Endocrine: Growth

Objectives

Endocrine Control of Growth

GROWTH
–Under influence of growth hormone:
•Net synthesis of ___
•↑___ of the long bones
•↑ size and number of ___ in soft tissues

-Factors other than GH affect growth: •Genetics
->Inheritance
->Abnormalities can cause various developmental defects

•Diet
->Malnourishment -> ↓ growth potential (__% brain development in first 2 years) ->Excess = ____, not growth

•Freedom from disease and stressful environment
->Prolonged stress-induced secretion of ___ -> stunted growth
(through protein break-down, ↓ __ ___ growth, inhibiting __ secretion)

–Normal levels of growth-influencing hormones:
•Thyroid hormone
•Insulin
•Sex hormones

Growth

Not continuous:
–FETAL growth
•___ hormones
•Genetic/environmental factors determine ___ at birth
•GH ___ involved

–CHILDREN
•Postnatal growth spurt:
–1st _ years
–After -> rate linearly ___ until puberty

•Pubertal growth spurt (11 yrs for females, 13 yrs for males):
–Marked ____ in linear growth
–Cause not well-understood
–Genetic/hormonal factors
» _ androgens -> protein synthesis and bone growth
»T from testes, adrenal androgens in ___
*BOTH _ & __ -> halt bone growth at end of puberty

Metabolic Effects of GH NOT Related to Growth

-GH is the MOST abundant ___ hormone secreted, even in adults, suggesting actions in ___ to growth

-Exerts actions by binding ____ to target tissues

-During prolonged FASTING or if energy requirements EXCEED available glucose stores:

->Adipose
»Breakdown triglycerides -> ↑ [fatty acid]blood

->Skeletal muscles
»↑ use of __ __ for fuel (glucose sparing)
»_ glucose uptake
[↑ [glucose]blood = conserved for glucose-dependent tissues (__ , __)]

–>Liver
» _ glucose output
[↑ [glucose]blood = conserved for glucose-dependent tissues (__ , __)]

->Also stimulates ___ synthesis -> _ [amino acid]blood
»May or may not be a direct action

Growth Hormone

Does NOT act ___ to exert effects on growth
–Actions mediated by insulin-like growth factors (__ & __)
•Structurally and functionally similar to insulin
•Produced by many tissues
•Have endocrine, paracrine, and autocrine actions
•Act via __ ___ pathway

IGF-I

–70 a.a. protein, synthesis stimulated by __

–Mediates GH’s growth-___ actions

–Major source = ___ (released into blood)
•Also produced locally by most other tissues (___) –> NOT released to blood

–Is paracrine secretion a major factor during postnatal growth (first _ years) period?
»Circulating [GH] and [IGF-I] are __ during this time

–Control of PRODUCTION (other than by GH):

•Nutrition:
[↓ intake -> _ IGF-I (but _ GH)]

•Age-related factors:
( _IGF-I accompanies _ GH at puberty -> pubertal growth spurt)

•Tissue-specific stimulatory factors:
–FSH/LH & sex steroids -> ↑ IGF-I within reproductive organs

Growth Hormone

IGF-II

–Production NOT influenced by __
–Major source = ___

PRIMARY ROLE:

•During FETAL development:
–Receptors expressed very __ in development (in contrast, IGF-I receptors not expressed until later in fetal life)
»Found in _____ cells (develops into the fetal portion of placenta)

–Stimulates ___ growth

–Stimulates both pre- and post-implantation embryonic growth

In NEWBORNS:
–IGF-II _, while IGF-I _

•Secreted during adulthood, but UNKNOWN role

–Patients with tumors that secrete IGF-II develop ____
»Binds to insulin receptors @ ___

-67 a.a.
-62% homology with IGF-1
-Immunologically ___ than IGF-1

Growth Hormone

-GH (acting through __) stimulates growth in soft tissues and skeleton

SOFT TISSUE

–Hyperplasia (_ # cells)
•↑ cell division
•↓ apoptosis

–Hypertrophy (↑ __ of cells)
• _ protein synthesis
–↑ amino acid uptake by cell
–↑ activity of synthesis machinery
»↑ DNA & RNA synthesis
»↑ incorporation of amino acids
into protein @ ribosome
•↓ protein ____

Growth Hormone Effects on Skeletal Growth

Effects on bone growth

BONE STRUCTURE:
~____~
–Extracellular matrix composed of collagen fibers and semisolid gel
»Responsible for tensile ___ of bone
–CaPO4 precipitation -> bone ____
»Responsible for resistance to ____

~____~
–Form bone by secreting osteoid

~_____~
–Dissolve bone tissues
»Release minerals to blood

•Relevant ANATOMY:
–Periosteum
»____ tissue surrounding bone

–Diaphysis
»___ of a long bone
»Hollow, central cavity
•Contains __ ___

–Epiphysis
»“___” at either end of long bone
•Where articulations are formed

–___ ___
»Cartilaginous growth region b/w diaphysis and epiphysis

Bone Growth

Ossification (bone ___)

•Thickness:
–Addition of new bone to surface of existing bone by osteo___ in the periosteum

–Osteo___ along inner surface remove bone to enlarge marrow cavity

Bone Growth

LENGTH

–Cartilage at ___ of epiphyseal plate is replaced with __:

»Chondrocytes along epiphysis edge of epiphyseal plate multiply (temporary widening of ____ ___)

»Older chondrocytes toward diaphysis _____

»Oldest hypertrophied cartilage is ____

»Chondrocytes die due to lack of access to ___

»Osteoclasts ___ away dead cells and calcified matrix

»Osteoblasts move in (with blood supply) and ___ bone (____)

Bone Growth

LENGTH

–Cartilage at ___ of epiphyseal plate is replaced with __:

