THERAPEUTIC EFFECTIVENESS OF ORAL TESTOSTERONE

1473

THERAPEUTIC EFFECTIVENESS OF ORAL

coded together with placebo tablets of identical size and shape. The code remained unbroken until the end of the tests. Serum-testosterone was measured by a modified specific radioligand assay.6 Ether extracts from serum were completely separated into testosterone, dihydrotestosterone, and androstanediols by chromatography on’Celite’ (kieselguhr) columns. After chromatography the relevant eluates were subjected to radioligand assay using an antiserum showing no cross-reactions with any testosterone metabolites other than those mentioned above. Thus, 17ketosteroids, presumably present in large amounts in some of the samples from the present study, did not interfere with the assay. Addition of labelled testosterone at the start of the assay indicated the recovery-rate. The day-today variation was ± 12 %. Only patients without testicular function were included in this study. The four patients in whom serum-testosterone levels were measured after testosterone tablets were ingested consisted of two men with severe cunuchoidism aged 24 and 37 years, a man of 21 who had lost both testicles in a machine accident 4 months before the study, and a female transvestite of 43 who wanted to change sex. The five male patients participating in the double-blind tablet trials all had severe eunuchoidism with complete testicular atrophy. They were aged from 23 to 44 years. These patients had all previously been In two on various forms of testosterone medication. patients this therapy was stopped 1-2 months before the trial, and in the other three it was continued until the beginning of the trial. This difference apparently had no effect upon the outcome of the double-blind test. None of the patients studied was obese.

were

TESTOSTERONE SVEND G.

EDGAR P. BENNETT V. GAUNØ JENSEN Hormone Department, Statens Seruminstitut,

JOHNSEN

Male

Hypogonadism Study Section,

Medical Outpatients’ Department, and Pharmacy, Rigshospitalet, Copenhagen, Denmark 200 mg. of free testosterone (2-5 µ particles compressed into conventional tablets) produced normal male serum-testosterone levels for 5-7 hours in four subjects without testicular

Summary

function. Serum-testosterone levels were still at least five times higher than initial values 6-8 hours after tablet ingestion. The clinical effectiveness of oral free testosterone 100 mg. 4 times a day was established in a double-blind trial in five eunuchs. It is concluded that artificial testosterone derivatives have no advantages, either in effect or cost, over oral androgen therapy. Adequate oral doses of natural free testosterone are fully effective in replacing hormonal testicular function. Introduction

EARLY workers stated that free testosterone was not effective when given by mouth.l2 The lack of effect was attributed to inactivation in the liver rather than to intestinal destruction or failure to be absorbed.3 Thus, the therapeutic use of oral free testosterone was abandoned. Free testosterone is clinically effective Results when it is slowly absorbed by the sublingual route2 Serum-testosterone after Testosterone Tablets and from suppositories in the rectum.4’However, Serum-testosterone levels before and after the neither of these methods of administration became of four 50 mg. testosterone tablets are administration widely used. Instead, artificial derivatives of testoin the shown accompanying figure. As expected, all sterone, capable of resisting inactivation in the liver, without testicular function had very low patients were developed for oral androgen therapy. 17a-methyllevels in the two blood-samples drawn testosterone testosterone has been used for more than 20 years. However, this compound affects liver function and may cause jaundice,s and side-effects of this sort are likely to occur.with other 17a-substituted androgens, such as fluoxymesterone. Mesterolone is a newer artificial testosterone derivative for oral use. However, the therapeutic effects of all artificial hormones are generally deduced from animal experiments, and such effects vary widely from one species to another. Precise data on the clinical effects of androgens are difficult to obtain in man. We have found that natural testosterone, which is now fairly cheap, is fully effective when given orally in sufficiently high doses. -

Material, Methods, and Patients Tablets of free testosterone were used in double-blind tests in eunuchs. Testosterone particle size was 3-5 A, with few particles greater than 12 JL (maximum 15 u). In the tablets used in the serum-testosterone studies the particle size of testosterone was 2-5 11. However, in these tablets there was a limited number of larger particles (size about 50 ju.). These large particles were less than 1% in number and accounted for about 10% of the surface area of testosterone. Testosterone tablets (25, 50, and 100 mg.) were made in the conventional way with lactose and potato starch. For the double-blind tests the tablets

Serum-testosterone levels before and after oral ingestion of 200 mg. free testosterone in 4 patients without testicular function.

Two eunuchs (1, 2), one male castrate (3), and one female transvestite (4) were studied. After two initial morning blood-samples testosterone in tablets was given at 8.30 A.M. followed by bread and tea (arrow). Normal lunch given at noon. Horizontal dotted lines indicate range of normal adult male serum-testosterone levels found in our laboratory (275-800 ng. per 100 ml.).

