Biology of Sex Differences - Most accessed articles

Strategies and Methods to Study Sex Differences in Cardiovascular Structure and Function: A Guide for Basic Scientists

Virginia Miller — 2011-12-12T00:00:00Z

Background: Cardiovascular disease remains the primary cause of death worldwide. In the United States, deaths due to cardiovascular disease for women exceed that of men. While cultural and psychosocial factors such as education, economic status, marital status and access to health care contribute to sex differences in adverse outcomes, physiological and molecular bases of differences between women and men that contribute to development of cardiovascular disease and response to therapy remain underexplored. Methods: This article describes concepts, methods and procedures to assist in the design of animal and tissue/cell based studies of sex differences in cardiovascular structure, function and models of disease. Results: To address knowledge gaps, study designs must incorporate appropriate experimental material including species/strain characteristics, sex and hormonal status. Determining whether a sex difference exists in a trait must take into account the reproductive status and history of the animal including those used for tissue (cell) harvest, such as the presence of gonadal steroids at the time of testing, during development or number of pregnancies. When selecting the type of experimental animal, additional consideration should be given to diet requirements (soy or plant based influencing consumption of phytoestrogen), life-span, frequency of estrous cycle in females, and ability to investigate developmental or environmental components of disease modulation. Stress imposed by disruption of sleep/wake cycles, patterns of social interaction (or degree of social isolation), or handling may influence adrenal hormones that interact with pathways activated by the sex-steroid hormones. Care must be given to selection of hormonal treatment and route of administration. Conclusion: Accounting for sex in the design and interpretation of studies including pharmacological effects of drugs is essential to increase the foundation of basic knowledge upon which to build translational approaches to prevent, diagnose and treat cardiovascular diseases in humans.

Oral contraceptives modify DNA methylation and monocyte-derived macrophage function

Ilaria Campesi — 2012-01-27T00:00:00Z

Background: Fertile women may be encouraged to use contraception during clinical trial to avoid drug effects on foetuses. However, hormonal contraception interferes with pharmacokinetics and pharmacodynamics and modifies internal milieus. Macrophages depend on the milieu to which they are exposed. Therefore, we assessed whether macrophage function would be affected by the use of combined oral contraceptives (OCs) and if this influence depended on the androgenic or non-androgenic properties of progestin. Methods: Healthy adult women were enrolled and stratified into two groups: women who did not use OCs (Fs) and women treated with OCs (FOCs). FOCs were further stratified as a function of androgenic (FOCA+) and non-androgenic (FOCA-) properties of progestins. Routine haematological, biochemical, inflammatory and endothelial dysfunction parameters were measured. Monocyte-derived macrophages (MDMs) were evaluated for the expression and activity of oestrogen receptors and androgen receptors, and release of tumour necrosis factor-alpha (TNF-alpha) was measured from unstimulated and lipopolysaccharide-stimulated cells. Results: As known, the use of OCs changed numerous parameters: the number of lymphocytes, iron levels, total iron-binding capacity of transferrin, triglycerides, high-density lipoprotein, total cholesterol, and C-reactive protein increased, while prothrombin time and alkaline phosphatase decreased. Hormonal asset also varied: cortisol was higher in FOCs, while luteinising hormone, follicle-stimulating hormone, and testosterone were lower in FOCs. Asymmetric dimethylarginine, an index of endothelial function, was lower in FOC than in Fs, as were cysteine and bilirubin. The androgenic properties of progestins affected the activity of OCs: in particular, white blood cell count, haemoglobin, high-density lipoprotein and calcium were higher in FOCA- than in FOCA+, whereas % oxygen saturation and gamma-glutamyl transpeptidase were lower in FOCA- than in FOCA+. Importantly, FOCs had a lower global DNA methylation, indicating that OC may have epigenetic effects on gene expression. OC did not modify the expression of androgen receptor but increased oestrogen receptor-alpha expression, more considerably in FOCA+, and decreased oestrogen receptor-beta, more considerably in FOCA-. Importantly, the activation state of oestrogen receptor-beta in FOCs was decreased, while oestrogen receptor-alpha was not active in either Fs or FOCs. Unstimulated MDMs obtained from FOCs showed higher release of TNF-alpha in comparison with Fs. After lipopolysaccharide stimulation, the release of TNF-alpha was significantly higher in Fs than in FOCs. Conclusions: OC use induced many changes in haematological and plasmatic markers, modifying hormonal asset, endothelial function, inflammation index and some parameters of redox state, producing a perturbation of the internal milieu that impacted macrophagic function. In fact, different levels of oestrogen receptor expression and release of TNF-alpha were observed in macrophages derived from OC users. Some of the above activities were linked to the androgenic properties of progestin. Even though it is not known whether these effects are reversible the results indicate that a single type of OC should be used during a single clinical trial.

