Embryology: Medical School Crash Course

Introduction to Embryology

"To download the audio version of this course, please visit our website"

www.AudioLearn.com

Contents Preface............................................................................................................................................ 1 Chapter 1: Female Reproductive Cycle in Early Pregnancy ................................................... 3 Follicular phase .......................................................................................................................... 3 Ovulation .................................................................................................................................... 7 Luteal Phase ............................................................................................................................... 8 Luteal Phase Defect.................................................................................................................... 9 Implantation Failure ................................................................................................................. 10 Key Takeaways ........................................................................................................................ 11 Quiz .......................................................................................................................................... 11 Chapter 2: Gametogenesis—oogenesis and spermatogenesis, Meiosis ................................. 14 Meiosis ..................................................................................................................................... 14 Meiosis I ................................................................................................................................... 16 Meiosis II ................................................................................................................................. 18 Oogenesis ................................................................................................................................. 18 Spermatogenesis....................................................................................................................... 19 Semen Analysis ........................................................................................................................ 21 Key Takeaways ........................................................................................................................ 23 Quiz .......................................................................................................................................... 23 Chapter 3: Fertilization, Blastulation, and Gastrulation ....................................................... 27 Human Fertilization ................................................................................................................. 27 Blastulation .............................................................................................................................. 30 Gastrulation .............................................................................................................................. 34 Key Takeaways ........................................................................................................................ 35 Quiz .......................................................................................................................................... 35 Chapter 4: Identical and Fraternal Twin Development ......................................................... 39 Fraternal Twins ........................................................................................................................ 39 Identical Twins ......................................................................................................................... 41 Types of Identical Twins.......................................................................................................... 43 Twinning Complications .......................................................................................................... 44 Twin to Twin Transfusion Syndrome ...................................................................................... 45 Managing Twin Births ............................................................................................................. 46 Key Takeaways ........................................................................................................................ 47 Quiz .......................................................................................................................................... 47 Chapter 5: Placental Formation and Function ....................................................................... 51 The Normal Placenta ................................................................................................................ 51 ii

Functions of the Placenta ......................................................................................................... 52 The Immune System and the Placenta ..................................................................................... 54 Summary of Important Functions of the Placenta.................................................................... 54 Common Placental Problems ................................................................................................... 55 Common Placental Diseases .................................................................................................... 55 Choriocarcinoma ...................................................................................................................... 56 Placental Abruption.................................................................................................................. 57 Placenta Accreta ....................................................................................................................... 58 Placenta Previa ......................................................................................................................... 60 Chorioamnionitis ...................................................................................................................... 60 Key Takeaways ........................................................................................................................ 61 Quiz .......................................................................................................................................... 61 Chapter 6: Second Week of Embryogenesis ............................................................................ 65 Embryo Development .............................................................................................................. 65 Division of the Blastocyst ........................................................................................................ 68 Embryoblast Division in the Second Embryological Week ..................................................... 70 Development of the Yolk Sac and the Extraembryonic Cavity ............................................... 71 Uteroplacental Circulatory System .......................................................................................... 72 Abnormalities of Week Two .................................................................................................... 73 Key Takeaways ........................................................................................................................ 74 Quiz .......................................................................................................................................... 74 Chapter 7: Third Week of Embryogenesis .............................................................................. 78 Directional Development ......................................................................................................... 78 The Gastrulation Process.......................................................................................................... 78 Notochord Formation ............................................................................................................... 79 Neural Tube Defects ................................................................................................................ 79 Somite Formation ..................................................................................................................... 81 The Allantois ............................................................................................................................ 81 The Chorion in the Third Week ............................................................................................... 82 The Formation of the Left and Right Axis ............................................................................... 82 Key Takeaways ........................................................................................................................ 83 Quiz .......................................................................................................................................... 83 Chapter 8: Fourth to Eighth Week of Embryogenesis ........................................................... 86 The Fourth Week of Development........................................................................................... 86 Differences in Neural and Digestive Development ................................................................. 87 Embryonic Shape Formation.................................................................................................... 87 Organogenesis .......................................................................................................................... 88 Development of the Limbs ....................................................................................................... 88 Development of Fetal Membranes ........................................................................................... 89 Key Takeaways ........................................................................................................................ 89 iii

