糖皮质激素对大鼠下丘脑亨廷顿蛋白相关蛋白1表达的影响

目的 探讨外源性糖皮质激素对大鼠下丘脑亨廷顿蛋白相关蛋白1（HAP1）表达的影响。 方法 成年雄性Wistar大鼠80只,随机分为实验对照组（注射生理盐水）、皮质酮注射组、皮质酮+皮质酮受体拮抗剂(RU38486)注射组、饮用氢化可的松组。皮质酮注射［(5mg/(kg.12h)］组又分为注射持续1d、3d、5d、7d组;皮质酮+皮质酮受体拮抗剂(RU38486)注射［(10mg/(kg.12h)］组注射持续3d;饮用氢化可的松组大鼠饮用水中加氢化可的松（0.01g/L）,连续1个月。应用RT-PCR、免疫印迹法观察大鼠下丘脑HAP1表达的变化。 结果 注射皮质酮1d和3d后,下丘脑HAP1表达明显减少,其mRNA的表达明显下调,5d后HAP1开始回升,7d 后恢复到正常水平,HAP1 mRNA表达5d后明显增加,并高于正常水平;长期(一个月)饮用氢化可的松的大鼠,其下丘脑中HAP1的表达明显减少;在皮质酮注射的同时注射RU38486,可以对抗由皮质酮注射所引起的下丘脑HAP1的变化。 结论 外源性过量糖皮质激素能影响下丘脑HAP1的表达,下丘脑中的HAP1可能参与下丘脑神经元或神经内分泌细胞的功能活动。     

Linomide,a novel immunomodulator that prevents death in four models of septic shock

Intravenous injections of 50 μ.g Staphylococcus aureus enterotoxin B (SEB) or bacterial lipopolysaccharide (LPS) are lethal, provided that mice are simultaneously sensitized with either N-galactosamine (GalN) or the anti-glucocorticoid RU-38486. Similar to the synthetic glucocorticoid (GC) receptor agonist dexamethasone, pharmacological doses of the immunomodulator linomide (quinoline-3-carboxamide) prevent death in all four models of lethal septic shock (LPS + GalN, LPS + RU-38486, SEB + GalN, and SEB + RU-38486) and inhibit the secretion of tumor necrosis factor, one of the major intermediate effector molecules of SEB and LPS toxicity. In this system, cyclosporine A (CsA), although effective in suppressing SEB toxicity, fails to counteract the lethal effect of LPS. This observation, together with the fact that linomide acts in the presence of excess amounts of GC receptor antagonist, indicates that linomide functions in a different way to that of known immunosuppressive agents like CsA and GC.     

Regulation of ischemic cell death by glucocorticoids and adrenocorticotropic hormone

Transient global ischemia results in delayed selective neuronal death of hippocampal CA1 pyramidal cells. Glucocorticoids increase and adrenalectomy decreases the rate of neuronal death; however, they also produce changes in brain temperature, serum glucose and adrenocorticotropic hormone levels. In order to understand the role of glucocorticoids in regulating ischemic cell death, we studied RU 38486, a glucocorticoid receptor blocker, and Org 2766, a non-steroidogenic adrenocorticotropic hormone 4-9 analog. Male Mongolian gerbils were subjected to 5 min of bilateral carotid artery occlusion under a controlled temperature environment (37.0-38.0 degrees C). Animals were injected with either physiological saline, Org 2766 (10 microg/kg/24 h) or RU 38486 (50 mg/kg/8 h), beginning just prior to the occlusion until killing at either day 4 or 7. Blood was collected for serum glucose and cortisol analysis. Damage was evaluated by blinded counts of CAI neurons. Both RU 38486 and Org 2766 treatment significantly (P<0.004) reduced hippocampal CA1 damage at day 4, but not on day 7. While RU 38486 raised serum cortisol and adrenocorticotropic hormone levels, neither treatment affected temperature or serum glucose. The fact that RU 38486 mimicked adrenalectomy without changing temperature suggests that the decreased rate of cell death resulted from either removal of glucocorticoids or increases in adrenocorticotropic hormone. The ability of Org 2766 to affect this rate strongly suggests that adrenocorticotropic hormone is the active regulatory hormone rather than glucocorticoids. While both RU 38486 and Org 2766 prolong the survival of CA1 neurons after transient global ischemia, only RU 38486, which is available and tested in both animals and humans, can block the detrimental effects of post-ischemia glucocorticoid elevations. Thus, the administration of RU 38486 may be a practical adjunct to other neuroprotective agents for victims of cardiac arrest, anesthetic accidents or drowning.     

