Combined treatment with 4-hydroxyandrostenedione and aminoglutethimide: effects on aromatase inhibition and oestrogen suppression.

The effects of a combination of aminoglutethimide (AG) 1,000 mg daily and 4-hydroxy-androstenedione (4OHA) 500 mg i.m. weekly on peripheral aromatase activity as measured by in vivo radioisotopic tracer methodology and serum oestrogen suppression were investigated in ten post-menopausal women with advanced breast cancer. Patients were treated for a minimum of 4 weeks with 4OHA before addition of AG for a minimum of 6 weeks. Aromatase inhibition was found to be nearly identical in the two treatment situations (92.5 +/- 4.7% and 93.8 +/- 3.8% respectively). There was no further significant suppression of plasma oestradiol or plasma oestrone levels when AG was added to 4OHA treatment (mean decrease of 7.6 +/- 12.1% and 2.8 +/- 12.0% respectively). In contrast, adding AG caused a further suppression of plasma oestrone sulphate (Oe1S) compared with 4OHA monotherapy (mean suppression of 35.2 +/- 9.1%, P < 0.025). This effect on Oe1S may be due to an influence of AG on oestrogen metabolism.     

Plasma and urinary oestrogens in breast cancer patients on treatment with 4-hydroxyandrostenedione.

Plasma and urinary oestrogens were measured in nine breast cancer patients (eight postmenopausal women and one man) before and during treatment with the aromatase inhibitor 4-hydroxyandrostenedione. Urinary oestrogens were measured by using a highly specific GC-MS method. Plasma levels of oestrone, oestradiol and oestrone sulphate were suppressed by 66.6% (+/- 3.6%), 57.7% (+/- 5.1%) and 51.8% (+/- 6.4%) respectively (P < 0.005 for all). Twenty-four hour urinary excretion of total oestrogens, oestradiol, oestriol, 2-hydroxyoestrone, 16 alpha-hydroxyoestrone and the minor metabolites 16 beta- and 15 alpha-hydroxyoestrone were all suppressed by mean values ranging from 60% to 82%, (oestradiol: P < 0.025, otherwise P < 0.005). There were no significant changes in the ratios between the different plasma oestrogens. The finding of sustained plasma and urinary oestrogens at 20-40% compared to their control levels indirectly support a hypothesis of alternative oestrogen sources in postmenopausal breast cancer patients on treatment with 4-hydroxyandrostenedione.     

Alterations in the production rate and the metabolism of oestrone and oestrone sulphate in breast cancer patients treated with aminoglutethimide

Plasma level, plasma clearance, production rate and interconversions of oestrone and oestrone sulphate were measured in six breast cancer patients receiving aminoglutethimide therapy. Three additional patients had the production rate of oestrone sulphate investigated. Plasma oestrone and oestrone sulphate levels were reduced by a mean of 46% (P less than 0.05) and 71% (P less than 0.005) respectively. These alterations were due to a combined action of aminoglutethimide inhibiting oestrogen production but also increasing oestrogen metabolism. While oestrone and oestrone sulphate production rate was reduced by a mean of 31% (P less than 0.05) and 41% (P less than 0.005) respectively, the plasma clearance rate of oestrone was found to be increased by a mean of 30% (P less than 0.05), and the plasma clearance rate of oestrone sulphate was increased by a mean of 112% during aminoglutethimide treatment. The fraction of oestrone sulphate converted into plasma oestrone was reduced by 52% (P less than 0.05), the transfer of circulating oestrone into sulphate was non-significantly reduced by a mean of 16%. The findings in this investigation show that aminoglutethimide treatment influences oestrogen disposition by mechanisms unrelated to aromatase inhibition. The possibility that such effects might be partly responsible for the mechanism of action of aminoglutethimide in advanced breast cancer should be considered.     

Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer.

The effect of anastrozole (''Arimidex'', ZD1033), a new, selective, non-steroidal aromatase inhibitor on in vivo aromatisation and plasma oestrogen levels was evaluated in post-menopausal women with breast cancer. Twelve patients progressing after treatment with tamoxifen were randomised to receive anastrozole 1 mg or 10 mg once daily for a 28 day period in a double-blinded crossover design. In vivo aromatisation and plasma oestrogen levels were determined before commencing treatment and at the end of each 4-week period. Treatment with anastrozole 1 and 10 mg reduced the percentage aromatisation from 2.25% to 0.074% and 0.043% (mean suppression of 96.7% and 98.1% from baseline) and suppressed plasma levels of oestrone, oestradiol and oestrone sulphate by > or = 86.5%, > or = 83.5% and > or = 93.5% respectively, irrespective of dose. Notably, several patients had their oestrone and oestradiol values suppressed beneath the sensitivity limit of the assays. In conclusion, anastrozole was found to be highly effective in inhibiting in vivo aromatisation with no difference in efficacy between the two drug doses. Contrary to previous studies on other aromatase inhibitors, this study revealed an internal consistency between the percentage aromatase inhibition and suppression of plasma oestrone sulphate.     

