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Chapter 16: Physiology of pregnancy, parturition, and puerperium.

CHAPTER OBJECTIVES:

* Describe the major changes in the physiology of the mother during pregnancy.

* Describe the major physiologic roles of the placenta, including transport and hormone production.

* Describe the mechanism of parturition.

* Describe how the maternal system recovers from pregnancy to resume reproductive activity.

OVERVIEW OF MAJOR CONCEPTS

In this chapter we will be concerned with the physiologic events that occur after the placenta is formed and the fetus establishes a physiologic relationship with the mother. The discussion is divided into three main areas: 1) mechanisms that maintain pregnancy, 2) mechanisms that terminate pregnancy, and 3) mechanisms that regulate the recovery of the mother from pregnancy. As the placenta forms and pregnancy is established, the maternal system undergoes numerous changes that allow the mother to cope with the nutritional demands of the fetus. Meanwhile the needs of the fetus change as it develops. The topic of fetal physiology is vast and will not be considered in this chapter. Likewise, pregnancy requires a re-setting of homeostatic mechanisms in the mother and as a consequence the maternal system undergoes numerous physiologic changes. An entire textbook is required to develop a comprehensive understanding of these phenomena. In light of these considerations, our discussion must be restricted to the most significant and best understood adjustments.

CHANGES IN MATERNAL PHYSIOLOGY DURING PREGNANCY

The success of viviparity (live birth) in mammals requires the creation and maintenance of a uterine environment that accommodates and supports fetal growth and development, a means by which the mother provides adequate amounts of the substances upon which the growth and development of the fetus depend, and a means to terminate pregnancy at a time when offspring can survive outside the womb. Each of these requirements is achieved by the actions of hormones produced by the mother's ovaries, the placenta, and the fetus (Figure 16-1). The ovarian hormones act to prepare the reproductive tract for pregnancy, whereas placental and fetal hormones act to complete the reproductive process. Once birth has occurred, the maternal system must recover from the physiologic changes associated with pregnancy. In many cases this results in a period of infertility following parturition.

[FIGURE 16-1 OMITTED]

Changes in the Maternal Uterine Environment

The most noticeable changes that occur during pregnancy are those of the female reproductive tract. Of these the changes, those associated with the uterine endometrium are most important with respect to maintaining a uterine environment that is compatible with pregnancy. The elevated levels of estradiol that characterize the follicular phase of the ovarian cycle promote proliferation of the uterine mucosa, particularly development of endometrial glands. The subsequent rise in progesterone during the luteal phase promotes secretory activity of these glands. The secretory products of the endometrial glands are known collectively as histotroph and consist of enzymes, growth factors, cytokines, lymphokines, hormones, transport proteins, and other substances. During the preimplantation period these products nourish the conceptus and promote its survival, development, production of pregnancy recognition factors, implantation, and placentation. This progestinized state of the endometrium is essential for embryo survival during both the preimplantation and postimplantation period. If progesterone is removed at any time during pregnancy, the conceptus will be aborted.

Changes in Water and Electrolyte Balance

The development of the placenta is one of the most remarkable changes associated with pregnancy. This vital organ must be supplied with adequate blood to function properly. This must occur without jeopardizing maternal tissues. One of the most important pregnancy-induced changes is an expansion of the maternal vasculature (blood volume) and blood contents (e.g., red blood cells), which accommodates fetal demands for water and oxygen. Expansion of blood volume involves increased retention of sodium, potassium, and calcium by the kidneys. As these ions are reabsorbed by the nephron, water follows to maintain blood osmolality. The bulk of the increased blood volume is retained in large veins. Sometimes blood pools in these areas and can lead to edema.

Changes in Hemodynamics

Profound changes occur in the dynamics of blood flow during pregnancy. These include not only a change in systemic blood flow, but also a change in the distribution of blood flow. In general, blood is shunted toward the utero-placental unit and mammary gland. One of the major consequences of increased flow to the uterus is facilitating loss of heat generated by fetal metabolism. This is an important aspect of the thermoregulatory abilities of both the mother and fetus. The increased blood flow to the mammary gland is related to the enhanced development of lactogenic tissue in preparation for lactation following parturition.

Cardiac output increases during pregnancy. This is due to an increase in heart rate as well as an increase in stroke volume. In spite of these changes, blood pressure doesn't deviate from the pre-pregnancy state. This is due to an overall decrease in vascular resistance. Major decreases in resistance occur in the vascular beds of the uterus and mammary glands. Blood flow to the skin also increases during pregnancy. This likely helps the mother dissipate heat generated by the fetus.

