Fertilization Pregnancy and Parturition

Once fertilization has occurred, the secondary oocyte completes meiotic division. It then undergoes mitosis, first forming a ball of cells and then an early embryonic structure called a blastocyst. Cells of the blastocyst secrete human chorionic gonadotropin, a hormone that maintains the mother's corpus luteum and its production of estradiol and progesterone.This prevents menstruation so that the embryo can implant into the endometrium,develop,and form a placenta. Birth is dependent upon strong contractions of the uterus, which are stimulated by oxytocin from the posterior pituitary.

Zona pellucida

Corona radiata

Zona pellucida

- Sperm cell nucleus inside ovum

■ Figure 20.39 The process of fertilization. As the head of the sperm cell encounters the gelatinous corona radiata of the secondary oocyte, the acrosomal vesicle ruptures and the sperm cell digests a path for itself by the action of the enzymes released from the acrosome. When the plasma membrane of the sperm cell contacts the plasma membrane of the ovum, they become continuous, and the nucleus of the sperm cell moves into the cytoplasm of the ovum.

During the act of sexual intercourse, the male ejaculates an average of 300 million sperm into the vagina of the female. This tremendous number is needed because of the high sperm fatality— only about 100 survive to enter each fallopian tube. During their passage through the female reproductive tract, the sperm gain the ability to fertilize an ovum. This process is called capacitation. Although the changes that occur in capacitation are incompletely understood, experiments have shown that freshly ejaculated sperm are infertile; they must be present in the female tract for at least 7 hours before they can fertilize an ovum.

A woman usually ovulates only one ovum a month, for a total of less than 450 ova during her reproductive years. Each ovulation releases a secondary oocyte arrested at metaphase of the second meiotic division. The secondary oocyte, as previously described, enters the uterine tube surrounded by its zona pellucida (a thin transparent layer of protein and polysaccharides) and corona radiata of granulosa cells (fig. 20.39).

Fertilization

Fertilization normally occurs in the uterine tubes. Each sperm contains a large, enzyme-filled vesicle above its nucleus, known as an acrosome, that is central to this task (fig. 20.40). The interaction of sperm with particular molecules in the zona pellucida triggers an acrosomal reaction. This involves the progressive fusion of the acrosomal membrane with the plasma membrane of the sperm, creating pores through which the acrosomal enzymes can be released by exocytosis. These enzymes, including a protein-digesting enzyme and hyaluronidase (which digests hyaluronic acid, a constituent of the extracellular matrix), allow the sperm to digest a path through the zona pellu-cida to the oocyte.

Before activation

Binding to zona pellucida stimulates fusion and exocytosis

After acrosomal reaction

Figure 20.40 The acrosome reaction. Prior to activation, the acrosome is a large, enzyme-containing vesicle over the sperm nucleus. After the sperm binds to particular proteins in the zona pellucida surrounding the egg, the acrosomal membrane fuses with the plasma membrane in many locations, creating openings through which the acrosomal contents can be released by exocytosis. When the process is complete, the inner acrosomal membrane has become continuous with the plasma membrane.

Figure 20.40 The acrosome reaction. Prior to activation, the acrosome is a large, enzyme-containing vesicle over the sperm nucleus. After the sperm binds to particular proteins in the zona pellucida surrounding the egg, the acrosomal membrane fuses with the plasma membrane in many locations, creating openings through which the acrosomal contents can be released by exocytosis. When the process is complete, the inner acrosomal membrane has become continuous with the plasma membrane.

Primary oocyte

Secondary oocyte

First polar body

First meiotic division

Secondary oocyte |-Degenerate-1

at metaphase II First polar Second polar

First polar Spindle body body body

Ovulation apparatus apparatus

Fertilization

Chromosomes

Nuclear membrane disappearing

Sperm cell nucleus

■ Figure 20.41 Changes in the oocyte following fertilization. A secondary oocyte, arrested at metaphase II of meiosis, is released at ovulation. If this cell is fertilized, it will complete its second meiotic division and produce a second polar body. The chromosomes of the two gametes are joined in the zygote.

Reproduction

As the first sperm tunnels its way through the zona pellu-cida and fuses with the plasma membrane of the oocyte, a number of changes occur that prevent other sperm from fertilizing the same oocyte. Polyspermy (the fertilization of an oocyte by many sperm) is thereby prevented; only one sperm can fertilize an oocyte. As fertilization occurs, the secondary oocyte is stimulated to complete its second meiotic division (fig. 20.41). Like the first meiotic division, the second produces one cell that contains all of the cytoplasm—the mature ovum—and one polar body. The second polar body, like the first, ultimately fragments and disintegrates.

