Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affecting all organ systems. It affects primarily female patients in the reproductive age. The disease has a variable course from very mild to severe and may be fatal. It is characterized by exacerbations of disease activity called flares. Estrogens seem to be involved in SLE pathogenesis as they have multiple immunomodulating properties. In SLE the autoimmune process affects the neuroendocrine axis. Stress modulates disease expression in lupus patients. The disease affects the endocrine system. Hypothyroidism occurs in SLE patients in a higher rate than that of the general population. Hyperthyroidism is also observed in SLE, however, in the rate expected for the general population. Hashimoto’s thyroiditis is observed in SLE in a higher rate than that of the general population. Hyperparathyroidism is also observed in SLE, primary and secondary in the context of renal insufficiency due to lupus nephritis. Addison’s disease is rare in SLE. Cushing’s disease due to an adrenal adenoma has been observed, but it is rare. Ovarian function may be compromised in SLE, due to autoimmune oophoritis or drug toxicity. The recognition of endocrine disease in SLE is important as it may guide proper management and symptom amelioration.
- systemic lupus erythematosus
- neuroendocrine axis
- Hashimoto’s thyroiditis
- ovarian function
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affecting all organ systems . It affects mainly joints, skin, blood vessels, heart, lung, kidneys, liver and the nervous system . It is the prototype of systemic autoimmune diseases. In patients with SLE the immune system attacks tissues and cells leading to inflammation and damage . The course of SLE is variable, and maybe either mild or severe leading sometimes to fatal damage and death . The disease is characterized by periods of exacerbation, which are called flares and periods of remission . SLE occurs nine times more often in the female gender mainly in the reproductive age, and it is more frequent in people of non-European descent . Different types of autoantibodies are present in SLE patients . The B lymphocyte is believed to play a major pathogenic role in the disease and many different autoantibodies are detected, therefore the disease is classified as a “B-cell disease” [8, 9]. However, T lymphocytes also play a role in the immunopathogenesis of SLE . Because of the presence of 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 . 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  (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 respects the adrenals, so that Addison’s disease is extremely rare in SLE.
2. The neuroendocrine axis in systemic lupus erythematosus
SLE is a systemic autoimmune disease characterized by a loss of self-tolerance . The immune system is activated in the disease and pro-inflammatory cytokines are secreted . The immune system and the neuroendocrine system are interconnected . 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 .
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 . However, the relationship between HPA axis reactivity 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 . 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 . 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, 28, 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 . Treatment with PRL breaks tolerance and induces a lupus like illness in autoimmune mice. PRL is in effect also a cytokine . PRL receptors are distributed in the immune system . 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 . Elevated PRL levels were associated with increased disease activity in SLE and prolactin may have a pathogenic role in SLE . 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 . High levels of prolactin may lead to the development or the exacerbation of an autoimmune disease such as SLE . 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 .
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 . Noradrenaline receptors are expressed by immune cells, namely T and B lymphocytes and macrophages . 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 .
The hypothalamic–pituitary–adrenal axis responds to inflammatory cytokines . 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  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 . Evidence exists implicating estrogens in the pathogenesis of SLE . An extensive cross-talk takes place between estrogen and the immune system. Estrogens are a major modulating factor of the immune response  (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 . 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) . 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 . Hormonal factors used for ovulation induction and in vitro fertilization may cause disease flare in SLE .
The main pathophysiologic processes of SLE are the loss of self-tolerance and the production of autoantibodies with consequent inflammatory response and organ injury . 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 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, 61, 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 . Estrogens promote the life span of lymphocytes by decreasing apoptosis of T and B cells . Thus, estrogens seem to play a key role in the development of autoimmunity. They suppress self-tolerance reducing Treg cells . They alter the Th1/Th2 ratio, favoring the predominance of humoral immunity. They prevent the deletion of autoreactive B cells . They induce the generation of autoantibodies and they stimulate the production of inflammatory cytokines .
3. Endocrine disorders in systemic lupus erythematosus
3.1 Thyroid disease in SLE
Autoimmune thyroid disease has been observed in patients with systemic lupus erythematosus, such as autoimmune Hashimoto’s thyroiditis, hypothyroidism and Graves’ disease.
Hypothyroidism is observed in patients with SLE in a higher rate than in the normal population. In particular, Munoz and Isenberg  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  in a Malaysian population of SLE patients observed a prevalence of hypothyroidism of 3.7%. Antonelli et al.  reported a prevalence of hypothyroidism of 4.5%. In an earlier report from the University College of London Hospital SLE cohort Pyne and Isenberg  reported a prevalence of hypothyroidism of 5.7%.
