The choice of estrogen preparations in the treatment of prostatic cancer A. MORALES, MD,
FRCS[c],
FACS; B.
PUJARI,* MD, FRCS,
DABU
Androgen suppression is established for the treatment of metastatic carcinoma estrogen therapy with diethylstilbestrol of the prostate. The present trend, (DES), chlorotrianisene or ethinyl however, is to delay the onset of ther¬ estradiol. During a mean follow-up apy until the patient has evidence of period of 26 months the incidence of urinary obstruction or until the meta¬ stases cause symptoms.1'2 The reason complications thromboembolic is twofold: estrogen therapy does not episodes, fluid retention and gynecomastia was recorded. Although necessarily increase survival3 and it has the incidence of cardiovascular been associated with increased morbid¬ complications was significantly higher ity and mortality, mostly from cardio¬ in the DES group, the differences in vascular complications.4 Recent studies on estrogen therapy mortality between the groups were not significant. The differences in incidence for prostatic cancer are based to a of fluid retention and gynecomastia large extent on the use of diethylstil¬ also lacked significance. All three bestrol (DES).5'6 Other natural and syn¬ thetic estrogenic compounds are avail¬ compounds produced adrenal cortical able and widely used; however, it has hyperplasia as indicated by the increased serum cortisol values. not been known whether their side ef¬ fects are comparable to those of DES. We therefore determined the inci¬ dence in 154 patients of side effects Resume: Le choix des estrogenes dans le traitement du cancer prostatique from three estrogenic preparations commonly used to treat prostatic can¬ Un total de 154 malades souffrant cer; we did not try to assess the oncode carcinome prostatique ont recu lytic merits of the drugs. Summary: A total of 154 patients with carcinoma of the prostate received
.
.
une
estrogenotherapie
avec
du diethylstilbestrol (DES), du chlorotrianisene ou de I'ethinyl estradiol. On a suivi ces malades pendant une periode moyenne de 36 mois et on a enregistre la frequence des complications episodes thromboemboliques, retention hydrique et gynecomastie. Malgre une incidence de complications cardiovasculaires significativement plus elevee dans le groupe traite par le DES, les differences de mortalite entre les divers groupes n'etaient pas significative. Les differences dans l'incidence de la retention hydrique et de la gynecomastie n'etaient pas significative davantage. Les trois medicaments ont entrame une hyperplasie du cortex de la .
glande surrenale, comme I'indiquait I'augmentation des concentrations du cortisol serique.
Methods
The 154 patients with prostatic can¬ divided into three treatment groups: the first group consisted of 54 patients (mean age, 73.4 years; aver¬ age duration of treatment, 37 months) who received 1 mg/d of DES; the second group consisted of 60 patients (mean age, 70.5 years; average dura¬ tion of treatment, 44 months) who re¬ ceived 12 mg/d of chlorotrianisene; and the third group consisted of 40 patients (mean age, 71.6 years; average duration of treatment, 30 months) who received 0.05 mg/d of ethinyl estra¬ diol. cer were
Table I.Incidence of in 154
patients
complications from
The development of side effects, such as thromboembolic episodes, fluid retention (manifested by peripheral edema) and gynecomastia, after institu¬ tion of estrogen therapy was recorded for each patient. In addition, serum cortisol concentrations were measured in 20 patients from each of the three groups who were treated for over 12 months; blood samples were taken at 8 am and 8 pm and the laboratory pro¬ cedure was that described by Murphy.7 Results
The incidence of complications in each treatment group is shown in Table I. The incidence of cardiovascular
(thromboembolic) complications was significantly higher in the DES group (P < 0.001; Mann-Whitney test), but the mortality due to cardiovascular causes differed little between the three groups; analysis of the three distribu¬ tions showed no significant differences. There were no significant differences between the three groups in incidence of peripheral edema or gynecomastia.
The serum concentrations of cortisol in a control and the DES group have been reported previously8 and are comr pared in Fig. 1 with the values in the chlorotrianisene group. In both groups of patients the values were increased throughout the day. Although this alteration was less in the chlorotrianisene group the difference was not signifi¬ cant.
