LANGE ENDOCRINE PHYSIOLOGY PDF

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Endocrine Physiology, Third Edition (LANGE Physiology Series) · Read more Vander's Renal Physiology, 7th Edition (LANGE Physiology Series) · Read more . a LANGE medical book Endocrine Physiology fourth edition Patricia E. Molina, MD, PhD Richard Ashman, PhD Professor Head, Department of Physiology. Endocrine Physiology, 5e. Patricia E. Molina. Go to Review Questions. Search Textbook Autosuggest Results. Chapter 1: General Principles of Endocrine.


Lange Endocrine Physiology Pdf

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"This book provides a concise discussion of endocrine physiology. First, there is a general discussion of hormone action. Next, individual chapters are devoted. Get Free Read & Download Files Endocrine Physiology Lange Physiology Series PDF. ENDOCRINE PHYSIOLOGY LANGE PHYSIOLOGY SERIES. Download. the book. endocrine physiology 4th edition pdf | download - endocrine physiology, fourth edition. (lange physiology series) by molina, patricia paperback.

These regulations occur by nuclear and mitochondrial genome pathways, mediated by THR and p43, respectively, and also by increased Pgc1a expression.

Overall, TH increases oxygen consumption and the resting metabolic rate. Citation: Journal of Endocrinology , 1; THRs also act as transcription factors independent of the ligand Ortiga-Carvalho et al. TH also triggers short-term effects in SM, such as regulation of the activity of membrane transporters Cordeiro et al. T4 rapidly stimulates the activity of the Na,K-ATPase in skeletal myotubes, resulting in an increase in the transmembrane resting potential and the frequency of spontaneously occurring action potentials Bannett et al.

T3 increases the pH in L6 myoblasts from rat SM culture via phospholipase C and intracellular calcium mobilization Incerpi et al. TH intracellular availability is a result of TH transport across the plasma membrane and the local activation or inactivation of T4 and T3. TH crosses the plasma membrane by facilitated diffusion, which is mediated by TH transporters. Furthermore, the activity of iodothyronine deiodinases type 2 D2 and 3 D3 contributes to the control of intracellular TH levels.

D2 converts T4 to T3, which increases T3 availability and likely its effects as well Bianco et al. D2 is constitutively expressed in rodent and human SM and its activity is higher in slow-twitch muscle than in fast-twitch muscle Visser et al. Hypothyroidism and cold exposure increase muscle D2 activity in rodents Marsili et al. In humans, D2 modulation by alterations in circulatory levels of TH is controversial.

However, short-term fasting decreased circulating T3 and increased SM D2 activity in euthyroid patients Visser et al.

Thyroid hormone and skeletal muscle physiology In the initial stages of postnatal development, different stimuli induce SM maturation, the muscle cell loses polyneuronal innervations, mechanical load to specific muscles increases and TH levels raise simultaneously Slater , Gambke et al. Both neuronal innervation and increased serum TH trigger the transformation of the muscle fibre profile, such as the loss of embryonic and neonatal myosin and an increase in adult fast or slow myosin genes in specific muscles Schiaffino et al.

Hypothyroid rats present a delay in the switch to adult myosin in fast muscle, but not in slow muscle Gambke et al. The postnatal development of slow fibres depends on weight-bearing activity and electrical stimulation, whereas in fast fibres, T3 signalling is crucial, especially for the transition of neonatal fibre to fibre IIb Gambke et al. Additionally, the denervation of neonatal fast muscle does not impair the switch of neonatal to adult myosin Gambke et al.

Therefore, physiological levels of TH contribute to the determination of the normal pattern of fibre distributions in each muscle Mahdavi et al.

T3 represses Myh7 expression, myosin from fibre type I, and stimulates Myh2, 1 and 4 expression, myosin from fibres IIa, IIx and IIb, respectively, inducing faster muscle contraction in rats Fig.

Additionally, T3 can alter twitch profiles by modulating miRNA expression. The slow-to-fast transition induced by T3 is impaired by miRa repression Zhang et al. Additionally, miRa-knockout mice have a fast-to-slow SM transition Liu et al. In , it was postulated that SM could participate in the regulation of serum T3 levels since SM is wildly distributed and has a large mass Maia et al.

Thyroid hormone affects skeletal muscle metabolism T3 treatment increases maximal oxygen consumption, which is more than two times bigger in the soleus than in the plantaris, which are slow-twitch oxidative fibres and fast-twitch mixed SM, respectively Bahi et al. The stimulus for switching from a glycolytic fibre to an oxidative one increases not only mitochondrial content but also mitochondrial fusion, forming elongated mitochondria.

As represented in Fig. T3 levels promote appropriate muscle responsiveness to insulin, and this effect depends on the conversion of T4 to T3 by local D2 as shown in D2-deficient myotube cultures, which present blunted insulin signalling Grozovsky et al. This effect is partly associated with the increase in glucose uptake by TH upregulation of Slc2a4 GLUT4 in basal and insulin-induced conditions Weinstein et al.

Slow and fast oxidative muscle fibres present a higher expression of GLUT4 and a greater glucose uptake capacity than fast glycolytic fibres Fig. Thus, hypothyroid mice present decreased glucose uptake induced by insulin.

Besides glucose uptake, TH stimulates oxidative pathways by increasing mitochondrial biogenesis. Additionally, D2 activity is important to treadmill exercise-induced PGC1A stimulation and its downstream effects on mitochondrial function of the soleus and gastrocnemius muscles Bocco et al. Recently, Lesmana and coworkers demonstrated that TH-induced mitochondrial biogenesis and activity are dependent on T3-induced autophagy Lesmana et al. Uncouple protein 2 and 3 UCP2, UCP3 are members of the mitochondrial carrier family and promote mitochondrial uncoupling in SM, thus dissipating energy in the form of heat and decreasing the energy efficiency of the cell.

T3 also increases the expression of citrate synthase, which performs the first step of the citric acid cycle Bahi et al. Furthermore, TH also stimulates oxidative phosphorylation in male rats due to the increased activity of cytochrome c oxidase 1 and 4 COX1 and COX4, respectively , the last enzymes in the electron transport chain of mitochondria Bahi et al. However, it is unknown whether there is a relationship between the substrate used and the TH levels. Therefore, the mechanism associated with T3 increased SM mitochondrial activity, and oxygen consumption is related to the stimulation of mitochondrial enzymes and UCP3 Barbe et al.

Furthermore, the intramyocellular lipid content increased in the soleus muscle of RTH subjects compared to the control Mitchell et al. Studying a mouse model of Thra deletion, it was observed that these animals preferentially use fat as fuel due to an increase in the expression of lipoprotein lipase in SM, and these mice present an increase in food consumption together with a leaner profile compared to WT mice Pelletier et al.

