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Infertility is defined as a reproductive disorder in which pregnancy is established, but normal fetal growth can never be achieved due to pregnancy loss. The pathogenesis of this disorder must be understood accurately to obtain optimal results in its management. Although genetic, anatomic and hormonal factors have been implicated as to its cause, a substantial proportion of cases remain unexplained. Recently, an immunologic etiology for this disorder has been proposed for many couples with infertility due to unexplained causes. Author has evaluated patients with infertility according to two immunologic aspects, namely "autoimmune" and "alloimmune", and assessed them pathophysiologically and clinically. [Autoimmune abnormality] Autoimmune diseases, especially SLE, have been associated with pregnancy loss, with autoantibody abnormalities being speculated to be causally related to this reproductive disorder. Especially among various autoantibodies, author noticed an antiphospholipid antibody (aPL) that has been associated with micro-thrombosis, and performed the enzyme-linked immunosorbent assay. Pathophysiological evaluations performed were as follows: 1. Inhibitory effect of aPL on prostacyclin production in cultured vascular endothelial cells. 2. Existence of aPL in the elute from placental tissue. Clinical evaluations were as follows: 1. Frequency of aPL positivity among patients with infertility. 2. Correlation between frequency of aPL positivity at the placental site and the outcome of pregnancy. 3. Correlation between the selected modes of medical therapy (e.g., administration of prednisolone, aspirin, etc.) in aPL-positive cases and the outcome of pregnancy. Based on the results of the above evaluations, it was suggested that IgG-aPL can be considered a useful diagnostic and prognostic variable in women with infertility. Moreover, it was considered that the inhibition of prostacyclin production due to aPL might disturb utero-placental circulation by vasoconstriction and local vascular thrombosis in the placenta and thus lead to pregnancy loss. It was confirmed that the combination of immunosuppressive and anticoagulant therapy is, to a certain extent, an effective treatment for aPL-positive pregnant women. [Alloimmune abnormality] When normal pregnancy is viewed from an immunological standpoint, there arises a basic question of how the fetus escapes immunological rejection despite being allograft. Explanations have been based on various mechanisms of maternal immunity and some experiments were therefore attempted to elucidate the immunological mechanisms. Points of evaluation were as follows: 1. Blocking activity of serum utilizing the mixed lymphocyte reaction with lymphocytes of the husband as stimulators and those of the wife as responders. 2. Detection of HLA-class II antibody, cold-B cell antibody, and anti-idiotype antibody as blocking antibodies in the serum.(ABSTRACT TRUNCATED AT 400 WORDS)

Two hundred and forty-nine healthy women at 36 weeks gestation and 38 women with pregnancy induced hypertension (PIH) underwent urinalysis for urinary calcium excretion to obtain the calcium/creatinine ratio. This ratio was significantly lower in the women with PIH than in the healthy pregnant women, and it was especially low in those with PIH who had no family history of hypertension. Three hundred forty-eight healthy women at 20 weeks of gestation underwent urinalysis to determine their calcium/creatinine ratio as a means to predict PIH in patients showing no symptoms. In the primiparous group with no family history 58% of the patients with a low calcium/creatine ratio eventually developed PIH. Using a receiver operator curve, we calculated a predictive threshold calcium value for PIH of 0.06 at six month's pregnancy. Thus urinary calcium excretion may be a useful early marker for PIH.

The C100-3 antibodies to HCV can be examined with a Chiron kit but only the antibody to non-structure-4 can be. The antibodies in sera of pregnant women were examined by a passive hemagglutination method (PHA), which is one of the second generation kits used in detecting antibodies to the hepatitis C virus. We studied the percentage of pregnant women in our hospital with antibodies to HCV, and tried to compare the C100-3 antibodies with PHA results in pregnant women. The results are as follows. 1) In the sera of 235 pregnant women both the PHA antibody and the C100-3 antibody were examined. Two women (0.85%) had the C100-3 antibody and 4 (1.7%) had the PHA antibody. 2) Two women positive for both PHA and C100-3 antibodies were positive for PCR during pregnancy. But 2 women positive for PHA only were negative for PCR during pregnancy and positive after delivery. So 4 women positive for PHA had HCV RNA. 3) Next, the sera of 1,198 pregnant women were examined by the PHA method, and nine women were positive. Only four of the 9 were positive for C100-3. 4) It is speculated that the positive rate for anti-HCV antibodies in the sera of pregnant women in Nagoya city is 0.75%. 5) There were 3 cases that were negative for PCR during pregnancy and positive after delivery. So it is speculated that HCV can be activated after delivery.

