[Molecular and clinical endocrinology of the endometrium]. / Molekulare und klinische Endokrinologie des Endometriums.

The ovarian steroid hormones estradiol and progesterone exert their effect by interacting with their intracellular receptors, which, after ligand binding translocate to the nucleus and bind to the promoter regions of target genes. The consequence is a change in the transcription rate of the target genes, followed by a change in production of the corresponding proteins. Target genes of the sexual steroid hormones include cytokines and growth factors, among them CSF-1, TGF-beta and LIF. The rhythm and activity of steroidogenesis, receptor modulation and transcription are reflected by cycle-specific proliferation and differentiation processes in the endometrium. Quantitative and/or qualitative molecular endocrinology is of increasing interest for better definition of morphological changes, although, as yet, the pathological laboratory test is of much less practical consequence than a suspicious vaginal sonography. In spite of the high standard of ultrasound techniques, however, most cases with slightly increased endometrial thickness show histologically benign changes of the endometrium rather than endometrial precancer or cancer. This is especially true for perimenopausal women with no other clinical findings. Yet, the cancer risk is increased in women under tamoxifen therapy. Hence, as a rule, these cases, when endometrial thickness exceeds 5 mm, need a diagnostic biopsy or abrasio.

Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome.

Premature stop codons of the human androgen receptor (AR) gene are usually associated with a complete androgen insensitivity syndrome. We, however, identified an adult patient with a 46,XY karyotype carrying a premature stop codon in exon 1 of the AR gene presenting with signs of partial virilization: pubic hair Tanner stage 4 and clitoral enlargement. No other family members were affected. A point mutation at codon position 172 of the AR gene was detected that replaced the original TTA (Leu) with a premature stop codon TGA (opal). Careful examination of the sequencing gel, however, also identified a wild-type allele, indicating a mosaicism. In addition, elimination of the unique AflII recognition site induced by the mutation was incomplete, thus confirming the coexistence of mutant and wild-type AR alleles in the patient. Normal R1881 binding and a normal 110/112-kDa AR doublet in Western immunoblots consolidated the molecular genetic data by demonstrating the expression of the wild-type AR in the patient's genital skin fibroblasts. Transfection analysis revealed that only relatively high plasmid concentrations carrying the mutated AR complementary DNA lead to expression of a shortened AR due to downstream reinitiation at methionine 189. Thus, reinitiation does not play a role in the presentation of the phenotype; rather, the partial virilization is caused by the expression of the wild-type AR due to a somatic mosaic. We conclude that somatic mosaicism of the AR gene can represent a substantial factor for the individual phenotype by shifting it to a higher degree of virilization than expected from the genotype of the mutant allele alone.

Combining B-mode ultrasound with pulsed wave Doppler for the assessment of tubal patency.

This study was conducted to determine whether the additional use of pulsed wave Doppler improves the diagnostic capacity in assessing tubal patency by hysterosalpingo contrast sonography (HyCoSy). A total of 210 women with a history of infertility were included in this study. HyCoSy was performed after intrauterine injection of Echovist 200. For the assessment of tubal patency B-mode scanning and pulsed wave Doppler ultrasound were performed in the proximal and distal tubal segments. With the combined sonographic procedure 297 tubes (74%) were rated patent, 35 (8%) incompletely obstructed and 70 (18%) completely obstructed. A total of 252 tubes were additionally examined by laparoscopy for reference purposes. Concordant results for both methods were found in 92% of tubes, nine had been rated false negative and 10 tubes appeared to have been rated false positive. The combined sonographic specificity was found to be 85% with a sensitivity of 95%. Peritubal adhesions detected by laparoscopy were found to be the reason for false positive sonographic results in 60% of cases. In conclusion, the combined B-mode and pulsed wave Doppler examination appears to be a non-invasive and low-cost test for the assessment of tubal patency, which should be performed during diagnostic work-up for infertility.

[Special clinical and follow-up aspects of invasive lobular breast cancer]. / Besonderheiten in Klinik und Verlauf beim invasiven lobulären Mammakarzinom.

We examined 121 invasive lobular breast carcinomas (ILCs) with regard to certain standardised prognosis parameters, such as tumour size, receptor status, histological grading, the presence of lymphangiosis carcinomatosa, and the histological nodal status of the axillae and correlated these findings with follow-up data obtained over a mean period of 65 months. The parameters, tumour size, presence of lymphangiosis carcinomatosa, and nodal status, were found to be correlated and to have a significant influence on the patients' overall survival time, but not on relapse-free survival. Receptor status appeared to have no significant influence on patient survival. However, the incidence of death, owing to tumour-related causes, was higher among patients with receptor-negative tumours than amongst those with receptor-positive carcinomas. In contrast, the histological grading of a tumour appeared to exercise no effect on tumour prognosis. At 30%, the rate of local tumour recurrence at the primary site was markedly higher than for other histological types of breast carcinoma. In nearly one-half (45%) of such relapses, however, further tumour progression did not occur. Most tumours, exhibiting only local recurrence were initially node-negative, whilst those that produced distant metastases later had usually exhibited axillary lymph node metastases at primary therapy. Bilateral carcinomas occurred more frequently (15.6%) than is the case amongst ductal carcinoma. The observed tendency amongst ILCs toward local recurrence and bilateral growth might be accounted for in terms of their high incidence of multicentral tumour growth and associated pre-invasive neoplastic alterations.(ABSTRACT TRUNCATED AT 250 WORDS)

[Locoregional breast cancer recurrence. Treatment following exclusively local therapy]. / Lokoregionäres Mammakarzinomrezidiv. Behandlung nach ausschliesslicher lokaler Therapie.

In 58 out of 515 patients with a primary carcinoma of the breast there was local-regional recurrence. Treatment consisted in generous excision and local radiation (50-60 Gy). After a mean observation period of 65.4 +/- 22.2 months, distant metastasization was found to have occurred in 22 patients (37.9%). Of the other 36 patients 23 (39.7%) had suffered no further recurrence at the end of this time, while 13 patients (22.4%) had a new local-regional recurrence. In a retrospective study a variety of parameters of prognosis were investigated in order to determine to their predictive value. It was found that there were significant differences in overall survival rates with tumors of histological differentiation stage I as compared to tumors of differentiation stages II and III (p = 0.003). There were no differences in the recurrence-free interval (p = 0.34). The presence or respectively lack of steroid receptors in the primary tumor made no significant differences to the recurrence-free interval and the survival rates. Those of the patients on whom this study was based whose axillary nodal status was N+ had received (adjuvant) treatment with cytostatics. This resulted in no differences in the recurrence-free interval (p = 0.28) or the overall survival rates (p = 0.3) when the N+ and N- patients were compared. The therapeutic conclusion drawn from these results is that breast carcinoma patients with an exclusively local-regional recurrence should initially receive local treatment only; systemic therapy should be reserved for the generalization stage.