**2. The neuroendocrine axis in systemic lupus erythematosus**

SLE is a systemic autoimmune disease characterized by a loss of self-tolerance [15]. The immune system is activated in the disease and pro-inflammatory cytokines are secreted [16]. The immune system and the neuroendocrine system are interconnected [17]. The two systems interact in a bidirectional manner (**Figure 2**). During the autoimmune inflammatory response cytokines released from immune cells affect the neuroendocrine axis [18, 19]. In turn the neuroendocrine system secretes hormones which modulate the immune response [20].

The main target of activation by cytokines is the hypothalamic–pituitary– adrenal (HPA) axis. Interleukin (IL) -1a and -1b, IL-6 and tumor necrosis factor (TNF)-a, which are released sequentially from macrophages upon activation, are powerful activators of the HPA axis. In vitro studies in isolated hypothalamic tissue have shown the ability of IL-1a, IL-1b, IL-6, IL-8 and TNF-a to initiate the release of corticotropin-releasing hormone (CRH) [21, 22]. In humans, a blunted HPA axis response to stimulation with hypoglycemia or CRH was shown in several autoimmune diseases, including rheumatoid arthritis, Sjogren's syndrome, fibromyalgia and SLE [23]. However, the relationship between HPA axis reactivity

**65**

tive B lymphocytes [29].

**2.1 Stress and systemic lupus erythematosus**

*Endocrine Manifestations of Systemic Lupus Erythematosus*

and inflammatory disease was challenged by experiments which showed that in high-stress situations, rats who had a robust corticosterone-response to stress developed more severe inflammation than rats who had a less profound corticosterone response [24]. Differences in the HPA axis response to stress may discriminate patients who seem to have the same disease, but may have different responses to treatment [25]. The HPA axis in important in regulating disease severity in SLE. However, the development of the disease may alter the HPA axis response.

*The interaction between the neuroendocrine and immune systems in systemic lupus erythematosus.*

Prolactin (PRL) is a peptide hormone produced by the anterior pituitary. PRL can be produced by lymphocytes, which in turn express PRL receptors [26, 27]. Thus, PRL may have immunomodulatory functions [27–29]. Increased PRL levels have been observed in male and female patients with lupus [30, 31]. Furthermore, suppression of PRL secretion with bromocriptine provides beneficial effects in murine lupus and possibly in lupus patients [32]. Treatment with PRL breaks tolerance and induces a lupus like illness in autoimmune mice. PRL is in effect also a cytokine [29]. PRL receptors are distributed in the immune system [33]. Mild and moderate hyperprolactinemia has been demonstrated in 20–30% of SLE patients and was associated with active disease. Hyperprolactinemia may have a role in lupus nephritis and CNS involvement of patients who have SLE [34]. Elevated PRL levels were associated with increased disease activity in SLE and prolactin may have a pathogenic role in SLE [35]. Thus, PRL, a peptide hormone derived from the anterior pituitary gland and lymphocytes participates in the regulation of the immune response, stimulates immune cells and belongs to a network of immune endocrine interaction. Hyperprolactinemia has been found in SLE and PRL may participate in SLE activation during pregnancy [35]. High levels of prolactin may lead to the development or the exacerbation of an autoimmune disease such as SLE [36]. Prolactin is a bioactive hormone acting both as a hormone as well as a cytokine and it may act as an immunomodulator affecting the negative selection of autoreac-

The adrenergic nervous system runs from the CNS to lymphoid organs, namely the thymus, spleen and lymph nodes. Its effects are mediated by noradrenaline which acts through the relevant receptors [37]. Noradrenaline receptors are expressed by immune cells, namely T and B lymphocytes and macrophages [38]. Noradrenaline and adrenaline stimulate IL-10 and transforming growth factor-b production, thus enhancing Th2 immunity [39, 40]. In SLE, a disease driven by

*DOI: http://dx.doi.org/10.5772/intechopen.97363*

**Figure 2.**

*Endocrine Manifestations of Systemic Lupus Erythematosus DOI: http://dx.doi.org/10.5772/intechopen.97363*

