A study of the effect of B-EP and naloxone on the function of the hypothalamo-pituitary-testicular axis of the rat.

To investigate whether endogenous opioid peptides (EOP) play an important role in intragonadal regulation of testicular function and regulation of the hypothalamic-pituitary-gonadal axis of the male rat, the authors employed two principal methods: culture of testicular Leydig cells and Sertoli cells, and in vitro perifusion of hypothalamo-pituitary Leydig cells of the adult rat. The results demonstrated that incubation of Leydig cells with B-endorphin (B-EP 10(-9) = 10(-6) mol/L) or naloxone (NAL 10(-5) = 10(-8) mol/L) manifested no significant changes of non-stimulated or hCG-stimulated testosterone secretion both in 20 and 60 day-old rats. Similar results were obtained when the cells were treated with B-EP (10(-10) = 10(-7) mol/L) for 48 h during culture. Pretreatment of incubated Leydig cells with B-EP in similar concentrations for 48 h showed no effect on the response to hCG stimulation. In addition, treatment with B-EP in vitro for 24 or 72 h manifested no effects on estradiol production by aromatization of cultured Sertoli cells. Neither NAL 10(-5) given in vitro nor NAL (5 mg/body weight) injected subcutaneously 1 h before decapitation affected LH and testosterone release from the perifused hypothalamo-pituitary Leydig cells system. These results could not support the hypothesis that B-EP is a local regulator of testicular function. The physiological significance of EOP in regulating the function of gonadal axis of adult male rat remains to be investigated further.

Pharmacokinetic and pharmacodynamic studies of vaginal rings releasing low-dose levonorgestrel.

Pharmacokinetic and pharmacodynamic effects of a vaginal ring releasing 20 micrograms/day levonorgestrel (L-NOG) have been studied in 15 women. Serum levels of L-NOG, estradiol and progesterone were measured three times a week in a control menstrual cycle and a treatment period of 3 months after the insertion of the first vaginal ring. All control cycles were normal ovulatory. Among the 36 treatment cycles 13 were ovulatory (36%), 5 ovulatory with inadequate luteal function (14%), 14 anovulatory but with marked follicle activity (39%) and 4 anovulatory (11%). In the groups with ovulatory reaction the serum levels of L-NOG showed a decline of 54% of the initial level at the end of the treatment period, calculated according to the linear regression equation of Y = 0.903-0.0142X, while in the groups without ovulation the L-NOG levels were higher and the decline was 24% of the initial level (Y = 1.034-0.0086X). There were distinct individual differences in the levels of L-NOG and ovarian reactions. Marked follicle activity with very high estradiol levels were found in correlation with high L-NOG in 7 treatment cycles, particularly in the B type of reaction (B = anovulatory cycle with marked follicle activity). More intermenstrual bleeding and spotting occurred in the second treatment cycles, particularly in those with anovulatory reactions.

Pharmacokinetic and pharmacodynamic studies of levonorgestrel-releasing intrauterine device.

Intrauterine devices releasing 20 micrograms/day levonorgestrel were inserted in 10 women (ages 25-34). Bleeding and spotting patterns were recorded on a menstrual card during one year of follow-up. Blood samples were collected for radioimmunoassays of LH, estradiol (E2), progesterone (P) and levonorgestrel (LNG) and for sex hormone binding globulin (SHBG) 3 times a week during the 1st month of use, and twice a week during the 6th and 12th treatment months. Among the 10 women, two experienced irregular cycles with prolonged intermenstrual spotting, four had amenorrhea in the latter part of treatment months, while the other four had regular cycles. According to the serum levels of E2 and P, the hormone profiles were divided into four types of reaction: A) anovulatory, B) anovulatory but with high follicular activity, C) ovulatory but with luteal insufficiency, and D) ovulatory. Among the 29 treatment cycles, there were 10 D-type, 3 C-type, 13 B-type and 3 A-type of ovarian reactions: 44.8% of the cycles were ovulatory (C + D) and 55.2% were anovulatory (A + B). In general, serum levels of levonorgestrel were low in ovulatory cycles and were high in anovulatory cycles. The difference was statistically significant. There were marked individual differences. The decline of serum LNG from the 1st (492 pmol/l) to the 6th (320 pmol/l) treatment months was 34.9% on average. The amenorrheic cycles coincided mostly with the hormonal profile of ovulatory types, which indicated that the cause of amenorrhea is due to the local effect of levonorgestrel on the endometrium. The levonorgestrel levels were significantly correlated with serum SHBG, r = 0.8856, p less than 0.001, and with E2, r = 0.4661, p less than 0.05.

