Interleukin 1alpha and tissue-lytic matrix metalloproteinase-1 are elevated in ectopic endometrium of patients with endometriosis.

BACKGROUND: Matrix metalloproteinases (MMP) play an essential role in tissue remodelling and menstruation and appear to be regulated by cytokines such as interleukin-1alpha (IL-1alpha). In order to investigate their role in the pathogenesis of endometriosis, the aim of the present study was to compare the protein localization of matrix metalloproteinase-1 (MMP-1) and of its main stimulatory cytokine IL-1alpha in eutopic and dystopic endometrium of patients with endometriosis. METHODS: MMP-1 and IL-1alpha protein localization was analysed retrospectively in paired paraffin-embedded tissue biopsies obtained simultaneously from the endometrial cavity and from endometrial lesions of 37 patients with peritoneal or ovarian endometriosis and in cycling endometria from 37 women without endometriosis. Protein localization was demonstrated by immunohistochemistry; antibody specificity was confirmed by western blot analysis. RESULTS: MMP-1 and IL-1alpha protein staining in women suffering from endometriosis was significantly more pronounced in endometriotic lesions than in eutopic endometrium. This held true for both epithelial MMP-1 and IL-1alpha staining (P < 0.006 and P < 0.001), and for stromal MMP-1 and IL-1alpha staining (P < 0.001 and P < 0.001). Furthermore, stromal MMP-1 and IL-1alpha were significantly co-expressed in dystopic endometriotic tissue (P = 0.045). Endometrial MMP-1 and IL-1alpha protein expression pattern in eutopic endometrium from women suffering from endometriosis, however, did not differ significantly from the pattern seen in healthy women. CONCLUSIONS: The increased expression of both matrix-degrading MMP-1 and its major stimulatory cytokine IL-1alpha in endometriotic lesions and the selective co-expression in the stroma of endometriotic foci clearly suggests their involvement in the pathogenic mechanisms leading to local invasion and tissue destruction.

Endometrial nuclear receptor co-factors SRC-1 and N-CoR are increased in human endometrium during menstruation.

Steroid hormone receptor co-factors are abundantly expressed in the uterus in order to modify steroid hormone receptor action, either leading to activation or repression of transcription in the endometrium. However, the role of co-factors in remodelling of the human endometrium has not been established. We therefore endeavoured to evaluate the presence of the co-activator SRC (steroid receptor co-activator)-1 and the co-repressors N-CoR (nuclear receptor co-repressor) and steroid co-repressor SMRT (silencing mediator of retinod and thyroid) receptors in the human endometrium during the different phases of the menstrual cycle. By using a real-time RT-PCR assay, we showed that SRC-1, N-CoR and SMRT mRNA are expressed in human endometrium during all phases of the menstrual cycle, as well as in inactive endometrium. Moreover, endometrial expression of SRC-1 and N-CoR mRNA increased during menstruation when compared with the other phases of the menstrual cycle (P < 0.001). Immunohistochemistry demonstrated that SRC-1 and N-CoR stain positive in the glandular epithelium and stroma in menstrual phase endometrium. The staining was weak in proliferative and secretory endometrium and absent in inactive endometrium. Our results suggest that differential expression of endometrial steroid receptor co-factors probably play a role in the regulation of human endometrium remodelling.

Interleukin-1 system and sex steroid receptor gene expression in human endometrial cancer.

OBJECTIVES: The interleukin-1 system is known to play a pivotal role in human physiology and reproduction. In the cycling endometrium, interleukin-1alpha activity is controlled by sex steroids and is confined to the perimenstrual phase, where it is involved in the events leading to tissue lysis and menstruation. Since local tissue degradation is also a feature of malignant tumors, our goal was to analyze the gene expression of interleukin-1alpha and other interleukin-1 family members and compare it with estrogen receptor alpha, estrogen receptor beta, and progesterone receptor mRNA expression in 27 endometrial carcinomas and 13 normal endometria. METHODS: Endometrial tumor tissues were obtained during hysterectomy for endometrial cancer, and normal endometrium was sampled in women undergoing surgical procedures for nonendometrial pathologies. Gene expression was analyzed by reverse transcription polymerase chain reaction. Protein expression was detected and localized by immunohistochemical staining. RESULTS: A strong gene expression of interleukin-1 type I receptor, estrogen recptor alpha, and progesterone receptor was detected in all tumor tissues and in the majority of benign endometrial tissues. However, in contrast to nonmalignant endometria, variable amounts of interleukin-1beta and interleukin-1 receptor antagonist mRNA were also detected in most of the tumor samples. Gene expression of interleukin-1alpha and estrogen receptor beta was considerably less frequent, with interleukin-1alpha being absent in all peri- and postmenopausal endometria and in all but one of the well-differentiated tumors. With decreasing differentiation interleukin-1alpha gene expression became more frequent. In these cases, interleukin-1alpha protein was detected predominantly in epithelial tumor cells of lower-grade tumors. CONCLUSION: We have demonstrated the presence of the interleukin-1 system in endometrial malignancies, and found a negative correlation between interleukin-1alpha and tumor differentiation. We hypothesize that the nonphysiological expression of interleukin-1alpha in less differentiated tumors might contribute to their invasiveness and malignant behavior.