Immunotherapy (immunization twice at 5 and 7 weeks of gestation with X-irradiated 200ml total blood or 1-200 x 10(6) mononuclear cells from the husband) was performed on 200 women without autoimmune abnormalities but experiencing habitual abortions of unknown causes between August, 1982 and September, 1990. One hundred fifty-seven babies were eventually born alive. The oldest offspring was 7 yrs 4 mos in August, 1991. We investigated the safety of the immunotherapy in terms of its effects on the women, conditions during pregnancy/labor and conducted long-term follow-up on offspring. Among 190 women whose pregnancy terminated by September, 1990, 152 cases gave birth, including 5 sets of twins. The successful rate was 80.0%. There were no complications among the 200 cases, only 2 small-for-dates babies (1.3%) among 157 babies born alive, and 1 baby born dead in the 3rd trimester, but that was not directly related with immunotherapy. Tsumori-Inage Infant Mental Development Test found no abnormalities (3 yrs and over). At 3 yrs, and only 1 child scored under the mean--2 standard deviation in height and weight. Thus, the safety of the immunotherapy was confirmed by long-term follow-up of both mother and child in which no notable complications resulting from immunotherapy with the husband's X-irradiated cells could be found.

Fleroxacin (FLRX), a new quinolone oral antibacterial agent, was studied in the field of obstetrics and gynecology, and the following results were obtained. 1. Clinical efficacy was evaluated in 105 patients (intrauterine infection 38, adnexitis 28, extragenital organ infection 29, others 10), with an exclusion of 9 patients out of a total of 114 patients. FLRX was orally administered at 200 mg or 300 mg once daily. 2. Clinical efficacy rates were 37/38 (97.4%) in intrauterine infection, 26/28 (92.9%) in adnexitis, 29/29 (100%) in extragenital organ infection and 10/10 (100%) in others. 3. Efficacy rates classified by isolated organisms were 23/23 (100%) in single infections by Gram-positive organisms, 11/13 (84.6%) in those by Gram-negative organisms, 8/9 (88.9%) in those by anaerobic organisms and 15/19 (78.9%) in mixed infections. 4. Side effects were observed in 4 cases (3.5%); gastrointestinal disorder with diarrhea and diarrhea in 1 patient each and insomnia in 2 patients. In laboratory examination, eosinophilia and elevation of GOT and GPT were noted in 1 patient each (1.9%). Based on the above results, we consider that FLRX is a useful drug for the obstetrical and gynecological infections.

It is generally difficult to treat patients with ovarian cancer. A Tenckhoff catheter was implanted in eighteen patients for intraperitoneal chemotherapy and drainage of ascites. Sixteen cases including 5 recurrent cases were treated with anticancer drug. It could not be used in two cases by bowel adhesion, so immediately catheters were removed. CDDP (100-150 mg/body) with or without Etoposide (180-300 mg/body) in 2 liters of saline was administered via Tenckhoff catheter over 30 minutes with a dwell time of 4 hours. We have studied the kinetics of CDDP and Etoposide in ascites and blood after intraperitoneal chemotherapy. High concentrations of free-CDDP and Etoposide were reached for 4 hours in the ascites but concentrations in the blood varied. These results showed obviously high values and direct effects on the tumor cells in the abdominal cavity and the peritoneal clearance depended on the severity of carcinomatous peritonitis in each case. Twelve cases showed decrease, but 4 cases increase of ascites. Five recurrent cases and one patient of stage IV died. Seven cases are outpatients and the disease free duration of their ranges are from 1 to 24 months. Three patients are now under treatment. Intraperitoneal chemotherapy elicited only mild nausea, myelosuppression and no significant changes of renal function. No patients had signs of catheter infection and peritonitis. These findings suggested that a Tenckhoff catheter was valuable to treat and manage ovarian cancer patients with little side effect.

