0163-769X/87/0801-0001$02.
00/0
Endocrine Reviews
Copyright © 1987 by The Endocrine Society
Biological Actions of Androgens
A. D. MOORADIAN, J. E. MORLEY, AND S. G. KORENMAN
Geriatric Research, Education and Clinical Center and Department of Medicine, Sepulveda Veterans
Administration Medical Center, Sepulveda, California 91343; and Department of Medicine, University of
California, Los Angeles, California 90024
HILE the role of estrogens in women has received
a great deal of scientific attention, the analogous
questions regarding the role of androgens in men have
received relatively little attention. To date we do not
know the frequency or extent to which men become
androgen deprived as they age, the consequences for
longevity, and the adverse effects of androgen deficiency
on the quality of life. This review is designed to focus on
the biological actions of androgens and on the conse-
quences of a decline in androgen availability. The secre-
tion and metabolism of androgens to biologically active
products will be discussed briefly. We will not emphasize
the developmental effects of androgens or elaborate on
the molecular mechanism of transcriptional control. We
will try to distinguish between physiological and phar-
macological effects of the hormones and will attempt to
identify the active product responsible for the action in
the tissue of interest.
Figure 1 outlines the hypothalamic-pituitary testicular
system. Testosterone (T), the principal circulating an-
drogen is secreted by testicular Leydig cells under LH
stimulation. Down-regulation (loss of available recep-
tors) and desensitization (loss of steroidogenic response)
rapidly follow continuous LH or human CG stimulation
(1, 2). Thus, the pituitary, and secondarily, the Leydig
cell have adapted to pulsatile release of GnRH followed
by pulsatile secretion of LH. Androgens appear to slow
the hypothalamic GnRH pulse generator while estrogens
derived from T seem primarily to affect pulse height at
the pituitary level (3, 4).
For tissues the available T (BT) is the sum of T weakly
bound to albumin and that unbound to a protein (see
Fig. 1), rather than dialyzable T (5, 6). Sex hormone
binding globulin (SHBG) is a hepatic secreted protein,
binding primarily T and other 17 /3-hydroxylated steroids
including estradiol (7). Its secretion is enhanced by es-
trogens and suppressed by androgens.
Address requests for reprints to: Dr. S. G. Korenman, Department
of Medicine, Sepulveda Veterans Administration Medical Center, Se-
pulveda, California 91343.
Vol. 8, No. 1
Printed in U.S.A.
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Secreted T is metabolized in the liver by oxidation to
4-androstenedione and by reduction to a series of 5-a- or
5-jS-reduced, 3,15, and 16 hydroxylated compounds. The
reduced metabolites are conjugated to yield glucuronides
or sulfates and are excreted in urine (8). These com-
pounds are largely inactive with the exception of 3a-
hydroxy-5/3-androstane-17-one (etiocholanolone) and
similar compounds that may have selective inflammatory
and hematopoietic effects (see below).
Although there is a diurnal and seasonal variation of
total T levels, there are no data on the fluctuations of
BT concentration (9, 10). The level of T peaks from
0600-0800 h, falls slowly by about 35% during the day,
and begins to rise again at about midnight. This peak is
attenuated in the elderly (10). The loss of diurnal varia-
tion occurs with a fall in the frequency of LH pulses (11).
T production and clearance both decline substantially
with age, with mean T and BT levels declining slowly
after the age of 50. Mean gonadotropin levels slowly rise.
The variance in these alterations is substantial, and
many men retain both normal androgen levels and sper-
matogenesis into advanced age (12-15).
T acts on most body tissues (Fig. 1). The active intra-
cellular hormone depends on the tissue responding. Adult
reproductive tissues convert T to 5a-dihydrotestosterone
(DHT); muscle utilizes T; and adipose tissue, certain
brain nuclei, and other tissues aromatize T to estradiol.
In reproductive tissues T is reduced to DHT via the
enzyme 5a-reductase (16). Because the androgen recep-
tor binds DHT with a higher affinity than T and is thus
activated at lower concentration, the androgenic effect
of circulating T is markedly enhanced (17). DHT is found
in high concentrations in the prostate, in benign pros-
tatic hyperplasia (BPH) tissue, and in other reproductive
tissues (18), and thus their androgenic state need not
relate very closely to the circulating T level. In reproduc-
tive targets, DHT is further metabolized to 3a-17/3-
androstanediol by a 3a-hydroxysteroid dehydrogenase
and to other 3j8-metabolites. These steps may be followed
by jS-glucuronide conjugation, which is believed to play a
 MOORADIAN, MORLEY, AND KORENMAN
Testis
AROMATIZATION 5 o, REDUCTION DIRECT
Adipose Sexual Behaviors Reproductive Tissues Muscle
FIG. 1. The hypothalamic-pituitary-testicular system. SHBG, Sex
hormone binding globulin.
major role in androgen removal from the reproductive
target, at least in prostate (19). Thus, the tissue concen-
tration of androgens is regulated by pathways of metab-
olism, and a disruption of the conjugation step could play
a role in the androgen excess found in prostatic hyper-
plasia.
T itself appears to stimulate an increase in muscle
mass and enhances oxygen consumption through the
action of a normal androgen receptor. Muscle 5«-reduc-
tase is present in only low concentrations so that DHT
cannot accumulate by local synthesis. The potential an-
drogenic action of circulating DHT in normal individuals
is not established.
T is aromatized to estradiol in certain central nervous
system nuclei, in Leydig and Sertoli cells, and in adipose
tissue to act presumably via the estrogen receptor to
produce effects on sexual behavior, spermatogenesis, and
other functions.
Androgens may also have biological effects as anties-
trogens by competing for the estrogen receptor (20, 21).
They may act in the liver on mixed function oxidases
and specific cytochrome P450 enzymes by mechanisms
that do not involve receptor activation. They may also
affect tissues such as the liver by secondary effects on
enzyme systems regulated through the hypothalamic-
pituitary axis.
Unlike the glucocorticoid, estrogen, and progesterone
receptors, the androgen receptor has not yet been cloned,
and its role in activating a specific gene(s) has not been
elucidated. The androgen receptor is localized primarily
to the nucleus. By analogy to the other steroid receptors
it should undergo a conformational change when its
Vol. 8, No. 1
steroid-binding domain is occupied upon exposure to
DHT. This makes it possible for the DNA-binding do-
main to attach to one or more specific regions of DNA
the promoter regions, within or near androgen-depend-
ent or modulated genes. The binding conformation prob-
ably makes available one or more newly discovered oli-
gopeptide sequences, termed fingers, that intercalate
closely with DNA. As a consequence of DNA binding, a
complex is formed that, in concert with other enhancer
and inhibitor proteins, initiates or accelerates androgen-
regulated transcription. Relatively little is known about
androgen gene products, i.e. androgen-dependent pro-
teins, and their roles in the body's economy.
This review will describe current knowledge concern-
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ing the effects of androgens in specific tissues. We hope
that by clarifying the roles of androgens, we will be
building a platform supporting a greater and more defin-
itive effort in andrology.
Reproductive Tissues
Reproductive tissues under androgenic control
undergo enormous prenatal and pubertal developmental
changes (22-27). Androgens are also required for their
maintenance so that castration in adulthood results in
regression of the male secondary sex tissues.
Prostate
Prostatic growth in the rat and dog is stimulated by
DHT which appears to be the principal intracellular
androgen in that tissue (28, 29). Evidence for the impor-
tance of DHT in human prostatic growth may be derived
from the absence of significant prostatic development in
subjects with a 5«-reductase deficiency despite their high
T levels (30-32). The use of a 5a-reductase inhibitor
with exogenous T administration inhibited prostate
DHT formation and caused regression of prostate size
(33, 34) indicating that intraglandular DHT formation
is essential for the anabolic effects of androgens on the
prostate. Castration prevents prostatic development in
dogs and humans (35, 36). In response to androgens the
periurethral prostate sends epithelial ductal branches
into the surrounding stroma throughout life. In rat pros-
tate, the level of several androgen-dependent enzymes,
including acid phosphatase and aldolase, increases mark-
edly in response to androgens (37, 38). Androgen-de-
pendent messenger RNAs (mRNAs) have been charac-
terized and cloned (39-44). Three of these code for pep-
tide subunits of prostatic binding protein, which com-
prises 50% of rat ventral prostate cytosolic protein (39,
40, 42) but is only a minor product of the dorsal lobe,
demonstrating the regulatory differences between the
lobes. There are quantitative differences in specific an-
February, 1987 BIOLOGICAL ACTIONS OF ANDROGENS
drogen-dependent nuclear proteins in ventral and dorsal
prostate as well (45-47).
The effects of androgens are modulated by other hor-
mones and even by glucose. Under in vitro conditions
glucose modulates the expression of some androgen-
controlled proteins (48) and induces protein synthesis in
the prostate of castrated T-treated rats, but has minimal
effect on the prostate of untreated castrated rats (48, 49).
Estradiol enhances androgen-mediated growth (50, 51)
and cytoplasmic DHT receptors in dog prostate (52).
The type of prostatic growth produced by the combina-
tion of an androgen and an estrogen is morphologically
distinct from that produced by androgens alone. While
androgens produce glandular hyperplasia, the combina-
tion of androstanediol and estradiol induces stromal
hyperplasia with squamous metaplasia and cyst forma-
tion (53,54) suggesting that estrogen action is not limited
to induction of androgen receptors.
PRL appears to have a synergistic role with T in the
regulation of acid phosphatase activity and its isozyme
pattern in rat prostate and seminal vesicles (55). A
variety of progestins have been found to have either
synandrogenic or antiandrogenic activity in prostate
(56). This is probably due to the intrinsic chemical
structure of the agents to act as agonists or antagonists
of androgen action.
BPH
In humans, dogs, and lions hyperplasia of the prostate
is common. While in dogs and lions rectal obstruction is
the principal symptom, in humans, obstruction of the
urethra is predominant. The periurethral glands whose
overgrowth produces the syndrome are the most andro-
gen-sensitive part of the human prostate. However, the
role of androgens in clinical BPH, beyond the permissive
one of androgen sufficiency for tissue growth and devel-
opment, has not been established. This is due, in part,
to the fact that intraprostatic androgens are only mar-
ginally related to circulating hormone concentrations.
BPH tissue accumulates androgen to a much greater
extent than normal prostate, although the rate of con-
version of T to DHT is similar (57, 58). The ratio of
DHT to 3a-androstanediol is much higher in BPH tissue
than in normal prostate (18, 57, 59-62).
Serum T and free T are reduced with age, and the
concentration of DHT is unchanged (10, 12-15). While
the production rate of T and its metabolic clearance is
reduced in the elderly, DHT production is not (63).
Evidence from Horton's laboratory (19) suggests that
clearance of androgens from the prostate involves local
irreversible 17/3-glucuronyl-conjugation of 3«-andro-
stanediol (a-diol) and release. Horton and co-workers
were able to show that virtually all of the a-diol in the
plasma or urine is formed in extrasplanchnic tissues such
as the prostate. This conversion as measured by the
transfer of injected [3H]T to a-diol and its glucuronide
is reduced with age and in BPH (63) suggesting failure
of androgen clearance from the prostate may be respon-
sible for the hyperandrogenic state of the prostate leading
to BPH.
Epididymis
Androgen dependency of the other accessory sex or-
gans such as epididymis, vas deferens, and seminal ves-
icles is also well established (64-66). Castration results
in rapid regression of the secretory epithelium of the
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epididymis along with depletion of specific androgen
receptors and reduction in 5a-reductase activity (67-70).
Most of these alterations can be reversed by adequate
androgen replacement. Exogenous androgen treatment
does not completely restore epididymal secretory func-
tion (71, 72). It is possible that some androgen-dependent
functions are regulated via seminiferous tubular fluid,
which delivers large amounts of T and DHT to the initial
segment of epididymis (73, 74). Such high tubular andro-
gen concentrations may be difficult to achieve by exog-
enous administration.
The process of sperm maturation in the rat epididymis
is dependent, at least in part, on specific secretory epi-
didymal proteins (SEP) (64, 75, 76). The two components
of SEP are glycoprotein C (60% of SEP) and glycoprotein
DE (40% of SEP) (76). Androgen regulation of these
specific proteins appears to occur both at the level of
synthesis (76) and of N-glycosylation (77).
Seminal vesicle
The structural and functional integrity of the seminal
vesicles, in particular the epithelial component, is andro-
gen dependent (78-86). T promotes the synthesis of
major secretory proteins (proteins S and F) by regulating
the steady state levels of their mRNAs (79, 80). Studies
in isolated seminal vesicle epithelium demonstrated that
administration of T, but not DHT, to adult castrated
male guinea pigs returned in vitro protein synthesis,
