Biomedical subjects

M Dowsett

Publications and source records attributed to M Dowsett.

At least 253 records · Page 14Linked to original sources

PubMed1985

Oestrogen-related changes in sex hormone binding globulin levels during normal and gonadotrophin-stimulated menstrual cycles.

Previous studies have identified no consistent change in sex hormone binding globulin (SHBG) levels during normal menstrual cycles. This is despite marked cyclical changes in plasma oestradiol concentration, and the observation that SHBG level increases in pregnancy, and after administration of exogenous gonadotrophin or synthetic oestrogens. The level of SHBG was measured in 19 normal females at 2 d intervals from day -8 to +10 where the preovulatory peak of oestradiol was designated as occurring on day 0. SHBG levels increased by a mean 15% +/- 4 (SEM) between the follicular and luteal phases (P less than 0.001) and this was due entirely to an increment between day 0 and +2. The change in SHBG levels was correlated with the change in oestradiol levels between days -8 and 0 (P less than 0.001). Fifty-six infertile patients were also studied. Twenty-seven received Pergonal alone whilst the other 29 received Pergonal after a preceding 5 d on Clomid. In both groups peak preovulatory oestradiol levels were greater than 3 times higher than in normal cycles. SHBG levels showed no change in the follicular phase but rose markedly during the luteal phase. These increases were significantly correlated with peak preovulatory oestradiol concentration but showed no relationship with mid-luteal progesterone concentration. We conclude that supranormal levels of oestradiol cause marked increases in SHBG binding capacity and increases in SHBG level of a lower order occur shortly after the preovulatory peak of oestradiol in the normal menstrual cycle.

Clomiphene↗

PubMed1985

Endocrine effects of low dose aminoglutethimide as an aromatase inhibitor in the treatment of breast cancer.

The endocrine effects of low dose (62.5 mg, twice a day) aminoglutethimide (AG), without hydrocortisone (HC), escalating at monthly intervals to a conventional dose of AG (500 mg twice a day) combined with HC, were studied in 33 postmenopausal breast cancer patients. Pretreatment serum concentrations of oestrone (E1) and oestradiol (E2) were significantly suppressed by 62.5 mg of AG twice a day. Although further suppression of E1 appeared to occur with 125 mg of AG twice a day, this was not statistically significant. For E1 and E2, higher doses of AG or combined AG and HC failed to cause further significant suppression compared with that obtained at 125 mg of AG twice a day. Significant rises in serum androstenedione were found with all doses of AG alone, although pretreatment concentrations of androstenedione were not significantly altered by combined AG and HC treatment. Mean pretreatment concentrations of dehydroepiandrosterone sulphate (DHA-S) were significantly suppressed by 62.5 mg of AG twice a day and further marked suppression occurred on combined AG and HC therapy. Serum cortisol, aldosterone and plasma ACTH concentrations showed no significant alterations throughout treatment. Aminoglutethimide is as effective at 125 mg twice a day without HC in its suppression of oestrogen levels as at 500 mg twice a day with HC, and its use in this form warrants clinical evaluation.

Adrenocorticotropic Hormone↗

PubMed1985

Spironolactone in combination with an oral contraceptive: an alternative treatment for hirsutism.

The clinical efficacy of a combination of spironolactone and an oral contraceptive pill (Conova 30) was assessed in 23 patients presenting with hirsutism of whom 20 completed 6 months of treatment. Of the 20 patients, 16 showed improvement on objective (Ferriman & Gallwey hair score) and subjective assessment. Serum levels of androgens (testosterone, androstenedione and 17-hydroxy progesterone) were suppressed and sex hormone binding globulins were elevated. Nausea was the only significant side effect.

Contraceptives, Oral, Combined↗

PubMed1984

4-Hydroxyandrostenedione in treatment of postmenopausal patients with advanced breast cancer.

4-hydroxyandrostenedione, a potent inhibitor of the aromatase (oestrogen synthetase) system, was given to 11 patients with metastatic breast cancer. After a single 500 mg intramuscular injection a sustained reduction of serum oestradiol was observed for at least 1 week in all patients in whom the steroid was measured. 4 patients responded to treatment for periods of up to 4 months, and healing of bone metastases and reduction in size of soft-tissue metastases was evident. The only side-effects were pain at the injection site and hot flushes. 4-hydroxyandrostenedione is a new and specific aromatase inhibitor which shows promise in the treatment of patients with metastatic breast cancer.