Nephrotoxicity is the major side effect of cisplatinum (CDDP) and it is often the dose limiting factor. We have studied the effect of urinastatin (US) to decrease the nephrotoxicity of CDDP administration. 28 patients with gynecological cancer treated by chemotherapy including CDDP (13 mg/m2 daily for 5 days) were assigned to two groups, the group with US (n = 14) and the group without US (n = 14). The former was added each 150,000 units of US before and after administration of CDDP. The BUN, serum creatinine (Cre), creatinine clearance (Ccr) and the excretion of beta 2-microglobulin (beta 2-MG) index and N-acetyl-beta-glucosaminidase(NAG)index were measured. The BUN, Cre and Ccr were within normal range during four cycles. However NAG index rose remarkably when CDDP was treated by CDDP. And the increase in NAG index, which reflect the magnitude of renal tubal damage, was less in the group with US than in the group without US. It was suggested that US had effects to reduce nephrotoxicity of CDDP in chemotherapy, and that we could treat patients by high dose CDDP.

Serum CA125 levels were measured by radioimmunoassay patients with various gynecological tumors. Elevated levels of CA125 were detected in the serum of patients with malignant ovarian tumors. Among patients with uterine tumors, CA125 levels were elevated in those with malignant uterine tumors, but not with uterine myomas. The correlations between tumor markers (CA125, IAP, ferritin, PTA) and malignant ovarian tumors were measured, and only CA125 levels were found to correlate with progression or regression of the disease in patients with malignant ovarian tumors. These results suggest that CA125 may be a useful marker for monitoring the response to treatment in patients with malignant ovarian tumors.

A case of advanced cancer of the vulva that was treated by cisplatin with good result, is reported. This case was adenocarcinoma of Bartholin gland, and the clinical stage was third stage. The method of administration was intravenous injection of cisplatin (150 mg/body) in hypertonic saline (3%) for the decrease of nephrotoxicity. After administration (450 mg/body), the tumor markedly reduced. Additional operation, one course of CDDP and irradiation were carried out. After discharge, there has been no sign of recurrence for one year and five months. In this case, we used CDDP in hypertonic saline to decrease the nephrotoxicity. During these courses, the nephrotoxicity was moderate. This shows that patients can be treated by higher-doses of cisplatinum by this method.

For the purpose of studying immunogenetic factors related to disease susceptibility to cervical carcinoma (squamous cell carcinoma), HLA-A,B and DR typings were performed by the standard microlymphocytotoxicity test using about 240 typing antisera in 66 Japanese patients with cervical carcinoma and 206 healthy individuals. The results obtained were as follows: 1) The patients had a significant association with HLA-Bw46 (gene frequency = 6.3%, relative risk = 3.9, p less than 0.025), compared with the controls (g.f. = 1.7%). 2) The patients had a significant association with HLA-DRw8 (g.f. = 17.3%, r.r. = 2.3, p less than 0.05), compared with the controls (g.f. = 8.9%). 3) When the patients with cervical carcinoma were divided into two groups, i.e. 53 patients with invasive carcinoma of the cervix and 13 patients with carcinoma in situ of the cervix, the former had a more significant association with both HLA-Bw46 (g.f. = 6.8%, r.r. = 4.3) and HLA-DRW8 (g.f. = 19.2%, r.r. = 2.6) than the total patients, compared with the controls. However, the latter showed only a negligible association when compared with the controls. 4) The significant linkage disequilibrium between HLA-Bw46 and HLA-DRw8 was found in the patients with cervical carcinoma (haplotype frequency = 0.059, delta = 0.047, p less than 0.002), but not in the controls (h.f. = 0.0097, delta = 0.0075). 5) On the other hand, the significant linkage disequilibrium between HLA-A2 and HLA-Bw46 was found in both the patients and the controls.

