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CA125, an antigenic determinant in conditioned media (Ham's F-12 supplemented with 15% fetal calf serum) of gynecologic neoplasms was detected by immunoradiometric assay using a monoclonal antibody (CA125 RIA KIT). Seven out of 9 ovarian malignant tumor cell lines and 6 out of 8 endometrial carcinoma cell lines produced ≥ 8 U/ml of CA125, while CA125 values in the conditioned media of 4 uterine cervical epidermoid carcinoma cell lines, 3 uterine sarcoma cell lines and normal cells were < 8 U/ml. Human ovarian carcinoma cell lines (HUOA, HTOA, HMOA and HYOA) and endometrial carcinoma cell line (HHUA) were cultured in HB101TM serum-free medium and their proliferation and CA125 producing activity were studied. HMOA and HTOA cells produced large amounts of CA125, while HUOA, HYOA and HHUA produced small amounts of CA125 in the conditioned media. Dibutyl cyclic adenosine monophosphate suppressed their proliferation and increased CA125 levels not only in the very CA125-productive cultures, but also in the less CA125-productive cultures.

Objective To investigate differences in the biological characteristics of ovarian clear cell adenocarcinoma based on the presence/absence of endometriosis and tumor proliferative activity. Methods Stage I ovarian clear cell adenocarcinoma patients were divided into groups with and without endometriosis, and immunohistochemical expression of proliferating cell nuclear antigen was determined in surgical specimens. Then xenograft models of human ovarian clear cell adenocarcinoma with or without human ectopic endometrium were created in severe combined immunodeficiency mice, and tumor growth was assessed from the wet weight and the bromodeoxyuridine uptake. Furthermore, a xenograft model of human endometriosis was made with or without ovarian clear cell adenocarcinoma and cytokine production was investigated. Results The proliferating cell nuclear antigen labeling index was significantly lower in the tumors of patients with endometriosis compared to the tumors of patients without endometriosis. In tumor-bearing mice, the tumor weight and bromodeoxyuridine uptake were both significantly lower when ovarian clear cell adenocarcinoma was associated with endometriosis than in its absence. Release of transforming growth factor-β1 and interleukin-6 from the ectopic human endometrium was greater in the presence of clear cell adenocarcinoma than without it, and transforming growth factor-β1 levels showed a significant difference. Conclusion The proliferative activity of early ovarian clear cell adenocarcinoma seems to depend on the association of this cancer with endometriosis. When endometriosis is associated with ovarian clear cell adenocarcinoma, there is a change of its cytokine production that may inhibit tumor growth.

This study investigated the value of the in vitro histoculture drug response assay (HDRA) for predicting the efficacy of chemotherapy in patients with endometrial cancer. Specimens were obtained from 115 patients with endometrial cancer treated at Keio University Hospital between 1994 and 2002. Tumor fragments were cultured on collagen sponge gel with cisplatin for 7 days, and cell viability was assessed. The cutoff value of the 50% inhibitory concentration of cisplatin was set at 23 microg/mL. Sensitivity of stage III or IV disease to chemotherapy was investigated, and differences of 5-year progression-free survival between patients with sensitive and resistant tumors were evaluated by the Kaplan-Meier method. Tumors were evaluable in 93.0% of patients (107/115). Among 38 patients in stages III or IV, 23 received chemotherapy containing cisplatin. Seven sensitive tumors did not recur, while recurrence/progression occurred within 6 months in 8/16 patients with tumors showing low sensitivity. Among stages III and IV patients, there was a significant difference of 5-year progression-free survival (P < 0.05) between those with tumors showing high or low sensitivity. Accordingly, the HDRA may predict the efficacy of chemotherapy for endometrial cancer.

Aim: The number of patients under 40 years of age with early-onset endometrial cancer is on the rise in Japan. Preservation of fertility in younger patients is a critical issue. In order to examine the clinical and pathological characteristics of these patients, cases of early-onset endometrial cancer at a single hospital were analyzed. Methods: Seventy-four patients were diagnosed with endometrial cancer before age 40 and included in this study after obtaining informed consent. Results: The clinical characteristics included a significantly higher prevalence of complications such as nulligravidity and nulliparity (P

We performed two-color fluorescence in situ hybridization (FISH) on direct touch smears and liquid-based thin-layer (ThinPrep) cytological preparations of endometrial tumors to detect alterations of chromosome 1 and 17 that present with high incidence in endometrial cancers. The DNA probes used for two-color FISH analysis were a combination of the probes designed for 17cen (cCI 17-321) and 17p13.3 (D17S34), and a combination of the probes designed for 1q12 (D1Z1) and 1p36 (cCI1-5335). Numerical or structural alterations of chromosome 1 and/or 17 were detected in 95% (19 of 20 cases) of the direct touch smears obtained from endometrial cancer, while these alterations were also detected in 93% (12 of 13 cases) of samples obtained from grade 1 endometrioid adenocarcinoma cases, including three cases that could not be diagnosed as positive by conventional Papanicolaou cytopathologic staining. Using ThinPrep cytopathologic preparations, numerical or structural abnormalities were found in 26 (90%) and five (100%) cases, respectively, of samples obtained transcervically from 29 endometrial cancer and five atypical endometrial hyperplasia cases. Therefore, two-color FISH may be a useful diagnostic method for endometrial adenocarcinoma and premalignant lesions that demonstrate only slight cellular atypia in conventional cytopathologic preparations.

OBJECTIVE To gain insight into the characteristics and current status of climacteric symptoms reported by middle-aged and older women in Japan, we surveyed women presenting at our menopause clinic. DESIGN The participants included 1,069 women, ranging in age from 40 to less than 60 years (mean age, 50.2 y). Climacteric (indefinite) symptoms were objectively assessed with the use of the Keio questionnaire, which grades the severity of 40 types of symptoms classified into 20 subgroups. The total scores obtained for the 40 symptoms were used to calculate symptom prevalence and severity. To evaluate ovarian function, concentrations of estradiol and follicle-stimulating hormone (FSH) in sera were measured. RESULTS The most frequent symptom was general fatigue, reported by 88.2% of the women. Shoulder stiffness was the symptom rated to be severe by the highest percentage of women (38.1%). The prevalence and severity of hot flushes (and sweats) were slightly higher in perimenopausal and early postmenopausal women than in premenopausal and late postmenopausal women. The prevalence and severity of hot flushes and sweats were higher in women with estradiol 40 mIU/mL than in those with estradiol > or = 25 pg/mL and FSH < or = 40 mIU/mL. CONCLUSION General fatigue and shoulder stiffness, symptoms with low hormone dependence, are the two most frequent climacteric symptoms in our clinic. Hot flushes and sweats, symptoms with high hormone dependence, are also common symptoms.

