Health Issues - Unit 1
Health Issues - Midterm 2 Study Notes
Embryology
The Egg (Oocyte): Precious Resource
Oogenesis begins in utero.
A female is born with approximately 1-2 million eggs, but only about 400-500 will actually ovulate throughout her lifespan.
Eggs are housed in the ovaries within structures known as follicles.
By the time of menstruation, the egg count reduces to approximately 300,000.
Ovarian Reserve
Ovarian reserve refers to the number of eggs remaining in a female's ovaries. Generally, younger females have a higher ovarian reserve.
Meiosis in the Oocyte
Meiosis is a special type of cell division that reduces the number of chromosomes in the eggs to 23 (haploid).
The process of oocyte meiosis begins before birth but pauses at prophase I for several years.
At the time of ovulation, the egg completes its first meiotic division.
The egg remains at the second meiotic division stage until fertilized by sperm.
The Sperm (Spermatozoon): Determined Traveler
Sperm are produced continuously from puberty initiation, a process called spermatogenesis.
Approximately 100-200 million sperm are produced each day (approximately 15,000 per heartbeat).
Structure of Sperm
Head: Contains haploid nucleus and is covered by an acrosome, an enzyme-filled sac crucial for penetrating the egg.
Midpiece: Packed with mitochondria that produce the energy necessary for the sperm’s journey.
Tail (flagellum): Functions as a powerful motor propelling the sperm forward.
Meiosis in Spermatogenesis
Meiosis in males begins with a precursor cell called spermatogonium.
Unlike females, meiotic divisions in males are continuous and efficient.
Spermatids: Four small, similarly sized, and viable haploid cells produced during spermatogenesis, which then mature into fully functional spermatozoa over approximately 74 days.
Epigenetics Refresher
Epigenetics refers to modifications to DNA that do not alter the nucleotide sequence itself but affect gene expression.
DNA methylation occurs at CpG sites acting like a dimmer switch that regulates gene expression.
Parental factors, including diet, stress, and exposure to toxins, can influence these epigenetic patterns.
Genetic imprinting ensures certain genes are silenced from either the mother or father, resulting in only one active copy in the embryo.
The Journey to Fertilization
Only a few thousand sperm successfully reach the fallopian tube.
Sperm must undergo capacitation (involves destabilization of the sperm head membrane and increased tail activity) to be capable of fertilizing the egg.
The oocyte releases chemoattractants that guide sperm on the final leg of their journey.
In cases where the oocyte is not released, sperm can remain viable in the fallopian tube for up to 5 days.
Fertilization: The Grand Finale
Steps of Fertilization
Step 1: Sperm must penetrate the outer layer of cells surrounding the egg, known as the corona radiata.
Step 2: The sperm reaches the Zona Pellucida, a thick glycoprotein shell, where its head binds to specific receptors on the surface of the zona.
Step 3: The binding process triggers the acrosome reaction, wherein the enzyme-filled cap of the sperm head releases enzymes that digest the zona to create a path for the sperm.
Step 4: The first sperm that burrows through the zona fuses with the egg membrane, delivering its nucleus into the egg's cytoplasm.
Sealing the Deal
Fertilization by more than one sperm (referred to as polyspermy) results in a non-viable embryo.
The moment the first sperm fuses with the egg, a wave of Ca²⁺ ions spreads through the egg's cytoplasm, prompting the cortical reaction.
This reaction causes thousands of tiny sacs located under the egg's membrane (cortical granules) to release their contents outward. Enzymes from these granules harden the zona and destroy sperm receptors, creating an impenetrable barrier against additional sperm.
This event also signals the egg to complete its second meiotic division.
The 1st Week of Life
Syngamy and Zygote Formation
Following fertilization, both the sperm and egg nuclei swell to form pronuclei.
Syngamy refers to the process where the two pronuclei fuse together, combining genetic material and restoring the diploid number of chromosomes (46) to create the first cell of the new organism: the zygote.
This single cell contains a complete genetic blueprint for a unique individual.
Cleavage Divisions
Starting approximately 30 hours after fertilization, the zygote undergoes a series of rapid divisions, known as cleavage, producing cells called blastomeres.
These divisions occur without an increase in the overall size of the embryo; therefore, blastomeres become progressively smaller while the initial volume of the cell remains constant.
The process is exponential: one cell divides into two cells, then four cells, and so on.
