Sexual Reproduction in Humans

Index to this page

The Problems to be Solved

Sexual reproduction is the formation of a new individual following the union of two gametes. In humans and the majority of other eukaryotes — plants as well as animals — the two gametes Gametes need In animals (and some plants), these two rather contrasting needs are met by anisogametes:

Sex Organs of the Human Male

The reproductive system of the male has two major functions: Sperm production — spermatogenesis — takes place in the testes.

Each testis is packed with seminiferous tubules (laid end to end, they would extend more than 20 meters) where spermatogenesis occurs.


Spermatogenesis

The walls of the seminiferous tubules consist of diploid spermatogonia, stem cells that are the precursors of sperm.

Spermatogonia

Meiosis of each spermatocyte produces 4 haploid spermatids. This process takes over three weeks to complete.

Then the spermatids differentiate into sperm, losing most of their cytoplasm in the process.

For simplicity, the figure shows the behavior of just a single pair of homologous chromosomes with a single crossover. With 22 pairs of autosomes and an average of two crossovers between each pair, the variety of gene combinations in sperm is very great.

Sperm

Sperm cells are little more than flagellated nuclei. Each consists of

This electron micrograph (courtesy of Dr. Don W. Fawcett and Susumu Ito) shows the sperm cell of a bat. Note the orderly arrangement of the mitochondria. They supply the ATP to power the whiplike motion of the tail.

An adult male manufactures over 100 million sperm cells each day. These gradually move into the epididymis where they undergo further maturation. The acidic environment in the epididymis keeps the mature sperm inactive.

In addition to making sperm, the testis is an endocrine gland. Its principal hormone, testosterone, is responsible for the development of the secondary sex characteristics of men such as the beard, deep voice, and masculine body shape. Testosterone is also essential for making sperm.
Link to more on testosterone.
Testosterone is made in the interstitial cells (also called Leydig cells) that lie between the seminiferous tubules.

LH

Interstitial cells are, in turn, the targets for a hormone often called interstitial cell stimulating hormone (ICSH). It is a product of the anterior lobe of the pituitary gland. However, ICSH is identical to the luteinizing hormone (LH) found in females, and I prefer to call it LH.

FSH

Follicle-stimulating hormone (also named for its role in females) acts directly on spermatogonia to stimulate sperm production (aided by the LH needed for testosterone synthesis). [Discussion]

Sex Organs of the Human Female

The responsibility of the female mammal for successful reproduction is considerably greater than that of the male.


She must

Oogenesis

Egg formation takes place in the ovaries.

In contrast to males, the initial steps in egg production occur prior to birth. Diploid stem cells called oogonia divide by mitosis to produce more oogonia and primary oocytes. By the time the fetus is 20 weeks old, the process reaches its peak and all the oocytes that she will ever possess (~4 million of them) have been formed (*). By the time she is born, only about 1 million of these remain (the others eliminated by apoptosis). Each has begun the first steps of the first meiotic division stopping at the diplotene stage of meiosis I.

No further development occurs until years later when the girl becomes sexually mature. Then the primary oocytes recommence their development, usually one at a time and once a month.

*Recent evidence in both mice and young women show the presence of oogonial stem cells that in vitro can develop into immature oocytes. Whether these can go on to develop enough to be fertilized AND whether such stem cells naturally produce new eggs in young women remains to be seen.

The primary oocyte grows much larger and completes meiosis I, forming a large secondary oocyte and a small polar body that receives little more than one set of chromosomes. Which chromosomes end up in the egg and which in the polar body is entirely a matter of chance.

In humans (and most vertebrates), the first polar body does not go on to meiosis II, but the secondary oocyte does proceed as far as metaphase of meiosis II and then stops.

Only if fertilization occurs will meiosis II ever be completed. Entry of the sperm restarts the cell cycle

Completion of meiosis II converts the secondary oocyte into a fertilized egg or zygote (and also a second polar body).

As in the diagram for spermatogenesis, the behavior of the chromosomes is greatly simplified.

