FERTILIZATION, PLACENTATION, AND LACTATION

Published on 19/03/2015 by admin

Last modified 22/04/2025

Print this page

This article have been viewed 3293 times

23 FERTILIZATION, PLACENTATION, AND LACTATION

FERTILIZATION

Two events must occur before fertilization: (1) sperm maturation in the epididymis and (2) sperm capacitation in the female reproductive tract.

Sperm released from the testis and entering the epididymal duct have circular motion. After a 2-week maturation process, following epididymal transit and storage in the tail or cauda of the epididymis, sperm acquire forward motility necessary for fertilization. After ejaculation, sperm undergo a capacitation process in the uterus and fertilization of the ovum or egg takes place in the oviduct.

Essentially, a fertilizing sperm must complete both maturation and capacitation before sperm-egg fusion. Capacitation is a biochemical event that can be induced in vitro, a procedure that permits in vitro fertilization. During capacitation, non-covalently bound epididymal and seminal glycoproteins are removed from the sperm plasma membrane. Membrane permeability to Ca²⁺ increases. An influx of Ca²⁺ maximizes intracellular cyclic adenosine monophosphate (cAMP) levels, resulting in an increase in sperm motility. This process is known as hyperactivation.

We have seen that the sperm head consists of three components: (1) the condensed elongated nucleus, (2) the acrosomal sac bound to the acroplaxome, a cytoskeletal plate anchoring the acrosome to the nuclear envelope, and (3) the plasma membrane. The head-tail coupling apparatus, containing a pair of centrioles and associated proteins, links the sperm head to its tail.

The condensed nucleus consists of DNA surrounded by very basic protamines. Nucleosomes are not present because somatic histones have been replaced by protamines that protect and stabilize the DNA during fertilization.

The acrosomal sac is formed by three constituents (Figure 23-1): (1) the outer acrosomal membrane, (2) the inner acrosomal membrane, and (3) hydrolytic enzymes (mainly hyaluronidase and acrosin, the latter derived from the precursor proacrosin). The thin portion of the acrosomal sac, extending toward the tail, is the equatorial segment.

Figure 23-1 Acrosome reaction

The three main events during fertilization are, sequentially the acrosome reaction, sperm binding to ZP3, a glycoprotein of the zona pellucida (ZP), and sperm-egg fusion (Figure 23-2).

Figure 23-2 Fertilization

In the proximity of the ovum, and in the presence of Ca²⁺, the sperm plasma membrane fuses with the outer acrosomal membrane. This event is known as the acrosome reaction. Small openings created by membrane fusion facilitate the release of hydrolytic enzymes (see Figures 23-1 and 23-2). The equatorial region of the acrosome does not participate in the plasma membrane-outer acrosome membrane fusion process. Male infertility may occur when the acrosome reaction fails to occur or takes place before the sperm reaches the egg.

Two membrane proteins have been shown to be essential for sperm-egg fusion, Izumo in the sperm and CD9 in the egg. Izumo is a sperm-specific membrane protein of the immunoglobulin superfamily that localizes to the sperm plasma membrane after the acrosomal reaction. CD9 is a member of the tetraspanin super family of transmembrane proteins (see Box 23-A). Izumo and CD9 may be involved in the organization or stabilization of plasma membrane protein complexes essential for the sperm-egg fusion reaction. Other proteins, such as ADAMs (a disintegrin and metalloprotease), may participate in this reaction. We discussed in Chapter 1, Epithelium, how the disintegrin domain of ADAMs participates in the shedding of the ectoplasmic portion of transmembrane proteins.

Box 23-A Tetraspanins

• Tetraspanins, first discovered on the human leukocyte surface, have four transmembrane domains, two extracellular loops (small and large), and short intracytoplasmic N- and C-terminal tails.

• The transmembrane domains enable the association of additional tetraspanins to assemble the tetraspanin web in which integrins are included. Tetraspanins function as surface organizers by grouping and interconnecting specific cell surface proteins.

• The large extracellular loop is involved in protein-protein interaction with laterally positioned proteins.

• The intracellular short tails are linked to intracellular cytoskeletal and signaling molecules.

• Tetraspanins behave as metastasis suppressor molecules. Decreased expression of tetraspanins correlates with increased invasive and metastasis potential.

Sperm-egg fusion causes a local mild depolarization of the egg plasma membrane that generates a calcium wave across the egg’s cytoplasm within 5 to 20 seconds. An increase in calcium concentration amplifies the depolarization signal and triggers the oocyte to resume cell division, complete meiosis II by releasing the second polar body into the perivitelline space, and start the early embryogenesis developmental program.

Zona pellucida during fertilization

The plasma membrane of mammalian eggs is surrounded by a 6- to 7-μm-thick zona pellucida (plural zonae pellucidae), a glycoprotein coat produced mainly by the primary oocyte during folliculogenesis, as early as during the primary follicle stage. The zona pellucida has important roles in fertilization and implantation of the embryo in the endometrium. In vitro fertilization overcomes most forms of infertility (see Box 23-B)

Box 23-B In vitro fertilization

• Fertilization of human sperm and eggs in vitro consists in the following steps:

• Preovulatory oocytes (about 10 or more) are collected by laparoscopy or transvaginally guided by ultrasound imaging, following stimulation of the ovaries by gonadotropin-releasing hormone and follicle-stimulating hormone administration. Oocytes are retrieved 34 to 38 hours after injection of human chorionic gonadotropin to mimic the luteinizing hormone surge.

