Springer Science and Business Media LLC

Sexual differentiation of the nervous system occurs via the interplay of genetics, endocrinology and social experience through development. Much of the research into mechanisms of sexual differentiation has been driven by an implicit theoretical framework in which these causal factors act primarily and directly on sexually dimorphic neural populations within the central nervous system. This review will examine an alternative explanation by describing what is known about the role of peripheral structures and mechanisms (both neural and non-neural) in producing sex differences in the central nervous system. The focus of the review will be on experimental evidence obtained from studies of androgenic masculinization of the spinal nucleus of the bulbocavernosus, but other systems will also be considered.

Alzheimer’s disease (AD) is notably associated with cognitive decline resulting from impaired function of hippocampal and cortical areas; however, several other domains and corresponding brain regions are affected. One such brain region is the hypothalamus, shown to atrophy and develop amyloid and tau pathology in AD patients. The hypothalamus controls several functions necessary for survival, including energy and glucose homeostasis. Changes in appetite and body weight are common in AD, often seen several years prior to the onset of cognitive symptoms. Therefore, altered metabolic processes may serve as a biomarker for AD, as well as a target for treatment, considering they are likely both a result of pathological changes and contributor to disease progression. Previously, we reported sexually dimorphic metabolic disturbances in ~ 7-month-old 3xTg-AD mice, accompanied by differences in systemic and hypothalamic inflammation. In the current study, we investigated metabolic outcomes and hypothalamic inflammation in 3xTg-AD males and females at 3, 6, 9, and 12 months of age to determine when these sex differences emerge. In agreement with our previous study, AD males displayed less weight gain and adiposity, as well as reduced blood glucose levels following a glucose challenge, compared to females. These trends were apparent by 6–9 months of age, coinciding with increased expression of inflammatory markers (Iba1, GFAP, TNF-α, and IL-1β) in the hypothalamus of AD males. These findings provide additional evidence for sex-dependent effects of AD pathology on energy and glucose homeostasis, which may be linked to hypothalamic inflammation. Alzheimer’s disease (AD), often associated with memory loss, can also affect other parts of the brain and body, resulting in several other symptoms. Changes in appetite and body weight are commonly seen in people with AD, often before they start showing signs of memory loss. These metabolism-related changes are likely due in part to AD affecting a part of the brain called the hypothalamus, which controls important functions like energy balance (calories in vs. calories out) and blood sugar levels. This study aimed to examine whether changes in metabolism and the hypothalamus could serve as early signs of AD, and even help in treating the disease. We also wanted to see if these changes were influenced by biological sex, as two-thirds of AD patients are women, and our previous studies showed many differences between males and females. In this study, we observed male and female mice at different ages to see when these changes began to appear. We found that male AD mice gained less weight, had less body fat, and had better blood sugar control, compared to female AD mice. These differences became noticeable at the same age that we noticed signs of increased inflammation in the hypothalamus of male mice. These findings suggest that AD affects males and females differently, particularly in terms of energy balance and blood sugar control, and this might be related to inflammation in the hypothalamus. This research could provide valuable insights into understanding, diagnosing, and treating Alzheimer’s disease.

Antarctica challenges human explorers by its extreme environment. The effects of these unique conditions on the human physiology need to be understood to best mitigate health problems in Antarctic expedition crews. Moreover, Antarctica is an adequate Earth-bound analogue for long-term space missions. To date, its effects on human physiology have been studied mainly in male cohorts though more female expeditioners and applicants in astronaut training programs are selected. Therefore, the identification of sex differences in stress and immune reactions are becoming an even more essential aim to provide a more individualized risk management. Ten female and 16 male subjects participated in three 1-year expeditions to the German Antarctic Research Station Neumayer III. Blood, saliva, and urine samples were taken 1–2 months prior to departure, subsequently every month during their expedition, and 3–4 months after return from Antarctica. Analyses included cortisol, catecholamine and endocannabinoid measurements; psychological evaluation; differential blood count; and recall antigen- and mitogen-stimulated cytokine profiles. Cortisol showed significantly higher concentrations in females than males during winter whereas no enhanced psychological stress was detected in both sexes. Catecholamine excretion was higher in males than females but never showed significant increases compared to baseline. Endocannabinoids and N-acylethanolamides increased significantly in both sexes and stayed consistently elevated during the confinement. Cytokine profiles after in vitro stimulation revealed no sex differences but resulted in significant time-dependent changes. Hemoglobin and hematocrit were significantly higher in males than females, and hemoglobin increased significantly in both sexes compared to baseline. Platelet counts were significantly higher in females than males. Leukocytes and granulocyte concentrations increased during confinement with a dip for both sexes in winter whereas lymphocytes were significantly elevated in both sexes during the confinement. The extreme environment of Antarctica seems to trigger some distinct stress and immune responses but—with the exception of cortisol and blood cell counts—without any major relevant sex-specific differences. Stated sex differences were shown to be independent of enhanced psychological stress and seem to be related to the environmental conditions. However, sources and consequences of these sex differences have to be further elucidated.

