Endometrial Expression of Estrogen Receptors and the Androgen Receptor in Women With Polycystic Ovary Syndrome: A Lifestyle Intervention Study.

CONTEXT: Polycystic ovary syndrome (PCOS) is a common cause of anovulation. It may also negatively affect the endometrium, which could lead to implantation failure and proliferative aberrations. OBJECTIVE: Our objective was to study sex hormone receptors in the endometrium of women with PCOS. DESIGN: This is a cross-sectional study and lifestyle intervention. SETTING: Clinical and laboratory research unit was undertaken at a university hospital. PARTICIPANTS: Twenty overweight/obese women fulfilling all three PCOS criteria (anovulation, hyperandrogenism, and polycystic ovaries), 10 body mass index-matched regularly menstruating controls, 11 normal-weight women with PCOS, and 11 normal-weight controls. INTERVENTION: Intervention for this study included dietary management and physical exercise. MAIN OUTCOME MEASURES: mRNA levels and immunostaining of estrogen receptor α (ERα) and ß (ERß), nongenomic estrogen receptor α36 (ERα36), and G-protein-coupled estrogen receptor-1 (GPER), and the androgen receptor (AR) on cycle days 6-8 and cycle days 21-23. RESULTS: Before intervention, mRNA levels of ERα, ERα36, and the ERα/ERß mRNA ratio were lower in proliferative endometrium of overweight/obese PCOS women compared with controls (P < .05). After intervention, ERα protein and the ERα/ERß protein ratio in proliferative endometrium increased and were higher in PCOS women with improved menstrual function than in those without improvement (P < .05). In the subgroup of PCOS women with restored ovulation, only higher protein levels of GPER were found in secretory endometrium (P < .01). However, PCOS women who remained anovulatory had higher protein levels of ERα, GPER, and AR on cycle days 21-23 than controls (P < .05). CONCLUSIONS: Lifestyle intervention alters, but does not fully restore, ER and AR expression in proliferative and secretory endometrium of obese women with PCOS.

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

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 THRß1 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 THRß 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.

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

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-ß, 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.