6) Anterior Pituitary Flashcards
How is the structure of anterior pituitary hormones similar?
They are all peptide hormones of varying lengths
Which anterior pituitary hormones have cAMP as the dominant second messenger system?
- ACTH
- LH
- FSH
- TSH
Which anterior pituitary hormones have STAT as the dominant second messenger system?
- GH
- Prolactin
What creates the shorter form of GH? How does it differ from the major form?
- Arises from proteolytic cleavage
- Possesses different biological activities (variants in tissue responsiveness)
How does the degree of glycosylation affect GH variants?
Affects their bioactivity, the strength of their signal, and the biological half-life
Human GH was used as a treatment for which illness? What problem occurred?
- Human GH acquired from cadavers was used to treat pituitary dwarfism
- Problems with prion contamination (Jacob Kreutzfeld disease)
What stimuli causes the release of GH?
- Deep sleep, exercise, stress
- Decrease in glucose
- Increase in amino acids
- Decrease in fatty acids
What hormone inhibits the release of GH from the anterior pituitary? What hormone stimulates the release of GH from the anterior pituitary?
- GHIH (somatostatin) inhibits
- GHRH stimulates
What are the metabolic actions of GH that are unrelated to growth?
- Increase in fat breakdown
- Decrease in glucose uptake by muscles
What mediates the growth-promoting actions of GH? What are they produced by?
- Somatomedins (IGFs)
- Produced by the liver
What are the growth-promoting actions of GH?
- Increase in cellular division
- Increase in protein synthesis (decrease in blood amino acids)
- Increase in bone growth
What are the direct actions of GH? (2)
- Mobilization of energy (anti-insulin like effects)
- Promotion of cell differentiation
What is the indirect action of GH?
- Induction of IGF-1 that promotes cell division and has insulin-like effects
- Promotes growth and endocrine effects
What are the direct anti-insulin like effects of GH?
- Reduced glucose transport and metabolism
- Increased lipolysis
- Increased amino acid transport
- Increased protein synthesis
Is IGF-1 GH-dependent or independent? What about IGF-2?
- IGF-1: GH-dependent
- IGF-2: GH-independent
How are the effects of IGF-1 release mediated?
- IGF-1 released from the liver acts in an endocrine fashion
- In other tissues, local production of IGF-1 allows it to act in a paracrine or autocrine fashion
What is the important function of IGF-2?
- Important role in fetal development
- Role in adults is less clear
How are IGF-binding proteins secreted?
Secreted by target cells together with specific proteases
What is the major function of IGF-binding proteins?
- Binding to a carrier protein prevents its degradation to remain at a relatively constant concentration
- May regulate bioavailability and turnover of IGFs
How do fluctuations of GH affect IGFs?
IGFs remain relatively constant over long periods of time, despite fluctuations in GH
During which life stages are the growth-promoting effects of GH via IGF-1 particularly important?
- During childhood growth
- Less important during gestation and for the neonate
What are the growth-promoting effects of GH via IGF-1 influenced by?
The nutritional status of an individual
How does aging affect GH pulses?
- Increase with age, with marked rise at puberty
- Then, decline with age
IGF-1 levels parallel _____________ in children.
growth rate
On the large-scale, how does GH and IGF-1 affect bone growth? When does that cease?
- Promote bone growth of long bones at the epiphyseal plates (proliferation of chondrocytes)
- Epiphyses fuse at the end of puberty and longitudinal growth ceases
Specifically, how does GH and IGF-1 affect bone growth?
- GH stimulates fibroblasts to differentiate into chondrocytes
- IGF increases the number of chondrocytes by stimulating mitosis, which increases the length of the bone
How does IGF-1 produced by the liver affect GH secretion?
Negatively feedbacks to the hypothalamus, decreasing GH secretion
Which tissues contain the GH-receptor? When are GH-receptors detectable?
- Most tissues
- 7 months of fetal age
How do GH-receptors act?
Via recruitment of tyrosine kinase and activation of STATs, MAPK, and PI-3K
What downregulates the GH-receptor?
- GH
- Other factors, such as sex hormones
What does the IGF-1 receptor ressemble?
- Insulin receptor
- Formed of a dimer of two glycoprotein subunits
How do IGF-1 receptors act?
Via intrinsic tyrosine kinase activity
What is the structure of IGF-2 receptors?
Single-chain spanning the membrane once
What does the IGF-2 receptor also bind?
Mannose-6-phosphate
How do IGF-2 receptors act?
