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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It seems apparent that the brain-pituitary-reproductive axis and the brain-thymus-lymphoid axis are linked by an array of internal mechanisms of communication that use similar signals (neurotransmitters, peptides, growth factors, hormones) acting on similar recognition targets. Moreover, such communication networks form the basis and control of each step and every level of reproductive physiology. This work has focused on the LHRH system, a primary central and peripheral clock of both neuroendocrine and immune functions. From the initiation of a sexually organized response, the detection of sexual odors, and the induction of mating behavior, extrahypothalamic and hypothalamic LHRH orchestrates the neuroendocrine modulation of gonadotropin secretion, while its expression within the ovary directly controls specific events such as follicular atresia. The presence of LHRH receptors in oocytes clearly anticipates a potential action of the decapeptide during the process of fertilization and/or implantation. Within the thymus and other peripheral immune organs, LHRH plays a unique role of immunomodulator, contributing to the sex-dependent changes in immune responsiveness during the estrous-menstrual cycle as well as pregnancy. The reciprocity of the neuroendocrine-immune signaling systems is further supported by the ability of sex steroids to modulate thymus-dependent immune functions via direct effects on specific target genes involved in the development of sex dimorphism and sex-dimorphic immune responses, including the downregulation of immune response observed during pregnancy. Such cyclic changes in immune responsiveness could have a physiological implication, such as the decrease or suppression in cell-mediated immunity observed in the postovulatory phase of the cycle and in pregnancy, respectively, and might play a role during the implantation process and the establishment of pregnancy. In this context, the ability of corticosterone to directly inhibit both GR transcript levels as well as a cell-mediated immune response within the thymus, and the modulation of such an inhibitory effect by the sex steroid hormone milieu, may offer an explanation and a molecular mechanism whereby stress may be deleterious for reproduction, also via immunomodulation. On the other hand, hormonally mediated alterations in immunity might also have a pathological implication in sexually related immune diseases. For example, in mouse and humans, lupus erythematosus is more prevalent in females and estrogen accelerates the disease process, while menstruation is known to exacerbate idiopathic thrombocytopenia purpura. Sex steroid hormone milieu might also have a role in controlling the stress response through immunomodulation. Within the placenta, an intricate network of signaling systems controls a delicate interplay between the neuroendocrine hormones, growth factors, and cytokines that are susceptible to play a major local role in the processes of implantation and the establishment and completion of pregnancy. The neuroendocrine and immunomodulatory role of LHRH continues well after parturition because the presence of LHRH-like material within the mammary gland and milk participates in the physiological modulation of hypophyseal, gonadal, and immune functions of the pups. Such a significant role played by the hypothalamic peptide in the modulation of immune responsiveness would indicate LHRH as the signal conveying information to both neuroendocrine and immune cells, with the role of informing and then transducing the messages into appropriate biological responses.(ABSTRACT TRUNCATED)
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PMID:Luteinizing hormone-releasing hormone (LHRH) receptors in the neuroendocrine-immune network. Biochemical bases and implications for reproductive physiopathology. 865 71

The hypothalamic homone gonadotropin-releasing hormone (GnRH) displays gender-specific actions. Pituitary responsiveness to GnRH is generally increased by estrogens and decreased by androgens. GnRH is now known to be produced by the immune system and to exert potent immunologic actions. Our central hypothesis is that gender differences in responsiveness to GnRH in the immune system play a pivotal role in the gender differences in immunity and autoimmunity. Studies in lupus-prone mice demonstrate that GnRH exacerbates murine lupus in a gender-specific fashion. Subsequent studies from our laboratory suggest that the gender differences in immunologic responsiveness to GnRH may relate to differences in the expression of the signal transducers through which GnRH acts, namely, the G proteins, Gs, and Gq/11. We have further demonstrated gender differences in second messengers for GnRH, IP3, and cAMF in immune cells. We have also demonstrated that GnRH agonist increases the quantities and/or activity of G proteins in immune cells in a gender-specific fashion. We speculate that gender differences in GnRH production and action, and in G protein expression play a role in a variety of autoimmune diseases that affect females predominantly.
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PMID:Gonadotropin-releasing hormone and G proteins: potential roles in autoimmunity. 1126 10

