PRINCIPLES OF ENDOCRINOLOGY
Homeostasis 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 hormones
Hormones 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-releasing
hormone(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 PROCESS
The 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 degradation
The 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 receptor
From 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 into
several 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 signal
transduction 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 Mechanisms
Whereas 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. Setpoints
There 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 RHYTHMS
The 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 circumvent
hormonal 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 DISEASE
Endocrine diseases can be divided into three major types of conditions: (1) hormone excess, (2) hormone deficiency, and (3) hormone resistance.
CAUSES OF HORMONE EXCESS
Syndromes 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
receptor tyrosine kinase, leads to thyroid C-cell hyperplasia in childhood before the development of medullary thyroid carcinoma. Elucidation of the pathogenic mechanism has allowed early genetic screening for RET mutations in individuals at risk for MEN-2, permitting identification of those who may benefit from prophylactic thyroidectomy and biochemical screening for pheochromocytoma and hyperparathyroidism.
Mutations that activate hormone receptor signaling have been identified in several GPCRs. For example, activating mutations of the LH receptor causes a dominantly transmitted form of male-limited precocious puberty, reflecting premature stimulation of testosterone synthesis in Leydig cells. Activating mutations in these GPCRs are located primarily in the transmembrane domains and induce receptor coupling to G s, even in the absence of hormone. Consequently, adenylate cyclase is activated and cyclic AMP levels increase in a manner that mimics hormone action. A similar phenomenon results from activating mutations in G s. When these occur early in development, they cause McCune-Albright syndrome. When they occur only in somatotropes, the activating G s mutations cause GH-secreting tumors and acromegaly.
In autoimmune Graves' disease, antibody interactions with the TSH receptor mimic TSH action, leading to hormone overproduction. Analogous to the effects of activating mutations of the TSH receptor, these stimulating autoantibodies induce conformational changes that release the receptor from a constrained state, thereby triggering receptor coupling to G proteins.
CAUSES OF HORMONE DEFICIENCY
Most examples of hormone deficiency states can be attributed to glandular destruction caused by autoimmunity, surgery, infection, inflammation, infarction, hemorrhage, or tumor infiltration. Autoimmune damage to the thyroid gland (Hashimoto's thyroiditis) and pancreatic islet cells (type 1 diabetes mellitus) are prevalent causes of endocrine disease. Mutations in a number of hormones, hormone receptors, transcription factors, enzymes, and channels can also lead to hormone deficiencies.
HORMONE RESISTANCE
Most severe hormone resistance syndromes are due to inherited defects in membrane receptors, nuclear receptors, or in the pathways that transduce receptor signals. These disorders are characterized by defective hormone action, despite the presence of increased hormone levels. In complete androgen resistance, for example, mutations in the androgen receptor cause genetic (XY) males to have a female phenotypic appearance, even though LH and testosterone levels are increased. In addition to these relatively rare genetic disorders, more common acquired forms of functional hormone resistance include insulin resistance in type 2 diabetes mellitus, leptin resistance in obesity, and GH resistance in catabolic states. The pathogenesis of functional resistance involves receptor downregulation and postreceptor desensitization of signaling pathways; functional forms of resistance are generally reversible.
Approach to the Patient
Because endocrinology interfaces with numerous physiologic systems, there is no standard endocrine history and examination. Moveover, because most glands are relatively inaccessible, the examination usually focuses on the manifestations of hormone excess or deficiency, as well as direct examination of palpable glands, such as the thyroid and gonads. For these reasons, it is important to evaluate patients in the context of their presenting symptoms, review of systems, family and social history, and exposure to medications that may affect the endocrine system. Astute clinical skills are required to detect subtle symptoms and signs suggestive of underlying endocrine disease. For example, a patient with Cushing's syndrome may manifest specific findings, such as central fat redistribution, striae, and proximal muscle weakness, in addition to features seen commonly in the general population, such as obesity, plethora, hypertension, and glucose intolerance. Similarly, the insidious onset of hypothyroidism with mental slowing, fatigue, dry skin, and other features can be difficult to distinguish from similar, nonspecific findings in the general population. Clinical judgment, based on knowledge of pathophysiology and experience, is required to decide when to embark on more extensive evaluation of these disorders. As described below, laboratory testing plays an essential role in endocrinology by allowing quantitative assessment of hormone levels and dynamics. Radiologic imaging tests, such as CT scan, MRI, thyroid scan, and ultrasound, are also used for the diagnosis of endocrine disorders. However, these tests are generally employed only after a hormonal abnormality has been established by biochemical testing. Hormone Measurements and Endocrine Testing
Radioimmunoassays are the most important diagnostic tool in endocrinology, as they allow sensitive, specific, and quantitative determination of steady-state and dynamic changes in hormone concentrations. Radioimmunoassays use antibodies to detect specific hormones. For many peptide hormones, these measurements are now configured as immunoradiometric assays (IRMAs), which use two different antibodies to increase binding affinity and specificity. There are many variations of these assays a common format involves using one antibody to capture the antigen (hormone) onto an immobilized surface and a second antibody, labeled with a fluorescent or radioactive tag, to detect the antigen. These assays are sensitive enough to detect plasma hormone concentrations in the picomolar to nanomolar range, and they can readily distinguish structurally related proteins, such as PTH from PTHrP. A variety of other techniques are used to measure specific hormones, including mass spectroscopy, various forms of chromatography, and enzymatic methods; bioassays are now used rarely.
Most hormone measurements are based on plasma or serum samples. However, urinary hormone determinations remain useful for the evaluation of some conditions. Urinary collections over 24 h provide an integrated assessment of the production of a hormone or metabolite, many of which vary during the day. It is important to assure complete collections of 24-h urine samples; simultaneous measurement of creatinine provides an internal control for the adequacy of collection and can be used to normalize some hormone measurements. A 24-h urine free cortisol measurement largely reflects the amount of unbound cortisol, thus providing a reasonable index of biologically available
hormone. Other commonly used urine determinations include: 17-hydroxycorticosteroids, 17-ketosteroids, vanillylmandelic acid (VMA), metanephrine, catecholamines, 5-hydroxyindoleacetic acid (5-HIAA), and calcium.
The value of quantitative hormone measurements lies in their correct interpretation in a clinical context. The normal range for most hormones is relatively broad, often varying by a factor of two- to tenfold. The normal ranges for many hormones are gender- and age-specific. Thus, using the correct normative database is an essential part of interpreting hormone tests. The pulsatile nature of hormones and factors that can affect their secretion, such as sleep, meals, and medications, must also be considered. Cortisol values increase fivefold between midnight and dawn; reproductive hormone levels vary dramatically during the female menstrual cycle.
For many endocrine systems, much information can be gained from basal hormone testing, particularly when different components of an endocrine axis are assessed simultaneously. For example, low testosterone and elevated LH levels suggest a primarily gonadal problem, whereas a hypothalamic-pituitary disorder is likely if both LH and testosterone are low. Because TSH is a sensitive indicator of thyroid function, it is generally recommended as a first-line test for thyroid disorders. An elevated TSH level is almost always the result of primary hypothyroidism, whereas a low TSH is most often caused by thyrotoxicosis. These predictions can be confirmed by determining the free thyroxine level. Elevated calcium and PTH levels suggest hyperparathyroidism, whereas PTH is suppressed in hypercalcemia caused by malignancy or granulomatous diseases. A suppressed ACTH in the setting of hypercortisolemia, or increased urine free cortisol, is seen with hyperfunctioning adrenal adenomas.
