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Ovarian surface epithelium during ovulatory and anovulatory ovine estrous cycles.

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THE ANATOMICAL RECORD 240:322-326 (1994)
Ovarian Surface Epithelium During Ovulatory and Anovulatory Ovine
Estrous Cycles
WILLIAM J. MURDOCH
Department of Animal Science, University of Wyoming, Laramie, Wyoming 82071
ABSTRACT
Background: Ovarian surface epithelial cells have been implicated in the mechanisms of ovulation and development of common ovarian cancers. An early indication of predisposition to neoplasia is the formation of ovarian epithelial inclusion cysts. It was unclear whether
morphological alterations along the ovarian surface are related directly to
ovulation per se or associated endocrine parameters of reproductive cyclicity.
Methods: Light microscopic disturbances in ovarian surface epithelium
were monitored during synchronous ovulatory and anovulatory estrous
cycles of sheep. Ovulation blockade accompanied by normal luteal phases
was induced by administration of indomethacin, a prostaglandin synthase
inhibitor.
Results: Degenerative cells were sloughed from the apical dome of periovulatory follicles. The resultant stigma of luteinizing follicles was void of
surface epithelium. Repair of the ovulatory wound by epithelium did not
occur until complete involution of the corpus luteum during the subsequent
estrous cycle. In a few cases inclusions containing entrapped ovarian surface epithelium were noted within adjacent stroma. Epithelia covering
luteinized unruptured follicles remained intact and was not incorporated
into the ovary during luteal resorption.
Conclusion: Localized damage to and subsequent remodelling of the ovarian surface occurs in a cyclic fashion conjoined with the physical process
of follicular rupture. 0 1994 Wiley-Liss, Inc.
Key words: Ovarian surface epithelium, Ovulation, Indomethacin, Sheep
The mammalian ovary is encased by a layer of epithelial cells (Anderson et al., 1976) derived from the
same peritoneal mesothelium that forms the embryonic Mullerian ducts (Byskov, 1986). These cells are
supported by a basal lamina located along the surface
of the tunica albuginea, the organized cortical connective tissue matrix of the ovary.
Ovarian surface epithelial cells have been implicated
in the mechanics of fqllicular rupture; they evidently
release lysosomal enzymes that facilitate the breakdown of the tunica albuginea (Cajander, 1976). It has
been hypothesized that aberrations in the proliferative
wound repair of the ovarian surface following ovulation can lead to expression of a malignant phenotype
and neoplasia. The majority of ovarian cancers arise
from surface epithelium that had presumably been
traumatized at ovulation (Rao and Slotman, 1991; Bast
et al., 1992; Godwin e t al., 1993).
Despite the pathophysiological significance of the
ovarian surface epithelium, fundamental information
concerning cyclic structural alterations in this cell
layer is lacking. The focus of the following experiment
was to examine surface epithelium associated with
dominant follicles and luteal glands during ovulatory
and anovulatory estrous cycles of sheep. Ovulation was
0
1994 WILEY-LISS. INC.
blocked using indomethacin, a n inhibitor of the cyclooxygenase pathway of arachidonate metabolism
(Flower, 1974). Intrafollicular injection of indomethacin during the preovulatory period caused formation of
luteinized unruptured follicles (Murdoch and Dunn,
1983).
MATERIALS AND METHODS
Mature western-range ewes were penned with vasectomized rams daily and observed for estrous behavior
(average cycle lengths = 17 days). Luteal regression
and the onset of the preovulatory surge of luteinizing
hormone (LH) were synchronized by intramuscular
(IM) treatment with 10 mg of prostaglandin (PG) F,a
tromethamine (Lutalyse; The Upjohn Co., Kalamazoo,
MI) on Day 14 of the estrous cycle followed 36 h later by
5 p,g of a n agonistic analogue of LH-releasing hormone
(des-Ala6-Glyl0 ethylamide; LHRH; Sigma Chemical
Co., St. Louis, MO). Follicles 6-8 mm in diameter will
consistently ovulate about 24 h after administration of
LHRH (Roberts et al., 1985).
