Autoimmunity Reviews 14 (2015) 536542

Contents lists available at ScienceDirect

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

Review

Hormonal modulation of the immune system A spotlight on the role

of progestogens
Irene J. Tan a, Elena Peeva b, Gisele Zandman-Goddard c,
a
b
c

Division of Rheumatology, Temple University School of Medicine, PA, United States

Division of Rheumatology, Albert Einstein College of Medicine, NY, United States
Department of Medicine, Wolfson Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Israel

a r t i c l e

i n f o

Article history:
Received 9 November 2014
Accepted 25 January 2015
Available online 16 February 2015
Keywords:
Progestogens
Synthetic progestins
Progesterone
Progesterone receptor
Sex hormones
Immunomodulation
Autoimmunity
Gender
T cells
Systemic lupus erythematosus
Rheumatoid arthritis
Multiple sclerosis

a b s t r a c t
This article reviews the effects of progestogens on the innate and adaptive immunity and its role in the pathogenesis
of autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and multiple
sclerosis.
The interplay between the sex hormones such as progestogens and the immune system is very complex.
Multiple factors affect immunomodulatory effects of the progestogens including uctuations in the endogenous sex hormone levels, stress, use of exogenous hormones (dose, route and the timing of administration), and alterations in the hormonal metabolism. Although immunomodulatory effects of progesterone,
especially progesterone's effect on T cells, T cell subsets and their ratios, dose effects, and the use of synthetic progestins have been studied, there are still wide open areas for further explorations of the progestogens'
multifaceted impact on the immune system. Better understanding of the intricate immunomodulatory
effects of the progestins may pave the path to developing clinically meaningful therapeutic interventions
in certain autoimmune diseases.
2015 Elsevier B.V. All rights reserved.

Contents
1.
2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Gender and autoimmunity . . . . . . . . . . . . . . . . . . . . . .
2.1.
Sexual dimorphism in immunity . . . . . . . . . . . . . . . .
2.2.
Immunomodulatory effects of sex hormones . . . . . . . . . . .
2.3.
Sex hormones and autoimmunity . . . . . . . . . . . . . . . .
2.4.
Progesterone and immune modulation . . . . . . . . . . . . . .
2.4.1.
Progestogens . . . . . . . . . . . . . . . . . . . . .
2.4.2.
Progesterone signaling . . . . . . . . . . . . . . . . .
2.4.3.
T cells . . . . . . . . . . . . . . . . . . . . . . . .
2.4.4.
Progesterone and pregnancy . . . . . . . . . . . . . .
2.5.
Differential effects of synthetic progestins, progesterone and estrogen
2.6.
Environmental sex hormones . . . . . . . . . . . . . . . . . .
3.
Progestogens and autoimmune diseases . . . . . . . . . . . . . . . .
3.1.
Progestogens and SLE . . . . . . . . . . . . . . . . . . . . .
3.2.
Progestogens and RA . . . . . . . . . . . . . . . . . . . . . .
3.3.
Progestogens and MS . . . . . . . . . . . . . . . . . . . . .
4.
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Corresponding author at: Department of Medicine C Wolfson Medical Center 61 Halochamim Street POB 63 Holon, Israel 58100.

http://dx.doi.org/10.1016/j.autrev.2015.02.004
1568-9972/ 2015 Elsevier B.V. All rights reserved.

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I.J. Tan et al. / Autoimmunity Reviews 14 (2015) 536542