It is not uncommon, however, for baseline hormone levels associated with pathologic endocrine conditions to overlap with the normal range. In this circumstance, dynamic testing is useful to further separate the two groups. There are a multitude of dynamic endocrine tests, but all are based on principles of feedback regulation, and most responses can be remembered based on the pathways that govern endocrine axes. Suppression tests are used in the setting of suspected endocrine hyperfunction. An example is the dexamethasone suppression test used to evaluate Cushing's syndrome. Stimulation tests are generally used to assess endocrine hypofunction. The ACTH stimulation test, for example, is used to assess the adrenal gland response in patients with suspected adrenal insufficiency. Other stimulation tests use hypothalamic-releasing factors such as TRH, GnRH, CRH, and GHRH to evaluate pituitary hormone reserve. Insulin-induced hypoglycemia evokes pituitary ACTH and GH responses. Stimulation tests based on reduction or inhibition of endogenous hormones are less commonly used. Examples include metyrapone inhibition of cortisol synthesis and clomiphene inhibition of estrogen feedback.
内科学题库内分泌及代谢疾病甲状腺功能亢进症单选题 1、与Graves病发病无关的因素是 A．遗传 B．免疫 C．精神紧张 D．感染 E．中毒 （标答：E） 2、不符合甲亢常见临床症状的是 A．食欲亢进 B．无汗 C．周围血管症 D．早博 E．突眼 （标答：B） 3、甲亢患者最常见的心律失常是 A．心动过缓 B．室性早博 C．房性早博 D．传导阻滞 E．室性心动过速
（标答：C） 4、Graves病的浸润性突眼特征是 A．突眼达30mm B．突眼不超过18mm C．少见胀痛、流泪 D．眼睑无明显肥厚 E．可完全闭合 （标答：A） 5、男性，38岁，有甲亢病史。近来工作劳累，上午出现发热，T：39.5。C，烦躁、心慌、气促、大汗淋漓，恶心呕吐，心率160次/分，血象示WBC15.6*109%，N88%。应首先考虑的诊断是 A．急性左心衰 B．病毒性心肌炎 C．大叶性肺炎 D．甲亢危象 E．急性胃炎 （标答：D） 6、TSH升高常见于 A．T3型甲亢 B．T4型甲亢
C．甲减 D．正常人 E．单纯性甲状腺肿 （标答：C） 7、关于甲状腺摄131I率的叙述，错误的是 A．3小时5%~25% B．24小时10%~45% C．高峰24小时 D．含碘药物不影响结果 E．甲亢患者高峰提前 （标答：D） 8、患者，女，30岁。性情急躁，体形适中。体检：无突眼及甲状腺肿大，心率80次/分。实验室检查：TT3、TT4、FT3、FT4正常，TSH降低。首先应考虑的诊断是 A．Graves病 B．桥本病 C．亚临床甲亢 D．亚临床甲减 E．甲状腺功能正常 （标答：C） 9、诊断甲亢危象的治疗首选药物是 A．复方碘液
第八章内分泌生理 【习题】 一、名词解释 1.激素 2.应激反应 3.垂体门脉系统 4.生长素介质 5.靶细胞 6.促垂体区 7.允许作用8.第二信使9.月经周期 二、填空题 1.激素按其化学本质可分为_____和_____两大类。作为药物应用时_____激素可被消化酶分解，故不易口服；_____激素不被消化酶分解，故可口服。 2.激素的传递方式有_____、_____和_____。大多数激素的传递方式是 _____。 3.甲状旁腺激素是由_____分泌的激素，它主要调节血中_____和_____的浓度。 4.甲状腺激素主要以_____的形式贮存于_____中。 5.幼年时期缺乏甲状腺激素导致_____，而成年人缺乏甲状腺激素将导致_____。 6.甲状腺分泌的激素，以_____为主，而活性以_____为高。 7.血钙增高，甲状旁腺素分泌_____；血磷升高，甲状旁腺素分泌_____。 8.胰岛素由胰岛_____分泌，其主要生理作用是_____、_____和_____。 9.胰岛素缺乏，组织对糖的利用_____，血糖_____。 10.腺垂体分泌四种促激素，它们是_____、_____、_____、_____。
11.盐皮质激素由肾上腺皮质_____分泌，糖皮质激素由肾腺皮质_____分泌，性激素可由肾上腺皮质_____和_____分泌。 12.糖皮质激素分泌受腺垂体分泌的_____控制。肾上腺髓质分泌活动受 _____控制。 13.糖皮质激素使血糖_____，肝外组织蛋白质_____，脂肪_____。 14.下丘脑分泌的各种调节性多肽，通过_____运送到_____，调节_____的分泌。 15.神经垂体释放的激素是_____和_____。 16.肾上腺髓质受交感神经_____支配，并受ACTH和_____的调节。 17.生长素对代谢的作用是促进蛋白质的_____，加速脂肪的_____，_____葡萄糖的利用，使血糖_____。 18.人绒毛膜促性腺激素是由_____分泌的，其主要生理作用是_____。 19.卵巢在卵胞期主要分泌_____，而黄体期还分泌_____。 20.生理剂量的甲状腺激素使蛋白质合成_____，而甲亢时蛋白质_____，呈负氮平衡。 21.卵巢的主要生理功能是产生_____，并分泌_____、_____和少量_____。 22.可以作为激素第二信使的物质是_____和_____等。 23.刺激和维持男性副性征的激素是_____；刺激女性副性征的激素是 _____。 24.LH作用于睾丸_____细胞，引起_____分泌。 25.月经周期中，由于血中_____和_____浓度下降，导致子宫内膜脱落、出血，形成月经。
