Changes In Estrogen Levels Research Articles

DEMO REVIEW - 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.

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.

Phytoestrogen Intake Correlate with Blood Pressure in Minangkabau Premenopausal People

Prevalence of hypertension increases in the premenopausal phase due to changes in estrogen levels. Phytoestrogens is known as estrogens like estrogen derived from plants. This study aims to elucidate the correlation of phytoestrogen intake with blood pressure in Minangkabau premenopausal people. A cross-sectional study was conducted in Minangkabau premenopausal people, aged 40–55 years old at Padang City in West Sumatera, Indonesia. Phytoestrogen intake examined to 76 subject by using food frequenty questionnaire (FFQ) that contain 200 kinds of food. Data were analyzed by using correlation test with significant levels p < 0.05. Blood pressure was measured in a sitting position after the subject rests for 10 minutes. Serum estradiol was measured by ELISA tecnique using E2 (estradiol) ELISA KIT from Elabscience. This study show that mean systolic blood pressure (SBP) is 119.74±16.1 mmHg and diastolic blood pressure (DBP) is 76.32±11.1 mmHg. Mean of phytoestrogens intake is 32.66±26.63 mg. The correlation test showed that there was a significant correlation between phytoestrogen intake with SBP (r=−0.255; p=0.26) and DBP (r=−0.246; p=0.032). Whereas serum estradiol levels did not show significant correlation with both SBP and DBP (r=−0.177; p=0.125 and r=−0.204: p=0.077) respectively. Phytoestrogens intake has significant correlation with blood pressure in Minangkabau premenopausal people.

Role of Sex Hormone Levels and Psychological Stress in the Pathogenesis of Autoimmune Diseases.

The aim of this review article is to assess the connection between psychological stress and sex hormones and their effect on the development of autoimmune diseases. Psychological stress describes what people feel when they are under mental, physical, or emotional pressure. We searched for online articles using MEDLINE®, Embase, Cochrane Library and Google Scholar. Our research yielded a total of 165 articles out of which 30 articles were considered for further perusal. The articles were reviewed from February 2016 to February 2017. Case reports and patients suffering from hematolymphoid malignancies and active infections were excluded from the review. Estrogen and testosterone are potential physiological regulatory factors for the peripheral development of CD4+CD25+ T regulatory cells. Stress at any age leads to the depletion of estrogen and testosterone stores in the body, leading to the loss of expansion of T regulatory cells, making the immature B cells evade the negative selection at the germinal center, or in other words, leading to the loss of central tolerance, a triggering event in autoimmune diseases like systemic lupus erythematosus. Autoimmune diseases in women are most likely due to changes in estrogen levels during mental, physical, pre-menopausal, post-menopausal, and pregnancy-induced stress. We conclude that modulating estrogen in females (pre-menopausal and post-menopausal) and testosterone in males can be used to treat stress-related immune imbalance resulting in autoimmune diseases in both sexes.

Abstract PD1-04: CSMD1 SNPs selectively affect anastrozole response in postmenopausal breast cancer patients