1. Introduction
Autoimmune diseases encompass a wide spectrum of between 70
and over 100 different disorders affecting 510% of the world population [1,2]. The disease induction and perpetuation of autoimmunity
are multifactorial and complex. In general, autoimmune diseases are
thought to result from an intricate interplay of genetic, epigenetic, gender, race, hormonal, environmental, and stochastic factors [2,3]. The
complexity of autoimmune mechanisms has been likened to a mosaic,
where rearranging much of the same starting materials, such as pieces
of genetic, hormonal, immunologic, and environmental factors in different orders, yield different pattern or a variation, of the same disease [4].
2. Gender and autoimmunity
Gender plays a critical role in the incidence and prevalence of autoimmune diseases. Females have a higher prevalence of autoimmune
diseases [2]. In the prototypic autoimmune disorder, systemic lupus erythematosus (SLE), the female-to-male ratio is 1012:1 [5]. This striking
predilection for female occurs in both mice and man [2,6]. SLE is not
unique in this regard. In a variety of other autoimmune diseases such
as Sjogren's syndrome, autoimmune thyroid disease (AITD) including
Graves' disease (GD) and Hashimoto's thyroiditis (HT), and scleroderma
more than 80% of the affected are women [2]. Likewise, in rheumatoid
arthritis (RA), multiple sclerosis (MS), and myasthenia gravis, the
affected are 6075% women [2]. The notion of X-chromosome dose
effect has been unraveled with recent genetic studies. Using a single
nucleotide polymorphism (SNP) genotype screen for X-chromosome
abnormalities which are subsequently validated by karyotyping,
Klinefelter syndrome (47, XXY) was found to be 10-fold more prevalent
in males with SLE than in general population [7]. Indeed, having an extra
X-chromosome like females, increases the risk of SLE in Klinefelter syndrome. Several lines of evidence from observational, experimental, and
epidemiological studies indicate that being female per se or having an
extra X-chromosome, confers a greater risk of developing both multiorgan and organ-specic autoimmune diseases [2,4,8].
2.1. Sexual dimorphism in immunity
There is clear disparity between the immune responses of female
and male. This well-established concept of sexual dimorphism is seen
in both human and animal models [9]. Females generally have a more
vigorous humoral and cellular immunity than males [9]. Females
experience lower burden of microbial infections by mounting stronger
and longer lasting humoral and cellular immune responses [9,10]. This
is manifested by higher absolute numbers of circulating CD4 T cells,
higher levels of circulating antibodies, enhanced cytokine productions
in response to infections, and more rapid rejection of skin allografts
compared to males [9,11]. The heightened immune response that
makes females more resistant to infections, however, also rendered
them more susceptible to autoimmune diseases [12].
2.2. Immunomodulatory effects of sex hormones
Sexual dimorphic modulation of immune response is best seen in
terms of infections, in the context of menstrual cycle, and during
pregnancy [913]. Male gender is associated with a less reactive
immune system and hence an independent risk factor for major infections after surgery [13]. These observations provide evidence that
female sex hormones, estrogen and progesterone, have differential
effects on the pathogenesis of different autoimmune diseases. In RA
and SLE, the severity of the disease symptoms varies with the phases
of the menstrual cycle [14,15]. Another evidence for the inuence of
sex hormones on autoimmune diseases comes from changes in disease
severity of RA, MS, and SLE during pregnancy [2,16,17]. In both RA and
MS, the disease activity decreases throughout pregnancy, and remits

