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Chapter 10: Dynamics of ovarian function in the adult female: ovarian cycles.

CHAPTER OBJECTIVES

* Introduce the concept of an ovarian cycle.

* Describe the basic characteristics of ovarian cycles in mammals.

* Compare and contrast the ovarian cycles of several types of mammals.

THE OVARIAN CYCLE AND REPRODUCTIVE ACTIVITY OF FEMALES

Our analysis of pubertal development in the female mammal revealed that ovarian activity is dynamic. In other words, on a given day the ovaries of developing females express different combinations of ovarian structures. Part of this phenomenon is due to waves of follicle growth. During the prepuberal period, large vesicular follicles develop, but then undergo atresia. Puberty occurs when a follicle reaches the preovulatory stage and then goes on to ovulate and form a corpus luteum. Once an individual becomes pubertal, this sequential pattern of ovarian activity (follicle growth-ovulation-corpus luteum formation) is continually repeated, and is known as the ovarian cycle. Before we consider the details of ovarian cycles, it may be helpful to note that in cases of multiple births more than one follicle reaches the pre-ovulatory stage and ovulates. In these cases, more than one corpus luteum develops. For simplicity, we will focus on cases involving single ovulations.

Figure 10-1 shows ovarian cycles associated with the pregnant and nonpregnant state. Females that do not conceive express a repeating pattern of follicle growth, ovulation, development of a corpus luteum, and regression of a corpus luteum. If the individual conceives after ovulation, regression of the corpus luteum is delayed until parturition. Following birth, the female will resume ovarian cycles that are characteristic of the nonpregnant state. In most cases, resumption of ovulation and occurrence of regular ovarian cycles is delayed for a period of time following parturition.

Follicular and Luteal Phases

The period of the ovarian cycle during which a follicle develops to the preovulatory stage is known as the follicular phase. During this phase of the cycle, the corpus luteum regresses and the dominant structure on the ovaries is a pre-ovulatory follicle. The follicular phase ends at ovulation and is followed by the luteal phase. During the luteal phase, a corpus luteum is the dominant ovarian structure. Although follicle growth occurs during the luteal phase, and large tertiary follicles develop, none of the follicles developing during this period reaches the pre-ovulatory stage. The end of the luteal phase is marked by regression of the corpus luteum; that is, luteolysis.

[FIGURE 10-1 OMITTED]

The cycle of ovarian activity is reflected by fluctuating patterns of ovarian hormones, namely estradiol and progesterone. During the follicular phase, estradiol concentrations in blood increase due to elevated production of this hormone by the dominant follicle. During the luteal phase, the corpus luteum produces large amounts of progesterone. In the nonpregnant female, this sequence of estradiol-ovulation-progesterone is repeated and coincides with the aforementioned pattern of follicular phase-ovulation-luteal phase. Pregnancy can be viewed as an extended luteal phase. In other words, if a pregnancy is established after ovulation, progesterone concentrations remain elevated until birth.

The cyclic release of estradiol and progesterone results in cyclic changes in activity of a variety of tissues that have receptors for these hormones. Effects on the genital tract are of particular importance. In general, the estrogenic portion of the ovarian cycle prepares the tract for receiving spermatozoa and fertilization, whereas the progesterone-dominated portion of the cycle prepares the tract for receiving and nurturing the embryo.

In most mammals, ovarian steroids produce profound effects on female reproductive behavior. "Estrus" was first used in 1900 to describe the particular period when mammalian females become sexually receptive. The term is derived from the Latin adaptation of the Greek word "oistros," which means frenzy. During estrus, females exhibit behaviors that promote sexual contact with males. Such behaviors are most prevalent soon before or at the time of ovulation and are caused by the high levels of estradiol. Because the behaviors associated with estrus are readily observable, and occur at regular intervals corresponding to the follicular phase of the ovarian cycle, species that express this pattern of sexual behavior are said to express estrous cycles. In the absence of pregnancy, females will express estrous behavior at regular intervals, whereas pregnant females will not exhibit estrus. Derivations of the word " estrus" are used describe other phases of the estrous cycle. Anestrus refers to a nonbreeding period when estrus and ovulation do not occur and the female resists males' attempts at mating. The estrous cycle is traditionally divided into four phases: proestrus, estrus, metestrus, and diestrus (Figure 10-2). Proestrus refers to the early portion of the follicular phase and includes events that cause an animal to come into heat. As noted previously estrus refers only to the time when the female is willing to copulate with a male, and corresponds to the latter portion of the follicular phase. During metestrus (also known as diestrus 1), a period corresponding to the early luteal phase, ovarian steroids prepare the genital tract for receiving the newly fertilized ovum. Diestrus (also known as diestrus 2) refers to the remaining portion of the luteal phase. During this phase the reproductive tract is in a state that can maintain pregnancy. If fertilization has not occurred, this phase is followed by a new proestrus period, marking the beginning of a new cycle.

