Indication of hysteroscopy in tamoxifen treated breast cancer patients.

The aim of this study was to indicate the patients treated with tamoxifen for breast cancer in which hysteroscopy with biopsy should be considered mandatory. 414 breast cancer patients who underwent hysteroscopy with bioptic evaluation were enrolled in the study. 334 subjects were treated with 20 mg of tamoxifen daily as adjuvant therapy for six up to a hundred months. Of the remaining 80 control patients, which had not received tamoxifen, 30 were in premenopause (Group IA) and 50, in postmenopause (Group IIA). The tamoxifen-treated patients were subdivided in premenopausal (Group IB = 72 patients) and in postmenopausal (Group IIB = 262 patients) groups. All patients were further classified in asymptomatic or symptomatic groups considering whether uterine bleeding was absent or present. The evaluation of the endometrial mucosa was performed by office hysteroscopy. In group IIB patients presenting uterine bleeding, malignant lesions were found in 7.8% of the cases. The incidence of premalignant and malignant lesions in IIB patients treated for longer than 3 years (11.7%) was higher than that observed in IIB patients treated for less than 3 years (1.3%). There was a significant difference in terms of endometrial pathology between Group IIB (32.8%) and Group IIA (8%) (p < 0.001); and between Group IIB (32.8%) and Group IB (13.9%) women (p = 0.003). Among IA and IIA patients there were no cases of endometrial hyperplasia or cancer; on the contrary, in IB and IIB women, 2 and 22 cases of atypical hyperplasia were observed, respectively. All cases of endometrial cancer were observed in Group IIB and had a diagnosis of poor prognosis. In conclusion the hysteroscopy with biopsy should be considered the first diagnostic procedure to perform in tamoxifen-treated postmenopausal patients presenting uterine bleeding and in postmenopausal women treated for longer than 3 years. In premenopause, hysteroscopy should be proposed to women with ultrasonographic abnormalities and/or with uterine bleeding to patients at high risk for endometrial cancer.

Expression and prognostic significance of urokinase and plasminogen activator inhibitor type-1 in endometrial hyperplasia and cancer.

Proteolytic enzymes, like urokinase (uPA) and plasminogen activator inhibitor type-1 (PAI-1), are involved in remodelling tissues during invasion and metastasis of tumor cells. The purpose of the study is to evaluate the expression and the prognostic significance of these enzymes in endometrial hyperplasia and cancer. We used immunohistochemical staining to localize uPA and PAI-1 antigens and evaluate their expression, and the enzyme-linked immunosorbent assay (ELISA) to measure their levels during the progression of endometrial carcinoma. The results show that the levels of uPA and PAI-1 detection are systematically weak in simplex hyperplasia and are moderate in complex hyperplasia. In the endometrial carcinoma a very strong reaction was observed in the most aggressive variant of epithelial tumors. A positive signal for uPA was found only in the cytoplasm of normal and hyperplastic cells while, in tumors, uPA was present also in the cellular areas surrounding the neoplastic glands and at the apex of the malignant cells. The PAI-1 immunoreactivity was weak to moderate in 95.4% of carcinomas, with a diffuse signal mostly distributed in the cytoplasm of neoplastic cells and tumor stroma. UPA antigen concentrations were significantly higher in endometrial carcinoma than in endometrial hyperplasia (p<0.05) and in normal endometrium (p<0.001). PAI-1 antigen concentrations in carcinoma samples were significantly higher than in normal endometrium (p=0.002), but the difference was not statistically significant with respect to that in endometrial hyperplasia. We did not find any correlation between uPA and PAI-1 concentrations and the standard prognostic parameters for evaluating endometrial carcinoma. In conclusion, this study demonstrates that in hyperplastic endometria and in endometrial carcinoma there is a progressive increase in expression of uPA and PAI-1 than in normal endometrial tissue. In carcinoma tissues, the high expression of uPA is unregulated in the surrounding stroma tissue, particularly in the most aggressive histopathologic variants. UPA and PAI-1 may be factors associated with invasive behavior in endometrial carcinoma independent of other clinicopathological parameters.

Activin A and inhibin B in extra-embryonic coelomic and amniotic fluids, and maternal serum in early pregnancy.

