Biological differences between focal and diffuse adenomyosis and response to hormonal treatment

Research question

Is there any difference in ovarian steroid receptor expression and pattern of fibrosis in focal and diffuse adenomyosis and response to hormonal treatment?

Cine magnetic resonance microscopy of the rat heart using cardiorespiratory-synchronous projection reconstruction

PURPOSE: To tailor a cardiac magnetic resonance (MR) microscopy technique for the rat that combines improvements in pulse sequence design and physiologic control to acquire high-resolution images of cardiac structure and function. MATERIALS AND METHODS: Projection reconstruction (PR) was compared to conventional Cartesian techniques in point-spread function simulations and experimental studies to evaluate its artifact sensitivity. Female Sprague-Dawley rats were imaged at 2.0 T using PR with direct encoding of the free induction decay. Specialized physiologic support and monitoring equipment ensured consistency of biological motion and permitted synchronization of imaging with the cardiac and respiratory cycles. RESULTS: The reduced artifact sensitivity of PR offered improved delineation of cardiac and pulmonary structures. Ventilatory synchronization further increased the signal-to-noise ratio by reducing inter-view variability. High-quality short-axis and long-axis cine images of the rat heart were acquired with 10-msec temporal resolution and microscopic spatial resolution down to 175 microm x 175 microm x 1 mm. CONCLUSION: Integrating careful biological control with an optimized pulse sequence significantly limits both the source and impact of image artifacts. This work represents a novel integration of techniques designed to support measurement of cardiac morphology and function in rodent models of cardiovascular disease.     

Improved spectral selectivity and reduced susceptibility in SSFP using a near zero TE undersampled three-dimensional PR sequence

PURPOSE: To improve the performance of fat/water separation and reduce the sensitivity to susceptibility variation in balanced SSFP sequences. MATERIALS AND METHODS: Decreasing the repetition time (TR) reduces susceptibility artifacts in SSFP imaging. A shorter TR may also improve the spectral selectivity obtained when linearly combining data acquired using different radiofrequency phase cycling schedules. The desired short TR is achieved by using an angularly undersampled three-dimensional radial acquisition sequence that achieves a near zero echo time (TE) and also a short TR. RESULTS: Images from human volunteers demonstrate broad coverage of the cervical spine and knee with isotropic resolution. Excellent fat/water separation is achieved in these studies. CONCLUSION: The short TR capability of the proposed sequence greatly improves the fat suppression in SSFP imaging. High-resolution volumetric T2-like contrast imaged with reduced susceptibility artifacts can be obtained from a single acquisition using this technique.     

The effect of Nestorone on gonadotropic cells in pituitary of rats

The implant containing Nestorone is a promising long-acting contraceptive especially suitable for lactating women. In this study, two experiments were designed to observe the effect of Nestorone on the gonadotropic cells in pituitary of rats for analyzing its antiovulation mechanism. In the first experiment, the ED₅₀ of Nestorone on inhibiting ovulation was found to be 1.32 mg/kg. The serum luteinizing hormone (LH) levels were significantly lower 60 h after being treated with Nestorone at 8:30–9:00 a.m. on Day 2 (D2) of estrus. Image analysis showed that the average size of the LH cells in groups treated with Nestorone at 2 or 4 mg/kg was larger than that of the control. In the group treated with 4 mg/kg, most of gonadotropic cells were regular round in shape. And, abundant granules in cytoplasm were found in those cells, which indicated that the LH stored in cells was not released. In the second experiment, the rats were treated with Nestorone at 5 mg/kg at 11:30–12:00 a.m. on D2 of estrus. The normal or higher expression of LHβ mRNA in pituitary suggested that the synthesis of LH was not inhibited by the treatment with Nestorone. The expression of PR mRNA in pituitary was significantly lower than that of the control at 33 h after treatment. This might be a direct effect of Nestorone, since there were no differences in the serum E₂ and P₄ levels between the treated and the control group. It is concluded that Nestorone prevents ovulation through inhibition of LH secretion and it has no effect on synthesis of LH. Progesterone receptors in pituitary might be involved in this process, but further study is needed to gain more evidence.     