Hyperthyroidism is observed in patients with SLE. In their cohort of 708 patients with SLE Munoz and Isenberg  observed a prevalence of hyperthyroidism of 1.41% (10/708 SLE patients), similar to that in the general population . Watad
3.1.3 Autoimmune Hashimoto’s thyroiditis
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 . The association of Hashinoto’s Hashimoto’s thyroiditis and anti-thyroid antibodies to the clinical, serological profile and disease activity as well as cumulative organ damage in this group was also investigated. In a group of 301 SLE patients and 141 controls TSH levels, T4 levels, antiTg antibodies and antiTPO antibodies were measured by chemiluminescence and immunometric methods. The serological and clinical profile of the patients was reviewed. SLE disease activity was measured using the SLEDAI index. The prevalence of Hashimoto’s thyroiditis was 12.6% in SLE as opposed to 5.6% in controls, the difference being statistically significant. A lower prevalence of malar rash and a higher prevalence of anti-Sm was noted in lupus patients with Hashimoto’s thyroiditis. No association was noted between Hashimoto’s thyroiditis and disease activity of cumulative organ damage. In conclusion, a two-fold increased risk of Hashimoto’s thyroiditis was noted in lupus patients. In a study performed in China 63 cases of lupus patients who also had Hashimoto’s thyroiditis were studied . Lupus patients were classified in four groups, those in remission, those with low disease activity, those with moderate and those with high disease activity. Free T3 levels were found to be negatively correlated with disease activity. In an effort to find a way to treat effectively Hashimoto’s thyroiditis and SLE a group of scientists  injected human amniotic epithelial cells in murine models of Hashimoto’s thyroiditis and SLE. They observed that levels of antiTg, antiTPO antibodies and TSH levels decreased as well as evidence of tissue destruction within the thyroid decreased. Additionally, the injection of human amniotic epithelial cells induced the disappearance of antidsDNA antibodies and ANA in mice with SLE and improved immunoglobulin profiles. It downregulated the ratio of Th17/Treg cells in both Hashimoto thyroiditis and SLE mice and upregulated the proportion of B10 cells. Human epithelial amniotic cells suppressed the levels of pro-inflammatory cytokines, IL-17A and IFN-γ and enhanced TGF-β in the murine models of Hashimoto’s thyroiditis and SLE, thus suggesting a common pathogenic substrate in both diseases.
3.1.4 Graves’ disease
Graves’ disease is a systemic autoimmune disease with multiple manifestations, affecting the thyroid, the eyes and the skin . Cases of Graves’ disease have been described in patients with SLE . The case of a patient with Graves’ disease who later developed SLE has been described in the literature .
3.2 Pancreatic dysfunction in SLE pathogenesis and form
3.2.1 Diabetes mellitus 1
Cases of diabetes mellitus 1 have been described in SLE. In a cohort of SLE patients in the UK the prevalence of diabetes mellitus 1 was investigated . The coexistence of diabetes mellitus 1, SLE and celiac disease has been described in a young female patient . It appears that diabetes mellitus 1 is rare among SLE patients. However, the risk of developing renal disease, retinal disease and peripheral neuropathy requires careful follow up of the patients. It is also important for the physician to decide which complication is due to lupus or diabetes as the management is different.
3.2.2 Diabetes mellitus 2
Diabetes mellitus type 2 is reported with increasing frequency nowadays . Hence, diabetes mellitus 2 has been reported in patients with SLE. In their cohort of 485 SLE patients Cortes et al.  reported 4 patients with diabetes mellitus 2 and two considered to have steroid induced diabetes mellitus. Thus, it appears that diabetes mellitus 2 is infrequent within lupus patients. This may be due to the fact, that lupus develops in a younger age than diabetes mellitus 2 . The relationship between SLE and gestational diabetes has been studied in a meta-analysis . It was found that SLE does not seem to increase the risk of gestational diabetes. However, steroid use in SLE may increase the risk of gestational diabetes.
3.3 Parathyroid disease in SLE
Primary hyperparathyroidism is frequently recognized nowadays due to the routine measurement of serum calcium levels. Primary hyperparathyroidism has been reported in patients with lupus. However, there are just a few case reports in the literature of patients with SLE and primary hyperparathyroidism. Primary hyperparathyroidism due to the presence of a parathyroid adenoma in a 47-year old female patient with SLE has been described . Hypercalcemia resolved in this patient after removal of the adenoma. Primary hyperparathyroidism due to a cystic parathyroid adenoma has also been described in a 62-year old female patient with SLE . In their cohort of 708 lupus patients Munoz and Isenberg  also identified 5 (0.70%) patients with hyperparathyroidism, 1 with primary hyperparathyroidism and 4 patients with secondary hyperparathyroidism in the context of chronic renal failure due to lupus nephritis. Hyperparathyroidism presented after lupus in all cases described.
3.4 Adrenal disease in SLE
3.4.1 Addison’s disease
Addison’s disease has been reported in patients with SLE. However, there are only a few case reports of Addison’s disease in patients with SLE. The case of a 29-year old female patient who presented with Addisonian crisis in the presence of SLE and responded therapeutically to corticosteroids, both as far as Addison’s and lupus is concerned has been described . In their cohort of lupus patients Munoz and Isenberg  did not identify any patient with Addison’s disease. It appears that Addison’s disease is a rare occurrence in lupus patients.
3.4.2 Cushing’s syndrome
The occurrence of Cushing’s syndrome due to an adrenal adenoma in patients with SLE is rare. The case of an 18-year old female patient with subclinical Cushing’s syndrome who developed lupus has been described . The patient was successfully treated by surgical removal of the adrenal adenoma. A case of a 51-year old woman with SLE who developed Cushing’s syndrome and was found to have a left adrenal adenoma has been described . The patient was successfully managed by laparascopic left adrenalectomy.