Activin A and inhibin B levels were measured, using a two-site enzyme immunoassay, in extra-embryonic coelomic fluid, amniotic fluid and maternal serum samples retrieved from 23 healthy pregnant women, at 8 (n=8), 9 (n=8), and 10 (n=7) weeks of gestation. Dimeric activin A and inhibin B were measurable in all samples. Median (+/-SEM) activin A concentrations in coelomic fluid (0.98+/-0.34 ng/ml) were significantly higher than in maternal serum (0.68+/-0.05 ng/ml) and in amniotic fluid (0.09+/-0.04 ng/ml) (P<0.05). Maternal serum activin A levels were significantly higher than amniotic fluid concentrations. Median (+/-SEM) inhibin B concentrations in coelomic fluid (24.32+/-6.02 pg/ml) were significantly higher than in maternal serum (5.94+/-0.97 pg/ml) and in amniotic fluid (6.31+/-1.53 pg/ml) (P<0.05), while no significant difference between maternal serum levels and amniotic fluid concentrations was found. No significant difference in activin A and inhibin B levels in extra-coelomic fluid, amniotic fluid, and maternal serum throughout the 3 weeks of pregnancy was found. The present study showed that coelomic fluid is an important reservoir of activin A and inhibin B, supporting the hypothesis that the extra-embryonic coelom may have a secretory role during the first 11 weeks of gestation.

Prospective evaluation of calcium and estrogen administration on bone mass and metabolism after ovariectomy.

We evaluated the effects of low-dose ethinylestradiol administration in the prevention of the rapid bone loss that follows ovariectomy in women. After 10-30 days from surgery, patients received either a sole calcium supplementation 500 mg/day (n = 20) or ethinylestradiol 20 micrograms/day in addition to the same daily calcium supplement (n = 21), for 12 months. In the control group, urinary hydroxyproline excretion, serum alkaline phosphatase and plasma bone Gla protein levels presented a substantial (p < 0.05) increase, while radial bone density significantly (p < 0.05) decreased 6 months after surgery. In the ethinylestradiol-treated group, the patterns of biochemical markers indicated that ethinylestradiol can restrain the bone remodelling processes. Radial bone density showed no significant modification during the 12 months' study period. In conclusions, these results demonstrate that the administration of 20 micrograms/day of ethinylestradiol can prevent the rapid bone loss that follows ovariectomy.

Treatment of postmenopausal vertebral osteopenia with monofluorophospate: a long-term calcium-controlled study.

The aim of the present study was to assess the effects of the new fluorine pro-drug monofluorophosphate (MFP) in postmenopausal women with vertebral osteopenia and high bone turnover. We enrolled postmenopausal women (PMW, 43-59 years) who had had a natural menopause 2-5 years before the study, had vertebral bone mineral density (BMD) < 1 SD from the premenopausal mean, and had at least one of the biochemical markers of bone remodeling > 1 SD over the mean for premenopausal women. Patients were randomly divided into two treatment groups (group 1, 500 mg/day of oral calcium; group 2, MFP at the dose of 20 mg F-equivalents + 600 mg calcium/day) for 2 years (n = 21 in each group). The lumbar vertebral (L2-4) BMD and total body bone mineral (TBBM) were measured by dual-energy X-ray absorptiometry (Lunar DPX, Lunar Corporation, USA). Urinary hydroxyproline excretion (OH-P/Cr), plasma bone Gla protein (BGP) and serum alkaline phosphatase (AP) were assayed. In group 1 the markers of bone turnover and vertebral BMD did not show any significant modification, while TBBM showed a significant (p < 0.05) decrease after 24 months. In group 2 a significant (p < 0.05) decrease in OH-P/Cr (-23.9 +/- 2.0%), and an increase in both BGP (+19.4 +/- 2.6%) and AP (+10.3 +/- 2.6%) levels were observed after 24 months of MFP administration. In this group, both vertebral BMD (+5.01 +/- 0.9%, p < 0.01) and TBBM (+4.0 +/- 0.6%, p < 0.05) showed a significant increase after 24 months. Present results suggest that, in osteopenic PMW, MFP administration induces a significant increase in vertebral BMD without impairment of cortical bone, with a reduction in bone resorption and an increase in bone formation rate.

Hormone replacement therapy in perimenopausal women with a low dose oral contraceptive preparation: effects on bone mineral density and metabolism.

