Imiquimod 5% cream versus cold knife excision for treatment of VIN 2/3: a five-year follow-up.

BACKGROUND: Vulvar intraepithelial neoplasia (VIN) is a premalingnant condition. For long time, surgery was considered the first-line therapy in the treatment of high grade VIN. Imiquimod was recently introduced as an alternative to surgery. AIM: To compare the overall complete response, the recurrence rate and the risk factors for relapse among patients with VIN 2/3 treated with Imiquimod or surgical excision. PATIENTS AND METHODS: Eighty women who had histological diagnosis of VIN 2 and VIN 3 were enrolled in this prospective study. Patients immunocompromised, with recurrent VIN, with well differentiated type VIN or VIN 1 and women treated more than once were excluded from the study. Patients were divided into two groups: group A was treated with Imiquimod, group B underwent surgical excision. Patients' characteristics analyzed were: age, smoking, degree of the primary lesion, state of margins, multifocal disease. We have evaluated the recurrence rate, the relapse rate, and the overall complete response, considering as recurrence the onset of a lesion after an initial complete response to Imiquimod and/or after the surgical treatment and as relapse all patients who had a recurrence plus those with medical treatment failure. RESULTS: Multifocal lesions (p = 0.03) and VIN 3 (p = 0.002) were associated with a higher risk of relapse. The recurrence rate was higher in the group B (p = 0.009), but the relapse rate was higher in the group A (p = 0.04). The overall complete response was better in the group B (p = 0.04). CONCLUSIONS: Although the advent of new medical options can decrease the morbidity associated with invasive surgical procedures, surgical treatments remain the best treatment modality for VIN with regard to relapse and overall complete response.

Luteinizing hormone-releasing hormone analogue: leuprorelin acetate for the prevention of menstrual bleeding in premenopausal women undergoing stem cell transplantation.

Prevention of uterine bleeding after stem cell transplantation was attempted in 30 consecutive premenopausal women affected by hematological malignancies. This was with luteinizing hormone-releasing hormone (LHRH) leuprorelin acetate depot 3.75 mg administered subcutaneously at least 30 days before the conditioning regimen and then 28 days after the first dose. Complete prevention resulted in all but one patient (96.5%) during the phase of profound thrombocytopenia. No side-effects related to leuprorelin were observed. All patients developed amenorrhea after transplantation. Gonadal function was periodically assessed by means of luteinizing hormone (LH), follicular stimulating hormone (FSH) and estradiol serum levels. Hormone levels were consistent with menopause in all patients. After transplantation, patients required hormone replacement with estroprogestinics or estrogens alone when indicated. Leuprorelin is highly effective in preventing uterine bleeding in premenopausal women undergoing stem cell transplantation and has an excellent toxicity profile and virtually no interface with hemostatic balance and hepatic function. The role of leuprorelin in gonadal protection is currently unclear and deserves further investigations.

Plasma androstenedione and oestrone levels in the climacteric syndrome.

Plasma androstenedione (A) and oestrone (E1) levels were measured by radioimmunoassay in a group of 78 healthy women who had undergone a natural menopause. Of this total, 23 were symptomless (Group 1), 39 presented with a moderate climacteric syndrome (Group 2) and 16 had a severe climacteric syndrome (Group 3). The average body weight was found to be significantly higher in Groups 2 (P less than 0.01) and 3 (P less than 0.05), than in Group 1, but the age distribution and number of years since the menopause were similar in all three groups. Nevertheless, significantly lower levels of A (0.75 +/- 0.06 ng/ml, P less than 0.01, in Group 2; 0.24 +/- 0.05 ng/ml, P less than 0.001, in Group 3) and E1 (20.80 +/- 2.18 pg/ml, P less than 0.05, in Group 2; 12.22 +/- 1.65 pg/ml, P less than 0.001, in Group 3) were observed in the women with climacteric symptoms than in those with no symptoms (A = 1.08 +/- 0.08 ng/ml, E1 = 27.73 +/- 2.22 pg/ml in Group 1). Since, after the menopause, the concentrations of A and E1 in the plasma represent the most important source of oestrogens, these results suggest that climacteric symptoms are related to oestrogen deficiency which is secondary to low A production.

