Tutoring at home

The decidua is a specialized, highly modified endometrium of pregnancy and is a function of hemochorial placentation. This form of placentation has in common the process of trophoblast invasion, and therefore considerable research has focused on the interaction between the cells within the decidua and the invading trophoblasts. Decidualization, the transformation of secretory endometrium to decidua, is dependent on the action of estrogen and progesterone and factors secreted by the implanting blastocyst during trophoblast invasion. The special relationship that exists between the decidua and the invading trophoblast seemingly defies the laws of transplantation immunology (Beer and Billingham, 1971). The success of this unique semiallograft not only is of great scientific interest but may involve processes that harbor insights leading to more successful transplantation surgery and perhaps even immunological treatment of neoplasia (Billingham and Head, 1986; Lala and colleagues, 2002).
Decidual Structure
William Hunter, the 18th-century British gynecologist, provided the first scientific description of the membrana decidua. According to Damjanov (1985), the term membrana denoted its gross anatomical appearance, while decidua was added with analogy to deciduous leaves to indicate an ephemeral nature and the fact that it is shed from the rest of the uterus after childbirth. The decidua of pregnancy is composed of three parts based on its anatomical location. The portion of the decidua directly beneath the site of blastocyst implantation is modified by trophoblast invasion and becomes the decidua basalis. That portion overlying the enlarging blastocyst, and initially separating it from the rest of the uterine cavity, is the decidua capsularis. The decidua capsularis is most prominent during the second month of pregnancy, consisting of decidual cells covered by a single layer of flattened epithelial cells without traces of glands. Internally, this portion of the decidua contacts the avascular, extraembryonic fetal membrane, the chorion laeve. The remainder of the uterus is lined by decidua parietalis, sometimes called the decidua vera at the point in development when decidua capsularis and decidua parietalis are joined.

During the early weeks of pregnancy, there is a space between the decidua capsularis and decidua parietalis because the gestational sac does not fill the entire uterine cavity. By 14 to 16 weeks, the expanding sac has enlarged enough to fill the uterine cavity. With fusion of the decidua capsularis and parietalis, the uterine cavity is functionally obliterated. In early pregnancy, the decidua begins to thicken, eventually attaining a depth of 5 to 10 mm. With magnification, furrows and numerous small openings, representing the mouths of uterine glands, can be detected. Later in pregnancy, as the fetus grows and the amnionic fluid expands, the thickness of the decidua decreases, presumably because of the pressure exerted by the expanding uterine contents.
The decidua parietalis and the decidua basalis, like the secretory endometrium, each are composed of three layers: a surface, or compact zone (zona compacta); a middle portion, or spongy zone (zona spongiosa), with remnants of glands and numerous small blood vessels; and a basal zone (zona basalis). The zona compacta and spongiosa together form the functional zone (zona functionalis). The basal zone remains after delivery and gives rise to new endometrium.
The Decidual Reaction
In human pregnancy, the decidual reaction is completed only with blastocyst implantation. Predecidual changes, however, commence first during the midluteal phase in endometrial stromal cells adjacent to the spiral arteries and arterioles, spreading thereafter in waves throughout the mucosa of the uterus and then from the site of implantation. The endometrial stromal cells enlarge to form polygonal or round decidual cells. The nuclei become round and vesicular, and the cytoplasm becomes clear, slightly basophilic, and surrounded by a translucent membrane. Each mature decidual cell becomes surrounded by a pericellular membrane. Thus, the human decidual cells clearly build walls around themselves and possibly around the fetus. The pericellular matrix surrounding the decidual cells may provide for attachment of cytotrophoblasts through cellular adhesion molecules. The pericellular decidual cell membrane also may provide for protection of the decidual cell against selected proteases of the cytotrophoblasts.
Decidual Blood Supply
This supply is changed as a consequence of implantation. The blood supply to the decidua capsularis is lost as the embryo-fetus grows and expands into the uterine cavity. The blood supply to the decidua parietalis through the spiral arteries persists, as in the endometrium during the luteal phase of the cycle. The spiral arteries in the decidua parietalis retain a smooth muscle wall and endothelium and thereby remain responsive to vasoactive agents that act on the smooth muscle or the endothelial cells of these vessels.