Discussion The results of the Veterans Admin¬ study on the role of androgen suppression therapy in the treatment of
istration
prostatic cancer9 initiated a controversy estrogen therapy for prostatic cancer Incidence of complications (%)
Cardiovascular
Estrogen department of urology, Queen's University, Kingston This work was supported by The Ontario Cancer Foundation, grant no. 292, and the Wm. S. Merrell Company. ?Present address: 1400 Bland St., Bluefield, WV 24701, USA Reprint requests to: Dr. A. Morales, Etherington Hall, Queen's University, Kingston, From the
ON K7L 3N6
preparation Diethylstilbestrol (n 54) =
Chlorotrianisene
Morbidity 22.2
Mortality 9.3
Fluid retention 7.4
Gynecomastia Total 14.8
44.0*
26.6 5.0 8.3 6.6 13.3 (n 60) Ethinyl estradiol 14.5 30.0 7.5 5.0 9.5 (n 40) ^Significantly higher (P < 0.001; Mann-Whitney test). CMA JOURNAL/NOVEMBER 8, 1975/VOL. 113 865 =
=
SEPTRA (Trimethoprim + Sulfamethoxazole)
* sequentially blocks two different bacterial enzymes (both vital for bacterial survival) * double blockade activity discourages development of resistance * achieves rapid, high blood levels; significant levels in lung tissue and sputum * well tolerated by most patients * convenient b.i.d. tablet dosage * licorice-flavored suspension well accepted by children IDSEPTRA 19(Summary INDICATIONS AND CLINICAL USES: Indicated for the following infections when caused hy susceptible organisms: URINARY TRACT INFECTIONS - acute, recurrent and chronic. GENITAL TRACT INFECTIONS - uncomplicated gonococcal urethrit is. UPPER AND LOWER RESPIRATORY TRACT INFECTIONS particularfy chronic bronchitis and acute and chronic otitis media. GASTROINTESTINAL TRACT INFECTIONS. SKIN AND SOFT TISSUE INFECTIONS. SEPTRA is not indicated in infections caused by Pseudomonas, Mycoplasma or viruses.This drug has not yet been fully evaluated in streptococcal infections. CONTRAINDICATIONS: Patients with evidence of marked liver parenchymal damage, blood dyscrasias, known hypersensitivity to trimethoprim or sulfonamides, marked renal impairment where repeated serum assays cannot he carried out; premature or newborn babies during the first few weeks of life. For the time being SEPTRA is contraindicated during pregnancy. If pregnancy cannot be excluded, the possible risks should be balanced against the expected therapeutic effect. PRECAUTIONS: As with other sulfonamide preparations, crifical appraisal of benefit versus risk should be made in patients with liver damage, renal damage, urinary obstruction, blood dyscrasias, allergies or bronchial asthma. The possibility of a superintection with a non-sensitive organism should be borne in mind. DOSAGE AND ADMINISTRATION: Adults and children over 12 years. Standard dosage: Two tablets twice daily (morning and evening). Minimum dosage and dosage for long-term treatment: One tablet twice daily. Maximum dosage: Overwhelming infections: Three tablets twice daily. Uncomplicated gonorrhea: Two tablets four times daily for two days. Children 12 years and under.' Young children should receive a dose according to biological age: Children under 2 years: 2.5 ml pediatric suspension twice daily. Children 2 to 5 years: One to two pediatric tablets or 2.5 to 5 ml pediatric suspension twice daily. Children 6 to 12 years: Two to four pediatric tablets or 5 to 10 ml pediatric suspension or one adult tablet twice daily. 'In children this corresponds to an approximate dose of 6 mg trimethoprim/kg body weight/day, plus 30 mg sulfamethoxazole/kg body weight/day, divided into two equal doses. DOSAGE FORMS: SEPTRA TABLETS, each containing 80 mg trimethoprim and 400 mg sulfamethoxazole, and coded WELLCOME Y2B. Bottles of 100 and 500, and unit dose packs of 100. SEPTRA PEDIATRIC SUSPENSION, each teaspoonful 15 ml) containing 40 mg trimethoprim and 200 mg sulfamethoxazole. Bottles of 100 and 400 ml. SEPTRA PEDIATRIC TABLETS, each containing 20 mg trimethoprim and 100 mg sulfamethoxazole, and coded WELLCOME H4B. Bottles of 100. Product monograph available on request.
