H U Schweikert

University of Tuebingen, Tübingen, Baden-Württemberg, Germany

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Publications (65)157.84 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: We investigated the effects of androgens, estradiol (E2) and insulin-like growth factor (IGF)-I on IGF-II, insulin-like growth factor binding protein (IGFBP)-2, -3 and -5 and mRNA in genital fibroblasts (GF) from patients with complete androgen insensitivity (CAIS) and normally virilized males (C). Proteins were measured by specific RIA and Western ligand blot, and specific mRNA levels by RT-PCR normalized by GAPDH levels. Secretion of IGF-II was lowered in CAIS (p<0.001) GF and by testosterone + IGF-I in C GF. Secretion of IGFBP-2 was higher (p<0.001) in CAIS GF and IGFBP-2 mRNA levels were increased by E2 in C GF (p<0.05). E2 stimulated IGFBP-2, -3 and -5 expression in CAIS GF. CAIS GF also secreted more IGFBP-3 (p<0.001) and accumulated 3-5 times more IGFBP-5 mRNA than C GF (p<0.001). In contrast to C GF, the availability of IGF-II in CAIS GF is apparently decreased by two facts: by the decreased expression and by increased expression of IGFBP-2, -3 and -5. Furthermore, E2 and IGF-I modulate the expression of IGF-II and IGFBP in GF. This may play a role in the failure to develop male external genitals in CAIS patients.
    Hormone Research 01/2003; 60(2):73-8. · 2.48 Impact Factor
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    ABSTRACT: The action of androgen by way of the AR is required for the development of male gonads and external genitalia. The interplay between androgens and the somatotropic axis, in particular the IGFs in sexual development, is currently under thorough investigation. The IGF system is thought to mediate the androgen action in androgen-responsive cells. To investigate the interaction of androgens with the IGF system, we compared the expression of IGFs and IGF-binding proteins in cultured genital skin fibroblasts from nine patients with the syndrome of complete androgen insensitivity with that in genital skin fibroblasts from 10 normally virilized males. Mutations in the AR gene and/or abnormalities of the AR protein in the immunoblot were detected in all complete androgen insensitivity genital skin fibroblast strains. They caused a complete failure of DHT binding. RIA and RT-PCR demonstrated that the genital skin fibroblast strains expressed IGF-II, IGF-binding protein-2, and IGF-binding protein-3, but no IGF-I. Most strikingly, complete androgen insensitivity genital skin fibroblast strains produced significantly lower IGF-II (P < 0.001; 42.2 +/- 9.7 vs. 106.9 +/- 11.8 ng/mg protein) and IGF-II mRNA (P < 0.01, by RT-PCR) than control genital skin fibroblast strains. The production of IGF-binding protein-2 was also decreased (P < 0.03) in complete androgen insensitivity genital skin fibroblasts, whereas that of IGF-binding protein-3 did not differ. Furthermore, high levels of IGF-binding protein-5 mRNA were detected in all genital skin fibroblast strains, whereby the 28-kDa band in the ligand blot, probably representing IGF-binding protein-5, was more abundant in complete androgen insensitivity genital skin fibroblasts. Exposure of the genital skin fibroblasts to T (5 x 10(-8) M) had only weak effects on the expression of IGFs and IGF-binding proteins. In conclusion, although the mechanism underlying these differences requires further study, it is conceivable that in addition to the endocrine actions of IGF-I, IGF-II and IGF-binding protein-2, as local growth factors, are involved in the mediation of androgen action and growth of genital tissues.
