PLASMA-TESTOSTERONE LEVELS IN KENYAN MEN IN RELATION TO CANCER OF THE NASOPHARYNX

1342

Seaton and Rose 1965), while of 100 overweight patients only 2 had lost weight after 2 years (Stunkard and McLaren-Hume 1959). Since the 19 patients who undertook repeated fasts were a selected proportion of the total, in that they requested further treatment by fasting, we cannot draw conclusions about the value of repeated fasts in general. It cannot be predicted, however, that the long-term benefit of repeated fasts will necessarily be greater than if only one fast were undertaken; the results shown in table 11 suggest that in some patients at least the end-result is no better. There are, on the other hand, some patients in whom rapid weight-loss is considered to be urgently indicated, and for them repeated fasts may be of particular value. Alternatively, a very prolonged single fast has been suggested, and patients have been successfully fasted for periods of 117 days (Drenick et al. 1964), 245 days (Henneman and King 1964), and 249 days (Thomson et al. 1966). For most patients and their physicians, however, intermittent 10-day fasts, with the patients in hospital only during the fasts, are more practicable, and the results may be as good. Thus our patient described above who underwent eight 10-days fasts, and carried on her normal life outside hospital between the fasts, lost the same amount of weight, and the same fraction of her original weight as the patient of Thomson et al. (1966) who fasted continuously in hospital for 249 days. It is not known why the benefits of fasting should persist in some patients beyond the period of starvation itself, but several factors may be responsible. During the first few days of fasting the weight-loss is due mainly to decrease in the amount of extracellular fluid and to protein catabolism, with high nitrogen excretion (Henneman and King 1964). At the same time hormonal changes occur, with a decrease in thyroid function (Alexander et al. 1964) and increased secretion of growth hormone (Roth et al. 1963) which result in decreased protein catabolism and increased mobilisation of fat. It is not known for how long these changes persist after the end of the fast; they may continue to promote weight-loss from fat-catabolism when eating is resumed. Secondly, it has been shown that patients’ appetites are less at the end of a fast than before it (Silverstone et al. 1966) so that fasting may enable some patients to become satisfied with a low-calorie diet although they found it insufficient before. Thirdly, the rapid weight-loss during fasting is of psychological benefit to patients who were previously convinced that " dieting " was hopeless or that they had a glandular disease. These patients may be sufficiently encouraged by the results of fasting to adhere more strictly than before to a weightreduction diet.

Summary

patients, who had previously attempted, unsuccessfully, to lose weight, were treated by a 10-day period of total fasting in hospital, followed by a weightreducing diet on discharge. The average weight-loss during the 10-day fast was 16-3 Ib. (7-4 kg.). In 5 patients, the fast had to be terminated because of gastrointestinal symptoms, and 1 other patient had suppurative parotitis. The remaining patients felt well throughout the fast and did not complain of hunger. The patients were followed up for 1-3 years after their fast. After 1 year, 40% of the patients had not returned to their original weight, and of 12 patients followed for 3 years, 4 had maintained their weight-loss. In 19 patients, 62 obese

two or more

fasts

were

undertaken but the results in these

patients were not significantly better than those in patients having only one period of fasting, except where rapid weight-loss was urgently indicated. Possible reasons for the long-term benefits of a short fast are discussed. The results are considerably better than those in patients attending weight-reduction clinics. Fasting in obesity is generally safe and not unpleasant, but it should be undertaken only in hospital. We thank Sir Edward whose care these patients

Wayne and Dr. W. D. Alexander, under were

admitted.

