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Embryology, Fertilization
Introduction
Fertilization is a complex multi-step process that is complete in 24 hours. Sperm from a male meets an ovum from a female to form a zygote; this is the point at which pregnancy begins and marks the start of a 280-day journey for the female. There are 2 ways to track this process, and they differ in the day counting begins. There are the post-ovulation age and the gestational age, calculated by adding 2 weeks to the last menstrual period. There are many steps that both the egg and sperm must go through for this process to be successful. Furthermore, the fertilized egg undergoes drastic changes. This topic details the process in the following sections.
Development
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Development
In the first weeks after fertilization, the zygote makes many changes and develops rapidly. The first 8 weeks of development are known as the organogenic period and constitute the embryonic stage. This period is a crucial phase of development for the embryo’s organs. During the first 3 weeks, teratogens have an all-or-nothing effect on the embryo. During the third through eighth weeks, growth and function are affected. Weeks 9 to 37 are known as the fetal period. This period is important for extensive growth and the continuous differentiation of organ systems. The respiratory system completes development just prior to birth. An important part of embryology that does not complete during the embryonic or fetal phase is gametogenesis. In both males and females, these processes begin during the fetal period and continue into puberty. This process is a mitotic and meiotic process that results in the production of an ovum and sperm.[1] Before gametogonia develop, embryonic development of gametes is the same in males and females, and by week 10 they can be differentiated. Primordial germ cells migrate from the dorsal endoderm of the yolk sac to the hindgut of the gonadal ridge, where they undergo mitotic divisions and become gametogonia.
Cellular
Once fertilization occurs, rapid changes occur at the cellular level in the zygote. The zygote is a single cell that undergoes mitosis to produce many cells. Once the zygote has reached the 32-cell stage, it becomes a morula. Day 4 begins blastulation, and cavities begin to form, starting with a hollow ball. Some studies suggest that the timing of this process may affect implantation.[2] There are now 2 different cell types, an inner and outer. The inner cells are called the inner cell mass, and the exterior is known as the trophoblast, which later helps form the placenta. The inner cell mass becomes the embryo. The inner cell mass further differentiates into the epiblast and the hypoblast. The hypoblast becomes the primitive yolk sac, and the epiblast becomes the amniotic sac. During this phase, the entity is a blastula, and the zona pellucida is absent, allowing growth and differentiation. During week 3, the tubes form, a process known as gastrulation. Movements during gastrulation are dependent on differential cell adhesion, chemotaxis, chemokinesis, and planar polarity.[3] During this time, 3 layers of cells make up different organ systems. These are known as the endoderm, mesoderm, and ectoderm. The ectoderm forms the epidermis, nails, hair, peripheral nervous system, brain, and spinal cord. The mesoderm forms the muscle, bone, connective tissue, notochord, kidney, gonads, and circulatory system. The endoderm forms the epithelial lining of the digestive tract, stomach, colon, liver, bladder, and pancreas. At 16 weeks, the primitive streak forms. The primitive streak establishes the midline of the body. The next stage in development is neurulation. At this stage, the notochord induces the ectoderm to form the neural plate, which eventually gives rise to the neural tube. The neural tube gives rise to the brain and spinal cord. The mesoderm divides into the axial, paraxial, intermediate, and lateral plate mesoderm, which give rise to different body parts — the paraxial mesoderm forms somites, which differentiate into cartilage, muscle, bone, and dermis. The intermediate mesoderm becomes the urogenital system, and the lateral plate mesoderm becomes the heart and vessels. The endoderm forms the gastrointestinal tract, and the ectoderm meets the endoderm, forming the mouth and anus. An important gene regulatory mechanism is Dkk1; the deletion of Dkk1 is known to cause an imperforate anus with a rectourinary fistula.[4]
Biochemical
