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Biomedical subjects

K D Schulz

Publications and source records attributed to K D Schulz.

At least 55 records · Page 3Linked to original sources
PubMed1993

Estrogen and androgen receptor mediated stimulation and inhibition of proliferation by androst-5-ene-3 beta,17 beta-diol in human mammary cancer cells.

Androst-5-ene-3 beta,17 beta-diol (ADIOL) and 5 alpha-androstane-3 beta,17 beta-diol (5 alpha A), which are metabolites of dehydroepiandrosterone and dihydrotestosterone, are known to have estrogenic properties. This study reevaluates the estrogenic effects of ADIOL and 5 alpha A in MCF-7 cells and demonstrates additionally androgen-like inhibitory properties of these compounds in human hormone-dependent mammary cancer cells. ADIOL and 5 alpha A (10-100 nM) stimulate the proliferation of estrogen-sensitive MCF-7 cells. Binding assays with the estrogen receptor and inhibition of stimulation with the antiestrogen tamoxifen support the involvement of the estrogen receptor. On the other hand, the mammary cancer cell line MFM-223 is strongly inhibited by ADIOL and 5 alpha A in the same concentration range. This cell line is androgen receptor positive and is inhibited by androgens, but unresponsive to estrogens and progestins. The inhibitory effects of ADIOL and 5 alpha A in MFM-223 cells are mediated by the androgen receptor as demonstrated by receptor studies and competition experiments with hormone antagonists. ADIOL and 5 alpha A thus possess estrogen- and androgen-like properties and can stimulate or inhibit proliferation of human mammary cancer cells. The reactions of mammary cancer cells to these steroids depend on the receptor content and the growth properties of the individual cell line.

Androstane-3,17-diol↗
PubMed1993

Ovarian steroids modulate endothelin-induced luteinizing hormone secretion from cultured rat pituitary cells.

It has been demonstrated that endothelins (ETs) induce LH secretory responses in cultured rat pituitary cells. Because estradiol and progesterone are known to be potent modulators of GnRH-induced gonadotropin secretion, we examined whether these steroids also influence the secretory responses of gonadotrophs to ETs. Cultured female rat pituitary cells were treated for 48 h with vehicle (0.2% ethanol), 1 nM estradiol alone, or a combination of 1 nM estradiol and 100 nM progesterone or for 48 h with 1 nM estradiol and a further 4 h with 100 nM progesterone and subsequently stimulated with 10 pM-100 nM ET-1 or ET-3. Forty-eight-hour estradiol treatment led to enhanced LH secretory responses to both ETs. This action was facilitated by short term progesterone treatment (3-fold vs. vehicle), while long term progesterone treatment was inhibitory. Perifusion experiments were performed to study the kinetics of individual and pulsatile LH secretory responses after steroid exposure of pituitary cells. ET-1 induced immediate biphasic LH responses that were augmented by long term estradiol treatment. Two-hour progesterone exposure led to marked increases in LH secretion, whereas 48-h progesterone treatment was inhibitory. Estradiol and progesterone were able to modulate both the initial spike and the secondary plateau phase of the secretory profile in response to ET-1, although these actions did not always reach statistical significance. The steroid treatment paradigms employed also induced inhibitory and stimulatory effects in cells that were stimulated with ET-3 in a pulsatile fashion. In these experiments it could be demonstrated that the facilitatory action of progesterone was present after 50 min of treatment and was maximum after 150 min (5-fold enhancement). The present data support the hypothesis that ETs are involved in the physiological regulation of gonadotropin secretion and demonstrate that ovarian steroids can act as potent modulators of ET-induced LH secretion.

Animals↗
PubMed1993

High affinity binding and direct antiproliferative effects of luteinizing hormone-releasing hormone analogs in human endometrial cancer cell lines.

