Autoimmune Disease and Estrogen Connection

Also see:
Vitamin E and Autoimmune Disease
Menstrual Cycle Related Epilepsy (Catamenial Epilepsy)
Ray Peat, PhD on the Benefits of the Raw Carrot
The effect of raw carrot on serum lipids and colon function
Autoimmunity and Intestinal Flora
How does estrogen enhance endotoxin toxicity? Let me count the ways.
Protective Bamboo Shoots
Endotoxin-lipoprotein Hypothesis
Endotoxin: Poisoning from the Inside Out
Alcohol Consumption – Estrogen and Progesterone in Women
Estrogen and Liver Toxicity
Estrogen, Endotoxin, and Alcohol-Induced Liver Injury
Oral Contraceptives, Estrogen, and Clotting

Quotes by Ray Peat, PhD:
“There is almost an obligatory medical genuflection toward “genetic causation” of disease, and especially of thyroid disease, autoimmune disease, and other chronic or degenerative diseases. The fact that thyroid disease and autoimmune diseases are from five to ten times more frequent in women than men is somehow hasn’t increased medical interest in the pathogenic role of estrogen, and it doesn’t prevent platoons of medical researchers from making claims to have discovered “which chromosome carries the disease.”

“The identity of an antibody isn’t really as clear as a lot of people have assumed. They’ve found that there’s a great cross-reaction between thyroid antibodies and joint antibodies. And that explains why people with thyroiditis and hypothyroidiism so often have arthritis and joint problems. And the whole issue of explaining disease, as blaming it on the immune system attacking the body. If you wrench your knee, and sort of damage the cartilage they’ve done experiments in rabbits, taking a piece of foreign cartilage (like, from a cow) and it will produce very few antibodies in the rabbit. But if you twist it a little bit, structurally damage it, then it produces a terrific immune reaction. And any organ that gets strained or overworked tends to leak some of its proteins, and the immune system’s function, largely, is to clean up any mess. In fact, there’s an alternative interpretation of what the immune system is doing: rather than looking for foreign invading pathogens, this theory says it’s primarily cleaning up messes caused by anything which is pathogenic. So, in one of the so-called autoimmune brain conditions, people demonstrated that the presence of the antibody to the brain tissue accelerates the recovery. So, cleaning up the mess is really constructive, and rather than always being the cause of deterioration.

“It is common knowledge, among people who study immunity, that radiation, polyunsaturated fatty acids, estrogens, and dioxins are toxic to the thymus gland, and can produce immuno-deficiency. They mimic or accelerate the thymic atrophy of aging, causing a deficient thymus-dependent immune response, usually without harming the ability of B cells to produce antibodies. There are probably many examples of damage to immune systems, besides immunodeficiency, caused by these agents. Slight damage to the immune system, such as can be produced by hypoglycemia or other energy deficit–creates an exaggerated inflammatory response, and the release of the mediators of inflammation, including histamine, serotonin, and prostaglandins, activates the stress hormone system, leading to further biological damage. Liver disease and several other “autoimmune” diseases involve abnormal immune responses, probably including thymic deficiency and an intensified inflammatory response. The fact that livers transplanted from female donors to male recipients are less successful than are livers from male donor transplanted into female recipients, is consistent with the idea that autoantibodies (which are far more common in women than in men) are a relatively harmless response to changes in the organs themselves.”

“Aging is characterized by loss of lean body mass, immunodeficiency, and a variety of autoimmune reactions. My perennial argument has been that decreased thyroid and progesterone, associated with increased estrogen and stress hormones, are largely responsible for those changes.”