The role of early post-implantation beta-HCG levels in the outcome of pregnancies following in-vitro fertilization

Daily plasma beta-HCG levels from days 11 to 18 after ovum retrieval(OR) were evaluated in a group of 73 women who became pregnantfollowing in-vitro fertilization and embryo replacement (IVF-ER).The 47 patients who had a normal ongoing pregnancy could bedistinguished from the 26 patients with a pathological pregnancy(pre-clinical abortion, clinical abortion and tubal pregnancy)by the mean daily beta-HCG levels, their mean daily increaseand the intercept and slope of the beta-HCG regression analysis.The mean daily beta-HCG levels of the normal pregnancies weresignificantly higher than: (i) pre-clinical abortions on days12–18 after OR; (ii) clinical abortions on days 12–16;and (iii) tubal pregnancies on days 12–17. Using quadraticdiscriminant analysis, normal and pathological pregnancies couldalso be distinguished by their absolute beta-HCG levels on day13 after OR with 27.6 mIU/ml being the cut-off point. Our resultsindicate that the outcome of pregnancy following IVF-ER couldbe predicted with a high degree of probability by monitoringdaily beta-HCG levels within the first 2 weeks following OR.     

5-HT1A receptors mediate detrimental effects of cocaine on long-term potentiation and expression of polysialylated neural cell adhesion molecule protein in rat dentate gyrus

The present study investigated the involvement of 5-HT_1A receptors in the inhibitory effect of single administration of cocaine (COC, 15 mg/kg i.p.) on the induction of long-term potentiation (LTP) in slices of rat dentate gyrus (DG), prepared 30 min and 2 days after COC administration. These effects of COC were blocked by an antagonist of 5-HT_1A receptors, WAY 100635 (0.4 mg/kg i.p.), which had been administered 20 min before COC. The detrimental effect of COC on LTP in slices prepared 30 min after COC administration could be prevented by blocking glucocorticoid receptors (GRs) using mifepristone (RU 38486, 10 mg/kg s.c. given 1 h before COC), similar as in slices obtained 2 days after COC as reported previously [Ma?kowiak et al. (2008) Eur J Neurosci 27:2928—2937]. After a single administration of an agonist of 5-HT_1A receptors, 8-OH-DPAT, (0.5 mg/kg i.p.), the level of LTP in slices prepared 2 days later was significantly decreased resembling the effect of COC. This effect of 8-OH-DPAT was antagonized by WAY 100635 (0.4 mg/kg i.p.), administered 20 min before 8-OH-DPAT and by RU 38486, given 1 h before 8-OH-DPAT. COC-induced inhibition of LTP could be blocked by the inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2), SL 327 (50 mg/kg i.p.), administered 1 h before COC, but not by the inhibitor of phosphatidylinositol 3-kinase (PI3-kinase), LY 294002 (80 mg/kg i.p.). COC-induced reduction in the number of polysialylated neural cell adhesion molecule (PSA-NCAM)—positive neurons in rat dentate gyrus could also be prevented by WAY 100635, given 20 min before COC. These data indicate that the indirect 5-HT_1A receptor activation by a single COC administration and subsequent stimulation of extracellular signal-regulated kinases (ERK 1/2) signaling pathway result in a decrease of the potential for long-term increase in synaptic efficacy in rat DG lasting at least two but less than 7 days, most likely via activation of the hypothalamic-pituitary-adrenal (HPA) axis.     

