PROGRESS

IN ENDOCRINOLOGY

AND METABOLISM

Neuropharmacologic Control of Neuroendocrine Function in Man Lawrence

A. Frohman

and Max E. Stachura

N

EUROENDOCRINOLOGY has developed during the past decade from a chemotransmitter theoretical discipline based on the established hypothesis of the control of anterior pituitary secretion to one in which specific central nervous system-pituitary relationships are being rapidly established. The painstaking efforts directed toward isolation and purification of active hypothalamic fractions, coupled with dramatic advances in peptide chemistry, have resulted in the chemical characterization and synthesis of three hormones affecting anterior pituitary function. At the same time, the development of radioimmunoassay techniques for each of the recognized pituitary hormones has led to extensive physiologic investigations aimed at defining hypothalamic hormone-pituitary hormone relationships with respect to specificity, mechanism of action, and inhibiting and/or potentiating feedback effects of target-organ hormones. In addition, evidence for possible extra-pituitary activities has been presented. For comprehensive reviews on this subject the reader is directed to the appropriate references. ‘p-7 Along with the studies of hypothalamic-pituitary relationships, extensive investigation has focused on the control of secretion of the hypothalamic hormones themselves. Since they are secreted by peptidergic neural cells (appropriately referred to as “transducer” cellsa) rather than by endocrine gland cells, the study of their control has of necessity involved an interdisciplinary bridge linking neuropharmacology and neurotransmitter chemistry. This, in turn, has led to reevaluation of the more classical feedback mechanisms involving pituitary and target-organ hormones. The observation that the hypothalamic hormones lack species specificity, the ability to measure all of the human anterior pituitary hormones, and the clinical proliferation of psychotropic agents have led to rather extensive accumulation of information during the past few years concerning the clinical neuropharmacology of hypothalamic hormone secretion .g This review will attempt to assess the current state of knowledge of this subject and indicate those areas in which future developments may be expected to occur. It will consider aspects of hypothalamic hormone-pituitary hormone relationships, neurotransmitter metabolism, and neurotransmitter-releasing hormone relationships. Finally, some speculation will be entertained with respect to specific diagnostic and/or therapeutic implications that have recently become apparent based on the above considerations. From the Division of Endocrinology and Metabolism. Departmenr of Medicme. Michael R~ete Medical Cenler. and the Pritzker School of Medicine, University of Chicago. Chicago. 111. Received for publication June 24. 1974. Reprinr requests should be addressed to Lawrence A. Frohman. M.D., Divi.Tionof Endocrinr)lr,RI and Metabolism. Michael Reese Medical Center, Chicago, 111.60616. ft 1975 bv Grune & Stratton, Inc. Metabolism,Vol. 24, No. 2 (February), 1975

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RELATIONSHIPS

Investigation of hypothalamic-pituitary interrelationships was initiated many years prior to the isolation of specific hypothalamic hormones. Consequently, many of our current concepts concerning hypothalamic-pituitary physiology have been derived from experiments involving physical or chemical ablation and/ or stimulation, the collection of blood from (and/or the introduction of substances into) the hypothalamic-hypophyseal portal vessels, and the use of crude hypothalamic tissue extracts subjected to varying (and frequently imprecisely detailed) degrees of purification. Many of the previously accepted concepts have required modification or rejection as hormone characterization and synthesis occurred, and it is to be anticipated that further reconsideration will be necessary as additional hypothalamic hormones are obtained in a purified state. At the present time three hypothalamic hormones have been characterized and synthesized: thyrotropin-releasing hormone (TRH),lovLL a tripeptide; luteinizing hormone releasing hormone (LHRH),ly also referred to as gonadotropin releasing hormone (GnRH), a decapeptide; and somatotropin release inhibiting factor (SRIF),13 or somatostatin, a tetradecapeptide. These hormones have been investigated extensively in both laboratory animals and in man, whereas experiments using crude or partially purified hypothalamic extracts have been generally limited to laboratory animals. In the description of hypothalamic-pituitary relationships that follows, therefore, it must be borne in mind that many of the concepts derived primarily from studies using impure extracts in animals remain to be confirmed in man and may well require modification. Classical concepts of hypothalamic control of secretion of adenohypophyseal hormones have been based on the concept of a single hypothalamic factor* for each pituitary hormone. The complexities of recent experimental results have challenged not only the unimodal nature of the control mechanism but also the specificity of hypothalamic hormone action. A summary of these hypothalamichypophyseal interrelationships follows: TRH-TSH. TRH was the first hypothalamic hormone identified, and it was originally believed to exhibit the simplest type of relationship between a hypothalamic and pituitary hormone: namely a direct, positive, stimulatory effect. The “simplicity” of the relationship has disappeared, however, as it has become apparent that whereas TRH administration elicits a dose-dependent TSH response14 the site of the target-gland hormone negative feedback is at the pituitary rather than the hypothalamic level. Thus thyroxine does not suppress TRH secretion,15 but rather suppresses the TSH response to TRH.16 In fact, there is even evidence that thyroxine stimulates TRH secretion.15 In addition, the peptide identified as TRH is not specific for the thyrotroph. At equal or even lower doses, TRH stimulates prolactin releaseI (see below) and. in acromegalics, growth hormone release. I8 There is also preliminary evidence to indicate that more than one TRH may exist.lg

*It should be indicated that the terms hypothalamic releasing (or inhibiting) “factor” and “hormone” have been used to distinguish between impure extracts and purified compounds, respectively, by some authors, whereas others have used the terms interchangeably or have selected one term to the exclusion of the other.

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CRF-ACTH. Corticotropin releasing factor (CRF) has been one of the more elusive hypothalamic factors. Despite more than 10 years of attempts at isolation and purification, CRF still remains unidentified. Its activity has been repeatedly detected in hypothalamic extracts and in plasma and has been distinguished from vasopressin, which also has ACTH releasing activity and is present in crude hypothalamic extracts. 2o However, attempts to purify CRF have invariably resulted in a loss of biologic activity at some step in the purification. It has been suggested that more than one CRF may exist,21 but resolution of this question is not possible at the present time. From the available data it appears that the effect of CRF on ACTH secretion is, like that of TRH on TSH, a direct, positive, stimulatory effect. LHRH (GnRH)-LH and FSH. Although the isolation and purification of the decapeptide LHRH was monitored primarily using parameters of LH release, both purified and synthetic LHRH release FSH as well as LH. The release kinetics of both pituitary hormones to exogenous LHRH are similar,22 although the effects on LH have generally been more dramatic and more consistently demonstrable. Evidence exists for the modulation of LHRH effects by estrogen,23 and it has been proposed that alterations in gonadal steroids are responsible for differential effects on LH and FSH release in response to LHRH.24 On the other hand, an alternate explanation is that hypothalamic hormones specific for the individual pituitary gonadotropins will be found. A recent report has described a synthetic peptide containing four of the amino acids in LHRH that stimulates LH but not FSH release.25 Although there is no evidence that this tetrapeptide is present in the hypothalamus, it is important as a model that supports the concept of separate releasing factors for LH and FSH. GHRF and SRZF-GH. For nearly 10 years all of the physiologic studies relating to neuroendocrine control of growth hormone (GH) secretion have been interpreted on the basis of only a GH releasing factor (GHRF). A few years ago a decapeptide was proposed as a GHRF,26 although its activity has not been demonstrable by measurements of plasma GH changes using radioimmunoassay. Crude and partially purified hypothalamic extracts, however, have been shown to contain radioimmunoassayable GH releasing activity.27*28It was therefore quite unexpected that the first hypothalamic factor influencing GH release to be identified and synthesized was an inhibitor. Somatostatin, or somatotropin release inhibiting factor (SRIF) inhibits both basalI and GHRF-stimulated2g GH release at a step beyond the formation of cyclic AMP.30 Although the existence of SRIF has forced a revision of the concept of hypothalamic control of GH secretion to one involving a duality, the accumulated physiologic experience does not appear to require such a control system. Very recent studies demonstrating a lack of specificity (SRIF also inhibits TRH-induced TSH release,31 glucoseinduced insulin release,32 and arginine-induced glucagon release33) have contributed to the confusion surrounding the assessment of the physiologic role of SRIF. PIF and PRF-Prolactin. The control of prolactin secretion has classically been interpreted on the basis of a negative, or inhibitory, hypothalamic influence (prolactin inhibiting factor, PIF) on the pituitary. The overwhelming majority of physiologic experiments in laboratory animals and the observations in humans

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following pituitary stalk transection have indicated that interruption of the integrity of the hypothalamic-pituitary unit results in increased prolactin secretion.34*35More recently, however, it has been necessary to consider the concept of dual control by both inhibitory and stimulatory factors. This was required by the serendipitous observation that TRH causes the release of prolactin as well as TSH.36 In fact, clinical studies have indicated that the prolactin response occurs at lower doses of TRH than does the TSH response.17 It is always possible to interpret experiments in the framework of a prolactin releasing factor (PRF) as well as a PIF.37 However, there appears to be no compelling physiologic reason to require both factors. The above considerations indicate that the interpretation of neuropharmacologic effects is limited by the fact that the end point of measurement is the circulating level of pituitary hormones. * Effects on those pituitary hormones for which both releasing and inhibiting factors appear to exist could be explained by alterations of either of the control mechanisms, or both. Despite this limitation, however, the observed effects on pituitary hormone secretion are quite distinct, and the potential clinical usefulness of neuropharmacologic agents still remains. NEUROTRANSMITTER

METABOLISM

The hormone-secreting (peptidergic) cells of the hypothalamus possess characteristics of both endocrine and neural cells. They are responsive to humoral signals such as adrenal and gonadal steroids and metabolic fuels, thereby functioning as part of an internal feedback system. More important, they are an integral part of the central nervous system control of endocrine gland function. Although a large number of compounds have been identified as neurotransmitters and an even greater number have been proposed as such, three specific monoamines have received the major attention of workers in this field. Interest has been focused on dopamine (DA) and norepinephrine (NE), which are catecholamines, and on serotonin (SER), an indoleamine. The concentration of these compounds is greater in the hypothalamus than in most other parts of the brain, and it has been proposed that these monoamine neurotransmitters serve as the final link between neural cells and the hormone-secreting cells of the hypothalamus. The brief summary of their synthesis and metabolism shown in Fig. 1 serves as a basis for much of the subsequent neuropharmacologic considerations. The precursor for both DA and NE is tyrosine. Although tyrosine readily crosses the blood-brain barrier, brain levels are relatively independent of those in plasma.41 Brain tyrosine concentrations are ten to twenty times greater than those of DA and NE, and only a small fraction of brain tyrosine serves as a precursor for DA and NE synthesis. Tyrosine is converted to dihydroxyphenylalanine (dopa) by tyrosine hydroxylase (Fig. 1: l), and this step has been considered to be rate-limiting in DA and NE biosynthesis. Dopa is immediately decarboxylated to dopamine (Fig. 1: 2), which serves both as a neurotransmitter *Assays for direct measurement of the specific hypothalamic hormones by radioimmunoassay have been described for TRH,3R LHRH,38 and SRIF.40 However, at the time of writing, measurement of hypothalamic hormones in peripheral human plasma is still quite preliminary.

