Sex Hormones and Immunoregulation

Sex Hormones and Immunoregulation

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


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 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].


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 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 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 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 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.


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.


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


  1. Ansar AS, Penhale WJ, Talal N. Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action. Am J Pathol 1985; 121(3): 531-51.
  2. Case AM, Reid RL. Effects of the menstrual cycle on medical disorders. Arch Intern Med 1998; 158(13): 1405-12.
  3. Skobeloff EM, Spivey WH, Silverman R, Eskin BA, Harchelroad F, Alessi TV. The effect of the menstrual cycle on asthma presentations in the emergency department. Arch Intern Med 1996; 156(16): 1837-40.
  4. Whitacre CC. Sex differences in autoimmune disease. Nat Immunol 2001; 2(9): 777-80.
  5. Murphy KM, Stockinger B. Effector T cell plasticity: flexibility in the face of changing circumstances. Nat Immunol 2010; 11(8): 674-80.
  6. Beato M, Sanchez-Pacheco A. Interaction of steroid hormone receptors with the transcription initiation complex. Endocr Rev 1996; 17(6): 587-609.
  7. Marino M, Galluzzo P, Ascenzi P. Estrogen signaling multiple pathways to impact gene transcription. Curr Genomics 2006; 7(8): 497-508.
  8. Dosiou C, Hamilton AE, Pang Y, Overgaard MT, Tulac S, Dong J et al. Expression of membrane progesterone receptors on human T lymphocytes and Jurkat cells and activation of G-proteins by progesterone. J Endocrinol 2008; 196(1): 67-77.
  9. Lamche HR, Silberstein PT, Knabe AC, Thomas DD, Jacob HS, Hammerschmidt DE. Steroids decrease granulocyte membrane fluidity, while phorbol ester increases membrane fluidity. Studies using electron paramagnetic resonance. Inflammation 1990; 14(1): 61-70.
  10. Suenaga R, Evans MJ, Mitamura K, Rider V, Abdou NI. Peripheral blood T cells and monocytes and B cell lines derived from patients with lupus express estrogen receptor transcripts similar to those of normal cells. J Rheumatol 1998; 25(7): 1305-12.
  11. Suenaga R, Mitamura K, Evans MJ, Abdou NI. Binding affinity and quantity of estrogen receptor in peripheral blood monocytes of patients with systemic lupus erythematosus. Lupus 1996; 5(3): 227-31.
  12. White MM, Zamudio S, Stevens T, Tyler R, Lindenfeld J, Leslie K, Moore LG. Estrogen, progesterone, and vascular reactivity: potential cellular mechanisms. Endocr Rev 1995; 16(6): 739-51.
  13. Weusten JJ, Blankenstein MA, Gmelig-Meyling FH, Schuurman HJ, Kater L, Thijssen JH. Presence of oestrogen receptors in human blood mononuclear cells and thymocytes. Acta Endocrinol (Copenh) 1986; 112(3): 409-14.
  14. Ben Hur H, Mor G, Insler V, Blickstein I, Amir-Zaltsman Y, Sharp A et al. Menopause is associated with a significant increase in blood monocyte number and a relative decrease in the expression of estrogen receptors in human peripheral monocytes. Am J Reprod Immunol 1995; 34(6): 363-9.
  15. Wada K, Itoh T, Nakagawa M, Misao R, Mori H, Tamaya T. Estrogen binding sites in peripheral blood monocytes and effects of danazol on their sites in vitro. Gen Pharmacol 1992; 23(4): 693-700.
  16. Phiel KL, Henderson RA, Adelman SJ, Elloso MM. Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunol Lett 2005; 97(1): 107-13.
  17. Molero L, Garcia-Duran M, Diaz-Recasens J, Rico L, Casado S, Lopez-Farre A. Expression of estrogen receptor subtypes and neuronal nitric oxide synthase in neutrophils from women and men: regulation by estrogen. Cardiovasc Res 2002; 56(1): 43-51.
  18. Komi J, Lassila O. Nonsteroidal anti-estrogens inhibit the functional differentiation of human monocyte-derived dendritic cells. Blood 2000; 95(9): 2875-82.
  19. Curran EM, Berghaus LJ, Vernetti NJ, Saporita AJ, Lubahn DB, Estes DM. Natural killer cells express estrogen receptor-alpha and estrogen receptor-beta and can respond to estrogen via a non-estrogen receptor-alpha-mediated pathway. Cell Immunol 2001; 214(1): 12-20.
  20. Cohen JH, Danel L, Cordier G, Saez S, Revillard JP. Sex steroid receptors in peripheral T cells: absence of androgen receptors and restriction of estrogen receptors to OKT8-positive cells. J Immunol 1983; 131(6): 2767-71.
  21. Stimson WH. Oestrogen and human T lymphocytes: presence of specific receptors in the T-suppressor/cytotoxic subset. Scand J Immunol 1988; 28(3): 345-50.
  22. Mansour I, Reznikoff-Etievant MF, Netter A. No evidence for the expression of the progesterone receptor on peripheral blood lymphocytes during pregnancy. Hum Reprod 1994; 9(8): 1546-9.
  23. Vegeto E, Pollio G, Pellicciari C, Maggi A. Estrogen and progesterone induction of survival of monoblastoid cells undergoing TNF-alpha-induced apoptosis. FASEB J 1999; 13(8): 793-803.
  24. Schust DJ, Anderson DJ, Hill JA. Progesterone-induced immunosuppression is not mediated through the progesterone receptor. Hum Reprod 1996; 11(5): 980-5.
  25. Szekeres-Bartho J. Progesterone receptors on lymphocytes. Hum Reprod 1995; 10(3): 695-6.
  26. Szekeres-Bartho J, Reznikoff-Etievant MF, Varga P, Pichon MF, Varga Z, Chaouat G. Lymphocytic progesterone receptors in normal and pathological human pregnancy. J Reprod Immunol 1989; 16(3): 239-47.
  27. Szekeres-Bartho J, Weill BJ, Mike G, Houssin D, Chaouat G. Progesterone receptors in lymphocytes of liver-transplanted and transfused patients. Immunol Lett 1989; 22(4): 259-61.
  28. Szekeres-Bartho J. Immunological relationship between the mother and the fetus. Int Rev Immunol 2002; 21(6): 471-95.
  29. Aerts JL, Christiaens MR, Vandekerckhove P. Evaluation of progesterone receptor expression in eosinophils using real-time quantitative PCR. Biochim Biophys Acta 2002; 1571(3): 167-72.
  30. Barakonyi A, Polgar B, Szekeres-Bartho J. The role of gamma/delta T-cell receptor-positive cells in pregnancy: part II. Am J Reprod Immunol 1999; 42(2): 83-7.
