In 1955 Shore, Brodie and coworkers (Shore, Silver and Brodie 1955, Pletscher, Shore and Brodie 1955) discovered that reserpine caused a marked decrease in the concentration of 5-hydroxytryptamine (5-HT) in tissues and a concomitant rise in the urinary excretion of the 5-HT metabolite 5-hydroxyindoleacetic acid. The deep physiological significance of this discovery became even more evident when reserpine soon afterwards was found to affect tissue catecholamines in a similar manner, an effect leading to block of adrenergic transmission mechanisms (Carlsson and Hillarp 1956a, Bertler, Carlsson and Rosengren 1956). Since then numerous papers have appeared, in which the effects of Rauwolfia alkaloids and a group of similarly acting benzoquinolizines (Pletscher, Besendorf and Bachtold 1958) have been further analyzed. Particular interest has been focussed on the mechanism of action on the abovementioned amines and on the relationship between this action and the various pharmacological effects of Rauwolfia alkaloids and benzoquinolizines. It is the aim of the present Chapter to review and discuss the pertinent literature dealing with these fundamental problems rather than to review in detail the enormous literature on the pharmacology of these agents.

Drugs which block the storage of 5-hydroxytryptamine and related amines

The nature of the steroids secreted by gonads of fish differs significantly from those of the mammals. The ‘classical teleost steroids’, oestradiol, testosterone, 11-ketotestosterone and 17,20βP, have been measured in a wide variety of teleosts but do not always reflect biological activities. There is increasing evidence that teleost gonads may produce a number of ‘non-classical steroids’ which may play an important role in their reproductive biology. Such products include metabolites reduced at C5 to 5α or 5β, at C3 to 3α or 3β, or hydroxylated at 6-, 7-, or 21. Conjugation, as either glucuronides or sulphates, may contribute either to localization of action within the gonad or to production of pheromones during the immediate pre-spawning period. Although it is often possible only to measure the steroids for which assays are readily available, it is important to recognize that there may be production of steroids that are not detected by such assays, but which nevertheless play a major role in reproductive activity. In evolutionary terms, the teleost hydroxylases probably originated in the very early fishes and show parallels with their analogues in amphibians and mammals. Gene sequencing may reveal a possible common ancestor for all vertebrate 6, 7 and 11-hydroxylases.

‘Classical’ and ‘non-classical’ reproductive steroids in fish

/pdf/the-role-of-cytochrome-p450-17-alpha-hydroxylase-and-3-beta-1vmup7j1j2.pdf

The role of cytochrome P450 17 alpha-hydroxylase and 3 beta-hydroxysteroid dehydrogenase in the integration of gonadal and adrenal steroidogenesis via the delta 5 and delta 4 pathways of steroidogenesis in mammals.

The spermatogenic process of normal rats at 20, 32, and 44 days of age was characterized. Variations in numbers of degenerating and abnormal cells were noted during the cycle in most age groups, indicating a stage-related vulnerability of these cells. The most advanced cell types that were seen at a particular age were frequently abnormal or degenerating. When the numbers of viable cells available to degenerate were considered, the degeneration rate in normal pubertal animals was about 15, 10, and 2 times greater in 20-, 32-, and 44-day-old animals, respectively, than in 75-day-old animals. In 32-day-old rats, neither hypophysectomy nor hypophysectomy and subsequent hormone supplementation resulted in an alteration in the qualitative pattern of germ cell degeneration during the spermatogenic cycle compared with that in the normal animal; however, the treatments did alter the quantitative response of cellular degeneration. Three days posthypophysectomy there was a marked increase in the numbers of total degenerating germ cells. FSH (60 micrograms) given twice daily (as were all hormones) reduced the numbers of degenerating cells significantly, as did LH (13 micrograms). Low dose LH (0.3 micrograms), representing the approximate contaminating dose of LH in the 60-micrograms FSH preparation, and low dose FSH (30 micrograms) did not elicit a response significantly different from that to hypophysectomy alone. LH (13 micrograms) plus FSH (60 micrograms) reduced the levels of degenerating cells such that there was no significant difference from levels in intact 32-day-old rats. The data indicated, for the cell types studied, a lack of specificity of various hormones or hormone combinations in the survival of specific germ cell types. It emphasizes the importance of FSH in pubertal spermatogenesis as well as the synergistic actions of LH and FSH.

Hormonal control of pubertal spermatogenesis.

