Transdermal estrogen replacement therapy and vasomotor response.

Previous studies have shown that acute administration of estrogen improves endothelial function in postmenopausal women, but there has been little investigation of the chronic effects of transdermal estrogen replacement therapy. The present study assessed the effect of transdermal estrogen replacement therapy (0.025 mg / day for 4 weeks, the normally applied dosage in Japan) on flow-mediated endothelium-dependent vasodilation of the brachial artery (B-mode ultrasound) and forearm cutaneous blood flow (laser Doppler flowmetry), and plasma hormonal and lipid levels in 12 normolipidemic postmenopausal women. Neither resting vascular diameter, flow-mediated vasodilation, nor time to peak vasodilation, showed significant changes after the estrogen therapy. In contrast, resting forearm cutaneous blood flow decreased significantly after the estrogen therapy. The time to the peak reactive hyperemia in the forearm skin was slightly shortened, and the % change in reactive hyperemia decreased slightly after the therapy. These findings seemed to reflect the inhibition of hot-flush symptoms associated with vasomotor abnormalities in cutaneous tissue. The lack of improvement in flow-mediated vasodilation of the brachial artery despite the inhibitory effect on cutaneous vasomotor abnormalities may be related to the low plasma estradiol concentration obtained with the present transdermal therapy (42.4+/-15.2 pg / ml), a finding which supports the estrogen threshold hypothesis in hormone replacement therapy.

A comparison of serum leptin concentrations in obese and normal weight Japanese women with regular menstrual cycle.

Leptin is a protein that is synthesized and secreted from adipose tissue. We examined the changes in serum leptin level during the menstrual cycle in 5 normal and 5 obese Japanese women, and compared the data with those of serum estradiol (E2) and progesterone (P4) concentrations. Serum leptin levels were highly correlated with body mass index (BMI) and percent body fat, being higher in the obese group than in the normal group. In the obese group, serum leptin level increased in the luteal phase in parallel with the rise in the serum E2 level. In the normal group, however, there was no significant change in serum level during the menstrual cycle. These results suggested that the serum leptin levels were influenced by the phase of menstrual cycle, probably through the action of E2, in different ways for obese and non-obese women.

Laparoscopy with ultrasonographic guidance of intraamniotic methotrexate injection for ectopic pregnancy. A report of two cases.

BACKGROUND: The efficacy of laparoscopic intratubal injection of methotrexate is reportedly controversial. CASES: A 29-year-old woman with an interstitial-isthmic pregnancy and a 30-year-old woman with an ampullary pregnancy surrounded by dense adhesions were treated with intraamniotic injection of methotrexate with ultrasonographically guided laparoscopy (LUS). The ectopic pregnancies resolved quickly, without further intervention. The human chorionic gonadotropin concentrations were negligible by 18 and 25 days. CONCLUSION: Intraamniotic methotrexate injection with LUS is an effective treatment for unruptured interstitial and tubal pregnancies in patients with dense adhesions.

Hepatic resection for metastatic squamous cell carcinoma from the uterine cervix.

A solitary hepatic tumor was diagnosed 3.5 years after a 67-year-old woman had undergone radical hysterectomy and postoperative irradiation for stage Ib squamous cell carcinoma of the cervix. Hepatic resection confirmed squamous cell carcinoma that had metastasized from the uterine cervix. One year and 10 months following hepatic resection, this patient is doing well with no evidence of any recurrence. This is a report of successful hepatic resection for metastatic carcinoma from the uterine cervix.

[Epidemiologic background and changes in patients infected with human papilloma virus].

Contagion with certain types of HPV was supposed to have a causal relationship with cervical neoplasia of the uterus. The rate of prevalence of HPV was investigated in pre-cancer and cancer patients with uterine cervical smear using virapap or viratype. According to the cytologic classification, among those whose cytology was diagnosed as class I or II, were found a few positive HPV, however, in cases in classes cytology IIIa, III and IIIb, the positive rate turned out to be 22.5, 41 and 72.4%, respectively. About 65% of patients whose post-operative diagnosis was cervical carcinoma, had been found positive in the pre-operative HPV.DNA check up. The statistical profiles of virally infected subjects were regarded as slightly younger females with early onset of menarche. A higher positive rate was found in such groups such as unmarried single and divorced single women, career employees with special skills, housewives and dwellers in residential and commercial sections. The follow up study of HPV infection was checked with subjects with dysplasia, and no case was recognized in which initially HPV negative dysplasia turned to positive during the observation period. But, in about 50% of those checked, initially HPV positive dysplasia turned to negative, during the follow up period. In the cases with long term (more than 8 years) dysplasia which was followed up, only one out of 10 was found to be HPV positive, while in middle term (more than 2 years but less than 8 years) followed up dysplasia, the positive rate was calculated as 47.8%.

