Gender difference, sex hormones, and immediate type hypersensitivity reactions.

Gender differences in the development and prevalence of human diseases have long been recognized. Immense interest grows in the understanding of the role of sex hormones in the homeostasis of immunity. Asthma predominates in boys before puberty and this gender preference reverses after puberty and in adulthood, when adult women tend to have a more severe disease, often recalcitrant to treatment. Atopic eczema in preschool children shows insignificant gender difference or male preponderance in different studies, with more adult females suffering from atopic eczema. The limited data on the prevalence of immediate hypersensitivity to hymenoptera venom show controversial results. Discrepancy exists regarding the gender difference in food allergy, with females reporting significantly more allergic reactions in questionnaire studies. In general, adverse reactions to nonionic iodinated radiocontrast media are more commonly observed in females. The course of allergic diseases varies unpredictably during pregnancy, whereas hormone replacement therapy in postmenopausal women usually has a favorable influence on the course of asthma. Experiments in rodents confirm an effect of estrogens on mast cell activation and allergic sensitization, while progesterone is shown to suppress histamine release but potentiate IgE induction. Dehydroepiandrosterone may antagonize the production of Th2 cytokines but the effect of testosterone and the other androgens remains less defined. Actual data from human studies are lacking.

Influencia del ejercicio físico en la respuesta inmunitaria en mujeres / Influence of exercise on women's immune response

En los últimos 20 años muchos estudios han propuesto que elejercicio físico provoca cambios en el sistema inmunitario, loque ha hecho posible la creación de la nueva área de investigación“Ejercicio, Estrés e Inmunidad”, ya que además se consideraque los mecanismos de respuesta del sistema inmunitario alejercicio no son muy diferentes a los de respuesta al estrés. Así,el estrés del ejercicio conduce a un incremento proporcional enlos niveles de hormonas de estrés y los cambios concomitantesen diversos aspectos de la inmunidad.Las hormonas sexuales juegan un papel muy importante modulandoel sistema inmunitario, y se han identificado diferencias enla respuesta inmunitaria en relación al género. Dada las diferenciashormonales entre hombres y mujeres y sus diferencias en larespuesta frente al ejercicio, la respuesta inmunitaria innata y/oinflamatoria es frecuentemente más acusada en éstas últimas.Esta mayor reactividad inmunitaria podía ser la causa de que enlas mujeres las enfermedades inflamatorias y/o autoinmunes seanmás frecuentes. Así, un aumento de la respuesta inmunitariainnata debido al ejercicio físico puede prevenir enfermedadesinfecciosas durante el mismo; pero una estimulación exageradade esta respuesta también podría aumentar el riesgo de apariciónde patologías de carácter inflamatorio o exacerbar las mismas.Con esta revisión, hemos pretendido poner de manifiesto que losestudios sobre ejercicio físico e inmunidad en mujeres son todavíamuy escasos y que en muchas ocasiones no presentan igualesrespuestas similares a las observadas en hombres. Este hecho loconsideramos importante sobre todo en mujeres sedentarias, queinician actividades deportivas, para poder evaluar los efectosbeneficiosos o no del ejercicio sobre la inmunidad (AU)

In the last 20 years many studies have proposed that exercisecauses changes on the immune system, this have created a newfield of investigation “Exercise, Stress and Immunity”, since it isconsidered that the immune system mechanisms in response toexercise are not very different to the ones in response to stress.Thus, exercise-induced stress leads to a proportional increase instress hormones and changes on several immunity aspects.Sexual hormones play a key role modulating the immune system,and differences in the immune response in relation to the genderhave been identified. Due to the hormone’s differences betweenmen and women and their different responses to exercise, innate/inflammatory immune response is more marked in women.These greater immune responses could be the reason that inflammatory/autoimmune pathologies are more common in women.So, an increase in the innate immune response due to exercisecould prevent from infectious diseases; but an excessive responsecould also increase the risk to develop these pathologies orexacerbate them.In this review we pretend to show that there is lack of studiesabout exercise and immunity in women, and that in some casesthe responses are not similar to the ones observed in men. Thisfact is important for sedentary women who start sports activities,in order to evaluate the beneficial or non-beneficial effects onimmunity (AU)

The role of intradermal skin testing and patch testing in the diagnosis of autoimmune progesterone dermatitis.

