The Female Reproductive System
PART ILecture 3
24-2-2016
Female reproductive functions can be divided into two major phases:
(1) preparation of the female body for conception and pregnancy(2) the period of pregnancy itself.
The reproductive system of women, unlike that of men, shows regular cyclic changes that teleologically may be regarded as periodic preparations for fertilization and pregnancy. In humans and other primates, the cycle is a menstrual cycle, and its most conspicuous feature is the periodic vaginal bleeding that occurs with the shedding of the uterine mucosa (menstruation). The length of the cycle is notoriously variable in women, but an average figure is 28 days from the start of one menstrual period to the start of the next. By common usage, the days of the cycle are identified by number, starting with the first day of menstruation ( CD1).
PHYSIOLOGIC ANATOMY OF THE FEMALE SEXUAL ORGANS
In the middle of each monthly sexual cycle, a single ovum is expelled from an ovarian follicle into the abdominal cavity near the open fimbriated ends of the two fallopian tubes. This ovum then passes through one of the fallopian tubes into the uterus; if it has been fertilized by a sperm, it implants in the uterus, where it develops into a fetus, a placenta, and fetal membranes-and eventually into a baby.During fetal life, the outer surface of the ovary is covered by a germinal epithelium, which embryologically is derived from the epithelium of the germinal ridges. As the female fetus develops, primordial ova differentiate from this germinal epithelium and migrate into the substance of the ovarian cortex. Each ovum then collects around it a layer of spindle cells from the ovarian stroma (the supporting tissue of the ovary) and causes them to take on epithelioid characteristics; they are then called granulosa cells. The ovum surrounded by a single layer of granulosa cells is called a primordial follicle. The ovum itself at this stage is still immature, requiring two more cell divisions before it can be fertilized by a sperm. At this time, the ovum is called a primary oocyte.
During all the reproductive years of adult life, between about 13 and 46 years of age, 400 to 500 of the primordial follicles develop enough to expel their ova-one each month; the remainder degenerate (become atretic). At the end of reproductive capability (at menopause), only a few primordial follicles remain in the ovaries, and even these degenerate soon thereafter.
SHAPE \* MERGEFORMAT
Female reproductive organsOOGENESIS AND FOLLICULAR DEVELOPMENT IN THE OVARIES
A developing egg (oocyte) differentiates into a mature egg (ovum) through a series of steps called oogenesis (Figure 82-3). During early embryonic development, primordial germ cells from the dorsal endoderm of the yolk
sac migrate along the mesentery of the hindgut to the outer surface of the ovary, which is covered by a germinal epithelium, derived embryologically from the epithelium of the germinal ridges. During this migration, the germ cells divide repeatedly. Once these primordial germ cells reach the germinal epithelium, they migrate into the substance of the ovarian cortex and become oogonia or primordial ova.
Each primordial ovum then collects around it a layer of spindle cells from the ovarian stroma (the supporting tissue of the ovary) and causes them to take on epithelioid characteristics; these epithelioid-like cells are then called granulosa cells. The ovum surrounded by a single layer of granulosa cells is called a primordial follicle. At this stage the ovum is still immature and is called a primary oocyte, requiring two more cell divisions before it can be fertilized by a sperm.
The oogonia in the embryonic ovary complete mitotic replication and the first stage of meiosis by the fifth month of fetal development. The germ cell mitosis then ceases and no additional oocytes are formed. At birth the ovary contains about 1 to 2 million primary oocytes.
The first meiotic division of the oocyte occurs after puberty. Each oocyte divides into two cells, a large ovum (secondary oocyte) and a small first polar body. Each of these cells contains 23 duplicated chromosomes. The first polar body may or may not undergo a second meiotic division and then disintegrates. The ovum undergoes a second meiotic division, and after the sister chromatids separate, there is a pause in meiosis. If the ovum is fertilized, the final step in meiosis occurs and the sister chromatids in the ovum go to separate cells.
When the ovary releases the ovum (ovulation) and if the ovum is fertilized, the final meiosis occurs. Half of the sister chromatids remain in the fertilized ovum and the other half are released in a second polar body, which then disintegrates.
At puberty, only about 300,000 oocytes remain in the ovaries, and only a small percentage of these oocytes become mature. The many thousands of oocytes that do not mature degenerate. During all the reproductive years of adult life, between about 13 and 46 years of age, only 400 to 500 of the primordial follicles develop enough to expel their ovaone each month; the remainder degenerate
(i.e., become atretic). At the end of reproductive capability (at menopause), only a few primordial follicles remain in the ovaries, and even these follicles degenerate soon thereafter.
