Search PubMed⌕ Search

Biomedical subjects

K Chwalisz

Publications and source records attributed to K Chwalisz.

At least 91 records · Page 5Linked to original sources
PubMed1983

A non-surgical technique for the transcervical administration of physiological and pharmacological agents into rat uteri.

A technique for the instillation of solutions into the rat uterine lumen is described. The method has been tested by following the receptor depletion/replenishment cycle after oestradiol injection and by checking on the stoichiometry of hormone/receptor translocation from the cytoplasmic compartment into the nucleus. Both crude sediments from frozen uteri and nuclei purified by a novel procedure were analyzed and gave identical results. The limitations and the advantages of the technique are discussed.

Animals↗
PubMed1980

[Radio-immunological determination of testosterone and of sexual hormone binding globulin in plasma of women with hirsutism (author's transl)].

Plasma-borne testosterone was determined in 176 women with hirsutism, and in 47 patients sexual hormone binding globulin was determined as well. The highest average testostercne values were recorded from cases with congenital AGS. In cases of postnatal AGS values were much lower, but they were clearly in excess of those recordable from Stein-Leventhal syndrome. Plasmaborne testosterone in cases of hirustism came very close to testosterone levels established in the context of Stein-Leventhal syndrome. Testosterone levels dropped with significance, following AGS treatment, using cortisol derivatives, and following wedge-shaped ovariectomy. Sexual hormone binding globulin was found to be strongly reduced in almost all women with hirsutism. Such reduction seemed to suggest the presence of increased amounts of free active testosterone in the blood of those patients. Determination of plasma-borne testosterone in cases of hirsutism is considered to be essential to both diagnosis of the endocrinological syndromes and monitoring of therapy.

Adrenal Hyperplasia, Congenital↗
PubMedDate not supplied

Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity.

Studies were conducted to assess progesterone antagonists (PAs) and progesterone receptor modulators (PRMs) with respect to PR agonistic and antagonistic activities in vivo. These properties are not always adequately reflected in transactivation in vitro models. Studies were performed in pregnant rats, estrogen-primed rabbits (McPhail -Test), and cycling and pregnant guinea pigs. Tested compounds included mifepristone (RU486), onapristone, J867, J956, J1042, and ZK137316. J-compounds induced sub-maximum endometrial transformation and, paradoxically, inhibited effects of progesterone in rabbits. Mifepristone, onapristone, and ZK137316 behaved as 'pure' antagonists in this species. Inhibition of uterine PGF(2alpha) secretion and inhibition of luteolysis in cycling guinea pigs were more sensitive parameters of PR-agonistic and antagonistic properties. 'Pure' PAs inhibited uterine PGF(2alpha) secretion and luteal regression completely. The PR agonist R5020 reversed both effects which demonstrates a PR mediation. Agonistic PRMs (J-substances and mifepristone) showed no or blunted antiluteolytic effects compared to the 'pure' PR antagonist onapristone. When tested in pregnant guinea pigs for their labor-inducing potential, PR agonistic PRMs had much reduced or abolished abortifacient activity compared to mifepristone (mifepristone > J956 > J867/J912 > J1042). However, in cycling animals, superior antiovulatory and antiproliferative properties of the J-substances were seen. Antiovulatory effects of 'pure' and agonistic PRMs are probably due to different mechanisms. The relevance of rodent studies for antiovulatory and uterine antiproliferative effects for the human is still uncertain. The non-abortifacient PRM J1042 induced stromal compaction and inhibition of endometrial proliferation in monkeys, but this effect was not stronger than that of the 'purer' PAs. 'Pure' PAs are important pharmacological tools analogous to PRKO models to study the role of PR in the menstrual cycle and in pregnancy.

Abortion, Induced↗
PubMedDate not supplied

Progestins, progesterone receptor modulators, and progesterone antagonists change VEGF release of endometrial cells in culture.

