Guyton and Hall Textbook of Medical Physiology, 12th Ed


Pregnancy and Lactation

imageIn Chapters 80 and 81, the sexual functions of the male and female are described to the point of fertilization of the ovum. If the ovum becomes fertilized, a new sequence of events called gestation, or pregnancy, takes place, and the fertilized ovum eventually develops into a full-term fetus. The purpose of this chapter is to discuss the early stages of ovum development after fertilization and then to discuss the physiology of pregnancy. In Chapter 83, some special aspects of fetal and early childhood physiology are discussed.

Maturation and Fertilization of the Ovum

While still in the ovary, the ovum is in the primary oocyte stage. Shortly before it is released from the ovarian follicle, its nucleus divides by meiosis and a first polar body is expelled from the nucleus of the oocyte. The primary oocyte then becomes the secondary oocyte. In this process, each of the 23 pairs of chromosomes loses one of its partners, which becomes incorporated in a polar body that is expelled. This leaves 23 unpaired chromosomes in the secondary oocyte. It is at this time that the ovum, still in the secondary oocyte stage, is ovulated into the abdominal cavity. Then, almost immediately, it enters the fimbriated end of one of the fallopian tubes.

Entry of the Ovum into the Fallopian Tube (Uterine Tube)

When ovulation occurs, the ovum, along with a hundred or more attached granulosa cells that constitute the corona radiata, is expelled directly into the peritoneal cavity and must then enter one of the fallopian tubes (also called uterine tubes) to reach the cavity of the uterus. The fimbriated ends of each fallopian tube fall naturally around the ovaries. The inner surfaces of the fimbriated tentacles are lined with ciliated epithelium, and the cilia are activated by estrogen from the ovaries, which causes the cilia to beat toward the opening, or ostium, of the involved fallopian tube. One can actually see a slow fluid current flowing toward the ostium. By this means, the ovum enters one of the fallopian tubes.

Although one might suspect that many ova fail to enter the fallopian tubes, conception studies suggest that up to 98 percent succeed in this task. Indeed, in some recorded cases, women with one ovary removed and the opposite fallopian tube removed have had several children with relative ease of conception, thus demonstrating that ova can even enter the opposite fallopian tube.

Fertilization of the Ovum

After the male ejaculates semen into the vagina during intercourse, a few sperm are transported within 5 to 10 minutes upward from the vagina and through the uterus and fallopian tubes to the ampullae of the fallopian tubes near the ovarian ends of the tubes. This transport of the sperm is aided by contractions of the uterus and fallopian tubes stimulated by prostaglandins in the male seminal fluid and also by oxytocin released from the posterior pituitary gland of the female during her orgasm. Of the almost half a billion sperm deposited in the vagina, a few thousand succeed in reaching each ampulla.

Fertilization of the ovum normally takes place in the ampulla of one of the fallopian tubes soon after both the sperm and the ovum enter the ampulla. But before a sperm can enter the ovum, it must first penetrate the multiple layers of granulosa cells attached to the outside of the ovum (the corona radiata) and then bind to and penetrate the zona pellucida surrounding the ovum. The mechanisms used by the sperm for these purposes are presented in Chapter 80.

Once a sperm has entered the ovum (which is still in the secondary oocyte stage of development), the oocyte divides again to form the mature ovum plus a second polar body that is expelled. The mature ovum still carries in its nucleus (now called the female pronucleus) 23 chromosomes. One of these chromosomes is the female chromosome, known as the X chromosome.

In the meantime, the fertilizing sperm has also changed. On entering the ovum, its head swells to form a male pronucleus, shown in Figure 82-1D. Later, the 23 unpaired chromosomes of the male pronucleus and the 23 unpaired chromosomes of the female pronucleus align themselves to re-form a complete complement of 46 chromosomes (23 pairs) in the fertilized ovum (Figure 82-1E).


Figure 82-1 Fertilization of the ovum. A, The mature ovum surrounded by the corona radiata. B, Dispersal of the corona radiata. C, Entry of the sperm. D, Formation of the male and female pronuclei. E,Reorganization of a full complement of chromosomes and beginning division of the ovum.

(Modified from Arey LB: Developmental Anatomy: A Textbook and Laboratory Manual of Embryology, 7th ed. Philadelphia: WB Saunders, 1974.)

What Determines the Sex of the Fetus That Is Created?

After formation of the mature sperm, half of these carry in their genome an X chromosome (the female chromosome) and half carry a Y chromosome (the male chromosome). Therefore, if an X chromosome from a sperm combines with an X chromosome from an ovum, giving an XX combination, a female child will be born, as explained in Chapter 80. But if a Y chromosome from a sperm is paired with an X chromosome from an ovum, giving an XY combination, a male child will be born.

Transport of the Fertilized Ovum in the Fallopian Tube

After fertilization has occurred, an additional 3 to 5 days is normally required for transport of the fertilized ovum through the remainder of the fallopian tube into the cavity of the uterus (Figure 82-2). This transport is effected mainly by a feeble fluid current in the tube resulting from epithelial secretion plus action of the ciliated epithelium that lines the tube; the cilia always beat toward the uterus. Weak contractions of the fallopian tube may also aid the ovum passage.


Figure 82-2 A, Ovulation, fertilization of the ovum in the fallopian tube, and implantation of the blastocyst in the uterus. B, Action of trophoblast cells in implantation of the blastocyst in the uterine endometrium.

The fallopian tubes are lined with a rugged, cryptoid surface that impedes passage of the ovum despite the fluid current. Also, the isthmus of the fallopian tube (the last 2 centimeters before the tube enters the uterus) remains spastically contracted for about the first 3 days after ovulation. After this time, the rapidly increasing progesterone secreted by the ovarian corpus luteum first promotes increasing progesterone receptors on the fallopian tube smooth muscle cells; then the progesterone activates the receptors, exerting a tubular relaxing effect that allows entry of the ovum into the uterus.

This delayed transport of the fertilized ovum through the fallopian tube allows several stages of cell division to occur before the dividing ovum—now called a blastocyst, with about 100 cells—enters the uterus. During this time, the fallopian tube secretory cells produce large quantities of secretions used for the nutrition of the developing blastocyst.

Implantation of the Blastocyst in the Uterus

After reaching the uterus, the developing blastocyst usually remains in the uterine cavity an additional 1 to 3 days before it implants in the endometrium; thus, implantation ordinarily occurs on about the fifth to seventh day after ovulation. Before implantation, the blastocyst obtains its nutrition from the uterine endometrial secretions, called “uterine milk.”

Implantation results from the action of trophoblast cells that develop over the surface of the blastocyst. These cells secrete proteolytic enzymes that digest and liquefy the adjacent cells of the uterine endometrium. Some of the fluid and nutrients released are actively transported by the same trophoblast cells into the blastocyst, adding more sustenance for growth. Figure 82-3 shows an early implanted human blastocyst, with a small embryo. Once implantation has taken place, the trophoblast cells and other adjacent cells (from the blastocyst and the uterine endometrium) proliferate rapidly, forming the placenta and the various membranes of pregnancy.


Figure 82-3 Implantation of the early human embryo, showing trophoblastic digestion and invasion of the endometrium.

(Courtesy Dr. Arthur Hertig.)

