Pineal gland interface between the photoperiodic environment and the endocrine system

Pineal Gland Interface Between the Photoperiodic Environment and the Endocrine System Russel J. Reiter The photoperiodic message that the pineal gland conveys to the organism is encoded in the circadian melatonin rhythm. Melatonin is a ubiquitously acting hormone that mediates seasonal changes in reproduction in nonhuman mammals and may have reproductive consequences in humans as well. Additionally, melatonin may relate to the function of the immune system, hormone-responsive tumor growth, circadian rhythm disturbances, and a number of other processes.

Photoperiod-dependent alterations in mammalian reproductive physiology, and indeed in endocrine physiology generally, are now known to depend on a hormone synthesized in the pineal gland. Melatonin (N-acetyl-5-methoxytryptamine) is the most thoroughly investigated pineal endocrine factor and its effects on the function of the neuroendocrine axis are both potent and well documented. The production and discharge of melatonin from the pineal gland is under control of the photoperiod acting by way of the suprachiasmatic nuclei (SCN) of the hypothalamus. Normally during the night, the SCN sends a neural signal to the pineal gland through the peripheral autonomic nervous system, where postganglionic sympathetic neurons release norepinephrine (NE) onto the pinealocytes, the endocrine cells of the pineal gland, resulting in the increased production of melatonin. Conversely, during the day retinal messages, via the requell the tinohypothalamic tract, activity of the SCN and shut down melatonin synthesis. The signal transduction mechanisms at the neurahpineal interface as well as the cellular biology

Russel J. Reiter is at the Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7762, USA.

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of indole metabolism are reasonably well understood, whereas the secretory processes involved in the discharge of melatonin from the pinealocyte are poorly defined. By virtue of the daily nighttime rise in blood melatonin levels every organ, endocrine and otherwise, is apprised of environment to the photoperiodic which the organism is exposed. Since animals in their natural habitat experience seasonal variations in day length, the melatonin signal provides important information that adjusts organisma1 physiology, certainly on a seasonal basis and possibly on a daily basis as well.

??

Melatonin

Biosynthesis

and Release

The release of NE from the postganglionic sympathetic neurons in the pineal gland is followed by the interaction of the catecholamine with adrenergic receptors in the pinealocyte membrane (Pangerl et al. 1990). P-Adrenergic stimulation of the pinealocyte activates the adenylate cyclase enzyme via a stimulatory guanine nucleotide-binding regulatory protein (G,) (Spiegel 1989); this results in a rapid, large (up to 60-fold in the rat pineal) increase in intracellular monophosphate cyclic adenosine (CAMP). CAMP serves as a second messenger in the nocturnal elevation of melatonin biosynthesis by activating a

CAMP-dependent protein kinase, transcription of mRNA, and an eventual rise in serotonin N-acetyltransferase (NAT), the presumed rate-limiting enzyme in melatonin production (Klein 1985). Whether new mRNA induces the de novo synthesis of NAT molecules or merely stimulates a NAT activator protein remains unknown, although recent studies suggest that the former possibility is more likely. The functional importance of NEstimulated Lu,-adrenergic receptors in augmenting the fi-adrenergic receptormediated nocturnal rise in pineal CAMP and melatonin synthesis is less well understood (Sugden 1989). The amplification response seems to involve protein kinase C (PKC), a Ca2’-activated, phospholipid-dependent enzyme (Figure 1). Phorbol esters, which are capable of directly activating PKC, duplicate the action of cu,-adrenergic agonists on pineal CAMP and NAT. Furthermore, in at least the rat pinealocyte, both phorbol esters and a,-adrenergic agonists stimulate the translocation and redistribution of PKC from the cytosol to the pinealocyte membrane (Ho et al. 1988); PKC activity in intact cells can only be activated when it is bound to the cell membrane. Ligand binding to the cwladrenergic receptor also increases intracellular free Ca” by activating a ligand-dependent channel and promoting the hydrolysis of phosphotidylinositol, which generates diacylglyccrol, resulting in the translocation and activation of PKC. PKC activation may augment the ,&adrenergic reccptor-mediated rise in pincalocyte cAMP by phosphorylating G, or adenylate cyclase itself (Figure 1) (Sugden 1989). Owing to the interactions, whatever they are, the P-receptor-mediated rises in pineal NAT activitv and melatonin are amplified by - 15% by simultaneous stimulation of p- and cu-adrenergic receptors in the pinealocyte membrane. Besides inducing high NAT activity, CAMP seems also to prevent the degradation of NAT. Whereas intracellular CAMP levels rise quickly after the pinealocyte is stimulated with NE, the actual timing of the rise in NAT activity and melatonin production is species specific. Thus, in the pineal gland of the Syrian hamster, pineal NAT activity and melatonin levels do not peak until -8 h after darkness onset, with the long lag period apparently being related to

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its chief hormonal product. How all this information is integrated into the circadian production of melatonin remains the subject of future investigations.

