Psychological interventions improve quality of life despite persistent pain in endometriosis: results of a 3-armed randomized controlled trial.

PURPOSE: Despite standard medical treatment endometriosis is often associated with disabling pain and poor quality of life (QoL). Studies indicate that psychological interventions (PIs) may improve pain and QoL, yet studies on the effects of PIs for women with endometriosis are sparse and limited by low-quality study designs. Therefore, this study aimed, in a rigorous three-armed design, to evaluate the effect of PIs on chronic pelvic pain (CPP) and QoL in women with endometriosis. METHODS: This three-armed parallel, multi-center randomized controlled trial included fifty-eight endometriosis patients reporting severe CPP [≥ 5 for pain intensity measured on a 0-10-point numeric rating scale (NRS)]. Patients were randomly assigned to (1) Specific mindfulness- and acceptance-based psychological intervention (MY-ENDO), (2) Carefully matched non-specific psychological intervention (Non-specific), or (3) A wait-list control group (WL). The primary outcome was pelvic pain intensity/unpleasantness measured on NRS. Secondary outcomes included endometriosis-related quality of life, workability, pain acceptance, and endometriosis-related symptoms. Differences in outcomes between groups at post-treatment follow-up were analyzed using mixed linear models. Analyses were performed on an intention-to-treat basis. RESULTS: Compared to WL, psychological intervention (MY-ENDO + Non-specific) did not significantly reduce pain. However, psychological intervention did significantly improve the QoL-subscales 'control and powerlessness', 'emotional well-being', and 'social support' as well as the endometriosis-related symptoms 'dyschezia' and 'constipation'. MY-ENDO was not superior to Non-specific. CONCLUSIONS: Women with endometriosis may have significant and large effects of psychological intervention on QoL despite an ongoing experience of severe CPP. TRIAL REGISTRATION: 12 April 2016, clinicaltrials.gov (NCT02761382), retrospectively registered.

Bowel Endometriosis Syndrome: a new scoring system for pelvic organ dysfunction and quality of life.

STUDY QUESTION: Is it possible to develop a validated score that can identify women with Bowel Endometriosis Syndrome (BENS) and be used to monitor the effect of medical and surgical treatment? SUMMARY ANSWER: The BENS score can be used to identify women with BENS and to monitor the effect of medical and surgical treatment of women suffering from bowel endometriosis. WHAT IS KNOWN ALREADY: Endometriosis is a heterogeneous disease with extensive variation in anatomical and clinical presentation, and symptoms do not always correspond to the disease burden. Current endometriosis scoring systems are mainly based on anatomical and surgical findings. STUDY DESIGN, SIZE, DURATION: The score was developed and validated from a cohort of 525 women with medically or surgically treated bowel endometriosis from Aarhus and Copenhagen University Hospitals, Denmark. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Patients filled in questionnaires on pelvic pain, quality of life (QoL) and urinary, sexual and bowel function. Items were selected for the final score using clinical and statistical criteria. The chosen variables were included in a multivariate analysis. Individual score values were designated items to form the BENS score, which was divided into 'no BENS', 'minor BENS' and 'major BENS.' Internal and external validations were performed. MAIN RESULTS AND THE ROLE OF CHANCE: The six most important items were 'pelvic pain', 'use of analgesics', 'dyschezia', 'straining to urinate', 'fecal urgency' and 'satisfaction with sexual life'. The range of the BENS score (0-28) was divided into 0-8 (no BENS), 9-16 (minor BENS) and 17-28 (major BENS). External validation showed a significant association between BENS score and QoL (P = 0.0001). LIMITATIONS, REASONS FOR CAUTION: The BENS scoring system is limited by the fact that it was developed from a single endometriosis unit in Denmark, making it susceptible to social, cultural and demographic bias. WIDER IMPLICATIONS OF THE FINDINGS: It is the first endometriosis classification system to be based directly on the symptomatology of the patient. Validation in other languages will promote comparison of treatments and results across borders. STUDY FUNDING/COMPETING INTEREST(S): No external funding was either sought or obtained for this study. A.F. is an investigator for Bayer, outside this work.

