Hormones and Growth Flashcards
What hormones have the most prominent role in growth?
- growth hormone
- thyroid hormones
- insulin
- androgens
- estrogens
- glucocorticoids
- peptide growth factors
What is the most important hormone in postnatal growth?
• Growth hormone
What types of growth are associated with growth hormone?
- skeletal (linear) growth
- stimulation of soft tissue growth (somatic growth)
- GH can be considered anabolic
Explain how GH affects linear growth? Soft tissue growth?
- linear growth via chondrogenesis.
* soft tissue growth via increasing cell number and cell size.
What is the relationship between HGH and Insulin?
• HGH antagonizes the actions of insulin on muscle and liver.
Growth hormone acts both directly and indirectly. What mediates GH’s effects in indirect stimulation?
• peptides: somatomedins.
How many major forms of HGH are there? What are other forms? (just know the general themes here)
- Two major forms of HGH, one of 22,000 daltons and one of 20,000 daltons
- A 45,000 dalton form (possibly an aggregate) and several biologically active small polypeptides (possibly fragments) are also found in pituitary stores.
- In addition, several large molecules known as “big” growth hormone (49,000 to 70,000 daltons) and “big-big” growth hormone (80,000 and 100,000 daltons) are found in the plasma
What are the most numerous cells in the anterior pituitary?
Where in the anterior pit are they found?
Are they acidophiles or basophiles?
- Somatotrope
- lateral wings (where the lactotrope cells are also found).
- like lactotropes, somatotropes are acidophiles
What are the some effects of growth hormone in terms of… Intracellular Tissue glucose levels mineral balance fat balance
- Increased protein synthesis and amino acid uptake by tissues (promotes positive N2 balance).
- Increased RNA and DNA synthesis.
- Increased connective tissue growth and skeletal growth.
- Increased acid mucopolysaccharide formation in skin and cartilage.
- Hyperglycemia. This is an antiinsulin or diabetogenic action.
- Increased retention of Na+, K+, Cl-, Mg++, PO4-3, and Ca++.
- Increased lipolysis — fat mobilization.
Explain the initial and longer term effects of GH on glucose and fat metabolism. What mediates the initial effects?
- first few minutes following administration ==> insulin-like activities on glucose uptake and on free fatty acid utilization.
- Then changes ==> anti-insulin effects of GH such as increasing plasma glucose levels (hyperglycemia) and increasing circulating FFA.
- The initial effects are now known to be due to somatomedins.
How does removal of the pituitary effect insulin requirements in Type 1 Diabetes?
• reduces insulin requirements
Is HGH available commercially?
- commercially available as a product of recombinant technology.
- Medical community must address ethical use.
Explain the effects on GH production and release…
• Blood sugar
• Amino acids (especially which?)
• Fatty acids
- Decreased blood sugar ==> GHRH ==> GH
- Increased blood sugar inhibits GH
- Increased amino acids (especially arginine) ==> ↑ GH for 2-4 hours after a meal
- High plasma fatty acids inhibits GH
Explain the effects on GH production and release…
• Sleep (what stages do what?)
• When are GH levels highest during the day?
- Deep sleep (stage III and IV) ==> GH release.
- REM (rapid eye movement sleep) DECREASES GH release.
- diurnal variation in GH release with peak levels in the evening and early morning hours.
- GH during sleep is important in children.
Explain the effects on GH production and release…
• Exercise
• Why?
- Exercise ==> ↑ GH in about 70% of cases.
* This is thought to correlate with requirements of FFA utilization for energy.
Explain the effects on GH production and release…
• Hypothalamus via what?
• Brain via what?
- Hypothalamus ==> GHRH
- brain ==> GHRP (growth-hormone releasing peptide) ==> GHRH and DECREASED release of somatostatin.
- GHRP is now thought to be Grelin.
Explain the effects on GH production and release… • Estrogen • Somatostain • Somatomedins • Hypothyroidism
- Estrogen ==> ↑ GH
- Somatostatin ==> ↓ GH
- Somatomedins ==> ↓ GH (via hypothalamus)
- Hypothyroidism ==> ↓ GH
What are somatomedins? Which organ is responsible for plasma levels of somatomedins?
