Effects of melatonin on the endometrial morphology and embryo implantation in rats

Objective: To determine the effects of melatonin on rat endometrium morphology and embryo implantation. Design: Experimental study. Setting: Federal University of Sao Paulo, Brazil. Animal(s): Forty female rats. Intervention(s): GI: control, GII: sham-operated, GIII: pinealectomized, and GIV: pinealectomized rats that received melatonin during 3 months. The GI, GII, and Gin groups received the vehicle of melatonin (NaCl + ethanol). At the end of the treatment, the animals were killed during the estrous phase; the uterus was removed for morphometric analysis. Urine was collected for 6-sulfatoxymelatonin. Blood was collected for estrogen (E) and progesterone (P) level determinations. In a second experiment, female rats were used to evaluate the endometrial embryo implantation. Main Outcome Measure(s): Endometrial morphology and embryo implantation. Result(s): Gin presented the highest values for endometrial area and thickness index, number of endometrial glands, and eosinophils. The number of vessels of groups I, II, and IV was fewer than that of Gin. The highest number of eosinophils was detected in Gin in comparison to other groups. The implantation rate in Gin was the lowest of all groups. This implantation rate was significantly increased and restored toward normal in GIV. Conclusion(s): Our data suggested that, in nonphotoperiodic animals such as rats, melatonin may positively affect the endometrial morphology and improve embryo implantation.

Effects of estradiol and norethisterone on lipids, insulin resistance and carotid flow

Objectives: To evaluate the lipid profile, insulin resistance and vasomotricity, and the interaction between these factors, in postmenopausal women receiving hormone therapy. Methods: A prospective, randomized, double-blind study was carried out in which 77 postmenopausal women received one of the three treatment regimens: (A) 2 mg oral micronized estradiol (E(2)) (n = 25); (B) 2 mg oral E(2) + 1 mg oral norethisterone acetate (NETA) (n = 28); or Q placebo (n = 24), daily for 6 months. Evaluations were carried out at baseline and at the end of treatment on lipid and lipoprotein profiles, homeostasis model assessment of insulin resistance (HOMA-IR) and pulsatility index (PI) of the internal carotid artery by Doppler ultrasonography. Results: Mean increases of 15.6% and 2.4% and a reduction of 6.4% in high-density lipoprotein (HDL) levels were found for the E(2), E(2) + NETA and placebo groups, respectively. Reductions of 9.5% and 3.7% and an increase of 12.1% in low-density lipoprotein (LDL), and reductions of 20.0% and 3.8% and an increase of 28.8% in the LDL:HDL ratio were found for the E(2), E(2) + NETA and placebo groups, respectively (p < 0.001 in all cases). Insulin levels and HOMA-IR decreased 12.8% and 12.3% in the E2 group and increased 12.9% and 16.0% in the E(2) + NETA group (p < 0.05), respectively. Carotid PI following treatment was 1.18 +/- 0.23, 1.38 +/- 0.20 and 1.41 +/- 0.21 for the E(2), E(2) + NETA and placebo groups, respectively (p = 0.0006). Conclusions: Oral estrogen therapy led to an improvement in lipid profile, insulin resistance and carotid blood flow, which was cancelled when NETA was associated. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

Ultrastructural evaluation of gingival glycosaminoglycans in ovariectomized rats: Effects of steroid hormone therapy

Background/Aims: To evaluate the behavior of glycosaminoglycans (GAGs) in rat gingiva and the effects of lack of sexual steroids and the hormonal therapy with estrogen and dexamethasone (DEX). Methods: 40 female rats were divided into four groups: GI: animals in permanent estrus; GII: ovariectomized (OVX) animals + vehicle; GIII: OVX animals treated with 17 beta-estradiol benzoate (10 mu g/kg), and GIV: OVX animals treated with 17 beta-estradiol benzoate (10 mu g/kg) + DEX (3 mg/kg). After treatment, the gingiva was removed and its GAGs content was evaluated by electronic microscopy after stained by cuprolinic blue technique. Results: The electron-microscopic data showed that low values of chondroitin sulfate were found in castrated animals (35.05 +/- 3.58%) compared to other groups (GI: 41.17 +/- 1.13; GIII: 48.04 +/- 2.60; GIV: 49.09 +/- 2.68%). In contrast, the amount of dermatan sulfate in GII (57.70 +/- 2.50%) was higher than in the other groups (GI: 46.12 +/- 1.30; GIII: 42.65 +/- 2.98; GIV: 42.68 +/- 5.43%). Conclusions: GAGs may be influenced by estradiol, and DEX did not seem to antagonize the role of estradiol in the GAGs of gingiva. The histotypical structure of gingiva is related to the amount of chondroitin sulfate. Consequently, the estrogen therapy may be important for gingival health. Copyright (C) 2007 S. Karger AG, Basel.

