Pituitary Hormone Function (GH/PRL) Flashcards
The Growth Hormone/Prolactin Family of Hormones
a. Prolactin (PRL) and growth hormone (GH) are members of the same family of hormones, and both are ~22-23 kD polypeptides of slightly less than 200 amino acids containing 2-3 disulfide bonds.
i. PRL and GH are ~16% similar at the level of primary sequence.
b. This class of hormones is also referred to as the somatomammotropin family.
c. A third member of this family is placental lactogen (hPL or chorionic somatomammotropin), which has 83% amino acid identity with GH.
Prolactin (PRL) Secretion from the Ant Pituitary
a. This hormone distinguishes itself by the fact that the hypothalamus tonically inhibits the secretion of PRL via PIH (prolactin-inhibiting hormone), or DA (dopamine).
b. If the hypothalamic influences to the anterior pituitary are prevented, the adenohypophysis will secrete much larger amounts of PRL, whereas the secretion of the other anterior pituitary hormones will not increase
i. Ant Pituitary will secrete large amounts of prolactin unless the hypothalamus stops it with PIH or DA
c. In some instances of hypersecretion of prolactin, administration of a dopamine agonist, such as bromocriptine, is effective in reducing the excess release of prolactin.
d. DA reduces release and synthesis of PRL, inhibits lactotroph cell division and DNA synthesis and increase destruction of PRL containing secretory granules (crinophagy).
i. Inhibition of cAMP formation appears to be involved in mediating these effects.
Prolactin Function
a. The cells that secrete PRL, lactotrophs, comprise 30% of the adenohypophysis (anterior pituitary)
b. The breast is the principal target of PRL action, where PRL plays a role in the production of milk.
c. In cases where there are prolactin-secreting tumors, there will be inappropriate milk secretion.
i. Reproduction is impaired, because high levels of prolactin inhibit pulsatile secretion of GnRH by hypothalamic neurons.
d. PRL is transported in the blood unmodified and has a short half-life of 20-30 min.
External causes that lead to increased Prolactin secretion
from the anterior pituitary
a. In females, suckling of the breast is an effective physiological stimulus leading to release of prolactin.
b. In addition, prolactin is released in both males and females in response to stress. Prolactin interacts with specific receptors found in the breast, liver, ovary, testis and prostate; the main site of action is the mammary gland
Prolactin receptors are members of the growth hormone/cytokine receptor families.
a. The long form of PRL receptors and the growth factor receptors are about 620 amino acids in length
i. They are single chain proteins crossing the membrane only once.
b. Upon ligand binding, receptors dimerize, leading to the activation of the JAK/STAT pathway.
i. Just as prolactin and growth hormone share structural homology, so do their receptors.
c. Human PRL receptors are well stimulated by GH.
Growth Hormone (GH)
Large Summary
a. Growth hormone is fundamental for postnatal growth, stimulates somatic growth and regulates metabolism.
b. GH is a peptide hormone as well as a secretory protein.
i. The principal and biologically most important form consists of 191 amino acids.
c. Similar to many other hormones, GH is synthesized as part of a prohormone.
i. Once the signal peptide is cleaved, GH is stored in secretory granules of somatotrophs of the adenohypophysis.
d. The synthesis of GH is evidently a major activity of the anterior pituitary, since 10% of the dry weight of the anterior pituitary is contributed by GH!
e. Secretion of GH is under the influence of the hypothalamic hormones GHRH and somatostatin.
i. GHRH and somatostatin stimulation of somatotrophs have opposing actions on cAMP levels; GHRH stimulation increases them, whereas somatostatin decreases them.
f. The majority of GH circulates in an unbound form and has a half-life of 20-45 min.
i. There is some evidence suggesting that a portion of plasma GH is bound specific binding proteins (GHBP), which are cleaved N-terminal peptides of its receptor.
Growth Hormone is a very specific peptide for its species
a. Human or primate GH are the only GH’s that are active in humans.
b. Previously, human GH isolated from cadavers was used therapeutically.
i. In 1985, it was noted that several individuals who had been treated with “cadaver” GH acquired Creutzfeld-Jacob disease, a devastating form of spongiform encephalopathy caused by prions.
c. Recombinant GH is now available and has become the sole source of GH replacement therapy.
