Endometriosis-induced vaginal hyperalgesia in the rat: Effect of estropause, ovariectomy, and estradiol replacement

Abstract

Endometriosis (ENDO) is a painful disorder defined by extrauteral endometrial growths. It is created in rats by autotransplanting pieces of uterus (which form cysts), or, for shamENDO, fat (no cysts). ENDO induces vaginal hyperalgesia, likely via central sensitization. The severity of this hyperalgesia correlates with estradiol levels during the estrous cycle, suggesting the hyperalgesia is estradiolmodulated. If so, then hyperalgesic severity should track estradiol changes during reproductive senescence (estropause) when estradiol levels initially decrease, then increase. Using psychophysical methods to assess vaginal nociception, we found that the severity of ENDO-induced hyperalgesia paralleled estradiol changes during estropause: hyperalgesia first decreased, then returned. Furthermore, the return occurred regardless of the presence of the cysts (excised in some rats). This finding provides further support for ENDO's likely centrally-mediated effects. Additionally, the results suggest that elimination of estradiol via ovariectomy (OVX) should alleviate ENDO-induced hyperalgesia and estradiol replacement should restore it. However, in healthy and shamENDO rats, OVX produces a vaginal hyperalgesia that is alleviated by estradiol, likely via estradiol's peripheral influences on the vagina. Hence, we tested the hypothesis that OVX in ENDO rats would trigger a different type of vaginal hyperalgesia dependent on the loss of estradiol. We predicted that the opposing influences of estradiol on ENDO-and OVX-induced hyperalgesia would cancel each other. As predicted, OVX had no effect on ENDO-induced hyperalgesia and estradiol replacement alleviated it. These results suggest that, in intact rats, ENDO-induced vaginal hyperalgesia is exacerbated by estradiol, and that different mechanisms underlie ENDO-induced versus OVXinduced vaginal hyperalgesia.

Innervation of endometrium and myometrium in women with painful adenomyosis and uterine fibroids

“…For example, when treated by combined OCs and progestogens, endometriotic lesions, pain symptoms, and nerve fiber density in ectopic and eutopic endometrium and myometrium are decreased and the levels of estrogen are reduced (8,17). It is suggested that the innervation of the endometrium and myometrium and pain symptoms in women with endometriosis are under the control of estrogen (18)(19)(20)(21)(22).…”

Hypercholesterolemia and 3-hydroxy-3-methylglutaryl coenzyme A reductase regulation in aged female rats

“…We chose, as an experimental model, 12 month-old female rats because only at 12 months is estrogen behavior similar to that occurring in human females at the onset of menopause (Berkley, 2007).…”

“…At the beginning of estropause (12 months of age), female rats --like women --cycle irregularly, but after cycling ceases, 17-β estradiol levels in rats --unlike those in women and mice --fall not to zero, but to steady moderate levels (for two months) and then increase again (Berkley et al, 2007). So we can consider 12-month-old female rats to be in a similar condition to that occurring in women at the onset of menopause.…”

Reduced sympathetic neurite outgrowth on uterine tissue sections from rats treated with estrogen

“…These results suggest that, under the influence of estrogen, the endometrial stroma produces inhibitory signals for sympathetic nerves, whereas epithelial basal laminas retain their ability to support neuritic growth. The relatively recent finding of an abnormal presence of sympathetic and other nerves in eutopic endometrium and ectopic endometriotic growths in women with endometriosis (Tokushige et al 2006(Tokushige et al , 2007 and in ectopic cysts of rats with experimental endometriosis (Berkley et al 2004(Berkley et al , 2007 have increased the relevance of understanding in detail the mechanisms regulating the innervation of the endometrium and its responses to estrogen. Recent studies have demonstrated that increased levels of NGF and other trophic molecules contribute to the abnormal innervation observed in eutopic endometrium and ectopic endometriotic growths in women with endometriosis (Anaf et al 2002;Tokushige et al 2006).…”