- Somatomedins are IGFs insulin-like growth factors.
- Somatomedins are locally produced growth factors that have their production increased by the action of hGH, and are necessary mediators of many hGH effects on tissues.
- Somatomedins released by the liver are mainly responsible for circulating levels of these peptides.
Why does hypothyroidism ↓ GH?
• inhibitory effects of excessive TRH on somatotropes.
How does one determine if there is a GH deficiency?
- large diurnal fluctuations ==> single determinations of plasma HGH concentrations are of little value
- necessary to evaluate a series of samples throughout a 24-hour period or
- use at least two provocative tests (e.g., arginine administration, insulin-induced hypoglycemia, L-dopa administration, clonidine administration)
- Plasma levels of somatomedin C also provide a good index of HGH release from the pituitary.
What are four “provocative” tests for GH (tests that ↑GH)?
- arginine administration
- insulin-induced hypoglycemia
- L-dopa administration
- clonidine administration
During the life cycle, when do GH levels rise and peak?
- values rise through childhood
- peak during adolescence
- fall to adult levels.
What is usually the cause of GH deficiency?
- A deficiency of HGH is most often associated with deficiencies of other pituitary hormones.
- Or growth hormone deficiency is caused by hypothalamic dysfunction or by a pituitary lesion.
What happens when GH is the only hormone that is deficient?
- pubertal development is delayed
- growth stunted
- dwarfism results.
When must children with GH deficiency be treated?
• before full bone maturation occurs, otherwise HGH has no effect on linear growth.
What are Laron Dwarfism and African Pigmyism?
What are HGH and Somatomedin C levels?
How are they different than GH deficiency?
- stunted growth can result from the failure of tissues to respond to growth hormone.
- HGH levels are high and somatomedin levels are subnormal
- a receptor or post-receptor defect leading to symptoms of severe growth hormone deficiency.
What causes Growth Hormone excess?
• functional tumor of the pituitary.
What happens if HGH hypersecretion occurs before the epiphyseal plates close?
- marked increase in linear growth takes place
* pituitary gigantism.
What happens if HGH hypersecretion occurs after the epiphyseal plates close?
• acromegaly
What is acromegaly?
What are HGH and Somatomedin C levels in giantism and acromegaly?
- connective tissue proliferation
- dermal overgrowth
- enlargement of the extremities.
- In both conditions, plasma HGH and somatomedin C levels are elevated.
What are treatments for giantism and acromegaly?
- microhypophysectomy (removal of the tumor)
- radiation therapy
- drugs such as bromocriptine that inhibit HGH secretion.
What does insulin do (again)?
- hypoglycemic agent
- promotes glucose utilization
- promotes amino acid uptake
- protein synthesis
- RNA synthesis
- DNA synthesis.
What does hyperinsulinism cause? What does Insulin deficiency cause?
- Hyperinsulinism before or after birth ==> excessive growth
* insulin deficiency ==> growth failure (e.g., lepricornism).
What is insulin’s role in growth?
- Has a”permissive” role.
- The growth-promoting effects of excess insulin might arise from its structural similarity to somatomedin C (also known as insulin-like growth factor 1, IGF-1), because it is now known to activate receptors to this substance.
Thyroid hormones (actually T3) play a dual role in stimulating catabolic and anabolic activity. What determines which role T3 will play?
• stage of development and the special functions of the cells on which they act.
When are thyroid hormones most important in brain development?
What is the mediating factor between Thyroid hormone and the brain?
- during the last part of gestation and for several months of postnatal development.
- nerve growth factor (NGF).
What happens to children with hypothyroidism (after early childhood?
• Thyroid hormones are required for normal growth in children and those with untreated hypothyroidism have severely retarded growth.
What are ways that Thyroid hormone modifies growth?
- increase protein and RNA synthesis.
- increases in DNA synthesis during the proliferative stage of cell growth.
- Absence of the hormones results in a proportional decrease in cell number and cell protein in many tissues.