I BurroughsWellcome Ltd. I LaSalle, Que. .Trade Mark
W-4046
that has not yet been settled. Their conclusions, which focused on the risk of thromboembolic sequelae following estrogen administration, have been supported by numerous reports of an increased incidence of thromboembolism in users of oral contraceptives.10'12 The increased coagulability noted during oral contraception has been attributed to increased blood viscosity,13 increased platelet adhesiveness and aggregation,14 increased circulating amounts of clotting factors VII and X11 and depressed plasminogen activation.16 These alterations have been attributed exclusively to the estrogen component of oral contraceptives, for they do not occur in patients receiving progestins alone.14 Furthermore, changes in serum concentrations of cholesterol and triglycerides have been found in patients with prostatic cancer receiving estrogen therapy.17 An increased incidence of complications with the use of DES as compared with the other two compounds was found in this study; it is largely due to the much higher incidence of thromboembolism in the DES group. The mortality figures for cardiovascular complications, however, showed only slight, insignificant differences between the three treatment groups. The incidence of fluid retention and that of gynecomastia were similar in the three groups. Estrogen-induced adrenocortical hyperplasia has been previously recognized'8 and increased values of serum cortisol with loss of the normal diurnal variation have been reported.19 The meaning of these changes is not yet clear, though a recent study20 has found an inverse relation between pretreatment serum cortisol values and prognosis in patients with prostatic cancer. A possible negative correlation between serum cortisol value and lymphocyte
count has been reported;21 the association of these findings with the adverse effect of estrogen on cell-mediated immunity22 remains to be determined. In early studies23'24 no changes in adrenal morphology were observed following chlorotrianisene administration. It is clear from the present study that these three estrogenic compounds induce functional alterations in the adrenal cortex suggestive of hyperplasia, as indicated by serum cortisol values. Results of the early studies, therefore, have not been substantiated.
References 1. BARNES RW, NINAN CA: Carcinoma of the prostate: biopsy and conservative therapy. J Urol 108: 897, 1972 2. BLACKARD CE, MELLINGER GT: Current status of estrogen therapy for prostatic carcinoma. Postgrad Med 51: 140, 1972 3. WHITMORE WF: The natural history of prostatic cancer. Cancer 32: 1104, 1973 4. BYAR DP: The Veterans Administration Cooperative Urological Research Group's study of cancer of the prostate. Cancer 32: 1127, 1973 5. Veterans Administration Cooperative Urological Research Group: Factors in prognosis of carcinoma of prostate. J UroL 100: 59, 1968 6. BAILAR JC iii, BYAR DP: Estrogen treatment for cancer of the prostate. Early results with 3 doses of diethyistilbestrol and placebo. Cancer 26: 257, 1970 7. MURPHY BEP: Some studies on the protein binding of steroids and their application to the routine micro measurements in body fluids by competitive binding radio assay. J Clin Endocrinol Metab 27: 913, 1967 8. MORALES A, KaAus AS, BRUCE AW: Estrogen therapy and serum cortisol in carcinoma of the prostate. Br J Urol 47: 283, 1975 9. Veterans Administration Cooperative Urological Research Group: Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstet 124: 1011, 1967 10. VAssEY MP, DOLL R: Investigations of relation between use of oral contraceptives and thrombcembolic disease. A further report. Br Med J 2: 651, 1969 11. Boston Collaborative Drug Surveillance Programme. Oral contraceptives and venous thromboembolic disease, gall bladder disease and breast tumours. Lancet 1: 1399, 1973 12. BADARACCO M, VassaY MP: Recurrence of venous thromboembolic disease and use of oral contraceptives. Br Med J 1: 215, 1974 13. ARONsoN HB, MAGORA F, SCHENKER JG: Effect of oral contraceptives on blood viscosity. Am .1 Obstet Gynecol 110: 997, 1971 14. ZUcK TF, BERGIN JJ, RAYMOND JT, et al: Platelet adhesiveness in symptomatic women taking oral contraceptives. Thromb Diath Haemorrh 26: 426, 1971 15. POLLER L, PRIEsT CM, THOMPSON JM: Platelet aggregation during oral contracep-
50 40 -j
0 U) I. 0 U
30
.
