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.
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.
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).
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.
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.
physician attitude; physician satisfaction; dissemination; cervical intraepithelial neoplasia; fluorescence and reflectance spectroscopy; optical spectroscopy
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.
development; parietal lobe; sex differences; surface area
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.
GPR30; estrogen receptors; cardiovascular; blood pressure; renin-angiotensin-aldosterone system
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.
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).
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.
opioid dependence; methadone; buprenorphine; pregnancy; neonatal abstinence syndrome; sex differences
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.
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.
Participants underwent separate 4-trial blocks of cutaneous pressure and thermal pain stimuli, and 1 trial of a cold pain stimulus in counterbalanced order.
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.
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.
blood pressure; children; gender differences; laboratory pain
Research in adult populations has highlighted sex differences in cortisol concentrations and laboratory pain responses, with men exhibiting higher cortisol concentrations and reduced pain responses compared with women. Yet, less is known about the relationship of cortisol concentrations to pain in children.
This study examined associations between sex, cortisol, and pain responses to laboratory pain tasks in children.
Salivary cortisol samples from subjects aged 8 to 18 years were obtained at baseline after entering the laboratory (SCb), after the completion of all pain tasks (SC1), and at the end of the session (SC2), 20 minutes later. Blood cortisol samples were also taken after completion of the pain tasks (BC1) and at the end of the session (BC2), 20 minutes later. Subjects completed 3 counterbalanced laboratory pain tasks: pressure, heat, and cold pressor tasks. Pain measures included pain tolerance, and self-reported pain intensity and unpleasantness for all 3 tasks.
The study included 235 healthy children and adolescents (119 boys, 116 girls; mean age, 12.7 years; range, 8–18 years; 109 [46.4%] were in early puberty; 94 [40.0%] white). Salivary and blood cortisol levels were highly correlated with each other. Salivary cortisol levels for the total sample and for boys and girls declined significantly from SCb to SC1 (P < 0.01), although there were no significant changes from SC1 to SC2. No significant sex differences in salivary or blood cortisol levels were evident at any assessment point. Separate examination of the cortisol–laboratory pain response relationships by sex (controlling for age and time of day) suggested different sex-specific patterns. Higher cortisol levels were associated with lower pain reactivity (ie, increased pressure tolerance) among boys compared with girls at SC1, SC2, and BC1 (SC1: r = 0.338, P = 0.003; SC2: r = 0.271, P = 0.020; and BC1: r = 0.261, P = 0.026). However, higher cortisol levels were related to higher pain response (ie, increased cold intensity [BC2: r = 0.229, P = 0.048] and unpleasantness [BC1: r = 0.237, P = 0.041]) in girls compared with boys.
These findings suggest important sex differences in cortisol–pain relationships in children and adolescents. Cortisol levels were positively associated with increased pain tolerance in boys and increased pain sensitivity in girls.
pain; children; cortisol; sex differences
Clinical investigations designed to determine risk profiles for the development of cardiovascular disease (CVD) and type 2 diabetes mellitus (DM) are usually performed in homogenous populations and often focus on body mass index (BMI), waist circumference (WC), and fasting triglyceride (TG) levels. However, there are major ethnic differences in the relationship of these risk factors to outcomes. For example, the BMI risk threshold may be higher in blacks than in whites and higher in women than in men. Furthermore, a WC that predicts an obese BMI in white women only predicts a BMI in the overweight category in black women. In addition, overweight black men have a greater risk of developing type 2 DM than do overweight black women. Although TG levels are excellent predictors of insulin resistance in whites, they are not effective markers of insulin resistance in blacks. Among the criteria sets currently available to predict the development of CVD and type 2 DM, the most well known is the metabolic syndrome. The metabolic syndrome has 5 criteria: central obesity, hypertriglyceridemia, low high-density lipoprotein (HDL) levels, fasting hyperglycemia, and hypertension. To make the diagnosis of the metabolic syndrome, 3 of the 5 factors must be present. For central obesity and low HDL, the metabolic syndrome guidelines are sex specific. Diagnostic guidelines should also take ethnic differences into account, particularly in the diagnosis of central obesity and hypertriglyceridemia.