  31. Polgar B, Barakonyi A, Xynos I, Szekeres-Bartho J. The role of gamma/delta T cell receptor positive cells in pregnancy. Am J Reprod Immunol 1999; 41(4): 239-44.
  32. Szekeres-Bartho J, Philibert D, Chaouat G. Progesterone suppression of pregnancy lymphocytes is not mediated by glucocorticoid effect. Am J Reprod Immunol 1990; 23(2): 42-3.
  33. Rife SU, Marquez MG, Escalante A, Velich T. The effect of testosterone on the immune response. 1. Mechanism of action on antibody-forming cells. Immunol Invest 1990; 19(3): 259-70.
  34. Chien EJ, Chang CP, Lee WF, Su TH, Wu CH. Non-genomic immunosuppressive actions of progesterone inhibits PHA-induced alkalinization and activation in T cells. J Cell Biochem 2006; 99(1): 292-304.
  35. Benten WP, Lieberherr M, Giese G, Wrehlke C, Stamm O, Sekeris CE et al. Functional testosterone receptors in plasma membranes of T cells. FASEB J 1999; 13(1): 123-33.
  36. Benten WP, Stephan C, Wunderlich F. B cells express intracellular but not surface receptors for testosterone and estradiol. Steroids 2002; 67(7): 647-54.
  37. Bebo BF, Jr., Schuster JC, Vandenbark AA, Offner H. Androgens alter the cytokine profile and reduce encephalitogenicity of myelin-reactive T cells. J Immunol 1999; 162(1): 35-40.
  38. Grimaldi CM. Sex and systemic lupus erythematosus: the role of the sex hormones estrogen and prolactin on the regulation of autoreactive B cells. Curr Opin Rheumatol 2006; 18(5): 456-61.
  39. Thongngarm T, Jenkins JK, Ndebele K, McMurray RW. Estrogen and progesterone modulate monocyte cell cycle progression and apoptosis. Am J Reprod Immunol 2003; 49(3): 129-38.
  40. Bain BJ, England JM. Variations in leucocyte count during menstrual cycle. Br Med J 1975; 2(5969): 473-5.
  41. Mathur S, Mathur RS, Goust JM, Williamson HO, Fudenberg HH. Cyclic variations in white cell subpopulations in the human menstrual cycle: correlations with progesterone and estradiol. Clin Immunol Immunopathol 1979; 13(3): 246-53.
  42. Bouman A, Moes H, Heineman MJ, de Leij LF, Faas MM. The immune response during the luteal phase of the ovarian cycle: increasing sensitivity of human monocytes to endotoxin. Fertil Steril 2001; 76(3): 555-9.
  43. Elenkov IJ, Wilder RL, Bakalov VK, Link AA, Dimitrov MA, Fisher S et al. IL-12, TNF-alpha, and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times. J Clin Endocrinol Metab 2001; 86(10): 4933-8.
  44. Apseloff G, Bao X, LaBoy-Goral L, Friedman H, Shah A. Practical considerations regarding the influence of the menstrual cycle on leukocyte parameters in clinical trials. Am J Ther 2000; 7(5): 297-302.
  45. Northern AL, Rutter SM, Peterson CM. Cyclic changes in the concentrations of peripheral blood immune cells during the normal menstrual cycle. Proc Soc Exp Biol Med 1994; 207(1): 81-8.
  46. Faas M, Bouman A, Moes H, Heineman MJ, de Leij L, Schuiling G. The immune response during the luteal phase of the ovarian cycle: a Th2-type response? Fertil Steril 2000; 74(5): 1008-13.
  47. Veenstra van Nieuwenhoven AL, Bouman A, Moes H, Heineman MJ, de Leij LF, Santema J, Faas MM. Cytokine production in natural killer cells and lymphocytes in pregnant women compared with women in the follicular phase of the ovarian cycle. Fertil Steril 2002; 77(5): 1032-7.
  48. Bouman A, Schipper M, Heineman MJ, Faas MM. Gender difference in the non-specific and specific immune response in humans. Am J Reprod Immunol 2004; 52(1): 19-26.
  49. Kumru S, Godekmerdan A, Yilmaz B. Immune effects of surgical menopause and estrogen replacement therapy in peri-menopausal women. J Reprod Immunol 2004; 63(1): 31-8.
  50. Burleson MH, Malarkey WB, Cacioppo JT, Poehlmann KM, Kiecolt-Glaser JK, Berntson GG, Glaser R. Postmenopausal hormone replacement: effects on autonomic, neuroendocrine, and immune reactivity to brief psychological stressors. Psychosom Med 1998; 60(1): 17-25.
  51. Auerbach L, Hafner T, Huber JC, Panzer S. Influence of low-dose oral contraception on peripheral blood lymphocyte subsets at particular phases of the hormonal cycle. Fertil Steril 2002; 78(1): 83-9.
  52. Lopez-Karpovitchs X, Larrea F, Cardenas R, Valencia X, Piedras J, Diaz-Sanchez V, Alarcon-Segovia D. Peripheral blood lymphocyte subsets and serum immunoglobulins in Sheehan’s syndrome and in normal women during the menstrual cycle. Rev Invest Clin 1993; 45(3): 247-53.
  53. Yang JH, Chen CD, Wu MY, Chao KH, Yang YS, Ho HN. Hormone replacement therapy reverses the decrease in natural killer cytotoxicity but does not reverse the decreases in the T-cell subpopulation or interferon-gamma production in postmenopausal women. Fertil Steril 2000; 74(2): 261-7.
  54. Giglio T, Imro MA, Filaci G, Scudeletti M, Puppo F, De Cecco L et al. Immune cell circulating subsets are affected by gonadal function. Life Sci 1994; 54(18): 1305-12.
  55. Gronroos M, Eskola J. In vitro functions of lymphocytes during high-dose medroxyprogesterone acetate (MPA) treatment. Cancer Immunol Immunother 1984; 17(3): 218-20.
  56. Porter VR, Greendale GA, Schocken M, Zhu X, Effros RB. Immune effects of hormone replacement therapy in post-menopausal women. Exp Gerontol 2001; 36(2): 311-26.
  57. Prieto GA, Rosenstein Y. Oestradiol potentiates the suppressive function of human CD4 CD25 regulatory T cells by promoting their proliferation. Immunology 2006; 118(1): 58-65.
  58. Tai P, Wang J, Jin H, Song X, Yan J, Kang Y et al. Induction of regulatory T cells by physiological level estrogen. J Cell Physiol 2008; 214(2): 456-64.