Hereditary nonpolyposis colorectal cancer (HNPCC) is among the representative familial cancers that are autosomally dominant inherited disorders. Because endometrial cancers develop at high rates in women with HNPCC, it is suggested that some endometrial cancers are familial cancers that are induced by mutations of the DNA mismatch repair (MMR) genes, as in HNPCC. To understand the clinical pathology of familial endometrial cancers that are associated with HNPCC, we surveyed the family histories of 385 patients with endometrial cancer and found that 0.5% of endometrial cancers met the new diagnostic criteria of HNPCC. From molecular and biological analyses, we found microsatellite instability in 30.8% of endometrial cancers and germline mutations of MMR genes in 8.3%. These results suggest a close relationship of MMR gene mutations to the development of endometrial cancers. For a better understanding of the clinical pathology of HNPCC-associated familial endometrial cancers, it is critical for gynecologists to perform a large multicenter study, including detailed family histories.

Objective. Human papillomavirus (HPV) infection is reported to be related to carcinogenesis in the uterine cervix. In Japan, screening for cervical cancer by cytology is performed in women over 30 years old. The purpose of this study was to determine whether there is an association between patient age and cervical neoplasia or HPV infection in Japanese women. Methods. Specimens from 881 randomly selected patients who came to our clinic were tested for HPV DNA by using Hybrid Capture II, whereas specimens from a 204-patient randomly selected subset diagnosed with cervical neoplasia were tested for HPV DNA by using polymerase chain reaction (PCR). HPV typing was performed in all the PCR-positive cases. Results. The HPV-positive rate in the 20- to 29-year-old patients (29.0% in the normal cytology/histology group and 85.5% in the abnormal group) was higher than in the 30- to 59-year-old patients, and the rate declined until age 60 when age increased. While HPV 18, HPV 52, other HPV types, and HPV types as a whole were frequently detected in 30- to 49-year-old patients, HPV 16 was detected more frequently in the younger group than the other HPV types ( P = 0.03). Among the HPV 16-positive patients with cervical neoplasia, the proportion of cervical intraepithelial neoplasia (CIN) 3 cases was high (44%) in the 20- to 29-year-old group. Conclusions. Screening for cervical neoplasia by cytology should also be performed in women under 30 years old in Japan. The HPV typing could be a tool to strictly follow-up younger women who were diagnosed with CIN.

Aim: Psychosocial elements are often found in the background of patients with menopausal disorders, and counseling based on these elements is essential for effective treatment. In the study presented here an attempt was made to extract psychosocial factors from Japanese cases of menopausal disorders in which the patients exhibited the impact of psychiatric elements and required counseling. Methods: A total of 97 cases in which the patients received counseling for the treatment of undefined complaints at our menopause clinic were analyzed. During counseling the patients were interviewed in regard to psychosocial factors and underwent psychological tests. Results: About half of them were found to have experienced various interpersonal problems as well as health-related problems. The frequency of problems such as empty nest syndrome and loss of relatives or friends was relatively low. Work-related anxiety or hardships of life were frequent among the premenopausal patients, while concern about aging was often noted in their postmenopausal counterparts. The incidence of empty nest syndrome was high among the ovariectomized women, but worry about aging was frequently reported by those undergoing natural menopause. Conclusion: This preliminary study revealed that problems related to families and the patient's health account for a large part of the psychosocial factors affecting the development of menopausal disorders in Japan. Incorporating these findings into counseling will make outpatient clinics services more acceptable to such patients.

Trophinin, tastin, and bystin have been identified as molecules potentially involved in human embryo implantation. Both trophoblasts and endometrial epithelial cells express trophinin, which mediates apical cell adhesion through homophilic trophinin-trophinin binding. We hypothesized that trophinin's function in embryo implantation is unique to humans and investigated the expression of trophinin, tastin, and bystin in ectopic pregnancy, a condition unique to humans. In tubal pregnancies, high levels of all three were found in both trophoblasts and fallopian tubal epithelia. Trophinin expression in maternal cells was particularly high in the area adjacent to the trophoblasts, whereas trophinin was barely detectable in intact fallopian tubes from women with in utero pregnancies or without pregnancies. When explants of intact fallopian tube were incubated with the human chorionic gonadotrophin (hCG), trophinin expression was enhanced in epithelial cells. Since the trophectoderm of the human blastocyst secretes hCG before and after implantation, these results suggest that hCG from the human embryo induces trophinin expression by maternal cells. As both β-subunit of hCG and trophinin genes have diverged in mammals, the present study suggests a unique role of hCG and trophinin in human embryo implantation, including the pathogenesis of ectopic pregnancy.

The regulation of estrogen activity through the formation and cleavage of sulfoconjugates of estrogens is known to be related to the progression and metastasis of estrogen-dependent breast carcinomas, but the involvement of sulfoconjugates in the steroid stimulation of endometrial functions and the progression of endometrial adenocarcinomas is not clearly understood yet. Estrogen sulfotransferase (EST) in the uterine endometria during the follicular phase was more active than during the luteal phase, but estrogen sulfate (ES) sulfatase exhibited lower activity during the follicular phase than during the luteal phase. However, ES sulfatase activities in cancerous tissues were lower than those in normal endometria and endometrial adenocarcinoma-derived cells, among which the activity was exceedingly high in Ishikawa cells, suggesting that ES sulfatase in Ishikawa cells contributes to the estrogen-dependent growth of these cells. EST activities higher than that in Ishikawa cells were found in only 3 of 24 cancerous tissues. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of the EST and ES sulfatase genes in carcinoma-derived cells demonstrated the extensive expression of both genes in Ishikawa cells. The isolated EST gene was transfected into Ishikawa cells with a mammalian expression vector to establish cell clones with enhanced EST activity, and the estrogen-dependent cell growth of the resultant cell clones was found to be abolished, due to the enhanced sulfoconjugation of estrogen. Since ES sulfatase activity in cancerous tissues was significantly lower than that in Ishikawa cells, it might be not involved in the enhancement of estrogen activity associated with the pathogenesis of endometrial adenocarcinoma tissues.

