Estrogen-progestin replacement therapy and atherosclerosis.
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Biomedical subjects
Publications and source records attributed to R Punnonen.
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OBJECTIVE: The levels of interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-10, and granulocyte-macrophage colony-stimulating factor were measured in the peritoneal fluid of 15 patients with endometriosis to characterize the type of immune response that occurs at the site of endometriosis. STUDY DESIGN: Cytokine levels in peritoneal fluid obtained during laparoscopy from 15 patients and 12 controls undergoing tubal ligation were determined by enzyme-linked immunosorbent assay. RESULTS: The mean levels of interleukin-6 in patients with endometriosis and controls were 797 +/- 407 pg/ml and 133 +/- 38 pg/ml, respectively (p < 0.02). Similarly, the mean concentration of interleukin-10 in peritoneal fluids of patients with endometriosis was significantly higher than that of controls (241 +/- 38 vs 128 +/- 21, p < 0.05). The levels of interleukin-2, interleukin-4, interleukin-5, and granulocyte-macrophage colony-stimulating factor were not significantly different between the two study groups. CONCLUSIONS: The levels of interleukin-6 and interleukin-10 are increased in the peritoneal fluids of patients with endometriosis, suggesting enhanced macrophage activity in these patients. Increased interleukin-6 and interleukin-10 production may partially contribute to the disturbed immune regulation observed in patients with endometriosis.
Twenty-two perimenopausal patients (aged 47-56 years) admitted for elective abdominal hysterectomy and salpingo-oophorectomy were selected to understand better the clinical significance of increasing gonadotropin levels as an indicator of target organ responsiveness. Prior to anesthesia, blood was drawn from the patients for subsequent analyses of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and 17beta-estradiol (E2) levels. Ovarian tissue was obtained during surgery and frozen at -70 degrees C for subsequent analyses for FSH and LH receptor content. The phase of the menstrual cycle of the patients or postmenopause was determined by serum gonadotropin and E2 levels and histological evaluation of the endometrium. Patients with no detectable FSH receptors showed significantly higher serum FSH and LH levels (4.7- and 4.3-fold, respectively) when compared to patients with detectable FSH receptors; FSH receptors were present in 27% of the patients, LH receptors were present in 68% of the patients and a negative correlation was found between serum LH levels and ovarian LH receptors. In postmenopausal patients, neither FSH receptors nor LH receptors were detectable. High serum gonadotropin levels in perimenopausal patients thus suggest the existence of low or undetectable ovarian gonadotropin receptor levels.
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Measurement of skin thickness has been proposed to be capable of predicting low bone mineral density and the risk of osteoporosis in postmenopausal women. In order to investigate the association between the two factors, we measured skin thickness on the leg, lower abdomen and forearm by ultrasound scanning, and bone mineral density at the lumbar spine, femoral neck and distal radius by dual-energy X-ray absorptiometry in 60 peri- and postmenopausal women. Only a loose association was found between skin thickness and bone mineral density at any site, the highest correlation being between lumbar bone mineral density and abdominal skin thickness. The results of our study confirm that there is some association between the two factors, but the measurement of skin thickness, although easy and reliable, is not a clinically sufficient method to predict bone mineral density.
OBJECTIVE: To examine the effect of topical oestradiol on skin collagen and elastin. SUBJECTS: Twelve postmenopausal women, aged 52 to 76 years. INTERVENTIONS: Topical oestradiol treatment on the skin of lower abdomen and the vehicle only on the contralateral site; once a day for three months. MAIN OUTCOME MEASURES: The content of skin hydroxyproline; the levels of the carboxyterminal propeptide of human type I procollagen (PICP) and of the aminoterminal propeptide of human type III procollagen (PIIINP). The number and the quality of collagen and elastic microfibrils. RESULTS: The amount of hydroxyproline in the skin significantly (P = 0.012) increased from 11.8 to 16.3 micrograms (38%) during oestradiol treatment. After treatment, the PICP level in the blister fluid was significantly (P = 0.024) higher on the treated site than on the control site. Also the level of PIIINP increased, but the change was not statistically significant. Electron microscopy showed morphologic improvement of elastic and collagen fibres, while the number of oxytalan and elaunin fibres was unchanged in light microscopy. CONCLUSIONS: Topical oestradiol treatment increases the amount of skin collagen. The increase in the level of PICP and PIIINP in skin blister fluid indicates that oestradiol treatment stimulates collagen synthesis. Furthermore, our results show that topical ostradiol treatment has a greater influence on the amount than on the quality of skin collagen. On the contrary, in elastic tissue the oestradiol treatment will only result in morphologic improvement.
