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Original Studies |
Research Institute for Endocrinology, Reproduction, and Metabolism (E.J.G., L.J.G.G.), Departments of Pathology (J.C.M.F., B.M.E.B.) and Clinical Chemistry (C.S.), University Hospital Vrije Universiteit, 1007 MB Amsterdam; and Department of Immunology, Erasmus University (H.A.D.), Rotterdam, The Netherlands
Address all correspondence and requests for reprints to: Erik J. Giltay, M.D., Department of Endocrinology, Division of Andrology, University Hospital Vrije Universiteit, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: giltay{at}dds.nl
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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In men, estrogens plus antiandrogens increased free cortisol levels in
24-h urine samples, decreased natural killer cell numbers, and slightly
inhibited the mitogen-induced interferon-
/interleukin-4 ratio, but
up-regulated the expression of TH1-associated chemokine
receptors, CCR1, CXCR3, and CCR5. Conversely, in women, androgens
slightly decreased free cortisol levels in 24-h urine samples and
enhanced the mitogen-induced interferon-/interleukin-4 ratio and
tumor necrosis factor-
production. At the single cell level no
TH1/TH2 shifts were found. Remarkably,
up-regulation of TH1 cytokines was accompanied by
down-regulation of CCR1, CXCR3, and CCR5 expression. Neither
CD4+ lymphocyte numbers nor IgG, IgM, and
antithyroperoxidase levels, although higher in women then in men, were
affected by cross-sex hormonal treatment.
These results demonstrate that the capacity to develop a TH1 phenotype of peripheral blood lymphocytes is stimulated by androgens and is slightly inhibited by estrogens. These changes may be direct or indirect through the effects on other hormones.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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T helper cells can be divided into the reciprocally suppressive T
helper type 1 (TH1) and TH2
subsets, which are defined by their profile of cytokine release and the
type of response they elicit. Polarized TH1 or
TH2 immune responses are associated, on the one
hand, with protective immunity against certain intracellular bacteria
and viruses or parasites, respectively, and, on the other hand, with
certain autoimmune diseases or allergy. TH1 cells
produce interleukin-2 (IL-2), interferon- (IFN), and, less
specifically, tumor necrosis factor- (TNF), stimulating
cell-mediated immune responses, whereas TH2 cells
produce IL-4, IL-5, IL-10, and IL-13, which provide help for humoral
immune responses (26, 27), such as the production of IgE and IgG4 (28, 29). The body distribution of these T cells is directed by the
differential expression on the cell membrane of distinct sets of
adhesion molecules and chemokine receptors. Chemokines are chemotactic
cytokines produced by a wide variety of cells to attract the relevant
leukocytes to sites of infection and inflammation (30, 31).
TH1 and TH2 cells express
different chemokine receptor profiles; TH1 cells
seem to preferentially express the CC chemokine receptors, CCR1, CXCR3,
and CCR5 (32, 33, 34, 35), facilitating their selective migration into
inflammatory lesions. The factors that influence chemokine receptor
expression in vivo are still largely unknown.