At fertilization, the sperm cell enters the cytoplasm of the much larger egg cell. Within 12 hours, the nuclear membrane in the ovum disappears, and the haploid number of chromosomes (twenty-three) in the ovum is joined by the haploid number of chromosomes from the sperm cell. A fertilized egg, or zygote, containing the diploid number of chromosomes (forty-six) is thus formed (fig. 20.41).

It should be noted that the sperm cell contributes more than the paternal set of chromosomes to the zygote. Recent evidence demonstrates that the centrosome of the human zygote is derived from the sperm cell and not from the oocyte. As described in chapter 3, the centrosome is needed for the organization of microtubules into a spindle apparatus, so that duplicated chromosomes can be separated during mitosis. Without a centrosome to form the spindle apparatus, cell division (and hence embryonic development) cannot proceed.

A secondary oocyte that has been ovulated but not fertilized does not complete its second meiotic division, but instead disintegrates 12 to 24 hours after ovulation. Fertilization therefore cannot occur if intercourse takes place later than 1 day following ovulation. Sperm, by contrast, can survive up to 3 days in the female reproductive tract. Fertilization therefore can occur if intercourse takes place within a 3-day period prior to the day of ovulation.

■ Figure 20.42 In vitro fertilization. A needle (the shadow on the right) is used to inject a single spermatozoon into a human oocyte in vitro.

The process of in vitro fertilization is sometimes used to produce pregnancies in women with absent or damaged uterine tubes or in women who are infertile for a variety of other reasons. A secondary oocyte may be collected by aspiration following ovulation (as estimated by waiting 36 to 38 hours after the LH surge). Alternatively, a woman may be treated with powerful FSH-like hormones that cause the development of multiple follicles, and preovulatory oocytes may be collected by aspiration guided by ultrasound and laparoscopy. The donor's sperm are treated so as to duplicate normal capacitation. The oocytes may be placed in a petri dish for 2 to 3 days, along with sperm collected from the donor, or newer techniques may be used to promote fertilization. These newer techniques include ICSI (for intracytoplasmic sperm injection), which involves the microinjection of sperm through the zona pellucida directly into the ovum (fig. 20.42). A number of embryos may be produced at the same time, and the surplus frozen in liquid nitrogen for later use. The embryos are usually transferred, three or more at a time, to the woman's uterus at their four-cell stage, 48 to 72 hours after fertilization. In some cases, the embryos may be transferred to the end of the uterine tube. The likelihood of a successful implantation is low (around 35%), and the procedure is expensive. The long-term safety of fertility drugs has also been questioned.

Cleavage and Blastocyst Formation

At about 30 to 36 hours after fertilization, the zygote divides by mitosis—a process called cleavage—into two smaller cells. The rate of cleavage is thereafter accelerated. A second cleavage, which occurs about 40 hours after fertilization, produces four cells. A third cleavage about 50 to 60 hours after fertilization produces a ball of eight cells called a morula (= mulberry). This very early embryo enters the uterus 3 days after ovulation has occurred (fig. 20.43).

Continued cleavage produces a morula consisting of thirty-two to sixty-four cells by the fourth day following fertilization. The embryo remains unattached to the uterine wall for the next 2 days, during which time it undergoes changes that convert it into a hollow structure called a blastocyst (fig. 20.44). The blastocyst consists of two parts: (1) an inner cell mass, which will become the fetus, and (2) a surrounding chorion, which will become part of the placenta. The cells that form the chorion are called trophoblast cells.

On the sixth day following fertilization, the blastocyst attaches to the uterine wall, with the side containing the inner cell mass positioned against the endometrium. The trophoblast cells produce enzymes that allow the blastocyst to "eat its way" into the thick endometrium. This begins the process of implantation, or nidation, and by the seventh to tenth day the blastocyst is completely buried in the endometrium (fig. 20.45). Approximately 75% of all lost pregnancies are due to a failure of implantation, and consequently are not recognized as pregnancies.

Cleavage

Morula

Blastocyst mm tiÊù

Zygote

Implanted blastocyst

cell nucleus

Sperm cell nucleus

Fertilization cell nucleus

Sperm cell nucleus

Sperm cells

Fertilization

Corpus luteum

Maturing follicle

Secondary oocyte

■ Figure 20.43 Fertilization, cleavage, and the formation of a blastocyst. A diagram showing the ovarian cycle, fertilization, and the events of the first week following fertilization. Implantation of the blastocyst begins between the fifth and seventh day and is generally complete by the tenth day.