Epidemiologists need tools to measure effects of gender, a complex concept originating in the social sciences which is not easily operationalized in the discipline. Our aim is to clarify useful concepts, measures, paths, effects, and analytical strategies to explore mechanisms of health difference between men and women. We reviewed concepts to clarify their definitions and limitations for their translation into usable measures in Epidemiology. Then we conducted methodological research using a causal framework to propose methodologically appropriate strategies for measuring sex and gender effects in health. (1) Concepts and measures. We define gender as a set of norms prescribed to individuals according to their attributed-at-birth sex. Gender pressure creates a systemic gap, at population level, in behaviors, activities, experiences, etc., between men and women. A pragmatic individual measure of gender would correspond to the level at which an individual complies with a set of elements constituting femininity or masculinity in a given population, place and time. (2) Main analytical strategy. Defining and measuring gender are not sufficient to distinguish the effects of sex and gender on a health outcome. We should also think in terms of mechanisms, i.e., how the variables are linked together, to define appropriate analytical strategies. A causal framework can help us to conceptualize “sex” as a “parent” of a gender or gendered variable. This implies that we cannot interpret sex effects as sexed mechanisms, and that we can explore gendered mechanisms of sex-differences by mediation analyses. (3) Alternative strategy. Gender could also be directly examined as a mechanism, rather than through a variable representing its realization in the individual, by approaching it as an interaction between sex and social environment. Both analytical strategies have limitations relative to the impossibility of reducing a complex concept to a single or a few measures, and of capturing the entire effect of the phenomenon of gender. However, these strategies could lead to more accurate analyses of the mechanisms underlying health differences between men and women.

Painful bladder syndrome/interstitial cystitis (PBS/IC) is a chronic disorder that is commonly seen in women who report a history of adversity in early life. Here, we test the hypothesis that early life stress (ELS) induces sexually dimorphic abnormalities in urinary bladder smooth muscle function in adulthood. Male and female rat pups were conditioned on postnatal (PN) days 8–12 with either a “predictable or “unpredictable” odor-shock, or odor only control treatment. In adulthood, urinary bladder function was assessed in vivo via urine spot analysis and in vitro via contractile responses to electrical field stimulation (EFS) and membrane depolarization with potassium chloride (KCl). In adulthood, we found that female rats exposed to unpredictable ELS showed a significant (p < 0.05) increase in urine voiding volume compared to predictable ELS or controls. We also found that detrusor muscle contractile responses to EFS were significantly (p < 0.001) decreased following unpredictable ELS in adult female rats compared to the predictable ELS or controls. In male rats exposed to ELS, there was no difference in voiding volume or EFS-induced contractility between groups. In adulthood, the myogenic smooth muscle response to KCl was not significantly different between groups. Histological analysis from adult female and male rats revealed no differences in the appearance of the urinary bladder in rats exposed to ELS. In summary, our findings provide evidence to support abnormalities in the nerve-mediated contractile responses of the detrusor smooth muscle in adult female rats following ELS. We speculate that these sexually dimorphic alterations in urinary bladder function may account, at least in part, for the female predominance of PBS/IC.

