Hormonal control of growth

From Iusmphysiology

Contents 1 Normal growth and development 2 Hormone regulation of growth 3 Control of GH 4 Example causes of pituitary dwarfism 5 GH Axis diseases 6 Control of GH secretion 7 GHRH receptor mutations 8 Growth hormone 9 Growth hormone / Prolactin superfamily 10 Insulin-like growth factors (IGFs) 11 GH signaling 12 Factors affecting GH release 13 GH secretion during sleep 14 GH changes with age 15 Physiological effects of human GH 16 Insulin-like versus "diabetogenic" effects of GH 17 Role of thyroid hormones in growth 18 Major disorders of growth hormone secretion 19 More on GH excess 20 Pituitary development 21 GH deficiency treatment 22 GH pathway deficiencies 23 Roles of prolactin 24 Control of PRL 25 Prolactin disorders 26 Non GH Dwarfism

Normal growth and development

• Normally the greatest growth rate occurs between zero and 20 weeks of gestation.
• Then there is a sharp decline in growth rate until birth and then a shallower decline until 40 weeks postpartum.
• After birth, one's growth rate is very high and decreasing rapidly until age 5, then is slowly decreasing, then goes back up for puberty (earlier for females), and then decreases rapidly before age 20.
• GH has its effects on the growth plates of the long bones.
• Estrogen helps close the growth plates; androgens also help close the growth plates.
  • But androgens come around later so boys grow taller.

Hormone regulation of growth

• At different stages of growth, different growth hormones are important to proper development.
  • Recall that IGFs, GH, T3, Sex steroids, and insulin are all growth hormones.
• Insulin is important throughout prenatal and post-natal development.
• IGFs are the other important prenatal growth factor.
• Growth hormone (GH) and T3 become important for post-natal development.
  • GH is the major stimulus for somatic growth.
  • T3 potentiates GH's affect and is crucial for CNS development.
• Finally, sex steroids are important for growth at puberty.
  • Androgens accelerate linear growth, close the epiphyseal plates, and increase muscle mass.
  • Estrogens decrease linear growth, close the epiphyseal plates, and while they increase GH in the plasma, they decrease somatomedin levels
• Glucocorticoids inhibit somatic growth.

Control of GH

• The general axis for GH secretion is the hypothalamus, the pituitary (somatotropes), and the target organs (liver, muscle, bone, adipose).
  • The hypothalamus releases growth hormone releasing hormone which acts on the somatotropes of the anterior pituitary to promote release of GH.
    • GHRH = growth hormone releaseing hormone = GRF = growth-hormone releasing factor = somatocrinin.
  • The hypothalamus releases somatostatin which acts on the somatotropes of the anterior pituitary to inhibit release of GH.
  • The somatotropes of the anterior pituitary release growth hormone (GH) which act on the liver, muscle, bone, and adipose tissues.
    • The liver releases IGFs in response to GH signaling.
    • The muscle, bone, and adipose likely produce IGFs for local signaling, also, in response to GH signaling.
    • Many tissues respond to GH and IGFs by growing: bones, soft tissues, gonads, viscera, etc.

• GH feedback occurs at all levels: ultrashort feedback, short (direct), and long (indirect).
  • Ultrashort feedback occurs when somatostatin and GHRH from the hypothalamus feedback on the cells of the hypothalamus to inhibit their actions (that is, somatostatin feedback will decrease release of somatostatin).

Is this autocrine or does it enter the blood stream and come back around?  Both
Does this feedback promote the production of the opposite factor?  That is, does somatostatin feedback on the hypothalamus promote production of GHRH?  There is evidence that feedback does promote the production of the opposite factor.

• • Short (direct) feedback occurs when GH from the somatotropes of the anterior pituitary feeds back on the hypothalamus to decrease production of GHRH.

Does this short feedback also promote release of somatostatin?  There is evidence that feedback does promote the production of the opposite factor.

• • Short (direct) feedback also occurs when IGFs from the liver feedback on the somatotropes of the anterior pituitary to decrease production of GH.
  • Long (indirect) feedback occurs when IGFs produced by the liver feedback on the the hypothalamus.