Obesity and associated metabolic and cardiovascular disease risk are correlated with reduced circulating adiponectin (APN) levels. Metabolic and cardiovascular disease risk is also increased following menopause and may be linked to disturbances in estrogen receptor (ER) signaling in adipose. We hypothesized that age-associated estrogen (E2)-deficiency alters the ERα/β ratio in adipose tissue and increases risk for metabolic disease via APN-dependant mechanisms. Visceral adipose was isolated from adult (6 mo) and aged (24 mo) female Fisher344 rats (n=5–6/group) with ovaries intact or removed (OVX) and subjected to western blotting. Notably, weight was greatest in aged OVX (p<0.01) and associated with a two-fold increase in ERβ protein vs adult intact rats (p<0.001). ERα levels were increased in aged OVX vs adult OVX. Intra-adipocyte APN was also increased in aged OVX vs all groups (p<0.01), while circulating APN levels decreased in aged OVX vs adult OVX (p<0.05). Endoplasmic reticulum protein of 44kDa (Erp44) levels remained the same (p=0.09). Adiponectin receptor (AdipoR)1 and peroxisome proliferator-activated receptor (PPAR)α were also unchanged. AdipoR2, PPARγ, and the activated AMP-dependant kinase (pAMPK)/total AMPK ratio all decreased with age (p<0.05). Collectively, these data suggest that age-associated increases in ERβ paired with decreased PPARγ levels may predispose E2-deficent post-menopausal women for increased adiposity, and associated metabolic and cardiovascular disease risk. Reduced circulating APN, and AdipoR2 levels may contribute to age and E2-deficiency linked disease progression.
estrogen receptor α; menopause; aging; metabolic syndrome; peroxisome proliferator-activated receptorγ
Background and Purpose
There are few population-based data regarding gender differences in signs and symptoms of acute ischemic stroke. Previously reported data have been inconsistent and conflicting. This study addresses these gender differences in a population-based study.
All patients with first ischemic stroke occurring in Rochester, MN residents during 1985-1989 were identified. Signs and symptoms were collected via review of the comprehensive medical records. Differences were identified by Pearson’s Chi-square test.
Symptoms at ischemic stroke presentation differed between men and women as follows: Women more commonly presented with generalized weakness (p=0.005) and mental status change (p=0.0001). Men more commonly presented with paresthesia (p=0.003), ataxia (p=0.006), and double vision (p =0.005). Signs at ischemic presentation of stroke differed between men and women as follows: Men more commonly presented with nystagmus (p=0.002) on exam. Significant trends were that women more commonly presented with fatigue (p=0.02), disorientation (p=0.04), and fever (p=0.02), and men more commonly presented with sensory abnormalities (p=0.02).
There are differences by gender in signs and symptoms at presentation of ischemic stroke. In addition to selected focal symptoms, women more commonly present with diffuse symptoms of generalized weakness, fatigue, disorientation, and mental status change.
gender; stroke; signs; symptoms; population-based study
The intrarenal renin–angiotensin system contributes to hypertension by regulating sodium and water reabsorption throughout the nephron. Sex differences in the intrarenal components of the renin–angiotensin system have been involved in the greater incidence of high blood pressure and progression to kidney damage in males than females.
This study investigated whether there is a sex difference in the intrarenal gene expression and urinary excretion of angiotensinogen (AGT) during angiotensin II (Ang II)–dependent hypertension and high-salt (HS) diet.
Male and female Sprague-Dawley rats were divided into 5 groups for each sex: Normal-salt control, HS diet (8% NaCl), Ang II–infused (80 ng/min), Ang II–infused plus HS diet, and Ang II–infused plus HS diet and treatment with the Ang II receptor blocker, candesartan (25 mg/L in the drinking water). Rats were evaluated for systolic blood pressure (SBP), kidney AGT mRNA expression, urinary AGT excretion, and proteinuria at different time points during a 14-day protocol.
