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Neuroendocrinology refers to the general area of endocrinology in which the nervous system interacts with the endocrine system, serving to link aspects of cognitive and noncognitive neural activity with metabolic and hormonal homeostatic activity. Neural cells that can secrete hormones, i.e., neurosecretory cells, serve as the final common pathway linking the brain with the endocrine system. The neurohypophyseal neurons originate from the paraventricular and supraoptic nuclei, traverse the hypothalamic-pituitary stalk, and release vasopressin and oxytocin from nerve endings in the posterior pituitary. The hypophysiotropic neurons, localized in specific hypothalamic nuclei, project their axons to the median eminence to secrete their peptide and bioamine release and inhibiting hormones into the proximal end of the hypothalamic-pituitary portal vessels (Fig. 201-1) (Figure Not Available) . Neurons from other nuclei within the hypothalamus and other parts of the brain influence pituitary hormone secretion by interacting with these specific neurons. The median eminence receives its blood supply from the superior hypophyseal artery, which arborizes into a rich capillary bed. The capillary loops extend into the median eminence and coalesce to form the long portal veins that traverse the pituitary stalk and end in the pituitary. The capillary walls are "fenestrated," allowing entry of peptides secreted by the axon terminals. At the pituitary end of the stalk, the portal vessels again branch to form an extensive capillary plexus.
The neuroendocrine system operates through a series of feedback loops that control pituitary and target organ hormone levels precisely. Target organ hormones feed back at both the hypothalamic and pituitary levels to complete the loop, and efferent controller factors from the hypothalamus include both stimulatory and inhibitory substances. The feedback loops can be perturbed, resulting in temporary or prolonged alterations of set points by such factors as length of day (circadian periodicity), stress, nutritional status, and systemic illness. The suprachiasmatic nuclei, located just above the optic chiasm, are important in regulating circadian rhythms of the body.
The regulation of pituitary hormones by hypophysiotropic hormones is quite complex, in part because of the multiplicity of substances present in the hypothalamus that can affect pituitary hormone secretion and in part because of the redundancy and overlapping nature of the feedback loops. In addition, some hypophysiotropic hormones exert effects on more than one pituitary hormone (Fig. 201-2) . Some of the hypophysiotropic hormones are also found elsewhere in the body, particularly the gastrointestinal tract and placenta, in which they may have significant physiologic functions. All of the hypophysiotropic hormones are also present in extrahypothalamic brain and function as neurotransmitters. Several hormones can occur in the same hypothalamic nucleus. In each instance, the action of the hypophysiotropic hormone is mediated first by binding to specific receptors and then by alteration of intracellular transduction mechanisms.
TRH is a tripeptide whose secretion is stimulated by norepinephrine and dopamine and inhibited by serotonin. The primary neuroendocrine functions of TRH are to stimulate the synthesis and release of thyroid-stimulating hormone (TSH) and prolactin (PRL). It has been estimated that a single molecule of TRH, through its TSH-releasing effect, induces the release of > 100,000 molecules of thyroxine from the thyroid. In hypothyroidism, TRH synthesis and binding to the pituitary are increased, resulting in increased basal and TRH-stimulated TSH and PRL levels. Correction of the hypothyroidism with thyroid hormones decreases the elevated TSH and PRL levels. Conversely, in hyperthyroidism, basal and TRH-stimulated TSH levels are markedly suppressed; basal PRL levels are not low, but the PRL response to TRH is markedly blunted and returns to normal with correction of the hyperthyroidism. The feedback effects of
Figure 201-1 (Figure Not Available) Neuroendocrine organization of the hypothalamus and pituitary
gland. The posterior pituitary is fed by the inferior hypophyseal
artery and the hypothalamus by the superior hypophyseal artery, both
branches of the internal carotid artery. Most of the blood supply to the
anterior
pituitary is venous by way of the long portal vessels, which connect the
portal capillary beds in the median eminence to the venous sinusoids in the
anterior pituitary. Hypophysiotropic neurons (2) terminate in the median
eminence
on portal capillaries. These neurons of the tuberoinfundibular system
secrete hypothalamic hormones into the portal veins for conveyance to the
anterior pituitary gland. Multiple inputs to such neurons can be stimulatory,
inhibitory, or neuromodulatory. Neuron 1 represents a peptidergic neuron
originating in the magnocellular nuclei and projecting directly to the
posterior
pituitary by way of the hypothalamic-neurohypophyseal tract. Neuron 3
represents a vasopressinergic neuron projecting to the median eminence.
(Modified from Lechan RM: Neuroendocrinology of pituitary hormone
regulation. Endocrinol
Metab Clinic North Am 16:475, 1987.)
Figure 201-2 Interrelationships between hypothalamic and pituitary hormones. (+)
indicates stimulatory effect and (-) indicates inhibitory effect. (See
text for abbreviations.)
Although TRH is the major regulator of TSH synthesis and secretion, the role of TRH as a physiologic PRL-releasing factor remains questionable. TRH can also stimulate growth hormone (GH) secretion in acromegaly, and in several states in which there is decreased insulin-like growth factor-1 (IGF-1) feedback on GH secretion, such as cirrhosis, renal insufficiency, anorexia nervosa, poorly controlled insulin-dependent diabetes mellitus, and malnutrition. Such responses are also seen in patients with depression and schizophrenia, which may be associated with disordered central bioaminergic regulation. TRH can also stimulate FSH secretion in some patients with gonadotroph adenomas but not in normal individuals. Obviously, somatotroph and gonadotroph cells must have TRH receptors, but "activation" of such receptors, which may involve alteration of intracellular transduction mechanisms, occurs only in special circumstances.
GnRH is a 10-amino acid peptide. Embryologic studies suggest that GnRH neurons originally develop in the epithelium of the medial part of the olfactory placode. During fetal development these cells migrate across the cribriform plate, enter the forebrain with the nervus terminalis and vomeronasal nerves, travel medial to the olfactory bulbs, and eventually enter the septal-preoptic region of the hypothalamus. The origin of GnRH-producing neurons from olfactory epithelium is of clinical interest with respect to the development of Kallmann s syndrome, in which GnRH deficiency is associated with anosmia due to agenesis of the olfactory bulbs. At least one form of Kallmann s syndrome is due to a gene defect resulting in loss of function of a protein that facilitates the embryologic migration of these GnRH-producing neurons. GnRH secretion is stimulated by dopamine and norepinephrine and inhibited by serotonin.
