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A patient with a huge intraabdominal fibromatosis connected by a pedicle to the posterior wall of the uterus is described. The blood supply to the tumor was exclusively from the uterus. CA 125 antigen in the patient's serum was elevated. The origin of the tumor is unknown but possibly from non-specific fibrous stroma in the uterus or peritoneum. We measured steroid receptors in the tumor and related tissues (peritoneum and cultured peritoneal fibroblasts), for information on steroid activity.

To evaluate the efficacy of imipenem/cilastatin sodium (IPM/CS) in the field of obstetrics and gynecology, fundamental (measurement of IPM/CS concentrations in mothers' milk) and clinical studies were performed. Concentrations of IPM/CS in mothers' milk were measured every 1 hour up to 6 hours after a 30-minute drip infusion of 500 mg/500 mg of IPM/CS. IPM/CS was distributed similarly to other cephalosporins. In the clinical study, a 500 mg/500 mg dose of IPM/CS was administered to 5 patients with puerperal intrauterine infections and to 3 patients with urinary tract infections by a 30-minute drip infusion b.i.d. or t.i.d. Good responses were observed in all 8 patients, though the infections were mild or moderate. From these results, IPM/CS appeared to be a useful drug for the treatment of perinatal infections.

Pharmacokinetic and clinical evaluations of ceftizoxime (CZX) in 3 obstetrical and gynecological clinics have substantiated the therapeutic usefulness of this drug in the relevant specialty. The results are summarized below. 1. The peak serum CZX concentration after drip infusion of 2 g given over 60 minutes was 115.3 micrograms/ml. The peak CZX concentration in the pelvic dead space exudate was 34.10 micrograms/ml which was attained 2.02 hours after beginning infusion. Half-lives of CZX in the serum and in the pelvic dead space exudate were 1.64 hours and 3.65 hours, respectively. 2. The passage of infused CZX to the umbilical cord serum was satisfactorily rapid, as evidenced by figures reaching 10 micrograms/ml or higher at 1 hour and 15 minutes and still as high as 3 micrograms/ml or higher at 6 hours after administration. 3. The passage of CZX to the milk of mothers receiving this drug was low, and no untoward effect on the infant was likely. 4. CZX would effectively prevent infections due to premature ruptures of membrane.

The effects of copper ions on the binding of steroids to receptors revealed that the inhibitory effect of Cu++ was apparent at 10(-6)M, ANd the binding capacities decreased to 10% at 10(-2)M Cu++. The kinetic study demonstrated that Cu++ was a competitive inhibitor of steroid hormone-receptor binding (Ki divided by 2.7 X 10(-5)M to estrogen receptor; Ki divided by 5.1 X 10(-6)M to progesterone receptor). These results indicate that copper ions interfere at the steroid-binding site of receptor and that progesterone receptor is more affected by copper ions than is estrogen receptor. The sedimentation pattern showed the dissociation and aggregation of receptor macromolecules by copper. These phenomena may indicate the biologic inactivation of receptor. In fact, morphologically, progestational proliferation was severely inhibited and estrogenic action seemed to be inhibited. The Timm stain showed copper uptake by endometrial epithelium and superficial stromata. The copper content apparently increased in the cytoplasm of uteri bearing a copper intrauterine device, compared with controls. In vivo, the concentration of cytoplasmic copper was approximately 1.4 X 10(-6)M, which was obviously inhibitory to steroid hormone-receptor interaction. However, complete morphologic suppression of the progestational effect by copper cannot exclude the coexistence of some other mechanism in these phenomena.

There is a strong association between preterm labor and infection, presumably through an increase in prostaglandin (PG) formation. The studies presented in this report were undertaken to evaluate whether bacterial products stimulate endogenous phospholipid hydrolysis and arachidonic acid liberation by the action of phospholipase A2, a rate-limiting step for PG synthesis. When human endometrial cells prelabelled with [3H]arachidonic acid to an isotopically steady state were exposed to a medium conditioned with Bacteroides fragilis, arachidonic acid liberation was stimulated, accompanied with lysophospholipid formation. Similar stimulatory effect on phospholipid degradation was also observed in the experiments with the bacterial extract. These results demonstrate that the organism produces phospholipase A2 acting on endogenous phospholipids and/or factor(s) activating phospholipase A2. Phospholipase A2 is suggested as a mechanism for the onset of labor associated with intra-amniotic infection and arachidonic acid liberation.