Quiz .......................................................................................................................................... 89 Chapter 9: Second Trimester Development ............................................................................ 93 Fourth Month of Pregnancy ..................................................................................................... 93 Fifth Month of Pregnancy ........................................................................................................ 93 Month Six of Pregnancy........................................................................................................... 94 Amniocentesis in the Second Trimester ................................................................................... 94 Key Takeaways ........................................................................................................................ 96 Quiz .......................................................................................................................................... 97 Chapter 10: Third trimester Development ............................................................................ 100 Week Twenty-eight of Pregnancy.......................................................................................... 100 Week Twenty-nine of Pregnancy ........................................................................................... 100 Week Thirty of Pregnancy ..................................................................................................... 100 Week Thirty-one of Pregnancy .............................................................................................. 100 Week Thirty-two of Pregnancy .............................................................................................. 101 Week Thirty-three of Pregnancy ............................................................................................ 101 Week Thirty-four of Pregnancy ............................................................................................. 101 Week Thirty-five of Pregnancy.............................................................................................. 101 Week Thirty-six of Pregnancy ............................................................................................... 101 Week Thirty-seven of Pregnancy ........................................................................................... 101 Week Thirty-eight of Pregnancy ............................................................................................ 102 Week Thirty-nine of Pregnancy ............................................................................................. 102 Week Forty of Pregnancy....................................................................................................... 102 Common Third Trimester Pregnancy Complications ............................................................ 102 Gestational Diabetes............................................................................................................... 102 Preeclampsia .......................................................................................................................... 103 Preterm Labor......................................................................................................................... 103 Premature Rupture of the Membranes ................................................................................... 104 Placenta Previa ....................................................................................................................... 104 Placental Abruption................................................................................................................ 104 Intrauterine Growth Restriction (IUGR) ................................................................................ 105 Post-term Pregnancy .............................................................................................................. 105 Malpresentation ...................................................................................................................... 106 Key Takeaways ...................................................................................................................... 106 Quiz ........................................................................................................................................ 106 Chapter 11: Embryological Birth Defects and Complications ............................................ 110 Implantation Failure ............................................................................................................... 110 Meiosis Disorders................................................................................................................... 111 Miscarriages ........................................................................................................................... 113 Fetal Alcohol Syndrome ........................................................................................................ 114 Key Takeaways ...................................................................................................................... 115 iv

Quiz ........................................................................................................................................ 115 Summary .................................................................................................................................... 119 Course Questions ...................................................................................................................... 121 Course Answers ..................................................................................................................... 146

v

Preface This course covers the basic topic of embryology, beginning with the female reproductive cycle, including the various factors that affect fertilization, and gametogenesis. Following that will be a variety of chapters that will cover the various development features that occur at different stages of the pregnancy.

Chapter one will include a discussion of the female reproductive cycle, including the hormones involved in ovulation. There needs to be a progressive and orderly release of certain hormones in order to have ovulation. Ovulation is necessary for fertilization and for the continuation of a pregnancy.

Chapter two will cover aspects of gametogenesis, including the way the egg cell develops in the female and the way the sperm cell develops in the male prior to fertilization. In actuality, there are similarities in the processes of meiosis in males and females, but there are significant differences as well.

The third chapter of the course will include a discussion of fertilization, the formation of the zygote, the way a zygote transforms into a blastula, and the process of gastrulation, in which a disc-shaped embryo becomes a three-dimensional structure.

In the fourth chapter of the course, we will have a discussion of how twins are made. There are two types of twins. Identical twins come from the same egg cell, while fraternal twins are the result of a woman ovulating two eggs at the same time and having both of those eggs fertilized by separate sperm.