Genetic testing for hereditary cancer predisposition: BRCA1/2, Lynch syndrome, and beyond.

Obstetrician/gynecologists and gynecologic oncologists serve an integral role in the care of women at increased hereditary risk of cancer. Their contribution includes initial identification of high risk patients, screening procedures like bimanual exam, trans-vaginal ultrasound and endometrial biopsy, prophylaxis via TAH and/or BSO, and chemoprevention. Further, gynecologists also serve a central role in the management of the secondary repercussions of efforts to mitigate increased cancer risks, including vasomotor symptoms, sexual function, bone health, cardiovascular disease, and mental health. The past several years has seen multiple new high and moderate penetrance genes introduced into the clinical care of women at increased risk of gynecologic malignancy. Awareness of these new genes and the availability of new multi-gene panel tests is critical for providers on the front-line of women's health.

Pelvic organ function before and after laparoscopic bowel resection for rectosigmoid endometriosis: a prospective, observational study.

OBJECTIVE: To assess urinary, sexual, and bowel function before and after laparoscopic bowel resection for rectosigmoid endometriosis. DESIGN: Prospectively collected data regarding the function of the pelvic organs. SETTING: Tertiary endometriosis referral unit, Aarhus University Hospital. SAMPLE: A cohort of 128 patients who underwent laparoscopic bowel resection for endometriosis. METHODS: The International Consultation on Incontinence Questionnaire (ICIQ), Sexual Function-Vaginal Changes Questionnaire (SVQ), and the Low Anterior Resection Syndrome (LARS) questionnaire were answered before and after surgery. Non-invasive urodynamic testing was performed. MAIN OUTCOME MEASURES: Pre- and postoperative function of the pelvic organs was compared, and risk factors for improved/impaired function were identified. RESULTS: A total of 96.1% of the women completed the 1-year follow-up. A significant decrease (P = 0.002) in bladder filling problems (F-score) was observed 1 year after surgery, primarily caused by a significant decrease in bladder pain (P = 0.0001). No change for urodynamic parameters was observed. A significant increase in overall sexual satisfaction (P = 0.0001) and decrease in worries about sexual life (P = 0.001) was seen 1 year after surgery. Frequency of defecation was significantly increased 1 year after surgery (P = 0.0001), but the overall bowel function measured by LARS score was unchanged. Patients with anastomotic leakage had a significantly higher risk (odds ratio, OR 5.40; P = 0.002) of increased incontinence problems (I-score) 1 year after surgery. CONCLUSION: A significant and clinically relevant improvement in urinary and sexual function 1 year after laparoscopic bowel resection for endometriosis was found. Except for anastomotic leakage, this could be observed independent of any patient- or treatment-related factor. Apprehension about impairment of urinary and sexual function should not be a contraindication for bowel resection in endometriosis patients. TWEETABLE ABSTRACT: Rectal resection for endometriosis does not impair urinary and sexual function 1 year after surgery.

Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots.

Recent studies of human populations suggest that the genome consists of chromosome segments that are ancestrally conserved ('haplotype blocks'; refs. 1-3) and have discrete boundaries defined by recombination hot spots. Using publicly available genetic markers, we have constructed a first-generation haplotype map of chromosome 19. As expected for this marker density, approximately one-third of the chromosome is encompassed within haplotype blocks. Evolutionary modeling of the data indicates that recombination hot spots are not required to explain most of the observed blocks, providing that marker ascertainment and the observed marker spacing are considered. In contrast, several long blocks are inconsistent with our evolutionary models, and different mechanisms could explain their origins.

Health-related quality of life in women with endometriosis: psychometric validation of the Endometriosis Health Profile 30 questionnaire using confirmatory factor analysis.

