Gender Medicine: The Journal for the Study of Sex & Gender Differences

Baroreflex Function in Females: Changes With the Reproductive Cycle and Pregnancy

Virginia L. Brooks, Priscila A. Cassaglia, Ding Zhao, Robert K. Goldman — 2012-04-01

Abstract: 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 hormone levels increase, 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. In contrast, pregnancy 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 presence of hypotensive challenges such as orthostasis and hemorrhage, a common event during delivery. As a result, peripartum hemorrhage is a major cause of human maternal death.

Y Chromosome Gene Expression in the Blood of Male Patients With Ischemic Stroke Compared With Male Controls

2012-02-27

Abstract: Background: Sex 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 males 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. Objective: We compared Y chromosome gene expression in males with ischemic stroke and male controls. Methods: Blood samples were obtained from 40 male patients ≤3, 5, and 24 hours after ischemic stroke and from 41 male controls (July 2003–April 2007). RNA was isolated from blood and was processed using Affymetrix Human U133 Plus 2.0 expression arrays (Affymetrix Inc., Santa Clara, California). Y chromosome genes differentially expressed between male patients with stroke and male control subjects were identified using an ANCOVA adjusted for age and batch. A P < 0.05 and a fold change >1.2 were considered significant. Results: Seven genes on the Y chromosome were differentially expressed in males with ischemic stroke compared with controls. Five of these genes (VAMP7, CSF2RA, SPRY3, DHRSX, and PLCXD1) are located on pseudoautosomal regions of the human Y chromosome. The other 2 genes (EIF1AY and DDX3Y) are located on the nonrecombining region of the human Y chromosome. 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 after ischemic stroke. These genes provide insight into potential molecular contributors to sex differences in ischemic stroke.

Pharmacologic Effects of 2-Methoxyestradiol on Angiotensin Type 1 Receptor Down-Regulation in Rat Liver Epithelial and Aortic Smooth Muscle Cells

Sivaramakrishna Koganti, Russell Snyder, Thomas Thekkumkara — 2012-02-27

Abstract: Background: Delayed onset of cardiovascular disease (CVD) in female patients is not well understood, but could be due in part 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. Objective: We examined the effects of the estrogen metabolite 2-methoxyestradiol (2ME2) on AT1R expression. Methods: Rat liver cells were exposed to 2ME2 for 24 hours, and angiotensin II (AngII) binding and AT1R mRNA expressions were assessed. Results: In the presence of 2ME2, cells exhibited significant down-regulation of AngII binding that was both dose and time dependent, 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, which suggests that the observed inhibitory effect is mediated through ERK1/2 signaling intermediates. Similar analyses in stably transfected CHO (Chinese hamster ovary) cell lines with a constitutively active cytomegalovirus promoter showed no change in AT1R expression, which suggests that 2ME2-mediated effects are through transcriptional regulation. The effects of 2ME2 on AT1R down-regulation through ERK1/2 were consistently reproduced in primary rat aortic smooth muscle cells. Conclusions: Because AT1R has a critical role in the control of CVD, 2ME2-induced changes in receptor expression may provide beneficial effects to the cardiovascular and other systems.

Effect of Gender on Awareness of Cardiovascular Risk Factors, Preventive Action Taken, and Barriers to Cardiovascular Health in a Group of Austrian Subjects

