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Home , Anterior pituitary, Endocrinology, Thyroid hormones

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Endocrinology Review – Adrenal and Disorders

LINDA S. GORMAN, JANELLE M. CHIASERA

LEARNING OBJECTIVES This article represents the first of three articles focusing 1. Define endocrinology and list the major endocrine on the . The first article will provide of the body. you with fundamental theory regarding the endocrine 2. Explain how feedback (positive and negative) system that will serve as a basis for understanding the Downloaded from promotes maintenance of normal levels of next two articles focusing on two specific endocrine . glands, the thyroid and adrenal glands. 3. Differentiate between and hormones with regard to their mechanism of Endocrinology is the branch of medical science that action. deals with the endocrine system, a system that consists

4. Provide examples of peptide and steroid hormones. of several glands located in different parts of the body http://hwmaint.clsjournal.ascls.org/ 5. Explain how endocrine disorders are categorized. that secrete hormones directly into the bloodstream. Although every system in the body may respond ABBREVIATIONS: ACTH - adrenocorticotropic hor- to hormones, endocrinology focuses specifically on mone; ADH - antidiuretic ; CRH – cortico- endocrine glands whose primary function is hormone tropin releasing hormone; DHEA – dehydroepian- . Major endocrine glands include the pituitary drosterone; FSH - follicle stimulating hormone; GHRH (anterior and posterior), , thyroid, - releasing hormone; GnRH – gona- parathyroid, pineal, , adrenal (cortex and dotropin releasing hormone; HPT - hypothalamus, medulla), and ( and testes). Figure 1 pituitary, target ; LH - ; shows the various locations of endocrine glands. MBST - membrane-bound signal transducer; SRE - on September 28 2021 steroid response element; TRH - thyrotropin releasing hormone; TSH - thyroid stimulating hormone

INDEX TERMS: Endocrine Glands, Hormones, Hy- drocortosone, Hypoalamo-hypophyseal System, Pitui- tary-Adrenal System,

Clin Lab Sci 2013;26(2):107

Linda S. Gorman, PhD, MLS (ASCP)CM, University of Kentucky, Lexington, KY

Janelle M. Chiasera, PhD, MT (ASCP), University of Alabama at Birmingham, Birmingham, Alabama

Address for Correspondence: Linda S. Gorman, PhD, Figure 1. Location of the Major Endocrine Glands. Image reprinted MLS (ASCP)CM, CLS Co-ordinator, Associate with permission of John Nagy. Professor, 900 S. Limestone Ave, Rm 126G CTW, University of Kentucky, Lexington, KY 40536-0200, The HPT Axis (859)-218-0855, [email protected] The endocrine system is part of the body’s extracellular communication system that links the to various

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FOCUS: ENDOCRINOLOGY parts of the body and acts to control body , Releasing Hormone (CRH), which affects adrenal growth and development, and . The hormones, to ones that foster sexual characteristics production and circulating levels of hormones are ( Releasing Hormone) and growth controlled by means of a feedback process that links the (Growth Hormone Releasing Hormone). Our focus hypothalamus to the pituitary and the pituitary to a here is on the thyroid and adrenal glands so we will target gland. This linkage is referred to as the leave the other hypothalamic hormones for others to hypothalamus, pituitary, target gland (HPT) axis.1,2 discuss. (Figure 2, Table 1.) Refer to Figure 2. Table 1. Releasing Hormones and Their Effect on Pituitary and Target Glands Hypothalmus

Releases trophic homormones that lead to release of smulators Hypothalamic Cellular Target/Pituitary Target Gland/Target Hormone Gland Hormone Gland Hormone(s) Downloaded from

Pituitary Corticotropin Releasing Corticotroph/ Hormone (CRH) ACTH () Smulang hormones are released that target the gland of interest Thyrotropin Releasing Thyrotroph/TSH Thyroid Gland/ Hormone (TRH) T3 and T4

Target gland http://hwmaint.clsjournal.ascls.org/ Growth Hormone Somatotroph/GH All tissues Once smulated, the gland releases the hormone for target Releasing Hormone (GHRH)