■ Figure 20.44 Scanning electron micrographs of preembryonic human development. A human ovum fertilized in a laboratory (in vitro) is seen at (a) the 4-cell stage. This is followed by (b) cleavage at the 16-cell stage and the formation of (c) a morula and (d) a blastocyst.

Progesterone, secreted from the woman's corpus lu-teum, is required for the endometrium to support the implanted embryo and maintain the pregnancy. A drug developed in France, and recently approved for use in the United States, promotes abortion by blocking the progesterone receptors of the endometrial cells. This drug, called RU486, has the generic name mifepristone. When combined with a small amount of a prostaglandin, which stimulates contractions of the myometrium, RU486 can cause the endometrium to slough off, carrying the embryo with it. Sometimes called the "abortion pill," RU486 has generated bitter controversy in the United States. A recent study found mifepristone followed by prostaglandin treatment to be 96% to 99% effective at terminating pregnancies of 49 days or less.

Embryonic Stem Cells and Cloning

Only the fertilized egg cell and each of the early cleavage cells are totipotent, a term that refers to their ability to create the entire organism if implanted into a uterus. The nuclei of adult somatic cells, however, can be reprogrammed to become totipotent if they are transplanted into egg cell cytoplasm. Through such somatic cell nuclear transfer, the cloning of an entire adult organism (often called reproductive cloning) is possible, and indeed has

Trophoblast Pink

Blastocyst cavity Trophoblast

Inner cell mass Embryonic pole

Endometrial epithelium

Endometrial capillary

Endometrial gland

Embryonic disc

Amniotic cavity Cytotrophoblast Syncytiotrophoblast

■ Figure 20.45 Implantation of the blastocyst. (a) A diagram showing the blastocyst attached to the endometrium on about the sixth day. (b) Implantation of the blastocyst at the ninth or tenth day.

been accomplished in sheep, cattle, cats, and other animals. The possible use of this technique to clone humans has been widely condemned by scientists and others for many reasons, including the low probability of producing healthy children.

This differs from the possibility of nuclear transplantation to produce stem cells, sometimes referred to as therapeutic cloning, for the purpose of growing specific tissues for the treatment of diseases. For example, nerve tissue produced by therapeutic cloning holds promise for the treatment of Parkinson's disease, multiple sclerosis, stroke, and spinal cord injury; cloning of islet of Langerhans beta cells may help treat diabetes mellitus; and other cloned tissues might offer new treatments for many other maladies. When nuclear transplantation is performed for the purpose of developing stem cells (therapeutic cloning), rather than for the purpose of reproductive cloning, the totipotent cell is not implanted into a uterus but is rather allowed to develop in vitro to the blastocyst stage.

Stem cell research uses cells that can be described as pluripotent or multipotent. Cells obtained from the inner cell mass of a blastocyst—termed embryonic stem (ES) cells—are pluripotent. Pluripotency refers to the ability to give rise to all tissues except the trophoblast cells of the placenta. This contrasts with adult stem cells, which have been described as multipotent because they can give rise to a number of differentiated cells. For example, neural stem cells (chapter 7) give rise to neurons and different types of glial cells, and hematopoietic stem cells (chapter 13) give rise to the different types of blood cells. There is also research suggesting that neural stem cells might be able to form blood and muscle cells, and that stem cells from the skin can be induced to develop into neurons, glial cells, smooth muscle cells, and adipocytes. The ability of adult stem cells to differentiate into such different tissue types, however, is incompletely understood and currently controversial.

In a recent report, scientists obtained neurons from cultured mouse ES cells and used these to reverse symptoms of Parkinson's disease in rats. However, the use of ES cells in this way does present some potential problems: the transplanted neurons derived from ES cells will likely be immunologically rejected by the host, and ES cells that are transplanted develop benign tumors containing different types of cells.

In another exciting recent report, scientists isolated what may be pluripotent stem cells from bone marrow cultures taken from adult humans, mice, and rats. When they injected the cells into mouse embryos, the descendants of those cells developed into almost every tissue type. It is not currently known if these cells normally exist in the bone marrow, or were created in the process of tissue culture. The scientists, hesitant at present to call these cells pluripotent, have named them "multipotent adult progenitor cells (MAPCs)." The potential health benefits of therapeutic cloning using ES cells, adult stem cells, and MAPCs have engendered excitement, hope, and ethical controversy.

Implantation of the Blastocyst and Formation of the Placenta

If fertilization does not take place, the corpus luteum begins to decrease its secretion of steroids about 10 days after ovulation. This withdrawal of steroids, as previously described, causes necrosis and sloughing of the endometrium following day 28 of the cycle. If fertilization and implantation have occurred, however, these events must obviously be prevented to maintain the pregnancy.

