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

The Hypothalamic-Pituitary-Endocrine Axis

Hormones that Integrate the Hypothalamic-Anterior Pituitary-Endocrine Axis Anterior Pituitary Hormone Hypothalamic Hormone Target Organ Primary Target Organ Hormone or Mediator Growth hormone (GH, somatotropin) Growth hormone-releasing hormone (GHRH) (+) Somatostatin (–) Liver, muscle, bone, kidney, and others Insulin-like growth factor-1 (IGF-1) Thyroid-stimulating hormone (TSH) Thyrotropin-releasing hormone (TRH) (+) Thyroid Thyroxine, triiodothyronine Adrenocorticotropin (ACTH) Corticotropin-releasing hormone (CRH) (+) Adrenal cortex Glucocorticoids, mineralocorticoids, androgens Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Gonadotropin-releasing hormone (GnRH) (+)2   Gonads Estrogen, progesterone, testosterone Prolactin (PRL) Dopamine (–) Breast —

Clinical Uses of Hypothalamic Hormones and Their Analogs Growth hormone-releasing hormone (GHRH) Used rarely as a diagnostic test for GH responsiveness Thyrotropin-releasing hormone (TRH, protirelin) Used rarely to diagnose hyper- or hypothyroidism Corticotropin-releasing hormone (CRH) Used rarely to distinguish Cushing's disease from ectopic ACTH secretion Gonadotropin-releasing hormone (GnRH) Used rarely in pulses to treat infertility caused by hypothalamic dysfunction   Analogs used in long-acting formulations to inhibit gonadal function in men with prostate cancer and women undergoing assisted reproductive technology (ART) or women who require ovarian suppression for a gynecologic disorder Dopamine Dopamine agonists used for treatment of hyperprolactinemia

Classification of Anterior Pituitary Hormones MASS (daltons) PEPTIDE CHAINS AMINO ACID RESIDUES CHROMOSOMAL LOCATION Somatotropic hormones      Growth hormone (GH) 22,000 1 191 17q22-24   Prolactin (PRL) 23,000 199 6p22.2-21.3   Placental lactogen (PL) 22,125 190 Glycoprotein hormones    Luteinizing hormone (LH) 29,400 2 α-92 β-121 6q12.q21 19q13.3   Follicle-stimulating hormone (FSH) 32,600 β-111 11p13   Human chorionic gonadotropin (hCG) 38,600 β-145   Thyroid-stimulating hormone (TSH), thyrotropin 28,000 β-118 1p13 POMC-derived hormones*  Adrenocorticotropic hormone (ACTH) 4500 39 2p22.3 α-Melanocyte-stimulating (α-MSH)  1650 13

Somatotropic Hormone Family: Growth Hormone Structure and Pharmacokinetics GH, a single polypeptide chain of 22 kDa and 20kDa, is secreted by the pituitary cells somatotropes as a heterogeneous mixture of peptides Daily GH secretion varies throughout life; high in children, peaks during puberty, and then decreases in an age-related manner in adulthood. GH is secreted in discrete but irregular pulses. The amplitude of secretory pulses is greatest at night, and the most consistent period of GH secretion is shortly after the onset of deep sleep. GH has a half-life of 20–25 minutes and is predominantly cleared by the liver.

Molecular and Cellular Bases of GH Action 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).

Somatotropic Hormone Family: Growth Hormone Developmental Actions: GH is required during childhood and adolescence for attainment of normal adult size and body composition; GH increases the production of IGF-1 in the liver, bone, cartilage, muscle, and the kidney. GH stimulates longitudinal bone growth Metabolic Effects: GH controls lipid and carbohydrate metabolism, and lean body mass. GH has anabolic effects in muscle and catabolic effects in lipid cells adipocytes. GH reduces insulin sensitivity, which results in mild hyperinsulinemia.

Regulation of GH Biosynthesis and Secretion Positive Regulators of GH GH-RH, produced by hypothalamic neurons found predominantly in the arcuate nucleus, binds to and activates specific GPCR on somatotropes; GH-RH receptor → Gs activation → cAMP and Ca2+→ GH secretion and release Ghrelin, a 28-amino acid peptide that is octanoylated at Ser3. Ghrelin is synthesized in endocrine cells in the fundus of the stomach. Ghrelin activates the GH secretagogue receptor and directly stimulates GH release. Both fasting and hypoglycemia stimulate circulating ghrelin levels.