We examined the cytosolic estrogen receptor (ER) level in tumor tissue from 77 patients: 36 meningiomas, 20 gliomas (12 glioblastomas, 2 cerebellar astrocytomas, 2 ependymomas, and 4 medulloblastomas), 8 neurinomas, 7 pituitary adenomas (2 prolactin-producing adenomas, 1 growth hormone-producing adenoma, and 4 nonfunctioning adenomas), and 6 metastatic brain tumors (1 from breast cancer, 4 from lung cancers, and 1 from colon cancer). Nuclear ER levels were assayed in 11 meningiomas and 2 glioblastomas. ER was determined by the dextran-coated charcoal method and calculated by Scatchard analysis. Cytosolic ER was detected in 100% of the pituitary adenomas, 50% of the meningiomas, 50% of the metastatic brain tumors, 25% of the neurinomas, and 15% of the gliomas. In gliomas, only medulloblastomas had ER activity. Nuclear ER was found in three premenopausal women with meningioma. The dissociation constant of the ER complex was, in each case, less than 10(-9) M. These observations suggest that some brain tumors may be responsive to estrogen via the cellular ER.

The relationship among the prognosis of a patient with cancer of the cervix and endocrine background [production of estrogen receptor (ER), progestogen receptor (PR), and androgen receptor (AR)], clinical stage, histological type, lymph node metastasis, age, and treatment was studied. ERs were detected in almost all cases, regardless of the histological type of cancer. The detection rate and level of PR were in the decreasing order of large-cell non-keratinizing (LNK) carcinoma, keratinizing (K) carcinoma, and small-cell non-keratinizing (SNK) carcinoma of the cervix. Thus, the presence and level of PR in squamous cell carcinoma of the cervix were considered to be an indicator of the degree of differentiation. PR was not detected in cases of adenocarcinoma of the cervix. This may explain the poor responsiveness to progestogen treatment in adenocarcinoma of the cervix. There was no relationship between the patient's prognosis and the presence of PR or AR, but the prognosis of patients with lesions rich in ER (greater than or equal to 5 fmol/micrograms DNA) tended to be better than that of patients with lesions poor in ER (less than 5 fmol/micrograms DNA). The prognosis of patients before menopause tended to be better than that postmenopause. These findings indicate a relationship between cancer of the cervix and endocrine background.

This study was designed to investigate the chromatin transcription in vitro by progesterone-receptor complex in the estrogen-primed rabbit uterus. RNA synthesis by the uterine chromatin was stimulated when progesterone-uterine cytosol complex was bound to the chromatin and the stimulation was dependent upon the dose of the bound progesterone-cytosol 8S complex and upon the incubation time of the complex in the presence of the chromatin. Either norethindrone- or dydrogesterone-uterine cytosol complex also stimulated the uterine chromatin transcription but the extent was less than that of progesterone complex. These results indicate that progesterone as well as synthetic progestogens can directly regulate chromatin transcription via progesterone receptor in the rabbit uterine cells.

This study was designed to detect either 5alpha-dihydrotestosterone (DHT) or 17beta-estradiol (E2)-binding protein in the testes of a 1-year-old patient with testicular feminization syndrome (TFS) and in the testes of patients with prostatic cancer. Sucrose gradient analyses revealed E27S protein binding (but no such 7S protein binding of DHT) in the testes of the patient with TFS, but both E2 and DHT 7 S protein binding was observed in normal senile testes. The dissociation constants (Kd) were measured by charcoal adsorption. The Kd of E2 protein binding in both testes of different status was approximately 1.3 x 10(-9) M, and the Kd of DHT protein binding was 2.0 x 10(-9) M in the senile testes. A ligand specificty study indicated characteristics of both E2 and DHT receptors in the senile testes. It is speculated that a deficiency of androgen receptor and the presence of estrogen receptor in the testes of patients with TFS lead to insensitivity to androgen as a result of the androgen receptor deficiency and to sensitivity to estrogen as a result of the presence of the estrogen receptor.