• The oocytes are incubated overnight with motile sperm in a defined culture medium to achieve fertilization in vitro. Embryos can then be transferred to the patient.

• Alternatively, in cases of a severe male infertility factor, a sperm can be injected into the oocyte by the process of intracytoplasmatic sperm injection (ICSI).

• In cases of azoospermia (absence of sperm in the ejaculate), sperm can be obtained surgically from the epididymis or the testes and used for ICSI.

• Embryos can be tested in vitro for the presence of a genetic or chromosomal abnormality by a procedure known as preimplantation genetics diagnosis. A sample can be a blastomere of the embryo, a piece of the trophoectoderm or even the oocyte polar body. Unaffected embryos can then be transferred to the patient.

• An excess of embryos can be cryopreserved in liquid nitrogen for later use. Propanediol or dimethylsulphoxide can be used as cryoprotectant for pre-blastocyst embryos, and glycerol is used for blastocysts.

The zona pellucida is composed of three glycoproteins (see Figure 23-2): ZP1, a dimer of 200 kd; ZP2, 120 kd; and ZP3, 83 kd. ZP2 and ZP3 interact to form a long filament complex interconnected by ZP1 dimers at regular intervals.

There are four functional aspects related to ZP3 that you should remember: (1) ZP3 is responsible for sperm binding, mediated by O-oligosaccharides linked to ZP3 with binding affinity to sperm receptors. (2) Only acrosome-reacted sperm can interact with ZP3. (3) ZP3 is essential for species specific sperm binding, preventing sperm from a different species from fertilizing the egg. (4) After the first sperm fertilizes the egg, proteases released from the cortical granules present in the egg remove oligosaccharides from ZP3 and partially cleave ZP2. This process, called cortical reaction, prevents polyspermy, an egg to be fertilized by more than one sperm. Polyspermy results in nonviable zygotes.

PLACENTATION

The placenta and embryonic-fetal membranes (amnion, chorion, allantois, and yolk sac) protect the embryo-fetus and provide for nutrition, respiration, excretion, and hormone production during development. The membranes are formed by the embryo. Both the embryo and the maternal endometrium begin to form the placenta as soon as the blastocyst implants in the endometrium.

You have learned in your Embryology course the pre-implantation developmental steps of embryo following fertilization in the ampulla of the oviduct. As you may recall, the first rounds of cell divisions of the zygote (the fertilized egg) are designated cleavage. The daughter cells are named blastomeres. The embryo consists of a compact or ball structure, called morula, once it has attained an 8-cell number.

Cell diversity is achieved in the blastocyst, when the trophectoderm and inner cell mass are recognized. In the late blastocyst, the trophectoderm is referred to trophoblast and is distributed in two regions: in direct contact with the inner cell mass, the polar trophoblast, and surrounding the blastocyst cavity, the mural trophoblast. The blastocyst hatches from its zona pellucida at 6 to 7 days and the the differentiation of the inner cell mas proceeds.

Implantation of the blastocyst

The implantation of the blastocyst into a nurturing endometrium involves (1) the initial unstable adhesion of the blastocyst to the endometrial surface, called apposition, followed by a stable adhesion phase and (2) the decidualization of the endometrial stroma (Figure 23-3).

Figure 23-3 Implantation of the blastocyst

The timing of preimplantation and implantation is extremely precise (see Box 23-C). So is the preparation of the implantation site.

Box 23-C Timetable of implantation

• Fertilization occurs in the oviduct or fallopian tube within 24 to 48 hours after ovulation.

• The development of the fertilized egg, called zygote, to the morula stage, occurs as the embryo—surrounded by the zona pellucida—travels through the fallopian tube.

• The morula appears in the uterine cavity about 2 to 3 days after fertilization.

• The embryo, now a blastocyst, hatches from the zona pellucida 72 hours after entering the uterine cavity.

• Implantation occurs 6 or 7 days after fertilization. Implantation involves two stages: (1) apposition of the blastocyst to the endometrial surface and (2) implantation of the blastocyst mediated by penetrating trophoblastic cells.

• The blastocyst is entirely embedded in the receptive endometrium by day 10 after fertilization. Uterine receptivity–corresponding to days 20 to 24 of a regular 28-day menstrual cycle—is defined by the optimal state of endometrial maturation for the implantation of the blastocyst. Uterine receptivity consists in a vascular and edematous endometrial stroma, secretory endometrial glands, and apical microprocesses, the pinopodes, on the apical domain of the luminal endometrial lining cells.

• Differentiated syncytiotrophoblastic cells invade part of the myometrium (interstitial invasion), as well as local uterine blood vessels (endovascular invasion).

• The uteroplacental circulation is established when trophoblastic cells are in direct contact with maternal blood (see Box 23-D).

On day 4 of pregnancy, the embryo—at the blastocyst stage—is within the uterine cavity. The coordinated effect of ovarian estrogens and progesterone has already conditioned the endometrium for implantation, including an increase in endometrial vascular permeability at the implantation site.

The blastocyst hatches from the zona pellucida and exposes its trophoblast epithelial lining to the uterine luminal epithelium. If zona pellucida hatching fails to occur, the embryo will not implant. Failure of the uterine stroma to undergo decidualization can lead to spontaneous abortion.

Trophoblast-mediated attachment and subsequent implantation depend on two conditions: (1) the apical surface of the endometrial epithelial cell must display membrane bound and soluble forms of heparin-bound epidermal growth factorlike factor (HB-EGF), a member of the transforming growth factor-α family; and (2) the surface of the trophoectoderm cells must autophosphorylate epidermal growth factor receptor (EGF-R) and have heparan sulfate proteoglycan (also called perlecan) to strongly bind to HB-EGF.

