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Studies Index: J Clin Psychiatry 1999;60
Supply 9:9-13 Weinstock LS
Social anxiety disorder is associated with significant impairment in social and occupational functioning. Gender differences in social anxiety disorder are apparent for treatment seeking and symptom clusters, and hormonal influences may affect the natural course of illness. The lifetime prevalence rate is 13.3%, with rates of 15.5% in women and 11.1% in men. Although most studies indicate that more women suffer from social anxiety disorder, it appears that men are more likely to seek treatment. Gender differences in the presentation and management of social anxiety disorder may be influenced by fluctuations in levels of endogenous or exogenous reproductive hormones. Neurotransmitter systems implicated in the etiology of mood and anxiety disorders may be affected by both estrogen and progesterone. There are also issues with regard to pregnancy in women who have social anxiety disorder. It is not known if untreated social anxiety disorder represents a significant risk to the fetus. However, social anxiety disorder often is complicated by comorbid depression, panic disorder, or substance abuse, all of which may pose risks to the fetus if left untreated. Treatment strategies for patients with social anxiety disorder should consider gender differences in response to pharmacotherapy, psychiatric comorbidity, oral contraceptive use, pregnancy status, and the specific nature of symptoms in the individual patient. PMID: 10335674, UI: 99266705 Breast Cancer Science 1978 Feb
17;199(4330):787-8 Zava DT, McGuire WL Growth of the human breast cancer cell line MCF-7 is enhanced by androgens, but only at pharmacological concentrations. Although physiological concentrations of androgens translocate the androgen receptor into the nucleus, no mitogenic effects are observed. By contrast, pharmacological androgens translocate not only the androgen receptor but also the estrogen receptor, and at these high doses significantly increase both DNA and estrogen-dependent protein synthesis.We therefore propose that androgens stimulate MCF-7 cell growth not through the androgen receptor but rather through the estrogen receptor.PMID: 622569, UI: 78096508 Metabolism 1978
Apr;27(4):487-501 McGuire WL, Horwitz KB, Zava DT, Garola RE, Chamness GC The role of cytoplasmic estrogen receptor (ER) assays in determining therapeutic strategies for advanced breast cancer is certainly well established. The use of ER assays in the primary breast tumor specimen to predict for early recurrence and ultimate survival is a new finding, however, and will probably be employed in future trials of adjuvant therapy. The prevalence and significance of nuclear-bound ER still requires additional clarification. Our previous suggestion that progesterone receptor measurements might be a useful marker for hormone dependence in advanced breast cancer is gaining support and may soon have a place in routine therapeutic decision-making. The emphasis on early adjuvant therapy has hastened the search for a safe endocrine therapy that would have good patient compliance and achieve remission rates comparable to previous agents and procedures. Antiestrogens show promise of meeting these requirements. We are now beginning an era in which primary and secondary systemic therapies for breast cancer can be based on sound biologic principles. The empirical approach is outdated. Publication Types: Review PMID: 345042, UI: 78134944 Science 1977 May
6;196(4290):663-4 Zava DT, Chamness GC, Horwitz KB, McGuire WL The human breast cancer cell line MCF-7 does not require estrogen for growth, but paradoxically its growth is inhibited by antiestrogens. Our results show that, unlike normal target cells, MCF-7 cells carry most of their estrogen receptors in their nuclei even when these receptors are not charged with estrogens. The receptors for androgen and for progesterone, on the other hand, are localized in the cytoplasm as usual. Therefore, it is possible that the growth of these abnormal cells is stimulated by estrogen receptor in spite of the absence of the hormone and that the binding of antiestrogen molecules antagonize this stimulation. PMID: 193182, UI: 77174644 Tumour Biol
Okuyama N, Hatano Y, Park Y, Shimatani S, Sasamoto S, Katou N, Takagi K, Yamazaki S, Inoue A, Hemmi H, Shimatake H, Yanagida M, Miura M Department of Thoracic Cardiovascular Surgery, Toho University School of Medicine, Tokyo, Japan. okuyama@med.toho-u.ac.jp Controversy exists regarding the relationship of the degree of c-erbB-2 amplification to other prognostic factors in breast cancer. To determine the degree of amplification of c-erbB-2 exactly, a sensitive and quantitative method is required. We have developed a competitive PCR method to quantitatively determine the amplification of the c-erbB-2 oncogene. Using this method, we evaluated DNA from 27 breast cancer tissue specimens and DNA from peripheral blood leukocytes from a normal individual. Regarding the relationship between the degree of c-erbB-2 amplification and clinicopathological factors, we found a greater degree of amplification of the c-erbB-2 oncogene in estrogen receptor- negative or progesterone receptor-negative specimens than in positive ones and in lymph node metastasis-positive specimens than in negative specimens, in stages II, III, and IV of disease compared with stage I disease, and in samples with positive lymphatic vessel invasion than with no lymphatic vessel invasion. Generally, these factors were seen in the group of patients who had a bad prognosis. By univariate analysis and multivariate analysis, reverse correlation was observed between amplification of c-erbB-2 and overall survival. Regarding disease-free survival, these relationships were observed only with univariate analysis in our group of patients. PMID: 10213923, UI: 99234304 J La State Med Soc 1999
