Loss of luteotropic prostaglandin E plays an important role in the regulation of luteolysis in women.

STUDY QUESTION: Do intraluteal prostaglandins (PG) contribute to luteal regulation in women? SUMMARY ANSWER: Prostaglandin E (PGE), which is produced in human granulosa-lutein cells stimulated with luteotropic hCG, exerts similar luteotropic effects to hCG, and the expression of PG synthetic and metabolic enzymes in the human CL is driven toward less PGE but more prostaglandin F (PGF) during luteolysis. WHAT IS KNOWN ALREADY: Uterine PGF is a major luteolysin in many non-primate species but not in women. Increases in the PGF synthase, aldo-ketoreductase family one member C3 (AKR1C3), have been observed in the CL of marmoset monkeys during luteolysis. PGE prevents spontaneous or induced luteolysis in domestic animals. STUDY DESIGN, SIZE, DURATION: Human CL tissues staged as the early-luteal (n = 6), mid-luteal (n = 6), late-luteal (n = 5) and menstrual (n = 3) phases were obtained at the time of hysterectomy for benign gynecological conditions. Luteinized granulosa cells (LGCs) were purified from follicular fluids obtained from patients undergoing assisted conception. PARTICIPANTS/MATERIALS, SETTING, METHODS: Upon collection, one half of the CL was snap-frozen and the other was fixed with formalin and processed for immunohistochemical analysis of a PGE synthase (PTGES). Quantitative RT-PCR was employed to examine changes in the mRNA abundance of PG synthetic and metabolic enzymes, steroidogenic enzymes, and luteolytic molecules in the staged human CL and in human LGCs in vitro treated with hCG, PGE and PGF. A PGE withdrawal experiment was also conducted in order to reveal the effects of the loss of PGE in LGCs. Progesterone concentrations in the culture medium were measured. MAIN RESULTS AND THE ROLE OF CHANCE: The key enzyme for PGE synthesis, PTGES mRNA was abundant in the functional CL during the mid-luteal phase (P < 0.01), while mRNA abundance for genes involved in PGF synthesis (AKR1B1 and AKR1C1-3) increased in the CL during the late-luteal phase and menstruation (P < 0.05-0.001). PTGES mRNA expression positively correlated with that of 3ß-hydroxysteroid dehydrogenase (HSD3B1; r = 0.7836, P < 0.001), while AKR1C3 expression inversely correlated with that of HSD3B1 (r = -0.7514, P = 0.0012) and PTGES (r = -0.6923, P = 0.0042). PGE exerted similar effects to hCG-promoting genes, such as steroidogenic acute regulatory protein (STAR) and HSD3B1, to produce progesterone and luteotropic PGE, suppress PGF synthetic enzymes and down-regulate luteolytic molecules such as ßA- and ßB-inhibin subunits (INHBA and INHBB) and bone morphogenetic proteins (BMP2, BMP4 and BMP6). PGE withdrawal resulted in reductions in the enzymes that produce progesterone (STAR; P < 0.001) and PGE (PTGES; P < 0.001), and the capacity to produce PGE decreased, while the capacity to produce PGF increased during the culture. The addition of PGF did not recapitulate the luteolytic effects of PGE withdrawal. LARGE SCALE DATA: None. LIMITATIONS, REASONS FOR CAUTION: Changes in mRNA expression of PG synthetic and metabolic enzymes may not represent actual increases in PGF during luteolysis in the CL. The effects of PGF on luteal cells currently remain unclear and the mechanisms responsible for decreases in the synthesis of PGE in vitro and at luteolysis have not been elucidated in detail. WIDER IMPLICATIONS OF THE FINDINGS: The results obtained strongly support a luteotropic function of PGE in regulation of the human CL. They suggest that the main PG produced in human luteal tissue changes from PGE to PGF during the maturation and regression of the CL, and the loss of PGE is more important than the effects of PGF during luteolysis in women. This may be accompanied by reduced effects of LH/hCG in luteal cells, particularly decreased activation of cAMP/protein kinase A; however, the underlying mechanisms remain unknown. STUDY FUNDING AND COMPETING INTEREST(S): This study was supported by the Cunningham Trust to WCD, a Postdoctoral Fellowship for Research Abroad from the Japan Society for the Promotion of Science and the Suntory Foundation for Life Sciences to J.N.-K.; W.C.D. is supported by an MRC Centre Grant G1002033 and a Scottish Senior Clinical Fellowship. The authors have nothing to disclose.

