1 Disorders of prolactin and growth hormone secretion

1 Disorders of Prolactin and Growth Hormone Secretion KlAN Y. HO WILLIAM S. EVANS MICHAEL O. THORNER

In this chapter we review the current status of the evaluation of disorders of prolactin and growth hormone (GH) secretion. Since the evaluation of disorders of secretion of each of the two hormones is so different, we have subdivided the chapter into two parts, the first discussing hyperprolactinaemia and the second disorders of GH secretion. DISORDERS OF PROLACTIN SECRETION Introduction Although a deficiency of prolactin secretion can lead to reduced reproductive potential in lower animals (Woods and Simpson, 1961; Bartke, 1966; Bartke et al, 1977), it is an excess of the hormone that is responsible for a significant amount of reproductive and sexual dysfunction in the human. Indeed, it has recently been suggested that hyperprolactinaemia is the most common hypothalamic-pituitary disorder currently recognized: of all pituitary tumours, 40% are prolactinomas (Faglia et aI, 1980). Moreover, upwards of 60-70% of pituitary tumours previously categorized as non-functional may be prolactinomas (Franks and Nabarro, 1977). The clinical manifestations of patients with hyperprolactinaernia appear to be a function of whether or not a large pituitary tumour is present. When associated with such a tumour, hyperprolactinaemia may present with signs of local compression such as headache and visual field compromise (Thorner and Besser, 1977; Carter et aI, 1978). Much more common, however, are the clinical problems resulting from supraphysiological concentrations of prolactin itself. Such disorders may include galactorrhoea and menstrual abnormalities and/or infertility in women and diminished libido and/or impotence in men. It should be noted, however, Clinics in Endocrinology and Metabolism-Vol. 14, No.1, February 1985

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that whereas women frequently present to the physician with complaints of galactorrhoea or reproductive dysfunction, men typically complain of headache and visual impairment. The latter correlates with the fact that , in contrast to women , men (unless diagnosed as hyperprolactinaemic during evaluation for infertility; Weber et aI, 1984) are generally found to have large pituitary tumours. Of interest, however, is the observation that a history of sexual dysfunction can quite frequently be obtained after diagnosis and treatment of the disorder. An appreciation of hyperprolactinaemia and its sequelae is of much more than mere academic interest , owing to the potential for successful treatment. Following the lowering of serum prolactin into the normal range, sexual and reproductive function may be restored to normal in 80-90% of cases (Reyes, Gomez and Faiman, 1977; Hardy, Beauregard and Robert, 1978; Thorner et aI, 1980). Although it is beyond the scope of this review to discuss the treatment modalities currently available, it is fair to state that suppression of the hormone into the normal range can be achieved in the majority of clinical situations. The balance of this chapter will address issues separate from the decisions concerned with management ; thus, we will consider the causes of hyperprolactinaemia and approaches to investigation of the disorder. Causes of hyperproiactinaemia (Table 1) An understanding of the pathophysiological situations which may result in enhanced prolactin release requires a knowledge of the physiology of prolactin secretion. Although thyrotrophin releasing hormone (TRH) is a potent stimulator of prolactin release, its role as a physiological prolactin releasing factor remains to be defined. Conversely, it is now well accepted that prolactin release by the lactotroph is under tonic inhibition by the catecholamine , dopamine (MacLeod, 1976; Thorner, 1977). Dopamine is secreted by the tuberoinfundibular neuronal system with cell bodies

Table 1. Causes of hyperprolactinaemia. Physiological Pregnancy Lactation Non-physiological Medications (e.g. alpha-methyldopa , reserpine, haloperidol, rnetoclopramide , oestrogen) Hypothyroidism Renal failure Hypothalamic-pituitary disea se Disease s of hypothalamus (e.g. tum our, inflammation , A -V malform ation) Stalk section/compression Pituitary tumours Non-prolactinornas (e .g. associated with acromegaly, Cu shing 's disease , non-functioning) Prolactinomas

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residing in the arcuate nucleus of the hypothalamus and nerve endings terminating in the proximity of the capillaries which form the hypothalamohypophyseal portal circulation . Thus, hypothalamic dopamine is transported via the portal system to the pituitary where it interacts with specific receptors on the lactotrophs . In a manner which remains to be fully elucidated, dopamine tonically inhibits the secretion of prolactin , the latter occurring in response to a number of complex post-receptor eventsincluding alterations in membrane phospholipids and changes in intracellular levels of calcium and cyclic AMP. From the above it is apparent that an increase in prolactin secretion could result from an abnormality at any of several functional levels. Thus, failure of the hypothalamus to synthesize and secrete dopamine, defective transport of dopamine to the lactotroph, lack of dopamine receptors or an inability of receptors to properly recognize and transduce the signal, or failure of post-receptor events to be executed in a normal fashion could result in the supraphysiological secretion of prolactin. Direct stimulation of the lactotroph such that normal dopaminergic inhibition is overridden or byp assed would have the same result. In addition , if the number of lactotrophs is greatly increased, basal prolactin levels may be elevated since even normal lactotrophs secrete a small amount of prolactin when tonic ally inhibited by dopamine or dopamine agoni sts .

Physiologi cal causes of hyp erprolactinaemia To a significant degree, a number of clinical situations and abnormalities associated with hyperprolactinaemia can be explained by one or more of th e above mechanisms. Although we, as clinicians, tend to focus on only the abnormal causes of hyperprolactinaemia , it must be recalled that the most common causes of high se ru m prolactin levels in the human are indeed ph ysiological. During normal pregnancy, se rum prolactin rises progressivel y. often achieving levels of 500 ng/ml by the third trimester. Thi s increase in prolactin has been attributed to direct effects of oestrogen o n the lactotrophs, including stimulation of mitotic activity (perhaps leading to the lactotroph hyperplasia observed in pregnancy ; Davies et aI, 1974). Moreover, in addition to its receptor-mediated effects, Gudelsky and colleagues have shown that dopamine may be incorporated into prolactin secretory granules; that this association may result in inhibition of prolactin release; and that oestrogen may block this incorporation, thus leading to enhanced prolactin release (Gudelsky, Nansel and Porter, 1981). Physiological hyperprolactinaemia also occurs during lactation. Although the mechanisms remain incompletely defined, it has been suggested that stimulation of the mammary nerve results in a brief but definite decrease in the release of dopamine by the hypothalamus (Plotsky and Neill, 1982). This physiological mechanism may underlie the hyperprolactinaemia which has been reported associated with chest wall injury and in response to stimulation of the breasts by a sexual partner (Noel et al , 1974).

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Non-physiological causes of hyperprolactinaemia Drugs. Certain medications , which are capable of effecting enhanced release of prolactin , may act in one of several fashions. For example, alpha-methyldopa and reserpine are capable of depleting central dopamine stores, thus resulting in a functional hypothalamic deficiency of dopamine (Del Pozo and Lancranjan , 1978). Other medications-including the phenothiazines, and butyrophenones (e.g. , haloperidol) and procainamide derivatives (e.g. , metoclopramide)-act as dopamine receptor blockers, thus preventing the normal interaction between hypothalamic dopamine and its receptors (Shader and Dimascio , 1970; de Rivera et al , 1976; McCallum et aI, 1976). Finally, exogenous oestrogens administered for purposes of contraception or as replacement therapy in hypogonadal women may result in hyperprolactinaemia (Yen, Emara and Siler, 1974; Abu-Fadil et aI, 1976), perhaps via the mechanisms discussed above in the section on physiological hyperprolactinaemia. However, it should be noted that the doses of oestrogen used in current 'low dose' oral contraceptives are probably inadequate to cause hyperprolactinaemia. Hypothyroidism. Although serum prolactin levels in patients with hypothyroidism are most often normal, such levels may be elevated (Edwards et al , 1971), and TRH-stimulated prolactin release is frequently exaggerated (Bowers et aI, 1971; Refetoff et al , 1974) . Although both basal and stimulated levels return to normal upon adequate replacement with thyroid hormone (Edwards et al, 1971; Refetoff et aI, 1974), this return to normal may require a period of up to six months. The mechanism underlying this form of hyperprolactinaemia remains incompletely defined but may relate, at least in the rat, to a diminished metabolic clearance rate for prolactin (Cave and Paul , 1980). Renal failure. Chronic renal failure is associated with excess levels of circulating prolactin in significant numbers of both men and women (Chirito et al, 1972; Nagel et al , 1973; Olgaard et al, 1975; Hagen et al, 1976; Sievertsen et al , 1980). In a recent study examining the possible mechanisms through which this effect is manifest, Sievertsen and colleagues documented both prolactin secretion and metabolic clearance rates (MCR) in patients with hyperprolactinaemia (Sievertsen et al, 1980). Compared to a normal control population, the MCR for prolactin was diminished in hyperprolactinaemic patients by 33% . However, the secretion rate of the hormone was increased approximately threefold and the response to a dopamine infusion diminished in patients with hyperprolactinaemia. These findings, in concert with those of others which demonstrate that prolactin levels do not necessarily fall after dialysis, suggest that this form of hyperprolactinaemia is due to more than a simple failure of the kidney to excrete the hormone ; rather, such hyperprolactinaemia may relate to the activity of a non-dialysable substance acting at the level of the lactotroph to block normal dopaminergic inhibition of prolactin release.