第八章 内分泌系统 重点内容提示 甲状腺、肾上腺以及垂体的位置和形态 甲状旁腺和松果体的位置 内分泌系统endocrine system由弥散于机体内部的内分泌腺和内分泌组织构成，是神经系统以外机体的一个重要调节系统（图1-8-1）。其主要功能是参与机体新陈代谢和生长发育，对体内器官、系统的功能活动进行调节，这种调节属于体液调节。 内分泌腺endocrine gland又称无管腺。它是存在于机体内的具有一定形态结构的器官，如甲状腺、甲状旁腺、肾上腺和垂体等，它们的特点是腺体无导管，体积小，血液供应丰富；内分泌组织endocrine tissue以细胞团的形式分散存在于机体的其他器官或组织内，如胰腺内的胰岛、睾丸内的间质细胞和卵巢内的卵泡等。内分泌腺和内分泌组织分泌的物质统称为激素hormone，激素能透过毛细血管和毛细淋巴管直接进入血液或淋巴，随血液循环运送到全身各处，作用于特定器官或组织。激素的特点是量微、作用大、具有特异性，即某种激素只针对特定的器官或细胞发挥作用。 人体在内分泌系统与神经系统的双重调节下，达到身体内、外环境之间的相
对平衡稳定和协调统一。一方面，内分泌系统受到神经系统的控制和调节，神经系统直接作用于内分泌腺，通过内分泌腺分泌的激素作用于效应器官或细胞，间接地调节人体各器官的功能，这种调节属于神经体液调节；另一方面，内分泌系统也影响神经系统的生长发育和功能活动，如甲状腺分泌的甲状腺素可影响脑的正常发育和基本功能的发挥。此外，神经系统的某些部分(如下丘脑)本身具有内分泌功能，通过体液调节的方式，影响许多器官的功能活动。 本章仅对内分泌器官（如：甲状腺、甲状旁腺、肾上腺、垂体和松果体）的位置、形态及其功能作简要描述。内分泌组织及其功能将在组织学和生理学中叙述。 第一节甲状腺 甲状腺thyroid gland(图1-8-2) 位于颈前部，舌骨下肌群深面。略呈“H”形，质地柔软，呈棕红色，分为左、右两个侧叶，中间以峡部相连。侧叶贴于喉下部和气管上部的两侧，上端可达甲状软骨中部，下端至第6气管软骨环，峡部一般位于第2～4气管软骨环的前方，从峡部向上伸出一个长短不一的锥状叶（有时缺如），甚至长达舌骨。甲状腺借筋膜形成的韧带固定于喉软骨上，故吞咽时
内分泌和代谢疾病习题A型题 1.皮质醇增多症时，下列哪项不正确 A.抑制脂肪合成 B.抑制蛋白质合成 C.嗜酸性粒细胞绝对值增高 D.血浆肾素增高 E.抑制垂体促性腺激素 2. Graves病时的代谢，下列哪项不正确 A.道糖吸收增加 B.糖原分解增加 C.肌酸排出增加 D.胆固醇增加 E.糖耐量异常 3.下列哪项对诊断妊娠甲亢无帮助 A.血中T3,T4升高 B.血FT3,FT4升高 C.体重不随妊娠月数增加 D.休息时脉率大于100次/分 E.四肢近端肌肉消瘦 4.甲基硫氧嘧啶最主要的副作用是 A.药物过敏
B.药物型甲低 C.脱发 D.粒细胞减少 E.胃肠道反应 5.内分泌性疾病最好的治疗方法是 A.病因治疗 B.对症治疗 C.手术治疗 D.支持疗法 E.纠正功能紊乱 6.哪种药物使用过程中应加服甲状腺素片 A.糖皮质激素 B.磺脲类药物 C.硫脲类药物 D.双胍类药物 E.同化激素 7.放射性131I治疗甲亢的最主要并发症是 A.状腺功能低下 B.眼恶化 C.细胞减少 D.危象 E.癌变
8.作尿糖试验的尿标本采集时间是 A.饭前1h B.饭后1h C.饭后立刻 D.四段尿 E.晨尿 9. Cushing病的病因 A.垂体性ACTH分泌过多 B.异位ACTH分泌过多 C.肾上腺皮质腺瘤 D.肾上腺皮质腺癌 E.不依赖ACTH的肾上腺大结节性增生B型题 A.甲状腺功能亢进 B.地方性甲状腺肿 C.亚急性甲状腺炎 D.甲状腺癌 E.甲低症 10.摄碘率降低、T3、T4增高 11.摄碘率升高，高峰提前 12.摄碘率明显升高，高峰不提前 A.单纯饮食控制
第八章内分泌机能 一、名词解释 激素应激反应应急反应 二、选择题 1、甲状腺主要分泌（） A.三碘甲腺原氨酸， B.四碘甲腺原氨酸， C.二碘酪氨酸， D.一碘酪氨酸。 2、糼儿时，甲状腺素分泌不足，可导致（）。 A.侏儒症， B.粘液性水肿， C.呆小症， D.糖尿病。 3、胰岛的β细胞分泌（）。 A.生长抑素 B.胰高血糖素 C.胰多肽 D.胰岛素 4、蛋白合成和贮存不可缺的激素是（）。 A.胰高血糖素， B.胰岛素， C.胰多肽， D.肾上腺素。 5、胰岛素缺乏将导致（）。 A.血糖浓度下降， B.血浆氨基酸浓度下降， C.血脂上升， D.肝糖原贮备增加。 6、调节胰岛素分泌最重要因素是（）。 A.血脂浓度， B.血中氨基酸的浓度， C.血中生长素的浓度， D.血糖浓度。 7、胰高血糖素的生理作用是（）。 A.促进糖原分解，抑制糖异生， B.促进脂肪分解，使酮体生成增加， C.抑制胰岛素分泌， D.促进胆汁和胃液分泌。 8、机体产生应激反应时血中主要增高的激素是（）。 A.氢化可的松与肾上腺素， B.肾上腺素与去甲肾上腺素， C.促肾上腺皮质激素与皮质醇， D.雄激素。 9、先天性腺垂体功能减退可引起（）。 A.侏儒症， B.呆小症， C.粘液性水肿， D.肢端肥大症。 10、关于生长素的错误叙述是（）。 A.加速蛋白质的合成， B.促进脂肪分解，
C.促进脂肪合成， D.生理水平的量可加速葡萄糖的利用。 三、填空题 1、先天性腺垂体功能减退可引起＿＿＿＿。 2、内分泌细胞所分泌的具有生物活性物质称为＿＿＿＿，其种类很多，依其化学性质可归纳为＿＿＿＿和＿＿＿＿两大类。 3、激素对生理功能的调节作用，表现为只能使正在进行的功能活动＿＿＿＿或＿＿＿＿，而不能产生＿＿＿＿。 4、凡能被激素作用的细胞称为＿＿＿＿，它之所以能够识别特异激素信息，是因为其＿＿＿＿或＿＿＿＿内存在着与该激素发生特异性结合的＿＿＿＿。 5、内分泌系统与神经系统的相互关系表现为：几乎所有的内分泌腺都＿＿＿＿受神经系统的影响，同时，激素也可以影响神经系统的＿＿＿＿。 6、内分泌腺分泌水平的相对稳定，主要是通过＿＿＿＿反馈机制实现的，当环境发生急剧变化时，＿＿＿＿系统也参与激素分泌的调节。 7、运动时，血浆生长素升高的运动强度临界点约＿＿＿＿。 8、甲状腺功能低下的婴糼儿，体内甲状腺激素缺乏，故＿＿＿＿生长发育受到障碍，表现为＿＿＿＿症。 9、胰岛素是由胰岛中的＿＿＿＿细胞所分泌,胰高血糖素是由胰岛中的＿＿＿＿细胞所分泌。 10、胰高血糖素可激活心肌细胞中的＿＿＿＿，使糖原分解＿＿＿＿。 11、胰高血糖素最主要的功能是促进＿＿＿＿分解和＿＿＿＿，使血糖浓度＿＿＿＿。 四、判断题 1、内分泌系统是由内分泌腺和具有内分泌作用的细胞共同组成的体内信息传递系统。（） 2、人体内所有细胞的膜上都有受体，它们均可对同一激素产生反应。（） 3、生长素的靶细胞是全身的骨骼肌和骨组织。（） 4、激素可加速或减慢体内原有的代谢过程，不能发动一个新代谢过程。（） 5、呆小症是由于糼儿时期垂体功能低下，生长素分泌不足造成。（） 6、甲状腺功能亢进时，人体基础代谢率升高。（）