Female Hormonal System
The female hormonal system, like that of the male, consists of three hormones, as follows:1-A hypothalamic releasing hormone, gonadotropin-releasing hormone (GnRH)
2-The anterior pituitary sex hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), both of which are secreted in response to the release of GnRH from the hypothalamus
3-The ovarian hormones, estrogen and HYPERLINK "http://www.studentconsult.com/content/bookcontent.cfm?xrefID=C08202401" \l "C08202401" \o "View drug information" \t "_parent" progesterone , which are secreted by the ovaries in response to the two female sex hormones from the anterior pituitary gland
These various hormones are not secreted in constant amounts throughout the female monthly sexual cycle; they are secreted at drastically differing rates during different parts of the cycle.
The amount of GnRH released from the hypothalamus increases and decreases much less drastically during the monthly sexual cycle. It is secreted in short pulses averaging once every 90 minutes, as occurs in the male.
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Internal structures of the uterus, ovary, and a uterine tube
Ovarian Cycle
From the time of birth, there are many primordial follicles under the ovarian capsule. Each contains an immature ovum. At the start of each cycle, several of these follicles enlarge, and a cavity forms around the ovum (antrum formation). This cavity is filled with follicular fluid. In humans, usually one of the follicles in one ovary starts to grow rapidly on about the sixth day and becomes the dominant follicle, while the others regress, forming atretic follicles. The atretic process involves apoptosis. It is uncertain how one follicle is selected to be the dominant follicle in this follicular phase of the menstrual cycle, but it seems to be related to the ability of the follicle to secrete the estrogen inside it that is needed for final maturation. When women are given highly purified human pituitary gonadotropin preparations by injection, many follicles develop simultaneously.The primary source of circulating estrogen is the granulosa cells of the ovaries; however, the cells of the theca interna of the follicle are necessary for the production of estrogen as they secrete androgens that are aromatized to estrogen by the granulosa cells.
At about the 14th day of the cycle, the distended follicle ruptures, and the ovum is extruded into the abdominal cavity. This is the process of ovulation. The ovum is picked up by the fimbriated ends of the uterine tubes (oviducts). It is transported to the uterus and, unless fertilization occurs, out through the vagina.
The follicle that ruptures at the time of ovulation promptly fills with blood, forming what is sometimes called a corpus hemorrhagicum. Minor bleeding from the follicle into the abdominal cavity may cause peritoneal irritation and fleeting lower abdominal pain ("mittelschmerz"). The granulosa and theca cells of the follicle lining promptly begin to proliferate, and the clotted blood is rapidly replaced with yellowish, lipid-rich luteal cells, forming the corpus luteum. This initiates the luteal phase of the menstrual cycle, during which the luteal cells secrete estrogen and progesterone. Growth of the corpus luteum depends on its developing an adequate blood supply, and there is evidence that vascular endothelial growth factor (VEGF) (see Chapter 32) is essential for this process.
If pregnancy occurs, the corpus luteum persists and usually there are no more periods until after delivery. If pregnancy does not occur, the corpus luteum begins to degenerate about 4 d before the next menses (24th day of the cycle) and is eventually replaced by scar tissue, forming a corpus albicans.
The ovarian cycle in other mammals is similar, except that in many species more than one follicle ovulates and multiple births are the rule. Corpora lutea form in some submammalian species but not in others.
In humans, no new ova are formed after birth. During fetal development, the ovaries contain over 7 million primordial follicles. However, many undergo atresia (involution) before birth and others are lost after birth. At the time of birth, there are 2 million ova, but 50% of these are atretic. The million that are normal undergo the first part of the first meiotic division at about this time and enter a stage of arrest in prophase in which those that survive persist until adulthood. Atresia continues during development, and the number of ova in both of the ovaries at the time of puberty is less than 300,000 (Figure 2510). Only one of these ova per cycle (or about 500 in the course of a normal reproductive life) normally reaches maturity; the remainder degenerate. Just before ovulation, the first meiotic division is completed. One of the daughter cells, the secondary oocyte, receives most of the cytoplasm, while the other, the first polar body, fragments and disappears. The secondary oocyte immediately begins the second meiotic division, but this division stops at metaphase and is completed only when a sperm penetrates the oocyte. At that time, the second polar body is cast off and the fertilized ovum proceeds to form a new individual. The arrest in metaphase is due, at least in some species, to formation in the ovum of the protein pp39 mos , which is encoded by the c-mos protooncogene. When fertilization occurs, the pp39 mos is destroyed within 30 min by calpain, a calcium-dependent cysteineprotease.
