Testing Anterior Pituitary Function

839

activity than norfloxacin but is better absorbed and gives good tissue levels. Possibly the most important differences apply to organisms at the edges of the spectrum-eg, ciprofloxacin and ofloxacin have good activity againstP aeruginosa, while a newagent,CI 934 (Warner Lambert), possibly to undergo clinical trials, has better activity against staphylococci.12 The new quinolones are equally effective against all staphylococci, irrespective of methicillin resistance; while this may suggest a significant use for the group, some strains of ciprofloxacin-resistant staphylococci have emerged during therapy. In addition to the agents already on trial, many new quinolones were on view at the Intersciences Conference on Antimicrobial Agents and Chemotherapy in Minneapolis last autumn, mostly identified by numbers. One paper 13 described tests on the combination of imipenem with ciprofloxacin, which acted in synergy against P aeruginosa, although the effect of this cocktail on normal human microbial flora belies the imagination. The quinolones also provide a powerful biochemical tool for studying DNA and DNA topoisomerases (gyrases), so much so that a biochemist at the Oxford meeting was heard to ask in all seriousness whether "these agents have any clinical value". The latest theory is that quinolones bind to DNA strands at the specific locations normally used for binding topoisomerases, rather than block the topoisomerases by direct interaction.’4 The gyrase may then be bound to form a covalent complex across which DNA polymerase cannot work. Nevertheless, direct binding of norfloxacin to the gyrase is implied by work on P aeruginosa, 15 which demonstrated that recovery from intermediate concentrations of norfloxacin and the bactericidal action of the drug depend on continued

protein synthesis. Side-effects have not so far been as frequent or severe as those of nalidixic acid, being mainly gut or minor central nervous system disorders. Another favourable feature is the low frequency of superinfections with candida, perhaps because quinolones have some anticandida activity. However enoxacin potentiates theophylline,16 and long-term use of norfloxacin in two immunosuppressed patients was linked with tendinitis." Some cartilage toxicity was found in animals treated with long-term nalidixic acid, so it seems sensible not to use the new drugs on patients whose skeletal growth is incomplete until more data are available. MA, Griffin TJ, Bien PA, Heifetz CL, Domagala JM. In vitro activity of CI-934 quinolone carboxylic acid active against gram positive and gram negative bacteria Antimicrobial Ag Chemother 1985; 28: 766-72. 13 Bustamante CJ, Drusano G, Wharton R, Moody MA, Wade JC. Synergism of imipenem and ciprofloxacin against Psuedomonas aeruginosa: Abstracts of the 25th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1985; (no 404) 14 Engle EC, Manes SH, Drlica K. Differential effect of antibiotics inhibiting gyrase. J Bacteriol 1983, 149: 92-98 15 Benbrook D, Miller RV. Effects of norfloxacin on DNA metabolism in Pseudomonas aeruginosa Antimicrobila Agents and Chemotherapy 1986; 29: 1-6. 16. Maesent FPV, Teengs JP, Baar C, Davies BJ. Quinolones and raised plasma 12 Cohen a

concentrations 17

of theophylline Lancet 1984; ii: 530. Kirk JA, Peddle RA. Norfloxacin induced rheumatic disease 96: 590.

Bailey RR, 1983,

N Z Med J

the quinolone scene contains several paradoxes. One is the failure in some countries to market any of these drugs-presumably because of understandable caution on the part of licensing authorities. Another is that here we have a group of highly active agents which could be used as a panacea, but to which bacterial resistance can develop. There may well be a conflict between use for common infections, or as life-savers for specific infections. And users may be spoilt for choice; doubtless, in the face of management budgets and DRGs, cost will be a significant factor. Thus

Testing Anterior Pituitary Function THE

principles governing regulation of anterior pituitary secretion by the hypothalamus have been elucidated

the past half century, and were summarised magnificently by the outstanding in investigator the field, Geoffrey Harris, in a lecture which was published posthumously.The past twentyfive years have witnessed the characterisation and synthesis of the hypothalamic stimulating and inhibiting factors,2 and clinicians have been quick to evaluate the hormonal responses to these newly available peptides, both alone and in various combinations. The most recent "super-cocktail" entails not only intravenous administration of four over

