
labelled steroid isolated from the removed tissue was 5aT (Pike et al. 1970) . These observations relate well to those of who found that the concentration of 5aT was on average five times greater in hyperplastic than in normal prostatic tissue in men, and that it was sited mostly in the peri-urethral zone of the gland. Possibly 5aT plays a role in the etiology of benign hyperplasia of the prostate in humans; the observation that some degree of prostatic hyperplasia was also induced when young castrated dogs were treated with 5aT (Gloyna et al. 1970) supports this idea.

In relation to these observations the tissue culture studies of Baulieu and his colleagues (Baulieu & Robel 1970 , Lasnitzki 1970 are particularly relevant. They showed that not only did testosterone and 5aT play some role in the maintenance of the functional integrity of rat prostate cells in culture, but also that other testosterone metabolites, the 5a-androstanediols which are also found in prostatic tissue, may control some aspects of cell metabolism. This suggests that testosterone and its various metabolites may possibly each have a particular function in the prostate, and that a change in the balance or relative concentrations of these steroids could be concerned with the induction of hyperplasia or neoplasia. A possible role of aestrogens in the control of these metabolic patterns requires further investigation.

Experiments conducted in our laboratories with rat, canine and human prostatic tissue in culture indicated that aestrogens affected testosterone metabolism by the tissue. CEstradiol-1 7p and diethylstilbestrol decreased both the uptake of radioactive testosterone by the tissue and the 5aT formed. The amount of radioactive 5aT isolated from nuclear preparations of culture tissue decreased when either oestradiol-17, or diethylstilbcestrol was present in the medium. Moreover, an identical effect was obtained with dihydrodibutylstilbeestrol, an analogue of diethylstilboestrol. This compound, synthesized in our laboratories , has 0-1 % of the cestrogenic activity of ostradiol-17P, and further studies on its biological activity in the rat and dog are currently in progress to assess any possible application to the treatment of prostatic dysfunction in men. One interesting series of experiments in this respect is concerned with the activity of the nuclear enzyme system, DNA polymerase, isolated from human prostatic tissue. When this isolated enzyme system was incubated with the appropriate co-factors, it was shown that 5aT and testosterone were capable of stimulating the activity of certain of the enzyme preparations from human hyperplastic prostatic tissue. Conversely, both diethylstilbeestrol and dihydrodibutylstilbeestrol inhibited the enzyme system isolated from both hyperplastic and malignant prostatic tissue, whereas other alkyl substituted derivatives of stilboestrol, such as dipropylstilboestrol and dibutylstilbeestrol, had little or no effect. It is possible, therefore, that dihydrodibutylstilboestrol exercises a direct action on this nuclear enzyme system in vivo, and further studies are in progress to ascertain the mechanism of this inhibitory effect and any possible application to the treatment of benign hyperplasia and carcinoma of the prostate in men. The low cestrogenicity of this compound could be a crucial factor in any practical considerations, particularly in view of the recent reservations about the place of diethylstilboestrol in the treatment of prostatic cancer (Arduino et The preparation used was 17a-hydroxyprogesterone caproate (Primolut Depot) and objective improvements were described in 3 of the 10 patients studied. Histologically, glandular atrophy was demonstrated in prostatic biopsy specimens obtained two or more months after the start of treatment.

At the time of Geller's report a further, more potent, derivative of hydroxyprogesterone had been synthesized, 17a-hydroxy-19-nor-progesterone caproate (gestronol hexanoate BP; Depostat Schering). The comparative activities of progesterone, hydroxyprogesterone caproate and gestronol hexanoate are set out in Table 1 . From this it will be noted that the latter preparation has some 25 times the potency of the one which Geller used. Both preparations have a depot action which reaches a peak about eight days after administration and falls off by the fourteenth day. This means that weekly administration gives an optimal biological availability. Animal studies with gestronol were carried out, with particular reference to the prostate; Hahn et al. (1968) demonstrated in male rats that both hydroxyprogesterone caproate and gestronol hexanoate, given in doses of 30 g/day over a six-week period, produced atrophy of the prostate and seminal vesicles and caused a slight decrease in testicular weight, but there was no loss of libido and testicular histology showed no interference with spermatogenesis. Schoonees et al. (1969) studied the baboon prostate, as this is very similar to the human both in structure and function. The results obtained were as follows:

(1) A statistically significant reduction in prostatic, seminal vesicular and testicular weight ratios was demonstrated in the treated group.

(2) A statistically significant reduction in zinc uptake by the prostate was found, thus indicating a reduction in prostatic function.

Clinical trials in humans were conducted both here and abroad and the results are shown in Table 2 . There was a high proportion of subjective improvement and a reduction in residual urine was also demonstrated in some cases. The main problem with early trials was that they were of a therapeutic-efficacy type and, in view of the very high placebo effect on symptoms of prostatism which had been noted by other workers, it was felt that a double-blind, cross-over study, in which the estimation of the two objective parameters of residual urine and peak flow rate were essential parts, would be a more valid means ofassessing the preparation. A pilot study showed improvement in peak urine flow rates in 6 out of 7 patients receiving 3 g gestronol hexanoate BP per week. The main purpose of this trial was, however, to confirm that there were no adverse effects on gonadotrophin levels, liver function or adrenal function and no hamatological changes.

A larger scale pilot study was carried out by Aubrey & Khosla (1971) , who noted subjective improvement in 22 out of 24 patients treated. Reduction in residual urine was obtained in 16 patients and a diminution in prostate size, as measured by cystourographic methods, was shown in 8. A study of the effect of gestronol hexanoate BP in a greater number of patients on a multicentre basis was established early in 1970 and the results are described in the following paper (Gingell 1972) .

{'paper_id': '199622277', 'title': 'Pills for the Benign Prostate', 's2_url': 'https://api.semanticscholar.org/CorpusID:199622277', 'source': 'S2ORC'}