Hormonal Cycles: Fertilization and Early Development


• explore in detail the events that occur during the ovarian and menstrual cycles

• describe in detail the process of fertilization followed by the subsequent development of the conceptus into the pre-embryonic period


The functions of the female reproductive cycle are to prepare the egg, often referred to as the gamete or oocyte, for fertilization by the spermatozoon (sperm), and to prepare the uterus to receive and nourish the fertilized oocyte. If fertilization has not taken place the inner lining of the uterus or endometrium and the oocyte are shed and bleeding occurs per vagina, and the cyclic events begin again.

Before the onset of puberty, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels are low. Pulsatile increases in gonadotrophin releasing hormone (GnRH), particularly at night, cause increase in LH secretion. This increasing surge of LH is established prior to menarche (Wennink et al 1990). It is also thought that the interaction of leptin with GnRH may have a role in the initiation of puberty. The first-ever occurrence of cyclic events is termed menarche, meaning the first menstrual bleeding. The average age of menarche is 12 years, although between the ages 8 and 16 is considered normal. The onset of menstrual bleeding (‘periods or menses) is a major stage in a girl’s life, representing the maturation of the reproductive system and physical transition into womanhood. For many women this monthly phenomenon signals and embodies the quintessence of being a ‘woman’.

Similarly, for other women it is regarded as an inconvenience, causing pain, shame and embarrassment (Chrisler 2011). Cultural and religious traditions affect how women and their communities feel about menstruation. The advent of hormonal contraception affords women, especially those in Western society, an element of control over their periods. Factors such as heredity, diet, obesity and overall health can accelerate or delay menarche.

Interference with the hormonal–organ relationship prior to and during the reproductive years is likely to cause menstrual cycle dysfunction which may result in failure to ovulate. The cessation of cyclic events is referred to as the menopause, and signifies the end of reproductive life. Each woman has an individual reproductive cycle that varies in length, although the average cycle is normally 28 days long, and recurs regularly from puberty to the menopause except when pregnancy intervene.


female reproductive system


The ovarian cycle is the name given to the physiological changes that occur in the ovaries essential for the preparation and release of an oocyte. The ovarian cycle consists of three phases, all of which are under the control of hormones.


The follicular phase

The formation of oogonia in the germinal epithelium of the ovaries is known as oogenesis. Primordial germ cells differentiate into oogonia in the ovaries during fetal life. These diploid stem cells divide mitotically and proliferate into millions of germ cells. Most of the germ cells degenerate (by atresia), however some develop further into primary oocytes, and enter the prophase of meiosis I cell division.

Meiotic arrest occurs and the process does not continue until after puberty (further meiotic division takes place at ovulation of the secondary oocyte and the process is only completed if fertilization occurs). Whilst in this arrested prophase stage of meiosis I the primary oocyte is surrounded by follicular cells and is hence known as the primordial follicle. There are up to 2 million primary oocytes in each ovary at birth and due to atresia, the number is reduced to approximately 40000 at puberty; 400 of these will mature and ovulate during the woman’s lifetime (Tortora and Derrickson 2011). Following puberty FSH and LH further stimulate the development of primordial follicles into primary and secondary follicles and subsequently into large preovulatory or Graafian follicles by a process known as folliculogenesis.

Low levels of estrogen and progesterone stimulate the hypothalamus to produce GnRH. This releasing hormone causes the production of FSH and LH by the anterior pituitary gland. FSH controls the growth and maturity of the Graafian follicles. The Graafian follicles begin to secrete estrogen, which comprises estradiol, estrone and estriol. Rising levels of estradiol cause a surge in LH. When estradiol reaches a certain peak, the secretion of FSH is inhibited. The reduced FSH secretion causes a slowing in follicle growth and eventually leads to follicle death, known as atresia. The largest and dominant follicle secretes inhibin, which further suppresses FSH. This dominant follicle prevails and forms a bulge near the surface of the ovary, and soon becomes competent to ovulate. The time from the growth and maturity of the

Graafian follicles to ovulation is normally around 1 week. Occasionally the follicular phase may take longer if the dominant follicle does not ovulate, and the phase will begin again. The differing lengths of menstrual cycle reported between individual women are as a result in the varying timespans in this pre-ovulatory phase. It can last 6–13 days in a 28-day cycle (Tortora and Derrickson 2011).


Graafian follicle

Graafian follicle


High estrogen levels cause a sudden surge in LH around day 12–13 of a 28 day cycle, which lasts for approximately 48 hours. This matures the oocyte and weakens the wall of the follicle and causes ovulation to occur on day 14.