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Hypothalamic-pituitary disease. Disorders of the hypothalamus and pituitary stalk may be associated with hyperprolactinaemia. Thus, tumours, inflammatory processes and arteriovenous malformations may diminish synthesis and/or release of dopamine from the tuberoinfundibular neurones. Similarly, any process which disrupts axonal transport of dopamine to the portal capillaries or transport via the capillaries to the pituitary will result in hyperprolactinaemia. Compression of the stalk by tumour or in the setting of inflammation or transsection of the stalk as a result of trauma may be aetiologic in such deranged transport (Molitch and Reichlin , 1984). Pituitary tumours: non-prolactinomas. Elevated levels of serum prolactin have been described in 25-51 % of patients with acromegaly (Franks and Nabarro, 1977; Lamberts et aI, 1979; Besser et ai, 1980). The basis of such prolactin secretion is, however, unclear. Possible explanations include secretion of prolactin from the GH secreting cell comprising the adenoma; from a cell type which has the potential to secrete both hormones (i.e., the rnammosomatotroph); or as a consequence of tumour-associated abnormalities in the portal blood flow which result in release of the normal lactotrophs from hypothalamic inhibition of prolactin secretion by dopamine . Hyperprolactinaemia has also been reported in Cushing's disease and Nelson's syndrome . While not associated with adrenal adenomas, Yamaji and colleagues found elevated prolactin levels in 23% of their patients with Cushing's disease and 50% ofthose with Nelson's syndrome (Yamaji et ai, 1984). This group suggested that hyperprolactinaemia may result from concomitant prolactin and ACTH secretion from corticotroph adenomas. However, since immunostaining of corticotroph adenomas from patients without hyperprolactinaemia was also positive for prolactin-containing cells , the pathogenic mechanism remains uncertain. It is also well recognized that non-prolactinomas may be associated with hyperprolactinaemia , albeit generally mild , presumably due to compression of the pituitary stalk and thus disruption of dopamine transport to the lactotroph. Pituitary tumours: prolactinomas. In a recent study, pituitaries from individuals with no history of pituitary disease were examined at autopsy (Burrows et al, 1981). Twenty-seven per cent were found to contain rnicroadenomas, of which 40% stained for prolactin. It is not surprising, then, that prolactinomas are the most frequent cause of hyperprolactinaemia when other possibilities such as drugs, hypothyroidism and renal failure have been eliminated. What remains unclear, however, are the reasons for the high incidence of prolactinomas which are apparently not associated with hyperprolactinaemia , and the events which surround the formation of prolactinomas which result in hyperprolactinaemia . Several mechanisms have been proposed as potential explanations for the hypersecretion of prolactin by adenomas. One hypothesis suggests that lactotrophs within prolactin-secreting adenomas fail to express dopamine

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receptors. A precedent for this possibility is to be found in both the GH 3 and 235-1 prolactin-secreting rat cell clones, neither of which exhibit dopamine receptors (Cronin et aI, 1980b; 1982a). However, as it is well known that dopamine agonists suppress prolactin secretion in humans harbouring prolactinomas, this explanation seems somewhat unlikely. Moreover, direct measurement of dopamine receptors in human prolactin microadenomas has now confirmed the existence of dopamine receptors (Bression et aI, 1980; Cronin et al, 1980a; Bethea et aI, 1982). However, the mere existence of such receptors does not attest to their functional integrity. Once again, animal models are available in which lactotrophs with apparently normal dopamine receptors fail to respond to dopamine with inhibition of prolactin secretion. It has thus been suggested that both the 7315a and M+TWI5 transplantable rat pituitary tumours which have dopamine receptors fail to respond to dopamine or its agonists due to a post-receptor defect (Cronin et aI, 1981; 1982b). Using human prolactinomas, however, an interaction of dopamine with its receptor results in appropriate inhibition of adenylate cyclase, suggesting that at least this particular second messenger system is functionally intact (Decamilli et aI, 1979). It remains to be demonstrated whether or not the number of dopamine receptors per cell and coupling to other second messenger systems are normal, or whether other intracellular mechanisms which are vital for the inhibition of prolactin secretion are functionally intact. Similarly, the possibility that deranged hypothalamic input is involved in adenoma formation (e.g., a chronic deficiency of dopamine synthesis and release or enhanced production of the putative prolactin releasing factor) must be addressed in future studies. Diagnostic investigations

It is our position that all patients presenting with hyperprolactinaemia should have basal and dynamic endocrine testing (including at least the measurement of serum thyroid hormone, gonadotrophin, and gonadal hormone levels and a test of GH and pituitary-adrenal reserve), documentation of visual fields utilizing the Goldmann apparatus, and examination of the pituitary with high resolution computerized tomography (Cf) scanning. Certainly, the patient presenting with headache and visual field defects, with a large tumour readily appreciated on CT scanning and with a clearly elevated serum prolactin level (e.g., greater than 250 ng/mI), with or without other demonstrable endocrine dysfunction, presents little problem in terms of diagnosis. However, it is well appreciated that patients harbouring large prolactin-secreting adenomas (i.e., macroadenomas, 10 mm or more in diameter) are relatively uncommon when compared to those with small tumours (microadenomas, 10 mm or less in diameter), and that patients harbouring small tumours may have no other readily apparent endocrine dysfunction except as related to the elevated circulating levels of prolactin. Exactly what constitutes the most appropriate approach to the investigation of patients suspected of having microadenomas beyond those studies noted above remains the focus of some debate.

