Introduction to Endocrine Pharmacology and Hormones of the Hypothalamus and Pituitary Gland

Published on 08/02/2015 by admin

Filed under Basic Science

Last modified 08/02/2015

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 4190 times

Chapter 38 Introduction to Endocrine Pharmacology and Hormones of the Hypothalamus and Pituitary Gland

Abbreviations
ACTH Adrenocorticotropic hormone
AVP Arginine vasopressin, antidiuretic hormone
cAMP Cyclic adenosine monophosphate
CNS Central nervous system
CRH Corticotropin-releasing hormone
DHEA Dehydroepiandrosterone
DHT Dihydrotestosterone
DI Diabetes insipidus
DNA Deoxyribonucleic acid
Epi Epinephrine
FDA United States Food and Drug Administration
FSH Follicle-stimulating hormone
GH Growth hormone
GHRH Growth hormone-releasing hormone
GI Gastrointestinal
GnRH Hypothalamic gonadotropin-releasing hormone
hCG Human chorionic gonadotropin
hGH Human growth hormone
hMG Human menopausal gonadotropin
IGF-1 Insulin-like growth factor-1
IM Intramuscular
IV Intravenous
LH Luteinizing hormone
RNA Ribonucleic acid
SC Subcutaneous
SRIF Somatostatin, somototropin-release inhibiting hormone
TRH Thyrotropin-releasing hormone
TSH Thyroid-stimulating hormone

The endocrine system is a complex communication system responsible for maintaining homeostasis throughout the body, and it is vital to individual and species survival and propagation as well as adaptation to the environment. The system consists of a diverse group of ductless glands that secrete chemical messengers called hormones into the circulation. The secreted hormones are transported in the bloodstream to target organs, where they act to regulate cellular activities. For a hormone to elicit a response, it must interact with specific receptors on the cells of the target organ, much like the interaction between neurotransmitters and receptors involved in the process of neurotransmission in the central and peripheral nervous systems (see Chapters 9 and 27). Receptors play a key role in the mechanisms of action of endocrine hormone systems; key receptor mechanisms pertinent to endocrine systems are summarized in Chapter 1.

In general, all endocrine systems share several common features. At the uppermost level, the secretion of each hormone is controlled tightly by input from higher neural centers in response to alterations in plasma levels of the hormone or other substances. The second component is the gland itself, where hormone synthesis and secretion occur in specialized cells. After synthesis, hormones are typically packaged and stored for later release, as needed. Signals from the nervous system or special releasing hormones, or both, bring about secretion of stored hormone.

HORMONES

Hormones are chemically and structurally diverse compounds and can be divided into three main classes based on chemical composition, viz., the amino acid analogs, the peptides, and the steroids. The amino acid analogs, often termed amine hormones, are all derived from tyrosine and include epinephrine (Epi) and the iodothyronines or thyroid hormones. The peptide hormones are subclassified on the basis of size and glycosylation state and may be single- or double-chain peptides. The steroid hormones are all derived from cholesterol and may be subclassified as adrenal steroids or sex steroids, the former synthesized primarily in the adrenal cortex and the latter synthesized in the ovaries or testes. The major endocrine glands and their associated hormones are listed in Box 38-1.

Hormones are generally distinguished from other types of modulatory factors (i.e., neurotransmitters) by a longer duration of effect and more extensive circulation in the body. While in the circulation, a hormone is frequently associated with one or more types of transport proteins from which it must dissociate to interact with responsive receptors. In addition, availability to tissues is dependent upon membrane exclusion mechanisms, susceptibility to tissue modification, and ultimately the rate of renal or hepatic metabolism, inactivation, and excretion. As mentioned, hormones exert their effects by binding to and activating receptors on target cells. These receptors can be located on the cell surface, as for peptide hormones, or within the cell, as in the case of steroids and thyroid hormones. After receptor activation, intracellular signaling pathways (e.g., second messenger systems or ligand-activated transcription factors) are modulated, which acutely or chronically alter cellular physiology and potentially whole organism physiology.