Overall, independent of the metabolized substrate, TH induces increased mitochondrial activity, oxidative phosphorylation and oxygen consumption through the stimulation of mitochondrial enzymes and UCP3 Fig. Thyroid hormone impact on myogenesis SM function depends on energy turnover, contraction and relaxation rates and on muscle tissue regeneration.

SM growth and regeneration are dependent on the proliferation and differentiation of the muscle stem cell population, satellite cells SC , in a process known as myogenesis. SC niches are located between the muscle fibre sarcolemma and the basal lamina, which are normally close to the endothelial area Fig.

The muscle stem cell niche location permits SCs to receive extrinsic signals from the bloodstream and intrinsic signals from the muscle fibres. Both stimuli can modulate the proliferation and differentiation of progenitor cells Beermann et al.

The myogenic process is summarized in Fig. The SC niches are next to blood vessels, between the basal lamina and the myofiber. Pax7 and Foxo3 are expressed by quiescent SCs, and these factors are involved in cell survival and self-renewal.

The low intracellular T3 favors the survival and cell proliferation. Pax7 regulates the expression of the myogenic regulatory factors MRF , a family of transcription factors that are essential to the progression of myogenesis, such as myogenic factor 5 MYF5 and MYOD1 Oustanina et al.

The control of intracellular T3 levels is fundamental to myogenesis progression Ambrosio et al. Dio3 expression is one of the controllers of proliferation and survival signalling in SCs Dentice et al. D3 is highly expressed in activated and proliferating SCs; however, it is downregulated during the differentiation process Fig. Foxo3 expression is also important in SC self-renewal, as it is associated with the return of SC quiescence after cell division Mammucari et al.

As indicated in Fig. These changes in expression lead to alterations in intracellular TH levels, which are required for myogenesis progression, suggesting that intracellular T3 should be maintained at a low level only in the beginning of the myogenic process Dentice et al.

Hormone receptors can also undergo upregulation. Upregulation of receptors involves an increase in the number of receptors for the particular hormone and frequently occurs when the prevailing levels of the hormone have been low for some time.

An example of this type of interaction is the upregulation of cardiac myocyte adrenergic receptors following sustained elevations in thyroid hormone levels. Th is variable pattern of hormone release is determined by the interaction and integration of multiple control mechanisms, which include hormonal, neural, nutritional, and environ- mental factors that regulate the constitutive basal and stimulated peak levels secretion of hormones.

The important role of the hypothalamus, and particularly of the photo-neuro-endocrine system in control of hormone pulsatility is discussed in Chapter 2.

Time Figure 1—8. Patterns of hormone release. Plasma hormone concentrations fluctuate throughout the day. Therefore plasma hormone measurements are not always a reflection of the function of a given endocrine system. Both cortisol and growth hormone GH undergo considerable variations in blood levels throughout the day. These can, in addition, be affected by sleep deprivation, light, stress, and disease and are dependent on their secretion rate, rate of metabolism and excretion, metabolic clearance rate, circadian pattern, fluctuating environment stimuli, internal endogenous oscillators as well as on biologic shifts induced by illness, night work, sleep, changes in longitude, and prolonged bed rest.

Reproduced with permission from Melmed S. Neural control of hormone release. Endocrine function is under tight regulation by the nervous system leading to the term neuroendocrine.

Hormone release by endocrine cells can be modulated by postganglionic neurons from the sympathetic SNS or parasympathetic nervous system PSNS using acetylcholine Ach or norepinephrine NE as neurotransmitters or directly by preganglionic neurons using acetylcholine as a neurotransmitter.

Therefore, pharmacologic agents that interact with the production or release of neurotransmitters will affect endocrine function. Neural control also plays an important role in the regulation of peripheral endocrine hormone release. Endocrine organs such as the pancreas receive sympathetic and para- sympathetic input, which contributes to the regulation of insulin and gluca- gon release.

Release of acetylcholine from preganglionic sympathetic nerve terminals at the adrenal medulla stimulates the release of epinephrine into the circulation see Figure 1—9. Hormonal Control Hormone release from an endocrine organ is frequently controlled by another hormone Figure 1— One example of this type of hormone release control is the regulation of glucocorticoid release by ACTH.

An example of this is the inhibition of growth hormone release by somatostatin. Hormonal inhibition of hormone release plays an important role in the process of negative feedback regulation of hormone release, described below and in Figure 1— In addition, hormones can stimulate the release of a second hormone in what is known as a feed-forward mechanism; as in the case of estradiol-mediated surge in luteinizing hormone at midmenstrual cycle see Chapter 9.

Hormonal control of hormone release. Hormones of this type are termed tropic hormones, and they are all Gland 1 Gland 2 released from the anterior pituitary gland adenohypophysis. Nutrient or ion regulation of hormone release. This is the simplest form of control mechanism, where the hormone is directly influenced by the circulating blood levels of the substrate that the hormone itself controls.

This sets up a simple control loop in which the substrate is controlling release of the hormone, which by its action s is altering the level of the substrate. Examples of this type of control are calcitonin and parathyroid hormone substrate is calcium , aldosterone substrate is potassium , and insulin substrate is glucose. This control mechanism is possible because of the ability of endocrine cells to sense the changes in substrate concentrations.

PTH, parathyroid hormone. Nutrient or Ion Regulation Plasma levels of nutrients or ions can also regulate hormone release Figure 1— In all cases, the particular hormone regulates the concentration of the nutrient or ion in plasma either directly or indirectly. Examples of nutrient and ion regulation of hormone release include the control of insulin release by plasma glucose levels and the control of parathyroid hormone release by plasma calcium and phosphate levels.

For example, insulin release is regulated by nutrients plasma levels of glucose and amino acids , neural sympathetic and parasympathetic stimulation , and hormonal somatostatin mechanisms. The ultimate function of these control mechanisms is to allow the neuroendocrine system to adapt to a changing environment, integrate signals, and maintain homeostasis. The respon- siveness of target cells to hormonal action leading to regulation of hormone release constitutes a feedback control mechanism.

A dampening or inhibition of the ini- tial stimulus is called negative feedback Figure 1— Stimulation or enhance- ment of the original stimulus is called positive feedback.

Negative feedback is the most common control mechanism regulating hormone release. The integrity of the system ensures that adaptive changes in hormone levels do not lead to patho- logic conditions. Furthermore, the control mechanism plays an important role in short- and long-term adaptations to changes in the environment. Feedback mechanisms. Three levels of feedback mechanisms controlling hormone synthesis can be identified: Hormones under negative feedback regulation stimulate the production of another hormone by their target organ.

The increasing circulating levels of that hormone then inhibit further production of the initial hormone.