Serotonin -

,JNe;Ao:oe$~-

/

HIOMT

Melatonin

Other Metabolites \

5Methoxytryptamine

Figure 1. Diagrammatic representation of the presumed signal transduction mechanisms between the postganglionic sympathetic neurons and the mammalian pinealocyte. AAAD, Iaromatic amino acid decarboxylase; AC, adenylate cyclase; ATP, adenosine triphosphate; CAMP, cyclic AMP; DG, diacylglycerol; G, guanine nucleotide-binding protein; G,, stimulatory G; HIOMT, hydroxyindole-0-methyltransferase; IP, inositol phosphate; MAO, moNE, norepinephrine; PI, phosphotidylinositol; noamine oxidase; NAT, N-acetyltransferase; PKC, protein kinase C; PLC, phospholipase C; TH, tryptophan hydroxylase; ol,, ol-adrenergic receptor; and 0, P-adrenergic receptor

the relatively slow synthesis of mRNA (Santana et al. 1990); in other species, such as the Djungarian hamster, maximal pineal NAT activity and melatonin levels are achieved within 1-2 h after darkness onset. The magnitude of the nocturnal rise in pineal NAT also varies greatly among species (Rudeen et al. 1973, being increased anywhere from two- to IOO-fold, depending on the species examined. Once NAT rises, serotonin converted to N-acetylserotonin in the presence of persistently droxyindole-0-methyltransferasc (HIOMT) activity, is quickly

is rapidly which, high hyconverted

to melatonin (Reiter 1988) (Figure 1). The often obvious correlation between the rise in NAT activity and the melatonin content of the pineal gland has led to the postulate that NAT limits the rate of melatonin formation (Klein 1985). Although this speculation is generally valid, there are instances when NAT and melatonin are poorly correlated, and it seems certain that the quantity of melatonin formed depends on a variety of factors, such as serotonin availability, NAT activity, and monoamine oxidase activity. Whereas both pineal NAT activity and melatonin content increase nightly, the activity of the enzyme that O-methylates N-acetylserotonin, that is, HIOMT, is essentially uniform through-

14

out the day and night. Despite this, HIOMT activity diminishes (by 70%) in chronically sympathetically denervated glands, suggesting that NE may be involved in the maintenance of basal HIOMT levels. Although the adrenergic innervation of the mammalian pineal gland is, by far, the most widely investigated of the central connections of the gland, it is clear that a variety of other neurotransmitters and neuromodulators arc capable of modulating the nocturnal rise in pineal melatonin synthesis (Cardinali et al. 1987; Ebadi et al. 1989) (Figure 2). Furthermore, substances that are not generally considered neurotransmit-

ters, such as prostaglandins (Cardinali et al. 1982) and interferon-y (Withyakamnarnkul et al. 1990). seem to influence the ability of the pineal to produce

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Blood levels of melatonin follow very closely the amount produced in the pineal at virtually the same moment. This parallelism suggests that the release mechanisms are rapid and that the major route of secretion of melatonin is into the blood; a release of melatonin directly into the cercbrospinal Iluid of the third ventricle has been prcviously proposed and, under some circumstances, it may exist. There is a general consensus that melatonin is released in a pulsatile manner from pinealocytcs, being especially apparent when levels are measured in pineal vcnous effluent (Reiter and Vaughan 1990). Because of its high lipophilicity and, thus, the case with which mclatonin passes through cell membranes, it was assumed that there were no intrapineal storage or release mechanisms for the indole hormone. Rather, it was believed that melatonin merely diffused out of the cells shortly after it was synthesized. Now that episodic release has been demonstrated, however, the existence of at least short-term storage and an active release mechanism of melatonin from the pinealocytes must be assumed.