537

in most individuals during the third trimester when both estrogen and
progesterone concentrations are highest [16,17]. This is followed by
an inevitable are of disease activity in the post-partum period when
both estrogen and progesterone concentrations normalize [16,17]. In
contrast, the disease activity of SLE either gets worse or remains unchanged during pregnancy [2]. The female immune system is characterized by not only higher reactivity which translates to better protection
from infections, but also increased autoreactivity. The incidence of the
prototypic autoimmune disease, SLE, is highest between menarche
and menopause when the female sex hormones are at their peak.
2.3. Sex hormones and autoimmunity
The female predominance in various autoimmune diseases, the
sexual dimorphism of immune response, and the immunomodulatory
effects of sex hormones generated tremendous interest in investigating
the inuence of sex hormones in autoimmunity. Scores of research was
launched focusing on the effects of estrogen, progesterone, testosterone,
and prolactin on autoimmune diseases [2,4,6,1820]. While considerable
studies have focused on estrogen, testosterone, and prolactin, much less
is known about progesterone. This review will summarize our current
understanding of the role of progestogens in autoimmune diseases.
2.4. Progesterone and immune modulation
2.4.1. Progestogens
Progestogens encompass both natural occurring progesterone and
synthetic progestins. Progesterone, a natural sex steroid hormone
derived from cholesterol, is produced by the adrenal glands, ovaries (by
the corpus luteum), testes, brain, and in the placenta during pregnancy,
and it is an intermediate in the biosynthesis of androgens, estrogens,
and corticosteroids [21]. The pleiotropic functions of progesterone
include physiologic role in the luteal phase of the menstrual cycle; key
hormone in maintaining pregnancy; and profound effects on regulation
of immune responses [22]. Progesterone is found in both female and
male of both humans and rodents. The basal levels of progesterone
between male, non-pregnant female rodents, and humans do not vary
much [23]. During pregnancy in both mice and humans however, progesterone could rise up to 10-fold basal rate in the maternal circulation and
up to 100-fold maternal circulation in the human placenta [24]. Structurally, progesterone consists of four interconnected cyclic hydrocarbons,
and like other steroids it is hydrophobic. Progesterone contains ketone
and oxygenated functional groups, as well as two methyl branches.
Progestins are man-made agents commonly used for contraception
and hormone replacement therapy. Progestins differ widely in their
chemical structures, functions, metabolism, pharmacokinetics, and
potency [25]. When classied according to their chemical structure, progestins may be described as resembling progesterone or testosterone
[25].
Progestins structurally related to progesterone are divided depending
on the presence (pregnanes) or absence (norpregnanes) of a methyl
group at carbon 10; then further divided depending on presence or absence of acetate-containing group [25]. The pregnane compounds with
an acetate group include: medroxyprogesterone acetate (MPA),
megestrol acetate, chlormadinone acetate, and cyproterone acetate. The
pregnane compounds without an acetate group include: dydrogesterone
and medrogestone. In the 19-norpregnanes containing an acetate group,
there is nomegestrol acetate and nesterone. In the 19-norpregnanes
without an acetate group, there is demegestone, promegestone, and
trimegestone. Progestins related to testosterone can be subdivided
into those with and without a 17-ethinyl group. Seventeen
ethinylated progestins consist of the families of norethindrone
(estranes) and levonorgestrel (13-ethylgonanes). They include norethindrone, norethindrone acetate, ethynodiol diacetate, norethynodrel,
lynestrenol, and tibolone. In the 13-ethylgonane category, there is
levonorgestrel, desogestrel, norgestimate, and gestodene. Finally, the

538

I.J. Tan et al. / Autoimmunity Reviews 14 (2015) 536542

Table 1
Progesterone receptor expression by human and murine immune cells and its reported effects of progesterone.
Cell type

Origin

Species

Reported effects of progesterone

Neutrophils

Peripheral blood

Eosinophils
Mast cells
NK cells

Peripheral blood
Nasal mucosa, cell line
Peripheral blood

M
H
H
H

Macrophage

Peritoneal uid

M
H

Myeloid DCs

Bone marrow

M
M

Superoxide release (h)

Apoptosis (h)
Chemotaxis
Degranulation (h)
Uterine inltration
Apoptosis (h, iPRs)
IFN- (h, iPRs)
Cytotoxicity
Nitric oxide
TNF
FcR expression
microparticle release (h)
IL-10 (h)
TNF, IL-6 (h)
IL-12p40, IL-12p70 (h)
CD80/86, MHC II
IFN at low dose Pg (h)
IFN at high dose Pg (h)
IL-4 (h)
Treg differentiation (h)
IFN- (h)
Proliferation (h)

Plasmacytoid DCs

CD4+ T cells

Peripheral blood
cell line

M
CD8+ T cells
B cells

Peripheral blood,
cell line
Peripheral blood

H
M
M

T-dependent antibody response (iPRs)

Th17 differentiation (h)
IL-6 receptor (h)
IFN-
cytotoxicity
primary and secondary antibody response
Class switch recombination (iPR)
T-dependent antibody response (iPR?)
Alter immunoglobulin glycosylation

Progesterone receptors

+
+ (h)
(iPRA, iPRB)
(m)
+ (h)

(m)
+

?
+ (h)
(mPR, mPR)

+ (m)
iPR
+ (h-luteal, mPR)
(m)

H or h = human or in human, IFN = interferon, IL = interleukin, M = murine, NK = natural killer, iPRA or iPRB = intracellular/nuclear progesterone receptor (isoform A or B), mPR or
mPR = membrane-associated progesterone receptor (isoform or ), Treg = regulatory T cells. + denotes present, denotes absent (adapted from Refs. [3,23,27,31,33]).

