L16 - Parnutrition
Establishment of Pregnancy
2.1. The Menstrual Cycle
Average Duration: Approximately 28 days, varying among individuals.
Hormones: The cycle is regulated by Oestrogen (Oestradiol) and Progesterone, produced primarily by the ovary, under the influence of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) from the brain.
Phases:
Post-Menstruation: After the shedding of the uterine lining, the endometrial stromal cells grow and proliferate rapidly under the stimulation of Oestradiol. This is the fastest dividing tissue in the body.
Ovulation: Around day 14, the egg is released from the ovary. The entire cycle aims to time the uterine lining's receptivity for the egg.
Egg Journey: The egg travels down the fallopian tube, developing into a blastocyst, which then implants in the prepared uterine lining.
Absence of Implantation: If implantation does not occur, luteolysis (collapse of the corpus luteum) happens. Progesterone production, primarily from the corpus luteum, falls, leading to the shedding of the uterine lining (menstruation).
Role of Progesterone: Progesterone is essential for maintaining the uterine lining. Blocking its receptor (e.g., with RU-486) terminates pregnancy in mammals.
2.2. Establishment of Pregnancy
HCG Signal: To prevent luteolysis and maintain progesterone production, the implanting blastocyst produces Human Chorionic Gonadotropin (HCG) from its outer cell layer. HCG tells the corpus luteum to continue producing progesterone, effectively "hijacking" the maternal physiology.
HCG Levels: HCG rises rapidly in early pregnancy (detected by pregnancy tests) and then declines from about 8−10 weeks due to the luteoplacental shift.
Hormone Levels in Pregnancy: Progesterone and Oestrogen levels increase dramatically throughout human gestation.
Progesterone: Remains essential for maintaining pregnancy; its blockade leads to termination.
Oestrogen: Plays a role in preparing the mother's body for birth, influencing breast changes and uterine development, and promoting pro-contractile agents later in gestation.
Placental Development and Fetal-Maternal Dialogue
3.1. Placental Invasion
In humans and great apes, the placenta is highly invasive, burrowing deeply into the uterine wall using specialized trophoblast cells.
These cells target maternal spiral arteries, establishing a single-layer interface for nutrient and gas exchange.
The maternal immune system is typically not activated despite this deep invasion due to mechanisms employed by endometrial stromal cells.
3.2. Hormone Synthesis in Pregnancy
Progesterone: Produced directly by the placenta from maternal cholesterol.
Oestrogen (in humans/great apes): Requires a complex pathway involving both the fetus and the placenta:
Maternal cholesterol goes to the specialized fetal adrenal cortex.
Fetal adrenal cortex converts cholesterol to dehydroepiandrosindione sulphate (DHEAS).
DHEAS crosses the placental barrier, is desulfated in the maternal liver to DHEA, and then converted by the placenta into Oestrogen (e.g., Oestradiol).
This circuitous route links Oestrogen production to fetal health and growth.
3.3. Fetal-Maternal-Placental Axis
This axis represents a dialogue between the growing fetus, the fetal membranes and placenta, and the mother.
Fetal Growth: Driven by cortisol and other hormonal factors, which mature fetal organs (e.g., gut, lungs, brain) for survival outside the womb.
Uterine Stretch: As the fetus grows, it stretches the uterus, signaling maternal readiness.
Positive Feedback Loop:
The fetal anterior pituitary secretes corticotrophin-releasing hormone (CRH), which stimulates the fetal adrenal gland.
The fetal adrenal gland produces DHEAS and cortisol. Cortisol matures fetal systems.
DHEAS is converted by the placenta into Oestrogens.
Oestrogens induce maternal changes: preparing breasts for milk production, growing the uterus, and promoting pro-contractile agents (e.g., prostaglandins, oxytocin receptors, gap junctions).
Progesterone largely resists these pro-contractile changes, maintaining uterine quiescence during gestation.
Placental CRH further amplifies this process, creating a positive feedback loop that signals the mother that the baby is ready and preparation for labor should begin.