Negative Regulators of GH Insulin-like growth factor 1 (IGF-1), acts in a negative feedback loop. IGF-1 inhibits GH by effecting GH release from the anterior pituitary gland. Somatostatin (SST) is synthesized in widely distributed neuronsas as a 92–amino acid precursor; proteolytic cleavage products are: SST-28 and SST-14. SST binds to and activates a family of five related GPCRs that signal through Gi to inhibit cyclic AMP accumulation and to activate K+ channels and protein phosphotyrosine phosphatases.

Regulation of GH Biosynthesis and Secretion

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.

Growth Hormone Treatment 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

Indications for Growth Hormone Treatment (rhGH) Treatment of children with short stature Children with Turner syndrome, Noonan's syndrome, Prader-Willi syndrome, or chronic renal insufficiency, children born small for gestational age, and children with idiopathic short stature In 2004, GH was approved for treatment of patients with short bowel syndrome. In this case, GH is administered with glutamine, which also has trophic effects on the intestinal mucosa. GH is a popular component of anti-aging programs by athletes for a purported increase in muscle mass and athletic performance. GH is one of the drugs banned by the Olympic Committee.

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); Somatrem refers to a derivative of GH with an additional methionine at the N-terminus that is no longer available in the U.S. Sermorelin (GEREF) is a synthetic form of human GHRH that corresponds in sequence to the first 29 amino acids of human GHRH (a 44–amino acid peptide) and has full biological activity. Sermorelin was withdrawn from the U.S. market in late 2008.

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.

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. GH treatment is contraindicated in a patient with a known malignancy. proliferative retinopathy is rare

Recombinant Human IGF-1 (mecasermin) Therapeutic Uses 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.

Excess Production of Growth Hormone Clinical Manifestations 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.

Growth Hormone Antagonists Somatostatin analogs: octreotide, octreotide acetate, lanreotide, vapreotide Pegvisomant , high affinity antagonist of GH receptor, prevents activation of GH receptor downstream signaling.

Octreotide 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.

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 that oversecrete TSH. 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.

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.

Growth Hormone Antagonists, Pegvisomant Pegvisomant (SOMAVERT) is a GH receptor antagonist that is FDA-approved for the treatment of acromegaly.. Pegvisomant is 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. Pegvisomant binds to the GH receptor but does not activate JAK-STAT signaling or stimulate IGF-1 Pegvisomant is administered subcutaneously as a 40-mg loading dose under physician supervision, followed by self-administration of 10 mg per day. Based on serum IGF-1 levels, the dose is titrated at 4- to 6-week intervals to a maximum of 40 mg per day. Pegvisomant should not be used in patients with an unexplained elevation of hepatic transaminases. Pegvisomant differs structurally from native GH and induces the formation of specific antibodies in 15% of patients. Pegvisomant provides a highly effective alternative for use in patients who have not responded to SST analogs.

Somatotropic Hormone Family: Prolactin Human prolactin is a 23 kDa peptide hormone produced in the anterior pituitary. It is synthesized by lactotropes and presents in dimeric and polymeric forms in circulation. 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. 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 GnRH release.

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

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.

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.

Hyperprolactinemia Acromegaly dopamine agonists are the standard medical treatment for hyperprolactinemia. they 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.

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.

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 The gonadotropins include LH, FSH, and hCG LH and FSH are synthesized and secreted by a single type of pituitary cell, 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. FSH stimulates the conversion by granulosa cells of androgens to estrogens. LH stimulates androgen production by theca cells in the follicular stage of the menstrual cycle In the luteal phase of the menstrual cycle, estrogen and progesterone production is primarily under the control first of LH and then, if pregnancy occurs, under the control of human chorionic gonadotropin (hCG). hCG is a placental protein nearly identical with LH; its actions are mediated through LH receptors. In men, FSH is the primary regulator of spermatogenesis, whereas LH is the main stimulus for the production of testosterone by Leydig cells. FSH helps to maintain high local androgen concentrations in the vicinity of developing sperm by stimulating the production of androgen-binding protein by Sertoli cells. FSH also stimulates the conversion by Sertoli cells of testosterone to estrogen.