non-ethinylated group of progestins structurally related to testosterone

includes dienogest and drospirenone [25].
The metabolism of action of progestins is poorly understood and
there are limited reliable data on the pharmacokinetics of most progestins. Due to a wide variation in their chemical structures, structure
function relationships, metabolism, pharmaco-kinetics, and potency,
there are profound differences in the progestational activity of the synthetic progestins observed between human and animal tissues [25]. In addition to the characteristic progestational activity of progestins, they may
also possess anti-estrogenic, androgenic, anti-androgenic, and/or antimineralocorticoid activities. The progestins can be administered orally
or parenterally. Parenteral routes of progestin administration include intramuscular, transdermal, vaginal, subcutaneous, nasal, and rectal [25].
Certain generalizations can be made about the potency of progestins.
Progestins that are structurally related to testosterone are considerably
more potent than progestins structurally related to progesterone, which
in turn is more potent than progesterone. When comparing the
commonly prescribed progestins, levonorgestrel is more potent than
norethindrone, which is more potent than MPA. All progestins are
more potent than natural progesterone [25].
2.4.2. Progesterone signaling
Progesterone exerts its function via binding to specic receptors.
Progesterone receptors are present within cell types of sexual tissues
and non-sexual tissues, including certain immune cells. To date, progesterone is found to have 2 intracellular receptors (iPR) and 3 membrane
receptors (mPR) of which 2 isoforms of each receptor type are found in
humans (iPRA, iPRB, mPR, and mPR) [26,27]. Intracellular or nuclear
progesterone receptor (iPR) expression on lymphocytes was initially
described in pregnant women [28]. In addition to playing a critical
role in gestation, the iPR is thought to regulate antibody responses in
both sexes [23]. More recently, membrane PR- (mPR) was detected
on T cells of non-pregnant women, and appears to be upregulated

during the luteal phase on CD8+ but not the CD4+ lymphocytes [27].
Receptors are also present in lymphoid organs [29]. Many studies suggest that sex hormones have effects on both the innate and adaptive immune systems [30]. As expected, the expression of the progesterone
receptors is found on various populations of both innate and adaptive
immune cells though not uniformly. Thus far, there is no evidence of
progesterone receptor expression on the neutrophils, mast cells, natural
killer (NK) cells, macrophage, T cells and B cells in the mouse models
[31,32]. In humans, progesterone receptor expression was also distinctly absent in neutrophils, eosinophils, and B cells [31,32]. Although not
completely characterized, progesterone receptor expression has been
found on human mast cells, NK cells, macrophage, plasmacytoid
dendritic cells (DCs), CD4 + T cells and CD8 + T cells [3,23,27,31,32].
Table 1 is a compilation of progesterone receptor expression by
human and murine immune cells [23,27,3134].
In addition to iPR and mPR, progesterone may also signal through
progesterone receptor membrane component (PRMC), and at high
physiologic concentrations during pregnancy, the glucocorticoid receptor (GR) [23]. Different forms (natural versus synthetic) and different
concentrations of progestogens are believed to have differential immune responses via different signaling pathways, i.e. via iPR, mPR,
PGRMC, or GR on different target tissues [23,35]. A number of interplays
have yet to be characterized in this knowledge gap regarding
progesterone's direct and indirect effects on the immune responses.
2.4.3. T cells
What is known is that T-cells play a central role in the
immunomodulation by sex hormones. T helper (Th) cells can be classied as Th1 cells, Th2 cells, Th17 cells or regulatory T (Treg) cells according to the type of cytokines they produce. Th1 cells produce interleukin
(IL)-2, tumor necrosis factor (TNF), and interferon (IFN)- that promote
cellular immunity (T cells) to ght viruses, other intracellular microbes,
cancer cells, and stimulate delayed type hypersensitivity skin reactions.

