Anterior Pituitary Gland: Chapter 3

• Anterior Pituitary Gland is the subject of Chapter 3.

Goals and Objectives

• Identify the three families of anterior pituitary hormones including their structural differences.
• Understand the mechanisms regulating anterior pituitary hormone production.
• Describe the actions of tropic hormones on target organs.
• Understand the signal transduction pathways leading to anterior pituitary gland hormone release.
• Diagram the short and long loop negative feedback control of anterior pituitary hormone secretion.
• Understand the effects of anterior pituitary gland diseases.

Hormone Nomenclature

• Releasing hormone stimulates another gland/tissue's chemical messenger secretion, such as GnRH.
• Release-inhibiting hormone inhibits another gland/tissue, such as SRIH.
• Tropic or stimulating hormone stimulates a process/gland for chemical messenger product secretion, such as PRL or TSH.
• "-medin" is used for "mediator", "-liberin" for "liberator", and "-statin" for "stasis" in hormone names.
• Lowercase prefix denotes species: h (human), b (bovine/cow), o (ovine/sheep), t (tilapia/fish); hGH/oPRL examples.
• "r" prefix signifies recombinant protein product, as in rBST for recombinant bovine somatotropin.

Hypophysiotropic Hormones Review

• Thyrotropin-releasing hormone (TRH) originates from the paraventricular nuclei which controls synthesis of thyroid-stimulating hormone (TSH) and prolactin and acts on thyrotrophs.
• Luteinizing hormone-releasing hormone originates from the anterior and medial hypothalamus, acting on gonadotrophs and controlling luteinizing hormone and follicle-stimulating hormone secretion.
• Corticotropin-releasing hormone (CRH) originates from the medial parvicellular portion of the paraventricular nucleus.
• CRH controls adrenocorticotropic hormone secretion which affects corticotrophs.
• Growth hormone-releasing hormone originates from the arcuate nucleus and controls growth hormone secretion by acting on somatotrophs.
• Somatostatin or growth hormone-inhibiting hormone originates from the anterior paraventricular area.
• Somatostatin controls growth hormone secretion, affecting somatotrophs.
• Dopamine originates from the arcuate nucleus which controls prolactin secretion and exerts its effects on lactotrophs.

The Adenohypophysis

• The adenohypophysis has a central role in endocrine regulation via tropic hormone production/release.
• Hypothalamic regulation controls it by hypophysiotropic neuropeptides released in the median eminence.
• Tropic hormones enter systemic circulation and bind target organs which often stimulates the release of a target organ hormone.
• Target organ hormones affect the anterior pituitary function, which is part of a feedback mechanism.

Functional Anatomy

• The anterior lobe of the pituitary (adenohypophysis) has an anterior part (pars anterior), intermediate part (pars intermedia) and Rathke's pouch remnant.

Hypothalamic Factor and Anterior Pituitary Cell Targets

• Lactotrophs produce prolactin in response to dopamine.
• Corticotrophs produce adrenocorticotropic hormone (ACTH), β-LPH, α-MSH, and β-endorphin,in response to CRH.
• Thyrotrophs produce thyroid-stimulating hormone (TSH) in response to TRH.
• Gonadotrophs produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in response to GnRH.
• Somatotrophs produce growth hormone (GH) in response to GHRH.

Regulation

• Hormone levels and negative feedback inhibition regulate hormone production.
• Circadian rhythms affect regulation.
• The nervous system is involved with an internal biologic clock with the suprachiasmatic nucleus of the hypothalamus involving light and dark periods.
• Sleep and circadian rhythm affects pituitary hormone release overall.
• The circadian clock regulates ACTH, cortisol, and melatonin.
• Sleep regulates prolactin, GH, and TSH.

Hormones of the Anterior Pituitary

• Anterior pituitary hormones include glycoproteins, proopiomelanocortin (POMC), growth hormone and prolactin.
• Glycoproteins have a common α-subunit, unique β-subunit and beta subunits confer biological specificity.
• Post-translational cleavage and generates ACTH, β-endorphin, α-, β- and γ-melanocyte stimulating hormones (MSH)
• Growth hormone and prolactin are structurally and genetically similar to human placental lactogen.

Glycoproteins

• Anterior pituitary glycoproteins are thyroid stimulating hormone (TSH), gonadotropins (follicle stimulating hormone (FSH) and luteinizing hormone (LH)) and Human Chorionic Gonadotropin (HCG).

Molecular Evolution of the Vertebrate Pituitary Glycoprotein Hormone (GP) Family

• Glycoprotein hormones have α and β subunits.
• The initial gene duplication created GTH and TSH lineages.
• The second duplication in the GTH gene yielded LH and FSH.

