Effect of oestrogen or cyproterone acetate treatment on adrenocortical function in prostate carcinoma patients
Th. Schürmeyer, J. Graff1, Th. Senge1 and E. Nieschlag Max-Planck-Gesellschaft,
Klinische Forschungsgruppe für Reproduktionsmedizin an der Universitäts-Frauenklinik, Münster, FRG and Universität Bochum1, Klinik für Urologie am Marienkrankenhaus, Herne, FRG
Abstract. The antiandrogen cyproterone acetate (CA), as well as oestrogens have been reported to influence pituitary-adrenal function in prostate cancer patients, but the clinical relevance of these findings is unknown. We therefore investigated serum cortisol (F), dehydro- epiandrosterone sulphate (DS), testosterone (T) and prolactin (Prl) levels in patients treated with CA or oestradiol undecylate for at least 6 months. Hypothala- mic-pituitary-adrenal function was further assessed by analysis of diurnal hormone variation and by ACTH stimulation and dexamethasone suppression tests. To differentiate between direct CA or oestrogen effects and secondary effects resulting from therapy-induced hypogonadism, we performed similar tests in untreated normogonadal and hypogonadal patients. CA treat- ment effected a significant decrease in serum F (-40%), DS (-73%) and T (-58%) levels and an increase in serum Prl (+118%). Oestrogen treatment resulted in markedly lowered T levels (-89%), slightly elevated serum F (+24%) and significantly increased serum Prl (+192%). Corresponding changes of F, DS and Prl could not be found in the untreated hypogonadal controls, thus indicating a direct drug-related effect. Neither diurnal rhythmicity of serum F nor adrenal response to ACTH stimulation or sensitivity to dexa- methasone suppression significantly changed under CA or oestrogen treatment. We conclude that, although serum F levels may decrease under CA or increase slightly under oestrogen therapy for prostate carci-
noma, these findings do not justify specific treatment, since neither clinical side effects nor an impairment of hypothalamic-pituitary-adrenal feedback occurs.
For decades, hormonal treatment regimens have been used in the management of patients with prostate cancer; a decrease in pain and an im- proved sense of well-being is almost invariably reported by the patients. Since, however, the over-all survival rate under treatment does not change (Lepor et al. 1982), the benefit and pos- sible harm of the treatment have to be weighed very carefully. So far, the possible side effects of hormonal treatment for prostate cancer on endo- crine glands other than the testes have not been investigated in detail, although there are many indications, e. g. of influence on adrenal function.
Cyproterone acetate (CA) treatment in children with precocious puberty clearly results in a sup- pression of their hypothalamic-pituitary-adrenal axis (Klemm et al. 1975; Jeffcoate et al. 1977; Mühlendahl et al. 1976; Girard et al. 1978; Stivel et al. 1982). On the other hand, there is no evidence of a similar effect in women treated for hirsutism (Chapman et al. 1982; Smals et al. 1978; Paulsen 1976) nor are normal men taking this drug for male fertility control affected (Paulsen 1976). The largest group of patients undergoing antiandrogen treatment, men suffering from pro- state cancer, has not been investigated for adrenal function to date.
Oestrogen treatment in prostate cancer patients
has been reported to elevate serum cortisol levels (Krause et al. 1982). Since oestrogen and andro- gen levels are known to influence hepatic cortisol binding globulin (CBG) production (Dunn et al. 1981), special tests are required to determine whether the elevation of serum cortisol represents a physiological adaptation or indicates pathologic adrenal function.
To investigate the influence of CA and oestro- gen treatment on adrenal function, we analysed the diurnal variation of serum cortisol and per- formed a corticotrophin stimulation test as well as a dexamethasone suppression test in patients treated with these steroids. In addition, we meas- ured serum Prl levels, since an interrelationship between serum Prl levels and adrenal androgen production may exist (Vermeulen & Ando 1978).
Materials and Methods
Patients
Thirty patients with prostate cancer and 5 men with benign hypertrophy of the prostate (BPH) gave consent to take part in this study. All diagnoses were based on histomorphological findings and none underwent orchidectomy or any hormonal treatment in addition to what is specifically stated below.
Ten of the prostate cancer patients (70.4 ± 6.2 years old, carcinoma stage T3-4LxMo) had been treated with oestradiol undecylate (Progynon®, 100 mg im per month) for more than 6 months (group E).