Changes in Respiration

In most mammals, pregnant females exhibit hyperventilation during pregnancy. This lowers the amount of carbon dioxide in the blood, which causes a slight alkalosis. The slight rise in blood pH does not have an appreciable effect on affinity of hemoglobin for oxygen. As the fetus grows, the expanding uterus will exert pressure on the diaphragm changing the configuration of the mother's thoracic cavity. This lowers the residual capacity of the lungs. The increased respiration rate along with a decrease in resistance of the airway compensate for the lower lung capacity.

Changes in Blood

Pregnancy has been referred to as a state of hypercoagulability. The ability of blood to coagulate is markedly increased during pregnancy. The adaptive significance of this change may be to protect the mother from blood loss.

Changes in Metabolism

As noted repeatedly in this book, successful reproduction depends on metabolic energy. Pregnancy increases the maternal requirements for energy and other nutrients. In order to complete pregnancy successfully, the mother must make metabolic adjustments directed toward several processes including 1) providing oxygen and nutrients for fetal growth and development, 2) providing the fetus with sufficient energy reserves to survive periods of maternal feed restriction, and 3) providing the mother with sufficient energy reserves to survive periods of feed restriction during pregnancy and subsequent lactation. The specific energy requirements of pregnancy can be divided into four main categories:

* Metabolic costs associated with growth and development of products formed during gestation (i.e., fetus, placenta, extraembryonic membranes, amniotic fluid, and maternal tissue).

* Metabolic costs of the biosynthetic processes that form these tissues.

* Metabolic costs of maintaining these tissues.

* Metabolic costs of external work associated with moving a heavier body mass.

In order to appreciate how the maternal system adjusts to the increased metabolic demands associated with pregnancy it is necessary to consider the concept of energy balance. The following equation is a common way to expresses such a relationship: [E.sub.Gross Intake] = [E.sub.Metabolism] + [E.sub.Accretion/Storage] + [E.sub.External Work] + [E.sub.Excreted]. Keeping this model in mind, it now becomes clear that there are several strategies available to increase the amount of metabolic energy available to meet the demands of pregnancy: 1) increase energy intake, 2) repartition energy substrates to various tissues, 3) increase absorption and storage of energy, 4) reduce work (physical activity), and 5) reduce loss due to excretion. Females rely on the first three approaches to accommodate the metabolic demands of pregnancy. It is common for food intake to increase in pregnant females. In addition, the rate of passage of food through the digestive tract slows during pregnancy resulting in enhanced absorption of nutrients. Finally, there are profound metabolic changes associated with pregnancy. Initially, intermediary energy metabolism promotes accretion of body fat. Later in pregnancy, metabolism shifts to promote transfer of energy substrates to the fetus. These changes in intermediary energy metabolism are orchestrated by several metabolic hormones that act on a variety of tissues including the liver, adipose tissue, and muscle. These hormones are produced by the placenta and the mother. In addition, steroid hormones produced by the ovaries and placenta influence release and actions of metabolic hormones. The extent to which females reduce energy loss due to excretion is unknown.

PLACENTAL PHYSIOLOGY

The idea that the placenta is involved with fetal nutrition can be traced to Aristotle. However, details regarding the morphology of this organ didn't emerge until the seventeenth century. Today the placenta is viewed as an organ that mediates the transfer of various chemicals between the maternal and fetal circulations as well as an important endocrine gland that influences maternal and fetal physiology.

PLACENTAL TRANSPORT

In eutherian mammals, the placenta consists of the chorioallantoic membrane of the fetus and the endometrial tissue of the uterus. Terminology referring to the fetal component can be confusing because the chorion is also referred to as either the trophectoderm or the trophoblast. The latter term was first used by Hubrecht in the late nineteenth century and will be used throughout this chapter. The functional unit of placental transfer is the barrier between the fetal and maternal blood and consists of the endothelial cell of the fetus, the microvillus of the trophoblast, and the maternal tissue of the uterus (Figure 16-2). The structure of this barrier varies considerably among mammals and affects the efficiency of transport between fetal and maternal circulations.

[FIGURE 16-2 OMITTED]

One source of variation in the maternal-fetal barrier is the structure of the trophoblast. The cells of this layer can function individually (cellular trophoblast) or as a syncytium (syncytial trophoblast) and can be arranged in either a single or multiple layers of cells. The barrier also varies with respect to the type of maternal cells that are apposed to the trophoblast. As noted in the previous chapter, the trophoblast makes contact with the uterine epithelium in ungulates, the endothelial cells of uterine capillaries in carnivores, and with blood in primates and rodents. The arrangement of fetal capillaries is a third source of variation. In primates and farm animals, they take on a villous (tree-like) arrangement, whereas in rabbits and rodents they form more complex labyrinths. Finally, the pattern of blood flow relative to the maternal circulation differs among species. Fetal blood can flow in a concurrent, crosscurrent, or countercurrent manner with respect to maternal blood flow (Figure 16-3). The arrangement of blood vessels affects the efficiency of transfer of solutes, gases, and heat between maternal and fetal systems. The countercurrent arrangement provides the most efficient transfer, whereas the concurrent provides the least efficient transfer.