Hypothalamic- releasing factors stimulate the release of tropic hormones from the anterior pituitary. The tropic hormone stimulates the production and release of hormone from the target organ.

The hormone produced by the target organ can inhibit the release of the tropic hormone and of the hypophysiotrophic factor by a long-loop negative feedback. The tropic hormone can inhibit the release of the hypothalamic factor in a short-loop negative feedback. The hypophysiotrophic factor can inhibit its own release in an ultrashort negative feedback mechanism.

The accuracy of this control mechanism allows the use of circulating levels of hormones, tropic hormones, and nutrients for assessment of the functional status of the specific endocrine organ in question. These are depicted in Figure 1— Alterations in target cell response can be caused by increased or decreased biologic responsiveness to a particular hormone Figure 1— The initial approach to assessment of endocrine function is measurement of plasma hormone levels.

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Hormone levels can be measured in plasma, serum, urine, or other biologic samples. Alterations in hormone biologic response. The maximal response produced by saturating doses of the hormone may be decreased because of a decreased number of hormone receptors, decreased concentration of enzyme activated by the hormone, increased concentration of noncompetitive inhibitor, or decrease in the number of target cells.

When there is a decrease in responsiveness, no matter how high the hormone concentration, maximal response is not achieved. The sensitivity of tissues or cells to hormone action is reflected by the hormone concentration required to elicit half-maximal response. This can be caused by decreased hormone- receptor affinity, decreased hormone receptor number, increased rate of hormone degradation, and increased antagonistic or competitive hormones.

Regulation of hormone release is a dynamic process that is constantly changing to adapt to the needs of the individual to maintain homeostasis. For example, because of the circadian rhythm of cortisol release, cortisol levels will be higher early in the morning than in late afternoon. Diseases and hour light periods like those in an intensive care unit alter the pulsatility and rhythm of hormone release. Some general aspects that should be considered when interpreting hormone measurements are as follows: The possible interpretations of altered hormone and regulatory factor pairs are summarized in Table 1—1.

Increased tropic hormone levels with low target hormone levels indicate primary failure of the target endocrine organ. Increased tropic hormone levels with increased target gland hormone levels indicate autono- mous secretion of tropic hormone or inability of target gland hormone to suppress tropic hormone release impaired negative feedback mechanisms.

Low tropic hormone levels with high target gland hormone levels indicate autonomous hormone secretion by the target endocrine organ. Dynamic measures of endocrine function provide more information than that obtained from hormone-pair measurements and rely on the integrity of the feed- back control mechanisms that regulate hormone release. These tests of endocrine function are based on either stimulation or suppression of the endogenous hor- mone production.

Examples of these tests are the use of ACTH to stimulate cortisol release see Chapter 6 and the use of an oral glucose load to stimulate insulin release see Chapter 7. Examples are the use of dexa- methasone, a synthetic glucocorticoid, to suppress pituitary ACTH and adrenal cortisol release. An example is the assessment of estrogen receptors in breast tumors to determine the applicability of hormone therapy.

Binding proteins regulate hormone availability and prolong hormone half-life. Physiologic effects of hormones require binding to specific receptors in target organs. Hormone release is under neural, hormonal, and product regulation. Hormones can control their own release through feedback regulation.

Interpretation of hormone levels requires consideration of hormone pairs or of the nutrient or factor controlled by the hormone. Which of the following statements concerning a particular hormone hormone X is correct? It will bind to cell membrane receptors in all cell types. It is lipid soluble and has an intracellular receptor. It circulates bound to a protein, and this shortens its half-life.

It is a small peptide; therefore, its receptor localization will be in the nucleus. Which of the following would be expected to alter hormone levels? Changes in mineral and nutrient plasma levels b.

Pituitary tumor c. Transatlantic flight d. Training for the Olympics e. All of the above 1—3. Which of the following statements concerning hormonal regulation is correct? A hormone does not inhibit its own release. Negative feedback regulation occurs only at the level of the anterior pituitary. Feedback inhibition may be exerted by nutrients and hormones. The structure of a newly discovered hormone shows that it is a large peptide with a glycosylated subunit.

The hormone is likely to: Bind to DNA and affect gene transcription b. Bind to adenylate cyclase and stimulate protein kinase C c. Bind to a cell membrane receptor d. Nuclear hormone receptors and gene expression. Physiol Rev. Physiological regulation of G protein-linked signaling. Y Understand the integration of hypothalamic and pituitary function and identify the 2 different pathways used for hypothalamic-pituitary interactions.

Y Identify the appropriate hypothalamic releasing and inhibitory factors controlling the secretion of each of the anterior pituitary hormones. Y Differentiate between the routes of transport of hypothalamic neuropeptides to the posterior and anterior pituitary. Y Identify the mechanisms that control the release of oxytocin and arginine vasopressin AVP.

Y Understand the physiologic target organ responses and the cellular mechanisms of oxytocin and AVP action. Most of these hypothalamic responses are mediated through hypothalamic control of pituitary function Figure 2—1. This control is achieved by 2 mechanisms: Because of this close interaction between the hypothalamus and the pituitary in the control of basic endocrine physiologic function, they are presented as an integrated topic.

Neuroendocrine regulation of homeostasis. The release of hypothalamic neuropeptides is regulated by afferent signals from other brain regions, from visceral afferents, and by circulating levels of substrates and hormones. The hormones released from the anterior and posterior pituitary regulate vital body functions to maintain homeostasis.

Anatomical and functional relationship between the hypothalamus and the pituitary. The hypothalamus is anatomically and functionally linked with the anterior and posterior pituitary.

They are closely related because of the portal system of blood supply. The superior, medial, and inferior hypophyseal arteries provide arterial blood supply to the median eminence and the pituitary.

Magnocellular neurons of the supraoptic SON and paraventricular PVN nuclei have long axons that terminate in the posterior pituitary. The axons of parvicellular neurons terminate in the median eminence where they release their neuropeptides. The long portal veins drain the median eminence, transporting the peptides from the primary capillary plexus to the secondary plexus that provides blood supply to the anterior pituitary. Adapted with permission from Melmed S. Medical progress: In addition, the median eminence is traversed by the axons of hypothalamic neurons ending in the pos- terior pituitary.

The median eminence funnels down to form the infundibular portion of the neurohypophysis also called the pituitary or infundibular stalk. In practical terms, the neurohypophysis or posterior pituitary can be considered an extension of the hypothalamus. Hypothalamic Nuclei In the hypothalamus, the neuronal bodies are organized in nuclei. These are clus- ters or groups of neurons that have projections reaching other brain regions as well as ending in other hypothalamic nuclei.

This intricate system of neuronal connec- tions allows continuous communication between the hypothalamic neurons and other brain regions. Some of the neurons that make up the hypothalamic nuclei are neurohormonal in nature.