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Under ideal circumstances, a hyperprolactinaemic patient would have radiographic findings specific for a prolactinoma and well-defined abnormalities in basal and dynamic endocrine testing to corroborate such. Unfortunately, matters are not quite so straightforward. As mentioned above, Burrows and colleagues (1981) in their autopsy series demonstrated that pituitary microadenomas are common in individuals exhibiting no clinical evidence of pituitary disease. Moreover, this same study revealed that pituitary hypocycloidal tomography, a radiographic technique in frequent use only a few years ago, was not specific for identifying such tumours: only 19% of the subjects with proven microadenomas had abnormal tomography. Furthermore, abnormal tomograms were found in 24% of the subjects without pituitary tumours. Although the purpose of this investigation was in part to evaluate the usefulness of one particular radiographic technique, the more general message is worrisome: even with the advent of radiographic techniques which are much more specific for identifying pituitary lesions (such as high resolution CT scanning), how is the physician to know whether or not a micro adenoma seen radiographically correlates with the lesion responsible for the hyperprolactinaemia? Similarly, how can a prolactin-secreting pituitary tumour be diagnosed in patients with no apparent abnormality on radiographic examination? Although approaches such as the combination of positron emission tomography with uptake of labelled dopamine agonist (Muhr et ai, 1984) would appear to have significant potential, currently available technology leaves these very basic questions unanswered. For some time there has been interest in the development of dynamic tests which would clearly separate hyperprolactinaemia associated with small pituitary tumours from that on a so-called 'functional' or nontumorous basis. To date, however, the results have been generally disappointing. For example, neither suppression of prolactin with L-dopa nor stimulation with chlorpromazine clearly separates patients with prolactinomas from those without tumours (Kleinberg et al, 1977; Boyd et ai, 1977). Similarly, the role of TRH-stimulated prolactin release as an indicator of tumour versus non-tumour is controversial. Although Kleinberg and colleagues have demonstrated blunted responses in subjects with prolactinomas and thus have suggested TRH to be a useful discriminator (Kleinberg et al, 1977), Boyd and colleagues reported significant TRHstimulated prolactin release in some patients with prolactin-secreting tumours (Boyd et al, 1977). More recently, the use of drugs which inhibit the uptake of dopamine in the central nervous system to discriminate between tumorous and non-tumorous hyperprolactinaemia has been proposed. Thus, Camanni and colleagues have suggested that nomifensine, which lowers prolactin in normal subjects and in patients with puerperal hyperprolactinaemia, fails to do so in patients with pituitary tumours (Camanni et ai, 1981). However, a variable response was noted in patients in whom there was hyperprolactinaemia of uncertain aetiology. Although the authors suggest that the unresponsive patients may harbour prolactinomas in an early stage of development, they concede that only longer-term studies will allow this hypothesis to be tested. In addition, Ferrari and

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colleagues found nomifensine capable of diminishing serum prolactin levels in subjects with pituitary tumours (Ferrari et aI, 1980). Therefore, at present, nomifensine must be categorized with i.-dopa, chlorpromazine and TRH, in that none of these agents has been shown to document the presence or absence of tumour. Currently, the best indicator of whether or not a prolactin-secreting pituitary tumour is present and, if so, the size of the tumour, appears not to be a radiographic procedure or dynamic endocrine test but rather the unstimulated serum prolactin level. A comprehensive review of these relationships by Hardy and his colleagues covers a ten-year period during which 355 patients were evaluated (Hardy, 1981). In this report emphasis is placed on preoperative status and findings at the time of surgery. Although there was variability as would be anticipated, the basal prolactin level correlated quite well with both the presence of a tumour and its size. Thus virtually all microadenomas were associated with prolactin levels below 300 ng/ml and the majority associated with levels less than 200 ng/ml. Conversely, most macroadenomas were harboured by patients with prolactin levels above 250 ng/ml, often in the range of 1000 ng/ml or more. Summary Although there are almost certain to be both radiological and pharmacological technical advances on the horizon which may allow for more conclusive methods of documenting a prolactin-secreting adenoma, such are not currently available. While there is variability in attempting to correlate basal serum prolactin levels with the presence and size of prolactinomas, this relatively simple measurement would appear to be the best predictor of a prolactin-secreting pituitary tumour at this time. In addition we would stress that the dilemma is more theoretical than practical since the vast majority of these patients can be treated with orally active dopamine agonist drugs.

DISORDERS OF GROWTH HORMONE SECRETION Introduction Although disturbances of body growth have been recognized for many centuries, it was not until the introduction of radioimmunoassays for measurement of GH in blood in the early sixties that the clinical syndromes of dwarfism, gigantism and acromegaly could be convincingly related to a deficiency or excess of GH secretion, respectively. Advances in our understanding of the neuroendocrine mechanisms controlling GH release, the discovery of the two important hypophysiotrophic factors, somatostatin and growth hormone releasing factor (GRF), and the realization that the action of GH is exerted by the production of growth factors called somatomedins (Sm) from a variety of tissues have not only helped us understand the mechanisms subserving many of the GH related disorders

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but also directed us to mould rational therapies for many of these disorders. In this section we will discuss the various tests used for the detection and diagnosis of growth disorders related to disturbances of GH secretion and highlight some of the problems and limitations pertaining to these tests. We will also discuss some of the possible roles that the recently discovered human GRF (hGRF) may play in the elucidation of the aetiology, diagnosis and therapy of some of these disorders. Abnormalities of growth arising as a result of a defect in GH action are not reviewed but are discussed where appropriate. Assessment of GH secretion None of the currently available tests of GH secretion can completely reflect or characterize the GH secretory status of the body. It is noteworthy, though rhetorical, to state that the best measure of GH secretory status is still body growth, and that none of the biochemical changes that are known to result from the action of GH can accurately and sensitively reflect the GH status, although in most instances they are a good guide. Table 2 lists the methods currently used to assess GH secretion. Table 2. Tests used in the assessment of GH secretion. 1. Basal GH 2. Provocative tests (a) Physiological sleep exercise (b) Pharmacological i.-dopa

arginine insulin-induced hypoglycaemia propranolol clonidine (c) GRF 3. GRF measurement 4. Suppression test: oral glucose tolerance test 5. Somatomedin C

Basal GH

The measurement of a single basal sample for the assessment of GH secretory status is of limited value. A 'normal range' for a single basal measurement cannot be adequately defined because GH is secreted episodically with most of the release occurring at night during sleep (Quabbe et al, 1966; Goldsmith and Glick, 1970; Finkelstein et ai, 1972). During the day, the concentration of GH in the circulation is frequently below the level of detection for long periods, and secretory spikes are few. Therefore a random basal GH measurement cannot be used to diagnose suspected cases of GH deficiency. In the same way, a detectable GH level in a short child does not exclude GH deficiency as some children with

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partial GH deficiency still continue to release GH episodically even though the frequency and magnitude of the GH pulses are reported to be decreased (Spilitos et aI, 1984). For this reason, measurement of GH levels following a provocative stimulus is required to establish the diagnosis of GH deficiency. The majority of patients with acromegaly have random GH levels which are sufficiently high to be virtually diagnostic. Nevertheless, circulating GH levels may be only mildly elevated or even within the established normal range in some cases of acromegaly (Mims and Bethune, 1974). Therefore a random GH level which is not elevated is never sufficient to exclude the diagnosis of acromegaly. A glucose tolerance test is mandatory. Conversely, a high GH level does not indicate excessive GH secretion as the sample may have been taken during the peak of a GH pulse.

Provocative tests of GH release These tests rely either on physiological (sleep or exercise) or pharmacological (arginine, insulin-induced hypoglycaemia, clonidine, i.-dopa, propranolol) stimulation of GH reserve. The precise mechanism by which GH is released is not known but probably occurs through modulation of hypothalamic GRF and somatostatin release. From the choices available it can be inferred that no one test, perhaps with the exception of the GRF test, can consistently and reliably stimulate the release of GH in normal subjects. This is because the effects of the various agents act through hypothalamic monoaminergic neural mechanisms which in turn modify GRF and/or somatostatin release. The effect is therefore not a direct one on pituitary somatotrophs. We believe the insulin tolerance test to be the most reliable in testing GH reserve. However, the procedure carries the greatest risk in patients who may also be glucocorticoid deficient; therefore, it is mandatory that this test be performed with medical supervision in an appropriate metabolic unit. Arginine and L-dopa are considered, together with insulin, to produce the more consistent GH responses (Eddy et aI, 1974). However, no one agent is completely reliable, and for this reason the diagnosis of GH deficiency is usually made following failed responses to two stimuli. Traditionally, we have used physiological stimuli such as sleep or exercise as screening procedures to detect GH deficiency and pharmacological stimuli as definitive tests. It is important to realize that GH release obtained during sleep or exercise is attained under conditions that cause GH release through physiological modulation of hypothalamic neuronal activity. It can be questioned whether the GH responses obtained using pharmacological means can completely reflect the physiological secretory status of GH. It has been assumed that the ability to induce significant release of GH from pituitary stores precludes the existence of partial GH deficiency. There are very few data supporting the notion that the functional integrity of day-to-day secretion of GH can be assessed or defined by a single provocative test. Indeed, there is now disquieting evidence that a significant number of short children, who by standard