4. Ovarian function
Reproductive function of young female patients with SLE is commonly perturbed by various pathophysiologic mechanisms . Ovarian reserve is diminished even in the presence of mild lupus suggesting a direct effect of the disease itself on ovarian function [90, 91] (Figure 4). It is possible that the underlying process is autoimmune oophoritis [92, 93, 94]. The clinical manifestations of these abnormalities are menstrual irregularity, amenorrhea, or premature ovarian failure. Menstrual irregularities are frequently observed in patients with SLE, and many of them are associated with the activity of the disease . SLE itself induces dysfunction in the hypothalamic–pituitary-ovarian axis and elevates serum prolactin [35, 96, 97]. A study compared the levels of anti–müllerian hormone (AMH) as a marker of ovarian reserve between SLE patients and control subjects and found that SLE patients had significantly lower AMH levels than did the control subjects. No correlation was observed between disease activity and AMH levels . Female SLE patients may have subfertility issues due to active disease, the use of immunosuppressive medications and delayed childbearing . These findings show that SLE itself has a negative influence on ovarian reserve and function.
SLE patients presenting with severe manifestations of the disease are treated with the alkylating agent cyclophosphamide [99, 100]. Cyclophosphamide is toxic to the ovaries [101, 102, 103]. SLE patients exposed to cyclophosphamide have a much higher risk of developing premature ovarian failure and infertility as compared to those receiving less toxic agents [91, 95, 104]. Cyclophosphamide leads to a decrease in reproductive life span and possibly premature ovarian failure. If the loss of ovarian function develops during or shortly after the completion of therapy, it is termed acute ovarian failure. For those who retain ovarian function after the completion of chemotherapy, a subset will go on to develop premature menopause before the age of 40 . The clinical manifestations of ovarian damage in women at reproductive age vary from temporary irregular menses to amenorrhea, infertility, and premature ovarian failure depending on the magnitude of the damage. The probability of developing permanent ovarian failure depends on the following factors: patient’s age and the type, dose, and duration of the treatment. If the patient is older and her ovarian reserve is low, they are less likely to retain or regain menstrual function than younger ones. Studies have documented that cyclophosphamide administration is the most significant risk factor for ovarian failure and that AMH is a sensitive and reliable marker of ovarian reserve and damage after exposure to cyclophosphamide in female patients with SLE [106, 107, 108]. In the case of cyclophosphamide administration in lupus patients fertility preservation may be attempted . Currently, embryo or oocyte freezing are the established methods used for fertility preservation in patients receiving gonadotoxic treatment [109, 110, 111]. Other options are ovarian tissue freezing and the use of gonadotropin-releasing (GnRH) hormone agonist treatment concurrently with chemotherapy [112, 113].
In conclusion, the reproductive function of female SLE patients can be adversely affected by various mechanisms such as, the chronic inflammatory state, autoimmune ovarian disease in the form of autoimmune oophoritis, lupus flares associated with hyperprolactinemia, which may interfere with ovulation and may modulate immune activity and temporary or even permanent premature ovarian failure as a result of the administration of cytotoxic agents such as cyclophosphamide.
SLE is a systemic autoimmune disease which affects all organ systems and occurs frequently in female patients in the reproductive period. Estrogens appear to modulate the immune response, induce loss of self-tolerance, alter the Th1/Th2 balance in favor of the Th2 process, induce the survival of T and B lymphocytes and the production of autoantibodies. Estrogens appear to be involved in the pathogenesis of SLE. In SLE neuroendocrine system function is affected by the autoimmune process, the neuroendocrine system affecting in turn the disease process. Stress appears to affect disease expression in lupus patients. In SLE hypothyroidism occurs oftener than in the general population, hyperthyroidism occurs in the same rate as in the general population and Hashimoto’s thyroiditis is present oftener than in a control population. Diabetes mellitus 1 occurs sometimes, diabetes mellitus 2 occurs less frequently than in the general population. Hyperparathyroidism has been observed in lupus patients. Addison’s disease is extremely rare in lupus patients. Cushing’s disease occurs infrequently in lupus patients. The ovarian function is affected in female SLE patients. Primary ovarian failure may occur due to autoimmune oophoritis. Cyclophosphamide in SLE is used and its use may be accompanied by the development of premature ovarian failure. The recognition of endocrine disease is important in SLE as symptoms may be similar to those of lupus, however management may be different. The recognition and treatment of an endocrine problem in SLE may guide treatment and lead to symptom amelioration and proper patient management.
Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis. Sep 2019;78(9):1151-1159. doi:10.1136/annrheumdis-2018-214819
Fava A, Petri M. Systemic lupus erythematosus: Diagnosis and clinical management. J Autoimmun. Jan 2019;96:1-13. doi:10.1016/j.jaut.2018.11.001
Durcan L, O'Dwyer T, Petri M. Management strategies and future directions for systemic lupus erythematosus in adults. Lancet. Jun 8 2019;393(10188):2332-2343. doi:10.1016/s0140-6736(19)30237-5
Tselios K, Gladman DD, Touma Z, Su J, Anderson N, Urowitz MB. Disease course patterns in systemic lupus erythematosus. Lupus. Jan 2019;28(1):114-122. doi:10.1177/0961203318817132
Schäfer VS, Weiß K, Krause A, Schmidt WA. Does erythrocyte sedimentation rate reflect and discriminate flare from infection in systemic lupus erythematosus? Correlation with clinical and laboratory parameters of disease activity. Clin Rheumatol. Jul 2018;37(7):1835-1844. doi:10.1007/s10067-018-4093-3
Gergianaki I, Bortoluzzi A, Bertsias G. Update on the epidemiology, risk factors, and disease outcomes of systemic lupus erythematosus. Best Pract Res Clin Rheumatol. Apr 2018;32(2):188-205. doi:10.1016/j.berh.2018.09.004
Tipton CM, Hom JR, Fucile CF, Rosenberg AF, Sanz I. Understanding B-cell activation and autoantibody repertoire selection in systemic lupus erythematosus: A B-cell immunomics approach. Immunol Rev. Jul 2018;284(1):120-131. doi:10.1111/imr.12660
Yap DYH, Chan TM. B Cell Abnormalities in Systemic Lupus Erythematosus and Lupus Nephritis-Role in Pathogenesis and Effect of Immunosuppressive Treatments. Int J Mol Sci. Dec 10 2019;20(24)doi:10.3390/ijms20246231
Ma K, Du W, Wang X, et al. Multiple Functions of B Cells in the Pathogenesis of Systemic Lupus Erythematosus. Int J Mol Sci. Nov 29 2019;20(23)doi:10.3390/ijms20236021
Makiyama A, Chiba A, Noto D, et al. Expanded circulating peripheral helper T cells in systemic lupus erythematosus: association with disease activity and B cell differentiation. Rheumatology (Oxford). Oct 1 2019;58(10):1861-1869. doi:10.1093/rheumatology/kez077
Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore). Sep 2003;82(5):299-308. doi:10.1097/01.md.0000091181.93122.55
Mistry P, Kaplan MJ. Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis. Clin Immunol. Dec 2017;185:59-73. doi:10.1016/j.clim.2016.08.010
Morel L. Immunometabolism in systemic lupus erythematosus. Nat Rev Rheumatol. May 2017;13(5):280-290. doi:10.1038/nrrheum.2017.43
Muñoz C, Isenberg DA. Review of major endocrine abnormalities in patients with systemic lupus erythematosus. Clin Exp Rheumatol. Sep-Oct 2019;37(5):791-796
Tsokos GC, Lo MS, Costa Reis P, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol. Nov 22 2016;12(12):716-730. doi:10.1038/nrrheum.2016.186
Kalsi JK, Grossman J, Kim J, et al. Peptides from antibodies to DNA elicit cytokine release from peripheral blood mononuclear cells of patients with systemic lupus erythematosus: relation of cytokine pattern to disease duration. Lupus. 2004;13(7):490-500. doi:10.1191/0961203303lu1060oa
Ashley NT, Demas GE. Neuroendocrine-immune circuits, phenotypes, and interactions. Horm Behav. Jan 2017;87:25-34. doi:10.1016/j.yhbeh.2016.10.004
Kim YK, Na KS, Myint AM, Leonard BE. The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression. Prog Neuropsychopharmacol Biol Psychiatry. Jan 4 2016;64:277-84. doi:10.1016/j.pnpbp.2015.06.008
Tsagarakis S, Gillies G, Rees LH, Besser M, Grossman A. Interleukin-1 directly stimulates the release of corticotrophin releasing factor from rat hypothalamus. Neuroendocrinology. Jan 1989;49(1):98-101. doi:10.1159/000125096
Bellavance MA, Rivest S. The neuroendocrine control of the innate immune system in health and brain diseases. Immunol Rev. Jul 2012;248(1):36-55. doi:10.1111/j.1600-065X.2012.01129.x
Turnbull AV, Rivier C. Regulation of the HPA axis by cytokines. Brain Behav Immun. Dec 1995;9(4):253-75. doi:10.1006/brbi.1995.1026
Turnbull AV, Rivier CL. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev. Jan 1999;79(1):1-71. doi:10.1152/physrev.1918.104.22.168
Silverman MN, Sternberg EM. Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction. Ann N Y Acad Sci. Jul 2012;1261:55-63. doi:10.1111/j.1749-6632.2012.06633.x
Chover-Gonzalez AJ, Jessop DS, Tejedor-Real P, Gibert-Rahola J, Harbuz MS. Onset and severity of inflammation in rats exposed to the learned helplessness paradigm. Rheumatology (Oxford). Jul 2000;39(7):764-71. doi:10.1093/rheumatology/39.7.764
