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Histological findings of endometrial specimens collected by hysteroscopy from 261 postmenopausal breast cancer patients with tamoxifen treatment (group I) and from endometrial specimens obtained following hysterectomy from 40 similar patients (group II) were compared. This comparison was performed in order to assess whether endometrial pathologies are more frequently diagnosed in specimens collected by hysterectomy than by those collected during hysteroscopy in such patients. Overall positive endometrial histological findings were significantly more common in group II patients than in group I patients (82.5 and 24.5%, respectively; p < 0.0001). Atrophic endometrium was significantly more common in group I patients than in group II patients (75.5 and 15.0%, respectively; p < 0.0001). All other different endometrial pathologies, except for proliferative endometrium, were significantly more common in group II patients than in group I patients (endometrial hyperplasia = 17.5 and 4.2%, respectively; p < 0.0003; endometrial polyps = 30.0 and 11. 5%, respectively; p < 0.006; endometrial polyps with hyperplasia = 17.5 and 4.2%, respectively; p < 0.0003; endometrial carcinoma = 15. 0 and 0.4%, respectively; p < 0.0001). These findings suggest that in postmenopausal breast cancer patients treated with tamoxifen, the frequency of various endometrial histological findings and of overall positive endometrial histological findings were significantly higher in specimens collected by hysterectomy than in specimens obtained by hysteroscopy.

In order to assess possible ovarian cell potential for interaction with tamoxifen, thus demonstrating possible effects of this agent on the development of ovarian pathologies through growth stimulation and cell proliferation, we measured estrogen receptors (ER) and progesterone receptors (PR) by immunohistochemical method in 16 benign ovarian tumors removed from 11 postmenopausal breast cancer patients treated with tamoxifen (study group). The results were compared with those measured in 7 similar ovarian tumors obtained from 5 similar patients without tamoxifen treatment (control group I), and in 9 similar tumors removed from 9 age-matched postmenopausal women (control group II). There were no significant differences with regard to ER or PR expression between the study group and control group I and II (ER = 18.75, 0.0 and 11%, respectively; PR = 43.75, 28.5 and 44%, respectively; p = NS). There were also no significant statistical differences between the three groups when subdividing the ovarian pathologies according to different histological types. From the results obtained in this study, it seems that tamoxifen probably does not have any direct influence on the ovaries of menopausal breast cancer patients.

Tamoxifen administration to postmenopausal women has been described as being associated with various endometrial and other gynecological pathologies. However, different coexisting gynecological pathologies in such patients have not yet been described. In the present study, we assessed the histopathological conditions diagnosed in endometrium, myometrium, and ovaries of 28 postmenopausal breast cancer patients who were treated with tamoxifen (study group) and compared the findings to those obtained from 14 similar patients without tamoxifen treatment (control group I) and from 28 age-matched healthy postmenopausal controls (control group II). All specimens were removed by total abdominal hysterectomy and bilateral salpingo-oophorectomy for various indications. The overall incidence of two or more different coexisting gynecological pathologies was significantly higher among the study group (92.9%) than in control group I or in control group II (42.9 and 50%, respectively; p = 0. 0001). There was no significant statistical difference between the control groups. Overall endometrial (and endometrial-like) origin of pathological conditions was significantly more common in the study group (92.6%) than in control group I (50%; p = 0.00072) and control group II (32.1%; p = 0.0000), while there was no significant difference between the latter two groups. These findings suggest that there might be an association between postmenopausal tamoxifen exposure and the development of such different coexisting or specific single gynecological pathologies originating from the endometrium.

Adenomyosis is an ectopic endometrial tissue located in the myometrium. It has been reported to develop at a higher rate among postmenopausal breast cancer patients on tamoxifen (TAM) treatment than in untreated patients. It has also been reported to be stimulated by estrogen. Assessing receptor levels in adenomyotic tissue may indicate the adenomyotic cell's potential to interact with TAM. In the present study the estrogen receptor (ER) and progesterone receptor (PR) were analyzed by an immunohistochemical technique in adenomyotic and the corresponding endometrial tissues of 14 postmenopausal breast cancer patients treated with TAM and in 15 healthy postmenopausal patients who served as controls. All TAM-treated patients had normal postmenopausal serum estradiol levels. Overall the ER and PR contents in adenomyotic tissue (42.9 and 71.4%) and in the endometriotic tissue (64.3 and 78.6%) obtained from the study patients were similar to those obtained from the control group (adenomyosis, ER and PR = 46.7 and 86.7%; endometrium, ER and PR = 40 and 73.3%; p = NS). In the study group, the ER content was lower in the adenomyotic (42.9%) than in the endometriotic tissue (64.3%). No correlation was found between the duration of TAM therapy, the TAM dosage level or the ER or PR content in the adenomyotic or endometrial tissues. The finding of a relatively low ER content in the adenomyotic tissue than in the endometriotic tissue in postmenopausal TAM-treated patients without endogenous estrogens, similar to that observed in healthy premenopausal women, may be attributed to the estrogen-like effect of TAM.

