Tenovus Institute for Cancer Research, Welsh National School of Medicine, The Heath, Cardiff CF4 4XX, U. K.
PLASMA STEROID AND PROTEIN HORMONE CONCENTRATIONS IN PATIENTS WITH PROSTATIC CARCINOMA, BEFORE AND DURING OESTROGEN THERAPY
By M. E. Harper, W. B. Peeling, T. Cowley, B. G. Brownsey, M. E. A. Phillips, G. Groom, D. R. Fahmy and K. Griffiths ABSTRACT Plasma testosterone, androstenedione, oestradiol-17\g=b\, follicle stimulating hormone (FSH) and luteinizing hormone (LH) were not significantly different in patients with prostatic cancer, with benign prostatic hyperplasia or in patients without prostatic disease. Plasma prolactin concentrations were significantly lower in the patients with benign disease than those with prostatic carcinoma. Endocrine therapy in the form of stilboestrol administration significantly decreased plasma levels of testosterone, oestradiol-17\g=b\, FSH and LH within 7 days of the treatment. After 7 days therapy prolactin levels increased significantly in all patients studied. Changes in growth hormone concentrations were more varied in response to stilboestrol, being elevated in several patients and remaining unchanged in others. Treatment of a few prostatic carcinoma patients who were receiving stilboestrol therapy with CB154, an inhibitor of prolactin secretion, brought an immediate decrease in prolactin levels which was sustained. Plasma testosterone, androstenedione and growth hormone were unchanged in these patients but a significant decrease in plasma oestradiol-17\g=b\ was noted in two patients during CB154 administration. ')
Department
of
Surgery, Royal
Gwent
Hospital, Newport, Gwent
NPT 2UB, U. K.
endocrine therapy in the form of castration or administration of is oestrogen now widely accepted as the most effective form of treatment for carcinoma of the prostate in man, the role of androgens in the aetiology of the disease remains unknown. The clinical data indicate that the carcinoma functionally depends upon androgenic stimulation yet Isurugi (1967) showed that there was no evidence of an elevated testosterone production rate in patients with prostatic cancer. It is interesting that although prostate disease generally occurs at a time when testicular function is declining, Kent 8c Acone (1966) have reported that the plasma concentration of testosterone in the male is maintained at a relatively constant level from the age of 20 to the ninth decade, resulting, however, from a decrease in the metabolic clearance rate of testosterone with age. Vermeulen el al. (1972) in contrast, found in their study that testosterone decreased after the 6th decade although the range in con¬ centration were very large. Plasma concentration of oestradiol-17/i increases with increasing age in the normal healthy adult male (Pirke 8c Doerr 1973) and there has been speculation that changes in the androgen-oestrogen balance in elderly men may be implicated in the aetiology of prostatic disease. Sommers (1957) considered that oestrogens were concerned in the pathogenesis of benign prostatic hypertrophy. At the same time, experimental studies in animals have suggested that pituitary hormones may influence prostatic growth and function. Hypophysectomy for example, results in a more marked prostatic atrophy than that seen after simple castration (Huggins 8c Rüssel 1946; Lostroh 8c Li 1957). Furthermore, testosterone and prolactin produce a greater increase in the fructose and citric acid content of the prostate of the hypophysectomizedcastrated rat than testosterone alone (Grayhack 8c Lebowitz 1967). Little is known, however, about the relationship between protein hormones and prostatic disease in man. As part of an investigation into the endocrinology of patients with prostatic dysfunction, certain steroid and protein hormones were determined in the plasma of a control group of patients, in a group with benign prostatic hyperplasia, and before and during treatment in patients with prostatic carcinoma. The change of plasma hormone levels after administration of compounds such as Synacthen (Tetracosactin, Ciba), dexamethasone and CB154 (2-bromoa-ergocryptine, Sandoz) was investigated in certain patients during treatment with oestrogen or after castration. As part of a major clinical research study, the plasma hormone concentra¬ tions of individual co-operative patients with prostatic cancer are being care¬ fully monitored in relation to the progression of the disease. There may be an association between these plasma hormone changes and the clinical response to therapy and the studies may provide insight into the relationship between the recurrence of the disease and the endocrine status of the patients.