The photomicrograph (courtesy of Turtox) shows polar body formation during oogenesis in the whitefish. Even allowing for the fact that fish eggs are larger than mammalian eggs, you can readily see how the polar body gets little more than one set of chromosomes.

These events take place within a follicle, a fluid-filled envelope of cells surrounding the developing egg.

The ripening follicle also serves as an endocrine gland. Its cells make a mixture of steroid hormones collectively known as estrogen. Estrogen is responsible for the development of the secondary sexual characteristics of a mature woman, e.g., Estrogen continues to be secreted throughout the reproductive years of women During this period, it plays an essential role in the monthly menstrual cycle.
Link to a discussion of the menstrual cycle and the hormones that regulate it.

There is growing evidence that in mice oocytes can continue to be produced throughout life (from germline stem cells in the bone marrow). It remains to be seen if that will turn out to be true for humans.

Ovulation

Ovulation occurs about two weeks after the onset of menstruation. In response to a sudden surge of LH, the follicle ruptures and discharges a secondary oocyte. This is swept into the open end of the fallopian tube and begins to move slowly down it.

Several sexually-transmitted diseases (STDs), especially gonorrhea and infections by chlamydia can cause scarring and blocking of the tubes and are a major cause of infertility.
In tubal ligation, the fallopian tubes are surgically cut and their ends tied to prevent pregnancy.

Copulation and Fertilization

For fertilization to occur, sperm must be deposited in the vagina within a few (5) days before or on the day of ovulation. Sperm transfer is accomplished by copulation. Sexual excitation dilates the arterioles supplying blood to the penis. Blood accumulates in three cylindrical spongy sinuses that run lengthwise through the penis. The resulting pressure causes the penis to enlarge and erect and thus able to penetrate the vagina.

Movement of the penis back and forth within the vagina causes sexual tension to increase to the point of ejaculation. Contraction of the walls of each vas deferens propels the sperm along. Fluid is added to the sperm by the seminal vesicles, Cowper's glands, and the prostate gland. [View] These fluids provide

The mixture of sperm and accessory fluids is called semen. It passes through the urethra and is expelled into the vagina.

Physiological changes occur in the female as well as the male in response to sexual excitement, although these are not as readily apparent. In contrast to the male, however, such responses are not a prerequisite for copulation and fertilization to occur.

Once deposited within the vagina, the sperm proceed on their journey into and through the uterus and on up into the fallopian tubes. It is here that fertilization may occur if an "egg" is present (strictly speaking, it is still a secondary oocyte until after completion of meiosis II).

Although sperm can swim several millimeters each second, their trip to and through the fallopian tubes may be assisted by muscular contraction of the walls of the uterus and the tubes. The trip is fraught with heavy mortality. An average human ejaculate contains over one hundred million sperm, but only a few dozen complete the journey, arriving within 15 minutes of ejaculation. And of these, only one will succeed in fertilizing the egg.

Sperm swim towards the egg by chemotaxis following a gradient of progesterone secreted by cells surrounding the egg. Progesterone opens CatSper ("cation sperm") channels in the plasma membrane surrounding the anterior portion of the sperm tail. This allows an influx of Ca2+ ions which causes the flagellum to beat more rapidly and vigorously.

Fertilization begins with the binding of a sperm head to the glycoprotein coating of the egg (called the zona pellucida). Exocytosis of the acrosome at the tip of the sperm head releases enzymes that digest a path through the zona and enable the sperm head to bind to the plasma membrane of the egg. Fusion of their respective membranes allows the entire contents of the sperm to be drawn into the cytosol of the egg. (Even though the sperm's mitochondria enter the egg, they are almost always destroyed — by autophagy — and do not contribute their genes to the embryo. So human mitochondrial DNA is almost always inherited from mothers only.)

Within moments, enzymes released from the egg cytosol act on the zona making it impermeable to the other sperm that arrive.

Soon the nucleus of the successful sperm enlarges into the male pronucleus. At the same time, the egg (secondary oocyte) completes meiosis II forming a second polar body and the female pronucleus.