cytoplasmic protein content, and wet weight to control
levels (82). Injection of diethylstilbestrol had an inhibi-
tory effect on these parameters, indicating an antiandro-
genic effect of estrogens in this tissue (82). The smooth
muscle of the guinea pig seminal vesicle is sensitive to
both androgens and estrogens, and the androgens appear
to have a permissive role in estrogenic action on seminal
vesicles (84, 87). Thus, estrogens and androgens have a
synergistic role in maintenance or restoration of the
smooth muscle component of seminal vesicles, whereas
in the epithelium estrogens appear to be antiandrogenic.
The observation that inhibition of prostaglandin syn-
 MOORADIAN, MORLEY, AND KORENMAN
thesis suppresses the proliferative response of the sem-
inal vesicle to T but not to DHT (88) suggests involve-
ment of prostaglandins in the mitogenic effect of T on
the seminal vesicles and further suggests that T and
DHT may have different mechanisms of action in this
gland.
Penis
Androgens are essential for normal organogenesis of
the penis, and castration causes mild involution. In the
rat, the penile spines, cornified structures projecting
from the surface of the glans penis, are androgen de-
pendent. Castration causes a decrease in their number
and size while androgen treatment restores normal mor-
phology (89, 90). These structures may function as tactile
sense organs (89) and influence sexual behavior. Hence,
in addition to the central nervous system effects, andro-
genic stimulation of sexual behavior in the rat is in part
due to peripheral effects. This peripheral component
must be a minor one because DHT, a potent peripheral
androgen that is presumably devoid of any central nerv-
ous system effect on libido, does not restore sexual activ-
ity in castrated male rats (91).
Testes
The effect of androgens on the testes is of special
interest because of its dual function as the major source
of androgens, and of gametogenesis. The identification
of specific androgen receptors in purified rat Leydig cells
suggests an autocrine function of androgens in these cells
(92). T is required for normal spermatogenesis in mam-
mals. T alone can stimulate spermatogenesis in hypophy-
sectomized rats (93, 94), monkeys (95), and in stalk-
sectioned rhesus monkeys in the absence of gonadotro-
pins and in the face of high PRL and estradiol levels
(96). Similar findings have been reported in hypogonadal
men, but the interpretation of these reports is compli-
cated by the fact that measurable endogenous gonadotro-
pins were found in these patients (97, 98). It has been
postulated that the androgenic action on spermatogene-
sis is mediated by the Sertoli cells. These cells possess
androgen receptors (99, 100) and show an appropriate
temporal relationship between nuclear accumulation of
androgen and stimulation of RNA polymerase II activity
(101).
Muscle
Skeletal muscle
In 1935, Kochakian (102) reported that the injection
of a fat-soluble extract from human male urine resulted
in a marked decrease in the urinary excretion of nitrogen
along with an increase in body weight in castrated dogs.
Vol. 8, No. 1
With the availability of synthetic T, the nitrogen-retain-
ing ability of androgens was soon documented in humans
as well (103). Subsequent experiments in castrated rats
and mice demonstrated that long term androgen admin-
istration resulted in alterations in body composition,
favoring the accumulation of muscle mass and loss of
adipose tissue (104-106). The response to androgens
differs among muscle groups with muscles from the
shoulder, back, and head showing a greater response than
muscles from the chest and the hind legs (Fig. 2) (107,
108). Castration or T administration does not alter the
number of myofibrils, and the changes in the weight of
the muscles are due to atrophy and hypertrophy of indi-
vidual fibers (22, 107, 108).
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The mechanism by which androgenic steroids affect
muscle remains largely unknown. Although the presence
of androgen receptors in skeletal muscles was once ques-
tioned (109-111), skeletal muscle and levator ani muscle
in the rat have androgen receptors with binding charac-
teristics similar to the receptors in other androgen tar-
gets (112-118). The higher level of cytosolic androgen
receptors in the levator ani muscle compared to other
skeletal muscle in the rat may explain the greater sen-
sitivity of this muscle to alterations in serum androgen
concentrations (116). The affinity and maximal binding
capacity of muscle androgen receptors are higher in
female rats, and short term castration eliminates the sex
differences, suggesting that the testes may have some
role in the regulation of androgen receptors (114).
T stimulates mitotic activity in a myoblast culture
system (119). The relevance of this observation to the
anabolic effect of androgen on muscle in vivo is not
readily apparent as T produces hypertrophy, not hyper-
plasia, of muscle. Androgens directly initiate a variety of
biochemical changes in skeletal muscle, including an
increase in RNA polymerase activity (120), enhanced
uptake and phosphorylation of 2-deoxyglucose (121,
122), enhanced glycogen synthesis (123, 124), and in-
creased uptake of radioactive xylose (121). T administra-
tion in rats resulted in a net increase in protein synthesis
and RNA polymerase activity in the gastrocnemius and
quadriceps (125). However, in normal rat gastrocnemius,
T administration did not alter the biochemical parame-
ters related to energy metabolism, indicating that the
effect of pharmacological doses of androgens on normal
muscle is minimal (126). This is in line with the results
of carefully conducted double-blind studies indicating
that androgenic anabolic steroids do not improve physi-
cal performance of male athletes (127-129). The question
remains open as to whether a slight improvement in
performance by some individuals may be crucial in com-
petition. Similarly, in rats, androgens do not influence
the compensatory hypertrophy due to muscle overload
(130).
February, 1987 BIOLOGICAL ACTIONS OF ANDROGENS
SCI HCADftNCCK SHOULOCN CXST BOOT WALL
••AC* ftSPINl
FlG. 2. The response of the individual muscles of the castrated male guinea pig to T stimulation. (Reproduced with permission from C. D.
Kochakian et al.\ Endocrinology 58:315,1956 (107).]
There are no purely myotropic or anabolic androgenic
steroids. Developing such an agent may be impossible
because the androgen receptors in muscle and accessory
sex organs appear to be identical (112-118, 131-133).
Thus, when a number of anabolic androgenic steroids
were tested, the ratio of the relative binding affinity in
rat muscle to that in the prostate was close to unity
(131). A major biochemical difference between muscle
and accessory sex organs is the low 5a-reductase activity
in muscle tissue compared to accessory sex organs (134-
135). Hence, it may be possible to dissociate myotropic
from androgenic effects if the candidate steroid were to
undergo a rapid and complete 5a-reduction in accessory
sex organs to inactive metabolites. The possible my-
otropic-androgenic dissociation of nortestosterone has
been attributed to a significant decrease in binding affin-
ity of dihydronortestosterone to the androgen receptor
compared to DHT (136, 137).
Cardiac muscle
A physiological role of androgens in heart muscle is
suggested by the presence of specific androgen receptors
in the myocardium of rats (138,139), baboons, and rhesus
monkeys (140,141). The affinity and binding capacity of
myocardial androgen receptors are similar to those of
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SCAPULA FOftCAftM SHANK
skeletal muscle. However, androgen concentrations are
higher in cardiac tissue than in striated muscle (142).
Myocardial 5a-reductase activity estimated indirectly
from the tissue DHT plus 5-androstane-3a,17/?-diol to T
ratio, like the 5a-reductase activity in striated muscle, is
low (142,143). Androgens can induce morphological (144,
145) and biochemical changes (146,147) in heart muscle.
Electron microscopic studies of left ventricular tissue of
rats treated with methandrostenolone revealed a signif-
icant increase of intermediate sized nonmyofibrillar fil-
aments which may function as a cytoskeleton to provide
support during ventricular contraction. Moreover, andro-
gens potentiate GH-induced cardiac growth (148),
whereas castration is associated with a reduced rate of
aortic banding-induced cardiac hypertrophy (149). This
effect was attributed to reduced nucleic acid and protein
synthesis. Castration inhibits cardiac growth in rats
(147) and mice (105), and T administration results in an
increase in myocardial RNA and protein content, indi-
cating (148) an anabolic effect.
Substantial alterations in left ventricular function
have been observed in rats using the isolated working rat
heart preparation. Schaible et al. (147) found that cas-
tration resulted in a significant downward shift in the
mean force-velocity relationship at moderate and high
left atrial pressures. The decrease in contractile function
 MOORADIAN, MORLEY, AND KORENMAN
was associated with a significant reduction in Ca++ my-
osin ATPase activity along with preferential accumula-
tion of the V3 myosin isoenzyme and reduction of the
VI isoenzyme. Since those experiments were carried out
in rats castrated prepubertally, it is not certain whether
these effects of androgens are exerted after puberty. In
mature female rats exercise-induced cardiac hypertrophy
is not associated with any alterations in ventricular
cytosol androgen receptor affinity or binding capacity,
or serum concentrations of total or free T and DHT.
Nevertheless the relatively high androgen levels in fe-
male rats suggest that androgens may play a significant
role in exercise-induced cardiac hypertrophy (139).
Smooth muscle
The effect of androgens on smooth muscle has not
been studied extensively. The smooth muscle of the
guinea pig seminal vesicle is sensitive to androgens with
castration resulting in a significant reduction in muscle
weight and cell size, while cell number and collagen
content do not change (84-87, 150). These alterations
could be reversed by 4 weeks of androgen treatment (84).
Androgens also regulate the stimulatory effects of estro-
gen on seminal vesicle smooth muscles without changing
estrogen receptor binding parameters (87). The under-
lying mechanism of this cooperative interaction is not
clear. The androgen sensitivity of smooth muscle tissue
from other organs has not been studied extensively.
Summary
Androgens produce their effects on muscle by direct
interaction with the T receptor (Fig. 3). The major effect
is muscle hypertrophy, with T producing minimal or no
EFFECTS ON MUSCLE ARE MEDIATED BY TESTOSTERONE
AS 5 aREDUCTASE LEVELS ARE LOW
SKELETAL MUSCLE
V t MUSCLE WEIGHT I 8UE 1. HYPERTROPHY
2. NO CHANGE M CELL NUMBER 2. NO CHANGE IN NUMBER
OR COLLAGEN CONTENT OF MYOFIBRILS
3.tPOLYMERA3E
4. t GLYCOGEN SYNTHESIS
5. • UPTAKE 1
PHOSPHORYLATION Of
2-OEOXY-GLUCOSE
CARDIAC MUSCLE
1. POTENTIATE GROWTH
HORMONE INOUCED
CARDIAC GROWTH
2. t INTERMEDIATE SIZE
NON-MYOFIBRILLAR ELEMENTS
GROWTH HORMONE 3.tMYOCARDIALRNA
FIG. 3. Diagramatic representation of the androgen effects on muscle.
Vol. 8, No. 1
effects on muscle cell number. T may potentiate mus-
cular growth produced by GH.
Central Nervous System
Since antiquity, humans have linked T status with
behavior (151). Thus, Areteus the Cappadocian docu-
mented some of the effects of T as follows: "For it is the
semen, when possessed by vitality, which makes us to be
men, well braced in limbs, hairy, well voiced, spirited,
strong to think and to act, as the characteristics of men
prove. For when the semen is not possessed of its vitality,
persons become shrivelled, have a sharp tone of voice,
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lose their hair and their beard and become effeminate,
as the characteristics of eunuchs prove." Leonardo da
Vinci reported on the relation of male hormones to
emotion and libido as follows: "Testicles witness of coi-
tion. These contain in themselves ardour, that is they
are augmenters of the animosity and ferocity of the
animals; and experience shows us this clearly in castrated
animals, of which one sees the bull, the boar, the ram
and the cock, very fierce animals, which after having
been deprived of their testicles, remain very cowardly; so
one sees a ram drive before it a herd of whethers, and a
capon put to flight by a number of hens."
From these shaky beginnings, today it is within the
central nervous system that the relative roles of T, DHT,
and estrogens in producing the varying effects of T
administration have been characterized best. Recently,
two excellent reviews of the effects of T on the central
nervous system have been published, and the reader is
referred to these for an in-depth overview of this subject
(152,153).
Studies by Phoenix and colleagues (154) in 1959
showed that androgens acted directly on the brain. They
suggested that androgens, during early development,
acted to organize neural pathways responsible for male
behaviors, while in adults, androgens acted on differen-
tiated pathways to activate previously organized behav-
iors.
Androgen receptors in brain tissues show similar phys-
icochemical properties to those of the prostate, recogniz-
ing both T and DHT (155). In primates and rodents
androgen receptors are concentrated in the pituitary,
hypothalamus, preoptic area, septum, and amygdala,
with the lowest concentrations being in the cerebellum
(152, 156). Aromatization of T to E2 varies from region
to region also with the enzymatic activity being absent
from the pituitary and cerebral cortex and present in the
hippocampus, amygdala, and preoptic area (152). The
activity of 5a-reductase is distributed throughout the
central nervous system and, thus, does not appear to be
a limiting factor in androgen occupancy of receptors
(152). However, 5a-reductase activity is higher perina-
February, 1987 BIOLOGICAL ACTIONS OF ANDROGENS