Sex differences on cytokine production in vivo have not been reported to date; nevertheless, sex steroids seem to differentially affect TH1 and TH2 cytokine production. During pregnancy, the TH1/TH2 balance is skewed toward TH2 (36), thereby preventing rejection of the antigenically foreign fetus by a cell-mediated immune attack (37, 38). The shift toward a TH2 response may be triggered by increased circulating levels of 17ß-estradiol and progesterone (39) during pregnancy (40). The in vitro influence of sex steroids on T cell cytokine production has been studied extensively (17, 18, 39, 41, 42), showing complex and diverse effects, but human in vivo studies apart from pregnancy are scarce. Healthy transsexual males and females, therefore, provide a unique opportunity to study the in vivo effects of cross-sex steroid hormones on the immune system. Here we examine 1) the effects of either estrogens plus antiandrogens or testosterone on normal humoral and cellular immune parameters, and 2) the incidence of TPO-Ab expression in transsexual males treated for at least 5 yr with estrogens compared to male controls.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We included 30 Caucasian male to female (M
F; median age, 26
yr; range, 18–45) and 30 Caucasian female to male (FM) transsexuals
(median age, 23 yr; range, 17–40). The body mass index was 20 ±
3 kg/m2 (mean ± SD) in MF
and 23 ± 5 kg/m2 in FM transsexuals. All
measurements were performed before and again after 4 (and 12) months of
cross-sex hormone administration. In both groups gonadectomy had not
yet taken place, but after cross-sex hormone administration their own
sex steroid production was suppressed (Table 1
). MF transsexuals were treated with
ethinyl estradiol (100 µg/day; Lynoral,
Organon, Oss, Netherlands) in combination with the
antiandrogen cyproterone acetate (100 mg/day; Androcur, Schering AG, Weesp, The Netherlands). FM transsexuals were treated
with either im testosterone esters (n = 27; Sustanon,
Organon; 250 mg/2 weeks) or oral testosterone undecanoate
(n = 3; Andriol, Organon; 160 mg/day). One FM
transsexual reported intake of oral contraceptives 6 months before
baseline. All other FM transsexuals had had regular menstrual cycles
(28–31 days) before cross-sex hormone administration. There was no
evidence of autoimmune disease, immune deficiencies, chronic infection
(e.g. with human immunodeficiency virus type 1), endocrine
diseases, or use of other sex hormones for 3 yr or more before
baseline. In all subjects, the body mass index
(weight/height2) was assessed, venous blood
samples were taken in the morning between 0900–1200 h after an
overnight fast, and 24-h urine was collected (during the 24 h
before blood sampling). For logistical reasons, most measurements were
obtained in randomly chosen subgroups (Table 1). The investigation
conformed with the principles outlined in the Declaration of Helsinki.
Informed consent was obtained from all subjects, and the study was
approved by the ethical review committee of the University Hospital
Vrije Universiteit.
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Standardized RIAs were used to determine serum levels of
testosterone (Coat-A-Count, Diagnostic Products, Los
Angeles, CA), 5-dihydrotestosterone (after extraction,
Intertech, Strassen, Luxembourg), dehydroepiandrosterone sulfate
(DHEAS; Diagnostic Products), 17ß-estradiol (Sorin
Biomedica, Saluggia, Italy), and, in 24-h urine samples, free cortisol
(after extraction; Coat-A-Count, Diagnostic Products). To
assess peripheral androgen activity, we measured serum
5-androstane-3,17ß-diol glucuronide (Adiol G) (43) by RIA
(Diagnostic Systems Laboratories, Inc., Webster, TX).
Immunometric luminescence assays were used to determine levels of FSH
(Amerlite, Amersham Pharmacia Biotech, Aylesbury, UK) and
LH (Amerlite). Immunoradiometric assays were used to measure serum
levels of GH (Sorin Biomedica, Saluggia, Italy) and PRL
(Biosource Technologies, Inc., Fleurus, Belgium).
Lymphocyte phenotyping
Measurements of lymphocyte subpopulations, cytokines, and
chemokine receptors were performed in a random subgroup of 10 MF
transsexuals (median age, 27 yr; range, 20–41) and 10 FM
transsexuals (median age, 26 yr; range, 18–40) at baseline and after 4
months of cross-sex hormone administration. In fresh heparinized venous
blood the numbers of CD3-, CD4-, CD8-, CD19-, and CD16/56-positive
cells were analyzed on a FACStar Plus (Simulset, Becton Dickinson and Co., San Jose, CA). These lymphocyte subpopulations are
expressed as percentages of the total number of lymphocytes.
