The specialty of endocrinology encompasses the study of glands and the hormones they produce.
The term “endocrine” was coined by Starling roughly 100 years ago to contrast actions of hormone secreted internally with those secrected externall which is termed “exocrine”.
In previous slides, we have discuss the sorces of hormones, and exactly those sorces compose endocrine system. Unlike many other specialties in medicine, such as the digestion system, the cardiovascular system, it is not possible to define endocrine system strictly along anatomic lines. The classic endocrine glands—pituitary, thyroid, parathyroid, pancreatic islets, adrenal, and gonads—communicate broadly with other organs through the nervous system, hormones, cytokines, and growth factors.
Figure on this slide shows the major endocrine organs in both genders including……., as well as the common disorders in these organs which will be disscused in following sections and the lectures presented by other professors.
The term hormone , derived from a Greek phrase meaning “to set in motion,” aptly describes the dynamic actions of hormones as they elicit cellular responses and regulate physiologic processes through feedback mechanisms.
This slide concludes the hormones produced by hypothalamus and pituitary, most of which are stimulating hormones, affecting the growth axis thyroid axis adrenal axis and other endocrine tissue. With no doubt, Hypothalamus Pituitary axis is the central site in endocrine hemostasis.
Amino acid derivatives and peptide hormones interact with cell surface membrane receptors, while steroids, TH, VitD and retinoid are lipid-soluable and interact with intracellular nuclear receptors
Hormone release is the end-product of a long cascade of intracellular events. As indicated in this slide, peptide hormone is often in the form of a precursor molecule that may itself be biologically inactive. This 'prohormone' may be further processed before being packaged into granules, in the Golgi apparatus. These granules are then transported to the plasma membrane before release. Hormone secretion is itself regulated by a complex combination of intracellular regulators. Hormone release may be in a brief spurt caused by the sudden stimulation of granules, often induced by an intracellular Ca2+-dependent process, or it may be 'constitutive' (immediate and continuous secretion)
Insulin is the key hormone involved in the storage and controlled release within the body of the chemical energy available from food The synthesis, intracellular processing and secretion of insulin by the beta-cell is typical of the way that the body produces and manipulates many peptide hormones. This figure illustrates the intracellular pathway of manufactrue and releasing of insulin in beta cells.
This large number of synthetic steps predisposes to multiple genetic and acquired disorders of steroidogenesis.
T4 has a half-life of 7-10 days and T3 of about 6-10 hours. Levels over the day, month and year show little variation . In contrast, secretion of the gonadotrophins, LH and FSH, is normally pulsatile, with major pulses released every 1-2 hours depending on the phase of the menstrual cycle. Continuous infusion of LH to produce a steady equivalent level does not produce the same result (e.g. ovulation in the female) as the intermittent pulsatility, and may indeed produce downregulation
In this figure,please note both the pulsatility and the shifting baseline. Normal ranges for 0900 h (180-700 nmol/L) and 2400 h (less than 100 nmol/L; must be taken when asleep) are shown in the orange boxes. Purple shading shows sleep. plasma cortisol levels measured over 24 hours - levels are highest in the early morning and lowest overnight. Additionally, cortisol release is pulsatile, following the pulsatility of pituitary ACTH. Thus 'normal' cortisol levels vary during the day and great variations can be seen in samples taken only 30 minutes apart
Other endocrine rhythms occur on a more rapid time scale. Many peptide hormones are secreted in discrete bursts every few hours. For example, on the background of long term ryththm of menstrual cycle, secretion of the gonadotrophins, LH and FSH, is normally pulsatile, with major pulses released every 1-2 hours depending on the phase of the menstrual cycle. Continuous infusion of LH to produce a steady equivalent level does not produce the same result (e.g. ovulation in the female) as the intermittent pulsatility, and may indeed produce downregulation. Since LH and FSH secretion are exquisitely sensitive to GnRH pulse frequency. Intermittent pulses of GnRH are required to maintain pituitary sensitivity, whereas continuous exposure to GnRH causes pituitary gonadotrope desensitization .