?? The

Melatonin Rhythm Nature of Its Message

and the

Unless there is a genetic deficit in the enzymatic machinery, a nighttime rise in pineal melatonin production is generally characteristic of both nocturnally and diurnally active mammals. The rhythm in melatonin is clearly driven by the photoperiodic environment to which the animals are exposed and can be interrupted by subjecting them to light at unusual times, that is, during darkness. The light intensity and wavelength requirements for interrupting melatonin production at these times have been defined for a small number of mammals, and they exhibit significant variations among species (Reiter 1985). In humans, light, exposure or phototherapy, which manipulates circulating melatonin levels, has been instituted as a treatment for a number of clinical entities, especially seasonal affective disorder (SAD or win-

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CENTRAL

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G*B*ERGlC GLUlAMERGlC

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Figure 2. Diagrammatic representation of the multiplicity of control mechanisms theoretically involved in the biosynthesis of melatonin. Figures such as this undergo frequent revision as new data become available. BZP, benzodiazepine; CaM, calmodulin; DA, dopamine; DAG, diacylglycerol; 2,.1-DIOX, 2,3-dioxygenase; GABA, y-aminobutyric acid; HIAA, 5-hydroxyindole acetic acid; HIOMT, hydroxyindole-0-methyltransferase; .5HT, serotonin; HTOH, 5hydroxytryptophol; HTP, 5-hydroxytryptophan; LTC, and LTD,, leukotrienes Cd and D4; MAO, monoamine oxidases; MIAA, 5-methoxytryptophol; MTOH, 5-methoxytryptophol; NAS, N-acetylserotonin; NE, norepinephrine; PG. prostaglandins; PDE, CAMP phosphodiesterase; PK, protein kinase; R, receptor; TP, tryptophan; and VIP, vasoactive intestinal peptide. From Cardinali et al. (1987)

ter depression) and other depressive states (Miles et al. 1988). Whereas melatonin is almost exclusively released from the pineal gland at night, the pattern of the nighttime blood melatonin rise seems to be species specific. The nocturnal blood melatonin patterns have been provisionally classified into three categories (Reiter 1987) (Figure 3). Whether these patterns are important in reference to the message that the pineal gland, via melatonin, conveys remains unestablished. However, regardless of the specific nocturnal melatonin pattern that a species displays, if the dark phase of the light-dark cycle is either shortened (summer photoperiod) or lengthened (winter photoperiod), elevated nighttime melatonin levels are proportionally influenced. Thus, it is generally accepted that, within limits, the daily

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duration of elevated melatonin is determined by the length of the night, that is, longer nights are associated with longer periods of high melatonin (Figure 3). Another generality that has been established is that, within a given individual (humans have been most frequently tested), the melatonin rhythm is highly reproducible during successive measurement periods and is essentially individual for that characteristic (Arendt 1988). On the other hand, what is not uniformly agreed upon is what constitutes a physiologically relevant rise in blood melatonin levels. The calculation of a nocturnal elevation of melatonin remains arbitrary; one-half the maximal nocturnal melatonin peak is not uncommonly accepted as a level of melatonin that may be functionally important for an animal, although there is no experimental documentation of this.

The advent of specific radioimmunoassays for melatonin has made its measurement routine, and both pineal and blood melatonin patterns have been defined in a progressively increasing number of mammals. These patterns are important because the message that the pineal gland conveys to the organism is encoded in these levels, as shown by the fact that alterations in these patterns significantly change the physiologic responses of the animal. The feature, that is, its high lipophilicity, which seems to allow for the rapid and easy escape of melatonin from the pineal gland is also what permits its quick transfer into many cells and bodily fluids. When examined ovet time, melatonin rhythms reminiscent of those found in the blood have also been uncovered in the cerebrospinal fluid, saliva, fluid of the anterior chamber of the eye, and ovarian follicular fluid; also, melatonin has been detected in male seminal fluid (whether a rhythm exists here has not been examined). Despite the fact that melatonin is produced in organs other than the pineal gland (Arendt 1988), its rhythm in the fluids mentioned above is believed to be a direct consequence of blood melatonin derived from the pineal gland (Reiter 1988). In view of

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Figure 3. Provisional classification (A, B, and C) of the melatonin rhythm in various mammalian species. The significance, if any, of these different rhythms remains unknown. Regardless of the type of rhythm a particular species displays, if the daily dark period is increased the duration of elevated melatonin is likewise prolonged (A’, B’, and C’). From Reiter (1987).