Autoimmune progesterone dermatitis is a rare clinical condition in which patients display hypersensitivity to endogenous progesterone. It manifests as a cyclical cutaneous eruption that flares during the luteal phase of the menstrual cycle, when progesterone levels peak, and resolves partially or completely a few days after menses. Its cutaneous manifestations are variable and include urticaria, eczematous eruptions, vesiculopustular eruptions, fixed drug eruptions, stomatitis, erythema multiforme, and anaphylaxis. Autoimmune progesterone dermatitis has been diagnosed previously with intradermal skin testing or intramuscular progesterone challenge. Treatment of progesterone hypersensitivity generally consists of ovulation inhibition with pharmaceutical agents or oophorectomy; other therapies (eg, thalidomide) have also been used with success. We report a case of cyclical erythema multiforme (EM) induced by hypersensitivity to endogenous progesterone in a patient with a history of past oral contraceptive use. After herpes simplex virus was ruled out as an etiologic factor, a diagnosis of progesterone hypersensitivity was confirmed with intradermal skin testing. Results of subsequent patch testing with various progesterone derivatives were negative. The EM outbreaks were suppressed temporarily by continuous administration of Loestrin (ethinyl estradiol plus norethindrone), which also increased the responsiveness of the outbreaks to prednisone tapers.

Increased titer of anti-beta2-glycoprotein I IgG antibody among factor V Leiden carriers during oral contraceptive use.

The risk of thromboembolism during oral contraceptive (OC) use is increased among factor V Leiden (FVL) carriers compared to women with wild-type genotype of the gene for coagulation factor V (FV). The carrier frequency in the general population is too high for FVL alone to be responsible for the reported association. Additional risk factors may be required to explain the increased risk of thromboembolism of carriers during OC use. We conducted a case-control study to compare the titer of anti-beta2-glycoprotein I immunoglobulin G (IgG) and the frequency of elevated titer of IgG type anti-beta2-glycoprotein I antibody between FVL carriers and individuals with FV wild-type genotype with and without pill use. An asymptomatic population of 313 unrelated nonpregnant women were screened for FVL and for the presence of anti-beta2-glycoprotein I IgG antibody. Sixty-six women were FVL carriers and 247 had normal genotype. One-hundred and thirty-five women used OC at the time of screening and 178 did not. Among FVL carriers, OC pill users had a higher mean anti-beta2-glycoprotein I IgG titer than nonusers (9.2 SGU/mL vs. 4.7 SGU/mL, p = 0.0485). Among women with FV wild-type genotype, there was no significant difference in anti-beta2-glycoprotein I IgG titers between users and nonusers of OCs (6.4 SGU/mL and 6.0 SGU/mL, respectively; p = 0.7010). The odds of an elevated anti-beta2-glycoprotein I IgG titer during OC use in FVL heterozygous women was 2.41 (95% confidence interval: 0.79-7.39) relative to users with-type genotype. FVL may contribute to the development of elevated titer of IgG type anti-beta2-glycoprotein I antibody during OC use. The elevated titer of IgG type anti-beta2-glycoprotein I antibody may select women among FVL carriers during OC use with an increased risk of thromboembolism.

Maternal oral contraceptive use and atopic diseases in the offspring.

BACKGROUND: This study examined the association of maternal oral contraceptive (OC) use - before and after birth - and atopic manifestations in the offspring. METHODS: A total of 2754 East German children aged 5-14 years participated in a cross-sectional survey in 1998-99. The standardized parental questionnaire in 1998-99 included data on atopic diseases, socio-economic factors, parental atopy and maternal OC use. Specific immunoglobulin E against common inhalant allergens was measured by radioallergosorbent test (RAST). RESULTS: Maternal OC use before birth was associated with a higher risk of atopic diseases in the offspring compared with children of mothers who had never taken OC [asthma: odds ratio (OR) 1.6; 95% confidence interval (CI): 0.9-3.0; allergic rhinitis: OR 1.5; CI: 0.96-2.2; atopic eczema: OR 2.6; CI: 1.6-4.3; atopic sensitization: OR 1.5; CI: 0.97-2.2]. However, the effect estimates for maternal OC use after birth compared with the never users showed quite similar effects for these atopic conditions. No relations were observed between the prevalences of atopic diseases and maternal age at beginning of OC use, the duration of OC use, the type of contraceptive or maternal age at birth. CONCLUSION: This study raises doubts in a true biological association between OC use and atopic diseases.

Antiphospholipid antibodies in young women with and without oral contraceptive use.

The role of thrombophilia in the elevated risk of thromboembolism during oral contraceptive use has been established. We performed a cross-sectional study among young women to survey the occurrence of antiphospholipid antibodies among users and non-users of oral contraceptives. Serum levels of immunoglobulin (Ig)G, IgA and IgM isotypes of anti-beta2-glycoprotein I and anticardiolipin antibodies were measured by validated enzyme-linked immunosorbent assay methods. Combining all types of antiphospholipid antibodies, pill-users had an elevated antibody titre more than twice as frequently as non-users (odds ratio, 2.3; 95% confidence interval, 1.1-5.1). The higher frequency of elevated antibody titre was related most commonly to IgG type anti-beta2-glycoprotein I antibodies. Oral contraceptive use increases the risk of elevated antiphospholipid antibody levels among asymptomatic young women.

