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High sensitivity to androgen as a contributing factor in sex differences in the immune response.

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HIGH SENSITIVITY TO ANDROGEN AS
A CONTRIBUTING FACTOR IN SEX DIFFERENCES
IN THE IMMUNE RESPONSE
D. A. COHN
The factors responsible for sex differences in the
immune response remain poorly understood despite the
numerous, often conflicting reports published on the effects of the sex chromosomes or sex hormones on immune responsiveness. In the first part of this work, attempts are made to draw together some of the findings
reported from different laboratories and to review
briefly the work on sex differences in the immune response. In the second part, data from our laboratory are
presented which suggest that in healthy, intact, untreated male mice a correlation exists between high sensitivity to androgen and low immune performance. We
show that sex differences in the immune response do not
invariably occur, but they do occur primarily in mouse
strains with high target organ responsiveness to androgen, the C57L/J and the RF/J. In these strains males
appear to be at a disadvantage immunologically in that
they have lower plasma immunoglobulin levels and lower
specific immune responses than females of the same
strains or males of low androgen responder strains, the
A/J and the 129/J. The low immune status of these
high androgen responder (HAR) males is not influenced
by altering postnatal concentrations of circulating
androgen, indicating that it is high sensitivity to androgen, not a high concentration of circulating androgen,
that correlates with poor immune performance. The low
responses of HAR males to a variety of unrelated anti-
gens and the fact that HAR males produce low antibody
responses to bovine IgG even when they carry the H-2
type for high immune responses suggest that high sensitivity to androgen may act as a nonspecific modulator of
the immune response. Possible mechanisms of action
are discussed.
Supported in part by grants from the National Institutes of
Health, Division of Research Resources (2 SMRR08153) and from
the City University of New York (PSC-BHE 11858).
Address reprint requests to D. A. Cohn, PhD, Associate Professor of Biology, York College, City University of New York, Jamaica, New York 11451
LITERATURE REVIEW
Arthritis and Rheumatism, Vol. 22, No. 11 (November 1979)
The lower resistance to infection and weaker immune responses of males compared to females are well
known to breeders, pediatricians, and animal care personnel, but the factors responsible for these phenomena
remain obscure. Differences in the sex chromosomes
and/or sex hormones have been suggested as possible
influences, and numerous reports have attempted to relate these differences to sex differences in the immune
response. Insight into the underlying mechanisms has
been hampered, however, by inability to reconcile the
inconsistencies and contradictions present in much of
the literature.
In our laboratory, we have approached the problem of sex differences in the immune response by evaluating in depth the immune responses of males. We
have speculated that a critical determinant in their
weaker immune responses is their degree of sensitivity
to androgen, not the concentration of their circulating
androgen. However, before our own results are presented, the literature is briefly reviewed so that the controversial nature of the field can be fully appreciated.
Reports dealing directly or indirectly with sex
differences in immune responses can be organized into
two general categories: 1) studies of intact individuals,
HIGH ANDROGEN SENSITIVITY
and 2) studies of hormonally altered subjects. In the
first category are: Observations of immunoglobulin levels, resistance to infection and immune responsiveness
in intact males and females, and comparisons of normal
females who are either pregnant or cycling. In the second category are experiments on gonadectomized individuals and individuals or cells exposed to exogenous
sex steroids.
Studies of intact individuals
Observations of intact males and females. The
data from different laboratories on untreated subjects
are fairly consistent. Most of the studies comparing immunoglobulin levels in normal males and females show
that females have higher levels of IgM than males (1-9),
with blacks as a group having levels higher than whites
(2,3,10) and black females the highest of all groups in
levels of IgM (2). In many (4,6,8) but not all (9,ll) studies, IgM levels correlate with the numbers of X chromosomes (4,6) or with regulatory factors on the X chromosome (8). IgG levels are not dependent on the X
chromosome. In the majority of reports, white females
have IgG values equal to those of white males (2,7,10).
The values of blacks as a group exceed those of whites
(3,7,10) with black females reported to be the highest of
all groups in IgG levels, according to one study (2) but
not another (7). Although an association between immunoglobulin levels and immune capacity is generally
accepted, high immunoglobulin levels do not always indicate protection from disease or superior immune performance. Despite this, the literature shows that when
the sexes are compared for susceptibility to infection or
immune responsiveness, intact females have a greater
resistance to infection (12-20) and higher specific immune responses than intact males (21-30).
Comparison of normal females who are pregnant
or cycling. To explain the lower resistance and weaker
immune performance of males, attention has focused on
the possibility that the sex hormones influence immune
responses. Experiments have been conducted on pregnant versus non-pregnant females and on intact females
at different stages of the ovulatory cycle to determine
whether naturally occurring sex hormones are responsible for the enhanced immune responses in females.
Most (31-36) but not all (37,38) reports indicate
that pregnancy is associated with a reduction in T cell
numbers (3 1,36) or T cell function (32-36). Whether the
immunosuppression observed is due to the presence of
gonadotrophins (39), progestins, a-fetoproteins (40),or
1219
other factors is not clarified. Increased B cell function
(32) and a reversal of B:T cell ratio (36) are also reported to occur during pregnancy. These findings, however, are not supported by others (41), and it has been
suggested that the increased numbers of cells bearing B
cell markers are actually monOcytes (42). During pregnancy IgG, IgA, and IgM levels are depressed in the
second and third trimesters (43), but IgE levels are unchanged (44) or variable (43). While non-pregnant cycling humans show no changes in total immunoglobulin
levels, antibodies to Cundidu ulbicuns, but not to other
antigens, are elevated when progesterone levels are high
during the luteal stage (45). On the other hand, in cycling mice both T and B cell responses are elevated
when estradiol levels are high during proesterus and
also when estradiol levels are reported to be low, during
metestrus (46).