Cytokine production in supernatants
IFN, IL-2, TNF, IL-4, IL-5, and IL-10 production by Ficoll
isolated (Lymfoprep, Nycomed, Pharma AS, Oslo, Norway) and
cryopreserved peripheral blood mononuclear cells (PBMC) was assessed in
culture supernatants. To eliminate the effect of interassay variation,
pre- and posttreatment samples from the same subject were analyzed in
the same run. Therefore, 2.5 x 106 PBMC/mL
were cultured for 36 h in Iscove’s Modified Dulbecco’s Medium
(BioWhittaker, Inc., Verviers, Belgium) supplemented with
10% human pooled serum (Central Laboratory Blood transfusion,
Amsterdam, The Netherlands), 100 µg/mL streptomycin, 100 IU/mL
penicillin, and 2 µg/mL anti-CD25 (CLB clone TB30). Cells were
stimulated with 10 µg/mL phytohemagglutinin (PHA; Murex Diagnostics
Ltd., Dartfort, UK). Supernatants were stored at -80 C until analyses.
All cytokines were measured by standard enzyme-linked immunosorbent
assay techniques with the following commercially available antibodies
or kits: IL-2 and IFN (Medgenix Diagnostics SA, Fleurs, Belgium);
IL-4, IL-6, and TNF (CLB compact enzyme-linked immunosorbent assay);
and IL-10 (PharMingen, San Diego, CA).
Cytokines production at the single cell level
Staining of intracellular cytokines was performed as described
by Jung et al. (44). In brief, 2 x
106/mL thawed PBMC were incubated for 4 h in
Iscove’s Modified Dulbecco’s Medium with the following supplements:
10% FBS (Integro, Leuvenheim, The Netherlands), penicillin,
streptomycin, 20 ng/mL phorbol myristate acetate (Sigma,
St. Louis, MO), 1 µmol/L calcium ionophore (Sigma), and
3 µmol/L monensin (Sigma). Subsequently, the cells were
washed with phosphate-buffered saline/0.5% BSA (Roche Molecular Biochemicals, Mannheim, Germany) and stained with
anti-CD3-RPE-Cy5 (DAKO Corp., Glostrup, Denmark) and
anti-CD8-fluorescein isothiocyanate (anti-CD8-FITC; Becton Dickinson and Co.). After washing, the cells were fixed with 4%
paraformaldehyde (Merck & Co., Inc., Darmstadt, Germany)
and permeabilized with phosphate-buffered saline with 0.1% saponin
(Merck & Co., Inc.), 0.5% BSA, and 10% human pooled
serum. Intracellular staining was performed with
anti-IFN-phycoerythrin (anti-IFN-PE), anti-IL-4-PE, and TNF-PE
(PharMingen). Cells were analyzed on a FACStar Plus. The
percentages of cytokine-producing cells were calculated within the
CD3+,
CD3+/CD8+, and
CD3+/CD8- cell
fractions.
Chemokine receptor expression at the single cell level
Unstimulated PBMC were incubated for 30 min with biotinylated anti-CCR1 (R&D Systems Europe, Abingdon, UK), anti-CXCR3-FITC (R&D Systems Europe), or anti-CCR5-FITC (PharMingen). The cells were additionally stained with anti-CD3-RPE-Cy5 (DAKO Corp.) and anti-CD8-PE (Becton Dickinson and Co.). The cells incubated with anti-CCR1 cells were subsequently stained with streptavidin-FITC (DAKO Corp.). After analyses on a FACStar Plus, the geometric mean surface expression as well as the percentages of chemokine receptor-positive cells were calculated within the CD3+, CD3+/CD8+, and CD3+/CD8- cell fractions.
