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.

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.

Dopamine supersensitivity, endorphin excess, and prostaglandin E1 deficiency: three aspects of the same schizophrenic elephant.

The author presents a hypothesis relating prostaglandin E1 (PGE1) deficiency to schizophrenia. The hypothesis is consistent with the importance of prolactin-stimulating properties in currently used antipsychotic drugs, the effect of prolactin on PGE1 synthesis, and the deficiency of PGE1 regulation in schizophrenic platelets. The author relates the PGE1 deficiency hypothesis to theories implicating dopamine and endorphins in the etiology of schizophrenia. A clinical trial in chronic schizophrenics has suggested the possible therapeutic efficacy of penicillin, a drug without dopamine-blocking actions which can stimulate PGE1 synthesis directly.

Pathogenesis of Woronoff ring in psoriasis.

As a result of ultraviolet light and coal tar therapy, a white ring (Woronoff) may develop in the normal skin adjacent to psoriatic plaques. Injection of prostaglandin E2 (PGE2) 1 cm outside of Woronoff ring produced redness in the ring, demonstrating that vessels within the ring were not unresponsive to PGE2. Whole skin homogenates from Woronoff ring contained an inhibitor of prostaglandin synthesis that was not found in uninvolved skin that was obtained from either psoriatics or normal controls. Prostaglandin E2 levels in the ring were one third of those in uninvolved skin from either psoriatics or normal controls. These findings suggest that the white ring that surrounds ultraviolet-light-treated psoriatic plaques is produced by a local inability to synthesize PGE2 in response to an ultraviolet light stimulus, resulting from the presence of an inhibitor of prostaglandin synthesis.

Prostaglandins and schizophrenia: a review.

1. Clinical observations and experimental findings are rendered which have raised the possibility that schizophrenia may be related to PGE deficiency and/or excess. 2. In favor of PGE1 deficiency are the findings that ADP-induced increase in synthesis and PGE1 stimulated cAMP accumulation are significantly lower in platelets of schizophrenic patients than in normal controls. 3. In favor of PGE excess are the findings that the concentration of immunoreactive PGE in cerebrospinal fluid of schizophrenics is higher than that of healthy controls, neurotic patients and patients undergoing neurological examination. 4. An argument against the PG excess hypothesis is that paracetamol, a substance which reduces PG levels has no therapeutic effect in schizophrenia. 5. The two hypotheses--PGE deficiency and PGE excess--are not compatible because of the bell shape dose response curve with PG's in certain biological systems.

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.

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.

A lack of essential fatty acids as a possible cause of hyperactivity in children.

The Hyperactive Children's Support Group (HCSG) in an organisation with over 70 branches in Britain devoted to helping such children and their families. We have carried out a detailed survey of the characteristics of many of our children and their families and have studied the literature in detail. We have come to the conclusion that many of these children have a deficiency of essential fatty acids (EFAs) either because they cannot metabolise linoleic acid normally, or because they cannot absorb EFAs normally from the gut, or because their EFA requirements are higher than normal. The main pieces of evidence are: 1. Most of the food constituents which cause trouble in these children are weak inhibitors of the conversion of EFAs to prostaglandins (PGs). 2. Boys are much more commonly effected than girls and males are known to have much higher requirements for EFAs than females. 3. A high proportion of our children have abnormal thirst and thirst is one of the cardinal signs of EFA deficiency. 4. Many of our children have eczema, allergies and asthma which some reports suggest can be alleviated by EFAs. 5. Many of our children are deficient in zinc which is required for conversion of EFAs to PGs. 6. Some of of our children are badly affected by wheat and milk which are known to give rise to exorphins in the gut which can block conversion of EFAs to PGE1. A preliminary study of EFA supplementation in a number of our children has given promising results. We hope that others with better facilities will be encouraged to test out this hypothesis.

Sjogren's syndrome and the sicca syndrome: the role of prostaglandin E1 deficiency. Treatment with essential fatty acids and vitamin C.

Lack of adequate synthesis of prostaglandin (PG) E1 may be the key factor in Sjogren's syndrome. PGE1 is important for lacrimal and salivary gland secretion and for T lymphocyte function: a deficiency could therefore account for the main features of Sjogren's syndrome and the sicca syndrome. PGE1 could also account for many of the other features often associated with these syndromes. These include the Raynaud's phenomenon, the abnormalities of renal function and the precipitation of the syndrome by vitamin C deficiency. Vitamin C is important in PGE1 biosynthesis. PGE1 treatment has been shown to correct the immunological abnormalities in the NZB/W mouse, the animal model of Sjogren's syndrome. An attempt to treat humans with Sjogren's syndrome by raising endogenous PGE1 production by administration of essential fatty acid PGE1 precursors, of pyridoxine and of vitamin C was successful in raising the rates of tear and saliva production.