I. A Contemporary Model for the Mechanism of Action of Androgens.- 1. Definitions.- 2. The Model for the Mechanism of Action of Androgens.- 3. Experimental Support for the Model.- a) Antiandrogens.- b) Experimental Testicular Feminisation Syndromes.- c) Specificity of Induction and Dose-Response Phenomena.- d) Temporal Integration of Steroid-Mediated Responses.- e) Tumours with Different Sensitivities to Androgens.- 4. Limitations of the Model of Androgen Action.- a) Fundamental Mechanisms of Hormone Action.- b) Redundant (Aberrant) Binding.- c) General Applicability of the Model.- d) Acute Tissue-Specificity of Androgenic Responses.- e) Androgen Responses Independent of the Receptor System.- f) Hormonal Synergism.- g) Responses Independent of Transcription.- 5. Conclusions.- II. The Metabolism of Androgens in Relation to Their Mechanism of Action.- 1. Relative Biological Activities of Testosterone and Its Metabolites.- 2. General Comments on the Metabolism of Androgens.- 3. Developmental Aspects of the Metabolism of Testosterone.- a) Foetal Development.- b) Neonatal Development.- c) Adult Development.- d) Fluctuations in the Circulating Concentrations of Androgens.- 4. Androgenic Responses Not Mediated by 5?-dihydrotestosterone.- 5. Interconversion of Steroid Hormones.- 6. Conclusions.- III. Initial Events in the Mechanism of Action of Androgens.- 1. The Uptake, Retention, and Release of Androgens: Studies on Rat Ventral Prostate Gland.- a) Transport of Testosterone and Related Steroids in Plasma.- b) Entry of Testosterone into Cells.- c) Cytoplasmic Receptors for Androgens.- d) Antiandrogens.- e) The Nuclear Binding of 5?-dihydrotestosterone.- f) Reconstituted, Cell-Free Systems for the Nuclear Transfer of 5?-dihydrotestosterone: the Acceptor Hypothesis.- g) The Structure of Chromatin and the Nature of Nuclear Acceptor Sites.- h) The Exit of 5?-dihydrotestosterone from the Prostate Gland: Receptor Cycling.- i) Binding of Steroids Other than 5?-dihydrotestosterone.- j) Purification of Receptor Proteins.- 2. The Binding of Androgens in Other Target Cells.- a) Distribution and Specificity of Receptors for Androgens and Related Steroids.- b) Physical Properties of Cytoplasmic and Nuclear Receptors.- c) Binding of Hormones Other than Androgens.- d) Specificity of Androgenic Responses.- 3. Initial Biochemical Events Stimulated by Androgens.- a) Protein Synthesis.- b) Activation of Protein Phosphokinases.- c) Stimulation of the Initiation Step of Protein Synthesis.- d) The Androgenic Regulation of RNA Synthesis: Receptor Effects in vitro.- 4. Conclusions.- IV.Early Events Stimulated by Androgens.- 1. Early Biochemical Changes Stimulated by Androgens.- 2. A More Detailed Enquiry into Enzyme Induction by Androgens: Aldolase in Rat Prostate.- 3. Experimental Models for Studying Tissue-Specific Responses.- a) Rat Seminal Vesicle.- b) Mouse Kidney.- 4. Morphologic Aspects of Androgenic Stimulation.- 5. Conclusions.- V.Late Events in the Mechanism of Action of Androgens.- 1. Cell Renewal and Morphologic Studies on the Mitogenic Activity of Testosterone and Its Metabolites.- 2. Biochemical Approaches to the Regulation of Mitosis in Rat Ventral Prostate Gland.- a) Enzymes Engaged in DNA Replication.- b) Proteins Regulating the Onset of Mitosis.- c) DNA-Unwinding Proteins.- d) Synthesis of Histones.- 3. Conclusions.- Overall Conclusions.- References.

The Mechanism of Action of Androgens

The biosynthesis of estrogens by cow follicles.

Influence of age on the formation of 5α-androstanediol and 7α-hydroxy-testosterone by incubated rat testes

The conversion of testosterone to 7α-hydroxy-testosterone by incubated rat testes

The influence of gonadotrophin (HCG) treatment on the steroidogenesis by incubated rat testes

Mammary tumors were induced in rats by treatment with dimethylbenz( a )anthracene. Cytosol receptors for 17β-estradiol and progesterone were estimated by means of suorose density gradient centrifugation, and the metabolism of [14C]progesterone, [14C]testosterone, and 17β-[14C]estradiol by minced tumor tissue was studied.

The estradiol receptor (ER) and progesterone receptor (PR) levels of the tumors varied considerably from <5 to 48 fmol/mg protein for ER and to 243 fmol/mg protein for PR. Considering a receptor level lower than 5 fmol/mg protein to be negative, four groups of tumors were found: ER-negative and PR-negative; ER-positive and PR-negative; ER-negative and PR-positive; ER-positive and PR-positive.

In dimethylbenz( a )anthracene-induced tumor tissue, high 5α-reductase and 20α-hydroxysteroid dehydrogenase activities and somewhat lower 3α-hydroxysteroid dehydrogenase and 6α-hydroxylase activities were found. No aromatization was detectable. Steroids, especially estradiol, were also metabolized in a high degree to unextractable metabolites. It was concluded that steroid metabolism of dimethylbenz( a )anthracene-induced rat mammary tumors was not related to the ER and/or PR concentration of tumor tissue.

https://cancerres.aacrjournals.org/content/canres/43/9/4260.full.pdf

W. Eechaute

Papers

The biosynthesis of estrogens by cow follicles.

Influence of age on the formation of 5α-androstanediol and 7α-hydroxy-testosterone by incubated rat testes

The conversion of testosterone to 7α-hydroxy-testosterone by incubated rat testes

The influence of gonadotrophin (HCG) treatment on the steroidogenesis by incubated rat testes

Steroid Metabolism and Steroid Receptors in Dimethylbenz(a)anthracene-induced Rat Mammary Tumors