[FIGURE 16-3 OMITTED]

The primate placenta has been the subject of numerous studies and therefore serves as a useful model for describing important principles of placental transport (Figure 16-4). The extent to which a substance (S) is transported into or out of the fetus can be expressed by the net transplacental flux ([J.sub.net]) of that substance. This term can be expressed mathematically by the following formula: [J.sub.net] = [J.sub.mf] - [J.sub.fm], where [J.sub.mf] is the maternal to fetal flux and [J.sub.fm] is the fetal to maternal flux. A positive number indicates that there is a net flux of the substance from the mother to the fetus, whereas a negative number indicates a net flux from the fetus to the mother. [J.sub.net] is a function of the effective concentration of a substance in the maternal blood, which is influenced by the following variables:

* Rate of maternal blood flow.

* Rate of dissociation from red blood cells or serum proteins (analogous to affinity between a hormone and receptor).

* Potential difference across the trophoblast.

* Thickness of unstirred area of maternal blood (not flowing) near the microvillus border.

[FIGURE 16-4 OMITTED]

The cellular mechanisms that mediate the transfer of materials from the maternal blood or extracellular space across the trophoblast include (Figure 16-5):

* Simple diffusion of lipophilic molecules across trophoblast (e.g., oxygen).

* Restricted diffusion of hydrophilic molecules through aqueous channels (e.g., mannitol).

* Facilitated diffusion (e.g., D-glucose).

* Active transport (e.g., amino acids).

* Receptor-mediated endocytosis (e.g., immunoglobulins).

[FIGURE 16-5 OMITTED]

It is beyond the scope of this chapter to include detailed descriptions of which molecules are transported across the placental barrier. A detailed account of concentrations of various nutrients and wastes can be found in the references included at the end of this chapter. Some of the more important substances transported between the mother to the fetus include glucose, lactate, amino acids, lipids, ions, calcium, phosphorous, magnesium, trace minerals, proteins, respiratory gases, and various drugs.

The Placenta as an Endocrine Organ

In addition to mediating transfer of nutrients and wastes to and from the fetus, the placenta produces numerous hormones. Placental steroidogenesis is limited to progesterone and estrogens. The major polypeptide hormones produced by the placenta include placental lactogen, a variant of growth hormone, prolactin, relaxin, and chorionic gonadotropin.

Placental Steroidogenesis

Progesterone is the major steroid hormone produced by the placenta. With the exception of primates, the placenta does not produce estradiol until the final stages of pregnancy and is related to the accompanying drop in progesterone production. The significance of this will become clear when we consider the regulation of parturition. Primates are unique in the sense that the placenta produces appreciable amounts of estradiol throughout pregnancy. Circulating concentrations of estradiol in women follow the general pattern of progesterone. Both hormones increase throughout pregnancy and then drop at the time of birth.

One of the more important concepts associated with the maintenance of pregnancy is the extent to which the placenta contributes to the circulating pool of progesterone. Recall that progesterone is essential to maintain pregnancy. However, the source of progesterone isn't important. In some species the placenta becomes the major source of progesterone during pregnancy. In others, the corpus luteum is the sole producer of progesterone throughout pregnancy. The timing of the so-called luteal-placental shift in progesterone production varies among mammalian species (Table 16-1).

Placental Polypeptide Hormones

We have previously considered the importance of chorionic gonadotropin, a secretory product of the trophoblast that is important in maternal recognition of pregnancy in primates and horses. Although release of this hormone diminishes to baseline levels by 30 days of pregnancy, its production is sustained throughout pregnancy. The corpus luteum eventually becomes refractory to chorionic gonadotropin and the placenta becomes the major source of progesterone. Whether this hormone plays an important role in regulating other processes is unclear. Some researchers have suggested that chorionic gonadotropin might support growth of the placenta, regulate steroid hormone synthesis in the fetal testes and adrenal cortex, and regulate secretion of thyroid hormones in the mother.

The placenta also produces placental lactogen (or somatomammotropin), a polypeptide that expresses prolactin-like and growth hormone-like activities. The growth-promoting activity of this hormone is believed to be important in regulating growth of the fetus, whereas the lactogenic activity seems to be important in stimulating mammary gland activity in the mother.

In the human, some of the lactogenic and growth-enhancing activity of the placenta is also attributed to prolactin and an isoform of growth hormone, each of which are produced by the anterior pituitary gland.