- They have NO signal activity
- But, they’re ultimate function may be via the IGF-1 receptor
What feedback control regulates GH release?
- IGF-1
- GH
How does stress influence GH release? What factors does stress include?
- Stress, including exercise, cold, anesthesia, surgery, hemorrhage
- Surge in GH
What metabolites increase GH release?
- Hypoglycemia (insulin administration)
- Amino acids (arginine)
What metabolites decrease GH release?
- Hyperglycemia (oral glucose)
- Free fatty acids
Glucose and fatty acids increase ________ release.
somatostatin
How does sleep influence GH secretion?
- Sleep induces fluctutations in GH
- Secretion every 1 to 2 hours in a pulsatile fashion
How does GH release vary between sexes? How does GH release vary with age?
- GH is higher in females
- With age, the amount of GH produced and the pulsatility of release decreases in amplitude and frequency
How do you test for the normal regulation of GH secretion?
- Inject glucose into individuals
- Glucose should suppress levels of GH, until the excessive glucose has cleared from the blood
How would glucose infusion affect GH secretion in acromegaly patients?
- Glucose infusion would not affect GH secretion, although it should
- These patients have lost their ability to regulate GH
How would you test for a deficiency of GH?
- Inject insulin into individuals
- Insulin should cause a hypoglycemic state, which would cause a quick release of GH
How do glucocorticoids affect GH release?
Decrease in GH release
How does estrogen affect GH release? Why?
- Increase in GH release
- Sensitizes somatotrophs to produce GH
How does thyroxin affect GH release? Why? What does that explain?
- Increase in GH release
- Thyroxin promotes transcription of the GH gene
- Hypothyroid children have stunted growth
When do higher levels of GH occur? When do lower levels occur?
- Higher levels are associated with puberty (peak)
- Decreases with adulthood (somatopause)
What causes GH to peak at puberty?
Stimulation of GH release by androgens and estrogens
How do IGF-1 levels vary with age?
- IGF-1 decreases as GH decreases with age
- The maximum levels of IGF-1 are associated with puberty
What benefits does exogenous GH treatment for elderly offer?
- Decreases body fat
- Increases lean muscle tissue and bone density
- Improves some cognitive functions
What side effects does exogenous GH treatment for elderly cause?
- Edema in extremities
- Joint pain
- Gynecomastia
- Metabolic imbalances
- Increased cancer risks
Is GH currently being used as a treatment for the elderly?
- No, since the risks of providing GH have to be carefully assessed
- But, GH may be purchased illegally
Is prolactin concentration in the pituitary lower or higher than GH?
10 times lower than GH
What is the major function of prolactin?
Post-partum activation of lactation
What hormones are involved in the growth of the duct system of the mammary gland?
- Estrogen
- GH
- Cortisol (adrenal steroids)
What hormones stimulate alveolar growth of the mammary gland?
- Estrogen
- Progesterone
- Cortisol
- Prolactin
The secretion of which hormones are essential for the initiation and maintenance of milk secretion?
- Prolactin
- Cortisol
How does a hypophysectomy affect milk production?
- Removal of the anterior pituitary gland
- Leads to the immediate cessation of milk production
How does an adrenalectomy affect milk production?
- Removal of the adrenal gland
- Gradual reduction in milk production
The reduction in which hormones after parturition is permissive for milk production?
- Estrogen
- Progesterone
How do prolactin and oxytocin collaborate to stimulate milk let-down?
- Prolactin stimulates milk secretion from alveolar epithelial cells (milk secretion)
- Oxytocin acts on myoepithelial cells to induce contraction of the alveoli (milk ejection)
Which neurotransmitter affects the release of prolactin? How?
- Dopamine
- Decreases release of prolactin
What are hyperprolactinemic conditions associated with?
- Hypogonadism (e.g. infertility)
- High levels of prolactin are associated breastfeeding are associated with lactational amenorrhea (brith control method)
How is lactational amenorrhea used as a birth control method?
- Prolactin at high concentrations suppresses the reproductive axis, inhibiting LH and FSH
- The baby must be fed by the breast consistently to maintain these effects
How is prolactin involved in immunomodulation?
- Prolactin receptors are found on B-cells, T-cells, and macrophages
- Prolactin acts as a mitogen and promotes survival (decreasing apoptosis)
Which tissues contain prolactin receptors?
Prolactin receptors are found in most tissues, where they act synergistically with many other hormones
The mechanism of action of prolactin is similar to which hormone?
GH
How is the regulation of the effects of prolactin unique?
