Human development begins at fertilization when a sperm fuses with an oocyte to form a single cell, the zygote . This highly specialized, totipotent cell (capable of giving rise to any cell type) marks the beginning of each of us as a unique individual. The zygote, just visible to the unaided eye, contains chromosomes and genes that are derived from the mother and father. The zygote divides many times and becomes progressively transformed into a multicellular human being through cell division, migration, growth, and differentiation.
Gametogenesis (gamete formation) is the process of formation and development of specialized generative cells, gametes (oocytes/sperms), from bipotential primordial germ cells . This development, involving the chromosomes and cytoplasm of the gametes, prepares these sex cells for fertilization. During gametogenesis , the chromosome number is reduced by half, and the shape of the cells is altered ( Fig. 2.1 ). A chromosome is defined by the presence of a centromere , the constricted portion of a chromosome. Before DNA replication in the S phase of the cell cycle, chromosomes exist as single-chromatid chromosomes ( Fig. 2.2 ). A chromatid (one of a pair of chromosome strands) consists of parallel DNA strands. After DNA replication, chromosomes are double-chromatid chromosomes.
The sperm and oocyte (male and female gametes) are highly specialized sex cells. Each of these cells contains half the number of chromosomes (haploid number) that are present in somatic (body) cells. The number of chromosomes is reduced during meiosis , a special type of cell division that occurs only during gametogenesis . Gamete maturation is called spermatogenesis in males and oogenesis in females. The timing of events during meiosis differs in the two sexes.
Meiosis is a special type of cell division that involves two meiotic cell divisions (see Fig. 2.2 ); diploid germ cells give rise to haploid gametes (sperms and oocytes).
The first meiotic division is a reduction division because the chromosome number is reduced from diploid to haploid by pairing of homologous chromosomes in prophase (first stage of meiosis) and their segregation at anaphase (stage when the chromosomes move from the equatorial plate). Homologous chromosomes, or homologs (one from each parent), pair during prophase and separate during anaphase, with one representative of each pair randomly going to each pole of the meiotic spindle (see Fig. 2.2 A to D ). The spindle connects to the chromosome at the centromere (the constricted part of the chromosome) (see Fig. 2.2 B ). At this stage, they are double-chromatid chromosomes.
The X and Y chromosomes are not homologs , but they have homologous segments at the tips of their short arms. They pair in these regions only. By the end of the first meiotic division, each new cell formed (secondary oocyte) has the haploid chromosome number, that is, half the number of chromosomes of the preceding cell. This separation or disjunction of paired homologous chromosomes is the physical basis of segregation, the separation of allelic genes (may occupy the same locus on a specific chromosome) during meiosis.
The second meiotic division (see Fig. 2.1 ) follows the first division without a normal interphase (i.e., without an intervening step of DNA replication). Each double-chromatid chromosome divides, and each half, or chromatid, is drawn to a different pole. Thus, the haploid number of chromosomes (23) is retained, and each daughter cell formed by meiosis has one representative of each chromosome pair (now a single-chromatid chromosome). The second meiotic division is similar to an ordinary mitosis except that the chromosome number of the cell entering the second meiotic division is haploid.
Provides constancy of the chromosome number from generation to generation by reducing the chromosome number from diploid to haploid, thereby producing haploid gametes
Allows random assortment of maternal and paternal chromosomes between the gametes
Relocates segments of maternal and paternal chromosomes by crossing over of chromosome segments, which “shuffles” the genes and produces a recombination of genetic material
Disturbances of meiosis during gametogenesis, such as nondisjunction ( Fig. 2.3 ), result in the formation of chromosomally abnormal gametes. If involved in fertilization, these gametes with numeric chromosome abnormalities cause abnormal development, as occurs in infants with the Down syndrome (see Chapter 20 ).
Spermatogenesis (a summary is presented here) is the sequence of events by which spermatogonia (primordial germ cells) are transformed into mature sperms; this maturation process begins at puberty and is regulated by testosterone signaling through androgen receptors in the Sertoli cells (see Fig. 2.1 ). Spermatogonia are dormant in the seminiferous tubules of the testes during the fetal and postnatal periods (see Fig. 2.12 ). They increase in number during puberty. After several mitotic divisions, the spermatogonia grow and undergo changes.