Initiation of Parturition (Labor)
Most of gestation, the uterus remains quiescent, providing a safe and sterile environment for fetal growth. Parturition is initiated when the fetus is ready for expulsion.
4.1. Key Hormones in Parturition
Oxytocin and prostaglandins are crucial for initiating and progressing labor.
4.2. Activation Phase (Weeks leading to Labor)
This phase involves significant physiological changes in different maternal tissues:
Uterus (Myometrium): Transforms from quiescent to excitable.
Changes in electrical coupling and ion channels, increasing general excitability of smooth muscle cells.
Increased number of contractile cells.
Upregulation of hormone receptors (e.g., oxytocin receptor, prostaglandin FP receptor), making cells more responsive to stimulatory events.
Decreased nitric oxide synthase, reducing relaxation of smooth muscle (nitric oxide typically relaxes smooth muscle).
Net effect: Increased electrical conductivity, excitability, and decreased relaxation, leading to a more contractile uterus.
Cervix (Ripening): Changes detected from approximately 2525 weeks gestation.
Characterized by an inflammatory response and breakdown of collagen fibers, which normally keep the cervix closed.
Decrease in the effect of the nitric oxide system.
Consequence: Dilation, where the cervix thins out and stretches upwards.
Amniotic Sac (Membranes):
The extracellular matrix of the lower pole of the amniotic sac degrades and weakens.
Tissue integrity decreases, increasing the likelihood of rupture (``water breaking''). This can be measured from 2020 weeks onwards.
Premature rupture of membranes can lead to preterm birth, presenting risks to the fetus.
Coordination: Precise coordination between these events is critical for a smooth delivery. For instance, contractions without cervical ripening are problematic.
4.3. Definitions of Parturition
Parturition: Literal expulsion of the products of conception.
**Timing-based Definitions (Human Gestation, approx. 38 completed weeks):
Spontaneous abortion/Miscarriage:** Before 2424 completed weeks.
Preterm Labor: Between 2424 and 3737 completed weeks.
Term Labor: Between 3737 and 4242 completed weeks (statistically ideal).
Post-term Labor: Greater than 4242 weeks (associated with increased fetal risk).
**Stages of Parturition (Scientific Terms):
Phase 0 (Quiescence):** The majority of gestation (up to 33−3433−34 weeks in humans). The uterus is quiet, with progesterone and prostacyclin (a relaxant prostaglandin) being dominant.
Phase 1 (Preparatory Phase/Activation): Changes occur in the uterus (increasing excitability), with increasing prostaglandin secretion and oxytocin receptor expression, and a decrease in relaxin (a hormone that keeps the uterus relaxed). Braxton Hicks contractions (practice contractions) may occur.
Phase 2 (Active Labor/Stimulation): Active contractions, cervical ripening, and membrane rupture. This stage involves active fetal delivery through the birth canal.
Phase 3 (Involution): Immediately post-delivery of the fetus and placenta. This crucial stage involves strong uterine contractions (mediated by oxytocin) to prevent postpartum hemorrhage, the most life-threatening event for the mother during delivery.
The Ferguson Reflex: A Positive Feedback Loop
Description: A neuroendocrine positive feedback loop crucial for the active stage of labor and placental expulsion. Positive feedback loops are rare in nature as they escalate rapidly.
Mechanism:
The baby's head maximally distends the cervix.
Sensory neurons in the cervix detect this stretch and send signals to the nucleus tractus solitarii in the brain.
This activates oxytocinergic neurons in the hypothalamus, leading to a large bolus release of oxytocin from the posterior pituitary into the circulation.
Oxytocin causes uterine contractions and simultaneously promotes the release of prostaglandins (which further enhance contractions and cervical changes).
This cycle escalates as long as cervical distention persists, driving the expulsion of the fetus.
Once the fetus is delivered, the distention ceases, breaking the feedback loop and switching off the signal.
Evidence in Humans: Plasma oxytocin levels significantly increase during maximal cervical distention and placental delivery. Intramuscular administration of oxytocin postpartum is a standard intervention to reduce the risk of postpartum hemorrhage.
