The Anterior Pituitary

Pituitary and Hypothalamus

The pituitary gland releases hormones that stimulate glands (trophic) or other organs involved in homeostasis

the anterior pituitary (adenohypophysis) arises from Rathke’s Pouch (somatic ectoderm)
the posterior pituitary (neurohypophysis) is a direct extension of hypothalamic neurons (neural ectoderm)
the hypothalamus directly controls both parts of the pituitary

The hypothalamus itself makes up the floor and walls of the 3^rd ventricle of the brain, above the diencephalon

thickened portion of the ventricular floor leads to the Tubular Infundibular Stalk (TIS); pituitary is suspended from this

Two Types of Hypothalamic Neurons that Involve the Pituitary:

(1) Magnocellular (large) Neurons – produce hormones to be released from the posterior pituitary

these neurons are actually contiguous with the posterior pituitary via the hypothalamic-hypophyseal nerve tract

they produce 2 peptide neurohormones – supraoptic nucleus Þ vasopressin; paraventricular nucleus Þ oxytocin

following production, hormones are transported in vesicles down axons of the TIS to the posterior pituitary

an action potential causes exocytosis, releasing hormone into the capillary plexus of the inferior hypophyseal artery

regulation occurs via neuronal feedback inhibition from target organs (kidney, breast, uterus)

(2) Parvicellular (small) Neurons – produce hypothalamic releasing hormones that control the anterior pituitary

secrete releasing hormones into the primary capillary plexus of the superior hypophysial artery (in median eminence at the base of the hypothalamus)

long hypophyseal portal veins carry releasing hormones to the secondary capillary plexus that surrounds ant. pituitary cells
the releasing hormones bind receptors on anterior pituitary cells; these then release hormone into systemic circulation
regulation occurs both at the hypothalamus and the anterior pituitary, via negative feedback by target organ products

Anterior Pituitary Cells – 5 cell types that release 6 hormones

(1) Corticotrophs – primarily secrete ACTH, which stimulates steroid production in adrenal cortex

Activating Hormone – corticotrophin releasing hormone (CRH) from parvicellular neurons

CRH receptor is coupled to Ga _S Þ stimulates production of pre-prohormone proopiomelanocortin

opio=endorphine; melano=MSH; cortin=ACTH

Action on Target Organ – proopiomelanocortin produces two substances that prepare body for stress and pain:

(a) b-LPH – has a processing site that generates endorphin (an endogenous opiate ligand) Þ analgesia

(b) Adrenocorticotropic Hormone (ACTH) –binds Ga _S-coupled receptors in adrenal cortex Þ steroid hormones

zona fasciculata – produce glucocorticoids (cortisol) – gluconeogenesis from amino acids (opposes insulin), stress regulation, water balance, smooth muscle tone

zona glomerulosa – produce mineralocorticoids (aldosterone) – Ý kidney retention of Na⁺⁺ to Ý blood volume

NOTE: renin/angiotensin system and direct negative feedback by ANF are probably more important than ACTH for aldosterone metabolism

(2) Thyrotrophs – release TSH, which activates thyroid gland activity

Activating Hormone – thyrotrophin releasing hormone (TRH) from parvicellular neurons

TRH receptor is coupled to Ga _S Þ production of thyroid stimulating hormone (TSH)

Action on Target Organ – TSH stimulates formation and secretion of T₃ and T₄ from thyroid follicle

T₃ and T₄ maintain basal metabolic rate and mediate maturation of the nervous, skeletal and reproductive systems

(3) Gonadotrophs – release LH and FSH, which have various effects on the gonads

Activating Hormone – Gonadotrophin Releasing Hormone (GnRH) from parvicellular neurons

GnRH receptor is coupled to Ga _S Þ production of luteinizing hormone (LH) and follicle stimulating hormone (FSH)

GnRH has a very short half life relative to other releasing hormones; it is released in pulsatile manner (m sec. injections)

non-pulsatile release will result in down-regulation of the receptor (due to its removal or uncoupling)

LH and FSH are also released in a pulsatile manner, with the same consequence for their receptors in gonads

Action on Target Organ – both hormones have many effects:

In the female – LH binds Ga _S-coupled receptors on thecal cells in the ovary – this stimulates testosterone production

