Pituitary Hormones_J..

PITUITARY HORMONES
Yulia Komarova, Ph.D.
312-996-1332
[email protected]
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Knowledge Objectives
1. Understand the regulation of growth hormone (GH) biosynthesis and secretion including
the roles of growth hormone releasing hormone (GH-RH) and Gh releasing peptides,
glucose levels, somatostatin, and dopamine
2. Understand the adverse effects of GH therapy in children and adults
3. Understand the regulation of prolactin biosynthesis, secretion and release by suckling;
effects of dopaminergic agonists and antagonists
4. Understand the medical problems related to hypersecretion of prolactin in the female and
in the male
5. Know the structure and actions of oxytocin and its roles in parturition and lactation
6. Know the uses of vasopressin for the treatments of diabetes insipidus
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Case Study
• A 3-year-old boy presents with short stature and mild generalized obesity.
• Normal birth weight and birth length, but a progressive fall off in height velocity
relative to age-matched normal ranges starting at 6 months of age.
• Genital examination reveals descended but small testes.
• Laboratory evaluation demonstrates growth hormone (GH) deficiency and a delayed
bone age of 18 months
Clinical Approach:
• The replacement with recombinant human GH at a dose of 40 mg/kg/d
subcutaneously.
Outcome:
• After 1 year of treatment, his height velocity has increased from 5 cm/yr to 11 cm/yr.
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Growth Hormone Deficiency
• GH deficiency is a result of a genetic mutations or damage to the
pituitary or hypothalamus by a tumor, infection, surgery, or radiation
therapy.
• In most patients, the deficiency is idiopathic, with normal production of
other pituitary hormones and no obvious structural abnormalities.
• Children with GH deficiency present with short stature, delayed bone
age, a low age-adjusted growth velocity, hypoglycemia and adiposity.
• Criteria for diagnosis are: (1) a growth rate below 4 cm per year and (2)
the absence of a serum GH response to two GH secretagogues.
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Growth Hormone (GH)
Structure
•
GH is a 191-amino-acid peptide with two sulfhydryl bridges. It
composed of the four-helix bundle with two pairs of parallel helices
joined antiparallel
Absorption, Metabolism, and Excretion
•
Circulating endogenous GH has a t1/2 ~ 20–25 minutes and is cleared by the liver
Developmental Actions
•
is required during childhood for attainment of normal adult size and body composition
•
stimulates longitudinal bone growth
Metabolic Effects
•
increases the production of Insulin-like Growth Factor (IGF)-1 in the liver, bone,
cartilage, muscle, and the kidney
•
controls lipid and carbohydrate metabolism, and lean body mass
•
reduces insulin sensitivity
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Regulation of GH Biosynthesis and Secretion
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Molecular and Cellular Effects of GH
hGH receptor contains 620 amino acids, approximately 250 of which are extracellular, 24 of which are
transmembrane, and 350 of which are cytoplasmic.
JAK2, a cytoplasmic tyrosine kinase of the Janus kinase family; STAT (Signal Transducers and Activators of
Transcription), Shc (an adapter protein that regulates the Ras/MAPK signaling pathway), and IRS-1 and IRS-2
(insulin-receptor substrate proteins that activate the PI3K pathway).
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Indications for Treatment with rhGH, Somatropin
Primary Therapeutic Objective
Clinical Condition
Growth
Growth failure in pediatric patients associated with:
Growth hormone deficiency
Chronic renal failure
Noonan syndrome
Prader-Willi syndrome
Short stature homeobox-containing gene deficiency
Turner syndrome
Small for gestational age with failure to catch up by age 2
Idiopathic short stature in pediatric patients
Improved metabolic state, increased lean body mass, sense of wellbeing
Growth hormone deficiency in adults
Increased lean body mass, weight, and physical endurance
Wasting in patients with HIV infection
Improved gastrointestinal function
Short bowel syndrome in patients who are also receiving
specialized nutritional support;
malabsorption syndrome
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Therapeutic Uses of Somatropin
• Somatropin is administered subcutaneously 6–7 times per week.
• In children, somatropin is administered in a dose of 25-50 mg/kg per day subcutaneously in
the evening; higher daily doses (e.g., 50-67 mg/kg) are employed for patients with Noonan's
syndrome or Turner's syndrome, who have partial GH resistance
• For adults, a typical starting dose is 150-300 mg per day, with higher doses used in younger
patients transitioning from pediatric therapy; lower doses are used in older patients (e.g., >60
years of age).