内分泌及代谢病学 内分泌及代谢病学 第一章总论[目的要求] 1．掌握内分泌疾病诊断共同规律，原则，方法及治疗原则。 2．熟悉内分泌系统疾病的范围和分类。 3．了解内分泌激素及其生理功能神经-内分泌-物质调节般了解临床内分泌学研究泛畴，国内外内分泌学发展的概况。 [教学内容] 1．概述内分泌系统的概念，神经-内分泌-物质调节，了解 丘脑-垂体-肾上腺轴的反馈调节。 2．一般了解内分泌系统分类原则，垂体，甲状腺，甲状旁腺，肾上腺体病及代谢病的糖尿病，低血糖病。 3．掌握内分泌疾病的诊断原则。 4．掌握内分泌疾病的治疗原则。 [教学方法] 多媒体教学[授课学时] 1 学时第八章甲状腺功能亢进症[目的要求] 1．掌握其他甲状腺病的主要临床表现，诊断原则及其与 Grave '病的鉴别。
2.熟悉Grave '病的发病机理；结合激素生理功能熟悉本病的临床表现，特殊临床表现。熟悉诊断方法及本病的治疗方法，同位素，手术治疗的适应症几甲亢危象的处理原则。 3．了解本病的病因分类。 [教学内容] 1．甲状腺机能亢进症的概念与分类2．Grave's 病病因的现代观点及病理特点。 3．临床表现重点讲述甲状腺激素增多时的临床特点及自体免疫的临床表现：突眼及甲状腺肿大。 4．特殊临床表现重点讲浸润性突眼，甲亢危象，甲亢心脏病， T3，T4 型甲亢。 5．诊断与鉴别诊断⑴ 根据临床表现。 ⑵ 重点讲述激素的实验室检测的临床意义及其功能检查，影像，同位素检查的意义。 ⑶鉴别诊断与其他甲状腺肿大疾病鉴别；与其任一临床 表现和体征鉴别。 5．治疗 各种治疗方法的适应症与不适应症。 阐述口服药物作用机理及副作用。 特殊临床表现的诊治原则首先介绍特殊临床表现的临床表现，提出诊断依据及治疗原
功能解剖生理学 第七章内分泌系统 一、填空题 1、内分泌系由____________和____________组成。 2、人体内分泌器官有____________、____________、____________、 ____________等。 3、甲状腺大部分位于___________的两侧，甲状腺峡位于第__________的前方。 4、肾上腺位于__________，左肾上腺呈_______形，右肾上腺为_______形。 5、垂体可分为____________和___________两部分。 6、神经垂体储存和释放的激素有____________和____________等。 7、幼年时期促生长素分泌过多，可引起____________症；分泌不足则引起_______________症。 8、肾上腺皮质由表向里依次分为____________、____________、____________三个带。 9、甲状腺分泌的激素包括_______________、____________，其中能影响到智力和生长发育的是____________。 10、肾上腺皮质中的球状带细胞分泌____________激素，束状带细胞分泌____________激素，网状带分泌____________激素。 11、肾上腺髓质主要由____________细胞构成，能分泌____________和____________激素。 二、判断 1.内分泌系统的结构特点是没有导管，富含血管。（） 2.含氮激素如胰岛素，可以口服应用。（） 3.甲状腺滤泡旁细胞可分泌甲状腺素。（） 4.胸腺是淋巴器官，兼有内分泌功能（） 5.内分泌细胞的分泌物称激素（） 6.神经垂体有分泌加压素和催产素的功能（） 7.甲状腺只分泌甲状腺素（） 8.肾上腺皮质分为三个带，由表及里依次是网状带、束状带和球状带。（） 9.肾上腺皮质分泌肾上腺素和去甲肾上腺素（） 10.内分泌腺分泌的激素通过导管输送到血液或淋巴管中去（） 11.肾上腺分泌肾上腺素和去甲肾上腺素。（） 三、选择 （一）单项选择题 1．关于内分泌系统的叙述，错误的是( ) A、由内分泌器官和内分泌组织组成 B、内分泌器官指结构上独立存在的内分泌腺 C、内分泌器官肉眼可见 D、与神经系统在功能和结构上无关系 2．不属于内分泌腺的是( ) A、甲状腺 B、肾上腺 C、垂体 D、腮腺 3．关于垂体的说法哪项是错误的( ) A、分腺垂体和神经垂体两部分 B、垂体是成对器官
第9单元内分泌 重点提示 本单元2000～2009年约考过22题，下丘脑的内分泌功能5道，腺垂体的内分泌功能5道，甲状腺激素1道，与钙、磷代谢调节有关的激素5道，肾上腺糖皮质激素4道，胰岛素2道。此部分每年都有2～3道。 此部分内容多属记忆性知识点，考生们在复习的时候要多注意各类激素的生理功能以及调节因素，再结合临床专业的知识点联合复习，会对巩固临床疾病有很大帮助。考试用书考点串讲 一、下丘脑的内分泌功能 (一)下丘脑与垂体之间的功能联系 1.下丘脑-垂体束联系下丘脑和神经垂体(2002、2005)。 2.垂体门脉系统这是下丘脑与腺垂体功能联系的基础，包括两重毛细血管网，第一级在正中隆起——垂体柄处，第二级在垂体前叶，下丘脑肽类激素通过门脉系统调节腺垂体促激素的释放，而垂体促激素通过门脉系统发挥反馈性调制作用。 (二)下丘脑调节肽 下丘脑促垂体区的肽能神经元能合成并分泌。一些调节腺垂体活动的肽类激素，称为下丘脑调节肽。下丘脑调节肽包括九种，分别是促甲状腺激素释放激素(TRH)、促性腺激素释放激素(GnRH)、生长激素释放抑制激素即生长抑素(GHRIH)、生长激素释放激素(GHRH)、促肾上腺廛质激素释放激素(CRH)、促黑素纽胞邀素释放因子(MRF)、促黑素细胞激素释放抑制因予(MIF)、催乳素释放因子(PRF)、催乳素释放抑制因子(PIF)等(2003)。 二、腺垂体的内分泌功能 (一)腺垂体激素的种类 在腺垂体分泌的激素中，促甲状腺激素、促肾上腺皮质激素、促卵泡激素与黄体生成素均有各自的靶腺，分别形成：①下丘脑一垂体一甲状腺轴;②下丘脑一垂体一肾上腺皮质轴; ③下丘脑一垂体一性腺轴。腺垂体的这些激素没有靶腺，是通过促进靶腺分泌激素而发挥作用，所以也把这些激素统称为“促激素”。生长素、催乳素与促黑(素细胞)激素没有靶腺，分别调节机体生长、乳腺发育与泌乳以及黑色素代谢等活动。 (二)生长素的生物学作用及其分泌调节 1.作用①促生长作用：幼年时缺乏患侏儒症、过多患巨人症，成年时生长素过多患肢端肥大症。②对代谢的作用：加速蛋白质的合成，促进脂肪分解。生理水平生长素加强葡萄糖的利用，过量生长素则抑制葡萄糖的利用。 2.分泌的调节受下丘脑GHRH与生长抑素的双重调节，而代谢因素、睡眠则间接影响其分泌。例如慢波睡眠、低血糖、血氨基酸增多、脂肪酸增多均可引起生长素分泌增加。 三、甲状腺激素 (一)生物学作用 1.对生长发育的作用影响基置塑中枢神经的发育(2000、2001)，婴幼儿缺乏甲状腺激素患呆小病(2007)。 2.对机体代谢的影响 (1)提高基础代谢率，增加产热量。 (2)对三大营养物质的代谢既有合成作用又有分解作用，剂量大时主要表现出分解作用。甲状腺功能低下时蛋白质合成水平低下会出现黏液性水肿。 (3)提高中枢神经系统及交感神经兴奋性，故甲状腺功能亢进患者表现为易激动、烦躁不安、多言等症状。 3.对心血管系统的作用使心率增快，心缩力增强。
第一章内分泌疾病总论 1.内分泌疾病的常见临床表现 性激素改变闭经、月经过少、性欲和性功能改变、毛发改变 生长发育儿童巨人症、成人肢端肥大症、侏儒症、呆小症、黏液性水肿 多毛毛发的分布主要与雄激素的作用有关 多饮与多尿见于尿崩症、糖尿病、原发性甲旁亢、发性醛固酮增多证 糖尿糖尿病、肢端肥大症、库欣综合征、甲亢、嗜铬细胞瘤 低血糖胰岛素瘤、胰岛B细胞增生、重症肝病 消化道症状食欲减退、呕吐、腹痛、便秘、腹泻 2.内分泌疾病的功能状态 激素分泌状态测定各腺体分泌的激素，了解垂体-靶腺轴的功能，如测定血中TSH、T3、T4.FSH、LH浓度等； 激素的动态功能测定疑诊激素分泌缺乏时行兴奋试验； 疑诊激素分泌过多时行抑制试验； 放射性核素功能检查如摄I131率的测定 激素调节的物质测定如血糖、电解质等的测定； 3.内分泌疾病的诊断原则
病因诊断自身抗体检测、染色体检查、HLA鉴定； 功能诊断临床表现对诊断内分泌疾病具有重要参考价值实验室检查-代谢紊乱的证据-电解质、脂质、血糖等； 激素浓度的测定； 动态功能测定-兴奋试验、抑制试验； 定位诊断影像学检查-X线片、分层摄影、CT、MRI、B 超； 放射性核素检查-甲状腺131I扫描； 细胞学检查-甲状腺细胞学穿刺； 静脉导管检查-岩下窦静脉取血测定垂体激素，诊断库欣病； 4.内分泌疾病的治疗原则 内分泌功能亢进的治疗 手术治疗-切除功能亢进的肿瘤或增生的组织； 放射治疗-毁损肿瘤或增生组织，减少激素分泌； 药物治疗-抑制肿瘤的合成和释放 奥曲肽可抑制GH、PRL、胰岛素等的分泌； 溴隐亭可抑制PRL、GH的分泌，并可缩小肿瘤； 赛庚啶和酮康唑治疗库欣综合征； 内分泌功能减退的治疗 替代治疗-补充激素（甲状腺激素、皮质醇）激素产生的效应物质（甲旁减补充钙、VitD )
内分泌系统疾病. (1) 库欣综合征（皮质醇增多症） (2) 糖尿病 (5) 甲状腺功能亢进症 (10) 内分泌系统疾病 内分泌基本概念：激素-内分泌细胞释放的高效能有机化学物质经体液传送后，对其他细胞或器官的功能起兴奋或抑制作用。 分泌方式： 内分泌- 内分泌腺体分泌激素，经血液循环到达靶组织发挥调节功能；旁分泌- 因子释放后不进入血液，通过组织间液在局部发挥作用；自分泌- 激素可作用于分泌它的细胞自身； 胞内分泌- 胞浆合成的激素直接转运到胞核影响靶基因的表达。神经内分泌- 激素由神经细胞分泌，通过轴突运送到储存部位或靶组织； 激素的分类： 含氮类-E、NE 5-HT、T3/T4、PTH 胰岛素；类固醇类- 糖皮质激素、性激素、VD；脂肪酸衍生物- 前列腺素 经典内分泌腺及其激素： 下丘脑-GHRH SS生长抑素、TRH CRH GnRH PRF催乳素释放因子RIF 催乳素释放抑制因子； 垂体前叶-GH TSH ACTH MSH LH黄体生成素、FSH卵泡刺激素、PRL催乳素；垂体后叶-ADH 0T缩宫素 甲状腺-T3/T4 ； 甲状旁腺-PTH；肾上腺皮质-糖皮质激素醛固酮性激素；肾上腺髓质-NE E；性腺-睾酮雌孕激素；胰腺-胰岛素胰高血糖素； 内分泌疾病分类： 激素分泌过多-功能亢进；原发由于靶腺异常，继发由于下丘脑垂体异常；激素分泌不足-功能减退衰竭； 生成异常激素； 激素不反应综合征； 内分泌疾病诊断思路： 功能诊断-正常、亢进、减退、衰竭； 部位诊断； 病因和病理诊断；
各种病因导致肾上腺分泌过多糖皮质激素所致的疾病的总称，最多见的是 ACTH分泌过多导致的库欣病（垂体瘤）； 分类： 依赖ACTH勺Cushing综合征： Cushing病-多为微腺瘤（＜1cn）、少数为垂体瘤（Nelson综合征，切除肾上腺后垂体瘤增大、皮肤变黑）；68% 异位ACTH分泌综合征（垂体外肿瘤，最多见于肺癌）；12% 不依赖ACTH的Cushing综合征： 肾上腺皮质腺瘤、腺癌（单侧）10%8% 双侧肾上腺大结节增生AIMAH （Bilateral Macro no dular Adre nal Hyperplasia ）1% 双侧肾上腺小结节增生PPNAD（PrimaryPigmented Nodular Adrenocortical Disease）（双侧）1% 肾上腺皮质激素的生理： 糖皮质激素的分泌： 球状带-醛固酮；束状带-皮质醇；网状带-性激素；属于甾体类激素；以胆固醇为原料合成，基本结构是环戊烷多氢菲： 分泌为脉冲式，早晨达到高峰，下午和夜晚为低水平，入睡1-2h后最低；糖皮质激素的生理作用： 调节代谢-升高血糖、促进蛋白质分解（氨基酸进入肝细胞进行糖异生）、四肢脂肪分解增加、躯干脂肪合成增加；可以增加肾小球滤过率，利于水的排出，有弱的盐皮质激素的作用，保钠排钾； 循环系统-提高血管平滑肌对儿茶酚胺的敏感性，维持血压、提高CO 消化系统-使胃酸和胃蛋白酶分泌增多； 骨骼系统-产生骨质疏松； CNS影响情绪、行为、神经活动，兴奋性增高； 免疫和炎症-抑制； 参与应激反应； 病理生理和临床表现： 代谢异常-导致糖耐量降低，部分患者出现类固醇性糖尿病，多饮多尿；向心性肥胖；机体负氮平衡状态，皮肤紫纹；皮质醇有少量盐皮质激素作用，保钠排钾导致低钾性碱中毒；水肿。 心血管疾病-高血压常见，由于脂代谢紊乱血液高凝，易发生血栓； 免疫系统-容易感染，皮肤真菌感染多见、化脓性感染不易局限；炎症反应不明显，发热不高； 造血系统-刺激骨髓造血导致红细胞增加、多血质面容；白细胞总数和中性 粒细胞增加，嗜酸性粒细胞和淋巴细胞减少；瘀斑 皮肤-色素沉着-异位ACTH综合征患者，肿瘤产生促黑素细胞活性的肽类，皮肤色素明显加
