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Biomedical subjects

M Dowsett

Publications and source records attributed to M Dowsett.

At least 235 records · Page 13Linked to original sources
PubMed1987

Use of the aromatase inhibitor 4-hydroxyandrostenedione in postmenopausal breast cancer: optimization of therapeutic dose and route.

4-Hydroxyandrostenedione (4-OHA) is a potent inhibitor of estrogen production by aromatase and causes suppression of plasma estradiol levels and disease regression in postmenopausal breast cancer patients. Groups of patients were given p.o. or parenteral 4-OHA, and plasma estradiol and 4-OHA levels were measured to enable the delineation of the minimal effective dose and optimal therapeutic regimen. A single injection of 500 mg i.m. suppressed estradiol levels to a mean 36.3 +/- 3.3% (SE) (n = 14) of base line after 4 to 7 days and maintained this suppression in six of seven patients for greater than 14 days. The half-life of 4-OHA was approximately 8 days, and when the level had fallen to less than 3 ng/ml, estradiol levels began to rise. Similar suppression was achieved by a single i.m. injection of 125 mg of 4-OHA and by 500 mg of 4-OHA p.o. daily after 1 wk, but escape from suppression was more rapid.

Administration, Oral↗
PubMed1987

Oral 4-hydroxyandrostenedione, a new endocrine treatment for disseminated breast cancer.

Thirty-one post-menopausal female patients, with locally advanced or disseminated breast cancer were treated with the aromatase inhibitor 4-hydroxyandrostenedione given orally at a dose of 500 mg daily. Twenty-nine patients had assessable disease. Eight patients (28%) had objective evidence of partial response and six remain in remission 7-10 months later. A further four patients (14%) had stabilisation of disease and 11 patients (37%) had progressive disease in spite of treatment. Plasma oestradiol levels were measured throughout therapy in 16 patients and were lowered to 53% +/- 8% of baseline levels within 7 days of commencing 4-hydroxyandrostenedione. With regard to toxicity, one patient developed a transient skin rash and another patient some facial swelling. A further patient developed a transient leucopaenia and treatment was therefore discontinued. Twenty-seven of the 30 evaluable patients (90%) experienced no side effects. These results indicate that oral administration of 4-hydroxyandrostenedione is an acceptable new treatment for post-menopausal women with disseminated breast cancer.

Administration, Oral↗
PubMed1987

Aromatase inhibitors: basic and clinical studies.

Application of aromatase inhibitors to the treatment of conditions in which estrogen plays, a role is discussed. Studies in vitro demonstrate that 4-hydroxyandrostenedione (4-OHA) is a potent inhibitor of aromatase. The compound reduces ovariant estrogen production and causes regression of carcinogen (DMBA)-induced mammary tumors in the rat. In the rhesus monkey, 4-OHA was also shown to inhibit peripheral aromatization. To date 58 postmenopausal breast cancer patients with advanced metastatic disease have received 500 mg im weekly while 31 patients received 250 mg 4-OHA orally per day. Estradiol levels were significantly reduced in all patients from a mean of 7.2 + 0.8 pg/ml to 2.8 + 0.3 pg/ml. Of patients receiving 4-OHA im 27% had partial or complete responses and in 10% of patients the disease was stabilized. Similar responses occurred in the patients receiving 4-OHA orally. These results suggest that 4-OHA is effective and that this compound and other aromatase inhibitors could be valuable new additions to the treatment of breast cancer.

Androstenedione↗
PubMed1987

The effects of low and high dose medroxyprogesterone acetate on sex steroids and sex hormone binding globulin in postmenopausal breast cancer patients.

The possibility that medroxyprogesterone acetate (MPA) is clinically effective at least in part by its suppression of adrenal steroidogenesis and a resultant reduction of circulating oestrogen levels was investigated in 49 postmenopausal patients with advanced breast cancer. Thirty-one patients were treated with low dose MPA (100 mg three times daily) and 16 patients with high dose MPA (250 mg four times daily). Plasma levels of androstenedione, testosterone, oestrone and oestradiol were all significantly reduced during treatment, with the suppression being most marked for the 17 beta hydroxysteroids, testosterone and oestradiol. The fall in oestradiol levels was to about 50% of pretreatment levels, but a concomitant fall in SHBG levels to less than 25% of baseline probably resulted in the fall in free, biologically active oestradiol being only to about 70-80% of pretreatment. It is unlikely that this is a major determinant of the activity of MPA in breast cancer.