    Journal of Clinical Endocrinology &amp Metabolism 10/2001; 86(10):4741-6. · 6.43 Impact Factor
  • K. D. Spindler, W. Weidemann, G. Romalo, H. U. Schweikert
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    ABSTRACT: Obwohl die Hypospadie zu den häufigsten männlichen kongenitalen Störungen zählt, sind die kausalen Ursachen dieser Fehlbildungen häufig unbekannt. Dies liegt vermutlich daran, dass für die Differenzierung des Penis eine Vielzahl von Faktoren in Frage kommen können. Differenzierungsstörungen können u. a. die Folge einer verringerten Testosteronsynthese, seltener auch einer reduzierten Umwandlung von Testosteron zu Dihydrotestosteron, bedingt durch Mutationen des 5α-Reduktase-Gen, sein. Ebenso können auch Mutationen im Androgenrezeptor-Gen, allerdings nur in seltenen Fällen, mit Hypospadie verknüpft sein. Darüberhinaus werden auch chromosomale Aberrationen sowie exogene Faktoren wie z. B. „endocrine disruptors“ mit Hypospadie in Verbindung gebracht. Hypospadias is one of the most common male congenital disorders. Nonetheless, the underlying molecular mechanisms are often unknown, presumably because many factors might be responsible for male sexual differentiation. Among these are reduced testosterone synthesis, mutations in the androgen receptor gene, and in rare cases also mutations in the 5α-reductase gene leading to reduced production of dihydrotestosterone. In addition, there is increasing evidence for a relationship between hypospadias and chromosomal aberrations as well as exogenous factors such as endocrine disrupters.
    Reproduktionsmedizin 05/2001; 17(3):170-176.
  • M Feix, L Wolf, H U Schweikert
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    ABSTRACT: In bone androgens and estrogens exert profound osteoprotective effects. Cultured human osteoblast (hOB)-like cells are able to metabolize circulating androgens or androgen precursors, such as testosterone and androstenedione, respectively, by aromatization (aromatase), 5alpha-reduction (5alpha-reductase) and reduction/oxidation at the 17beta-position (17-beta-hydroxysteroid dehydrogenases, 17beta-HSDs). In this study it was demonstrated that cultured normal human osteoblast-like cells as well as the osteosarcoma cell lines HOS and MG 63 express 17beta-HSDs types 1, 2, 3 and 4.
    Molecular and Cellular Endocrinology 02/2001; 171(1-2):163-4. · 4.04 Impact Factor
  • K.-D. Spindler, W. Weidemann, H. U. Schweikert
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    ABSTRACT: Zum Thema Androgenresistenz (Androgeninsensivittssyndrom, AIS) ist charakterisiert durch ein vollstndiges oder partielles Ausbleiben der Androgenwirkung trotz eines normalen oder erhhten Serumtestosteronspiegels. Das klinische Erscheinungsbild der Betroffenen kann dabei das ganze Spektrum von einem typischen weiblichen Phnotyp (komplette Androgenresistenz, CAIS) ber unterschiedlich ausgeprgte intersexuelle Formen bis zu einem mehr oder minder normalen mnnlichen Phnotyp umfassen (partielle Androgenresistenz, PAIS). Hauptschlich werden Defekte im Androgenrezeptor (AR) als Ursache fr AIS verantwortlich gemacht. Mit Ausnahme von seltener auftretenden schwerwiegenden Gendefekten (u. a. grere Deletionen, Nonsense-Mutationen) besteht keine eindeutige Korrelation zwischen AR-Genmutation und klinischem Erscheinungsbild. Da darber hinaus selbst identische Mutationen zu unterschiedlich starken Virilisierungsstrungen fhren knnen, und auch AIS-Flle ohne AR-Genmutation bekannt sind, reichen die Bestimmung des Rezeptorstatus und eine Sequenzanalyse nicht in allen Fllen aus, das jeweilige Krankheitsbild kausal zu erklren.
    Der Urologe B 09/1999; 39(5):402-406.
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    ABSTRACT: We describe a novel mutation in exon 1 of the androgen receptor gene in a patient with complete androgen insensitivity (CAIS). Endocrine findings were typical for androgen insensitivity (testosterone serum levels in the upper limit of normal males and increased LH serum concentrations). Biochemical investigations in cultured genital skin fibroblasts of the patient showed a normal 5alpha-reductase activity but a complete absence of androgen binding. Western blot analysis revealed no detectable protein product. Sequence analysis of the entire coding region of the androgen receptor gene resulted in the identification of a 2-bp deletion in codon 472, causing frameshift and introduction of a premature stop codon 27 codons downstream of the mutation.