the apparent accessibility of melatonin to virtually all organs, ubiquitous sites of action and numerous physiologic actions of melatonin are postulated. This has led to the common assumption that melatonin modulates many physiologic events, not only those associated with endocrine and reproductive functions (Arendt 1988; Reiter 1988). Which aspect of the melatonin rhythm actually conveys the endocrine message to a specific organ system remains debated. Several testable hypotheses have been proposed (Reitcr 1987). The most widely accepted theory to explain melatonin’s action, and the one for which there is the most experimental support, is what is referred to as the duration hypothesis. According to this view, seasonal fluctuations in day length (that occur at all points on the Earth) alter the duration of elevated melatonin and adjust organismal physiology, for example, reproduction, on an annual basis. Documentation of the theory appears to be well founded experimentally (Carter and Goldman 1983; Bittman et al. 1984). It does appear, however, that although originally proposed as purely an absolute duration phenomenon, the direction of change of nightly elevated melatonin, that is, whether clcvated levels are is an becoming longer or shorter, of the equally important component et al. duration hypothesis (Hoffman 1986).

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Message:

Although initially described over a decade ago, reliable characterization of

I” Late

Md-

Reading the Melatonin Melatonin Receptors

A second theory of the mclatonin message emphasizes the possibility of two separate rhythms that must be synchronizcd bcforc melatonin has physiologic consequences. These arc referred to as coincidence models, that is, ir?teunal and external coincidence (Rcitcr 1987). Accordingly, only when nightly elevated melatonin levels overlap an increased sensitivity of the mclatonin rcceptor (window of sensitivity) is a physiologic forthcoming. The response phasing of the rhythm in melatonin rcceptor sensitivity may also be determined by the prevailing light-dark cycle or by melatonin itself (Chen et al. 1980); certainly, the action of a number of hormones on their receptors determines the subsequent immediate inllucnce of additional hormone on the same receptor. If melatonin regulates the sensitivity of its own receptor, it may only do so under specific conditions that are determined by the internal milieu of the organism. The coincidence models of melatonin’s action have some experimental support. The final theory, the amplitude hypothesis, states that it is the amplitude of the nocturnal rise that is the critical feature in determining melatonin’s functional significance. Although this theory is rarely used to define melatonin’s effects in nonhuman mammals, it is not uncommonly invoked when the melatonin rhythm is defined in humans (Berga et al. 1988).

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melatonin receptors stems to have come only recently (Stankov 1990). Whereas many of these studies have described melatonin binding sites in the medial basal hypothalamus (MBH), their presence outside of this area of the brain as well as in extraneural locations is not uncommon. Within the medial basal hypothalamus the most definitive studies have localized melatonin binding in the SCN (Reppert et al. 1988). Recall that these nuclei are a relay station in the neural pathway that connects the retinas to the pineal gland, leaving open the possibility that blood titers of melatonin could have a feedback influence, either positive or negative, on the neural control of pineal indole metabolism although, to date, such an association has not been detected. Also, although it remains to be established, it is usually tacitly implied that melatonin signal detection sites in the SCN mediate the effects of this hormone, at least in part, on the neuroendocrine-reproductive axis. The molecular mechanisms of melatonin’s interactions with cells in the SCN as well as in other sites are currently under active investigation. The other site of major intcrcst in refcrence to the autoradiographic localization of the cxogenously administered radioactive melatonin is the pars tuberalis of the pituitary gland (Morgan and Williams 1989). The close anatomic association of these cells with the median eminence Icd to some initial confusion when it was proposed that the receptors were, in fact, in the median eminence proper rather than in the pars tuberalis. The high density of melatonin binding sites in these presumed aberrant pituitary cells, but not in anterior pituitary lobe (pars distalis, with which the pars tuberalis is continuous), generally has been confounding. Judging from the large size and activc-looking appearance of the pars tuberalis cells as well as the presence of numerous mitochondria and high RNA content, an active metabolism has been inferred (Allanson ct al. 1959). Perhaps their activity is somehow related to signal transduction mechanisms whereby melatonin modulates the function of

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the gonadotropes of the anterior pituitary gland. Melatonin binding has also been described

in a variety

thalamic

neurons,

of other

nonhypo-

such as septum,

hip-

pocampus, reticular formation, and so on (Zisapel 1988). The functional importance of these melatoninbinding neurons in the regulation of the neuroendocrine svstem remains undocumented. Within many of the sites where melatonin binding has been described, the density of the binding sites varies over the 24-h period; this observation has been used as a theoretical explanation for the internal coincidence model of melatonin’s action (Zisapel 1988).