Apr;151(4):209-13 Yu H, Berkel H Section of Cancer Prevention and Control, Feist-Weiller Cancer Center, Louisiana State University Medical Center, Shreveport, USA. Prostate-specific antigen (PSA) is a valuable tumor marker for prostate cancer. It was believed that PSA was produced exclusively by the epithelial cells of the prostate gland, but a large body of evidence demonstrates that PSA is not a prostate-specific molecule. PSA has been shown to be expressed in many forms of female tissues. The breast is a major female organ able to produce PSA. PSA is detected in both normal and abnormal breast tissues, as well as in various breast fluids including milk, nipple aspirate, and cyst fluid. Androgens and progesterones, via their receptors, regulate the production of PSA in breast tissue. Clinical studies demonstrate that PSA in breast cancer is associated with the expression of estrogen receptor and progesterone receptor. Women with PSA-positive breast cancer have better disease-free survival as well as overall survival than those with PSA-negative breast cancer. PSA levels in nipple aspirate fluid may be indicative of breast cancer risk. High concentrations of PSA are found in amniotic fluid and the levels change with gestational age. Pregnant women have elevated serum PSA. PSA levels in serum also vary during menstrual cycles and increase in women with excess androgen. Clinical implications of PSA in amniotic fluid and female serum have been suggested. More studies are needed to further explore their utilities. PMID: 10234897, UI: 99251205 CMAJ 1992 Jul
1;147(1):45-9 Devitt JE, To T, Miller AB Department of Surgery, Ottawa Civic Hospital, Ont. OBJECTIVE: To study the occurrence of breast cancer in women with breast cysts. DESIGN: Prospective follow-up study. SETTING: Office surgical practice. PATIENTS: All 742 women referred to the practice with breast cysts diagnosed by means of aspiration or, occasionally, biopsy between 1969 and 1985. MAIN OUTCOME MEASURES: The incidence of breast cancer and the number of years between diagnosis of breast cyst and diagnosis of cancer. The observed number of cases of breast cancer was compared with the expected number, calculated from Ontario rates of breast cancer. RESULTS: Fifteen of the women died but did not have breast cancer. No follow-up information was available for five women. Another 38 were lost to follow-up; they did not have breast cancer at the last contact, after 2 to 17 years of follow-up. These patients were withdrawn from the study in the year in which they died or were last observed. By 1990, 34 (5%) of the women had breast cancer. The overall ratio of observed: expected cases of cancer was 3.04 (95% confidence interval 2.09 to 4.28). Breast cancer developed after 7.5 years, but the average length of follow-up was only 10.1 years. Only 3.8% of 374 women after 10 years and 5.4% of 141 women after 15 years had breast cancer. CONCLUSION: Women who have a gross breast cyst are at moderately increased risk of breast cancer, which usually develops only after many years. PMID: 1393887, UI: 93007566 Histopathology 1999
Apr;34(4):310-9 Nakopoulou L, Michalopoulou A, Giannopoulou I, Tzonou A, Keramopoulos A, Lazaris AC, Davaris PS Department of Pathology, Medical Faculty of Athens University, Athens, Greece. AIM: A role for altered programmed cell death in cancer stems from the description of alterations on tumour-associated genes involved in the regulation of apoptosis such as p53 and bcl-2. The balance between the latter may have significant implications for the pathobiology of breast cancer. This study was therefore undertaken to evaluate the expression of these two gene products with opposite functions. METHODS AND RESULTS: A total of 142 paraffin-embedded tumour blocks were evaluated for nuclear p53 (a marker of p53 inactivation) and cytoplasmic bcl-2 immunohistochemistry. The results were semiquantitated. The bcl-2 protein was found within the infiltrating neoplastic cells of 97 (68%) specimens but it was also detectable in tumours' in situ compartments and in benign mammary tissue. We identified a strong correlation between bcl-2 immunoreactivity and oestrogen receptor positivity (P = 0.03), while bcl-2 expression also correlated significantly with small tumour size (P = 0.006) and low nuclear grade (P = 0.01), but it did not correlate with the expression of p53. bcl-2 presence tended to diminish with disease progression (P = 0.06). Quantitatively increased bcl-2 immunostaining was significantly associated with older patients (P = 0.02) as well as with presence of progesterone receptors (P = 0.01). Thirty-seven tumours (26%) were judged positive for p53 protein expression. The p53 positivity status was independent of all classical histopathological variables; however, high p53 expression was negatively linked to oestrogen receptors (P = 0.005). CONCLUSION: In breast cancer, bcl-2 protein is associated with a prognostically favourable phenotype and appears to be related to hormonal regulation, rather than to disabled p53 gene function. PMID: 10231398, UI: 99248092 Cancer Detect Prev
