Medical Embryology Lecture 3: First Week of Development (PDF)

College of Medicine Dr. Firas Al-Masoody Second stage Medical Embryology Lecture 3 First Week of Development: Ovulation to Implantation Learning objectives 1. Define ovarian cycle, menstrual cycle, ovulation, a...

College of Medicine Dr. Firas Al-Masoody Second stage Medical Embryology Lecture 3 First Week of Development: Ovulation to Implantation Learning objectives 1. Define ovarian cycle, menstrual cycle, ovulation, and fertilization. 2. Explain Mechanisms and barriers involved in sperm transport. 3. Discuss changes that occur in the spermatozoa prior to fertilization. 4. Discuss changes that occur in the oocyte after sperm penetration. 5. Define polyspermy and steps to prevent it. 6. List some contraceptive methods. 7. Explore infertility and types of assisted conception. Folliculogenesis, Ovarian Cycle, and Menstrual Cycle When woman reaches puberty, also called menarche, and until menopause, several decades later, monthly cycles in the secretion of hypothalamic, pituitary, and ovarian hormones control a menstrual cycle, which results each month in the production of a female gamete (oocyte) and a uterus primed to receive a fertilized embryo. The hypothalamus secrets gonadotropin releasing hormone (GnRH) that stimulates the anterior pituitary gland to secrete gonadotropin hormones (LH-Luteinizing hormone and FSH-Follicle-stimulating hormone). Both FSH and LH stimulate and control cyclic changes in the ovary. The ovaries in turn secrete female sex hormones (estrogen and progesterone) to stimulate the uterus and breasts to prepare for possible fertilization. (see figure below). Specifically, this 28-day cycle consists of the following: Monthly recruitment and growth of about 15 to 20 primary follicles under the influence of pituitary hormones. Concurrent proliferation of the uterine endometrium. Process of ovulation by which the oocyte is released from the ovary. Usually, a single follicle reaches full maturation and results in ovulation. Following ovulation, continued development of the follicle into an endocrine corpus luteum. The other follicles degenerate and become atretic, and replaced by connective tissue, forming the corpus atreticum. Sloughing of the uterine endometrium and involution of the corpus luteum (unless a fertilized ovum implants in the uterus and begins to develop) 1 Menstrual cycles The menstrual cycle is considered to begin with menstruation (also called the menses), the shedding of the degenerated uterine endometrium from the previous cycle. Menstrual cycle are usually 28-day cycles during which the endometrium undergoes changes under hormonal control from the pituitary gland and ovaries. It consists of three phases: 1- The menstrual phase: Usually, last 4-5 days. The first day of menstruation is the beginning of the menstrual phase, during which the functional layer of the endometrium is sloughed and discarded with the menstrual flow. 2- The proliferative phase: Coincides with the growth of ovarian follicles and is under the influence of estrogen. It begins at the end of the menstrual phase and last for approximately 9 days. 3- The secretory phase: Is under the influence of progesterone produced by the corpus luteum. It begins after ovulation. Last approximately 13-14 days. Ovarian Cycle The classic ovarian cycle also lasts an average of 28 days. It is divided into three phases: the follicular phase, ovulation, and the luteal phase. During the Follicular phase, the follicles undergo three stages of development: 1. Primary follicle: The flat follicular cells of primordial follicle become cuboidal and stratified; forming the granulosa cells surrounding the follicles. 2. Secondary, vesicular or antral follicle: fluid –filled spaces appear between the granulosa cells. Coalescence of these spaces form the antrum, which is crescent shaped initially, but with time, it enlarges. The ovarian stromal cells surrounding the follicle differentiate to the theca cells that are arranged as an inner vascular theca interna and outer fibrous theca externa. 3. Mature vesicular follicle or mature Graafian follicle: The antrum increases in size and granulosa cells surrounding the oocyte form the cumulus oophorus. At this point, the oocyte still has not resumed meiosis. 