Six patients with prostate cancer (69.1+ 4.3 years old, carcinoma stage T3-4LxMo) had been treated with cyproterone acetate (Androcur®, 100 mg po per day) for at least 6 months (group A).
Twenty-two patients had not been previously treated with hormones. On the first day of the investigation 10 patients with carcinoma of the prostate (stage T3-4LxMo) and 3 men with BPH had a mean serum testosterone level higher than 10 nmol/l. These men were considered as normogonadal controls (group N, 656 ± 4.7 years old). Nine of the untreated patients, 7 with prostate cancer (stage T3-4LxMo) and 2 with BPH had mean serum testosterone levels below 10 nmol/l. To differentiate whether the results of the tests performed in groups A and F. represent an unspecific effect of treatment-induced hypogonadism or a specific treat- ment effect, the hypogonadal group (group H, 67.6 ± 5.4 years) underwent the same test protocol as the normogonadal controls and groups treated with oestro- gen and antiandrogens.
Study design
On the first day at 8 a.m., 2 p.m., and 6 p.m. blood samples were obtained for testosterone (T), dehydro-
epiandrosterone sulphate (DS), cortisol (F) and prolac- tin (Prl) measurement to investigate the circadian varia- tion of these hormones. At 10 p. m. all patients received a single iv injection of 1.5 mg dexamethasone (Forte- cortin®). Further blood samples were obtained at 8 and 9 a. m. on day 2. On day 3 at 9 a. m. all pateints received
8 a.m. W/A 12 a.m.
6 p.m.
SERUM TESTOSTERONE (nmol/l)
20
E
A
H
N
15
10
5
p <
1000
0.005
0.05
0.05
0.005
SERUM CORTISOL Inmol/l
800
600
400
200
p <
0.05
0.05
N.S.
0.001
4
SERUM DS (umol i)
3
2
1
p
<
1000
N.S.
N.S.
N.S.
N.S.
SERUM PROLACTIN (U ml)
800
600
400
200
מ
<
N.S.
N.S.
N.S.
N.S.
Diurnal variations in serum testosterone, cortisol, de- hydroepiandrosterone sulphate (DS) and prolactin (mean ± SEM). E: oestrogen-treated prostate carcinoma patients. A: cyproterone acetate-treated prostate car- cinoma patients. H: hypogonadal controls. N: normo- gonadal controls.
| Oestrogen n = 10 | Antiandrogen n = 6 | Hypogonadal n = 9 | Normogonadal n = 13 | |
|---|---|---|---|---|
| Serum cortisol (nmol/I) | ||||
| Before dexamethasone | 509 ± 94 | 147 ± 42 | 469 ± 88 | 323 ± 49 |
| After dexamethasone | 111 ± 22 | 44 ± 9 | 87 ± 13 | 62 ± 11 |
| Decrease (nmol/l) | 398 | 103 | 382 | 261 |
| Per cent | 78% | 70% | 81% | 81% |
an iv injection of 0.25 mg corticotrophin (Synacthen®). Subsequent blood samples were obtained 1 and 2 h later. All serum samples were kept at -20℃ until hormone analysis.
Hormone determinations
Serum T was measured by RIA according to the proce- dure of Nieschlag & Loriaux (1972) without chromato- graphy. Detection limit of this assay was 0.6 nmol/l. Commercial kits were used to measure DS (Amersham), F (Amersham) and Prl (Serono) by radioimmunoassay.
Analysis of data
Results are expressed as mean ± SE. Undetectable se- rum T concentration was assigned the value of the detection limit. Student’s two-tailed t-test was used for all comparisons between groups and paired t-tests were performed for analysis of effects observed in the same subject.
Results
Compared to group N, T levels of group E. were lowered by 89%, group A was 58% lower and group H was reduced by 45%. On the first day, serum T showed a significant evening decrease in all four groups (Fig. 1A).
A diurnal variation of serum cortisol was found in all but the hypogonadal group. All subjects of the control groups had basal F serum concentra- tions in the normal range. Mean serum F during the day was significantly lower (P < 0.001) in patients treated with antiandrogens when com- pared to all three other groups, but the diurnal rhythm was not abolished. The morning F level of group E showed a non-significant trend towards elevation when compared with group N or H (Fig. 1B).
umol/I
6
E
A
H
N
4
2
A
B
A
B
A
B
A
B
Decrease in:
8/10
1/6
8/9
8/13
Subject
1400
E
A
H
1200
SERUM CORTISOL (nmol/l)
1000
800
600
400
200
4
0
1
2
0
1
2
0
1
2 h
SERUM DS (µmol/l)
3
E
A
H
2
1
0
1
2
0
1
2
0
1
2
h
Serum DS levels of the patients treated with CA were significantly decreased. The 73% decrease of DS, if compared with group N, exceeded the decrease of T (58%) and F (40%). No significant difference of serum DS could be observed be- tween group E, H and N (Fig. 1C).