The fifth chapter of the course will involve a discussion of the placenta and how it forms. There are tissues separate from the embryo itself that burrow into the uterine wall and differentiate to become the human placenta that carries forth throughout the pregnancy and nourishes the fetus.

In chapter six, there will be a thorough discussion of the second week of embryogenesis. It is during this time that embryo is disc-shaped and begins to develop from a few cells into a trilayered organism. Cells begin to differentiate into the ectoderm, the mesoderm, and the endoderm.

In the seventh chapter of the course, the way the embryo develops into a three-dimensional structure will be the focus of the discussion. During this time, some of the earliest organs begin to develop, with the circulatory system developing first.

1

In chapter eight, the fourth through eighth week of embryonic development will be the focus of discussion. This is a time when the embryo develops most of its organs and begins to take on the shape of a normal human being. By the end of this time, the embryo is called a fetus.

In chapter nine, the focus of the discussion will be on the basics of second trimester development. During this time, the fetus grows much longer, the organs develop further, and an amniocentesis can be done to evaluate the fetus for any chromosomal or genetic defects.

In chapter ten, the growth and development of the third trimester fetus will be discussed. During this time, the fetus picks up a lot of weight and its lungs develop so that it can live outside of the womb. Common complications of the third trimester will also be discussed.

In the eleventh and final chapter of the course, abnormalities of embryogenesis will be discussed, including nondisjunction, events that cause miscarriages, implantation problems, and the various problems faced by a child exposed to alcohol in utero.

2

Chapter 1: Female Reproductive Cycle in Early Pregnancy The study of embryology begins with an understanding of the female reproductive cycle. In this chapter, we will discuss the female reproductive cycle as it relates to the proliferative phase, ovulation, and the luteal phase, which is after the egg and sperm have united. There will be a discussion of the process of turning a fertilized egg into a whole human being. In this chapter, you will learn about female hormones and how they produce the optimal environment for fertilization and implantation.

Follicular phase The female human goes through a 28-day cycle, the first day of which is the first day of menstrual flow. The process of menstruation begins at approximately 12 years of age in the United States; however, with improved nutrition, more young girls are undergoing menstruation the first time at an age much younger than this. The onset of menses for the first time is called menarche. During the first few cycles, females most likely doesn’t ovulate and have irregular cycles that gradually become more regular as they get older.

The purpose of the menstrual cycle is to prepare the reproductive system of the female to accept a fertilized egg in the process of implantation and to begin a pregnancy. Of course, most menstrual periods do not end in a pregnancy but begin again with another cycle. Technically, a female can begin having pregnancies as soon as menarche begins; however, most women do not have their first pregnancy until they reach approximately 20 years of age.

In females, the menstrual cycle is periodic with elevations of estrogen, progesterone, luteinizing hormone (LH), and follicular stimulating hormone (FSH) that occur at various times of the cycle.

There is a hormone-releasing factor that is made in the hypothalamus and carried into the hypophyseal portal system to the anterior lobe of the pituitary gland, causing the cyclical release of these gonadotropic hormones.

Follicle-stimulating hormone, as its name implies, is involved in stimulating the growth of multiple follicles in the female ovary. It is ultimately secreted by the anterior pituitary gland and begins to rise during the first few days of the female menstrual cycle. This rise in FSH level causes approximately five to seven tertiary stage ovarian follicles to begin developing. These stimulated follicles are called Graafian follicles. Another name for these types of follicles is an antral follicle. These follicles compete with one another for dominance until only one follicle reaches maturity. In a few pregnancies, two different follicles reach maturity and if both are

3

fertilized, fraternal twins can develop. The process of follicular competition is called folliculogenesis and actually takes place over several months.

Under the stimulation of FSH, granulosa cells are proliferated inside the developing follicles.

