Ovulation
Lawrence
L. Espey, Trinity University, San Antonio, TX 78212
Encyclopedia
of Reproduction VOLUME 3, Academic Press,
1999, pp. 605-614.
I. Introduction
II. Anatomy of Ovulation
III. Biochemistry of Ovulation
IV. Current Hypothesis on Ovulation
differential display a series
of molecular procedures involving extraction of RNA from tissues, conversion of
the mRNA into cDNA, amplification of radio-labelled cDNA by the polymerase
chain reaction, and electrophoresis of the cDNA on an acrylamide gel for the
purpose of detecting differential expression of genes between control and
experimental (or pathological) tissues.
gonadotropin any of a number of
glycoprotein hormones such as luteinizing hormone (LH), follicle stimulating
hormone (FSH), and human chorionic gonadotropin (hCG), that stimulate ovarian
follicles to develop and ovulate.
hypothalamo/hypophyseal axis
the neuronal and vascular associations between the hypothalamus at the base of
the brain and the hypophysis (pituitary gland) that regulate gonadotropin
secretion and the sexual cycle.
inflammation a complex sequence of
metabolic changes leading to vasodilatation, hyperemia, exudation, edema,
proteolysis and eventual tissue remodelling in response to microbial invasion,
radiation, friction, chemical irritation, or other factors such as acute
stimulation of target tissues by glycoprotein hormones.
luteinization the physical and metabolic
transformation of a mature ovarian follicle into a corpus luteum, principally
characterized by a marked increase in follicular progesterone synthesis in
response to an ovulatory surge in luteinizing hormone.
mature follicle an
ovarian follicle that has acquired an adequate concentration of gonadotropin
receptors to undergo an ovulatory response when stimulated by a surge in
endogenous LH (and/or FSH), or by an adequate amount of exogenous chorionic
gonadotropin such as hCG.
ovulatory a term used in reference to
events that follow initiation of the ovulatory process by gonadotropic
hormone(s).
ovulatory process a term
used synonymously with ovulation to indicate the complete sequence of physical
and chemical events that begin when a mature ovarian follicle is stimulated by
an ovulatory surge in gonadotropic hormones and ends when the follicle releases
an egg.
preovulatory a term used in reference to
events that precede initiation of the ovulatory process by gonadotropic hormone(s).
postovulatory a term used in reference to
events that follow expulsion of the oocyte from the follicle.
OVULATION is the release of fertile eggs from the adult ovary.
Mammalian ovulation is a clearly defined biological process that begins when
gonadotropic hormone(s) stimulate mature ovarian follicles, and it ends when
the follicles rupture and release fertile eggs into the oviduct. The duration
of the ovulatory process is a species specific interval of time, ranging from
10 hours in the rabbit to possibly as much as 30-36 hours in the human.
I. Introduction
Mammalian ovaries have two principal functions. They produce sex
steroids to prepare the adult female for reproduction, and they release eggs at
appropriate intervals during the fertile years of the organism. It is generally
thought that the underlying mechanisms of hormone action leading to fertility
and ovulation are homologous in all mammals.
A. The Sexual Cycle and Ovulation
At sexual maturity (puberty), the female begins a sexual cycle
(i.e., a menstrual cycle in humans) that is based on rhythmic interaction
between the hypothalamo/hypophyseal axis and the ovaries. A given cycle is
initiated when the hypothalamus begins secreting gonadotropin-releasing hormone
(GnRH) into the hypothalamo-hypophyseal portal system where it travels to the
anterior hypophysis (pituitary) and stimulates gonadotropes to secrete follicle
stimulating hormone (FSH) and luteinizing hormone (LH). Under the influence of
these two gonadotropic hormones from the pituitary, primordial follicles begin
growing in the ovary. During this developmental process known as
folliculogenesis, a large antral cavity forms in the center of the follicle and
a thick layer of collagenous connective tissue forms around its perimeter. As
the follicle grows, it begins secreting androgens and estrogens. Ovarian b
-estradiol promotes the expression of gonadotropin receptors on the plasma
membranes of follicular cells. A follicle is said to be mature when it is
endowed with an adequate population of gonadotropin receptors that are
responsive to LH and/or FSH. At this stage of the sexual cycle, the elevated
level of circulating b -estradiol induces a sudden increase in GnRH secretion
from the neurosecretory cells of the hypothalamus, and this releasing hormone
causes a surge in LH and FSH secretion from the pituitary gland. This surge in
gonadotropins initiates the ovulatory process. During the next several hours,
androgen and estrogen secretion is replaced by a marked increase in ovarian
progesterone synthesis. The rise in this progestin signals the onset of
luteinization of the ovarian follicle. In addition, the elevation in
circulating progesterone inhibits further secretion of GnRH, LH, and FSH. The
hypothalamo/hypophyseal axis begins to secrete these hormones once again to
initiate the next sexual cycle only after the corpus luteum begins to
deteriorate (i.e., undergo luteolysis) and progesterone secretion is
diminished.
