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Chapter 12: Dynamics of ovarian function: the corpus luteum.

CHAPTER OBJECTIVES

* Describe the pattern of progesterone release during the luteal phase of the ovarian cycle.

* Describe the structural and hormonal changes exhibited by the corpus luteum during the luteal phase.

* Describe the mechanisms regulating formation, maintenance, and regression of the corpus luteum.

OVERVIEW

The focus of this chapter is the fate of the ruptured follicle following ovulation. Within several days after ovulation the remaining follicular tissue is transformed into the corpus luteum. The mediator of this response is luteinizing hormone (LH) and the process includes both morphologic and biochemical changes (Figure 12-1). The major biochemical change involves steroidogenesis. Unlike the follicle, which synthesizes testosterone and estradiol, the corpus luteum produces only progesterone. Concentrations of progesterone in blood parallel the growth and regression of the corpus luteum (Figure 12-2). In animals that have multiple ovulations, concentrations of progesterone are directly proportional to the number of corpora lutea that form.

Progesterone plays an important role in regulating reproductive activity in mammalian females. In addition to being an important reproductive hormone, progesterone is a key intermediate in the synthesis of other steroid hormones. All cells that produce steroid hormones produce progesterone. Progesterone is the major secretory product of the corpus luteum and the placenta, but is also produced by the adrenal cortex. What little progesterone is produced in males comes from the testes and adrenal glands. The only physiologic role of progesterone discovered in males is serving as a precursor for androgen synthesis. Our concern in this chapter will be progesterone production by the corpus luteum.

The major target tissues for progesterone are the hypothalamo-pituitary system and the female genital ducts (Figure 12-1). Progesterone plays a central role in regulating the ovarian cycle. Its major actions in this regard include 1) exerting a negative feedback action on GnRH release and 2) preventing estradiol from inducing an LH surge. These effects serve to regulate the length of the ovarian cycle. In other words, ovulation cannot occur as long as progesterone remains elevated. This is due to the fact that progesterone prevents the high-frequency pulses of LH necessary to induce follicle development to the preovulatory stage and prevents induction of an LH surge by estradiol.

[FIGURE 12-1 OMITTED]

[FIGURE 12-2 OMITTED]

With respect to effects on the genital ducts, progesterone's main action is to prepare the female reproductive tract for pregnancy. In the uterus, progesterone acts on the endometrium to 1) inhibit proliferation of mucosal cells, 2) stimulate secretion from glandular cells, and 3) enhance release of proteins that support early embryonic development. Progesterone also acts on the myometrium. Its major effect is to make the uterus quiescent. This action involves disruption of interactions among smooth muscle cells, interference with contractile mechanisms within smooth muscle cells, and blocking estradiol's ability to induce contractions.

GENERAL DESCRIPTION OF THE LUTEAL PHASE

The luteal phase of the ovarian cycle is defined as the period between ovulation and regression of the corpus luteum. In mammals with estrous cycles, the luteal phase encompasses metestrus and diestrus (Figure 12-2). During the first several days of the luteal phase (metestrus) what tissue remains from the ovulated follicle undergoes luteinization. As the tissue of the ruptured follicle is transformed into luteal tissue, production of estradiol ceases and progesterone production increases. During the early luteal phase, circulating concentrations of progesterone increase rapidly. The corpus luteum is fully functional by the time of diestrus, but it continues to increase in size throughout the luteal phase, releasing increasing amounts of progesterone as it grows. At the end of diestrus, the corpus luteum regresses and progesterone production ceases.

As described previously, progesterone provides the primary negative feedback signal regulating LH release in the adult female. Average concentrations of LH are low when progesterone concentrations are high (e.g., during diestrus), and high when progesterone concentrations are low (e.g., during metestrus and proestrus). This variation in LH concentrations is due to changes in the pulsatile pattern of LH release. LH is released in a high-amplitude, low-frequency mode during progesterone negative feedback. In the absence of this feedback LH is released in a low-amplitude, high-frequency mode. Progesterone suppresses the pulsatile release of LH by acting on the hypothalamus to reduce frequency of GnRH pulses. In addition to its effects on the pulsatile release of LH, progesterone inhibits the ability of estradiol to induce an LH surge. This is most likely due to effects on the anterior pituitary gland (i.e., reducing responsiveness to GnRH).

