Module 1: The endocrine system

Growth Hormone (GH), as the name suggests, is the major hormone that controls
growth in children. Whilst GH receptors are expressed in all cells the body, GH
stimulates the production of IGF-1 and the two hormones work together to stimulate
the growth of tissues. Beside stimulating growth, GH also plays important metabolic
roles, having a well-characterised protein anabolic and fat catabolic actions. GH
also increases blood glucose concentrations and is diabetogenic.

By the end of this unit, you should be able to:

Describe the regulation of Growth Hormone secretion from the somatotrophs.

Explain the somatomedin hypothesis for growth, and how the original
hypothesis has been modified.

List the metabolic actions of Growth Hormone.

Explain the difference between short-loop and long-loop negative feedback.

Growth Hormone

Growth
Hormon
e (GH) is
one of
the
anterior
pituitary
hormone
s,
secreted
from the
somatot
roph
cells. It
is a 191 amino acid single chain polypeptide, folded into a globular small protein (see
figure). It is the major hormone that regulates somatic cell growth in the body, hence
its older name was 'somatotropin'.

Image source: 'Human growth hormone, hGH, somatotropin molecule' by bacsica, Adobe Stock.

GH - Physiological actions

GH is the major determinant of growth. In general the actions of GH are generally

anabolic, promoting tissue growth through an increase in the number of cells
(hyperplasia) and size of cells (hypertrophy). This effect of GH occurs is both in soft
and hard tissues (bone). In children, prior to the closure of the growth plates on long
bones, GH promotes skeletal growth, increasing the length of long bones and
therefore increasing stature.

Somatomedin Hypothesis (for Growth)

Experiments performed some 70 years ago came to the conclusion that somatic
growth was not due to GH (somatropin) acting directly on cells, but rather through
intermediates, called somatomedins, that were produced by the liver in response to
GH. It became a hypothesis, known as the somatomedin hypothesis, and in part still
holds true today.

Image source: Kenneth Lopez-Loo, UQ.

However, over time, the somatomedin hypothesis to describe the endocrine control
of growth in the body has become modified. First, the identity of the somatomedin
hormone was revealed, and the main somatomedin in post-natal growth was
identified as insulin-like growth factor I (IGF-1). Indeed, GH acting via GH receptors
in the liver stimulates the release of IGF-1 and IGF-1 circulates to influence tissue
growth.

The next major discovery was that, whilst the liver expressed GH receptors in great
quantities, many other cells in the body also expressed GH receptors. This meant
that some growth effects were direct due to GH, and were not mediated through
IGF-1 (see left hand side of figure).

Image source: Kenneth Lopez-Loo, UQ.

Then another major scientific advance was that, in addition to liver hepatocytes,
many other cells could produce IGF-1 in response to GH and other hormones. This
IGF-1 produced locally within tissues (right hand side of figure), could act in a
paracrine manner to stimulate local cell growth. Lastly, it was possible that some
local IGF-1 entered circulation, and added to liver derived IGF-1, and acted as
classical endocrine hormone stimulating growth of distant target cells.

Today, our perspective is that the endocrine control of growth is that the
somatomedin hypothesis has been augmented, with still quite some unresolved
issues, although both GH and IGF1 are the key molecules that drive post-natal
growth.

Metabolic Actions of GH

GH also has metabolic effects, which are somewhat distinct from effects on growth.
In adults these metabolic effects are important because pulstaile release of GH from
the somatrophs declines with age.

Muscle tissue - protein anabolic

stimulates amino acid uptake

inhibits protein breakdown

inhibits glucose uptake*

Adipose tissue - fat catabolic

stimulates fat breakdown - lipolysis

inhibits glucose uptake*

Liver

stimulates glucose output via gluceoneogenesis*

Overall GH results in an increase in muscle mass, decrease in fat deposits, and an

increase in blood glucose concentrations. In regards to blood glucose regulation,
GH has anti-insulin effects (those marked with asterisk), and is said to be
diabetogenic. Excess GH secretion can lead to diabetes mellitus.

Negative Feedback Loops

Recall that previously we stated the GH acted in its own right (to stimulate cell
growth), and was not part of an hypothalamic-pituitary-endocrine gland axis,
although we stated such was not strictly true. Indeed there is a "growth hormone
axis" although it is not like the other hypothalamic - pituitary axes, where the sole
function of the anterior pituitary hormone is to stimulate another endocrine gland.

Nevertheless when we consider the regulation of GH it is important to consider the

growth hormone axis and the somatomedin IGF-1. There are two negative feedback
loops that operate to regulate GH. First (left hand side on figure), there is short-loop
negative feedback. This is where the anterior pituitary gland hormone itself, GH in
this case, acts upon GH receptors in the hypothalamus to inhibit GHRH and stimulate
somatostatin, bringing about homeostatic regulation.

Image source: Stephen Anderson, UQ.

There is also long-loop negative feedback by IGF-1. IGF-1 is signals in feedback at

both the hypothalamic level (via inhibition of GHRH and stimulation of SS), as well as
at the anterior pituitary somatotrophs to inhibit the synthesis of GH mRNA.