Early Nutrition of the Embryo

In Chapter 81, we pointed out that the progesterone secreted by the ovarian corpus luteum during the latter half of each monthly sexual cycle has an effect on the uterine endometrium, converting the endometrial stromal cells into large swollen cells containing extra quantities of glycogen, proteins, lipids, and even some minerals necessary for development of the conceptus (the embryo and its adjacent parts or associated membranes). Then, when the conceptus implants in the endometrium, the continued secretion of progesterone causes the endometrial cells to swell further and to store even more nutrients. These cells are now called decidual cells, and the total mass of cells is called the decidua.

As the trophoblast cells invade the decidua, digesting and imbibing it, the stored nutrients in the decidua are used by the embryo for growth and development. During the first week after implantation, this is the only means by which the embryo can obtain nutrients; the embryo continues to obtain at least some of its nutrition in this way for up to 8 weeks, although the placenta also begins to provide nutrition after about the 16th day beyond fertilization (a little more than 1 week after implantation). Figure 82-4 shows this trophoblastic period of nutrition, which gradually gives way to placental nutrition.


Figure 82-4 Nutrition of the fetus. Most of the early nutrition is due to trophoblastic digestion and absorption of nutrients from the endometrial decidua, and essentially all the later nutrition results from diffusion through the placental membrane.

Function of the Placenta

Developmental and Physiologic Anatomy of the Placenta

While the trophoblastic cords from the blastocyst are attaching to the uterus, blood capillaries grow into the cords from the vascular system of the newly forming embryo. About 21 days after fertilization, blood also begins to be pumped by the heart of the human embryo. Simultaneously, blood sinuses supplied with blood from the mother develop around the outsides of the trophoblastic cords. The trophoblast cells send out more and more projections, which become placental villi into which fetal capillaries grow. Thus, the villi, carrying fetal blood, are surrounded by sinuses that contain maternal blood.

The final structure of the placenta is shown in Figure 82-5. Note that the fetus’s blood flows through two umbilical arteries, then into the capillaries of the villi, and finally back through a single umbilical veininto the fetus. At the same time, the mother’s blood flows from her uterine arteries into large maternal sinuses that surround the villi and then back into the uterine veins of the mother. The lower part of Figure 82-5 shows the relation between the fetal blood of each fetal placental villus and the blood of the mother surrounding the outsides of the villus in the fully developed placenta.


Figure 82-5 Above, Organization of the mature placenta. Below, Relation of the fetal blood in the villus capillaries to the mother’s blood in the intervillous spaces.

(Modified from Gray H, Goss CM: Anatomy of the Human Body, 25th ed. Philadelphia: Lea & Febiger, 1948; and from Arey LB: Developmental Anatomy: A Textbook and Laboratory Manual of Embryology, 7th ed. Philadelphia: WB Saunders, 1974.)

The total surface area of all the villi of the mature placenta is only a few square meters—many times less than the area of the pulmonary membrane in the lungs. Nevertheless, nutrients and other substances pass through this placental membrane mainly by diffusion in much the same manner that diffusion occurs through the alveolar membranes of the lungs and the capillary membranes elsewhere in the body.

Placental Permeability and Membrane Diffusion Conductance

The major function of the placenta is to provide for diffusion of foodstuffs and oxygen from the mother’s blood into the fetus’s blood and diffusion of excretory products from the fetus back into the mother.

In the early months of pregnancy, the placental membrane is still thick because it is not fully developed. Therefore, its permeability is low. Further, the surface area is small because the placenta has not grown significantly. Therefore, the total diffusion conductance is minuscule at first. Conversely, in later pregnancy, the permeability increases because of thinning of the membrane diffusion layers and because the surface area expands many times over, thus giving the tremendous increase in placental diffusion shown in Figure 82-4.

Rarely, “breaks” occur in the placental membrane, which allows fetal blood cells to pass into the mother or, even less commonly, the mother’s cells to pass into the fetus. Fortunately, it is rare for the fetus to bleed severely into the mother’s circulation because of a ruptured placental membrane.

Diffusion of Oxygen Through the Placental Membrane

Almost the same principles for diffusion of oxygen through the pulmonary membrane (discussed in detail in Chapter 39) are applicable for diffusion of oxygen through the placental membrane. The dissolved oxygen in the blood of the large maternal sinuses passes into the fetal blood by simple diffusion, driven by an oxygen pressure gradient from the mother’s blood to the fetus’s blood. Near the end of pregnancy, the mean PO2 of the mother’s blood in the placental sinuses is about 50 mm Hg, and the mean PO2 in the fetal blood after it becomes oxygenated in the placenta is about 30 mm Hg. Therefore, the mean pressure gradient for diffusion of oxygen through the placental membrane is about 20 mm Hg.

One might wonder how it is possible for a fetus to obtain sufficient oxygen when the fetal blood leaving the placenta has a PO2 of only 30 mm Hg. There are three reasons why even this low PO2 is capable of allowing the fetal blood to transport almost as much oxygen to the fetal tissues as is transported by the mother’s blood to her tissues.

First, the hemoglobin of the fetus is mainly fetal hemoglobin, a type of hemoglobin synthesized in the fetus before birth. Figure 82-6 shows the comparative oxygen dissociation curves for maternal hemoglobin and fetal hemoglobin, demonstrating that the curve for fetal hemoglobin is shifted to the left of that for maternal hemoglobin. This means that at the low PO2 levels in fetal blood, the fetal hemoglobin can carry 20 to 50 percent more oxygen than maternal hemoglobin can.


Figure 82-6 Oxygen-hemoglobin dissociation curves for maternal and fetal blood, showing that fetal blood can carry a greater quantity of oxygen than can maternal blood for a given blood PO2.

(Data from Metcalfe J, Moll W, Bartels H: Gas exchange across the placenta. Fed Proc 23:775, 1964.)

Second, the hemoglobin concentration of fetal blood is about 50 percent greater than that of the mother; this is an even more important factor in enhancing the amount of oxygen transported to the fetal tissues.

Third, the Bohr effect, which is explained in relation to the exchange of carbon dioxide and oxygen in the lung in Chapter 40, provides another mechanism to enhance the transport of oxygen by fetal blood. That is, hemoglobin can carry more oxygen at a low PCO2 than it can at a high PCO2. The fetal blood entering the placenta carries large amounts of carbon dioxide, but much of this carbon dioxide diffuses from the fetal blood into the maternal blood. Loss of the carbon dioxide makes the fetal blood more alkaline, whereas the increased carbon dioxide in the maternal blood makes it more acidic.

These changes cause the capacity of fetal blood to combine with oxygen to increase and that of maternal blood to decrease. This forces still more oxygen from the maternal blood, while enhancing oxygen uptake by the fetal blood. Thus, the Bohr shift operates in one direction in the maternal blood and in the other direction in the fetal blood. These two effects make the Bohr shift twice as important here as it is for oxygen exchange in the lungs; therefore, it is called the double Bohr effect.

By these three means, the fetus is capable of receiving more than adequate oxygen through the placental membrane, despite the fact that the fetal blood leaving the placenta has a PO2 of only 30 mm Hg.

The total diffusing capacity of the entire placenta for oxygen at term is about 1.2 milliliters of oxygen per minute per millimeter of mercury oxygen pressure difference across the membrane. This compares favorably with that of the lungs of the newborn baby.

Diffusion of Carbon Dioxide Through the Placental Membrane

Carbon dioxide is continually formed in the tissues of the fetus in the same way that it is formed in maternal tissues, and the only means for excreting the carbon dioxide from the fetus is through the placenta into the mother’s blood. The PCO2 of the fetal blood is 2 to 3 mm Hg higher than that of the maternal blood. This small pressure gradient for carbon dioxide across the membrane is more than sufficient to allow adequate diffusion of carbon dioxide because the extreme solubility of carbon dioxide in the placental membrane allows carbon dioxide to diffuse about 20 times as rapidly as oxygen.