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Tr yptophon

I 9

I

5-OH-Tryptophwl I

+

5at+Tryptarnlne

(serotonln~

Rolorring A

lnhiblting Factors

Fig. 1. Schematic representation of potential monoamine relationships to the hormone-secreting neurons of the hypothalamus. The numbers refer to enzymatic steps or to sites of possible neuropharmacologic effect and are discussed in the text.

and as a precursor of NE, which is formed by beta hydroxylation (Fig. 1: 3) within the catecholamine storage granules. Upon stimulation, both DA and NE are released from nerve terminals into synaptic clefts to serve as transmitters by attaching to specific receptor sites on the postsynaptic membrane (Fig. 1: 4-6). Both (Y- and P-adrenergic receptors have been described within the central nervous system. The secretory process is terminated principally by reuptake of the neurotransmitter into the presynaptic nerve terminals (Fig. 1: 7). Neurotransmitter inactivation occurs in the synaptic cleft by catechol-o-methyltransferase. In addition, most of the catecholamines within nerve terminals are inactivated by monoamine oxidase (Fig. 1: 8) without ever exerting neurotransmitter function. Brain tryptophan, the precursor of SER, is also derived from plasma tryptophan. In contrast to tyrosine, however, brain tryptophan and SER levels fluctuate in relation to plasma tryptophan concentrations42 and are therefore dependent upon both food intake and hormone levels. 43.44Brain tryptophan concen-

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trations are also many times greater than are those of SER. Tryptophan is hydroxylated to 5-hydroxytryptophan (Fig. 1: 9) in a manner analogous to tyrosine hydroxylation. 5-hydroxytryptophan is rapidly decarboxylated to 5hydroxytryptamine (serotonin) (Fig. 1: lo), which functions as a neurotransmitter, as has been described for DA and NE. The metabolism of brain SER is less well understood than that of catecholamines. It is metabolized primarily through oxidative deamination by monoamine oxidase. Whether it is inactivated by reuptake into nerve terminals is not entirely clear. Like DA, however, SER serves both as a neurotransmitter and a precursor substance. In the pineal, SER is converted to melatonin, a neurotransmitter that may act upon serotonergic neurons. In addition to the biochemical mechanisms described above, anatomic relationships must also be considered. The cell bodies of the peptidergic neurons are believed to be located within the hypophysiotropic region of the ventral hypothalamus, and their axons extend into the outer layer of the median eminence. The hypothalamic hormones are secreted into the capillaries of the primary portal plexus. There are consequently several loci at which hypothalamic hormone secretion could be affected by neurotransmitters. The most likely role of neurotransmitter function is in stimulating or inhibiting secretory activity of these peptidergic neurons. The site at which this occurs could be at the cell body of the neuron, or less likely within the nerve terminal of the neuron. In addition to a direct action on a hormone-secreting neuron, neurotransmitters are involved in the entire neural circuit that eventually terminates at the hormone-secreting cell, and the effects could therefore be quite remote. Finally, the possibility exists that neurotransmitters could be secreted into the portal vessels along with the releasing and inhibiting hormones and thereby modify their actions on the pituitary. Evidence for the latter possibility, however, is far from convincing. It is evident, upon considering the monoamine synthetic and metabolic pathways, that a number of sites exist at which pharmacologic manipulation might influence the functional activity of neurotransmitters. For the past several years a number of pharmacologic agents of various types, including enzyme inhibitors, neurotransmitter depleters and releasers, receptor blockers, and uptake inhibitors, have been extensively studied and shown to affect endocrine function. The use of most of these agents has been limited to animal experimentation, but an increasing number and variety of agents are becoming available for clinical investigation. The following discussion includes by no means an all-inclusive list, but rather serves to represent the types of agents that have been used, and some indication of their mechanism of action. These and other pharmacologic actions are described in detail in an excellent review of drug effects on central nervous system amines. Synthesis inhibitors. Synthesis can be inhibited by substituted amino acids such as a-methyl-p-tyrosine or p-chlorophenylalanine, which reversibly inhibit the enzymatic conversion of the natural monoamine precursors. Other substituted amino acids such as a-methyl-m-tyrosine or cY-methyldopa are converted into methylated monoamines and function as false neurotransmitters upon release from nerve terminals. A specific alteration of the synthesis of a single neu-

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rotransmitter is produced by disulfiram or FLA 63. These compounds inhibit dopamine-/3-hydroxylase, thereby blocking the conversion of DA to NE. Agents such as reserpine deplete NE, DA, and SER stores Amine depletors. by interfering with amine storage. As a consequence, however, there is an increase in monoamine turnover in an attempt to compensate for the depletion. The tricyclic antidepressants, which include imipramine Uptake inhibitors. and desipramine, block uptake of monoamines by nerve termals, resulting in increased concentrations at the receptor site. As a result, however, there are secondary effects on amine release and turnover. Amphetamine and methylamphetamine are examples of Amine releasers. agents that stimulate the release of newly synthesized NE and DA. However, they also mimic the effect of tricyclics in blocking catecholamine uptake. Receptor blockers. There are many agents that affect monoamine neurotransmitter function by blocking the postsynaptic receptor. These include w adrenergic (phentolamine) and &adrenergic (propranolol) receptor blockers as well as DA-receptor (haloperidol) and SER-receptor (cyproheptadine) blockers. Specificity of the receptor blockers, with a few exceptions, however, is not complete. For example, chlorpromazine and most other phenothiazines have some blocking action on the DA, NE, and SER receptors. In addition, a secondary increase in monoamine synthesis occurs following phenothiazine administration. Monoamine precursors. Both L-dopa, a precursor of DA and NE, and 5hydroxytryptophan, a precursor of SER, can be given systemically and will cross the blood-brain barrier. They are converted to their respective monoamines and enhance transmission. However, overloading with SER, for example, can lead to the uptake of this monoamine by nerve terminals, which normally contain DA and NE, and result in SER release as a false or inappropriate neurotransmitter upon stimulation of neurons, which normally release DA. The above observations indicate the need for caution in interpreting the results of experiments in which neuropharmacologic agents are used to alter neuroendocrine function. First, it is evident that whenever one aspect of monoamine metabolism is affected, interrelated and compensatory effects on other aspects can be anticipated. Second, the limited number of neurotransmitters under consideration, coupled with the multiple possible sites of control and the number of hypothalamic hormones involved, implies that a single neurotransmitter ma:y have effects on the secretion of several hypothalamic hormones. Conversely, more than one neurotransmitter may be involved in the control of individual hormone secretion. NEUROTRANSMITTERS

AND

HYPOTHALAMIC-PITUITARY

HORMONE

SECRETION

Growth Hormone

Evidence for the neurotransmitter control of GH secretion has been accumulating rapidly during the past few years. Although neurotransmitters are involved in the mediation of hypothalamic and suprahypothalamic stimulatory and inhibitory signals that affect GH secretion, the hypothalamic neurons that secrete the GH releasing and inhibiting factors are also affected by the circulating levels of

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certain metabolic fuels. The recent discovery of somatostatin (SRIF) requires that interpretation of neuroendocrine influences on GH secretion be compatible with a dual stimulatory-inhibitory control system. In time, when assays for both GHRF and SRIF in plasma become available, neural influences on the individual hypothalamic factors will be established and fluctuations in GH secretion should be determined to be the net result of the two influences. However, since the only reliable measurement at the present is GH itself, the following discussions will be based on presumed increases or decreases in GHRF levels alone. Catecholaminergic control of GH secretion is mediated through both (Y-and /3adrenergic receptor mechanisms, with the former being stimulatory and the latter inhibitory. Systemic administration of epinephrine, in combination with propranolol, a &receptor blocker, causes an elevation of plasma GH,4s and this effect can be blocked by phentolamine, an a-receptor blocker.47 Phentolamine and propranolol are capable of altering the response to several physiologic and pharmacologic stimuli of GH secretion, although in the hands of most investigators these agents alone are ineffective .* Thus phentolamine blocks the GH response to insulin hypoglycemia,50 vasopressin,5L arginine,52 and L-dopa,53 while propranolol enhances the GH response to insulin hypoglycemia,54 glucagon,55 amphetamines,56 aminophylline,57 L-dopa,53 and possibly arginine.4g*50 The site of action of the adrenergic blocking effect, however, remains open to question. Though propranolol does cross the blood-brain barrier,58 epinephrine does not appreciably,5g and evidence concerning phentolamine is lacking. Although phentolamine does block GH secretion when placed into the ventromedial hypothalamus in baboons, 6o it is entirely possible that the blocking effects of systemically administered phentolamine occur outside of the central nervous system. It has also been reported that thymoxamine, another a-receptor blocker, is unable to inhibit the GH response to amphetamine, which is believed due to a stimulation of central catecholamine release.56*61 The anatomic locus within the central nervous system, and even within the hypothalamus, at which metabolic fuels and neurotransmitters interact also requires precise identification. It is not known whether, for example, the hypothalamic neurons that are sensitive to changing concentrations of glucose, free fatty acids, and amino acids are identical to the GHRF- or SRIF-secreting cells or whether they merely transmit via neurotransmitters their influences to the neurosecretory cells. Numerous attempts to define the catecholaminergic role in GH secretion have been reported using a large number of neuropharmacologic agents originally introduced for the treatment of neurologic and psychiatric disorders. The GH response to insulin hypoglycemia is blocked by both reserpinee2 and chlorpromazine,63 although the lack of specificity of these agents with respect to individual neurotransmitters precludes attributing the effects to a precise mechanism. The introduction of L-dopa for treatment of Parkinson’s disease was followed shortly by the observation that oral L-dopa stimulated GH release.64 Studies with adrenergic receptor blockers revealed a similar response pattern: enhancement of *An exception to this observation has been reported by Japanese workers, who have found that and that the response can be blocked by glucose.4o propranolol alone stimulates GH secretiorP