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Sexual receptivity of some mammals is not confined to a particular portion of the ovarian cycle (Figure 10-3). In most species of primates, females engage in sexual activity throughout the cycle. Because these individuals do not express repeating patterns of sexual activity, it is inappropriate to refer to their ovarian cycles as estrous cycles. In these cases, the name of the ovarian cycle is based on other outward signs of changing ovarian activity; that is, menstruation. Menstruation (also known as menses) refers to the sloughing of the endometrium accompanied by bleeding. As noted earlier, fluctuations in estradiol and progesterone concentrations associated with the follicular and luteal phases exert important effects on the genital tract. For example, these hormones work together to promote changes in the uterine endometrium that support pregnancy. The drop in progesterone concentrations during the transition between the follicular and luteal phases of the ovarian cycle causes cells of endometrium to slough off and is accompanied by bleeding. In the nonpregnant state, menstruation occurs at regular intervals associated with the transition between the follicular and luteal phases. Species that exhibit this are said to express menstrual cycles. The vast majority of mammalian species that exhibit menstrual cycles are primates.

[FIGURE 10-3 OMITTED]

Ovarian Cycles of Various Species of Mammals

Among mammalian species there is considerable variation in lengths of ovarian cycles. Table 10-1 summarizes the major characteristics of ovarian cycles in several species for the nonpregnant state. The estrous cycles of domestic ungulates such as the sheep, pig, cow, and horse are approximately 3 weeks in length. In each case the length of the follicular phase is shorter than that of the luteal phase. The menstrual cycles of higher primates last approximately 4 weeks and lengths of the follicular and luteal phases are approximately the same (14 days).

Rodents such as rats and mice have very short estrous cycles, due to a truncated luteal phase. In these species, females exhibit estrus and ovulate once every 4 to 5 days with follicular and luteal phases each lasting 2 to 3 days. Interestingly, the length of the luteal phase is lengthened to 11 to 12 days if female rodents are mated to infertile males or if the cervix is stimulated mechanically. Because this pattern of luteal development and progesterone production is similar to that seen in the pregnant female, the lengthened luteal phase is referred to as pseudopregnancy.

[FIGURE 10-4 OMITTED]

The data for the rabbit may be confusing at first glance. In the absence of mating the rabbit doe has a very short ovarian cycle consisting of only a follicular phase and estrus; that is, a large tertiary follicle develops, but undergoes atresia instead of ovulating (Figure 10-4). This cycle of follicle growth and atresia continues so long as the doe in not mated. The pattern of follicle growth and regression is commonly referred to as a wave of follicle growth or follicular wave (Figure 10-4). Unlike the previous examples, where ovulation occurs spontaneously at the end of each follicular phase, rabbit does will not ovulate unless they copulate. Animals with this sort of ovulatory mechanism are known as induced ovulators, meaning that they exhibit a luteinizing hormone (LH) surge and ovulation only if the cervix is stimulated. When a doe mates with an infertile buck (or if its cervix is mechanically stimulated), ovulation is induced and corpora lutea will develop and produce progesterone for 13 days; that is, pseudopregnancy (Figure 10-5). Other induced ovulators include the cat, ferret, black bear, camel, and llama.

Figure 10-6 compares the mechanisms of ovulation for induced ovulators and spontaneous ovulators. In both cases high levels of estrogen, produced by large preovulatory follicles, induce sexual receptivity in the female. In spontaneous ovulators, the high levels of estrogen act on the hypothalamus and pituitary gland to induce an LH surge, which then causes ovulation. In induced ovulators, the LH surge is induced by a neural reflex; that is, stimulation of the cervix during copulation stimulates afferent nerves, which induce a surge of GnRH release from the hypothalamus.

[FIGURE 10-5 OMITTED]

[FIGURE 10-6 OMITTED]

Animals that exhibit estrous cycles can be further classified based on the number of times they express cycles in a year (see Table 10-1). Nonseasonal breeders such as cattle and swine will express estrous cycles continuously throughout the year and are referred to as polyestrous animals. Seasonal breeders such as sheep, goats, and horses express estrous cycles continuously, but only during a particular time of year (the breeding season). Each year these seasonal breeders experience an anestrous period during which they fail to exhibit ovarian cycles. These are the seasonally polyestrous mammals. The pattern of estrus in canids is rather unique. Wild canids such as wolves and coyotes express only one estrus annually and are classified as monoestrous species. In contrast, most breeds of domestic dogs express estrus biannually, but it is not uncommon for some bitches (especially the smaller breeds) to express several cycles in a given year. It is important to note that this classification scheme applies to both spontaneous and induced ovulators.

COMPARATIVE ANALYSIS OF OVARIAN CYCLES IN SEVERAL TYPES OF MAMMALS

As noted in the previous sections, the ovarian cycles of mammals share some important characteristics, namely that ovulation is sandwiched between periods of dominance by the preovulatory follicle (producing high levels of estradiol) and the corpus luteum (producing high levels of progesterone). In the next two chapters we will study the mechanisms of follicle growth, ovulation, and the development and regression of the corpus luteum. Before we enter such discussions, it is important to develop an understanding of how the various reproductive hormones interact to regulate these events. Your understanding of these regulatory mechanisms will be facilitated if you keep in mind the following concepts:

* Regulation of ovarian activity depends on communication between the ovaries and the hypothalamic-pituitary unit.

* Pituitary gonadotropins (LH and [follicle-stimulating hormone [FSH]) are the primary regulators of follicles and the corpus luteum, including secretion of hormones by these ovarian structures.

* Hormones produced by the ovaries feed back on the hypothalamic-pituitary unit to inhibit or enhance release of LH and FSH.

* Endocrine interactions between the ovaries and the hypothalamic-pituitary unit result in distinct patterns of ovarian and pituitary hormones, which characterize each phase of the ovarian cycle.