Renal involvement associated with preeclampsia is well investigated, especially from the aspect of glomerular lesion and coagulation. On the other hand, only a few studies on tubular dysfunction during normal pregnancy and preeclampsia have been reported. The first study was carried out to clarify and estimate the chronological changes in tubular function. Pregnant women without obvious tubular dysfunction and toxemia (group A) were investigated using serum Cl, Na minus Cl (Na-Cl index), uric acid and urinary beta 2-microglobulin (u-beta-MG) at the 10th, 20th, 30th and 36th weeks of gestation. The second study was carried out to determine the significance of tubular dysfunction accompanied by preeclampsia. Patients with severe preeclampsia (group B) and normal pregnancy (group C) were examined by the same index of tubular dysfunction. The diagnosis of severe preeclampsia was confirmed with hypertension (over 170/110 mmHg), proteinuria (beyond 3 g/day) and severe edema. The following results were obtained: Urinary beta-MG and serum Cl increased during the third trimester in group A, but the Na-Cl index decreased. The serum uric acid concentration increased during the third trimester in group A. Tubular dysfunction was evident during the third trimester in normal pregnancy. Every index of tubular dysfunction including u-beta-MG, serum Cl, Na-Cl index and uric acid in group B was significantly higher than in group C. In group B, 4 fetuses died and 7 out of 15 cases required Cesarean sections. The critical line of tubular dysfunction for fetal prognosis was Cl 110 mEq/l, Na-Cl index 28 mEq/l, uric acid 6.0 mg/dl and u-beta-MG 1,000 micrograms/l.(ABSTRACT TRUNCATED AT 250 WORDS)

A continuous subcutaneous infusion of peplomycin was performed on 15 patients with cervical cancer. Eight patients received 5 mg of peplomycin a day and 7 patients received 2.5 mg a day. The peplomycin concentrating in the serum after infusion for 24 hours thus were 0.094 microgram/ml and 0.056 microgram/ml, respectively. The concentration of peplomycin in the tumor was found to be higher than in normal cervical tissue, and in the lymph nodes it was equal or higher than in the serum. Histological changes were minimum. A Grade IIa determination, however, was found in one patient, which may have been due to the total dose and/or the time of the examination. No pulmonary toxicity developed in any patients.

In the present study, comparison of the therapeutic effects of CDDP and the analogues (CBDCA, 254S, DWA2114R and NK121) on human gynecological carcinomas transplanted into nude mice (uterine cervical cancer; UZ-1-N, endometrial cancer; UE-1-N, ovarian cancer; OCl-1-N, OS-4-N and OS-8-N) was made. CDDP (5 mg/kg), CBDCA (50 mg/kg), 254S (25 mg/kg), DWA (50 mg/kg) and NK121 (18 mg/kg) were administered intraperitoneally every four days at three doses. Simultaneously the tumor size and the body weight were measured and the peripheral WBC and BUN were examined. The results were as follows: 1) The administration of 254S caused a marked inhibition of the tumor growth against all xenografts into nude mice. 2) CDDP and CDDP analogues except 254S were not effective against UE-1-N, but in this xenograft antitumor activity of 254S was remarkable. 3) With 254S, there were a decrease in body weight and the peripheral leukopenia and the elevation of BUN level were more severe. Although 254S has severe side effects, 254S is seemed to be recommendable for the treatment of gynecological malignancies.

The T/t complex in the mouse is considered to be a gene locus that brings about neural tube defects. This locus is found to exist near the H-2 complex, which is the MHC of the mouse. Accordingly, it is conceivable that there exists a T/t-like complex near the HLA complex in humans. Studies on the HLA-A, -B, -DR, -DRw52, -53 and DQ loci of parents with anencephalus and affected offspring were undertaken with the aim of revealing the relationship between anencephalus and the HLA complex. The following results were obtained: The gene frequency of HLA-DR5 in a mother with anencephalus was significantly higher than in controls. HLA-DR materno-paternal compatibility was significantly higher than in control couples. An increase in HLA-DR, -DRw52, -53 and DQ homozygosity were observed among the affected offspring. These results indicated that there may exist an anencephalus immunogenetic factor in the HLA-D region.