The endocrinological profile of normal menstrual cycles in a population of Chinese women.

Endocrinological profiles of normal menstrual cycles were studied in 41 Chinese women. Daily serum concentration of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), estradiol (E2) and progesterone (P) were determined by RIA. Thirty-four cycles were of normal length (26-35 days) and 6 cycles were prolonged up to 40 days with a follicular phase of 22-26 days. One cycle was anovulatory. Cyclical changes of LH, FSH, E2 and P were typical of ovulatory cycles in other populations as reported in the literature. In the normal cycle group the geometric mean of the LH midcycle peak level was 46 IU/1, the FSH peak was 10 IU/1, the preovulatory estradiol peak was 1229 pmol/1 and the progesterone luteal maximum was 50 nmol/1. The pattern of cyclical changes in the prolonged ovulatory cycles was similar to the normal length cycles, except that there were significantly higher levels of LH in both follicular and luteal phases, lower FSH in luteal phase, and lower progesterone in luteal phase. A majority of cycles had a midcycle elevation of prolactin and mean PRL levels in the late luteal phase were higher than those in the follicular phase.

The comparative trial of TCu 380A IUD and progesterone-releasing vaginal ring used by lactating women.

The objective of this paper was to compare the efficacy, acceptability, safety, and bleeding pattern of TCu 380A intrauterine device (IUD) and progesterone-releasing vaginal ring used by breastfeeding women. The study population included 97 breastfeeding women using IUD and 100 women using vaginal ring. Of the IUD users, no insertion failure, perforation, or accidental pregnancy occurred in 12 months. There was one IUD expulsion. There were no discontinuations of IUD due to medical reasons other than expulsion. The total discontinuation rate was 2.3%. In the ring group, no accidental pregnancy occurred. The major reasons for discontinuation were ring use-related problems and vaginal problems. The total discontinuation rate was 65.4% within 1 year. The frequency of any one complaint among the ring users was higher than that among the IUD users. There were no differences in the proportion of women having no sexual activity and in the weight of their babies between the two groups. Compared with the IUD users, the median number of bleeding/spotting (B/S) episodes and B/S days of the vaginal ring users were fewer; consequently, the mean length of B/S-free interval was longer in all four reference periods; the mean length of B/S episode and segment were the same; the occurrence of amenorrhea was more frequent; in contrast, the proportions of normal bleeding patterns were fewer. The frequencies of prolonged bleeding, frequent bleeding, and infrequent bleeding patterns did not differ between the two groups. The percentage of irregular bleeding was fewer only in the first two reference periods. It is concluded that the TCu 380A IUD and progesterone-releasing vaginal ring used by breastfeeding women are safe and effective. The higher discontinuation rate of the ring users was mainly because of use-related problems. Breastfeeding women with TCu 380A IUD had better tolerance and acceptability. The TCu 380A IUD does not, but the progesterone-releasing vaginal ring does, suppress the recovery of ovarian function. However, once return of menstruation occurred, there were no differences in bleeding patterns between the two contraceptive methods.

PIP: The efficacy, acceptability, and bleeding patterns associated with use of the Copper T 380A IUD and the progesterone-releasing vaginal ring during lactation were compared in a 12-month study conducted in Beijing City, China. Enrolled were 97 breast-feeding IUD users and 100 lactating vaginal ring acceptors. The devices were inserted 29-64 days postpartum. In the IUD group, there was one expulsion during the study period, but no cases of perforation, pelvic inflammatory disease, or pregnancy. The two IUD discontinuations (2.3/100 woman-years) were attributable to user rather than medical-related reasons. There were no accidental pregnancies in the ring group either. However, there were 50 medical-related and four user-related discontinuations among ring users, for a 12-month discontinuation rate of 65.4/100 woman-years. Three women discontinued ring use due to menstrual problems, 10 requested removal for vaginal problems such as increased discharge and vaginitis, seven experienced frequent ring expulsion, 12 left the device out for more than 48 hours, and 13 found the ring unpleasant to use. Significantly more ring than IUD users had at least one complaint at the 1-, 3-, and 6-month post-insertion visits. Menstruation diaries revealed bleeding/spotting immediately post-insertion in both groups, followed by a variable period of amenorrhea until resumption of menses. The median number of bleeding/spotting episodes and the occurrence of amenorrhea were more frequent in the vaginal ring group. Once menstruation resumed, there were no differences in bleeding patterns between the two contraceptive methods. The results indicated progesterone suppresses the recovery of ovulation in breast-feeding women but does not interrupt the regulation of menstruation.