Serum levels of Ig (sub)classes
Measurements were performed in 25 MF transsexuals (median
age, 29 yr; range, 18–43) and 25 FM transsexuals (median age, 23
yr; range, 16–37) at baseline and after 4 months of cross-sex hormone
administration and in a subgroup of 13 MF and 13 FM transsexuals
again at 12 months. Serum levels of IgA, IgM, IgG, and IgG4, the human
equivalent of murine IgG1, were assessed by kinetic nephelometry
[Array Protein System 360, Beckman Coulter, Inc.,
Fullerton, CA; interassay coefficients of variation (CV), <2.5%;
interassay CV, <2.8%); IgE was assessed by fluoroimmunoassay
(Pharmacia CAP System, Pharmacia & Upjohn, Inc.,
Bridgewater, NJ; intraassay CV, 6%; interassay CV, 6%).
Cross-sectional study of TPO-Ab expression
We included 186 MF transsexuals [median age, 43 yr; range,
21–70, because a sex difference in having TPO-Ab was found in the age
range from 20–70 yr (8, 9)], who had been treated with cross-sex
hormones for 5 yr or more. The mean duration of estrogen administration
was 12 yr (range, 5–32), and the mean duration since the sex
reassignment surgery (i.e. orchidectomy) was 10 yr (range,
3–25). Current treatment consisted of oral ethinyl
estradiol (Lynoral, 12.5–150 µg/day; n = 114),
transdermal 17ß-estradiol (25–100 mg twice per week; Estraderm TTS,
Novartis, Basel, Switzerland; n = 37), oral
conjugated estrogens (Premarin, Wyeth-Ayerst,
Philadelphia, PA; or Dagynil, Dagra, Pharma, Diemen, The
Netherlands; 0.625–2.5 mg/day; n = 26), oral
17ß-estradiol (Progynova, Schering AG; 1–4
mg/day; n = 7), or parenteral 17ß-estradiol (Progynon-depot,
Schering AG, Berlin, Germany; 10/2 weeks; n = 2).
Some combined their treatment with the antiandrogen cyproterone acetate
(Androcur, Shering; 2–100 mg/day; n = 47) or
spironolactone (Aldactone, Searle, Chicago, IL; 100–200 mg/day;
n = 3). For every MF transsexual, a control male was selected
of similar age (±2 yr), with a median age of 42 yr (range, 20–72);
they were MF transsexuals before hormone administration (n =
131) and healthy nontranssexual males (n = 55). Male controls were
eugonadal by clinical and laboratory criteria: testosterone, 20 ±
7 nmol/L (mean ± SD); 17ß-estradiol,
86 ± 24 pmol/L; and LH, 3.1 ± 1.6 U/L. Serum PRL levels,
available in 129 MF transsexuals and 131 male controls, were used as
an index of estrogen administration. Serum TPO-Ab titers were assayed
using the Milenia-test (Diagnostic Products) and titers of
10 IU/mL or more were considered positive.
Statistical analysis
Variables with distributions that were skewed to the right
(cytokine levels and expression, chemokine receptor expression, Ig
isotype levels) were logarithmically transformed before analysis to
normalize their distributions. Antilogarithms of the transformed means
were used to obtain geometric means and 95% confidence intervals (CI)
of the means. Mann-Whitney tests for independent samples were used to
compare baseline differences. Wilcoxon’s signed ranks test was used to
analyze the effects of cross-sex hormones after 4 months for all
measurements as well as for comparisons of PRL and TPO-Ab levels
between MF transsexuals and male controls. Spearman’s correlation
coefficients were used for intercorrelations. In the MF and the
FM groups separately, an ANOVA for repeated measurements was used to
analyze the effects of cross-sex hormones at three time points on Ig
(sub)class levels as well as to compare at two time points the effects
of estrogens plus antiandrogens with those of androgens. If values were
below the lower limit of detection, the value of that lower limit was
used for statistical calculations (for 17ß-estradiol, 90 pmol/L; for
testosterone, 1.0 nmol/L; for 5-dihydrotestosterone, 0.1 nmol/L; for
LH, 0.3 IU/L; for FSH, 0.5 IU/L; for IgE, 2 U/mL). A two-tailed
P value of less than 0.05 was considered statistically
significant. The software used was SPSS for Windows 8.0 (SPSS, Inc., Chicago, IL).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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After estrogen plus antiandrogen administration to MF
transsexuals, serum levels of total testosterone,
5-dihydrotestosterone, Adiol G, DHEAS, LH, and FSH were
significantly suppressed, mostly to undetectable levels. The
ethinyl estradiol that had been administered could not be
detected by the assay used, but there were clear physical signs of
estrogen effects in these subjects. Free cortisol excretion in 24-h
urine samples and serum PRL levels showed a significant increase,
whereas serum GH levels slightly increased (Table 1
).