    Journal of Clinical Endocrinology &amp Metabolism 06/1999; 84(5):1751-3. · 6.43 Impact Factor
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    ABSTRACT: Subjects with androgen insensitivity syndromes (AIS) are characterized by a 46, XY karyotype, presence of testes, normal or elevated androgen levels in blood, and impairment of the usual response to androgens associated with various aberrations of male differentiation and virilization ranging from slightly undervirilized men to phenotypic females. Here we describe a novel proline to serine mutation in codon 892 (exon 8) of the androgen receptor in a patient with complete androgen insensitivity. The mutation is located in the direct vicinity of the proposed C-terminal alpha-helix of the ligand binding domain containing the AF-2 transcriptional activating function core. Investigation of androgen binding in cultured testicular fibroblasts of the patient revealed a reduced AR binding capacity (11 fmol/mg protein) and a highly elevated Kd value (3.1 nM) in comparison to control genital skin fibroblasts. Cotransfection studies with an androgen-responsive reporter gene revealed a diminished transactivation property of the mutant androgen receptor.
    Molecular and Cellular Endocrinology 03/1999; 148(1-2):47-53. · 4.04 Impact Factor
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    ABSTRACT: Androgens exert important biological effects on the brain, and 5alpha-reductase plays a crucial role in androgen metabolism. Therefore, we investigated the expression of the two isozymes of 5alpha-reductase in the human temporal lobe to determine the predominant isoform and to elucidate the existence of possible sex differences and differences between children and adults. We studied biopsy materials from the temporal lobe of 34 women, 32 men, and 12 children. Quantification of 5alpha-reductase 1 and 2 messenger ribonucleic acid (mRNA) was achieved by competitive RT-PCR. 5Alpha-reductase activity was determined in tissue homogenates using [1,2-3H]androstenedione as the substrate. Only 5alpha-reductase 1 mRNA was expressed in human temporal lobe tissue; 5alpha-reductase 2 mRNA was not expressed. 5Alpha-reductase 1 mRNA concentrations did not differ significantly in the cerebral cortex of women [25.9+/-7.9 arbitrary units (aU); mean +/-SEM] and men (20.4+/-2.8 aU) or in the cerebral cortex (23.3+/-4.4 aU) and the subcortical white matter of adults (32.6+/-5.6 aU), but they were significantly higher in the cerebral cortex of adults than in that of children (6.4+/-2.3 aU; P < 0.005). The apparent Km of 5alpha-reduction did not show significant differences between the two sexes. In conclusion, 5alpha-reductase 1 mRNA is expressed in the temporal lobe of children and adults, but 5alpha-reductase 2 mRNA is not. 5Alpha-reductase 1 mRNA concentrations did not differ significantly in the sexes, but they were significantly higher in specimens of adults than in those of children.
    Journal of Clinical Endocrinology &amp Metabolism 10/1998; 83(10):3636-42. · 6.43 Impact Factor
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    ABSTRACT: Supplemental androgen therapy has enhanced virilization in only a few patients with partial androgen insensitivity (PAIS). We herein report on virilization in a patient with PAIS and a point mutation in the DNA-binding domain of the androgen receptor. At the age of 19 yr, the patient sought medical attention because of undervirilization. Endocrine findings were typical for androgen insensitivity, but 5alpha-reductase activity and androgen binding characteristics in fibroblasts cultured from genital skin were normal. In an attempt to improve virilization, high dose testosterone enanthate treatment (250 mg by i.m. injection once a week) was begun. After 3.5 yr of this treatment, marked promotion of virilization was achieved, i.e. lowering of voice, male pattern secondary hair distribution, marked growth of beard and coarse body hair, increase in phallic size, increase in bone mineral density, and decrease in mammary gland size. In addition, serum lipid levels were not affected. To our knowledge this is the first documentation of successful treatment in a patient with PAIS and a point mutation in the DNA-binding domain of the androgen receptor.