  59. Page ST, Plymate SR, Bremner WJ, Matsumoto AM, Hess DL, Lin DW et al. Effect of medical castration on CD4+ CD25+ T cells, CD8+ T cell IFN-gamma expression, and NK cells: a physiological role for testosterone and/or its metabolites. Am J Physiol Endocrinol Metab 2006; 290(5): E856-E863.
  60. Fries LF, Brickman CM, Frank MM. Monocyte receptors for the Fc portion of IgG increase in number in autoimmune hemolytic anemia and other hemolytic states and are decreased by glucocorticoid therapy. J Immunol 1983; 131(3): 1240-5.
  61. Schreiber AD, Chien P, Tomaski A, Cines DB. Effect of danazol in immune thrombocytopenic purpura. N Engl J Med 1987; 316(9): 503-8.
  62. Friedman D, Netti F, Schreiber AD. Effect of estradiol and steroid analogues on the clearance of immunoglobulin G-coated erythrocytes. J Clin Invest 1985; 75(1): 162-7.
  63. Beutler BA, Milsark IW, Cerami A. Cachectin/tumor necrosis factor: production, distribution, and metabolic fate in vivo. J Immunol 1985; 135(6): 3972-7.
  64. Asai K, Hiki N, Mimura Y, Ogawa T, Unou K, Kaminishi M. Gender differences in cytokine secretion by human peripheral blood mononuclear cells: role of estrogen in modulating LPS-induced cytokine secretion in an ex vivo septic model. Shock 2001; 16(5): 340-3.
  65. Schwarz E, Schafer C, Bode JC, Bode C. Influence of the menstrual cycle on the LPS-induced cytokine response of monocytes. Cytokine 2000; 12(4): 413-6.
  66. Posma E, Moes H, Heineman MJ, Faas M. The effect of testosterone on cytokine production in the specific and non-specific immune response. Am J Reprod Immunol 2004; 52: 237-43.
  67. Brannstrom M, Friden BE, Jasper M, Norman RJ. Variations in peripheral blood levels of immunoreactive tumor necrosis factor alpha (TNFalpha) throughout the menstrual cycle and secretion of TNFalpha from the human corpus luteum. Eur J Obstet Gynecol Reprod Biol 1999; 83(2): 213-7.
  68. Bouman A, Schipper M, Heineman MJ, Faas M. 17b-estradiol and progesterone do not influence the production of cytokine from lipopolysaccharide-stimulated monocytes in humans. Fertil Steril 2004; 82 (suppl 3): 1212-9.
  69. Rogers A, Eastell R. Effects of estrogen therapy of postmenopausal women on cytokines measured in peripheral blood. J Bone Miner Res 1998; 13(10): 1577-86.
  70. Denison FC, Kelly RW, Calder AA. Differential secretion of chemokines from peripheral blood in pregnant compared with non-pregnant women. J Reprod Immunol 1997; 34(3): 225-40.
  71. Parker MG. Transcriptional activation by oestrogen receptors. Biochem Soc Symp 1998; 63: 45-50.
  72. Rogers A, Eastell R. The effect of 17beta-estradiol on production of cytokines in cultures of peripheral blood. Bone 2001; 29(1): 30-4.
  73. Ralston SH, Russell RG, Gowen M. Estrogen inhibits release of tumor necrosis factor from peripheral blood mononuclear cells in postmenopausal women. J Bone Miner Res 1990; 5(9): 983-8.
  74. Cannon JG, Dinarello CA. Increased plasma interleukin-1 activity in women after ovulation. Science 1985; 227(4691): 1247-9.
  75. Polan ML, Loukides JA, Honig J. Interleukin-1 in human ovarian cells and in peripheral blood monocytes increases during the luteal phase: evidence for a midcycle surge in the human. Am J Obstet Gynecol 1994; 170(4): 1000-6.
  76. Morishita M, Miyagi M, Iwamoto Y. Effects of sex hormones on production of interleukin-1 by human peripheral monocytes. J Periodontol 1999; 70(7): 757-60.
  77. Trinchieri G. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol 1995; 13: 251-76.
  78. Matalka KZ. The effect of estradiol, but not progesterone, on the production of cytokines in stimulated whole blood, is concentration-dependent. Neuro Endocrinol Lett 2003; 24(3-4): 185-91.
  79. McKane WR, Khosla S, Peterson JM, Egan K, Riggs BL. Circulating levels of cytokines that modulate bone resorption: effects of age and menopause in women. J Bone Miner Res 1994; 9(8): 1313-8.
  80. Kania DM, Binkley N, Checovich M, Havighurst T, Schilling M, Ershler WB. Elevated plasma levels of interleukin-6 in postmenopausal women do not correlate with bone density. J Am Geriatr Soc 1995; 43(3): 236-9.
  81. Rachon D, Mysliwska J, Suchecka-Rachon K, Wieckiewicz J, Mysliwski A. Effects of oestrogen deprivation on interleukin-6 production by peripheral blood mononuclear cells of postmenopausal women. J Endocrinol 2002; 172(2): 387-95.
  82. Cioffi M, Esposito K, Vietri MT, Gazzerro P, D’Auria A, Ardovino I et al. Cytokine pattern in postmenopause. Maturitas 2002; 41(3): 187-92.
  83. Straub RH, Hense HW, Andus T, Scholmerich J, Riegger GA, Schunkert H. Hormone replacement therapy and interrelation between serum interleukin-6 and body mass index in postmenopausal women: a population-based study. J Clin Endocrinol Metab 2000; 85(3): 1340-4.
  84. Jilma B, Dirnberger E, Loscher I, Rumplmayr A, Hildebrandt J, Eichler HG et al. Menstrual cycle-associated changes in blood levels of interleukin-6, alpha1 acid glycoprotein, and C-reactive protein. J Lab Clin Med 1997; 130(1): 69-75.
  85. Al Harthi L, Wright DJ, Anderson D, Cohen M, Matity Ahu D, Cohn J et al. The impact of the ovulatory cycle on cytokine production: evaluation of systemic, cervicovaginal, and salivary compartments. J Interferon Cytokine Res 2000; 20(8): 719-24.
  86. Abrahamsen B, Stilgren LS, Rettmer E, Bonnevie-Nielsen V, Beck-Nielsen H. Effects of the natural and artificial menstrual cycle on the production of osteoprotegerin and the bone resorptive cytokines IL-1beta and IL-6. Calcif Tissue Int 2003; 72(1): 18-23.
  87. Verthelyi D, Klinman DM. Sex hormone levels correlate with the activity of cytokine-secreting cells in vivo. Immunology 2000; 100(3): 384-90.
  88. Konecna L, Yan MS, Miller LE, Scholmerich J, Falk W, Straub RH. Modulation of IL-6 production during the menstrual cycle in vivo and in vitro. Brain Behav Immun 2000; 14(1): 49-61.