Diffusion of Foodstuffs Through the Placental Membrane

Other metabolic substrates needed by the fetus diffuse into the fetal blood in the same manner as oxygen does. For instance, in the late stages of pregnancy, the fetus often uses as much glucose as the entire body of the mother uses. To provide this much glucose, the trophoblast cells lining the placental villi provide for facilitated diffusion of glucose through the placental membrane. That is, the glucose is transported by carrier molecules in the trophoblast cells of the membrane. Even so, the glucose level in fetal blood is 20 to 30 percent lower than that in maternal blood.

Because of the high solubility of fatty acids in cell membranes, these also diffuse from the maternal blood into the fetal blood, but more slowly than glucose, so that glucose is used more easily by the fetus for nutrition. Also, such substances as ketone bodies and potassium, sodium, and chloride ions diffuse with relative ease from the maternal blood into the fetal blood.

Excretion of Waste Products Through the Placental Membrane

In the same manner that carbon dioxide diffuses from the fetal blood into the maternal blood, other excretory products formed in the fetus also diffuse through the placental membrane into the maternal blood and are then excreted along with the excretory products of the mother. These include especially the nonprotein nitrogens such as urea, uric acid, and creatinine. The level of urea in fetal blood is only slightly greater than that in maternal blood because urea diffuses through the placental membrane with great ease. However, creatinine, which does not diffuse as easily, has a fetal blood concentration considerably higher than that in the mother’s blood. Therefore, excretion from the fetus depends mainly, if not entirely, on the diffusion gradients across the placental membrane and its permeability. Because there are higher concentrations of the excretory products in the fetal blood than in the maternal blood, there is continual diffusion of these substances from the fetal blood to the maternal blood.

Hormonal Factors in Pregnancy

In pregnancy, the placenta forms especially large quantities of human chorionic gonadotropin, estrogens, progesterone, and human chorionic somatomammotropin, the first three of which, and probably the fourth as well, are all essential to a normal pregnancy.

Human Chorionic Gonadotropin Causes Persistence of the Corpus Luteum and Prevents Menstruation

Menstruation normally occurs in a nonpregnant woman about 14 days after ovulation, at which time most of the endometrium of the uterus sloughs away from the uterine wall and is expelled to the exterior. If this should happen after an ovum has implanted, the pregnancy would terminate. However, this is prevented by the secretion of human chorionic gonadotropin by the newly developing embryonic tissues in the following manner.

Coincidental with the development of the trophoblast cells from the early fertilized ovum, the hormone human chorionic gonadotropin is secreted by the syncytial trophoblast cells into the fluids of the mother, as shown in Figure 82-7. The secretion of this hormone can first be measured in the blood 8 to 9 days after ovulation, shortly after the blastocyst implants in the endometrium. Then the rate of secretion rises rapidly to reach a maximum at about 10 to 12 weeks of pregnancy and decreases back to a lower value by 16 to 20 weeks. It continues at this elevated level for the remainder of pregnancy.


Figure 82-7 Rates of secretion of estrogens and progesterone, and concentration of human chorionic gonadotropin at different stages of pregnancy.

Function of Human Chorionic Gonadotropin

Human chorionic gonadotropin is a glycoprotein having a molecular weight of about 39,000 and much the same molecular structure and function as luteinizing hormone secreted by the pituitary gland. By far, its most important function is to prevent involution of the corpus luteum at the end of the monthly female sexual cycle. Instead, it causes the corpus luteum to secrete even larger quantities of its sex hormones—progesterone and estrogens—for the next few months. These sex hormones prevent menstruation and cause the endometrium to continue to grow and store large amounts of nutrients rather than being shed in the menstruum. As a result, the decidua-like cells that develop in the endometrium during the normal female sexual cycle become actual decidual cells—greatly swollen and nutritious—at about the time that the blastocyst implants.

Under the influence of human chorionic gonadotropin, the corpus luteum in the mother’s ovary grows to about twice its initial size by a month or so after pregnancy begins. Its continued secretion of estrogens and progesterone maintains the decidual nature of the uterine endometrium, which is necessary for the early development of the fetus.

If the corpus luteum is removed before approximately the seventh week of pregnancy, spontaneous abortion almost always occurs, sometimes even up to the 12th week. After that time, the placenta secretes sufficient quantities of progesterone and estrogens to maintain pregnancy for the remainder of the gestation period. The corpus luteum involutes slowly after the 13th to 17th week of gestation.

Effect of Human Chorionic Gonadotropin on the Fetal Testes

Human chorionic gonadotropin also exerts an interstitial cell–stimulating effect on the testes of the male fetus, resulting in the production of testosterone in male fetuses until the time of birth. This small secretion of testosterone during gestation is what causes the fetus to grow male sex organs instead of female organs. Near the end of pregnancy, the testosterone secreted by the fetal testes also causes the testes to descend into the scrotum.

Secretion of Estrogens by the Placenta

The placenta, like the corpus luteum, secretes both estrogens and progesterone. Histochemical and physiological studies show that these two hormones, like most other placental hormones, are secreted by the syncytial trophoblastcells of the placenta.

Figure 82-7 shows that toward the end of pregnancy, the daily production of placental estrogens increases to about 30 times the mother’s normal level of production. However, the secretion of estrogens by the placenta is quite different from secretion by the ovaries. Most important, the estrogens secreted by the placenta are not synthesized de novo from basic substrates in the placenta. Instead, they are formed almost entirely from androgenic steroid compounds, dehydroepiandrosterone and 16-hydroxydehydroepiandrosterone, which are formed both in the mother’s adrenal glands and in the adrenal glands of the fetus. These weak androgens are transported by the blood to the placenta and converted by the trophoblast cells into estradiol, estrone, and estriol. (The cortices of the fetal adrenal glands are extremely large, and about 80 percent consists of a so-called fetal zone, the primary function of which seems to be to secrete dehydroepiandrosterone during pregnancy.)

Function of Estrogen in Pregnancy

In the discussions of estrogens in Chapter 81, we pointed out that these hormones exert mainly a proliferative function on most reproductive and associated organs of the mother. During pregnancy, the extreme quantities of estrogens cause (1) enlargement of the mother’s uterus, (2) enlargement of the mother’s breasts and growth of the breast ductal structure, and (3) enlargement of the mother’s female external genitalia.

The estrogens also relax the pelvic ligaments of the mother, so the sacroiliac joints become relatively limber and the symphysis pubis becomes elastic. These changes allow easier passage of the fetus through the birth canal. There is much reason to believe that estrogens also affect many general aspects of fetal development during pregnancy, for example, by affecting the rate of cell reproduction in the early embryo.

Secretion of Progesterone by the Placenta

Progesterone is also essential for a successful pregnancy—in fact, it is just as important as estrogen. In addition to being secreted in moderate quantities by the corpus luteum at the beginning of pregnancy, it is secreted later in tremendous quantities by the placenta, averaging about a 10-fold increase during the course of pregnancy, as shown in Figure 82-7.

The special effects of progesterone that are essential for the normal progression of pregnancy are as follows:

1. Progesterone causes decidual cells to develop in the uterine endometrium, and these cells play an important role in the nutrition of the early embryo.

2. Progesterone decreases the contractility of the pregnant uterus, thus preventing uterine contractions from causing spontaneous abortion.