Consequences of the Melatonin Message: Regulation of Reproduction That the photoperiod, via the pineal gland and its hormonal product, has a profound influence on reproduction is no longer contested. The most widely accepted mechanism whereby melatonin is believed to alter the function of the hypothalamo-adenohypophyscalgonadal axis is through its ability to modify the firing frcqucncy of the hypo-

thalamic

gonadotropin-releasing

hor-

mone pulse generator (Robinson 1987) (Figure 4); presumably melatonin is able to do this through its binding sites in either the SCN or the pars tuberalis, although this link has never been established. Although the consequences of the melatonin message in terms of reproduction are obvious, some investigators have implied that these effects arc always of a negative nature, that is, that melatonin acts exclusivelv as an antigonadotropin. This idea was propagated in part by the early observ,ations that showed the marked suppressive etfeet of melatonin on virtually all aspects of reproductive physiology. More recent investigations have shown, however, that melatonin merely mediates the effects of the photoporiod on reproductive physiology; although this inlluencc is often of an inhibitory nature, it can likewise be stimulator-y or inconscqucntial. The actual response of the neuroendocrine-reproductive axis to mclatonin may depend, among other factors, on the internal hormonal milieu. In a sense then, the melatonin mcssage is a passive one, with the endocrine response being dictated by the manner in which the melatonin mes-

Figure 4. Presumed

association between the environment, the hypothalamic gonadotropinreleasing hormone (G&H) pulse generator, the secretion of luteinizing hormone (LH) from the anterior pituitary gland, and ovarian function in mammals. The mediator of the photoperiodic effects on the pulse generator is the pineal hormone melatonin. Melatonin is generally believed to modify the firing rate of the pulse generator therrbv regulating reproductive physiology. From Robinson (1987). ENVIRONMENT EXTERNAL

a

PHOTOPERIOO

LH-PULSE

GENERATOR

INTERNAL SIGNALS GONAML

sTEROos

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sage is read.

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how a given

group of melatonin receptor-containing cells translates a given melatonin message into an either negative or positive response, or how it ignores the signal completely (such as during periods of refractoriness) (Reiter et al. 1979), remains a challenge for future researchers. Melatonin has obvious effects on the maturation of the gonadal system as well as on the function of the system after adulthood is achieved. In specific reference to sexual development, mclatonin seems to be exclusively inhibitory; the species that have been most widely investigated in this regard have been the rat (Lang 1986) and the sheep (Ebling and Foster 1989). Whereas appropriately timed melatonin can delay the maturation 01 the hypothalamic GnRH pulse generator as well as the peripheral reproductive organs, it cannot prevent them from eventually developing to the adult state (Rciter 1986). Whereas in most species tested the delay in reproductive maturation is obvious following melatonin administration, the Syrian hamster (Mesocricet~s utlrut~s) is a notable exception since, despite many attempts, neither the pineal gland nor melatonin either delay or advance the ability of the pituitarygonadal axis to reach maturity; this is quite remarkable, aincc this is the mammal in which the regulation of reproduction by the pineal gland after adulthood was initially unequivocally established (Reiter 1980). All animals in their natural habitat are exposed to waxing and waning day lengths, with thcsc variations becoming progressively more exaggerated at increasingly higher latitudes. The naturally occurring photoperiodic variations impel seasonal fluctuations in reproductive competence in photoperiod species. These rhythms in seasonal reproduction are now known to depend on the pineal gland as the interface between the photic environment and the pituitary-gonadal axis (Reiter 1980; Arendt 1988; Bartness and Goldman 1989). Pinealectomy removes the ability of the animal’s reproductive system to properly respond to changing photoperiods, whereas cxogenously administered melatonin induces the entire annual cycle of reproduction. During seasonal reproduction, long daily elevated melatonin levels (during short

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r

. Acknowledgment

Lights Out

Work by the author during rcccnt year-s was supported NSF grant by DCB8711241.