The primary function of GnRH is to stimulate the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Although early studies suggested the presence of separate LH- and FSH-releasing factors, there is only one identified GnRH and differential secretion of LH and FSH is due to variations in sensitivity of feedback effects of steroid and peptide hormones and variations in sensitivity to GnRH. GnRH pulsatile secretion also directly up-regulates its own receptors; i.e., it causes an increase in GnRH receptor number. In contrast, continuous administration of GnRH is associated with a down-regulation of gonadotropin synthesis and secretion due to decreased receptor numbers as well as postreceptor mechanisms.
In women, positive and negative steroid hormone feedback regulation of the hypothalamic-pituitary-gonadal axis occurs at both the pituitary and hypothalamic levels, the hypothalamic effects being the alteration of GnRH pulse amplitude and frequency and the pituitary effects being the modulation of the gonadotropin response to GnRH. In the follicular phase of the menstrual cycle estrogen feeds back negatively on gonadotropin secretion. At mid-cycle, estrogen feedback becomes positive and rising estrogen levels from the developing follicle stimulate the ovulatory surge of LH and FSH. Following ovulation, the feedback again becomes negative, and the estrogen and progesterone produced by the corpus luteum result in decreasing levels of LH and FSH. In the male, testosterone decreases GnRH pulsatile secretion with resultant decreased gonadotropin pulse amplitude and frequency as well as the gonadotropin response to exogenous GnRH.
The negative feedback effects of inhibin, a peptide produced by testicular Sertoli cells and ovarian granulosa cells, are predominantly on FSH at the pituitary. Inhibin causes a dose-related decrease in the sensitivity of gonadotrophs to GnRH, but there may also be a hypothalamic site of action. The related ovarian protein, activin, stimulates FSH synthesis and release from the pituitary. Another gonadal peptide, follistatin, also inhibits the oophorectomy-and GnRH-induced rises in FSH selectively, primarily by binding to activin. These ovarian peptides are also found in the pituitary and therefore may have additional local effects on gonadotropin secretion.
The hormone levels and feedback loops mentioned are primarily those of mature adults. In children, gonadotropin and gonadal steroid levels are very low. At puberty, negative feedback of steroid hormones decreases and gonadotropin and steroid levels gradually rise. During this pubertal development, in females the variation in negative and positive estrogen feedback develops, eventually resulting in the ovulatory menstrual cycle. At menopause, ovarian estrogen production ceases, gonadotropin levels rise markedly, and the symptoms associated with estrogen deficiency develop. In men, aging sometimes produces a decrease in testosterone production with a modest rise in gonadotropins, but there is no clinical syndrome similar to menopause.
GnRH has been successfully administered in a pulsatile manner to individuals with hypogonadotropic hypogonadism due to GnRH deficiency, resulting in restoration of normal sexual function and fertility. Long-acting GnRH agonists have been used to down-regulate GnRH receptors and gonadotropin secretion in a variety of conditions, including precocious puberty, prostate cancer, breast cancer, uterine fibroids, and endometriosis. Direct GnRH antagonists that competitively compete for the GnRH receptor are being explored for similar conditions.
Somatostatin (also known as somatotropin release-inhibiting factor (SRIF)) is a tetradecapeptide; a 28-amino acid precursor also has GH inhibitory properties. Somatostatin blocks the rise in GH that occurs with all stimuli in a dose-dependent manner. The interaction of somatostatin and growth hormone-releasing hormone (GHRH) on GH secretion is complex. GH secretory episodes are associated with increased GHRH secretion often accompanied by low somatostatin levels; the basal or trough GH levels are associated with low GHRH levels and more elevated somatostatin levels. Somatostatin also inhibits basal and stimulated TSH secretion. However, dose-response studies in humans using somatostatin infusions have shown that GH is about 10-fold more sensitive to inhibition by somatostatin than is TSH. This suggests that the physiologic role of somatostatin in inhibiting TSH secretion is limited.
Somatostatin is also present in the D cells of the pancreatic islets and the gut mucosa as well as the myenteric neural plexus. Via paracrine and endocrine actions it suppresses the secretion of insulin, glucagon, cholecystokinin, gastrin, secretin, vasoactive intestinal polypeptide (VIP), and other gastrointestinal hormones, as well as such functions as gastric acid secretion, gastric emptying, gallbladder contraction, and splanchnic blood flow. Recently, analogues of somatostatin have been found to be effective in the treatment of acromegaly, carcinoid tumors, VIP-secreting tumors, TSH-secreting pituitary tumors, islet-cell tumors, and diarrhea of a number of causes.
CRH releases ACTH, beta-endorphin, beta-lipotropin, melanocyte-stimulating hormone (MSH), and other peptides generated from pro-opiomelanocortin (POMC) in equimolar amounts. CRH mediates 75% of the ACTH response to stress, and the remaining 25% is due to vasopressin. CRH and vasopressin have synergistic effects on ACTH release. In fact, CRH and vasopressin coexist in about half of the CRH-containing paraventricular neurons and even in the same neurosecretory granules. CRH and vasopressin are not always released coordinately, however, and stress has been shown to selectively activate the vasopressin-containing subset of CRH neurons.
Cortisol feeds back to decrease ACTH secretion at both the hypothalamic and pituitary levels. ACTH and beta-endorphin also feed back negatively to decrease CRH release by the hypothalamus. Morphine suppresses the ACTH response to CRH in humans, acting presumably through opioid µ receptors. Central bioamines and peptides
Monokines released by inflammatory tissue, such as interleukin-1 and tumor necrosis factor-alpha stimulate the synthesis and release of CRH and vasopressin from the hypothalamus and the release of ACTH by the pituitary. The consequent increase of cortisol then reduces the intensity of the inflammatory response and release of these monokines, completing the feedback loop. Thus, this neuroendocrine-immune loop serves to modulate the inflammatory response.
Both ovine and human CRH have been given to humans in a variety of experimental paradigms, although CRH has not yet been approved by the U.S. Food and Drug Administration for commercial use. These preparations have been found to be of some use in stimulating ACTH secretion during petrosal sinus sampling in the differential diagnosis of Cushing s disease versus ectopic ACTH syndrome.
GHRH dose-dependently stimulates GH secretion, and in some individuals GHRH is capable of eliciting a small increase in PRL as well. With repetitive administration every 3 hours, GHRH can cause the release of sufficient GH in children with GHRH deficiency to result in an increase in IGF-I levels and an acceleration of growth. Both IGF-I and GH itself feed back negatively on GH secretion, mediated by both a decrease in GHRH and an increase in somatostatin. This feedback effect of IGF-I is clinically relevant, as documented by the high circulating GH levels that occur in IGF-I-deficient states, such as renal insufficiency and cirrhosis. In children with mutations of the GH receptor resulting in their not being responsive to GH (GH insensitivity syndrome, also known as Laron-type dwarfism), IGF-I levels are very low and GH levels are correspondingly elevated. alpha2 -Adrenergic receptors and serotonin activate GHRH and GH secretion, but gamma-aminobutyric acid (GABA) is inhibitory to GHRH secretion.