releasing hormones acting on growth hormone (GH), corticotropin, gonadotropins, thyrotropin, and prolactin, but also intramuscular injection of desmopressin (arginine vasopressin). Desmopressin enhanced release of corticotropin as anticipated,4and also of growth hormone. Moreover, peak cortisol and growth hormone levels exceeded those produced by insulin-induced hypoglycaemia. The new test is reputedly without major side-effects; might it therefore assume the role of the total anterior pituitary function test and save considerable time? The cost of materials is said to be L65 per test, but it is unclear whether purchase of the expensive large peptides-growthhormone releasing factor (1-29 amide) and human corticotropin releasing factor-was included in this estimate. Almost certainly it would be optimistic to expect that there could be a single all-purpose anterior pituitary test which would encompass all aspects of function; in practice the most critical question is whether a patient can respond to stressful stimuli with adequate cortisol secretion, for which the entire hypothalamo-pituitaryadrenal axis must be tested. Releasing factors can be used only to assess pituitary reserve, which is of more 1. Harris GW. Humours and hormones. J Endocrinol 1972; 53: ii-xxiii. 2. Belchetz PE. Physiology of the anterior pituitary gland. In: Belchetz PE, ed. Management of pituitary disease. London: Chapman and Hall, 1984: 38-68. 3. Sandler LM, Burrin JM, Joplin GF, Bloom SR. Combined use of vasopressin and synthetic hypothalamic releasing factors as a new test of anterior pituitary function. Br Med J 1986; 292: 511-14. 4. Gillies GE, Linton EA, Lowry PJ. Corticotrophin releasing activity of the new CRF is potentiated several times by vasopressin. Nature 1982; 299: 355-57.

840

limited clinical relevance, and dissociation between the two kinds of tests is well documented, not only in patients with primary hypothalamic disorders but also in those with large pituitary tumours with suprasellar extensions.5 In such patients pituitary dysfunction is partly caused by disturbance of the portal vascular link with the hypothalamus. For assessment of stress-released cortisol secretion the insulin tolerance test is well-proven and reliable, provided adequate hypoglycaemia is achieved.6,7 The difficulty is in finding a satisfactory alternative for patients with cardiac disease, epilepsy, or basal adrenal insufficiency, for whom hypoglycaemia is contraindicated. The metyrapone test, much used in North America, enjoys little favour in the UK because it tests negative feedback rather then stress-related mechanisms and the two pathways are not invariably damaged in parallel.The pyrogen test’s unpleasant effects led to its demise long ago, but at least it was a genuine physiological stress.9 The lysine vasopressin tests is similarly outdated, partly because of side-effects including coronary spasm. Lysine vasopressin acts in synergy with corticotropin-releasing factor to enhance corticotropin release," and on its own it will stimulate GH secretion." Probably the best alternative to the insulin tolerance test is subcutaneous glucagon, which stimulates secretion of cortisol as well as GH.12 GH is not vital in adults; the importance of assessing its secretory reserve lies in detection of early pituitary dysfunction since it appears to be the most vulnerable adenohypophyseal hormone in several disorders including pituitary tumours’3 and hypothalamic damage consequent upon cranial irradiation.’4 The episodic nature of GH secretion (normal individuals may have undetectable levels during the day) means that dynamic tests are necessary in order to assess reserve. Unfortunately there is poor reproducibility of GH response if several tests-eg, insulin tolerance test,6 oral clonidine,15 and even exogenous GH

5.

Lytras N, Grossman A, Perry L, et al. Corticotropin releasing factor. Response in normal subjects and patients with disorders of the hypothalamus and pituitary. Clin

Endocrinol 1984; 20: 71-84. 6. Greenwood FC, Landon J, Stamp TCB. The plasma sugar, free growth hormone response to insulin. I. In control subjects.

releasing factor’6-are repeated in the same individual. Subcutaneous glucagon appears to be a safe and reliable test in adults.17 The diagnosis is more critical with short children who may be GH deficient,l8 and measurement of sleep-induced GH release has been advocated. 19

Gonadotropin secretion is also susceptible to early pituitary damage-this can not readily be adjudged by basal hormone measurements of follicle-stimulating hormone (FSH) and luteinising hormone (LH) (except in postmenopausal women) but is best detected by finding inappropriately low sex-steroid levels. Use of gonadotropin-releasing hormone often discloses surprising pituitary reserves, as in the secondary hypogonadism accompanying hyperprolactinaemia. However, it is not a test which reliably distinguishes between hypothalamic and pituitary disorders,2° for which a "pulsatility study"-repeated measurements of LH at 15 min intervals for several hours followed by an exogenous gonadotropin releasing test-is often helpful. The study protocol is now well established and has reduced the indications for the clomiphene test (which extends over many days). The first releasing hormone test to be introduced-for thyrotropin-will probably be used less frequently once the ultrasensitve thyrotropin assays, which can measure subnormal levels, become routine. Very rarely this test produces serious sideeffects resembling pituitary apoplexy.2’ Insulininduced hypoglycaemia, and thyrotropin and gonadotropin releasing hormones are commonly used in combination.22,23 For patients with syndromes a different

suspected hypersecretory approach is required.