A high-frequency pattern of LH release is necessary for a follicle to develop to the preovulatory stage. Such a pattern is present before the corpus luteum develops and following luteal regression. This explains why follicular waves occur during each of these periods. The reason the dominant follicle fails to ovulate during the first wave (during metestrus) is because the rising concentrations of progesterone prevent estradiol from inducing an LH surge. You may recall in cattle that some cows have a follicular wave during diestrus, a time during which LH pulse frequency is low. It is unclear how a dominant follicle can undergo deviation during conditions of low LH concentrations. Apparently, the pattern of LH that exists at this time is sufficient to promote follicle growth. Nevertheless, the dominant follicle of this wave does not ovulate because the high progesterone concentrations block induction of an LH surge.

A key concept to remember from this discussion is that progesterone plays a central role in regulating ovarian cycles. Some reproductive physiologists view progesterone as the "organizer" of the ovarian cycle. As mentioned earlier, the inter-ovulatory period is directly related to the period of time when progesterone concentrations are elevated. Thus it is possible to shorten the estrous cycle by inducing premature regression of the corpus luteum as well as extend the length of the cycle by administering progesterone. This concept is the basis of estrous synchronization techniques (see Box 12-1).
BOX 12-1 Focus on Fertility: Synchronizing Estrus and Ovulation

The ability to regulate timing of estrus and ovulation
is essential for effective superovulation and embryo
transfer and also enhances effectiveness of artificial
insemination. One of the major factors restricting the
use of artificial insemination in beef cattle is the
labor required to round up and handle a herd of
cows. The following example illustrates how estrus
synchronization can reduce the amount of labor associated
with artificial insemination. In a herd of
100 cows, an average of only 5 would express heat
each day during a 3-week period. In contrast estrous
synchronization methods can result in as many as 80
to 90 cows expressing heat in a 3-day period.

Development of estrus synchronization
technologies has been a major focus of reproductive
physiology research during the past 40 years and has
occurred in five distinct phases (Table 12-1). Phases
I and III (the use of progestins and [PGF.sub.2[alpha]]) are
arguably the most important since all of the other methods
have evolved from these two basic approaches.

The first attempts to control the estrous cycles
of female farm animals are based on the knowledge
that progesterone prevents ovulation and expression
of estrus (Figure 12-3). A common approach is to
treat cyclic cows with progesterone or a progesterone-like
compound (a progestin) for 14 days. There
are three theoretical outcomes resulting from such a
treatment: 1) creation of an artificial luteal phase
(if treatment begins between luteolysis and the estrus
of the next cycle), 2) extension of the luteal
phase (if treatment begins when a corpus luteum
(CL) is present and the CL regresses before treatment
is withdrawn), and 3) no effect on the cycle
(if treatment begins within several days after estrus
and coincides with the presence of a new CL). In
the first case, the dominant follicle does not ovulate
until the progestin is withdrawn. In the second
case, the corpus luteum regresses at the expected
time, but the exogenous progestin delays estrus and
ovulation. In the third case, the exogenous progestin
exerts no effect on the formation and regression
of the corpus luteum. The important point to understand
from this example is that in each animal
estrus and ovulation occur within several days of
progestin withdrawal.