Although specific binding sites for LH-releasing hormone (LHRH) and its analogs have been demonstrated in biopsy samples of human endometrial cancer, their biological significance remains obscure. In this study we evaluated whether binding sites for LHRH are also present in the human endometrial cancer cell lines HEC-1A and Ishikawa and if such sites could mediate antiproliferative effects of LHRH analogs. Using [125I,D-Trp6]LHRH as a ligand, a high affinity/low capacity binding site was detected in both lines: HEC-1A line, dissociation constant (Kd)1 = 5.7 x 10(-9) mol/L, binding capacity (Bmax)1 = 78 fmol/10(6) cells; Ishikawa line, Kd1 = 4.2 x 10(-9) mol/L, Bmax1 = 29 fmol/10(6) cells. In addition, a second class of low affinity/high capacity binding sites for LHRH was demonstrated (HEC-1A line, Kd2 = 1.4 x 10(-6) mol/L, Bmax2 = 21 pmol/10(6) cells; Ishikawa, Kd2 = 4 x 10(-6) mol/L, Bmax2 = 32 pmol/10(6) cells). In the presence of 10(-5) mol/L agonist [D-Trp6]LHRH (triptorelin), the proliferation of HEC-1A and Ishikawa cell lines was significantly reduced to 76 +/- 2% and 88 +/- 4% of controls, respectively, after 24 h and to 64 +/- 2% and 62 +/- 2%, respectively, after 6 days. Dose-response experiments showed that lower concentrations (10(-9) mol/L) of the agonist decreased the proliferation to 80 +/- 1% for the HEC-1A line and 71 +/- 2% of controls for the Ishikawa line after 6 days. Antiproliferative effects are enhanced by increasing the doses of triptorelin and were maximal in this series of experiments at 10(-5) mol/L, the proliferation in the HEC-1A line being 62 +/- 1% and in the Ishikawa line 52 +/- 2% of controls, respectively. Similar time- and dose-dependent antiproliferative effects were obtained in both cell lines with the LHRH antagonist SB-75 (cetrorelix). These data suggest that LHRH analogs can directly inhibit the proliferation of human endometrial cancer cells in vitro. This direct action could be mediated through the high affinity LHRH binding sites.

Amino Acid Sequence↗
PubMed1993

Degradation of bradykinin by neutral endopeptidase (EC 3.4.24.11) in cultured human endothelial cells.

The presence of neutral endopeptidase 24.11 was demonstrated in human umbilical vein endothelial cells by immunostaining. Enzymatic activity of neutral endopeptidase was determined as 0.167 +/- 0.02 mU/mg protein in the membrane fraction of human umbilical vein endothelial cells, using the fluorogenic peptide substrate, dansyl-D-Ala-Gly-Phe(pNO2)-Gly. No activity was found in the cytosolic fraction of endothelial cells. The role of this peptidase in the degradation of the endogenous vasodilator bradykinin was investigated by incubating human umbilical vein endothelial cell monolayers with bradykinin (10(-8) mol/l). The inhibitor of neutral endopeptidase, phosphoramidon (10(-8) mol/l), decreased the degradation of bradykinin in the supernatant of endothelial cells; the half-life of bradykinin was then increased from 29 +/- 1 to 46 +/- 2 minutes. The angiotensin-converting enzyme inhibitor, lisinopril (10(-8) mol/l), increased the half-life of bradykinin to 244 +/- 20 minutes; the combination of both inhibitors increased the half-life of bradykinin to 381 +/- 51 minutes. Inhibitors of aminopeptidase (amastatin) and carboxypeptidase (2-mercaptomethyl-3-guanidinoethyl-thiopropionic acid) caused no significant effect. The effect of phosphoramidon was small in comparison with that of lisinopril, but was pronounced in combination with lisinopril. Neutral endopeptidase activity is localized in the membranes of human endothelial cells and seems to be involved in the degradation of bradykinin by the vascular endothelium, particularly during angiotensin converting enzyme inhibition.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

The response of uterine fibroids to GnRH-agonist treatment can be predicted in most cases after one month.

