Sex Hormones and Immunoregulation

Sex Hormones and Immunoregulation
OVERVIEW ARTICLE

The sexual dimorphism in immune responses in humans is well known; females have more vigorous cellular and humoral immune responses, they are more resistant to many infections, and they suffer a higher incidence of autoimmune diseases as compared with males [reviewed in Reference 1].

Moreover, in women disease expression appears to be affected by their reproductive status. Patients with immune-based diseases, such as multiple sclerosis (MS), asthma or systemic lupus erythematosus (SLE), may have exacerbations during specific periods of the menstrual cycle or during pregnancy [2-4]. The differences in immune responses between the sexes and the reproductive phases in women are accompanied by variations in sex hormones. Therefore, these variations in levels of sex hormones have been suggested to cause the different immune responses. The actions of sex hormones, however, are extremely complex. In this overview, we will therefore discuss what is known about the effects of sex hormones on the function of the different immune cells in isolation. Moreover, we will also discuss briefly how sex hormones affect immune responses in complex situations like models of immune-mediated diseases related to specific and non-specific immune responses.

Sex hormones

Three classes of sex hormones exist: androgens (mainly testosterone), estrogens (which is mainly 17beta-estradiol in the ovarian cycle), and progesterone. In males, plasma testosterone concentrations are relatively stable throughout life, although testosterone production declines with age. In females, the production of sex hormones 17beta-estradiol and progesterone fluctuates during the menstrual cycle. In response to pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH), fluctuations in sex hormone concentrations in the menstrual cycle include increasing 17beta-estradiol, but low progesterone plasma concentrations in the follicular phase and high plasma 17beta-estradiol and progesterone concentrations in the luteal phase (see also Fig. 1).

sex hormones immunity figure 1Fig. 1. The menstrual cycle consist of 2 phases: the follicular phase and the luteal phase. The follicular phase starts at the beginning of menstruation. Follicle stimulating hormone (FSH) starts to rise (produced by the pituitary) and stimulates growth of follicles. The 17beta-estradiol produced by the follicles inhibits FSH production and 1 dominant follicle is selected. 17beta-estradiol continues to rise due to the growing dominant follicle and high concentrations of this hormone trigger the production of Luteinizing Hormone (LH) by the pituitary. LH then induces ovulation. After ovulation, the luteal phase starts. The remainder of the follicle develops into the corpus luteum, which starts producing progesterone and 17beta-estradiol. If pregnancy does not occur, the corpus luteum regresses after about 12 days and progesterone and 17beta-estradiol concentrations decrease, menstruation starts and a new cycle can begin.

If pregnancy occurs, luteolysis is prevented and 17beta-estradiol and progesterone levels remain high. When the ovarian follicles are depleted later in female life (after menopause) sex hormone concentrations drop to low levels. Hormone replacement therapy (HRT) and the use of oral contraceptives (OCC) increase (synthetic) estrogen and progesterone concentrations.

Immune system

There are two arms of the immune system: the nonspecific (innate or natural) immune system and the specific (acquired or adaptive) immune system. The nonspecific immune response is the first line of defense against infections. It recognizes structures specific for microbes. The effector cells of the nonspecific immune response are monocytes, macrophages, granulocytes (neutrophils, eosinophils and basophils), dendritic cells and natural killer (NK) cells. These cells attack microbes that have entered the body. They do so by phagocytosing the microbe (neutrophils, monocytes and macrophages), by lysis of infected cells (NK cells), or by producing cytokines to enhance nonspecific immune and specific immune responses (all cells). Dendritic cells are (together with monocytes and macrophages) the most important antigen presenting cells. They take up foreign antigens (including viruses or pathogens), process the antigens, present antigen peptides in the context of MHC II molecules on their surface and present them to the specific immune system mainly helper T lymphocytes.

T lymphocytes and B lymphocytes are the cellular components of the specific immune response. Within the T lymphocyte population, cytotoxic T lymphocytes (Tc cells) can directly kill foreign or infected cells. The helper T lymphocytes (Th cells) provide help to other immune cells by producing cytokines. These Th cells can be divided into 5 subsets, i.e. the Th1 subset producing interferon (IFN) gamma to promote cellular immune responses, the Th2 subset producing mainly interleukin (IL)-4, IL-13 and IL-5 to provide optimal help for humoral immune responses, the Th17 subset producing IL-17, which plays a crucial role in autoimmunity and allergen-specific immune responses and the regulatory T cell (Treg) subset that is in the centre of immunoregulation and is capable of suppressing both Th1- and Th2-mediated specific immune responses. A Th9 subset has also been described. This population has only been studied in vitro and it is unclear whether this is a real subset or an adapted Th2 population [5].