These cells express luteinizing hormone receptors, which ultimately respond to the LH released by the pituitary gland at the time of ovulation. How this happens involves activation of aromatase and p450 enzymes, which cause the granulosa cells to secrete estrogen. This feeds back onto the hypothalamus, stimulating the production of gonadotropin-releasing hormone (GnRH).

Upon stimulation by gonadotropin-releasing hormone, the thecal cells of the ovary produce androgens that allow for the proliferation, secretion, and differentiation of the follicle cells, which also increases their LH receptor expression. Throughout this phase, the estrogen level continues to rise, stimulating the growth and thickness of the endometrium and myometrium of the female uterus. This is what prepares the uterus to accept a fertilized egg if one should occur.

It is the endometrial cells that mostly respond to rising progesterone levels later in the cycle. The follicular phase is also known as the proliferative phase because this is when endometrial cells are proliferating the most.

A couple of days before LH levels rise, on about the seventh day of the menstrual cycle, generally only one of the recruited follicles achieves dominance. It is believed that this follicle releases so much estrogen that it suppresses the hypothalamus’s secretion of GnRH, which causes the lowering of LH and FSH. As these hormone levels decrease, cellular death of the nondominant follicles occurs with ongoing maturation of the dominant follicle.

High estrogen levels during the follicular phase allows for the formation of the endometrial layer of the uterus, which at this stage is known as the proliferative endometrium. Cervical mucus is stimulated by cells in the cervix called crypts. These crypts cells increase the alkalinity of the vagina, which creates a hospitable environment for the male sperm. This mucus also takes on a texture that is more fluid, clearer, and stretchier. This characteristic mucus is most prominent around the time of ovulation. It allows for the sperm to travel up the vagina, through the uterus, and into the fallopian tubes where fertilization generally occurs. The high estrogen levels are also responsible for a slightly lowered basal body temperature just prior to ovulation.

The period of time from the initial recruitment of tertiary stage follicles through the time of ovulation takes about two weeks. This corresponds the days 1 to 14 of the menstrual cycle. If a woman’s menstrual cycle is long, it is usually this phase that is responsible for this additional length. If no dominant follicle is recruited, more tertiary follicles are recruited and the process starts over. Some women will experience more than one follicular wave in which follicles are developing and no dominant follicle has declared itself.

4

The process of follicle maturation is called folliculogenesis. The process involves the maturation of an immature oocyte into a fully mature follicle. In contrast to male spermatogenesis, which can happen throughout a man’s life, folliculogenesis only occurs during a specific period in a woman’s life, which begins at menarche and ends at menopause.

The main role of the developing follicle is to support the egg cell as it develops. The female human has as many eggs cells as she will ever have while she is still in her mother’s uterus.

These eggs cells remain dormant until puberty went folliculogenesis begins. The first thing that happens is that these primordial follicles become primary follicles, after which they become secondary follicles. Following this, the follicles transition into tertiary follicles that are dependent on the hormonal milieu of the female body. Only the late tertiary or preovulatory follicle actually ruptures, discharging the egg cell into the abdominal cavity, ending the process of folliculogenesis.

Folliculogenesis is a continuous process. This means that at any given point in time, the female ovary contains follicles at all stages of development. The vast majority of follicles die off and never reach full development. It is only the late tertiary follicle that ruptures in the process of ovulation.

There are several stages an egg cell goes through. Small, dormant, primordial oocytes contain only one layer of flat granulosa cells and are the type of cells found in the prepubertal girl.

Primary follicles are larger and contain cuboidal granulosa cells that are undergoing mitosis. The presence of thecal cells indicates a secondary follicle. At this stage, there are many layers of granulosa cells and the follicle is bigger. The tertiary follicle is divided into five different classes.

These are primarily based on their size.

The early tertiary follicle is no bigger than 5 mm in diameter. The late tertiary follicle is about 10 mm in diameter. The late tertiary follicle is a fully formed antrum that undergoes no further differentiation. The follicle becomes preovulatory, and it releases so much estrogen that at all the other follicles die off.