STUDY QUESTION: Which of the competing models of the Endometriosis Health Profile 30 Questionnaire (EHP-30) factor structure is best supported by confirmatory factor analysis (CFA)? SUMMARY ANSWER: Findings support a five-factor first-order model of the EHP-30, thereby lending support to the model originally suggested by the questionnaire developers. WHAT IS KNOWN ALREADY: Endometriosis has a negative impact on quality of life, and measures specifically developed to address this impact, such as the EHP-30, are vital in research and disease management. Previous studies have found different models of the EHP-30 factor structure, and generated uncertainty regarding how to use the questionnaire. CFA can be applied to compare competing factor models and determine the underlying structure of a questionnaire. STUDY DESIGN SIZE DURATION: This cross-sectional multicenter study included 304 women with endometriosis recruited from three different public health service endometriosis clinics (referral centers for treatment of severe endometriosis) and the Danish Endometriosis Patients Association from 2014 to 2015. PARTICIPANTS/MATERIALS SETTING METHODS: Diagnosis of endometriosis was confirmed in medical records for 84.2% and by histology for 66.8% of participants. Questionnaires (the licensed Danish version of the EHP-30) were sent by post two times with a 6- to 12-week interval. CFA was used to examine construct validity and Bland-Altman plots to examine test-retest reliability and the convergent validity with the Short Form 36 version 2. MAIN RESULTS AND THE ROLE OF CHANCE: Response rate was high (87.6%). CFA supported the original first-order five-factor structure of the EHP-30, and thereby, the use of five separate scale-scores in clinical and research practice. Visual inspection of Bland-Altman plots suggested excellent test-retest reliability of the EHP-30 and supported the use of a disease specific quality of life instrument for women with endometriosis. LIMITATIONS REASONS FOR CAUTION: Diagnosis could not be confirmed through histology data in 33.2% of participants. However, subgroup analyses based on women with confirmed histology only, yielded similar results. Data related to menstrual cycle stage and the use of hormonal and pain medication during questionnaire completion were not collected. A larger study, including data from different countries on different continents, would be better designed to exclude potential population bias. WIDER IMPLICATIONS OF THE FINDINGS: EHP-30, with its original five-factor structure, appears to be a valid, stable, and specific quality of life measure for women with endometriosis. It seems easy to understand, quick to administer, and importantly, scoring might be unaffected by cyclical/menstrual pain symptoms related to endometriosis. The finding of a five-factor model from different studies across several countries supports the crosscultural validity of the EHP-30. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Danish Endometriosis Association, which is a nongovernmental organization run by women with endometriosis and by a scholarship from the Health Research Fund of Central Denmark Region. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: The Danish Data Protection Agency (J.nr: 2013-41-2264).

Genetic counselor opinions of, and experiences with telephone communication of BRCA1/2 test results.

BRCA1/2 test disclosure has, historically, been conducted in-person by genetics professionals. Given increasing demand for, and access to, genetic testing, interest in telephone and Internet genetic services, including disclosure of test results, has increased. Semi-structured interviews with genetic counselors were conducted to determine interest in, and experiences with telephone disclosure of BRCA1/2 test results. Descriptive data are summarized with response proportions. One hundred and ninety-four genetic counselors completed self-administered surveys via the web. Although 98% had provided BRCA1/2 results by telephone, 77% had never provided pre-test counseling by telephone. Genetic counselors reported perceived advantages and disadvantages to telephone disclosure. Thirty-two percent of participants described experiences that made them question this practice. Genetic counselors more frequently reported discomfort with telephone disclosure of a positive result or variant of uncertain significance (p < 0.01) than other results. Overall, 73% of participants reported interest in telephone disclosure. Many genetic counselors have provided telephone disclosure, however, most, infrequently. Genetic counselors identify potential advantages and disadvantages to telephone disclosure, and recognize the potential for testing and patient factors to impact patient outcomes. Further research evaluating the impact of testing and patient factors on cognitive, affective, social and behavioral outcomes of alternative models of communicating genetic information is warranted.

Evaluation of an adjustment group for people with multiple sclerosis: a pilot randomized controlled trial.

