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Autoimmunity Reviews 11 (2012) A460A464

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Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev

Review

Estrogen metabolism and autoimmunity


Maurizio Cutolo a,, Alberto Sulli a, 1, Rainer H. Straub b, 2
a
b

Research Laboratory and Academic Unit of Clinical Rheumatology, Dept. Internal Medicine, University of Genova Italy, Viale Benedetto XV, 6-16132 Genova, Italy
Laboratory of NeuroEndocrino-Immunology, Division of Rheumatology, Department of Internal Medicine I, University Hospital, D-93042 Regensburg, Germany

a r t i c l e

i n f o

Available online 2 December 2011


Keywords:
Estrogens
Immune response
Autoimmune rheumatic diseases
Hydroxylated estrogen metabolites
Aromatases
Rheumatoid arthritis

a b s t r a c t
Epidemiological and experimental immunological evidence suggest that estrogens enhance the humoral
immune response, and at the same time, seem to play important roles in pathophysiology of autoimmune
rheumatic diseases. Estrogens in human subjects are generally considered as enhancers of cell proliferation
(anti-apoptotic), however, rather than through their serum levels (that may exert opposite dose-related effects), they play important roles through their peripheral metabolites especially in autoimmune rheumatic
diseases. Several investigations strongly support an accelerated aromatase-mediated peripheral metabolic
conversion of upstream androgen precursors to estrogen metabolites in peripheral tissues affected by
immune/inammatory reactions, both, in male and female patients. In RA synovial tissue, biological effects
of these metabolites as a consequence of altered peripheral sex hormone synthesis (intracrine, e.g., at the
level of macrophages and broblasts) mainly results in stimulation of cell proliferation and cytokine production
(i.e. TNF). It was shown that RA synovial cells mainly produce the cell proproliferative 16alpha-hydroxyestrone
which, in addition to 16alpha-hydroxy-17beta-estradiol, is the downstream estrogen metabolite that interferes
with monocyte proliferation. Therefore, a preponderance of 16alpha-hydroxylated estrogens is an unfavorable
sign, at least, in synovial inammation and possibly related synovial tissue hyperplasia. Interestingly, urinary concentration and total urinary loss of 2-hydroxyestrogens was found 10 times higher in healthy subjects compared to
RA or SLE patients irrespective of prior prednisolone treatment or sex. The intracrine synthesis of active estrogen
metabolites at the level of cells involved in the immune response (e.g. macrophages and broblasts) represents a
common pathway that characterizes a similar nal immune reactivity in both male and female patients.
2011 Elsevier B.V. All rights reserved.

Contents
1.
2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Estrogens and the immune response . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Proliferative effects of peripherally synthesized estrogens what we learn from tumors
2.2.
The peripheral estrogen metabolism and the local inammatory inuence . . . . . . .
2.3.
Peripheral estrogen metabolism and autoimmune rheumatic diseases . . . . . . . . .
2.4.
Effects of anti-TNFalpha therapy on sex hormones in RA patients . . . . . . . . . . .
3.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction
The majority of hormones involved in pathogenesis/treatment of
rheumatic diseases are cholesterol derivatives and are steroid hormones modulating a broad range of signaling mechanisms mainly
linked to the immune response [1,2]. Cholesterol is precursor for six

Corresponding author. Tel.: + 39 010 353 7994, + 39 010 353 8885 (Secretary),
+ 39 335 233621 (Mobile); fax: + 39 010 353 8885.
E-mail addresses: mcutolo@unige.it (M. Cutolo), albertosulli@unige.it (A. Sulli),
rainer.straub@klinik.uni-regensburg.de (R.H. Straub).
1
Tel.: + 39 010 353 7779.
2
Fax: + 49 941 944 7121.
1568-9972/$ see front matter 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.autrev.2011.11.014

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steroid hormone classes: progestagens (i.e. progesterone), glucocorticoids (i.e. cortisol), mineralcorticoids (i.e. aldosterone), androgens
(i.e. testosterone), estrogens (i.e. 17beta estradiol) and nally D hormone (vitamin D). During its metabolism, cholesterol is hydroxylated
and shortened to the C21 intermediates pregnenolone and progestagen that act also as precursors for the male and female sex hormones
androgens (C19) and estrogens (C18), respectively [1].
2. Estrogens and the immune response
Based on epidemiological and immunological evaluations, estrogens in normal conditions enhance the humoral B cell immune response in humans, and at the same time seem to play important

