Hormonal modulation of connective tissue homeostasis and sex differences in risk for osteoarthritis of the knee.

Young female athletes experience a higher incidence of ligament injuries than their male counterparts, females experience a higher incidence of joint hypermobility syndrome (a risk factor for osteoarthritis development), and post-menopausal females experience a higher prevalence of osteoarthritis than age-matched males. These observations indicate that fluctuating sex hormone levels in young females and loss of ovarian sex hormone production due to menopause likely contribute to observed sex differences in knee joint function and risk for loss of function. In studies of osteoarthritis, however, there is a general lack of appreciation for the heterogeneity of hormonal control in both women and men. Progress in this field is limited by the relatively few preclinical osteoarthritis models, and that most of the work with established models uses only male animals. To elucidate sex differences in osteoarthritis, it is important to examine sex hormone mechanisms in cells from knee tissues and the sexual dimorphism in the role of inflammation at the cell, tissue, and organ levels. There is a need to determine if the risk for loss of knee function and integrity in females is restricted to only the knee or if sex-specific changes in other tissues play a role. This paper discusses these gaps in knowledge and suggests remedies.

Addressing the gaps: sex differences in osteoarthritis of the knee.

An introduction to the accompanying three papers.

Mechanical contributors to sex differences in idiopathic knee osteoarthritis.

The occurrence of knee osteoarthritis (OA) increases with age and is more common in women compared with men, especially after the age of 50 years. Recent work suggests that contact stress in the knee cartilage is a significant predictor of the risk for developing knee OA. Significant gaps in knowledge remain, however, as to how changes in musculoskeletal traits disturb the normal mechanical environment of the knee and contribute to sex differences in the initiation and progression of idiopathic knee OA. To illustrate this knowledge deficit, we summarize what is known about the influence of limb alignment, muscle function, and obesity on sex differences in knee OA. Observational data suggest that limb alignment can predict the development of radiographic signs of knee OA, potentially due to increased stresses and strains within the joint. However, these data do not indicate how limb alignment could contribute to sex differences in either the development or worsening of knee OA. Similarly, the strength of the knee extensor muscles is compromised in women who develop radiographic and symptomatic signs of knee OA, but the extent to which the decline in muscle function precedes the development of the disease is uncertain. Even less is known about how changes in muscle function might contribute to the worsening of knee OA. Conversely, obesity is a stronger predictor of developing knee OA symptoms in women than in men. The influence of obesity on developing knee OA symptoms is not associated with deviation in limb alignment, but BMI predicts the worsening of the symptoms only in individuals with neutral and valgus (knock-kneed) knees. It is more likely, however, that obesity modulates OA through a combination of systemic effects, particularly an increase in inflammatory cytokines, and mechanical factors within the joint. The absence of strong associations of these surrogate measures of the mechanical environment in the knee joint with sex differences in the development and progression of knee OA suggests that a more multifactorial and integrative approach in the study of this disease is needed. We identify gaps in knowledge related to mechanical influences on the sex differences in knee OA.

Neural and psychosocial contributions to sex differences in knee osteoarthritic pain.

People with osteoarthritis (OA) can have significant pain that interferes with function and quality of life. Women with knee OA have greater pain and greater reductions in function and quality of life than men. In many cases, OA pain is directly related to sensitization and activation of nociceptors in the injured joint and correlates with the degree of joint effusion and synovial thickening. In some patients, however, the pain does not match the degree of injury and continues after removal of the nociceptors with a total joint replacement. Growth of new nociceptors, activation of nociceptors in the subchondral bone exposed after cartilage degradation, and nociceptors innervating synovium sensitized by inflammatory mediators could all augment the peripheral input to the central nervous system and result in pain. Enhanced central excitability and reduced central inhibition could lead to prolonged and enhanced pain that does not directly match the degree of injury. Psychosocial variables can influence pain and contribute to pain variability. This review explores the neural and psychosocial factors that contribute to knee OA pain with an emphasis on differences between the sexes and gaps in knowledge.

Current challenges in female veterans' health.

Abstract Women in the U.S. military are technically barred from serving in combat specialties, positions, or units; however, since Operation Desert Storm, women have served in forward positions in greater numbers. This increased involvement in combat zones has resulted in exposures to trauma, injury, and a myriad of environmental hazards associated with modern war. Some of these hazards present new health risks specifically relevant to women who have been deployed to or recently returned from Iraq or Afghanistan or both. To address this evolving public health concern, the Society for Women's Health Research (SWHR) convened a 1-day interdisciplinary scientific conference, with speakers and attendees from civilian, military, and veteran settings. The purpose of the conference was to reveal the state-of-the-science on the health of the female veteran and to focus attention on recent advances in biomedical research related to female veterans' health. The following topics were discussed: mental health (posttraumatic stress disorder [PTSD] and depression), urogenital health, musculoskeletal health, and traumatic brain injury (TBI).