After parenteral testosterone administration to FM transsexuals, the
serum levels of total testosterone, 5-dihydrotestosterone, and Adiol
G significantly increased, whereas serum levels of 17ß-estradiol, LH,
and FSH levels were slightly, but significantly, suppressed. Serum
levels of DHEAS, PRL, and GH as well as free cortisol excretion in 24-h
urine samples did not change significantly (Table 1).
Leukocytes and lymphocyte subpopulations
After estrogen plus antiandrogen administration to males, the mean
number of leukocytes increased, whereas no change occurred after
testosterone administration to females. There was a tendency toward a
lower number of CD4+ T cells (P =
0.052) and a lower
CD4+/CD8+ ratio
(P = 0.08) in males compared to females (Table 1). Upon
cross-sex hormone administration there were no changes in either the
total number of lymphocytes or the relative number of
CD4+ and CD8+ T cells in
male or in female transsexuals (Table 1 and Fig. 1). After estrogen plus antiandrogen
administration to males, both absolute (data not shown;
P = 0.03) and relative numbers of NK cells decreased
(P = 0.01), whereas a slight increase was found in the
absolute (data not shown; P = 0.24) and relative number
(P = 0.11; Table 1 and Fig. 1) of B cells. Upon
testosterone administration to females, changes in NK and B cells, were
less obvious and did not reach statistical significance (Table 1 and
Fig. 1). However, the effects of estrogen plus antiandrogen were the
opposite of those of testosterone (P = 0.02 for NK
cells and P = 0.07 for B cells, for differences between
MF and FM transsexuals by ANOVA for repeated measurements).
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Before hormone administration, males produced higher levels of
IFN upon PHA stimulation than females (P = 0.02).
The number of IFN-producing T cells also tended to be higher in
males (P = 0.07; Table 1). Upon hormone administration,
no significant differences were found for individual cytokines, either
in supernatants upon PHA stimulation or by intracellular staining,
except for the PHA-stimulated production of TNF-, which increased
significantly upon testosterone administration (P =
0.03; Table 1). However, an overall shift toward a
TH1 phenotype, as evaluated by the PHA-stimulated
production ratio of IFN to IL-4, was found in females upon
testosterone administration (P = 0.008), whereas this
TH1 phenotype tended to be down-regulated in
males upon estrogen and antiandrogen administration (P
= 0.14 and P = 0.001 for the difference between MF
and FM transsexuals in an ANOVA for repeated measurements; Table 1
and Fig. 2).
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To investigate to what extent the predominant
TH1 profile found in males would be reflected by
phenotypic analyses of TH1-associated chemokine
receptors on the lymphocyte surface, we studied baseline and
hormone-induced changes in CCR1, CXCR3, and CCR5 expression. Before
hormone administration, no sex differences were found in these
chemokine receptor profiles. At baseline, inverse, but weak,
correlations were found between the geometric mean surface expression
of these chemokine receptors and the IFN/IL-4 ratio in both
PHA-stimulated supernatants and cytokine-producing T cell numbers
(Table 2).
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and Fig. 3). The fraction of
CD3+ T cells expressing CCR1 increased from 2.9%
to 5.4%, the fraction that expressed CXCR3 increased from 20.7% to
27.9%, and the fraction that expressed CCR5 increased from 11.9% to
17.9%. After androgen administration to women, no significant effects
were found (Table 1 and Fig. 3).