Example causes of pituitary dwarfism

• There are many reasons that GH signaling could fail and thus cause dwarfism.
  • A defect in the GHRH receptor would mean that the somatotropes of the anterior pituitary would never get the signal to release GH.
  • A pituitary development disorder would mean there are no somatotropes to generate GH.
  • A GH defect would result in a signal that fails to produce the desired effect in target tissues.
  • A GH receptor defect would result in failure to produce the desired effect in target tissues.
  • A GH binding protein defect would result in failure to get the GH to the target tissues.
  • A STAT defect would result in improper signaling at the target tissue and a lack of transcription regulation.
  • IGF1 defects would result in target tissue response that was ineffective.
  • IGF receptor defects would result in secondary target tissue response that was ineffective.

GH Axis diseases

• Short statures is the result of diseases of the GH axis.
• We know of diseases at every level of the axis.

Control of GH secretion

• Recall that the hypothalamus releases both somatostatin (anti-growth hormone) and GHRH (pro-growth hormone).
  • Somatostatin signals through SRIF and SST receptors on somatotropes.
  • GHRH signals through the GHRH receptor on somatotropes.
• Recall that GH and IGFs (from the liver and other GH target tissues) negatively feedback on somatotropes (receptors not given).
• Ghrelin is a pro-GH factor from the stomach.
  • Ghrelin signals through the GHS receptor on somatotropes.

• GHRH
  • Also called GRF and somatocrinin
  • GHRH is a neuropeptide (44 amino acids).
  • GHRH causes GH release at the somatotropes and also causes somatotrope proliferation.
  • GHRH is related to secretin and glucagon

Why does this make sense?

• • GHRH binds a 7-transmembrane helix receptor on the somatotrope.
  • GHRH signals through elevation of cAMP levels.

• Somatostatin (SST)
  • Somatostatin (SST) is also called somatotropin release-inhibiting factor (SRIF)
  • Like GHRH, SST (somatostatin) is a neuropeptide (14 amino acids).
  • Just as GHRH causes increased cAMP levels in the somatotropes, somatostatin (SST) causes a decrease in cAMP; this makes sense because GHRH and SST have opposite affects on GH release by the somatotropes.
  • Somatostatin also has roles in the gut, pancrease, etc.
    • Somatostatin arrests nearly every secretion of the gut.

Why does this make sense?
Are the levels that affect the somatotropes similar to those that affect the gut?  Not sure
How much does eating correlate with growth?  Prof thinks gut SST is mostly paracrine.

• Ghrelin
  • Knew the receptor far longer than the signal (ghrelin) but kept looking at the hypothalamus for the signal but it comes from the gut!
  • Ghrelin is released by endocrine neurons of the stomach.
  • Ghrelin causes increased secretion of GH at the somatotropes of the anterior pituitary.
  • Ghrelin signals through the GHS receptor (growth hormone secretagogue receptor).
    • The growth hormone secretagogue receptor (GHS-R) signals through an IP3/DAG/Ca++ pathway to cause release of GH.
    • The fact that the secretagogue receptor uses a separate pathway than the GHRH and SST pathway is significant.

GHRH receptor mutations

• The GHRH receptor is annotated as GHRH-R.
• Mutations in the GHRH-R cause short stature.
  • These mutations are rare.
• Mutations of the receptor occur in most parts of the protein.

Growth hormone

• Growth hormone (GH) is also called somatotrophin (STH) or somatotropin (ST).
• GH is made by somatotropes in the anterior pituitary.
• Growth hormone is carried in the plasma by proteins called growth hormone binding proteins.
• Growth hormone is secreted in bursts.

Are these bursts dependent on eating or independent?  (Think ghrelin and somatostatin.)  "There is some evidence that eating stimulates GH secretion but precise correlation with burst, I’m not sure. (also ghrelin stimulates food intake and growth hormone secretion)"

• Growth hormone is also released on a 24 hour (circadian) rhythm and is high during sleep.
• BST given to bovine is bovine somatotropin.
  • Causes cow to produce more milk.

Growth hormone / Prolactin superfamily

• Growth hormone is a member of the prolactin superfamily.
  • Both GH and PRL use JAK-STAT signaling mechanisms.
  • Recall that prolactin is also made in the anterior pituitary (by lactotrophs) and stimulates lactation in post-partum females.
  • There is only one copy of the prolactin gene in mammals.

• There are many copies of the GH gene in mammals.
  • GH-N is the version expressed in the anterior pituitary; it is also called GH1.
  • Copies of the growth hormone gene (including GH1) are found on chromosome 17.
  • Some copies of the growth hormone gene are called chorionic somatotropin because they are expressed in the placenta.
    • These paralogs to growth hormone are labeled "CS" as in "CS-A", "CS-B", etc.
    • These paralogs are sometimes called "placental lactogens", too.

