By: M ajid A hmad G anaie M. Pharm., P h.D. Assistant Professor Department of Pharmacology E mail: P harmacology – III PHL-418 Endocrine Pharmacology Lecture 1: Endocrine system Introduction Hypothalamic and Pituitary Hormones

Content Layout with List ENDOCRINE SYSTEM INTRODUCTION CLASSES OF HORMONES SOURCES OF HORMONES HYPOTHALAMIC AND ANTERIOR PITUITARY HORMONES HORMONES OF THE POSTERIOR PITUITARY

The Endocrine System The endocrine system controls many body functions Exerts control by releasing special chemical substances into the blood called hormones Hormones affect other endocrine glands or body systems The neuroendocrine system, which is controlled by the pituitary and hypothalamus, coordinates body functions by transmitting messages between individual cells and tissues. This contrasts with the nervous system, which communicates locally through electrical impulses and neurotransmitters directed through neurons to other neurons or to specific target organs, such as muscle or glands. HORMONE: A substance that is released in one tissue and travels through the circulation (usually) to the target tissue. Hormones reach all parts of the body, but only target cells are equipped to respond Hormones are secreted in small amounts and often in bursts (pulsatile secretion)

Endocrine System Functions: Maintain Internal Homeostasis Support Cell Growth Coordinate Development Coordinate Reproduction, fertility, sexual function Facilitate Responses to External Stimuli

4 Classes of Hormones Peptide/ Protein (Range from 3 amino acids to hundreds of amino acids in size. ) Steroid Amine (Thyroid hormones and Catecholamines) Eicosanoid (Fatty acid derivatives ) On cell surface: Peptides and proteins In cytoplasm: Steroids In nucleus: Thyroid hormones Location of receptors

NUCLEUS Signal receptor (a)(b) TARGET CELL Signal receptor Transport protein Water- soluble hormone Fat-soluble hormone  The hormones fall into two general classes based on their solubility in water.  The water soluble { amine and peptide/protein hormones} are secreted by exocytosis, travel freely in the bloodstream, and bind to cell-surface receptors.  The lipid soluble hormones { thyroid hormone, steroid hormones and Vitamin D3}. diffuse across cell membranes, travel in the bloodstream bound to transport proteins, and diffuse through the membrane of target cells.

Mechanisms of endocrine disease Hormone deficiency treated with Hormone replacement therapy (HRT) Hormone excess treated with Specific antagonists or release inhibitors. Hormone resistance treated with Sensitizers Sources of hormones: -Natural: Human (GH; LH & FSH; hCG); Animal (Insulin, T 3 & T 4 ) -Biosynthetic: Insulin (Porcine & Bovine) -Synthetic: Most hormones and their antagonists DNA recombinant technology

 The hormones secreted by the hypothalamus and the pituitary are all peptides or low molecular weight proteins that act by binding to specific receptor sites on their target tissues. The hormones of the anterior pituitary are regulated by neuropeptides that are called either “releasing” or “inhibiting” factors or hormones. These are produced in the hypothalamus, and they reach the pituitary by the hypophyseal portal system.  Each hypothalamic regulatory hormone controls the release of a specific hormone from the anterior pituitary.  Hormones of the anterior and posterior pituitary are administered intramuscularly (IM), subcutaneously, or intranasally because their peptidyl nature makes them susceptible to destruction by the proteolytic enzymes of the digestive tract. HYPOTHALAMIC AND ANTERIOR PITUITARY HORMONES

A. Adrenocorticotropic hormone (corticotropin) Mechanism of action: ACTH binds to receptors on the surface of the adrenal cortex, thereby activating G protein– coupled processes that ultimately stimulate the rate-limiting step in the adrenocorticosteroid synthetic pathway (cholesterol to pregnenolone) Therapeutic uses: As a diagnostic tool for differentiating between primary adrenal insufficiency (Addison disease, associated with adrenal atrophy) and secondary adrenal insufficiency (caused by the inadequate secretion of ACTH by the pituitary). Adverse effects: Short-term use of ACTH is usually well tolerated. With longer use, toxicities are similar to those of glucocorticoids and include hypertension, peripheral edema, hypokalemia, emotional disturbances, and increased risk of infection.

