1. 1 PITUITARY HORMONES Yulia Komarova, Ph.D. ykomarov@uic.edu

2. 2 HORMONE MASS (daltons) PEPTIDE CHAINS AMINO ACID RESIDUES CHROMOSOMAL LOCATION Somatotropic hormones Growth hormone (GH)22,000119117q22-24 Prolactin (PRL)23,00011996p22.2-21.3 Placental lactogen (PL)22,125119017q22-24 Glycoprotein hormones Luteinizing hormone (LH)29,4002 α-92 β-121 6q12.q21 19q13.3 Follicle-stimulating hormone (FSH) 32,6002 α-92 β-111 6q12.q21 11p13 Human chorionic gonadotropin (hCG) 38,6002 α-92 β-145 6q12.q21 19q13.3 Thyroid-stimulating hormone (TSH), thyrotropin 28,0002 α-92 β-118 6q12.q21 1p13 POMC-derived hormones Adrenocorticotropic hormone (ACTH) 45001392p22.3 α-Melanocyte-stimulating (α-MSH) 1650113 Classification of Anterior Pituitary Hormones

3. 3 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.

4. 4 Indications for Growth Hormone Treatment (rhGH) 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

5. 5 Recombinant Human Growth Hormone (rhGH) Human GH is produced by recombinant DNA technology Somatropin refers to the many GH preparations whose sequences match that of native 22 aa peptide GH (ACCRETROPIN, GENOTROPIN, HUMATROPE, NORDITROPIN, NUTROPIN, OMNITROPE, SAIZEN, SEROSTIM, TEV-TROPIN, VALTROPIN, and ZORBTIVE);

6. 6 Therapeutic Uses of Somatropin GH is administered subcutaneously, with a bioavailability of 70%. t 1/2 of GH is only 20 minutes, its biological t 1/2 is considerably longer, and once-daily administration is sufficient. In GH-deficient children, somatropin typically 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. In the setting of AIDS-related wasting, considerably higher doses (e.g., 100 g/kg) have been used.

7. 7 Somatropin Toxicity & Contraindications Children: rarely intracranial hypertension, which may manifest as vision changes, headache, nausea, or vomiting. 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. carpal tunnel syndrome can occur. proliferative retinopathy is rare GH treatment is contraindicated in a patient with a known malignancy.

8. 8 Therapeutic Uses of Recombinant Human Insulin-like growth factor-1 (IGF-1)(mecasermin) for patients with impaired growth secondary to mutations in the GH receptor or postreceptor signaling pathway, patients with GH deficiency who develop antibodies against GH that interfere with its action, and the very rare patients with IGF-1 gene defects that lead to primary IGF-1 deficiency 40-80 g/kg per dose twice daily by subcutaneous injection, with a maximum of 120 g/kg per dose twice daily.

9. 9 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

10. 10 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 Pegvisomant, high affinity antagonist of GH receptor, prevents activation of GH receptor downstream signaling.

11. 11 Therapeutic Uses of Octreotide octreotide (100 g) administered subcutaneously three times daily is virtually 100% bioactive, 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. octreotide has been used to treat symptoms associated with metastatic carcinoid tumors (e.g., flushing and diarrhea) and adenomas secreting vasoactive intestinal peptide (e.g., watery diarrhea). octreotide is used for treatment of acute variceal bleeding and for perioperative prophylaxis in pancreatic surgery. octreotide has significant inhibitory effects on TSH secretion, and it is the treatment of choice for patients who have thyrotrope adenomas. octreotide labeled with indium or technetium has been used for diagnostic imaging of neuroendocrine tumors such as pituitary adenomas and carcinoids (OCTREOSCAN); modified forms labeled with emitters such as 90 Y have been used in selective destruction of SST 2 receptor-positive tumors.

12. 12 Toxicity & Contraindications of SST analogs 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%). octreotide reduces insulin secretion to a lesser extent as SST and only infrequently affects glycemic control.

13. 13 Growth Hormone Antagonists, Pegvisomant Pegvisomant (SOMAVERT) is a GH receptor antagonist that is FDA-approved for the treatment of acromegaly.. the polyethylene glycol (PEG) derivative of a mutant GH, B2036, 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 is administered subcutaneously as a 40-mg loading 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. should not be used in patients with an unexplained elevation of hepatic transaminases. differs structurally from native GH and induces the formation of specific antibodies in 15% of patients. provides a highly effective alternative for use in patients who have not responded to SST analogs.

14. 14 Somatotropic Hormone Family: Prolactin Prolactin is the principal hormone responsible for lactation. Milk production is stimulated by prolactin when appropriate circulating levels of estrogens, progestins, corticosteroids, and insulin are present. 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 A deficiency of prolactin—which can occur in rare states of pituitary deficiency—is manifested by failure to lactate. 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).