Harbuz MS, Chover-Gonzalez AJ, Jessop DS. Hypothalamo-pituitary-adrenal axis and chronic immune activation. Ann N Y Acad Sci. May 2003;992:99-106. doi:10.1111/j.1749-6632.2003.tb03141.x
Recalde G, Moreno-Sosa T, Yúdica F, et al. Contribution of sex steroids and prolactin to the modulation of T and B cells during autoimmunity. Autoimmun Rev. May 2018;17(5):504-512. doi:10.1016/j.autrev.2018.03.006
Saha S, Tieng A, Pepeljugoski KP, Zandamn-Goddard G, Peeva E. Prolactin, systemic lupus erythematosus, and autoreactive B cells: lessons learnt from murine models. Clin Rev Allergy Immunol. Feb 2011;40(1):8-15. doi:10.1007/s12016-009-8182-6
Borba VV, Zandman-Goddard G, Shoenfeld Y. Prolactin and Autoimmunity. Front Immunol. 2018;9:73. doi:10.3389/fimmu.2018.00073
Borba VV, Zandman-Goddard G, Shoenfeld Y. Prolactin and autoimmunity: The hormone as an inflammatory cytokine. Best Pract Res Clin Endocrinol Metab. Dec 2019;33(6):101324. doi:10.1016/j.beem.2019.101324
Jacobi AM, Rohde W, Ventz M, Riemekasten G, Burmester GR, Hiepe F. Enhanced serum prolactin (PRL) in patients with systemic lupus erythematosus: PRL levels are related to the disease activity. Lupus. 2001;10(8):554-61. doi:10.1191/096120301701549688
Jacobi AM, Rohde W, Volk HD, Dörner T, Burmester GR, Hiepe F. Prolactin enhances the in vitro production of IgG in peripheral blood mononuclear cells from patients with systemic lupus erythematosus but not from healthy controls. Ann Rheum Dis. Mar 2001;60(3):242-7. doi:10.1136/ard.60.3.242
Walker SE. Treatment of systemic lupus erythematosus with bromocriptine. Lupus. 2001;10(3):197-202. doi:10.1191/096120301666625458
Leite De Moraes MC, Touraine P, Gagnerault MC, Savino W, Kelly PA, Dardenne M. Prolactin receptors and the immune system. Ann Endocrinol (Paris). 1995;56(6):567-70
Vera-Lastra O, Jara LJ, Espinoza LR. Prolactin and autoimmunity. Autoimmun Rev. Dec 2002;1(6):360-4. doi:10.1016/s1568-9972(02)00081-2
Jara LJ, Medina G, Saavedra MA, et al. Prolactin has a pathogenic role in systemic lupus erythematosus. Immunol Res. Apr 2017;65(2):512-523. doi:10.1007/s12026-016-8891-x
Vieira Borba V, Sharif K, Shoenfeld Y. Breastfeeding and autoimmunity: Programing health from the beginning. Am J Reprod Immunol. Jan 2018;79(1)doi:10.1111/aji.12778
Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. Dec 2000;52(4):595-638
Sharma D, Farrar JD. Adrenergic regulation of immune cell function and inflammation. Semin Immunopathol. Dec 2020;42(6):709-717. doi:10.1007/s00281-020-00829-6
Elenkov IJ, Papanicolaou DA, Wilder RL, Chrousos GP. Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications. Proc Assoc Am Physicians. Sep 1996;108(5):374-81
Elenkov IJ, Chrousos GP, Wilder RL. Neuroendocrine regulation of IL-12 and TNF-alpha/IL-10 balance. Clinical implications. Ann N Y Acad Sci. 2000;917:94-105. doi:10.1111/j.1749-6632.2000.tb05374.x
Da Costa D, Dobkin PL, Pinard L, et al. The role of stress in functional disability among women with systemic lupus erythematosus: a prospective study. Arthritis Care Res. Apr 1999;12(2):112-9. doi:10.1002/1529-0131(199904)12:2<112::aid-art6>3.0.co;2-2
Pawlak CR, Witte T, Heiken H, et al. Flares in patients with systemic lupus erythematosus are associated with daily psychological stress. Psychother Psychosom. May-Jun 2003;72(3):159-65. doi:10.1159/000069735
Pawlak CR, Jacobs R, Mikeska E, et al. Patients with systemic lupus erythematosus differ from healthy controls in their immunological response to acute psychological stress. Brain Behav Immun. Dec 1999;13(4):287-302. doi:10.1006/brbi.1999.0553
Szyper-Kravitz M, Zandman-Goddard G, Lahita RG, Shoenfeld Y. The neuroendocrine-immune interactions in systemic lupus erythematosus: a basis for understanding disease pathogenesis and complexity. Rheum Dis Clin North Am. Feb 2005;31(1):161-75, x. doi:10.1016/j.rdc.2004.10.004
Yasin SA, Costa A, Forsling ML, Grossman A. Interleukin-1 beta and interleukin-6 stimulate neurohypophysial hormone release in vitro. J Neuroendocrinol. Apr 1994;6(2):179-84. doi:10.1111/j.1365-2826.1994.tb00570.x
Kostoglou-Athanassiou I, Costa A, Navarra P, Nappi G, Forsling ML, Grossman AB. Endotoxin stimulates an endogenous pathway regulating corticotropin-releasing hormone and vasopressin release involving the generation of nitric oxide and carbon monoxide. Article. Journal of Neuroimmunology. Jun 1998;86(1):104-109. doi:10.1016/s0165-5728(98)00028-9
