This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hickey, M. Articles by Salamonsen, L. A. Search for Related Content PubMed PubMed Citation Articles by Hickey, M. Articles by Salamonsen, L. A. Related Collections Female Endocrinology

Menopausal Hormone Therapy and Irregular Endometrial Bleeding: A Potential Role for Uterine Natural Killer Cells?

School of Women’s and Infants’ Health (M.H., J.C., D.D.) and Department of Clinical Immunology and Biochemical Genetics (J.P.G.), Royal Perth Hospital and School of Surgery and Pathology, University of Western Australia, Perth 6008, Western Australia; Department of Clinical Immunology and Biochemical Genetics (C.S.W., F.T.C.), Royal Perth Hospital, Perth 6847, Western Australia; Sydney Centre for Reproductive Health Research (I.S.F.), Family Planning Association Health and Department of Obstetrics and Gynaecology, University of Sydney, Sydney 2006, Australia; and Prince Henry’s Institute of Medical Research (L.A.S.), Melbourne, Victoria 3168, Australia

Address all correspondence and requests for reprints to: Martha Hickey, Associate Professor, School of Women’s and Infants’ Health, King Edward Memorial Hospital, Subiaco, Perth 6008, Western Australia. E-mail: mhickey{at}obsgyn.uwa.edu.au.

Context: Irregular bleeding affects many users of combined menopausal hormone therapy (HT) and commonly leads to invasive and expensive investigations to exclude underlying malignancy. In most cases no abnormality is found.

Objective: The main objective of this study was to explore the role of uterine natural killer (uNK) cells and their regulatory cytokine IL-15 in irregular bleeding in HT users.

Design: This was a prospective observational study conducted between 2002 and 2004.

Setting: The study was conducted in a tertiary referral menopause clinic at King Edward Memorial Hospital, Western Australia.

Patients: Patients included 117 postmenopausal women taking combined HT.

Interventions: Outpatient endometrial biopsies were taken during and outside bleeding episodes.

Main Outcome Measures: The relationship between endometrial uNK cells (CD56+) and bleeding patterns was measured. We also addressed the impact of HT exposure on uNK cell populations, the relationship between endometrial IL-15 expression and uNK cell populations, and killer Ig like receptor genotype in subjects with irregular bleeding.

Results: Endometrial CD56+ uNK cells were significantly increased in biopsies obtained during bleeding episodes (P < 0.001), compared with HT users with no bleeding. The highest level of IL-15 expression was also seen in biopsies taken during bleeding. No clear relationship between killer Ig like receptor genotype and bleeding on HT was observed.

Conclusions: Little is known about the mechanisms underlying irregular bleeding in HT users. This is the first report of uNK cells and their association with regulating cytokines in postmenopausal endometrium and demonstrates a possible mechanism by which HT may induce irregular bleeding.

This article has been cited by other articles:

				S Daayana and C M Holland Hormone replacement therapy and the endometrium Menopause Int, September 1, 2009; 15(3): 134 - 138. [Abstract] [Full Text] [PDF]

				K. Kitaya and T. Yasuo Dermatan sulfate proteoglycan biglycan as a potential selectin L/CD44 ligand involved in selective recruitment of peripheral blood CD16(-) natural killer cells into human endometrium J. Leukoc. Biol., March 1, 2009; 85(3): 391 - 400. [Abstract] [Full Text] [PDF]

				M. Hickey, D.A. Doherty, I.S. Fraser, D.M. Sloboda, and L.A. Salamonsen Why does menopausal hormone therapy lead to irregular uterine bleeding? Changes to endometrial blood vessels Hum. Reprod., April 1, 2008; 23(4): 912 - 918. [Abstract] [Full Text] [PDF]

				N. B Morison, J. Zhang, T. J Kaitu'u-Lino, I. S Fraser, and L. A Salamonsen The long-term actions of etonogestrel and levonorgestrel on decidualized and non-decidualized endometrium in a mouse model mimic some effects of progestogen-only contraceptives in women Reproduction, January 1, 2007; 133(1): 309 - 321. [Abstract] [Full Text] [PDF]

				M. Hickey, J. Crewe, L. A. Mahoney, D. A. Doherty, I. S. Fraser, and L. A. Salamonsen Mechanisms of Irregular Bleeding with Hormone Therapy: The Role of Matrix Metalloproteinases and Their Tissue Inhibitors J. Clin. Endocrinol. Metab., August 1, 2006; 91(8): 3189 - 3198. [Abstract] [Full Text] [PDF]

				A. Peloggia, C. A. Petta, L. Bahamondes, M. Oliveira-Ribeiro, J. Zhang, and L. Salamonsen Endometrial chemokines, uterine natural killer cells and mast cells in long-term users of the levonorgestrel-releasing intrauterine system Hum. Reprod., May 1, 2006; 21(5): 1129 - 1134. [Abstract] [Full Text] [PDF]