The influences of the synthetic progestin, medroxyprogesterone acetate (MPA), the progesterone receptor modulator J867, and the antagonist ZK137316 were studied in vitro on isolated endometrial epithelial cells, as well as endometrial fibroblasts. We evaluated the expression of estrogen receptor alpha (ER) and the progesterone receptor (PR) by RT-PCR. ER and PR were strongly expressed in the fibroblasts and epithelial cells under treatment with 10(-8) M 17beta-estradiol (E(2)). Treatment with 10(-6) M J867 or ZK137316 upregulated the PR expression as did E(2), in contrast to treatment with 10(-6) M MPA, which caused a downregulation of PR in epithelial cells, but not in fibroblasts. In addition, the vascular endothelial growth factor (VEGF) release into the cell culture medium was analyzed by a VEGF-ELISA. VEGF which plays an important role in angiogenesis, is regulated by steroid hormones as well as hypoxia. E(2) stimulates VEGF release into the medium in both cell types. MPA reduces VEGF release significantly in the fibroblast cell culture, but increases it in the epithelial cell culture. ZK137316, in the presence or absence of E(2), reduces VEGF release in fibroblast cell culture. J867 increases the VEGF production in fibroblasts only in the presence of E(2). Both compounds show no significant effects, compared to E(2), in epithelial cell culture. The different results for the epithelial cells and fibroblasts indicate that the pharmacological effects of PR modulators (PRMs) and progesterone antagonists (PAs) may be cell specific and depend on the presence or absence of partial progestagenic agonistic activities. This observation opens up new perspectives for various clinical applications.

Cell Culture Techniques↗
PubMedDate not supplied

Antiproliferative effects of progesterone antagonists and progesterone receptor modulators on the endometrium.

Progesterone antagonists (PAs, antiprogestins) can modulate estrogenic effects in various estrogen-dependent tissues. These modulatory effects are complex and depend on species, tissue, type of compound, dose, and duration of treatment. In non-human primates, PAs, including mifepristone, ZK 137 316 and ZK 230 211, inhibit endometrial proliferation and induce amenorrhea. When administered chronically at relatively low doses, these compounds block the mitotic activity of endometrial epithelium and induce stromal compaction in a dose-dependent manner in both spayed and intact monkeys at high estradiol concentrations. These effects were accompanied by an atrophy of spiral arteries. The antiproliferative effects were endometrium-specific, since the estrogenic effects in the oviduct and vagina were not inhibited by PAs. Similar endometrial antiproliferative effects were also found after treatment with the progesterone receptor modulator (PRM), mesoprogestin J1042. The endometrial antiproliferative effects of PAs, particularly within the endometrial glands, were also observed in spayed rabbits. In spayed rats, however, the PAs did not inhibit, but rather enhanced, various estrogen responses, including endometrial proliferation, pointing to species-specific differences. In conclusion, our studies indicate that both pure PAs and PRMs selectively inhibit estrogen-dependent endometrial proliferation in the primate endometrium without affecting estrogenic response in other estrogen-dependent tissues or inducing unscheduled bleeding. Our studies indicate that the spiral arteries, which are unique to the primate endometrium, are the primary targets that are damaged or inhibited by PAs and PRMs. The damage to these unique vessels may underlay the paradoxical, endometrium-specific, antiproliferative effects of these compounds. Hence, the properties of PAs and PRMs (mesoprogestins) open up new applications in gynecological therapy and hormone replacement therapy.

Animals↗
PubMedDate not supplied

Progesterone receptor modulators and progesterone antagonists in women's health.

