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467


Summary

  1. The placenta forms an interface between the maternal and fetal cir­
    culations. At implantation, the trophoblastic tissue of the fertilized
    egg invades the endometrial tissue of the uterus by means of
    chorionic villi containing the fetal capillaries. As a result of this
    invasive behavior, the spiral arteries of the uterus are eroded and spill
    their blood into the spaces between adjacent chorionic villi. In this
    way a dialysis pattern of blood flow is set up within the placenta such
    that fetal capillaries essentially dip into maternal blood spaces.

  2. During fetal life, the placenta carries out the functions normally per­
    formed in the adult by the lungs, kidneys, and gastrointestinal tract.

  3. Many substances, including oxygen, carbon dioxide, and essential
    nutrients, cross the placenta by means of either passive diffusion or
    carrier-mediated transport. Although the placental barrier itself is
    relatively impermeable to polar molecules, the surface area available
    for exchange is immense, due to the considerable branching of the
    chorionic villi. The dialysis pattern of the fetal and maternal blood
    supplies within the placenta optimizes concentration gradients for
    solutes, thereby ensuring efficient exchange.

  4. Oxygen diffuses passively from maternal to fetal blood, although full
    equilibration does not occur. Carbon dioxide diffuses in the opposite
    direction. Glucose and amino acids move across the placenta from the
    maternal to the fetal plasma by carrier-mediated transport, while free
    fatty acids diffuse passively across the lipid-rich placental barrier.
    Fetal waste products such as urea and bilirubin diffuse from fetal to
    maternal plasma down their concentration gradients.

The major placental steroids are:

  • estrogens;

  • progesterone.

The physiological role of each of these hormones will be considered in turn.

Human chorionic gonadotropin

This hormone was discussed in some detail in Section 20.3. It is secreted from a very early stage of pregnancy by the tropho­blastic tissue of the embryo, and it is believed that it forms the signal that enables the mother to recognize the existence of a fer­tilized egg. It is a powerfully luteotropic hormone that prolongs the life of the corpus luteum beyond the normal 12--14 days. As a result, progesterone secretion continues, shedding of the uterine endometrium is prevented, and spontaneous contractile activity of the myometrium is inhibited. Luteal progesterone is required for about the first 6—8 weeks of pregnancy. After this time, the placenta takes over as the main source of progesterone and the pregnancy is said to become autonomous. Indeed, levels of hCG output decline sharply after about 10 weeks although the hormone continues to be produced by the placenta for the remainder of the pregnancy (see Fig. 20.3).

In addition to its luteotropic role, a number of other actions have been attributed to hCG. It has been suggested that hCG may exert a direct effect on the maternal hypothalamus to

inhibit the synthesis of FSH and LH. If so, this might contribute to the suppression of ovulation during pregnancy. hCG is also thought to possess immunosuppressive activity which may prevent the mother rejecting the fetus as foreign tissue.

hCG exerts a stimulatory effect on the Leydig cells of the testes in male fetuses and plays a part in the differentiation of the male reproductive tract. Plasma levels of hCG are high during the period of wolffian duct development and the start of differentiation of the external genitalia.

Human placental lactogen

The pattern of secretion of this hormone (sometimes known as human chorionic somatomammotropin, or hCS) is shown in Fig. 20.3. From this it can be seen that it begins to appear in the maternal circulation at about the time that hCG levels are beginning to fall, at around 8 weeks of gestation. Levels of hPL then continue to rise during the pregnancy, reaching a peak at around week 35. This hormone is secreted by the syncytiotro-phoblastic tissue of the placenta, and unlike hCG, which appears equally in both the fetal and maternal circulations, hPL is secreted preferentially into the maternal blood.

Like hCG, human placental lactogen is structurally and func­tionally related to other peptide hormones. It has a high degree of homology with both growth hormone and prolactin, two hor­mones secreted by the anterior pituitary. Like these hormones, hPL can stimulate both somatic growth and milk secretion, though only weakly. Its principal action is to encourage the pro­liferation of breast tissue during pregnancy in preparation for lactation following delivery.

In addition to its mammotropic action, hPL exerts some important metabolic effects. These are concerned mainly with adjusting maternal levels of certain metabolites in order to favor fetal uptake via the placenta, without undue depletion of the maternal plasma. Maternal glucose levels, for example, tend to rise under the influence of hPL as a result of the inhibition of glucose uptake into cells (the so-called anti-insulin or diabeto­genic effect). Gluconeogenesis (the synthesis of glucose from amino acids) also appears to be suppressed by hPL, leading to an increase in maternal amino acid levels, while increased lipolysis causes an increase in plasma free fatty acids. By these actions it is thought that hPL counteracts the fall in metabolites which might otherwise occur as a result of fetal uptake and ensures the maintenance of favorable gradients of important nutrients for placental transport.

