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P Art 1 Foundations of Endocrinology

P Art 1 Foundations of Endocrinology

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Part 1 Foundations of Endocrinology

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CHAPTER 1 Overview of e ndocrinology

Key t opics

■ A brief history of endocrinology and diabetes 4 ■ The role of 5 ■ Classification of hormones 8 ■ Organization and control of endocrine organs 9 ■ Endocrine disorders 13 ■ Key points 13

Learning o bjectives

■ To be able to define endocrinology ■ To understand what endocrinology is as a basic science and a clinical specialty ■ To appreciate the history of endocrinology ■ To understand the classification of hormones into peptides, and derivatives ■ To understand the principle of feedback mechanisms that regulate production This chapter details some of the history to endocrinology andd diabetes, and introduces basic principles that underpin the subsequent chapters

Essential Endocrinology and Diabetes, Sixth Edition. Richard IG Holt, Neil A Hanley. © 2012 Richard IG Holt and Neil A Hanley. Publlished 2012 by Blackwell Publishing Ltd. 4 / Chapter 1: Overview of endocrinology

An organism comprised of a single or a few cells A b rief h istory of e ndocrinology analyzes and responds to its external environment and d iabetes with relative ease. No is more than a short dif- fusion distance from the outside world or its neigh- The term ‘ hormone ’ , derived from the Greek word bours, allowing a constancy of internal environment ‘ hormaein ’ meaning ‘ to arouse ’ or ‘ to excite ’ , was (‘ homeostasis ’ ). This simplicity has been lost with first used in 1905 by Sir Ernest Starling in his the evolution of more complex, larger, multicellular Croonian Lecture to the Royal College of Physicians; organisms. Simple diffusion has become inadequate in larger animal species where functions localize to specific organs. In humans, there are ∼ 1014 cells of (a) Endocrine (b) Autocrine (A) and 200 or more different types. With this compart- Paracrine (P) mentalized division of purpose comes the need for Target cell effective communication to disseminate informa- Hormone Target cell tion throughout the whole organism – only a few cells face the outside world, yet all respond to it. Two communication systems facilitate this: the A P endocrine and nervous systems (Box 1.1 ). Local hormone The specialized ductless glands and tissues of the release chemical messengers – hormones – into the extracellular space, from where (c) Neuroendocrine (d) they enter the bloodstream. It is this blood- borne transit that defines endocrinology; however, the Nerve cell Neurone principles are similar for hormone action on a neighbouring cell (‘ para crinology ’ ) or, indeed, itself ( ‘auto - or intra - crinology ’ ) (Figure 1.1 ). Axon The nervous and endocrine systems interact. Endocrine glands are under both nervous and hor- Axon Neurone monal control, while the central nervous system is terminal affected by multiple hormonal stimuli – features Neurotransmitter reflected by the composite science of neuroendo- crinology (Figure 1.1 ). Blood vessel Target cell