At implantation (see Figure 23-3), cytoplasmic processes of trophoblastic cells interact with small processes on the apical surface of the endometrial epithelial cells, called pinopodes, and penetrate the intercellular spaces of the endometrial cells. Penetration is facilitated by a decrease in the number of desmosomes linking the endometrial epithelial cells that undergo apoptosis.

As you recall, the endometrial lamina propria has undergone a decidual transformation during the secretory phase of the menstrual cycle. This primary decidual zone is remodeled by the action of metalloproteinases (see Figure 23-5), and a secondary decidual zone houses the implanting embryo.

Differentiation of the trophoblast

The trophoblast differentiates into (1) an inner layer of mitotically active mononucleated cytotrophoblastic cells and (2) an outer layer of multinucleated syncytiotrophoblastic cells at the embryonic pole, facing the endometrium. The syncytiotrophoblast mass invades the endometrium (formed by glands, stroma, and blood vessels) and rapidly surrounds the entire embryo.

The blastocyst has a cavity containing fluid and the eccentric inner cell mass, which gives rise to the embryo and some extraembryonic tissues. The mural trophoblastic cells proximal to the inner cell mass begin to develop the chorionic sac. The chorionic sac consists of two components: the trophoblast and the underlying extraembryonic mesoderm.

Invasion of the endometrium and the inner third of the myometrium, a process called interstitial invasion, is determined by the action of secretory proteolytic enzymes released by the syncytiotrophoblast. Proteases erode the branches of the spiral uterine arteries to form spaces or lacunae of maternal blood within the syncytiotrophoblast mass. This endometrial eroding event, called endovascular invasion, initiates the primitive uteroplacental circulation and represents the starting point of the future intervillous space. Decidualization allows an orderly access of trophoblastic cells to the maternal nutrients by modulating the invasion of uterine spiral arteries.

The syncytiotrophoblast begins the secretion of human chorionic gonadotropin (hCG) into the maternal lacunae. The secretion of estrogens and progesterone by the corpus luteum is now under the control of hCG.

Role of the decidual cells during implantation

On the maternal side, decidual cells, close to the mass of invading syncytiotrophoblastic cells, degenerate and release glycogen and lipids, thus providing, together with maternal blood in the lacunae, the initial nutrients for embryonic development.

The decidua provides an immune-protective environment for the development of the embryo. The decidual reaction involves (1) the production of immunosuppressive substances (mainly prostaglandins) by decidual cells to inhibit the activation of natural killer cells at the implantation site and (2) infiltrating leukocytes in the endometrial stroma that secrete interleukin-2 to prevent maternal tissue rejection of the implanting embryo. Syncytiotrophoblastic cells do not express major histocompatibility complex class II. Therefore, the syncytiotrophoblast cannot present antigens to maternal CD4⁺ T cells.

Formation of primary, secondary, and tertiary villi

At the end of the second week, cytotrophoblastic cells proliferate under the influence of the extraembryonic mesoderm, and extend into the syncytiotrophoblast mass, forming the primary villi (Figure 23-4).

Figure 23-4 Primary and secondary chorionic villi

Figure 23-5 Tertiary chorionic villi (3rd week, late)

Primary villi represent the first step in the development of the chorionic villi of the placenta. In cross section, a primary villus is formed by a core of cytotrophoblastic cells covered by syncytiotrophoblast.

Early in the third week, the extraembryonic mesoderm extends into the primary villi, forming the secondary villi (see Figure 23-4). Secondary villi cover the entire surface of the chorionic sac. In cross section, a secondary villus is formed by a core of extraembryonic mesoderm surrounded by a middle cytotrophoblast layer and an outer layer of syncytiotrophoblast.

Soon after, cells of the extraembryonic mesoderm differentiate into capillary and blood cells, forming the tertiary villi (Figure 23-5). The difference between the secondary and tertiary villi is the presence of capillaries in the latter. The capillaries in the tertiary villi interconnect to form arteriocapillary networks leading to the embryonic heart.

In cross section, a tertiary villus is formed by a core of extraembryonic mesoderm with capillaries, surrounded by a middle cytotrophoblast layer and an outer layer of syncytiotrophoblast.

The following events occur as the chorionic tertiary villi continue to develop:

1. Cytotrophoblastic cells extend beyond the syncytiotrophoblast to form the cytotrophoblastic shell, attaching the chorionic sac to the endometrium.

2. Some villi, the stem or anchoring villi, attach to the cytotrophoblastic shell.

3. Branch or terminal villi grow from the sides of the stem villi and are in direct contact with maternal blood in the intervillous space.

The chorionic villi cover the entire chorionic sac until the beginning of the eighth week. Then, villi associated with the decidua capsularis degenerate, forming a smooth chorion (chorion laeve).

Histologic features of the placenta

The mature placenta is 3 cm thick, has a diameter of 20 cm, and weighs about 500 g. The fetal side is smooth and associated with the amniotic membrane. The maternal side is partially subdivided into 10 or more lobes by decidual septa derived from the decidua basalis and extending toward the chorionic plate. The decidual septa do not fuse with the chorionic plate.

Each lobe contains 10 or more stem villi and its branches. The 50- to 60-cmlong and 12-mm-thick and twisted umbilical cord is attached to the chorionic plate and contains two umbilical arteries (transporting deoxygenated blood) and one umbilical vein (transporting oxygen-rich blood). The umbilical vessels (Figure 23-6) are embedded in embryonic connective tissue, called Wharton’s jelly (see Chapter 4, Connective Tissue). The cord is lined by amniotic epithelium.

