L. De Cecco

Immune cell circulating subsets are affected by gonadal function

Influence on the immune system activity by sex hormones has been widely reported. Fertile women are proner to the onset of autoimmune diseases than men, but this increased susceptibility disappears after menopause. The hormonal changes are very likely to be responsible for this event, but precise correlations between sex hormone levels and immune functions have not been defined. For this reason we have analyzed phenotype and natural cytotoxicity of peripheral blood lymphocytes (PBL) from 35 women in menopause, comparing them with the same parameters of 28 fertile and 8 postmenopausal women and correlating them with the hormonal pattern of each group. We have also considered 8 women with premature menopause. Hormonal levels have been detected by radioimmune assays, while PBL phenotype has been studied by immunofluorescence and FACS analysis. The natural killer (NK) cell activity has been calculated on the basis of a chromium release assay. Postmenopausal women showed a reduction of the number of total lymphocytes (1650 +/- 215 cells/mmc) in comparison to fertile women (2081 +/- 200 cells/mmc, P < 0.01). The decrease mainly involved B and CD4+ T lymphocyte subpopulations (P < 0.05 and P < 0.01, respectively). Women with premature menopause had lower percentage of CD4 lymphocytes (34% vs 47%, P < 0.01) and higher percentage of CD8 (30% vs 22%, P < 0.02) and NK cells (32% vs 14%, P < 0.009) than fertile women of the same age. The percentage of circulating lymphocytes expressing HLA class II antigens also resulted as being increased (22% vs 9%, P < 0.01). The number of total, CD2, CD4 T lymphocytes, B and NK cells correlated positively with LH and negatively with FSH serum levels (P < 0.05 and P < 0.002, respectively). PRL positively influenced CD2, CD4 and B lymphocyte numbers (P < 0.001). FSH and 17 beta-estradiol inversely affected CD8 and B lymphocyte numbers (P < 0.005 and P < 0.02, respectively). In conclusion, the increase of FSH and the decrease of PRL levels appear to be involved in the reduction of B and CD4 T lymphocytes thus lowering the risk for the onset of autoimmune diseases during and after menopause. Generalized activation of the immune system (raised expression of HLA class II antigens) with elevated numbers of cytotoxic subpopulations (CD8 and NK lymphocytes) is present in women affected by premature menopause suggesting the involvement of autoimmune dysregulation in the pathogenesis of this syndrome.

Effects of Three Low-Dose Oral Contraceptive Formulations on Lipid Metabolism

Three oral contraceptive preparations were studied in 60 healthy women. This randomized, comparative, baseline controlled study was designed to investigate the effects of the preparations on plasma lipids and lipoproteins. The following formulations were studied: a monophasic preparation containing ethinylestradiol and desogestrel (M‐DSG) and two triphasic formulations containing ethinylestradiol and gestodene or levonorgestrel respectively (T‐GSD and T‐LNG). These preparations were studied for six treatment cycles. Total cholesterol and apoprotein B did not change in any group. Low density lipoprotein (LDL) cholesterol was significantly decreased in the groups of women treated with M‐DSG and T‐GSD respectively. No changes were observed in the T‐LNG group. With M‐DSG, significant increases were observed in high‐density lipoprotein (HDL) cholesterol and HDL3 cholesterol, whilst HDL2 cholesterol did not change. With both T‐GSD and T‐LNG, no changes were observed in HDL cholesterol, whilst a significant increase in HDL3 cholesterol together with a trend to decrease in HDL2 cholesterol were observed. Apolipoprotein AI increased with the following ranking M‐DSG > T‐GSD > T‐LNG. The LDL/HDL cholesterol ratio significantly decreased with both M‐DSG and T‐GSD. In the T‐LNG group there was no change in this ratio. Triglycerides increased to the same extent in all treatment groups. As far as concerns the risk of arterial diseases, these three oral contraceptive formulations mostly induced negligible and/or partly favorable changes in plasma lipids and lipoproteins; however, the lipoprotein pattern during M‐DSG treatment resulted better than during T‐GSD, and the latter turned out to be better than during T‐LNG.

Role of growth factors in the human endometrium during aging

The aim of this study was to investigate the possible role of epidermal growth factor (EGF) and of insulin-like growth factor-I (IGF-I) in physiological and pathological changes of the endometrial tissue during aging. Thirty-four patients undergoing hysterectomy were divided into three groups: (A) premenopausal women with regular menses, (B) pre-menopausal women with irregular bleeding and (C) post-menopausal women. Endometrial samples were collected after the removal of uterus and were used for immunohistochemical evaluation of EGF, EGF receptor (EGFr) and IGF-I and also for Northern blot analysis of IGF-I gene expression. Plasma levels of 17 beta-oestradiol (E2), D4-androstenedione (D4-A) and oestrone (E1) were also assayed. The immunohistochemical scores (HSCORES) for EGF, EGFr and IGF-I were significantly higher in groups A and B than in group C. Independently from the menstrual history, significantly higher HSCORES of EGF, EGFr and IGF-I were present in hyperplastic endometrium than in those which were proliferative and atrophic. Moreover, IGF-I mRNA expression was observed in all pre-menopausal women, whereas only 1 post-menopausal women with hyperplastic endometrium showed detectable RNA encoding for IGF-I. Higher levels of D4-A were also significantly correlated (P < 0.05) with higher HSCORES of EGF, EGFr and IGF-I. Our results suggest that the above mentioned growth factors could act as mediators of oestrogens on the endometrial functional activity.

