[Experience in establishing a certified endoprosthesis center]. / Erfahrungen mit der Einrichtung eines zertifizierten Endoprothesenzentrums.

BACKGROUND: It is well known that morbidity rates of arthroplasties are inversely related to procedure volume. In the department of orthopaedics at a German medical school, a performance of certification of high-volume center for total hip and knee arthroplasties, called the EndoCert(®) Initiative, was started. This project was initiated by the German society of orthopaedic surgery (DGOOC) to secure the quality of total knee and hip arthroplasties. OBJECTIVES: The aim of this study is to evaluate effects of certification, pathwaycontrolled therapy and quality indicators on outcome in arthroplasty three years after implentation. MATERIALS AND METHODS: Arthroplasties performed in this certified center for total hip and knee arthroplasties were evaluated. Outcome was evaluated after the implementation of quality indicators and clinical pathways. RESULTS: After establishment of certification in the center for total hip and knee arthroplasties morbidity rates decreased as quality increased. CONCLUSION: The implementation of pathway-controlled therapy and quality indicators in a high-volume center for total joint arthroplasties shows better clinical results. Capital investment and efforts are legitimated.

A prostaglandin E2 receptor antagonist prevents pregnancies during a preclinical contraceptive trial with female macaques.

STUDY QUESTION: Can administration of a prostaglandin (PG) E2 receptor 2 (PTGER2) antagonist prevent pregnancy in adult female monkeys by blocking periovulatory events in the follicle without altering menstrual cyclicity or general health? SUMMARY ANSWER: This is the first study to demonstrate that a PTGER2 antagonist can serve as an effective non-hormonal contraceptive in primates. WHAT IS KNOWN ALREADY: The requirement for PGE2 in ovulation and the release of an oocyte surrounded by expanded cumulus cells (cumulus-oocyte expansion; C-OE) was established through the generation of PTGS2 and PTGER2 null-mutant mice. A critical role for PGE2 in primate ovulation is supported by evidence that intrafollicular injection of indomethacin in rhesus monkeys suppressed follicle rupture, whereas co-injection of PGE2 with indomethacin resulted in ovulation. STUDY DESIGN, SIZE, DURATION: First, controlled ovulation protocols were performed in adult, female rhesus monkeys to analyze the mRNA levels for genes encoding PGE2 synthesis and signaling components in the naturally selected pre-ovulatory follicle at different times after the ovulatory hCG stimulus (0, 12, 24, 36 h pre-ovulation; 36 h post-ovulation, n = 3-4/time point). Second, controlled ovarian stimulation cycles were utilized to obtain multiple cumulus-oocyte complexes (COCs) from rhesus monkeys to evaluate the role of PGE2 in C-OE in vitro (n = 3-4 animals/treatment; ≥3 COCs/animal/treatment). Third, adult cycling female cynomolgus macaques were randomly assigned (n = 10/group) to vehicle (control) or PTGER2 antagonist (BAY06) groups to perform a contraceptive trial. After the first treatment cycle, a male of proven fertility was introduced into each group and they remained housed together for the duration of the 5-month contraceptive trial that was followed by a post-treatment reversibility trial. PARTICIPANTS/MATERIALS, SETTING, METHODS: Quantitative real-time PCR, COC culture and expansion, immunofluorescence/confocal microscopy, enzyme immunoassay, contraceptive trial, ultrasonography, complete blood counts, serum biochemistry tests and blood lipid profiles. MAIN RESULTS AND THE ROLE OF CHANCE: Several mRNAs encoding proteins involved in PGE2 synthesis, metabolism and signaling increase (P < 0.05) in the periovulatory follicle after administration of an ovulatory hCG bolus. PGE2 signaling through PTGER2 induces cumulus cell expansion and production of hyaluronic acid, which are critical events for fertilization. Moreover, chronic administration of a selective PTGER2 antagonist resulted in a significant (P < 0.05 versus vehicle-treated controls) contraceptive effect without altering steroid hormone patterns or menstrual cyclicity during a 5-months contraceptive trial. Fertility recovered as early as 1 month after ending treatment. LIMITATIONS, REASONS FOR CAUTION: This is a proof-of-concept study in a non-human primate model. Further investigations are warranted to elucidate the mechanism(s) of PTGER2 antagonist action in the primate ovary. Although PTGER2 antagonist treatment did not produce any obvious undesirable effects, improvements in the mode of administration, as well as the efficacy of these compounds, are necessary to consider such a contraceptive for women. WIDER IMPLICATIONS OF THE FINDINGS: Monitoring as well as improving the efficacy and safety of female contraceptives is an important public health activity. Even though hormonal contraceptives are effective for women, concerns remain regarding their side-effects and long-term use because of the widespread actions of such steroidal products in many tissues. Moreover, some women cannot take hormones for medical reasons. Thus, development of non-hormonal contraceptives for women is warranted. STUDY FUNDING/COMPETING INTEREST(S): Supported by Bayer HealthCare Pharmaceuticals, The Eunice Kennedy Shriver NICHD Contraceptive Development and Research Center (U54 HD055744), NIH Office of the Director (Oregon National Primate Research Center P51 OD011092), and a Lalor Foundation Postdoctoral Basic Research Fellowship (MCP). The use of the Leica confocal was supported by grant number S10RR024585. Some of the authors (N.B., A.R., K.-H.F., U.F., B.B. and B.L.) are employees of Bayer Healthcare Pharma.

