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Sex "rgans of the #uman $ale Spermatogenesis Sperm %# &S# Sex "rgans of the #uman &emale "ogenesis "vulation 'opulation and &ertili(ation )regnancy o *he placenta is an allograft +ssisted ,eproductive *echnology ("+,*") o In -itro &ertili(ation (I-&) o Intracytoplasmic Sperm Injection (I'SI) o "oplasmic *ransfer .irth and %actation .irth 'ontrol

/BiologyPages/S/Sexual_Reproduction.h tml Sexual Reproduction in Humans

he Problems to be Sol!ed
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 differ in structure ("anisogamy") and are contri uted y different parents. !ametes need motility to e a le to meet and unite food to nourish the developing em ryo.

In animals (and some plants)/ these two rather contrasting needs are met y anisogametes0 sperm that are motile (and small) eggs that contain food.

Sex "rgans o# the Human $ale

*he reproductive system of the male has two major functions0 production of sperm delivery of these to the reproductive tract of the female. Sperm production spermatogenesis takes place in the testes. 1ach testis is packed with semini#erous tubules (laid end to end/ they would extend more than 23 meters) where spermatogenesis occurs.

Spermatogenesis
*he walls of the seminiferous tu ules consist of diploid spermatogonia/ stem cells that are the precursors of sperm. Spermatogonia divide y mitosis to produce more spermatogonia or differentiate into spermatocytes. $eiosis of each spermatocyte produces 4 haploid spermatids. *his process takes over three weeks to complete. *hen the spermatids differentiate into sperm/ losing most of their cytoplasm in the process. &or simplicity/ the figure shows the ehavior of just a single pair of homologous chromosomes with a single crossover. 5ith 22 pairs of autosomes and an average of two

crossovers etween each pair/ the variety of gene com inations in sperm is very great.

Sperm
Sperm cells are little more than flagellated nuclei. 1ach consists of a head/ which has o an acrosome at its tip and o contains a haploid set of chromosomes in a compact/ inactive/ state. a midpiece containing mitochondria and a single centriole a tail which is a flagellum. *his electron micrograph (courtesy of 6r. 6on 5. &awcett and Susumu Ito) shows the sperm cell of a at. 7ote the orderly arrangement of the mitochondria. *hey supply the +*) to power the whiplike motion of the tail. +n adult male manufactures over 833 million sperm cells each day. *hese gradually move into the epididymis where they undergo further maturation. *he 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 responsi le for the development of the secondary sex characteristics of men such as the eard/ deep voice/ and masculine ody shape. estosterone is also essential #or making sperm. %ink to more on testosterone. *estosterone is made in the interstitial cells (also called %eydig cells) that lie etween the seminiferous tu ules.

%H
Interstitial cells are/ in turn/ the targets for a hormone often called interstitial cell stimulating hormone (&'SH). It is a product of the anterior lo e of the pituitary gland. #owever/ I'S# is identical to the luteini(ing hormone (%H) found in females/ and I prefer to call it %#.

(SH
&ollicle9stimulating hormone (also named for its role in females) acts directly on spermatogonia to stimulate sperm production (aided y the %# needed for testosterone synthesis). :6iscussion;

Sex "rgans o# the Human (emale

*he responsi ility of the female mammal for successful reproduction is considera ly greater than that of the male.

She must manufacture eggs e e<uipped to receive sperm from the male provide an environment conducive to fertili(ation and implantation nourish the developing a y not only efore irth ut after.

"ogenesis
1gg formation takes place in the o!aries. In contrast to males/ the initial steps in egg production occur prior to irth. 6iploid stem cells called oogonia divide y mitosis to produce more oogonia and primary oocytes. .y the time the fetus is 23 weeks old/ the process reaches its peak and all the oocytes that she will ever possess (=4 million of them) have een formed. .y the time she is orn/ 8>2 million

of these remain. 1ach has egun the first steps of the first meiotic division stopping at the diplotene stage of meiosis I. 7o further development occurs until years later when the girl ecomes sexually mature. *hen the primary oocytes recommence their development/ usually one at a time and once a month. *he 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. 5hich chromosomes end up in the egg and which in the polar ody is entirely a matter of chance. In humans (and most verte rates)/ the first polar ody does not go on to meiosis II/ ut the secondary oocyte does proceed as far as metaphase of meiosis II and then stops. "nly if #ertili)ation occurs will meiosis II ever e completed. 1ntry of the sperm restarts the cell cycle

reaking down $)& ($9phase promoting factor) and turning on the anaphase9promoting complex (+)').