In view of these concepts, our approach to understanding the mechanisms controlling ovarian cycles will be to consider each of the major phases of the ovarian cycle. We will first examine patterns of reproductive hormones, and then consider regulation of these hormone patterns as well as the physiologic implications of them.

Regulation of Ovarian Cycles of Rodents

The ovarian cycle of the rat is the most thoroughly documented one among mammalian species. As noted earlier, the domestic rat has been the primary subject of medical research since the early twentieth century. Much of what we know about reproductive biology was first discovered in rats. Today this animal continues to be the focus of most research dealing with reproductive physiology.

Rats that do not copulate express estrus once every 4 to 5 days (Figure 10-7). Proestrus, estrus, metestrus (diestrus 1), and dietestrus (diestrus 2) each lasts approximately 1 day. When studying estrous cycles, the time of ovulation serves as a useful reference point that divides events of the cycle into those leading to and those resulting from this important event. In rats, ovulation occurs approximately 8 to 10 hours after the beginning of estrus. Figure 10-7 shows patterns of the major reproductive hormones throughout the rat estrous cycle. These patterns reflect concentrations of hormones measured at 2-hour intervals throughout the 4-day cycle. Due to this infrequent mode of blood sampling, pulsatile patterns are not evident.

[FIGURE 10-7 OMITTED]

Estradiol

The major physiologic features of estradiol patterns can be summarized as follows:

* Concentrations are lowest during estrus, but then increase gradually throughout the cycle, reaching peak levels during proestrus.

* The pattern is attributed to the pattern of follicle growth. By the time estrus begins, a group of follicles becomes committed to a preovulatory pool. These follicles were members of a larger group of follicles that initiated growth 16 days earlier.

* Follicles selected for ovulation grow throughout the estrous cycle and attain maximal size during proestrus. The increase in estradiol concentrations between estrus and proestrus reflects the follicles' enhanced capacity to produce this hormone.

* Once follicles ovulate, they lose their capacity to produce estradiol. Consequently, concentrations of estradiol fall abruptly during proestrus and reach minimal levels by the morning of estrus.

Progesterone

Patterns of progesterone during the cycle are similar to those of estradiol in some respects and different in others.

* Concentrations begin to increase during diestrus and peak for the first time during metestrus.

* The source of progesterone during this part of the cycle is the corpora lutea that develop following ovulation. As noted earlier, the life span of these structures is short and they lose their ability to produce progesterone by early metestrus.

* A second peak of progesterone occurs during proestrus. Unlike the previous peak, the source of progesterone in this case is the preovulatory follicles, and the stimulus for this response is the LH surge that occurs during proestrus. The precipitous drop in progesterone seen during late proestrus is attributed to the reduced capacity of follicles needed to produce this steroid following ovulation.

Luteinizing Hormone

The profile of LH concentrations shown in Figure 10-7 does not reveal all of the physiologically important features of LH secretory patterns. When LH concentrations are measured in sequential blood samples collected at more frequent intervals (e.g., once every 10 to 15 minutes) over several hours, it becomes clear that LH concentrations fluctuate in a pulsatile manner throughout the cycle.

With respect to the LH profile presented in Figure 10-7, the most physiologically relevant features are:

* Concentrations of LH remain low until the afternoon of proestrus, when there is a surge of LH.

* The LH surge is caused by the positive feedback actions of estradiol. As estradiol concentrations increase they enhance LH secretion, which in turn stimulates release of more estradiol from pre-ovulatory follicles.

* The stimulatory effects of estradiol on LH secretion involve both enhanced GnRH release from the hypothalamus and increased responsiveness of the anterior pituitary gland to GnRH.

* It is unclear whether the LH surge is caused by a single constant pulse of LH or a series of high-frequency LH pulses.

* The physiologic effects of the LH surge include rupture of preovulatory follicles (ovulation), completion of oocyte maturation, and transformation of follicular cells into luteal cells (luteinization).

The mechanism mediating the positive feedback action of estradiol deserves special attention because it is somewhat unique among mammals. Three conditions seem to be necessary for an LH surge to be induced in the rat.

* Neuronal mechanisms responsible for evoking this response.

* A surge of estradiol.

* A surge of progesterone.

The neuronal mechanism that mediates the positive feedback effects of estradiol on LH release appears to be controlled by an endogenous circadian rhythm. In other words, this mechanism becomes operative only during a 1- to 2-hour period each day. The timing of the operative period is dependent on the daily photoperiod. For example, in rats maintained on a daily cycle of 12 hours of light and 12 hours of dark, this so-called critical period will occur between 2:00 and 3:45 p.m. The reason the LH surge occurs only during proestrus is due to the fact that high levels of estradiol and progesterone are required to evoke this response. Moreover, the proestrus surge of progesterone appears to prevent release of surge amounts of LH during the days following proestrus (estrus, diestrus, and metestrus).

The physiologic effects of LH are not limited to those associated with the pre-ovulatory surge of this hormone. LH also plays an important role in development of pre-ovulatory follicles.

The major stimulus for the increased secretion of estradiol by follicles between diestrus and proestrus is the high-frequency pattern of pulsatile LH release.

Follicle-Stimulating Hormone

The most important characteristics of FSH patterns during the estrous cycle include the following:

* A surge of FSH occurs concomitantly with the LH surge during proestrus.

* The elevated concentrations of estradiol and progesterone constitute the major stimuli for inducing this surge, and the neuronal mechanisms that bring about this response are probably the same as those controlling the LH surge.