Sex differences in autoimmune disease

Rhonda Voskuhl — 2011-01-04T00:00:00Z

Women are more susceptible to a variety of autoimmune diseases including systemic lupus erythematosus (SLE), multiple sclerosis (MS), primary biliary cirrhosis, rheumatoid arthritis and Hashimoto's thyroiditis. This increased susceptibility in females compared to males is also present in animal models of autoimmune diseases such as spontaneous SLE in (NZBxNZW)F1 and NZM.2328 mice, experimental autoimmune encephalomyelitis (EAE) in SJL mice, thyroiditis, Sjogren's syndrome in MRL/Mp-lpr/lpr mice and diabetes in non-obese diabetic mice. Indeed, being female confers a greater risk of developing these diseases than any single genetic or environmental risk factor discovered to date. Understanding how the state of being female so profoundly affects autoimmune disease susceptibility would accomplish two major goals. First, it would lead to an insight into the major pathways of disease pathogenesis and, secondly, it would likely lead to novel treatments which would disrupt such pathways.

Influence of ERbeta selective agonism during the neonatal period on the sexual differentiation of the rat hypothalamic-pituitary-gonadal (HPG) axis

Heather Patisaul — 2012-01-19T00:00:00Z

Background: It is well established that sexual differentiation of the rodent hypothalamic-pituitary-gonadal (HPG) axis is principally orchestrated by estrogen during the perinatal period. Here we sought to better characterize the mechanistic role the beta form of the estrogen receptor (ERbeta) plays in this process. Methods: To achieve this, we exposed neonatal female rats to three doses (0.5, 1 and 2 mg/kg) of the ERbeta selective agonist diarylpropionitrile (DPN) using estradiol benzoate (EB) as a positive control. Measures included day of vaginal opening, estrous cycle quality, GnRH and Fos co-localization following ovariectomy and hormone priming, circulating luteinizing hormone (LH) levels and quantification of hypothalamic kisspeptin immunoreactivity. A second set of females was then neonatally exposed to DPN, the ERalpha agonist propyl-pyrazole-triol(PPT), DPN+PPT, or EB to compare the impact of ERalpha and ERbeta selective agonism on kisspeptin gene expression in pre- and post-pubescent females. Results: All three DPN doses significantly advanced day of vaginal opening and induced premature anestrus. GnRH and Fos co-labeling, a marker of GnRH activation, following ovariectomy and hormone priming was reduced by approximately half at all doses, the magnitude of which was not as large as with EB or what we have previously observed with the ERalpha agonist PPT. LH levels were also correspondingly lower, compared to control females. No impact of DPN was observed on the density of kisspeptin immunoreactive (-ir) fibers or cell bodies in the arcuate (ARC) nucleus, and kisspeptin-ir was only significantly reduced by the middle (1 mg/kg) DPN dose in the preoptic region. The second experiment revealed that EB, PPT and the combination of DPN+PPT significantly abrogated preoptic Kiss1 expression at both ages but ARC expression was only reduced by EB. Conclusion: Our results indicate that selective agonism of ERbeta is not sufficient to completely achieve male-typical HPG organization observed with EB or an ERalpha agonist.

