Immunology of normal and abnormal menstruation.

Normal menstruation is an inflammatory process, where the endometrial concentrations and functions of several leukocyte types can change greatly through the menstrual cycle, especially during the premenstrual and menstrual phases. These leukocytes probably have a range of functions related to mucosal protection, decidualization, embryo implantation, and the process of menstrual tissue breakdown, repair and remodeling. Some of these leukocyte changes are apparently linked to changes in the pattern of circulating leukocytes. Many immune cells have been identified in the endometrium, and those with most relevance to the processes of menstruation include uterine natural killer cells, macrophages, mast cells, neutrophils, dendritic cells and Tregs. A range of disturbances in endometrial immune cell numbers, distributions and functions, and in a range of different inflammatory and other mediators, have been identified in women with heavy menstrual bleeding or endometriosis. Sufficient evidence exists to implicate these immune changes in some of the functional disturbances and symptoms identified in these women. This field is greatly under-researched, and ripe for the wider application of modern molecular and cellular techniques in human and animal model studies.

Gynecological issues after organ transplantation.

Organ transplantation has become universally accepted treatment of end-stage organ failure. The main problem focuses on preventing the graft from rejection with the use of immunosuppressive agents. High incidence of infection is the most frequent adverse effect of immunosuppressive therapy. Symptoms of inflammation are often reduced in immunosuppressed patients. All invasive diagnostic and therapeutic procedures should be associated with the increase in dose of steroids and prophylactic antibiotics. Ovarian and menstrual function is usually restored in transplanted women. Function of the hypothalamus-pituitary-ovary axis in transplanted women is believed to be normal. Most common abnormal uterine bleeding in graft recipient are: prolonged and profuse menstruation and inter-menstrual bleeding or spotting. Among the underlying diseases are lesions of the uterus (fibroids, endometrial or cervical polyps), infections of sex organs or hormonal disturbances. Higher rate of endometrial hyperplasia (without atypia) is reported in renal graft recipients. Organ transplantation results in the restored fertility thus effective family planning method is necessary in women of reproductive age who do not want to conceive. Vaginal diaphragms are not advised and intrauterine device are contradicted. Observational studies indicate for safety and high rate of acceptance of oral and transdermal hormonal contraception in transplanted women. Over ten-year experiences of HRT administration in graft recipient have proved the benefits of the therapy. Patients after organ transplantation have three to four-fold increased incidence of malignancy compared with general population. All transplant women must undergo regular gynecological screening for premalignant and malignant lesions of sex organs and breast.

Gender-medicine aspects in allergology.

Despite the identical immunological mechanisms activating the release of mediators and consecutive symptoms in immediate-type allergy, there is still a clear clinical difference between female and male allergic patients. Even though the risk of being allergic is greater for boys in childhood, almost from adolescence onwards it seems to be a clear disadvantage to be a woman as far as atopic disorders are concerned. Asthma, food allergies and anaphylaxis are more frequently diagnosed in females. In turn, asthma and hay fever are associated with irregular menstruation. Pointing towards a role of sex hormones, an association of asthma and intake of contraceptives, and a risk for asthma exacerbations during pregnancy have been observed. Moreover, peri- and postmenopausal women were reported to increasingly suffer from asthma, wheeze and hay fever, being even enhanced by hormone replacement therapy. This may be on account of the recently identified oestradiol-receptor-dependent mast-cell activation. As a paradox of nature, women may even become hypersensitive against their own sex hormones, resulting in positive reactivity upon intradermal injection of oestrogen or progesterone. More importantly, this specific hypersensitivity is associated with recurrent miscarriages. Even though there is a striking gender-specific bias in IgE-mediated allergic diseases, public awareness of this fact still remains minimal today.

Individual differences in self-regulatory failure and menstrual dysfunction predict upper respiratory infection symptoms and antibody response to flu immunization.

