[Stress and fertility]. / A stressz és a fertilitás.

In Western countries, sperm quality and fertility of men significantly worsened. Female infertility does not show a better trend either. Subtle defects in the reproductive functions can not be explained by the current methods, and "unexplained infertility" is becoming a more common diagnosis. Every year 1 million couples seek expensive and time consuming fertility treatment in the world. Deeper understanding of an unhealthy lifestyle and the environmental damages may lead to personalized treatments to increase the chance of conception.The effects of various stressors on the male and female reproductive performance were scientifically substantiated by Selye and coworkers in 1976. Cognitive therapy methods can be applied against emotional stressors, supplementation by antioxidants against reactive oxygen compounds, and administration of vitamins and trace elements, especially when deficiency is found, may help before medical intervention on a rational and economical way in the fight against infertility.

Inappropriate angiogenic response as a novel mechanism of duodenal ulceration and impaired healing.

BACKGROUND: Despite recent advances and better understanding of the etiology and the pathogenesis of gastrointestinal ulcer diseases, e.g., duodenal ulcer, the molecular events leading to ulcer development, delayed healing, and recurrence remain poorly elucidated. AIMS: After we found that duodenal ulcers did not heal despite increased levels of vascular endothelial growth factor (VEGF), we tested the hypothesis that an imbalance in angiogenic VEGF and anti-angiogenic endostatin and angiostatin might be important in the development and delayed healing of experimental duodenal ulcers. METHODS: Levels of VEGF, endostatin, and angiostatin, and the expression and activity of related matrix metalloproteinases (MMP) 2 and 9 were measured in scrapings of rat proximal duodenal mucosa in the early and late stages of chemically induced duodenal ulceration. Furthermore, animals were treated with recombinant endostatin and MMP 2 inhibitor to test the relationship between MMP2 and endostatin and their involvement in healing of experimental duodenal ulcers. RESULTS: A concurrent increase of duodenal VEGF, endostatin, and angiostatin was noted during duodenal ulceration. Endostatin treatment aggravated duodenal ulcer. Levels of MMP2, but not MMP9, were increased. Inhibition of MMP2 reduced levels of endostatin and angiostatin, and attenuated duodenal ulcers. CONCLUSIONS: Increased levels of endostatin and angiostatin induced by MMP2 delayed healing of duodenal ulcers despite concurrently increased VEGF. Thus, an inappropriate angiogenic response or "angiogenic imbalance" may be an important new mechanism in ulcer development and impaired healing.

Cosegregation of gastrointestinal ulcers and schizophrenia in a large national inpatient discharge database: revisiting the "brain-gut axis" hypothesis in ulcer pathogenesis.

The lifetime prevalence of duodenal ulcer in the United States is 8 to 10%, whereas another 1% of the population is affected by gastric ulcer. Both central and peripheral dopamine pathways may influence ulcer pathogenesis. Dopamine agonists prevent whereas antagonists augment stress- and chemically induced gastrointestinal ulcers in preclinical models. The dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,36-tetrahydropyridine (MPTP) depletes central dopamine and induces lesions in the substantia nigra, and, if given in high doses, MPTP induces a Parkinson disease-like syndrome and gastric ulcers. Because schizophrenia is attributed, in part, to an overactive dopaminergic system, persons with schizophrenia may display a reduced susceptibility toward gastrointestinal ulcers. A case-control study was conducted in patients represented in the 2002 National Inpatient Sample, the largest all-payer inpatient care database in the United States, consisting of 5 to 8 million inpatient hospital stays per year, which approximates a 20% sample of community hospitals. A significant association was observed between schizophrenia and diminished risk for duodenal (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.45-0.67) and gastric (OR 0.54; 95% CI 0.46-0.63) (p < .01) ulcers but not for gastrojejunal ulcers (OR 0.44; 95% CI 0.16-1.20) (p = .11). Potential confounders such as age, gender, race, tobacco or alcohol dependence, and Helicobacter pylori infection were controlled in multivariate analyses. This observational study in a large sample of patients in community hospitals suggests that schizophrenia and attendant neurobiologic mechanisms (eg, variability in dopamine pathways) may act in concert to modify the composite risk for gastrointestinal ulcers. Dopamine pathways warrant further prospective research as new potential drug targets in ulcer disease.

