In primates, treatment with antiprogestins including RU 486 and ZK 137 316 will both block progesterone (P) action, and also inhibit estrogen stimulated proliferation in the endometrium. This action of antiprogestins would be of benefit to women treated with estrogen replacement therapy as a method of blocking untoward effects of estrogen on the endometrium. ZK 230 211 (ZK211) is a potent new generation antiprogestin produced by Schering AG, that can be administered both orally and systemically. The goal of this research was to determine if ZK211 will inhibit the proliferative actions of estrogen delivered continuously for 5 months. Six groups of rhesus macaques (n = 5 each) were treated with estradiol (E2)-filled implants for 5 months. Three of the groups were also injected daily with 3 different doses of ZK211 (0. 01, 0.05 and 0.25 mg/kg). P is known to oppose the proliferative action of E2 in the endometrium. Therefore, for comparison, 1 group received E2 plus a low dose of P (2 cm P implants) and one group received E2 plus a high dose of P (6 cm P implants). Control animals (group 6) received estrogen alone. Treatment with ZK211 resulted in a severe reduction of endometrial mass, which was associated with a dose dependent inhibition of epithelial cell proliferation. At higher doses of ZK211, this effect resulted in the upper portions of the glands degenerating and trapping secretory material. These higher doses led to formation of moderate size endometrial cysts, which appeared to contain trapped secretory material. There was no evidence of endometrial hyperplasia or metaplasia. As anticipated, long-term E2 + P treatment resulted in a dose-dependent decidualization response that was marked by extensive spiral artery hypertrophy. This effect on the spiral arteries was opposite to the reaction to that seen with ZK 211 which inhibited vascular development. We conclude that inhibition of vascular development by ZK 211 may be the key factor underlying the degenerative inhibition and blockade of estrogen-dependent endometrial proliferation induced by this antiprogestin. FUNDING Contract with Schering AG, Berlin, Germany PUBLICATIONS None

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
7P51RR000163-41
Application #
6312910
Study Section
Project Start
1978-05-01
Project End
2004-04-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
41
Fiscal Year
2000
Total Cost
$201,978
Indirect Cost
Name
Oregon Health and Science University
Department
Type
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Okoye, Afam A; Hansen, Scott G; Vaidya, Mukta et al. (2018) Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound. Nat Med 24:1430-1440
Jensen, Jeffrey T; Hanna, Carol; Mishler, Emily et al. (2018) Effect of menstrual cycle phase and hormonal treatments on evaluation of tubal patency in baboons. J Med Primatol 47:40-45
Toro, C A; Aylwin, C F; Lomniczi, A (2018) Hypothalamic epigenetics driving female puberty. J Neuroendocrinol 30:e12589
Bulgarelli, Daiane L; Ting, Alison Y; Gordon, Brenda J et al. (2018) Development of macaque secondary follicles exposed to neutral red prior to 3-dimensional culture. J Assist Reprod Genet 35:71-79
Prola-Netto, Joao; Woods, Mark; Roberts, Victoria H J et al. (2018) Gadolinium Chelate Safety in Pregnancy: Barely Detectable Gadolinium Levels in the Juvenile Nonhuman Primate after in Utero Exposure. Radiology 286:122-128
Moccetti, Federico; Brown, Eran; Xie, Aris et al. (2018) Myocardial Infarction Produces Sustained Proinflammatory Endothelial Activation in Remote Arteries. J Am Coll Cardiol 72:1015-1026
Blue, Steven W; Winchell, Andrea J; Kaucher, Amy V et al. (2018) Simultaneous quantitation of multiple contraceptive hormones in human serum by LC-MS/MS. Contraception 97:363-369
Jeon, Sookyoung; Li, Qiyao; Rubakhin, Stanislav S et al. (2018) 13C-lutein is differentially distributed in tissues of an adult female rhesus macaque following a single oral administration: a pilot study. Nutr Res :
Slayden, Ov Daniel; Friason, Francis Kathryn E; Bond, Kise Rosen et al. (2018) Hormonal regulation of oviductal glycoprotein 1 (OVGP1; MUC9) in the rhesus macaque cervix. J Med Primatol 47:362-370
Dissen, G A; Adachi, K; Lomniczi, A et al. (2017) Engineering a gene silencing viral construct that targets the cat hypothalamus to induce permanent sterility: An update. Reprod Domest Anim 52 Suppl 2:354-358

Showing the most recent 10 out of 492 publications