Twenty-seven patients with uterine fibroids were treated for 3 months with the GnRH-agonist goserelin prior to surgical myomectomy. Ovarian function was suppressed reliably in all patients. After three applications, 15 fibroids were reduced in volume by more than 50%, and one complete remission was achieved. Seven patients showed a decrease of 10-50% in volume. However, in 5 cases there was no significant reduction. Analysing the time course of the fibroid reduction, the response can be predicted in most cases as early as four weeks after the first injection. Retrospective statistical analysis showed that a 50% reduction in fibroid size due to GnRH treatment is preceded by a 35% reduction after 4 weeks in 81% of cases, and after 8 weeks in all cases. Only 2 of 12 fibroids, which showed a smaller response (less than 50%) to GnRH therapy, were reduced by more than 35% after 4 and 8 weeks. In most cases it seems to be possible to estimate the individual response to GnRH-application after the first injection, so that it is possible to stop therapy in non-responding patients.

Buserelin↗
PubMed1992

Regulation of androgen receptor mRNA and protein level by steroid hormones in human mammary cancer cells.

The regulation of the human androgen receptor (AR) by steroid hormones in human mammary cancer cells was investigated using immunocytochemical and ligand binding assays for its protein and Northern blot analyses for the corresponding mRNA. MFM-223 cells contain high levels of ARs and are growth-inhibited by dihydrotestosterone (DHT). The AR protein is down-regulated to 57% of the control by 10 nM DHT after 24 h, and the corresponding mRNA is also reduced. The nonsteroidal antiandrogen hydroxyflutamide had no effect on the AR level, whereas after incubation with 1 microM cyproterone acetate a slight down-regulation was observed. The AR level was restored completely after release from a 7 day treatment with DHT. However, only 60% of the control level was restored, if the cells wer grown in the presence of DHT for 6 weeks. In androgen-pretreated cells the proliferation rate remained decreased even after the withdrawal of DHT. Concomitantly the distinct growth inhibition was lost. Transfection experiments demonstrated a reduced activity of the residual androgen receptor in these pretreated cells. In addition to the AR, EFM-19 cells also contain significant amounts of estrogen and progesterone receptors. EFM-19 cells are not growth inhibited by physiological concentrations of DHT. Autoregulation of AR was also found in this cell line. Additionally, reduced levels of AR protein and mRNA were found in EFM-19 cells after treatment with the synthetic progestin R5020. The maximum effect of R5020 was observed at the high concentration of 1 microM. Estrogen treatment with 10 nM 17 beta-estradiol for 3 days reduced the AR level only by 25%.

Blotting, Northern↗
PubMed1992

Intracellular actions of gonadotropic and peptide hormones and the therapeutic value of GnRH-agonists in ovarian cancer.

During the last two decades, considerable experimental evidence has been collected indicating that epithelial ovarian cancer might be gonadotropin dependent. LH and FSH receptors have been described in some of these tumors. The proliferation of ovarian cancer cells could be stimulated in vitro by gonadotropins. Suppression of endogenous LH and FSH secretion by GnRH-agonist treatment inhibited the growth of experimental or heterotransplanted ovarian cancers in various animal models. A number of recent phase II clinical trials have shown that the application of GnRH-agonists can lead to remission or stable disease in patients with relapsed advanced ovarian cancer. At present, prospective controlled clinical studies are being performed to assess the efficacy of GnRH-agonist treatment in addition to conventional surgical and cytostatic therapy in ovarian cancer in FIGO stages III and IV. Also, direct effects of GnRH analogues on ovarian cancer seem possible: a GnRH-like protein has been found in the human ovary. Our group discovered and partially characterized a specific GnRH-binding site (mol. wt 63.2 kDa) in ovarian cancer which is very similar to other human extrapituitary GnRH-binding sites of the low affinity, high capacity type, e.g. in breast cancer or the placenta. Recently, other groups have described also high affinity GnRH-agonist binding sites in ovarian cancer as well as in other extrapituitary tissues. First results from our laboratory indicate that the proliferation of certain ovarian cancer cell lines in vitro is reduced by both agonistic and antagonistic analogues of GnRH. Other authors were able to inhibit gonadotropin-induced in vitro proliferation of ovarian cancer cell lines by co-incubation with a GnRH-agonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

[Condylomata acuminata and associated infections--possibilities for therapy with interferon].