New molecular mechanisms of duodenal ulceration.

Stress is a major etiologic factor in the pathogenesis of gastric and duodenal ulceration, as first described in rats by Hans Selye. In patients with "peptic ulcers" duodenal ulcers are more frequent than gastric ulcers (except in Japan). Thus, our research during the last three decades focused on the molecular mechanisms of duodenal ulcer in rodent models of chemically induced duodenal ulceration, and here we review our three recent findings: Endothelins (ET-1), the immediate early gene egr-1 and imbalance of angiogenic/antiangiogenic molecules. Namely, we found an enhanced expression and release of ET-1 within 15-30 min after the administration of duodenal ulcerogen cysteamine, resulting in local ischemia that triggers the expression of hypoxia-inducible factors (HIF-1alpha). Our gene expression studies also revealed an early (0.5-2 h) increase in the expression of egr-1 that is followed (12-24 h) by upregulation of angiogenic growth factors (e.g., VEGF, bFGF, PDGF). Surprisingly, this event is also associated with an enhanced production of angiostatin and endostatin that probably counteract the beneficial effect of angiogenic molecules. Thus, the initial injury to endothelial and epithelial cells in duodenal ulceration seems to be aggravated (and not initiated) by HCl and proteolytic enzymes. The resulting mucosal necrosis does not rapidly heal because of the imbalance of VEGF and angiostatin/endostatin, hence duodenal ulcers develop. The experimental ulcers Selye described morphologically are now characterized at the molecular and genome level, involving unexpected mediators like ET-1, egr-1 and angiogenesis-related molecules.

Suppression of early growth response factor-1 with egr-1 antisense oligodeoxynucleotide aggravates experimental duodenal ulcers.

Previously, we demonstrated that cysteamine releases endothelin-1 in the rat duodenal mucosa, followed by increased expression of early growth response factor-1 (egr-1). We hypothesized that egr-1 is a key mediator gene in the multifactorial mechanisms of duodenal ulcer development and healing because its protein, transcription factor product Egr-1, regulates the expression of angiogenic growth factors. We wanted to determine the effect of egr-1 antisense oligonucleotide on cysteamine-induced duodenal ulcers as well as on the expression of bFGF, PDGF, and VEGF, of which synthesis is modulated by Egr-1. An antisense oligonucleotide to egr-1 was used to inhibit the synthesis of Egr-1 and to determine its effect on ulcer formation in the rat model of cysteamine-induced duodenal ulceration. Real-time RT-PCR and Western blot analysis were used to assess the expression of Egr-1 mRNA and protein as well as ERK, bFGF, PDGF, and VEGF. The antisense Egr-1 oligonucleotide inhibited the expression of egr-1 mRNA and protein and increased the duodenal ulcer size from 8.1 +/- 1.8 mm(2) in controls to 20.7 +/- 4.0 mm(2) (P < 0.01). Cysteamine induced phosphorylation of ERK1/2 and enhanced the synthesis of bFGF, PDGF, and VEGF in the preulcerogenic stages of duodenal ulceration, whereas egr-1 antisense oligonucleotide markedly decreased the expression of these growth factors in the duodenal mucosa. We also demonstrated that Egr-1 expression relates to the ulcerogenic effect of cysteamine because these actions were not exerted by the toxic analog ethanolamine. Thus Egr-1 seems to play a critical role in duodenal ulceration because Egr-1 downregulation aggravates experimental duodenal ulcers, most likely through the transcriptional inhibition of bFGF, PDGF, and VEGF synthesis.