Growth, Metabolism & Sex Steroids – Detailed Class Notes

Administrative & Course Logistics

• Instructor may end class early due to building A/C repairs.
• First exam average: 79 %; described as the “simplest exam.”
  • Content difficulty will escalate (e.g., embryogenesis).
• Bonus Quiz #1 (next class): covers last Thursday + today’s lecture.
• Embryogenesis slides will be uploaded and topic will begin Tuesday.

Building Difficulty Curve & Study Advice

• Material is shifting from familiar (basic physiology) to specialized reproductive endocrinology.
• Students advised to begin studying earlier and in more depth as unfamiliar content appears.

Thyroid Hormones \text{T}3 & \text{T}4

• Classified as major metabolic hormones; virtually every tissue is a target.
• Primary growth-related functions discussed:
  • Control rate of nutrient uptake/utilization.
  • Up-regulate mitochondrial biogenesis & size → ↑ ATP and heat.
• Organs/tissues heavily influenced ("metabolic regulators"):
  • Liver – central metabolic organ: metabolizes nutrients & xenobiotics.
  • Pancreas (insulin production).
  • Skeletal muscle – largest glucose sink; continual ATP demand even at rest.
  • White adipose tissue (WAT) – long-term energy store; endocrine.
  • Brown adipose tissue (BAT) – rich in mitochondria, neonatal thermogenesis.

Insulin & Glucose Metabolism

• Insulin’s “big job”: transports glucose into cells → substrate for ATP in mitochondria.
• Thyroid hormones indirectly support insulin action by expanding mitochondrial capacity.
• Skeletal muscle is the major insulin-sensitive glucose sink.

Macronutrient Hierarchy & Metabolic Costs

• Carbohydrates: most readily digested; rapid energy but rapid depletion (kid-with-candy-bar example).
• Proteins / Lipids: provide energy + building blocks; costlier to catabolize.
• Liver can perform gluconeogenesis under \text{T}3/\text{T}4 stimulation during prolonged fasting.

Steroid Hormones – General Introduction

• Powerful growth modifiers; widely manipulated in livestock industry.
• Two broad categories covered today:
  • Sex steroids: estrogens, progesterone, androgens.
  • Adrenal steroids (briefly via ACTH influence).

Hypothalamic–Pituitary–Gonadal (HPG) Axis

• Hypothalamus (arcuate nucleus) secretes \text{GnRH}.
  • In females there is an additional ovulatory center (supraoptic/surge), ignored for simplicity.
• \text{GnRH} → portal blood (median eminence) → anterior pituitary.
• Pituitary secretes \text{LH} & \text{FSH} (both sexes).
• \text{LH/FSH} → gonads: testes (Leydig) or ovaries (theca + granulosa) → sex-steroid synthesis.
• Negative feedback:
  • Males: testosterone (and estradiol via aromatization) suppress \text{GnRH}, \text{LH}, \text{FSH}.
  • Females: estrogen & progesterone generally negative; real physiology is cyclic/complex.

Steroidogenesis Pathway Snapshot

• Starts with cholesterol.
• Enzyme = gene product; no “testosterone gene,” only enzymes that convert substrates.
• Key branch points:
  • \text{Cholesterol} \to \text{Progesterone}.
  • Progesterone → androgens (e.g., testosterone).
  • Single critical enzyme: Aromatase converts testosterone → estrogens.
  • End of pathway = estrogens.

Estrogens

• “Estrogens” = family of 3 molecules:
  • Estrone (E1) – one OH.
  • Estradiol (E2) – two OH (most potent).
  • Estriol (E3) – three OH.
• Primary source = ovary; extra-gonadal production possible (adrenal, liver, skin, neurons) if aromatase present.
• Two-Cell/Two-Gonadotropin theory (follicle):
  • Theca → androgens.
  • Granulosa (has aromatase) → estrogens.
• Estrogen actions:
  • ↑ IGF-1 production in liver; \text{IGF-1} feeds back ↑ estrogen (positive loop).
    • \text{IGF-1} drives differentiation, hyperplasia, hypertrophy.
  • Accelerates skeletal growth; stimulates protein synthesis > degradation → ↑ muscle; promotes moderate fat deposition.
  • Stimulates BAT, increases metabolic heat.
• Special physiology / anecdotes:
  • Excess aromatase → hyper-estrogenized male (student case; migraines, mood swings; treated with aromatase inhibitor).
  • Fetal brain sexing: male brain masculinized by locally aromatized estrogen; female fetus protected by α-fetoprotein binding circulating estrogens.