Serum Prl levels were significantly higher (P > 0.001) in both groups receiving hormones, while no difference could be observed between the two untreated groups (Fig. 1D).
Dexamethasone administration caused a drastic drop in serum F of all four groups. Although starting from different cortisol levels, the decrease in per cent was similar in group E, H and N (78-81%) and only slightly lower (70%) in group A (Table 1). After dexamethasone administration serum DS did not change consistently, but most subjects (25 of 35) showed a decrease in DS levels (Fig. 2).
No difference between group E, H and N in
response of serum F to corticotrophin was found (Fig. 3). Peak levels after ACTH administration were significantly lower (P <0.001) in the CA treated group, but since initial levels were much lower, the absolute increase was not different from that of the other groups. DS levels were not significantly altered after ACTH administration.
T response to dexamethasone and ACTH is shown in Fig. 4. Since reports from the literature concerning the influence of adrenal suppression or stimulation on serum T levels are contradictory and averaging of individual changes may be mis- leading, the individual data are shown here. Dexa- methasone decreases serum T almost uniformly in the oestrogen-treated patients, but does not blunt the morning increase of serum T in normogo- nadal controls. Conversely, ACTH decreases T in group N and increases T in group E.
For reasons similar to those mentioned above, Prl responses to dexamethasone are plotted in- dividually (Fig. 5). Both the adrenal stimulation test and suppression with dexamethasone effect a small decrease in serum Prl levels in most subjects in all four groups.
nmol/l
+8
I
+7
E
A
H
N
+6
+5
+4
+3
+2
+1
14
0
-1
-2
-3
+4
E
A
H
N
II
+3
+2
+1
fanta
0
-1
-2
-3
— 4
5
pU/ml
E
A
H
N
+400
+300
+200
+100
0
-100
-200
-300
919
μU/ml
E
A
H
N
+300
+200
+100
0
-100
-200
300
-400
633
Į
II
Discussion
In prostate cancer patients treated with CA we observed significantly lowered serum F levels. The decrease in serum F is apparently due to the CA treatment and not to the decrease in T pro- duction, as was shown by comparison with a hypogonadal control group. Similar observations have been reported in children treated with CA over long periods for precocious puberty (Klemm et al. 1975; Jeffcoate et al. 1977; Stivel et al. 1982; Girard & Baumann 1975; Rager et al. 1978). In adult male and female volunteers, however, serum F levels were reported to be normal after a single dose of CA (Scheuer et al. 1980), as were F levels of hirsute women under a combined treat- ment with CA and ethinyl-oestradiol (Chapman et al. 1982; Smals et al. 1978).
In addition to the decrease in serum F, children with precocious puberty show a loss of the hor- mone’s diurnal rhythm due to the antiandrogen treatment (Heinze et al. 1978). It should, how- ever, be considered that circadian periodicity of plasma corticosteroid levels does not develop be-
fore 3 to 8 years of age even in normal child- ren (Mühlendahl et al. 1977). In hirsute women treated with cyproterone acetate (Chapman et al. 1982) and in volunteers (Mühlendahl et al. 1976) diurnal serum cortisol variations were normal. Our patients showed a diurnal variation of serum despite their decreased levels. This indicates that hypothalamic-pituitary control of adrenal func- tion remains intact in these patients.
Reports in the literature about more specific tests for hypothalamic-pituitary-adrenal function under cyproterone acetate are contradictory. In rats the pituitary-adrenal response towards stress is blunted (Girard et al. 1978). Most responses to ACTH- and insulin-tolerance tests in CA treated children were absent or subnormal (Klemm et al. 1975; Mühlendahl et al. 1976, 1977; Rager et al. 1978; Heinze et al. 1978). In other schedules, however, no alterations in pituitary-adrenal re- sponsiveness (Jeffcoate et al. 1977; Stivel et al. 1982; Girard & Baumann 1975) could be observed. When hirsute women (Chapman et al. 1982; Smals et al. 1978) and male volunteers (Paulsen 1976) under CA treatment were tested, a normal response could be measured, but in adult volunteers the ACTH response to metyrapone seemed to be diminished when the compound was administered along with a single dose of CA (Girard et al. 1978). All our patients treated with the antiandrogen showed a response to ACTH. The serum F levels after ACTH stimulation were lower than in the controls, but since the basal levels were also lower, the increment of F over basal was similar. This indicates an adequate re- sponse of the adrenal to ACTH. Since no clinical signs of adrenal insufficiency were observed and neither ACTH test response nor the diurnal variation of serum F indicates a disturbance in hypothalamic-pituitary-adrenal feedback, there seems to be no need for glucocorticoid substitu- tion in spite of the low serum cortisol levels.
