Cols=2 gutter=18> 21. 1 Introduction
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| 21.6 Temperature regulation in the newborn infant 21.8 Development of the male and female reproductive tissues Self-test questions |
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483   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
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). ^ 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
2  1.7 The gastrointestinal tract of the fetus and neonateThe 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
' 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. ^ 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 differentiationS  ex 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.
m  atrix 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
R   ecommended readingBegley, 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. ^ 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 daysof 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. |
he fetal adrenal gland consists of a medullary region; a small,-zoned
newborn infant can lose heat very rapidly. Its high surface area to
umans have 46 chromosomes, one pair of which are the sex1 2