In situ oestrone synthesis in normal breast and breast tumour tissues: effect of treatment with 4-hydroxyandrostenedione

An isotopic infusion technique has been used in an attempt to determine the contribution that local, in situ, oestrone synthesis makes to the oestrogen content of breast tumours. 3H-Androstenedione and 14C-oestrone were infused into women with advanced breast cancer for 12 hr before operation. At surgery, normal breast and breast tumour biopsy samples were obtained and 3H-androstenedione, 3H-oestrone derived from 3H-androstenedione and 14C-oestrone were isolated and measured. DNA polymerase alpha activity, a marker of cellular proliferation, was also measured to examine whether local synthesis of oestrone exerted a biological effect. The study was repeated after patients had been treated with the aromatase inhibitor, 4-hydroxyandrostenedione, before undergoing further surgery for removal of their tumours. In 4/6 tumours examined, in situ synthesis of 3H-oestrone from 3H-androstenedione accounted for the major part (84.3 +/- 9.0%) of the 3H-oestrone detected, while no significant in situ synthesis occurred in 2 other tumours. Although treatment with 4-hydroxyandrostenedione did not significantly alter the uptake of 3H-androstenedione or 14C-oestrone into breast tissues, in situ formation of 3H-oestrone was only detected in one tumour sample after treatment. DNA polymerase alpha activity decreased in 4/6 tumours after treatment with 4-hydroxyandrostenedione. Overall, however, there was no significant correlation between the level of 3H-oestrone formed in situ and DNA polymerase alpha activity (r = 0.38, NS). It is concluded that in some, but not all, breast tumours in situ formation of oestrone can make an important contribution to the oestrogen content of breast tumours.     

Aminoglutethimide enzyme induction: pharmacological and endocrinological implications

Summary Aminoglutethimide is an aromatase inhibitor that is successfully used for endocrine treatment of advanced breast cancer. This drug also stimulates the activity of hepatic mixed-function oxidases, increasing the metabolism of several drugs, including warfarin, digitoxin, antipyrine and theophylline. It also increases the plasma clearance rate of oestrone sulphate. As this oestrogen may be an important substrate for tumour cells, stimulation of oestrone sulphate metabolism may be a component of the mechanism of action of aminoglutethimide.     

Concentrations of oestrone and 4-hydroxyandrostenedione in malignant and normal breast tissues

4-Hydroxyandrostenedione (4-OHA) is a specific inhibitor of aromatase activity used for the treatment of breast cancer in post-menopausal women. Treatment with 4-OHA has been shown to inhibit the peripheral conversion of androstenedione to oestrone and reduce plasma oestrogen concentrations, but the effect of treatment on breast-tissue oestrone concentrations is not known. We have therefore examined the effect of treatment with 4-OHA on oestrone concentrations in normal and malignant breast tissues and also measured plasma and tissue 4-OHA concentrations. Changes in tumour oestrone concentrations were related to DNA polymerase alpha activity, a marker of cellular proliferation. Blood and breast-tissue samples were obtained before and 36 hr after treatment with 4-OHA. The mean plasma concentration of 4-OHA was 27.9 +/- 19.3 ng/ml, compared with levels of 33.7 +/- 25.6 ng/g for breast tumour and 13.5 +/- 11.5 ng/g for normal breast tissue. There was a significant correlation between 4-OHA concentrations in plasma and normal breast tissue (r = 0.91, p less than 0.001). Treatment with 4-OHA resulted in a significant (p less than 0.02) decrease in breast-tissue oestrone concentrations. For 3/4 tumour samples, a marked decrease in the concentration of oestrone (78 +/- 4%) was associated with a similar decrease (64 +/- 16%) in DNA polymerase alpha activity. It is concluded that treatment with 4-OHA effectively reduces breast-tissue exposure to oestrogen.     

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.     

Aromatase inhibition in the treatment of advanced breast cancer: is there a relationship between potency and clinical efficacy?