Sex and gender differences in Alzheimer's disease: recommendations for future research.

Alzheimer's disease (AD) disproportionately affects women in both prevalence and severity; however, the biologic mechanisms underlying these sex differences are not fully understood. Sex differences in the brain, such as in brain anatomy, age-related declines in brain volume, and brain glucose metabolism, have been documented and may be important in understanding AD etiology. The full impact of sex as a basic biologic variable on this neurodegenerative disease remains elusive. To address the evidence for sex differences in AD, the Society for Women's Health Research (SWHR) convened an interdisciplinary roundtable of experts from academia, clinical medicine, industry, and the government to discuss the state-of-the-science in sex and gender differences in AD. Roundtable participants were asked to address gaps in our knowledge and identify specific sex-based research questions for future areas of study.

Behavior and obesity in women across the life span: a report by the Society for Women's Health Research.

In October 2006, the Society for Women's Health Research convened a workshop that focused on the behavioral and social influences on obesity in women across the life span with an emphasis on ethnicity, socioeconomic status, and mental health. The purposes of the workshop were to examine the current state of the science related to behavioral influences on obesity in women across the life span; to determine the mechanisms, methods, and technical advances required for research progress in this area; and to develop an agenda for future research on behavioral influences on obesity in women. The workshop participants included psychologists, social scientists, clinicians, health educators, health services researchers, nutrition specialists, and epidemiologists, among others, who have expertise in obesity at critical life stages in women (childhood, adolescence, pregnancy, menopause, and older age). Discussions during the workshop focused on 4 specific topics: (1) the relationship between mental or emotional health and obesity in women; (2) the impact of social, cultural, and environmental factors on obesity in women; (3) the improvement of obesity research methodology; and (4) the development of obesity prevention and intervention strategies. Based on these discussions, participants proposed recommendations for future research.

Future research in sex differences in obesity and cardiovascular disease: report by the Society for Women's Health Research.

Obesity has become an international public health concern. In the United States, the rates of overweight and obesity have escalated dramatically in the last several decades. The health implications of obesity stem from its relationship with the development and progression of several health complications and diseases. Cardiovascular disease, which is the number one killer of women and men, is strongly influenced by obesity. The exact biological relationship between these two conditions is difficult to understand because several overlapping physiological systems and processes influence their development. One important component that affects obesity and cardiovascular disease is the sex of the individual. Although this basic biological variable is an obvious area for scientific study, research analyzing the influence of sex on obesity and cardiovascular disease is gravely lacking. The Society for Women's Health Research convened a workshop of obesity and cardiovascular disease experts in November 2005 to identify the gaps in scientific knowledge and crucial next steps in research related to sex differences in obesity and cardiovascular disease. This meeting report describes the workshop attendees' recommendations in detail.

Truncated estrogen receptor product-1 stimulates estrogen receptor alpha transcriptional activity by titration of repressor proteins.

The truncated estrogen receptor product-1 (TERP-1, or TERP) is a pituitary-specific isoform of estrogen receptor alpha (ERalpha), and its expression is regulated by estrogen. TERP modulates the transcriptional activity of ERalpha but has no independent effect on transcription of estrogen-response element-containing promoters. At low concentrations, TERP stimulates ERalpha transcriptional activity in transient transfection assays. At TERP concentrations equal to or greater than full-length ERalpha, TERP forms dimers with ERalpha and reduces both ligand-dependent and -independent transcription. A dimerization mutant of TERP, TERP L509R, stimulated ERalpha transcription at all concentrations. We hypothesized that TERP stimulates ERalpha transcriptional activity by titrating suppressors of ERalpha activity. We found that repressor of estrogen receptor activity (REA), originally isolated from human breast cancer cells, is present in mouse pituitary gonadotrope cell lines. Levels of REA vary slightly throughout the rat reproductive cycle, but TERP mRNA and protein vary much more dramatically. In transfection experiments, REA suppressed ERalpha transcriptional activity, and TERP L509R was able to alleviate transcriptional suppression by REA. In glutathione S-transferase pull-down assays, TERP bound to REA more efficiently than did ERalpha at equivalent concentrations, suggesting that REA will preferentially bind to TERP. Our findings suggest that the stimulation of pituitary ERalpha activity by low concentrations of TERP can occur by titration of corepressors such as REA.