20
w U)
I0 0 CONTROL !ZZ2Bam
DES
OTA
Bpm
FIG. 1-Serum cortisol concentrations (.'g/ml) in control group and groups of patients receiving diethylstilbestrol (DES) or chlorotrianisene (CTA).
tion. Br Med 1 4: 273, 1969 16. POLLER L, THOMPSON JM, TAslowo A, et al: Progesterone oral contraception and blood coagulation. Br Med 1 1: 554, 1969 17. SHAMANESH M, BOLTON CH, FENELEY RCL, et al: Metabolic effects of oestrogen treatment in patients with carcinoma of prostate: a comparison of stilbestrol and conjugated equine oestrogens. Br Med 1 2: 512, 1973 18. FaRoussoN JD: Endocrine therapy in malignant disease, first ed, London, Saunders, l9.2, p 244 19. BURKE CW: Biologically active cortisol in plasma of estrogen treated and normal subjects. Br Med 1 2: 798, 1969 20. BLACKARD CE, BYAR DP, SEAL US, et al: Correlation of pretreatment serum corticosteroid with survival in prostatic cancer. N Engi I Med 291: 751, 1974 21. MORALES A, BRUCE AW: Effects of inhibition of steroid biosynthesis on the lymphoid system. Invest Urol 12: 54, 1974 22. ASLIN RJ, BRUNS GR, GUINAN P: The effect of estrogen on the incorporation of 3-H thymidine by PHA stimulated human peripheral blood lymphocytes. I Immunol 113: 705, 1974 23. CAROLL G, BRENNAN RV: TACE in prostatic cancer: clinical and biochemical siderations. J Urol 72: 497, 1954
con-
24. GissoN GP, N.WBERNE JW, KHIJN WL, et al: Comparative chronic toxicity of three oral estrogens in rats. Toxicol Appi Pharmacol 11: 489, 1967
CMA JOURNAL/NOVEMBER 8, 1975/VOL. 113 867
FRCS[c],
FACS; B.
PUJARI,* MD, FRCS,
DABU
Androgen suppression is established for the treatment of metastatic carcinoma estrogen therapy with diethylstilbestrol of the prostate. The present trend, (DES), chlorotrianisene or ethinyl however, is to delay the onset of ther¬ estradiol. During a mean follow-up apy until the patient has evidence of period of 26 months the incidence of urinary obstruction or until the meta¬ stases cause symptoms.1'2 The reason complications thromboembolic is twofold: estrogen therapy does not episodes, fluid retention and gynecomastia was recorded. Although necessarily increase survival3 and it has the incidence of cardiovascular been associated with increased morbid¬ complications was significantly higher ity and mortality, mostly from cardio¬ in the DES group, the differences in vascular complications.4 Recent studies on estrogen therapy mortality between the groups were not significant. The differences in incidence for prostatic cancer are based to a of fluid retention and gynecomastia large extent on the use of diethylstil¬ also lacked significance. All three bestrol (DES).5'6 Other natural and syn¬ thetic estrogenic compounds are avail¬ compounds produced adrenal cortical able and widely used; however, it has hyperplasia as indicated by the increased serum cortisol values. not been known whether their side ef¬ fects are comparable to those of DES. We therefore determined the inci¬ dence in 154 patients of side effects Resume: Le choix des estrogenes dans le traitement du cancer prostatique from three estrogenic preparations commonly used to treat prostatic can¬ Un total de 154 malades souffrant cer; we did not try to assess the oncode carcinome prostatique ont recu lytic merits of the drugs. Summary: A total of 154 patients with carcinoma of the prostate received
.
.
une
estrogenotherapie
avec
du diethylstilbestrol (DES), du chlorotrianisene ou de I'ethinyl estradiol. On a suivi ces malades pendant une periode moyenne de 36 mois et on a enregistre la frequence des complications episodes thromboemboliques, retention hydrique et gynecomastie. Malgre une incidence de complications cardiovasculaires significativement plus elevee dans le groupe traite par le DES, les differences de mortalite entre les divers groupes n'etaient pas significative. Les differences dans l'incidence de la retention hydrique et de la gynecomastie n'etaient pas significative davantage. Les trois medicaments ont entrame une hyperplasie du cortex de la .
glande surrenale, comme I'indiquait I'augmentation des concentrations du cortisol serique.