Elevated serum F levels have been reported in prostate cancer patients undergoing oestrogen treatment (Krause et al. 1982) and a similar trend could be observed in the few oestrogen treated patients taking part in this study. However, no sign of hypercortisolism as was described by others for patients with prostatic cancer or benign hypertrophy of the prostate (Drafta et al. 1982; Zumoff et al. 1982) was found. Neither the ana- lysis of diurnal F variation nor of the ACTH stimulation test or - most important - the dexa-
methasone suppression test point to a disturbance in hypothalamic-pituitary-adrenal feedback in the controls or in the oestrogen treated group. Oestrogens are known to stimulate hepatic CBG synthesis and F levels tend to be higher in females than in males (Dunn et al. 1981). Therefore under oestrogen treatment the elevation in serum F represents an increase in CBG bound cortisol. With regard to free F levels, the elevation of total F in the patients indicates a feedback mechanism functioning correctly rather than its disturbance.
Treatment with either CA or oestradiol unde- cylate resulted in increased Prl levels. The Prl- raising effect of oestrogens is well known (Harper et al. 1976; Bartsch et al. 1977), which results in 50% higher Prl levels in females than in males (Guyda & Friesen 1973). In our patients we ob- served that both dexamethasone and adrenal stimulation by ACTH resulted in lowered Prl levels. In contrast, CA-treated patients, who had decreased F serum levels, showed an increase in Prl as was observed by others as well (Isurugi et al. 1980; Rost et al. 1981). It seems that Prl secretion is influenced by gonadal and adrenal steroid levels as well.
DS levels were significantly lower in patients treated with CA. The decrease exceeded the de- crease in T and F. As expected (Nieschlag et al. 1973; Vaitukatitis et al. 1969), no consistent pat- tern in diurnal variation was found for this ste- roid. Long-term stimulation of the adrenal ele- vates DS levels (Yamaji & Ibayashi 1969), but no consistent change can be observed until several hours after ACTH administration. This is pos- sibly due to the small magnitude of change in view of the large circulating DS pool (Nieschlag et al. 1973). In none of the groups could a significant elevation of this steroid be measured 1 or 2 h after ACTH. As was expected (Parker & Odell 1980), most of the patients showed a decrease in serum DS 10 to 11 h after dexamethasone administra- tion.
Serum T concentrations of our patients with oestrogens or CA are in good agreement with results obtained in similar protocols (Varenhorst et al. 1982; Vermeulen et al. 1982). Dexametha- sone is known to decrease serum T levels by approximately 30 to 40% (Nieschlag & Kley 1975; Schaison et al. 1978). This effect is mainly due to a suppression of the nocturnal T rise (Doerr & Pirke 1979) and can only be observed if a rela- tively high dexamethasone dose is administered
over several days (Nieschlag & Kley 1975; Schai- son et al. 1978; Doerr & Pirke 1979). A single, small dose (2 mg po) blocks the nocturnal rises in cortisol, androstenedione and dehydroepiandro- sterone, but not in T (Judd et al. 1973). Accord- ingly in the untreated groups we observed a rise in serum T during the night in most subjects even under dexamethasone (Fig. 4). In contrast, most of the oestrogen-treated patients experienced a small decrease, possibly caused by a block of their only source of androgens, the adrenals.
Conversely, ACTH stimulated serum T in the oestrogen-treated subjects. This is in good agree- ment with similar observations made by Cowley et al. (1976). In most of the untreated patients a decrease occurred, as was described by others (Schaison et al. 1978; Beitins et al. 1973; Cowley et al. 1976). Since up to one third of serum T may derive from adrenal precursors (Chapdelaine et al. 1965), it might be speculated that the decrease in serum T observed after ACTH is due to a lack of substrate e.g. pregnenolone for transformation to T, as was similarly demonstrated in patients with adrenal insufficiency (Nieschlag & Kley 1975). In oestrogen-treated patients, however, who no longer possess any significant testicu- lar steroidogenesis, ACTH effects an increase in serum testosterone by stimulating adrenal andro- gen synthesis. In normogonadal men this en- hanced adrenal androgen synthesis is compen- sated by the decrease in testicular androgen syn- thesis.