The spiral arterial system supplying the decidua basalis directly beneath the implanting blastocyst, and ultimately the intervillous space surrounding the syncytiotrophoblast of the placenta, is altered remarkably. These spiral arterioles and arteries are invaded by the cytotrophoblasts, and during this process the walls of the vessels in the basalis are destroyed, leaving only a shell without smooth muscle or endothelial cells. As a consequence, these vascular conduits of maternal blood—which become the uteroplacental vessels—are not responsive to vasoactive agents. By contrast, the fetal chorionic vessels, which transport blood between the placenta and the fetus, contain smooth muscle and do respond to vasoactive agents.
Decidual Histology
The decidua is composed of a variety of cell types, which varies with the stage of gestation (Loke and King, 1995). The primary cellular components of the decidua are the true decidual cells that differentiated from the endometrial stromal cells and numerous bone marrow–derived cells. The compact layer of the decidua consists of large, closely packed, epithelioid, polygonal, lightly staining cells with round nuclei. Many stromal cells appear stellate, with long protoplasmic processes that anastomose with those of adjacent cells. This is particularly so when the decidua is edematous. Numerous small round cells, which contain very little cytoplasm, are scattered among the decidual cells, especially in early pregnancy. Most of these are a particular type of natural killer lymphocyte and are referred to as endometrial large granular lymphocytes (LGLs), in which a special and unusual phenotype has been defined (Vince and Johnson, 2000). These are bone marrow-derived cells that at one time entered endometrium from peripheral blood. But thereafter, these large granular lymphocytes arise primarily by replication in the endometrium in situ at specific times in the menstrual cycle and during the first trimester.
Early in pregnancy, the spongy layer of the decidua consists of large distended glands, often exhibiting marked hyperplasia and separated by minimal stroma. At first, the glands are lined by typical cylindrical uterine epithelium. They have abundant secretory activity that contributes to the nourishment of the blastocyst. As pregnancy progresses, the epithelium gradually becomes cuboidal or even flattened, later degenerating and sloughing to a greater extent into the lumens of the glands. Later in pregnancy the glandular elements of the decidua largely disappear. In comparing the decidua parietalis at 16 weeks with the early proliferative endometrium of a nonpregnant woman, it is clear that there is marked hypertrophy but only slight hyperplasia of the endometrial stroma during decidual transformation.
The decidua basalis contributes to the formation of the basal plate of the placenta, and differs histologically from the decidua parietalis in two important respects. First, the spongy zone of the decidua basalis consists mainly of arteries and widely dilated veins, but by term, the glands have virtually disappeared. Second, the decidua basalis is invaded by large numbers of interstitial trophoblast cells and trophoblastic giant cells. Although most abundant in the decidua, the giant cells commonly penetrate the upper myometrium. Their number and invasiveness may be so extensive as to be confused with choriocarcinoma by the inexperienced observer.

Where invading trophoblasts meet the decidua, there is a zone of fibrinoid degeneration, the Nitabuch layer. Whenever the decidua is defective, as in placenta accreta, the Nitabuch layer is usually absent. There is also a more superficial, but inconsistent deposition of fibrin—Rohr stria—at the bottom of the intervillous space and surrounding the anchoring villi. McCombs and Craig (1964) found that decidual necrosis is a normal phenomenon in the first and probably the second trimester. Thus, necrotic decidua obtained through curettage after spontaneous abortion in the first trimester should not necessarily be interpreted as either a cause or an effect of the pregnancy loss.
Decidual Prolactin Production
Convincing evidence has been presented that the decidua is the source of the prolactin that is present in enormous amounts in amnionic fluid during human pregnancy (Golander and colleagues, 1978; Riddick and colleagues, 1979). Decidual prolactin is not to be confused with placental lactogen (hPL), which is produced only by the syncytiotrophoblast. Rather, decidual prolactin is a product of the same gene that encodes for prolactin that is secreted by the anterior pituitary, and the amino acid sequence of prolactin in both tissues is identical. In decidua, however, an alternative promoter is used within the prolactin gene to initiate transcription (Telgmann and Gellersen, 1998). This alternative prolactin promoter through novel transcription factors is thought to explain the different mechanisms that regulate expression in the decidua versus pituitary (Christian and colleagues, 2002a, 2000b).