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pharmacological testing are deemed GH sufficient, actually have partial GH deficiency (see below). Nevertheless, these provocative agents have stood the test of time in helping us diagnose GH deficiency. The criteria were necessarily strict because of the very limited availability of hGH. However, we are beginning to realize that a spectrum of partial GH-deficient states exists for which the traditional tests are not adequate or sufficiently sensitive to detect. GRF test

Two GH-releasing peptides, both isolated from pancreatic tumours causing acromegaly, have been recently available for use in man. These two peptides, hGRF 1-40 (Thorner et aI, 1983) and hGRF 1-44 (Gelato et ai, 1983; Rosenthal et al, 1983) specifically stimulate the release of GH in man. When used in doses ranging from 0.1 to 10 ug/kg given intravenously, the GH response is brisk, and although no definite dose response relationship of peak GH was observed, the higher doses tended to cause a more prolonged and biphasic response (Vance et aI, 1984). hGRF 1-40 and hGRF 1-44 appear to be equipotent in man (S. L. Kaplan, 1984, personal communication). Several recent studies have compared the effectiveness of GRF as a stimulus of GH release to that of conventional pharmacological agents. In the one study comparing the responses in normal subjects, peak GH responses to G RF using doses up to 10 ug/kg were similar to those obtained with insulin-induced hypoglycaemia (Vance et aI, 1984). All other studies to date have compared GH responses in short children and in children with known GH deficiency. Studies in GH-deficient children have provided important information regarding the aetiology of this disorder. Such studies have shown that a significant number of 'GH-deficient' children identified by conventional testing are able to release GH. Rogol et al (1984) reported that four of ten GH-deficient children achieved peak GH levels of to to 42 ng/rnl. Schriock et al (1984) found that of 20 children with severe GH deficiency (defined as a peak response of less than 3 ng/ml to arginine, insulin or i.-dopa) four had GH peaks in excess of 4 ng/ml when given GRF. Eleven of 24 GH-deficient children studied by Takano et al (1984) had peak levels exceeding 5 ng/ml following GRF. The implications of these studies are important. First, some patients with GH deficiency may actually have hypothalamic GRF deficiency as the cause of their GH deficiency. Second, with the doses used (1-5 ug/kg) , hGRF appears to be a more powerful stimulus of GH release in children with apparent GH deficiency. The response criteria used to diagnose absolute or relative GH deficiency with conventional provocative stimuli cannot be applied to the GRF test. At the moment, there is no information as to what a normal GRF-induced GH response is in normal children. A true normal range can only be defined by studying children of normal stature matched for chronological age, sex and bone age. Third, GRF can be used as a pharmacological tool to diagnose endogenous GRF deficiency. However, failure to respond to GRF does not rule out hypothalamic GRF deficiency, as somatotroph function is presumably dependent on prior exposure to

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GRF and, like gonadotrophs, a period of pnrmng may be necessary (Yoshimoto et ai, 1975). The conditions necessary to attain optimal priming of somatotrophs are presently not known.

Suppression test: oral glucose tolerance test Roth et al (1963) first made the observation that GH fails to suppress following glucose administration in acromegaly. Several investigators confirmed this finding and rapidly established oral glucose loading as a valuable test to aid the diagnosis of acromegaly (Beck et ai, 1966; Earll et ai, 1967; Boden et ai, 1968; Cryer et ai, 1973). The normal GH response to oral glucose is biphasic. A fall in GH (often to undetectable levels) occurs in the first 60 minutes at the time that blood glucose levels rise, and is then followed by a rise of GH when blood glucose levels start to fall. In acromegaly complete suppression of GH does not occur, although occasionally there may be partial suppression. In about 20% of acromegalies, a paradoxical rise of GH occurs following glucose administration. Suppression into the defined normal range (usually less than 10 ng/ml) has been reported in some acromegalies (Earll et ai, 1967; Cryer and Daughaday, 1977) but never to less than 2.0 ng/ml (4 mID/I) which we believe should be the criterion for normal suppression. In a study of 155 acromegalies, Jadresic et al (1982) found no patients who suppressed below 4 ng/ml (8 mID/I). It is important to note that the diagnosis of acromegaly should be made on clinical grounds and that an abnormal GH response to glucose cannot be taken as diagnostic. This is because abnormal GH responses have been reported in a variety of conditions, including anorexia nervosa (Smith et ai, 1974), chronic renal failure (Wright et ai, 1968), Wilson's disease (Martin, 1973), acute intermittent porphyria (Pelroth et ai, 1967) and thyrotoxicosis (Vinik et ai, 1968).

Measurement of circulating GRF Measurement of circulating GRF levels may help to identify ectopic GRF production as the cause of acromegaly. In a collaborative study involving 177 acromegalic patients from 15 medical centres, markedly elevated plasma GRF levels occurred in only three patients (Thorner et al, 1984). These three patients were known, prior to the study, to have ectopic GRF production from a peripheral tumour. GRF levels in the other acromegalic patients ranged from undetectable to 82 pg/ml, a range which was not significantly different from that of normal subjects. In another study Penny et al (1984) found that three of 79 acromegalic patients who did not have clinical evidence of extra-hypothalamic GRF production had elevated levels of immunoreactive GRF ranging from 92 to 1111 pg/ml (normal range up to 60 pg/ml). Two of the three patients had long-standing acromegaly and in the third extensive venous catheterization failed to disclose the source of GRF. The authors could not be certain if the immunoreactivity may have reflected interference in the assay from an unidentified factor in plasma. However, they considered a hypothalamic source unlikely in view of the marked dilution of this source of GRF upon

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entering the systemic circulation. Pituitary tumours causing acromegaly are believed by some to be secondary to hypothalamic dysfunction in which there may be uncontrolled release of hypothalamic GRF (Melmed et aI, 1983). Whether this source of GRF can be detected in peripheral blood is at present unclear. However, hamartomas residing within the hypothalamus are a recognized source of GRF and may be associated with acromegaly (Asa et al, 1984). Ectopic GRF production is an uncommon cause of acromegaly. However, for the individual patient, we believe that it is important that the cause of acromegaly be correctly determined before ablative pituitary therapy. A single plasma GRF level should be determined as this will in the long term lead to optimal -cost-effective medical care of patients with this rare condition. Somatomedin C

Somatomedin C (Sm C) is a member of a family of growth factors believed to mediate the growth-promoting actions of GH. The growth factors that have been identified and studied include Sm A, Sm C, insulin-like growth factor (IGF) I, IGF II and multiple-stimulating activity (MSA). The terms somatomedin and IGF were employed by two groups of investigators who used different extraction and bioassay methods for identification and characterization of the growth factors under study. These two terms are now used synonymously, although IGF infers structural similarity to the insulin molecule while Sm infers GH dependency. It was established from radioligand assays that Sm C and IGF I are very similar (Van Wyk et aI, 1980) and recently Klapper et al (1983) reported through determination of the amino acid sequences that these two factors are identical. This section addresses the usefulness of Sm C, the most intensively studied of the growth factors, in the assessment of GH-related disorders. The development of highly specific radioimmunoassays for Sm C measurement has made it possible to measure accurately its concentration in all biological fluids. Radioreceptor assays and plasma binding protein assays are also available but suffer from lack of specificity in that other insulin-like growth factors are also measured in the system. The reader should be aware of some of the technical difficulties associated with the measurement of Sm C in various assay systems, and the manner in which extraction procedures influence Sm C binding to its specific plasma binding proteins and may significantly affect assay measurement (Clemmons and Van Wyk, 1984). One further problem is the unavailability of an international reference preparation which limits meaningful comparison of results between groups of investigators. The unit of measurement is frequently based on the average concentration of Sm C in serum obtained tItom a large adult population. Despite these limitations, Sm C measurements have proved to be of considerable use in the diagnosis and treatment of GH-related disorders. Sm C values vary considerably with age (Furlanetto et aI, 1977). Values are low during the first few years of life and rise gradually to a peak between 13 and 15 years of age (Clemmons and Van Wyk, 1984).