Abstract BACKGROUND: Based on prospective clinical trials, there is no evidence for differences in efficacy between the 3 aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole. The purpose of this study was to identify germline genetic variants associated with response to AIs and to help identify novel mechanisms associated with drug disease efficacy. METHODS: A genome-wide association study (GWAS) was performed for 624 patients (Steroids 2015;99:32-38) to identify SNPs associated with estrogen level change in women with estrogen receptor (ER) positive breast cancer treated with anastrozole. Replication of associated SNPs was performed in a GWAS from the MA.27 trial that compared adjuvant anastrozole and exemestane treatment of post-menopausal women with ER+ breast cancer. Functional studies were subsequently performed to determine SNP effects and underlying mechanisms. RESULTS: Our initial GWAS identified SNPs within CSMD1 that were associated with changes in estrogen levels during anastrozole therapy. An additional SNP in CSMD1 was also associated with breast cancer events in CCTG MA.27. Functionally, we showed that CSMD1 regulates CYP19 expression in a SNP-, and in an anastrozole- dependent fashion. These phenomena were not observed for either letrozole or exemestane. In MA.27, an anastrozole- specific effect was also seen with the minor allele having a protective effect on time to distant metastasis (HR=0.49, p=0.00259), but this was not the case for exemestane (HR=0.71, p=0.111). Our in vitro functional studies indicated that overexpression of CSMD1 sensitized anastrozole or letrozole resistant cells to anastrozole but not to the other two AIs. The SNP in CSMD1 that was associated with increased CSMD1 and CYP19 expression levels increased anastrozole sensitivity, but not letrozole or exemestane in lymphoblastoid cell lines (LCLs) homozygous for either WT or variant CSMD1 SNP genotypes. Based on these observations, we explored whether anastrozole has additional mechanisms beyond its function as a CYP19 inhibitor. Utilizing an estrogen response element (ERE) luciferase reporter assay in a CYP19 CRISPR knockout breast cancer T47D cell line and a surface plasmon resonance (SPR) assay, we found that anastrozole can also function as an ERα agonist, and can bind to, and result in, proteasome dependent ERα degradation, especially in the presence of E2. Treatment of these CYP19 CRISPR knockout cells with anastrozole in the presence of increasing concentrations of E2 results in greater sensitivity compared with anastrozole alone, while the addition of E2, as expected, does not improve letrozole or exemestane sensitivity. These same observations were also seen in letrozole and anastrazole resistant cells. CONCLUSIONS: Our findings suggest that anastrozole might be more effective than letrozole or exemestane in patients with the CSMD1 SNP. Furthermore, anastrozole can function as an ERα agonist, binding to ERα and resulting in its degradation, especially in the presence of E2. These findings should help to make it possible to develop precision endocrine therapies for women who are candidates for AIs. Citation Format: Cairns J, Ingle J, Dudenkov T, Kalari K, Buzdar A, Kubo M, Robson M, Ellis M, Goss P, Shepherd L, Goetz M, Weinshilboum R, Wang L. CSMD1 SNPs selectively affect anastrozole response in postmenopausal breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD1-04.

Nerve conduction studies during various phases of menstrual cycle

Background: Menstrual cycle is associated with hormonal fluctuations during various phases. Changes in estrogen levels are associated with swings in mood and cognitive functions. Against this background, this study was undertaken to observe differences in various parameters of nerve conduction during various phases of menstrual cycle. Aims and Objectives: Observe changes in sensory and motor nerve conduction during various phases of menstrual cycle. Materials and Methods: A cross-sectional study was carried out on 35 healthy female volunteers aged 18-35 years. Nerve conduction studies consisting of sensory and motor conduction velocity, distal latencies, compound muscle action potential amplitude, sensory nerve action potential amplitude, and the F wave latencies were carried out on ulnar, common peroneal, and the sural nerve during four phases of the menstrual cycle. Statistical analysis of the results was done using analysis of variance. Results: Nerve conduction parameters did not vary significantly with various phases of the menstrual cycle. Conclusions: Although synaptic conduction and release of neurotransmitters is modulated by estrogen and progesterone but these appear to have no significant role on the normal axonal conduction. Hence, no significant changes were observed in peripheral nerve conduction across various phases of the menstrual cycle.

Poor sleep in middle-aged women is not associated with menopause per se.