Two-thirds of breast tumours are oestrogen-receptor positive and 60-70% of these tumours respond to interventions that reduce the effects of oestrogen. Until recently, tamoxifen was the drug of choice for the treatment of hormone-responsive early and advanced breast cancer. However, tamoxifen is associated with increased incidences of endometrial cancer and thromboembolic disease, and many tumours eventually become resistant to treatment with tamoxifen. Thus, there is a need for alternative therapies with different mechanisms of action. In postmenopausal women, aromatase inhibitors (AIs) suppress oestrogen levels by inhibiting oestrogen synthesis via the aromatase enzyme pathway. The third-generation AIs (anastrozole, letrozole and exemestane) are more potent than the earlier AIs (aminoglutethimide, formestane and fadrozole) with respect to both aromatase inhibition and oestrogen suppression. While the earlier AIs were unable to show any benefit over megestrol acetate or tamoxifen as second- and first-line therapy, respectively, in postmenopausal women with advanced breast cancer, third-generation AIs have shown significant benefits in both settings. Comparison of aromatase inhibition and oestrogen suppression between the third-generation AIs anastrozole and letrozole showed a small but significantly greater difference in the degree of suppression of oestrone and oestrone sulphate (but not oestradiol), with letrozole. In an open-label trial, there were no significant differences between letrozole and anastrozole for the clinical end points of time to progression (primary end point), time to treatment failure, overall survival, clinical benefit, duration of clinical benefit, time to response, duration of response or objective response rate in patients with confirmed hormone receptor-positive tumours. Together these data suggest that once a certain threshold of aromatase inhibition is reached, small differences in oestrogen suppression between the third-generation AIs do not lead to clinically significant differences in overall efficacy.     

A comparative trial of transsphenoidal hypophysectomy and estrogen suppression with aminoglutethimide in advanced breast cancer.

We compared two treatment regimens, transsphenoidal hypophysectomy and estrogen suppression with aminoglutethimide in women with metastatic breast carcinoma. Three of fourteen patients experienced partial objective tumor regression with a median duration of 4.6 months following hypophysectomy, whereas 10 of 21 women receiving aminoglutethimide responded (2 complete, 8 partial) with a median duration of 11.5 months. Side effects in the medical group were minimal while surgical complications included 2 cases of CSF rhinorrhea, one leading to meningitis and death. In patients receiving aminoglutethimide, urinary free cortisol and plasma dehydroepiandrosterone sulfate fell significantly as did plasma estrone and estradiol. In the hypophysectomy group, anterior-pituitary function testing postoperatively revealed adequate suppression of gonadotropin and prolactin secretion but incomplete inhibition of the ACTH-cortisol axis in 4 of 7 surgical patients studied. Five patients initially treated with hypophysectomy experienced a further reduction of plasma (and urinary) estrone and estradiol levels when given aminoglutethimide. We conclude that estrogen suppression therapy with aminoglutethimide is a feasible alternative to surgical hypophysectomy in providing endocrine suppression and palliation in advanced breast carcinoma.     

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.     

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 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.     

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.     

A randomized, open, parallel-group trial to compare the endocrine effects of oral anastrozole (Arimidex?) with intramuscular formestane in postmenopausal women with advanced breast cancer

Background: This study provides a direct randomized comparison of a new-generation, non-steroidal aromatase inhibitor, anastrozole (Arimidex®), with a steroidal aromatase inhibitor (formestane) with respect to oestrogen (oestradiol, oestrone, and oestrone sulphate) suppression and tolerability.Patients and methods: Sixty postmenopausal women with advanced breast cancer were randomized to receive either anastrozole 1 mg once daily orally (n = 29), or formestane 250 mg once every two weeks by intramuscular injection (n = 31). Treatment was continued until progression of disease or withdrawal from the study. The primary endpoints of this study were oestradiol suppression and tolerability. The secondary endpoints included oestrone and oestrone sulphate suppression. All laboratory analyses were conducted blind of the randomized drug treatment.Results: Anastrozole produced a greater and more consistent suppression of oestradiol levels compared with formestane. Based on two- and four-week measurements, the mean fall from baseline (pre-dose) in oestradiol level was 79% and 58% in the anastrozole and formestane groups, respectively (P = 0.0001). After four weeks of treatment, oestrone and oestrone sulphate levels were also suppressed to a greater extent by anastrozole compared with formestane (oestrone: 85% versus67%, respectively, P = 0.0043; oestrone sulphate: 92% versus 67%, respectively, P = 0.0007). No statistical differences were seen between the two drugs in the incidence of adverse events.Conclusions: Anastrozole provides a more consistent and significantly more effective suppression of oestradiol compared with formestane. Similar results were observed for oestrone and oestrone sulphate. The clinical significance of these differences in total oestrogen suppression remains to be established.     