[Postoperative irradiation of cervical carcinoma without lymph nodal involvement or parametrial invasion].

Radical hysterectomy for uterine cervical cancer was performed on 469 patients without metastasis in either the parametrium (P) or pelvic node (N). In 225 of the patients, the tumor had invaded deeply, with the remaining non-invaded myometrium being less than 5 mm deep. In 54 of the patients, the tumor had invaded the vagina. These two sets of cases (postoperative advanced Ib and IIa) were the subjects of the present examination. Eighty-three of the 225 patients were given postoperative irradiation, and 142 were not. The 5-year survival rates were 84% (70/83) in patients with irradiation and 92% (131/142) in those without irradiation (p less than 0.10). Eight patients with irradiation died of causes which might be attributable to the irradiation. The rates of recurrence were similar in both groups (8.4%, 7/83 vs 9.2%, 3/142). However, there was a significant difference (p less than 0.025) between these two groups (1.2%, 1/83 vs 2.8%, 4/142) in the recurrence rate when only the areas of irradiation were considered. In the 54 patients with IIa cancer, the 5-year survival rates and the rates of recurrence were not significantly different for those patients with irradiation from those without irradiation. Therefore, these results indicate that postoperative irradiation may not be essential for P(-)N(-) patients.

Post-hysterectomy extra-uterine endometrial stromal sarcoma: a case report.

Endometrial stromal sarcoma is a relatively rare form of uterine sarcoma. The present paper reports on a patient who was found to have contracted endometrial stromal sarcoma eight years after a hysterectomy. A postoperative specimen revealed this sarcoma to have originated in extra-uterine endometrium of the rectovaginal septum.

Mechanisms for the stimulation of prostanoid synthesis by cyclosporine and bacterial lipopolysaccharide.

Both cyclosporine and bacterial lipopolysaccharide enhance prostanoid synthesis and regulate the immune response. This study was designed to establish whether these agents affect prostanoid synthesis by common or different mechanisms. CsA and LPS stimulate prostanoid synthesis both in human monocytes and smooth muscle cells from guinea pig aorta. Only LPS stimulates synthesis in the presence of exogenous arachidonic acid. Dexamethasone totally blocks CsA but only partially inhibits LPS. CsA and LPS both enhance the release of labeled metabolites from cells labeled with arachidonic acid, but indomethacin only blocks the effect of LPS. CsA and the releasing agent calcium ionophore (A23187) both increase PGE2 and PGI2 synthesis without changing their relative concentrations, cause the release of free arachidonic acid, and lead to the formation of new metabolites that are not products of cyclooxygenase activity. Preincubation with either CsA or A23187 and a subsequent wash deplete the arachidonic acid pool available for prostanoid synthesis. Thus, A23187 and CsA have very similar effects on arachidonic acid metabolism. In contrast, LPS increases PGE2 and PGI2 synthesis and alters their relative concentrations, diminishes the relative concentration of free arachidonic acid, and enhances the formation of new metabolites that are products of cyclooxygenase activity. These differences are explained by mechanisms in which CsA promotes prostanoid synthesis through arachidonic acid release, and LPS promotes prostanoid synthesis through increased cyclooxygenase activity.

Brain eicosanoid levels in spontaneously hypertensive rats after ischemia with reperfusion: leukotriene C4 as a possible cause of cerebral edema.