This study shows that both CA and oestrogen treatment influence adrenal function in prostate cancer patients. However, since the physiological feedback control of adrenal function is not im- paired and physiological mechanisms achieve a new balance, no side effects occur and hence no special treatment is warranted.
Our study furthermore indicates the complex interrelationship between testes and adrenals which should not be overlooked when treating either set of organs.
Acknowledgments
The technical assistance of Ms D. Lemkuhl and the secretarial help of Ms I. Oberschachtsiek is gratefully acknowledged.
References
Bartsch W. Horst H-J, Becker H & Nehse G (1977): Sex hormone binding globulin binding capacity, testoste- rone, 5a-dihydrotestosterone, oestradiol and prolac- tin in plasma of patients with prostatic carcinoma under various types of hormonal treatment. Acta Endocrinol (Copenh) 85: 650-664.
Beitins I Z, Bayard F, Kowarski A & Migeon C J (1973): The effect of ACTH administration on plasma testo- sterone, dihydrotestosterone and serum LH concen- trations in normal men. Steroids 21: 553-563.
Chapdelaine A, Macdonald P C, Gonzales O, Gurpide E, Wiele R L. & Lieberman S (1965): Studies on the secretion and interaction of the androgens. IV. Quantitative results in a normal man whose gonadal and adrenal function was altered experimentally. J Clin Endocrinol Metab 25: 1569-1579.
Chapman M G, Jeffcoate S I. & Dewhurst C J (1982): Effect of cyproterone acetate-ethinyloestradiol treat- ment on adrenal function in hirsute women. Clin Endocrinol (Oxf) 17: 577-582.
Cowley T H. Brownsey B G, Harper M E, Peeling W B & Griffiths K (1976): The effect of ACTH on plasma testosterone and androstenedione concentrations in patients with prostatic carcinoma. Acta Endocrinol (Copenh) 81: 310-320.
Doerr P & Pirke K M (1979): Dexamethasone-induced suppression of the circadian rhythm of plasma testo- sterone in normal adult males. J Steroid Biochem 10: 81-86.
Drafta D, Proca E, Zamfir V, Schindler A E, Neacsu E & Stroe E. (1982): Plasma steroids in benign prostatic hypertrophy and carcinoma of the prostate. J Steroid Biochem 17:689-693.
Dunn J F, Nisula B C & Rodbard D (1981): Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticoste- roid-binding globulin in human plasma. J Clin Endo- crinol Metab 53: 58-68.
Girard J & Baumann J B (1975): Secondary adrenal insufficiency due to cyproterone acetate. Pediatr Res 9:669.
Girard J, Bauman J B, Buehler U, Zuppinger K, Haas H G, Traub J J & Wyss H I (1978): Cyproterone acetate and ACTH adrenal function. J Clin Endo- crinol Metab 47: 581-586.
Guyda H J & Friesen H G (1973): Serum prolactin levels in humans from birth to adult life. Pediatr Res 7: 534-546.
Harper M E, Peeling W B. Cowley T, Brownsey B G, Phillips M E A, Groom G, Fahmy D R & Griffiths K (1976): Plasma steroid and protein hormone concen- trations in patients with prostatic carcinoma, before and during oestrogen therapy. Acta Endocrinol (Copenh) 81: 409-426.
Heinze F, Teller W M, Fehm H L & Joos A (1978):
The effect of cyproterone acetate on adrenal cortical function in children with precocious puberty. Eur J Pediatr 128:81-88.
Isurugi K, Fukutani I K, Ishida H & Hosoi Y (1980): Endocrine effects of cyproterone acetate in patients with prostatic cancer. J Urol 123: 180-183.
Jeffcoate W J, Edwards C R W, Rees L H & Besser G M (1977): Cyproterone acetate. Lancet 1: 1160-1161.
Judd H L., Parker D C, Rakoff J, Hopper B R & Yen S S C (1973): Elucidation of mechanism(s) of the noctur- nal rise of serum testosterone in men. J Clin Endo- crinol Metab 38: 134-141.