Hornonally altered subjects
Experiments exploring the influence of sex hormones on the immune response through in vivo hormonal manipulation follow a typical pattern. Levels of
circulating hormones can be either lowered by castration or elevated by administration of appropriate agents
into intact or gonadectomized subjects. Following this,
some aspects of immune function are assayed. From the
enhanced immune responses (29,30,47) or increased resistance to infection (16,18), observed in males following gonadectomy, it has been inferred that male hormones are immunosuppressive. However, experimental
results also show that gonadectomy is beneficial in females as well as in males. In both sexes, gonadectomy
can result in enhanced immune responses (23,26,48)
and increased resistance to disease (19,49,50). On the
other hand, in both sexes, gonadectomy can have no effect at all on defense mechanisms (20,29,51) or, depending upon the experimental design, no effect in females
(14,29), no effect in males (47), or detrimental effects in
either sex (16,5233).
The effects of exogenous female hormones or
their analogs on immune responses and protection
from disease also constitute areas of controversy. Administration of estrogen is reported to enhance immune
responses to sheep red blood cells (SRBC) (21,54), retard the normal decay of antibody titers ( 5 9 , and protect mice against some bacterial infections (13,5637).
However, similar doses of estrogen are reported to
depress immune responses to SRBC (21), delay the rise
of peak antibody titers (59, and reduce resistance to
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viral (13,16,18) and bacterial (58) infections. Although
it is reported that estradiol increases the number of antibody forming cells (59) and that diethylstilbesterol increases anaphylactic antibody responses (60), estrogen
treatment has no effect in other assays (60,61) and is
clearly suppressive in immune responses to Escherichia
coli (62), type 3 pneumococcal polysaccharide (SIII)
(63), SRBC (64-66), tumor cells (23), in graft rejection
(48,64,65,67), in phytohemagglutinin (PHA) responses
(68), in cell mediated immunity associated with resistance to Toxoplasma gondii (50), and in the delayed hypersensitivity characteristic of adjuvant polyarthritis
(69). Furthermore, rather than being beneficial, estrogen when administered to neonatal (64) or sublethally
irradiated (65) mice not only depresses immune responses, it results in failure to thrive, severe wasting,
and death.
Experiments on the effects of androgen treatment have yielded the same type of conflicting results.
With respect to altered resistance to disease, early in
vivo studies have reported that administration of testosterone increases virus growth through its anabolic
rather than immunosuppressiveeffects on the host (70).
Later studies show that if administered to castrated animals, testosterone negates the protective effects of gonadectomy and reduces resistance to viral infections
(16,18), but if administered to castrated animals of another strain the protective effects of gonadectomy (49)
are not reversed. While testosterone has a slight effect in
reducing resistance to streptococcal infections (14), in
pneumococcal pneumonia it increases resistance (56).
Studies of the immune response show that in castrated
animals, the accelerated graft rejection resulting from
gonadectomy can be negated either by administration
of testosterone (47) or by implantation of testes into
castrated females. A similar reversal occurs following
implantation of ovaries into castrated males, but it is
weaker in effect (26). In autoimmune diseases, testosterone treatment can interfere with development of auto
allergic thyroiditis (71) but have no effect on the incidence of adjuvant arthritis (69). In immune responses
per se, depending upon the laboratory or assay, testosterone can be shown to enhance (54) or inhibit antibody
responses to SRBC (72), dinitrophenyl (DNP) (60), or
tumor cells (23) and to have no effect in the graft versus
host response, graft rejection (72), or antibody responses
to SRBC (73).
The most consistent influence exerted by androgen on the immune system is the immunosuppression
produced in chickens. Following the administration of
androgens into 5- or 12-day chick embryos, antibody responses to bovine serum albumin (BSA) (74,75), endotoxin, influenza type A (75), human gamma globulin
(HGG), Brucella (75,76), DNP-bovine gamma globulin
(BGG), SRBC, and X phage (76) are suppressed in
newly hatched (74) and 8-month-old (76) chickens. Testosterone treatment arrests duct and vesicle growth in
the bursa (77) resulting in involution, maldevelopment,
or agenesis, the extent of which depends upon the time
and dose of androgen (74-78). Administration of androgens also produces cortical atrophy of the thymus (75).
If normal bursae are transplanted into testosterone
treated hosts, host bursae fail to develop, but host lymphoid precursors are available (78) suggesting that the
inhibitory action of testosterone is exerted on the epithelial, not the lymphoid, component of the bursa. This
hypothesis is strengthened by recent findings of androgen target cells among nonlymphoid elements of the
bursa (79).
Since immune responsiveness depends in part
upon the functional capacity and availability of participating cells, the possibility of differential effects exerted
by sex steroids on these parameters must be considered
if sex differences in the immune response are to be understood.
With respect to function, lymhocytes cultured in
the presence of pregnant or postpartum serum (33) or
with progesterone (80-82) or estradiol (80-82) produce
depressed PHA (33,80-82), conconavalin A (Con A)
(80), mixed leukocyte culture (MLC) (82), and purified
protein derivative (PPD) (81) responses. PPD responses
are reported to be slightly enhanced at low concentrations of steroids (8 1). In vitro immunosuppression does
not occur in cells cultured with estriol or 16-hydroxy
progesterone (82). When testosterone is added to lymphocyte cultures, the results are the same as those seen
with estradiol or progesterone (80-82). Depressed PHA
(80-82), Con A (80), MLC (82), and PPD responses (81)
occur with slight augmentation of PPD responses when
low concentrations of testosterone are used (81).
