title: Effects of an antiprogestin onapristone on the endometrium of bonnet monkeys: morphometric and ultrastructural studies.
abstract: Our previous studies demonstrated the ability of low doses of antiprogestin ZK 98.299 (onapristone) to inhibit fertility in bonnet monkeys. In the present study cumulative effects of low doses of ZK 98.299 on the endometrial cytoarchitecture of bonnet monkeys were analyzed. Treatment with either the vehicle (n = 3) or onapristone at 2.5 mg (n = 4) or 5.0 mg (n = 3) was initiated on Day 5 of the first menstrual cycle and thereafter repeated every third day for four to seven consecutive cycles. The last treatment cycles were anovulatory in two animals treated with 2.5 mg and all animals treated with 5.0 mg. Endometrial biopsies were collected on Day 8 after the midcycle estradiol peak in ovulatory menstrual cycles and on Day 20 in anovulatory menstrual cycles during the last treatment cycle. Ultrathin sections of the fixed endometrium were stained with toluidine blue for morphometric analysis and uranyl acetate and lead citrate for ultrastructural analysis. The ZK 98.299-treated animals showed a dose-dependent endometrial atrophy as evident by a decrease in the height and diameter of the glands and early signs of compaction in the stroma. Ultrastructural analysis also revealed dose-dependent degenerative changes in the subcellular organelles such as the nucleus, mitochondria, endoplasmic reticulum, lysosomes, and Golgi apparatus. This suggests that long-term treatment with low doses of ZK 98.299 leads to the suppression of estrogen-dependent endometrial proliferation. However, this blockade operates independent of estradiol receptor (ER) and progesterone receptor (PR) concentrations as the expressions of these steroid receptors did not show any significant changes even after prolonged treatment. The study demonstrated an antiestrogenic effect of ZK 98.299 on endometrium after prolonged treatment in bonnet monkeys.
authors.affiliation: National Institute for Research in Reproductive Health, Indian Council of Medical Research, Parel, Mumbai 400012, India.
authors.forename: Kamala
authors.initials: K
authors.lastname: Gopalkrishnan
authors.forename: R R
authors.initials: RR
authors.lastname: Katkam
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Sachdeva
authors.forename: S D
authors.initials: SD
authors.lastname: Kholkute
authors.forename: Varsha
authors.initials: V
authors.lastname: Padwal
authors.forename: C P
authors.initials: CP
authors.lastname: Puri
mesh_terms: D000818:Animals; D048429:Cell Size; D004717:Endometrium / Q000033:anatomy & histology / Q000187:drug effects* / Q000648:ultrastructure; D004958:Estradiol / Q000097:blood; D005260:Female; D006067:Gonanes / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology*; D008255:Macaca radiata; D008854:Microscopy, Electron; D011374:Progesterone / Q000097:blood; D011372:Progestins / Q000037:antagonists & inhibitors*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors; D013347:Subcellular Fractions / Q000187:drug effects / Q000648:ultrastructure
chemical_list: D006067:Gonanes; D006727:Hormone Antagonists; D011372:Progestins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011374:Progesterone; D004958:Estradiol; C053238:onapristone