Our principle hypothesis is that the hypothalamic hormone, gonadotropin-releasing hormone (GnRH), is an immunostimulatory hormone and plays a pivotal role in the gender differences in immunity and/or autoimmunity. As a general rule, females display heightened immune responses and heightened endocrinological responsiveness to GnRH compared to males. We have previously demonstrated that GnRH receptor antagonists are effective in ameliorating murine lupus and that GnRH receptor agonists exacerbate murine lupus. GnRH exerts its actions via stimulatory G proteins, specifically via Galpha(s) and the homologous G proteins Galpha(q) and Galpha(11) (referred to together as Galpha(q/11)). We have previously demonstrated that females express higher levels of Galpha(q/11) mRNA and protein compared to males. We hypothesized that antisense inhibition of these specific G proteins would lead to a reduction in inflammatory cytokines and to an amelioration of disease in a mouse model of lupus. We randomized gonadectomized female (NZB x NZW) F1 hybrid mice to treatment with antisense oligonucleotides to Galpha(q/11) or to missense oligonucleotides. Administration of antisense oligonucleotides to Galpha(q/11) led to significant reductions in autoantibody levels, serum IgG levels, hematuria, and proteinuria compared to missense oligos. A trend toward prolonged survival was also noted. In vitro co-culture experiments demonstrated that antisense to Galpha(q/11) significantly inhibited IL-6 production compared to control.
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PMID:Administration of antisense oligonucleotides to Galpha(Q/11) reduces the severity of murine lupus. 1282 80

Androgens and estrogens exert potent divergent feedback effects on gonadotropin-releasing hormone (GnRH) production at the level of the hypothalamus and GnRH action at the level of the pituitary. Androgens exert generally suppressive effects on GnRH production and action, whereas rising levels of estradiol increase both GnRH release and action. In addition to its known endocrine actions, GnRH possesses immunomodulatory effects. We have previously demonstrated gender differences in immune responsiveness to GnRH that parallel gender differences in endocrine responsiveness: females appear to be more immunologically responsive to GnRH than males. GnRH exerts its actions via the stimulatory G protein Galpha(q) and Galpha(11) (referred to collectively as Galpha(q/11)) as well as via Galpha(s). We have recently demonstrated that the heightened immune responsiveness to GnRH in lupus-prone female mice correlated with increased expression of Galpha(q/11) in lymphoid cells from females compared to males. We hypothesize that the hormonal milieu of females may contribute to increased expression of stimulatory G proteins and to the heightened immune and endocrine responsiveness to GnRH. In this report, we document gender differences in expression of Galpha(q/11) protein in lymphoid organs in non-autoimmune DBA/2 mice. In an effort to address the mechanisms for the gender differences in G-protein expression, we used competitive reverse transcription PCR to quantitate mRNA for stimulatory G proteins in immune cells under various hormonal conditions. We quantitated the expression of Galpha(q/11) mRNA and protein under physiologic hormonal alterations, i.e. throughout the estrous cycle in female mice. We demonstrate that expression of Galpha(q/11) mRNA and protein in lymphoid organs is significantly increased on the afternoon of proestrus compared to metestrus. Additional studies demonstrate that exposure to GnRH or to estrogens significantly increases the expression of Galpha(q/11) mRNA in immune cells. These findings support an active role for hormonal modulation of G proteins in the gender differences in endocrinologic and immunologic responsiveness to GnRH.
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PMID:Gender differences and hormonal modulation of G proteins Galpha(q/11) expression in lymphoid organs. 1451 7

