Pseudopregnant Research Articles

Estrogen receptor alpha drives proliferation in PTEN-deficient prostate carcinoma by stimulating survival signaling, MYC expression and altering glucose sensitivity.

While high doses of estrogen, in combination with androgens, can initiate prostate cancer (PCa) via activation of the estrogen receptor α (ERα), the role of ERα in PCa cells within established tumors is largely unknown. Here we show that expression of ERα is increased in high grade human PCa. Similarly, ERα is elevated in mouse models of aggressive PCa driven by MYC overexpression or deletion of PTEN. Within the prostate of PTEN-deficient mice, there is a progressive pattern of ERα expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This expression significantly correlates with the proliferation marker Ki67. Furthermore, in vitro knockdown of ERα in cells derived from PTEN-deficient tumors causes a significant and sustained decrease in proliferation. Depletion of ERα also reduces the activity of the PI3K and MAPK pathways, both downstream targets of non-genomic ERα action. Finally, ERα knockdown reduces the levels of the MYC protein and lowers the sensitivity of cellular proliferation to glucose withdrawal, which correlates with decreased expression of the glucose transporter GLUT1. Collectively, these results demonstrate that ERα orchestrates proliferation and metabolism to promote the neoplastic growth of PCa cells.

Ezetimibe prevents the formation of oestrogen-induced cholesterol gallstones in mice.

Oestrogen is an important risk factor for cholesterol cholelithiasis not only in women of childbearing age taking oral contraceptives and postmenopausal women undergoing hormone replacement therapy, but also in male patients receiving oestrogen therapy for prostatic cancer. In women, hormonal changes occurring during pregnancy markedly increase the risk of developing gallstones. We investigated whether the potent cholesterol absorption inhibitor ezetimibe could prevent the formation of oestrogen-induced cholesterol gallstones in mice. Following ovariectomy, female AKR mice were implanted subcutaneously with pellets releasing 17β-estradiol at 6μg/day and fed a lithogenic diet supplemented with ezetimibe in doses of 0 or 8mg/kg/day for 8weeks. Cholesterol crystallization and gallstone prevalence, lipid concentrations and composition in bile, and biliary lipid output were analysed by physical-chemical methods. Intestinal cholesterol absorption efficiency was determined by faecal dual-isotope ratio methods. Ezetimibe inhibited intestinal cholesterol absorption, while significantly reducing hepatic secretion of biliary cholesterol. Consequently, bile was desaturated through the formation of numerous unsaturated micelles and gallstones were prevented by ezetimibe in mice exposed to high doses of oestrogen and fed the lithogenic diet. Ezetimibe did not influence mRNA levels of the classical oestrogen receptors α (ERα) and ERβ, as well as a novel oestrogen receptor the G protein-coupled receptor 30 (GPR30) in the liver. Ezetimibe protects against the oestrogen-mediated lithogenic actions on gallstone formation in mice. Our finding may provide an efficacious novel strategy for the prevention of cholesterol gallstones in high-risk subjects, especially those exposed to high levels of oestrogen.

The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer.