B. Rupture of the Ovarian Follicle
Mammalian ovulation is a unique biological phenomenon in that it
requires the physical disruption of healthy tissue at the surface of the ovary.
Initially, during the first several hours after a mature ovarian follicle has
been stimulated by an ovulatory surge in pituitary gonadotropins, there is no conspicuous
change in the appearance of an ovulatory follicle. However, 4-6 hours into the
ovulatory process, a follicle will begin to blush. There is clear evidence that
the capillaries in the follicle wall have dilated, and the tissue has become
hyperemic. There is negligible other macroscopic, or microscopic, evidence of
pending rupture until 1-2 hours before the follicle wall will actually burst.
As the time of rupture nears, the apex of a mature follicle protrudes more and
more above the surface of the ovary and the follicle wall itself gradually
becomes thinner. Eventually, the apical most portion of the follicle becomes
translucent and rapidly balloons above the normal curvature of the follicle
wall to form a stigma. This nipple-like bleb may not form in all species of
mammals, and will not occur if the vascular supply to the ovary has been
impaired. However, a follicle will usually rupture within several minutes after
the stigma forms. The eventual rupture of a follicle is dependent on adequate
degradation of the collagenous connective tissue in the follicle wall and on a
modest, but essential, intrafollicular pressure of about 20 mm Hg that arises
from capillary hydrostatic pressure. After the follicle wall bursts, the oocyte
and surrounding cumulus cells are usually extruded within 1-2 minutes.
Ovulation is complete when the egg-bearing cumulus mass is expelled from the
ovary.
II. Anatomy of Ovulation
At the apex of a mature follicle, where a stigma forms and the
follicle ruptures, there are five different layers of cells (see Figure
1). The outermost layer is the surface epithelium, a single-cell layer of
cuboidal epithelial cells. The second layer is the tunica albuginea, consisting
of fibroblasts and collagen that form a tenacious sheath around the entire
ovary. The third layer is the theca externa, the follicle’s own capsule of
collagenous connective tissue which delineates its boundary. The fourth layer
consists of the secretory cells of the theca interna, just inside the theca
externa. The fifth and innermost layer is the stratum granulosum, from which
extends the cumulus mass and its oocyte.
This section examines the morphophysiological changes that occur
in these layers of the follicle wall during the hours preceding the release of
the egg. Although the details of the changes are based on ultrastructural
studies of ovulatory follicles from the rabbit, most reproductive physiologists
agree that the basic anatomy of mammalian follicles are comparable from one
species to the next, and it is generally thought that the mechanism of
follicular rupture is basically the same in all species of mammals. In the case
of the rabbit, the ovulatory process normally requires about 10 hours.
Therefore, this analysis will examine the morphophysiological aspects of the
follicle wall at 10 hours before follicular rupture (i.e., at the beginning of
the ovulatory process) (Figure
1), at approximately ˝-1 hour before rupture (Figure
2), and at about 1-5 minutes before rupture (Figure
3).