tally than in the adult, suggesting a role for DHT in

ESTRADIOL: t NEURONAL SIZE )
neuronal organization (157-159). SPACING \
Perhaps the best studied aspects of sex steroid effects DHT: t CELL NUMBER J
ALL NUCLEI: ESTRADIOL or
TESTOSTERONE MASCULINIZE;
HV DHT IS INEFFECTIVE

on the brain have been the reports of large anatomical

sex dimorphisms. In 1973, Raisman and Field (160)
showed that dendritic synapses in the rat preoptic area
differed between sexes and could be manipulated by
alterations in neonatal androgen levels. In 1976, Toran-
Allerand (161) demonstrated that both androgens and
estrogens enhance neurite outgrowth from hypothalamic
explants in neonatal mice. Since then, five androgen-
dependent anatomical areas have been clearly identified:
1. Greater size of brain regions involved in vocalization

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in male passerine birds than in females (162).
2. The sexually dimorphic nucleus of the preoptic area
which is much larger in male rats (163).
3. Increased size in the middle portion of the medial
amygdaloid nucleus in male rats (164).
4. Male/female differences in the neuronal number of
motor neurons innervating the bulbocavernosus (165).
5. The smaller size of the superior cervical ganglion in
females compared to male rats (152).
In many songbird species, the male sings whereas the
female does not. Song has been shown to be a learned,
complex, steroid-dependent behavior. The anatomical
substrate of birdsong has been elucidated and consists of
five forebrain nuclei as well as single nuclei in the thal-
amus, midbrain, and hindbrain (Fig. 4A and Ref. 166).
Several of these areas selectively take up androgens
(167), and in species such as the zebra and Bengalese FIG. 4. A, Diagramatic representation of the effects of T and its
finch, where the female fails to sing even after admin- metabolites on the anatomical areas involved in birdsong. B, Diagra-
stration of exogenous T, there are marked differences in matic representation of the masculinizing effects of T on the sexually
the size of the brain nuclei involved in generating song dimorphic nucleus of the preoptic area (SDN-POA).
(166). The larger size of the male song nuclei appears to
be due to neonatal sex steroid effects. Neonatal admin- the preoptic area (SDN-POA). Castration of the newborn
istration of estradiol masculinizes (increases the volume rat markedly decreases the volume of this nucleus, and
of) the hyperstriatum ventrale pars caudale (HVc) and the castration effects can be reversed by administration
the robust nucleus of the archistriatum (RA), while hav- of T (163). Estrogens administered postnatally to females
ing no effect on the nucleus intercollicularis (ICo) (168). increase the volume of this nucleus, suggesting that it is
On the other hand, DHT has less effect on the HVc and the aromatization of T to estrogen that produces the
the RA, while increasing the volume of the ICo. In the masculinizing effects on the SDN-POA (165, 171). Fur-
RA, estradiol doubles neuronal size and increases the ther evidence for the role of estrogen in masculinization
spacing between neurons but has only a very small effect of the nucleus comes from the testicular feminized mu-
on cell number. On the other hand, DHT exerts its major tant rats (Tfm) in whom the volume of the SDN-POA is
effect on cell number (169). Further, estradiol neonatally normal in adults, despite a marked decrease in androgen
appears to protect against cell death and sensitizes the receptors (170). The amygdala is one of the main com-
song system of adult females to androgen treatment. It ponents of the extrahypothalamic gonadotropin-regulat-
should be noted that while both neonatal estradiol and ing system and plays a role in the regulation of a number
T masculinize the female vocal system, DHT is ineffec-
of male behaviors. Electrophysiological studies have sug-
tive (166)
gested that male rats have more synaptic connections
Within the preoptic area, a cluster of intensely staining projecting from the medial amygdala to the POA than
neurons, which has 3 to 7 times greater volume in the do female rats or neonatally castrated rats. Nishizuka
male rat, has been identified (Fig. 4B and Ref. 170). This and Arai (164) have shown that the middle part of the
area has been named the sexually dimorphic nucleus of medial amygdaloid nucleus of male rats has a significant
8 MOORADIAN, MORLEY, AND KORENMAN
increase in shaft synapses made on dendritic spines
compared to female. Neonatal administration of T to
females increases the number of synapses to male levels,
and neonatal orchiectomy decreases the number to fe-
male levels. Thus, the medial portion of the amygdala
appears to be another sexually dimorphic area of the
brain.
The lumbar spinal cord nucleus of the bulbocavernosus
(SNB) provides motor neurons to the bulbocavernosus
and the levator ani which are attached to the penis in
the male and are absent in the female rat. The female
has only one-third the number of neurons in the SNB
that the male has (172). Castration in adult male rats
decreased both dendritic length and soma size of these
neurons (173). These effects were reversed by T treat-
ment. The Tfm mutation has very few SNB neurons,
suggesting that it is T and not estrogen that controls
development of this nucleus (172, 174). Perinatally, the
antiandrogen, flutamide, decreases the size of the male
SNB, whereas androgens masculinize the female SNB
(153). T appears to control the neuronal number whereas
DHT has a more potent effect on neuronal size (175,
176).
The superior cervical ganglion of adult male rats is
23% larger and contains 16% more ganglion neurons
than does that of adult females (177). Neonatal T ad-
ministration to females increased the number of neurons
in this ganglion (178). This T-induced increase in post-
ganglionic neuron number has been ascribed to the abil-
ity of T to increase nerve growth factor (179). Nerve
growth factor increases neuronal survival (180, 181). T,
however, fails to increase the numbers of preganglionic
axons or the nuclear diameter of postganglionic neurons,
effects which are produced by nerve growth factor (180-
182). This suggests that T produced its effects independ-
ently of nerve growth factor.
The role of aromatization and 5«-reductase activity in
producing the effects of T on adults is less well studied.
However, Morali and colleagues (183) have shown that
aromatase blockers inhibit T-induced sexual behavoir in
castrated male rats. This suggests that aromatization of
T to estrogen plays an important role in the facilitation
of male sexual behavior. DHT given alone has minimal
effects on restoring sexual behavior in castrated animals
(184, 185). On the other hand, 17/3-estradiol does not
produce the complete pattern of male sexual behavior
(186), whereas combinations of estradiol and DHT do
fully restore sexual behavior. Gray et al. (187) found that
in castrated male rats DHT restores penile erection while
estradiol activates mounting behavior but does not pro-
duce erections.
At the neuronal level, both T and estradiol have been
shown to modulate firing in preoptic tissue slices (188).
Neurons that are purely responsive to T have been
Vol. 8, No. 1
identified, as well as estradiol-sensitive neurons. Thus,
individual neurons may be sensitive to different active T
products. Aromatization of T in the central nervous
sytem is enhanced by high concentrations of cAMP
(189). The rapidity at which neurons respond to ionto-
phoretically applied T suggests that some of these effects
may be due to direct membrane effects rather than to
changes in protein synthesis after nuclear binding. Fur-
ther evidence for this hypothesis comes from the dem-
onstration that estradiol can directly modulate neuronal
activity by altering potassium channels. However, it is
not clear whether the local hormone concentration re-
mains in the physiological range under these circum-
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stances.
The regulation of food intake and body weight is a
complex process involving the integrative effects of mul-
tiple neurotransmitters and hormones (190). Adult male
rats eat more and exercise less than adult females (191).
Castration of adult male rats decreases food intake and
locomotor activity (192-194). Low replacement doses of
T restore food intake, whereas pharmacological doses
further reduce food intake. DHT increases food intake
(191). The decrease in food intake by high doses of T is
blocked by progesterone, as is the inhibitory effect of
estradiol on feeding, suggesting that this effect is due to
aromatization of T. On the other hand, estradiol stimu-
lates physical activity in castrated males, while DHT is
ineffective (195). Antiestrogens attenuate T-induced ac-
tivity (196), while the antiandrogen, cyproterone acetate,
failed to inhibit androgen-induced running (197). Thus,
T and DHT appear to be the main hormones enhancing
feeding in males, while aromatization to estrogens is
necessary for enhancement of physical activity in male
rats.
In the above section, it can be clearly seen that aro-
matization of T and 5«-reductase activity play a role
both in producing specific organizational effects on the
central nervous system during the perinatal period (Fig.
4) and in activating specific behaviors in the adult (Fig.
5).
Human sexual behavior
The relevance of androgens to sexual function is con-
troversial. In men, androgens appear to be necessary but
not sufficient for usual libido. In healthy older men,
higher T levels are associated with greater sexual activity
(198) whereas in younger men, no such relationship can
be discerned (199, 200). Lange et al. (201) suggested that
latency to erection stimulated by erotic material corre-
lates with T levels.
Three studies have shown that withdrawal of andro-
gens in hypogonadal males leads to a decline of libido 3-
4 weeks later (202-204). T replacement restores sexual
February, 1987 BIOLOGICAL ACTIONS OF ANDROGENS
COPULATION ACTIVITY
ESTROGENS ESTROGENS
-Aromatase Block era — - T 7 i
TESTOSTERONE'
SaReductase