FSH binds Ga _S-coupled receptors on granulosa cells – causes cell enlargement and several other changes:

stimulates follicle development

Ý expression of aromatase, which produces estrogen from testosterone that diffuses in from thecal cells

Ý expression of LH receptors, which assist in regulation of estrogen development

LH stimulates rupture of follicle Þ ovulation Þ formation of corpus luteum Þ progesterone (helps maintain pregnancy)

In the male – LH binds Ga _S-coupled receptors on Leydig cells in the testes – this stimulates testosterone production

FSH binds Ga _S-coupled receptors on Sertoli cells – this causes:

promotion of gametogenesis (in the presence of LH)

Ý synthesis of ABP (androgen binding glycoprotein) – buffers testosterone conc., critical for maturing sperm

aromatase is located in skin and adipose and provides a source of estrogen for males

Estrogen – Ca⁺⁺ homeostasis, fat metabolism and distribution, puberty initiation, pituitary hormone secretion, liver proteins

Testosterone – bone maturation, appetite, RBC production, water/electrolyte metabolism

(3) Lactotrophs (mammotrophs) – secretes PRL, which stimulates lactation

Activating Hormone – dopamine from parvicellular neurons

dopamine gives rise to a tonic negative inhibition of prolactin (PRL) secretion (because PRL secretion is always ON)

Action on Target Organ – PRL binds a receptor tyrosine kinase coupled to a JAK/STAT signaling pathway

In the female:

stimulates mammary gland alveoli formation during early pregnancy(along with estrogen, progesterone, cortisol, and GH)
after delivery, estrogen and progesterone levels drop, removing their inhibitory effect on lactation

In the male:

has unknown function; possibly interacts with immune system

(4) Somatotrophs – secrete GH, which stimulates growth in a variety of tissues

Activating Hormone – Growth Hormone Releasing Hormone (GHRH) from parvicellular neurons

GHRH receptor is coupled to Ga _S Þ stimulates release of Growth Hormone (GH)

GH has some homology with PRL and can cross-react with PRL receptors at very high GH levels Þ Galactorrhea

Action on Target Organs

Direct Action:

Bone – epiphyseal plate closure

Adipose tissue – ß glucose uptake; Ý lipolysis; ß fat

Muscle – ß glucose uptake; Ý a.a. uptake; Ý protein synthesis Þ Ý lean body mass

Liver – Ý gluconeogenisis; Ý RNA and protein synthesis; ß glucose uptake Þ antagonizes effects of insulin

Indirect Action:

Production of somatomedins (insulin-like growth factors, IGF) in the liver – the most significant action of GH!!!

somatomedins Ý long bone linear growth and Ý protein synthesis in many tissues (heart, kidney, pancreas, intestine)

somatomedins can also bind insulin receptors (and vice versa) – clinical significance:

fetus born to diabetic mother makes insulin which binds to somatomedin receptors Þ Ý Ý soft tissue

tumors can make somatomedin that binds to insulin receptors Þ hypoglycemia

GH is diabetogenic because it opposes insulin; greatly increases serum glucose levels

Hormone Structure

TSH, LH, FSH, and HCG (human chorionic gonadotrophin) are all part of the same unique glycoprotein family.

Each is made from 2 genes on separate chromosomes that generate 2 subunits:

Common a subunit – common to all 4 glycoproteins; necessary for biological activity

b subunit – unique to each hormone; responsible for that hormone’s effect

The subunits are non-covalently bonded and have a high K_d (i.e., they are not very stable and dissociate rapidly)

Pituitary Ontogeny

During development of the anterior pituitary, the common a subunit (see Hormone Structure above) appears first

Some cells then develop the cAMP-dependent transcription factor Pit-1, and others do not:

Pit-1 Dependent Lineage – somatotrophs, lactotrophs, some thyrotrophs (in caudomedial region)

Pit-1 Indepenent Lineage – gonadotrophs, some thyrotrophs (in rostral tip region), corticotrophs

A mutation in Pit-1 will result in Pan-hypopituitaryism that involves dysfunction of a subset of pituitary cells

this will lead to a clinical syndrome that results in no lactation (no PRL), poor growth (no GH), and cretinism (low TSH)
the Pit-1 independent cells will not be affected – normal gonads, normal adrenal cortex