Whether sleep problems of menopausal women are associated with vasomotor symptoms and/or changes in estrogen levels associated with menopause or age-related changes in sleep architecture is unclear. This study aimed to determine if poor sleep in middle-aged women is correlated with menopause. This study recruited women seeking care for the first time at the menopause outpatient department of our hospital. Inclusion criteria were an age ≥40 years, not taking any medications for menopausal symptoms, and no sleeping problems or depression. Patients were assessed with the Pittsburgh Sleep Quality Index (PSQI), modified Kupperman Index (KI), and Menopause Rating Scale (MRS). A PSQI score of <7 indicated no sleep disorder and ≥7 indicated a sleep disorder. Blood specimens were analyzed for follicle-stimulating hormone and estradiol levels. A total of 244 women were included in the study; 103 (42.2%) were identified as having a sleep disorder and 141 as not having one. In addition, 156 (64%) women were postmenopausal and 88 (36%) were not menopausal. Follicle-stimulating hormone and estradiol levels were similar between the groups. Patients with a sleep disorder had a significantly higher total modified KI score and total MRS score (both, P<0.001) compared with those without a sleep disorder. Correlations of the PSQI total score with the KI and MRS were similar in menopausal and non-menopausal women. These results do not support that menopause per se specifically contributes to sleep problems.

Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol

Pharmacologically increased estrogen levels have been shown to lower hepatic and plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels in animals and humans. We hypothesized that physiological changes in estrogen levels influence circulating PCSK9, thereby contributing to the known wide inter-individual variation in its plasma levels, as well as to the established increase in LDL cholesterol (LDL-C) with normal aging. Circulating PCSK9, estradiol, and other metabolic factors were determined in fasting samples from 206 female and 189 male healthy volunteers (age 20–85 years), The mean levels of PCSK9 were 10% higher in females than in males (P

The Effects of Perinatal Androgen Deprivation on Body Weight and Spatial Working Memory in Male Rats

Testosterone and its metabolites—estrogen and dihydrotestosterone— are involved in the brain sex differentiation during the perinatal period by binding to androgen receptors (AR) or estrogen receptors (ER). However, in the presence of flutamide, testosterone that is metabolized to estrogen will only bind to ER. Blockade of AR using flutamide during the perinatal period could affect the levels of estrogen, which in turn, may modulate the sex differentiation of the brain. Any such change in estrogen levels is expected to alter memory. This study tested perinatal androgen deprivation on estrogen levels and in turn, its effects on spatial working memory (SWM) in male rats. Long- Evans rats (N=37) were divided into two groups: Group 1 was administered flutamide (20 mg/kg; SC) during perinatal period (prenatal day 4 - postnatal day 4), Group 2 served as control. On postnatal day 65, these groups were divided into 3 subgroups:A. finasteride (FIN; 20 mg/kg, SC), an α-reductase inhibitor, B. letrozole (2 mg/kg, SC), an aromatase inhibitor and C. vehicle (VEH) and injected 5 days/week x 7 weeks. Prior to performing Radial Arm Maze Test to assess their SWM, animals were placed on a 60 % food restriction. Subsequently, serum estrogen levels were measured using ELISA. Animals from Group 1-FIN and -VEH exhibited greater choice accuracy in locating arms with food suggesting improved SWM. Moreover, Group 1 showed a significant increase in body weight compared to Group 2 as well as higher serum estrogen levels implying a relationship between body weight, memory and estrogen.

Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol

Pharmacologically increased estrogen levels have been shown to lower hepatic and plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels in animals and humans. We hypothesized that physiological changes in estrogen levels influence circulating PCSK9, thereby contributing to the known wide inter-individual variation in its plasma levels, as well as to the established increase in LDL cholesterol (LDL-C) with normal aging. Circulating PCSK9, estradiol, and other metabolic factors were determined in fasting samples from 206 female and 189 male healthy volunteers (age 20-85 years), The mean levels of PCSK9 were 10% higher in females than in males (P < 0.05). PCSK9 levels were 22% higher in postmenopausal than in premenopausal (P < 0.001) females. Within the group of premenopausal females, circulating PCSK9 correlated inversely to estrogen levels, and PCSK9 was higher (305 ng/ml) in the follicular phase than in the ovulatory (234 ng/ml) or the luteal (252 ng/ml) phases (P < 0.05). Changes in endogenous estrogen levels during the menstrual cycle likely contribute to the broad inter-individual variation in PCSK9 and LDL-C in normal females. PCSK9 levels increase in females after menopause but not in men during this phase in life. This likely contributes to why LDL-C in women increases in this period.