15. 15 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.

16. 16 Therapeutic Uses of Dopamine Agonists Dopamine agonists suppress prolactin release very effectively in patients with hyperprolactinemia. Dopamine agonists reduce GH release in patients with acromegaly, although not as effectively. Cabergoline and bromocriptine are also used in Parkinson's disease to improve motor function and reduce levodopa requirements 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.

17. 17 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.

18. 18 Toxicity & Contraindications of Dopamine Agonists nausea, headache, light-headedness, orthostatic hypotension, and fatigue. occasional psychiatric manifestations high dosages of ergot-derived preparations 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.

19. 19 The Glycoprotein Hormones: TSH and the Gonadotropins Thyroid-stimulating hormone(TSH) release is regulated by thyrotropin-releasing hormone (TRH) and inhibited by thyroid hormones, thyroxine and triiodothyronine Gonadotropins nclude Luteinizing hormone (LH), Follicle-stimulating hormone (FSH), and Human chorionic gonadotropin (hCG) LH and FSH are synthesized and secreted by the gonadotroph, which make up 10% of the hormone- secreting cells in the anterior pituitary hCG is synthesized by the syncytiotrophoblast of the placenta. In women FSH directs ovarian follicle development LH stimulates androgen production in the follicular stage of the menstrual cycle In men FSH is the primary regulator of spermatogenesis, LH is the main stimulus for the production of testosterone by Leydig cells.

20. 20 Thyroid-stimulating hormone (TSH) Thyrotropin is used for diagnostics of thyroid function in patients who have been treated surgically for thyroid carcinoma, to test for recurrence Follicle-Stimulating Hormone (FSH) Urofollitropin (uFSH), is a purified preparation of human FSH that is extracted from the urine of postmenopausal women, is used to induce ovulation in women with anovulation that is secondary to hypogonadotropic hypogonadism, polycystic ovary syndrome, obesity, and other causes and to treat male infertility. Recombinant forms of FSH (rFSH): follitropin-α and follitropin-β, are used for controlled ovulation hyperstimulation in women, infertility in men due to hypogonadism Luteinizing Hormone (LH) Lutropin-α, the recombinant form of human LH, has only been approved for use in combination with follitropin-α for stimulation of follicular development in infertile women with profound LH deficiency. Human Chorionic Gonadotropin (hCG) Choriogonadotropin -α (rhCG), a recombinant form of hCG, is used for controlled ovulation and hyperstimulation ovarian follicle development in women with hypogonadotropic hypogonadism

21. 21 Ovulation Induction Gonadotropins are used to induce ovulation in women with anovulation that is secondary to hypogonadotropic hypogonadism, polycystic ovary syndrome, obesity. Gonadotropins are also used for controlled ovarian hyperstimulation in assisted reproductive technology procedures. Toxicity & Contraindications the ovarian hyperstimulation syndrome and multiple pregnancies. the ovarian hyperstimulation syndrome occurs in 0.5–4% of patients. It is characterized by ovarian enlargement, ascites, hydrothorax, and hypovolemia, sometimes resulting in shock. the risk of multiple pregnancy is 15–20% headache, depression, edema, precocious puberty, and (rarely) production of antibodies to hCG.

22. 22 Male Infertility treatment of infertility in hypogonadal men requires the activity of both LH and FSH. initial treatment for 8–12 weeks with injections of 1000–2500 IU hCG several times per week following human menopausal gonadotropins (hMG) injection at a dose of 75–150 units three times per week. In men with hypogonadal hypogonadism, it takes an average of 4–6 months of such treatment for sperm to appear in the ejaculate. an advance that has indirectly benefited gonadotropin treatment of male infertility is intracytoplasmic sperm injection (ICSI), in which a single sperm is injected directly into a mature oocyte that has been retrieved after controlled ovarian hyperstimulation of a female partner. Toxicity & Contraindications the risk of gynecomastia is directly correlated with the level of testosterone produced in response to treatment.