Neurohormonal refers to the ability of these neurons to synthesize neu- ropeptides that function as hormones and to release these neuropeptides from axon terminals in response to neuronal depolarization. Two types of neurons are important in mediating the endocrine functions of the hypothalamus: The magnocellular neurons are predominantly located in the paraventricular and supraoptic nuclei of the hypothalamus and produce large quantities of the neurohormones oxy- tocin and arginine vasopressin AVP.

The unmyelinated axons of these neu- rons form the hypothalamo-hypophysial tract, the bridge-like structure that traverses the median eminence and ends in the posterior pituitary. Oxytocin and AVP are released from the posterior pituitary in response to an action potential. Parvicellular neurons have projections that terminate in the median eminence, brainstem, and spinal cord. These neurons release small amounts of releasing or inhibiting neurohormones hypophysiotropic hormones that control anterior pituitary function.

Blood Supply The specialized capillary network that supplies blood to the median eminence, infundibular stalk, and pituitary plays an important role in the transport of hypo- physiotropic neuropeptides to the anterior pituitary. Branches from the internal carotid artery provide the blood supply to the pituitary. The supe- rior hypophysial arteries form the primary capillary plexus that supplies blood to the median eminence.

Magnocellular neurons are larger in size and produce large quantities of neurohormones. Located predominantly in the paraventricular and supraoptic nuclei of the hypothalamus, their unmyelinated axons form the hypothalamohypophyseal tract that traverses the median eminence ending in the posterior pituitary.

They synthesize the neurohormones oxytocin and vasopressin, which are transported in neurosecretory vesicles down the hypothalamohypophyseal tract and stored in varicosities at the nerve terminals in the posterior pituitary. Parvicellular neurons are small in size and have projections that terminate in the median eminence, brain stem, and spinal cord.

They release small amounts of releasing or inhibiting neurohormones hypophysiotrophic hormones that control anterior pituitary function will be discussed in the next chapter.

These are transported in the long portal veins to the anterior pituitary where they stimulate the release of pituitary hormones into the systemic circulation. The hypophysiotropic peptides released at the median eminence enter the primary plexus capillaries.

Endocrine Physiology, Fourth Edition (4th ed.)

From there, they are transported to the anterior pituitary via the long hypophysial portal veins to the secondary plexus. The secondary plexus is a network of fenestrated sinusoid capillaries that provides the blood supply to the anterior pituitary or adenohy- pophysis. The blood supply to the posterior pituitary and to the pituitary stalk is provided mostly by the middle and inferior hypophysial arteries and, to a lesser extent, by the superior hypophysial arteries.

Short portal vessels provide venous connec- tions that originate in the neural lobe and pass across the intermediate lobe of the pituitary to the anterior lobe.

This structure allows neuropeptides released from the posterior pituitary to have access to cells in the anterior pituitary, so that the functions of the 2 main regions of the pituitary cannot be dissociated from each other. Blood from the anterior and posterior pituitary drains into the intercavern- ous sinus and then into the internal jugular vein, entering the systemic venous circulation.

Hypothalamic Neuropeptides As described earlier, 2 general types of neurons constitute the endocrine hypothalamus: The neuropeptides released from the parvicellular neu- ron terminals in the median eminence corticotropin-releasing hormone, growth hormone—releasing hormone, thyrotropin-releasing hormone, dopamine, lutein- izing hormone—releasing hormone, and somatostatin control anterior pituitary function Table 2—1. The hypothalamic hypophysiotropic peptides stimulate the release of anterior pituitary hormones.

The products released from both the ante- rior pituitary adrenocorticotropic hormone [ACTH], prolactin, growth hor- mone [GH], luteinizing hormone [LH], follicle-stimulating hormone [FSH], and thyroid-stimulating hormone [TSH] and the posterior pituitary oxytocin and AVP are transported in the venous blood draining the pituitary that enters the intercavernous sinus and the internal jugular veins to reach the systemic circu- lation see Figure 2—2.

Several neuropeptides have been isolated from the hypo- thalamus, and many continue to be discovered. However, only those that have been demonstrated to control anterior pituitary function hypophysiotropic hor- mones and, therefore, play an important role in endocrine physiology will be discussed.

Among the environmental factors, light plays an important role in generating the circadian rhythm of hormone secretion. Key aspects of hypophysiotropic hormones Predominant Hypophysiotropic hypothalamic Anterior pituitary hormone nuclei hormone controlled Target cell Thyrotropin- Paraventricular Thyroid-stimulating Thyrotroph releasing hormone nuclei hormone and prolactin Luteinizing Anterior and medial Luteinizing hormone Gonadotroph hormone-releasing hypothalamus; and follicle- hormone preoptic septal areas stimulating hormone Corticotropin- Medial parvicellular Adrenocorticotropic Corticotroph releasing hormone portion of hormone paraventricular nucleus Growth hormone- Arcuate nucleus, Growth hormone Somatotroph releasing hormone close to median eminence Somatostatin or Anterior Growth hormone Somatotroph growth hormone- paraventricular area inhibiting hormone Dopamine Arcuate nucleus Prolactin Lactotroph The 6 recognized hypophysiotropic factors and the predominant locations of their cells of origin are listed in the left columns.

The right columns list the anterior pituitary hormone that each hypophysiotropic factor regulates and the cell that releases the specific hormones.

Melatonin is a hormone synthesized and secreted by the pineal gland at night. Melatonin conveys infor- mation concerning the daily cycle of light and darkness to body and participates in the organization of circadian rhythms.

One can think of the hypothalamus as a center for integration of the information that the body is continuously processing. In addition, circulating hormones produced by endocrine organs and substrates such as glucose can regulate hypothalamic neuronal function. Therefore, hypothalamic hormone release is under environmental, neural, and hormonal regulation. The ability of the hypothalamus to integrate these signals makes it a center of command for regulat- ing endocrine function and maintaining homeostasis.

This control mechanism of negative or positive feedback regulation, discussed in detail in Chapter 1, consists of the ability of a hormone to regulate its own cascade of release see Figure 1— For example, as discussed in greater detail in Chapter 6, cortisol produced from the adrenal gland can inhibit the release of CRH, thus inhibiting the production of proopi- omelanocortin and ACTH and consequently decreasing adrenal gland synthesis of cortisol.

This loop of hormonal control and regulation of its own synthesis is critical in maintaining homeostasis and preventing disease. A shorter loop of negative feedback inhibition also exists, which depends on the inhibition of hypo- physiotropic neuropeptide release by the pituitary hormone that it stimulates.