Figure 1.1 Cells that secrete regulatory substances to communicate with their target cells and organs. (a) Endocrine. Cells secrete hormone into the blood vessel, where it is carried, potentially over large distances, to its target cell. (b) Autocrine (A): hormones Box 1.1 Functions of the such as insulin- like growth factors can act on the cell e ndocrine and n ervous s ystems, that produces them, representing autocrine control. the t wo m ain c ommunication Paracrine (P): cells secrete hormone that acts on s ystems nearby cells (e.g. and act on adjacent β -cells within the pancreatic islet to influence • To monitor internal and insulin secretion). (c) Stimulated neuroendocrine cells external environments secrete hormone (e.g. the hypothalamic hormones that maintain • To allow appropriate regulate the anterior pituitary) from axonic terminals homeostasis adaptive changes into the bloodstream. (d) Neurotransmitter cells secrete • To communicate via substances from axonic terminals to activate adjacent chemical messengers } neurones. Chapter 1: Overview of endocrinology / 5 however, the specialty is built on foundations that crine syndromes. Since then, our understanding has are far older. Aristotle described the pituitary, while advanced through: the associated condition, gigantism, due to excess growth hormone (GH), was referred to in the Old • Successful quantification of circulating Testament, two millennia or so before the 19th hormones century recognition of the gland ’ s anterior and pos- • Pathophysiological identification of endocrine terior components by Rathke, and Pierre Marie ’ s dysfunction connection of GH- secreting pituitary tumours to • Molecular genetic diagnoses acromegaly. • Molecular unravelling of complex hormone Diabetes was recognized by the ancient action. Egyptians. Areteus later described the disorder in the second century ad as ‘ a melting down of flesh Some of the landmarks from the last 100 years and limbs into urine’ – diabetes comes from the are shown in Box 1.2 , and those researchers who Greek word meaning siphon. The pancreas was only have been awarded the for , implicated relatively recently when Minkowski real- or Chemistry for discoveries that have ized in 1889 that the organ ’ s removal in dogs mim- advanced endocrinology and diabetes are listed in icked diabetes in humans. Table 1.1 . The roots of reproductive endocrinology are Traditionally, endocrinology has centred on spe- equally long. The Bible refers to eunuchs and cialized hormone -secreting organs (Figure 1.2 ), Hippocrates recognized that mumps could result in largely built on the ‘ endocrine postulates’ of Edward sterility. Oophorectomy in sows and camels was Doisy (Box 1.3 ). While the focus of this textbook used to increase strength and growth in ancient remains with these organs, many tissues display Egypt. The association with technology is also long- appreciable degrees of hormone biosynthesis, and, standing. For instance, it took the microscope in the equally relevant, modulate hormone action. All 17th century for Leeuwenhoek to visualize sperma- aspects are important for a complete appreciation tozoa and later, in the 19th century, for the mam- of endocrinology and its significance. malian ovum to be discovered in the Graafian follicle. The r ole of h ormones During the last 500 years, other endocrine organs and axes have been identified and character- Hormones are synthesized by specialized cells ized. In 1564, Bartolommeo Eustacio noted the (Table 1.2 ), which may exist as distinct endocrine presence of the adrenal glands. Almost 300 years glands or be located as single cells within other later (1855), Thomas Addison, one of the forefa- organs, such as the gastrointestinal tract. The chap- thers of clinical endocrinology, described the con- ters in Part 2 are largely organized on this anatomi- sequences of their inadequacy. Catecholamines were cal basis. identified at the turn of the 19th century, in parallel Endocrinology is defined by the secretion of with Oliver and Schaffer’ s discovery that these hormones into the bloodstream; however, autocrine adrenomedullary substances raise blood pressure. or paracrine actions are also important, often mod- This followed shortly after the clinical features of ulating the hormone - secreting cell type. Hormones myxoedema were linked to the thyroid gland, when, act by binding to specific receptors, either on the in 1891, physicians in Newcastle treated hypothy- surface of or inside the target cell, to initiate a roidism with sheep thyroid extract. This was an cascade of intracellular reactions, which frequently important landmark, but long after the ancient amplifies the original stimulus and generates a final Chinese recognized that seaweed, as a source of response. These responses are altered in hormone iodine, held valuable properties in treating ‘ goitre ’ , deficiency and excess: for instance, GH deficiency swelling of the thyroid gland. leads to short stature in children, while excess Early clinical endocrinology and diabetes tended causes over- growth (either gigantism or acromegaly; to recognize and describe the features of the endo- Chapter 5 ). 6 / Chapter 1: Overview of endocrinology

Box 1.2 Some l andmarks in e ndocrinology over the l ast 100 y ears or so 1905 First use of the term ‘ hormone’ by Starling in the Croonian Lecture at the Royal College of Physicians 1909 Cushing removed part of the pituitary and saw improvement in acromegaly 1914 Kendall isolated an iodine- containing substance from the thyroid 1921 Banting and Best extracted insulin from islet cells of dog pancreas and used it to lower blood sugar Early 1930s Pitt - Rivers and Harrington determined the structure of the thyroid hormone, thyroxine 1935 – 40 Crystallization of testosterone 1935 – 40 Identification of oestrogen and progesterone 1940s Harris recognized the relationship between the hypothalamus and anterior pituitary in the ‘ portal - vessel chemotransmitter hypothesis’ 1952 Gross and Pitt- Rivers identified tri- iodothyronine in human serum 1955 The Schally and Guillemin laboratories showed that extracts of hypothalamus stimulated adrenocorticotrophic hormone (ACTH) release 1956 Doniach, Roitt and Campbell associated antithyroid antibodies with some forms of hypothyroidism – the first description of an autoimmune phenomenon 1950s Adams and Purves identified thyroid stimulatory auto- antibodies Gonadectomy and transplantation experiments by Jost led to the discovery of the role for testosterone in rabbit sexual development 1955 Sanger reported the primary structure of insulin 1957 Growth hormone was used to treat short stature in patients 1966 First transplant of human pancreas to treat type 1 diabetes by Kelly, Lillehei, Goetz and Merkel at the University of Minnesota 1969 Hodgkin reported the three- dimensional crystallographic structure of insulin 1969 – 71 Discovery of thyrotrophin- releasing hormone (TRH) and gonadotrophin- releasing hormone (GnRH) by Schally ’ s and Guillemin’ s groups 1973 Discovery of somatostatin by the group of Guillemin 1981 – 2 Discovery of corticotrophin- releasing hormone (CRH) and growth hormone- releasing hormone (GHRH) by Vale 1994 Identification of leptin by Friedman and colleagues 1994 First transplantation of pancreatic islets to treat type 1 diabetes by Pipeleers and colleagues in Belgium 1999 Discovery of ghrelin by Kangawa and colleagues 1999 Sequencing of the human genome – publication of the DNA code for chromosome 22 2000 Advanced islet transplantation using modified immunosuppression by Shapiro and colleagues to treat type 1 diabetes