1999;23(3):238-44 Ashba J, Traish AM Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA. We examined the concentrations of estrogen (ER) and progesterone receptors (PR) and the distribution of tumor phenotypes as a function of age in breast cancer patients. ER and PR concentrations were determined in tissue biopsies from 1739 patients with primary breast cancer, using ligand binding assays. Tumors were classified as estrogen receptor positive (ER+) or negative (ER-) and progesterone receptor positive (PR+) or negative (PR-) based on the presence or absence of receptor binding activity. Tumors were stratified into four phenotypes: ER+PR+; ER+PR-; ER-PR+; and ER-PR-. Significant positive associations were found between ER concentration and age (p = 0.0001) and between PR concentration and age (p = 0.0002). The median ER concentrations were statistically different by age groups, with the greatest levels in older versus younger patients. The prevalence of ER+PR+ tumor phenotype increased with age. In contrast, the prevalence of ER-PR- and ER-PR+ tumor phenotypes decreased with age. The median PR-to-ER ratio decreased with age (p = 0.0001), and this trend was attributed to increased ER concentration with age. The prevalence of ER-PR- and ER-PR+ tumor phenotypes is greater in younger patients suggesting that hormonal regulation of ER gene expression may be responsible for the observed age disparity of tumor phenotypes in breast cancer. PMID: 10337003, UI: 99270828 Pathol Int 1999
Mar;49(3):198-202 Honda H, Ohi Y, Umekita Y, Takasaki T, Kuriwaki K, Ohyabu I, Yoshioka T, Yoshida A, Taguchi S, Ninomiya K, Akiba S, Nomura S, Sagara Y, Yoshida H Department of Pathology, Faculty of Medicine, Kagoshima University, Japan. yoshida@med4.kufm.kagoshima-u.ac.jp [Medline record in process] Possible relationships between risk factors, such as obesity and a family history of breast cancer, and prognostic factors of mammary carcinomas were investigated by examining the body mass index of patients and the expression of estrogen (ER) and progesterone receptors (PgR), c-erbB-2 and p53, grade of histology, size of tumors and nodal status of mammary carcinomas. There was no significant difference in the body mass index of premenopausal patients either with or without a family history. For postmenopausal patients, the body mass index was significantly low in patients with a family history compared with patients without a family history. In premenopausal patients with or without a family history and in postmenopausal patients with a family history, there was no significant difference in the body mass index regardless of the mammary carcinoma prognostic factor, such as expression of ER, PgR, c-erbB-2 and p53, grade of histology, size of tumors and nodal status. However, in postmenopausal patients without a family history, body mass index was significantly high for patients with mammary carcinomas that had PgR expression and node metastasis. These results suggest that obesity may affect the PgR status and nodal status of mammary carcinomas in postmenopausal patients without a family history. PMID: 10338073, UI: 99268395 Am J Pathol 1999
Apr;154(4):1245-57 Akoum A, Lavoie J, Drouin R, Jolicoeur C, Lemay A, Maheux R, Khandjian EW Laboratoire d'Endocrinologie de la Reproduction, Centre de Recherche, Pavillon Saint-Francois d'Assise, Centre Hospitalier Universitaire de Quebec, Universite Laval, Quebec, Canada. ali.akoum@crsfa.ulaval.ca The study of misplaced endometrial cells, which abnormally implant and grow outside the uterine cavity, is of considerable interest for the understanding of the pathophysiology of endometriosis. However, endometriotic cells, particularly epithelial cells, required for primary cell culture are not easily available. We report here the characterization of an endometriotic cell line immortalized after infection of primary endometriotic cell cultures with simian virus 40. Transformed cells express T-antigen, and blot hybridization analysis showed that the viral genome is present as an episome. Cytogenetic analysis revealed a polyploid karyotype with numerical and structural rearrangements involving mainly the same chromosomes (6, 10, 11, 15, and 17). The cell line has been maintained in culture for over 80 passages and was still proliferating without any noticeable change in the biological properties investigated. Transformed endometriotic cells expressed both progesterone and estradiol receptors and were stimulated by these ovarian hormones to secrete monocyte chemotactic protein-1, a factor that may play an important role in the recruitment and activation of peritoneal macrophages. In addition, this response was enhanced in interleukin-1-treated cells. Taken together, these findings support the view that this cell line may be an interesting tool for the study of the pathophysiology of endometriosis. PMID: 10233862, UI: 99252440 Neurology
Kim S, Liva SM, Dalal MA, Verity MA, Voskuhl RR Department of Neurology, University of California Los Angeles School of Medicine, USA. OBJECTIVE: To evaluate the use of estriol in the treatment of experimental autoimmune encephalomyelitis (EAE) and other cell mediated autoimmune diseases. BACKGROUND: Experimental autoimmune encephalomyelitis is a T helper 1 (Th1)-mediated autoimmune demyelinating disease that is a useful model for the study of immune responses in MS. Interestingly, both EAE and MS have been shown to be ameliorated during late pregnancy. METHODS: Estriol, progesterone, and placebo pellets were implanted in mice during the effector phase of adoptive EAE. Disease scores were compared between treatment groups, and autoantigen-specific humoral and cellular responses were examined. RESULTS: Estriol treatment reduced the severity of EAE significantly compared with placebo treatment whereas progesterone treatment had no effect. Estriol doses that induced serum estriol levels that approximated estriol levels during late pregnancy were capable of ameliorating disease. Estriol-treated EAE mice had significantly higher levels of serum antibodies of the immunoglobulin (Ig) G1 isotype specific for the autoantigen myelin basic protein (MBP). Further, MBP-specific T-lymphocyte responses from estriol-treated EAE mice were characterized by significantly increased production of the Th2 cytokine interleukin 10 (IL-10). T lymphocytes were shown to be the primary source of IL-10 within antigen-stimulated splenocyte populations. CONCLUSIONS: Estriol as a hormone involved in immune changes during pregnancy may provide a basis for the novel therapeutic use of estriol for MS and other putative Th1-mediated autoimmune diseases that improve during late pregnancy. PMID: 10214749, UI: 99229562 J Mammary Gland Biol
