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1.  Estrogen and Progesterone Affect Responses to Malaria Infection in Female C57BL/6 Mice 
Gender medicine  2008;5(4):423-433.
Background
Previous data from our laboratory suggest that gonadally intact C57BL/6 male mice are more likely than their female counterparts to die from Plasmodium chabaudi infection, to recover more slowly from weight loss and hematocrit loss, and to have reduced interferon-gamma (IFN-γ) and interleukin (IL)-10 responses. Removal of the ovaries, and hence, the primary production of sex steroids in females, reverses these differences.
Objective
We hypothesized that sex differences in response to P. chabaudi may be mediated by differential synthesis of IFN-γ and IL-10 that is influenced by estrogen, progesterone, or both.
Methods
C57BL/6 female mice ( n = 200; n = 10/time point/treatment/experiment) were ovariectomized (OVX) and implanted with either a 21-day controlled-release pellet containing 0.1 mg of 17β-estradiol (E2), 10 mg of progesterone (P4), 0.1 mg of E2 plus 10 mg of P4, or cholesterol (placebo). Females were inoculated with 106 P. chabaudi-infected erythrocytes. Body mass, body temperature, hematocrit, parasitemia, cytokine production, and antibody responses were monitored 0, 3, 5, 7, 10, 14, and 21 days postinoculation.
Results
Administration of E2, either alone or in combination with P4, mitigated infection-induced weight loss, hematocrit loss, and hypothermia, as compared with females receiving placebo pellets (P < 0.05 in each case). Hormone treatment did not affect levels of parasitemia. Females administered E2 alone or in combination with P4 produced 50–150 times more IFN-γ and IL-10 during peak parasitemia than did females implanted with pellets containing either P4 alone or placebo (P < 0.05 in each case). Exposure to E2, either alone or in combination with P4, increased anti-P. chabaudi immunoglobulin G (IgG1) responses and the ratio of IgG1 to IgG2c (P < 0.05 in each case).
Conclusion
This animal study suggests that physiological levels of estrogen, rather than progesterone, enhance immunity and, possibly, protect females from disease symptoms during malaria infection.
doi:10.1016/j.genm.2008.10.001
PMCID: PMC4155322  PMID: 19108815
estrogen; interferon-γ; interleukin-10; malaria; progesterone; sex difference; sex steroid
2.  Diagnosis and Referral Delay in Women With Parkinson’s Disease 
Gender medicine  2011;8(3):209-217.
Background
Gender differences in Parkinson’s disease may be attributable to biological and environmental factors as well as health care–seeking behaviors and diagnosis bias.
Objective
The goal of this pilot study was to determine whether there are gender discrepancies in diagnosis and time to present to a movement disorder specialist, and to assess whether clinical and referral factors account for these differences.
Methods
We report data on diagnosis, health care–seeking patterns, and clinical features in men and women with early Parkinson’s disease treated at a tertiary care center.
Results
A total of 109 patients with Parkinson’s disease (53 women and 56 men; median age at onset, 60.3 years) were included in this study. Although men and women did not differ in time from symptom onset to first physician visit, duration from symptom onset to movement disorder specialist visit was longer in women than in men. The expected duration from onset to movement disorder specialist visit for women was 61% greater than for men in the unadjusted model (P = 0.002).
Conclusion
There were gender differences in time to present to a movement disorder specialist in these patients with early Parkinson’s disease, and further study in larger samples is warranted.
doi:10.1016/j.genm.2011.05.002
PMCID: PMC3966522  PMID: 21664587
diagnosis; gender differences; Parkinson’s disease; referral; women
3.  Epidemiologic differentiation of diagnostic and screening populations for the assessment of cervical dysplasia using optical technologies 
Gender medicine  2012;9(1 0):10.1016/j.genm.2011.10.006.
Background
We report here the logistic modeling of the epidemiologic differences between a diagnostic and screening population recruited for the study of optical technologies for cervical cancer detection.
Methods
Epidemiologic data were obtained from a risk factor interview as a component of a multicenter Phase II clinical trial which employed fluorescence and reflectance point spectroscopy to diagnose cervical disease. Participants with a recent or past abnormal Papanicolaou smear were grouped into the diagnostic (high-risk) population, while those with a history of normal Papanicolaou smears and no cervical treatments were grouped into the screening (low-risk) population.
Results
Our model revealed that non-white race, greater than a high school education, and peri- and postmenopausal status were associated with the screening population. Meanwhile, a history of genital infections, current OC use, HPV positivity (by Hybrid Capture II and consensus PCR), and histology at clinic visit were important predictors of being in the diagnostic group.
Conclusions
We were successful in recruiting two distinctive populations, and we anticipate being able to use these results to more correctly classify women at higher risk for cervical lesions in our future studies of optical spectroscopy.
doi:10.1016/j.genm.2011.10.006
PMCID: PMC3874883  PMID: 22340639
cervical dysplasia; epidemiology; optical technologies; risk factors
4.  Gender Differences in Anthropometric Predictors of Physical Performance in Older Adults 
Gender medicine  2012;9(6):445-456.
