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Receptors for thyrotropin-releasing hormone, thyroid-stimulating hormone, and thyroid hormones in the macaque uterus: effects of long-term sex hormone treatment

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

doi: 10.1097/gme.0b013e318252e450
Original Articles

Objective Thyroid gland dysfunction is associated with menstrual cycle disturbances, infertility, and increased risk of miscarriage, but the mechanisms are poorly understood. However, little is known about the regulation of these receptors in the uterus. The aim of this study was to determine the effects of long-term treatment with steroid hormones on the expression, distribution, and regulation of the receptors for thyrotropin-releasing hormone (TRHR) and thyroid-stimulating hormone (TSHR), thyroid hormone receptor α1/α2 (THRα1/α2), and THRβ1 in the uterus of surgically menopausal monkeys.

Methods Eighty-eight cynomolgus macaques were ovariectomized and treated orally with conjugated equine estrogens (CEE; n = 20), a combination of CEE and medroxyprogesterone acetate (MPA; n = 20), or tibolone (n = 28) for 2 years. The control group (OvxC; n = 20) received no treatment. Immunohistochemistry was used to evaluate the protein expression and distribution of the receptors in luminal epithelium, glands, stroma, and myometrium of the uterus.

Results Immunostaining of TRHR, TSHR, and THRs was detected in all uterine compartments. Epithelial immunostaining of TRHR was down-regulated in the CEE + MPA group, whereas in stroma, both TRHR and TSHR were increased by CEE + MPA treatment as compared with OvxC. TRHR immunoreactivity was up-regulated, but THRα and THRβ were down-regulated, in the myometrium of the CEE and CEE + MPA groups. The thyroid-stimulating hormone level was higher in the CEE and tibolone groups as compared with OvxC, but the level of free thyroxin did not differ between groups.

Conclusions All receptors involved in thyroid hormone function are expressed in monkey uterus, and they are all regulated by long-term steroid hormone treatment. These findings suggest that there is a possibility of direct actions of thyroid hormones, thyroid-stimulating hormone and thyrotropin-releasing hormone on uterine function.

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

Received December 20, 2011; revised and accepted February 27, 2012.

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