The male and female pronuclei move toward each other while duplicating their DNA in S phase. Their nuclear envelopes disintegrate. A spindle is formed (following replication of the sperm's centriole), and a full set of dyads assembles on it. The fertilized egg or zygote is now ready for its first mitosis. When this is done, 2 cells — each with a diploid set of chromosomes — are formed.

In sea urchins, at least, the block to additional sperm entry and the fusion of the pronuclei are triggered by nitric oxide generated in the egg by the sperm acrosome. [Link]

Pregnancy

Development begins while the fertilized egg is still within the fallopian tube. Repeated mitotic divisions produces a solid ball of cells called a morula. Further mitosis and some migration of cells converts this into a hollow ball of cells called the blastocyst. Approximately one week after fertilization, the blastocyst embeds itself in the thickened wall of the uterus, a process called implantation, and pregnancy is established.

The blastocyst produces two major collections of cells:

The placenta grows tightly fused to the wall of the uterus. Its blood vessels, supplied by the fetal heart, are literally bathed in the mother's blood. Although there is normally no mixing of the two blood supplies, the placenta does facilitate the transfer of a variety of materials between the fetus and the mother.

But the placenta is not simply a transfer device. Using raw materials from the mother's blood, it synthesizes large quantities of proteins and also some hormones.
Link to discussion of the placenta
as an endocrine gland.
The metabolic activity of the placenta is almost as great as that of the fetus itself.

The umbilical cord connects the fetus to the placenta. It receives deoxygenated blood from the iliac arteries of the fetus and returns oxygenated blood to the liver and on to the inferior vena cava.

Because its lungs are not functioning, circulation in the fetus differs dramatically from that of the baby after birth. While within the uterus, blood pumped by the right ventricle bypasses the lungs by flowing through the foramen ovale and the ductus arteriosus.

Although the blood in the placenta is in close contact with the mother's blood in the uterus, intermingling of their blood does not normally occur. However, some of the blood cells of the fetus usually do escape into the mother's circulation — where they have been known to survive for decades. This raises the possibility of doing prenatal diagnosis of genetic disorders by sampling the mother's blood rather than having to rely on the more invasive procedures of amniocentesis and chorionic villus sampling (CVS).

Fragments of fetal DNA (~ 300 bp long) from apoptotic cells of the placenta are also found in the mother's plasma as early as 5 weeks after implantation. These can be tested for various forms of aneuploidy, e.g. the trisomy 21 of Down syndrome [More].

Far rarer is the leakage of mother's blood cells into the fetus. However, it does occur. A few pregnant women with leukemia or lymphoma have transferred the malignancy to their fetus. Some babies have also acquired melanoma from the transplacental passage of these highly-malignant cells from their mother.

During the first 2 months of pregnancy, the basic structure of the baby is being formed. This involves cell division, cell migration, and the differentiation of cells into the many types found in the baby. During this period, the developing baby — called an embryo — is very sensitive to anything that interferes with the steps involved. Virus infection of the mother, e.g., by rubella ("German measles") virus or exposure to certain chemicals may cause malformations in the developing embryo. Such agents are called teratogens ("monster-forming"). The tranquilizer, thalidomide, taken by many pregnant European women between 1954 and 1962, turned out to be a potent teratogen and was responsible for the birth of several thousand deformed babies.

After about two months, all the systems of the baby have been formed, at least in a rudimentary way. From then on, development of the fetus, as it is now called, is primarily a matter of growth and minor structural modifications. The fetus is less susceptible to teratogens than is the embryo.

Pregnancy involves a complex interplay of hormones. These are described in a separate page. [Link to it.]

The placenta is an allograft

One of the greatest unsolved mysteries in immunology is how the placenta survives for 9 months without being rejected by the mother's immune system. Every cell of the placenta carries the father's genome (a haploid set of his chromosomes); including one of his #6 chromosomes where the genes for the major histocompatibility antigens (HLA) are located.