* The primary surge of FSH is followed by a secondary surge during early estrus.

* The secondary surge of FSH is likely brought about by an abrupt decrease in inhibin, a peptidergic ovarian hormone (produced by the granulosa cells of follicles) that serves as the major negative feedback signal controlling FSH release.

* Concentrations of FSH are minimal during diestrus and metestrus due to the combined inhibitory feedback effects of estradiol, progesterone, and inhibin.

The main physiologic effect of FSH is to stimulate development of secondary follicles to the tertiary stage. We will discuss details of follicle growth and development (folliculogenesis) in the next chapter. For the moment it is only important to understand that the secondary surge of FSH promotes growth of secondary follicles such that they enter a growing pool of follicles on estrus. The subsequent exposure of these follicles to consecutive surges of LH and FSH associated with the next four to five cycles further enhances growth of these follicles such that they become pre-ovulatory follicles. Thus, as mentioned earlier, follicles that ovulate during a particular cycle are selected during an estrus that occurred 20 days earlier.

Prolactin

The most significant features of prolactin patterns during the nonmated state can be summarized as follows (Figure 10-8):

* The pattern of prolactin during the rat estrous cycle is very similar to that of LH; that is, a proestrus surge followed by low concentrations during the remainder of the cycle.

* The major stimulus for the prolactin surge is the rising concentrations of estradiol between metestrus and early proestrus.

* Estrogen induces the prolactin surge by acting directly on the anterior pituitary gland as well as on the hypothalamus.

* Like the LH surge, the timing of the prolactin surge is subject to regulation by a circadian clock.

* The physiologic effects of the prolactin surge of proestrus appear to be minimal.

In nonmated female rats, the corpora lutea persist for only a brief interval. In contrast, mating or mechanical stimulation of the cervix prevents regression of corpora lutea. As noted earlier in this chapter, a fertile mating extends the lifespan of the corpora lutea for 20 to 22 days, whereas mating with a sterile male or mechanical stimulation of the cervix extends the lifespan of corpora lutea for 12 to 14 days (pseudopregnancy). This extended luteal function is caused by unique changes in prolactin secretion (Figure 10-8). The specific nature of this effect in the pseudopregnant rat can be summarized as follows.

* During pseudopregnancy, female rats express two daily surges of prolactin for approximately 2 weeks.

* The daily prolactin surges peak during the early (5 to 7 p.m.) and late (3 to 7 a.m.) dark periods.

* The end of pseudopregnancy is marked by an abrupt termination of the prolactin surges, which appears to be caused by the reduction in progesterone attributed to regressing corpora lutea.

* The physiologic significance of the mating-induced prolactin surges deals with maintenance of pregnancy. These high levels of prolactin are necessary for corpora lutea to produce progesterone, which is essential for maintaining pregnancy.

[FIGURE 10-8 OMITTED]

Regulation of the Ovarian Cycles of Induced Ovulators

Induced or reflex ovulators are widespread among the orders of mammals. However, this type of ovulation seems to predominate in Insectivores, Lagomorphs, and Carnivores. At least 22 species of mammals have been documented to be induced ovulators, and another 25 species may ovulate in this manner. As noted earlier, ovulation in these species occurs only after copulation. However, ovulation can be induced experimentally by mechanical stimulation of the cervix. The general mechanism of induced ovulation was discussed in an earlier section of this chapter (Figure 10-6). You should recognize this as a neuroendocrine reflex arc. During mating various stimuli (e.g., tactile) are detected by various receptor organs. This generates neuronal signals that are conducted to the central nervous system via afferent neurons. Integration of these various inputs occurs within the hypothalamus to evoke a hormonal response. In the case of induced ovulation, the hormonal response is a surge of LH that induces ovulation of ovarian follicles.

Induced ovulation has been studied most in the rabbit doe. However, the domestic queen is probably the induced ovulator with which most people are familiar. Figure 10-9 summarizes the ovarian cycle of the queen. The ovarian cycle of the unmated queen consists only of proestrus and estrus. Proestrus refers to the period separating consecutive estrous periods and is the time during which preovulatory follicles develop. This is most likely brought about by a high-frequency pattern of pulsatile LH release. As follicles reach the preovulatory stage and they produce large amounts of estradiol and induce behavioral estrus. If the queen does not copulate, the large follicles will become atretic and estradiol production will cease. By the time estrus ends, a new crop of follicles is recruited to enter the preovulatory stage. The duration of estrus in the queen is approximately 9 days and occurs once every 17 days in the nonmated state. Notice that concentrations of progesterone remain extremely low during the ovarian cycles of nonpregnant queens.

[FIGURE 10-9 OMITTED]

Like the rat, mating induces dramatic changes in the ovarian cycle of induced ovulators. Mating or stimulation of the cervix induces a surge of LH. The LH surge induces ovulation, and luteinization of ruptured follicles resulting in formation of corpora lutea. The corpora lutea persist for approximately 2 months, whether or not the mating is fertile. In the case where pregnancy does not occur the queen is said to be in a state of pseudopregnancy.

We know less about the role of FSH in regulation of the feline estrous cycle than we do in regulation of the ovarian cycles of rodents, higher primates, and domestic farm animals. In rabbits, two surges of FSH occur postcoitus. The first is smaller and rises at a slower rate than the LH surge, and is probably due to a rise in gonadotropin-releasing hormone (GnRH) brought about by cervical stimulation. The secondary surge of FSH occurs 12 to 24 hours after mating and is the result of a sudden drop in inhibin caused by follicle rupture and ovulation. Presumably this response is the stimulus for initiating development of a new crop of preovulatory follicles.