The endocrine hormones affect the activities of most organs and many types of cells. These actions occur by means of extremely intricate pathways, including positive- and negative-feedback control loops and sequences involving hormones from endocrine glands that act to control hormones secreted by other glands. A given hormone typically exerts multiple actions, and several different hormones influence a given function. Physiological functions affected by endocrine systems include:

To facilitate the appropriate biological response, hormone levels must be maintained within a physiological range, which can be cyclic or relatively constant. Failed regulation of cell processes leads to increased or decreased levels of metabolic products, which become disruptive to cellular, organ, and whole body processes and function. Altered circulating levels of hormones are often related to defects in regulation of hormone release, distribution, metabolism, and excretion, or hormone-secreting organ pathology. In addition, alterations in target tissue hormone sensitivity may be involved and result from defects in the levels or affinities of hormone receptors, effectiveness of second messenger transduction mechanisms, or defective receptor-mediated cellular/metabolic processes.

To understand and manage this problem, an association among hormone levels, tissue sensitivity, and symptoms must be properly established by measuring the levels of appropriate hormone(s). This assessment allows development of rational pharmacological approaches to reverse an abnormal process; dampen physiological consequences of hormonal imbalance; and restore or mimic normal endocrine function. When decreased hormone levels are detected, hormonal balance may be restored by increasing the production of endogenous hormones or by administering exogenous hormones or hormone analogs. The effectiveness of this approach depends on the success of restoration of the natural pattern of hormone levels without producing periods of excessive or deficient biological activity that can provoke pathological conditions. Failure of this approach can be associated with tissue insensitivity, which, if treatable, requires modification of hormone-responsive cellular metabolism.

Excessive levels of endogenous hormones may result from excessive organ secretion or unregulated ectopic formation. Hormone overproduction by a secreting organ is commonly associated with excessive stimulation or a malignancy (or hyperplasia). Successful management of this situation includes blockade of the stimulatory agent, if identifiable, or interference with hormone formation, secretion, or action. Ectopic production of a biologically active form of the hormone by tissues is complicated by the lack of feedback mechanisms to regulate hormone production and is typically associated with tissue malignancy or infection. The primary determinant of successful intervention frequently requires a combination of ablation of the secreting tissue and pharmacological agents to antagonize the effects of elevated hormone levels. The success of this technique hinges on the ability of the responsible tissue to respond to pharmacological intervention. If it is not possible or detrimental to directly reduce hormone levels, a situation often encountered before or immediately after surgery, or when the cause of the elevated hormone levels is unknown or uncorrectable, alternative, patient-specific strategies to reduce the effects of elevated hormone levels must be used. A summary of strategies to manage the levels and action of hormones is presented in Box 38-2. A list of drugs that affect hormonal balance and their mechanisms of action are in Box 38-3.

BOX 38–3 Drugs Known to Affect Hormonal Balance

Steroid Biochemistry and Physiology

All secreted steroids are synthesized from cholesterol, which can be synthesized de novo or derived from circulating lipoproteins. Similar metabolic pathways mediate steroid synthesis in all organs (Fig. 38-1). The organ-specific formation of secreted steroids depends on the presence of specific catalytic enzymes (Table 38-1).

The action of steroids is mediated largely by altering gene transcription through interaction with promoter deoxyribonucleic acid (DNA) of genes. Steroid receptors are dimeric and coupled with accessory proteins until activated by ligands outside the nucleus. The steroid-receptor complex is phosphorylated and translocated to the nucleus through a nuclear pore, facilitated by the importin protein. The interaction with the gene promoter region occurs through steroid-specific palindromic nucleotide sequences within the receptor. The interaction of DNA and the steroid-receptor complex is dependent on steroid structural differences, amino acid sequence of the DNA binding domain, the nucleotide sequence of the DNA binding site, and the architecture of the gene promoter. The structures of the primary circulating steroids are shown in Figure 38-2.