The inhibitory component of hypothalamic regulation of PRL secretion predominates over the stimulatory component. Dopamine (DA) is the predominant, physiologic PIF, and the concentration of DA found in the pituitary stalk plasma is sufficient to decrease PRL levels. It is likely that in most physiologic circumstances that cause a PRL rise, such as lactation, there is a simultaneous fall in DA along with a rise in a PRL-releasing factor (PRF), such as vasoactive intestinal peptide (VIP). Blockade of endogenous DA receptors by a variety of drugs, such as the neuroleptics, causes a rise in PRL. Lesions that interrupt the basal hypothalamic neuronal pathways carrying dopamine to the median eminence or that interrupt portal blood flow result in decreased dopamine reaching the pituitary and hyperprolactinemia.
A number of hypothalamic peptides other than TRH have also been shown to have PRF activity. VIP stimulates PRL synthesis and release at concentrations found in hypothalamic-pituitary portal blood. Within the VIP precursor is another similarly sized peptide known as peptide histidine methionine (PHM), which also has PRF activity. Complicating the role of VIP as a PRF is the finding that VIP is also synthesized by anterior pituitary tissue. The precise roles of VIP versus PHM and hypothalamic VIP versus pituitary VIP still are not clear.
The endogenous opioid peptides have only a minor role in neuroendocrine regulation. There are three major opioid peptide receptors and three major groups of opioid peptides, but the correspondence is not one for one. The µ receptor mediates most of the endocrine effects and analgesia; morphine is its prototypic agonist and naloxone is its prototypic antagonist; the primary peptide ligand for the µ receptor is beta-endorphin. The delta receptor mediates behavioral, analgesic, and some endocrine effects and has as its primary peptide ligands met- and leuenkephalins, which are derived from proenkephalin A. The kappa receptor mediates sedation and ataxia and binds primarily dynorphin and the neoendorphins, which are derived from proenkephalin B (prodynorphin). All neuronal perikarya containing POMC-derived peptides are located in the arcuate nucleus, from which beta-endorphin-and alpha-MSH-containing fibers project to the median eminence, other parts of the hypothalamus, and other areas of the brain. Anterior pituitary beta-endorphin is secreted with ACTH with CRH and vasopressin stimulation.
Various opioid peptides are linked to a number of bodily functions, including stress, mental illness, narcotic tolerance and dependence, eating, drinking, gastrointestinal function, learning, memory, reward, cardiovascular responses, respiration, thermoregulation, seizures, brain electrical activity, locomotor activity, pregnancy, and neuroimmune activity. The anterior pituitary itself is poor in opioid receptors, but the hypothalamus is quite rich. It has been suggested that the effects of opioid peptides on anterior pituitary hormone secretion occur via modulation of hypothalamic bioamines and hypophysiotropic factors. In general, endogenous opioids have an inhibitory influence on gonadotropin secretion through action on GnRH secretion, probably by inhibition of noradrenergic neuronal input. Opioids feed back negatively on ACTH and beta-endorphin secretion and naloxone can increase basal and stimulated ACTH levels. Endogenous opioids have minimal effects on GH, PRL, and TSH secretion.
Pituitary hormones are secreted in a pulsatile fashion with a number of rhythms superimposed. The pulse amplitude of a pituitary hormone reflects the amount of releasing hormone as well as factors that may alter sensitivity to that releasing hormone. Thus, the amplitude can be altered by inhibitory factors (e.g., GHRH versus somatostatin), nutritional factors, feedback effects of target organ hormones, and prior stimulation that depletes a readily releasable pool of hormone. The frequency is generally governed by the frequency of release of the hypophysiotropic factor, regulated by the hypothalamic pulse generator system.
The pituitary has an intrinsic rhythm of small amplitude with a frequency of every 2 to 10 minutes. Superimposed upon this intrinsic rhythm is that from the pulsatile release of hypophysiotropic releasing factors, with or without the withdrawal of a corresponding inhibitory factor. Rhythms that are shorter than a day are referred to as ultradian rhythms. The next layer of rhythmicity is the circadian rhythm, i.e., rhythms with approximately 24-hour periodicity. These rhythms are usually synchronized with the 24-hour period by a periodic environmental cue, such as the dark-light cycle. The suprachiasmatic nucleus functions as a circadian pacemaker and receives light-induced electrical impulses from the retina via the retinohypothalamic tract, finally transmitting those impulses to the pineal, where they are converted to hormonal signals. Signals for a rhythm with a periodicity longer than 24 hours, i.e., an infradian rhythm, include the gravitational influence of the moon, giving rise to the menstrual cycle.
A number of factors may influence circadian and infradian rhythms. One of the most important is the sleep-wake cycle. GH, TSH, PRL, ACTH, and pubertal LH secretion are all entrained more to the sleep-wake cycle than the dark-light cycle. Each has an increase and maximal level that occur following sleep onset. The profound diurnal variation of cortisol and ACTH is often used as an index of "normality" of the system. Loss of this diurnal rhythm occurs with disordered regulation by CRH, which may be due to endogenous depression or excessive alcohol intake, as well as autonomous secretion of ACTH in Cushing s disease. Loss of diurnal rhythm of cortisol has been used as a diagnostic test for Cushing s syndrome.
Interesting changes occur in gonadotropin secretion as the child passes through puberty into adulthood. Early in puberty the amplitude of pulses increases during sleep at night, especially for LH, but in adulthood this nocturnal rise is lost. In patients with anorexia nervosa, the pattern of gonadotropin secretion often reverts to this pubertal pattern, only to lose this pattern again with weight gain. This suggests that body composition may in some way affect the regulation of the pulsatile secretion of the gonadotropins. In fact, the percentage of body composition that is fat has been proposed as being important in the timing of the onset of puberty.
Endocrine rhythms appear to reflect a rather primitive organizing influence that helps the animal to adapt to the environment. The circadian synchronization with the light-dark cycle and sleep and the infradian synchronization with seasonal changes are present very early phylogenetically. However, because humans are able to alter
Frohman LA, Downs TR, Chomzczynski P: Regulation of growth hormone secretion. Front Neuroendocrinol 14:344, 1992. A thorough, molecularly oriented review of the regulation of GH secretion.
Lechan RM: Neuroendocrinology of pituitary hormone regulation. Endocrinol Metab Clinic North Am 16:475, 1987. An excellent discussion of the anatomic features of neuroendocrine regulation. MRI scans and accompanying diagrams clarify hypothalamic structural anatomy.
