A progesterone metabolite enhances the activity of the GABAA receptor complex at the pituitary level.

The interaction of 5 alpha-pregnane-3 alpha-ol-20-one (5 alpha 3 alpha P), a progesterone metabolite, with the GABAA receptor chloride channel complex was investigated at the pituitary level. In nanomolar concentrations this steroid potentiated the inhibitory effect of muscimol (a GABAA agonist) on prolactin release from rat pituitary cells in culture. In micromolar concentrations 5 alpha 3 alpha P had a direct inhibitory effect, similar to that of muscimol, with an IC50 value of 370 nM.

How the study of the biological activities of antiandrogens can be oriented towards the clinic.

Antiandrogens can be used in various androgen-dependent diseases. Depending upon the therapeutic indication, they can be administered systemically or topically. Systemic treatment with an antiandrogen will inhibit androgen action not only in the desired target site but also in all other target tissues; thus, it will block the androgen-dependent feedback regulating the secretion (hypothalamo-pituitary-testis axis) or the action (protein factors) of androgens.

Autoradiographic localization of glucocorticosteroid binding sites in rat brain after in vivo injection of [3H]RU 28362.

The autoradiographic distribution of glucocorticosteroid binding sites in the brain of adrenalectomized rats was studied following in vivo injection of a potent synthetic glucocorticosteroid agonist [3H]RU 28362. Analysis of the autoradiograms revealed a specific and dense labeling in the pyramidal cell layer of the Ammon's horn and in the granular cell layer of the dentate gyrus of the hippocampus. In the hypothalamus, the labeling was particularly high in the paraventricular nucleus (site of CRF synthesis), the arcuate, periventricular and the supraoptic nuclei as well as in the median eminence.

The antiandrogen anandron potentiates the castrating effect of the LH-RH agonist buserelin in the rat.

When buserelin (0.04-25 micrograms/kg/day), a potent LH-RH agonist, was administered s.c.

Binding and action of glucocorticoids and mineralocorticoids in rabbit mammary gland. Exclusive participation of glucocorticoid type II receptors for stimulation of casein synthesis.

In order to ascertain whether the effect of corticoids upon casein synthesis in pregnant rabbit mammary gland culture is due to interactions with classical glucocorticoid or type I (mineralocorticoid) receptors we have demonstrated the existence of both types of receptors in the tissue and have studied the effects of aldosterone and the specific glucocorticoid agonist RU 28362 upon casein synthesis in tissue culture. Both compounds significantly stimulated prolactin-induced casein synthesis. On dose-response studies RU 28362 proved to be as active as dexamethasone, cortisol was active at intermediate concentrations and aldosterone was the least active.

Design of antiandrogens and their mechanisms of action: a case study (anandron).

The design of a new drug is conditioned by knowledge of the biochemical mechanisms involved in the etiology of the disease to be treated. With regard to endocrine pathologies, such knowledge can be obtained in the clinic from systematic assays of urinary and plasma hormones, enzyme activities and target tissue receptor concentrations. The present paper describes the results of our assays of plasma 3 alpha-androstanediol glucuronide, 5 alpha-reductase and androgen receptor in prostate cancer patients.

Pharmacological and clinical studies of the antiandrogen Anandron.

This paper summarizes the animal and human studies with Anandron available at the time of the meeting. The following was demonstrated in the rat and confirmed in man: interaction of Anandron with the prostatic androgen receptor, antiandrogen activity against testosterone (in particular against the early transient rise induced by LHRH analogs) and adrenal androgens. Thus, as shown in 4 different double blind studies performed in stage D2 prostrate cancer patients, the combination of Anandron with surgical or chemical castration enhanced the beneficial effects of castration alone and thus seems a step forward in the hormonal treatment of prostatic carcinoma.

Corticosteroid receptors in rat hippocampal sections: effect of adrenalectomy and corticosterone replacement.

Rat brain sections, located at the hippocampal level, were used to study the effect of bilateral adrenalectomy, with or without corticosterone treatment, on the number and affinity of corticosteroid binding sites. Adrenalectomy induces an increase of corticosterone receptor binding sites whereas adrenalectomy followed by in vivo corticosterone treatment produces a 50% decrease of binding site number. Increases and decreases of binding site number were not associated with a significant modification of the affinity for corticosterone.

[Cancer of the prostate: biologic bases for the use of an antiandrogen in its treatment].

Although orchiectomy, estrogens and LHRH agonists suppress testicular androgens, they are without effect on adrenal androgens which are converted into dihydrotestosterone in the prostate. It is therefore necessary to develop substances able to block the action of all androgens, whatever their source, on target organs. The non-steroid, Anandron (RU 23908), when administered orally, gives rise to a high and sustained plasma level of intact compound that inhibits testosterone binding to its receptor.

Pharmacology of an antiandrogen, anandron, used as an adjuvant therapy in the treatment of prostate cancer.

To improve the inhibition of prostate cancer growth obtained by surgical or chemical castration (estrogens or LHRH analogs), blockade of the action of residual androgens of adrenal origin has been proposed. Among antiandrogens acting through the androgen receptor (AR), the nonsteroid anandron (RU 23908) has several advantages over available compounds: megestrol acetate and cyproterone acetate, both steroids, bind substantially to other hormone receptors (progestin, gluco- and mineralocorticoid); and anandron binds only to AR. The nonsteroid flutamide is a prodrug converted to the active metabolite, hydroxyflutamide; anandron is well absorbed on oral administration of an active dose and intact compound disappears slowly from plasma.

Transient transcriptional inhibition of the transferrin gene by cyclic AMP.