Plasma androstenedione and oestrone levels before and after the menopause. I. Glandular hyperplasia and adenocarcinoma of the endometrium.

Plasma androstenedione (A) levels and plasma oestrone (E1) levels were measured by radioimmunoassay in a total of 135 healthy women (the control group), around the menopause. Both A and E1 plasma levels were found to drop significantly in the post-menopausal women (P less than 0.001). The mean plasma levels of A and E1 found in these healthy women were compared with the same plasma levels found in a total of 96 hospitalized women who were found to have various gynaecological disorders. Out of the total 96 patients, 29 were post-menopausal and had adenocarcinoma of the endometrium. The mean plasma levels of A and E1 were not significantly different in comparison with the norm. The mean body weight of the tumour patients was slightly higher than the mean body weight of the healthy women. There were 25 other patients, around the menopause, who had glandular hyperplasia of the endometrium. The mean plasma levels of androstenedione found in these women were significantly higher than the mean levels found in the healthy group of women; both groups were similar in body weight. The oestrone levels found in these patients were within the normal range. The remaining 42 patients, around the menopause, were affected with dysfunctional uterine bleeding, without endometrial hyperplasia. The plasma androstenedione levels were within the normal range. Oestrone plasma levels were not measured in this group of women. This study investigates the possible differences found in the endocrine plasma levels of women with glandular hyperplasia and adenocarcinoma of the endometrium.

Plasma androstenedione and oestrone levels before and after the menopause. II. Non-endocrine ovarian tumours and cysts.

Plasma androstenedione (A) and oestrone (E1) levels were measured by radioimmunoassay in 45 hospitalized patients who had non-endocrine benign or malignant ovarian tumours or cysts. The findings of these measurements were compared with the findings of the mean steroid levels which we determined previously (see previous article) in 135 healthy women, around the menopause, of similar weight. Of the total number of patients, 26 had non-endocrine benign ovarian tumours and cysts and were in the reproductive and pre-menopausal ages. The mean plasma A level was found to be significantly higher than the normal value (P less than 0.001). However, the plasma E1 level was not different from the norm. The remaining 19 patients, all around the menopause, had non-endocrine malignant epithelial ovarian tumours. The mean plasma levels of both A and E1 were found to be significantly higher (P less than 0.001) than the normal values. Since increased plasma A levels are associated with non-endocrine ovarian tumours and cysts, it seems likely that the measurement of plasma A may be used as an endocrine detector of non-endocrine ovarian tumours.

Gonadotrophin response to releasing hormone in post-menopausal patients with ovarian tumours.

Gonadotrophin response to intravenous administration of 100 micrograms synthetic gonadotrophin-releasing hormone (GnRH) was evaluated in 14 post-menopausal women (aged 53-77) with non-endocrine ovarian tumours and 11 post-menopausal control subjects. Neither in the case of follicle-stimulating hormone (FSH) or luteinizing hormone (LH) levels, was any significant difference seen between the mean basal levels in the tumour and the control subjects. No significant release was seen in either group as regards FSH response. The mean increases in serum FSH in the tumour patients were not significantly different from those in the control subjects. In the case of LH response, the mean percentage increases in the tumour group as well as the mean area under the curves were significantly greater (P less than 0.01) than those in the control subjects. Androstenedione and oestrone levels were also evaluated in the two groups. Significantly increased levels of these hormones were seen in the tumour group in relation to those in the control group (P less than 0.001). These data are consistent with an increased LH response to GnRH in post-menopausal patients with ovarian tumours. The augmented LH release may be related to increased steroid plasma levels.

Four cases of pregnancy with low estrogen production due to placental enzymatic deficiency.