Orth DN: Corticotropin-releasing hormone in humans. Endocr Rev 13:164, 1992. A thorough review of CRH: its tissue distribution, blood levels, responses to its administration in normals and patients, its diagnostic use, and its secretion ectopically.
Reichlin S: Neuroendocrine-immune interactions. N Engl J Med 329:1246, 1993. A critical review of the various interactions between the endocrine and the immune systems, including possible psychological influences. It asks more questions than it answers in this exciting new field.
Schwanzel-Fukuda M, Jorgenson KL, Bergen HT, et al.: Biology of normal luteinizing hormone-releasing hormone neurons during and after their migration from olfactory placode. Endocrine Rev 13:623, 1992. Reviews the fascinating unfolding story regarding the migration of GnRH neurons from the olfactory placode to the hypothalamus. Defects in this migration result in Kallman s syndrome.
Van Cauter E: Diurnal and ultradian rhythms in human endocrine function: A minireview. Horm Res 34:45, 1990. Reviews the physiology and clinical relevance of the rhythms characterizing hormone secretion.
Diseases may affect the hypothalamus by being localized to the hypothalamus, by being part of more generalized central nervous system (CNS) disease, such as neurosarcoidosis, or by indirect means, such as by causing hydrocephalus (Table 201-1) (Table Not Available) . Furthermore, hormonal changes may occur in a variety of psychiatric disorders, mediated by functional alterations in hypothalamic regulation.
The axons projecting to the median eminence that contain the various hypophysiotropic factors are concentrated in the basal portion of the hypothalamus. Thus, lesions located within this final common pathway might be expected to cause significant decreases in the secretion for some or all of the pituitary hormones except PRL, which may increase because of the elimination of the tonic inhibition by dopamine. Diabetes insipidus may also occur. Other functions of the hypothalamus are more diffusely located, such as the regulation of temperature, food intake, and blood pressure.
Symptoms due to hypothalamic dysfunction are related to size of the lesion and consequently to the area of the hypothalamus involved, as well as to the rapidity of increase in lesion size. Slowly growing lesions tend to cause problems of hormone dysregulation rather than dramatic symptoms. Large, slowly growing lesions can cause more acute problems, however, when a slight increment in growth eliminates remaining vestiges of vasopressin or ACTH secretion or completely occludes the aqueduct of Sylvius, causing hydrocephalus.
The best way of discerning lesions affecting the hypothalamus is by magnetic resonance imaging (MRI) with gadolinium enhancement, although computed tomographic (CT) scanning with intravenous contrast is also quite good. Formal visual field testing may discern impingement of the optic nerves and chiasm by hypothalamic lesions, including the suprasellar extension of pituitary tumors. Detailed testing of hypothalamic-pituitary function may reveal evidence of functional hypothalamic disruption with great sensitivity.
The most common embryopathic disorders to affect the hypothalamus are the midline cleft syndromes, which cause varying degrees of defects of midline structures, especially the optic and olfactory tracts, the septum pellucidum, the corpus callosum, the anterior commissure, the hypothalamus, and the pituitary. The clinical presentation of patients with midline cleft defects varies in severity from cyclopia to cleft lip and from isolated hypothalamic hormone defects to panhypopituitarism. The combination of absent septum pellucidum associated with optic nerve hypoplasia is referred to as septo-optic dysplasia and is associated with abnormalities of hypothalamic and other diencephalic
Kallmann s syndrome is an autosomal dominant condition characterized by anosmia or hyposmia and hypogonadotropic hypogonadism. It is due to a gene defect resulting in loss of function of a protein that facilitates the embryologic migration of GnRH-producing neurons. The pituitary is usually intact, and treatment with pulsatile GnRH therapy or gonadotropins results in spermatogenesis and normal gonadal function. In some patients, other neurologic abnormalities may be present, including cerebellar ataxia, nerve deafness, color blindness, cleft lip and palate, mental retardation, and disordered thirst.
The most common tumors affecting the hypothalamus are pituitary adenomas that have significant suprasellar extension. These tumors can cause varying degrees of hypopituitarism, diabetes insipidus, and hyperprolactinemia by either compressing the normal pituitary or, more commonly, affecting the pituitary stalk and mediobasal hypothalamus. Evidence that hypopituitarism is from pituitary compression includes a low serum PRL level and a lack of TSH response to TRH; pituitary function in such cases usually
Craniopharyngiomas are the next most common tumors affecting the hypothalamus. Microscopically, craniopharyngiomas consist of cysts alternating with stratified squamous epithelium. The cyst fluid is usually thick and dark and the material is often calcified. They arise from remnants of Rathke s pouch. A closely related, less common lesion is Rathke s cleft cyst, which develops from the space between the anterior and rudimentary intermediate lobes. Rathke s cleft cysts are lined with cuboidal as opposed to squamous epithelium, and the cyst fluid is usually white and mucoid. Craniopharyngiomas sometimes recur postoperatively whereas Rathke s cleft cysts rarely recur. Craniopharyngiomas most commonly present during childhood, but they also may occur in adults and even the elderly. These tumors present because of mass effects, including headache, vomiting, visual disturbance, seizures, hypopituitarism, and polyuria. Some patients present with galactorrhea, amenorrhea, and hyperprolactinemia, suggestive of a prolactinoma. Careful endocrine testing reveals varying degrees of hypopituitarism in 50 to 75% and modest hyperprolactinemia in 25 to 50%. Surgical extirpation of craniopharyngiomas commonly causes a worsening of pituitary function, often resulting in complete panhypopituitarism and diabetes insipidus because of stalk section. Irradiation may also be helpful, especially in children.
Suprasellar dysgerminomas arise from primitive germ cells that have migrated to the CNS during fetal life and structurally are identical to germ cell tumors of the gonads. They most commonly occur in children, where they cause decreased growth because of hypopituitarism, diabetes insipidus, and visual problems. Hyperprolactinemia occurs in > 50%, and 10% have precocious puberty due to the production of chorionic gonadotropin by the tumor. As opposed to craniopharyngiomas, these tumors are very radiosensitive, and radiation therapy is the preferred treatment.
A hypothalamic hamartoma is a nodule of growth of hypothalamic neurons attached by a pedicle to the hypothalamus between the tuber cinereum and the mammillary bodies and extending into the basal cistern. Asymptomatic hamartomas may be present in up to 20% of random autopsies; rarely, these lesions may enlarge, causing disruption of hypothalamic function because of compression of adjacent tissue. A variant of the hamartoma consisting of similar tissue within the anterior pituitary but without a neural attachment to the hypothalamus is called a choristoma or gangliocytoma. These neuronal tumors are of particular endocrine interest because they can produce hypophysiotropic hormones. A number of cases associated with precocious puberty have been reported in which the hamartomas produce GnRH. Successful treatment has been reported with surgery and with the administration of a long-acting GnRH analogue, which suppresses gonadotropin secretion but does not affect the tumor itself. Medical therapy with the GnRH analogue may be the best choice, as surgery can be noncurative or even fatal, if the hamartoma does not cause other problems from mass effects. Some gangliocytomas have been reported which produce GHRH and acromegaly and CRH and Cushing s syndrome.