[FIGURE 12-3 OMITTED]

The second fundamental approach for synchronizing
estrus is based on the knowledge that
[PGF.sub.2[alpha]] induces regression of the corpus luteum
(Figure 12-4). Injections of this hormone would be
expected to induce luteolysis in any animal that has
a corpus luteum at the time of injection. Since a cow
has a corpus luteum for 14 days of the cycle (between
days 3 and 17), there is a probability that 14
out of 21 or 67 percent of the cows would respond to
[PGF.sub.2[alpha]] and express estrus within 72 hours after treatment.
In addition, cows receiving the injection on
days 18 through 21 (14 percent) would undergo
spontaneous luteolysis and also express estrus within
the 72-hour time frame. Therefore, in a herd of 100
cows approximately 81 percent (67 percent + 14
percent) would come into heat within 72 hours of a
single injection of [PGF.sub.2[alpha]]. A higher degree of synchrony
is achieved if cows are given a second injection
of [PGF.sub.2[alpha]] 8 to 14 days after the first injection. In
this way almost all of the animals will have a corpus
luteum present at the time of the second injection.

[FIGURE 12-4 OMITTED]

TABLE 12-1 Phases in development of
methods to synchronize estrus
in cattle

Phase    Approach

I        Use of progestins.

II       Use of progestins combined with
         estrogens and gonadotropins.

III      Use of [PGF.sub.2[alpha]].

IV       Use of progestins in combination with
         [PGF.sub.2[alpha]].

V        Use of GnRH in combination with
         progestins and [PGF.sub.2[alpha]].


Having reviewed the general features of the luteal phase, it is now possible to consider the corpus luteum in detail. Our discussion will be divided into three major sections: 1) development of the corpus luteum, 2) regulation of corpus luteum function, and 3) regression of the corpus luteum.

DEVELOPMENT OF THE CORPUS LUTEUM

The process by which the ruptured follicle is transformed into a corpus luteum (i.e., luteinization) involves both morphologic and biochemical changes. Morphologic changes consist of a rearrangement of the remaining follicular tissue and vascular infiltration. Biochemical changes involve changing from the ability to produce estradiol to the ability to produce progesterone. We will consider each of these processes separately. The bulk of information presented in this chapter will derived from domestic ruminants, primarily the cow and the ewe, because research on the CL of these species is extensive and has great historical relevance in the field of reproductive physiology.

Morphologic Changes

In addition to inducing ovulation, the LH surge also causes luteinization of the remaining follicular tissue. The major morphologic changes induced by the LH surge involve transforming the residual granulosa and theca interna cells into large and small luteal cells, respectively (Figure 12-5). Both types of luteal cells produce progesterone. In primates these cells are called granulosa-lutein and theca-lutein cells. In addition to changing the morphology of the granulosa and thecal cells, the LH surge induces a remarkable reorganization of follicular tissue. In nonprimate species, the basement membrane that separates granulosal and thecal cells disintegrates and allows the large and small luteal cells to intermingle with fibroblasts, pericytes, and endothelial cells. In primates much of the basement membrane remains and separates the two cell types. As the corpus luteum develops it also increases in size. In the ewe, there is, on average, a 16-fold increase in mass of the ovulatory tissue over several days. This growth is attributed to hypertrophy of small and large luteal cells as well as hyperplasia of small luteal cells, fibroblasts, and endothelial cells. The rate of mitosis in the developing corpus luteum is comparable to that of rapidly growing tumors. Moreover, a little over 20 percent of the mass of the CL is attributed to development of an extensive capillary plexus. The corpus luteum is one of the most richly vascularized tissues in the female and the rate of blood flow through this tissue exceeds that of all other tissues. This corresponds to its extremely high rate of oxygen consumption (per unit of mass), second only to that of the brain.

[FIGURE 12-5 OMITTED]

The mechanisms by which LH induces luteinization are not well understood. However, it is clear that LH induces the expression of various genes that give rise to several regulatory factors that induce tissue reorganization and growth via paracrine mechanisms.

Biochemical Changes

The major biochemical change associated with the transformation of a ruptured follicle into a corpus luteum results in a change in pattern of steroidogenesis. As described earlier, the preovulatory follicle produces estradiol at a very high rate, and this process requires cooperation between granulosa and theca interna cells. In the follicle, thecal cells express the enzymes necessary for converting cholesterol to testosterone, but not those mediating the conversion of testosterone into estradiol. In contrast, granulosa cells express the enzymes necessary to produce progesterone and convert testosterone into estradiol. In the follicle, steroidogenesis is controlled by LH and follicle-stimulating hormone (FSH). During luteinization the steroidogenic pathways of these follicular cells are altered such that they produce only progesterone. This involves an increase in expression of enzymes necessary to convert cholesterol into progesterone. In addition, luteal cells are not responsive to FSH.