Adult↗

PubMed1984

Low-dose aminoglutethimide in treatment of advanced breast cancer.

The clinical and endocrine effects of low-dose aminoglutethimide without hydrocortisone in patients with advanced breast cancer were investigated. In a dose escalation study low-dose aminoglutethimide alone (62.5-125 mg twice daily) was as effective as conventional doses with hydrocortisone in lowering serum oestrone and oestradiol concentrations but caused minimum adrenal inhibition, as assessed by serum dehydroepiandrosterone sulphate. 11 of 57 (19%) evaluable patients had tumour regression by objective criteria on this treatment, but the frequency of side-effects was similar to that with conventional doses. Low-dose aminoglutethimide is active in the treatment of breast cancer. It appears to work by inhibition of the aromatase enzyme system in peripheral tissues rather than adrenal suppression.

Adrenal Glands↗

PubMed1984

Validation and use of centrifugal ultrafiltration-dialysis in the measurement of percent free oestradiol in serum.

The validity of the centrifugal ultrafiltration-dialysis method in the measurement of the percentage of oestradiol and testosterone which is not bound to protein (free) in human serum was assessed. In an initial validation, the values of % free steroid obtained for oestradiol and testosterone in protein-free ultrafiltrates of human serum were higher than expected. Filter paper discs used in the system were shown to adsorb [3H]oestradiol from protein-free solution. Their replacement with glass-fibre discs, which did not adsorb oestradiol, decreased but did not eliminate the discrepancy between observed and expected results for % free oestradiol in ultrafiltrates. The use of polyethylene rather than polypropylene vials then reduced the discrepancy to insignificant levels. The estimates for % free oestradiol in serum were reduced by these modifications.

Centrifugation, Density Gradient↗

PubMed1984

Hydrocortisone alone vs hydrocortisone plus aminoglutethimide: a comparison of the endocrine effects in postmenopausal breast cancer.

The endocrine effects of replacement doses of hydrocortisone in postmenopausal women with advanced breast cancer were compared with the same doses of hydrocortisone plus aminoglutethimide. Fifteen patients received aminoglutethimide (AG) 250 mg three times a day plus hydrocortisone (HC) 20 mg twice a day for 2 weeks, then AG was increased to 250 mg four times a day. Another 13 patients received HC alone for 2 weeks, then AG was added. HC alone significantly suppressed oestrone (75% of baseline) and oestradiol (50% of baseline). Addition of AG to these patients produced further oestrone suppression (50% of baseline) significantly greater than HC alone. HC alone suppressed dehydroepiandrosterone sulphate as much as AG + HC. delta 4-androstenedione (delta 4A) and dehydroepiandrosterone (DHA) were suppressed by HC alone. Addition of AG produced a rise of delta 4A to basal levels. These results show that 3-beta-ol de hydrogenase is not induced by AG. AG plus HC together from day 1 produced significantly greater oestrone suppression (50% of baseline) than HC alone. Because high-dose steroids may induce aromatase and replacement doses produced marked peripheral endocrine effects, the use of replacement hydrocortisone should be reassessed in advanced breast cancer.

Aminoglutethimide↗

PubMed1984

Endocrine and clinical consequences of combination tamoxifen-aminoglutethimide in postmenopausal breast cancer.

By analogy with combination chemotherapy, endocrine agents with different mechanisms of action have been combined in the treatment of patients with advanced breast cancer. The clinical use of tamoxifen+aminoglutethimide+hydrocortisone showed no clinical benefit over the individual use of tamoxifen or aminoglutethimide+hydrocortisone. The endocrine changes occurring in postmenopausal patients as a consequence of their treatment with tamoxifen+aminoglutethimide+hydrocortisone have been examined. Suppression of gonadotrophin and oestrogen levels and increased levels of sex hormone binding globulin were observed. These changes might be expected to be of benefit in the treatment of advanced breast cancer, and do not explain the lack of clinical benefit in combining the treatments. Non-responders to this combination therapy had higher levels of oestrone and dehydroepiandrosterone sulphate whilst on treatment than responders, confirming previous observations in patients treated with aminoglutethimide+hydrocortisone.

Aminoglutethimide↗

PubMed1984

Response to aminoglutethimide and cortisone acetate in advanced prostatic cancer.

