Effects of age and exposure to cyclic ovarian hormones on mouse myometrium

Delaying first childbirth is associated with a range of pregnancy complications, but the mechanisms underlying this are unclear. We have hypothesized that prolonged, cyclical, pre-pregnancy exposure to estrogen and progesterone contributes to age-related deterioration of uterine function. We conducted a series of studies in virgin mice of varying age and exposure to hormonal manipulations. We compared the myometrial transcript profile from young (10-12 weeks, n=7) and old (28-30 weeks, n=7) mice. We validated this list using a second experiment of young versus old mice housed in a different animal facility and comparing animals of 10-12 (n=8) and 38-40 (n=7) weeks of age. The pattern of change in these transcripts was very similar. We determined whether removal of the ovaries in early life (8-10 weeks of age) prevented age-related changes. When we compared old animals (38-40 weeks) which had early ovariectomy (n=7) with sham operated controls of the same age (n=7), we found that the transcripts which had been down-regulated by age were upregulated in old animals that had an early ovariectomy. The converse was observed for genes which had been downregulated by age. Hence, early ovariectomy prevented changes in myometrial gene expression associated with aging. We then studied the effect of prolonged, continuous exposure to progesterone between 8 and 36 weeks of age. When we compared old animals (38-40 weeks) that received progesterone implants from 8 to 36-38 weeks (n=10) with old animals receiving implants containing only vehicle (n=5), transcripts which had been down-regulated by age were upregulated by prolonged exposure to progesterone. The converse was observed for genes which had been downregulated by age. Hence, prolonged exposure to progesterone also ameliorated changes in myometrial gene expression associated with aging.

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Chong HP, Cordeaux Y, Ranjan YS, Richardson S, Liquet B, Smith GC, Charnock-Jones DS