Hypothalamic and Pituitary Hormones: GH and Prolactin

Question 1

First lets go through the various hormones of the anterior pituitary. First up in Growth Hormone, what are some features of this?

Answer 1

Activation of receptors belonging to the JAK/STAT superfamily promotes growth of the entire body by affecting protein formation, cell multiplication and cell differentiation

Question 2

Next anterior pituitary hormones are LH and FSH. What are some features?

Answer 2

Control growth of the ovaries and testes, as well as their hormonal and reproductive activities through activation of G protein coupled receptors

Question 3

Next anterior pituitary hormone is Thyroid Stimulating Hormone (thyrotropin). what are some features?

Answer 3

Controls the rate of secretion of thyroxine and triiodothyronine by the thyroid gland by activating G protein coupled receptors. The thyroid hormones control the rates of most intracellular chemical reactions in the body.

Question 4

Next anterior pituitary hormone is Adrenocorticotropin (corticotropin), what are some features?

Answer 4

Activation of G protein coupled receptors controls the secretion of the adrenocortical hormones, which affect the metabolism of glucose, proteins and fats

Question 5

The last anterior pituitary hormone is Prolactin, what are some features?

Answer 5

Activates receptors of JAK/STAT superfamily to promote mammary gland development and milk production

Question 6

The synthesis and release of anterior pituitary hormones are positively regulated by the hypothalamic releasing hormones, which are released from hypothalamic neurons and reach the anterior pituitary through the hypothalamic-adenohypophyseal portal system. What are these hormones?

Answer 6

1. Growth hormone releasing hormone (GHRH): causes release of growth hormones and somatostatin, which inhibits release of growth hormone (also inhibits TSH and prolactin release)
2. Gonadotropin Releasing Hormone (GnRH): causes release of LH and FSH
3. Thyrotropin Releasing Hormone (TRH): causes release of thyroid stimulating hormone
4. Corticotropin Releasing Hormone (CRH): causes release of adrenocorticotropin
5. Dopamine: causes inhibition of prolactin secretion

Question 7

How do feedback loops closely regulate the hypothalamic-pituitary axes?

Answer 7

Provide levels of control at each stage of action
–systemic hormones produced by target organs negatively regulate the pituitary and hypothalamus to maintain an equilibrium level of hormone release.

Question 8

The posterior lobe hormones are synthesized in the hypothalamus and transported via the neurosecretory fibers in the stalk of the pituitary to the posterior lobe, from where they are released in the circulation. What are these hormones?

Answer 8

Antidiuretic hormone (vasopressin): controls the rate of water excretion into the urine 
Oxytocin: helps express milk from the glands of the breast to the nipples during suckling and helps stimulate uterine contractions

Question 9

Drugs that mimic or block the effects of the hypothalamic and pituitary hormones have pharmacologic applications in three primary areas?

Answer 9

1. As replacement therapy for hormone deficiency states
2. As antagonists for diseases caused by excess production of pituitary hormones
3. As diagnostic tools for identifying several endocrine abnormalities

Question 10

All pharmacological preparations (recombinant or analog) have to be delivered via nonoral routes, why?

Answer 10

Due to hormones being peptides or low molecular weight proteins

Question 11

First lets discuss growth hormone (GH) also called somatotropin, does not function through a target gland but exerts its effects on all or almost all tissues in the body. What is the secretion of GH like in adults and kids?

Answer 11

Kids: secretion is high and reaches max at puberty
Adult: decreases in an age related manner
–secreted at irregular pulses and between these pulses GH is undetectable
–max secretion is at night –shortly after deep sleep onset

Question 12

Explain the relationship between GNRH and GH?

Answer 12

GNRH stimulates GH by binding to a specific G protein coupled receptor on somatotropes.
–upon binding GNRH, the GNRH receptor couples to Gs to elevate cAMP and Ca2+ concentrations and that stimulates GH synthesis and secretion.

Question 13

GH and its peripheral effector, insulin like growth factor-1 (IGF-1), act in negative feedback loops to suppress GH secretion. Explain the negative effects of IGF-1 and GH

Answer 13

IGF-1: Through direct effects on the anterior pituitary gland
GH: is mediated in part by somatostatin (SST)
–SST binds to G protein coupled receptors that signal through Gi to inhibit cAMP accumulation

Question 14

What things stimulate GH secretion?

Answer 14

Neurotransmitters: dopamine, 5-HT, and alpha 2 receptor agonists
Other stimuli: hypoglycemia, exercise, stress, emotional excitement,and protein rich foods.
In contrast: beta adrenergic receptor agonists, free fatty acids, IGF-1 and GH inhibit release

Question 15

All the effects of GH result from its interactions with the GH receptor. Receptor activation results from the binding of a single GH molecule to two identical receptor molecules, forming a ligand occupied receptor dimer that brings the intracellular domains of the receptor in close proximity to activate cytosolic components critical for cell signaling. The ligand-occupied receptor dimer does not have tyrosine kinase activity but rather what?