[FIGURE 10-10 OMITTED]

The Ovarian Cycles of Canids

The ovarian cycles of canids are rather unique among mammals. First, as noted earlier, most wild canids and many of the larger breeds of the domestic dogs do not experience more than one or two cycles each year. Thus the bitch experiences a long (5 months) period of anestrus. Another unique feature of the bitch's estrous cycle is that the diestrus period is indistinguishable between pregnant and nonpregnant states. Figure 10-10 summarizes highlights of the ovarian cycle of the bitch.

Toward the end of anestrus, circulating concentrations of LH begin to increase due to onset of a high-frequency mode of pulsatile LH secretion. This pattern of LH release persists throughout proestrus and culminates in a surge of LH, which marks the onset of estrus. Concentrations of LH remain low following the LH surge. As in the previous two examples, the high-frequency pattern of LH enhances development of preovulatory follicles and the LH surge induces ovulation of these follicles.

Concentrations of ovarian steroids are low during anestrus. Concentrations of estradiol fluctuate in accordance with waves of follicle growth, but do not reach levels that induce estrus or a pre-ovulatory surge of LH. The onset of high-frequency LH pulses during the final stages of anestrus prevent large antral follicles from becoming atretic and stimulate them to the pre-ovulatory stage of development. This results in elevated concentrations of estradiol, which induce an LH surge as well as behavioral estrus. The LH surge lasts several days (24 to 96 hours) and induces multiple ovulations within 2 to 3 days. As follicles ovulate, they lose their ability to produce large amounts of estradiol. Therefore, concentrations of this steroid hormone fall leading to the end of estrus.

As corpora lutea develop from ruptured follicles they produce increasing amounts of progesterone. These structures persist for approximately 2 months in dogs regardless of the reproductive state of the bitch. Like in rodents and induced ovulators, persistence of corpora lutea in the absence of pregnancy is referred to as pseudopregnancy.

The Ovarian Cycles of Domestic Ungulates

The estrous cycles of the major livestock species (cattle, sheep, swine, and horses) have been extensively studied. By far the greatest emphasis has been on the cycles of the cow and ewe. The cow has received attention because of the economic importance of reproductive management in the dairy and beef industries. The ewe has been the focus of a tremendous number of studies because the smaller body size of sheep makes this species more suitable to some difficult experimental techniques and its seasonal reproductive activity makes it a good model for studying seasonal control of reproductive activity. Tremendous insight into the regulation of ovarian cycles in domestic ungulates can be gained by focusing on either the cow or the ewe. We shall focus our analysis on the ewe because information on the neuroendocrine control of its estrous cycle is more complete than that of the cow. Moreover, in a later chapter we will use the sheep as a model to study the effects of season on reproductive activity.

The estrous cycle of the ewe averages 17 days in length. There appears to be little variation in this trait among sheep. Approximately 95 percent of the cycles last between 16 and 19 days. Like the rat, the ovarian cycle of the sheep consists of a follicular phase and a luteal phase. These phases can be subdivided into proestrus, estrus, diestrus, and metestrus (Figure 10-11). Proestrus and estrus make up the follicular phase, whereas metestrus and diestrus make up the luteal phase. During proestrus, one or two preovulatory follicles are developing. Ovulation occurs during the latter part of estrus. Metestrus refers to the time during which the corpus luteum is forming. The corpus luteum is fully functional during diestrus, and the regression of the corpus luteum marks the end of this period and the beginning of proestrus.

[FIGURE 10-11 OMITTED]

Our approach to analyzing the ovine estrous cycle will be similar to the one we used for the estrous cycle of the rat. The pattern of each reproductive hormone will be considered separately. Each of the following discussions refers to hormone patterns depicted in Figure 10-11.

Progesterone

By now it should be clear that circulating concentrations of progesterone reflect activity of the corpus luteum. More specifically, concentrations of progesterone are directly proportional to both the size and number of corpora lutea. Thus concentrations of progesterone are low during proestrus and estrus due to the lack of functional corpora lutea. Within the first 3 days following ovulation, concentrations of this steroid are extremely low. However, between days 3 and 8 progesterone concentrations increase as the ruptured follicles develop into corpora lutea and gain the capacity to produce large amounts of this steroid. Concentrations of progesterone increase gradually throughout the luteal phase of the cycle (between days 8 and 14). The end of the luteal phase is marked by an abrupt decrease in progesterone concentrations. This occurs over a 1- to 2-day period.

The pattern of progesterone during the ovine estrous cycle is the result of the following regulatory mechanisms.

* The rise in progesterone levels during metestrus is a consequence of ovulation and subsequent transformation of tissue from ovulated follicles into luteal tissue. These events are mediated by the LH surge.

* The elevated concentrations of progesterone during the luteal phase are sustained by the luteotrophic actions of LH.

* The drop in progesterone marking the end of the luteal phase is due to the death of luteal tissue brought about by increased release of prostaglandins [F.sub.2[alpha]] ([PGF.sub.2[alpha]]) by the uterus.

