ANTERIO PITUITARY

Learning Objectives• Describe pituitary gland structure & its relationship to

function• Define anterior pituitary cell types & hormones

secreted• Discuss effects, regulation, mechanism of secretion of

growth hormone• Describe conditions due to abnormal pituitary

function & GH secretion and their treatment

*Pars intermedia – no BV; divides posterior to anterior*Rathke’s pouch – origin of anterior pituitary*Neural crest – origin of posterior pituitary

Cells and Hormones (see last page for table)

Hypothalamic – Pituitary Hormone Axis

CASE Patient is a 50-year-old man, with identical twin

o Visual-field impairment, headache, feet enlargement, increased sweating, joint stiffness

Laboratory Result:o Serum IGF-I = 56.5 nmol/L (mean for

age = 17 nmol/L)o Oral glucose tolerance test (OGT) = 5

mU/L (Normal: <2 mU/L)

QUESTIONS: What are the possible causes of this condition? How would you test for them? What is the relevance of the signs and

symptoms to the patient & the condition? What is the relevance of the tests requested to

physiological events? (Describe the expected normal physiological response.)

What is the diagnosis and how would you treat it?

Growth Hormone (Somatotropin)- Causes growth of all or most body tissues

o Prerequisite: Sufficient insulin activity & CHO- Stimulates increased:

o Mitosiso Cell size – hypertrphy – inc cell sizeo Cell number - hyperplasia

- Promotes differentiation of specific cell types (e.g., bone growth cells)

- Single chain; 191 AA residues- Pulsatile secretion – heart beat like secretion- Relatively low during the day

- ↑s during first 2 hours of deep sleep- Regular nocturnal peak: 1 hour after Stage 3 or 4

deep sleep onset- Preceded by nocturnal plasma GHRH peak

- Biological t½ = 20 mins - Serum GH level varies widely- GH secretion in women > men (highest before

ovulation- Rate: highest in late puberty, neonate; lowest in

older/obese adults, hypothyroidism, Type 2 DM- Average plasma concentration

- 5-20 years old: 6 ng/ml- 20-40 years old: 3 ng/ml- 40-70 years old: 1.6 ng/mL

Pattern of GH Secretion• Pre-puberty

- Stabilization of 24-hour pulsatile GH secretion

rates (200-600 μg/day)- Approximate those in post-pubertal young adults

• Puberty- 1.5-3-fold ↑ pulsatile GH secretion - With proportionate ↑ in plasma insulin-like growth

factor-I (IGF-I)- Physiological GH hypersecretion driven by onset of

↑ sex-steroid hormones- Correlate with rate of ↑ in height

- GHRH response: tall adults > ave height- Final height (FH) may partly be determined by

inherent GH secretory capacity- In normal children with idiopathic short stature -

GH treatment significantly ↑ FH in a dose-dependent manner - Mean gain = 1.3 SDS (8 cm) and a broad

range of response from no gain to 3 SDS

compared to a mean gain of 0.2 SDS in the untreated controls. (Albertsson-Wikland, 2008)

• Adulthood- Starting 18-25 y/o GH secretion ↓s up to pre-

pubertal level (<25-50% of mid- to late-pubertal levels)

- Exponential decline (t½ = 7 yrs) of 24-hr mean serum [GH]

- By 12% per decade after middle age- Despite adult level sex steroid hormones- With gradual ↓ in IGF-I- Unknown mechanism (genetically programmed)

• Aging- ↓ GH secretion - Correlated to

- ↑ total body & visceral fat %- Muscle wasting- ↓ physical fitness - ↓ [testosterone ] or menopause

- Partly responsible for: - ↓ lean body mass - ↓ protein synthesis - ↓ metabolic rate - ↑ adipose tissue

- Evidence: (Giustina & Veldhuis, 2008)- Excessive somatostatin release - ↓/deficiency GHRH secretion in aging human

Growth hormone is ao Protein anabolic hormoneo Lipolytic hormoneo Diabetogenic hormone – increase blood glucoseo Growth promoter hormone

*Linear bone growth does not happen when the epiphyseal plates close (epiphyseal closure), only grows wider