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the L-dopa stimulation by propranolol and inhibition by phentolamine.53 The last observation, however, has been controversial. e5 The L-dopa response was not. blocked by fusaric acid, an inhibitor of dopamine j3-hydroxylase,sa implying that the stimulation was due to DA rather than to NE. Additional evidence supporting this conclusion is provided by the report that apomorphine, a relatively specific: stimulator of DA reeceptors, also stimulates GH secretion.83 Glucose adminis tration can block the L-dopa response if given before67 but not if given afterG.’ L-dopa. Taken together, these reports tend to implicate DA as a stimulatory neurotransmitter in the control of GH secretion, and they underscore the lack of specificity of phentolamine for the a-adrenergic receptor. These observations, along with those previously mentioned, support the concept that a variety of neural and humoral impulses impinge on a final common pathway (the GHRFor SRIF-secreting neurons) and that signals generated by altered levels of metabolic fuels can, given the appropriate conditions, override the neural signals. Growth hormone is released physiologically in association with the onset of stage III-IV sleep, and the neurotransmitter mechanism involved has been the subject of considerable investigation. The sleep-associated GH rise can be inhibited by imipramine, a tricyclic antidepressant that blocks NE reuptake,BS but is not influenced by LY-or ,&adrenergic receptor b1ockers6g or by chlorpromazine.68 Elevations of free fatty acids, however, are effective in inhibiting sleep-induced GH secretion70 and in blocking the response to insulin hypoglycemia and arginine, 71stimuli that are inhibited by a-receptor blockade. These findings again demonstrate the metabolic fuel-neural signal interrelationship. Partly on the basis of the association of SER with sleep,72 the relation of this monoamine to GH secretion has come under observation. Systemic administration of 5-hydroxytryptophan (5-HTP), the immediate precursor of SER, which unlike SER crosses the blood-brain barrier, stimulates GH release.73 As with L-dopa, the 5-HTP effect is blocked by glucose administration.73 Cyproheptadine, a SER-receptor blocker, inhibits the 5-HTP-induced GH release and also inhibits the GH release in response to arginine.74 Of interest is the report that blindness in rats is associated with low levels of pituitary GH, a phenomenon that can be reversed by pinealectomy. Decreased environmental light increases the conversion of SER to melatonin, and in rats the latter can block the GH response to 5-HTP, an effect presumed to occur at the level of the SER receptor.75 These observations must be kept in context, however, since blind human subjects m whom no slow-wave sleep induction of GH release occurs76 do not show evidence of retardation in linear growth. Prolac tin

The recent availability of a radioimmunoassay for PRL has resulted in numerous observations on the effects of drugs associated with galactorrhea on PRL secretion. Chlorpromazine, along with other phenothiazines, elevates PRL leve1s.77 By blocking brain catecholamine and SER receptors, chlorpromazine is believed to decrease hypothalamic secretion of PIF, resulting in increased PR.L secretion. Alpha-methyldopa, reserpine, and tricyclic antidepressants such as imipramine produce similar results,2~78 all through mechanisms that decrease effective catecholamine levels. L-dopa, in contrast, decreases PRL secretion pre-

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sumably by increasing hypothalamic catecholamines and presumably PIF secretion.77 This effect occurs irrespective of the initial PRL level,7g but does not occur in patients with hypothalamic damage.80 L-dopa blocks the rise of PRL seen after chlorpromazine,61 presumably by increasing hypothalamic catecholamines, thereby overcoming the receptor blockade due to chlorpromazine. An elegant series of experiments in rats has extended the above observations and confirmed the important role of both DA and NE on PRL secretion.*2 Inhibition of catecholamine synthesis by cY-methyltyrosine increased PRL secretion, an effect attributed to the reduction of an inhibitory catecholamine action (i.e., a decrease in PIF release), while restoration of NE levels by dihydroxyphenylserine, a precursor of NE that does not affect DA levels, did not reduce PRL levels. In addition, L-dopa decreased PRL levels even when conversion to NE was blocked by diethyldithiocarbamate, a dopamine #&hydroxylase inhibitor. These results all support the role of DA as an inhibitor of PRL secretion, presumably by stimulating PIF release. These conclusions are supported by the recent reports that apomorphine, which directly stimulates DA receptor sites without affecting NE receptors, decreases serum PRL levels but does not inhibit chlorpromazine-stimulated PRL release. This lack of effect may be explained by either a competition of the two drugs at a single DA receptora or effects at separate receptors. Other drugs have been reported to alter PRL release, although the site of action is not certain. Prostaglandin F,, , when used as an abortogen, is followed by an increase in PRL in rat.9’ and by lactation in humans.*5 Ergot alkaloids, especially ergocryptine (CB-154), decrease PRL levels in normalsa and in patients with puerperaP7 and nonpuerperals8 galactorrhea. Since both of these agents exert their effects on isolated pituitary glands in vitro, it has been generally assumed that the same mechanism of action occurs in vivo. However, the possibility of a prostaglandin effect on neurotransmitter metabolism has not been excluded, and ergocryptine also possesses DA-like activity.89 The above effects have all been explained in terms of an alteration in PIF release. Consequently the demonstration of a PRL releasing effect of TRH in humansgo has led to considerable controversy concerning the question of whether endogenous TRH exerts a physiologic role in the control of PRL secretion, The resolution of this question will most likely depend upon the measurement of circulating TRH levels. Until such measurements become available, however, similarities and differences in PRL and TSH secretion provide the basis for current speculation. Estrogen increases and thyroxine decreases the PRL response to TRH, presumably at the level of the pituitary. More significantly, although galactorrhea and/or breast engorgement are frequently seen in primary hypothyroidism and subside with thyroxine therapy,g1 serum PRL levels are not generally elevated.po If endogenous TRH levels are increased in hypothyroidism (evidence presented in the next section suggests they are not), then they are seemingly ineffective in elevating PRL levels. L-dopa blocks the PRL response to TRH,g2 which implies an action at the pituitary. An even more intriguing possibility is that L-dopa-induced stimulation of PIF release may block the effect of a PRF, in analogy to the relationship between somatostatin and GHRF.2g

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Also of interest is the report that estrogen enhances the stimulatory effect of perphenazine.g3 Either an estrogen-induced increase in the secretory rate of the uninhibited pituitary or an enhancement of the release of a PRF could explain this observation. Two different types of evidence have recently been presented suggesting that some aspects of neuroregulation of PRL secretion do not involve a DA control mechanism. PRL has been reported to decrease renal water excretiong4 and acute water loading has been reported to decrease PRL levels in normal subjects.Q5 This response was observed as well in patients with “functional” galactorrhea, but not in patients with PRL-secreting pituitary tumors. Since many patients with such tumors have been shown to respond to L-dopa (as will be described in a later section), these results raise the possibility of other neurotransmitters and perhaps a mechanism other than PIF. As with GH, PRL secretion also appears to be under the influence of serotonergic as well as catecholaminergic neurons. Administration of 5-HTP causes an increase in serum PRL levels, an effect reduced by cyproheptadine,g” although the mechanism remains open to speculation. Serotonin could either decrease PIF release or increase the release of a PRF.

TSH The neurotransmitter regulation of TRH and TSH secretion is less clearly defined than might be expected on the basis of TRH having been the first hypothalamic hormone to be fully characterized. This is in part due to the fact that alterations in circulating levels of triiodothyronine and thyroxine exert a major role in controlling the secretion of TSH by a negative-feedback mechanism at the pituitary. Thyroxine also exerts a positive feedback on TRH secretion by increasing TRH synthetase activity. l5 Consequently any claims of effects attributable to TRH based on changes in TSH levels must be derived from experiments in which circulating thyroid hormone concentrations remain unchanged. Cold exposure is a stimulus to TSH secretion that satisfies these conditions. TSH levels are increased in infants,Q7 although not in adults,Q8 and also in ratsI upon exposure to decreased environmental temperature. Elevations in urinary TRH in rats have also been reported in response to cold exposure.gg Neurotrans mitter mediation of this response has not been reported, although considerable evidence has implicated both SER and NE as important neurotransmitters in the response to cold stress.‘OO Administration of L-dopa has been reported not to alter TSH secretion in normal subjects,1o1 although the TSH levels in these subjects were near the limit of detectability. L-dopa decreases the elevated plasma TSH levels in patients with primary hypothyroidism. 7QThe mechanism of L-dopa suppression could involve an action on either the hypothalamus or the pituitary. The possibility of an effect on the pituitary is supported by the observation that L-dopa also inhibits the TSH response to TRH. Q2The alternative explanation of a hypothalamic locus of action would seemingly require the postulation of a thyrotropin inhibiting factor (somatostatin ?) that is stimulated by L-dopa, since measurement of urinary TRH in rats suggests that TRH secretion is decreased rather than increased in hypothyroidism. lo2 These considerations require that some caution be exercised