Receptors for sex hormones on immune cells

Sex hormones are steroid hormones. Due to their lipophilic nature, steroid hormones can diffuse across the cell membrane; classical steroid hormone receptors can thus be found intracellularly and have direct genomic effects [6]. More recently, also non-genomic effects of steroid hormones have been described, which are most likely regulated via more recently described membrane receptors for steroid hormones [7,8]. An alternative explanation is that by their lipophilic nature, sex steroids can alter membrane properties by integrating into the membrane, thereby changing the function of the immune cells [9].

Classical intracellular estrogen receptors are present in human monocytes [10-16], human neutrophils [17], human dendritic cells [18], murine peripheral NK cells [19], human Tc lymphocytes and B lymphocytes [20,21]. There is no evidence that classical intracellular progesterone receptors are expressed on resting lymphocytes [22-28], monocytes [24], neutrophils [29], NK cells, B lymphocytes, Treg cells and dendritic cells. Various studies, however, demonstrated that activated lymphocytes, for instance lymphocytes during pregnancy, can upregulate progesterone receptors [25-28,30,31]. More recently membrane-bound progesterone receptors have been shown to be present on resting lymphocytes [8,32]. Androgen receptors have long been considered not to be present on T lymphocytes [20,33]. More recent studies, however, have demonstrated testosterone receptors in Th lymphocytes in mice [34] and membrane-bound testosterone receptors on lymphocytes, which are different from the classical intracellular testosterone receptors [35]. B-lymphocytes do express intracellular androgen receptors [36]. Androgen receptor expression was also found in murine macrophages [37] and androgen receptor mRNA was found in human macrophages [38]. There are no reports about the presence of androgen receptors on human monocytes, neutrophils, NK cells, dendritic cells or Treg cells.

Influence of estrogen, progesterone and testosterone on immune cells

The most obvious effects of sex hormones on the immune response are the effects of these hormones on the numbers of circulating immune cells. In the peripheral blood, about 65% of the leukocytes are granulocytes (90% neutrophils), 5-10% is monocytes, and 30% are lymphocytes (85-90% T lymphocytes and 10-15% B lymphocytes). Sex hormones have been shown to affect these cell numbers by affecting proliferation or apoptosis of the cells or by recruitment of new cells from the bone marrow [39,40]. Although total white blood cell counts did not differ between males and females, an increase in white blood cells counts was observed in the luteal phase (and during pregnancy) as compared with the follicular phase of the ovarian cycle [40-43]. This may be largely due to an increase in granulocyte numbers in these reproductive conditions [42,44-47]. This suggests a role for progesterone and/or estrogen in increasing the numbers of granulocytes. In addition, various studies point to a decrease of monocyte numbers in the presence of estrogen, as shown by increased numbers of monocytes in males and menopausal women as compared with women in the follicular phase of the ovarian cycle [14,48]. However, the presence of estrogen together with progesterone may increase monocyte numbers as monocyte numbers are increased in the luteal phase and during pregnancy as compared with the follicular phase. Whether sex hormones also affect B and T lymphocyte numbers remains to be established. Conflicting results have been published [41,42,46,49-56]. Treg cell numbers may be modulated by sex hormones, since it has been shown that both estrogen [57,58] and testosterone [59] increase Treg cells numbers.

Cells of the nonspecific immune system

Monocytes

One of the functions of monocytes is ingesting and killing micro-organisms by a process of phagocytosis. A few studies have indicated that sex hormones may affect this function of monocytes. For instance, numbers of Fc receptors on monocytes, which are involved in the binding and phagocytosis of Ig coated particles, are increased on monocytes from females as compared with males [60]. In addition, it has been shown that androgens may decrease the number of Fc receptors on monocytes in certain patient groups [61], while animal studies have shown that estrogen is capable of enhancing clearance of IgG coated red blood cells [62].

Another important function of monocytes is to direct immune responses by the production of cytokines. Cytokines mostly studied in this respect are: tumor necrosis factor (TNF)-alpha, IL-1beta, IL-12, and IL-6.

TNF-alpha

TNF-alpha has pleiotropic actions and has emerged as an especially important mediator in pro-inflammatory responses and activation of T cells [63]. Various observations suggest that sex hormones may influence monocyte TNF-alpha production: in males endotoxin-stimulated monocytes produce more TNF-alpha as compared to females [48,64,65]. Whether this is due to direct effects of high levels of testosterone in males remains uncertain since in vitro studies showed no effect of testosterone upon monocyte TNF-alpha production [66]. Furthermore, endotoxin-stimulated monocytes of women in the luteal phase produce more TNF-alpha as compared to monocytes of women in the follicular phase [7,42,67]. Although this suggests a role for the female sex hormones in increasing monocyte TNF-alpha production, hormone replacement therapy (HRT) in postmenopausal women and OCC use did not affect TNF-alpha production by monocytes [68,69]. These observations indicate that also other factors, apart from estrogen and progesterone, may affect monocyte TNF-alpha production.