2 FSH also stimulate follicular cells (Theca interna cells) to produce estrogen, which will: 1. Stimulate uterine endometrium to enter the follicular or proliferative phase. 2. Cause thinning of the cervical endometrium to allow passage of the sperm. 3. Stimulate the pituitary to secrete LH (LH-surge). Ovulation At mid-cycle (about day 13 or 14) levels of FSH and LH suddenly rise very sharply. This ovulatory surge in pituitary gonadotropins will cause the following: 1. Stimulate the oocyte of the mature follicle to resume meiosis I and initiate meiosis II. 2. Stimulate production of progesterone by the corpus luteum. 3. Rupture of the follicle and ovulation of a secondary oocyte. Once meiosis II is initiated, the oocyte is arrested in metaphase about 3 hours before ovulation. The oocyte, in metaphase II, known as secondary oocyte, is discharged from the ovary (the process of ovulation) together with a large number of cumulus oophorus cells. Meiosis II is completed only if the oocyte is fertilized; otherwise, the cell degenerates approximately 24 hours after ovulation. The first polar body may undergo a second division. The luteal phase Following ovulation, granulosa cells of the ruptured follicle change into lutein cells, which form the corpus luteum. The corpus luteum is an endocrine structure that secretes steroid hormones (mainly progesterone). Luteal progesterone stimulates the uterine endometrium to thicken further (secretory phase), in preparation for implantation of the embryo. Fate of the corpus luteum A. If the egg is not fertilized or an embryo does not implant in the uterus, the corpus luteum degenerates and converted to a scar-like structure called the corpus albicans. Levels of progesterone fall causing the thickened endometrium, which is dependent on progesterone, to degenerate and and begin to slough (menstrual phase), which is, by convention, the start of the next cycle. B. If pregnancy occurs, the corpus luteum will continue to grow and form the corpus luteum of pregnancy (corpus luteum gravidatis). This will continue to secrete progesterone until the fourth month of pregnancy. After which the placenta itself begins to secrete large amounts of progesterone and the corpus luteum slowly involutes, becoming a corpus albicans 3 Oocyte transport Ovulated oocyte will enter the fallopian tube (oviduct) by the sweeping movement of the fimbriae. Once in the tube, the oocyte is then propelled into the uterine cavity by peristaltic muscular contraction of the tube and by cilia in the tubal mucosa. Fertilization The process by which male and female gametes (sperm and oocyte, respectively) fuse. It occurs in the ampulla of the uterine tube (the widest part of the tube and is close to the ovary). As many as 300 million spermatozoa may be deposited in the vagina by a single ejaculation. Only 1% of sperm enter the cervix where they survive for many hours. Sperm then moves from the cervix to the uterus and then to the uterine tube. Capacitation The final step of sperm maturation consists mainly of changes in the acrosome that prepare it to release the enzymes required to penetrate the zona pellucida, a shell of glycoprotein surrounding the oocyte. These changes include removal of glycoprotein coat and seminal plasma proteins from the acrosome. Only capacitated sperm can pass through the zona pellucida. Capacitation takes place within the female genital tract and is thought to require contact with secretions of the oviduct. Spermatozoa used in IVF procedures are artificially capacitated. Acrosome reaction When a spermatozoon reaches the oocyte, it binds with sperm receptor in the zona pellucida (called ZP3). As a result of this binding, the acrosome is induced (Acrosome 4 reaction) which involve changes in the acrosome to release enzymes (such as acrosin- and trypsin-like substances) required to penetrate the zona pellucida. Changes occur in the oocyte following sperm penetration Fusion of the spermatozoon cell membrane with the oocyte membrane results in the formation of a calcium wave that radiates over the surface of the egg, and release of cortical granules. These two events alter the sperm receptor molecules, causing the zona pellucida to become impenetrable by additional spermatozoa (zona reaction). Therefore, these changes prevent polyspermy or fertilization of the oocyte by more than one spermatozoon. The membrane fusion of the oocyte and spermatozoon also causes the oocyte to resume and complete the second meiotic division, producing definitive oocyte and second polar body. The main results of fertilization: 1: Restoration of the diploid number of chromosomes 2. Determination of the sex of the new individual 3. Initiation of cleavage Phases of fertilization 1. Penetration of corona radiate: only capacitated sperm pass through the corona cells. 