Other tumors and space-occupying lesions occurring in the suprasellar area include arachnoid cysts, meningiomas, gliomas, astrocytomas, chordomas, infundibulomas, cholesteatomas, neurofibromas, lipomas, and metastatic cancer (particularly breast and lung). Any such lesion may present with varying degrees of hypopituitarism, diabetes insipidus, and hyperprolactinemia, and surgical therapy often worsens the hormonal deficit.
CNS involvement in sarcoidosis occurs in 1 to 5% of patients, as determined on clinical grounds, and in up to 16% of cases at autopsy. Isolated CNS sarcoidosis is quite uncommon, however. When sarcoidosis does involve the CNS, the hypothalamus is involved in 10 to 20%. Sarcoid granulomas can involve the hypothalamic stalk or pituitary and may be infiltrative or present as a mass lesion. The most common endocrine findings are varying degrees of hypopituitarism, diabetes insipidus, and hyperprolactinemia. Obesity due to hypothalamic involvement by sarcoidosis has also been reported. In patients with isolated CNS sarcoidosis, the diagnosis may be extremely difficult. Examination of the CSF usually shows elevated protein levels, low glucose levels, a pleocytosis, and variable elevations of angiotensin-converting enzyme. However, biopsy is often necessary. Although corticosteroid therapy has been reported to at least partially reverse the thirst disorders, anterior pituitary hormone deficits usually do not respond. Langerhans cell histiocytosis or eosinophilic granulomatous infiltration of the hypothalamus may cause diabetes insipidus, varying degrees of hypopituitarism, and hyperprolactinemia. It is the most common cause of diabetes insipidus in children. Usually this infiltration appears as a thickening of the pituitary stalk, but it may also appear as a mass lesion of the hypothalamus or the pituitary. Osteolytic lesions may be present in the jaw or mastoid and radiographs of the jaw are a worthwhile part of the diagnostic evaluation of an unknown suprasellar mass or diabetes insipidus for this reason. Therapy consists of local surgery, focal irradiation, or chemotherapy with alkylating agents and high-dose corticosteroids.
An enlarging aneurysm may present as a mass lesion of the hypothalamic-pituitary area and may cause hypopituitarism and visual field defects. Obviously, the distinction must be made before surgery. Tumors and aneurysms may also coexist, and careful radiologic evaluation with MRI is necessary to discern this. Hypothalamic disease due to vascular infarction is extremely rare.
Head trauma can cause defects ranging from isolated ACTH deficiency to panhypopituitarism with diabetes insipidus. Within the first 72 hours of trauma, GH, LH, ACTH, TSH, and PRL levels may actually be elevated in blood, perhaps due to acute release. These levels subsequently fall, and patients either return to normal or develop hypopituitarism. In patients dying of head injury, anterior pituitary infarction has been found in 16% of cases, posterior pituitary hemorrhages in 34%, and hypothalamic hemorrhages or infarction in 42% of cases. The paraventricular and supraoptic nuclei and median eminence are particularly involved with microhemorrhages, resulting in the high frequency of panhypopituitarism with diabetes insipidus. With frontal injuries, the brain travels backward but the pituitary cannot move, resulting in the pituitary stalk becoming avulsed, with interruption of the portal vessels. Most patients with head injury are hyperprolactinemic, confirming clinically that the hypothalamus and/or stalk is the primary site of injury.
Whole brain irradiation for intracranial neoplasms frequently results in hypothalamic dysfunction, as evidenced by endocrine abnormalities and behavioral changes. The most common endocrine abnormality is hyperprolactinemia, but hypopituitarism can also occur. When the radiation therapy is targeted to the hypothalamic area, as in patients with tumors in that area or nasopharyngeal carcinomas, hypopituitarism occurs even more frequently. The frequencies of loss of pituitary function are so high that all patients who have had their pituitary and hypothalamic areas irradiated must be followed closely to detect these deficits when they occur.
Hypothalamic disease can cause both pituitary hyperfunction and hypofunction in varying degrees of severity. Although severe disease can cause absolute deficiencies of the various hormones, milder disease may cause a subtle alteration of feedback loops and timing such that, for example, the integration of signals necessary for menstrual cycling is lost, resulting in "hypothalamic" amenorrhea. Furthermore, the hypothalamic defects may be interrelated, so that the rather common finding of hyperprolactinemia occurring with hypothalamic dysfunction causes a hypogonadotropic hypogonadism that is reversible when the elevated PRL levels are brought down to normal. In many cases no structural lesion can be found on MRI, and a functional defect due to altered neurotransmitter regulation is invoked.
Loss of normal GH secretion is the most common hormonal defect occurring with structural hypothalamic disease. Congenital idiopathic GH deficiency (IGHD) is a heterogeneous disorder consisting of hypothalamic and pituitary defects. The diagnosis is usually made between 1 and 3 years of age because of impaired growth. Between 5 and 30% of IGHD subjects have an affected relative, and thus their defect is thought to have a genetic basis; some have been associated with a deletion of the GH gene. In about three-quarters of cases there is a normal GH response to exogenous GHRH, suggesting that the defect is likely disordered hypothalamic regulation. Children with IGHD should be treated with biosynthetic GH, although experimental studies suggest that GHRH treatment is also often successful. Other hormonal defects that may be present also must be treated simultaneously, although therapy with gonadal steroids should be delayed to prevent epiphyseal closure
The primary defect in this group of disorders involves secretion of GnRH, with resultant impairment in pituitary gonadotropin secretion and gonadal function. The disorders causing these conditions may be primary, i.e., congenital defects, or acquired. Depending upon the time of onset, they present either as delayed puberty, interruption of pubertal progression, or loss of adult gonadal function. The lesions causing these disorders may cause loss of other hormones or may be isolated to GnRH. Loss of gonadotropin secretion as the result of hypothalamic structural damage is the second most common defect after GH deficiency. However, a substantial portion of these defects is due to hyperprolactinemia and is reversible with correction of the hyperprolactinemia.
Lesions presenting prepubertally result in the failure of onset of puberty or incomplete progression of puberty if the defect is partial. If the disorder is limited to GnRH and the gonadotropins, prior growth and development are normal. However, the growth spurt occurring at puberty is lost. The most common congenital lesion causing prepubertal GnRH deficiency is Kallmann s syndrome, comprising 50% of males and 37% of females presenting with isolated gonadotropin deficiency. In patients with idiopathic GnRH deficiency, the GnRH gene appears to be normal. However, indirect measures of functional GnRH secretion show that there may be disorders of pulse amplitude and/or frequency. When hyperprolactinemia occurs before puberty, it can prevent the onset of puberty and must always be looked for in this setting.