Neoplasia Shyamala G Division of Life Sciences, Lawrence Berkeley National Laboratory, University of California, Berkeley 94720, USA. shyamala_harris@lbl.gov Progesterone was identified as a mammogenic hormone several years ago but until now its precise role in mammary development has remained obscure. Recently with the generation of several transgenic mouse models and development of reagents for analysis of progesterone receptor expression, the role of progesterone signaling in mammary development is becoming more clear. The most significant observations to emerge from these studies are (1) progesterone receptors (PR) are present in a heterogeneous manner in the epithelial cells and undetectable in the surrounding fat pad; (2) they are essential for lobuloalveolar and not for ductal morphogenesis; (3) progesterone signaling through progesterone receptors, leading to lobuloalveolar development, is initiated in the epithelium and may occur through paracrine mechanisms; and (4) a regulated expression of the two isoforms of progesterone receptor is critical for maintaining appropriate responsiveness to progesterone and hence, epithelial cell replicative homeostasis. These studies also reveal that the consequences of progesterone signaling through progesterone receptor may depend on the cell context, cell-cell and cell-extracellular matrix interactions, the dynamics of PR turnover and the fate of PR positive cells. PMID: 10219909, UI: 99235315 Fertil Steril 1997
Jul;68(1):90-4 Rosen B, Irvine J, Ritvo P, Shapiro H, Stewart D, Reynolds K, Robinson G, Thomas J, Neuman J, Murphy J Toronto Hospital, University of Toronto, Ontario, Canada. BROSEN@TORHOSP.TORONTO.ON.CA OBJECTIVE: To determine the feasibility of asking women undergoing fertility treatment the maximum increased risk of ovarian cancer they would be willing to tolerate in order to take ovulation-induction drugs. DESIGN: A prospective pilot study of women attending fertility clinics over a 2-month period. SETTING: Two tertiary care fertility clinics in Toronto. PATIENT(S): Sixty-one English-speaking women were approached and 85% (n = 52) were enrolled. INTERVENTION(S): A self-administered questionnaire with fertility-specific questions. Thirty-eight women also were asked to complete standardized scales of anxiety and optimism. MAIN OUTCOME MEASURE(S): Women's report of the maximum level of lifetime risk of ovarian cancer they were willing to tolerate in order to undergo fertility treatment. RESULT(S): Seventy-nine percent were willing to accept an increased risk of ovarian cancer. Only 24% understood that treatment for ovarian cancer usually was not curative. CONCLUSION(S): A majority of patients were willing to tolerate a modest increase in their lifetime risk of ovarian cancer because of fertility treatment, most basing their estimate of acceptable risk on limited awareness of the issue. PMID: 9207590, UI: 97351308 Acta Obstet Gynecol Scand
1997 Feb;76(2):177-81 Malignant tumors of the ovary or the breast in association with infertility: a report of thirteen cases. Unkila-Kallio L, Leminen A, Tiitnen A, Lehtovirta P, Wahlstrom T, Ylikorkala O Department of Obstetrics and Gynecology, Helsinki University Hospital, Finland. BACKGROUND: Many questions have
been raised recently about the relationship between infertility, fertility
drugs and cancer. This prompted us to evaluate our patients having ovarian or
breast cancer with a known history of infertility. METHODS: We report thirteen
women who had been examined and/or treated for infertility before the
occurrence of malignant tumors of the ovary or the breast at an age under 50
years in 1990-1995 in our unit. RESULTS: Mean age of the patients was 35 years
(s.d. 5.9 years, range 28-47 years). Of the 11 ovarian tumors, one was a
malignant teratoma, two were granulosa cell tumors and eight epithelial ovarian
cancers. Ten women had received either clomiphene citrate alone or together
with gonadotrophins, one had used only gonadotrophins, and in two patients
ovarian cancer was detected during an infertility work-up but before any
treatment. Four women had used clomiphene for more than twelve cycles. Two
patients had ductal breast cancer. CONCLUSIONS: Our patients emphasize the need
for follow-up and long-term prospective studies in infertile women who have
been evaluated or treated for infertility. PMID: 9049294, UI:
97201508 Curr Opin Obstet Gynecol