Methods
The 154 patients with prostatic can¬ divided into three treatment groups: the first group consisted of 54 patients (mean age, 73.4 years; aver¬ age duration of treatment, 37 months) who received 1 mg/d of DES; the second group consisted of 60 patients (mean age, 70.5 years; average dura¬ tion of treatment, 44 months) who re¬ ceived 12 mg/d of chlorotrianisene; and the third group consisted of 40 patients (mean age, 71.6 years; average duration of treatment, 30 months) who received 0.05 mg/d of ethinyl estra¬ diol. cer were
Table I.Incidence of in 154
patients
complications from
The development of side effects, such as thromboembolic episodes, fluid retention (manifested by peripheral edema) and gynecomastia, after institu¬ tion of estrogen therapy was recorded for each patient. In addition, serum cortisol concentrations were measured in 20 patients from each of the three groups who were treated for over 12 months; blood samples were taken at 8 am and 8 pm and the laboratory pro¬ cedure was that described by Murphy.7 Results
The incidence of complications in each treatment group is shown in Table I. The incidence of cardiovascular
(thromboembolic) complications was significantly higher in the DES group (P < 0.001; Mann-Whitney test), but the mortality due to cardiovascular causes differed little between the three groups; analysis of the three distribu¬ tions showed no significant differences. There were no significant differences between the three groups in incidence of peripheral edema or gynecomastia.
The serum concentrations of cortisol in a control and the DES group have been reported previously8 and are comr pared in Fig. 1 with the values in the chlorotrianisene group. In both groups of patients the values were increased throughout the day. Although this alteration was less in the chlorotrianisene group the difference was not signifi¬ cant.
Discussion The results of the Veterans Admin¬ study on the role of androgen suppression therapy in the treatment of
istration
prostatic cancer9 initiated a controversy estrogen therapy for prostatic cancer Incidence of complications (%)
Cardiovascular
Estrogen department of urology, Queen's University, Kingston This work was supported by The Ontario Cancer Foundation, grant no. 292, and the Wm. S. Merrell Company. ?Present address: 1400 Bland St., Bluefield, WV 24701, USA Reprint requests to: Dr. A. Morales, Etherington Hall, Queen's University, Kingston, From the
ON K7L 3N6
preparation Diethylstilbestrol (n 54) =
Chlorotrianisene
Morbidity 22.2
Mortality 9.3
Fluid retention 7.4
Gynecomastia Total 14.8
44.0*
26.6 5.0 8.3 6.6 13.3 (n 60) Ethinyl estradiol 14.5 30.0 7.5 5.0 9.5 (n 40) ^Significantly higher (P < 0.001; Mann-Whitney test). CMA JOURNAL/NOVEMBER 8, 1975/VOL. 113 865 =
=
SEPTRA (Trimethoprim + Sulfamethoxazole)
* sequentially blocks two different bacterial enzymes (both vital for bacterial survival) * double blockade activity discourages development of resistance * achieves rapid, high blood levels; significant levels in lung tissue and sputum * well tolerated by most patients * convenient b.i.d. tablet dosage * licorice-flavored suspension well accepted by children IDSEPTRA 19(Summary INDICATIONS AND CLINICAL USES: Indicated for the following infections when caused hy susceptible organisms: URINARY TRACT INFECTIONS - acute, recurrent and chronic. GENITAL TRACT INFECTIONS - uncomplicated gonococcal urethrit is. UPPER AND LOWER RESPIRATORY TRACT INFECTIONS particularfy chronic bronchitis and acute and chronic otitis media. GASTROINTESTINAL TRACT INFECTIONS. SKIN AND SOFT TISSUE INFECTIONS. SEPTRA is not indicated in infections caused by Pseudomonas, Mycoplasma or viruses.This drug has not yet been fully evaluated in streptococcal infections. CONTRAINDICATIONS: Patients with evidence of marked liver parenchymal damage, blood dyscrasias, known hypersensitivity to trimethoprim or sulfonamides, marked renal impairment where repeated serum assays cannot he carried out; premature or newborn babies during the first few weeks of life. For the time being SEPTRA is contraindicated during pregnancy. If