CYP17 polymorphism and hot flushes in postmenopausal women

Objective To investigate the association between the CYP17 alpha gene polymorphism and hot flushes in postmenopausal women. Methods Ninety-three non-hysterectomized, postmenopausal women were enrolled in this study. Vasomotor symptoms were assessed at the baseline visit and based on information provided by each participant. The genotypic polymorphism of CYP17 alpha gene was analyzed by PCR-RFLP assay using genomic DNA isolated from peripheral blood lymphocytes. Results Thirty-six women reported hot flushes of mild intensity, 25 reported hot flushes of moderate intensity and 32 of severe intensity. There was no significant difference between the severity of hot flushes and the CYP17 genotype or allele frequencies, 0.58 and 0.67 respectively. No association was found between hot flush severity and the CYP17 allele (odds ratio = 1.17, p = 0.61). Conclusion The results of this study suggest that the CYP17 MspAI polymorphism was not significantly associated with an increased risk of reporting hot flushes. At the World Congress on Menopause in Madrid, May 2008, Dr Massad-Costa was awarded the Robert Greenblatt Prize for Basic Science for the study reported in this paper.

The effects of cinnarizine on menopausal symptoms in women

Objective To evaluate the effectiveness and safety of cinnarizine in the treatment of menopausal symptoms. Design A total of 100 climacteric and symptomatic women participated in a double-blind, placebo-controlled study. They were divided into two groups of the same size: Gcin, intake of 25 mg of cinnarizine every 12 h for 6 months (n = 50); and Gpla, placebo intake every 12 hours for 6 months (n = 50). Menopausal symptoms were evaluated according to the Kupperman menopausal index on the first visit and at 6 months of treatment. A total of 62 women completed the study: 27 from the Gcin group and 35 from the Gpla group. Results Based on the Kupperman menopausal index, there were no statistically significant differences between the two groups before and after the treatment. Conclusion Our data suggest cinnarizine is not effective on menopausal symptoms because it had no more efficacy than placebo.

Evaluation of melatonin on the precocious puberty: a pilot study

Objective. To evaluate the effect of 6-sulphatoxymelatonin on the sleep quality of girls with precocious puberty. Study design. Ninety-nine girls were divided into three groups: GI, precocious puberty; GII, normal prepubescent; GIII, normal puberty. Questionnaires containing demographic and clinical data were applied. Blood was collected for hormonal evaluation for 6-sulphatoxymelatonin. The modified Rush Sleep Diary was used. Results. The levels of 6-sulphatoxymelatonin were highest in the group without pubertal development (75.23 +/- 10.84 ng/ml), second highest in the group with normal puberty (45.66 +/- 3.87 ng/ml, p < 0.001) and lowest in the group with true precocious puberty (37.04 +/- 5.47 ng/ml). The amount of day sleep was greater in the group without pubertal development compared to other groups. Conclusion. Despite the sleep data, melatonin may be involved in the precocious puberty process.

Longitudinal Follow-Up of Bipolar Disorder in Women With Premenstrual Exacerbation: Findings From STEP-BD

Objective: The impact of hormonal fluctuation during the menstrual cycle on the course of bipolar disorder is poorly understood. The authors determined the course of illness and time to relapse of bipolar disorder in prospectively followed women with premenstrual exacerbation. Method: Participants were 293 premenopause-age women with bipolar disorder who were followed prospectively for 1 year as part of the Systematic Treatment Enhancement Program for Bipolar Disorder. Frequency of mood episodes was compared between 191 women with premenstrual exacerbation (65.2%) and 102 women without. Among 129 women who were in recovered status at baseline, time to relapse was compared between 66 women with premenstrual exacerbation (51.2%) and 63 without. Results: During follow-up, the group with premenstrual exacerbation had more episodes (primarily depressive) than did the group without, but they were not more likely to meet criteria for rapid cycling during this period. In contrast, they were more likely to report rapid cycling retrospectively. Women with premenstrual exacerbation had a shorter time to relapse and were at greater risk for relapse, but this association was not significant after adjustment for retrospectively reported rapid cycling. Women with premenstrual exacerbation had more depressive and mood elevation symptoms overall. Conclusions: Women with bipolar disorder and premenstrual exacerbation have a worse course of illness, a shorter time to relapse, and greater symptom severity, but they are not more likely to meet criteria for rapid cycling. Premenstrual exacerbation may be a clinical marker predicting a more symptomatic and relapse-prone phenotype in reproductive-age women with bipolar disorder.