Atherosclerotic changes associated with long-term hormone replacement therapy (HRT) were evaluated in 20 postmenopausal women (mean age, 62.8 +/- 6.1 years). The duration of hormone therapy was 10.1 +/- 3.4 (SD) years. For 9 women the HRT was sequential estradiol valerate plus levonorgestrel, for 6 women estradiol valerate plus medroxyprogesterone acetate and for 5 women estradiol valerate alone. Examinations consisted of histologic and biochemical studies of the uterine artery and ultrasonographic examinations of carotid arteries, aorta and iliac arteries. The findings were compared with those in 20 postmenopausal women of similar age and with similar body mass indexes who had never received HRT. Additionally, the same examinations were performed on 10 premenopausal women (48.3 +/- 4.6 years). The uterine artery was histologically normal in all the premenopausal women studied. Among the postmenopausal women without HRT, a histologically normal uterine artery was found in 5% and in women on HRT in 55% of cases (P < .01). In medicolegal autopsies, atherosclerosis in the uterine artery correlated significantly with atherosclerosis in the coronary artery and aorta. The free cholesterol content of the intima media in premenopausal women was lower than in postmenopausal women without HRT. The percentage of linoleic acid in the intima was significantly lower and that of docosapentaenoic acid significantly higher in premenopausal women and in postmenopausal women on HRT than in postmenopausal women without HRT. In the ultrasonographic examination atherosclerosis in the carotid artery was less common in premenopausal women and in women on HRT than in postmenopausal women without HRT. In this material, histologic, biochemical and radiologic studies showed that HRT may be protective against atherosclerosis.
We have analysed products of lipid peroxidation reactions and activities of antioxidant enzymes in cancerous breast tissue and in corresponding reference tissue. In addition, the serum lipid peroxidation and peroxyl-radical-trapping capacity of breast cancer patients were compared to those of healthy subjects. A total of 23 patients with breast cancer participated in this study. In the cancerous tissue, catalase activity was lower than in the reference tissue, while the activities of superoxide dismutase, glutathione peroxidase and the hexose monophosphate shunt were elevated. The content of thiobarbituric-acid-reactive material was slightly lower in the cancerous tissues, but the levels in serum were found to be elevated in patients with breast cancer. The amounts of conjugated diene double bonds were essentially equal both in the cancerous and in the reference tissue. Moreover, in breast cancer patients the serum levels of diene conjugation and the peroxyl-radical-scavenging capacity did not differ from those measured in healthy subjects. This study indicates that the antioxidant defence system is altered in cancerous breast tissues, but does not support the hypothesis suggesting that formation of lipid peroxides in the tumour tissue itself is of primary importance in the carcinogenesis.
Thyroid function and ultrasonographically determined thyroid volume were studied in nine pregnant women with diagnosed autoimmune thyroid disease at regular intervals during pregnancy and two months after delivery. The results were compared to the findings in ten healthy pregnant women. In ultrasound examinations seven of the patients showed definite morphological changes such as hypoechogeneity and inhomogeneity of the thyroid gland, which did not change during the course of pregnancy nor during the post-partum period of eight weeks. There were no morphological changes in the thyroid glands of the control group. The mean thyroid volume did not significantly change during pregnancy and after delivery in both the patient group and controls. The mean thyroid volume was smaller in the study group, with 7.55 ml (SD 6.01) compared to the controls with 11.29 ml (SD 5.61), a difference which was not statistically significant. Neither course of pregnancy nor fetal outcome was influenced by inactive autoimmune disease of the thyroid.