The levels of prolactin in amnionic fluid may reach 10,000 ng/mL during the 20th to 24th weeks (Tyson and colleagues, 1972). This is extraordinarily high compared with the 350 ng/mL seen in the fetus or 150 to 200 ng/mL seen in maternal plasma. Prolactin produced in decidua preferentially enters amnionic fluid, and little or none enters maternal blood. This is a classical example of paracrine function between maternal and fetal tissues.
The factors that regulate prolactin production in decidua are not clearly defined. Most of the agents known to inhibit or stimulate anterior pituitary prolactin secretion, including dopamine, dopamine agonists, and thyrotropin-releasing hormone, do not alter the rate of decidual prolactin secretion either in vivo or in vitro. Brosens and colleagues (2000) demonstrated that progestins act synergistically with cyclic adenosine monophosphate on human endometrial stromal cells in culture to increase the expression of prolactin. These findings suggest that the level of progesterone receptor expression may determine the decidualization process, as marked by prolactin production. It has been reported that arachidonic acid, but not PGF2 or PGE2, attenuates the rate of decidual prolactin secretion (Handwerger and colleagues, 1981). In addition, a variety of cytokines and growth factors, including ET-1, IL-1, IL-2, and epidermal growth factor, act to decrease decidual prolactin secretion (Chao and colleagues, 1994; Frank and colleagues, 1995).
The exact physiological roles of prolactin produced in decidua are still unknown. Prolactin action is mediated by the relative expression of two unique prolactin receptors as well as the amount of intact (full-length) prolactin protein versus the truncated (16-kDa) form (Jabbour and Critchley, 2001). Receptor expression has been demonstrated in decidua, chorionic cytotrophoblasts, amnionic epithelium, and placental syncytiotrophoblast (Maaskant and colleagues, 1996). Because all (or most) of the prolactin produced in decidua enters amnionic fluid, it has been speculated that there may be a role for this hormone in solute and water transport across the amniochorion, and thus in the maintenance of amnionic fluid volume homeostasis. It also has been shown, however, that prolactin receptors are present in a number of bone marrow–derived immune cells, and that prolactin may act on human T cells in an autocrine or paracrine manner (Pellegrini and colleagues, 1992). Therefore, prolactin produced in decidua may act in regulating immunological functions in this tissue during pregnancy. Prolactin also may play a role in the regulation of angiogenesis that occurs during implantation. In this regard, the intact (full-length) prolactin protein can enhance angiogenesis while the proteolytic fragment (16-kDa) form can inhibit angiogenesis. Thus, the role of prolactin may vary dramatically at different periods of gestation based on the type of receptors expressed and the relative form of prolactin present.

In the catarrhine primates, the midluteal–secretory phase of the endometrial cycle is a critical branch point in the development and differentiation of the endometrium. With rescue of the corpus luteum and continued progesterone secretion, the process of decidualization continues. If, however, the corpus luteum production of progesterone drops as a result of luteolysis, the events leading to menstruation will be initiated. Many of the molecular mechanisms involving endometrial progesterone withdrawal, as well as the subsequent inflammatory response that causes the sloughing of the endometrium, have been defined (Critchley and colleagues, 2001).
A notable histological characteristic of the late premenstrual-phase endometrium is the infiltration of the stroma by polymorphonuclear leukocytes, giving a pseudoinflammatory appearance to the tissue. The infiltration of neutrophils occurs primarily on the day or two immediately preceding the onset of menstruation. The endometrial stromal and epithelial cells produce interleukin-8 (IL-8), a chemotactic–activating factor for neutrophils (Arici and colleagues, 1993). IL-8 may be one of the agents that serve to recruit neutrophils to the endometrium just prior to the onset of menstruation. Similarly, the endometrium is capable of synthesizing monocyte chemotactic protein-1 (MCP-1), a potent chemoattractant for monocytes (Arici and colleagues, 1995). The rates of synthesis of IL-8 and MCP-1 in endometrial stromal cells appear to be modulated, in part, by circulating sex steroid hormones and local production of transforming growth factor- (Arici and colleagues, 1996a, 1996b).