The copper-IUD has been proved to be more effective for contraception than the popular IUD. To understand this mechanism of action, the effects of metallic ions on estrogen and progesterone receptors were examined in the cytosol of estrogen primed with female rabbits. The 274,200 X G supernatant of the uterine homogenate was used as the cytosol. The cytosol and 3H-progesterone (3.12 X 10(-9)M) or 3H-estradiol-17 beta (3.46 X 10(-9)M), with or without various metallic ions of different concentrations had been incubated for 2 hours. Bindings of steroids were estimated by the dextran coated charcoal assay (0.001% dextran and 0.1% Norite A) and were evaluated by 5 approximately 20% sucrose linear gradient centrifugation 1) Effect of various metallic ions on steroid hormone-receptor binding (determined by dextran coated charcoal assay. Fig. 1) : Thesteroid hormone-receptor interactions were markedly inhibited by Cu++, Fe++, and Zn++ ions and moderately by Mn++, but K+ and Ca++ increased of slightly affected the binding at concentrations between 10(-2)M and 10(-4)M. There were some differences between estrogen and progesterone receptors in their sensitivities to various metallic ions. 2) The effect of copper ion on the binding of steroid to the receptor : The dextran coated charcoal assay (Fig. 2) demonstrated that the inhibitory effect of Cu++ appeared at 10(-6)M and the steroidhormone-receptor bound decreased down to 10% at 10(-2)M Cu++. The estrogen receptor was less affected by copper than the progesterone receptor. It was demonstrated by 5 approximately 20% sucrose linear gradient centrifugation (Fig 3) that estrogen and progesterone receptors, which both sedimented at 8 S, were changed to more sedimenting forms in the presence of 10(-4)M Cu++, and were dissociated to 6.5 S form with moderate loss of steriod hormone binding affinity in 10(-2)M Cu++. The kinetic study (Fig 4), determined by dextran coated charcoal, showed that Cu++ was a competitive inhibitor against steroid hormone receptor bindings with Ki in equilibrium 2.7 X 10(-5)M to estrogen receptor (Kd in equilibrium 1.4 X 10(-9)M), and with Ki in equilibrium 5.1 X 10(-6M to progesterone receptor (Kd in equilibrium 8.1 X 10(-10)M). These results indicate the inhibiting factor of copper is the direct interference at the steriod binding site of the receptor, resulting in the increase in the effectiveness of the IUD. While progesterone receptor is more affected by copper ion than estrogen receptor, it is suggested that estrogen receptor survives longer than progesterone receptor and thus the biolgoical effect of copper seems to be somewhat estrogenic.

Estrogen receptor (ER) in the C3H mouse mammary tumor was characterized in the cytosol and determined in the nuclear KCl extract and the nuclear KCl unextractable fraction (non-extract). In the cytosol, the estradiol (E2)-ER complex was sedimented in the 8S region by 5-20% linear sucrose gradient centrifugation. A steroid specificity study showed the presence of estrogen-specific binder with a dissociation constant (Kd) of approximately 2 nM. ER levels in the cytosol, the nuclear KCl extract, and the suspension of nuclear KCl unextractable fraction were determined by Scatchard analyses, using the dextran-coated charcoal (DCC) adsorption method for the former two and the sedimentation method for the latter. Although ER was present in the nuclear fractions, it seems more plausible that cytosol ER contributes to nuclear translocation of the estrogen-ER complex. The results suggest the presence of an intranuclear mechanism for the estrogen action.

The nuclear translocation of receptor-progestogen complex was investigated in the estrogen-primed rabbit uterus. To avoid the influence of the in vivo steroid metabolism, the incubation of cytosol with progestogens, and that of the nuclear suspension with steroid-cytosol complex were performed in the in vitro systems. The quantity of the steroid receptor translocated by progestogens to the nucleus was measured using the [3H]-progesterone exchange assay. [3H]-progesterone-receptor complex in the cytosol was exchanged for cytosolic receptor sites by progesterone, dydrogesterone or norethindrone effectively. When the steroid receptors translocated to the nucleus by such steroids in the in vitro system were determined using exchange assay, progesterone translocated the receptor to the nucleus much more than did dydrogesterone or norethindrone. It was suggested that progesterone was potent in the ability of the nuclear translocation of its own receptor. The highly potent biological activities of norethindrone and dydrogesterone in vivo must be explained in the other way.