'ompletion of meiosis II converts the secondary oocyte into a fertili(ed egg or (ygote (and also a second polar ody). +s in the diagram for spermatogenesis/ the ehavior of the chromosomes is greatly simplified. *he photomicrograph (courtesy of *urtox) shows polar ody formation during oogenesis in the whitefish. 1ven allowing for the fact that fish eggs are larger than mammalian eggs/ you can readily see how the polar ody gets little more than one set of chromosomes. *hese events take place within a #ollicle/ a fluid9filled envelope of cells surrounding the developing egg. *he ripening follicle also serves as an endocrine gland. Its cells make a mixture of steroid hormones collectively known as estrogen. 1strogen is responsi le for the development of the secondary sexual characteristics of a mature woman/ e.g./ a roadening of the pelvis development of the reasts growth of hair around the genitals and in the armpits development of adipose tissue leading to the more rounded ody contours of adult women.

1strogen continues to e secreted throughout the reproductive years of women 6uring this period/ it plays an essential role in the monthly menstrual cycle. %ink to a discussion of the menstrual cycle and the hormones that regulate it. *here is growing evidence that in mice oocytes can continue to e produced throughout life (from germline stem cells in the one marrow). It remains to e seen if that will turn out to e true for humans.

"!ulation
"vulation occurs a out two weeks after the onset of menstruation. In response to a sudden surge of %#/ the follicle ruptures and discharges a secondary oocyte. *his is swept into the open end of the #allopian tube and egins to move slowly down it. Several sexually9transmitted diseases (S*6s)/ especially gonorrhea and infections y chlamydia can cause scarring and locking of the tu es and are a major cause of infertility. In tu al ligation/ the fallopian tu es are surgically cut and their ends tied to prevent pregnancy.

'opulation and (ertili)ation

&or fertili(ation to occur/ sperm must e deposited in the vagina within a few (?) days efore or on the day of ovulation. Sperm transfer is accomplished y copulation. Sexual excitation dilates the arterioles supplying lood to the penis. .lood accumulates in three cylindrical spongy sinuses that run lengthwise through the penis. *he resulting pressure causes the penis to enlarge and erect and thus a le to penetrate the vagina. $ovement of the penis ack and forth within the vagina causes sexual tension to increase to the point of ejaculation. 'ontraction of the walls of each !as de#erens propels the sperm along. &luid is added to the sperm y the seminal !esicles/ 'owper@s glands/ and the prostate gland. :-iew; *hese fluids provide a source of energy (fructose) an alkaline environment to activate the sperm/ and perhaps in other ways provide an optimum chemical environment for them. *he mixture of sperm and accessory fluids is called semen. It passes through the urethra and is expelled into the vagina. )hysiological 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 prere<uisite for copulation and fertili(ation to occur.

"nce deposited within the vagina/ the sperm proceed on their journey into and through the uterus and on up into the fallopian tu es. It is here that fertili(ation may occur if an "egg" is present (strictly speaking/ it is still a secondary oocyte until after completion of meiosis II). +lthough sperm can swim several millimeters each second/ their trip to and through the fallopian tu es may e assisted y muscular contraction of the walls of the uterus and the tu es. *he trip is fraught with heavy mortality. +n average human ejaculate contains over one hundred million sperm/ ut only a few do(en complete the journey/ arriving within 8? minutes of ejaculation. +nd of these/ only one will succeed in fertili(ing the egg. Sperm swim towards the egg y chemotaxis following a gradient of progesterone secreted y cells surrounding the egg. )rogesterone opens 'atSper ("cation sperm") channels in the plasma mem rane surrounding the anterior portion of the sperm tail. *his allows an influx of 'a2A ions which causes the flagellum to eat more rapidly and vigorously. &ertili(ation egins with the inding of a sperm head to the glycoprotein coating of the egg (called the )ona pellucida). 1xocytosis of the acrosome at the tip of the sperm head releases en(ymes that digest a path through the (ona and ena le the sperm head to ind to the plasma mem rane of the egg. &usion of their respective mem ranes allows the entire contents of the sperm to e drawn into the cytosol of the egg. (1ven though the sperm@s mitochondria enter the egg/ they are almost always destroyed and do not contri ute their genes to the em ryo. So human mitochondrial 67+ is almost always inherited from mothers only.) 5ithin moments/ en(ymes released from the egg cytosol act on the (ona making it impermea le to the other sperm that arrive. Soon the nucleus of the successful sperm enlarges into the male pronucleus. +t the same time/ the egg (secondary oocyte) completes meiosis II forming a second polar body and the #emale pronucleus. *he male and female pronuclei move toward each other while duplicating their 67+ in S phase. *heir nuclear envelopes disintegrate. + spindle is formed (following replication of the sperm@s centriole)/ and a full set of dyads assem les on it. *he fertili(ed egg or )ygote is now ready for its first mitosis. 5hen this is done/ 2 cells each with a diploid set of chromosomes are formed. In sea urchins/ at least/ the lock to additional sperm entry and the fusion of the pronuclei are triggered y nitric oxide generated in the egg y the sperm acrosome. :%ink;