The successful use of high-dose synthetic estrogens to treat postmenopausal metastatic breast cancer is the first effective 'chemical therapy' proven in clinical trial to treat any cancer. This review documents the clinical use of estrogen for breast cancer treatment or estrogen replacement therapy (ERT) in postmenopausal hysterectomized women, which can either result in breast cancer cell growth or breast cancer regression. This has remained a paradox since the 1950s until the discovery of the new biology of estrogen-induced apoptosis at the end of the 20th century. The key to triggering apoptosis with estrogen is the selection of breast cancer cell populations that are resistant to long-term estrogen deprivation. However, estrogen-independent growth occurs through trial and error. At the cellular level, estrogen-induced apoptosis is dependent upon the presence of the estrogen receptor (ER), which can be blocked by nonsteroidal or steroidal antiestrogens. The shape of an estrogenic ligand programs the conformation of the ER complex, which, in turn, can modulate estrogen-induced apoptosis: class I planar estrogens (e.g., estradiol) trigger apoptosis after 24 h, whereas class II angular estrogens (e.g., bisphenol triphenylethylene) delay the process until after 72 h. This contrasts with paclitaxel, which causes G2 blockade with immediate apoptosis. The process is complete within 24 h. Estrogen-induced apoptosis is modulated by glucocorticoids and cSrc inhibitors, but the target mechanism for estrogen action is genomic and not through a nongenomic pathway. The process is stepwise through the creation of endoplasmic reticulum stress and inflammatory responses, which then initiate an unfolded protein response. This, in turn, initiates apoptosis through the intrinsic pathway (mitochondrial) with the subsequent recruitment of the extrinsic pathway (death receptor) to complete the process. The symmetry of the clinical and laboratory studies now permits the creation of rules for the future clinical application of ERT or phytoestrogen supplements: a 5-year gap is necessary after menopause to permit the selection of estrogen-deprived breast cancer cell populations to cause them to become vulnerable to apoptotic cell death. Earlier treatment with estrogen around menopause encourages growth of ER-positive tumor cells, as the cells are still dependent on estrogen to maintain replication within the expanding population. An awareness of the evidence that the molecular events associated with estrogen-induced apoptosis can be orchestrated in the laboratory in estrogen-deprived breast cancers now supports the clinical findings regarding the treatment of metastatic breast cancer following estrogen deprivation, decreases in mortality following long-term antihormonal adjuvant therapy, and the results of treatment with ERT and ERT plus progestin in the Women's Health Initiative for women over the age of 60. Principles have emerged for understanding and applying physiological estrogen therapy appropriately by targeting the correct patient populations.

Grade IV Asherman in Post Endometrial Koch’s

This video demonstrates a management of a 29 year old nullipara unmarried female who presented with secondary amenorrhoea not responding to withdrawal on estrogen progesterone combination. Ultrasonography revealed very thin endometrium. Diagnostic hysteroscopy and biopsy of endometrium was positive for tuberculosis. ATT was given for 9 months. Review hysteroscopy done showed reduced cavity size and thick adhesions. Adhesiolysis was done with the help of scissors and cavity was widened. Foley’s catheter was used as splint for 2 months with high dose of estrogen. Now patient had 3 regular cycles. Proper technique and post operative management in Asherman will prevent recurrence.

Abstract 2106: Estrogen receptor alpha drives proliferation of prostate cancer through PI3K and MAPK signaling

Abstract Prostate cancer, a hormone-dependent disease of aging men, occurs as the relative levels of estrogen compared to testosterone are increasing. Indeed, high doses of estrogen, in combination with androgens, can initiate prostate cancer. This effect is attributed to the activity of the estrogen receptor α (ERα), but a paucity of suitable models means that the precise role of ERα in prostate cancer is still poorly understood. In this study we observed increased ERα expression in three different models of prostate cancer, PTEN null mice, Hi-Myc mice, and high grade human tumor specimens. Within the PTEN null prostate, there was a consistent pattern of ERα expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This pattern significantly correlated with the levels of the proliferative marker Ki67. There was also a significant correlation between ERα and Ki67 within individual malignant glands in the anterior prostate. Furthermore, we demonstrated that ERα sustained the in vitro proliferation of cells derived from a PTEN null tumor in 2D and 3D assays. There was a significant decrease in proliferation in cells treated with TPSF, a non-competitive ERα antagonist, or with ERα-specific shRNA. Loss of ERα caused a significant decrease in the levels of MYC and other ERα target genes. It also reduced the activity of both the PI3K and MAPK pathways as measured by decreased levels of phosphorylated erk1/2, S6 kinase and other downstream factors. This effect was reversed in rescue experiments with expression constructs for both full length ERα, capable of genomic and non-genomic actions, and membrane-only ERα, only able to trigger rapid non-genomic signalling. Collectively, these results demonstrate that ERα levels increase in prostate cancer, which promotes proliferation through classical genomic and rapid non-genomic signalling. Citation Format: Itsuhiro Takizawa, Mitchell Lawrence, Helen Pearson, John Pedersen, Normand Pouliot, Australian Prostate Cancer BioResource, Patrick Humbert, Luc Furic, Gail Risbridger. Estrogen receptor alpha drives proliferation of prostate cancer through PI3K and MAPK signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2106. doi:10.1158/1538-7445.AM2014-2106

Recent oral contraceptive use by formulation and breast cancer risk among women 20 to 49 years of age.