Various papers describe in vitro experiments in which stimulated monocytes were incubated with estrogen or progesterone. The results are conflicting and vary from a down regulation of endotoxin-induced TNF-alpha production by estrogen at both physiological and supraphysiological levels [64,70] to no effect of either estrogen or progesterone upon TNF-alpha production in stimulated monocytes [16,68,71-73].

IL-1beta

Production of IL-1beta, which mediates a wide variety of immune responses, also shows differences in different reproductive stages. In the luteal phase an increased IL-1beta plasma concentration and an increased frequency of IL-1beta-producing monocytes after endotoxin stimulation was demonstrated as compared to the follicular phase [42,74,75]. This suggests a potentiating effect of estrogen and/or progesterone on monocyte IL-1beta production. However, also other mechanisms may be present since in males a higher frequency of IL-1beta-producing monocytes after endotoxin stimulation was demonstrated as compared with females in the follicular phase [48]. The effect of testosterone upon monocyte IL-1beta production in vitro was also studied by us and others. Although we showed that incubation of whole blood with physiological concentrations of testosterone increased monocyte IL-1beta production [66], Morishita et al [76] did not find this.

IL-12

IL-12 is mainly produced by monocytes and macrophages and plays an important role in the induction of cell-mediated immunity; i.e. together with IFN gamma it is a major inducer of Th1 differentiation [77]. IL-12 is thus an important cytokine that links the nonspecific immune system to the specific immune system. We have shown no differences in IL-12 production after LPS-stimulation when comparing monocytes from the luteal phase with those from the follicular phase in women [42]. In men, however, the IL-12 production by monocytes after LPS stimulation was increased as compared with women [42,48]. This may suggest that testosterone stimulates monocyte IL-12 production. Indeed, physiological levels of testosterone increased IL-12 production by LPS-stimulated monocytes in vitro [66], while no effect of estrogen on LPS-stimulated IL-12 production was found [43]. However, others found a decreasing effect [78] or an increasing [71] effect of estrogen on stimulated IL-12 production; progesterone did not affect the production of IL-12 in vitro [43,78].

IL-6

IL-6 stimulates B lymphocyte and T lymphocyte differentiation and activates macrophages and NK cells, while it also possesses anti-inflammatory properties. It is generally thought that IL-6 production is decreased by estrogen. Indeed, plasma IL-6 levels are increased after menopause [79-82] and decreased by HRT treatment [18,81,83]. However, no variations in plasma IL-6 levels or spontaneous leukocyte IL-6 production during the menstrual cycle [7,67,84-88] were found. Whether the production of IL-6 after LPS is stimulation is also influenced by estrogen is unclear. No difference [86,89], an increase [88] or a decrease [65] in IL-6 production was found between the follicular and luteal phase when whole blood was stimulated with LPS. Moreover, stimulated IL-6 production was either decreased [90] or not affected [69,91] by the estrogenic compound in HRT.

The effects of gender and reproductive condition upon monocyte functions are obvious. The most consistent effects are: plasma IL-6 levels appear to be decreased by estrogens; LPS-stimulated TNF-alpha and IL-1beta productions are increased in males as compared to females, and these are also increased in the luteal phase as compared to the follicular phase of the ovarian cycle; LPS-stimulated IL-12 production is only increased in males and not affected by the ovarian cycle. These differences in monocyte function may play a role in the differences in immune responses between sex and reproductive condition. Whether these differences are due to direct effects of sex hormones remains uncertain, since in vitro experiments in which monocytes were incubated with sex hormones revealed conflicting results upon monocyte cytokine production. Such conflicting results may be due to differences in experimental setup. For instance incubations with sex hormones are performed using whole blood, peripheral blood mononuclear cells or isolated monocytes.

Macrophages

Macrophages are tissue-residing cells derived from monocytes [92]. In these tissues they stand guard against foreign invaders and alert the adaptive immune system with signals and through antigen presentation. In order to maximize their effector functions, macrophages need to be activated and the type of activation determines its effector functions [93]. Presently, two major macrophage activation states have been described: the classically activated state and the alternatively activated state [93]. The first one is associated with increased generation of oxygen radicals and cell killing to remove invading microorganisms and the second one with increased expression of phagocytic receptors to remove cell debri and increased tissue remodeling to reconstruct the tissue during wound healing. In addition, macrophages with a nonactivated, anti-inflammatory phenotype have been described, these are called the immunosuppressive macrophages [93]. These producers of IL-10 are important in controlling inflammation and collateral damage associated with excessive inflammation [93]. Sex hormones have been found to affect these activation states and effector functions in macrophages and their effects are reviewed below.

