Pregnancy-associated diabetes insipidus in Japan-a review based on quoting from the literatures reported during the period from 1982 to 2019.

This Review Article overviews the literature on diabetes insipidus (DI) associated with pregnancy and labor in Japan published from 1982 to 2019. The total number of patients collected was 361, however, only one-third of these cases had detailed pathophysiologic information enabling us to identify the respective etiology and subtype. Pregnancy-associated DI can be divided into 3 etiologies, central (neurogenic) DI, nephrogenic DI, and excess vasopressinase-associated DI. Neurogenic DI has various causes: for example, DI associated with tumoral lesions in the pituitary and neighboring area, DI associated with Sheehan's syndrome and/or pituitary apoplexy, and DI associated with lymphocytic infundibuloneurohypophysitis (LINH, stalkitis). Nephrogenic DI results from defective response of the kidney to normal levels of vasopressin. However, the most interesting causal factor of pregnancy-associated DI is excess vasopressinase, caused either by excess production of vasopressinase by the placenta or defective clearance of vasopressinase by the liver. Hepatic complications resulting in pregnancy-associated DI include acute fatty liver of pregnancy (AFLP) and HELLP syndrome (syndrome of hemolysis, elevated liver enzymes, low platelets), as well as pre-existing or co-incidental hepatic diseases. A possible role of glucose uptake in putative stress-induced DI and the importance of correct diagnosis and treatment of pregnancy-associated DI, including use of 1-deamino 8-D arginine vasopressin, are also discussed.

Aminopeptidases in Cardiovascular and Renal Function. Role as Predictive Renal Injury Biomarkers.

Aminopeptidases (APs) are metalloenzymes that hydrolyze peptides and polypeptides by scission of the N-terminus amino acid and that also participate in the intracellular final digestion of proteins. APs play an important role in protein maturation, signal transduction, and cell-cycle control, among other processes. These enzymes are especially relevant in the control of cardiovascular and renal functions. APs participate in the regulation of the systemic and local renin-angiotensin system and also modulate the activity of neuropeptides, kinins, immunomodulatory peptides, and cytokines, even contributing to cholesterol uptake and angiogenesis. This review focuses on the role of four key APs, aspartyl-, alanyl-, glutamyl-, and leucyl-cystinyl-aminopeptidases, in the control of blood pressure (BP) and renal function and on their association with different cardiovascular and renal diseases. In this context, the effects of AP inhibitors are analyzed as therapeutic tools for BP control and renal diseases. Their role as urinary biomarkers of renal injury is also explored. The enzymatic activities of urinary APs, which act as hydrolyzing peptides on the luminal surface of the renal tubule, have emerged as early predictive renal injury biomarkers in both acute and chronic renal nephropathies, including those induced by nephrotoxic agents, obesity, hypertension, or diabetes. Hence, the analysis of urinary AP appears to be a promising diagnostic and prognostic approach to renal disease in both research and clinical settings.

Altered Serum Oxytocinase and Enkephalin-Degrading Aminopeptidase Activities in Patients With Fibromyalgia.

OBJECTIVES: Fibromyalgia (FM) is a chronic pain condition of unclear etiology. We have analyzed, for the first time, the activity of a broad spectrum of aminopeptidases (APs) in patients with FM and controls to investigate whether they are involved in the pathophysiology of this syndrome. METHOD: In this case-control study, we fluorometrically measured specific AP activities in serum samples of 75 patients with FM and 29 healthy controls. The predictive value of AP activities in FM was determined by receiver operating characteristic (ROC) analysis. RESULTS: Oxytocinase activity was higher in patients with FM than in controls (p < .001). A subgroup of patients with FM (n = 18; 24%) showed low levels of enkephalin-degrading aminopeptidase (EDA) activity when compared with the healthy controls (p < .001) and with the rest of FM patients (p < .001). There were no significant differences in the activity levels of aminopeptidase A, aminopeptidase B, aspartyl aminopeptidase, insulin-regulated aminopeptidase, pyroglutamyl aminopeptidase, or aminopeptidase N between FM patients and controls. According to ROC analysis, oxytocinase activity may be a good marker for differentiating individuals with FM from healthy subjects. CONCLUSIONS: Our findings show that serum oxytocinase activity is increased in patients with FM, which could alter the metabolism of peptides with analgesic effects such as oxytocin and enkephalins. The determination of serum oxytocinase activity may aid in FM diagnosis. Additionally, we have identified a subpopulation of FM patients with abnormally low serum EDA activity.