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Thereafter, Sm C levels gradually diminish with increasing age. Fasting causes a marked decrease in Sm C (Clemmons et al, 1981) which is evident within 24 hours. Merimee et al (1982) showed that Sm C levels did not rise in response to GH administration after a three-day fast. Oestrogens appear to have dual effects; in acromegalies, acute administration of high-dose oestrogens causes a significant reduction in Sm C, while in Turner's syndrome low-dose oestrogen treatment causes an increase in Sm C (Ross et aI, 1983). The latter effect may be secondary to stimulation of GH secretion although this was not directly studied. Sm C measurements are of limited use in the management of disorders of GH deficiency owing to the fact that Sm C levels in GH-deficient children may overlap with those in age-matched normal children (Dean et aI, 1982; Cohen and Blethen, 1983). Therefore a low Sm C level is never diagnostic of GH deficiency. Moreover, non-GH related factors such as malnutrition or systemic disease can suppress Sm C. Nevertheless, the finding of a low Sm C in a short child does raise the likelihood of GH deficiency. Moore et al (1982) found from screening short children that 50% of those with low Sm C were GH-deficient. Rudman et al (1981) reported that the Sm C response to short-term GH therapy was a good indicator of linear growth response to chronic GH therapy. However, other investigators (Rosenfeld et aI, 1981; Dean et aI, 1982) could not find such a correlation. Although the majority of patients had an increase in growth velocity and Sm C levels, individual responses were highly variable. The measurement of Sm C is more useful in disorders of GH excess. Clemmons et al (1979) found in 179 acromegalic subjects that Sm C levels were clearly separated from those of normal adult subjects. Rieu et al (1982) reported similar findings in that in all acromegalic patients IGF levels were above the mean + 2 s.d. of the control value. They also noted a correlation between IGF concentration and disease activity. It should be noted, however, that during the pubertal growth spurt Sm C levels may be in the 'acromegalic' range. Likewise, Sm C may be high in pregnancy, and therefore interpretation of Sm C values under these physiological conditions should be made cautiously. Whether changes in Sm C accurately reflect changes in disease activity during treatment is not resolved. Some investigators have found that clinical improvement paralleled reduction in Sm C (Clemmons et al, 1979; Rieu et al, 1982; Wass et al, 1982). However, Stonesifer et al (1981) and Moses et al (1981) could not find such a relationship. The reasons for these contradictions are not clear but may be related to different response criteria employed as well as the different methods used for measuring Sm C and the small number of patients studied. Furthermore, changes in local tissue concentrations may be more important than circulating levels (D'Ercole et al, 1984). Deficiency of GH secretion

The diagnosis of GH deficiency in a short child is made when the GH response fails to exceed 7 ng/ml in response to at least two provocative

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15

stimuli of GH release. GH deficiency is characterized by severe short stature (the height being less than the third percentile), a subnormal growtlfyelocity of less than 4 em/year over at least one year, and a delayed bone' age. A reduction in growth velocity is particularly important. The vast majority of short children do not have GH deficiency and older children who are GH-deficient often present with delayed puberty. GH-deficient infants are of normal weight and length when born (Rabin and McKenna, 1982). Therefore fetal GH is not necessary for intrauterine growth. However, neonatal hypoglycaemia may occur (Wilber and Odell, 1965). Affected male infants may have small genitalia (Lovinger et al, 1975). In severely deficient children, the growth rate may be less than 1 em/year. In a study of GH-deficient subjects who had attained adulthood, it was found that the mean age of menarche was 16 years, and in males the mean age of sexual development was 19 years. Fertility and lactation were not adversely affected. The mean height age at full growth was 8.7 years. The upper to lower body segment rate was 1.14, which is greater than that of normal adults so that the body proportions are childlike. Affected subjects have soft, finely wrinkled skin and tend to look prematurely old. They are highly insulin-sensitive but are insulopenic in response to a glucose challenge (Merimee et aI, 1968). Sm C levels are low in GH deficiency and in severely affected individuals may not be detectable (Clemmons and Van Wyk, 1984). Because of the variability of Sm C levels in normal children, measurement of Sm C cannot by itself identify GH-deficient children even when these levels are matched for age (Dean et aI, 1982; Clemmons and Van Wyk, 1984). Sm C levels rise significantly by 12 hours after GH administration. During GH therapy, the magnitude of the Sm C response, however, does not correlate with the subsequent growth response (Dean et aI, 1982; Gertner et aI, 1984). Table 3 lists the various conditions that are known to cause GH deficiency. However, only some of these conditions-including idiopathic deficiency and some of the functional disturbances of GH-will be discussed in detail, as important new advances have been made in these areas.

Table 3. Classification of GH deficiency. Idiopathic GH deficiency Isolated GH deficiency Multiple pituitary hormone deficiency Destructive and ablative lesions to the hypothalamus or pituitary Tumours of the hypothalamo-pituitary area Inflammatory and infiltrative lesions Cranial irradiation Functional defects in GH secretion Some forms of short stature Psychosocial dwarfism Metabolic diseases Endocrine diseases

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Idiopathic GH deficiency GH deficiency may occur in isolation or as part of multiple pituitary hormone deficiency. It is becoming increasingly clear that so-called isolated GH deficiency is a heterogeneous group of disorders which can be classified on a metabolic, hormonal or hereditary basis (Merimee et ai, 1969; Rabin and McKenna, 1982). It has been recognized that, on a hereditary basis, there are at least three forms: a familial form which is autosomal dominant; a form which is X-linked recessive and is associated with hypogammaglobulinaemia (Fleisher et aI, 1980); and a form which is autosomal recessive and can be further divided into types I and Ia (Rimoin, 1976), the latter being due to complete deletion of the hGH-N gene (Phillips et ai, 1982). The development of GH deficiency, especially in

#1

7.0

Maximum Serum GH(ng/ml)

5.0

#4

3.0

#3

#2

1.0

<0.5

& 1 5 = = = - - - - -..... #6 Pre

hpGRF-40Rx

Post

Figure 1. Maximum serum GH levels (nglml) in six adults with idiopathic GH deficiency after intravenous bolus hGRF-40 (10 l1g1kg) administration before (Pre) and at the termination of (Post) 5 days of hGRF-40 treatment (0.33 ug/kg, intravenous bolus given every 3 h). (With kind permission from the Editor, Journal of Clinical Endocrinology and Metabolism.)

PROLACTIN AND GROWTH HORMONE SECRETION

17

those cases with multiple pituitary hormone deficits , has been associated with perinatal trauma (Goodman et ai, 1968; Bierich, 1972; Rona and Tanner, 1977). There is an increased incidence of breech and forceps deliveries (Rona and Tanner, 1977). Many of the cases of GH deficiency are in all likelihood due to hypothalamic GRF deficiency, including those without any history of birth trauma. Somatotrophs appearing normal by light and electron microscopy using immunocytochemical methods have been found in the pituitary gland of patients with documented isolated GH deficiency (Merimee et ai, 1975; Schechter et ai, 1984). The incidence of GRF deficiency as a cause of isolated GH deficiency is presently not known but, based on available data, may be at least 30 to 40% and possibly as high as 80% (Borges et al, 1983a; Wood et al , 1983; Rogol et ai, 1984; Schriock et ai, 1984; Takano et al, 1984). Some patients who do not demonstrate a GH response to hGRF may only do so after a protracted period of exposure to the peptide (Borges et ai, 1983a; Schriock et ai, 1984). Borges et al (1984) have very recently reported a significant increase in the GH response to GRF after five days of intermittent GRF administration in six adult patients with isolated GH deficiency (see Figure 1). More importantly they found a marked increase in Sm C levels from a mean (± s.e.m .) of 0.24 ± 0.07 U/ml pretreatment to 0.78 ± 0.32 U/ml, despite the modest elevation of GH during the five days of intermittent administration (see Figure 2) . The rise in serum Sm C to normal levels is encouraging, since Sm C may be more important than the increase in GH levels as an index for induction of linear growth. This demonstration of biological effects of GRF without any serious adverse effects suggest that hGRF has promise in the therapy of GH deficiency resulting from hypothalamic GRF deficiency. The ultimate test is the therapeutic linear growth response when compared to presently available natural or synthetic GH preparations. Indeed, in preliminary studies we have demonstrated acceleration of linear growth in two children with organic GH deficiency by GRF administration over six months (Thorner et al, 1985). Patients with organic hypopituitarism as a result of sellar or parasellar lesions can also be investigated as to the predominant cause of GH deficiency. Cranial irradiation for childhood head and neck tumours and leukaemias is now an important cause of acquired GH deficiency (Shalet et al , 1976; Blatt et ai, 1984; Romshe et ai, 1984), presumably the result of a progressive defect in hypothalamic GRF secretion (Chroussos et ai, 1982; Blatt et al, 1984; Grossman et al, 1984).