I.J. Tan et al. / Autoimmunity Reviews 14 (2015) 536542

Th2 cells produce IL-4, IL-5, and IL-13 and promote humoral immunity
(B cells) against extracellular microbes by upregulating antibody production [36]. Th17 cells produce proinammatory cytokine, IL-17,
which is important in the induction of inammation [37,38]. IL-17 is
implicated in several autoimmune diseases, such as RA, psoriasis, MS,
inammatory bowel disease, and acute transplant rejection [37,38].
Lastly, Treg cells produce IL-10 and TGF- and they have crucial roles
in induction and maintenance of peripheral tolerance and prevention
of autoimmunity [39,40]. Treg cells inhibit proliferation and cytokine
production in both CD4+ and CD8+ T cells, immunoglobulin production by B cells, cytotoxic activity of natural killer (NK) cells, and maturation of dendritic cells (DCs), resulting in induction of tolerance [39,40].
There appears to be plasticity between these Th cell lineages with interplay that has not been fully claried [37].
2.4.4. Progesterone and pregnancy
Pregnancy is a highly evolved immunomodulatory state for fetal tolerance, both at the maternalfetal interface and in the maternal circulation [41]. Th1 immune response can lead to miscarriage via
implantation failure and fetal resorption [42]. IL-2 has been found to
have fatal effects on the fetus leading to rst trimester miscarriages
[43]. Th1 and Th2 cells appear to have mutually inhibitory effects [42].
It was thus observed that during normal pregnancy, there is a predominant shift towards the Th2 response coupled with suppressed Th1 response to prevent fetal loss [27,42,4446]. This slight polarization
towards Th2 response may be attributed to the dramatic surge in circulating levels of 17-estradiol and progesterone [42,44,47].
Progesterone is thought to be responsible for much of fetal tolerance during pregnancy. Studies of human cord blood fetal T cells
found that progesterone has a potent Treg induction activity [48].
This Treg activity promotes the production of anti-inammatory cytokines TGF1 and IL10 [22]. Progesterone was also found to suppress
fetal T cell differentiation into inammatory-associated Th17 cells
[48]. The pleiotropic effects of progesterone work in concert to regulate
fetal T cell differentiation for promotion of immune tolerance during
pregnancy [48]. In both humans and mice, maternal serum progesterone levels rise 510-fold higher during pregnancy while placental tissue
levels of progesterone can be 10100-fold higher than those in the maternal circulation, high enough to engage glucocorticoid receptors [24].
Fetal or villous prolactin also has a role in sustaining pregnancy by
inhibiting the expression of IL-2 which is detrimental to implantation,
at the maternalfetal interface [43].
2.5. Differential effects of synthetic progestins, progesterone and estrogen
Early on, certain generalization regarding the effects of each sex
hormone was made. Various studies suggested that androgens and
progesterone have immunosuppressive effects while estrogens have
immunostimulatory effects [49]. We now know that these concepts
are oversimplistic. Estrogen has both immunostimulatory and immunosuppressive effects depending on the concentration [30,50]. Example of
this biphasic effects of estradiol came from a study of human T cell
clones in which estradiol enhanced the secretion of IFN- at low concentrations (Th1 response) but enhanced IL-10 secretion by the same
cells at higher concentration (Treg response) [30,50]. In contrast, the
type of progestogen denes the differential physiologic effects. Synthetic progestins, such as medroxyprogesterone acetate (MPA) and
norethisterone acetate (NET-A), were found to have different glucocorticoid agonist properties compared with natural progesterone [51].
MPA was found to have higher relative binding afnity for human
glucocorticoid receptor (GR), a greater glucocorticoid transactivation
agonist potency, and the induction of different conformational changes
in the liganded-GR than either NET-A or progesterone [51]. These differential effects in the glucocorticoid-like properties between MPA, NET-A,
and progesterone would also demonstrate different side effects via the
GR [51]. MPA with signicant glucocorticoid activity led to relative loss

