Cytokine Production by Lymphocytes in Pregnancy

PROBLEM: In the presence of progesterone lymphocytes of pregnant women release a 34- kDa protein named the progesterone-induced blocking factor (PIBF). PIBF mediates the immunomodulatory and anti-abortive effects of progesterone and its presence is related to the outcome of pregnancy. PIBF induces production of Th2 type cytokines by activated lymphocytes. The in vivo relationship between PIBF- and cytokine production of pregnancy lymphocytes and the outcome of pregnancy was investigated. METHOD OF STUDY: Interleukin (IL)-12 and IL-10 production and PIBF expression in peripheral lymphocytes of 111 healthy pregnant women and 120 women at risk for premature pregnancy termination were detected by immunocytochemistry. RESULTS: We found increased IL-12 and low PIBF and IL-10 expression on lymphocytes of “risk” patients, and a high rate of IL-10 and PIBF positivity on lymphocytes from healthy pregnant women. The cytokine production pattern of the lymphocytes was related to the presence or absence of previous abortions as well as to the outcome of pregnancy. CONCLUSION: These data suggest the involvement of an altered cytokine production pattern in the immunologic effects of progesterone.     

Progesterone and environmental tobacco smoke act synergistically to exacerbate the development of allergic asthma in a mouse model

BACKGROUND: Asthma affects males and females differently. Females have a higher incidence than males after the onset of puberty. This suggests a hormonal component to the development of the disease. Progesterone, a female hormone, has previously been shown to illicit a T-helper type 2 (TH2) immune response similar to that seen in allergic asthma. Previous studies performed by our laboratory have shown that exposure to environmental tobacco smoke (ETS) enhances the immune response to allergens. OBJECTIVE: To determine if the combination of exposure to ETS and progesterone would further exacerbate the immune response in a mouse model of allergic asthma. METHODS: Female mice were ovariectomized and then implanted with time-release progesterone pellets. Mice were housed in either filtered air (FA) or ETS chambers and half were exposed to aerosolized house dust mite allergen (HDMA). Bronchoalveolar lavage was performed for cell differentials; lung and spleen cells were harvested to compare IL-4 and IFN-gamma production by ELISPOT. RESULTS: Progesterone pellet implantation resulted in increased serum progesterone levels (28.3+/-8.43 vs. 13.5+/-7.22 ng/mL in placebo-treated mice, P<0.0001). Serum total IgE levels were significantly greater in progesterone vs. non-progesterone treated animals that were also exposed to HDMA. ETS exposure enhanced total IgE levels as well. Lung homogenate cells from HDMA/progesterone-treated animals stimulated with Concavalin A produced significantly more IL-4 compared with HDMA/placebo-treated animals (200+/-17.6 vs. 146+/-17.5 spots/well, P<0.01 in ETS exposed animals and 221+/-28.9 vs. 167+/-23.4 spots/well, P<0.01 in animals housed in FA). HDMA/ETS-treated animals had higher eosinophilia in lavage than all other groups. CONCLUSION: Increased serum progesterone levels exacerbate the allergic asthmatic phenotype in a mouse model. These effects are further exacerbated by the addition of environmental tobacco smoke. Progesterone provides a major contribution to the gender differences seen in the development and elicitation of the asthmatic response.     

肺肿瘤细胞雌激素、孕激素和凝集素受体的组化研究

用酶联亲合组化法对46例肺肿瘤细胞进行了雌激素受体(ER)和孕激素受体(PR)检测。同时测定14例肺瘤肿患者血清雌二醇(E_2)浓度。结果表明:肺肿瘤 ER 阳性率为36.9%,PR 阳性率为13.0%。阳性率与性别、病理类型及血浆 E_2浓度无关。认为肺癌的发生发展可能与雌激素有依赖关系,提示内分泌疗法可能会成为原发肺肿瘤的一种治疗手段。另用 ABC 法对上述46例肺肿瘤中的29例进行了花生凝集素受体(PNA-R)和麦胚凝集素受体(WGA-R)的检测,PNA-R 在腺癌大都为顶浆型分布,鳞癌和透明细胞癌则多为胞膜型分布。结果提示 PNA-R 是肺癌分化过程中的一种标志,对肺癌分型、预后判断有一定协助作用。同时将29例肺肿瘤 PNA-R 与 ER 状况作对比研究,探讨了二者之间的相关性及可能的发生机制。     

Epidermal growth factor receptor in human breast cancers: Correlation with estrogen and progesterone receptors

Epidermal growth factor receptor (EGFR), determined by the Scatchard curve method, was found in 22 cases of a random series of 100 patients with breast carcinoma. Two groups of patients were identified, one (n = 16) with a low concentration (0–50 fm/mg protein) of EGFR but with a high affinity (Kd = 3.2 nM), and the other (n = 6) with a high concentration (90–210 fm/mg protein) of EGFR but with a lower affinity (Kd = 6.3 nM).A significant inverse relationship was found between the presence of EGFR and receptors for estrogen (p<0.001) and progesterone (p = 0.001). EGFR was found in no (0/8) tumors with Grade I histoprognostic grade, 17% (10/58) Grade II, and 38% (11/29) Grade III (p<0.05). EGFR is present therefore in poorly differentiated tumors and associated with other factors of poor prognosis. Ourin vivo analyses confirm results found in tissue culture derived from human breast carcinoma cells.With the technical assistance of J. Barraque.     