Prior research indicates that cognitive priming manipulations that activate personal goals acutely increase or decrease natural killer cell cytotoxicity depending on whether individuals see themselves as making or failing to make progress toward their goals. Those findings in a laboratory setting revealed a psychobiological pathway whereby experiences of failure can influence health, but did not assess the impact of chronic perceived success/failure in goal pursuit on actual health outcomes. Three new studies investigated whether individual differences in perceived failure to attain personal goals influenced the self-reported symptoms of upper respiratory infections (URIs) as well as antibody response to flu immunization. Based on pilot data in young women, it also was hypothesized that the occurrence of menstrual dysfunction might interact with goal pursuit failure to more specifically predict cold and flu symptoms and optimal responses to vaccination. Perceived failure to attain goals did predict the reporting of URI symptoms as well as antibody levels post-immunization, both alone and in combination with menstrual dysfunction.

Inflammation and endometrial cancer: a hypothesis.

Endometrial cancer is the most common gynecologic malignancy in the United States. Substantial epidemiologic data implicate an imbalance of estrogens and progestogens in the etiology of this disease. We propose that inflammation also plays a role in endometrial cancer development. Emerging laboratory data suggest that elevated levels of prostaglandin E(2) may underlie the transformation of normal endometrium to neoplastic tissue and that in vitro nonsteroidal anti-inflammatory drugs may inhibit endometrial cancer cell growth. In this review, we suggest that the risk factors for endometrial cancer--unopposed estrogens, anovulation, polycystic ovary syndrome, excessive menstruation, early menarche, and late menopause--may be viewed as factors increasing the exposure of the endometrium to inflammation, whereas pregnancy and smoking, two likely protective factors, have the opposite effect. Chronic inflammation can induce rapid cell division, increasing the possibility for replication error, ineffective DNA repair, and subsequent mutations. A proinflammatory milieu can also directly increase estrogen production. Hence, inflammation may work in conjunction with or in addition to estrogen exposure in the development of endometrial cancer.

Treatment of autoimunne ovarian damage in adolescent girls.

INTRODUCTION: To investigate levels of antiovarian autoantibodies in girls and young women with disturbances of menstrual cycle before and during treatment with hormonal therapy. To explain morphological changes in ovarian structure in these patients. MATERIAL AND METHODS: Studied group included 39 patients. 18 patients were treated for primary amenorrhoea, 21 for menstrual cycle disorders. Patients included in the study were repeatedly examined at the beginning of the study and after six months during which they were treated by estrogen and gestagen. In all patients we have tested FSH, LH and FSH/LH ratio, presence of antiovarian antibodies. Results were compared with those obtained in control women. 21 antiovarian antibodies positive patients were indicated for laparoscopic biopsy. Bioptic sample was examined using light and electron microscopy. RESULTS: Our treatment with hormonal therapy lead to the reduction of ovarian antigens. In 85% of the cases marked decrease of antiovarian autoantibodies levels was observed, while in 28% of the cases the levels were undetectable. From morphological changes of the bioptic sample enhanced atresia of follicules at different developmental stages was frequently observed. It evoked marked reduction of follicular apparatus up to its complete disappearing. CONCLUSION: The results of our study and mapping of the antiovarian antibodies positivity support our hypothesis that the antiovarian antibodies positivity corresponds with the clinical symptoms. Appropriate treatment with hormonal replacement therapy minimizes ovarian destruction, preserves ovarian hormonal functions and saves healthy ovarian tissue necessary for future fertility.

Menstrual variation of autonomic balance may be a factor in exacerbations of certain diseases during the menstrual cycle.