Effects of gonadotrophin-releasing hormone agonist on uterine fibroids and bone density.

Bone density (BD) was evaluated by single photon absorptiometry (SPA) in 18 women treated with Buserelin a gonadotrophin-releasing hormone (LHRH) analogue, for uterine fibroids. Buserelin was administered for a period of 6 mth. Amenorrhoea and oestradiol levels in the follicular-phase range were recorded in all patients during treatment. Fibroid volume was evaluated by means of ultrasound. SPA was performed at the 1/3 proximal radius and at the 1/10 distal radius sites before starting therapy and every 2 mth subsequently for 12 mth. BD was also measured in a control group of 18 normally-menstruating premenopausal women, matched for age and body mass index. No significant changes in BD at the proximal or distal radius sites were observed in either the cases or the controls during the study. Moreover, comparison of the data on the cases and the controls revealed no differences in BD at 0, 6 or 12 mth. Thus, although LHRH analogue treatment proved effective in reducing fibroids, it did not cause any significant changes in BD.

Effect of lisuride on inhibition of lactation and serum prolactin

Lisuride, a new semisynthetic ergot derivative, was given to 53 women to inhibit lactation; 26 women had 300 ug daily and 27 had 600 ug daily for seven days. Eight lactating women acted as controls. Lisuride effectively inhibited lactation and also suppressed the serum prolactin levels; the latter effect was dose related. Lisuride produced no untoward side effects.

Suppression of puerperal lactation by terguride: A double-blind study

Clinical efficacy, prolactin (PRL)-lowering effect and tolerance of terguride (an 8-alpha-ergoline derived from Lisuride which acts as a partial dopaminergic agonist) were investigated in a double-blind study on inhibition of puerperal lactation using three different daily doses of the drug (0.25, 0.5 and 1.0 mg). With 0.5 and 1.0 daily therapeutical regimens PRL levels were suppressed in a dose-dependent manner and lactation was prevented. Terguride was highly well tolerated.

Effects of lisuride and bromocriptine on inhibition of lactation and on serum prolactin levels: Comparative double-blind study

The effects of lisuride (Schering) and bromocriptine (Parlodel, Sandoz), two dopaminergic drugs, on the inhibition of puerperal lactation were compared in a double-blind study. At the dosages selected, lisuride was as effective as bromocriptine for the inhibition of lactation but bromocriptine was more effective in lowering serum prolactin levels.

Effect of terguride on prolactin levels in normal, puerperal and hyperprolactinaemic women

SummaryTerguride, is an 8 — alpha — ergoline derived from lisuride, acts as a partial dopamine (DA) agonist.The effect and tolerance of terguride has been investigated by an acute administration of 0.2 mg p.o. to 8 normal women, 8 patients with hyperprolactinaemia and 8 women with puerperal hyperprolactinaemia. Prolactin (PRL) levels were markedly suppressed in all subjects, with no significant differences between the groups.Treatment for 5 days with terguride 0.4 mg/day or 0.8 mg/day was studied as an inhibitor of lactation. PRL levels were suppressed in a dose-related manner. No untoward side-effects were noted.

Itraconazole Plasma and Vaginal Mucosal Levels in Patients with Chronic Vaginal Candidosis Treated with Itraconazole 200mg Once Daily for 3 Consecutive Days

Summary20 nonpregnant patients with chronic vaginal candidosis were divided randomly into 5 groups of 4 patients. They all received itraconazole 200mg once daily for 3 consecutive days. A blood sample and vaginal biopsy were obtained 1 hour after each administration as well as 25 and 50 hours after the last drug intake. The results show that the itraconazole levels in the vaginal mucosa are comparable with the corresponding blood levels, but that after the end of treatment, drug levels in the vagina remain elevated for much longer than the corresponding blood levels. These data suggest that a regimen of itraconazole 200mg once daily for 3 days results in therapeutic tissue levels at the site of infection for more than 5 days.

The biological basis of medical treatment of endometriosis.

Efficacy of medical treatment for the management of endometriosis has been documented in several trials, but clinical results cannot always be maintained after the suspension of treatment. Surgical treatment, either laparotomic or laparoscopic, is affected by up to 20% in the recurrence of clinical symptoms after long-term follow-up. The appearance of endometriosis is heterogeneous, its functional status is variable and could lack hormone responsiveness. After medical, surgical or combined treatment the persistence of the failure of defence mechanisms accounts for the recurrence of disease. Unfortunately, all schemes to classify stages of endometriosis have so far failed to identify manifestations of the disease that respond in a predictable way to specific treatments. An analysis of the morphological appearance, implant biological activity and immune system involvement might better define the roles for medical management of endometriosis.