Forty patients with metastatic adenocarcinoma of the prostate were evaluated for response to treatment with aminoglutethimide plus cortisone acetate. All had relapsed from or failed to respond to primary endocrine treatment with orchidectomy or stilboestrol. Nineteen patients (48%) showed subjective response, in most cases relief of bone pain. Side effects limited treatment in only 3 patients. We conclude that aminoglutethimide plus cortisone acetate is a useful addition to the treatment available for this difficult group of patients. The mechanism by which this treatment has a beneficial effect remains unclear.

Adenocarcinoma↗

PubMed1984

Absence of prolactin receptors in normal and malignant uterine cervix.

Bromocriptine has been found to be an effective agent in the treatment of advanced cancer of the uterine cervix, and it was thus possible that the tumours were prolactin-dependent. A prolactin receptor assay was established and validated, but no receptors were found in cervical tissue whether normal or with benign or malignant disease. It is unlikely that cervical tumours are prolactin-dependent.

Animals↗

PubMed1984

Endocrine effects of danazol in the treatment of endometriosis.

The effects of danazol therapy on circulating gonadotrophins, oestradiol and sex hormone-binding globulin (SHBG) binding capacity have been studied in eight patients with endometriosis. There was a significant rise in luteinizing hormone (LH) in the first week of treatment with a fall in oestradiol levels. There was a marked fall in SHBG in the first week which continued up to 4 weeks. It is concluded that danazol is not 'anti-gonadotrophic' as frequently claimed and that its therapeutic actions, side effects and the endocrine changes could be explained by an effect on SHBG production. The rationale of its use in other conditions requires reconsideration.

Adult↗

PubMed1984

Endocrine changes associated with relapse in advanced breast cancer patients on aminoglutethimide therapy.

About one third of unselected postmenopausal women with advanced breast cancer respond to treatment with aminoglutethimide and hydrocortisone, but they all eventually relapse, and further progression of disease occurs. In this study, 36 patients who initially responded to this treatment were evaluated to determine whether clinical relapse was associated with escape from endocrine suppression. Plasma estrone levels rose significantly (mean increase, 6.8 pg/ml) during the final 15% of time on treatment before relapse. Mean plasma estradiol, dehydroepiandrosterone sulfate, and androstenedione levels also rose with the approach of the relapse, but the increases were not statistically significant. The increase in estrone may contribute to the progression of disease.

Aminoglutethimide↗

PubMed1983

Aminoglutethimide dose and hormone suppression in advanced breast cancer.

The effect of the dose of aminoglutethimide on the suppression of oestrone, oestradiol and dehydroepiandrosterone sulphate (DHAS) levels was studied in 36 women with advanced postmenopausal breast cancer, all of whom received 20 mg hydrocortisone twice daily as replacement glucocorticoid. Aminoglutethimide (AG) 250 mg twice a day was as effective as AG 250 mg 3 times a day or AG 250 mg 4 times a day. Side-effects were less at the lowest dosage and were age-related. On-treatment oestrone levels were higher in non-responders to treatment. Lower doses of AG than are currently used may be as effective therapeutically.

Adult↗

PubMed1983

Endocrine effects of low dose aminoglutethimide alone in advanced postmenopausal breast cancer.

The site of action of aminoglutethimide (AG) has been investigated. An initial study was performed on 10 postmenopausal patients with advanced breast cancer who had taken 1000 mg AG per day and 20 mg hydrocortisone (HC) twice daily (b.d.) for greater than 3 months. There was a 15.5 +/- 5.6 s.e.-fold rise in 17-OH progesterone and a 4.9 +/- 0.9 s.e.-fold rise in 4 delta androstenedione but no rise in cortisol or oestrone 30 min after short Synacthen tests. These results suggested that peripheral aromatisation was a more important site of AG action than adrenal desmolase, and that adrenal 11 beta hydroxylase was inhibited. Since aromatase is more sensitive than desmolase to AG in vitro, lower doses of AG alone (i.e. without HC) were assessed for endocrine effects in 13 further post-menopausal women with advanced breast cancer. All of these patients tolerated 125 mg AG b.d., but 3 could not tolerate the conventional maximum dose. Oestrone levels on 125 mg AG b.d. were suppressed below pretreatment levels and were not significantly different from those on 500 mg AG b.d. alone, or with the addition of HC. Oestradiol levels were suppressed to a similar extent. Dehydroepiandrosterone sulphate (DHA-S) levels were not suppressed by AG alone, but fell on addition of HC. The endocrine results show low dose AG alone is an effective and well tolerated inhibitor of the peripheral production of oestrogens in postmenopausal patients. Therapeutic trials are now possible. DHA-S is not a marker of AG effect.