Figure 2. Hypothalamus, Pituitary, Target Gland (HPT) axis Gonadotropin Releasing Gonadotroph/ Gonads/ Hormone (GnRH) LH and FSH and In general terms, hormones are produced by specialized glands in one part of the body and travel through the bloodstream to result in a biological effect at a distant In the hypothalamus the tropic releasing hormones site. The hypothalamus is considered to be the “master come from in the anterior hypothalamus and gland” of this axis as it takes signals from cortical are released thru the portal to the pituitary inputs, autonomic function, and other environmental sinusoids. The hypothalamic hormones stimulate the on September 28 2021 triggers and delivers signals (via releasing hormones) to selective pituitary release of hormones, often called 4 target types in the . The pituitary “stimulating hormones”. The links the gland responds by releasing hormones that act on target with the part of the hypothalamus glands to produce specific target gland hormones. For that secretes anti- hormone (ADH) and 4 example, thyrotrophin releasing hormone (TRH) . These hormones are associated with the produced by the hypothalamus acts on thyrotroph cells posterior pituitary and not of interest here. of the pituitary gland to produce thyroid stimulating hormone (TSH). Thyroid stimulating hormone acts The Thyrotrophic releasing hormone (TRH) and directly on the thyroid gland (target gland) to produce Corticotrophic releasing hormones of the hypothalamus . Refer to Table 1 for other examples are released into the hypothalamic portal system of releasing hormones and their effect on pituitary and that is separate from the general human circulatory target glands.1,2 system. These releasing hormones can travel thru the portal veins to the pituitary without being evident in 4 The hypothalamus gland is located in the brain above the venous . Once the tropic hormones enter the the brain stem and below the .3 In humans, the pituitary sinusoids they can stimulate the pituitary to hypothalamus is the size of an almond. Its functions produce/secrete specific stimulating hormones, such as include releasing the trophic hormones called “releasing Thyroid Stimulating Hormone (TSH) if the hormones”. These trophic hormones span from hypothalamus sends TRH or Adenocorticotropic Thyrotropin Releasing Hormone (TRH), which affects hormone (ACTH) if the hypothalamus sends CRH. the release of thyroid hormones, Corticotropin (Figures 3 and 4)

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Mechanism of Action Hypothalmus All hormones act on their specific glands/tissues Corticotropin Releasing Hormone or CRH through receptors located on the surface or within the cytosol of the cell. The binding between the hormones and the serves as an initial signal resulting in a Pituitary cascade of events that result in the production of a Adrenocorticotropic Hormone or ACTH . Hormones are divided into two broad categories, peptide (water soluble) and steroid (water insoluble). Refer to Table 2. While all hormones react Adrenal Gland (cortex) with receptors, their mechanism of action varies Cortisol hormone depending on how they are categorized. Because they are water soluble, peptide hormones must interact with receptors that are located at the surface of the cell. Once Downloaded from Figure 3. Adrenal gland stimulation to produce cortisol hormone. bound to its receptor, the complex activates a membrane-bound signal transducer (MBST). Hypothalmus Often this signal transducer is guanine nucleotide- yroid Releasing Hormone or TRH binding regulatory protein, also called the G-protein complex. The MBST is coupled to the adenylate cyclase http://hwmaint.clsjournal.ascls.org/ and phospholipase systems and once activated Pituitary results in the production of a . Due to yroid Stimulating Hormone or TSH their water insoluble nature, steroid hormones may diffuse across the surface of the and bind to their receptors in either the cytoplasmic or nuclear yroid gland fractions of the cells. Once the binds yroid T4 yroid T3 to its receptor, the receptor undergoes a conformational change resulting in activation of the entire hormone receptor complex. The activated complex has an Figure 4. Thyroid stimulation by TSH to produce thyroid increased affinity for chromatin at a site referred to as hormones T4 and T3. the steroid response element (SRE). The SRE binding on September 28 2021