Androstenedione↗
PubMed1986

Aromatase inhibitors and the treatment of breast cancer.

Inhibition of aromatase to reduce estrogen production by peripheral and ovarian tissue could be a useful approach to treating hormone-dependent breast cancer. Several C19, 17 keto steroids have been identified as aromatase inhibitors. The most potent of these cause rapid competitive inhibition followed by enzyme inactivation. Injections of the compounds caused inhibition of peripheral aromatization in monkeys. In rats, these treatments result in inhibition of ovarian aromatase and estrogen secretion, accompanied by marked regression of carcinogen(DMBA or NMU)-induced mammary tumors. To date, 60 postmenopausal patients with advanced metastatic breast cancer and unselected for the presence of estrogen receptors have been treated with once weekly injections of 4-OHA. The mean estradiol level measured in 14 patients was significantly reduced to 36% of pretreatment values after 1 month and remained at this level for up to 4 months. There was no effect of treatment on gonadotropin levels. Although all patients had relapsed from previous therapy, complete or partial tumor regression occurred in 30% of patients while 15% had static disease. The results indicate that in these patients the responses are due to inhibition of peripheral aromatization and that 4-OHA may be of value in treating postmenopausal breast cancer.

Adult↗
PubMed1986

Aromatase inhibitors and their potential clinical significance.

Estrogen biosynthesis occurs not only in reproductive tissues of the female but also in such diverse sites as testes, adipose and muscle. Our rationale for the clinical use of aromatase inhibitors is that compounds interacting with aromatase in all tissues could provide both selective and effective inhibition of estrogen production. The most potent inhibitor identified by us to date is 4-hydroxyandrostene-3,17-dione (4-OHA). This compound causes rapid competitive inhibition followed by irreversible inactivation of aromatase. Treatment of rats with 4-OHA results in inhibition of ovarian aromatase and estrogen secretion, accompanied by marked regression of carcinogen induced mammary tumors. Using rhesus monkeys, marked inhibition of peripheral aromatization by 4-OHA was also demonstrated. The first clinical study with a selective aromatase inhibitor was recently carried out using once weekly injections of 500 mg 4-OHA in 60 postmenopausal patients with advanced metastatic breast cancer and unselected for the presence of estrogen receptors. The mean serum estradiol level reduced to 36% of pretreatment values for at least 4 months. No effect of treatment on gonadotropin levels occurred indicating that the reduction in estrogen levels was due to inhibition of peripheral aromatization. In spite of the fact that all patients had relapsed from previous therapy, complete or partial tumor regression occurred in 30% of patients while 15% had static disease. Although the optimum dose of 4-OHA has not yet been established, this aromatase inhibitor appears to be of value in treating postmenopausal breast cancer and may be beneficial in other diseases associated with estrogens.

Androstenedione↗
PubMed1986

Role of aminoglutethimide in male breast cancer.

Five men with advanced breast cancer were treated with aminoglutethimide (AG) plus replacement dose hydrocortisone. None of the 4 patients with intact testes responded, although 3 did so subsequently to tamoxifen. The previously orchidectomized patient responded to aminoglutethimide for 14 months. Oestrone and oestradiol were suppressed by AG in all patients, but not to the levels achieved by orchidectomy. AG produced substantial further oestrogen suppression in the orchidectomized patient and should only be used after orchidectomy.

Aminoglutethimide↗
PubMed1986

A comparison of the effects of danazol and gestrinone on testosterone binding to sex hormone binding globulin in vitro and in vivo.