In terms of the effects of sex steroids on the availability of cells of the lymphomyeloid system, administration of estrogen produces dramatic effects. Large
doses of estrogen lead to granulocytopenia and lymphopenia (83). In transplantation, when lethally irradiated
recipient mice reconstituted with bone marrow cells are
treated with estrogen (65,84) or when donor bone marrow cells are derived from estrogen-treated donors (84),
the result is accelerated death of the irradiated host.
Histologic and hematologic studies indicate that death
+
HIGH ANDROGEN SENSITIVITY
is due to failure of lymphocyte precursors to proliferate
(65). In animals surviving lethal irradiation, bone marrow replacement, and estrogen treatment, although
erythropoiesis persists, the number of pluripotential
stem cells (CFU) is sharply reduced (85). In addition,
estrogen treatment of either the recipient or the donor
reduces the number of myelocytic colonies that will
form in recipient spleens following transplantation (86).
In contrast to the effects of estrogens on the bone
marrow, the stimulatory effects of androgens on
erythropoiesis and granulopoiesis are well documented
(87-90). In both the erythroid (87,88) and the granulocytic lines (87,89,90) androgens act not only on committed stem cells such as the erythroid colony (CFU-E)
(87) or the granulocyte/monocyte colony (CFU-C) (89,
90) forming cells, they also act on less differentiated
stem cells, such as the pluripotential stem cell, the CFU
(88,89,9 1-93). (Pluripotential stem cells are capable of
giving rise to all cells of the blood including lymphocytes, but they are normally not actively mitotic.) Earlier studies had shown (73) that following multiple injections of testosterone, the thymus and bone marrow
were temporarily depleted of lymphoid cells, and a transient lymphocytosis developed which was accompanied
by an elevated hematocrit and sustained granulocytosis.
Since lympholysis was not evident, it was concluded
that androgen had stimulated the release of lymphocytes from the thymus and accelerated differentiation of
marrow cells into erythroid or granulocytic lines. Recent studies with the tritiated thymidine suicide method
suggest that these conclusions are probably correct. Pluripotential stem cells can be triggered by androgen, not
estrogen, to divide and ultimately differentiate into a
committed compartment containing granulocytic, erythroid, or lymphoid elements, depending upon the environment (91-93).
Discussion of review
In presenting this review the purpose has not
been to determine if sex differences in the immune response occur. They do occur. Females have higher levels of immunoglobulins (1-9), higher specific immune
responses (21-30), and a greater resistance to infection
(12-20) than males. The review has not been conducted
to investigate whether sex hormones modify immune responses. Both estrogens (16,18,21,23,54,56,62,64,68) and
androgens (16,18,26,54,56,70,71) can be shown to alter
immune responses and resistance to infection. The aim
of this review has been to evaluate the evidence for or
against the possibility that one of the sex hormones ex-
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erts a unique and lasting effect on immune responsiveness.
Space does not permit critical analyses of each
experiment. Taken as a group, however, the arguments
used to prove that testosterone is immunosuppressive or
estrogen immunoenhancing are based on results obtained following either gonadectomy or hormone treatment.
The gonadectomy experiments, however, contain
several serious problems that render interpretation of
experimental results almost impossible: 1) Following
gonadectomy, the effects, whether positive or negative,
are similar in both sexes (19,20,23,26,29,49-5 1). 2) The
results of gonadectomy vary with the laboratory. Reports show that gonadectomy enhances immune responses and resistance to infection (16,18,19,
23,26,29,30,48-50), has no effect on either (14,20,29,5 l),
or is deleterious (16,5233). 3) Where immunoenhancement occurs, the immunoenhancement or protection following gonadectomy does not persist (30,49).
One obvious explanation is that the concentrations
of adrenal androgens and gonadotrophins increase
following castration, and either of these might be immunosuppressive. An alternate explanation is that the apparent loss of immunoenhancement is actually a return
to the original state of 'immune capacity following recovery from stress, because the early postoperative immunoenhancement has not resulted from testosterone
depletion but from stress factors acting on suppressor
cells. In fact, stimulation of antibody synthesis following surgery has been reported (94). 4) In several complex gonadectomy experiments, no sham operated controls were included (14,16,30,47,48,50). Under these
conditions, it is diflicult to prove that the postoperative
results are caused by extirpation of the organ and depletion of its product, and not by the immunosuppressive
effects of surgical stress (95). Furthermore, without
sham operated controls it is not possible to assess the influence of surgery per se on helpers, suppressors, or
other cell populations participating in the immune response. 5 ) Replacement of testosterone following its depletion by castration does not uniformly reverse the effects of gonadectomy (23,49), suggesting that the
postoperative results observed could be caused by other
factors.
The results following androgen treatment do not
provide conclusive evidence that testosterone is immunosuppressive. While administration of androgen to
intact or gonadectomized individuals lowers resistance to disease and reduces immune responses
1222
(16,18,23,26,47,60,70,72), in other assays it either has no
effect (49,72,73) or increases immune responses and resistance to disease (54,56). The results of androgen
treatment on allergic thyroiditis (7 1) and in glomerulonephritis (96), however, suggest that in special conditions, such as autoimmune diseases, androgens may
modify immune responsiveness by acting on suppressor
cells (96).