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in attributing all actions of systemically administered L-dopa to an alteration in releasing-factor secretion. In contrast to serotonin, 5hydroxytryptophan can cross the blood-brain barrier and has been shown to decrease plasma TSH values in hypothyroid, though not euthyroid, individualslo The mechanism of action is again not clear in light of the above report of decreased TRH secretion in hypothyroidism. In addition to the possibility of an action at the pituitary, or via a hypothetical thyrotropin inhibiting factor, two other alternatives must be considered. Either pituitary secretion of TSH requires the presence of minimal (permissive) amounts of TRH, or, to explain a hypothalamic etiology for certain patients with hypothyroidism, a thyrotropin releasing factor other than TRH must exist. Both L-dopa and 5hydroxytryptophan could then inhibit either TRH or the postulated second factor. Specific effects of neurotransmitters on TRH secretion have been reported in rats, and the results only partially support the above observations in humans. Serotonin inhibits the release of TRH by rat hypothalami in vitro, supporting the last mentioned hypothesis. However, both NE and DA increase, while reserpine decreases TRH release in vitro.15 These observations, therefore, leave open to question the mechanism of action of L-dopa on TSH secretion. L H and FSH

The control of gonadotropin secretion by neurotransmitters in humans remains unclear. There is considerable evidence that episodic pulsatile secretion of both LH and FSH occurs in both normal men and women.*04-‘W The pulses of LH are greater in magnitude and more consistent than those of FSH.‘07 This pattern is compatible with the concept of a single hypothalamic releasing hormone for both gonadotropins, inasmuch as the LH response to exogenous LHRH is greater than is that of FSH.lo8 Variations in the frequency and amplitude of the pulsatile gonadotropin release are modulated by ovarian steroids,‘o0 which act at both hypothalamic and pituitary levels. Although the neurotransmitter mediation of the estrogen effect is unknown, it is likely that a complex mechanism exists, since estrogens can exhibit both a stimulatory and inhibitory influence on gonadotropin release. Ilo Evidence for a direct stimulatory effect of estrogen on LHRH secretion in humans has recently been presented, based on bioassay”’ of this hypothalamic hormone in plasma. Studies in rats have implicated catecholamines, particularly DA, as stimulatory neurotransmitters in gonadotropin secretion,112 although there is considerable variability in the observed results depending on the experimental design of the studies. For example, small amounts of DA injected into the third ventricle were followed by enhanced LH and FSH release; but larger doses were ineffective, and DA stimulation was blocked by reserpine. Serotonin administration decreased LH release, yet SER-depleting agents failed to alter LH levels.s2 Further evidence for the role of catecholamines in the control of gonadotropin secretion has been provided by the reports of increased hypothalamic NE It has been suggested that these changes turnover following gonadectomy. 113*114 were due to elevated levels of FSH rather than to decreased estrogen effects.lL5

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Agents altering catecholamine-mediated responses in humans have not been effective in influencing gonadotropin levels. L-dopa administration has repeatedly been reported to be without effect on plasma LH levels,101~116 and a-adrenergic blockade with phentolamine and chlorpromazine was ineffective in modifying the pulsatile pattern of LH secretion.‘07 There is as yet no convincing documentation of serotonin effects on gonadotropin secretion in humans. However, disorders of the pineal gland, especially tumors, have been associated with altered gonadotropin secretion (i.e., precocious or delayed puberty associated with pinealomas). Two pineal factors (melatonin and a peptide) have been shown to possess gonadotropin-inhibiting activity in animals,‘17*11salthough their roles in human gonadotropin secretion are not known. The possible involvement of melatonin, the formation of which is inhibited by light, is inferred by a report that links superovulation with the duration of daylight, the implication being that inhibition of melatonin formation during periods of increased daylight resulted in a decrease in an inhibitory effect on LHRH release.‘Lg ACTH Numerous control mechanisms of ACTH secretion have been recognized and extensively documented. The convergence of various stimuli upon the CRFsecreting neurons results in a complicated pattern of CRF secretion based on circulating steroid levels, circadian influences, and acute stress, both internal and external. Moreover, the response to a given stimulus is dependent upon the preexisting set point of hypothalamic-hypophyseal function.‘20~121 There are extensive reports on the neurotransmitter control of ACTH secretion in laboratory animals. In general, basal ACTH secretion is increased by cholinergic, serotonergic, and adrenergic pathways and decreased by dopaminergic pathways. Stress responses appear to be mediated by both cholinergic and catecholaminergic pathways, while serotonergic and cholinergic mechanisms are involved in the circadian rhythm of ACTH secretion.122 There are conflicting reports concerning noradrenergic influences, which appear to be inhibitory in the rat’23 and dog,124yet stimulatory in the baboon.60 Much of the conflicting literature may well be explained by differences in the experimental design with respect to site of drug administration, condition of the test animal, and lack of specificity of the neuropharmacologic agents used. As with gonadotropins, there appears to be a very intricate relationship between steroid feedback influences and neurotransmitter-mediated impulses of central origin on the activation of the CRF-secreting neurons. Studies in human subjects are quite limited and provide only fragmentary evidence concerning neurotransmitter control. However, many of the concepts derived from animal experimentation appear to have been confirmed. For example, suppression of the pulsatile secretion of ACTH requires only half as much glucocorticoid administration as does suppression of basal ACTH levels, suggesting that the steroid effect may occur by more than one mechanism or, alternatively, that it alters the sensitivity of the CRF neuron to neurotransmittermediated stimuli of different intensity. Diphenylhydantoin and carbamazepine decrease the CNS sensitivity to steroid feedback, but do not abolish the normal

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circadian rhythmicity. lz5 During diphenylhydantoin administration there is evidence for enhanced pulsatile ACTH secretion125 and decreased responsiveness to metyrapone, lz6yet normal responses to stress’*’ and vasopressin.128 The effect of diphenylhydantoin may be due to its ability to stabilize membrane excitability while not altering other cellular function. 12gThese results support the postulated role of steroids in decreasing the CRF response to neural stimuli. An example of experimental conditions modifying the response to a stimulus is provided by the differential effect of ethanol on ACTH secretion. Alcohol raises plasma cortisol levels in normal subjects. In contrast, alcohol withdrawal in addicted humans elevates plasma cortisol, while readministration of alcohol or amylobarbitone decreases plasma cortisol. This effect of alcohol administration is not merely a relief of the withdrawal stress, since diazepam, which also relieves the clinical symptoms, does not decrease plasma cortisol.‘30 The neurotransmitter mediation of these alcohol effects remains to be determined. There have been limited reports of the effects of agents that alter neurotransmitter function on ACTH secretion in humans. L-dopa is without apparent effect,‘O* although both amphetamine and methylamphetamine appear to have a stimulatory effect on ACTH secretion, and the response is completely blocked by the cu-adrenergic blocker thymoxamine. 56,61Similarly, propranolol enhances and phentolamine suppresses the plasma ACTH response to insulin hypoglycemia.13’ A presumed NE stimulation of ACTH release is consistent with the results in baboons, 6o but the physiologic circumstances under which such conditions occur remain to be clarified. Stimulation of ACTH secretion in response to 5-HTP has been reported,131 and a possible role for serotonin mediation of the ACTH response to insulin hypoglycemia has recently been proposed based on the inhibition of the response in subjects pretreated with the serotonin blocker cyproheptadine.132 However, since methysergide, another serotonin blocker, was ineffective in inhibiting this response, one must question whether the cyproheptadine effect could have involved a mechanism other than serotonin receptor blockade. NEUROPHARMACOLOGIC

APPROACHES

NEUROENDOCRINE

TO DISORDERS

OF

FUNCTION

On the basis of the concepts and experimental observations already presented, it is now possible to consider the evidence for neurotransmitter dysfunction as an etiology for specific neuroendocrine disorders and to assess the potential of neuropharmacologic approaches to therapy. Growth Hormone

De$ciency States

Two specific entities, idiopathic growth hormone deficiency133 and deprivation dwarfism,13* are currently believed to represent disorders of the central nervous system rather than being of pituitary origin. The belief is based on indirect (i.e., inferential) data, and final proof will not be possible until GHRF becomes available for clinical studies and until methods are developed for the measurement of circulating levels of GHRF. Patients with deprivation dwarfism exhibit GH deficiency, as judged by their responses to standard testing procedures when studied immediately upon ad-

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mission to the hospital. Within a short period of time, and in association with an increase in linear growth rate, the GH responses revert to normal.‘34 This phenomenon suggests the existence of both an intact pituitary somatotroph and an intact GHRF-secreting hypothalamic neuron and raises the possibility that altered neurotransmitter activity could be responsible for impaired GHRF secretion (or for the alternate explanation of increased SRIF secretion). The possibility that affective disorders can impair GH responses is supported by the recent reports of decreased GH responses to insulin hypoglycemia and L-dopa in patients with depressive (though, interestingly, not manic-depressive) disorders.135.136Further support for this hypothesis is provided by a report of a single patient with deprivation dwarfism in whom an exaggerated GH response occurred to insulin hypoglycemia during propranolol pretreatment, despite an absent-to-poor response to insulin alone. 137This report, if confirmed, would imply that the lack of GH secretion in deprivation dwarfism is associated with enhanced B-adrenergic activity. In certain depressive illnesses drugs that enhance nonadrenergic transmission cause clinical improvement. This has led to the hypothesis of the existence of a functional NE depletion.‘38 The enhanced /3adrernergic activity as an explanation for the impaired GH secretion in deprivation dwarfism would appear to be inconsistent with this hypothesis. Neurotransmitter function must also be considered with respect to idiopathic GH deficiency. As in deprivation dwarfism there is a suggestion that propranolol restores to normal the GH responses to standard stimuli,131 although there is some controversy about this point. The possibility must also be considered that idiopathic GH deficiency represents a heterogeneous group of disorders and that fl-adrenergic overactivity may be present in only one subgroup. The crucial question is whether restoration of linear growth can be accomplished by neuropharmacologic means, since it could represent a major advance in treatment, which is currently dependent upon the limited availability of human GH. Growth Hormone Excess States The other end of the spectrum of GH secretion, as represented by acromegaly, has also been the subject of considerable investigation. The results of these studies suggest that at least in some acromegalics (1) GH secretion is under hypothalamic control, (2) the control mechanisms are abnormal both quantitatively and qualitatively, and (3) altered neurotransmitter function may be responsible for these abnormalities. Hypothalamic control of GH secretion in acromegalics has been conclusively demonstrated by several groups of investigators.‘3g*140 Plasma GH responses to stimuli such as arginine and insulin hypoglycemia have generally been qualitatively similar to responses in normals, although often quantitatively abnormal. However, in response to glucose administration, some acromegalics have exhibited a paradoxical increase in plasma GH levels.13g A tabulation of the GH responses to neuropharmacological agents also results in some conflicting reports that are difficult to explain. As was predicted from results in normal subjects,63 chlorpromazine has been reported to decrease plasma GH levels in some’41 but not all acromegalics. 142Similar decreases in plasma GH in some acromegalics have been observed with phentolamine and with dexamethasone

