1. Hormonal Control of Growth

2. Growth of an individual or an organ involves:
Increase both in cell number and cell size
Differentiation of cells to perform highly specialized functions
and tissue remodeling that may require apoptosis as well as new cell formation
Most of these processes depend on locally produced growth factors that operate through paracrine or autocrine mechanisms
Many continue to operate throughout life providing not only cell renewal, but also for adaptations to meet changing physiological demands

3. Growth Hormone
Growth hormone, which is also called somatotropin (STH), is the single most important hormone required for normal growth
Attainment of adult size is absolutely dependent on GH; in its absence growth is severely limited

4. Synthesis, secretion, and metabolism
Although the anterior pituitary gland produces at least six hormones, more than one-third of its cells synthesize and secrete GH
90% of the GH produced by somatotropes is comprised of 191 amino acids and has a molecular weight of ~ 22,000
The remaining 10% has a molecular weight of 20,000 and comprised of 176 amino acids
Both forms are products of the same gene
Both forms of hormone are secreted and have similar growth-promoting activity, although metabolic effects of the 20K form are reduced

5. Synthesis, secretion, and metabolism
About half the GH in blood circulates bound to a protein that has the same amino acid sequence as the extracellular domain of the GH receptor
GH that crosses the glomerular membrane is reabsorbed and destroyed in the kidney, which is the major site of GH degradation
GH also is degraded in its various target cells following uptake by receptor mediated endocytosis

6. Mode of action
Like other peptide and protein hormones GH binds to its receptor on the surface of target cells
GH produces its effects in various cells by stimulating the transcription of specific genes

7. Physiological actions of growth hormone
Effects on skeletal growth
The ultimate height attained by an individual is determined by the length of the skeleton and, in particular, the vertebral column and long bones of the legs
The somatomedin hypothesis
GH may not act directly to promote growth but, instead, stimulates the liver to produce an intermediate, blood borne substance (somatomedin) that activates chondrogenesis and perhaps other GH-dependent growth processes in other tissues
Somatomedins are a group of hormones that promote cell growth and division in response to stimulation by growth hormone

8. Physiological actions of growth hormone
Somatomedin was found to consist of two closely related substances that also produce the insulin-like activity
These substances now are called insulin-like growth factors , or IGF-I and IGF-II
IGF-I is more important mediator of the actions of GH
Children whose growth is more rapid than average have higher than average concentrations of IGF-I
It is now apparent that GH stimulates secretion of IGFs, which act locally in an autocrine or paracrine manner to stimulate:
cell division, chondrocyte maturation, secretion of extracellular matrix proteins, and bone growth

9. Physiological actions of growth hormone
Effects of GH/IGF-I on body composition
The bodies of growth hormone-deficient animals and human subjects have a relatively high proportion of fat, compared to water and protein, in their bodies
Most internal organs grow in proportion to body size, except liver and spleen, which may be disproportionally enlarged by prolonged treatment with GH
When human subjects or experimental animals are given GH repeatedly for several days, there is net retention of nitrogen, reflecting increased protein synthesis

10. Regulation of GH secretion
In humans, GH secretion is pulsatile
Frequent bursts of secretion occur throughout the day, with the largest being associated with the early hours of sleep
In addition, stressful changes in the internal and external environment can produce brief episodes of hormone secretion
Effects of age
GH secretion, though most active during the adolescent growth spurt, persists throughout life, long after growth has stopped

11. Regulation of GH secretion
In addition to spontaneous pulses, secretory episodes are induced by such metabolic signals as:
a rapid fall in blood glucose concentration
or an increase in certain amino acids
Traumatic and psychogenic stresses are also powerful inducers of GH secretion in humans
whether increased secretion of GH is beneficial for coping with stress is not established
Three hormones are involved in regulation and somatotropes express receptors for all three hormones:
GH-releasing hormone (GHRH)
Somatostatin
And ghrelin

12. Regulation of GH secretion
Growth hormone releasing hormone provides the primary drive for GH synthesis and secretion
Somatostatin reduces or blocks secretion of GH in response to GHRH, but has little or no influence on GH synthesis
constant secretion of somatostatin restrains secretion of GH
Periodic interruptions in secretion produces a rebound release of GH
PVN: periventricular nuclei; ARC: arcuate nuclei; SST: somatostatin; GHRH growth hormone releasing hormone; IGF-I insulin-like growth factor-I; (+) stimulation. (─) inhibition

13. Regulation of GH secretion
Ghrelin increases responses of somatotropes to GHRH
stimulation of GH secretion by ghrelin requires costimulation by GHRH
Negative feedback control sets the overall level of GH secretion by regulating the amounts of GH secreted in each pulse

14. Role of Thyroid Hormones
Growth is stunted in children suffering from deficiency of thyroid hormones
Treatment of hypothyroid children with thyroid hormone results in rapid “catch up” growth and accelerated
The effects of thyroid hormones on growth are closely entwined with GH
T3 and T4 have little, if any, growth-promoting effect in the absence of GH
Thyroid hormones affect synthesis of human GH indirectly by increasing the expression GHRH receptors by somatotropes

15. Role of Insulin
insulin may serve as a growth-promoting hormone during the fetal period
Infants born of diabetic mothers often are larger than normal, especially when the diabetes is poorly controlled
Because glucose readily crosses the placenta, high concentrations of glucose in maternal blood increase fetal blood glucose and stimulate the fetal pancreas to secrete insulin
Structurally, insulin is closely related to IGF -I and IGF-II and when present in adequate concentrations can activate IGF-I receptors

16. Role of Gonadal Hormones
Awakening of the gonads at the onset of sexual maturation is accompanied by a dramatic acceleration of growth
At the same time that gonadal steroids promote linear growth, they accelerate closure of the epiphyses and therefore limit the final height that can be attained
Most, and possibly all, of the increase in height stimulated by estrogens or androgens at puberty is due to increased secretion of GH

17. Role of Glucocorticoids
Glucocorticoids are required for synthesis of GH and have complex effects on GH secretion
When given acutely, they may enhance GH gene transcription and increase responsiveness of somatotropes to GHRH
However, GH secretion is reduced by excessive glucocorticoids, probably as a result of increased somatostatin production
Impairment of growth is seen in children treated chronically with high doses of glucocorticoids to control asthma or inflammatory disorders
Consistent with their catabolic effects in muscle and lymphoid tissues, glucocorticoids also antagonize the actions of GH