    Journal of Clinical Endocrinology &amp Metabolism 04/1998; 83(4):1173-6. · 6.43 Impact Factor
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    M J McPhaul, H U Schweikert, D R Allman
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    ABSTRACT: Mutations of the androgen receptor (AR) cause defects in virilization and can result in a spectrum of phenotypic abnormalities of male sexual development that includes patients with a completely female phenotype (complete testicular feminization) and individuals with less severe defects of virilization, such as Reifenstein syndrome. These phenotypes are not specific for mutations of the AR gene, however, and defects in other genes can also result in similar abnormalities of male development. For this reason, the diagnosis of an AR defect is laborious and requires data from endocrine studies, the family history, and in vitro binding experiments. To assist in the evaluation of patients with possible AR defects, we previously employed the use of a recombinant adenovirus to deliver an androgen-responsive gene into fibroblast cultures to assay AR function in normal subjects and patients with complete forms of androgen resistance. Although these studies demonstrated measurable differences between these two groups of subjects, we did not assay samples from patients with partial defects of androgen action. In the current study, we have modified this method to examine AR function in three groups of patients with known or suspected defects of AR function: patients with Reifenstein syndrome, patients with spinobulbar muscular atrophy, and patients with severe forms of isolated hypospadias. When assayed using this method, the AR function of patients with Reifenstein syndrome was intermediate between that of normal control subjects and that of patients with complete testicular feminization. Using the parameters established by the aforementioned experiments, we found that defective AR function can be detected in fibroblasts established from patients with spinobulbar muscular atrophy and in some patients with severe forms of isolated hypospadias, including two with a normal AR gene sequence. These results suggest that this method may have some utility in screening samples to detect defects of AR function, particularly when viewed in the context of other AR assays results.
    Journal of Clinical Endocrinology &amp Metabolism 07/1997; 82(6):1944-8. · 6.43 Impact Factor
  • H. U. Schweikert, W. Weidemann, Gabriele Romalo
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    ABSTRACT: Zusammenfassung Fehlentwicklungen der embryonalen Sexualdifferenzierung lassen sich in solche des chromosomalen, gonadalen und phnotypischen Geschlechts unterteilen. Bei der Gonadendysgenesie und der Gemischten Gonadendysgenesie handelt es sich um Fehlentwicklungen des chromosomalen Geschlechts. Whrend die Reine Gonadendysgenesie sich infolge von Aberrationen des gonadalen Geschlechts entwickelt, stellt die testikulre Feminisierung eine Fehlentwicklung des phnotypischen Geschlechts dar. Strungen der phnotypischen Identitt liegen dann vor, wenn das chromosomale und gonadale Geschlecht zwar bereinstimmen, die phnotypische Entwicklung jedoch davon abweicht. Man unterscheidet daher den mnnlichen vom weiblichen Pseudohermaphroditismus. Als Ursachen kommen die inadquate Hormonsynthese in der Nebennierenrinde oder den Gonaden sowie eine Unempfindlichkeit der Zielorgane gegenber Sexualhormonen (Hormonresistenz) in Frage.
    Der Urologe B 01/1997; 37(1):14-23.
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    ABSTRACT: Androgen insensitivity syndromes (AIS) in subjects with 46, XY karyotype and normal or even elevated androgen blood levels are characterized by various aberrations in male differentiation and virilization. AIS is often accompanied by a broad spectrum of abnormal binding characteristics of the androgen receptor (AR). In order to investigate the correlation between the degree of virilization defect and the type of androgen binding abnormalities and/or the nature of the mutation in the AR gene, we determined androgen binding characteristics of the AR protein and the sequence of the AR gene in clinically and biochemically well characterized patients with various degrees of androgen resistance. The activity of 5 alpha-reductase and the binding of androgen to its receptor (KD-values, Bmax, thermolability) were determined in genital skin fibroblasts from 20 patients with various degrees of defects in virilization (2 CAIS, complete AIS; 18 PAIS, partial AIS patients). The AR gene of these 20 subjects was characterized by PCR-SSCP analysis. In case of aberrant electrophoretic mobility the corresponding exon was sequenced. The 2 patients with CAIS and 7 with PAIS showed a mutation in the AR gene. In two, the mutation was in the DNA binding domain, and in all others in the ligand binding domain. In 11 patients with severe virilization defects no abnormal behaviour was detected in the PCR-SSCP. Transcriptional activation studies of two mutant ARs revealed that an approximately tenfold higher androgen concentration (methyltrienolone) is necessary to achieve maximal response as compared to the wild type AR. There is no obvious relation between the degree of androgen resistance and the binding parameters of the AR and/or the nature of mutation in the AR gene. Androgen insensitivity syndrome can occur despite normal androgen binding and presumably non-mutated AR genes. Even if there is abnormal binding of androgen and/or a mutation in the AR gene there is no clear-cut relationship between these parameters and the degree of virilization defects. Thus, in a proportion of patients, neither the determination of binding parameters of the AR nor the detection of mutations in the AR gene are sufficient to understand the mechanisms underlying the androgen insensitivity syndrome.
