Fabrizio Pollio

Clinical response, vascular change, and angiogenesis in gonadotropin-releasing hormone analogue-treated women with uterine myomas

Objective: Basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) are involved in the pathogenesis of leiomyomas and influence angiogenesis, which is necessary for growth of leiomyomas. Gonadotropin-releasing hormone analogue (GnRH-a) treatment might modify the growth factor expression and the blood supply in myomas. We investigated the effects of GnRH-a treatment on some clinical parameters, on the immunohistochemical expression of bFGF, VEGF, and PDGF, and on the vasculature of leiomyomas. Methods: Thirty-one women were treated with leuprolide acetate for 3 months; 55 untreated patients formed the control group. Hematologic parameters were assessed at the admission, after GnRH-a treatment, and after surgery. Uterine volume was evaluated by ultrasonography. The immunoexpression of bFGF, VEGF, and PDGF and of the endothelial markers CD34 and CD105, as well as the vascular pattern, were studied in leiomyomas, comparing treated and untreated patients. Results: Hematologic parameters improved and uterine volumes decreased after GnRJH-a treatment. The immunoexpression of bFGF, VEGF, and PDGF decreased in treated myomas, together with the total number of vessels and the angiogenetic vessels. Conclusion: This study confirms the clinical response of uterine shrinkage after GnRH-a treatment. A pathogenetic role of bFGF, VEGF, and PDGF in myoma growth and vascularization is suggested. Finally, this study indirectly confirms the importance of the vasculature in leiomyoma growth.

Preoperative administration of GnRH-a plus tibolone to premenopausal women with uterine fibroids: evaluation of the clinical response, the immunohistochemical expression of PDGF, bFGF and VEGF and the vascular pattern.

Aim of the study is to compare the effects of preoperative therapy with tibolone plus gonadotropin-releasing hormone analogue (GnRH-a) in premenopausal women with those of GnRH-a alone on clinical response, uterine volume, immunohistochemical expression of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and vascular features of myomas. Seventy women with symptomatic uterine fibromatosis were treated for four months with leuprorelin acetate alone or plus tibolone. Untreated patients were submitted to uterine surgery directly. Uterine volume, hematological data, BMD, myoma-related symptoms and hot flushes were evaluated at the admission and before surgery. Immunohistochemical expression of PDGF, bFGF and VEGF, vascular changes and CD105 expression, as a marker of angiogenesis, were evaluated in myomas obtained after surgery. Uterine volume and myoma-related symptoms reduced and hematological variables increased in treated patients. BMD decreased in patients treated with GnRH-a alone. Hot flushes were less in GnRH-a plus tibolone group than in GnRH-a group. Immunohistochemical expression of PDGF, bFGF and VEGF, vascularization and angiogenesis reduced in treated patients in comparison with untreated ones. In conclusion, the administration of tibolone plus GnRH-a before uterine surgery does not change the clinical and immunohistochemical effects of GnRH-a alone.

Preoperative Treatment of Uterine Leiomyomas: Clinical Findings and Expression of Transforming Growth Factor-β3 and Connective Tissue Growth Factor

Objective: To evaluate the clinical features and the expression of transforming grwoth factor-β3 (TGF-β3) and connective tissue growth factor (CTGF) in myometrium and uterine leiomyomas after preoperative treatment with gonadotropin-releasing hormone-analogs (GnRH-a) and tibolone. Methods: Twenty-three patients received 3.75 mg leuprolide acetate depot for 4 months. Twenty-two ptients received the same therapy plus 2.5 mg tibolone daily. Patients underwent uterine surgery after therapy. Twenty-two untreated patients underwent surgery directly. Hematologic tests, bone mineral density (BMD) measurement, and ultrasonographic evaluation of uterine volume were performed before and after treatment. Menorrhagia and pelvic pain were evaluated with a visual analog scale. Hot flushes were recorded in daily diaries. Immunohistochemical expression of TGF-β3 and CTGF in myometrium and myoma samples was evaluated semiquantitatively. Results: After therapy, hemoglobin and iron levels similarly increased in both groups. BMD significantly decreased only in the GnRH-a group. Uterine volume similarly decreased in both groups. No patient had menorrhagia or pelvic pain at the end of therapy. The number of hot flushes increased after the first month in the GnRH-a group; in the GnRH-a plus tibolone group, it remained constant and was lower. In untreated cases, TGF-β3 and CTGF smooth muscle cell immunoexpression was lower in myometrium than in leiomyomas. After medical treatment, growth factor immunoexpression remained unchanged in myometrial samples and was reduced in leiomyomas. Endothelial cells showed strong immunopositivity, both in untreated and in treated cases. Conclusion: This study focuses on the effects of GnRH-a and tibolone on TGF-β3 and CTGF expression in myometrium and myomas and supports the hypothesis of a pathogenetic role of these growth factors in uterine fibromatosis.