3. Progesterone contributes to the development of the conceptus even before implantation because it specifically increases the secretions of the mother’s fallopian tubes and uterus to provide appropriate nutritive matter for the developing morula (the spherical mass of 16 to 32 blastomeres formed before the blastula) and blastocyst. There is also reason to believe that progesterone affects cell cleavage in the early developing embryo.

4. The progesterone secreted during pregnancy helps the estrogen prepare the mother’s breasts for lactation, which is discussed later in this chapter.

Human Chorionic Somatomammotropin

A more recently discovered placental hormone is called human chorionic somatomammotropin. It is a protein with a molecular weight of about 22,000, and it begins to be secreted by the placenta at about the fifth week of pregnancy. Secretion of this hormone increases progressively throughout the remainder of pregnancy in direct proportion to the weight of the placenta. Although the functions of chorionic somatomammotropin are uncertain, it is secreted in quantities several times greater than all the other pregnancy hormones combined. It has several possible important effects.

First, when administered to several types of lower animals, human chorionic somatomammotropin causes at least partial development of the animal’s breasts and in some instances causes lactation. Because this was the first function of the hormone discovered, it was first named human placental lactogen and was believed to have functions similar to those of prolactin. However, attempts to promote lactation in humans with its use have not been successful.

Second, this hormone has weak actions similar to those of growth hormone, causing the formation of protein tissues in the same way that growth hormone does. It also has a chemical structure similar to that of growth hormone, but 100 times as much human chorionic somatomammotropin as growth hormone is required to promote growth.

Third, human chorionic somatomammotropin causes decreased insulin sensitivity and decreased utilization of glucose in the mother, thereby making larger quantities of glucose available to the fetus. Because glucose is the major substrate used by the fetus to energize its growth, the possible importance of such a hormonal effect is obvious. Further, the hormone promotes the release of free fatty acids from the fat stores of the mother, thus providing this alternative source of energy for the mother’s metabolism during pregnancy. Therefore, it appears that human chorionic somatomammotropin is a general metabolic hormone that has specific nutritional implications for both the mother and the fetus.

Other Hormonal Factors in Pregnancy

Almost all the nonsexual endocrine glands of the mother also react markedly to pregnancy. This results mainly from the increased metabolic load on the mother but also, to some extent, from the effects of placental hormones on the pituitary and other glands. Some of the most notable effects are the following.

Pituitary Secretion

The anterior pituitary gland of the mother enlarges at least 50 percent during pregnancy and increases its production of corticotropin, thyrotropin, and prolactin. Conversely, pituitary secretion of follicle-stimulating hormone and luteinizing hormone is almost totally suppressed as a result of the inhibitory effects of estrogens and progesterone from the placenta.

Increased Corticosteroid Secretion

The rate of adrenocortical secretion of the glucocorticoids is moderately increased throughout pregnancy. It is possible that these glucocorticoids help mobilize amino acids from the mother’s tissues so that these can be used for synthesis of tissues in the fetus.

Pregnant women usually have about a twofold increase in the secretion of aldosterone, reaching a peak at the end of gestation. This, along with the actions of estrogens, causes a tendency for even a normal pregnant woman to reabsorb excess sodium from her renal tubules and, therefore, to retain fluid, occasionally leading to pregnancy-induced hypertension.

Increased Thyroid Gland Secretion

The mother’s thyroid gland ordinarily enlarges up to 50 percent during pregnancy and increases its production of thyroxine a corresponding amount. The increased thyroxine production is caused at least partly by a thyrotropic effect of human chorionic gonadotropin secreted by the placenta and by small quantities of a specific thyroid-stimulating hormone, human chorionic thyrotropin, also secreted by the placenta.

Increased Parathyroid Gland Secretion

The mother’s parathyroid glands usually enlarge during pregnancy; this is especially true if the mother is on a calcium-deficient diet. Enlargement of these glands causes calcium absorption from the mother’s bones, thereby maintaining normal calcium ion concentration in the mother’s extracellular fluid even while the fetus removes calcium to ossify its own bones. This secretion of parathyroid hormone is even more intensified during lactation after the baby’s birth because the growing baby requires many times more calcium than the fetus does.

Secretion of “Relaxin” by the Ovaries and Placenta

Another substance besides the estrogens and progesterone, a hormone called relaxin, is secreted by the corpus luteum of the ovary and by placental tissues. Its secretion is increased by a stimulating effect of human chorionic gonadotropin at the same time that the corpus luteum and the placenta secrete large quantities of estrogens and progesterone.

Relaxin is a 48-amino acid polypeptide having a molecular weight of about 9000. This hormone, when injected, causes relaxation of the ligaments of the symphysis pubis in the estrous rat and guinea pig. This effect is weak or possibly even absent in pregnant women. Instead, this role is probably played mainly by the estrogens, which also cause relaxation of the pelvic ligaments. It has also been claimed that relaxin softens the cervix of the pregnant woman at the time of delivery.

Response of the Mother’s Body to Pregnancy

Most apparent among the many reactions of the mother to the fetus and to the excessive hormones of pregnancy is the increased size of the various sexual organs. For instance, the uterus increases from about 50 grams to 1100 grams, and the breasts approximately double in size. At the same time, the vagina enlarges and the introitus opens more widely. Also, the various hormones can cause marked changes in a pregnant woman’s appearance, sometimes resulting in the development of edema, acne, and masculine or acromegalic features.

Weight Gain in the Pregnant Woman

The average weight gain during pregnancy is about 25 to 35 pounds, with most of this gain occurring during the last two trimesters. Of this, about 8 pounds is fetus and 4 pounds is amniotic fluid, placenta, and fetal membranes. The uterus increases about 3 pounds and the breasts another 2 pounds, still leaving an average weight increase of 8 to 18 pounds. About 5 pounds of this is extra fluid in the blood and extracellular fluid, and the remaining 3 to 13 pounds is generally fat accumulation. The extra fluid is excreted in the urine during the first few days after birth, that is, after loss of the fluid-retaining hormones from the placenta.

During pregnancy, a woman often has a greatly increased desire for food, partly as a result of removal of food substrates from the mother’s blood by the fetus and partly because of hormonal factors. Without appropriate prenatal control of diet, the mother’s weight gain can be as great as 75 pounds instead of the usual 25 to 35 pounds.

Metabolism During Pregnancy

As a consequence of the increased secretion of many hormones during pregnancy, including thyroxine, adrenocortical hormones, and the sex hormones, the basal metabolic rate of the pregnant woman increases about 15 percent during the latter half of pregnancy. As a result, she frequently has sensations of becoming overheated. Also, owing to the extra load that she is carrying, greater amounts of energy than normal must be expended for muscle activity.

Nutrition During Pregnancy

By far the greatest growth of the fetus occurs during the last trimester of pregnancy; its weight almost doubles during the last 2 months of pregnancy. Ordinarily, the mother does not absorb sufficient protein, calcium, phosphates, and iron from her diet during the last months of pregnancy to supply these extra needs of the fetus. However, anticipating these extra needs, the mother’s body has already been storing these substances—some in the placenta, but most in the normal storage depots of the mother.

If appropriate nutritional elements are not present in a pregnant woman’s diet, a number of maternal deficiencies can occur, especially in calcium, phosphates, iron, and the vitamins. For example, the fetus needs about 375 milligrams of iron to form its blood, and the mother needs an additional 600 milligrams to form her own extra blood. The normal store of nonhemoglobin iron in the mother at the outset of pregnancy is often only 100 milligrams and almost never more than 700 milligrams. Therefore, without sufficient iron in her food, a pregnant woman usually develops hypochromic anemia. Also, it is especially important that she receive vitamin D, because although the total quantity of calcium used by the fetus is small, calcium is normally poorly absorbed by the mother’s gastrointestinal tract without vitamin D. Finally, shortly before birth of the baby, vitamin K is often added to the mother’s diet so that the baby will have sufficient prothrombin to prevent hemorrhage, particularly brain hemorrhage, caused by the birth process.