J Endocrinol Invest. 1993 Sep;16(8):619-24.
Hormonal pattern in women affected by rheumatoid arthritis.
Valentino R, Savastano S, Tommaselli AP, Riccio A, Mariniello P, Pronesti G, De Divitiis PM, Lombardi G.
Gonadal sex hormones may account for the sexual dimorphism in the immune response and for the greater incidence of autoimmune disease in females. We have previously reported the presence of progesterone (P) deficiency in female patients with thyroid and ovarian autoimmune disease. In this context, the hormonal profile in 9 women with rheumatoid arthritis (RA) and in 9 age-matched ealthy women, were evaluated to verify the presence of a steroid hormone secretion impairment in a systemic autoimmune disease, further supporting our hypothesis of P deficiency involvement. P and androgen plasma levels, in the luteal phase, were significantly lower (p < 0.05 and 0.005, respectively) in RA patients than in the control group, with a consequent decrease of the free androgen index. Moreover, despite normal cortisol values, corticosterone (B) plasma levels were significantly higher in the RA patients (p < 0.01 and 0.05 in follicular and luteal phase, respectively). Therefore, our present data confirm the androgen deficiency in patients with a systemic autoimmune disease, such as RA and support the immunomodulator effect of P. Finally, the higher B plasma levels in RA patients may suggest the presence of a slight impairment of the immune hypothalamic-pituitary-adrenal axis (HPAA), supporting its role in certain phases of RA pathogenesis. In conclusion, in addition to androgens, the immunomodulator role of P should also be taken into account in the pathogenesis of the systemic autoimmune disease.

Clin Exp Rheumatol. 2008 Sep-Oct;26(5):903-9.
Hydroxylated estrogen metabolites influence the proliferation of cultured human monocytes: possible role in synovial tissue hyperplasia.
Capellino S, Montagna P, Villaggio B, Soldano S, Straub RH, Cutolo M.
17Beta-estradiol, estrone, and several of their hydroxylated metabolites, have been found to be significantly increased in synovial fluid of rheumatoid arthritis (RA) patients. In this study, we investigated whether the estrogen metabolites are able to exert direct effects on monocyte cell proliferation, which is important in RA synovial tissue activation and growth.
Human monocytes (THP-1) were treated with the following estrogen metabolites at different concentrations (from 10-8M, 10-9M, 10-10M to 10-11M) for 24, 48 and 72 hours: 16-hydroxyestrone (16OH-E1), 16-hydroxyestradiol (16OH-E2), 4-hydroxyestrone (4OH-E1), 4-hydroxyestradiol (4OH-E2), 2-hydroxyestrone (2OH-E1) and 2-hydroxyestradiol (2OH-E2). Monocytes were activated with interferon-gamma (INF-gamma). Cell cultures were also performed in presence of tamoxifen (10-7M) to evaluate whether the estrogen metabolites act through the estrogen receptors (ER). Cell growth was detected by MTT test and cell viability through the LDH release assay.
4OH-E1 and 2OH-E1 significantly increased cell growth at low concentration (10-10M), whereas they significantly reduced cell proliferation at high concentrations (10-9M). 16OH-E2 and 4OH-E2 induced opposite effects: cell proliferation at high concentration and antiproliferative action at low doses. On the contrary, 16OH-E1 and 2OH-E2 were found to be estrogen metabolites that induced cell proliferative effects for most of the tested doses. Tamoxifen caused the loss of effects on cell proliferation for almost all the metabolites.
This study first demonstrates that different downstream estrogen metabolites interfere with monocyte proliferation and generally might modulate the immune response. Therefore, since estrogen metabolite/ratios are altered in the synovial fluid of RA patients, they might play important roles at least in RA synovial tissue hyperplasia.

BMJ -VOLUME 303 6 JULY 1991
Sex hormones, autoimmune diseases, and immune response
More implications for research than treatment

Autoimmune diseases are far more common in women than in men. For example, the female to male ratio is 9:1 in systemic lupus erythematosus and 4:1 in rheumatoid arthritis.’ These observations suggest that sex hormones may help to determine this susceptibility. Though some research findings seem to confirm this suggestion, others are more equivocal; and more recent work suggests a much more complex role for sex hormones in autoimmune diseases. Some of the most suggestive evidence for the influence of sex hormones relates to rheumatoid arthritis. Thus rheumatoid arthritis begins more commonly in the childbearing years, and both the onset of disease and exacerbations are associated with the postpartum period. Pregnancy is also associated with spontaneous remissions and may itself reduce the risk of developing rheumatoid arthritis. Similarly, autoimmune thyroiditis is encountered as a transient postpartum disorder.