Do these placental lactogens come from the baby and signal the mother's mammary glands?  They come from the placenta.

• Growth hormone promotes the growth of long bone and the closure of the epiphyseal plates.
  • It is hypothesized that this effect occurs by GH signaling on the liver, the liver responding by producing IGF 1 and IGF 2, and IGF 1/2 signaling proliferation of the epiphyseal cartilage and subsequent sulfation.
  • Sulfation can be followed (and thus experiments can measure the effect of GH / IGF 1/2 on bone formation) via incorporation of radioactive sulfur (S³⁵).
  • IFG1 and IGF2 are called somatomedins because they are the result of GH signaling.

Insulin-like growth factors (IGFs)

• Insulin-like growth factors are small peptides (as in insulin).
• IGFs (insulin-like growth factors) are bound to IGF binding proteins when circulating in the blood; these are called IGFBPs.
• IGF1 is an important growth factor for all stages of growth.
  • The IGF1 receptors looks much like the insulin receptor.
  • Recall that the insulin receptor uses a tyrosine kinase mechanims (as does the IGF1 receptor).

Is IGF1 important for tissue maintenance type growth or just growth as in pre-20 year old growth?  Both

• IGF2 is primarily important for fetal growth.
  • The IGF2 receptor (IGF2R) can bind IGF2 and mannose-6-phosphate.
  • It has been observed that IGF2R knockouts are larger than their peers.
    • Therefore it has been suggested that IGF2R may be responsible not only for IGF2 signaling but also for destruction of excess IGF2.

How does a receptor transduce a signal but also control excess signal?  "I understand the igf2r to be less of a signaling receptor and more of a mechanism to remove excess igf2"

GH signaling

• GH induces a JAK-STAT signaling pathway.
  • Recall that JAK-STAT pathways use dimerization of receptors (in this case the GHR) to recruit janus kinases.
  • JAK = janus autophophorylating kinase so remember that JAKs autophosphorylate.
  • Upon autophosphorylation, STAT proteins are recruited, phosphorylated, and dimerized.
• Prolactin also uses JAK-STAT signaling.
• JAK2 and STATs 1, 3, and 5 (especially STAT5)

Factors affecting GH release

• There are neurogenic, metabolic, and hormonal influences upon GH release.
  • These can be either pro-GH release or anti-GH release.
  • Stimulators:
    • Neurogenic stimulators of GH release: non-REM sleep, stress
    • Metabolic stimulators of GH release: hypoglycemia, low FFA levels, amino acids
    • Hormonal stimulators of GH release: GHRH, estrogens
  • Inhibitors:
    • Neurogenic inhibitors of GH release: REM sleep, emotional deprivation
    • Metabolic inhibitors of GH release: hyperglycemia, high FFA levels, obesity

Why does it make sense that high sugar should slow growth?  Seems opposite.  "I think that this is confusing because GH is both a metabolic hormone and a growth hormone"

• • • Hormonal inhibitors of GH release: somatostatin (SST), large doses of corticosteroids, somatomedins (like IGFs)

GH secretion during sleep

• Growth hormone levels are highest during sleep.
• Use a bolus of arginine to cause the pit to dump all it's GH.

GH changes with age

• Growth hormone concentrations decrease with age (at 20 years old).
• Some have wondered if we should give GH replacement therapy to promote longer, better life.

Do IGF levels follow the same curve?  Yes
Are there other factors that promote IGFs?  "Not sure"

• GH is not just for growth but for bone strength, etc. May have some role in cancer resistance, too.

Physiological effects of human GH

• Growth hormone has prominent effects on adipose, liver, muscle, chondrocytes, bone, heart, and lung.
  • In general, GH causes growth and generates free energy for the body.
• In liver, GH causes an increase of gluconeogenesis (generates free energy for the body) and IGF production (growth).
  • Note that IGF production at the liver will go on to signal growth in muscle, bone, and cartilage.
• In adipose, GH causes decreased glucose use and increased lypolysis (generates free energy for the body).
• In muscle, GH causes decreased glucose uptake (generates free energy for the body) yet increases amino acid uptake and increased protein production (growth).
• In chondrocytes, GH causes proliferation, collagen production, and chondroitin sulfate production (growth).
  • Note that GH induces growth of cartilage indirectly through IGFs produced by the liver.
• In bone, heart, and lung, GH causes increased cell size and number (growth).
  • Note that GH induces growth of cartilage indirectly through IGFs produced by the liver.
• Finally, kidney, pancreas, intestine, and many other tissues respond to IGFs as the bone, heart, and lungs do--growth via IGF signaling.