Functional disturbances of GH secretion Short stature . It has long been suspected that some short children may have a subtle disturbance of GH secretion which cannot be detected by conventional provocative testing. Recently, several authors, using different methods for assessing GH secretion and action, have identified subsets of short children 'with adequate GH reserve' (as classified by conventional criteria) who should be treated.

18

K. Y. HO ET AL

10

f

1

Adult Normal Range (mean±2SD)

Serum Somatomedin C

(U/mll

0.1

<0.01

Pre

Maximum During hpGRF-40Rx

Figure 2. Serum somatomedin C levels (Unit per ml) before (Pre) and maximum levels during 5 days of intermittent pulsatile hGRF-40 administration. Note the logarithmic scale. (With kind permission from the Editor. Journal of Clinical Endocrinology and Metabolism.)

Among the first investigators to address this problem were Daughaday and co-workers, who reported the existence of GH-dependent growth failure in two children in 1978 and a further five in 1982 (Kowarski et aI, 1978; Frazer et aI, 1982). These short children with normal GH reserve had low Sm C levels and responded to GH administration with an increase in serum Sm C and acceleration in skeletal growth. However, measurement of circulating GH in a homologous GH receptor assay revealed low radioreceptor assayable GH as compared to the measurement obtained by radioimmunoassay. Daughaday and co-workers therefore concluded that these children secreted a functionally abnormal GH. This condition is analogous to the secretion of an abnormal insulin as a cause of diabetes. Rudman and co-workers (1981) also identified two subgroups among children with normal-variant short stature who are probably similar to the patients of Daughaday and co-workers with GH-dependent growth failure. They defined normal variant stature as children with normal birth weights, heights below the third percentile , growth rates less than 2.5 em/year , and

PROLACTIN AND GROWTH HORMONE SECRETION

19

whose clinical evaluation revealed no organic or emotional cause of growth retardation. Rudman et al (1981) were able to divide their children into four subgroups using a ten-day protocol to evaluate metabolic responses to GH. Children in two of the four subgroups who showed metabolic responses to ten days of GH subsequently benefited from six months of GH therapy. The ratio of GH measured by radioreceptor assay to radioimmunoassay was low, thus suggesting that this subgroup of short children produced a GH with subnormal bioactivity. Blethen and Chasalow (1983) have recently shown that a two-site immunoradiometric assay for GH may also help to identify such children. To be detected in the assay, a GH molecule must react simultaneously with two different monoclonal antibodies, each specific for a different region of the GH molecule. In their study of eight children with GH-dependent growth failure, Blethen and Chasalow found that the ratio of GH measured by the two-site assay to that in the conventional radioimmunoassay was significantly lower than that observed in normal individuals. Spilitos et al (1984) have recently drawn attention to an important and treatable cause of short stature due to partial GH deficiency which could only be detected by studying the GH secretion over 24 hours. The authors described this abnormality of neurosecretory dysfunction in a subgroup of seven children with heights below the first percentile, growth velocities below 4 ern/year, bone ages greater than two years behind chronological age, and low Sm C levels but normal GH increases to pharmacological agents. Blood samples were taken every 20 minutes and parameters relating to total 24-hour GH secretion-the mean 24-hour GH concentration, integrated 24-hour GH secretion, number of GH pulses and mean pulse amplitude-were all significantly decreased in the neurosecretory dysfunction group. Growth velocity increased in six of the seven children in response to GH treatment, and this was accompanied by a doubling of Sm C levels. The authors speculate, on the basis of their observations, that there is a spectrum of GH neurosecretory abnormalities ranging from absolute deficiency to a problem of GH regulation not readily identified by provocative testing. This type of neurosecretory disturbance may also result from cranial irradiation. Romshe et al (1984) described diminished pulsatile GH secretion in six of nine such children who had normal GH responses to arginine and L-dopa. Blatt et al (1984) identified five of eight children who underwent cranial irradiation for leukaemia who had normal or borderline GH responses to insulin-induced hypoglycaemia but markedly diminished spontaneous GH output over 24 hours. Several important issues are raised by these studies. First, they reveal the limitations of current provocative tests for GH deficiency to reflect normal GH secretion throughout the day. Second, our concepts of GH deficiency may be too restrictive and, unless the guidelines are changed, many GH-deficient children may be overlooked. Third, there is an urgent need for a simple sensitive test for GH secretion which will allow the detection of such qualitative defects in GH secretion. Whether the GH responses following the use of hGRF are able to reflect physiological GH secretory activity is currently being investigated. At present, a 24-hour

20

K . Y . HO ET AL

blood sampling schedule appears best to reflect physiological GH secretion . Indeed, Albertson-Wikland et al (1983) observed that children with growth rates above two standard deviations of normal had more frequent and larger GH pulses than normal subjects. An important question to consider is the improved growth rates in the children when treated with GH (Rudman et al , 1981; Spilitos et al , 1984). Two groups of investigators have recently reported that GH treatment improved the growth rate in short children without GH deficiency (Van Vliet et al, 1983; Gertner et ai , 1984). However, in none of these children were 24-hour secretory studies performed , nor were efforts made to detect a biologically defective GH molecule . It is therefore not possible to know if these children had some identifiable cause for the short stature. If they did not , then one possible explanation is that treatment with sufficient GH is likely to make any child grow faster. This is not surprising, as gigantism is the result of excessive GH secretion before epiphyseal closure . We must be circumspect in accepting increased growth rate during GH treatment as evidence of either a quantitative or qualitative defect of GH detection.

Psychosocial dwarfism. It has been recognized for some time that short stature and failure to thrive can result from a socially and psychologically stressful environment. Powell et al (1967) described a group of emotionally deprived children with stunted growth simulating idiopathic hypopituitarism. GH responses to insulin-induced hypoglycaemia were subnormal. These investigators showed that the group of socially deprived children attained normal growth rates and normalization of GH responses after a period of hospitalization (Powell et al, 1973). The primary defect appears related to hypothalamic dysfunction resulting from influences from higher cortical centres which may also cause impaired ACTH secretion (Powell et ai, 1967). Twenty-four-hour studies in these patients reveal very little spontaneous GH secretion and no sleep-associated GH rise (Powell et ai, 1973; Miller et al, 1982). Endocrine abnormalities . Although childhood hypothyroidism is a wellrecognized cause of retarded growth, the mechanisms responsible are complex. There is a delay in bone age which frequently exceeds that seen with isolated GH deficiency. The impairment of GH release to provocative stimuli (MacGillivray et ai , 1968; Turnbridge et ai, 1973) is corrected by thyroxine replacement. Studies in hypothyroid rats suggest that the reduced GH reserve is a result of decreased pituitary GH production (Peake et al, 1973) rather than a result of hypothalamic dysfunction (Smyth et al, 1982). Circulating Sm C concentrations are low in hypothyroidism (Chernausek et al , 1983) and often are in the range found in GH-deficient children (Furlanetto et al, 1977). Hypothyroidism does not appear to cause peripheral GH resistance, as the Sm C response to the administration of GH is comparable to that seen in euthyroid GH-deficient children (Chernausek et al , 1983). It is likely that the mechanisms of growth failure in hypothyroidism are also dependent on non -GH related factors .Treatment of a hypothyroid patient with GH was ineffective in