Both male and female rats exhibited similar increases in urinary AGT, with increases in SBP during chronic Ang II infusion. HS diet greatly exacerbated the urinary AGT excretion in Ang II–infused rats; males had a 9-fold increase over Ang II alone and females had a 2.5-fold increase. Male rats displayed salt-sensitive SBP increases during Ang II infusion and HS diet, and female rats did not. In the kidney cortex, males displayed greater AGT gene expression than females during all treatments. During Ang II infusion, both sexes exhibited increases in AGT gene message compared with same-sex controls. In addition, HS diet combined with Ang II infusion exacerbated the proteinuria in both sexes. Concomitant Ang II receptor blocker treatment during Ang II infusion and HS diet decreased SBP and urinary AGT similarly in both sexes; however, the decrease in proteinuria was greater in the females.
During Ang II–dependent hypertension and HS diet, higher intrarenal renin-angiotensin system activation in males, as reflected by higher AGT gene expression and urinary excretion, indicates a mechanism for greater progression of high blood pressure and might explain the sex disparity in development of salt-sensitive hypertension.
angiotensinogen; intrarenal RAS; mRNA; proteinuria; sex differences; Sprague-Dawley rats; systolic blood pressure
It has been demonstrated that 46– 48% of individuals with bipolar disorder (BD) are at least partially non-adherent with prescribed medication. While some reports note male gender as a predictor of treatment non-adherence in BD, findings have been inconsistent. The construct of gender may also be a matter of cultural orientation, and psychological gender, as a component of self-perception may affect the experience of mental illness. Gender identity is the subjective experience of one’s individuality as male or female. This cross-sectional study evaluated gender and gender identity among men and women with BD as it relates to self-reported medication treatment adherence.
This secondary analysis of a larger study on treatment adherence evaluated 70 men and 70 women with bipolar disorder, being treated with mood stabilizing medications in a public mental health setting. Gender identity and adherence were evaluated with the Bem Sex Role Inventory (BSRI) and Tablets Routine Questionnaire (TRQ) respectively. Other measures included BD symptoms with the Hamilton Depression Rating Scale (HAM-D), and Young Mania Rating Scale (YMRS) as well as locus of control with the Multidimensional Health Locus of Control Scale (MHLC) and social support with the Interpersonal Support Evaluation List (ISEL).
Women with BD had mean scores on the BSRI consistent with general population norms while men with BD had scores suggesting lower levels of self-perceived masculinity than population norms. There were no differences between men and women on adherence, however men with high BSRI masculinity scores had less adherence compared to other men in the sample (p=.04). Lower scores on the “powerful others” dimension of locus of control was associated with lower adherence. For women there was no relationship between BSRI masculinity scores and adherence.
Gender identity in men with BD differs from general population norms and appears related to adherence. Treatment approaches that are intended to optimize adherence need to consider the construct of gender identity or gender role.
adherence; compliance; gender; gender identity; bipolar disorder; treatment attitudes
Previous investigations suggest that agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) may mediate a hypertensive response through dysregulation of the endothelin-1 system. AT1-AA induced hypertension is attenuated by AT1 receptor and/or Endothelin-1 type A receptor antagonists. This study was undertaken to determine if AT1-AA induced hypertension is associated with renal endothelial dysfunction.
We compared the vascular reactivity of renal interlobar arteries from normal pregnant control rats and AT1-AA chronically infused pregnant rats in the presence and absence of endothelin type A (ETA) receptor antagonism. Renal endothelial function was tested using isolated renal interlobar arteries in a pressure myograph that were exposed to acetylcholine or sodium ntiroprusside.
Vasodilatory responses to the endothelial dependent agonist acetylcholine were impaired in AT1-AA rats (74±10%) compared to NP controls (95±5%, p<0.05). In the presence of endothelin type A (ETA) receptor antagonism, no differences were observed between controls or the AT1-AA treated group in regard to endothelial dependent (acetylcholine) relaxation.
AT1-AA induced hypertension during pregnancy is associated with disparate renal endothelial responses to acetylcholine. The difference in renal vascular responses between AT1-AA and NP rats is abolished by ETA receptor blockade.