M. Cutolo et al. / Autoimmunity Reviews 11 (2012) A460A464

roles in pathophysiology of autoimmune rheumatic diseases [1]. As a


matter of fact, clinical evidences show that menstrual cycle, pregnancy, and menopausal status that are characterized by uctuations of
endogenous estrogens signicantly inuence the course of autoimmune diseases [2,3].
On the other hand, different concentrations used in vitro or in vivo
testing, might render estrogens friend or foe in immunoinammatory conditions and different cells involved in the immune
system react in an opposite manner to different estrogen concentrations [1,2]. In addition, the efciency of the functional estrogen receptors (ER-alpha or ER-beta) found in macrophages and lymphocytes
might be quite different under inammatory conditions depending
on the microenvironment and the type of disease [1,46] (Fig. 1).
Generally, estrogens enhance cell proliferation and reduce cell apoptosis [2,7]. For example, 17-estradiol was found to induce in dendritic cells via p38 and MAPKs the expression of CD40 which is a
costimulatory molecule and plays a crucial role in modulating the immune response of effector cells [8].
Interestingly, different downstream estrogen metabolites (especially hydroxylated) interfere with monocyte proliferation and generally might modulate the immune response (see next paragraphs) [9].
Differently, estrogen treatment was found to protect isolated primary
B cells from B cell receptor-mediated apoptosis [10]. These latter
studies suggested that estrogen induces a genetic program that alters
survival and activation of B cells in a B cell-autonomous fashion and
thus skews the naive immune system toward autoreactivity and
proliferation [10] (Fig. 1). In summary, if a disease is based on B
cell-driven pathophysiology, estrogens can be harmful, while T celldriven disease might be inhibited by estrogens.
2.1. Proliferative effects of peripherally synthesized estrogens what we
learn from tumors
The role of peripheral metabolism of estrogens is crucial in disease
progression. Important perspectives arise from the observation that
the production of estrogens from androgens is peripherally mediated
by the aromatase enzyme complex, the aberrant expression of which

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plays a critical role in the development of malignancy in a number of


tissues such as the prostate [11]. In fact, the altered promoter utilization can lead to an altered testosterone:estrogen ratio that is associated with the development of disease. Increased tissue estrogens on the
basis of elevated endogenous estrogens due to aromatase overexpression cause initial prostatic inammation [12]. Stimulation of estrogen
receptors (ERalpha) leads to aberrant proliferation, inammation and
pre-malignant pathology [12]. Interestingly, inhibition of estrogen
receptor-positive breast cancer (BCa) cell growth/proliferation has
been reported which was mediated by calcitriol-dependent downregulation of aromatase transcription suggesting that calcitriol has a potential benet for BCa therapy [13].
As a matter of fact, aromatase inhibitors can also be used for
neoadjuvant therapy of BCa in which they have achieved better
therapeutic efcacy than tamoxifen since local aromatase produces
sufcient estrogen for its proliferation [14].

2.2. The peripheral estrogen metabolism and the local inammatory


inuence
Several investigations strongly support an accelerated peripheral
metabolic conversion of upstream androgen precursors to estrogen
metabolites in peripheral tissues affected by immune/inammatory
reactions both in male and female patients [15]. High estrogen concentrations have been found particularly in synovial uids of RA patients of both sexes and the most acceptable explanation might
originate from recent studies showing that inammatory cytokines
(i.e. TNF, IL-6, IL-1), particularly increased in RA synovitis, are able
to markedly stimulate aromatase activity [1517] (Fig. 2).
A signicant correlation was found between aromatase activity
and IL-6 production in tissues rich in macrophages, and aromatase
has also been found in broblast synoviocytes [18]. Therefore, the increased aromatase activity induced by locally produced inammatory
cytokines (i.e. TNF, IL-1, IL-6) might explain the altered balance
resulting in lower androgens and higher estrogens in synovial uid
of active RA patients [4,17].

Fig. 1. Presence of estrogen receptors in cells involved in the immune response. Functional receptors have been found at the level of macrophages, T and B cells (see red circles).

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M. Cutolo et al. / Autoimmunity Reviews 11 (2012) A460A464

sign, at least, in synovial inammation and possibly related synovial


tissue hyperplasia.
The complex action of estrogen metabolites was recently investigated by evaluating the conversion of estrone/17beta-estradiol to various
estrogen metabolites in RA and OA synovial cells together with their
effects on TNF secretion [15]. Using estrone and 17beta-estradiol as
substrates, RA and OA synovial cells produced 16alpha-, 4-, and 2hydroxylated estrogens and their 4- and 2-methylation products
(Fig. 3). The levels of 16alpha-hydroxylated estrone/17beta-estradiol
(16alpha-hydroxyestrone/16alpha-hydroxy-17beta-estradiol) were
higher than the levels of all other estrogen metabolites. In particular,
RA synovial cells produced more 16alpha-hydroxyestrone than did OA
synovial cells [15]. Importantly, the 16alpha-hydroxylated estrogens
did not inhibit TNF secretion, whereas all other estrogen metabolites
had marked inhibitory effects [15].
Fig. 2. Peripheral metabolic conversion of upstream androgen precursors to estrogen
metabolites in synovial tissues of patients affected by rheumatoid arthritis (RA).
Increased estrogen to androgen ratio in synovial uids of RA patients of both sexes,
originates from the augmented aromatase activity under the effects of the inammatory
cytokines (i.e. TNFalpha, IL-6, IL-1).