Patients with Cushing’s syndrome characteristically exhibit increased midnight cortisol levels when compared to normal individuals. In contrast, morning cortisol levels are similar in these groups, as cortisol is normally high at this time of day in normal individuals. Therefor when testing an individual with suspected Cushing disease or Cushing syndrom, blood sample should be taken at 0 am as well. It is also important to be aware of the pulsatile nature of hormone secretion and the rhythmic patterns of hormone production when relating serum hormone measurements to normal values. Moreover, in order to profile the pulse frequency and amplitude of some hormones accurately, we have to pool three to four samples drawn at about 30-min intervals.And such pulsatile secretion makes it difficult to establish a narrow normal range. Recognition of rhythms of hormonal secretion guides the treatments in some disease. For example, replacement therapy of glucocoticoid requires larger dose in the morning than in the afternoon, since this mimics its circadian rhythm and may reduce the side effect. Adminstation of ong-acting GnRH agonists is used to treat central precocious puberty or to decrease testosterone levels in the management of prostate cancer, because Intermittent pulses of GnRH are required to maintain pituitary sensitivity, whereas continuous exposure to GnRH causes pituitary gonadotrope desensitization.
Physiological 'stress' and acute illness produce rapid increases in ACTH and cortisol, growth hormone (GH), prolactin, epinephrine (adrenaline) and norepinephrine (noradrenaline). These can occur within seconds or minutes Secretion of GH and prolactin is increased during sleep, especially the rapid eye movement (REM) phase. Many hormones regulate the body's control of energy intake and expenditure and are therefore profoundly influenced by feeding and fasting. Thus, secretion of insulin is increased and growth hormone decreased after ingestion of food, and secretion of a number of hormones is altered during prolonged food deprivation
Most classical hormones are secreted into the systemic circulation where they travel to have effects elsewhere in the body. In contrast, hypothalamic releasing hormones are released into the pituitary portal system so that much higher concentrations of the releasing hormones reach the pituitary than occur in the systemic circulation . Many hormones are bound to proteins within the circulation. In most cases, only the free (unbound) hormone is available to the tissues and thus biologically active. This binding serves to buffer against very rapid changes in plasma levels of the hormone, and some binding protein interactions may also be involved in the active regulation of hormone action. Many tests of endocrine function often measure total rather than free hormone, since binding proteins are frequently altered in disease states. Binding proteins comprise both specific, high-affinity proteins of limited capacity, such as thyroxine-binding globulin (TBG) and other less-specific low-affinity ones, such as prealbumin and albumin
Hormones act by binding to specific receptors in the target cell, which may be at the cell surface and/or within the cell. Most hormone receptors are proteins with complex tertiary structures, parts of which complement the tertiary structure of the hormone to allow highly specific interactions, while other parts are responsible for the effects of the activated receptor within the cell. Many hormones bind to specific cell-surface receptors where they trigger internal messengers, while others bind to nuclear receptors which interact directly with DNA. Cell-surface receptors usually contain hydrophobic sections which span the lipid-rich plasma membrane, while nuclear receptors contain characteristic amino-acid sequences to bind nuclear DNA as in the glucocorticoid receptor. In order to achieve their intracellular effects, hormone receptors interact with a variety of other regulatory factors within the cell membrane, in the cytosol or within the nucleus of the cell. In each case, binding of the hormone to its receptor results in a conformational change in the structure of the receptor, which may result in a number of possible outcomes which are illustrated in this figure. 1. activation of, or modified binding to, other regulatory factors within the cell membrane or cytosol (e.g. binding of transmembrane receptors to the cell-membrane G-proteins, thereby activating the stimulatory or inhibitory effects of the latter on other intracellular mediators) 2. activation of enzyme activity in the receptor or its regulatory factors (e.g. receptor adenylate cyclase, other protein kinases, phospholipase C) to generate a variety of intracellular 'second messengers' (e.g. cAMP, cGMP, phosphatidylinositol metabolites, calmodulin) which usually form a complex, branching and interacting intracellular cascade of enzyme activation and inhibition and/or mobilization of intracellular stores of ions (primarily calcium) 3. altered binding of the receptor to DNA or to nuclear transcription factors in order to stimulate or inhibit transcription of one or more genes 4. altered activity of cell-membrane channels or transporters (e.g. for glucose, potassium or for other ions) 5. dimerization of the receptor, or internalization of some cell-surface receptors. These immediate effects of hormone binding may then cause rapid alterations in cell-membrane ion transport or intracellular calcium concentrations, or slower responses such as DNA, RNA and protein synthesis In each case, binding of the hormone to its receptor is the first step in a complex cascade of interrelated intracellular events which eventually lead to the overall effects of that hormone on cellular function Common 'second messengers' involved in these cascades include cyclic AMP (for adrenocorticotrophic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and parathyroid hormone (PTH)), a calcium-phospholipid system (for thyrotrophin-releasing hormone (TRH), vasopressin and angiotensin II), tyrosine kinase and other intracellular kinases (for insulin and insulin-like growth factor-1 (IGF-1)) and membrane-bound phosphoinositide pathways .
