Hum. Reprod. Advance Access originally published online on January 23, 2008
Human Reproduction 2008 23(4):912-918; doi:10.1093/humrep/dem418
Why does menopausal hormone therapy lead to irregular uterine bleeding? Changes to endometrial blood vessels
1 School of Women's and Infants' Health, King Edward Memorial Hospital, University of Western Australia, Subiaco, Perth, Western Australia 6008, Australia 2 Sydney Centre for Reproductive Health Research, F.P.A. Health and Department of Obstetrics and Gynaecology, University of Sydney, Australia 3 Prince Henry’s Institute of Medical Research, Melbourne, Victoria, Australia 4 The Liggins Institute, The University of Auckland, Private Bag 92019, Auckland, New Zealand
5Correspondence address. Tel: +61-8-9340-1330; Fax: +61-8-9381-3031; E-mail: mhickey{at}meddent.uwa.edu.au
BACKGROUND: Abnormal bleeding is common in hormone therapy (HT) users. We aimed to determine how HT alters endometrial blood vessels and stromal factors known to regulate vascular growth and integrity.
METHODS: Prospective observational study of 165 post-menopausal women in Western Australia. The following were measured in endometrial biopsies: vascular density (vessels/mm2), total vessel area (total area enclosed by peripheral vascular immunostaining for perivascular pericytes in mm2), total luminal area (mm2) and vessel wall area (total vessel area minus luminal area), stromal expression of matrix metalloproteinases (MMP) -1, -3, -9 and -14, their tissue inhibitors (TIMPs) -1-4 and vascular endothelial growth factor (VEGF) by immunohistochemistry.
RESULTS: Total vessel area was greater during bleeding compared with HT users with no bleeding (P = 0.028) or with a prior irregular bleeding (P = 0.039). Total vessel area was greater in non-HT users compared with HT users with no bleeding (P = 0.021). In HT users, vessel luminal area was greater during bleeding compared with HT users with no bleeding (P = 0.030) and vessel wall area was also increased (P = 0.025). During bleeding there was an increase in stromal TIMP-2 staining (P = 0.044). No significant changes in endometrial MMP or VEGF were seen.
CONCLUSIONS: Abnormal bleeding in HT users is associated with changes in endometrial vessel size and in stromal expression of factors known to regulate vascular growth and integrity. These changes may contribute to abnormal bleeding.
Key words: menopause/irregular bleeding/hormone therapy/endometrium/blood vessels
Submitted on January 1, 2007; resubmitted on December 5, 2007; accepted on December 13, 2007.