Elevated Prostaglandin Levels Research Articles

Nonsteroidal anti-inflammatory drugs and changing attitudes toward dysmenorrhea

Dysmenorrhea, which may be primary or secondary, is the occurrence of painful uterine cramps during menstruation. Until a decade ago, medical and social attitudes toward dysmenorrhea were shrouded with folklore, psychoanalytical profiles, or psychosomatic bases. In secondary dysmenorrhea, there is a visible pelvic lesion to account for the pain, whereas only a biochemical abnormality is responsible for primary dysmenorrhea. Recent advances in the biochemistry of prostaglandins and their role in the pathophysiology of primary dysmenorrhea and intrauterine device (IUD)-induced dysmenorrhea have now firmly established a rational basis for the disorder. In primary dysmenorrhea, menstrual prostaglandin release is significantly increased but can be readily suppressed to normal levels when nonsteroidal anti-inflammatory drugs (NSAIDs) capable of inhibiting cyclo-oxygenase are given during menstruation. Many clinical trials (controlled and uncontrolled) have demonstrated the efficacy of NSAIDs such as the fenamates, indole-acetic acid derivatives, and arylpropionic acid derivatives in relieving primary dysmenorrhea as well as IUD-induced dysmenorrhea that is also due to elevated prostaglandin levels. With a few of these NSAIDs, it has been shown that the relief of pain is associated with a significant decrease in menstrual fluid prostaglandin levels. Cumulative data of clinical trials indicate that with the effective NSAIDs, 80 percent of patients with significant primary dysmenorrhea can be adequately relieved. Ongoing studies suggest that in some women, endometrial leukotriene, but not PGF 2a production, is increased. With the official approval and availability of several effective NSAIDs for the specific treatment of primary dysmenorrhea in the United States, women who have primary dysmenorrhea have been greatly relieved and their productivity increased. Primary dysmenorrhea affects 50 percent of postpubescent women and absenteeism among the severe dysmenorrheics has been estimated to cause about 600 million lost working hours or 2 billion dollars annually. Thus, an effective, simple, and safe treatment of primary dysmenorrhea for two to three days during menstruation will not only have a positive economic impact but will also enhance the quality of life. The availability of effective dysmenorrhea therapy with NSAIDs has induced greater expectations of relief by the patient, as well as greater willingness to seek medical help, a more rational approach to patient management by physicians, changes in attitude toward women with primary dysmenorrhea, and the debunking of myths about dysmenorrhea that often have been perpetuated as fact. NSAIDs have undoubtedly revolutionized a painful disorder.

Prostaglandin concentrations in cerebrospinal fluid of rabbits under normal and ischemic conditions.

Clinical studies have demonstrated elevated levels of both arachidonic acid and prostaglandins in the cerebrospinal fluid of humans after ischemic stroke and subarachnoid hemorrhage. Such increases in free fatty acid, arachidonic acid, and prostaglandin concentrations suggest excessive production and accumulation of these substances in the ischemic brain. We used a rabbit model of ischemic infarction to examine the relation between controlled central nervous system ischemia and cerebrospinal fluid prostaglandin levels. We found that following stroke PGF2 alpha and not PGD2 was the predominant prostaglandin present in the cerebrospinal fluid. PGF2 alpha also underwent the largest percent increase over control prostaglandin concentrations. This is similar to human and dog cerebrospinal fluid studies, which demonstrate PGF2 alpha as the predominant prostaglandin following ischemic injury. The lack of PGD2 elevation under ischemic conditions may suggest that the rabbit model is more like stroke in humans than the rat or gerbil models. Our preliminary work demonstrates that it is practical to study postischemic prostaglandin changes in cerebrospinal fluid rather than in brain tissue in a rabbit model of central nervous system ischemia.

Production of uric acid in cerebrospinal fluid after subarachnoid hemorrhage in dogs: investigation of the possible role of xanthine oxidase in chronic vasospasm.

Based on accumulating evidence of the role of xanthine oxidase (XO) in generating oxygen free radicals and causing tissue damage during ischemia, we examined the possible role of XO in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). After inducing SAH in dogs by two autologous blood injections 2 days apart, chronic vasospasm of the basilar artery was reliably produced. There was a 3.5-fold elevation in uric acid (UA), the product of XO, in the cerebrospinal fluid (CSF) of these animals. Parenteral administration of allopurinol (i.v., 25 mg/kg, every 6 hours), a specific blocker of XO, successfully abolished the elevation in CSF uric acid levels due to SAH. However, angiographic vasospasm measured on Day 7, morphological changes observed by electron microscope, and elevated CSF prostaglandin levels were not altered by the treatment. It can be concluded that the observed activation of the enzyme XO, which is a well-known source of oxygen free radicals in ischemia in various organs, is not playing a major role in the pathogenesis of chronic cerebral vasospasm in this animal.