■ Figure 20.46 The secretion of human chorionic gonadotropin (hCG). This hormone is secreted by trophoblast cells during the first trimester of pregnancy, and it maintains the mother's corpus luteum for the first 5>2 weeks. After that time, the placenta becomes the major sex-hormone-producing gland, secreting increasing amounts of estrogen and progesterone throughout pregnancy.

Chorionic Gonadotropin

The blastocyst saves itself from being eliminated with the en-dometrium by secreting a hormone that indirectly prevents menstruation. Even before the sixth day when implantation occurs, the trophoblast cells of the chorion secrete chorionic gonadotropin, or hCG (the h stands for "human"). This hormone is identical to LH in its effects and therefore is able to maintain the corpus luteum past the time when it would otherwise regress. The secretion of estradiol and progesterone is thus maintained and menstruation is normally prevented.

IK All pregnancy tests assay for the presence of hCG in blood or urine because this hormone is secreted by ^ \ ^ the blastocyst but not by the mother's endocrine glands. Modern pregnancy tests detect the beta subunit of hCG, which is unique to hCG and provides the least amount of cross-reaction with other hormones. Accurate and sensitive immunoassays for hCG in pregnancy tests employ antibodies that are produced by a clone of lymphocytes—termed monoclonal antibodies (chapter 15)—against the specific beta subunit of hCG. Home pregnancy kits that use these antibodies are generally accurate in the week following the first missed menstrual period.

The secretion of hCG declines by the tenth week of pregnancy (fig. 20.46). Actually, this hormone is required for only the first 5 to 6 weeks of pregnancy because the placenta itself becomes an active steroid hormone-secreting gland. By the fifth to sixth week, the mother's corpus luteum begins to regress (even in the presence of hCG), but by this time the placenta is secreting more than sufficient amounts of steroids to maintain the endometrium and prevent menstruation.

Clinical Investigation Clues

Remember that Gloria's pregnancy test was negative.

■ What did they specifically test for?

■ If the test came out positive, what physiological mechanism would account for her amenorrhea?

Chorionic Membranes

Between days 7 and 12, as the blastocyst becomes completely embedded in the endometrium, the chorion becomes a two-cell-thick structure that consists of an inner cytotrophoblast layer and an outer syncytiotrophoblast layer (see fig. 20.45b). Meanwhile, the inner cell mass (which will become the fetus) also develops two cell layers. These are the ectoderm (which will form the nervous system and skin) and the endoderm (which will eventually form the gut and its derivatives). A third, middle embryonic layer—the mesoderm—is not yet seen at this stage. The embryo at this stage is a two-layer-thick disc separated from the cytotrophoblast of the chorion by an amniotic cavity.

As the syncytiotrophoblast invades the endometrium, it secretes protein-digesting enzymes that create numerous blood-filled cavities in the maternal tissue. The cytotrophoblast then forms projections, or villi (fig. 20.47), that grow into these pools of venous blood, producing a leafy-appearing structure called the chorion frondosum (frond = leaf). This occurs only on the side of the chorion that faces the uterine wall. As the embryonic structures grow, the other side of the chorion bulges into the cavity of the uterus, loses its villi, and takes on a smooth appearance.

Since the chorionic membrane is derived from the zygote, and since the zygote inherits paternal genes that produce proteins foreign to the mother, scientists have long wondered why the mother's immune system doesn't attack the embryonic tissues. The placenta, it seems, is an "immunologically privileged site." Recent studies suggest that this immune protection may be due to FAS ligand, which is produced by the cytotrophoblast. As you may recall from chapter 15, T lymphocytes produce a surface receptor called FAS. The binding of FAS to FAS ligand triggers the apoptosis (cell suicide) of those lymphocytes, thereby preventing them from attacking the placenta.

Formation of the Placenta and Amniotic Sac

As the blastocyst implants in the endometrium and the chorion develops, the cells of the endometrium also undergo changes. These changes, including cellular growth and the accumulation of glycogen, are collectively called the decidual reaction. The maternal tissue in contact with the chorion frondosum is called the decidua basalis. These two structures—chorion frondosum (fetal tissue) and decidua basalis (maternal tissue)—together form the functional unit known as the placenta.

Structural Diagram Decidua

Chorion Amnion

Amniotic sac containing amniotic fluid Yolk sac

Placenta

Villi of chorion frondosum

Placenta

Umbilical blood vessels

■ Figure 20.47 The extraembryonic membranes. After the syncytiotrophoblast has created blood-filled cavities in the endometrium, these cavities are invaded by extensions of the cytotrophoblast (a). These extensions, or villi, branch extensively to produce the chorion frondosum (b). The developing embryo is surrounded by a membrane called the amnion.