High-dose ibuprofen therapy associated with esophageal ulceration after pneumonectomy in a patient with cystic fibrosis: a case report.

BACKGROUND: Lung disease in patients with cystic fibrosis is thought to develop as a result of airway inflammation, infection, and obstruction. Pulmonary therapies for cystic fibrosis that reduce airway inflammation include corticosteroids, rhDNase, antibiotics, and high-dose ibuprofen. Despite evidence that high-dose ibuprofen slows the progression of lung disease in patients with cystic fibrosis, many clinicians have chosen not to use this therapy because of concerns regarding potential side effects, especially gastrointestinal bleeding. However, studies have shown a low incidence of gastrointestinal ulceration and bleeding in patients with cystic fibrosis who have been treated with high-dose ibuprofen. CASE PRESENTATION: The described case illustrates a life-threatening upper gastrointestinal bleed that may have resulted from high-dose ibuprofen therapy in a patient with CF who had undergone a pneumonectomy. Mediastinal shift post-pneumonectomy distorted the patient's esophageal anatomy and may have caused decreased esophageal motility, which led to prolonged contact of the ibuprofen with the esophagus. The concentrated effect of the ibuprofen, as well as its systemic effects, probably contributed to the occurrence of the bleed in this patient. CONCLUSIONS: This report demonstrates that gastrointestinal tract anatomical abnormalities or dysmotility may be contraindications for therapy with high-dose ibuprofen in patients with cystic fibrosis.

Prostaglandin deficiency promotes sensitization of adenylyl cyclase.

Inhibition of prostaglandin synthesis by the drug indomethacin suppresses the synthesis of the cyclic AMP antagonist, prostaglandylinositol cyclic phosphate (cyclic PIP), and leads to a metabolic state comparable to type II diabetes. It was of interest whether prostaglandin-deficiency likewise causes sensitization of adenylyl cyclase, as this has been reported for the diabetic state. In liver plasma membranes of indomethacin-treated male rats, basal and forskolin-stimulated cyclic AMP synthesis remained unchanged when compared to untreated control rats. In control rats, stimulation of cyclic AMP synthesis by fluoride (2.2-fold) or glucagon (3.5-fold) was much lower than stimulation by forskolin (6.6-fold). In contrast, in indomethacin-treated rats, stimulation of cAMP synthesis by fluoride (4.6-fold) or glucagon (5.2-fold) nearly matched the stimulation by forskolin (6.4-fold). The level of alpha1-adrenergic receptors was slightly reduced, from 450 to 320 fmol/mg protein, by the indomethacin treatment. Independent of the treatment by indomethacin, stimulation of cyclic AMP synthesis by adrenaline failed, in agreement with the low density of adrenergic beta-receptors. In conclusion, PGE deficiency sensitizes adenylyl cyclase in rat liver for G protein-coupled receptors (glucagon) and also for fluoride.

Are disturbances of omega-6-fatty acid metabolism involved in the pathogenesis of atopic dermatitis?

Recent evidence indicates that the primary defect in atopic dermatitis (AD) might concern the maturation and differentiation of T cells which infiltrate the skin or are unable to control T cell infiltration of the skin. Unfortunately, there is no information on thymus hormones, T cell differentiation factors or cytokines during early T cell maturation in atopic infants. One of these factors at fault might involve a deficiency of essential long-chain omega-6-fatty acids and E-type prostaglandins which are important for thymic T cell maturation and thymus hormone action. Deficiencies of 6-desaturated omega-6-fatty acids have been observed in plasma phospholipids, epidermal and red cell phospholipids of patients with AD, in umbilical cord plasma lecithin of newborn infants with increased cord blood IgE levels, in cord blood T-cells of 'atopy-at-risk' newborn infants, in atopic monocytes, in adipose tissue lipids of patients with AD, in breast milk lipids of mothers with a history of AD, and in breast milk lipids of mothers of infants with AD. Reduced release of arachidonic acid has been measured in atopic monocytes and platelets. Diminished formation of prostaglandin E2 (PGE2) has been observed in atopic monocytes under stimulated and unstimulated conditions and in inflamed and non-inflamed atopic epidermis. PGE2 is able to suppress interleukin 4-induced IgE synthesis of human non-atopic mononuclear cells in vitro. We have demonstrated a suppressive effect of PGE1 and PGE2 on in vitro IgE synthesis of mononuclear blood cells of patients with AD and respiratory allergies.(ABSTRACT TRUNCATED AT 250 WORDS)

The GI T-lymphocyte theory of schizophrenia: some new observations.