#### **Figure 2.**

*Lupus - Need to Know*

**Figure 1.**

many different autoantibodies, SLE is classified as a "B-cell disease." Patients with SLE present with symptoms and inflammatory involvement that can affect virtually every organ [11]. The main features of SLE include the production of antinuclear antibodies and the deposition of immune complexes in basement membranes throughout the body where they induce an inflammatory response [12, 13]. Genetic, epigenetic, and environmental factors contribute to the development of this autoimmune process. Endocrine manifestations as expected also occur in patients with systemic lupus erythematosus [14] (**Figure 1**). Hypothyroidism has been observed in a higher rate than that expected in the general population. Hyperthyroidism has also been observed. Autoimmune Hashimoto's thyroiditis has been observed in a higher rate than that expected in the general population. Graves' disease has been observed in patients with SLE. Hyperparathyroidism has been observed in patients with SLE, mainly in the context of lupus nephritis. Hypoparathyroidism has also been observed. Autoimmune oophoritis leading to ovarian failure has been observed in patients with SLE. Despite the multisystem nature of the disease, it appears that it

*Common endocrine disorders in systemic lupus erythematosus.*

respects the adrenals, so that Addison's disease is extremely rare in SLE.

**2. The neuroendocrine axis in systemic lupus erythematosus**

secretes hormones which modulate the immune response [20].

SLE is a systemic autoimmune disease characterized by a loss of self-tolerance [15]. The immune system is activated in the disease and pro-inflammatory cytokines are secreted [16]. The immune system and the neuroendocrine system are interconnected [17]. The two systems interact in a bidirectional manner (**Figure 2**). During the autoimmune inflammatory response cytokines released from immune cells affect the neuroendocrine axis [18, 19]. In turn the neuroendocrine system

The main target of activation by cytokines is the hypothalamic–pituitary– adrenal (HPA) axis. Interleukin (IL) -1a and -1b, IL-6 and tumor necrosis factor (TNF)-a, which are released sequentially from macrophages upon activation, are powerful activators of the HPA axis. In vitro studies in isolated hypothalamic tissue have shown the ability of IL-1a, IL-1b, IL-6, IL-8 and TNF-a to initiate the release of corticotropin-releasing hormone (CRH) [21, 22]. In humans, a blunted HPA axis response to stimulation with hypoglycemia or CRH was shown in several autoimmune diseases, including rheumatoid arthritis, Sjogren's syndrome, fibromyalgia and SLE [23]. However, the relationship between HPA axis reactivity

**64**

*The interaction between the neuroendocrine and immune systems in systemic lupus erythematosus.*

and inflammatory disease was challenged by experiments which showed that in high-stress situations, rats who had a robust corticosterone-response to stress developed more severe inflammation than rats who had a less profound corticosterone response [24]. Differences in the HPA axis response to stress may discriminate patients who seem to have the same disease, but may have different responses to treatment [25]. The HPA axis in important in regulating disease severity in SLE. However, the development of the disease may alter the HPA axis response.

Prolactin (PRL) is a peptide hormone produced by the anterior pituitary. PRL can be produced by lymphocytes, which in turn express PRL receptors [26, 27]. Thus, PRL may have immunomodulatory functions [27–29]. Increased PRL levels have been observed in male and female patients with lupus [30, 31]. Furthermore, suppression of PRL secretion with bromocriptine provides beneficial effects in murine lupus and possibly in lupus patients [32]. Treatment with PRL breaks tolerance and induces a lupus like illness in autoimmune mice. PRL is in effect also a cytokine [29]. PRL receptors are distributed in the immune system [33]. Mild and moderate hyperprolactinemia has been demonstrated in 20–30% of SLE patients and was associated with active disease. Hyperprolactinemia may have a role in lupus nephritis and CNS involvement of patients who have SLE [34]. Elevated PRL levels were associated with increased disease activity in SLE and prolactin may have a pathogenic role in SLE [35]. Thus, PRL, a peptide hormone derived from the anterior pituitary gland and lymphocytes participates in the regulation of the immune response, stimulates immune cells and belongs to a network of immune endocrine interaction. Hyperprolactinemia has been found in SLE and PRL may participate in SLE activation during pregnancy [35]. High levels of prolactin may lead to the development or the exacerbation of an autoimmune disease such as SLE [36]. Prolactin is a bioactive hormone acting both as a hormone as well as a cytokine and it may act as an immunomodulator affecting the negative selection of autoreactive B lymphocytes [29].

