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UBC Theses and Dissertations

Gonadal steroids regulate ADAMTS-1 expression in human endometrial stromal cells in vitro Wen, Jiadi


Gonadal steroids are regulators of the ECM remodeling events that occur in the human endometrium during each menstrual cycle. The ADAMTS represent a novel family of MMPs, the best characterized of which is the initially identified member, ADAMTS-1. ADAMTS-1 has recently been found to be spatiotemporally expressed in the human endometrium during the menstrual cycle with mice null-mutant for this ADAMTS subtype also exhibiting endometrial dysfunction. To date, the factors capable regulating ADAMTS-1 in the human endometrium have not been identified. In view of these observations, I hypothesized that ADAMTS-1 plays a central role in the steroid-mediated remodeling events that occur in the human endometrium during each reproductive cycle. In the studies presented in this thesis, I have examined the ability of the gonadal steroids, progesterone (P4), 17β-estradiol (E2) or the non-aromatisable androgen, dihydrotestosterone (DHT), alone or in combination to regulate ADAMTS-1 mRNA and protein levels in primary cultures of human endometrial stromal cells in a time- and concentration-dependent manner. In addition, I determined whether the anti-steroidal compounds, RU486 (an antiprogestin), ICI 182, 780 (an anti-estrogen) or hydroxflutamide (an anti-androgen) were capable of inhibiting the regulatory effects of these gonadal steroids on stromal ADAMTS-1 levels. Real-time PCR and Western blotting revealed that P4 and DHT increased ADAMTS-1 expression levels whereas E2 alone had no regulatory effect on the expression levels of this ADAMTS subtype in these primary cell cultures. A combination of DHT and P4 potentiated the increase in the levels of the ADAMTS-1 protein species present in these cell cultures whereas E2 was capable of attenuating the stimulatory effects of both P4 and DHT on stromal ADAMTS-1 mRNA and protein expression levels. In contrast, RU486 and hydroxyflutamide specifically inhibited the increase in ADAMTS-1 expression levels mediated by P4 and DHT, respectively. In summary my studies, demonstrate that the regulation of ADAMTS-1 mRNA and protein expression levels in human endometrial stromal cells by gonadal steroids involves a complex interplay between progestins, estrogens and androgens.

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