  89. Angstwurm MW, Gartner R, Ziegler-Heitbrock HW. Cyclic plasma IL-6 levels during normal menstrual cycle. Cytokine 1997; 9(5): 370-4.
  90. Berg G, Ekerfelt C, Hammar M, Lindgren R, Matthiesen L, Ernerudh J. Cytokine changes in postmenopausal women treated with estrogens: a placebo-controlled study. Am J Reprod Immunol 2002; 48(2): 63-9.
  91. Brooks-Asplund EM, Tupper CE, Daun JM, Kenney WL, Cannon JG. Hormonal modulation of interleukin-6, tumor necrosis factor and associated receptor secretion in postmenopausal women. Cytokine 2002; 19(4): 193-200.
  92. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5(12): 953-64.
  93. Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci 2008; 13: 453-61.
  94. Rettew JA, Huet YM, Marriott I. Estrogens augment cell surface TLR4 expression on murine macrophages and regulate sepsis susceptibility in vivo. Endocrinology 2009; 150(8): 3877-84.
  95. Lezama-Davila CM, Isaac-Marquez AP, Barbi J, Cummings HE, Lu B, Satoskar AR. Role of phosphatidylinositol-3-kinase-gamma (PI3Kgamma)-mediated pathway in 17beta-estradiol-induced killing of L. mexicana in macrophages from C57BL/6 mice. Immunol Cell Biol 2008; 86(6): 539-43.
  96. Calippe B, Douin-Echinard V, Laffargue M, Laurell H, Rana-Poussine V, Pipy B et al. Chronic estradiol administration in vivo promotes the proinflammatory response of macrophages to TLR4 activation: involvement of the phosphatidylinositol 3-kinase pathway. J Immunol 2008; 180(12): 7980-8.
  97. Lezama-Davila CM, Isaac-Marquez AP, Barbi J, Oghumu S, Satoskar AR. 17Beta-estradiol increases Leishmania mexicana killing in macrophages from DBA/2 mice by enhancing production of nitric oxide but not pro-inflammatory cytokines. Am J Trop Med Hyg 2007; 76(6): 1125-7.
  98. Azenabor AA, Yang S, Job G, Adedokun OO. Expression of iNOS gene in macrophages stimulated with 17beta-estradiol is regulated by free intracellular Ca2+. Biochem Cell Biol 2004; 82(3): 381-90.
  99. Hu SK, Mitcho YL, Rath NC. Effect of estradiol on interleukin 1 synthesis by macrophages. Int J Immunopharmacol 1988; 10(3): 247-52.
  100. Salem ML. Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Curr Drug Targets Inflamm Allergy 2004; 3(1): 97-104.
  101. Miller L, Alley EW, Murphy WJ, Russell SW, Hunt JS. Progesterone inhibits inducible nitric oxide synthase gene expression and nitric oxide production in murine macrophages. J Leukoc Biol 1996; 59(3): 442-50.
  102. Su L, Sun Y, Ma F, Lu P, Huang H, Zhou J. Progesterone inhibits Toll-like receptor 4-mediated innate immune response in macrophages by suppressing NF-kappaB activation and enhancing SOCS1 expression. Immunol Lett 2009; 125(2): 151-5.
  103. Jones LA, Anthony JP, Henriquez FL, Lyons RE, Nickdel MB, Carter KC et al. Toll-like receptor-4-mediated macrophage activation is differentially regulated by progesterone via the glucocorticoid and progesterone receptors. Immunology 2008; 125(1): 59-69.
  104. Miller L, Hunt JS. Regulation of TNF-alpha production in activated mouse macrophages by progesterone. J Immunol 1998; 160(10): 5098-104.
  105. Rettew JA, Huet-Hudson YM, Marriott I. Testosterone reduces macrophage expression in the mouse of toll-like receptor 4, a trigger for inflammation and innate immunity. Biol Reprod 2008; 78(3): 432-7.
  106. Mohan PF, Jacobson MS. Inhibition of macrophage superoxide generation by dehydroepiandrosterone. Am J Med Sci 1993; 306(1): 10-5.
  107. Rom WN, Harkin T. Dehydroepiandrosterone inhibits the spontaneous release of superoxide radical by alveolar macrophages in vitro in asbestosis. Environ Res 1991; 55(2): 145-56.
  108. Falagas ME, Mourtzoukou EG, Vardakas KZ. Sex differences in the incidence and severity of respiratory tract infections. Respir Med 2007; 101(9): 1845-63.
  109. Klein SL. Hormonal and immunological mechanisms mediating sex differences in parasite infection. Parasite Immunol 2004; 26(6-7): 247-64.
  110. Beery TA. Sex differences in infection and sepsis. Crit Care Nurs Clin North Am 2003; 15(1): 55-62.
  111. Routley CE, Ashcroft GS. Effect of estrogen and progesterone on macrophage activation during wound healing. Wound Repair Regen 2009; 17(1): 42-50.
  112. Frisancho-Kiss S, Coronado MJ, Frisancho JA, Lau VM, Rose NR, Klein SL, Fairweather D. Gonadectomy of male BALB/c mice increases Tim-3(+) alternatively activated M2 macrophages, Tim-3(+) T cells, Th2 cells and Treg in the heart during acute coxsackievirus-induced myocarditis. Brain Behav Immun 2009; 23(5): 649-57.
  113. Angele MK, Knoferl MW, Schwacha MG, Ayala A, Cioffi WG, Bland KI, Chaudry IH. Sex steroids regulate pro- and anti-inflammatory cytokine release by macrophages after trauma-hemorrhage. Am J Physiol 1999; 277(1 Pt 1): C35-C42.
  114. Jacobs B, Wuttke M, Papewalis C, Seissler J, Schott M. Dendritic cell subtypes and in vitro generation of dendritic cells. Horm Metab Res 2008; 40(2): 99-107.
  115. Huck B, Steck T, Habersack M, Dietl J, Kammerer U. Pregnancy associated hormones modulate the cytokine production but not the phenotype of PBMC-derived human dendritic cells. Eur J Obstet Gynecol Reprod Biol 2005; 122(1): 85-94.
  116. Kyurkchiev D, Ivanova-Todorova E, Hayrabedyan S, Altankova I, Kyurkchiev S. Female sex steroid hormones modify some regulatory properties of monocyte-derived dendritic cells. Am J Reprod Immunol 2007; 58(5): 425-33.
  117. Hughes GC, Thomas S, Li C, Kaja MK, Clark EA. Cutting edge: progesterone regulates IFN-alpha production by plasmacytoid dendritic cells. J Immunol 2008; 180(4): 2029-33.
