Biomedical subjects
Publications and source records attributed to M Sillem.
Laparoscopy holds a key role in daignosing and treating endometriosis. The present paper aims at clarifying the correct indication for this procedure. To this end, relevant guidelines as well as considerations regarding incidence, pathogenesis as well as diagnostic and therapeutic alternatives are presented. An algorithm for clinical practice is presented.
The ENZIAN-Score is presented as a new instrument to classify the deep infiltrating endometriosis. Especially the retroperitoneal part of the severe endometriosis is focussed on. In analogy to an oncological staging four different stages are pronounced. The localisation and the expansion of the endometriosis nodule was indicated to different subgroups. The still used rAFS-score is of no clinical evidence, as we pointed out in a retrospective study of our patients with severe intestinal endometriosis.
As well as providing reliable contraception, modern low-dose oral contraceptives may offer some non-contraceptive advantages. Positive effects on problems such as edema with weight increase and breast tenderness, bloating, dysmenorrhea, and an improvement in skin and hair condition have been reported in several studies using an oral contraceptive containing drospirenone. If these disorders are cycle-dependent, use of the contraceptive in an extended regimen may be of additional benefit. The study reported in this paper followed 1433 women, 175 of whom took the drospirenone-containing pill continuously for between 42 and 126 days. Some symptoms of the premenstrual syndrome were influenced very satisfactorily by administration in an extended regimen.
OBJECTIVE: To determine whether alterations in the secretion and regulation of matrix metalloproteinases (MMPs) and their inhibitors are present in uterine endometrial cells from endometriosis patients. STUDY DESIGN: In an in vitro study, uterine endometrial cells from 19 regularly cycling women with and 32 without endometriosis were treated with diethyl stilbestrol, promegestone (R5020), interleukin-1 (IL-1) and tumor necrosis factor a (TNF-alpha). Culture supernatants were assayed for MMPs 1, 2, 3, and 9, and for tissue inhibitors of MMP (TIMP-1 and TIMP-2) by ELISA. RESULTS: MMP-3 was secreted in high concentrations, moderate concentrations were seen for MMP-1 and MMP-2, and very low concentrations for MMP-9. Substantially more TIMP-1 than TIMP-2 was secreted. MMP-1 and MMP-3 were uniformly attenuated by R5020, while MMP-2 was not influenced by hormone treatment. MMP-3 was upregulated by TNF-alpha in all samples while IL-1 only increased secretion in cells from endometriosis patients. CONCLUSION: The upregulation of MMP-3 by IL-1 may contribute to an increased invasiveness of uterine endometrial fragments in endometriosis patients.
OBJECTIVES: (1) to demonstrate specificity of integrin function in endometrial cell adhesion; (2) to investigate their regulation by tumor necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1); and (3) to detect differences between cells from patients with and without endometriosis. STUDY DESIGN: Endometrial cell cultures from ten patients with and 13 without endometriosis were tested for their expression of integrins alpha2beta1, alpha5beta1, alpha(v)beta3, and alpha4beta1 by immunocytochemistry and for their adhesion to collagen type IV, laminin, and fibronectin. RESULTS: Integrin expression was independent of cytokine treatment. Addition of antiintegrin antibodies inhibited adhesion. A significant increase in adhesion to laminin and fibronectin was seen in endometriosis after IL-1 treatment and additionally to collagen after TNF alpha. Cells from women without endometriosis showed a significant increase only to fibronectin. CONCLUSIONS: Human endometrial cells express functional integrins in vitro. TNF alpha and IL-1 had more pronounced effects on adhesion in endometriosis. Inflammatory cytokines in the peritoneal cavity may facilitate adhesion of retrogradely menstruated endometrial fragments in endometriosis.
To investigate the effect of medrogestone on bone mineral density (BMD) and bone turnover under conditions of estrogen withdrawal, premenopausal women with endometriosis were treated with goserelin (Zoladex), combined with either placebo (group A, n = 12) or 10 mg medrogestone (Prothil, group B, n = 11) for six months, and followed for an additional six months. Lumbar spine BMD was measured at 0 and 6 month. Markers of bone turnover were serum bone alkaline phosphatase (sBAP) and osteocalcin (sOC) by ELISA, and urinary total pyridinoline (uPYD) and deoxypyridinoline crosslinks (uDPD) by HPLC. Patients in both groups had a similar and significant decrease in BMD after 6 months (4%, p < 0.01). The time course of changes in bone turnover, in contrast, was different in both groups. In group A, crosslink excretion increased from one month onwards, while no changes were seen in group B. In group A, sBAP levels rose during treatment, while in group B, this rise was delayed until treatment was terminated. Additionally, group B showed an initial suppression of sBAP and sOC. In both groups, sOC increased after treatment was discontinued. Medrogestone at 10 mg/d does not prevent lumbar bone loss in premenopausal women under estrogen deprivation. In the medrogestone add back group, the changes in bone turnover are compatible with low turnover bone loss,as ooposed to a state of high turnover seen in the unopposed goserelin group. This effect may be due to glucocorticoid receptor mediated actions of medrogestone on bone.