Spermatogonia are transformed into primary spermatocytes , the largest germ cells in the seminiferous tubules of the testes (see Fig. 2.1 ). Each primary spermatocyte subsequently undergoes a reduction division— the first meiotic division —to form two haploid secondary spermatocytes, which are approximately half the size of primary spermatocytes. Subsequently, the secondary spermatocytes undergo a second meiotic division to form four haploid spermatids , which are approximately half the size of secondary spermatocytes (see Fig. 2.1 ). The spermatids (cells in a late stage of development of sperms) are gradually transformed into four mature sperms by a process known as spermiogenesis ( Fig. 2.4 ). The entire process, which includes spermiogenesis, takes approximately 2 months. When spermiogenesis is complete, the sperms enter the lumina of the seminiferous tubules (see Fig. 2.12 ).
Sertoli cells lining the seminiferous tubules support and nurture the developing male germ cells and are involved in the regulation of spermatogenesis. Testosterone produced by the Leydig (interstitial) cells is an essential factor that promotes spermatogenesis. Sperms are transported passively from the seminiferous tubules to the epididymis, where they are stored and become functionally mature during puberty. The epididymis is an elongated coiled duct (see Fig. 2.12 ). The epididymis is continuous with the ductus deferens , which transports the sperms to the urethra (see Fig. 2.12 ).
Mature sperms are free-swimming, actively motile cells consisting of a head and a tail ( Fig. 2.5 A ). The neck of the sperm is the junction between the head and tail. The head of the sperm forms most of the bulk of the sperm and contains the nucleus. The anterior two thirds of the head is covered by the acrosome , a cap-like saccular organelle containing several enzymes (see Figs. 2.4 and 2.5 A ). When released, the enzymes facilitate dispersion of follicular cells of the corona radiata and sperm penetration of the zona pellucida during fertilization (see Figs. 2.5 A and C and 2.14 A and B ).
The tail of the sperm consists of three segments: middle piece, principal piece, and end piece (see Fig. 2.5 A ). The tail provides the motility of the sperm that assists its transport to the site of fertilization. The middle piece contains mitochondria , which provide adenosine triphosphate (ATP), necessary to support the energy required for motility.
Many genes and molecular factors are implicated in spermatogenesis. For example, recent studies indicate that retinoic acid and proteins of the Bcl-2 family are involved in the maturation of germ cells, as well as their survival at different stages . At the molecular level, HOX genes influence microtubule dynamics and the shaping of the head of the sperm and formation of the tail. For normal spermatogenesis, the Y chromosome is essential; microdeletions result in defective spermatogenesis and infertility .
Oogenesis is the sequence of events by which oogonia (primordial germ cells) are transformed into mature oocytes. All oogonia develop into primary oocytes before birth; no oogonia develop after birth. Oogenesis continues to menopause , which is the permanent cessation of the menstrual cycle (see Figs. 2.7 and 2.11 ).
Prenatal Maturation of Oocytes
During early fetal life, oogonia proliferate by mitosis (reproduction of cells). Oogonia enlarge to form primary oocytes before birth; for this reason, no oogonia are shown in Figs. 2.1 and 2.3 . As the oocytes form, connective tissue cells surround them and form a single layer of flattened, follicular cells (see Fig. 2.8 ). The primary oocyte enclosed by this layer of cells constitutes a primordial follicle (see Fig. 2.9 A ). As the primary oocyte enlarges during puberty, the follicular epithelial cells become cuboidal in shape and then columnar, forming a primary follicle (see Fig. 2.1 ).
The primary oocyte is soon surrounded by a covering of amorphous, acellular, glycoproteinaceous material, the zona pellucida (see Figs. 2.8 and 2.9 B ). Scanning electron microscopy of the surface of the zona pellucida reveals a regular mesh-like appearance with intricate fenestrations. Primary oocytes begin the first meiotic divisions before birth (see Fig. 2.3 ), but completion of prophase (see Fig. 2.2 A to D ) does not occur until adolescence (beginning with puberty). The follicular cells surrounding the primary oocytes secrete a substance, oocyte maturation inhibitor , which keeps the meiotic process of the oocyte arrested.