Effects of complement fragments on pulmonary and vascular smooth muscle.

Effects of complement fragments on pulmonary and vascular smooth muscle.

Ionophore A23187 stimulates [formula omitted] to release prostaglandin F 2α

High performance liquid chromatography and radioimmunoassay were used to identify the rostaglandins synthesized by Entamoeba histolytica (NIH:200 Strain) Ca 2+ ionophore A 23187 stimulated amebae produced elevated levels of prostaglandin F 2α when compared with the control cells. There were no significant differences in the levels of prostaglandin E 2 and thromboxane B 2. This is the first report of a stimulated non-mammalian cell producing prostaglandin F 2α.

Arachidonic acid metabolites in cutaneous carcinomas. Evidence suggesting that elevated levels of prostaglandins in basal cell carcinomas are associated with an aggressive growth pattern.

There is evidence suggesting a role of eicosanoids in the growth of certain tumors. In this study, tissue samples were collected from basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) of the skin. Both BCCs and SCCs contained more prostaglandin E2 and F2 alpha (PGE2 and PGF2 alpha) than normal epidermis. In vitro incubation of tumor samples with arachidonic acid also resulted in PGE2 and PGF2 alpha formation. Basal cell carcinomas exhibiting a histologically aggressive growth pattern contained higher levels of prostaglandins than those with a nonaggressive growth pattern, both in vivo and after in vitro incubation. Lipoxygenase products (12- and 15-hydroxyeicosatetraenoic acid) were present in smaller amounts than cyclo-oxygenase products (PGE2 and PGF2 alpha) in vivo. Compared with normal epidermis, SCCs and, particularly, BCCs produced smaller amounts of 12-hydroxyeicosatetraenoic acid during in vitro incubation with arachidonic acid. The levels of lipoxygenase products were not related to the tumor growth pattern. These results indicate that excessive prostaglandin levels in BCCs may be associated with an aggressive growth pattern.

Development of a model system to study leukotriene-induced modification of radiation sensitivity in mammalian cells

Leukotrienes (LT) are an important class of biological mediators, for which no information exists concerning their synthesis following a radiation insult, or on their ability to modify cellular response to a subsequent radiation exposure. LT are derived from arachidonic acid, as are prostaglandins, although by a separate enzyme system. Prostaglandins are able to modify radiosensitivity of mammalian cells in vivo and in vitro. In addition, the cytoprotective effect induced by prostaglandins may have significance in cancer therapy since certain breast cancers which secrete elevated levels of prostaglandins are more resistant to therapy than similar tumors without the prostaglandin elevation. The objective of this study was to define a model system in which the metabolic fate of the LT could be monitored, and the effort of LT on the ionizing radiation sensitivity of mammalian cells in vitro could also be characterized.

Mechanism of enhanced fibroblast arachidonic acid metabolism by mononuclear cell factor.

Chronic inflammation is associated with an infiltration of mononuclear cells, fibroblast proliferation, and elevated levels of prostaglandin (PG) E2. Mononuclear cell conditioned factor (MNCF) medium (5%) stimulated a 100-fold increase in basal human dermal fibroblast PGE2 release over 48 h as compared with fibroblasts that were incubated with control medium (conditioned medium prepared without cells). The MNCF-induced PGE2 production was suppressed by protein synthesis inhibitors. Fibroblasts pretreated with control medium released PGE2 only modestly in response to 1 nM bradykinin for 1 h (basal, 50 +/- 7 pg PGE2/micrograms protein; stimulated, 104 +/- 12 pg PGE2/micrograms protein), whereas cells that had been pretreated with MNCF showed a greatly facilitated bradykinin-induced release of PGE2. (basal, 297 +/- 59 pg PGE2/micrograms protein; stimulated, 866 +/- 85 pg PGE2/micrograms protein). The exaggerated agonist response is not specific for bradykinin because platelet-derived growth factor elicits a similar response. Exogenous arachidonic acid conversion to PGE2 was also facilitated (two- to threefold) by MNCF pretreatment as compared with control. Both the enhanced agonist-stimulated and exogenous arachidonic acid-induced PGE2 release from the MNCF pretreated cells were inhibited by actinomyin D or cycloheximide. A kinetic study of microsomal cyclooxygenase prepared from fibroblasts pretreated with MNCF showed a threefold increase in the maximum velocity (Vmax) but the same Michaelis constant (Km) as control-treated cells. This augmented arachidonic acid metabolism and subsequent enhanced PGE2 production may play an important role in macrophage-fibroblast interactions at sites of inflammation.

