Pre & Post-natal Growth
Fetal organ development, hormonal regulation (GH, IGF, thyroid, steroids), maternal adaptation, and neonatal physiology (Lectures 8–11)
Growth Fundamentals & Fetal Development
Growth vs Development
Growth
Increase in weight, length, or height of an animal, organ, or tissue.
Development
Coordinated cell growth and differentiation that alters organ/body structure to impact function until maturity.
Growth Patterns
- Allometric: Body parts develop differentially through life (most mammals). Head proportionally large early, limbs catch up later.
- Sigmoid curve: Body weight × age — most rapid gain in fetal and postnatal periods until maturity
- Curvilinear: Daily gain (g/d) peaks postnatally then slows before puberty
- Growth starts at fertilization and ends at puberty (long bone growth). Estrogen causes growth plate closure in both sexes.
Gestation Trimesters
1st Trimester
Axis orientation, embryo stage, placental attachment
2nd Trimester
Fetal stage, organ and limb formation
3rd Trimester
Organ and body growth with function
Stress or disease in each stage causes abnormalities in the cells dividing most rapidly at that time.
Comparative Fetal Development
| Species | Maternal Wt (kg) | Birth Wt (kg) | Litter Size | Gestation (d) | Fetal Growth (g/d) |
|---|---|---|---|---|---|
| Cow | 545 | 35 | 1 | 280 | 125 |
| Pig | 180 | 1.3 | 12 | 115 | 11.3 |
| Sheep | 70 | 4.5 | 2 | 150 | 30 |
| Human | 56 | 3.5 | 1 | 280 | 12.5 |
| Cat | 5 | 0.1 | 7 | 63 | 1.59 |
| Rat | 0.15 | 0.005 | 7 | 21 | 0.24 |
As maternal body size increases: heavier total litter birth weight (r=0.99), heavier placenta (r=0.90), higher fetal growth rate (r=0.95). Maternal weight is moderately related to gestation length (r=0.62).
Fetal Organ Development
Neural System
Develops rapidly in 2nd and 3rd trimesters. Sensory systems functional.
Circulatory
Heart and large vessels formed by start of 2nd trimester. Functional.
Skeleton
Limbs well formed by 3rd trimester. Primary bone formed as cartilage is removed and replaced. Secondary bone postnatal.
Lungs
Form in 2nd trimester, lobes/passages clear by 3rd. Not functional — does not contribute to fetal O₂.
Kidneys
Form in 2nd trimester, nephrons complete in 3rd. Functional — amniotic fluid originates from fetal kidneys, helps eliminate N waste.
Liver
Forms in 2nd trimester. Functional in glycogen storage, gluconeogenesis, amino acid breakdown, fatty acids, erythropoiesis.
GI System
Not functional — placenta supplies nutrients. Maturity at birth varies by species.
Reproductive / Endocrine
Gonadotropins from fetal pituitary bind gonads. Testes produce testosterone, ovary produces some testosterone → estrogen. Thyroid active early in 2nd trimester. Adrenal active in 3rd trimester (cortisol increase).
Precocial vs Altricial Species
Precocial
Well-developed at birth, able to stand, feed, run. More muscle/skeleton at birth. Cows, horses, sheep, pigs.
Altricial
Immature development, unable to survive alone. Dogs, cats, humans, rodents. Closed eyes, some without hair.
Growth Hormone & IGF
Growth Hormone (GH)
- ~191 aa protein synthesized by anterior pituitary
- Released in 6–8 pulses/night (sleep-dependent)
- Stimulated by GHRH (hypothalamus), inhibited by somatostatin
- Major target organ: liver (highest GHR density). Also bone, muscle, and fat.