1996 Feb;8(1):32-7 Bristow RE, Karlan BY Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California, USA. Recently, much attention in both the medical and lay communities has been focused on a possible association between fertility drug use and invasive ovarian cancer, and ovarian tumors of low malignant potential. A causal relationship, if shown to exist, has important implications. In the past year, several large case-control and cohort studies have attempted to address this issue. However, interpretation of the available data has been hampered by a number of factors. Retrospective study designs, small numbers of ovarian cancer cases, and inconsistent reporting of fertility drug use and type of infertility have all been common methodological shortcomings. The known ovarian cancer risk factors of low parity and infertility have been particularly difficult to separate from any effect of ovulation induction. The current epidemiologic data are insufficient to implicate conclusively specific fertility medications in ovarian carcinogenesis. The data do suggest that women with refractory infertility may constitute a high-risk population for developing ovarian cancer, independent of fertility drug use. Until the relationship between ovulation induction and ovarian cancer risk is defined more accurately, a high index of clinical suspicion for ovarian neoplasms is indicated before, during, and after treating women for infertility. PMID: 8777256, UI: 96260572 Am J Epidemiol 1998 Jun
1;147(11):1038-42 Modan B, Ron E, Lerner-Geva L, Blumstein T, Menczer J, Rabinovici J, Oelsner G, Freedman L, Mashiach S, Lunenfeld B Department of Clinical Epidemiology, Chaim Sheba Medical Center, Tel Hashomer, Israel. Among 2,496 infertile Israeli women treated between 1964 and 1974, 143 cancer cases were observed as compared with 116.1 expected (standardized incidence ratio (SIR) = 1.2, 95% confidence interval (CI) 1.0-1.5) through 1991. Site-specific analysis revealed 12 ovarian cancers versus 7.2 expected (SIR = 1.6, 95% CI 0.8-2.9), 21 endometrial cancers versus 4.3 expected (SIR = 4.85, 95% CI 3.0-7.4), and 59 breast cancers versus 46.6 expected (SIR = 1.3, 95% CI 0.96-1.6). Sensitivity analysis revealed that confounding was unlikely to explain the raised risk of endometrial cancer, but nulliparity might explain the increased risk of ovarian cancer. The excess of endometrial cancer was prominent among patients with normal estrogen production but progesterone deficiency (SIR = 9.4, 95% CI 5.0-16.0). The risk for ovarian cancer was similar among the total groups of treated and untreated patients (SIR = 1.7 vs. 1.6). The standardized incidence ratio for endometrial cancer was higher among the treated group than the untreated group, although not significantly. Treatment with ovulation-inducing drugs does not appear to increase the risk for ovarian cancer, but its role cannot be completely excluded. PMID: 9620047, UI: 98281346 Menstrual Cycle Hum Reprod 1999
Apr;14(4):913-8 Messinis IE, Milingos SD, Alexandris E, Kariotis I, Kollios G, Seferiadis K Department of Obstetrics and Gynaecology, University of Thessalia, Greece. To study the relationships between gonadal steroids and leptin, 20 women with normal cycles were investigated during the postoperative period following a laparotomy. Fourteen women underwent bilateral ovariectomy plus total hysterectomy either in the mid- to late follicular phase (n = 7, group 1) or in the early to midluteal phase (n = 7, group 2). The remaining six of the 20 women underwent cholocystectomy in the early to midfollicular phase of the cycle and were used as controls (group 3). In all three groups, serum leptin values decreased rapidly up to post-operative day 4. Then, leptin values increased significantly only in group 3 (P < 0.05). Leptin values before and after the operation showed significant positive correlations with body mass index (BMI), oestradiol and progesterone. However, with multiple regression analysis, BMI was the only parameter significantly correlated with leptin in group 3 (days 0 and 4-7), whereas in groups 1 and 2 progesterone and BMI showed independent significant correlations with leptin (days 0 and 8, r = 0.601 and r = 0.602 respectively). These results demonstrate for the first time a significant reduction in leptin concentrations in normal women following bilateral ovariectomy. Although BMI seems to be the predominant factor, it is also suggested that oestradiol and progesterone may participate in the control of leptin production during the human menstrual cycle. PMID: 10221218, UI: 99237575 Hum Reprod 1999
Apr;14(4):970-5 Zhu P, Liu X, Luo H, Gu Z, Cheng J, Xu R, Lian S, Wu S, Wang J National Research Institute for Family Planning, Beijing, China. Thirty-four women bearing a levonorgestrel-releasing intrauterine device, 20 micrograms/day (LNG-IUD-20), for 12-15 months were recruited. Endometrial biopsies were collected during the late proliferative phase of the cycle (on cycle days 10-12) before (control) and after the use of the IUD for 12 months, and assayed for oestrogen receptors (ER) and progesterone receptors (PR). An immunohistochemical technique with the peroxidase-antiperoxidase detection system (PAP method) was employed. D75 and JZB39 were the primary antibodies for ER and PR respectively. The immunostaining semiquantitative analysis was performed with a computerized microscope image processor, and expressed as 'grey value'. Both endometrial ER and PR populations were significantly lower after insertion of the IUD (P < 0.01) than in control biopsies. The intensity of nuclear staining and the percentage of positively stained cells for ER and PR in women with LNG-IUD were each about 50% of those in control biopsies. The results suggested that LNG released locally from the IUD has a depressive action on the ER and PR, which may contribute to the contraceptive effectiveness of this type of IUD and also to the possible causes of LNG-IUD-induced irregular bleeding and amenorrhoea. PMID: 10221229, UI: 99237586 Proc Natl Acad Sci U S A