一、总论 选择题 1.下列哪一种激素是由腺垂体合成： A.ADH B.CRF C.LRH D.GH E.SS 2.有关内分泌腺本身疾病基本病理变化的下述论点，哪项是错误的： A.机能（病理生理）异常 B.形态（病理解剖）异常 C.机能分为亢进、减退和正常 D.病变部位分原发性和继发性 E.功能正常者病理解剖无异常 3.下列哪一种激素为氨基酸类激素: A.甲状旁腺素 B.甲状腺素 C.糖皮质激素 D.雄激素 4.下述哪一项不属于内分泌系统疾病的功能检查手段： A.物质代谢的平衡试验 B.血中激素水平的检测 C.甲状腺的同位素扫描 D.免疫荧光细胞学鉴定 E.尿中激素代谢产物测定 5.下面哪一种疾病不是自身免疫性内分泌疾病： A.Graves病 B.addison病 C.Hashimoto甲状腺炎 D.假性甲状旁腺功能减退 E.l型糖尿病 6.内分泌机能减退性疾病的替代治疗,目前最普遍使用的方法是： A.补充生理需要量的靶腺激素 B.补充药理剂量的靶腺激素 C.补充生理需要量的垂体激素 D.补充药理剂量的垂体激素 E.补充调节神经递质的药物 7.成人皮质醇增多症的最常见的原因是： A.肾上腺皮质腺瘤 B.肾上腺皮质增生 C.肾上腺皮质癌 D.异位促肾上腺皮质激素综合症 E.医源性 8.长期服用乙胺碘呋酮最可能引起： A.碘源性甲亢 B.垂体性甲亢 C.腺瘤样甲状腺肿伴甲亢 D.异源性TSH综合征 E.神经垂体瘤 9.根据不同病因分类,最常见的甲状腺机能亢进症是： A.垂体性甲亢 B.自主性高功能性甲状腺腺瘤 C.弥漫性甲状腺肿伴甲状腺功能亢进症 D.碘甲亢 E.多结节性甲状腺肿伴甲亢 二、肾上腺疾病 选择题 1.成人皮质醇增多症的最常见的原因是： A.肾上腺皮质腺瘤 B.肾上腺皮质增生 C.肾上腺皮质癌 D.异位促肾上腺皮质激素综合症 E.医源性
第39章内分泌系统疾病总论、甲亢与甲减 一、A 型题：在每小题给出的A 、B 、C 、D 四个选项中，只有一项是最符合题目要求的。 1277. 完整的内分泌疾病的诊断一般不包括 A. 定位诊断 B. 病因诊断 C. 病理诊断 D. 功能诊断 1278. 对于内分泌疾病的诊断，首先易于确定的是 A. 病理诊断 B. 病因诊断 C. 定位诊断 D. 功能诊断 1279. Graves 病的自身抗体TSAb 是针对哪个自身抗原的抗体？ A. 促甲状腺激素 B. 促甲状腺激素受体 C. 甲状腺球蛋白 D. T3 f 1280. 目前认为Graves 病的发生与自身免疫有关，导致Graves 病的致病性抗体是 A. TSAb B. TRAb C. TSBAb D. TSH 坛1281 . 关于G~aves 病的病理生理，下列哪项不正确？ A. 甲状腺滤泡上皮细胞增生 B. 滤泡腔内胶质减少 C. 滤泡间有T 细胞等浸润 D. Graves 眼病是由于大量黏蛋白沉积所致 1282. 女，45 岁。间断发作心悸、大汗、手抖6 个月余。发作时伴饥饿感，无黑朦、眩晕等。查体：血压140/90mmHg, 险结膜无苍白。心率68 次／分，律齐。发作时测血压与平素无明显变化。心悸反复发作最可能的病因是 A. 贫血 B. 甲状腺功能亢进症 C. 低血糖症 D. 急性心肌炎 1283. 毒性甲状腺肿患者，男性，25 岁，长跑后突然双下肢不能活动，膝反射减退，但无肌萎缩，最可能是 A. 甲亢性肌病 B. 甲状腺毒症性周期性瘫痪 C. 甲亢合并重症肌无力 D. 甲亢并颅内出血 1284. 甲亢患者外周血的改变不包括 A. 淋巴细胞比例增加 B. 单核细胞增加 C. 白细胞计数增加 D. 血小板计数减少 1285. 下列哪项眼征不是由交感神经兴奋性增高引起的？ A. Joffroy 征 B. Mobius 征 C. Stellw吨征 D. 浸润性突眼 1286. 甲状腺危象的诱发因素不包括 A. 感染 B. 抗甲状腺药物量过少 C. 手术创伤 D. 精神剌激 1287. 关千淡漠型甲亢的叙述，不正确的是 A. 多见于老年患者 B. 消瘦、乏力、心悸常见 C. 甲状腺明显肿大 D. 易被误诊 1288 . 关于飞型甲亢的叙述，错误的是 A. 在老年人群和缺瑛地区常见 B. 血清TT4、FT4水平正常 C. 血清TT3、TSH水平增高 D. TSH 增高 1289. 患者血清T3, 兀正常，TSH 降低的疾病是 A. 甲亢性心脏病 B. 亚临床甲亢 C. 淡漠型甲亢 D. 妊娠甲亢 1290. 关千胫前黏液性水肿的叙述，错误的是 A. 多见于胫前中1/3 B. 可与Graves 病伴发
内科学——内分泌学（二） 单选题（234题，100分） 1、男性，65岁，食欲亢进、体重增加1年。体检：身高170cm，体重85kg，腹部、臀部脂肪肥厚，下腹部及大腿上部可见淡红色紫纹。血压150/100mmHg。初步诊断为Cuslung综合征。患者口服地塞米松0.5mg/6h，连续2天。服药后24h尿17羟、17酮较服药前下降67.0%。此时可能的诊断为0.43分 A.多囊卵综合征 B.单纯性肥胖 C.原发性醛固酮增多症 D.皮质醇增多症 E.原发性高血压 正确答案：B 答案解析：患者血皮质醇有节律性，应考虑单纯性肥胖，为进一步排除Cushing综合征，可进行小剂量地塞米松试验以助两者鉴别。 2、双胍类药物与胰岛素合用可0.43分 A.减轻药物不良反应 B.增强降血糖作用 C.减少胰岛素用量 D.诱发乳酸性酸中毒 E.增加胰岛素用量 正确答案：C 答案解析：双胍类药物与胰岛素合用可减少胰岛素用量。 3、糖尿病病情控制最有价值的指标是0.43分 A.0GTT B.糖化血红蛋白 C.24h尿糖测定 D.空腹血糖 E.餐后2h血糖 正确答案：B 答案解析：糖化血红蛋白是反应近期血糖控制的水平。 4、女性，18岁。心悸、多汗，多食、消瘦4月余。体检：甲状腺Ⅱ度肿大，右上极可闻及血管杂音。患者被诊断为Graves病，宜首选哪种治疗0.43分 A.甲状腺次全切除术 B.放射性核素治疗 C.抗甲状腺药物治疗 D.普萘洛尔治疗 E.复方碘溶液治疗 正确答案：C 答案解析：该患者临床考虑甲亢可能性最大，故在患者初诊时应首先行甲状腺功能检查明确诊断。TSAb测定主要有助于Graves病的诊断，并对判断病情的活动、是否复发、是否停药有重要意义；T3抑制试验主要用于鉴别甲状腺肿伴碘摄取率增高的原因为单纯性甲状腺肿或甲亢，及药物治疗后预测停药后复发可能性参考；TRH兴奋试验可辅助甲亢病因诊断，但由于TSAb等检测方法推广，目前已少用；碘摄取率测定诊断甲亢符合率较高，但单纯性甲
