Anterior Pituitary

Outline

• Regulation of hormone secretion: Feedback inhibition

• Properties of hypothalamic releasing hormones

• Anterior pituitary hormones:

– Growth Hormone

– Prolactin

– ACTH

Anterior pituitary Posterior pituitary There are several types of cells in the anterior pituitary.

Each of them secretes a different hormone and affects a different tissue.

MSH

Skin

Pigmentation

or -Hypothalamic releasing or release-inhibiting hormone

Anterior pituitary hormone

Final hormone

Short feedback loop

Long feedback loop

Properties of Hypothalamic Releasing Hormones

• Most are peptides or small proteins

• Secreted in pulses, often diurnal pattern

• Modulate specific GPCR on specific anterior pituitary cells

• Short half life

What do hypothalamic releasing & release-inhibiting hormones look like?

* Most are Peptides or Small Proteins

TRH Glu-His-Pro (3 amino acids)

LHRH Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys(14 amino acids)

Dopamine Derivative of Tyrosine (1 amino acid that has been hydroxylated and decarboxylated)

• Fluctuation of neural activity• Rhythmic release of anterior pituitary hormones• Exhibits pronounced diurnal cycle, with underlying pulsatile pattern

Diurnal (24 hr) secretion of Growth Hormone:

Control of Growth Hormone Secretion

Source: Somatotrophs of anterior pituitary

Actions:

Control: ♦ Stimulated by GHRH, sleep

♦ Inhibited by somatostatin, IGF-1 (negative feedback)

Growth Hormone (GH) Growth Hormone (GH)

12 yr old boy, 6’5”Adult man 12 yr old boy

Excess: Pituitary tumor of somatotroph cells• Gigantism if GH excess occurs early in life (rare)• Acromegaly (excess soft tissue growth) if GH excess

occurs after body stops growingTreatment: tumor removal; somatostatin analog octreotide; dopamine agonist bromocriptine, GH antagonist pegvisomant

Gigantism-characterized by tall stature.Robert Pershing Wadlow (8’11”) and father (5’11”)The tallest man in recorded history.Height due to hypertrophy of the pituitary.

Acromegaly-characterized by enlargement of soft tissues of the extremities (face, hands, feet) and prominent jaw & brow.

Pegvisomant: Growth Hormone Receptor Antagonist to treat Acromegaly

• Growth Hormone Receptor is a tyrosine kinase. • Growth hormone binding to the dimerized growth-

hormone receptor results in a conformational change of the membrane-bound receptor and activation of the downstream signal-transduction pathway via tyrosine phosphorylation

• Pegvisomant is a 191 amino acid modified analog of human GH that acts as a receptor antagonist.

• Binding site 1 of pegvisomant contains eight amino acid substitutions that improve binding of this molecule to the receptor.

• Binding site 2 contains a single amino-acid substitution (Gly120Arg) that blocks the conformational change of the growth-hormone receptor and thereby inhibits downstream signal transduction.

Neggers & van der Lely (2009)

Growth Hormone (GH)

Deficiency: Hypothalamic (GHRH deficiency) and pituitary lesions (tumor, injury, infection, congenital & genetic causes) leading to primary GH deficiency

• dwarfism if occurs early in life (~10% due to pituitary hormonal causes; rest from other causes (e.g. fibroblast growth factor receptor, collagen, etc). Dwarfism due to GH deficiency results in short stature, with proportional limbs & trunk.

• adult hypopituitarism: weakness, fine wrinkling & pale skin, loss of sex drive, genital atrophy, menstrual cycle cessation

Other reasons for decreased growth (i.e. GH is normal)• GH receptor defect in target tissues (Laron Syndrome)• IGF-1 deficiency

Treatment: GH (Somatotropin) and IGF-1 (Mecasermin) replacement

Variations in IGF-1 Control Small Size in Canines

• Researchers found that small dogs carry a sequence variation of the growth gene IGF-1.

• Small, but not large breeds, and small individuals within a breed carry the particular IGF-1 allele.

• The IGF-1 allele was probably inherited from a miniature wolf about 15,000 years ago.

Sutter et al (2007) Science 316, 112-5.

Control of Growth Hormone Secretion

Recombinant IGF-1(Mecasermin)

Pegvisomant(GH antagonist)

-

Bromocriptine(DA agonist)

-

Hormone Excess:• Often due to benign tumor in pituitary or target tissue• Remove tumor• Or treat with inhibitor:

– Analog of hypothalamic release inhibiting hormone (e.g. somatostatin, dopamine)

– Inhibitor of synthetic pathway for final hormone (e.g. for thyroid hormone or cortisol excess)

– Inhibitor or modulator of receptor for final hormone

Hormone Deficiency:• Hypothalamic releasing hormones used diagnostically,

but not therapeutically• Replacement of anterior pituitary hormone (growth

hormone)• Replacement of final hormone (e.g. IGF-1, cortisol,

thyroid hormones)

Some General Principles

Control of Prolactin Secretion

Oxytocin

↑ Milk Production

Prolactin causes feedback inhibition by ↑DA release

-

• Lactotrophs of anterior pituitary

• Promotes growth & function of mammary gland—milk productin• Increased maternal behavior• Decreases LH & FSH release and/or response of ovaries; ↓ovulation;

basis for natural contraceptive while breast feeding

• Predominantly inhibited by hypothalamic dopamine, via D2 receptor• Stimulated by oxytocin, suckling

• Hyperprolactinemia: most common form of pituitary hyperfunction caused by microadenomas of lactotrophs (majority of cases of pituitary tumors

• Dopamine receptor blockers (side effect of some antipsychotic drugs is lactation)

• Dopamine agonist (Bromocryptine) suppresses prolactin secretion & shrinks prolactinomas– Used to ↓ lactation– Treat prolactin-secreting pituitary tumors

• Rare

Source:

Actions:

Control:

Excess:

Deficiency:

Treatment:

Prolactin

Control of Prolactin Secretion

Oxytocin

↑ Milk Production

Bromocryptine(DA agonist)

Stress Regulation of ACTH and Cortisol

ACTH regulates cortisol synthesis, not its release. Why?

ACTH and Cortisol Secretion Exhibit a Daily Cycle

DHEA

Affects kidneys to regulate salt metabolism

↑ catabolic rxns, ↑ metabolic fuels,↑ blood glucose

Source of androgens

Summary

• Hypothalamic releasing hormones are small peptides that are secreted in a diurnal pulsatile rhythm

• Tight control of [hormones] by feedback inhibition

• Growth hormone released in response to GHRH (inhibited by somatostatin); causes release of IGF-1 from liver to stimulate bone & tissue growth

• Prolactin released in response to oxytocin, suckling (inhibited by dopamine); causes milk production

• ACTH released in response to CRH (stimulated by stress); causes cortisol synthesis; increases glucose, metabolic fuels