\ either T decreases or estrogens increase the TSH re-
ESTROGENS WHYDROTESTOSTERONE
SEATING SEATING
FIG. 5. Diagramatic representation of the effects of T in activating
specific behavior in the adult.
interest in a dose-related manner (203, 205-209). Spon-
taneous erections are impaired in hypogonadal men
(210), and T replacement improves the latency, fre-
quency, and magnitude of the nocturnal penile tumes-
cence response (206, 211) as well as the frequency of
early morning erections (203, 207, 209). Androgens have
no effect on erections in response to erotic films (211,
212). Which of these effects are due to T per se and
which are due to aromatization to estrogens is unknown
as both cyproterone acetate and ethinyl estradiol impair
the erectile response to fantasy (213).
Pituitary Glycoprotein Hormones
LH
T clearly exerts a negative feedback on plasma levels
of gonadotropins in males. This feedback is at the level
of the pituitary as T inhibits LH secretion in response
to GnRH both in vivo (214) and in vitro (215). As T is
not aromatized to estrogen in the pituitary (vide supra),
it seems highly unlikely that it produces its effect as a
result of aromatization. The studies by Krey et al. (207)
clearly demonstrated that androgen receptors, rather
than estrogen receptors, mediate the inhibition of LH
secretion.
It is possible that the negative feedback effect of T is
dependent on 5«-reductase activity because the pituitary
androgen receptor binds both T and DHT (208, 216) and
the anterior pituitary converts T to DHT (209, 217, 218).
DHT more potently inhibits LH secretion in vivo (214,
219) and in vitro (215, 220). However, Liang et al. (221)
have shown, using two potent reversible 5a-reductase
inhibitors, viz. 17/^JV,JV-diethylcarbamoyl-4-methyl-4-
aza-5«-androstan-3-one and 17/?-iV,iV-diisopropylcar-
bomoyl-4-aza-5a-androstan-3-one, that the inhibitory
activity of T on LH release by pituitary cells in culture
does not require 5a-reduction.
TSH
The TSH response to TRH is greater in women than
in men (222). Primary hypogonadal men with increased
estradiol to T ratios have enhanced TSH responses to
TRH similar to normal women (223). This suggests that
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sponse. A number of studies have suggested that estro-
gens given to men may increase the TSH response to
TRH (224-226), although this has not been universally
the case (227, 228). Ethinylestradiol in hypogonadal
women enhances the TSH response to TRH (229). T
therapy has produced variable effects on the TSH re-
sponse to TRH (230-232). In order to examine the effect
of T per se on the TSH response to TRH, Morley et al.
(233) administered the nonaromatizable androgen, fluox-
ymesterone, to hypogonadal men. They showed that
fluoxymesterone impaired the TSH response to TRH
while not altering the PRL response. This suggests that
T per se can directly modulate pituitary TSH secretion.
It seems likely that estrogens enhance TSH response,
accounting for the controversial results obtained with
aromatizable forms of T.
In rats, sex steroids appear to have opposite effects.
The serum TSH concentration is elevated in male rats
(222), and T increases the basal and TRH-stimulated
TSH response (234). Estrogen effects are variable (222).
Thus, it seems that in rats T has a major effect on
modulating TSH secretion, although the effect is oppo-
site to that seen in humans.
GH
T therapy in boys with constitutionally delayed pu-
berty results in an increase in the 24-h integrated con-
centration of GH. T augments the GH response to argi-
nine or insulin. T enhances somatomedin-C concentra-
tions in prepubertal boys who can secrete GH but not in
those who are GH deficient. It is possible that the effects
of T on GH and somatomedin-C are secondary to aro-
matization to estrogens as physiological doses of estradiol
increase GH and somatomedin-C in postmenopausal
women.
Liver
A dependence of liver on testicular secretions was first
suspected when Kochakian (22) reported a small de-
10 MOORADIAN, MORLEY, AND KORENMAN
crease in the rate of growth of liver in castrated mice.
These gross morphological observations were supple-
mented with the finding of substantial androgen depend-
ence of certain hepatic enzymes such as fumarase and
catalase in the mouse (22, 235) and aspartic-glutamic
transaminase, alanine-glutamic transaminase, and d-
amino acid oxidase in the rat (22, 236). The effect of
androgens on these enzymes is tissue and species specific.
Castration results in a reduction of enzyme activity, and
T administration restores it to normal levels (22, 235,
236). However, the effect of androgens on hepatic enzyme
activity, in particular some steroid-metabolizing en-
zymes, can be inhibitory. Thus, castration increases the
activity of 5a-reductase and several hydroxylase enzyme
activities, and T treatment restores the levels (237-240).
Of particular interest are the male-specific T 16a-hy-
droxylase activity (241-244) and the female-specific 15/3-
hydroxylase (male concentration < 0.03% of the female)
(245,246). T treatment of female animals suppresses the
activity of the latter enzyme, while castration of the male
does not influence enzyme activity (245, 247). The 16a-
hydroxylase enzyme is induced at puberty, and neona-
tally it is "imprinted." This term refers to a property of
enzymes whereby neonatal androgens affect enzyme level
and responsiveness in adulthood. This phenomenon has
been described for both totally androgen-dependent and
partially androgen-dependent enzymes (237). It is note-
worthy that the effect of T on the activity of a family of
closely related enzymes such as the glutathione S-trans-
ferases substantially differ from the effects of 5a-reduced
metabolites (248), including DHT. This dichotomy in
the effect of closely related androgens indicates the com-
plex nature of the androgen effect on hepatic enzymes.
Although it is possible that some effects of androgen
on the liver are mediated via androgen receptor activa-
tion (249-252), it appears that most of the in vivo effects
of androgens on steroid metabolism are indirect and
involve the interaction of androgens with other hormonal
stimuli. Hypophysectomy abolishes the sex differences
in hepatic steroid metabolism (253-255). Similarly, the
effect of estrogens on reversing neonatal imprinting (256,
257) or feminizing the hepatic metabolism of the male
(258) could not be observed in hypophysectomized ani-
mals (259). Of the pituitary hormones tested, only GH
administration results in an increase of 5a-reductase
activity and a decrease in 6-hydroxylase and 16«-hy-
droxylase activities, suggesting that GH or a related
factor is responsible for the feminization of hepatic ste-
roid metabolism (260). Somatostatin also appears to be
involved in the feminization of steroid metabolism (237).
Intrapituitary or intrahypothalamic implantation of
estradiol results in feminization of steroid metabolism in
the liver, while sc injections of the same estrogen prep-
aration have no effect on this enzyme system (247).
Vol. 8, No. 1
Subcutaneous treatment of intact females with methyl-
trienolone, a nonaromatizable androgen with slight pro-
gestational activity, causes masculinization of hepatic
steroid metabolism but has no effect in animals with
anterior hypothalamic deafferentation (247). The finding
of modest hepatic trophic effects of the combination of
androgenic steroids and flutamide (androgen receptor
antagonist), in contrast to the lack of effect of either
agent alone (261), underscores the complexity of the
effects of androgens on the liver.
Hepatic microsomal drug-metabolizing enzyme activ-
ities are greater in male than in female rats. Orchiectomy
reduces the activities of these enzymes, and androgens
stimulate them (262). In this system, androgens appear
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to have two distinct effects (263): a nonreceptor-me-
diated stimulant effect on microsomal protein content
and total liver weight and receptor-dependent effects
that control, in part, the cytochrome P450-dependent
system. The response of this system to androgens is
attenuated by the use of flutamide (antiandrogen). In
Tfm rats, with an inherited defect of androgen receptors,
the hepatic microsomal enzymes do not respond to T
treatment (264). The response of individual microsomal
enzymes to androgens can be highly variable. The re-
sponses of the microsomal ethanol oxidizing system and
microsomal steroid sulfatase are concordant in the male.
In the intact female, T treatment induces microsomal
ethanol oxidizing system activity (265) but produces a
decline in sulfatase activity (266). In the castrated fe-
male, T treatment did not alter steroid sulfatase activity
(266). These observations indicate that androgen-de-
pendent control of hepatic steroid sulfatase is different
from that of other microsomal enzymes, in that it can be
modulated by estrogen or other ovarian factors.
a-2/n-Globulin accounts for greater than 50% of uri-
nary proteins in male rats, and the mRNA for this
protein makes up approximately 2% of the total hepatic
RNA. Excretion of this protein increases rapidly at pu-
berty in males while females excrete only trace amounts.
Its synthesis is induced by androgens and inhibited by
estrogens. The effects of gonadal steroids are mediated
by specific receptors that bind both DHT [dissociation
constant (Kd) 4.5 x 10"8 M] and estradiol (3.5 x 10~7 M).
This receptor shows sexual dimorphism and is absent in
females and in Tfm male rats. It fails to bind the antian-
drogens, cyproterone actetate and flutamide, and these
androgen antagonists fail to inhibit hepatic synthesis of
a-2n globulin. Like other androgen-dependent liver pro-
teins, a-2/i-globulin induction is dependent on an intact
hypothalamic-pituitary axis. Insulin also appears neces-
sary for the androgen effect as diabetic animals have an
80% reduction in synthesis and mRNA for a-2^-globulin.
The spectrum of androgen effects on the liver and
interactions with estrogens are demonstrable in the re-
February, 1987 BIOLOGICAL ACTIONS OF ANDROGENS 11