Ovulation is the process whereby the dominant Graafian follicle ruptures and discharges the secondary oocyte into the pelvic cavity. Fimbrae guide it into the uterine tube where it awaits fertilization. During the time of ovulation, meiotic cell division resumes and the diploid oocyte becomes haploid (with a first polar body). During ovulation some women experience varying degrees of abdominal pain known as mittelschmerz, which can last several hours. There may be some light bleeding caused by the hormonal changes taking place. Stringy clear mucus appears in the cervix, ready to accept the sperm from intercourse. Following ovulation, the fertilized or unfertilized oocyte travels to the uterus.


The luteal phase

The luteal phase is the process whereby the cells of the residual ruptured follicle proliferate and form a yellow irregular structure known as the corpus luteum. The corpus luteum produces estrogen, relaxin, inhibin and progesterone for approximately 2 weeks, to develop the endometrium of the uterus, which awaits the fertilized oocyte. Small amounts of relaxin cause uterine quiescence, which is an ideal environment for the fertilized oocyte to implant. The corpus luteum continues its role until the placenta is adequately developed to take over. During the luteal phase the cervical mucus becomes sticky and thick.

In the absence of fertilization, the corpus luteum degenerates and becomes the corpus albicans (white body), and progesterone, estrogen, relaxin and inhibin levels decrease. In response to low levels of estrogen and progesterone the hypothalamus produces GnRH. The rising levels of GnRH stimulate the anterior pituitary gland to produce FSH and the ovarian cycle commences again (Stables and Rankin 2010). The luteal phase is the most constant part of the ovarian cycle, lasting 14 days out of a 28day cycle (Tortora and Derrickson 2011).



The menstrual cycle is the name given to the physiological changes that occur in the endometrial layer of the uterus, and which are essential to receive the fertilized oocyte. The menstrual cycle consists of three phases.

The menstrual phase

This phase is often referred to as menstruation, bleeding, menses, or a period. Physiologically this is the terminal phase of the reproductive cycle of events and is simultaneous with the beginning of the follicular phase of the ovarian cycle. Reducing levels of estrogen and progesterone stimulate prostaglandin release that causes the spiral arteries of the endometrium to go into spasm, withdrawing the blood supply to it, and the endometrium dies, referred to as necrosis. The endometrium is shed down to the basal layer along with blood from the capillaries, the unfertilized oocyte tissue fluid, mucus and epithelial cells. Failure to menstruate (amenorrhea) is an indication that a woman may have become pregnant. The term eumenorrhea denotes normal, regular menstruation that lasts for typically 3–5 days, although 2–7 days is considered normal.

The average blood loss during menstruation is 50–150 ml. The blood is inhibited from clotting due to the enzyme plasmin contained in the endometrium. The menstrual flow passes from the uterus through the cervix and the vagina to the exterior. The term menorrhagia denotes heavy bleeding. Some women experience uterine cramps caused by muscular contractions to expel the tissue. Severe uterine cramps are known as dysmenorrhea.


The proliferative phase

This phase follows menstruation, is simultaneous with the follicular phase of the ovary and lasts until ovulation. There is the formation of a new layer of endometrium in the uterus, referred to as the proliferative endometrium. This phase is under the control of estradiol and other estrogens secreted by the Graafian follicle and consist of the re-growth and thickening of the endometrium in the uterus. During the first few days of this phase the endometrium is re-forming, described as the regenerative phase. At the completion of this phase the endometrium consists of three layers.

The basal layer lies immediately above the myometrium and is approximately 1 mm thick. It contains all the necessary rudimentary structures for building new endometrium.

The functional layer, which contains tubular glands, is approximately 2.5 mm thick, and lies on top of the basal layer. It changes constantly according to the hormonal influences of the ovary.

The layer of cuboidal ciliated epithelium covers the functional layer. It dips down to line the tubular glands of the functional layer. If fertilization occurs, the fertilized oocyte implants itself within the endometrium.


The secretory phase

This phase follows the proliferative phase and is simultaneous with ovulation. It is under the influence of progesterone and estrogen secreted by the corpus luteum. The functional layer of the endometrium thickens to approximately 3.5 mm and becomes spongy in appearance because the glands are more tortuous. The blood supply to the area is increased and the glands produce nutritive secretions such as glycogen. These conditions last for approximately 7 days, awaiting the fertilized oocyte.



Human fertilization, known as conception, is the fusion of genetic material from the haploid sperm cell and the secondary oocyte (now haploid), to form the zygote. The process takes approximately 12–24 hours and normally occurs in the ampulla of the uterine tube. Following ovulation, the oocyte, which is about 0.15 mm in diameter, passes into the uterine tube. The oocyte, having no power of locomotion, is wafted along by the cilia and by the peristaltic muscular contraction of the uterine tube.

