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paratively low (85—95 per cent of the filtered load). The exact reasons for this difference are not clear but may partly be explained by a low tubular sensitivity to aldosterone. Fetal glucose reabsorption is thought to occur by sodium-dependent transport as in the adult. Furthermore, the tubular maximum for reabsorption (when corrected for the lower GFR) is higher than that of the adult, as is the renal plasma threshold for glucose.

The fetal kidney plays a part in the regulation of acid—base balance during gestation. Between 80 and 100 per cent of the filtered bicarbonate is reabsorbed by the tubules. The fetal response to metabolic acidosis is relatively poor but in severe acidosis there is an increase in hydrogen ion excretion.

Renal changes occurring at or soon after birth

Although the changes in kidney function that accompany birth are less dramatic than those in the respiratory and cardiovascular systems, they are just as important. Once the placenta is lost, the kidneys of the newborn infant become solely responsible for maintaining fluid balance and disposing of waste products.

GFR and urine output increase gradually over the first weeks of life, although adult levels (relative to body surface area) are not reached for 2 or 3 years. Tubular function is difficult to assess in neonates, although it is thought that while glucose and phos­phate are reabsorbed efficiently, bicarbonate and amino acids are reabsorbed less well. Babies cannot concentrate their urine to the degree seen in adults. Possible reasons for this include immatur­ity of the tubules, shorter loops of Henle, lower sensitivity to ADH, and a low plasma concentration of urea. The reason for this lack of urea is that nearly all the amino acids derived from the protein in a baby's diet are used in the formation of new tissue—very few are metabolized in the liver to form urea.

Summary

  1. The fetal adrenal gland consists of a medullary region; a small,-zoned
    'definitive' cortex; and a larger fetal zone.

  2. The medulla secretes catecholamines, the fetal zone provides the
    precursors for the synthesis of estrogens by the placenta, while the
    definitive zone converts progesterone to Cortisol.

  3. Fetal Cortisol has several key functions. It stimulates surfactant pro­
    duction, accelerates maturation of the liver, and probably has a role in
    the initiation of parturition.

  4. The fetal kidneys play a part in fluid and acid—base balance. Urine is
    produced from about 8 weeks' gestation. The fetal kidneys cannot
    concentrate urine effectively so the urine is generally hypotonic.

  5. Glucose reabsorption is comparable to that of adults relative to GFR,
    but sodium reabsorption is comparatively low.

  6. At birth, the kidneys assume sole responsibility for fluid balance and
    waste disposal. GFR and urine output increase gradually, as does the
    ability to concentrate urine.

Newborn babies are at risk from dehydration

The inability of young babies to concentrare their urine efficiently means that they can quickly become dehydrated, par­ticularly during episodes of diarrhea and vomiting. It is essential that fluids are replenished by mourh and, if this is not possible, intravenous fluid replacemenr may be needed (see also Section 28.4).

^ 21.6 Temperature regulation in the newborn infant

The fetus has no problems with temperature regulation as it is surrounded by amniotic fluid which is at body temperature. The mother is responsible for generating and dissipating heat. At delivery, the newborn infant has to make a rapid adjustment from the warm, moist, constant environmenr of its mother's uterus to an outside world in which the temperature is much lower and hear is readily losr by radianr, convective, and eva-porarive routes. The neonate has a high surface area to volume ratio, which means rhat heat is readily losr from the skin's surface; irs cardiac output is high in relation to its surface area; and its layer of insulating far is comparatively thin. These factors combine to cause the core temperature of the baby to drop to around 35 °C during the first hours of its life.

