内分泌总论.

PRINCIPLES OF ENDOCRINOLOGYHomeostasis requires the proper function of a variety of control mechanisms. One of the more prominent of these involves negative feedback loops, whereby a particular substance (e.g. glucose) controls its own concentration. The control systems required for homeostasis necessarily became much more complex with the development of multicellular organisms. Not only were control loops required for maintenance of a proper intracellular environment as for unicellular organisms, but in addition, mechanisms needed to be developed to maintain homeostasis in the extracellular environment (e.g.interstitial fluid and blood). In the latter case, especially, methods for cell-cell communication were a critical invention.One general strategy that was developed to accomplish cell-cell communication (organ-organ, as well) involved creation of the central and autonomic nervous systems. A second strategy involved development of endocrine or hormone signals. The term endocrine was coined by Starling to contrast the actions of hormones secrected internally(endocrine) with those secreted externally(exocrine) or into a lumen, such as the gastrointestinal tract. The term hormone, derived from a Greek phrase meaning “to set in motion,” describes the dynamic actions of these circulating substances as they elicit cellular responses and regulate physiologic processes through feedback mechanisms. The subject of this part of the physiology course, hormones originally were defined as discrete molecules that were produced by a particular cell and released from that cell to act on some other cell or regulatory process.Nature of hormonesHormones can be divided into five major classes: 1)amino acid derivatives such as dopamine, catecholamines, and thyroid hormone;2)small neuropeptides such as gonadotropin-releasing hormone( GnRH), thyrotropin-releasinghormone(TRH),somatostatin, and vasopressin;3)large proteins such as insulin and thyroid stimulating hormone (TSH);4) steroid hormones such as estradiol, testosterone and cortisol, 5)vitamin derivatives such as retinoids(vitamin A) and vitamin D. HORMONE SYNTHESIS AND PROCESSThe synthesis of peptide hormones occurs through a classic pathway of gene expression: tanscription→mRNA→protein→posttranslational protein processing→intracellular sorting, membrane integration, or secretion. Though endocrine genes contain regulatory DNA elements similar to those found in many other genes, their exquisite control by other hormones also necessitates the presence of specific hormone response element. For example, the TSH genes are repressed directly by thyroid hormones acting through the thyroid hormone receptor, a member of the nuclear receptor family. For some hormones, substantial regulation occurs at the level of translational efficiency. Insulin biosynthesis, while requiring ongoing gene transcription, is regulated primarily at the translational level in response to elevated levels of glucose or amino acids.Many hormones are embedded within larger precursor polypeptides that are proteolytically processed to yield the biologically active hormone. In many cases, such as POMC and proglucagon, these precurors generate multiple biologically active peptides. It is provocative that hormone precursors are typically inactive, presumably adding an additional level of regulatory control. This is true not only for peptide hormones but also for certain steroids and thyroid hormone.Synthesis of most steroid hormones is based on modifications of the precursor, cholesterol. Multiple regulated enzymatic steps are required for the synthesis of testosterone, estradiol, and vitamine D. This large number of synthetic steps predisposes to multiple genetic and acquired disorders of steroidonesesis.Hormone secretion, transport, and degradationThe circulating level of a hormone is determined by its rate of secretion and its circulating half-life. After protein processing, peptide hormones are stored in secretory granules. As these granules mature, they are poised beneath the plasma membrane for imminent release into the circulation. In most instances, the stimulus for hormone secretion is a releasling factor or neural signal that induces rapiud changes in intracellular calcium concentrations, leading to secretory granule fusion with the plasma membrane and release of its contents into the extracellular environment and blood stream. Steroid hormones, in contrast, diffuse into the circulation as they are synthesized. Thus, their secretory rates are closely aligned with rates of synthesis.Hormone transport and degradation dictate the rapidity with which a hormone signal decays. Some hormonal signals are evanescent, whereas others are longer lived. Because somatostatin