- Prolactin is mainly under INHIBITORY* control
- In the absence of an inhibitor (dopamine), prolactin secretion increases
When do prolactin levels increase during the day?
During sleep
Which releasing hormones from the hypothalamus stimulate the release of prolactin?
- TRH
- VIP
How is ACTH derived?
Proteolytic cleavage of a large precursor molecule (POMC)
Which hormone may be derived from ACTH? What is its function?
- Melanocyte-stimulating hormone
- Darkening of the skin
What hormone may be derived, apart from ACTH, from POMC? What is its function?
- Beta-endorphin
- Morphine-like activity
Is the tanning response an endocrine or paracrine response?
Paracrine response
What skin cells does UV light reach? Are they nucleated or enucleated?
- UV light passes through the enucleated surface skin cells
- They reach paragnocytes, which are nucleated
What are the effects of UV light on nucleated skin cells? What are the two possible responses?
- UV light damages DNA
- Synthesis of p53 protein
- Or, if the damage of the cell is too great, apoptosis occurs, which results in the loss of skin
What is the function of p53 in skin cells that may be repaired?
- p53 stimulates the translation of POMC, which produces MSH
- MSH binds to a receptor on a melanocyte, activating a signal transduction pathway to produce melanosomes (coloured granules)
What is the function of melanosomes in the protection of the skin?
Melanosomes are translocated from the melanocyte to the paragnocyte, forming a barrier to deflect UV light
What intracellular mechanism occurs following the binding of ACTH to its cognate receptor in the adrenal gland?
- Activates G(alpha)s-protein
- Increase in cAMP
What are the effects of ACTH on cholesterol?
- Enhanced mobilization of cholesterol
- Increased conversion of cholesterol to pregnenolone
What induces CRH secretion?
Stress (pain, fear, fever, hypoglycemia)
What are the effects of light/dark cycles on CRH secretion?
- Lowest secretion at midnight
- Increases until a morning peak, and then declines
CRH action is potentiated by other hormones, such as what?
Vasopressin
What is the structural composition of TSH?
- Two glycosylated protein chains
- Alpha and beta subunit
What does the beta subunit of TSH provide?
Hormone specificity
The alpha subunit of which hormones are the same? What differentiates them?
- LH, FSH, TSH
- The beta subunit is different
What intracellular mechanism occurs following the binding of TSH to its cognate receptor in the thyroid gland?
- Receptor signalling via G(alpha)s
- Increase in cAMP
What is the overall function of TSH?
- Stimulates metabolism of thyroid follicular cells
- Major factor controlling the formation of thyroid hormones
What are the three functions of LH in females?
1) Steroidogenesis in the ovarian follicle
2) Induction of ovulation
3) Maintenance of steroidogenesis by the corpus luteum
What is the function of LH in males?
Stimulation of testosterone production in the Leydig cells of the testes
What is the function of FSH in females?
Stimulation of the development of ovarian follicles and their estradiol secretion
What is the function of FSH in males?
Spermatogenesis
What is a function of FSH that is present in males and females?
Secretion of inhibin, which has a negative feedback on FSH
What is the major function of inhibin?
- Negative feedback on FSH
- Controls how much LH and FSH are produced relative to each other
Describe the release of LH and FSH.
- Pulsatile, occurring every 60 minutes
- In response to GnRH pulses
What is the major common cause of disorders of the anterior pituitary?
Benign tumours of the pituitary (adenomas)
What is the characteristic growth of an adenoma?
They are typically slow-growing
Differentiate microadenomas and macroadenomas.
- Microadenomas: <10 mm
- Macroadenomas: >10 mm
Benign tumours of the pituitary gland arise from which types of cells?
Adenohypophyseal
Which population group do functional tumours typically affect? What about non-functional tumours?
- Functional tumours: younger
- Non-functional tumours: older
Differentiate functional and non-functional tumours.
- Functional tumours cause over-secretion
- Non-functional tumours inhibit secretion
Which adenoma type has the largest prevalence?
Prolactin cell adenoma
Why does prolactin cell adenoma have the highest prevalence?
- Because it is under INHIBITORY control
- If the connection between the hypothalamus and pituitary is disconnected, the cells react autonomously because the inhibitory control is removed
- Prolactin is also a mitogen, so if the control is dysregulated, the number of cells will expand
What are signs and symptoms of pituitary adenomas usually due to?
- Hypofunction
- Hyperfunction
- Mass effect, associated with the location of the adenoma
Which structure may be damaged by a pituitary adenoma? What does that result in?