Loss of delta-6-desaturase activity as a key factor in aging.

Aging is characterized by a wide variety of defects, particularly in the cardiovascular and immune systems. Cyclic AMP levels fall, especially in lymphocytes. Delta-6-desaturase (D6D) levels have been found to fall rapidly in the testes and more slowly in the liver in aging rats. D6D is an enzyme which converts cis-linoleic acid to gamma-linolenic acid (GLA). Other factors which inhibit D6D activity are diabetes, alcohol and radiation, all of which may be associated with accelerated aging. In meat eaters or omnivores which can acquire arachidonic acid from food, the main consequences of D6D loss will be deficiencies of GLA, dihomogamma-linolenic acid (DGLA) and prostaglandin (PG) E1. PGE1 activates T lymphocytes, inhibits smooth muscle proliferation and thrombosis, is important in gonadal function and raises cyclic AMP levels in many tissues. It is a good candidate for a key factor lost in aging. Moderate food restriction, the only manoeuvre which consistently slows aging in homoiotherms, raises D6D activity by 300%. Other factors important in regulating D6D and the conversion of GLA to PGE1 are zinc, pyridoxine, ascorbic acid, the pineal hormone, melatonin, and possibly vitamin B3. GLA administration to humans has been found to lower blood pressure and cholesterol, and to cause clinical improvement in patients with Sjogren's syndrome, scleroderma and alcoholism. These diseases are associated with some features of accelerated aging. The proposition that D6D loss is not only a marker of aging but a cause of some of its major manifestations is amenable to experimental test even in humans. The blocked enzyme can be by-passed by giving GLA directly.

A biochemical basis for alcoholism and alcohol-induced damage including the fetal alcohol syndrome and cirrhosis: interference with essential fatty acid and prostaglandin metabolism.

Alcohol has at least two actions on essential fatty acid (EFA) and Prostaglandin (PG) metabolism. It enhances the conversion of dihomogammalinolenic acid (DGLA) to PGE1 but it blocks the activity of the delta-6-desaturase, an enzyme necessary for replenishment of DGLA stores from dietary precursors. The acute effect of ethanol is therefore an increased production of PGE1 but chronic consumption will lead to depletion of DGLA and PGE1. Withdrawal from alcohol will lead to a precipitous fall in PGE1. PGE1 is known to have profound effects on the nervous system and behaviour. Patients with mania produce more PGE1 than normal while those with depression make less. Alcoholics may drink to maintain a normal PGE1 level, something which will require more and more ethanol as DGLA is depleted. In both animals and humans PGE1 or its precursor, gamma-linolenic acid (GLA) have been shown to attenuate the acute withdrawal syndrome. PGE1 injections prevent the development of fatty liver in alcohol-treated animals. Defective EFA and PGE1 metabolism are known to lead to increased fibrosis, reproductive failure, cardiomyopathy, cardiovascular disorders, gastritis and pancreatitis and could therefore be the basis for these disorders in alcoholics. A PGE1 deficiency could also be responsible for the fetal alcohol syndrome. Three other agents are known to produce constellations of fetal defects very similar to those found in the alcohol syndrome. These other factors are dihphenylhydantoin, lithium, and a deficiency of zinc. These three factors and excessive alcohol consumption all lead to PGE1 deficiency by different routes. If this concept is correct, the key to the management of alcoholism and its medical complications lies in the provision of GLA or DGLA, fatty acids which by-pass the alcohol blocked step and which are unfortunately unlikely to be present in any normal diet. Unlike many concepts of alcoholism and alcohol damage, the EFA/PGE1 idea is very readily testable and already has considerable experimental support.

The regulation of prostaglandin E1 formation: a candidate for one of the fundamental mechanisms involved in the actions of vitamin C.

Vitamin C stimulates the formation of PGE1 in human platelets. The effect occurs over the physiologically relevant range of concentrations. PGE1 is required for T lymphocyte function and plays a major part in the regulation of immune responses. PGE1 is also important in the regulation of collagen and ground substance metabolism, in cholesterol metabolism and in regulation of responsiveness to insulin. It is proposed that defective formation of PGE1 could account for many of the features of scurvy and for many of the reported therapeutic effects of vitamin C. If correct, vitamin C will be of value only in conjunction with an adequate supply of dihomogammalinolenic acid, the precursor of PGE1. Essential fatty acids, pyridoxine and zinc are all required to achieve this.

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)

[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.

[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.