  118. Hickey MJ, Kubes P. Intravascular immunity: the host-pathogen encounter in blood vessels. Nat Rev Immunol 2009; 9(5): 364-75.
  119. Miyagi M, Aoyama H, Morishita M, Iwamoto Y. Effects of sex hormones on chemotaxis of human peripheral polymorphonuclear leukocytes and monocytes. J Periodontol 1992; 63(1): 28-32.
  120. Molloy EJ, O’Neill AJ, Grantham JJ, Sheridan-Pereira M, Fitzpatrick JM, Webb DW, Watson RW. Sex-specific alterations in neutrophil apoptosis: the role of estradiol and progesterone. Blood 2003; 102(7): 2653-9.
  121. Bekesi G, Kakucs R, Varbiro S, Racz K, Sprintz D, Feher J, Szekacs B. In vitro effects of different steroid hormones on superoxide anion production of human neutrophil granulocytes. Steroids 2000; 65(12): 889-94.
  122. Cassidy RA. Influence of steroids on oxidant generation in activated human granulocytes and mononuclear leukocytes. Shock 2003; 20(1): 85-90.
  123. Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 1991; 88(11): 4651-5.
  124. Garcia-Duran M, de Frutos T, Diaz-Recasens J, Garcia-Galvez G, Jimenez A, Monton M et al. Estrogen stimulates neuronal nitric oxide synthase protein expression in human neutrophils. Circ Res 1999; 85(11): 1020-6.
  125. Stefano GB, Prevot V, Beauvillain JC, Fimiani C, Welters I, Cadet P et al. Estradiol coupling to human monocyte nitric oxide release is dependent on intracellular calcium transients: evidence for an estrogen surface receptor. J Immunol 1999; 163(7): 3758-63.
  126. Yovel G, Shakhar K, Ben Eliyahu S. The effects of sex, menstrual cycle, and oral contraceptives on the number and activity of natural killer cells. Gynecol Oncol 2001; 81(2): 254-62.
  127. Souza SS, Castro FA, Mendonca HC, Palma PV, Morais FR, Ferriani RA, Voltarelli JC. Influence of menstrual cycle on NK activity. J Reprod Immunol 2001; 50(2): 151-9.
  128. Baker DA, Hameed C, Tejani N, Milch P, Thomas J, Monheit AG, Dattwyler RJ. Lymphocyte subsets in women on low dose oral contraceptives. Contraception 1985; 32(4): 377-82.
  129. Scanlan JM, Werner JJ, Legg RL, Laudenslager ML. Natural killer cell activity is reduced in association with oral contraceptive use. Psychoneuroendocrinology 1995; 20(3): 281-7.
  130. Stopinska-Gluszak U, Waligora J, Grzela T, Gluszak M, Jozwiak J, Radomski D et al. Effect of estrogen/progesterone hormone replacement therapy on natural killer cell cytotoxicity and immunoregulatory cytokine release by peripheral blood mononuclear cells of postmenopausal women. J Reprod Immunol 2006; 69(1): 65-75.
  131. Ferguson MM, McDonald FG. Oestrogen as an inhibitor of human NK cell cytolysis. FEBS Lett 1985; 191(1): 145-8.
  132. Sulke AN, Jones DB, Wood PJ. Hormonal modulation of human natural killer cell activity in vitro. J Reprod Immunol 1985; 7(2): 105-10.
  133. Uksila J. Human NK cell activity is not inhibited by pregnancy and cord serum factors and female steroid hormones in vitro. J Reprod Immunol 1985; 7(2): 111-20.
  134. Sulke AN, Jones DB, Wood PJ. Variation in natural killer activity in peripheral blood during the menstrual cycle. Br Med J (Clin Res Ed) 1985; 290(6472): 884-6.
  135. Thyss A, Caldani C, Bourcier C, Benita G, Schneider M. Comparison of natural killer activity during the first and second halves of the menstrual cycle in women. Br J Cancer 1984; 50(1): 127-8.
  136. White D, Jones DB, Cooke T, Kirkham N. Natural killer (NK) activity in peripheral blood lymphocytes of patients with benign and malignant breast disease. Br J Cancer 1982; 46(4): 611-6.
  137. Mendes R, Bromelow KV, Westby M, Galea-Lauri J, Smith IE, O’Brien ME, Souberbielle BE. Flow cytometric visualisation of cytokine production by CD3-CD56+ NK cells and CD3+CD56+ NK-T cells in whole blood. Cytometry 2000; 39(1): 72-8.
  138. Biassoni R, Ferrini S, Prigione I, Pelak VS, Sekaly RP, Long EO. Activated CD3- CD16+ natural killer cells express a subset of the lymphokine genes induced in activated alpha beta + and gamma delta + T cells. Scand J Immunol 1991; 33(3): 247-52.
  139. Bouman A, Moes H, Heineman MJ, de Leij LF, Faas MM. Cytokine production by natural killer lymphocytes in follicular and luteal phase of the ovarian cycle in humans. Am J Reprod Immunol 2001; 45(3): 130-4.
  140. Klein SL. The effects of hormones on sex differences in infection: from genes to behavior. Neurosci Biobehav Rev 2000; 24(6): 627-38.
  141. Roberts CW, Walker W, Alexander J. Sex-associated hormones and immunity to protozoan parasites. Clin Microbiol Rev 2001; 14(3): 476-88.
  142. Marriott I, Huet-Hudson YM. Sexual dimorphism in innate immune responses to infectious organisms. Immunol Res 2006; 34(3): 177-92.
  144. Marriott I, Huet-Hudson YM. Sexual dimorphism in innate immune responses to infectious organisms. Immunol Res 2006; 34(3): 177-92.
  145. Beagley KW, Gockel CM. Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. FEMS Immunol Med Microbiol 2003; 38(1): 13-22.
  146. Choudhry MA, Bland KI, Chaudry IH. Trauma and immune response–effect of gender differences. Injury 2007; 38(12): 1382-91.
  147. Gilliver SC, Ruckshanthi JP, Hardman MJ, Nakayama T, Ashcroft GS. Sex dimorphism in wound healing: the roles of sex steroids and macrophage migration inhibitory factor. Endocrinology 2008; 149(11): 5747-57.
  148. Herrick S, Ashcroft G, Ireland G, Horan M, McCollum C, Ferguson M. Up-regulation of elastase in acute wounds of healthy aged humans and chronic venous leg ulcers are associated with matrix degradation. Lab Invest 1997; 77(3): 281-8.
  149. Ashcroft GS, Horan MA, Ferguson MW. Aging alters the inflammatory and endothelial cell adhesion molecule profiles during human cutaneous wound healing. Lab Invest 1998; 78(1): 47-58.