Postnatal Maturation of Oocytes
Beginning during puberty, usually one ovarian follicle matures each month and ovulation (release of oocyte from the ovarian follicle) occurs (see Fig. 2.7 ), except when hormonal contraceptives are used. The long duration of the first meiotic division (up to 45 years) may account in part for the relatively high frequency of meiotic errors , such as nondisjunction (failure of paired chromatids of a chromosome to dissociate), that occur with increasing maternal age. The primary oocytes in suspended prophase (dictyotene) are vulnerable to environmental agents such as radiation.
No primary oocytes form after birth , in contrast to the continuous production of primary spermatocytes (see Fig. 2.3 ). The primary oocytes remain dormant in ovarian follicles until puberty (see Fig. 2.8 ). As a follicle matures, the primary oocyte increases in size, and shortly before ovulation, the primary oocyte completes the first meiotic division to give rise to a secondary oocyte (see Fig. 2.10 A and B ) and the first polar body. Unlike the corresponding stage of spermatogenesis, however, the division of cytoplasm is unequal. The secondary oocyte receives almost all the cytoplasm (see Fig. 2.1 ), and the first polar body receives very little. The polar body is a small cell destined for degeneration.
At ovulation, the nucleus of the secondary oocyte begins the second meiotic division, but it progresses only to metaphase (see Fig. 2.2 E ), when division is arrested. If a sperm penetrates the secondary oocyte, the second meiotic division is completed, and most cytoplasm is again retained by one cell, the fertilized oocyte (see Fig. 2.1 ). The other cell, the second polar body , is also formed and will degenerate. As soon as the polar bodies are extruded, maturation of the oocyte is complete.
There are approximately 2 million primary oocytes in the ovaries of a neonate, but most of them regress during childhood so that by adolescence, no more than 40,000 primary oocytes remain. Of these, only approximately 400 become secondary oocytes and are expelled at ovulation during the reproductive period. Very few of these oocytes, if any, are fertilized.
Comparison of Gametes
The gametes (oocytes/sperms) are haploid cells (have half the number of chromosomes) that can undergo karyogamy (fusion of nuclei of two sex cells). The oocyte is a massive cell compared with the sperm, and it is immotile, whereas the microscopic sperm is highly motile (see Fig. 2.5 A ). The oocyte is surrounded by the zona pellucida and a layer of follicular cells, the corona radiata (see Fig. 2.5 C ).
With respect to sex chromosome constitution , there are two kinds of normal sperms, 23,X and 23,Y, whereas there is only one kind of secondary oocyte, 23,X (see Fig. 2.1 ). By convention, the number 23 is followed by a comma and an X or Y to indicate the sex chromosome constitution; for example, 23,X indicates that there are 23 chromosomes in the complement, consisting of 22 autosomes (chromosomes other than sex chromosomes) and 1 sex chromosome (X in this case). The difference in the sex chromosome complement of sperm forms the basis of primary sex determination.
The ideal biologic maternal age for reproduction is from 20 to 35 years. The likelihood of chromosomal abnormalities in an embryo gradually increases as the mother ages. In older mothers, there is an appreciable risk of Down syndrome (trisomy 21) or other forms of trisomy in the infant (see Chapter 20 ). The likelihood of a fresh gene mutation (change in DNA) also increases with age. Sperm quality and testicular function decline with age, and advanced paternal age increases the number of offspring with genetic abnormalities. Therefore, the older the parents are at the time of conception, the more likely they are to have accumulated mutations that the embryo might inherit.
During gametogenesis, homologous chromosomes sometimes fail to separate, a pathogenic process called nondisjunction ; as a result, some gametes have 24 chromosomes and others only 22 (see Fig. 2.3 ). If a gamete with 24 chromosomes unites with a normal one with 23 chromosomes during fertilization, a zygote with 47 chromosomes forms (see Chapter 20 , Fig. 20.2 ). This condition is called trisomy because of the presence of three representatives of a particular chromosome, instead of the usual two. If a gamete with only 22 chromosomes unites with a normal one, a zygote with 45 chromosomes forms. This condition is called monosomy because only one representative of the particular chromosome pair is present. For a description of the clinical conditions associated with numeric disorders of chromosomes, see Chapter 20 .