Why Does Jack and not Jill Break His Crown: Sex Disparity in Brain Tumors

Tao Sun — 2012-01-25T00:00:00Z

It is often reported that brain tumors occur more frequently in males, and that males suffer a worse outcome from brain tumors than females. If correct, these observations suggest that sex plays a fundamental role in brain tumor biology. The following review of the literature regarding primary and metastatic brain tumors, reveals that brain tumors do occur more frequently in males compared to females regardless of age, tumor histology or region of the world. Sexually dimorphic mechanisms that might control tumor cell biology, as well as immune and brain microenvironmental responses to cancer, are explored as the basis for this sex disparity. Elucidating the mechanisms by which sex chromosomes and sex hormones impact on brain tumorigenesis and progression will advance our understanding of basic cancer biology and is likely to be essential for optimizing the care of brain tumor patients.

Promoting the understanding of sex differences to enhance equity and excellence in biomedical science

Arthur Arnold — 2010-11-04T00:00:00Z

From the moment of our conception, each of us has a sex. Sex has a major role in determining the physical attributes of our bodies, the structure of our brains, our behavioral tendencies, our susceptibility and reaction to diseases, the environment in which we grow up, our place in society, the attitudes of others towards us, and our conception of self. Although sex may be considered to be determined primarily biologically, our gender (i.e., the social perception and implications of our sex) is arguably equally or more important for our lives. Sex and gender differences are created by an intricate reciprocal interaction of numerous biological and environmental forces.

Women with knee osteoarthritis have more pain and poorer function than men, but similar physical activity prior to total knee replacement

Shalome Tonelli — 2011-11-10T00:00:00Z

Background: Osteoarthritis of the knee is a major clinical problem affecting a greater proportion of women than men. Women generally report higher pain intensity at rest and greater perceived functional deficits than men. Women also perform worse than men on function measures such as the 6-minute walk and timed up and go tests. Differences in pain sensitivity, pain during function, psychosocial variables, and physical activity levels are unclear. Further the ability of various biopsychosocial variables to explain physical activity, function and pain is unknown. Methods: This study examined differences in pain, pain sensitivity, function, psychosocial variables, and physical activity between women and men with knee osteoarthritis (N = 208) immediately prior to total knee arthroplasty. We assessed: (1) pain using self-report measures and a numerical rating scale at rest and during functional tasks, (2) pain sensitivity using quantitative sensory measures, (3) function with self-report measures and specific function tasks (timed walk, maximal active flexion and extension), (4) psychosocial measures (depression, anxiety, catastrophizing, and social support), and (5) physical activity using accelerometry. The ability of these mixed variables to explain physical activity, function and pain was assessed using regression analysis. Results: Our findings showed significant differences on pain intensity, pain sensitivity, and function tasks, but not on psychosocial measures or physical activity. Women had significantly worse pain and more impaired function than men. Their levels of depression, anxiety, pain catastrophizing, social support, and physical activity, however, did not differ significantly. Factors explaining differences in (1) pain during movement (during gait speed test) were pain at rest, knee extension, state anxiety, and pressure pain threshold; (2) function (gait speed test) were sex, age, knee extension, knee flexion opioid medications, pain duration, pain catastrophizing, body mass index (BMI), and heat pain threshold; and (3) physical activity (average metabolic equivalent tasks (METS)/day) were BMI, age, Short-Form 36 (SF-36) Physical Function, Kellgren-Lawrence osteoarthritis grade, depression, and Knee Injury and Osteoarthritis Outcome Score (KOOS) pain subscale. Conclusions: Women continue to be as physically active as men prior to total knee replacement even though they have significantly more pain, greater pain sensitivity, poorer perceived function, and more impairment on specific functional tasks.

Tempests and Tales: Challenges to the Study of Sex Differences in the Brain.

Margaret McCarthy — 2011-04-28T00:00:00Z

We here review two recent popular press books which challenge the notion that there are biological sex differences in the brain, Rebecca J. Jordan-Young's "Brainstorm: The Flaws in the Science of Sex Differences" (2010 Harvard University Press) and Cordelia Fine's "Delusions of Gender: How our Minds, Society and Neurosexism Create a Difference" (2010 W.W. Norton Company, New York). While there is much of merit in each, both resort to hyperbole and superficiality, with numerous inaccurate representations of the current state of the art.