Probing glucocorticoid-dependent osteogenesis in rat and chick cells in vitro by specific blockade of osteoblastic differentiation with progesterone and RU38486

Glucocorticoids and sex-steroids can modulate osteogenesis in vivo and in vitro. Although the effects of glucocorticoids on bone cells in vitro have been described in detail, the role of sex-steroids is not as well defined. We examined whether sex-steroids influence bone metabolism indirectly by regulating glucocorticoid effects on bone. Interactions of the sex-steroid progesterone or its analog RU38486 with the glucocorticoid dexamethasone (dex) were studied in functional assays of osteogenesis. Three osteoblastic models were evaluated:(1) the rat bone marrow stromal cell (RBMC) nodule system; (2) the chick periosteal osteogenesis (CPO) model; and (3) ROS 17/2.8 cells. RU38486, progesterone, and unlabelled dex competitively inhibited ³H-dex uptake by ROS 17/2.8 cells as well as its (³H-dex) binding to cytosol preps. Both RU38486 and progesterone inhibited dex-induced increases in alkaline phosphatase in CPO cultures, in RBMC cultures, and in ROS 17/2.8 cells. Dex-induced decreases in cell proliferation in ROS 17/2.8 cells were reversed by RU38486 but dex-induced increases in proliferation in the CPO model were not affected. In CPO cultures, dex-induced increases in collagen synthesis were inhibited completely by RU38486 and progesterone, Dex-dependent nodule formation in the RBMC was blocked by RU38486. Both RU38486 and dex mediated reduction of calcium uptake in the CPO model but did not affect mineralized tissue area. The data indicate that RU38486 and progesterone competitively inhibit dex-mediated stimulation of osteogenesis in vitro; this inhibition is exerted on early but not late stage differentiation events of osteoprogenitor cells. © 1995 Wiley-Liss, Inc.     

Comparison between 1 year oral and transdermal oestradiol and sequential norethisterone acetate on circulating concentrations of leptin in postmenopausal women

BACKGROUND: Oral and transdermal postmenopausal hormone replacement therapy (HRT) affects lipid and glucose metabolism differently, which is of significance in the release of leptin by adipocytes. Moreover, oestrogen and progesterone can stimulate leptin secretion in women of reproductive age. Therefore, we compared the effects of oral and transdermal oestrogen plus progestin regimen on plasma leptin in 38 healthy postmenopausal women with normal body mass index (BMI), who wished to use HRT to control incapacitating climacteric symptoms. METHODS: The women were randomized to treatment with oral HRT (2 mg oestradiol on days 1--12, 2 mg oestradiol plus 1 mg norethisterone acetate (NETA) on days 13--22, and 1 mg oestradiol on days 23--28, n = 19), or with transdermal HRT (50 microg/day of oestradiol on days 1--13, and 50 microg oestradiol plus 250 microg/day NETA on days 14--28, n = 19) for 1 year. Plasma samples were collected before and at oestradiol + NETA phase after 2, 6 and 12 months treatment and were assayed for leptin. RESULTS: The baseline leptin, ranging from 3.3 to 34.9 microg/l, was significantly associated with BMI (r = 0.78, P < 0.0001 ), but showed no difference between women in oral HRT (geometric mean 13.9 microg/l, 95% confidence interval (CI) 10.1--17.6 microg/l) or transdermal HRT group (geometric mean 12.0 microg/l, 95% CI 9.7--14.3 microg/l). Neither oral nor transdermal oestradiol + NETA caused any significant changes in plasma leptin (or BMI) after 2, 6, or 12 months of treatment. CONCLUSION: Leptin is an unsuitable factor to detect oestradiol + NETA-induced metabolic changes in postmenopausal women.     

Serum inhibins,estradiol, progesterone and FSH in surgical menopause: a demonstration of ovarian pituitary feedback loop in women

BACKGROUND: The objective of this study was to confirm the source and study the acute changes and relationship between inhibins and FSH at surgical menopause. METHODS: Regularly cycling women (42-47 years; n = 10) undergoing bilateral oophorectomy for non-ovarian pathology were recruited for this study. One blood sample was taken before surgery and after removal of the ovaries, samples were taken every 15 min up to 1 h, hourly up to 6 h, after 12 h and daily during the hospital admission (3 days). RESULTS: There were five women in the follicular phase and five women in the luteal phase of the cycle. For women in both phases, levels of inhibin A, inhibin B, estradiol (E(2)) and progesterone decreased after the removal of the ovaries. Serum FSH levels started to rise after 12 h in both follicular and luteal phase women after the surgical menopause. Correlation analysis showed that inhibin A and E(2) were significantly negatively correlated in both phases with FSH concentration. Inhibin B had a negative correlation in the follicular phase and progesterone had a negative correlation in the luteal phase. CONCLUSIONS: This study showed that ovarian inhibin A and B were cleared from the circulation within 12 h of oophorectomy, whereas E(2) and progesterone remain in the circulation for longer. Negative correlation between FSH, inhibin A and inhibin B suggests that inhibins may contribute to the observed early rise in FSH after the surgical menopause.     

