Photo: Colorized transmission electron micrograph of an endocrine cell from the anterior pituitary gland. The secretory vesicles (brown) contain hormones. From: Seeley’s Anatomy & Physiology 10th ed New York, NY: McGraw-Hill 2010.
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Learning Objectives 1. Neuroendocrine Pharmacology: Hypothalamic and Pituitary Hormones 1. The physiology of neuroendocrine hormonal regulation, including a) Hypothalamus-Pituitary-Growth Hormone Axis, b) Hypothalamus-Pituitary-Reproductive Axis, c) Hypothalamus-Pituitary-Prolactin Axis 2. The use of specific neuroendocrine agents in treatment of following neuroendocrine disorders: a) growth hormone deficiency b) growth hormone excess c) infertility d) hyperprolactinemia 3. The indications, mechanism of action, adverse effects, contraindications and therapeutic considerations for the major neuroendocrine hormones and pharmacological agents. Marc Imhotep Cray, MD
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Some hormones and drugs affecting the hypothalamus, pituitary, and thyroid HYPOTHALAMIC AND ANTERIOR PITUITARY HORMONES
HCG Corticotropin Cosyntropin Follitropin alfa Follitropin beta Goserelin Histrelin Leuprolide Menotropins Nafarelin Octreotide Pegvisomant Somatropin Urofollitropin Marc Imhotep Cray, MD
Corticorelin (CRH) Gonadorelin (GnRH) Octreotide Protirelin (TRH) Sermorelin Somatostatin Triptorelin GnRH antagonists Ganirelix Cetrorelix
HORMONES OF THE POSTERIOR PITUITARY
Desmopressin DDAVP Oxytocin Vasopressin (ADH) DRUGS AFFECTING THE THYROID
Iodine and potassium iodide Liothyronine Levothyroxine Methimazole Propylthiouracil (PTU)
NB (note well [Lat. nota bene]) The ending –relin indicates a hypothalamus-related hormone. Drugs that end in –tropin are related to the pituitary hormones.
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Hypothalamic and Pituitary Disorders
Marc Imhotep Cray, MD
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Marc Imhotep Cray, MD
Baron SJ and Lee CI. Lange Pathology Flash Cards. New York: McGraw-Hill, 2009
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Hormones secreted by anterior pituitary include: FSH, LH, ACTH, TSH, prolactin, and GH FLAT P(i)G is a useful mnemonic to remember these hormones
Marc Imhotep Cray, MD
Modified from: Whalen K. Lippincott Illustrated Reviews: Pharmacology 6th Ed. Wolters Kluwer, 2015
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Case 39 Drugs Active on the Hypothalamus and Pituitary Gland A 67-year-old man complains of pain in his right hip for the past few weeks. He has had no injury to the area and describes the pain as a “bone ache� that does not radiate. Review of systems is positive only for some weakness of urinary stream and having to get up twice a night to go to the bathroom. His general physical examination is normal. His hip examination is normal with a full range of motion and no tenderness. Examination of his prostate reveals it to be firm, enlarged, and nodular. Blood tests show a markedly elevated prostate-specific antigen (PSA), and biopsy of the prostate shows carcinoma. A bone scan confirms the presence of metastatic disease in the right hip. Along with other adjuvant therapies, a decision is made to start depot leuprolide acetate. _ Leuprolide acetate is an analog of which hypothalamic hormone? _ What is the mechanism of action of leuprolide acetate? _ Which pituitary hormones are affected by leuprolide acetate, and how are they affected? Marc Imhotep Cray, MD
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Marc Imhotep Cray, MD
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Sanders, 2014
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Regulation of Hypothalamic & Pituitary Hormones Hypothalamus and pituitary control a complex neuroendocrine system that governs metabolism, growth, and reproduction Hypothalamus produces both inhibitory and releasing neuropeptides and hormones which reach pituitary via a hypophysial portal system Hypothalamic hormones trigger release of anterior pituitary hormones which are sent to target organs where they induce hormone synthesis Endocrine-organ systems function via negative feedback, o eg, hypothalamic CRH stimulates pituitary ACTH secretion stimulates adrenal cortisol secretion which in turn inhibits CRH and ACTH secretion
Marc Imhotep Cray, MD
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Hypothalamic and pituitary hormones (2) Hypothalamic and pituitary hormones are used as tools in stimulation tests to diagnose hypofunctioning or hyperfunctioning endocrine states For example, ACTH and CRH, which target adrenal cortex, aid adrenal insufficiency diagnosis Pituitary hormones are also used as replacement therapy for deficiencies such as hypopituitarism
Marc Imhotep Cray, MD
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Marc Imhotep Cray, MD
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Sanders, 2014
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Hypopituitarism Hypopituitarism may be partial or complete and may result from hypothalamic disease (leading to deficiency of hypothalamic releasing hormones) or intrinsic pituitary disease (causing pituitary hormone deficiency) Patients may present with, for ex., adrenal insufficiency or hypothyroidism
Clinical signs depend on degree and rapidity of onset of deficiency For example, basal cortisol secretion is normal in partial ACTH deficiency, but during an illness, adrenal insufficiency may occur In complete ACTH deficiency, cortisol secretion is always subnormal
Marc Imhotep Cray, MD
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Hypopituitarism (2) Diagnosis of complete deficiency is relatively easy: most patients have symptoms, and serum levels of target-organ hormone (eg, cortisol, thyroxine, and testosterone in men) and pituitary hormone (eg, ACTH, thyrotropin, and luteinizing hormone, respectively) are low Causes of hypopituitarism include pituitary tumor (most common) hypothalamic tumor or cyst infiltrative and vascular disorders and pituitary or cranial radiotherapy
