Anabolic Steroids

236 Pages·1968·2.89 MB·English

by  H.-L. Krüskemper (Auth.)

ANABOLIC STEROIDS
By Dr. med. H.-L. KRUSKEMPER
PROFESSOR FUR KLINISCHE ENDOKRINOLOGIE
MEDIZINISCHEN HOCHSCHULE
HANNOVER, GERMANY
Translated by Charles H. Doering
HUNTINGTON LABORATORIES
MASSACHUSETTS GENERAL HOSPITAL
BOSTON, MASSACHUSETTS
A C A D E M IC PRESS New York and London 1968
COPYRIGHT © 1968, BY ACADEMIC PRESS, INC.
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United Kingdom Edition published by
ACADEMIC PRESS INC. (LONDON) LTD.
Berkeley Square House, London W.l
Originally published in the German language
under the title "Anabole Steroide" and
copyrighted in 1963 by George Thieme Verlag, Stuttgart.
LIBRARY OF CONGRESS CATALOG CARD NUMBER: 66-30090
PRINTED IN THE UNITED STATES OF AMERICA
Preface to First German Edition
General endocrinology has been extended during the past decade
to include the new hormone-like compounds. Progress of bio-
chemical-analytical methodology and organic-preparative tech-
niques have provided biologic research with numerous synthetic
derivatives of natural hormones.
Experience with these new compounds necessitated certain
procedural changes in assaying compounds with hormonal prop-
erties. Beyond the customary quantification of the main effect of a
compound in comparison with a standard hormone, the qualitative
evaluation of biologic data has gained significance. No longer are
relationships of isolated effects compared exclusively, but entire
activity spectra are compared. The object of this research is to find
derivatives with dissociated hormonal effects. The compounds
sought after would have activity spectra with different maxima or
shifted emphasis compared to the corresponding natural hormones.
Medical applications benefit enormously from these compounds
because undesirable side-effects, inevitable in (nonsubstituting)
therapy with natural hormones, are largely avoided. Then too,
many more conditions become amenable to "hormonal" therapy.
Although this is a recent development in the field of polypeptide
hormones, many new compounds have been synthesized and applied
successfully clinically, especially in the area of iodothyronines and
steroid hormones.
v
vi PREFACE TO FIRST GERMAN EDITION
This monograph deals with anabolic steroids derived from natural
androgens and characterized by their stimulatory action on the bio-
synthesis of tissue protein and by their simultaneous low andro-
genicity. The biochemical part is a review of substantiated and
current knowledge based largely on experimental results with
animals, while the clinical part attempts to bring out the patho-
physiological rationale of therapy with anabolic steroids, again
based on experimental data. It was not the intention to present a
sharply delineated compilation of therapeutic indications.
I would like to thank Professor F. Tiemann, Professor W.
Dirscherl, Professor H. Breuer (Bonn), and Dr. R. I. Dorfman for
critical discussions and valuable advice in the preparation of the
manuscript.
H.-L. KRUSKEMPER
CHAPTER I
Introduction
The knowledge of steroids effective in the anabolism of proteins
has now reached a point where it is feasible to set down a critical
review of these substances. This monograph attempts to trace their
development in the chemical, experimental biological, and clinical
disciplines and to present a precise outline of the present state of
substantiated knowledge.
Anabolic steroids may be defined as those steroids one of whose
main functions is to generally stimulate the synthesis of cellular
protein.
Other terms for the same group of substances, such as anabolic
hormones, anabolites, anabolica, and steroanabolica, are neither
exact nor specific enough, or too similar to the names of pharma-
ceutical specialties to be useful and consequently should be avoided.
Within the framework of this monograph, the expressions anabolism,
catabolism, and isobolism refer exclusively to the metabolism of
protein and designate different forms of nitrogen balance. Anabolism
in this context means a preponderance of protein synthesis, a
constructive metabolism which is recognized by a positive nitrogen
balance; whereas in catabolism, breakdown predominates and
nitrogen balance is negative. Isobolism describes the state of
equilibrated nitrogen balance as it prevails in the healthy adult
before the age of involution. In no case are these concepts to refer
to phases of the molecular mechanisms of protein metabolism.
The anabolic and androgenic activities of steroids are distin-
guished rather for systematic reasons and not because of inherent
properties of these steroids. The androgenic effect differs from the
anabolic effect only in its location and not in its essence. Andro-
1
2 I. INTRODUCTION
genicity, therefore, signifies the anabolic effect in the area of the
sex organs. When, in the following chapters, we speak of the
anabolic effect then we mean the shift of the nitrogen balance to
the positive side or, in the common usage of the term, the extra-
genital stimulation of protein synthesis by steroids.
CHAPTER II
Nomenclature and Chemistry
of Anabolic Steroids
All steroids are compounds whose carbon skeleton is that of
cyclopentanoperhydrophenanthrene. In the present monograph,
the nomenclature and structural formulas are based on the follow-
ing rules (1-6):
1. The numbering of carbon atoms and the designation of Rings