A. 10 Hours before Follicular Rupture
1. Surface Epithelium: In mature
ovarian follicles, the surface epithelium is a single layer of cuboidal cells
that are loosely attached to a thin basal lamina at the surface of the
connective tissue (the tunica albuginea) surrounding the ovary (Figure
1). The most conspicuous feature of these cells is the dense cytoplasmic
spheres that are common on the basal side of the cells. The composition of
these dense granules is unknown, but it is unlikely that they are involved in
the ovulatory process, because the surface epithelium can be gently scraped
from the surface of a mature follicle, yet the follicle will still ovulate in
response to adequate stimulation by gonadotropin(s). The other interesting
feature of the surface epithelium is that the cells contain polymorphous nuclei
that somewhat resemble the nuclei of polymorphonuclear leukocytes. It is
possible that the surface epithelium functions as a first line of defense to
protect the vital procreative elements of the ovary.
2. Tunica Albuginea: Beneath the
ovarian surface epithelium is the layer of dense collagenous connective tissue
known as the tunica albuginea. This layer, which surrounds the entire ovary,
consists almost entirely of fibroblasts, along with extracellular collagen and
related ground substance (Figure
1). The collagen usually is not readily visible by transmission electron
microscopy unless the tissue is treated with 1% phosphotungstic acid, or some
other stain that increases the electron density of collagen. The fibroblasts in
this thecal tissue give the appearance of spindle-shaped smooth muscle cells if
the follicle is sectioned on a plane perpendicular to the apical follicle wall.
However, if one cuts thin sections of a follicle on a plane that is tangential
to the surface of the ovary, then the cells in this layer appear round, or
ovoid, and it is quite obvious that they are platter-shaped fibroblasts that
produce substantial amounts of collagen.
3. Theca Externa: The
follicle itself is surrounded by its own layer of collagenous connective tissue
called the theca externa. This tissue is quite similar to the tunica albuginea,
and these two layers of thecal tissue are so contiguous at the apex of a
follicle that it is difficult to distinguish them from one another (Figure
1). The theca externa usually contains a few more fibroblasts than the
tunica albuginea, but the outer tunic of connective tissue contains more
collagenous extracellular material. There is not a conspicuous difference in
the cellular composition of the theca externa at the apex of a follicle (where
rupture will occur) versus the base of the follicle (which is surrounded by
ovarian stromal tissue).
4. Theca Interna: This
highly differentiated thecal tissue is a thin layer of steroidogenically active
cells that are supplied by a number of large capillaries which collectively
comprise the bulk of the ovarian circulation (Figure
1). Fibroblasts and collagen are sparse in this thin layer. The secretory
cells of the theca interna are characterized by large oval nuclei with prominent
nucleoli; and, like most steroid-secreting cells, their cytoplasm is dominated
by lipid droplets, numerous mitochondria, and Golgi networks that are
distributed throughout their smooth endoplasmic reticulum. These cells are
sometimes referred to as "interstitial cells" in the current
literature. The interior border of the theca interna is clearly delineated by a
thin, but conspicuous, basal lamina called the membrana propria. This basal
lamina has been erroneously referred to as a double membrane because of its
close association to the plasma membranes of the granulosa cells that adhere to
its inner border.
5. Stratum Granulosum: The
granulosa layer at the inner most surface of the follicle wall arises from a
single layer of epithelial cells which surround the oocytes of primordial
follicles. The granulosa cells that are attached to the membrana propria extend
in a columnar pattern from this basement membrane (Figure
1). The remaining cells toward the follicular antrum are more cuboidal and
are distributed inward for a total depth of 3-10 cells, depending on the
species of animal. The cells of the granulosa layer are metabolically
integrated by an extensive labyrinth of gap junctions that couple this layer
into a syncytium with the cumulus oophorus. In the vicinity of the tight
junctions between granulosa cells it is common to observe invaginations from
one cell to the other that become pinched-off and form phagocytic-like vesicles
within one or the other of the abutting cells. These vesicles constitute the
transfer of cytoplasm from one granulosa cell to another, and their contents
can include mitochondria, lipid droplets, or other large areas of cytoplasm.
The cumulus mass, which includes the oocyte, consists of granulosa-like cells
that protrude inward from any portion of the stratum granulosum, i.e., from
either the apical or the basal region of this innermost layer of the follicle.