An understanding of circulating hormone half-life is important for achieving physiologic hormone replacement, as the frequency of dosing and the time required to reach steady state are intimately linked to rates of hormone decay . T4, for example, has a circulating half-life of 7 days. Consequently, ＞ 1 month is required to reach a new steady state, but single daily doses are sufficient to achieve constant hormone levels. T3, in contrast, has a half-life of 1 day. Its administration is associated with more dynamic serum levels and it must be administered two to three times per day
1.TRH (thyrotrophin-releasing hormone) is secreted in the hypothalamus and travels via the portal system to the pituitary where it stimulates the thyrotrophs to produce thyroid-stimulating hormone (TSH). 2.TSH is secreted into the systemic circulation where it stimulates increased thyroidal iodine uptake and thyroxine (T4) and triiodothyronine (T3) synthesis and release. 3.Serum levels of T3 and T4 are thus increased by TSH; in addition, the conversion of T4 to T3 (the more active hormone) in peripheral tissues is stimulated by TSH. 4.T3 and T4 then enter cells where they bind to nuclear receptors and promote increased metabolic and cellular activity. 5.Levels of T3 (from the blood and from local conversion of T4) are sensed by receptors in the pituitary and possibly the hypothalamus. If they rise above normal, TRH and TSH production is suppressed, leading to reduced T3 and T4 secretion. 6.Peripheral T3 and T4 levels thus fall to normal. 7.If, however, T3 and T4 levels are low (e.g. after thyroidectomy), increased amounts of TRH and thus TSH are secreted, stimulating the remaining thyroid to produce more T3 and T4; blood levels of T3 and T4 may be restored to normal, although at the expense of increased TSH drive, reflected by a high TSH level ('compensated euthyroidism'). Conversely, in thyrotoxicosis when factors other than TSH itself are maintaining high T3 and T4 levels, the same mechanisms lead to suppression of TSH secretion.
Corticotropin-releasing hormone (CRH ) is secreted in the hypothalamus in response to circadian rhythm, stress and other stimuli. CRH travels down the portal system to stimulate ACTH release from the anterior pituitary. ACTH is derived from the prohormone pro-opiomelanocortin, which undergoes complex processing within the pituitary to produce ACTH and a number of other peptides including beta-lipotrophin and beta-endorphin. Many of these peptides, including ACTH, contain melanocyte-stimulating hormone (MSH)-like sequences which cause pigmentation when levels of ACTH are markedly raised. Circulating ACTH stimulates cortisol production in the adrenal. The cortisol secreted (or any other synthetic corticosteroid administered to the patient) causes negative feedback on the hypothalamus and pituitary to inhibit further CRH/ACTH release. The set-point of this system clearly varies through the day according to the circadian rhythm, and is usually overridden by severe stress. Following adrenalectomy or other adrenal damage (e.g. Addison's disease), cortisol secretion will be absent or reduced; ACTH levels will therefore rise.
Fasting and postprandial effects of insulin. In the fasting state insulin concentrations are low and it acts mainly as a hepatic hormone, modulating glucose production (via glycogenolysis and gluconeogenesis) from the liver. Hepatic glucose production rises as insulin levels fall. In the postprandial state insulin concentrations are high and it then suppresses glucose production from the liver and promotes the entry of glucose into peripheral tissues (increased glucose utilization).