MONTHLY OVARIAN CYCLE; FUNCTION OF THE GONADOTROPIC HORMONES
The normal reproductive years of the female are characterized by monthly rhythmical changes in the rates of secretion of the female hormones and corresponding physical changes in the ovaries and other sexual organs. This rhythmical pattern is called the female monthly sexual cycle (or, less accurately, the menstrual cycle). The duration of the cycle averages 28 days. It may be as short as 20 days or as long as 45 days in some women, although abnormal cycle length is frequently associated with decreased fertility.
There are two significant results of the female sexual cycle. First, only a single ovum is normally released from the ovaries each month, so that normally only a single fetus will begin to grow at a time. Second, the uterine endometrium is prepared in advance for implantation of the fertilized ovum at the required time of the month.
SHAPE \* MERGEFORMAT Approximate plasma concentrations of the gonadotropins and ovarian hormones during the normal female sexual cycle. FSH, follicle-stimulating hormone; LH, luteinizing hormone.
GONADOTROPIC HORMONES AND THEIR EFFECTS ON THE OVARIES
The ovarian changes that occur during the sexual cycle depend completely on the gonadotropic hormones FSH and LH, secreted by the anterior pituitary gland. In the absence of these hormones, the ovaries remain inactive, which is the case throughout childhood, when almost no pituitary gonadotropic hormones are secreted. At age 9 to 12 years, the pituitary begins to secrete progressively more FSH and LH, which leads to onset of normal monthly sexual cycles beginning between the ages of 11 and 15 years. This period of change is called puberty, and the time of the first menstrual cycle is called menarche. Both FSH and LH are small glycoproteins having molecular weights of about 30,000.
During each month of the female sexual cycle, there is a cyclical increase and decrease of both FSH and LH. These cyclical variations cause cyclical ovarian changes, which are explained in the following sections.
Both FSH and LH stimulate their ovarian target cells by combining with highly specific FSH and LH receptors in the ovarian target cell membranes. In turn, the activated receptors increase the cells' rates of secretion and usually the growth and proliferation of the cells as well. Almost all these stimulatory effects result from activation of the cyclic HYPERLINK "http://www.studentconsult.com/content/bookcontent.cfm?xrefID=C08202401" \l "C08202401" \o "View drug information" \t "_parent" adenosine monophosphate second messenger system in the cell cytoplasm, which causes the formation of protein kinase and multiple phosphorylations of key enzymes that stimulate sex hormone synthesis.
OVARIAN FOLLICLE GROWTH-"FOLLICULAR" PHASE OF THE OVARIAN CYCLE
When a female child is born, each ovum is surrounded by a single layer of granulosa cells; the ovum, with this granulosa cell sheath, is called a primordial follicle, as shown in the figure. Throughout childhood, the granulosa cells are believed to provide nourishment for the ovum and to secrete an oocyte maturation-inhibiting factor that keeps the ovum suspended in its primordial state in the prophase stage of meiotic division. Then, after puberty, when FSH and LH from the anterior pituitary gland begin to be secreted in significant quantities, the ovaries, together with some of the follicles within them, begin to grow.The first stage of follicular growth is moderate enlargement of the ovum itself, which increases in diameter twofold to threefold. Then follows growth of additional layers of granulosa cells in some of the follicles; these follicles are known as primary follicles
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Stages of follicular growth in the ovary, also showing formation of the corpus luteum.
Development of Antral and Vesicular Follicles
During the first few days of each monthly female sexual cycle, the concentrations of both FSH and LH secreted by the anterior pituitary gland increase slightly to moderately, with the increase in FSH slightly greater than that of LH and preceding it by a few days. These hormones, especially FSH, cause accelerated growth of 6 to 12 primary follicles each month. The initial effect is rapid proliferation of the granulosa cells, giving rise to many more layers of these cells. In addition, spindle cells derived from the ovary interstitium collect in several layers outside the granulosa cells, giving rise to a second mass of cells called the theca. This is divided into two layers. In the theca interna, the cells take on epithelioid characteristics similar to those of the granulosa cells and develop the ability to secrete additional steroid sex hormones (estrogen and HYPERLINK "http://www.studentconsult.com/content/bookcontent.cfm?xrefID=C07902401" \l "C07902401" \o "View drug information" \t "_parent" progesterone ). The outer layer, the theca externa, develops into a highly vascular connective tissue capsule that becomes the capsule of the developing follicle.After the early proliferative phase of growth, lasting for a few days, the mass of granulosa cells secretes a follicular fluid that contains a high concentration of estrogen, one of the important female sex hormones (discussed later). Accumulation of this fluid causes an antrum to appear within the mass of granulosa cells. The early growth of the primary follicle up to the antral stage is stimulated mainly by FSH alone. Then greatly accelerated growth occurs, leading to still larger follicles called vesicular follicles. This accelerated growth is caused by the following: (1) Estrogen is secreted into the follicle and causes the granulosa cells to form increasing numbers of FSH receptors; this causes a positive feedback effect, because it makes the granulosa cells even more sensitive to FSH. (2) The pituitary FSH and the estrogens combine to promote LH receptors on the original granulosa cells, thus allowing LH stimulation to occur in addition to FSH stimulation and creating an even more rapid increase in follicular secretion. (3) The increasing estrogens from the follicle plus the increasing LH from the anterior pituitary gland act together to cause proliferation of the follicular thecal cells and increase their secretion as well.