Endometrial cancer is the second most common malignancy in patients with hereditary nonpolyposis colorectal cancer (HNPCC). This cancer is caused by germline mutations in one of the DNA mismatch repair (MMR) genes. The present study was undertaken to analyze the relation between microsatellite instability (MSI) and germline mutations of MMR genes. We analyzed MSI in 38 cases of endometrial cancer. MSI was present in one or more (out of 5 examined) regions in 11 (29%) cases. Furthermore, alterations in MLH1 and MSH2, two culprit genes representative of HNPCC, were examined in the 11 MSI-positive patients using polymerase chain reaction-single-strand conformation polymorphism and sequencing. Germline mutations, namely, 1) a missense mutation at codon 688 (ATG-->ATA, Met-->Ile) and 2) a missense mutation at codon 390 (CTT-->TTT, Leu-->Phe) of the MSH2 gene, were found in 2 of the 11 patients (18%). Although these two cases do not fulfill the new Amsterdam criteria, they had strong family histories of colorectal and endometrial carcinoma. Our results show that genetic testing is important in cases of endometrial cancer with a history suggestive of HNPCC even if the new Amsterdam criteria are not fulfilled.

As human papillomavirus (HPV) infection is the main risk factor for squamous cell carcinoma of the cervix and overexpression of p16 INK4a occurs when retinoblastoma protein is inactivated by high-risk HPV, the authors studied the association of HPV infection and expression of p16 INK4a in cervical adenocarcinomas. Specimens of cervical glandular neoplasias were immunostained with a p16 INK4a -specific monoclonal antibody (clone E6H4). Approximately 80% of glandular neoplasms showed overexpression of p16 INK4a . Exfoliated cells from 14 adenocarcinomas were further examined by p16 INK4a -specific immunocytochemistry, and 12 cases showed overexpression of p16 INK4a , suggesting that immunostaining for p16 INK4a may be a useful diagnostic tool for cervical adenocarcinomas. The authors further examined HPV DNA in cervical adenocarcinomas with the polymerase chain reaction method. Overexpression of p16 INK4a was positive in 94% of cases in which HPV 16 or 18DNA was positive, a finding suggesting that HPV16 or 18 may play an important role in cervical adenocarcinomas. Overexpression of p16 INK4a may be an indicator of pathogenic activity of high-risk HPVs.

Carcinogenesis of cervical cancer has been investigated, and p16(INK4a) overexpression in squamous cell carcinoma of the cervix has been reported as a result of infection by human papillomavirus (HPV) (eg, HPV 16), and the consequence of the retinoblastoma (Rb) protein inactivation by HPV E7 protein. However, to our knowledge, there have been no studies on the relation between p16(INK4a) overexpression associated with HPV and small cell carcinoma of the cervix, which behaves more aggressively clinically than squamous cell carcinoma. The purpose of this study was to determine whether p16(INK4a) is overexpressed in small cell carcinoma, and if p16(INK4a) is overexpressed, the types of HPV that are related to this cancer. We reviewed 10 cases of small cell carcinoma and examined them for p16(INK4a) overexpression by immunohistochemistry. We also performed HPV typing with polymerase chain reaction (PCR)-sequencing analysis and in situ hybridization and found that p16(INK4a) was overexpressed in every case. PCR-sequencing analyses revealed that all cases were HPV-positive and that 9 cases were positive for HPV 18. Five of the 9 cases positive for HPV 18 were also positive by in situ hybridization and yielded a punctate signal, considered to represent the integrated form. In conclusion, p16(INK4a) was overexpressed and HPV 18 was frequently detected in an integrated form in small cell carcinoma. Therefore, inactivation of Rb protein by HPV 18 E7 protein may be associated with carcinogenesis of small cell carcinoma the same as inactivation of Rb protein by HPV 16 E7 protein is associated with carcinogenesis of squamous cell carcinoma.

The androgen receptor (AR) has two transactivation functions that have been mapped to the N- and C-terminal domains and designated as activation function-1 (AF-1) and AF-2, respectively. While the molecular basis for AF-2 function has been well studied, little is known about AF-1 coregulators. Therefore, we attempted to identify AF-1-interacting proteins from HEK293 cells by biochemical purification followed by mass fingerprinting by matrix-assisted laser desorption ionization–time-of-flight mass spectrometry (MALDI–TOF MS). Purified AF-1 region-interacting proteins were found to contain nuclear RNA-binding protein p54 nrb , polypyrimidine tract-binding protein-associated splicing factor (PSF), paraspeckle protein 1 (PSP1), and PSP2, which are assumed to be involved in pre-mRNA processing. p54 nrb interacted with AR via the A/B domain in a ligand-dependent manner. Reflecting the physical interaction between p54 nrb and the AR A/B domain, AR AF-1 function was potentiated by p54 nrb . Our results suggest that p54 nrb functions as a coactivator of AR that potentiates transcription, and presumably splicing as well.

Background: This prospective observational study was designed to determine whether the bone mineral density (BMD) of the lumbar spine decreases before menopause. Methods: The change in BMD of the second through fourth lumbar vertebrae (Δ%L2–4BMD) over the course of 12 months was measured in 197 pre- and perimenopausal Japanese women aged 48.2 ± 2.3 (mean ± SD) years. Results: Overall, Δ%L2–4BMD decreased significantly, with a greater decrease seen in perimenopausal women. This group also had a significantly higher level of FSH (p < 0.05, t = 7.356), a significantly lower level of estradiol (p < 0.05, t = 4.245), and significantly higher levels of the bone metabolic markers, alkaline phosphatase (p < 0.05, t = 3.841), calcium (p < 0.05, t = 3.939), and osteocalcin (p < 0.05, t = –3.295). Overall, there was a significant positive correlation between osteocalcin and Δ%L2–4BMD (r = –0.194, p = 0.0479). Conclusion: A subset of perimenopausal women with transient decreases in ovarian function that do not respond to increased FSH may be at increased risk for abnormally low BMD, and may benefit from early management of bone mass.

Frozen or resin sections of normal human endometrium, endometrial adenocarcinoma, and ovarian adenocarcinoma were examined with two monoclonal antibodies for galactosyltransferase associated with tumor (GAT) by immunofluorescence and immunoelectron microscopy. One antibody (MAb8628) stained the trans-cisternae of the Golgi apparatus, the trans-Golgi network, and the intracytoplasmic vesicles more intensely in cancer cells than in normal endometrial glandular cells. The other antibody (MAb8513) stained intracytoplasmic vesicles more intensely in cancer cells than in normal cells. MAb8513 also showed moderate staining of the trans-cisternae of the Golgi apparatus and trans-Golgi network in cancer cells, but only faint staining of these structures in normal glandular cells, indicating that GAT was overexpressed in the cancer cells. An immunofluorescence study using serial semithin cryosections (1 μm) demonstrated that the staining pattern of each antibody was different inside a single cancer cell, conforming to the two patterns mentioned above. The reason for this difference in staining remains unclear. GAT is a soluble form of β1,4-galactosyltransferase, so a difference in the cleavage site of the membrane-bound peptide may cause changes in immunoreactivity after its conversion to the soluble form (i.e., GAT) in endometrial or ovarian adenocarcinoma cells.