Both progesterone receptor modulators (PRMs) as well as pure progesterone antagonists (PAs) have numerous proven and potential therapeutic applications in female health care. Mifepristone, a PRM with only marginal agonistic activity, together with a prostaglandin can terminate pregnancies of less than 9 weeks duration; mifepristone is also used in the preparation of women at later gestational stages whose pregnancies are terminated with prostaglandins or surgery. Mifepristone causes expulsion of the uterine contents following intrauterine fetal death and promotes dilation of the non-pregnant primigravid uterus. It is also effective in the treatment of missed abortion. Together with methotrexate, mifepristone can be used in the medical treatment of ectopic pregnancy. Both PAs and PRMs display antiproliferative effects on the endometrium. Because of this, they have application in the treatment of endometriosis, an estrogen-dependent condition. They may also be utilized to reduce myoma size, acting as both a PA and antiproliferative agent. Unlike GnRH agonists, long-term use in endometriosis and myoma is not associated with loss of bone and hypoestrogenism. PRMs may also be useful in IVF programs to prevent a premature LH surge and to delay the emergence of the implantation window. Some PRMs have potential use as hormone replacement therapy in women during menopause or in those with dysfunctional uterine bleeding.

Abortifacient Agents, Nonsteroidal↗
PubMedDate not supplied

Expression of receptors for corticotropin-releasing factor in the vasculature of pregnant rats.

OBJECTIVE: To identify and localize the receptor(s) responsible for modulating vascular effects of corticotropin-releasing factor (CRF) during pregnancy. METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR), competitive RT-PCR, and Western blot analyses were used to study the expression of CRF receptors (CRFR(1), CRFR(2alpha), and CRFR(2beta)) in the aorta and uterine vascular bed of nonpregnant and late (day 18) and term pregnant (day 22) Sprague-Dawley rats. Immunohistochemistry was done to localize the CRF receptor in the aortic wall. There were six rats in each study group. RESULTS: Only CRFR(2beta) was identified in the aorta and uterine vascular bed by RT-PCR and Western blot analyses. The PCR product was sequenced to confirm its identity. Competitive RT-PCR and Western blot analyses showed that expression of CRFR(2beta) is not different in late pregnancy compared with the nonpregnant but is decreased at term. Immunohistochemistry showed high expression of CRFR(2beta) on the aortic endothelial surface but low expression in the smooth-muscle layer. CONCLUSION: Only CRFR(2beta) is expressed in vasculature of nonpregnant and pregnant rats and may mediate the vasorelaxant effect of CRF. This receptor is present predominantly in the vascular endothelium and to a lesser extent in the smooth muscle. The expression of CRF receptor in pregnant rat vasculature is down-regulated at term of gestation.

Animals↗
PubMedDate not supplied

The nitric oxide pathway in pre-eclampsia: pathophysiological implications.

Pre-eclampsia, one of the most significant health problems in human pregnancy, complicates approximately 6-8% of all gestations and is the leading cause of fetal growth retardation, infant morbidity and mortality, premature birth and maternal death. Recent research implicates free radicals in the pathophysiology of pre-eclampsia. This review covers the biochemistry of nitric oxide (NO) and possible interactions with other free radicals. Studies in the rat show that pregnancy is associated with enhanced production and responsiveness to NO in both reproductive tissues and blood vessels. Rats infused with NG-nitro-L-arginine methyl ester (L-NAME, a NO synthase inhibitor) have been used as an animal model of pre-eclampsia, and the effects of steroid hormones on blood pressure in this model have been tested. Results suggest that pre-eclampsia may be a state of NO deficiency. However, in humans there seem to be contradictions regarding the involvement of NO in maternal adaptation to pregnancy. It is suggested that NO may be one of several systems that act in concert to maintain a symbiotic relationship between mother and fetus. However, the input of each system may be genetically determined.

Animals↗
PubMedDate not supplied

Modulation of oestrogenic effects by progesterone antagonists in the rat uterus.