»Chondrocytes along epiphysis edge of epiphyseal plate multiply (temporary widening of ____ ___)

»Older chondrocytes toward diaphysis _____

»Oldest hypertrophied cartilage is ____

»Chondrocytes die due to lack of access to ___

»Osteoclasts ___ away dead cells and calcified matrix

»Osteoblasts move in (with blood supply) and ___ bone (____)

Bone Growth

Role of GH (via IGF-I)

•Causes growth in both ___ and ___

• __ proliferation of epiphyseal cartilage

• __ osteoblast activity

–↑ length of long bones IF epiphyseal plate remains ____

»Sex hormones -> complete ____ (closure)
•Normally at ___

REVIEW:

Growth:
-Factors affecting growth
-Not continuous

Growth Hormone:
-Direct role in metabolism
-Indirect role n growth
-IGF-1 vs. IGF-2

GH on soft tissues:
-via IGF-1
-hyperplasia & hypertrophy

GH & Bone Growth:
-cartilage cells (chondrocytes)
-osteoclasts
-osteoblasts
-epiphyseal plate
-Laying down of bone @ the epiphyseal plate

Regulation of Secretion

–GHRH and GHIH (____)
•G-protein coupled receptors, with GHRH ____ and GHIH ____ cAMP

•Negative feedback loops involve ____ of stimulatory factors and ____ of inhibitory factors

–Factors affecting GH secretion
•Displays ____ rhythm

Recall that GH promotes ___ conservation for the brain:
•Exercise & stress = __ [glucose]blood

GROWTH HORMONE

During these extraneous situations:

–↓ fat stores & ↑ body proteins

• -> change in body composition
–Away from ___ deposition
–Toward muscle ____
(GH mary meditate effects of exercise)

–If ↑protein meal -> _ [amino acid]blood -> _ GH secretion ->protein synthesis

–↓ [fatty acid]blood -> _ GH secretion -> mobilizes fat -> ___ [fatty acid]blood

–Ghrelin (from ___) -> _ GH secretion •Coordination of growth with nutrient acquisition

GROWTH HORMONE

Summary of regulation

–Aimed at adjusting glucose, amino acids, and fatty acids

–NO known ___-related signals influence growth hormone secretion

•Levels of GH in early childhood, a period of accelerated growth, are ___ to those seen in adulthood

•Why don’t soft tissues continue to grow under influence of GH?
–GH may only be high enough during deep ___

»Time spent in deep sleep greatest during infancy and ___ with age

»Time still spent in deep sleep in adulthood, yet we still ___ grow larger

Growth Hormone DEFICIENCY

Causes

–Primary: ___ defect (lack __)

–Secondary: ___ dysfunction (lack ___)

Deficiency in CHILDHOOD:
–Dwarfism
» ___secretion of GH
»Impeded skeletal growth -> short stature
»Poorly developed muscles
•_ protein synthesis
»Excess subcutaneous fat stores
•_ fat mobilization

–Laron dwarfism
»Abnormal ___ receptors
•No response to __
•[GH]blood very ___
–GH adequate, but ___ is low
(Target cell responsiveness to GH normal, but IGF-1 lacking)
»Ex: African pygmies

___secretion during ADULTHOOD:

–↓ skeletal muscle mass
»↓ strength
–↓ bone density
»__ osteoblast activity during remodeling
–↑ risk for ___ failure

Growth Hormone EXCESS

Primary cause:
–____ tumor of somatotropes

•Symptoms dependent on ___ of onset:

->Childhood: (prior to epiphyseal plate ___)
»Rapid growth in height without distortion of body proportions (____)

–Post-adolescence:
»No more ___ in height

»Bones thicken
•Extremities & face
•Jaws and cheekbones become more ___

»Soft tissue proliferation
•Skin, connective tissues

»Hands and feet ___
•Fingers and toes thicken

->Disproportionate growth pattern
(______)

Other Hormones Essential for Growth

Thyroid Hormone:
_____
•Not directly responsible for promoting growth

•Stunted growth in ___thyroid children (but not opposite effect if hyperthyroid)

•Insulin–Deficiency = ___ growth
–Excess = excessive growth
–Promotes protein synthesis
–Structurally resembles __ (so interaction with IGF-I receptor is possible)

•Androgens
–Effects depend on presence of __
•Stimulate protein synthesis
–Linear growth, weight gain, muscle mass

->Eventually, stop growth by promoting epiphyseal plate closure following conversion to ___

•Estrogens
–Promote epiphyseal plate ___

•Other “poorly” understood peptide growth factors:
–Stimulate mitotic activity in specific tissues
(Ex: epidermal growth factor)

SEX Differences in Growth

•Puberty occurs ~ 2 years ___ in girls

–Boys have ~ 2 more years of ___

•Average boy is ___ at beginning of the pubertal growth spurt than average girl

•Greater ___-induced growth spurt in boys
(↑ growth prior to plate closure)

•Pubertal estrogen ↑ -> ↓ pubertal growth spurt
(____ growth prior to closure)

•_____ program brain for masculine GH secretion pattern
(↑ cyclic peaks -> ↑ height in males)

REVIEW

Regulation of GH secretion:
GHRH
GHIH (somatostatin)
Reytemincinty
Exercise
Stress
Glucose
Amino acids
Fatty acids
Ghrelin

GH Disorders:
Hyposecretion:
Dwarfism (childhood)
Laron Dwarfism (receptor insufficiency)
Lack of IGF-1 (African Pygmies)
Adulthood (minor symptoms)

Hypersecretion:
Gigantism
Acromegaly

Other hormones that influence growth: Thyroid, insulin, androgens, estrogens, peptide growth factors