Danazol and gestrinone are both effective agents in the treatment of endometriosis. Their mechanism of action is unknown but may be related to their androgenic activity, which is at least partly dependent on increases in the proportion of testosterone which circulates unbound to plasma protein. We have quantified these increases in patients on treatment, and by experimentation in vitro have demonstrated the relative importance of the reduction of sex hormone binding globulin (SHBG) binding capacity and competition with testosterone for SHBG binding sites by the drugs and some of their metabolites. The mean SHBG binding capacity in patients treated with danazol (400 mg/d, n = 7) and gestrinone (5 mg/week, n = 7) fell from 66.9 and 56.4 nmol/l to 36.1 and 28.1 nmol/l, after 1 week's treatment and to 11.1 and 7.1 nmol/l after 4 weeks respectively. Despite the similarity between the falls in SHBG binding capacity there was a significantly greater increase in % free testosterone in plasma samples from patients treated with danazol than in those from patients treated with gestrinone at 1 week. Experiments in vitro suggest that this was largely due to ethisterone (a major metabolite of danazol) competing with testosterone for SHBG binding sites. After 4 weeks on treatment there was a similar, near maximal reduction in SHBG binding of testosterone in both treatment groups. At the low levels of SHBG binding capacity reached by this time the extra effect of any competition for binding sites was much reduced.

Danazol↗
PubMed1986

Dosage-related effects of danazol on sex hormone binding globulin and free and total androgen levels.

Danazol is known to cause marked suppression of sex hormone binding globulin (SHBG) levels in plasma and to increase the proportion of plasma testosterone unbound to protein but the effect on the concentration of total and free testosterone is unclear. Twenty-five patients with endometriosis were treated daily for 6 months with doses of danazol ranging from 50 to 600 mg. The fall in SHBG and rise in percent free testosterone was dose-related during the early part of treatment. Suppression of total testosterone and 5 alpha-dihydrotestosterone levels occurred and was probably due to increases in metabolic clearance rates. The observed fall in androstenedione levels was related to the incidence of menstrual abnormality, suggesting that this might be due to reduced ovarian activity. The concentration of free testosterone increased by a factor of two in the first week but subsequently returned to levels of between 25 and 50% above pretreatment levels. This pattern of changes may be due to the rise in metabolic clearance rates being dependent on induction of enzymes of androgen metabolism.

Clinical Trials as Topic↗
PubMed1986

Biochemical basis for the antagonism between aminoglutethimide and danazol in the endocrine treatment of breast cancer.

Only 13% of postmenopausal advanced breast cancer patients responded to endocrine treatment with aminoglutethimide plus danazol whilst 33% responded to aminoglutethimide alone, despite a similar suppression of serum oestradiol levels in the two groups. The patients on aminoglutethimide and danazol showed a marked suppression of sex hormone binding-globulin binding capacity and a consequent rise in percent-free oestradiol. This led to the concentration of free oestradiol being less well suppressed than that of total oestradiol and in some patients free oestradiol concentrations were higher on treatment than before. Patients on aminoglutethimide alone showed no change in the binding of oestradiol and the percentage suppression of the free oestradiol concentration was similar to that of total oestradiol. The opposing effects of danazol and aminoglutethimide on the concentration of the free, biologically active fraction of oestradiol in the circulation may explain the poor therapeutic efficacy of this combination in breast cancer patients.

Aminoglutethimide↗
PubMed1986

Spironolactone in the treatment of hirsutism.

Spironolactone (100 mg) for 25 days in each menstrual cycle was assessed over 6 months for treatment of hirsutism in 35 patients. Five patients withdrew due to either nausea or polymenorrhea. the latter problem was encountered in 16 patients. Of the 30 remaining patients, 17 had a significant reduction in hair growth as assessed by Ferriman and Gallwey hair scores (p less than 0.05). The only significant change in endocrine parameters was a reduction in serum testosterone (p less than 0.05). Treatment with spironolactone alone was inferior to our previous experience with the cyproterone acetate--estrogen combination.

Female↗
PubMed1986

Treatment of advanced postmenopausal breast cancer with an aromatase inhibitor, 4-hydroxyandrostenedione: phase II report.