Revista Medica De Chile (1993) Volume: 121, Issue: 9, Pages: 1045-1052
Role of sex hormones in autoimmune diseases
by M Cuchacovich, H Gatica, A N Tchernitchin
There is increasing body of evidence to suggest that sex hormones may be closely involved in the pathogenesis of autoimmune diseases in humans. In the present article we discuss heteroimmune response differences between males and females and the roles of gender and sex hormones in autoimmune diseases in various species. The general conclusions are the following. Androgens and perhaps progestogens may protect from autoimmune disease; however oestrogens seems to have a dualistic effect on the immune system. Is has been demonstrated that oestrogens suppress antigen-specific T-cell dependent immune reactions while enhance B-cell activities.

Lupus. 2004;13(4):217-22.
Possible mechanisms of gender bias in SLE: a new hypothesis involving a comparison of SLE with atopy.
Sekigawa I, Naito T, Hira K, Mitsuishi K, Ogasawara H, Hashimoto H, Ogawa H.
The prevalence of systemic lupus erythematosus (SLE) is far higher in females than in males, and numerous investigations of this gender bias have been performed from several perspectives. Sex hormones, particularly estrogens, may be significant in causing the gender discrepancy. This article discusses the possible importance of estrogens in regulating the expression of and responsivity to autoantigens in SLE and in atopic disorders, which are associated with hyperreactivity to exogenous antigens. Estrogens seem to play an important role in the overexpression of endogenous autoantigens, such as human endogenous retroviruses (HERV), and this may be related to the existence of a gender bias in the incidence of SLE but not atopy.

J Rheumatol Suppl. 1987 Jun;14 Suppl 13:21-5.
Interleukin 2, T cell receptor and sex hormone studies in autoimmune mice.
Talal N, Dang H, Ahmed SA, Kraig E, Fischbach M.
Systemic lupus erythematosus (SLE) is a disease of immune dysregulation in which B cell hyperactivity and T cell deficiency are important characteristics. Sex factors also play a major role in the pathogenesis based on the physiologic effects of estrogen in promoting immunologic hyperactivity. Our findings suggest that a posttranscriptional mechanism is responsible for the functional interleukin 2 (IL-2) defect since transcription of the IL-2 message occurs after mitogenic stimulation. The proliferating cell in the MRL/lpr mouse model of lupus may be an immature T cell. The T cell receptor in these mice has a lower molecular weight than normal. This aberrant T cell receptor might be explained by a defect in glycosylation. The administration of estrogen to pregnant mice late in gestation results in offspring with a permanently altered immune system. These mice develop features of autoimmunity similar to those that occur spontaneously in genetically susceptible autoimmune mice. This phenomenon may have etiopathological significance for familial SLE.

J Endocrinol Invest. 1993 May;16(5):384-91.
Thyroid autoimmunity and female gender.
Chiovato L, Lapi P, Fiore E, Tonacchera M, Pinchera A.
Sexual dimorphism exists in regard to the immune response between women and men, and it accounts for the greater prevalence of thyroid autoimmunity in women. Similarly to the human situation a sex-related susceptibility to autoimmune thyroiditis is evident in animal models. A direct influence of genes on sex chromosomes (X or Y) on the immune response has been postulated in some models of autoimmune thyroiditis in rats. On the other hand sex hormones have been implicated to explain the majority of sex differences in the autoimmune response against the thyroid. A state of immune suppression during pregnancy influences the clinical course of autoimmune thyroid diseases, in that a typical amelioration during pregnancy is accompanied by aggravation following delivery. This immunologic rebound phenomenon may also underly the post partum thyroid dysfunction in otherwise healthy women with a genetic predisposition to autoimmune thyroid disease. Thyroid autoimmunity also interferes with the female reproductive function. Hypothyroidism and less frequently hyperthyroidism due to thyroid autoimmune disorders may produce menstrual dysfunction, anovulation and eventually infertility. Maternal hyper- or hypothyroidism can affect the outcome of pregnancy, producing a higher incidence of miscarriages, maternal complications, and congenital malformations. Untreated maternal hypothyroidism produced by Hashimoto’s disease during pregnancy can impair the neurological development of the fetus due to a reduced availability of maternal thyroxine during early gestation.2+ More specifically, fetal and/or neonatal hypo- or hyperthyroidism produced by the transplacental passage of maternal thyroid autoantibodies can impair growth and neuropsychological development of affected children.