Compaction and the Morula
At the 16-32 cell stage, the embryo forms a solid ball of cells known as a morula.
During compaction, the outer blastomeres flatten and form tight junctions, creating a sealed outer surface and separating the cells into two groups: an outer layer and an inner cluster.
Formation of Blastocyst
Following compaction, fluid is pumped into the morula, resulting in a cavity termed the blastocoel.
The embryo is now referred to as a blastocyst and consists of two distinct cell types:
Trophectoderm: The outer layer of cells that encloses the cavity and will contribute to the fetal portion of the placenta.
Inner Cell Mass (ICM): A small cluster of cells located on one side of the cavity that contains pluripotent stem cells and will differentiate into the fetus.
Fate of Cells
The two cell lineages (Trophectoderm and ICM) have very different destinies:
Trophectoderm: Will form extraembryonic tissue and will not become part of the fetus.
Inner Cell Mass (ICM): Will develop into the actual fetus.
Hatching from Zona
Throughout the early developmental period, the embryo is protected by the tough outer shell of the Zona.
Around days 5 or 6, the expanding blastocyst must hatch from this layer, a process termed hatching.
Hatching is essential as it allows trophectoderm cells to make direct contact with the uterine wall to initiate implantation.
Implantation
The uterine lining, known as the endometrium, must be in a receptive state for implantation, which is facilitated by hormonal changes.
Trophectoderm cells begin to make contact with the endometrium, actively invading and burrowing into the uterine tissue.
The maternal endometrial tissue transforms into decidua, a specialized tissue rich in blood vessels and nutrients needed to support the developing embryo.
Formation of Germ Layers
Once implantation occurs, the ICM enters a process called gastrulation where its cells migrate and organize into three distinct layers known as primary germ layers.
Gastrulation is among the most fundamental events in development as it gives rise to all body parts through the following layers:
Ectoderm (outer): Forms the nervous system (brain, spinal cord, nerves) and the epidermis (outer layer of skin, hair, nails).
Mesoderm (middle): Forms structural components such as muscles, bones, cartilages, and the entire circulatory system (heart, blood vessels, and cells).
Endoderm (inner): Forms epithelial linings of internal tracts, including the digestive system, respiratory system, liver, and pancreas.
Early Placental Development
Trophectoderm cells multiply rapidly and differentiate into an invasive outer layer called the syncytiotrophoblast, which burrows deep into the uterine wall, establishing blood supply.
Notably, syncytiotrophoblast cells produce significant quantities of hCG (human chorionic gonadotropin).
Carnegie Stages (Weeks 0-8) of Embryonic Development
To study the earliest phases of embryonic development, scientists utilize Carnegie stages.
This is a standardized system of 23 stages classifying embryos based on their external and internal morphological developments, not merely by age or size.
It spans 8 weeks of development from fertilization to the beginning of the fetal period.
From Embryo to Fetus
A critical transition occurs at the end of the 8th week following fertilization:
Embryonic Period (Weeks 1-8): During this phase, organogenesis occurs, leading to the formation of major organs and body systems; the developing human is termed an embryo.
Fetal Period (Weeks 9 to Birth): Post-embryonic development, where the developing human is referred to as a fetus and involves significant growth and maturation of existing structures.
Key Developments by Trimester
1st Trimester (Weeks 1-12): Encompasses the entire embryonic period; key developments include:
Heart begins to beat (around week 4).
Neural tube closure.
All major organs present in rudimentary form.
Most critical period for development—high susceptibility to teratogen effects (e.g., alcohol, medications, infections).
2nd Trimester (Weeks 13-27): Known as the growth trimester; notable developments include:
Fetus experiences significant increases in length and weight.
Ongoing maturation of organs and functions.
Skeleton hardens (ossification), and details such as fingerprints and hair become noticeable.
Mother may begin to feel fetal movements (quickening).
3rd Trimester (Weeks 28 to Approximately 40): Focuses on maturation and preparing for life post-birth:
Lungs mature rapidly, producing surfactant, essential for breathing after birth.
Fetus gains significant weight, driven by body fat accumulation for temperature regulation.
Maternal transfer of antibodies provides temporary immunity to the fetus.
Maternal Changes During Pregnancy
Cardiovascular System: Blood volume increases by 40-50% to ensure adequate blood flow to the placenta, leading to a significant rise in cardiac output.
Respiratory System: Increased oxygen demand results in deeper breathing and higher respiratory rates.