Effects of gonadotropin-releasing hormone agonists on uterine volume and vasculature and on the immunohistochemical expression of basic fibroblast growth factor (bFGF) in uterine leiomyomas.

We investigated the effect of the GnRH agonist (GnRH-a) on the uterine volume and on the immunohistochemical expression of basic fibroblast growth factor (bFGF) and the vasculature of leiomyomas. Twenty-five women were treated with leuprorelin acetate for 3 months; 46 untreated patients were enrolled as a control group. The uterine volume was measured by ultrasonography. After myomectomy or hysterectomy, the immunoexpression of bFGF and the endothelial marker, CD34, was studied and compared in treated and untreated leiomyomas. Uterine volume decreased after therapy. The number of cells expressing bFGF and the vascularity were diminished in treated leiomyomas. Reduction in the blood supply might be responsible, in part, for uterine-volume shrinkage after GnRH-a therapy.

Telecardiotocography in prenatal telemedicine

Sir, Prenatal telemedicine aims to extend specialized medical expertise to pregnant women who cannot access specific prenatal clinical services, either because of logistical difficulties or in emergencies. Some realtime digital systems for monitoring the fetal heart rate (FHR) in the patient’s home by telephone have been reported in previous studies of prenatal telemedicine programmes1–4. We have established a prenatal telemedicine project in Italy based on FHR monitoring obtained by computerized telecardiotocography. The system operates in three phases: first, cardiotocographic information is recorded at a peripheral location using remote data-collection units; second, the data are transmitted via modem to an operations centre; and third, the data are analysed at the operations centre and a report is faxed back to the peripheral unit.

Atrial natriuretic factor in amniotic fluid and in maternal venous blood of pregnancies with fetal cardiac malformations and chromosomal abnormalities.

Objective: We evaluated the levels of atrial natriuretic factor (ANF) in amniotic fluid and in maternal venous blood in pregnancies with fetal cardiac malformations and chromosomal abnormalities. Method: Between the 16th and 18th week of pregnancy, 151 women were divided into three groups. Group A included patients at lowest risk, carrying a fetus with a normally developing heart and normal karyotype (control group). Group B included women with a fetus suffering from cardiac malformations, with or without associated chromosomal abnormalities. Group C included women carrying a fetus affected with chromosomal abnormalities without congenital cardiopathies. ANF was evaluated by radioimmunoassay. Results: In maternal venous blood, the mean levels of ANF were 42.1, 53.1 and 38.7 pg/ml in groups A, B and C, respectively. In amniotic fluid, the mean levels of ANF were 34.2, 101.8 and 35.8 pg/ml in groups A, B and C, respectively. In group A (control group) there was no statistical difference in ANF levels across the gestational age range of 16-18 weeks, either in amniotic fluid or in maternal venous blood. A significant difference of ANF content in maternal venous blood was revealed in comparing group A with group B (p < 0.01), and group C with group B (p < 0.01). A statistically significant difference in ANF levels was also found in amniotic fluid between group A and group B (p < 0.01), and between group C and group B (p < 0.01). No statistically significant differences were found between group C and group A in comparing ANF levels in maternal venous blood and amniotic fluid. Conclusion: ANF levels in amniotic fluid and in maternal venous blood are increased early in the case of fetuses with cardiac malformations, with or without associated karyotype alteration. Chromosomally abnormal fetuses without heart malformations have normal ANF levels. These results could be useful for elucidating fetal pathophysiology mechanisms.

