Endocrine Control of Growth

Endocrine glands

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

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)

Original Somatomedin Hypothesis

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

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"

Adipose Tissue↓ Glucose Uptake↑ Lipolysis

↓ Adiposity

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 SizeOrgan Function

IGF-1Local production

Muscle↓ Glucose Uptake↑ Amino Acid Uptake↑ Protein Synthesis

↑ Lean Body Mass

Liver↑ RNA Synthesis↑ Protein Synthesis↑ Gluconeogenesis↑ IGF-1

HGH

Daily GH Levels (24hr)

Somatomedin-C (IGF-1) LevelsPeak about 1 yr after PHV

Growth Plate

GH & IGF Interactions in Long Bone Growth

Germinal Zone

Proliferative Zone

IGF-2

IGF-2IGF-2

Hypertrophic Zone

Stimulates proliferation of chondrocyte precursors and thus expands the proliferative chondrocyte pool and the hepatic and/or local production of IGF-1

GH

Promotes chondrocyte hypertrophy

Stimulates clonal expansion by autocrine/paracrine mechanisms

IGF-2

IGF-1

Hypopituitarism

16 year old boy with hypopituitarism due to craniopharyngioma

Height = 137 cm

Acromegaly Greek akros "extreme" or "extremities" and megalos "large"

Andre the Giant

Yao Ming

Jaws – James Bond Movie

Richard Kiel 7’ 1.5” The Spy Who

Loved Me, 1977

Thyroid

3–4 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.

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 18–20 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.

Goiter

“Derbyshire neck”

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)

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

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

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

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

Parathyroids

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

Pancreas

Pancreas

INSULIN

CARBOHYDRATES– used preferentially and excess is stored as fat

ABSENCE OF INSULIN– Fatty acids are mobilized and utilized in place of

carbohydrates

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

↑ HGH

↑ Insulin

↑ IGF-1↑ Protein Synthesis

↑ Growth

↓↑Caloric Storage

Protein Intake

Complex Interaction between GH and Insulin

↓ HGH

↑ Insulin

↓↑ IGF-1↓↑ Protein Synthesis

↓↑ Growth

↑Caloric Storage

Carbohydrate Intake

↑ HGH

↓ Insulin

↓ IGF-1↓ Protein Synthesis

↓ Growth

↑Caloric Mobilization

Fasting

Insulin Imbalance

Insulin Deficiency• Can retard growth nearly as much as GH

deficiency

Hyperinsulinism• Can result in accelerated growth

– (but also accelerated maturity rate)

Gonadal Growth

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

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.

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

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

Sexual Development

Removal of gonads leads to female developmentLocal 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

FSH

LH

Testosterone

FSH (ICSH (ant. pit.)) causes release of testosterone

Androgens are also produced by the testes

Sex Steroids

More related to maturation

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

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.

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

Androgens

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

Adrenal Hyperplasia

5 year old girl with congenital adrenal hyperplasia.

Bone age = 10 yrs Enlarged clitoris Pubic hair

development

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

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

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

Gonads were testes but slightly developed with massive hypertrophy of the Leydig cells.

No uterus or fallopian tubes present

Male Pseudohermaphroditismin a 13 year old girl

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

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

Hermaphrodite

2.5 year old truehermaphrodite

Well formed uterus One side - testis

and ductus deferens

Other side ovotestis and fallopian tube