Effects of dienogest on surgically induced endometriosis in rats after repeated oral administration.

BACKGROUND: Dienogest demonstrates efficacy for lesion reduction and pain relief in clinical trials of endometriosis. The current study investigated an intraperitoneal animal model of endometriosis to further characterize the effects of dienogest. METHODS: Endometrial-like lesions were induced in rats by autotransplantation of uterine tissue into the peritoneal cavity. Dienogest 0.3 or 1.0 mg/kg/day, danazol 100 mg/kg/day, or vehicle control were administered orally for 28 days. Changes in endometrial-like lesion size during treatment were assessed at laparotomy. Uterine horn weight was also measured as an index of the estrogenic effects of treatment. RESULTS: Dienogest 0.3 mg/kg/day significantly reduced the total endometrial lesion area, with an effect equivalent to danazol 100 mg/kg/day. Unlike dienogest 1.0 mg/kg/day, dienogest 0.3 mg/kg/day had no effect on uterine horn weight, indicating an absence of estrogenic effects for this dose in rodents. CONCLUSION: Dienogest 0.3 mg/kg/day for 28 days demonstrated potent inhibitory activity on the growth of endometrial tissue in this model, providing supportive evidence for the efficacy of dienogest in lesion reduction.

[Establishing the differential indication for anatomical and reversed shoulder endoprostheses in rheumatoid arthritis]. / Zur Differenzialindikation anatomischer und inverser Schulterendoprothesen bei chronischer Polyarthritis.

BACKGROUND: In addition to joint destruction, there is often also a loss of rotator cuff function in rheumatism patients. Thus, joint replacement alone using an anatomical prosthesis is unable to achieve satisfactory results. A half-linked inverse prosthesis, on the other hand, achieves improved function even in the presence of non-functioning rotator cuffs. PATIENTS AND METHODS: Of 157 shoulder prostheses that were followed up, 21 had been implanted in patients with rheumatoid arthritis. An anatomical endoprosthesis was implanted in 15 cases and an inversed endoprosthesis in six cases (average age 55.5/66.6 years). RESULTS: The Constant score improved from 23 to 65 points for the anatomical prosthesis and from 15 to 67 points for the inversed endoprosthesis. An analogous improvement was also noted for mobility, strength and pain relief. CONCLUSION: The results of anatomical prostheses depend substantially on the extent of damage to the rotator cuff. Implantation of a semi-constrained inversed prosthesis provides a solution for severely damaged joints since it has a fixed centre of rotation. One prerequisite of success, however, is a sufficient bone stock in the glenoid region. The indication for bipolar prostheses, in contrast, is particularly strong when implantation of an inverse prosthesis is no longer possible.

[Manifestation of generalized osteoarthritis in a genealogically investigated population]. / Manifestation der generalisierten Osteoarthrose in einer genealogisch überprüften Patientengruppe.