Changes in the Maternal Circulatory System During Pregnancy

Blood Flow Through the Placenta, and Maternal Cardiac Output Increases During Pregnancy

About 625 milliliters of blood flows through the maternal circulation of the placenta each minute during the last month of pregnancy. This, plus the general increase in the mother’s metabolism, increases the mother’s cardiac output to 30 to 40 percent above normal by the 27th week of pregnancy; then, for reasons unexplained, the cardiac output falls to only a little above normal during the last 8 weeks of pregnancy, despite the high uterine blood flow.

Maternal Blood Volume Increases During Pregnancy

The maternal blood volume shortly before term is about 30 percent above normal. This increase occurs mainly during the latter half of pregnancy, as shown by the curve of Figure 82-8. The cause of the increased volume is likely due, at least in part, to aldosterone and estrogens, which are greatly increased in pregnancy, and to increased fluid retention by the kidneys. Also, the bone marrow becomes increasingly active and produces extra red blood cells to go with the excess fluid volume. Therefore, at the time of birth of the baby, the mother has about 1 to 2 liters of extra blood in her circulatory system. Only about one fourth of this amount is normally lost through bleeding during delivery of the baby, thereby allowing a considerable safety factor for the mother.


Figure 82-8 Effect of pregnancy to increase the mother’s blood volume.

Maternal Respiration Increases During Pregnancy

Because of the increased basal metabolic rate of a pregnant woman and because of her greater size, the total amount of oxygen used by the mother shortly before birth of the baby is about 20 percent above normal and a commensurate amount of carbon dioxide is formed. These effects cause the mother’s minute ventilation to increase. It is also believed that the high levels of progesterone during pregnancy increase the minute ventilation even more, because progesterone increases the respiratory center’s sensitivity to carbon dioxide. The net result is an increase in minute ventilation of about 50 percent and a decrease in arterial PCO2 to several millimeters of mercury below that in a nonpregnant woman. Simultaneously, the growing uterus presses upward against the abdominal contents, which press upward against the diaphragm, so the total excursion of the diaphragm is decreased. Consequently, the respiratory rate is increased to maintain the extra ventilation.

Maternal Kidney Function During Pregnancy

The rate of urine formation by a pregnant woman is usually slightly increased because of increased fluid intake and increased load of excretory products. But in addition, several special alterations of kidney function occur.

First, the renal tubules’ reabsorptive capacity for sodium, chloride, and water is increased as much as 50 percent as a consequence of increased production of salt and water retaining hormones, especially steroid hormones by the placenta and adrenal cortex.

Second, the renal blood flow and glomerular filtration rate increase up to 50 percent during normal pregnancy due to renal vasodilation. Although the mechanisms that cause renal vasodilation in pregnancy are still unclear, some studies suggest that increased levels of nitric oxide or the ovarian hormone relaxin may contribute to these changes. The increased glomerular filtration rate likely occurs, at least in part, as a compensation for increased tubular reabsorption of salt and water. Thus, the normal pregnant woman ordinarily accumulates only about 5 pounds of extra water and salt.

Amniotic Fluid and Its Formation

Normally, the volume of amniotic fluid (the fluid inside the uterus in which the fetus floats) is between 500 milliliters and 1 liter, but it can be only a few milliliters or as much as several liters. Isotope studies of the rate of formation of amniotic fluid show that, on average, the water in amniotic fluid is replaced once every 3 hours and the electrolytes sodium and potassium are replaced an average of once every 15 hours. A large portion of the fluid is derived from renal excretion by the fetus. Likewise, a certain amount of absorption occurs by way of the gastrointestinal tract and lungs of the fetus. However, even after in utero death of a fetus, some turnover of the amniotic fluid is still present, which indicates that some of the fluid is formed and absorbed directly through the amniotic membranes.

Preeclampsia and Eclampsia

About 5 percent of all pregnant women experience a rapid rise in arterial blood pressure to hypertensive levels during the last few months of pregnancy. This is also associated with leakage of large amounts of protein into the urine. This condition is called preeclampsia or toxemia of pregnancy. It is often characterized by excess salt and water retention by the mother’s kidneys and by weight gain and development of edema and hypertension in the mother. In addition, there is impaired function of the vascular endothelium and arterial spasm occurs in many parts of the mother’s body, most significantly in the kidneys, brain, and liver. Both the renal blood flow and the glomerular filtration rate are decreased, which is exactly opposite to the changes that occur in the normal pregnant woman. The renal effects also include thickened glomerular tufts that contain a protein deposit in the basement membranes.

Various attempts have been made to prove that preeclampsia is caused by excessive secretion of placental or adrenal hormones, but proof of a hormonal basis is still lacking. Another theory is that preeclampsia results from some type of autoimmunity or allergy in the mother caused by the presence of the fetus. In support of this, the acute symptoms usually disappear within a few days after birth of the baby.

There is also evidence that preeclampsia is initiated by insufficient blood supply to the placenta, resulting in the placenta’s release of substances that cause widespread dysfunction of the maternal vascular endothelium. During normal placental development, the trophoblasts invade the arterioles of the uterine endometrium and completely remodel the maternal arterioles into large blood vessels with low resistance to blood flow. In patients with preeclampsia, the maternal arterioles fail to undergo these adaptive changes, for reasons that are still unclear, and there is insufficient blood supply to the placenta. This, in turn, causes the placenta to release various substances that enter the mother’s circulation and cause impaired vascular endothelial function, decreased blood flow to the kidneys, excess salt and water retention, and increased blood pressure.

Although the factors that link reduced placental blood supply with maternal endothelial dysfunction are still uncertain, some experimental studies suggest a role for increased levels of inflammatory cytokinessuch as tumor necrosis factor-α and interleukin-6. Placental factors that impede angiogenesis (blood vessel growth) have also been shown to contribute to increased inflammatory cytokines and preeclampsia. For example, the antiangiogenic proteins soluble fms-related tyrosine kinase 1 (s-Flt1) and soluble endoglin are increased in the blood of women with preeclampsia. These substances are released by the placenta into the maternal circulation in response to ischemia and hypoxia of the placenta. Soluble endoglin and s-Flt1 have multiple effects that may impair function of the maternal vascular endothelium and result in hypertension, proteinuria, and the other systemic manifestations of preeclampsia. However, the precise role of the various factors released from the ischemic placenta in causing the multiple cardiovascular and renal abnormalities in women with preeclampsia is still uncertain.

Eclampsia is an extreme degree of preeclampsia, characterized by vascular spasm throughout the body; clonic seizures in the mother, sometimes followed by coma; greatly decreased kidney output; malfunction of the liver; often extreme hypertension; and a generalized toxic condition of the body. It usually occurs shortly before birth of the baby. Without treatment, a high percentage of eclamptic mothers die. However, with optimal and immediate use of rapidly acting vasodilating drugs to reduce the arterial pressure to normal, followed by immediate termination of pregnancy—by cesarean section if necessary—the mortality even in eclamptic mothers has been reduced to 1 percent or less.