In-vitro synthesis of steroid hormones in corpora lutea from normal women and women treated with 300 micrograms norethisterone.

The in-vitro oestradiol (E2) and progesterone (P) production by corpora lutea (CL) obtained at sterilization from 30 untreated women and 43 women treated with norethisterone (NET) 300 micrograms daily was measured. The CL were obtained at different stages of the luteal phase in the untreated women [luteinizing hormone (LH) 0 to +3, n = 7; LH +4 to +7, n = 7; LH +8 to +11, n = 9; LH +12 to menses, n = 7] and on days LH +8 to +11 or cycle days 22 to 26 in the NET-treated women. In the treated women, four types of ovarian reaction were identified. Four women showed ovarian reaction Type A (completely inhibited ovarian activity), 14 women Type B (marked follicular activity, but no luteal function), 12 women Type C (normal follicular activity, followed by insufficient luteal function) and 13 women Type D (apparently normal follicular and luteal activity). The CL were incubated in Eagle's medium with and without stimulation by human chorionic gonadotrophin (HCG) for 2 and 4 h. In the untreated women, P and E2 production increased significantly with both incubation time and stimulation by HCG throughout the luteal phase, except in the late luteal phase (LH +12 to menses) where P increased (P less than 0.01) only after 4 h stimulation by HCG. The maximal production of P was found after 4 h incubation with HCG stimulation of CL tissue in the early-mid luteal phase (LH +4 to +7).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pregnancy: The effect of RU486 on progesterone and oestrogen receptor concentration in human decidua on early pregnancy

Concentrations of progesterone receptor (PR) and oestrogen receptor(ER) were measured by radioligand assay in decidual tissue ofwomen undergoing termination of early pregnancy (amenorrhoeaup to 49 days). Pregnancies were terminated by vacuum aspirationat 12 or 36 h after oral administration of placebo or antiprogestinRU486 in different doses. Treatment with RU486 decreased decidualPR content, the effect being observed at 12 h as well as at36 h after 600 mg RU486 and at 36 h after 3 x 25 mg RU486 givenat 12 h intervals. PR concentration 12 h after a single doseof 25 mg RU486 was not affected. ER content was unchanged at12 h after RU486 but increased 36 h after 600 mg and 3 x 25mg RU486. Our data suggest that apart from blocking progesteroneaction, RU486 may exert its abortifacient effect through decreasingthe PR concentration. The simultaneous decrease of PR concentrationand an increase of ER concentration changes the balance betweenthem in favour of ER, which might also play a role in the abortifacienteffect of RU486.     

Assessment of changes in volume and vascularity of the ovaries during the normal menstrual cycle using three-dimensional power Doppler ultrasound

BACKGROUND: Our aim was to describe changes in the volume and vascularization of both ovaries, the dominant follicle and the corpus luteum during the normal menstrual cycle using three-dimensional (3D) power Doppler ultrasound. METHODS: Fourteen healthy volunteers underwent serial transvaginal 3D ultrasound examinations of both ovaries on cycle day 2, 3 or 4, then daily from cycle day 9 until follicular rupture and 1, 2, 5, 7 and 12 days after follicular rupture. The volume and vascular indices of the ovaries, the dominant follicle and the corpus luteum were calculated off-line using virtual organ computer-aided analysis (VOCAL) software. RESULTS: The volume of the dominant ovary increased during the follicular phase, decreased after follicular rupture and then increased again during the luteal phase. Vascular indices in the dominant ovary and the dominant follicle/corpus luteum increased during the follicular phase, the vascular flow index (VFI) in the dominant follicle being on average (median) 1.7 times higher on the day before ovulation than 4 days before ovulation (P=0.003). The vascular indices continued to rise after follicular rupture so that VFI in the corpus luteum was on average (median) 3.1 times higher 7 days after ovulation than in the follicle on the day before ovulation (P=0.0002). The volume and vascular indices in the non-dominant ovary manifested no unequivocal changes during the menstrual cycle. CONCLUSIONS: Substantial changes occur in volume and vascularization of the dominant ovary during the normal menstrual cycle. 3D power Doppler ultrasound may become a useful tool for assessing pathological changes in the ovaries, for example, in subfertile patients.     