Baraczka K, Nékám K, Pozsonyi T, Szüts I, Ormos G. Investigation of cytokine (tumor necrosis factor-alpha, interleukin-6, interleukin-10) concentrations in the cerebrospinal fluid of female patients with multiple sclerosis and systemic lupus erythematosus. Eur J Neurol. Jan 2004;11(1):37-42. doi:10.1046/j.1351-5101.2003.00706.x
Margery-Muir AA, Bundell C, Nelson D, Groth DM, Wetherall JD. Gender balance in patients with systemic lupus erythematosus. Autoimmun Rev. Mar 2017;16(3):258-268. doi:10.1016/j.autrev.2017.01.007
Lahita RG. The importance of estrogens in systemic lupus erythematosus. Clin Immunol Immunopathol. Apr 1992;63(1):17-8. doi:10.1016/0090-1229(92)90086-4
Cutolo M, Capellino S, Sulli A, et al. Estrogens and autoimmune diseases. Ann N Y Acad Sci. Nov 2006;1089:538-47. doi:10.1196/annals.1386.043
Lahita RG. The role of sex hormones in systemic lupus erythematosus. Curr Opin Rheumatol. Sep 1999;11(5):352-6. doi:10.1097/00002281-199909000-00005
Costenbader KH, Feskanich D, Stampfer MJ, Karlson EW. Reproductive and menopausal factors and risk of systemic lupus erythematosus in women. Arthritis Rheum. Apr 2007;56(4):1251-62. doi:10.1002/art.22510
Buyon JP, Petri MA, Kim MY, et al. The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann Intern Med. Jun 21 2005;142(12 Pt 1):953-62. doi:10.7326/0003-4819-142-12_part_1-200506210-00004
Scofield RH, Bruner GR, Namjou B, et al. Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum. Aug 2008;58(8):2511-7. doi:10.1002/art.23701
Lateef A, Petri M. Systemic Lupus Erythematosus and Pregnancy. Rheum Dis Clin North Am. May 2017;43(2):215-226. doi:10.1016/j.rdc.2016.12.009
Eudy AM, Siega-Riz AM, Engel SM, et al. Effect of pregnancy on disease flares in patients with systemic lupus erythematosus. Ann Rheum Dis. Jun 2018;77(6):855-860. doi:10.1136/annrheumdis-2017-212535
Stojan G, Baer AN. Flares of systemic lupus erythematosus during pregnancy and the puerperium: prevention, diagnosis and management. Expert Rev Clin Immunol. Jul 2012;8(5):439-53. doi:10.1586/eci.12.36
Lourenço EV, La Cava A. Cytokines in systemic lupus erythematosus. Curr Mol Med. Apr 2009;9(3):242-54. doi:10.2174/156652409787847263
Luo CY, Wang L, Sun C, Li DJ. Estrogen enhances the functions of CD4(+)CD25(+)Foxp3(+) regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro. Cell Mol Immunol. Jan 2011;8(1):50-8. doi:10.1038/cmi.2010.54
Liblau RS, Singer SM, McDevitt HO. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today. Jan 1995;16(1):34-8. doi:10.1016/0167-5699(95)80068-9
Constant SL, Bottomly K. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol. 1997;15:297-322. doi:10.1146/annurev.immunol.15.1.297
Street NE, Mosmann TR. Functional diversity of T lymphocytes due to secretion of different cytokine patterns. Faseb j. Feb 1991;5(2):171-7. doi:10.1096/fasebj.5.2.1825981
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. Feb 1999;42(2):328-37. doi:10.1002/1529-0131(199902)42:2<328::aid-anr16>3.0.co;2-#
Kim WU, Min SY, Hwang SH, Yoo SA, Kim KJ, Cho CS. Effect of oestrogen on T cell apoptosis in patients with systemic lupus erythematosus. Clin Exp Immunol. Sep 2010;161(3):453-8. doi:10.1111/j.1365-2249.2010.04194.x
Polanczyk MJ, Hopke C, Vandenbark AA, Offner H. Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway. J Neurosci Res. Aug 1 2006;84(2):370-8. doi:10.1002/jnr.20881
Seto K, Hoang M, Santos T, Bandyopadhyay M, Kindy MS, Dasgupta S. Non-genomic oestrogen receptor signal in B lymphocytes: An approach towards therapeutic interventions for infection, autoimmunity and cancer. Int J Biochem Cell Biol. Jul 2016;76:115-8. doi:10.1016/j.biocel.2016.04.018
Liao ZH, Huang T, Xiao JW, et al. Estrogen signaling effects on muscle-specific immune responses through controlling the recruitment and function of macrophages and T cells. Skelet Muscle. Jul 29 2019;9(1):20. doi:10.1186/s13395-019-0205-2
Ong SG, Choy CH. Autoimmune thyroid disease in a cohort of Malaysian SLE patients: frequency, clinical and immunological associations. Lupus. Jan 2016;25(1):67-74. doi:10.1177/0961203315593164
Antonelli A, Fallahi P, Mosca M, et al. Prevalence of thyroid dysfunctions in systemic lupus erythematosus. Metabolism. Jun 2010;59(6):896-900. doi:10.1016/j.metabol.2009.10.010