Clin Exp Immunol. 1993 Mar;91(3):442-8.
Gender-related influences on the development of chronic graft-versus-host disease-induced experimental lupus nephritis.
Treurniet RA, Bergijk EC, Baelde JJ, De Heer E, Hoedemaeker PJ, Bruijn JA.
Autoimmune diseases are far more common in women than in men. In the incidence of systemic lupus erythematosus (SLE), the female-to-male ratio is as high as 10:1. This suggests that sex hormones may play a fundamental role in determining the susceptibility to these diseases. In order to investigate the sex-related differences in the inducibility of chronic graft-versus-host disease-related experimental lupus nephritis, lymphocytes from female DBA/2 donor mice were administered to either male or female (C57BL10 x DBA/2)F1 recipients. An additional group of male recipients received lymphocytes from male DBA/2 donors. After four cell transfers, female recipients developed a significantly higher albuminuria than both male groups. Serum concentrations of autoantibodies against glomerular basement membrane (GBM), collagen IV, and laminin were significantly higher in females 2-4 weeks after induction. Levels of circulating autoantibodies against renal tubular epithelial antigens (RTE) and nuclear antigens were not different between the sexes. In transfer studies, the necessity of the presence of anti-GBM and anti-RTE autoantibodies for the development of glomerulonephritis was confirmed. These findings indicate that: (i) in this model of lupus nephritis, susceptibility to glomerulonephritis is strongly influenced by sex-related genes; and (ii) among the variety of autoantibodies occurring in this model of SLE, both anti-GBM and anti-RTE autoantibodies play a key role in the pathogenesis of glomerulonephritis.

Int Immunopharmacol. 2001 Jun;1(6):983-93.
Sex hormones as immunomodulators in health and disease.
Verthelyi D.
In addition to their effects on sexual differentiation and reproduction, sex hormones influence the immune system. This results in a gender dimorphism in the immune function with females having higher immunoglobulin levels and mounting stronger immune responses following immunization or infection than males. The greater immune responsiveness in females is also evident in their increased susceptibility to autoimmune diseases. However, a clear understanding of the myriad of effects that sex hormones have on the immune system is lacking. Studies in normal mice show that estrogen treatment induces polyclonal B cell activation with increased expression of autoantibodies characteristic of autoimmune diseases. Several mechanisms appear to contribute to the break in tolerance and the increase in plasma cell activity including a reduction of the mass of the bone marrow and the thymus, the emergence of sites of extramedullary hematopoiesis and altered susceptibility of B cells to cell death. In addition, sex hormone levels in both humans and experimental models correlated with the activity of their cytokine-secreting cells indicating that sex hormones influence the cytokine milieu and suggesting that altered sex hormonal levels in autoimmune patients contribute to the skewed cytokine milieu characteristic of systemic lupus erythematosus (SLE). While sex hormones alone do not cause autoimmune disease, abnormal hormone levels may provide the stage for other factors (genetic, infectious) to trigger disease. Understanding the physiology of the interaction between sex hormones and immune function and its potential pathological consequences may provide insight into the autoimmune diseases and new directions for their treatment.

Cell Immunol. 1998 Nov 1;189(2):125-34.
Estrogen increases the number of plasma cells and enhances their autoantibody production in nonautoimmune C57BL/6 mice.
Verthelyi DI, Ahmed SA.
The immunological consequences of chronic estrogen exposure in normal individuals are not known, particularly in relation to B cells. In this study, by employing ELIspot, image cytometry, flow cytometry, cytology, and ELISA, we show that long-term exposure of normal mice to estrogen activates B cells to produce higher numbers of not only immunoglobulin-producing cells, but also autoantibody-producing cells. Estrogen promoted a decrease in B220(+) splenic lymphocytes, but resulted in a 10-fold increase in plasma cells. Further, the output of immunoglobulins including autoantibodies from individual plasma cells from estrogen-exposed mice was markedly increased, suggesting B cell hyperactivity. Importantly, our findings show that treatment of normal mice, solely with estrogen, can override B cell tolerance and promote autoreactive B cells in normal individuals.