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References

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Allanson M, Foster CL, Menzics G: Some observations on the cytology of the adcnohypophysis of the non-parous female rabbit. Q J Micro Sci 1959; 100:463. Arcndt J: Melatonin. 1988; 29:205.

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Bartness TJ, Goldman BD: Mammalian pineal hormone: a clock for all seasons. Expcrientia 1989; 45:93Y. 18

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Clock Hours Figure 5. Twenty-four-hour serum melatonin (MELA) rhythms in normal control (NC) women and in women with hypothalamic amenorrhea (HA). HA subjects have abnormally high nighttime melatonin titers as well as melatonin levels elevated for a longer interval such as this suggest, but do not prove, a relationship between melaevery night. Findings tonin and reproduction in the human. From Berga et al. (1988).

days of the year) may be associated with reproductive quiescence (for example, in the Syrian hamster) (Reiter 1980) or with maximal reproductive capacity (for instance, in the sheep) (Robinson 1987). Additionally, there are periods when the melatonin message seems to be totally ignored, that is, the reproductive system is refractory to melatonin (Reiter et al. 1979; Reiter 1980). ?? Final

Comment

Many issues concerning the control of melatonin production as well as its interactions with the hypothalamo-pituitary-gonadal axis require experimental resolution. Clearly, the role of melatonin in controlling reproduction has been well defined in a number of nonhuman mammals, and there are strong reasons to suspect that it may have similar functions in terms of human reproductive physiology. An association of age-related reductions in nocturnal melatonin levels with puberty has been reported (Waldhauser and Dietzel 1985). Furthermore, what are considered to be abnormal or unusual melatonin rhythms have been observed

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in females with hypothalamic amcnorrhea (Bcrga et al. 1988) (Figure 5), in patients with reproductive dysfunction associated with anoxeria nervosa (Tortosa et al. 1989), and in males with oligospermia or aspermia (Karasek et al. 1990). Additionally, conditions such as seasonal affective disorder, “jet lag,” hormone-responsive tumor growth, immunoincompetence, sleep, and even sudden infant death syndrome (SIDS) have been provisionally related to melatonin and/or the pineal gland. Although this survey concentrates on the reproductive consequences of the pineal gland and melatonin, the reader should not be lulled into thinking that melatonin only functions in sexual physiology. Indeed, mclatonin’s actions are not exclusive to this system and, in fact, the reproductive effects may be secondary to its more important role of adjusting the entire physiology of the organism on a seasonal basis, for cxample, thyroid physiology, fur coloration, white and brown fat metabolism, skin pigmentation, and body temperature regulation (Reitcr 1984; Binkley 1988). Indeed, melatonin’s actions may be as widespread as those of the anterior pituitary lobe hormones.

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Robert F. Gage1

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There has been sustained progress toward the identification of the gene for multiple endocrine neoplusiu type 2. Closely linked and flunking DNA markers have been identified, and it is now possible to assign gene carrier status in informutive fumilies at risk with u >90% certainty by the use of moleculur genetic techniques. Applicution of these techniques, however, requires un understunding of their current limitations and caution in their use of‘clinical decision making.

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More than two decades have passed since multiple endocrine neoplasia type 2’ (MEN 2) was formally identified as a clinical syndrome (Steiner et al. 1968). ’ The current nomenclature for multiple endocrine neoplasia type 2 and medullary thyroid carcinoma is outlined in Multiple endocrine neoplasia type 2 syndromes: nofrom the menclature recommendations workshop organizing committee in the Third International Workshop on MEN 2 (Henry Ford Hosp Med J 1989; 82:99). Robert F. Gage1 is at Baylor College of Medicine and VA Medical Center, Houston, TX 77030, USA.

CZ 1991, Elsevier

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Publishing

Co., Inc.,

Over this time, techniques have been dcveloped for the early diagnosis and treatment of the three cardinal manifestations of this syndrome-medullary pheochromocycarcinoma, thyroid toma, and parathyroid hyperplasia. It now seems reasonable to believe that early diagnosis of the medullary thyroid carcinoma and treatment by total thyroidectomy is curative (Cance and Wells 1985; Gage1 et al. 1988; Telander et al. 1986). Advances in the diagnosis and treatment of pheochromocytoma and parathyroid hyperplasia have similarly improved the clinical outcome of pa-

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