Manifestaciones reumáticas por el uso de anticonceptivos orales en mujeres sanas y su influencia en el lupus eritematoso sistémico / Rheumatic manifestations by use of oral contraceptives in patients with systemic lupus erythemotosus

Existe evidencia tanto experimental como clínica de que la alta incidencia de enfermedades autoinmunes en mujeres se relaciona con las hormonas sexuales femeninas. Los anticonceptivos orales (AO) son uno de los productos farmacológicos más efectivos con un tremendo impacto en los aspectos sociales, morales, sexuales y económicos de nuestra sociedad. Su uso en algunas mujeres sanas se ha relacionado con alteraciones inmunológicas (células LE, anticuerpos antinucleares, factor reumatoide y proteína C reactiva positivos); manifestaciones musculoesqueléticas (mialgias, artralgias, artritis, edema de manos o fibrositis) y cutáneas (fotosensibilidad, alopecia, fenómeno de Raynaud, eritema nodoso) que pueden simular enfermedad autoinmune. Asimismo, se realizó una revisión del uso de AO en pacientes con lupus eritematoso sistémico (LES) y su relación con exacerbación de la enfermedad, riesgo de desarrollo de lupus, complicaciones relacionadas con el uso de AO asociadas a LES o síndrome antifosfolípido y empleo de terapia hormonal de reemplazo en mujeres posmenopáusicas y LES. Noventa referencias

Absence of antisteroid antibodies in oral contraceptive users presenting with vascular events.

Previous reports speculated that vascular events could be related to the development of antibodies against synthetic steroids contained in oral contraceptives or other hormonal treatments. This study describes original immunoassays designed to detect antisynthetic steroid antibodies. In a first step, the assays were characterized and validated using animal-raised antisteroid antibodies. In a second step, a population of 88 oral contraceptive users, 47 of them having developed a vascular thrombosis during synthetic steroid use and 41 serving as healthy control users, were tested. Detection of antibodies against ethinylestradiol, levonorgestrel, norethisterone, cyproterone acetate, and gestodene showed that the values obtained in normal oral contraceptive users as well as thrombosis patients are very low, and show no statistically significant difference between the two groups tested. Taken together, these data indicate that the "immunological hypothesis" related to antisteroid antibodies is unlikely to explain the pathogenesis of vascular events in oral contraceptive users.

Anti-oestrogen antibodies in users of oral contraceptives and in patients with systemic lupus erythematosus.

Recent studies have demonstrated that many patients with SLE have elevated plasma levels of the minor oestrogen metabolite 16 alpha-hydroxyestrone (16 alpha OHE). This oestrogen is unique in its ability to react with lysine residues and form stable, covalent Heyns products with proteins. Increased levels of 16 alpha OHE-modified proteins have been found to occur on the membranes of red cells and lymphocytes in patients with SLE. In the present study, patient and control sera were analysed for the presence of circulating immunoglobulins which react with an oestrogen hapten. Anti-oestrogen antibodies were detected in 26% (9/34) of male and female SLE patients, and were found to correlate both with levels of plasma 16 alpha OHE (P less than 0.001) and with the presence of active disease (P less than 0.005). Surprisingly, this antibody activity was also observed in 25% (13/52) of normal, disease-free women who had a history of oral contraceptive use. No detectable activity was observed in normal men, women who had not taken oral contraceptives, or patients with a variety of other immunological diseases. The possible role of anti-oestrogen antibodies in both the hormonal exacerbation of SLE and in the long-term sequelae of oral contraceptive usage is discussed.

Problems in the measurement of putative serum immune complexes by the method of Beaumont.

A methodological investigation of the procedure used by Beaumont et al for measuring a "serum immune complex" precipitated by 25% ammonium sulfate and alleged to contain an ethynyl-estradiol binding immunoglobulin has found major problems with reproducibility and with the correlation of total protein as measured by the Lowry method and the IgG content as determined by a specific nephelometric procedure.

Production of antisera against contraceptive steroids.

A four step synthesis of 6-(0-carboxymethyl) oximinoethynylestradiol is reported. This compound, 6-(0-carboxymethyl) oximinomestranol, the 3-(0-carboxymethyl) oximes of norethindrone and norgestrel and the 3-hemisuccinate of ethynylestradiol were synthesized and conjugated with bovine serum albumin. Rabbits were immunized at 3 dose levels of haptene (20, 66 and 200 nmoles) and eight weeks later with a booster containing 66 nmoles of haptene. The antibody titer and association constant of responding rabbits was nearly independent of dose although most antibody production occurred after the booster injection. Antibodies to mestranol crossreacted more than 100 percent with ethynylestradiol and to a small extent with norethindrone and norgestrel.