Transformation-associated expression of Le(b) (Lewis antigen-b) or Le(Y) in human colorectal carcinomas has been well described. To examine the expression of glycosphingolipids (GSLs) bearing Lewis-phenotypes in human gynecological carcinoma-derived cells, we determined the concentrations of all GSLs. Although neither Le(b) nor Le(Y) was present in HEC-108 cells established from the poorly differentiated type of endometrial adenocarcinoma, other cell lines from moderately or well-differentiated types expressed either Le(b) or Le(Y), or both, at concentrations of 0.01 to 0.03 microg per mg of dry cells, which comprised 0.3 to 1.3% of the total GSLs. In the cervical and ovarian carcinoma-derived cell lines, Lewis phenotypes tended to be carried by nLc(4)Cer, which was accumulated in the cells without sialylation or fucosylation. These results indicated that expression of Le(b)- or Le(Y)-phenotypes was strongly dependent on the metabolic ability to supply the precursor GSLs. Both Le(b) and Le(Y) were successfully detected by monoclonal antibody MSN-1, which was a useful probe for the simultaneous detection of Le(b) and Le(Y). On application of MSN-1, either Le(b) or Le(Y) was detected in tissues from patients with well- and moderately differentiated types of endometrial adenocarcinoma at concentrations of 0.01 to 0.04 microg per mg of dry tissues, but not in the tissues of poorly differentiated type. Normal endometria at the follicular and luteal phases also contained the antigens, but the concentrations and the frequency of antigen expression were lower than those in the well- and moderately differentiated types of endometrial adenocarcinoma.

Cytosolic sulfotransferases play essential roles in regulating the activities and transfer of steroids. To evaluate their biological significance in the murine uterus and placenta during the course of gestation, we determined their activities with several steroids as substrates. Activated estrogen sulfotransferase (EST) was found in the placenta and uterus during the late gestational period. Reverse-transcribed cDNA of murine placental EST (mpEST) was isolated from mouse placenta at 18 days of gestation and its expression in the tissue coincided with a change in its enzyme activity. The open-reading frame of mpEST encodes a protein composed of 296 amino acids with a predicted molecular mass of 35.5 kDa and was revealed to be an isoform of the murine testis-specific EST gene (99.7%). Also, the amino acid sequence of mpEST showed 49.6 and 77.9% homology with human placental and endometrial EST, respectively, showing that it corresponds to human endometrial EST. COS-7 cells transfected with mpEST exhibited sulfotransferase activity with the phenolic hydroxy groups of steroids and artificial substrates. The best acceptor substrate was estrogen.

The variation of the E6 region of human papillomavirus type 16 (HPV16) is associated with a high risk for cervical carcinogenesis. To see whether the same is the case with HPV33, 52 and 58, known to have high homology with HPV16, we analyzed the E6 sequence variation of these HPVs in 107 Japanese women with cervical intraepithelial neoplasia (CIN) or invasive cervical cancer (ICC): 20 HPV33-positive, 46 HPV52-positive and 41 HPV58-positive cases. HPV33 variants were more frequently observed in CINs I/II than in CIN III/ICCs (71% (5/7) versus 15% (2/13), P=0.02). In HPV52-positive cases, a single E6 variant was detected in 98% of the cases, whereas the prototype accounted for 98% of HPV58-positive cases. In summary, the distribution of E6 variants is different among HPV types tested, suggesting a link between E6 variation and oncogenic potential being type-specific.

Cisplatin (DDP) is one of the key drugs used to treat patients with ovarian cancer, although resistance to DDP can occur. Paclitaxel and SN-38 (an active metabolite of irinotecan (CPT-11)) are two drugs that are effective in patients with DDP-resistant ovarian cancer. To study how these drugs may overcome the intrinsic and / or acquired resistance of cancer cells to DDP, we investigated the effect of a combination of DDP with paclitaxel and a combination of DDP with SN-38 on three ovarian cancer cell lines, RTSG (intrinsically resistant cell line), KF (DDP-sensitive cell line), and KFra (acquired resistant cell line obtained from KF). We found that these combinations showed additive to synergistic antitumor activity. A time-dependent platinum (Pt) accumulation was observed in the DDP-sensitive KF cell line, while a decrease occurred in the KFra cell line. Little accumulation was observed in RTSG. Intracellular Pt accumulation was increased in all three cell lines by exposure to paclitaxel or SN-38. Ouabain, a Na(+),K(+)-ATPase inhibitor, decreased Pt accumulation in KF and KFra cell lines and inhibited the paclitaxel- and SN-38-induced increases in Pt accumulation in these cell lines. When we assessed the mRNA levels of the multidrug resistance-associated protein (MRP), which may be an efflux pump for DDP, the combination of paclitaxel or SN-38 with DDP down-regulated these levels, which are up-regulated by DDP alone. These results suggest that paclitaxel and SN-38 overcome DDP resistance of ovarian cell lines by controlling intracellular accumulation of DDP via both the influx and efflux systems.

Objective: The purpose of this report is to estimate the effectiveness of gonadotropin-releasing hormone analogue (Gn-RHa) therapy for peritoneal inclusion cysts. Methods: Patients who had cystic masses that developed after gynecological surgery and were strongly suspected of being peritoneal inclusion cysts based on the results of ultrasound, magnetic resonance imaging (MRI), and tumor marker studies, were treated with a Gn-RHa (buserelin acetate or leuprorelin acetate). Buserelin acetate was administered at a dose of 900 μg/day, and leuprorelin acetate at a dose of 3.75 mg/month. Ultrasonography was performed in the outpatient clinic every 2 weeks after the start of administration to measure the diameter of cysts. Results: We treated 8 patients with peritoneal inclusion cysts conservatively with a Gn-RHa. The cysts resolved in 7 of the patients. Two of them developed a recurrence, but further Gn-RHa therapy was followed by complete resolution of the cysts in one patient and we resume Gn-RHa therapy to the other patient. The peritoneal inclusion cysts failed to shrink in only one patient. Conclusion: It is suggested that Gn-RHa therapy is effective in some cases of peritoneal inclusion cysts.

