Gender Medicine: The Journal for the Study of Sex & Gender Differences - Articles in Press

Age-Dependent Reductions in Mitochondrial Respiration are Exacerbated by Calcium in the Female Rat Heart - Corrected Proof

J. Craig Hunter, Alexandra M. Machikas, Donna H. Korzick — 2012-05-03

Background: Cardiovascular disease mortality increases rapidly after menopause by poorly defined mechanisms. Objective: Because mitochondrial function and Ca2+ sensitivity are important regulators of cell death after myocardial ischemia, we sought to determine whether aging and/or estrogen deficiency (ovariectomy) increased mitochondrial Ca2+ sensitivity. Methods: Mitochondrial respiration was measured in ventricular mitochondria isolated from adult (6 months; n = 26) and aged (24 months; n = 25), intact or ovariectomized female rats using the substrates α-ketoglutarate/malate (complex I); succinate/rotenone (complex II); ascorbate/N,N,N′,N′-tetramethyl-p-phenylenediamine/antimycin (complex IV). State 2 and 3 respiration was initiated by sequential addition of mitochondria and adenosine diphosphate. Ca2+ sensitivity was assessed by Ca2+-induced swelling of de-energized mitochondria and reduction in state 3 respiration. Propylpyrazole triol (PPT) was administered intraperitoneally 45 minutes before euthanasia to assess mitochondrial protective effects through estrogen receptor (ER) α activation. Results: 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 ovariectomized 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. Conclusions: 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.

Diabetic Polyneuropathy Relates to Bone Metabolism and Markers of Bone Turnover in Elderly Patients with Type 2 Diabetes: Greater Effects in Male Patients - Corrected Proof

Sazan Rasul, Aysegul Ilhan, Ludwig Wagner, Anton Luger, Alexandra Kautzky-Willer — 2012-04-16

Background: There is evidence that diabetic polyneuropathy (PNP) is associated with reduced bone mineral density (BMD) in type 1 diabetes but little is known about the impact of diabetic PNP on bone metabolism in type 2 diabetes. Objectives: The aim of this study was to evaluate differences in bone metabolism by measuring markers of bone turnover and BMD in men and postmenopausal women with type 2 diabetes and diabetic PNP compared with those without PNP. Gender differences were analyzed for both groups of patients. Methods: One hundred twenty patients with type 2 diabetes, 68 without PNP (43 men, 25 women, mean age 62 [8] years) and 52 with PNP (28 men, 24 women, mean age 64 [8] years) were studied. Clinical parameters with bone turnover biomarkers such as osteocalcin, bone alkaline phosphatase, procollagen type 1 amino-terminal propeptide, and carboxy-terminal telopeptide of type 1 collagen were measured in all patients. Dual energy x-ray absorptiometry to evaluate BMD was performed in a subgroup of patients. Results: After controlling for age, body mass index, duration of diabetes, smoking, glycosylated hemoglobin, homeostasis model assessment index for insulin resistance, serum C-reactive protein, creatinine, calcium, gamma-glutamyltransferase, parathyroid and sex hormones levels, presence of micro/macrovascular complications, statin- as well as diabetes-related therapies, levels of carboxy-terminal telopeptide of type 1 collagen and procollagen type 1 amino-terminal propeptide were significantly higher among patients with PNP when compared with patients without PNP (P = 0.01 and P = 0.03, respectively). Differences in bone biomarkers were more pronounced among men with diabetes. BMD did not differ significantly between patients with and without PNP, independent of gender. Conclusions: Male patients with PNP exhibit a higher rate of bone turnover than men without PNP. High rate of bone turnover increases the susceptibility for developing osteoporosis. Prevention of diabetic PNP might also reduce the incidence of osteoporosis and fractures in patients with type 2 diabetes.

Agonistic Autoantibodies to the Angiotensin II Type I Receptor Cause Pathophysiologic Characteristics of Preeclampsia - Corrected Proof

Babbette LaMarca, Marc R. Parrish, Kedra Wallace — 2012-04-13

Background: Preeclampsia (PE), new-onset hypertension with proteinuria during pregnancy, is associated with increased reactive oxygen species, the vasoactive peptide endothelin-1 (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). Objectives: One important area of investigation for our laboratory was to determine what role AT1-AA plays in the pathophysiology associated with PE. Methods: 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 on increased blood pressure, ET-1, reactive oxygen species, and sFlt-1 in normal pregnant rats (NP). Results: We 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 infused purified rat AT1-AA (1:50) into NP rats, and analyzed blood pressure and soluble factors. We consistently found that AT1-AA infused rats had significantly increased AT1-AA and blood pressure above NP rats. This hypertension was associated with significantly increased ET-1 in renal cortices (11-fold) and placenta (4-fold), and there was an approximately 2- to 3-fold increase in placental oxidative stress. Furthermore, antiangiogenic factors sFlt-1 and sEng were significantly increased in the AT1-AA induced hypertensive group compared with the NP controls. Conclusions: Collectively, these data indicated an important role for AT1-AA stimulated in response to placental ischemia that caused hypertension during pregnancy.