The most convincing arguments used to show
that androgens suppress immune function or immune
capacity have been the effects of androgen treatment on
the bursa and on hemopoietic stem cells. The effects of
androgens on the bursa, however, are not unique. Although earlier studies established that androgen treatment during critical periods in development prevented
development of the bursa and suppressed immune responses after hatching (74-78), inhibitory effects can
also be demonstrated following treatment with estrogen
and progesterone. Results vary depending upon the dosage and the vehicle (97). Recent studies indicate that in
addition to the presence of androgen receptors, the
bursa contains receptors for estrogen, progestin, and
other hormones (98). With respect to hemopoietic stem
cells, the evidence that androgens can modify immune
capacity by reducing the pool of uncommitted stem cells
is largely theoretical. Androgens and other pharmacologically active agents, but not estrogens, stimulate pluripotential stem cells to cycle and differentiate (91-93).
That androgens restrict immune potential by shifting
uncommitted precursors into granulocytic or erythroid
compartments remains to be proved.
With respect to estrogens, arguments demonstrating that female hormones are immunoenhancing
include the results following castration or hormone
treatment. If estrogens are immunoenhancing, it should
be possible to show that depletion of estrogen following
ovariectomy weakens the individual. Few reports, however, show deleterious effects following ovariectomy
(16,5233). The majority show that ovariectomy results
in enhanced immune responses (23,26,48) and increased
resistance to disease (19,4930). A few show that ovariectomy makes no difference at all (14,29). If estrogen
exerts a beneficial effect on immune responsiveness, it
should be possible to show that treatment with estrogens but not androgens leads to consistently higher resistance or immune response. Few reports show this
(57,59,60). The majority show that estrogen treatment
leads to reduced resistance to infection, depressed immune responses (23,48,50,62-69), and severe defects in
bone marrow cells (65,8486,99).
COHN
It is clear that, based upon experimental evidence in the literature, no unifving conclusions can be
drawn at this time concerning the effects of sex hormones on immune responsiveness. Neither androgens
nor estrogens exert a unique and lasting effect. Problems exist both at the level of the experiments themselves and at the level of interpretation. Inconsistent results following modification of hormonal environment,
however, should not be surprising when one considers
the multitude of factors that can influence hormone responses. Dosage, suspending vehicle, and route of administration, as well as strain, age, and physiologic state
of the animal all contribute to variability of response.
The fact that androgens can serve as estrogen precursors
and androgens can function through estrogen receptors
(100) further complicates the issue. Experimental design
is another problem. Real or apparent differences in results can be maximized or masked by differences in the
interval between hormone treatment and immune assay,
by differences in the nature of the immune assay, and
by the statistical methods used to treat the samples. At
the level of interpretation, the previously held assumptions must now be questioned. If useful information is
to be gained from the older literature, it is necessary to
reinterpret past work in light of current theories of suppressor cell function, developmental influences on immune potential, and variation in sensitivity to hormones.
SENSITIVITY TO ANDROGEN AND
THE IMMUNE RESPONSE
The main objective of these studies has been to
gain an understanding of the mechanisms underlying
sex differences in the immune response-a phenomenon
which may contribute in part to the lower resistance
(12-20) and shorter lifespan (101-104) of males compared to females. Past studies which have focused on
differences in the sex chromosomes or the sex hormones
have provided some information, but the codicting results reported have raised additional questions. For example, do sex differences in immune responses invariably occur? Are there some males who are lower in
immune capacity than females and also poorer in these
respects than other males? If androgens influence immune responsiveness or immune potential, at what period of life does this occur? Do all males respond to
androgen with the same degree of sensitivity?
In surveying the literature, it is apparent that sex
differences in immune responsiveness are not evident in
1223
HIGH ANDROGEN SENSITIVITY
. .
I
Figure 1. Plasma immunoglobulin levels in male and female 0 mice
of strains with high (C57L/J) and low (A/J) seminal vesicle responses
to androgen. (Twenty mice per group.)
all assays. One possible explanation for this could be
that real differences are masked due to pooling techniques or insensitivity of the methods. Another explanation could be that sex differences in immune responsiveness do not invariably occur but appear only in
certain strains or under special experimental conditions.
In addressing these problems, we have designed
our experiments so that all assays are performed individually and mice are selected from strains in which the
males are expected to have lower immune responses
than the females.
Previous studies in humans had shown that
white males not only had lower immunoglobulin levels
(1,2,4,6,8) and a poorer survival following certain diseases (104) than white females, but that they were
weaker in these respects than males of other races
(2,10,104). Since some androgen dependent secondary
sex characteristics are more developed in whites than in
other races (109, the possibility was suggested that high
sensitivity to androgen might be a factor influencing the
lower immunoglobulin levels of these individuals. If this
hypothesis were correct, then male mice with high target organ responses to androgen would also have low
immunoglobulin levels. Accordingly, for our initial experiments we selected mice with high sensitivity to
androgen, expecting that such mice would show sex differences in immune responsiveness.
The seminal vesicle (SV) response to testosterone
was the parameter used to determine high or low sensitivity to androgen. Although other target organ responses to androgen could have been assayed, the SV
system was selected because it is the conventional
bioassay for androgen (106,107) and because SV
growth, structure, and function are dependent upon the
continuous presence of androgen.