Serum protease activity in chronic kidney disease patients: The GANI_MED renal cohort.

Serum or plasma proteases have been associated with various diseases including cancer, inflammation, or reno-cardiovascular diseases. We aimed to investigate whether the enzymatic activities of serum proteases are associated with the estimated glomerular filtration rate (eGFR) in patients with different stages of chronic kidney disease (CKD). Our study population comprised 268 participants of the "Greifswald Approach to Individualized Medicine" (GANI_MED) cohort. Enzymatic activity of aminopeptidase A, aminopeptidase B, alanyl (membrane) aminopeptidase, insulin-regulated aminopeptidase, puromycin-sensitive aminopeptidase, leucine aminopeptidase 3, prolyl-endopeptidase (PEP), dipeptidyl peptidase 4 (DPP4), angiotensin I-converting enzyme, and angiotensin I-converting enzyme 2 (ACE2) proteases was measured in serum. Linear regression of the respective protease was performed on kidney function adjusted for age and sex. Kidney function was modeled either by the continuous Modification of Diet in Renal Disease (MDRD)-based eGFR or dichotomized by eGFR < 15 mL/min/1.73 m2 or <45 mL/min/1.73 m2, respectively. Results with a false discovery rate below 0.05 were deemed statistically significant. Among the 10 proteases investigated, only the activities of ACE2 and DPP4 were correlated with eGFR. Patients with lowest eGFR exhibited highest DPP4 and ACE2 activities. DPP4 and PEP were correlated with age, but all other serum protease activities showed no associations with age or sex. Our data indicate that ACE2 and DPP4 enzymatic activity are associated with the eGFR in patients with CKD. This finding distinguishes ACE2 and DPP4 from other serum peptidases analyzed and clearly indicates that further analyses are warranted to identify the precise role of these serum ectopeptidases in the pathogenesis of CKD and to fully elucidate underlying molecular mechanisms. Impact statement • Renal and cardiac diseases are very common and often occur concomitantly, resulting in increased morbidity and mortality. Understanding of molecular mechanisms linking both diseases is limited, available fragmentary data point to a role of the renin-angiotensin system (RAS) and, in particular, Ras-related peptidases. • Here, a comprehensive analysis of serum peptidase activities in patients with different stages of chronic kidney disease (CKD) is presented, with special emphasis given to RAS peptidases • The serum activities of the peptidases angiotensin I-converting enzyme 2 and dipeptidyl peptidase 4 were identified as closely associated with kidney function, specifically with the estimated glomerular filtration rate. The findings are discussed in the context of available data suggesting protective roles for both enzymes in reno-cardiac diseases. • The data add to our understanding of pathomechanisms underlying development and progression of CKD and indicate that both enzymes might represent potential pharmacological targets for the preservation of renal function.

Associations between serum placental leucine aminopeptidase and pregnancy outcomes.

OBJECTIVE: To investigate the association between serum concentrations of placental leucine aminopeptidase (P-LAP) and hypertensive disorders in pregnancy (HDP), gestational diabetes mellitus (GDM), and perinatal mortality. METHODS: In a prospective study, women with singleton pregnancies and affected by HDP, GDM, or fetal death, and those who were healthy, were enrolled at Shenzhen Seventh People's Hospital, Shenzhen, China, between January 2014 and July 2015. Serum P-LAP concentrations at delivery/fetal death were compared among the groups. The predictive value of serum P-LAP levels in fetal death was evaluated. RESULTS: Serum P-LAP concentrations were (mean ± SEM) 74.02 ± 8.45 U/L in the HDP group (n=38), 72.57 ± 12.03 U/L in the GDM group (n=35), and 3.76 ± 3.02 U/L in the fetal death group (n=14), all of which were significantly lower than the mean concentration of 107.11 ± 30.68 U/L in the control group (n=30; P=0.031, P=0.042, and P<0.001, respectively). On the basis of the receiver operating characteristic curve, low serum P-LAP levels had high sensitivity and specificity for predicting fetal death (100% and 78.9%, respectively, for a serum P-LAP cutoff of 47.07 U/L). CONCLUSION: Serum P-LAP levels were reduced among patients with HDP and GDM, and extremely low among patients affected by fetal death. Serum P-LAP is potentially a viable predictor of fetal death.