The disc-shaped human placenta is continuous at its outer surface with the smooth part of the chorion, which bulges into the uterine cavity. Immediately beneath the chorionic membrane is the amnion, which has grown to envelop the entire embryo (fig. 20.48). The embryo, together with its umbilical cord, is therefore located within the fluid-filled amniotic sac.

Amniotic fluid is formed initially as an isotonic secretion. Later, the volume is increased and the concentration changed by urine from the fetus. Amniotic fluid also contains cells that are sloughed off from the fetus, placenta, and amniotic sac. Since all of these cells are derived from the same fertilized ovum, all have the same genetic composition. Many genetic abnormalities can be detected by aspiration of this fluid and examination of the cells thus obtained. This procedure is called amniocentesis (fig. 20.49).

Amniocentesis is usually performed at about the sixteenth week of pregnancy. By this time the amniotic sac contains between 175 to 225 ml of fluid. Genetic diseases such as Down

Amniotic Fluid Between Placenta

■ Figure 20.48 The amniotic sac and placenta. Blood from the embryo is carried to and from the chorion frondosum by umbilical arteries and veins. The maternal tissue between the chorionic villi is known as the decidua basalis; this tissue, together with the chorionic villi, forms the functioning placenta. The space between chorion and amnion is obliterated, and the fetus lies within the fluid-filled amniotic sac.

syndrome (characterized by three instead of two chromosomes number 21) can be detected by examining chromosomes; diseases such as Tay-Sachs disease, in which degeneration of myelin sheaths results from a defective enzyme, can be detected by biochemical techniques.

The amniotic fluid that is withdrawn contains fetal cells at a concentration too low to permit direct determination of genetic or chromosomal disorders. These cells must therefore be cultured in vitro for 10 to i4 days before they are present in sufficient numbers for the laboratory tests required. A newer method, called chorionic villus biopsy, is now available to detect genetic disorders earlier than permitted by amniocentesis. In chorionic villus biopsy, a catheter is inserted through the cervix to the chorion and a sample of a chorionic villus is obtained by suction or cutting. Genetic tests can be performed directly on the villus sample because it contains much larger numbers of fetal cells than does a sample of amniotic fluid. Chorionic villus biopsy can provide genetic information at 12 weeks' gestation. Amniocentesis, by contrast, cannot provide such information before about 20 weeks.

Major structural abnormalities that may not be predictable from genetic analysis can often be detected by ultrasound. Sound-wave vibrations are reflected from the interface of tissues with different densities—such as the interface between the fetus and amniotic fluid—and used to produce an image. This technique is so sensitive that it can be used to detect a fetal heartbeat several weeks before it can be heard using a stethoscope.

Exchange of Molecules Across the Placenta

The umbilical arteries deliver fetal blood to vessels within the villi of the chorion frondosum of the placenta. This blood circulates within the villi and returns to the fetus via the umbilical vein. Maternal blood is delivered to and drained from the cavities within the decidua basalis that are located between the chorionic villi (fig. 20.50). In this way, maternal and fetal blood are brought close together but never mix within the placenta.

The placenta serves as a site for the exchange of gases and other molecules between the maternal and fetal blood. Oxygen diffuses from mother to fetus, and carbon dioxide diffuses in the opposite direction. Nutrient molecules and waste products likewise pass between maternal and fetal blood; the placenta is, after all, the only link between the fetus and the outside world.

Reproduction 673

The placenta is not merely a passive conduit for exchange between maternal and fetal blood, however. It has a very high metabolic rate, utilizing about a third of all the oxygen and glucose supplied by the maternal blood. The rate of protein synthesis is, in fact, higher in the placenta than in the liver. Like the liver, the placenta produces a great variety of enzymes capable of converting hormones and exogenous drugs into less active molecules. In this way potentially dangerous molecules in the maternal blood are often prevented from harming the fetus.

Endocrine Functions of the Placenta

The placenta secretes both steroid hormones and protein hormones. The protein hormones include chorionic gonadotropin (hCG) and chorionic somatomammotropin (hCS), both of which have actions similar to those of some anterior pituitary hormones (table 20.7). Chorionic gonadotropin has LH-like effects, as previously described; it also has thyroid-stimulating ability, like pituitary TSH. Chorionic somatomammotropin likewise has actions that are similar to two pituitary hormones: growth hormone and prolactin. The placental hormones hCG and hCS thus duplicate the actions of four anterior pituitary hormones.

