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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.

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