1. 1 PITUITARY HORMONES Yulia Komarova, Ph.D. 312-996-1332ykomarov@uic.edu

2. 2 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

3. 3 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  g/kg/d subcutaneously. Outcome: After 1 year of treatment, his height velocity has increased from 5 cm/yr to 11 cm/yr.

4. 4 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.

5. 5 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 t 1/2 ~ 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

6. 6 Regulation of GH Biosynthesis and Secretion

7. 7 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).

8. 8 Indications for Treatment with rhGH, Somatropin Primary Therapeutic ObjectiveClinical Condition GrowthGrowth 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 enduranceWasting in patients with HIV infection Improved gastrointestinal functionShort bowel syndrome in patients who are also receiving specialized nutritional support; malabsorption syndrome

9. 9 Somatropin is administered subcutaneously 6–7 times per week. In children, somatropin is administered in a dose of 25-50  g/kg per day subcutaneously in the evening; higher daily doses (e.g., 50-67  g/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  g 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

10. 10 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

11. 11 Drug Interactions Before using somatropin, tell your doctor if you use insulin or take oral (by mouth) medicine to treat diabetes. Somatropin may affect blood sugar levels and you may need to adjust your dose of the diabetes medication. Do not change the dose of your diabetes medication without your doctor's advice. Tell your doctor if you use any type of steroid medicine such as cortisone, dexamethasone, methylprednisolone, prednisone, and others. Steroids can make somatropin less effective and your doses may need to be adjusted. Do not stop using a steroid suddenly. Follow your doctor's instructions. Tell your doctor about all other medications you use, especially cyclosporine (Gengraf, Neoral, Sandimmune), seizure medication, birth control pills, anabolic steroids, or hormone replacement medications for men or women. This list is not complete and other drugs may interact with somatropin. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. 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

12. 12 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  g/kg per dose twice daily by subcutaneous injection, with a maximum of 120  g/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)

13. 13 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

14. 14 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. Trp 8 and Lys 9 are essential, whereas conservative substitutions at Phe 7 and Thr 10 are permissible. active SST analogs retain this core segment constrained in a cyclic structure by a disulfide bond Somatostatin (SST) and SST Analogs

15. 15 acromegaly metastatic carcinoid tumors gastrinoma glucagonoma nesidioblastosis hypokalemia and achlorhydria (WDHA) syndrome the watery and diabetic diarrhea Octreotide (50-200  g) is administered subcutaneously three times daily, peak effects are seen within 30 min, serum t 1/2 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

16. 16 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

17. 17 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

18. 18 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 D 2 receptor on lactotropes to inhibit prolactin secretion

19. 19 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

20. 20 Dopamine Agonists Quinagolide, a drug approved in Europe, is a nonergot agent with similarly high D 2 receptor affinity. Bromocriptine and cabergolineare ergot derivatives with a high affinity for dopamine D 2 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.

21. 21 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.

22. 22 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

23. 23 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. B romocriptine 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.

24. 24 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.

25. 25 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

26. 26 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

27. 27 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

28. 28 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.

29. 29 Literature: Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor Basic & Clinical Pharmacology, 12e, Chapter 37 Hypothalamic & Pituitary HormonesHypothalamic & 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 AxisIntroduction To Endocrinology: The Hypothalamic- Pituitary Axis