What type of receptors Growth hormone interacts with
At a cellular level, GH interacts with GH receptors in the plasma membrane of target cells. Both GH receptors and their signaling mechanisms are similar to that of PRL
Direct actions of Growth Hormone-
These are metabolic effects (Counter-regulatory or diabetogenic)
- Adipose tissue- The net effect is to increase lipolysis and lead to mobilization of lipid and thus an increase in plasma free fatty acids (FFAs). Eventually, the effect of GH on fat metabolism will be evidenced by a loss in subcutaneous fat. In this action GH antagonizes the action of insulin.
- Muscle-GH has a strong anabolic action on muscle. Amino acid transport is increased, and protein synthesis is increased.
- Liver-Increased RNA, protein and glucose synthesis. Further, IGF-I will be secreted, which mediates the indirect effects.
- The increase in glucose levels is mainly due to an increase in gluconeogenesis and not due to glycogenolysis.
General Effect of Growth Hormone
a. In general, GH’s effects are anti-insulin like, i.e. glucose uptake will be decreased and plasma glucose levels will rise.
i. Note that the increased plasma FFA is providing an alternate energy source and the increased plasma glucose is reserved for the CNS.
b. Importantly, protein is spared.
i. This contrasts with the actions of cortisol, the subject of another lecture.
Indirect Actions of Growth Hormone:
a. In addition to its metabolic effects, GH also has effects on muscle and skeletal growth mediated by another hormone-the Insulin-like growth factor (IGF).
b. There are two forms of IGF that have been shown to exist (IGF-I and IGF-II).
i. Of these, IGF-I is the predominant form in postnatal tissues.
c. The production of IGF requires both GH and insulin and occurs in a number of tissues (e.g. liver, bone marrow).
Insulin-like Growth Factor I (IGF-I):
summary
a. IGF-I is structurally related to proinsulin (hence its name) and has many insulin like actions (especially in adipose tissue and muscle).
b. IGF-I is a powerful mitogen and growth-promoting agent.
c. Elevated IGF-I levels increase slowly from birth until puberty, when there is usually a much more pronounced elevation.
d. Although growth hormone usually promotes secretion of IGF-I production, there are some stimuli that have different effects on GH and IGF-I levels.
i. For example, during fasting, GH levels are elevated, while IGF-I levels are depressed.
e. IGF receptors belong to the EGF/ Insulin receptor family.
i. These receptors contain an inherent tyrosine kinase activity and upon ligand binding can readily phosphorylate themselves (auto phosphorylation) and other proteins of the signal transduction pathway.
f. The major pathway activated by IGF receptors is initiated by the binding of Insulin Receptor Associated proteins 1 and 2 (IRS I&II). IRS in turn can bind to other molecules to activate either the MAP kinase pathway or transduction mediated by PI-3 kinase.
IGF receptors belong to the EGF/ Insulin receptor family.
a. These receptors contain an inherent tyrosine kinase activity and upon ligand binding can readily phosphorylate themselves (auto phosphorylation) and other proteins of the signal transduction pathway.
b. The major pathway activated by IGF receptors is initiated by the binding of Insulin Receptor Associated proteins 1 and 2 (IRS I&II).
c. IRS in turn can bind to other molecules to activate either the MAP kinase pathway or transduction mediated by PI-3 kinase.
Growth Hormone actions mediated via IGF-I
- Bone/cartilage - Long bone growth is promoted by the stimulated proliferation of epiphyseal cartilage. After puberty, the epiphyses seal and IGF-I no longer has this effect on linear growth.
- Muscle - stimulates proliferation, differentiation and protein synthesis
- Adipose tissue - stimulates uptake of glucose and inhibits lipolysis. This action of IGF is insulin like and antagonizes that of GH.
Control of GH secretion by products of Intermediary metabolism:
summary
a. Other stimuli include hypoglycemia, amino acids (arginine), low free fatty acid levels, α-adrenergic agonists (clonidine), β-adrenergic antagonists (propranolol) and estrogens.
b. Conversely, hyperglycemia, high free fatty acid levels, obesity, α-adrenergic antagonists, β-adrenergic agonists as well as pharmacological doses of corticosteroids inhibit GH secretion.
c. In assessing GH levels and secretion, it is important to obtain measurements several times over the course of a day.
i. Stimulation of GH secretion by exercise or high doses of arginine is often used to assess GH status.
ii. In addition, measurement of IGF-I levels is very helpful, especially since its levels are subject to less diurnal variation