REGULATION OF THE CORPUS LUTEUM

We now turn to a consideration of the mechanisms that regulate the activity of the corpus luteum. Luteinizing hormone appears to play critical roles in both the development and maintenance of the corpus luteum, but other hormones also contribute to these processes. The regression of the corpus luteum cannot be attributed simply to a removal LH. Rather, there are hormonal mechanisms that actively induce the demise of the corpus luteum. The next three sections will be devoted to detailed accounts of the mechanisms regulating the development, maintenance, and regression of the CL.

Regulation of CL Development

Insight into the endocrine regulation of the CL can be gained from the extensive research done with sheep. In the ewe, disruption of LH secretion via hypophysectomy (surgical removal of the pituitary gland) on day 5 of the estrous cycle prevents growth of the CL as well as the rise in progesterone that marks the early luteal phase. The underdevelopment of corpora lutea in these animals is attributed to a decrease in numbers of luteal cells and fibroblasts as well as a reduction in size of both small and large luteal cells, compared to normal. In addition, the capacity to synthesize progesterone is compromised in these cells.

The effects of hypophysectomy on luteal development are not entirely due to a deficiency of LH. When hypophysectomized ewes are given LH replacement therapy, progesterone production is restored to normal levels, but the size of the corpus luteum remains smaller than normal. The combination of growth hormone, another pituitary hormone, and LH will restore both the size and function of the CL.

Maintenance of the Corpus Luteum

In addition to playing an important role in development of the CL, LH is crucial to the maintenance of normal CL function. Removal of the pituitary gland or selective disruption of LH secretion results in regression of the CL in sheep, cattle, swine, and monkeys. Although LH appears to be the primary requirement for maintaining the CL in these species, the combined effects of LH and growth hormone (GH) may be necessary for normal CL function.

The mechanisms regulating the growth and maintenance of corpora lutea in rodents and rabbits are quite different from those in domestic ruminants. In rodents and rabbits, estradiol appears to be the major luteotrophic hormone. In rabbits, the role of LH is to sustain follicular production of estradiol, which then acts on the luteal cells to stimulate progesterone production. In the rat, prolactin is required for luteal cells to express receptors for estradiol and LH. The role of LH is to stimulate luteal production of estradiol, which then acts to stimulate progesterone synthesis.

Regulation of Progesterone Synthesis/Secretion

As discussed in the previous section, LH is necessary, but perhaps not sufficient for maintaining the corpus luteum. A comprehensive understanding of how progesterone synthesis is maintained in this tissue requires an understanding of how the small and large luteal cells function. In most mammals the basal (hormone-independent) production of progesterone in large luteal cells is 2 to 40 times greater than that in small luteal cells. Moreover, progesterone synthesis in small luteal cells requires LH. Regulation of progesterone production in large luteal cells appears to be LH-independent, but is regulated by other hormones including GH, insulin-like growth factor-1 (IGF-1), and prostaglandin [E.sub.2].

Although the activities of small and large luteal cells are regulated by different hormones, the basic biosynthetic pathway for progesterone synthesis is the same in each cell type (Figure 12-6). Cholesterol is the precursor for all steroid hormones. Steroid-producing cells derive most of their cholesterol from low-density lipoproteins (LDL), which are produced by the liver and serve as a means of cholesterol transport in blood. The structure of an LDL is analogous to a cell consisting only of its membrane; that is, a shell containing several types of lipids including cholesterol into which proteins are embedded. One of these proteins (apoprotein B) serves as a ligand for a specific receptor located on the membranes of most cells. Binding of the LDL to its receptor is a prerequisite for cholesterol uptake. The major steps in this process include:

* Internalization of the LDL-receptor complex.