23. 23 Regulation of Gonadotropin Synthesis and Secretion the hypothalamic peptide GnRH is the predominant regulator of gonadotropin synthesis and secretion. GnRH release is pulsatile and is governed by a neural pulse generator in the hypothalamus, primarily in the arcuate nucleus, that controls the frequency and amplitude of GnRH release. The intermittent release of GnRH is crucial for the proper synthesis and release of the gonadotropins; the continuous administration of GnRH leads to desensitization and down- regulation of GnRH receptors on pituitary gonadotropes and forms the basis for the clinical use of long-acting GnRH agonists to suppress gonadotropin secretion

24. 24 Structures of GnRH and GnRH Analogs AMINO ACID RESIDUE GnRH CONGENER (TRADE NAME) 12345678910 DOSAGE FORMS Agonists GnRH (FACTREL, LUTREPULSE) PyroGluHisTrpSerTyrGlyLeuArgPro Gly-NH 2 IV, SC Goserelin (ZOLADEX) —————D-Ser(tBu)——— AzGly-NH 2 SC implant Nafarelin (SYNAREL) —————D-Nal————IN Triptorelin (TRELSTAR DEPOT, LA) —————D-Trp————IM depot Buserelin* (SUPREFACT) —————D-Ser(tBu)—— Pro- NHEt IN, SC Deslorelin*—————D-Trp—— Pro- NHEt, depot Histrelin (VANTAS, SUPPRELIN LA) —————D-His(Bzl)—— Pro- NHEt SC implant Leuprolide (LUPRON, ELIGARD) —————D-Leu—— Pro- NHEt, depot Antagonists Abarelix* (PLENAXIS) Ac-D-NalD-CpaD-Pal—Tyr(N-Me)D-Asn— (iPr) — D-Ala-NH 2 SC depot Cetrorelix (CETROTIDE) Ac-D-NalD-CpaD-Pal——D-Cit——— D-Ala-NH 2 SC Ganirelix (ANTAGON) Ac-D-NalD-CpaD-Pal——D-hArg(Et) 2 — —D-Ala-NH 2 SC

25. 25 Synthetic GnRH Agonists Gonadorelin is an acetate salt of synthetic human GnRH. Synthetic GnRH analogs: goserelin, histrelin, leuprolide, nafarelin, and triptorelin. These analogs all have D-amino acids at position 6, and all but nafarelin have ethylamide substituted for glycine at position 10. Both modifications make them more potent and longer-lasting than native GnRH and gonadorelin. Pharmacokinetics Gonadorelin can be administered intravenously or subcutaneously. GnRH analogs can be administered subcutaneously, intramuscularly, via nasal spray (nafarelin), or as a subcutaneous implant. The duration of clinical uses of GnRH agonists varies from a few days for ovulation induction to years for treatment of metastatic prostate cancer.

26. 26 Therapeutic Uses of Synthetic GnRH Agonists pulsatile intravenous administration of gonadorelin every 1–4 hours stimulates FSH and LH secretion. continuous administration of gonadorelin or its longer-acting analogs produces a biphasic response. The first 7–10 days, an agonist effect results in increased concentrations of gonadal hormones in males and females. The continued presence of GnRH results in an inhibitory action that manifests as a drop in the concentration of gonadotropins and gonadal steroids. Female and Male Infertility Diagnosis of LH Responsiveness Controlled Ovarian Hyperstimulation Endometriosis Uterine Leiomyomata (Uterine Fibroids) Prostate Cancer Central Precocious Puberty

27. 27 Toxicity headache, light-headedness, nausea, and flushing. local swelling at subcutaneous injection sites. Generalized hypersensitivity dermatitis has occurred after long-term subcutaneous administration. In women, continuous treatment with a GnRH analog (leuprolide, nafarelin, goserelin) causes the symptoms of menopause including hot flushes, sweats, and headaches. Depression, diminished libido, generalized pain, vaginal dryness, and breast atrophy may also occur. Ovarian cysts may develop within the first 2 months of therapy and generally resolve after an additional 6 weeks Reduced bone density and osteoporosis may occur with prolonged use, so patients should be monitored with bone densitometry before repeated treatment courses. Contraindications to the use of GnRH agonists in women include pregnancy and breast-feeding. In men treated with continuous GnRH agonist administration, adverse effects include hot flushes and sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density, asthenia. GnRH analog treatment of children is generally well tolerated.

28. 28 Synthetic GnRH Receptor Antagonists Ganirelix,cetrorelix, abarelix, and degarelix inhibit the secretion of FSH and LH in a dose- dependent manner. canirelix and cetrorelix are approved for use in controlled ovarian hyperstimulation procedures abarelix and degarelix are approved for men with advanced prostate cancer. Pharmacokinetics Administration of 0.25 mg of Ganirelix and cetrorelix daily maintains GnRH antagonism. A single 3.0-mg dose of cetrorelix suppresses LH secretion for 96 hours. Abarelix reaches a peak concentration 3 days after injection and has a half-life of 13 days. After three initial doses on days 1, 13, and 28, abarelix is administered every 4 weeks.