Babies generate large quantities of heat

through the metabolism of brown adipose

tissue

Normally, when a critical temperature difference of 1.5 °C is reached berween the skin and the environment, thermogenesis begins and oxygen consumption increases, in order to restore the body temperature to normal. While thermoregulatory mechan­isms are only partly functional at birth, newborns are capable of maintaining their body tempetature above ambient temperature. They respond to a lowered ambient temperarure by increased muscular movement, although this is limired, and only in a very minor way by shivering. These responses cannot account for all rhe heat generared in response to cold. The extra heat is gener­ated by nonshivering thermogenesis via the metabolism of brown adipose tissue or brown fat which is abundanr in the infant. It is situated between the scapulae, at the nape of the neck, in the axillae, between the trachea and the esophagus, and in large amounts around the kidneys and adrenal glands (see Fig. 26.6). In all, the neonate possesses about 200 g of brown far, which represents a relatively high proportion of rhe total body mass.

The brown far is well vascularized and exhibirs unique meta­bolic properties which are triggered eirher by increased plasma levels of circulating catecholamines or by norepinephrine released by sympathetic nerve endings. Cold stress results in an increase in symparhetic nerve activity and an increased secretion

484

21 Fetal and neonatal physiology




Heat

Fig. 21.8 The metabolism of a brown fat cell. Activation of /3-adrenoceptors on the cell surface leads to a signal cascade that results in an increased breakdown of triglycerides. These are metabolized in the mitochondria to generate heat (see text for further details).

of epinephrine and norepinephrine by the adrenal medulla. These hormones stimulate the metabolism of brown fat cells by interacting with /3-adrenoceptors on the cell surface to activate a lipase (hormone-sensitive lipase, or HSL) which then releases glycerol and free fatty acids from cellular stores of triglyceride (Fig. 21.8). Most of these free fatty acids are resynthesized directly into triglyceride by the incorporation of α-glycerophos-phate, so the brown fat stores are not unduly depleted. The inner mitochondrial membrane of brown fat cells contains a protein that uncouples oxidation from ATP generation and heat is gen­erated instead of the energy being stored as ATP for subsequent release during cellular metabolism. Furthermore, the free fatty acids and glyceride that are not immediately resynthesized become available for oxidation by the usual biochemical pathway, to provide still more heat energy. Since the tissue is well supplied with blood, the heat that is generated by this pathway is carried quickly to the rest of rhe body, and in this way the brown fat acts as a rather effective source of heat for the newborn baby.

Premature infants have special thermoregulatory problems

Premature babies have even greater difficulty in maintaining their body temperature than normal infants born at full term. Their surface area to volume ratio is even bigger, allowing more rapid heat loss, their insulating fat layer even thinner, and their brown fat stores less well developed. For this reason it is almost always necessary to keep premarure babies in a thermally con­trolled environmenr—an incubator—until their thermoregula­tory mechanisms develop sufficiently to permit independent temperature regulation.

Summary

  1. A newborn infant can lose heat very rapidly. Its high surface area to
    volume ratio, relatively high cardiac output, and lack of insulating
    fat combine to cause a drop in core temperature after birth.

  2. Babies can generate large quantities of heat through the metabolism
    of brown fat, a well-vascularized tissue situated around the kidneys,
    at the nape of the neck, between the scapulae, and in the axillae. The
    metabolism of brown fat is stimulated by catecholamines released in
    response to cold stress.

  3. Premature infants have even greater difficulty in maintaining their
    body temperature and frequently need to be kept in a thermally
    controlled incubator.

21.7 The gastrointestinal tract of the fetus and neonate

The role of the placenta in delivering essential nutrients to the fetus has been described in Section 20.5. The fetus obtains glucose, amino acids, and fatty acids from its mother. Towards the end of gestation, glycogen is stored in the muscles and liver of the fetus, while deposits of both brown and white fat are laid down. These stores will be crucial to the survival of the infant immediately after its birth.

The gut of the fetus is relatively immature, with limited movements and secretion of digestive enzymes. Some salivary and pancreatic secretion commences during the second half of gestation. Gastric glands appear at around the same time, although they do not appear to be secretoty since the gastric contents are neutral at birth. Most of the major gastrointestinal hormones are secreted during fetal life although at a low level. Motilin is especially low, possibly accounting for the low level of gut motility when compared with that of the adult.