Increased Uterine Excitability Near Term

Parturition means birth of the baby. Toward the end of pregnancy, the uterus becomes progressively more excitable, until finally it develops such strong rhythmical contractions that the baby is expelled. The exact cause of the increased activity of the uterus is not known, but at least two major categories of effects lead up to the intense contractions responsible for parturition: (1) progressive hormonal changes that cause increased excitability of the uterine musculature and (2) progressive mechanical changes.

Hormonal Factors That Increase Uterine Contractility

Increased Ratio of Estrogens to Progesterone

Progesterone inhibits uterine contractility during pregnancy, thereby helping to prevent expulsion of the fetus. Conversely, estrogens have a definite tendency to increase the degree of uterine contractility, partly because estrogens increase the number of gap junctions between the adjacent uterine smooth muscle cells, but also because of other poorly understood effects. Both progesterone and estrogen are secreted in progressively greater quantities throughout most of pregnancy, but from the seventh month onward, estrogen secretion continues to increase while progesterone secretion remains constant or perhaps even decreases slightly. Therefore, it has been postulated that the estrogen-to-progesterone ratio increases sufficiently toward the end of pregnancy to be at least partly responsible for the increased contractility of the uterus.

Oxytocin Causes Contraction of the Uterus

Oxytocin is a hormone secreted by the neurohypophysis that specifically causes uterine contraction (see Chapter 75). There are four reasons to believe that oxytocin might be important in increasing the contractility of the uterus near term: (1) The uterine muscle increases its oxytocin receptors and, therefore, increases its responsiveness to a given dose of oxytocin during the latter few months of pregnancy. (2) The rate of oxytocin secretion by the neurohypophysis is considerably increased at the time of labor. (3) Although hypophysectomized animals can still deliver their young at term, labor is prolonged. (4) Experiments in animals indicate that irritation or stretching of the uterine cervix, as occurs during labor, can cause a neurogenic reflex through the paraventricular and supraoptic nuclei of the hypothalamus that causes the posterior pituitary gland (the neurohypophysis) to increase its secretion of oxytocin.

Effect of Fetal Hormones on the Uterus

The fetus’s pituitary gland secretes increasing quantities of oxytocin, which might play a role in exciting the uterus. Also, the fetus’s adrenal glands secrete large quantities of cortisol, another possible uterine stimulant. In addition, the fetal membranes release prostaglandins in high concentration at the time of labor. These, too, can increase the intensity of uterine contractions.

Mechanical Factors That Increase Uterine Contractility

Stretch of the Uterine Musculature

Simply stretching smooth muscle organs usually increases their contractility. Further, intermittent stretch, as occurs repeatedly in the uterus because of fetal movements, can also elicit smooth muscle contraction. Note especially that twins are born, on average, 19 days earlier than a single child, which emphasizes the importance of mechanical stretch in eliciting uterine contractions.

Stretch or Irritation of the Cervix

There is reason to believe that stretching or irritating the uterine cervix is particularly important in eliciting uterine contractions. For instance, the obstetrician frequently induces labor by rupturing the membranes so that the head of the baby stretches the cervix more forcefully than usual or irritates it in other ways.

The mechanism by which cervical irritation excites the body of the uterus is not known. It has been suggested that stretching or irritation of nerves in the cervix initiates reflexes to the body of the uterus, but the effect could also result simply from myogenic transmission of signals from the cervix to the body of the uterus.

Onset of Labor—A Positive Feedback Mechanism for Its Initiation

During most of the months of pregnancy, the uterus undergoes periodic episodes of weak and slow rhythmical contractions called Braxton Hicks contractions. These contractions become progressively stronger toward the end of pregnancy; then they change suddenly, within hours, to become exceptionally strong contractions that start stretching the cervix and later force the baby through the birth canal, thereby causing parturition. This process is called labor,and the strong contractions that result in final parturition are called labor contractions.

We do not know what suddenly changes the slow, weak rhythmicity of the uterus into strong labor contractions. However, on the basis of experience with other types of physiological control systems, a theory has been proposed for explaining the onset of labor. The positive feedback theory suggests that stretching of the cervix by the fetus’s head finally becomes great enough to elicit a strong reflex increase in contractility of the uterine body. This pushes the baby forward, which stretches the cervix more and initiates more positive feedback to the uterine body. Thus, the process repeats until the baby is expelled. This theory is shown in Figure 82-9, and the observations supporting it are the following.


Figure 82-9 Theory for the onset of intensely strong contractions during labor.

First, labor contractions obey all the principles of positive feedback. That is, once the strength of uterine contraction becomes greater than a critical value, each contraction leads to subsequent contractions that become stronger and stronger until maximum effect is achieved. Referring to the discussion in Chapter 1 of positive feedback in control systems, one can see that this is the precise nature of all positive feedback mechanisms when the feedback gain becomes greater than a critical value.

Second, two known types of positive feedback increase uterine contractions during labor: (1) Stretching of the cervix causes the entire body of the uterus to contract, and this contraction stretches the cervix even more because of the downward thrust of the baby’s head. (2) Cervical stretching also causes the pituitary gland to secrete oxytocin, which is another means for increasing uterine contractility.

To summarize, we can assume that multiple factors increase the contractility of the uterus toward the end of pregnancy. Eventually a uterine contraction becomes strong enough to irritate the uterus, especially at the cervix, and this increases uterine contractility still more because of positive feedback, resulting in a second uterine contraction stronger than the first, a third stronger than the second, and so forth. Once these contractions become strong enough to cause this type of feedback, with each succeeding contraction greater than the preceding one, the process proceeds to completion—all because positive feedback initiates a vicious circle when the gain of the feedback is greater than a critical level.

One might ask about the many instances of false labor, in which the contractions become stronger and stronger and then fade away. Remember that for a vicious circle to continue, each new cycle of the positive feedback must be stronger than the previous one. If at any time after labor starts some contractions fail to re-excite the uterus sufficiently, the positive feedback could go into a retrograde decline and the labor contractions would fade away.

Abdominal Muscle Contractions During Labor

Once uterine contractions become strong during labor, pain signals originate both from the uterus and from the birth canal. These signals, in addition to causing suffering, elicit neurogenic reflexes in the spinal cord to the abdominal muscles, causing intense contractions of these muscles. The abdominal contractions add greatly to the force that causes expulsion of the baby.

Mechanics of Parturition

The uterine contractions during labor begin mainly at the top of the uterine fundus and spread downward over the body of the uterus. Also, the intensity of contraction is great in the top and body of the uterus but weak in the lower segment of the uterus adjacent to the cervix. Therefore, each uterine contraction tends to force the baby downward toward the cervix.

In the early part of labor, the contractions might occur only once every 30 minutes. As labor progresses, the contractions finally appear as often as once every 1 to 3 minutes and the intensity of contraction increases greatly, with only a short period of relaxation between contractions. The combined contractions of the uterine and abdominal musculature during delivery of the baby cause a downward force on the fetus of about 25 pounds during each strong contraction.

It is fortunate that the contractions of labor occur intermittently, because strong contractions impede or sometimes even stop blood flow through the placenta and would cause death of the fetus if the contractions were continuous. Indeed, overuse of various uterine stimulants, such as oxytocin, can cause uterine spasm rather than rhythmical contractions and can lead to death of the fetus.

In more than 95 percent of births, the head is the first part of the baby to be expelled, and in most of the remaining instances, the buttocks are presented first. When the baby enters the birth canal with the buttocks or feet first, this is called a breech presentation.