Schizophrenic patients have low concentrations of PGE-1, n-6 fatty acids, vitamin C and zinc, elevated brain levels of dopamine and high plasma levels of interleukin-2 receptors (IL-2R). IL-2R plasma titers can be raised in celiac patients by administering wheat. These findings are both consistent with and supportive of the GI T-lymphocyte theory of schizophrenia.

Are deficiencies of prostaglandin-E-mediated immunoregulation involved in increased IgE synthesis of atopic mononuclear cells in vitro?

We demonstrate that spontaneous in vitro immunoglobulin E synthesis of atopic peripheral blood mononuclear cells could be suppressed by the addition of 10(-6) M to 10(-5) M prostaglandin E1 (PGE1) or PGE2. Impaired suppressor T lymphocyte maturation and function in atopic individuals are explained by an insufficient transmission of prostaglandin E (PGE) signals during thymic lymphocyte differentiation as well as an impaired ability of the atopic immune system to activate suppressor T cells by PGE-mediated feed back mechanisms. Decreased levels of 6-desaturated PGE-precursor fatty acids in plasma, T lymphocytes, monocytes, adipose tissue and breast milk have been observed in atopic individuals. These insights might offer a novel approach to the prevention of atopic disease by substitution of the atopic pregnant and nursing woman and her newborn infant with long-chain omega-6-fatty acids.

Prostaglandin E1 suppression of platelet aggregation response in schizophrenia.

The inhibitory effects of prostaglandin E1 (PGE1) on the platelet aggregation response (PAR) to adenosine diphosphate (ADP) in 103 schizophrenics, 55 patients with other mental disorders, and 71 controls were examined. The three groups did not differ in PAR to ADP. However, schizophrenic patients, especially in the acute state, showed a significant reduction in the inhibitory effects of PGE1 on PAR compared to the other two groups. These results suggest PGE1 hyposensitivity exists in some schizophrenic patients, which may result from PGE1 deficiency. As clinical characteristics of the subgroup showing platelet PGE1 subsensitivity, relatively successful heterosexual relations, less anergia, and a more severe activation factor on BPRS were identified. Furthermore, the relationship between platelet sensitivity to PGE1 and brain morphology, using magnetic resonance imaging on 39 male schizophrenics was examined. Of 11 parameters obtained from MRI measurements, only callosum: brain ratio showed a significant negative correlation with a platelet sensitivity to PGE1. The current study suggested existence of a subgroup of schizophrenia having platelet hyposensitivity and a definite clinical feature as state markers and small corpus callosum as a trait marker.

[Prostaglandins E1 and psychopathogeny of schizophrenia]. / Prostaglandines E1 et psychopathogénie des schizophrénies.

The authors assess the results of several studies, fundamental or clinical with therapeutic tests, to demonstrate a possible role of prostaglandins--specially of a possible lack of PGE1--in the pathogeny of certain forms of schizophrenia. The heterogeneousness of the results leads one to think there's heterogeneousness of the illness. Meanwhile, in certain cases, the contribution of a direct precursor of PGE1 the GLA, has given possible noticeable clinical results, mainly with deficiency symptoms.

[Prostaglandins and endogenous psychoses]. / Prostaglandine und endogene Psychosen.

The authors refer to the biochemical investigation of the occurrence and metabolism of essential fatty acids in the CNS and to significant differences in results between those obtained in animal experiments and those involving human beings, taking into account hypotheses that have not yet met with general acceptance. Discussed is the possible connection between eicosanic acid and schizophrenia, notably Horrobin's hypothesis of PGE1 deficiency in schizophrenic patients. The probability of a pathogenetic connection between changes in the metabolism of fatty acids and the occurrence of endogenous psychoses is assumed.

[Trial of onager oil in the treatment of schizophrenia in connection with the prostaglandin deficiency hypothesis]. / Essai de l'huile d'onagre dans le traitement de la schizophrénie en rapport avec l'hypothèse d'un déficit en prostaglandine.

Ten schizophrenic patients were treated with onager oil. It was hypothesized that E1 prostaglandin deficiency underlies the different biological disorders of schizophrenia. The clinical and biological results were disappointing. However the fact that the patients had been severely ill for a long time might have to be taken into account. Moreover, the blood level of gamma-linolenic acid was normal, at the start, in all the patients.