539

in bone mineral density when compared with NET-A, a progestin that

does not have signicant glucocorticoid activity [52].
Estrogen and progesterone are found to have some level of interdependent relationship [53]. Progesterone has a number of physiological
effects that are amplied in the presence of estrogen. Estrogen also
upregulates the expression of progesterone receptors via estrogen transcription stimulation [53].
Various synthetic progestins, progesterone, and doses of estrogen
have differential effects on the immune system which add another
level of complexity to the working of immune system on autoimmunity.
2.6. Environmental sex hormones
Sex hormones in the environment may also play a role in modulating immune responses, especially in the lupus spectrum of diseases
[54]. Most research data are available on environmental estrogen than
on environmental progestogens. Exogenous sources of estrogen which
include oral contraceptives, hormone replacement therapy, preparation
for in-vitro fertilization, preparation for sex reassignment surgery, estrogens found in plastic bottles (phthalates), pesticides (DDT), alternative medicine (phytogens), and other sources may play an additional
role in the development or exacerbation of SLE and lupus spectrum of
diseases [54]. In one study, blockade of estrogen effects with selective
estrogen receptor modulators may have a benecial effect on disease
activity of lupus-prone mice [32,54]. Therapy with estrogen as a hormone replacement therapy for post-menopausal women was associated
with mild lupus are in one study [55]. A randomized, double-blind, controlled study on the efcacy of estrogen plus progestin on menopausal
symptoms in women with SLE found that the treatment arm improved
only the vasomotor symptoms of peri- and postmenopausal lupus patients, but not other menopausal symptoms such as psychological,
subjective-somatic, and organic-somatic factors [56]. Effects on the
lupus disease activity were not one of the outcomes measured in this
study. However, given the increased risk of thrombosis in the treatment
arm compared with the placebo, combination estrogen plus progestin for
menopausal hormone therapy should only be used in lupus patients
with signicant vasomotor symptoms [56].
Early reports suggested a slight increased risk of developing SLE associated with past use of oral contraceptives (OC) in the Nurses' Health
Study. Later studies of SLE patients failed to identify an association with
OC use [57]. Some studies also suggested increased risk of disease are
of SLE with OC use which later reports did not support the ndings
[57,58]. Epidemiologic studies also found no association between OC
use and RA [58].
Two of the best quality randomized, placebo controlled trials which
showed safety of estrogen-containing contraceptive methods in SLE
were done prospectively with a 12-month follow-up. Both studies independently showed that the use of combined OC does not lead to increased ares of disease or worsening disease activity in women with
inactive or stable active SLE [5760]. The U.S. trial used triphasic ethinyl
estradiol 35 g plus norethindrone 0.51 mg for 12 cycles of 28 days in
91 women in treatment group and 92 women in placebo. The Mexican
trial used 3-arms without placebo group. The 3 treatment arms
consisted of combined OC (ethinyl estradiol 30 g plus levonorgestrel
150 g), a progestin-only pill (30 g levonorgestrel), or a copper intrauterine device (TCu 380A). In both randomized trials, the primary outcome was lupus are with graded severity as measured by the
Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) over
time [59,60].
Environmental hormonal manipulations of progestogens include
combination estrogen plus progestin mentioned above, and synthetic
progestin-only method of contraception. Several forms are used commonly: daily pills, every 3-month injections (Depo-Provera, DPMA),
3-year implant (Implanon, etonogestrel implant), an IUD (Mirena,
levonorgestrel-releasing intrauterine system), and emergency contraception (Plan B, levonorgestrel) [58]. Earlier studies found that in

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SLE, progestin-only OC did not trigger a are or have the same frequency of ares as SLE patients not on OC [57]. These studies garnered the
support for progestin-only contraceptive technique as a safer form of
contraception for SLE patients. Given the lack of thrombotic tendencies
in progestin-only OC, this form of birth control may also be indicated in
other autoimmune disorders with elevated risks of thrombosis.
Progestin-only OC is deemed safer to use in patients with
antiphospholipid syndrome (APS) with history of thrombosis or for individuals with positive APS antibodies with additional risk factors [57].
Those risk factors may be genetic hypercoagulable states such as factor
V Leiden, prothrombin mutation G20210A, hyperhomocysteinemia, due
to mutations in the MTHFR gene, and deciencies of proteins C, S, and
antithrombin III, or lifestyle and medical risk factors such as cigarette
smoking, use of combination OCs, prolonged immobilization, malignancy, pregnancy, severe illness, or surgery [57]. The progestin-only
methods have androgenic and progestational effects [61]. Progestin
does not appear to increase immune activity and is not associated
with increased disease ares. The dose used in contraceptives does
not increase the risk for thrombosis [58]. Progestin might also share
some anti-inammatory properties with the endogenous steroids that
could help reduce the activity of SLE [61]. All the above are consistent
with the older observations that progestin-only contraceptives have
fewer deleterious effects on SLE activity than estrogen-containing contraceptives, and progestin-only is considered safe for women with rheumatologic disease [58,62].