The infiltration of leukocytes is considered key to initiation of extracellular matrix breakdown of the functionalis layer. The invading leukocytes secrete enzymes that are members of the matrix metalloproteinase family of proteins. These metalloproteinases add to the proteases already produced by the endometrial stromal cells. The rising level of metalloproteinases tips the balance between proteases and protease inhibitors, effectively initiating degradation of the matrix. This phenomenon has been proposed to initiate the events leading to menstruation (Dong and colleagues, 2002).
A classical study by Markee (1940) described the tissue and vascular changes that occur in endometrium before menstruation. He observed 432 separate cyclical alterations in endometrial tissue explants that he had transplanted to the anterior chamber of the eye of rhesus monkeys. There were marked changes in blood flow to the endometrium during the time of growth regression, which are essential for menstruation. As the regression of the endometrium occurs, the coiling of the spiral arteries becomes sufficiently severe that the resistance to blood flow in these vessels is increased strikingly, causing hypoxia of the endometrium. The resultant stasis is the primary cause of endometrial ischemia and then tissue degeneration. A period of vasoconstriction precedes the onset of menstruation and is the most striking and constant event observed in the menstrual cycle. The intense vasoconstriction of the spiral arteries serves to limit blood loss during menstruation. Blood flow in the spiral arteries appears to be regulated in an endocrine manner by sex steroid hormone–induced modifications of a local (paracrine-mediated) vasoactive peptide system.

The fluctuating levels of ovarian steroids are the direct cause of the endometrial cycle. Recent advances in the molecular biology of receptors for estrogen and progesterone have greatly improved our understanding of how sex steroids regulate the endometrium. 17 -Estradiol, the most biologically potent naturally occurring estrogen, is secreted by the granulosa cells of the dominant ovarian follicle and luteinized granulosa cells of the corpus. Estrogen is the essential hormonal signal on which most events in the normal menstrual cycle depend. Estradiol action is complex and appears to involve two classical nuclear hormone receptors, which have been designated estrogen receptor (ER and estrogen receptor (ER ) (Katzenellenbogen and colleagues, 2001). These isoforms are the product of separate genes and can exhibit distinct tissue differences in relative expression. Both estradiol-receptor complexes act as transcriptional factors that become associated with the estrogen response element of specific genes. Both share a robust activation by estradiol, but there are differences in the binding of other estrogens, making these receptors targets for selective estrogen receptor modulators.
The interaction with steroid ligands brings about estrogen receptor–specific initiation of gene transcription, which promotes the synthesis of specific messenger RNAs, and thereafter the synthesis of specific proteins. Among the many proteins synthesized in most estrogen-responsive cells are additional estrogen receptors and progesterone receptors. In addition, estradiol has been proposed to act at the cell surface to stimulate nitric oxide production in endothelial cells, leading to the rapid vasoactive properties of estradiol (Shaul, 2002). The ability of estradiol to work in the cell nucleus through classical ligand-regulated nuclear hormone receptors and at the cell surface to cause rapid changes in cell signaling molecules is one explanation for the complex responses seen as a result of estrogen therapies.
It is likely that estradiol and other bioactive estrogens cause replication of the endometrium indirectly (through actions on stromal cells). The expression pattern of ER and ER in the various cellular components of the endometrium has been examined using immunohistochemistry (Lecce and colleagues, 2001). ER is expressed in glands, stroma, and vascular cells of the endometrium. ER levels are highest during the proliferative phase of the cycle. With the development and widespread use of selective estrogen receptor modulators, the differential expression and roles of the two isoforms of estrogen receptor within the endometrium will need careful study.