Rinsho Shinkeigaku. 1993 Sep;33(9):995-7.
A case of Hashimoto’s encephalopathy with a relapsing course related to menstrual cycle.
[Article in Japanese]
Ishii K, Hayashi A, Tamaoka A, Mizusawa H, Shoji S.
A case of 43-year-old woman with Hashimoto’s encephalopathy who experienced three relapses closely associated with the menstrual cycle is reported. In April 1992, she began to experience occasional tremors in her arms. Three months later, she experienced a generalized seizure and was transferred to our hospital. Hashimoto’s thyroiditis was diagnosed on the basis of high thyroid microsomal titer and mild hypothyroidism. Neurological findings in admission included action tremor in both hands, myoclonus in all extremities, cerebellar ataxia, confusion, and hyperreflexia. Cerebrospinal fluid showed elevated protein level without pleocytosis. Electroencephalogram showed diffuse slowing and magnetic resonance imaging of brain was normal. Hashimoto’s encephalopathy was diagnosed from these findings. These episodes of remission and exacerbation were observed during the admission. Her symptoms started at ovulation, worsened during the luteal phase, and improved when menstruation started. After the third relapse, she was treated with oral thyroxine for hypothyroidism and with an estrogen and progesterone combination to regulate the menstrual cycle. Her thyroid function gradually became euthyroid and she did not experience any subsequent relapses. The relation between the relapsing course and menstrual cycle suggests that the periodic alteration of gonadotrophic and/or gonadal hormones or the menstrual regulating center itself in the brain may be an important factor of pathogenetic mechanism of the disorder.

Neurology November 26, 2002 vol. 59 no. 10 1633-1635
Hashimoto’s encephalopathy: Exacerbations associated with menstrual cycle
F. Sellal, MD, C. Berton, MD, M. Andriantseheno, MD and C. Clerc, MD
The authors report a patient who had five relapses of encephalopathy with seizures and aseptic meningitis that coincided with the end of the menstrual cycle. High titers of antithyroid antibodies and the patient’s response to corticosteroids suggested Hashimoto’s encephalopathy. Pharmacologic suppression of the menstrual cycle made it possible to withdraw corticosteroids.

Baillieres Clin Rheumatol. 1996 May;10(2):259-71.
Hormones and autoimmunity: animal models of arthritis.
Wilder RL.
Hormones, particularly those involved in the hypothalamic-pituitary-gonadal and -adrenal axes (HPG and HPA), play important roles in various animal models of autoimmunity such as systemic lupus erythematosus in mice and collagen-induced arthritis (CIA) in mice and rats, and the streptococcal cell wall, adjuvant and avridine arthritis models in rats. Intimately linked to the subject of hormones and autoimmunity are gender, sex chromosomes and age. The importance of these factors in the various animal models is emphasized in this chapter. Several major themes are apparent. First, oestrogens promote B-cell dependent immune-complex mediated disease (e.g. lupus nephritis) but suppress T-cell dependent pathology (CIA in mice and rats), and vice versa. Second, testosterone’s effects are complicated and depend on species and disease model. In rats, testosterone suppresses both T-cell and B-cell immunity. In mice, the effects are complex and difficult to interpret, e.g. they tend to enhance CIA arthritis and suppress lupus. Sex chromosome/sex hormone interactions are clearly involved in generating these complicated effects. Third, studies in Lewis and Fischer F344 rats exemplify the importance of corticosteroids, corticotrophin releasing hormone and the HPA axis in the regulation of inflammation and the predisposition to autoimmune diseases. Fourth, the HPA axis is intimately linked to the HPG axis and is sexually dimorphic. Oestrogens stimulate higher corticosteroid responses in females. The animal model data have major implications for understanding autoimmunity in humans. In particular, adrenal and gonadal hormone deficiency is likely to facilitate T-cell dependent diseases like rheumatoid arthritis, while high oestrogen levels or effects, relative to testosterone, are likely to promote B-cell dependent immune-complex-mediated diseases such as lupus nephritis.

