PreM Women Research Articles

Abstract P6-14-15: Impaired Nuclear Translocation of Estrogen Receptor Alfa Could Be Associated with the Antineoplastic Effect of Iodine in Premenopausal Breast Cancer

Abstract Several laboratories including ours have shown that iodine (I2) intake exhibits potent antiproliferative and apoptotic effects in vivo and in vitro models of mammary cancer. Molecular analysis of these effects indicates that antioxidant; cellular arrest and apoptotic pathways are involved. As the cellular mechanism that triggers these antineoplastic effects we have proposed that I2 could act in 2 possible ways, directly as antioxidant or indirectly by generating an iodinated arachidonic acid (6-iodoloctone) which exhibits apoptotic effects and is a specific ligand of proliferative peroxisome activated receptor gamma (PPARg). In previous preliminary reports, we corroborated an antiproliferative I2 effect (decreased PCNA) in premenopausal (pre-M) and an apoptotic action (triggering the Bax-Caspase pathway) in both pre-M and post menopausal (post-M) women with early stage breast cancer. In the present report we raise the casuistic and deeply in the analysis of mechanisms involved in this antineoplastic effect of I2. This study includes 22 women (average age 52.9 ± 12.6) diagnosed with early stage breast cancer (IIa and IIb). Patients were divided according to hormonal status into pre-M and post-M groups and were supplemented with I2 (5 mg daily) or placebo (vegetable dye) for2-5 weeks before surgery. Thyroid status (T3 and TSH; RIA) and iodine intake (urine, HPLC) were analyzed. In biopsies (beginning) and/or tumors (final), the level and location (cytosol or nuclear) of estrogen receptor alfa (ERα) and beta (ERb) were analyzed by immunohistochemistry. In tumors, we measured PPARg expression, invasive potential [hypoxia-inducible factor (HIF) and vascular endothelial growth factor (VEGF) by real time PCR] and fibrosis content (Masson's trichromic method). The results show that I2 supplementation in pre-M women is accompanied by a significant increase in the concentration of total ERα and PPARg and no change in total ERb; however, the fraction of ERα in the nucleus was significant lower, and the fibrosis content was higher (70%) than in the placebo group (40%). In contrast, I2 supplements significantly decreased HIF and VEGF expression in both pre-and post-M women. In conclusion, our data show that, in addition to the apoptotic and anti-invasive effects on mammary cancer exhibited by I2 that are independent of hormonal status, in pre-M women, I2 also acts to diminish the effects of estrogen (decreases nuclear translocation of ERα). Experiments that analyze the possible role of PPARg in these actions are in progress. We thank Dr. Jorge Alvarez-Aguirre2,3, Dr. Alonso Gallegos-Corona2, Lic. Concepción Correa-Tinajero3, Alejandro Nuñez-Nolasco2,3, Dra. Norma Uribe Uribe4, Jaime Ayala García4 and Dr. Dorothy Pless1. This work was supported by in part by PAPIIT-UNAM IN201210 and CONACyT 78955 and 85952. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-15.

Correlation between leptin level and hypertension in normal and obese pre- and postmenopausal women

The present study was aimed at evaluating the correlation between leptin and hypertension in normal and obese hypertensive pre- (Pre-M) and postmenopausal (Post-M) women of Jalandhar city (Punjab, India). For the present study, 78 Pre-M and Post-M women were recruited in four categories as follows: i) normal normotensive, ii) obese normotensive, iii) normal hypertensive, and iv) obese hypertensive. Body mass index was considered as the index of obesity. Guidelines given by JNC-VII were followed for the assessment of hypertension. Leptin was assayed by sandwich ELISA, and estradiol (E(2)) was assayed by competitive ELISA. Leptin level was found to be significantly higher in normal Pre-M women (P<0.02) than that of normal Post-M women. Obese subjects had significantly higher leptin level (P<0.001) than the normal women. In the case of hypertensive subjects, leptin level was significantly higher than that of normotensive counterparts. E(2) level was found significantly lower in Post-M women (P<0.001) than that of Pre-M women as well as in hypertensive women than that of normotensive subjects. A positive correlation was observed between blood pressure (BP) and leptin, but significant association was observed in hypertensive normal and obese Pre-M and Post-M women only. It is concluded from the present findings that leptin contributes to the regulation of BP in hypertensive normal as well as in the obese Pre-M and Post-M women. So, leptin may be a regulator of BP in hypertensive women independent of the degree of obesity and the menopausal status.