OBJECTIVE: The aim was to evaluate a group treatment for people with multiple sclerosis and low mood. DESIGN: Randomized controlled trial. SETTING: Community. PARTICIPANTS: Patients with multiple sclerosis and low mood, scoring >7 on the Hospital Anxiety and Depression Scales or >2 on the General Health Questionnaire 12. INTERVENTIONS: Participants either attended an adjustment group for six, 2-hour group treatment sessions or were on a waiting list to attend the group. OUTCOMES: Hospital Anxiety and Depression Scale, General Health Questionnaire 12, Multiple Sclerosis Self Efficacy Scale, Multiple Sclerosis Impact Scale and Short Form 36 administered 3 and 6 months after random allocation. RESULTS: Of the 219 patients identified, 100 (46%) reported depressive symptoms and 126 (58%) anxiety symptoms. Forty participants were recruited, aged 25-68 (mean 47.7 SD 9.7) and eight were men. Patients allocated to the group intervention reported fewer depressive symptoms than those in the control group (U 109.5, P<0.05) but there were no significant differences in anxiety symptoms, self-efficacy or quality of life. CONCLUSION: Depressive symptoms were reduced following group intervention, which suggests this may be an effective psychological treatment and warrants further evaluation.

Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer.

Taxol, an antimicrotubule agent, has shown promise for efficacy in treatment of breast cancer, but severe hypersensitivity reactions led to cessation of many phase I clinical trials. Consequently, investigators and the National Cancer Institute recommended that phase I and II studies of this agent use 24-hour infusions and antiallergic medications. Using a premedication regimen effective in preventing hypersensitivity reactions, we have performed a phase II trial of taxol in patients with metastatic breast cancer. Taxol was administered to 25 patients at a dose of 250 mg/m2 by 24-hour infusion every 21 days. These patients had received only one prior chemotherapy regimen, either adjuvant to surgery or for metastatic disease; all but two had received doxorubicin. In 60% of the patients, the dominant site of disease was the viscera. All patients were assessable. In April 1991, at a median time on study of 9 months (range, 5-13+ months), the objective response rate was 56% (12% complete and 44% partial; 95% confidence interval, 35%-76%). Disease progressed in only 8% of the patients. The median number of courses of therapy was 11. Granulocytopenia was the dose-limiting toxic effect, but neutropenia with fever occurred in only 5% of 232 courses. A chronic glove-and-stocking neuropathy developed in most patients, but no allergic reactions occurred. We conclude that taxol is an active agent in the treatment of metastatic breast cancer and that it warrants continued study. Currently, we are conducting a phase I trial of taxol plus doxorubicin. Future trials should address the optimal effective dose, the optimal sequencing of combinations, mechanisms of drug resistance in tumors, and dose-limiting toxic effects (particularly cardiac toxic effects of taxol given as a single agent or in drug combinations).

Human breast cancer cells contain elevated levels and activity of the protein kinase, PKR.

PKR is a double-stranded (ds) RNA activated protein kinase whose expression is induced by interferon. Activated PKR phosphorylates its cellular substrate, eIF2, an essential initiation factor of translation. Prior evidence from a murine model system suggested that PKR may act as a tumor suppressor, but the evidence from human tumors is equivocal. To study PKR function in human breast cancer, PKR activity was measured in mammary carcinoma cell lines and nontransformed mammary epithelial cell lines. If PKR functioned as a tumor suppressor in this system, its activity would be higher in nontransformed cells than in carcinoma cells. On the contrary, PKR autophosphorylation and the phosphorylation of its substrate, the alpha-subunit of eIF2, is 7 - 40-fold higher in lysates prepared from breast carcinoma cell lines than in those from nontransformed epithelial cell lines. Correspondingly, a larger proportion of eIF2alpha is present in a phosphorylated state in carcinoma cell lines than in nontransformed cell lines. Protein synthesis is not inhibited by the high eIF2alpha phosphorylation in carcinoma cells, probably because they contain higher levels of eIF2B, the initiation factor that is inhibited by eIF2alpha phosphorylation. The dramatically lower PKR activity in nontransformed cell lines is partially due to lower PKR protein levels (2 - 4-fold) as well as to the presence of a PKR inhibitor. The nontransformed cells contain P58, a known cellular inhibitor of PKR that physically interacts with PKR and may be responsible for the low PKR activity in these cells. Taken together, these observations call into question the role of PKR as a tumor suppressor and suggest a positive regulatory role of PKR in growth control of breast cancer cells.