This random morphological arrangement positions the oocyte toward the center of
the follicular antrum and probably facilitates its dislodgement and expulsion
from the follicle at the time of ovulation. Also, this central location of the
fragile germ cell may serve to protect it from the degradative events that
occur within the thecal layers of the follicle wall during the ovulatory
process.
B. ˝-1 Hour before Follicular Rupture
1. Surface Epithelium: Within the
last several hours of the ovulatory process, conspicuous morphological changes
take place in the epithelial cells on the apical surface where rupture is
destined to occur. The cells of the surface epithelium develop numerous
vacuoles within their cytoplasm, and the cells appear to be necrotic (Figure
2). There is no evidence that the mucin-like dense granules in these cells
release their contents into the thecal layers of the follicle, or contribute in
any way to the mechanism of ovulation. During the final hour of the ovulatory
process, these cells begin to slough from the stigma area of the follicle, and
they are usually absent at the time of rupture.
2. Tunica Albuginea: The tunica
albuginea that covers the ovarian surface of most preovulatory follicles
consists of quiescent fibroblasts. However, conspicuous changes occur in this
collagenous connective tissue during the final several hours prior to
follicular rupture. The fibroblasts begin to project long cytoplasmic process
from their central mass, and on their longitudinal plane these cells become as
much as 100 microns in length (Figure
2). The tips of these cytoplasmic processes oftentimes consist of unusual
multivesicular structures that probably contain bioactive agents that
contribute to the decomposition of the extracellular collagenous elements
during the final stages of the ovulatory process. In addition to these cellular
changes, the extracellular matrix of collagen and ground substance begins to
dissociate during the hour preceding follicular rupture.
3. Theca Externa: As a
follicle approaches the moment of rupture, the collagenous connective tissue of
the theca externa undergoes changes similar to the overlying tunica albuginea (Figure
2). The fibroblasts become much more elongated, their cytoplasmic processes
exhibit the same type of multivesicular structures, and the extracellular
matrix of this layer is less integrated. The fibroblasts of both the theca
externa and tunica albuginea are transformed from quiescent, resting cells into
active, proliferating fibroblasts. As these activated cells become motile and
begin moving around within the local area of the follicle, they probably
secrete proteolytic enzymes that soften the extracellular matrix and facilitate
movement of the fibroblasts. In this weakened state, the tissue in the apical
area of a follicle begins to separate under the force of a relatively low, but
steady, intrafollicular pressure of 15-20 mm Hg. The result of this
dissociation is a gradually thinning of the follicle wall at the site where
rupture will eventually occur.
4. Theca Interna: The
principal ovulatory changes in the theca interna occur in the extensive network
of capillaries that is characteristic of this area of the follicle wall. Within
4-6 hours after initiation of the ovulatory process there is a measurable
increase in ovarian blood flow and the follicles become hyperemic. Follicles
become visibly redder as their capillaries dilate, and their blood content
increases as much as 5-fold. In addition, the permeability of the thecal
capillaries increases significantly during ovulation. These marked changes in
the vasculature result in occasional extravasation of blood and the formation
of petechiae in the walls of some follicles. Also, there is an increase in the
number of polymorphonuclear leukocytes in the patent blood vessels (Figure
2). However, macrophages, or other derivatives of leukocytes are rarely
observed in the thecal tissues outside the vascular compartment prior to
follicular rupture. Therefore, although some investigators believe that
leukocytic cells may contribute the proteolytic enzymes that are thought to
degrade the follicular connective tissue during ovulation, it is probably more
likely that leukocytes begin to accumulate in ovulatory follicles in response
to leukotactic agents that are generated by an acute inflammatory reaction that
activates the thecal fibroblasts and initiates ovulatory decomposition of the
follicular wall prior to infiltration of the area by leukocytes.
