cosyntropin and Breast-Neoplasms

The pharmacologic inhibition of aromatase activity has been the focus of clinical trials in patients with advanced stage breast cancer. Recent developments with imidazole compounds that inhibit aromatase activity suggest their clinical use as potent inhibitors of estrogen biosynthesis in postmenopausal breast cancer patients. In this Phase I, open-label, dose-range finding study, we examined the inhibitory potency of CGS 20267 on blood and urine levels of estradiol, estrone and estrone sulfate in 8 patients with metastatic breast cancer. Studies included evaluation of adrenal and thyroid function to look for evidence of general hydroxylase inhibition at dose levels effective for aromatase blockade. Patients were administered CGS 20267 at doses of 0.1 and 0.25 mg, once a day in ascending doses over a 12-week period. Preliminary data reveal that CGS 20267 elicits a striking suppression in plasma estradiol, estrone and estrone sulphate which was observed in some patients as quickly as within 24 h of the first dose. Estrogen suppression of over 90% was achieved within 2 weeks of therapy. No alterations in either baseline or ACTH (cortrosyn) stimulated cortisol and aldosterone levels were observed through the 12 weeks of therapy. In addition, 24 h urine sodium and potassium values were not appreciably altered during therapy. We conclude that CGS 20267 is a potent, specific inhibitor of estrogen biosynthesis in postmenopausal patients with metastatic breast cancer and effectively reduces blood and urine estrogens to undetectable levels.

Topics: Aldosterone; Anti-Inflammatory Agents, Non-Steroidal; Aromatase Inhibitors; Breast Neoplasms; Cosyntropin; Estradiol; Estrogens; Estrone; Female; Humans; Hydrocortisone; Letrozole; Neoplasm Staging; Nitriles; Potassium; Sodium; Time Factors; Triazoles

0.5 mg tetracosactrin is considered to be equivalent to 40 mg methylprednisolone with regard to the induced cortisol secretion. 97 female breast cancer patients who received their first two FEC courses (epirubicin 50-75 mg/m2, 5-fluorouracil 500 mg/m2, cyclophosphamide 500 mg/m2) entered this randomised crossover study (76 had previously received an adjuvant treatment); tetracosactrin was administered intramuscularly and methylprednisolone intravenously immediately before chemotherapy administration. The tolerability was evaluated using a diary card during 5 days and patients were asked for their preference at the end of the two cycles. There was no difference either for vomiting (dry heaves were included) or nausea between the two treatments (the analysis was performed on day 1, the worse day of days 2 and 3 and the worse day of days 4 and 5). At day 1, 49% of the patients experienced no or mild nausea after tetracosactrin and 62% after methylprednisolone (not significant) (first period analysis); a complete control of vomiting (including dry heaves) was observed in 49% of the patients after tetracosactrin and 53% after methylprednisolone (not significant). No difference was observed between patients with or without previous chemotherapy. However, slightly more patients preferred tetracosactrin (P = 0.048).

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cosyntropin; Cyclophosphamide; Epirubicin; Female; Fluorouracil; Humans; Methylprednisolone; Nausea; Quality of Life; Vomiting

Adrenal suppression has been noted in patients who are receiving medroxyprogesterone acetate (MPA). Megestrol acetate (MA) is used to treat patients with advanced breast carcinoma, cachaexia related to acquired immune deficiency syndrome, and disseminated carcinomatosis, and it is believed to have fewer side effects than MPA. The aim of this study was to test for secondary adrenal suppression in patients receiving MA therapy for advanced metastatic cancer.. Ten postmenopausal female patients receiving long term MA therapy, nine with advanced metastatic breast carcinoma and one with metastatic ovarian carcinoma, were recruited consecutively from the oncology outpatient clinic at Ninewells Hospital in Dundee, Scotland. A short synacthen test and a corticotrophin-releasing hormone (CRH) stimulation test were performed on two separate occasions. Urine collection for 24-hour urinary free cortisol was performed on 6 patients. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and free thyroxine (T4) were measured in eight patients. An insulin stress test (IST) was performed on two patients.. Nine of 10 patients had a poor cortisol response to the short synacthen test. The CRH test had abnormal results in eight of nine patients. In all patients tested, 24-hour urinary free cortisol excretion was low, indicating adrenal suppression. Basal serum FSH, LH, TSH, and free T4 values indicated normal pituitary function. Adrenocorticotrophic hormone response in the CRH test varied and is discussed in this article.. MA causes secondary adrenal suppression that is thought to be due to its effect at the hypothalamic level. The authors recommend a short course of steroid replacement for patients receiving MA at times of acute illness.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Aged; Antineoplastic Agents; Breast Neoplasms; Corticotropin-Releasing Hormone; Cosyntropin; Female; Humans; Hydrocortisone; Hypoaldosteronism; Hypothalamo-Hypophyseal System; Megestrol Acetate; Middle Aged; Ovarian Neoplasms; Pituitary-Adrenal System