Marc Imhotep Cray, MD
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Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Sanders, 2014
Growth Hormone (somatotropin) normal physiologic functions and regulation GH secretion occurs primarily at night and in response to various stressors such as starvation and hypoglycemia When released during a good night of sleep, its anabolic actions on muscle and bone are of primary importance When released in response to physiologic stressors such as starvation and hypoglycemia, its metabolic actions to conserve carbohydrate fuels (for use by the central nervous system [CNS] and other glucose-dependent tissues) and maintain protein stores (to preserve muscle strength needed for mobility) take center stage GH secretion is inhibited by elevated somatostatin, glucose levels, emotional stress, illness, malnutrition, obesity, glucocorticoids, and decreased thyroid hormone Triiodothyronine (T3) is required for normal function of GH Marc Imhotep Cray, MD
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Physiologic actions of growth hormone
Marc Imhotep Cray, MD
Brown TA. Rapid Review Physiology 2nd Ed. Philadelphia: Mosby, 2012
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Somatomedins Somatomedins are produced, predominantly by liver, when growth hormones act on target tissue Somatomedins inhibit release of growth hormones by acting directly on anterior pituitary and by stimulating secretion of somatostatin from hypothalamus Somatomedins are a group of hormones that promote cell growth and division in response to stimulation by growth hormone (GH) also known as somatotropin (STH) Somatomedins have similar biological effects to somatotropin Marc Imhotep Cray, MD
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Somatomedins cont. In addition to their actions that stimulate growth, somatomedins also stimulate production of somatostatin, which suppresses growth hormone release Thus, levels of somatomedins are controlled via negative feedback through intermediates of somatostatin and growth hormone Somatomedins are produced in many tissues and have autocrine and paracrine actions in addition to their endocrine action liver is thought to be predominant source of circulating somatomedins
Three forms include: somatomedin A, another name for insulin-like growth factor 2 (IGF-2) somatomedin B, derived from vitronectin somatomedin C, another name for insulin-like growth factor 1 (IGF-1) Marc Imhotep Cray, MD
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Growth Hormone Deficiency and Treatment Growth hormone promotes linear growth by regulating endocrine and paracrine production of IGF-1 (insulin-like growth factor 1) Besides disruption in growth, GH deficiency also causes
increased subcutaneous visceral fat reduced muscle mass reduced bone density and Reduced exercise performance
Children have short stature and low growth velocity for age and pubertal stage Adults, who usually have had pituitary tumors or head trauma, show
low energy reduced strength weight gain anxiety reduced libido and impaired sleep
Marc Imhotep Cray, MD
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GH Deficiency and Treatment (2) GH therapy goals differ in children and adults In adults, they are to improve conditioning and strength, restore normal body composition, and improve quality of life In children, therapy promotes linear growth and restores body composition Synthetic Growth hormone is effective for children with GH deficiency as long as epiphyses are not closed Side effects include o o o o o o o
edema muscle and joint pain benign intracranial hypertension hair loss hypothyroidism hypoglycemia or hyperglycemia, and risk of cancer
Marc Imhotep Cray, MD
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Question A 38-year-old man presents complaining of gradually enlarging hands and feet over the past several years. In comparison with a photo from 15 years ago, his facial features have become obviously coarsened. Laboratory evaluation shows mildly elevated plasma glucose, and MRI of the brain reveals an enlarged mass in the sella turcica. Given the suspected diagnosis, specialized testing is performed in which GH levels are measured following administration of an oral glucose load; no measurable decrease is seen. What is the diagnosis? Note: One good way to diagnose this disorder is to look at an old picture of the patient and compare it with the patient’s current appearance. Because the physical changes take place over decades, family members and friends often do not recognize them. Marc Imhotep Cray, MD
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GH Excess (Acromegaly) and Treatment Acromegaly is a disfiguring hormonal disorder caused by excessive GH secretion from a pituitary tumor Signs of Acromegaly include coarse facial features and enlarged hands, feet, tongue, and internal organs (which lead to heart disease, hypertension, diabetes, arthralgias) Treatments includes surgical removal of tumor and (or) radiation, or subcutaneous use of octreotide a GH inhibitor, available in a longacting depot form or pegvisomant (growth hormone receptor antagonist) Marc Imhotep Cray, MD
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Marc Imhotep Cray, MD
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Sanders, 2014
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A. A 26-year-old attractive woman prior to acromegaly changes. B. Facial changes 20 years later in the same woman. Note the coarse facial features with large nose, lips, and chin. Protrusion of lower jaw is visible.