We determined DNA content, S-phase fraction, and estrogen (ER) und progesterone receptor (PR) levels in 36 stage I endometrial adenocarcinomas and in 22 hyperplastic lesions to obtain information on the genesis and progression of endometrial malignancy. DNA aneuploidy was detected in 12/36 (33%) carcinomas and in none of the hyperplastic lesions. DNA aneuploidy was significantly more common in poorly and moderately differentiated carcinomas than in the well-differentiated ones. Similarly, the highest number of cells in S-phase were found in poorly and moderately differentiated carcinomas, whereas well-differentiated carcinomas and all hyperplasias had an equally small S-phase fraction. Mean ER and PR levels were highest in hyperplastic lesions, especially those with atypical features, whereas carcinomas of all grades had significantly lower values. Thus, it is likely that the loss or decreased expression of steroid receptors is an early event during carcinogenesis in human endometrium, whereas an increase in the cell proliferation rate and the formation of DNA aneuploidy occur later during tumor progression.
Antioxidant enzyme activities and lipid peroxidation were analysed in normal endometrium and endometrial cancer tissues from Finnish and Japanese patients. The catalase and glutathione peroxidase activities of normal endometrium were significantly lower in Finns than in Japanese. Lipid peroxidation was slightly higher in endometrial cancer as compared with normal endometrium both in the Finns and in the Japanese. When cancer tissues were compared with normal endometrium both in Finns and Japanese the activity of superoxide dismutase was significantly lower in cancer tissue than in normal endometrium. In Finns glutathione S-transferase activity was also lower in endometrial cancer tissue than in normal endometrium, and a similar tendency was also found in Japanese. This study suggests that endometrial cancer tissue is associated with an impaired enzymic antioxidant defence system.
A novel serological test, IPAzyme Chlamydia (Savyon Diagnostics Ltd., Beer Sheva, Israel), was compared with an enzyme immunoassay (EIA) for the ability to detect serum immunoglobulin G and A antibodies in the diagnosis of acute chlamydial pelvic inflammatory disease. In comparison with cell culture, which is the "gold standard," IPAzyme Chlamydia and EIA exhibited sensitivities of 63 and 68% and specificities of 76 and 87%, respectively. Thus, IPAzyme Chlamydia offers no advantages over the EIA, and neither serological test can be recommended for the diagnosis of acute Chlamydia trachomatis infection. So far, conventional cell culture remains the most reliable diagnostic test for chlamydial pelvic inflammatory disease.
Serum antibodies to early proteins of human papillomavirus type 16 (HPV 16 E2 protein) and herpes simplex virus type 2 (HSV 2 ICP8) can be measured by ELISA. In the serum of 122 newly diagnosed cervical carcinoma patients and age-matched controls, enhanced IgA antibody levels to an HPV-16 E2 protein derived peptide no. 245 indicated a 9.5-fold (95% confidence limits 2.8-57.2) relative risk of cervical carcinoma. No significant risk was found with a corresponding HPV 6 E2 peptide or HSV 2 ICP8. To evaluate the HPV 16 E2 peptide as a possible tumor marker for cervical carcinoma serial postoperative serum samples were tested from 27 women with cervical carcinoma. Antibody responses to the HPV 16 E2 peptide depended on the clinical stage. Stage I and II patients showed decreasing posttreatment IgA and/or IgG antipeptide antibody levels. Stage III and IV patients initially showed decreasing antipeptide antibody levels followed by increasing levels. These patients also showed increasing IgG antibody levels to the HSV 2 ICP8. However, increasing antibody levels to the HPV 16 E2 peptide indicated significantly (P less than 0.05) worse 2-year disease free survival (recurring disease) than did stable or decreasing antibody levels. The results suggest that serum antipeptide antibodies to the HPV 16 E2 peptide no. 245 can be used for the monitoring of cervical carcinoma.
In the present study we have measured the concentrations of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) in preovulatory follicular fluid (FF) samples obtained from patients undergoing ovulation induction with human menopausal gonadotropin/human chorionic gonadotropin. In 13 of the 24 (54%) FF samples obtained from 20 patients, TNF-alpha was detected. In contrast, IL-1 beta was observed in none of the 16 samples assessed. In the samples with detectable levels of TNF-alpha, the mean concentration was 40.1 pg/ml (range 20-74 pg/ml). In addition, we found an association between the presence of TNF-alpha in the FF and the serum level of 17 beta-estradiol (E2) and progesterone (P). The E2 and P levels were significantly lower in patients with detectable levels of TNF-alpha in FF than in patients with no detectable TNF-alpha in FF. In summary, the present study shows the presence of TNF-alpha and the absence IL-1 beta in hyperstimulated human preovulatory FF. In addition, our results show an association between the presence of TNF-alpha in FF and low E2 and P levels in serum, suggesting a role for TNF-alpha in the regulation of human steroidogenesis.