Previous studies of oral contraceptives and breast cancer indicate that recent use slightly increases risk, but most studies relied on self-reported use and did not examine contemporary oral contraceptive formulations. This nested case-control study was among female enrollees in a large U.S. integrated health care delivery system. Cases were 1,102 women ages 20 to 49 years diagnosed with invasive breast cancer from 1990 to 2009. Controls were randomly sampled from enrollment records (n = 21,952) and matched to cases on age, year, enrollment length, and medical chart availability. Detailed oral contraceptive use information was ascertained from electronic pharmacy records and analyzed using conditional logistic regression, ORs, and 95% confidence intervals (CI). Recent oral contraceptive use (within the prior year) was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.3-1.9) relative to never or former OC use. The association was stronger for estrogen receptor-positive (ER(+); OR, 1.7; 95% CI, 1.3-2.1) than estrogen receptor-negative (ER(-)) disease (OR, 1.2, 95% CI, 0.8-1.8), although not statistically significantly different (P = 0.15). Recent use of oral contraceptives involving high-dose estrogen (OR, 2.7; 95% CI, 1.1-6.2), ethynodiol diacetate (OR, 2.6; 95% CI, 1.4-4.7), or triphasic dosing with an average of 0.75 mg of norethindrone (OR, 3.1; 95% CI, 1.9-5.1; Pheterogeneity compared with using other oral contraceptives = 0.004) was associated with particularly elevated risks, whereas other types, including low-dose estrogen oral contraceptives, were not (OR, 1.0; 95% CI, 0.6-1.7). Our results suggest that recent use of contemporary oral contraceptives is associated with an increased breast cancer risk, which may vary by formulation. If confirmed, consideration of the breast cancer risk associated with different oral contraceptive types could impact discussions weighing recognized health benefits and potential risks.

Risks of Malignant and Non-Malignant Tumours in Tall Women Treated with High-Dose Oestrogen during Adolescence

Background/Aim: High-dose oestrogen treatment has been used to reduce growth in tall adolescent girls. The long-term safety with regard to cancer has not been clarified. Our aim was to study if this growth reduction therapy affects cancer risk later in life. Methods: A cohort study of 369 (172 treated, 197 untreated) Swedish women who in 1973-1993 were assessed for tall adolescent stature was designed. Data were collected from university hospital records, patient questionnaires, and the Swedish Cancer Register. Results: Risks are presented as odds ratios (ORs) with 95% confidence intervals comparing treated to untreated subjects. In treated subjects, the overall OR for having a tumour (malignant or non-malignant) was 1.7 (0.8-3.8). The ORs were 2.3 (0.4-12.8) for breast tumours, 0.8 (0.2-2.6) for gynaecological tumours, and 6.1 (1.04-∞) for melanoma. When limiting to malignant tumours, the crude ORs were of similar magnitude. Conclusion: The OR for any melanoma was higher in treated than in untreated women, suggesting an increased risk of melanoma associated with high-dose oestrogen treatment during adolescence. Although the risk estimates were increased for overall tumours, breast tumours, malignant gynaecological tumours, and malignant melanoma, these associations were not statistically significant. Our results need to be verified in a larger cohort.

GnRH agonists and the rapidly increasing use of combined androgen blockade in prostate cancer.

The discovery of medical castration with GnRH agonists in 1979 rapidly replaced surgical castration and high doses of estrogens for the treatment of prostate cancer. Soon afterwards, it was discovered that androgens were made locally in the prostate from the inactive precursor DHEA of adrenal origin, a mechanism called intracrinology. Taking into account these novel facts, combined androgen blockade (CAB) using a pure antiandrogen combined with castration in order to block the two sources of androgens was first published in 1982. CAB was the first treatment shown in randomized and placebo-controlled trials to prolong life in prostate cancer, even at the metastatic stage. Most importantly, the results recently obtained with the novel pure antiandrogen enzalutamide as well as with abiraterone, an inhibitor of 17α-hydroxylase in castration-resistant prostate cancer, has revitalized the CAB concept. The effects of CAB observed on survival of heavily pretreated patients further demonstrates the importance of the androgens made locally in the prostate and are a strong motivation to apply CAB to efficiently block all sources of androgens earlier at start of treatment and, even better, before metastasis occurs. The future of research in this field thus seems to be centered on the development of more potent blockers of androgens formation and action in order to obtain better results at the metastatic stage and, for the localized stage, reduce the duration of treatment required to achieve complete apoptosis and control of prostate cancer proliferation before it reaches the metastatic or noncurable stage.