Ann Rheum Dis. 1991 December; 50(12): 897–898.
Sex hormone modulation in systemic lupus erythematosus: still a therapeutic option?
R A Asherson and R G Lahita

Arthritis Rheum. 1979 Nov;22(11):1195-8.
Alterations of estrogen metabolism in systemic lupus erythematosus.
Lahita RG, Bradlow HL, Kunkel HG, Fishman J.
Estradiol metabolism in 10 patients with systemic lupus erythematosus (SLE) and 29 normal controls was studied by measurement of urinary metabolites after injection of labeled 3H-estradiol. Patients with SLE manifested increased 16-hydroxylation of estrone. Diseases men differed from diseases women to the extent that only 16 alpha-hydroxyestrone was elevated in men, whereas women had elevations of both 16 alpha-hydroxyestrone and estriol. These data suggest that patients with SLE have abnormal patterns of estradiol metabolism, leading to increased estrogenic activity.

Am J Kidney Dis. 1982 Jul;2(1 Suppl 1):206-11.
Abnormal estrogen and androgen metabolism in the human with systemic lupus erythematosus.
Lahita RG, Bradlow HL, Fishman J, Kunkel HG.
Humans with SLE were studied with regard to their ability to metabolize estradiol and testosterone. Significant abnormalities in the patterns of metabolism of both classes of sex steroids were found. Estradiol hydroxylation at C-16 was more extensive in both males and females with SLE — leading to more estrogenic metabolites; and testosterone oxidation was elevated in patients with SLE resulting in a decrease in total androgens. Some normal first degree relatives of patients with SLE also had abnormalities of estradiol hydroxylation.

Inflammation. 1996 Dec;20(6):581-97.
Estriol: a potent regulator of TNF and IL-6 expression in a murine model of endotoxemia.
Zuckerman SH, Ahmari SE, Bryan-Poole N, Evans GF, Short L, Glasebrook AL.
The increased incidence of autoimmune disease in premenopausal women suggests the involvement of sex steroids in the pathogenesis of these disease processes. The effects of estrogen on autoimmunity and inflammation may involve changes in the secretion of inflammatory mediators by mononuclear phagocytes. Estradiol, for example, has been reported to regulate TNF, IL-6, IL-1 and JE expression. In the present study the effects of the estrogen agonist, estriol, on cytokine expression have been investigated in mice administered a sublethal lipopolysaccharide, LPS, challenge. Pretreatment of mice with pharmacologic doses of estriol, 0.4-2 mg/kg, resulted in a significant increase in serum TNF levels in both control and autoimmune MRL/lpr mice, following LPS challenge. This increase in TNF over the placebo group was blocked by the estrogen antagonist tamoxifen. Estriol treated mice also exhibited a rapid elevation in serum IL-6 levels following LPS challenge with the peak increase occurring 1 hr post LPS. This contrasted with the placebo group in which maximal serum IL-6 levels were detected at 3 hrs post challenge. This shift in the kinetics of IL-6 increase by estriol was inhibited by tamoxifen. The estriol mediated effects of TNF and IL-6 serum levels were consistent with the changes in TNF and IL-6 mRNA observed ex vivo in elicited peritoneal macrophages. Macrophage cultures from estriol treated animals however, did not demonstrate significant differences from the placebo group for TNF or NO secretion following in vitro LPS challenge. These results suggest that the estrogen agonist estriol can have significant quantitative, TNF, and kinetic, IL-6, effects on inflammatory monokines produced in response to an endotoxin challenge.

Although medical people have been taught to believe that aging isn’t an estrogenic state, contrary to the clear evidence that estrogen production (by aromatase enzymes) in many tissues increases with age, an experiment (Greenstein, et al., 1992) has demonstrated that giving an aromatase inhibitor to old rats caues their thymus to regenerate. -Ray Peat, PhD