Automated direct assay system for RU38486, an antiprogesterone-antiglucocorticoid agent, and its metabolites using high performance liquid chromatography

An automated direct assay system using high performance liquid chromatography was developed for the measurement of RU38486 and its three metabolites (RU42698, RU42848, RU42633) in human serum. Serum concentrations of these compounds were measured up to 144 h following single oral administration of 200 (200 mg group, n = 3) or 400 mg (400 mg group, n = 3) of RU38486 to healthy female volunteers. The serum half-lives (200 mg group-400 mg group) of RU38486, RU42698, RU42848 and RU42633 were 31.8-33.1 h, 41.2-39.3 h, 33.9-36.6 h and 29.2-36.6 h, respectively. Our system could quantify them easily and simultaneously, and was considered to be valuable in studies on the relationship between the pharmacokinetics and the clinical effects of RU38486.     

The glucocorticoid antagonist RU38486 mimics interleukin-1 in its sensitization to the lethal and interleukin-6-inducing properties of tumor necrosis factor.

Although tumor necrosis factor (TNF) is undoubtedly a major mediator of the antitumor and shock-inducing activities of lipopolysaccharide (LPS), the outcome of a challenge with TNF is highly dependent on the presence or absence of other substances or conditions. We have previously shown that to obtain lethality in mice after TNF administration both TNF receptor (TNF-R) types have to be triggered. This is illustrated by the fact that recombinant human (rh) TNF, which is a selective murine (m) TNF-R55 agonist, is not lethal, whereas mTNF, which binds both mTNF-R55 and mTNF-R75, is lethal in mice. Triggering of TNF-R75 is, however, no longer needed when sensitizers such as galactosamine or low doses of LPS or interleukin (IL)-1 are also present. Here, we report that this selective species specificity of TNF is also reflected in patterns of induced IL-6: both rmTNF and rhTNF could induce considerable IL-6 peak levels in the plasma (up to 10 ng/ml) 2 to 3 h after TNF administration. However, only rmTNF was capable of inducing the same pattern of sustained IL-6 levels previously observed after lethal LPS doses, while rhTNF only caused induction of transient IL-6 levels, as found after nonlethal LPS doses. We also observed that the sensitizer IL-1 could complement rhTNF to induce such a sustained IL-6 induction. Since we were interested in sensitizers with a defined mechanism of action, we further investigated the effects of the glucocorticoid and progesterone inhibitor RU38486 on the lethal and IL-6-inducing properties of TNF. We observed that RU38486 closely mimicked IL-1: both had similar effects on IL-6 induction and sensitized mice to the lethal effects of TNF with comparable efficiency and kinetics. Using a monoclonal anti-IL-1R antibody, we finally observed that the effects of RU38486 were most probably not mediated by IL-1. These observations suggest that a glucocorticoid-antagonistic activity might be a key factor in the pathways leading to septic shock and that such activity could be a key target for the pharmacological manipulation of sepsis.     

Does ovarian stimulation for in-vitro fertilization induce a hypercoagulable state?

Effects on blood coagulation and fibrinolytic activity during ovarian stimulation for in-vitro fertilization (IVF) were examined in 12 women. Blood samples were taken prior to hormonal stimulation (days 2-3 of the menstrual cycle, mean serum oestradiol concentration 0.16 nmol/l) and the day after ovulation induction with human chorionic gonadotrophin (HCG) (days 10-12, mean serum oestradiol concentration 5.35 nmol/l). We measured whole blood clotting time, whole blood clot lysis time, plasma fibrinogen, factor VII and antithrombin III. The whole blood clotting time was slightly, but not significantly shortened after ovarian stimulation. A significant rise in plasma fibrinogen (P less than 0.001) and reduction in antithrombin III (P less than 0.001) were observed, whereas no change in factor VII was found. The blood fibrinolytic activity was significantly reduced as evaluated by an increase in the clot lysis time (P less than 0.02). These results indicate that ovarian stimulation for IVF may create a state of hypercoagulability.     