1999 May 11;96(10):5722-7 Lau KM, Mok SC, Ho SM Department of Biology, Tufts University, Medford, MA 02155, USA. Our understanding of the roles played by sex hormones in ovarian carcinogenesis has been limited by a lack of data concerning the mode of sex hormone action in human ovarian surface epithelial (HOSE) cells, the tissue of origin of >90% of ovarian cancers. We have compared the relative abundance of estrogen receptor (ER)alpha, ERbeta, progesterone receptor (PR), and androgen receptor (AR) mRNA in four primary cultures of HOSE cells obtained from postmenopausal women to those found in late serous adenocarcinoma primary cell cultures and established ovarian cancer cell lines. We observed coexpression of ERalpha and ERbeta mRNA along with AR and PR transcripts in normal HOSE cells and disruption of ERalpha mRNA expression as well as dramatic down-regulation of PR and AR transcript expression in most ovarian cancer cells. In contrast, levels of ERbeta mRNA were unaffected by the malignant state. Additionally, a novel mutation involving a 32-bp deletion in exon 1 of ERalpha transcripts was detected in the SKOV3 cell line. This mutation would explain why SKOV3 was reported to be ER-positive but estrogen-insensitive. Taken together, these findings suggest that estrogens, signaling via either or both ER subtypes, may play an indispensable role in regulating normal HOSE cell functions. Therefore, loss of ERalpha, PR, and AR mRNA expression in HOSE cells may be responsible for neoplastic transformation in this cell type. In contrast, the roles played by ERbeta in normal and malignant HOSE cells remain elusive. Finally, the coexistence of mutated ERalpha mRNA and normal ERbeta transcripts in SKOV3 argues in favor of a dependency of ERbeta action on functional ERalphas. PMID: 10318951, UI: 99254108 Biol Signals Recept 1999
May-Jun;8(3):160-77 Liu YX State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, PRC. Liuyx@panda.ioz.ac.cn Extracellular matrix (ECM) not only provides a structural support for the organism, but also actively conducts cell-to-cell signal transduction and regulates cell proliferation, migration, development and metabolism. The targeted ECM degradation generated by plasminogen activator (PA) and regulated by plasminogen activator inhibitor (PAI) is, therefore, an event that affects a wide variety of physiological and pathological processes. The ovary is the best model to study the regulation and function of extracellular proteolysis mediated by multicomponents like the PA system. Studies carried out over the past 10 years in a number of laboratories have elucidated some of the biochemical events related to the function and regulation of the PA system in the ovary: hormone-induced proteolytic activity provided by tissue-type PA(tPA) and modulated by PAI-1 in the preovulatory follicles is responsible for a controlled and directed proteolysis leading to rupture of selected follicles during ovulation, whereas the coordinated expression of urokinase-type PA (uPA) and PAI-1 in the early growing follicle may be important in ECM degradation during cell proliferation and migration; the PA system may also play a role in the control of corpus luteum (CL) development through an autocrine or paracrine mechanism. Increase in tPA and PAI-1 expression in CL at a later stage is well correlated with a sharp decrease in CL progesterone production, while the increase in uPA mRNA levels and activity in the early stage of CL development is correlated with an increase in progesterone secretion. PMID: 10213845, UI: 99234381 Histopathology 1999
May;34(5):462-9 Devouassoux-Shisheboran M, Schammel DP, Tavassoli FA Department of Gynecological and Breast Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA. AIM: The clinicopathological, immunohistochemical and ultrastructural features of two ovarian hepatoid yolk sac tumours (H-YST) from our files are reviewed. METHODS AND RESULTS: Using avidin-biotin-peroxidase complex technique, the immunoprofile of these tumours was compared to that of a classic yolk sac tumour and to that previously reported for hepatocellular carcinomas. The clinicopathological and morphological features of our cases are similar to the seven previously reported ovarian cases. This rare germ cell tumour occurs in young females (mean age = 17.6 years) and presents most commonly with abdominal pain and a large ovarian mass (average size = 140 mm). Histologically, the tumours display a striking resemblance to hepatocellular carcinoma. The absence of an associated typical pattern of yolk sac tumour or other germ cell neoplasm may make it difficult to recognize the germ cell origin of this lesion. Our cases demonstrated positive staining for alpha-fetoprotein and alpha-1-antitrypsin. In addition, there was immunoreactivity with polyclonal carcinoembryonic antigen (CEA) antiserum in a canalicular pattern, focal staining for inhibin, oestrogen and progesterone receptors and absence of immunoreactivity for CK7 that contrasts with the immunophenotype of a usual yolk sac tumour. CONCLUSIONS: Ovarian H-YST and hepatocellular carcinoma share a similar immunoprofile. Ovarian H-YST is a highly aggressive tumour, most patients exhibit recurrence or die of disease within 2 years of diagnosis. PMID: 10231422, UI: 99248118 Fertil Steril 1996