Background
Both high body fat and low muscle mass have been associated with physical disability in older adults. However, men and women differ markedly in body composition, where men generally have more absolute and relative lean muscle mass and less fat mass than women. It is not known how these anthropometric differences differentially impact physical ability in men and women.
Objectives
This study examines differences in anthropometric predictors of physical performance in older women and men.
Methods
Participants were 470 older women and men aged 72.9±7.9y. Body composition was measured using DXA. Maximum leg strength and power were measured using a leg press. Muscle quality (MQ) was calculated as relative strength (leg press strength per kg of leg muscle mass). Gait speed and chair rise were used to assess mobility performance and functional strength.
Results
BMI, age and muscle quality emerged as predictors (p<0.05) of functional strength and mobility in men and women somewhat differently. After accounting for age and sample, leg muscle quality was related to chair rise time and gait speed in men but not women. BMI was related to gait speed in both men and women, but BMI was related to chair rise time in only women and not men.
Discussion
Results implicate the prioritized importance of healthy weight and muscle maintenance in older women and men, respectively for maintained physical functioning with aging.
doi:10.1016/j.genm.2012.10.004
PMCID: PMC3536819  PMID: 23123187
Physical Function; Muscle Strength; Muscle Mass; Aging; Body Composition
5.  Donor-Recipient Sex Mismatch in Kidney Transplantation 
Gender medicine  2012;9(5):335-347.e2.
Background
The lack of reliable human proxies for minor (i.e., non-HLA) histocompatibility loci hampers the ability to leverage these factors toward improving transplant outcomes. Despite conflicting reports of the effect of donor-recipient sex mismatch on renal allografts, the association between acute rejection of renal allografts and the development of human alloantibodies to the male H-Y antigen suggested to us that donor-recipient sex-mismatch deserved re-evaluation.
Objective
To evaluate whether relations between donor sex and allograft failure differed by recipient sex.
Methods
We studied recipients of deceased- (n=125,369) and living-donor (n=63,139) transplants in the United States Renal Data System (USRDS). Using Cox proportional hazards models stratified by donor type we estimated the association between donor-recipient sex-mismatch and death-censored allograft failure with adjustment for known risk factors, with and without use of multiple imputation methods to account for potential bias and/or loss of efficiency due to missing data.
Results
The advantage afforded by male donor kidneys was more pronounced among male than among female recipients (8% vs. 2% relative risk reduction; interaction p<0.01). This difference is of the order of magnitude of several other risk factors affecting donor selection decisions.
Conclusions
Donor-recipient sex mismatch affects renal allograft survival in a direction consistent with immune responses to sexually determined minor histocompatibility antigens. Our study provides a paradigm for clinical detection of markers for minor histocompatibility loci.
doi:10.1016/j.genm.2012.07.004
PMCID: PMC3478108  PMID: 22906727
gender; H-Y; kidney transplant; minor histocompatibility; sex
6.  Endogenous Androgen Deficiency Enhances Diet-Induced Hypercholesterolemia and Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice 
Gender medicine  2012;9(5):319-328.
Background
Despite numerous clinical and animal studies, the role of sex steroid hormones on lipoprotein metabolism and atherosclerosis remain controversial.
Objective
We sought to determine the effects of endogenous estrogen and testosterone on lipoprotein levels and atherosclerosis using mice fed a low-fat diet with no added cholesterol.
Methods
Male and female low-density lipoprotein receptor-deficient mice were fed an open stock low-fat diet (10% of kcals from fat) for 2, 4, or 17 weeks. Ovariectomy, orchidectomy, or sham surgeries were performed to evaluate the effects of the presence or absence of endogenous hormones on lipid levels, lipoprotein distribution, and atherosclerosis development.
Results
Female mice fed the study diet for 17 weeks had a marked increase in levels of total cholesterol, triglycerides, apolipoprotein-B containing lipoproteins, and atherosclerosis compared with male mice. Surprisingly, ovariectomy in female mice had no effect on any of these parameters. In contrast, castration of male mice markedly increased total cholesterol concentrations, triglycerides, apolipoprotein B-containing lipoproteins, and atherosclerotic lesion formation compared with male and female mice.
Conclusions
These data suggest that endogenous androgens protect against diet-induced increases in cholesterol concentrations, formation of proatherogenic lipoproteins, and atherosclerotic lesions formation. Conversely orchidectomy, which decreases androgen concentrations, promotes increases in cholesterol concentrations, proatherogenic lipoprotein formation, and atherosclerotic lesion formation in lowdensity lipoprotein receptor-deficient mice in response to a low-fat diet.
doi:10.1016/j.genm.2012.08.003
PMCID: PMC3483072  PMID: 22981166
androgen; atherosclerosis; cholesterol; estrogen
7.  Sexual dimorphism in development of kidney damage in the aging Fischer-344 (F344) rat 
Gender medicine  2012;9(4):219-231.
