Endometrial repair after menstruation

Summary

Using laser capture, microarray analyses, real-time PCR and immunohistochemistry on tissues from both our mouse model of menstruation and repair and human endometrial tissues, we are determining the molecular mechanisms of repair of the endometrium immediately after menstruation. We hypothesise that disturbances of repair result in abnormal uterine bleeding.

Description

Uterine bleeding problems are a major health issue for women and the major reason for women visiting a gynaecologist. Abnormal bleeding results in lower quality of life and many days off work for the affected women.

The mechanisms underlying normal uterine bleeding (menstruation: in which the endometrium is shed) and the tissue repair following menstruation are little understood. In part this is because it is very difficult to study: only women and a few old world primates menstruate and hence there are no natural animal models.

We have had a long term interest in this problem which lead us to establish a mouse model of endometrial breakdown and repair, and also a cell culture model using human endometrial cells. These, along with immunohistochemical studies on women during menstruation and repair, are enabling us to understand the unique processes of normal endometrial breakdown and the very rapid scar-free repair that follows very rapidly.

Uterine bleeding is also an important issue relating to acceptability of long acting progestin-only contraceptives: many of these women have bleeding and spotting that results in discontinuation of use of these very effective contraceptives. We have been addressing this problem, initially in association with the World Health Organisation and subsequently with support from the NIH.

We are currently working with a unique cohorts of tissues, collected by our clinical colleagues, to apply findings from our studies on normal menstruation that will enable us to better understand the mechanisms of this abnormal bleeding.

We are also currently using our mouse model and cell culture models along with laser capture of repairing cells and gene array analyses to establish the molecular basis of endometrial repair.

Funding

National Health and Medical Research Council

Outcomes

Developed and validated a mouse model for endometrial breakdown and repair
Showed that matrix metalloproteinases are active during menstruation and responsible for the widespread tissue breakdown
Shown that neutrophils are a necessary component of endometrial repair
Endometrial repair occurs even in the absence of oestrogen
Activin A is important for endometrial repair

Selected Publications

Weisberg E, Hickey M, Palmer D, O'Connor V, Salamonsen LA, Findlay JK, Fraser IS (2009). A randomised controlled trial of treatment options for troublesome uterine bleeding in Implanon users. Human Reproduction (accepted March 16)

Kaitu'u-Lino TJ, Phillips DJ, Morison NB, Salamonsen LA (2009) A new role for activin in endometrial repair after menses. Endocrinology [Epub Nov 20 2008] ‘Recommended article' in F1000 Medicine.

Morison NB, Kaitu'u-Lino TJ, Fraser IS, Salamonsen LA. (2008) Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen-only contraceptives. Reproduction 136(2):267-274

Hickey M, Salamonsen LA (2008) Endometrial structural and inflammatory changes with exogenous progestogens. Trends in Endocrinol Metabol 19:167-174.

Kaitu'u-Lino TJ, Morison NB, Salamonsen LA (2007) Estrogen is not essential for full endometrial restoration following breakdown: lessons from a mouse model. Endocrinology 148(10):5105-5111

Kaitu'u-Lino T, Morison N, Salamonsen L (2007) Neutrophil depletion retards endometrial repair in a mouse model. Cell Tissue Research 328(1):197-206

Hickey M, Crewe J, Mahoney LA, Doherty DA, Fraser IS, Salamonsen LA (2006) Mechanisms of irregular bleeding with hormone therapy: The role of matrix metalloproteinases and their tissue inhibitors. J Clin Endocrinol Metab 91(8): 3189-3198.

Salamonsen L.A., Kovacs,G. & Findlay J.K. (1999) Current concepts of the mechanisms of menstruation. In Baillière's Clinical Obstetrics and Gynaecology; Dysfunctional Uterine Bleeding. S.K.Smith (Ed) Baillière Tindall, London. 13(2): 161-179

PHI Research Team