Received March 1, 1994; accepted May 16, 1994
OVARIAN SURFACE EPITHELIUM AND OVULATION
323
Eight hours following injection of LHRH, ewes were
treated with 500 mg IM of indomethacin (Sigma Chemical Co., St. Louis, MO) suspended in 8 ml of phosphatebuffered saline solution (PBS) or that vehicle alone
(controls). Drug was given after the anticipated completion of the LH surge and before the preovulatory
follicular rise in prostaglandin production (Murdoch et
al., 1986). Animals (sidgroup) were killed by barbiturate overdose a t 24 h after injection of LHRH (Day l),
Day 4, Day 12, or Day 4 of the ensuing (synchronized)
estrous cycle (N = 48). Ovaries were removed immediately, rinsed in chilled PBS, and immersed in 10%
buffered formalin.
Blocks of fixed tissues containing surface-oriented
periovulatory follicles or luteal structures were isolated from ovaries using a single-edged razor blade.
Special care was taken not to handle the surface of the
ovaries (Gillett, 1991) during removal or preparation
for histology. Specimens were dehydrated in a graded
series of ethanol, cleared, and infiltrated with and embedded in paraffin. Tissues were serially cross-sectioned at 3-6 pm thickness, rehydrated to water, and
stained in hematoxylin and eosin. Sections were examined under a n Olympus Vanox light microscope.
Sera samples for radioimmunoassay of progesterone
(Murdoch and Dunn, 1983) were collected by jugular
venipuncture each day from ewes in which tissue collections were made on Day 4 of the second estrous cycle
after treatment (control vs. indomethacin). These data
were evaluated by split-plot analysis of variance.
RESULTS
Follicles of control ewes obtained at 24 h after LHRH
had either recently ruptured or exhibited a n ovulatory
papilla. Luteal tissues of controls characteristically
protruded from the surface of the ovary. There was no
evidence of impending ovulation in indomethacintreated ewes. Enlarged, hyperemic follicles of these animals were smooth surfaced, which would have formed
unruptured, fluid-containing luteal glands (Fig. 1).
One-to-three dominant follicles or corpora lutea and
corpora albicantia (Day 1 and Days 4) were obtained
from the pair of ovaries of each animal for histological
inspection.
Epithelia covering sheep ovaries was simple or pseudostratified cuboidal. Epithelial cells were generally
absent from the ovarian surface juxtaposed to periovulatory follicles. Strands of degenerative cells were
sometimes observed sloughing from the ovarian surface. This reaction was localized; it did not extend to
the ovary in general. Loosely affixed cells were often
noted a t the margins of the follicular protrusion. Exposed surfaces of luteinizing ruptured follicles and developed corpora lutea were not covered by epithelium.
The ovulatory defect was mended only after structural
regression of the corpus luteum was achieved by Day 4
of the subsequent estrous cycle. Small nests of intraovarian surface epithelial cells were observed in proximity to a corpus albicans in a few cases (3/34 [Day 41
specimens of different animals examined over two cycles). Epithelial coverings of anovulatory luteinized follicles of indomethacin-treated ewes remained intact
and appeared healthy at each time of tissue collection;
there was no detection of epithelial invaginations or
Fig. 1 . Ovaries of control (At and indomethacin-treated(B) ewes on
Day 4 after injection of LHRH. CL, corpus luFum. LUF, luteinized
unruptured follicle.
intraovarian inclusions associated with retrogressive
luteal tissues in these animals (Fig. 2).
Circulatory levels of progesterone did not differ significantly (P > 0.05) between control and indomethacin-treated ewes (Fig. 3).
DISCUSSION
This study indicates that during the process of ovulation in sheep epithelial cells are shed from the surface of the ovary. A similar phenomenon has been observed in hamsters and mice (Talbot et al., 1987).
It appears th a t ovarian surface epithelial cells undergo localized death following the surge of LH. Biochemical interaction, within a limited diffusion radius
of the preovulatory follicle, is evidently a prerequisite
of this response. Prostaglandins (mainly PGE,) induced chromatin condensation and DNA fragmentation in incubated surface epithelial cells isolated from
sheep ovaries (Ackerman and Murdoch, 1993). Indeed,
indomethacin, at a dose known to effectively inhibit
preovulatory follicular prostaglandin biosynthesis
(Murdoch and McCormick, 1991), prevented the loss of
surface epithelial cells typical of ovulatory follicles. A
human adenocarcinoma ovarian cancer cell line
(OVCAR-3)resistant in vitro to clinically relevant concentrations of adriamycin, cisplatin, and cyclophosphamide was not sensitive to the lethal effect of prostaglandins (Ackerman and Murdoch, 1993). Cancerous
transformations of ovarian surface epithelial cells may
Fig. 2.