As many as 10% of sperms ejaculated are grossly abnormal (e.g., with two heads), but it is believed that these abnormal sperms do not fertilize oocytes due to their lack of normal motility. Most morphologically abnormal sperms are unable to pass through the mucus in the cervical canal. Measurement of forward progression is a subjective assessment of the quality of sperm movement. Such sperms are not believed to affect fertility unless their number exceeds 20%. Although some oocytes have two or three nuclei, these cells die before they reach maturity. Similarly, some ovarian follicles contain two or more oocytes, but this phenomenon is rare.
Uterus, Uterine Tubes, and Ovaries
A brief description of the structure of the uterus, uterine tubes, and ovaries is presented as a basis for understanding reproductive ovarian cycles and the implantation of blastocysts ( Figs. 2.6 and 2.7 , and see Fig. 2.20 ).
The uterus is a thick-walled, pear-shaped muscular organ, averaging 7 to 8 cm in length, 5 to 7 cm in width at its superior part, and 2 to 3 cm in wall thickness. The uterus consists of two major parts (see Fig. 2.6 A and B ): the body , the superior two thirds, and the cervix , the cylindric inferior one third.
The body of the uterus narrows from the fundus , the rounded superior part of the body, to the isthmus , the 1-cm-long constricted region between the body and cervix (see Fig. 2.6 A ). The cervix of the uterus is its tapered vaginal end that is nearly cylindric in shape. The lumen of the cervix, the cervical canal , has a constricted opening at each end. The internal os (opening) of the uterus communicates with the cavity of the uterine body, and the external os communicates with the vagina (see Fig. 2.6 A and B ).
The walls of the body of the uterus consist of three layers (see Fig. 2.6 B ):
Perimetrium, the thin external layer
Myometrium, the thick smooth muscle layer
Endometrium, the thin internal layer
The perimetrium is a peritoneal layer that is firmly attached to the myometrium (see Fig. 2.6 B ). During the luteal (secretory) phase of the menstrual cycle, three layers of the endometrium can be distinguished microscopically (see Fig. 2.6 C ):
A thin, compact layer consisting of densely packed connective tissue around the necks of the uterine glands
A thick, spongy layer composed of edematous (having large amounts of fluid) connective tissue containing the dilated, tortuous bodies of the uterine glands
A thin, basal layer containing the blind ends of the uterine glands
At the peak of its development, the endometrium is 4 to 5 mm thick (see Fig. 2.6 B and C ). The basal layer of the endometrium has its own blood supply and is not sloughed off during menstruation (see Fig. 2.7 ). The compact and spongy layers, known collectively as the functional layer , disintegrate and are shed during menstruation and after parturition (delivery of a fetus).
The uterine tubes , approximately 10 cm long and 1 cm in diameter, extend laterally from the horns of the uterus (see Fig. 2.6 A and B ). Each tube opens at its proximal end into the horn of the uterus and into the peritoneal cavity at its distal end. For descriptive purposes, the uterine tube is divided into four parts: infundibulum , ampulla , isthmus , and uterine part (see Fig. 2.6 B ). One of the tubes carries an oocyte from one of the ovaries; the tubes also carry sperms entering from the uterus to reach the fertilization site, the ampulla (see Figs. 2.6 B and 2.21 ). The uterine tube is lined with cilia and, together with muscular contractions by the tube, conveys the cleaving zygote to the uterine cavity.
The ovaries are almond-shaped reproductive glands located close to the lateral pelvic walls on each side of the uterus. The ovaries produce oocytes (see Fig. 2.6 B ) and estrogen and progesterone, the hormones responsible for the development of secondary sex characteristics and regulation of pregnancy.