The expression level of Lewisb(Leb) antigen was previously shown to correlate with the five−year survival rate of human endometrial cancer patients. Variant cell lines with high(SNG−S) and low(SNG−W) levels of cell surface Leb antigen were isolated from the heterogeneous endometrial cancer cell line SNG-II cells to characterize the biological significance of Leb antigen on endometrial cancer cells. SNG−S cells mainly expressed Leb, whereas SNG−W cells mainly expressed H type 1 carbohydrate antigen alternatively. In an in vitro system, SNG−W cells showed a greater capacity to adhere to cytokine−activated human umbilical vein endothelial cells. Their adhesion to human umbilical vein endothelial cells was partially inhibited by pretreatment of antibody specific for H type 1 carbohydrate antigen. These results suggested that the H type 1 carbohydrate antigen expressed on endometrial cancer cells is involved in the adhesion to endothelial cells.

The efficacy, safety, and optimum clinical dose of recombinant human interleukin-3 (rhIL-3) was examined in ovarian cancer patients with thrombocytopenia after cancer chemotherapy. In cases with a platelet count < 75,000/mm3 during the control observation period, rhIL-3 was administered subcutaneously at a dose of 5 or 10 micrograms/kg, once a day for 10 days starting from day 4 of the subsequent chemotherapy course. Comparison between the control observation period and the rhIL-3 administration period showed a significant improvement or a tendency toward improvement in increasing the nadir platelet count and the recovery of the platelet count. The major adverse reactions were pyrexia, fatigue, and headache, which were well controlled by the use of antipyretics, analgesics, and antiinflammatory agents. Adverse reactions were for the most part transient and disappeared quickly during or after rhIL-3 administration. Although severe adverse reactions were not observed, the incidence of grade 2 and 3 adverse reactions according to a World Health Organization (WHO) Toxicity Scale were slightly higher in the 10 micrograms/kg/d group. As a consequence, the 5 micrograms/kg/d dose was considered to have a slightly better safety profile than the 10 micrograms/kg/d dose. Although there was no significant difference in the efficacy (the platelet count) between the two doses, the safety profile of the 5 micrograms/kg/d dose was slightly better than the 10 micrograms/kg/d group. Therefore, the 5 micrograms/kg/d was considered to be the optimum clinical dose.

Calcium signaling plays important roles in mammalian fertilization, such as the calcium wave in egg and the acrosome reaction (AR) in sperm. The calcium wave is accompanied by a transient increase of cytosolic calcium, which is mediated by inositol 1, 4, 5-triphosphate (IP3) induced calcium release (IICR). During AR, it is commonly recognized that influx of extracellular calcium causes a dramatic increase of cytosolic calcium. Participation of IICR in the phenomena, however, remains unclear. To investigate whether IICR also participates in calcium mobilization during AR, the present study examined the existence of the IP3 receptor family (IP3R type 1, 2 and 3) in human sperm and their changes during the reaction. Immunoblot analyses showed the existence of IP3R types 1 and 3 in human sperm, but IP3R type 2 was undetectable. The expression of IP3R type 1 was diminished after AR and was also detected in the vesiculated membrane fragment which was released by the fusion of the plasma membrane and the outer acrosomal membrane during AR. In contrast, the expression of IP3R type 3 on the blot was similar before and after the reaction. Immunohistochemical observations suggested that IP3R type 1 localized in the anterior portion of the sperm head and the expression was decreased after AR. IP3R type 3 was observed in the posterior portion of the sperm head, midpiece, and tail, and little change was found even after AR. The [ 3 H]-IP3 binding assay suggested stoichiometric interactions between IP3 and IP3Rs of nonacrosome reacted and acrosome reacted human sperm.

Background: To develop a supplementary diagnostic method for endometrial cancer by measuring the reactivity of various endometrial lesions with two monoclonal antibodies. Methods: We investigated the reactivity of various endometrial lesions with two monoclonal antibodies (MSN-1 and MSN-3) by flow cytometry (one-color and two-color methods). Results: The two-color method appeared to be suitable for use in place of simultaneous performance of the one-color methods with MSN-1 and MSN-3. The positivity rate for normal endometrium was 16.0% with the two-color method, which was lower than the rate of 30.0% obtained with concomitant used of the one-color methods. The positivity rate for endometrial cancer was high, 84.0%, with the two-color method. The positivity rate was 85.7% for well-differentiated endometrial cancer, 71.4% for moderately differentiated cancer, and 100.0% for poorly differentiated cancer; thus, the rate was high irrespective of the cellular differentiation. Conclusions: The two-color method is more useful than the one-color method as a supplementary diagnostic procedure for endometrial cancer. Cytometry 36:150–156, 1999. © 1999 Wiley-Liss, Inc.

Various risk factors were investigated in 167 cervical intra-epithelial neoplasia (CIN) case and control pairs in Japan. CIN cases showed evidence of nine known risk factors including smoking and sexual behaviour. However, after adjustment for papillomavirus infection, the highest determinant, the only remaining risk factors were: being married, early age at first pregnancy and multiparity. © 1999 Cancer Research Campaign

Human papillomavirus type 16 (HPV16) is known to be a major causative agent of cervical cancer. To test the hypothesis that an enhanced Th1 response favors the natural course of cervical intraepithelial neoplasia (CIN), we measured IgG subclasses toward HPV16 L1-capsids because IgG1/IgG2 balance reflects Th2 and Th1 responses, respectively. We examined IgG2/IgG1 ratios in sera from 67 anti-HPV16 L1-positive women; 18 were cytologically normal women, 29 were CIN patients, and 20 were cervical cancer patients. The IgG2 dominance (IgG2/IgG1 ratio >1) was observed in 94, 48, and 5%, respectively (p < 0.001). The regression rate of CIN lesions was significantly different between patients with and without IgG2 dominance: 83.3% (5/6) versus 16.7% (1/6), respectively (p < 0.05). These findings raise the possibility that IgG2 dominance toward HPV16 L1-capsids, i.e., Th1 dominance, may be a useful marker to predict viral clearance or the regression of HPV16-positive CIN.

Objective. Ovarian clear cell carcinoma is commonly associated with pelvic endometriosis. We retrospectively evaluated clinicopathological data on the association between ovarian clear cell carcinoma and pelvic endometriosis. Methods. Between 1984 and 1995, we evaluated clinicopathological data on 53 Japanese patients with primary ovarian clear cell carcinoma who had been initially treated at Keio University Hospital. The clinical backgrounds and 5-year survival rates were evaluated. Results. Twenty (37.7%) of the 53 patients had carcinoma accompanied by pelvic endometriosis. These 20 cases were classified as FIGO stage I ( n = 13, 65%), stage II ( n = 1, 5%), stage III ( n = 6, 30%), or stage IV ( n = 0). The other 33 cases of ovarian clear cell carcinoma had no evidence of association with endometriosis and were classified as stage I ( n = 19, 57.6%), stage II ( n = 2, 6.1%), stage III ( n = 9, 27.2%), or stage IV ( n = 3, 9.1%). The incidence of a positive intraperitoneal cytology in stage Ic was significantly less in the group with endometriosis than in that without the endometriosis ( n = 1, 14.3% vs n = 9, 64.3%, P = 0.03). The 5-year survival rate of stage I patients was significantly greater in ovarian clear cell carcinoma with pelvic endometriosis (100%) than in that without it (60%, P Conclusion. Patients having ovarian clear cell carcinoma with pelvic endometriosis exhibited a better prognosis than those without endometriosis, especially those patients with stage I cancer.