Pituitary-like Hormones from the Placenta

The importance of chorionic gonadotropin in maintaining the mother's corpus luteum for the first 5/2 weeks of pregnancy has been previously discussed. There is also some evidence that hCG may in some way help to prevent immunological rejection of the implanting embryo. Chorionic somatomammotropin acts together with growth hormone from the mother's pituitary to produce a diabetic-like effect in the pregnant woman. The effects of these two hormones promote (1) lipolysis and increased plasma fatty acid concentration; (2) glucose-sparing by maternal tissues and, therefore, increased blood glucose concentrations;

Intervillous pool of maternal blood

Plazentaschranke Zotte

■ Figure 20.50 The circulation of blood within the placenta. Maternal blood is delivered to and drained from the spaces between the chorionic villi. Fetal blood is brought to blood vessels within the villi by branches of the umbilical artery and is drained by branches of the umbilical vein.

Amniotic fluid

Amniotic fluid

Placental Disease Hereditary

■ Figure 20.49 Amniocentesis. In this procedure, amniotic fluid containing suspended cells is withdrawn for examination. Various genetic diseases can be detected prenatally by this means.

Table 20.7 Hormones Secreted by the Placenta

Hormones

Effects

Pituitary-like Hormones Chorionic gonadotropin (hCG)

Chorionic somatomammotropin (hCS)

Similar to LH; maintains mother's corpus luteum for first 5M weeks of pregnancy; may be involved in suppressing immunological rejection of embryo; also exhibits TSH-like activity Similar to prolactin and growth hormone; in the mother, hCS acts to promote increased fat breakdown and fatty acid release from adipose tissue and to promote the sparing of glucose for use by the fetus ("diabetic-like" effects)

Sex Steroids

Progesterone

Helps maintain endometrium during pregnancy; helps suppress gonadotropin secretion; stimulates development of alveolar tissue in mammary glands

Estrogens

Help maintain endometrium during pregnancy; help suppress gonadotropin secretion; help stimulate mammary gland development; inhibit prolactin secretion; promote uterine sensitivity to oxytocin; stimulate duct development in mammary glands

and (3) polyuria (excretion of large volumes of urine), thereby producing a degree of dehydration and thirst. This diabetic-like effect in the mother helps to ensure a sufficient supply of glucose for the placenta and fetus, which (like the brain) use glucose as their primary energy source.

Steroid Hormones from the Placenta

After the first 5M weeks of pregnancy, when the corpus luteum regresses, the placenta becomes the major sex-steroid-producing gland. The blood concentration of estrogens, as a result of pla-cental secretion, rises to levels more than 100 times greater than those existing at the beginning of pregnancy. The placenta also secretes large amounts of progesterone, changing the estrogen/progesterone ratio in the blood from 100:1 at the beginning of pregnancy to close to 1:1 toward full-term.

The placenta, however, is an "incomplete endocrine gland" because it cannot produce estrogen and progesterone without the aid of precursors supplied to it by both the mother and the fetus. The placenta, for example, cannot produce cholesterol from acetate, and so it must be supplied with cholesterol from the mother's circulation. Cholesterol, which is a steroid containing twenty-seven carbons, can then be converted by enzymes in the placenta into steroids that contain twenty-one carbons—such as progesterone. The placenta, however, lacks the enzymes needed to convert progesterone into androgens (which have nineteen carbons). Therefore, androgens produced by the fetus are needed as substrates for the placenta to convert into estrogens (fig. 20.51), which have eighteen carbons.

In order for the placenta to produce estrogens, it needs to cooperate with the steroid-producing tissues (principally the adrenal cortex) in the fetus. Fetus and placenta thus form a single functioning system in terms of steroid hormone production. This system has been called the fetal-placental unit (fig. 20.51).

The ability of the placenta to convert androgens into estrogen helps to protect the female embryo from becoming masculinized by the androgens secreted from the mother's adrenal glands. In addition to producing estradiol, the placenta secretes large amounts of a weak estrogen called estriol. The production of estriol increases tenfold during pregnancy, so that by the third trimester estriol accounts for about 90% of the estrogens excreted in the mother's urine. Since almost all of this estriol comes from the placenta (rather than from maternal tissues), measurements of urinary estriol can be used clinically to assess the health of the placenta.

Maternal blood

Cholesterol —

Progesterone -«

Estrogens

Placenta

Cholesterol

Progesterone Androgens " Estrogens

Fetus

Progesterone

Androgens

■ Figure 20.51 Interactions between the embryo and placenta produce the steroid hormones. The secretion of progesterone and estrogen from the placenta requires a supply of cholesterol from the mother's blood and the cooperation of fetal enzymes that convert progesterone to androgens.

