Doses Of Estrogen Research Articles

ACUTE PULMONARY EMBOLISM FOLLOWING TWO DOSES OF INTRAVENOUS CONJUGATED ESTROGEN

SESSION TITLE: Medical Student/Resident Pharmacotherapeutics SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Estrogens can increase the synthesis of several clotting factors and increase platelet aggregation.Intravenous estrogen therapy is used to manage uterine bleeding in hospitalized patients.The intravenous route is preferred for a more rapid response.Venous thromboembolism (VTE) is a potentially life-threatening consequence of estrogen therapy.This report describes a case of acute pulmonary embolism following two doses of intravenous conjugated estrogen in a female with no identifiable risk factors for VTE CASE PRESENTATION: 41 year old G3 P3 003 female presented with recurrent heavy vaginal bleed associated with clots and fatigue.Three weeks prior to this, she was admitted with weakness, fatigue, vaginal bleed was found to have a hemoglobin of 3.5g/dl, received 4 units of packed red blood cells.Transvaginal ultrasound at the time revealed a fibroid in the lower uterine segment and she was discharged with oral iron supplementation with her hemoglobin at discharge being 8.7g/dl. She was then referred for surgical management of the bleed. During the current admission for recurrent vaginal bleeding, hemoglobin was 9.8/dl. Physical examination revealed a prolapsed fibroid encompassing the cervical os. She received a one dose of 25mg of intravenous Premarin (conjugated estradiol).The same afternoon while receiving the second dose, she experienced severe chest pain and shortness of breath with desaturation, with an oxygen saturation of 79%. A Computed tomography angiography showed filling defects in the right lateral and posterior lower lobe segmental pulmonary artery embolus. She was started on a heparin drip and eventually underwent uterine artery embolization, which helped control her presenting symptoms. The intravenous Premarin was discontinued and she was transferred to the Intensive care unit.She was discharged on Rivaroxaban for 6 months. Given the fact that she was ambulatory and had no other risk factors for thromboembolic disease, Premarin was the presumed cause of her pulmonary embolus. DISCUSSION: Given that our patient is a young female with no comorbidities who was ambulatory, non-obese and a non-smoker with no family history of thrombophilia developed a pulmonary embolus during her inpatient stay, we would attribute the most likely cause of the event to be the dose of premarin that she received. Use of the Naranjo probability scale indicated a possible relationship between IV estrogen and development of pulmonary embolism in this patient.(1) CONCLUSIONS: The causal effect of dose of estrogen and the risk of thromboembolism has been previously established in those using oral contraceptives.(2) It has been determined that there is a direct correlation with dose and incidence of VTE and has been found to be the highest within the first three months of use. It would be of interest to analyze the risk of thromboembolic events with minimal estrogen exposure such as in our patient. Reference #1: Naranjo CA et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239245. Reference #2: van Hylckama Vlieg A et al. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type. BMJ 2009 Aug 13 DISCLOSURES: No relevant relationships by Nikhil Jagan, source=Web Response No relevant relationships by Mridula Krishnan, source=Web Response No relevant relationships by Mark Malesker, source=Web Response No relevant relationships by Michael Sanley, source=Web Response

Intracellular aggregated TRPV1 is associated with lower survival in breast cancer patients.

BackgroundBreast cancer is a malignant disease that represents an important public health burden. The description of new molecular markers can be important to diagnosis, classification, and treatment. Transient receptor potential vanilloid 1 (TRPV1) polymodal channel is expressed in different neoplastic tissues and cell lines of breast cancer and associated with the regulation of tumor growth, tumor neurogenesis, cancer pain, and malignant progression of cancer. In primary and metastatic breast cancer tumors, TRPV1 is expressed during neoplastic transformation, invasive behavior, and resistance to cytotoxic therapy.ObjectiveThe objective of this study was to describe the subcellular distribution of TRPV1 in invasive breast carcinomas and its association with survival.MethodsIn 33 cases of invasive breast carcinomas, we identified immunohistochemical and immunofluorescent expression patterns of TRPV1 compared to healthy breast tissue. We characterized the expression of TRPV1 induced by estrogens in breast cancer cell lines MCF-7 and MDA to establish a model of the TRPV1–estrogen relationship regarding the malignant potential. We examined the association of TRPV1 patterns with patients’ survival with the Kaplan–Meyer model, using the log-rank test at 5 years of follow-up. The relation of TRPV1 expression patterns to the St. Gallen breast cancer subtypes was also tested.ResultsBased on immunohistochemical expression pattern of TRPV1, we distinguished two main categories of breast cancer tissue, a “classical category” that exhibited diffuse expression of the channel and a “non-classical category” that expressed the channel in aggregates at the ER/Golgi and/or surrounding these structures. The classical pattern of TRPV1 was associated with a higher survival rate. In breast cancer cell lines, increasing doses of estrogens induced increased TRPV1 expression with nonclassical patterns at higher doses via a mechanism dependent on ER α.ConclusionThe expression and distribution of TRPV1 in invasive breast carcinomas may be considered as a biomarker for prognosis of the disease and a probable therapeutic target.