Some neuropeptides also possess an ultrashort feedback loop, in which the hypophysiotropic neuropeptide itself is able to modulate its own release. As an example, oxytocin stimulates its own release, creating a positive feedback regulation of neuropeptide release. These feedback loops are illustrated in Figure 1—12, Chapter 1.

This continuous regulation of hormonal release is dynamic; it is continuously adapting to changes in the environment and in the internal milieu of the individ- ual.

Throughout a given day, the hypothalamus integrates a multitude of signals to ensure that the rhythms of hormone release are kept in pace with the needs of the organism.

Disruption of these factors can alter the patterns of hormone release. For example, a patient in the intensive care unit, where the lights are on through- out the 24 hours of the day, will have a disrupted cycle of hormone release. Other situations that disrupt the normal cycles of hormone release are travel across time zones, night-shift employment, and aging.

These neurons gen- erate and propagate action potentials, producing membrane depolarization and exocytosis of the contents of their secretory granules. The neuropeptides produced by the magnocellular neurons, and consequently released from the posterior pitu- itary, are oxytocin and AVP.

As the axons leave the supraoptic and paraventricular nuclei, they give rise to collaterals, some of which terminate in the median eminence. Oxytocin and AVP are closely related peptides consisting of 9 amino acids nonapeptides with ring structures Figure 2—4. They are synthesized as part of a larger precursor protein, consisting of a signal peptide, the hormone, a peptide called neurophysin 2, and a glycopeptide called copeptin.

Following cleavage of the signal peptide in the endoplasmic reticulum, the remaining precursor folds, dimerizes, exits from the Golgi apparatus, and moves down the neurohypophyseal axons packaged within neurosecretory vesicles see Figure 2—4.

Hormone processing occurs during this stage yielding hormone and neurophysins. Figure 2—4. In the Golgi apparatus GA , they are packaged in secretory granules and are transported down the hypothalamo- hypophysial tract. During transport, the precursor hormones are processed, yielding the final hormone and the respective neurophysins. The contents of the neurosecretory vesicles are released by exocytosis from the axon terminals in the posterior pituitary. The increase in intracellular calcium triggers the movement and docking of the secre- tory vesicles on the plasma membrane, resulting in exocytosis of the vesicle con- tents into the extracellular space.

These neuropeptides enter the systemic circulation through venous drainage of the posterior pituitary into the intercav- ernous sinus and internal jugular vein. In the systemic circulation, oxytocin and AVP circulate unbound. They are rapidly cleared from the circulation by the kid- ney and, to a lesser extent, by the liver and brain. Their half-life is short and is estimated to range between 1 and 5 minutes. Neurophysins Neurophysins are by-products of post-translational prohormone processing in the secretory vesicles.

The release of AVP and oxytocin is accompanied by the release of neurophysins from the secretory granules. Although the exact function of these by-products is not clear, it appears that neurophysins play an important role in AVP release.

Impairment in hormone targeting leads to retention of the mutated neuropeptide precursor in the endoplasmic reticulum of the magnocellular neurons, and these cells progress to programmed cell death apoptosis. Oxytocin The neuropeptide oxytocin is synthesized by magnocellular neurons in the supra- optic and paraventricular nuclei of the hypothalamus and is released from the posterior pituitary into the peripheral circulation.

The release of oxytocin is stimu- lated by sucking during breast-feeding lactation and stretch of the cervix during childbirth parturition Figure 2—5. In the lactating breast, oxytocin stimulates milk ejection by producing contraction of the myoepithelial cells that line the alveoli and ducts in the mammary gland. In the pregnant uterus, oxytocin produces rhythmic smooth muscle contractions to help induce labor and to pro- mote regression of the uterus following delivery see Chapter 9.

Physiologic effects and regulation oxytocin release. The release of oxytocin is stimulated by the distention of the cervix toward the term of pregnancy as well as by the contraction of the uterus during parturition. The signals are transmitted to the paraventricular PVN and supraoptic SON nuclei of the hypothalamus where they provide a positive feedback regulation of oxytocin release.

The increased number in oxytocin receptors, the increase number in gap junctions between smooth muscle cells, and the increased synthesis of prostaglandins enhance the responsiveness of the uterine muscle. The suckling of the nipple of the lactating breast also stimulates oxytocin release. The afferent sensory signals elicit an increase in oxytocin release into the circulation.

This increased sensitivity to oxytocin is caused by an increased density upregulation of oxytocin receptors in the uterine muscle. Receptor levels can be times greater at the onset of labor than in the nonpregnant uterus. The increased density of oxy- tocin receptors is mediated by steroid hormone regulation of oxytocin-receptor synthesis. Responsiveness of the uterus is also enhanced by increased gap-junction formation between smooth muscle cells, facilitating conduction of action poten- tials between one cell and the next; and by increased synthesis of prostaglandin, a known stimulator of uterine contraction toward the end of gestation.

All of these factors enhance myometrial contractile activity in response to oxytocin at term see Chapter 9. Hence, the contractile activity of the uterus acts through positive feedback mecha- nisms during parturition to stimulate oxytocin neurons, and this further increases the secretion of oxytocin. This modulation of oxytocin release is partly caused by the declining blood levels of progesterone and increasing levels of estrogen during late pregnancy.

The neurotransmitters involved in stimulating oxytocin release are thought to be acetylcholine and dopamine. Oxytocin release is also triggered by stimulation of tactile receptors in the nipples of the lactating breast by suckling see Figure 2—5. Breast-feeding gen- erates sensory impulses that are transmitted to the spinal cord and then to the oxytocin-producing neurons in the hypothalamus.

The function of this intrahypothalamic release of oxytocin is to control the activity of oxytocin neurons in an autocrine fashion by a positive feedback mechanism, increasing the neurohypophysial release of oxytocin. The release of oxytocin is inhibited by severe pain, increased body temperature, and loud noise. Note how the environmental, hormonal, and neural mechanisms of hypothalamic hormone regulation are in play to regulate oxytocin release at the appropriate time of gestation and in response to the relevant stimuli.

The role of oxytocin in males is not clear, although recent studies have suggested that it may participate in ejaculation. Receptor-mediated oxytocin effects. Binding of oxytocin to the receptor activates phospholipase C PLC , producing an increase in inositol trisphosphate IP3 and 1,2-diacylglycerol, which in turn results in an increase in cytosolic calcium concentrations.

The phosphorylated myosin filament combines with the actin filament leading to smooth muscle contraction. Arginine Vasopressin AVP, also known as antidiuretic hormone ADH , is the other neuropeptide pro- duced by magnocellular neurons of the hypothalamus and released from the posterior pituitary.

In addition, AVP increases vascular resistance. This function of AVP may be important during periods of severe lack of responsiveness to other vasoconstrictors, as may occur during severe blood loss hemorrhagic shock or systemic infection sepsis.