ultimately causes the production of the nuclear product- The Pituitary -a specific protein.6,7 Peptide hormones are synthesized The pituitary gland, with its stimulating hormones, is as preprohormones and are packaged into secretory like a bus stop or railroad station. The pituitary takes in vesicles providing a ready available storage pool of the messages from hypothalamic released hormones and hormones to draw from. Steroid hormones, on the responds by sending out its own stimulating hormones. other hand, are all produced from and are By itself the pituitary is the size of a pea5 and is located available bound to . Because they are protein between the two optic nerves in the brain. This gland bound their action takes longer to initiate; however, has 2 compartments with the anterior section made of once initiated their action is sustained due to the individual cells that can produce individual stimulating increased half life from being protein bound. hormones such as TSH, ACTH, LH/FSH, or Growth hormone. These stimulating cells are Hormone Regulation and Transport individualized in their function. The 5 functional units A unique feature of the endocrine system is that all of the anterior pituitary can be thought of as individual hormones are controlled through positive and negative sections that do their job of producing only one type of feedback systems. This feedback system involves two stimulating hormone per functional unit. The posterior production units. The hormones from one unit usually section takes what has been sent to it from the cause the second unit to increase its hormone hypothalamus, namely ADH and oxytocin and sends production. The second unit’s hormones then feed back these hormones into the blood circulation so they can to the first unit to control any further output from the exert their respective affects. first unit. It is through this feedback loop that the hu-

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man body is able to maintain normal levels of Table 2. Peptide and Steroid Hormones (note: this is not an circulating hormones. Various textbooks1,2,4 and exhaustive list of all endocrine hormones). articles3,5,7 on hormones refer to the “” mechanism as the predominant mechanism by which Hormone Category Hormones Peptide Thyroid Stimulating Hormone endocrine hormones are regulated in the . Follicle Stimulating Hormones Figures 5 and 6 are included here to help demonstrate Luteinizing Hormone the negative feedback mechanism as it applies to the thyroid and adrenal gland in humans. Growth Hormone Adrenocorticotropic Hormone Negative feedback mechanisms are used to prevent Thyroid Hormones overproduction of hormones from the gland and to Pancreatic hormones inhibit the releasing and stimulating hormones

Steroid Testosterone produced from the hypothalamus and pituitary, Downloaded from sulfate respectively. Figure 6 shows the negative feedback loop for the adrenal gland. Cortisol from the adrenal gland is Cortisol circulated in the blood back to the hypothalamus and pituitary so that inhibition of the ACTH and CRH will occur. As long as the level of cortisol hormone is http://hwmaint.clsjournal.ascls.org/ meeting the body’s needs the pituitary and Hypothalmus hypothalamus will not stimulate the adrenal gland. Thyroid Releasing Hormone or TRH Once the cortisol level becomes low or inadequate in the function of this hormone the osmotic stimulation to the brain will cause the hypothalamus CRH to be Pituitary released, stimulating the pituitary to release ACTH and Thyroid Smulang Hormone or TSH leading to the adrenal glands release of cortisol once again.

Thyroid gland Pituitary and hypothalamic hormones are stimulated to Thyroid T4 Thyroid T3 be released in a minute-by-minute pulsatile fashion. In on September 28 2021 addition to the pulsatile feature, pituitary hormones also

Figure 5. Thyroid hormone acting as Negative feedback to Pituitary exhibit a biorhythmic pattern. Biorhythms with a 24 and Hypothalmus. hour time span are referred to as circadian (diurnal). The circadian (diurnal) cycle is controlled by both light cycles and patterns and therefore any disruption to light cycles and/or sleep patterns may alter the normal diurnal cycle of hormones. While pituitary hormones exhibit circadian rhythm, this rhythm will differ Adrenal Pituitary Hypothalmus depending on the pituitary hormone produced. For example, highest concentrations of adrenocorticotrophic   • • , ≠ • ≠ hormone (ACTH) are seen at 0800 with lowest • Cortisol • ACTH • CRH concentrations seen at midnight. Highest concentra- tions of Thyroid Stimulating Hormone (TSH) are seen just before midnight and lowest levels are seen midday. The pulsatile and diurnal features of endocrine hormones warrant closer consideration when interpreting their concentrations in light of making a 1,2 Figure 6. Cortisol Negative Feedback Mechanism inhibits the clinical diagnosis. Pituitary and Hypothalmus of stimulation. Steroid hormones circulate in the body bound to