Female Reproductive Cycles
Commencing at puberty (10 to 13 years of age), females undergo reproductive cycles (sexual cycles), involving activities of the hypothalamus of the brain, pituitary gland, ovaries, uterus, uterine tubes, vagina, and mammary glands (see Fig. 2.7 ). These monthly cycles prepare the reproductive system for pregnancy.
A gonadotropin-releasing hormone is synthesized by neurosecretory cells in the hypothalamus. This hormone is carried by a capillary network, the portal hypophyseal circulation (hypophyseal portal system), to the anterior lobe of the pituitary gland. The hormone stimulates the release of two hormones produced by this gland that act on the ovaries:
Follicle-stimulating hormone (FSH) stimulates the development of ovarian follicles and the production of estrogen by the follicular cells.
Luteinizing hormone (LH) serves as the “trigger” for ovulation (release of a secondary oocyte) and stimulates the follicular cells and corpus luteum to produce progesterone.
These hormones also induce growth of the ovarian follicles and the endometrium.
FSH and LH produce cyclic changes in the ovaries—the ovarian cycle (see Fig. 2.7 )—development of follicles ( Fig. 2.8 ), ovulation (release of an oocyte from a mature follicle), and corpus luteum formation . During each cycle, FSH promotes the growth of several primordial follicles into 5 to 12 primary follicles ( Fig. 2.9 A ); however, only one primary follicle usually develops into a mature follicle and ruptures through the surface of the ovary, expelling its oocyte ( Fig. 2.10 ).
Growth and differentiation of a primary oocyte
Proliferation of follicular cells
Formation of the zona pellucida
Development of the theca folliculi
As the primary follicle increases in size, the adjacent connective tissue organizes into a capsule, the theca folliculi (see Fig. 2.7 ). This theca soon differentiates into two layers, an internal vascular and glandular layer, the theca interna , and a capsule-like layer, the theca externa . Thecal cells are thought to produce an angiogenesis factor that promotes growth of blood vessels in the theca interna, which provide nutritive support for follicular development. The follicular cells divide actively, producing a stratified layer around the oocyte (see Fig. 2.9 B ). The ovarian follicle soon becomes oval and the oocyte eccentric in position. Subsequently, fluid-filled spaces appear around the follicular cells, which coalesce to form a single large cavity, the antrum , which contains follicular fluid (see Figs. 2.8 and 2.9 B ). After the antrum forms, the ovarian follicle is called a vesicular or secondary follicle .
The primary oocyte is pushed to one side of the follicle, where it is surrounded by a mound of follicular cells, the cumulus oophorus , that projects into the antrum (see Fig. 2.9 B ). The follicle continues to enlarge until it reaches maturity and produces a swelling (follicular stigma) on the surface of the ovary (see Fig. 2.10 A ).
The early development of ovarian follicles is induced by FSH, but final stages of maturation require LH as well. Growing follicles produce estrogen , a hormone that regulates development and function of the reproductive organs. The vascular theca interna produces follicular fluid and some estrogen (see Fig. 2.10 B ). Its cells also secrete androgens that pass to the follicular cells (see Fig. 2.8 ), which, in turn, convert them into estrogen. Some estrogen is also produced by widely scattered groups of stromal secretory cells, known collectively as the interstitial gland of the ovary .
Around the middle of the ovarian cycle, the ovarian follicle, under the influence of FSH and LH, undergoes a sudden growth spurt , producing a cystic swelling or bulge on the surface of the ovary. A small avascular spot, the stigma , soon appears on this swelling (see Fig. 2.10 A ). Before ovulation, the secondary oocyte and some cells of the cumulus oophorus detach from the interior of the distended follicle (see Fig. 2.10 B ).
Ovulation is triggered by a surge of LH production ( Fig. 2.11 ). Ovulation usually follows the LH peak by 12 to 24 hours. The LH surge, elicited by the high estrogen level in the blood, appears to cause the stigma to balloon out, forming a vesicle (see Fig. 2.10 A ). The stigma soon ruptures, expelling the secondary oocyte with the follicular fluid (see Fig. 2.10 B to D ). Expulsion of the oocyte is the result of intrafollicular pressure, and possibly by contraction of smooth muscle in the theca externa (sheath) owing to stimulation by prostaglandins.