Thyroid hormone acts on many, if not all, of the its role in the survival and growth of many cell types 200 plus cell types in the body. The basal metabolic in laboratory culture. In contrast, other hormones rate increases if it is present in excess and declines may act only on one tissue. Thyroid - stimulating if there is a deficiency (see Chapter 8 ). Similarly, hormone (TSH), adrenocorticotrophic hormone insulin acts on most tissues, implying its receptors are (ACTH) and the gonadotrophins are secreted by widespread. Its importance is also underlined by the anterior pituitary and have specific target tissues Chapter 1: Overview of endocrinology / 7

Table 1.1 Nobel prize winners for discoveries relevant to endocrinology and diabetes

Year Prize winner(s) For work on . . . 1909 Physiology, pathology and surgery of the thyroid gland 1923 Frederick Grant Banting and John James Discovery of insulin Richard Macleod 1928 Adolf Otto Reinhold Windhaus Constitution of the sterols and their connection with the vitamins 1939 Adolf Friedrich and Johann Butenandt Sex hormones 1943 George de Hevesy Use of isotopes as tracers in the study of chemical processes 1946 James Batcheller Summer, John Howard Discovery that enzymes can be crystallized and Northrop and Wendell Meredith Stanley prepared in a pure form 1947 Carl Ferdinand Cori, Getty Theresa Cori Discovery of the course of the catalytic conversion (ne é Radnitz) and Bernardo Alberto of glycogen Houssay 1950 Edwin Calvin Kendall, Tadeus Reichstein Discoveries relating to the hormones of the and Philip Showalter Hench adrenal cortex, their structure and biological effects 1955 Vincent du Vigneaud Biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormone 1958 Frederick Sanger Structures of proteins, especially that of insulin 1964 Konrad Bloch and Discoveries concerning the mechanism and regulation of cholesterol and metabolism 1966 Charles Brenton Huggins Discoveries concerning hormonal treatment of prostatic cancer 1969 Derek HR Barton and Odd Hassel Development of the concept of conformation and its application in chemistry 1970 , and Julius Discoveries concerning the humoral transmitters in Axelrod the nerve terminals and the mechanism for their storage, release and inactivation 1971 Earl W Sutherland Jr Discoveries concerning the mechanisms of the action of hormones 1977 , Andrew V Schally and Discoveries concerning peptide hormones in the Rosalyn Yalow production in the brain and the development of radioimmunoassay from peptide hormones 1979 Allan M Cormack and Godfrey N Development of computer- assisted tomography Hounsfield (Continued ) 8 / Chapter 1: Overview of endocrinology

Table 1.1 (Continued )

Year Prize winner(s) For work on . . . 1982 Sune K Bergströ m, Bengt I Samuelson Discoveries concerning and related and John R Vane biologically active substances 1985 Michael S Brown and Joseph L Goldstein Discoveries concerning the regulation of cholesterol metabolism 1986 Stanley Cohen and Rita Levi- Montalcini Discoveries of growth factors 1992 Edmond H Fischer and Edwin G Krebs Discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism 1994 Alfred G Gilman and Discovery of G- proteins and the role of these proteins in in cells 2003 Peter Agre and Roderick MacKinnon Discovery of water channels, and the structural and mechanistic studies of ion channels 2003 and Sir Discoveries concerning magnetic resonance imaging