Up until the preovulatory stage, the follicle that contains the primary oocyte is arrested in prophase of meiosis I. At the time of the late follicular stage, this egg cell progresses further until it reaches metaphase II. It stays at this phase until the time of fertilization, when meiosis continues, the egg and sperm unite, and a fertilized egg is developed.

The female ovary contains approximately 5 million primordial follicles at approximately 20 weeks after conception. This is the most number of follicles a girl will ever have, with a maximum of about 7 million follicles total. These follicles are surrounded by granulosa cells which support the follicles throughout the girl’s development. These cells show little biological 5

activity and can lie dormant for up to 50 years. Many of these follicles never develop at all. The total number of follicles decreases slightly before a child is born so that only approximately 180,000 follicles are available for development at the time of puberty. At menopause, only about 1000 follicles remain.

In a primary follicle, the granulosa cells change from being flat in shape to a more cuboidal structure. When this happens, the follicle is said to be primary. The genetic material inside the egg cell is activated, specific genes inside the cell begin to be transcribed, and proteins are translated. Basic signaling pathways are activated that allow communication between egg cells.

These primary follicles express FSH receptors but are independent and grow in the absence of gonadotropins until they reach the antral stage. The presence of FSH encourages the growth of the follicle. Primary follicles have a glycoprotein polymer layer called the zona pellucida, which separates it from the other egg cells. The zona pellucida remains intact until after ovulation when it breaks down in order for the sperm to penetrate egg cell.

Secondary follicles contain thecal cells. They surround outermost layer of the follicle called the basal lamina and eventually become the theca externa and the theca interna. A rudimentary circulatory system develops that allows blood to nourish the follicle. The late secondary follicle is fully grown and has a zona pellucida, which is about nine layers thick, consisting of granulosa cells.

The antrum is a fluid-filled space just next to the oocyte that designates the follicle as being the primary, or antral, follicle. This antral follicle is also known as a Graafian follicle. Antral follicles are more developed than primordial follicles but are not as developed as the tertiary, or final, follicle.

In the tertiary follicle, the mature follicle has already formed and no new cells are made. There are both thecal cells and granulosa cells that are undergoing mitosis and there is an increase in the volume of the antrum. This follicle is now dependent completely on FSH for its growth and development. There are four subtypes of granulosa cells in the tertiary follicle. These are those that form the corona radiata (around the zona pellucida), membrana cells (just inside the basal lamina), periantral cells (near the antrum), and the cumulus oophorous cells that are connective cells.

The theca interna cells of the growing follicle are the cells that express luteinizing hormone receptors. Simulation of these receptors causes androgens to made by the theca cells.

Androstenedione is the major androgen produced by these cells; it further differentiates into the estrogen made by the granulosa cells. As a result, the estrogen level rises.

6

Just prior to ovulation, most of the growing follicles have died off in a process known as atresia.

This involves programmed cell death of all of the cells of the follicle, including the egg cell. No one knows exactly how this happens; however, elevated levels of FSH will prevent this programmed cell death. By the 13th day of the menstrual cycle, about 5 to 7 cells are competing for dominance, although only one cell reaches complete maturity by the 14th day of the menstrual cycle.

As the FSH level rises, antral follicles secrete both estrogen and inhibin, which exert a negative feedback loop reducing the number of FSH receptors on each cell. The cells with the least number of FSH receptors will cease growing and will die off. Only the dominant follicle with the most number of FSH receptors will continue to grow and will become the preovulatory follicle.

Interestingly, the mature follicle is not a spherical structure but becomes oval in shape. The oocyte places itself at an eccentric position on one side of the follicle because of greater cellular proliferation on just one side of the follicle. Other side of the follicle is fluid-filled and is called the follicular antrum. When a follicle reaches this size and shape, it is known as a vesicular follicle. The egg cell is protected by a cellular mound called the cumulus oophorus, which sticks out into the antrum. Final follicular development depends on LH as well as FSH.