The majority of effects of progesterone on the female reproductive tract are mediated through nuclear hormone receptors. Progesterone enters cells by diffusion and in responsive tissues becomes associated with progesterone receptors (Conneely and colleagues, 2002). There are two distinct isoforms of the human progesterone receptor, viz., the progesterone receptor type A (PR-A) and type B (PR-B). Both arise from a single gene, are members of the steroid receptor superfamily of transcription factors, and regulate transcription of target genes. These receptors may have unique actions within cells. When the PR-A and PR-B receptors are co-expressed, it appears that the PR-A can act as an inhibitor of PR-B gene regulation. The repressor effect of PR-A may extend to actions on other steroid receptors, including estrogen receptors. In addition, progesterone may act by receptor-independent nongenomic mechanisms. Membrane receptors for progesterone have been best characterized in human spermatozoa, but their role in other human tissues is not currently clear (Luconi and colleagues, 2002).
The expression patterns of PR-A and PR-B receptors in the human endometrium have been examined using immunohistochemistry (Mote and colleagues, 1999). The endometrial glands and stroma appear to have different expression patterns for PR-A and PR-B, which vary over the menstrual cycle. The glands express both receptors in the proliferative phase, suggesting that both receptors are involved with subnuclear vacuole formation. After ovulation the glands continue to express PR-B through the midluteal phase, suggesting that glandular secretion seen during the luteal phase is PR-B regulated. In contrast, the stroma and predecidual cells express only PR-A throughout the menstrual cycle, suggesting that progesterone-stimulated events within the stroma are mediated by this receptor. Progesterone receptor expression has not been observed in inflammatory cells or in endothelial cells of the endometrial vessels. Dissecting the role of these two receptor isoforms in the regulation of human menstruation may be difficult, however, studies in animal models have given evidence that the PR-A receptor regulates the antiproliferative effects of progesterone seen in the secretory phase. Specifically, ablation of PR-A expression in mice blocks decidualization and implantation. These observations imply that the two progesterone receptor isoforms play distinct roles in the endometrium during the menstrual cycle. In addition, distinct roles for PR-A and PR-B have been proposed for the regulation of the myometrium during the initiation of labor (Mesiano and colleagues, 2002).

The development of predictable, regular, cyclical, and spontaneous ovulatory menstrual cycles is regulated by complex interactions of the hypothalamic–pituitary axis, the ovaries, and the genital tract. The average duration of the cycle in women of reproductive age is approximately 28 days, with a range of 25 to 32 days. The sequence of hormonal events leading to ovulation dictates the menstrual cycle. The cyclical changes in endometrial histology are faithfully reproduced during each ovulatory ovarian cycle. In 1937, Rock and Bartlett suggested that the histological features of the endometrium were sufficiently characteristic to permit “dating” of the ovarian cycle of the woman from whom the endometrial tissue was obtained. The follicular (proliferative) phase and the postovulatory (luteal or secretory) phase of the ovarian–endometrial cycle are customarily divided into early and late stages.
Follicular (Preovulatory) Ovarian Phase
In the human ovary, 2 million oocytes are found at birth, and about 400,000 follicles are present at the onset of puberty (Baker, 1963). The remaining follicles are depleted at a rate of approximately 1000 follicles per month until 35 years of age, when this rate accelerates (Faddy and colleagues, 1992). Only 400 follicles are normally ovulated during female reproductive life. Therefore, more than 99.9 percent of follicles undergo the degenerative process known as atresia through a process of cell death termed apoptosis (Gougeon, 1996; Hsueh and colleagues, 1994; Kaipia and Hsueh, 1997). Human follicular development consists of several stages, which include the gonadotropin-independent recruitment of primordial follicles from the resting pool and growth of these follicles to the antral stage. This process appears to be under the control of locally produced growth factors. The production of two members of the transforming growth factor- family, viz., growth differentiation factors 9 and 10, regulates the proliferation and differentiation of the granulosa cells as the primary follicles grow (Aaltonen and colleagues, 1999; Hreinsson and colleagues, 2002). These factors are produced by the oocytes, suggesting that the early steps in follicular development are in part oocyte controlled. As the antral follicles develop, the surrounding stromal cells are recruited in a yet-to-be-defined mechanism to become thecal cells.
