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PITUITARY HORMONES

Yulia Komarova, Ph.D.312-996-1332

ykomarov@uic.edu

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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

Knowledge Objectives

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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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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

Growth Hormone (GH)

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 well-being

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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• 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.

Therapeutic Uses of Somatropin

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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

Somatropin Side Effects & Contraindications

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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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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

Recombinant Human Insulin-like growth factor-1 (IGF1) (mecasermin)

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• 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.

Excess Production of Growth Hormone

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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

Somatostatin (SST) and SST Analogs

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• 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.

Therapeutic Uses of Octreotide

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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

Side Effects & Interactions

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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 self-administration 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

Pegvisomant, GH Receptor Antagonist

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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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• 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).

Excess Production of Prolactin

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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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• 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.

Therapeutic Uses of Dopamine Agonists

Hyperprolactinemia

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 HormonesOxytocin 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 Hypothalamic-Pituitary Axis