The monitoring of hPL levels during pregnancy can have clinical importance. hPL can be measured accurately and simply by a variety of techniques, including radioimmunoassay, and its levels in the maternal plasma give a valuable indication of pla­cental sufficiency. Although it is not unknown for pregnancies to proceed successfully in the absence of hPL (in the case of specific genetic deficiencies for example), in general, falling levels of this hormone are indicative of placental insufficiency which may put the fetus at risk.

^ 468

20 Fertilization and pregnancy






Other placental polypeptide hormones

In addition to the two major placental peptide hormones described above, a large number of other proteins are produced by the placenta. New agents continue to be discovered, but in the majority of cases no specific actions have been ascribed to them as yet. Among the more important of the placental pep­tides are a chorionic FSH, and a chorionic thyrotropin. Clinically these hormones are of value in assessing possible risks to the fetus from placental insufficiency.

The placenta secretes huge amounts of progesterone and estrogens

It should be clear from Section 19.8 that for a pregnancy to proceed successfully to term, adequate amounts of the steroid hormone progesterone are crucial. There is no recorded case of a pregnancy continuing normally in the face of insufficient progesterone secre­tion. During the early weeks after conception, this progesterone is supplied by the corpus luteum, rescued from its declining phase by hCG. By about 8 weeks, however, the placenta is becoming well established and starts to produce large amounts of progesterone. For the remainder of gestation, placental progesterone output is extremely high. The pattern of progesterone secretion by the pla­centa is illustrated in Fig. 20.8. To give some idea of the scale of progesterone secretion, during late gestation it is produced at a rate of 250—350 mg day-1 as compared with about 20 mg day-1 during the luteal phase of the menstrual cycle. The placental tissue is capable of synthesizing progesterone without the need for pre­cursors from elsewhere, so levels of this hormone during pregnancy are determined solely by the synthetic and secretory capacity of the placenta itself. Consequently, plasma progesterone provides another valuable clinical index of placental performance.

Fig. 20.8 The plasma levels of various steroid hormones during pregnancy. Note that progesterone secretion dominates the period of gestation, falling only after parturition.


Why is progesterone so important during pregnancy? A number of different functions have been suggested for proges­terone during pregnancy, but the most important of these appear

to be the maintenance of a quiescent myometrium and the pre­vention of endometrial shedding prior to placentation. Stimulation of breast development, suppression of ovulation, and inhibition of immunorejection of the embryo may also be significant actions of this steroid.

In addition to its progesterone production, the placenta secretes large amounts of a number of estrogenic hormones, including estrone, estriol, and estradiol-17/3. The patterns of secretion of these hormones are illustrated in Fig. 20.8. By com­paring these values with those seen in nonpregnant women, it is possible to get some idea of the scale of estrogen secretion during pregnancy. In the nonpregnant state, the principal estro­gen (secreted by the developing follicle) is estradiol-17/3 and in pregnancy the levels of this hormone rise to about 100 times the nonpregnant values. Circulating levels of the other estrogens of pregnancy are even higher.

What is the role of estrogens in pregnancy? This question remains largely unanswered. Although it is usual for high levels of estrogens to be present throughout pregnancy, it is not unknown for pregnancies to continue successfully in the pres­ence of rather low levels. Estrogens, however, do seem to have a role in preparing the body for giving birth and for lactation. They seem to bring about relaxation of the symphysis pubis and to act alongside hPL to stimulate proliferation of the mammary tissue. They may also play a part in the initiation of par­turition—this will be discussed in more detail below (Section 20.7).

Summary

  1. The placenta secretes a wide variety of peptide and steroid hormones.

  2. The major peptide hormones are human chorionic gonadotropin
    (hCG) and human placental lactogen (hPL).

  3. hCG is a potent luteotropic agent, the central function of which
    seems to be to prevent regression of the corpus luteum to ensure
    the continued secretion of progesterone during the early weeks of
    pregnancy.

  4. hPL is secreted from around week 10 of gestation. It contributes to
    the proliferative changes seen in the mammary tissue in preparation
    for lactation and exerts important metabolic effects in the mother. It
    stimulates an increase in the maternal plasma levels of glucose, amino
    acids, and free fatty acids. It is believed that these actions ensure that
    placental transport of essential metabolites from mother to fetus is
    optimized.

  5. Stetoid hormones are produced in huge amounts by the placenta
    throughout gestation. Ptogesterone is essential for successful preg­
    nancy, and the placenta takes over from the corpus luteum as the
    major source of this steroid at around week 10. Progesterone main­
    tains the endometrium and reduces myometrial excitability as well as
    stimulating mammary development in readiness for lactation.

  6. A variety of estrogenic hormones are secreted by the placenta, using
    precursors of both maternal and fetal origin. Their precise role in
    pregnancy is unclear, although they appear to ptepare the body for
    labor and lactation.