2010 Robert G Edwards Development of in vitro fertilization

– the thyroid gland, the adrenal cortex and the Some peptide hormones have complex tertiary gonads, respectively (Table 1.2 ). structures or are comprised of more than one peptide chain. Oxytocin and vasopressin, the two posterior pituitary hormones, have ring structures Classification of h ormones linked by disulphide bridges. Despite being remark- ably similar in structure, they have very different There are three major groups of hormones accord- physiological roles (Figure 1.3 ). Insulin consists of ing to their biochemistry (Box 1.4 ). Peptide or α - and β - chains linked by disulphide bonds. Like protein hormones are synthesized like any other several hormones, it is synthesized as an inactive cellular protein. Amino acid- derived and precursor that requires modification prior to release hormones originate from a cascade of biochemical and activity. To some extent this regulation protects reactions catalyzed by a series of intracellular the synthesizing cell from being overwhelmed by its enzymes. own hormone action. The gonadotrophins, follicle - stimulating hormone (FSH) and LH, TSH and human chorionic gonadotrophin (hCG) also have Peptide h ormones two chains. However, these α - and β - subunits are The majority of hormones are peptides and range synthesized quite separately, from separate genes. in size from very small, only three amino acids The α- subunit is common; the distinctive β - subunit [thyrotrophin - releasing hormone (TRH)], to small of each confers biological specificity. proteins of over 200 amino acids, such as TSH or luteinizing hormone (LH). Some peptide hormones Amino a cid d erivatives are secreted directly, but most are stored in granules, the release from which is commonly controlled These hormones are small water- soluble com- by another hormone, as part of a cascade, or by pounds. Melatonin is derived from tryptophan, innervation. whereas tyrosine derivatives include thyroid hor- Chapter 1: Overview of endocrinology / 9

Box 1.3 The ‘ Endocrine Pituitary gland: Hypothalamus anterior and and median Postulates’ : Edward Doisy, posterior eminence St Louis University School of Medicine, USA , 1936 Four parathyroid Thyroid glands gland • The gland must secrete something (an ‘ internal secretion’ ) • Methods of detecting the secretion must be available • Purified hormone must be obtained from gland extracts • The pure hormone must be isolated, its structure determined and synthesized

To this could be added: Two adrenal Stomach • The hormone must act on specific target glands: cortex Kidney and medulla cells via a such that excess or Pancreas: deficiency results in a specific phenotype Duodenum Islets of Langerhans Two ovaries (o) stituent of the . Produced by the adrenal cortex, gonad and placenta, steroid hor- Two testes mones are insoluble in water and largely circulate (o) bound to plasma proteins.

Organization and c ontrol of

Figure 1.2 The sites of the principal endocrine e ndocrine o rgans glands. The stomach, kidneys and duodenum are The synthesis and release of hormones is regulated also shown. Not shown, scattered cells within the by control systems, similar to those used in engineer- gastrointestinal tract secrete hormones. ing. These mechanisms ensure that hormone signals can be limited in amplitude and duration. Central to the regulation of many endocrine organs is the mones, catecholamines, and dopamine, which anterior pituitary gland, which, in turn, is controlled regulates prolactin secretion in the anterior pitui- by a number of hormones and factors released from tary. The catecholamines from the adrenal medulla, specialized hypothalamic neurones (see Chapter 5 ). epinephrine (adrenaline) and norepinephrine Thus, major endocrine axes comprise the hypotha- (noradrenaline), are also sympathetic neurotrans- lamus, anterior pituitary and end organ, such as the mitters, emphasizing the close relationship between adrenal cortex, thyroid, testis or ovary. An under- the nervous and endocrine systems (see Figure 1.2 ). standing of these control mechanisms is crucial for Like peptide hormones, they are stored in granules appreciating both regulation of many endocrine prior to release. systems and their clinical investigation.