2012-03-23

Abstract: Background: The incidence of cardiovascular disease (CVD) is increasing in industrialized countries. Preventive action is an important factor in minimizing CVD-associated morbidity and mortality. However, it is not known whether gender differences affect CVD or risk factor awareness influencing self-assessment of personal risk and preventive action. Objective: This study was performed to assess individual CVD and risk factor awareness, preventive action taken, and barriers to cardiovascular health. Methods: The study included 573 women and 336 men, randomly chosen to complete an anonymous questionnaire to assess individual CVD and risk factor awareness, preventive action taken, and barriers to cardiovascular health. The data were analyzed using SAS software. Results: Cardiovascular disease was identified in 75% of patients, in both sexes, as the leading cause of death; however, both groups showed significant lack of knowledge about CVD risk factors. Type 2 diabetes was identified correctly in only 27.5%. Preventive action was linked more often to family members in 66.5% of women and 62.8% of men. The primary barrier to cardiovascular health in adults was incorrect assessment of personal CVD risk. More than half of female respondents (56.4%) and male respondents (52.7%) underestimated their risk of CVD. Conclusion: Knowledge about risk factors for CVD needs to be improved in members of both sexes. Because women, in particular, have difficulty in correctly assessing their personal CVD risk, future education programs are warranted to inform both women and men about CVD and its risk factors, thereby helping them to correctly assess their individual risk. However, greater effort is needed to inform men, compared with women, about the various ways in which to prevent CVD and to motivate them to take preventive action.

The Vasodilatory Effect of Testosterone on Renal Afferent Arterioles

Yan Lu, Yiling Fu, Ying Ge, Luis A. Juncos, Jane F. Reckelhoff, Ruisheng Liu — 2012-03-26

Abstract: Background: Sex differences exist in a variety of cardiovascular and renal diseases, and testosterone may contribute to the discrepancy. Afferent arterioles (Af-Arts) are the major resistance vessels in the kidney, and they play an important role in the development of renal injury and hypertension. Objective: We sought to determine the acute effect and underlying mechanism(s) of action of testosterone on Af-Arts. Methods: The mRNA expression of androgen receptors (ARs) in microdissected Af-Arts was measured by reverse transcription–polymerase chain reaction (RT-PCR). An in vitro microperfusion model was used to measure the diameter of Af-Arts in mice. Nitric oxide (NO) was evaluated by an NO-sensitive fluorescent dye, 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate. Results: Testosterone had no effect on microperfused Af-Arts when added to the bath. Therefore, we preconstricted the Af-Arts to approximately 30% with norepinephrine (10–6 M); administration of testosterone (10–9–10–7 M) subsequently dilated the Af-Arts in a dose-dependent manner (P < 0.001; n = 7). The AR mRNA was expressed in microdissected Af-Arts measured by RT-PCR. An AR antagonist, flutamide (10–5 M), totally blocked the testosterone (10–8 M)-induced vasodilator effect. Mean (SEM) NO production of the Af-Art wall was increased when testosterone was added to the bath solution after norepinephrine treatment, from 278.4 (12.1) U/min to 351.2 (33.1) U/min (P < 0.05; n = 3). In the presence of NO inhibition with NG-nitro-l-arginine methyl ester (3 × 10–4 M), the testosterone-induced dilatation was blunted compared with norepinephrine (P < 0.05). Conclusions: Testosterone dilated preconstricted mouse Af-Arts in a dose-dependent manner by activation of ARs and partially mediated by NO.

Gender, Brain-Derived Neurotrophic Factor Val66Met, and Frequency of Methamphetamine Use

Keith G. Heinzerling, Steven Shoptaw — 2012-03-26

Abstract: Background: Frequency of pretreatment methamphetamine (MA) use 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 the frequency of MA use. Estrogen increases expression of brain-derived neurotrophic factor (BDNF), which has effects on MA-induced striatal dopamine release and protects against MA-induced neurotoxicity. Objective: We examined potential effects of sex, the Val66Met polymorphism in BDNF, and their interaction on frequency of MA use among 60 Caucasian MA-dependent volunteers screening for a clinical trial. Methods: Data was taken from 60 Caucasian MA-dependent volunteers screening for a clinical trial. Results: Females reported significantly more pretreatment days with MA use in the past 30 days 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. Conclusions: These results, although preliminary, add to the literature documenting sexual dimorphism in response to stimulants, including MA, and suggest a potential biological mechanism involving BDNF that might contribute to these differences. Additional research characterizing the biological basis of altered response to MA among females is warranted.