Int J Immunopharmacol. 1992 May;14(4):541-53.
Aromatase inhibitors regenerate the thymus in aging male rats.
Greenstein BD, de Bridges EF, Fitzpatrick FT.
The thymus can be regenerated in aging rats by surgical or chemical castration and regeneration is inhibited by testosterone, which may exert this effect, at least in part, through its conversion to estradiol. An attempt has been made to regenerate the thymus in intact aging rats using inhibitors of the aromatase system, in the hope that this maneuver could lead to the use of such chemical intervention in the treatment of immunodeficiency syndromes. Young adult and aging (18-month-old) male rats were orchidectomized under ether anesthesia and 7 days later given s.c. implants of testosterone in silicone elastomer (SILASTIC) tubing. Some rats received testosterone together with a five-fold excess of the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD). One group of young intact rats received implants containing 25 mg ATD and a group of 18-month-old intact rats received 125 mg ATD or 25 mg of another, more powerful aromatase inhibitor 4-hydroxyandrostenedione (4-OH). On the 28th day after implanting, rats were killed and the thymus, spleen, prostate gland and seminal vesicles removed for weighing and histology. In addition, estrogen receptors were measured in the thymus. The thymus was enlarged after orchidectomy and greatly restored in aging rats. In aging rats, both aromatase inhibitors restored the thymus, which appeared normal histologically. In addition, ATD enlarged the thymus in young intact animals. Doses of testosterone which restored the accessory sex organs to weights measured in intact rats prevented the effects of orchidectomy on the thymus, and in old rats the effects of testosterone were blocked by ATD in both thymus and spleen. Available cytosolic estrogen receptors were reduced in thymus of testosterone-treated orchidectomized rats, and this effect blocked by ATD, which itself was apparently able to induce estrogen receptors. Receptors could not be detected in thymus from aging rats, but were measureable in cytosols from thymus of orchidectomized or ATD-treated old rats. It is therefore possible to restore the thymus in intact aging rats without recourse to surgical or chemical castration, and such a maneuver may possibly be of use to enhance an immune system weakened by aging or disease.

Am J Pathol. 1985 Dec;121(3):531-51.
Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action.
Ansar Ahmed S, Penhale WJ, Talal N.
Immune reactivity is greater in females than in males. In both experimental animals and in man there is a greater preponderance of autoimmune diseases in females, compared with males. Studies in many experimental models have established that the underlying basis for this sex-related susceptibility is the marked effects of sex hormones. Sex hormones influence the onset and severity of immune-mediated pathologic conditions by modulating lymphocytes at all stages of life, prenatal, prepubertal, and postpubertal. However, despite extensive studies, the mechanisms of sex hormone action are not precisely understood. Earlier evidence suggested that the sex hormones acted via the thymus gland. In recent years it has become apparent that sex hormones can also influence the immune system by acting on several nonclassic target sites such as the immune system itself (nonthymic lymphoid organs), the central nervous system, the macrophage-macrocyte system, and the skeletal system. Immunoregulatory T cells appear to be most sensitive to sex hormone action among lymphoid cells. Several mechanisms of action of sex hormones are discussed in this review. The possibility of using sex hormone modulation of immune responses for the treatment of autoimmune disorders is a promising area for future investigation.

Acta Neurol Scand. 1999 Feb;99(2):91-4.
Correlation between sex hormones and magnetic resonance imaging lesions in multiple sclerosis.
Bansil S, Lee HJ, Jindal S, Holtz CR, Cook SD.
To determine if sex hormones play a role in the pathogenesis of multiple sclerosis (MS) by correlating serum estradiol and progesterone levels with gadolinium (Gd) enhancing lesions on magnetic resonance imaging (MRI) in MS.
Thirty patients with MS were studied with Gd enhanced brain MRI and simultaneous serum estradiol and progesterone levels either during the early follicular, late follicular or luteal phases of their menstrual cycle. Correlation between hormone levels and number of Gd enhancing lesions was determined.
Patients with high estradiol and low progesterone levels had a significantly greater number of Gd enhancing lesions than those with low levels of both these hormones. Patients with a high estrogen to progesterone ratio had a significantly greater number of active MRI lesions than those with a low ratio.
Estradiol and progesterone may influence disease activity in MS. If further studies confirm these results, it may be possible to develop therapy by altering levels of these hormones.

Rheum Dis Clin North Am. 2000 Nov;26(4):951-68.
Sex hormones and systemic lupus erythematosus.
Lahita RG.
Lupus is one disease in which sex hormones and gender are quite important. Studies of autoimmune diseases like lupus have made the hormone connection more important and increased our overall understanding of the sexual dimorphism of the immune system. It is clear that some fundamental biologic mechanism is at work here and that only knowledge of the molecular mechanisms behind the action of the hormones can help us to understand the gender preference in this illness. Hormones may be potent regulators of cytokine levels and, consequently, disease activity.

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