To support the estrogen hypothesis in the pathogenesis of leiomyoma, total cellular estrogen receptor (ER) levels (the sum of levels in cytosol and nuclear KCl-extractable and nuclear non-KCl-extractable fractions) were assayed and compared with levels of progestin (PR) and androgen (AR) receptors in the leiomyoma and the corresponding myometrium. The ratios of ER to PR or AR levels were higher (with statistical significance) in leiomyoma than in the corresponding normal myometrium, both in terms of total cellular levels in each individual case and nuclear levels. It appears that estrogen sensitivity is higher in the leiomyoma than in the corresponding myometrium, due to the relative increase in ER.

To assess the action of some components of herbal medicine, glycyrrhizin, glycyrrhetinic acid, and paeoniflorin, on steroids, their binding to several classes of intracellular and serum steroid-binding proteins were studied in the rabbit. The affinity (inhibitor constant) for binding of dihydrotestosterone-sex hormone binding globulin in the serum (dissociation constant of 2.0 nmol/L for dihydrotestosterone) was approximately 520 nmol/L, and that for the binding of cortisol-corticosteroid-binding globulin in the serum (dissociation constant of 2.0 nmol/L for cortisol) was approximately 10 mumol/L. In the uterine cytosol, the inhibitor constant value for estradiol receptor binding (dissociation constant of 1.0 nmol/L) was 0.9 mumol/L, and these compounds did not influence progestin receptor binding (dissociation constant of 1.4 nmol/L). The inhibitor constant values for glucocorticoid receptor binding (dissociation constant of 1.0 nmol/L) in the liver cytosol were 3.0 nmol/L for paeoniflorin, 2.0 nmol/L for glycyrrhizin, and 1.7 nmol/L for glycyrrhetinic acid, and those for mineralocorticoid receptor binding (dissociation constant = 1.1 nmol/L) in the kidney cytosol were 3.5 nmol/L for paeoniflorin and glycyrrhetinic acid and 3.0 nmol/L for glycyrrhizin. These results suggest that herbal extracts such as the above compounds influence steroid effects by glucocorticoid and mineralocorticoid receptors and to a lesser extent by estrogen receptors or serum sex hormone-binding globulin and corticosteroid-binding globulin.

Concentrations of receptors for estrogen (ER), progestin (PR) and androgen (AR) were measured in the cytoplasm and nucleus of human endometrium, throughout the normal menstrual cycle. Endometrial cellular ER and PR levels gradually increased during the preovulatory and immediate postovulatory phases, remained constant at the maximal level during the mid-secretory phase and gradually decreased to the lowest level at the end of the cycle. There was a difference between ER and PR nuclear levels in the mid-secretory endometrium, where maximum levels of PR and low levels of ER were noted. This PR abundance indicates the necessity of progesterone action for implantation. During the menstrual cycle, AR sites did not change noticeably and far fewer were found than those of the other receptors. This finding indicates that androgen plays a less important role in female reproduction.