Hyperprolactinaemia is the commonest form of pituitary hypersecretion and dynamic tests probably add little to basal prolactin measurements-at most three separate samples should provide a reliable indication of representative prolactin secretion.24 The failure of GH suppression during an oral glucose tolerance test remains the diagnostic standard for acromegaly, but it is often useful to document aberrant

fatty acid, cortisol, and J Clin Invest 1966; 45:

16. Thorner MO, Rivier J, Spiess J, et al. Human pancreatic growth-hormone-releasing factor selectively stimulates growth-hormone secretion in man. Lancet 1983; i

7. 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 and adrenal function. II. In patients with hypothalamic or pituitary dysfunction or anorexia nervosa. J Clin Invest 1966; 45: 437-49. 8. Landon J, James VHT, Stoker DJ. Plasma-cortisol response to lysine-vasopressin. Lancet 1965; ii 1156-59. 9. Melby JC. Assessment of adrenocorticotrophic activity with bacterial pyrogen in hypopituitary states J Clin Invest 1959; 38: 1025. 10. Lamberts SWJ, Verleun T, Oosterom R, de John F, Hackeng WHL. Corticotropin-

17. Cam JP, Williams GH, Dluhy RG. Chicago-initiated human growth hormone release: A comparative study. Can Med Assoc J 1972; 167: 617-22. 18. Milner RDG, Burns BC. Investigation of suspected growth hormone deficiency. Arch Dis Child 1982; 57: 944-47. 19. Hindmarsh PC, Smith PJ, Taylor BJ, Pringle PJ, Brook CGD. Comparison between a physiological and pharmacological stimulation of growth hormone secretion Response to stage IV sleep and insulin-induced hypoglycaemia. Lancet 1985; ii:

437-49.

11.

12. 13. 14.

24-28.

releasing factor (ovine) and vasopressin exert a synergistic effect on adrenocorticotropin release in man. J Clin Endocrinol Metab 1984; 58: 298-303. BrostoffJ, James VHT, Landon J. Plasma corticosteroid and growth hormone response to lysine-vasopressin in man. J Clin Endocrinol Metab 1968; 28: 511-18. Bloom S, Millar JGB, Nabarro JDN, et al. Glucagon stimulation of the anterior pituitary. J Endocrinol 1972; 53: xliii. Fraser R. Human pituitary disease. Br Med J 1970; 4: 449-55. Shalet SM, Beardwell CG, Morris-Jones PH, Pearson D. Pituitary function after treatment

of intracranial

tumours

in children. Lancet

1975; ii: 104-07.

15. Health Service Human Growth Hormone Committee. Comparison of the intravenous

insulin and oral clonidine tolerance Child 1981; 56: 852-54.

tests

for growth hormone

secretion.

Arch Dis

1033-35. 20. Mortimer

21.

CH, Besser GM, McNeilly AS, et al. Luteinizing hormone and follicle stimulating hormone-releasing hormone test in patients with hypothalamicpituitary-gonadal dysfunction. Br Med J 1973; iv: 73-77. Drury PL, Belchetz PE, McDonald WI, Thomas DGT, Besser GM. Transient amaurosis and headache after thyrotropin releasing hormone. Lancet 1962; i:

218-19. 22. Harsoulis P, Marshall 23.

JC, Kuku SF, et al. Combined test for assessment of anterior pituitary function. Br Med J 1973; 4: 326-29. Mortimer CH, Besser GM, McNeilly AS, et al. Interaction between secretion of the gonadotrophins, prolactin, growth hormone, thyrotrophin and corticosteroids in man: The effects of LH/FSH-RH, TRH and hypoglycaemia alone and in

combination. Clin Endocrinol 1973; 2: 317-26. 24. Moult PJA, Dacie JE, Rees LH, Besser GM. Prolactin pulsatility in gonadal dysfunction. Clin Endocrinol 1981; 34: 387-94.

patients

with

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GH stimulation with thyrotropin releasing hormone since this occurs in about 80% of acromegalies. 25 The suppressibility ofGH with bromocriptine is also worth determining-this too occurs in approximately, but not necessarily the same, 80%. Cushing’s disease is still a challenging disorder to diagnose and treat, and it remains true that no single test should be relied on, certainly not the use of corticotropin-releasing