    Clinical Endocrinology 01/1997; 45(6):733-9. · 3.40 Impact Factor
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    ABSTRACT: Androgen receptor defects can cause severe hypospadias. To examine the possibility that androgen receptor defects are a common cause of such deficiencies, we have determined the coding sequence of the androgen receptor gene in nine patients with severe hypospadias. The analysis of the androgen receptor coding sequence predicts a normal amino acid sequence for the androgen receptor of eight of the nine patients, indicating that the observed defects in virilization are infrequently caused by mutations of the open-reading frame of the androgen receptor. These findings demonstrate the importance of family history and endocrine studies in identifying patients likely to harbor coding sequence mutations in the androgen receptor gene, and they serve to focus attention on other genes that may influence androgen action in this group of patients.
    Journal of Clinical Endocrinology &amp Metabolism 10/1995; 80(9):2697-9. · 6.43 Impact Factor
  • Annals of the New York Academy of Sciences 10/1995; 768:227-30. · 4.38 Impact Factor
  • H U Schweikert, L Wolf, G Romalo
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    ABSTRACT: Peripheral aromatization of testosterone and androstenedione is the principal source for circulating oestrogens in men and in castrated and post-menopausal women. Since human bone is a target organ for androgens and oestrogens, aromatase activity was assessed in human spongiosa obtained from patients who were undergoing orthopaedic surgery. In initial experiments for assessing aromatization, oestrogen formation from 1,2,6,7-3H-androstenedione was compared with the release of tritiated water from 1 beta-3H-androstenedione. Since the rates of enzyme activity were similar with the two methods, rates of oestrogen formation were determined under standardized conditions with the tritiated water generation technique in bone specimens obtained from 4 men and 11 post-menopausal women. The apparent Km of the aromatase ranged between 6 and 50 nM (20.4 +/- 3.9; mean +/- SEM), values in the range of those reported for human placental microsomes. The maximum velocity (Vmax) of the aromatase activity ranged between 0.14 and 1.23 nmol/g DNA/h. Oestrogens formed in human bone may play a physiological role in steroid hormone action in this tissue.
    Clinical Endocrinology 08/1995; 43(1):37-42. · 3.40 Impact Factor
  • Annals of the New York Academy of Sciences 01/1995; 768(1):227-230. · 4.38 Impact Factor
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    ABSTRACT: X-linked recessive bulbospinal neuronopathy is a motoneuron disorder to be distinguished from amyotrophic lateral sclerosis, Effective treatment is not known. Patients with X-linked recessive bulbospinal neuronopathy may show gynecomastia and testicular atrophy, and a mutation in the androgen receptor gene has been found associated with the disease. Intermediate steps leading from the androgen receptor abnormality to the clinical syndrome have not yet been elucidated. Therefore, binding of androgen ([3H]dihydrotestosterone) to its specific receptor by genital skin fibroblasts cultured from a patient with X-linked recessive bulbospinal neuronopathy and confirmed androgen receptor mutation was studied. Markedly decreased binding capacity was found. We treated the patient for 6 months with nandrolone-decanoate. No effect on his neuromuscular status was observed during 2 years of follow-up.
    The Clinical Investigator 12/1994; 72(11):892-7.