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(with a high degree of concordance), although their responses or lack thereof could not be predicted on the basis of the GH response to glucose.143 From our knowledge of the mechanism of action of these agents, it is only logical to suggest that GH hypersecretion in acromegalics responsive to these drugs might be caused by excessive catecholamine stimulation of the GHRF-secreting cells. Recently, however, plasma GH levels in acromegalics have been reported to decrease following L-dopa administration.‘44 This paradoxical response to L-dopa is difficult to explain, even if it is proposed that the effect is mediated through the stimulation of SRIF, which does lower plasma GH in acromegalics,31,33 because the GH responses to L-dopa in normals are incompatible with this explanation. While the exact mechanism of action of neuropharmacologic agents in acromegaly is unclear, it is not unreasonable to expect that they may have an important role to play in the therapy of this disease. Along with SRIF, which may also have limitations due to its many other effects, it may be possible to offer pharmacologic therapeutic approaches to selective patients with acromegaly. Two other conditions in which GH hypersecretion has been reported also raise questions of abnormal neurotransmitter regulation. Recent reports have indicated that GH hyperresponsiveness occurs in association with exercise in patients with diabetes mellitus.145 Whereas the GH responses return to normal upon rigid control of the blood glucose level, they can also be corrected by a-adrenergic blockade using phentolamine. 146This observation suggests that the normal metabolic changes that occur during exercise and that are responsible for stimulating GH release are enhanced in uncontrolled diabetics and that stimulation of LYadrenergic receptors are involved in this mechanism. It must still be proved, however, that the action of phentolamine is within the central nervous system rather than in the periphery. The entire question of GH secretion in diabetes as related to the microangiopathy is of even greater significance. The possibility of reducing growth hormone secretion either neuropharmacologically or by SRIF as a means of preventing or retarding diabetic retinopathy and nephropathy appears feasible in the near future and can be expected to receive considerable attention. Another disease in which GH hypersecretion has been reported is anorexia nervosa.14’ Although the abnormalities of GH regulation may represent nothing more than the response to severe starvation, the overall pattern of hormone and metabolic dysfunction in this disease raises the possibility of a generalized disorder of neurotransmitter metabolism. To date there have been insufficient data reported either to substantiate or refute this possibility, and it therefore still remains merely an attractive hypothesis. Prolactin Hypersecretion States Hyperprolactinemia is associated with numerous pathologic conditions, including hypothyroidism and advanced renal failure, as well as diseases involving the hypothalamus or pituitary. Some of these patients exhibit galactorrhea, although the correlation with prolactin levels is poor. Hypothalamic-pituitary disorders are generally divided into two categories: those with demonstrable lesions in the hypothalamus and/or pituitary (such as PRL-secreting pituitary tumors, craniopharyngiomas, and sarcoidosis) and those in which no abnormalities

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can be identified (“functional” or Chiari-Frommel syndrome). Whether the functional group is indeed distinct from the PRL-secreting tumor group is not entirely clear, because attempts to distinguish between the two on the basis of the responsiveness of PRL levels to stimuli and inhibitors such as L-dopa and chlorpromazine have not been uniformly successful. Recently it has been proposed that this distinction can be made on the basis of the hormonal response or lack of response of both the functo synthetic releasing hormones. 148The hyperprolactinemia tional variety and some pituitary tumors can be diminished by L-dopa.2 This implies that PRL-secreting tumors, as well as some GH-secreting tumors, may result from alterations in hypothalamic neurotransmitter function resulting m excessive PRL secretion. Of additional interest is the frequent association of amenorrhea and lack of cyclic gonadotropin secretion in patients with elevated PRL levels and galactorrhea, and the return of normal menses following suppression of PRL secretion by L-dopa. 14gThe known effects of catecholamines on gonadotropin secretion suggest that a functional deficiency of catecholamine metabolism may exist in such patients and that L-dopa could be correcting this abnormality. Attempts to stimulate FSH and LH secretion acutely with L-dopa :in patients with either functional or pituitary-tumor-associated amenorrhea-galactorrhea syndrome have been unsuccessful. I50However, chronic administration of L-dopa has resulted in increased levels of circulating gonadotropins.‘“’ Ergocryptine has also been reported to produce similar results,S6 supporting the concept of a central-nervous-system locus for its site of actions9 An alternate explanation for the ergocryptine effect, however, is that the amenorrhea is secondary to elevated prolactin levels, as has recently been suggested,‘52 and that normal menses return subsequent to inhibition of prolactin secretion by the drug at the level of the pituitary. Considerable interest has been generated concerning the possibility that prolactin hypersecretion might be in some way pathogenetically related to brearst cancer. Although there is considerable controversy over this question, studies are currently under way to evaluate the effect of suppression of prolactin secretion on tumor growth using L-dopa and ergocryptine.2 A preliminary report has indicated subjective improvement in two patients with osseous metastases in association with a decrease in serum prolactin levels,‘53 and the significance of this finding, if it is confirmed in larger numbers of patients, does not need amplification. OTHER NEUROENDOCRINE

DISORDERS

NEUROTRANSMITTER

POSSIBLY

RELATED TO

DYSFUNCTION

Among other diseases of presumed hypothalamic etiology, there are several rn which altered neurotransmitter function should be considered. These include adrenal cortical hyperplasia (Cushing’s syndrome), polycystic ovarian hyperplasia (Stein-Levinthal syndrome), psychogenic amenorrhea, menstrual cycle irregularities associated with asynchronous midcycle FSH and LH secretion, hypothalamic hypothyroidism, anorexia nervosa, and lipoatrophic diabetes. This list will undoubtedly require frequent revision and expansion. Evidence for the implication of abnormal neurotransmitter function in these disorders does not yet exist. Yet the lack of degenerative, infiltrative, or neoplastic changes in histologic examinations of brains from patients with these disorders supports the

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hypothesis that the “functional” abnormalities may be on the basis of alterations in neurotransmitter metabolism. In certain ways Cushing’s syndrome shares many pathophysiologic attributes with acromegaly. In both diseases there is elevated secretion of a pituitary hormone (ACTH or GH); functioning microadenomata of the pituitary are often present; evidence for hypersecretion of specific releasing factors is present (CRF or GHRF); control of pituitary-hormone secretion (and, by implication, releasing-factor secretion), while abnormal, is not completely unresponsive to physiologic feedback or stimulation mechanisms.15* Consequently it is only reasonable to predict that mechanisms will be found to reduce elevated CRF and ACTH levels by neuropharmacologic means, as have been described in acromegaly. To date there has been little success in neuropharmacologic blockade of CRF, in contrast to the pharmacologic methods that are effective in blocking cortisol synthesis in the adrenal.155*156 Even less has been reported concerning neurotransmitter function in those disorders characterized by abnormal gonadotropin secretion. In both adrenal corticosteroid and gonadal steroid feedback systems, it has not yet been conclusively determined whether the steroid-sensitive neurons are identical to the peptidergic releasing factor-secreting neurons. If they are, manipulation of neurotransmitter function might be less easily demonstrated than if different populations of neurons are involved. of altered neurotransmitter function in The possible contribution also remains to be determined. On the basis hypothalamic hypothyroidism 157*158 of the reported ability of L-dopa to depress the elevated TSH level in primary hypothyroidism, one might be tempted to propose that catecholamine receptors are inhibitory to TRH release. It must be remembered, though, that there is no evidence to suggest an elevation of TRH secretion in primary hypothyroidism, and in fact TRH synthesis and urinary TSH are decreased in the hypothyroid state.15*102Moreover, DA and NE increase TRH in vitro.15 Further studies will be required in order to resolve these seemingly conflicting observations. Lastly, in two metabolic disorders, anorexia nervosa15s and lipoatrophic diabetes,lso hypothalamic functional disorders have been postulated, and in the latter a dopaminergic hyperactivity has been suggested. If additional studies can confirm and delineate the role of neurotransmitters in the pathogenesis of these disorders, then a rational approach to pharmacologic therapy may provide new and potentially useful therapeutic agents. REFERENCES 1. Blackwell RE. Guillemin R: Hypothalamic control of adenohypophyseal secretions. Ann Rev Physiol35:357, 1973 2. Friesen H, Hwang P: Human prolactin. Ann Rev Med 24:25 I, 1973 3. Kastin AJ, Gual C, Schally AV: Clinical experience with hypothalamic releasing hormones. Part 2. Luteinizing hormone-releasing hormone and other hypothalamic releasing hormones. Recent Prog Horm Res 28:201,1972 4. Martin JB: Neural regulation of growth

hormone secretion. N Engl J Med 288:1384, 1973 5. Mtiller EE: Nervous control of growth hormone secretion. Neuroendocrinology I l:338, 1973 6. Schally AV: Hypothalamic regulatory hormones. Science 179:341, 1973 7. Wilber JF: Thyrotropin releasing hormone: Secretion and actions. Ann Rev Med 24353, 1973 8. Wurtman RJ: Brain monoamines and