Although not required for early stages of follicular development, follicle-stimulating hormone (FSH) is required for further development of large antral follicles (Hillier, 2001). During each ovarian cycle, a group of antral follicles, known as a cohort, begins a phase of semisynchronous growth as a result of their state of maturation at the time of the FSH rise during the late luteal phase of the previous cycle. This FSH rise leading to the development of follicles is called the selection window of the ovarian cycle (Macklon and Fauser, 2001). Only the follicles progressing to this stage develop the capacity to produce estrogen.
During the follicular phase, estrogen levels rise in parallel to the growth of the dominant follicle and the increase in its number of granulosa cells (see Fig. 3–1). The granulosa cells are the exclusive site of FSH receptor expression. The increase in circulating FSH during the late luteal phase of the previous cycle stimulates an increase in FSH receptors and, subsequently, the ability to aromatize thecal cell–derived androstenedione into estradiol. The requirement for thecal cells that respond to luteinizing hormone (LH) and granulosa cells that respond to FSH represents the two-gonadotropin, two-cell hypothesis for estrogen biosynthesis described by Short (1962) and shown in Figure 3–2. FSH induces the enzyme aromatase and expansion of the antrum of the growing follicles. The follicle within the cohort that is most responsive to FSH is likely to be the first to produce estradiol and initiate expression of LH receptors.
After the appearance of LH receptors, the preovulatory granulosa cells begin to secrete small quantities of progesterone. The preovulatory secretion of progesterone, although somewhat limited, is believed to exert positive feedback on the estrogen-primed pituitary to either cause or help augment release of LH. In addition, during the late follicular phase, LH stimulates thecal cell production of androgens, particularly androstenedione, which are then transferred to the adjacent follicles where they are metabolized to estradiol. During the early follicular phase, the granulosa cells also produce inhibin B, which can feed back on the pituitary to inhibit FSH release (Groome and colleagues, 1996). As the dominant follicle begins to grow, the production of estradiol and the inhibins increases, resulting in a decline of follicular-phase FSH. This drop in FSH is responsible for the failure of other follicles to reach preovulatory status—the Graafian follicle stage—during any one cycle. Thus, 95 percent of plasma estradiol produced at this time is secreted by the dominant follicle, which is destined to ovulate. The contralateral ovary is relatively inactive.
Ovulation
The onset of the gonadotropin surge resulting from increasing secretion of estrogen by preovulatory follicles is a relatively precise predictor of the time of ovulation, occurring some 34 to 36 hours before the release of the ovum from the follicle. The peak of LH secretion occurs 10 to 12 hours before ovulation and stimulates the resumption of the meiosis process in the ovum with the release of the first polar body. At this time a protrusion of the follicular wall (the stigma) develops, which then ruptures, allowing release of the oocyte–cumulus complex. It has long been suggested that the actual rupture of the follicle is controlled by the plasminogen activator group of proteases (Beers, 1975). Current studies suggest that in response to LH, increased production of progesterone and prostaglandins activates members of both the plasminogen activator and matrix metalloproteinases. Activation of these proteases is likely to play a pivotal role in the weakening of the follicular basement membrane and ovulation (Ny and colleagues, 2002).
Luteal (Postovulatory) Phase of the Ovary
Following ovulation, the corpus luteum develops from the remains of the dominant or Graafian follicle in a process referred to as luteinization. Rupture of the follicle initiates a series of morphological and chemical changes leading to transformation into the corpus luteum (Browning, 1973). The basement membrane separating the granulosa-lutein and theca-lutein cells breaks down, and by day 2 postovulation, blood vessels and capillaries invade the granulosa cell layer. The rapid neovascularization of the once avascular granulosa may be due to a variety of angiogenic factors. These include vascular endothelial growth factor and others produced in response to LH by the theca-lutein and granulosa-lutein cells (Albrecht and Pepe, 2003; Fraser and Wulff, 2001). During luteinization, these cells undergo hypertrophy and increase their capacity to synthesize hormones.