We now know that cancer is many different diseases, with great variation even within a single histological subtype. With the current emphasis on developing personalized approaches to cancer treatment, it is astonishing that we have not yet systematically incorporated the biology of sex differences into our paradigms for laboratory and clinical cancer research. While some sex differences in cancer arise through the actions of circulating sex hormones, other sex differences are independent of estrogen, testosterone, or progesterone levels. Instead, these differences are the result of sexual differentiation, a process that involves genetic and epigenetic mechanisms, in addition to acute sex hormone actions. Sexual differentiation begins with fertilization and continues beyond menopause. It affects virtually every body system, resulting in marked sex differences in such areas as growth, lifespan, metabolism, and immunity, all of which can impact on cancer progression, treatment response, and survival. These organismal level differences have correlates at the cellular level, and thus, males and females can fundamentally differ in their protections and vulnerabilities to cancer, from cellular transformation through all stages of progression, spread, and response to treatment. Our goal in this review is to cover some of the robust sex differences that exist in core cancer pathways and to make the case for inclusion of sex as a biological variable in all laboratory and clinical cancer research. We finish with a discussion of lab- and clinic-based experimental design that should be used when testing whether sex matters and the appropriate statistical models to apply in data analysis for rigorous evaluations of potential sex effects. It is our goal to facilitate the evaluation of sex differences in cancer in order to improve outcomes for all patients.

Men have a higher risk for cardiovascular disease (CVD) early in life, while women have a higher risk later in life. The sex-related differences in CVD risk, especially by age, could be related to sphingolipid metabolism. We compared plasma sphingolipid concentrations and its increase by age in men and women. Plasma concentrations of 13 types of sphingolipids were measured by liquid chromatography-tandem mass spectrometry in a random subsample of 328 men and 372 women of Dutch and South-Asian Surinamese ethnic origin, participating in the HELIUS study. Sphingolipid concentrations were compared between men and women by age group (18–39, 40–55, and 56–70 years). Multiple linear regression was used to determine sex differences in age trends in sphingolipids stratified by ethnicity. Analyses were performed without adjustment and adjusted for body mass index (BMI) and waist circumference. At age 18–39 years, sphingolipid concentrations were lower in women than those in men, but at age 56–70 years this was reversed. At higher age, women showed higher concentrations than men. In line, we observed a more rapid increase of sphingolipid concentrations by age in women than in men. The observed sex differences were not explained by BMI or waist circumference. Patterns of sex differences were similar across ethnic groups, although the strength of associations differed. Mean sphingolipid concentrations increase more rapidly with age in women than in men. Therefore, plasma lipid concentrations of sphingolipids, although lower in women than in men at younger age, are higher in women than in men at older age.

Previous studies have indicated that inefficient energy utilization may play a pivotal role in hypertrophic cardiomyopathy (HCM). However, whether plasma free fatty acid (FFA), a main energy substrate of heart, has an effect on HCM remains unclear. Besides, several studies have suggested sex-related differences in HCM features and FFA metabolism. Here, we aimed to explore the association between plasma FFA levels and HCM and potential effects of sex on this relation. A total of 412 patients (age 47.8 ± 12.7 years, 243 males (59.0%)) with HCM were recruited. Complete medical history was collected. Echocardiography and cardiovascular magnetic resonance imaging (CMRI) were performed. Fasting plasma FFA was determined by clinical laboratory. Left ventricular mass (LVM), maximum wall thickness (MWT), and left atrium diameter (LAD) were assessed with CMRI. The median FFA levels were 0.38 (interquartile range (IQR) 0.27–0.52) mmol/L in men and 0.40 (IQR 0.30–0.59) mmol/L in women. The FFA levels were significantly lower in men compared with those in women (p = 0.005). Compared with women, men had greater LVM index (LVMI) (96.8 ± 37.6 vs. 78.6 ± 31.5 g/m2, p < 0.001). FFA levels in male patients correlated positively with LVM, LVMI, LAD, cholesterol levels, high-density lipoprotein-cholesterol (HDL-C) levels, heart rate, and systolic blood pressure (SBP). However, none of these variables were significantly associated with sqrt (FFA) in female patients except a borderline correlation of LAD (p = 0.050). Multiple linear regression analysis was performed in male patients and revealed that HDL-C (β = 0.191, p = 0.002), heart rate (β = 0.182, p = 0.004), SBP (β = 0.167, p = 0.007), LVMI (β = 0.132, p = 0.032), and LAD (β = 0.165, p = 0.009) were independently associated with increasing FFA levels. In patients with HCM, LVMI, LAD, HDL-C, SBP, and heart rate were independently associated with increasing plasma FFA levels in males, whereas not in females. These results suggest that sex may affect the pathogenesis of HCM through influencing FFA metabolism. And these sex-related differences should be taken into account in therapeutic approaches to influence myocardial FFA metabolism in HCM.

