Menopausal hormone therapy and irregular endometrial bleeding: a potential role for uterine natural killer cells?
BACKGROUND
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.


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


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


METHODS
Patients included 117 postmenopausal women taking combined HT.


METHODS
Outpatient endometrial biopsies were taken during and outside bleeding episodes.


METHODS
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.
Hickey
M
M
School of Women's and Infants' Health, Royal Perth Hospital, Perth 6008, Western Australia, Australia. mhickey@obsgyn.uwa.edu.au
Crewe
J
J
Goodridge
J P
JP
Witt
C S
CS
Fraser
I S
IS
Doherty
D
D
Christiansen
F T
FT
Salamonsen
L A
LA
D019002:CD56 Antigen / Q000276:immunology; D004717:Endometrium / Q000473:pathology*; D004958:Estradiol / Q000009:adverse effects / Q000627:therapeutic use; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D004966:Estrogens, Conjugated (USP) / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006470:Hemorrhage / Q000503:physiopathology*; D006801:Humans; D007150:Immunohistochemistry; D019409:Interleukin-15 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology*; D018655:Lymphocyte Count; D008593:Menopause / Q000187:drug effects*; D008875:Middle Aged; D011971:Receptors, Immunologic / Q000235:genetics; D014599:Uterus / Q000166:cytology / Q000503:physiopathology*
D019002:CD56 Antigen; D004966:Estrogens, Conjugated (USP); D019409:Interleukin-15; D011971:Receptors, Immunologic; D004958:Estradiol