#### **2.1 Stress and systemic lupus erythematosus**

The adrenergic nervous system runs from the CNS to lymphoid organs, namely the thymus, spleen and lymph nodes. Its effects are mediated by noradrenaline which acts through the relevant receptors [37]. Noradrenaline receptors are expressed by immune cells, namely T and B lymphocytes and macrophages [38]. Noradrenaline and adrenaline stimulate IL-10 and transforming growth factor-b production, thus enhancing Th2 immunity [39, 40]. In SLE, a disease driven by

excess IL-10, disease activity may increase during states of high catecholamine release, such as acute stress. In a prospective study of patients with SLE, disease flares were associated with emotional stress or with the number or severity of daily stressors [41, 42]. Additionally, the effect of acute psychological stress induced differential immune response in SLE patients as compared to controls [43].

The hypothalamic–pituitary–adrenal axis responds to inflammatory cytokines [44]. It has been demonstrated that inflammatory cytokines, such as IL-1a and IL-1b, IL-6 and TNF-a are powerful activators of the hypothalamic–pituitary–adrenal axis [45, 46]. In SLE patients with central nervous system involvement elevated levels of inflammatory cytokines were observed in the cerebrospinal fluid [47] suggesting an involvement of these inflammatory cytokines in disease pathogenesis.

#### **2.2 Estrogens in the pathogenesis of systemic lupus erythematosus**

SLE is a disease affecting primarily female patients in the reproductive age [48]. Evidence exists implicating estrogens in the pathogenesis of SLE [49]. An extensive cross-talk takes place between estrogen and the immune system. Estrogens are a major modulating factor of the immune response [50] (**Figure 3**). Epidemiological evidence implicates estrogens in the pathogenesis of SLE, as during childhood where estrogen secretion is minimal the female: male ratio is 3:1 as opposed to 9:1 in the reproductive age. In the postmenopausal period the ratio is 8:1 [51]. Evidence has shown that women with early menarche, or treated with oral contraceptives or hormone replacement therapy have an increased risk for SLE [52, 53]. The presence of the X chromosome appears also to be important for the pathogenesis of SLE. There appears to be a gene dose effect, as the prevalence of SLE in Klinefelter's syndrome (XXY) is 14-fold that in the general male population, whereas it is decreased in female patients with Turner's syndrome (XO) [54]. Pregnancy, in which the concentration of estrogens is extremely increased can cause a disease flare or even trigger the development of lupus [55, 56]. The puerperium is characterized by an increased risk for disease relapse [57]. Hormonal factors used for ovulation induction and in vitro fertilization may cause disease flare in SLE [52].

The main pathophysiologic processes of SLE are the loss of self-tolerance and the production of autoantibodies with consequent inflammatory response and organ injury [15]. Estrogens are capable of inducing these alterations in the immune system. Treg cells, immunosuppressive regulatory T cells, play an important role in the maintenance of self-tolerance and the prevention of autoimmunity. SLE

**67**

*Endocrine Manifestations of Systemic Lupus Erythematosus*

patients have decreased numbers of Treg cells. Estradiol diminishes Treg cells [52, 58, 59]. In SLE, there is a switch from a type 1 (Th1) to a type 2 (Th2) T cell response where serum levels of Th2 cytokines, such as interleukin 4 (IL-4), IL-6, and IL-10, are elevated and there is decreased production of Th1 cytokines, such as IL-2 and interferon γ [60–62]. Estrogens alter Th1/Th2 ratio thus altering the balance between cellular and humoral immunity. Estrogens induce the development of Th2 lymphocytes and B cell hyperactivity leading to enhanced antibody production [63]. Estrogens promote the life span of lymphocytes by decreasing apoptosis of T and B cells [64]. Thus, estrogens seem to play a key role in the development of autoimmunity. They suppress self-tolerance reducing Treg cells [65]. They alter the Th1/Th2 ratio, favoring the predominance of humoral immunity. They prevent the deletion of autoreactive B cells [66]. They induce the generation of autoantibodies

and they stimulate the production of inflammatory cytokines [67].