Once the antral follicles begin to grow, their growth occurs almost explosively. The ovum itself also enlarges in diameter another threefold to fourfold, giving a total ovum diameter increase up to 10-fold, or a mass increase of 1000-fold. As the follicle enlarges, the ovum itself remains embedded in a mass of granulosa cells located at one pole of the follicle.
Only One Follicle Fully Matures Each Month, and the Remainder Undergo Atresia
After a week or more of growth-but before ovulation occurs-one of the follicles begins to outgrow all the others; the remaining 5 to 11 developing follicles involute (a process called atresia), and these follicles are said to become atretic.The cause of the atresia is unknown, but it has been postulated to be the following: The large amounts of estrogen from the most rapidly growing follicle act on the hypothalamus to depress further enhancement of FSH secretion by the anterior pituitary gland, in this way blocking further growth of the less well developed follicles. Therefore, the largest follicle continues to grow because of its intrinsic positive feedback effects, while all the other follicles stop growing and actually involute.
This process of atresia is important, because it normally allows only one of the follicles to grow large enough each month to ovulate; this usually prevents more than one child from developing with each pregnancy. The single follicle reaches a diameter of 1 to 1.5 centimeters at the time of ovulation and is called the mature follicle.
Ovulation
Ovulation in a woman who has a normal 28-day female sexual cycle occurs 14 days after the onset of menstruation. Shortly before ovulation, the protruding outer wall of the follicle swells rapidly, and a small area in the center of the follicular capsule, called the stigma, protrudes like a nipple. In another 30 minutes or so, fluid begins to ooze from the follicle through the stigma, and about 2 minutes later, the stigma ruptures widely, allowing a more viscous fluid, which has occupied the central portion of the follicle, to evaginate outward. This viscous fluid carries with it the ovum surrounded by a mass of several thousand small granulosa cells, called the corona radiata.Surge of LH Is Necessary for Ovulation
LH is necessary for final follicular growth and ovulation. Without this hormone, even when large quantities of FSH are available, the follicle will not progress to the stage of ovulation.About 2 days before ovulation (for reasons that are not completely understood but are discussed in more detail later in the chapter), the rate of secretion of LH by the anterior pituitary gland increases markedly, rising 6- to 10-fold and peaking about 16 hours before ovulation. FSH also increases about 2-fold to 3-fold at the same time, and the FSH and LH act synergistically to cause rapid swelling of the follicle during the last few days before ovulation. The LH also has a specific effect on the granulosa and theca cells, converting them mainly to progesterone-secreting cells. Therefore, the rate of secretion of estrogen begins to fall about 1 day before ovulation, while increasing amounts of HYPERLINK "http://www.studentconsult.com/content/bookcontent.cfm?xrefID=C08202401" \l "C08202401" \o "View drug information" \t "_parent" progesterone begin to be secreted.
It is in this environment of (1) rapid growth of the follicle, (2) diminishing estrogen secretion after a prolonged phase of excessive estrogen secretion, and (3) initiation of secretion of HYPERLINK "http://www.studentconsult.com/content/bookcontent.cfm?xrefID=C07402401" \l "C07402401" \o "View drug information" \t "_parent" progesterone that ovulation occurs. Without the initial preovulatory surge of LH, ovulation will not take place.
CORPUS LUTEUM-"LUTEAL" PHASE OF THE OVARIAN CYCLE
During the first few hours after expulsion of the ovum from the follicle, the remaining granulosa and theca interna cells change rapidly into lutein cells. They enlarge in diameter two or more times and become filled with lipid inclusions that give them a yellowish appearance. This process is called luteinization, and the total mass of cells together is called the corpus luteum. A well-developed vascular supply also grows into the corpus luteum.