In an attempt to assess the hypothesis that different endometrial sites may respond differently to tamoxifen exposure in postmenopausal women, hysteroscopic selected endometrial histology was investigated in 175 postmenopausal breast cancer patients who received continuous treatment with tamoxifen, and in 27 similar patients not treated with tamoxifen who served as controls. In the tamoxifen-treated patients 14 (8.0%) developed endometrial polyps. Of 14 patients, 8 (57.2%) each displayed atrophic endometrium in the same histologic specimen, 5 (35.7%) each had coexisting simple hyperplasia, and 1 (7.1%) other had complex hyperplasia. Another 21 (12.0%) developed simple or complex hyperplasia. The endometrial hyperplasia coexisted with atrophic endometrium in all these patients. All these lesions were selectively identified by hysteroscopic examination prior to the endometrial biopsy. In the control group 3 (11.0%) had simple hyperplasia and 2 (7.4%) had endometrial polyps. The above results support the hypothesis that the endometrium of postmenopausal breast cancer patients on tamoxifen treatment may possess different responses to tamoxifen exposure.

Pathologic evaluation for adenomyosis in uterine specimens as well as demographic characteristics, health habits and risk factors for endometrial cancer were compared in 28 postmenopausal breast cancer patients with tamoxifen (TAM) treatment and in 11 similar patients without TAM treatment in order to determine the association between postmenopausal TAM exposure and the frequency of adenomyosis. The same comparison was also made between TAM-treated patients with adenomyosis and TAM-treated patients without adenomyosis. Adenomyosis was histologically diagnosed in 53.6% TAM-treated patients and in 18.2% non-TAM patients. Overall, there were no significant statistical differences in all parameters tested between the 2 groups, as well as between the TAM-treated patients with adenomyosis and the TAM-treated patients without adenomyosis. It can be concluded that adenomyosis was significantly more common among postmenopausal breast cancer patients who were treated with TAM as compared to similar patients without TAM treatment (p = 0.0186). This significant high rate of adenomyosis may be attributed to the continuous and unopposed exposure to TAM. It is, however, impossible to predict which postmenopausal breast cancer patient will develop adenomyosis after treatment with TAM.

As there are no proven optimal serum estradiol levels, we sought to evaluate the pharmacokinetic profiles of serum estradiol levels following a single oral dose of 2 mg estradiol and 1 mg of estriol (Trisequens) among 26 surgically induced, postmenopausal patients. Their serum estradiol levels were periodically measured over 24 h following oral administration of the drug. They were divided into two groups according to the computed hourly mean estradiol values: group A, < 250 pg/ml/h ( < 918 pmol/l/h) and group B, > 250 pg/ml/h ( > 918 pmol/l/h). The mean peak estradiol concentrations were noted 2 h after drug administration and amounted to 595 +/- 190 pg/ml (2,184 +/- 697 pmol/l) in the entire cohort; 435 +/- 117 pg/ml (1,597 +/- 430 pmol/l) in group A and 712 +/- 142 pg/ml (2,614 +/- 521 pmol/l) in group B (p < 0.001). The mean total area under the curve in group A was 4,887 pg/ml (17,940 pmol/l), which was significantly lower than that of 7,995 +/- 652 pg/ml/24 h (29,350 +/- 2,393 pmol/l/24 h) found for group B (p < 0.001). The mean body mass index showed a significant difference (p < 0.003) between group A and group B (29.4 +/- 0.56 vs. 24.3 +/- 0.24). We found that 57% of our patients were exposed to excessively high levels of estradiol during the 24-hour period following drug ingestion. We advise monitoring estradiol levels and individualizing estrogen replacement therapy, to avoid the long-term exposure of postmenopausal patients to superphysiological estradiol levels.

Three patients with findings suggestive of invasive gestational trophoblastic neoplasm and lung metastasis were assessed by color Doppler transvaginal ultrasound, before and during chemotherapy. The sonographic findings were correlated with beta-hCG levels measured at various stages of treatment. Results were compared with blood flow indices found during normal first trimester pregnancies, and those following elective termination of pregnancy. The mean resistance indices were significantly lower in the patients treated with chemotherapy (0.410 +/- 0.04) than in the early pregnancy control group (5-8 weeks gestation; n = 20, resistance index = 0.494 +/- 0.06). The difference between the groups was statistically significant (chi 2; p < 0.05). No pathological flow patterns could be discerned in 10 patients, who after termination of pregnancy had beta-hCG levels below 5 IU/ml. The response of gestational trophoblastic neoplasms to chemotherapy could be reliably assessed by observing the changes in flow resistance, which paralleled the gradual decrements in serial measurements of beta-hCG levels. Thus, the statistically significant results of our study are very encouraging and may indicate that color Doppler flow is a noninvasive, reproducible, useful and highly reliable new diagnostic approach for the diagnosis and management of patients suffering from uterine malignant gestational trophoblastic disease.