Neuropeptidase activities in plasma after acute restraint stress. Interaction with cortico-limbic areas.

OBJECTIVE: To evaluate the influence of acute restraint stress (ARS) on plasma enkephalinase and oxytocinase activities. ARS modifies basal activities in cortico-limbic regions of rats and induces changes in the correlations observed between these regions. The interactions between plasma and cortico-limbic activities will be also evaluated. METHODS: Enkephalinase (AlaAP and LeuAP) and oxytocinase (P-LeuAP) activities were fluorometrically determined in plasma of control and stressed rats using aminoacyl-ß-naphthylamides (aaNNap), AlaNNap and LeuNNap as substrates. RESULTS: No differences in enzymatic activities were observed between control and stressed animals in plasma. In contrast, highly significant positive and negative correlations between plasma and cortico-limbic regions were demonstrated in controls. Stress conditions significantly alter the pattern of these correlations. CONCLUSION: The present results clearly support a connection between plasma and brain involving certain neuropeptidase activities that change under stress conditions.

Vasopressinase Activity: A Potential Early Biomarker for Detecting Cardiopulmonary Bypass-Associated Acute Kidney Injury?

Background Acute kidney injury (AKI) is a common and serious complication of surgeries that include cardiopulmonary bypass (CPB). Currently, increases in serum creatinine levels are used to diagnose AKI, but this change may be slow to detect. Animal studies pertaining to renal hypoxia suggest a correlation between vasopressinase activity and AKI. The objective of this study is to determine if vasopressinase activity can be used as an early biomarker for renal hypoxia and CPB-associated AKI. This could potentially help improve the diagnosis and subsequent treatment of the condition. Materials and Methods We conducted a single-center, prospective observational study which analyzed serum vasopressinase activity and creatinine levels at seven time points from 31 patients undergoing CPB. We also measured urine vasopressinase activity in 19 of the 31 patients at five of the time points. Results Results show that serum and urine vasopressinase activity peak at the time of arrival to the ICU for patients undergoing CPB. This increase occurred earlier than the increase in creatinine, which generally occurred on postoperative day 2. In the five patients who were diagnosed with AKI, vasopressinase activity peaked 30 minutes into CPB while creatinine peaked on postoperative day 2. Conclusion Our findings suggest that vasopressinase might be a potential early biomarker for AKI. Further studies with other AKI biomarkers are required to determine if the vasopressinase response can be directly attributed to the presence of AKI.

Relationship of angiotensinase and vasopressinase activities between hypothalamus, heart, and plasma in L-NAME-treated WKY and SHR.

The renin-angiotensin system (RAS), vasopressin, and nitric oxide (NO) interact to regulate blood pressure at central and peripheral level. To improve our understanding of their interaction and their relationship with the hypothalamus and the cardiovascular system, we analyzed angiotensin- and vasopressin-metabolizing activities in hypothalamus (HT), left ventricle (LV), and plasma, collected from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) treated or not with L-NAME [N(G)-nitro-L-arginine methyl ester], which inhibits the formation of NO and over-activates the sympathetic nervous system. Previous observations in WKY suggested higher formation of Ang III and Ang IV in the HT and higher availability of Ang II in plasma after L-NAME treatment. Our current results show higher formation of Ang IV and higher metabolism of vasopressin after treatment with L-NAME in the LV of WKY rats. In SHR treated with L-NAME, there is higher availability of Ang III in the HT leading to higher release of vasopressin together with lower formation of Ang 2-10. In their LV, however, there is an increase of vasopressinase. Interestingly, while the enzymatic activities in the HT and LV of WKY rats and control SHR are poorly correlated, they are well but inversely correlated in the L-NAME treated SHR. On the other hand, no significant correlations between enzymatic activities in HT or LV and plasma were noticed. Our results suggest that eNOS inhibition in SHR induces or enhances an inverse reciprocal interaction between HT and LV involving the RAS and vasopressin, which may be mediated by the autonomic nervous system.

Hypooxytocinaemia in obese Zucker rats relates to oxytocin degradation in liver and adipose tissue.

