Transcript Anterior pituitary hormones

Anterior pituitary hormones
• Five secretory cells producing 6 different
hormones
– Cortocotroph
• ACTH
– Gonadotroph
• LH and FSH
– Somatotroph
• GH
– Lactotroph
• Prolactin
– Thyrotroph
• TSH
ACTH
• Part of larger protein
– Pro-opiomelanocortin
• One gene (8kb, three
exons and two introns)
– Codes for one large
protein
• Transcription of gene
– Activated by CRH,
arginine vasopressin,
cytokines
– Inhibted by
glucocorticoids
• Transcription of POMC gene
– CRH type 1 receptor
• Production of cAMP and activation of protein
kinase A pathway
– Activation of CREB transcription factor
• Activation of MAP-Kinase pathway
– Cytokine receptor (LIF)
• Activation of JAK/Stat pathway
– Interaction with CRH signaling pathway
• Pro-opiomelanocortin
– 266 amino acids
– Proteolytically cleaved
to produce
corticotrophic, opioid,
and melanotrophic
peptides
• Secretion of ACTH
– Complex regulation
through HPA
(hypothalamus-pituitaryadrenal) axis
– Circadian and ultradian
rhythm
• Hypothalamic control
(CRH)
– Activity of nuclei
regulated by
glucocorticoids
• Pulse amplitude rather
than frequency determines
circadian rhythm
Regulation of ACTH secretion
• Exercise (short and exhausting)
– Increased secretion of ACTH
• Hypercortisolism in athletes
• Stress
– Increased production of cortisol
• Integration of information received by the CNS
• Constrain the inflammation
Action of ACTH
• Primary function
– Proper maintenance of adrenal gland
– Adrenal steroidogenesis
• Cholesterol transport
• Conversion to pregnenolone
• Inhibited by glucocorticoids
Gonadotropins
• Two hormones from one type of cells
– LH and FSH
• Glycoprotein hormones
– Two subunits
• Alpha
– Universal among all glycoprotein hormones
• Beta
– Hormone specific
• Combination of alpha and beta subunits
– Essential for biological activity
Synthesis of gonadotropins
• Alpha subunit
– Generated from different gene
• Chromosome 6
– Increased synthesis by GnRH and TRH
• Beta subunits
– Determinant of biological activity
• LH beta on chromosome 19
• FSH beta on chromosome 11
• Transcription of LH beta subunit mRNA
– GnRH
– SF-1
– Estrogen
• Transcription of FSH beta
– Role of GnRH and steroids
• Unclear
• Different promoter structure from LH
Regulation of gonadotropin
secretion
• Pulsatile secretion
– Mirror image of GnRH pulses
• Frequency and amplitude
• LH more sensitive to changes in GnRH
• Gonadal steroid hormones
– Testosterone
• Inhibits secretion
• Enhances FSH beta subunit mRNA transcription
– Estrogens
• Dual function (stimulatory/inhibitory)
• Cyclic changes in female during reproductive cycle
• Gonadal peptides
– Inhibins
• Inhibits secretion of FSH
– Activins
• Stimulates FSH secretion and action
– Follistatin
• Inhibits FSH secretion and action
Function of gonadotropins
• Receptors for LH and FSH
– Highly homologous
• 50 % of extracellular domain
• 80 % of transmembrane domain
• Steroidogenesis in male and female
– cAMP production
• Increased cholesterol availability via increased
production of steroidogenic acute regular protein
(StAR)
• Increased enzyme activity
Function of gonadotropins
• Receptors for LH and FSH
• Steroidogenesis in male and female
– cAMP production
• Increased cholesterol availability via increased
production of steroidogenic acute regular protein
(StAR)
• Increased enzyme activity
• Development and function of gonadal cells and
gametes
– FSH
Growth hormone
• Human GH gene
– Located in chromosome 17
• 66 kb in length
• Cluster of genes that encode closely related genes
– GH-V
– Placental lactogen/chorionic somatotropins
– Transcription of GH mRNA
• POUF1 transcription factor
– Pituitary specificity
– Interacts with protein kinase A pathway
• Large polypeptide
hormone
– 191 amino acids
• Four alpha helices looped
together
• Interacts with binding
protein (GHBP)
– Extends half-life of GH
– Found in rodents, rabbits,
and humans
• Extracellular domain of
GH receptor in human and
rabbit
• Product of alternative
transcription in rodents
Regulation of GH secretion
• Major GH pulses (70 % of total daily
output)
– Slow sleep (deep sleep)
– Age-related loss of GH
• Decrease quality of sleep
• Obesity and diabetes
– Decreased GH release
– Nutritional status
• One of the major regulatory factor of GH secretion
• Hormones
– Steroids
• Acute elevation in glucocorticoids (+)
• Chronic elevation in glucocorticoids (-)
• Gonadal steroids (+)
– Thyroid hormones
• Inhibitory
Action of GH
• Growth and metabolism
– Action mediated by IGF-I
• Mediation of growth
• Endocrine IGF-I
– Liver
• Local (autocrine/paracrine) IGF-I
• Gender-specific pattern of GH secretion
– Affects amount of steroidogenic enzymes
• Gender-specific pattern of steroidogenesis
– Gender-specific pattern of liver enzyme
expression
– Gender-specific action of GH
• Mediated by STAT 5b activity
TSH
• Glycoprotein hormone
– Alpha and beta subunits
• Alpha is identical to that of gonadotropins
• Thyrotroph-specific expression
– Different region of gene promoter
– Gene for TSH beta subunit
• Located on chromosome 1
• Transcription regulated by Pit-1
• Post-translational modification
– Glycosylation
• Affects proper molecular folding
• Combination of alpha and beta subunits
• Regulated by TRH (+) and T3 (-)
Secretion of TSH
• Bioactivity of TSH
– Glycosylation
• Clearance rate
• Pulsatile secretion
– Not as pronoused as gonadotropins or GH
• Low variation in concentrations
– Circadian pattern
• Increased secretion during night
– Independent of sleep
• Hormonal regulation
– Major factor of TSH secretion
• Thyroid hormone concentrations
– Extremely important
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•
TRH
Dopamine (-)
Glucocorticoids (-)
SS (-)
Action of TSH
• Thyroid hormone production
– G-protein coupled receptor
• Thyroid cell integrity maintenance
Prolactin
• Structurally similar to
GH
– Common ancestry
• Chromosome 6
• Prolactin gene
expression
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–
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–
Estrogen
Dopamine
TRH
Thyroid hormones
• Exits as monomer or polymer in circulation
– 23 kDa (monomer)
• Most bioactive
– 48-56 kDa (dimer)
– > 100 kDa (polymer)
– Glycosylated
• Less active
• Binds to prolactin binding protein
Regulation of prolactin secretion
• Inhibitory
– Hypothalamic
• Dopamine
• Calcitonin
– Paracrine factors
• Endothelin-1
• TGF-beta 1
• Stimulatory
– Growth factors
• bFGF
• EGF
– Gut hormone
• VIP
– Estrogen
Function of prolactin
• Essential for survival
– Lactation
• Prolactin surge during labor
– Essential for initiation of lactation
• Not required for maintenance of lactation
– Immune function
• Stimulates lymphocyte development
– Reproduction
• Essential for rodents