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.