exerts effects in virtually every tissue, a short half-life allows it concentrations and actions to be controlled locally. Structural modifications that impair somatostatin degradation have been useful for generating long-acting therapeutic analogues. On the other hand, the actions of TSH are highly specific for the thyroid gland. Its prolonged half-life accounts for relatively constant serum levels, even though TSH is secreted in discrete pulses.Many hormones circulate in assocaiation with serum-binding proteins. For example, T4 and T3 binding to thyroxine-binding globulin(TBG), albumin, and thyroxine-binding prealbumin(TBPA). These interaction provide a hormonal reservoir, prevent otherwise rapid degradation of unbound hormones, restrict hormone access to certain sites ,and modulation of unbound hormones, restrict hormone access to certain sites, and modulate the unbound, or “free” hormone concentrations. Only free hormone is available to binding receptors and thereby elicit a biologic response. Short-term perturbations in binding proteins change the free hormone concentration, which in turn induces compensatory adaptations through feedback loops.Hormone action through receptorFrom the point of view of mechanism of action, it has been useful to think of two basic classes of hormones. The members of one class are hydrophilic and, therefore, have difficulty crossing cell membranes. The members of the second class are hydrophobic and, thus, have easy access to the interior of the cell.1. Hydrophilic: peptide/protein hormones, amines.2. Hydrophobic: Steroid hormones, thyroid hormone.3. A new class: the gases (e.g. nitric oxide, carbon monoxide).General Mechanisms: Hydrophilic hormones.The correspondent receptor for hydrophilic hormones located on cell membrane, it is also called membrane receptor. Membrane receptors for hormones can be divided intoseveral major groups:1)seven transmembrane GRCRs.2) tyrosine kinase receptors. 3) cytokine receptors, and 4) serine kinase receptors.The seven transmembrane GPCR family binds a remarkable array of hormones including large proteins (eg. LH, PTH), small peptides( e.g. TRH, somatostatin), catecholamine (epinephrine, dopamine), and even minerals( e.g. calcium). The extracellular domains of GPCRs vary widely in size and are the major binding site for large hormones. The transmembrane-spanning regions are composed of hydrophobic -helical domains that traverse the lipid bilayer. Like some channels, these domains are thought to circularize and form a hydrophobic pocket into which certain small ligands fit. Hormone binding induces conformational changes in these domains, transducing structural changes to the intracellular domain, which is a docking site for G proteins.The large family of G proteins, so named because they bind guanine nucleotides (GTP, GDP), provides great diversity for coupling to different receptors. G proteins form a heterotrimeric complex that is composed of various and subunits. The subunit contains the guanine nucleotide-binding site and hydrolyzes GTP GDP. The subunits are tightly associated and modulate the activity of the subunit, as well as mediating their own effector signaling pathways. G protein activity is regulated by a cycle that involves GTP hydrolysis and dynamic interactions between the and subunits. Hormone binding to the receptor induces GDP dissociation, allowing G to bind GTP and dissociate from the complex. Under these conditions, the G subunit is activated and mediates signal transduction through various enzymes such as adenylate cyclase or phospholipase C. GTP hydrolysis to GDP allows reassociation with the subunits and restores the inactive state. As described below, a variety of endocrinopathies result from G protein mutations or from mutations in receptors that modify their interactions with G proteins.There are more than a dozen isoforms of the G subunit. G s stimulates, whereas G i inhibits adenylate cyclase, an enzyme that generates the second messenger, cyclic AMP, leading to activation of protein kinase A. G q subunits couple to phospholipase C, generating diacylglycerol and inositol triphosphate, leading to activation of protein kinase C and the release of intracellular calcium.The tyrosine kinase receptors transduce signals for insulin and a variety of growth factors, such as IGF-I, epidermal growth factor (EGF), nerve growth factor, platelet-derived growth factor, and fibroblast growth factor. The cysteine-rich extracellular ligand-binding domains contain growth factor binding sites. After ligand binding, this class of receptors undergoes autophosphorylation, inducing interactions with intracellular adaptor proteins such as Shc and insulin receptor substrates 1 to 4. In the case