Severe secondary postpartum hemorrhage 3 weeks after cesarean section: Alternative etiologies of uterine scar non‐union

A case of secondary postpartum hemorrhage that occurred 3 weeks after cesarean section requiring total abdominal hysterectomy is reported. The patients history and pathologic features of the removed uterus did not allow the authors to clearly recognize a previous reported cause of this potentially life‐threatening complication. Alternative causes of the non‐union of the uterine incision are suggested.

Expression of proliferating cell nuclear antigen and Bcl-2 during a pseudomenopausal state induced by presurgical treatment of uterine leiomyomas with gonadotropin-releasing hormone analogues plus tibolone

Gonadotropin-releasing hormone analogues (GnRH-a) are widely used for the preoperative treatment of uterine leiomyomas in premenopausal patients. They induce a pseudomenopausal hypoestrogenic state, resulting in decreased uterine and fibroid volumes, significantly improved preand postoperative hemoglobin and hematocrit, and reduced intraoperative blood loss. After pretreatment with GnRH-a therapy, hysterectomy seems to be easier, the operating time is reduced, and a greater proportion of hysterectomies can be performed avoiding the abdominal approach (1). The low estradiol levels induced by GnRH-a treatment may cause hypoestrogenism-related side effects, such as hot flushes and bone loss, that occur even during shortterm therapies (2). Tibolone, a tissue-selective synthetic steroid [(7a,17a)17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3one] with combined progestogenic, estrogenic, and androgenic properties, is used as hormone replacement therapy and to prevent osteoporosis in postmenopausal women (3). The compound itself does not bind with high affinity to any of the known steroid receptors (4). Depending on the activity of the different enzymes during passage through the intestine and liver, tibolone can be converted by 3b-hydroxysteroid dehydrogenase into its D isomer or its 3b-derivative and/or by 3a-hydroxysteroid dehydrogenase into its 3a-reduced derivative (5). In contrast to tibolone itself, these metabolic products show higher affinity binding to several steroid receptors; D-tibolone binds to progesterone and androgen receptors, and 3a-OH-tibolone and 3b-OH-tibolone bind to estrogen receptors (4). Tibolone is reported to increase bone mass density and to have beneficial effects on hypoestrogenic symptoms. It does not cause uterine bleeding in most women and has no proliferative effects on the endometrium (6). Tibolone has been shown to be a good add-back agent to GnRH-a, even in the short-term preoperative treatment of women with uterine fibroids (2). It reduces the menopausal-like symptoms without influencing the therapeutic effects of GnRH-a (7). The mechanism by which GnRH-a treatment causes uterine and fibroid volume shrinkage is still unclear. Decreased cell proliferation and increased apoptosis are among the hypotheses, but data are conflicting. Routine histological examinations of leiomyomas after GnRHa administration have failed to show changes in cell proliferation (8). However, some authors reported reduced expression of Ki67 and/or proliferating cell nuclear antigen (PCNA), which label proliferating cells (9,10); others found significant overexpression of PCNA antigen and significant elevation of Ki67 antigen after GnRH-a therapy (11). The expression of the inhibitor of apoptosis Bcl-2, which controls the survival and death of cells, has been From the Department of Obstetrical-Gynaecological and Urological Science and Reproductive Medicine (M.D.F., F.P., M.P., F.C., A.D.L.) and Department of Biomorphological and Functional Science (S.S., G.S., G.M.), University ‘‘Federico II’’ of Naples, Napoli, Italy. Address correspondence and reprints requests to Prof. Andrea Di Lieto, Via L. Giordano, 120-80127 Naples, Italy. E-mail: dilieto@unina.it International Journal of Gynecological Pathology 24:286–291, Lippincott Williams & Wilkins, Baltimore 2005 International Society of Gynecological Pathologists