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21

restoring normal growth (Blizzard et aI, 1974). Not infrequently, when hypothyroidism develops during GH therapy, the growth rate in GHdeficient children is improved with correction of hypothyroidism (Lippe et aI, 1975). Finally, animal experiments show that thyroid hormone and GH act in synergy to stimulate cartilage growth (Glasscock and Nicoll, 1981). While glucocorticoid excess causes growth arrest, such growth retardation is probably not due to deficiency of GH secretion. The GH hormone response to insulin-induced hypoglycaemia (Morris et ai, 1968) and nocturnal GH rise (Krieger et ai, 1972) are not altered by corticosteroid administration. However, in patients with Cushing's disease there is a loss of sleep-associated rise of GH and a blunting of GH responses to provocative stimuli. These changes in GH secretion are considered by Krieger and Glick (1972) to be a manifestation of disturbed hypothalamic function rather than secondary to the effects of corticosteroids. It is generally believed that glucocorticoids retard growth by inhibiting Sminduced stimulation of cartilage sulphation (Kilgore et al, 1979). Sm C levels are normal in hypercortisolism and treatment with GH is ineffective (Solomon and Schoen, 1976). Excess of GH secretion Acromegaly The most common cause of acromegaly is a pituitary tumour secreting GH. There is still considerable controversy as to whether this cause of excessive GH secretion arises from a primary abnormality of pituitary somatotrophs or from an underlying defect involving hypothalamic control of pituitary function. The case for hypothalamic dysfunction is supported by the observation that peripherally administered glucose and dopamine, agents which are thought to alter GH secretion via hypothalamic neuronal mechanisms, cause qualitatively different GH responses in acromegalic subjects. As excessive GRF production from an ectopic source can cause acromegaly, it is possible that defective regulation of hypothalamic GRF secretion can also do so. Rare hypothalamic hamartomas that secrete GRF have been reported to cause acromegaly (Asa et ai, 1984). The finding that acromegalies are GRF-responsive suggests the presence of intact GRF receptors on GH-producing adenoma cells, a finding which does not support autonomy of GH secretion arising from a pituitary defect (Wood et ai, 1983). Further evidence of apparently normal somatotroph function is the demonstration by Ishibashi and Yamaji (1984) that dopamine suppresses GH release from Gl-l-producing adenomas to the same degree as that in normal pituitaries in vitro. However, a number of observations favour the hypothesis of a primary pituitary defect as the cause of acromegaly. The finding of GH response to TRH and LHRH suggests the presence of functional somatotroph abnormality. However, there is recent in vivo and in vitro evidence that GRF may permit or facilitate GH responsiveness to TRH (Thorner et ai, 1982; Borges et ai, 1983b). Second, microscopic examination of pituitaries removed from acromegalic patients

22

K. Y. HO ET AL

shows that adenomas are well demarcated and that somatotrophs located outside the tumour boundary are not hyperplastic and appear normal (Landolt, 1979; Melmed et aI, 1983). More importantly, the finding that normal GH-secretory dynamics are restored following selective microadenectomy strongly argues in favour of an underlying pituitary defect (Hoyte and Martin, 1975; Faglia et aI, 1978). However, apparent clinical remission following surgery is not always accompanied by normalization of GH responses (Shaisons et ai, 1983). The question as to what constitutes a cure of acromegaly is critical to current concepts regarding its pathogenesis. It is clear that various investigators have used different clinical and biochemical criteria to evaluate therapeutic outcome, and it is notable that remission of disease is frequently described as a cure. We believe that a cure can only be considered if there is (1) complete disappearance of clinical symptoms, (2) normalization of basal GH and Sm C levels, (3) complete suppression of GH release to oral glucose loading, (4) disappearance of paradoxical GH responses to TRH, LHRH and dopamine agonists, and (5) re-establishment of a normal circadian pattern of GH secretion. It is important to note that recurrence of hyperprolactinaemia (Serri et al , 1983) has occurred after documented clinical and biochemical remission in the early months post-surgery in patients with prolactinsecreting pituitary tumours. Long-term follow up and evaluation of surgically treated patients with acromegaly is necessary before any definitive statements can be made. The diagnosis of acromegaly is made on clinical grounds with hormonal measurements merely serving to confirm the diagnosis. The limited usefulness of a random GH sample has already been discussed. Several cases of acromegaly with 'normal' basal levels established from repeated GH measurement have been described (Mims and Bethune, 1974; Cryer and Daughaday, 1977). In these cases, the abnormal GH responses to oral glucose helped confirm the diagnosis. We have already discussed that this test can lack specificity in certain circumstances. The question as to whether GH suppression in acromegaly can ever be normal has not been resolved. Mims (1978) reported 15 patients with clinical features of acromegaly in whom GH responses to L-dopa and glucose were normal. He used the term acromegaloidism to describe this syndrome which he defined as a condition resembling acromegaly by its clinical manifestation but not due to pituitary or hypothalamic dysfunction. Sm concentrations were not measured in these patients. Hoffenberg et al (1977) described two similar cases in whom Sm levels were found to be elevated. More recently five patients with so-called acromegaloidism have been shown to have a growth-promoting factor in their serum (Aschraft et aI, 1983). The GH response to TRH is also considered a useful diagnostic test in acromegaly (Irie and Tsushima, 1972). However, like the GH responses to oral glucose loading, this test lacks specificity. TRH-induced GH responsiveness has been described in anorexia nervosa (Maeda et aI, 1976), diabetes mellitus (Ceda et aI, 1982), and chronic renal failure (GonzalesBarcena et aI, 1973). Evain-Broin et al (1983) noted that a paradoxical GH response to TRH occurred in three of 11 children investigated for tall

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23

stature. They suggested that some forms of constitutional tall stature may be due to disturbed regulation of GH secretion, as abnormal GH responses to oral glucose loading also occurred in two of the three children. However, Pieters et al (1980) have reported that defective GH suppression to oral glucose occurs frequently (up to 80%) in adolescent children irrespective of whether they had normal or tall stature. Furthermore, the defective GH responses disappeared when some of the children were restudied at a later stage. Although the exact mechanism causing these GH responses in puberty is not known, the data of Pieters et al suggest that they may be a normal phenomenon of the process of sexual maturation. Clearly, until the GH responsivity to oral glucose and TRH in normal children undergoing puberty is better defined, the interpretation of such tests in adolescent children must be done cautiously. Of the several growth factors identified, Sm C has the most relevance in the diagnosis and management of acromegaly. It has long been recognized that GH levels do not accurately reflect disease activity (Clemmons et aI, 1979), and there is increasing evidence that Sm C may be a better indicator. We believe that the measurement of Sm C plays an important role in establishing the diagnosis in view of the findings by Clemmons et al (1979) and Rieu et al (1982) that levels of this growth factor did not overlap with the normal range for adults. The question as to whether Sm C should playa major role in monitoring treatment response is controversial.