sponse of a variety of serum proteins to the hormones
(Table 1; see also text and Refs. 267-273). Although the
serum protein changes resulting from androgen treat-
ment generally tend to be in the opposite directions from
those produced by estrogens, there is concordance in the
net response of some proteins (32-39).
Androgens can sometimes be considered antiestrogenic
and at other times estrogenic. It is of interest that oral
17-alkyl-androgen therapy has been implicated in caus-
ing hepatic lesions (274-276) similar to those caused by
estrogen use, suggesting that the morphological changes
of the liver induced by these antagonistic steroids can be
comparable. Although the liver clearly shows sexual di-
morphism, it appears that the majority of these differ-
density lipoprotein cholesterol (HDL-C) is lower in men
and that triglyceride levels are higher compared to pre-
menopausal women (278, 279). There are no substantial
differences in serum HDL or triglyceride levels in pre-
pubertal children (267, 280-282). Cross-sectional and
longitudinal studies indicate that, during adolescence,
HDL-C decreases while low-density lipoprotein choles-
terol (LDL-C) and triglycerides increase in males (283-
285). Administration of T (286, 287) or anabolic steroids
(286-290) at high concentrations causes a reduction of
plasma HDL-C levels. On the other hand, inhibition of
T production with a GnRH analog in normal men pro-
duces a reduction of LDL-C and an increase in HDL-C
concentrations (291). A carefully controlled study in

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ences is due to indirect effects of gonadal steroids on the
production of pituitary hormones. In the majority of
cases the T effects appear to be stimulatory and the
estrogenic effects inhibitory suggesting a primary effect
of T rather than aromatization to estrogen. Although
androgen-binding proteins have been identified in the
liver, they appear to be different from the classical an-
drogen receptors and may be more involved in steroid
metabolism than in gene regulation.
Lipids
The effect of androgens on different lipoproteins is of
particular interest because it may explain, in part, the
higher prevalence of atherosclerosis and shorter life span
of men than women. In in vitro studies of rat hepatocyte
cultures, T has concentration-dependent, biphasic ef-
fects on triglyceride synthesis with lower doses being
inhibitory and higher doses losing this inhibitory effect
(277). Epidemiological studies have indicated that high-
TABLE 1. Effect of androgens and estrogens on circulating serum
protein concentrations
healthy people concluded that T has a strong negative
association with HDL in men and women when con-
trolled for other variables (292). Overall, the evidence
indicates that androgens lower HDL-C levels.
The androgen effect could be due to enhanced catab-
olism of HDL. Sexual dimorphism has been documented
in two of the enzymes responsible for HDL metabolism.
Lipoprotein lipase is greater in women than in men (293,
294), and hepatic endothelial triglyceride lipase is greater
in men (295) and is stimulated by androgens and sup-
pressed by estrogens (296). This is the enzyme primarily
responsible for the clearance of HDL. Oral anabolic
androgenic agents in women oppose the stimulatory ef-
fects of estrogens on the formation of HDL and very low
density lipoproteins, and enhance the HDL clearance by
the hepatic triglyceride lipase (297, 298). The observation
that boys with the highest estradiol levels had the great-
est fall in HDL-C and the highest ratio of LDL-C to
HDL-C with increasing T levels during puberty sug-
gested that at least part of the androgen effect is me-
diated by estrogens (284).

Androgens Estrogens Kidney

Total serum proteins 4 The response of mouse kidney to androgen has been
Albumin -* 4
T4-binding globulin used extensively in studies of the mechanism of androgen
1 T action (299, 300). Castration leads to atrophy, and an-
T4-binding prealbumin —> —*
Corticosteroid-binding globulin 4 T drogenic stimulation causes hypertrophy (22, 104, 301,
Sex hormone binding globulin 4 T 302). This phenomenon is species specific in that the rat
Transferrin 4 kidney shows only a modest response while guinea pig
Ceruloplasmin T and hamster kidneys show none (22, 303).
Haptoglobin t-> 4
ai-Antitrypsin T T The stimulatory effect of androgens on kidney weight
/3-Glucuronidase T T is accompanied by changes in the epithelial cells of
Sialic acid T 4 convoluted tubules, parietal cells of Bowmen's capsule
Orsomucoid T 4
Plasminogen
(22), and glomerular volume (304) occurring concomi-
-T t tantly with increased RNA and protein synthesis (305,
Fibrinogen 4 T
Clotting factors -T T 306). In ovariectomized female rats, treatment with es-
HDL 4 T tradiol, 19-nortestosterone, DHT, or methyltrienolone
LDL t 4 resulted in an increase in renal mass (307). Simultaneous
Very low-density lipoprotein 4 T administration of flutamide with methyltrienolone or
12 MOORADIAN, MORLEY, AND KORENMAN Vol. 8, No. 1

DHT could block the renotrophic effect of these andro-
gens, indicating that androgen receptors are involved.
The coadministration of maximum doses of estrogens
and androgens to male or female castrates leads to an
increase in renal mass exceeding the normal female/male
range (307), suggesting independent action of these two
gonadal steroids.
It is possible that some of the effects of androgens on
the kidney could be mediated via progestogen receptors.
It is noteworthy that the classification of progestins as
androgenic, synandrogenic, or antiandrogenic is based
on their ability to mimic, potentiate, or inhibit the effects
of androgens on the rate of synthesis of /?-glucuronidase
in renal proximal tubules and the rate of excretion of
reduction in azotemia is due to improved glomerular
filtration (320). Administration of anabolic steroids to
elderly, nonuremic subjects results in significant in-
creases in glomerular filtration rate, renal plasma flow,
and excretory rate of para-aminohippurate (TmPAH)
(321). With the exception of the last parameter, these
alterations are transient and attributed to the androgen-
induced hypervolemia. The persistent enhancement of
TmPAH levels by anabolic steroids deserves further
evaluation.
In summary, T has a direct effect on mouse kidney
growth and enzyme activity, independent of aromatiza-
tion. Some of the effects of androgens on the kidney are
blunted by hypophysectomy, suggesting that they may