Hypertension; angiotensin; pregnancy; endothelial dysfunction
It has been well documented that cocaine and methamphetamine use can lead to the onset of psychotic symptoms similar to schizophrenia. However, the research and literature on gender differences and stimulant-induced psychosis have been mixed.
The primary aim of this study was to investigate gender differences in the reporting of psychotic symptoms in cocaine-versus methamphetamine-dependent individuals.
Participants were recruited from the Los Angeles, California, community via radio and newspaper advertisements. All met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for cocaine or methamphetamine dependence, and all reported either methamphetamine or cocaine as their primary drug of abuse. During a screening interview, participants answered questions from the Psychotic Symptom Assessment Scale, which characterizes various types of psychotic symptoms during drug use (“while high”) or during periods of nonuse (“while abstinent”).
Participants included 42 cocaine-dependent individuals (27 men, 15 women) and 43 methamphetamine-dependent individuals (25 men, 18 women). Among cocaine users, there were no significant differences between men and women with regard to ethnicity, years of use, route of administration, and amount used in the past week, though they differed significantly with regard to age (P = 0.029). In the “while abstinent” condition, women were significantly more likely than men to report experiencing auditory hallucinations (13% vs 0%, respectively; P = 0.050) and tactile hallucinations (20% vs 0%; P = 0.016), whereas men were more likely to report delusions of grandeur (48% vs 6%; P = 0.006). During the “while high” condition, women were significantly more likely than men to report delusions of grandeur (13% vs 0%, respectively; P = 0.050), tactile hallucinations (33% vs 0%; P = 0.001), and olfactory hallucinations (13% vs 0%; P = 0.050). Among methamphetamine users, there were no significant differences between men and women with regard to age, ethnicity, years of use, route of administration, or amount used in the past week. In the “while abstinent” condition, women were significantly more likely than men to report feeling that something was wrong with the way a part of their body looked (72% vs 32%, respectively; P = 0.009), olfactory hallucinations (39% vs 8%; P = 0.010) and dressing inappropriately (22% vs 0%; P = 0.010). During the “while high” condition, women were more likely than men to report delusions of grandeur (33% vs 16%, respectively; P = 0.030), paranoia (50% vs 16%; P = 0.017), and tactile hallucinations (61% vs 32%; P = 0.050).
The findings of the present study revealed that cocaine- and methamphetamine-dependent women were more likely than their male counterparts to report experiencing various psychotic symptoms. This information may be useful for clinicians and mental health professionals, who should take these symptoms into account as potential barriers that may impede effective treatment.
cocaine; methamphetamine; stimulant; psychosis; gender
Although the incidence of sepsis is higher in men than women, it is controversial whether there are gender differences in sepsis-associated mortality.
To test the hypothesis that hospital mortality is higher in men compared to women with severe sepsis or septic shock and requiring intensive care.
Retrospective cohort study of 18,757 intensive care unit (ICU) patients, including 8,702 women (46%), with severe sepsis or septic shock in the Cerner Project IMPACT database.
Hospital mortality was higher in women vs. men (35% vs. 33%, p = 0.006). After adjusting for differences in baseline characteristics and processes of care, women had a higher likelihood of hospital mortality than men (OR = 1.11, 95% CI = 1.04 – 1.19, p = 0.002). Women were less likely than men to receive deep venous thrombosis prophylaxis (OR = 0.90, 95% CI = 0.84 – 0.97), invasive mechanical ventilation (OR = 0.81, 95% CI = 0.76 – 0.86), and hemodialysis catheters (OR = 0.85, 95% CI = 0.78 – 0.93). Women were more likely than men to receive red blood cell transfusions (OR = 1.15, 95% CI = 1.09 – 1.22) and code status limitations (OR = 1.31, 95% CI = 1.18 – 1.47).