5. Stratum Granulosum: During the
last hour preceding follicular rupture, the cells of the granulosa layer become
less firmly attached to one another. As the apical area dissociates and the
follicle wall becomes thinner, the innermost granulosa cells begin to slough
from the wall and become dispersed in the follicular fluid (Figure
2). Those cuboidal cells that remain attached to the membrana propria
usually contain an increasing number of lipid droplets that were not present a
few hours earlier. Thus, the granulosa cells become steroidogenically active
during the hours preceding follicular rupture. Otherwise, there are negligible
changes in the ultrastructure of the granulosa cells at the apex of an
ovulatory follicle.
C 1-5 Minutes before Follicular Rupture
It has been possible to obtain electron micrographs of rabbit
follicles only a few minutes before rupture (Figure
3). Shortly before the follicle wall breaks, it balloons out to form a
stigma at the apical most area where it will rupture. Only traces of the
surface epithelium remain clinging to the disintegrated tunica albuginea and
theca externa. Extravasated erythrocytes appear more frequently in the vicinity
of the theca interna, and most of the stigmal region is void of capillaries.
Essentially all of the granulosa cells have sloughed into the follicular fluid,
or have retracted toward the base of the stigma as the membrana propria disintegrates
and the follicle wall undergoes its final thinning before rupture. Rupture
ultimately occurs at the apical most area of the follicle simply because this
is, morphologically, the thinnest (i.e., the weakest) site along the ovarian
surface.
A.
Historical Background
1. The
1960’s: In the 1960's, it became apparent
that ovarian follicles do not rupture as a consequence of any significant
increase in intrafollicular pressure. A variety of evidence revealed that
rupture is probably due, instead, to the action of proteolytic enzymes that
decompose the collagenous connective tissue in the thecal layers of the
follicle wall and the ovarian tunic. By the end of the 1960's, it was also
apparent that ovarian steroid metabolism changes markedly in response to an
ovulatory surge in gonadotropin. Progesterone synthesis increases within
several hours after initiation of the ovulatory process, while ovarian
estrogens and androgens decline in a reciprocal pattern.
2. The
1970’s: In the early 1970's, it was
discovered that there was a significant increase in ovarian prostanoid
synthesis during ovulation. This information, together with considerable
evidence that anti-inflammatory agents like indomethacin can inhibit ovulation,
led to the general assumption that prostaglandins E2 and F2a are
essential for ovulation, yet other data raises questions about the role of
ovarian prostanoids in the mechanism of ovulation. In that same decade it became
apparent that ovarian plasminogen activator also increases in response to most
gonadotropic hormones. It has been hypothesized that this serine protease might
contribute to the ovulatory process by digesting connective tissue components
of the follicle wall, or by activating a procollagenase. However, targeted
deletion of the genes for several types of plasminogen activator has not
yielded an anovulatory phenotype. Therefore, the precise role of plasminogen
activator in ovulation remains unclear.
3. The
1980’s: By the 1980's, more attention was
being given to the fact that ovulatory follicles are hyperemic, and that such a
vascular response is a cardinal sign of inflammation. In addition, it became
evident that a wide variety of non-steroidal anti-inflammatory drugs can
inhibit ovulation. This information, along with other supporting data, led to
the hypothesis that an ovulatory dose of gonadotropin initiates an
inflammatory-like response in mature ovarian follicles. Subsequently, it was
demonstrated that ovarian kallikrein activity increases, and that kinin
formation might contribute to the ovarian vascular changes during ovulation. As
this decade ended, there were reports that cytokines, platelet-activating
factor, growth factors, and metalloproteases might also influence the
inflammatory response that occurs in ovarian follicles during ovulation.
B. Current
Knowledge about the Biochemistry of Ovulation
To augment
the above knowledge about the biochemical events of ovulation, several
laboratories have characterized the hormonal regulation of genes for enzymes
involved in the synthesis of steroids, eicosanoids, proteases, and other agents
that have been implicated in the ovulatory process.