of the insulin receptor, multiple kinases are activated including the Raf-Ras-MAPK and the Akt/protein kinase B pathways. The tyrosine kinase receptors play a prominent role in cell growth and differentiation as well as in intermediary metabolism.The GH and PRL receptors belong to the cytokine receptor family. Analogous to the tyrosine kinase receptors, ligand binding induces receptor binding to intracellular kinases the Janus kinases (JAKs), which phosphorylate members of the signaltransduction and activators of transcription (STAT) family as well as other signaling pathways (Ras, PI3-K, MAPK). The activated STAT proteins translocate to the nucleus and stimulate expression of target genes.The serine kinase receptors mediate the actions of activins, transforming growth factor , mullerian-inhibiting substance (MIS, also known as anti-mullerian hormone, AMH), and bone morphogenic proteins (BMPs). This family of receptors (consisting of type I and II subunits) signal through proteins termed smads(fusion of terms for Caenorhabditis elegans sma mammalian mad). Like the STAT proteins, the smads serve a dual role of transducing the receptor signal and acting as transcription factors. The pleomorphic actions of these growth factors dictate that they act primarily in a local (paracrine or autocrine) manner. Binding proteins, such as follistatin (which binds activin and other members of this family), function to inactivate the growth factors and restrict their distribution.A series of specific steps are involved in the process by which hydrophilic hormones act on mammalian cells. These include:1. External signal (Hormone).2. Surface Receptor(s).3. Transducer (e.g. G-proteins).4. Amplifier (e.g. Adenylate Cyclase).5. Second messenger (e. g. cyclic-AMP).6. Effector (e.g. protein kinases).7. Response (e.g. glycogen mobilization).One also should note in the above scheme, the cross-talk / integration that occurs between hormone signaling pathways, the first reminder that hormones never work in isolation from one another.All signal mechanisms amplify the original signal as the response proceeds. The most usual mechanism for doing this is to employ catalytic reactions involving enzymes. Recently an important new mechanism has been discovered for hormones that work through surface receptors, at least those that act as growth factors (e.g. EGF, PDGF). In this case, when a hormone molecule binds to its receptor, the signal somehow is spread laterally through the membrane to other receptors even if the neighboring receptors are unoccupied. This may involve the well-known phenomenon whereby activated surface receptors dimerize. The unoccupied dimer may become activated (e.g. phosphorylated) even if not occupied and then dissociate and dimerize with another partner activating that receptor as well. Thus, focal stimulation potentially allows activation of all surface receptors for the hormone.General mechanisms: Hydrophobic hormones (steroid hormones, thyroid hormone). The family of nuclear receptors has grown to nearly 100 members, many of which are still classified as orphan receptors because their ligands, if they exist, remain to be identified. Otherwise, most nuclear receptors are classified based on the nature of their ligands. Though all nuclear receptors ultimately act to increase or decrease gene transcription, some (e.g., glucocorticoid receptor) reside primarily in the cytoplasm,whereas others (e.g., thyroid hormone receptor) are always located in the nucleus. After ligand binding, the cytoplasmically localized receptors translocate to the nucleus.The structures of nuclear receptors have been extensively studied, including by x-ray crystallography. The DNA binding domain, consisting of two zinc fingers, contacts specific DNA recognition sequences in target genes. Most nuclear receptors bind to DNA as dimers. Consequently, each monomer recognizes an individual DNA motif, referred to as a "half-site." The steroid receptors, including the glucocorticoid, estrogen, progesterone, and androgen receptors, bind to DNA as homodimers. Consistent with this twofold symmetry, their DNA recognition half-sites are palindromic. The thyroid, retinoid, PPAR, and vitamin D receptors bind to DNA preferentially as heterodimers in combination with retinoid X receptors (RXRs). Their DNA half-sites are arranged as direct repeats. Receptor specificity for DNA sequences is determined by (1) the sequence of the half-site, (2) the orientation of the half-sites (palindromic, direct repeat), and (3) the spacing between the half-sites. For example, vitamin D, thyroid and retinoid receptors recognize similar tandemly repeated half-sites (TAAGTCA), but these DNA repeats are spaced by three, four, and five