Acquired Thrombophilia

Acquired thrombophilia is associated with an increased risk of venous thromboembolism (VTE). Antiphospholipid syndrome (APS) is the most prevalent acquired thrombophilia and is associated with both venous and arterial thromboses. Human immunodeficiency virus (HIV) is another form of acquired thrombophilia. Risk factors associated with VTE in this population include those related to the disease itself, host factors, and the pharmacotherapy for HIV. A significant proportion of VTE events occur in patients with malignancies. There is an increase in mortality associated with patients having cancer who experience VTE when compared to patients having cancer without VTE. Combination oral contraceptive (COC) use infers risk of thromboembolic events. The risk is dependent upon the presence of an underlying inherited thrombophilia, the estrogen dose, and generation of progestin. Patients at highest risk of VTE include those receiving high-dose estrogen and fourth-generation, progesterone-containing contraceptives. With the exception of APS, thrombophilia status does not alter the acute treatment of an initial VTE in nonpregnant patients.

Effect of Intrauterine Instillation of Granulocyte Colony-stimulating Factor on Endometrial Thickness and Clinical Pregnancy Rate in Women undergoing in vitro Fertilization Cycles: An Observational Cohort Study

ABSTRACTIntroductionIn spite of significant advances in the field of reproductive medicine, repeated implantation failure (RIF) is a challenging and extremely disappointing problem. The success ofin vitrofertilization and embryo transfer (IVF-ET) cycles depends mainly on uterine receptivity and embryo quality. Successful evaluation of endometrial receptivity conducive to embryo implantation continues to be a challenge in assisted reproductive technology (ART). Several researcher groups have reported the successful use of granulocyte-colony stimulating factor (G-CSF) during IVF cycles in terms of achieving higher clinical pregnancy rates on account of increased endometrial thickness. Women who fail to achieve adequate endometrial thickness despite conventional treatment with high dose estrogen or those with a history of repeated implantation failures in spite of normal endometrial thickness often do not achieve pregnancy and resort to gestational surrogacy. A new therapeutic approach to achieve successful pregnancy in such patients would be very desirable.Study objectivesTo assess the efficacy of a single dose of intrauterine G-CSF on endometrial thickness, implantation and clinical pregnancy rates in women who either had a thin endometrium after estrogen priming (< 8 mm) or a history of repeated implantation failures at IVF, undergoing embryo transfer after 10 days of priming with oral estradiol and vaginal slidenafil.Materials and methodsTwo hundred and thirty-one women (between 24 and 46 years of age) undergoing IVF-ET were recruited for the study. All cases were prospectively studied at the Mumbai Fertility Clinic and IVF Center (a subdivision of Kamala Polyclinic and Nursing Home) over a period of 6 months from January to June 2014, after their written informed consent. Subgroup I consisted of 117 patients who had a persistently thin endometrium (< 8 mm) in spite of high dose oral estradiol valerate and vaginal sildenafil priming. Subgroup II consisted of 114 patients who had a history of repeated (two or more) implantation failures (RIF) at IVF-ET cycles despite adequate endometrium (≥8 mm). All were infused with a single dose of G-CSF (300 mcg) in the uterine cavity after 10 days of priming with oral estradiol valerate and vaginal sildenafil citrate. Endometrial thickness was reassessed 4 days after G-CSF instillation. This was followed by administration of intramuscular progesterone in oil (100 mg) daily with embryo transfer on day 5 of progesterone for all patients. All embryo transfers for patients undergoing oocyte donation or embryo donation were done at the 4-cell stage on day 2. All Frozen embryo transfers (FET) of vitrified embryos were at 8 cell stage. Estimation of serum beta hCG was at 14 days post-embryo transfer for all patients. Successful implantation and net clinical pregnancy rate was confirmed based on appearance of gestational sac on sonogram after 10 days and observation of fetal cardiac activity after 20 days of positive β-hCG results.ResultsOut of total 231 patients recruited in the study, 95% patients from subgroup I (n = 111) and 94% patients from subgroup II (n = 107) showed mean increase in endometrial thickness by at least 2.5 mm within 4 days of G-CSF single dose instillation. A total of 218 patients from both subgroups underwent S. β-hCG estimation 14 days post IVF-ET. Out of 103 β-hCG positive patients, 83 showed net clinical pregnancy (fetal cardiac activity present) giving a net pregnancy rate of 38.07% for the whole study group with 37% in the subgroup with thin endometrium (< 8 mm) and 39.25% in the subgroup with adequate (≥8 mm) endometrium with history of two or more failed implantation at previous IVF-ET cycles. There were no adverse events for the whole study population.ConclusionThere can be a strong possibility with a single dose of 300 mcg intrauterine infusion of G-CSF to achieve significant increase in the endometrial thickness with higher successful pregnancy rate among infertile women under- going IVF-ET cycles with a history of a persistently thin endometrium or repeated implantation failures (rather difficult to treat patients). G-CSF could be a valuable tool to consider before advising the option of surrogacy. In the absence of a control group, our conclusions warrant conduct of further studies.How to cite this articleShah J, Gangadharan A, Shah V. Effect of Intrauterine Instillation of Granulocyte Colony-stimulating Factor on Endometrial Thickness and Clinical Pregnancy Rate in Women undergoingin vitroFertilization Cycles: An Observational Cohort Study. Int J Infertil Fetal Med 2014;5(3):100-106.