20.7 What triggers parturition?

469


^ 20.7 The infant is delivered around 38 weeks after conception—what triggers parturition?

In humans, as in all mammals, the length of the gestation period is remarkably constant under normal conditions—40 weeks after the start of the last menstrual period or 38 weeks after concep­tion. This constancy suggests that there is a well coordinated trigger for the onset of parturition (the process of expulsion of the fetus). Unfortunately, the exact nature of this trigger is unclear. The central question that must be addressed is what brings about the conversion from the stable maintenance of pregnancy with minimal myometrial activity to one in which the cervix dilates and the myometrium contracts efficiently to expel the fetus.

What are the critical signals that bring pregnancy to an end? Over the past few years, a considerable research effort has gone into trying to shed more light upon this problem. Most of this work has been carried out on small laboratory animals, such as the rat, and on larger domestic animals, particularly sheep. It is now apparent that there is no single trigger for the initiation of labor but rather a combination of different factors, both physical and endocrine.

The physical factors that seem most likely to contribute to the onset of parturition are stretching of the myometrium and placental insufficiency. The uterine musculature or myometrium is progressively stretched as the fetus grows during gestation. As it stretches it becomes thinner and its excitability increases. Once a certain level of excitability is reached, spontaneous con­tractions occur which tend to squeeze the contents of the uterus down towards the cervix. Small areas of myometrium act as pacemaker cells ro initiare action potentials which are then conducted throughout the myometrium, which behaves as a syncytium.

The second physical factor that may play a part in the process of parturition is the increasing inability of the placenta to meet the ever-growing nutritional demands of the fetus. Growth of the fetus far outstrips that of the placenta after the first trimester of pregnancy and the fetal capillaries tend to become clogged with clots and other debris as the pregnancy nears term. As a result the placenta becomes less efficient as an organ of exchange and, although it is difficult to verify experimentally, this decline may contribute to the onset of labor.

The fetus may control the timing of its own birth

Whether or not the physical changes described above form a truly significant part of the trigger for labor is open to question. What is clear, however, is that a number of hormonal factors also have a role to play, at least in nonhuman species. Several observa­tions have led to the belief that the endocrine system of the fetus itself plays a key role in rriggering its own delivery. For example:

• anencephalic fetuses (i.e. fetuses in whom the brain is absent or severely damaged) are frequently born post­mature; that is, after the normal gestation time;

• in sheep, an infusion of Cortisol or ACTH to the fetus

brings about premature delivery.

Such findings have led to the idea that maturation of the fetal adrenal cortex is in some way responsible for triggering the onset of parturition. Using a sensitive assay for Cortisol in the sheep, it has been shown that fetal plasma Cortisol rises 15—20 days before full term. This rise correlates well with an increase in fetal adrenal enzyme activity and in the abundance of ACTH recep­tors on the adrenal cortical cells. As might be expected, fetal ACTH levels appear to rise as term approaches and the paraven­tricular nucleus of the hypothalamus shows an increased content of both CRH and arginine vasopressin, the hormones that act as releasing factors for ACTH (see Chapter 12). The mechanisms that underpin this series of changes in the fetus at the end of gestation are unclear at present.

^ At the end of gestation the uterus is released from

the 'progesterone block' that has dominated

pregnancy

The experimental findings discussed above suggest very strongly that fetal Cortisol plays a significant role in the onset of labor, at least in some species. It has been recognized for some time that a variety of other hormones also show marked changes in their pattern of secretion as pregnancy proceeds. Throughout most of the gestation period, placental progesterone secretion outstrips that of estrogens (although these are also secreted in very large amounts; see above). This is, of course, vital for the success of the pregnancy since progesterone acrs as a myometrial relaxant which prevents premature expulsion of the fetus from the uterus. It also reduces the sensitivity of the uterine smooth muscle ro other spasmogenic agents. Estrogens, on the other hand, increase myometrial excitability and enhance its sensitivity to other sub­stances that may cause increased contractile activity. An estrogen-primed uterus is highly sensitive to agents such as histamine, oxytocin, acetylcholine, and prostaglandins, reflecting alterations in resting membrane potential of the smooth muscle cells.

^ Fetal Cortisol may initiate the switch from progesterone to estrogen dominance

It is known that Cortisol stimulates the conversion of progesterone to estrogens in the placenta. The following is a hypothetical sequence of events that could lead up to the onset of parturition. Figure 20.9 shows a diagrammatic representation of the scheme.

  1. Fetal Cortisol stimulates the conversion of progesterone to
    estrogens in the placenta and so redirects placental
    steroidogenesis in favor of the myometrial stimulant.

  2. Estrogens in turn stimulate the production of prosta­
    glandin F-2a (PGF-2a) by the placenta which may help to
    enhance rhythmical contractions of the Uterus.