nucleotides, respectively.The carboxy-terminal hormone-binding domain mediates transcriptional control. For type II receptors, such as TR and RAR, co-repressor proteins bind to the receptor in the absence of ligand and silence gene transcription. Hormone binding induces conformational changes, triggering the release of co-repressors and inducing the recruitment of coactivators that stimulate transcription. Thus, these receptors are capable of mediating dramatic changes in the level of gene activity. Certain disease states are associated with defective regulation of these events. For example, mutations in the thyroid hormone receptor prevent co-repressor dissociation, resulting in a dominant form of hormone resistance. In promyelocytic leukemia, fusion of RAR to other nuclear proteins causes aberrant gene silencing and prevents normal cellular differentiation. Treatment with retinoic acid reverses this repression and allows cellular differentiation and apoptosis to occur. Type 1 steroid receptors do not interact with co-repressors, but ligand binding still mediates interactions with an array of coactivators. X-ray crystallography shows that various SERMs induce distinct receptor conformations. The tissue-specific responses caused by these agents in breast, bone, and uterus appear to reflect distinct interactions with coactivators. The receptor-coactivator complex stimulates gene transcription by several pathways including (1) recruitment of enzymes (histone acetyl transferases) that modify chromatin structure, (2) interactions with additional transcription factors on the target gene, and (3) direct interactions with components of the general transcription apparatus to enhance the rate of RNA polymerase II-mediated transcription.C. Overlapping MechanismsWhereas the above mechanisms are thought generally to hold for hydrophilic (e.g. amine, peptide, protein) and hydrophobic (e.g. steroid) hormones, there clearly is some overlap. For example, it has been known for some time that plasma membrane receptors exist for steroid hormones (e.g. estradiol, progesterone) and that those receptors must be activated to produce a second messenger in order for all of the actions of the hormone to occur.D. Integration between signal pathways.Hormones do not act in isolation from one another. They interact in three principal ways, as will be illustrated in the endocrine section:1. A permissive hormone sensitizes target tissues to some other hormone(s). One example is that thyroid hormone sensitizes cells to the actions of catecholamines. A second is that cortisol somehow is necessary for second messenger control systems of most other hormones to work: without cortisol, the body cannot respond to external signals or stresses.2. A synergistic hormone reinforces the action of some other hormone(s). An example that will be discussed is the synergy between epinephrine and glucagon in terms of raising blood sugar level.3. An antagonistic hormone acts in opposition to some other hormone(s). Here, the term, anatgonistic, is used somewhat loosely. It refers to opposite consequences of the actions of two hormones. For example, insulin works to lower blood sugar level and glucagon works to raise it.E. Specificity.With so many common denominators, it is legitimate to ask what are the mechanisms that lead to hormone specificity. There are several explanations for why this is possible.1. Receptors. Receptors are highly specific for a particular hormone or ligand. Thus, the presence or absence of a particular receptor on or in the cell will go a long way in determining specificity.2. Effector pathways. Even if receptors are present, the effector pathways necessary for a hormone to act must both be present and accessible to the hormone-receptor complex.3. Location. The concept that the location in a cell is important in determining the actions of a hormone already has been introduced. The relative locations of receptors and effector pathways in a cell also is an important factor in determining specificity.HORMONE FEEDBACK CONTROL SYSTEMS..Hormones allow cell communication in three different ways. First, the hormone released from a cell can act on the same cell in an AUTOCRINE fashion. Second, the released hormone can work on neighboring cells in a PARACRINE fashion, but not on cells at distant locations in the organism. Third hormones can travel through the extracellular space (blood) to act on distant cells to act in an ENDOCRINE fashion, as mentioned above endocrine means ductless.Hormones generally secreted at some (non-zero) resting rate or baseline. Secretion regulated up or down by some signal. A chain of endocrine responses is usually initiated by neurohormone. Nerve cells are stimulated by neural activity, release