The aging kidney exhibits slowly developing injury and females are usually protected compared to males, in association with maintained renal nitric oxide (NO). Here, we compared renal injury in Fischer 344 (F344) rats in intact, ovariectomized, and ovariectomized + estrogen replaced young (6 month) and old (24 month) female rats with young and old intact male rats and measured renal protein abundance of NO synthase isoforms and oxidative stress. There was no difference in age-dependent glomerular damage between young or old intact male and female F344, and neither ovariectomy nor estrogen replacement affected renal injury; however, tubulointerstitial injury was greater in old males than old females. These data suggest that ovarian hormones do not influence these aspects of kidney aging in F344 rats and that the greater tubulointerstitial injury is caused by male sex. Old males had greater kidney cortex NOS3 abundance than females, and NOS1 abundance (alpha and beta isoforms) was increased in old males compared to both young males and old females. NOS abundance was preserved with age in intact females, ovariectomy did not reduce NOS1 or 3 protein abundance, and estrogen replacement did not uniformly elevate NOS proteins, suggesting that estrogens are not primary regulators of renal NOS abundance in this strain. NADPH oxidase-dependent superoxide production and nitrotyrosine immunoreactivity were increased in the aging male rat kidney compared to the female which could compromise renal NO production and/or bioavailability. In conclusion, the kidney damage expressed in the aging F344 is fairly mild and is not related to loss of renal cortex NOS3 or NOS1 alpha. This is in contrast to the aging male Sprague Dawley rat [1] where kidney damage is exacerbated and NOS3 and NOS1 alpha are lost compared to the old female.
doi:10.1016/j.genm.2012.06.003
PMCID: PMC3461833  PMID: 22819558
Nitric oxide; oxidative stress; tubulointerstitial injury; estrogen; ovariectomy
8.  Gender Differences in Cardiovascular Risk in Adolescents with Type 1 Diabetes 
Gender medicine  2012;9(4):251-258.
Cardiovascular disease is seen at a younger age and at a higher prevalence in patients with type 1 diabetes (T1D) than in the general population. It is well described that women with T1D have a higher relative risk for cardiovascular disease than men with T1D, unlike that seen in the general population. The pathophysiology behind this is unknown. We did a cross-sectional study to examine gender differences in cardiovascular risk factors in adolescents with T1D between the ages of 13-20 years, compared to children of a similar age without T1D. All subjects underwent Dual Energy X-ray Absorptiometry (DXA scan) to measure body composition, and an HDI/Pulsewave CR-2000 test measure of arterial elasticity. Fasting serum lipids, apolipoprotein B and apolipoprotein C-III were measured in each subject. 29 children with T1D (10 F, 19 M) and 37 healthy children (18F, 19 M) participated. Although no gender differences for body mass index (p = 0.91) and A1C (p =0.69) were seen, females with T1D had a significantly higher trunk % fat compared to males (p=0.004). No gender differences were found (p > 0.05) for trunk % fat in adolescents without diabetes. There was no gender difference among any other cardiovascular risk factors in both children with and without diabetes. Thus we conclude that female adolescents with T1D have more centrally distributed fat which may contribute to their relatively higher cardiovascular risk. Attenuation of the central distribution of fat through exercise and dietary modifications may help ameliorate their subsequent cardiovascular disease burden.
doi:10.1016/j.genm.2012.05.003
PMCID: PMC3481996  PMID: 22795492
body composition; cardiovascular disease; type 1 diabetes
9.  Gender Differences in Posttraumatic Stress Disorder Among Primary Care Patients After the World Trade Center Attack of September 11, 2001 
Gender medicine  2005;2(2):76-87.
Background
Debate surrounds the nature of gender differences in rates of posttraumatic stress disorder (PTSD).
Objective
The goal of this study was to quantify and explore the reasons for gender differences in rates of PTSD in low income, primary care patients after the World Trade Center (WTC) attack of September 11, 2001.
Methods
A survey was conducted at a large primary care practice in New York City 7 to 16 months after the WTC attack. The study involved a systematic sample of primary care patients aged 18 to 70 years. The main outcome measures were the Life Events Checklist, the Posttraumatic Stress Disorder Checklist–Civilian Version, and the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire, all administered by a bilingual research staff.
Results
A total of 3807 patients were approached at the primary care clinic. Of the 1347 who met eligibility criteria, 1157 (85.9%) consented to participate. After the addition of the WTC/PTSD supplement to the study, the total number of patients was 992, of whom 982 (99.0%) completed the survey. Both sexes had high rates of direct exposure to the WTC attack and high rates of lifetime exposure to stressful life events. Overall, females had lower rates of exposure to the attack compared with males (P < 0.05). Hispanic females had the highest rate of PTSD in the full sample. Gender differences in rates of PTSD were largely accounted for by differences in marital status and education. The rate of current major depressive disorder (MDD) was higher in females than in males (P < 0.001), and the reverse was true for substance abuse (P < 0.001). Gender differences for MDD and substance abuse persisted even after adjustments for demographic differences between the sexes.
Conclusions
The increased rate of PTSD in women attending a primary care clinic was mediated by their social and economic circumstances, such as living alone without a permanent relationship and with little education or income. The increased rate of MDD in women appeared to be less dependent on these circumstances. These findings have implications for the treatment of women with PTSD in primary care and for research on gender differences in rates of psychiatric disorders.