Phase II study of docetaxel in patients with epithelial ovarian carcinoma refractory to platinum.

We analyzed the efficacy and toxicity of docetaxel in patients with ovarian cancer who failed previous chemotherapy with platinum. Fifty-five patients with measurable ovarian cancer were entered in this Phase II study at The University of Texas M. D. Anderson Cancer Center. Treatment consisted of 100 mg/m2 docetaxel given i.v. every 3 weeks. Because of hypersensitivity reactions, premedication with steroids and antihistamine was initiated during the study. Twenty-two (40%) patients responded (there were 3 complete responders and 19 partial responders). Twenty-one (38%) patients had stable disease. The median survival was 10 months. The main toxicity was neutropenia (98% of patients), with 13 episodes of neutropenic fever. Cumulative fluid retention was the main reason for dose modification and required a combination of diuretics and steroids for palliation. Other side effects were alopecia (100%); anemia (87%); dermatitis (67%); gastrointestinal disorders (53%); stomatitis (49%); neurotoxicity (45%); excessive lacrimation (33%); and hypersensitivity reactions (11%), which in one case were life threatening (loss of consciousness, fluid resuscitation). Docetaxel as a single agent proved to be active in heavily pretreated ovarian cancer patients but is associated with significant side effects. Objective toxicity consisted mainly of neutropenia and fluid retention. Neutropenia was dose limiting and required therapy with granulocyte colony-stimulating factor. Fluid retention was improved but not eliminated by diuretics and corticosteroids. Additional studies of docetaxel in ovarian carcinoma are indicated to define the activity in relation to paclitaxel and in platinum combination therapy.

NaCl-induced renal vasoconstriction in salt-sensitive African Americans: antipressor and hemodynamic effects of potassium bicarbonate.

In 16 African Americans (blacks, 14 men, 2 women) with average admission mean arterial pressure (MAP, mm Hg) 99.9+/-3.5 (mean+/-SEM), we investigated whether NaCl-induced renal vasoconstriction attends salt sensitivity and, if so, whether supplemental KHCO3 ameliorates both conditions. Throughout a 3-week period under controlled metabolic conditions, all subjects ate diets containing 15 mmol NaCl and 30 mmol potassium (K+) (per 70 kg body wt [BW] per day). Throughout weeks 2 and 3, NaCl was loaded to 250 mmol/d; throughout week 3, dietary K+ was supplemented to 170 mmol/d (KHCO3). On the last day of each study week, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) using renal clearances of PAH and inulin. Ten subjects were salt sensitive (SS) (DeltaMAP >+5%) and 6 salt resistant (SR). In NaCl-loaded SS but not SR subjects, RBF (mL/min/1.73 m2) decreased from 920+/-75 to 828+/-46 (P<0.05); filtration fraction (FF, %) increased from 19. 4+/- to 21.4 (P<0.001); and renal vascular resistance (RVR) (10(3)xmm Hg/[mL/min]) increased from 101+/-8 to 131+/-10 (P<0.001). In all subjects combined, DeltaMAP varied inversely with DeltaRBF (r =-0.57, P=0.02) and directly with DeltaRVR (r = 0.65, P=0.006) and DeltaFF (r = 0.59, P=0.03), but not with MAP before NaCl loading. When supplemental KHCO3 abolished the pressor effect of NaCl in SS subjects, RBF was unaffected but GFR and FF decreased. The results show that in marginally K+-deficient blacks (1) NaCl-induced renal vasoconstrictive dysfunction attends salt sensitivity; (2) the dysfunction varies in extent directly with the NaCl-induced increase in blood pressure (BP); and (3) is complexly affected by supplemented KHCO3, GFR and FF decreasing but RBF not changing. In blacks, NaCl-induced renal vasoconstriction may be a pathogenetic event in salt sensitivity.

Normotensive salt sensitivity: effects of race and dietary potassium.