Klemm W. Rager K. Gupta D & Bierich J R (1975): Reduced levels of adrenal steroids in plasma before and after ACTH due to treatment with cyproterone acetate. Acta Endocrinol (Copenh), Suppl 199: 367.
Krause W, Weidner E & Rothauge C F (1982): Endo- krine Veränderungen während der Hormonbehand- lung des metastasierenden Prostatakarcinoms. Urol Int 37: 400-409.
Lepor H, Ross A & Walsh P C (1982): The influence of hormonal therapy on survival of men with advanced prostatic cancer. J Urol 128: 335-340.
Mühlendahl K E, Korth-Schuetz S, Mueller-Hess R, Helge H & Weber B (1976): Cyproterone acetate and adrenocortical function. Lancet 2: 1140.
Mühlendahl K E, Weber B, Mueller-Hess R, Korth- Schuetz S, Schwartz D & Helge H (1977): Nebennie- renrindeninsuffizienz bei Cyproteronacetat-Behand- lung. Dtsch Med Wochenschr 102: 1074.
Nieschlag F. & Loriaux D L (1972): Radioimmunoassay for plasma testosterone. J Clin Chem Clin Biochem 10:164-168.
Nieschlag E, Loriaux D I., Ruder H J, Zucker I R, Kirschner M A & Lipsett M B (1973): The secretion of dehydroepiandrosterone and dehydroepiandro- sterone sulphate in man. J Endocrinol 57: 123-134.
Nieschlag E & Kley H K (1975): Possibility of adrenal- testicular interaction as indicated by plasma andro- gens in response to hCG in men with normal, sup- pressed and impaired adrenal function. Horm Metab Res 7: 326-330.
Parker I. H & Odell W D (1980): Control of adrenal androgen secretion. Endocr Rev 1: 392-410.
Paulsen C A (1976): Cyproterone acetate. Lancet 1: 1246.
Rager K, Klemm W & Gupta D (1978): Effect of cyproterone acetate on the adrenal cortex. J Steroid Biochem 9: 858.
Rost A, Schmidt-Gollwitzer M, Hantelmann W & Brosig W (198I): Cyproterone acetate, testosterone, LH, FSH and prolactin levels in plasma after intramuscu- lar application of cyproterone acetate in patients with prostatic cancer. Prostate 2: 315-322.
Schaison G, Durant F & Mowszowicz I (1978): Effect of glucocorticoids on plasma testosterone in men. Acta Endocrinol (Copenh) 89: 126-131.
Scheuer A, Hagen Ch, Loeck M & Müller R (1980): Der Einfluß von Cyproteroneacetate auf die Nebennieren und Gonadenfunktion. Med Welt 31: 1557- 1559.
Smals A G H, Kloppenborg P W C, Goverde H J M & Benraad Th J (1978): The effect of cyproterone acetate on the pituitary adrenal axis in hirsute wo- men. Acta Endocrinol (Copenh) 87: 352-358.
Stivel M S, Kauli R, Kaufman H & Laron Z (1982): Adrenocortical function in children with precocious sexual development during treatment with cyproter- one acetate. Clin Endocrinol (Oxf) 16: 163-169.
Vaitukaitis L, Dale S L & Melby J C (1969): Role of ACTH in the secretion of free dehydroepiandroster- one and its sulphate ester in man. J Clin Endocrinol Metab 29: 273-278.
Varenhorst E, Wallentin L & Carlström K (1982): The effect of orchidectomy, estrone and cyproterone acetate on plasma testosterone, LH and FSH concen- trations in patients with carcinoma of the prostate. Scand J Urol Nephrol 16: 31-36.
Vermeulen A & Ando S (1978): Prolactin and adrenal androgen secretion. Clin Endocrinol (Oxf) 8: 295- 303.
Vermeulen A, Schelfhout W & Deby W (1982): Plasma androgen levels after subcapsular orchiectomy or estrogen treatment for prostatic carcinoma. Prostate 3: 115-121.
Yamaji T & Ibayashi H (1969): Plasma dehydroepi- androsterone sulfate in normal and pathological con- ditions. J Clin Endocrinol Metab 29: 273-278.
Zumoff B, Levin J, Strain G W, Rosenfeld R S, O’Connor J, Freed S Z, Kream J, Whitemore W S, Fukushima D K & Hellman L (1982): Abnormal levels of plasma hormones in men with prostate cancer: evidence toward a ‘two disease’ theory. Prostata 3: 579-588.
Received on May 28th, 1985.