Marc Imhotep Cray, MD
Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. McGraw-Hill, 2013
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GH Excess (Acromegaly) and Treatment (2) Octreotide effects mimic those of natural hormone somatostatin (GHIF), ie., inhibition of GH and IGF-1 levels suppression of response of LH to GnRH By normalizing levels of GH and IGF-1-both markers for acromegalyoctreotide controls clinical signs and symptoms Common adverse effects of octreotide are gastrointestinal more serious effects include cardiac arrhythmias hypoglycemia or hyperglycemia suppression of thyrotropin pancreatitis and biliary tract abnormalities Marc Imhotep Cray, MD
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Case 39 Answers: Drugs Active on Hypothalamus and Pituitary Gland Summary: A 67-year-old man with metastatic prostate cancer is to receive depot leuprolide acetate. • Leuprolide acetate is an analog of which hypothalamic hormone: Gonadotropin releasing hormone (GnRH). • Mechanism of action of leuprolide acetate: Chronic administration of GnRH analog results in the reduction of the number of GnRH receptors in the pituitary (downregulation), with resultant decreases in pituitary gonadotropin production. • Pituitary hormones affected: Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) production is reduced. Marc Imhotep Cray, MD
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Case 39 Answers: Drugs Active on Hypothalamus and Pituitary Gland cont. CLINICAL CORRELATION The hypothalamic-pituitary-gonadal axis is a classic example of a hormonal stimulation- negative feedback system. The hypothalamus produces GnRH, which binds to specific receptors on pituitary gonadotropic cells. These cells then produce LH and FSH, which act on the gonads. LH and FSH regulate the female menstrual cycle by their effects on the ovarian follicles and the ovarian production of estrogen and progesterone. In males, LH and FSH regulate spermatogenesis and the production of testosterone in the testes. Estrogen, progesterone, and testosterone then function as feedback signals for the hypothalamic production of GnRH. Leuprolide acetate is a synthetic 9-amino acid analog of GnRH. Marc Imhotep Cray, MD
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Case 39 Answers: Drugs Active on Hypothalamus and Pituitary Gland cont. When initially administered, leuprolide acetate results in increases in LH, FSH, and gonadal steroid production because of its action as a GnRH agonist. However, with chronic administration, there is a reduction in the number of GnRH receptors in the pituitary gonadotropic cells. This causes a reduction in FSH or LH production and a resultant reduction in gonadal hormone production. In women this effect may be beneficial in conditions such as endometriosis, where estrogen stimulates the growth and activity of the ectopic endometrial tissue, which causes symptoms. Marc Imhotep Cray, MD
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Case 39 Answers: Drugs Active on Hypothalamus and Pituitary Gland cont. The effect in men is to lower the production of testosterone to near castrate levels. Because prostate cancer is often testosterone dependent, leuprolide acetate can be used as a treatment for prostate cancer in those who are not surgical candidates, do not desire surgery, or have metastatic disease. Leuprolide acetate must be administered parenterally, and it has a depot form which is active for up to 3 months. It commonly causes “menopausal� side effects, such as hot flashes, as a result of the reduction in gonadal hormone production. Other antiandrogenic drugs such as abiraterone, which blocks conversion of pregnenolone to androgens by inhibiting CYP17, can be used in combination with leuprolide or as sole therapeutic agents.
Marc Imhotep Cray, MD
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THE END
See next slide for further study. Marc Imhotep Cray, MD
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Sources and further study: eLearning Endocrine cloud folder tools and resources MedPharm Guidebook: Unit 5 Drugs Used In Disorders of Endocrine System Endocrine and Reproductive System Pharmacology eNotes Clinical Pharmacology Cases 39 to 44 (Learning Triggers) Textbooks Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011 Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill, 2012 Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009 Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014 Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014. Marc Imhotep Cray, MD
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