  150. Ashcroft GS, Greenwell-Wild T, Horan MA, Wahl SM, Ferguson MW. Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response. Am J Pathol 1999; 155(4): 1137-46.
  151. Ashcroft GS, Horan MA, Ferguson MW. Aging alters the inflammatory and endothelial cell adhesion molecule profiles during human cutaneous wound healing. Lab Invest 1998; 78(1): 47-58.
  152. Gilliver SC, Wu F, Ashcroft GS. Regulatory roles of androgens in cutaneous wound healing. Thromb Haemost 2003; 90(6): 978-85.
  153. Deonarine K, Panelli MC, Stashower ME, Jin P, Smith K, Slade HB et al. Gene expression profiling of cutaneous wound healing. J Transl Med 2007; 5: 11.
  154. Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol 1975; 78(1): 71-100.
  155. Grossman CJ. Regulation of the immune system by sex steroids. Endocr Rev 1984; 5(3): 435-55.
  156. Mendelsohn J, Multer MM, Bernheim JL. Inhibition of human lymphocyte stimulation by steroid hormones: cytokinetic mechanisms. Clin Exp Immunol 1977; 27(1): 127-34.
  157. Wyle FA, Kent JR. Immunosuppression by sex steroid hormones. The effect upon PHA- and PPD-stimulated lymphocytes. Clin Exp Immunol 1977; 27(3): 407-15.
  158. Mori T, Kobayashi H, Nishimura T, Mori TS, Fujii G, Inou T. Inhibitory effect of progesterone on the phytohaemagglutinin- induced transformation of human peripheral lymphocytes. Immunol Commun 1975; 4(6): 519-27.
  159. Van Voorhis BJ, Anderson DJ, Hill JA. The effects of RU 486 on immune function and steroid-induced immunosuppression in vitro. J Clin Endocrinol Metab 1989; 69(6): 1195-9.
  160. McMurray RW, Suwannaroj S, Ndebele K, Jenkins JK. Differential effects of sex steroids on T and B cells: modulation of cell cycle phase distribution, apoptosis and bcl-2 protein levels. Pathobiology 2001; 69(1): 44-58.
  161. White HD, Crassi KM, Givan AL, Stern JE, Gonzalez JL, Memoli VA et al. CD3+ CD8+ CTL activity within the human female reproductive tract: influence of stage of the menstrual cycle and menopause. J Immunol 1997; 158(6): 3017-27.
  162. Takao T, Kumagai C, Hisakawa N, Matsumoto R, Hashimoto K. Effect of 17beta-estradiol on tumor necrosis factor-alpha-induced cytotoxicity in the human peripheral T lymphocytes. J Endocrinol 2005; 184(1): 191-7.
  163. Giron-Gonzalez JA, Moral FJ, Elvira J, Garcia-Gil D, Guerrero F, Gavilan I, Escobar L. Consistent production of a higher TH1:TH2 cytokine ratio by stimulated T cells in men compared with women. Eur J Endocrinol 2000; 143(1): 31-6.
  164. Agarwal SK, Marshall GD, Jr. Perimenstrual alterations in type-1/type-2 cytokine balance of normal women. Ann Allergy Asthma Immunol 1999; 83(3): 222-8.
  165. Piccinni MP, Giudizi MG, Biagiotti R, Beloni L, Giannarini L, Sampognaro S et al. Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones. J Immunol 1995; 155(1): 128-33.
  166. Cutolo M, Sulli A, Capellino S, Villaggio B, Montagna P, Seriolo B, Straub RH. Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus 2004; 13(9): 635-8.
  167. Cioffi M, Esposito K, Vietri MT, Gazzerro P, D’Auria A, Ardovino I et al. Cytokine pattern in postmenopause. Maturitas 2002; 41(3): 187-92.
  168. Kamada M, Irahara M, Maegawa M, Ohmoto Y, Murata K, Yasui T et al. Transient increase in the levels of T-helper 1 cytokines in postmenopausal women and the effects of hormone replacement therapy. Gynecol Obstet Invest 2001; 52(2): 82-8.
  169. Maskill JK, Laird SM, Okon M, Li TC, Blakemore AI. Stability of serum interleukin-10 levels during the menstrual cycle. Am J Reprod Immunol 1997; 38(5): 339-42.
  170. Nakashima A, Ito M, Yoneda S, Shiozaki A, Hidaka T, Saito S. Circulating and decidual Th17 cell levels in healthy pregnancy. Am J Reprod Immunol 2010; 63(2): 104-9.
  171. Tai P, Wang J, Jin H, Song X, Yan J, Kang Y et al. Induction of regulatory T cells by physiological level estrogen. J Cell Physiol 2008; 214(2): 456-64.
  172. Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M, Vandenbark AA, Ziegler SF, Offner H. Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J Immunol 2004; 173(4): 2227-30.
  173. Polanczyk MJ, Hopke C, Huan J, Vandenbark AA, Offner H. Enhanced FoxP3 expression and Treg cell function in pregnant and estrogen-treated mice. J Neuroimmunol 2005; 170(1-2): 85-92.
  174. Giltay EJ, Fonk JC, von Blomberg BM, Drexhage HA, Schalkwijk C, Gooren LJ. In vivo effects of sex steroids on lymphocyte responsiveness and immunoglobulin levels in humans. J Clin Endocrinol Metab 2000; 85(4): 1648-57.
  175. Butterworth M, McClellan B, Allansmith M. Influence of sex in immunoglobulin levels. Nature 1967; 214(94): 1224-5.
  176. Lichtman MA, Vaughan JH, Hames CG. The distribution of serum immunoglobulins, anti-gamma-G globulins (“rheumatoid factors”) and antinuclear antibodies in White and Negro subjects in Evans County, Georgia. Arthritis Rheum 1967; 10(3): 204-15.
  177. Grundbacher FJ. Human X chromosome carries quantitative genes for immunoglobulin M. Science 1972; 176(32): 311-2.
  178. Eidinger D, Garrett TJ. Studies of the regulatory effects of the sex hormones on antibody formation and stem cell differentiation. J Exp Med 1972; 136(5): 1098-116.
  179. Gomez E, Ortiz V, Saint-Martin B, Boeck L, Diaz-Sanchez V, Bourges H. Hormonal regulation of the secretory IgA (sIgA) system: estradiol- and progesterone-induced changes in sIgA in parotid saliva along the menstrual cycle. Am J Reprod Immunol 1993; 29(4): 219-23.
  180. Bisset LR, Griffin JF. Humoral immunity in oral contraceptive users. II. In vitro immunoglobulin production. Contraception 1988; 38(5): 573-8.
  181. Bisset LR, Griffin JF. Humoral immunity in oral contraceptive users. I. Plasma immunoglobulin levels. Contraception 1988; 38(5): 567-72.