Effects of the addition of methyltestosterone to combined hormone therapy with estrogens and progestogens on sexual energy and on orgasm in postmenopausal women

Objective To evaluate the effect of the addition of methyltestosterone to estrogen and progestogen therapy on postmenopausal sexual energy and orgasm. Methods Sixty postmenopausal women in a stable relationship with a partner capable of intercourse, and presenting sexual complaints that appeared after menopause, were randomly divided into two groups: EP (n=29) received one tablet of equine estrogens (CEE) 0.625mg plus medroxyprogesterone acetate (MPA) 2.5mg and one capsule of placebo; EP+A (n=31) received one tablet of CEE 0.625mg plus MPA 2.5mg and one capsule of methyltestosterone 2.0mg; The treatment period was 12 months. The effects of treatment on sexual energy were assessed using the Sexual Energy Change Scale. The ability to reach orgasm in sexual relations with the partner was verified through monthly calendars and by calculating the ratio between monthly frequency of orgasms in sexual relations and monthly sexual frequency. Results There was a significant relationship between improvement in level of sexual energy and the addition of methyltestosterone to CEE/MPA treatment (p=0.021). No significant effect on orgasmic capacity was noted after the treatment period. Conclusion Addition of methyltestosterone to CEE/MPA therapy may increase sexual energy, but might not affect the ability to obtain orgasm in sexual relations.

Meningeal carcinomatosis in breast cancer: prognostic factors and outcome

Meningeal carcinomatosis (MC) occurs in up to 5% of breast cancer patients. Few studies have evaluated prognostic markers in breast cancer patients with MC. Our aim was to describe the treatment of breast cancer patients with MC, and identify prognostic factors related to survival. Sixty breast cancer patients that had a diagnosis of MC between January 2003 and December 2009 were included. The median age was 46 years (range 27-76). Most patients had invasive ductal carcinoma (78.3%) and high histological/nuclear grade (61.7/53.3%). Estrogen and progesterone receptors were positive in 51.7 and 43.3% of patients, respectively, and 15% were HER-2-positive. Symptoms at presentation were headache, cranial nerve dysfunction, seizures, and intracranial hypertension signals. Diagnosis was made by CSF cytology in 66.7% of cases and by MRI in 71.7%. Intrathecal (IT) chemotherapy was used in 68.3% of patients, and 21.6% received a new systemic treatment (chemo- or hormone therapy). Median survival was 3.3 months (range 0.03-90.4). There was no survival difference according to age, nuclear grade, hormonal and HER-2 status, CSF features, sites of metastasis, systemic and IT chemotherapy, or radiotherapy. However, histological grade and performance status had a significant impact on survival in the multivariate analysis. Only four papers have addressed prognostic factors in breast cancer patients with MC in the last two decades. The results of those reports are discussed here. High histological grade and poor performance status seem to impact survival of breast cancer patients with MC. Prospective studies are necessary to clarify the role of IT and systemic treatment in the treatment of those patients.

Apolipoprotein E genotype and Cognition in Bipolar Disorder

Apolipoprotein E (APOE) has been extensively studied as a risk factor for sporadic and late onset Alzheimer`s Disease (AD). APOE allele *3, the most frequent variant, is not associated to cognitive dysfunction (CD) or to increased AD risk. Differently, the *4 allele is a well-established risk factor for CD, while the *2 allele is associated with survival and longevity. CD is an important feature of Bipolar Disorder (BD) and recent data suggest that CD may be one of its endophenotypes, although controversial results exist. The aim of this research is to study the association of APOE genotype (APOE) and neurocognitive function in a sample of drug free young BD-type I patients. Sample consisted of 25 symptomatic BD (type I) patients (age 18-35 years old). They were submitted to an extensive neuropsychological evaluation and genotyped for APOE. Subjects with allele *2 presented better cognitive performance. The presence of allele *4 was associated with worse performance in a few executive tasks. APOE *3*3 was associated with overall severe dysfunction on cognitive performance. In young individuals with nontreated BD-type I, APOE may predict cognitive performance. Further and larger studies on APOE and cognition in BD are required to clarify whether APOE is a BD cognitive endophenotype.