Classically activated macrophages: Macrophages become classically activated after exposure to IFN gamma or microbial products like LPS and they upregulate mechanisms to destroy microorganisms [93]. As the classically activated phenotype has been known for the longest time, most studies investigating effects of sex hormones on macrophage activation have studied this phenotype. Many studies have described upregulation of inducible nitric oxide (NO) synthase (iNOS) and NO production, increased production of proinflammatory cytokines and increased cell surface expression of Toll-like receptor (TLR)4 in macrophages [94-99] after treatment with estrogens. This may lead to enhanced killing of microorganisms and thus to increased resistance to extracellular bacteria and infections in the presence of estrogen [100]. Progesterone on the other hand was found to inhibit NO production, TLR4 expression and proinflammatory cytokine production [101-104], counteracting the effects of estrogens. The net effect on classical activation of macrophages therefore seems to depend on the ratio of these two hormones, though this has not been studied yet to the best of our knowledge.

Like progesterone, androgens have also been found to reduce classical activation by inhibiting TLR4 expression and oxygen radical formation [105-107], and this may explain the increased susceptibility of men for infections [108-110]

Alternatively activated macrophages: Macrophages become alternatively activated after exposure to IL-4 and/or IL-13 and they adopt a phenotype intent on taking up apoptotic cells and cell debri and reconstructing damaged tissues. This phenotype has been discovered relatively recently and the effects of sex hormones have not been studied much in relation to alternative activation. The few studies published that did investigate sex hormones and alternative activation showed increased alternative activation of macrophages after treatment with either progesterone or estrogen and decreased alternative activation after treatment with androgens [111,112].

Immunosuppressive macrophages: This subset is the least-known of the subsets and little to no data are available about the effects sex hormones have on this phenotype. One study did investigate IL-10 production by macrophages from hemorrhaged mice treated with estrogens or androgens and found reduced production by estrogen and increased production by androgen [113]. These findings are again in line with the anti-inflammatory effects usually found for androgens.

Dendritic cells

Dendritic cells are also tissue-residing cells derived from monocytes [92]. Immature dendritic cells reside in the tissues. They may be activated by microbial products or inflammatory cytokines after which they differentiate into mature dendritic cells [114], while migrating to lymph nodes to present antigen to naive T cells. In human dendritic cells, derived from monocytes in vitro, both estrogen and progesterone upregulated IL-10 production by mature and immature dendritic cells [115,116]. These hormones also increased apoptosis of dendritic cells [116]. On the other hand, neither progesterone, nor estrogen affected the phenotype of mature and immature dendritic cells [115] or the T cell stimulatory capacity [116]. Although analysis of subpopulations of dendritic cells is still difficult, it has been shown recently that progesterone inhibited IFN gamma production by plasmacoid dendritic cells [117]. Since IFN gamma is necessary to fight viruses and also primes antiviral responses of the specific immune system, progesterone may therefore inhibit antiviral responses [117].

Neutrophils

Neutrophils play a key role in the first-line defense against invading pathogens by phagocytosis, the release of anti-microbials and the generation of neutrophil extracellular traps [118]. Therefore, they need to be able to respond to chemotactic stimuli to get to the place of action and they need to be able to produce those anti-microbial factors. Studies have shown that progesterone enhanced chemotactic activity of neutrophils, while estrogens decreased this activity [119]. Various groups have also investigated the effects of progesterone and estrogen on free radical production by neutrophils. This has been shown to be increased [120], decreased [121] or not affected [122] by estrogen or progesterone incubations in vitro. Sex hormones also affect NO production via NOS activity. NO production by neutrophils was found to have anti-inflammatory effects since it prevented neutrophil adhesion to the endothelium [123]. NO-synthase in neutrophils varies with reproductive condition: increased NO synthase expression was observed in vivo in the luteal phase as compared with the follicular phase and in postmenopausal women on estrogen therapy as compared with untreated postmenopausal women [124]. This is in line with in vitro results showing that estrogen upregulated NOS expression in neutrophils in vitro [124,125].

Taken together, it appears that both sex and reproductive condition affect neutrophil function. In general, estrogen has anti-inflammatory effects on neutrophils, while progesterone has pro-inflammatory effects on these cells. Therefore, sex hormones can affect nonspecific immune responses in vivo by modulating neutrophil function.

NK cells

There are various reports on the effects of the reproductive condition and gender sex on the main function of NK cells, i.e. their ability to lyse other cells. Various studies have shown a negative association of the lysing activity of NK cells with estrogen or progesterone levels: an increased potency to lyse other cells was found in postmenopausal women and in males as compared to females with a regular menstrual cycle and women on OCC [126,127]. In addition, exposure to OCC caused a reduction in NK-activity as compared to non-users [126,128,129], while NK cell activity was decreased in postmenopausal women using HRT [130]. Indeed, in vitro studies have directly demonstrated that estrogen decreased the potency of NK cells to lyse other cells [131,132], while no effect of progesterone on NK cell activity was demonstrated [132,133]. Unfortunately, the suppressive effect of estrogen on NK cell activity is not always observed during the menstrual cycle, since results vary from no difference between follicular and luteal phase, as well as highest NK cell activity in follicular phase, periovulatory phase or luteal phase [126,127,134-136]. Such different results may be due to different time points in the ovarian cycle of measuring the NK cell activity.