REFERENCES

Alexander, W. D., Harrison, M. T., Harden, R. McG., Koutras, D A. (1964) Metabolism, 13, 587. Bloom, W. L. (1959) ibid. 8, 214. Cubberley, P. T., Polster, S. A., Schulman, C. L. (1965) New Engl. J. Med. 272, 628. Drenick, E. J., Joven, C. B., Swenseid, M. E. (1966) ibid. 274, 937. Swenseid, M. E., Blahd, W. H., Tuttle, S. G. (1964) J. Am. med. Ass. 187, 100. Duncan, G. G. (1964) in Diseases of Metabolism (edited by G. G. Duncan); p. 974. London. Duncan, T. G., Schless, G. L., Cristofori, F. C. (1965) Ann. N.Y. Acad. Sci. 131, 632. Jenson, W. K., Cristofori, F. C., Schless, G. L. (1963) Am. J. med. Sci. 245, 515. Henneman, P. H., King, A (1964) Clin. Res. 12, 457. Hunscher, M. A. (1966) Metabolism, 15, 383. Metropolitan Life Insurance Co. (1962) Statist. Bull. 43, 1. Roth, J., Glick, S. M., Yalow, R. S., Berson, S. A. (1963) Science, N.Y. 140, —

-

-

987.

Seaton, D. A., Rose, K. (1965) J. chron. Dis. 18, 1007. Silverstone, J. T., Stark, J. E., Buckle, R. M. (1966) Lancet, i, 1343. Stunkard, A., McLaren-Hume, M. (1959) Archs intern. Med. 103, 79. Thomson, T. J., Runcie, J., Miller, V. (1966) Lancet, ii, 992. van Riet, H. G., Schwarz, F., der Kinderen, P. J. (1964) Metabolism, 13, 291. Walker, H. C., Jr. (1954) Archs intern. Med. 93, 951.

PLASMA-TESTOSTERONE LEVELS IN KENYAN MEN IN RELATION TO CANCER OF THE NASOPHARYNX D. Y. WANG M.Sc., Ph.D.Lond.

R. D. BULBROOK M.Sc., Ph.D.Lond

OF THE DIVISION OF CHEMISTRY AND

RESEARCH

BIOCHEMISTRY,

IMPERIAL CANCER

FUND, LINCOLN’S INN FIELDS, LONDON W.C.2

PETER CLIFFORD N.U.I., D.L.O.

M.Ch.

CONSULTANT-IN-CHARGE, DEPARTMENT OF HEAD AND NECK SURGERY, KENYATTA NATIONAL HOSPITAL, NAIROBI, KENYA

Clifford and Bulbrook (1966) found that African men excreted less urinary 11-deoxy-17-oxosteroids and more urinary oestrogens than British men. They concluded that the urinary assay results were evidence for hyperoestrogenisation in the Africans and that this might be a contributory factor in the high prevalence of nasopharyngeal cancer in Kenyan men. Deductions concerning the physiological stimuli to a target organ that are based on results of assays of urinary steroid metabolites must be regarded with some caution. A more direct approach is the measurement of plasma levels of the hormones from which the urinary steroids are derived. The most important androgen in men is testosterone, and the levels of this hormone could have an important bearing on the net oestrogenic stimulus to the nasopharyngeal epithelium. This paper reports on comparison between the levels of plasma-testosterone in Kenyan men of the Central Bantu or Nilo-hamitic ethnic groups and those of British men. Methods

Heparinised blood-samples (20 ml.) were collected from Kenyan men shortly after admission to hospital. Except for 7 patients with cancer, the remaining Africans were admitted

1343 testosterone

(0-05g.)

of

9-7, 10-6, 9-8, and 10-0. A

replicate standard is shown in fig. 1.

curve

Estimations of the

plasma samples were car-

Fig. t—Ca!ibration-curve of standard

testosterone.

wide variety of minor illnesses not connected with their endocrine systems. The plasma was separated and stored at - 20°C. The samples were packed in solid carbon dioxide and sent by air to London. All arrived still frozen. Blood was similarly collected from British men admitted to hospital for minor surgery. All plasmas were stored at -20°C until

for

a

assayed. There were 21 Kenyans whose ages ranged from eleven to seventy years (mean thirty-four years) and 17 British men (range twenty to seventy-three years: mean age, forty-nine

years). Plasma-testosterone was assayed by the method of Burger al. (1964), modified as described by Wang, Bulbrook and Hayward (1966). Standard curves comprising a water blank, 0-025, 0-075, and 0-100 g. of testosterone were analysed for each batch of tritiated acetic anhydride. As an example, one batch of acetic anhydride gave IH/ 14 C ratios of the water blanks of 2-5, 2-6, 2-5, and 2-6 and ratios for the standard et