a neurohormone that then alters secretion of second hormone. Neurohormones transduce a neural signal into an endocrine signal.Sets of endocrine glands are usually organized into hierarchical loops that allow feedback or closed loops to regulate responses. They conclude Short loop, which means hormone A affects secretion of hormone B, and hormone B affects secretion of A, and there is no intervening steps, and Long loop, which means hormone A affects secretion of B,hormone B affects secretion of C, and hormone C affects secretion of A, Intermediate steps occur.NEGATIVE FEEDBACK: Mechanism that RESTORES abnormal values to normal; reverses a change. POSITIVE FEEDBACK: Mechanism that makes ABNORMAL values MORE ABNORMAL; strengthens / reinforces change.A. Negative Feedback.Negative feedback loops play a dominant role in endocrine feedback systems. Here, as classically described, the amount of a substance regulates its own concentration, albeit often times indirectly. When concentration rises to above desired levels, a series of steps is taken to cause the concentration to fall. Conversely, steps are taken to increase concentration when the level is too low.Additionally, there are feedback loops that involve hormones regulating themselves. Examples here include thyroid hormone, cortisol and the hormones of the reproductive system. In these cases, a critical negative feedback relationship exists between the endocrine gland which makes a particular hormone and the adenohypophysis which controls the gland.Feedback is usually negative, so that endocrine response is self-limiting; secretion modulates itself and does not 'run away'.B. Positive Feedback.Feedback is sometimes positive, when a quick, large response is necessary. Positive feedback creates instability and leads to explosive, rapidly-amplified changes. Examples that you have learned about involve oxytocin and uterine contractions, the events leading to ovulation (LH spike), the actions of angiotensin II on its receptor and clotting. When a system shows positive feedback, it will run away (like a microphone held near an amplifier) unless something changes to stop the positive feedback. They all are involved with situations where rapid amplification is in the body’s best interest.C. SetpointsThere are times when it is important to change the level of the hormone circulating in the blood. For example, it is important to reduce thyroid hormone levels during starvation. Similarly, in times of stress, it is critical to increase the circulating level of adrenal gluccorticoids. This is made possible because the body can change the setpoint of the feedback loop, by changing the nature of the signals coming, in these two specific cases, from the central nervous system and hypothalamus. Again, by previous analogy, those organs are the equivalent to the person who can change the temperature setting of the thermostat.D. Good feedback systems must be able to be turned on AND off rapidly.A key principle of any good control system is that there must not only be mechanisms for turning on a signal quickly, but there also must be mechanisms for turning it off quickly. We will see examples of this too. It is only via such rapidly acting on AND off mechanisms that the body can respond adequately to challenges to homeostasis. Otherwise, there would be very large fluctuations due to over-compensation of the substance or process being regulated. For example, a fall in blood sugar will cause a rise in pancreatic glucagon within seconds. There must be a mechanism for turning off the glucagon signal rapidly or blood sugar would continue to rise to dangerously high levels. One mechanism for this is that glucagon in the blood is degraded very rapidly. Thus,sustained high levels of glucagon require its continued release from the pancreas. Release is immediately reduced as soon as blood sugar rises to above normal levels.E. Negative feedback loops embedded within negative feedback loops.Partly because of the need for mechanisms to turn signals off rapidly, in many cases there are negative feedback loops within negative feedback loops. These will be discussed at some length. Two examples that play a prominent role in endocrine regulation involve negative regulation of a hormone's receptor by the hormone itself and negative feedback loops within the second messenger systems that allow cells to respond to hormones. Autocrine, paracrine and endocrine systems do not act alone in the pursuit of homeostasis. Two other major control systems involve the central and autonomic nervous systems. Indeed, these systems all must act in concert if an environment compatible with life is to be maintained. Hormones participate in the regulation of almost everything. This