Another important function of NK cells is cytokine production. The cytokine repertoire of peripheral NK cells is mainly type 1 cytokines (IFN gamma) [137,138]. Although there are many studies into cytokine production of uterine NK cells during pregnancy, little is known about cytokine production by peripheral NK cells in relation to reproductive condition or separate effects of sex hormones on peripheral NK cells. During pregnancy, induced IFN gamma production of peripheral NK cells was found to be decreased, however, no effect of the menstrual cycle upon IFN gamma production of NK cells was found [139]. This suggests that during pregnancy other mechanisms rather than sex hormones affect IFN gamma production by NK cells.

Effect of sex hormones on the nonspecific immune response in vivo

Acute immune actions, which are part of the innate immune system, appear to work favorably for women as compared to men. In general, men are more susceptible to viral, bacterial, fungal and parasitic infections (with the exception of sexually transmitted diseases) then women [140,141]. They also have a higher risk of developing more severe disease [142]. This may be due to the effects of androgens and estrogens on the innate immune cells. As described above, in general androgens have been shown to suppress innate immune cell function, resulting in suppression of the resistance to infections [105], whereas estrogens were found to stimulate innate immune cells, which can promote resistance to infections [143]. The effects of androgen and estrogen on non-specific immune responses are also obvious from the fact that male sex is a significant risk factor for the development of sepsis. This is supported by many animal models of endotoxemia and bacterial challenge in which females demonstrate better survival when subjected to severe sepsis than males [142]. In males infections can more easily progress to damaging inflammation, hence the increased susceptibility for sepsis. More on the mechanisms can be read in some excellent reviews on the subject [144-146].

Wound healing also differs between males and females [147]. Recent studies have suggested that the male genotype is a strong risk factor for impaired wound healing in the elderly [148-150]. These sex effects are mediated by estrogens and androgens, since wound healing increases after estrogen treatment [151] and after deprivation of androgens after castration of male mice [152]. The striking acceleration of wound regeneration after androgen deprivation was associated with a reduced inflammatory response [152]. Although exact mechanisms by which sex hormones affect wound healing are not clear yet, it seems likely that the effects are, at least partly, mediated by the effects of sex hormones on the nonspecific immune response. For instance, the effects of sex hormones on the macrophage subsets may be important in wound healing, since a subset switching of macrophages is essential in wound healing [153,154]. The types of macrophages present in wounds determine whether chronic inflammation will occur or whether proper healing is started [111]; classically activated macrophages are needed in the first stage, whereas alternatively activated macrophages have been found important in the wound healing stage. Both estrogen and progesterone have been found to promote wound healing by enhancing alternative activation of macrophages and failure to switch was associated with chronic inflammation of wounds [111].

Cells of the specific immune system

Cytotoxic T lymphocytes (Tc)

Sex hormones have been described to affect Tc lymphocyte function (reviewed by Grossman et al., Reference 155). Many studies (vitro and in vivo) have shown that both estrogen and progesterone suppress cell-mediated immune responses [155]. Although the exact mechanisms are unclear, estrogen and progesterone inhibited proliferation of Tc lymphocytes (or Tc lymphocyte cell lines) after stimulation with mitogenic substances [156-159]. In addition, both hormones have also been shown to increase apoptosis in activated Tc lymphocytes [160]. Only a few studies have evaluated the role of sex hormones on Tc lymphocyte cytolytic activity. One study suggested that cytolytic activity of Tc lymphocytes in the uterine endometrium is depressed by estrogen and progesterone [161] and another study suggested that progesterone decreased cytolytic activity of these lymphocytes from the decidua [162]. Also, cytotoxicity in peripheral Tc lymphocytes was decreased by estrogen [162].

Helper T lymphocytes (Th)

The main function of Th lymphocytes is cytokine production. As indicated above, Th lymphocytes can be subdivided in Th1, Th2, Th9, Th17 and Treg. The effects of sex hormones on these subtypes will be discussed below.

Th1 subtype: The most important cytokine produced by Th1 cells is IFN gamma. Although various studies have evaluated the effects of sex hormones on IFN gamma production, it remains elusive whether there are direct effects of sex hormones on lymphocyte IFN gamma production. Increased IFN gamma production [163] as well as similar IFN gamma production [48] by stimulated male lymphocytes as compared to female lymphocytes was found. Furthermore, no effect of the menstrual cycle upon induced IFN gamma production was found [46], while induced IFN gamma was decreased in HRT-treated postmenopausal women as compared to untreated postmenopausal women [130]. Others, however, found no effect of synthetic hormones on lymphocyte IFN gamma production [90,164]. These in vivo results are in line with in vitro experiments in which neither progesterone, estrogen nor testosterone altered IFN gamma  production [66,163,165].