A-D have been carried out as in the example of cholesterol (Fig. 1).
21
CH
3
HO
FIG. 1. Cholesterol (I).
2. In structural formulas, carbon and hydrogen atoms are not
usually written out but are represented in a simplified symbolic
manner by merely drawing the basic hydrocarbon skeleton (Fig. 2).
3. Reference groups for the stereochemical designations are the
angular methyl groups (C-18 and C-19), which must be visualized as
projecting up from the plane of the paper. All substituents with
this same orientation are designated by the prefix cis, or normal, or
j8, whereas substituents which are on the opposite side to the angu-
lar methyl groups receive the designation trans, or alio, or a. Dotted
3
4 II. NOMENCLATURE AND CHEMISTRY
lines indicate a-configuration; heavy lines, ^-configuration (Fig. 2).
4. Double bonds in the ring system are indicated by a change of
the suffix "ane" to "ene" (e.g., androstane to androstene). The
position of the double bond is indicated by the number of the carbon
H H
(ii) (m)
FIG. 2. 5«-Androstane (II); 5/3-androstane (III).
atom which has the lower number of the pair and is placed before
the suffix "ene" (e.g., androst-4-ene and the alternative, A4-an-
drostene). In cases in which the double bond does not lie between
numerically consecutive carbon atoms, the second carbon atom of
the double bond is indicated in parentheses (e.g., androst-5(10)-
ene or androst-9(l l)-ene).
5. Hydroxyl groups are indicated by the suffix "ol" or by the
prefix "hydroxy." Keto groups are designated by the prefix "oxo" or
"keto" or the suffix "one."
6. Following the only-one-suffix rule, we never use more than
one suffix, that is, a designation such as androst-4-en-17/3-ol-3-one
is avoided, and among suffixes we include only the abbreviations of
functional groups.
As an example, we now are going to apply these various rules to
17a-methyltestosterone (Fig. 3). In the following tabulation we
have listed various possible names of this same compound:
(a) Methyltestosterone (trivial name)
(b) Methylandrostenolone (trivial name)
(c) 17a-Methyl-A4-androsten-17/3-ol-3-one
(d) 17a-Methyl-4-androsten-17£-ol-3-one
(e) 17a-Methylandrost-4-en-17j8-ol-3-one
(f) 17a-Methyl-17/3-hydroxy-A4-androsten-3-one
(g) 17a-Methyl-17/3-hydroxy-4-androsten-3-one
(h) 17a-Methyl-17j8-hydroxyandrost-4-en-3-one
NOMENCLATURE AND CHEMISTRY 5
Version (h) shall be the prototype of the systematic nomenclature
adopted in this monograph.
(IV) (v)
(VI)
FIG. 3. Testosterone (IV); 17a-methyltestosterone (V); 19-nortestosterone (VI).
7. Trivial names or common names of anabolic steroids will not
be used, with the exception of testosterone. The same is true for
semisystematic designations, such as chlorotestosterone, dihy-
drotestosterone, or other similar ones; the only exceptions to this
rule are 17a-methyltestosterone and 19-nortestosterone.
All other compounds will be named according to systematic
nomenclature. Although this procedure renders the text less read-
able, it is more precise and eliminates any confusion which could
arise from the use of various trivial names found in different
languages.
Some of the more frequently found trivial names and their corre-
sponding systematic designations are gathered in Table 1.
8. The prefix "nor-" is used for substances in which a methyl
group has been replaced by a hydrogen atom; 19-norsteroids, con-
sequently, are steroids in which the C-19 methyl group is missing
(Fig. 3). The terminology of the anabolically active 19-norsteroids
has become muddled by the possibility of two derivations. For one,
6 II. NOMENCLATURE AND CHEMISTRY
TABLE 1
Trivial Names and Systematic Designations of
Therapeutically Used Anabolic Steroids
Abbreviation or trivial name Systematic designation
Methandienone; 17a-Methyl-17/3-hydroxyandrosta-1,4-dien-3-one
methandrostenolone
Methenolone 1 -Methyl-17/3-hydroxy-5a-androst-1 -en-3-one
Oxymetholone 17a-Methyl-17/3-hydroxy-2-hydroxymethylene-
5a-androstan-3-one
Fluoxymesterone 17a-Methyl-11/3,17/3-dihydroxy-9a-fluoro-
androst-4-en-3-one
Norethandrolone; 17a-Ethyl-17/3-hydroxy-19-norandrost-4-en-
ethylestrenolone 3-one
Nandrolone phenylpropionate; 17£-Hydroxy-19-norandrost-4-en-3-one
NTPP phenylpropionate
Ethylestrenol 17a-Ethyl-19-norandrost-4-en-17/3-ol; 1 la-
Ethylestr-4-en-17j3-ol
Oxymesterone 17a-Methyl-4,17/3-dihydroxyandrost-4-en-3-one
Stanolone; androstanolone; 17/3-Hydroxy-5a-androstan-3-one
dihydrotestosterone
Androstanazole; stanazole 17a-Methyl-17/3-hydroxy-5a-androstane-(3,2-c)-
pyrazole
Chlortestosterone 17/3-Hydroxy-4-chloroandrost-4-en-3-one
Methylandrostenediol; 17a-Methylandrost-5-en-3/3,17j8-diol
MAD; methandriol
Norbolethone DL- 13/3,17a-Diethyl-17j8-hydroxygon-4-en-3-one
Bolasterone 7a, 17a-Dimethyl-17/3-hydroxyandrost-4-en-
3-one
Dimethazine 2a, 17a-Dimethyl-17j8-hydroxy-5a-androstan-
3,3'-azine
compounds can be derived from 19-norandrostane, and on the other,
from the basic hydrocarbon of the estrogens, estrane (compare
Table 1: ethylestrenolone and ethylestrenol). Since there is a tend-
ency to associate substances having the core designation "estr"
with estrogenic activity, we will use exclusively derivations from
the 19-norandrostane series. This also corresponds much better
with the historical development. The steroidal hydrocarbon skeleton
gonane differs from androstane by the absence of both the C-18
and C-19 methyl groups (e.g., see Fig. 12).