Current concepts in aesthetic endocrinology.

The extragenital effects of ovarian steroids are relevant to the metabolism of skin and hair, the changes in body composition and the alterations of the subcutaneous fat distribution throughout life. When ovarian steroids become deficient or are produced in excess, different problems may arise in these tissues and some of these problems, i.e., obesity and cellulite, display gender-specific components. Therefore, a new field in endocrine research known as aesthetic endocrinology is gaining more interest. Because sex steroids are small molecules they can be transported into the skin by topical application when properly formulated. This possibility is used in aesthetic endocrinology in order to achieve local effects but to avoid systemic reactions. After reviewing the current data it collectively seems legitimate to recommend estrogens, either orally or topically, in order to counteract the aging of the skin after menopause. Although a reconstitution of juvenile skin cannot be achieved through this method, a slowing in the skin aging process seems a reasonable expectation. In contrast, the successful treatment of hair loss in women is only confirmed for the application of the non-hormonal compound minoxidil. Apart from the difficult problem of hirsutism, acne and changes in body composition offer promising therapeutical options for endocrinological methods.

Flexible versus rigid endoscopes for outpatient hysteroscopy: a prospective randomized clinical trial.

To evaluate patient acceptance, optical properties and the clinical feasibility of flexible compared with rigid hysteroscopes, 142 patients undergoing outpatient hysteroscopy were included in a prospective, randomized clinical trial. The flexible hysteroscope was used in 70 patients, and the rigid instrument in 72. At different stages of the hysteroscopy the level of pain experienced by the women was assessed using a 10 cm visual analogue scale. Optical properties characterized by the parameters intrauterine visibility, hysteroscopic view and diagnostic accuracy were ranked by the surgeons using a 5-point scale (1 = excellent to 5 = insufficient), and duration of the hysteroscopy was measured. Hysteroscopy was successful in 87.5 and 100% of patients in the flexible and rigid groups respectively. With the use of rigid telescopes, discomfort at introduction and during the hysteroscopy was significantly greater (median 1.7 versus 0.7, P = 0.003; 3.1 versus 1.2, P < 0.001 respectively), but optical properties were judged to be far superior (P < 0.001 for all three comparisons) and procedure time was significantly shorter (median 70 versus 120 s, P = 0.003). In conclusion, outpatient hysteroscopy seems to be less painful when using flexible telescopes. However, rigid hysteroscopes provide superior optical qualities and permit a more rapid performance with higher success rates at much lower cost.

[Hormone replacement therapy with a transdermal estradiol gel and oral micronized progesterone. Effect on menopausal symptoms and lipid metabolism]. / Die Hormonersatztherapie mit einem perkutan wirksamen Oestradiol-Gel und oral verabreichtem mikronisierten Progesteron. Auswirkung auf klimakterische Symptome und den Lipidstoffwechsel.

In a multicenter observational study, the efficacy and acceptance of two different regimens of postmenopausal hormone replacement therapy in the form of a combination of 17 beta-estradiol in percutaneous gel application and micronized oral progesterone were evaluated. Forty-eight patients (aged 40-66 years) received 2.5 g estradiol gel plus either continuously micronized progesterone 100 per day (group A) or, sequentially, 200 mg per day between day 16 and 25 of a monthly cycle (group B) for two months. A significant reduction in typical menopausal symptoms, especially vasomotor complaints like hot flushes or sweating, was observed in both groups (score average at the beginning for hot flushes: 2.0 in group A and 1.8 in group B; after two months of treatment, 0.7 in group A and 0.4 in group B). Cholesterol levels were slightly reduced but statistically significant (235.9 +/- 49.55 mg/dl vs. 226.3 +/- 52.24 mg/dl; p < 0.05) only in group A; a trend towards lower cholesterol was observed in group B (236.5 +/- 47.82 mg/dl vs. 227.4 +/- 44.72 mg/dl). Lipoprotein (a) was also significantly reduced in group A (32.57 +/- 36.52 mg/dl vs. 28.28 +/- 31.03 mg/dl in group A; 31.7 +/- 28.42 mg/dl vs. 28.34 +/- 23.71 in group B; p < 0.05). The overall acceptance of this therapy was excellent or good in 91.3% of group A and 92.8% of group B patients.