PMCID: PMC3683844  PMID: 16115602
posttraumatic stress disorder; gender; World Trade Center; primary care
10.  Age-Dependent Reductions in Mitochondrial Respiration are Exacerbated by Calcium in the Female Rat Heart 
Gender Medicine  2012;9(3):197-206.
Cardiovascular disease mortality increases rapidly following menopause by poorly defined mechanisms. Since mitochondrial function and Ca2+ sensitivity are important regulators of cell death following myocardial ischemia, we sought to determine if aging and/or estrogen deficiency (ovx) increased mitochondrial Ca2+ sensitivity. Mitochondrial respiration was measured in ventricular mitochondria isolated from adult (6mo; n=26) and aged (24mo; n=25), intact or ovariectomized female rats using the substrates: α-ketoglutarate/malate (Complex I); succinate/rotenone (Complex II); ascorbate/TMPD/Antimycin (Complex IV). State 2 and State 3 respiration was initiated by sequential addition of mitochondria and ADP. Ca2+ sensitivity was assessed by Ca2+-induced swelling of de-energized mitochondria and reduction in state 3 respiration. Propylpyrazole triol (PPT) was administered i.p. 45 min prior to euthanasia to assess mitochondrial protective effects through estrogen receptor (ER) α activation. Aging decreased the respiratory control index (RCI; state 3/state 2) for Complexes I and II by 12% and 8%, respectively, independent of ovary status (p<0.05). Of interest, Ca2+ induced a greater decrease (18–30%; p<0.05) in Complex I state 3 respiration in aged and ovx animals, and mitochondrial swelling occurred twice as quickly in aged (vs. adult) female rats (p<0.05). Pretreatment with PPT increased RCI by 8% and 7% at Complexes I and II, respectively (p<0.05) but surprisingly increased Ca2+ sensitivity. Age-dependent decreases in RCI and sensitization to Ca2+ may explain in part the age-associated reductions in female ischemic tolerance; however protection afforded by ER agonism involves more complex mechanisms.
doi:10.1016/j.genm.2012.04.001
PMCID: PMC3374891  PMID: 22555015
estrogen receptors; permeability transition pore; myocardium; senescence
11.  Postoperative estradiol levels associate with the development of primary graft dysfunction in lung transplant patients 
Gender Medicine  2012;9(3):154-165.
Primary graft dysfunction (PGD) frequently complicates lung transplantation in the immediate postoperative period. Both female gender and estradiol modulate the body’s response to injury and may influence the rate of alveolar fluid clearance. We hypothesized that female gender and higher estradiol levels would be associated with a lower risk of PGD after lung transplantation. We measured plasma estradiol levels pre-operatively, 6 hours postoperatively and 24 hours postoperatively in a cohort of 111 lung transplant recipients at two institutions. The mean age was 57 years (+/− 12.5) and 52% were female. The median postoperative estradiol level was 63.9 pg/ml (IQR 28.8–154.3) in men and 65.1 pg/ml (IQR 28.4–217.2) in females. Contrary to our hypothesis, higher estradiol levels at 24 hours were associated with an increased risk of PGD at 72 hours in males (p=0.001). This association was preserved when accounting for other factors known to be associated with PGD. However, there was no relationship between gender and risk of PGD or between estradiol levels and PGD in females. These findings suggest that there may be different biologic effects of estrogens in males and females and highlight the importance of considering gender differences in future studies of PGD.
doi:10.1016/j.genm.2012.01.009
PMCID: PMC3374892  PMID: 22361838
Lung transplantation; gender; acute lung injury; acute respiratory distress syndrome; estrogen; alveolar fluid clearance
12.  Agonistic autoantibodies to the angiotensin II type I receptor cause pathophysiological characteristics of preeclampsia 
Gender medicine  2012;9(3):139-146.
Preeclampsia, (PE) new onset hypertension with proteinuria during pregnancy, is associated with increased reactive oxygen species, the vasoactive peptide ET-1, T and B lymphocytes, soluble antiangiogenic factors sFlt-1 and sEndoglin (sFlt-1 and sEng) and agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA). One important area of investigation for our laboratory has been to determine what role AT1-AA play in the pathophysiology associated with PE. To achieve this goal we examined the effect of AT1-AA suppression on hypertension in response to placental ischemia as well as the effect of AT1-AA to increase blood pressure, ET-1, ROS, and sFlt-1 in normal pregnant rats (NP). We have demonstrated reductions in uterine perfusion pressure (RUPP) to be a stimulus for AT1-AA during pregnancy. We utilized the technique of B cell depletion to suppress circulating AT1-AA in RUPP rats and found that AT1-AA suppression in RUPP rats was associated with lower blood pressure and ET-1 activation. To determine a role for AT1-AA to mediate hypertension during pregnancy we have chronically infused purified rat AT1-AA (1:50) into NP rats and analyzed blood pressure and soluble factors. We have consistently shown that AT1-AA infused rats significantly increased AT1-AA and blood pressure above NP rats. This hypertension is associated with significantly increased ET-1 in renal cortices (11-fold) and placenta (4-fold), and approximately 2 to 3 fold increase in placental oxidative stress. Furthermore, antiangiogenic factors sFlt-1 and sEng were significantly increased in AT1-AA induced hypertensive group compared to the NP controls. Collectively, these data indicate an important role for AT1-AA stimulated in response to placental ischemia to cause hypertension during pregnancy.
doi:10.1016/j.genm.2012.03.001
PMCID: PMC3483641  PMID: 22498426
13.  Effects of Two Estradiol Regimens on Anxiety and Depressive Behaviors and Trophic Effects in Peripheral Tissues in a Rodent Model 
Gender medicine  2009;6(1):300-311.