• Because estrogen inhibits GH action, women taking oral—but not transdermal—estrogen may
require larger GH doses to achieve the target IGF-1 level.
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Somatropin Side Effects & Contraindications
Children:
• rarely intracranial hypertension, which may manifest as vision changes, headache, nausea
• pseudotumor cerebri
• hyperglycemia
• scoliosis as a result of rapid growth
• upper airway obstruction or sleep apnea
• patients with Turner syndrome have an increased risk of otitis media.
• hypothyroidism , pancreatitis, gynecomastia, and nevus growth
Adults:
• peripheral edema, myalgias, and arthralgias (especially in the hands and wrists) occur
commonly but remit with dosage reduction.
• rarely proliferative retinopathy
Contraindications:
known malignancy
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Drug Interactions
• Patients with diabetes mellitus: dose of insulin or oral medicine should be adjusted
• Steroids such as cortisone, dexamethasone, methylprednisolone, prednisone can make
somatropin less effective
• Some other medications, especially cyclosporine (Gengraf, Neoral, Sandimmune),
seizure medication, anabolic steroids can make somatropin less effective
•Oral estrogens may reduce the serum IGF-I response to somatropin treatment. Patients
receiving oral estrogen replacement may require greater somatropin dosages
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Recombinant Human Insulin-like
growth factor-1 (IGF1) (mecasermin)
Uses
• impaired growth secondary to mutations in the GH receptor or postreceptor signaling pathway
• in patients with GH deficiency who develop antibodies against GH
• in patients with IGF-1 gene defects that lead to primary IGF-1 deficiency
Doses
• 40-80 mg/kg per dose twice daily by subcutaneous injection, with a maximum of 120 mg/kg
per dose twice daily. Administrated shortly after meal.
Side Effects
• Hypoglycemia and tonsillar hypertrophy in >10%
• Cardiac murmur, dizziness, headache, convulsion, lipohypertrophy, thymus hypertrophy, ear
problems <10%
Drug Interactions
• Patients with diabetes mellitus: dose of
insulin or oral medicine should be adjusted
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Excess Production of Growth Hormone
•Acromegaly , a result GH-secreting pituitary
adenomas, which is characterized by abnormal
growth of cartilage and bone tissue, and many
organs including skin, muscle, heart, liver, and
the gastrointestinal tract.
Gigantism is a result of GH-secreting adenoma occurring
before the long bone epiphyses close.
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Somatostatin (SST) and SST Analogs
SST - inhibits the release of GH, TSH, glucagon,
insulin, and gastrin.
Somatostatin analogs: octreotide, octreotide
acetate, lanreotide, vapreotide
• the amino acid residues in positions 7-10 of the
SST-14 peptide (Phe-Trp-Lys-Thr) are the major
determinants of biological activity. Trp8 and Lys9
are essential, whereas conservative substitutions at
Phe7 and Thr10 are permissible.
• active SST analogs retain this core segment
constrained in a cyclic structure by a disulfide bond
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Therapeutic Uses of Octreotide
• acromegaly
• metastatic carcinoid tumors
• gastrinoma
• glucagonoma
• nesidioblastosis
• hypokalemia and achlorhydria (WDHA) syndrome
• the watery and diabetic diarrhea
•Octreotide (50-200 mg) is administered subcutaneously three times daily, peak effects are seen within
30 min, serum t1/2 is 90 min, and duration of action is 12 hour.
• Octreotide acetate, a long-acting, slow-release form (SANDOSTATIN-LAR DEPOT) in which
the active species is incorporated into microspheres is administered intramuscularly in a dose of 20 40 mg every 4 week. A lower dose of 10 mg per injection should be used in patients requiring
hemodialysis or with hepatic cirrhosis.
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Side Effects & Interactions
Side effects
• GI side effects—including diarrhea, nausea, and abdominal pain—occur in up to 50% of patients
• 25% of patients develop gallbladder sludge or even gallstones, presumably due to decreased
gallbladder contraction and bile secretion.
• cardiac effects include sinus bradycardia (25%) and conduction disturbances (10%)
Drug Interactions
•Octreotide acetate may have an effect on absorption of orally administered drugs.
