1 PITUITARY HORMONES Yulia Komarova, Ph.D.

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. 2. Know the physiological conditions that elicit growth hormone secretion and how specific diagnostic maneuvers can elicit GH secretion. 3. Understand the regulation of prolactin biosynthesis secretion and release by suckling; effect of dopaminergic and serotonergic 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 roles in parturition and lactation. 6. Know the effects of vasopressin on receptor subtypes and signal transduction systems in vascular smooth muscle. Knowledge Objectives

3 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 has 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, which results in mild hyper-insulinemia

4 Regulation of GH Biosynthesis and Secretion

5 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).

6 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.

7 Indications for Treatment with rhGH, Somatropin Primary Therapeutic ObjectiveClinical 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 functionShort bowel syndrome in patients who are also receiving specialized nutritional support; malabsorption syndrome

8 Somatropin is administered subcutaneously 6–7 times per week. Peak levels occur in 2–4 hours and active blood levels persist for approximately 36 hours. In children, somatropin is administered in a dose of g/kg per day subcutaneously in the evening; higher daily doses (e.g., 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 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

9 Children: rarely intracranial hypertension, which may manifest as vision changes, headache, nausea scoliosis as a result of rapid growth 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 Toxicity & Contraindications

10 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 g/kg per dose twice daily by subcutaneous injection, with a maximum of 120 g/kg per dose twice daily Recombinant Human Insulin-like growth factor-1 (IGF1) (mecasermin)

11 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

12 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 octreotide and lanreotide bind to the SST subtypes with the following order of selectivity: SST 2 > SST 5 > SST 3 ≫ SST 1 and SST 4. Growth Hormone Antagonists

13 acromegaly metastatic carcinoid tumors gastrinoma glucagonoma nesidioblastosis the watery diarrhea and diabetic diarrhea 90 Y-labled octreotide is used in selective destruction of SST 2 receptor-positive tumors Octreotide ( 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. 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 or 30 mg once 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

14 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%). Toxicity & Contraindications of SST analogs

15 Pegvisomant, high affinity antagonist of GH receptor, prevents activation of GH receptor downstream signaling the polyethylene glycol (PEG) derivative of a mutant GH, which has increased affinity for one site of the GH receptor but a reduced affinity at its second binding site. binds to the GH receptor but does not activate JAK-STAT signaling or stimulate IGF-1 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 Contraindications: an unexplained elevation of hepatic transaminases Pegvisomant, GH Receptor Antagonist

16 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

17 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

18 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, whereas of Bromocriptine has the half-life about 7 hours.

19 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.

20 Toxicity & Contraindications of Dopamine Agonists 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 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 rare reports of stroke or coronary thrombosis in postpartum women taking bromocriptine to suppress postpartum lactation

21 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.

22 Oxytocin Oxytocin is a peptide hormone secreted by the posterior pituitary that participates in labor and delivery and elicits milk ejection in lactating women. Oxytocin acts via a specific GPCR, OXT, coupled to G q /G 11 and activating the PLC-IP 3 - Ca 2+ pathway and enhancing activation of voltage-sensitive Ca 2+ channels. Oxytocin stimulates the release of prostaglandins and leukotrienes that augment uterine contraction. Oxytocin causes contraction of myoepithelial cells surrounding mammary alveoli, which leads to milk ejection.

23 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

24 Vasopressin Vasopressin is a peptide hormone released by the posterior pituitary in response to rising plasma tonicity or falling blood pressure. A deficiency of this hormone results in diabetes insipidus Vasopressin activates V 1a subtypes of G protein-coupled receptors on vascular smooth muscle cells and mediate vasoconstriction. V 2 receptors are found on renal tubule cells and reduce diuresis through increased water permeability and water resorption in the collecting tubules. Extrarenal V 2 -like receptors regulate the release of coagulation factor VIII and von Willebrand factor.

25 Signal Transduction in SMC

26 Therapeutic Uses of Vasopressin [Phe 2, Ile 3, Orn 8 ] vasotocin is the most specific V 1 vasoconstrictor agonist that is selective for vasoconstrictor activity. Terlipressin (triglycyl lysinevasopressin), a synthetic vasopressin analog that is converted to lysine vasopressin in the body, is more selective for V 1 receptors and has a longer half-life. Vasopressin and its analogues are effective in the treatment of vasodilatory shock states and in some cases of esophageal variceal bleeding and colonic diverticular bleeding due to its V 1a agonist activity. The V 1a antagonists, the peptide antagonist d(CH2) 5 [Tyr(Me) 2 ]AVP and nonpeptide, orally active V 1a - receptor antagonists, relcovaptan and SRX251 are potential therapeutic agents for the treatment of Raynaud's disease, hypertension, heart failure, brain edema, motion sickness, cancer, preterm labor, and anger reduction.

27 Literature: Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor Basic & Clinical Pharmacology, 11e, 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