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). Analysis of their individual
proportional changes after 4 months showed that, similar to baseline
values, these changes were inversely correlated with the
TH1 phenotype, as evaluated by IFN/IL-4
production and intracellular expression ratio by T cells (Table 2 and
Fig. 4). Concerning CCR5 expression by
the helper subset of T cells, the proportional changes correlated
inversely not only with the IFN/IL-4 ratio, but also with the
numbers of TNF-producing cells (data not shown).
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At baseline, significantly higher serum IgG and IgM levels were
found in females compared to males (Table 1). Serum IgG4 and IgE levels
were significantly correlated (r = 0.33; P =
0.02). After 4 months of estrogen plus antiandrogen administration to
males, only the serum IgA level and the IgG4/IgG ratio decreased
slightly (Table 1). After 4 months of androgen administration to
females, serum IgA levels decreased also, but serum IgM levels
increased (Table 1). The effects of estrogen plus antiandrogen and
androgen treatment were not different after 4 or 12 months when
comparing 13 MF to 13 FM transsexuals with complete data (for
all, P 
0.10 in ANOVAs for repeated measurements),
except for IgE levels (P = 0.03), which decreased in
MF after 12 months and did not change in FM transsexuals
(P = 0.04 and P = 0.31, respectively;
12 month data not shown). Sex differences in IgG and IgM were not
essentially affected after cross-sex hormone administration (Fig. 5). Proportional individual changes after
4 months in serum levels of IgM, IgA, and IgG correlated strongly and
positively (for all, P < 0.001).
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Figure 6 shows the cross-sectional
data on serum levels of PRL and TPO-Ab in 186 MF transsexuals and
186 age-matched male controls. As expected, significantly higher PRL
levels were found in MF transsexuals compared to the male controls
(P < 0.001, by Wilcoxon’s signed ranks test). Fifteen
MF transsexuals as well as 15 male controls (8.0% for both) had a
TPO-Ab titer of 10 U/mL or more. Also, when TPO-Ab levels in MF
transsexuals were compared to their matched control levels, no
significant difference was found (P = 0.23, by
Wilcoxon’s signed ranks test; Fig. 6). The duration of estrogen
administration was not associated with TPO-Ab levels in MF
transsexuals (data not shown). Compared to the age-adjusted prevalences
of TPO-Ab in a previous study (9) a significant difference was found
between MF transsexuals and females (8.0% vs. 14.1%;
P < 0.001, by 
2 test), but no
significant difference was found between MF transsexuals and males
(8.0% vs. 6.4%; P = 0.13, by
2 test).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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TPO-Ab were chosen as an example of autoantibodies with a relative high prevalence in females, i.e. 13% compared to 6.1% in males (9). Although estrogen treatment and castration of male animals result in increased autoantibody levels in murine models (21, 22, 23, 24, 25), we found a similar frequency (8%) and similar titers of TPO-Ab in orchidectomized males on long term estrogen treatment and in age-matched, male controls. Hyperprolactinemia, induced by long term estrogen therapy and found to be related to TPO-Ab in a previous study (53), was not associated with elevated TPO-Ab levels. Reports on the in vivo effects of endogenous and exogenous estrogens on IgA, IgG, and IgM levels conflict (54, 55, 56). In the present study we confirm the finding of higher IgG and IgM levels at baseline in women compared to men (3, 4, 5, 6). Upon cross-sex hormone administration, however, only minor changes could be observed after 4 and 12 months, and the sex differences before treatment were not reversed. Moreover, the effects on IgA, IgG, and IgM levels of estrogen plus antiandrogen administration in men were largely similar compared to those of testosterone administration in women. Administration of sex steroids may cause body water retention (57, 58), and the increased plasma volume may have diluted the concentrations of circulating Igs in both treatment groups. This concept is supported by the strong positive correlations between changes in IgA, IgG, and IgM levels.