Norethindrone (ENT), which is a representative in estrane series of progestogen, is not only strongly progestational but also estrogenic and in some cases, antiestrogenic. To understand progestational effect and antiestrogenic effect, the interactions of ENT on estrogen and progestogen receptors were studied in the uterine cytosol of white female rabbit. The 274,200 X G supernatant of uterine homogenate was used as cytosol. 3H-Estradiol, 3H-Progesterone, 3H-ENT or cold ENT were incubated with uterine cytosol at 4 degrees C for 2 hours. Results are as follows: 1. Sucrose gradient centrifugation [5 approximately 20% linear and 40,000 rpm (159,200 X G) for 16 hours at 4 degrees C]: ENT was bound to extrogen 8S receptor in immature rabbit uterus (Fig. 2 & 3), and to progestogen 8S receptor in estrogen primed rabbit uterus (Fig. 5). 2. Kinetic study, determined by dextran coated charcoal (0.001% dextran and 0.1% charcoal): (1) In the uterine cytosol of immature rabbit, 3H-estradiol-receptor binding was observed with Kd divide by 3.6 X 10-9 M and it was revealed that ENT was a competitive inhibitor to this binding with Ki divide by 2.6 X 10-6 M, as in Fig. 6. (2) 8S component, obtained by centrifugation of uterine cytosol (Fig. 1) in estrogen primed rabbit, binds 3H-progesterone with Kd divide by 8.1 X 10-10 M and Bm (maximal binding sites) divide by 5.0 X 10-8 M/mg of protein, and ENT was a competitive inhibitor in this binding with Ki divide by 2.3 X 10-9 M (FIG. 7 & 8). 3H-ENT-8S binding was demonstrated with Kd divide by 1.1 X 10-9 M and Bm divide by 8.7 X 10-8 M/mg of cytosol protein (Fig. 8). These results indicate: (a) ENT is bound to both estrogen and progestogen receptors in 8S macromolecules of uterine cytosol, (b) competitive inhibition of ENT to these bindings indicated that ENT is bound to these receptors at the steroid binding sites where estradiol and progesterone bind to, (c) ENT has much more affinity to progestogen receptor (Ki divide by 2.3 X 10-9 M) than to estrogen receptor (Ki divide 2.6 X 10-6 M), (d) while ENT is bound to progestogen and estrogen receptors at the same time, Bm of ENT (8.7 X 10-8 M/mg of cytosol protein) is more than Bm of progesterone (5.0 X 10-9 M/mg of cytosol protein), and Kd of ENT (1.1 X 10-9 M) was less than Ki of ENT (2.3 X 10-9 M) in the binding to progesterone-receptor. Biologically, while ENT is bound to progestogen -receptor with high affinity and to estrogen receptor with low affinity, ENT is actually progestational in low dose and antiestrogenic in high dose but the anti-estrogenicity seems to be incomplete in vivo as ENT may be metabolized to a potent estrogenic compound, ethinyl estradiol

To understand the mechanism of action of danazol, the binding of danazol to multiple classes of intracellular steroid binding proteins was studied in the human uterine endometrium. Danazol bound to endometrial receptors for estrogen, progesterone, and androgen and seemed to bind to endometrial intracellular corticosteroid-binding globulin and sex-hormone-binding globulin. Danazol occupies almost all binding sites of steroids in the steroid target cells in spite of the presence of endogenous steroids. It is speculated that the binding behavior of danazol may be related to its therapeutic effect on endometriosis.

Clinical study was performed to review the treatment of carcinoma of the uterine cervix in 525 cases treated by surgery, radiotherapy, the combination of both, and others at Dept. of Obstetrics and Gynecology, Gifu University Hospital during 10 years from April 1, 1972 through March 31, 1982. 1) Of 525 cases, 80 were classified as stage 0 by the criteria of FIGO, 178 as stage I (39 as Ia, 139 as Ib), 164 as stage II(8 as IIa, 156 as IIb), 98 as stage III and 5 as stage IV. 2) The five year cumulative survival rate was 78.2% for all invasive 445 cases excluding stage 0, 93.8% for stage I, 82.3% for stage II, 45.9% for stage III, and 20.0% for stage IV. 3) The five year cumulative survival rate was 85.1% for stage II cases which were treated by surgery or the combination of surgery and radiotherapy, and 63.8% for stage III. However the five year cumulative survival rate was 60.0% for stage II cases which were treated by radiotherapy only, and 32.0% for stage III. 4) The rate for the cases with adenocarcinoma was 3.8% (17/445) in all invasive carcinoma of the uterine cervix. The five year cumulative rate was 47.1% for the cases with adenocarcinoma, and 79.4% for those with squamous cell carcinoma.