Steroid h ormones Simple c ontrol Steroid hormones are lipid- soluble molecules An elementary control system is one in which the derived from cholesterol, which is itself a basic con- signal itself is limited, either in magnitude or 10 / Chapter 1: Overview of endocrinology

Table 1.2 The endocrine organs and their hormones*

Gland Hormone Molecular characteristics Hypothalamus/ Releasing and inhibiting hormones: median eminence Thyrotrophin - releasing hormone (TRH) Peptide Somatostatin (SS; inhibits GH)) Peptide Gonadotrophin - releasing hormone (GnRH) Peptide Corticotrophin - releasing hormone (CRH) Peptide Growth hormone- releasing hormone (GHRH) Peptide Dopamine (inhibits prolactin) Tyrosine derivative Anterior pituitary Thyrotrophin or thyroid- stimulating hormone Glycoprotein (TSH) Luteinizing hormone (LH) Glycoprotein Follicle - stimulating hormone (FSH) Glycoprotein Growth hormone (GH) (also called Protein somatotrophin) Prolactin (PRL) Protein Adrenocorticotrophic hormone (ACTH) Peptide Posterior pituitary Vasopressin [also called antidiuretic hormone Peptide (ADH)] Oxytocin Peptide Thyroid Thyroxine (T4) and tri- iodothyronine (T3) Tyrosine derivatives Calcitonin Peptide Parathyroid Parathyroid hormone (PTH) Peptide Adrenal cortex Aldosterone Steroid Cortisol Steroid Androstenedione Steroid Dehydroepiandrosterone (DHEA) Steroid Adrenal medulla Epinephrine (also called adrenaline) Tyrosine derivative Norepinephrine (also called noradrenaline) Tyrosine derivative Stomach † Peptide Pancreas (islets Insulin Protein of Langerhans)† Glucagon Protein Somatostatin (SS) Protein Duodenum and Protein jejunum† Protein Chapter 1: Overview of endocrinology / 11

Table 1.2 (Continued )

Gland Hormone Molecular characteristics Liver Insulin- like I (IGF- I) Protein Ovary Oestrogens Steroid Progesterone Steroid Testis Testosterone Steroid

* The distinction between peptide and protein is somewhat arbitrary. Shorter than 50 amino acids is termed a peptide in this table. † The list is not exhaustive for the gastrointestinal tract and the pancreas (see Chapter 11).

Vasopressin regulates water excretion Figure 1.3 The structures of vasopressin and oxytocin are 3 8 remarkably similar, yet the Cys – Tyr – Phe – Gln – Asn – Cys – Pro – Arg – Gly (NH ) 2 physiological effects of the two hormones differ profoundly. SS Oxytocin uterine contraction

3 8

Cys – Tyr – IIe – Gln – Asn – Cys – Pro – Leu – Gly (NH2)

SS

in enzymology, the product frequently inhibits Box 1.4 Major h ormone g roups further progress of the catalyzed reaction. In endo- • Peptides and proteins crinology, a hormone may act on its target cell to • Amino acid derivatives stimulate a response (often secretion of another • Steroids hormone) that then inhibits production of the first hormone (Figure 1.4 a). Hormone secretion may also be regulated by metabolic processes. For instance, duration, so as to induce only a transient response. the pancreatic β - cell makes insulin in response to Certain neural impulses are of this type. Refinement high ambient glucose. The effect is to lower glucose, allows discrimination of a positive signal from which, in turn, inhibits further insulin production. background ‘ noise ’ to ensure that the target cell The hypothalamic– anterior pituitary– end organ cannot or does not respond below a certain thresh- axes are a more complex extension of this model. old level. An example is the pulsatile release of The hypothalamic hormone [e.g. corticotrophin - gonadotrophin- releasing hormone (GnRH) from releasing hormone (CRH)] stimulates release of the hypothalamus. anterior pituitary hormone (e.g. ACTH) to increase peripheral hormone production (e.g. cortisol), which then feeds back on the anterior pituitary and Negative f eedback hypothalamus to reduce the original secretions. Negative feedback is the commonest form of regula- Figure 1.4 b illustrates the anterior pituitary and end - tion used by many biological systems. For example, organ components of this model. 12 / Chapter 1: Overview of endocrinology

(a) (b) Endocrine Endocrine organ organ +

– –

Hormone Response Hormone 1 Hormone 2

Target Target Target tissue endocrine tissue organ

Response

Figure 1.4 Two models of feedback regulating produces hormone 1, which acts on a second hormone synthesis. (a) The endocrine organ releases endocrine gland to release hormone 2. In turn, a hormone, which acts on the target tissue to hormone 2 acts dually on the target tissue to induce stimulate a response. The response usually feeds a response and feeds back negatively onto the back to inhibit ( – ) the endocrine organ to decrease original endocrine organ to inhibit further release of further supply of the hormone. Occasionally, the hormone 1. This model is illustrative of the axes feedback can act to enhance the hormone secretion between the anterior pituitary and the peripheral ( + , positive feedback). (b) The endocrine organ end - organ targets.