Figure 23-6 Differences between umbilical vein and umbilical artery

Maternal and fetal components

The placenta consists of a maternal and a fetal component (Figure 23-7). The maternal component is represented by the decidua. The decidua (Latin deciduus, falling off; a tissue shed at birth) is the endometrium of the gravid uterus.

Figure 23-7 Uterine and fetal membranes

There are three regions of the decidua, named according to their relation to the developing fetus:

1. The decidua basalis is the maternal component of the placenta. Chorionic villi facing the decidua basalis are highly developed and form the chorion frondosum (bushy chorion).

2. The decidua capsularis is the superficial layer covering the developing fetus and its chorionic sac.

3. The decidua parietalis is the rest of the decidua lining the cavity of the uterus not occupied by the fetus.

The fetal component is represented by the chorion frondosum. The chorion frondosum consists of the chorionic plate and derived villi. Chorionic villi facing the decidua capsularis atrophy, resulting in the formation of the chorion laeve (smooth chorion).

The intervillous space between the maternal and fetal components contains circulating maternal blood (Figures 23-8 and 23-9). Arterial blood, derived from the open ends of the spiral arteries, flows into the intervillous space and moves blood into the uterine veins. A plug of cytotrophoblastic cells and the contraction of the smooth muscle wall of the artery control the flow of blood.

Figure 23-8 Anatomy and histology of the placenta

Figure 23-9 Structure of the chorionic villus

Placental blood circulation

Placental blood circulation has two relevant characteristics: (1) the fetal blood circulation is closed (within blood vessels). (2) The maternal blood circulation is open (not bound by blood vessels). Maternal blood enters the intervillous space under reduced pressure, regulated by the cytotrophoblastic cell plugs, and leaves through the uterine veins after exchanges occur with the fetal blood in the terminal branched villi (see Box 23-D).

Box 23-D Trophoblastic cells

• The blastocyst has two distinct cell populations: (1) trophoblastic cells, derived from the trophoectoderm and surrounding the blastocyst; and (2) the inner cell mass, which gives rise to the embryo.

• Trophoblastic cells (the collective designation of cytotrophoblastic cells and syncytiotrophoblastic cells) are always the outermost layer of fetal cells covering the mesenchyme and fetal capillaries of the chorionic villi.

• The wall of maternal blood vessels is infiltrated and ruptured by trophoblastic cells. Maternal blood is released into the intervillous space, and the outer layer of the chorionic villi (syncytiotrophoblastic cells) is immersed in maternal blood like a sponge in a container of blood.

• The uterine spiral arteries are converted to uteroplacental arteries. Trophoblastic cells replace the endothelium and tunica media of the uteroplacental arteries, which deliver blood, at low pressure, to the intervillous space. Basal straight arteries are not involved in these changes.

• When trophoblast cell replacement of spiral arteries is incomplete, the development of uteroplacental arteries is deficient and blood flow is reduced. Reduced development of the branches of the chorionic villus tree, and limited fetal growth, a manifestation of preeclampsia, occur.

The umbilical vein has a subendothelial elastic lamina; the two umbilical arteries lack an elastic lamina (see Figure 23-6). The umbilical vein carries 80% oxygenated fetal blood. Although the partial pressure of oxygen in fetal blood is low (20 to 25 mm Hg), the higher cardiac output in organ blood flow, higher hemoglobin concentration in fetal red blood cells, and higher oxygen saturation provide adequate oxygenation to the fetus. The umbilical arteries return deoxygenated fetal blood to the placenta.

Structure of the chorionic villus

The chorionic villus is the basic structure involved in maternal-fetal exchanges. It originates from the chorionic plate and is formed by a stem villus giving rise to villous branches. When you examine a histologic preparation of placenta, you are visualizing cross sections of villi corresponding to the villous branches. You may also be able to see a longitudinal section of a stem villus.

Each villus has a core of mesenchymal connective tissue and fetal blood vessels (arterioles and capillaries).

The mesenchymal core contains two major cell types:

1. Mesenchymal cells, which differentiate into fibroblasts, involved in the synthesis of various types of collagens (types I, III, V, and VI) and extracellular matrix components (Figure 23-10).

2. Hofbauer cells, phagocytic cells predominant in early pregnancy.

Figure 23-10 Fine structure of the chorionic villus

The mesenchymal core is covered by two cell types:

1. Syncytiotrophoblastic cells, in contact with the maternal blood in the intervillous space.

2. Cytotrophoblastic cells, subjacent to the syncytiotrophoblast and supported by a basal lamina.

Several important structural characteristics define the cytotrophoblast and syncytiotrophoblast:

1. Cytotrophoblastic cells divide by mitosis and differentiate into syncytiotrophoblastic cells. In contrast, the syncytiotrophoblastic cell is postmitotic.

2. Cytotrophoblastic cells are linked to each other and to the overlying syncytiotrophoblast by desmosomes.

3. The apical surface of the syncytiotrophoblast contains numerous microvilli.

4. Deposits of fibrin are frequently seen on the villus surface on areas lacking syncytiotrophoblastic cells and preceding reepithelialization.

Fetal vessels are separated from maternal blood in the intervillous space by the placental barrier (Figure 23-11), which is formed by (1) endothelial cells and basal lamina of the fetal blood capillaries and (2) the cytotrophoblast and syncytiotrophoblast and supporting basal lamina.