At the same time the cervix, which is under the influence of estrogen, secretes a flow of alkaline mucus that attracts the spermatozoa. In the fertile male at intercourse approximately 300 million sperm are deposited in the posterior fornix of the vagina. Approximately 2 million reaches the loose cervical mucus, survive and propel themselves towards the uterine tubes while the rest are destroyed by the acid medium of the vagina. Approximately 200 sperm will ultimately reach the oocyte (Tortora and Derrickson 2011). Sperm swim from the vagina and through the cervical canal using their whip-like tails (flagella). Prostaglandins from semen and uterine contractions as a result of intercourse facilitate the passage of the sperm into the uterus and beyond. Once inside the uterine tubes (within minutes of intercourse), the sperm undergo a process known as capacitation. This process takes up to 7 hours.

Influenced by secretions from the uterine tube the sperm undergo changes to the plasma membrane, resulting in the removal of the glycoprotein coat and increased flagellation. The zona pellucida of the oocyte produces chemicals that attract capacitated sperm only. The acrosomal layer of the capacitated sperm becomes reactive and releases the enzyme hyaluronidase known as the acrosome reaction, which disperses the corona radiata (the outermost layer of the oocyte) allowing access to the zona pellucida. Many sperm are involved in this process. Other enzymes, such as acrosin, produce an opening in the zona pellucida. The first sperm that reaches the zona pellucida penetrates it.

Upon penetration the oocyte releases corticol granules; this is known as the cortical reaction. The cortical reaction and depolarization of the oocyte cell membrane makes it impermeable to other sperm. This is important as there are many sperm surrounding the oocyte at this time. The plasma membranes of the sperm and oocyte fuse. The oocyte at this stage completes its second meiotic division, and becomes mature. The pronucleus now has 23 chromosomes, referred to as haploid. The tail and mitochondria of the sperm degenerate as the sperm penetrates the oocyte, and there is the formation of the male pronucleus.

The male and female pronuclei fuse to form a new nucleus that is a combination of the genetic material from both the sperm and oocyte, referred to as a diploid cell. The male and the female gametes each contribute half the complement of chromosomes to make a total of 46. This new cell is called a zygote.

Dizygotic twins (fraternal twins) are produced from two oocytes released independently but in the same time frame fusing with two different sperm; they are genetically different from each other. Monozygotic twins develop from a single zygote for a variety of reasons, where cells separate into two embryos, usually before 8 days following fertilization. These twins are genetically identical.




The development of the zygote can be divided into three periods. The first 2 weeks after fertilization, referred to as the pre-embryonic period, includes the implantation of the zygote into the endometrium; weeks 2–8 are known as the embryonic period; and weeks 8 to birth are known as the fetal period.


The pre-embryonic period

During the first week the zygote travels along the uterine tube towards the uterus. At this stage a strong membrane of glycoproteins called the zona pellucida surrounds the zygote. The zygote receives nourishment, mainly glycogen, from the goblet cells of the uterine tubes and later the secretory cells of the uterus. During the travel the zygote undergoes mitotic cellular replication and division referred to as cleavage, resulting in the formation of smaller cells known as blastomeres. The zygote divides into two cells at 1 day, then four at 2 days, eight by 2.5 days, 16 by 3 days, now known as the morula. The cells bind tightly together in a process known as compactation. Next cavitation occurs whereby the outermost cells secrete fluid into the morula and a fluid-filled cavity or blastocele appears in the morula.

This results in the formation of the blastula or blastocyst, comprising 58 cells. The process from the development of the morula to the development of the blastocyst is referred to as blastulation and has occurred by around day 4.

The zona pellucida remains during the process of cleavage, so that despite an increase in number of cells the overall size remains that of the zygote and constant at this stage. The zona pellucida prevents the developing blastocyst from increasing in size and therefore getting stuck in the uterine tube; it also prevents embedding occurring in the tube rather than the uterus, which could result in an ectopic pregnancy. Around day 4 the blastocyst enters the uterus. Endometrial glands secrete glycogen-rich fluid into the uterus which penetrates the zona pellucida. This and nutrients in the cytoplasm of the blastomeres provides nourishment for the developing cells. The blastocyst digests its way out of the zona pellucida once it enters the uterine cavity. The blastocyst possesses an inner cell mass or embryoblast, and an outer cell mass or trophoblast. The trophoblast becomes the placenta and chorion, while the embryoblast becomes the embryo, amnion and umbilical cord (Carlson 2004; Tortora and Derrickson 2011).