This study was carried out to clarify the effect of pregnancy on chronic glomerulonephritis (CGN). Fifteen patients with CGN diagnosed by renal biopsy were studied throughout 17 pregnancies. The following criteria were adopted: 1) Creatinine clearance (Ccr) over 70 ml/min and serum creatinine (s-Cr) 1.2 mg/dl or less. 2) Blood pressure lower than 140/90 mmHg when not receiving any medicine. 3) No evidence of active progress of nephropathy. In two patients excluded from the criteria, renal function was adversely affected, but there was no evidence that pregnancy affected the natural course of the underlying renal disease. In the patients to which the criteria were applied, the outcome of pregnancy and renal function were good. In conclusion, we recognized that there was no relationship between the body weight of the newborn and maternal serum albumin but that there was a significant correlation between serum uric acid and body weight (r = -0.67). These results show that serum uric acid is a useful indicator of placental dysfunction and fetal growth. In the patients with preeclampsia, the serum uric acid concentration was higher than in the CGN group (8.95 +/- 2.58 mg/dl vs 5.88 +/- 1.49 mg/dl: Scheffe method p less than 0.001). There was no significant difference between the CGN and normal control (5.88 +/- 1.49 mg/dl vs 4.51 +/- 0.68: Scheffe method p less than 0.1). Uric acid serves to distinguish CGN and preeclampsia.

An intraarterial high-dose CDDP, using a balloon catheter, has been infused into five patients with a recurrent ovarian cancer. The dose of CDDP was 150 mg-200 mg/body. Two patients experienced a partial tumor regression, whereas three showed no change. With regard to the toxicity, the NAG index (NAG activity/urinary creatinine) rose markedly in all patients, but toxicity was almost similar to that seen from a systemic administration. No significant catheter complication occurred.

Pharmacokinetic and clinical studies on a new cephalosporin antibiotic, cefodizime (THR-221, CDZM), were performed and the results obtained are summarized as follows: 1. At about 84 minutes after a bolus injection of 1 g dose of CDZM, the drug was transferred well into tissues of internal genital organs and remained there at therapeutic levels for 285 minutes. The drug was also transferred quickly and sufficiently into exudate from pelvic dead space and its levels were still kept at high levels at 6 hours after administration. 2. CDZM was given to 8 women affected with gynecologic infections. The outcome of CDZM therapies showed that the drug was effective in all 8 of patients (100%) clinically and bacteriologically. 3. Notable adverse effects or abnormal laboratory test results were not observed except for 2 patients with transient and slight elevation of transaminase levels. Based on these results, it may be concluded that CDZM is a highly effective and a very safe antibiotic for the treatment on infectious diseases in gynecologic field.

The antitumor effects of human recombinant TNF (PAC-4D) were examined on three human gynecological carcinomas transplanted into CD-1 nude mice (uterine cervical carcinoma: UZ-1-N; ovarian carcinoma: OCl-1-N and OS-4-N). PAC-4D was administered intratumorally at a dose of 1,000 U, 3,000 U or 10,000 U/head from day 0 to day 4. Tumor size, body weight and peripheral WBC were measured on days 0, 4, 8, 12 and 16 and histological studies were made on day 6. The results were as follows: With UZ-1-N, intratumoral administration of PAC-4D at doses of 3,000 U and 10,000 U/head caused a marked inhibition of the tumor growth. Similarly, antitumor activity of PAC-4D against OCl-1-N was remarkable at a dose of 10,000 U/head. The administration of PAC-4D at doses of 3,000 U and 10,000 U/head was not effective against OS-4-N. The histological changes of grade II A-B by Ohboshi-Shimosato criteria of response were observed in the tumor of the effective groups against PAC-4D. There were no influences on the body weight and WBC after administration of PAC-4D. Although tumor cells possessed different sensitivities to PAC-4D, PAC-4D is strongly recommended for the treatment of gynecological malignancies.

A new platinum coordination complex, l-OHP [oxalato (1R, 2R-cyclohexanediammine) platinum (II)], has been shown to be an active anticancer agent in animals. In the present study comparisons of the effects on human ovarian carcinomas transplanted into nude mice (OCl-1-N, OS-4-N, OY-1-N) between l-OHP and CDDP, were investigated. l-OHP (6 mg/kg, 9 mg/kg) and CDDP (3 mg/kg, 6 mg/kg) were administered intraperitoneally in a schedule of every four days for three doses. Simultaneously the tumor size and the body weight were measured and the peripheral WBC and serum BUN were examined. The results were as follows: 1) The antitumor activity of l-OHP corresponded to that of CDDP in proportion to the Pt content and mouse LD50. 2) In l-OHP, there was no elevation of the BUN value and less decrease in body weight, but the peripheral leukopenia was more severe, although reversible. l-OHP is an active anticancer agent against xenografts in nude mice and is strongly recommended for clinical application.

