Hormonal regulation of the primate uterus : effects of hormone treatment and lifestyle intervention

The uterus is a major hormone-responsive reproductive organ in primates. Hormones promote their effect via different pathways. Receptors involved in steroid hormone, thyroid hormone and insulin signaling have been found in the endometrium. Several lines of evidence suggest that endocrine and metabolic disturbances may affect the endometrium adversely, leading to abnormalities and reproductive failure. This has stimulated research on factors and potential mechanisms that are related to endometrial dysfunction. The overall aim of this project was to increase the understanding of hormone receptor regulation of the primate uterus, and in particular to investigate the effects of different hormone treatments and lifestyle intervention on endometrial receptor expression.

In paper I and II, 88 ovariectomized cynomolgus macaques were treated with conjugated equine estrogens (CEE), a combination of CEE + medroxyprogesterone acetate or tibolone (TIB), a compound with estrogenic, progestogenic and androgenic activity. At the end of the treatment period uterine tissues were collected and the presence and localization of receptors for steroid hormone and thyroid hormone signaling were investigated. In contrast to conventional hormone treatment, TIB treatment did not decrease the immunostaining of estrogen receptors in the endometrium of macaque uterus. However, androgen receptor expression in endometrial stroma in this group was higher as compared to controls, which could be one mechanism to explain the endometrial atrophy and beneficial bleeding profile that is associated with TIB treatment. Immunostaining of thyrotropin-releasing hormone (TRH) receptor, thyroid-stimulating hormone (TSH) receptor and thyroid hormone receptors was detected in all compartments of macaque uterus. Their expression was affected in a specific way by long-term sex hormone treatment. Thus, TRH, TSH and thyroid hormones may have direct effects on the endometrium and thereby influence its function.

In paper III and IV, 20 overweight/obese women with polycystic ovary syndrome (OBPCOS) were recruited to a three months lifestyle intervention, aiming at weight reduction. Endometrial biopsies were collected at mid-proliferative and mid-secretory phases of the menstrual cycle. The endometrial expression of receptors involved in insulin and estrogen signaling was evaluated. Gene and protein expression of molecules involved in insulin signaling was up-regulated following lifestyle intervention, indicating improvement of glucose homeostasis and thereby endometrial functioning in these women. Moreover, lifestyle intervention influenced estrogen receptor expression towards normalization in the follicular phase of the menstrual cycle. In six OB-PCOS women ovulation was confirmed. Despite restored ovulation, endometrial expression of the proliferation marker Ki67 was higher in the secretory phase of OB-PCOS women as compared to controls. The elevated endometrial expression of the non-genomic estrogen receptor, G-protein coupled estrogen receptor-1, may be proposed as one mechanism behind the high proliferation activity in PCOS women.

List of scientific papers

I. Hulchiy M, Zhang H, Cline M, Hirschberg A.L, Sahlin L. Effects of long-term tibolone treatment on nuclear sex steroid hormone receptors and G-protein-coupled estrogen receptor-1 expression in macaque uterus. Menopause. 2012;19:332-338.
https://doi.org/10.1097/gme.0b013e318230f3be

II. Hulchiy M , Zhang H, Cline M, Hirschberg A.L, Sahlin L. Receptors for thyrotropin-releasing hormone, thyroid-stimulating hormone, and thyroid hormones in the macaque uterus: effects of long-term sex hormone treatment. Menopause. 2012;19:1253-1259.
https://doi.org/10.1097/gme.0b013e318252e450

III. Ujvari D, Hulchiy M, Calaby A, Nybacka Å, Byström B, Hirschberg A.L. Lifestyle intervention up-regulates gene and protein levels of molecules involved in insulin signaling in the enometrium of overweight/obese women with polycystic ovary syndrome. Human reproduction. 2014;29:1526-1535.
https://doi.org/10.1093/humrep/deu114

IV. Hulchiy M, Nybacka Å, Sahlin L, Hirschberg A.L. Endometrial expression of nuclear estrogen receptors and non-genomic estrogen receptor α36 and G-protein coupled estrogen receptor-1 in women with polycystic ovary syndrome. [Manuscript]