black breast feathers of the Brown Leghorn capon, was carried out as described by Parkes (1937), who also discusses the relevant points of the physiology of feather growth.…”

“…The significant facts in this connexion have been re cently reviewed (Parkes 1937). A constant total dose of oestrone, oestradiol or ovarian extract in either oily or aqueous solution, is much more effective if given as a series of small doses than if given as a single dose.…”