Recombinant alpha-Interferon can be used in primary therapy of condylomata acuminata. In our patients we found a response rate of 53%. Besides use in primary therapy the significant low rate of recurrences is important, thus offering the possibility of adjuvant interferon therapy after primary surgical treatment, where laser-vaporisation is best applied. Possible applications for primary and secondary treatment are shown. The rate of additional infections is of great importance; besides common agents for vaginal infections we found an elevated rate of HPV 16/18 with 47%.

Administration, Topical↗
PubMed1991

Androgen sensitivity of the new human breast cancer cell line MFM-223.

The mammary carcinoma cell line MFM-223 is characterized by high androgen and low estrogen and progesterone receptor levels. With the dextran charcoal method, androgen binding was determined at 160 fmol/mg protein corresponding to approximately 100,000 binding sites per cell in whole cell binding assays. The estrogen and progesterone receptor contents were between 8 and 18 fmol/mg protein. The proliferation of MFM-223 cells was significantly inhibited by doses greater than 0.01 nM dihydrotestosterone. The androgenic inhibition of cell proliferation was antagonized by the antiandrogens cyproterone acetate and hydroxyflutamide. In spite of the low estrogen receptor content, MFM-223 cell proliferation was slightly enhanced by 10 nM 17 beta-estradiol. Treatment with 17 beta-estradiol or dihydrotestosterone failed to provoke an increase of the progesterone receptor level. MFM-223 cells have characteristic patterns of isoenzyme polymorphism and of karyotype alterations revealing marker chromosomes and homogeneously staining regions. In the spectrum of human mammary carcinoma cell lines, MFM-223 cells offer a unique model to investigate molecular mechanisms of androgen receptor action.

Breast Neoplasms↗
PubMed1991

Rupture of an aneurysm of the splenic artery and pregnancy: a case report.

The mortality risk in rupture of an aneurysm of the splenic artery is 69.4% for pregnant women and 90.8% for the foetus. 95% of all patients are asymptomatic up to this stage. If the aneurysm is diagnosed earlier, the maternal mortality rate can be reduced to 0.5% by prophylactic surgery. 25% of patients with symptoms display prodromes which, with accurate knowledge of the syndrome, make it possible to make an early diagnosis. Characteristics of the disorder, its risk factors, signs for early diagnosis and therapeutic measures, as well as an up-to-date review of the literature are presented here, illustrated by one of our own case studies.

Adult↗
PubMed1991

[Manifestations of ruptured liver hematoma as a severe complication of HELLP syndrome].

A case of a ruptured haematoma of the liver with intra-abdominal bleeding is reported. The 26-year old primigravida was admitted in the 31st week of gestation because of a HELLP syndrome. She presented additional symptoms, that are considered typical for a HELLP syndrome, complicated by a ruptured haematoma of the liver: severe right upper-quadrant pain, decrease of haemoglobin content, enlarged liver with structural irregularities and free fluid in the abdominal cavity as examined by sonography. During Caesarean section, a subcapsular haematoma of the liver, combined with a 5 cm laceration of the organ surface, was found. The defect was closed with collagen gauze and clotted with fibrin. Additionally the liver was compressed by abdominal compression towels, which were removed 2 days later. The postoperative development was, in the main, complication free.

Adult↗
PubMed1990

LHRH-receptors and LHRH-agonist treatment in ovarian cancer: an overview.