Ovulation The end of the follicular phase is marked by high estrogen levels. This results in a surge of both the LH and FSH level that lasts up to 36 hours and results in the eventual rupture of the primary ovarian follicle. The egg cell is released and enters the oviduct of the fallopian tube.

The process proceeds like this: proteolytic enzymes are secreted by the primary follicle that open up an area at one end of the follicle, causing the egg cell to be extruded from the follicle and into the oviduct. This is all under the influence of LH. The hole in the follicle is called the stigma.

Through the stigma, the egg cell enters the peritoneum and is pushed along by cilia so that it preferentially enters the oviduct and begins its journey toward the uterus.

At this point in time, the egg cell has reached meiosis I and is actually two cells. The larger cell is called the secondary egg cell; it contains all the cytoplasmic material necessary for the egg cell survival. The smaller cell is called a polar body and contains very little cytoplasm. Following this, meiosis II occurs, but the process is arrested at metaphase until the time of fertilization. If no fertilization happens, the egg cell will degenerate at approximately 24-hour’s after ovulation.

More than one egg cell is released in a single ovulatory cycle about 1 to 2% of the time. If this happens and both eggs are fertilized, this results in the formation of fraternal twins.

The ovulatory phase of the female reproductive cycle is the shortest phase. It occurs between the 12th and 16th day of the cycle and lasts only 1 to 2 days. Most women can tell that they have 7

ovulated because of a slight drop in their basal body temperature at the time of ovulation and because of changes in the cervical mucus that support sperm transport. Some women will experience pain at this time. Ovulation pain is also called mittelschmerz pain and, while it is not dangerous, it can be uncomfortable for some women.

Luteal Phase The luteal phase begins after the fertilization of the egg or, if the egg is not fertilized, after the egg is released from the ovary. After the egg is released, the follicle becomes a corpus luteum.

This is a temporary endocrine structure responsible for making progesterone, estradiol, and inhibin A. The corpus luteum is made entirely from granulosa cells that remain behind after the follicle has ruptured and after the egg cell as entered the fallopian tube.

Surrounding blood vessels provide a blood supply to the corpus luteum so that these cells can produce hormones that ultimately support the egg cell after fertilization. Granulosa cells increase in size and make up about 80% of the corpus luteum. At this time, they are known as granulosa lutein cells. They secrete very little protein and instead secrete estradiol, of which the base form is androstendione.

The theca interna cells turn into theca lutein cells and contribute to the outer aspect of the corpus luteum. These are much smaller cells than the granulosa cells and are responsible for steroid synthesis. Overall, the corpus luteum is rather large and increases even further in size during pregnancy. The corpus luteum and pregnancy is called a corpus luteum graviditatis, which can be up to a third of the size of the total ovary. The corpus luteum remains functional unless the egg is fertilized, at which time it becomes a structure called the corpus albicans.

When it comes to the endometrium, the luteal phase is also called the secretory phase or progestational phase. This is the phase in which the endometrium becomes the most receptive to the implantation of the fertilized egg. The endometrial layer is thick and rich with vasculature as would be necessary if an embryo were to implant and require the circulation necessary to attach to the embryo and start building the connections that will ultimately become the uterine/placental boundary.

During this phase, the estrogen made by the corpus luteum is responsible for the inhibition of FSH in the pituitary gland. This is evolutionarily appropriate because it means that there is no chance of multiple ovulations and there is a genetic benefit to having just a single fertilized egg that implants into the uterus to become the embryo and, eventually, the fetus.

The corpus luteum reaches peak size and peak development on the ninth day after ovulation. If there is no more stimulation from luteinizing hormone, the two cell types that make up the corpus luteum (the theca cells and the granulosa cells) will undergo apoptosis and die off. This 8

immediately lowers the progesterone production and the secretory endometrium cannot support itself. Two things happen after this. The endometrial lining cannot last and begins to break down, eventually sloughing off at the beginning of the next cycle. In addition, a new crop of follicles starts growing so that there will be a new batch of follicles developing during the next menstrual cycle.

