The half-life of somatostatin in the peripheral circulation is only 2 to 4 minutes. Mice overexpressing somatostatin have been generated. Mice deficient in somatostatin receptor type 2 do not respond to the negative feedback of GH 45 and have high gastric acid secretion.
CRH was the first hypothalamic-releasing hormone to be recognized. However, it was not until that Vale and his colleagues first reported the isolation and characterization of ovine CRH as a amino acid peptide. Immunoreactive CRH was found in the posterior pituitary, thalamus, cerebral cortex, cerebellum, pons, medulla oblongata, and spinal cord.
There is evidence that CRH, like GnRH, is released in regular episodic pulses from a pulse generator intrinsic to the hypothalamus Fig. Pulsatile release of corticotropin-releasing hormone CRH from the hypothalamus of the cynomolgus monkey. The regular pulses, occurring at minute intervals, are reminiscent of the gonadotropin-releasing hormone pulse generator.
Endocrinology , In initial studies, intracerebroventricular injection of CRH in rats activated the sympathetic nervous system, which increased plasma levels of epinephrine, norepinephrine, glucose, glucagon, and insulin. CRH may also play a role in depression, because elevated concentrations of CRH-like peptides have been reported in the cerebrospinal fluid of depressed patients.
Outside the central nervous system, CRH has been localized to pancreas, stomach, duodenum, liver, lung, placenta, and adrenal gland. In clinical studies, the half-life of human CRH is 5 minutes when injected into the circulation. Knockout mice have a decreased glucocorticoid response to stress, with males much more severely affected. The most interesting finding in CRH-deficient mice was the effect of CRH deficiency on the offspring; lack of lung maturation led to neonatal death within 12 hours of life.
The mice could be rescued by the administration of glucocorticoid to the maternal drinking water. Mice deficient in CRH receptor type 1 also show glucocorticoid deficiency but display increased exploratory activity and decreased anxiety, suggesting a role for CRH in stress and the anxiety response. CRH administration is limited to research and diagnostic applications. CRH may be useful in the differentiation between pituitary and nonpituitary Cushing's syndrome. A new member of the CRH family, urocortin, was cloned from rat brain.
The most recent hypothalamic-releasing factor to be characterized, sequenced, and synthesized is growth hormone-releasing hormone GHRH.
Because many brain peptides have been localized outside the central nervous system, it was not surprising that GHRH was isolated from two patients with pancreatic tumors that induced acromegaly. From these tumors, two peptides 40 and 44 amino acids long were isolated that possessed GH-releasing properties.
Studies in patients with acromegaly have demonstrated no significant different responses to GHRH, 72 whereas in patients with hyperprolactinemia and galactorrhea responses to GHRH are blunted.
A number of other neuropeptides that are localized to the circumventricular nuclei have been shown to modulate release of prolactin, GH, and GnRH. To review the interaction of these peptides is beyond the scope of this chapter; however, four of the better-known neuropeptides are discussed. Neuropeptide Y NPY is the most abundant neuropeptide in the brain. It is one of several gastrointestinal peptides that are also localized in the CNS.
NPY shares many similarities with the pancreatic family of peptides, showing a high degree of homology to peptide YY and pancreatic peptide Table 1. There is considerable evidence that NPY plays a significant role in the regulation of appetite, body weight, and reproduction.
In this capacity, NPY may be an important factor in the complex interplay between nutrition and reproduction. NPY is a amino acid peptide and is the only member of the pancreatic peptide family with localization in the CNS. NPY has a CNS distribution that is similar to somatostatin and is localized to the many hypothalamic nuclei, including the arcuate nucleus, median eminence, amygdala, septum, cortex, and the hippocampus.
Considerable evidence supports a major role for NPY in the control of reproductive function. The stimulatory effect of NPY on LH release was later shown to be mediated by an increase in the hypothalamic release of GnRH, in estrogen-treated animals or tissues. NPY has a pronounced inhibitory effect on sexual behavior. NPY is recognized as the most potent appetite-stimulating substance in the brain.
Injection of NPY into the brains of satiated rats consistently stimulates ongoing feeding behavior and the development of obesity. Evidence that NPY is an endogenous appetite stimulator came from the neutralization of NPY by administration of NPY antibody, which eliminated the normal feeding pattern of rats.
