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Meiosis

The creation of life begins when the mother’s egg and father’s sperm fuse and eventually produce an embryo; however, before this can happen both egg and sperm (gametes) must be produced. The sperm and egg have 23 chromosomes each (haploid number), whilst a normal human cell has 46 chromosomes or 23 pairs of chromosomes (diploid number). When a normal cell undergoes division (mitosis) the 46 chromosomes are duplicated. When a gamete is produced with 23 chromosomes, a process called meiosis is used and it insures genetic diversity.

Meiosis has two stages of division and each stage, like mitosis, can be divided into four phases. Prior to the first stage, called reduction division, a cell’s chromosomes duplicate after this the cell enters the four phases of reduction division.

• Prophase 1 – The chromosomes shorten and thicken, the nuclear envelope disappears, the mitotic spindle appears and the chromosomes become arranged in their 23 homologous pairs. Crossing-over can occur during this stage which means portions of one chromosome in a homologous pair may be exchanged with the other. This insures genetic diversity so that the resulting daughter cells are genetically dissimilar.

• Metaphase 1 - Homologous chromosomes (the two chromosomes that belong to a pair) align at the equatorial plate of the cell.

• Anaphase 1 – The homologous pairs are separated but sister chromatids remain held together by a centromere. (In mitosis the sister chromatids split apart at this phase.)

• Telophase 1 – The cell undergoes cytokinesis (splitting into two) and two daughter cells are formed. Each daughter cell contains only one chromosome of the homologous pair (joined to its duplicate) and has the haploid number of chromosomes (23).

There is little or no interphase between the first and second or equatorial division of meiosis. In addition, there is no replication of DNA prior to commencement of equatorial division. The phases of equatorial division (prophase II, metaphase II, anaphase II, and telophase II) are similar to those of reduction division, but during anaphase II the centromeres divide and sister chromatids migrate separately to each pole. The cell then undergoes cytokinesis and the resulting cells contain 23 single chromosomes.

One parent cell produces four daughter cells. Daughter cells have half the number of chromosomes found in the original parent cell and with crossing over, are genetically different.

Maturation of Spermatozoa

Sperm is produced in the seminiferous tubules of the testes in a process called spermatogenesis. The process takes about 74 days. Spermatogenic cells form the sperm and these can be found in various stages of development. They begin as spermatogonia that are derived from primordial germ cells that enter the testes from the yolk sac during early fetal development. The primordial germ cells differentiate to spermatogonia and remain that way until puberty when they undergo mitotic proliferation (cell division and replication).

When spermatogonia undergo mitosis some of the resulting daughter cells develop to become diploid primary spermatocytes. Other daughter cells remain undifferentiated in order to provide for future sperm production.

Stage one of meiosis now occurs and the primary spermatocytes enlarge and then undergo nuclear division. The two cells formed in the reduction division are called secondary spermatocytes.

The equatorial division produces spermatids that contain a single copy of the 23 chromosomes. The two divisions of the primary spermatocyte produce four haploid spermatids, with a random assortment of maternal and paternal DNA.

Spermiogenesis is the final stage of spermatogenesis and sees the maturation of spermatids into sperm. Each spermatid develops into a single sperm cell (spermatozoon) and develops a head with an acrosome (enzyme-containing granule) and a flagellum (tail). The enzymes held in the acrosome are important for penetration of the egg cell in the female during fertilization.

The release of the sperm cell from its connection to the sustentacular cell is called spermiation. Sperm enters the lumen of the seminiferous tubules and flow towards ducts of the testes.

Factors Responsible for Spermatogenesis

Leutenising Hormone (LH) and Follicle Stimulating Hormone (FSH) secretion from the anterior pituitary gland increase at the onset of puberty. Their secretion is controlled by Gonadotropin Releasing Hormone (GnRH) secreted by the hypothalamus. LH stimulates the release of testosterone, and FSH acts indirectly to stimulate spermatogenesis.