Pregnancy
6evelopment egins while the fertili(ed egg is still within the #allopian tube. ,epeated mitotic divisions produces a solid all of cells called a morula. &urther mitosis and some

migration of cells converts this into a hollow all of cells called the blastocyst. +pproximately one week after fertili(ation/ the lastocyst em eds itself in the thickened wall of the uterus/ a process called implantation/ and pregnancy is esta lished. *he lastocyst produces two major collections of cells0 *hree or four lastocyst cells develop into the inner cell mass/ which will form o B extraem ryonic mem ranes0 amnion/ yolk sac/ and (a

vestigial) allantois and in a out 2 months/ ecome the fetus and/ ultimately/ the a y. *he remaining 833 or so cells form the trophoblast/ which will develop into the chorion that will go on to make up most of the placenta. +ll the extraem ryonic mem ranes play vital roles during development ut will e discarded at the time of irth.
o

*he placenta grows tightly fused to the wall of the uterus. Its lood vessels/ supplied y the fetal heart/ are literally athed in the mother@s lood. +lthough there is normally no mixing of the two lood supplies/ the placenta does facilitate the transfer of a variety of materials etween the fetus and the mother.

receiving food receiving oxygen and discharging car on dioxide discharging urea and other wastes receiving antibodies (chiefly of the Ig! class). *hese remain for weeks after irth/ protecting the a y from the diseases to which the mother is immune.

.ut the placenta is not simply a transfer device. Csing raw materials from the mother@s lood/ it synthesi(es large <uantities of proteins and also some hormones. %ink to discussion of the placenta as an endocrine gland. *he meta olic activity of the placenta is almost as great as that of the fetus itself. *he umbilical cord connects the fetus to the placenta. It receives deoxygenated lood from the iliac arteries of the fetus and returns oxygenated lood to the liver and on to the inferior vena cava. .ecause its lungs are not functioning/ circulation in the fetus differs dramatically from that of the a y after irth. 5hile within the uterus/ lood pumped y the right ventricle ypasses the lungs y flowing through the #oramen o!ale and the ductus arteriosus.

+lthough the lood in the placenta is in close contact with the mother@s lood in the uterus/ intermingling of their lood does not normally occur. #owever/ some of the lood cells of the fetus usually do get into the mother@s circulation where they have een known to survive for decades. *his raises the possi ility of doing prenatal diagnosis of genetic disorders y sampling the mother@s lood rather than having to rely on the more invasive procedures of amniocentesis and chorionic villus sampling ('-S). &ar rarer is the leakage of mother@s lood cells into the fetus. #owever/ it does occur. + few pregnant women with leukemia or lymphoma have transferred the malignancy to their fetus. Some a ies have also ac<uired melanoma from the transplacental passage of these highly9malignant cells from their mother. 6uring the first 2 months of pregnancy/ the asic structure of the a y is eing formed. *his involves cell division/ cell migration/ and the differentiation of cells into the many types found in the a y. 6uring this period/ the developing a y called an embryo is very sensitive to anything that interferes with the steps involved. -irus infection of the mother/ e.g./ y ru ella ("!erman measles") virus or exposure to certain chemicals may cause malformations in the developing em ryo. Such agents are called teratogens ("monster9forming"). *he tran<uili(er/ thalidomide/ taken y many pregnant 1uropean women etween 8D?4 and 8DE2/ turned out to e a potent teratogen and was responsi le for the irth of several thousand deformed a ies. +fter a out two months/ all the systems of the a y have een formed/ at least in a rudimentary way. &rom then on/ development of the #etus/ as it is now called/ is primarily a matter of growth and minor structural modifications. *he fetus is less suscepti le to teratogens than is the em ryo. )regnancy involves a complex interplay of hormones. *hese are descri ed in a separate page. :%ink to it.;

he placenta is an allogra#t
"ne of the greatest unsolved mysteries in immunology is how the placenta survives for D months without eing rejected y the mother@s immune system. 1very cell of the placenta carries the father@s genome (a haploid set of his chromosomes)F including one of his GE chromosomes where the genes for the major histocompatibility antigens (#%+) are located. "ne partial exception0 none of the genes on the father@s H chromosome are expressed. 5hile H9chromosome inactivation is random in the cells of the fetus/ it is 7"* random in the cells of the tropho last. In every cell of the tropho last and its descendants it is the paternal H chromosome that is inactivated. :6iscussion of H9chromosome inactivation.; .ut this does not solve our pro lem ecause the genes for all the major histocompati ility antigens are located on chromosome E/ which is not inactivated. 6iscussion of the human major histocompati ility complex ($#')

