Claude Bonne

Methyltrienolone, a specific ligand for cellular androgen receptors

Methyltrienolone (R 1881), 17beta-hydroxy-17alpha-methyl-estra-4,9,11-trien-3-one, a very active androgen, binds specifically to rat prostate cytosol with a higher affinity than androstanolone. Unlike the physiological hormone, however, it is not bound by human sex steroid plasma binding protein, SBP. This specific ligand is thus a useful tool for the detection of elusive androgen receptors and for their study, for instance, in human tumors where interference from plasma contamination has to be circumvented.

Assay of androgen binding sites by exchange with methyltrienolone (R 1881)

Methyltrienolone (R 1881 - 17beta-hydroxy-17alpha-methyl-estra-4,9,11-trien-3-one) binds specifically to androgen receptor in rat prostate cytosol where, unlike androstanolone, it is not metabolized. By exchanging bound endogenous hormone in rat prostate cytosol with labelled R 1881, it is possible to measure total (free anc occupied) binding sites. This assay method has also been applied to the measurement of androgen receptor sites in human benign prostatic hypertrophy where R 1881 has the added advantage of not being bound by any contaminating plasma protein (sex hormone binding protein).

Action of a non-steroid anti-androgen, RU 23908, in peripheral and central tissues.

Abstract RU 23908 (5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-2,4-imidazolidinedione) is a non-steroid anti-androgen with potent peripheral and central activity. In the rat, it inhibits androgen-induced prostate weight increase and negative androgen-dependent gonadotrophin feedback giving rise to an increase in LH and in testosterone. Association with a pituitary inhibitor counteracts this increase and enables full expression of its anti-androgen potential. Its mechanism of action would seem to be comparable to that of steroid anti-androgens in that it is able to inhibit effectively testosterone binding to the cytoplasmic androgen receptor after short but not long incubation times, i.e. it associates and dissociates very rapidly from this receptor thus preventing the full response of the endogenous hormone by transiently occupying available binding sites.

Specific binding of [3H]-methyltrienolone to both progestin and androgen binding components in human benign prostatic hypertrophy (BPH)

Abstract As previously reported. [ 3 H]-R1881, a stable tracer having high affinity for both androgenic and progestin binding components, binds to BPH cytosol with a predominant progestin-like specificity. However, when incubation was performed in the presence of a large excess of triamcinolone acetonide, a typical androgen binding specificity was demonstrated. This is explained by masking of the progestin binding component by triamcinolone acetonide, a steroid which has high affinity for the progestin receptor and no affinity for the androgen binding component. The present data clearly show that [ 3 H]-R1881, in the presence of triamcinolone acetonide, can be efficiently used for determination of androgen binding in BPH, a tissue which contains both androgen and progestin binding components. A similar approach could be adopted for other tissues containing these two receptors.

Androgen receptor in human skin

Cytosol androgen receptor was assayed in 18 human skin biopsies by an exchange technique with a labelled potent synthetic androgen, methyltrienolone (R 1881), under conditions which measured total (i.e. both free and occupied) binding sites. Androgen binding sites were only present in skin biopsies from patients with marked seborrhoea often accompanied by acne (8 cases) and no sites were detected in normal skin biopsies (7 cases). Three biopsies from seborrhoeic patients, however, did not contain androgen receptor. Although no direct quantitative correlation could be drawn between binding site concentration and sebum excretion, it would seem that the androgen receptor content nevertheless constitutes an important parameter in the study of the hormonal control of seborrhoea.

Screening for anti-hormones by receptor studies

Abstract The class of steroidal anti-hormones which exert their effect by interaction with the target cell cytosol receptor has been studied with a view to developing a method of screening for highly specific antihormonal agents. It has been shown that compounds with moderate affinity for the receptor may be classified as either true agonists or impeded agonists with possible antagonistic activity, whereas compounds with weak affinity are weak agonists, but also likely antagonists. These studies have been carried out on the androstanolone, estradiol, aldosterone and progesterone receptors and are illustrated by the results obtained with a potent anti-androgen (R 2956), anti-estrogen (RU 16117), anti-aldosterone (spironolactone) and anti-progesterone (R 2323). The primary advantage of running studies in parallel on several receptors resides in the possibility of classifying the anti-hormones according to whether they possess affinity for a given receptor, thus providing a criterion for the selection of highly specific compounds virtually devoid of hormonal side-effects. Moreover, since similar hormonal receptors with the same physico-chemical parameters and specificity exist in various species including man, animal receptor data may be extrapolated to human studies, allowance being made in the evaluation of activity for variations in pharmacokinetics and metabolism.

SCREENING FOR ANTI-HORMONES BY RECEPTOR STUDIES

SUMMARY The class of steroidal anti-hormones which exert their effect by interaction with the target cell cytosol receptor has been studied with a view to developing a method of screening for highly specific anti-hormonal agents. It has been shown that compounds with moderate affinity for the receptor may be classified as either true agonists or impeded agonists with possible antagonistic activity, whereas compounds with weak affinity are weak agonists, but also likely antagonists. These studies have been carried out on the androstanolone, estradiol, aldosterone and progesterone receptors and are illustrated by the results obtained with a potent anti-androgen (R 2956), anti-estrogen (RU 16117), anti-aldosterone (spironolactone) and anti-progesterone (R 2323). The primary advantage of running studies in parallel on several receptors resides in the possibility of classifying the anti-hormones according to whether they possess affinity for a given receptor, thus providing a criterion for the selection of highly specific compounds virtually devoid of hormonal side-effects. Moreover, since similar hormonal receptors with the same physico-chemical parameters and specificity exist in various species including man, animal receptor data may be extrapolated to human studies, allowance being made in the evaluation of activity for variations in pharmacokinetics and metabolism.

Inhibition of 5α-reductase activity of rat prostate by estradiol derivatives

Summary The in vitro inhibitory effect of estradiol and of three of its estrogenic and non-estrogenic derivatives on 5α-reductase activity in rat prostate microsomes is studied. The results establish that this effect is not correlated with their uterotrophic activity, nor with their in vitro affinity for the uterus cytosol estrogen receptor.