Trophinin, tastin, and bystin comprise a complex mediating a unique homophilic cell adhesion between trophoblast and endometrial epithelial cells at their respective apical cell surfaces. In this study, we prepared mouse monoclonal antibodies specific to each of these molecules. The expression of these molecules in the human placenta was examined immunohistochemically using the antibodies. In placenta from the 6th week of pregnancy, trophinin and bystin were found in the cytoplasm of the syncytiotrophoblast in the chorionic villi, and in endometrial decidual cells at the utero placental interface. Tastin was exclusively present on the apical side of the syncytiotrophoblast. Tissue sections were also examined by in situ hybridization using RNA probes specific to each of these molecules. This analysis showed that trophoblast and endometrial epithelial cells at the utero placental interface express trophinin, tastin, and bystin. In wk 10 placenta, trophinin and bystin were found in the intravillous cytotrophoblast, while tastin was not found in the villi. After wk 10, levels of all three proteins decreased and then disappeared from placental villi.

In vitro studies have shown that ipriflavone affects both bone formation and bone resorption, but the effect in early-stage postmenopausal women with low bone mass and a high turnover of bone metabolism is unknown. In this prospective study, we randomly assigned 60 patients with postmenopausal osteopenia or osteoporosis to receive either 600 mg/day of ipriflavone or 0.8 g/day calcium lactate, and compared the effects on bone mineral density (BMD) from the 2nd to 4th lumbar vertebrae (L2–4) and bone metabolic markers before and after one year of treatment. In the iprifravone-treated (IP) group, L2–4 BMD was similar before and after treatment (0.78 and 0.77 g/cm2, respectively), but in the calcium lactate-treated (CL) group, L2–4 BMD decreased significantly from 0.81 to 0.79 g/cm2 after 1 year of treatment (p < 0.0001). Furthermore, the rate of the decrease in L2–4 BMD was significantly greater in the CL group than in the IP group (p < 0.01). The median deoxypyridinoline (Dpd) level was significantly lower after 1 year of treatment (5.8 mmol/mmol creatinine [Cr]) than the baseline value (10.2 mmol/mmol Cr) in the IP, but not in the CL group, suggesting that IP treatment suppresses bone resorption.

At fertilization, mammalian sperm has to undergo morphological changes of acrosome, namely acrosome reaction (AR), during which a dramatic increase of cytosolic calcium in consequence of extracellular calcium influx induces acrosomal exocytosis. It has been reported that progesterone is capable of inducing mammalian sperm AR. Several authors insisted that the agent, which was so far understood to bind with intracellular receptor, might act as an agonist against cell surface r-aminobutyric acid with type A (GABAA) receptor. The mode of action is, however, still in controversy. To investigate whether progesterone-induced AR is mediated by GABAA receptor, the present study examined pharmacologically the actions of progesterone on the morphological changes of acrosome and calcium mobilization during human sperm AR. Progesterone (15 microM) stimulated AR and increased cytosolic calcium, and the AR rate was further promoted by the coexistence of GABA (15 microM). Then these phenomena were suppressed by an antagonist of GABAA receptor (bicuculline, 10 microM), a blocker of GABAA receptor-coupled chloride channel (picrotoxin, 200 microM) and an antagonist of receptor-operated calcium channel (Lantan, 250 microM), respectively. These results indicated that the complex work of GABAA receptor-chloride channel and receptor operated calcium channel might participate in progesterone-induced AR and the transient increase of cytosolic calcium.

The Rac1, a member of the Rho family proteins, regulates actin organization of cytoskeleton and cell adhesion. We used genetic analysis to elucidate the role of Rac1 in mouse embryonic development. The rac1 deficient embryos showed numerous cell deaths in the space between the embryonic ectoderm and endoderm at the primitive streak stage. Investigation of the primary epiblast culture isolated from rac1 deficient embryos indicated that Rac1 is involved in lamellipodia formation, cell adhesion and cell migration in vivo. These results suggest that Rac1-mediated cell adhesion is essential for the formation of three germ layers during gastrulation.

Objectives: Menopause is associated with a rise in serum lipid concentrations. We compared a regimen of pravastatin alone with pravastatin and hormone therapy in postmenopausal women with hyperlipidemia. Methods: We performed a double-blind, randomized, multicenter controlled study in postmenopausal women with hyperlipidemia. The women were randomly assigned to receive pravastatin alone (M group; n =25) or pravastatin and hormone replacement therapy (HRT) (MC group; n =32) for 12 weeks. Serum lipid and estrogen concentrations were measured at baseline and after 4 weeks and 12 weeks of treatment. Results: The two groups were similar with respect to baseline demographic characteristics such as age, height, and body weight. As compared with baseline, the total cholesterol (TC) concentration was 15.0% lower at 4 weeks and 17.7% lower at 12 weeks in the M group and 15.1% lower at 4 weeks and 18.3% lower at 12 weeks in the MC group. The low-density-lipoprotein cholesterol (LDL-C) concentration decreased by 25.0% at both 4 weeks and 12 weeks in the M group and by 26.8% at 4 weeks and 30.0% at 12 weeks in the MC group. Serum TC and LDL-C concentrations were significantly lower in the MC group than in the M group after 4 weeks of treatment, but there was no significant difference between the groups in serum lipid concentrations after 12 weeks. Pravastatin combined with HRT was therefore suggested to lower serum lipid concentrations earlier than pravastatin alone. There were no significant differences between the treatment groups in serum high-density-lipoprotein cholesterol concentrations or triglyceride concentrations after the initiation of therapy. In the MC group, there was a significant positive correlation between the percentage change in serum lipid concentrations and that in estrogen concentrations, suggesting that the HRT-induced rise in estrone (E1) as well as that in estradiol (E2) contributed an improved serum lipid profile. TC and E2, and LDL-C and serum E1 had significant negative correlation at 12 weeks and 4 weeks, respectively. Pravastatin had no apparent effect on endogenous estrogen levels and was not associated with any side effects, which confirmed that pravastatin is safe, either alone or in combination with HRT. Conclusions: The combination of pravastatin and HRT in the management of hyperlipidemia in postmenopausal women is very useful therapeutically, because it additionally provides the broad benefits of HRT, without compromising the lipid lowering effects of either treatment.