4 cases of normal pregnancies associated with low estriol excretion and resulting in healthy infants are described, in which by in vitro studies on the placentas a steroid 3-sulfatase deficiency was found in 3 cases and a lack of activity of the aromatizing system was found in the 4th case. A reduced activity of the aromatizing system was also shown in one of the cases affected by steroid 3-sulfatase defect. The placental 3 beta-hydroxysteroid dehydrogenase, delta 4,5-isomerase system was measured in 3 cases and results were normal. The repetition of the specific lack of steroid 3-sulfatase was observed in 2 successive pregnancies of the same patient (case T.C.). It is interesting to note that, at variance with other reports, this patient delivered 2 fetuses, both female.

[A zinc sulfate and usnic acid preparation used as post-surgical adjuvant therapy in genital lesions by Human Papillomavirus]. / Terapia adiuvante con un preparato a base di zinco solfato e acido usnico delle lesioni genitali da Human Papilloma virus (HPV) dopo trattamento chirurgico distruttivo.

BACKGROUND: To evaluate the efficacy and safety of intravaginal administration of a zinc sulphate and usnic acid compound as adjuvant therapy of Human Papillomavirus (HPV) genital infection, after radiosurgical treatment (RS). METHODS: One hundred patients affected by HPV genital infection were enrolled in the study from October 1996 to July 1998. Patients were classified according to colposcopic and cytologic criteria and treated with RS. Patients were randomized into three groups: the first group did not follow any therapy after RS (control group), (n = 50); the second group was pharmacologically treated with intravaginal administration of a usnic acid and zinc sulphate compound (Zeta N, Bergamon Italia) before and after RS (n = 25), the third group was pharmacologically treated only after RS (n = 25). The last two groups were considered together for the statistical analysis. Patients were reevaluated after one, two, three and six months from electrocoagulation. The safety of treatment was also investigated. RESULTS: One month after RS. HPV lesions disappeared in 93% of the patients in the control group and in 100% of patients treated with usnic acid and zinc sulphate. After one month, reepithelization was complete in 65% of cases treated with usnic acid and zinc sulphate and in only 28% of the control group (p = 0.001). Two months later reepithelization was 94% in the patients pharmacologically treated compared to 76% of the control group (p = 0.06). Treatment prior to RS resulted in a reduction of the overall area of lesions in 88% of cases. Three months after RS, there was a significant reduction of recurrence in the group treated with usnic acid and zinc sulphate (p = 0.01). This reduction was still significant at six months (p = 0.005). CONCLUSIONS: Usnic acid and zinc sulphate adjuvant treatment improved time of reepithelization and reduce the recurrence with few side effects and a good compliance.

[Therapy of bacterial vaginosis. Prospective clinical study ot the efficacy and tolerability of quaternary ammonium salts vs. clindamycin]. / La terapia delle vaginosi batteriche. Studio clinico prospettico sull'efficacia e tollerabilità dei sali quaternari d'ammonio versus clindamicina.

BACKGROUND: To evaluate the efficacy and safety of intravaginal quaternary ammonium antimicrobial compounds (SQA) versus clindamycin 2% intravaginal cream (CL) in the treatment of bacterial vaginosis (VB). MATERIALS AND METHODS: One hundred-thirty-three patients affected by VB were enrolled in the study from January 1995 to October 1997. Patients were classified according to Amsel's criteria and/or to the indications of the Scandinavian Society of Bacterial Vaginosis. Twenty-three patients were initially excluded from the study, and 110 patients were randomized in two groups, SQA versus CL. Patients were reevaluated after 3 weeks, 3 months and 6 months from the end of therapy. The safety of treatment was also investigated. RESULTS: Of 110 patients, 59 were treated with SQA and 51 with CL. One hundred (90.9%) patients completed the therapy and were subjected to the first control after 3 weeks from the end of therapy. A significant reduction of most of the symptoms and all signs of VB was observed in the group treated with SQA. Similarly, a significant reduction of most of the symptoms (vaginal and urinary in particular) and all signs of VB was observed in the group treated with CL. The percentage of response was 86.7% for SQA group and 87.2% for CL group. Moreover, after 3 months from the end of therapy, 47.2% and 50% of the patients treated with SQA and CL, respectively, recurred, and after 6 months 78.5% and 75% of the patients recurred, respectively. CONCLUSIONS: SQA treatment conferred 86.7% of response after 3 weeks from the end of therapy, with poor side effects and a good compliance in good keeping with the results obtained with CL treatment.