In a 2-year longitudinal, calcium-controlled study we evaluated bone density and metabolism in perimenopausal women with initial ovarian failure, and the effects of hormone replacement with a low dose oral contraceptive preparation (OC). In perimenopausal oligomenorrhoic women (n = 16) a significant (P < 0.01) increase in cycle length and plasma FSH levels as well as a parallel decrease in plasma estradiol levels (P < 0.01) were evident. In this group, despite the calcium supplementation (500 mg/day), a significant (P < 0.001) increase in the biochemical markers of bone remodelling paralleled a significant (P < 0.001) decrease (-3.4% after 24 months) in bone density. Conversely, in premenopausal oligomenorrhoic women treated with a low dose oral contraceptive (OC) formulation (30 mcg ethinyl estradiol plus 75 mcg gestodene, n = 16), bone markers showed a significant (P < 0.01) decrease, that paralleled a slight but significant (P < 0.01) increase (+1.71%) in bone density. These data suggest that premenopausal administration of OC can prevent the acceleration of bone turnover and reverse the decrease in bone density that follows the premenopausal impairment of ovarian function.

Ipriflavone prevents the bone mass reduction in premenopausal women treated with gonadotropin hormone-releasing hormone agonists.

In the present study we assessed the effects of ipriflavone in the prevention of increased bone turnover and the rapid bone loss that follows medical induced hypogonadism caused by the administration of a gonadotropin hormone-releasing hormone agonist (GnRH-A). In a double blind, placebo-controlled study, ipriflavone (600 mg/day, tdd (three divided doses)) or identical placebo tablets were given with 500 mg/day of calcium to patients treated with 3.75 mg leuproreline acetate every 30 days, for 6 months. In placebo-treated subjects (n = 39), urinary hydroxyproline excretion and plasma bone GLA protein levels showed a substantial (P < 0.01) increase, while spine bone density and total body bone density significantly (P < 0.01) decreased after 3 and 6 months of GnRH-A administration. Conversely, in ipriflavone treated group (n = 39), no significant difference in bone markers and bone density was evidenced. These data indicate that ipriflavone can restrain the bone remodeling processes and prevent the rapid bone loss that follows medical induced hypogonadism. Thus, ipriflavone administration can be of value in the prevention of osteopenia in women treated with GnRH-A.

Longitudinal evaluation of perimenopausal vertebral bone loss: effects of a low-dose oral contraceptive preparation on bone mineral density and metabolism.

OBJECTIVE: To characterize the pattern of biochemical markers of bone metabolism and vertebral bone mineral density in eumenorrheic and oligomenorrheic perimenopausal women and to assess the effects of a combined oral contraceptive (OC) preparation on bone mass and metabolism. METHODS: Bone biochemical markers and vertebral bone density were evaluated in a longitudinal 2-year follow-up study conducted in healthy, normally menstruating perimenopausal women, perimenopausal oligomenorrheic women, and age-matched oligomenorrheic OC-treated women (20 micrograms ethinyl estradiol [E2] plus 0.15 mg desogestrel) (n = 27 in each group). The results were analyzed by factorial or repeated-measures analysis of variance, as appropriate. RESULTS: During our observation period, there were no significant modifications in menstrual cycle, plasma FSH and E2 levels, biochemical markers of bone turnover, and vertebral bone density in normal women. Conversely, oligomenorrheic women showed an increase in the cycle length with a concomitant decrease of plasma E2 and a corresponding rise in circulating plasma FSH levels (P < .05). In this group, an increase in both urinary excretion of hydroxyproline and plasma osteocalcin levels paralleled a significant decrease in vertebral bone density (P < .0001). In OC-treated women, the pattern of osteocalcin showed no modification, whereas urinary excretion of hydroxyproline showed a decrease, which paralleled a significant (P < .001) increase in vertebral bone density. CONCLUSION: Perimenopausal OC administration can prevent the increase in bone turnover and the decrease in bone density that follow the perimenopausal impairment of ovarian function.

Bone loss in perimenopausal women: a longitudinal study.

A longitudinal evaluation of bone mineral density (BMD) and metabolism was performed in premenopausal women. During the 2-year observation period, the menstrual pattern, plasma estradiol and FSH levels as well as the values of bone markers and BMD did not show any significant modification in a group of eumenorrhoic women (n = 37). Conversely, in age-matched oligomenorrhoic women (n = 37) a significant (P < 0.05) increase in the cycle length with a concomitant significant (P < 0.05) increase in circulating plasma FSH and parallel decrease of plasma estradiol levels (P < 0.05) was evident. In this group a significant (P < 0.05) increase in both urinary excretion of OH-P/Cr and plasma BGP levels paralleled a significant (P < 0.05) decrease in radial BMD. These data suggest that premenopausal impairment of ovarian function can lead to a bone loss in a significant proportion of women in which prevention should be considered before menopause.