4-Hydroxyandrostenedione (4-OHA), a potent new aromatase inhibitor, was given i.m. (500-1000 mg) to 58 patients with advanced postmenopausal breast cancer. Of 52 assessable patients 14 responded (27%), in 10 (19%) the disease stabilized, and in 28 (54%) the disease progressed. Sterile abscesses occurred at the injection site in 6 patients and painful lumps were found in a further 3 patients. Two patients developed allergic-type reactions and 4 developed lethargy, suspected to be treatment induced. Plasma estradiol levels were suppressed from a mean of 7.2 +/- 0.8 (SE) pg/ml before treatment to 2.6 +/- 0.2, 2.7 +/- 0.2, and 2.8 +/- 0.3 pg/ml after 1, 2, and greater than 4 months, respectively, of treatment and remained suppressed in patients whose disease relapsed. No significant fall in estrone levels was seen. Similarly, dehydroepiandrosterone sulfate, sex hormone binding globulin, and gonadotrophin levels were unaltered after 6 months of treatment. Plasma 4-OHA levels were measured in a radioimmunoassay for androstenedione after chromatographic separation of 4-OHA from androstenedione. Drug concentrations ranged from 0.7 to 23.2 (7.8 +/- 1.1) ng/ml after 2 months on treatment. 4-OHA is an effective drug in the management of postmenopausal patients with breast cancer and does not produce notable systemic side effects.

Adult↗
PubMed1986

Endocrine effects of low dose aminoglutethimide with hydrocortisone--an optimal hormone suppressive regimen.

The endocrine effects of aminoglutethimide 125 mg twice daily and hydrocortisone 20 mg twice daily were assessed in 45 postmenopausal women with advanced breast cancer. Oestrone and oestradiol levels were suppressed by 60% within 2 weeks and suppression was maintained for more than 6 months of chronic treatment. In contrast to conventional dose AG with hydrocortisone, or low dose AG without hydrocortisone, delta 4 androstenedione was suppressed by 65%. This effect may contribute to optimal oestrogen suppression.

Aminoglutethimide↗
PubMed1985

Antagonism of aminoglutethimide and danazol in the suppression of serum free oestradiol in breast cancer patients.

The response rate of advanced postmenopausal breast cancer patients to treatment with aminoglutethimide (AG) + danazol was significantly worse than that with AG alone. The suppression of serum oestradiol levels by AG + danazol was similar to that by AG alone, but the combination treatment also suppressed sex hormone binding globulin (SHBG) levels and increased the % free oestradiol, whilst these parameters were unaffected by AG alone. The degree of suppression by AG + danazol of free oestradiol concentrations was less than the suppression of total oestradiol level and in some patients the concentration of the free fraction was increased above pretreatment levels. These effects on the presumed biologically active unbound fraction of oestradiol may explain the poor clinical response rate to AG + danazol.

Aminoglutethimide↗
PubMed1985

Effective inhibition by low dose aminoglutethimide of peripheral aromatization in postmenopausal breast cancer patients.

Aminoglutethimide without glucocorticoid has been shown to be a clinically effective treatment for postmenopausal breast cancer in low dosage (250 mg day-1). The mechanism of action of this approach is thought to be the inhibition of peripheral aromatase, the enzyme which converts androstenedione to oestrone. The activity of this enzyme was measured in vivo by injection with 3H-androstenedione and 14C-oestrone and found to be 0.20% +/- 0.05 in 5 patients on low dose AG therapy. In comparison with previously published data this demonstrates a 92% inhibition of peripheral aromatase activity confirming aromatase inhibition as a viable aim in the endocrine treatment of breast cancer.

Aged↗
PubMed1985

A comparison of the endocrine effects of low dose aminoglutethimide with and without hydrocortisone in postmenopausal breast cancer patients.

The endocrine effects of 125 mg (low dose) aminoglutethimide (AG) twice daily (b.d.) were compared with those of 125 mg AG + 20 mg hydrocortisone (HC) b.d. in 23 and 45 postmenopausal patients with advanced breast cancer, respectively. The patients in each group were drawn from two separate populations, but the mean age and weight of the groups were similar and there were no significant differences between the pretreatment serum levels of the hormones investigated. Serum oestrone and oestradiol levels were suppressed by both treatments, but there was a significantly greater suppression by AG + HC. This greater suppression is probably due to the observed increase in serum androstenedione (i.e. precursor) levels with AG alone, whilst with AG + HC these levels were found to be reduced. In terms of suppression of serum oestrogen levels it is of benefit to combine low dose AG with HC.

Adult↗