Possible association of oestrogen and Cryba4 with masticatory muscle tendon-aponeurosis hyperplasia.

Masticatory muscle tendon-aponeurosis hyperplasia, which is associated with limited mouth opening, progresses very slowly from adolescence. The prevalence rates of this disease are higher among women than among men, suggesting oestrogen involvement. As parafunctional habits are frequently observed, mechanical stress is likely involved in the pathogenesis and advancement of this disease. To elucidate the pathological condition, we examined the effect of oestrogen on tenocyte function and the relationship between mechanical stress and crystallin beta A4 (Cryba4), using murine TT-D6 tenocytes. Cell proliferation assays, RT-PCR, real-time RT-PCR, Western blot analysis and mechanical loading experiments were performed. The physiological dose of oestrogen increased the levels of scleraxis and tenomodulin in TT-D6 tenocytes. In contrast, forced expression of Cryba4 inhibited scleraxis expression in these cells. Surprisingly, oestrogen significantly promoted cell differentiation in the Cryba4-overexpressing TT-D6 tenocytes. Moreover, tensile force induced Cryba4 expression in these tendon cells. Oestrogen and Cryba4 may be associated with the progression of masticatory muscle tendon-aponeurosis hyperplasia.

Estrogen-alone therapy and invasive breast cancer incidence by dose, formulation, and route of delivery: findings from the WHI observational study.

Research on the relationships between different hormone therapy doses, formulation and routes of delivery, and subsequent breast cancer incidence has been limited. This study directly compared different estrogen doses, formulations, and route of delivery of estrogen alone among women with a hysterectomy in relation to invasive breast cancer incidence. The Women's Health Initiative Observational Study is a large multicenter prospective cohort study conducted at 40 US sites. Analyses included 26,525 postmenopausal women with a hysterectomy, aged 50 to 79 years, at study entry, recruited between September, 1993 and December, 1998, with annual follow-up through September 12, 2005. Average follow-up was 8.2 years. For conjugated equine estrogen (CEE) users, no difference was observed between low-dose CEE (<0.625 mg) compared with conventional-dose CEE (0.625 mg) for breast cancer (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.65, 1.48)]. Compared with conventional-dose CEE, transdermal estrogen was associated with a nonsignificant lower risk of invasive breast cancer (HR 0.75, 95% CI 0.47, 1.19). The low prevalence of transdermal use likely limited power for this comparison, and for a comparison of oral estradiol to conventional-dose CEE (HR 1.20, 95% CI 0.84, 1.39). Our results indicate that invasive breast cancer risk did not differ appreciably in women with a hysterectomy using estrogen-alone when directly comparing different doses, formulations, and routes of delivery to the conventional oral CEE. These findings suggest that the lower breast cancer risk found in the WHI estrogen-alone trial may extend to lower doses of CEE. Additional research is needed to confirm these hypotheses.

Relationship between serum estrogen concentration and propofol consumption: A prospective observational study of patients undergoing oocyte retrieval.

Controlled ovarian hyperstimulation results in elevated levels of estrogen during in vitro fertilization (IVF). Although serum ovarian steroid hormones were found to influence central nervous system and anesthetic requirements, the relationship between propofol requirements and serum estrogen concentration in women undergoing oocyte retrieval has not been studied. The aim of this study was to determine the relationship between serum estrogen and progesterone concentrations and the required propofol dose for loss of consciousness (LOC). Ninety patients undergoing oocyte retrieval for IVF were enrolled. Anesthesia was induced by administration of 200 mL/h propofol (1%) infusion to reach LOC. Anesthesia was maintained with a propofol infusion guided by entropy. The correlation between estrogen, progesterone levels and propofol dose at the time of LOC was analyzed. Emergence time from anesthesia and total propofol consumption were recorded. The mean serum estradiol concentration was 1825 ±1135 pg/mL. There was a significant positive correlation between serum estradiol and propofol dose required for LOC (Pearson's correlation r = 0.28, P = 0.008). Progesterone had no significant correlation with total propofol dose at the time of LOC. Patients with high estradiol levels (higher than the median value) had similar propofol requirement for LOC, total propofol consumption and emergence time with patients who had low (below the median value) levels. Although increased estrogen levels create a positive correlation with propofol dose for LOC, estrogen does not seem to be the only factor for anesthetic requirement of patients undergoing controlled ovarian hyperstimulation.