To assess the role of interleukin-1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF alpha) in the physiological host defence mechanisms against malignancies, the production of these cytokines in sera, ascitic and cyst fluids and in the tumour tissues of patients with benign or malignant ovarian tumours was studied. IL-1 beta was found neither in the sera nor in the ascitic fluids of these patients. It was also virtually absent from the cyst fluid samples. However, a mean value of 790 pg IL-1 beta/g tumour was found. Like IL-1 beta, TNF alpha was virtually absent in the serum samples. It was, however, detectable in the ascitic and cyst fluids and tumour tissues. The TNF alpha concentrations were highest in the tumour tissues, with a mean level of 328 pg/g tumour. When comparing the level of IL-1 beta and TNF alpha in patients with benign tumours to that seen in patients with malignant tumours, no differences in production were observed, regardless of the origin of the test samples. Our results indicate the production of IL-1 beta and TNF alpha in patients with ovarian tumours. More importantly, the finding that the production of these cytokines in patients with benign tumours is similar to that in patients with malignant tumours supports the conclusion that the production of these cytokines is more a nonspecific indicator of an inflammatory process than a specific response to a malignant process.
In an open, multicentre study, transdermal administration of oestradiol (E2) by means of skin patches was investigated in a Finnish patient population suffering from typical post-menopausal symptoms. A total of 249 women applied a patch twice weekly for 6 months. Whereas 85% of the subjects were experiencing hot flushes and 83.5% sweating before therapy, only 5.7% and 11.8%, respectively, reported these symptoms at the end of the trial. Furthermore, 97.6%, 95.7% and 94.8% of the subjects reported that depression, headache and sleep disturbances, respectively, had disappeared during therapy. Skin irritation occurred in 18.2% of these predominantly fair-skinned women. Frequent sauna bathing did not interfere with the patch therapy. General acceptance of the treatment was excellent, 84.8% of the patients completing the treatment, of whom 78% were willing to continue the treatment after the trial. These results show that transdermal administration of E2 is effective in relieving post-menopausal symptoms. Local tolerability was good and the majority of the patients considered the transdermal treatment to be superior to their previous oral replacement therapy.
Transvaginal ultrasound showed tubo-ovarian abscess in 10 patients admitted for acute pelvic inflammatory disease, and transvaginal ultrasound-guided aspiration of tubo-ovarian abscess was performed under antimicrobial treatment. Only light sedation was required and the procedure was well tolerated by the patients. The short-term recovery of all patients was quick and uncomplicated. This new technique is a useful alternative for the diagnosis and treatment of tubo-ovarian abscess.
Sera from 35 patients with acute pelvic inflammatory disease (PID) with and without Chlamydia trachomatis confirmed by culture and sera from 19 control patients with neither evidence of pelvic infection nor C trachomatis infection were studied for the presence of serum IgG, IgA, and IgM antibodies to C trachomatis using enzyme immunoassay (EIA) and immunoblotting techniques. There was no correlation between the antibody concentrations in the EIA and the spread of chlamydial infection, as determined by cervical, endometrial, and laparoscopic sampling for chlamydia. The immunoblot analysis showed antibodies to the major outer membrane protein (MOMP) of C trachomatis elementary bodies in all patients who had had C trachomatis isolated. Reactivity was also frequently observed against the 68, 62, 60, 45, and 31 kilodalton antigens. About 20 antigenic polypeptides were identified. Differences in antibody prevalence to specific chlamydial antigens, however, were not related to the site of chlamydial isolation or serum antibody concentrations observed with the EIA. The results indicate that patients with PID with and without upper genital tract infection with C trachomatis cannot be differentiated by reactivity of sera to specific chlamydial polypeptide antigens. The determination of a specific serum IgA antibody response by EIA was the most effective single test to discriminate between patients with and without acute chlamydial infection.