Estradiol

Our previous analyses of ovarian cycles firmly established the relationship between estradiol concentrations and follicle activity. These same principles apply to the ovarian cycle of the sheep. Specifically, circulating concentrations of estradiol reflect both the number and size of follicles. With this in mind the patterns of estradiol associated with the ewe's estrous cycle can be readily understood. The principal rise in estradiol occurs during the 2- to 3-day follicular phase (proestrus), beginning after the aforementioned drop in progesterone concentrations and peaking at the onset of estrus. The existence of other peaks in estradiol concentrations is unclear. A secondary rise in this hormone may occur on day 4 of the cycle. This is consistent with what occurs in the cow. Cows experience a wave of follicle development soon after ovulation, which results in an increase in estradiol during diestrus. Some cows experience another follicular wave and corresponding increase in estradiol concentrations during the middle of the luteal phase.

The pattern of estradiol concentrations during proestrus and estrus are strictly the result of follicular activity which can be summarized as follows.

* The increase in estradiol concentrations during proestrus reflects growth and activity of a preovulatory follicle, which begins during late diestrus.

* The decrease in estradiol concentrations during estrus are due to ovulation.

* Increases in estradiol concentrations during other times of the cycle are attributed to additional waves of follicle growth, which end with follicular atresia rather than ovulation.

LH

One of the more dramatic features of the estrous cycle is the pre-ovulatory surge of LH. In the ewe, the LH surge is tightly coupled with the onset of estrus. This massive increase (50- to 100-fold increase) in LH concentrations begins at the onset of estrus, peaks 4 to 8 hours later and ends within 12 hours of its initiation. During other phases of the estrous cycle, LH is released tonically. Average concentrations increase during diestrus, then decrease and remain low during most of metestrus. When concentrations of progesterone drop, tonic levels of LH begin to increase and continue to rise throughout proestrus. The rate of increase rises abruptly with the onset of the LH surge.

[FIGURE 10-12 OMITTED]

The day-to-day changes in LH patterns shown in Figure 10-11 are caused by changes in the pulsatile secretion of this hormone. Figure 10-12 illustrates pulsatile patterns of LH for the follicular and mid-luteal phases. The increase in LH concentrations during proestrus is due to the onset of a high-frequency pattern of release. The lower concentrations of the luteal phase reflect a low-frequency pattern of release. You might have noticed that the amplitude of LH pulses is also different between phases of the cycle. Generally, pulse amplitude is a function of pulse frequency. More specifically, a lower pulse frequency usually results in higher pulse amplitude.

Ovarian steroids play a primary role in regulating patterns of LH during the estrous cycle. In particular, the positive and negative feedback effects of estradiol and progesterone regulate both the pattern of GnRH release from the hypothalamus and the responsiveness of the anterior pituitary gland to GnRH. Highlights of these regulatory mechanisms are listed below.

* The high levels of estradiol on proestrus induce the preovulatory surge of LH by increasing GnRH release and by enhancing responsiveness of the pituitary gland to GnRH.

* The high levels of progesterone found during the luteal phase block the positive feedback actions of estradiol on LH release.

* The low-frequency pattern of LH, characteristic of the luteal phase, is caused by the negative feedback actions of progesterone on hypothalamic release of GnRH.

* The high-frequency pattern of LH, characteristic of proestrus and diestrus, is due to the absence of a negative feedback signal; i.e., progesterone.

FSH

Patterns of FSH have been more difficult to assess due to unique problems associated with measuring this hormone in the blood. It is clear that a surge of FSH occurs coincident with the LH surge during estrus. It is also well accepted that a secondary peak in FSH occurs 24 hour after the first peak. Other increases in FSH might occur during the luteal phase, but these have not been consistently identified. However, careful monitoring of FSH patterns in cows reveals that increases in FSH concentrations occur at the onset of follicular waves.

Regulation of FSH secretion has not been studied to the same extent as the regulation of LH secretions in sheep. However, it is clear that ovarian hormones play significant roles in controlling FSH release. The following aspects of this control are noteworthy.

* It is generally agreed that the preovulatory surge of FSH is controlled by the same mechanisms as those controlling the LH surge; that is, the high concentrations of estradiol present during proestrus appear to be induce the FSH surge, and luteal phase concentrations of progesterone block this effect.

* The positive feedback effects of estradiol on FSH release are mediated by enhanced release of GnRH. It remains unclear if estradiol enhances pituitary response to GnRH.

* The secondary surge of FSH (and other increases that precede follicular waves) is due to reductions in ovarian hormones that exert negative feedback actions on FSH. Estradiol and inhibin are among the most important of these hormones.

* Throughout the estrous cycle there is an inverse relationship between concentrations of FSH and concentrations of estradiol and inhibin, hormones produced by follicles.

Prostaglandin [F.sub.2[alpha]]

One of the most important events regulating the estrous cycle is luteolysis. Recall that luteal phase concentrations of progesterone prevent the high-frequency pattern of LH release as well as the preovulatory surge of LH. Therefore, ovulation cannot occur until luteal regression. In Chapter 12, we will explore the details of the mechanisms controlling this important event. For the time being it is only important to understand that luteolysis is induced by [PGF.sub.2[alpha]]. During the luteal phase, release of this hormone by the uterine endometrial cells is minimal. However, between days 12 and 14 large surges of [PGF.sub.2[alpha]] appear in the circulation due to increased production by the uterus. The major consequence of this response is regression of luteal tissue which results in a rapid decrease in progesterone concentrations. The mechanisms controlling [PGF.sub.2[alpha]] release and luteolysis will be examined in detail in Chapter 12.