-Normotensive salt sensitivity, a putative precursor of hypertension, might be quite frequent in African Americans (blacks) and less frequent in Caucasian Americans (whites), but only when dietary potassium is deficient and not when maintained well within the normal range. We tested this hypothesis in 41 metabolically controlled studies of 38 healthy normotensive men (24 blacks, 14 whites) who ate a basal diet low in sodium (15 mmol/d) and marginally deficient in potassium (30 mmol/d) for 6 weeks. Throughout the last 4 weeks, NaCl was loaded (250 mmol/d); throughout the last 3, potassium was supplemented (as potassium bicarbonate) to either mid- or high-normal levels, 70 and 120 mmol/d. Salt sensitivity, defined as an increase in mean arterial blood pressure >/=3 mm Hg with salt loading, was deemed "moderate" if increasing

Reduced dietary potassium reversibly enhances vasopressor response to stress in African Americans.

Acute vasopressor responses to stress are adrenergically mediated and hence potentially subject to differential modulation by dietary potassium and sodium. The greater vasopressor responsiveness in blacks compared with whites might then be consequent not only to a high dietary salt intake but also to a marginally reduced dietary potassium intake. Under controlled metabolic conditions, we compared acute vasopressor responses to cold and mental stress in black and white normotensive men during three successive dietary periods: (1) while dietary potassium was reduced (30 mmol K+/70 kg per day) and salt was restricted (10 to 14 days); (2) while salt was loaded (15 to 250 mmol Na+/70 kg per day) (7 days); and (3) while salt loading was continued and potassium was either supplemented (70 mmol K+/70 kg per day) (7 to 21 days) in 9 blacks and 6 whites or continued reduced (30 mmol K+/70 kg per day) (28 days) in 4 blacks (time controls). At the lower potassium intake, cold-induced increase in forearm vascular resistance in blacks was twice that in whites during both salt restriction and salt loading. Normalization of dietary potassium attenuated cold-induced increases in both forearm vascular resistance and systolic and diastolic blood pressures in blacks but only in systolic pressure in whites. In blacks but not in whites, normalization of dietary potassium attenuated mental stress-induced increases in systolic and diastolic pressures. In normotensive blacks but not whites, a marginally reduced dietary intake of potassium reversibly enhances adrenergically mediated vasopressor responsiveness to stress. That responsiveness so enhanced over time might contribute to the pathogenesis of hypertension in blacks.

Persistent neurotoxicity of systemically administered interferon-alpha.

Fourteen cancer patients had evidence of persistent neurotoxicity of interferon-alpha therapy long after their treatment was discontinued. Although most of the cognitive symptoms were mild to moderate in severity, they were incapacitating to these individuals in their usual work. The neuropsychological test abnormalities were not attributable to subsequent therapy, disease status, or other medical problems. The pattern of deficits was consistent with frontal-subcortical dysfunction. Of the four patients who had follow-up assessment, two had improved and two had deteriorated. These findings suggest that in some cases interferon neurotoxicity is not reversible.

Effect of endogenous vasoconstrictors on maternal intramyometrial and fetal stem villous arteries in pre-eclampsia.

The contractile responses to various endogenous vasoactive agents were investigated in isolated human uteroplacental arteries from normotensive (NT) patients and patients with pre-eclampsia (PE) undergoing caesarian section. Tissue samples were obtained from the uterine incision and from macroscopically normal cotyledons. Vascular ring preparations of intramyometrial and stem villous arteries (length 1.0-1.3 mm, outer diameter 400-600 microns) were dissected and mounted in organ baths and isometric tension was recorded. Concentration-response relationships for vasopressin (VP), oxytocin (OX), angiotensin II (Ang II), noradrenaline (NA), 5-hydroxytryptamine (5-HT), prostaglandin F2 alpha (PGF2 alpha) and prostaglandin E2 (PGE2) were assessed. For each compound, the mean maximum contractile effect (Emax) and the drug concentration producing half-maximal response (EC50) were determined. In intramyometrial arteries from NT and PE patients, VP, Ang II, NA, 5-HT and PGF2 alpha induced contraction while OX and PGE2 produced weak or no responses. Preparations from PE patients showed higher Emax values, while no differences in EC50 were found between the two groups. In fetal stem villous arteries, Ang II, 5-HT, PGF2 alpha and PGE2 induced contractions, while VP, NA and OX produced weak responses. No differences in Emax or EC50 values were found between the fetal vessels of PE and NT patients. No qualitative differences were demonstrated in response to the agents tested between the vessels (fetal and maternal) from NT women at term and PE patients. However, the results may reflect quantitative differences, suggesting increased contractility of maternal uteroplacental arteries from women with PE.