The relative contributions of menopause and aging to postmenopausal vertebral osteopenia.

Lumbar spine bone mineral density (BMD) was measured by dual energy x-ray absorptiometry in 2190 normal postmenopausal women (PMW). BMD was loosely correlated (r = 0.15) with height, but stronger positive relations were found with body mass index (BMI; r = 0.25) and body weight (r = 0.31). BMD decreased with age (r = 0.25), but the relation with years since menopause (YSM) was the most potent (r = 0.36). BMD shows a rapid and highly significant (P < 0.0001) decrease in the first 5 YSM, when no relation between BMD and age is present. As the menopausal bone loss is not linear, the BMD values were regressed on the logarithmic transformation of YSM, and the equation was y = -0.183 logYSM + 1.149 (r = 0.44; P < 0.0001). When lumbar BMD was simultaneously regressed on different variables, the correlation with BMI and logYSM remained highly significant, whereas the correlation with age was not significant. The age-related component accounts for a linear 0.4% decrease/yr, starting at the age of 55 yr. In 139 pairs of PMW up to and over 60 yr of age (58 +/- 1.9 and 62.5 +/- 1.5 yr, respectively), matched for YSM (10.3 +/- 2.3), no significant differences in height, weight, or BMI were found. The BMD was significantly (P < 0.001) lower in the younger (0.945 +/- 0.13 g/cm2) than in older PMW (1.006 +/- 0.18 g/cm2) despite their identical YSM. In conclusion, the menopausal (hormonal) component of bone loss and a younger at the menopause represent the major factors in determining involutional vertebral osteopenia in women.

Effects of ipriflavone administration on bone mass and metabolism in ovariectomized women.

The aim of the present study was to assess the effects of ipriflavone administration in the prevention of the rapid bone loss that follows ovariectomy in women. After 10-30 days from bilateral ovariectomy, patients received either the sole calcium supplementation (500 mg/day, n = 16) or ipriflavone (600 mg/day, n = 16) in addition to the same daily calcium supplement for 12 months. In calcium-treated subjects urinary hydroxyproline excretion, serum alkaline phosphatase and plasma bone Gla protein levels showed a substantial (p < 0.01) increase, while radial bone density significantly (p < 0.01) decreased 6 months after surgery. In ipriflavone treated group the patterns of biochemical markers indicated that ipriflavone can restrain the bone remodeling processes and radial bone density showed no significant modification during the 12 month study period. These results demonstrate that ipriflavone administration prevents the rapid bone loss that follows ovariectomy. Thus, ipriflavone can represent an attractive alternative for the prevention of osteoporosis in postmenopausal women who present contraindications to the estrogen replacement therapy.

Effects of continuous and cyclic nasal calcitonin administration in ovariectomized women.

The aim of the present study was to assess the effects of continuous and cyclic salmon calcitonin (sCT) administration in the prevention of the rapid bone loss that follows ovariectomy in humans. Patients who had undergone bilateral ovariectomy 10-30 days previously received either calcium supplementation alone (500 mg/day, n = 12) or such supplementation together with nasal sCT (200 IU/day) according to a continuous (n = 20) or a cyclic (3 months on, 1 month off) regimen (n = 16) for 2 years. In the calcium-only-treated subjects urinary hydroxyproline excretion, serum alkaline phosphatase and plasma bone Gla protein levels showed a substantial increase (P < 0.01) 6 months after surgery, while radial bone density was found to have decreased significantly (P < 0.01). The patterns of biochemical markers in the sCT-treated groups indicated that nasal sCT can positively uncouple the two bone remodelling processes without inducing any significant change in radial bone density over a 2-year period. No differences were observed between the two sCT-treated groups. These results demonstrate that the rapid bone loss that follows ovariectomy can be prevented by either cyclic or continuous nasal sCT administration. Thus, cyclic nasal sCT represents an attractive alternative for the prevention of osteoporosis in postmenopausal women with contraindications to oestrogen replacement therapy.