Androgens in relationship to cardiovascular risk factors in the menopausal transition

Objective To establish the relationship between androgens and cardiovascular disease (CVD) risk factors in the menopausal transition.Methods A total of 124 women were divided into four groups: 29 premenopausal (PreM), 35 women in the menopausal transition still menstruating (MTM), 29 women in the menopausal transition with 3–6 months amenorrhea (MTA), and 31 postmenopausal women (PostM). Levels of triglycerides, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, glucose and insulin were assayed in all samples and waist circumference was measured. In a subgroup of 83 women (19 PreM, 21 MTM, 28 MTA and 15 PostM), levels of total testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS) and estradiol were determined. The free androgen index, Homeostasis Model Assessment (HOMA) index, Quantitative Insulin Sensitivity Check Index (QUICKI) and McAuley index, estradiol/total testosterone and triglyceride/HDL cholesterol ratios were calculated.Results Androstenedione was higher in MTA vs. PostM women (p < 0.05); DHEAS was higher in PreM women vs. the other three groups (p < 0.05). Sex hormone binding globulin (SHBG) in MTM women was higher than in MTA women (p < 0.05); the free androgen index was lower in MTM women than in MTA and PostM women. SHBG and the free androgen index showed negative and positive correlations, respectively with waist circumference, insulin resistance and lipids. In a multiple regression analysis, considering waist circumference, neither free androgen index nor SHBG showed significant differences between groups. The waist circumference correlated only with SHBG (p = 0.022) and correlations between SHBG and insulin resistance markers continued to be significant, but relationships between SHBG and lipoproteins and all correlations found with free androgen index were lost.Conclusions An increment in the androgenic milieu that correlates with abdominal fat, insulin resistance and atherogenic lipoproteins becomes evident after the menopausal transition and suggests that evaluation of cardiovascular disease risk in these women should include androgens, considering that abdominal obesity is one of the main determinants of the relationship between androgenic parameters and cardiovascular risk factors.

Prevalence of metabolic syndrome during menopausal transition Tehranian women: Tehran Lipid and Glucose Study (TLGS)

Objective This study was conducted to assess the prevalence of metabolic syndrome (MetS) in Tehranian women during menopausal transition. Design In this cross sectional study 2182 subjects, pre-menopausal (pre-M) n = 537, menopausal (M) n = 311 and post-menopausal (post-M) n = 1334 were selected from 15005 participants of the TLGS and assessed for MetS risk factors. All MetS components were evaluated following age adjustment according to the ATPIII criteria. Results The mean ages of post-M, M and pre-M women were 61.0 ± 4.3, 53.0 ± 4.0 and 47.0 ± 1.9 years, respectively. The prevalence of MetS in subjects was 63% (53%, 54% and 69%) in pre-M, M and post-M women respectively. HDL-c levels was significantly higher in post-M women in comparison to pre-M women ( p < 0.001). TG levels, FPG and waist circumference was significantly higher in post-M women in comparison to pre-M women ( p < 0.05). The most frequent markers of MetS were low HDL-c and high diastolic blood pressure in post-M women. Conclusion It is concluded that the frequency of MetS is significantly higher in post-M women as compared to pre-M women; low HDL-c and high diastolic blood pressure is the most frequent feature in comparison to other factors.

Metabolic syndrome throughout the menopausal transition: influence of age and menopausal status