BACKGROUND: The definition of generalized osteoarthritis in the literature is just as controversial as the discussion about correlations between GOA and Heberden's nodes (HN). Therefore, both questions were investigated in patients with proven heredity in a genealogical study of 931 family members. MATERIAL AND METHODS: In 106 patients with HN and 109 control subjects, 70 joints and spinal segments were investigated with respect to characteristic functional parameters. In addition, 44 joints and spinal segments were investigated radiologically. RESULTS: GOA affects both the small and large joints as well as the spine. This phenomenon is the more pronounced the more finger joints are affected by Heberden's and Bouchard's nodes. CONCLUSIONS: GOA affects the entire musculoskeletal system. The varying manifestation in individual joints and spinal segments is probably attributable to multifactorial local and systemic factors. In an earlier study, a genetic disposition with a maximum HA prevalence of 30% was identified in the study population. Since HA is considered a genetic marker for GOA, it can be assumed that the same is true of GOA prevalence.

Intraperitoneal inflammation decreases endometriosis in a mouse model.

BACKGROUND: The role of the immune system in the pathogenesis of endometriosis remains elusive. It has been shown that patients have an altered peritoneal environment with increased levels of inflammatory cytokines, activated macrophages and reduced clearance of retrogradely transported endometrial fragments. However, it is not known if this unique inflammatory situation is cause or consequence of endometriosis. This study investigates the impact of a pre-existing peritoneal inflammation on endometriosis establishment in a mouse model. METHODS: Endometriosis was induced by intraperitoneal injection of enhanced green fluorescent protein (EGFP)-expressing endometrium in mice. In parallel, a peritonitis model was established via intraperitoneal injection of thioglycolate medium (TM). Finally, endometriosis was induced in the inflamed peritoneal cavity and lesion establishment as well as morphological and histological characteristics were analysed. RESULTS: Induction of endometriosis in an inflamed peritoneal cavity resulted in fewer lesions and significantly lower sum of lesion surface area per mouse in the TM-treated group. Additionally, a higher amount of non-attached debris could be detected in the peritoneal cavity of TM-treated mice. CONCLUSIONS: An intraperitoneal inflammation decreases endometriosis establishment in this mouse model. Thus, a pre-existing peritoneal inflammation might not be a factor favouring the development of endometriosis.

Amino acid sequences in the alpha 1 domain and not glycosylation are important in HLA-A2/beta 2-microglobulin association and cell surface expression.

The role of the single carbohydrate moiety present on the HLA-A2 molecule was studied by introducing several amino acid substitutions (by site-directed mutagenesis of the HLA-A2 gene) in the consensus glycosylation sequence Asn-X-Ser. Two different amino acid substitutions of the asparagine residue at position 86 (glutamine and aspartic acid) resulted in the synthesis of ca. 39,000-molecular-weight nonglycosylated heavy chains that were detected in the cytoplasm but not on the surface of mouse L-cell transfectants. However, a low level of surface expression was detected following transfection of human (rhabdomyosarcoma) cells or mouse L cells containing human beta 2-microglobulin. The defect in surface expression was not due to the absence of the glycan moiety, since the substitution of a glycine for a serine at amino acid 88 did not have the same drastic effect in the presence of human beta 2-microglobulin. These and other data suggest that the asparagine residue may play a critical role in the conformation of the HLA heavy chain and its interaction with beta 2-microglobulin. Immunofluorescence microscopy following permeabilization of the transfectants demonstrated that the unglycosylated HLA heavy chains are sequestered in an unidentified cellular compartment that is different from the Golgi structure.

The v-erb A oncogene causes repression of erythrocyte-specific genes and an immature, aberrant differentiation phenotype in normal erythroid progenitors.