Development of an Image-Guided Orthotopic Xenograft Mouse Model of Endometrial Cancer with Controllable Estrogen Exposure.

Endometrial cancer (EC) is the most common gynaecological malignancy in Western society and the majority of cases are estrogen dependent. While endocrine drugs proved to be of insufficient therapeutic value in the past, recent clinical research shows promising results by using combinational regimens and pre-clinical studies and identified potential novel endocrine targets. Relevant pre-clinical models can accelerate research in this area. In the present study we describe an orthotopic and estrogen dependent xenograft mouse model of EC. Tumours were induced in one uterine horn of female athymic nude mice using the well-differentiated human endometrial adenocarcinoma Ishikawa cell line—modified to express the luciferase gene for bioluminescence imaging (BLI). BLI and contrast-enhanced computed-tomograph (CE-CT) were used to measure non-invasive tumour growth. Controlled estrogen exposure was achieved by the use of MedRod implants releasing 1.5 μg/d of 17β-estradiol (E2) in ovariectomized mice. Stable E2 serum concentration was demonstrated by LC-MS/MS. Induced tumours were E2 responsive as increased tumour growth was observed in the presence of E2 but not placebo, assessed by BLI, CE-CT, and tumour weight at sacrifice. Metastatic spread was assessed macroscopically by BLI and histology and was seen in the peritoneal cavity, in the lymphovascular space, and in the thoracic cavity. In conclusion, we developed an orthotopic xenograft mouse model of EC that exhibits the most relevant features of human disease, regarding metastatic spread and estrogen dependency. This model offers an easy to manipulate estrogen dosage (by simply adjusting the MedRod implant length), image-guided monitoring of tumour growth, and objectively measurable endpoints (including tumour weight). This is an excellent in vivo tool to further explore endocrine drug regimens and novel endocrine drug targets for EC.

A moderate oestradiol level enhances neutrophil number and activity in muscle after traumatic injury but strength recovery is accelerated.

The female hormone oestrogen may protect muscle from injury by reducing inflammation but this is debatable. In this study, the inflammatory response of injured muscle from oestrogen-replete mice was comprehensively compared to that from oestrogen-deficient mice. We show that oestrogen markedly promotes movement of neutrophils, an inflammatory white blood cell type, into muscle over the first few days after injury but has only a minor effect on the movement of macrophages, another inflammatory cell type. Despite the enhancement of inflammation by oestrogen in injured muscle, we found strength in oestrogen-replete mice to recover faster and to a greater extent than it does in oestrogen-deficient mice. Our study and others indicate that lower doses of oestrogen, such as that used in our study, may affect muscle inflammation and injury differently from higher doses. Oestrogen has been shown to protect against skeletal muscle injury and a reduced inflammatory response has been suggested as a possible protective mechanism. There are, however, dissenting reports. Our objective was to conduct an unbiased, comprehensive study of the effect of oestradiol on the inflammatory response following muscle injury. Female C57BL6/J mice were ovariectomized and supplemented with and without oestradiol. Tibialis anterior muscles were freeze injured and studied primarily at 1-4days post-injury. Oestradiol supplementation increased injured muscle gene expression of neutrophil chemoattractants (Cxcl1 and Cxcl5) and to a lesser extent that of monocyte/macrophage chemoattractants (Ccl2 and Spp1). Oestradiol markedly increased gene expression of the neutrophil cell surface marker (Ly6g) but had less consistent effects on the monocyte/macrophage cell surface markers (Cd68, Cd163 and Cd206). These results were confirmed at the protein level by immunoblot with oestradiol increasing LY6G/C content and having no significant effect on CD163 content. These findings were confirmed with fluorescence-activated cell sorting counts of neutrophils and macrophages in injured muscles; oestradiol increased the proportion of CD45+ cells that were neutrophils (LY6G+ ) but not the proportion that were macrophages (CD68+ or CD206+ ). Physiological impact of the oestradiol-enhanced neutrophil response was assessed by strength measurements. There was no significant difference in strength between oestradiol-supplemented and -unsupplemented mice until 2weeks post-injury; strength was 13-24% greater in supplemented mice at 2-6weeks post-injury. In conclusion, a moderate level of oestradiol supplementation enhances neutrophil infiltration in injured muscle and this is associated with a beneficial effect on strength recovery.