Age- and Ethnic-Specific Sex Differences in Stroke Risk

2012-03-26

Abstract: Background: In white populations, age seems to modify the effect of sex on stroke risk, and compared with men, women are protected from stroke until approximately age 75 to 85 years, after which the protection is lost or reversed. Compared with non-Hispanic whites (NHWs), Mexican Americans (MAs) are at higher risk of stroke; however, age- and sex-specific stroke incidence data are currently not available for this population. Objective: This study was performed to compare the age-specific sex differences in stroke risk in MAs and NHWs. Methods: Data were derived from the BASIC (Brain Attack Surveillance in Corpus Christi) Project, a population-based stroke surveillance study conducted in Nueces County Texas. Incident strokes (n = 2421, including ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage) that occurred between January 1, 2000 and May 25, 2007 in individuals aged 45 years or older were included in the analysis. Poisson regression using the generalized additive models framework was used to analyze the relationship between sex, age (5-year intervals), and race/ethnicity (NHW or MA) and incident stroke risk. Results: Among both NHWs and MAs aged 45 to 79 years, men were at higher risk of stroke than women were. The magnitude of increased stroke risk in men compared with women diminished with age, and after age 79 years, no sex difference in stroke risk was observed. Conclusions: Reasons for the loss of protection from stroke in aging women of all races/ethnicities are not fully understood, and further study is warranted.

Mesenchymal Stem Cell Therapy Following Muscle Trauma Leads to Improved Muscular Regeneration in Both Male and Female Rats

2012-02-24

Abstract: Background: Mesenchymal stem cell (MSC) therapy has the potential to enhance muscular regeneration. In previous publications, our group was able to show a dose-response relationship in female animals between the amount of transplanted cells and muscle force. The impact of sex on the regeneration of musculoskeletal injuries following MSC transplantation remains unclear. Objective: We investigated histologic and biomechanical regeneration parameters in rats after autologous transplantation of MSCs. Our hypothesis was that female rats have greater muscle regeneration potential than male rats after autologous MSC transplantation. Methods: Thirty-six Sprague-Dawley rats received an open crush trauma of the left soleus muscle. One week after trauma, 2.5 × 106 autologous MSCs, harvested from tibial biopsies, were transplanted locally (female, n = 9; male, n = 9). Control animals received saline solution (female, n = 9; male, n = 9). Histologic analysis and biomechanical evaluation by in vivo muscle force measurement were performed 3 weeks after transplantation. Results: MSC therapy improved the force of the injured soleus in male rats significantly (twitch: treated, 0.76 [0.51–1.15]; twitch: untreated, 0.45 [0.32–0.73] [P = 0.01]; tetany: treated, 0.63 [0.4–1.21], tetany: untreated, 0.34 [0.16–0.48] [P = 0.04]). Force measurements in females also revealed significant improvements (twitch: treated, 0.71 [0.38–0.96]; twitch: untreated, 0.36 [0.18–0.63] [P = 0.005]; tetany: treated, 0.53 [0.21–0.68]; tetany: untreated, 0.27 [0.11–0.47] [P = 0.01]). The intersexual comparison of fast twitch and tetanic contraction forces revealed no significance (twitch, P = 0.55; tetany, P = 0.19). The histologic analysis showed no differences in the amount of fibrotic tissue (male, P = 0.9; female, P = 0.14) and the size of muscle area (male, P = 0.2; female, P = 0.56) following treatment. Male animals showed higher values for muscle area (P = 0.011) and less fibrosis (P = 0.028), independent of treatment. Conclusion: The outcome of skeletal muscle regeneration after injury can be improved in animals of both sexes with MSC transplantation.

Correction

2012-04-01

In the article by O. Montgomery et al, titled “The 2010 Annual Sex and Gender Research Forum at Drexel University and Drexel University College of Medicine: An Institute for Women's Health and Leadership Initiative,” on page S1 in the February 2012 supplement, the second and third sentences were changed to read: “This forum is among the research events that combine both the college of medicine and the University. There are other research forums that are separate at each entity: Discovery Day at the College of Medicine and Research Day at the University.”

Editorial Board

2012-04-01