Relaxant effects of hexosamines on isolated small human placental arteries.

Wharton's jelly contains large amounts of hyaluronic acid, and glucosamine is an important constituent of this macromolecule. In order to evaluate the placental vascular effects of this aminosugar, small chorionic and stem villous arteries were dissected from placental specimens obtained at normal term vaginal deliveries (n = 15). Ring preparations were mounted in organ baths, and isometric wall tensions were measured. Glucosamine and its epimer galactosamine (5 X 10(-4) to 10(-2) M) produced marked relaxation of contractions induced by PGF2 alpha (10(-5) M) in both chorionic and stem villous arteries. The effect was unchanged after pretreatment with atropin, propranolol and indomethacin. The relaxant effect of the neutral sugar mannose was less pronounced compared with that of the hexosamines. Total tissue concentrations of placental hexosamines have been reported within the range needed to produce placental vascular relaxation in the present study. However, the major part of these compounds is integrated in macromolecules, and the tissue level of free hexosamine is probably far below the total concentrations. Accordingly, the effects of hexosamines demonstrated in the present study might not be of physiological importance in the regulation of fetal placental medial smooth muscle tension.

Effects of vasoactive intestinal polypeptide and substance P on human intramyometrial arteries and stem villous arteries in term pregnancy.

The effects of vasoactive intestinal polypeptide (VIP) and substance P on isolated human intramyometrial arteries and fetal stem villous arteries obtained from term pregnant women were compared. Ring preparations of small intramyometrial arteries and fetal stem villous arteries obtained at caesarean section were mounted in organ baths, and isometric tension was recorded. None of the peptides affected resting tension. In intramyometrial arteries precontracted by vasopressin (2.8 x 10(-9) M) both substance P (10(-12) to 10(-8) M) and VIP (10(-8) to 10(-6) M) caused relaxation. In fetal stem villous arteries precontracted by prostaglandin F2 alpha (10(-5) M) cumulative addition of substance P (10(-11) to 10(-6) M) did not produce significant changes in tension as compared with controls, while addition of single doses produced moderate relaxation. VIP (10(-8) to 10(-6) M) induced relaxation with similar effects for the addition of cumulative and single doses. The responses to VIP and substance P remained unaffected after pretreatment by atropine (10(-6) M), propranolol (10(-6) M), and indomethacin (10(-6) M). The results support a role for VIP and substance P in the regulation of uteroplacental blood flow in term pregnancy.

Digoxin inhibition of relaxation induced by prostacyclin and vasoactive intestinal polypeptide in small human placental arteries.

Small chorionic plate arteries were obtained from human placentae following normal vaginal delivery. Tubal vascular preparations were dissected, mounted in organ baths, and their isometric tension was recorded. Digoxin (10(-6) M) caused a rise in basic tension, reaching a maximum of 17 per cent of contractions induced by potassium (124 mM) depolarization. Pretreatment with digoxin did not significantly influence the concentration-dependent contractile responses to 5-hydroxytryptamine and prostaglandin F2 alpha (PGF2 alpha). In preparations contracted with PGF2 alpha, cumulative addition of prostacyclin (PGI2) and vasoactive intestinal polypeptide (VIP) produced concentration dependent relaxations. Digoxin (10(-8) to 10(-6) M) inhibited and finally abolished these relaxant effects of PGI2 and VIP in a concentration-dependent fashion. Pretreatment by digoxin (10(-8) to 10(-6) M) diminished the relaxant effect of sodium nitroprusside, but the effect was less pronounced than that on PGI2- and VIP-induced relaxation. As PGI2 and VIP may be of importance for the maintenance of a low resistance of the fetal placental vascular bed, the finding that digoxin decreases the vasodilating effects of these agents might imply effects on placental resistance of cardiac glycosides when used in late human pregnancy.