-

1474 in the

morning. 200

mg. of oral free testosterone

was

at 8.30 A.M. followed by bread and tea, and blood was drawn at 9 A.M. and thereafter every hour for 6 hours. In one patient further samples were drawn 8and 232hours after the tablets were taken. -L 2- 11 hours after the tablets were taken, serum-testosterone levels rose at least 5-fold and came well within the range for normal men. Normal levels were maintained for at least 5 hours with only a slow decline. Even after 6 hours, and in the one patient after 8t hours, serum-testosterone was more than 4 times higher than before the tablets were administered and was still within the normal range. In the patient examined next morning, there was no more testosterone in the blood than before the tablets were taken.

given

Testosterone in Eunuchs In a pilot experiment four eunuchs were given coded tablets containing either 25 mg. micronised testosterone or placebo. Four tablets a day were given for 14 days, after which the patient changed to the next batch of coded tablets. After each batch of tablets the patient was asked about sexual desire, erections, ejaculations, and general wellbeing. A reduction in these indices or disappointment on the part of the patient was recorded as a negative response. Increases and/or satisfaction on the part of the patient was recorded as a positive effect. When the tablet code was broken, it was found that the testosterone tablet had not been effective in any of the patients in replacing hormonal testicular function. We concluded that the dose of testosterone given was too small. A second double-blind trial of testosterone tablets was set up. This time the coded tablets contained One 100 mg. micronised testosterone or placebo. tablet was given 4 times a day (at breakfast, lunch, dinner, and bedtime) for 21 days. After each treatment period the patient was questioned as in the first trial and then continued with the next batch of coded tablets. Five eunuchs took tablets for six 21-day periods. If possible, responses were converted to positive or negative answers. In two of the thirty treatment periods this was impossible. After the table of responses was completed the tablet code was broken. Results are shown in the accompanying table. The responses of one eunuch (no. 1) did not distinguish correctly between testosterone tablets and placebo, whereas the answers in the four other eunuchs accorded remarkably well with expected effect of the substance administered. If the first patient is included, in 15 periods with testosterone tablets, 12 were regis-

Double-blind Trial

of Oral

RESULTS OF DOUBLE-BLIND TRIAL OF 100 MG. TESTOSTERONE TABLETS IN 5 MEN WITH SEVERE EUNUCHOIDISM

*

4 tablets per

+ Effect

on

day for 21 days.

sexual ability.

0 No effect on sexual ability. ? Unclassifiable answer.

by the patients as being effective, and 3 as ineffective. 2 placebo periods were unclassifiable and were excluded. Of the remaining 13 placebo periods, 11 were characterised by the patients as being without effect and 2 as being with effect. If these 28 conclusive periods are regarded as 28 independent observations, the effectiveness of the testosterone tablets in the double-blind test is established statistically (P= 0-0009) (Fisher’s exact test). tered

Discussion Our results demonstrate that the effectiveness of micronised free testosterone by mouth depends on dosage. Our clinical double-blind trials in eunuchs showed that 100 mg. testosterone per day was ineffective, whereas 400 mg. per day was fully effective. These results accord with our finding that 200 mg. free testosterone given once orally can maintain a normal male serum-testosterone level for many hours in patients without testicular function. The figure indicates that the half-life of testosterone in serum after ingestion of tablets is about 5-7 hours. This is surprising, since the turnover of testosterone in blood is very rapid.7,8 The reason why high testosterone levels are maintained in the blood for a considerable time after ingestion of testosterone tablets seems to be that testosterone is absorbed very slowly from the The fact that the tablets used to study intestine. serum-testosterone contained a few large particles of testosterone can hardly explain the long effect, since these large particles did not constitute more than about 10% of the surface area of testosterone. The extended effect is an advantage during therapy, and we intend to change our standard treatment with oral testosterone to tablets only twice a day. We recommend an oral testosterone dose in total testicular failure of 400 mg. per day (2 X 200 mg.). This dose in mg. substance is 3-4 times higher than that recommended for methyltestosterone or mesterolone. Free testosterone is reasonably cheap and 100200 mg. testosterone tablets made conventionally by hospital pharmacies will cost the same as commercial tablets containing patented artificial testosterone derivatives. An oral dose of 400 mg. testosterone per day is no less than 20-40 times greater than the endogenous testosterone secretion in normal men, and could be regarded as a heavy load on liver metabolism. However, testosterone follows a metabolic pathway in the liver (reduction and coupling to glucuronic acid) which is common to various substances, including drugs and normal metabolic breakdown products. The capacity of this pathway is presumably very large. We have used oral free testosterone as a standard androgen treatment for 4 years in a considerable number of hypogonadal men, with good results and without producing any side-effects. 100 mg. testosterone undecanoate taken orally in oil increased serum-testosterone in normal men by about 40%. Because of unknown interference with endogenous testosterone secretion, it is difficult to assess the effect of testosterone administered to normal men. However, the effect of this new compound could hardly be greater than that produced by free testosterone in

1475

there is no rationale for using ester of testosterone instead of artificial patented the free hormone for oral therapy.

eunuchs

we

studied, and

a

Requests for reprints should be addressed to S. G. J., Hormone Department, Statens Seruminstitut, DK-2300 Copenhagen S, Denmark. REFERENCES 1. 2. 3. 4. 5. 6.