Figure 23-11 Components of the placental barrier

After the fourth month of pregnancy, the fetal blood vessels become dilated and are in direct contact with the subepithelial basal lamina. Cytotrophoblastic cells decrease in number and syncytiotrophoblastic cells predominate. The fetal connective tissue of the villus is not prevalent in the mature placenta.

Clinical significance: Disorders of the placenta

Ectopic pregnancy

The implantation of the blastocyst outside the uterine cavity is called ectopic pregnancy. About 95% of ectopic gestations occur in the oviduct (tubal pregnancy), mainly in the ampullary region. A predisposing factor is salpingitis, an inflammatory process of the oviduct.

A major complication is profuse bleeding and rupture of the wall of the oviduct caused by the trophoblastic erosion of blood vessels and tissue layers. Abdominal pain, amenorrhea, and vaginal bleeding in a sexually active woman of reproductive age are symptoms of a suspected tubal pregnancy. A rapid and precise diagnosis of ectopic pregnancy is essential to reduce the risk of complications or death.

Placenta previa (second half of pregnancy)

The abnormal extension of the placenta over or close to the internal opening of the cervical canal is called placenta previa. A possible cause is abnormal vascularization.

There are three types of placenta previa (Figure 23-12): (1) low implantation of the placenta, when the margin of the placenta lies close to the internal cervical os (marginal placenta previa); (2) partial placenta previa, when the edge of the placenta extends across part of the internal ostium; and (3) total placenta previa, when the placenta covers the internal cervical ostium.

Figure 23-12 Abnormal implantation of the placenta

Spontaneous painless bleeding, caused by partial separation of the placenta from the lower portion of the uterus and cervix due to mild uterine contractions, is commonly observed.

Placental abruption, or abruptio placentae (second half of pregnancy)

The premature separation of the normally implanted placenta is called placental abruption. Hemorrhage into the decidua basalis leads to premature placental separation and bleeding. Separation of the placenta from the uterus impairs oxygenation of the fetus.

Possible causes include trauma, maternal hypertension (preeclampsia or eclampsia), blood clotting abnormalities, and cocaine use by the mother.

Spontaneous painful bleeding and uterine contractions are typical symptoms.

Uterine atony

The separation of the placenta from the uterus is determined by a cleavage at the decidua basalis region. After separation, the placenta is ejected by strong uterine contractions, which also constrict the spiral arteries of the vascular placental bed to prevent excessive bleeding.

In uterine atony, the contractions of the uterine muscles are not strong enough and postpartum bleeding occurs. Predisposing factors of uterine atony include abnormal labor, substantial enlargement of the uterus (hydramnios), or uterine leiomyomas (benign tumors of the myometrium). Intravenous infusion of oxytocin stimulates uterine contractions and decreases the possibility of uterine atony.

Placenta accreta

A placenta can be retained in the uterine cavity when the process of cleavage or ejection is incomplete. After expulsion, every placenta must be inspected to detect missing lobes, which may remain inside the uterus. When some placental tissue remains in the uterus, uterine contractions are deficient and excessive bleeding is observed. Curettage with a suction apparatus may remove the retained tissue.

The separation of the placenta from the uterus is defective when placental villi penetrate deep into the uterine wall to form a placenta accreta. No separation of the placenta occurs when the abnormal attachment involves the entire placenta.

Penetration of the placenta into the uterine muscle is called placenta increta.

Extensive invasion of the placenta through the thickness of the uterine muscle is known as placenta percreta.

Clinical significance: Gestational trophoblastic disease

Hydatidiform mole designates the partial or complete replacement of normal trophoblastic tissue by dilated or hydropic (edematous) villi.

Complete moles are of paternal origin and result from the fertilization of a blighted (empty) ovum by a haploid sperm that reduplicates within the egg (Figure 23-13). The frequent karyotype of a complete mole is 46,XX, and no fetus is observed.

Figure 23-13 Molar pregnancy

The fetus of a partial mole is usually 69,XXY (triploid): one haploid set of maternal chromosomes (23,X) and two haploid sets of paternal chromosomes (46,XY; arising from meiotic nondisjunction or two haploid fertilizing sperm). Extremely high levels of hCG are characteristic in patients with hydatidiform mole. Failure of high levels of hCG to regress after initial removal of intrauterine contents suggests a need for further treatment.

Choriocarcinoma is observed in about 20% of patients with molar pregnancies.

Clinical significance: Functions of the placenta

The main function of the placenta is the regulation of the fetal-maternal exchange of molecules, ions, and gases. This function is accomplished at specialized areas of the syncytiotrophoblast adjacent to fetal capillaries. The transfer of molecules across the placental barrier can follow intercellular and transcellular pathways. Figure 23-14 illustrates the main functional aspects of the placenta that are of clinical and physiologic relevance.

Figure 23-14 Functions of the placenta

Exchange of gases

Oxygen, carbon dioxide, and carbon monoxide exchange through the placenta is by simple diffusion. Nitrous oxide anesthesia (used in the treatment of dental disease) should be avoided during pregnancy.

Transfer of maternal immunoglobulins

Maternal antibodies, mainly immunoglobulin G (IgG), are taken up by the syncytiotrophoblast and then transported to fetal capillaries for passive immunity. The larger immunoglobulin M (IgM) molecules do not cross the placental barrier.

Rh (D antigen) isoimmunization

Maternal antibodies against D antigen (present in the Rh system of fetal red blood cells) cause hemolytic disease (erythroblastosis fetalis). The fetus is Rh-positive (Rh D antigen received from the father), but the mother lacks the D antigen (she is Rh-negative). Isoimmunization refers to maternal exposure and sensitization to fetal Rh⁺ red blood cells, mainly during delivery. In a subsequent pregnancy, antibodies to D antigen (IgG) cross the placenta and cause hemolysis of fetal red blood cells (see Chapter 6, Blood and Hematopoiesis).