[Technique and results of laparoscopic conservative organ-preserving myoma enucleation]. / Technik und Resultate der laparoskopisch konservativen, organerhaltenden Myomenukleation.

Myoma is one of the most common benign diseases of the female genital tract. The surgical management of this entity has been altered over the last years from complete hysterectomy to conservative enucleation of the myomas. We retrospectively compared our data concerning laparoscopic or open myomectomies. Over a period of 2 years, we operated 207 myomas in 102 patients. Of this collective, 69 (67.6%) were operated on laparoscopically and 33 (32.4%) via an open approach. In both groups, the median number of myomas was 2 (1-7). The mean diameter of the largest myoma was 5.1 +/- 2.4 cm (laparoscopy) and 6.2 +/- 2.6 cm (laparotomy), respectively. The additive diameter of myomas was 7.7 +/- 5.1 cm (laparoscopy) and 9.8 +/- 4.1 cm (laparotomy), respectively. There was no relevant difference between the groups in terms of operating time and blood loss. Four (3.9%) laparoscopies had to be converted to an open approach. In three cases (2.9%) a laparoscopically assisted enucleation had to be performed, requiring a mini-laparotomy 4 to 5 cm in length. We encountered no severe complications. Given appropriate indication, laparoscopic myomectomy is an easy-to-perform and minimally invasive technique with a low complication rate.

Diagnostic hysteroscopy for the investigation of abnormal uterine bleeding in premenopausal patients.

The aim of this observational clinical study was to evaluate the feasibility and diagnostic accuracy of outpatient diagnostic hysteroscopy in premenopausal patients suffering from abnormal uterine bleeding. Between September 1996 and September 1999, 819 patients were referred to our outpatient hysteroscopy clinic, 317 of which were premenopausal, and presenting with menstrual symptoms. All hysteroscopies were performed using a standard 30 degrees 5-mm hysteroscope, and the uterine cavity was generally distended with normal saline. Hysteroscopy was completed successfully in 305 cases (96.2%), but since the routine use of lidocaine spray in 1998 this figure increased up to 98.9%. Intrauterine pathology was diagnosed in almost 34% of patients, the most frequent being submucous myomas (14%) and endometrial polyps (14%); there was no case of endometrial cancer in this subset of patients. Moreover, there was an age-related distribution of intrauterine pathology, with the highest incidence in patients aged 41-50 years. Diagnostic hysteroscopy is a simple and safe technique, well accepted by the vast majority of patients; due to its excellent diagnostic accuracy, and its high success rate as an outpatient procedure, we wonder why inpatient D&C under general anesthesia is still regarded a diagnostic or even therapeutic option for patients with abnormal uterine bleeding.

Endometrial cell dissemination at diagnostic hysteroscopy: a prospective randomized cross-over comparison of normal saline and carbon dioxide uterine distension.

The incidence of pelvic spreading of endometrial cells at diagnostic hysteroscopy was studied comparing the two distension media carbon dioxide (CO(2)) and normal saline (N/Saline). Thirty patients requiring laparoscopy and hysteroscopy were included in this study, the main indication for surgery being subfertility. Hysteroscopy was performed using both CO(2) and N/Saline distension on each patient, the order of the distension media being randomly allocated. Samples of peritoneal fluid were aspirated from the pouch of Douglas before and after hysteroscopy with each distension medium, and the specimens were investigated cytologically for the presence of endometrial cells. Endometrium was present in 2/30 (6.7%) peritoneal aspirates before and in 15/60 (25%) collected after the hysteroscopies. There was no major difference between liquid or gaseous distension, transtubal reflux of endometrial cells occurring in 7/30 (23.3%) and in 8/30 (26.7%) hysteroscopies respectively. Positive peritoneal cytology was observed significantly more often in patients who were in the proliferative phase of the menstrual cycle [9/14 (64.3%) versus 0/11, P < 0.004]. In conclusion, transtubal dissemination of endometrium occurs in about one quarter of patients, irrespective whether N/Saline or CO(2) is used for uterine distension; there is no advantage to using gaseous distension for hysteroscopy when investigating high-risk cases for endometrial malignancy.