There are significant changes that the egg and sperm must undergo for fertilization to occur; these begin as soon as sperm is deposited in the vagina. Sperm undergoes capacitation to have increased motility and metabolism to help it make the journey to the fallopian tube. Capacitation occurs due to the acidic environment of the vagina. It activates ATPases in the sperm cytosol. The process of capacitation is important because it alters the plasma membrane by changing its lipid and glycoprotein composition, which is 1 of the 2 changes sperm undergo.[5] The second change helps penetrate the matrix. The egg’s extracellular matrix is difficult to penetrate. The acrosome on the sperm contains important lysosomal enzymes. These enzymes are thought to be released by exocytosis and are required for egg penetration.[6] Hyaluronidase from the acrosome digests the cells embedded in hyaluronic acid surrounding the oocyte. This process exposes acrosin, which is in the inner membrane of the sperm. Acrosin is necessary to digest the zona pellucida. Once the acrosome reaction takes place, no other sperm may penetrate the zona pellucida; this is imperative to ensure that the appropriate number of chromosomes is available and that there is no trisomy zygote. The fusion of the acrosome of the sperm to the zona pellucida induces a rise in calcium. This rise in calcium stimulates the release of contents from secretory vesicles known as cortical granules, thereby modifying the extracellular matrix. The cortical granules release enzymes that render the zona pellucida impenetrable to sperm entry by digesting the sperm receptor glycoproteins ZP2 and ZP3, so that they can no longer bind to spermatozoa.[7]
Molecular Level
We have discussed in previous sections changes occurring at the biochemical and cellular levels. Here, we discuss the molecular changes that occur during fertilization. Before fertilization occurs, sperm travel to the fallopian tubes, where they penetrate the egg. The spermatozoa in ejaculate vary, and the make-up of each spermatozoon contributes to its ability to get to the egg and fertilize it.[8] Spermatozoa have differences in DNA fragmentation status, motility, morphology, and sensitivity to signaling molecules. Diving even deeper into this topic, research has shown that spermatozoa with stable chromatin reach the fertilization site more readily and bind more effectively.[9] The sperm and egg are 2 haploid nuclei that join to form a diploid nucleus. Once the sperm and egg have fused, the zygote undergoes mitotic divisions. As mentioned before, the changes the egg undergoes once 1 acrosome has penetrated its membrane, keeping other sperm out and preventing triploidy, are crucial from a molecular standpoint. Sperm play a vital role by providing a centriole, which helps organize and assemble the mitotic spindle.[10]
Function
The function of fertilization is to create a diploid(2N) zygote. Fertilization by a sperm activates the ovum, which takes place in the distal third of the fallopian tube. Once the sperm has entered the ovum, immediate changes take place to prevent further penetration of the ovum. These exact changes are in the biochemical section of this topic. Once the sperm has penetrated the ovum, the sex of the embryo is determined by the presence or absence of a Y chromosome, which contains the SRY gene, known as the testis-determining factor and also as sex-determining region Y.
Mechanism
A follicle must mature from an oocyte to a Graafian follicle to be ready for fertilization. During ovulation, the follicle is released and swept into the fallopian tube. If sperm were deposited in the last 10 hours, they would have made their way to this location, and fertilization can occur. Fertilization must take place within 24 hours of ovulation; otherwise, the ovum is available to be fertilized and ends in menses. The follicle has 2 layers that the sperm must penetrate, both the corona radiata and the zona pellucida. The first step is the penetration of the corona radiata. The acrosome of the spermatozoa then releases enzymes that aid in the digestion of this layer and allow access to the secondary oocyte.
Testing
Infertility is a common problem encountered in the medical community. If a female patient cannot become pregnant after 1 year of unprotected intercourse performed regularly, an evaluation is in order. An important consideration is the patient’s body mass index. If a patient is overweight, weight loss may improve her chances of becoming pregnant.[11] It is essential to consider labs in patients who are unable to become pregnant because abnormalities of the thyroid gland or androgen excess may indicate an endocrinopathy. A commonly encountered endocrinopathy that causes issues with fertility is polycystic ovarian syndrome. In PCOS, testosterone increases, which interferes with egg maturation.[12] A physical exam is also useful in evaluating infertility. Masses or tenderness in the adnexae or the pouch of Douglas is consistent with endometriosis or chronic pelvic inflammatory disease. Furthermore, structural abnormalities may suggest an infection, leiomyoma, malignancy, or Mullerian anomaly. In women who are not suspected of ovulating, it is crucial to perform a thorough hormone analysis to determine whether ovulation is occurring. A mid-luteal progesterone level should be measured 1 week before the expected menstruation. To show proof of ovulation, a progesterone level greater than 3 ng/mL is expected. Another useful hormone to evaluate female fertility is the anti-Mullerian hormone.[13] This hormone is in the TGF-beta family and expresses itself by small early antral follicles. These levels reflect the size of the primordial follicle pool and are a good indicator of ovarian function.
Clinical Significance
There are numerous clinical scenarios in which fertilization comes into play. Fertilization and the subsequent development are delicate and complex processes that can result in defects. Hormones are important for preparing the female body to implant a fertilized egg and to support its growth and nourishment. FSH, which causes the release of estrogen from the ovaries, aids the cervical mucus in being more hospitable to sperm movement through the vaginal canal and cervix. An LH surge is necessary for the release of an egg from the ovary out of the follicle and into the fallopian tube, where it can undergo fertilization. Progesterone, produced by the corpus luteum and later by the placenta, creates and maintains a thickened endometrium to allow a nourishing environment for implantation and growth. Pregnancy tests detect fertilization by measuring beta-human chorionic gonadotrophin released by the growing placenta after implantation. Another important clinical significance is neural tube defects, which are central nervous system birth defects that occur when the neural tube fails to close completely.[14] Folic acid supplementation during pregnancy has been shown to help prevent neural tube defects; thus, it is a commonly recommended prenatal supplement. Another important clinical consideration is the group of genes known as Hox genes, which play a significant role in body plan and development along the cephalic-to-caudal axis. If there are mutations in these genes, body parts may develop in the wrong locations.[15]
References
Che D, Wang Y, Bai W, Li L, Liu G, Zhang L, Zuo Y, Tao S, Hua J, Liao M. Dynamic and modular gene regulatory networks drive the development of gametogenesis. Briefings in bioinformatics. 2017 Jul 1:18(4):712-721. doi: 10.1093/bib/bbw056. Epub [PubMed PMID: 27373733]
Franasiak JM, Forman EJ, Patounakis G, Hong KH, Werner MD, Upham KM, Treff NR, Scott RT Jr. Investigating the impact of the timing of blastulation on implantation: management of embryo-endometrial synchrony improves outcomes. Human reproduction open. 2018:2018(4):hoy022. doi: 10.1093/hropen/hoy022. Epub 2018 Dec 20 [PubMed PMID: 30895262]
Solnica-Krezel L, Sepich DS. Gastrulation: making and shaping germ layers. Annual review of cell and developmental biology. 2012:28():687-717. doi: 10.1146/annurev-cellbio-092910-154043. Epub 2012 Jul 9 [PubMed PMID: 22804578]
Level 3 (low-level) evidenceGuo C, Sun Y, Guo C, MacDonald BT, Borer JG, Li X. Dkk1 in the peri-cloaca mesenchyme regulates formation of anorectal and genitourinary tracts. Developmental biology. 2014 Jan 1:385(1):41-51. doi: 10.1016/j.ydbio.2013.10.016. Epub [PubMed PMID: 24479159]
Level 3 (low-level) evidenceDe Jonge C. Biological basis for human capacitation-revisited. Human reproduction update. 2017 May 1:23(3):289-299. doi: 10.1093/humupd/dmw048. Epub [PubMed PMID: 28115407]
Okabe M. Mechanism of fertilization: a modern view. Experimental animals. 2014:63(4):357-65 [PubMed PMID: 24974794]
Level 3 (low-level) evidenceGeorgadaki K, Khoury N, Spandidos DA, Zoumpourlis V. The molecular basis of fertilization (Review). International journal of molecular medicine. 2016 Oct:38(4):979-86. doi: 10.3892/ijmm.2016.2723. Epub 2016 Aug 31 [PubMed PMID: 27599669]
Holt WV, Fazeli A. Sperm selection in the female mammalian reproductive tract. Focus on the oviduct: Hypotheses, mechanisms, and new opportunities. Theriogenology. 2016 Jan 1:85(1):105-12. doi: 10.1016/j.theriogenology.2015.07.019. Epub 2015 Jul 22 [PubMed PMID: 26277704]
Tsakmakidis IA, Lymberopoulos AG, Khalifa TA. Selectivity of porcine zona pellucida to bind spermatozoa with normal chromatin structure. Andrologia. 2011 Oct:43(5):358-60. doi: 10.1111/j.1439-0272.2010.01074.x. Epub 2011 Jun 20 [PubMed PMID: 21689133]
Level 3 (low-level) evidenceDebec A, Sullivan W, Bettencourt-Dias M. Centrioles: active players or passengers during mitosis? Cellular and molecular life sciences : CMLS. 2010 Jul:67(13):2173-94. doi: 10.1007/s00018-010-0323-9. Epub 2010 Mar 19 [PubMed PMID: 20300952]
Level 3 (low-level) evidenceTalmor A, Dunphy B. Female obesity and infertility. Best practice & research. Clinical obstetrics & gynaecology. 2015 May:29(4):498-506. doi: 10.1016/j.bpobgyn.2014.10.014. Epub 2014 Nov 7 [PubMed PMID: 25619586]
Morgante G, Massaro MG, Di Sabatino A, Cappelli V, De Leo V. Therapeutic approach for metabolic disorders and infertility in women with PCOS. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2018 Jan:34(1):4-9. doi: 10.1080/09513590.2017.1370644. Epub 2017 Aug 29 [PubMed PMID: 28850273]
Level 2 (mid-level) evidencePastore LM, Christianson MS, Stelling J, Kearns WG, Segars JH. Reproductive ovarian testing and the alphabet soup of diagnoses: DOR, POI, POF, POR, and FOR. Journal of assisted reproduction and genetics. 2018 Jan:35(1):17-23. doi: 10.1007/s10815-017-1058-4. Epub 2017 Oct 2 [PubMed PMID: 28971280]
Greene ND, Copp AJ. Neural tube defects. Annual review of neuroscience. 2014:37():221-42. doi: 10.1146/annurev-neuro-062012-170354. Epub [PubMed PMID: 25032496]
Level 3 (low-level) evidenceQuinonez SC, Innis JW. Human HOX gene disorders. Molecular genetics and metabolism. 2014 Jan:111(1):4-15. doi: 10.1016/j.ymgme.2013.10.012. Epub 2013 Oct 29 [PubMed PMID: 24239177]
Level 3 (low-level) evidence