Ovine uterine gland knock-out model: Effects of gland ablation on the estrous cycle

Ovine endometrial gland development is a postnatal event that can be inhibi ted epigenetically by chronic exposure of ewe lambs to a synthetic progesti n from birth to puberty. As adults, these neonatally progestin-treated ewes lack endometrial glands and display a uterine gland knockout (UGKO) phenot ype that is useful as a model for study of endometrial function. Here, obje ctives were to determine: 1) length of progestin exposure necessary from bi rth to produce the UGKO phenotype in ewes; 2) if UGKO ewes display normal e strous cycles; and 3) if UGKO ewes could establish and/or maintain pregnanc y. Ewe lambs (n = 22) received a Norgestomet (Nor) implant at birth and eve ry two weeks thereafter for 8 (Group I), 16 (Group II), or 32 (Groups III a nd IV) weeks. Control ewe lambs (n = 13) received no Nor treatment (Groups V and VI). Ewes in Groups I, II, III, and VI were hemihysterectomized (Hhx) at 16 weeks of age. After puberty, the remaining uterine horn in Hhx ewes was removed on either Day 9 or 15 of the estrous cycle (Day 0 = estrus). Hi stological analyses of uteri indicated that progestin exposure for 8, 16, o r 32 weeks prevented endometrial adeno-genesis and produced the UGKO phenot ype in adult ewes, Three endometrial phenotypes were consistently observed in Nor-treated ewes: 1) no glands, 2) slight glandular invaginations into t he stroma, and 3) limited numbers of cyst- or gland-like structures in the stroma, Overall patterns of uterine progesterone, estrogen, and oxytocin re ceptor expression were not different in uteri from adult cyclic control and UGKO ewes. However, receptor expression was variegated in the ruffled lumi nal epithelium of uteri from UGKO ewes, Intact UGKO ewes displayed altered estrous cycles with interestrous intervals of 17 to 43 days, and they respo nded to exogenous prostaglandin F-2 proportional to (PGF) with luteolysis a nd behavioral estrus. During the estrous cycle, plasma concentrations of pr ogesterone in intact control and UGKO ewes were not different during metest rus and diestrus, but levels did not decline in many UGKO ewes during late diestrus. Peak peripheral plasma concentrations of PGF metabolite, in respo nse to an oxytocin challenge on Day 15, were threefold lower in UGKO compar ed to control ewes. Intact UGKO ewes bred repeatedly to intact rams did not display evidence of pregnancy based on results of ultrasound. Collectively , results indicate that 1) transient, progestin-induced disruption of ovine uterine development from birth alters both structural and functional integ rity of the adult endometrium; 2) normal adult endometrial integrity, inclu ding uterine glands, is required to insure a luteolytic pattern of PGE prod uction; and 3) the UGKO phenotype, characterized by the absence of endometr ial glands and a compact, disorganized endometrial stroma, limits or inhibi ts the capacity of uterine tissues to support the establishment and/or main tenance of pregnancy.