•Concomitant administration of octreotide acetate with cyclosporine may decrease blood levels of
cyclosporine and result in transplant rejection
• Patients receiving insulin, oral hypoglycemic agents, beta blockers (e.g., metoprolol, propranolol,
calcium channel blockers (e.g., diltiazem, verapamil), or agents to control fluid and electrolyte
balance, may require dose adjustments of these therapeutic agents
•Concomitant administration of octreotide and bromocriptine (dopamine agonist) increases the
availability of bromocriptine
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Pegvisomant, GH Receptor Antagonist
Uses
•Pegvisomant (SOMAVERT) is FDA-approved therapy for the treatment of acromegaly and provides a
highly effective alternative for use in patients who have not responded to SST analogs.
• is administered subcutaneously as a 40-mg initial dose under physician supervision, followed by selfadministration of 10 mg per day. The dose is titrated at 4- to 6-week intervals to a maximum of 40 mg
per day
Side Effects
• an allergic reaction
• liver problems (yellowing of the skin or eyes, vomiting, abdominal pain, unusual fatigue, loss of
appetite, itching, clay-colored stools, or dark urine)
Contraindications
•an unexplained elevation of hepatic transaminases
Drug Interactions
• Patients receiving insulin, oral hypoglycemic agents may require dose reductions of insulin and/or oral
hypoglycemic agents
• In clinical studies, patients taking opioids often needed higher SOMAVERT doses to normalize IGF-I
concentrations compared with patients not receiving opioids. The mechanism of this interaction is not
known
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Regulation of Prolactin Secretion
• Hypothalamic regulation of prolactin secretion is predominantly inhibitory.
• The major regulator of prolactin secretion is DA, which is released by
tuberoinfundibular neurons and interacts with the D2 receptor on lactotropes to
inhibit prolactin secretion
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Excess Production of Prolactin
• Hyperprolactinemia is developed as a result of impaired transport of dopamine (prolactin-inhibiting
hormone) to the pituitary or more commonly, as a result of prolactin-secreting adenomas.
•Hyperprolactinemia produces a syndrome of amenorrhea and galactorrhea in women, and loss of
libido and infertility in men.
•Hypogonadism and infertility associated with hyperprolactinemia result from inhibition of release of
Gonadotropin-releasing hormone (GnRH).
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Dopamine Agonists
•Quinagolide, a drug approved in Europe, is a nonergot agent with similarly high D2 receptor affinity.
•Bromocriptine and cabergolineare ergot derivatives with a high affinity for dopamine D2 receptors.
Pharmacokinetics
•All dopamine agonists are oral preparations, which are eliminated by metabolism.
•Cabergoline, with a half-life of approximately 65 hours, has the longest duration of action.
•Quinagolide has a half-life of about 20 hours
•Bromocriptine has the half-life about 7 hours.
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Therapeutic Uses of Dopamine Agonists
Hyperprolactinemia
• dopamine agonists shrink pituitary prolactin-secreting
tumors, lower circulating prolactin levels, and restore
ovulation in approximately 70% of women with
microadenomas and 30% of women with macroadenomas
•Cabergoline is initiated at 0.25 mg twice weekly orally or
vaginally. It can be increased gradually up to a maximum of 1
mg twice weekly.
•Bromocriptine is generally taken daily after the evening meal
at the initial dose of 1.25 mg; the dose is then increased as
tolerated. Most patients require 2.5–7.5 mg daily.
Acromegaly
•A dopamine agonist alone or in combination with pituitary surgery, radiation therapy, or octreotide
administration can be used to treat acromegaly
•The doses are 20–30 mg/d of bromocriptine unless the pituitary tumor secretes prolactin as well as GH.
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Side Effects & Contraindications of Dopamine
Agonists
Side Effects
• nausea, headache, light-headedness, orthostatic hypotension, and fatigue
• occasional psychiatric manifestations
• high dosages can cause cold-induced peripheral digital vasospasm
• pulmonary infiltrates have occurred with chronic high-dosage therapy
• rare reports of stroke or coronary thrombosis in postpartum women taking bromocriptine to suppress
postpartum lactation
Contraindications
• uncontrolled high blood pressure
• a history of heart valve problems or certain fibrotic (scarring) disorders (eg, of the lung, heart, kidneys)
•a rare hereditary problem of galactose intolerance, severe lactase deficiency, or glucose-galactose
malabsorption
•therapy during the early weeks of pregnancy has not been associated with an increased risk of
spontaneous abortion or congenital malformations
•patients with very large adenomas continue a dopamine agonist treatment throughout pregnancy
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Drug Interactions
Cabergoline
•should not be administered concurrently with D2-antagonists, such as phenothiazines, butyrophenones,
thioxanthenes, or metoclopramide.