Pyne D, Isenberg DA. Autoimmune thyroid disease in systemic lupus erythematosus. Ann Rheum Dis. Jan 2002;61(1):70-2. doi:10.1136/ard.61.1.70
Vanderpump MP. The epidemiology of thyroid disease. Br Med Bull. 2011;99:39-51. doi:10.1093/bmb/ldr030
Watad A, Mahroum N, Whitby A, et al. Hypothyroidism among SLE patients: Case-control study. Autoimmun Rev. May 2016;15(5):484-6. doi:10.1016/j.autrev.2016.01.019
Chan AT, Al-Saffar Z, Bucknall RC. Thyroid disease in systemic lupus erythematosus and rheumatoid arthritis. Rheumatology (Oxford). Mar 2001;40(3):353-4. doi:10.1093/rheumatology/40.3.353
Posselt RT, Coelho VN, Skare TL. Hashimoto thyroiditis, anti-thyroid antibodies and systemic lupus erythematosus. Int J Rheum Dis. Jan 2018;21(1):186-193. doi:10.1111/1756-185x.13089
Liu H, Yang LH, Yin G, Xie QB. [Correlation of Thyroid Autoantibodies,System Lupus Erythematosus Immunologic Indicators and Disease Activity in SLE with HT]. Sichuan Da Xue Xue Bao Yi Xue Ban. Mar 2018;49(2):179-182
Tan B, Yuan W, Li J, et al. Therapeutic effect of human amniotic epithelial cells in murine models of Hashimoto's thyroiditis and Systemic lupus erythematosus. Cytotherapy. Oct 2018;20(10):1247-1258. doi:10.1016/j.jcyt.2018.04.001
Smith TJ, Hegedüs L. Graves' Disease. N Engl J Med. Oct 20 2016;375(16):1552-1565. doi:10.1056/NEJMra1510030
Ferrari SM, Elia G, Virili C, Centanni M, Antonelli A, Fallahi P. Systemic Lupus Erythematosus and Thyroid Autoimmunity. Front Endocrinol (Lausanne). 2017;8:138. doi:10.3389/fendo.2017.00138
Zhanga Y, Xiaoa X, Haoa Q , Lia X, Renb J, Hu Z. The onset of systemic lupus erythematosus and thyroid dysfunction following Graves’ disease – A case report and literature review. Srp Arh Celok Lek. Nov-Dec 2016;144(11-12):639-44. doi:10.2298/sarh1612639z
Cortes S, Chambers S, Jerónimo A, Isenberg D. Diabetes mellitus complicating systemic lupus erythematosus - analysis of the UCL lupus cohort and review of the literature. Lupus. Nov 2008;17(11):977-80. doi:10.1177/0961203308091539
Zeglaoui H, Landolsi H, Mankai A, Ghedira I, Bouajina E. Type 1 diabetes mellitus, celiac disease, systemic lupus erythematosus and systemic scleroderma in a 15-year-old girl. Rheumatol Int. Apr 2010;30(6):793-5. doi:10.1007/s00296-009-0988-2
Wu Y, Ding Y, Tanaka Y, Zhang W. Risk factors contributing to type 2 diabetes and recent advances in the treatment and prevention. Int J Med Sci. 2014;11(11):1185-200. doi:10.7150/ijms.10001
Dong Y, Dai Z, Wang Z, et al. Risk of gestational diabetes mellitus in systemic lupus erythematosus pregnancy: a systematic review and meta-analysis. BMC Pregnancy Childbirth. May 22 2019;19(1):179. doi:10.1186/s12884-019-2329-0
Galrão LD, Lima IV, Santos L, Santiago MB. [Primary hyperparathyroidism in a patient with systemic lupus erythematosus]. Arq Bras Endocrinol Metabol. Aug 2004;48(4):555-8. Hiperparatireoidismo primário em paciente com lúpus eritematoso sistêmico. doi:10.1590/s0004-27302004000400017
Jiang J, Zhang M, He R, Shen M, Liu W. Functional parathyroid cyst in a patient with systemic lupus erythematosus: a case report. Endocrinol Diabetes Metab Case Rep. 2015;2015:140100. doi:10.1530/edm-14-0100
Godswill OC, Odigie OO. Primary Adrenal Insufficiency (Addison's Disease) Associated with Systemic Lupus Erythematosus: A Rare Occurrence. Int J Prev Med. 2014:1324-7. vol. 10
Nakayama Y, Taura D, Shibue K, Kuramoto N, Mimori T, Inagaki N. A case of systemic lupus erythematosus complicated by subclinical Cushing's syndrome: case report. Mod Rheumatol Case Rep. Jan 2020;4(1):16-20. doi:10.1080/24725625.2019.1638049
Shimizu M, Kawata M, Okada T, et al. Concomitant Cushing's syndrome due to adrenal adenoma in a patient with systemic lupus erythematosus. Intern Med. Nov 2002;41(11):1044-6. doi:10.2169/internalmedicine.41.1044
Oktem O, Guzel Y, Aksoy S, Aydin E, Urman B. Ovarian function and reproductive outcomes of female patients with systemic lupus erythematosus and the strategies to preserve their fertility. Obstet Gynecol Surv. Mar 2015;70(3):196-210. doi:10.1097/ogx.0000000000000160
Medeiros PB, Febrônio MV, Bonfá E, Borba EF, Takiuti AD, Silva CA. Menstrual and hormonal alterations in juvenile systemic lupus erythematosus. Lupus. Jan 2009;18(1):38-43. doi:10.1177/0961203308094652
Lawrenz B, Henes J, Henes M, et al. Impact of systemic lupus erythematosus on ovarian reserve in premenopausal women: evaluation by using anti-Muellerian hormone. Lupus. Oct 2011;20(11):1193-7. doi:10.1177/0961203311409272