PIP: The methods of synthesis of the 6-(0-carboxymethyl) oxime derivative of 6-oxoethynylestradiol-17beta, the 3-succinyl derivative of ethiny estradiol-17beta and the 3-carboxymethyl oxime derivative of norethindrone and norgestrel as well as the synthesis of the corresponding bovine serum albumin (BSA) conjugates required for the specific antisera for mestranol, ethinyl estradiol, norethindrone, and norgestrel in rabbits are described. The synthesis of 6-(0-carboxymethyl) oxime derivative involves a 4-step synthesis and a chromatographic purification which is an improvement over past methods. Conjugation to BSA was by the carbodiimide method. Response of immunization was measured in terms of titer, association constant, and cross-reactivity as a function of time after immunization with 3 dose levels of each antigen. Titer response was independent of dose for the original injection. Ethiny estradiol-3-conjugates had very low titers.

Erythema nodosum associated with pregnancy and oral contraceptives.

Erythema nodosum recurred in a woman during each of her four pregnancies and every time she was started on oral contraceptives. The lesions always disappeared in the fifth month of gestation or when contraceptives were withdrawn. Erythema nodosum is mediated by immune mechanisms, and both pregnancy and oral contraceptive use can interfere with the immune system. The concentrations of oestrogen and progesterone or the ratio between them may be critical to the development of erythema nodosum. The observation that the lesions spontaneously resolved in the fifth month of pregnancy supports this hypothesis.

PIP: The case of a woman with erythema nodosum occurring during each of 4 pregnancies and every time she was started on oral contraceptives (OCs) is reported. The onset of the disease was between the 2nd-5th months of pregnancy, disappearing after the 5th month. During a period in which she had been taking DL-norgesgrel .25 mg and ethinyl estradiol .05 mg the erythema nodosum was found to be resistant to cessation of OC therapy and to treatment. At examination she was found to have a sedimentation rate of 84 mm in 1 hour, raised seromucous levels, and considerably increased IgA. 8 days after all medication was stopped the erythrocyte sedimentation rate dropped.to 21 mm in 1 hour. Erythema nodosum is mediated by immune mechanisms. Both OCs and pregnancy can disrupt the immune system. The concentration of estrogen to progesterone may be criticalin the development of the symptoms as can be seen by the disappearance of the disorder in the 5th month of pregnancy.

[Monoclonal human immunoglobulin (IgG lambda) with antiethinylestradiol activity, oral contraceptives, and arterial pulmonary thrombosis]. / Immunoglobuline humaine monoclonale (IgG lambda) anti-éthinylaestradiol, contraceptif oral et thrombose artérielle pulmonaire

In a 36-year-old woman taking an oral contraceptive containing 50 mug of ethinyloestradiol each day, a pulmonary arterial thrombosis and a monoclonal gammapathia were associated. The monoclonal IgI lambda Mai... was prepared. When purified, this IgG lambda binds ethinyloestradiol with strong affinity (Ka= 2.7 times 10(7)M-1) and also 17-beta-oestradiol with a little less affinity (Ka = 0.4 times 10(7)M-1. For those ligands each IgG lambda Mai... molecule has two sites of same affinity and specificity so that a Scatchard plot of the experimental values gives a straight line. It is likely that the antibody sites of the IgG lambda Mai... are the binding sites. These facts support the hypothesis of an immunological mechanism of the thromboembolic disease which may be induced by oral contraceptives.

PIP: An IGG lambda was purified and its binding properties analyzed from the serum of a woman who had suffered a pulmonary embolism after taking an oral contraceptive (50 mcg ethinyl estradiol and 500 mcg norethisterone) for over 2 years. The purification steps were 1) precipitation with 25% ammonium sulfate; 2) gel filtration on DEAE Sepha dex A25-Sephadex G-25 at pH 10.5 with 6 M urea; 3) repeat gel filtration, but at pH 8.6 without urea; 4) chromatography on Sepharose 4B CNBr coupled with ethinyl estradiol. The activities of the fractions were analyzed by double diffusion immunoelectrophoresis. Scatchard plots by both dialysis and by ultracentrifugation generated an association constant of 2.7 X 10 7 M -1 for ethinyl estradiol, .4 X 10 7 M -1 for 17beta-estradiol, and a valence of 2. Normal human sera had such low affinities for ethinyl estradiol that the Ka could not be calculated. Immunoelectrophoresis showed only a single protein, of about 150,000 molecular weight in polyacrylamide gel. Equilibrium dialysis against other steroids demonstrated that the IgC was specific for ethinyl estradiol, but binding was inhibited to a lesser extent by the following, in order of potency: 17beta-estradiol, progesterone, estr adiol, testosterone, and estrone. The Ka was midway between that of albuinn and the highly specific steroid binding protein. The relationships between oral contraception, this apparent monoclonal gammapathy, and the pulmonary embolism are discussed.