Local invasiveness is an important prognostic factor in endometrial carcinoma. To study the role of two groups of secreted proteinases (serine proteinases and matrix metalloproteinases) in this process, we examined three endometrial cancer cell lines (Ishikawa HEC 1A, AN3CA) for their invasiveness in vitro. Additionally, we considered the secretion of urokinase type plasminogen activator (uPA), plasminogen activator inhibitor 1 and 2 (PAI-1 and PAI-2), as well as matrix metalloproteinases (MMP) 1, 2, 3, and 9, and their inhibitors TIMP-1 and TIMP-2. Compared to the highly invasive fibrosarcoma cell line HT 1080, Ishikawa displayed low and AN3CA moderate invasiveness, while HEC 1A cells were almost as invasive as HT 1080 cells. Ishikawa cells secreted the highest amounts of proteinases. Cytokine and steroid treatments upregulated MMP-1 in all cell lines while the effects were heterogeneous regarding other proteinases and inhibitors. No effect of these treatments on invasiveness could be detected. Both basal secretion and regulation of the proteinases tested in this set of experiments seem to be markers of differentiation rather than of invasiveness.
BACKGROUND: Endometriosis is one of the most common benign gynaecological diseases, and attachment of retrogradely shed viable endometrial cells is considered to be important in its development. CD44 is a multifunctional adhesion molecule that undergoes alternative splicing, giving rise to different isoforms. METHODS: The expression of cell surface-associated CD44 std, v4, v5, v6 and v10 variants before and after cytokine treatment was investigated in endometrial cultures derived from 10 endometriosis patients and 22 women without the disease using immunocytochemistry. The immunoreactivity of soluble CD44 std, v5 and v6 variants was measured in culture medium using an enzyme immunoassay kit. RESULTS: We report on the presence of soluble CD44 in endometrial culture supernatants. In particular, circulating CD44 standard form levels were significantly higher than levels of splice variants. We also found that both epithelial and stromal cells express surface-associated CD44 molecules in a distinct pattern and that this expression is not modulated by tumour necrosis factor (TNF)-alpha or/and interleukin 1 (IL-1) alpha/beta. Finally, cell surface-associated as well as soluble CD44 expression was similar in the two groups. CONCLUSION: Our results indicate that endometrial cells can serve as a source of circulating CD44, but a direct role in the pathogenesis of endometriosis is rather improbable.
This study was undertaken to investigate the influence of activated autologous blood therapy on immunological parameters and on the clinical outcome in patients with recurrent spontaneous abortion. In a prospective trial, 36 women with recurrent spontaneous abortion were treated with intramuscular reinjections of extracorporally haemolysed and ultraviolet irradiated autologous blood. A comprehensive immunological investigation revealed significant changes in lymphocyte subpopulations, plasma complement levels, mitogen stimulation and immunoglobulin levels during the treatment period. No side-effects were reported by the patients. From June 1994 to November 1995, 22 intrauterine and one extrauterine pregnancies occurred, resulting in 19 (86%) live births, two (9%) spontaneous abortions and one (4%) artificial abortion compared with a 64% live birth rate in the historical control group. We conclude that activated autologous blood therapy has detectable effects on the immune system, and seems to be promising for further investigation concerning the treatment of idiopathic recurrent spontaneous abortion.
OBJECTIVE: To examine the regulation of endometrial integrin expression by estrogens and progestins in vitro. DESIGN: Immunocytochemical study. SETTING: Academic research unit. PATIENT(S): Twenty-five regularly cycling women without endometrial pathology, of whom seven had endometriosis. INTERVENTION(S): Endometrial cells obtained by aspiration curettage were treated with diethylstilbestrol, promegestone, and antiprogestin. Immunocytochemistry was performed with antibodies directed against integrins alpha 1 beta 1, alpha 2 beta 1, alpha 4 beta 1, alpha 5 beta 1, alpha v beta 3, and beta 3 integrin subunit. MAIN OUTCOME MEASURE(S): Semiquantitative staining score. RESULT(S): Endometrial cells express several integrins in vitro in a consistent and cell specific pattern. Neither differences between treated and untreated cells nor an effect of treatment duration or dosage were observed. Cells from patients with and without endometriosis showed similar patterns. CONCLUSION(S): The cellular distribution of integrin expression was similar to that described in vivo. In contrast, a steroid regulated expression could not be detected in vitro. Rather, a derepression by a factor not included in our model could be responsible for the cyclic appearance of some integrins. In endometriosis, no fundamental difference of integrin expression was detected.