Treatment of hyperstimulation during in-vitro fertilization

In 33 patients treated with a combination of an LHRH agonist (LHRH-A) and gonadotrophin in a long protocol, a biological hyperstimulation occurred (E2 greater than 2500 pg/ml on the day of HCG administration and 4722 +/- 1190 pg/ml the day after, with greater than 10 follicles greater than 12 mm on each ovary). The replacement of fresh embryos were deferred and LHRH-A was continued, and an endometrial biopsy was performed on the theoretical day of replacement (2 days after oocyte recovery). With this technique, we obtained a mean number of 17.9 +/- 7 oocytes, a fertilization rate of 49% and a replacement rate of 87% in a deferred cycles. The overall pregnancy rate of frozen-thawed embryos was 27% in the seven spontaneous cycles, 12 induced cycles and 10 artificial cycles. Only one severe hyperstimulation occurred and this case emphasizes that caution remains necessary even with this technique.     

Repair of long-segment congenital tracheal stenosis

Long-segment tracheal stenosis in infants and small children is difficult to manage and can be life-threatening. A retrospective review of 12 patients who underwent surgery for congenital tracheal stenosis between 1996 and 2004 was conducted. The patients' median age was 3.6 months. All patients had diffuse tracheal stenosis involving 40-61% (median, 50%) of the length of the trachea, which was suspected to be associated with complete tracheal ring. Five patients had proximal bronchial stenosis also. Ten patients had associated cardiac anomalies. Three different techniques were performed; pericardial patch tracheoplasty (n=4), tracheal autograft tracheoplasty (n=6), and slide tracheoplasty (n=2). After pericardial tracheoplasty, there were 2 early and 2 late deaths. All patients survived after autograft and slide tracheoplasty except one who died of pneumonia one year after the autograft tracheoplasty. The duration of ventilator support was 6-40 days after autograft and 6-7 days after slide tracheoplasty. The duration of hospital stay was 13-266 days after autograft and 19-21 days after slide tracheoplasty. Repeated bronchoscopic examinations were required after pericardial and autograft tracheoplasty. These data demonstrate that pericardial patch tracheoplasty show poor results, whereas autograft or slide tracheoplasty gives excellent short- and long-term results.     

Luteal phase and clinical outcome after human menopausal gonadotrophin/gonadotrophin releasing hormone antagonist treatment for ovarian stimulation in in-vitro fertilization/intracytoplasmic sperm injection cycles.

The luteal phase hormonal profile and the clinical outcome of 69 patients undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) after ovarian stimulation with human menopausal gonadotrophin (HMG) and the gonadotrophin-releasing hormone (GnRH) antagonist Cetrorelix were analysed. Twenty-four patients received Cetrorelix 0.5 mg (group I) while in 45 patients Cetrorelix 0.25 mg was administered (group II). Human chorionic gonadotrophin (HCG) was used as luteal support. Nine clinical pregnancies were obtained in group I (37.5%) and 12 in group II (26. 6%). These results were not significantly different. Serum progesterone and oestradiol concentrations did not differ between the two groups either in pregnant or non-pregnant patients. An expected decrease of the same hormones was observed 8 days after the pre-ovulatory HCG injection in non-pregnant women. With regard to serum luteinizing hormone concentrations, a decrease was observed 2 days after the pre-ovulatory HCG injection and was maintained at almost undetectable levels throughout the entire luteal phase in both conception and non-conception cycles of group I and group II. This study demonstrates that different doses of GnRH antagonist do not have any impact on the luteal phase of IVF/ICSI cycles when hormonal support is given.     