Foss, G. L. Lancet, 1939, i, 502. Escamilla, R. F., Gordan, G. S. J. clin. Endocr. Metab. 1950, 10, 248. Dorfman, R. I., Shipley, R. A. Androgens: Biochemistry, Physiology and Clinical Significance. New York, 1956. Hamburger, C. Acta endocr., Copenh. 1958, 28, 529. Foss, G. L., Simpson, S. L. Br. med. J. 1959, i, 259. Coyotupa, J., Parlow, A. F., Abraham, G. E. Analyt. Lett. 1972, 5, 329.

Bardin, C. W., Lipsett, M. B.J. clin. Invest. 1967, 46, 891. Southren, A. L., Gordon, G. G., Tochimoto, S., Pinzon, G., Lane, D. R., Stypulkowski, W.J. clin. Endocr. Metab. 1967, 27, 686. 9. Hirschhäuser, C., Hopkinson, C. R. N. I.R.C.S. (Clin. Pharm. Endocr. Physiol. Reprod.) 1974, 2, 1451.

7. 8.

MORTALITY FROM MALIGNANT DISEASE IN PATIENTS WITH ASTHMA MICHAEL ALDERSON Medical Information Unit, Wessex Regional Health

Authority, Romsey Road, Winchester, Hampshire Case-control studies suggest that a lower proportion of people with malignant disease give histories of allergic disorders than patients with other diseases. Seven hundred and sixty-five men and one thousand one hundred and twenty-seven women with asthma were followed up As expected, mortality from over a 20-year period. disease was higher than in the general respiratory population. Deaths from all cancers excluding lung cancer were significantly reduced in both men and women with asthma; deaths from lung cancer among men were reduced but not significantly. These results are compatible with a mechanism which protects against death from cancer in people with asthma.

Summary

Introduction 1

FISHERMAN

that topic disease was in significantly patients with malignant disease compared with age-matched controls. Four other case-control studies 2-5 found that the proportion of patients with malignant disease reporting allergic disorders was significantly reduced; one of these studies was restricted to females,2 whilst another3 reported a significant reduction among female patients but not among males. Other comparable investigations less

reported

common

have produced equivocal

I ,

or

negative findings. Logan

and Saker6 questioned a hundred and four patients with carcinoma of the cervix and a smaller sample with miscellaneous malignant conditions together with ninety-seven control patients (who had not been matched for age and sex); 27% of each of the groups with malignant disease and only 11 % of the control group reported an allergy. Two groups of workers 7,8 questioned patients before their diagnoses had been confirmed; subsequent analysis revealed no significant difference in reporting symptoms of allergy in those

found to have cancer compared with the other patients. Another study9 on patients with Hodgkin’s disease did not collect any data from controls. Though the weight of this evidence seems to suggest some diminution in the risk of malignant disease developing in patients with allergic disorders, the findings are variable ; and how much of this variation is due to (1) chance, (2) the method of data collection, (3) the categories of patients used, or (4) the biases inherent in case-control studies cannot immediately be determined. Fedullo 10 criticised the use of the case-control approach; we report on a large sample of patients known to have asthma who have been followed over several years and examine the death-rates from malignant disease. Method From the late 1930s to the early 1950s a special asthma clinic was held at the Manchester Royal Infirmary; the records for the clinic were filed separately from other patients’ histories and were subsequently transferred to microfilm. The microfilm records have been examined, and attention paid to the history, clinical findings, results of investigation, and response to treatment. Patients under the age of 25 were excluded, since their deathrate from malignant disease within 20 years would be too low to justify the cost of follow-up. Patients over 60 have been excluded because of overlap between asthma, other chronic respiratory disease, hypertension, and cardiac problems. Patients were included if they had a history of wheezing dyspnrea with intervening periods of complete symptomatic remission and a normal chest X-ray. Most patients had positive responses on skin testing to a range of antigens and eosinophilia; they had been recommended to have de-sensitisation or other conventional treatment for asthma. Patients with chronic bronchitis, tuberculosis, obvious heart-disease, hypertension, or sinus disease were excluded; one or two patients gave a history typical of byssinosis and these patients were also excluded. A record card was sent to the National Health Service Central Register for each patient in the study. This record card contained the surname, forename (where provided), marital status for women, the (full) postal address, and the age of the patients on the date on which they attended the clinic. These identification particulars are somewhat limited, particularly as no full date of birth was available and for some patients initials were available rather than forenames. Whilst tracing these individuals on the N.H.S.C.R. the full date of birth was obtained; for those who had died, a copy of the entry of the cause of death was obtained. Using the patient’s date of birth, the date of first attendance at the clinic, and the last known date alive or the date of death, the number of years of life were calculated by sex, 5-year calendar periods, and 5-year age-groups. Applying the age and calendar period death-rates for England and Wales, it was possible to calculate the expected numbers of deaths from all causes, all cancer, lung The expected cancer, leukaemia, and Hodgkin’s disease. number of deaths so derived was then corrected for area mortality using data published by the Registrar General 11 for the North-West region in 1936-55, while for 1956-70 the material has been corrected for the known mortality in the Manchester Regional Hospital Board area. Each cause of death obtained from the general register office was classified according to the rules prevailing at the time of death, and the deaths were then grouped by cause. The basic hypothesis being tested was that the general mortality from all causes would be considerably