Insulin-like versus "diabetogenic" effects of GH

• Growth hormones has some effects that are insulin like and some that oppose the actions of insulin.
  • Recall that insulin generally tells the body that there is lots of energy and tissues should feel free to use glucose and to do what they are designed to do.
  • Note that "diabetogenic" actions usually only occur when GH is found in great excess.
• Growth hormone is insulin-like in that it causes:
  • increases amino acid uptake and protein synthesis by muscle
• Growth hormone opposes insulin's action in that:
  • GH promotes lipolysis (GH frees up energy so the body can grow but insulin is correlated with glucose so it doesn't have to signal for freeing of energy)
  • GH increases glucose production by the liver (again, GH frees up energy so the body can grow but insulin only comes along when glucose is present so it doesn't have to signal for free of energy at the liver via glycogenolysis)
  • GH inhibits glucose uptake by muscle and fat

Since GH is telling the muscle to grow (make proteins) it is surprising to me that GH specifically tells the muscle not to use glucose.  How does this make sense?  "I think that this is confusing because GH is both a metabolic hormone and a growth hormone."

• • GH makes muscle and fat resistant to insulin

See question from above

• • GH--in excess--can cause diabetes like disease and acromegaly.

Role of thyroid hormones in growth

• T3 has both direct and indirect affects on growth; the indirect affects work by potentiating the affect of GH.
• T3 directly affects growth by increasing protein production of some structural proteins (important for growth) in liver, skeletal muscle, heart, and other tissues.
• T3 indirectly affects growth by way of a TRE (thyroid response element) on the GR-N gene.
  • Recall that the GR-N gene is the gene that is expressed by somatotropes of the anterior pituitary and produces GH.
  • Recall that thyroid hormones act through nuclear receptors that affect transcription by their interaction with TREs.

Major disorders of growth hormone secretion

• GH disorders are bisected by two vectors: insufficiency / deficiency and child / adult.
• In children:
  • Childhood GH excess is called gigantism and manifests an increased growth velocity.
  • Childhood GH deficiency is called dwarfism and manifests as a decreased growth velocity, retarded skeletal development, poorly developed musculature, excessive subcutaneous fat, and delayed perbertal development
• In adults:
  • Adult GH excess is called acromegaly and manifests as connective tissue proliferation, dermal overgrowth, enlargement of the extremities, skull deformities, peripheral neuropathy, and insulin resistance.
    • Recall that GH normally causes insulin resistance so at excessive levels, there will be far too much insulin resistance.
    • Because growth plates are closed in adults, the only room for growth is out and around, thus the skull deformities and enlargement of extremities (before they close).
  • Adult GH deficiency is not named and manifests as increased insulin sensitivity, decreased muscle strength, and decreased bone density.

More on GH excess

• In children, GH excess is called giantism.
  • Giantism often results from somtaotropic tumors.
  • Often, excessive production of GH in the pituitary is coupled with decreased production of LH and FSH.
    • This causes decrease in sex hormones and therefore non-closure of the long bones. We call this the "double whammy".
    • This causes decreased production of sex hormones.
    • Decreased sex hormones causes growth plates to remain open for longer.

• In adults, GH excess is called agromegaly.
  • In adults the growth plates are closed so growth is seen in the jaw, thickening fingers, thickened skin, overgrowth of visceral organs, etc.

• Famous people with excessive GH include:
  • Robert Wadlow: the gentleman giant, double whammy
  • Sandy allen: from Indianapolis
  • Charles Byrne: the Irish giant, AIP mutation -> pituitary adenoma (via DNA from teeth)

Pituitary development

• GH deficiency (dwarfism and unnamed adult condition) can arise from mutations in transcriptions factors that control pituitary development.
• Though the picture is easier to interpret, important transcription factors for development of somatotropes include: HESX1, LHX4, PROP1, and PIT1.
• Factors important for thyrotrope development include: all those for somatotropes as well as LHX3.
  • Recall that TSH -> T3 -> GH so loss of LHX3 -> loss of thyrotropes -> loss of TSH -> loss of T3 -> decrease of GH
• Mutations of LHX3 and PROP1 have been observed and result in short stature.