FSH and testosterone work together to stimulate the secretion of androgen binding protein (ABP) into the interstitial fluid around spermatogenic cells. ABP causes the concentration of the testosterone to remain high near seminiferous tubules and testosterone stimulates the final stages of spermatogenesis.

A negative feedback system controls the level of testosterone production. GnRH is inhibited when testosterone levels are adequate and activated when levels are too low. The hormone inhibin stops the secretion of FSH when sperm levels are adequate. When it is too low there is less inhibin and more FSH.

Maturation of Ovum

The ovaries are the female gonads and are homologous to the male testes; they hold oocytes (egg cells) in various stages of development. Ultimately, the ovaries release a haploid sex cell called a gamete or secondary oocyte. This develops into an embryo when fused with the male gamete or sperm. The formation of secondary oocytes in the ovaries is called oogenesis and it consists of several phases.

The process begins when the woman is still a fetus, primordial germ cells move to the fetal ovaries from the yolk sac. They then differentiate into oogonia that are diploid cells that divide mitotically to produce millions of germ cells. Before birth many of these germ cells degenerate in a process called atresia, whilst some develop into primary oocytes that enter, but do not complete until puberty, prophase of reduction division¹.

Between 200,000 and 2,000,000 oogonia and primary oocytes are in the ovaries at birth, but only about 400 of these will mature and ovulate during a woman’s reproductive years. The rest experience atresia.

A layer of follicular cells creating a structure called a primordial follicle surrounds primary oocytes. These structures periodically start to grow to become primary or preantral follicles. As they grow, follicles undergo a series of structural changes to become secondary follicles. When puberty arrives the gonadotropin hormones (FSH & LH) cause meiotic division to resume in one secondary follicle each month. The primary oocyte completes reduction division and two haploid cells of unequal size are produced. The smaller of the two cells (first polar body) is discarded, whilst the larger cell (secondary oocyte) enters metaphase of equatorial division¹ and stops. The follicle within which this occurs is called the mature or Graafian follicle. At ovulation the follicle ruptures to release the secondary oocyte into the pelvic cavity. It is then swept into the fallopian tube where it awaits the arrival of a sperm for fertilization.

Factors Responsible for Ovulation (The Female Cycle)

In females capable of reproduction the growth and release of the secondary oocyte occurs in a cycle called the female reproductive cycle. The term is used to encompass changes in the uterus, ovaries, cervix and breasts and differences in hormone levels that control these factors. The cycle ranges in length from 24 to 35 days and it has three phases: menstrual, preovulatory, and postovulatory.

The menstrual phase falls roughly on the first five days of the cycle, and by convention marks the start of the cycle. During this phase about 20 of the secondary follicles in the ovaries begin to enlarge. A decline in the hormones estrogen and progesterone cause arteries in the uterus to constrict starving cells of nutrients and killing them. This causes about 50 – 150 ml of blood, tissue fluid, mucus, and epithelial cells to flow out of the uterus for discharge via the vagina.

The preovulatory phase is the time between menstruation and ovulation, and varies greatly between women. In a 28-day cycle it occurs between days 6 to 13. During this phase the 20 secondary follicles continue to grow and begin to secrete estrogen and the hormone inhibin under the control of Follicle Stimulating Hormone (FSH). One follicle outgrows the others and becomes dominant. Estrogen and inhibin reduce the secretion of FSH, causing other follicles to stop growing, and undergo atresia. The dominant follicle becomes the ‘mature follicle’ and becomes ready for ovulation. The follicle bulges out of the side of the ovary and continues to secrete estrogen under the influence of Leutenising Hormone (LH). In the uterus, endothelial cells lost during the menstrual phase are repaired by the action of estrogen, and its walls begin to thicken.

Ovulation occurs on day 14 of a 28-day cycle. There are high levels of estrogen just prior to ovulation which exert positive feedback on the LH and Gonadotropin Releasing Hormone (GnRH). A surge of LH promotes the rupture of the follicle and release of the oocyte. After rupturing the follicle collapses and clots due to minor bleeding and forms the corpus haemorrhagicum. The remaining follicular cells enlarge and become the corpus luteum, which, stimulated by LH, secretes progesterone, relaxin and inhibin.