Thyroid Stimulating Hormone

• Glycoprotein synthesized and secreted from thyrotrophs in the anterior pituitary.
• Release happens in response to TRH (thyrotropin-releasing hormone) stimulation coming from the PVN (paraventricular nucleus) of the hypothalamus.
• TRH binds GPCR.
• Binding to GPCR activates PLC.
• Activation of PLC increases phosphoinositide turnover.
• The effects lead to calcium mobilization.
• Calcium mobilization leads to TSH release.
• TSH signaling happens when it binds GPCR in the thyroid.
• Thyroid hormone synthesis and release is increased.
• Its main control is negative feedback inhibition by thyroid hormone.

Gonadotropins: LH and FSH

• Glycoproteins are synthesized and secreted by gonadotrophs in the anterior pituitary.
• Released in response to GnRH stimulation from PVN (paraventricular nucleus) of the hypothalamus.
• GnRH binds GPCR.
• Binding of GnRH activates PLC.
• PLC activation increases phosphoinositide turnover.
• PLC activation leads to calcium mobilization.
• Calcium mobilization increases transcription of FSH and LH.
• The effects include increased release of FSH and LH into circulation.
• GnRH is released in a pulsatile manner.

FSH and LH Signaling

• Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) target ovarian granulosa cells, theca interna cells, testicular Sertoli cells and Leydig cells.
• FSH and LH bind GPCR in ovaries and testes.
• FSH binding increases sex hormone synthesis, spermatogenesis, folliculogenesis and ovulation.
• Positive and negative control via gonadal steroids and peptides main regulation.

Proopiomelanocortin-Derived Hormones

• POMC serves as a precursor of pro-hormones and is produced by corticotrophs.
• Regulated by corticotropin-releasing hormone (CRH) from the hypothalamus.
• Binds to GPCR (mainly CRH-1).
• Binding of CRH to GPCR activates adenylate cyclase.
• Results in increased cAMP levels and leads to POMC synthesis and release.
• POMC is post-translationally cleaved to adrenocorticotropic hormone (ACTH), β-endorphin and melanocyte stimulating hormone.
• POMC-derived peptides bind melanocortin receptors.
• These peptides have diverse functions, including skin and melanin synthesis, thermoregulation, adrenal steroid hormone production, feeding behavior, and appetite regulation.

Adrenocorticotropic Hormone

• Psychological and physical stress stimulate adrenocorticotropic hormone release.
• Adrenocorticotropic hormone or ACTH release follows a pulsatile manner which is highest at 4am, and lowest in the afternoon.
• ACTH binds to the Melanocortin Receptor (MC2R).
• The binding stimulates GPCR.
• GPCR activation activates adenylate cyclase and increases cAMP.
• The results stimulate activated PKA.
• The stimulation prompts production and release of glucocorticoids (cortisol) and mineralocorticoids (aldosterone).
• The main target of ACTH is the adrenal cortex.

Melanocyte Stimulating Hormone

• Melanocyte stimulating hormone is produced in the pars intermedia of the pituitary gland.
• Binds to MC1R in melanocytes, endothelial cells, monocytes, and keratinocytes.
• GPCR activation happens as a result and activates adenylate cyclase.
• Results in cAMP increases and activates PKA.
• Melanin synthesis is increased in melanocytes.

B-Endorphin

• β-Endorphin is an abundant endogenous opioid peptide.
• Functions through opiate receptors resulting in analgesia and behavioral effects.
• β-Endorphin is involved in neuromodulatory effects.
• Neuromodulatory effects include: inhibition of GnRH release; mechanisms involved in alcohol and drug addiction.

Growth Hormone, Insulin Like Growth Factors and Prolactin

• Growth hormone, insulin-like growth factors, and prolactin.

Molecular Evolution of Growth Hormone and Prolactin

• The GH family probably originated from a molecule with a primordial function of growth promotion which underwent subsequent duplications to form SL and PRL in an early stage of gnathostome evolution.
• The disulfide loop near the N-terminal region might be deleted into the evolution of the teleosts.

Growth Hormone

• Growth hormone or GH is a 191 amino peptide hormone (22kDa) which half life of 20 minutes.
• Release happens at the somatotrophs in a pulsatile bursts.
• The hypothalamus and peripheral tissues are signals that stimulate hormones.
• Growth hormone releasing hormone (stimulatory)
• Somatostatin (inhibitory) are signals for the hypothalamus.
• Insulin like growth factor 1 (inhibitory) is a signal from the peripheral tissues.
• Growth hormone is affected by nutrtional, metabolic, age, steriods, adrenal and thyroid hormones and the overall renal and hepatic function.
• Once released, it is bound to growth hormone binding protein.