- Mostly species-specific — cross-species injections generally not bioactive
IGF (Insulin-like Growth Factor)
- IGF-I: single chain 70 aa peptide, 50% homology with insulin
- IGF binds IGF1R (also binds insulin receptor with low affinity)
- GH stimulates both IGF-I and IGFBP-3 synthesis (mostly in liver)
- IGFBPs (1–6) modulate IGF action — 99% of circulating IGF bound to IGFBPs. IGFBP-3 is most prevalent (>80% bound to IGF-I)
- Paracrine/autocrine IGF has greater impact on growth than endocrine IGF — most tissues make IGFs locally
GH-IGF Effects on Tissues
| Target | Effect |
|---|---|
| Liver | ↑ IGF-I production, ↓ amino acid oxidation (spares), ↑ glucose release (glycogenolysis), ↓ insulin responsiveness |
| Muscle | ↑ amino acid uptake (protein synthesis), ↑ glucose uptake, mobilizes glycogen stores |
| Adipose | ↓ lipogenesis (lowers insulin sensitivity), ↑ lipolysis |
| Bone | ↑ long bone growth (before puberty). Estrogen causes growth plate closure at puberty. |
Fetal vs Postnatal IGF
Fetal
IGF-I in fetal circulation correlates with fetal size. Placenta is the primary source for most of gestation. Liver becomes major source in late gestation. Fetal GH is NOT required — fetal hypophysectomy has minimal effect on birth weight (nutritional factors from placenta drive fetal IGF).
Postnatal
IGF-I increases after birth due to GH acting on liver. IGF-I levels parallel body weight across species. GH-dependent and required for postnatal growth. Maternal GH and IGF do not cross placenta.
Conditions for Growth
Positive (growth)
Blood glucose (+), Insulin (+), Amino acids (+), GH (+)
Negative (catabolism)
Low IGF-I, elevated FFA, high GH (negative feedback)
GH Disorders
- Gigantism: Excess GH before puberty → excessive bone elongation (often pituitary tumor)
- Acromegaly: Excess GH after puberty → enlarged hands, feet, jaw (epiphyseal plates already closed, no height increase)
- Dwarfism: Low GH before puberty → limited long bone growth. Inability to produce/bind GH or IGF → miniature body with normal proportions.
Thyroid & Steroid Hormones on Growth
Thyroid Hormones (T3 / T4)
- T3 and T4 (thyroxine) produced in feedback loop: TRH (hypothalamus) → TSH (pituitary) → T3/T4 (thyroid)
- TSH induces thyroid growth, iodine uptake, T3/T4 production
- T3/T4 bind nuclear receptors → increase O₂ consumption, maintain cell metabolism
- Essential for thermogenesis — hypothyroidism causes cold/heat intolerance
- Hypothyroid children: slowed growth, reduced long bone growth → dwarfism
Fetal Thyroid
- T3/T4 in fetal circulation correlated with birth weight. IUGR fetuses have low T3/T4.
- T3/T4 cannot cross placenta in many species → fetus must develop thyroid early (HPX-thyroid loop develops in 2nd trimester)
- All species show placental transport of iodide (Na⁺/I⁻ symporter) for fetal thyroid function
- Fetal thyroidectomy (sheep): reduced birthweight, organ weights, skeleton size, less protein in organs. Remedied by T4 infusion.
- Requires IGF and insulin for growth effects
Glucocorticoids
- C-21 steroids (cortisol or corticosterone) synthesized in adrenal cortex via CRH (hypothalamus) → ACTH (pituitary) feedback loop
- Bound to CBG or albumin in circulation; only free form is active
- Deals with long-term stressors to supply energy (vs epinephrine for short-term fight/flight)
- Anti-insulin effects: ↑ blood glucose, ↑ hepatic glycogenolysis/gluconeogenesis, ↑ muscle protein catabolism, ↑ lipolysis (short-term)
- Free cortisol can cross placenta → implications for fetal stress
- P4 (progesterone) and cortisol compete for same precursors (cholesterol pathway)
Sex Steroids & Growth
- Synthesized from cholesterol (C-27). Lipophilic — freely cross cell membranes, bind cytoplasmic/nuclear receptors → transcription factors.
- Prenatal: placenta is a major source. Sex steroids determine sex-specific development of reproductive system (2nd trimester).