Th2 subtype: As estrogen has been shown to enhance humoral immune responses [166] it seems likely that it would also affect Th2 cytokine production. IL-4 is released predominantly by Th2 lymphocytes. In males and after menopause IL-4 production is similar to fertile women [163,167,168], suggesting no effect of sex hormones on the production of IL-4. In contrast to this suggestion the production of IL-4 was significantly increased in Th cells in the luteal phase as compared with the follicular phase of the ovarian cycle [46]. This may be due to increased progesterone concentrations in the luteal phase, since one study demonstrated an increase in IL-4 production by Th lymphocytes after incubation with progesterone [165]. Synthetic hormones, such as in OCC or HRT, have not been found to affect IL-4 production by lymphocytes [90,163,168].

Interleukin-10 (IL-10), another Th2 type cytokine was not produced differently by lymphocytes of both males or postmenopausal women and premenopausal women [48,163]. In addition, during the menstrual cycle IL-10 production by lymphocytes after stimulation is stable [46,169], suggesting no effect of sex hormones on IL-10 production. Results with oral contraceptives, which do not influence IL-10 production [164] and in vitro experiments, which showed no effect of estrogen, progesterone or testosterone on IL-10 production [66,163,165] after polyclonal stimulation of whole T lymphocyte populations, corroborate this suggestion.

Th17 and Th9 subtype: Unfortunately, at this time no data exist showing an effect of sex hormones on the Th17 or Th9 subtype. Apart from pregnancy, in which the number of Th17 cells does not differ from non-pregnant individuals, also no data are available on the effect of the reproductive condition on Th17 or Th9 cells [170].

Treg subtype: Numbers of Treg cells appear to be influenced by estrogen [57,58] and testosterone [59], but not much is known whether Treg cells function is also under control of sex hormones. Human data are scarce at this moment. One study showed that estrogen increases suppressive function of Treg cells [57]. This potentiating of suppressive function by estrogen has been confirmed in mice studies. Estrogen increased Foxp3 expression in mice Treg cells in vitro [58,171,172]. Foxp3 is a transcription factor present in Treg cells that controls the development and function of Treg cells [171,172]. An increase in this factor by estrogen thus suggests that estrogen increases Treg cell function. In vivo studies in mice corroborated this suggestion: estrogen treatment upregulated Foxp3 expression together with Treg cell function in mice [58,173].

B lymphocytes

The main function of B lymphocytes is the production of antibodies. Effects of sex on B cell function can therefore be derived from differences in plasma levels of antibodies. Females have higher serum levels of total IgM and IgG as compared to males [174-178] with no changes during the menstrual cycle [52,179]. During OCC use immunoglobulin levels and immunoglobulin production are unaltered as compared to females not taking OCC [180,181], but others found immunoglobulin levels to be decreased [182] or even increased [183] in females using OCC as compared to females not using OCC. The higher serum levels of immunoglobulin in females may suggest a stimulating effect of female sex hormones or an inhibiting effect of testosterone upon this parameter or both. Indeed, in vitro studies, have shown that estrogen induced polyclonal activation of human B cells and increased IgG and IgM production by PBMCs [184,185]. Testosterone inhibited immunoglobulin IgG and IgM productions [186]. It has also been shown that estrogen increased and testosterone decreased autoantibody production by PBMC in patients with SLE [187,188]. Animal data have shown that estrogen also induced a switch in antibody isotype. In mice treated with estrogen, autoantibody production was increased and the antibodies were mainly of the IgG isotype [189,190]. Present evidence to date thus points towards an important role for estrogen and testosterone in antibody production.

In conclusion, there are obvious effects of sex hormones on lymphocytes. As described above, both female sex hormones seem to inhibit Tc cytotoxicity, while estrogen and testosterone also affect humoral immunity: estrogen upregulates (auto)antibody production and testosterone inhibits (auto)antibody production. Whether sex hormones also affect lymphocyte cytokine production remains to be established. More recently, it has been shown that sex hormones also affect Treg: estrogen both increased Treg cell numbers and Treg cell function.

Effects of sex hormones on specific immune responses in vivo

The effects of sex hormones on the immune response in vivo can be studied using immune disease models and study the effects of gender, reproductive condition and sex hormone treatment on the incidence and course of the disease. The ability to mount more vigorous cell-mediated and humoral immune responses in women increases their chances of developing unwanted Th1, Th2, Th9, and Th17-mediated responses to self-antigens or otherwise innocuous compounds such as allergens. The result is increased incidences of autoimmune diseases like multiple sclerosis (MS) and allergic diseases like asthma in women. Until recently these self-reactive and allergen-reactive processes were primarily thought to be associated with Th1 cells and Th2 cells, but with the discovery of Th17 and Th9 cells, the disease mechanisms appear to be far more complex [191]. Unfortunately, little to no data is available about the effects of sex hormones on these new subsets in the context of autoimmune diseases and asthma. Therefore, we will shortly discuss the effects of sex hormones on the development and course of MS as an example of a Th1-mediated disease and asthma as a Th2-mediated disease and keep Th17 and Th9 out of this context for the moment.

Multiple sclerosis (MS)

MS is an autoimmune disease characterized by a Th1 and Th17-mediated chronic inflammatory demyelinating process of axons in the central nervous system and is more common in women than in men [191,192]. In 80% of the cases, MS starts with a relapsing/remitting phenotype and may become progressive after several years [193]. Changes in MS symptoms have been related to reproductive status. About 40% of women with relapsing/remitting MS have reported an increase in symptoms in the time preceding menstruation when both estrogen and progesterone levels have dropped [194,195]. In contrast, in the third trimester of pregnancy when estrogen and progesterone levels are highest, the rate of relapse significantly reduces, only to increase again post-partum when hormone levels have dropped [196,197]. Little data exists on the effects of OCC and HRT use. Two studies have reported an improvement of MS symptoms in women using OCC [194,195] and one study reported an improvement in most women using HRT during menopause [198].

The effects of sex hormones on MS development have been tested quite extensively in a model of MS called experimental autoimmune encephalitis (EAE), as reviewed by Van den Broek et al., recently [199]. The role of estrogen in MS and EAE is complex and seems to be dichotomous: on the one hand it appears to increase the risk of developing the disease, while on the other hand high concentrations were found to be beneficial on the clinical manifestations of EAE. Most of the studies have focused on the protective effects of sex hormones in the course of the disease. There may be different mechanisms by which estrogen affects MS. The protective effect of high concentrations of estrogen may be due to an increase of the anti-inflammatory IL-10 production of specific T cell clones directed against proteins of the myelin sheath [200]. Also the homing of destructive Th1 and Th17 cells into the central nervous system was limited by estrogen [201]. Furthermore, Treg cell function and numbers were found increased by high levels of estrogen and these can limit the expansion of Th1 effector cells [57,58,202,203]. A regulatory B cell mediated protection has also been shown [204]. Finally, the effect of estrogen may also be mediated through decreased numbers of macrophages and dendritic cells in the central nervous system [205].

Progesterone also has protective effects on experimental MS [206-209] as it attenuated disease severity and reduced the inflammatory response. The high progesterone and estrogen during pregnancy may thus explain the improvement of MS signs during pregnancy [210]. It was speculated that the Th2-promoting effects of progesterone [199] may be responsible for tipping the Th1/Th2 balance in a protective direction, but no formal evidence for this hypothesis exists. The neuroprotective effects of progesterone were accompanied by increased IL-10 production and increased infiltration of B cells, possibly regulatory B cells, and cytotoxic T cells into the spinal cord [207].

Administration of androgen significantly delayed onset and progression of EAE and its protective effects are postulated to be responsible for the reduced susceptibility of men for MS [211-213]. Both castration of male mice and treatment of female mice with androgens showed similar results. Androgen was found to inhibit infiltration of Th1 cells into the spinal cord [214] as well as reduce the expression of Th1 cytokines [212] and increase the production of anti-inflammatory cytokine IL-10 [199].

The effects of female sex hormones on Th1 inflammation in the context of EAE all point at protection against disease. This may explain why women remit during pregnancy, but it fails to explain why women are at risk of developing MS in the first place. This particular question needs more research. The effects of androgens on EAE development are consistent with what is found in men: androgens inhibit EAE development, which is why men are less susceptible to the disease.

Asthma

Like autoimmune diseases, asthma is also more prevalent among women in the reproductive stages of life than men [215,216]. Asthma is a common chronic inflammation of the airways, which is characterized by a Th2 polarization with an overabundance of eosinophils, mast cells, and activated Th2 lymphocytes in the lungs and increased levels of IgE in serum.

There is substantial support for a role of female sex hormones in the development of asthma, starting with the fact that the prevalence of asthma and other atopic conditions is higher in boys than girls before puberty and reverses to a higher prevalence in girls and women after puberty when female sex hormone levels have increased [217].

Also other observations suggest a link between female sex hormones and the development of asthma since an earlier menarche increases the risk of developing asthma in females [218,219]. As described above for MS, the effects of estrogen on asthma also appear to be dichotomous. Although it may increase the incidence of asthma, estrogen also appears to be beneficial, since 30% to 40% of menstruating female asthmatics experience perimenstrual asthma worsening with increased symptoms and a greater likelihood of hospitalization [220,221]. Since estrogen levels are low perimenstrually, this suggests a protective effect of estrogen on asthma. Indeed, most of the limited number of case reports and studies investigating OCC use suggest a small beneficial effect on perimenstrual asthma and mild asthma in general among women [218,220,222]. With the Th2 dominance during pregnancy, one would expect an increase in asthma severity in pregnant women with asthma. However, this does not seem to be the case in women with mild asthma: in an equal number of women symptoms worsen, stay the same, or decrease with pregnancy. Only in women with severe asthma, symptoms may increase with pregnancy [223]. After menopause asthma incidence declines in women as compared to men and younger women, but not in women who receive HRT to treat symptoms of menopause [224-228].