The fetus passes little, if any, feces while it remains in the uterus. The contents of the large intestine accumulate as meco­nium, a sticky, greenish-black substance. Meconium does not normally enter the amniotic fluid, although if the fetus becomes distressed, for example during a prolonged or difficult labor,

21.8 Development of the male and female reproductive tissues

485






motilin levels rise, gut motility increases, and meconium is passed. Meconium-stained amniotic fluid is recognized as a sign of fetal distress and can cause damage to the lungs if it is aspirated.

At birth placental nutrients are lost but oral feeding is not yet established

With clamping of the umbilical cord soon after delivery, intra­venous nutrition of the baby ceases. It will, however, be several days before oral feeding is fully established. During this time the neonate must rely on the stores of fat and carbohydrate laid down during late gestation. Most importantly, glycogen is broken down to glucose under the influence of catecholamines secreted by the adrenal medulla. Premature or low birth-weight babies may experience problems because of inadequate stores and may require intravenous nutrition.

As milk feeds are established, the chief

metabolic substrate switches from

glucose to fat

As the first milk feeds are ingested by the baby, its gut increases rapidly in size to accommodate the relatively large volume of fluid it must now handle. At the same time, secretion of diges­tive juices is stimulated and motility increases. Mature human milk is rich in fat (see Section 22.3) and this becomes the major metabolic substrate. Lactose, the chief carbohydrate of milk, is hydrolyzed by lactase, a specific enzyme located in the brush border of the small intestine. A specific lack of this enzyme, or a more generalized reduction in pancreatic enzymes as occurs, for example, in cystic fibrosis, will result in a substantial reduction in digestion and absorption. The meconium, which was present in the fetal large intestine, is usually passed during the first few days, after which the semiliquid stools change to green then yellowish-brown in color. Bowel movements are generally fre­quent in young babies, although there is also great variability— there may be as many as 12 stools a day or as few as 1 every 3 or 4 days.

Summary

  1. The fetal gut is relatively immature. The fetus is nourished solely by
    the placenta, and the chief metabolic substrate is glucose. There is a
    limited degree of motility and secretory activity.

  2. The contents of the fetal large intestine accumulate as meconium,
    which may be passed into the amniotic fluid during fetal distress.

' 3. After birth, but before the full establishment of oral feeding, the baby relies largely on stores of fat and carbohydrate laid down during late gestation.

4. With the establishment of milk feeds, the major metabolic substrate switches to fats. Digestive juice secretion and motility increase.

^ 21.8 Development of the male and female reproductive tissues

Humans have 46 chromosomes, one pair of which are the sex chromosomes. In the female both of these are X chromosomes and all her ova will carry a single X chromosome. In the male, however, the sex chromosomes consist of one X and one Y. Sperm may therefore carry either an X or a Y chromosome. In humans, the female is said to be the homogametic sex (XX), while the male is the heterogametic sex (XY). It follows that if an ovum is fertilized by a sperm carrying an X chromosome, the resulting baby will be a girl, while fertilization by a sperm carry­ing a Y chromosome will produce a boy (Fig. 21.9). Studies of patients with a range of chromosomal abnormalities have revealed that the presence of a Y chromosome is the critical determinant of 'maleness', at least as far as gonadal development in the embryo is concerned. If a Y chromosome is present, male gonads (testes) will develop, but in the absence of a Y chromo­some female gonads (ovaries) will form. Recently it has been shown that only a small part of the Y chromosome is actually required for the determination of'maleness'. This is the so-called sex-determining region of the Y chromosome, rhe SRY gene or genes, in whose presence restes develop. Indeed, studies using mice have shown that the SRY gene(s) can induce maleness in XX individuals otherwise lacking in all orher genes normally carried by the Y chromosome.