pregnancy cannot be excluded, the possible risks should be balanced against the expected therapeutic effect. PRECAUTIONS: As with other sulfonamide preparations, crifical appraisal of benefit versus risk should be made in patients with liver damage, renal damage, urinary obstruction, blood dyscrasias, allergies or bronchial asthma. The possibility of a superintection with a non-sensitive organism should be borne in mind. DOSAGE AND ADMINISTRATION: Adults and children over 12 years. Standard dosage: Two tablets twice daily (morning and evening). Minimum dosage and dosage for long-term treatment: One tablet twice daily. Maximum dosage: Overwhelming infections: Three tablets twice daily. Uncomplicated gonorrhea: Two tablets four times daily for two days. Children 12 years and under.' Young children should receive a dose according to biological age: Children under 2 years: 2.5 ml pediatric suspension twice daily. Children 2 to 5 years: One to two pediatric tablets or 2.5 to 5 ml pediatric suspension twice daily. Children 6 to 12 years: Two to four pediatric tablets or 5 to 10 ml pediatric suspension or one adult tablet twice daily. 'In children this corresponds to an approximate dose of 6 mg trimethoprim/kg body weight/day, plus 30 mg sulfamethoxazole/kg body weight/day, divided into two equal doses. DOSAGE FORMS: SEPTRA TABLETS, each containing 80 mg trimethoprim and 400 mg sulfamethoxazole, and coded WELLCOME Y2B. Bottles of 100 and 500, and unit dose packs of 100. SEPTRA PEDIATRIC SUSPENSION, each teaspoonful 15 ml) containing 40 mg trimethoprim and 200 mg sulfamethoxazole. Bottles of 100 and 400 ml. SEPTRA PEDIATRIC TABLETS, each containing 20 mg trimethoprim and 100 mg sulfamethoxazole, and coded WELLCOME H4B. Bottles of 100. Product monograph available on request.
I BurroughsWellcome Ltd. I LaSalle, Que. .Trade Mark
W-4046
that has not yet been settled. Their conclusions, which focused on the risk of thromboembolic sequelae following estrogen administration, have been supported by numerous reports of an increased incidence of thromboembolism in users of oral contraceptives.10'12 The increased coagulability noted during oral contraception has been attributed to increased blood viscosity,13 increased platelet adhesiveness and aggregation,14 increased circulating amounts of clotting factors VII and X11 and depressed plasminogen activation.16 These alterations have been attributed exclusively to the estrogen component of oral contraceptives, for they do not occur in patients receiving progestins alone.14 Furthermore, changes in serum concentrations of cholesterol and triglycerides have been found in patients with prostatic cancer receiving estrogen therapy.17 An increased incidence of complications with the use of DES as compared with the other two compounds was found in this study; it is largely due to the much higher incidence of thromboembolism in the DES group. The mortality figures for cardiovascular complications, however, showed only slight, insignificant differences between the three treatment groups. The incidence of fluid retention and that of gynecomastia were similar in the three groups. Estrogen-induced adrenocortical hyperplasia has been previously recognized'8 and increased values of serum cortisol with loss of the normal diurnal variation have been reported.19 The meaning of these changes is not yet clear, though a recent study20 has found an inverse relation between pretreatment serum cortisol values and prognosis in patients with prostatic cancer. A possible negative correlation between serum cortisol value and lymphocyte
count has been reported;21 the association of these findings with the adverse effect of estrogen on cell-mediated immunity22 remains to be determined. In early studies23'24 no changes in adrenal morphology were observed following chlorotrianisene administration. It is clear from the present study that these three estrogenic compounds induce functional alterations in the adrenal cortex suggestive of hyperplasia, as indicated by serum cortisol values. Results of the early studies, therefore, have not been substantiated.