Steroid hormone production: The fetoplacental unit

The placenta can synthesize progesterone but lacks 17-hydroxylase activity to synthesize estrogens from progesterone. The fetal adrenal cortex cannot synthesize progesterone.

A fetal-maternal cooperation—known as the fetoplacental unit—enables the transport of placental progesterone to the adrenal cortex and its conversion to dehydroepiandrosterone (DHEA), which can be sulfated to form DHEA sulfate (DHEAS) (see Figure 23-14).

When DHEA and DHEAS are transported to the syncytiotrophoblast, the conversion to estrone (E₁) and estradiol (E₂) occurs. DHEA can be hydroxylated in the liver and serves as a substrate for the synthesis of estriol (E₃) by the syncytiotrophoblast.

Protein hormone production: The luteal-placental shift

Chorionic gonadotropin, instead of maternal luteinizing hormone, maintains the corpus luteum during pregnancy. This transition is called the luteal-placental shift. Placental lactogen (also called chorionic somatomammotropin) stimulates fetal growth and conditions the mammary gland for lactation. Placental lactogen has a diabetogenic effect: It increases the resistance of peripheral tissues and liver to the effects of insulin. Pregnancy is characterized by maternal hyperglycemia, hyperinsulinemia, and reduced tissue response to insulin.

Active transport of ions and glucose

The transport of ions is mediated by an adenosine triphosphate (ATP)—dependent mechanism. Glucose enters the placenta by facilitated diffusion using a glucose transporter. Fetal glucose levels depend on maternal levels. The fetus does not depend on maternal insulin.

Fetal alcohol syndrome

The excessive ingestion of alcohol during pregnancy is the cause of fetal mental retardation and craniofacial abnormalities. Alcohol can cross the placenta and fetal blood-brain barrier causing direct toxicity. Indirect toxicity is mediated by the alcohol metabolite acetaldehyde.

Infectious agents

Rubella (German measles), cytomegalovirus, herpes simplex, toxoplasmosis, syphilis, and human immunodeficiency virus type 1 (HIV-1) are potential infectious agents. Rubella viral infection in the first trimester can cause spontaneous abortion or the congenital rubella syndrome (fetal congenital heart disease, mental retardation, deafness, and cataracts).

LACTATION

The mammary glands

The breast, or mammary gland, develops as a downgrowth of the epidermis. The nipple is surrounded by the areola, a modified skin with abundant sebaceous glands. About 15 to 20 lactiferous ducts open at the tip of the nipple through individual lactiferous sinuses.

In the lactating mammary gland, each lactiferous duct drains one lobe. The nipple contains connective tissue and smooth muscle cells, forming a circular sphincter.

Like most branched (compound) glands, the mammary gland contains a duct system, lobes, and lobules (Figure 23-15). Each lobe contains a branching lactiferous duct that extends into the fibroadipose tissue of the breast. Each lactiferous duct is lined by a simple columnar or cuboidal epithelium and a discontinuous outer layer of myoepithelial cells. Each duct is surrounded by loose connective tissue and a capillary network.

Figure 23-15 Structure of the mature female mammary gland

In the resting, nonlactating state, the mammary glands consist of lactiferous ducts, each ending in a group of blind, saccular evaginations (see Figure 23-15).

During pregnancy, the ducts branch and end in clusters of saccules (alveoli or acini), forming a lobule. Each lobule consists of various secretory tubuloacinar units. A lobe consists of a group of lobules drained by a lactiferous duct. Lobules and lobes are not seen in the nonpregnant mammary gland.

Development of the mammary glands

Placental lactogen and estrogen stimulate the development of the mammary gland. The development involves epithelial-mesenchymal interactions and consists of two phases (Figure 23-16): (1) the formation of the nipple and (2) the development of the mammary gland.

Figure 23-16 Development of the mammary gland

The nipple is visible by week 6 as an accumulation of ectodermic epithelial cells along the mammary line (extending from the axilla to the groin), forming a depression, the inverted nipple. After birth, the nipple region protrudes and the areola becomes elevated as areolar glands develop around the nipple.

During development of the mammary gland, an ectodermic epithelial cell bud, the mammary bud, enters the underlying mesoderm. Epithelial buds sprout during the first trimester to give rise to 15 to 25 solid epithelial mammary cords. During the second trimester, the mammary cords become hollow, and alveoli develop by the end of the third trimester (see Figure 23-16). The mammary ducts become lactiferous ducts.

The mesoderm differentiates into a connective and adipose stroma as well as into the smooth muscle of the nipple. Luminal epithelial cells of ducts and alveoli are precursors of the myoepithelial cells, which migrate to the basal region of the lining epithelium. The epithelial-myoepithelial conversion also occurs in the mature mammary gland.

The epithelium of the lactiferous duct of the mammary glands of newborns of both sexes can respond to maternal hormones and may produce a secretion containing α-lactalbumin, fat, and leukocytes. This secretion is called “witch’s milk.” In most cases, the simple embryonic-fetal mammary duct system remains unchanged in the infant until the onset of puberty.

In the male fetus, the developing duct system undergoes involution in the presence of testosterone. The role of the mesoderm and testosterone receptors is well demonstrated in the androgen insensitivity syndrome (testicular feminization syndrome; see later).