  182. Klinger G, Graser T, Mellinger U, Moore C, Vogelsang H, Groh A et al. A comparative study of the effects of two oral contraceptives containing dienogest or desogestrel on the human immune system. Gynecol Endocrinol 2000; 14(1): 15-24.
  183. Lali P, Chandra L, Gupta RP. Serum immunoglobulin levels during contraceptive use of depot-medroxyprogesterone acetate in Indian women: a preliminary study. Contraception 1996; 53(6): 363-5.
  184. Kanda N, Tamaki K. Estrogen enhances immunoglobulin production by human PBMCs. J Allergy Clin Immunol 1999; 103(2 Pt 1): 282-8.
  185. Weetman AP, McGregor AM, Smith BR, Hall R. Sex hormones enhance immunoglobulin synthesis by human peripheral blood lymphocytes. Immunol Lett 1981; 3(6): 343-6.
  186. Kanda N, Tsuchida T, Tamaki K. Testosterone inhibits immunoglobulin production by human peripheral blood mononuclear cells. Clin Exp Immunol 1996; 106(2): 410-5.
  187. Kanda N, Tsuchida T, Tamaki K. Estrogen enhancement of anti-double-stranded DNA antibody and immunoglobulin G production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Arthritis Rheum 1999; 42(2): 328-37.
  188. Kanda N, Tsuchida T, Tamaki K. Testosterone suppresses anti-DNA antibody production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Arthritis Rheum 1997; 40(9): 1703-11.
  189. Verthelyi D, Ansar Ahmed S. Characterization of estrogen-induced autoantibodies to cardiolipin in non-autoimmune mice. J Autoimmun 1997; 10(2): 115-25.
  190. Latham KA, Zamora A, Drought H, Subramanian S, Matejuk A, Offner H, Rosloniec EF. Estradiol treatment redirects the isotype of the autoantibody response and prevents the development of autoimmune arthritis. J Immunol 2003; 171(11): 5820-7.
  191. Jager A, Kuchroo VK. Effector and regulatory T-cell subsets in autoimmunity and tissue inflammation. Scand J Immunol 2010; 72(3): 173-84.
  192. Voskuhl RR. Gender issues and multiple sclerosis. Curr Neurol Neurosci Rep 2002; 2(3): 277-86.
  193. Lassmann H, Bruck W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol 2007; 17(2): 210-8.
  194. Holmqvist P, Wallberg M, Hammar M, Landtblom AM, Brynhildsen J. Symptoms of multiple sclerosis in women in relation to sex steroid exposure. Maturitas 2006; 54(2): 149-53.
  195. Zorgdrager A, De KJ. The premenstrual period and exacerbations in multiple sclerosis. Eur Neurol 2002; 48(4): 204-6.
  196. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med 1998; 339(5): 285-91.
  197. Korn-Lubetzki I, Kahana E, Cooper G, Abramsky O. Activity of multiple sclerosis during pregnancy and puerperium. Ann Neurol 1984; 16(2): 229-31.
  198. Smith R, Studd JW. A pilot study of the effect upon multiple sclerosis of the menopause, hormone replacement therapy and the menstrual cycle. J R Soc Med 1992; 85(10): 612-3.
  199. van den Broek HH, Damoiseaux JG, De Baets MH, Hupperts RM. The influence of sex hormones on cytokines in multiple sclerosis and experimental autoimmune encephalomyelitis: a review. Mult Scler 2005; 11(3): 349-59.
  200. Gilmore W, Weiner LP, Correale J. Effect of estradiol on cytokine secretion by proteolipid protein-specific T cell clones isolated from multiple sclerosis patients and normal control subjects. J Immunol 1997; 158(1): 446-51.
  201. Lelu K, Delpy L, Robert V, Foulon E, Laffont S, Pelletier L et al. Endogenous estrogens, through estrogen receptor alpha, constrain autoimmune inflammation in female mice by limiting CD4+ T-cell homing into the CNS. Eur J Immunol 2010; 40(12): 3489-98.
  202. Polanczyk MJ, Hopke C, Huan J, Vandenbark AA, Offner H. Enhanced FoxP3 expression and Treg cell function in pregnant and estrogen-treated mice. J Neuroimmunol 2005; 170(1-2): 85-92.
  203. Matejuk A, Bakke AC, Hopke C, Dwyer J, Vandenbark AA, Offner H. Estrogen treatment induces a novel population of regulatory cells, which suppresses experimental autoimmune encephalomyelitis. J Neurosci Res 2004; 77(1): 119-26.
  204. Subramanian S, Yates M, Vandenbark AA, Offner H. Oestrogen-mediated protection of experimental autoimmune encephalomyelitis in the absence of Foxp3(+) regulatory T cells implicates compensatory pathways including regulatory B cells. Immunology 2010.
  205. Polanczyk MJ, Jones RE, Subramanian S, Afentoulis M, Rich C, Zakroczymski M et al. T lymphocytes do not directly mediate the protective effect of estrogen on experimental autoimmune encephalomyelitis. Am J Pathol 2004; 165(6): 2069-77.
  206. Yu HJ, Fei J, Chen XS, Cai QY, Liu HL, Liu GD, Yao ZX. Progesterone attenuates neurological behavioral deficits of experimental autoimmune encephalomyelitis through remyelination with nucleus-sublocalized Olig1 protein. Neurosci Lett 2010; 476(1): 42-5.
  207. Yates MA, Li Y, Chlebeck P, Proctor T, Vandenbark AA, Offner H. Progesterone treatment reduces disease severity and increases IL-10 in experimental autoimmune encephalomyelitis. J Neuroimmunol 2010; 220(1-2): 136-9.
  208. Garay L, Deniselle MC, Meyer M, Costa JJ, Lima A, Roig P, De nicola AF. Protective effects of progesterone administration on axonal pathology in mice with experimental autoimmune encephalomyelitis. Brain Res 2009; 1283: 177-85.
  209. Garay L, Deniselle MC, Lima A, Roig P, De nicola AF. Effects of progesterone in the spinal cord of a mouse model of multiple sclerosis. J Steroid Biochem Mol Biol 2007; 107(3-5): 228-37.
  210. Nicot A. Gender and sex hormones in multiple sclerosis pathology and therapy. Front Biosci 2009; 14: 4477-515.
  211. Offner H, Zamora A, Drought H, Matejuk A, Auci DL, Morgan EE et al. A synthetic androstene derivative and a natural androstene metabolite inhibit relapsing-remitting EAE. J Neuroimmunol 2002; 130(1-2): 128-39.
  212. Du C, Khalil MW, Sriram S. Administration of dehydroepiandrosterone suppresses experimental allergic encephalomyelitis in SJL/J mice. J Immunol 2001; 167(12): 7094-101.