Maternal ultrasound bone density in normal pregnancy.

OBJECTIVES: The aim of the study was to investigate the effect of pregnancy on maternal bone mineral density by an ultrasound device. STUDY METHODS: Two hundred and thirty consecutive healthy pregnant women were evaluated by ultrasound densitometry during the 1st (n=45), the 2nd (n=56) and the 3rd (n=129) trimester of pregnancy, measuring the velocity (SoS) and frequency attenuation (BUA) of an ultrasound wave as it passes through the os calcis. Speed of sound (SoS) and Broadband Ultrasound Attenuation (BUA) values are combined in order to express a relational variable (Stiffness), indicator of bone quality. RESULTS: Statistically significant reductions in SoS, BUD and Stiffness values were observed during the 3rd trimester vs the 1st and the 2nd trimesters. Negative statistically significant relations were found between the gestational age and ultrasound densitometry parameters. CONCLUSION: A linear reduction of ultrasound bone density was observed throughout pregnancy, reaching a statistical significance in the 3rd trimester, when the greatest calcium transfer from the mother to the fetus occurs.

Adjuvant topical treatment with imiquimod 5% after excisional surgery for VIN 2/3.

OBJECTIVE: Vulvar intraepithelial neoplasia (VIN) is a premalignant lesion of the vulva. The incidence of VIN is increasing. The surgery is currently the gold standard therapy for VIN, but Imiquimod could be a completion to surgery. The aim of this study is to compare the overall complete response, the recurrence rate and the risk factors for recurrence among two groups of patients: women with high grade VIN underwent surgery and patients treated with surgery plus Imiquimod. PATIENTS AND METHODS: 80 patients with histologically diagnosed VIN 2/3 were enrolled in this prospective study. Our patients were divided into two groups: 40 women underwent surgery (A) and 40 patients were treated with surgery plus Imiquimod (B). All women had a 5-year follow-up. Recurrence rate and complete response were evaluated. The following patients' characteristics were analyzed: smoke, multifocal disease, multicentric disease, degree of the lesion. RESULTS: In the group A recurrence rate was 44.8%, in the group B it was 48.4%. In both groups the presence of multifocal lesions (p = 0.02) and VIN 3 (p = 0.006) before treatment was associated with a higher risk of recurrence. CONCLUSIONS: This study found that surgery remains the principal approach for VIN with regard to relapse and complete response since the treatment with Imiquimod associated with surgery didn't show a lower recurrence rate. Although the surgical treatments remain the best therapeutic option for VIN with regard to recurrence and overall complete response, the combined therapy seems to be an interesting modality, but further studies are needed.

HPV-DNA testing for cervical cancer precursors: from evidence to clinical practice.

The large amount of literature published over the last two decades on human papillomavirus (HPV)-DNA testing has definitely demonstrated the association between high-risk viral genotypes (hrHPV) and cervical cancer. Moreover, hrHPV-DNA testing has shown excellent performance in several clinical applications, from screening settings to the follow-up of treated patients, compared to conventional cytology or colposcopy options. On the other hand, when a huge number of reports are published on the same subject in a relatively short period of time, with many variations in settings, study designs and applications, the result is often confusion and decreased comprehension by readers. In daily office practice, several different situations (in symptomatic or asymptomatic women) can be positively managed by the correct use of hrHPV-DNA testing. Validated hrHPV-DNA testing and, specifically, the HC2® assay, due to its excellent sensitivity and negative predictive value together with optimal reproducibility, currently represent a powerful tool in the clinician's hands to optimally manage several situations related to HPV infection and the potential development of cervical cancer.

Human placental delta 5-3 beta-hydroxysteroid dehydrogenase, delta 4,5 isomerase: in vitro effect of dehydroepiandrosterone and allyestrenol.