Although
PATIENTS AND METHODS
Patients
Thirty-three patients various stages of the
with carcinoma of the prostate, histologically-proven, but at disease, forty-one patients with benign prostatic hyperplasia and
thirty-five hospitalized patients without evidence of prostatic disease were studied. The control patients had no history of urinary difficulties nor a high plasma acidphosphatase level. Ages ranged from 55-83 years, mean 73 years for the prostatic cancer group; 52-81 years, mean 71 years for the patients with benign disease; 59-79 years, mean 70 years for the control group. Blood samples were taken in the morning, as near to 09.00 h as possible. Twenty patients with carcinoma of the prostate were treated with either Honvan (diethylstilboestrol diphosphate: 100 mg b. d.) or diethylstilboestrol (1 mg t. d. s.) and their plasma hormone concentrations measured prior to therapy and at 3 and 7 days and 1 and 3 months after the commencement of endo¬ crine therapy. Another patient was treated with bilateral orchidectomy and plasma hormone concentration subsequently determined over several months. Four patients with prostatic carcinoma who had been treated with Honvan for at least six months were given CB154 2.55 mg daily for periods up to 6 weeks. Plasma samples were obtained for analysis before and during CB154 treatment. Most of the patients, controls, those with benign prostatic hypertrophy and those with prostatic carcinoma were subjected to an adrenal stimulation test. Patients with prostatic carcinoma were subsequently given a second test during the period of the endocrine therapy. On two consecutive days, at 09.30 and 16.30 h, blood was taken from patients by venepuncture. Synacthen depot (/J'-aí-corticotrophin zinc complex, Ciba, 1 mg) was given im immediately after the 09.30 h blood sample had been taken on the second day. Some of the patients also received dexamethasone (8 mg daily for 3 days). All tests were undertaken after the consent of the patient had been received. Al¬ though reasonable volumes of plasma were taken, occasionally insufficient material was
available to undertake all assays.
Assays Plasma measured
luteinizing hormone (LH) and follicle stimulating hormone (FSH) were by double antibody radioimmunoassay shown to be specific for these hor¬ mones (Groom et al. 1971). The sensitivity of each assay was 0.5 mIU/ml of MRC 63/15 and 2nd-IRP-HMG, respectively. Plasma growth hormone (GH) was estimated by a specific double antibody radioimmunoassay (Schalch Se Parker 1964) using puri¬ fied human growth hormone (MRC 69/46) and rabbit antiserum to growth hormone (Wellcome Reagents Ltd.). Plasma prolactin was measured by a homologous double antibody radioimmunoassay in which there was negligible cross-reaction with FSH, LH, TSH, GH and chorionic somatomammotrophin (Cole Se Boyns 1973). The sen¬ sitivity of the assay was 10 milliampoules/ml (mamp/ml) of MRC 71/222. Total plasma testosterone was measured by a specific radioimmunoassay, the sensitivity of the method being 15 pg/ml (Hillier et al. 1973). Plasma androstenedione was measured using a specific radioimmunoassay with a sensitivity of 110 pg/ml (Cowley et al. 1976). Plasma oestradiol was measured using the method of Cameron 8c Jones (1972) with a sensitivity of 3 pg/ml. Statistical analyses were performed using the multiple ¿-test.
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PLASMA STEROID AND PROTEIN HORMONE CONCENTRATIONS IN PATIENTS WITH PROSTATIC CARCINOMA, BEFORE AND DURING OESTROGEN THERAPY
By M. E. Harper, W. B. Peeling, T. Cowley, B. G. Brownsey, M. E. A. Phillips, G. Groom, D. R. Fahmy and K. Griffiths ABSTRACT Plasma testosterone, androstenedione, oestradiol-17\g=b\, follicle stimulating hormone (FSH) and luteinizing hormone (LH) were not significantly different in patients with prostatic cancer, with benign prostatic hyperplasia or in patients without prostatic disease. Plasma prolactin concentrations were significantly lower in the patients with benign disease than those with prostatic carcinoma. Endocrine therapy in the form of stilboestrol administration significantly decreased plasma levels of testosterone, oestradiol-17\g=b\, FSH and LH within 7 days of the treatment. After 7 days therapy prolactin levels increased significantly in all patients studied. Changes in growth hormone concentrations were more varied in response to stilboestrol, being elevated in several patients and remaining unchanged in others. Treatment of a few prostatic carcinoma patients who were receiving stilboestrol therapy with CB154, an inhibitor of prolactin secretion, brought an immediate decrease in prolactin levels which was sustained. Plasma testosterone, androstenedione and growth hormone were unchanged in these patients but a significant decrease in plasma oestradiol-17\g=b\ was noted in two patients during CB154 administration. ')
Department
of
Surgery, Royal
Gwent
Hospital, Newport, Gwent
NPT 2UB, U. K.