17-alpha-Hydroxyprogesterone↗

PubMed1983

Prognostic significance of serum prolactin levels in advanced breast cancer.

Serum prolactin concentrations were measured in 135 postmenopausal patients with advanced breast cancer prior to their treatment with one of 3 endocrine therapies: aminoglutethimide (AG), tamoxifen (T) + AG, or T + AG + danazol. The mean level of prolactin was higher, and there were more individuals with levels of prolactin greater than or equal to 500 mIUl-1, in the group of patients who did not respond to treatment. Of the patients whose disease progressed, those with prolactin levels greater than or equal to 500 mIUl-1 had a significantly shorter survival. It appears that high prolactin levels indicate a poor prognosis to endocrine therapy and the probability of a shorter than average survival time.

Aminoglutethimide↗

PubMed1983

Aminoglutethimide induced hormone suppression and response to therapy in advanced postmenopausal breast cancer.

Eighty-one postmenopausal women with advanced breast cancer were studied for the effects of treatment with aminoglutethimide (AG) plus hydrocortisone on peripheral hormones and response to therapy. There were 40 responders (R) and 41 non-responders (NR) at 3 months from the start of treatment. Plasma oestrone concentrations were higher in non-responders at 1 and 2 months after starting AG (Means: NR 106 +/- 50, R 84 +/- 26 pmol l-1, P less than 0.05; highest value NR 121 +/- 51, R 99 +/- 24 pmol l-1, P less than 0.05). High oestrone levels were correlated with bulky liver secondaries, but not with age, tumour-free interval, time from last menstrual period, time from relapse to start of AG or body weight. Non-responders had higher mean prolactin levels on treatment (prolactin less than 500 mIUl-1 in 14/40 NR, 2/35 R, P less than 0.01). High oestrone or prolactin levels were present in 28/41 NR and 6/40 R (P less than 0.001). Dehydroepiandrosterone sulphate suppression did not differ between R and NR. The differences in peripheral endocrine environment in non-responding patients suggest that oestrogen metabolism may differ in non-responding patients and that sub-groups could be selected for rational endocrine therapy.

Adult↗

PubMed1982

Effects of endocrine therapy on steroid-receptor content of breast cancer.

In order to determine the mechanisms of relapse following response to endocrine therapy, we have measured the oestrogen receptor (RE) content of biopsies of breast cancer in patients receiving various types of endocrine treatment. RE content fell in responding (means of 260.2 to 12 fmol/mg protein) and in nonresponding (means of 155.1 to 31.8 fmol/mg protein) patients who had measurable receptor at the start of treatment. Some of these patients, and a further group of responders to endocrine therapy, were monitored until relapse. Tumour biopsies at the time of relapse showed that 10/14 tumour samples contained significant RE (mean of 86.7 fmol/mg protein; range less than 10-271 fmol/mg protein) after successful endocrine therapy. No relationship could be found between RE content and plasma gonadotrophin or steroid-hormone concentration, but the fall in RE content correlated with reduced numbers of tumour cells in the biopsy. These results indicate that relapse following successful endocrine therapy in breast cancer does not appear to be due to the emergence of RE-negative tumour cells. The fall in RE content during response to endocrine therapy may be due to reduced tumour-cell content of the biopsy.

Adult↗

PubMed1982

Endocrine and therapeutic effects of aminoglutethimide in premenopausal patients with breast cancer.

Aminoglutethimide in combination with hydrocortisone provides an effective therapy in postmenopausal advanced breast cancer patients, with response rates of 37.5--50% having been found. Treatment with aminoglutethimide of only four premenopausal breast cancer patients has been reported in which two patients responded. The clinical and endocrine effects of 1000 mg aminoglutethimide daily and 20 mg hydrocortisone twice daily were studied in 18 premenopausal patients with breast cancer. Eight patients developed menstrual abnormalities, but there were no objective tumor responses in the 14 patients with assessable disease. Adrenal suppression was produced in all patients, with dehydroepiandrosterone sulfate levels suppressed to 20% of baseline values. Estrone and estradiol levels were not suppressed into the postmenopausal range. However, the therapeutic regime resulted in suppression of estrogen peaks after Pergonal administration, thus demonstrating a partial block of ovarian estrogen synthesis.

Adult↗