The ideal therapy for patients with GnRH deficiency is the replacement of GnRH via subcutaneous administration every 2 hours using a portable pump. This causes a rapid rise in the LH and FSH responses to the GnRH and a rise in testosterone to normal, as well as development of normal spermatogenesis. Similar studies in women result in ovulatory cycles in 80%. In men, comparable results can be obtained with exogenous gonadotropins given three times per week. Replacement with testosterone alone causes adequate androgenization but does not result in an increase in testicular size or in spermatogenesis.
Loss of formerly normal GnRH secretion in adults may be due to structural hypothalamic damage such as a tumor, a functional change unassociated with a detectable lesion, or hyperprolactinemia. Structural disease must be excluded in such patients by CT or MR scanning. Most but not all functional hypogonadotropic hypogonadism occurs in women, the most common causes being weight loss, excessive exercise, or psychogenic stress. In some the exercise results in a loss of body fat not detected with total body weight measures and it is unclear whether the hypogonadism is directly due to the loss of body fat or to the exercise per se. Studies of pulsatile gonadotropin secretion in such patients reveal absent pulses. Usually there is a normal gonadotropin response to injected GnRH. Regain of weight and stopping of the exercise result in resumption of normal gonadal function. Hyperprolactinemia occurring postpubertally can also decrease GnRH and the pulsatile secretion of LH and FSH, resulting in anovulation with oligo/amenorrhea in women and impotence and infertility in men.
Therapy should be directed at the underlying process, if possible. Efforts at weight gain and restricting exercise should be made when appropriate. In idiopathic, functional hypogonadotropic amenorrhea there are two goals: (1) restoration of a normal estrogen status to promote well-being and to prevent osteoporosis and (2) facilitation of ovulation for fertility. The former can generally be achieved with cyclic estrogen and progesterone, whereas the latter may require clomiphene, GnRH, or gonadotropin therapy.
Precocious puberty is defined as the onset of puberty before the ages of 8 in girls and 9 in boys. "Pseudo"-precocious puberty is that due to peripheral (gonadal or adrenal) causes. Central, "true," or GnRH-dependent precocious puberty is characterized by hormonal changes similar to those that occur at the time of normal puberty, i.e., an increase in the pulsatile release of LH, an increase in the gonadotropin response to GnRH, and an increase in gonadal steroid secretion. GnRH-dependent precocious puberty therefore represents a premature activation of this GnRH pulse generator by a variety of lesions, or it may also be idiopathic. Less than one-quarter of cases of central precocious puberty occur in boys, but they tend to have more serious underlying disease. In boys with central, GnRH-dependent precocious puberty, hypothalamic hamartomas account for 38% of cases, other CNS lesions represent 31%, familial disease accounts for 23%, and idiopathic disease accounts for only 8%. The picture is quite different in girls, however, as hypothalamic hamartomas account for only 15% of cases, other CNS lesions represent 14%, the McCune-Albright syndrome (polyostotic fibrous dysplasia) accounts for 6%, and fully 65% are idiopathic. Dysgerminomas in the suprasellar or pineal region can produce hCG, which acts like LH in its stimulation of gonadal function. Usually such tumors cause increased sex steroid formation but fail to cause ovulation.
Therapy of central GnRH-dependent precocious puberty consists of surgical removal of the tumor or medical therapy with a long-acting GnRH analogue. The latter can suppress gonadotropin and sex steroid hormone levels and cause a stabilization or even regression of secondary sex characteristics and a slowing of growth and bone maturation in most cases. When therapy is discontinued at the normal time of puberty, sex steroid levels increase, secondary sexual characteristics again develop, growth increases, and regular menses develop spontaneously. For those patients who do not respond to the GnRH analogues, treatment with medroxyprogesterone acetate or testolactone, an aromatase inhibitor, is indicated.
Structural or infiltrative lesions of the hypothalamus, such as those discussed above, can decrease the amount of dopamine reaching the lactotrophs, causing modest hyperprolactinemia. PRL elevations due to such lesions rarely exceed 150 ng per milliliter and usually are less than 100 ng per milliliter. Similar elevations are also seen in patients with an empty sella. Because their therapy is quite different, it is very important to differentiate nonsecreting pituitary adenomas with extensive suprasellar extension causing PRL elevations in this range from PRL-secreting adenomas which, when of such a large size, usually cause PRL elevations 5 to 50 times higher. A number of medications can cause hyperprolactinemia, primarily by interfering with central catecholamines, dopamine in particular (Table 201-2) (Table Not Available) .
Therapy is generally directed at the underlying cause. The hyperprolactinemia itself may impair gonadal function so that efforts may also be made to lower PRL levels with bromocriptine or other dopamine agonists. PRL levels usually fall quite readily in such patients.
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Idiopathic hyperprolactinemia is a diagnosis of exclusion. PRL levels in this condition are usually < 100 ng per milliliter. In such cases, small pituitary or hypothalamic tumors could exist that are beyond the resolution of current imaging techniques, but when such patients are followed for many years, it is very uncommon for tumors to later be visualized. Idiopathic hyperprolactinemia can cause amenorrhea, galactorrhea, impotence, infertility, and loss of libido, just as occurs with hyperprolactinemia of other causes, and therefore may need to be treated. Premature osteoporosis related to the estrogen deficiency may also occur. The only possible treatment is bromocriptine or another dopamine agonist, and these are successful in > 90% of cases. Alternatively, cyclic estrogen/progesterone replacement may be given, but fertility will not be restored.
Hypothalamic hypothyroidism, also referred to as tertiary hypothyroidism, is due to a central lesion that impairs the secretion of TRH, usually along with loss of other hormones. It occurs considerably less commonly than hypothalamic GH and gonadotropin deficiency. TSH levels in this syndrome generally are normal or even slightly elevated, and the response to TRH is delayed, peaking at 60 to 120 minutes rather than at 20 to 30 minutes. TSH in these patients is biologically less active than normal and binds to the TSH receptor less well owing to altered glycosylation as a result of the TRH deficiency. Treatment is with L-thyroxine.