Our data showed that testosterone administration increased the
IFN/IL-4 production ratio of peripheral blood T cells in women,
whereas estrogens plus antiandrogens slightly decreased this ratio in
men. Differential effects of sex steroids on cytokine production
profiles may be of clinical importance for the outcome of
immune-mediated inflammatory disease. For example, the higher risk of
developing systemic lupus erythematosus (59) and the increased number
of flares (60) in response to pregnancy or estrogen use may be due to
potentiation of the TH2 pathway by estrogens.
Estrogen-induced inhibition of TH1 responsiveness
against human papillomavirus infections (61) in women using oral
contraception could partially explain the epidemiological association
among oral contraception, urogenital infection, and cervical cancer
(16). The risk of cardiovascular disease, preceded by infiltration of
macrophages and T cells in the blood vessel wall (62), may be reduced
in women who receive estrogen therapy (63). It could be hypothesized
that a reduced IFN production may contribute to this reduced
cardiovascular risk, as illustrated by the reduction of atherosclerotic
lesions in IFN receptor knockout mice (64).
As phenotypic markers for TH1-like T cells, we
assessed the expression of the chemokine receptors CCR1, CXCR3, and
CCR5 (32, 33, 34, 35). Unexpectedly, upon estrogen plus antiandrogen
administration, but not upon testosterone administration, these
chemokine receptors were up-regulated on T cells, which consequently
may affect their ability to migrate. Although proinflammatory cytokines
can stimulate chemokine production and chemokine receptor expression
in vitro (30, 65, 66), our in vivo data suggested
that CCR1, CXCR3, and CCR5 expression is inversely associated with the
TH1/TH2 balance. In fact,
negative correlations were found in PBMC suspensions tested between
CCR1, CXCR3, and CCR5 expression and the ratio of IFN to IL-4.
However, this phenomenon could not be evaluated at the single cell
level, because the expressions of chemokine receptors and cytokines
were not determined in a double staining. Apparently, CCR1, CXCR3, and
CCR5 expression does not provide a simple phenotypic marker for PBMC
propensity toward TH1 cytokine production. The
increased CCR5 expression on helper T cells (11.6% to 18.1%) upon
estrogen plus antiandrogen administration may have some implications
for AIDS pathogenesis (66), because CCR5 serves as coreceptor for the
entry into macrophages and activated T cells of the macrophage-tropic
strain of human immunodeficiency virus-1 (30, 67).
The observed changes in immune parameters may be caused directly by the administered hormones themselves or may be secondary to complex paracrine responses from adjacent cells and mechanisms affecting other hormones, such as adrenal hormones. We noted in this study that free cortisol, known for its antiinflammatory TH1-suppressive properties (68), was increased in 24-h urine samples after estrogen plus antiandrogen administration and was slightly decreased after testosterone administration. Especially estrogens may induce a hyperresponsiveness of the hypothalamic-pituitary-adrenal axis (69, 70). Expected effects on the secretion of norepinephrine and epinephrine as well as observed effects on cortisol (70), as part of the stress system, could explain part of the observed effects on immune parameters. Additionally, in present and previous (71, 72) studies of cross-sex hormone administration, we observed changes in dehydroepiandrosterone, PRL, GH, insulin-like growth factor I, LH, and FSH, all of which have potentially immunostimulatory properties (41, 73, 74, 75). Especially, the effects of testosterone may be indirect through changes in other hormones or via dendritic cells (76), because T cells do not contain testosterone-binding sites (14, 15).
The interpretation of our results is limited by the inclusion of a relatively small number of subjects in the prospective part of the study and the lack of a placebo group due to the nature of the study population and the treatment indication. Furthermore, the effects of sex steroids in humans depend on the route of administration and the dosage. Our study assessed the effects of androgens in women and of estrogens plus antiandrogens in men. We cannot be sure whether sex-appropriate sex steroids would have had similar effects. To date, effects of sex steroids on immune responsiveness have only been studied in vitro (17, 18, 39, 41, 42). To the best of our knowledge, this is the first experimental study in humans reporting on overall in vivo effects.