In some species, the placenta produces relaxin, a hormone that plays an important role in parturition. This hormone is produced by the placentas of horses, primates, carnivores, swine, and rabbits, but not by ruminant placentas. In the latter case, the corpus luteum is the major source of this hormone.

PARTURITION

One of the more intriguing questions in reproductive physiology is what determines the length of gestation. The prevailing hypothesis is that some type of biological clock governs the timing of parturition. The precise nature of such a mechanism has not been elucidated for most mammals, but three general types seem possible. First, there may be a mechanism that tracks the number of cell divisions that occur from the time of fertilization. Second, the time elapsed since syngamy may be an important regulatory signal. This would involve some sort of endogenous rhythm in some biological variable within the mother, placenta, or fetus. Finally, the timing of parturition might be programmed within the genome of the fetus. In other words, at a particular stage of development fetus generates a signal that induces parturition. The third possibility clearly applies to the sheep. In this species, parturition appears to be dependent on the sequential development of the hypothalamic-pituitary-adrenal system. Work in other species such as humans suggests that alternative mechanisms exist. In spite of this variation there are important similarities among those mammals studied. In all cases, parturition involves changes in the contractility of the uterine myometrium. High levels of progesterone suppress motility of the myometrium resulting in weak and poorly coordinated contractions (known as Braxton-Hicks contractions in the human). In late pregnancy, progesterone concentrations decrease allowing the uterus to prepare for stimuli that can induce the type of strong and rhythmic contractions necessary to expel the fetus from the uterus and birth canal. These stimuli can be generated by the fetus, placenta, or mother. In almost all cases studies, [PGF.sub.2[alpha]] appears to be the most important signal initiating the intense uterine contractility that is necessary for parturition.

Control of Parturition in the Ewe

One of the most important concepts regarding timing of parturition in sheep is that the signal that induces birth originates within the fetus (Figure 16-6). This idea arises from the fact that disruption or removal of the anterior pituitary or adrenal gland delays or prevents parturition. Unless these altered fetuses are aborted, they will continue to enlarge and distend the uterus to the point where it interferes with the mother's ability to eat.

The signal that triggers parturition in the sheep is cortisol. At a particular point in development (the last few days of pregnancy), the fetal hypothalamic-pituitary-adrenal axis awakens resulting in an increase in production of cortisol by the fetal adrenal gland. This increase in cortisol release is due to several changes. First there is an increase in release of corticotrophin-releasing hormone (CRH) from the hypothalamus. This together with an increased responsiveness of the anterior pituitary gland to CRH causes release of adrenocorticotrophin (ACTH), which in turn acts on the adrenal cortex to stimulate synthesis and release of cortisol, a steroid hormone. With respect to parturition, the major target tissue of cortisol is the placenta. Recall that in sheep the bulk of progesterone is produced by the placenta after day 50 of pregnancy. Fetal cortisol acts on this tissue to increase the expression of enzymes that are necessary to convert progesterone into estradiol. Thus cortisol causes an increase in the ratio of estradiol to progesterone. This change in steroid milieu activates the enzyme-governing synthesis of prostaglandins. In addition, the drop in progesterone removes the block on myometrial contractility. Moreover, the increase in estradiol increases numbers of myometrial receptors for oxytocin and prostaglandins. Prostaglandin sets the stage for a positive feedback loop that leads to intense, rhythmic contractions that eventually lead to expulsion of the fetus (Figure 16-7). Oxytocin and prostaglandins exert positive effects on uterine motility. The increase in prostaglandin release initiates powerful contractions of the uterus and pushes the fetus against the cervix. Sensory neurons detect this movement and send impulses to the hypothalamus to stimulate release of oxytocin from the posterior pituitary gland. Oxytocin is released in a pulsatile manner, which results in rhythmic uterine contractions. This sets into motion a positive feedback relationship between cervical stimulation and release of oxytocin (called the Ferguson reflex in humans). The feedback loop is broken once the fetus is pushed out of the birth canal.

[FIGURE 16-6 OMITTED]

[FIGURE 16-7 OMITTED]

In addition to pushing the fetus through the birth canal, cortisol triggers two other events that are necessary for successful birth. First, the increase in estradiol release from the placenta acts directly on the female reproductive tract to enhance secretions, which serve to lubricate the birth canal. Second, prostaglandin causes luteolysis and release of relaxin from the corpus luteum. Relaxin causes the ligaments that support the pelvis to relax thereby enlarging the pelvic opening.

Control of Parturition in Other Mammals

Cortisol appears to play an important role in timing parturition in swine, goats, and cattle. The mechanism in the cow appears to be similar, if not identical, to that in the ewe. However, the regulation of parturition in the doe and sow are slightly different from that in the ewe. The major difference between the sheep and these other ungulates is the source of progesterone during pregnancy. In the sow and doe, the corpus luteum, rather than the placenta, is the primary source of progesterone during pregnancy. In these cases, cortisol induces synthesis of prostaglandin by the placenta, and this raises the estradiol: progesterone ratio by inducing regression of the corpus luteum. The importance of cortisol in control of parturition in horses is equivocal, but an increase in prostaglandin plays a pivotal role in the cascade of events leading to increased myometrial activity.