The intracrine effects and role of local sex hormone concentrations


at the level of inammatory foci are of great importance in order to
explain the modulatory effects exerted by these hormones on the immune/inammatory reaction [19]. In particular, estradiol, estrone,
and several of their downstream hydroxylated metabolites have
been found to be signicantly increased in the synovial uid of RA patients of both sexes, clearly due to the local overexpression of cellular
aromatase [17].
It was shown that RA synovial cells mainly produce the cell proproliferative 16alpha-hydroxyestrone which, in addition to 16alphahydroxy-17beta-estradiol, is the downstream estrogen metabolite
that interferes with monocyte proliferation [9] (Fig. 3). Therefore, a
preponderance of 16alpha-hydroxylated estrogens is an unfavorable

2.3. Peripheral estrogen metabolism and autoimmune rheumatic


diseases
Local effects of altered peripheral sex hormone synthesis in autoimmune rheumatic diseases, such as RA, seem to consist mainly in
modulation by estrogens of cell proliferation and cytokine production
(i.e., TNF, IL-1, IL-12) [20].
Since 17beta-estradiol administered during hormone replacement
therapy will rapidly increase estrone sulfate after conversion in adipose
tissue by aromatases, hormone replacement therapy can have proinammatory effects by providing estrone sulfate to the inamed synovial
tissue [21]. Interestingly, RA patients when treated with both selective
agonists for estrogen receptor-beta (ER-beta) and alpha (ER-alpha)
showed negative results or worsening of the disease [22,23].
Estrogens may reduce the therapeutical effects of disease modifying
drugs (DMARDs) by acting at the level of immune/inammatory cells in
RA patients. Recently, the combinatory effects of leunomide (LEF), an
antiproliferative agent used in RA treatment (active metabolite A77
1726 LEF-M), and 17beta-estradiol were evaluated with respect to inammatory cytokine production by cultured human macrophages

Fig. 3. RA synovial cells mainly produce the cell proproliferative 16alpha-hydroxyestrone, which, in addition to 16alpha-hydroxy-17beta-estradiol, are the two downstream estrogen
metabolites (yellow box) that interfere with monocyte proliferation and TNF synthesis.

M. Cutolo et al. / Autoimmunity Reviews 11 (2012) A460A464

[24]. Macrophages were cultured with LEF-M alone and in combination


with 17beta-estradiol. Secretion of IL-6, TNF and TGF-beta was evaluated by immunocytochemistry (ICC), Western blot (WB), and RT-PCR.
ICC, as well as WB and RT-PCR, showed that LEF-M, compared to
untreated cells, signicantly decreased cytokine release [24]. On the
contrary, 17beta-estradiol increased cytokine release, a result that was
signicantly reversed when LEF-M was subsequently added. Therefore,
17beta-estradiol seems to contrast the LEF-M activity. These results
might support a more efcient therapeutical effect of LEF in male compared to female RA patients [25].
Similarly, in SLE patients, aromatase activity evaluated in skin and
subcutaneous tissue showed a tendency towards an increase when
compared with control individuals [26]. In fact, in SLE patients, the
aromatase activity varied inversely with disease activity and the patients had decreased androgen and increased estrogen serum levels
[26]. Furthermore, tissue aromatase activity showed signicant direct
correlation with estrogen levels in SLE patients. All these data suggest
that abnormally increased aromatase activity can partially explain abnormalities of peripheral estrogen synthesis in SLE, as well as the altered serum sex-hormone levels and ratio found in RA patients (i.e.
decreased androgens) [27].
Recently, it was stressed that estrogens and their catechol metabolites seem to play an important role in SLE [28]. The possible mechanism involves quinonesemiquinone redox cycling of catechol
metabolites to generate free radicals that can cause DNA damage.
This would probably alter immunogenicity of DNA leading to induction and elevated levels of SLE autoantibodies crossreacting with native DNA [28].
On the other hand, recent data suggest that estrogens inhibit
activation-induced apoptosis of SLE T cells by down-regulating the
expression of FasL and estrogen inhibition of T cell apoptosis may
allow for the persistence of autoreactive T cells, thereby exhibiting
the detrimental action of estrogen on SLE activity [29].
Interestingly, since in RA and SLE patients 17beta-estradiol was
thought to play a dual pro- and antiinammatory role depending on
its concentration or probably conversion to downstream mitogenic
16alpha-hydroxyestrone or naturally occurring antiestrogens such
as 2-hydroxyestrone, the renal excretion of these 2 types of estrogens
in healthy subjects and RA/SLE patients was carefully evaluated [30].
Urinary concentration and total urinary loss of 2-hydroxyestrogens
was found 10 times higher in healthy subjects compared to RA or SLE
patients irrespective of prior prednisolone treatment or sex. The urinary
concentration and loss of 16alpha-hydroxyestrone did not differ between healthy subjects and RA/SLE patients. The ratio of urinary
16alpha-hydroxyestrone/2-hydroxyestrogens was more than 20 times
higher in RA and SLE than healthy subjects irrespective of prior glucocorticoid treatment or sex [30]. These data demonstrate a large shift
to mitogenic estrogens in relation to endogenous antiestrogens. Both
steroids are converted from the precursor 17beta-estradiol and estrone.
In RA and SLE patients, the magnitude of conversion to the mitogenic
16alpha-hydroxyestrone is greatly upregulated, which likely contributes to maintenance of the proliferative state in these diseases [30].
In addition, estrogens also seem to be involved in other chronic
autoimmune diseases such as systemic sclerosis (SSc) [31]. For example, 17beta-estradiol has been found to exert a probrotic effect on
cultured normal and SSc broblasts by increasing the synthesis of extracellular matrix proteins (ECM) [32]. Primary cultures of SSc broblast were treated for 24 h with 17beta-estradiol (10( 10)M)
alone or in combination with tamoxifene (TAM, 10(7)M) as an estrogen receptor (ER) antagonist. Interestingly, 17beta-estradiol induced a signicant increase of bronectin, collagen type I, and
laminin synthesis both in normal and SSc broblasts when compared
to untreated broblasts. TAM induced a signicant decrease of ECM
protein synthesis when compared to E2-treated TAM-untreated broblasts. Thus, increased estrogen tissue concentrations might be a
stimulatory condition in SSc. [32].