At puberty (Figure 23-17), circulating estrogen (in the presence of prolactin) stimulates the development of the lactiferous ducts and the enlargement of the surrounding fat tissue.

Figure 23-17 Mammary gland at puberty and during pregnancy

Epithelial cells lining the lactiferous ducts contain cytosolic and nuclear estrogen receptors. Progesterone stimulates the formation of new alveolar buds, replacing old, regressing buds, which eventually disappear at the end of the ovarian cycle. These cyclic changes are observed in each menstrual cycle.

During pregnancy (see Figure 23-17), prolactin and placental lactogen, in the presence of estrogen, progesterone, and growth factors, stimulate the development of lactiferous ducts and secretory alveoli at the ends of the branched ducts.

During lactation, the lactiferous duct system and the lobular alveolar tissue are fully developed and functional (Figure 23-18). Prolactin stimulates secretion by alveolar cells.

Figure 23-18 Histology of the inactive and active mammary gland

Suckling during lactation

A neural stimulus at the nipple resulting from suckling determines:

1. The ejection of milk by the release of oxytocin. Oxytocin causes contraction of myoepithelial cells surrounding the alveoli.

2. The inhibition of the release of luteinizing hormone—releasing factor by the hypothalamus, resulting in the temporary arrest of ovulation.

Milk contains (Figure 23-19; see Box 23-E):

1. Proteins (casein, α-lactalbumin, and large amounts of parathyroid hormone—related protein [PTH-RP]), released by merocrine secretion together with lactose.

2. Lipids (triglycerides and cholesterol), released by apocrine secretion.

3. Sugar (in particular lactose, produced in the Golgi apparatus from glucose and uridine diphosphogalactose). Lactose osmotically draws water into secretory vesicles, a process that accounts for the large volume of milk.

Figure 23-19 Function of the mammary alveolar cell

Box 23-E Lactation

• Colostrum: early milk (called fore milk) with a lower fat concentration but higher concentration of proteins and minerals. The fat content increases over the next several minutes (mature milk or hind milk).

• Milk: a unique species-specific fluid with nutritive, immunologic, and growth-promoting components.

• Lipids are surrounded by cytosol (called milk-fat globule). The cytosol becomes a stabilizing interface between fat and the aqueous components of the milk. The cytosol interface allows controlled lipolysis and formation of a micellar aqueous suspension useful for absorption in the small intestine. Lipids include cholesterol, triglycerides, short-chain fatty acids, and long-chain polyunsaturated fatty acids.

• Immunoglobulins: the most abundant immunoglobulin is secretory dimeric immunoglobulin A (IgA). It provides passive acquired defense for several weeks before the baby can produce its own secretory IgA in the small intestine.

• Protective functions of human milk: Milk contains lactoferrin, lysozyme, oligosaccharides, and mucins. These components enable some intestinal bacteria to become established while others are inhibited.

In addition, plasma cells present in the stroma surrounding the alveolar tissue secrete dimeric IgA. Dimeric IgA is taken up by alveolar cells and transported to the lumen by a mechanism similar to that discussed in Chapter 16, Lower Digestive Segment.

After nursing, prolactin secretion decreases, the mammary alveoli regress, and the lactiferous duct system returns to its normal nonpregnant stage within several months.

Clinical significance: Androgen insensitivity syndrome

In this genetic condition, genetic males (XY) lack testosterone receptor, encoded by a gene on the X chromosome.

In normal males, the lactiferous ducts undergo rapid involution by an inductive mechanism mediated by the mammary mesenchyme. Lactiferous ducts developing in the absence of testosterone or a functional androgen receptor, as in the androgen insensitivity syndrome, assume a female pattern of development.

Clinical significance: Benign breast diseases and breast cancer

Each of the tissues of the mammary gland (connective tissue, ducts, and acini) can be the source of a pathologic condition. Breast cancer is the most common malignancy in women.

Fibrocystic changes are the most common of all benign mammary gland conditions in 20- to 40-year-old patients. Hormonal imbalances are associated with fibrocystic changes. In this condition, a proliferation of the connective tissue stroma and cystic formation of the ducts are observed. Pain (mastalgia) tends to be cyclic as cysts expand rapidly.

Fibroadenoma, the second most common form of benign breast disease, occurs in young women (20 to 30 years old). Fibroadenomas are slow-growing masses of epithelial and connective tissues and are painless.

Gynecomastia, the enlargement of the male breast, is caused by a shift in the adrenal cortex estrogen-testis androgen balance. It may be observed during cirrhosis, because the liver is responsible for the breakdown of estrogens. Gynecomastia is a typical feature of Klinefelter’s syndrome (47,XXY).

About 80% of breast cancers originate in the epithelial lining of the lactiferous ducts (Figure 23-20). Epithelial cells lining the lactiferous ducts have estrogen receptors and about 50% to 85% of breast tumors have estrogen receptors.

Figure 23-20 Breast cancer

There are two types of estrogen receptors, α and β. The α receptor has a higher binding affinity for estrogen than the β receptor. The β receptor acts as a physiologic regulator of the α receptor. The expression of the α receptor is higher than the β receptor in invasive tumors than in normal breast tissue. This finding suggests that a balance between the receptors is important in determining the sensitivity of tissue to estrogen and the relative risk of breast tumor development. A large number of estrogen-dependent tumors regress after antiestrogen therapy (treatment with the antiestrogen tamoxifen).