The role of the fetal adrenal gland in humans appears to be much less important than in sheep, swine, goats, and cattle. Unlike these animals, the signal that triggers the cascade leading to parturition is generated by the placenta, not the fetus (Figure 16-8), suggesting that this event may be regulated by a placental clock. The human placenta produces appreciable amounts of CRH late in pregnancy. This hormone then establishes two positive feedback loops; that is, one with the fetal pituitary-adrenal system and the other involving the fetal membranes. With respect to the first loop, CRH acts on the fetal pituitary gland to enhance ACTH release, which then acts on the fetal adrenal to elevate production of cortisol. Cortisol then feeds back positively on the placenta to further enhance CRH release. The resulting rise in cortisol alters placental steroidogenesis to favor production of estradiol, which then acts on the myometrium to enhance its motility. A second positive feedback loop involves CRH and prostaglandins. CRH produced by the placenta induces synthesis of prostaglandins by the amnion and these hormones feedback on amniotic tissue to induce production of CRH. This positive feedback loop causes a rapid increase in prostaglandins, which then act on the myometrium to induce contractions. Once contractions begin, the Ferguson reflex ensues and parturition soon follows.

Stages of Parturition

The cascade of endocrine events leading to parturition corresponds to visible changes in the mother during labor. For convenience these changes can be grouped into three distinct phases. The first stage marks the beginning of labor and is brought on by an increasing estradiol:progesterone ratio. The two major events that characterize this stage are 1) a progressive relaxation and dilation of the cervix and 2) increased motility of the myometrium resulting in distinct and noticeable contractions of the uterus. These contractions increase the pressure on the cervix, which establishes the positive feedback loop between cervical stimulation and oxytocin release. The end of this phase is marked by movement of the fetus into the birth canal. The duration of this stage of parturition averages 1 to 12 hours in most mammals.

[FIGURE 16-8 OMITTED]

The second stage of parturition is characterized by strong and rhythmic contractions of the uterus, which culminate in the delivery of the infant (Figure 16-9). It is difficult to interrupt this stage because of the positive feedback loop, which generates the contractions. These contractions, together with application of intense abdominal pressure by the mother, lead to expulsion of the fetus. This stage progresses quickly as long as the fetus is situated properly in the birth canal. In most cases, this amounts to a head-first presentation with the front legs fully extended. Once the fetus is in the birth canal, the allantochorion ruptures and releases fluid ("breaking water"). At this point the amniotic membrane appears as a fluid-filled sac protruding from the vulva. This soon ruptures and the mother begins regular bouts of abdominal straining until the infant is expelled. This stage can last as little as 5 minutes or as long as 12 hours.

[FIGURE 16-9 OMITTED]

The third and final stage of labor involves detachment and expulsion of the placenta. These processes are largely the result of continued myometrial contractions that may continue for several days after birth. The duration of this stage varies greatly. In some cases (cats) the placenta is expelled with the neonate. In other cases, it may take several hours for the placenta to be expelled.
BOX 16-1 Focus on Fertility: Preventing Birth

Although research in reproductive biology has provided
the basis for numerous technologies that enhance
reproduction, results of such work have also
been applied to developing methods for preventing
birth. Birth control methods have been sought
and valued by all human societies. People have
always expressed the desire to control if and when
they have children. It is also important to prevent
birth in livestock. For example, it is sometimes
necessary to terminate a pregnancy in heifers or
cows in the case of an accidental breeding or
during certain pathologic conditions. Birth control
has also been considered as a means to manage
reproduction in pets as well as feral animals that
have become pests. Figure 16-10 lists the major
categories of birth control methods currently used
in humans. Similar methods have been developed
and adopted for use in other species of mammals.

[FIGURE 16-10 OMITTED]

The earliest methods of birth control most
likely involved management of sexual behaviors.
Most of these are still practiced in many cultures.
Behavioral methods of birth control include 1) abstinence;
2) outercourse (masturbation and alternatives
to penile-vaginal intercourse), 3) coitus
interruptus (withdrawal of the penis from the
vagina prior to ejaculation), 4) fertility awareness
(avoiding sexual intercourse during the fertile
period of the ovarian cycle), and 5) extended
breast-feeding (prolongs lactational amenorrhea).
With the exception of abstinence and outercourse,
none of these methods have proven to be highly
reliable as a means to prevent birth.