Animal Models to Understand Regulation of Parturition: Insights from Mice
Studying the activation phase in humans is challenging; animal models like mice offer detailed insights, though differences exist.
6.1. Prostaglandin Cascade in Mice
Mechanism:
Membrane phospholipids are cleaved by cytosolic phospholipase A2 (cPLA2) to generate arachidonic acid.
Arachidonic acid is converted by cyclooxygenase 1 (COX1) and prostaglandin F synthase into prostaglandin F2 alpha (PGF2αα).
PGF2αα acts upon the corpus luteum via the FP receptor, causing a decrease in progesterone production. This is a crucial difference from humans where progesterone continues to rise.
The fall in progesterone then leads to an increase in uterine contractility and the onset of labor.
Genetic Evidence: Deletion of cPLA2, COX1, or the FP receptor in mice results in a ``no labor'' phenotype. This can be rescued by surgically removing the corpus luteum (mimicking physiological progesterone withdrawal) or by administering PGF2αα.
Progesterone Levels: In mice, progesterone concentrations drop sharply around day 17 of gestation due to the collapse of the corpus luteum.
Regulation: While cPLA2 is always active, COX1 and PGF synthase are upregulated from day 10 of gestation. Additionally, prostaglandin dehydrogenase (an enzyme that degrades prostaglandins) decreases, further increasing prostaglandin levels.
6.2. Role of Oxytocin in Mice
Historical View: Historically, oxytocin was believed to be the primary cause of labor onset.
Oxytocin Knockout (KO) Mice (1996): Unexpectedly, oxytocin KO mice delivered normally. However, their pups died postpartum due to the lack of milk letdown reflex, indicating oxytocin's role in maternal care.
COX1 KO + Oxytocin KO Mice: This double knockout resulted in normal labor onset but a protracted labor (lasting two days), leading to pup death in the birth canal. This suggests redundancy between oxytocin and prostaglandins.
Dose-Dependent Actions: Experiments show that low concentrations of oxytocin can delay labor by supporting the corpus luteum and maintaining progesterone. However, higher concentrations of oxytocin can overwhelm this system and induce preterm birth.
Receptor Expression: The location and timing of oxytocin receptor expression (high in ovary mid-gestation, high in uterus late-gestation after progesterone withdrawal) control these opposing luteotrophic (corpus luteum support) and luteolytic (labor induction) actions.
Compensation: In a COX1 knockdown mouse model with very low prostaglandins, the system compensated by significantly upregulating oxytocin receptor levels, ensuring the delivery mechanism. This highlights the inherent redundancy in the parturition system.
6.3. Summary of Mouse Parturition
Day 13: Ovary produces progesterone, keeping the uterus quiescent. PGF2αα is low, but COX1 and PGF synthase begin to increase.
Day 16: Progesterone production continues, PGF2αα levels rise (due to increased synthesis and decreased degradation).
Day 19: Prostaglandins dominate. The ovary's vascular structure collapses (corpus luteum involutes), progesterone dramatically falls. The ``brakes are off,'' leading to increased expression of genes for contractions and the activation of the Ferguson reflex as pups enter the birth canal.
Implications for Human Therapy
Redundancy Principle: Animal models (like the double knockout mouse and sheep experiments) demonstrate significant stimulatory redundancy between oxytocin and prostaglandins in initiating labor. If one pathway is inhibited, the other can compensate.
Sheep Model Evidence: In sheep, labor induced by dexamethasone (which reduces progesterone) can be indefinitely delayed by blocking both prostaglandins (with nemesulide) and oxytocin (with atosiban). Blocking only prostaglandins causes a delay but not a permanent inhibition, suggesting oxytocin compensation.
Therapeutic Challenge for Preterm Labor: To effectively stop preterm labor in humans, it's likely necessary to block both the oxytocin and prostaglandin pathways to overcome these redundant compensatory mechanisms. Single-agent therapies often fail, as observed in clinical trials, but combining agents presents challenges for drug companies due to increased complexity and perceived risks.