3. Progestogens and autoimmune diseases

3.1. Progestogens and SLE
In the prototypic autoimmune disease SLE there is a striking femaleto-male ratio of 1012:1 [5], the etiology is unknown, the hallmark is autoantibody formation, and the clinical manifestations are protean. Some
aberrant sequences of events or factors take place, and a disease phenotype is engendered. A pathogenic humoral response with B cell hyperactivity and autoantibody production are the major characteristics of SLE
[63]. There is a marked increase in Th2 response, a reduction in the Th1
response, and a fall in the CD8 cells in SLE.
The relationship between female hormones and autoimmunity is
complex. The role of estrogen has been extensively studied in many autoimmune diseases. In SLE, estrogens have a pathogenic role, contributing to disease severity and triggering ares by inducing Th2 responses
(B cell hyperactivity and antibody production) [17,18]. By contrast, in
MS and RA, estrogen appears to exert a protective role, promoting a
shift from Th1 and Th2 responses [64].
The relationship between progestogens and SLE may be just as complex, if more studies were to be done. Many studies have reported a predominant Th2-type immunologic response and suppressed Th1-type
response during pregnancy, when progesterone levels are high [42,
45]. During normal pregnancy in maternal circulation, both estrogen
and progesterone surge continuously from the rst to third trimester
reaching peak levels at the third trimester [64]. This surge is followed
by a precipitous drop in both hormones upon delivery of the
fetus [64]. When compared with healthy pregnant controls, pregnant
SLE patients were found to have reduction of progesterone and
dihydrpepiandrosterone (DHEA) , and to a greater degree, reduction
of estradiol during the second trimester [65]. The blunting of the hormonal surge of both progesterone and estrogen in pregnant SLE patients
was even more pronounced during the third trimester, and it was
thought to be the effect of placental compromise [65]. The marked
blunting of the hormonal surge in the third compared with the second
trimester may result in lower than expected humoral immune responses, which in turn account for the decrease in disease activity observed during the third, compared with the second trimester of
pregnant SLE patients [65].

A hallmark of SLE is the increased expression of interferon (IFN) type

1 inducible genes, so-called IFN type 1 signature [66]. Type 1 interferon
(IFN- and IFN-) signaling and immune cell development resulted
from the actions of transcription factors known as interferon regulatory
factor-5 and 7 (IRF-5, IRF-7) [67]. A direct association was found
between the levels of IRF-5 transcript expression and the levels of
circulating IFN in SLE [68]. This critical relationship between the type I
IFN signature and SLE disease pathogenesis led to the identication of
IRF-5 as a SLE susceptibility gene [68].
Progestogens impair IRF activation in plasmacytoid dendritic cells
(pDCs) [69] and may have therapeutic potential in SLE. Plasmacytoid
DCs are professional antigen presenting cells and a major source of
type I IFN [70]. IFN signaling is activated upon recognition of viruses
through toll-like receptors (TLR7 and TLR9) [69,70]. Progesterone
inhibits TLR9-induced IFN- production by human and mouse pDCs
while depo-MPA (DMPA) inhibits TLR9- and virus-induced IFN- production by pDCs in mice. This was thought to occur through selective
blockade of IRF-7 activation [69]. Thus, both progesterone and synthetic
progestin DMPA impair IFN- production by pDCs via TLRs [69].
Therapy with progestogens may ameliorate both IFN signature and
SLE disease activity.
3.2. Progestogens and RA
RA is a systemic autoimmune disease causing progressive, inammatory polyarthritis with potential to affect the skin, eye, heart, and
lung as well. RA has a female to male ratio of 27:1 [71] affecting approximately 1% of the adult population worldwide [72]. Both pregnancy
and OC are believed to be protective against development of the disease,
although they probably delay or modify the course of the disease rather
than conferring immunity [72]. In collagen induced arthritis (CIA), a
murine model of RA, decreased disease activity is seen during pregnancy similar to the human counterparts [73].
The disease severity of RA tends to uctuate with menstrual cycles
[14] and pregnancy [16,74,75]. The chance of RA disease onset is reduced during pregnancy and increased in the rst year post-partum
[74,75]. Once the disease is established, amelioration of RA activity occurs in about 3/4 of pregnancies [16], and may remit in most during
the third trimester [74,75]. Disease activity inevitably recurs within 3
to 4 months of delivery [75].
In normal pregnancy, there is predominant Th2 response with suppressed Th1 immune response [42,45] for the maintenance of pregnancy. Treg may play a role in this delicate balance [37]. IL-17 plays a
pathologic role in RA [37,38]. The symptoms of RA usually improve
during pregnancy [42] and consistent with this, Th17 cells in third
trimester of pregnancy was found to be signicantly lower compared
to non-pregnant women [76]. Keeping the Th1/Th2 balance at the
pregnancy-like level or the use of MPA or other synthetic progestins
may yet be a potential therapeutic approach.
3.3. Progestogens and MS
MS is a neurodegenerative disease characterized by chronic inammation and demyelination that is at least two times more prevalent in
women than in men [77]. Women tend to develop a milder, more benign relapsingremitting type of MS, whereas men tend to follow a
rapid, progressive course with more disability until death [78,79]. Men
more frequently develop less inammatory, but more neurodegenerative lesions [79,80]. Gender differences in MS are attributed, at least in
part, to sex hormones.
The central nervous system (CNS) is both a target for sex steroids released by peripheral tissues, as well as an organ that produces steroids
de novo [81]. These neurosteroids are synthesized by reactive astrocytes as a protective and anti-inammatory response to traumatic injury [82]. More recently, the gender difference in MS lesion pathogenesis
was attributed to the sex hormone receptor expression. Apparently,

