Sex hormones and mucosal wound healing

Abstract

Wound healing studies, which have chiefly examined dermal tissues, have reported a female advantage in healing rates. In contrast, our laboratory recently demonstrated women heal mucosal wounds more slowly than men. We hypothesized sex hormones influence wound healing rates, possibly through their modulating effects on inflammation. This study involved 329 younger subjects aged 18-43 (165 women, 164 men) and 93 older subjects aged 50-88 (60 women, 33 men). A 3.5mm diameter wound was created on the hard oral palate and videographed daily to assess wound closure. Blood collected at the time of wounding was used to assess circulating testosterone, progesterone and estradiol levels, and in vitro cytokine production in response to LPS. No strong associations were observed between healing times and estradiol or progesterone levels. However, in younger subjects, lower testosterone levels related to faster wound closure. Conversely, in older women higher testosterone levels related to (1) lower inflammatory responses; and (2) faster healing times. No such relationships were seen in older men, or in women taking oral contraceptives or hormone replacement therapy [HRT]. Older women (50-54 years) not yet experiencing menopause healed similarly to younger women and dissimilarly from age-matched post-menopausal women. This suggests that the deleterious effects of aging on wound healing occur secondary to the effects of menopause. Supporting this, there was evidence in post-menopausal women that HRT augmented wound closure. Overall, this study suggests that human mucosal healing rates are modulated by testosterone levels. Based upon when between-group differences were observed, testosterone may impact upon the proliferative phase of healing which involves immune processes such as re-epithelialization and angiogenesis.

Fig 1

Young men with higher testosterone levels exhibited delayed wound closure on days 5-7 compared to young men with lower testosterone levels (based on median split). No such differences were seen in older men. Error bars represent standard error of the mean (SEM). * p<0.05, # p<.10

Fig 2

In naturally cycling young women, individuals with higher testosterone levels exhibited delayed wound closure on days 3-7 compared to individuals with lower testosterone levels (based on median split). These effects were not seen in women taking OCs. Error bars represent SEM. * p<.05, ** p<0.01, # p<0.10

Fig 3

In post-menopausal women, those taking HRT exhibited a trend for faster wound closure compared to those not taking HRT. Error bars represent SEM. # p<.10

Fig 4

In post-menopausal women not taking HRT, those with higher testosterone levels exhibited faster wound closure on days 5-6 compared to those with lower testosterone levels (based on median split). Error bars represent SEM. * p<.05

Fig 5

Older women who were pre-menopausal (50-54 years; n=6) showed a pattern of healing similar to that of young women (n=160) and dissimilar to that of age-matched (50-55 years) post-menopausal women not taking HRT (n=13). This suggests that age is not a negative factor on wound healing in women until menopause begins. Error bars represent SEM. * p<.05, # p<.10