Effect on Protein Metabolism• Anabolic

- Stimulates AA uptake & CHON deposition- ↓ protein breakdown- Effect begins in minutes- Stimulates collagen synthesis

• Produces: - (+) Nitrogen balance- ↓ BUN & AA (decreased renal function)- ↑ excretion of AA 4-hydroxyproline

Effect on Electrolyte Metabolism• ↑ GI absorption of Ca2+

• ↓ Na+ and K+ excretion – most probably due to diversion from kidneys to growing tissues

• (+) P balance; ↑ plasma P

Effect on Fat Metabolism• Lipolytic• ↑ FA mobilization & use for energy

• ↑ FA to Acetyl CoA conversion

• ↑ FFA may contribute to GH-induced insulin resistance

• Effect begins in hours

Summary of GH Actions• ↑ protein synthesis rate in most body cells

• ↓ Adiposity:

• ↑ lipolysis / FA mobilization from adipose tissue

• ↑ FA in blood

• ↑ FA use as fuel

• ↓ glucose uptake

• ↑ linear growth

• ↑ organ size & function

• ↑lean body mass

Tissue/Organ Effect Overall Effect

Adipose Tissue ↓ glucose uptake(hyperglycemic hormone)↑ lipolysis

↓ adiposity

Liver ↑ RNA synthesis↑ protein synthesis↑ gluconeogenesis↑ IGF/somatomedin

Facilitation of GH effect on:organs (size & function)muscle (body mass)chondrocytes (linear growth)

Muscle ↓ glucose uptake↑ AA uptake↑ protein synthesis

↑ lean body mass

Somatomedins (Insulin-like Growth Factors I & II)• Mediate action of GH on chondrocytes & linear

growth, protein metabolism & organ size, and lean body mass

• Polypeptide growth factors• Secreted by liver & other tissues• Types:

• IGF-I (Somatomedin C) - skeletal & cartilage growth

- Increases in parallel with GH- Both GH- & insulin-dependent- Lower in old age: angina pectoris, myocardial

infarction, atherosclerosis- Earlier death in aging men with low levels

• IGF-II – fetal growth regulator; increased by PRL• GH & somatomedins can act both in cooperation and

independently to stimulate pathways that lead to growth

Excessive Growth Hormone• Gigantism

• Excessive activation of somatotropes or (+) acidophilic pituitary tumors

• Excessive GH before puberty/ fusion of epiphyses with shaft

• Rapid growth of all body tissues• Hyperglycemia

- Eventual degeneration of overactive pancreas- DM development

• Panhypopituitarism in most, if untreated:- Death by early adulthood

• Management:- microsurgical tumor removal - Pituitary gland irradiation

Tissue/Organ Effect Overall Effect

Bone, heart, lung, kidney,pancreas, intestines, glands,skin, connective tissue

↑ protein synthesis↑ RNA & DNA synthesis↑ cell size and number

↑ organ size& function

Chondrocytes ↑ AA uptake↑ protein synthesis↑ RNA & DNA synthesis↑ collagen & chondroitin sulfate↑ cell size & number

↑ linear growth

• Acromegaly• Excessive GH after puberty / epiphyseal fusion with

shaft• Thicker & enlarged bones

- Hands, feet- Membranous bones (cranium, nose, forehead,

supraorbital ridge, mandible, vertebrae)

• Continued growth of soft tissues (tongue, liver, kidneys)

• Prognathism, huge brows, huge tongue, large hands with spade fingers

• Deep guttural voice• Oily skin • Joint deformities or frank arthritis• Secondary DM• Sleep apnea• Kyphosis• ↑ coronary risk:

- Poor glucose tolerance- Hypertension - Lipid problems

• Life shorter by average 10 years (vs. normal person)

• Normalized by treatment of adenoma (surgery, octreotide, radiation)

CASEPatient is a 50-year-old man, with identical twinVisual-field impairment, headache, feet enlargement, increased sweating, joint stiffnessDiagnosed with obstructive sleep apnea few months earlier Coarse facial featuresAcral enlargement (nose & lips)Facial soft tissue enlargement (skin folds & infraorbital puffiness)

Laboratory ResultSerum IGF-I = 56.5 nmol/L (mean for age = 17 nmol/L)Oral glucose tolerance test (OGT) = 5 mU/L (Normal: <2 mU/L)MRI: pituitary adenoma with extrasellar extension

QUESTIONS:What are the possible causes of this condition?How would you test for them?