includes other hormones, foodstuffs, minerals, water and even behavior.HORMONAL RHYTHMSThe feedback regulatory systems described above are superimposed on hormonal rhythms that are used for adaptation to the environment. Seasonal changes, the daily occurrence of the light-dark cycle, sleep, meals, and stress are examples of the many environmental events that affect hormonal rhythms. The menstrual cycle is repeated on average every 28 days, reflecting the time required to follicular maturation and ovulation. Essentially all pituitary hormone rhythms are entrained to sleep and the circadian cycle, generating reproducible patterns that are repeated approximately every 24 h. The HPA axis, for example, exhibits characteristic peaks of ACTH and cortisol production in the early morning, with a nadir in the afternoon and evening. Recognition of these rhythms is important for endocrine testing and treatment. 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. The HPA axis is more susceptible to suppression by glucocorticoids administered at night as they blunt the early morning rise of ACTH. Understanding these rhythms allows glucocorticoid replacement that mimics diurnal production by administering larger doses in the morning than in the afternoon.Other endocrine rhythms occur on a more rapid time scale. Many peptide hormones are secreted in discrete bursts every few hours. 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. This feature of the hypothalamic-pituitary-gonadotrope (HPG) axis forms the basis for using long-acting GnRH agonists to treat central precocious puberty or to decrease testosterone levels in the management of prostate cancer.It is 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. For some hormones, integrated markers have been developed to circumventhormonal fluctuations. Examples include 24-h urine collections for cortisol, IGF-I as a biologic marker of GH action, and HbA1c as an index of long-term (weeks to months) blood glucose control.Often, one must interpret endocrine data only in the context of other hormonal results. For example, parathyroid hormone levels are typically assessed in combination with serum calcium concentrations. A high serum calcium level in association with elevated PTH is suggestive of hyperparathyroidism, whereas a suppressed PTH in this situation is more likely to be caused by hypercalcemia of malignancy or other causes of hypercalcemia. Similarly, TSH should be elevated when T4and T3concentrations are low, reflecting reduced feedback inhibition. When this is not the case, it is important to consider other abnormalities in the hormonal axis, such as secondary hypothyroidism, which is caused by a defect at the level of the pituitary.PATHOLOGIC MECHANISMS OF ENDOCRINE DISEASEEndocrine diseases can be divided into three major types of conditions: (1) hormone excess, (2) hormone deficiency, and (3) hormone resistance.CAUSES OF HORMONE EXCESSSyndromes of hormone excess can be caused by neoplastic growth of endocrine cells, autoimmune disorders, and excess hormone administration. Benign endocrine tumors, including parathyroid, pituitary, and adrenal adenomas, often retain the capacity to produce hormones, perhaps reflecting the fact that they are relatively well differentiated. Many endocrine tumors exhibit relatively subtle defects in their "set points" for feedback regulation. For example, in Cushing's disease, impaired feedback inhibition of ACTH secretion is associated with autonomous function. However, the tumor cells are not completely resistant to feedback, as revealed by the fact that ACTH is ultimately suppressed by higher doses of dexamethasone (e.g., high-dose dexamethasone test). Similar set point defects are also typical of parathyroid adenomas and autonomously functioning thyroid nodules.The molecular basis of some endocrine tumors, such as the MEN syndromes (MEN-1, -2A, -2B), have provided important insights into tumorigenesis. MEN-1 is characterized primarily by the triad of parathyroid, pancreatic islet, and pituitary tumors. MEN-2 predisposes to medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. The MEN1gene, located on chromosome 11q13, encodes a putative tumor-suppressor gene. Analogous to the paradigm first described for retinoblastoma, the affected individual inherits a mutant copy of the MEN1gene, and tumorigenesis ensues after a somatic "second hit" leads to loss of function of the normal MEN1 gene (through deletion or point mutations).In contrast to inactivation of a tumor-suppressor gene, as occurs in MEN-1 and most other inherited cancer syndromes, MEN-2 is caused by activating mutations in a single allele. In this case, activating mutations of the RET proto-oncogene, which encodes a。