Indomethacin in the treatment of postoperative cystoid macular edema

The author postulates that prostaglandins and other inflammatory mediators synthesized in the ocular tissues during surgery play a role in the manifestation of postsurgical cystoid macular edema (CME). Thus, topical indomethacin was used before and shortly after intracapsular lens extraction and retinal detachment surgery, and was found to reduce the incidence of postoperative CME. Radioimmunoassay measurements of prostaglandins in subjects immediately after lens extraction and also in subjects with vitreous incarceration to anterior segments and persistent CME showed substantially elevated levels of prostaglandins. These findings indicate that inflammatory mediators including prostaglandins play a role in the manifestation of postsurgical CME. The factors that make CME chronic and the rationale for using vitrectomy in persistent CME are discussed in relation to the prostaglandin theory. This review primarily covers the author's previous studies.

Effect of Prostaglandin E2 on Adult Pig Articular Cartilage Slices in Culture

Confirming earlier work by other investigators in isolated chondrocyte cultures, prostaglandin E2 (PGE2) (25 micrograms/ml) causes rapid inhibition of in vitro articular cartilage proteoglycan synthesis in adult pig cartilage slices. The potential impact of E prostaglandins on articular cartilage should be considered in clinical situations associated with elevated intra-articular prostaglandin levels (trauma, meniscal injury, arthritis, etc.).

Radioimmunologic identification of prostaglandins produced by serum-stimulated mouse embryo palate mesenchyme cells

High-performance liquid chromatography and radioimmunoassay were used to identify the prostaglandins synthesized by mouse embryo palate mesenchyme cells. Serum stimulated the release of several different metabolites of arachidonic acid including 6-ketoprostaglandin F 1α (the stable product of prostacyclin, prostaglandin I 2), prostaglandin E 2 and prostaglandin F 2α. Compared to control cells, the serum-stimulated cells produce elevated levels of prostaglandin E 2 (36-fold), 6-ketoprostaglandin F 1α (15-fold) and prostaglandin F 2α (7-fold). The acetylenic analogue of arachidonic acid, 5,8,11,14-eicosatetraynoic acid prevented this accelerated synthesis.

Post-partum release of prostaglandin F 2α and uterine involution in the cow

Peripheral plasma levels of the main blood plasma metabolite of PGF 2α (15-keto-13,14-dihydro-PGF 2α) and progesterone were investigated during the immediate, post-partum period in 59 normally calving cows. Uterine involution was monitored by weekly rectal palpations. The levels of the prostaglandin metabolite were high at parturition and remained thereafter elevated for periods varying up to 7–23 days. Uterine involution was completed during periods ranging from 16–53 days. According to the clinical findings, the animals were divided into three groups. Group A comprises 46 animals which had an uncomplicated, puerperal period. A significant (p<0.001) correlation between the duration of elevated prostaglandin levels and the time for completed uterine involution (Y=29.6 − 1.3 (X − 13.5)) was found for these animals. Group B animals (n=8) had periods of varying length with uterine discharge during the first 30 days post-partum. When compared to group A animals, the animals in group B had comparatively longer periods of prostaglandin release and also longer periods for completion of uterine involution. Group C animals (n=5) at times had palpable, thin-walled, cystlike structures in the ovaries during the first 30 days post-partum. In this group of animals, the periods of high prostaglandin levels, as well as for the completion of uterine involution, were similar to those for the animals in group A. Progesterone levels remained low during the immediate post-partum period and in no case were elevated levels found until the prostaglandin release had ceased.

Elevated levels of prostaglandins D 2, E 2 and F 2∝ in suction blister fluid from psoriatic lesions as compared with levels in uninvolved and clinically normal skin

Elevated levels of prostaglandins D 2, E 2 and F 2∝ in suction blister fluid from psoriatic lesions as compared with levels in uninvolved and clinically normal skin

Poly I:C accelerates ovum transport in the rabbit by a prostaglandin-mediated mechanism.