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this and other lysosomal enzymes into urine (308). be indirectly mediated through the hypothalamic pitui-
There is a great diversity of response to androgens (22, tary axis. With the exception of stimulating erythropoi-
309-314) (Table 2). Of the many enzymes affected, the etin secretion, there does not seem to be any important
inductions of /3-glucuronidase and ornithine decarboxyl- effects on human kidney.
ase (ODC) have been studied extensively to elucidate the
molecular mechanisms of androgen action. Similar to Hematopoietic System
androgen effects on liver, some androgenic responsive-
ness of the kidney is mediated by the hypothalamic Over the last two decades numerous studies have in-
pituitary unit. Hypophysectomy reduces ODC activity in dicated that androgen may be beneficial in the treatment
the rat kidney but has no effect on ODC activity of of a variety of primary anemias and bone marrow failures
mouse kidney (315, 316). Similarly, androgenic control (322). The effect of androgens on erythropoiesis has been
of mouse renal alcohol dehydrogenase and D-amino oxi- inferred from the general observation that the circulating
dase activities is independent of the pituitary gland, hemoglobin concentration increases in boys at puberty
while /3-glucuronidase activity is partially dependent on concomitantly with the increase in serum T (323). In
pituitary hormones (316, 317). Androgens may also stim- hypogonadal males, the hemoglobin level is reduced, and
ulate endocytosis as well as hexose and amino acid trans- T replacement therapy restores the level to the average
port in mouse kidney cortex (318). This effect has been male levels or above (324, 325). Women receiving andro-
related to the androgenic stimulation of extracellular gens for treatment of arthritis have significant increases
calcium influx and mobilization of intracellular calcium in red cell mass (326).
(319). The erythropoietic action of androgens involves the
There is no apparent human analogy to the reno- stimulation of erythropoietin production via receptor-
trophic effect of androgens in rodents. Although anabolic mediated transcriptional control and a direct effect on
steroids have been used in humans with acute and bone marrow. Androgen administration to polycythemic
chronic renal failure, there is no evidence that the modest or starved rats and mice results in increased circulating
erythropoietin levels (327-329). Although the kidney is
TABLE 2. The diversity of androgen effects of various renal enzyme the major source of erythropoietin, extrarenal sources
activities are also involved since androgens can produce an eryth-
Castra- Androgen
roid response in anephric patients (330), and severe
Enzyme hemorrhage induces erythropoietin secretion in nephrec-
tion Treatment
tomized rats (331).
1. Alkaline phosphatase 1 | (small dose);
Androgens also have direct stimulatory effects on the
| (large dose)
2. Acid phosphatase 1 stem cell of the bone marrow leading to the proliferation
3. Adenosine triphosphatase
t of other blood cell lines (for a review, see Ref. 322). In
1 t
4. Aspartic-glutamic transaminase 1 t vitro bone marrow culture studies have shown that T
5. Alanine-glutamic transaminase 1 t can induce erythropoiesis (332, 333). T enhances the two
6. Glutamine dehydrogenase
7. Arginase erythroid stimulators, the colony-forming unit (CFU-E)
—* t and the burst-forming unit (BFU-E) (334-336). In ad-
8. d-Amino acid oxidase i T
9. /S-Glucuronidase i t dition, the synthesis of heme (A) and globin was stimu-
10. ODC 4 T lated by androgens. The effects of androgens on granu-
11. Cytochrome c oxidase 1 T lopoiesis and platelet production were demonstrated in
February, 1987 BIOLOGICAL ACTIONS OF ANDROGENS
the accelerated recovery of the white blood cell and
platelet count after radiation or chemotherapy (337-
340). Similarly, rats pretreated with T have less depres-
sion of hemoglobin, white blood cell, and platelet counts
from 32P therapy (341). At present, it is not clear whether
the granulopoietic effect of androgens involves the stim-
ulation of the granulocyte trophic hormone or colony
stimulating factor (342, 343). Overall, the doses required
to produce these effects tend to be in the pharmacological
range.
Male rats have greater predisposition to arterial
thrombosis formation and platelet aggregation than fe-
males (344, 345). However, the administration of T or
oxandrolone to white carneau pigeons does not alter
collagen, ADP, or arachidonic acid-induced aggregation
or the synthesis of prostaglandins in thrombocytes (346).
Different T metabolites appear to be active in different
tissues. The 5/?-metabolites (5/3-DHT and etiocholano-
lone) act directly on the stem cells while 5a-derivatives
(5a-DHT) increase erythropoietin levels (322). The re-
ceptor for T and 5/3-steroids in hematopoietic liver cells
does not exhibit the same specificity as that in prostate
(347). In adult bone marrow cells, the nuclear fraction
exhibits a high accumulation of radiolabeled androgens
(348, 349). Mice with testicular feminization (Tfm/y)
have normal hematocrits, suggesting that the classical
androgen receptor may not be important in hemato-
poiesis (350, 351). Similarly, antiandrogens may or may
not block the erythropoietic effects of T or 5a-DHT
(352-354).
Although estrogens have an inhibitory effect on eryth-
ropoiesis (355), the trophic effect of androgens does not
appear to be an antiestrogenic effect because estrogens
do not alter the proliferation of erythroid precursors in
culture (356) and the in vivo stem cell-suppressive effect
of estrogen is not observed in human tissue. In a study
comparing the erythropoietic, androgenic, and myogenic
activities of 29 different T derivatives (357), 1-dehydro-
17-methyltestosterone, an anabolic steroid, demon-
strated erythropoietic and myogenic activities without
substantially stimulating the growth of ventral prostate
and seminal vesicles. Similarly studies in polycythemic
mice demonstrated that the administration of a-deriva-
tives of androgenic steroids enhances red cell production
to the same degree regardless of whether they were
predominantly androgenic or anabolic (358), suggesting
that the erythropoietic activity can be independent of
the androgenic or anabolic effects of the steroids. Thus,
the action of androgens in the hematopoietic cells ap-
pears to be different from that in the reproductive tissues.
In summary, androgens increase red cell mass in man
indirectly by increasing erythropoietin levels and directly
by acting through a nonandrogenic, nonestrogenic recep-
tor in the bone marrow. The clinical use of androgens to
13
stimulate erythropoiesis in uremics and patients with
aplastic anemia is obsolete with the availability of syn-
thetic human erythropoietin.
Immune System
Kochakian (22) observed that T administration to
rodents led to regression of the thymus gland. Subse-
quently, Kaplan and Brown (359) reported that T injec-
tions could prevent irradiation-induced thymic lympho-
mas in C57 black mice. Similarly, administration of
androgens to birds causes the involution and disappear-
ance of the lymphoid follicles in the bursa of Fabricus
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(360-362), the primary lymphoid organ producing differ-
entiation of B cells. On the other hand, the antibody
response to antigens or tissue injury may be improved
by T administration presumably due to inhibition of T
suppressor cell function (363, 364). In NZB/NZW Fl
female mice, a murine lupus model, androgen therapy
significantly reduced mortality (365, 366). The titers of
antinuclear antibodies are also reduced. T also sup-
pressed the development of cytotoxic antibodies against
T lymphocytes which are common in this model. Simi-
larly, studies in twins (367, 368) and in patients with
Klinefelter's syndrome (369) suggested that hyperestro-
genemia or relative hypoandrogenemia facilitates the
development of autoimmune diseases such as systemic
lupus erythematosis.
An antiinflammatory effect of androgens has been
suggested by the observation that metandienone admin-
istration attenuates the symptoms after smallpox vaccine
(370). On the other hand, studies of in vitro lymphocyte
cultures (371) and clinical observations of antibody re-
sponses in children to diphtheria and tetanus vaccines
(372) suggest an immune-potentiating effect of andro-
gens. Thus, it appears that androgens have multiple
effects on different components of the immune system.
Furthermore, the interaction of androgen with the im-
mune system is complicated by the fact that the antian-
drogen, cyproterone acetate, also inhibits the lymphoid
system (373). The latter effect might be attributed to the
immunosuppressive, progestational effect of this antian-
drogen (374). Although the overall effect of androgens
on the autoimmune disorder of NZB/NZW mice is an-
tagonistic to that of estrogens (365, 366), the fact that,
compared to T, larger doses of DHT are required to
ameliorate the autoimmune disorder, invokes the possi-
bility that a metabolite of T with antiestrogenic activity
rather than a pure androgenic agent may contribute to
the immune system modulation in this murine model.
The role of androgens in regulating the immune system
of humans requires careful investigation.
14 MOORADIAN, MORLEY, AND KORENMAN
Adipose Tissue and Feeding Behavior
Sex hormones appear to play a role in the distribution
of body fat, with males having a greater proportion of
upper body fat and females a greater proportion of lower
body fat. Upper body fat appears to be identified with
the metabolic complications of obesity (375). Evans et
al. (376) have demonstrated that women with a prepon-
derance of upper body fat have an increased free T
compared to those with lower body fat preponderance
(low waist to hips circumference ratio). Females with
upper body fat preponderance have an enlargement of
abdominal adipocytes and an imbalance of glucose-in-
sulin homeostasis.
In castrated adults rats, T replacement in low doses
(50-200 /xg/day) produces an increase in food intake and
weight gain, whereas with high doses (1-2 mg/day) there
is a reduction in body weight (377,378). T is more effec-
tive in stimulating weight gain than is DHT (379). The
suppressive effect of high doses of T on weight gain is
predominantly due to decreases in body fat content
(380,381). It should be noted that the weight-reducing
effects of T did not only occur at hyperphysiological
concentrations as the increased T levels associated with
intense copulatory activity produced both a decrease in
body weight and carcass fat content (383).
The decrease in body weight produced by T appears to
be due to its aromatization to estrogens. The major site
of aromatization is adipose tissue. Both T and estradiol
reduce body weight by reducing fat mass (384). DHT in
doses as high as 20 mg/day fails to suppress weight gain
(385). Both progesterone, which antagonizes the weight-
reducing actions of T, and an aromatase inhibitor (385)
inhibit the weight-reducing effects of T. Low doses of
androgens increase adipose tissue lipoprotein lipase ac-
tivity while high doses and estrogens inhibit the activity
of this enzyme (385-387). Reductions in lipoprotein li-
pase produced by high doses of T are prevented by
concurrent administration of an aromatase inhibitor.
In summary, low doses of T increase adipose tissue
mass, and this effect does not involve 5a-reductase activ-
ity. In humans, this effect is seen predominantly in the
upper torso and is associated with increased morbidity
and mortality. High physiological doses of T suppress
adipose tissue mass and lipoprotein lipase as a result of
aromatization to estrogens.
Skin and Appendages
There are marked differences in the androgen concen-
trations of various skin sites. In both men and women,
there are much higher concentrations of androgens in
skin derived from the external genital analage in the
urogenital ridge, e.g. prepuce, clitoris, scrotum, and labia
majora, than in nonsexual skin, e.g. thigh. In androgen
Vol. 8, No. 1
target skin, there is high 5a-reductase activity, whereas
in nonandrogenic skin, 3a-reductase activity predomi-
nates. There is evidence that in the skin, in contrast to
other organs, 50-metabolites are not produced (382).
Skin is also capable of converting the relatively weak
androgen, dehydroepiandrosterone, to T and DHT (382).
There are significant decreases in the androgen concen-
tration of skin with aging. There are very low concentra-
tions of estrogen receptors in male genital skin, confirm-
ing that the androgen effects are produced by DHT.
Surprisingly, in view of the numerous studies on skin
metabolism of androgens, there is little information on
the effects of androgens on skin. Williamson et al. (388)
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recently demonstrated a marked increase in collagen
solubility of castrated male rats, suggesting that lysylox-
idase activity is modulated by T. Castration also pre-
vented the diabetes-induced decrease in collagen solubil-
ity. These changes could be indirect as lysyloxidase ac-
tivity is also reduced by hypophysectomy (389), and
studies on the effect of T replacement in hypophysectom-
ized animals have not been undertaken.
Anabolic androgens can block the inhibitory effect of
glucocorticoids on epidermal cell proliferation without
altering their antiinflammatory responses (391). The
antiandrogen, cyproterone acetate, inhibits the induction
of mouse skin papillomas and epidermal DNA synthesis
without altering epidermal ODC activity (390). These
effects are partially, but not completely, reversed by T,
suggesting the possibility that they are mediated through
a combination of androgenic and progestational effects.
Sebaceous glands
Androgenic control of sebaceous glands has been ex-
tensively evaluated because acne vulgaris is a common,
disfiguring dermatological problem. Androgens regulate
the development and secretory activity of sebaceous
glands on the face, upper back, and chest. Sebum pro-
duction and histological size of facial sebaceous glands
are dependent on T exposure and are suppressed by
estrogens (Fig. 6).
As in skin, the major androgen in sebaceous glands is
DHT, which is assumed to be the active hormone. Nor-
mal facial skin more readily converts T to DHT than
does skin from the back, and acne-bearing skin produces
2- to 20-fold more DHT than does normal skin (392,393).
Marynick et al. (394) reported that most patients with
resistant cystic acne have androgen excess, in particular,
elevated dehydroepiandrosterone sulfate levels. Positive
correlations between acne and serum androgen levels
have been reported by several groups (395-399). How-
ever, some women and men with severe acne do not have
a high serum androgen concentration (400,401). It is
possible that the in situ conversion of dehydroepiandros-
February, 1987 BIOLOGICAL ACTIONS OF ANDROGENS 15