That LH is the primary luteotropic factor was well established in studies of hypophysectomized women (Vande Wiele and colleagues, 1970). In these women, the life span of the corpus luteum is dependent on repeated injections of LH or human chorionic gonadotropin (hCG). In addition, LH injections can extend the life span of the corpus luteum in normal women by 2 weeks (Segaloff and colleagues, 1951). In normal cycling women, the corpus luteum is maintained by low-frequency, high-amplitude pulses of LH secreted by gonadotropes in the anterior pituitary (Filicori and colleagues, 1986).
The pattern of hormone secretion by the corpus luteum is different from that of the follicle (see Fig. 3–1). The increased capacity of the granulosa-lutein cells to produce progesterone is the result of increased access to considerably more steroidogenic precursors through blood-borne low-density lipoprotein (LDL)–derived cholesterol (Carr and colleagues, 1981b). It is due as well to changes in the level of steroidogenic acute regulatory protein, which allows rapid use of this cholesterol for progesterone biosynthesis (Devoto and colleagues, 2002). The important role for LDL in progesterone biosynthesis is supported by the observation that women with extremely low levels of LDL cholesterol exhibit low progesterone secretion during the luteal phase (Illingworth and colleagues, 1982). In addition, high-density lipoprotein (HDL) may contribute to progesterone production in granulosa-lutein cells (Ragoobir and colleagues, 2002).
Estrogen levels follow a more complex pattern of secretion. Specifically, just after ovulation, estrogen levels decrease followed by a secondary rise that reaches a peak production of 0.25 mg/day of 17 -estradiol at the midluteal phase. Toward the end of the luteal phase there is a secondary decrease in estradiol production. Ovarian production of progesterone peaks at 25 to 50 mg/day during the midluteal phase. If pregnancy occurs, the corpus luteum continues production of progesterone in response to embryonic hCG, which will bind and activate luteal cell LH receptors.
The human corpus luteum is a transient endocrine organ that, in the absence of pregnancy, will rapidly regress 9 to 11 days after ovulation. The mechanisms that control luteolysis of the human corpus luteum remain unclear. In part luteolysis results from the combination of decreased levels of circulating LH in the late luteal phase and decreased LH sensitivity of luteal cells (Duncan and colleagues, 1996; Filicori and colleagues, 1986). The role of other luteotropic factors in women is less clear, however, prostaglandin F2 (PGF2 ) appears to be luteolytic in nonhuman primates as well as in women (Auletta, 1987; Wentz and Jones, 1973). Within the corpus luteum, luteolysis is characterized by a loss of luteal cells due to an increase in apoptotic cell death (Vaskivuo and colleagues, 2002). The endocrine effects, consisting of a dramatic drop in circulating levels of estradiol and progesterone, are critical to allow the follicular development and ovulation of the next ovarian cycle. In addition, the regression of the corpus luteum and drop in circulating steroids signal the endometrium to initiate the molecular events that will lead to menstruation.

The endometrium–decidua is the anatomical site of blastocyst apposition, implantation, and placental development. From an evolutionary perspective, the human endometrium is highly developed to accommodate interstitial implantation and a hemochorial type of placentation. Endometrial development of a magnitude similar to that observed in women—that is, with special spiral (or coiling) arteries—is restricted to only a few primates, such as humans, great apes, and Old World monkeys. Trophoblasts of the blastocyst invade these endometrial arteries during implantation and placentation to establish uteroplacental vessels.
These primates are the only mammals that menstruate, which is a process of endometrial tissue shedding with hemorrhage that is dependent on sex steroid hormone–directed changes in blood flow in the spiral arteries. With nonfertile, but ovulatory, ovarian cycles, menstruation effects desquamation of the endometrium. New endometrial growth and development must be initiated with each cycle, so that endometrial maturation corresponds rather precisely with the next pregnancy (implantation) opportunity. There seems to be a very narrow window of endometrial receptivity to blastocyst implantation in the human that corresponds approximately to menstrual cycle days 20 to 24.