Menopause

The female reproductive system matures in a continuous, natural process from menarche to menopause as the finite numbers of oocytes produced during fetal development are gradually lost to ovulation and senescence. Menopause is defined as the permanent cessation of menses; by convention, the diagnosis of menopause is not made until the individual has had 12 months of amenorrhea. Menopause is thus characterized by the menstrual changes that reflect oocyte depletion and subsequent changes in ovarian hormone production. However, hormonal changes, rather than the cessation of menstruation itself, cause the manifestations that occur around the time of menopause. Therefore, a woman who has undergone a hysterectomy but who retains her ovaries can experience normal menopausal symptoms as oocyte depletion leads to changes in estrogen levels, even though cessation of menstruation occurred with surgery. This review covers definitions, natural menopause, menopausal transition and postmenopausal symptom management, and premature ovarian insufficiency. Figures show stages of reproductive aging, serum concentrations of hormones during menopausal transition and postmenopause, hormonal changes associated with reproductive aging, symptoms of menopausal transition and menopause, treatment algorithm(s), and Women’s Health Initiative findings: risks and benefits of estrogen alone and estrogen plus progestin by age group: 50 to 59, 60 to 69, and 70 to 79 years. Tables list target tissues, physical manifestations, and menopausal symptoms; selective estrogen receptor modulators used in postmenopausal women; differential diagnosis and evaluation of common menopausal symptoms; estrogen doses; progestogen dosing for endometrial protection; nonhormonal pharmaceutical hot flash therapies; and pharmacologic therapy for genitourinary atrophy. This review contains 6 highly rendered figures, 7 tables, and 119 references.

Leukemia inhibitory factor and its receptor: expression and regulation in the porcine endometrium throughout the estrous cycle and pregnancy.

ObjectiveLeukemia inhibitory factor (LIF) binds to a heterodimeric receptor composed of LIF receptor (LIFR) and glycoprotein 130 (GP130) to transmit signals into the cell. LIF plays an important role in reproduction by regulating immune response, decidualization, and implantation in several species. However, the expression of LIF and LIFR in the endometrium throughout the estrous cycle and pregnancy in pigs is not fully understood.MethodsWe analyzed the expression of LIF and LIFR in the endometrium on days 0 (estrus), 3, 6, 9, 12, 15, and 18 of the estrous cycle, and days 12, 15, 30, 60, 90, and 114 of pregnancy, in conceptuses on days 12 and 15, and in chorioallantoic tissues on days 30, 60, 90, and 114 of pregnancy in pigs. We also determined the effects of estrogen and progesterone on the expression of LIF and LIFR in endometrial tissues.ResultsThe expression of LIF increased in the endometrium during the late diestrus phase of the estrous cycle and during mid- to late- pregnancy, while the expression of LIFR increased during early pregnancy. The expression of LIF was induced by increasing doses of estrogen, whereas the expression of LIFR was induced by increasing doses of progesterone.ConclusionThese results indicate that the expression of LIF and its receptor LIFR in the endometrium is regulated in a stage-specific manner during the estrous cycle and pregnancy, suggesting that LIF and its receptor signaling system may play critical roles in regulating endometrial function in pigs.

Oral contraceptive use and cutaneous melanoma risk: A French prospective cohort study