It was expected that a mouse deficient in NPY would display alterations in feeding behavior and body weight, but this is not the case. NPY-deficient mice maintain a normal body weight and have normal reproductive function.
Surprisingly, NPY-deficient mice have an increased propensity for seizure activity. Galanin is an important neurosecretory peptide. Originally isolated in in extracts of porcine intestine, galanin is composed of 29 amino acids in all species except humans, in whom it is 30 amino acids long. Galanin is recognized as a neurosecretory peptide, with wide distribution in the central nervous system.
Most important is its secretion from the hypothalamus, which also has a high concentration of galanin receptors. There is evidence that hypothalamic galanin has physiologic roles involving feeding, cognition, gastrointestinal function, and regulation of hypothalamic and pituitary hormone secretion. The galanin gene was cloned in from rat pituitary and hypothalamus. Like all other neurosecretory peptides, the galanin receptor GALR is a member of the G protein-coupled receptors with seven transmembrane domains.
The first GALR was cloned from a human melanoma in Galanin has a well-recognized role in reproductive function. One of the first indications of this action was the demonstration that galanin expression is markedly stimulated by estrogen. In this regard, galanin secretion is modulated by estrogen and testosterone levels and varies with the estrus cycle, peaking in proestrus with the LH surge. Galanin, in conjunction with NPY and other hypothalamic neuropeptides, has a well-characterized role in the regulation of feeding and body weight.
There is evidence that galanin secretion from one particular site within the hypothalamus, the anterior paraventricular nucleus, mediates these effects. These effects tend to increase body weight, especially of adipose tissue. A knockout mouse for the galanin gene has been developed and characterized. The mice have a normal body weight compared with wild-type littermates. The mice do demonstrate a significant reduction in pituitary prolactin content, supporting an important role of galanin in the development or maintenance of the lactotroph cell.
Mammary development was also delayed. Affected mothers cannot lactate, so that the pups die shortly after birth if not transferred to a foster mouse.
The mice also demonstrate several neurologic abnormalities, including important changes in the responses of sensory neurons to injury and pain. Two neurosecretory peptides, NPY and galanin, play major physiologic roles in nutrition and reproduction, suggesting that these peptides may be involved in the reproductive changes seen in disorders such as anorexia nervosa and the chronic anovulation of obesity.
The most important part of this puzzle was the discovery of the obesity hormone leptin. Produced by fat tissue, circulating levels of leptin correlate directly with the amount of adipose tissue present. In this model the "lipostat" hypothesis of body weight regulation , leptin serves as the feedback signal to the hypothalamus that allows the animal to maintain body weight in a narrow range, despite daily fluctuations in food consumption and energy expenditure.
It is likely that the primary mechanism by which leptin modulates appetite and energy balance is through its effects on NPY, galanin, and possibly other neurosecretory peptides, such as melanin-concentrating hormone MCH , opiates, and CRH. Taken together, the interaction of leptin, NPY, galanin, and other neuropeptides is beginning to shed light on the long-recognized link between nutritional status and reproductive function.
Substance P was one of the first nonhypothalamic-releasing hormones shown to affect pituitary function. It is related to the tachykinin family of neuropeptides and has been localized to the brain stem, amygdala, cortex, medulla, and hippocampus. Although angiotensin II is well known for its regulation of salt-water balance, this octapeptide is also found in the paraventricular and supraoptic nuclei.
It is often colocalized with another osmoregulating hormone, vasopressin. With regard to its modulatory role on pituitary function, angiotensin II has been shown to stimulate LH release and inhibit prolactin release.
For many years, the existence of endogenous opiate compounds similar to morphine was postulated. However, it was not until that two endogenous opiate-like substances, methionine enkephalin and leucine enkephalin, were discovered by Hughes and coworkers. These observations led to a series of elegant experiments by Eipper and Main. This precursor was subsequently named proopiomelanocortin POMC.
The sequence for POMC was determined by genetic engineering techniques. Since the discovery of the POMC family of peptides, three other classes of opioid peptides have been characterized: enkephalins, dynorphins, and the newest opioid peptide, nociceptin or orphanin FQ. The endogenous opiate peptides are all derived from posttranslational processing of larger precursor peptides i.