In this large cohort of ICU patients, women with severe sepsis or septic shock had a higher risk of dying in the hospital than men. This difference remained after multivariable adjustment. We also found significant gender disparities in some aspects of care delivery, but these did not explain the higher mortality in women.
gender; sex distribution; sepsis; infection; shock; critical care
An increase in gastrointestinal (GI) symptoms, including bowel discomfort, abdominal pain/discomfort, bloating, and alterations in bowel patterns, has been reported during premenses and menses menstrual cycle phases and the perimenopause period in women with and without irritable bowel syndrome (IBS).
This article reviews the literature related to one possible physiological mechanism—declining or low ovarian hormone levels—that may underlie the occurrence or exacerbations of abdominal pain/discomfort at times of low ovarian hormones (menses, menopause) in women with or without IBS.
To identify English-only review and data-based articles, PubMed was searched between January 1980 and September 2008 using the following terms: irritable bowel syndrome, functional gastrointestinal disorders, gastrointestinal motility, immune, pain, hyperalgesia, menstrual cycle, menopause, pregnancy, estrogen, estradiol (E2), and progesterone. Studies in animals and in humans were included; drug trials were excluded.
From our review of the literature, 18 papers were identified that were related either to the mechanisms accounting for menstrual cycle fluctuations (n = 12) or to the impact of menopausal status on symptoms of IBS (n = 6). One study reported that visceral pain sensitivity was significantly higher during menses than at other menstrual cycle phases in women with IBS (P < 0.05). Other menstrual cycle phase–linked symptoms, dysmenorrheal symptoms (cramping pain) in particular, were more intense in women with IBS. Animal studies have shed some light on the relationship of ovarian hormones to GI sensorimotor function.
The increase in GI symptoms around the time of menses and early menopause occurs at times of declining or low ovarian hormones, suggesting that estrogen and progesterone withdrawal may contribute either directly or indirectly. This review highlights the need for confirmatory preclinical and clinical studies to unravel the role of ovarian hormones in women with IBS.
irritable bowel syndrome; menstrual cycle; menopause; estrogen; progesterone; gastrointestinal symptoms; pregnancy; immune; pain
Sry is a transcription factor and our research group has shown that there are multiple copies of Sry in WKY and SHR rats and they have novel functions separate from testes determination. We hypothesized that exogenously delivered Sry3 to the normotensive WKY male kidney would activate the renin-angiotensin system (RAS) and raise blood pressure based on previous in vitro studies.
Sry3 or control vector was electroporated to the left kidney of male WKY rats and blood pressure measured by telemetry, renin angiotensin measures by RIA, plasma and tissue catecholamines by HPLC with electrochemical detection, Na by flame photometry and inulin by Elisa.
Sry3 raised BP 10–20 mmHg compared to controls (p<0.01) and produced a significant 40% decrease in urine sodium compared to controls (p<0.05). Sry3 increased renal angiotensin II (Ang II) and plasma renin activity by more than 100% when compared to controls (p<0.01, p<0.05, respectively).
the findings presented here confirm and extend the argument for Sry3 as one of the genes responsible for the SHR hypertensive Y chromosome phenotype and are consistent with an increased tissue renin-angiotensin system activity due to Sry3 and increased Na reabsorption.
renin-angiotensin; catecholamines; glomerular filtration; sodium reabsorption
Polycystic ovary syndrome (PCOS) is the most common reproductive dysfunction in premenopausal women. PCOS is also associated with increased risk of cardiovascular disease at the time of PCOS and later in life. Hypertension, a common finding in women with PCOS, is a leading risk factor for cardiovascular disease. The mechanisms responsible for hypertension in women with PCOS has not been elucidated.
To characterize the cardiovascular-renal consequences of hyperandrogenemia in a female rat model.
Female Sprague Dawley rats, aged 4–6 weeks, were implanted with DHT or placebo pellets lasting 90 days. Following 10–12 weeks, blood pressure (by radiotelemetry), renal function (glomerular filtration rate, morphology, protein and albumin excretion), metabolic parameters (plasma insulin, glucose, leptin, cholesterol, oral glucose tolerance test), inflammation (plasma TNF-α), oxidative stress (mRNA expression of NADPH oxidase subunits, p22phox, p47phox, gp91phox, and NOX4, nitrate/nitrite excretion), and mRNA expression of components of the renin-angiotensin system (RAS) (angiotensinogen, angiotensin-I-converting enzyme (ACE), AT1 receptor) were determined.