Hypothalamic ACTH deficiency due to hypothalamic lesions is uncommon. It may occur with loss of other hormones but may also appear as an isolated deficiency. In the absence of CNS lesions or a history of trauma, most cases of isolated ACTH deficiency appear to be a pituitary autoimmune disorder. However, in patients with hypothalamic disease as the cause, basal ACTH levels are low and the ACTH response to injected CRH may be prolonged and exaggerated, much as is the TSH response to TRH. The best test remains the comparison of the ACTH responses to hypoglycemia, which is clearly mediated by the hypothalamus, and to CRH. The ACTH response is low in response to hypoglycemia but increased and delayed in response to CRH in most patients with hypothalamic CRH deficiency. Treatment is with glucocorticoids, and mineralocorticoids are not needed.
Diabetes insipidus can develop as a result of destructive lesions in the supraoptic and paraventricular nuclei or in the mediobasal hypothalamus in the path of the neural fibers containing vasopressin that are passing on to the posterior pituitary. Irritative lesions can trigger the release of vasopressin in an unregulated fashion, resulting in the syndrome of inappropriate ADH (vasopressin) secretion (SIADH).
A number of functions that affect the internal milieu, in addition to anterior and posterior pituitary function, are regulated, at least in part, by the hypothalamus, including temperature control, behavior, consciousness, memory, sleep, food intake, and carbohydrate metabolism.
Body weight is kept relatively constant in nonobese individuals through an integration of a number of factors relating to the intake of nutrients and the output of energy, which are affected by hormonal, environmental, and genetic factors. As with the regulation of hormone secretion, the regulation of food intake can be conceptually regarded as an adjustment of food intake and energy expenditure around "set-points," which may be different for body weight, total body fat, and lean body mass. A number of areas of the hypothalamus are involved in the regulation of energy balance.
Destruction of the mediobasal hypothalamus sometimes inhibits satiety and may result in hyperphagia and hypothalamic obesity. The hyperphagia is due to destruction of noradrenergic fibers originating in the paraventricular nucleus that pass through the mediobasal hypothalamus. Because of their location, such lesions usually also produce hypopituitarism and diabetes insipidus. There are a number of rare syndromes in which obesity is a major part for which a hypothalamic cause has been postulated. Prader-Willi is the most common of these syndromes, occurring in 1 in 25,000 births. It is characterized by hypotonia, obesity, short stature, mental deficiency, hypogonadism, and small hands and feet. About half have a chromosome 15 deletion. In the few cases studied at autopsy, no discernible hypothalamic lesions were detected. In the other syndromes (Laurence-Moon-Biedl-Bardet, Altrom-Hallgren), no specific hypothalamic lesions have been found.
Lesions of the lateral hypothalamus, which destroy nigrostriatal dopaminergic fibers that pass through this area, produce hypophagia along with an increase in peripheral norepinephrine turnover and metabolic rate. This syndrome is very rare, probably owing to the requirement of bilateral lesions. The hormonal changes that occur in anorexia nervosa appear to be all secondary to the weight loss, and there is no evidence for a primary hypothalamic disorder in this syndrome.
Hypothalamic activation as part of the generalized response to stress can cause a release of GH, PRL, and ACTH, which serve as counterregulatory hormones with respect to insulin. Of more importance in the acute response to stress, this hypothalamic response results in sympathetic activation with release of catecholamines that inhibit insulin secretion and stimulate glycogenolysis. In rare circumstances of acute hypothalamic injury from trauma, stroke, or infection, severe hyperglycemia can occur which is similar to the hyperglycemia seen in animals when the floor of the fourth ventricle is pricked with a needle, a phenomenon referred to as "piqure" diabetes by Claude Bernard.
The anterior hypothalamus and preoptic area contain temperature-sensitive neurons that respond to internal temperature changes by initiating certain thermoregulatory responses necessary to maintain a constant temperature. Measures that dissipate heat include cutaneous vasodilation, sweating, panting, and behavioral changes that result in attempts to alter the environment. Measures that increase body heat include increasing metabolic heat production, shivering, cutaneous vasoconstriction, and similar behavioral changes. In humans, much of the increase in metabolic heat production occurs via sympathetic activation. The thermosensitive neurons are affected by endogenous pyrogens and drugs that alter thermoregulation as well as input from thermoreceptors in the skin and spinal cord.
Rare patients have been reported with anterior hypothalamic lesions that caused sustained hypothermia due to failure of heat generation by shivering and vasoconstriction but who had intact heat dissipation or downward resetting of the temperature set point. Paroxysmal hypothermia lasting for minutes to days due to the sudden onset of sweating, vasodilation, and a fall in core temperature has been reported in a number of patients in association with demonstrated lesions such as tumors and agenesis of the corpus callosum. Some of these patients had evidence of other hypothalamic dysfunction, including diabetes insipidus, hypogonadism, and precocious puberty.
Fever as a manifestation of hypothalamic disease is uncommon but has been reported in relation to trauma or bleeding into the region of the anterior hypothalamus. Such fevers rarely persist more than two weeks. Paroxysmal hyperthermia due to hypothalamic dysfunction also occurs. Some cases of paroxysmal hypothermia and hyperthermia respond to anticonvulsant medications, suggesting that the neuronal discharge causing the temperature changes is seizure-like.
Poikilothermia results from the inability to dissipate or generate heat to keep the body temperature constant in the face of varying ambient temperatures. This condition results from bilateral lesions in the posterior hypothalamus and rostral mesencephalon, which are the areas responsible for the final integration of thermoregulatory neural efferents. Patients with this condition do not feel discomfort with temperature changes and are unaware of having a problem. Depending upon the ambient temperature, they may present with life-threatening hypothermia or hyperthermia. Poikilothermia is normally present in infants and frequently occurs in elderly individuals.
Abrahams JJ, Trefelner E, Boulware SD: Idiopathic growth hormone deficiency: MR findings in 35 patients. AJNR 12:155, 1991. In this series of children with idiopathic GH deficiency, a high proportion were found to have structural abnormalities of the pituitary stalk, making these disorders of midline embryologic development. As imaging techniques improve, more and more "idiopathic" disorders may be found to have structural causes.
Chapelon C, Ziza JM, Piette JC, et al.: Neurosarcoidosis: Signs, course and treatment in 35 confirmed cases. Medicine 69:261, 1990. Features of neurosarcoidosis are reviewed and the hypothalamic dysfunction that may occur is described.
Constine LS, Woolf PD, Cann D, et al.: Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 328:87, 1993. In this series of 32 patients, more than two thirds had some hormonal dysfunction 2 to 13 years following cranial irradiation. Studies like this point out the need for endocrine evaluation of all patients undergoing cranial irradiation.
Loes DJ, Barloon TJ, Yuh WTC, et al.: MR anatomy and pathology of the hypothalamus. AJR 156:579, 1991. This article shows what can be achieved with modern imaging techniques. Hypothalamic anatomy and pathology are shown with great clarity.