In this report, the maternal and fetal risks in a patient with paroxysmal nocturnal hemoglobinuria (PNH) were evaluated. A patient with PNH carried a pregnancy to successful delivery, with a healthy male infant, and suffered from postpartum cerebral subcortical, but not hepatic, thrombosis followed by recovery. An elevation of serum levels of lactate dehydrogenase isoenzyme, alpha-hydroxybutyrate dehydrogenase, was observed during pregnancy. The level was ameliorated to the non-pregnant level by delivery. However, hemoglobin concentrations during pregnancy and post-partum were at least 8 g/dl. This is a first report that shows tight coupling between an onset of intravenous hemolysis and pregnancy. The management of pregnancies in such patients is also discussed.

The structural elements of 19-norprogestogens which may be essential for binding to progesterone and estradiol-17beta(E2) receptors were investigated in the rabbit uterine cytosol. The kinetic study showed that 19-nor-progestogens are competitive inhibitors of progesterone-receptor (8S) binding and E2-receptor binding. The affinities of steroids for the progesterone receptor were as follows: norethindrone (Ki of 2.3 X 10(-9)M) greater than 5alpha-dihydronorethindrone greater than norethindrone acetate greater than lynestrenol greater than 17alpha-ethynyl-estra-4-ene-3beta, 17beta-diol greater than ethynodiol diacetate (Ki of 1.3 X 10(-7) M). The affinities of steroids for the E2 receptor were as follows: ethynodiol diacetate (Ki of 1.3 X 10(-7)M) greater than 17alpha-ethynyl-estra-4-ene-3beta, 17beta-diol greater than norethindrone acetate greater than norethindrone greater than 5alpha-dihydronorethindrone greater than lynestrenol (Ki of 8.4 X 10(-7)M). The results indicate that 3-ketone and 17beta-hydroxyl groups, and the plane of ring A/B of 19-norprogestogen are important for binding to the progesterone receptor. The affinities of 19-nor-progestogens for the E2 receptor were very weak. Their affinities for the E2 receptor increased with addition of acetate or hydroxyl groups at the 3beta and 17beta positions, and were decreased by the elimination of a 3 oxygen function or the reduction of ring A.

A case of upper gastrointestinal dilatation associated with fluid collection in the peritoneal cavity is reported where the prenatal diagnosis was made sonographically in a non-immunologic hydrops fetalis. Neither generalized edema nor pleural effusion were detected. Polyhydramnios was complicated. Almost complete drainage of the abdominal fluid was accomplished with rapid re-accumulation of fetal ascites and no resolution of intestinal dilatation. After delivery by Cesarean section, the male infant died the next day due to respiratory distress syndrome. Postmortem histologic examination failed to confirm the ultrasonographic findings including ileal obstruction and subsequent hypoplasia in the colon. Despite the discrepancy between clinical and pathologic findings, the findings of this case would improve the etiology of hydrops where no possible cause is found.

To assess the action of herb extracts, glycyrrhizin and paeoniflorin, upon steroids, their binding to several classes of intracellular and serum steroid-binding proteins was studied in the rabbit. Glycyrrhizin and paeoniflorin exhibited similar binding behaviors. They bound minimally to estrogen and androgen receptors, but not to the progesterone receptor in uterine cytosol, and exhibited a moderate binding activity to glucocorticoid receptors in liver cytosol. They also exhibited weak binding activity to both cortico-steroid-binding globulin and sex-hormone-binding globulin.

Stimulated inositolphospholipid turnover has been proposed to constitute a signal-transducing mechanism in many cell types. To determine the inositolphospholipid turnover during stimulation by 17 beta-estradiol, the turnover kinetics of phospholipids was investigated in human endometrial fibroblasts. In cells incubated with [32P] phosphate for 1 h, estradiol rapidly and persisitently (for at least 30 min) enhanced the rate of 32P-labeling of phosphatidic acid (PA). On the other hand, after a lag time of 5 min, 32P-labeling of phosphatidylinositol (PI) was also increased also. These sequential 32P-labeling of PA and PI demonstrated that inositolphospholipid turnover was stimulated in fibroblasts exposed to estradiol. The rapid estrogen-stimulated inositolphospholipid turnover may not be through the mechanism associated with classical action of estrogen.