- Androgens (testosterone): direct anabolic effects on muscle and bone via androgen receptor (AR)
- Adrenal androgens (DHEA, androstenedione): <20% activity of testosterone, can be converted to testosterone or estrogen in fat/other tissues
- Estrogen: indirect anabolic effects. Low levels promote bone growth. At puberty, increased levels cause epiphyseal plate closure (cumulative depletion of proliferative zone).
- Females reach puberty earlier → earlier estrogen rise → growth ends sooner
Long Bone Growth & Closure
Endochondral ossification: chondrocytes (cartilage) → osteoblasts (bone formation) → osteoclasts (bone resorption). These cells have androgen and estrogen receptors. Adrenal androgens induce growth before puberty. Estrogen at puberty fuses the growth plate, ending height increase.
Placenta, Maternal Adaptation & Neonatal Physiology
Placental Function
- Metabolic interchange between mother and fetus; has endocrine activity
- Acts as a selective barrier — no cells, no large molecules/proteins pass. But small molecules (drugs, alcohol, antibiotics, steroids) can cross freely.
- Gases (O₂, CO₂) and water pass by simple diffusion
- Electrolytes (Na, Cl, Ca, P, K) move with water or via ATP-dependent channels
Placental Nutrient Transfer
Glucose
Facilitated diffusion (GLUT carriers). Primary energy source for fetus. Higher in maternal than fetal circulation.
Proteins
Too large to pass — fetus must synthesize its own from maternal amino acids. IgG transported in some placental types.
Lipids
Do not cross — bound to carriers. Placenta hydrolyzes TGs and phospholipids. Small lipophilic steroids cross freely.
Oxygen
Maternal RBCs supply O₂ via placenta. Three fetal shunts bypass non-functional organs: (1) foramen ovale (right → left atrium, bypasses lungs), (2) ductus arteriosus (pulmonary artery → aorta, bypasses lungs), (3) ductus venosus (umbilical vein → IVC, bypasses liver). Fetal Hb has higher O₂ affinity than adult Hb. All three shunts close at birth.
Maternal Adaptations to Pregnancy
- Cardiovascular: Heart size increases, vasodilation increases blood volume by 30%, increased blood flow to uterus and all organs
- Respiratory: More RBCs needed, increased lung volume for O₂ demand
- Calcium: Increased gut absorption and renal retention, mobilization from maternal bone for fetal skeleton
- Energy (early): Adipose hypertrophy, lipogenesis, increased insulin sensitivity → fat and glycogen accumulation
- Energy (late): Reduced insulin sensitivity, lipolysis, hepatic gluconeogenesis → provides more energy for rapidly growing fetus. Appetite increases.
- Digestive: Slower gut passage rate
- Immune: Tightly regulated to prevent response against paternal antigens
- Mammary gland: Development during gestation
Fetal Programming & Epigenetics
- Dutch Hunger Winter (1944–45): 500–600 cal/day → lower birthweight babies, and their grandchildren also had lower birthweights
- Slow prenatal growth (IUGR) is a major risk factor for non-communicable diseases
- Epigenetic changes (DNA methylation, histone modification) induced by maternal environment become heritable without altering the genetic code
- Walton & Hammond horse experiment: Shire × Shetland crosses showed uterine environment (maternal size) affected birth weight and size at 3 years
- Uterine space affects fetal development in litter-bearing species — more fetuses compete for space and resources
Parturition
As fetus grows, fetal hypothalamic-pituitary-adrenal axis matures. Fetal adrenal releases cortisol → stimulates placental prostaglandin → uterine contractions. Space limitation may be the initiating stress.
Neonatal Transition
- Energy: Must have liver glycogen stores when umbilical cord ruptures and maternal glucose supply ends
- Oxygen: Newborn lungs must take over gas exchange. Survival linked to surfactant enzyme production (lung flotation test for stillborn).
- Gut: Must quickly adapt to absorb colostrum/milk
- Kidneys: Take over water and ion balance
- Thermoregulation: Body must regulate temperature independently
- Newborns tolerate brief periods of asphyxia, trauma, and hypothermia better than adults
Neonatal Fat Storage
Fat synthesis begins near 2nd trimester using glucose → fatty acids → triglycerides. Highly variable at birth: