The Effects of Sex Hormone Supplementation on Respiratory Function in Male SCI Rats

Sex hormones significantly influence respiratory function and the expression of respiratory neuroplasticity. For example, 17ß‐ estradiol (E2), the most prevalent and neuroactive sex steroid in females, is necessary for expression of phrenic long‐term facilitation (pLTF), a well characterized form of plasticity induced by acute intermittent hypoxia (AIH) in both females and males. To meet this requirement for E2, males aromatize testosterone to E2 in order to express respiratory neuroplasticity. However, on its own (i.e., without aromatase conversion to E2), testosterone has also been shown to enhance breathing. Since both E2 and testosterone have individually demonstrated the capacity to enhance respiratory function, we hypothesized that supplementation of these sex hormones would improve respiratory function in rats 2 weeks post experimental cervical spinal cord injury (SCI). Adult male Sprague‐Dawely rats received a C2 hemi‐section SCI (or Sham laminectomy) and recovered with standard post‐op care. One‐week post‐injury, a controlled‐release hormone pellet was placed subcutaneously in SCI rats to deliver a pre‐determined dose of daily hormone supplementation for the duration of the study. Pellets contained either E2 (β‐estradiol 3‐benzoate, 10 μg/day), 5α‐dihydrotestosterone (DHT), a testosterone derivative that is not converted to E2 (50 μg/day), or blank placebo pellets (50 μg/day). Respiratory function was measured 7 days later (2 weeks post SCI) using Whole‐Body Barometric Plethysmography. Consistent with prior reports, our preliminary findings demonstrated that placebo treated SCI rats breathed with increased respiratory frequency, but reduced tidal volume production. DHT supplementation had little impact on these respiratory parameters, with values remaining similar to placebo control rats. However, one week of E2 supplementation led to reductions in respiratory frequency and increased tidal volume production during baseline room‐air conditions and in response to a strong respiratory challenge (10.5% O2/5% CO2), suggesting improved overall ventilation. These data suggest that estrogen supplementation may facilitate improvements in breathing function in the early stages of spinal cord injury recovery. Support or Funding Information This work was supported by funding from The Minnesota Office of Higher Education, The University of Minnesota Division of Physical Therapy, and The University of Minnesota Department of Rehabilitation Medicine