The second major category of birth control
includes the barrier methods. The most common
devices include 1) male condoms (a polyurethane
sheath that fits over the penis), 2) female condoms
(a polyurethane sheath that fits into the vagina),
3) vaginal sponge (disk-shaped polyurethane
device that contains spermicide), 4) spermicide
alone (foam, cream, film, or suppositories with
spermicidal properties), and 5) diaphragms and
cervical caps (dome-shaped rubber disks the cover
the anterior vagina creating a barrier to prevent
sperm from entering the cervix). The effectiveness
of these barrier methods is highly variable, ranging
between 10 and 50 percent (i.e., percentage of
pregnancies occurring when used).

Hormonal methods have been shown to be the
most effective method of birth control other than
complete abstinence (less than one birth per
100 women per year). All of the hormonal methods
currently available are administered to women.
Although the method of delivery varies among
methods, the modes of action are essentially the
same; that is, induction of a progestational state
(pseudopregnancy). Hormonal methods differ in
terms of delivery method and whether or not they
consist of progestin alone or progestin plus estrogen.
The "combined" birth control pill, the first
oral contraceptive, consists of both types of steroids
and acts by preventing ovulation. The socalled
minipill is also an oral contraceptive, but
contains only progestin. Its primary mode of action
is to thicken the cervical mucus, thereby preventing
sperm from reaching the oocyte. Contraceptive
hormones can also be provided by means other
than pills. Alternative methods include: 1) skin
patch, 2) vaginal ring (flexible ring inserted into
the vagina and releases progestins and estrogens),
3) injection (progestin alone or progestin plus
estrogen), and 4) subcutaneous implant (six
matchstick-sized rubber rods filled with progestin).

A fourth approach to human birth control is
the intrauterine device. This is a T-shaped object
that contains copper. It is inserted into the uterus
where it prevents fertilization, but the mode of
action is poorly understood.

The fifth method of birth control is surgical
sterilization. This approach includes tubal ligation
in women (occlusion of the fallopian tubes) and
vasectomy in men (transaction of the ductus deferens).
Both of these procedures disrupt transport
of gametes, thereby preventing the interaction
between sperm and oocyte.

Each of the aforementioned birth control methods
is classified as contraceptive; i.e., preventing
conception. These approaches are fundamentally
different from the sixth method of birth control:
induced abortion. Induced abortion can be defined
as the intentional termination of pregnancy. There
are two major types of abortion: surgical and chemical.
Surgical abortion involves the use of special
instruments to remove the fetus and membranes
from the uterus. A chemical abortion is induced by
administering drugs (abortifacients) that terminate
pregnancy. In humans this procedure is known as
medical abortion. There are two major approaches
to medical abortions: methotrexate and mifepristone
(RU-486) in combination with a prostaglandin
analogue. Methotrexate inhibits the metabolism of
folic acid, which interferes with implantation of the
embryo into the uterus. Mifepristone acts as a
progestin receptor antagonist. In other words, it
prevents progesterone from binding to its receptor.
The resulting lack of progesterone support causes
menstruation and softening of the cervix, conditions
that are disruptive to pregnancy. Prostaglandin
analogues are given within a few days after
RU-486 to induce uterine contractions and promote
emptying of the womb.


POSTPARTUM PERIOD

As noted earlier, parturition can be understood as a sudden disruption of the maternal-fetal exchange system. Viewed in this way, it is not difficult to imagine that the maternal system may not be equipped to establish a new pregnancy soon after the birthing process. Indeed, in most mammals, females enter a period of infertility during the postpartum period. The period following parturition has been referred to as the puerperium (from the Latin puerpera, which means woman in childbirth). This term refers specifically to the period during which the uterus involutes, or returns to its normal size. Involution involves expulsion of the fluid remains of the placenta (lochia), repair of the endometrium, and reduction in size of the uterus accompanied by an increase in its tone. Although it is true that the uterus is resistant to implantation before the completion of uterine involution, other mechanisms contribute to the infertility that is characteristic of the postpartum period. In general, the time required for females to resume fertile ovarian cycles is not highly correlated with the time required for the uterus to recover from pregnancy. For example, uterine involution is completed by 30 days in beef cows, but these animals typically resume ovarian cycles 50 to 60 days after parturition. In dairy cows, the uterus is completely involuted by 45 to 50 days, whereas ovarian activity resumes much earlier (10 to 25 days postpartum).

Lactation appears to be the major factor responsible for the postpartum hiatus in reproductive activity in cows, ewes, sows, and most primates, but not in the bitch, queen, or mare. Part of this effect is due to a negative energy balance that results from the heavy metabolic demands associated with milk production. However, the suckling stimulus itself also appears to suppress reproductive activity of the mother. In all species studied so far, the suckling-induced inhibition of reproductive activity involves suppression of pulsatile luteinizing hormone (LH) release, which prevents development of ovarian follicles to the preovulatory stage. Eventually, the maternal system overcomes these inhibitory effects and the female resumes ovarian cyclicity. The first postpartum ovarian cycle is typically characterized by a lack of estrus and a short luteal phase. The second cycle is usually normal, but may be less fertile than subsequent ones.