If a pregnancy does occur, the corpus luteum must be preserved at all costs. This is because the corpus luteum secretes progesterone that continues to support and endometrium that is healthy enough for a growing embryo. It is the trophoblast of the embryo that produces human chorionic gonadotropin, a hormone that is similar to luteinizing hormone, which prevents the breakdown of the corpus luteum. This keeps the corpus luteum alive, keeps the endometrium thick, and allows a healthy pregnancy to proceed. The corpus luteum in pregnancy is extremely large and remains large for up to five months—secreting necessary hormones, including progesterone, until the placenta is able to make enough estrogen and progesterone to support both itself and the endometrial lining.

If the egg cell is not fertilized, the corpus luteum is unable to support itself and eventually degenerates approximately 10 to 12 days after ovulation. At this point in time, it becomes a corpus luteum of menstruation, undergoes apoptosis, which is programmed cell death and is eventually phagocytized. The structure left over is nothing more than a scar. The egg is fertilized, corpus luteum grows and its stromal cells differentiate. If by some chance the corpus luteum is removed before the fourth month of pregnancy, the pregnancy cannot survive. The death of the corpus luteum is called luteolysis and happens every cycle that does not end in a pregnancy.

There is a feedback loop associated with the luteal phase that is worth mentioning. The corpus luteum produces hormones that ultimately suppress secretion of FSH and LH. The corpus luteum needs these hormones to maintain itself. In the absence of pregnancy, this feedback loop results in the death of the corpus luteum and falling levels of estrogen and progesterone. This is what triggers menstruation. If the egg is fertilized, the trophoblast makes hCG which supports the corpus luteum throughout the first part of pregnancy.

Luteal Phase Defect There is a medical condition known as luteal phase defect in which the woman does not produce enough progesterone from the corpus luteum to last the entire luteal phase. End result is a shortened luteal phase and an inability of the corpus luteum is supports the embryo. There are several mechanisms believed to be behind this problem.

The first mechanism is thought to be related to abnormal follicular development. It is believed that there is not enough FSH and LH being secreted by the pituitary gland, which results in 9

under-stimulation of the granulosa cells in the developing follicle so that not enough estradiol is made. The follicle does not develop normally and does not make enough progesterone to support a healthy pregnancy. The end result is that even if an egg is fertilized, the corpus luteum cannot support it.

Another theory behind a luteal phase defect is that there is not enough luteinizing hormone released by the pituitary gland, which results in abnormal amounts of androstenedione to be secreted by the theca cells of the follicle. This also leads to low estradiol levels, an abnormal follicle, and low levels of progesterone in the luteal phase. Another theory is that there are abnormalities in the vasculature of the endometrium that make the endometrium unresponsive to normal progesterone levels. Lastly, women who have hyperprolactinemia and hypothyroidism are at a greater risk of having a luteal phase defect. These conditions have an adverse effect on the relationship between the hypothalamus and the pituitary gland.

Women with a luteal phase defect have several treatment options. Women with hypothyroidism can be treated with the levothyroxine and women with unexplained luteal phase defect can be treated with vaginal progesterone suppositories. Suppositories and gel are preferred methods of getting progesterone because they give better levels and can be continued for several weeks into the pregnancy. Synthetic progesterone has been found to be better than non-synthetic progesterone. An additional treatment for luteal phase defect is clomiphene citrate, which improves the development of the follicle.

Implantation Failure Implantation failure is another problem that can be associated with the luteal phase. It involves the inability of the uterus to be receptive to the implantation of the embryo. Two thirds of the time the problem is related to the uterine receptacle and one third of the time the problem is related to the embryo. Implantation failure can be improved by optimizing the endometrial cavity.