One partial exception: none of the genes on the father's X chromosome are expressed. While X-chromosome inactivation is random in the cells of the fetus, it is NOT random in the cells of the trophoblast. In every cell of the trophoblast — and its descendants — it is the paternal X chromosome that is inactivated. [Discussion of X-chromosome inactivation.] But this does not solve our problem because the genes for all the major histocompatibility antigens are located on chromosome 6, which is not inactivated.
Discussion of the human major histocompatibility complex (MHC)

Thus the placenta is immunologically as foreign to the mother as a kidney transplant would be.

Yet it thrives.

Despite a half-century of research, the mechanism for this immunologically privileged status remains uncertain. But one thing is clear:

The mother is not intrinsically tolerant of the father's antigens.

Some evidence:

So what accounts for the phenomenon? Some possibilities:

Assisted Reproductive Technology ("ART")

On July 25, 2010 Louise Brown celebrated her 32th birthday. She was the first of what today number some four million (worldwide) "test tube babies"; that is, she developed from an egg that was fertilized outside her mother's body — the process called in vitro fertilization (IVF).

In Vitro Fertilization (IVF)

IVF involves

Intracytoplasmic Sperm Injection (ICSI)

Successful IVF assumes the availability of healthy sperm. But many cases of infertility arise from defects in the father's sperm. Often these can be overcome by directly injecting a single sperm into the egg.

In the U.S. today, some two-thirds of ART procedures employ ICSI (even though as many as half of these do not involve male infertility).

Ooplasmic Transfer

Infertility in some cases may stem from defects in the cytoplasm of the mother's egg. To circumvent these, cytoplasm can be removed from the egg of a young, healthy woman ("Donor egg") and injected — along with a single sperm — into the prospective mother's egg.

Although a few healthy children have been born following ooplasmic transfer, the jury is still out on its safety, and it is not approved for use in the U.S.

One reason for concern is that ooplasmic transfer results in an egg carrying both the mother's mitochondria and mitochondria from the donor (in normal fertilization, all the mitochondria in the father's sperm are destroyed in the egg). This condition — called heteroplasmy — creates a child having two different mitochondrial DNA genomes in all of its cells.

In rare, but important, cases, the defect in the prospective mother's cytoplasm is the result of her having mitochondria with a mutant gene (link to examples]. Ooplasmic transfer is of no help in these cases because the fertilized egg will still contain a preponderance of the mother's defective mitochondria. But researchers in Oregon reported in the 17 September 2009 issue of Nature that they had been able to produce 4 healthy rhesus monkeys with no mitochondria from their biological mother.

Their procedure:

If this technique could be applied to humans, it would allow women carrying defective mitochondria to bear babies free of the ailment.


The Upside of ART

The Downside of ART

Birth and Lactation

Exactly what brings about the onset of labor is still not completely understood. Probably a variety of integrated hormonal controls are at work.
Link to a discussion of hormones involved in birth and lactation.
The first result of labor is the opening of the cervix. With continued powerful contractions, the amnion ruptures and the amniotic fluid (the "waters") flows out through the vagina. The baby follows, and its umbilical cord can be cut.

The infant's lungs expand, and it begins breathing. This requires a major switchover in the circulatory system. Blood flow through the umbilical cord, ductus arteriosus, and foramen ovale ceases, and the adult pattern of blood flow through the heart, aorta, and pulmonary arteries begins. In some infants, the switchover is incomplete, and blood flow through the pulmonary arteries is inadequate. Failure to synthesize enough nitric oxide (NO) is one cause.

Shortly after the baby, the placenta and the remains of the umbilical cord (the "afterbirth") are expelled.

At the time of birth, and for a few days after, the mother's breasts contain a fluid called colostrum. It is rich in calories and proteins, including antibodies that provide passive immunity for the newborn infant.

Three or four days after delivery, the breasts begin to secrete milk.

Birth Control

Methods of birth control are discussed on a separate page. Link to it.

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12 September 2013