Testosterone restores respiratory long term facilitation in old male rats by an aromatase‐dependent mechanism

Non‐technical summary Steroidal sex hormones (testosterone, oestradiol and progesterone) play an important role in the neural control of breathing. Hormone levels typically change throughout life. Testosterone levels increase during puberty in boys, but from ∼30 years of age levels decline gradually. The typical age of onset for obstructive sleep apnoea, a prominent breathing disorder of older humans, is ∼50 years of age in men. In a study in old male rats, we show that testosterone supplementation can reverse the age‐associated decrease in one measurement of the neural control of breathing. We conclude that testosterone supplementation can potentially be used to enhance upper airway function in the elderly. Steroidal sex hormones play an important role in the neural control of breathing. Previous studies in our laboratory have shown that gonadectomy in young male rats (3 months) eliminates a form of respiratory plasticity induced by intermittent hypoxia, known as long term facilitation (LTF). Testosterone replenishment restores LTF in gonadectomized male rats, and this is dependent on the conversion of testosterone to oestradiol by aromatase. By middle age (12 months), male rats no longer exhibit LTF of hypoglossal motor output; phrenic LTF is significantly reduced, and this persists into old age. We tested the hypothesis that LTF can be restored in old male rats by administration of testosterone. Intact Fischer 344 rats (>20 months) were implanted with Silastic tubing containing testosterone (T), T plus an aromatase inhibitor (T+ADT), or 5α‐dihydrotestosterone (DHT), a form of testosterone not converted to oestradiol. One week post‐surgery, LTF of hypoglossal and phrenic motor output was measured. By comparison with control rats, hypoglossal LTF was increased in testosterone‐treated rats, with levels approaching that of normal young rats. LTF was not restored in T+ADT or DHT‐treated rats. Aromatase levels in hypoglossal and phrenic nuclei did not change with age. As serum testosterone levels did not decline with age, local bioavailability of testosterone in old rats may be a limiting factor in the expression of this form of respiratory plasticity. Our findings suggest that testosterone supplementation could potentially be used to enhance upper airway control in the elderly.