Receptor-stimulated hydrolysis of polyphosphoinositides by action of phospholipase C appears to be an important mediator of cell activation through the generation of the second messengers, in particular inositol triphosphate (IP3). In order to understand placental function better, activity of IP3 production from membrane in cell-free system was examined. Incubation of membrane preparation from [3H]inositol-labelled human placenta with Ca2+ in the presence of 1 mM ATP and 1 mM GTP resulted in the rapid production of IP3 in a dose dependent manner; half-maximal effect occurred at 10 microM. On the other hand, little effect was observed in the case of membrane prepared from [3H]arachidonic acid-labelled placenta, suggesting higher requirement of Ca2+ for phospholipase A2 activation. These data suggest that placenta contains phospholipase C hydrolyzing polyphosphoinositide at physiological concentration of Ca2. This is the first report to provide direct evidence of transmembrane signalling mechanisms in the human placenta, and may provide a clue to the etiology of placental disorders.

Cefodizime (CDZM, THR-221), a newly developed injectable cephem antibiotic agent, was evaluated for its distribution in intrapelvic genital organ tissues, penetration into exudate of retroperitoneal space and breast milk and therapeutical effects on some infections in obstetrics and gynecology. The results obtained are summarized as follows. 1. When 1 g of CDZM was administered by drip infusion over a 60 minutes period, its serum concentration reached 53.51 micrograms/ml at the completion of drip infusion, then declined rapidly. Peak concentrations of CDZM in intrapelvic genital organ tissues were higher than 20 micrograms/g at different times. CDZM was transferred to the exudate of retroperitoneal space and its concentration reached a peak of 7.01 micrograms/ml at 2.67 hours after initiation of 60 minutes drip infusion at a dose of 1 g, then declined slowly but stood at 4.93 micrograms/ml even at 8 hours. The transfer of CDZM to breast milk was similar to other cephem antibiotic agents and peak levels of CDZM in milk were 0.13-0.36 microgram/ml at 2 or 3 hours after administration of a dose of 1 g. 2. In the clinical study, CDZM was administered by drip infusion over 60 minutes to 6 patients with obstetrical and gynecological infections at a daily dose of 2-6 g. Clinical results were good in 5, poor in 1, and the efficacy rate was 83.3%. No side effects nor abnormal laboratory test results were observed.

In four ovarian cancer patients with malignant ascites, 10 KE of OK-432 was intraperitoneally administered four times every other day for priming, and 40 KE of OK-432 in a single dose by the same route on day 13 for triggering. The changes in peripheral blood monocytes and intraperitoneal macrophages and the production of tumor necrosis factor (TNF) by peripheral blood mononuclear cells (PBMC) and ascitic lymphoid cells (ALC) were examined. In two of the four patients in whom TNF was induced in the ascites, the TNF production by PBMC and ALC was noted during priming, and after triggering, an increase in both the number of intraperitoneal macrophages and the TNF production by ALC was noted. In two other patients in whom TNF was not detected in the ascites, the ratio of intraperitoneal macrophages to ALC did not change throughout the whole period, and the TNF production by ALC was not augmented. These findings suggest that the priming administration of OK-432 can induce both intraperitoneal macrophages and peripheral blood monocytes into a primed state, and the triggering administration of OK-432 can increase the number of intraperitoneal OK-432-primed macrophages and induce TNF release from these cells.

To clarify the relation between steroids and prolactin (PRL) production in human decidua, the levels of estrogen receptors (ERs), progesterone receptors (PRs), and androgen receptors (ARs) and the level of PRL in the decidua were determined simultaneously during early pregnancy. Cytosol, nuclear, and total ER levels and the cytosol PRL level were found to increase with the advance of gestation; whereas levels of PRs and ARs remained constant. Multiple regression analysis showed that the multiple correlation coefficient in the relationships of cellular ERs and cytosol PRL with gestational age was 0.722 and relatively high among the others. These results suggest an association between estrogen and decidual growth. Significant correlations between the cytosol PRL level and cellular PR or AR levels were seen during early pregnancy, suggesting that progestin and androgen may regulate PRL synthesis.