The metabolic action of oxytocin has recently been intensively studied to assess the ability of the peptide to regulate energy homeostasis. Despite the obvious weight-reducing effect of oxytocin observed in experimental studies, plasma oxytocin levels were found to be unchanged or even elevated in human obesity. The aim of our study was to evaluate the changes in the oxytocin system in Zucker rats, an animal model closely mirroring morbid obesity in humans. Plasma oxytocin levels were measured in obese Zucker rats and lean controls by enzyme immunoassay after plasma extraction. The expression of oxytocin and oxytocin receptor (OXTR) was assessed at the mRNA and protein levels by quantitative real-time PCR and immunoblotting respectively. Plasma and tissue activity of oxytocinase, the main enzyme involved in oxytocin degradation, were measured by fluorometric assay using an arylamide derivate as the substrate. Obese Zucker rats displayed a marked reduction in plasma oxytocin levels. Elevated liver and adipose tissue oxytocinase activity was noticed in obese Zucker rats. Hypothalamic oxytocin gene expression was not altered by the obese phenotype. OXTR mRNA and protein levels were upregulated in the adipose tissue of obese animals in contrast to the reduced OXTR protein levels in skeletal muscle. Our results show that obesity is associated with reduced plasma oxytocin due to increased peptide degradation by liver and adipose tissue rather than changes in hormone synthesis. This study highlights the importance of the oxytocin system in the pathogenesis of obesity and suggests oxytocinase inhibition as a candidate approach in the therapy of obesity.

Acute diabetes insipidus mediated by vasopressinase after placental abruption.

CONTEXT: Postpartum, diabetes insipidus (DI) can be part of Sheehan's syndrome or lymphocytic hypophysitis in combination with anterior pituitary hormone deficiencies. In contrast, acute onset of isolated DI in the postpartum period is unusual. CASE PRESENTATION: This patient presented at 33 weeks gestation with placental abruption, prompting a cesarean delivery of twins. Immediately after delivery, she developed severe DI. The DI could be controlled with the vasopressinase-resistant 1-deamino-8-D-arginine vasopressin (DDAVP), but not with arginine vasopressin (AVP), and it resolved within a few weeks. OBJECTIVE: The aim of this study was to demonstrate that the postpartum DI in this patient was caused by the release of placental vasopressinase into the maternal bloodstream. METHODS AND RESULTS: Cells were transiently transfected with the AVP receptor 2 (AVPR2) and treated with either AVP or DDAVP in the presence of the patient's serum collected postpartum or 10 weeks after delivery. The response to the different treatments was evaluated by measuring the activity of a cAMP-responsive firefly luciferase reporter construct. The in vitro studies demonstrate that the patient's postpartum serum disrupts activation of the AVPR2 by AVP, but not by the vasopressinase-resistant DDAVP. CONCLUSIONS: Placental abruption can rarely be associated with acute postpartum DI caused by release of placental vasopressinase into the bloodstream. This clinical entity must be considered in patients with placental abruption and when evaluating patients presenting with DI after delivery.

Revisão da leucina aminopeptidase no trabalho de parto pré-termo e na pré-eclampsia / Revision of the leucine aminopeptidase in preterm labor and in preeclampsia

Realizou-se um levantamento bibliográfico, com artigos de revisão, analisando e discutindo os trabalhos publicados sobre os efeitos da leucina aminopeptidase e aminopeptidase A no trabalho de parto pré-termo e na pré-eclampsia. A proposta deste trabalho sobre o tema é que grande parte das questões de saúde materna parece pueril, principalmente quanto ao atendimento voltado para os cuidados maternos, no qual, a cada 20minutos, morre uma mulher em decorrência de parto, no mundo todo. Por isso, tais doenças poderão receber mais atenção do que outras. Esse fato fez com que houvesse certa preocupação com o índice de natalidade e morbidade materna, bem como morbidade e mortalidade perinatal. Portanto, abordou-se sobre sua biologia geral, fisiologia de reprodução, síntese de evolução genética, habitação, alimentação, manejo, dor e eutanásia, técnicas de riscos desenvolvidos na experimentação animal, estudos de experimentos farmacológicos e toxicológicos observados dentro dos artigos de revisão. Embora tendências atuais preconizem a utilização de métodos alternativos (estudo in vitro), os modelos animais, como as ratas, apresentam como principal vantagem o fornecimento de informações sobre o organismo como um todo, fato que não é obtido com outros métodos, o que ainda possibilita o seu emprego em pesquisas científicas.