The granulosa cells in the corpus luteum develop extensive intracellular smooth endoplasmic reticula that form large amounts of the female sex hormones HYPERLINK "http://www.studentconsult.com/content/bookcontent.cfm?xrefID=C08202401" \l "C08202401" \o "View drug information" \t "_parent" progesterone and estrogen (more HYPERLINK "http://www.studentconsult.com/content/bookcontent.cfm?xrefID=C08202401" \l "C08202401" \o "View drug information" \t "_parent" progesterone than estrogen). The theca cells form mainly the androgens androstenedione and HYPERLINK "http://www.studentconsult.com/content/bookcontent.cfm?xrefID=C07902401" \l "C07902401" \o "View drug information" \t "_parent" testosterone rather than female sex hormones. However, most of these hormones are also converted by the granulosa cells into the female hormones.
In the normal female, the corpus luteum grows to about 1.5 centimeters in diameter, reaching this stage of development 7 to 8 days after ovulation. Then it begins to involute and eventually loses its secretory function as well as its yellowish, lipid characteristic about 12 days after ovulation, becoming the corpus albicans; during the ensuing few weeks, this is replaced by connective tissue and over months is absorbed.
Luteinizing Function of LH
The change of granulosa and theca interna cells into lutein cells is dependent mainly on LH secreted by the anterior pituitary gland. In fact, this function gives LH its name-"luteinizing," for "yellowing." Luteinization also depends on extrusion of the ovum from the follicle. A yet uncharacterized local hormone in the follicular fluid, called luteinization-inhibiting factor, seems to hold the luteinization process in check until after ovulation.Secretion by the Corpus Luteum: An Additional Function of LH. The corpus luteum is a highly secretory organ, secreting large amounts of both HYPERLINK "http://www.studentconsult.com/content/bookcontent.cfm?xrefID=C08202401" \l "C08202401" \o "View drug information" \t "_parent" progesterone and estrogen. Once LH (mainly that secreted during the ovulatory surge) has acted on the granulosa and theca cells to cause luteinization, the newly formed lutein cells seem to be programmed to go through a preordained sequence of (1) proliferation, (2) enlargement, and (3) secretion, followed by (4) degeneration. All this occurs in about 12 days. There is another hormone with almost exactly the same properties as LH, chorionic gonadotropin, which is secreted by the placenta, can act on the corpus luteum to prolong its life-usually maintaining it for at least the first 2 to 4 months of pregnancy
Involution of the Corpus Luteum and Onset of the Next Ovarian Cycle.
Estrogen in particular and HYPERLINK "http://www.studentconsult.com/content/bookcontent.cfm?xrefID=C07402401" \l "C07402401" \o "View drug information" \t "_parent" progesterone to a lesser extent, secreted by the corpus luteum during the luteal phase of the ovarian cycle, have strong feedback effects on the anterior pituitary gland to maintain low secretory rates of both FSH and LH.In addition, the lutein cells secrete small amounts of the hormone inhibin, the same as the inhibin secreted by the Sertoli cells of the male testes. This hormone inhibits secretion by the anterior pituitary gland, especially FSH secretion. Low blood concentrations of both FSH and LH result, and loss of these hormones finally causes the corpus luteum to degenerate completely, a process called involution of the corpus luteum.
Final involution normally occurs at the end of almost exactly 12 days of corpus luteum life, which is around the 26th day of the normal female sexual cycle, 2 days before menstruation begins. At this time, the sudden cessation of secretion of estrogen, HYPERLINK "http://www.studentconsult.com/content/bookcontent.cfm?xrefID=C08202401" \l "C08202401" \o "View drug information" \t "_parent" progesterone , and inhibin by the corpus luteum removes the feedback inhibition of the anterior pituitary gland, allowing it to begin secreting increasing amounts of FSH and LH again. FSH and LH initiate the growth of new follicles, beginning a new ovarian cycle. The paucity of secretion of HYPERLINK "http://www.studentconsult.com/content/bookcontent.cfm?xrefID=C08202401" \l "C08202401" \o "View drug information" \t "_parent" progesterone and estrogen at this time also leads to menstruation by the uterus, as explained later.
ASS. PROF. DR. SABAH MAHDI HUSSEIN ALKINDY COLLEGE OF MEDICINE REPRODUCTIVE MODULE The Female Reproductive System L 3