Sex-steroid regulation of relaxin receptor isoforms (RXFP1 & RXFP2) expression in the patellar tendon and lateral collateral ligament of female WKY rats.

The incidence of non-contact knee injury was found higher in female than in male and is related to the phases of the menstrual cycle. This raised the possibility that female sex-steroids are involved in the mechanism underlying this injury via affecting the expression of the receptors for relaxin, a peptide hormone known to modulate ligament laxity. Therefore, this study aims to investigate the effect of sex-steroids on relaxin receptor isoforms (RXFP1 & RXFP2) expression in the ligaments and tendons of the knee. Methods: Ovariectomized adult female WKY rats were treated with different doses of estrogen (0.2, 2, 20 μg/kg), progesterone (4mg) and testosterone (125 & 250μg/kg) for three consecutive days. At the end of the treatment, the animals were sacrificed and the patellar tendon and lateral collateral ligament were harvested for mRNA and protein expression analyses by Real Time PCR and Western blotting respectively. Results: RXFP1, the main isoform expressed in these knee structures and RXFP2 showed a dose-dependent increase in expression with estrogen. Progesterone treatment resulted in an increase while testosterone caused a dose-dependent decrease in the mRNA and protein expression of both relaxin receptor isoforms. Discussion: Progesterone and high dose estrogen up-regulate while testosterone down-regulates RXFP1 and RXFP2 expression in the patellar tendon and lateral collateral ligament of rat's knee. Conclusion: Relaxin receptor isoforms up-regulation by progesterone and high dose estrogen could provide the basis for the reported increase in knee laxity while down-regulation of these receptor isoforms by testosterone could explain low incidence of non-contact knee injury in male.

Surgical vs Natural Menopause: Cognitive Issues

Abstract Objective Women who undergo both natural and surgical menopause experience the loss of cyclic ovarian production of estrogen, but hormonal and demographic differences distinguish these two groups of women. Our objective was to review published evidence on whether the premature cessation of endogenous estrogen production in women who underwent a surgical menopause has deleterious consequences for cognitive aging and to determine whether consequences differ for women if they undergo natural menopause. Studies of estrogen-containing hormone therapy are relevant to this issue. Design We reviewed evidence-based research, including the systematic identification of randomized clinical trials of hormone therapy with cognitive outcomes that included an objective measure of episodic memory. Results As inferred from very small, short-term, randomized, controled trials of high-dose estrogen treatment, surgical menopause may be accompanied by cognitive impairment that primarily affects verbal episodic memory. Observational evidence suggests that the natural menopausal transition is not accompanied by substantial changes in cognitive abilities. For initiation of hormone therapy during perimenopause or early postmenopause when the ovaries are intact, limited clinical trial data provide no consistent evidence of short-term benefit or harm. There is stronger clinical trial evidence that initiation of hormone therapy in late postmenopause does not benefit episodic memory or other cognitive skills. Conclusion Further research is needed on the long-term cognitive consequences of surgical menopause and long-term cognitive consequences of hormone therapy initiated near the time of surgical or natural menopause. A potential short-term cognitive benefit might be weighed when a premenopausal woman considers initiation of estrogen therapy at the time of, or soon after, hysterectomy and oophorectomy for benign conditions, although data are still quite limited and estrogen is not approved for this indication. Older postmenopausal women should not initiate hormone therapy to improve or maintain cognitive skills.