2. Penetration of zona Pellucida: binding of zp3 to molecules on the acrosomal cap of the sperm cell. This binding initiates the acrosomal reaction. 3. Penetration of oocyte plasma membrane. Clinical correlate: Contraceptive methods: 1. Barrier methods: include male condom, female condom and diaphragm. 2. Hormonal contraception: also called birth control bills, they act by inhibiting ovulation, changing the lining of the uterus and thickening of cervical mucus. 3. Intrauterine device (IUD). Infertility: it affects about 15% of couples. 5  Male infertility may be a result of insufficient number of sperm (oligospermia), poor motility (asthenospermia) and/or abnormal shape sperm (teratospermia). Female infertility may be due a number of causes including occluded uterine tube (most commonly due to pelvic inflammatory diseases), hostile cervical mucus, absence of ovulation and others. Treatment of infertility: (Intrauterine insemination, In vitro fertilization (IVF), IntraCytoplasmic sperm injection (ICSI). After penetration of the oocyte by the sperm, the nuclei of the oocyte and sperm swell within the zygote and are called the female and male pronuclei, respectively. Their nuclear membranes quickly disappear as both maternal and paternal chromosomes are replicated in preparation for the first cleavage. Cleavage Within 24 hours after fertilization, the zygote initiates a rapid series of mitotic cell divisions called cleavage. These divisions are not accompanied by cell growth, so they subdivide the large zygote into many smaller daughter cells called blastomeres. The first cleavage division divides the zygote to produce two daughter cells. The second division produces four equal blastomeres. By 3 days, the embryo consists of 6 to 12 cells, and by 4 days, it consists of 16 to 32 cells. The embryo at this stage is called a morula After the third cleavage, blastomeres maximize their contact with each other, forming a compact ball of cells held together by tight junctions. This process is called compaction. Inner cells of the morula constitute the inner cell mass, and surrounding cells compose the outer cell mass. The inner cell mass gives rise to tissues of the embryo proper, and the outer cell mass forms the trophoblast, which later contributes to the placenta. 6 BLASTOCYST FORMATION The morula reaches the uterine cavity, between 3 and 4 days of development. By day 4, the morula, consisting of around 30 blastomeres, begin to absorb fluid. As a result, a large cavity called the blastocyst cavity (blastocele) forms within the morula. At this time, the embryo is called a blastocyst. Cells of the inner cell mass, now called the embryoblast, are at one pole, and those of the outer cell mass, or trophoblast, flatten and form the epithelial wall of the blastocyst. End of first week By day 5, the blastocyst hatches from the zona pellucida. The blastocyst becomes tightly adherent to the uterine lining. Adjacent cells of the endometrial stroma respond to the presence of the blastocyst and to the progesterone secreted by the corpus luteum by differentiating into secretory cells called decidual cells. This response is called the decidual reaction. The endometrial glands near the embryo also enlarge, and the local uterine wall becomes more highly vascularized and edematous. Clinical correlate Implantation in abnormal site results in ectopic pregnancy: a blastocyst can implant in the peritoneal cavity, on the surface of the ovary, or within the oviduct. Embryonic stem cells (ES cells): Are derived from inner cell mass and have the ability to cure many diseases. Abnormal zygote: may occur due to chromosomal abnormalities. Usually they are lost within 2-3 weeks of fertilization. With the use of IVF, genetic study can be performed at a single blastomere of early-stage embryo for DNA analysis. 7