In the early embryo, the gonads of males and females are indistinguishable

Fig. 21.9 An outline of the sequence of prenatal development of gender, including differentiation of the appropriate gonads and genitalia.


For the first 5 or 6 weeks of fetal life the gonads of both males and females develop identically. They are made up of two dif­ferent types of tissue, somatic mesenchymal tissue, which forms the

486

21 Fetal and neonatal physiology


Box 21.1 Abnormalities of sexual differentiation

Sex is determined genetically in humans. The normal male chromosomal karyotype is XY, while that of the female is XX. As described in the main text, in the presence of a Y chromosome, testes develop, while in its absence ovaries are formed. Subsequent differentiation of the male and female genitalia depends upon the existence of either functional ovaries or testes. Genetic errors can result in anatomical aberrations and distortion of sexual differentiation. A few of the more widely occurring abnormalities of this kind are described below.

1. Turner's syndrome (karyotype XO). Here there is only a single
sex chromosome and, in the absence of either a second
X chromosome to stimulate normal ovarian development or a

Y chromosome to stimulate testicular formation, the gonad
remains as a primitive streak. In the absence of functional
testes, the external genitalia develop as the female type.

2. Klinefelter's syndrome (karyotype XXY). In this condition, the
internal and external genitalia develop as male, because a

Y chromosome is present, but the ability of the testes to carry
out spermatogenesis is severely impaired by the presence of an
additional X chromosome. Females who carry additional
X chromosomes (e.g. karyotype XXX or XXXX) may also
have a shortened or impaired reproductive life because of
damage to germ cell function, although the mechanism for
this is not understood.

  1. Certain individuals with a notmal XY (male) karyotype lack
    the capacity to respond to androgens due to a receptor
    deficiency. Such individuals will develop testes but show no
    growth or development of the wolffian ducts nor masculin-
    ization of the external genitalia.

  2. Certain enzymatic deficiencies in otherwise normal XX indi­
    viduals can result in overproduction of androgens during fetal
    life. In such cases there may be mild or severe masculinization
    of the external genitalia, despite the presence of normal
    ovaries.

matrix of the organ, and the primordial germ cells, which form the gametes. Ridges of mesenchymal tissue (the primitive sex cords) develop on either side of the dorsal aorta between 3 and 4 weeks of gestation. The primordial germ cells originate outside these ridges but migrate via the developing hindgut, gut mesentery, and the region of the kidneys to lie between and within the sex cords by the sixth week of fetal life. At the same time the population of germ cells is expanding by mitosis.

The development of testes depends on the presence of a Y chromosome

Up until around 6 weeks of gestation, the gonads of males and females are indistinguishable and are said to be 'indifferent'. After completion of the migration of the germ cells to the primitive sex cords, divergence of the gonads resulting from

Y-chromosome determination of 'maleness' starts to become apparent. The primitive sex cords of the male embryo undergo considerable proliferation to make contact with ingrowing mesonephric tissue and form a structured organ surrounded by a fibrous layer, rhe tunica albuginea. The cells of the sex cords, incorporating primordial germ cells, secrete a basement mem­brane and are now known as rhe seminiferous cords, which will give rise to the seminiferous tubules of the fully developed testis. Within these cords the primordial germ cells will give rise ro spermatozoa while the mesenchymal cord cells will form the Sertoli cells. The specific endocrine Leydig cells form as clusters within the stromal mesenchymal tissue lying between the cords.

The presence of a Y chromosome within the mesodermal cells of the genital ridge initiates the conversion of an indifferent gonad into a testis. In the absence of a Y chromosome, the changes in gonadal organization described above do not occur—the develop­ing female gonad appears to remain indifferent. The primordial germ cells continue to proliferate mitotically and the primitive sex cords disappear. A second set of cords arises in the cortical region of the gonad and these break up into clusters of cells sur­rounding the germ cells. In this way the primitive follicles that characterize the ovary are laid down—the germ cells forming the oocytes and the cord cells forming the granulosa cells of the folli­cles. Between the follicles groups of interstitial cells are laid down.

