A new treatment for endometriosis.
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Administration, Cutaneous↗
Biomedical subjects
M Dowsett
Publications and source records attributed to M Dowsett.
Dose-related endocrine effects and pharmacokinetics of oral and intramuscular 4-hydroxyandrostenedione in postmenopausal breast cancer patients.
4-Hydroxyandrostenedione (CGP32349; 4-OHA) is a clinically effective treatment for advanced postmenopausal breast cancer by both the parenteral and p.o. routes, as a result of its inhibition of aromatase and consequent suppression of plasma estrogen levels. Thirty patients were randomized to treatment with 250 mg 4-OHA orally once, twice, and 4 times daily for 2 weeks and 29 of these plus a further 11 patients were then randomized to treatment with 250 or 500 mg i.m. every 2 weeks to determine the optimal dose for each route according to the suppression of serum estradiol levels. There was no significant difference between the 3 oral doses in their suppression of estradiol levels indicating that the maximum required p.o. dose of 4-OHA is probably 250 mg daily. Suppression by the parenteral dose of 250 mg every 2 weeks was marginally suboptimal but clinical considerations of response and tolerability indicate this as the optimal dose for i.m. injection. 4-OHA had no effect on serum levels of androstenedione, testosterone, or 5 alpha-dihydrotestosterone when given by either route but p.o. treatment with 4 doses of 250 mg daily reduced sex hormone-binding globulin levels by a mean of 34%. Serum levels of estrone as measured by gas chromatography-mass spectrometry were suppressed to approximately 40% of baseline by parenteral treatment. The half-life of 4-OHA p.o. was approximately 3 h, whereas the apparent half-life of injected drug was between 5 and 10 days after a more rapid clearance during the first 4 days after injection.
Administration, Oral↗
Chemoprevention of breast cancer.
The hypothesis that oestrogen is an important promoter of human breast cancer raises the possibility that endocrine intervention could prevent the disease. Various methods of reducing oestrogenic activity have been proposed including dietary control, progestin therapy, and ovarian ablation. Tamoxifen is a synthetic anti-oestrogen of low toxicity with proven anti-proliferative activity in endocrine sensitive breast cancer which makes it an attractive alternative for a trial of endocrine prevention. We have undertaken a double-blind placebo-controlled pilot study to assess the feasibility of mounting a large multicentre study of tamoxifen in the prevention of breast cancer in high risk women. Two hundred women were randomised to tamoxifen or placebo during an 18 month accrual period. Acute toxicity was mild and serial studies of blood lipids, clotting factors, and bone mineral density suggested that no long-term deleterious effects are likely to be seen. It is estimated that 10,000 women would be required with a 10-15 year follow up in order to detect a 25% prevention effect.
Adult↗
Lack of diurnal variation in plasma levels of androstenedione, testosterone, estrone and estradiol in postmenopausal women.
Plasma 4-en-androstenedione, testosterone, estradiol and estrone were measured during the day in six healthy postmenopausal women and in six breast cancer patients, three of whom received treatment with glucocorticoids. Blood samples were obtained at 8 a.m., 10 a.m., 12 noon, 4 p.m., 8 p.m. and 12 midnight. There was a considerable variation in plasma levels of all steroids during the day; for 4-en-androstenedione the mean within patient coefficient variation was 61.4%, for testosterone it was 28.9%, for estrone it was 17.8% and for estradiol it was 29.2%. While the plasma levels for all steroids tended to be higher in the morning than in the evening, the changes were not statistically significant (Friedman's test: P greater than 0.10). We conclude that although a moderate diurnal variation in the plasma level of these steroids may occur, it is of a moderate magnitude compared to variations due to other causes.
Androstenedione↗
Zoladex: endocrine and therapeutic effects in post-menopausal breast cancer.
The endocrine and therapeutic effects of the LHRH agonist Zoladex have been assessed in 28 post-menopausal women with advanced breast cancer. Fourteen had responded to previous hormone therapy and 14 had no previous hormone therapy. There were two partial responses and two patients with stable disease for more than 6 months in the former group, and one partial response and two with stable disease for more than 6 months in the latter group. Toxicity was minimal. All responses occurred in soft tissue. Six out of seven patients who received tamoxifen after progression of disease on Zoladex showed a response. Peripheral oestradiol levels were measured, and they fell after 1 month from 33 pmol l-1 (+/- 20, s.d.) to 22 pmol l-1 (+/- 11, s.d.) (P less than 0.005). Responders and non-responders showed similar changes in oestradiol. Oestrone levels did not change significantly. These results suggest that Zoladex acts indirectly via changes in peripheral hormones, rather than directly on LHRH receptors on the tumour.
Adult↗
Treatment of breast cancer with aromatase inhibitors--current status and future prospects.
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Aromatase Inhibitors↗
A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer.