The relation of brain eicosanoids to progression of cerebral edema was studied in stroke-resistant spontaneously hypertensive rats subjected to incomplete global brain ischemia induced by bilateral occlusion of the common carotid arteries. Thromboxane B2 and 6-keto prostaglandin F1 alpha levels were significantly elevated 5 minutes after reperfusion but returned to control levels by 30 minutes. In contrast, leukotriene C4 levels increased 2 hours after bilateral common carotid artery occlusion and peaked 30 minutes after reperfusion, with higher levels persisting until 60 minutes after reperfusion. Cerebral ischemia was accompanied by cerebral edema early after reperfusion. The edema correlated with increased leukotriene C4 levels. That the increased brain water content was causally related to an increase in leukotriene C4 was supported by results obtained following administration of the 5-lipoxygenase inhibitors ONO-LP-016 and AA-861. Both inhibitors suppressed the increased leukotriene C4 and brain water contents after reperfusion. Our results indicate that leukotriene C4 is closely associated with an induction of ischemic cerebral edema.

A rapid serum estrogen assay suitable for office use in monitoring follicular maturation.

Ovulation induction often requires the determination of serum estradiol levels. A rapid, sensitive, and simple non-radioactive serum estrogen assay was developed by modifying a hemagglutination-inhibition kit (Hi-Estrotec) originally designed to measure total urinary estrogens. With a minimum sensitivity of 100 pg of 17-beta-estradiol, the modified procedure generally takes less than 2.5 hours to complete and requires no special equipment or instrumentation. Randomly obtained serum samples assayed by both the hemagglutination-inhibition assay and radioimmunoassay achieved a correlation coefficient of 0.885 (P less than .001). Comparison of serum obtained from women undergoing ovulation induction with human menopausal gonadotropin-human chorionic gonadotropin measured by both techniques showed the same fluctuation pattern for serum estradiol levels during the stimulated cycles. The rapidity and reproducibility of this serum estrogen assay make it suitable for office use in monitoring ovulation induction and superovulation in in vitro fertilization-embryo transfer programs.

Frequency of chromosomally unbalanced gametes in male and female hamsters heterozygous for reciprocal translocation.

By using male and female Chinese hamsters heterozygous for reciprocal translocation, T(2;10) 3Idr and T(1;2)9Idr, features of metaphase II cells were observed, and the difference in frequency of each class of cells derived from quadrivalents was investigated. The result showed no difference between sexes in the segregation ratio of chromosomes from the quadrivalents in either strain. In four-day embryos from crosses between normal animals and translocation heterozygotes in both strains, the incidence of embryos with unbalanced chromosomes was significantly higher in the group from crosses between females heterozygous for the translocation and normal males than in the group from heterozygous males and normal females. These results suggest that in males unbalanced gametes are selectively eliminated during the period between the formation of gametes and fertilization.

Effect of an oral dose of vitamin E on the vitamin E and cholesterol content of tissues of the vitamin E-deficient rat.

Weanling rats (female Sprague-Dawley) were fed until maturity a vitamin E-deficient diet or the deficient diet supplemented with 66 IU RRR-alpha-tocopheryl acetate/kg. Vitamin E, vitamin E quinone and total cholesterol levels in plasma, liver, paraovarian adipose tissue, lung, ovary and adrenal tissue were measured by high performance liquid chromatography. Vitamin E levels were greatly diminished, but cholesterol levels were unchanged in all tissues except adipose tissue of animals fed the deficient diet. Vitamin E-deficient animals received a single oral dose of 2 or 16.7 mg of RRR-alpha-tocopherol, and tissues were examined at 12 and 48 h. Plasma and liver formed a vitamin E pool that peaked at 12 h, had a high vitamin E/cholesterol ratio at 12 h and contained only trace amounts of vitamin E quinone. Adipose tissue, lung, ovary and adrenal concentrated vitamin E throughout the 48-h period, had low vitamin E/cholesterol ratios and contained small but significant amounts of vitamin E quinone. Vitamin E levels (micrograms/gram) at 48 h in lung, ovary and adrenal were higher than the vitamin E level in liver but the liver contained much more vitamin E (micrograms/organ) than the other tissues combined. Cholesterol levels (micrograms/gram) in plasma and liver decreased 45 to 55% in a dose- and time-dependent manner when a single oral dose of vitamin E was administered to deficient animals. Cholesterol levels in adipose tissue, lung and ovary were unchanged while the cholesterol level in adrenal increased 122% in a time-dependent manner with a single oral dose of vitamin E. These data show that a single oral dose of vitamin E has a profound effect on cholesterol levels in short-time experiments with the vitamin E-deficient rat. This rat model is appropriate for studies on the relationship between vitamin E and cholesterol metabolism in plasma, liver and the adrenal.