Progesterone

• Produced mainly by corpus luteum (CL); adrenal minor contributor.
• Classical role: maintain pregnancy.
• Regulation: negative feedback via \text{LH/FSH}; modulated by \text{IGF-1} & \text{ACTH}.
• Metabolic / growth effects:
  • Enhances feed-to-gain ratio (pregnant animals lay down weight efficiently).
  • Strongly promotes fat deposition to support gestation & impending lactation.
  • Alters basal metabolism (works with \text{T}3/\text{T}4); pregnant animals are more lethargic.

Androgens

• Four major androgens:
  • Testosterone (T) – testes > adrenal.
  • Dihydrotestosterone (DHT) – derived from T; drives virilization (odor, mane/crest, secondary sex traits).
  • Dehydroepiandrosterone (DHEA) – adrenal.
  • Androstenedione (A4) – adrenal.
• HPG feedback identical to estrogen description but simpler (no cycles).
• Growth actions (relative arrows indicate strength vs estrogen):
  • Bone length & density: $\uparrow\uparrow\uparrow.
  • Protein synthesis / lean mass: $\uparrow\uparrow\uparrow.
  • Fat deposition: \sim 0.5 arrow (minor).
• Puberty surge accelerates animals toward genetic growth potential; castration removes this surge → lower mature size & lean mass.

Comparative Growth Summary (Qualitative)

Peripheral Aromatase & Assay Contamination Note

• Skin, adipose, brain, and other tissues can express aromatase → local estrogen production.
• Laboratory assays easily contaminated by ambient estrogen/androgen; lab personnel of opposite sex excluded during runs.

Leptin – The Adipostat Hormone

Discovery & Genetics

• Identified in 1990s via ob/ob mouse (morbidly obese).
  • Parabiosis (surgically fused Circulation): obese mouse lost weight when joined to lean littermate → blood-borne satiety factor.
• Gene name from Greek leptos = “thin.”
• Highly conserved: >80 % AA identity down to frogs; mutations rare (≈0.001 % in humans, often inbred lineages).

Physiological Targets (positive arrows = stimulation)

• \rightarrow Growth (↑ GH axis)
• \rightarrow Reproduction (permits puberty & fertility)
• \rightarrow Metabolic rate (thyroid & CNS centers)
• \rightarrow Immune system (lymphoid tissues)
• \dashv Appetitive centers (↓ food intake)
• \dashv Steroidogenesis (modest suppression)

Regulation

• Insulin is the only definitively confirmed up-regulator.
  • Post-prandial insulin spike → adipocyte leptin synthesis.
• Glucocorticoids / other “counter-regulatory” hormones: context-dependent, unresolved.

Metabolic Actions

• ↑ Satiety: signals meal termination & inter-meal satiety.
• ↑ Lean mass proportion by two mechanisms:
  1. Stimulates muscle anabolism indirectly (CNS-mediated).
  2. Promotes lipolysis within adipocyte but prevents FFA release; fatty acids oxidized in mitochondria → heat (non-shivering thermogenesis).
  • Avoids hyperlipidemia; analogous to BAT thermogenic pathway.

Industry & Clinical Relevance

• Livestock producers favor weak leptin alleles (less potent satiety) → animals eat more, finish faster, deposit marbling.
• Genetic tests now available to select for leptin haplotypes in feed-lot cattle.
• Human weight-loss trials with recombinant leptin largely failed because of:
  • Leptin-binding proteins in human plasma (not present in livestock).
  • Leptin resistance in common obesity.
• Contrast with GLP-1 analogs (Ozempic®); GLP-1 acts via gut→brain axis and often causes nausea/vomiting (weight loss partly secondary to malaise).

Anecdotes & Illustrative Examples

• Kid + candy bar: illustrates rapid carb digestion and “sugar crash.”
• Into the Wild story: humans can’t subsist on grass – lignin/cellulose + lack of rumen microbes.
• Student with aromatase excess: migraines, mood swings; brief aromatase inhibition normalized sex steroids.
• Parabiosis mouse experiment demonstrates endocrine communication.
• Lab protocol: female staff removed during androgen assays & vice-versa to prevent sample contamination.

Connections to Previous & Upcoming Lectures

• Builds on prior material: GH, \text{IGF-1}, TRH, CRH, growth curves.
• Sets stage for future unit on embryogenesis (starts Tuesday).

Numerical / Chemical Pointers

• Exam 1 average = 79\%.
• Estradiol contains 2 hydroxyl groups; estrone 1; estriol 3.
• Thyroxine (T4) = 4 iodine atoms; Triiodothyronine (T3) = 3.
• Puberty roughly corresponds to the inflection point on logistic growth curve.

Ethical & Practical Implications

• Manipulating steroid hormones or leptin alleles can improve carcass traits but raises welfare & consumer perception concerns.
• Understanding fetal brain sex differentiation informs discussions on endocrine disruptors and developmental programming.