Hormonal System: A massive surge in hormones such as estrogen, progesterone, and hCG orchestrates physiological changes and maintains pregnancy.
Assisted Reproduction and Genetics
Challenges in Embryonic Development
Some embryos thrive while others fail due to:
Chromosomal errors.
Poor gamete quality.
Miscommunications between the embryo and the endometrium.
Twin Gatekeepers
Factors contributing to twin births are intrinsic embryo competence and endometrial receptivity.
The Burden of Infertility
Infertility is defined as the inability to conceive after 12 months of regular, unprotected intercourse, with a shortened timeline of more than 6 months for women over 35 years old.
Approximately 1 in 6 couples face infertility, affecting 15% of couples. Most (around 70%) achieve live births with treatment, although such treatments can be expensive, invasive, and must be tailored individually.
History of IVF
Louise Joy Brown, born on July 25, 1978, was the first human conceived through IVF; her mother had a blocked fallopian tube.
The technique was developed by Dr. Robert Edwards, Patrick Steptoe, and nurse/embryologist Jean Purdy.
Assisted Reproductive Technology (ART)
A range of treatments from simpler interventions to complex lab-based procedures includes:
Lifestyle changes: Adjusting sexual timing, using certain lubricants, or monitoring ovulation.
Medications: Used for stimulating follicular recruitment.
IUI (Intrauterine insemination): Directly delivering prepared sperm into the uterus, bypassing cervical/vaginal barriers.
IVF (In Vitro Fertilization): A full process involving ovarian hyperstimulation and embryo transfer.
Overview of Standard IVF Process
Diagnostic Workup: Includes blood work, ultrasound, sperm analysis to assess whether IUI is a viable option first.
Controlled Ovarian Hyperstimulation: Involves home injections to stimulate follicle growth if IUI is inappropriate.
Ovum Retrieval: Utilizing suction to extract eggs from ovarian follicles.
Fertilization: Using either ICSI (Intracytoplasmic Sperm Injection) or traditional IVF methods.
Embryo Culture (Days 0-6): Embryos are placed in a warm incubator.
Genetic Testing (Optional): Preimplantation Genetic Testing for Aneuploidy (PGT-A).
Embryo Vitrification: Freezing the embryos in liquid nitrogen or transferring embryos directly.
ICSI (Intracytoplasmic Sperm Injection)
Selection of sperm involves the choice of forward-moving sperm with a straight tail and a uniform, paddle-shaped head.
The process includes:
a) Penetrating both the zona and ooplasm.
b) Aspirating to break the sperm membrane.
c) Dispensing the selected sperm into the egg.
How Many Embryos Should Be Transferred?
IVF may yield between 0 to 10 morphologically normal embryos.
The current trend is toward single embryo transfer to decrease the risks associated with multiples, which include preterm births, low birth weights, preeclampsia, and gestational diabetes.
Embryo selection traditionally hinges on morphology, but genetic analysis is steadily becoming the norm.
Preimplantation Genetic Testing (PGT-A)
Identifying the inner cell mass
Aspirating 5-10 trophectoderm cells
Employing a laser pulse to separate tissue
Sending for whole genome amplification and sequencing
PGT-A screens for the correct number of chromosomes, aiming to select euploid (normal) embryos to improve the chances of a healthy pregnancy.
It is also possible to conduct PGT-M (for monogenic disorders) and PGT-SR (for structural rearrangements).
Types of Aneuploidy
Meiotic (uniform): One gamete is aneuploid before fertilization.
Mitotic Aneuploidy: Occurs post-fertilization and may lead to mosaicism.
Defining Success in ART
Success rates can be misleading; hence, the focus should be on the live birth rate per embryo transfer, rather than merely the pregnancy rate.
Success rates are heavily influenced by maternal age due to oocyte quality.
Risks and Considerations
Ovarian Hyperstimulation Syndrome (OHSS): A serious condition that may be life-threatening and simultaneously reduces the chances of achieving pregnancy.
Increased risk of multiple births, including:
Monozygotic (identical) twins
Dizygotic (fraternal) twins
The financial burden can be significant, alongside emotional and psychological tolls from treatments.
Summary and Key Takeaways
Infertility is a common condition with numerous causes.
ART, particularly IVF, offers effective solutions to overcome biological challenges.
Genetic testing (PGT) enables the selection of chromosomally normal embryos, enhancing outcomes.
These technologies evoke complex ethical questions for society.