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endocrine function. Neurosci Res Program Bull 9:172,1971 9. Frohman LA: Clinical neuropharmacology of hypothalamic releasing factors. N Engl J Med 286:1391, 1972 10. Burgus R, Dunn TF, Desiderio D, Guillemin R: Structure moleculaire du facteur hypothalamique hypophysiotrope TRF d’origine ovine: evidence par spectrometrie de masse de la sequence PCA-His-Pro-NH,. C R Acad Sci [D] (Paris) 269:1870, 1969 11. B#er J, Enzmann F, Folkers K: The identity of chemical and hormonal properties of the thyrotropin releasing hormone and pyroglutamyl-histidyl-proline amide. Biochem Biophys Res Commun 37:705, 1969 12. Matsuo H, Baba Y, Nair RMG, Arimura A, Schally AV: Structure of the porcine LH- and FSH-releasing hormone. I. The proposed amino acid sequence. Biochem Biophys Res Commun 43:1334, 1971 13. Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, Guillemin R: Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179:77, 1973 14. Haigler ED Jr, Pittman JA Jr, Hershman JM, Baugh CM: Direct evaluation of pituitary thyrotropin reserve utilizing synthetic thyrotropin releasing hormone. J Clin Endocrinol Metab 33:573, 1971 15. Reichlin S, Martin JB, Mitnick MA, Boshans RL, Grimm Y, Bollinger J, Gordon J, Malacara J: The hypothalamus in pituitarythyroid regulation. Recent Prog Horm Res 28229.1972 16. Mittler JC, Redding TW, Schally AV: Stimulation of thyrotropin (TSH) secretion by TSH-releasing factor (TRF) in organ cultures of anterior pituitary. Proc Sot Exp Biol Med 130:406,1969 17. Jacobs LS, Snyder PJ, Wilber JF, Utiger RD. Daughaday WH: Increased serum prolactin after administration of synthetic thyrotropin releasing hormone (TRH) in man. J Clin Endocrinol Metab 33:996, 1971 18. Irie M, Tsusbima T: Increase of serum growth hormone concentration following thyrotropin-releasing hormone injection in patients with acromegaly and gigantism. J Clin Endocrinol Metab 35:97, 1972 19. LaBella FS, Vivian SR: Effect of synthetic TRF on hormone release from bovine anterior pituitary in vitro. Endocrinology 88:787, 1971 20. Hedge GA, Yates MB, Marcus R, Yates FE: Site of action of vasopressin in causing

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corticotropin release. Endocrinology 79:328, 1966 21. Saffran M, Pearlmutter AF, Rapino E: Pressinoic acid: A peptide with potent corticotropin-releasing activity. Biochem Biophys Res Commun 49:748, 1972 22. Kastin AJ, Schally AV, Gual C, Midgley AR, Bowers CY, Diaz-Infante A: Stimulation of LH release in men and women by LH-releasing hormone purified from porcine hypothalami. J Clin Endocrinol Metab 29:1046, 1969 23. Keye WR Jr, Jaffe RB: Modulation of pituitary gonadotropin response to gonadotropin-releasing hormone by estradiol. J Clin Endocrinol Metab 38:805, 1974 24. Yen SSC, Vandenberg G, Rebar R, Ehara Y: Variation of pituitary responsiveness to synthetic LRF during different phases of the menstrual cycle. J Clin Endocrinol Metab 35:931, 1972 25. Chang JK, Sievertsson H, Bogentoft 0, Currie BL, Folkers K: Activity of a new synthetic tetrapeptide in hypothalamic luteinizing and follicle stimulating releasing hormone assay systems. Biochem Biophys Res Commun 44:414, 1971 26. Schally AV, Baba Y, Nair RMG, Bennet CD: The amino acid sequence of a peptide with growth hormone releasing activity isolated from porcine hypothalamus. J Biol Chem 246:664’7, 1971 27. Frohman LA, Maran JW, Dhariwal APS: Plasma growth hormone responses to intrapituitary injections of growth hormone releasing factor (GRF) in the rat. Endocrinology 88:1483, 1971 28. Malacara JM, Valverde RC, Reichlin S, Bollinger J: Elevation of plasma radioimmunoassayable growth hormone in the rat induced by porcine hypothalamic extract. Endocrinology 91:1189, 1972 29. Martin JB: Inhibitory effect of somatostatin (SRIF) on the release of growth hormone (GH) induced in the rat by electrical stimulation. Endocrinology 94:497, 1974 30. Vale W, Brazeau P, Grant G, Nussey A, Burgus R, Rivier R, Ling N, Guillemin R: Premieres observations sur le mode d’action de la somatostatine, un facteur hypothalamique qui inhibe la secretion de I’hormone de croisance. (3 R Acad Sci (Paris) 275:2913, 1972 31. Hall R, Besser GM, Schally AV, Coy DH., Evered D, Goldie DJ, Kastin AJ, McNielly BS, Mortimer CH, Phenekos C, Tunbridge WMG, Weightman D: Action of growth-hormonerelease inhibitory hormone in healthy men and in acromegaly. Lancet 2:581, 1973

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32. Alberti KGMM, Juel Christensen N. Christensen SE, Prange Hansen A, Iversen J, Lundback K, Seyer-Hansen K, Orskov H: Inhibition of insulin secretion by somatostatin. Lancet 2:1299, 1973 33. Mortimer CH, Tunbridge WMG, Carr D, Yeomans L, Lind T, Coy DH, Bloom SR, Kastin A, Mallinson CN, Besser GM, Schally AV, Hall R: ElTects of growth hormone release inhibiting hormone on circulating glucagon, insulin, and growth hormone in normal diabetic, acromegalic, and hypopituitary patients. Lancet 1:697,1974 34. Everett JW: The control of the secretion of prolactin, in Harris GW, Donovan BT (eds): The Pituitary Gland. London, Butterworths, 1966, p 166 35. Turkington RW, Underwood LE, Van Wyk JJ: Elevated serum prolactin levels after pituitary stalk secretion in man. N Engl J Med 285:707, 1971 36. Tashjian AH Jr, Barowsky NJ, Jensen DK: Thyrotropin releasing hormone: Direct evidence for stimulation of prolactin production by pituitary cells in culture. Biochem Biophys Res Commun 43:516,1971 37. Valverde-R C, ChietTo V, Reichlin S: Failure of reserpine to block ether-induced release of prolactin: Physiological evidence that stress induced prolactin release is not caused by acute inhibition of PIF secretion. Life Sci 12:327, 1973 38. Bassiri RM, Utiger RD: The preparation and specificity of antibody to thyrotropin releasing hormone. Endocrinology 90:722, 1972 39. Nett TM, Akbar AM, Niswender GD, Hedlund MT, White WF: A radioimmunoassay for gonadotropin releasing hormone in serum. J Clin Endocrinol Metab 36:880, 1973 40. Arimura A, Sato H, Coy DH: A radioimmunoassay method for GH-release inhibiting factor. Program of the Endocrine Society, 56th annual meeting (A-196) 1974 41. Zigmond MJ, Wurtman RJ: Daily rhythm in the accumulation of brain catecholamines synthesized from circulating 3H-tyrosine. J Pharmacol Exp Ther 172:416, 1970 42. Fernstrom JD, Wurtman RJ: Brain serotonin content: Physiological dependence on plasma tryptophan levels. Science 173:149, 1971 43. Fernstrom JD, Wurtman RJ: Brain serotonin content: Increase following ingestion of carbohydratediet. Science 174:1023, 1971 44. Fernstrom JD, Wurtman RJ: Elevations of plasma tryptophan by insulin in rat. Metabolism 21:337, 1972

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45. Sulser F, Sanders-Bush E: Effect of drugs on amines in the CNS. Ann Rev Pharmacol 11:290, 1971 46. Blackard WG, Hubbell GJ: Stimulatory effect of exogenous catecholamines on plasma HGH concentrations in the presence of beta adrenergic blockade. Metabolism 19:547, 1970 47. Massara F, Camanni F: Plasma human growth hormone levels following the administration of various adrenergic drugs. Presented at the Second International Symposium on Growth Hormone, Milan, Italy, May S-7, 1971 48. Imura H, Kato Y, Ikeda M, Morimoto M, Yawata M, Fukase M: Increased plasma levels of growth hormone during infusion of propranolol. J Clin Endocrinol Metab 28:1079, 1968 49. Imura H, Kato Y, Morimoto M, Ikeda M, Yawata M: Effect of adrenergic-blocking or -stimulating agents on plasma growth hormone, immunoreactive insulin and blood free fatty acid levels in man. J Clin Invest 50:1069, 1971 50. Blackard WG, Heidingsfelder SA: Adrenergic receptor control mechanism for growth hormone secretion. J Clin Invest 47:1407, 1968 51. Heidingsfelder SA, Blackard WG: Adrenergic control mechanism for vasopressininduced plasma growth hormone response. Metabolism 17:1019, 1968 52. Buckler JMH, Bold AM, Taberner M, London DR: Modification of hormonal response to arginine by a-adrenergic blockade. Br Med J 3:153, 1969 53. Kansal PC, Buse J, Talbert OR, Buse M: The effect of L-dopa on plasma growth hormone, insulin, and thyroxine. J Clin Endocrinol Metab 34:99, 1972 54. Parra A, Schultz RB, Foley TP Jr, Blizzard RM: Influence of epinephrine-propranolol infusions on growth hormone release in normal and hypopituitary subjects. J Clin Endocrinol Metab 30: 134, 1970 55. Mitchell ML, Suvunrungsi P, Sawin CT: Effect of propranolol on the response of serum growth hormone to glucagon. J Clin Endocrinol Metab 32:470, 1971 56. Rees L, Butler PWP, Gosling C, Besser GM: Adrenergic blockade and the corticosteroid and growth hormone responses to methylamphetamine. Nature (London) 288:565, 1970 57. Ensinck JW, Stall RW, Gale CC, Santen RJ, Touker JL, Williams RH: Effect of aminophylline on the secretion of insulin, glucagon, luteinizing hormone and growth hormone in humans. J Clin Endocrinol Metab 31:153, 1970