The postovulatory phase runs from day 15 to 28 in a 28-day cycle. It represents the time between ovulation and menstruation. During this time the corpus luteum continues to secrete high levels of progesterone. If the oocyte is fertilized the corpus luteum continues to secrete progesterone beyond its normal two week life span. This action is promoted by human chorionic gonadotropin (hCG) produced by the chorionin embryo, which eventually becomes part of the placenta. When the placenta develops it takes on the role of secreting estrogen to support pregnancy, and progesterone to support pregnancy and development of the breasts. In the uterus the hormones produced by the corpus luteum are busy creating a nice home for an embryo. The endometrium thickens and becomes more vascularized. These changes continue for about one week after ovulation.

If fertilization does not occur the corpus luteum ceases hormone excretion and degenerates to a scar called the corpus albicans after two weeks. The drop in estrogen and progesterone causes the body to realise fertilization has not occurred and menstruation commences. The drop in estrogen and progesterone provides the feedback necessary for increased secretion of GnRH, LH, and FSH.

In summary, the uterine and ovarian cycles are controlled by Gonadotropin Releasing Hormone (GnRH) which stimulates the release of Leutenising Hormone (LH) and Follicle Stimulating Hormone (FSH). FSH stimulates the release of estrogen by growing follicles, whilst LH stimulates further development of ovarian follicles and their full secretion of estrogen, brings about ovulation, promotes formation of the corpus luteum, and stimulates the production of estrogens, progesterone, relaxin, and inhibin by the corpus luteum ¹.

The functions of the main female sex hormones as they relate the reproductive process are summarised in table 1.

Table 1 Female hormones involved in reproduction

Fertilization

When the sperm meets the ovum, fertilization can occur. The genetic material from each merge to form a single nucleus. Fertilization usually occurs in the fallopian tube about 12 – 24 hours after ovulation. Sperm is viable for about 48 hours after entry into the female, and the secondary oocyte about 24 hours after ovulation. Although sperm matures in the testes they must undergo further changes within the female to become viable, this is called capacitation. During capcitation the membrane around the acrosome (tip of the head of the sperm) becomes fragile and enzymes are released from the sperm collectively to enable penetration of the secondary oocyte. Normally only one sperm enters the oocyte, it causes the release of calcium ions that stimulate changes in walls of the oocyte blocking other sperm from entry.

When the sperm and secondary oocyte meet metaphase II resumes in the secondary oocyte producing a large haploid cell, the ovum or mature egg, and a small haploid cell, (second polar body). The sperm and ovum form a male and female pronucleus respectively, and fuse to form a segmentation nucleus containing 46 chromosomes. The segmentation nucleus, cytoplasm and zona pellucida are called a zygote. The zygote divides rapidly forming many cells but not increasing the size of the embryo. These cells are contained within the zona pellucida and this structure is called the morula. This is formed in three days.

After four days the number of cells increases and the morula moves towards the uterus. Between the fourth and fifth day the morula enters the uterus and is now called a blastocyst. The blastocyst eventually attaches to the uterus wall. The zona pellucida disintegrates and the blastocyst can get larger. Nourishment is derived from the secretions of the endometrial glands that are rich in glycogen. At about six days after fertilization, the blastocyst attaches to the endometrium and eventually becomes buried in it.

Embryonic and Fetal Development

Gestation, the period of time that the zygote, embryo and fetus are carried in the uterus, typically lasts for thirty-eight weeks. During this period there are several changes in the developing child and in the mother.

The first two months of development are generally considered the embryonic period, and after the second month development is termed the fetal period. By the end of the embryonic period, the rudiments of all the principal adult organs are present and the embryonic membranes are developed. By the end of the third month the placenta, the site for exchange of nutrients and waste between mother and fetus is functioning. The phases of embryonic and fetal development are summarised in table 2.

Table 2 Evolution of embryo and fetus during gestation ¹.

