Fertilization And Implantation

Gamete Transport

Fertilization takes place in a distal portion of the oviduct called the ampulla, far from the site of sperm deposition in the vagina. To reach the ovum, sperm must swim through the cervical canal, cross the entire length of the uterine cavity, and then travel up through the muscular isthmus of the oviduct. Even with the aid of contractions of the female reproductive tract, the journey is formidable. Only about one of every million sperm deposited in the vagina reach the ampulla; here, if they arrive first, they await the arrival of the ovum. Sperm usually remain fertile within the female reproductive tract for 1 to 2 days, but as long as 4 days is possible. Access to

Tgrowth and activity of cilia estrogen-+ T"

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Tgrowth and activity of cilia estrogen-+ T"

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FIGURE 1 Actions of estrogen to promote sperm transport.

ovary follicle

— ampulla isthmus uterus cervix vagina

FIGURE 1 Actions of estrogen to promote sperm transport.

the upper reaches of the reproductive tract is heavily influenced by ovarian steroid hormones.

Estrogen is secreted in abundance late in the follicular phase of the ovarian cycle and prepares the reproductive tract for efficient sperm transport (Fig. 1). Glycogen deposited in the vaginal mucosa under its influence provides substrate for the production of lactate, which lowers the pH of vaginal fluid. An acidic environment increases the motility of sperm that is essential for their passage through the cervical canal. In addition, the copious watery secretion produced by cells lining the cervical canal under the influence of estrogen increases access to the uterine cavity. When estrogen is absent or when its effects are opposed by progesterone, the cervical canal is filled with a viscous mucus that resists sperm penetration. Vigorous contractions of the uterus propel sperm toward the oviducts, where they may appear anywhere from 5 to 60 minutes after ejaculation. Prosta-glandins present in seminal plasma and oxytocin released from the pituitary in response to intercourse may stimulate contraction of the highly responsive estrogen-dominated myometrium.

Role of the Oviducts

The oviducts are uniquely adapted for facilitating transport of sperm toward the ovary and transporting the ovum in the opposite direction toward its rendezvous with sperm. It is also within the oviducts that sperm undergo a process called capacitation, which prepares them for a successful encounter with the ovum and its adherent mass of granulosa cells, the cumulus oophorus. Capacitation is an activation process that involves both enhancement of flagellar activity and the biochemical and structural changes in the plasma membrane of the sperm head that prepare sperm to undergo the acrosomal reaction. The acrosome is a membranous vesicle that is positioned at the tip of the sperm head. It is filled with several hydrolytic enzymes. Contact of the sperm head with the zona pellucida that surrounds the ovum initiates fusion of the acrosomal membrane with the plasma membrane and the exocytotic release of enzymes that digest a path through the zona pellucida, clearing a path for sperm to reach the ovum. The acrosome reaction and the events that produce it are highly reminiscent of the sequelae of hormone receptor interactions and involve activation of membrane calcium channels, tyrosine phosphorylation, phospholipase C, and other intracellu-lar signaling mechanisms. Initiation of the acrosomal reaction is facilitated by progesterone secreted by the mass of cumulus cells that surround the ovum. The sperm plasma membrane contains progesterone receptors that trigger an influx of calcium within seconds. These membrane-associated receptors differ from the classical nuclear receptors.

In response to estrogens or perhaps other local signals associated with impending ovulation, muscular activity in the distal portion of the oviduct brings the infundibulum into close contact with the surface of the ovary. At ovulation, the ovum, together with its surrounding granulosa cells, is released into the peritoneal cavity and is swept into the ostium of the oviduct by the vigorous, synchronous beating of cilia on the infundibular surface. Development of cilia in the epithelial lining and their synchronized rhythmic activity are consequences of earlier exposure to estrogens. Movement of the egg mass through the ampulla toward the site of fertilization near the ampullar-isthmic junction depends principally on currents set up in tubal fluid by the beating of cilia and to a lesser extent by contractile activity of the ampullar wall to produce a churning motion.

Propulsion of sperm through the isthmus toward the ampulla is accomplished largely by muscular contractions of the tubal wall. Circular smooth muscle of the isthmus is innervated with sympathetic fibers and has both a-adrenergic receptors, which mediate contraction, and ^-adrenergic receptors, which mediate relaxation. Under the influence of estrogen, the a receptors predominate. Subsequently, as estrogenic effects are opposed by progesterone, the p receptors prevail, and isthmic smooth muscles relax. This reversal in the response to adrenergic stimulation may account for the ability of the oviduct to facilitate sperm transport through the isthmus toward the ovary and subsequently to promote passage of the embryo in the opposite direction toward the uterus.

After fertilization, the oviduct retains the embryo for about 3 days and nourishes it with secreted nutrients before facilitating its entry into the uterine cavity. These complex events, orchestrated by the interplay of estrogen, progesterone, and autonomic innervation, require participation of the smooth muscle of the walls of the oviduct as well as secretory and ciliary activity of the epithelial lining. As crucial as these mechanical actions may be, however, the oviduct does not contribute in an indispensable way to fertility of the ovum or sperm or to their union, as modern techniques of in vitro fertilization bypass it with no ill effects.