The BUN, serum creatinine, creatinine clearance and the urinary excretion of leucine aminopeptidase (LAP), alkaline phosphatase (ALP), beta 2-microglobulin (beta-m), and N-acetyl-beta-glucosaminidase (NAG), were measured in 21 gynecological cancer patients treated with CAPF (CPA + ADM + CDDP + 5-FU) to evaluate the sensitivity of these indices to renal tubular damage. After receiving CDDP almost all patients displayed an increase in excretion of beta-m but no urinary enzyme activities. However, NAG index (NAG activity/urinary creatinine) rose markedly in all patients. We concluded that NAG index is a valuable method in providing sensitive indices for detecting renal tubular damage caused by CDDP.

Aztreonam (AZT), a new monocyclic beta-lactam antibiotic was studied on clinical efficacy for infectious disease in gynecological field. At about 80 minutes following intravenous injection of 1 g dose of AZT, it penetrated well into internal genital organs at therapeutic levels. Moreover it transferred very fast and enough into intrapelvic dead space exudate, and its level was kept still as high at 12 hours after administration. AZT was given to 20 women affected with gynecological infectious disease. The outcome of AZT therapy was as follows: effective in 5 out of 6 patients (83.3%) administered intravenously and in all of 14 patients (100%) received intramuscularly. Notable adverse effects or abnormal laboratory findings were not observed except 1 case of diarrhea and 2 cases of transient and slight elevation of serum CPK and transaminases. Based on these results, we may conclude that AZT is a highly effective and a very safe antibiotic for the treatment of infectious disease in gynecological field.

In our series of investigations concerning immunopotentiators, we evaluated the host immunocompetence of patients triggered by PSK. Our subjects for screening consisted of seven patients with malignant tumors of female reproductive organs chosen at random from our patients. Four of them were treated with chemotherapy (CAPF) alone and served as controls, whereas the other three were administered PSK, 3.0 g/day, plus chemotherapy as above. Cellular and humoral immunities were measured at three points. Firstly prior to chemotherapy, secondly, two weeks after the start of chemotherapy, and thirdly, prior to next chemotherapy. The results indicated higher values of T-cell subset ratio OKT-4/8 of 2.73 +/- 0.56 on the average for cellular immunocompetence as compared to 1.35 +/- 0.45 for normal subjects in the PSK-administered group, whereas there was no increase in the non-PSK-administered group, in which the value was 1.28 +/- 0.30. Thus, PSK was considered to extert an immunopotentiating effect on the T-lymphocytes.

Primary squamous cell carcinoma of the endometrium is extremely rare. The patient reported here with squamous cell carcinoma of the endometrium and a synchronous adenocarcinoma of the cervix, represents an extreme, unique example of multiple Müllerian neoplasms. The 70-year-old female had a three-month history of vaginal bleeding. On July 13, 1984, she underwent a radical hysterectomy with a pelvic lymphadenectomy. A histological examination substantiated keratinizing squamous cell carcinoma of the endometrium this tumor extending outside the uterus, and an adenocarcinoma of the cervix. Post-operatively she received chemotherapy and irradiation therapy, but metastases reoccurred and she died on December 1, 1984.

Eight patients with gynecologic cancer (cervix: 6, corpus: 1 and vulva: 1) were treated with combination chemotherapy, PPM therapy consisting of continuously infused PEP 4mg/m2 days 1-5, CDDP 13 mg/m2 days 1-5, and MMC 3mg/m2 day 1. This was repeated every three to five weeks. Six of the eight patients were evaluable, two had a complete response and one had a partial response, for an overall response rate of 50%. Because of hematological toxicity, blood transfusion was carried out in four patients. Nephrotoxicity and pulmonary toxicity were slight. Nausea and vomiting were controlled with dexamethasone and domperidone. PPM therapy is considered to be an effective and useful combination chemotherapy for patients with gynecologic cancer.