To place repetitive menstruation in perspective, the lifetime cumulative blood loss associated with normal endometrial shedding is 10 to 20 liters or more, an amount of blood that contains at least three times the total body iron content of the average adult woman. The approximately 38-year reproductive lifetime cumulative production of progesterone by corpora lutea and placenta in the woman who has two pregnancies and 450 nonfertile ovarian cycles is about 150,000 mg (150 g), which is similar to the cumulative amount of cortisol secreted by the adrenal cortices during the same 38 years. This incredible investment in endometrial tissue growth provides for regular renewal of the functional portion of this tissue in preparation for the next pregnancy opportunity.

All obstetricians should be aware of the basic reproductive biological processes that are required for women to successfully achieve ovulation, fertilization, and implantation. A number of abnormalities can affect each of these processes and lead to infertility or pregnancy loss. In most women, spontaneous, cyclical ovulation at 25- to 35-day intervals continues throughout almost 40 years between the time of menarche and menopause. For women who never use contraception, there are approximately 400 opportunities for pregnancy, which may occur with sexual intercourse on any of 1200 days (the day of ovulation and the 2 preceding days). This narrow window available for fertilization is controlled by tightly regulated production of ovarian steroids that cause the optimal regeneration of endometrium that begins with the ending of menstruation.
Should fertilization occur, the events that unfold after the initial implantation of the blastocyst onto the surface of the endometrium through to parturition result from a unique interaction between the trophoblasts of the fetus and the endometrium–decidua of the mother. The ability of mother and fetus to coexist as two distinct immunological systems results from endocrine, paracrine, and immunological modification of fetal and maternal tissues in a manner not seen elsewhere. The placenta mediates a unique fetal–maternal communication system, which creates a hormonal environment that helps initially to maintain pregnancy and eventually initiates the events leading to parturition. The following sections address the physiology of the ovarian–endometrial cycle, implantation, the placenta and fetal membranes, and the specialized endocrine arrangements between fetus and mother.

Compared with each other, as well as between women, the ovaries vary considerably in size. During childbearing years, they are from 2.5 to 5 cm in length, 1.5 to 3 cm in breadth, and 0.6 to 1.5 cm in thickness. After menopause, ovarian size diminishes remarkably. The position of the ovaries also varies, but they usually are situated in the upper part of the pelvic cavity and rest in a slight depression on the lateral wall of the pelvis between the divergent external and internal iliac vessels—the ovarian fossa of Waldeyer. The ovary is attached to the broad ligament by the mesovarium. The utero-ovarian ligament extends from the lateral and posterior portion of the uterus, just beneath the tubal insertion, to the uterine pole of the ovary. Usually, it is several centimeters long and 3 to 4 mm in diameter. It is covered by peritoneum and is made up of muscle and connective tissue fibers. The infundibulopelvic or suspensory ligament of the ovary extends from the upper or tubal pole to the pelvic wall; through it course the ovarian vessels and nerves.
In young women, the exterior surface of the ovary is smooth, with a dull white surface through which glisten several small, clear follicles. As the woman ages, the ovaries become more corrugated, and in elderly women, the exterior surfaces may be convoluted markedly.
The ovary consists of two portions, the cortex and medulla. The cortex is the outer layer, which varies in thickness with age and becomes thinner with advancing years. It is in this layer that the ova and graafian follicles are located. The cortex is composed of spindle-shaped connective tissue cells and fibers, among which are scattered primordial and graafian follicles in various stages of development. As the woman ages, the follicles become less numerous. The outermost portion of the cortex, which is dull and whitish, is designated the tunica albuginea. On its surface, there is a single layer of cuboidal epithelium, the germinal epithelium of Waldeyer.
The medulla is the central portion, which is composed of loose connective tissue that is continuous with that of the mesovarium. There are a large number of arteries and veins in the medulla and a small number of smooth muscle fibers that are continuous with those in the suspensory ligament.
The ovaries are supplied with both sympathetic and parasympathetic nerves. The sympathetic nerves are derived primarily from the ovarian plexus that accompanies the ovarian vessels. Others are derived from the plexus that surrounds the ovarian branch of the uterine artery. The ovary is richly supplied with nonmyelinated nerve fibers, which for the most part accompany the blood vessels. These are merely vascular nerves, whereas others form wreaths around normal and atretic follicles, and these give off many minute branches that have been traced up to, but not through, the membrana granulosa.