Missile therapy, which destroys cancer cells specifically, has been advocated as an effective modality for the treatment of carcinoma. We have developed an immunoconjugate consisting of the monoclonal antibody MSN-1 (IgM), which reacts strongly with endometrial adenocarcinomas, combined with a plant hemitoxin named gelonin via a disulfide bond using N-succinimidyl-3-(2-pyridyldithio) propionate and 2-iminothiolane, and examined its selective cytotoxicity in athymic mice. The reductions in resected weights of target tumor cells, at the local site of MSN-1-gelonin immunoconjugate treatment, were 96% with local administration and 75% with caudal vein administration, as compared with the untreated group. There was no weight loss in treated mice. Our results suggest that this MSN-1-gelonin immunoconjugate has potential clinical applications in the treatment of endometrial adenocarcinomas.

Monitoring of cyclosporine A in 40 whole blood samples from renal transplantation patients by high performance liquid chromatography with aryl oxalate-sulforhodamine 101 chemiluminescence detection is described. These data were compared with fluorescence polarized immunoassay (Cyclosporine-SP DynapackTM using monoclonal antibody for whole blood), with good results (r = 0.88, y = 0.80 + 5.07). These values are the same as reported by high performance liquid chromatography with photometric detection. By using a solid phase extraction cartridge, cyclosporine A was analyzed within 30 min. The analysis time could be shortened to one tenth that previously reported. The proposed method has the same sensitivity as fluorescence polarized immunoassay.

Cells of the human tumor cell line RMG-1, derived from a clear-cell adenocarcinoma of the ovary, were injected intraperitoneally into nude mice, and the cells obtained from the tumor nodules in the mesenterium were found to form a larger number of, and larger-sized, tumor nodules than the original RMG-1 cells. The RMG-1-h cells, transferred into culture from the tumor nodules after a 4th in vivo passage, showed a dissemination potential as high as that of cells disseminating directly from the tissues, and exceedingly higher than that of RMG-1 cells. To assess the molecular bases of the different biological properties of RMG-1 and RMG-1-h cells, we compared the content and expression of various carbohydrate antigens in both cells. The chromosomal profile of RMG-1-h cells revealed their human origin and was identical to that of the original RMG-1 cells. In contrast to the broad histogram for the Le(x)-bearing cells among RMG-1 cells in flow cytometry, the weakly and moderately positive cells toward anti-Le(x) antibody were found to be eliminated from the histogram for the RMG-1-h cells, resulting in the enrichment of cells strongly expressing Le(x), which may account for the high dissemination potential. In addition, the adhesion of RMG-1 cells to mesothelial cells was found to be significantly inhibited by pretreatment of the cells with anti-Le(x) antibody, indicating Le(x)-mediated cell-to-cell interaction between ovarian cancer cells and mesothelial cells. By TLC-immunostaining, two Le(x)-glycolipids, III3Fuc alpha-nLc4Cer and V3Fuc alpha-nLc6Cer were detected in both RMG-1 and RMG-1-h cells, and their total concentrations were not significantly different from each other. However, the hydrophobic moieties of Le(x)-glycolipids in RMG-1-h cells were different from those in RMG-1 cells, suggesting that a difference in the structure of the hydrophobic moieties of Le(x) is partly involved in the enhanced reactivity of RMG-1-h cells toward anti-Le(x) antibody. Thus, the high dissemination potential of ovarian cancer cells was shown to be mediated by the Le(x)-determinant and the Le(x)-bearing cells are enriched by repeated in vivo passage of the cells into nude mice.

In the present study, to achieve quantitative assessment of human sperm acrosome reaction by using fluorescein isothiocyanate conjugated Concanavalin A (FITC-Con A), the optimum conditions for microscopic observation were established by comparing the fluorescent images between the purified human sperm with the intact acrosome (non-acrosome reacted sperm; non-AR sperm) and those with exposed inner acrosomal membrane (acrosome reacted sperm; AR sperm). FITC-Con A stained not only the inner acrosomal membrane but also the other portions. These non-specific bindings were excluded by the competitive dissociation with alpha-D-mannose (Man) solution, the specific labeling of the inner acrosomal membrane with FITC-Con A was accomplished in the presence of 0.5 mg/mL Man. The influence of methanol fixation on the acrosome status were examined. The assessment of the acrosome reaction should evaluate whether the inner acrosomal membrane is exposed or masked by the plasma membrane, and methanol fixation is often employed in the histochemical stain. By methanol fixation, the fluorescent profiles of AR sperm were not altered before and after the treatment, bright fluorescence were found in the acrosomal regions. On the other hand, non-AR sperm gave weak fluorescence on the sperm heads before the treatment, the acrosomal regions fluoresced brightly after the treatment similar to those of AR sperm. Methanol fixation caused false positive results, it might denaturate the plasma membranes and facilitate permeability of FITC-Con A. FITC-Con A fluorescent stain and the modified triple stain (rose bengal stain) gave good positive correlation to evaluate AR sperm. This result concluded that the optimum conditions with FITC-Con A stain in the present procedure might be an useful tool for observation of human sperm acrosome reaction.

Clinically relevant animal models of human cancer are important for studies of cancer biology, invasion and metastasis, and for investigating new forms of prognostic diagnosis and therapy. An ovarian tumor line (RMG-1: human clear cell carcinoma of the ovary) previously grown subcutaneously was implanted orthotopically as intact tissue into the ovarian capsule of 22 nude mice. The tumors showed progressive growth at the orthotopic site in all animals. Tumor-associated serum galactosyltransferase (GAT) tended to be positive in all nude -mice. The tumors invaded or metastasized to the contralateral ovary, retroperitoneum, mesentery and peritoneum, and omentum, and metastasized to the subcutaneous tissue, lymph nodes and distant organs including the liver, kidney, pancreas, and diaphragm. In striking contrast, subcutaneous transplantation of this tumor resulted in growth in only 2 of 5 animals with local lymph node and kidney involvement but no retroperitoneal or peritoneal involvement. These findings suggest that orthotopic implantation provides a suitable micro-environment in which ovarian cancer can express its intrinsic clinically-relevant properties. This approach is relevant to the clinical features of ovarian cancer and is thought to be a useful model for studies of therapy for this cancer.