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proteins or in the free form. Bound hormones are either elevated levels of thyroid hormones this disorder is high or low affinity protein bound hormones. Several referred to as secondary .1,2 proteins serve as carriers of hormones including general hormone binders such as albumin and prealbumin and high affinity specific binders such as thyroid binding Specific endocrine organ are beyond the globulin. Refer to Table 3 for a list of hormone scope of this article. Testing for the diagnosis of transport proteins. It is important to note that some disorders involving the endocrine system is complex due steroid hormones lack a specific binding protein such as to the overlapping signs and symptoms produced. dehydroepiandrosterone (DHEA). In this case, DHEA Testing may include basal levels of hormones and/or is sulfated to increase its solubility and promote its provocative testing including stimulation and/or transport without a specific protein.1,2 suppression tests. The surrounding and the details of diagnosing thyroid and adrenal disorders are

Table 3 Transport Proteins for Hormones and Their being covered in the two associated articles. Downloaded from Bioavailability

Summary Transport Protein Hormones Binding Strength/Availability The endocrine system comprises part of the body’s Albumin All Weak/Bioavailable communication system that links the brain to its organs Prealbumin All Weak/Bioavailable and functions to control metabolism, growth & http://hwmaint.clsjournal.ascls.org/ Cortisol Binding Cortisol Strong/Not bioavailable development and reproduction. Control of this system Globulin is predominantly through a complex feedback system Thyroid Binding T3 and T4 Strong/Not bioavailable that works to maintain . When there is Globulin Thyroxine Binding T4 Strong/Not bioavailable disruption to an or to the feedback Prealbumin system, it can lead to endocrine disturbance. Due to the Sex Hormones Strong/Not bioavailable complexity of the endocrine system, diagnosis and Binding Globulin interpretation of endocrine pathology can be challenging.

Pathology and Testing REFERENCES:

Diseases in the endocrine system are categorized using 1. Clines GA, Demers LM. General Endocrinology. In: Kaplan on September 28 2021 two processes 1) by the level of circulating hormone and LA, Pesce AJ. eds. : Theory, Analysis, 2) by the endocrine gland causing the disorder. Diseases Correlation. 5th ed. St. Louis:Mosby Inc.;2010:929-47. categorized by the level of circulating hormones are 2. Kleerekoper M. Hormones. In: Burtis CA, Ashwood ER, Bruns DE. eds. Tietz Fundamentals of Clinical Chemistry. 6th ed. categorized as either hyper or hypo. Disorders causing Philadelphia:W.B. Saunders Company;2008:837. increased levels of thyroid hormones in circulation are 3. Ananya, M. Nov 5,2012 (hypothalamus) http://www.news- categorized as hyperthyroidism while those resulting in medical.net/health/What-is-the-Hypothalamus.aspx. Accessed low levels of circulating thyroid hormones are 2013 January 28 4. Jones, RE, In:Michael L. Bishop,Edward P. Fody, Larry E. categorized as . Diseases categorized by Schoeff,eds. , Clinical Chemistry: Techniques, Principles, the gland causing the disorder are categorized as Correlations, 6th ed. Philadelphia: Lippincott, Williams and primary when the disorder is caused by the target gland, Wilkins; 2010:445-55. secondary when the gland causing the disorder is the 5. Department. What is the pituitary gland © pituitary gland, and tertiary when the gland causing the 2001-12 Department of Neurosurgery, University of Pittsburgh, http://www.neurosurgery.pitt.edu/minc/skullbase/ disorder is the hypothalamus. Using the example above, pituitary/index.html. Accessed 2013 January 8 when a disorder involving the thyroid gland is caused by 6. Alberts B, Johnson A, Lewis J, et al. Molecular biology of the the target gland itself (the thyroid) and results in cell. 4th ed. New York: Garland Science; 2002. Signaling elevated levels of thyroid hormones this disorder is through G-Protein-Linked Cell-Surface Receptors. Available from: http://www.ncbi.nlm.nih.gov/books/NBK26912/ referred to as primary hyperthyroidism. When a Accessed 2013 February 25 disorder involving the thyroid gland is caused by an 7. Chan L, O’Malley BW. Mechanism of action of sex steroid abnormality with the pituitary gland and results in hormones. N Engl J Med 1976;294:1322-8.

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