CYPROTERONE ACETATE IN TREATMENT OF POST-ORCHIDECTOMY HOT FLUSHES

1336

CYPROTERONE ACETATE IN TREATMENT OF POST-ORCHIDECTOMY HOT FLUSHES Double-blind Cross-over Trial A. C. EATON

N. MCGUIRE

Department of Urology, Norfolk and Norwich Hospital, 12

Summary

patients

Discussion

with troublesome hot flushes

orchidectomy (as a primary treatment prostatic carcinoma) were treated with cyproterone

in a double-blind cross-over trial. The hot flushes was significantly reduced during the three weeks that cyproterone acetate (100 mg three times a day) was given. 5 patients complained of lassitude while on cyproterone acetate, but in none was it necessary to discontinue treatment. acetate or

placebo

frequency of

Introduction HOT flushes are not common after total orchidectomy for carcinoma of the prostate, but when they do occur they are often very troublesome and difficult to treat. In menopausal women high gonadotropin concentrations are believed to be responsible for hot flushes and a recent repon1 has suggested that the same mechanism operates in men. We have assessed the effect of cyproterone acetate, an anti-androgen that also inhibits release, in the treatment of postorchidectomy hot flushes.

gonadotropin

Patients and Methods

post-orchidectomy hot flushes (mean age 67.4 years, range 63-5-72-5) entered the trial. Each patient received cyproterone acetate (100 mg three times daily) for three weeks and placebo for three weeks. Patients recorded on diary charts the frequency of hot flushes each day during each three-week period. A one-week washout period was allowed between each limb of the trial. Allocation to treatment was by computer-generated random 12

patients

with

numbers. Patients were reviewed in clinic at the end of each phase of and were asked to report any side-effects of treatment.

treatment

Results For the first three weeks of the study 8 patients received cyproterone acetate and 4 patients received placebo. We calculated the mean daily number of hot flushes for each

patient during each, treatment period (see accompanying table). We used a paired t test to compare mean values for each treatment. There was a statistically significant reduction (p<0 001) in the incidence of hot flushes whilst patients were on

cyproterone

acetate treatment.

5 of the 12 patients complained of lassitude while on cyproterone acetate, but it was not necessary to discontinue treatment. In 1 patient this side-effect was severe. In this MEAN DAILY NUMBER OF FLUSHES OVER

21

DAY PERIOD

treatment was

Norwich

after

for

to such a degree that when after continued completion of the study, the dosage had to be reduced to 100 mg daily. This dosage completely suppressed symptoms and was without sideeffects.

patient asthenia developed

(± SEM)

Hot flushes are the most common menopausal symptoms in women; they occur in up to 70% of subjects. 2,3 Hot flushes have been reported in a few men with acute testicular insufficiency4 and a recent report of post-orchidectomy hot flushes suggests a similar aetiology in both sexes. The hot flush is characterised by a sudden and transient

