# Sex Specific Associations of Sex hormone With Brain Volumes and Cerebral Blood Flow: A Cross Sectional Observational Study Within the Look AHEAD Type 2 Diabetes Cohort

## TL;DR

Postmenopausal women with detectable testosterone levels have larger brain volumes relative to skull size, suggesting testosterone may protect brain health in women with diabetes.

## Contribution

This study explores the sex-specific association of testosterone with brain volume in postmenopausal women with Type 2 Diabetes.

## Key findings

- Females with detectable total testosterone had higher brain volume to intracranial volume ratio compared to those with undetectable levels.
- No significant associations were found between estradiol or testosterone levels and brain measures in males.
- The observed association in females was weakened after adjusting for age and BMI.

## Abstract

Females have greater brain volume and cerebral blood flow than males when controlling for intracranial volume and age. Brain volume decreases after menopause, suggesting a role of sex hormones. We studied the association of sex hormones with brain volume, white matter hyperintensity volumes and cerebral blood flow in people with Type 2 Diabetes and with overweight and obesity conditions that accelerate brain atrophy.

We analyzed data from 215 participants with overweight or obesity and Type 2 Diabetes from the Look AHEAD Brain Magnetic Resonance Imaging ancillary study (mean age 68 years, 73% postmenopausal female). Estradiol and total testosterone levels were measured with electrochemoluminescence assays. The ratio of brain measurements to intracranial volume was analyzed to account for body size. We analyzed sex hormones as quantitative measures in males, whereas in females we grouped those with detectable vs. undetectable hormone levels (Estradiol <73 pmol/L [20 pg/mL]: 79%; Total Testosterone < 0.07 mmol/L [0.02 ng/mL]: 37% undetectable in females).

Females with detectable total testosterone levels had higher brain volume to intracranial volume ratio (median [25th, 75th percentile]: 0.85 [0.84, 0.86]) as compared to those with undetectable Total Testosterone levels (0.84 [0.83, 0.86]; rank sum p=0.04). This association was attenuated after age and body mass index adjustment (p=0.08). Neither white matter hyperintensity volumes or cerebral blood flow in females, nor any brain measures in males, were significantly associated with Estradiol or Total Testosterone.

In postmenopausal females with Type 2 Diabetes with overweight and obesity, detectable levels of total testosterone were associated greater brain volume relative to intracranial volume, suggesting a protective role for testosterone in female brain health. Our findings are limited by a small sample size and low sensitivity of hormone assays. Our suggestive findings can be combined with future larger studies to assess clinically important differences.

NCT00017953

Females have a larger relative size of the brain and blood flow than males after accounting for skull cavity size. Also, brain volume reduces after menopause, suggesting that sex hormones may affect brain size and health. This may be important in people with diabetes, a condition affecting brain health, but has not been well studied. In a smaller sample of 156 postmenopausal females and 59 similar-aged males within the Look AHEAD study of people with diabetes, we tested if levels of the sex hormones estradiol and testosterone were related to brain volumes, blood flow and the burden of early abnormalities known as white matter hyperintensities using Magnetic Resonance Imaging. We found no relationships between sex hormone levels and brain measures among males. Among postmenopausal females, brain volumes as a percentage of skull cavity volume was larger in females with detectable testosterone levels as compared to those without detectable hormone levels. This relationship was similar but not as strong when we took age and body mass index into account. Our results may be weaker than the actual relationship between sex hormones and brain volumes and health because our study sample was small, and the measurement of sex hormones was not sensitive enough for most postmenopausal females. However, our findings suggest a role for testosterone levels in preserving brain size in females and highlight the need for larger studies with sensitive hormone measurements to confirm and expand our results.