[COX-2-expression in extragenital endometriosis lesions as a novel therapeutical approach?]. / COX-2-Expression in extragenitalen Endometrioseläsionen als neuer Therapieansatz?

OBJECTIVE: Extragenital endometriosis is a rare form of endometriosis. Due to its invasive and metastatic properties it resembles some features of malignant tumours. Cyclooxygenase (COX)-2 is a rate-limiting enzyme in the biosynthesis of prostaglandins and is mainly expressed in inflammatory and malignant processes. In this study we investigated the COX-2 expression in extragenital endometriosis. MATERIAL AND METHODS: Tissue was obtained of 13 women with rectal and vaginal endometriosis, scar endometriosis and endometriosis of the omentum majus. The COX-2 expression was investigated by immunohistochemistry. RESULTS: In the glandular epithelium a COX-2 overexpression was found in all cases and in the stroma a weak to moderate COX-2 expression was found in half of the cases. A hormonal therapy at the time of surgery had no influence on the COX-2 expression in extragenital endometriosis. CONCLUSION: The high COX-2 expression in extragenital endometriosis is believed to be strongly correlated with the pathological abnormalities this of disease.

[Endometrial carcinoma using GnRH analogues therapy in endometriosis]. / Endometriumkarzinom unter GnRH-Analoga-Therapie bei Endometriose.

Endometriosis affects a 10 % of women during their reproductive years. Unequoral statistics concerning the incidence of adenomyosis are not available although a combined occurrence of both diseases is found in a 20 % of cases. The risk that malignancy arises from endometrioid tissue typical for endometriosis is between a 0.3-1 %. 75 % of these malignancies are ovarian cancer in conjunction with pre-existing ovarian endometriosis; less frequently extraovarian malignancies are found. The development of malignancy of adenomyosis is very rarely reported. In this report we present the case of a 35 year old patient who suffered from both, endometriosis and adenomyosis and who underwent a therapy using GnRH analogues. After five months and before the completion of the therapy a hysterectomy with conservation of the ovaries was performed at the request of the patient (carcinophobia). The histology confirmed the diagnosis of adenomyosis and demonstrated the unexpected finding of an endometrium carcinoma. This latter arose from a complex atypical hyperplasia surrounded by hypoplastic endometrium. There is some evidence that suggests a slightly elevated risk of breast and ovarian cancer as well as haematological malignancies amongst patients with endometriosis. However, there does not appear to be an increased risk of endometrial carcinoma. Adipositas leads to an increased risk for the development of endometrial carcinoma due to the increased conversion of testosterone to estrone in fat. The peripheral synthesis of estrone is unaffected by GnRHa-therapy. A progesterone containing HRT should be added to a GnRHa-therapy in overweight patients to prevent the development of endometrial hyperplasia and/or carcinoma. In conclusion a careful indication has to be made for GnRHa-therapy in overweight patients and before and during the therapy high resolution ultrasound scan should be performed to evaluate the endometrium in those patients.

Could a combined administration of dexamethasone and 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) be a more effective alternative to dexamethasone alone in the prevention of RDS?

OBJECTIVE: To test whether the combined application of dexamethasone (DEXA) and 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT) induces the synthesis of surfactant protein A (SP-A) mRNA at a higher rate than both substances given alone? STUDY DESIGN: Organoid culture of fetal rat lungs (Wistar rats; day 19 of gestation) was prepared. After 48h of incubation we added DEXA (10(-5), 10(-7), 10(-8) and 10(-9)mol/l), DIMIT (10(-5), 10(-7) and 10(-9)mol/l) and the combination of DEXA in 10(-8)mol/l with various concentrations of DIMIT. After another 48h of incubation, northern blot and hybridization with a 32P-labeled SP-A cDNA probe was performed. One-way-variance-analysis with a Scheffé-test, Levene-test and one-sample-t-test were used for statistical analysis. RESULTS: DEXA alone above 10(-8)mol/l resulted in a significant increase, DIMIT resulted in a decrease of SP-A mRNA induction. Combined application of DIMIT and DEXA resulted in a significant increase compared to the controls. Compared to DEXA alone in 10(-8)mol/l, we found an increased induction, but the data were not significant. CONCLUSIONS: The combined application of DEXA and DIMIT shows a higher induction of SP-A mRNA than both drugs given alone.

Kinetic studies on rabbit liver glucocorticoid 5alpha-reductase.