Development of the mother during pregnancy

Although pregnancy is not a disease it has a significant impact on the anatomy and physiology of the mother. By the end of the third month of pregnancy the uterus occupies most of the pelvic cavity. As the fetus grows the uterus extends higher into the abdominal cavity. Toward the end of a full term the uterus fills almost the entire abdominal cavity, pushing the intestines, liver and stomach superiorly, elevating the diaphragm and widening the thoracic cavity.

The effects of all these changes on the mother’s physiology are summarised in table 3.

Table 3 Changes to the mother during gestation.

Parturition (Labour)

The process of childbirth is called labour or parturition. At the end of gestation the level of estrogen overcomes the level of progesterone and the factors that maintained gestation are reduced. Rhythmic contractions of the muscles of the uterus mark the commencement of labour, and they are brought about mainly by ovarian and placental hormones. Oxytocin from the posterior pituitary stimulates contractions of the uterus and relaxin relaxes the pubic symphysis to aid in dilation of the uterine cervix.

There are three stages of labour: dilation, expulsion, and placental.

During the first stage uterine contractions are not strong initially and occur at long intervals, but they gradually become stronger and more frequent. This stage does not cause much distress and is called the quiet phase². Often this lasts eight to nine hours in a mother’s first labour and four hours in subsequent labours. Each contraction shortens the muscle fibres of the uterus and pulls on the cervix. This shortens the cervix and pulls it up the vagina till it is flush. The cervix is then pulled into dilation. At four to five centimetres dilation the cervix is halfway to full dilation and the ‘quiet phase’ is over! At this point the contractions become stronger and more frequent and the mother may(!) request drugs. When the cervix is fully dilated the uterus and vagina form a curved passage along which the baby will pass.

In the second stage the mother must start helping the process, and it usually lasts one and a half-hours or more². Often this stage commences with the breaking of the waters, which is a rupturing of the amniotic sac. The mother will get the urge to push owing to the pressure of the baby’s head on the tissues in the middle of the pelvis. The baby is pushed downward and the shapes of the muscles cause the baby’s head to turn so that it comes to look towards the mother’s posterior. Contractions and the mother’s pushing moves the head toward the vulval cleft. Eventually the child fully emerges (after much pain and screaming!)

The third stage is the time from birth to the expulsion of the after birth consisting mainly of the placenta. The contractions at this time aid in constricting ruptures that occurred during expulsion reducing the risk of haemorrhage.

Lactation

Lactation is the secretion and ejection of milk by the mammary glands. Prolactin, a hormone produced by the anterior pituitary gland is principally involved in the process. Its release is stimulated by prolactin releasing hormone (PRH) secreted by the hypothalamus. Prolactin levels increase throughout pregnancy but milk secretion is inhibited by the presence of progesterone.

Suckling initiates a nerve response to the hypothalamus resulting in the release of PRH and thus prolactin, and a decrease in the release of prolactin inhibiting hormone (PIH). At the same time oxytocin is released by the posterior pituitary gland that causes contraction of muscles surrounding the alveoli thus ejecting milk. The oxytocin also contracts the uterine muscles: speeding recovery of the uterus to normal size.

During the first few days of feeding a fluid called colostrum is secreted. It is not as nutritious as true milk which begins on the fourth day. Milk secretion normally declines within seven to nine months but can be maintained indefinitely through sustained nursing.

Breast-feeding inhibits the release of GnRH and thus FSH and LH, but it is not a reliable form of birth control.

Breast-feeding carries the following benefits for mother and child ¹:

• Nutrients in the milk are more easily absorbed and metabolized than those in cow’s milk;
• Antibodies are transferred from mother to infant;
• Breast milk for premature babies appears to be specifically adapted with increased protein than normal full-term breast milk;
• There is a decreased risk of allergic reaction;
• There is bonding between mother and child;
• The baby has control over the intake of nourishment.

References

1. Tortora, G.J., Grabowski, S.R., Principles of Anatomy and Physiology - 8^th Edition, Harper Collins, NY, 1996.

2. Llewellyn-Jones, D., Everywoman – 3^rd Edition, Faber & Faber, Suffolk, 1982.