MALES drogens markedly decreases the volume of the smooth

Re otive sebum production endoplasmic reticulum in intact male rats and prevents
C) 1* 2* 3* 4 * the enlargement associated with T treatment in castrated
Prepubertol -•• ] animals. Ebling (409) demonstrated the effects of andro-
« •small dose ondrogen gens in hypophysectomized animals, suggesting that the
•MMMMi
androgenic effect is a direct one. They also showed that,
• • large «
1 whereas a number of steroids stimulated cell division,
Puberty 1 only 5«-androstane-3jS,17/3-diol regulated the secretion
Castrates ••••••• j processes in this species.
Costrote* steroid (odrenal suppression)---
Vermorken et al. (410) have shown that the size of the
\

pigmented spot and the sebaceous gland tissue associated

Puberty* estrogens
1 with the female hamster flank organ are regulated by
Pituitory insufficiency — D topical androgens. The stimulatory effect of T on the

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Acromegoly
Adrenol corticol hyperoctivity —
FEMALES
Prepubertol 1 while 30-androstanediol was ineffective.
Prepubertol*large dose ondrogens
1 glands that secrete mainly waxes consisting of linear
Puberty
I Ml.
1 saturated fatty acids esterified by linear saturated diols.
Puberty • estrogens Z3
Pituitory insufficiency
1 ture male quails have higher concentrations of Ci2 diols
Acromegoly
Polycystic ovaries, ovarian ondrogen
producing tumors
FIG. 6. Effects of different androgen states on sebum production (Re-
produced with permission from F. Parker: Textbook of Endocrinology
(edited by R. H. Williams), W. B. Saunders, Philadelphia, 1981, p 1080
(382).]
terone to more potent androgens may explain some of
the cases of acne in the absence of increased serum
androgen levels (402,403), but direct evidence for this
hypothesis is still lacking. Women with acne have in-
creased levels of 3«-androstanediol glucuronide, a metab-
olite of DHT, reflecting a high conversion rate of andro-
gens in target tissues in these women (404) and greater
androgen bioactivity.
Castration of male rats produces a striking reduction
in the volume of the sebaceous glands, while subsequent
administration of T increases the volume of the glandular
cells (405) and enhanced cellular proliferation (405).
Ultrastructurally, castration produces a reduction in the
volume and density of the vesicular endoplasmic reticu-
lum throughout the cytoplasm, and this effect is reversed
by T (406). Sebum is composed of disintegrating seba-
ceous cells containing large amounts of lipids, and it is
thought that this lipid material is synthesized by the
vesicular endoplasmic reticulum (407). Secchi et al. (408)
have demonstrated that topical administration of antian-
size of the pigmented spot is inhibited by high doses of
progesterone (which blocks conversion of DHT), but
these same doses of progesterone failed to reduce the size
of the sebaceous structure. In a further study, the same
group (411) reported that T, 5a-DHT, and 3a-andro-
stanediol stimulated growth of the sebaceous structure
The uropygial (preen) glands of birds are sebaceous
Androgen receptors (412,413) and 5a-reductase activity
(414) are present in this gland, and histological changes
occur after androgen administration (415). Sexually ma-
I compared to sexually quiescent birds (416). Castration
1 of sexually mature birds results in a decrease in Ci2 diol
activity which could be reversed by T treatment. The
antiandrogen, cyproterone acetate, decreased C12 diols in
sexually active birds and partially prevented the increase
in T-treated castrated quails. Androgen treatment does
not alter fatty acids in this gland.
In summary, androgens have a direct effect on seba-
ceous gland growth and also modulate the quality of
sebaceous secretions. The effects do not appear to involve
aromatization.
Hair
Hair can be divided into nonsexual hair, such as that
on the eyebrows and lashes, and on the extremities;
ambosexual hair, such as in the axilla and lower pubic
triangle, which is responsive to low androgen concentra-
tions; and male sexual hair, such as beard, ears, prester-
nal region, and the upper pubic triangle, which is respon-
sive only to high androgen concentrations.
The extent of male facial hair growth is determined by
circulating androgens and genetic factors (417-419). An-
drogenic stimulation of hair growth has been shown in
rats (420,421) and mice (422). Guarrera et al. (423) found
that in in vitro cultures of rat embryo skin explants, T
stimulates the differentiation of hair follicles. Hair fol-
16 MOORADIAN, MORLEY, AND KORENMAN
licles are not only target tissues; in addition, they are
active sites of T metabolism (424-428). Hair follicles
metabolize T to either DHT or androstenedione. One
biochemical difference between the resting phase of hair
growth (telogen) and the active growth phase (anagen)
is the activation of the hexose monophosphate shunt
which results in the production of large amounts of
NADPH (382). The 5«-reductase pathway requires
NADPH, resulting in growing hair follicles converting
larger amounts of T to DHT than do resting ones. DHT
inhibits adenyl cyclase activity in scalp hair follicles
while estrone stimulates it (429). In frontal and vortex
scalp hairs from the male stump-tailed Macaque (who
develops baldness at puberty) and in balding men there
is an increase in 5«-reductase activity (382,430). In pa-
tients with 5a-reductase deficiency, there is decreased
body hair, scant beard, and no temporal hairline reces-
sion (382).
Excess androgen production may be an etiological
factor in hirsutism (431-433). Serum-free T concentra-
tion is increased in hirsute patients, although more than
half of such patients have normal serum concentrations
of total T (434,435). The ovaries are the major source of
serum androgens in these women (436). Although in most
women with significant hirsutism, hyperandrogenemia
can be documented (437,438), in some hirsute women
serum total and free androgen concentrations are nor-
mal. It has been postulated that increased sensitivity of
hair follicles to circulating androgens may explain such
cases of idiopathic hirsutism (439), as supported by the
recent demonstration of increased plasma levels and
urinary excretion of 3a-androstanediol glucuronide in
hirsute women (440), indicating increased target tissue
metabolism of T via DHT. However, studies in isolated
hairs from women with hirsutism could not demonstrate
increased DHT formation or altered androgen metabo-
lism (441,442), although one group of investigators has
reported increased 5a-reductase activity of whole skin in
hirsute women (443,444). The androgen-binding capacity
in cytosol from pubic skin fibroblasts of hirsute women
was found to be reduced (445,446), yet the total (cytosolic
plus nuclear) androgen-binding capacity was similar in
men and hirsute or nonhirsute women (444), indicating
that increased androgen binding capacity cannot explain
excess hair growth in hirsute women. However, the pos-
sibility of enhanced nuclear translocation of androgen
receptor cannot be excluded as a cause of increased
androgen sensitivity. The precise underlying etiology of
idiopathic hirsutism remains unclear, and further studies
are required to clarify this complex problem.
In summary, the effects of androgens on hair growth
depend on the site being studied and on the phase of hair
growth. Androgens have multiple effects on energy me-
tabolism pathways, thus altering the energy supply for
Vol. 8, No. 1
keratin synthesis. Most of the effects of androgens on
hair follicles appear to be due to DHT, whose concentra-
tion is controlled by the phase of hair growth. However,
the potential role of androstenedione in telogen and
catagen has not been explored. It is also possible that T
may play a role in initiating anagen either through aro-
matization to estrogens or due to effects on progestin
receptors.
Salivary Glands
Sexual dimorphism of salivary glands in rodents is well
established (447-450). Rat submaxillary glands have T
receptors (451) and 5«-reductase activity (452). The ma-
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jor metabolite formed from T in salivary glands is 3a-
androstanediol (453). The salivary gland concentrations
of protease (454), sialic acid (455), glucagon (456), and
epidermal growth factor (457) are induced by androgens.
The few available studies do not allow assignment of T's
effects to a specific active metabolite.
Mammary Gland
Growth of the mammary gland in men depends, to a
large extent, on the balance between estrogenic and
androgenic stimulation. Gynecomastia may occur as a
consequence of T deficiency and may or may not be
associated with a increase in estrogen levels (458). This
suggests that androgens may have an inhibitory effect
on the growth of the mammary gland. In a study of 30
males with gynecomastia of varying etiologies, the only
common hormonal denominator was a decreased ratio of
T to estrogen levels (459). Similar alterations in andro-
gen to estrogen ratios have been invoked to explain
pubertal gynecomastia, but two studies failed to docu-
ment an increase in estrogen to T ratios in adolescents
with breast enlargement (460,461). It is essential, how-
ever, to assess bioactive hormone concentrations as sex
hormone binding globulin levels are high during puberty.
It is possible that the high prevalence of gynecomastia
in elderly men (462) may be due to age-related reductions
in free T concentrations in the absence of a significant
increase in serum estrogen levels (10,12, 13, 15).
Androgens administered during pregnancy inhibit the
formation of the mammary anlagen in the fetus (463,464)
and prevent lactation when administered to postpubertal
rats. However, the mammary glands in castrated male
rats show a dose-dependent increase of weight in re-
sponse to androgens. The response correlates more
closely with the levator ani response than with the re-
sponse of the seminal vesicles and has been used as an
assay of anabolic activity (465). The weight increase of
the mammary glands in response to T could have been
due to its aromatization locally. However, a nonaroma-
tizable androgen, methyl T, has also been associated with
February, 1987 BIOLOGICAL ACTIONS OF ANDROGENS 17