Early luteal phase treatment with mifepristone (RU 486) for fertility regulation

Mifepristone (RU 486) is an antiprogestin which interacts withprogesterone at the receptor level. Administration of mifepristoneimmediately after ovulation does not upset the menstrual cycle.However, the maturation and function of the endometrium is inhibitedand uterine contractility is changed. To test if these effectsare sufficient to prevent implantation, 21 women agreed to useone single treatment with 200 mg mifepristone on day luteinizinghormone (LH) + 2 monthly as their only contraceptive method.The women were treated for 1– 12 months. The time of theLH peak was determined in the urine by the women themselvesusing a rapid LH test (Ovu-quick, Organon). The overall numberof cycles studied was 169. In 12 cycles the women were unableto detect the LH peak. In these cycles no treatment was givenand the women advised to use barrier methods during the timeto menstruation. The remaining 157 cycles with a detectableLH peak were all ovulatory based on plasma progesterone measurement.One pregnancy occurred. On the basis of the time of the LH peak,it was retrospectively calculated that in 124 cycles at leastone act of intercourse occurred during the period 3 days beforeto 1 day after ovulation. The probability of pregnancy in thisperiod of the menstrual cycle is thus 0.008. The women did notcomplain of any treatment-related side-effects apart from slightbleeding for 2–3 days starting a few days after the dayof treatment in 35% of the cycles. The results show that theeffect of mifepristone on the endometrium is sufficent to preventpregnancy and indicate that treatment with antiprogestin canalso be used for contraceptive purposes.     

Serum relaxin and the major endometrial secretory proteins in in-vitro fertilization and down-regulated hormone-supported and natural cycle frozen embryo transfer

Relaxin has been postulated to be a modulator of the expressionof the endometrial secretory proteins, insulin-like growth factorbinding protein (IGFBP-1) and placental protein 14(PP14). Thisstudy evaluated the expression of relaxin in relation to concentrationsof these secretory proteins along with oestradiol, progesteroneand human chorionic gonadotrophin in groups of pregnant andnon-pregnant patients who underwent differing assisted conceptiontreatments. Serum samples were taken from 88 patients at 8 and12 days after embryo transfer. At 12 days after embryo transfer,relaxin concentrations in the pregnant patients who had undergonein-vitro fertilization (IVF) or natural cycle frozen embryotransfer were significantly higher than those who did not conceivein these groups (mean concentrations 8334 versus 28 and 2608versus 62 pg/ml respectively, P <0.001). However concentrationsin the pregnant patients who had hormone support and transferof frozen embryos were not significantly different from thepatients who did not conceive after the same treatment. Althoughrelaxin expression was associated with corpus luteum activity,it was not related to the number of corpora lutea in IVF patients.A wide range of relaxin concentrations was seen to be compatiblewith a healthy pregnancy. These serum relaxin concentrationswere not found to be directly related to the serum concentrationsof IGFBP-1, PP14 or the other factors assessed in this study.     

Mifepristone (RU38486) influences the core temperature response of term pregnant rats to intraperitoneal lipopolysaccharide

Pregnancy alters the cytokine, prostanoid and core temperature responses of rats to infectious stimuli at a time when blood levels of the endogenous glucocorticoid corticosterone are elevated. Given that glucocorticoids attenuate bacterial pyrogen-induced fever in rats, the present experiments were carried out to test the hypothesis that administration of RU38486, a glucocorticoid type II receptor antagonist, would restore the febrile response to E. coli lipopolysaccharide (LPS) in pregnant rats on day 21 of gestation. Pregnant rats were randomly allocated to one of four experimental groups depending upon whether they received RU38486 (20 mg kg(-1) intragastric) or vehicle followed by E. coli LPS (160 microg kg(-1)i.p.; a minimal dose that elicits maximal febrile response in non-pregnant rats) or vehicle. Basal core temperature was not altered by intragastric administration of RU38486 or vehicle. Following intragastric administration of vehicle, intraperitoneal administration of E. coli LPS produced a significant hypothermia with latency, duration and magnitude of 0.5 h, 2 h and -1.3 degrees C, respectively. Following intragastric administration of RU38486, however, intraperitoneal administration of E. coli LPS elicited only a minimal decrease in core temperature which was not significantly different from control values. Thus, our data provide evidence that endogenous glucocorticoids play a role in modulating the early core temperature response to a relatively large dose of bacterial pyrogen in rats at term of pregnancy.