We have compared the effects of the v-erb A oncogene on proliferation and differentiation of normal erythroid progenitors with those of tyrosine kinase oncogenes, e.g. v-sea. For this, a v-erb A retrovirus containing the neomycin resistance gene as a selectable marker or, alternatively, a v-erb A-ts v-sea retrovirus were used to infect normal bone marrow cells. V-erb A induced the outgrowth of immature, erythropoietin(EPO)-dependent erythroid cells from infected bone marrow which ceased to proliferate and disintegrated after 9 to 18 divisions. In contrast, ts-v-sea erythroblasts grew for the expected 25 to 40 population doublings in the absence of EPO. Transcription of the erythrocyte genes carbonic anhydrase II and erythrocyte anion transporter was significantly inhibited in v-erb A infected erythroblasts, indicating that v-erb A alone was sufficient for the repression of the erythrocyte-specific genes observed in AEV-transformed leukemic cells. A detailed analysis of the differentiation phenotype induced by v-erb A in erythroblasts (in the presence or absence of a temperature-inactivated ts sea oncogene) indicates that v-erb A-erythroblasts express a partially mature, aberrant phenotype characterized by the coexpression of mature and immature differentiation antigens. This phenotype clearly differs from that induced by tyrosine kinase oncogenes in erythroid cells.

Recent developments in molecular action of antihormones.

Antihormones are by definition antagonists of steroid hormone action. They interact with the ligand binding domains of steroid hormone receptors and competitively inhibit the action of the receptors by mechanisms that are not quite understood. In certain cases antihormones also exhibit agonistic activity especially in connection with certain naturally occurring receptor mutants. These observations together with findings of indiscriminate interaction of antihormones with several classes of steroid receptors have necessitated a search of more effective and reliable antihormones. Recent advances in the resolution of the crystal structure of the ligand binding domains of certain members of the steroid receptor family and identification of non-liganded activation of steroid receptors have produced considerable information that can be harnessed into a fruitful search for a new generation of antihormones.

Comparative messenger ribonucleic acid analysis of immediate early genes and sex steroid receptors in human leiomyoma and healthy myometrium.

To shed light on the molecular mechanisms involved in the pathogenesis of uterine leiomyomas, transcript levels of the immediate early genes c-fos, c-myc, and c-jun and of the estrogen receptor (ER) and progesterone receptor (PR) were determined in tissue samples of human myometrium and leiomyoma. The messenger RNA (mRNA) content was analyzed by RT-PCR. mRNAs for c-fos, c-myc, c-jun, ER, and PR were detected in all 18 samples of leiomyoma and corresponding myometrial tissue collected in this study. Interestingly, in contrast to healthy tissues, we found a distinct and significant reduction of c-fos mRNA in the tumor. These data were substantiated by the finding of lowered c-Fos protein levels in leiomyomas tissues. Moreover, transcripts of c-jun and c-myc were less abundant in most of the leiomyomas than in the myometrium. This different expression of the protooncogenes in leiomyomas and myometrium was independent of the phase of the menstrual cycle in which samples were collected. In contrast to the reduced transcript levels observed for the immediate early genes, the ER and PR mRNA contents of the leiomyomas and myometrium did not differ. These results were confirmed by immunohistochemical studies for ER and PR protein. In conclusion, our data show that the deregulated expression of protooncogenes, especially of c-fos, is linked to the pathogenesis of leiomyomas. Confirmation of a potential role of downregulated c-fos levels for the benign character of these tumors requires further investigation. Additionally, the findings suggest that sex steroids do not influence the different expression patterns of c-fos, c-myc, and c-jun in leiomyomas, as compared with myometrium.

Synthesis and biological activity of a novel, highly potent progesterone receptor antagonist.

Herein we describe the chemical synthesis and pharmacological characterization of a novel, highly potent progesterone receptor (PR) antagonist, ZK 230211. The introduction of a 17alpha-pentafluorethyl side chain in the D-ring of the steroid skeleton allowed the combination of high antiprogestagenic activity with little or no other endocrinological effects. In contrast to many other antiprogestins, ZK 230211 did not convert to an agonist in the presence of protein kinase A (PKA) activators and showed high antiprogestagenic activity on both PR isoforms PR-A and PR-B. This high antiprogestagenic activity could also be demonstrated in several in vivo models. Furthermore, this compound displayed only marginal antiglucocorticoid effects. In tumor models ZK 230211 exhibited strong antiproliferative action. The pharmacological properties of ZK 230211 may prove useful in the treatment of endometriosis, leiomyomas, breast cancer, and in hormone replacement therapy.