the development of gynecomastia possibly via its effects
on hepatic function (466).
These effects are probably indirect, possibly related to
alterations in pituitary hormone release. The direct ef-
fects of androgens on the breast have not been well
studied, but in in vitro studies on midpregnancy mouse
mammary tissue, cultured in a chemically defined me-
dium, various androgens inhibit the rate of DNA synthe-
sis. In addition, androgens can inhibit the stimulatory
effects of insulin, hydrocortisone, and PRL on the rate
of casein synthesis (467).
Bone
and rat mandibular bone has been reported to convert T
to DHT and androstenedione (480,481). This suggests
the possibility that the effects on bone may be mediated
by DHT or other T metabolites.
Summary and Conclusions
Though unnecessary for life itself, androgens are es-
sential for the propagation of the species and for estab-
lishment and maintenance of the quality of life of males
through their support of sexual behavior and function,
muscle strength, and sense of well-being. In carrying out
its many functions, T acts both as hormone and prohor-

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It is well recognized that estrogens protect females
against the development of osteoporosis. The role of
androgens in the prevention of osteoporosis is much less
clear, but male hypogonadism is associated with osteo-
porosis (468-471). There is a direct relationship between
bone mass and T in aging men (472,473). Short term
replacement therapy with T in hypogonadal males results
in increased rates of bone formation and mineralization
(469), and androgen therapy with methandrostenolone
increases bone mass as measured by neutron activation
analysis in women with postmenopausal osteoporosis
(474). Two patients with 5a-reductase deficiency had
retardation in bony maturation compared to age-
matched controls (475). Exner et al. (476) treated five
boys with familial tall stature with T esters and observed
that there was an increase in trabecular and compact
bone density as measured by computed tomography.
Castrated male rats develop a form of osteoporosis which
is reversed by T (477). The mechanism by which andro-
gens alter bone metabolism is uncertain, as neither bone
resorption (478) nor collagen synthesis (479) are affected
by T in vitro. However, the spongiosa of human bone
TABLE 3. The effector hormones of the various biological actions of T in the male
mone. It is an outstanding example of the diverse evo-
lutionary utilization of a primitive informational mole-
cule both among and within species. Not only does T act
through the androgen receptor both unchanged and via
5a-reduction, but it acts in tissues with a high aromatase
level as an estrogen via the estrogen receptor. Further-
more, DHT, binding to the estrogen receptor, can act as
an inhibitor of estrogen action. The products of androgen
metabolism may also play active regulatory roles in he-
matopoiesis and in the regulation of certain hepatic
enzymes. Table 3 summarizes the actions of secreted T
in males indicating the probable effector hormone.
While gross hypogonadism is uncommon, mild andro-
gen insufficiency may be much more frequent, especially
in older men, and in those receiving treatment for chronic
medical conditions. It is quite possible that such individ-
uals would benefit from appropriate androgen therapy
were it available, but the current forms of replacement
therapy are not very satisfactory. Better approaches are
required.
With the exception of a small number of secreted
proteins, the products of transcription induced by andro-
gens are not, as yet, known. When the androgen receptor

Indirect
DHT Estrogen Others
(Pituitary factor)
Testis0 Prostate Testis (Leydig cells, Liver Hematopoiesis
Seminal vesicles" Epididymis" Sertoli cells)" Kidney" Bone
Epididymis" Penis" Seminal vesicles" Mammary gland
Penis"
Central nervous system Central nervous Central nervous sys-
SNB (spinal cord nucleus of system" tem"
bulbo cavernosus)" SNB° Male sexual behavior
Male sexual behavior Increased eating Increased activity
Muscle LH Decreased eating
TSH (decrease)" Hair TSH (increase)"
GH" Skin GH"
Kidney" Sebaceous Adipose tissue"
Immune system glands
Adipose tissue (increase)" Bone"
Salivary glands
1
More than one effector hormone.
18 MOORADIAN, MORLEY, AND KORENMAN
gene is cloned it will be possible to identify androgen -
regulated genes and their products. It will then be pos- 22.
sible to design agents selectively producing specific de-
sired androgenic effects. 23.
24.
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5-alpha-reductase deficiency: evidence that a single enzyme is crinology 94:325

8th International Congress of Histochemistry and Cytochemistry

July 31-August 5, 1988
Omni Shoreham Hotel, Washington, D.C.
Dr. C. P. Leblond, Honorary President
Topics include: Immune-cytochemistry, Neurohistochemistry, Histochemistry in Pathology, Hematologic
Cytochemistry, Cytochemistry in Cell Biology, Enzyme Histochemistry, In Situ Hybridization, Lectin
Cytochemistry, Histochemistry of the Endocrine System, Image Analysis, Flow Cytometry, X-ray Micro-
analysis, Cell Differentiation, Histochemistry of the Extracellular Matrix, Cytochemistry of the Cell
Surface, Histochemistry in Botany, and Radioautography.
For more information contact: Dr. Constance Oliver, Chairman, Organizing Committee, NIH-NIDR,
Building 10, Room 1A23, Bethesda MD 20892. (301) 496-2922.

IV Pan American Congress of Andrology

Serono Symposium on Human Reproduction
Sao Paulo, Brazil May 4-6, 1987
The IV Pan American Congress of Andrology will be held in conjunction with the Serono Symposium on
Human Reproduction. The meeting is organized by a Program Committee consisting of: A. Negro-Vilar
(USA) (Chairman) R. Abdelmassih (Brazil), M. P. de Castro (Brazil), F. Comhaire (Belgium), A. Isidori
(Italy), L. Martini (Italy), and J. Paulson (USA). During this three-day event a series of Symposia will
cover every important aspect in the fields of Andrology, Reproductive Endocrinology, and Infertility, with
special emphasis on modern approaches for diagnosis and treatment of reproductive disorders in both
sexes. Several lectures are also dedicated to recent advances in basic aspects of Reproductive Endocrinology
and their potential application to fertility and sterility problems.
Forty internationally recognized scientists will present invited lectures on their work in the following
areas:
New Techniques of gamete evaluation
Artificial methods for induction of pregnancy
Neuroendocrinology, basic and clinical aspects
Hormonal and gonadal factors
Sexual inadequacy
Diagnosis and treatment of infertility
Registration forms and additional information can be requested from the Organizing Secretariat: Ares-
Serono Symposia, Via Ravenna, 8, 1-00161 Rome, Italy.