Background
With aging and menopause, which are associated with decreases in ovarian steroids such as 17β-estradiol (E2), women might experience negative psychological symptoms, including anxiety and depression. Some women use E2-based therapies to alleviate these symptoms, but E2 has been associated with trophic effects that might increase vulnerability to some steroid-sensitive cancers, such as breast cancer, in both premenopausal and postmenopausal women.
Objective
This study investigated the relationships between the possible beneficial effects of E2 on anxiety and depressive behaviors concurrent with trophic effects using an animal model of E2 decline and replacement.
Methods
Dose-dependent effects of E2 on affective, sexual, and motor behavior of young adult rats were studied. Ovariectomized (OVX) rats were administered the chemical carcinogen 7,12-dimethylbenz(a) anthracene (DMBA) 1.25 mg or inactive vehicle (vegetable oil; control) by gavage. E2 (0.03 or 0.09 mg/kg) or vehicle was administered subcutaneously 44 to 48 hours before assessments of anxiety (light–dark transition), depression (forced swim test), sexual (lordosis), and motor (activity monitor) behaviors. Fourteen weeks after carcinogen exposure, E2 concentrations in plasma and brain regions (cortex, hippocampus, and hypothalamus) were determined. Incidences and numbers of tumors and uterine weight were analyzed.
Results
Administration of E2 (0.09 mg/kg) was associated with significant increases in antianxiety-like behavior in the light–dark transition task, antidepressant-like behavior in the forced swim test, and physiologic circulating and central E2 concentrations compared with E2 (0.03 mg/kg) and vehicle. Compared with vehicle, E2 (0.9 > 0.3 mg/kg) was associated with significant increases in lordosis and uterine weight. Administration of DMBA was associated with significant increases in the incidences and numbers of tumors; this effect was augmented by E2 administration.
Conclusion
Based on the findings in this rat model, the hypothesis that E2 may be effective in reducing anxiety and depressive behaviors and enhance sexual behavior in OVX rats, concurrent with trophic effects in the periphery, was supported. Moderate physiologic levels of E2 might have beneficial effects on affective and sexual behaviors in female rodents, but regimens including E2 might increase tumorigenic capacity.
doi:10.1016/j.genm.2009.04.004
PMCID: PMC3616371  PMID: 19467526
estrogen; anxiety; depression; menopause; breast cancer
14.  Gender, BDNF Val66Met, and Methamphetamine Use Frequency 
Gender Medicine  2012;9(2):112-120.
Pre-treatment methamphetamine (MA) use frequency is an important predictor of outcomes of treatment for MA dependence. Preclinical studies suggest females self-administer more MA than males but few clinical studies have examined potential sex differences in MA use frequency. Estrogen increases expression of brain-derived neurotrophic factor (BDNF) which has effects on MA-induced striatal dopamine release and protects against MA-induced neurotoxicity. Therefore, we examined potential effects of sex, the Val66Met polymorphism in BDNF, and their interaction, on MA use frequency among 60 Caucasian MA dependent volunteers screening for a clinical trial. Females reported significantly more pre-treatment days with methamphetamine use in the past 30 than males. There was a significant interaction between sex and BDNF Val66Met with the highest frequency of MA use among females with Val/Val genotype. These results, although preliminary, add to the literature documenting sexual dimorphism in response to stimulants including methamphetamine and suggest a potential biological mechanism involving BDNF that may contribute to these differences. Additional research characterizing the biological basis of altered response to methamphetamine among females is warranted.
doi:10.1016/j.genm.2012.02.005
PMCID: PMC3322259  PMID: 22445683
BDNF Val66Met; Brain-derived neurotrophic factor; Gender; Methamphetamine
15.  Pharmacological Effects of 2-Methoxyestradiol on Angiotensin Type 1 Receptor Down-Regulation in Rat Liver Epithelial and Aortic Smooth Muscle Cells 
Gender Medicine  2012;9(2):76-93.