sensation of increased body warmth (especially facial) associated with profuse sweating. Attacks last only a few minutes and may be precipitated by minor stress or change in environmental temperature. The frequency is variable but several patients in this series were experiencing up to five attacks per hour. The menopausal flush is essentially a vascular phenomenon and plethysmographic studies have demonstrated an appreciable rise in blood flow in the hand at the onset of symptoms.5 This increased flow is sustained over 3-4 min, returning to normal over 6-7 min. During this phase blood pressure remains stable although the pulse rate rises. The genesis of the hot flush remains obscure. A sudden reduction in the level of sex steroids clearly precipitates the vasomotor dysfunction. Increased levels of gonadotropins have been implicated in the aetiology,6although there is no correlation between the severity and frequency of hot flushes and gonadotropin concentrations. The virtual absence of hot flushes in men and the high frequency in women is believed to reflect the gradual reduction in male gonadal function with age as compared with the abrupt change in female hormones at the menopause.7 The advanced age and hence reduced hormone concentrations of men undergoing orchidectomy for carcinoma of the prostate is thought to explain the low frequency of hot flushes after this operation. Furthermore many patients undergoing orchidectomy for prostatic carcinoma have already been on stilboestrol therapy for months or even years. This treatment produces gradual testicular atrophy, and additionally stilboestrol is a very potent inhibitor of gonadotropin release. With long-term treatment this suppression may become permanent. Patients included in this study had all undergone orchidectomy as a primary treatment for prostatic cancer. Hot flushes had developed from one to six weeks after surgery and in 4 patients had persisted for six months. Treatment of hot flushes after orchidectomy for prostatic carcinoma is difficult. Androgens, whilst they are totally effective in relieving symptoms,4 are clearly contraindicated. Stilboestrol also relieves symptoms8 but its use is usually contraindicated for the same reasons that orchidectomy was chosen as the primary treatment. Total orchidectomy abruptly disturbs the hormone balance in much the same way as does the menopause in women. Other studies 1,4 have demonstrated an expectedly high rise in gonadotropin concentrations in patients after orchidectomy. Cyproterone acetate was effective in suppressing hot flushes. The dosage required and the duration of treatment must be further investigated. Cyproterone acetate acts as an anti-androgen by blocking androgen receptors. In addition it has progestagenic activity which exerts a negative feedback effect on the hypothalamic receptors and diminishes

1337

release. We believe that reduction of concentrations is responsible for the improvement observed in our patients. We are currently studying the exact mechanism of action.

gonadotropin gonadotropin

We thank Mr M. H. Ashken and Mr N. A. Green, consultant urological surgeons to the Norfolk and Norwich Hospital, for permission to study the patients included in this trial. REFERENCES 1 2. 3

Ginsburg J, O’Reilly B. Climacteric flushing in a man. Br Med J 1983; 287: 262. Thompson B, Hart SA, Durno D. Menopausal age and symptomatology in general practice. J Biosoc Sci 1973; 5: 71-82. Soc Med 1974; 28: McKinlay SM, Jeffreys M. The menopausal syndrome. Br Prev J 108-15.

4. Feldman

JM, Postlethwaite RW, Glenn JF. Hot flushes and sweats in men with insufficiency. Arch Intern Med 1976; 136: 606-08. 5. Ginsburg J, Swinhoe J, O’Reilly B. Cardiovascular responses during the menopausal hot flush Br J Obstet Gynaecol 1981; 88: 925-30. 6. Casper RF, Yen SSC. Menopausal flushes; Effect of pituitary gonadotrophin desensitisation by a potent luteinising hormone releasing factor agonist. J Clin Endocrinol Metab 1981; 53: 1056-58. 7. Stearns EL, McDonnel JA, Kaufmann BJ, et al. Declining testicular function with age: Hormonal and clinical correlates. Am J Med 1974, 57: 761-66. 8. Steinfeld AD, Reinhardt C. Male climacteric after orchiectomy in patients with prostatic cancer. Urology 1980; 16: 620-22. testicular

TOPICAL CHOLESTEROL TREATMENT OF RECESSIVE X-LINKED ICHTHYOSIS GERT LYKKESFELDT

HENRIK HØYER

Department of Dermatology, and Department of Obstetrics and Gynaecology, Rigshospital, University of Copenhagen, Denmark open prospective half-side trial, containing 10% cholesterol or 10% urea were applied to lesions in 20 steroidsulphatase-deficient male patients with recessive X-linked ichthyosis. In 18 there was a good response to the cholesterol cream. In 13 patients the response to cholesterol was better