Plasma DHT was increased 3-fold in hyperandrogenemic female 1 rats, whereas plasma estradiol levels were not different compared to control females. HAF rats exhibited estrus cycle dysfunction. They also had increased food intake and body weight, increased visceral fat, glomerular filtration rate, renal injury, insulin resistance and metabolic dysfunction, oxidative stress, and increased expression of angiotensinogen and ACE and reduced AT1 receptor expression.
The HAF rat is a unique model that exhibits many of the characteristics of PCOS in women and is a useful model in order to study the mechanisms responsible for hypertension.
angiotensinogen; leptin; insulin resistance; cholesterol; oxidative stress
Inflammation contributes to metabolic and cardiovascular disease. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder that predominantly affects young women. Cardiovascular disease is a major cause of mortality in patients with SLE. We recently reported that a model of SLE (female NZBWF1 mice) develops characteristics of the metabolic syndrome. In the present study, we tested the hypothesis that high dietary fat during SLE accelerates the development of cardiovascular risk factors such as central obesity and vascular dysfunction. Twenty four week old female SLE mice (NZBWF1) were fed either control diet (SLE, 10% kcal) or high fat diet (SLE+HF, 45% kcal) for a total of 14 weeks. Body weight was similar between SLE (42±1g, n=5) and SLE+HF (45±2g, n=6) and weight gain was not different in the SLE+HF mice (+18.0±3.0%) compared with controls (+15.8±3.6%) and food intake was not different (SLE, 2.2±0.3 vs. SLE+HF, 2.1±0.2 g/24 hours). Fifty seven percent of the SLE+HF mice exhibited signs of albuminuria (>100 mg/dL) compared with only 20% of the control SLE mice at the end of the experiment. Endothelial dependent relaxation in isolated carotid arteries was impaired in the SLE+HF group compared to SLE. Ovarian fat was increased in SLE+HF mice (6.6±0.5g) when compared to control SLE (5.4±0.1g, p<0.05) and liver weight was decreased in SLE+HF (1.6±0.1g) mice compared to control mice (1.9±0.1g, p<0.03). These data suggest that dietary fat accelerates renal injury and peripheral vascular dysfunction and promotes visceral obesity in a disease model with chronic inflammation.
Lupus; Endothelial; Adipose
Previous studies on blood pressure (BP) indices as predictor of coronary heart disease (CHD) have provided equivocal results and generally relied upon Cox Proportional Hazards regression methodology with age and gender accounting for most of the predictive capability of the model.
The aim of the present study was to use serially-collected BP measurements to examine age- and gender-related differences in BP indices for predicting CHD.
We investigated the predictive accuracy of time-dependent BP indices for CHD using a method of risk prediction based on posterior probabilities calculated from mixed-effects regression to utilize intra-individual differences in serial BP measurements according to age changes within gender groups. Data were collected prospectively from two community-dwelling cohort studies in the U.S. and Europe, with a total of 152,633 participants (ages 30 to 74) and 610,061 BP measurements.
During mean follow-up of 7.5 years, 2,457 non-fatal and fatal CHD events were observed. In both study populations, pulse pressure (PP) and systolic blood pressure (SBP) performed best as individual predictors of CHD in females [areas under the receiver operating characteristic curves (AUC) between 0.83 and 0.85 for PP, and 0.77 and 0.81 for SBP]. Mean arterial pressure (MAP) and diastolic blood pressure (DBP) performed better for males than for females. The degree of discrimination was overall greater but more varied over all BP indices for females than males in both populations.