Adrenocorticosteroids

In the adrenal gland, the primary secreted steroids are aldosterone, cortisol, and dehydroepiandrosterone (DHEA) (see Fig. 38-2). Aldosterone is the primary mineralocorticoid and acts at the luminal epithelia to promote renal reuptake of Na+, which conserves Na+ and can elevate blood pressure. In the zona glomerulosa, the lack of CYP17 is associated with nearly exclusive formation of aldosterone. Further, the release of aldosterone from the zona glomerulosa is regulated by the renin-angiotensin pathway as a result of activation angiotensin II-receptors, which are linked to the formation of 1,4,5-inositol triphosphate. The amount of aldosterone released is relatively low (50 to 150 µg/day); aldosterone is transported in the blood through an interaction with albumin with a bound/free ratio of 70/30.

The primary adrenal androgen DHEA is released from the zona reticularis, and daily secretion levels can reach 30 mg. DHEA has weak androgenic activity and can be converted to testosterone and ultimately estradiol in tissues expressing aromatase, for example, adipose tissue. Although DHEA production is relatively high, with levels rivaling that of cortisol, synthesis declines with age; the biological role of DHEA remains poorly understood, but it has been implicated to play a role in the aging process.

The complement of enzymes in the zona fasciculata and zona reticularis permits the formation of cortisol, the primary circulating glucocorticoid (see Chapter 39). The release of cortisol is dependent on a tightly regulated hypothalamic-anterior pituitary-adrenal cortex axis. The biological role of glucocorticoids is complex and temporal. The liver has the greatest level of nuclear receptors or steroid-activated transcription factors, although they are present in many tissues. The primary systems affected by cortisol include self-regulation of formation via suppression of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secretion, storage of hepatic glycogen, response to stress, and suppression of the immune system. The daily production of cortisol ranges from 10 to 20 mg, and plasma levels follow a diurnal pattern with the highest levels in the morning. In the blood, cortisol is bound to a specific hepatic protein, corticosteroid-binding protein (aka transcortin), which promotes its transport and increases its duration of action.

Androgenic Steroids

The primary testicular androgen, testosterone, is converted to dihydrotestosterone (DHT) in tissues expressing 5α-reductase. The actions of androgens include development of male reproductive tract and accessory tissues, stimulation of secondary sexual traits, growth, and development of the central nervous system (CNS) (see Chapter 41). As shown in Figure 38-1, the expression of steroid metabolizing enzymes promotes the formation of DHEA and androstenedione leading to the formation of testosterone; the expression of aromatase in ovarian cells permits conversion of testosterone to β-estradiol.

Therapeutic Overview

Pharmacology of Hypothalamic and Pituitary Hormones

The hypothalamus and pituitary gland work in concert to regulate endocrine systems throughout the body. Peptides and biogenic amines synthesized and secreted by specialized neurons within the hypothalamus are transported to the anterior pituitary by the hypothalamic-hypophyseal portal circulation, where they act through specific receptors to stimulate or inhibit hormone secretion (Fig. 38-3). Anterior pituitary hormones trigger peripheral endocrine organs to produce hormones, which have individual functions and provide feedback to the hypothalamus and pituitary to regulate the synthesis and release of their tropic hormones. As mentioned, GnRH (also called luteinizing hormone releasing hormone) stimulates the secretion of LH and FSH by the pituitary. LH and FSH promote gametogenesis and gonadal hormone production by the ovaries and testes (see Chapters 40 and Chapter 41). Thyrotropin-releasing hormone (TRH) stimulates secretion of thyroid-stimulating hormone (TSH), which in turn controls thyroid function (see Chapter 42) CRH stimulates the secretion of ACTH, which promotes the secretion of cortisol by the adrenal cortex (see Chapter 39). Growth hormone-releasing hormone (GHRH) stimulates and somatostatin (also called somatotropin-release inhibiting factor, SRIF) inhibits the production of growth hormone (GH), which has numerous effects on growth and metabolism. Hypothalamic dopamine functions to tonically inhibit secretion of prolactin, the hormone primarily responsible for lactation and suppression of fertility while nursing.