Several strains of mice obtained from the Jackson Laboratory were assayed for target organ responsiveness to androgen (for details, see 108-110). Briefly,
males were gonadectomized at 70 days of age. After 2
weeks, they were given daily injections of graded doses
of testosterone propionate for 14 days. At 100 days (14
weeks) they were killed and their SV weighed. Comparisons of the magnitude of response at each dose
showed that the C57L/J and RF/J mice had significantly heavier seminal vesicles than the A/J and 129/J.
The former were henceforth designated high androgen
responder (HAR) strains and the latter low androgen
responder (LAR) strains.
The first series of experiments involved the assay
of intact, normal, untreated animals with genetically determined (106,111,112) physiologic differences in androgen responsiveness. Individual assays of plasma immunoglobulins were performed by quantitative radial
immunodiffusion according to procedures previously
described (108). More than 20 mice per group were used
and all assays were performed when the mice were 14
weeks of age. Data were analyzed by two-way analyses
of variance (ANOVA) for sex and strains followed by
multiple comparisons tests. The results, as shown in
Figure 1, indicate that sex differences in levels of IgM
Figure 2. Plasma immunoglobulin levels in castrated and sham operated 0 males of high (C57L/J) and low (A/J) androgen responder
strains. (Eight to 17 mice per group.)
COHN
1224
-
C 5 7 L /J
'"1
A/J
m
Figure 3. Antibody responses to type 3 pneumococcal polysaccharide
(SIII) in high (C57L/J) and low (A/J) androgen responder males
and females U (Twenty mice per group.)
and IgG2 occurred only in the HAR C57L/J strain but
not in the LAR A/J strain. Furthermore, HAR C57L/J
males not only had lower levels of IgM (0.27 f 0.01 mg/
ml) than HAR C57L/J females (0.63 f 0.06 mg/ml),
they also had lower levels of IgM than LAR A/J males
(0.45 f 0.03 mg/ml). The same finding applied to IgG2.
HAR C57L/J males not only had lower levels of IgG2
(4.07 f 0.13 mg/ml) than HAR C57L/J females (6.17 f
0.33 mg/ml), they were lower in IgG2 than LAR A/J
males (7.89 f 0.30 mg/ml).
To determine the role that circulating androgen
might be playing in the low immunoglobulin levels of
HAR C57L/J males, the next experiments involved the
assay of immunoglobulins in HAR and LAR mice who
had been gonadectomized within 3 days of birth. As
previously described (108), all assays were performed
individually when the mice were 14 weeks of age. Data
were analyzed by three-way ANOVAs for sex, strain,
and surgery followed by multiple comparisons tests.
The results (as indicated in Figure 2) showed that depletion of circulating androgen did not result in elevated immunoglobulin levels compared with those of
sham operated mice. The low levels of IgM and
DAY 5
C57L/J
A/J
IgG2 seen in the HAR C57L/J mice remained low regardless of the level of circulating androgen. This suggested that low immunoglobulin levels correlate with
high sensitivity to androgen but not with the concentration of circulating androgen.
The mouse data indicating a correlation in males
between high sensitivity to androgen and low immunoglobulin levels were consistent with observations in humans. However, the biologic significance of differences
in immunoglobulin levels was open to question. Immunoglobulin levels are considered to be a reflection of
overall responses to environmental antigens (1 13), but a
dissociation between immunoglobulin levels and immune competence has also been demonstrated (1 14). It
was therefore necessary to evaluate the specific immune
responses of the HAR mice in order to determine
whether high sensitivity to androgen actually correlated
with low immune performance.
Males and females of the HAR C57L/J and
LAR A/J strains were injected with 100 ng of pneumococcal polysaccharide (SIII). After 9 days they were assayed individually for antibody responses to SIII by using a direct radioimmunoassay procedure as previously
described (109). The results, as shown in Figure 3, indicate that sex differences occurred only in the HAR
C57L/J strain but not in the LAR A/J strain. HAR
C57L/J males produced 1059 f 94 ng/ml of antibody
N compared to 2020 f 139 ng/ml in HAR C57L/J females. With respect to the males, differences in antibody
response between the HAR C57L/J and LAR A/J
males were not significant following 100 ng of SIII.
However, as shown in Figure 4, following 50 ng of SIII,
HAR C57L/J males had significantly lower levels of
anti-SIII than LAR A/J males 5 and 9 days after immunization (566 versus 1416 ng/ml and 670 versus 1052
ng/ml).
Earlier experiments had shown that depletion of
DAY 9
C57L/J
A/J
DAY 13
C57L/J
A/J
Figure 4. Antibody responses in males of high (C57L/J) and low (A/J) androgen responder strains at different
intervals after doses of either 50 ng =or 100 ng 0 of SIII. (Ten mice per group.)
1225
HIGH ANDROGEN SENSITIVITY
NOT
INJECTED
TESTOSTERONE
(80Opg 1
VEHICLE
INJECTED
15 i
Figure 5. Antibody responses to SIII in castrated and sham operated 0 high androgen responder C57L/J males given subcutaneous
pellets of testosterone or the polydimethylsiloxanevehicle in which
the testosterone is suspended. Other castrates and shams were not injected with any pellets. (Ten mice per group.)
testosterone did not lead to elevated immunoglobulin
levels (Figure 2). To rule out any inhence exerted by
circulating testosterone, it was also necessary to show
that administration of exogenous androgen did not inhibit immune responses as had been claimed by others.
LAR A/J males were not used for these studies because
this strain did not show sex differences in immunoglobulin levels (Figure 1) or in specific immune responses
(Figure 3).