References 1. BARNES RW, NINAN CA: Carcinoma of the prostate: biopsy and conservative therapy. J Urol 108: 897, 1972 2. BLACKARD CE, MELLINGER GT: Current status of estrogen therapy for prostatic carcinoma. Postgrad Med 51: 140, 1972 3. WHITMORE WF: The natural history of prostatic cancer. Cancer 32: 1104, 1973 4. BYAR DP: The Veterans Administration Cooperative Urological Research Group's study of cancer of the prostate. Cancer 32: 1127, 1973 5. Veterans Administration Cooperative Urological Research Group: Factors in prognosis of carcinoma of prostate. J UroL 100: 59, 1968 6. BAILAR JC iii, BYAR DP: Estrogen treatment for cancer of the prostate. Early results with 3 doses of diethyistilbestrol and placebo. Cancer 26: 257, 1970 7. MURPHY BEP: Some studies on the protein binding of steroids and their application to the routine micro measurements in body fluids by competitive binding radio assay. J Clin Endocrinol Metab 27: 913, 1967 8. MORALES A, KaAus AS, BRUCE AW: Estrogen therapy and serum cortisol in carcinoma of the prostate. Br J Urol 47: 283, 1975 9. Veterans Administration Cooperative Urological Research Group: Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstet 124: 1011, 1967 10. VAssEY MP, DOLL R: Investigations of relation between use of oral contraceptives and thrombcembolic disease. A further report. Br Med J 2: 651, 1969 11. Boston Collaborative Drug Surveillance Programme. Oral contraceptives and venous thromboembolic disease, gall bladder disease and breast tumours. Lancet 1: 1399, 1973 12. BADARACCO M, VassaY MP: Recurrence of venous thromboembolic disease and use of oral contraceptives. Br Med J 1: 215, 1974 13. ARONsoN HB, MAGORA F, SCHENKER JG: Effect of oral contraceptives on blood viscosity. Am .1 Obstet Gynecol 110: 997, 1971 14. ZUcK TF, BERGIN JJ, RAYMOND JT, et al: Platelet adhesiveness in symptomatic women taking oral contraceptives. Thromb Diath Haemorrh 26: 426, 1971 15. POLLER L, PRIEsT CM, THOMPSON JM: Platelet aggregation during oral contracep-
50 40 -j
0 U) I. 0 U
30
.
20
w U)
I0 0 CONTROL !ZZ2Bam
DES
OTA
Bpm
FIG. 1-Serum cortisol concentrations (.'g/ml) in control group and groups of patients receiving diethylstilbestrol (DES) or chlorotrianisene (CTA).
tion. Br Med 1 4: 273, 1969 16. POLLER L, THOMPSON JM, TAslowo A, et al: Progesterone oral contraception and blood coagulation. Br Med 1 1: 554, 1969 17. SHAMANESH M, BOLTON CH, FENELEY RCL, et al: Metabolic effects of oestrogen treatment in patients with carcinoma of prostate: a comparison of stilbestrol and conjugated equine oestrogens. Br Med 1 2: 512, 1973 18. FaRoussoN JD: Endocrine therapy in malignant disease, first ed, London, Saunders, l9.2, p 244 19. BURKE CW: Biologically active cortisol in plasma of estrogen treated and normal subjects. Br Med 1 2: 798, 1969 20. BLACKARD CE, BYAR DP, SEAL US, et al: Correlation of pretreatment serum corticosteroid with survival in prostatic cancer. N Engi I Med 291: 751, 1974 21. MORALES A, BRUCE AW: Effects of inhibition of steroid biosynthesis on the lymphoid system. Invest Urol 12: 54, 1974 22. ASLIN RJ, BRUNS GR, GUINAN P: The effect of estrogen on the incorporation of 3-H thymidine by PHA stimulated human peripheral blood lymphocytes. I Immunol 113: 705, 1974 23. CAROLL G, BRENNAN RV: TACE in prostatic cancer: clinical and biochemical siderations. J Urol 72: 497, 1954
con-
24. GissoN GP, N.WBERNE JW, KHIJN WL, et al: Comparative chronic toxicity of three oral estrogens in rats. Toxicol Appi Pharmacol 11: 489, 1967
CMA JOURNAL/NOVEMBER 8, 1975/VOL. 113 867