An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signalling in hepatocarcinogenesis and in the resistance of hepatocarcinoma cells against drug-induced apoptosis

Strong evidence emphasizes the role of the insulin-like growth factor (IGF) system and of type-I IGF receptor (IGF-IR) signalling in tumourigenesis. In this connection: (i) changes in the expression pattern of components of the IGF system (autocrine/paracrine expression of IGF-I and -II, overexpression of IGF-IR, decreased expression of IGF-binding proteins (IGFBPs) and of type-II IGF receptor/cation-independent mannose-6-phosphate receptor (IGF-II/M6PR) and (ii) increased serum concentrations of proteases that cleave the IGFBPs (e.g., cathepsin D) were observed in patients with hepatocellular carcinomas (HCC), in human hepatoma cell lines and in their conditioned culture medium, as well as in rodent models of hepatocarcinogenesis. Accordingly, studies carried out with animal models do suggest that the IGF system and IGF-IR signalling may play a role in hepatocarcinogenesis and in deregulated proliferation and apoptosis of HCC cells. Finally the instrumental role of Raf/MEK/ERK, one of the signalling cascades stimulated by IGF-IR, in anthracycline-induced apoptosis of HepG2 and Huh-7 human hepatoma cell lines emphasizes that care must be taken when designing combinations of antitumoural molecules for antineoplastic treatment. This review addresses the putative roles of the IGF system in primary HCC, with a special focus on the underlying molecular mechanisms. In a second part it emphasizes the putative interference of IGF-IR signalling with chemotherapeutic drug-induced apoptosis in human hepatoma cells.     

Developmental toxicity of estrogenic chemicals on rodents and other species

ABSTRACT  Antenatal sex-hormone exposure induces lesions in mouse reproductive organs, which are similar to those in humans exposed in utero to a synthetic estrogen, diethylstilbestrol. The developing organisms including rodents, fish and amphibians are particularly sensitive to exposure to estrogenic chemicals during a critical window. Exposure to estrogens during the critical period induces long-term changes in reproductive as well as non-reproductive organs, including persistent molecular alterations. The antenatal mouse model can be utilized as an indicator of possible long-term consequences of exposure to exogenous estrogenic compounds including possible environmental endocrine disrupters. Many chemicals released into the environment potentially disrupt the endocrine system in wildlife and humans, some of which exhibit estrogenic activity by binding to the estrogen receptors. Estrogen responsive genes, therefore, need to be identified to understand the molecular basis of estrogenic actions. In order to understand molecular mechanisms of estrogenic chemicals on developing organisms, we are identifying estrogen responsive genes using cDNA microarray, quantitative RT-PCR, and differential display methods, and genes related to the estrogen-independent vaginal changes in mice induced by estrogens during the critical window. In this review, discussion of our own findings related to endocrine distuptor issue will be provided.     

Expression of progesterone receptors A and B and insulin-like growth factor-I in human myometrium and fibroids after treatment with a gonadotropin-releasing hormone analogue

OBJECTIVE: To determine mRNA and protein expression of the progesterone receptor (PR) and insulin-like growth factor-I (IGF-I) in myometrium and fibroids. DESIGN: Retrospective clinical study.SETTING: Hospital-based and university-affiliated research laboratories. PATIENT(S): Twelve women in the proliferative phase and six women treated with GnRH analogue (GnRH-a). INTERVENTION(S): Blood sampling and collection of myometrium and fibroids. MAIN OUTCOME MEASURE(S): PR and IGF-I mRNA levels in fibroids and myometrium were analyzed by solution hybridization and in situ hybridization whereas the proteins were localized by immunohistochemistry. RESULT(S): Fibroids and myometrium from women in the proliferative phase showed significantly higher PR mRNA than the corresponding tissues from GnRH-a-treated women. The amount of cells positively stained for PR-AB and PR-B in fibroids and myometrium decreased after GnRH-a treatment compared with in the proliferative phase. The IGF-I mRNA in both fibroids and myometrium in the proliferative phase was significantly higher than those after GnRH-a treatment. The immunostaining of IGF-I showed no difference between the two tissues. There was weaker immunostaining in the GnRH-a-treated group compared with in the proliferative phase group. CONCLUSION(S): The shrinkage of fibroids after steroid deprivation is associated with alterations in PR and IGF-I expression.     