More-Severe Strokes in Women Surviving 3 Months Despite Lower 3-Month Case Fatality in Women than Men: Explaining Poorer Outcomes in Women - Corrected Proof

Tom Skyhøj Olsen, Zorana Jovanovic Andersen, Klaus Kaae Andersen — 2012-04-13

Background: Women who survive stroke are more disabled and more often institutionalized than men. Objective: We explore this phenomenon by studying case fatality and stroke severity in stroke survivors separately for men and women. Methods: A Danish stroke registry (2000−2007) contains information about 26,818 patients with first-ever ischemic stroke, including stroke severity (Scandinavian Stroke Scale, 0 worst to 58 best), computed tomography scan, cardiovascular risk factors, and death 3 months after stroke. We modeled stroke severity by generalized additive linear model and 3-month case fatality with logistic model adjusting for age and cardiovascular risk factors. Results: Male to female ratio was 51.5% to 48.5%. Mean age was 68.8 (SD 12.6) years in men; 73.7 (13.8) years in women. Stroke was more severe in women (mean [SD] Scandinavian Stroke Scale, 42.2 [16.0]) than in men (mean [SD] Scandinavian Stroke Scale, 45.6 [14.2]) also after adjustment for age and cardiovascular risk factors; significant in patients older than 75 years. In survivors at 3 months, stroke was more severe in women than men, given same age and cardiovascular risk factor profile; significant in patients older than 75 years. More women (11.9%) had died within 3 months than men (8.6%). However, adjusting for age, stroke severity, and risk factor profile, 3-month case fatality was lower in women than men; significant in patients older than 78 years. Conclusions: Although 3-month case fatality was lower in women than men, strokes were more severe among survivors at 3 months in women than in men. In addition, strokes were more severe in women. Our data help elucidate why women survive stroke better but have poorer functional outcomes that require more care than men.

Postoperative Estradiol Levels Associate With Development of Primary Graft Dysfunction in Lung Transplantation Patients - Corrected Proof

2012-02-24

Abstract: Background: 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 can influence the rate of alveolar fluid clearance. Objective: We hypothesized that female gender and higher estradiol levels would be associated with a lower risk of PGD after lung transplantation. Methods: We measured plasma estradiol levels preoperatively, 6 hours postoperatively, and 24 hours postoperatively in a cohort of 111 lung transplant recipients at 2 institutions. Results: Mean age was 57 years (12.5) and 52% were female. Median postoperative estradiol level was 63.9 pg/mL (interquartile range, 28.8−154.3 pg/mL) in male and 65.1 pg/mL (interquartile range, 28.4−217.2 pg/mL) in female patients. Contrary to our hypothesis, higher estradiol levels at 24 hours were associated with an increased risk of PGD at 72 hours in male patients (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. Conclusion: These findings suggest that there might be different biologic effects of estrogens in males and females, and highlight the importance of considering gender differences in future studies of PGD.

Sex-Dependent Programming of Glucose and Fatty Acid Metabolism in Mouse Offspring by Maternal Protein Restriction - Corrected Proof

2012-02-23

Background: Nutritional conditions during fetal life influence the risk of the development of metabolic syndrome and cardiovascular diseases in adult life (metabolic programming). Impaired glucose tolerance and dysregulated fatty acid metabolism are hallmarks of metabolic syndrome. Objective: We aimed to establish a mouse model of metabolic programming focusing on the sex-specific effects of a maternal low-protein diet during gestation on glucose and lipid metabolism in the adult offspring. Methods: Pregnant C57BL/6 mice received a control or a low-protein diet (18% vs 9% casein) throughout gestation. Male and female offspring received a low-fat or a high-fat diet from 6 to 22 weeks of age. Results: Maternal low-protein diet during gestation led to deteriorated insulin sensitivity on high-fat feeding in female offspring, as determined by biochemical and microarray analyses. Female offspring of control diet–fed dams were relatively resistant to high-fat diet–induced metabolic dysregulation. In contrast, maternal low-protein diet did not specifically affect the metabolic parameters addressed in male offspring. In males, the high-fat diet led to insulin insensitivity regardless of the diet of the dam. Conclusions: Our findings show that fetal malnutrition has a limited impact on male mouse offspring, yet it does influence the metabolic response to a high-fat diet in females. These findings may have implications for future early diagnostics in metabolic syndrome and for the development of sex-specific treatment regimens.

Evaluating Sex and Gender Competencies in the Medical Curriculum: A Case Study - Corrected Proof

Virginia M. Miller, Priscilla M. Flynn, Keith D. Lindor — 2012-02-03

Abstract: Background: Sex and gender differences exist in the manifestation and prevalence of many conditions and diseases. Yet many clinician training programs neglect to integrate this information across their curricula. Objective: This study aimed to measure the sex and gender medical knowledge of medical students enrolled in a program without an explicit directive to integrate sex and gender differences across a block system of core subjects. Methods: A forced-choice instrument consisting of 35 multiple-choice and true or false questions was adapted from an evaluation tool used in the European Curriculum in Gender Medicine held at Charité Hospital, Berlin, in September 2010. Results: Fourth-year (response rate 93%) and second-year (response rate 70%) students enrolled in Mayo Medical School completed the instrument. More than 50% of students in both classes indicated that topics related to sex and gender were covered in gynecology, cardiology, and pediatrics, and <20% of students indicated inclusion of such topics in nephrology, neurology, and orthopedics. More than twice as many second-year students indicated that topics dealing with sex and gender were included in immunology course material compared with fourth-year students. A consensus of written comments indicated that concepts of sex and gender-based medicine need to be embedded into existing curriculum, with an emphasis on clinically relevant information. Conclusions: Although this study represents only one medical school in the United States, information regarding sex and gender aspects of medicine is not consistently included in this curriculum without an explicit directive. These results can provide guidance for curriculum improvement to train future physicians.