There is consensus among reproductive biologists that the mechanisms regulating luteolysis in the other major livestock species are similar to the one described for the sheep. It is also likely that a similar mechanism exists in rodents. We know little about the control of luteolysis in induced ovulators and canids. In addition, luteolytic mechanisms in higher primates have been elusive until recently.

Ovarian Cycles of Higher Primates

The task of understanding the menstrual cycles of higher primates is facilitated by our analysis of estrous cycles in other species. Much of what we know about regulation of ovarian activity in livestock, rodents, and induced ovulators applies to regulation of menstrual cycles. In both types of ovarian cycles, ovulation is a convenient reference point with which to begin. The major difference between estrous and menstrual cycles is not as much biological as much as how the cycle is described. More specifically the terminology used to describe the stages of the cycle. With respect to estrous cycles, estrus is typically referred to as day 0. In contrast, day 0 of the menstrual cycle is typically defined as the day menstruation begins (Figure 10-13). The menstrual cycle is often divided into two phases, based on activity of the ovaries; that is, follicular and luteal phases. However, the cycle is also described based on the activity of the uterine endometrium. The follicular phase consists of a 5-day period of menses and a 9-day proliferative phase. During the luteal phase, the uterus is said to be in the secretory phase. Menses refers to the sloughing of blood and endometrial tissue. This is followed by the proliferative phase during which the endometrium increases in thickness. This is largely due to formation of glands in the endometrial mucosa. During the secretory phase, the endometrium attains maximal thickness and uterine glands begin to secrete fluids, which help create an environment favorable to pregnancy. At this time small spirally shaped arteries proliferate and extend through the submucosa to supply blood to the endometrial glands. The physiologic connections between the two ovarian phases and the three uterine phases are the ovarian hormones. The proliferative phase of the uterus is due to the high levels of estradiol found during the follicular phase, whereas the secretory phase is due to the high levels of progesterone and estradiol characteristic of the luteal phase. Menses is induced by the sudden drop in progesterone, which marks the end of the luteal phase. This decrease in progesterone induces constriction of the spiral arteries which results in ischemia and then necrosis of the endometrium. Dead tissue and blood then slough off into the lumen of the uterus. One shouldn't develop the notion that these phases of uterine activity are unique to animals with menstrual cycles. The uteri of other mammals undergo similar changes in association with changes in ovarian steroid secretion. However, the extensive endometrial sloughing and bleeding does not occur in these nonprimate species.

[FIGURE 10-13 OMITTED]

Our discussion of the menstrual cycle will rely heavily on what is known about the human. However, many of the details concerning regulation of the menstrual cycle have been elucidated based on research done with Old World monkeys, in particular the Rhesus monkey. Figure 10-13 shows patterns of the major reproductive hormones throughout the menstrual cycle of women. As you will soon learn, the mechanisms responsible for these patterns are similar to those described for the aforementioned species.

Progesterone

The pattern of progesterone during the menstrual cycle should be quite familiar by this point. Briefly, concentrations remain low during the follicular phase and are elevated during the luteal phase. Progesterone concentrations begin to increase within 3 days after ovulation, reach peak levels by the middle of the luteal phase, and then wane thereafter. Progesterone levels reach minimal concentrations 14 days following ovulation. The primary source of progesterone is the corpus luteum. As in other species, the LH surge is responsible for inducing ovulation, luteinizing the ruptured follicle, and maintaining function of the corpus luteum. The precise mechanism controlling regression of the corpus luteum remains elusive. However, it seems clear that the corpus luteum begins to lose its ability to respond to LH during the latter half of the luteal phase. Whether or not there is a luteolytic agent inducing luteal regression is unclear. It is clear that the uterus does not produce a luteolysin as in many nonprimate species. This topic will be addressed further in Chapter 13.

Estradiol

Fluctuations in estradiol concentrations during the menstrual cycle are similar to those of the various estrous cycles described earlier. Estradiol concentrations increase during the follicular phase due to increased production by a developing preovulatory follicle. Selection of a preovulatory follicle occurs during the follicular phase. During this time the fastest growing follicle suppresses development of other antral follicles and becomes the major source of estradiol.

Concentrations of estradiol also increase during the luteal phase, but this is not due to follicular development. Rather, the source of this secondary rise in estradiol is the corpus luteum. Follicles contribute little to circulating estradiol concentrations during the luteal phase because there is very little follicular growth beyond the early antral stage during this phase.

LH and FSH

Concentrations of LH are highest during the mid-cycle LH surge. During most of the follicular and luteal phases, LH levels are minimal. Intensive blood sampling reveals that concentrations of this hormone fluctuate in a pulsatile manner throughout the cycle. A high-frequency pattern of LH pulses is present throughout the follicular phase. At this time the frequency of LH pulses is approximately one per hour. This pattern is maintained during the LH surge, but the amplitudes of pulses increases greatly at this time. During the luteal phase LH pulse frequency decreases to one pulse every few hours.

Concentrations of FSH are also highest during mid-cycle. A preovulatory surge of FSH occurs coincidently with the LH surge. Like LH, concentrations of FSH are minimal during other times of the cycle. However, unlike LH, concentrations of FSH increase during menses but then decline and remain low during the follicular phase. FSH concentrations fluctuate in a pulsatile manner but these patterns have not been as thoroughly characterizes as the pulsatile patterns of LH.

