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Effects of long-term tibolone treatment on nuclear sex steroid hormone receptors and G-protein–coupled estrogen receptor-1 expression in the macaque uterus

Hulchiy, Mariana MD1,2,3; Zhang, Hua MD, PhD1,4; Cline, J. Mark DVM, PhD5; Hirschberg, Angelica Lindén MD, PhD2; Sahlin, Lena PhD1

Menopause: The Journal of The North American Menopause Society: March 2012 - Volume 19 - Issue 3 - p 332–338
doi: 10.1097/gme.0b013e318230f3be
Original Articles

Objective Tibolone is an alternative hormone treatment for managing climacteric symptoms in postmenopausal women. The aim of this study was to determine the effects of long-term tibolone (TIB) treatment in comparison with conventional hormone therapy on the expression and distribution of estrogen receptor (ER) α, ER-β, G-protein–coupled ER-1 (GPER), progesterone receptor (PR) A, PRB, androgen receptor (AR), and syndecan-1 in the macaque uterus.

Methods Eighty-eight cynomolgus macaques (Macaca fascicularis) were ovariectomized and treated orally with TIB, a combination of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA), CEE alone, or vehicle for 2 years. Immunohistochemistry was used to evaluate the protein expression and distribution of the receptors in the monkey uterus.

Results In the TIB group, immunostaining of ER-α and GPER was higher in the luminal and glandular epithelium, respectively, as compared with the CEE + MPA group. PRA and PRB protein expression was increased in the stroma and myometrium of the TIB group as compared with the controls. AR immunoreactivity was also up-regulated by TIB treatment in the stroma as compared with no treatment. Furthermore, epithelial immunoreactivity of AR was higher after TIB treatment as compared with CEE + MPA treatment.

Conclusions TIB treatment influences the protein expression of sex hormone receptors in monkey endometrium differently from that observed after conventional hormone therapy. We suggest that the observed differences in AR expression by TIB as compared with combined treatment may be of importance for endometrial atrophy as well as for the beneficial bleeding profile associated with this treatment.

Tibolone treatment influences protein expression of sex-hormone receptors in monkey endometrium differently from that observed when using conventional hormone therapy.

From the 1Division for Reproductive Endocrinology and 2Division ofObstetrics and Gynecology, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; 3National O. Bohomolets Medical University, Kyiv, Ukraine; 4Department of Obstetrics and Gynecology, TheFirst Affiliated Hospital of Chongqing Medical University, Chongqing, China; and 5Wake Forest University School of Medicine, Winston-Salem, NC.

Received June 29, 2011; revised and accepted July 28, 2011.

Mariana Hulchiy and Hua Zhang contributed equally to this work.

Funding/support: This study received financial support from The Swedish Research Council (projects 20137 [L.S.] and 20324 [A.L.H.]) and Karolinska Institutet. Financial support was also provided through the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and Karolinska Institutet. The parent study was supported by NV Organon. Hua Zhang was a post doctoral fellow supported by the Chinese Government (grant 2008850544).

Financial disclosure/conflicts of interest: None reported.

Address correspondence to: Lena Sahlin, PhD, Division for Reproductive Endocrinology and the Pediatric Endocrinology Unit, Department of Women’s and Children’s Health, Q2:08, Karolinska University Hospital-Solna, SE-171 76, Stockholm, Sweden. E-mail:

©2012The North American Menopause Society