Positive f eedback establish positive feedback that is only terminated by delivery of the baby. The role of oxytocin in the Under certain, more unusual, circumstances, suckling – milk ejection reflex is similar – a positive hormone feedback enhances, rather than inhibits, feedback loop that is only broken by cessation of the initial response. This is called positive feedback the baby ’ s suckling. (an example is shown alongside the more usual negative feedback in Figure 1.4 a). This is intrinsi- Inhibitory c ontrol cally unstable. However, in some biological systems it can be transiently beneficial: for instance, the The secretion of some hormones is under inhibitory action of oestrogen on the pituitary gland to induce as well as stimulatory control. Somatostatin, a the ovulatory surge of LH and FSH (see Chapter hypothalamic hormone, prevents the secretion of 7 ); or during childbirth, stretch receptors in the GH, such that when somatostatin secretion is dim- distended vagina and nerves to the brain stimulate inished, GH secretion is enhanced. Prolactin is oxytocin release. This hormone causes the uterus to similarly controlled, under tonic inhibition from contract, further activating the stretch receptors to dopamine. Chapter 1: Overview of endocrinology / 13

genetic defect. For example, in congenital adrenal Box 1.5 Endocrine c ycles hyperplasia, the lack of 21- hydroxylase causes Circadian = 24 - h cycle failure to synthesize cortisol (see Chapter 6 ). Other • Circa = about, dies = day pathways remain intact, leading to excess produc- tion of sex steroids that can masculinize aspects of Ultradian < 24 - h cycle the female body. Endocrine disorders may also arise • E.g. GnRH release from abnormalities in hormone receptors or down- stream signalling pathways. The commonest Infradian > 24 - h cycle example is type 2 diabetes, which arises in part from • E.g. menstrual cycle resistance to insulin action in target tissues (see Chapter 13 ). For those endocrine glands under regulation by Endocrine r hythms the hypothalamus and anterior pituitary, disorders can also be categorized according to site. Disease in Many of the body’ s activities show periodic or cyclical the end organ is termed ‘ primary ’ . When the end changes (Box 1.5 ). Control of these rhythms com- organ is affected downstream of a problem in the monly arises from the nervous system, e.g. the hypoth- anterior pituitary (either underactivity or overactiv- alamus. Some appear independent of the environment, ity), it is secondary, while in tertiary disease, the whereas others are coordinated and ‘ entrained ’ by pathology resides in the hypothalamus. external cues (e.g. the 24 - h light/dark cycle that Like in other specialties, tumourigenesis impacts becomes temporarily disrupted in jetlag). Cortisol on clinical endocrinology. Most commonly, these secretion is maximal between 0400h and 0800h as we tumours are sporadic and benign, but they may awaken and minimal as we retire to bed. In contrast, oversecrete hormones, and are described in the GH and prolactin are secreted maximally ∼ 1 h after appropriate organ - specific chapters in Part 2. falling asleep. Clinically, this knowledge of endocrine However, endocrine tumourigenesis may also form rhythms is important as investigation must be refer- part of recognized multiorgan clinical syndromes. enced according to hour - by - hour and day - to - day vari- These are described in Chapter 10 . ability. Otherwise, such laboratory tests may be invalid or, indeed, misleading. Key p oints

Endocrine d isorders • Endocrinology is the study of hormones and forms one of the body ’ s major The chapters in Part 2 largely focus on organ - communication systems specific endocrinology and associated endocrine • A hormone is a chemical messenger, disorders. Diabetes in Part 3, incorporating obesity, commonly distributed via the circulation, has now become its own specialized branch of endo- that elicits specific effects by binding to a crinology. Nevertheless, it is possible to regard all receptor on or inside target cells endocrine abnormalities as disordered , too much or • The three major types of hormones are too little production of hormone. Some clinical fea- peptides, and the derivatives of amino tures can occur because of compensatory over - acids and cholesterol production of hormones. For example, Addison • Negative and, occasionally, positive disease is a deficiency of cortisol from the adrenal feedback, and cyclical mechanisms cortex (see Chapter 6 ), which reduces negative feed- operate to regulate hormone production, back on ACTH production at the anterior pituitary. commonly as part of complex multiorgan ACTH rises and stimulates melanocytes in the systems or axes skin to increase pigmentation – a cardinal sign of • Clinical endocrine disorders usually arise Addison disease. through too much, too little or disordered Imbalanced hormone production may occur hormone production when a particular enzyme is missing because of a

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