*hus the placenta is immunologically as foreign to the mother as a kidney transplant would e. Iet it thrives. 6espite a half9century of research/ the mechanism for this immunologically privileged status remains uncertain. .ut one thing is clear0 *he mother is not intrinsically tolerant of the father@s antigens. Some evidence0

She will promptly reject a skin transplant from the father. She develops anti odies against his histocompati ility antigens expressed y the fetus. In fact/ women who have orne several children y the same father are often excellent sources of anti9#%+ serum for use in tissue typing.

So what accounts for the phenomenonJ Some possi ilities0 *he placenta does not express class II histocompati ility antigens.

6iscussion of the role of class II antigens in immunity. 7or does it express the strongly9immunogenic class I histocompati ility antigens (#%+9+/ #%+9.). It does express #%+9'/ ut this is only weakly immunogenic. *he cells of the placenta secrete progesterone/ which is immunosuppressive. In la rats the em ryos (and the mother@s endometrium) secrete corticotropin9 releasing hormone (',#). *his hormone induces the expression of &as ligand ((as%) on the cells of the placenta. +ctivated * cells express (as so any threatening * cells would commit suicide y apoptosis when they encounter &as% on their target. %ink to more of the story of the role of &as and &as% in apoptosis. ( ut note: the example you will see is the re!erse of the story hereF that is/ the cytotoxic * cell is using its own &as% to kill a target cell that is expressing &as ut not &as%.) In la oratory mice the cells of the placenta degrade the amino acid tryptophan. *ryptophan is essential for *9cell function. 5hen mice are treated with an inhi itor of the *rp9degrading en(yme/ their fetuses are promptly a orted y the action of the mother@s lymphocytes. (6. #. $unn/ et. al./ Science/ *+,: 88D8/ 28 +ug 8DDK.) )erhaps most important of all is the increased production in the mother of immunosuppressive regulatory cells (*reg). o 6epletion of *reg cells in pregnant mice leads to spontaneous a ortion while o injection of *reg cells into mice that are otherwise prone to a ortion ena les them to carry their fetuses to term. o In humans/ the num er of *reg cells rises during pregnancy (in the fetus as well as the mother).

-ssisted Reproducti!e echnology ./-R /0

"n Luly 2?/ 2383 %ouise .rown cele rated her B2th irthday. She was the first of what today num er some four million (worldwide) "test tu e a ies"F that is/ she developed from an egg that was fertili(ed outside her mother@s ody the process called in !itro #ertili)ation (&1().

&n 1itro (ertili)ation .&1(0

I-& involves harvesting mature eggs from the mother. *his is not an easy process. *he mother must undergo hormonal treatments to produce multiple eggs/ which then must e removed (under anesthesia) from her ovaries. harvesting sperm from the father. #arvesting is usually no pro lem/ ut often the sperm are defective in their a ility to fertili(e (so setting the stage for I'SI)F mixing sperm and eggs in a culture vessel ("in vitro")F culturing the fertili(ed eggs for several days until they have developed to at least the K9cell stageF placing two or more of these into the mother@s uterus (which her hormone treatments have prepared for implantation)F keeping one@s fingers crossed only a out one9third of the attempts result in a successful pregnancy)

&ntracytoplasmic Sperm &njection .&'S&0

Successful I-& assumes the availa ility of healthy sperm. .ut many cases of infertility arise from defects in the father@s sperm. "ften these can e overcome y directly injecting a single sperm into the egg. In the C.S. today/ some two9thirds of +,* procedures employ I'SI (even though as many as half of these do not involve male infertility).