Delayed onset of cardiovascular disease among females is not well understood, but could be in part due to the protective effect of estrogen before menopause. Experimental studies have identified the angiotensin type 1 receptor (AT1R) as a key factor in the progression of CVD. In this study, we examined the effects of the estrogen metabolite, 2-methoxyestradiol (2ME2), on AT1R expression. Rat liver cells were exposed to 2ME2 for 24 h and angiotensin II (AngII) binding and AT1R mRNA expressions were assessed. In the presence of 2ME2, cells exhibited significant down-regulation of AngII binding in a dose and time dependent manner, independent of estrogen receptors (ERα/ERβ). Down-regulation of AngII binding was AT1R specific with no change in receptor affinity. Under similar conditions, we observed lower expression of AT1R mRNA, significant inhibition of AngII mediated increase in intracellular Ca2+, and increased phosphorylation of ERK1/2. Pretreatment of cells with the MEK inhibitor PD98059 prevented 2ME2 induced ERK1/2 phosphorylation and down-regulation of AT1R expression, suggesting that the observed inhibitory effect is mediated through ERK1/2 signaling intermediate(s). Similar analyses in stably transfected CHO cell lines with a constitutively active cytomegalovirus (CMV) promoter showed no change in AT1R expression suggesting that 2ME2 mediated effects are through transcriptional regulation. The effect of 2ME2 on AT1R down-regulation through ERK1/2 were consistently reproduced in primary rat aortic smooth muscle cells. As AT1R plays a critical role in the control of cardiovascular diseases, 2ME2-induced changes in receptor expression may provide beneficial effects to the cardiovascular as well as other systems.
doi:10.1016/j.genm.2012.01.008
PMCID: PMC3322289  PMID: 22366193
Cardiovascular disease; 2-methoxyestradiol (2ME2); hypertension; MAP- kinase
16.  The vasodilatory effect of testosterone on renal afferent arterioles 
Gender Medicine  2012;9(2):103-111.
Background
Gender differences exist in a variety of cardiovascular and renal diseases, and testosterone may contribute to the discrepancy. Afferent arterioles (Af-Art) are the major resistance vessels in the kidney, and play an important role in the development of renal injury and hypertension.
Objective
The present study aimed to determine the acute effect and underlying mechanism(s) of testosterone on Af-Art.
Methods
The mRNA expression of androgen receptors (AR) in microdissected Af-Art was measured by RT-PCR. An in vitro microperfusion model was used to measure the diameter of Ar-Art in mice. Nitric oxide (NO) was evaluated by an NO-sensitive fluorescent dye, 4-amino-5-methylamino-2′,7′-difluorofluorescein (DAF-FM) diacetate.
Results
Testosterone had no effect on microperfused Af-Art when added into the bath. Therefore we pre-constricted the Af-Art to about 30% with norepinephrine (NE, 10−6mol/L); administration of testosterone (10−9 to 10−7mol/L) subsequently dilated the Af-Art in a dose-dependent manner (p<0.001; n=7). AR mRNA was expressed in microdissected Af-Art measured by RT-PCR. An AR antagonist, flutamide (10−5mol/L), totally blocked testosterone (10−8mol/L)-induced vasodilator effect. NO production of Af-Art wall was increased when testosterone was added into the bath solution after NE treatment, from 278.4 ± 12.1 units/min to 351.2 ± 33.1 units/min (p<0.05; n=3). In the presence of NO inhibition with NG-nitro-L-arginine methyl ester (L-NAME, 3×10−4mol/L), the testosterone-induced dilatation was blunted compared with NE (p<0.05).
Conclusions
We conclude that testosterone dilates pre-constricted mouse Af-Art in a dose-dependent manner by activation of AR and partially mediated by NO.
doi:10.1016/j.genm.2012.02.003
PMCID: PMC3322301  PMID: 22445695
kidney; testosterone; androgen receptors; nitric oxide
17.  Baroreflex function in females: changes with the reproductive cycle and pregnancy 
Gender Medicine  2012;9(2):61-67.
This review briefly describes the changes in baroreflex function that occur during female reproductive life, specifically during the reproductive cycle and pregnancy. The sensitivity or gain of baroreflex control of heart rate and sympathetic activity fluctuates during the reproductive cycle, reaching a peak when gonadal hormones rise, during the follicular phase in women and proestrus in rats. The increase in baroreflex sensitivity (BRS) is likely mediated by estrogen, because ovariectomy in rats eliminates the BRS increase, the cyclic profile of changes in BRS mirror the changes in estrogen, and estrogen acts in the brainstem to increase BRS. Pregnancy, on the other hand, depresses both BRS and the maximal level of sympathetic activity and heart rate evoked by severe hypotension. The decrease in BRS may be mediated by a reduction in the actions of insulin in the arcuate nucleus to support the baroreflex. In addition, increased levels of the neurosteroid progesterone metabolite, 3α-OH-DHP, act downstream in the rostral ventrolateral medulla to suppress maximal baroreflex increases in sympathetic activity. Consequently, these changes in baroreflex function impair blood pressure regulation in the face of hypotensive challenges like orthostasis and hemorrhage, a common event during delivery. As a result, peripartum hemorrhage is a major cause of human maternal mortality.
doi:10.1016/j.genm.2012.02.004
PMCID: PMC3350105  PMID: 22483197
18.  Y Chromosome gene expression in the blood of male ischemic stroke patients compared to male controls 
Gender medicine  2012;9(2):68-75.e3.
Background and Purpose
Gender is suggested to be an important determinant of ischemic stroke risk factors, etiology and outcome. However, the basis for this remains unclear. The Y chromosome is unique in males. Genes expressed in men on the Y chromosome that are associated with stroke may be important genetic contributors to the unique features of males with ischemic stroke, which would be helpful for explaining sex differences observed between men and women.