29. 29 Therapeutic Uses of Synthetic GnRH receptor Antagonists Suppression of Gonadotropin Production GnRH antagonists are approved for preventing the LH surge during controlled ovarian hyperstimulation. GnRH antagonists produce an immediate antagonist effect, their use is shorter as compared to GnRH agonist and treatment can be delayed until day 6–8 of the in vitro fertilization cycle. Advanced Prostate Cancer Abarelix is approved for the treatment of symptomatic advanced prostate cancer in men for whom a GnRH agonist is not appropriate and who decline surgical castration. Abarelix and Degarelix reduce symptoms in patients with vertebral or skeletal metastasis, or bladder outlet obstruction. Toxicity ganirelix and cetrorelix are well tolerated when used for controlled ovarian hyperstimulation. nausea and headache. abarelix has elicited immediate-onset allergic responses that manifested as skin reactions or as hypotension and syncope, and it also prolonged the QT interval. abarelix leads to signs and symptoms of androgen deprivation, including hot flushes and sweats, gynecomastia, decreased libido, decreased hematocrit, and reduced bone density.

30. 30 Adrenocorticotropic hormone (ACTH) ACTH a single peptide that is cleaved from a larger precursor that also contains the peptide –endorphin ACTH release is stimulated by corticotropin-releasing hormone (CRH). Production of ACTH is inhibited by cortisol Diagnostic Use ACTH is used test for a cortisol response in patients suspected of adrenal insufficiency ACTH is used to identify 21-hydroxylase deficiency, 11-hydroxylase deficiency, and 3 - hydroxy- 5 steroid dehydrogenase deficiency, in patients suspected of congenital adrenal hyperplasia

31. 31 Posterior Pituitary Hormones Vasopressin and oxytocin 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.

32. 32 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 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.

33. 33 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 to oxytocin include fetal distress, prematurity, abnormal fetal presentation, cephalopelvic disproportion, and other predispositions for uterine rupture.

34. 34 Vasopressin (Antidiuretic Hormone, ADH) 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 two 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. Desmopressin acetate (DDAVP, 1-desamino-8-D-arginine vasopressin) is a long-acting synthetic analog of vasopressin with minimal V 1 activity and an antidiuretic-to-pressor ratio 4000 times that of vasopressin. Desmopressin is modified at position 1 and contains a D-amino acid at position 8.

35. 35 Therapeutic Uses of Vasopressin and Desmopressin Vasopressin and desmopressin are treatments of choice for pituitary diabetes insipidus. The dosage of desmopressin is 10–40 mcg (0.1–0.4 mL) in two to three divided doses as a nasal spray or, as an oral tablet, 0.1–0.2 mg two to three times daily. The dosage by injection is 1–4 mcg (0.25–1 mL) every 12–24 hours as needed for polyuria, polydipsia, or hypernatremia.. Vasopressin infusion is effective in some cases of esophageal variceal bleeding and colonic diverticular bleeding. Desmopressin is also used for the treatment of coagulopathy in hemophilia A and von Willebrand's disease. Toxicity & Contraindications Headache, nausea, abdominal cramps, agitation, and allergic reactions occur rarely. Overdosage can result in hyponatremia and seizures. Vasopressin (but not desmopressin) can cause vasoconstriction and should be used cautiously in patients with coronary artery disease.

36. 36 Summary: Hypothalamic and Pituitary Hormones SubclassMechanism of ActionEffectsClinical Applications Pharmacokinetics, Toxicities, Interactions Growth hormone (GH) Somatropin Recombinant form of human GH acts through GH receptors to increase production of insulin-like growth factor-1 (IGF-1) Restores normal growth and metabolic GH effects in GH- deficient individuals increases final adult height in some children with short stature not due to GH deficiency Replacement in GH deficiency increased final adult height in children with certain conditions associated with short stature (see Table 37–4) wasting in HIV infection short bowel syndrome SC injection 3–7 x/wk Toxicity: Scoliosis, edema, gynecomastia, intracranial hypertension, myalgia, arthralgia, carpal tunnel syndrome, increased CYP450 activity IGF-1 agonist Mecasermin Recombinant form of IGF-1 that stimulates IGF-1 receptors Restores normal growth and metabolic IGF-1 effects in individuals with IGF-1 deficiency Replacement in IGF-1 deficiency that is not responsive to exogenous GH SC injection 2 x/d also contains recombinant human IGF-binding protein-3, which prolongs the half-life of the rIGF-1 Toxicity: Hypoglycemia, intracranial hypertension, increased liver enzymes Somatostatin analogs Octreotide Agonist of somatostatin receptors Inhibits production of GH and, to a lesser extent, of glucagon, insulin, and gastrin Acromegaly and several other hormone-secreting tumors acute control of bleeding from esophageal varices SC injection 3–7 x/d long- acting formulation injected IM monthly Toxicity: Gastrointestinal disturbances, gallstones, bradycardia, and other cardiac conduction problems Lanreotide: Similar to octreotide and available as a long-acting formulation for acromegaly