1. Steroid
Metabolism: Several members of the cytochrome
P450 family of enzymes are now known to be expressed in ovarian tissue in a
pattern that is consistent with what is presently known about ovarian progestin
and estrogen synthesis during ovulation. Transcription of the gene for
cytochrome P450 side chain cleavage enzyme, which increases progesterone
synthesis by increasing the rate of conversion of cholesterol to pregnenalone,
is up-regulated in ovarian follicles (mainly in the theca interna and stratum
granulosum) several hours after the ovulatory process has been initiated by
gonadotropins. Conversely, the gene for cytochrome P450 aromatase, which
converts testosterone into 17b -estradiol, is concomitantly down-regulated in a
pattern parallel to the decline in ovarian estrogen synthesis at the time of
ovulation.
2.
Eicosanoid Metabolism: Two prostaglandin synthase
genes have been identified in ovarian follicular tissues. Prostaglandin
synthase-1 is constituitively expressed and has been localized to thecal cells
and luteal cells. Prostaglandin synthase-2 is rapidly and transiently induced
by the ovulatory surge in luteinizing hormone, and it is localized inclusively
in the granulosa cells of those follicles destined to ovulate. The expression
of these genes leads to enzymatic activity that causes 50-100-fold increases in
prostaglandins E2 and F2a in follicular tissue during ovulation. In addition to
these two eicosanoids, there is more recent evidence that lipoxygenase enzymes
cause marked increases in 12- and 15-hydroxyeicosatetranoic acids associated
with bioactive agents such as the lipoxins.
3.
Expression of Other Bioactive Factors: Recent
work at the molecular level has revealed ovarian increases of mRNAs for nerve
growth factor, oxytocin, tissue inhibitor of metalloproteinase (TIMP),
kallikrein, and vascular endothelial growth factor/vascular permeability factor
(VEG/PF) after the stimulation of follicles by gonadotropin. Regarding NGF,
both the growth factor, itself, and the receptor for NGF are expressed by
thecal fibroblasts of ovulatory follicles. Most of the evidence indicates that
oxytocin mRNA is expressed in the granulosa layer, but the function of this
neuropeptide in the ovary is uncertain. TIMP is also expressed in the granulosa
layer, and this inhibitor may modulate ovarian proteolytic activity in the vicinity
of the oocyte during ovulation. Ovarian kallikrein activity produces kinins
that promote vasodilatation and contribute to the hyperemic reaction in
ovulatory follicles. The increase in VEG/PF causes follicular capillaries to
become more permeable and promotes angiogenesis during the luteinization of
ovulatory follicles.
4.
Detection of Novel Biochemicals in Ovulation by Differential Display: It is likely that innumerable other mediators of the ovulatory
process remain to be elucidated. The new molecular protocol known as
"differential display" is a valuable method that is now being used to
isolate and identify mRNAs of genes that are uniquely expressed in the ovary
during ovulation. This molecular technique, which was developed by P. Liang and
A.B. Pardee at Harvard University in 1992, is based on the display of
differentially expressed mRNA/cDNA by electrophoresis on an acrylamide gel
following rtPCR amplification of subpopulations of gene transcripts from
different groups of experimental tissues. This method has been used recently to
discover the unique expression during ovulation of genes for a carbonyl
reductase with 20b -hydroxysteroid dehydrogenase activity, a long interspersed
nucleotide element (LINE) that is highly repeated in mammalian genomes, and a
nerve growth factor-induced substance (NGFI-A). This latter substance, NGFI-A,
is usually expressed concomitantly with the proto-oncogene c-fos and the
metalloproteinase stromelysin-1, and therefore it is quite likely that the
transcription of genes for these factors is also up-regulated during ovulation.
Thus, in the future, the differential display procedure has the potential of
elucidating many other biochemical agents that are involved in the ovulatory
process.
IV.
Current Hypothesis on Ovulation
The above
background information on ovulation, along with the current literature on this
topic, serve as the basis for the following "working hypothesis" on
the mechanism of mammalian ovulation: The ovulatory surge in LH (or, exogenous
hCG) initiates acute changes in steroid and eicosanoid metabolism in the
granulosa cells of mature follicles. The ensuing increases in local
prostaglandins, lipoxins, kinins, platelet-activating factor, VEG/PF, and other
vasoactive agents collectively cause substantial dilatation of the capillaries
in the theca interna of the follicle wall. This significant change in the
capillaries of ovulatory follicles results in a 4-fold increase in the volume
of the ovarian vascular compartment. Concomitant with this hyperemic response,
the permeability of the thecal capillaries increases to the extent that serum
proteins are exuded into the interstitial spaces of the follicle in a manner
characteristic of inflamed tissues. Since blood serum is well known for its
ability to activate fibroblasts, it can be predicted that the exuded serum
stimulates the quiescent fibroblasts in the theca externa and tunica albuginea
of an ovulatory follicle and causes them to transform into proliferating cells.