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58. Laverty R, Taylor KM: Propranolol uptake into the central nervous system and the effect on rat behavior and amine metabolism. J Pharm Pharmacol20:605,1968 59. Axelrod J: The metabolism, storage, and release of catecholamines. Recent Prog Horm Res 21597, 1965 60. Toivola PTK, Gale CC: Stimulation of growth hormone release by microinfusion of norepinephrine into hypothalamus of baboons. Endocrinology 90895, 1972 61. Besser GM, Butler PWP, Landon J, Rees L: Influence of amphetamines on plasma corticosteroid and growth hormone levels in man. Br Med J 4:529, 1969 62. Cavagnini F, Peracchi M: Effect of reserpine on growth hormone response to insulin hypoglycaemia and to arginine infusion in normal subjects and hyperthyroid patients. J Endocrinol51:651, 197I 63. Sherman L, Kim S, Benjamin F, Kolodny HD: Effect of chlorpromazine on serum growth hormone concentration in man. N Engl J Med 284:72, 1971 64. Boyd AE III, Lebovitz HE, PfeiIfer JB: Stimulation of human-growth-hormone secretion by L-dopa. N Engl J Med 283: 1425, 1970 65. Imura H, Nakai Y, Matsukura S, Matsuyama H: Effect of intravenous infusion of Ldopa on plasma growth hormone levels in man. Horm Metab Res 5:41, 1973 66. Hidaka H, Nagasaka A, Takeda A: Fusaric (5-butylpicolinic) acid: Its effect on plasma growth hormone. J Clin Endocrinol Metab 37:145, 1973 67. Mims RB, Scott CL, Modebe OM, Bethune JE: Prevention of L-dopa induced growth hormone stimulation by hyperglycemia. J Clin Endocrinol Metab 37:660, 1973 68. Takahashi Y, Kipnis DM, Daughaday WH: Growth hormone secretion during sleep. J Clin Invest 47:2079, 1968 69. Lucke C, Glick S: Experimental modification of the sleep induced peak of growth hormone secretion. J Clin Endocrinol Metab 32:729, 1971 70. Lipman RL, Taylor AL, Schenk A, Mintz DH: Inhibition of sleep related growth hormone release by elevated free fatty acids. J Clin Endocrinol Metab 35:592, 1972 71. Blackard WG, Hull EW, Lopez-S A: Effect of lipids on growth hormone secretion in humans. J Clin Invest 50:1439,1971 72. Jouvet M: Biogenic amines and the states of sleep. Science 163:32, I969 73. Imura H, Nakai Y, Yoshima T: Effect of S-hydroxytryptophan on growth hormone and

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ACTH release in man. J Clin Endocrinol Metab 36:204,1973 74. Nakai Y, Imura H, Sakurai H, Kurchachr H, Yoshima T: Effect of cyproheptadine on. human growth hormone secretion. J Clin Endocrinol Metab 38:446, 1974 75. Smythe GA, Lazarus L: Growth hormone: regulation of melatonin and serotonin. Nature 244:230,1973 76. Krieger DT, Glick SM: Absent sleep peak of growth hormone release in blind subjects: Correlation with sleep EEG stages. J Clin Endocrinol Metab 33:847,1971 77. Friesen H, Guyda H, Wang P, Tyson JE, Barbeau A: Functional evaluation of prolactin secretion-A guide to therapy. J Clin Invest 5 1:706,1972 78. Turkington RW: The clinical endocrinology of prolactin. Adv Intern Med 18363, 1972 79. Rapoport B, Refetoff S, Fang VS, Friesen HG: Suppression of serum thyrotropin (TSH) by L-dopa in chronic hypothyroidism: Interrelationships in the regulation of TSH and prolactin secretion. J Clin Endocrinol Metab 36:256, 1973 80. Jacobs LS, Bauman JE, Daughaday WH: Hypothalamic influences on prolactin secretion in man. J LabClin Med 78:818, 1971 81. Kleinberg DL, Noel GL, Frantz AG: Chlorpromazine stimulation and L-dopa suppression of plasma prolactin in man. J Clin Endocrinol Metab 33:873, 197I 82. Donoso AO, Bishop W, Fawcett CP, Krulich L, McCann SM: Effects of drugs that modify brain monoamine concentrations on plasma gonadotropin and prolactin levels in the rat. Endocrinology 89:774,197 I 83. La1 S, de la Vega CE, Sourkes TL, Friesen HG: Effect of apomorphine on growth hormone, prolactin, luteinizing hormone and follicle stimulating hormone in human serum. J Clin Endocrinol Metab 37:7 19, 1973 84. Deis RP, Vermouth NT: Prolactin release induced by prostaglandin F,, in pregnant rats. Abstracts of IV International Congress of Endocrinology, Washington, D.C., 1972, p 191 85. Smith ID, Shearman RP, Korda AR: Lactation following therapeutic abortion with prostaglandin F,, . Nature 240:411, 1972 86. del Pozo E, Brun del Re R, Varga L. Friesen H: The inhibition of prolactin secretion in man by CB-154 (2-Br-a-ergocryptine). J Clin Endocrinol Metab 35:768, 1972 87. Varga L, Lutterbeck PM, Pryor JS, Wenner R, Erb H: Suppression of puerperal lactation with an ergot alkaloid: A double blind study. Br Med J 2~743, 1972

232

88. Lutterbeck PM, Pryor JS, Varga L, Wenner R: Treatment of non-puerperal galactorrhea with an ergot alkaloid. Br Med J 3:228, 1971 89. Corrodi H, Fuxe K, Hokfelt T, Lidbrink P, Ungerstedt U: Effect of ergot drugs on central catecholamine neurons: Evidence for a stimulation of central dopamine neurons. J Pharm Pharmacol25:409,1973 90. Jacobs LS, Snyder PJ, Wilber JF, Utiger RD, Daughaday WH: Increased serum prolactin after administration of synthetic thyrotropin releasing hormone (TRH) in man. J Clin Endocrinol Metab 33:996, 1971 91. Van Wyk JJ, Grumbach MM: Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism: An example of hormonal overlap in pituitary feedback. J Pediatr 57:416, 1960 92. Refetoff S, Fang VS, Rapoport B, Friesen HG: interrelationships in the regulation of TSH and prolactin secretion in man: Effects of Ldopa, TRH and thyroid hormone in various combinations. J Clin Endocrinol Metab 38:450, 1974 93. Buckman MT, Peake GT: Estrogen potentiation of phenothiaxine induced prolactin secretion in man. J Clin Endocrinol Metab 37:977, 1973 94. Horrobin DF, Burstyn PG, Lloyd IJ, Dunkin N, Lipton A, Muiruri KL: Actions of prolactin on human renal function. Lancet 2:352, 1971 95. Buckman MT, Kaminsky N, Conway M, Peake GT: Utility of L-dopa and water loading in evaluation of hyperprolactinemia. J Clin Endocrinol Metah 36:9 11,1973 96. Kato Y, Nakai Y, Imura H, Chihara K, Ohgo S: Effect of 5-hydroxytryptophan (5-HTP) on plasma prolactin levels in man. J Clin Endocrinol Metab 38:695, 1974 97. Wilber JF, Baum D: Elevation of plasma TSH during surgical hypothermia. J Clin Endocrinol Metab 31:372, 1970 98. Hershman JM, Read DG, Bailey AL, Norman VD, Gibson JB: Effect of cold exposure on serum thyrotropin. J Clin Endocrinol Metab 30:430, 1970 99. Montoya E, Seibel MJ, Wilkes J: Studies of thyrotropin-releasing hormone (TRH) in the rat by means of radioimmunoassay: Normal values and response to cold response. 55th annual meeting of the Endocrine Society (A- 138), 1973 100. Feldberg W: Monoamines of the hypothalamus as mediators of temperature response, in Martin L, Motta M, Fraschini F @is): The Hypothalamus. New York, Academic, 1970, p 213

FROHMAN

AND

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101. Eddy RL, Jones AL, Chakmakjian ZH, Silverthorne MC: Effect of levodopa (L-dopa) on human hypophysial trophic hormone release. J Clin Endocrinol Metab 33:709, 1971 102. Jackson IMD, Gage1 R, Papapetrou P, Reichlin S: Pituitary, hypothalamic and urinary thyrotropin releasing hormone concentration in altered thyroid states of rat and man. Clin Res 22:342A, 1974 103. Yoshimura M, Ochi Y, Miyazaki T, Shiomi K, Hachiya T: Effect of L-5-HTP on release of growth hormone, TSH and insulin. Endocrinol Jap 20:135,1973 104. Midgeley AR Jr, Jaffe RB: Regulation of human gonadotropins. X. Episodic fluctuation of LH during the menstrual cycle. J Clin Endocrinol Metab 33:962,197 1 105. Nankin HR, Troen P: Repetitive luteinizing hormone elevations in serum of normal men. J Clin Endocrinol Metab 33:558, 1971 106. Naftolin F, Yen SSC, Tsai CC: Rapid cycling of plasma gonadotropins in normal men as demonstrated by frequent sampling. Nature [New Biol] 236:92, 1972 107. Santen RJ, Barden CW: Episodic luteinizing hormone secretion in man. Pulse analysis, clinical interpretation, physiologic mechanisms. J Clin Invest 52:2617, 1973 108. Yen SSC, Rebar R, VandenBerg G, Naftolin F, Ehara Y, Engblom S, Ryan KJ, Benirschke K: Synthetic luteinizing hormonereleasing factor: A potent stimulator of gonadotropin release in man. J Clin Endocrinol Metab 34:1108, 1972 109. Yen SSC, Tsai CC, Naftolin F, VandenBerg G, Ajabor L: Pulsatile patterns of gonadotropin release in subjects with and without ovarian function. J Clin Endocrinol Metab 34:671, 1972 110. Yen SSC, Tsai CC: The biphasic pattern in the feedback action of ethanyl estradiol on the release of pituitary FSH and LH. J Clin Endocrinol Metab 33:882, 1971 111. Seyler LE Jr, Canalis E, Reichlin S: Estrogen stimulated luteinizing hormone releasing factor (LRF) secretion in hypogonadal males. Clin Res 22:349A, 1974 112. McCann SM: Neurohormonal correlates of ovulation. Fed Proc 29:1888, 1970 113. Anton-Tay F, Wurtman RJ: Norepinephrine: Turnover in rat brains after gonadectomy. Science 159:1245, 1968 114. Bapna J, Neff NH, Costa E: A method for studying norepinephrine and serotonin metabolism in small regions of rat brain: Effect of ovariectomy on amine metabolism in anterior