Sex differences in estradiol-induced progestin receptor immunoreactivity in the guinea pig preoptic area and hypothalamus

Progesterone exerts on the central nervous system a number of effects, some of which are estrogen dependent mostly in the preoptic area and the mediobasal hypothalamus. In these regions, an immunocytochemical study was used to evaluate differences in progesterone receptor (PR) immunoreactivity between the male and the female guinea pig in response to 10 μg/day estradiol benzoate (EB) for 5 consecutive days. Compared to EB-treated females, EB-treated males showed a slightly lower number of PR-immunoreactive cells in the preoptic area whereas PR-immunoreactivity appeared in more cells in the anterior part of the ventrolateral nucleus. The numbers of PR-immunoreactive cells in the arcuate nucleus did not differ significantly between males and females. These results show that regionally localized sex differences exist in the induced PR system after 5 days exposure to EB.     

乙醇对人绒毛孕酮分泌的影响

本工作利用灌流技术观察了四种不同浓度的乙醇(0.5％、1％、2.5％、5％)对妊娠早期人工流产新鲜胎盘绒毛分泌孕酮的影响。结果表明,乙醇具有促进孕酮分泌的作用,并存在剂量依赖的关系。提示乙醇可能破坏胎盘激素内分泌的平衡,从而影响胎儿的正常生长与发育。     

The regulatory role of FSH in steroid formation by luteinized human granulosa cells in culture

Granulosa cells were aspirated from human pre-ovulatory folliclesfollowing a combined clomiphene-gonadotrophin stimulation inan in-vitro fertilization (IVF) programme. The cells were culturedfor 8 days in medium M199 containing 10% bovine fetal calf serumunder 5% CO₂ in air. Pure human FSH and human LH were addedalone or in combination to the culture in various concentrationsand the progesterone (P) and oestradiol-17 (E₂) levels in themedium were measured every second day by a conventional RIAtechnique. In the presence of FSH or LH the formation of P increased2- to 3-fold with the pronounced effect after 4 to 6 days inculture. Addition of testosterone (T) (3 ? 10^–7 M) tothe culture medium affected neither basal nor gonadotrophinstimulated P formation. In this system, only minute amountsof E₂ were formed and neither FSH nor LH stimulated its formation.When the medium was fortified with T, basal E₂ formation increased50- to 100-fold. FSH further stimulated this conversion significantlyafter 6 and 8 days of culture, while LH had no significant influence.     

The Role of Sex Steroids in Forming Anxiety States in Female Mice

Natural fluctuations in sex hormones during the ovarian cycle have enormous influences on ongoing psychological status in the female body. We report here studies of the effects of exogenous sex steroids on anxiety levels in female mice, as evaluated in the elevated cross maze test. Female NMRI mice were subjected to bilateral oophorectomy and one week later received s.c. injections of solvent (sesame oil, controls) or estradiol benzoate for 7 days, either alone or with an additional dose of progesterone on day 7. Elevated maze tests performed 6 h later showed that animals given progesterone had the highest levels of anxiety and the highest levels of grooming reactions as compared with the other groups. Immunohistochemical analysis of the distribution of progesterone receptors in different parts of the brain demonstrated significant increases in the numbers of immunopositive cells after injections of estradiol benzoate alone, with further increases after progesterone injections. Thus, the data obtained here suggest that the genomic effects of sex steroids are important, as they appear to be involved in non-sexual forms of behavior, particularly the level of anxiety.     

乳腺癌ER,PR状态与细胞超微结构变化的形态定量分析

用免疫组化ＰＡＰ法检测３０例乳腺癌雌激素受体（ＥＲ）和孕激素受体（ＰＲ），从中选取ＥＲ、ＰＲ阳性者（Ｅ＾＋Ｐ＾＋）６例，阴性者（Ｅ＾－Ｐ＾－）５例作透射电镜观察，对部分细胞器连接的变化进行形态定量分析。结果Ｅ＾－Ｐ＾－组癌细胞内线粒体、粗面内质网及溶酶体的含量明显高于Ｅ＾＋Ｐ＾＋组，且差异有显著性（Ｐ＜０．０５，０．０１，０．０１）；Ｅ＾－Ｐ＾－组细胞间的桥粒及镶嵌连接有减少趋势，但差异无显著性     

Serum progesterone at the time of human chorionic gonadotrophin does not predict pregnancy in in-vitro fertilization and embryo transfer

Controversy exists as to whether the serum concentration ofprogesterone on the day of human chorionic gonadotrophin (HCG)administration following ovarian stimulation for in-vitro fertilization(IVF) and embryo transfer can be used to predict the likelihoodof success. This retrospective study was undertaken to answerthis question by analysing a large population of IVF and embryotransfer cycles (n = 756). In addition to the concentrationof progesterone on the day of HCG administration, all variablesknown to impact on IVF and embryo transfer success (such aspatient age), indication for IVF and embryo transfer, numberof oocytes retrieved and the number of embryos generated andtransferred were examined. There was a significant increasein the number of oocytes retrieved with increasing progesteroneconcentration at the time of HCG administration. However, therewas no correlation of progesterone concentration at HCG administrationwith pregnancy and implantation rates. It is concluded thatprevious reports associating a slight elevation of progesteronein gonadotrophin- releasing hormone agonist ovarian stimulationcycles for IVF and embryo transfer may be misleading becauseof a small sample size or the presence of confounding variablesthat affect IVF and embryo transfer success.