Epidemiological and experimental evidence indicates that oestrogens are involved in the carcinogenic promotion of human breast cancer. We have undertaken a pilot trial of tamoxifen, an anti-oestrogen, compared to placebo given to 200 women at a high risk of developing breast cancer. The results of this trial show that acute toxicity is low and that accrual and compliance are satisfactory. Furthermore, biochemical monitoring of lipids and clotting factors indicate that tamoxifen may reduce the risk of cardiovascular deaths. At this stage no untoward long-term risks have been identified, and it is therefore proposed that a large multicentre trial should be started.
Adult↗
Use of luteinising hormone-releasing hormone agonist (leuprorelin) in advanced post-menopausal breast cancer: clinical and endocrine effects.
Fifteen post-menopausal patients with advanced breast cancer were treated with the LH-RH agonist leuprorelin (D-leu6-des-gly10-Gn-RH-ethylamide) given in a dosage of 7.5 mg as a monthly subcutaneous depot injection, to assess the clinical activity and endocrine response to treatment. None of the 15 patients showed an objective response to treatment, although four patients had stable disease for at least 6 months. No toxicity was demonstrated. Endocrine effects after 4 weeks' treatment were as follows: mean levels of serum gonadotrophins fell to 10% of their pretreatment values; there were no significant changes in the levels of prolactin on treatment; there was a significant decrease in the levels of serum testosterone in 12 out of 14 patients; there were no significant changes in the levels of oestradiol, androstenedione and oestrone. The lowering of serum testosterone suggests that androgens in post-menopausal women may be partly produced by the ovaries, stimulated by LH and FSH. This fall in testosterone may explain why some post-menopausal breast cancer patients in other studies have been reported to respond to treatment with LH-RH agonists, as it would decrease the substrate for the peripheral synthesis of oestrogens.
Aged↗
Endocrinology of Zoladex in postmenopausal women.
In the postmenopausal woman, low plasma oestrogen levels are due to the cessation of ovarian follicular activity, and residual oestrogen is thought to result from the adrenal glands and ovaries, both sources of androgens for peripheral oestrogen synthesis. In a study of 21 postmenopausal women with advanced breast cancer, Zoladex (goserelin), 3.6 mg depot, monthly, had no affect on the adrenal-derived androgens, but a direct effect on ovarian secretion of androgens is thought to have occurred. Thus, in such women, medical adrenalectomy is likely to produce an incomplete suppression of plasma androgens, but its combination with Zoladex may provide a new therapeutic option.
Androgens↗
Zoladex: therapeutic effects in postmenopausal breast cancer.
The endocrine and therapeutic effects of the luteinising hormone-releasing hormone (LHRH) analogue, Zoladex, have been assessed in 28 postmenopausal women with advanced breast cancer. Fourteen had responded to previous hormone therapy and 14 had received no previous hormone therapy. Zoladex treatment resulted in 2 partial responses and 2 patients with stable disease for more than 6 months in the former group, and 1 partial response and 2 with stable disease for more than 6 months in the latter group. Toxicity was minimal. All responses occurred in soft tissue disease. Peripheral oestradiol levels fell after 1 month of Zoladex from 33 pmol/l (+/- 20 SD) to 22 pmol/l (+/- 11 SD) (p less than 0.005) and both responders and nonresponders showed similar changes in oestradiol. Oestrone levels did not change significantly. Six out of 7 patients who received tamoxifen after progression of disease on Zoladex, showed a response. These results suggest that Zoladex acts indirectly via changes in peripheral hormone levels rather than directly on LHRH receptors on the tumour.
Adult↗
Three methods compared for estimating the fraction of testosterone and estradiol not bound to sex-hormone-binding globulin.
Here we propose and validate, both theoretically and experimentally, a new technique for measuring the percentage of non-sex-hormone-binding globulin (SHBG) bound to testosterone and estradiol. In this method, SHBG is saturated with 1 mumol of 5 alpha-dihydrotestosterone per liter and the non-protein-bound fraction is subsequently measured in treated and untreated samples by centrifugal ultrafiltration dialysis (CUFD). We compared this technique with two previously published methods for measuring the percentage of albumin-bound steroid--ammonium sulfate precipitation and heat denaturation of SHBG followed by CUFD--and also with previously published computer predictions. The ammonium sulfate precipitation gave results closest to the computer-predicted percentage of albumin-bound testosterone and estradiol. Of the two techniques involving CUFD, the 5 alpha-dihydrotestosterone saturation method was the more reproducible. Results by both CUFD methods were higher than the computer-based predictions for albumin-bound steroid in pregnancy serum, in part perhaps because the CUFD measurements represent the non-SHBG-bound fraction rather than that which is albumin-bound alone.
Ammonium Sulfate↗
Aromatase inhibitors as new endocrine therapy for breast cancer.
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Animals↗
The inhibitory effects of danazol, danazol metabolites, gestrinone, and testosterone on the growth of human endometrial cells in vitro.