Patients with an elevated level of urokinase plasminogen activator (uPA) in breast cancer tissue have an adverse prognosis. This study evaluated the prognostic relevance of uPA detection in disseminated tumour cells in bone marrow. Bone marrow was sampled intraoperatively from both iliac crests in 280 patients with primary breast cancer. Interphase cells were enhanced and stained immunocytologically with two antibodies: 2E11, which detects TAG 12--a tumour-associated glycoprotein typically expressed by almost all breast cancer cells--and the anti-uPA antibody HD-UK9. Thirty-five of the 2E11-positive women (n = 132, 47%) developed metastatic disease (median follow-up time 44 months). Of these, most were uPA positive (n = 23, 65%) and only 12 were uPA negative. Patients with uPA-positive cells in bone marrow (n = 98, 35%) had a significantly shorter metastasis-free interval (36 months) than women who were uPA negative (44.5 months). The worst prognosis was seen in patients positive for both markers (29.5 months), followed by those who were uPA negative and 2E11 positive (37 months). The detection of uPA on disseminated tumour cells characterizes a subgroup of patients with an even worse prognosis, who should undergo more aggressive adjuvant systemic therapy. For the first time, it was possible to evaluate an important qualitative parameter involved in the process of breast cancer metastases.
Extracellular matrix degradation by secreted proteases, e.g. plasmin, is essential for endometrial functions such as blastocyst implantation and menstruation. We investigated whether the expression of plasmin(ogen) activating or inhibiting factors in endometrial cells from women with endometriosis was different from women without the disease. Endometrial biopsies were obtained from 10 patients with and 16 women without endometriosis. Cells were cultured in Dulbecco's modified Eagle's medium (DMEM)/F12 supplemented with diethylstilboestrol (10(-10) M) alone or combined with promegestone (5 x 10(-8) or 5 x 10(-6) M). Urokinase plasminogen activator (uPA), plasminogen activator inhibitor (PAI)-1 and -2, and soluble uPA receptor (suPA-R) concentrations were assayed by enzyme-linked immunosorbent assay (ELISA) in the conditioned media. uPA and PAI-2 concentrations were not influenced by steroid treatment and did not differ between women with and without endometriosis, whereas PAI-1 was significantly up-regulated by promegestone in both groups. In contrast, suPA-R expression was not influenced by steroid treatment but was significantly higher in cells from endometriosis patients. This is the first report on suPA-R secretion in endometrial cells and the results indicate an altered activation of plasmin(ogen) in endometrium from women with endometriosis that could lead to a higher proteolytic potential of retrogradely menstruated endometrial fragments with consecutive development of endometriotic foci.
Disorders of the female genital tract caused by endocrine disturbances commonly lead to two presenting complaints: dysfunctional uterine bleeding and infertility. In oestrogen deficiency, sequelae of vaginal atrophy may also be present. The common pathogenic "turntable" of these clinical signs is an impaired ovarian function, for which primary (i.e. intraovarian) and secondary (i.e. resulting from dysfunctions of other endocrine systems) causes are known. Primary ovarian failure can be the result of gonadal dysgenesis or premature menopause. Secondary ovarian dysfunction may be caused by hypothalamic-pituitary dysregulation, hyperprolactinaemia, thyroid disorders, and hyperandrogenaemia, which often also has an intraovarian component. For clinical considerations, several severities of ovarian dysfunction can be distinguished, ranging from corpus luteum insufficiency which is only relevant for the selection of infertility treatment to the complete absence of ovarian steroidogenesis leading to severe long term sequelae of the skeletal, cardiovascular and probably central nervous systems. Diagnosis and differential diagnosis are made by clinical examination, vaginal ultrasound, hormone assays, curettage and laparoscopy. Rarely, additional techniques like magnetic resonance imaging of the pituitary or the adrenals, or sequential catheterization of the inferior vena cava are needed.