* Liberation of cholesterol from the LDL.

* Uptake and esterification of cholesterol by lipid droplets.

Cholesterol is stored in lipid droplets in the form of cholesteryl esters. Cells that produce steroid hormones have numerous lipid droplets. Enzymes known as esterases break down the esterified form of cholesterol and free cholesterol is then liberated from the lipid droplets. Since cholesterol is a lipid it is insoluble in the cytoplasm. A protein known as sterol carrier protein-2 (SCP-2) interacts with the cytoskeleton to facilitate transport of cholesterol across the cytoplasm. A protein called steroidogenic acute regulatory protein (StAR) seems to play a role in transporting the cholesterol molecule from the outer mitochondrial membrane to the inner mitochondrial membrane where it encounters the side-chain cleavage enzyme. This enzyme converts cholesterol to pregnenolone. The rate at which this reaction proceeds is directly proportional to the availability of cholesterol, and is the rate-limiting step in progesterone synthesis. Once pregnenolone is formed it is translocated out of the mitochondria and transported to the smooth endoplasmic reticulum where it is converted to progesterone by the enzyme 3[beta]-hydroxysteroid dehydrogenase. Most of the newly synthesized progesterone leaves the cell and enters the extracellular fluid.

[FIGURE 12-6 OMITTED]

Having described the role of cholesterol in steroidogenesis it is now possible to discuss how LH and other hormones regulate progesterone synthesis in the corpus luteum. LH governs the acute regulation of progesterone synthesis in small luteal cells (Figure 12-6). In this case, the interaction of LH with its receptor results in generation of cyclic AMP (cAMP), which activates protein kinase A, an enzyme that phosphorylates regulatory proteins including StAR. Once phosphorylated, StAR binds cholesterol and facilitates its transport across mitochondrial membranes. Thus LH stimulates progesterone synthesis by increasing the availability of cholesterol, the rate-limiting substrate in this biosynthetic pathway. The more chronic effects of LH on progesterone synthesis may include increasing internalization of the LDL-receptor complex and increasing liberation of cholesterol from lipid droplets.

Less is known about the molecular mechanisms regulating progesterone synthesis in large luteal cells. As mentioned earlier, several hormones seem to play a role in this process. These cells have membrane receptors for GH, IGF-1, and prostaglandin [E.sub.2]. In addition, each of these hormones has been shown to enhance progesterone secretion in large luteal cells. GH and IGF-1 most likely interact to promote progesterone synthesis. In other words, GH may act directly on these cells as well as stimulate secretion of IGF-1, which acts in an autocrine/paracrine manner to further stimulate progesterone synthesis. The effects of GH, IGF-1, and prostaglandin [E.sub.2] in large luteal cells are presumably similar to those of LH on small luteal cells; that is, they enhance the rate-limiting step in progesterone synthesis.

REGRESSION OF THE CORPUS LUTEUM

The regression of the corpus luteum which marks the end of the luteal phase is commonly referred to as luteolysis (i.e., degradation of luteal tissue). This process appears to involve two steps. During the initial step, luteal cells lose their ability to synthesize and release progesterone. This is followed by the destruction of cells that make up the corpus luteum. The decrease in progesterone production is likely attributed to reduced blood flow to the corpus luteum as well as a compromised ability to synthesize progesterone.