We have carried out a literature review, with review articles, analyzing and discussing the works that have already been published on the effects of leucine aminopeptidade and aminopeptidase A in pre-term labor and preeclampsia. The proposal of this work on the subject is that most of the issues of maternal health seems childish, especially for service oriented maternity care, where, every 20 minutes, a woman dies due to childbirth, worldwide. Therefore, such diseases may receive more attention than others. This led to worry about the birth rate and maternal morbidity and perinatal morbidity and mortality. Therefore, it was addressed their general biology, physiology of reproduction, synthesis of evolution, genetics, housing, feeding, pain and euthanasia techniques developed for animal experimentation risks, studies of pharmacological and toxicological experiments observed within the review articles. Although current trends have preconized the use of alternative methods (in vitro study), animal models, such as rats, have as main advantage the provision of information on the organism as a whole, a fact that is not achieved with other methods, which also allows its use in scientific research.

Angiotensinase and vasopressinase activities in hypothalamus, plasma, and kidney after inhibition of angiotensin-converting enzyme: basis for a new working hypothesis.

Reducing angiotensin II (Ang II) production via angiotensin-converting enzyme (ACE) inhibitors is a key approach for the treatment of hypertension. However, these inhibitors may also affect other enzymes, such as angiotensinases and vasopressinase, responsible for the metabolism of other peptides also involved in blood pressure control, such as Ang 2-10, Ang III, Ang IV, and vasopressin. We analyzed the activity of these enzymes in the hypothalamus, plasma, and kidney of normotensive adult male rats after inhibition of ACE with captopril. Aspartyl- (AspAP), glutamyl- (GluAP), alanyl- (AlaAP) and cystinyl-aminopeptidase (CysAP) activities were measured fluorimetrically using arylamides as substrates. Systolic blood pressure (SBP), water intake, and urine flow were also measured. Captopril reduced SBP and increased urine flow. In the hypothalamus, GluAP and AspAP increased, without significant changes in either AlaAP or CysAP. In contrast with effects in plasma, GluAP was unaffected, AspAP decreased, while AlaAP and CysAP increased. In the kidney, enzymatic activities did not change in the cortex, but decreased in the medulla. These data suggest that after ACE inhibition, the metabolism of Ang I in hypothalamus may lead mainly to Ang 2-10 formation. In plasma, the results suggest an increased formation of Ang IV together with increased vasopressinase activity. In the kidney, there is a reduction of vasopressinase activity in the medulla, suggesting a functional reduction of vasopressin in this location. The present data suggest the existence of alternative pathways in addition to ACE inhibition that might be involved in reducing BP after captopril treatment.

Alteration of circulating Placental Leucine Aminopeptidase (P-LAP) activity in preeclampsia.

OBJECTIVE: Placental Leucine Aminopeptiadse (P-LAP) also known as oxytocinase, is secreted by syncytiotrophoblast and increases gradually during pregnancy until delivery. It is a regulator of uterine contractions, of vascular resistance and of volume of the retroplacental blood pool. Recently, it was shown that it could also regulate metalloproteinase 9 activity and thus, invasiveness of trophoblastic cells. Since development of preeclampsia could be initiated by decreased cytotrophoblastic invasion of spiral arterioles and a reduced uteroplacental perfusion, we speculate that circulating P-LAP activity could be decreased during preeclampsia. MATERIALS AND METHODS: Case-control study was evaluated in 84 women. P-LAP activity was measured in n=51 healthy pregnant women at term, and compared with n=16 normotensive women delivering preterm and n=17 women diagnosed with pre-eclampsia. P-LAP activity was determined by colorimetry in plasma samples using L-Leucine-p-nitroanilide as substrate. RESULTS: P-LAP activity was significantly lower in sera of preeclamptic women (0.91+/-0.122 mDO/min) as compared to normotensive controls (1.41+/-0.103 mDO/min; p=0.003) irrespective of time of delivery. CONCLUSIONS: These findings confirm the probable involvement of P-LAP in trophoblast invasion and development of preeclampsia.

Vasopressin is a physiological substrate for the insulin-regulated aminopeptidase IRAP.