Current practice of family planning in China.

Current practice of family planning in China is based on the population policy and strategy of the country. Comprehensive contraceptive methods are provided in family planning clinics at all levels. Among the methods used, intrauterine devices and tubal sterilization are most popular. Vasectomy is popular in some provinces. Oral pills, injectables and subdermal implants occupy a small proportion. Incidence of abortion is high due to failure of methods and unprotected intercourse. Attention is paid to the adoption of emergency contraception to prevent unwanted pregnancy. Improvement in quality of care is the key to a successful family planning program. Basic research is essential for development of new contraceptive technology.

The use of isolated rat hepatocyte in prescreening of hepatotoxicants: observation on toxic effects of 14 compounds.

Fourteen compounds, differing in structure, mechanism of action, and primary target organs, were tested for cytotoxic responses in isolated hepatocyte suspensions prepared by a nonperfusion method from male Sprague-Dawley rats. The trypan blue exclusion test, measurement of enzyme activities in supernatants, and enzyme histochemistry were taken as indexes of cytotoxicity. All 14 compounds inhibited enzyme activities in hepatocytes. However, the activities of GOT and LDH in supernatants increased after exposure to the three haloalkanes, but decreased after exposure to the other chemicals (Na2CrO4, etc.). The number of dyed cells increased after exposure to six haloalkanes and the order of their relative toxicities in vitro was roughly in concordance with that of their in vivo hepatoxicities. These results indicate that isolated hepatocytes are useful for prescreening of potential hepatotoxicants; the so-called "enzyme leakage" should be replaced by "enzyme in supernatant" to reflect toxicities of different kinds of compounds; enzyme histochemistry is also a sensitive index in toxicological tests with isolated rat hepatocytes.

Short-term test for the induction of lung tumor in mouse by chloroprene.

In a previous study by the authors, positive results from both a case-control study and a cohort study were reported. In the present study a short-term test for the induction of mouse lung tumor by chloroprene was conducted to confirm whether chloroprene monomer itself can induce tumors. Kunming albino mice weaned at 2 weeks were subjected to inhaling 0, 2.9 +/- 0.3, 19.2 +/- 1.9, and 189.0 +/- 13.3 mg/m3 chloroprene (GC purity, 99.8%) 4 h daily (except Sunday) for 7 months. All survivors were killed at the end of the 8th month or when moribund. No lung tumors were found before the 6th month. Thus, survivors at the 6th month were counted as effective animals. Most lung tumors observed were papilloadenomas (50/57), and a few were adenomas (7/57). The tumor incidence in the 2.9 mg/m3 group was 8.1% in comparison to 1.3% in the control group, with the significance level at P less than 0.05. The higher the concentration, the higher the incidence. Examination of the multiplicity of tumor induction also demonstrated a dose-response relationship, and the number of tumors per mouse in the 189 mg/m3 group was significant at P less than 0.01.

[Changes of hormone levels in follicular fluid in women with normal menstruation].

Levels of estradiol (E2), progesterone (P0), androstenedione (A), testosterone (T), follicle stimulating hormone (FSH), luteinizing hormone (LH) and prolactin (PRL) in ovarian follicles of different sizes and at different phases of normal menstrual cycles were determined and, their relationships with those in peripheral blood were studied. According to the diameters, the follicles were divided into large (greater than 14 mm), median (8-14 mm) and small (less than 8 mm) ones. The results showed that the levels of E2, P0, FSH and LH were lower, whereas those of A and T were higher in small and median follicles, as compared with the large follicles. In the large follicles, particularly at the preovulatory phase, E2, P0, FSH and LH reached maximum levels. The concentration of E2 was 9815 nmol/L, P0, 3316 nmol/L, FSH 1.34 IU/L and LH 3.91 IU/L at the preovulatory phase. The concentrations of A and T were much lower in large follicles, being 280 nmol/L and 137 nmol/L respectively. No significant difference was found in PRL levels in follicles of different sizes. The steroid hormones in the follicular fluid were about 7-20,000 times higher than those in the peripheral blood, while FSH and LH were only about 10-80% and PRL was slightly higher than in peripheral blood.