What is the relevance of the signs and symptoms to the patient & the condition?What is the relevance of the tests requested to physiological events? (Describe the expected normal physiological response.)What is the diagnosis and how would you treat it?

Growth Hormone DeficiencyIf adult onset – typically with other AP hormone deficienciesIf childhood onset – dwarfism

• Panhypopituitarism• ↓ secretion of all AP hormones

• May be congenital, slowly or suddenly develop• Causes:

- Pituitary tumor- Suprasellar cysts- Enlarged Rathke’s pouch remnants- Pituitary infarction & necrosis from post-partum

hemorrhage (Sheehan syndrome – does not produce milk in mothers)

• (Pituitary) Dwarfism• Causes:o Panhypopituitarism during childhood

Hypothalamic dysfunction, GHRH deficiency

Pituitary destruction, GH deficiencyo Isolated GH deficiency

Biologically incompetent GH

GH receptor deficiencyo Unresponsive GH receptor (Laron dwarf/ GH

insensitivity)• Hereditary inability to form somatomedin C (IGF-I)

(African pygmy; Levi-Lorain dwarf)• Manifestations:

- Proportional body parts- Short stature- Delayed skeletal maturation- Greatly ↓ development rate- Does not go through puberty- Insufficient gonadotropic hormones for sexual

maturation- If only GH deficient (1/3) → mature sexually &

reproduce

• Panhypopituitarism in Adult• Causes:

- Pituitary destruction - Tumors: Pituitary adenoma, craniopharyngioma,

chromophobe tumors- Surgery, radiation, trauma

- Sheehan’s syndrome- Empty sella syndrome – very small non-

functioning pituitary gland- Stroke- Infectious meningitis (e.g., TB meningitis)

- Vascular problems (e.g., cavernous sinus

thrombosis, sarcoidosis)- Post-surgical cure of acromegaly

• Manifestation:- Hypothyroidism (e.g., lethargy)- Depressed glucocorticoid production by adrenals

(e.g., weight gain)- Suppressed gonadotropic hormone secretion

(e.g., lost sexual function)

• Most signs & symptoms treatable by adrenocortical & thyroid hormones

Medical Uses of Human Growth Hormone• Dwarfism & replacement therapy in growth-deficient

children- Human GH synthesized by E. coli- if purely GH deficiency → completely treatable if

given early • Turner's syndrome

- 2nd X chromosome in females either absent or

deformed → growth & development problems• Renal insufficiency (kidney failure) • HIV - to treat muscle wasting

- Prevents HIV wasting syndrome• Anti-aging:

- Increased protein deposition, esp. in muscles- ↓ fat deposits- Feeling of invigoration of energy- GH + exercise: ↑ type II muscle fibers in elderly

• Physical performance enhancer in sports- Used for perceived anabolic effects on muscle

growth & recovery (e.g., in weight lifting, body building, football, etc.)

- Combined with anabolic steroids, erythropoietin- Studies: no ↑ muscle size or strength after hGH

injection

Cells and Hormones

Cell Type Hormone Product Stain Affinity Hypothalamic Hormone Control

Target Peripheral Hormone Involved

Corticotrope10-20%

Adrenocortico-tropic hormone (ACTH)

Basophilic CRH Adrenal, Adipose Cortisol

Somatotrope30-50%

Growth hormone (GH)/ Somatotropin

Acidophilic GHRH, GHIH (somatostatin)

AllTissuesLiver(major)

Insulin-like growth factor-I (IGF-I)

Gonadotrope10-15%

Follicle –stimulating hormone (FSH)Luteinizing hormone (LH)

Basophilic GnRH Gonads EstrogenProgesteroneTestosteroneInhibin

Lactotrope (Mammotrope)10-30%

Prolactin (PRL) Acidophilic PIH Breast, Gonads None

Thyrotrope3-5%

Thyroid-stimulating hormone (TSH)

Basophilic TRH Thyroid gland Triiodo-thyronine