Pulsed intravenous cyclophosphamide is considered as standard therapy for lupus nephritis and several other severe manifestations of systemic lupus erythematosus (SLE). While the response rate to intravenous cyclophosphamide is substantial, concern has arisen about its toxicity. In addition to increased susceptibility to infection, bone marrow suppression, alopecia, hemorrhagic cystitis and malignancy, ovarian failure is an important side effect associated with the use of cyclophosphamide. Prior research on cyclophosphamide-treated women has consistently demonstrated that the risk of sustained amenorrhea depends on the age of the patient and the cumulative dose received. Sustained amenorrhea is difficult to avoid in women 32 years or older, even with very short intravenous cyclophosphamide courses. Younger women seem to have a substantially lower incidence of ovarian failure, but this side effect may be far more problematic for these patients. In these young women the risk may be modulated by the prior SLE disease duration, the presence of anti-U1RNP antibodies and anti-Ro antibodies. Co-treatment with gonadotropin-releasing hormone agonists may preseserve the future fertility and ovarian function in young women. Ovarian banking before administration of cyclophosphamide should be considered in selected patients.
Lupus 2004
PMID:Ovarian failure in systemic lupus erythematosus patients treated with pulsed intravenous cyclophosphamide. 1548 1

The possibilities to preserve fertility in women exposed to chemotherapy are: in vitro fertilization plus embryo cryopreservation, ovarian cryopreservation, unfertilized ova cryopreservation, and the administration of a gonadotropin-releasing hormone (GnRH) agonist. Because none of these methods is ideal, combination of several methods should be considered. Because the chances of preserving gonadal function following combined-modality treatment are significantly better for girls than for boys, simulation of a prepubertal milieu was applied only to women of reproductive age. The administration of GnRH agonists to women with Hodgkin's disease, breast cancer, and other malignancies, or to patients with lupus nephropathy, in parallel with chemotherapy, by others and by us, has demonstrated a significantly lower rate of premature ovarian failure in survivors than in nonrandomized controls. Several prospective, randomized studies are ongoing. A recent meta-analysis found that the administration of a GnRH agonist, in addition to chemotherapy, to patients with breast cancer was associated with less recurrence and superior survival. Several possibilities to explain the beneficial effect of GnRH agonists to minimize chemotherapy-associated gonadotoxicity are suggested: (a) The hypogonadotropic milieu decreases the number of primordial follicles entering the differentiation stage, which is more vulnerable to chemotherapy; (b) The hypoestrogenic state decreases ovarian perfusion and delivery of chemotherapy to the ovaries; (c) A direct effect of the GnRH agonist on the ovary occurs independently of the gonadotropin level; (d) GnRH agonists may upregulate an intragonadal antiapoptotic molecule such as sphingosine-1-phosphate; (e) The GnRH agonist may protect ovarian germline stem cells.
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PMID:How to preserve fertility in young women exposed to chemotherapy? The role of GnRH agonist cotreatment in addition to cryopreservation of embrya, oocytes, or ovaries. 1791 76

Administration of cyclophosphamide (CYC), an alkylating agent used to treat malignancies and severe rheumatic diseases, creates a risk of ovarian insufficiency that is related to the intensity and duration of therapy and the age of the patient. To preserve reproductive capacity in the appropriate clinical setting, oocyte, embryo, and/or ovarian tissue cryopreservation are recommended. Medical protection with depot gonadotropin-releasing hormone agonists (GNRHa) has emerged as a potential means to preserve both fertility and ovarian function through the suppression of ovarian activity during treatment with alkylators. We review the trials of GNRHa for ovarian protection in both cancer and rheumatic disease patients. Trials in cancer patients receiving CYC alone, or in combination with other gonadotoxic agents that have employed several different GNRHa have yielded mixed results. Trials in lupus patients receiving lower doses of CYC alone utilizing depot leuprolide acetate have tended to show favorable results.
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PMID:Ovarian protection with gonadotropin-releasing hormone agonists during cyclophosphamide therapy in systemic lupus erythematosus. 3186 83