HAR C57L/J adult males were either gonadectomized or sham operated and were then divided into 3
groups (for details see reference 109). One group of
gonadectomized and sham operated mice were left untreated. The second group received a subcutaneous pellet containing 800 pg of testosterone mixed with a polydimethylsiloxane-silica vehicle, and the third group
received a pellet containing only the vehicle. Previous
studies (110) had established that a pellet containing
800 pg of testosterone prepared and used according to
our procedures released testosterone in physiologic
amounts sufficient to restore normal SV weight. In addition, the pellets released effective amounts of testosterone during the entire experimental period. The data
were analyzed by two-way ANOVAs for surgery and
treatment. As shown in Figure 5, regardless of the surgery or treatment, no significant differences were seen
among the groups in antibody responses to SIII. Depletion of circulating testosterone following gonadectomy
did not result in increased antibody levels compared to
those of sham operated mice. On the other hand, treatment with physiologic doses of testosterone did not result in suppressed antibody responses to SIII compared
to those of untreated or vehicle treated mice. The lower
levels of antibody apparent in vehicle treated mice were
not significantly different from the other groups. The
data showed that regardless of whether the mice were
depleted of androgen, depleted then restored, normal,
or high in testosterone levels, antibody responses to SIII
were similar. The low immune responses of HAR
C57L/J males remained low, independent of changes in
their testosterone levels.
To determine whether these low antibody responses to SIII were unique to the C57L/J males or
were associated in general with high sensitivity to
androgen, another pair of HAR and LAR strains, the
HAR RF/J and LAR 129/J, were assayed for their responses to SIII. As shown in Figure 6, although the
HAR RF/J did not show sex differences in antibody responses to 100 ng of SIII, as a strain, the HAR RF/J
were significantly lower than the LAR 129/J. HAR
RF/J males and females produced 1,420 and 1,500 ng/
ml of antibody N compared to 2,292 and 2,031 ng/ml
antibody N produced by the 129/J. In addition, differences between HAR and LAR males were significant
even after 100 ng of antigen.
Results of experiments assaying either immunoglobulin levels or specific immune responses to polysaccharide antigen indicated that males with high responses to androgen appeared to be at a disadvantage
immunologically, whether in relation to females of the
same strain or when compared to males of LAR strains.
To determine how broad this phenomenon was, experiments were now performed using protein antigens.
Antibody responses following a 50 pg dose of bovine serum albumin (BSA) emulsified with complete
Freund’s adjuvant (CFA) were assayed 14 and 21 days
after immunization. A modification of the Farr method
described previously was used (109). As shown in Figure 7, marked sex differences were evident among the
RF/J
25 1
129/J
T
201510 5ng/ml
x
lo2
Figure 6. Antibody responses to SIII in hi& (RF/J) and low (129/J)
androgen responder males and females U (Fifteen mice per group.)
COHN
1226
I2l
8
DAY 14
C57L/J
A/J
h
DAY 21
C57L/J
A/J
.
d
F w e 7. Antibody responses to bovine serum albumin (BSA) conjugated with complete Freund's adjuvant in high (C57L/J) and low
(A/J) androgen responder males W and females 0. (Ten mice per
group.)
HAR C57L/J both 14 and 21 days after injection.
Among the LAR A/J, males had lower levels of antibody to BSA on day 14 before peak responses developed. By day 21, the responses of the LAR A/J males
and females were similar. When the strains were compared, all HAR C57L/J mice had consistently lower
levels of anti-BSA than all A/J mice. Of all groups assayed on both days, the HAR males had the lowest values.
In the next experiments, antibody responses to
bovine IgG (B-IgG) were assayed to determine whether
differences in androgen sensitivity influenced immune
responses controlled in part by H-linked Ir genes.
Strains which differ both in sensitivity to androgen and
in H-2 type were used. These included the HAR RF/J
which are H-2k, the LAR A/J which are H-2, and the
LAR 129/J which are H-2b. H-2' and H-2' had been
found to be associated with high responses and H-2b
with low responses to B-IgG (115,116). Mice were immunized with a single injection containing 50 pg of BIgG emulsified with CFA. They were bled from the orbital plexus 21 days after immunization because this
time coincided with early peak responses. B-IgG was radioiodinated by the method of Hunter and Greenwood
(117). Antibody determinations were performed individually in duplicate by using the Farr technique (1 18)
with the following modification: 0.2 ml of saturated ammonium sulfate was used per 0.5 ml of '''I-B-IgG. Under these conditions antigen antibody complexes were
precipitated, but not antigen alone. Precipitates were
centrifuged. Pellets were dissolved and counted by liquid scintillation. A standard curve was prepared, and
antibody nitrogen was calculated from the standard
curve. As shown in Figure 8, sex differences in response
to B-IgG occurred only in the HAR RF/J strain, with
males markedly lower than females (480 versus 1,794
ng/ml antibody N). In the LAR strains, males and females produced similar results. The expected strain differences based upon H-2 type were evident in all groups
except the HAR RF/J males. Among the LAR strain,
the A/J (H-2') produced the expected high responses
(2,978 f 127 and 3,206 f 129 ng/ml) and the 129/J (H2b) produced the expected low responses (648 f 57 and
780 f 172 ng/ml). Among the HAR RF/J mice, the females were comparatively high as expected (1,794 ng/
ml), but the males, although H-2*, produced the lowest
levels of antibody of all mice assayed (480 f 180 ng/
ml).