The in vitro effects of dehydroepiandrosterone (DHA) and allylestrenol on human placental delta 5- 3 beta-hydroxysteroid dehydrogenase, delta 4,5 isomerase activity (delta 5-3 beta-HSDH) was investigated by incubation of subcellular fractions with [4-14C] pregnenolone. It has been found that DHA inhibits the delta 5-3 beta-HSDH activity up to -81% at 5 X 10-5 M concentration while allylestrenol seems to be able to lightly stimulate the delt a 5-3 beta-HSDH activity with a maximum effect (+15-26%) at 5 X 10-7 M concentration. The data concerning allylestrenol, seem of particular interest as this compound is used as a progestative drug during pregnancy, if one consider the inhibitory effect exerted by several natural and synthetic steroids on the delta 5-3 beta-HSDH activity.

Effects of dehydroepiandrosterone and 16 alpha-hydroxydehydroepiandrosterone on the reduction of glucose to glucitol by the human placenta.

The metabolism of glucose by subcellular preparations of human full term placentae has been investigated. It has been shown that in the presence of NADPH two transformation products can be detected of which one has been identified as glucitol. The effects of dehydroepiandrosterone and 16alpha-hydroxydehydroepiandrosterone on the reduction of glucose to glucitol have also been studied. It has been found that at a concentration of DHA 1.2 X 10(-4)M, the reduction of glucose is strongly inhibited (35-51%), while at a concentration of DHA 5.8 X 10(-6)M this reaction is stimulated by 13 +/- 2.3%. 16alpha-hydroxyepiandrosterone at concentrations ranging from 1.2 X 10(-4)M to 3 X 10(-6)M inhibits the formation of glucitol from 63% to 9%.

Diagnostic significance of steroid hormones in patients with ovarian cancer.

One hundred and fourteen pre- and postmenopausal patients with nonendocrine tumors or simple cysts of the ovary were studied. These patients had androstenedione (A) plasma levels determined preoperatively. Some of these subjects had estrone (E1) and 17 beta-estradiol (E2) determinations also. Of the tumor patients, 58 had also measured the postoperative steroid levels. The results were compared with the hormone levels found in 188 normal women, who were of similar weight and reproductive status. Significantly increased (p less than 0.001) A, E1 and E2 plasma concentrations were found in postmenopausal patients with nonfunctioning tumors. In the tumor patients before the menopause, the levels of A were significantly elevated (p less than 0.001). In the patients with simple cysts, these steroid levels were within the normal range. Following ovariectomy, the decrease of plasma A suggested that the origin of the high levels of this steroid was the ovary where the neoplasm resided. For possible diagnostic purposes, both A and E1 abnormal test results showed adequate sensitivity and good specificity to permit detection of ovarian carcinoma after the menopause. Plasma levels of A were partially related to the histological types and FIGO Stages of the tumor.

Ovarian and peripheral steroid hormones in a case of Sertoli-Leydig cell tumor.

The clinical course, histology, and steroid secretion of a 59-year-old postmenopausal woman with a 4-yr history of virilizing well-differentiated Sertoli-Leydig cell tumor of the right ovary are reported. Hormone secretion was examined by measuring peripheral and ovarian venous gradients and pre-and postoperative levels of some delta 4 and delta 5 steroids, estrogens, gonadotropins and Sex Hormone Binding Globulin levels. The preoperative responsiveness to ACTH, dexamethasone and hCG is also reported. The results are consistent with a Sertoli-Leydig cell tumor producing mainly testosterone and, to a lesser degree, androstenedione, progesterone, estrone and 17 alpha-hydroxyprogesterone. The tumor hormone secretion may be in part responsive to hCG.

A case of mucinous cystadenocarcinoma of the ovary associated with virilization: pre and post-operative steroid plasma levels.

A premenopausal woman with a mucinous carcinoma of one ovary, and a mucinous adenoma of the other, together with secondary virilization, is reported. Preoperative levels of androstenedione, testosterone and dehydroepiandrosterone sulphate were high, suggesting the presence of a virilizing tumor. Preoperative plasma estrone (E1), but not estradiol (E2), was elevated along with inversion of the E2/E1 ratio, suggesting a peripheral origin of the estrogens. FSH and LH plasma concentrations were low. After bilateral ovariectomy, levels of all steroids measured significantly decreased and gonadotropins rose to the postmenopausal range.