The Rat

Rats are prolific creatures. Females have the ability to give birth to one litter of pups immediately after weaning a previous litter. This reproductive strategy reflects the fact that the female rat expresses estrus and ovulates within 24 hours of birth. Gestation length in rats averages 21 days and pups are usually weaned by 30 days of age. This means that females could give birth to one litter while they are taking care of another. How does the female avoid nurturing two litters of pups? The answer lies in a phenomenon known as delayed implantation (Figure 16-11). If conception occurs while the female is nursing, the blastocyst will form, but then enter a quiescent state and not implant until 5 to 7 days later than normal. This strategy is used by other species to synchronize birth with environmental conditions that favor rearing of offspring. The delay in implantation extends the length of pregnancy to 30 days, a time by which weaning of the previous litter occurs.

If the female rat conceives during lactation, the corpora lutea of pregnancy do not fully regress. Therefore, the ovaries contain two sets of corpora luteus: those remaining from the previous pregnancy and the newly formed ones. This is due to the high circulating levels of prolactin which are caused by the suckling stimulus. During the early portion of lactation, large antral follicles regress, and the ovaries contain only those of small and medium sizes. This is due to the low-frequency pattern of pulsatile LH secretion that characterizes this period. The suppression of LH pulse frequency is due to a direct effect of suckling on gonadotropin-releasing hormone (GnRH) release as well as the aforementioned hyperprolactinemia. It is also noteworthy that suckling attenuates the positive feedback actions of estradiol on LH release during this period. Toward the end of lactation, pulsatile LH resumes and the estradiol-LH positive feedback system is restored. This leads to the resumption of follicle growth, estrus, and ovulation.

[FIGURE 16-11 OMITTED]

Domestic Ungulates

The sow, ewe, and cow express distinct periods of anestrus and infertility following parturition. The duration of these periods is an important determinant of lifetime reproductive rate. In domestic livestock this can be translated to mean lifetime production efficiency. The length of time a female is not reproductively active affects how much meat and/or milk she can produce each year. The economic importance of this trait has provided incentive for numerous studies regarding the control of the postpartum anestrus in domestic animals. In all cases, lactation suppresses pulsatile release of LH, which prevents development of follicles to the preovulatory stage and therefore estrus and ovulation. The average length of the postpartum anestrus is 3 to 6 weeks for sows and ewes and between 30 and 150 days in cows. In all cases, frequency of LH pulses increases gradually throughout the postpartum period (Figure 16-12). During this time, the ovaries will exhibit waves of follicle growth, but formation of an ovulatory follicle does not occur until LH pulse frequency reaches some threshold level. As in the rat, the ability of estradiol to induce an LH surge is compromised until late in the postpartum period. One of the major differences in mechanisms regulating postpartum anestrus is the nature of the stimulus that suppresses LH secretion. In sows and ewes, it is clear that suckling exerts a direct effect on hypothalamic release of GnRH. In cows, the presence of calves rather than suckling per se may be the mediating signal. In none of these cases is hyperprolactinemia a factor in suppressing LH secretion. Although circulating levels of prolactin are elevated in each case during lactation, there is no evidence to support the idea that prolactin inhibits LH secretion in these species. Finally, it should be noted that other environmental variables interact with suckling to affect length of the postpartum interval in livestock. A negative energy balance due to poor nutrition and/or parasite infestation prolongs the postpartum anestrus. Photoperiod is another confounding variable. For example, ewes normally lamb in the spring, which is the time of onset for seasonal anestrus. Thus it is difficult, if not impossible, to distinguish between a seasonal and postpartum anestrus in this case. Studies of postpartum anestrus in sheep have been done with ewes mated during the late breeding season such that they lamb during the earlyto mid-breeding season, long before onset of seasonal anestrus. Although domestic cattle are not facultative seasonal breeders, photoperiod has been shown to influence the length of the postpartum anestrous period. In general, long day lengths shorten the interval between calving and first estrus.

[FIGURE 16-12 OMITTED]

Primates

The apes (including humans), Old World Monkeys, and most New World monkeys exhibit a lactation-induced infertility following parturition. In all cases, the early portion of the postpartum period is characterized by a low frequency of LH pulses and an absence of ovulatory follicles. Eventually, the frequency of LH pulses increases, resulting in follicle maturation, ovulation, and resumption of menses. The time required for resumption of cycles is directly proportional to the intensity of suckling by the infant. Although suckling causes hyperprolactinemia, there is no support for the idea that high prolactin levels are responsible for the low pulsatile secretion of LH. However, the elevated concentrations of prolactin provide support for the corpus luteum of pregnancy, which delays luteolysis, causing the structure to remain and produces some progesterone during lactation.