Endocrine Regulation

In nonprimate species, luteolysis is dependent on the uterus. In other words, hysterectomy during the mid-luteal phase causes a delay in luteolysis. The socalled luteolysin in these species appears to be prostaglandin [F.sub.2[alpha]] ([PGF.sub.2[alpha]]), a hormone produced by the mucosa cells of the endometrium. In species such as the guinea pig, sheep, cow, and pig [PGF.sub.2[alpha]] is released into the capillaries of the submucosa and leaves the uterus via the utero-ovarian vein. Collateral channels and venules extending from this vein intertwine with and form numerous contacts with the tortuous ovarian artery (Figure 12-7A). These two blood vessels have thin walls at sites of contact which might favor diffusion of [PGF.sub.2[alpha]] directly from the utero-ovarian vein into the ovarian artery. This counter-current exchange mechanism ensures that high levels of P G[F.sub.2[alpha]] flow directly from the uterus to the ovary without entering the pulmonary circulation where most of it is degraded. In species such as the horse and rabbit, luteolysis is induced by [PGF.sub.2[alpha]] produced by the uterus, but the hormone does not travel directly to the uterus via a countercurrent exchange system. Anatomic studies reveal that the utero-ovarian vein and ovarian artery are not as intimately related as in species such as the sheep (Figure 12-7B). In species such as the horse and rabbit, [PGF.sub.2[alpha]] travels from the uterus through the general circulation before reaching the ovaries.

[FIGURE 12-7 OMITTED]

Aside from anatomic studies that characterized the vasculature of the female reproductive tract, the most compelling evidence that [PGF.sub.2[alpha]] can be transported directly from the uterus to the ovary comes from several important studies (Table 12-2). First, the fact that the lifespan of the CL is extended after removal of the uterine horn on the same side as the ovary with the CL, but not after removal of the horn on the side opposite to the CL demonstrates that the luteolytic activity of the uterus involves localized effects. These results, together with evidence showing that when [PGF.sub.2[alpha]] is injected into the uterus it is preferentially transferred to the ovarian artery (Figure 12-7) support the hypothesis that the hormone travels from the uterus to the ovary via a counter-current mechanism.

Luteolysis appears to be a tightly regulated event and appears to depend on the pattern of [PGF.sub.2[alpha]] secretion. Release of [PGF.sub.2[alpha]] is low and nonpulsatile during most of the luteal phase. However, during the late luteal phase (e.g., day 14 in cows) release of the hormone increases dramatically and circulating concentrations take on a pulsatile pattern (Figure 12-9). The pulses last several hours and occur once every 6 to 8 hours. The onset of this pulsatile release of [PGF.sub.2[alpha]] appears to be the physiologic trigger for the onset of luteolysis.

At this point you might be wondering what causes the increase in [PGF.sub.2[alpha]] release. There is consensus that the trigger is estradiol produced by the preovulatory follicle that is growing rapidly at this time in the ovarian cycle. The increase in estradiol appears to initiate a positive feedback loop between oxytocin and [PGF.sub.2[alpha]] (Figures 12-10). According to this hypothesis estradiol stimulates release of oxytocin from the posterior pituitary gland. At about the time estradiol concentrations are increasing, the endometrium begins to express receptors for oxytocin. Thus oxytocin can act on the uterus to stimulate release of [PGF.sub.2[alpha]] which then stimulates release of additional oxytocin from the corpus luteum. Thus a positive feedback loop is established between uterine [PGF.sub.2[alpha]] and oxytocin produced by the CL. This relationship causes the two hormones to be released in a pulsatile manner. Each pulse of [PGF.sub.2[alpha]] is preceded by a pulse of oxytocin. The reason these hormones are not released continuously is that the uterus becomes refractory to [PGF.sub.2[alpha]] following each pulse of [PGF.sub.2[alpha]] and the luteal tissue becomes refractory to oxytocin following each pulse of oxytocin.

[FIGURE 12-8 OMITTED]

[FIGURE 12-9 OMITTED]

[FIGURE 12-10 OMITTED]

Regulation of luteolysis in other domestic ungulates appears to be similar to that described for the ewe. In contrast, the mechanism in primates appears to be quite different. Removal of the uterus does not extend the life of the CL in humans and other primates. Although the precise mechanism controlling luteolysis in these species has not been elucidated, the prevailing theory to explain this process is summarized in Figure 12-11. Briefly, luteal regression is brought about by enhanced production of [PGF.sub.2[alpha]] by the ovary. The resulting decline in production of estradiol and progesterone induces an increase in uterine production of [PGF.sub.2[alpha]], which causes constriction of the spiral arteries that supply blood to the endometrium. The resulting necrosis of tissue leads to menstrual bleeding and sloughing of the endometrial lining.