The activated thecal fibroblasts begin secreting a metalloproteinase (perhaps
stromolysin-1, which is regulated by NGF) that degrades the extracellular
matrix of collagenous connective tissue in the follicle wall. Ultimately, the
follicle wall loses its tensile strength and eventually ruptures under the
force of a modest, but effective, intrafollicular pressure.
Acknowledgment
This
presentation is supported in part by NIH Grant HD31634.
Further
Reading
Adashi, E.
Y.: The potential relevance of cytokines to ovarian physiology: The emerging
role of resident ovarian cells of the white blood cell series. Endocr Rev
11:454-464, 1990.
Curry, T.
E., Jr., Mann, J. S., Estes, R. S. & Jones, P. B.: Alpha 2-macroglobulin
and tissue inhibitor of metalloproteinases: collagenase inhibitors in human
preovulatory ovaries. Endocrinology 127:63-68, 1990.
Dissen, G.
A., Hill, D. F., Costa, M. E., Dees, W. L. Lara, H. E., & Ojeda, S. R.: A
role for TrkA nerve growth factor receptors in mammalian ovulation. Endocrinology
137:198-209, 1996.
Espey, L.
L.: Ovulation as an inflammatory reaction—A hypothesis. Biol Reprod 22:73-106,
1980.
Espey, L.
L.: Ultrastructure of the ovulatory process. In: Ultrastructure of the
Ovary (Familiari, G., Makabe, S. & Motta, P., eds.), Norwell, Kluwer,
pp.143-159, 1991.
Espey, L. L.:
A review of factors that could influence membrane potentials of follicular
cells during mammalian ovulation. Acta Endocrinol 126 (Suppl 2):1-32,
1992.
Espey, L.
L.: Current status of the hypothesis that mammalian ovulation is comparable to
an inflammatory reaction. Biol Reprod 50:233-238, 1994.
Espey, L.
L. & Lipner, H.: Ovulation. In: The Physiology of Reproduction
(Knobil E. & Neill, J.D., eds.), New York, Raven, pp. 725-780, 1994.
Hartman,
C. G.: Ovulation and the transport and viability of ova and sperm in the
female genital tract. In: Sex and Internal Secretions (Allen, E., ed.),
Baltimore, Williams & Wilkins, pp. 647-688, 1932.
Koos, R.
D.: Increased expression of vascular endothelial growth/permeability factor in
the rat ovary following an ovulatory gonadotropin stimulus: Potential roles in
follicle rupture. Biol Reprod 52:1426-1435, 1995.
Liang, P.
& Pardee, A. B.: Recent advances in differential display. Cur Opin
Immunol 7:274-280, 1995.
Richards,
J. S.: Hormonal control of gene expression in the ovary. Endocr Rev 15:725-751,
1994.
Wathes, D.
C. & Denning-Kendall, P. A.: Control of synthesis and secretion of ovarian
oxytocin in ruminants. J Reprod Fert 45 (Suppl):39-52, 1992.
Legends
Figure
1. Ultrastructure of the apex of a rabbit follicle 10 hours before
rupture. See the text on "Anatomy of Ovulation " for further details.
(Width of the electron micrograph is approximately 56 microns.)
Figure
2. Ultrastructure of the apex of a rabbit follicle ˝-1 hour before
rupture. See the text on "Anatomy of Ovulation" for further details.
(Width of the electron micrograph is approximately 56 microns.)
Figure
3. Ultrastructure of the apex of a rabbit follicle 1-5 minutes
before rupture. See the text on "Anatomy of Ovulation" for further
details. (Width of the electron micrograph is approximately 56 microns.)