The head acts as a wedge to open the structures of the birth canal as the fetus is forced downward. The first major obstruction to expulsion of the fetus is the uterine cervix. Toward the end of pregnancy, the cervix becomes soft, which allows it to stretch when labor contractions begin in the uterus. The so-called first stage of labor is a period of progressive cervical dilation, lasting until the cervical opening is as large as the head of the fetus. This stage usually lasts for 8 to 24 hours in the first pregnancy but often only a few minutes after many pregnancies.

Once the cervix has dilated fully, the fetal membranes usually rupture and the amniotic fluid is lost suddenly through the vagina. Then the fetus’s head moves rapidly into the birth canal, and with additional force from above, it continues to wedge its way through the canal until delivery is effected. This is called the second stage of labor, and it may last from as little as 1 minute after many pregnancies to 30 minutes or more in the first pregnancy.

Separation and Delivery of the Placenta

For 10 to 45 minutes after birth of the baby, the uterus continues to contract to a smaller and smaller size, which causes a shearing effect between the walls of the uterus and the placenta, thus separating the placenta from its implantation site. Separation of the placenta opens the placental sinuses and causes bleeding. The amount of bleeding is limited to an average of 350 milliliters by the following mechanism: The smooth muscle fibers of the uterine musculature are arranged in figures of eight around the blood vessels as the vessels pass through the uterine wall. Therefore, contraction of the uterus after delivery of the baby constricts the vessels that had previously supplied blood to the placenta. In addition, it is believed that vasoconstrictor prostaglandins formed at the placental separation site cause additional blood vessel spasm.

Labor Pains

With each uterine contraction, the mother experiences considerable pain. The cramping pain in early labor is probably caused mainly by hypoxia of the uterine muscle resulting from compression of the blood vessels in the uterus. This pain is not felt when the visceral sensory hypogastric nerves, which carry the visceral sensory fibers leading from the uterus, have been sectioned.

However, during the second stage of labor, when the fetus is being expelled through the birth canal, much more severe pain is caused by cervical stretching, perineal stretching, and stretching or tearing of structures in the vaginal canal itself. This pain is conducted to the mother’s spinal cord and brain by somatic nerves instead of by the visceral sensory nerves.

Involution of the Uterus After Parturition

During the first 4 to 5 weeks after parturition, the uterus involutes. Its weight becomes less than half its immediate postpartum weight within 1 week, and in 4 weeks, if the mother lactates, the uterus may become as small as it was before pregnancy. This effect of lactation results from the suppression of pituitary gonadotropin and ovarian hormone secretion during the first few months of lactation, as discussed later. During early involution of the uterus, the placental site on the endometrial surface autolyzes, causing a vaginal discharge known as “lochia,” which is first bloody and then serous in nature, continuing for a total of about 10 days. After this time, the endometrial surface becomes re-epithelialized and ready for normal, nongravid sex life again.


Development of the Breasts

The breasts, shown in Figure 82-10, begin to develop at puberty. This development is stimulated by the estrogens of the monthly female sexual cycle; estrogens stimulate growth of the breasts’ mammary glands plus the deposition of fat to give the breasts mass. In addition, far greater growth occurs during the high-estrogen state of pregnancy, and only then does the glandular tissue become completely developed for the production of milk.


Figure 82-10 The breast and its secretory lobules, alveoli, and lactiferous ducts (milk ducts) that constitute its mammary gland (A). The enlargements show a lobule (B) and milk-secreting cells of an alveolus (C).

Estrogens Stimulate Growth of the Ductal System of the Breasts

All through pregnancy, the large quantities of estrogens secreted by the placenta cause the ductal system of the breasts to grow and branch. Simultaneously, the stroma of the breasts increases in quantity, and large quantities of fat are laid down in the stroma.

Also important for growth of the ductal system are at least four other hormones: growth hormone, prolactin, the adrenal glucocorticoids, and insulin. Each of these is known to play at least some role in protein metabolism, which presumably explains their function in the development of the breasts.

Progesterone Is Required for Full Development of the Lobule-Alveolar System

Final development of the breasts into milk-secreting organs also requires progesterone. Once the ductal system has developed, progesterone—acting synergistically with estrogen, as well as with the other hormones just mentioned—causes additional growth of the breast lobules, with budding of alveoli and development of secretory characteristics in the cells of the alveoli. These changes are analogous to the secretory effects of progesterone on the endometrium of the uterus during the latter half of the female menstrual cycle.

Prolactin Promotes Lactation

Although estrogen and progesterone are essential for the physical development of the breasts during pregnancy, a specific effect of both these hormones is to inhibit the actual secretion of milk. Conversely, the hormone prolactin has exactly the opposite effect on milk secretion—promoting it. This hormone is secreted by the mother’s anterior pituitary gland, and its concentration in her blood rises steadily from the fifth week of pregnancy until birth of the baby, at which time it has risen to 10 to 20 times the normal nonpregnant level. This high level of prolactin at the end of pregnancy is shown in Figure 82-11.


Figure 82-11 Changes in rates of secretion of estrogens, progesterone, and prolactin for 8 weeks before parturition and 36 weeks thereafter. Note especially the decrease of prolactin secretion back to basal levels within a few weeks after parturition, but also the intermittent periods of marked prolactin secretion (for about 1 hour at a time) during and after periods of nursing.

In addition, the placenta secretes large quantities of human chorionic somatomammotropin, which probably has lactogenic properties, thus supporting the prolactin from the mother’s pituitary during pregnancy. Even so, because of the suppressive effects of estrogen and progesterone, no more than a few milliliters of fluid are secreted each day until after the baby is born. The fluid secreted during the last few days before and the first few days after parturition is called colostrum; it contains essentially the same concentrations of proteins and lactose as milk, but it has almost no fat and its maximum rate of production is about 1/100 the subsequent rate of milk production.

Immediately after the baby is born, the sudden loss of both estrogen and progesterone secretion from the placenta allows the lactogenic effect of prolactin from the mother’s pituitary gland to assume its natural milk-promoting role, and over the next 1 to 7 days, the breasts begin to secrete copious quantities of milk instead of colostrum. This secretion of milk requires an adequate background secretion of most of the mother’s other hormones as well, but most important are growth hormone, cortisol, parathyroid hormone, and insulin. These hormones are necessary to provide the amino acids, fatty acids, glucose, and calcium required for milk formation.

After birth of the baby, the basal level of prolactin secretion returns to the nonpregnant level over the next few weeks, as shown in Figure 82-11. However, each time the mother nurses her baby, nervous signals from the nipples to the hypothalamus cause a 10- to 20-fold surge in prolactin secretion that lasts for about 1 hour, which is also shown in Figure 82-11. This prolactin acts on the mother’s breasts to keep the mammary glands secreting milk into the alveoli for the subsequent nursing periods. If this prolactin surge is absent or blocked as a result of hypothalamic or pituitary damage or if nursing does not continue, the breasts lose their ability to produce milk within 1 week or so. However, milk production can continue for several years if the child continues to suckle, although the rate of milk formation normally decreases considerably after 7 to 9 months.

Hypothalamus Secretes Prolactin Inhibitory Hormone

The hypothalamus plays an essential role in controlling prolactin secretion, as it does for almost all the other anterior pituitary hormones. However, this control is different in one aspect: The hypothalamus mainly stimulatesproduction of all the other hormones, but it mainly inhibits prolactin production. Consequently, damage to the hypothalamus or blockage of the hypothalamic-hypophysial portal system often increases prolactin secretion while it depresses secretion of the other anterior pituitary hormones.