Trends in the prescription of psychotropic drugs and hormone substitutes in Austria.

INTRODUCTION: Psychological instability as a result of changing hormone levels are commonly observed during menopause. We examined the question whether the prescription of psychotropic drugs is related to age or gender and whether the increase in the prescription rate of hormone substitutes has an impact on this phenomenon. METHODS: Age and gender-specific prescription rates of psychotropic drugs and hormone substitutes were examined in a retrospective study using data of the European Pharmaceutical Market Research Association of Austria. The relevant Austrian figures were established on the basis of representative samples. RESULTS: There are no gender-specific differences in terms of prescription frequency up to the age of 45 years. After the age of 45, there is a significant increase in the prescription of psychotropic drugs for women. When comparing the years 1991 and 1996, we find a reduction in the number of prescriptions of psychotropic drugs and an increase in the prescription rate of hormone replacement drugs. DISCUSSION: An increase in the prescription rate of hormone substitutes may contribute to the psychological stabilisation of menopausal women and thereby reduce the need for psychotropic drugs.

[Effectiveness and tolerance of a gonadotropin releasing hormone (goserelin) in treatment of symptomatic endometriosis]. / Wirksamkeit und Verträglichkeit eines Gonadotropin Releasing Hormones (Goserelin) zur Behandlung der symptomatischen Endometriose.

Endometriosis is one of the most common benign gynecological diseases, affecting an estimated 10-15% of all premenopausal women. In this open multicentric prospective study, we investigated the effectiveness and tolerance of a gonadotropin releasing hormone agonist (goserelin) for the treatment of symptomatic endometriosis. One hundred and thirteen patients were included in the study. During the treatment, we documented a relevant reduction in the rAFS score and in the additive diameter of the implants. In addition, we noted a reduction in pelvic pain and an improvement of symptoms on pelvic examination. These effects were also reported during the follow up visits (24 weeks). Only 12 patients had intolerable side effects (hot flushes, sweating during the night, vaginal dryness, depression), which could be managed with transdermal 17 beta estradiol, without reducing therapeutic effectiveness. In conclusion, gonadotropin releasing hormone analogs proved to be an excellent treatment for symptomatic endometriosis and are generally well tolerated.

[Ambulatory hysteroscopy in evaluation of postmenopausal bleeding]. / Die ambulante Hysteroskopie in der Abklärung der postmenopausalen Blutung.

INTRODUCTION: Diagnostic hysteroscopy is the most precise procedure to evaluate diseases involving the uterine cavity. There is, however, only limited data concerning the use of hysteroscopy carried out as an outpatient procedure in patients with postmenopausal bleeding. MATERIALS AND METHODS: In this study we report on 360 postmenopausal patients with erratic bleeding, who were referred to our outpatient hysteroscopy clinic. 185 women had frank postmenopausal bleeding (PMB) and another 175 had abnormal uterine bleeding while taking hormone replacement therapy (AUB). The mean age was 57.9 years (range: 42-86). All hysteroscopies were performed using a standard 5-mm hysteroscope with a 30 degrees fore-oblique lens; the uterine cavity was generally distended with normal saline. RESULTS: Outpatient hysteroscopy was performed successfully in 339 patients (94.2%). In 166 cases (46.1%) cervical dilatation was necessary, and 138 required (38.3%) intracervical anaesthesia. Intrauterine pathology was diagnosed in 49.6% of cases, with endometrial polyps (20.9%) and fibroids (15.9%) being the most common abnormalities. While there was no difference in the incidence of intrauterine lesions between patients with AUB and those with PMB, endometrial carcinoma was more common in the latter group (PMB: n = 11 vs. AUB: n = 1; p < 0.002). CONCLUSION: Due to its high accuracy and patient acceptance, outpatient diagnostic hysteroscopy should become a first line investigation in postmenopausal patients with bleeding disorders.

Elevation of inducible nitric oxide synthase activity in human endometrium during menstruation.