Labor and Parturition

Powerful contractions of the uterus are needed to expel the fetus in the sequence of events called labor. These uterine contractions are known to be stimulated by two agents: (1) oxytocin, a polypeptide hormone produced in the hypothalamus and released by the posterior pituitary (and also produced by the uterus itself), and (2) prostaglandins, a class of cyclic fatty acids with paracrine functions produced within the uterus. The particular prostaglandins (PGs) involved are PGF2a and PGE2. Labor can indeed be induced artificially by injections of oxytocin or by insertion of prostaglandins into the vagina as a suppository.

Although labor is known to be stimulated by oxytocin and prostaglandins, the factors responsible for the initiation of labor are incompletely understood. In all mammals, labor is initiated by activation of the fetal adrenal cortex. In mammals other than primates, the fetal hypothalamus-anterior pituitary-adrenal cortex axis sets the time of labor. Corticosteroids secreted by the fetal adrenal cortex then stimulate the placenta to convert progesterone into estrogens. This is significant because progesterone inhibits activity of the myometrium, while estrogens stimulate the ability of the myometrium to contract. However, the initiation of labor in humans and other primates is more complex. Progesterone levels do not fall because the human placenta cannot

Fetus

Placenta

Mother

Hypothalamus CRH

Hypothalamus

Dehydroepiandrosterone

Estradiol-17ß

Estriol

Placental CRH

Dehydroepiandrosterone

Estradiol-17ß

Estriol

Posterior pituitary

Oxytocin

+ Prostagland E2

Prostaglandin F2a

1. Increased receptors for oxytocin and prostaglandins

2. Increased gap junctions in myometrium

Placental CRH

Labor

■ Figure 20.52 Labor in humans. The fetal adrenal gland secretes dehydroepiandrosterone sulfate (DHEAS) and cortisol upon stimulation by CRH (corticotropin releasing hormone) and ACTH (adrenocorticotropic hormone). In turn, cortisol stimulates the placenta to secrete CRH, producing a positive feedback loop. The DHEAS is converted by the placenta into estriol, which is needed, together with prostaglandins and oxytocin, to stimulate the myometrium of the mother's uterus to undergo changes leading to labor. The plus signs emphasize activation steps critical to this process.

convert progesterone into estrogens; it can only make estrogen when it is supplied with androgens from the fetus (fig. 20.51).

The fetal adrenal lacks a medulla, but the cortex itself is composed of two parts. The outer part secretes cortisol, as does the adult adrenal cortex. The inner part, called the fetal adrenal zone, secretes the androgen dehydroepiandrosterone sulfate (DHEAS). Once the DHEAS from the fetus travels to the pla centa, it is converted into estrogens. The rising secretion of estrogens (primarily estriol), in turn, stimulates the uterus to (1) produce receptors for oxytocin; (2) produce receptors for prostaglandins; and (3) produce gap junctions between myome-trial cells in the uterus (fig. 20.52). The increase in oxytocin and prostaglandin receptors makes the myometrium more sensitive to these agents. The gap junctions (which function as electrical synapses—see chapter 7) help to synchronize and coordinate the contractions of the uterus.

This chain of events may be set in motion by the placenta, through its secretion of corticotropin-releasing hormone (CRH). The CRH produced by the placenta, like the CRH produced by the hypothalamus (chapter 11), stimulates the anterior pituitary to secrete ACTH (adrenocorticotropic hormone). There is also evidence for CRH receptors in the fetal adrenal gland, suggesting that the CRH produced by the placenta can itself stimulate adrenal secretion. Thus, CRH from the placenta directly and indirectly (via stimulation of ACTH secretion) stimulates the fetal adrenal cortex to secrete cortisol and DHEAS.

The secretion of cortisol from the fetal adrenal cortex helps to promote maturation of the fetus's lungs; it also stimulates the placenta to secrete CRH, resulting in a positive feedback loop that also increases secretion of DHEAS (fig. 20.52). The placenta can then convert the increased amounts of DHEAS into increased amounts of estriol. The estriol, in turn, activates the myometrium to become more sensitive to oxytocin and prostaglandins, as previously described. Thus, the chain of events the culminates in parturition may be set in motion by the placenta's secretion of CRH. How this "placental clock" is timed, however, is not currently understood.

Studies in rhesus monkeys demonstrate that there is a rise in the oxytocin concentration of the mother's plasma during the night, but not during the day. The uterus also produces oxytocin, which may act as a paracrine regulator along with prosta-glandins to stimulate contractions and supplement the actions of the oxytocin released by the posterior pituitary. The concentration of oxytocin receptors in the myometrium increases dramatically as a result of estrogen stimulation, as previously described, making the uterus more sensitive to oxytocin. These effects culminate in parturition, or childbirth.