Rối loạn lưỡng cực (BD) ảnh hưởng đến cả hai giới, nhưng có sự khác biệt quan trọng về giới tính liên quan đến triệu chứng và các bệnh đi kèm. Ví dụ, chu kỳ nhanh (RC) gặp nhiều hơn ở phụ nữ, trong khi rối loạn sử dụng rượu (AUD) lại phổ biến hơn ở nam giới. Chúng tôi giả thuyết rằng các biến thể trên nhiễm sắc thể X có thể liên quan đến các đặc điểm khác nhau theo giới tính của BD. Một số ít nghiên cứu đã khám phá vai trò của nhiễm sắc thể X trong BD, điều này trở nên phức tạp bởi quá trình bất hoạt nhiễm sắc thể X (XCI). Quá trình này đạt được "bù trừ liều lượng" cho nhiều gen trên nhiễm sắc thể X bằng cách làm tắt một trong hai bản sao ở phụ nữ, và hầu hết các phương pháp thống kê đều bỏ qua việc xảy ra XCI hoặc giả định sai rằng một bản sao bị bất hoạt ở tất cả các vị trí. Chúng tôi giới thiệu các phương pháp thống kê mới không có những giả định này. Chúng tôi đã điều tra giả thuyết này trên 1001 bệnh nhân BD từ Mạng thông tin Liên kết Di truyền (GAIN) và 957 bệnh nhân BD từ Ngân hàng sinh học Rối loạn lưỡng cực Mayo Clinic. Chúng tôi đã kiểm tra mối liên hệ của hơn 14.000 biến dị đơn nucleotide (SNP) trên nhiễm sắc thể X với các đặc điểm BD liên quan đến giới tính bằng cách sử dụng hai phương pháp thống kê tính đến việc một SNP có thể đang trải qua hoặc thoát khỏi XCI. Trong "phương pháp thông tin XCI", chúng tôi đã áp dụng mô hình hồi quy logistic điều chỉnh giới tính giả định các hiệu ứng di truyền cộng gộp, trong đó chúng tôi mã hóa SNP bằng cách giả định một bản sao được biểu hiện hoặc hai bản sao được biểu hiện dựa trên kiến thức trước đó về các vùng bị bất hoạt. Trong "phương pháp vững chắc XCI", chúng tôi đã áp dụng mô hình hồi quy logistic với các hiệu ứng giới tính, SNP và tương tác SNP-giới tính, có độ linh hoạt cho việc vùng này có bị bất hoạt hay không. Sử dụng "phương pháp thông tin XCI", chỉ xem xét hiệu ứng chính của SNP và không cho phép hiệu ứng của SNP khác nhau theo giới tính, không có mối liên hệ đáng kể nào được xác định cho bất kỳ kiểu hình nào. Sử dụng "phương pháp vững chắc XCI", SNP liên gen rs5932307 có liên quan đến BD (P = 8.3 × 10−8), với hiệu ứng mạnh hơn ở phụ nữ (tỉ lệ odds ở nam giới (ORM) = 1.13, tỉ lệ odds ở phụ nữ cho sự thay đổi của hai bản sao alen (ORW2) = 3.86). Các nghiên cứu liên quan đến nhiễm sắc thể X nên sử dụng các phương pháp tính đến sinh học độc đáo của nó. Cần có những nghiên cứu trong tương lai để xác nhận các liên hệ đã được xác định với BD, để đánh giá chính thức hiệu suất của cả hai phương pháp dưới các kiến trúc di truyền thực sự khác nhau, và để áp dụng những phương pháp này trong việc nghiên cứu sự khác biệt về giới tính trong các điều kiện khác.