Introduction Evidence suggests that cutaneous melanoma, the most lethal form of skin cancer, may be influenced by sex hormones. Oral hormones are the leading contraception method in industrialized countries and represent a significant source of exogenous hormone use. Several studies reported a positive association between oral contraceptive (OC) use and melanoma risk. However, findings were conflicting and data from large prospective studies are lacking. Our aim was to explore the associations between OC use and melanoma risk in women. Methods E3 N is a prospective cohort of 98,995 French women aged 40–65 years at inclusion in 1990. Use of oral hormones for contraception was collected through a self-administered questionnaire at baseline, and detailed information on lifetime use of OCs was then recorded every 2–3 years from 1992. We computed hazard ratios (HRs) and 95% Confidence Intervals (CIs) using Cox regression models adjusted for age, birth cohort, pigmentary traits, residential UV exposure in county of birth and at inclusion, and family history of skin cancer. We stratified the results according to melanoma site and histological type using competing-risk models. To examine potential confounding by sun exposure, we used data from E3N-SunExp, a nested case-control study in which a specific questionnaire on lifetime residential and recreational UV exposures was sent to all incident skin cancer cases and 3 controls per case (matched on age, county of birth, education, and length of follow-up in the cohort) in 2008. Analyses in the sub-cohort were performed through logistic regression modelling. Results Between 1992 and 2008, 539 melanoma cases were ascertained among 79,365 women. In age-adjusted models, there was a modest association between ever use of OCs and melanoma risk (HR = 1.18, 95% CI = 0.98–1.42), which was reduced after full adjustment (HR = 1.14, 95% CI = 0.95–1.38). The association was stronger in long-term users (HR = 1.33, 95% CI = 1.00–1.75 for a duration of use of at least 10 years, compared with never use of OCs). Among ever users, there was an inverse association with age at first use (Ptrend = 0.01), consistent with longer durations of OC use in women with a younger age at first use. However, we found no evidence of an association with age at last use or time since last use. When exploring different formulations, the association between ever use of OCs and melanoma risk was restricted to OCs containing high doses of estrogen (≥ 50 μg of ethinyl estradiol) (HR = 1.26, CI = 1.03–1.53). In subtype- and site-specific analyses, ever use of OCs appeared positively associated with all types and sites of melanoma, except the trunk, although no heterogeneity was detected across subtypes (Phomogeneity = 0.54) or sites (Phomogeneity = 0.23). In the E3N-SunExp population, associations between OC use and melanoma risk were not substantially modified after adjustment for residential or recreational UV exposure. However, while we found no association between OC use and sun exposure, we observed that OC use was positively associated with sunscreen use (Ptrend = 0.04 from no protection to increasing SPF) and tanning bed use (odds ratio = 1.14, 95% CI = 1.01–1.29 for ever vs. never use), even after adjusting for age and year of birth. Conclusions Overall, our findings do not support a strong association between OC use and melanoma risk. OC users were more likely to use sunscreen and tanning beds, suggesting a specific profile of OC users regarding their attitude towards tanning. Therefore, we cannot exclude that the observed relation between OC use and melanoma risk, which has been debated in the literature for almost 40 years, could relate to particular sun exposure behaviors in users. Further research, including social and behavioral description of OC users, is thus critical to increase our understanding of the risk profile of women diagnosed with melanoma, and to question the hypothesis of a hormonal influence on melanoma risk.

Estrogen Regulation of T-Cell Function and Its Impact on the Tumor Microenvironment

Epidemiologic studies demonstrate significant gender-specific differences in immune system function. Males are more prone to infection and malignancies, while females are more vulnerable to autoimmune diseases. These differences are thought to be due to the action of gonadal hormones: Estrogen increases the inflammatory response and testosterone dampens it. More specifically, estrogen stimulation induces inflammatory cytokine production including interferon γ, interleukin (IL) 6, and tumor necrosis factor α, while testosterone induces IL-10, IL-4, and transforming growth factor β. More recent studies demonstrate threshold effects of estrogen stimulation on immune cell function: physiologic doses of estrogen (approximately 0.5 nmol/L) stimulate inflammatory cytokine production, but superphysiologic dosages (above 50 nmol/L) can result in decreased inflammatory cytokine production. This review reports findings concerning the impact of estrogen on CD8+cytotoxic T cells and the overall immune response in the tumor microenvironment. Variables examined include dosage of hormone, the diversity of immune cells involved, and the nature of the immune response in cancer. Collective review of these points may assist in future hypotheses and studies to determine sex-specific differences in immune responses that may be used as targets in disease prevention and treatment.

Abstract 2157: Chemotherapeutic tolerability and estrogen dose response in the B6;129-Rag2 tm1Fwa IL2rg tm1Rsky/DwlHsd (R2G2) mouse model

Abstract The B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd (R2G2) knockout mouse was developed by backcrossing an IL2rg (common gamma) knockout model to a RAG2 (recombinase activating gene) knockout model. The resulting mouse lacks various cytokines including IL-2, IL-4, IL-7, IL-9 and IL-15. In addition, this model lacks B cells, T cells, NK cells and has a deficit in lymphocyte development. This model was developed to provide another immunodeficient option for the oncology and immunology fields. The literature supports better tolerability of DNA-damaging oncology treatments for models that do not carry the SCID mutation. We have already reported in a white paper that the R2G2 mouse model is more tolerant of whole-body radiation than a model with the SCID mutation. Herein we describe a study examining chemotherapeutic tolerability of common DNA-damaging oncology drugs including 5-fluorouracil (5-FU), doxorubicin (Doxo), and cyclophosphamide (CTX) (n = 10 per group). 5-FU was given at 30, 60 or 100 mg/kg, intraperitoneally, twice weekly for five weeks. Doxo was given at 2 or 5 mg/kg, intraperitoneally, once weekly for three weeks. CTX was given at 100 or 140 mg/kg intraperitoneally, once weekly for three weeks. The low dose was chosen based on the average dose used in immunodeficient mouse models and the high dose was chosen based on the average dose used in immunocompetent mouse models. This was done to determine if the R2G2 mouse model can tolerate higher doses of these chemotherapeutic agents compared to other immunodeficient mouse models. Results show that the R2G2 mouse model tolerates higher doses of these chemotherapeutic drugs than doses found in the literature for SCID models. Exogenous estrogen tolerance is another common concern in oncology research as some immunodeficient mouse models cannot tolerate the subcutaneous estrogen pellets, developing negative secondary effects resulting in removal from study. We performed an estrogen pellet dose-response study using four doses of 60-day release 17-β estradiol pellets at 0.18, 0.36, 0.72, and 1.7 mg/pellet (n = 10 per group). R2G2 mice show dose-dependent effects of estrogen on morbidity. These data will allow researchers to determine the optimal dose for use in the R2G2 model. In conclusion, these data support that the R2G2 mouse model may be a good alternative to SCID models when administering DNA-damaging chemotherapies or when estrogen supplementation is required for xenograft growth. Citation Format: Jamie L. Naden, Michele Melton, Athena Bast, Jermaine Gardner. Chemotherapeutic tolerability and estrogen dose response in the B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd (R2G2) mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2157.

Endocrine treatment of aging transgender people.

High quality empirical data assessing morbidity and mortality and cancer incidence among transgender people are almost non-existent. Sex hormone treatment of conditions in older non-transgender people might as yet be taken as the best available analogy to hormone administration to aging transgender persons. Testosterone administration to transgender men carries little risk with regard to cardiovascular disease and cancer. A dose adaptation may be needed in men with a high hematocrit or cardiac insufficiency. In transgender men, even after breast ablation, breast cancer may occur in residual mammary tissue. Treatment with estrogens (specifically oral ethinylestradiol) of transgender women, particularly in combination with progestins, carries a significant relative risk of developing cardiovascular disease (almost a twofold incidence compared to the general population). The dose of estrogens may have to be reduced with aging. A change from oral to probably safer transdermal estrogens must be considered. Though rare, tumors of the breasts, prostate, meninges and pituitary have been encountered. Based upon the available expertise, initiation of cross-sex hormone treatment in elderly subjects is without disproportionate risks.

Risk of venous thromboembolism events in postmenopausal women using oral versus non-oral hormone therapy: A systematic review and meta-analysis

IntroductionHormone therapy (HT) is an effective treatment for climacteric symptoms. Nevertheless, combined estrogen-progestin therapy and the oral route seem to entail higher risk of venous thromboembolism (VTE) than estrogen-only therapy and transdermal administration. The present study aimed to investigate the risk of thromboembolic events in postmenopausal women using non-oral estrogen compared to women using oral estrogen and control groups (women receiving placebo or non-users of HT), as well as to assess the thrombotic impact of estrogens alone vs. combined estrogen-progestin therapy. Materials and methodsSystematic review of MEDLINE, Cochrane CENTRAL, EMBASE, and ClinicalTrials.gov according to PRISMA guidelines. ResultsTwenty-two studies were included in the meta-analyses (9 case-control studies, 9 cohort studies, and 4 randomized controlled trials). As compared to control groups, VTE risk was not increased with non-oral HT, including users of estrogens and estrogens plus progestins (OR 0.97 [0.9–1.06]), non-oral estrogen therapy (ET)-only (OR 0.95 [0.81–1.10]), and non-oral combined estrogen-progestin therapy (OR 0.92 [0.77–1.09]). Conversely, increased risk of VTE was observed as compared with control groups in users of oral HT, including users of estrogens and estrogens plus progestins HT (OR 1.72 [1.47–2.01]), oral ET-only (OR 1.43 [1.34–1.53]), and combined oral estrogen-progestin HT (OR 2.35 [1.9–2.9]). The comparison of non-oral vs. oral HT showed increased VTE risk with oral HT (OR 1.66 [1.39–1.98]). ConclusionsVTE risk was increased in postmenopausal women with no previous thromboembolic events using oral HT. Non-oral HT did not significantly affect this risk. The quality of the evidence produced in our meta-analyses is low to moderate, and further clinical trials are needed to sort out the impact of different types of progestin and different estrogen doses and administration routes on VTE risk.

Effects of varying doses of estrogen and caudal pressure on wheel running in orchidectomized male mice.