Our findings indicate differences in discrimination between men and women in the accuracy of longitudinally collected BP measurements for predicting CHD, implicating the usefulness of gender-specific BP indices to assess individual CHD risk.
blood pressure indices; coronary heart disease; epidemiology; gender; prospective study; random effects models
Estrogens; hyperglycemia; dyslipidemia; obesity; hypertension; sex hormones; heart
Across all ages, the incidence and rate of progression of most nondiabetic renal diseases are markedly higher in men compared with age-matched women. These observations suggest that female sex may be renoprotective. In the setting of diabetes, however, this female protection against the development and progression of renal disease is diminished.
This review aimed to summarize our current understanding of sex differences in the development and progression of diabetic renal disease, and of the contribution of sex hormones, particularly estrogens, to the pathophysiology of this disease. We also attempted to answer why female sex does not protect the diabetic kidney.
The review employed PubMed as a search database using terms such as gender, sex, diabetes, diabetic nephropathy, estrogens, sex hormones, as well as targeted searches such as gender/sex differences in diabetic renal disease. Manuscripts identified from cited references were also used. Searches were restricted to English-language articles, while no restrictions were imposed on the publication dates.
Although the existing data regarding the sex differences in the incidence and progression of diabetic renal disease are inconclusive, the undisputed fact is that women with either type 1 or type 2 diabetes mellitus exhibit a much higher incidence of renal disease compared with nondiabetic women. It is conceivable that the loss of female sex as a renoprotective factor in diabetes may be related to the abnormal regulation of sex hormone concentrations. Both clinical and experimental data suggest that diabetes may be associated with an imbalance in estradiol concentrations. Supplementation with 17β-estradiol or administration of selective estrogen receptor modulators reduces the incidence of diabetes and attenuates the progression of diabetic renal disease.
Serum concentrations of ovarian hormones may provide a new means for predicting future risk of renal complications in diabetes. Exogenous steroid hormones may be an effective treatment for attenuating the progression of diabetic nephropathy.
estrogen; diabetes; diabetic nephropathy; sex hormones
The incidence of chronic renal disease in women increases with aging especially after menopause suggesting that the loss of sex hormones contributes to the development and progression of renal disease. However, the mechanisms by which sex hormones, estrogens in particular, contribute to the disease process are unclear.
The present study examined the effects of ovariectomy (OVX) with or without 17β-estadiol (E2) supplementation (OVX+E2) on the expression of inducible (iNOS) and endothelial (eNOS) nitric oxide synthase in the kidney.
The study was performed in young (4 months, 4M) and aged (12 months, 12M) Dahl salt sensitive (DSS) rats fed a low salt (0.1% NaCl) diet.
OVX in the aged rats was associated with 35% and 25% decreases, respectively, in medullary iNOS (4M OVX, 1.81±0.14 vs. 12M OVX, 1.17±0.16, P<0.05) and eNOS (4M OVX, 1.91±0.09 vs. 12M OVX, 1.43±0.15, P<0.05) protein expression and a 25-fold increase in the abundance of CD68-positive cells indicating macrophage infiltration (4M OVX, 1.18±0.09 vs. 12M OVX, 30.0±0.74, P<0.001). E2 supplementation either partially or completely attenuated these changes in iNOS (4M OVX+E2, 2.26±0.08 vs. 12M OVX+E2, 1.70±0.09, P<0.05), eNOS (4M OVX+E2, 2.03±0.07 vs 12M OVX+E2, 1.77±0.11) and CD68 (4M OVX+E2, 1.46±0.07 vs. 12M OVX+E2, 6.87±1.6, P<0.01) associated with OVX in the aging kidney.
These data suggest that ovarian E2 loss with aging may contribute to the development of age-related renal disease through downregulation of iNOS and eNOS protein abundance and increased renal inflammation. Furthermore, E2 supplementation may be protective in the aging kidney by attenuating these changes.
kidney; aging; estradiol; hypertension; nitric oxide; nitric oxide synthase
Among adults, asthma predominates in women. Only recently have sex and gender role influences on asthma been studied and only one study has focused on asthma management by women with the condition. That investigation showed that one year subsequent to an intervention addressing sex and gender role factors, women's asthma status improved. This paper presents data from the two year follow-up to determine if there were longer term effects of the intervention on the quality of life and asthma status of the participants.