**3. Endocrine disorders in systemic lupus erythematosus**

Autoimmune thyroid disease has been observed in patients with systemic lupus erythematosus, such as autoimmune Hashimoto's thyroiditis, hypothyroidism and

Hypothyroidism is observed in patients with SLE in a higher rate than in the normal population. In particular, Munoz and Isenberg [14] reported a rate of 5.22% hypothyroidism, i.e. 37 patients, in their cohort of 708 patients with SLE in University College of London Hospital, as compared to 1–2% in the general UK population. In this cohort the onset of hypothyroidism occurred after the onset of SLE oftener. Other reports confirmed a higher than in the general population rate of hypothyroidism in SLE. In particular, Ong and Choy [68] in a Malaysian population of SLE patients observed a prevalence of hypothyroidism of 3.7%. Antonelli et al. [69] reported a prevalence of hypothyroidism of 4.5%. In an earlier report from the University College of London Hospital SLE cohort Pyne and Isenberg [70] reported

Hyperthyroidism is observed in patients with SLE. In their cohort of 708 patients with SLE Munoz and Isenberg [14] observed a prevalence of hyperthyroidism of 1.41% (10/708 SLE patients), similar to that in the general population [71]. Watad *et al* [72] and Ong *et al* [68] reported a prevalence of hyperthyroidism in SLE patients of 2.59% and 2.6%, respectively. Chan *et al* [73] observed a prevalence of 5.8% of hyperthyroidism in a study of 69 SLE patients. However, only 2.9% had a

Autoimmune Hashimoto's thyroiditis is frequently observed in patients with SLE. The prevalence of Hashimoto's thyroiditis in patients with SLE as opposed to control subjects was investigated in a study [74]. The association of Hashinoto's Hashimoto's thyroiditis and anti-thyroid antibodies to the clinical, serological

*DOI: http://dx.doi.org/10.5772/intechopen.97363*

**3.1 Thyroid disease in SLE**

a prevalence of hypothyroidism of 5.7%.

*3.1.3 Autoimmune Hashimoto's thyroiditis*

Graves' disease.

*3.1.1 Hypothyroidism*

*3.1.2 Hyperthyroidism*

clinical hyperthyroidism.

**Figure 3.** *The effect of estrogens on the immune system.*

*Endocrine Manifestations of Systemic Lupus Erythematosus DOI: http://dx.doi.org/10.5772/intechopen.97363*

patients have decreased numbers of Treg cells. Estradiol diminishes Treg cells [52, 58, 59]. In SLE, there is a switch from a type 1 (Th1) to a type 2 (Th2) T cell response where serum levels of Th2 cytokines, such as interleukin 4 (IL-4), IL-6, and IL-10, are elevated and there is decreased production of Th1 cytokines, such as IL-2 and interferon γ [60–62]. Estrogens alter Th1/Th2 ratio thus altering the balance between cellular and humoral immunity. Estrogens induce the development of Th2 lymphocytes and B cell hyperactivity leading to enhanced antibody production [63]. Estrogens promote the life span of lymphocytes by decreasing apoptosis of T and B cells [64]. Thus, estrogens seem to play a key role in the development of autoimmunity. They suppress self-tolerance reducing Treg cells [65]. They alter the Th1/Th2 ratio, favoring the predominance of humoral immunity. They prevent the deletion of autoreactive B cells [66]. They induce the generation of autoantibodies and they stimulate the production of inflammatory cytokines [67].
