245. Endometrial changes in a mouse model for long-term progestin exposure: implications for break-through bleeding
N. B. Morison A , J. Shen A , J. Zhang A , T. J. Kaitu’u A and L. A. Salamonsen APrince Henry’s Institute of Medical Research, Clayton, VIC, Australia
Reproduction, Fertility and Development 17(9) 97-97 https://doi.org/10.1071/SRB05Abs245
Submitted: 26 July 2005 Accepted: 26 July 2005 Published: 5 September 2005
Abstract
A mouse model of menstruation1 was modified to evaluate the effects of long-term progestagens on the endometrium. Many women using long-acting progestin (P)-only contraceptives experience break-through bleeding (BTB) and this is the main reason for discontinuation of their use by 30% of users. To understand the mechanisms involved in BTB, ovariectomised mice treated with a strict steroid hormone regime, had etonogestrel- or levonorgestrel-releasing implants inserted subcutaneously. A decidualizing stimulus (oil) was administered into one uterine horn; decidualisation was maximal 48 h later, designated day 0 (d0). The implant was left in place for a further 45 days. Uteri were collected at 5-day intervals and analysed for morphological changes, leukocyte infiltration, and matrix metalloproteinase (MMP) expression.
In uteri from mice treated with etonogestrel and examined at d0, decidualisation was maximal and very few leukocytes were present (neutrophils, NEU; Macrophages, Mac; uterine natural killer cells, uNK). Some loss of tissue integrity was seen at 5d, associated with some MMP-9 positive leukocytes. However, substantial stromal breakdown was observed at 10d and this progressed until 25d. A large infiltrate of NEU and uNKs, as well as increased MMP-9 expression, was observed at these times. At 25d there was evidence of re-epithelialisation and by 45d the tissue had fully repaired back to its pre-decidualised state. Re-epithelialisation was associated with a decline in NEU and uNKs, as well as MMP-9 positive immunostaining. The morphology of uteri from mice treated with levonorgestrel implants was compared to mice treated with etonogestrel. The changes observed were very similar with a loss of tissue integrity at 5d and tissue destruction at 10d.
This mouse model mimics the changes in leukocyte populations and MMP expression observed in endometria of some women using P-only contraceptives.
(1) Brasted M, White CA, Kennedy TG, Salamonsen LA. (2003) Biololgy of Reproduction 69(4), 1273–1280.