SUMMARY OF MAJOR CONCEPTS

* Hormones associated with pregnancy alter maternal physiology in ways that prepare the mother for pregnancy and lactation and allow her to successfully complete the pregnancy.

* The major functions of the placenta are to provide a means for transferring nutrients, gases, and wastes between the fetal and maternal systems.

* Parturition is induced by a prostaglandin-induced increase in motility of the myometrium. The signal that triggers this response varies among species and can originate in either the fetus or placenta.

* The reproductive strategies of mammals include a postpartum period of infertility that is regulated to a large extent by suckling and involves suppression of pulsatile release of LH.

DISCUSSION

1. Pregnant women frequently suffer from edema (fluid accumulation), especially in the lower extremities. Explain how this occurs.

2. If you had the choice between using either oxytocin or cortisol to induce parturition in a ewe, which would you prefer? Explain your answer.

3. RU-486 is a progesterone receptor antagonist. In other words, it binds to the progesterone receptor but does not elicit a biological response. This drug is also known as "the abortion pill." Explain how such drug induces abortion. Would you expect the drug to be more effective at a particular time in pregnancy? Why or why not?

4. The postpartum anestrus is shorter in the milked dairy cow than the suckled beef cow. Propose a hypothesis to explain this difference. How might you go about testing this hypothesis?

REFERENCES

Jenkin, G. and I.R. Young. Mechanisms responsible for parturition; the use of experimental models. Animal Reproduction Science 82-83:567-581.

McLean, M. and R. Smith. 2001. Corticotrophin-releasing hormone and human parturition. Reproduction 121:493-501.

McNeilly, A.S. 1994. Suckling and the control of gonadotropin secretion. In: E. Knobil and J.D. Neill, The Physiology of Reproduction Vol. 2., second Edition. New York: Raven Press, pp. 1179-1212.

Morriss, Jr., F.H., R.D.H. Boyd, and D. Mahendran. 1994. Placental transport. In: E. Knobil and J.D. Neill, The Physiology of Reproduction Vol. 2., second Edition. New York: Raven Press, pp. 813-861.

Norman, S. and R.S. Youngquist. 2007. Parturition and dystocia. In: R.S. Youngquist and W.R. Threfall, Current Therapy in Large Animal Theriogenology, second Edition. St. Louis: Saunders Elsevier, pp. 310-335.

Ogren, L. and F. Talamantes. 1994. The Placenta as an endocrine organ: polypeptides. In: E. Knobil and J.D. Neill, The Physiology of Reproduction Vol. 2., Second Edition. New York: Raven Press, pp. 875-945.

Planned Parenthood. 2006. Report: A History of Birth Control Methods. Katharine Dexter McCormick Library, New York.

Rivera, R., I. Yacobson, D. Grimes. 1999. The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices. American Journal of Obstetrics and Gynecology 181:1263-1269.

Solomon, S. 1994. The primate placenta as an endocrine organ: steroids. In: E. Knobil and J.D. Neill, The Physiology of Reproduction Vol. 2., Second Edition. New York: Raven Press, pp. 863-873.

Spencer, T.E. and F.W. Bazer. 2004. Conceptus signals for establishment and maintenance of pregnancy. Reproductive Biology and Endocrinology 2:49-63.

Stewart, C.L. and E.B. Cullinan. 1997. Review--Preimplantation development of the mammalian embryo and its regulation by growth factors. Developmental Genetics 21:91-101.

Stock, M.K. and J. Metcalfe. 1994. Maternal physiology during gestation. In: E. Knobil and J.D. Neill, The Physiology of Reproduction Vol. 2., Second Edition. New York: Raven Press, pp. 947-983.

Wiebe, E., S. Dunn, E. Guilbert, F. Jacot, and L. Lugtig. 2002. Comparison of abortions induced by methotrexate or mifepriston followed by misoprostol. Obstetrics and Gynecology 99:813-819.

Keith K. Schillo, PhD

Department of Animal and Food Sciences

University of Kentucky

Lexington, Kentucky
TABLE 16-1 Length of gestation and timing of the luteal-placental
shift in progesterone production in several species of mammals

          Length of            Luteal-Placental Shift in Progesterone
Species   Gestation (months)   (day or month of gestation)

Canids    2                    None
Felids    2                    None
Sheep     5                    50 days
Horses    11                   70
Cattle    9                    6-8 months
Swine     3.8                  None
Human     9                    60-70 days
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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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