Objective To assess the relationship between the main components of both the metabolic syndrome and insulin resistance and menopausal status in the menopausal transition.Methods A total of 124 healthy women were divided into four groups according to their menstrual status: the first group consisted of 35 women in menopausal transition with menstrual bleeding (MTM) and with cycles between 35 and 80 days; the second group was composed of 29 women in menopausal transition with 3–6 months of amenorrhea (MTA). The third group consisted of 31 postmenopausal women (PostM) and the fourth group of 29 premenopausal women (PreM) with regular cycles. The metabolic syndrome was evaluated following the ATP III criteria. Evaluation of insulin resistance was made through the HOMA, QUICKI and McAuley indices and the triglycerides/high density lipoprotein (HDL) cholesterol ratio.Results The triglycerides/HDL cholesterol ratio increased in MTM, MTA and PostM women in comparison with PreM women. A slight decrease in the QUIKI index (p = 0.06) and a decrease in the McAuley index (p < 0.001) were observed in MTM, MTA and PostM women in comparison to PreM women. The relative frequencies of metabolic syndrome in the four groups were: PreM, 0%; MTM, 20%; MTA, 21%; and PostM, 22% (p = 0.0001). The most frequent markers of the metabolic syndrome were increased waist circumference, low HDL cholesterol levels and hypertension. Linear regression between menopausal status and metabolic syndrome was lost when age was added to the model.Conclusions The frequency of metabolic syndrome increased from the time of the menopausal transition to the postmenopause. Abdominal obesity was the most frequent feature observed. Nevertheless, aging erased the effect of the menopause on the metabolic syndrome. In order to prevent cardiovascular disease, the metabolic syndrome must be evaluated from the time of the menopausal transition.

Hypoactive sexual desire disorder in menopausal women in the US

(1) Determine the proportion of menopausal women with Hypoactive Sexual Desire Disorder (HSDD); (2) Assess the degree and nature of the distress associated with HSDD; (3) Determine the relationship between desire, arousal, and orgasm; (4) Assess the relationship between sexual desire and sexual activity, and; (5) Study the relationship between sexual desire and overall relationship and sexual satisfaction. The Women’s International Study of Health and Sexuality (WISHeS) was conducted by mail among US women, aged 20–70 yrs. 85% of women who agreed to participate in the study completed and returned the survey. The survey included: (1) questions on women’s sexual activity and behavior, sexual and marital or relationship satisfaction, (2) the Profile of Female Sexual Function (PFSF), a validated instrument designed to assess sexual desire in women, and, (3) the Personal Distress Scale (PDS), a validated scale used to assess distress associated with low sexual desire in women. The following populations of women (n=1235) were compared: (1) premenopausal (PreM) women (20–49 yrs) were compared to surgically menopausal (SM) women (20–49 yrs), and (2) surgically menopausal women (50–70 yrs) were compared with naturally menopausal (NM) women (50–70 yrs). Cut-off scores on the Desire Domain of the PFSF and the PDS were used, respectively, to classify women with low sexual desire and women with low desire who were distressed by it. About 1 in 4 PreM women and 1 in 3 SM or NM women were classified as having low sexual desire. Younger SM women were significantly more likely to be distressed about their low sexual desire and to be classified as having HSDD than PreM, older SM, or NM women. About 1 in 4 younger SM women, 1 in 6 PreM and older SM, and 1 in 10 NM women were classified as having HSDD. Women in all populations with low sexual desire were found to have co-morbid low sexual arousal. These women also initiated sexual activity, had intercourse, experienced orgasm and sexual pleasure significantly less often than women without low sexual desire. Low sexual desire was significantly correlated with decreased feelings of being sexually desirable (r=0.58) and lower satisfaction with sex life (r=0.49). Low satisfaction with sex life was significantly correlated with lower overall relationship satisfaction (r=0.56). HSDD is prevalent and distressing to many menopausal women. It is associated with reduced sexual and overall relationship satisfaction. The sexual experience and behavior of women with low sexual desire is different than women without low desire, i.e., they initiate sex less frequently, experience fewer orgasms and report diminished sexual pleasure. These results demonstrate that HSDD is a clinically relevant condition that warrants clinical attention.

Relationship of blood and bone lead to menopause and bone mineral density among middle-age women in Mexico City.