  213. Dalal M, Kim S, Voskuhl RR. Testosterone therapy ameliorates experimental autoimmune encephalomyelitis and induces a T helper 2 bias in the autoantigen-specific T lymphocyte response. J Immunol 1997; 159(1): 3-6.
  214. Bebo BF, Jr., Zelinka-Vincent E, Adamus G, Amundson D, Vandenbark AA, Offner H. Gonadal hormones influence the immune response to PLP 139-151 and the clinical course of relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol 1998; 84(2): 122-30.
  215. Melgert BN, Postma DS. All men are created equal?: new leads in explaining sex differences in adult asthma. Proc Am Thorac Soc 2009; 6(8): 724-7.
  216. Melgert BN, Ray A, Hylkema MN, Timens W, Postma DS. Are there reasons why adult asthma is more common in females? Curr Allergy Asthma Rep 2007; 7(2): 143-50.
  217. Chen W, Mempel M, Schober W, Behrendt H, Ring J. Gender difference, sex hormones, and immediate type hypersensitivity reactions. Allergy 2008; 63(11): 1418-27.
  218. Salam MT, Wenten M, Gilliland FD. Endogenous and exogenous sex steroid hormones and asthma and wheeze in young women. J Allergy Clin Immunol 2006; 117(5): 1001-7.
  219. Varraso R, Siroux V, Maccario J, Pin I, Kauffmann F. Asthma severity is associated with body mass index and early menarche in women. Am J Respir Crit Care Med 2005; 171(4): 334-9.
  220. Vrieze A, Postma DS, Kerstjens HA. Perimenstrual asthma: a syndrome without known cause or cure. J Allergy Clin Immunol 2003; 112(2): 271-82.
  221. Skobeloff EM, Spivey WH, Silverman R, Eskin BA, Harchelroad F, Alessi TV. The effect of the menstrual cycle on asthma presentations in the emergency department. Arch Intern Med 1996; 156(16): 1837-40.
  222. Ensom MH, Chong G, Zhou D, Beaudin B, Shalansky S, Bai TR. Estradiol in premenstrual asthma: a double-blind, randomized, placebo-controlled, crossover study. Pharmacotherapy 2003; 23(5): 561-71.
  223. Gluck JC. The change of asthma course during pregnancy. Clin Rev Allergy Immunol 2004; 26(3): 171-80.
  224. Lange P, Parner J, Prescott E, Ulrik CS, Vestbo J. Exogenous female sex steroid hormones and risk of asthma and asthma-like symptoms: a cross sectional study of the general population. Thorax 2001; 56(8): 613-6.
  225. Troisi RJ, Speizer FE, Willett WC, Trichopoulos D, Rosner B. Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma. A prospective cohort study. Am J Respir Crit Care Med 1995; 152(4 Pt 1): 1183-8.
  226. Barr RG, Wentowski CC, Grodstein F, Somers SC, Stampfer MJ, Schwartz J et al. Prospective study of postmenopausal hormone use and newly diagnosed asthma and chronic obstructive pulmonary disease. Arch Intern Med 2004; 164(4): 379-86.
  227. Gomez RF, Svanes C, Bjornsson EH, Franklin KA, Gislason D, Gislason T et al. Hormone replacement therapy, body mass index and asthma in perimenopausal women: a cross sectional survey. Thorax 2006; 61(1): 34-40.
  228. Siroux V, Curt F, Oryszczyn MP, Maccario J, Kauffmann F. Role of gender and hormone-related events on IgE, atopy, and eosinophils in the Epidemiological Study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy. J Allergy Clin Immunol 2004; 114(3): 491-8.
  229. Hellings PW, Vandekerckhove P, Claeys R, Billen J, Kasran A, Ceuppens JL. Progesterone increases airway eosinophilia and hyper-responsiveness in a murine model of allergic asthma. Clin Exp Allergy 2003; 33(10): 1457-63.
  230. Ligeiro de Oliveira AP, Oliveira-Filho RM, da Silva ZL, Borelli P, Tavares de LW. Regulation of allergic lung inflammation in rats: interaction between estradiol and corticosterone. Neuroimmunomodulation 2004; 11(1): 20-7.
  231. Riffo-Vasquez Y, Ligeiro de Oliveira AP, Page CP, Spina D, Tavares-de-Lima W. Role of sex hormones in allergic inflammation in mice. Clin Exp Allergy 2007; 37(3): 459-70.
  232. Dimitropoulou C, Drakopanagiotakis F, Chatterjee A, Snead C, Catravas JD. Estrogen replacement therapy prevents airway dysfunction in a murine model of allergen-induced asthma. Lung 2009; 187(2): 116-27.
  233. de Oliveira AP, Domingos HV, Cavriani G, Damazo AS, Dos Santos Franco AL, Oliani SM et al. Cellular recruitment and cytokine generation in a rat model of allergic lung inflammation are differentially modulated by progesterone and estradiol. Am J Physiol Cell Physiol 2007; 293(3): C1120-C1128.
  234. de Oliveira AP, Peron JP, Damazo AS, Franco AL, Domingos HV, Oliani SM et al. Female sex hormones mediate the allergic lung reaction by regulating the release of inflammatory mediators and the expression of lung E-selectin in rats. Respir Res 2010; 11: 115.
  235. Yu CK, Liu YH, Chen CL. Dehydroepiandrosterone attenuates allergic airway inflammation in Dermatophagoides farinae-sensitized mice. J Microbiol Immunol Infect 2002; 35(3): 199-202.
  236. Hayashi T, Adachi Y, Hasegawa K, Morimoto M. Less sensitivity for late airway inflammation in males than females in BALB/c mice. Scand J Immunol 2003; 57(6): 562-7.
  237. Okuyama K, Wada K, Chihara J, Takayanagi M, Ohno I. Sex-related splenocyte function in a murine model of allergic asthma. Clin Exp Allergy 2008; 38(7): 1212-9.
  238. Melgert BN, Oriss TB, Qi Z, xon-McCarthy B, Geerlings M, Hylkema MN, Ray A. Macrophages: regulators of sex differences in asthma? Am J Respir Cell Mol Biol 2010; 42(5): 595-603.
  239. Melgert BN, Postma DS, Kuipers I, Geerlings M, Luinge MA, van der Strate BW et al. Female mice are more susceptible to the development of allergic airway inflammation than male mice. Clin Exp Allergy 2005; 35(11): 1496-503.

    Related stories you may like: Pregnancy and arthritis activity
    Sex steroids hormones and autoimmunity
    Testosterone protection against arthritis

Source: Cover Image Credit:;

You must be logged in to post a comment Login