Considerable evidence exists that ovarian cancer might be gonadotrophin-dependent. Receptors for LH and FSH have been discovered in these tumors. Proliferation of ovarian cancer cells in vitro could be stimulated by gonadotrophins. Withdrawal of LH and FSH in animal models of ovarian cancer inhibited growth of these tumors. Phase-II clinical studies have shown that suppression of endogenous gonadotrophins by LHRH-agonists can be beneficial in women with advanced ovarian cancer. Respective controlled clinical trials are performed at present. Also direct effects of LHRH analogues on ovarian tumors have been reported. An LHRH like protein was found in human ovarian tissue. We discovered a specific LHRH binding site (mol. wt 63.2 kDa) in ovarian cancer tissue which is very similar to other human extrapituitary LHRH binding sites, of the low-affinity, high-capacity type, e.g. in breast cancer and the placenta. In the latter tissues, LHRH or a related substance has been proposed as an autocrine regulator of cellular function. If this was also the case in ovarian cancer, direct effects of LHRH analogs on the tumor cells could be used as additional therapeutical points of attack.

Animals↗
PubMed1990

Down-regulation of androgen receptor by progestins and interference with estrogenic or androgenic stimulation of mammary carcinoma cell growth.

The regulatory influence of medroxyprogesterone acetate (MPA) on estrogen and androgen receptors of the human breast cancer cell lines MCF-7 and EFM-19 was explored in conjunction with the growth-promoting properties of these steroids. In the absence of steroidal stimulation, up to 1 microM MPA had no effect on the proliferation of the MCF-7 cell strain used and of EFM-19 cells. Under stimulation with 10 nM 17 beta-estradiol or 1 microM dihydrotestosterone, dose-dependent inhibition of the cell proliferation rates by 0.1-1 microM MPA was observed. Binding of MPA to the androgen receptor (Kd = 2.1 nM) but not to the estrogen receptor was demonstrable. During incubation of MCF-7 or EFM-19 cells with 1 microM MPA for 7 days, the estrogen and androgen receptor contents were down-regulated by approximately 50% and 60%, respectively. Likewise, the number of androgen-binding sites was reduced to 35% of the untreated controls after incubation of MCF-7 cells with 1 microM synthetic progestin R5020 for 7 days. The results indicate down-regulation of estrogen and androgen receptors by progestins in the absence of stimulatory effects on the proliferation of mammary carcinoma cells.

Breast Neoplasms↗
PubMed1990

C-reactive protein is a marker for the diagnosis of adnexitis.

The study reports the C-reactive protein (CRP) plasma concentrations in 115 women with a presumed diagnosis of acute adnexitis. In addition to CRP, blood sedimentation rate, white blood cell count and the body temperature were evaluated and compared with the clinical findings. Diagnosis was confirmed or excluded by laparoscopy (n = 69) or laparotomy (n = 9). Clinical examinations and conventional laboratory examinations were of limited value in the diagnosis of acute adnexitis. In contrast, CRP was a highly sensitive indicator of inflammatory pelvic disease. Furthermore, the CRP determination was superior in assessing the efficacy of an antibiotic treatment.

Anti-Bacterial Agents↗
PubMed1990

[Preoperative reduction of uterine leiomyoma by the GnRH-analog goserelin (zoladex)].

The administration of GnRH analogues is expected to improve treatment by avoiding hysterectomy, since problems connected with the surgical removal of leiomyomata are correlated with their size. In this study the GnRH analogue goserelin in its depot formulation (Zoladex, ICI, Plankstadt) was used for treating isolated leiomyomata of the uterus. All patients were treated for 3 months before myomectomy was performed. The complete regression of a large myoma (206 cm3) was observed in 1 of 11 patients. In 5 cases a reduction in volume of more than 50% was achieved. Ovarian function was suppressed by goserelin, after a short-term stimulation, within 7 +/- 3 days. Serum levels of 17 beta-oestradiol were found to be generally less than 25 pg/ml. All patients reported climacteric complaints, but in no case had therapy to be discontinued. After cessation of goserelin, restoration of ovarian function was observed in all patients.

Adult↗