Published epidemiological studies of traumatic brain injury (TBI) of all severities consistently report higher incidence in men. Recent increases in the participation of women in sports and active military service as well as increasing awareness of the very large number of women who sustain but do not report TBI as a result of intimate partner violence (IPV) suggest that the number of women with TBI is significantly larger than previously believed. Women are also grossly under-represented in clinical and natural history studies of TBI, most of which include relatively small numbers of women, ignore the role of sex- and age-related gonadal hormone levels, and report conflicting results. The emerging picture from recent studies powered to detect effects of biological sex as well as age (as a surrogate of hormonal status) suggest young (i.e., premenopausal) women are more likely to die from TBI relative to men of the same age group, but this is reversed in the 6th and 7th decades of life, coinciding with postmenopausal status in women. New data from concussion studies in young male and female athletes extend this finding to mild TBI, since female athletes who sustained mild TBI are significantly more likely to report more symptoms than males. Studies including information on gonadal hormone status at the time of injury are still too scarce and small to draw reliable conclusions, so there is an urgent need to include biological sex and gonadal hormone status in the design and analysis of future studies of TBI.

Aromatase, the last and obligatory enzyme catalyzing estrogen biosynthesis from androgenic precursors, can be labeled in vivo with ¹¹C-vorozole. Aromatase inhibitors are widely used in breast cancer and other endocrine conditions. The present study aimed to provide baseline information defining aromatase distribution in healthy men and women, against which its perturbation in pathologic situations can be studied. Methods: ¹¹C-vorozole (111–296 MBq/subject) was injected intravenously in 13 men and 20 women (age range, 23–67 y). PET data were acquired over a 90-min period. Each subject had 4 scans, 2 per day separated by 2–6 wk, including brain and torso or pelvis scans. Young women were scanned at 2 discrete phases of the menstrual cycle (midcycle and late luteal). Men and postmenopausal women were also scanned after pretreatment with a clinical dose of the aromatase inhibitor letrozole. Time–activity curves were obtained, and standardized uptake values (SUV) were calculated for major organs including brain, heart, lungs, liver, kidneys, spleen, muscle, bone, and male and female reproductive organs (penis, testes, uterus, ovaries). Organ and whole-body radiation exposures were calculated using OLINDA software. Results: Liver uptake was higher than uptake in any other organ but was not blocked by pretreatment with letrozole. Mean SUVs were higher in men than in women, and brain uptake was blocked by letrozole. Male brain SUVs were also higher than SUVs in any other organ (ranging from 0.48 ± 0.05 in lungs to 1.5 ± 0.13 in kidneys). Mean ovarian SUVs (3.08 ± 0.7) were comparable to brain levels and higher than in any other organ. Furthermore, ovarian SUVs in young women around the time of ovulation (midcycle) were significantly higher than those measured in the late luteal phase, whereas aging and cigarette smoking reduced ¹¹C-vorozole uptake. Conclusion: PET with ¹¹C-vorozole is useful for assessing physiologic changes in estrogen synthesis capacity in the human body. Baseline levels in breasts, lungs, and bones are low, supporting further investigation of this tracer as a new tool for detection of aromatase-overexpressing primary tumors or metastases in these organs and optimization of treatment in cancer and other disorders in which aromatase inhibitors are useful.

Significance: Obesity is a major public health problem in a growing proportion of children and adults in the developed world. Estrogen influences body weight and behavioral responses to appetitive stimuli. Estrogen biosynthesis is catalyzed by the enzyme aromatase in all organs measured, including the brain. Using the aromatase radiotracer [ ¹¹ C]vorozole, we measured aromatase availability in the amygdala in healthy-weight to obese adults. Obesity was associated with lower aromatase availability and less constraint independent of sex and age. Variability in brain estrogen synthesis may contribute to obesity by directly regulating feeding and broadly by affecting self-control. These findings suggest that brain aromatase imaging offers a method for characterizing the role of brain estrogen in obesity and other impairments in self-regulation.