Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gonadal steroids play an important role in the development and regulation of the immune system. Their effects may be mediated through a thymus-hypothalamus-pituitary-gonadal axis. The thymus gland secretes factor(s), including thymosin beta 4, that affect the release of gonadotropin releasing hormone (GnRH). GnRH regulates the subsequent release of luteinizing hormone, thereby affecting early ovarian development. Thymic factors may be modulated by gonadal steroids. Studies indicate that levels of thymosin beta 4 decrease in postmenopausal and ovariectomized women. In diseases such as systemic lupus erythematosus, abnormal patterns of estrogen metabolism may affect thymic function and contribute to the etiology of the disease.
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PMID:The role of the thymus-hypothalamus-pituitary-gonadal axis in normal immune processes and autoimmunity. 332 9

Infertility represents one of the main remote sequelae of cytotoxic chemotherapy given for various malignant diseases. The impairment of gonadal function after cytotoxic chemotherapy is more frequent in the male than in the female. Because dividing cells are more sensitive to the cytotoxic effects of alkylating agents than are cells at rest, it has been hypothesized that inhibition of the pituitary-gonadal axis by gonadotropin-releasing hormone (GnRH) agonists would render the germinal epithelium less susceptible to the cytotoxic effects of chemotherapy. This hypothesis has not been thoroughly clinically tested until recently, although several investigators have demonstrated that GnRH-agonistic analogues (GnRH-a) inhibit chemotherapy-induced ovarian follicular depletion in the rat and Rhesus monkeys. Based on this rationale, we have undertaken a prospective evaluation to determine whether GnRH-a administration during combination chemotherapy for Hodgkin's and non-Hodgkin's lymphoma could prevent posttreatment ovarian damage in women by inducing a temporary prepubertal hormonal milieu. While over 93% of the surviving patients in the GnRH-a and chemotherapy group resumed spontaneous ovulation and menses, less than 40% of the women in the control group of chemotherapy without the GnRH-a cotreatment resumed normal ovarian cyclic activity. More than 60% of the women experienced premature ovarian failure (POF) in the chemotherapy alone group. Our preliminary results suggest that GnRH-a cotreatment protects against POF during cytotoxic chemotherapy. The GnRH-a and chemotherapy cotreatment may be also suggested for young women treated by cyclophosphamide pulse therapy or other gonadotoxic treatments for systemic lupus erythematosus, organ transplantation and other autoimmune diseases. The technology of cryopreservation of human ova for future fertility in these patients awaits clinical validation and substantiation. This review discusses possibilities to prevent gonadal damage induced by cytotoxic therapy and presents the clinical data currently available.
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PMID:Prevention of gonadal damage during cytotoxic therapy. 924 Jun 25

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

Much progress has been made in the understanding of the impact of the neuroendocrine immune interactions and the pathogenic role in systemic lupus erythematosus, clinically and at the molecular level. This article focuses on the intertwining networks that involve the hypothalamic-pituitary-adrenal axis, cytokines within the central nervous system, and the sympathetic system. Hormones (estrogen, prolactin, gonadotropin-releasing hormone, and leptin) play an important role as immunomodulatory agents.
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PMID:The neuroendocrine-immune interactions in systemic lupus erythematosus: a basis for understanding disease pathogenesis and complexity. 1563 61

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