Patterns of gonadotropins during the menstrual cycle are the consequence of the feedback actions of ovarian hormones on the hypothalamic-pituitary unit. Specifically,

* The low frequency of LH pulses during the luteal phase is due to the negative feedback actions of progesterone, whereas the high frequency of LH pulses characteristic of the follicular phase is due to the absence of this negative feedback.

* The preovulatory surges of LH and FSH are due to the positive feedback actions of estradiol on the hypothalamus and pituitary gland.

* The elevation in FSH during menses is due to the absence of large follicles; that is, a lack of estradiol and inhibin, or major negative feedback signals regulating FSH release.

HORMONAL REGULATION OF OVARIAN CYCLES

Although there are significant differences in hormone patterns associated with the ovarian cycles of various mammals, it is possible to draw some firm conclusions regarding how these hormones interact to regulate these cycles. Figure 10-14 summarizes the major sequence of events that occur during the follicular and luteal phases of the estrous cycles of spontaneous ovulators.

[FIGURE 10-14 OMITTED]

SUMMARY OF MAJOR CONCEPTS

* The ovarian cycle of mammals consists of a repeating sequence of events, which includes follicular development-ovulation-corpus luteum development-corpus luteum regression.

* The ovarian cycle is typically divided into two major phases: a follicular phase, when the dominant ovarian structure is a preovulatory follicle producing high levels of estradiol and inhibin, and a luteal phase, when the dominant ovarian structure is a corpus luteum producing high levels of progesterone.

* Ovarian hormones determine the pattern of gonadotropin secretion during the ovarian cycle and gonadotropins in turn regulate development and activity of ovarian structures.

* A lack of negative feedback allows a high-frequency mode of LH secretion during the follicular phase, whereas progesterone negative feedback sustains a low-frequency mode of LH secretion during the luteal phase. High levels of estradiol induce a pre-ovulatory surge of LH at the end of the follicular phase.

* Estradiol and inhibin are the major negative feedback regulators of FSH secretion. High levels of these hormones suppress FSH during the follicular phase, but the maximal levels of estradiol induce a preovulatory surge of FSH. In some species the decline in inhibin and estradiol coincident with ovulation cause a secondary surge in FSH.

* Specifically, FSH and LH interact to govern follicle growth, whereas LH induces ovulation and luteinization of follicles and sustains luteal activity.

* In many species the regression of the corpus luteum is caused by an increase in release of PGF by the uterus.

DISCUSSION

1. Some reproductive physiologists have used the pseudopregnant rabbit as a model to study the estrous cycle. Does this make sense? Explain your answer.

2. Suppose you discover a new species of mammal and you want to determine the length of its ovarian cycle. Unfortunately all you have to work with is a small herd of females and your observation skills. Describe how you might go about estimating the length of this species' ovarian cycle.

3. Thinking in terms of evolution theory, what might be an advantage of induced ovulation?

REFERENCES

Freeman, M.E. 1994. The neuroendocrine control of the ovarian cycle of the rat. In E. Knobil and J.D. Neill, The Physiology of Reproduction Vol. 2. Second Edition. New York: Raven Press, pp. 613-658.

Goodman, R.L. 1994. Neuroendocrine control of the ovine estrous cycle. In E. Knobil and J.D. Neill, The Physiology of Reproduction Vol. 2. Second Edition. New York: Raven Press, pp. 659-709.

Hotchkiss, J. and E. Knobil. 1994. The menstrual cycle and its neuroendocrine control. In E. Knobil and J.D. Neill, The Physiology of Reproduction Vol. 2. Second Edition. New York: Raven Press, pp. 711-749.

Johnston, S.D., M.V. Root Kustritz, and P.N.S. Olson. 2001. Canine and Feline Theriogenology. Philadelphia: Saunders.

Ramirez, V.D. and W. Lin Soufi. 1994. The neuroendocrine control of the rabbit ovarian cycle. In E. Knobil and J.D. Neill, The Physiology of Reproduction Vol. 2. Second Edition. New York: Raven Press, pp. 585-611.

Stevenson, J.S. 2007. Clinical reproductive physiology of the cow. In R.E. Youngquist and W. R. Threlfall, Current Therapy in Large Animal Theriogenology 2. St. Louis: Saunders, pp. 258-270.

Keith K. Schillo, PhD

Department of Animal and Food Sciences

University of Kentucky

Lexington, Kentucky
TABLE 10-1 Ovarian cycles of different mammalian species

          Classification   Classification   Length of Cycle
Species   (Estrus)         (Ovulation)      (Days)

Human     Menstrual        Spontaneous      24-32
          cycle
Cattle    Polyestrous      Spontaneous      20-21
Swine     Polyestrous      Spontaneous      19-21
Sheep     Seasonally       Spontaneous      16-17
          polyestrous
Horse     Seasonally       Spontaneous      20-22
          polyestrous
Rabbit    Polyestrous      Induced          1-2 (non-mated) 14-15
                                            (infertile male)
Rat       Polyestrous      Spontaneous      4-5 (non-mated) 13-14
                                            (infertile male)
Dog       Monoestrous -    Spontaneous      84-252
          polyestrous

          Follicular     Luteal Phase
Species   Phase (Days)   (Days)

Human     10-14          12-15
Cattle    2-3            18-19
Swine     5-6            15-17
Sheep     1-2            14-15
Horse     5-6            15-16
Rabbit    1-2            0 (non-mated) 13
                        (infertile male)
Rat       2              2-3 (non-mated)
                         11-12 (infertile
                         male)
Dog       18             63
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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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