Insulin-regulated aminopeptidase (IRAP) is a membrane aminopeptidase and is homologous to the placental leucine aminopeptidase, P-LAP. IRAP has a wide distribution but has been best characterized in adipocytes and myocytes. In these cells, IRAP colocalizes with the glucose transporter GLUT4 to intracellular vesicles and, like GLUT4, translocates from these vesicles to the cell surface in response to insulin. Earlier studies demonstrated that purified IRAP cleaves several peptide hormones and that, concomitant with the appearance of IRAP at the surface of insulin-stimulated adipocytes, aminopeptidase activity toward extracellular substrates increases. In the present study, to identify in vivo substrates for IRAP, we tested potential substrates for cleavage by IRAP-deficient (IRAP(-/-)) and control mice. We found that vasopressin and oxytocin were not processed from the NH(2) terminus by isolated IRAP(-/-) adipocytes and skeletal muscles. Vasopressin was not cleaved from the NH(2) terminus after injection into IRAP(-/-) mice and exhibited a threefold increased half-life in the circulation of IRAP(-/-) mice. Consistent with this finding, endogenous plasma vasopressin levels were elevated twofold in IRAP(-/-) mice, and vasopressin levels in IRAP(-/-) brains, where plasma vasopressin originates, showed a compensatory decrease. We further established that insulin increased the clearance of vasopressin from control but not from IRAP(-/-) mice. In conclusion, we have identified vasopressin as the first physiological substrate for IRAP. Changes in plasma and brain vasopressin levels in IRAP(-/-) mice suggest a significant role for IRAP in regulating vasopressin. We have also uncovered a novel IRAP-dependent insulin effect: to acutely modify vasopressin.

[Prenatal ACTH-depot therapy]. / Prenatalna terapia ACTH-depot.

ACTH-depot therapy is one of the therapeutic methods in threatening abortion or premature labor, introduced by Prof. R. Klimek in the 60-ies of the last century. Administration of syntetic ACTH is the method of first choice in treatment of neuroendocrinologically complicated pregnancy, safe for mother as for infant. The first trials of application of this method disclosed good results determined by very high birth rate of at term pregnancies (96%) and delivery of live infants, in comparison to 18.5% or 37% supported pregnancies treated conservatively, in the same group of women previously. Because hypothalamic hormones induce synthesis of enzyme-oxytocinase, it becomes possible to observe the development of pregnancy in women treated with ACTH-depot by CAP-level determination. In women with hypothalamic hypofunction, level of oxytocinase is low, increasing slowly, sometimes even its decrease is observed. Current multiple ACTH-depot doses: 0.5 mg i.m. are routinely used, instead of hitherto applied series of 3 injections in the second and third trimester. Number of doses depend on: levels of oxyto-cinase, rate of its increase, reactivity of patient and progression of pregnancy. Administration of ACTH-depot seems to be more beneficial than aministration of corticoids, because this hormone does not cross the placenta, but increases the production of endogenic hormones. Unwelcome symptoms of ACTH-depot treatment are similar to those observed in course of the corticold therapy, but they are less expressed. Development of features connected with hypercatabolism of proteins like: muscular atrophy, striae and osteoporotic changes, are not observed. Only single therapy with ACTH-depot causes regression of clinical symptoms of threatening premature labor, without necessity of tocolitic treatment. Thanks to steroidogenesis, normalisation of the number of preterm labors and respiratory disorders decreases.

[Influence of ACTH-depot doses on neuroendocrine gestosis treatment]. / Wplyw dawkowania acth-depot na leczenie neuroendogennej gestozy.

OBJECTIVE OF THE STUDY: Two dosing methods of ACTH-depot therapy were compared dependently on gestational age and sequence of applied injections. It has been concluded that better efficacy was observed in single doses method comparing to serial doses in 2nd trimester. MATERIAL AND METHODS: Retrospectively, 380 pregnancies were analyzed, in which ACTH-depot therapy was applied using 0,5 mg doses. In 140 subjects (Group I, 1990-1991) 3 injection series every 2nd day with additional antibiotic (i.e. Monural 3g) were administrated. In the rest 240 (Group II, 1997-2002) single doses were applied during the whole period of pregnancy due to recurrent vomiting or decreased CAP1 serum levels under 0,8 micromol/l/min and CAP2 under 1,4 micromol/l/min in 1st trimester and compulsory in ACTH serum levels under 5,0 pg/ml. RESULTS: Clinical results can be compared with oxytocinase and ACTH serum levels, what allows to understand enzymatic control of internal maternal state. Role of ACTH not only in lung maturation, but also in onset of labor was proved in the mechanism of influence on immunologic tolerance. In hormonal threatening pregnancies enzymatic component is less helpful in predicting birth date because of common irregular oxitocinase pattern in such patients. On the other hand constant enzymatic increase proves effectiveness of ACTH-depot therapy in neurendocrine-gestoses, or in insulin-requiring pregnant patients. CONCLUSIONS: Acquired results of neonatal state proved that: 1. in pregnancies after infertility treatment early application of substitutional hormonotherapy wsith single doses of 0,5 mg ACTH-depot in early gestational weeks is more efficient method of ACTH dosing than 3 injections method in 2nd trimester 2. serum prelabour oxitocinase levels were precise factors of clinical results.