Methods
Blood samples were obtained from 40 males at ≤ 3, 5 and 24 hours following ischemic stroke and from 41 male controls (July 2003- April 2007). RNA was isolated from blood and processed on Affymetrix Human U133 Plus 2.0 Arrays. Y chromosome genes differentially expressed between male stroke and male control subjects were identified using an analysis of covariance (ANCOVA) adjusted for age and batch. A p<0.05 and fold change (FC) > ∣1.2∣ were considered significant.
Results
Seven genes on the Y chromosome were differentially expressed in males with ischemic strokes compared to controls. Five of these genes (VAMP7, CSF2RA, SPRY3, DHRSX, PLCXD1,) are located on pseudoautosomal regions (PARs) of the human Y chromosome. The other two genes (EIF1AY and DDX3Y) are located on the non-recombining region of the human Y chromosome (NRY). The identified genes were associated with immunology, RNA metabolism, vesicle fusion and angiogenesis.
Conclusions
Specific genes on the Y chromosome are differentially expressed in blood following ischemic stroke. These genes provide insight into potential molecular contributors to sex differences in ischemic stroke.
doi:10.1016/j.genm.2012.01.005
PMCID: PMC3454519  PMID: 22365286
gene expression; ischemic stroke; gender; blood; Y chromosome
20.  Optical Technologies and Molecular Imaging for Cervical Neoplasia: A Program Project Update 
Gender Medicine  2011;9(1 Suppl):S7-S24.
There is an urgent global need for effective and affordable approaches to cervical cancer screening and diagnosis. For developing nations, cervical malignancies remain the leading cause of cancer death in women. This reality is difficult to accept given that these deaths are largely preventable; where cervical screening programs are implemented, cervical cancer deaths decrease dramatically. In the developed world, the challenges with respect to cervical disease stem from high costs and over-treatment. We are presently eleven years into a National Cancer Institute-funded Program Project (P01 CA82710) that is evaluating optical technologies for their applicability to the cervical cancer problem. Our mandate is to create new tools for disease detection and diagnosis that are inexpensive, require minimal expertise to use, are more accurate than existing modalities, and will be feasibly implemented in a variety of clinical settings. Herein, we update the status of this work and explain the long-term goals of this project.
doi:10.1016/j.genm.2011.08.002
PMCID: PMC3289763  PMID: 21944317
21.  Physician attitudes toward dissemination of optical spectroscopy devices for cervical cancer control: An Industrial-Academic collaborative study 
Gender Medicine  2012;9(1 Suppl):S67-S77.e6.
Introduction
Optical Spectroscopy has been studied for biologic plausisbility, technical efficacy, clinical effectiveness, patient satisfaction and cost-effectiveness. We sought to identify healthcare provider attitudes or practices that might act as barriers or to the dissemination of this new technology.
Methods
Through an academic-industrial partnership, we conducted a series of focus groups to examine physician barriers to optical diagnosis. The study was conducted in two stages. First, a pilot group of ten physicians (8 obstetrician gynecologists and two family practitioners) was randomly selected from 8 regions of the US and interviewed individually. They were presented with the results of a large trial (N=980) testing the accuracy of a spectroscopy based device in the detection of cervical neoplasia. They were also shown a prototype of the device and were given a period of time to ask questions and receive answers regarding the device. They were also asked to provide feedback of a questionnaire (provided in Appendix A) which was then revised and presented to three larger focus groups (n=13, 15, 17 for a total n=45). The larger focus groups were conducted during national scientific meetings with 20 obstetrician gynecologists and 25 primary care physicians (family practitioners and internists).
Results
When asked about the dissemination potential of the new cervical screening technology, all study groups tended to rely on established clinical guidelines from their respective professional societies with regard to the screening and diagnosis of cervical cancer. In addition, study participants consistently agreed that real-time spectroscopy would be viewed positively by their patients. Participants were positive about the new technology's potential as an adjunct to colposcopy and agreed that the improved accuracy would result in reduced healthcare costs (due to decreased biopsies and decreased visits). However, while all saw the potential of real-time diagnosis, there were many perceived barriers. These barriers included: changes in scheduling and work-flow, liability, documentation, ease of use, length of training, device cost, and reimbursement by third party payers.
Conclusion
Barriers exist to the dissemination of optical technologies into physician practice. These will need to be addressed before cervical screening and diagnosis programs can take advantage of spectroscopy-based instruments for cancer control.
doi:10.1016/j.genm.2011.11.004
PMCID: PMC3292768  PMID: 22340642
physician attitude; physician satisfaction; dissemination; cervical intraepithelial neoplasia; fluorescence and reflectance spectroscopy; optical spectroscopy
22.  Sex Differences in Parietal Lobe Structure and Development 
Gender Medicine  2012;9(1):44-55.