"oplasmic rans#er
Infertility in some cases may stem from defects in the cytoplasm of the mother@s egg. *o circumvent these/ cytoplasm can e removed from the egg of a young/ healthy woman ("6onor egg") and injected along with a single sperm into the prospective mother@s egg. +lthough a few healthy children have een orn following ooplasmic transfer/ the jury is still out on its safety/ and it is not approved for use in the C.S. "ne reason for concern is that ooplasmic transfer results in an egg carrying oth the mother@s mitochondria and mitochondria from the donor (in normal fertili(ation/ all the mitochondria in the father@s sperm are destroyed in the egg). *his condition called

heteroplasmy creates a child having two different mitochondrial 67+ genomes in all of its cells. In rare/ ut important/ cases/ the defect in the prospective mother@s cytoplasm is the result of her having mitochondria with a mutant gene (link to examples;. "oplasmic transfer is of no help in these cases ecause the fertili(ed egg will still contain a preponderance of the mother@s defective mitochondria. .ut researchers in "regon reported in the 8M Septem er 233D issue of 2ature that they had een a le to produce 4 healthy rhesus monkeys with no mitochondria from their iological mother. *heir procedure0 ,emove the spindle with all its attached chromosomes from the mother@s oocyte at metaphase II of meiosis. *hey managed to do this without any of her mitochondria eing withdrawn as well. 1nucleate the oocyte of the mitochondria donor and then insert the mother@s chromosomes still attached to the spindle into it. *hen inject a sperm from the father. +llow the fertili(ed egg to develop into a lastocyst. Implant this in the uterus of a surrogate mother. *he result0 4 healthy a ies each with the nuclear genes of their mother and father ut none of the mitochondria of their mother.

If this techni<ue could e applied to humans/ it would allow women carrying defective mitochondria to ear a ies free of the ailment.

he 3pside o# -R

It has allowed some four million previously9infertile couples to have children. It permits screening (on one cell removed from the K9celled morula) for the presence of genetic disorders thus avoiding starting a pregnancy if a disorder is found. %ink to a discussion.

"ne can use fro(en sperm allowing fatherhood for a man who is no longer a le to provide fresh sperm. .ecause a num er of morulas are created/ the extras can e fro(en/ stored/ and used later o if the initial attempt fails (the prospective mother must still receive hormones to prepare her uterus for implantation and the success rate is lower with thawed morulas). o 5here regulations permit/ the extras can e used as a source of em ryonic stem (1S) cells. 6iscussion

he 4o5nside o# -R

+lthough improving/ the success rate is still sufficiently low (=B?N) that the process often has to e repeated. .ecause several morulas are usually transferred/ multiple irths are common (a out ?3N)/ and as is the case with most multiple irths/ the a ies are orn early and weigh less. *o reduce the num er of twins/ triplets/ etc./ more +,* centers are turning to /single6embryo trans#er/ (S1*). Some +,* centers find that they can increase the success rate and thus rely more on S1* y culturing the morulas for ?>E days/ instead of the usual 2>B days/ efore transferring them ( y now they have ecome lastocysts) to the mother. *he risk of irth defects is a out dou led (from =4N in "normal" pregnancies to =KN in +,* pregnancies). +,* procedures in experimental animals often result in a failure of correct gene imprinting. 5hether this will pose a pro lem for humans remains to e seen.

Birth and %actation

1xactly what rings a out the onset of la or is still not completely understood. )ro a ly a variety of integrated hormonal controls are at work. %ink to a discussion of hormones involved in irth and lactation. *he first result of la or is the opening of the cervix. 5ith continued powerful contractions/ the amnion ruptures and the amniotic fluid (the "waters") flows out through the vagina. *he a y follows/ and its um ilical cord can e cut. *he infant@s lungs expand/ and it egins reathing. *his re<uires a major switchover in the circulatory system. .lood flow through the um ilical cord/ ductus arteriosus/ and

foramen ovale ceases/ and the adult pattern of lood flow through the heart/ aorta/ and pulmonary arteries egins. In some infants/ the switchover is incomplete/ and lood flow through the pulmonary arteries is inade<uate. &ailure to synthesi(e enough nitric oxide (7") is one cause. Shortly after the a y/ the placenta and the remains of the um ilical cord (the "after irth") are expelled. +t the time of irth/ and for a few days after/ the mother@s reasts contain a fluid called colostrum. It is rich in calories and proteins/ including anti odies that provide passive immunity for the new orn infant. *hree or four days after delivery/ the reasts egin to secrete milk. Its synthesis is stimulated y the pituitary hormone prolactin .PR%0. Its release is stimulated y a rise in the level of oxytocin when the a y egins nursing. $ilk also contains an inhibitory peptide. If the reasts are not fully emptied/ the peptide accumulates and inhi its milk production. *his autocrine action thus matches supply with demand.

Birth 'ontrol
$ethods of irth control are discussed on a separate page. %ink to it. 5elcomeO7ext Search 84 "cto er 2388