endocrine therapy in the form of castration or administration of is oestrogen now widely accepted as the most effective form of treatment for carcinoma of the prostate in man, the role of androgens in the aetiology of the disease remains unknown. The clinical data indicate that the carcinoma functionally depends upon androgenic stimulation yet Isurugi (1967) showed that there was no evidence of an elevated testosterone production rate in patients with prostatic cancer. It is interesting that although prostate disease generally occurs at a time when testicular function is declining, Kent 8c Acone (1966) have reported that the plasma concentration of testosterone in the male is maintained at a relatively constant level from the age of 20 to the ninth decade, resulting, however, from a decrease in the metabolic clearance rate of testosterone with age. Vermeulen el al. (1972) in contrast, found in their study that testosterone decreased after the 6th decade although the range in con¬ centration were very large. Plasma concentration of oestradiol-17/i increases with increasing age in the normal healthy adult male (Pirke 8c Doerr 1973) and there has been speculation that changes in the androgen-oestrogen balance in elderly men may be implicated in the aetiology of prostatic disease. Sommers (1957) considered that oestrogens were concerned in the pathogenesis of benign prostatic hypertrophy. At the same time, experimental studies in animals have suggested that pituitary hormones may influence prostatic growth and function. Hypophysectomy for example, results in a more marked prostatic atrophy than that seen after simple castration (Huggins 8c Rüssel 1946; Lostroh 8c Li 1957). Furthermore, testosterone and prolactin produce a greater increase in the fructose and citric acid content of the prostate of the hypophysectomizedcastrated rat than testosterone alone (Grayhack 8c Lebowitz 1967). Little is known, however, about the relationship between protein hormones and prostatic disease in man. As part of an investigation into the endocrinology of patients with prostatic dysfunction, certain steroid and protein hormones were determined in the plasma of a control group of patients, in a group with benign prostatic hyperplasia, and before and during treatment in patients with prostatic carcinoma. The change of plasma hormone levels after administration of compounds such as Synacthen (Tetracosactin, Ciba), dexamethasone and CB154 (2-bromoa-ergocryptine, Sandoz) was investigated in certain patients during treatment with oestrogen or after castration. As part of a major clinical research study, the plasma hormone concentra¬ tions of individual co-operative patients with prostatic cancer are being care¬ fully monitored in relation to the progression of the disease. There may be an association between these plasma hormone changes and the clinical response to therapy and the studies may provide insight into the relationship between the recurrence of the disease and the endocrine status of the patients.
Although
PATIENTS AND METHODS
Patients
Thirty-three patients various stages of the
with carcinoma of the prostate, histologically-proven, but at disease, forty-one patients with benign prostatic hyperplasia and
thirty-five hospitalized patients without evidence of prostatic disease were studied. The control patients had no history of urinary difficulties nor a high plasma acidphosphatase level. Ages ranged from 55-83 years, mean 73 years for the prostatic cancer group; 52-81 years, mean 71 years for the patients with benign disease; 59-79 years, mean 70 years for the control group. Blood samples were taken in the morning, as near to 09.00 h as possible. Twenty patients with carcinoma of the prostate were treated with either Honvan (diethylstilboestrol diphosphate: 100 mg b. d.) or diethylstilboestrol (1 mg t. d. s.) and their plasma hormone concentrations measured prior to therapy and at 3 and 7 days and 1 and 3 months after the commencement of endo¬ crine therapy. Another patient was treated with bilateral orchidectomy and plasma hormone concentration subsequently determined over several months. Four patients with prostatic carcinoma who had been treated with Honvan for at least six months were given CB154 2.55 mg daily for periods up to 6 weeks. Plasma samples were obtained for analysis before and during CB154 treatment. Most of the patients, controls, those with benign prostatic hypertrophy and those with prostatic carcinoma were subjected to an adrenal stimulation test. Patients with prostatic carcinoma were subsequently given a second test during the period of the endocrine therapy. On two consecutive days, at 09.30 and 16.30 h, blood was taken from patients by venepuncture. Synacthen depot (/J'-aí-corticotrophin zinc complex, Ciba, 1 mg) was given im immediately after the 09.30 h blood sample had been taken on the second day. Some of the patients also received dexamethasone (8 mg daily for 3 days). All tests were undertaken after the consent of the patient had been received. Al¬ though reasonable volumes of plasma were taken, occasionally insufficient material was
available to undertake all assays.
Assays Plasma measured
luteinizing hormone (LH) and follicle stimulating hormone (FSH) were by double antibody radioimmunoassay shown to be specific for these hor¬ mones (Groom et al. 1971). The sensitivity of each assay was 0.5 mIU/ml of MRC 63/15 and 2nd-IRP-HMG, respectively. Plasma growth hormone (GH) was estimated by a specific double antibody radioimmunoassay (Schalch Se Parker 1964) using puri¬ fied human growth hormone (MRC 69/46) and rabbit antiserum to growth hormone (Wellcome Reagents Ltd.). Plasma prolactin was measured by a homologous double antibody radioimmunoassay in which there was negligible cross-reaction with FSH, LH, TSH, GH and chorionic somatomammotrophin (Cole Se Boyns 1973). The sen¬ sitivity of the assay was 10 milliampoules/ml (mamp/ml) of MRC 71/222. Total plasma testosterone was measured by a specific radioimmunoassay, the sensitivity of the method being 15 pg/ml (Hillier et al. 1973). Plasma androstenedione was measured using a specific radioimmunoassay with a sensitivity of 110 pg/ml (Cowley et al. 1976). Plasma oestradiol was measured using the method of Cameron 8c Jones (1972) with a sensitivity of 3 pg/ml. Statistical analyses were performed using the multiple ¿-test.
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