Deficiency of vitamin E in the alveolar fluid of cigarette smokers. Influence on alveolar macrophage cytotoxicity.

Cigarette smoking produces oxidant-mediated changes in the lung important to the pathogenesis of emphysema. Since vitamin E can neutralize reactive oxygen species and prevent peroxidation of unsaturated lipids, it may constitute an important component of the lung's defense against oxidant injury. To better characterize the antioxidant protective role of vitamin E, young asymptomatic smokers and nonsmokers were evaluated by bronchoalveolar lavage before and immediately after a 3-wk course of oral vitamin E (2,400 IU/d). Smoker alveolar fluid at baseline was relatively deficient in vitamin E compared with nonsmoker fluid (3.1 +/- 0.7 ng/ml vs. 20.7 +/- 2.4 ng/ml, P less than 0.005). Although smoker alveolar fluid vitamin E levels increased to 9.3 +/- 2.3 ng/ml after supplementation, the levels remained significantly lower than nonsmoker baseline levels (P less than 0.01). This deficiency was explained, in part, by the increased oxidative metabolism of vitamin E to the quinone form in the lungs of smokers compared with nonsmokers. Although the significance of a lower concentration of alveolar fluid vitamin E is unclear, it may compromise the antioxidant protection afforded by the alveolar fluid as it coats the lung's epithelial surface. The protective role of vitamin E was assessed by cytotoxicity experiments, which demonstrated that the killing of normal rat lung parenchymal cells by smoker alveolar macrophages was inversely related to the vitamin E content of the parenchymal cells. These findings suggest that vitamin E may be an important lower respiratory tract antioxidant, and that the deficiency seen in young smokers may predispose them to an enhanced oxidant attack on their lung parenchymal cells.

Fatty acid metabolism and cell proliferation. VII. Antioxidant effects of tocopherols and their quinones.

The antioxidant capacities of alpha- and gamma-tocopherols (alpha-E and gamma-E) and their quinones (alpha-EQ and gamma-EQ) were determined in non-biological and biological systems. The non-biological system consisted of arachidonic acid [20:4 (n-6)], the oxidant cumene hydroperoxide, and a Fe3+ catalyst to facilitate malondialdehyde (MDA) formation from lipid peroxides. alpha-E and gamma-E had similar antioxidant capacities in this system. alpha-EQ also functioned as an antioxidant, while gamma-EQ exhibited a crossover effect by functioning as an antioxidant at low concentrations and a prooxidant at high concentrations. Biological lipid peroxidation in smooth muscle cells challenged with 20:4 (n-6) was measured both by MDA formation in confluent cultures and by cell growth in proliferating cultures. alpha-E, gamma-E and alpha-EQ had similar antioxidant capacities, but gamma-EQ was highly cytotoxic for cells in both confluent and proliferating cultures. Cellular retention of antioxidants was estimated indirectly from MDA formation when cells were loaded with an antioxidant (preincubation) and then incubated for varying periods of time in fresh media containing 20:4 (n-6). Cellular retention also was measured directly with tritiated alpha-E and tritiated alpha-EQ. These studies showed that cellular retention decreased in the sequence gamma-E greater than alpha-E greater than alpha-EQ. Thus, cellular retention does not explain the enhanced antioxidant capacity of alpha-E compared to gamma-E that has been reported for animal systems. The antioxidant capacity of alpha-E evidently is enhanced by its metabolism to a quinone which, unlike the quinone from gamma-E, functions as a biological antioxidant.

[Cerebral metastasis of choriocarcinoma].

One hundred and eighty-two cases of choriocarcinoma were treated in our clinic during the 26 years period from 1957 to 1982. Forty-one patients among them (2.3%) had cerebral metastases. Analysis on the autopsy findings of patients with cerebral metastases of choriocarcinoma proved neurosurgical resectability in most cases. Craniotomy and removal of cerebral metastatic lesion has been adopted since 1972, and a significant difference was noted in the surviving time between surgically treated group and the group without surgery. The risk factors for developing brain metastases were analyzed. Patients whose uterine lesion showed immature type of histopathology (p less than 0.01), patients without uterine lesion (p less than 0.05) and patients with pulmonary metastasis (p less than 0.01) had higher risk of developing cerebral metastasis.