Administration of poly I:C (1 mg/kg i.v.) to rabbits 24 h after an ovulating injection of hCG caused accelerated ovum transport; only 30% of the ova were still found in the oviducts 24 h later compared with 79% of ova in control animals. This action of poly I:C was prevented by concomitant administration of indomethacin. Poly I:C (0.5 mg/kg i.v.) given to anaesthetized rabbits produced significantly increased levels of prostaglandins (PGs) E and F in uterine vein blood up to 2 h later. Production of PGs by lung, oviduct and myometrium was unaffected 2 h after poly I:C administration, but production of both PGE and PGF by endometrium was significantly elevated at the same time. Metabolism of PGs by cytosols of lung, oviduct and uterus was inhibited to various degrees at 2 h after poly I:C (1 mg/kg i.v.), but by 4 h after treatment this process was reduced to 70--80% of pretreatment values. It is concluded that poly I:C accelerates ovum transport through the oviduct by a PG-mediated mechanism, and that elevated levels of PGs in oviduct are due to inhibition of metabolism of PGs.

Dysmenorrhoea and prostaglandins: pharmacological and therapeutic considerations.

Primary dysmenorrhoea is characterised by painful menstrual cramps which appear to have no macroscopically identifiable pelvic pathology. 50% of postpubescent females suffer from dysmenorrhoea, and 10% are incapacitated for 1 to 3 days each month. Many of these patients have an increased synthesis of prostaglandins in their endometrial tissue with increased prostaglandin release in the menstrual fluid. The increased amount of prostaglandins induces incoordinate hyperactivity of the uterine muscle resulting in uterine ischaemia and pain. Recent clinical and laboratory studies have shown that many of the non-steroidal anti-inflammatory drugs such as ibuprofen, naproxen, flufenamic acid, mefenamic acid and indomethacin are capable of relieving primary dysmenorrhoea. These drugs are inhibitors of the prostaglandin synthetase enzymes which are necessary for prostaglandin biosynthesis. Thus, with ibuprofen it has been shown that clinical relief of the dysmenorrhoeic symptoms accompanies the reduction of menstrual fluid prostaglandins. With the oral contraceptive pill there is good relief of primary dysmenorrhoea, significant decrease in menstrual fluid prostaglandins, but no reduction in menstrual fluid volume; this suggests that the reduction in prostaglandins is secondary to the inhibition of endometrial growth and development. In some forms of secondary dysmenorrhoea elevated prostaglandin levels have been implicated. However, the evidence is less conclusive for dysmenorrhoea secondary to endometriosis and uterine myomas than for dysmenorrhoea associated with intrauterine devices. With the intrauterine device, prostaglandin synthetase inhibitors such as flufenamic acid, ibuprofen and naproxen are able not only to relieve dysmenorrhoea but also to reduce menstrual blood loss to normal levels. Thus, the use of appropriately selected prostaglandin synthetase inhibitors can offer effective relief from the miseries of some types of dysmenorrhoea with subsequent restoration of normal daily activities.

What is a geriatric nurse?

The popular accepted explanation for the pathogenesis of primary dysmenorrhea is elevated levels of uterine prostaglandins. Aetiological studies report that production of prostaglandins is controlled by the sex hormone progesterone, with prostaglandins and progesterone displaying an inverse relationship (i.e. increased progesterone levels reduce prostaglandin levels). Pro-inflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-α]) are also implicated in the pathogenesis of primary dysmenorrhea. High-intensity aerobic exercise is effective for decreasing pain quality and intensity in women with primary dysmenorrhea. However, why and how aerobic exercise is effective for treatment of primary dysmenorrhea remain unclear. Our preliminary non-randomized controlled pilot study to examine the effects of high-intensity aerobic exercise on progesterone, prostaglandin metabolite (13,14-dihydro-15-keto-prostaglandin F2 alpha (KDPGF2α), TNF-α, and pain intensity found increases in progesterone and decreases in KDPGF2α, TNF-α, and pain intensity following high-intensity aerobic exercise relative to no exercise. Given these promising preliminary findings, as well as what is known about the pathogenesis of primary dysmenorrhea, we propose the following scientific hypothesis: high-intensity aerobic exercise utilizes hormone (progesterone) and inflammatory cytokine-mediated mechanisms to reduce the pain associated with primary dysmenorrhea.