The best treatment for implantation failure is to support the luteal phase with progesterone. This has been known to increase the success rate of implantation and to improve the development of the early embryo, thereby promoting a healthy corpus luteum. Women who are known to have at least three implantation failures using assisted reproduction have been found to have improvement in implantation after providing them with low molecular weight heparin. This improves the live birth rate by 80%.

10

Key Takeaways • • •

There are four main phases of the menstrual cycle. These are the menstrual phase, the follicular phase, the ovulatory phase, and the luteal phase.

It is the corpus luteum that supports both the fertilized egg and the endometrium in order to begin a healthy pregnancy.

Human chorionic gonadotropin mimics luteinizing hormone so that the corpus luteum does not die off.

Quiz 1. Approximately how many follicles are stimulated at the time of the follicular phase of the menstrual cycle to become Graafian follicles? a. Two b. Four c. Six d. Twenty Answer: c. About five to seven follicles are stimulated by FSH each cycle to become what are known as Graafian follicles. Of these, only one reaches full maturity in the vast majority of cases.

2. Which female reproductive cells are ultimately responsible for releasing the estrogen that stimulates the hypothalamus to release GnRH? a. Thecal cells b. Follicular cells c. Granulosa cells d. Myometrial cells Answer: c. It is the granulosa cells of the follicle that produce estrogen and that cause the hypothalamus to release GnRH, beginning the female reproductive cycle.

3. Which reproductive hormone is only secreted by the hypothalamus as part of the female reproductive cycle? a. Luteinizing hormone b. Gonadotropin-releasing hormone c. Follicle stimulating hormone d. Human chorionic gonadotropin 11

Answer: b. The cells of the hypothalamus secrete gonadotropin-releasing hormone or GnRH as part of the female reproductive cycle.

4. Which type of follicle in the female ovary is considered completely depended on FSH for its growth and development? a. Primordial b. Late-tertiary c. Secondary d. Graafian Answer: b. The late-tertiary cell is completely dependent on FSH for its continued growth and development, while the other types of follicles will grow independent of the concentration of FSH in the female body.

5. What does the dominant follicle express on its surface the most that makes it become more dominant over the other follicles? a. FSH receptors b. LH receptors c. Progesterone receptors d. Estrogen receptors Answer: a. The dominant follicle becomes dominant because it expresses the most FSH receptors on its surface. As a result, it continues to grow, while the other follicles undergo atresia and die off.

6. Which hormone triggers proteolytic enzymes to open a hole in one end of the follicle in order to release the egg cell? a. GnRH b. LH c. FSH d. Estrogen Answer: b. It is the influence of LH that causes the formation of a hole in the end of the follicle, allowing for the release of the egg at ovulation.

12

7. Which phase of the female reproductive cycle is potentially the longest phase? a. Menstrual phase b. Follicular phase c. Ovulatory phase d. Luteal phase Answer: b. The follicular phase varies in length with the length of the cycle and is potentially the longest phase of the reproductive cycle.

8. Which endometrial phase involves an endometrial lining that is most receptive to the implantation of the embryo? a. Follicular phase b. Menstrual phase c. Ovulatory phase d. Secretory phase Answer: d. The secretory phase of the endometrium is the time when the endometrium is most receptive to the implantation of the embryo.

9. What is the ultimate fate of the corpus luteum should fertilization never occur in a given cycle? a. It becomes a fibrotic shell b. It becomes phagocytized by phagocytes after programmed cell death c. It regresses and is available for re-recruitment the next cycle d. It swells and releases antral fluid into the peritoneal space Answer: b. The ultimate fate of the corpus luteum is that it undergoes programmed cell death and is phagocytized by phagocytes so that it no longer exists.

10. How does clomiphene citrate help women with luteal phase defect? a. It creates more than one follicle so the progesterone level is higher. b. It speeds up the ovulation process, shortening the menstrual cycle. c. It helps in folliculogenesis so the follicle produces more progesterone. d. It supports the corpus luteum in the luteal phase of the cycle.

Answer: c. Clomiphene citrate helps folliculogenesis so that the follicle produces more progesterone.

13