Fig. 2-Radiochemical purity cation steps (Burger

et

of testosterone acetate during purifial. 1964).

ried out with batches of six plasmas, one water blank, and a testosterone standard (0-05 g.). The precision of the method was estimated by carrying out five determinations on pooled plasma. The mean testosterone value was 0-48 g. per 100 ml. plasma, with a coefficient of variation of 7°o. Errors of this order have been reported previously (Hudson, et al. 1963). The specificity of the method was checked by determining the 3H/1’C ratios for the last four

chromatographic

steps

Fig. 3-Testosterone-levels in plasma from Kenyan and British men. A and C, patients with carcinoma of the nasjpharynx; B patient with carcinoma of the antrum.

The the method. ratios are shown in fig. 2, and it is clear that the testosterone acetate is radiochemically pure. Results in

plasma-testosterone levels in African and British shown in fig. 3. Although the mean testosterone level in Kenyan men (0-39 g. per 100 ml.) is slightly higher than the mean British level (0-32 g. per 100 ml.) the difference is not significant. It is of interest that 2 Kenyans with nasopharyngeal cancer and 1 with cancer The

men are

of the

antrum were among

those with the lower levels of

plasma-testosterone. The variation of the levels of plasma-testosterone with age are shown in fig. 4. In agreement with the results of Kent and Acone (1965), there is no correlation between the two variables.

Fig. 4-Distribution of plasma-testosterone levels with Kenyan and British men.

age in

1344 The mean levels of plasma-testosterone reported here are lower than those previously reported (Hudson et al. 1963, Riondel et al. 1963, Kent and Acone 1965) although the values lie within the lower range of male plasmatestosterone obtained by Kent and Acone (1965). It seems improbable that the reason for this is methodological, since notionally the method can only overestimate, rather than underestimate, the plasmatestosterone levels. The low values reported here may stem from the fact that all subjects were admitted to hospital and were sedentary or supine (Dray et al. 1965, Southren et al. 1965). Discussion

Our main finding is that plasma-testosterone levels in and British men are similar. This does not support the simple thesis that the high prevalence of nasopharyngeal cancer in African men and the reversal of the sex ratio is due to an excessive oestrogenic stimulus in the general population at risk. This result is puzzling, in that the results of Clifford and Bulbrook (1966) showing a low excretion of androgen metabolites and a high excretion of urinary oestrogens appeared to support the anthropomorphological findings of Trowell (1948)

Kenyan

and Davies (1949). There are, however, several complicating factors. For example, pronounced feminisation can occur in persons with a male phenotype who have the feminising-testis syndrome. These persons may have normal male levels of testosterone (Deshpande, Wang, Bulbrook, and McMillan 1965). Again, Japanese males have less body hair than European males, but Kobayashi et al. (1966) have reported that there is no difference in the plasmatestosterone levels between Japanese males resident in the United States and American European males. The total urinary neutral 17-oxosteroid excretion, however, was lower in the Japanese group than in the European. This latter difference also existed if correction was made for body size between the two groups. Tissue responsiveness to androgens can be blocked permanently by administration of anti-androgens to pregnant rats, when the males of the litter are born with a syndrome that is very similar to that found in men with feminising testes (Neumann and Elger 1965). Thus, foetal and neonatal hormone abnormalities may determine the future reactivity of a tissue to hormonal stimuli. Another problem already touched upon by Clifford and Bulbrook (1966) is that nasopharyngeal cancer in Kenya shows a preponderance of 4-5 to 1 for males compared with females. On a simple " oestrogenic stimulus " hypothesis the long-term stimulus would have to be assumed to be greater in men than in women. Long periods of lactation in which oestrogen excretion (and possible secretion) were low might partly account for this. Finally, whether testosterone influences the growth and metabolism of the nasopharyngeal epithelium has still to be determined. Testosterone may conceivably act synergisticaily with the oestrogens as it was reported to do in the development of the mammary gland of the

monkey (Speert 1948). The investigation of hormonal influences in nasopharyngeal cancer is obviously an extremely complicated The present findings indicate that further matter. investigations might profitably start with an examination of foetal and neonatal hormonal exposure, with an investigation of the synergistic and antagonistic effects of

various hormones on the nasopharyngeal epithelium, and with measurement of tissue response to the endocrine environment. Above all, direct measurements of the oestrogens in blood are required.