[Changes in histopathology and enzyme histochemistry of thymus in cadmium exposure mice].

The changes in histopathology and enzyme histochemistry of thymus induced by a single intraperitoneal injection of sublethal doses of cadmium chloride into Kunming male mice were examined. The swollen endothelium of capillaries was observed, with an obviously decreased activity of ICDH, LDH and ATPase, which seemed to be due to direct inhibition by cadmium at the 4th hour. The necroses of the cortex thymocytes were found at the 8th hour after injection and reached an extreme at the 16-24th hour, while few necroses of the lymphocytes in the medulla. Beginning 4th to 8th hour after exposure, the activity of enzymes was located in mitochondria of the cortex thymocytes, i.e., SDH, ICDH, CCO and ATPase, was decreased gradually. It suggested that thymic cortex had a marked impairment of blood supply and anoxia. Within 2 days after a single injection the cortex of the gland was mainly populated by epithelial reticular cells except a few lymphocytes. It was noted that there were some bigger cells which were characterized by their large size, basophilic cytoplasma, rough chromatin and high mitotic ability and activity of MDH, LDH, G-6-PD increased in these cells. From above observation the author concluded that the cause of cadmium-induced acute thymic atrophy was lymphocyte necroses within thymic cortex. The mechanism of the cortex thymocytes necrosis was possibly secondary to an anoxia of cortex resulting from capillary damage in the cortex. The ability of thymic regeneration is strong after being damaged. The regenerate cells possessed characteristics of morphology and enzyme histochemistry of immature cells, which probably came from the bone marrow.

[Lung tumors induction short-term test of chloroprene in mice].

In a previous report by the authors, positive results in both case-control study mouse lung tumor induction short-term test of chloroprene for carcinogenicity was conducted to determine whether chloroprene monomer itself could induce tumor. Kuangming albino mice weaned 2 wk were subjected to inhale 0.0, 2.9 +/- 0.34, 19.18 +/- 1.89, 189.00 +/- 13.26 mg/m3, chloroprene (GC purity 99.69%) 4 h daily (except Sunday) for 7 month. All survivors were killed at the end of the 8th month or when moribund. No lung tumor was found before the 6th month. Thus survivors at the 6th month were counted as effective animals. Most lung tumors observed were papillo-adenoma (50/57), and a few were adenoma (7/57). Tumor incidence of the 2.9 mg/m3 group increased to 8.1% in comparison with that of the control group (1.3%) at a significant level of P less than 0.05; and the higher the concentration the higher the incidence. Examination of the multiplicity of tumors also demonstrated the dose-response relationship, and the number of tumors per mouse in the 189 mg/m3 group was significant at P less than 0.01.

A randomized double-blind comparison of two single doses of mifepristone for emergency contraception.

BACKGROUND: Previous trials have shown the potential of 10 mg of mifepristone in emergency contraception. The aim of this trial was to investigate whether 10 mg of mifepristone has the same efficacy as 25 mg. METHODS: This double-blind, randomized trial was carried out in 10 family planning institutes and hospitals in China. Women who met recruitment criteria and requested emergency contraception within 120 h of a single act of unprotected coitus were randomized using a computer-generated list to either 10 or 25 mg of mifepristone within each centre. RESULTS: Among 3052 women enrolled, the outcome was known for 3030 women, 1516 in the 10 mg group and 1514 in the 25 mg group. Seventeen pregnancies occurred in each group, giving a pregnancy rate of 1.1%. The relative risk of pregnancy for women treated with 10 mg mifepristone compared with those treated with 25 mg was 1.0 (95% CI: 0.51-1.95) and equivalence was demonstrated within a two-fold margin. Both doses prevented 85-86% of pregnancies expected to have occurred if no treatment had been given. The pregnancy rate nearly doubled if women had further acts of intercourse. Efficacy decreased with treatment delay. Side-effects were uncommon and mild. CONCLUSIONS: A dose of 10 mg of mifepristone is sufficient for emergency contraception. Earlier treatment is preferable, although the method can be used effectively for up to 5 days after intercourse.