Endocrine System Hormones

• The objective is to learn about the hypothalamus-hypophysis-organs endocrine axis.
• The objective is to know the main drugs that can interact with this endocrine axis.
• The objective is to learn the mechanism of action and adverse effects of drugs that can modify/interact with hypothalamic and pituitary hormones.

Hypothalamic & Pituitary Hormones and Their Target Organs

• The hypothalamus produces hormones including: GnRH, CRH, TRH, PRH, and GHRH, plus the inhibiting hormone Dopamine
• GnRH affects the anterior pituitary
• CRH affects the anterior pituitary
• TRH affects the anterior pituitary
• Prolactin affects the anterior pituitary
• Dopamine, from the Hypothalamus, inhibits the anterior pituitary
• GHRH affects the anterior pituitary
• Somatostatin, from the Hypothalamus, inhibits the anterior pituitary
• FSH/LH is relased from the anterior pituitary
• ACTH is released from the anterior pituitary
• TSH is released from the anterior pituitary
• Prolactin is released from the anterior pituitary
• GH is released from the anterior pituitary
• ADH is released from the posterior pituitary
• Oxytocin is released from the posterior pituitary
• FSH/LH target the gonads
• ACTH targets the adrenal cortex
• TSH targets the thyroid
• Prolactin targets the mammary glands
• GH targets the lover and the whole body
• ADH targets the kidney
• Qytocin targets the mammary gland

Anterior Hypophysis Drugs

• Target the anterior hypophysis gland
• This focuses on the mechanism of action of these drugs
• The drugs included modulate GH (Growth Hormone), affect Prolactin, and target the Posterior Hypophysis

Growth Hormone and Related Drugs

• Agonists include: Somatotropin (recombinant GH), Somapacitam (GH analog), Mecasermin (recombinant IGF-1, Macimorelin (ghrelin agonist)
• Antagonists include: Somatostatin analogs (Somatostatin, Octreotide , Lanreotide, Pasireotide), and GH Receptor antagonist (Pegvisomant)

Prolactin Antagonist

• A dopamine Receptor agonist, these include: Bromocriptine, Cabergoline, Quinagolide (non-ergot)

Oxytocin Hormone

• Agonist is Oxytocin
• Antagonist is Atosiban

Anti-Diuretic Hormone

• Agonists are: Vasopressin, Desmopressin
• Antagonists are: Conivaptan, Tolvaptan

GH Agonist Mechanism of Actions

• The first step is the binding and dimerization of the GHR (Growth Hormone Receptor)
• Activation and phosphorylation of the GHR-associated JAK2 tyrosine kinase follows
• Recruitment and activation of MAP kinases, IR substrates, PIEK, DAG, PKC, Intracellular CA2+, and STAT transcription factors.
• Induction of changes mediated by GH occurs
• Enzymatic activity, transport function, and gene expression follow
• Finally, growth and metabolism occur

Somatostatin Mechanism Of Action

• Somatostatin binds to any of the 5 subtypes of somatostatin receptors
• The SSTRs are 7TM-coupled to "G" protein receptor family
• Activation of inward K+ current and inhibition of inward Ca++ current follow
• This leads to activation of phosphotyrosine phosphatase and MAPK
• These actions then decrease the levels of cAMP and intracellular calcium
• SST-1 inhibits the secretion of GH, Prolactin, anf calcitonin
• SST-2 inhibits gastrin, histamine, parietal acid secretion as well as GH, adrenocorticotropin, glucagon, insulin, and interferon-y
• SST-3 and SST-5 induce reduction if cell proliferation, and anti-tumor angiogenesis

Bromocriptine Mechanism of Actions

• Bromocriptine binds to the Dopamine type 2 receptor
• The D2 receptor is a 7TM-coupled to 'G" proteins
• Activation of the D2 receptor induces the inhibition of adenylyl cyclase
• This action decreases cAMP and intracellular calcium
• MAPK is inhibited, mediated by c-Raf and B-Raf
• D2 in the tuberoinfundibular pathway inhibits prolactin secretion

Oxytocin Hormone Actions

• Binds to the 7TMCGP receptor
• Calmodulin and Ca++ induce phosphorylation of MLCK
• This leads to uterine smooth muscle contractions
• The receptor phosphorylates the phospholipase C-B
• Intracellular CA++ increases the activity of calmodulin
• In the epithelial cells prostacyclin and prostaglandin are induced, which increases inducing the secretion
• PLC interacts with PIP2 and produces IP3 and DAG
• IP3 increases intracellular CA++ and DAG activate PKC
• In the CNS is activates trust, motivates social participation, and group preference

Vasopressin Hormone Actions

• Vasopressin bounds to the 7TMCGP receptors
• In the epithelial cells the receptor activates AC
• The increased cAMP activates PKA and phosphorylation of AQP-2
• In the vascular smooth muscle the receptor phosphorylates the phospholipase C-B
• In vascular smooth muscle induce contraction
• The increase of cAMP activates PKA and phosphorylation of AOP-2
• AQP-2 is transfered to the apical membrane and facilitates the H2O inward
• PLC interacts with PIP2 and produces IP3 and DAG
• Calmodulin and CA++ induce phosphorylation of MLCK
• IP3 increases intracellular CA++ and DAG activate PKC.
• Intracellular Ca++ increases the activity of calmodulin

Select Hypothalamic and Pituitary Drugs

• Somatropin is used for: Pediatric patients who lack adequate endogenous GH secretion, chronic renal insufficiency, Turner syndrome, Noonan Syndrome, Wasting in patients with HIV injection
• Somapacitan is used for the: Replacement of endogenous growth hormone in adults with growth hormone deficiency
• Mecasermin is used for: Growth failure in children with severe IGF-1 deficiency unresponsive to growth hormone administration
• Octreotide is used for patients with acromegaly
• Pegvisomant is used for: Acromegaly in patients who are resistant to somatostatin analogs
• Cabergoline is used for: Hyperprolactinemia
• Desmopressin is used for: Diabetes insipidus, children with nocturnal enuresis, hemorrhagic conditions
• Conivaptan is used for: Euvolemic and hypervolemic hyponatremia
• Oxytocin is used to: Induce contractions during labor, prevent postpartum hemorrhage, and to stimulate milk let-down in nursing mothers
• Atosiban is used for: Delaying imminent pre-term birth in pregnant adult women

Somatotropin Adverse Effects

• Can cause: Leukemia, Histiocytosis X, Osteogenic sarcoma, Craniopharyngioma, Gliobastoma or Giloma, Astrocytoma, Diabetes mellitus, Intracranial hypertension, Slipped capital femoral epiphysis, Scoliosis and Pancreatitis

Mecasermin Adverse Effects

• Can cause: Hypoglycemia and Acromegaly

Octreotide Adverse Effects

• Can cause: Hyperglycemia, Abdominal Distress, High Blood Pressure, and Nausea

Oxytocin Adverse Effects

• Can cause: Pathological Heart Rhythm, Water Intoxication, Seizures and Uterine Contractions

Vasopressin Adverse Effects

• Can cause: Hyponatremia, High blood pressure, Xerostomia, and Facial Flushing