Genes Differentially Expressed in Prolactinomas Responsive and Resistant to Dopamine Agonists

Background/Aims: Prolactin (PRL) secretion and its gene expression are inhibited by dopamine. Prolactinomas are the most common secreting pituitary adenomas, and dopamine agonists (DA) are the first choice for their treatment. However, a subset of patients is resistant to DA. As the mechanisms involved in DA resistance are not fully understood, the aim of this study was to obtain new insights regarding the molecular differences between the prolactinomas that are responsive to DA and those that are resistant. Methods: Tumor tissue samples were collected from 17 patients who harbored prolactinomas, which were classified as responsive or resistant according to their clinical and laboratorial reaction to DA. The expression of 6 genes was evaluated by real-time polymerase chain reaction: dopamine receptor type 2 (DRD 2), nerve growth factor-beta (NGFB) and its receptor (NGFR), estrogen receptor-alpha (ERA), estrogen receptor-beta (ERB) and the pituitary tumor transforming gene (PTTG). Results: Median DRD 2 and NGFR expression in responsive patients was significantly higher than in resistant ones (p = 0.029 and p = 0.020, respectively). Moreover, the expressions of DRD 2 and NGFR were positively correlated with PRL decrease during treatment (r = 0.66, p = 0.005 and r = 0.57, p = 0.044, respectively). Furthermore, ERB expression was positively correlated to PTTG expression (r = 0.68, p = 0.032) and negatively correlated to NGFB expression (r = -0.75, p = 0.02). Conclusions: DRD2 and NGFR expressions are related to the responsiveness of prolactinoma to DA. However, PTTG, ERB and ERA expressions are not. Also ERB, ERA and PTTG expressions did not present a clear correlation to tumor aggressiveness. Furthermore, the response of prolactinomas to DA should be viewed as a spectrum ranging from the most responsive to the most resistant ones. Copyright (c) 2008 S. Karger AG, Basel

Obesity, estrone, and coronary artery disease in postmenopausal women

Objectives: The link between obesity and endogenous estrogen with coronary artery disease (CAD) in postmenopausal women is uncertain. In this prospective study we analyzed the association of body mass index (BMI) and blood levels of estrone in postmenopausal women with known CAD or with a high risk factor score for CAD. Methods: Participants were 251 female clinic patients aged 50-90 years who were postmenopausal and not using estrogen therapy. Clinical and behavioral characteristics and fasting blood for estrone and heart disease risk factors were collected at baseline, and again at I and 2 years. Women were grouped according to their BMI (kg/m(2)) as normal (18.5 <= BMI < 25), overweight (25 <= BMI < 30) or obese (BMI >= 30), and by low and high estrone levels (< 15 and >= 15 pg/mL, respectively). Fatal and nonfatal events were recorded for 2 years after baseline. Results: Women with a low estrone level were older, thinner, and had less hypertension, diabetes, and lower triglyceride and glucose levels. BMI was positively associated with estrone levels, hypertension, and diabetes and inversely associated with HDL cholesterol. There were 14 deaths, 8 attributed to CAD. The Kaplan-Meier survival curve showed a nonsignificant trend (p = 0.074) of greater all cause mortality in women with low estrone levels (< 15 mL). In this model, adjusted for BMI, age [OR 1.08; p = 0.03], C-reactive protein [OR = 1.24; p = 0.024] and hypertension [OR = 6.22; p = 0.003] were independent predictors of all cause mortality. Conclusions: Postmenopausal women with low estrone levels (< 15 pg/mL) had a trend for increased mortality over the next 2 years. Larger, longer studies are needed. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

CXCL12 rs1801157 polymorphism and expression in peripheral blood from breast cancer patients