To determine whether the correlation between
high sensitivity to androgen and low immunoglobulin
levels previously observed also occurred in these strains,
plasma immunoglobulin levels were assayed in males
and females of the HAR RF/J and LAR 129/J strains
by using quantitative radial immunodiffusion as previously described (108). Individual assays were performed in duplicate when the mice were 14 weeks of
age. Immunodiffusion plates and reference sera were
supplied by Meloy Laboratories (Springfield, Virginia).
The data were analyzed by two-way ANOVAs for sex
and strain and multiple comparisons tests were performed. The results, as shown in Table 1, indicate that
for all immunoglobulins assayed, the HAR RF/J males
had lower values than the LAR 129/J males. In IgG2b
the RF/J males were lower than RF/J females. In IgM
and IgG2a the RF/J as a strain were low. Among the
RF/J
A /J
129/J
30 -
20 -
10ng/ml-
x 102
Figure 8. Antibody responses to bovine IgG (B-IgG) conjugated with
complete Freund's adjuvant in high (RF/J) and low (A/J and 129/J)
androgen responder strains. RF/J and A/J mice are H-2k and H-2"
respectively and would be expected to produce high responses to BIgG. The 129/J are H-2b and would be expected to produce low antiand females 0. (Ten mice per
body responses to B-IgG. Males
group.)
=
HIGH ANDROGEN SENSITIVITY
1227
Table 1. Levels of plasma immunoglobulins comparing additional strains of mice with high (RF/J) and low (129/J) seminal vesicle responses to
androgen
Plasma immunoglobulin levels
(arithmetic mean f SEM in mg/ml)*
Strains
Malest
Femalest
Strain
Sex
RF/J
129/J
0.14 f 0.01
0.38 f 0.028
0.15 f 0.01
0.30 f 0.021
(P< 0.01)
F = 101.1
NS*
RF/J
129/J
1.79 f 0.17
4.48 f 0.298
2.21 f 0 . 2 w
RF/J
129/J
0.43 f 0.01
0.76 f 0.038
IgG2a
IgG2b
*5
Two-way ANOVA
F = 51.8
1.85 f 0.14
F
(P< 0.01)
5
27.1
(P< 0.01)
0.61 f 0.29..
F = 62.6
F = 7.9
0.75 f 0.038
(P< 0.01)
(P< 0.01)
Interaction
F = 5.96
(P< 0.01)
F = 18.8
(P< 0.01)
F = 10.5
(P< 0.01)
Multiple comparisons tests (Q at P = 0.05).
t Fifteen mice per group, each mouse assayed individually.
Not significant.
Significantly different from both RF/J males and females.
1Significantly different from RF/J males; RF/J females, and 129/J males.
# Significantly different from 129/J males.
** Significantlydifferent from RF/J males.
LAR 129/J, the males had equal or higher values than
the females. This was an unusual finding and particularly interesting in view of the fact that the 129/J are
considered to be high estrogen responders (1 19). If estrogens exert a beneficial effect and if immunoglobulin
levels are a reflection of immune status, then one might
expect that high estrogen responder females would have
higher, not lower, levels of immunoglobulin.
In summary, the data presented indicate that
HAR males had consistently low responses compared to
females of the same strain or compared to LAR mice.
When the concentration of circulating testosterone in
HAR C57L/J males was depleted by gonadectomy or
augmented by exogenous androgen, there were no
changes in their low immunoglobulin and low anti-SIII
levels compared to sham operated controls. Sex differences with males at a disadvantage occurred primarily
in the HAR C57L/J or RF/J strains. In contrast, in the
two LAR strains, the A/J and 129/J, males generally
had responses equal to or greater than those of their respective females. In assays in which the HAR C57L/J
and RF/J did not show sex differences, the HAR strains
as a whole, females as well as males, produced lower responses than LAR mice. Females of HAR strains, therefore, varied in their immune responses and sometimes
produced low responses. Males of HAR strains, on the
other hand, consistently produced low immune responses.
DISCUSSION
With this data, some new thoughts on an old
problem are presented. We suggest that in normal, intact, untreated mice, high target organ responsiveness to
androgen in males correlates with low immune performance. Changing the level of circulating androgen either
by gonadectomy or exogenous hormone does not influence the low immune performance of HAR males. The
Table 2. Summary of results comparing high and low androgen responder males in immune competence
Immune competence
Strain
C57L/J
RF/J
A/J
l29/J
H-2
type
Androgen
sensitivity
b
High
High
Low
k
a
b
Immunoglobulin
levels
Low
SIII
rCSponsC
LOW
Low
Low
High
High
LOW
High
High
BSA
response
*
*
Low
High
B-IgG
response
Expected*
B-IgG responses
High
Low
High
High
L OW
LOW
NTt
LOW
* See references 115, 116.
*
t Not tested because a low response would be expected.
BSA assays discontinued because of irregularities in different batches and because the genetics of the immune response have not been established.
COHN
1228
data indicate that sex differences in immune responsiveness are not uniformly present in all strains in all studies, but in strains with high sensitivity to androgen, sex
differences occur in immunoglobulin levels and in antibodies to SIII, BSA, and B-IgG. In the few cases where
sex differences do not occur in HAR strains, the strain
as a whole is low with females as well as males producing low reponses.