Prostaglandins in Hypothalamo-Pituitary and Ovarian Function

Some aspects of prostaglandin (PG) functions are reviewed including: 1) the role of PGs in the hypothalamic and pituitary control of gonadotropin secretions; and 2) their roles in ovulation, 3) in luteinization, and 4) in corpus luteum regression. PGE1 is known for its role in stimulation of increased cyclic adenosine 3',5' monophosphate (cAMP) and hormone secretion in the anterior pituitary. Direct effects of PGs on the secretion of luteinizing hormone, follicle stimulating hormone, and adrenal cortex hormones are not clearly known, but surmised. Such actions may not be the direct effects of PGs on pituitary action. Instead, more studies on receptor functions for PGs in pituitary cells are needed. Systemic administration of PGs has been shown to increase circulating levels of gonadotropins, adrenal cortex hormones, prolactin, follicle stimulating hormone, and luteinizing hormone; and in general, PGs of the E series are more potent than those of the F series. This response to systemic administration seems to be caused by an hypothalamic site of action, a conclusion based on several observations, including the observation that direct application of PGs to brain tissue causes a mimicking of endogenous PG effects of gonadotropin secretion. PGs also play a role in ovulation. Elevated PG levels in follicular tissues are induced by gonadotropins; cyclic nucleotides may be involved in mediating the action of gonadotropins on follicular PG production; a recognized time lag after exposure of the follicle to gonadotropin or cyclic nucleotides indicates that macromolecular synthesis may be involved in follicular PG production; and plasminogen activator may play a role in the process of follicular rupture that leads ot ovulation. The role of PGs in luteinization has been suggested by experiments which showed that granulosa cells cultured with PGE1 and PGE2 luteinized. PGs, particularly PGF2 alpha, cause luteal regression in many species, except perhaps in humans. And PGF2 alpha may be an antagonist of gonadotropin action in the corpus luteum. A proposed mechanism of PGF2 alpha-induced luteolysis in rats is also presented.

Corticosteroid-induced Avascular Necrosis

New Zealand white rabbits were divided into 4 groups for the study of the etiology of corticosteroid-induced osteonecrosis (avascular necrosis). Group A and B received intramuscular injections of methylprednisolone acetate and methylprednisolone succinate respectively. Group C, on semirestricted diets, and Group D, on ad libitum diets, were controls. Osteocyte death, necrotic debris and intravascular fat emboli were evident in sections of proximal and distal femur by the 2nd week in experimental animals. Blood analysis revealed elevated lipid and prostaglandin levels. Osteoporosis was first observed at 6 weeks. Evidence of advanced osteonecrosis was present histologically at 18 weeks. It is concluded that osteonecrosis probably develops as the result of the interaction of several corticosteroid-induced alterations, including circulating fat emboli and inflammatory unbound free fatty acids or prostaglandins. Osteoporosis may also be a factor in explaining the sporadic nature of the disorder.

Prevention of cystoid macular edema after lens extraction by topical indomethacin (III) radioimmunoassay measurement of prostaglandins in the aqueous during and after lens extraction procedures

The amounts of Prostaglandin (PG) E and F2alpha in the aqueous humor were measured by radioimmunoassay techniques before and immediately after intracapsular and extracapsular cataract extractions. We found that: 1. The levels of PG E and PG F2alpha are elevated by cataract extraction. 2. The elevated levels of PGs can all be prevented by preoperative applications of topical indomethacin. 3. No differences in the amounts of PGs biosynthesized during intracapsular and extracapsular lens extraction were found. 4. In some cases, the levels of PG E were still elevated one week after surgery. These findings were used as the basis for our attempts to define the causes of cystoid macular edema (CME) following lens extractions.

Prostaglandin: Increased Production by Renal Cell Carcinoma

The syndrome of hypercalcemia in patients with renal cell carcinoma without metastasis to bone, in association with elevated levels of immunoreactive prostaglandin E and normal parathyroid hormone levels, prompted the investigation of an etiologic relationship of increased prostaglandin in this syndrome.Ethyl acetate extracts of tissue culture effluents, primary and metastatic renal cell carcinoma, and plasma were chromatographed on silicic acid columns and assayed by double antibody immunoprecipitative methods for immunoreactive prostaglandins A and E. Increased levels of immunoreactive prostaglandins A and E were found 1) to be generated in parallel with cell growth during a period of time by renal cell carcinoma in monolayer growth, 2) in extracts of primary and metastatic renal cell carcinoma tissue and 3) in the venous effluent of a kidney bearing a renal cell carcinoma. These findings support the hypothesis that renal cell carcinoma can produce prostaglandins. Furthermore, reported syndromes of patients with renal cell carcinoma associated with elevated prostaglandin levels may result from the autonomous production of prostaglandins in vivo by the tumor.