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

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

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

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

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

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

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

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

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

In vivo ultrasound guided transvaginal oocyte collection in the cow

Στην εργασία αυτή περιγράφονται οι τεχνικές και παρουσιάζονται τα αποτελέσματα της in vivo διακολπικής συλλογής ωαρίων από 8 αγελάδες, κατά τη διάρκεια τριών διαδοχικων οιστρικών κύκλων με συσκευή μικροαναρρόψησης υπό την καθοδήγηση υπερηχογράφου. Σε τέσσερις αγελάδες μάρτυρες γινόταν μονό διακολπική επισκόπηση των ωοθηκών με υπερηχογραφία. Τα ζώα ήταν ηλικίας 4-6 ετών και βρίσκονταν σε κατάσταση μη εγκυμοσύνης και παρατεταμένη ξηρά περίοδο. Η συλλογή των ωαρίων γινόταν τρεις φορές κατά τη διάρκεια κάθε φυσιολογικού οιστρικού κύκλου (ημέρες 3-4, 9-11 και 14-17). Αναρροφήθηκε το περιεχόμενο 326 ωοθυλακίων διαμέτρου 4 -15 mm και συλλέχθηκαν 1Θ4 ωάρια (31,9%) ή 1.55 ωάρια ανά αγελάδα σε κάθε αγωγή. Το ποσοστό συλλογής αυξήθηκε μετά τους τρεις πρώτους πειραματισμούς (από 13,04% σε 35,0%). Σε τέσσερις πειραματισμούς το ποσοστό συλλογής κρίνεται πολύ ικανοποιητικό (41,6% έως 52,6%). Περισσότερα ωοθυλάκια ( 133 ή 40,8%) αναρροφήθηκαν στις ημέρες 9-11 έναντι 111 (34%) στις ημέρες 14-17 και 82 (25%) στις ημέρες 3-4 (Ρ<0.05). Από τα 104 ωάρια που συλλέχθηκαν τα 60 (57,7%) κρίθηκαν κατάλληλα για περαιτέρω χειρισμούς. Το ποσοστό συλλογής και η ποιότητα των ωαρίων δεν επηρεάσθηκαν σημαντικά από το στάδιο του οιστρικού κύκλου και τη θέση (αριστερά - δεξιά) της ωοθήκης. Η διάρκεια του οιστρικού κύκλου των πειραματόζωων (21,6±.1,4 ημέρες) και των μαρτύρων (22,37±1,0), όπως επίσης και οι συγκεντρώσεις της προγεστερόνης σε δείγματα αίματος που συλλέγονταν καθημερινά δεν παρουσίασαν σημαντική διαφορά μεταξύ των ζώων των δύο ομάδων. Τα αποτελέσματα της εργασίας συγκρίνονται με τα αποτελέσματα εφαρμογής λαπαροσκοπικών μεθόδων και γίνεται αναφορά στη σκοπιμότητα και στις δυνατότητες εφαρμογής της μεθόδου σε προγράμματα γενετικής βελτίωσης των αγελάδων.This paper describes the results of the in vivo ultrasound guided follicular aspiration for ovum pick υρ (OPU) in the cow. Twelve non pregnant dry cows aged 4-6 years were used in this experiment. Eight cows underwent OPU during three successive oestrous cycles and another four cows were used as controls having only transvaginal ultrasound scanning of their ovaries. Oocyte collection took place three times during the luteal phase of each natural oestrous cycle (days 3-4,9-11 and 14-17). The content of 326 follicles with a diameter of 4-15mm was aspirated and 104 oocytes were collected (recovery rate 31.9% or 1.55 oocytes per cow and session). The oocyte recovery rate increased after the first three sessions (from 13.04% to 35.0%) and reached levels of υρ to 52.6%. More follicles were aspirated on days 9-11 (133 follicles 40.8%) compared to 111 (34%) follicles on days 14-17 and 82 (25%) on days 3-4) (P<0.05). The evaluation of the collected oocytes revealed that 60 oocytes (57.7%) were suitable for further in vitro manipulation. Neither the origin of the oocyte (left or right ovary) nor the stage of the oestrous cycle affected the recovery rate or the quality of the collected oocytes. There was no significant difference either in the length of the oestrous cycle between the experimental animals and the controls (21.6± 1.4 vs. 22.37±1.0 respectively), or in plasma progesterone concentration in daily collected blood samples from the animals of the two groups. The results of this study are compared to those from the international literature and to the results from endoscopical methods for oocyte recovery. The feasibility of application of this technique to projects designed to improve the genetic merit of cows is discussed