Molitch ME: Pathologic hyperprolactinemia. Endocrinol Metab Clin North Am 21:877, 1992. Covers current knowledge of regulation of prolactin secretion, various causes of hyperprolactinemia, and therapies available.
Stein DT: New developments in the diagnosis and treatment of sexual precocity. Am J Med Sci 303:53, 1992. This review carefully delineates the pathophysiology of sexual precocity, diagnostic maneuvers necessary to establish a precise diagnosis, and various treatment modalities.
The mammalian pineal is located in the "center" of the brain (above the quadrigeminal plate, just behind the posterior commissure) but is actually outside of the blood-brain barrier. Postganglionic neurons from the superior cervical ganglia release norepinephrine that stimulates beta1 -adrenergic receptors on the pinealocytes (Fig. 201-3) (Figure Not Available) . This results in the synthesis and release into the CSF and venous circulation of melatonin, the principal putative hormone of the pineal gland. The (paired) suprachiasmatic nuclei are the source of an approximately 24-hour rhythm in melatonin production that persists in conditions of constant darkness or blindness. Photic input, conveyed to the suprachiasmatic nuclei (SCN) via the retinohypothalamic
Figure 201-3 (Figure Not Available) Schematic diagram for the neuroanatomic regulation of the
timing of mammalian melatonin production (see text).
(Adapted by permission
of the publisher from "Biochemistry and regulation of mammalian
melatonin production" by AJ Lewy, in The Pineal Gland, edited by RM
Relkin, pp 77-128. Copyright 1983 by Elsevier Science Publishing Co.,
Inc.)
Melatonin production by the human pineal is decreased by beta-blockers and alpha2 agonists and is increased by certain tricyclic antidepressants that block reuptake of norepinephrine. Melatonin production is also increased by extreme physical exercise, norepinephrine, and psoralen. In general, diet and activity have no effect. Increased melatonin in manic states and decreased melatonin in depression probably occur but most likely represent epiphenomena following changes in adrenergic activity.
The function of melatonin in humans remains elusive. In some fish and reptiles melatonin coalesces melanin-containing melanosomes and in this way causes blanching, but this effect has been lost in most animals. Melatonin may possibly have this effect on the mammalian retinal pigmented epithelium. The association of pineal tumors with disorders of puberty is most likely explained by compression of the hypothalamus, since no melatonin-secreting tumor has yet been found. Furthermore, it now appears that the main effect of melatonin on the reproductive system lies in its ability to communicate the time of the year to animals that are seasonal breeders. In such animals it can have either anti- or progonadal activity depending on whether the species is a spring or fall breeder, respectively. Reproductive and endocrine effects of exogenous melatonin administration, not to mention endogenous melatonin secretion, have not been well documented in humans, with the possible exception that melatonin at certain doses can increase prolactin levels in humans.
Melatonin is produced only during nighttime darkness in both diurnal and nocturnal animals with an approximately 12-hour "on" phase and 12-hour "off" phase. Many blind people with a complete absence of light perception have free-running endogenous circadian rhythms. When these individuals melatonin rhythms are out of phase with their sleep-wake cycles (which have remained more or less synchronized to clock time), they are prone to develop nocturnal insomnia and daytime sleepiness. A pattern of insomnia that recurs every few weeks is almost pathognomonic for free-running circadian rhythms in totally blind individuals.
Although darkness does not induce melatonin production, in sighted people exposure to sufficiently bright light during the night immediately suppresses melatonin production. Two models have been proposed to explain how the nightly melatonin profile is shaped. In the two-pacemaker model, it is hypothesized that separate endogenous pacemakers control the onset and offset of melatonin production, cued primarily to dusk and dawn, respectively. In the "clock-gate" model, the suppressant effect of light (unique to melatonin) participates in the shortening of the duration of nighttime melatonin production during long photoperiods. Both models attempt to explain the shorter duration of melatonin secretion during the briefer summer nights compared to the longer winter nights.
The changing duration of nighttime melatonin secretion during the calendar year seems to be responsible for the reproductive effects of the light-dark cycle in seasonal breeders. Seasonal rhythms have not been well documented in humans, but it is clear that humans have most, if not all, of the circadian rhythms found in other higher animals. Whereas seasonal rhythms respond to the duration of the photoperiod or scotoperiod, circadian rhythms respond to the 24-hour light-dark cycle. In animals, the light-dark cycle s phase-shifting effects on circadian rhythms can be described by a phase response curve (PRC). This appears to be the case in humans as well. The PRC can be explained as follows: Delay responses (shifts to a later time) result when exposure to light occurs during the first part of the night; advance responses (shifts to an earlier time) result when exposure occurs during the latter part of the night. These phase shifts are greatest in magnitude in the middle of the night and are least during the middle of the day.
Although the suppressant effect of light is unique to melatonin, phase-shifting by light affects the endogenous circadian pacemaker (SCN) and all of its driven rhythms. In fact, the timing of the SCN s circadian rhythms is best measured by the circulating levels of melatonin. In some species injections of exogenous melatonin
Three main types of tumors that usually arise in the pineal are (1) pineoblastomas or pineocytomas, the term used depending on the degree of differentiation of this tumor of the pineal parenchyma; (2) germ cell tumors, including germinomas and embryonal carcinomas; and (3) glial tumors. Symptomatic enlargement of pineal by cysts has also been reported, but these are almost always asymptomatic. Destruction of pineal tissue can reduce or even ablate melatonin production, but pineocytomas have rarely been associated with increased circulating levels of melatonin. Melatonin production decreases with age, but this does not seem to be related to pineal calcification. By occluding the cerebral aqueduct, pineal tumors can produce symptoms associated with increased intracranial pressure, sometimes necessitating a shunt. Through pressure on the quadrigeminal plate, pineal tumors can produce Parinaud s syndrome, which includes paresis of upward conjugate gaze. Some germinomas and embryonal carcinomas secrete human chorionic gonadotropin, which has been implicated in cases of delayed onset of puberty. Treatment modalities include surgical extirpation, radiation, and chemotherapy, depending on tumor type and location and the absence or degree of metastases.
Lewy AJ, Sack RL, Singer CM, et al.: Winter depression and the phase shift hypothesis for bright light s therapeutic effects: History, theory and experimental evidence. J Biol Rhythms 3:121, 1988.
Lewy AJ, Wehr TA, Goodwin FK, et al.: Light suppresses melatonin secretion in humans. Science 210:1267, 1980.
Lewy AJ, Ahmed S, Jackson JML, Sack RL: Melatonin shifts circadian rhythms according to a phase-response curve. Chronobiol Int 9:380, 1995.
Neuwelt EA (ed.): Diagnosis and Treatment of Pineal Region Tumors. Baltimore, Williams & Wilkins, 1984.
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