To the best of our knowledge, this is the first report of in vivo endometrial estrogen and progesterone receptor induction as a result of tamoxifen exposure in a postmenopausal breast cancer patient. The following observations, that the postmenopausal endometrium is sensitive to tamoxifen, that this agent can act as an estrogen-like substance, and that it may cause proliferation of the endometrium in the absence of progestin, may explain the endometrial decidual changes described herein as a protective mechanism against possible neoplastic endometrial changes.

The influence of a local injection of 0.05 ml/kg weight of 8 mg/ml methotrexate (MTX) was evaluated in 6 rabbit oviducts and compared with saline injections to the contralateral oviducts. Cell cultures of bovine oviducts were incubated in vitro for 7 days and then incubated for 24 h with 100-nmol MTX. Forty-eight and 72 h following the exposure to MTX, the treated and control cultures were harvested. Specimens and cultures were examined by light and scanning electron microscopy. In the in vivo cohort, no differences were observed between MTX and control groups. However, in MTX-treated cell culture, ciliated cells demonstrated partially adherent cilia in about 30% of the cells. The effect of MTX observed only in vitro treated cells may be due to the rapid proliferation of epithelial cells in culture which does not represent the physiological role of the oviduct in vivo.

The association between plasma calcitonin and beta-endorphin has been shown in various studies with analgesic and thermoregulatory effects. In the present study, we sought a similar association between those chemicals and physiological menopausal hot flush. Plasma calcitonin and beta-endorphin levels were measured in 5 women in physiologic menopause who suffered from frequent episodes of hot flushes. An increase in plasma calcitonin levels was noted during the hot flushes, although it was not significant. In contrast, plasma beta-endorphin levels fell significantly at onset of the hot flush, as compared to their levels 5-20 min earlier (p less than 0.005), and rose 5-15 min following the hot flush episode.

A case control study was performed to examine possible morbidity associated with Chlamydia trachomatis in 15 pregnant women with idiopathic preterm premature rupture of the membranes (PROM; group A), and in two control groups, 35 healthy preterm pregnant women (group B), and 43 healthy pregnant women at term (group C). Serum C. trachomatis IgG and IgA specific antibodies were determined using the single serovar (L2) inclusion immunoperoxidase assay. There were no significant differences in the prevalence rate of elevated levels of chlamydia IgG specific antibodies (titer greater than or equal to 1:128) between pregnant women suffering from idiopathic preterm PROM, as compared to healthy preterm and term pregnant women (20, 28 and 26%, respectively). Nor were there any significant differences in the prevalence rate of elevated levels of chlamydia IgA specific antibodies (titer greater than or equal to 1:16) between pregnant women with idiopathic preterm PROM, as compared to healthy preterm and term pregnant women (20, 20 and 17%, respectively). These findings do not support the assumption that C. trachomatis may play role in preterm PROM.

A study was undertaken to examine possible transplacental passage of Chlamydia trachomatis from pregnant women who were seropositive for chlamydia, but with no cervical C. trachomatis infection. Forty asymptomatic pregnant women, scheduled for diagnostic amniocentesis at 15-19 weeks of gestation, were tested for the presence of high serum IgA and IgG chlamydial specific antibodies and for cervical chlamydia infection. Five (12.5%) had both high serum IgA and IgG antibody levels and 10 (25%) had high serum IgG antibody levels. Overall, 15 (37.5%) had high serum chlamydia specific antibody levels (all were free of cervical chlamydial infection). The evaluation of the amniotic fluid specimens of these 15 seropositive pregnant women, who were free of cervical chlamydial infection, proved negative for direct C. trachomatis antigen detection and for chlamydial IgA and IgG specific antibodies. These negative results could be attributed to the lack of transplacental passage of C. trachomatis or to the antimicrobial activity of amniotic fluid against C. trachomatis, which has been previously described. The discrepancy between maternal infection and maternal serum antibody levels may suggest that the serologic test does not predict the presence of an antigen in the cervix.

The fetal heart rate (FHR) response to a vibroacoustic stimulation was studied in 100 women during active labor. Three types of FHR responses were noted: acceleration, tachycardia of duration longer than 2 min, and combined acceleration-deceleration response. The last type was significantly more common in labors with abnormal FHR tracings. All fetuses demonstrating FHR response to the stimulation, including those with abnormal FHR tracings, had good outcome. The vibroacoustic stimulation is easily performed, noninvasive, and has no contraindications. Its possible application as an intrapartum test of fetal well-being awaits further clinical confirmation.