hormone.26 HIGH TECH FOR THE SIGHTLESS YEARS ago in Malawi a blind man, in order to find his way, used a quasi-computer. He had programmed it with a clear plan of where he wanted to go, which enabled him to move at a steady rate in the desired direction. The aid responded to obstacles with speech-synthesised warnings, and indicated how to circumvent dangers. When it came to crossing a road it managed to halt his progress if there was a moving hazard in sight. There was no need for him to use a cane in order to follow the kerb, and stones that might have tripped up those not equipped like he were easily circumambulated. In the developed world, we find grandchildren leading the blind with long rods too expensive, and therefore turn to electrons. A NATO Advanced Institute on electronic spatial sensing for the blind’ now reveals aspects of the problem which it may be interesting to ventilate. It is an old gibe that, once blindness has become incurable, interest in the expatient is relinquished by the ophthalmologist and taken up by the social worker. It is clear, however, that we have not begun to solve the difficulties posed by loss of sight, despite the helpful advances made, for example, by A. G. Dodds and A. D. Heyes and their colleagues in Nottingham. One reason for this state of affairs is almost certainly that we have failed to evolve a physiology of the blind. We are so eye-centred that we cannot see beyond a functional ocular prosthesis for those deprived of the use of their eyes. But the efficiency of vision depends not only on the anatomical intactness of the visual pathways but also on its quality during one or more of the socalled sensitive periods, observed to exist in early infancy, when the retinocortical pathways are especially plastic and so amenable to modification by both favourable and noxious influences. Not for nothing does E. Foulke stress that what man can do with his space depends chiefly on what he remembers about it. Assisting a congenitally sightless person who has never been able to visualise space, and whose tactile responses have never been integrated with a corresponding visual stimulus, is very different from helping someone who, though deprived of sight, yet has the advantage of earlier visual experience to guide him. The former has to be taught a language proper to him, the latter translation into a foreign one. But if this simile is acceptable the next question is inevitable: how is one to teach the language if one does not oneself speak it? The traditional solution has always been a compensation for the loss of one sensory modality by an increased demand on others. P. Bach-y-Rita has been trying for decades to project tactile "images" on large smooth body surfaces such as the abdomen. For a long time his advances were identified 25

Liuzzi A, Chiodini PG, Botalla L, et al. Growth hormone (GH)-releasing activity of TRH and GH-lowering effects of dopaminergic drugs in acromegaly: Homogeneity in the two responses. J ClinEndocrinol Metab 1974; 39: 871-76 26 Orth DN. The old and the new in Cushing’s syndrome.NEngl JMed 1984; 310: 649-51 1 Warren DH, Strelow ER, eds. Electronic spatial sensing for the blind.NATO ASI Series Series E: Applied Sc 99. Dordrecht: Martinus Nijhoff, 1985

with a highly contrasted china donkey, the photic image of which was transduced into punctate stimulation of dermal touch receptors. Although progressive miniaturisation has lightened the power supply, and reduced the weight to be carried when the mobility aid is in use (as C. C. Collins and M. F. Deering also show in remarkable duplication) a large transducing surface is needed also in contemporary versions if the information input is to be adequate. A clear advantage of the shape of the eye is that a spherical surface is the most economical on which to project a visual field: flat abdomina are expensive in terms of information transfer. Development of sonar devices has found its echoes in aids for spatial perception of the visually handicapped, but L. Kay draws attention to the restricted market for these and, indeed, other, electronic devices. There are those who argue that aids should not have to depend on the use of hearing, because the ears may be needed for direct verbal information rather than be usurped for synthesised vocal guidance on one’s progress through space. A survey of London’s pavements shows clearly that electrons have not caught on amongst the sightless, although the long cane evidently has. M. Brambring notes its limitations. Introduced after the 1939-45 war (perhaps as a result of the development of lightweight materials), it came to be recognised as valuable in the exploration of immediate space at ground level. Here lasers have also been able to play a constructive role-the sharp pencil of light that they provide acts as an "optical cane". But the future must surely lie with the computer. J. T. Tou and M. Adjouadi examine the requirements of computer vision and devise an operational algorithm for the exploration of surrounding space. It is based on use ofspeaking camera, at present limited by the narrowness of its field. Will such a system, even if perfected, represent the ultimate achievement of our endeavours? Consider for a moment how our senses inform us about the environment and why vision is preeminent. Rated by the distance at which they can signal danger, they follow this decreasing order: sight, hearing, smell, touch, and taste. What route is the input of information going to follow to the brain? Bach-y-Rita and others have opted for touch receptors; some have chosen hearing. There is little doubt that, with vision lost, the broadest band-width is provided by the auditory channel. As long as the sightless person is not deaf, this should (and will) be the chosen path. Since voice synthesis is making rapid progress, it will be possible to program a computer with scenarios that the user is likely to encounter, and for the photic camera and sonar aids to stimulate the voice to say what is being "seen". Remember that our use of space is determined by the quality of our memory, and there is no reason within the present context why this should not reside within the computer. Chemical detection is not to be lightly dismissed, especially if it can be made more sensitive than the nose: while the sighted may see smoke, it is as well to detect it and other common chemical hazards by other means. On this view, the photic and sonar cameras and odour detectors will combine their inputs to enable the voice to say which of the scenes is being matched by the memory. Programming will have to be done with, pardon the term, insight-eg, ornamental colour may trigger the photic camera, but only traffic and warning signals are likely to have a high chromatic priority. Again, while our seeing eyes may be caught by a vehicle crossing our path at right angles a long way ahead, this is probably not very important from the point of view of danger to the person. The main difficulty in