Answer 15

Provides docking sites for two molecules of JAK2
–the juxtaposition of two JAK2 molecules leads to trans-phosphorylation and autoactivation of JAK2, with consequent tyrosine phosphorylation of cytoplasmic proteins that mediate downstream signaling events (STAT proteins, SHC, IRS-1 and IRS-2)

Question 16

What are some physiological effects of GH?

Answer 16

Stimulation of longitudinal growth of bones
Increase in bone mineral density after longitudinal growth ceases and epiphyses closed
Increased muscle mass
Increased GFR
Development and function of immune system
Anti-insulin effects in both the liver and peripheral sites

Question 17

GH acts directly on adipocytes to increase lipolysis and on hepatocytes to stimulate gluconeogenesis, but its anabolic and growth promoting effects are mediated by what?

Answer 17

Through the induction of IGF-1
–type 1 IGF receptor is closely related to the insulin receptor. Insulin can activate the type I IGF receptor, but with an affinity approx two orders of less magnitude than IGF.

Question 18

The administration of IGF-1 may cause hypoglycemia why?

Answer 18

Because of its insulin like effects

Question 19

Individuals with congenital or acquired deficiency of GH during childhood or adolescence fail to?

Answer 19

Reach adult height and have disproportionately increased body fat and decreased muscle mass.
–hypoglycemia can also occur due to the actions of insulin being unopposed.

Question 20

Moving on to the GH hormone drugs is Recombinant GH. What are these drugs?

Answer 20

Somatropin: recombinant form of GH and is identical to the native form of human GH
Somatrem: derivative of GH with an additional methionine

Question 21

Growth hormone has its greatest effects on patients with GH deficiency and growth. However what other conditions can exogenous GH be used for?

Answer 21

Wasting in patients with AIDS
Increase intestinal growth and improve function
Tx of patients with short bowel syndrome

Question 22

Some children with growth failure have IGF-1 deficiency that is not responsive to exogenous GH. What is used?

Answer 22

Mecasermin

–recombinant human IGF-1 (Hypoglycemia with this drug)

Question 23

What are the side effects of GH therapy in children?

Answer 23

Within first 8 weeks
–intracranial hypertension with papilledema, visual changes, headache, nausea or vomiting
–increased incidence of type 2 diabetes
Patients with Turners syndrome have increased risk of otitis media

Question 24

What are the side effects of GH therapy in adults?

Answer 24

Peripheral edema, carpal tunnel syndrome, arthralgia, and myalgia
Increased activity of cytochrome P450 isoforms
Contraindicated in patients with known active malignancy (again GH targets all tissues even malignant)

Question 25

GH excess is usually do to what?

Answer 25

Somatotroph adenoma

• -if epiphyses are unfused, GH excess causes increased longitudinal growth, resulting in Giantism.
• -In adults with closed epiphyses, GH excess causes acromegaly

Question 26

Pharmacological options for tx of GH excess include somatostatin analogs, dopamine agonists, and GH receptor antagonists. First lets discuss Somatostatin analogs. What is the role of Somatostatin?

Answer 26

Inhibits the release of GH, TSH, glucagon, insulin, and gastrin
–short duration of action and multiple effects in secretory systems so analogs have been made
Octreotide Analog
–side effects: diarrhea, nausea, and abdominal pain in about half of patients and usually go away with time
–25% develop gallstones
–Bradycardia and conduction disturbances
–other uses: bleeding control from esophageal varices (vasoconstriction) and tx of secretory diarrhea

Question 27

Moving on to the next treatment for GH excess are dopamine agonists. How do these drugs work?

Answer 27

Decrease GH secretion in some patients with acromegaly (Remember that normally dopamine receptor agonist stimulate GH secretion) – with the best response in patients with tumors secreting both GH and prolactin

Question 28

Bromocriptine and Cabergoline are dopamine agonists (cant give these orally) with a high affinity for dopamine D2 receptors) and can treat hyperprolactinemia as well. What are the side effects?

Answer 28

Bromocriptine: n/v, headache, postural hypotension
Cabergoline: longer half life, higher affinity and greater selectivity for the D2 receptor and has much lower tendency to induce nausea but can still cause dizziness and hypotension

Question 29

Finally the GH receptor antagonists is Pegvisomant and is approved for tx of acromegaly. What is the action?

Answer 29

Binds to the GH receptor but does not activate JAK-STAT signaling or stimulate IGF-1

Question 30

Quick note on Prolactin, it is an anterior pituitary hormone in that hypothalamic regulation of its secretion is predominantly inhibitory. The main regulator of prolactin secretion is dopamine. What does prolactin do?

Answer 30

Principle hormone responsible for lactation and has no therapeutic uses

Question 31

Hyperprolactinemia is a common endocrine abnormality that can result form hypothalamic or pituitary diseases that interfere with the delivery of inhibitory dopaminergic signals. Hyperprolactinemia is caused by what?

Answer 31

Prolactin secreting pituitary adenoma
–therapeutic options include surgery, radiation, and tx with dopamine receptor agonists (Bromocriptine and Cabergoline) that suppress prolactin production via activation of D2 receptors