Thyroid-stimulating hormone (TSH) Thyrotropin is used for diagnostic thyroid function in patients who have been treated surgically for thyroid carcinoma, to test for recurrence by assessing TSH-stimulated whole-body 131I scans and serum thyroglobulin determinations Follicle-Stimulating Hormone Urofollitropin, also known as uFSH, is a purified preparation of human FSH that is extracted from the urine of postmenopausal women. Recombinant forms of FSH (rFSH): follitropin alfa and follitropin beta. Luteinizing Hormone Lutropin alfa, the recombinant form of human LH, has only been approved for use in combination with follitropin alfa for stimulation of follicular development in infertile women with profound LH deficiency. Human Chorionic Gonadotropin (hCG) Choriogonadotropin alfa (rhCG) is a recombinant form of hCG.

Ovulation Induction Toxicity & Contraindications 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 is a serious complication that 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 estimated to be 15–20%, whereas the percentage of multiple pregnancies in the general population is closer to 1%. headache, depression, edema, precocious puberty, and (rarely) production of antibodies to hCG.

Toxicity & Contraindications 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 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.

Regulation of Gonadotropin Synthesis and Secretion the hypothalamic peptide GnRH is the predominant regulator of gonadotropin synthesis and secretion. GnRH is a decapeptide with blocked amino and carboxyl termini derived by proteolytic cleavage of a 92–amino acid precursor peptide. 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 GnRH pulse generator is active late in fetal life and for 1 year after birth but decreases considerably thereafter, presumably secondarily to CNS inhibition. Shortly before puberty, CNS inhibition decreases and the amplitude and frequency of GnRH pulses increase, particularly during sleep. 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

Regulation of Gonadotropin Synthesis and Secretion

Structures of GnRH and GnRH Analogs AMINO ACID RESIDUE GnRH CONGENER (TRADE NAME)  1 2 3 4 5 6 7 8 9 10 DOSAGE FORMS Agonists    GnRH (FACTREL, LUTREPULSE)  PyroGlu His Trp Ser Tyr Gly Leu Arg Pro Gly-NH2   IV, SC Goserelin (ZOLADEX)  — D-Ser(tBu) AzGly-NH2   SC implant Nafarelin (SYNAREL)  D-Nal IN Triptorelin (TRELSTAR DEPOT, LA)  D-Trp IM depot Buserelin* (SUPREFACT)  Pro-NHEt IN, SC Deslorelin* , depot Histrelin (VANTAS, SUPPRELIN LA)  D-His(Bzl) Leuprolide (LUPRON, ELIGARD)  D-Leu Antagonists  Abarelix* (PLENAXIS)  Ac-D-Nal D-Cpa D-Pal Tyr(N-Me) D-Asn (iPr) D-Ala-NH2   SC depot Cetrorelix (CETROTIDE)  D-Cit SC Ganirelix (ANTAGON)  D-hArg(Et)2  

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.

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

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.

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.

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.

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

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.

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 through G protein-coupled receptors and the phosphoinositide-calcium second-messenger system to contract uterine smooth muscle. 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.

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.

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.

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.

Summary: Hypothalamic and Pituitary Hormones Subclass Mechanism of Action Effects Clinical 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 

GH receptor antagonist    Pegvisomant Blocks 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 alfa Activates 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 

(GnRH) analogs    Leuprolide Agonist 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    Ganirelix Blocks 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 D2 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 

  Oxytocin Activates oxytocin receptors Increased 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    Atosiban Blocks oxytocin receptors Decreased uterine contractions Tocolysis for preterm labor IV infusion Toxicity: Concern about rates of infant death  Vasopressin receptor agonists    Desmopressin Activates vasopressin V2 receptors much more than V1 receptors   Acts in the kidney to decrease the excretion of water acts on extrarenal V2 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 V1a and V2 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 V2 receptors   

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. Knollmann Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e Chapter 38 Introduction To Endocrinology: The Hypothalamic-Pituitary Axis