Endocrine Control of Growth

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Endocrine Control of Growth
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Endocrine glands
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Pituitary

• Anterior pituitary - oral ectoderm.
• Posterior pituitary - neuroectoderm.
• Hypothalamic hormones are secreted to the
  anterior lobe by way of a special capillary
  system, called the hypothalamic-hypophysial
  portal system
• The anterior pituitary synthesizes and secretes
• Growth hormone ('HGH' or 'GH' or somatotropin),
  released under influence of hypothalamic Growth
  Hormone-Releasing Factor (GHRF), inhibited by
  hypothalamic somatostatin
• Thyroid-stimulating hormone (TSH), released under
  influence of hypothalamic Thyrotropin-releasing
  Factor (TRF) inhibited by somatostatin

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Pituitary

• Adrenocorticotropic hormone (ACTH), released
  under influence of hypothalamic
  Corticotropin-Releasing Factor (CRF)
• Gonadotropins
• Luteinizing hormone (also referred to as
  'Lutropin' or 'LH').
• Follicle-stimulating hormone (FSH), both released
  under influence of Gonadotropin-Releasing Hormone
  (GnRH)

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Original Somatomedin Hypothesis
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Insulin-like Growth Factor System

• 3 ligands
• IGF-1 Somatomedin-C
• IGF-2
• Insulin
• 6 binding proteins
• IGFBP-1 to -6
• Cell surface receptors that mediate the ligand
  action

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Growth Hormone

• Pulsatile secretion from anterior pituitary
  maximum during early stages of deep sleep
• Increases DNA synthesis and cell multiplication
• Adequate levels of thyroid hormone
  required"permissive"

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HGH
Adipose Tissue ? Glucose Uptake ? Lipolysis ?
Adiposity
Muscle ? Glucose Uptake ? Amino Acid Uptake ?
Protein Synthesis ? Lean Body Mass
Liver ? RNA Synthesis ? Protein Synthesis ?
Gluconeogenesis ? IGF-1
IGF-1 Local production
Chondrocytes ? Amino Acid Uptake ? Protein
Synthesis ? RNA Synthesis ? DNA Synthesis ?
Collagen ? Chondroitin Sulphate ? Cell Size and
Number ? Linear Growth
Bone, Heart, Lungs etc ? Amino Acid Uptake ?
Protein Synthesis ? RNA Synthesis ? DNA
Synthesis Organ Size Organ Function
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Daily GH Levels (24hr)
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Somatomedin-C (IGF-1) LevelsPeak about 1 yr
after PHV
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Growth Plate
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GH IGF Interactions in Long Bone Growth
Stimulates proliferation of chondrocyte
precursors and thus expands the proliferative
chondrocyte pool and the hepatic and/or local
production of IGF-1
Germinal Zone
GH
IGF-2
Proliferative Zone
IGF-2
IGF-2
IGF-2
Stimulates clonal expansion by autocrine/paracrine
mechanisms
Promotes chondrocyte hypertrophy
Hypertrophic Zone
IGF-1
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Hypopituitarism

• 16 year old boy with hypopituitarism due to
  craniopharyngioma
• Height 137 cm

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Acromegaly Greek akros "extreme" or
"extremities" and megalos "large"
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Andre the Giant
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Yao Ming
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Jaws James Bond Movie

• Richard Kiel
• 7 1.5
• The Spy Who Loved Me, 1977

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Thyroid

• 34 weeks of gestation, the thyroid gland appears
  as an epithelial proliferation in the floor of
  the pharynx at the base of the tongue
• Over the next few weeks, it migrates to the base
  of the neck, passing anterior to the hyoid bone.

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Thyroid

• Thyrotropin-releasing factor (TRF) and
  thyroid-stimulating hormone (TSH) start being
  secreted from the fetal hypothalamus and
  pituitary at 18-20 weeks of gestation
• Fetal production of thyroxine (T4) reach a
  clinically significant level at 1820 weeks.
• Fetal triiodothyronine (T3) remains low until 30
  weeks of gestation
• Fetal thyroid hormones tend to protect the fetus
  against brain development abnormalities caused by
  maternal hypothyroidism.

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• Goiter
• Derbyshire neck

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Thyroid Hormones

• TSH (Thyrotropin) from Ant. Pituitary stimulates
  production of Thyroxine
• Tri-iodothyronine is mainly produced in target
  peripheral tissues from Thyroxine
• Tri-iodothyronine is more potent and rapidly
  acting being calorigenic (stimulate oxygen uptake
  and energy expenditure)

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Thyroid Hormones

• Essential for RNA synthesis
• Increase in metabolic rate
• Increased thyroxine causes
• weight reduction
• increased heart rate and force of contraction
• increased nervous system activity

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Thyroid Hormones

• Cretins seldom appear hypothyrotic until several
  weeks after birth but do have retarded bone
  growth at birth
• They can have irreparable brain damage although
  therapy was started within 1 or 2 months

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• 8 day old twins
• most athyrotic children are born with normal size
  but retarded bone development
• Athyrotic (left)
• 3.5 kg, 53cm
• Euthyrotic (right)
• 2.9 kg, 50cm

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Hyperthyroidism

• Graves disease
• Autoimmune disease
• Exopthalmus bug-eyes
• High metabolic Rate
• Early death from heart attacks