Physical inactivity is a leading cause of hypokinetic diseases – obesity, heart disease, diabetes, and certain types of cancers. Increased city walkability, better access to fitness facilities, and remediation of socioeconomic barriers prove successful for limited populations within the confines of stringently controlled environments; however, these strategies fail to reverse the ever‐increasing physical inactivity epidemic on a global scale indicating the existence of other unidentified factors. These purported biological factors remain critical targets to understand the regulation of this complex phenotype. An estrogenic mechanism that incompletely or slowly adjusts physical activity levels following reintroduction of estrogenic compounds to surgically gonadectomized mice has been postulated to exist. Currently, this mechanism remains scrutinized due to concerns that elevated estrogen levels induce urinary bladder distension. The distension of the urinary bladder may mechanically disrupt physical activity, masking any physiological effects estrogen has on physical activity. The purpose of this study was to evaluate the effects of estrogen on physical activity levels while employing dose‐related strategies to alleviate distension in mice. Wheel running data were collected under normal physiological conditions, following removal of endogenous sex steroids via orchidectomy, and during estrogen replacement at various doses (0%, 10%, 50% or 100% estrogen‐containing implants) to induce varying degrees of urinary bladder distension. Wheel running distance (P = 0.005) and duration (P = 0.006) decreased after orchidectomy, but slowly increased following estrogen replacement. During the study, wheel running did not return to the levels observed in physiologically intact mice. Significant distension was not observed between estrogen treatment groups indicating that a slow‐responding estrogen effect exists in male mice that prevents wheel running from returning to normal levels immediately following steroid reintroduction. The limited increase in wheel running during estrogen treatment following orchidectomy is not an artifact of induced urinary bladder distension.

Characterizing PTGER4 as a Target Gene of Autism Protein E6AP

BackgroundAutism spectrum disorder (ASD) has been found to be associated with duplication or triplication of the UBE3A gene, which encodes for E6‐associated protein (E6AP, an E3 ubiquitin ligase and transcriptional coactivator). Mice with three copies of UBE3A exhibit core ASD features and humans with Dup15q share many symptoms with ASD. However, the few E6AP ubiquitination substrates found do not explain ASD pathology. Our lab has identified and characterized E6AP as a coactivator of steroid hormone receptor signaling. Estrogens (E2) affect learning, memory and many other brain processes via estrogen receptors, which are transcription factors.ObjectivesThis study tests the hypothesis that deregulation of E6AP‐mediated steroid hormone receptor transcriptional signaling in the brain leads to the development of ASD. The project aims are to identify steroid hormone‐dependent E6AP target genes in neurons and to study the role of these target genes in the pathogenesis of ASD. Identification of new molecular pathways that are transcriptionally regulated by E6AP will broaden our understanding of ASD.MethodsPotential E6AP target genes were identified by microarray of MCF‐7 breast cancer cells. Cells from the mouse neuroblastoma Neuro2a cell line were cultured. Cells were transfected with E6AP or had E6AP knocked down by siRNA and then were treated with physiologically relevant doses of estrogen, the estrogen receptor antagonist tamoxifen, or vehicle. Assays included western blot, co‐immunoprecipitation, qRT‐PCR, and microscopy.Results1) E6‐AP and ER colocalize in mouse HPC neurons. 2) E6‐AP and ERα translocate to the nucleus of Neuro2a (N2a) cells upon E2 treatment. 3) E6‐AP and ERα complex in N2a. 4) The learning and memory gene for prostaglandin E receptor 4, PTGER4, is an E6AP‐dependent target gene that is downregulated in the presence of E6AP or estrogen.ConclusionsWe have identified a memory and learning gene that is regulated by E6AP and E2‐dependent: PTGER4. This is evidence that PTGER4 may be altered in ASD, leading to learning and memory symptoms. PTGER4 allows phosphorylation of glycogen synthase kinase 3 (GSK3). GSK3 has a large role in apoptosis and has been implicated in neuropsychiatric disorders such as Alzheimer's disease and bipolar disorder. Given that GSK3 is amyloidogenic and ASD patients exhibit increased beta amyloid deposition, increased E6AP leading to decreased PTGER4 may lead to decreased inhibitory phosphorylation of GSK3. In a case study, the GSK3 inhibitor ketamine actually improved an adult ASD patient's symptoms, supporting this theory. Further experiments will be necessary to confirm these promising findings.Support or Funding InformationUniversity of Miami

Hormonal contraceptives and breast cancer: Clinical data.