The circulating concentra- tions of AVP range from 1. It is found in the liver, smooth muscle, brain, and adrenal glands. It activates phospholipases C, D, and A 2 and stimulates the hydrolysis of phosphatidylinositol, resulting in an increase in intracellular calcium concentrations.

V2R is coupled to Gs and is expressed in the kidney. Binding of AVP to the V3R recep- tor stimulates the activity of phospholipase C, resulting in an increase in intracel- lular calcium.

Cellular mechanism of arginine vasopressin AVP water conservation. The principal function of AVP is to increase water reabsorption and to conserve water. The insertion of water channels into the membrane increases the permeability to water.

Water reabsorbed through these water channels leaves the cell through aquaporin 3 AQP3 and aquaporin 4 AQP4 , which are constitutively expressed in the basolateral membrane of the principal cells.

AQP2 Exclusively expressed in the collecting ducts. The only aquaporin directly regulated by ADH. Binding to the V2 AVP receptor stimulates insertion into the luminal membrane. Enhance water reabsorption following AQP2 insertion into the luminal membrane.

The importance of AVP is better understood in terms of the total amount of urine that would be excreted in its absence. This is fold higher than the volume of urine output 1. The increase in cAMP that is stimulated by AVP binding to the receptor located in the basolateral membrane activates protein kinase A and subsequently the phos- phorylation of AQP2, another protein. Phosphorylation of AQP2 is essential for its movement from cytoplasmic pools and its insertion in the luminal apical epithelial cell membrane of the collecting duct cells.

The result is an increase in the number of functional water channels in the luminal membrane, making it more permeable to water. Thus, AVP-mediated insertion of AQP2 into the lumi- nal membrane results in water conservation and urine concentration. This event is a short-term regulation of water permeability in response to an increase in cir- culating levels of AVP. In addition, AVP is thought to regulate water permeability over hours to days as a result of an increase in the total cellular amount of AQP2 caused by increased protein synthesis.

AQP2, one of several members of the aquaporin family, is exclusively expressed in the collecting ducts of the kidney. Water reabsorption through this mechanism is driven by the hydroosmotic gra- dient generated by a countercurrent mechanism in the renal medulla. The result is an increase in the concentration and reduction of urine volume, which minimizes urinary water loss. As mentioned above, this could translate into excessive urine output and reduced urine osmolarity.

AVP also binds the V1 receptor, expressed in vascular smooth muscle, pro- ducing contraction and increasing peripheral vascular resistance Figure 2—8. AVP circulates unbound and is distributed in a volume approximately equal to that of the extracellular space. Because of its relatively low molecular weight, AVP permeates peripheral and glomerular capillaries readily, so the uri- nary excretion rate of AVP is extraordinarily high.

Cellular mechanism of AVP vasoconstrictor effects. AVP also known as vasopressin binds the V1 receptor, expressed in vascular smooth muscle, producing contraction and increasing peripheral vascular resistance.

The changes in osmotic pressure are detected by special osmo- receptor neurons located in the hypothalamus and in 3 structures associated with the lamina terminalis: Dehydration produces loss of intra- cellular water from the osmoreceptors, resulting in cell shrinkage, which signals the AVP magnocellular neurons to stimulate AVP release.

Integration of signals that trigger arginine vasopressin AVP release. Release of AVP is stimulated by an increase in plasma osmolarity and by a decrease in blood volume.

A decrease in blood volume sensitizes the system and increases the responsiveness to small changes in plasma osmolarity. The afferent signals are transmitted by the 9th and 10th cranial nerves. These signals increase sympathetic tone, therefore decreasing magnocellular neuron inhibition and stimulating AVP release.

The sensitivity of this system is quite high. Decreases in blood volume or blood pressure are detected by pressure-sensitive receptors in the cardiac atria, aorta, and carotid sinus. Factors that reduce cardiac output, such as a decrease in blood volume, orthostatic hypo- tension, and positive-pressure breathing, are all potent stimuli for AVP release.

These signals are transmitted to the central nervous system by neurons of the vagus and glossopharyngeal nerves. The reduced stimulation pro- duces a decrease in tonic inhibition of AVP release, leading to an increase in AVP release from the magnocellular neurosecretory neurons.

In addition to signaling the brain to stimulate the release of AVP, the decrease in blood pressure is also perceived by the macula densa in the kidney. This results in stimulation of renin release from the juxtaglomerular apparatus in the kidney. Renin catalyzes the conversion of angiotensinogen produced in the liver to angiotensin I, which is then converted to angiotensin II, by angiotensin-converting enzyme. The result- ing rise in circulating levels of angiotensin II sensitizes the osmoreceptors, lead- ing to enhanced AVP release.

This is another example of hormonal regulation of hypothalamic neuropeptide release. The volume-induced sensitization of AVP release results in a more accentu- ated AVP response to changes in plasma osmolarity.

However, AVP secretion is far more sensitive to small changes in plasma osmolarity than to changes in blood volume. Above this threshold, the plasma AVP concentration increases steeply in direct proportion to plasma osmolarity. Because of this extraordinary sensitivity, the osmore- ceptor plays the primary role in mediating the antidiuretic response to changes in water balance.

In contrast, the response to pressure-volume changes is exponential. Release of AVP can be modulated by estrogen and proges- terone, opiates, nicotine, alcoholic beverages, and atrial natriuretic factor. The concentrations of AVP may be altered in various chronic pathophysiologic con- ditions, including congestive heart failure, liver cirrhosis, and nephritic syndrome.

The third, excess water intake does not involve alterations in ADH release. Nephrogenic DI can be inherited or acquired and is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of AVP. A small number of cases of inherited nephrogenic DI are caused by mutations in the AQP2 water channel gene.

Acquired nephrogenic DI can result from lithium treatment, hypo- kalemia, and postobstructive polyuria. Plasma levels of AVP are interpreted together with the indirect assessment of antidiuretic activity triggered by a dehydration test.

This test determines the ability of the body to increase the production and release of AVP during water deprivation. Normal function consists of an increase in urine osmolarity and a decrease in urine output during water depriva- tion alone. Another way of testing the system is by a challenge test with synthetic AVP.

Individuals with normal pituitary function do not exhibit a further increase in urine osmolarity following the administration of a synthetic AVP analog des- mopressin. These examples illustrate that understanding the etiol- ogy of the disease requires an understanding of the normal physiologic regulation of the endocrine system in question.

Syndrome of inappropriate antidiuretic hormone secretion—An increase or excess in the release of ADH, in the absence of a physiologic stimuli for its release thus the name inappropriate is known as SIADH. This may be the result of brain injury or tumor production of AVP. The tumor can be located in the brain, but malignancies of other organs, such as the lung, have also been shown to produce high levels of AVP.