- Impingement on the optic chiasm, causing visual field defects
- Double vision, drooping eyelids, altered facial sensation
What is the most common cause of hypopituitarism? What are other causes?
- Most commonly caused by pituitary adenomas
- Other causes include surgery, radiation, and trauma
What is the sequence of function loss from mass effect of hypopituitarism? (4)
1) GH
2) LH and FSH
3) ACTH
4) TSH
Why is there no function loss for prolactin from mass effect of hypopituitarism?
Because hypofunctioning of prolactin is a rare event, as it is controlled by inhibiting factors
What are the effects of GH deficiency?
- Decreased muscle strength and exercise tolerance
- Diminished libido
- Increased body fat
What are the effects of gonadotrophin deficiency?
- Oligo/amenorrhea
- Diminished libido
- Infertility
- Hot flashes
- Impotence
What are the effects of ACTH deficiency?
- Malaise
- Fatigue
- Anorexia
- Hypoglycemia
What are the effects of TSH deficiency?
- Malaise
- Leg cramps
- Fatigue
- Dry skin
- Cold tolerance
What is the most common cause of hyperpituitarism?
Benign tumours of the pituitary gland
How may tumours in the pituitary gland arise?
- De novo
- Or, because of the lack of feedback control (e.g. Cushing disease)
Tumours secreting which pituitary hormones are common?
- Prolactin
- GH
- ACTH
Tumours secreting which pituitary hormones are rare?
- TSH
- LH
- FSH
What is the most common cure for pituitary adenomas?
- Surgery through the nose
- Remove excess tissue, while still maintaining enough tissue for function
What are effects of prolactin excess?
- Oligo/amenorrhea
- Galactorrhea
- Infertility
- Decreased libido
- Headaches
- Visual field defects
Decreased libido, headaches, and visual field defects are symptoms associated with prolactin excess in which population groups?
Men and post-menopausal women
What are effects of GH excess?
- Gigantism (young)
- Acromegaly (adults)
Why do younger individuals develop gigantism, and not acromegaly?
Younger individuals have not finished their growth spurt, which means that their epiphyseal plates are not closed, allowing for the growth of their long bones
Describe the release of GH in the presence of a functional pituitary tumour.
- GH produced at a high level without pulsatility
- IGFs are elevated as a consequence
How is GH excess due to a functional pituitary tumour treated?
- Long-acting somatostatin analogues
- The best treatment is surgical removal
What are the effects of GH therapy in children that have hypofunctioning pituitary glands?
Administration of GH allows growth to catch-up
What hormone does Cushing’s disease affect?
Excess ACTH, leading to excess production of cortisol
What are symptoms of Cushing’s disease?
- Buffalo hump
- Moon face
- Acne
- Decrease in immune function (cortisol suppresses the immune system)
What are effects of excess TSH?
- Heat intolerance
- Weight loss
- Weakness
- Heart failure
What delays the diagnosis of pituitary tumours?
The non-specific nature of many symptoms
Which technique is used to diagnose pituitary tumours? What may it reveal?
- MRI
- Tests can reveal whether the adenoma is hypo- or hyperfunctional
How is a deficiency of GH diagnosed?
- Insulin tolerance test
- GH-RH/arginine test
- IGF-1 levels
How is a deficiency of gonadotrophins diagnosed?
- Sexual history
- Menstrual history
- FSH/LH/estradiol/prolactin/testosterone levels
How is a deficiency of ACTH diagnosed?
- Cortisol levels in the AM
- Insulin tolerance test
How does ACTH respond to hypoglycaemia?
ACTH increases
How is a deficiency of TSH diagnosed?
T4 and TSH levels
How is an excess of prolactin diagnosed?
- Prolactin level
- Drug history
- Clinical setting (e.g. pregnancy, breast stimulation, stress, hypoglycemia)
What does prolactin level over 200 ng/mL along with a large adenoma suggest?
Stalk compression
How is acromegaly diagnosed?
- IGF-1 levels
- Oral glucose tolerance test
How is Cushing’s disease diagnosed?
- 24-hour urine cortisol
- Overnight dexamethasone suppression test
How is an excess of TSH diagnosed?
Free T4, T3, and TSH levels
What is the first line of treatment for prolactinoma?
Dopamine agonist therapy, which suppresses the secretion of prolactin
What is the mechanism of action of dopamine agonist therapy?
- Treatment with bromocriptine
- Binds and activates dopamine receptors, inhibiting prolactin secretion
What is being used as a treatment for TSH-producing adenomas and acromegaly?
Somatostatin analogs