Transferrin mRNA content and gene transcription rate were measured in the liver of rats submitted to iron overload or depletion, castration, treatment with sexual steroid hormones, glucagon and cyclic AMP. The influence of puberty in males and females and of pregnancy was also analysed. Glucagon and cyclic AMP reduced mRNA level by about 50% at the 12th hour of treatment and transferrin gene transcription by as much as 95% at the 30th minute of drug infusion, with a secondary increase of the transcription rate for a protracted treatment.

In vitro binding of tritiated glucocorticoids directly on unfixed rat brain sections.

We describe a new technique for measuring specific in vitro binding of tritiated adrenal steroids on unfixed cryostat brain sections. The specific binding of [3H]corticosterone represents about 70% of the initial binding. Kinetic studies show that specific binding for [3H]corticosterone reaches equilibrium after 15 min incubation at room temperature.

RU 38486: potent antiglucocorticoid activity correlated with strong binding to the cytosolic glucocorticoid receptor followed by an impaired activation.

In order to explain the potent antiglucocorticoid activity of RU 38486 and the absence of agonist effect in spite of its very strong interaction with the cytoplasmic glucocorticoid receptor (GR), we investigated the compound's ability to promote GR "activation" and nuclear translocation. We have compared the dissociation-rates of the "non-activated" (molybdate stabilized) and of the "activated" (25 degrees C pre-heated) GR complexes formed either with [3H]RU 38486 or with different tritiated glucocorticoid agonists. While agonists dissociated more slowly from the "activated" than from the "non-activated" complex, RU 38486 dissociated much faster from the "activated" than from the "native" receptor.

Cytosolic and nuclear sex steroid receptors in meningioma.

To determine the nature of the hormone dependency of meningioma, particularly whether progestin receptor (PR) and tumor growth are estrogen-dependent, we measured the cytosol estrogen receptor (ER) and PR separately by an exchange assay with [3H]R 2858 (for ER) and [3H]RU 27987 (for PR) in 21 meningiomas. We correlated these receptors with age, plasma estradiol and progesterone concentrations, histological subtypes, clinical data such as uterine fibromas, and finally preoperative glucocorticoid therapy. ER was detected at low levels in the cytosol and in the nucleus of a few tumors whereas PR was found in 20 of 21 cases at moderate to high levels, usually with higher concentrations in the cytosol than in the nucleus.

The pure antiandrogen RU 23908 (Anandron), a candidate of choice for the combined antihormonal treatment of prostatic cancer: a review.

The nonsteroidal antiandrogen RU 23908 ( Anandron ) weakly interacts with the prostatic cytosolic androgen receptor and shows a fast dissociation rate. When administered to immature castrated rats up to the daily dose of 100 mg/kg, it is devoid of any androgenic activity but efficiently blocks the growth-promoting activity of androgens on ventral prostate and seminal vesicle weight, thus showing the characteristics of a pure antiandrogen. In intact animals, on the other hand, the antiandrogen administered alone exerts only a partial inhibition of prostate and seminal vesicle weight.

[Steroid receptors in the central nervous system. Implications in neurology].

This review deals with steroid hormones and receptors in relation to the physiology and the pathology of the central nervous system (CNS) and meninges. In recent years experiments performed in animals showed that: 1) endogenous steroid hormones cross the blood brain barrier: 2) radiolabelled steroid hormones bind in specific areas of the CNS; 3) all five classes of steroid receptors, i.e.

Steroid hormone receptors in human meningiomas, gliomas and brain metastases.

Progestin, estrogen, androgen, glucocorticoid as well as mineralocorticoid receptors (PR, ER, AR, GR and MR, respectively) were all evaluated with specific synthetic radioligands (biochemical assays) in 25 meningiomas, 9 gliomas and 4 brain metastases. In meningiomas the main steroid hormone receptors appeared to be the progestin receptor, present in 24/25 cases (mean level: 7 105 fmol/gT) and the androgen receptor, present in 23/25 cases (mean level: 2 265 fmol/gT). Progestin receptor levels were found to be significantly lower in meningiomas of the fibroblastic subtype whereas none of the steroid hormone receptors were detected in the anaplastic case.

Ornithine decarboxylase induction by glucocorticoids in brain and liver of adrenalectomized rats.

Ornithine decarboxylase (ODC), the rate-limiting enzyme in the biosynthesis of polyamines, was measured in the brain and the liver of adrenalectomized rats after an acute s.c. treatment with glucocorticoids.

Inhibition of progesterone secretion during the luteal phase by two luteinizing hormone-releasing hormone agonists in Macaca fascicularis.

The administration of 200 microgram of the potent luteinizing hormone-releasing hormone (LHRH) agonist [D-Leu6,des-Gly-NH2(10)]LHRH ethylamide on day 6 following the plasma estradiol peak to 11 female monkeys (Macaca fascicularis) during two consecutive menstrual cycles decreased plasma progesterone levels by 40.0% +/- 3.9% as compared with previous control cycles.

[Molecular basis for the use of steroids in psychiatry (author's transl)].

In animals, estrogens and progestins modulate food intake, running wheel activity and sexual behavior, androgens stimulate sexual behavior and aggression, and corticoids influence cerebral electrolyte regulation, sleep and memory. In this and other studies, we have established that soluble receptors binding steroid hormones are present, often in high concentration, in various central structures such as hypothalamus, cortex, hippocampus and amygdala and have shown that some of the effects of steroids on behavior can be related to their interaction with these receptors and the resultant biochemical events. Thus, in the rat, the induction of sexual behavior by estrogens and progesterone can be related to the increase in progestin receptor induced in the hypothalamus by estrogens.