PITUITARY HORMONES

1. PITUITARY HORMONES YuliaKomarova, Ph.D. ykomarov@uic.edu

2. Classification of Anterior Pituitary Hormones

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. Indications for Growth Hormone Treatment (rhGH)

5. Recombinant Human Growth Hormone (rhGH) • Human GH is produced by recombinant DNA technology • Somatropinrefers 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. Therapeutic Uses of Somatropin • GH is administered subcutaneously, with a bioavailability of 70%. t1/2 of GH is only 20 minutes, its biological t1/2 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. 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. 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. 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.

10. Growth Hormone Antagonists • 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 • octreotide and lanreotide bind to the SST subtypes with the following order of selectivity: • SST2 > SST5 > SST3 ≫ SST1 and SST4. Pegvisomant, high affinity antagonist of GH receptor, prevents activation of GH receptor downstream signaling.

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 t1/2 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 90Y have been used in selective destruction of SST2 receptor-positive tumors.

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. 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. 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 D2 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 galactorrheain 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. 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, whereas of • Bromocriptine has the half-life about 7 hours.

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. 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.

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. 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 • GonadotropinsncludeLuteinizing 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. Thyroid-stimulating hormone (TSH) • Thyrotropinis 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 hypogonadotropichypogonadism, polycystic ovary syndrome, obesity, and other causes and to treat male infertility. • Recombinant forms of FSH (rFSH): follitropin-αandfollitropin-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-αfor 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 hypogonadotropichypogonadism

21. Ovulation Induction • Gonadotropins are used to induce ovulation in women with anovulation that is secondary to hypogonadotropichypogonadism, 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. 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 hypogonadalhypogonadism, 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. 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. Structures of GnRH and GnRH Analogs

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. 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. 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. 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. 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 Degarelixreduce 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. 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. 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. Oxytocin • Oxytocinis a peptide hormone secreted by the posterior pituitary that participates in labor and delivery and elicits milk ejection in lactating women. • Oxytocinstimulates 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. 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. 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. • V2 receptors are found on renal tubule cells and reduce diuresis through increased water permeability and water resorption in the collecting tubules. • Extrarenal V2-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 V1 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. 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. Summary: Hypothalamic and Pituitary Hormones

40. Literature: Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor Basic & Clinical Pharmacology, 11e, Chapter 37 Hypothalamic & Pituitary Hormones Laurence L. Brunton, Bruce A. Chabner, Björn C. KnollmannGoodman & Gilman's The Pharmacological Basis of Therapeutics, 12e Chapter 38 Introduction To Endocrinology: The Hypothalamic-Pituitary Axis