DNA-binding of androgen receptor overexpressed in mammalian cells.

In order to investigate the DNA-binding properties of the rat androgen receptor (rAR) in mammalian cells after addition of androgens and antiandrogens, we established a gel-shift assay with extract from COS-1 cells (CV-1 cells transformed with the DNA-tumour virus SV40) over-expressing the rAR. First, the rAR was overexpressed in COS-1 cells. Therefore the full-length AR cDNA was inserted immediately downstream from the SV40 early promoter of pECE to generate pECE-AR. Expression of the rAR driven by the SV40 early promoter yields constant and high levels of rAR protein. In addition, the vector contains the SV40 origin of replication for obtaining high copy vector numbers in COS-1 cells. The rAR-containing expression vector was transiently transfected into COS-1 cells using Transfectam Reagent, in order to achieve high transfection efficiency. Expression of biologically active receptor was tested by analyzing the effect of the synthetic androgen R1881 on induction of transiently transfected pMMTV-CAT. Steroid binding assays were carried out to confirm overexpression of biologically active AR and to determine the binding of different hormones and antihormones to AR in COS-1 cells transiently transfected with pECE-AR. Gel-shift experiments performed with whole cell extract of those cells, containing approximately 700 fmol AR/mg protein, and labeled AR-binding GRE (glucocorticoid responsive element) showed that R1881 induced the formation of a protein-GRE complex. Furthermore, the R1881-induced formation of the protein-GRE complex could be completed by addition of unlabeled excess of GRE but not of unspecific oligonucleotides, confirming sequence-specific binding of the R1881-induced protein-GRE complex.

Stable transfection of androgen receptor and MMTV-CAT into mammalian cells: inhibition of cat expression by anti-androgens.

A hormone-inducible transcriptional system has been established, based on the stable transfection of the rat androgen receptor (rAR) and a reporter plasmid containing the mouse mammary tumour virus promoter linked to the chloramphenicol acetyltransferase gene (pMMTV-CAT) into steroid receptor-negative CV-1 cells. First, the rAR was stably introduced into CV-1 cells. Single clones were tested for stable expression of functionally active AR by analysing the effect of dihydrotestosterone on induction of transiently transfected pMMTV-CAT. Stable transfection and the expression of AR was confirmed by steroid-binding assays. In a second step, a clone expressing physiological amounts of AR protein (30 fmol/mg protein) was stably transfected with pMMTV-CAT to yield a permanent cell line that stably expresses functional AR and MMTV-CAT sequences. This cell line provides a powerful tool for the efficient and accurate determination and quantification of the effects of androgens and anti-androgens on reporter gene transcription. This was demonstrated by investigating the action of the three anti-androgens hydroxyflutamide, casodex and cyproterone acetate. The three compounds were shown to reverse the effects of the androgen R1881 on gene expression but were themselves devoid of agonistic activity.

Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity.