Subcutaneous Human C1-Inhibitor with Recombinant Human Hyaluronidase for the Prevention of Angioedema Attacks in Patients with Hereditary Angioedema: Results of a Randomized, Double-Blind, Dose-Ranging, Crossover Study

T U E S D A Y 902 The Icatibant Outcome Survey: Trigger Factors and Premonitory Symptoms of Angioedema Attacks in Patients with Hereditary Angioedema Teresa Caballero, Marcus Maurer, Hilary Longhurst, Werner Aberer, Laurence Bouillet, Vincent Fabien, Andrea Zanichelli, MD; Hospital La Paz Institute for Health Research (IdiPaz), Biomedical Research Network on Rare Diseases (CIBERER, U754), Madrid, Spain, Department of Dermatology and Allergy, Allergie-CentrumCharit e, Charit e Universit€atsmedizin Berlin, Berlin, Germany, Department of Immunology, Barts Health NHS Trust, London, United Kingdom, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria, National Reference Centre for Angioedema, Internal Medicine Department, Grenoble University Hospital, Grenoble, France, Shire, Zug, Switzerland, Dipartimento di Scienze Biomediche e Cliniche Luigi Sacco, Universit a degli Studi di MilanoOspedale Luigi Sacco, Milano, Italy. RATIONALE: Hereditary angioedema (HAE) is a potentially lifethreatening, bradykinin-mediated disease characterized by attacks of non-pruritic, non-pitting, subcutaneous edema with unpredictable frequency and severity. We report the most common triggers and prodromal symptoms of attacks in patients with HAE type I/II in the Icatibant Outcome Survey (IOS). METHODS: IOS (NCT01034969) is an observational study monitoring safety and effectiveness of icatibant in a real-world setting. Patients with HAE reported triggers and prodromes for attacks that occurred before IOS (historical) and those occurring during IOS. Data were collected from July 2009–April 2014. RESULTS: Of 512 patients (59.6% female) with HAE type I/II, 306 reported historical triggers (most common: emotional distress [54.9%], physical trauma [38.9%], infection [20.6%], change in estrogen levels [20.3%]), and 294 reported historical prodromes (most common: tiredness [22.4%], tight/prickling sensation in skin [16.7%], nausea [16.0%], erythema marginatum [15.6%]). During IOS, 314 patients reported 1410 attacks. Of these patients, 109 reported triggers for 324 attacks, and 89 reported prodromes for 329 attacks.Most common triggers were emotional distress (n540 attacks, 19 patients), change in estrogen levels (n523 attacks, 9 patients), and physical trauma (n59 attacks, 9 patients). Most common prodromes were erythema marginatum (n549 attacks, 23 patients), tiredness (n523 attacks, 7 patients), irritability and nausea (both n512 attacks, 9 and 4 patients, respectively). CONCLUSIONS: The most common triggers in IOS were emotional distress, change in estrogen levels and physical trauma. A variety of prodromes, including tiredness and erythema marginatum, were recognized by patients. Understanding triggers and prodromesmay help patients better recognize attack onset.

The Icatibant Outcome Survey: Trigger Factors and Premonitory Symptoms of Angioedema Attacks in Patients with Hereditary Angioedema