Are the DNA, RNA, and cell proliferation effects of thyroid hormone due to thyroid hormone itself?
What other hormones might play a role?
- these effects may not be direct ones and the hormones could often fulfill a permissive role.
- thyroid hormones and growth hormone are interrelated so that hypothyroidism can result in decreased storage and release of HGH.
- although T4/T3 are themselves incapable of causing the release of somatomedins, they appear to play an important role in priming tissues (e.g., liver) so that optimal release occurs from the action of growth hormone.
What other hormones might play a role?
- these effects may not be direct ones and the hormones could often fulfill a permissive role.
- thyroid hormones and growth hormone are interrelated so that hypothyroidism can result in decreased storage and release of HGH.
- although T4/T3 are themselves incapable of causing the release of somatomedins, they appear to play an important role in priming tissues (e.g., liver) so that optimal release occurs from the action of growth hormone.
• Both gonadal and adrenal androgens play principal roles in regulating growth.
• Both gonadal and adrenal androgens play principal roles in regulating growth.
How do gonadal and adrenal androgens affect N2 balance?
• These hormones promote protein synthesis and hence N2 retention.
Explain the roles of androgens in growth spurts in females and males. Do androgens function independently?
- Androgens ==> adolescent growth spurt in males and females
- androgenation is associated with muscular growth.
- No growth hormone, androgens ==> no effect on growth
- Androgens are synergistic with HGH ==> linear growth.
- However, they also ==> closure of the epiphyseal plates and growth cessation.
Do androgens play a role in somatic growth?
• Androgens may also play a role in somatic growth by promoting the growth hormone release of somatomedins.
What is the influence of estrogens on growth?
What other hormone is the effect on estrogen mediated through?
How does early puberty in women affect linear growth?
- estrogens seem to exhibit inhibitory effects on growth.
- Like androgens, they are important in promoting closure of the epiphyseal plates.
- Some inhibitory effects of estrogens on growth may be mediated by their reduction of somatomedin release in response to growth hormone.
- Precocious puberty can lead to stunted growth.
Explain when glucocorticoids have catabolic vs anabolic effects.
- when present in high amounts ==> general catabolic effect on peripheral growth.
- Cortisol ==> some anabolic effects on liver, and is required as a “permissive” agent in a number of processes.
What is the relationship between glucocorticoids and growth hormone?
- DOES NOT reduce the GH-stimulated release of somatomedins
* DOES interfere with the action of somatomedin C on cartilage.
Although generally catabolic, under what conditions can corticosteroids become anabolic?
- adrenal virilizing hyperplasia (congenital adrenal hyperplasia?) ==> glucocorticoids can be successfully used to promote growth.
- Also glucocorticoids ==> protein synthesis-enhancing when given with certain tissue growth factors.
Somatomedins (Insulin-like Growth Factors). These are peptides that are currently believed to mediate many of the growth-promoting actions of growth hormone.
Somatomedins (Insulin-like Growth Factors). These are peptides that are currently believed to mediate many of the growth-promoting actions of growth hormone.
Somatomedin C = IGF-1
IGF-1 and IGF-2 = somatomedins
Somatomedin C = IGF-1
IGF-1 and IGF-2 = somatomedins
Explain the structural similarities between IGF-1 and proinsulin.
- IGF-1 and proinsulin can be divided into three domains (A, B and C).
- About 50% of the structure in the A and B domains is identical with proinsulin, but the C domain has no resemblance to the C-peptide of proinsulin.
- Unlike proinsulin, the structure of IGF-1 remains intact.
What causes the release of IGF-1 and IGF-2?
- Growth Hormone ==> liver releases IGF-1 and IGF-2 (determines plasma levels)
- Growth Hormone ==> many tissues locally produce autocrine and paracrine IGF-1 and IGF-2
Why is monitoring serum levels of somatomedin important?
Describe serum levels of Somatomedin C during…
Lifecycle
Hypopituitary dwarfs
Acromegaly
- Provides index of growth hormone activity on target tissues.
- Rise prepubertal children, peak during puberty, and fall in adulthood.