Drospirenone (ZK 30595; 6 beta, 7 beta, 15 beta, 16 beta-dimethylen-3-oxo-17 alpha-pregn-4-ene-21, 17-carbolactone) is a novel progestogen under clinical development. Drospirenone is characterized by an innovative pharmacodynamic profile which is very closely related to that of progesterone. Potential applications include oral contraception, hormone replacement therapy and treatment of hormonal disorders. The pharmacological properties of drospirenone were investigated in vitro by receptor binding and transactivation experiments and in vivo in appropriate animal models. In qualitative agreement with progesterone, the compound binds strongly to the progesterone and the mineralocorticoid receptor and with lower affinity to androgen and glucocorticoid receptors. There is no detectable binding to the estrogen receptor. Steroid hormone agonistic and antagonistic activities of progesterone and drospirenone were compared in transactivation experiments. Individual steroid hormone receptors were artificially expressed together with a reporter gene in appropriate cell lines. Both hormones were unable to induce any androgen receptor-mediated agonistic activity. Rather, both progesterone and drospirenone distinctly antagonized androgen-stimulated transcriptional activation. Likewise, both compounds only very weakly activated the mineralocorticoid receptor but showed potent aldosterone antagonistic activity. Drospirenone did not induce glucocorticoid receptor-driven transactivation. Progesterone was a weak agonist in this respect. Drospirenone exerts potent progestogenic and antigonadotropic activity which was studied in various animal species. It efficiently promotes the maintenance of pregnancy in ovariectomized rats, inhibits ovulation in rats and mice and stimulates endometrial transformation in the rabbit. Furthermore, drospirenone shows potent antigonadotropic, i.e., testosterone-lowering activity in male cynomolgus monkeys. The progestogenic potency of drospirenone was found to be in the range of that of norethisterone acetate. The majority of clinically used progestogens are androgenic. Drospirenone, like progesterone, has no androgenic but rather an antiandrogenic effect. This property was demonstrated in castrated, testosterone propionate substituted male rats by a dose-dependent inhibition of accessory sex organ growth (seminal vesicles, prostate). In this model, the potency of drospirenone was about a third that of cyproterone acetate. Drospirenone, like progesterone, shows antimineralocorticoid activity, which causes moderately increased sodium and water excretion. This is an outstanding characteristic which has not been described for any other synthetic progestogen before. Drospirenone is eight to ten times more effective in this respect than spironolactone. The natriuretic effect was demonstrable for at least three weeks upon daily treatment of rats with a dose of 10 mg/animal. Drospirenone is devoid of any estrogenic, glucocorticoid or antiglucocorticoid activity. In summary, drospirenone, like progesterone, combines potent progestogenic with antimineralocorticoid and antiandrogenic activity in a similar dose range.(ABSTRACT TRUNCATED AT 400 WORDS)

Gangliosides mediate inhibitory effects of tetanus and botulinum A neurotoxins on exocytosis in chromaffin cells.

Bovine chromaffin cells in monolayer culture were preloaded with 3H-NA (noradrenaline) and subsequently stimulated with carbachol. Botulinum A neurotoxin partially inhibited the evoked release of 3H-NA and the basal efflux of the hormone. The inhibition of evoked release did not exceed 40%, although the cells were exposed to 10 micrograms/ml of toxin for 6 days. The inhibitory effect of botulinum A neurotoxin was neutralized by its antibodies. In contrast to botulinum A neurotoxin, tetanus toxin at even higher concentrations did not influence evoked release. This difference in sensitivity could be explained by the ganglioside pattern of chromaffin cells. Ganglioside GD1a, a putative receptor for botulinum A neurotoxin, could be identified in lipophilic extracts, whereas the tetanus toxin binding gangliosides GT1b and GD1b could not be detected by means of thin-layer chromatography. Treatment of the cells with neuraminidase abolished both, GD1a and the inhibitory effect of botulinum A neurotoxin. Incubation of chromaffin cells with a mixture of gangliosides (21% GM1, 44% GD1a, 15% GD1b, 20% GT1b) not only increased the efficacy of botulinum A neurotoxin but also made the cells sensitive towards tetanus toxin. The concentration-response curve of botulinum A neurotoxin was shifted to the left about five-fold and the maximum inhibition of evoked release was increased up to 60%, even though the cells were exposed to the toxin for 3 days only. In contrast, the maximum inhibition that could be achieved by tetanus toxin was 40%. The results indicate that polysialogangliosides are important for the intracellular accumulation of these clostridial neurotoxins.

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.

Characterization of the novel progestin gestodene by receptor binding studies and transactivation assays.