The endocrine background of breast cancer has raised questions about the increase in risk that might bear the use of hormonal contraceptives. This has been a particular issue in the case of young women, who constitute the population of contraceptive consumers. Observational studies have been the main source of evidence, which has mainly limited to the combined estrogen-progestogen preparations, the popular pill. Studies in the 80's and 90's of the past century found a small, around a 20%, increase in risk. The translation in absolute number of excess cases has been exiguous because the prevalence of the disease is relatively small in premenopausal women. Moreover, the risk slowly seemed to disappear after 5-10 years of use. The more sophisticated analyses provided by new technologies, together with the powerful central registries in some countries, has confirmed increased risk of similar size. Recent preparations, with lower doses of estrogens and new progestogenic molecules, have not substantially modified the risk size. The impact of progestogen only alternatives, either pills or progestogen-loaded intrauterine devices, seems to be similar, but the evidence is still insufficient. Whether there is a preferential effect on histological or molecular subtypes of breast tumours is being debated yet. The data on women at higher risk, either with mutations of the BRCA1/2 genes or with familial weight, have not found specific response patterns, but the experience is still meagre. It is of interest that long-term follow up data on women who enrolled in the initial cohorts, like that of the Royal College of General Practitioners', have shown a considerable protection against cancer of the ovary (relative risk, RR 0.67), endometrium (RR 0.66), or colorectum (RR 0.81).

Systematic review and meta-analysis of the association of combined oral contraceptives on the risk of venous thromboembolism: The role of the progestogen type and estrogen dose

IntroductionCurrently available combined oral contraceptives (COC) reportedly increase the risk of venous thromboembolism (VTE). We aimed to quantify this risk considering both progestogen type and estrogen dose. Materials and methodsPubMed, Embase and LIVIVO were searched for relevant publications until April 2017. Case-control and cohort studies including healthy women taking COC and assessing incident VTE as outcome were selected. Adjusted relative risks (RR) with 95% confidence intervals (CI) derived from random effects model using a generic inverse-variance approach are reported. ResultsOverall, 1,359 references were identified and 17 studies were included in the meta-analysis. The pooled RR of VTE was associated with various COC, with the association depending on their respective estrogen dose and progestogen type. Compared to the reference, levonorgestrel with 30–40 μg ethinylestradiol, the overall risk of VTE was higher for all other COC. Preparations with desogestrel with 30–40 μg estrogen showed the highest relative risk (RR: 1.46; 95% CI: 1.33–1.59), while RRs for drospirenone (30–40 μg ethinylestradiol) and desogestrel (30–40/20 μg ethinylestradiol) were lower. COC containing gestodene and cyproterone with 30–40 μg estrogen showed the lowest risk (RR: 1.27; 95% CI: 1.15–1.41 and RR: 1.29; 95% CI: 1.12–1.49, respectively). ConclusionsCompared to levonorgestrel with 30–40 μg ethinylestradiol, all COC showed a significantly increased VTE risk. The association varied depending on the progestogen type and the dose of estrogen. Our results suggest that the prescription of COC with the lowest possible dose of ethinylestradiol may help to avoid VTE cases among young, healthy women.

Neuronal activity in the sagittalis nucleus of the hypothalamus after ovarian steroid hormone manipulation and sexual behavior in female rat

During extended observation of estrogen receptor (ER) α-immunoreactive neurons in the hypothalamus, we previously identified a novel nucleus, the Sagittalis Nucleus of the Hypothalamus (SGN), in the interstitial area between the arcuate nucleus and the ventromedial hypothalamic nucleus. The SGN exhibits sexual dimorphism in its volume and cell count, and estrous cycle related variations in ERα-immunoreactivity. These characteristics of the SGN implicate the nucleus in sex-biased brain functions and behaviors. In this study, we examined involvement of the SGN in sexual arousal in female rats. Immunohistochemical staining of c-Fos, a marker of neuronal activity was performed after administration of an estrus-inducing dose of estrogen and progesterone in ovariectomized female rats. Analysis of microscopic images showed a significant increase in the number of c-Fos-expressing neurons in the SGN following hormonal manipulation. Moreover, neuronal activity in the region exhibited a further increase after each animal was coupled with a male and allowed to mate. These results suggest that the SGN plays an important role in sexual activity in female rat.

Hormonal Contraception and Breast Cancer Risk.

Contemporary hormonal contraception formulations contain lower doses of estrogen, have new synthetic progestin components, and provide novel methods of delivery that have not been studied extensively in relation to breast cancer risk. Given that hormonal contraception is the leading method of birth control in the United States, it is important to reevaluate risk using current formulations. Recent studies including contemporary hormonal contraception formulations will be described.