To understand the mechanism of biological action of gestrinone (R2323), which has a therapeutic effect against endometriosis, the binding of gestrinone to numerous classes of intracellular steroid binding proteins was studied in the human uterine endometrium. Gestrinone bound to endometrial receptors for estrogen, progesterone and androgen, but seemed not to bind to endometrial intracellular corticosteroid-binding globulin and sex hormone-binding globulin. Gestrinone occupies all specific binding sites of steroids in the steroid target cells despite the presence of endogenous steroids. It is speculated that the binding behavior of gestrinone may be related to its therapeutic effect on endometriosis. Gestrinone's more avid affinity for estrogen receptor may be the reason for the ability to use a lower clinical dose of gestrinone.

Steroid receptors in endometriosis and adenomyosis were investigated to clarify their clinical significance. The receptor levels were determined by Scatchard plot analysis (4 degrees C, by dextran-coated charcoal). In the cytosols of both tissues, the 17 beta-estradiol-estrogen receptor (ER) complex demonstrated a dissociation constant (Kd) of 4.5 x 10(-10) M; the Kd of the progesterone-progesterone receptor (PR) complex was 1.5 x 10(-9) M; and the Kd of the dihydrotestosterone-androgen receptor (AR) complex was 4.0 x 10(-10) M. Seven cases of ovarian endometriosis were studied. The ER and PR levels in endometriosis seemed to be lower than those in the corresponding normal endometrium. AR was also present. There was a suggestion that most endometriosis is least responsive to progestogens. Ten cases of adenomyosis were studied. Histologic dating revealed a delay in the most aberrant endometrial tissue in adenomyosis, as compared with dating of corresponding normal endometrial tissue. ER and AR were detected in all cases. PR was not detected in some cases and, when detected, the content seemed to be lower, possibly suggesting the delayed dating.

To four ovarian cancer patients with malignant ascites, 10 KE of OK-432 was intraperitoneally administered four times at 2 day intervals for priming, and 40 KE of OK-432 was given on the 13th day after the first injection for triggering. The changes in blood monocyte and peritoneal macrophage levels and the production of tumor necrosis factor (TNF) by blood mononuclear cells (BMCs) and ascitic lymphoid cells (ALCs) were examined. In the two patients in whom TNF was induced in the ascites, TNF production by BMCs and ALCs was noted during priming. After triggering, increases in both the number of peritoneal macrophages and TNF production by ALCs were noted. In the other two patients, in whom TNF was not detected in the ascites, the ratio of peritoneal macrophages to ALCs did not change throughout the study period, and TNF production by the ALCs was not augmented. These findings suggest that OK-432 can exert a primary effect on both peritoneal macrophages and blood monocytes, and that OK-432 triggering can promote an increase in primed peritoneal macrophages and the release of TNF from these cells.

The cooperative effects of recombinant human tumor necrosis factor (rH-TNF) and recombinant human interferon-gamma (rH-IFN-gamma) against the proliferation of four human gynecologic tumor cell lines (HHUA, ISHIKAWA, HeLa S3, and SCH) were examined in vitro. The effect of rH-IFN-gamma on TNF receptors was also examined. ISHIKAWA and SCH cells were highly responsive to rH-TNF alone, HHUA cells exhibited a minimal degree of responsiveness to rH-TNF, and HeLa S3 cells were unresponsive to rH-TNF alone. HHUA, HeLa S3, and SCH cells were responsive dose-dependently to rH-IFN-gamma, and ISHIKAWA cells were unresponsive to rH-IFN-gamma alone. A synergistic antiproliferative effect of rH-TNF and rH-IFN-gamma appeared in HHUA, ISHIKAWA, and HeLa S3 cells. The effectiveness of rH-TNF increased in these cell lines pretreated with rH-IFN-gamma, but not vice versa. rH-IFN-gamma did not change the binding affinity of TNF receptors in the four cell lines, but increased the number of binding sites for TNF in HeLa S3 and SCH cells. These findings suggest that there is no relationship between the increase in TNF binding sites by rH-IFN-gamma and the synergistic antiproliferative effect of rH-IFN-gamma and rH-TNF. The combination therapy of rH-IFN-gamma and rH-TNF will be a new approach against cancers.