GH deficiency treatment

• We used to use GH extracts from human cadavers but that lead to some Crutzfeld-Jacob prion disease infections.
  • Injected
• Now we use recombinant GH.
  • Injectable, expensive

GH pathway deficiencies

• Laron dwarfism results from GH receptor (GHR) defects and results in short stature.
  • Note that the same gene that codes for the GHR also codes for the GH-binding protein that transports GH in the blood.
  • We treat defects in the receptor with IGFs b/c that's the downstream effector.
  • Laron pts have very low levels of cancer and low levels of diabetes.
    • We don't yet know why.

• STAT5b mutations break the GH signaling pathway and result in short stature.
  • Recall that STAT5 is the primary stat used by GH in the JAK-STAT signalling pathway.

• IGF-1 gene mutations cause pre- and post-natal growth failure as well as sensoneural hearing loss and mental retardation.
  • In IGF1 gene mutation disease states, GH levels are consistently elevated without the normal periods of undetectability of GH.
  • Can be treated with IGF1 replacement.

• IGF1R mutations cause pre- and post-natal growth retardation

Roles of prolactin

• There is one prolactin gene in humans.
• Prolactin gene is expressed by the pituitary's lactotropes, by the placenta, and sometimes by the immune system

Is "expressed by the immune system" just refering to the use of AIRE to express most genes in the thyroid?  "PRL is regulated by PIT1, ER, etc in pituitary and other mechanisms in other tissues. Also some specific differences (remember one PRL gene in humans, many PRL-like in some other animals)"

• Rodents have many extra paralogs of the PRL gene.
• Prolactin has a diverse set of roles that have been important to evolution:
  • affects water drive

What is water drive?  "The behavioral drive to seek water environments and in amphibians the drive to mate."

• • affects osmolarity regulation
  • affects lutotropic related regulation in rodents (much like hCG in humans)
• Recall that prolactin, as with its paralog GH, uses a JAK-STAT signaling mechanism.
  • PRL receptors have short and long forms; only the long forms activate the signaling pathway.
  • GH and cytokines also have short and long receptors.

Can short and long receptors heterodimerize?  There is some evidence for this.
If so, what happens then?  Reduced signaling.
What happens when the short receptor binds?  No signaling.
Is this how "one" receptor can control excess and also signal (as with IGFs)?  Prof deferred that topic above.

• Prolactin has many roles in humans:
  • mammary gland development
  • maintenance of lactation
  • lymphocyte regulation

In what sense?

• • osmotic effects on the kidney
  • liver function (details?)
  • affects ovarian regulation and corpus luteum status
  • affects gonadal steroid production
  • affects sexual gratification (orgasm)
  • lots of other stuff, too.

Control of PRL

• The prolactin axis includes the hypothalamus (and its release of many PRL-affecting factors), lactotropes of the anterior pituitary, and target tissues (mammary glands, liver, kidneys, gonads, lymphocytes).
• The hypothalamus generates both anti-PRL and pro-PRL factors.
  • Anti-PRL factors generated by the hypothalamus include dopamine.
  • Pro-PRL factors generated by the hypothalamus include PrRPs (prolactin releasing peptides, TRH, OT, and VIP.
• Lactotropes of the anterior pituitary are stimulated to release PRL by binding of prolacin releasing peptides (PrRPs), thyroid releasing hormone (TRH), oxytocin (OT, from the posterior pituitary), and VIP (from the hypothalamus and the gut).
• Estrogen is also a pro-PRL factor that signals to lactotropes.
  • Estrogen comes from the gonads and fetus.
• Note that prolactin is primarily under inhibitory control by dopamine.
  • Dopamine acts through receptors that inhibit cAMP levels.

Prolactin disorders

• The most common pituitary tumor in humans is a prolactinoma.
  • Excessive amounts of prolactin causes breast development, galactorrhea (unexplained milk secretion), irregular menses, infertility, and impaired sexual function.
  • Tumors of the pituitary can also impinge the optic nerve causing visual damage.
• Treatment for prolacinomas includes removal of the tumor and / or suppression with dopamines like bromocriptine or pergolide or cabergoline (criptines or golines).

Non GH Dwarfism

• A mutation in the PCNT gene (pericentrin) causes primordial dwarfism.
  • Primordial dwarfism is also called MOPD II = microcephalic osteodysplastic primordial dwarfism type II.
• This condition involves a gene that affects the centrosome and chromosome segregation.
• MOPD type II has it's etiology in poor repair, dysregulated cell cycle, and aberrations in chromosome separation.
  • This is especially important in stem cells and results in mitotic arrest, cell death, loss of cellularity, and growth restriction.
• Primordial dwarfism manifests as decreased height and a very small brain yet near-normal intelligence.