Jan;65(1):13-8 Shushan A, Paltiel O, Iscovich J, Elchalal U, Peretz T, Schenker JG Hebrew University, Hadassah Ein-Karem Medical Center, Jerusalem, Israel. OBJECTIVE: To determine whether women with epithelial ovarian cancer are more likely to have been exposed to fertility drugs, and in particular hMG, than healthy population controls. DESIGN: A nationwide case-control study. PATIENTS: Two hundred living women 36 to 64 years of age, with a histologically confirmed diagnosis of primary invasive or borderline epithelial ovarian cancer that was first diagnosed and reported to the Israel Cancer Registry between January 1, 1990 and September 1, 1993 were enrolled. There were 164 (82%) invasive and 36 (18%) borderline epithelial ovarian tumors among the 200 cases. The controls were 408 women from the same dialing areas selected by random digit dialing. Cases and controls were interviewed using a standard questionnaire. A multivariate logistic model was used to assess the association of fertility drug use and ovarian cancer, controlling for variables found to be statistically associated with this outcome on univariate analysis. RESULTS: Twenty-four women with epithelial ovarian cancer (12%) and 29 healthy controls (7.1%) reported that they had used any fertility drug (adjusted odds ratio [OR] 1.31; 95% confidence interval [CI] 0.63 to 2.74). Among cases and controls, respectively, 22 and 24 reported that they had used hMG alone or in combination with clomiphene citrate (adjusted OR 1.42, 95% CI 0.65 to 3.12), and 11 and 6 reported that they had used hMG alone (adjusted OR 3.19, (95% CI 0.86 to 11.82). The risk was increased particularly in the subgroup of women with borderline ovarian tumors who had used hMG (adjusted OR 9.38, 95% CI 1.66 to 52.08). CONCLUSIONS: We conclude that the use of ovulation induction agents, in particular hMG, may increase the risk of epithelial ovarian tumors. PMID: 8557128, UI: 96109026 Am J Obstet Gynecol 1985
Mar 1;151(5):574-7 Yemini M, Borenstein R, Dreazen E, Apelman Z, Mogilner BM, Kessler I, Lancet M Eighty pregnant women at high risk of giving birth prematurely were divided randomly into two groups. Treatment with either 17 alpha-hydroxyprogesterone caproate, 250 mg by intramuscular injection once a week, or a placebo was given in a double-blind fashion. Imminent premature labor occurred in 29.0% of the treated group and in 59.4% of the control group (p less than 0.025). The rate of premature deliveries was also significantly lower in the treated group (16.1%) than in the control group (37.82%) (p less than 0.05). There were no cases of perinatal death or fetal malformations in either group. The mean birth weight of all infants of the treated group was significantly higher than in those of the control group (3111.9 +/- 905 gm versus 2680 +/- 813.4 gm, p less than 0.05). The results support treatment with progesterone caproate for the prevention of premature labor. Publication Types:* Clinical trial * Randomized controlled trial PMID: 3976757, UI: 85146038 Int J Gynaecol Obstet
1988 Aug;27(1):79-83 Ashkenazy M, Kessler I, Czernobilsky B, Nahshoni A, Lancet M Department of Obstetrics and Gynecology, Kaplan Hospital, Rehovot, Israel. Thirty-eight women were operated for an ovarian tumor diagnosed during pregnancy, with an incidence of 1/2328 deliveries. The diameter of all tumors was above 5 cm. Of the 31 women operated before delivery, seven were untreated and 24 received supportive progestational therapy. The rate of abortions was 85.7% in the untreated group and 10% in the hydroxy-progesterone-caproate group (HPC) (P less than 0.02). When the women received a total dose of HPC of more than 300 mg, 9 of 10 pregnancies reached term with a live child. Two ovarian malignancies were found, 5.3% of all cases. In 42.9% of the women there were fertility problems later in life. Ovarian tumors during pregnancy should be removed as soon as possible, irrespective of the age of the pregnancy. If fully progesterone therapy is given, the danger of abortions is reduced to a minimum. Prophylactic antibiotic treatment should also be administered. PMID: 2905304, UI: 89091639 Schweiz Med Wochenschr
1986 Jul 19;116(29):971-3 Pirovino M, Walti E, Akovbiantz A, Arrenbrecht S, Zava D, Buhler H, Schmid M The estrogen and progesterone receptor content of liver cytosol was measured in female patients with focal nodular hyperplasia associated with oral contraceptive use and compared with the receptor content of non-tumorous liver and of primary hepatocellular carcinomas. Receptors were found in very low concentrations or were not measurable at all. In one case of focal nodular hyperplasia the estrogen receptor content of the tumor was higher than that in the adjacent normal liver. Malignant liver tumors and the male liver were characterized by a low or non-measurable receptor content. The study of nuclear receptors combined with the use of monoclonal antibodies may be more helpful in elucidating the complex relationship between oral contraceptive use, benign liver tumors and hepatic steroid receptors. PMID: 3020682, UI: 87018744 Mol Hum Reprod 1999
Apr;5(4):291-8 Duncan WC, Cowen GM, Illingworth PJ MRC Reproductive Biology Unit, Centre for Reproductive Biology, Edinburgh, UK. In a human conception cycle, the expected decline in progesterone production by the corpus luteum during the late luteal phase is prevented by human chorionic gonadotrophin (HCG) secreted by the implanting blastocyst. This study investigated the expression of components of the synthetic pathway for progesterone in human corpora lutea in the presence and absence of HCG in vivo. Corpora lutea were obtained from: (i) normally cycling women at the time of hysterectomy and classified on the basis of the urinary luteinizing hormone (LH) surge as early (n = 3), mid- (n = 3), or late luteal (n = 3); or (ii) women who had received daily doubling doses of HCG (n = 3) to 'rescue' the corpus luteum. Expression patterns of steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage (P450scc) and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) were investigated by Northern blotting, in-situ hybridization and immunohistochemistry. Luteal 'rescue' with HCG was associated with the continued expression of these components. In the late luteal phase, in the absence of HCG, expression remained but was more variable. The expression of 3beta-HSD mRNA was significantly reduced during the luteal phase (P<0.01). In conclusion, during luteal 'rescue', HCG acts to maintain the steroidogenic pathway. In the absence of HCG, the decline in progesterone production begins in the presence of the main components of the steroidogenic pathway. While unlikely to initiate this decline, the altered expression levels of these components, particularly that of 3beta-HSD, may contribute to the continued reduction in progesterone production. PMID: 10321799, UI: 99253716 Chung Kuo Chung Hsi I
Chieh Ho Tsa Chih 1997 Obstetric and Gynecology Hospital, Shanghai Medical University. OBJECTIVE: To explore the effect of traditional Chinese medicine (TCM) on abnormal maternal-fetal immune and endocrine in 24 cases of threatened abortion (TA) and 68 cases of recurrent spontaneous abortion (RSA). METHODS: The levels of blocking effect (BE), antiidiotype antibody (AIA), cytotoxin antibody (CTA), beta-human chorionic gonadotropin (beta-hCG), progesterone (P), estradiol (E2) were measured in all 92 patients. RESULTS: Incidence rates of the lack of BE, AIA and CTA in 92 cases were 60.87%, 57.61% and 72.83% respectively. The lower levels of BE, AIA and CTA were elevated significantly (P < 0.05-0.01), and the serial levels of beta-hCG, P and E2 were markedly increasing (P < 0.01) in all successful pregnant patients. The rate of the successful pregnancy of 92 cases was 89.13% (to TA 91.67%, to RSA 88.24% respectively). CONCLUSIONS: It suggests that the lack of blocking antibody (BA) and endocrine hormone deficiency may result in spontaneous abortion during early pregnancy. The therapeutic mechanism of those herbs in treating spontaneous abortion was associated with the growing levels of BA and hormone by regulating the maternal-fetal immunity and endocrine. J Assist Reprod Genet
1999 May;16(5):242-6 Lindheim SR, Cohen MA, Chang PL, Sauer MV Department of Obstetrics and Gynecology, Columbia University College of Physicians & Surgeons, Columbia-Presbyterian Medical Center, New York, New York, USA. PURPOSE: Our purpose was to assess if periovulatory serum progesterone is reflective of ovarian responsiveness in controlled ovarian hyperstimulation (COH). METHODS: One-hundred forty-two in vitro fertilization-embryo transfer cycles in women using GnRH-a suppression and human menopausal gonadotropin (hMG) stimulation were evaluated. Responses were studied according to ovarian response to hMG and age. Outcome measures included peak serum estradiol, serum progesterone and estrogen/progesterone ratios on the day of hCG injection, number of harvested oocytes, fertilization rates, and delivered pregnancy rates. RESULTS: A periovulatory rise in serum progesterone (> 0.9 ng/ml) occurred only among younger women (< 40 years old) with a good response (P < 0.05). Though the number of oocytes was greater in good responders, fertilization and pregnancy rates were similar among all women regardless of age and ovarian response. CONCLUSIONS: Periovulatory levels of serum progesterone vary according to ovarian response to COH. Elevations in progesterone do not appear to be a manifestation of poor responders. Reduced periovulatory progesterone may reflect inadequate steroidogenesis. PMID: 10335470, UI: 99267951 Circulation 1999 May
25;99(20):2688-93 Hodges YK, Richer JK, Horwitz KB, Horwitz LD Department of Medicine, Division of Cardiology, University of Colorado Health Sciences Center, Denver, Colo. 80262, USA. BACKGROUND: Estrogens stimulate growth of breast or uterine cells but have the opposite effect on vascular smooth muscle cells, in which they protect against coronary artery disease with or without concomitant administration of progesterone. A possible cause of differences in hormone action is variable tissue-specific expression of hormone receptor. Therefore, we analyzed the structure of estrogen receptors (ERs) and progesterone receptors (PRs) in human vascular smooth muscle. METHODS AND RESULTS: RNA was isolated from human vascular smooth muscle, and the functional domains of ER-alpha and PR were characterized by reverse transcriptase and polymerase chain reaction. Interestingly, in addition to wild-type ER-alpha and PR, 5 variant ER-alpha and 2 variant PR transcripts were found. These variants contained precise deletions of exons encoding regions of the hormone-binding domain. The PR transcripts lacked exon 4 (PRDelta4) and exon 6 (PRDelta6). The ER-alpha transcripts were missing exon 4 (ERDelta4), exon 5 (ERDelta5), exon 6 (ERDelta6), exon 7 (ERDelta7), and exons 6 and 7, (ERDelta6,7). ER-beta variants were also detected. The PR variants were functionally characterized, and PRDelta6 was found to be a dominant-negative transcription inhibitor of wild-type receptors. Variant PR was present in premenopausal women but absent in postmenopausal women. CONCLUSIONS: Variant PR and ER transcripts are extensively expressed in human vascular smooth muscle. The complex tissue-specific effects of sex hormones may be mediated by the expression of heterogeneous forms of their cognate receptors. The presence of variant ERs and PRs may be of importance in altering the physiological effects of estrogens or progestins in vascular smooth muscle. PMID: 10338464, UI: 99270852 |
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