The excess production of AVP results in the production of very small volumes of concentrated urine and dilu- tional hyponatremia. The hypothalamus integrates information from various brain regions, the environ- ment, and peripheral organs and mediates systemic responses that help maintain homeostasis. Oxytocin and AVP are neuropeptides made in hypothalamic neurons and released from the posterior pituitary into the systemic circulation.

Prohormone posttranslational modification and processing of oxytocin and AVP occur inside the secretory granules during axonal transport and generate neurophysins. AVP binds to the V2 receptor in tubular collecting-duct epithelial cells, stimulating the insertion of AQP2 into the apical luminal membrane leading to increased water reabsorption.

The release of AVP is more sensitive to small changes in plasma osmolarity than to small changes in blood volume. Deficiency of AVP results in the production of large volumes of dilute urine.

Excess AVP release results in small volumes of concentrated urine and hemodilu- tion leading to hyponatremia. A year-old male trauma victim has been a patient in the surgical intensive care unit for the past 6 days.

You suspect he has a neuroendocrine abnormality of traumatic origin. Which set of laboratory values would be compatible with your differential diagnosis? You request additional tests on the urine of this patient. Which of the following would you expect to be the set of results compatible with his condition? Increased production and release of arginine vasopressin b. Increased urinary release of cAMP c. Decreased free water reabsorption d.

Increased sodium reabsorption 2—4. Rupture of membranes, without active labor in a year-old patient during her 40th week of gestation leads you to start induction of labor and delivery with an intravenous drip of oxytocin analog Pitocin. A year-old male patient recovering from a surgical procedure complains of headache, difficulty concentrating, impaired memory, muscle cramps, and weak- ness of 48 hours duration.

On examination, vital signs are all within normal range, and there are no signs of dehydration or of edema. Which of the following would be compatible with a differ- ential diagnosis of syndrome of inappropriate ADH secretion? Low plasma AVP levels b. Osmoreceptors in the central nervous system. Annu Rev Physiol.

J Neuroendocrinol. Gimpl G, Fahrenholz F. The oxytocin receptor system: Melmed S. Y Understand the mechanisms that regulate anterior pituitary hormone production and describe the actions of tropic hormones on target organs.

Endocrine Physiology 4th Edition

Y Diagram the short-loop and long-loop negative feedback control of anterior pituitary hormone secretion. Y Predict the changes in secretory rates of hypothalamic anterior pituitary and target gland hormones caused by oversecretion or undersecretion of any of these hormones or receptor deficit for any of these hormones. Y Explain the importance of pulsatile and diurnal hormone secretion. The anterior pituitary, or adenohypophysis, plays a central role in the regulation of endocrine function through the production and release of tropic hormones Figure 3—1.

The function of the anterior pituitary, and thereby the production of tropic hormones, is under hypothalamic regulation by the hypophysiotropic neuropeptides released in the median eminence, as dis- cussed in Chapter 2 and summarized in Table 3—1.

The tropic hormones produced by the anterior pituitary are released into the systemic circulation, from where they reach their target organs to produce a physiologic response, most frequently involving the release of a target organ hormone see Figure 3—1.

The pars inter- media is of minor importance in human physiology. Anterior pituitary hormones, target organs, and physiologic effects. Thyroid-stimulating hormone TSH stimulates the thyroid gland to produce and release thyroid hormones that regulate growth, differentiation, and energy balance. Luteinizing hormone LH and follicle-stimulating hormone FSH stimulate gonadal production of sex steroids, which mediate reproductive function and behavior. Adrenocorticotropic hormone ACTH stimulates the adrenal glands to produce steroid hormones, which regulate water and sodium balance, inflammation, and metabolism.

Prolactin Prl stimulates breast development and milk production. Growth hormone GH exerts direct effects on tissue growth and differentiation and indirect effects through the stimulation of insulin-like growth factor 1 production, which mediates some of the growth and differentiation effects of GH. The pituitary cells that line the capillaries produce the tropic hormones: All of these hormones are released into the systemic circulation.

The cells of the anterior pituitary are named according to the hormone that they produce. For example, the gonadotrophs and somato- trophs GH-producing cells are more numerous in the posterolateral region of the anterior pituitary, making them vulnerable to mechanical damage of the pituitary. The corticotrophs ACTH-producing cells and the thyrotrophs TSH-producing cells are located predominantly in the anteromedial region, making them more resilient to traumatic injury.

Endocrine Physiology, 5e

The lactotrophs prolactin- producing cells are dispersed throughout the pituitary, and this too is a resil- ient cell population. The posterior pituitary is of nervous origin. The neurohormones released from the posterior pituitary have been discussed in Chapter 2. This chapter will focus on the endocrine function of the anterior pituitary. The release of anterior pituitary hormones is cyclic in nature, and this cyclic pattern of hormone release is governed by the nervous system.

Most rhythms are driven by an internal biologic clock located in the hypothalamic suprachiasmatic nucleus; this clock is synchronized or entrained by external signals such as light and dark periods. These observations have highlighted the importance of trying to simulate, as much as possible, the endogenous cyclic patterns of hormone release when giving hormone replacement therapy to a patient. Therefore, the natural cyclic pattern of hypothalamic, pituitary, and target organ hormone release is of central importance to normal endocrine function.

Classification of anterior pituitary hormones. Growth hormone and prolactin are structurally similar to human placental lactogen. Glycoproteins Glycoprotein hormones are among the largest hormones known to date. TRH is synthesized in the paraventricular nuclei of the hypothalamus, predominantly by parvicellular neu- rons, and is released from nerve terminals in the median eminence.

TSH stimulates all the events involved in thyroid hormone synthesis and release see Chapter 4. In addition, it acts as a growth and survival factor for the thyroid gland.

The release of TSH from the anterior pitu- itary gland is under negative feedback inhibition by thyroid hormone, particularly triiodothyronine, as discussed in detail in Chapter 4.

GnRH is synthesized and secreted by the hypothalamus in a pulsatile manner. Among the target cells for gonadotropins are ovarian granulosa cells, theca interna cells, testicular Sertoli cells, and Leydig cells. The physiologic responses produced by the gonadotropins include stimulation of sex hormone synthesis steroidogenesis , spermatogenesis, folliculogenesis, and ovulation. Therefore, their central role is the control of reproductive function in both males and females. The complexity of the regulation of synthesis and release of anterior pituitary hormones is best illustrated by the cyclic nature of FSH and LH release.

The pattern of GnRH pulses changes during the menstrual cycle in women, as sum- marized in Table 3—2 and discussed in detail in Chapter 9.