Danazol and gestrinone are effective drugs in the treatment of endometriosis. Their mechanism of action remains uncertain, but may be related to their androgenic activity. The authors examined the effect of danazol on human endometrial cells cultured in vitro, its two major metabolites, ethisterone and 2 hydroxymethyl ethisterone, gestrinone, and testosterone (T) at 1X and 10X expected plasma concentrations. Danazol and T suppressed growth by 20.8 and 25.0% (P less than 0.01), respectively, at the lower dose, and by 26.9 and 35.5% (P less than 0.01), respectively, at the 10-fold higher dose. No significant suppression of growth occurred with gestrinone, ethisterone, or 2 hydroxymethyl ethisterone. The results provide further evidence that danazol and T (but not gestrinone) may act by a direct effect on endometrial tissue.
Cell Division↗
The pharmacokinetics of medroxyprogesterone acetate following two different loading dose schedules in advanced carcinoma of the breast.
A loading dose of MPA employing a regimen of 1,000 mg six hourly for 8 doses can achieve plateau levels above 100 ng ml-1 within the first 36 h of treatment, without any untoward toxicity. This raises the possibility of shortening the time to response for this agent. The additional factor of the time required to achieve adequate serum levels may explain the apparent contradictions between reports correlating response rates and dose and those correlating serum level and response.
Antineoplastic Agents↗
High dose ketoconazole: endocrine and therapeutic effects in postmenopausal breast cancer.
Ketoconazole, an antifungal agent, inhibits in vitro C17-C20 lyase, an enzyme involved in androgen biosynthesis. Since adrenal and ovarian androgens are the main precursors of oestrogens in postmenopausal women, the endocrine and therapeutic effects of high dose ketoconazole (400 mg three times a day) were evaluated in 14 postmenopausal women with advanced breast cancer. Testosterone levels were suppressed significantly (37%, P less than 0.025), as was dehydroepiandrosterone sulphate, and androstenedione levels showed a similar but non-significant fall. Seventeen hydroxyprogesterone levels rose significantly, as would be expected if C17-C20 lyase was inhibited. There was no suppression of cortisol or oestrone levels. There was a small suppression of oestradiol concentrations, reflecting a decrease in its precursor, testosterone. Sex hormone binding globulin levels rose, which may be due to a decrease in testosterone. All the changes are compatible with C17-C20 lyase as a major site of action in vivo. No responses occurred in 12 patients treated with ketoconazole alone, but in 2 patients who were progressing on aminoglutethimide, testosterone levels were suppressed and in one patient a partial response occurred. Ketoconazole was poorly tolerated due to gastrointestinal toxicity. This study shows that C17-C20 lyase is a potential target for hormone therapy, and that sequential blockade of enzymes involved in oestrogen biosynthesis should be further evaluated.
17-alpha-Hydroxyprogesterone↗
The effects of aminoglutethimide and hydrocortisone, alone and combined, on androgen levels in post-orchiectomy prostatic cancer patients.
Aminoglutethimide has been used in combination with hydrocortisone in patients with advanced prostatic cancer with the rationale that it causes a 'medical adrenalectomy'. Both objective and subjective responses have been recorded. We have examined the effect of AG and HC alone and in combination on plasma androgen levels throughout the day in two studies on 11 such patients. Whilst AG combined with HC led to a significant suppression of both testosterone and androstenedione levels, the suppression with HC alone was significantly greater, indicating that any beneficial clinical effects of AG in these patients is not due to its suppression of adrenal androgen secretion.
Aged↗
Oestradiol assays: applications and guidelines for the provision of a clinical biochemistry service.
This paper reports on the provision of a clinical biochemistry service for serum oestradiol. The pathophysiology and recognised applications of oestradiol assays are discussed and the current availability of assay reagents and methodologies reviewed. Data are presented on the analytical performance of assays for serum oestradiol in the UK External Quality Assessment Scheme (UKEQAS) and general guidance is offered to laboratories providing a diagnostic service for this analyte.
Adult↗
Suppression of postmenopausal ovarian steroidogenesis with the luteinizing hormone-releasing hormone agonist goserelin.
Twenty-one postmenopausal women with advanced breast cancer were treated with monthly 3.6-mg sc injections of the LHRH agonist goserelin [D-Ser-(But)6, Azgly10-LHRH] to determine whether the resultant endocrine changes could provide an explanation for the clinical responses that occur during therapy with this agent. After 4 weeks, serum gonadotropin levels were less than 10% of pretreatment levels, whereas serum PRL levels did not change. A significant decrease in serum testosterone occurred in 19 of 20 patients; this fall was associated with a 22% fall in serum estradiol levels. Serum androstenedione levels also decreased, but serum estrone and dehydroepiandrosterone sulfate (DHAS) levels did not. The lack of fall in serum DHAS levels indicates that the changes in androgen levels were a result of reduced ovarian secretion, and the reduced estradiol levels were a consequence of reduced precursor (i.e. testosterone) availability. The continued dependence of ovarian androgen secretion on gonadotropin stimulation after the menopause may explain the responses of some patients to LHRH agonists and some other therapeutic agents of unknown or uncertain modes of action.
Aged↗