Therefore, it is believed that anterior pituitary secretion of prolactin is controlled either entirely or almost entirely by an inhibitory factor formed in the hypothalamus and transported through the hypothalamic-hypophysial portal system to the anterior pituitary gland. This factor is called prolactin inhibitory hormone. It is almost certainly the same as the catecholamine dopamine, which is known to be secreted by the arcuate nuclei of the hypothalamus and can decrease prolactin secretion as much as 10-fold.

Suppression of the Female Ovarian Cycles in Nursing Mothers for Many Months After Delivery

In most nursing mothers, the ovarian cycle (and ovulation) does not resume until a few weeks after cessation of nursing. The reason seems to be that the same nervous signals from the breasts to the hypothalamus that cause prolactin secretion during suckling—either because of the nervous signals themselves or because of a subsequent effect of increased prolactin—inhibit secretion of gonadotropin-releasing hormone by the hypothalamus. This, in turn, suppresses formation of the pituitary gonadotropic hormones—luteinizing hormone and follicle-stimulating hormone. However, after several months of lactation, in some mothers, especially in those who nurse their babies only some of the time, the pituitary begins to secrete sufficient gonadotropic hormones to reinstate the monthly sexual cycle, even though nursing continues.

Ejection (or “Let-Down”) Process in Milk Secretion—Function of Oxytocin

Milk is secreted continuously into the alveoli of the breasts, but it does not flow easily from the alveoli into the ductal system and, therefore, does not continually leak from the breast nipples. Instead, the milk must be ejected from the alveoli into the ducts before the baby can obtain it. This is caused by a combined neurogenic and hormonal reflex that involves the posterior pituitary hormone oxytocin, as follows.

When the baby suckles, it receives virtually no milk for the first half minute or so. Sensory impulses must first be transmitted through somatic nerves from the nipples to the mother’s spinal cord and then to her hypothalamus, where they cause nerve signals that promote oxytocin secretion at the same time that they cause prolactin secretion. The oxytocin is carried in the blood to the breasts, where it causes myoepithelial cells (which surround the outer walls of the alveoli) to contract, thereby expressing the milk from the alveoli into the ducts at a pressure of +10 to 20 mm Hg. Then the baby’s suckling becomes effective in removing the milk. Thus, within 30 seconds to 1 minute after a baby begins to suckle, milk begins to flow. This process is called milk ejection or milk let-down.

Suckling on one breast causes milk flow not only in that breast but also in the opposite breast. It is especially interesting that fondling of the baby by the mother or hearing the baby crying often gives enough of an emotional signal to the hypothalamus to cause milk ejection.

Inhibition of Milk Ejection

A particular problem in nursing a baby comes from the fact that many psychogenic factors or even generalized sympathetic nervous system stimulation throughout the mother’s body can inhibit oxytocin secretion and consequently depress milk ejection. For this reason, many mothers must have an undisturbed period of adjustment after childbirth if they are to be successful in nursing their babies.

Milk Composition and the Metabolic Drain on the Mother Caused by Lactation

Table 82-1 lists the contents of human milk and cow’s milk. The concentration of lactose in human milk is about 50 percent greater than in cow’s milk, but the concentration of protein in cow’s milk is ordinarily two or more times greater than in human milk. Finally, only one third as much ash, which contains calcium and other minerals, is found in human milk compared with cow’s milk.

Table 82-1 Composition of Milk


Human Milk (%)

Cow’s Milk (%)













Lactalbumin and other proteins






At the height of lactation in the human mother, 1.5 liters of milk may be formed each day (and even more if the mother has twins). With this degree of lactation, great quantities of energy are drained from the mother; approximately 650 to 750 kilocalories per liter (or 19 to 22 kilocalories per ounce) are contained in breast milk, although the composition and caloric content of the milk depends on the mother’s diet and other factors such as the fullness of the breasts. Large amounts of metabolic substrates are also lost from the mother. For instance, about 50 grams of fat enter the milk each day, as well as about 100 grams of lactose, which must be derived by conversion from the mother’s glucose. Also, 2 to 3 grams of calcium phosphate may be lost each day; unless the mother is drinking large quantities of milk and has an adequate intake of vitamin D, the output of calcium and phosphate by the lactating mammae will often be much greater than the intake of these substances. To supply the needed calcium and phosphate, the parathyroid glands enlarge greatly and the bones become progressively decalcified. The mother’s bone decalcification is usually not a big problem during pregnancy, but it can become more important during lactation.

Antibodies and Other Anti-infectious Agents in Milk

Not only does milk provide the newborn baby with needed nutrients, but it also provides important protection against infection. For instance, multiple types of antibodies and other anti-infectious agents are secreted in milk along with the nutrients. Also, several different types of white blood cells are secreted, including both neutrophils and macrophages, some of which are especially lethal to bacteria that could cause deadly infections in newborn babies. Particularly important are antibodies and macrophages that destroy Escherichia coli bacteria, which often cause lethal diarrhea in newborns.

When cow’s milk is used to supply nutrition for the baby in place of mother’s milk, the protective agents in it are usually of little value because they are normally destroyed within minutes in the internal environment of the human being.


Alexander B.T., Bennett W.A., Khalil R.A., et al. Preeclampsia: linking placental ischemia with cardiovascular-renal dysfunction. News Physiol Sci. 2001;16:282.

Augustine R.A., Ladyman S.R., Grattan D.R. From feeding one to feeding many: hormone-induced changes in bodyweight homeostasis during pregnancy. J Physiol. 2008;586:387.

Barnhart K.T. Clinical practice. Ectopic pregnancy. N Engl J Med. 2009;361:379.

Ben-Jonathan N., Hnasko R. Dopamine as a prolactin (PRL) inhibitor. Endocr Rev. 2001;22:724.

Freeman M.E., Kanyicska B., Lerant A., et al. Prolactin: structure, function, and regulation of secretion. Physiol Rev. 2000;80:1523.

Gimpl G., Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev. 2001;81:629.

Goldenberg R.L., Culhane J.F., Iams J.D., Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371:75.

Khalaf Y. ABC of subfertility: tubal subfertility. BMJ. 2003;327:610.

Labbok M.H., Clark D., Goldman A.S. Breastfeeding: maintaining an irreplaceable immunological resource. Nat Rev Immunol. 2004;4:565.

LaMarca H.L., Rosen J.M. Hormones and mammary cell fate—what will I become when I grow up? Endocrinology. 2008;149:4317.

Murphy V.E., Smith R., Giles W.B., et al. Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus. Endocr Rev. 2006;27:141.

Osol G., Mandala M. Maternal uterine vascular remodeling during pregnancy. Physiology (Bethesda). 2009;24:58.

Roberts J.M., Gammill H.S. Preeclampsia: recent insights. Hypertension. 2005;46:1243.

Shennan D.B., Peaker M. Transport of milk constituents by the mammary gland. Physiol Rev. 2000;80:925.

Sherwood O.D. Relaxin’s physiological roles and other diverse actions. Endocr Rev. 2004;25:205.

Simhan HN, Caritis SN: Prevention of preterm delivery, N Engl J Med 357:477, 2–7.

Smith R. Parturition. N Engl J Med. 2007;356:271.

Wang A., Rana S., Karumanchi S.A. Preeclampsia: the role of angiogenic factors in its pathogenesis. Physiology (Bethesda). 2009;24:147.

Wu G., Bazer F.W., Cudd T.A., et al. Maternal nutrition and fetal development. J Nutr. 2004;134:2169.


If you find an error or have any questions, please email us at Thank you!