The low antibody responses of the HAR RF/J
males to B-IgG is a critical finding because it indicates
that even when they have the H-2 type associated with
high immune responsiveness (H-2') (1 15,116), HAR
males produce low levels of antibody. This may explain
the findings of Vaz and Levine who reported in 1970
that 3 of the 9 H-2' strains produced unexpectedly low
antibody responses to benzylpenicilloyl,, conjugated
bovine gamma globulin. The three H-2' strains were the
C57BR/cdj, the MA/J, and the RF/J (115). Since that
time in our laboratory, we have assayed these strains
and found all three to be high androgen responders
(110,120). Consistent with these findings are preliminary results in C57BR/cdj which show that the HAR
C57BR/cdj, like other HAR strains, produce low antibody responses to SIII when compared with LAR A/J
mice (120).
Although the precise manner in which high
androgen sensitivity influences immune function remains to be elucidated, certain facts about target organ
responsiveness to androgen are known. First, sensitivity
to androgen is a genetically controlled trait thought to
be regulated by polygenes (106) with loci postulated at
the Hom-1 locus near the K end of the H-2 complex
(111) or at the Tfm locus on the X chromosome (1 12).
Second, sensitivity to androgen is not directly linked to
H-2 type. C57L/J (H-2b)are high and 129/J (H-2b)low
responders to androgen. Conversely, RF/J and C57BR/
cdj (both H-2') are high and A/J (H-2') low androgen
responders (108,109,120). H-2' and H-2' share the same
left end of the H-2 complex where the Hom-1 and Ir
genes map (123). Third, the degree of target organ responsiveness to androgen is not necessarily proportional
to the concentration of circulating hormone but may
vary with it inversely (107). Fourth, in strains highly
sensitive to androgen, females may manifest the trait as
well as males. This is demonstrated in white leghorn
fowl by increased comb growth (122) and in C57L/J females by their high incidence of polycystic ovary (123).
The data presented indicate that it is high sensitivity to androgen that correlates with low immune responses, not a high concentration of postnatal androgen. This finding does not rule out the possibility that,
during prenatal development, androgens present in the
fetus exert a critical influence on the immune system.
Fetal androgens are normally produced by the testes,
adrenals, and placenta. They are potent agents in organogenesis. It is possible that in addition to stimulating the
development of the male reproductive tract and the
masculinization of the hypothalamus, they act on other
organ systems as well.
Based upon experimental results, fetal androgens
could act on the developing lymphomyeloid system
through the bone marrow or through the thymus. With
respect to the first possibility, androgens have been
shown to trigger hemopoietic stem cells into cycling
(91-93). If immune potential is directly related to the
number of immunocompetent precursors available
(124) and if there are finite numbers of precursor cells
or cell divisions, it is possible that in animals highly sensitive to this steroid, androgens reduce immune potential by triggering uncommitted stem cells into acceler-
806040-
20me
4WEEKS
8 WEEKS
14 WEEKS
20 WEEKS
Figure 9. Weights of thymuses in high androgen responder (C57L/J) males (M) and females
and low androgen responder (A/J) males (M) ahd females (F) at 4,8, 14, and 20 weeks of age. (Five mice per group.)
1229
HIGH ANDROGEN SENSITIVITY
ated cycling or by shifting them into non-lymphoid
compartments.
On the other hand, androgens have been shown
to ablate antibody responses by acting on the epithelial
component of the thymus or bursa (76,77). Precisely
how alterations in the epithelium lead to defective lymphoid function is not clear. It is possible that some type
of modscation occurs which shifts the microenvironment to one that favors the development of suppressor cells or suppressor factors. In our laboratory,
preliminary studies comparing the growth of the thymus
in HAR and LAR strains indicate that HAR C57L/J
males have consistently heavier thymuses than LAR A/J
males, despite the low immune responses of the C57L/J
males (See Figure 9). Treatment with antithymocyte
serum leads to a greater enhancement of anti4111 responses in HAR males than in the LAR A/J. Further
studies are required to determine whether the heavier
thymuses of the HAR C57L/J do indeed contain suppressor cells and whether it is suppressor cells of the
thymus that are responsible for the low immune responses of HAR males.
Our hypothesis would be strengthened if we
knew the answers to the following questions: D o current
theories of steroid action require that androgens affect
all target cells through one common mechanism? If receptors have not as yet been isolated in hemopoietic
cells, does this preclude the possibility that androgens
influence stem cell function? Does receptor occupancy
correlate with biologic response? By what mechanisms
could steroid induced changes in the epithelium of the
bursa or thymus influence lymphoid function? Finally,
in experiments involving exogenous hormones, how can
we prove that the responses observed are directly due to
the action of the administered hormone and not due to
complex metabolic readjustments or the synergistic effects of endogenous hormones? The answers to these
questions should contribute substantially to our understanding of the interface between endocrinology and
immunology.
In the meantime, data have been presented from
our laboratory which show that among healthy, intact,
untreated mice, males with genetically determined high
target organ responses to androgen consistently produce
low immune responses regardless of their H-2 type, the
concentration of their postnatal testosterone, or the nature of the immune assay. Our tentative hypothesis is
that high sensitivity to androgen contributes to sex differences in the immune response by acting as a non-spe&c modulator of the immune system. We suggest that
in individuals highly sensitive to this steroid, androgens
produced by the fetal testes, adrenals, or placenta act on
the developing lymphomyeloid complex to create an
immune system programmed for low immune responses.
ACKNOWLEDGMENTS
This manuscript was prepared with the assistance of
Robert Champer, Diana Lopez, Maria Pascua, David Roman,
and Ada Williams, all of whom are past or present student
participants in the NIH Minority Biomedical Support Program at York College, City University of New York.
The author is indebted to Dr. Gerald Schieman for
his advice and the use of his facilities at Downstate Medical
Center and to Dorothy Gonzalez for her expert typing.
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