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-pituitary-adrenal) 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

• 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– 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