37. 37 GH receptor antagonist PegvisomantBlocks GH receptors Ameliorates effects of excess GH production Acromegaly SC injection 3–7 x/wk Toxicity: Increased liver enzymes Gonadotropins: Follicle-stimulating hormone (FSH) analogs Follitropin alfaActivates FSH receptors Mimics effects of endogenous FSH Controlled ovulation hyperstimulation in women infertility due to hypogonadism in men SC injection 3–7 x/wk Toxicity: Ovarian hyperstimulation syndrome and multiple pregnancies in women gynecomastia in men headache, depression, edema in both sexes Follitropin beta: A recombinant product with the same peptide sequence as follitropin alfa but differs in its carbohydrate side chains Urofollitropin: Human FSH purified from the urine of postmenopausal women Menotropins (hMG): Extract of the urine of postmenopausal women; contains both FSH and LH activity Gonadotropins: Luteinizing hormone (LH) analogs Human chorionic gonadotropin (hCG) Agonist of the LH receptor Mimics effects of endogenous LH Initiation of ovulation during controlled ovulation hyperstimulation ovarian follicle development in women with hypogonadotropic hypogonadism IM Toxicity: Ovarian hyperstimulation syndrome and multiple pregnancies in women gynecomastia in men headache, depression, edema in both sexes Choriogonadotropin alfa: Recombinant form of hCG Lutropin: Recombinant form of human LH Menotropins (hMG): Extract of the urine of postmenopausal women that contains both FSH and LH activity

38. 38 (GnRH) analogs LeuprolideAgonist of GnRH receptors Increased LH and FSH secretion with intermittent administration reduced LH and FSH secretion with prolonged continuous administration Ovarian suppression, controlled ovarian hyperstimulation, central precocious puberty advanced prostate cancer Administered IV, SC, IM or intranasally depot formulations are available Toxicity: Headache, light- headedness, nausea, injection site reactions symptoms of hypogonadism with continuous treatment Gonadorelin is synthetic human GnRH Other GnRH analogs: Goserelin, histrelin, nafarelin, and triptorelin Gonadotropin-releasing hormone (GnRH) receptor antagonists GanirelixBlocks GnRH receptors Reduces endogenous production of LH and FSH Prevention of premature LH surges during controlled ovulation hyperstimulation SC injection Toxicity: Nausea, headache Cetrorelix: Similar to ganirelix and approved for controlled ovarian hyperstimulation Abarelix, degarelix: Approved for advanced prostate cancer; can cause immediate-type hypersensitivity reactions Dopamine agonists Bromocriptine Activates dopamine D 2 receptors Suppresses pituitary secretion of prolactin dopaminergic effects on CNS motor control and behavior Treatment of hyperprolactinemia and Parkinson's disease Administered orally or vaginally Toxicity: Gastrointestinal disturbances, orthostatic hypotension, headache, psychiatric disturbances, vasospasm and pulmonary infiltrates in high doses Cabergoline: Another ergot derivative with similar effects

39. 39 OxytocinActivates oxytocin receptorsIncreased uterine contractions Induction and augmentation of labor control of uterine hemorrhage after delivery IV infusion Toxicity: Fetal distress, placental abruption, uterine rupture, fluid retention, hypotension Oxytocin receptor antagonist AtosibanBlocks oxytocin receptors Decreased uterine contractions Tocolysis for preterm labor IV infusion Toxicity: Concern about rates of infant death Vasopressin receptor agonists Desmopressin Activates vasopressin V 2 receptors much more than V 1 receptors Acts in the kidney to decrease the excretion of water acts on extrarenal V 2 receptors to increase factor VIII and von Willebrand factor Pituitary diabetes insipidus hemophilia A and von Willebrand disease Oral, IV, SC, or intranasal Toxicity: Gastrointestinal disturbances, headache, hyponatremia, allergic reactions Vasopressin: Available for treatment of diabetes insipidus and sometimes used to control bleeding from esophageal varices Vasopressin receptor antagonist Conivaptan Antagonist of vasopressin V 1a and V 2 receptors Reduced renal excretion of water in conditions associated with increased vasopressin Hyponatremia in hospitalized patients IV infusion Toxicity: Infusion site reactions Tolvaptan: Similar but more selective for vasopressin V 2 receptors

40. 40 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