Structural MRI studies provide evidence for sex differences in the human brain. Differences in surface area and the proportion of gray to white matter volume are observed, particularly in the parietal lobe. To our knowledge, there are no studies examining sex differences of parietal lobe structure in younger populations or in the context of development. The current study evaluated sex difference in the structure of the parietal lobe in children (7-17 years of age). Also, by adding the cohort of previously studied adults (18-50 years of age), sex differences of parietal lobe morphology were examined across the age span of 7-50 years. In the youth sample, we found that, similar to adults, the ratio of parietal lobe cortex to white matter was greater in females. Unlike the adult sample, there were no sex differences in surface area. When examining effects of age, surface area had a significant sex-by-age interaction. Males had essentially no decrease in surfaces area over time, but females had a significant decrease in surface area over time. These findings support the notion of structural sex differences in the parietal lobe, not only in the context of cross sectional assessment, but also in terms of differences of developmental trajectories.
doi:10.1016/j.genm.2012.01.003
PMCID: PMC3326392  PMID: 22333522
development; parietal lobe; sex differences; surface area
23.  Evidence that the G-Protein Coupled Membrane Receptor GPR30 Contributes to the Cardiovascular Actions of Estrogen 
Gender medicine  2011;8(6):343-354.
While female protection from cardiovascular diseases declines with the fall in circulating sex hormones experienced during menopause, clinical trials in older women fail to demonstrate beneficial effects for hormone replacement therapy. The recent discovery of GPR30, a membrane-bound estrogen receptor which is structurally and functionally unique from the steroid receptors ERα and ERβ, has unveiled additional signaling pathways by which estrogen may influence cardiovascular health. This review takes an organ-based approach to assess the expression and function of GPR30 in the cardiovascular system. We conclude that while the current literature indeed suggests a cardiovascular role for GPR30, additional exploration is necessary to fully elucidate the estrogenic actions mediated by this novel receptor.
doi:10.1016/j.genm.2011.10.004
PMCID: PMC3240864  PMID: 22153880
GPR30; estrogen receptors; cardiovascular; blood pressure; renin-angiotensin-aldosterone system
24.  Are male neonates more vulnerable to neonatal abstinence syndrome than female neonates? 
Gender medicine  2011;8(6):355-364.
Objective
Prior studies have shown an increased vulnerability among males, to adverse outcomes during the postnatal period. The majority of children exposed to opioids and other medication in utero develop a neonatal abstinence syndrome (NAS), yet individual predisposition for NAS is poorly understood. This investigation examines the role of neonatal sex in the postnatal period, for neonates exposed to standardized opioid maintenance treatment in utero with a focus on the neonatal abstinence syndrome (NAS) regarding severity, medication requirements and duration.
Patients and Methods
This is a secondary analysis of data collected in a prospective randomized, double-blind, double-dummy multi-center trial examining the comparative safety and efficacy of methadone and buprenorphine during pregnancy (Maternal Opioid Treatment: Human Experimental research MOTHER – study). 131 neonates born to opioid-dependent women randomized at six US sites (n=74) and one European site (n=37) were analyzed. Sex-based differences in birth weight, length, head circumference, NAS duration, NAS severity, and treatment parameters of full-term neonates were assessed.
Results
Males had a significantly higher birth weight (p=0.027) and head circumference (p=0.017) than females, with no significant sex difference in rates of preterm delivery. No significant sex-related differences were found for NAS development, severity, duration, or medication administered with non significant differences in concomitant drug consumption during pregnancy (p =0.959).
Conclusions
This unique prospective study shows similar postnatal vulnerability for both sexes, suggesting that factors other than sex are the major determinants of clinically significant NAS.
doi:10.1016/j.genm.2011.10.001
PMCID: PMC3241965  PMID: 22088886
opioid dependence; methadone; buprenorphine; pregnancy; neonatal abstinence syndrome; sex differences
25.  Relationship Between Resting Blood Pressure and Laboratory-Induced Pain Among Healthy Children 
Gender Medicine  2011;8(6):388-398.
Background
Adult studies have demonstrated that increased resting blood pressure (BP) levels correlate with decreased pain sensitivity. However, few studies have examined the relationship between BP and experimental pain sensitivity among children.
Objectives
This study investigated the association between resting BP levels and experimental pain tolerance, intensity, and unpleasantness in healthy children. We also explored whether these BP–pain relationships were age and gender dependent.
Methods
Participants underwent separate 4-trial blocks of cutaneous pressure and thermal pain stimuli, and 1 trial of a cold pain stimulus in counterbalanced order.
Results
A total of 235 healthy children (49.6% female; mean age 12.7 [2.9] years; age range 8–18 years) participated. The study revealed specific gender-based BP–pain relationships. Girls with higher resting systolic BP levels were found to have lower thermal intensity ratings than girls with lower resting systolic BP levels; this relationship was stronger among adolescent girls than among younger girls. Among young girls (8–11 years), those with higher resting diastolic BP (DBP) levels were found to have lower cold intensity and unpleasantness as well as lower thermal intensity ratings than did young girls with lower resting DBP levels; these DBP–pain response relationships were not seen among adolescent girls.
Conclusions
Age, rather than resting BP, was predictive of laboratory pain ratings in boys. The findings suggest that the relationship between BP and experimental pain is age and gender dependent. These aspects of cardiovascular relationships to pain in males and females need further attention to understand their clinical importance.
doi:10.1016/j.genm.2011.07.002
PMCID: PMC3319441  PMID: 22035675
blood pressure; children; gender differences; laboratory pain

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