A randomized controlled design was used with 808 female patients with asthma assigned to a control group or a female-oriented intervention that focused on particular management challenges related to sex and gender role factors. Data were collected at baseline and two years post intervention by telephone interview and review of medical records. Measures included asthma related quality of life (QoL), health care and medicine use for asthma, level of self regulation, confidence to manage the condition, sex and gender role related asthma problems, and days of missed work or school because of asthma. Data were analyzed using both GEE logistic and log linear regression.
Despite randomization, intervention group women had more persistent asthma at baseline. At two years, no significant health care use differences were evident. However, intervention women had significantly greater decrease of asthma symptoms with sexual activities (p=0.01) and greater annual reduction in days missed work for asthma in winter months (p=0.03) were bothered significantly less by asthma symptoms during sexual activity (p=0.01), missed fewer days of work for asthma in the winter months (p=0.03), had grater important in regulating (p=.0.01) confident to manage asthma (p=0.01), and had higher levels of asthma related QoL (p=0.02). They also had greater reduction in administrations of short term beta agonists (p=0.05) i.e. rescue medicines.
An intervention focused on female-specific aspects of asthma management can result in improved health status and QoL for women with asthma evident two years post intervention.
Asthma; Women; Gender; Telephone Counseling
Steroid hormones, such as progesterone, are known to have immunomodulatory effects. Our research group previously reported direct effects of progesterone on dendritic cells (DCs) from female rodents. Primarily affecting mature DC function, progesterone effects included inhibition of proinflammatory cytokine secretion, downregulation of cell surface marker (major histocompatibility complex class II, CD80) expression, and decreased T-cell proliferative capacity, and were likely mediated through progesterone receptor (PR) because the PR antagonist RU486 reversed these effects.
The goal of this study was to assess differences in response to progesterone by DCs from female and male rodents.
Using real-time reverse-transcriptase polymerase chain reaction, transcriptional expression of steroid hormone receptors was measured in immature bone marrow-derived DCs (BMDCs) from male and female rats. Expression of steroid hormone receptor protein was also assessed in these cells using flow cytometry and fluorescence microscopy. To evaluate functional differences between BMDCs from female and male rats in response to the steroid hormone progesterone, levels of secreted cytokines were measured using enzyme-linked immunosorbent assay.
Higher numbers of immature BMDCs from males expressed glucocorticoid receptor (GR) and androgen receptor (AR) proteins compared with females (males vs females, mean [SD]: GR = 68.75 [7.27] vs 43.61 [13.97], P = NS; AR = 75.99 [15.38] vs 8.25 [1.88], P = 0.002), whereas higher numbers of immature BMDCs from females expressed PR protein compared with males (females vs males: PR = 74.19 [12.11] vs 14.14 [4.55], P = 0.043). These differences were not found at the level of transcription (females vs males: GR = 0.088 vs 0.073, P = NS; AR = 0.076 vs 0.069, P = NS; PR = 0.075 vs 0.065, P = NS). Compared with those from females, mature BMDCs from males produced higher quantities of cytokines (tumor necrosis factor-α [TNF-α], interleukin [IL]-1β, IL-10) (females vs males: TNF-α = 920.0 [79.25] vs 1100.61 [107.97], P = NS; IL-1β = 146.60 [38.04] vs 191.10 [10.47], P = NS; IL-10 = 167.25 [4.50] vs 206.15 [23.48], P = NS). Conversely, BMDCs from females were more sensitive to progesterone, as indicated by a more dramatic reduction in proinflammatory cytokine secretion (females vs males, highest concentration of progesterone: TNF-α = 268.94 [28.59] vs 589.91 [100.98], P = 0.04; IL-1β = 119.50 [10.32] vs 154.35 [6.22], P = NS).
These findings suggest that progesterone effects on DCs in rodents may be more pronounced in females than in males, and this is likely due to differences in PR protein expression. Our observations may help elucidate disparities in the incidence and severity of autoimmune disorders between females and males, and the role specific steroid hormones play in regulating immune responses.
steroid hormone receptors; immunomodulation; cytokines; gender differences