To summarize the early development of the fetal gonads: activ­ity of a small part of the Y chromosome appears to play an essen­tial role in triggering the divergence of the primitive sex organs. If it is present, the indifferent gonad is converted to a testis with seminiferous cords, primordial germ cells that will form sperm, and tissue that will give rise to the Serroli and Leydig cells. In rhe absence of a Y chromosome the indifferent organ forms an ovary containing a population of primordial follicles.

Subsequent development of the male and

female genitalia depends on the hormones

secreted by the gonads

Once the fetal gonads are established, the role of the sex chromo­somes in the determinarion of sex is largely complete. Subsequent steps in the development of the male and female genital organs seem ro be determined by the nature of rhe gonads themselves. This is particularly so in the case of the male, in whom the fetal testes secrete two hormones that appear to play a key role in differentiation of the male genitalia. These are: testosterone from the Leydig tissue and a substance known as miillerian inhibiting hormone (MIH) from the Sertoli cells. In their absence, i.e. when ovaries are present, female genitalia are formed (Figs 21.9 and 21.10).

The fetus possesses two primordial internal genital tissues: the wolffian duct, which forms male organs; and the miillerian duct, which gives rise to female parts. In a female fetus in whom ovaries have developed, the male (wolffian duct) disappears (possibly as a consequence of the lack of testosterone), and the

21.8 Development of the male and female reproductive tissues

487





Fig. 21.10 The role of the sex hormones in the development of the internal and external genitalia. In the upper panel one of the testes is shown in the process of descent.

mullerian ducts go on to develop into the fallopian tubes, uterus, cervix, and upper vagina. In a male fetus, however, testosterone seems to stimulate development of the wolffian ducts to give tise to the epididymis, seminal vesicles, and vas deferens. At the same time, the female mullerian ducts regress under the influence of MIH secreted by the Sertoli cells. As with the divergence of the fetal sex organs, the male pattern of differ­entiation must actively be induced whereas, in the absence of intervention, the female pattern develops inherently.

Fetal testosterone also plays a part in the development of the male external genitalia, bringing about fusion of the urethral folds to enclose the urethral tube and fusion of the genital swellings to fotm the scrotum. There is also enlargement of the genital tubercle to form the penis. In the female, the urethral folds and genital swellings temain separate to form the labia, while the genital tubercle forms the small clitoris. These stages of development are represented diagrammatically in Figs 21.10 and 21.11.

488

21 Fetal and neonatal physiology





Fig. 21.11 The timing of the prenatal sexual differentiation of the internal and external genitalia of the human fetus.

Summary

  1. Humans have 46 chromosomes, one pair of which are the sex
    chromosomes. The female (homogametic sex) has two X chromo­
    somes while the male (heterogametic sex) has one X and one
    Y chromosome.

  2. In the presence of a Y chromosome the indifferent gonads of the fetus
    develop as testes but in its absence, ovaries develop. Subsequent steps
    in the development of the male and female genital organs seem to
    depend on the gonads themselves.

  3. Androgens from the fetal testes play a particularly important role in
    stimulating the development of the internal male genitalia from the
    wolffian ducts. In the presence of ovaries, the miillerian ducts develop
    into fallopian tubes, uterus, cervix, and upper vagina.

Recommended reading

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

reproduction and developmental biology, Chapters 11 and 13. MacMillan Press, London.

Case R. M. and Waterhouse J. M. (ed) (1994) Human physiology: age stress and the environment. (2nd edn) Chapter 2. Oxford University Press, Oxford.

GnfEn, N. E. and Ojeda, S. R. (1 992). Textbook of endocrine physiology, (2nd edn) Oxford University Press, Oxford.

Johnson, M. H. and Everitt, B. J. (1995). Essential reproduction, (4th edn), Chapter 11. Blackwell Scientific, Oxford.