Insulin and estrogen receptor ligand influence the FGF-2 activities in MCF-7 breast cancer cells

From the MCF-7 cell line we have developed, a human mammary cancer cell subline with the same karyotype as the mother strain and named MCF-7(SF), able to grow in serum-free chemically defined medium. This cell subline was firstly used to analyze the effect of basic fibroblast growth factor (FGF-2) in estrogen-receptor-positive human breast cancer cells. FGF-2 like estradiol is able to increase cell proliferation and pS2 expression but was also found to inhibit progesterone receptor (PR) expression. The anti-estrogen tamoxifen partly counteracts the effects of FGF-2 and to discriminate between its two main mediators (estrogen receptor vs. anti-estrogen binding site, AEBS) we compare the efficacies of pure anti-estrogen (ICI 182,780) and AEBS ligand (PBPE). It appears that pure anti-estrogen counteracts cell growth and pS2 effects of FGF-2 since AEBS ligand inhibits the cell growth but has no activity on pS2 expression. Secondly, adding insulin (10(-6)M) in the culture medium induces a strong increase in cell proliferation, which then elicits an inhibitory effect of FGF-2 and addition of anti-estrogens, are less efficient to further decrease growth, since the effects of FGF-2 and anti-estrogens on pS2 expression are conserved.     

Population-based case-control study of soyfood intake and breast cancer risk in Shanghai

We evaluated the association of soyfood intake and breast cancer risk in a population-based case-control study among Chinese women in Shanghai. Included in the study were 1459 cases and 1556 age-matched controls, with respective response rates of 91.1% and 90.3%. Usual soyfood intake was assessed using a food frequency questionnaire (FFQ). Separate analyses were performed for all subjects and for the subset who reported no recent change in soyfood intake. The intake levels of soyfoods among women in Shanghai are high, with 96.6% women reporting soyfood consumption at least once a week. A statistically non-significant reduced risk (odds ratio (OR) = 0.78 95% CI = 0.52-1.16) of breast cancer was observed among those who reported eating soyfood at least once a week. Compared to those in the lowest decile intake group, women in the highest decile intake group had a 30% reduced risk of breast cancer (OR = 0.66, 95% CI = 0.46-0.95), but no monotonic dose-response relation was observed (P for trend, 0.28). Stratified analyses showed that the inverse association was restricted primarily among women who had a high body mass index (BMI), with an adjusted OR of 0.30 (95% CI = 0.10-0.94) observed for the highest intake group. The reduction in risk was stronger for breast cancer positive for both oestrogen receptor (ER) and progesterone receptor (PR) (OR = 0.44, 95% CI = 0.25-0.78) than those with other ER/PR status. More pronounced inverse associations were observed in analyses among those who reported no recent change in soyfood intake than those conducted in all subjects. A dose-response relation between soyfood intake and breast cancer risk was observed in this subset of women (P for trend, 0.02), with an OR of 0.46 (95%CI = 0.28-0.75) for those in the highest decile intake group. No clear monotonic dose-response relation was found between soyfood intake and breast cancer risk among regular soy eaters, but nevertheless the results suggest that regular soyfood consumption may reduce the risk of breast cancer, particularly for those positive for ER and PR; the effect may be modified by body mass index.