Novel Hydroxysteroid (17β) Dehydrogenase 1 Inhibitors Reverse Estrogen-Induced Endometrial Hyperplasia in Transgenic Mice Taija Saloniemi, Päivi Järvensivu,

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Novel Hydroxysteroid (17β) Dehydrogenase 1 Inhibitors Reverse Estrogen-Induced Endometrial Hyperplasia in Transgenic Mice Taija Saloniemi, Päivi Järvensivu, Pasi Koskimies, Heli Jokela, Tarja Lamminen, Sadaf Ghaem-Maghami, Roberto Dina, Pauliina Damdimopoulou, Sari Mäkelä, Antti Perheentupa, Harry Kujari, Jan Brosens, Matti Poutanen The American Journal of Pathology Volume 176, Issue 3, Pages 1443-1451 (March 2010) DOI: 10.2353/ajpath.2010.090325 Copyright © 2010 American Society for Investigative Pathology Terms and Conditions

Figure 1 Endometrial hyperplasia in HSD17B1TG females. Endometrial hyperplasia was observed in HSD17B1TG females at the age of 4 months: hyperplastic glands growing inwards and normal luminal epithelium (A), hyperplastic glands growing inwards and nuclear atypia of the luminal epithelium (B), wild-type endometrium at proestrous, which corresponds to the human proliferative phase (C), wild-type endometrium at diestrous, which corresponds to the human secretory phase (D). The sites of the inserts are shown with dash-lined boxes. The expression of a proliferation marker PCNA in hyperplasia without atypia (E), atypical hyperplasia (F), and normal wild-type (G) at proestrous and diestrous. Examples of PCNA-positive cells are indicated by arrows. HSD17B1TG females presented with anovulatory ovaries lacking CLs (H), whereas CLs were abundant in the ovaries of the wild-type littermates (I). CL = corpus luteum. The American Journal of Pathology 2010 176, 1443-1451DOI: (10.2353/ajpath.2010.090325) Copyright © 2010 American Society for Investigative Pathology Terms and Conditions

Figure 2 Human HSD17B1 expression enhances uterine response to weak estrogen estrone. Estrogen action was enhanced in the presence of E1 in HSD17B1TG uterus as indicated by the fact that the uterus weight of HSD17B1TG females increased more with a small dose of E1 than the weight of wild-type uterus. The different growth response was observed in the weights both by including (A) and excluding (B) the uterine secretory products, ie, full and empty uterus, respectively. Macroscopic images (C) of wild-type and HSD17B1TG uteri treated with placebo, and with equal dose of E1 (1 μg/kg/d) and E2 (50 μg/kg/d). E1 = estrone, E2 = estradiol, Pla = placebo, *P < 0.05, ***P < 0.001. The American Journal of Pathology 2010 176, 1443-1451DOI: (10.2353/ajpath.2010.090325) Copyright © 2010 American Society for Investigative Pathology Terms and Conditions

Figure 3 Human HSD17B1 induces estradiol production from estrone in vivo. Increased conversion of E1 to E2 was observed in HSD17B1TG mice in all extra-gonadal tissues studied, as compared with wild-type littermate tissues. E1 = estrone, E2 = estradiol, white bars represent wild-type mice, black bars represent HSD17B1TG mice, *P < 0.05, ***P < 0.001. The American Journal of Pathology 2010 176, 1443-1451DOI: (10.2353/ajpath.2010.090325) Copyright © 2010 American Society for Investigative Pathology Terms and Conditions

Figure 4 Treatment of endometrial hyperplasia of HSD17B1TG females with progestins. Multiple CLs were induced in adult HSD17B1TG ovaries by gonadotophin (PMSG/hCG) treatment (A). The gonadotrophin treatment also reversed endometrial hyperplasia in HSD17B1TG mice (B). Treating HSD17B1TG mice with progestin (MPA) also reversed endometrial hyperplasia (C), but the ovary remained anovulatory (D). CL = corpus luteum. The American Journal of Pathology 2010 176, 1443-1451DOI: (10.2353/ajpath.2010.090325) Copyright © 2010 American Society for Investigative Pathology Terms and Conditions

Figure 5 Treatment of endometrial hyperplasia of HSD17B1TG females with an HSD17B1 inhibitor. The treatment with an HSD17B1 inhibitor reversed the hyperplastic glandular morphology in adult TG females to normal (A, B), while the luminal epithelium appeared as normal or prolonged proestrous-like (C). The sites of the inserts in C are indicated with dash-lines boxes in A and B. Several stages of hyperplasia were observed in placebo-treated HSD17B1TG females: hyperplasia without atypia (D) and hyperplasia with atypia (E). The inhibitor did not induce ovulation in the HSD17B1TG ovary (F). N = normal, P = prolonged proestrous. The American Journal of Pathology 2010 176, 1443-1451DOI: (10.2353/ajpath.2010.090325) Copyright © 2010 American Society for Investigative Pathology Terms and Conditions