The serum concentration of active glucocorticosteroids depends not only on adrenal synthesis but also on enzymatic activation of 11-dehydro-glucocorticoids in the liver by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). In order to define the respective involvement of other regulative enzymes in the metabolism of 11-dehydro-glucocorticoids in the liver, the objective of this study was to evaluate the kinetic behavior of NADPH:delta 4-3-ketosteroid-5alpha-reductase (5alpha-reductase, EC 1.3.99.5). The interrelations to liver 11beta-HSD1 will be discussed. The kinetic properties of 5alpha-reductase of the rabbit liver were measured by a radioenzymatic assay and characterized with respect to protein-, substrate-, cosubstrate-, and pH-dependence. Michaelis-Menten enzyme kinetic parameters (Km and Vmax) were obtained for the formation of 5alpha-reduced 11-dehydrocorticosterone and corticosterone metabolites. We found that both 11-dehydrocorticosterone (Km 4.2 x 10(-6) mol/l, Vmax 2,600 pmol x min(-1) x mg(-1)) and corticosterone (Km 0.5 x 10(-6) mol/l, Vmax 38 pmol x min(-1) x mg(-1)) exhibit a high affinity to 5alpha-reductase. With respect to cosubstrate-, pH-dependence and finasteride inhibition, it is likely that 11-dehydrocorticosterone metabolism is primarily controlled by isoenzyme 5alpha-reductase type 1. This study shows that the deactivation of GCS especially of 11-dehydro-glucocorticoids via 5alpha-reductase is an important metabolic pathway in the liver. The metabolic activation of GCS by 11beta-HSD could possibly lead to an excess of GCS in the hepatocytes. Due to 5alpha-reductase activity this excess can be limited - on the level of CORT as well as of 11-DHC.

Effect of dexamethasone, triiodothyronine and dimethyl-isopropyl-thyronine on lung maturation of the fetal rat lung.

Our purpose was to elucidate why clinical studies have up to now failed to demonstrate a positive effect of TRH combined with glucocorticosteroids on fetal lung maturity. Morphological and biochemical lung maturation were determined by electron microscopy, choline incorporation, and surfactant-protein-A m-RNA synthesis in rat lung organoid cultures after exposure with a series of concentrations of dexamethasone, triiodothyronine, and dimethyl-isopropyl-thyronine. Thyroid hormones improved morphogenesis of lung histotypic structures but had a negative effect on surfactant synthesis whereas glucocorticosteroids had a positive effect on the surfactant synthesis but a negative effect on morphogenesis. The combination of both substances even had the most negative effect on morphogenesis. Since morphogenesis of lung histotypic structures is prerequisite for surfactant synthesis and secretion, we hypothesize that a sequential treatment of thyroid hormones to improve morphogenesis followed by the application of glucocorticosteroids might be an option to improve neonatal lung function.

Congenital cystic adenomatoid malformation of the lung and fetal hydrops--a case with favourable outcome.

We present a case of congenital cystic adenomatoid malformation of the lung (CCAM) diagnosed at 23 weeks of gestation with concomitant fetal hydrops. The sonographical picture of CCAM disappeared in the third trimester of pregnancy and fetal hydrops resolved under medication with digitalis to the mother. The neonate showed mild dyspnea; the prenatal diagnosis of CCAM was confirmed by chest X-ray and computed tomography. The affected lung segments were dissected at 5 days of age. The diagnosis of CCAM type III was confirmed histologically.

Short-term treatment with levonorgestrel does not antagonize the ethinyl estradiol-induced increase of uterine blood flow in postmenopausal women.

The aim of this study was to determine the effect of a short-term ethinyl estradiol/levonorgestrel medication on blood flow in the uterine arteries in postmenopausal women in a prospective placebo-controlled double-blind study. Twenty-one healthy postmenopausal woman at least 2 years after menopause received 60 micrograms ethinyl estradiol (EE) for 14 days followed by 40 micrograms EE plus 125 micrograms levonorgestrel (LNG) for 12 days (total treatment period 26 days). Sonographically, uterine volume, endometrial thickness, and blood flow in the uterine arteries [as reflected by pulsatility (PI) and resistance indices (RI)] were measured. Uterine size increased from 44 to 80 mL (day 14, p < 0.001) and 87 mL (day 26, p = NS). Endometrium grew from 3 to 8 mm (day 14, p < 0.001) and 11 mm (day 26, p = NS). Uterine arterial PI fell from 2.76 to 1.37 (day 14, p < 0.001) and 1.34 (day 26, p = NS), whereas RI fell from 0.9 to 0.68 (day 14 and day 26, p < 0.001). In conclusion, short-term treatment with LNG does not antagonize the vascular effect of EE on the uterine arteries as reflected by PI and RI. This result might have clinical significance in the selection of the progestin used in hormonal replacement therapy.

PIP: The aim of this study was to determine the effect of a short-term ethinyl estradiol (EE)/levonorgestrel (LNG) medication on blood flow in the uterine arteries in postmenopausal women in a prospective placebo-controlled double-blind study. 21 healthy postmenopausal women, at least 2 years after menopause, received 60 mcg EE for 14 days followed by 40 mcg EE plus 125 mcg LNG for 12 days (total treatment period: 26 days). Sonographically, uterine volume, endometrial thickness, and blood flow in the uterine arteries [as reflected by the pulsatility index (PI) and the resistance index (RI)] were measured. Uterine volume increased from 44 to 80 ml (day 14, p 0.001) and 87 ml (day 26, p = NS). Endometrial thickness increased from 3 to 8 mm (day 14, p 0.001) and 11 mm (day 26, p = NS). Uterine arterial PI fell from 2.76 to 1.37 (day 14, p 0.001) and 1.34 (day 26, p = NS), whereas RI fell from 0.9 to 0.68 (day 14 and day 26, p 0.001). In conclusion, short-term treatment with LNG does not antagonize the vascular effect of EE on the uterine arteries as reflected by PI and RI. This result might have clinical significance in the selection of the progestin used in hormonal replacement therapy.