Nitric oxide (NO) is a known agonist of programmed cell death (apoptosis). In order to discover its potential role during menstrual shedding, a process associated with extensive apoptosis, we evaluated activity and mRNA levels of the inducible and constitutive isoforms of NO synthase (NOS) in endometrial specimens of the proliferative (n = 11), late-secretory (n = 7), and menstrual (n = 17) phase of the cycle. These levels were compared with the proportion of apoptotic cells by detection of histochemically labeled DNA fragments. Inducible NOS (iNOS) activity during menstruation was six times that of the proliferative or late-secretory phase (p < 0.05), whereas constitutive NOS activity remained unchanged. Competitive reverse transcription-polymerase chain reaction revealed 146% and 77% increases of iNOS mRNA expression in the late-secretory and menstrual phases, respectively, compared to the proliferative phase (p < 0.05), whereas constitutive NOS mRNA expression remained constant. Inducible NOS immunostaining was restricted to epithelial cells, whereas constitutive NOS immunostainig was confined to vascular endothelia. In addition, the proportion of apoptotic cells within the glands of late-secretory or menstrual endometrium was twice that of the proliferative phase (p < 0.05). We conclude that local production of NO is involved in the signal transduction mechanisms leading to endometrial breakdown during menstruation.

Progesterone and neurology.

Neurological diseases are frequently observed in perimenopausal women and can be characterized by their gender-specific occurrence. These observations raise the question whether sex steroids are also involved in neurological diseases. Epidemiological data have shown that in Austria in 1993, the prescription rate of psychotropics, hypnotics, and analeptics for women aged 50-55 years increased over 300% compared to other age groups. In males of the same age, an increase of the prescription rate was not observed. Molecular pharmacology research over the last ten years has shown that sex steroids may interact with the central nervous system via GABA receptors as well as with the peripheral nervous system. These observations confirm the epidemiological finding that neurological and psychological functions may also be directly influenced by sex steroids and their metabolites.

The effect of hormone replacement therapy on carotid arteries: measurement with a high frequency ultrasound system.

OBJECTIVE: To evaluate the effect of hormone replacement therapy (HRT) on carotid arteries in postmenopausal women with a high frequency ultrasound system. METHODS: In a clinical cross-sectional study carotid artery layers were measured in 82 postmenopausal women receiving a sequential regimen of HRT (oestradiol valerate 2 mg and dydrogesterone 10 mg) and in 70 postmenopausal women without HRT. Measurements of the left carotid artery layers (externa, media, intima) were taken with a single mechanically activated 22.5-MHz transducer with an effective band width of 8 MHz. RESULTS: A statistically significant increase in thickness of the media layer of the carotid artery was observed in the HRT group (0.34 +/- 0.06 mm) as compared to the untreated group (0.27 +/- 0.03 mm). The media/intima ratio of the treated group was statistically significantly higher than that of the untreated group (P < 0.05). The mean strength of the carotid wall was 0.70 +/- 0.17 mm in the 70 postmenopausal women without HRT and 0.76 +/- 0.24 mm in the 82 patients undergoing HRT. CONCLUSION: HRT has a morphological effect on the carotid arteries in postmenopausal women. These findings support a cardioprotective effect, especially in terms of prevention of atherosclerosis. This effect can be measured non-invasively by high frequency ultrasound.

[The role of nitric oxide in reproduction]. / Die Rolle des Stickstoffmonoxids bei der Reproduktion.

Nitrix oxide (NO) is a highly reactive and short-lived radical (half-life time: 10-12 s), which is derived from L-arginine by the NO synthases (NOS) in several organ systems. The release of NO by endothelial cells leads to rapid relaxation of vascular smooth muscle cells, whereas release by several neuronal cells causes neurotransmission. When NOS is actively induced in immune cells or certain epithelia it causes cytotoxicity and/or apoptosis of these cells. In the reproductive organs NO is now considered to be an important trigger molecule for several physiological mechanisms. Follicular synthesized NO is involved in rupture of the follicle during ovulation. Moreover, NO participates in the acrosome reaction of spermatozoa during capacitation. Apoptosis and collagenolysis of the functional endometrium may be involved in endometrial shedding during menstruation. Since NO induces both apoptosis and collagenolysis, the newly discovered production of NO in late secretory endometrium could act as a key mechanism in the process of menstrual disintegration of the endometrium. Additionally, NO is necessary to support and maintain the decidualization process and plays a pivotal role in implantation.