development of the zygote

During week 2, the trophoblast proliferates and differentiates into two layers: the outer syncytio-trophoblast or syncytium and the inner cytotrophoblast (cuboidal dividing cells). Implantation of the trophoblast layer into the endometrium, now known as the decidua, begins. Implantation is usually to the upper posterior wall. At the implantation stage the zona pellucida will have totally disappeared. The syncytiotrophoblast layer invades the decidua by forming finger-like projections called villi that make their way into the decidua and spaces called lacunae that fill up with the mother’s blood. The villi begin to branch, and contain blood vessels of the developing embryo, thus allowing gaseous exchange between the mother and embryo. Implantation is assisted by proteolytic enzymes secreted by the syncytiotrophoblast cells that erode the decidua and assist with the nutrition of the embryo. The syncytiotrophoblast cells also produce human chorionic gonadotrophin (hCG), a hormone that prevents menstruation and maintains pregnancy by sustaining the function of the corpus luteum.

Simultaneous to implantation, the embryo continues developing. The cells of the embryoblast differentiate into two types of cells: the epiblast (closest to the trophoblasts) and the hypo-blast (closest to the blastocyst cavity). These two layers of cells form a flat disc known as the bilaminar embryonic disc. A process of gastrulation turns the bilaminar disc into a tri-laminar embryonic disc (three layers).

During gastrulation, cells rearrange themselves and migrate due to predetermined genetic coding. Three primary germ layers are the main embryonic tissues from which various structures and organs will develop. The first appearance of these layers, collectively known as the primitive streak, is around day 15.


• The ectoderm is the start of tissue that covers most surfaces of the body: the epidermis layer of the skin, hair and nails. Additionally, it forms the nervous system.

• The mesoderm forms the muscle, skeleton, dermis of skin, connective tissue, the urogenital glands, blood vessels, and blood and lymph cells.

• The endoderm forms the epithelial lining of the digestive, respiratory and urinary systems, and

glandular cells of organs such as the liver and pancreas.


The epiblast separates from the trophoblast and forms the floor of a cavity, known as the amniotic cavity. The amnion forms from the cells lining the cavity. The cavity is filled with fluid, and gradually enlarges and folds around the bilaminar disc to enclose it. This amniotic cavity fills with fluid (amniotic fluid) derived initially from maternal filtrate; later the fetus contributes by excreting urine. Fetal cells can be found in the amniotic fluid and can be used in diagnostic testing for genetic conditions via a procedure known as amniocentesis.

At about 16 days mesodermal cells form a hollow tube in the midline called the notochordal process; this becomes a more solid structure, the notochord, about a week later. Specialized inducing cells and responding tissues cause development of the vertebral bodies and intervertebral discs to occur. The neural tube is developed from further cell migration, differentiation and folding of embryonic tissue. This occurs in the middle of the embryo and develops towards each end. The whole process is known as neurulation. Teratogens, diabetes or folic acid deficiency may lead to neural tube defects.

The hypoblast layer of the embryoblast gives rise to extra-embryonic structures only, such as the yolk sac. Hypoblast cells migrate along the inner cytotrophoblast lining of the blastocele-secreting extracellular tissue which becomes the yolk sac. The yolk sac is lined with extraembryonic endoderm, which in turn is lined with extraembryonic mesoderm. The yolk sac serves as a primary nutritive function, carrying nutrients and oxygen to the embryo until the placenta fully takes over this role.

The endoderm and mesoderm cells contribute to the formation of some organs, such as the primitive gut arising out of the endoderm cells. An outpouching of endodermic tissue forms the allantois, this extends to the connecting stalk around which the umbilical cord later forms. Growth of blood vessels is induced, connecting separately to vessels of the embryo and placenta (Kay et al 2011). Blood islands that later go on to develop blood cells arise from the mesodermal layer; the remainder resembles a balloon floating in front of the embryo until it atrophies by the end of the 6th week when blood-forming activity transfers to embryonic sites. After birth, all that remains of the yolk sac is a vestigial structure in the base of the umbilical cord, known as the vitelline duct.

The pre-embryonic period is crucial in terms of initiation and maintenance of the pregnancy and early embryonic development. Inability to implant properly can results in ectopic pregnancy or miscarriage. Additionally chromosomal defects and abnormalities in structure and organs can occur during this time (Moore and Persaud 2003).

During embryological development stem cells under predetermined genetic control become specialized giving rise to further differentiation with a varying functionality according to their predefined role.



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