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2.4. Effects of anti-TNFalpha therapy on sex hormones in RA patients


Androgens, such as dehydroepiandrosterone sulfate (DHEAS) and
testosterone are markedly lower in postmenopausal women with RA
than in controls. In contrast, compared to controls, serum levels of estrogens are normal or elevated in women with RA.
Since TNF alters production of these hormones, changes of sex
hormones during 12 weeks of anti-TNF antibody (anti-TNF) therapy
with adalimumab in long-standing RA have been investigated
[33,34]. In a recent longitudinal anti-TNF therapy study, 13 patients
with longstanding RA without prior prednisolone (after 7 infusions
of anti-TNFalpha at week 0, 2, 4, 6, 8, 10, and 12 serum concentrations
of IL-6, androstenedione, DHEA, DHEAS, free testosterone, estrone,
and 17beta-estradiol were measured. Levels of these hormones in patients were compared to serum levels of 31 age and sex-matched
healthy controls.
Upon treatment with anti-TNF, there was an impressive decrease
of clinical markers of inammation, erythrocyte sedimentation rate,
and serum levels of IL-6. Serum levels of DHEAS and free testosterone
were markedly lower at baseline in patients compared to controls,
but this did not change during anti-TNF therapy [34]. Serum levels
of DHEA and 17beta-estradiol were signicantly elevated in patients
compared to controls, but similarly, anti-TNF therapy did not change
initially increased levels. Molar ratios of hormones, which reect hormone shifts via converting enzymes, showed typical alterations at
base line, but did not change markedly during anti-TNF therapy.
In conclusion, therapy (3 months) with anti-TNF did not change
altered serum levels of typical sex hormones in patients with RA, although baseline values were largely different. In patients with at
least long-standing RA, this indicates that alterations of sex hormones
and altered activity of respective converting enzymes are imprinted
for a long-lasting period over at least 12 weeks [34].
3. Conclusions
Estrogens in human subjects are generally considered as enhancers of cell proliferation (anti-apoptotic) and as stimulators of
the humoral B cell immune response. However, rather than through
their serum levels (that may exert opposite dose-related effects), estrogens play important roles through their peripheral metabolites in
autoimmune rheumatic diseases. An increase of aromatase activity
in normal tissues during aging represents the major source for peripheral estrogens and related pathophysiological effects including
possible modulation of immune reactivity and cell proliferation.
The intracrine synthesis of active estrogen metabolites at the level
of cells involved in the immune response such as macrophages represents a common pathway that induces a similar immunostimulatory
activity in both male and female patients. Different peripheral estrogen metabolites (hydroxylated) exert also different effects on the
synthesis of proinammatory cytokines (i.e. TNF). Here, the
16alpha-hydroxylated forms have immunostimulatory and proproliferative effects.
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