To investigate the mechanism of adrenal suppression by high-dose MPA, we performed direct and indirect stimulation tests in postmenopausal women with disseminated breast cancer who were receiving MPA and in a postmenopausal breast cancer control group. A partial adrenal insufficiency was found during Synacthen stimulation, confirmed by a slight increase of 11-desoxycortisol after metyrapone, despite a sufficient rise in ACTH levels. Peak levels of androstenedione and 17-OH progesterone after Synacthen correlated with those after metyrapone. Peak cortisol levels after Synacthen also correlated with the sum of cortisol and 11-desoxycortisol values after metyrapone, indicating the presence of a maximum adrenal response and a sufficient rise of endogenous ACTH after metyrapone. As the peak levels of cortisol and androstenedione were highly correlated with baseline values, a short Synacthen stimulation test may give a good indication as to whether adrenal suppression by MPA is adequate. The adrenal androgen androstenedione is the precursor of the main postmenopausal oestrogen, oestrone. In this way, adrenal suppression may constitute an important therapeutic effect of high-dose MPA.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Insufficiency; Aged; Androstenedione; Breast Neoplasms; Cosyntropin; Female; Humans; Hydrocortisone; Hydroxyprogesterones; Medroxyprogesterone; Medroxyprogesterone Acetate; Metyrapone; Middle Aged

In postmenopausal women estrogens are mainly produced by aromatase mediated conversion of adrenal 4-ene-steroids in peripheral tissue, a process which is inhibited by aminoglutethimide (AG). To assess possible fluctuations in adrenocortical steroid secretion and the impact on plasma estrogen levels the effect of physiological ACTH doses was studied in 24 postmenopausal women with advanced breast cancer treated with AG 4 X 250 mg and hydrocortisone 2 X 10 + 1 X 20 mg daily. Synthetic 1-24 ACTH (Synacthen) 0.5 mg was injected i.m. at 8.30 a.m. (t0), 10 h after the last AG + hydrocortisone dose. A definite decrease of t0 levels of the 5-ene-steroids dehydroepiandrosterone and its sulphate, and androstenediol was found at 1 month, with no further decrease at 2 months. 5-Ene-steroids responded decreasingly to ACTH under treatment. The 4-ene-steroids progesterone, androstenedione and testosterone, before and after ACTH were not suppressed by 1 or 2 months of treatment. Basal (t0) cortisol remained normal. Cortisol response to ACTH (delta max) was drastically diminished, but still present. Plasma estrogens were decreased. Estradiol (E2) at t0, being low from the start, fell by 50%. Estrone (E1) at t0 dropped to 30%. ACTH had measurable influence on E2, but did cause a transient increase of E1 (mean delta max 40% of baseline value) under treatment. The following conclusions are drawn: Treatment with AG + hydrocortisone for postmenopausal breast cancer reduces plasma estrogens, particularly E1. Plasma E1 reduction is not stable as demonstrated by the response to a physiological ACTH dose. The responses of 4-ene-steroids to ACTH are not affected by treatment, except for the response of cortisol which is significantly diminished.

Topics: Adrenocorticotropic Hormone; Aminoglutethimide; Breast Neoplasms; Cosyntropin; Drug Therapy, Combination; Estrogens; Female; Humans; Hydrocortisone; Menopause; Neoplasms, Hormone-Dependent; Radioimmunoassay; Steroids

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.

Topics: 17-alpha-Hydroxyprogesterone; Adult; Aged; Aminoglutethimide; Androstenedione; Breast Neoplasms; Cosyntropin; Dehydroepiandrosterone; Drug Administration Schedule; Drug Therapy, Combination; Estrone; Female; Hormones; Humans; Hydrocortisone; Hydroxyprogesterones; Menopause; Middle Aged