Abstract P1-14-04: Subsequent endocrine therapy after becoming to resistance of ‘estrogen therapy’ is beneficial as a salvage treatment for the late stage metastatic breast cancer

Abstract BACKGROUND: Aromatase inhibitor (AI) is a most commonly used as the endocrine therapy in postmenopausal hormone-dependent breast cancer. Paradoxically, estrogen additive therapy, high-dose estrogen using ethinylestradiol, can be useful after long-term estrogen deprivation therapies with AI. Furthermore, there is a possibility of the beneficial effect of AI or fulvestrant as a subsequent endocrine therapy after EE2 failure. METHODS: Ethinylestradiol (EE2; 3mg/day, TID) therapy was performed in 22 patients with metastatic breast cancer (median; 62 years-old, the mean observation time: 13.6 months.), who were heavily treated by sequential endocrine therapies (3rd or more line) including cytotoxic chemotherapies. We examined the efficacy of a subsequent endocrine therapy using aromatase inhibitor or fulvestrant after becoming resistance to the EE2 therapy in the patients who got the disease control by the prior EE2 therapy. The primary endpoint was clinical benefit rate (CBR) and the secondary endpoint was time to treatment failure (TTF). (Registration number; UMIN 000002831, additional analysis) RESULTS: Median of TTF of EE2 treatment was 46 weeks (23-62+, 2 cases were ongoing). The response rate was 41% (9/22), the clinical benefit rate was 50% (11/22). The stable disease (< 6 months) was 18% (4/22) and another 3 cases were judged as progressive disease. Four cases withdrew due to nausea, fatigue and muscle-skeletal pain. In 13 cases progressed after disease control (SD or more) of EE2, a subsequent endocrine therapy, fulvestrant for 6 cases and AI for 7 cases, was performed. Fulvestrant group showed 50% (3 in 6) of CBR and 15 weeks (5-55+) of TTF, and AI-treated group showed 43% (3 in 7) of CBR and 19 weeks (5-33+) of TTF. Two in three cases, who became resistance to anti-estrogen treatment, got long SD by further EE2 re-therapy. DISCUSSION: EE2 therapy could be beneficial for heavily treated metastatic breast cancer. Some cases showed clinical benefits of a subsequent therapy by AI or fulvestrant after becoming to EE2 failure. Taken together, sequential use of estrogen and anti-estrogen therapy (vice versa) could be one of the options as a salvage endocrine therapy for the end stage breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-14-04.

Tamoxifen as a therapeutic agent in acromegaly

Administration of high doses of estrogens to patients with acromegaly has been shown to improve symptomatology of acromegaly and glucose tolerance more than 50 years ago. Selective estrogen receptor modulators (SERMs) mimic the effects of estrogen in bone, liver and the cardiovascular system, but function as an anti-estrogen in endometrial and breast tissue. In this study, we evaluated hormonal effects of a SERM, tamoxifen, in active acromegalic patients with particular emphasis on its use in males. We studied 15 men and 2 post-menopausal women with biochemically-active acromegaly despite the fact that other modalities were ineffective in normalizing their insulin-like growth factor-1 (IGF-1) levels. All patients were treated with tamoxifen 20-40 mg daily for 2-11 months (median of 4 months). IGF-1 and growth hormone (GH) levels were assessed immediately before the beginning of treatment and at 2-4 monthly intervals thereafter. Baseline and treatment levels of total and bioavailable testosterone were measured in men. Tamoxifen did not affect basal GH secretion, but it decreased circulating IGF-I in 14 patients (82%) by an average of 90 ± 4 mcg/L, (p = 0.005), and normalized plasma IGF-I in 8 patients (47%). Total and bioavailable testosterone levels increased in all evaluable men (n = 8). Tamoxifen was well tolerated. Tamoxifen might be useful in the treatment of patients with biochemically-mild active acromegaly, but longer term studies are warranted.