Growth Hormone Releasing Hormone and Growth Hormone Release

• GHRH stimulates GH release mediated by GPCR binding in anterior pituitary.
• GPCR binding activates adenylate cyclase.
• Increasing cAMP and activating protein kinase A (PKA) increases pituitary specific transcription factor 1 (PIT-1).
• The transcription increase increase GH and GHRH receptor gene transcription

Somatostatin Inhibits Growth Hormone Release

• Somatostatin, synthesized in PVN, AN, and VMN of the hypothalamus, inhibits GH release.
• Somatostatin stimulates protein tyrosine phosphatase which reduces growth.
• Protein tyrosine phosphatase leads to a decrease GH transcription.
• Somatostatin binds to GPCR.
• Binding activation decreases adenylate cyclase activity and calcium (Ca2+) concentrations.
• Somatostatin inhibits action potentials.
• It also binds potassium (K+) channels increasing leads to neurons hyperpolarization for GH release.

Factors Regulating GH Release

• Stimulation of GH release: GHRH, Dopamine, Catecholamines, Excitatory amino acids and Thyroid hormone.
• Inhibition of GH release: Somatostatin, IGF-1, Glucose and fatty acids or FFA

Growth Hormone Receptor

• The growth hormone receptor triggers the JAK-STAT pathway for signal transduction.
• Hormone binding causes receptors to form dimers and triggers the associated JAK tyrosine kinases to bind.
• JAK kinases self-phosphorylate and then receptors self-phosphorylate.
• The phosphorylated JAKs then phosphorylate STAT kinases.
• STAT kinases dimerize, translocate to the nucleus, and activate transcription factors.

Insulin Like Growth Factors

• Insulin Like Growth Factors is a family of insulin-related peptides.
• Some member that belong to it are insulin, relaxin, and IGF-1, and IGF-2.
• IGF is made in the liver in endocrine-hormone form and it is affected by growth, parathyroid hormone and sex hormone.
• Its activity is then regulated by six IGFBPs.

IGF-1 Physiological Effects

• IGF-1 receptor binding regulates somatic growth, cell proliferation, transformation, apoptosis, bone formation and growth promotion.
• Enhances replication of osteoblasts, collagen synthesis, and bone resorption while decreasing collagen degradation.
• IGF-1 increases DNA, RNA, and protein synthesis, inhibits protein degradation, and promotes glucose uptake in muscle.
• Also contributes to neuronal cell survival and myelin synthesis.

Prolactin

• Polypeptide hormone synthesized in lactotrophs.
• Highest when estrogen levels high during pregnancy and during sleep, but lowest during waking hours.
• Regulated by inhibition of hypothalamic dopaminergic neurons and GABA, activating potassium channels and blocking Ca2+ channels.
• Stimulation comes from serotoninergic pathways, opioidergic pathways, GnRH, and galanin.

Dopamine Inhibits Release of Prolactin from Lactotrophs

• Dopamine interacts with GPCRs.
• Binding interaction decreases adenylate cyclase.
• Decreases prolactin release, and decrease in prolactin gene expression happens.

Prolactin Physiologic Effects

• Prolactin's targets are Mammary gland and brain.
• Prolactin stimulates growth and development of mammary glands, maintenance of milk secretion, and milk synthesis.
• Involved in stimulating synthesis of B-casein, Q-lactalbumin, lactose, milk fats, glucose and amino acid uptake.
• Impacts ovary via Progesterone biosynthesis and Luteal cell hypertrophy during pregnancy.
• Causes Inhibition GnRH release, Impacts reproductive behavior and modulates parental behavior in the brain.

Diseases of the Anterior Pituitary

• Absence of GH action gives short stature.
• Cases include: hypopituitary short stature (pituitary dwarfism) and Laron syndrome relating to unresponsiveness of liver to GH.
• Excess GH results in overgrowth.
• Cases include gigantism relating to GH excess during early postnatal life and acromegaly which relates to GH excess during adult life.
• Impaired ability to form bone from cartilage relates to achondroplasia.

Achondroplasia

• Impaired ability to form bone from cartilage (endochondral bone formation).
• Achondroplasia follows autosomal dominant inheritance (homozygous lethal).
• Gain-of-function mutation in fibrobast growth factor receptor-3 (FGFR3) gene on human chromosome 4 result in Achondroplasia (constitutively active receptor).