LaBarbera AR, Miller MM, Ober C, Rebar RW. Autoimmune etiology in premature ovarian failure. Am J Reprod Immunol Microbiol. Mar 1988;16(3):115-22. doi:10.1111/j.1600-0897.1988.tb00180.x
Chang YS, Lai CC, Chen WS, Wang SH, Chou CT, Tsai CY. Protein-losing enteropathy and premature ovarian failure in a young woman with systemic lupus erythematosus. Lupus. Oct 2012;21(11):1237-9. doi:10.1177/0961203312449492
Pasoto SG, Viana VS, Mendonca BB, Yoshinari NH, Bonfa E. Anti-corpus luteum antibody: a novel serological marker for ovarian dysfunction in systemic lupus erythematosus? J Rheumatol. May 1999;26(5):1087-93
Shabanova SS, Ananieva LP, Alekberova ZS, Guzov, II. Ovarian function and disease activity in patients with systemic lupus erythematosus. Clin Exp Rheumatol. May-Jun 2008;26(3):436-41
Joob B, Wiwanitkit V. Prolactin and systemic lupus erythematosus. Immunol Res. 2017:975. vol. 4
Song GG, Lee YH. Circulating prolactin level in systemic lupus erythematosus and its correlation with disease activity: a meta-analysis. Lupus. Oct 2017;26(12):1260-1268. doi:10.1177/0961203317693094
Nusbaum JS, Mirza I, Shum J, et al. Sex Differences in Systemic Lupus Erythematosus: Epidemiology, Clinical Considerations, and Disease Pathogenesis. Mayo Clin Proc. Feb 2020;95(2):384-394. doi:10.1016/j.mayocp.2019.09.012
Petri M. Cyclophosphamide: new approaches for systemic lupus erythematosus. Lupus. 2004;13(5):366-71. doi:10.1191/0961203303lu1028oa
Kado R, McCune WJ. Ovarian protection with gonadotropin-releasing hormone agonists during cyclophosphamide therapy in systemic lupus erythematosus. Best Pract Res Clin Obstet Gynaecol. Apr 2020;64:97-106. doi:10.1016/j.bpobgyn.2019.10.008
Spears N, Lopes F, Stefansdottir A, et al. Ovarian damage from chemotherapy and current approaches to its protection. Hum Reprod Update. Nov 5 2019;25(6):673-693. doi:10.1093/humupd/dmz027
Luan Y, Edmonds ME, Woodruff TK, Kim SY. Inhibitors of apoptosis protect the ovarian reserve from cyclophosphamide. J Endocrinol. Feb 1 2019;240(2):243-256. doi:10.1530/joe-18-0370
Xiong Y, Liu T, Wang S, Chi H, Chen C, Zheng J. Cyclophosphamide promotes the proliferation inhibition of mouse ovarian granulosa cells and premature ovarian failure by activating the lncRNA-Meg3-p53-p66Shc pathway. Gene. Jan 5 2017;596:1-8. doi:10.1016/j.gene.2016.10.011
Harward LE, Mitchell K, Pieper C, Copland S, Criscione-Schreiber LG, Clowse ME. The impact of cyclophosphamide on menstruation and pregnancy in women with rheumatologic disease. Lupus. Jan 2013;22(1):81-6. doi:10.1177/0961203312468624
Chemaitilly W, Mertens AC, Mitby P, et al. Acute ovarian failure in the childhood cancer survivor study. J Clin Endocrinol Metab. May 2006;91(5):1723-8. doi:10.1210/jc.2006-0020
Mok CC, Chan PT, To CH. Anti-müllerian hormone and ovarian reserve in systemic lupus erythematosus. Arthritis Rheum. Jan 2013;65(1):206-10. doi:10.1002/art.37719
Appenzeller S, Blatyta PF, Costallat LT. Ovarian failure in SLE patients using pulse cyclophosphamide: comparison of different regimes. Rheumatol Int. Apr 2008;28(6):567-71. doi:10.1007/s00296-007-0478-3
Mersereau J, Dooley MA. Gonadal failure with cyclophosphamide therapy for lupus nephritis: advances in fertility preservation. Rheum Dis Clin North Am. Feb 2010;36(1):99-108, viii. doi:10.1016/j.rdc.2009.12.010
Rienzi L, Gracia C, Maggiulli R, et al. Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance. Hum Reprod Update. Mar 1 2017;23(2):139-155. doi:10.1093/humupd/dmw038
Rajabi Z, Aliakbari F, Yazdekhasti H. Female Fertility Preservation, Clinical and Experimental Options. J Reprod Infertil. Jul-Sep 2018;19(3):125-132
Levi-Setti PE, Patrizio P, Scaravelli G. Evolution of human oocyte cryopreservation: slow freezing versus vitrification. Curr Opin Endocrinol Diabetes Obes. Dec 2016;23(6):445-450. doi:10.1097/med.0000000000000289
Yding Andersen C, Mamsen LS, Kristensen SG. FERTILITY PRESERVATION: Freezing of ovarian tissue and clinical opportunities. Reproduction. Nov 2019;158(5):F27-f34. doi:10.1530/rep-18-0635
Del Mastro L, Lambertini M. Temporary Ovarian Suppression With Gonadotropin-Releasing Hormone Agonist During Chemotherapy for Fertility Preservation: Toward the End of the Debate? Oncologist. Nov 2015;20(11):1233-5. doi:10.1634/theoncologist.2015-0373