B. Growth hormone (somatotropin) GH is released in a pulsatile manner, with the highest levels occurring during sleep. Somatotropin influences a wide variety of biochemical processes (for example, cell proliferation and bone growth are promoted) Mechanism of action: Although many physiologic effects of GH are exerted directly at its targets, others are mediated through the somatomedins—insulin-like growth factors 1 and 2 (IGF-1 and IGF-2). Therapeutic uses: Somatropin is used in the treatment of GH deficiency or growth failure in children. Somatropin is administered by subcutaneous or IM injection. Although the half-life of GH is short (approximately 25 minutes), it induces the release of IGF-1 from the liver, which is responsible for subsequent GH-like actions. Adverse effects: Adverse effects of somatropin include pain at the injection site, edema, arthralgias, myalgias, flu-like symptoms, and an increased risk of diabetes.

C. Somatostatin (Growth hormone-inhibiting hormone) In the pituitary, somatostatin binds to receptors that suppress GH and thyroid-stimulating hormone release. Somatostatin not only inhibits the release of GH but also that of insulin, glucagon, and gastrin. Octreotide and lanreotide are synthetic analogs of somatostatin. Their half-lives are longer than that of the natural compound, and depot formulations are available, allowing for administration once every 4 weeks. They have found use in the treatment of acromegaly and in diarrhea and flushing associated with carcinoid tumors. Adverse effects of octreotide include diarrhea, abdominal pain, flatulence, nausea, and steatorrhea. Gallbladder emptying is delayed, and asymptomatic cholesterol gallstones can occur with long-term treatment.

D. Gonadotropin-releasing hormone Pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus is essential for the release of the gonadotropins follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. However, continuous administration of GnRH inhibits gonadotropin release through down-regulation of the GnRH receptors on the pituitary. Continuous administration of synthetic GnRH analogs, such as leuprolide, goserelin, nafarelin, and histrelin, is effective in suppressing production of the gonadotropins Suppression of gonadotropins, in turn, leads to reduced production of gonadal steroid hormones (androgens and estrogens). Thus, these agents are effective in the treatment of prostate cancer, endometriosis, and precocious puberty. They are contraindicated in pregnancy and breast-feeding.

E. Gonadotropins The gonadotropins (FSH and LH) are glycoproteins that are produced in the anterior pituitary. The regulation of gonadal steroid hormones depends on these agents. They find use in the treatment of infertility. Menotropins (also known as human menopausal gonadotropins or hMG) are obtained from the urine of postmenopausal women and contain both FSH and LH. Urofollitropin is FSH obtained from postmenopausal women and is devoid of LH. Follitropin alfa and follitropin beta are human FSH products manufactured using recombinant DNA technology. Human chorionic gonadotropin (hCG) is a placental hormone that is excreted in the urine of pregnant women. The effects of hCG and choriogonadotropin alfa (made using recombinant DNA technology) are essentially identical to those of LH. All of these hormones are injected via the IM or subcutaneous route.

F. Prolactin Prolactin is a peptide hormone that is also secreted by the anterior pituitary. Its primary function is to stimulate and maintain lactation. Its secretion is inhibited by dopamine acting at D2 receptors. Drugs that act as dopamine antagonists (for example, metoclopramide and antipsychotics such as risperidone) can increase the secretion of prolactin. Hyperprolactinemia, which is associated with galactorrhea and hypogonadism, is treated with D2 receptor agonists, such as bromocriptine and cabergoline. Both of these agents also find use in the treatment of pituitary microadenomas.

 In contrast to the hormones of the anterior lobe of the pituitary, those of the posterior lobe, vasopressin and oxytocin, are not regulated by releasing hormones. Instead, they are synthesized in the hypothalamus, transported to the posterior pituitary, and released in response to specific physiologic signals, such as high plasma osmolarity or parturition. HORMONES OF THE POSTERIOR PITUITARY  Both hormones are administered intravenously and have very short half-lives.

A. Oxytocin Oxytocin is used in obstetrics to stimulate uterine contraction and induce labor. Oxytocin also causes milk ejection by contracting the myoepithelial cells around the mammary alveoli. B. Vasopressin Vasopressin (antidiuretic hormone) is structurally related to oxytocin. Vasopressin has both antidiuretic and vasopressor effects. In the kidney, it binds to the V2 receptor to increase water permeability and reabsorption in the collecting tubules. Thus, the major use of vasopressin is to treat diabetes insipidus. Other effects of vasopressin are mediated by the V1 receptor, which is found in liver, vascular smooth muscle (where it causes constriction), and other tissues. Desmopressin, an analog of vasopressin, has minimal activity at the V1 receptor, making it largely free of pressor effects. This analog is longer acting than vasopressin and is preferred for the treatment of diabetes insipidus and nocturnal enuresis. For these indications, desmopressin may be administered intranasally or orally.

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