Gestodene is a novel progestin used in oral contraceptives with an increased separation of progestogenic versus androgenic activity and a distinct antimineralocorticoid activity. This specific pharmacological profile of gestodene is defined by its pattern of binding affinities to a variety of steroid hormone receptors. In the present study the affinity of gestodene to the progesterone receptor (PR), the androgen receptor (AR), the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR) and the estrogen receptor (ER) was re-evaluated by steroid binding assays and compared to those obtained for 3-keto-desogestrel and progesterone. The two synthetic progestins displayed identical high affinity to rabbit PR and similar marked binding to rat AR and GR, while progesterone showed high affinity to PR but only low binding to AR and GR. Furthermore, 3-keto-desogestrel exhibited almost no binding to MR, whereas gestodene, similar to progesterone, showed marked affinity to this receptor. In addition to receptor binding studies, transactivation assays were carried out to investigate the effects of gestodene on AR-, GR- and MR-mediated induction of transcription. In contrast to progesterone, which showed antiandrogenic activity, gestodene and 3-keto-desogestrel both exhibited androgenic activity. Furthermore, all three progestins exhibited weak GR-mediated antagonistic activity. In contrast to progesterone, which showed almost no glucocorticoid activity, gestodene and 3-keto-desogestrel showed weak glucocorticoid action. In addition, gestodene inhibited the aldosterone-induced reporter gene transcription, similar to progesterone, whereas unlike progesterone, gestodene did not induce reporter gene transcription. 3-Keto-desogestrel showed neither antimineralocorticoid nor mineralocorticoid action.

The novel progestin drospirenone and its natural counterpart progesterone: biochemical profile and antiandrogenic potential.

Drospirenone is a novel progestin under clinical development that is similar to the natural hormone progesterone, combining potent progestogenic with antimineralocorticoid and antiandrogenic activities. This specific pharmacological profile of drospirenone is defined by its pattern of binding affinities to a variety of steroid hormone receptors. In the present study the affinity of drospirenone to the progesterone receptor (PR), the androgen receptor (AR), the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the estrogen receptor (ER) was re-evaluated by steroid binding assays and compared to those obtained for the natural hormone progesterone. Drospirenone displayed high affinity to PR and MR and low binding to AR, similar to progesterone. Unlike progesterone, which showed considerable binding to GR, drospirenone exhibited only low binding to this receptor. Neither drospirenone nor progesterone did bind to the ER. In addition to receptor binding studies, transactivation assays were carried out to investigate the effects of drospirenone and progesterone on AR-, GR-, and MR-mediated induction of transcription. Both progestins showed no androgenic but antiandrogenic activity by inhibiting AR-mediated transcription in a dose-dependent manner. This observation could be confirmed by in vivo experiments carried out with orchiectomized male rats, where the antiandrogenic potency of drospirenone was found to be about five- to ten-fold higher than that of progesterone. In contrast to progesterone, drospirenone was devoid of glucocorticoid activity. Both progestins did not show any antiglucocorticoid action. Furthermore, drospirenone and progesterone both showed considerable antimineralocorticoid activity and weak mineralocorticoid activity.

PIP: In various research laboratories in Germany, researchers conducted receptor binding studies and transactivation assays in vitro and studied antiandrogenic activity in juvenile castrated male rats of the new progestin drospirenone and of the natural hormone progesterone. Drospirenone exhibited high affinity to the progesterone receptor (PR) and the mineralocorticoid receptor (MR), while it exhibited low affinity to the androgen receptor (AR). Progesterone also had low affinity to AR. Neither the new progestin nor progesterone bound to the estrogen receptor (ER). Neither drospirenone nor progesterone displayed androgenic activity. On the other hand, they thwarted AR-mediated transcription in a dose-dependent manner, therefore displaying antiandrogenic activity. The in vivo studies confirmed the antiandrogenic activity of drospirenone and progesterone. In fact, these studies revealed that drospirenone had an antiandrogenic potency 5-10 times greater than progesterone. Unlike progesterone, drospirenone exhibited no glucocorticoid activity, but both drospirenone and progesterone exhibited antiglucocorticoid activity. They also displayed strong antimineralocorticoid activity and weak mineralocorticoid activity.

[Nephroblastoma, partly appearing as a sarcoma botryoides of the renal pelvis (author's transl)]. / Nephroblastom, teils unter dem Bild eines Sarcoma botryoides des Nierenbeckens.

A renal tumour in a 4-year old girl morphologically appeared as both a nephroblastoma and, in parts, as a sarcoma botryoides of the renal pelvis. The histogenesis of this dysontogenetic tumour is most probably due to a disturbance of growth and differentiation both of the metanephrogenic blastema as well as partly of the urethral bud. This type of dysontogenetic tumour is extremely rare. Problems of diagnosis and operative therapy and the possibility of postoperative radiation therapy and cystostatic treatment are discussed.