Ethinylestradiol is beneficial for postmenopausal patients with heavily pre-treated metastatic breast cancer after prior aromatase inhibitor treatment: a prospective study

Background:Oestrogens usually stimulate the progression of oestrogen receptor (ER)-positive breast cancer. Paradoxically, high-dose oestrogens suppress the growth of these tumours in certain circumstances.Methods:We prospectively examined the efficacy and safety of ethinylestradiol treatment (3 mg per day oral) in postmenopausal patients with advanced or recurrent ER-positive breast cancer who had previously received endocrine therapies, especially those with resistance to aromatase inhibitors.Results:Eighteen patients were enrolled with the median age of 63 years and the mean observation time of 9.2 months. Three cases withdrew within 1 week due to oestrogen flare reactions with nausea, fatigue and muscle-skeletal pain. The response rate was 50% (9 out of 18), and the clinical benefit rate was 56% (10 out of 18). The stable disease (<6 months) was 17% (3 out of 18) and another 2 cases were judged as progressive disease. Time-to-treatment failure including 2 on treatment was a median of 5.6 months (range 0.1 to 14.5+). Although vaginal bleeding or endometrial thickening was observed in patients receiving long-term treatment, there were no severe adverse events, such as deep venous thrombosis or other malignancies.Conclusion:Although the mechanism of this treatment has not been fully understood, our data may contribute to change the common view of late-stage endocrine therapy.

Estrogen modulates in vitro T cell responses in a concentration- and receptor-dependent manner: Effects on intracellular molecular targets and antioxidant enzymes

Estrogen is a key hormone in facilitating ovulation and maintenance of pregnancy in young females and subsequent decline in its production contributes to the development of age-associated disorders such as hormone-dependent cancer, osteoporosis, and cardiovascular diseases. The mechanisms through which estrogen promotes female-specific diseases with advancing age are unclear especially, its effects on immune system which is vital for the maintenance of homeostasis and health. Although the diverse effects of estrogen on Th immunity (Th1 vs. Th2) have been characterized in several cell-types and animal models, there is no direct mechanistic study to understand its immunomodulatory actions. The purpose of this study is to investigate whether the in vitro effects of 17β-estradiol on lymphocytes from the spleen influence cell-mediated immune responses based on its concentration and type of estrogen receptors (ERs) and to assess its mechanism of action at the cellular level. Lymphocytes from the spleens of young Sprague-Dawley rats were isolated and incubated with various concentrations of 17β-estradiol (10−6–10−14M) and specific ERα- and β-agonists (10−6M, 10−8M and 10−10M) without or with concanavalin A (Con A) to measure T lymphocyte proliferation, IFN-γ and IL-2 production, p-ERK 1/2, p-CREB, and p-Akt, activities of antioxidant enzymes[superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)], and nitric oxide (NO) production. The specificity of ER-mediated actions in lymphocytes was examined by coincubation with nonspecific ER antagonists ICI(182,780) or tamoxifen. Lower concentrations of 17β-estradiol enhanced proliferation of T lymphocytes and IFN-γ production without or with Con A stimulation but had no effect on IL-2 production. ERα and ERβ agonists induced an increase in T cell proliferation and IFN-γ production and these effects were inhibited by tamoxifen. ERβ agonist alone enhanced IL-2 production by the lymphocytes. Coincubation with 17β-estradiol and ERα- and β-agonists augmented p-ERK 1/2, p-CREB, and p-Akt expression in the lymphocytes and tamoxifen reversed the ER agonist-induced effects on these molecular targets. Estrogen increased the activities of SOD, CAT, and GPx in both non-stimulated and Con A-stimulated splenocytes in a concentration-dependent manner. Both ERα- and β-agonists enhanced CAT and GPx activity while ERα-agonist decreased SOD activity and ERβ-agonist increased SOD activity. The effects of ER agonists on the antioxidant enzymes were reversed by ICI(182,780). Coincubation of lower doses of 17β-estradiol with Con A and both ER agonists enhanced NO production while higher dose of estrogen with Con A and ERα agonist suppressed its production and these effects were reversed by tamoxifen. Taken together, these results suggest that the effects of estrogen on the cell-mediated immune responses are dependent upon its concentrations and mediated through specific estrogen receptors involving intracellular signaling pathways and antioxidant enzymes.