OBJECTIVE: To identify factors influencing the development of endometrial autografts in a monkey model of endometriosis. DESIGN: Prospective, comparative study. SETTING: Animal research unit. SUBJECTS: Thirty regularly cycling cynomolgus monkeys in three groups of 10 each. INTERVENTIONS: Endometrium was minced and spilled into the cul-de-sac in group 1. In group 2, the tissue additionally was digested enzymatically. In group 3, the tissue was incubated with a protease inhibitor. MAIN OUTCOME MEASURES: Staging laparotomies after 3 weeks and 3 months. RESULTS: In groups 1, 2, and 3, moderate or severe disease was seen in eight, two, and four monkeys, respectively, after 3 weeks and in eight, three, and two monkeys, respectively, at 3 months. CONCLUSIONS: An intact structure leads to ectopic implantation of endometrial fragments in most cases. Conversely, enzymatic digestion of endometrial fragments and treatment with proteinase inhibitor impair ectopic growth. Intrinsic endometrial factors that influence extracellular matrix remodeling may play a role in the pathogenesis of human endometriosis.
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Add-back hormone replacement therapy has been shown to alleviate some of the hypo-oestrogenic side effects associated with gonadotrophin-releasing hormone agonists, including demineralisation of bone. Studies on patients with uterine fibroids have shown that concomitant add-back therapy reduced the efficacy of these agents, but that deferred administration was less detrimental. This trial set out to investigate if deferred add-back therapy could offer any advantages to patients with endometriosis compared with immediate therapy. Zoladex [goserelin acetate (3.6 mg every 4 weeks)] was given for 24 weeks either with placebo, with medrogestone (10 mg/day) for 24 weeks (immediate add-back therapy), or with placebo for 12 weeks followed by medrogestone (10 mg/day) for 12 weeks (deferred add-back therapy) to 123 patients. The number of responders measured using the Revised American Fertility Society score (decrease in this score of > or = 50%) was greatest in the immediate add-back therapy group, although there were no significant differences between groups. All three treatment groups showed significant decreases in bone mineral density compared with baseline but smaller losses were generally observed in the add-back groups. A significantly smaller number of patients in the immediate add-back group reported hot flushes during the first 12 weeks of treatment compared with the deferred add-back group. In conclusion, it appears that there is no extra advantage to patients with endometriosis being treated with goserelin in delaying the start of add-back therapy.
To evaluate the utility of human papillomavirus (HPV) DNA as molecular marker for diagnostic screening of lymph nodes for cancer metastases, we examined 16 involved and 124 histologically cancer-free nodes of 34 patients with cervical, vulval, or vaginal carcinomas associated with HPV 6, 16, 18, 31, 33, 45, or X. All metastases of HPV-positive tumors contained viral DNA of the same type as the primary cancer but in one case the copy number of viral genomes was dramatically reduced. In a varying proportion of histologically normal nodes of 7 of 23 patients with HPV 16-positive cancers HPV 16 DNA was revealed by Southern blot hybridization and/or PCR. Histologic reevaluation showed a metastasis in one case. Three examples of tumor heterogeneity regarding physical state or copy number of viral DNA are presented. Tumor heterogeneity is discussed as possible explanation for apparently inconsistent results such as HPV-negative metastases of HPV-positive tumors.
1. Electromyogram (e.m.g.) responses of the leg musculature and the corresponding joint movements were studied following a perturbation of the limb during walking on a treadmill, produced by a randomly timed treadmill acceleration impulse, either predictable, or unpredictable in its amplitude and rate of acceleration. 2. The rate of rise of ipsilateral gastrocnemius e.m.g. response following a perturbation was dependent on the rate of treadmill acceleration. For a given acceleration rate the amplitude of the e.m.g. response and the timing of its peak was dependent on the amplitude of the impulse and the rate of rise of the gastrocnemius response was the same for impulses of both small and large amplitude. The onset latency was shorter (65 ms) for high accelerations and longer (85 ms) for lower ones. 3. The amplitude of the ipsilateral biceps femoris response was much smaller than the gastrocnemius response but was larger following unpredictable than predictable impulses. 4. The initial gastrocnemius response was followed by a tibialis anterior activation associated with a gastrocnemius depression and sometimes with a second, weak gastrocnemius activation. The gastrocnemius depression ended within a fixed time range relative to the onset of the response. The tibialis anterior activation was most pronounced when unpredictable impulses with high acceleration but a small amplitude were induced. 5. It is concluded that generation of the first gastrocnemius response is obviously under continuous control by muscle proprioceptive information and can be best described in terms of a stretch reflex response. It is suggested that, on the evidence of the diphasic or triphasic e.m.g. pattern, a close interaction occurs between a central programme and muscle proprioceptive input in order to generate the appropriate e.m.g. pattern. 6. On the basis of earlier work (Berger, Dietz & Quintern, 1984a) and on the present results it is suggested that the e.m.g. responses may be mediated mainly by muscle proprioceptive input from group II afferents. This input is modulated and processed by spinal interneuronal circuits, closely connected with spinal locomotor centres. The mode of processing depends on various factors, such as the predictability of the nature of the impulse.