Summary

In

an

creams

than that to urea. None showed a better response to urea than to cholesterol. A reduction in the cholesterol content of the stratum corneum may be responsible for abnormal cornification in recessive X-linked ichthyosis. Introduction IN recessive X-linked

ichthyosis (RXLI), the second most form of ichthyosis, prolonged retention of the stratum corneum leads to the scaly appearance of the skin.! The basic abnormality in RXLI is now considered to be a deficiency of the enzyme steroid sulphatase (STS) in the skin and other tissues.2 STS deficiency results in an inability to remove the sulphate moiety from 3-hydroxysteroid sulphates such as dehydroepiandrosterone sulphate (DHEAS) and cholesterol sulphatebut the mechanism by which STS-deficiency causes ichthyosis is not completely clear. Cholesterol sulphate accumulates in the stratum corneum of RXLI patients, and there is a concomitant decrease in free sterols.4 Moreover, drugs that interfere with cholesterol synthesis may produce an ichthyosis-like dermatosis.5 Until now, however, the improved understanding of the biochemical basis of RXLI has had no impact on the treatment of the skin disorder, which has been purely symptomatic. Application, once or twice daily, of urea-containing creams is considered to be an appropriate have been found as a treatment,5,6 but no long-term benefits result of any topical or other therapy.33 We have attempted to determine whether topical cholesterol is better than urea in the local treatment of RXLI. common

Patients and Methods 20 male patients with typical RXLI, 13 children aged 1-13 years and 7 adults aged 17-39 years, were assigned to the study. In all, the diagnosis of RXLI was confirmed by the virtual absence of STS activity in cultured skin fibroblasts and leucocytes when 3H-dehydroepiandrosterone sulphate was used as substrate

Damkjaer Nielsen M, Lykkesfeldt AE, patients the scaly lesions of the extremities were completely symmetrical on entering the study, and their intensity and extension to anterior and posterior aspects of upper arms, forearms, thighs, and lower legs was recorded on a scale from (Lykkesfeldt

unpublished).

G,

In all

0 to 3. The clinical effects of 10% cholesterol and 10% urea, both in an inert cream base, were compared in an open prospective half-side trial. Blinding was impossible because of an obvious difference in consistency and appearance of the two creams. Patients were instructed to apply the cholesterol-containing cream twice daily to the skin of the arm and leg of one side, and the urea-containing cream to the other side. Patients were examined every 2 weeks. In an individual patient, one treatment was judged to be superior to the other treatment if a greater reduction of the original scores was obtained in all four areas treated with this cream than in the symmetrical areas treated with the other cream. If no difference could be established after 6 weeks, the trial was terminated.

Results Treatment with cholesterol cream produced significantly better results than treatment with urea cream (X2 corrected for

continuity= 11 ’08, p< 0-001) (see accompanying table). In the 13 patients who responded more favourably to cholesterol than to urea, lesions were completely cleared in 8 (7 children and 1 adult), while in 5 (1child and 4 adults) they were significantly improved. The difference was demonstrated after an average treatment period of 3 weeks (2-4 weeks) in the children, and 5 weeks (4-6 weeks) in the adults, probably because the turnover rate in the epidermis is slower in adults. In the 7 patients in whom no difference could be established between the two sides at the end of 6 weeks, the lesions on both sides were almost cleared in 2 (children), uniformly improved in 3 (2 children and 1 adult), whereas there was no clinical improvement in 2 patients (1 child and 1 adult). In total, 18 out of 20 patients responded well to the cholesterol treatment. No untoward effects were noted with either treatment, and the cholesterol treatment was well accepted by all patients. RESULTS OF CLINICAL HALF-SIDE TRIAL OF A 10% CHOLESTEROL CREAM VERSUS A 10% UREA CREAM IN PATIENTS WITH RECESSIVE X-LINKED ICHTHYOSIS AND STEROID SULPHATASE DEFICIENCY

Discussion

Topical application of cholesterol had a beneficial effect on patients, and gave results which were clearly superior to those produced by treatment with urea. The possibility that cholesterol sulphate and cholesterol may be involved in a hypothetical adhesive which holds the stratum corneum cells together has been discussed.8 A surplus of cholesterol sulphate would produce too much cohesion of the stratum corneum,’ leading to a scaly desquamation, while free cholesterol would have the opposite effect. Ichthyosis developed in hairless mice fed an agent blocking the synthesis of cholesterol in the skin.9 This the skin of RXLI