- low in hypopituitary dwarfs
- elevated in acromegaly.
What are treatments for hypopituitarism?
- Treatment with HGH restores somatomedin levels seen in hypopituitarism
- somatomedin C has been used successfully to treat some hypopituitary growth problems.
How are somatomedins transported in the blood? What are plasma levels of IGF-1 and IGF-2 in adults?
- 85% are bound to IGFBPs produced by the liver and by G.H. target tissues.
- In normal adults, plasma levels of IGF-1 and IGF-2 average about 200 and 650 ng/ml, respectively.
Describe the IGF-1 receptor and the level of cross activity between IGF-1 and Insulin.
- IGF-1 receptor (type 1) on cell membranes and has α- and β-subunits linked by disulphide bonds.
- Insulin binds to IGf-1 receptor with low affinity
- IGF-1 binds to insulin receptor with low affinity
What does IGF-1 do?
- stimulates DNA synthesis and cell division.
- promotes sulphate incorporation into proteoglycans of cartilage and connective tissue
- differentiation of myoblasts into myotubules in muscle
- myoblast proliferation.
- Exhibits insulin-like actions (possibly by combining with insulin receptors) and in adipose tissue can stimulate glucose oxidation and the synthesis of lipids.
Describe the IGF-2 receptor and the level of cross activity between IGF-2 and Insulin.
- IGF-2 receptor
- Insulin shows no binding affinity of this receptor.
- IGF-2 shows a higher binding affinity than IGF-1 for insulin receptors and therefore exhibits more potent insulin-like actions on muscle and adipose tissues.
What does IGF-2 do?
- promotes cell division
- RNA synthesis
- protein synthesis
- The insulin-like effects of the somatomedins are not believed to be of physiological significance.
What is the basic structure of Platelet-Derived Growth Factor (PDGF)?
• Peptide with alpha and beta subunits connected by disulphide bridge.
What does PDGF do?
- promotes growth of fibroblasts and smooth muscle cells by acting as a “competence factor” (it initiates cellular processes required for mitosis).
- Once cells become competent they can undergo mitosis in response to appropriate stimuli, such as that from IGF-1 or EGF (see below).
What happens to cell 1 if the cytosol from PDGF-stimulated cell 2 is transferred to cell 1?
• Cytosol from PDGF-stimulated cells is able to transfer this state of competence to cells that have not been exposed to PDGF.
The receptor to PDGF is a 180,000 dalton membrane protein.
The receptor to PDGF is a 180,000 dalton membrane protein.
What is the cell signaling mechanism of PDGF?
• ==> tyrosine kinase activity ==> PIP2 ==> IP3 and DAG.
What illness is PDGF related to?
• atherosclerosis.
What is Fibroblast Growth Factors?
- peptide, with molecular weight of 13,000 daltons that has been isolated from pituitary and brain.
- it seems to stimulate cell proliferation by acting as a competence factor.
What is Epithelial Growth Factor?
• This active peptide has a paracrine or autocrine role and stimulates cell proliferation not only in epithelial cells (from which the name derives) but also in cells of mesodermal origin.
Describe the production of Epithelial Growth Factor? (I doubt we need to know this)
• 1200 amino acid precursor ==> two molecules of EGF and two molecules of a binding subunit ==> The binding subunit serves to cleave the precursor to form an active peptide ==> 53 amino acid peptide that has 3-disulphide bridges
Describe the EGF receptor.
- Transmembrane glycoprotein
- The intracellular portion is a tyrosine kinase ==> autophosphorylation upon activation
- Following EGF binding the entire hormone-receptor complex becomes internalized
What is Erythropoietin?
- sialoprotein produced by the kidneys.
- stimulates the proliferation of primitive hematopoietic stem cells and promotes conversion of proerythrocytes to erythrocytes.
- stimulated by hypoxia.
What is Nerve Growth Factor (NGF)? What are its functions in fetal and postnatal life?
- produced by a number of tissues
- IS a differentiating factor
- IS NOT a mitogenic factor
- Fetal ==> growth of ganglia
- postnatal ==> maintain the sympathetic nervous system.