I.J. Tan et al. / Autoimmunity Reviews 14 (2015) 536542

induction of estrogen synthesis and signaling was found in male MS lesions, while progesterone synthesis and signaling was found in female
MS lesions [79]. Tumor necrosis factor (TNF) was also found to be elevated in the male MS lesions compared with female lesions. These highly sexual dimorphic immune responses would be major targets for
therapeutic strategies [79].
The experimental autoimmune encephalomyelitis (EAE) is the animal model for MS. The immunomodulatory effects of estrogen, progesterone, and pregnancy on the EAE mice have been studied extensively.
Attenuated disease activity during pregnancy and decreased relapse
rate particularly during the third trimester are rather striking in both
EAE and MS [17,73]. In EAE, estrogen was found to decrease inammatory
cytokines and demyelination in the spinal cord of EAE mice with increase
in the number of Tregs [83]. At the onset of EAE, animals were randomly
assigned to receive either a subcutaneous progesterone implant (100 mg
60 day release) or placebo treatment. Progesterone was also found to reduce disease activity in the EAE mice by the increase of IL-10 accompanied by increased CD19+ cells and CD8+ cells. Progesterone also
decreased the secretion of pro-inammatory cytokines IL-2 and IL-17.
Treatment with progesterone in MS decreased disease severity, demyelination, and lesions in the spinal cord [83]. Cross-reactivity between progesterone and the glucocorticoid receptor makes it possible that some
effects of progesterone seen in the current study are due to glucocorticoid
activity [83]. Hormonal manipulations of these highly sexual dimorphic
immune responses would be major targets for therapeutic strategies.
4. Conclusion
The diverse immunologic effects of progestogens defy simple
generalization. This review summarizes the effects of progestogens
on the immune cells of both innate and adaptive immune systems;
as well as the effects on a number of systemic and organ-specic autoimmune diseases from both animal models and human studies.
The interplay between the immune system and progestogens, or
any sex hormones for that matter, remains intricate and complex.
Age, the route, the timing of administration of exogenous hormones,
the type, the dose of progestogens used, the ratio relative to other
sex hormones, the uctuations in sex hormones, stress, and the metabolism of hormones all have differential effects on the immune
system. More research is needed to continue unraveling the intricate
relationship between progestogens and autoimmunity. Mechanisms
of action of progesterone on immune cells, especially progesterone's
effect on Th1:Th2 and Th17:Treg ratios, possible dose effects, and the
use of synthetic progestins are all potential areas for further explorations. Better understanding may pave the way to developing clinically
meaningful therapeutic intervention with progestogens in certain
autoimmune diseases.

Take-home messages
Progestogens, both natural occurring progesterone and synthetic
progestins, have immunomodulatory functions.
Interplay of multiple factors including sex hormones can lead to a dysregulation of the immune system and development of autoimmunity.
Various immune cells (e.g. mast cells, NK cells, macrophage,
plasmacytoid dendritic cells, CD4+ T cells and CD8+ T cells) express
receptors for progesterone.
Progesterone favors the Th2 properties by promoting production of
IL-4 and IL-5 and suppresses the Th1 responses.
Estrogen and progesterone have an interdependent relationship; a
number of the physiological effects of progesterone are amplied in
the presence of estrogen mainly by the increased expression of progesterone receptors.
Progestogens play a differential role in the pathogenesis of SLE, RA
and MS.

541

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