• Marty Feldman
• -bug-eyed British comedian
• Died at 39 of a heart attack
• Video Young Frankenstein

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Parathyroids
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Parathyroids - Parathormone

• Essential for regulation of calcium and phosphate
  metabolism
• Particularly important for normal bone and tooth
  development
• Maintains stable plasma calcium concentrations by
  stimulating osteoclastic activity
• Thyrocalcitonin (from thyroid) has opposite
  effects

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Pancreas
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Pancreas
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INSULIN

• CARBOHYDRATES
• used preferentially and excess is stored as fat
• ABSENCE OF INSULIN
• Fatty acids are mobilized and utilized in place
  of carbohydrates

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Potent effects of Insulinon Protein Metabolism

• Increased rate of transport of amino acids
  through cell membrane
• Increased formation of RNA
• Increased formation of protein by ribosomes

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Complex Interaction between GH and Insulin
? HGH
? Protein Synthesis ? Growth
??Caloric Storage
Protein Intake
? IGF-1
? Insulin
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? HGH
?? Protein Synthesis ?? Growth
?Caloric Storage
Carbohydrate Intake
?? IGF-1
? Insulin
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? HGH
? Protein Synthesis ? Growth
?Caloric Mobilization
Fasting
? IGF-1
? Insulin
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Insulin Imbalance

• Insulin Deficiency
• Can retard growth nearly as much as GH deficiency
• Hyperinsulinism
• Can result in accelerated growth
• (but also accelerated maturity rate)

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Gonadal Growth

• The size and structure of the gonads does not
  change much prior to puberty.

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Gonadal Hormones

• Both sexes Androgens estrogens (adrenals) in
  small, constant levels in the urine
• Gonadotrophins from Ant. pituitary stimulate
  development and function of the gonads
• Androgens and Estrogens also produced by
  Adrenals.
• Increased production at puberty.

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Biological Activity of Androgens

• Relative influence of gonadal or adrenal sources
  unknown.
• Testicular androgens have greater biological
  activity than adrenal androgens
• Young castrates Adrenals not able to compensate
  for lost testicular production
• IN FEMALES After puberty most androgenic effects
  are produced by the adrenals
• Majority of testosterone produce in the liver
• IN MALES Testes secrete estrogens

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Sexual Development

• Males and females follow the same pattern of
  growth to 6 weeks of gestation
• At 12 weeks sex can be determined by external
  appearance

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Sexual Development

• Removal of gonads leads to female development
• Local application of high concentrations of
  androgens causes
• development of Wolffian elements no effect on
  mullerian elements
• Destruction of one testis can lead to
• normal male development on unaffected side
  mullerian structures developing on affected side

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FSH
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LH
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Testosterone

• FSH (ICSH (ant. pit.)) causes release of
  testosterone
• Androgens are also produced by the testes

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Sex Steroids
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More related to maturation
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Metabolic action of Testosterone

• Protein anabolism dependent on critical level of
  insulin
• increased protein formation
• increased cholesterol, triglycerides and F.F.A.
  production
• decrease in phospholipids
• increased retention of sodium, chlorides
  potassium
• increased muscular development

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Metabolic action of Testosterone

• Increased rate of skeletal maturation and closure
  of epiphyses.
• closure of epiphyses more affected than linear
  growth
• greater effect closer to puberty
• facial development
• Spermatogenesis complete 2 to 3 years after
  puberty.

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External Hormonal Influence

• 3.5 year old girl with hypertrophy of the
  clitoris. Genitals otherwise normal
• mother received norethindrone (nortestosterone)
  during pregnancy for habitual abortion

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Androgens

• Larger more vascular penis
• Scrotum, prostate seminal Vesicles
• Laryngeal development
• Genital and facial hair

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Adrenal Hyperplasia

• 5 year old girl with congenital adrenal
  hyperplasia.
• Bone age 10 yrs
• Enlarged clitoris
• Pubic hair development

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Adrenal Hyperplasia

• 3 year old boy with congenital virilizing adrenal
  hyperplasia.
• Height age is 5 years. Bone age is 7 years.
• Infantile testes are hidden by the
  adolescent-sized penis

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Estrogens

• At puberty
• Linear growth
• Accelerate maturation of skeleton
• Growth development of genitalia
• Increase lipid metabolism in adipose tissue
• Breasts are earliest sign of puberty

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External Hormonal Influence

• 2.5 year old girl with breast development
• Rubbed once daily for several months with a
  beauty cream containing oestrogen derivative.
• No other signs of precocious puberty

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Male Pseudohermaphroditism in a 13 year old girl

• Gonads were testes but slightly developed with
  massive hypertrophy of the Leydig cells.
• No uterus or fallopian tubes present

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Constitutional Precocious Puberty

• A age 3, B age 11.5 years
• Breast development from 2 years of age
• menarche at age 5
• Height stopped at 153cm (age 11.5 yrs)
• Short limbs

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Precocious puberty

• 1.5 year old boy with precocious puberty caused
  by tumour of the third ventricle.
• Puberal development began at 6 months of age

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Hermaphrodite

• 2.5 year old truehermaphrodite
• Well formed uterus
• One side - testis and ductus deferens
• Other side ovotestis and fallopian tube