Exacerbation of certain medical conditions during specific phases of the menstrual cycle has long been recognized. Mechanisms of the cyclic variations are poorly understood, but are often attributed to fluctuations in reproductive hormones. We hypothesize that normal variations in autonomic balance during the menstrual cycle, which likely evolved as adaptations for reproduction, may contribute to catamenial variations in diseases independent of hormonal variations. Emerging evidence suggests that autonomic balance shifts towards sympathetic bias during the second half of the menstrual cycle. This shift can be seen as an evolutionary adaptation to address the immunologic and physiologic demands for successful implantation and gestation. Through direct modulation of lymphoid system and activation of the cortisol pathway, sympathetic bias promotes a shift to relative T helper (Th)-2-biased immunity which may favor maternal tolerance of the embryo by attenuating Th-1-mediated interference of implantation. Immune variance during the menstrual cycle has been implicated in menstrual fluctuations of many diseases, but until now the immune variance has been attributed to female hormonal changes. We propose that shifts in autonomic balance independently contribute to fluctuations in diseases by modulating the immune system. Still further, we propose that many other diseases fluctuate due to the direct nervous system actions of shifts in autonomic balance. Our hypothesis portends new therapeutic paradigms based on cyclical modulation of autonomic balance to address catamenial variations of medical conditions.

Immunology and endometriosis.

PROBLEM: Accumulating data suggests that aberrant immune responses during retrograde menstruation may be involved in the development of endometriosis. METHOD OF STUDY: The role of immunology in the etiology of endometriosis is reviewed and summarized from the available literature. RESULTS: Immunologic factors may affect a woman's susceptibility to implantation of exfoliated endometrial cells. Immune alterations include increased number and activation of peritoneal macrophages, decreased T cell reactivity and natural killer cell cytotoxicity, increased circulating antibodies, and changes in the cytokine network. CONCLUSION: There is substantial evidence that immunologic factors play a role in the pathogenesis of endometriosis and endometriosis-associated infertility. Decreased natural killer cell cytotoxicity leads to an increased likelihood of implantation of endometriotic tissue. In addition, macrophages and a complex network of locally produced cytokines modulate the growth and inflammatory behavior of ectopic endometrial implants.

Premenarchal and postmenarchal girls with insulin-dependent diabetes mellitus: ovarian and other organ-specific autoantibodies, menstrual cycle.

STUDY OBJECTIVE: To estimate various organ-specific autoantibodies and detect other endocrine autoimmune disorders and menstrual cycle characteristics in girls with Type 1 insulin dependent diabetes mellitus (IDDM). DESIGN: Prospective cohort study from 1993 to 1998, duration 4.5 years. SETTING: Diabetes & Endocrine Clinic of the University Hospital, Motol, Prague. PATIENTS: 53 IDDM girls (group A--43 postmenarchal, group B--10 premenarchal), 15.5 +/- 2.5 (8-19) years old, 6.2 +/- 4.3 years after IDDM onset. MAIN OUTCOME MEASURES: Ovarian autoantibodies directed to ooplasm, zona pellucida, membrana granulosa, theca folliculi interna, and lutein cells, insulin autoantibodies, thyroid peroxidase and thyroglobulin autoantibodies. Menstrual cycle character, endocrine glands disturbance. Diabetes control, body mass index, duration of IDDM. RESULTS: Ovarian autoantibodies in at least one of the followed structures were found in 67.9% of the IDDM girls. In the control group of 21 healthy girls of corresponding age, the positive findings in lutein cells were found in only 4.8% of the girls (P < 0.01 versus IDDM girls). The lutein cells commonly associated with theca folliculi interna cells were the most frequent immunopositive structures in diabetic girls (P < 0.05 versus another positive ovarian autoimmune structure). Autoantibodies directed to ovarian steroid producing cells were frequent in IDDM patients with both irregular and normal menstrual cycles. Irregular menstrual cycles were diagnosed in 27.9% of IDDM girls, polymenorrhea in half of them, and oligomenorrhea in the remainder. Diabetes control in our patients (glycosylated hemoglobin HbA1c in postmenarchal girls 10.1 +/- 2.0%) did not differ between those with regular and those with irregular menstrual cycles. Over a follow-up period one-third of the girls with oligomenorrhea and a long-term noncompliance (HbA1c 13.5%) developed secondary amenorrhea. Insulin autoantibodies were found in 67.8%, thyroid peroxidase autoantibodies in 12.5%, and thyroglobulin autoantibodies in 10.4% of the IDDM girls. Autoimmune thyroiditis was diagnosed in 5 IDDM patients (9.4%); hypothyroidism developed in 3 of them. Menstrual cycle was irregular in 4 of the 5 girls with autoimmune thyroiditis (polymenorrhea in 1, oligomenorrhea in another 3 girls). CONCLUSIONS: An increased incidence of various circulating autoantibodies may be markedly demonstrated in IDDM girls. Their reproductive function might have an important relationship to an evidence of ovarian autoantibodies. Menstrual cycle disturbances could be linked to the poor diabetes control, to the presence of ovarian and other autoantibodies, and also to other autoimmune disease.