Thorburn, G. D. and Harding, R. (1994). Textbook of fetal physiology. Oxford Medical Publications, Oxford.

^ Self-test questions

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

1. a. Blood returning to the fetus via the umbilical vein is

fully saturated with oxygen.

b. Fetal hemoglobin has a higher affinity for oxygen than
adult hemoglobin.

c. Fetal blood has a higher hemoglobin content than adult
blood.

d. Blood perfusing the btain of a ferus has the same PaO7
as that of blood in the descending aorta.

2. a. The fetal heart rate is neatly double that of a healthy

adult.

b. All the blood in the umbilical vein enters the right
atrium.

c. The ductus arteriosus carries blood from the pulmonary
artery to the descending aorta.

Answers

489


d. The three fetal shunts normally close within a few days
of birth.

e. Fetal blood pressure is similar to that of an adult.

3. a. The fetus performs breathing movements in utero.

b. The first breath is achieved by large changes in the
intrathoracic pressure.

c. Lung compliance in the newborn is much lower than
that of an adult.

d. Lack of surfactant in the neonate may cause respiratory
distress.

e. The peripheral chemoreceptors are active in the fetus.

f. Immediately after birth all of the output of the right
ventricle passes through the lungs.

4. a. Fetal Cortisol stimulates the production of pulmonary

surfactant by alveolar type II cells.

b. The fetal zone of the adrenal gland synthesizes large
quantities of progesterone.

c. The fetal kidneys produce a hypotonic urine after about
8 weeks' gestation.

d. The kidneys play an important role in the regulation of
acid—base balance of the fetus.

5. a. The neonate regulates its temperature mainly by

shivering.

b. The development of the fetal gonads into the male type
depends on the presence of testosterone.

c. The sex of an individual is determined by a single gene
on the Y chromosome.

d. In the absence of a Y chromosome the development of
the gonads will follow the female pattern.

Answers

1. The blood in the umbilical vein is about 80 per cent saturated with O2 but as fetal blood has a higher hemo­globin content and as fetal hemoglobin has a higher affinity for O2 than adult hemoglobin, the O2 content of blood in the umbilical vein is about 16mldl_1. As the blood perfusing the brain is supplied via the ascending aorta and as the ductus arteriosus supplies deoxygenated blood to the descending aorta, the blood perfusing the brain has a higher Po2 than that of the descending aorta.

a. False;

b. True;

c. True;

d. False.

2. Because of the operation of the crista dividens, most of
the blood returning in the umbilical vein passes directly to
the left atrium via the foramen ovale. Fetal blood pressure
is normally low (9/6 kPa or 70/45 mmHg).

a. True;

b. False;

c. True;

d. True;

e. False.

3. To inflate the lungs for the first time, the neonate gen­
erates a very large negative intrathoracic pressure (about
10—15 times the pressure needed for a normal inspiration
in a healthy adult). To exhale the first breath requires a
large positive intrathoracic pressure. The fact that very
large pressure changes are required during the establish­
ment of breathing demonstrates that the lung compliance
is very low compared to the adult. The central chemo­
receptors are active but not the peripheral chemoreceptors,
which become progressively more sensitive in the weeks
following birth. Although the proportion of the right ven­
tricular output passing through the lungs greatly increases
after the first breath, it is some days before closure of the
ductus arteriosus results in all of the blood from the right
ventricle passing through the lungs.

a. True;

b. True;

c. True;

d. True;

e. False;

f. False.

4. The fetal zone of the adrenal gland synthesizes large
amounts of estrogen precursors which are converted to
estrogenic hormones by the placenta.

a. True;

b. False;

c. True;

d. True.

5. The neonate is unable to generate very much heat by
shivering, instead it utilizes nonshivering thermogenesis.
Much of this additional heat is generated by the metab­
olism of brown adipose tissue.

a. False;

b. True;

c. True;

d. True.
1   2

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