Sex differences in resting hemodynamics and arterial stiffness following 4 weeks of resistance versus aerobic exercise training in individuals with pre-hypertension to stage 1 hypertension

Scott Collier — 2011-08-25T00:00:00Z

Background: Hypertension (HTN) exhibits sexual dimorphism; the incidence for women surpasses men during the sixth decade of life, while the pharmacological treatments are less effective and produce more side-effects in women than in men. Aerobic exercise (AE) has been shown to prevent and treat HTN; however, resistance exercise (RE) is not recommended as a strategy to treat HTN. In this study, we investigated the potential sex differences of AE versus RE in a cohort of unmedicated patients with hypertension. Methods: In total, 40 moderately active, pre-hypertensive or stage 1 essential hypertensive male (M) and female (F) participants aged 40 to 60 years were randomly divided into four groups: M AE, M RE, F AE, and F. Each group exercised at moderate intensity, 3 days/week for 4 weeks. Hemodynamic, vascular and blood-flow data were collected before and after exercise training. Results: Men showed a significant increase in central pulse wave velocity following RE while females showed no significant changes (12 ± to 13.9 ± vs. 9.2 ± to 9.6 ± m/s, respectively). RE showed significantly greater increases in peak blood flow when compared to AE (F RE 15 ± to 20 ± vs. F AE 17.5 ± to19.5 ±, M RE 19 ± to 24 ± vs M AE 21 ± to 25 ± ml* 100 ml*min, respectively). In addition, systolic and diastolic BP decreased greater for women following RE when compared to AE whereas men showed comparable decreases in BP following either exercise mode. Conclusion: Moderate-intensity RE training may be a more favorable for women as a treatment option for hypertension because of greater decreases in diastolic BP and significant increases in flow-mediated dilation without concomitant increases in arterial stiffness, compared with their male counterparts.

Alterations in vasomotor systems and mechanics of resistance-sized mesenteric arteries from SHR and WKY male rats following in vivo Testosterone manipulation

Jonathan Toot — 2012-01-03T00:00:00Z

Background: Testosterone (T) and the sympathetic nervous system each contribute to the pathology of hypertension. Altered blood vessel reactivity is also associated with the pathology of high blood pressure. The purpose of this study was to examine the effects of T manipulation in the regulation of resistance-sized blood vessel reactivity. Methods: Adult spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) male rats at 8 weeks of age were used. The rats were divided into groups consisting of gonadally intact controls (CONT), castrate with sham implant (CAST) and castrate with T implant (CAST + T) (n = 6 to 12 per group). Following a short-term period of T treatment (approximately 4 weeks), plasma norepinephrine (NE) and plasma T were assessed by performing high-performance liquid chromatography and RIA, respectively. Resistance-sized mesenteric artery reactivity was assessed on a pressurized arteriograph for myogenic reactivity (MYO), phenylephrine (PE) responsiveness and passive structural mechanics. Results: SHR and WKY males exhibited similar physiological trends in T manipulation, with castration significantly lowering plasma T and NE and T replacement significantly increasing plasma T and NE. T manipulation in general resulted in significant alterations in MYO of second-order mesenteric arteries, with T replacement decreasing MYO in SHR (P < 0.05) compared to CONT, T replacement increasing MYO, and CAST decreasing MYO in WKY rats (P < 0.001) compared to CONT rats. Additionally, PE-induced constriction was significantly altered in both strains following T treatment, with the effective concentration of PE to constrict the vessel to 50% of the total diameter significantly increased in the CAST + T SHR compared to CONT (P < 0.05). Comparisons of passive structural mechanics between SHR and WKY treatment groups indicated in SHR a significantly increased wall-to-lumen ratio and decreased circumferential wall stress compared to WKY treatment groups. Conclusions: These data suggest that T and NE are involved in a complex interaction with both myogenic reactivity and structural alterations of resistance-sized blood vessels and that these factors likely contribute to the development and maintenance of hypertension.