Insulin-regulated aminopeptidase/placental leucil Aminopeptidase (IRAP/P-lAP) and angiotensin IV-forming activities are modified in serum of rats with breast cancer induced by N-methyl-nitrosourea.

BACKGROUND: In previous reports, changes in oxytocinase activity in human breast cancer tissue and in the serum of N-methyl-nitrosourea (NMU)-induced rat mammary tumors were described. Insulin-regulated aminopeptidase (IRAP) has been identified with oxytocinase and has also been referred to as placental leucine aminopeptidase (P-LAP). MATERIALS AND METHODS: The IRAP/P-LAP activity in rat serum was assayed to analyze the putative role that IRAP/P-LAP may play in regulating mammary gland carcinogenesis induced by NMU. Furthermore, as it has been recently described that IRAP/P-LAP is the angiotensin IV (Ang IV) receptor AT4, the activities of Ang IV-forming aminopeptidase N (APN) and aminopeptidase B (APB) were also assayed. RESULTS: Changes in serum IRAP/P-LAP and Ang IV-forming APB activities were found in rats with mammary tumors induced by NMU. Both activities were greatly increased, although the Ang IV-forming APN activity was not modified. CONCLUSION: These changes in aminopeptidase activities may reflect the local functional status of their substrates, which can be selectively activated or inhibited in the affected tissue as a result of specific conditions brought about by the tumor. Thus, these enzymatic activities may be involved in the promotion and progression of breast cancer through oxytocin (OT), vasopressin (AVP) and/or renin-angiotensin system (RAS) misregulation.

The level of maternal immune tolerance and fetal maturity.

OBJECTIVES: Fetal maturity does not seem to be directly connected with the phenomenon of immune tolerance during pregnancy although the fetal maturation influences the process of initiation of the labor at term finishing the immune tolerance during pregnancy. CAP and RCAS1 are expressed by the trophoblast cells and afterwards by the placenta, these proteins are able to modulate the maternal immune response. MATERIALS AND METHODS: 160 patients were randomly selected to our study. The patients were divided into two groups using K score according to the newborn's maturity: maturated and not fully maturated. Within the groups of matured and not fully matured newborns the subgroups were selected according to the type of the labor: spontaneous or induced. The oxytocinase plasma activity was established in plasma samples obtained from pregnant women a few days before delivery. The placental RCAS1 relative amount was assessed by Western blot analysis. RESULTS: The differences in oxytocinase plasma level with respect to the fetal maturity were identified in our study however no RCAS1 expression changes were found regarding the fetal maturation. We determined the alterations in RCAS1 expression with respect to the occurrence of clinical symptoms of the spontaneous beginning of the labor in maturated and not-fully maturated groups of newborns. CONCLUSIONS: Oxytocinase seems to be a useful marker of normal fetal development. The assessment of RCAS1 in placenta directly after delivery appears to indicate the level of maternal immune tolerance during the labor initiation. The level of the immune tolerance at the moment of the delivery drops independently of the fetal maturity.

[Enzymatic diagnostics in obstetrics and gynecology. Part I]. / Enzymatyczna diagnostyka w poloznictwie i ginekologii. Czesc I.

The object of this paper is to highlight the importance of enzymatic diagnostics in obstetrics and gynecology. Enzymatic diagnostics through the assessment of oxytocinase allows to monitor the pregnancy and predict the delivery. Oxytocinase and its isoenzymes reflect the present state of the mother, the fetus and the placenta. The constant increase of oxytocinase in maternal blood up to the time of delivery and its appropriate level indicates the proper development of pregnancy. Low lewel and above all decrease in level instead of the normal constant increase precedes by several weeks clinical symptoms of abortions and preterm deliveries. Maternal blood levels of cystine-amino-peptidases (CAP1 and CAP2) show high correlation with the fetal and placental mass as well as fetal maturity. The levels of oxytocinase allow to objectivize the duration of pregnancy and to reduce induced and operative deliveries.