T U E S D A Y 902 The Icatibant Outcome Survey: Trigger Factors and Premonitory Symptoms of Angioedema Attacks in Patients with Hereditary Angioedema Teresa Caballero, Marcus Maurer, Hilary Longhurst, Werner Aberer, Laurence Bouillet, Vincent Fabien, Andrea Zanichelli, MD; Hospital La Paz Institute for Health Research (IdiPaz), Biomedical Research Network on Rare Diseases (CIBERER, U754), Madrid, Spain, Department of Dermatology and Allergy, Allergie-CentrumCharit e, Charit e Universit€atsmedizin Berlin, Berlin, Germany, Department of Immunology, Barts Health NHS Trust, London, United Kingdom, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria, National Reference Centre for Angioedema, Internal Medicine Department, Grenoble University Hospital, Grenoble, France, Shire, Zug, Switzerland, Dipartimento di Scienze Biomediche e Cliniche Luigi Sacco, Universit a degli Studi di MilanoOspedale Luigi Sacco, Milano, Italy. RATIONALE: Hereditary angioedema (HAE) is a potentially lifethreatening, bradykinin-mediated disease characterized by attacks of non-pruritic, non-pitting, subcutaneous edema with unpredictable frequency and severity. We report the most common triggers and prodromal symptoms of attacks in patients with HAE type I/II in the Icatibant Outcome Survey (IOS). METHODS: IOS (NCT01034969) is an observational study monitoring safety and effectiveness of icatibant in a real-world setting. Patients with HAE reported triggers and prodromes for attacks that occurred before IOS (historical) and those occurring during IOS. Data were collected from July 2009–April 2014. RESULTS: Of 512 patients (59.6% female) with HAE type I/II, 306 reported historical triggers (most common: emotional distress [54.9%], physical trauma [38.9%], infection [20.6%], change in estrogen levels [20.3%]), and 294 reported historical prodromes (most common: tiredness [22.4%], tight/prickling sensation in skin [16.7%], nausea [16.0%], erythema marginatum [15.6%]). During IOS, 314 patients reported 1410 attacks. Of these patients, 109 reported triggers for 324 attacks, and 89 reported prodromes for 329 attacks.Most common triggers were emotional distress (n540 attacks, 19 patients), change in estrogen levels (n523 attacks, 9 patients), and physical trauma (n59 attacks, 9 patients). Most common prodromes were erythema marginatum (n549 attacks, 23 patients), tiredness (n523 attacks, 7 patients), irritability and nausea (both n512 attacks, 9 and 4 patients, respectively). CONCLUSIONS: The most common triggers in IOS were emotional distress, change in estrogen levels and physical trauma. A variety of prodromes, including tiredness and erythema marginatum, were recognized by patients. Understanding triggers and prodromesmay help patients better recognize attack onset.

Effects of silencing connexin43 on expression of pituitary tumor-transforming gene in prolactinomas

Objectives:Pituitary tumor transforming gene (PTTG) is thought to play an important role in prolactinomas, and its overexpression is influenced by estrogen action in the pituitary. Changes in estrogen levels in the rat anterior pituitary increase the number of gap junctions (GJs) increasing both Connexin43 (Cx43) expression and intercellular communication, contributing to pituitary tumor growth. The aim of this study was to investigate the effect of Cx43 on PTTG expression by silencing Cx43 expression using RNA interference (RNAi) in vivo.Methods:An experimental rat model of prolactinoma induced by estradiol (E2) treatment was used. Connexin43 RNAi was applied in vivo through the arachnoid space by injection of double-stranded RNA (dsRNA). Pituitary Cx43 immunostaining was examined using immunofluorescence and Cx43 and PTTG expression by both reverse-transcription-PCR (RT-PCR) and western blotting, respectively.Results:(1) Pituitaries treated with E2 were hypertrophic, but this was reduced by dsRNA treatment. (2) Pituitary Cx43 immunofluorescence increased following E2 treatment, but returned to normal levels following dsRNA treatment. (3) Estradiol induced Cx43 and PTTG expression, which decreased following dsRNA treatment.Discussion:Altered Cx43 expression modulates PTTG expression, which correlates with prolactinoma development. Thus, inhibiting gap junction intercellular communication (GJIC) as a means of weakening the pathologic role PTTG in prolactinomas may be of therapeutic interest.