The familial inheritance of two autosomal dominant genes, BRCA1 and BRCA2, has been determined in 20% to 30% of patients with breast cancer. BRCA1 and BRCA2 encode tumor suppressor proteins interacting with other nuclear proteins. Wild-type BRCA1 can suppress estrogen-dependent transcription pathways related to the proliferation of epithelial cells of the mammary gland. A mutation of BRCA1 can determine the loss of this ability, facilitating tumorigenesis. Women with BRCA1 and BRCA2 mutations have a lifetime risk of invasive breast and ovarian cancer. Prophylactic bilateral total mastectomy has been shown to drastically reduce the incidence of breast cancer among women with a BRCA1 or BRCA2 mutation.

Estrogen-replacement therapy in postmenopausal women has been implicated as a risk factor for breast cancer. In premenopausal women, the ovaries are the predominant source of estrogen. In postmenopausal women, estrogen derives predominantly from aromatization of adrenal (see Adrenal Gland in Chapter 19, Endocrine System) and ovarian androgens in the liver, muscle, and adipose tissue.

The mammary gland has a rich blood and lymphatic system, which facilitates metastases. Axillary lymph node metastases are the most important prognostic factor.

Concept mapping

Fertilization, Placentation, and Lactation

Essential concepts | Fertilization, Placentation, and Lactation

• Fertilization encompasses three events: (1) acrosome reaction, (2) sperm binding to the egg zona pellucida, and (3) sperm-egg plasma membrane fusion.

The acrosome and the condensed nucleus are components of the sperm head. As discussed in Chapter 21 (Spermatogenesis), the sperm tail is attached to the head by a head-tail coupling apparatus derived from the centrosome (organized by the proximal and distal centrioles and pericentriolar matrix). The tail consists of a middle piece, a principal piece, and an end piece. The major components of the middle piece are the axoneme and the surrounding outer dense fibers and mitochondrial helical sheath. The major components of the principal piece are the axoneme surrounded by outer dense fibers and the concentric ribs of the fibrous sheath anchored to longitudinal columns.

The acrosome sac contains hydrolytic enzymes (mainly hyaluronidase and proacrosin; the latter gives rise to acrosin during the acrosome reaction). The sac consists of an outer acrosomal membrane facing the plasma membrane, and an inner acrosomal membrane facing the acroplaxome anchored to the nuclear envelope of the condensed nucleus. The acrosome reaction occurs when the outer acrosomal membrane fuses at different points with the plasma membranes in the presence of Ca²⁺.

Acrosomal-derived hyaluronidase facilitates sperm penetration between granulosa cells of the corona radiata. Acrosin enables sperm penetration of the zona pellucida. When the first sperm binds to the zona pellucida (consisting of three glycoproteins: ZP1, ZP2, and ZP3), proteases from the cortical granules in the egg cytoplasm are released. This event is called cortical reaction. Consequently, components of the zona pellucida change their molecular organization to prevent polyspermy.

The following molecules are involved in fertilization: The sperm plasma membrane contains receptors with binding affinity to O-oligosaccharides of ZP3 and Izumo, a protein member of the immunoglobulin superfamily. The egg plasma membrane has CD9, a member of the superfamily of tetraspanins. Izumo and CD9 condition the plasma membranes of the sperm and egg for fusion. Other proteins, such as ADAMs (a disintegrin and metalloprotease) and integrins participate in sperm-egg fusion.

• Placentation starts with the implantation of the blastocyst into the endometrium after the blastocyst hatches from the zona pellucida exposing the trophoblast layer.

Implantation consists in the adhesion of the blastocyst to the endometrial surface (a process called apposition) followed by implantation into the decidualized endometrial stroma with the help of the invasive trophoblastic cells (a process called interstitial invasion). Uterine receptivity is the optimal state of the endometrium for the implantation of the blastocyst. A primary decidual zone is remodeled into a secondary decidual zone by the action of local metalloproteinases and their inhibitors.

The trophoblast differentiates into an inner cell layer, the mitotically dividing cytotrophoblast, and an outer cell layer, the postmitotic syncytiotrophoblast. Proteolytic enzymes released by the syncytiotrophoblast erode the branches of the spiral uterine arteries, forming lacunae. This event, called endovascular invasion, initiates the uteroplacental circulation. Lacunae represent the starting point of the future intervillous space of the placenta.

A primary villus, the first step in the development of chorionic villi, is formed at the end of the second week. A primary villus consists of a cytotrophoblast core surrounded by the syncytiotrophoblast layer.

A secondary villus is formed early in the third week. A secondary villus consists of a core of extraembryonic mesoderm surrounded by the cytotrophoblast in the middle and an outer syncytiotrophoblast layer.

A tertiary villus is seen late in the third week. The tertiary villus has a structure similar to the secondary villus but it contains fetal arteriocapillary networks in the extraembryonic mesoderm.

The placenta consists of (1) the chorionic plate (fetal component) and (2) the decidua basalis (maternal component). These two components are the limits of the intervillous space containing maternal blood.

The intervillous space is subdivided by decidual septa into compartments, called lobes. The decidual septa, extending from the decidua basalis into the intervillous space, do not reach the chorionic plate. Therefore, the lobes are incomplete and the intervillous spaces are interconnected.

A chorionic villus consists of a stem giving rise to numerous villous branches. The core of the stem and villous branches contains extraembryonic mesoderm (mesenchymal cells), fetal blood vessels, and Hofbauer cells (a macrophage-like cell seen in early pregnancy). The surface of the stem and its branches is lined by an outer syncytiotrophoblast layer and an inner cytotrophoblast layer supported by a basal lamina. The apical domain of syncytiotrophoblastic cells displays short microvilli extending into the maternal blood space.