Principles of Endocrinology Department of Endocrinology First Affiliated Hospital Sun Yet-sen University Cao Xiaopei
Principles of Endocrinology <ul><li>Glands </li></ul><ul><li>Hormones </li></ul>
Endocrine <ul><li>hormones from specialized cells in glands or tissue are secrected and transported in the blood to a distant site of action(classic “endocrine” effect), or act directly upon nearby cells which is called “paracrine” activity. </li></ul>
Exocrine <ul><li>products from glands are secrected externally or into a lumen, such as the gastrointestinal tract. </li></ul>
Endocrine System <ul><li>Elements of endocrine system: </li></ul><ul><li>Endocrine organs </li></ul><ul><li>APUD system </li></ul><ul><li>Hormonal secrentory cells </li></ul>
Major endocrine organs and common endocrine problems
Hormone Chemical messengers produced by a variety of specialized secretory cells Chemical signals secreted into the blood stream that act on distant tissues, usually in a regulatory fashion
Sources of Hormones <ul><li>Hormone secretory cells (found around human body) </li></ul><ul><li>Endocrine glands </li></ul><ul><li>Tissues or cells of endocrine function: neurosecretory cells in hypothalamus, hormone secretory cells/organ cells with endocrine function in GI tract, kidney, heart, lung, etc </li></ul>
Hormones involved in Hypothalamus-Pituitary axis and their function
Synthesis, Storage and Release of Hormones <ul><li>Steroid hormone: </li></ul><ul><li>Synthesis of most steroid hormones is based on modifications of the precursor and cholesterol. </li></ul><ul><li>Multiple regulated enzymatic steps are required for the synthesis of testosterone, estradiol, cortisol and vitamin D . </li></ul>
Patterns of secretion <ul><li>Hormone secretion is continuous(e.g. thyroid hormone) or intermittent(e.g. LH,FSH). </li></ul><ul><li>Biological rhythms ------ Circadian </li></ul><ul><li>Circadian means changes over the 24 hours of the day-night cycle and is best shown for the pituitary-adrenal axis. </li></ul>
Plasma cortisol levels during a 24-hour period
Hormonal and follicular changes during the normal menstrual cycle The menstrual cycle is the best example of a longer and more complex (28-day) biological rhythm.
Patterns of secretion <ul><li>Clinical significance of recognising rhythms of hormonal secretion: </li></ul><ul><li>1. Testing the hormone concentration </li></ul><ul><li>2. Hormonal replacement therapy </li></ul>
Patterns of secretion <ul><li>Other regulatory factors </li></ul><ul><li>Stress </li></ul><ul><li>Sleep </li></ul><ul><li>Feeding and fasting </li></ul>
Plasma Transport of Hormones Cortisol-binding globulin (CBG) Cortisol IGF-binding proteins (mainly IGF-BP3) Insulin-like growth factor-I (IGF-l) Sex hormone-binding globulin (SHBG) Testosterone, estradiol Thyroxine-binding globulin (TBG) Albumin Triiodothyronine (T3) (less bound than T4) Albumin Thyroxine-binding prealbumin (TBPA) Thyroxine-binding globulin (TBG) Thyroxine (T4) Binding protein(s) Hormone
Degradation of Hormones <ul><li>Hormone transport and degradation dictate the rapidity with which a hormonal signal decays. Some hormonal signals are evanescent (e.g.somatostatin), whereas others are longer lived (e.g. TSH) </li></ul><ul><li>Most hormones are deactivated in live, kidney or peripheral tissues. Thus it must be noted that hepatic insufficiency or renal insufficiency may result in prolonged half life of some hormones </li></ul>
<ul><li>Metabolism </li></ul><ul><li>organ function </li></ul><ul><li>growth </li></ul><ul><li>development reproduction </li></ul><ul><li>Maintainance of homostasis of internal enviroment </li></ul>Functions of Hormones
Feedback Hypothalamus Pituitary-target gland axis Hypothalamus Pituitary thyroid axis Hypothalamus Pituitary adrenal axis Hypothalamus Pituitary gonad axis Endocrine and metabolism Insulin vs glucose PTH vs calcium ADH vs plasma osmotic pressure
Classification of endocrine disease 1. primary endocrine disorder 2. secondary to other disease 3. ectopic endocrine disorder 4. due to receptor dysfunction 5. heredity abnormal hormones 6. iatrogenic
Clinical picture history 、 symptom 、 sign Lab findings evidence of metabolic disturbance: target tissue or/and organs function evidence of inappropriate hormone ： hormones or their metabolite of endocrine function test immunology Diagnosis
Imageology X ray ， CT ， B ultrasound ， isotope Histology and cytology Cytogenetics Diagnosis
Typical features in endocrine disease dwarfism gigantism acromegaly
Typical features in endocrine disease Cushing syndrome hyperthyroidism Cretinism Addison disease