| Summary: | 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. === Medicine, Faculty of === Obstetrics and Gynaecology, Department of === Graduate
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