Preproenkephalin A is processed to yield four met-enkephalins, one leu-enkephalin, and two other modifications of met-enkephalin. Preprodynorphin, or preproenkephalin B, gives rise to dynorphins A and B, and neoendorphin. In a similar manner, nociceptin and perhaps other uncharacterized peptides are derived from pronociceptin. The primary action of the opioidergic peptides is through binding to specific opioid receptors.
In the past, pharmacologic studies suggested the presence of many different opiate receptor subtypes. Molecular biologic techniques have determined four major classes of opioid receptors, each arising from a separate gene. A fourth opiate receptor, known as ORL-1, was cloned in Proposed functions include pain, appetite, diuresis, and neuroendocrine regulation.
Pharmacologic data are largely derived from studies on the guinea pig ileum, which has a high density of these receptors. In the search for opioid receptor subtypes, a fourth opioid receptor, initially designated an "orphan opiate receptor" or ORL-1, was identified. The POMC-derived peptides have a ubiquitous distribution and have been identified in the placenta, gastrointestinal tract, and brain Table 4.
TABLE 4. Distribution of Proopiomelanocortin-Derived Peptides. Pituitary gland Male reproductive tract Vas deferens Epididymis Seminal vesicles. Placenta Gastrointestinal tract Stomach Pancreas Intestine. Lung Adapted from Krieger DT: The multiple faces of proopiomelanocortin, a prototype precursor molecule. Clin Res , The enkephalin family of peptides is also widely distributed in the brain, with the concentrations of met-enkephalin exceeding leu-enkephalin by a ratio.
Areas that have high concentrations include medial hypothalamus, amygdala, mesencephalon globus pallidus, and the substantia gelatinosa of the spinal cord.
The third major opioid peptide group, dynorphin, has been localized to the supraoptic and paraventricular nucleus of the hypothalamus and the posterior pituitary. Nociceptin and its receptor are widely distributed in the central nervous system, where it has a primarily inhibitory effect. Nociceptin is highly expressed in the hippocampus, stria terminalis, amygdaloid nucleus, and selective thalamic nuclei.
Measurement of these peptides requires confirmation by rigorous chromatographic characterization. Beyond the analgesic effects of opiates, the behavioral effects in humans have not been well characterized. After one dose of morphine, human volunteers report a positive euphoric effect, mild nausea, giddiness, and a subjective sense of mental clouding. In contrast, injection of nociceptin into mice increases their sensitivity to pain hence the name nociceptin.
Animal studies suggest that the opioidergic system may influence memory, blood pressure, temperature, feeding, and sexual activity.
These findings are not surprising, because it appears that the opioidergic system can modulate other major neuron systems. Opioid Modulation of Anterior Pituitary Function. Two approaches have been used to study the effects of opiates.
In initial studies, morphine or opiate analogs were administered to animals or humans, and corresponding changes in hormonal levels were measured.
While the anterior lobe shoulders most of the work in producing hormones, the posterior lobe stores and releases only two: oxytocin and antidiuretic hormone ADH , or vasopressin. Secretes in response to uterine distention and stimulation of the nipples. Stimulates smooth muscle contractions of the uterus during childbirth, as well as milk ejection in the mammary glands. Secretes in response to dehydration, blood loss, pain, stress; inhibitors of ADH secretion include high blood volume and alcohol.
Decreases urine volume to conserve water, decreases water loss through sweating, raises blood pressure by constricting arterioles. Even though it's very small, the pituitary gland isn't free from ailment—nothing is completely foolproof, after all. Most disorders of the pituitary glands are tumors, which are common in adults. These growths are not considered brain tumors, nor are they always malignant.
In fact, they're almost always benign in nature! There are two types of pituitary tumors—secretory and non-secretory. A secretory tumor produces too much of a hormone, while a non-secretory tumor does not.
Regardless, if the tumor is big enough, it can hinder normal pituitary function. These tumors can be removed, or monitored and controlled with medication.
Problems caused by tumors fall into certain categories:. Hyposecretion: Too little of a hormone is produced, interfering in normal function. Hypersecretion: Too much of a hormone is produced, interfering in normal function. Mass effects: The tumor presses on the pituitary or other areas of the brain, causing pain, vision issues, or other problems.