325
OVARIAN SURFACE EPITHELIUM AND OVULATION
PROGESTERONE (ng/ml)
1
2
3
4
5
6 7
8
9 101112131415 1
2
3
4
D A Y POST-LHRH
Fig. 3. Mean patterns of sera concentrations of progesterone during ovulatory (control)and anovulatory
(indomethacin) ovine estrous cycles. Abrupt declines in progesterone are indicative of PGF,a-induced
functional luteolysis.
be related to escape from programmed death ordinarily man, 1992). Apparently the undisturbed ovarian suraffiliated with follicular prostaglandin production and face of luteinized unruptured follicles is not likely to
ovulatory tissue dissolution.
become involved in inclusion cyst formation.
There has been debate over whether the causative
LITERATURE CITED
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tosis of ovarian surface epithelial cells. Prostaglandins, 45r475485.
Barri, 1993). Pregnancy and oral contraceptive use
E., G. Lee, R. Letourneau, D.F. Albertini, and S.M. Meller
confer significant protection against epithelial neopla- Anderson,
1976 Cytological observations of the ovarian epithelium in mamsia (Piver e t al., 1991). Cyclic alterations in ovarian
mals during the reproductive cycle. J . Morphol., 150:135-166.
surface epithelium in sheep were specifically inte- Balasch, J . and P.N. Barri 1993 Follicular stimulation and ovarian
cancer? Human Reprod., 8r990-996.
grated with the actual process of follicular rupture, and
I. Jacobs, and A. Berchick 1992 Malignant transformation
not to the hormonal environments of estrous cycles. Bast,ofR.C.,
ovarian epithelium. J . Natl. Cancer Inst., 84t556-558.
Timings of luteal regression and levels of preovulatory Byskov, A.G. 1986 Differentiation of mammalian embryonic gonad.
gonadotropin secretion were managed by exogenous
Physiol. Rev., 66r71-117.
PGF,a and LHRH. And luteal phases of anovulatory Cajander, S. 1976 Structural alterations of rabbit ovarian follicles
after mating with special reference to the overlying surface epi(indomethacin) cycles were essentially identical to conthelium. Cell Tiss. Res., 173r437-449.
trol ovulatory cycles. Infertile menstrual cycles during Flower, R.J. 1974 Drugs that inhibit prostaglandin biosynthesis.
which ovulation in response to the gonadotropin surge
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fails but luteal progesterone output progresses nor- Gillett, W.R. 1991 Artefactual loss of human ovarian surface epithelium: Potential clinical significance. Reprod. Fertil. Dev., 3t93mally (luteinized unruptured follicle syndrome) closely
98.
resemble unaffected estrous cycles observed in experi- Godwin, A.K., J.R. Testa, and T.C. Hamilton 1993 The biology of
mental mammals after inhibition of preovulatory folovarian cancer development. Cancer, 71r530-536.
licular prostaglandin production (Killick and Priddy, Killick, S.R. and A.R. Priddy 1988 Eicosanoids and the mechanism of
ovulation. Med. Sci. Res., 161257-1260.
1988; Murdoch et al., 1993).
Murdoch, W.J. and T.G. Dunn 1983 Luteal function after ovulation
Ovarian inclusions of epithelial cells were noted in a
blockade by intrafollicular injection of indomethacin in the ewe.
minority of histological sections of involuted corpora
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indomethacin on ovulation in the sheep: Relationship to follicular
ovarian resorption of nonfunctional luteal tissues.
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Fig. 2. Representative light photomicrographs of ovarian sections.
A: Normal appearance of ovarian surface epithelium. B Degenerative epithelial cells becoming detached from the ovary, control Day 1.
C: Exposed ovarian surface basement membrane, control Day 1. D:
Perimeter of ovulatory follicle, control Day 1. E: Surface of CL, control
Day 12. F Surface invagination, control Day 4. G Inclusion of epithelial cells, control Day 4. H: Intact epithelium, indomethacin Day 1.
x 400, except F, x 180.
Murdoch, W.J., T.A. Peterson, E.A. Van Kirk, D.L. Vincent, and E.K.
Inskeep 1986 Interactive roles of progesterone, prostaglandins,
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Rao, B.R. and B.J. Slotman 1991 Endocrine factors in common epithelial ovarian cancer. Endo. Rev., 12r14-26.
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W.J. MURDOCH
lation in proestrous ewes: Identification of the ovulatory follicle
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Talbot, P., G.G. Martin, and H. Ashby 1987 Formation of the rupture
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4t608-615.
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