During the luteal to follicular phase transition, pulses of GnRH release occur every 90— minutes, and FSH secretion predominates. After ovulation, ovarian progesterone production predominates. Progesterone increases hypothalamic opioid activity and slows GnRH pulse secretion. Feedback regulation of pituitary hormone release. Hypothalamic neurohormones eg, gonadotropin-releasing hormone stimulate the anterior pituitary to produce and release tropic hormones eg, follicle-stimulating hormone and luteinizing hormone.

Tropic hormones bind to receptors in target organs and elicit a physiologic response. In most cases, the response involves the production of a target organ hormone, which, in turn, mediates physiologic effects at the target organ eg, uterus.

With involution of the corpus luteum and the sharp decline in estradiol, inhibin A, and progesterone, the frequency of GnRH pulse secretion is increased.

In the absence of estradiol and inhibin A inhibitors of FSH release , a selective FSH release predominates and initiates the next wave of follicular development. Proopiomelanocortin-Derived Hormones POMC is a precursor pro-hormone produced by the corticotrophs of the ante- rior pituitary. The production and secretion of POMC-derived hormones from the anterior pituitary are regulated predominantly by corticotropin-releasing hormone CRH produced in the hypothalamus and released in the median eminence.

CRH binds to a Gs protein—coupled receptor whose actions are medi- ated through activation of adenylate cyclase and elevation of cAMP production see Figure 3—3. Stimulation of POMC synthesis and peptide release is mediated by the CRH-1 receptor, which is expressed in many areas of the brain as well as in the pituitary, gonads, and skin. CRH-2 receptors are expressed on brain neurons located in neocortical, limbic, and brainstem regions of the central nervous system and on pituitary corticotrophs and in peripheral tissues eg, cardiac myocytes, gastrointestinal tract, lung, ovary, and skeletal muscle.

The role of CRH-2 receptors is not com- pletely understood. MC4R is expressed in the brain and has been implicated in feeding behavior and appetite regulation. The release of ACTH is stimulated by psychologic and physical stress such as infection, hypoglycemia, surgery, and trauma and is considered critical in mediating the stress or the adaptive response of the individual to stress see Chapter The hormone is released in pulses, with the highest concentrations occurring at approximately 4: The feedback inhibition of ACTH and of CRH release by cortisol is mediated by glucocorticoid receptor binding in the hypothalamus and in the anterior pituitary.

The involvement of this paracrine system in the development of skin cancer has received considerable attention because of the localized produc- tion and paracrine actions of this peptide and the greater expression of MC1R in melanoma than in normal skin.

Cellular signaling pathways involved in hypothalamo-pituitary hormone-mediated effects. All hypothalamic releasing and inhibiting factors mediate their effects predominantly via G protein—coupled receptors. Most of the cellular responses elicited by anterior pituitary hormones that bind to G protein—coupled receptors are mediated by modulation of adenylate cyclase activity. The cellular responses evoked by anterior pituitary binding to class 1 cytokine receptors are mediated through protein kinase activation.

Proopiomelanocortin POMC processing. Corticotropin-releasing hormone stimulates the production, release, and processing of POMC, a preprohormone synthesized in the anterior pituitary. GH is released from the somatotrophs, an abundant cell type in the anterior pituitary. GH is released in pulsatile bursts, with the majority of secretion occurring nocturnally in asso- ciation with slow-wave sleep Figure 1—8.

Most of the GH in the circulation is bound to growth hormone binding protein. GH release is also inhibited by insulin-like growth factor 1 IGF-1 , the hormone produced in peripheral tissues in response to GH stimulation.

IGF-1 derived from hepatic synthesis is part of a classic nega- tive feedback mechanism of GH release. The overall contribution of ghrelin to regulation of GH release in humans is still not fully elucidated. Growth hormone-releasing hormone— GHRH stimulates GH secretion from somatotrophs through increases in GH gene transcription and biosyn- thesis and somatotroph proliferation.

GHRH binds to Gs protein—coupled receptors on anterior pituitary somatotrophs, activating the catalytic subunit of adenylate cyclase. The stimulation of adenylate cyclase by Gs protein leads to intracellular cAMP accumulation and activation of the catalytic subunit of protein kinase A see Figure 3—4. Somatostatin—The stimulated release of GH is inhibited by somatostatin, a peptide synthesized in most brain regions, predominantly in the periventricu- lar nucleus, arcuate nucleus, and ventromedial nucleus of the hypothalamus.

Somatostatin is also produced in peripheral organs, including the endocrine pan- creas, where it also plays a role in the inhibition of hormone release. Axons from somatostatin neurons run caudally through the hypothalamus to form a discrete pathway toward the midline that enters the median eminence. The expression of somatostatin receptors is modulated by hormones and by the nutritional state of the individual.

Growth hormone GH release and effects. GH release from the anterior pituitary is modulated by several factors. GH secretion is also part of a negative feedback loop involving insulin-like growth factor 1 IGF GH also feeds back to inhibit GHRH secretion and probably has a direct autocrine inhibitory effect on secretion from the somatotroph.

Integration of all the factors that affect GH synthesis and secretion lead to a pulsatile pattern of release. GH effects in peripheral tissues are mediated directly by GH binding to its receptor and through the synthesis of IGF-1 by the liver and at the tissue level.

AA, amino acid; FFA, free fatty acid. Other regulators— In addition to regulation by GHRH and somatostatin, GH is regulated by other hypothalamic peptides and neurotransmitters, which act by regulation of GHRH and somatostatin release, as summarized in Table 3—3. Decreased blood glucose concentra- tions hypoglycemia stimulate GH secretion in humans. In contrast, amino acids, particularly arginine, increase GH release by decreasing somatostatin release.

GH is released from the anterior pituitary into the systemic circulation. This protein is derived from proteolytic cleavage of the GH membrane receptor by metalloproteases and serves as a reservoir for GH, prolong- ing its half-life by decreasing its rate of degradation.Furthermore, TH also stimulates oxidative phosphorylation in male rats due to the increased activity of cytochrome c oxidase 1 and 4 COX1 and COX4, respectively , the last enzymes in the electron transport chain of mitochondria Bahi et al.

These receptors are transcription factors that have binding sites for the hormone ligand and for DNA and function as ligand hormone -regulated transcription factors.

Receptor levels can be times greater at the onset of labor than in the nonpregnant uterus. Training for the Olympics e. Plasma hormone concentrations fluctuate throughout the day. Critical illnesses frequently lead to diaphragm muscle dysfunction.

Growth hormone e. The signals are transmitted to the paraventricular PVN and supraoptic SON nuclei of the hypothalamus where they provide a positive feedback regulation of oxytocin release. This process is an important feature in placental protection of the fetus. The apical surface of the follicular cell faces the follicular lumen, where colloid is stored.

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