Summary The plasma-testosterone levels in Kenyan and British men do not differ nor are they correlated with age. These findings do not support the view that the high prevalence of nasopharyngeal cancer in African men is due to an excessive cestrogenic stimulus in the general population at risk. We are grateful to Dr. W. U. Gardner and the trustees of the Anna Fuller Fund for their support; Mr. J. W. Smith, laboratory superintendent, Medical Research Laboratory, Nairobi for careful packing and shipping of specimens from Nairobi to London; Mr. Gideon Shadrack and Mr. Indiazi Ephraim (clinical assistants) for their help; and Miss Vicky Amor and Miss Lesley Peacock for their skilled technical assistance. Requests for reprints should be addressed to D.Y.W., Imperial Cancer Research Fund, Lincoln’s Inn Fields, London W.C.2. REFERENCES

Burger, H. G., Kent, J. R., Kellie, A. E. (1964) J. clin. Endocr. 24, 432. Clifford, P., Bulbrook, R. D. (1966) Lancet, i, 1228. Davies, J. N. P. (1949) Br. med. J. ii, 676. Deshpande, N., Wang, D. Y., Bulbrook, R. D., McMillan, M. (1965) Steroids, 6, 437. Dray, F., Reinberg, A., Sebaoun, J. (1965) C.r. Acad. Sci., Paris 261, 573. Hudson, B., Coghlan, J., Dulmanis, A., Wintour, M., Ekkel, I. (1963) Aust. J. exp. Biol. med. Sci. 41, 235. Kent, J. R., Acone, A. B. (1965) Proceedings Second Symposium on Steroid Hormones, Ghent; p. 31. Kobayashi, T., Lobotsky, J., Lloyd, C. W. (1966) J. clin. Endocr. 26, 610. Neumann, F., Elger, W. (1965) Proceedings Second Symposium on Steroid Hormones, Ghent; p. 168. Riondel, A., Tait, J. F., Gut, M., Tait, S. A. S., Joachim, E., Little, B. (1963) J. clin. Endocr. 23, 620. Southren, A. L., Tochimoto, S., Carmody, N. C., Isurugi, K. (1965) ibid. 25, 1441. Speert, H. (1948) Contr. Embryol. 208, 11. Trowell, H. C. (1948) E. Afr. med. J. 25, 311. Wang, D. Y., Bulbrook, R. D., Hayward, J. L. (1966) Eur. J. Cancer 2, 373.

CLINICAL DIFFERENTIATION BETWEEN PRIMARY AND METASTATIC BRAIN TUMOURS M.B.

ARNOLD BARNETT W’srand, F.C.P.S.A., M.R.C.P. REGISTRAR

PAUL MILLAC Cantab., M.R.C.P.

M.B.

M.R.C. CLINICAL RESEARCH ASSOCIATE

From the University Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne 1

EXPERIENCE in many countries has shown an increasing incidence of neoplastic diseases, especially bronchogenic carcinoma. In an appreciable number of these patients cerebral metastasis develops, often before the primary growth has become apparent, and in many the presenting early symptoms and signs suggest a primary cerebral tumour. Great difficulty may be experienced in distinguishing these syndromes from those due to primary intracranial neoplasms. Since neurosurgical investigations are expensive in money and time and not entirely free from risk, we have compared two series of patients with primary and metastatic brain tumours in an endeavour to establish valid criteria for differential diagnosis. Patients 90 patients (63 consecutive patients with proven primary intracranial tumours and 27 with proven metastatic brain tumours) were investigated and treated in the neurological departments either of the Royal Victoria Infirmary or of the