内分泌及代谢疾病 2、甲状腺 3、甲状旁腺 4、胰腺内分泌部 5、肾上腺 6、 性腺7、胸腺8 内分泌细胞：分布于脑(内啡肽、胃泌素)，胃肠(30多种胃肠肽，如胃泌素、缩胆囊素、促胰液素、抑胃肽、胃动素)，胰(生长抑素、胰多肽)，肾 (肾素、前列腺素)，肝(血管紧张素原)，血管内皮细胞(内皮素、NO)， 心房肌细胞(心房钠尿肽)，脂肪细胞(瘦素Leptin) 低钾血症 病因： 1. 摄入不足：长期饥饿、昏迷、吸收障碍、神经性厌食 2. 排出过多： ①非肾性失钾：过多出汗、腹泻、呕吐 ②肾性失钾：醛固酮增多症、库欣综合征、利尿药、肾盂肾炎、急性肾功能衰 竭多尿期、肾小管性酸中毒、镁缺失 3.钾向细胞内转移：代谢性碱中毒、过量胰岛素使用、大量细胞生成、周期性瘫 痪 临床表现： 1. 心血管：洋地黄毒性耐受下降、心律失常、加重心衰，甚至心脏骤停 2. 肌肉：肌无力、疼痛、痉挛，麻痹性肠梗阻、尿潴留 3. 肾脏：引起加重代谢性碱中毒 40~80mmol不等 2. 对因治疗：纠正碱中毒、改用保钾利尿剂 3. 注意：①禁用洋地黄类药物；②见尿补钾；③氯离子可以提高肾的保钾能力 高钾血症 病因： 1. 摄入过多：高钾食物、含钾药物、输入库存血 2. 排除减少： ①肾小球滤过下降：急性肾衰竭 ②肾小管分泌减少：醛固酮减少症 3. 钾向细胞外转移：酸中毒、大量细胞坏死（挤压、烧伤）、应用高渗药物 临床表现： 1. 心血管：心律失常，甚至心脏骤停 2. 神经-肌肉：兴奋性先升后降，感觉异常、嗜睡、乏力 3. 内分泌：引起加重代谢性酸中毒，胰岛素分泌增加 2. 促使钾离子转入细胞内：
①输注碳酸氢钠溶液 ②输注葡萄糖溶液及胰岛素，再加入葡萄糖酸钙可对抗心肌毒性 3. 促进钾离子排泄: ①排钾利尿剂 ②阳离子交换树脂 ③血液透析 高渗性脱水 病因： 1. 摄入不足：吞咽因难，重危病人的给水不足，断绝水源 2. 丧失过多：高热大量出汗、甲亢、大面积烧伤、尿崩、呕吐、腹泻 临床表现： 轻度缺水：口渴 中度缺水：极度口渴。乏力、尿少和尿比重增高。唇舌干燥，皮肤失去弹性，眼窝下陷。烦躁不安 重度缺水：除上述症状外，出现躁狂、幻觉，甚至昏迷 治疗： 1. 去除病因 2. 补水：每丧失1%体重补液400~500ml，分两天补完，加上当天需要量(2000ml) 3. 适当补钠、补钾(因醛固酮增多) 低渗性脱水 病因： 1. 胃肠道消化液持续性丢失：反复呕吐、胃肠减压 2. 大创面慢性渗液 3. 肾性：应用排钠利尿剂、醛固酮分泌不足、肾小管酸中毒 临床表现： 1. 不口渴 2. 多尿、低比重尿，晚期少尿 3. 皮肤失去弹性，眼窝下陷 4. 神志淡漠、肌痉挛性疼痛、腱反射减弱、昏迷 治疗： 1. 去除病因 2. 需补充的钠量(mmol)=[血钠的正常值(142mmol/L)-血钠测得值(mmol/L)]×体重(kg)×男O.6//女0.5 分两天补足 还要加上当天需要量4.5g氯化钠 等渗性脱水 病因： 1. 消化液的急性丧失：肠外瘘、大量呕吐 2. 体液丧失在感染区或软组织内：腹膜后感染、肠梗阻、烧伤、抽腹水
【内科学总结】内分泌系统 腺垂体功能减退症hypopituitarism： 常见病因垂体瘤、产后腺垂体坏死萎缩。 临床症状 激素分泌不足 泌乳素（产后无乳），促性腺激素（毛发脱落、性腺萎缩、第二性征发育不全、长期闭经不育），促甲状腺激素（继发甲状腺功能减退），促肾上腺皮质激素（乏力、体弱、低血糖症、肤色变浅），生长激素。肿瘤压迫症状（头痛、偏瘫、失明）。 治疗 高热量高蛋白饮食、激素替代疗法（糖皮质激素首选氢化可的松hydrocortisone、甲状腺激素、性激素）、垂体瘤手术切除。 垂体危象： 各种应激诱发，表现为高热、低温、低血糖、循环衰竭、水中毒、精神失常、昏迷。 治疗 ①快速静脉注射葡萄糖 ②液体中加入氢化可的松 ③控制循环衰竭和感染 ④低温者用热水浴疗法 ⑤高温者用物理降温法 ⑥水中毒者口服糖皮质激素 禁用麻醉、镇静、降血糖药物。
库欣综合征/皮质醇增多症Cushing Syndrome 病因分类 1.依赖ACTH：Cushing病（垂体微腺瘤）；异位肿瘤 2.不依赖ACTH：肾上腺皮质腺瘤；肾上腺皮质瘤；小结节增生；大结节增生 临床 满月脸、多血质外貌、向心性肥胖、皮肤紫纹、痤疮、高血压、骨质疏松。 病因 多见ACTH依赖性（垂体微腺瘤、异位肿瘤）。临床表现满月脸和向心性肥胖（脂肪动员分解增加、脂肪重新分布），近侧肌软弱无力而远侧肌尚可（蛋白负平衡、肌肉消耗多），骨质疏松（骨量丢失），雪茄烟样外貌（皮肤变薄、皮下毛细血管显露），紫纹（皮下脂肪增多使弹性纤维断裂、看见薄皮下血管，色深、宽>1cm），类固醇性糖尿病，低钾碱中毒，RBC和Hb增多。小剂量地塞米松Dex抑制试验阴性。经蝶窦显微切除垂体微腺瘤可治愈。 主要掌握其临床表现。 肾上腺皮质功能减退症Addison’s disease 临床 肾上腺病变（特发性、结核性），皮质激素分泌不足，反馈性血浆ACTH增高。慢性原发典型表现皮肤粘膜色素沉着（棕褐色，脸、手、指甲暴露摩擦部位），继发者反而肤色苍白。 诊断
第七节 胰岛素及胰岛素类似物（重要考点） 胰岛中有不同的细胞，各自分泌不同的激素。其中α细胞分泌胰高血糖素，可促使 血糖升高；β细胞分泌胰岛素，促使血糖水平降低；δ细胞分泌生长抑素，可抑制生长 激素、胰高血糖素及胰岛素的分泌。三种激素共同调节和维持血糖的水平。 一、药理作用与临床评价 （一）作用特点 胰岛素可增加葡萄糖的利用，能加速葡萄糖的无氧酵解和有氧氧化，促进肝糖原和 肌糖原的合成和贮存，抑制糖原分解和糖异生，因而能使血糖降低。此外，还能促进脂 肪的合成，抑制脂肪分解，使酮体生成减少，纠正酮症酸血症的各种症状。能促进蛋白 质的合成，抑制蛋白质分解。 根据胰岛素作用时间分类 （1）超短效胰岛素：门冬胰岛素、赖脯胰岛素。（2）短效胰岛素：速效胰岛素目 前主要有动物来源和重组人胰岛素来源两种。 （3）中效胰岛素：最常见是低精蛋白锌 胰岛素。（4）长效胰岛素：最常见的就是精蛋白锌胰岛素。(5）超长效胰岛素：甘精 胰岛素和地特胰岛素。（6）预混胰岛素：即“双时相胰岛素”，是指含有两种胰岛素 的混合物，可同时具有短效和长效胰岛素的作用。 （二）典型不良反应 常见低血糖反应，一般于注射后发生。 （三）禁忌证 1.对胰岛素过敏者和低血糖者禁用。 2.低血糖、肝硬化、溶血性黄疸、胰腺炎、肾炎等患者禁用精蛋白锌胰岛素、门冬 胰岛素等。 3.精蛋白锌胰岛素和低精蛋白锌胰岛素含有鱼精蛋白，对鱼精蛋白过敏者禁用。 （四）药物相互作用 1.口服抗凝血药、水杨酸盐、磺胺类药、甲氨蝶呤可与胰岛素竞争血浆蛋白，使血 中游离胰岛素升高，增强胰岛素的作用。 2.口服降血糖药与胰岛素有协同作用。 3.蛋白同化激素能减低葡萄糖耐量，增强胰岛素的作用。 4.肾上腺皮质激素、甲状腺素、生长激素能升高血糖，合用时能对抗胰岛素的降血 糖作用。 5.β 受体阻断剂可阻断肾上腺素的升高血糖反应，干扰机体调节血糖功能，与胰 岛素合用时，要注意调整剂量，否则易引起低血糖。 二、用药监护（考点） （一）治疗中需监测低血糖 对非糖尿病患者，低血糖症的诊断标准为血糖<2.8mmol/L;而接受药物治疗的糖尿 病患者只要血糖水平≤3.9mmol/L 就属低血糖范畴。 （二）注意胰岛素的正确应用 1.使用纯度不高的动物胰岛素易出现注射部位皮下脂肪萎缩或肥厚，可能是由于胰 岛素中的大分子物质产生的免疫刺激引起的一种过敏反应。 2.胰岛素过量会致饥饿感、精神不安，必须及时给予静脉葡萄糖或口服糖类等抢救。 3.混悬型胰岛素注射液（低精蛋白锌胰岛素等）禁用于静脉注射。 （三）注意胰岛素类似物的过敏反应 三、主要药品（考点） 胰岛素]【医保（甲）]基][典[ 【适应证】