CONTROL

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and posterior hypothalamus. Endocrinology 89:1345, 1971 115. Anton-Tay F, Pelham RW, Wurtman RJ: Increased turnover of 3H-norepinephrine in rat brain following castration or treatment with ovine follicle stimulating hormone. Endocrinology 84: 1489, 1969 116. Sinhamahapatra SB, Kirschner MA: Effect of L-dopa on testosterone and luteinizing hormone production. J Clin Endocrinol Metab 34~756, 1972 117. Motta M, Fraschini F, Martini L: Endocrine effects of pineal gland and of melatonin. Proc Sot Exp Biol Med 126:431, 1967 118. Benson B, Matthews MJ, Rodin AE: A melatonin-free extract of bovine pineal with antigonadotropin activity. Life Sci 10:607, 1971 119. Timonen S, Carpen E: Multiple pregnancies and photoperiodicity. Ann Chir Gynaecol Fenn 57:135, 1968 120. Hofer MA, Wolff CT, Friedman SB, Mason JB: A psychoendocrine study of bereavement. Part 1. 17-hydroxycorticosteroid excretion rates of parents following death of their children from leukemia. Psychosom Med 34:48 1, 1972 121. Hofer MA, Wolff CT, Friedman SB, Mason JW: A psychoendocrine study of bereavement. Part II. Observations on the process of mourning in relation to adrenocortical function. Psychosom Med 341492, 1972 122. Krieger DT: Neurotransmitter regulation of ACTH release. Mt Sinai J Med 40:302, 1973 123. Van Loon GR, Scapagnini U, Cohen R, Ganong WF: Effect of intraventricular administration of adrenergic drugs on the adrenal venous 17-hydroxycorticosteroid response to surgical stress in the dog. Neuroendocrinology 8:257, 1971 124. Van Loon GR, Hilger L, Cohen R: Evidence for a hypothalamic adrenergic system that inhibits ACTH secretion in the dog. Fed Proc 28:438, 1969 125. Kobberling J, zur Muhlen AV: The influence of diphenylhydantoin and carbamazepine on the circadian rhythm of free urinary corticoids and on the suppressibility of the basal and the “impulsive” activity by dexamethasone. Acta Endocrinol72:308, 1973 126. Krieger DT: Elfect of diphenylhydantoin interrelations. J Clin on pituitary-adrenal Endocrinol Metab 22:490, 1962 127. Meikle AW, Jubiz W, Matsukura S, West CD, Tyler FH: Eflect of diphenylhydantoin on the metabolism of metyrapone and the release

233

of ACTH in man. J Clin Endocrinol Metab 29:1553, 1969 128. Rinne UK: Site of the inhibiting action of diphenylhydantoin on the release of corticotrophin in epileptic patients. Med Pharmacol Exp 17:409, 1967 129. Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics. New York, London, Macmillan, 1970, p 209 130. Merry J, Marks V: The effect of alcohol, barbiturate, and diazepam on hypothalamic/ pituitary/adrenal function in chronic alcoholics. Lancet 2:990, 1972 131. Imura H, Nakai Y, Kato Y, Yoshimoto Y, Moridera K: Effect of adrenergic agents on growth hormone and ACTH secretion, in Scow RO (ed): Endocrinology. Amsterdam, Excerpta Medica, 1973, p 156 132. Plonk JW, Bivens CH, Feldman JM: Inhibition of hypoglycemia-induced cortisol secretion by the serotonin antagonist cyproheptadine. J Clin Endocrinol Metab 38:836, 1974 133. Goodman HG, Grumhach MM, Kaplan SL: Growth and growth hormone. II. A comparison of isolated growth hormone deficiency and multiple pituitary hormone deficiencies in 35 patients with idiopathic hypopituitary dwarfism. N Engl J Med 27857, 1968 134. Powell GF, Brasel JA, Raiti S, Blizzard RM: Emotional deprivation and growth retardation stimulating idiopathic hypopituitarism. I. Clinical evaluation of the syndrome. N Engl J Med 2761271, 1967 135. Sachar EJ, Mushrush G, Perlow M, Weitzman ED, Sassin J: Growth hormone responses to L-dopa in depressed patients. Science 178:1304, 1972 136. Sachar E, Finkelstein J, Hellman 1,: Growth hormone responses in depressive illness. I. Response to insulin tolerance test. Arch Gen Psychiatry 25:263, 1971 137. lmura H, Yoshimi T, Ikekubo K: Growth hormone secretion in a patient with deprivation dwarfism. Endocrinol Jap 15:301, 197 I 138. Davis JM: Possible biochemical mechanism of depression in Pfeiffer CC, Smythies JR (eds): International Review of Neurobiology, vol 12. New York. Academic, 1970, p 145 139. Beck P. Parker ML, Daughaday WH: Paradoxical hypersecretion of growth hormone in response to glucose. J Clin Endocrinol Metab 261463, 1966 140. Lawrence AM, Goldfine ID, Kirstens L: Growth hormone dynamics in acromegaly. J Clin Endocrinol Metab 31:239, 1970

234

141. Kolodny HD, Sherman L, Singh A, Kim S, Benjamin F: Acromegaly treated with chlorpromazine: A case study. N Engl J Me-d 284:819, 1971 142. Dimond RC, Brammer SR, Atkinson RL Jr, Howard WJ, Earl1 JM: Chlorpromazine treatment and growth hormone secretory responses in acromegaly. J Clin Endocrinol Metab 36:1189, 1973 143. Nakagawa K, Mashimo K: Suppressibility of plasma growth hormone levels in acromegaly with dexamethasone and phentolamine. J Clin Endocrinol Metab 37:238, 1973 144. Luixzi A, Chiodini PG. Botalla L, Cremascoli G, Silvestrini F: Inhibitory effects of Ldopa on GH release in acromegalic patients. J Clin Endocrinol Metab 35941.1972 145. Hansen AP: Abnormal serum growth hormone response to exercise in juvenile diabetics. J Clin Invest 49:1467, 1970 146. Hansen AP: The effect of adrenergic receptor blockade in the exercise-induced serum growth hormone rise in normals and juvenilediabetics. J Clin Endocrinol Metab 33:807, 1971 147. Landon J, Greenwood FC, Stamp TCB, Wynn V: The plasma sugar, free fatty acid, cortisol and growth hormone response to insulin, and the comparison of this procedure with other tests of pituitary adrenal function. II. In patients with hypothalamic or pituitary dysfunction or anorexia nervosa. J Clin Invest 45:437, 1966 148. Zarate A, Jacobs LS, Canales ES, Schally AV, de la Cruz A, Soria J, Daughaday WH: Functional evaluation of pituitary reserve in patients with the amenorrhea-galactorrhea syndrome utilizing luteinizing hormone-releasing hormone (LH-RH), L-dopa and chlorpromazine. J Clin Endocrinol Metah 37:855, 1973 149. Turkington RW: Inhibition of prolactin secretion and successful therapy of ForbesAlbright syndrome with L-dopa. J Clin Endocrinol Metab 34:306, 1972

FROHMAN

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150. Zarate A, Canalis ES, Soria J, Maneiro PJ, MacGregor C: Effect of acute administration of t-dopa on serum concentration of FSH and LH in patients with the amenorrhea and galactorrhea syndrome. Neuroendocrinology 12:321, 1973 151. Zarate A, Canales ES, Jacobs LS, Maneiro PJ, Soria J, Daughaday WH: Restoration of ovarian function in patients with the amenorrhea-galactorrhea syndrome after longterm therapy with L-dopa. Fertil Steril 24:340, 1973 152. Tyson JE, Huth J, Khojandi M: Inhibition of cyclic gonadotropin secretion by human prolactin. Clin Res 22:35 IA, 1974 153. Minton JP, Dickey RP: Prolactin, FSH, and LH in breast cancer: Effect of levodopa and oophrectomy. Lancet 1:1069,1972 154. Krieger DT: The central nervous system and Cushing’s syndrome. Mt Sinai J Med 39:416, 1972 155. Dexter RN, Fishman LM, Ney RL, Liddle GW: Inhibition of adrenal corticosteroid synthesis by amino-glutethimide: Studies of the mechanism of action. J Clin Endocrinol Metab 27~473, 1967 156. Temple TE Jr, Jones DJ Jr, Liddle GW, Dexter RN: Cushing’s disease: Correction of hypercortisolism by o,p’DDD. N Engl J Med 281:801, 1969 157. Pittman JA, Haigler ED Jr, Hershman CS: Hypothalamic hypoJM, Pittman thyroidism. N Engl J Med 285:844, 197I 158. Shenkman L, Mitsuma T, Suphavai A, Hollander CS: Hypothalamic hypothyroidism. JAMA 222:480, 1972 159. Frohman LA: The hypothalamus and metabolic control, in Ioachim HL (ed): Pathobiology Annual 1971. New York, Appleton-century-crofts, 1971, p 353 160. Upton GV, Corbin A: Hypothesis: Hypothalamic dysfunction and lipoatrophic diabetes. Yale J Biol Med 46:314, 1973

Neuropharmacologic control of neuroendocrine function in man.

PROGRESS IN ENDOCRINOLOGY AND METABOLISM Neuropharmacologic Control of Neuroendocrine Function in Man Lawrence A. Frohman and Max E. Stachura N...
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