In conclusion, estrogens plus antiandrogens in men decreased the number of NK cells and up-regulated the expression of TH1-associated chemokine receptors. In addition, our data provide evidence for a role of sex steroids as one of the many signals involved in regulation of the TH1/TH2 balance in men and women and suggest that testosterone drives peripheral blood T cells down a TH1 pathway, whereas estrogens may skew differentiation toward TH2. These changes may be direct or indirect through the effects on other hormones, especially those of the hypothalamic-pituitary-adrenal axis.
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Acknowledgments |
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Received September 28, 1999.
Revised January 13, 2000.
Accepted January 12, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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 S. T. Page, S. R. Plymate, W. J. Bremner, A. M. Matsumoto, D. L. Hess, D. W. Lin, J. K. Amory, P. S. Nelson, and J. D. Wu Effect of medical castration on CD4+CD25+ T cells, CD8+ T cell IFN-{gamma} expression, and NK cells: a physiological role for testosterone and/or its metabolites Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E856 - E863. [Abstract] [Full Text] [PDF]
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 W. M. Mlynarski, G. P. Placha, P. P. Wolkow, J. P. Bochenski, J. H. Warram, and A. S. Krolewski Risk of Diabetic Nephropathy in Type 1 Diabetes Is Associated With Functional Polymorphisms in RANTES Receptor Gene (CCR5): A Sex-Specific Effect Diabetes, November 1, 2005; 54(11): 3331 - 3335. [Abstract] [Full Text] [PDF]
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 A. Bouman, M. J. Heineman, and M. M. Faas Sex hormones and the immune response in humans Hum. Reprod. Update, July 1, 2005; 11(4): 411 - 423. [Abstract] [Full Text] [PDF]
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 R. Mo, J. Chen, A. Grolleau-Julius, H. S. Murphy, B. C. Richardson, and R. L. Yung Estrogen Regulates CCR Gene Expression and Function in T Lymphocytes J. Immunol., May 15, 2005; 174(10): 6023 - 6029. [Abstract] [Full Text] [PDF]
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S. S. Soldan, A. I. A. Retuerto, N. L. Sicotte, and R. R. Voskuhl Immune Modulation in Multiple Sclerosis Patients Treated with the Pregnancy Hormone Estriol J. Immunol., December 1, 2003; 171(11): 6267 - 6274. [Abstract] [Full Text] [PDF]
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 S. L. Glaser, C. A. Clarke, R. A. Nugent, C. B. Stearns, and R. F. Dorfman Reproductive Factors in Hodgkin's Disease in Women Am. J. Epidemiol., September 15, 2003; 158(6): 553 - 563. [Abstract] [Full Text] [PDF]
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J. R. Cerhan, C. M. Vachon, T. M. Habermann, S. M. Ansell, T. E. Witzig, P. J. Kurtin, C. A. Janney, W. Zheng, J. D. Potter, T. A. Sellers, et al. Hormone Replacement Therapy and Risk of Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia Cancer Epidemiol. Biomarkers Prev., November 1, 2002; 11(11): 1466 - 1471. [Abstract] [Full Text] [PDF]
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 G. Haliloglu, B. Anlar, S. Aysun, M. Topcu, H. Topaloglu, G. Turanli, and D. Yalnizoglu Gender Prevalence in Childhood Multiple Sclerosis and Myasthenia Gravis J Child Neurol, May 1, 2002; 17(5): 390 - 392. [Abstract] [PDF]
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A. F. Muller, H. A. Drexhage, and A. Berghout Postpartum Thyroiditis and Autoimmune Thyroiditis in Women of Childbearing Age: Recent Insights and Consequences for Antenatal and Postnatal Care Endocr. Rev., October 1, 2001; 22(5): 605 - 630. [Abstract] [Full Text] [PDF]
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