  • R Hagen, G Romalo, B Schwab, F Hoppe, H U Schweikert
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    ABSTRACT: Since the publications of Martin, et al. (1948) and Schiff (1959), who were the first to report on the administration of sex hormones to juvenile nasopharyngeal fibroma (JNF) patients, several authors have described the different clinical effects and histologic changes after androgen and estrogen application. Since the mechanism of action of sex steroids in juvenile nasopharyngeal fibroma is almost unknown, the authors have studied androgen receptor binding in cultured tumor fibroblasts from three patients with JNF. Maximum androgen binding (Bmax) of the tumor fibroblasts approximated to that of genital skin fibroblasts, which served as a control androgen target tissue with high receptor density. Furthermore, in vitro experiments showed that the growth rate of tumor fibroblasts increased when testosterone was added to the culture medium, while the addition of two antiandrogens, cyproterone and flutamide, caused a reduction in growth rate. It is concluded from these results that JNF is a hormone-dependent tumor stimulated by testosterone whose growth rate may, at least in vitro, be reduced by antiandrogens such as cyproterone and flutamide.
    The Laryngoscope 10/1994; 104(9):1125-9. · 1.98 Impact Factor
  • H J Niederprüm, H U Schweikert, K S Zänker
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    ABSTRACT: The inhibition of testosterone 5oc-reductase (EC 1.3.99.5) (5αR) in vitro by lipophilic extracts from Sabal serrulata fruits effective on Benign Prostatic hyperplasia (BPH) treatment is due entirely to free fatty acid content. In order to find out structure-inhibition activity relationships of the action of free fatty acids on the enzyme, we investigated the influences of chain-length, esterification, saturation degree, and oxidation on fatty acid 5aR inhibition activity. For fatty acid-like 5αR inhibition a strongly polar end-group and a molecular skeleton allowing nonpolar interactions with the enzyme are required. 5αR activity in prostate tissue may be influenced by lipid environment.
    Phytomedicine 09/1994; 1(2):127-33. · 2.97 Impact Factor
  • P Staib, N Kau, G Romalo, H U Schweikert
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    ABSTRACT: Hypospadias is the most common birth defect in males. In most cases the aetiology is unknown. Since penile development is androgen dependent and oestrogen can modify androgen action, we compared the formation of oestrogen in penile tissue from patients with hypospadias to those with normal penile development. Oestrogen formation was assessed in fibroblast monolayers grown from biopsies of genital and non-genital skin from 11 males with normal genital development (controls) and 18 males with severe hypospadias utilizing the incorporation of tritium into H2O resulting from the aromatization of 1 beta-3H-androstenedione. In paired fibroblast strains from genital and non-genital skin of nine males with hypospadias, oestrogen formation was significantly (P < 0.025) lower in non-genital skin. Rates of oestrogen formation were also higher in a subset of foreskins from subjects with hypospadias than in normal controls and the remaining hypospadias subjects. In addition, oestrogen formation in this subset of fibroblast strains from patients with hypospadias was markedly enhanced by incubation of intact monolayers with either cholera toxin or forskolin, agents known to stimulate cAMP formation. Oestrogen formation in the remaining cell strains (controls and hypospadias) was also enhanced in most instances by cholera toxin and forskolin, although to a much lower degree. Thus, we identified in the hypospadias group a subgroup of fibroblast strains in which unstimulated and stimulated oestrogen formation was markedly higher than in other strains examined. Since oestrogen can modify certain androgen effects within cells and since formation of the male genitalia during embryogenesis is mediated by androgens, elevated oestrogen formation in male genital tissue might be a causative factor of hypospadias in some instances.
    Clinical Endocrinology 09/1994; 41(2):237-43. · 3.40 Impact Factor

Publication Stats

687 Citations
3 Downloads
2k Views
157.84 Total Impact Points

Institutions

  • 2001
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
  • 1987–2001
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 1997–1999
    • Heinrich-Heine-Universität Düsseldorf
      • Institute of Physical Biology
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1994–1995
    • Universität Witten/Herdecke
      • Institute of Imunology
      Witten, North Rhine-Westphalia, Germany
    • University of Wuerzburg
      Würzburg, Bavaria, Germany
  • 1993
    • University of Innsbruck
      Innsbruck, Tyrol, Austria
  • 1990
    • University of Bonn - Medical Center
      Bonn, North Rhine-Westphalia, Germany