Antiprogestins can modulate oestrogenic effects in various oestrogen-dependent tissues, dependent on species, tissue, dose and duration of treatment. Enhanced oestrogenic responses to mifepristone and onapristone occur in vitro and in vivo. However, the antiprogestins mifepristone, onapristone, and ZK 137 316 can block the ability of oestradiol to increase endometrial growth in non-human primates. Our purposes were firstly, to decide whether mifepristone and onapristone had direct oestrogenic activity in vitro and in the uterus of spayed and immature rats, and secondly, to discover whether antiprogestins exhibit inhibitory effects on oestrogen action in the uterus in spayed, oestrogen-substituted rats. In transactivation assays, mifepristone induced oestrogenic response, whereas onapristone had only marginal effects on reporter gene transcription. In immature rats, onapristone and mifepristone markedly increased uterine weights, and onapristone, but not mifepristone significantly enhanced endometrial luminal epithelial height, a sensitive oestrogen parameter. Conversely, in spayed and adrenalectomized rats, neither onapristone nor mifepristone changed uterine weights or endometrial morphology, indicating that their effects in immature rats were indirect. In spayed, oestrogen-substituted rats, antiprogestins did not block oestradiol-stimulated endometrial growth and luminal and glandular epithelium were stimulated more after antiprogestin plus oestrogen, than after oestradiol alone. All compounds induced compaction of the uterine stroma. In spayed rats, onapristone and some other 13alpha-configured (type 1) antagonists (ZK 135 569, ZK 131 535) reduced oestradiol-stimulated myometrial proliferation and induced an overall uterine weight reduction in animals treated with oestrogen and antiprogestins, in comparison with oestradiol-treated controls. 13beta- configured (type II) antagonists, including mifepristone, lilopristone and ZK 112 993, were not effective. In the uteri of spayed rats, onapristone was also found to enhance the oestradiol-stimulatory effect on expression of the oestrogen-dependent proto-oncogene, c-fos. In conclusion, antiprogestins do not inhibit, but rather enhance, oestrogen-induced uterine glandular and luminal epithelium in spayed rats, contrary to their effects in primates. The rat model is unsuitable to study endometrial antiproliferative effects of antiprogestins in primate uteri.

Animals↗
PubMedDate not supplied

Control and assessment of the uterus and cervix during pregnancy and labour.

Preterm labour and resultant preterm birth are the most important problems in perinatology. Countless efforts have failed to establish a single effective treatment of preterm labour, partly because the mechanisms regulating the uterus and cervix during pregnancy are not well understood. New knowledge is needed to inhibit early progression of labour (uterine contractility and cervical ripening), and adequate quantitative tools to evaluate the uterus and cervix during pregnancy are lacking. In this review, we outline studies showing that the uterus (myometrium) and cervix pass through a conditioning step in preparation for labour. This step is not easily identifiable with present methods to assess the uterus or cervix. In the uterus, this seemingly irreversible step consists of changes in the electrical properties to make muscle more excitable and responsive to produce forceful contractions. In the cervix, the step consists of softening of the connective tissue components. Progesterone appears to have a dominant role in controlling both the uterus and cervix, as antiprogestins induce early, preterm conditioning leading to preterm labour. Apparently, nitric oxide (NO) also controls conditioning of the uterus and cervix. In the uterus, NO, in concert with progesterone, inhibits uterine contractility. At term, NO production by the uterus and placenta are decreased and allow labour to progress. In contrast, NO in the cervix increases at the end of pregnancy and it may be the final pathway for stimulating cervical ripening by activation of metalloenzymes. The progress of labour can be assessed non-invasively using electromyographic (EMG) signals from the uterus (the driving force for contractility) recorded from the abdominal surface. Uterine EMG bursts detected in this manner characterize uterine contractile events during human and animal pregnancy. A low uterine EMG activity, measured transabdominally throughout most of pregnancy, rises dramatically during labour. EMG activity also increases substantially during preterm labour in humans and rats. This method may be used one day to predict impending preterm labour and identify control steps and treatments. A quantitative method also assesses the cervix, using an optical device which measures collagen fluorescence in the cervix. The collascope estimates cervical collagen content from a fluorescent signal generated when collagen cross-links are illuminated with excitation light of about 340 nm. The system has proved useful in rats and humans at various stages of pregnancy, and indicates that cervical softening occurs progressively in the last one-third of pregnancy. In rats, collascope readings correlate with resistance measurements made in the isolated cervix, which may help to assess cervical function during pregnancy, and indicate control and treatments.

Animals↗