The role of chemokines has been extensively analyzed both in cancer risk and tumor progression. Among different cytokines, CXCR4 and its ligand CXCL12 have been recently subjected to a closer examination. The single-nucleotide polymorphism (SNP) rs1801157 (previously known as CXCL12-A/SDF1-3`A) in the CXCL12 gene and the relative expression of mRNA CXCL12 in peripheral blood were assessed in breast cancer patients, since the chemokine CXCL12 and its receptor CXCR4 regulate leukocyte trafficking and many essential biological processes, including tumor growth, angiogenesis and metastasis of different types of tumors. Genotyping was performed by PCR-RFLP (polymerase chain reaction followed by restriction fragment length polymorphism) using MspI restriction enzyme and the expression analyses by quantitative RT-PCR. No difference in GG genotype and allele A carrier frequencies were observed between breast cancer patients and healthy blood donors and nor when CXCL12 mRNA expression was assessed among patients with different tumor stages. However a significant difference was observed when CXCL12 mRNA relative expression was analyzed in breast cancer patients in accordance to the presence or absence of the CXCL12 rs1801157 allele A. Allele A breast cancer patients presented a mRNA CXCL12 expression about 2.1-fold smaller than GG breast cancer patients. Estrogen positive patients presenting CXCL12 allele A presented a significantly lower expression of CXCL12 in peripheral blood (p = 0.039) than GG hormone positive patients. Our findings demonstrated that allele A is associated with low expression of CXCL12 in the peripheral blood from ER-positive breast cancer patients, which suggests implications on breast cancer clinical outcome. (C) 2011 Elsevier Ltd. All rights reserved.

Parathyroid hormone secretion in women in late menopause submitted to EDTA-induced hypocalcemia

Objective: The physiological role of parathormone (PTH) in the maintenance of bone mass in humans has not been fully defined. The main objective of the present study was to evaluate basal and EDTA-stimulated PTH levels in Young women (Group Y = 30.9 years, N = 7) and in women in late menopause (Group M = 64.7 years, N = 7) and their relationship to bone mineral density. Methods: The PTH secretion test was performed by induction of hypocalcemia through intravenous administration of EDTA for 2 h. Blood samples were collected every 10 min and used for ionic calcium and PTH measurements. During the basal period, an additional sample was collected for the determination of osteocalcin, FSH, and estradiol. A sample of early morning second voided urine was collected for analysis of deoxypiridinoline and creatinine Lis well as bone mass density (BMD) was determined by dual X-ray energy absorptiometry (DEXA). Results: The aged patients presented lower femoral BMD (Y = 0.860 g/cm(2) vs. M = 0.690 g/cm(2), P < 0.01), With four of them having a T score lower than - 2.5 S.D. Basal, and during the EDTA infusion, PTH values were similar in both groups. However, among aged volunteers, the rise in PTH levels was higher for subjects with normal bone mass (NM: peak = 236 pg/ml) than for subjects with osteoporosis (OM: peak = 134.4 pg/ml). Conclusions: The present results suggest that PTH can have a modulating effect on the rate of bone loss during late menopause. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Assessment of Vascular Effects of Tamoxifen and Its Metabolites on the Rat Perfused Hindquarter Vascular Bed

Tamoxifen has been suggested to produce beneficial cardiovascular effects, although the mechanisms for these effects are not fully known. Moreover, although tamoxifen metabolites may exhibit 30-100 times higher potency than the parent drug, no previous study has compared the effects produced by tamoxifen and its metabolites on vascular function. Here, we assessed the vascular responses to acetylcholine and sodium nitroprusside on perfused hindquarter vascular bed of rats treated with tamoxifen or its main metabolites (N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen, and endoxifen) for 2 weeks. Plasma and whole-blood thiobarbituric acid reactive substances (TBARS) concentrations were determined using a fluorometric method. Plasma nitrite and NOx (nitrite + nitrate) concentrations were determined using an ozone-based chemiluminescence assay and Griess reaction, respectively. Treatment with tamoxifen reduced the responses to acetylcholine (pD(2) = 2.2 +/- 0.06 and 1.9 +/- 0.05 after vehicle and tamoxifen, respectively; P < 0.05), while its metabolites improved these responses (pD(2) = 2.5 +/- 0.04 after N-desmethyl-tamoxifen, 2.5 +/- 0.03 after 4-hydroxy-tamoxifen, and 2.6 +/- 0.08 after endoxifen; P < 0.01). Tamoxifen and its metabolites showed no effect on endothelial-independent responses to sodium nitroprusside (P > 0.05). While tamoxifen treatment resulted in significantly higher plasma and whole blood lipid peroxide levels (37% and 62%, respectively; both P < 0.05), its metabolites significantly decreased lipid peroxide levels (by approximately 50%; P < 0.05). While treatment with tamoxifen decreased the concentrations of markers of nitric oxide formation by approximately 50% (P < 0.05), tamoxifen metabolites had no effect on these parameters (P > 0.05). These results suggest that while tamoxifen produces detrimental effects, its metabolites produce counteracting beneficial effects on the vascular system and on nitric oxide/reactive oxygen species formation.