Following delivery of the baby, oxytocin is needed to maintain the muscle tone of the myometrium and to reduce hemorrhaging from uterine arteries. Oxytocin may also play a role in promoting the involution (reduction in size) of the uterus following delivery; the uterus weighs about 1 kg (2.2 lb) at term but only about 60 g (2 oz) by the sixth week following delivery.

Pectoralis minor

Deep fascia

Lobe

J V;

Lobule

■" i * r

\

M 2

ù

Sex And Nipple Stimulation For Labor

Secondary tubules

Moon

Ampulla

■ Figure 20.53 The structure of the breast and mammary glands. (a) A sagittal section and (b) an anterior view partially sectioned.

Genetic screening of neonates (newborns) is done in hospitals using only a drop of blood obtained by pricking the foot. Most of these blood tests do not involve DNA or chromosomal testing, yet they can detect a variety of genetic disorders, including phenylketonuria, hypothyroidism, cystic fibrosis, hemoglobin disorders such as sickle-cell anemia, and many others. Also, umbilical cord blood banking may be performed after birth. As described in chapter 13, this is done because the umbilical cord blood contains a high concentration of hematopoietic stem cells, which can replenish the blood cell forming ability of bone marrow that has been damaged (by chemotherapy of leukemia, for example). Indeed, one unit of cord blood can reconstitute a person's entire hematopoietic system. Using banked umbilical cord blood for transplantation later in life minimizes immunological rejection.

Lactation

Each mammary gland is composed of fifteen to twenty lobes, divided by adipose tissue. The amount of adipose tissue determines the size and shape of the breast but has nothing to do with the ability of a woman to nurse. Each lobe is subdivided into lobules, which contain the glandular alveoli (fig. 20.53) that secrete the milk of a lactating female. The clustered alveoli secrete milk into a series of secondary tubules. These tubules converge to form a series of mammary ducts, which in turn converge to form a lactiferous duct that drains at the tip of the nipple. The lumen of each lactiferous duct expands just beneath the surface of the nipple to form an ampulla, where milk accumulates during nursing.

The changes that occur in the mammary glands during pregnancy and the regulation of lactation provide excellent examples of hormonal interactions and neuroendocrine regulation. Growth and development of the mammary glands during pregnancy requires the permissive actions of insulin, cortisol, and thyroid hormones. In the presence of adequate amounts of these hormones, high levels of progesterone stimulate the development of the mammary alveoli and estrogen stimulates proliferation of the tubules and ducts (fig. 20.54).

The production of milk proteins, including casein and lact-albumin, is stimulated after parturition by prolactin, a hormone secreted by the anterior pituitary. The secretion of prolactin is controlled primarily by prolactin-inhibiting hormone (PIH), which is believed to be dopamine produced by the hypothalamus and secreted into the portal blood vessels. The secretion of PIH is stimulated by high levels of estrogen. In addition, high levels of estrogen act directly on the mammary glands to block their stimulation by prolactin. During pregnancy, consequently, the high levels of estrogen prepare the breasts for lactation but prevent prolactin secretion and action.

After parturition, when the placenta is expelled as the afterbirth, declining levels of estrogen are accompanied by an in crease in the secretion of prolactin. Milk production is therefore stimulated. If a woman does not wish to breast-feed her baby she may take oral estrogens to inhibit prolactin secretion. A different drug commonly given in these circumstances, and in other conditions in which it is desirable to inhibit prolactin secretion, is bromocriptine. This drug binds to dopamine receptors, and thus promotes the action of dopamine. The fact that this action inhibits prolactin secretion offers additional evidence that dopamine functions as the prolactin-inhibiting hormone (PIH).

The act of nursing helps to maintain high levels of pro-lactin secretion via a neuroendocrine reflex (fig. 20.55). Sensory endings in the breast, activated by the stimulus of suckling, relay impulses to the hypothalamus and inhibit the secretion of PIH. There is also indirect evidence that the stimulus of suckling may cause the secretion of a prolactin-releasing hormone, but this is controversial. Suckling thus results in the reflex secretion of high levels of prolactin that promotes the secretion of milk from the alveoli into the ducts. In order for the baby to get the milk, however, the action of another hormone is needed.

The stimulus of suckling also results in the reflex secretion of oxytocin from the posterior pituitary. This hormone is produced in the hypothalamus and stored in the posterior pituitary; its release results in the milk-ejection reflex, or milk letdown. This is because oxytocin stimulates contraction of the lactiferous ducts as well as of the uterus.

Anterior pituitary

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Hypothalamus

Mammary glands

Placenta

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Responses

  • rita
    What are fertilization implantation and parturition?
    10 months ago

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