While the pituitary and hypothalamus can run into the above issues, on the whole they work a balancing act on your body. So the next time you're feeling juuuust right , you can thank the pituitary, hypothalamus, and all the other organs of the endocrine system. The pituitary gland is cradled within the sellaturcica of the sphenoid bone of the skull. It consists of two lobes that arise from distinct parts of embryonic tissue: the posterior pituitary neurohypophysis is neural tissue, whereas the anterior pituitary also known as the adenohypophysis is glandular tissue that develops from the primitive digestive tract.
The hormones secreted by the posterior and anterior pituitary, and the intermediate zone between the lobes are summarized in Table 1. Figure 1. The hypothalamus region lies inferior and anterior to the thalamus. It connects to the pituitary gland by the stalk-like infundibulum. The pituitary gland consists of an anterior and posterior lobe, with each lobe secreting different hormones in response to signals from the hypothalamus. The posterior pituitary is actually an extension of the neurons of the paraventricular and supraoptic nuclei of the hypothalamus.
The cell bodies of these regions rest in the hypothalamus, but their axons descend as the hypothalamic—hypophyseal tract within the infundibulum, and end in axon terminals that comprise the posterior pituitary Figure 2. Figure 2. Neurosecretory cells in the hypothalamus release oxytocin OT or ADH into the posterior lobe of the pituitary gland.
These hormones are stored or released into the blood via the capillary plexus. The posterior pituitary gland does not produce hormones, but rather stores and secretes hormones produced by the hypothalamus.
The paraventricular nuclei produce the hormone oxytocin, whereas the supraoptic nuclei produce ADH. These hormones travel along the axons into storage sites in the axon terminals of the posterior pituitary.
In response to signals from the same hypothalamic neurons, the hormones are released from the axon terminals into the bloodstream. Throughout most of pregnancy, oxytocin hormone receptors are not expressed at high levels in the uterus. Toward the end of pregnancy, the synthesis of oxytocin receptors in the uterus increases, and the smooth muscle cells of the uterus become more sensitive to its effects.
Oxytocin is continually released throughout childbirth through a positive feedback mechanism. As noted earlier, oxytocin prompts uterine contractions that push the fetal head toward the cervix. In response, cervical stretching stimulates additional oxytocin to be synthesized by the hypothalamus and released from the pituitary. This increases the intensity and effectiveness of uterine contractions and prompts additional dilation of the cervix.
The feedback loop continues until birth. As the newborn begins suckling, sensory receptors in the nipples transmit signals to the hypothalamus.
In response, oxytocin is secreted and released into the bloodstream. Secondly, in both males and females, oxytocin is thought to contribute to parent—newborn bonding, known as attachment.
Oxytocin is also thought to be involved in feelings of love and closeness, as well as in the sexual response. The solute concentration of the blood, or blood osmolarity, may change in response to the consumption of certain foods and fluids, as well as in response to disease, injury, medications, or other factors. Blood osmolarity is constantly monitored by osmoreceptors —specialized cells within the hypothalamus that are particularly sensitive to the concentration of sodium ions and other solutes.
In response to high blood osmolarity, which can occur during dehydration or following a very salty meal, the osmoreceptors signal the posterior pituitary to release antidiuretic hormone ADH. The target cells of ADH are located in the tubular cells of the kidneys.
Its effect is to increase epithelial permeability to water, allowing increased water reabsorption. The more water reabsorbed from the filtrate, the greater the amount of water that is returned to the blood and the less that is excreted in the urine. A greater concentration of water results in a reduced concentration of solutes. Thus, the anterior pituitary contains at least six distinctive endocrinocytes. The cells that secrete thyroid-stimulating hormone do not also secrete growth hormone, and they have receptors for thyroid-releasing hormone, not growth hormone-releasing hormone.
The image below is of a section of canine anterior pituitary that was immunologically stained for luteinizing hormone black stain and prolactin purple stain. The unstained cells in the image are those that secrete the other pituitary hormones. Anatomy of the Hypothalamus and Pituitary Gland. Growth Hormone.
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