The period of fertility is short; from the time the ovum is shed until it can no longer be fertilized is only about 6 to 24 hours. As soon as a sperm penetrates the ovum, the second polar body is extruded, and the fertilized ovum begins to divide. By the time the fertilized egg enters the uterine cavity, it has reached the blastocyst stage and consists of about 100 cells. Timing of the arrival of the blastocyst in the uterine cavity is determined by the balance between antagonistic effects of estrogen and progesterone on the contractility of the oviductal wall. Under the influence of estrogen, circularly oriented smooth muscle of the isthmus is contracted and bars passage of the embryo to the uterus. As the corpus luteum organizes and increases its capacity to secrete progesterone, p-adrenergic receptors gain ascendancy, muscles of the isthmus relax, and the embryonic mass is allowed to pass into the uterine cavity. Ovarian steroids can thus "lock" the ovum or embryo in the oviduct or cause its delivery prematurely into the uterine cavity.

Implantation and Formation of the Placenta

The blastocyst floats freely in the uterine cavity for about a day before it implants, normally on about the fifth day after ovulation. Experience with in vitro fertilization indicates that there is about a 3-day period of uterine receptivity in which implantation leads to full-term pregnancy. It should be recalled that this period of endometrial sensitivity coincides with the period of maximal progesterone output by the corpus luteum (Fig. 2). In the late luteal phase of the menstrual cycle, the outer layer of the endometrium differentiates to form the decidua. Decidualized stromal cells enlarge and transform from an elongated spindle shape to a rounded morphology with accumulation of glycogen. Decidualization requires high concentrations of progesterone and may be enhanced by activity of cytokines and relaxin. Decidual cells express several proteins that may facilitate implantation, but the precise roles of these proteins either in implantation or pregnancy have not been determined definitively. One such protein is the hormone prolactin, which continues to be secreted throughout pregnancy. Another is the IGF-1 binding protein (IGFBP-1).

At the time of implantation, the blastocyst consists of an inner mass of cells destined to become the fetus and an outer rim of cells called the trophoblast. It is the trophoblast that forms the attachment to maternal decidual tissue and gives rise to the fetal membranes and the definitive placenta (Fig. 3). Cells of the trophoblast proliferate and form the multinucleated syncytial trophoblast, the specialized functions of which enable it to destroy adjacent decidual cells and allow the blastocyst to penetrate deep into the uterine endometrium. Killed decidual cells are phagocytosed by the trophoblast as the embryo penetrates the subepithelial connective tissue and eventually becomes completely enclosed within the endometrium. Products released from degenerating decidual cells produce hyperemia and increased capillary permeability. Local extravasation of blood from damaged capillaries forms small pools of blood that are in direct contact with the trophoblast and provide nourishment to the embryo until the definitive placenta forms. From the time the ovum is shed until the blasto-cyst implants, metabolic needs are met by secretions of the oviduct and the endometrium.

The syncytial trophoblast and an inner cytotropho-blast layer of cells soon completely surround the inner cell mass and send out solid columns of cells that further erode the endometrium and anchor the embryo. These columns of cells differentiate into the placental villi. As they digest the endometrium, pools of extravasated maternal blood become more extensive and fuse into a complex labyrinth that drains into venous sinuses in the endometrium. These pools expand and eventually receive an abundant supply of arterial blood. By the third week, the villi are invaded by fetal blood vessels as the primitive circulatory system begins to function (see Chapter 66).

Although much uncertainty remains regarding details of implantation in humans, it is perfectly clear that progesterone secreted by the ovary at the height of luteal

LH peak

LH peak

FIGURE 2 Relation between events of early pregnancy and steroid hormone concentrations in maternal blood (estradiol and progesterone concentrations are redrawn from data given in Fig. 10 of Chapter 46). By the 10th day after the LH peak, there is sufficient hCG to maintain and increase estrogen and progesterone production, which would otherwise decrease (dotted lines) at this time.

FIGURE 2 Relation between events of early pregnancy and steroid hormone concentrations in maternal blood (estradiol and progesterone concentrations are redrawn from data given in Fig. 10 of Chapter 46). By the 10th day after the LH peak, there is sufficient hCG to maintain and increase estrogen and progesterone production, which would otherwise decrease (dotted lines) at this time.

function is indispensable for all of these events to occur. Removal of the corpus luteum at this time or blockade of progesterone secretion or progesterone receptors prevents implantation. Progesterone is indispensable for maintenance of decidual cells, quiescence of the myometrium, and formation of the dense, viscous cervical mucus that essentially seals off the uterine cavity from the outside. It is noteworthy that the implanting trophoblast and the fetus are genetically distinct from the mother, yet the maternal immune system does not reject the implanted embryo as a foreign body. Progesterone plays a decisive role in immunological acceptance of the embryo. It promotes tolerance by regulating accumulation of lymphocyte types in the uterine cavity, by suppressing lymphocyte toxicity, and by inhibiting the production of cytolytic cytokines. The importance of progesterone for implantation and retention of the blastocyst is underscored by the development of a progesterone antagonist (RU486) that prevents implantation or causes an already implanted conceptus to be shed along with the uterine lining.

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