Sex, Gender, and Transgender: Metabolic Impact of Cross Hormone Therapy.

Most preclinical and clinical, animal, and human research has been biased with respect to sex and even more so with respect to gender. In fact, little is known about the impact of sex and even less about the influence of gender on overall metabolic processes. The National Institutes of Health has recognized this gap in scientific knowledge and now mandates that studies be conducted in both sexes and to include gender as variables influencing physiological processes such as metabolism. It is therefore critical to understand and appreciate how to incorporate sex and gender in preclinical and clinical research in order to enhance our understanding of the mechanisms by which metabolic processes differ by sex and gender. In this chapter, we define sex and gender and discuss when sex and gender are not aligned, such as that which occurs in transgender individuals, and how this impacts metabolic processes. We discuss the importance of understanding the influence and interactions between sex hormones and sex chromosomes rather than focusing on their relative contributions to metabolism in isolation. This knowledge will optimize therapies specific for individuals which need to encompass sex and gender.

PI3K in the ventromedial hypothalamic nucleus mediates estrogenic actions on energy expenditure in female mice.

Estrogens act in the ventromedial hypothalamic nucleus (VMH) to regulate body weight homeostasis. However, the molecular mechanisms underlying these estrogenic effects are unknown. We show that activation of estrogen receptor-α (ERα) stimulates neural firing of VMH neurons expressing ERα, and these effects are blocked with intracellular application of a pharmacological inhibitor of the phosphatidyl inositol 3-kinase (PI3K). Further, we demonstrated that mice with genetic inhibition of PI3K activity in VMH neurons showed a sexual dimorphic obese phenotype, with only female mutants being affected. In addition, inhibition of VMH PI3K activity blocked effects of 17ß-estradiol to stimulate energy expenditure, but did not affect estrogen-induced anorexia. Collectively, our results indicate that PI3K activity in VMH neurons plays a physiologically relevant role in mediating estrogenic actions on energy expenditure in females.

Overweight postmenopausal women with different plasma estradiol concentrations present with a similar pattern of energy expenditure and substrate oxidation rate before and after a fatty meal challenge.

Menopause-related withdrawal of ovarian estrogens is associated with reduced energy metabolism and overall impairment of substrate oxidation. Estradiol's withdrawal after menopause is associated with a reduction in energy metabolism and impaired substrate oxidation, which contributes to weight gain and visceral fat accumulation. Here we aimed to investigate the association between plasma estradiol concentrations and energy expenditure (EE)/substrate oxidation in a group of overweight postmenopausal women before and after a fatty meal challenge. Women were divided into three groups according to their plasma estradiol concentrations (E2): group 1 - E2 ≤ 39, group 2 - 40 ≤ E2 ≤ 59, and group 3 - E2 ≥ 60 pg/mL. VO2 and VCO2 volumes were collected following indirect calorimetry 5 h following a single lipid overload meal (1100 kcal, 72% of fat). For comparisons between groups and within the same group, a linear regression model with mixed effects was applied (P < 0.05). Forty-four women aged 55 ± 0.7 years-old, 8 ± 1.1 years following menopause, with a BMI of 30.5 ± 0.5 kg/m2, and 41.9 ± 0.7% of body fat were enrolled the study. Plasma E2 concentrations were: group 1 - 30.4 ± 1.9, group 2 - 46.9 ± 1.5, and group 3 - 91.3 ± 12.0 pg/mL (P < 0.0001). EE at baseline and in the resting state was 1320 ± 24.3 kcal/d, and increased to 1440 ± 27.0 kcal/d 30 min following ingestion of the fatty meal (P < 0.0001), and rose again to an average of 1475 ± 30.3 kcal/d at the completion of experiment (P < 0.0001). Carbohydrate oxidation (Chox) was 0.155 ± 0.01 g/min at resting, maintained as 0.133 ± 0.00 g/min 30 min after ingestion of the fatty meal, and was 0.123 ± 0.01 g/min at the end of the testing period. Lipid oxidation (Lipox) was 0.041 ± 0.003 g/min at resting, increasing to 0.054 ± 0.003 g/min at 30 min (P = 0.01), and reaching 0.063 ± 0.003 g/min at the end of the experiment (P < 0.0001). There was no difference between groups for EE, Chox or Lipox. Our data suggest that EE and substrate oxidation were modulated following a lipid-meal challenge equally in all groups and this did not differ with plasma E2 concentrations.

Sexual dimorphism in body fat distribution and risk for cardiovascular diseases.

The prevalence of obesity has dramatically increased over the past decade along with the cardiovascular and other health risks it encompasses. Adipose tissue, which is distributed in the abdominal viscera, carries a greater risk for cardiovascular disorders than adipose tissue subcutaneously. There is a sex difference in the regional fat distribution. Women have more subcutaneous fat, whereas men have more visceral fat. Therefore, obesity-related metabolic disorders are much lower in premenopausal women than men. Peripheral metabolic signals like leptin and insulin are involved in the food intake, body weight, body fat distribution, and cardiovascular disease. Key areas in the brain, including the hypothalamus, integrates these peripheral adiposity signals to maintain overall adiposity levels, and these brain regions are directly influenced by sex hormones. Therefore, differences in cardiovascular disease may be under the influence of sex hormones either directly in the brain or through their influence of body fat distribution. The role of estrogen in mediating body fat distribution and cardiovascular disease is the focus of this review.