In this study, we determined the concentrations of acidic lipids, including cholesterol sulfate (CS), sulfatide and GM3 ganglioside, in human sera of non-pregnant state and during the course of pregnancy. In human sera of non-pregnant women, GM3 was present at a concentration of 8 nmol/ml and the concentrations of CS and sulfatides were less than 20% of that of GM3. The concentration of sulfatides in sera at the second trimester of gestation was decreased, but CS gradually increased from the first to the third trimester of gestation with a correlation coefficient of 0.66, and a correlation between the concentration of CS and weeks of gestation (p

A novel estrogen receptor, estrogen receptor beta (ERbeta), has recently been cloned from a rat prostate cDNA library. In bone, which is an important target tissue of estrogen, ER alpha has been reported to be present preferentially in osteoblasts, but the mechanism of action of estrogen in bone is still not known. In the present study, we examined expression of ERbeta mRNA in bone. Expression of ERbeta mRNA was evident in primary osteoblastic cells isolated from 1-day-old rat calvaria and rat osteosarcoma cells (ROS 17/2.8), and its level was higher than that of ER alpha mRNA. When osteoblastic cells were cultured for 28 days to induce differentiation into mature osteoblasts capable of forming bone nodules, ERbeta mRNA was constantly and highly expressed during the entire culture period. In contrast, the level of ER alpha mRNA was very low at the beginning of culture and it gradually increased during the differentiation of osteoblastic cells. Various tissues including bone were isolated from 8-week-old rats of both sexes, and total RNA was extracted to compare the tissue distribution of expression levels of ERbeta mRNA. In cancellous bone of the distal femoral metaphysis and lumbar vertebra, expression of ERbeta mRNA was obvious, and its level was equivalent to those in the uterus and testis, but lower than those in the ovary and prostate. The level of ERbeta mRNA in femoral cortical bone was lower than that in cancellous bone. There was no appreciable differences between female and male rats in the distribution and expression levels of ERbeta mRNA in bone. These results indicate that ERbeta mRNA is highly expressed in osteoblasts in rat bone, suggesting that there is a distinct mechanism of estrogen action mediated by ERbeta in bone.

We have developed a new procedure for the selective determination of beta 1-3 and beta 1-4 galactosyltransferases with Lc3Cer as the substrate and the microsomes of fetal and adult porcine livers as the enzyme sources. This method was based on the detection of such products as Lc4Cer for beta 1-3 galactosyltransferase (beta 1-3GT) and nLc4Cer for beta 1-4 galactosyltransferase (beta 1-4GT), with monoclonal anti-Lc4Cer and anti-nLc4Cer antibodies, respectively. This method thus enabled us to differentiate the activity of beta 1-3GT from that of beta 1-4GT with a high degree of sensitivity. The method was then used to determine the activities of both enzymes in human gynecological carcinoma-derived cells. Four of the five cell lines derived from uterine endometrial cancer expressed significantly high levels of specific activity of beta 1-3GT among the cell lines examined, while their beta 1-4GT activities were less than 20% of that for beta 1-3GT in the endometrial carcinoma-derived cells. On the other hand, a higher specific activity of beta 1-4GT than that of beta 1-3GT was detected in the cell lines derived from uterine cervical and ovarian cancers. These findings were thus found to correlate closely with the rate of expression of Lc4Cer- and nLc4Cer-based carbohydrate chains in the cell lines based on the results of immunohistochemical staining.

Objective: To clarify the behavior of endometrial hyperplasia in a prospective study. Method: Fifty-one patients with endometrial hyperplasia were followed up for 6 months. Samples of endometrial tissues were taken by uterine endometrial biopsy every 4 weeks during the first 3 months and at the end of follow-up. Results:/ In 69% (35/51) of the patients histological picture of the endometrium became normal during the observation period. The lesions persisted in 17% (6/35) of the patients with simple hyperplasia, in 25% (1/4) of those with complex hyperplasia, in 14% (1/7) of those with simple atypical hyperplasia, and in 80% (4/5) of the patients with complex atypical hyperplasia. In the remaining 3 patients with simple hyperplasia, the lesions progressed to complex atypical hyperplasia by the end of follow-up, after showing a normal endometrium. Conclusion: Most cases of endometrial hyperplasia, except for complex atypical hyperplasia, disappeared spontaneously within a short period of time.

BACKGROUND Dienogest is a synthetic progestational steroid that is used for contraception. It is being studied for the treatment of endometriosis, but its anticancer activity remains unknown. The authors investigated the anticancer effect of dienogest on hormone-dependent cancers. METHODS The authors used two cell lines derived from human endometrial carcinoma (HEC-88nu cells expressing estrogen receptors [ER] but not progesterone receptors [PR] and Ishikawa cells expressing both ER and PR) and a cell line derived from human breast carcinoma (MCF-7 cells expressing both ER and PR). The authors examined the in vivo antitumor activity and the antiuterotropic activity of dienogest in mice and compared it with the activity of several progestins. RESULTS At oral doses of 0.01-1 mg/kg/day, dienogest significantly suppressed the 17β-estradiol benzoate (E2)-dependent tumor growth of HEC-88nu cells, which were unresponsive to known progestins such as medroxyprogesterone acetate (MPA, 100 mg/kg/day, administered orally) and norethisterone (NES, 100 mg/kg/day, administered orally). The suppressive effect of dienogest on tumor growth was not diminished in the presence of excess MPA. Dienogest also suppressed the E2-dependent tumor growth of both Ishikawa and MCF-7 cells, both of which responded to MPA. However, the minimum effective dose of dienogest (0.01-1 mg/kg/day) was much lower than that of MPA (100 mg/kg/day). In contrast, dienogest did not suppress the E2-induced increase in uterine weight, whereas MPA and NES suppressed it significantly. CONCLUSIONS Dienogest showed potent anticancer activity against hormone-dependent cancers at doses at which progestins show no activity. Cancer 1997; 79:169-76. © 1997 American Cancer Society.

This investigation was conducted to examine the presence of fibrinogen-like substance and thrombin-like enzyme in human semen (human seminal plasma) after liquefaction. The human seminal plasma contained small amounts of respective substances which are absorbed on anti-fibrinogen and anti-thrombin III affinity columns, respectively. The thrombin-like enzyme with Gly-Pro-Arg-pNA amidolytic activity was inhibited by human seminal plasma trypsin-like enzyme inhibitor (HSP-TI) and antithrombin III. The fibrinogen-like substance reacted with the thrombin-like enzyme, forming a fibrin-like substance. It would appear that certain aspects of the coagulation process in human semen constitute the same process as the final stage of the blood coagulation system.