Inhibition of Progesterone Synthesis/Secretion

The decline in progesterone concentrations that characterizes the end of the luteal phase is the result of two [PGF.sub.2[alpha]]-induced events (Figure 12-12): 1) reduced blood flow to the corpus luteum and 2) inhibition of progesterone synthesis.

[PGF.sub.2[alpha]] is well known as a vasoconstrictor. During the early stages of luteolysis [PGF.sub.2[alpha]] induces constriction of the arterioles that bring blood into the luteal tissue. This action may be mediated by endothelin-1. In addition, receptors for [PGF.sub.2[alpha]] have been detected on endothelial cells indicating that this hormone might have direct effects on luteal blood vessels. It has been proposed that [PGF.sub.2[alpha]] induces degeneration of capillaries in the corpus luteum. The combination of these effects on luteal vasculature causes a marked reduction in blood flow to the gland and deprives it of vital nutrients (energy substrates and oxygen), substrates for progesterone synthesis (LDL), and luteotrophic support (LH).

[FIGURE 12-11 OMITTED]

[FIGURE 12-12 OMITTED]

In addition to depriving luteal cells of the support necessary to produce progesterone [PGF.sub.2[alpha]] also acts within luteal cells to disrupt progesterone synthesis. The primary mode of action appears to be an inhibition of intracellular cholesterol transport. [PGF.sub.2[alpha]] has been shown to decrease concentrations of the cholesterol transporter (SCP-2) as well as proteins that make up the cytoskeleton. Each of these components is necessary for movement of cholesterol from lipid droplets to the mitochondria.

It should be noted that the aforementioned effects of [PGF.sub.2[alpha]] on progesterone production have been documented in the large luteal cells. We know substantially less about the mechanisms by which [PGF.sub.2[alpha]] inhibits progesterone synthesis in small luteal cells. It has been postulated that oxytocin, or some other luteal factor disrupts cholesterol transport to bring about a decrease in progesterone synthesis.

Morphologic Changes in Luteal Tissue

Morphologic changes can be observed in luteal tissue soon after progesterone secretion diminishes. These structural changes are attributed to the previously described effects of [PGF.sub.2[alpha]] on blood flow to the tissue, as well as direct effects of the hormone on the various cell types found in the tissue. Within 24 hours following administration of [PGF.sub.2[alpha]], the size of the corpus luteum decreases. Endothelial cells are the first cells to display morphologic changes. As noted in the previous section, these cells begin to degenerate thus destroying the extensive capillary network that supplies the corpus luteum with blood. Soon after there is a marked reduction in the numbers of large and small luteal cells. Other noteworthy changes include infiltration by leukocytes and degradation of the extracellular matrix, the connective tissue that provides support for the luteal tissue.

Apoptosis

The disappearance of cells from the corpus luteum during luteolysis is the result of a process known as apoptosis. This is the mechanism by which cells self-destruct. It is commonly observed when support of endocrine cells is removed. For example, when the nondominant follicles undergo atresia due to a decline in FSH, apoptosis is initiated in granulosa cells. Characteristic changes that occur in cells undergoing apoptosis include 1) fragmentation of the nucleus, 2) fragmentation of DNA, and 3) formation of membrane-bound vesicles that contain cytoplasmic materials. The extent to which P G[F.sub.2[alpha]] plays a role in inducing apoptosis is unclear, but it has been implicated in domestic ungulates, rats and humans.

Oxidative Stress

Oxidizing agents such as superoxide anion radicals, hydroxyl radicals, and hydrogen peroxide accumulate in luteal tissue during its regression. These so-called free radicals are toxic to cells and may play important roles in luteolysis. The source of most of these compounds is likely to be macrophages that infiltrate the corpus luteum during luteolysis to degrade the extracellular matrix and phagocytize the byproducts of tissue degeneration.