  3. Contractions, in their turn, stimulate the secretion of oxy­
    tocin from the posterior pituitary via the reflex described
    in Section 12.2 . Oxytocin increases the excitability of the
    musculature during labor itself.

470

20 Fertilization and pregnancy




Fig. 20.9 Some endocrine factors involved in the initiation of parturition.

It cannot be overemphasized that this scheme is purely specu­lative—the nature of the interactions between the neural and hormonal changes that occur as pregnancy nears full term is far from clear, even in well-studied species such as sheep. Understanding of human parturition is even less well under­stood, as obvious ethical difficulties surround research using humans.

Evidence from nonhuman primates suggests that there is a rise in fetal ACTH secretion just prior to delivery and that maternal estrogen levels rise close to full term. Furthermore, removal of the fetus but not the placenta some days before the expected date of delivery delays expulsion of the placenta for up to 50 days after full term. This is highly suggestive of a role for the fetus itself in controlling the onset of labor.

Summary

  1. Parturition is an integrated, multifactorial process involving diverse
    mechanisms in both the maternal and the fetal nervous and endocrine
    systems.

  2. The nature of the trigger for parturition is still poorly understood
    but it is widely believed that the fetus plays a part in determining
    the time of its own birth.

3. Fetal Cortisol appears to initiate a switch in the placenta away from
progesterone synthesis to allow estrogenic hormones to dominate the
hormonal profile in the last days of pregnancy. Estrogens and other
spasmogenic agents, such as PGF-2ct and oxytocin, may then increase
the contractility of the myometrium still further to bring about
delivery of the infant.

^ Recommended reading

Begley, D. J., Firth, J. A., and Hoult, J. R. S. (1980). Human

reproduction and developmental biology, Chapters 7 and 12. MacMillan Press, London.

Case, R. M. and Waterhouse, J. M. (ed.) (1994). Human physiology: age, stress and the environment. (2nd edn) chapter 1. Oxford Science Publications, Oxford.

Ferin, M., Jewckwicz, R., and Warres, M. (1993). The menstrual cycle. Oxford University Press, Oxford.

Griffin, N. E. and Ojeda, S. R. (1992). Textbook of endocrine physiology, (2nd edn), Oxford University Press, Oxford.

Johnson, M. H. and Everitt, B.J. (1995). Essential reproduction, (4th edn), Chapters 8-10, 12, and 14. Blackwell Scientific, Oxford.

^ Self-test questions

Each statement is either true or false. The answers are given below.

1. a. Erection is a sympathetic reflex.

b. Erection is due to pooling of blood in the erectile
tissues of the penis.

c. During ejaculation the sperm are mixed with secretions
from the prostate and seminal vesicles.

d. Fertilization normally occurs in the uterus.

e. Fertilization may occur 3 or more days after ovulation.

2. a. A normal sperm count is about 20 million.

b. Immediately after ejaculation the sperm are capable of
fertilizing an ovum.

c. The fertilized egg is also known as a zygote.

d. Following fertilization the egg completes its second
meiotic division.

e. The fertilized egg secretes hCG to maintain the corpus
luteum.

3. a. The placenta nourishes the fetus by establishing a

dialysis pattern for exchange between the maternal and fetal circulations.

b. The placental barrier is very thin and freely permeable
to glucose and amino acids.

c. The Po2 of the blood of the umbilical vein is the same
as that in the maternal arterial blood.

d. The placenta secretes about 10 times as much pro­
gesterone as the corpus luteum.

e. The estrogens secreted by the placenta tend to increase
uterine excitability during late pregnancy.

Answers

1. Erection is initiated by activity in the parasympathetic nerves arising from S2—S4 which cause the vessels of the

Answers 471

pudendal artery to dilate. Fertilization normally occurs in one of the fallopian tubes. Since the unfertilized egg is believed to be viable for only 12—24 hours after ovulation, fertilization must take place within this period.

a. False;

b. True;

c. True;

d. False;

e. False.

A normal sperm count is about 200 million. Values as low as 20 million are associated with male infertility. Sperm must undergo the acrosome reaction before they can fer­tilize an egg. This is known as capacitation and normally takes place in the female reproductive tract.

a. False;

b. False;

c. True;

d. True;

e. True.

3. The placental barrier is relatively thick and impermeable. This prevents fetal proteins passing into the maternal circulation and eliciting a immune response. While blood gases cross the placental barrier by passive diffusion, glucose and amino acids pass from mother to fetus by carrier-mediated facilitated diffusion. The Po1 of the blood in the umbilical vein is about 4.25 kPa (c.32 mmHg) which is much lower than that in the uterine artery where the PO2 is about 12.6 kPa (95 mmHg).

a. True;

b. False;

c. False;

d. True;
1   2   3

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