Anti-corpus luteum antibody: a novel serological marker for ovarian dysfunction in systemic lupus erythematosus?

OBJECTIVE: To investigate the presence of autoantibodies directed to corpus luteum (CoL) in systemic lupus erythematosus (SLE) sera and its correlation with menstrual disturbances. METHODS: We evaluated 87 female patients with SLE, < 40 years old, and 23 women with normal menses as controls. Anti-corpus luteum antibody was detected by immunoblot technique. RESULTS: Reactivity to a bovine CoL antigen was found in 22% of SLE sera. Characterization of the target antigen revealed a 67 kDa glycoprotein highly enriched in corpus luteum, but nearly absent in total ovary extract. Similarly, target antigen was also weakly detectable in tissues that produce or metabolize steroids, such as testis, adrenal cortex, and liver, and it was absent in adrenal medulla or HEp-2 cells. Anti-CoL antibody was easily distinguished from other frequent reactivities of SLE sera, including anti-RNP, anti-Sm, anti-Ro/La, anti-dsDNA, or anticardiolipin. The observation of anti-67 kDa reactivity to human CoL suggests a possible pathogenic role in gonadal dysfunction. Indeed, we observed an inverse association of anti-CoL antibody with the duration of hypergonadotropic amenorrhea. Supporting this hypothesis, in patients with normal or irregular menses, the presence of this antibody was associated with elevated serum level of follicle stimulating hormone, an early and specific sign of ovarian lesion. CONCLUSION: Anti-CoL antibody seems to be associated with early stages of ovarian dysfunction in SLE. Moreover, since similar association of antiovarian antibodies has been observed in an experimental model of autoimmune oophoritis, our findings raise the possibility of autoimmune ovarian lesion in patients with SLE.

Treatment of common gynecologic-endocrinologic symptoms by allergy management procedures.

The technique of managing allergies by optimum-dose (provocative neutralization) testing and treatment using aqueous progesterone has been studied in 132 women having progesterone-related symptoms due to the menstrual cycle, pregnancy, or exogenous hormone administration. When extremely small doses of progesterone (0.0016 mg or below, up to maximum of 2.5 mg) were administered following determination of specific dose requirement by skin testing, startlingly rapid and effective clearing of symptoms was observed. With these individualized doses, symptoms cleared completely or almost completely within 30 minutes in the majority of patients. A single-blind technique was employed to rule out placebo effect. Some common problems found to respond well to the procedure were nausea and vomiting during pregnancy (100%), premenstrual syndrome (96%), and dysmenorrhea (84%).

Sensitivity to endogenous progesterone. Report of a case.

A patient with a cyclic premenstrual eruption, clearing spontaneously with the menstrual flow, is reported. Hypersensitivity to endogenous progesterone in this case was confirmed by positive intradermal and leukocyte migration inhibition tests. Treatment with conjugated estrogens was followed by remission of symptoms. The importance of awareness to the possibility of progesterone autoimmune mechanisms is emphasized.