THU0481 Aromatase Inhibitor Treatment and Musculoskeletal Adverse Events: SNP Modulated, Estrogen-Dependent Variation in Ccr6/Ccl20 Expression

BackgroundJoint pain and stiffness are major side effects associated with aromatase inhibitor (AI) therapy. In a recent genome-wide association study, we identified 4 SNPs near the T-cell leukemia 1A (TCL1A)...

Estrogen-related genome-based expression profiling study of uterosacral ligaments in women with pelvic organ prolapse

The aim of the study was to identify the differential expression of estrogen-related genes that may be involved in the menopause and pelvic organ prolapse (POP) using microarray analysis. An age, parity, and menopausal status-matched case-control study with 12 POP patients and 5 non-POP patients was carried out. The study was conducted from January to December 2010 at Yonsei University, Severance Hospital. We examined microarray gene expression profiles in uterosacral ligaments (USLs) from POP and non-POP patients. Total RNA was extracted from USL samples to generate labeled cDNA, which was hybridized to microarrays and analyzed for the expression of 44,049 genes. We identified differentially expressed genes and performed functional clustering. After clustering, we focused on transcriptional response and signal transduction gene clusters, which are associated with estrogen, and then validated the changes of gene expression levels observed with the microarray analysis using quantitative polymerase chain reaction (qPCR). The data from the microarray analysis using more than a 1.5-fold change with p value <0.05 resulted in 143 upregulated genes and 87 downregulated genes. Of 59 genes identified to be associated with signal transduction and transcription, 4 genes were chosen for qPCR that have been classified to be associated with estrogen. We found that estrogen receptor-related receptor-α (ERRα) was downregulated and that the expression of death-associated protein kinase 2 (DAPK 2), signal-transducing adaptor protein-2 (STAP-2), and interleukin (IL)-15 were upregulated. We found four differentially expressed genes by microarray analysis that may account for the way in which changes in estrogen level affect POP pathophysiology.

Effect of estrogens on base excision repair in brain and liver mitochondria of aged female rats

Changes in the endocrine system have been suggested to act as signaling factors in the regulation of age-related events. Among the different hormones that have been linked to the aging process, estrogens have been widely investigated. They have been associated with inflammatory and oxidative processes and several investigations have established a relationship between the protective effects of estrogens and the mitochondrial function. Mitochondrial DNA is subjected to continuous oxidative attack by free radicals, and the base excision repair (BER) pathway is the main DNA repair route present in mitochondria. We have investigated the effect of estrogen levels on some of the key enzymes of BER in brain and liver mitochondria. In both tissues, depletion of estrogens led to an increased mitochondrial AP endonuclease (mtAPE1) activity, while restoration of estrogen levels by exogenous supplementation resulted in restitution of control APE1 activity only in liver. Moreover, in hepatic mitochondria, changes in estrogen levels affected the processing of oxidative lesions but not deaminations. Our results suggest that changes in mtAPE1 activity are related to specific translocation of the enzyme from the cytosol into the mitochondria probably due to oxidative stress changes as a consequence of changes in estrogen levels.

Why Do Girls Sustain More Anterior Cruciate Ligament Injuries Than Boys?