SUMMARY OF MAIN CONCEPTS

* The luteal phase of the ovarian cycle encompasses the period between ovulation and regression of the corpus luteum and is divided into three main phases: 1) an early phase during which the CL forms and gains the ability to produce progesterone, 2) a middle phase during which the corpus luteum is maintained and progesterone secretion is sustained, and 3) a late phase during which the corpus luteum regresses.

* Progesterone serves two main functions: 1) providing the major negative feedback signal regulating LH release in the adult and 2) preparing the female reproductive tract for pregnancy.

* Leutinizing hormone induces luteinization of the ruptured follicle and is the primary luteotrophic hormone in most species of mammals.

* [PGF.sub.2[alpha]] induces luteolysis by reducing blood flow to luteal tissue and by disrupting the biosynthetic pathway for progesterone.

DISCUSSION

1. The corpus luteum of the cow is responsive to [PGF.sub.2[alpha]] by day 4 of the estrous cycle. In addition, the corpus luteum begins to regress by day 18 of the cycle. Using this information, calculate the percentage of a group of nonpregnant cows (selected at random) that would be expected to ovulate following an injection of [PGF.sub.2[alpha]].

2. Suppose on day 1 of the estrous cycle you provided a cow with an implant that produced physiologic amounts of progesterone. If you leave the implant in the cow for 30 days, what would you expect to happen to the corpus luteum that formed between days 0 and 5? In other words, would you expect it to regress as normal, or continue functioning until the implant is removed? Explain your answer.

3. Based on your understanding of the relationship between progesterone and LH, explain the physiologic basis for using progesterone treatments as a means to prevent pregnancy.

4. What effect would a massive injection of LH (to mimic an LH surge) have on the dominant follicle that emerges early in the luteal phase?

REFERENCES

Ginther, O.J. 1974. Internal regulation of physiological processes through venoarterial pathways: a review. Journal of Animal Science 39:550-564.

Hixon, J.E. and W. Hansel. 1974. Evidence for preferential transfer of prostaglandin [F.sub.2[alpha]] to the ovarian artery following intrauterine administration in cattle. Biology of Reproduction 11:543-552.

Inskeep, E.K. and R.L. Butcher. 1966. Local component of utero-ovarian relationships in the ewe. Journal of Animal Science 25:1164-1168.

Johnson, S.K. 2005. Possibilities with today's reproductive technologies. Theriogenology 64:639-656.

Niswender, G.D., Juengel, J.L., Silva, P.J., Rollyson, M.K., and McIntush, E.W. Mechanisms Controlling the Function and Life Span of the Corpus Luteum. Physiological Reviews 80:1-29.

Patterson, D.J. and M.E. Smith. 2007. Progesterone-based estrus synchronization for beef replacement heifers and cows. In R.E. Youngquist and W. R. Threlfall, Current Therapy in Large Animal Theriogenology 2. St. Louis: Saunders, pp. 496-508.

Silvia, W.J., Lewis, G.S., McCraken, J.A., Thatcher, W.W., and Wilson, Jr., L. 1991. Hormonal regulation of uterine secretion of prostaglandin [F.sub.2[alpha]] during luteolysis in ruminants. Biology of Reproduction 45:655-663.

Keith K. Schillo, PhD

Department of Animal and Food Sciences

University of Kentucky

Lexington, Kentucky
TABLE 12-2 Results of two studies showing the effects of hysterectomy
on lifespan of the corpus luteum (CL) in sheep

Treatment                                    Lifespan of CL (days)

None                                         15-17

Hysterectomy (a)                             148

Unilateral hysterectomy (contralateral to    15-17
ovary with CL) (b)

Unilateral hysterectomy (ipsilateral to      From 24 to > 36
ovary with CL) (b)

(a) Both uterine horns removed (Wiltbank and Hansel, 1956).

(b) One uterine horn removed (Inskeep and Butcher, 1966).
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Author:Schillo, Keith K.
Publication:Reproductive Physiology of Mammals, From Farm to Field and Beyond
Geographic Code:1USA
Date:Jan 1, 2009
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