To describe the relationship of blood lead levels to menopause and bone lead levels, we conducted a cross-sectional study on 232 pre- or perimenopausal (PreM) and postmenopausal (PosM) women who participated in an osteoporosis-screening program in Mexico City during the first quarter of 1995. Information regarding reproductive characteristics and known risk factors for blood lead was obtained using a standard questionnaire by direct interview. The mean age of the population was 54.7 years (SD = 9.8), with a mean blood lead level of 9.2 microg/dL (SD = 4.7/dL) and a range from 2.1 to 32.1 microg/dL. After adjusting for age and bone lead levels, the mean blood lead level was 1.98 microg/dL higher in PosM women than in PreM women (p = 0.024). The increase in mean blood lead levels peaked during the second year of amenorrhea with a level (10.35 microg/dL) that was 3.51 microg/dL higher than that of PreM women. Other important predictors of blood lead levels were use of lead-glazed ceramics, schooling, trabecular bone lead, body mass index, time of living in Mexico City, and use of hormone replacement therapy. Bone density was not associated with blood lead levels. These results support the hypothesis that release of bone lead stores increases during menopause and constitutes an internal source of exposure possibly associated with health effects in women in menopause transition.

Increased bone resorbing activity of peripheral monocyte culture supernatants in elderly women.

Accelerated bone loss occurs in the years after menopause, and is an ongoing phenomenon in elderly women. The role of cytokines in bone loss after estrogen deficiency has been shown in ovariectomized rat and mice models. In humans, the involvement of bone resorbing cytokines is now well established. In the early years after menopause, monocyte activation leads to increased cytokine production. We have previously shown that the bone resorbing activity (BRA) of peripheral blood monocyte culture supernatants from postmenopausal women is higher than in premenopausal (Pre-M) women. This increased activity was related to interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha levels. We here investigate whether monocyte activation still occurs in older women and whether this relates to bone resorption. We studied 19 healthy Pre-M, and 24 early (E-Post-M, menopause < 10 yr) and 24 late (L-Post-M, menopause > 10 yr) postmenopausal women. Peripheral blood monocytes were cultured for 48 h with 20% autologous plasma. BRA of monocyte supernatants (expressed as the ratio of monocyte supernatant over control bones supernatant) was assessed using fetal long-bone resorbing assays. Bone resorption was determined by urinary total pyridinoline excretion. BRA was significantly increased in E-Post-M and L-Post-M, compared with Pre-M subjects (1.20 +/- 0.10 and 1.15 +/- 0.20 vs. 0.73 +/- 0.10, respectively, both P < 0.05). Moreover, BRA of bones cultured with the supernatant of Pre-M was lower than BRA of control bones. BRA was significantly correlated with levels of IL-1, IL-6, and tumor necrosis factor-alpha in supernatant. Supernatant IL-1 levels were increased in E-Post-M, compared with Pre-M women (506 +/- 180 vs. 122 +/- 30, P < 0.05). Similarly, pyridinoline levels were increased in E-Post-M and L-Post-M, compared with Pre-M subjects (8.8 +/- 1 and 10.5 +/- 0.9 vs. 5.8 +/- 0.5, respectively, both P < 0.05). BRA was significantly correlated to pyridinoline levels. These data indicate the presence of monocyte activation in L-Post-M, which may be responsible for the increased bone resorption and bone loss observed in this elderly population.

Simultaneous Investigation of Dietary and Plasma Copper, Zinc, Iron and Selenium in Pre- and Post-menopausal Omnivores, Vegetarians and Patients with Early Breast Cancer

Total plasma iron, copper, zinc and selenium and the dietary intake of these elements were determined in pre-menopausal (pre-m) and post-menopausal (post-m) women mainly with stage I breast cancer (BCA), and in omnivorous (OMN) and vegetarian (VEG) controls. The OMN groups comprised 14 pre-m women (33 ± 6 (SD) years) and II post-m women (57 ± 5 years), and the VEG groups comprised 12 pre-m women (34 ± 7 years) and 11 post-m women (59 ± 5 years). There were 13 pre-m BCA patients (39 ± 7 years) and 10 post-m BCA patients (66 ± 6 years). Fasting plasma samples were obtained on 3 consecutive days, typically four times a year. Dietary assessment was over 5 days by weighing dietary components on a letter balance and analyzing for nutrient components using a computer program. Overall geometric means (1 SD range) for plasma (μmol 1 -1)/dietary (mg/day) elements were: Fe 15-5 (10-3-19-4)/'12-4 (9-4-14-8), Cu 17-5 (14-3-20-7)/1-46 (1-04-1-78), Zn 13-9 (11-2-16-2)/10 0 (7-6-1 l-9), Se 1-41 (1-20-1-59)/31-0 μg/day (8...