A small number of investigations in animal models have tried to elucidate how female sex hormones affect asthma. The few studies published have focused little on mechanisms but rather on inflammatory and allergic endpoints like airway hyperresponsiveness, IgE levels and eosinophils. Yet these studies failed to come up with conclusive proof of the effects of female sex hormones on asthma development because they reported both inhibition and aggravation of airway inflammation by estrogen and progesterone [229-234]. The effects of testosterone on the other hand are clear: testosterone has been shown to suppress Th2 inflammation in the lungs [235,236]. In addition, in an interesting study by Okuyama et al. it was shown that sex differences in airway inflammation are not only caused by the hormonal environment during inflammation, but also by intrinsic differences between male and female immune cells [237]. These intrinsic differences between males and females are probably partly due to local regulation of airway inflammation by macrophages and not by T cells [238,239].

Results from these animal models show that the influence of female sex hormones on Th2-type inflammations is most likely a complex interplay of estrogens, progesterone and their receptors. To be able to tease out their effects we need to understand which parts of the Th2 immune response cascade are different between males and females to identify the most likely targets for the modulation by sex hormones. The effects of androgens are clearer showing inhibition of Th2-type inflammation, which explains the reduced susceptibility of men.

Conclusions

The aim of this review was to describe the effects of sex hormones, both female (estrogen and progesterone) as well as male sex hormones (testosterone), on immune responses in humans. Available evidence from animal studies suggests that sex hormones regulate immune responses in vivo (as reviewed in Reference 1). Since clinical data on human immune responses are largely lacking, we focused on the effects of sex hormones on isolated human immune cells and on human data of effects of sex and reproductive condition on two immune mediated diseases (MS and asthma) as well as on experiments studying the role of sex hormones in animal models for these data.

In the past, the effects of gender and the reproductive condition upon the specific immune response have gained much more attention then the effects on the nonspecific immune response. It is now much clearer that there are also important effects of sex hormones on cells of the nonspecific immune response. This should not be surprising, since many reproductive processes, such as ovulation and menstruation, are regulated by nonspecific immune responses. Ovaries therefore have an interest in regulating the nonspecific immune response. Sex hormones regulate nonspecific immune responses, by affecting monocyte, macrophage, granulocyte and NK cell numbers, but also by affecting the function of these cells.

Many studies have been performed on the effects of sex hormones on the specific immune response. At present, evidence points towards an important role for estrogens and testosterone in the humoral response i.e. (auto)antibody production; estrogen increases, while testosterone decreases antibody production. Sex hormones also have prominent effects on the cellular immune response, by affecting T lymphocytes. Numbers of T lymphocytes are decreased in males and female sex hormones appear to inhibit T cell proliferation and cytotoxicity of Tc lymphocytes. Th cells are also affected by female sex hormones: progesterone induces Th2 development and estrogen seems to increase the number and function of regulatory T cells.

Unfortunately, in vivo studies on the effects of sex hormones on immune responses in humans are largely lacking. Although the female preponderance in autoimmune diseases has been known for many years, the mechanisms for this are not clear. Effects of the reproductive condition and sex hormone treatment on symptoms of autoimmune diseases and asthma are not consistent. This may amongst others be due to a lack of standardization how and when symptoms are scored and what sex hormone treatment is given (combination of progesterone/estrogen treatment, duration of treatment, amount of hormones given). Such a lack of standardization is also seen in animal models. Therefore in order to get more insight into the effects of sex hormones on immune responses and immune based diseases, it is important to standardize experiments and not only study effects of sex hormones separately but also in combination and in different concentrations and for different time periods.

It is obvious from this review that we have decades worth of research, which have already taught us a lot about how sex hormones influence the immune system. However, with every new discovery more questions emerge. For instance, the recent discovery of Th9, Th17 and Treg subsets make us wonder how sex hormones affect these subsets. Future research should focus on these subsets, but also on how these hormones work together in more complicated set-ups than isolated cells. This is not an easy task, but with the ever-expanding research tools and the increased interest in sex differences in disease development and management we should be able to move forward in this challenging field.

Author(s) Affiliation

MM Faas – Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Centre Groningen and University of Groningen
P de Vos – Immunoendocrinology, Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Centre Groningen and University of Groningen
BN Melgert – Department of Pharmacokinetics, Toxicology and Targeting, University Center for Pharmacy, University of Groningen, Groningen, The Netherlands

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