第八章内分泌系统 一、大纲要求 1. 理解甲状腺的位置和形态。 2. 掌握甲状腺的微细结构。 3. 理解甲状旁腺的位置和形态。 4. 理解甲状旁腺的微细结构。 5. 理解肾上腺的位置和形态。 6. 掌握肾上腺的微细结构。 7. 理解垂体的位置、形态和分部。 8. 掌握垂体的微细结构。 二、内容概要 形态：扁椭圆形小体 垂体位置：蝶骨体上面的垂体窝内 分部：前部：腺垂体；后部：神经垂体 形态：“H”形，分左、右侧叶和中央的峡部 甲状腺位置：位于喉和气管上部的前方及两侧 结构：有甲状腺滤泡和滤泡旁细胞 内分泌器官形态：棕黄色扁圆形小体，上、下各一对 甲状旁腺位置：甲状腺侧叶的后面 结构：有主细胞和嗜酸性细胞两种 形态：左侧为半月形，右侧为三角形 内分泌系统肾上腺位置：肾的上端 结构：皮质：有球状带、束状带、网状带 胰岛 黄体和卵泡 内分泌组织睾丸间质细胞 其它内分泌细胞团 三、测试题
（一）名词解释 1．内分泌腺 2. 内分泌组织 3. 分泌神经元4．嗜铬细胞 （二）填空题 1. 内分泌系统由________________和________________两部分组成。 2. 人体内的内分泌器官主要有________、________、________、________、________和_________等。 3. 甲状腺侧叶紧贴于__________和___________的两侧，峡部位于第______气管软骨环的前方。 4. 甲状腺可通过_________固定于___________，因此，甲状腺可随吞咽而上、下移动。 5．甲状旁腺常位于_________的后方。 6. 右侧肾上腺呈__________形，左侧肾上腺呈_________形。 7．肾上腺皮质由外向内依次分为__________、___________和___________三个带，各可产生___________、____________、___________和少量__________等激素。 8. 肾上腺髓质中的细胞为_________细胞，可分泌___________和___________两种激素。 9．垂体由前部的_________和后部的_________两部分组成。 10. 腺垂体中的腺细胞有三种，其中____________细胞可分泌____________和_____________两种激素，_____________细胞可分泌___________、___________和___________三种激素，__________细胞无分泌功能。 11．神经垂体主要由__________和__________构成，可储存和释放___________和____________两种激素。 （三）是非判断题 1．吞咽时，甲状腺不会上、下移动。( ) 2．甲状腺滤泡上皮细胞可分泌降钙素。( ) 3．肾上腺皮质的最深层叫网状带。( ) 4．盐皮质激素由肾上腺皮质球状带分泌。( ) 5．腺垂体嗜酸性细胞分泌促生长素和催乳激素。( ) 6．促甲状腺激素由甲状腺分泌。( ) 7．促肾上腺皮质激素由肾上腺皮质分泌。( )
第八章药物对内分泌系统的毒性作用 学习要求 掌握：药物对内分泌系统毒性作用的类型、常见药物。 熟悉：药物内分泌系统毒性作用的机制。 了解：内分泌系统药物毒性作用的检测方法。 内分泌系统分泌微量激素，通过血液循环到达靶细胞，与相应的受体相结合，发挥其特定的全身性作用。作为一个信息传递系统，内分泌系统与神经系统相互配合，共同调节机体各种功能活动，以维持内环境的相对稳定。许多药物能干扰内分泌腺体合成和释放激素，对其功能甚至结构产生影响，从而引起各种药源性内分泌系统疾病。内分泌器官的化学损伤最常发生在肾上腺，其次为甲状腺、胰腺、垂体和甲状旁腺。 第一节内分泌系统的生理学特点 一、内分泌系统的组成 内分泌系统由内分泌腺及内分泌细胞组成。内分泌腺主要包括垂体、甲状腺、甲状旁腺、肾上腺、胰岛、性腺及松果体和胸腺。内分泌细胞分布于特定组织器官中，如心、肺、肾(肾素等)、肝(血管紧张素原等)、脑(内啡肽等)等。 二、分泌方式 激素需要借助于体液在体内传递化学信息。激素从分泌部位经血液运输至距离较远的靶组织，称为远距分泌，是经典的内分泌方式；经组织液直接扩散并作用于邻近的细胞，称为旁分泌方式，如胃肠激素；激素还可作用于分泌自身的细胞，如前列腺素，称为自分泌方式。 三、激素分泌的调节 激素一般以相对恒定速度(如甲状腺素)或一定节律(如皮质醇，性激素)释放，但激素分泌总量会随机体的需要而发生相应的变化以维持机体内环境的稳定。下丘脑与垂体组成了一个完整的神经内分泌功能系统。此系统可分为两部分：①下丘脑-腺垂体系统，二者问是神经体液性联系；②下丘脑-神经垂体系统，两者有直接神经联系。下丘脑弓状核分泌释放激素和释放抑制激素，主要有促甲状腺激素释放激素(TRH)、促性腺激素释放激素(GnRH，或促黄体生成激素释放激素，LHRH)、生长素释放激素(GHRH)、生长激素释放抑制激素(GHRIH)、促肾上腺皮质激素释放激素(CRH或CRF)、促黑激素释放因子(MRF)和促黑激素释放抑制因子(MRIF)、催乳素释放因子(PRF)及催乳素抑制因子(PIF)等。腺垂体分泌至少8种蛋白质激素：促甲状腺激素(TSH)、促肾上腺皮质激素(ACTH)、黄体生成素(LH，或间质细胞刺激素，ICSH)、卵泡刺激素(FSH)、生长激素(GH)、催乳素(PRH)、促脂激素(LPH)、黑素细胞刺激素(MSH)。下丘脑视上核产生抗利尿激素(血管加压素，ADH)，而室旁核产生催产素(缩宫素，OP)，并通过长轴突转运释放到神经垂体的血管中。下丘脑的释放激素或释放抑制激素经垂体门脉系统进入腺垂体，促进或抑制垂体激素的分泌，并进一步影响靶腺的功能。垂体激素、靶器官激素也反馈作用于下丘脑或垂体。形成了3个主要的调节轴：下丘脑-腺垂体-甲状腺轴、下丘脑-腺垂体-肾上腺轴、下丘脑-腺垂体-陛腺轴。 第二节药物对内分泌系统损伤的类型 一、药物对甲状腺的毒性作用 血液中的碘被摄取进入甲状腺，可在甲状腺球蛋白的酪氨酸残基上发生碘化，经一系列反应合成甲状腺激素。甲状腺激素主要有两种：四碘甲状腺原氨酸(甲状腺素，T4和