DIAGNOSIS AND TREATMENT OF PSEUDOPREGNANCY IN A NON-DESCRIPTIVE DOE

Pseudopregnancy in goats occurs usually after mating or post-oestrus without breeding or early embryonic death with persistent corpus luteum (Moraes et al., 2007). The life span of corpus luteum (CL) is determined by the luteotrophic and luteolytic mechanisms. A disturbance in any one of the mechanisms may be the underlying cause of the persistent luteal function in case of pseudopregnancy. Furthermore, the persistence of luteal function which was associated with plasma progesterone level, higher than 2 ng/ml; induced fluid accumulation in the uterus (Kornalijnslijper et al., 1997a). The increased life span of CL in pseudopregnant goats reflects the absence of acute luteolytic signal of uterine origin (Currie et al., 1988). The levels of progesterone in the plasma at the start and during the course of pseudopregnancy seemed to be influenced by the intrauterine events. The levels of plasma progesterone in pseudopregnant goats were lower than those in pregnant goats from the very beginning of the luteal phase, indicating less luteotrophic support, because of the absence of conceptus (Kornalijnslijper et al., 1997b). The spontaneous resolution of pregnancy did not eliminate all the uterine fluid and that the remaining fluid may be responsible for the recurrence of pseudopregnancy by preventing luteolysis (Lopes et al., 2001).

Traitements médicaux chez la femme ayant des myomes symptomatiques en période d’activité génitale

The most frequent symptom with leiomyoma is menometrorrhagia. However, it can be responsible of pelvic pain, dysmenorrhea or urinary and digestive compression when it is particularly voluminous. If no therapy is able to have them disappear, various drugs may reduce their related symptoms. Tranexamic acid, non-steroidal anti-inflammatory drugs and high dose of oestrogen may be useful in the management of acute hemorrhagic disorders. Progestin, such as lynestrenol induces small reduction in leiomyoma volume and moderate increase in hemoglobin level before surgery. Pregnane and nor-pregnane may improve menstrual bleeding in short or mild delays. The use of GnRH agonists can reduce menstrual bleeding with hemoglobin recovery. Add-back therapy using tibolone seems interesting since secondary effects encountered with GnRH agonists may be reduced. Levonorgestrel-releasing intrauterine system is proven to reduce increased menstrual bleeding and restore hemoglobin level. Aminoglutethimide and fadrozole have been underevaluated to conclude when letrozole seems as efficient as GnRH agonists to reduce leiomyoma volume and provide less hotflushes. Anastrozol is associated with reduction in leiomyomata volume, pain and menstrual bleeding. Mifepristone reduces the size of uterine leiomyomata, improves symptomatology, but could be associated with development of endometrial hyperplasia. SPRM evaluated in females have shown to improve leiomyoma related symptomatology. Ulipristal could be useful to reduce leiomyoma related symptoms in short terms.

Scientific rationale for postmenopause delay in the use of conjugated equine estrogens among postmenopausal women that causes reduction in breast cancer incidence and mortality

High-dose synthetic estrogens were the first successful chemical therapy used in the treatment of metastatic breast cancer in postmenopausal women, and this approach became the standard of care in postmenopausal women with metastatic breast cancer between the 1950s and the end of the 1970s. The most recent analysis of the Women's Health Initiative estrogen-alone trial in hysterectomized women revealed a persistently significant decrease in the incidence of breast cancer and breast cancer mortality. Although estrogens are known to induce the proliferation of breast cancer cells, we have shown that physiologic concentrations induce apoptosis in breast cancer cells with long-term estrogen deprivation. We have developed laboratory models that illustrate the new biology of estrogen-induced apoptosis or growth to explain the effects of estrogen therapy. The key to the success of estrogen therapy lies in a sufficient period of withdrawal of physiologic estrogens (5-10 y) and the subsequent regrowth of nascent breast tumor cells that survive under estrogen-deprived conditions. These nascent tumors are now vulnerable to estrogen-induced apoptosis.

Estrogens in the time of blood-thinners.

Estrogens in the time of blood-thinners.