When is NGF production stimulated?
• by androgens and thyroid hormones.
What is the structure of NGF? What is its active subunit?
- 118 amino acids that is derived from a 130,000 dalton dimer comprised of three subunits.
- The β-subunit is the biologically active form.
What are Interleukins?
• peptide products of lymphocytes.
What does IL-1 do?
- stimulates thymocyte mitosis
- growth of activated T-lymphocytes
- T-lymphocyte reacivity.
What initiates IL-2 production? What cells produce IL-2?
- single-chain product of monocyte macrophages
* production is stimulated by endotoxin or by exposing macrophages to antigen.
What cells produce IL-2? What initiates IL-2 production?
- produced by lymphoid and spleen cells
* formation is stimulated by IL-1
What is IL-3?
IL-3 is a 28,000 dalton glycoprotein.
What do IL-2 and IL-3 do?
Both IL-2 and IL-3 stimulate growth and differentiation of lymphocytes.
Other Peptide Growth Factors. There is, additionally, a long list of tissue-specific growth peptides that include the Transforming Growth Factors (TGF∂, TGFß), Thymic Peptides (Thymosin, Thymopoietin), and the Colony Stimulating Factors (CSF-G, CSF-M).
Other Peptide Growth Factors. There is, additionally, a long list of tissue-specific growth peptides that include the Transforming Growth Factors (TGF∂, TGFß), Thymic Peptides (Thymosin, Thymopoietin), and the Colony Stimulating Factors (CSF-G, CSF-M).
Describe Growth Hormones role in bone growth.
- widens epiphyseal plate and ↑ growth of cartilage (chondrogenesis)
- incorporation of sulphate into chondriotin sulphate and of proline into collagen.
- cartilage cells proliferate
- ↑ osteocyte activity ==>ossification, but by far its major influence is on cartilage.
Is growth hormone the main stimulator or is there an intermediary in bone growth?
• Most of this activity has been attributed to somatomedins, but it is becoming clear that HGH has some direct actions and synergistic ones as well.
Explain the role of thyroid hormones in bone growth.
- stimulate cartilage breakdown and bone deposition
* under normal conditions they promote bone maturation, or osteogenesis, and growth.
Do thyroid hormones act alone in bone growth?
• T4/T3 work synergistically with HGH and somatomedins
Insulin is necessary for normal bone growth to occur, but its role is currently unknown.
Insulin is necessary for normal bone growth to occur, but its role is currently unknown.
What is the role of glucocorticoids on bone growth?
- direct action ==> inhibitory to growth.
- promote osteoporosis ==> decreased bone formation and increased bone resorption.
- cortisol may be important for bone modelling during growth and bone repair.
How do glucocorticoids inhibit bone growth?
• directly inhibit the actions of somatomedins on bone.
The calcium-regulating hormones such as PTH, calcitonin, and dihydroxyvitamin D3, all play important roles in the formation of bone and its modelling during growth.
The calcium-regulating hormones such as PTH, calcitonin, and dihydroxyvitamin D3, all play important roles in the formation of bone and its modelling during growth.
Oncogenes and Growth Factors. Oncogenes are genes expressed when normal cells undergo transformation to cancer cells. Some are of viral origin while other represent normally suppressed genes that become translocated to promotor regions. The products of many oncogenes are now known to be related to recognized growth factors, to growth factor receptors, or to proteins responsible for the intracellular action of growth factors. For example, one oncogene encodes a nuclear protein similar to the receptor for thyroid hormone (T3), while another encodes the intracellular portion of the EGF receptor (tyrosine kinase).
Oncogenes and Growth Factors. Oncogenes are genes expressed when normal cells undergo transformation to cancer cells. Some are of viral origin while other represent normally suppressed genes that become translocated to promotor regions. The products of many oncogenes are now known to be related to recognized growth factors, to growth factor receptors, or to proteins responsible for the intracellular action of growth factors. For example, one oncogene encodes a nuclear protein similar to the receptor for thyroid hormone (T3), while another encodes the intracellular portion of the EGF receptor (tyrosine kinase).