Other conditions associated with excessive GH secretion Metabolic disorders such as diabetes mellitus, chronic renal failure and hepatic insufficiency, and nutritional disorders such as anorexia nervosa, are associated with an excess of GH secretion. In these conditions, the biological and clinical effects of GH excess are not present. Sm C levels tend to be normal or low, and it is believed that in some of these disorders there may be as yet unidentified factors in the circulation which inhibit GH generation of somatomedin or block its action. The excessive GH secretion is believed to be due to hypothalamic dysfunction, as GH responses to glucose loading are frequently abnormal. The high GH and accompanying low Sm C levels seen with protein caloric malnutrition return to normal once normal body weight is attained (Phillips and Unterman, 1984). The excessive GH secretion that accompanies poorly controlled diabetes can be normalized with improved control on insulin pump therapy (Tamborlane et aI, 1981). Summary A large range of tests is now available to help us understand, diagnose and manage GH-related growth disorders. The traditional provocative tests of GH secretion will identify short children with severe GH deficiency. However, evidence is emerging that these pharmacological tests may not be sufficiently sensitive to identify some subjects with GH deficiency arising from neurosecretory disturbance of GH release. There is a need for

24

K. Y.HOETAL

a simple sensitive test that will detect subtle GH secretion of this type. hGRF administration is a reliable test of GH reserve and, when used in combination with conventional tests, may help to identify GH-deficient children with hypothalamic GRF deficiency. Whether the GH responses following GRF administration reflects physiological GH secretory activity needs to be established. The diagnosis of acromegaly is made on clinical grounds. The abnormal GH responses to glucose and TRH support the diagnosis, but by themselves should not be considered to be diagnostic of acromegaly. An elevated Sm C level also helps to establish the diagnosis, although Sm C concentrations may be elevated to the same degree in pregnancy and during puberty. The use of Sm C to monitor disease activity remains to be established. Circulating GRF levels should be measured in patients with acromegaly so that ectopic production of GRF can be identified. Acknowledgements This work was supported in part by HD-00439 (WSE), and HD-13197 and AM-32632 (MOT). Dr Ho is supported by the CRC Blackburn Travelling Fellowship of the Royal Australasian College of Physicians and the Medical Foundation, University of Sydney. We thank Mrs Donna Harris and Mrs Ina Hofland for preparing the manuscript.

REFERENCES Abu-Fadil S, DeVane G, Siler TM & Yen SSC (1976) Effects of oral contraceptive steroids on pituitary prolactin secretion. Contraception 13: 79-85. Albertson-Wikland K, Isaksson 0, Rosberg S & Westphal 0 (1983) Secretory pattern of growth hormone in children of different growth rates. Acta Endocrinologica 103 (Supplement 256): 72. Asa SL, Scheithauer BW, Bilboa JM et al (1984) A case for hypothalamic acromegaly: hypothalamic gangliocytomas producing somatoliberin. A clinicopathologic study in six cases. Journal of Clinical Endocrinology and Metabolism 58: 796-803. Aschraft MW, Hartzband PI, Van Herte AJ, Bersch N & Golde DW (1983) A unique growth factor in patients with acromegaloidism. Journal of Clinical Endocrinology and Metabolism 57: 272-276. Bartke A (1966) Influence of prolactin on male fertility in dwarf mice. Journal of Endocrinology 35: 419-420. Bartke A, Goldman BD, Bex F & Dalterio S (1977) Effects of prolactin (PRL) on pituitary and testicular function in mice with hereditary PRL deficiency. Endocrinology 101: 1760-1766. Beck P, Parker ML & Daughaday WH (1966) Paradoxical hypersecretion of growth hormone in response to oral glucose. Journal of Clinical Endocrinology and Metabolism 26: 463-469. Besser GM, Wass JAH & Thorner MO (1980) Bromocriptine in the medical management of acromegaly. In Goldstein M, Caine DB, Lieberman A & Thorner MO (eds) Ergot Compounds and Brain Function: Neuroendocrine and Neuropsychiatric Aspects, pp 191-198. New York: Raven Press. Bethea CL, Ramsdell JS, Jaffe RB, Wilson CB & Weiner RI (1982) Characterization of the dopaminergic regulation of human prolactin-secreting cells cultured on extracellular matrix. Journal of Clinical Endocrinology and Metabolism 54: 893-902. Bierich JR (1972) On the aetiology of hypopituitary dwarfism. In Pecile A & Muller EE (eds) Growth and Growth Hormone, pp. 408-415. Amsterdam: Excerpta Medica.

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Blatt J, Bercu BB, Gillin C, Mendelson WB & Poplack DG (1984) Reduced pulsatile growth hormone secretion in children after therapy for acute lymphoblastic leukemia. Journal of Pediatrics 104: 182-186. Blethen SL & Chasalow FI (1983) Use of a two-site immunoradiometric assay for growth hormone (GH) in identifying children with GH-dependent growth failure. Journal of Endocrinology and Metabolism 57: 1031-1035. Blizzard RM, Thompson RG, Baghdassarian A et al (1974) The interrelationship of steroids, growth hormone and other hormones on pubertal growth. In Grumbach MM, Grove GO & Mayer FE (eds) Control of the Onset of Puberty, pp. 342-349, New York: John Wiley. Boden G, Soeldner 1S, Steinke J et al (1968) Serum human growth hormone (hGH) response to iv glucose: diagnosis of acromegaly in females and males. Metabolism 17: 1-9. Borges JLC, Blizzard RM, Gelato MC et al (1983a) Effects of human pancreatic tumour growth hormone releasing factor on growth hormone and somatomedin C levels in patients with idiopathic growth hormone deficiency. Lancet ii: 119-123. Borges JLC, Uskovitch DR, Kaiser DL et al (1983b) Human pancreatic growth-hormone releasing factor-40 (hpGRF-40) allows stimulation of GH release by TRH. Endocrinology 113: 1519-1521. Borges JLC, Blizzard RM, Evans WS et al (1984) Stimulation of growth hormone (GH) and somatomedin C in idiopathic GH-deficient subjects by intermittent pulsatile administration of synthetic pancreatic tumor GH-releasing factor. Journal of Clinical Endocrinology and Metabolism 59: 1-6. Bowers CY, Friesen HG, Hwang P, Guyda HJ & Folkers K (1971) Prolactin and thyrotropin release in man by synthetic pyroglutamyl-histidyl-prolinamide. Biochemical and Biophysical Research Communications 45: 1033-1041. Boyd AE III, Reichlin S & Turksoy RN (1977) Galactorrhea-amenorrhea syndrome: diagnosis and therapy. Annals of Internal Medicine 87: 165-175. Bression 0, Brandi AM, Martres MP et al (1980) Dopaminergic receptors in human prolactin-secreting adenomas: a quantitative study. Journal of Clinical Endocrinology and Metabolism 51: 1037-1043. Burrows GN, Wortzman G, Rewcastle NB, Holgate RC & Kovacs K (1981) Microadenomas of the pituitary and abnormal sella tomograms in an un selected autopsy series. New England Journal of Medicine 304: 156-158. Camanni F, Genazzani AR, Massara F et al (1981) Prolactin responsiveness to nomifensine in patients with hyperprolactinemia of tumorous or uncertain etiology. Journal of Clinical Endocrinology and Metabolism 51: 650-653. Carter IN, Tyson JE. Tolis G et al (1978) Prolactin-secreting tumors and hypogonadism in 22 men. New England Journal of Medicine 299: 847-852. Cave WT & Paul MA (1980) Effects of altered thyroid function on plasma prolactin clearance. Endocrinology 107: 85-91. Ceda GP, Speroni G, Dall'aglio E, Valenti G & Butturi U (1982) Non-specific growth hormone response to thyrotropin releasing hormone in insulin-dependent diabetics: sex and age related pituitary responsiveness. Journal of Clinical Endocrinology and Metabolism 55: 170-174. Chernausek SO, Underwood LE, Utiger RD & Van Wyk JJ (1983) Growth hormone secretion and plasma somatomedin-C in primary hypothyroidism. Clinical Endocrinology 19: 337-344. Chirito Gonda A & Friesen H (1972) Prolactin in renal failure. Clinical Research 20: 423. Chroussos GP, Poplack 0, Brown T et al (1982) Effects of cranial radiation on hypothalamic adenohypophyseal function: abnormal GH secretory dynamics. Journal of Clinical Endocrinology and Metabolism 54: 1135-1139. Clemmons DR & Van Wyk JJ (1984) Somatomedin C in blood. Clinics in Endocrinology and Metabolism 13: 113-143. Clemmons DR, Van Wyk JJ, Ridgway, EC et al (1979) Evaluation of acromegaly by radioimmunoassay of somatomedin-C. New England Journal of Medicine 301: 11381142. Clemmons DR, Klibanski A, Ridgway EC et al (1981) Reduction in immunoreactive somatomedin-C during fasting. Journal of Clinical Endocrinology and Metabolism 53: 1247-1250.

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