Sport is the leading cause of injury among adolescents and girls incur more non-contact anterior cruciate ligament (ACL) ruptures than boys, with this gender disparity in injury incidence apparent from the onset of puberty. Although the mechanisms for this gender disparity in ACL injuries are relatively unknown, hormonal, anatomical and biomechanical factors have been implicated. Puberty is associated with rapid skeletal growth and hormonal influx, both of which are thought to contribute to alterations in ACL metabolic and mechanical properties, as well as changes in lower limb strength and flexibility, ultimately influencing landing technique. Therefore, the aim of this review is to explain (i) the effects of changes in estrogen levels on the metabolic and mechanical properties of the ACL; (ii) changes in musculoskeletal structure and function that occur during puberty, including changes in knee laxity, and lower limb flexibility and strength; and (iii) how these hormonal and musculoskeletal changes impact upon the landing technique displayed by pubescent girls. Despite evidence confirming estrogen receptors on the ACL, there are still conflicting results as to how estrogen affects the mechanical properties of the ACL, particularly during puberty. However, during this time of rapid growth and hormonal influx, unlike their male counterparts, girls do not display an accelerated muscle strength spurt and the development of their hamstring muscle strength appears to lag behind that of their quadriceps. Throughout puberty, girls also display an increase in knee valgus when landing, which is not evident in boys. Therefore, it is plausible that this lack of a defined strength spurt, particularly of the hamstring muscles, combined with the hormonal effects of estrogen in girls, may contribute to a more ‘risky’ lower limb alignment during landing, in turn, contributing to a greater risk of ACL injury. There is, however, a paucity of longitudinal studies specifically examining the lower limb musculoskeletal structural and functional changes experienced by girls throughout puberty, as well as how these changes are related to estrogen fluctuations characteristic of puberty and their effects on landing biomechanics. Therefore, further research is recommended to provide greater insight as to why pubescent girls are at an increased risk of non-contact ACL injuries during sport compared with boys. Such information will allow the development of evidence-based training programmes aimed at teaching girls to land more safely and with greater control of their lower limbs in an attempt to reduce the incidence of ACL ruptures during puberty.

Rapid Changes in Cardiac Myofilament Function following the Acute Activation of Estrogen Receptor-Alpha

Estrogens have well-recognized and complex cardiovascular effects, including altering myocardial contractility through changes in myofilament function. The presence of multiple estrogen receptor (ER) isoforms in the heart may explain some discrepant findings about the cardiac effects of estrogens. Most studies examining the impact of estrogens on the heart have focused on chronic changes in estrogen levels, and have not investigated rapid, non-genomic pathways. The first objective of this study was to determine how acute activation of ERα impacts cardiac myofilaments. Nongenomic myocardial estrogen signaling is associated with the activation of a variety of signaling pathways. p38 MAPK has been implicated in acute ER signaling in the heart, and is known to affect myofilament function. Thus, the second objective of this study was to determine if acute ERα activation mediates its myofilament effects through p38 MAPK recruitment. Hearts from female C57Bl/6 mice were perfused with the ERα agonist PPT and myofilaments isolated. Activation of ERα depressed actomyosin MgATPase activity and decreased myofilament calcium sensitivity. Inhibition of p38 MAPK attenuated the myofilament effects of ERα activation. ERα stimulation did not affect global myofilament protein phosphorylation, but troponin I phosphorylation at the putative PKA phosphorylation sites was decreased. Changes in myofilament activation did not translate into alterations in whole heart function. The present study provides evidence supporting rapid, non-genomic changes in cardiac myofilament function following acute ERα stimulation mediated by the p38 MAPK pathway.

Aromatase Inhibition in Obese Women: How Much Is Enough?

Aromatase Inhibition in Obese Women: How Much Is Enough?

Gynecologic disorders and menstrual cycle lightheadedness in postural tachycardia syndrome

ObjectiveTo assess differences in gynecologic history and lightheadedness during menstrual cycle phases among patients with POTS and healthy control women. MethodsIn a prospective, questionnaire-based study carried out at Paden Autonomic Dysfunction Center, Vanderbilt University, between April 2005 and January 2009, a custom-designed questionnaire was administered to patients with POTS (n=65) and healthy individuals (n=95). The results were analyzed via Fisher exact test and Mann–Whitney U test. ResultsPatients with POTS reported increased lightheadedness through all phases of the menstrual cycle phases as compared with healthy controls. Both groups experienced the greatest lightheadedness during menses, and a decrease in lightheadedness during the follicular phase. Patients with POTS reported a higher incidence of gynecologic diseases as compared with healthy controls. ConclusionThe severity of lightheadedness was found to vary during the menstrual cycle, which may relate to changes in estrogen levels. Patients with POTS also reported an increase in estrogen-related gynecologic disease.