•The dose of some antipsychotic medications (such as chlorpromazine, haloperidol, thiothixene) might be
adjusted
•Certain azole antifungals (such as itraconazole, ketoconazole, posaconazole), macrolide antibiotics (such
as clarithromycin, erythromycin), HIV protease inhibitors (such as ritonavir, saquinavir) can affect the
removal of cabergoline from a body.
Bromocriptine
• ethanol can increase nervous system side effects of bromocriptine such as dizziness, drowsiness, and
difficulty concentrating.
• bromocriptine may interact with dopamine antagonists, butyrophenones; this results in a decreased
efficacy of bromocriptine.
•the concomitant use of macrolide antibiotics such as erythromycin was shown to increase the plasma
levels of bromocriptine.
•concomitant use of bromocriptine with other ergot alkaloids is not recommended.
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Posterior Pituitary Hormones
Oxytocin and Vasopressin are synthesized in neuronal cell bodies in the hypothalamus and transported
via their axons to the posterior pituitary, where they are stored and then released into the circulation.
Oxytocin is a 9-amino-acid peptide with an intrapeptide disulfide cross-link. Its amino acid sequence
differs from that of vasopressin at positions 3 and 8.
Desmopressin acetate (DDAVP, 1-desamino-8-D-arginine vasopressin) is a long-acting synthetic analog
of vasopressin.
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Therapeutic Uses of Oxytocin
•Oxytocin is used to induce labor for conditions requiring early vaginal delivery such as Rh
problems, maternal diabetes, preeclampsia, or ruptured membranes.
•It is also used to augment abnormal labor that is protracted or displays an arrest disorder.
•Oxytocin is usually administered intravenously via an infusion pump with an initial infusion
rate of 0.5–2 mU/min.
•For induction of labor, rate is increased every 30–60 minutes until a physiologic contraction
pattern is established. The maximum infusion rate is 20 mU/min.
•For postpartum uterine bleeding, 10–40 units are added to 1 L of 5% dextrose, and the
infusion rate is titrated to control uterine atony.
Contraindications:
•fetal distress
•prematurity, abnormal fetal presentation
•cephalopelvic disproportion
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Side Effects and Interactions of Oxytocin
Side Effects
•Anaphylactic reaction
•Postpartum hemorrhage
•Cardiac arrhythmia
•Fatal afibrinogenemia
•Nausea
•Vomiting
•Premature ventricular contractions
•Pelvic hematoma
•Hypertensive episodes
•Rupture of the uterus
Drug Interactions
• Severe hypertension may occur if combined with prophylactic administration of a
vasoconstrictor
• Cyclopropane anesthesia may modify oxytocin's cardiovascular effects, so as to produce
unexpected results such as hypotension
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Vasopressin
•Vasopressin is a peptide hormone released by the posterior pituitary in response to rising
plasma tonicity or falling blood pressure.
•A deficiency of Vasopressin results in diabetes insipidus
• is used for the treatments of pituitary diabetes insipidus
• is administered intramuscularly or subcutaneously at three-or four-hour intervals. The
dose by injection is 5 to 10 U repeated two or three times daily as needed
• may be administered intranasally on cotton pledgets, by nasal spray, or by dropper
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Side Effects and Interactions of Vasopressin
Side Effects
•anaphylaxic shock has been observed shortly after injection of vasopressin.
•cardiac arrest, arrhythmias, decreased cardiac output, angina, myocardial ischemia,
peripheral vasoconstruction and gangrene.
•abdominal cramps, nausea, vomiting.
•tremor, "pounding" in head.
•bronchial constriction.
•sweating, urticaris, cutaneous gangrene.
Drug Interactions
• concurrent use of carbamazepine; chlorpropamide; clofibrate; urea; fludrocortisone;
tricyclic antidepressants may potentiate the antidiuretic effect of vasopressin
•demeclocyline; norepinephrine; lithium; heparin, alcohol may decrease the antidiuretic
effect of vasopressin
• ganglionic blocking agents may produce a marked increase in sensitivity to the pressor
effects of vasopressin.
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Literature:
• Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor
Basic & Clinical Pharmacology, 12e,
Chapter 37 Hypothalamic & Pituitary Hormones
• Laurence L. Brunton, Bruce A. Chabner, Björn C. Knollmann
Goodman & Gilman's The Pharmacological Basis of
Therapeutics, 12e
Chapter 38 Introduction To Endocrinology: The HypothalamicPituitary Axis
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