Influence of treatment with aminoglutethimide on plasma and red-blood-cell glutathione status in breast cancer patients

Purpose: Elevated cellular glutathione has been associated with resistance to cancer chemotherapy. Treatment with the aromatase inhibitor aminoglutethimide increases the concentration of γ-glutamyl transpeptidase (γ-GT) in breast cancer patients. This enzyme catalyzes the first step in the degradation of extracellular glutathione, and the products formed may act as precursors for intracellular glutathione synthesis. Methods: Plasma and red-blood-cell glutathione levels were determined in 26 patients suffering from advanced breast cancer before and during treatment with aminoglutethimide (n=16) or the steroidal aromatase inhibitors exemestane or formestane (n=10) and in 5 cancer patients receiving dexamethasone. Results: Pretreatment values for γ-GT in the total patient group (n=31) correlated negatively with the level of reduced (P<0.0001), oxidized (P<0.025), and total glutathione (P<0.005) in plasma. Plasma γ-GT levels increased by a mean value of 249% during treatment with aminoglutethimide. The concentration of reduced and oxidized glutathione in plasma decreased to 42.7% (P<0.0005) and 80.6% (P < 0.005) of their pretreatment levels, respectively. This fall in reduced plasma glutathione correlated negatively with the increase in -GT (P<0.001). The ratio of oxidized to reduced glutathione increased by 88.9% (P<0.005), and this increase correlated positively with the increase in γ-GT (P<0.005). Treatment with the steroidal aromatase inhibitors (exemestane and formestane) or dexamethasone did not influence the plasma thiol status. Conclusions: We conclude that aminoglutethimide influences plasma glutathione disposition by mechanisms not related to estrogen suppression or due to glucocorticoids given in concert. Received: 13 July 1997 / Accepted: 27 October 1997     

Vorozole results in greater oestrogen suppression than formestane in postmenopausal women and when added to goserelin in premenopausal women with advanced breast cancer

The high potency and selectivity of new aromatase inhibitors has translated to greater efficacy and improved tolerability in comparison with established secondline hormonal agents for advanced breast cancer in phase III clinical trials. Two pharmacological studies are reported which assess the use of one of these inhibitors, vorozole, in combination or comparison with wellestablished methods of oestrogen deprivation in pre and postmenopausal patients. When combined with the gonadotrophinreleasing hormone agonist (GnRHa) goserelin in 10 premenopausal patients, vorozole markedly enhanced the suppression of serum levels of oestrone, oestradiol and, oestrone sulphate beyond that achieved by goserelin alone (by a mean 74%, 83%, and 89%, respectively). The combination was welltolerated and had no significant effects on androgen levels. Vorozole was compared with formestane in 13 postmenopausal women and serum oestrone, oestradiol, and oestrone sulphate levels were suppressed by 47%, 30%, and 70%, respectively, more by vorozole than by the steroidal aromatase inhibitor. Again the tolerability was excellent. The plasma oestrogen levels in the postmenopausal patients on vorozole were lower than in the premenopausal patients on goserelin plus vorozole, indicating that ovarian oestrogen synthesis may be relatively resistant to aromatase inhibition, even during GnRHa treatment. Thus, in both pre and postmenopausal patients substantially greater suppression of oestrogen can be achieved by vorozole compared with alternative approaches. Existing clinical–pharmacological correlates suggest that these increases in pharmacological effectiveness may result in enhanced clinical effectiveness.     

The clinical and endocrine effects of 4-hydroxyandrostenedione alone and in combination with goserelin in premenopausal women with advanced breast cancer

The aromatase inhibitor, 4-hydroxyandrostenedione (4OHA) is an effective treatment for advanced post-menopausal breast cancer. The clinical and endocrine effects of 4OHA treatment were studied in five pre- and perimenopausal women with metastatic breast cancer. Serum oestradiol levels were not significantly reduced as a result of treatment with 500 mg of 4OHA by weekly i.m. injections and no patient had a tumour response. Four patients were subsequently treated with the luteinising hormone releasing hormone (LHRH) analogue, gosereline, and three had objective responses. The endocrine effects of combined treatment with goserelin (Zoladex), and 4OHA were studied in a further five premenopausal women. Serum oestradiol levels after treatment with goserelin alone were typical of post-menopausal women. Addition of 4OHA led to a further suppression of oestradiol to within the range observed in post-menopausal patients treated with further suppression of oestradiol to within the range observed in post-menopausal patients treated with 4OHA. Six patients whose tumours had regressed as a result of goserelin treatment and who subsequently relapsed were then given combined treatment. Four of the six experienced a second remission. We conclude that while 4OHA alone is unlikely to be a satisfactory treatment for premenopausal patients with advanced breast cancer, 4OHA in conjunction with goserelin leads to profound suppression of oestradiol. The combination of LHRH analogue and aromatase inhibitor may prove to be a superior treatment to LHRH analogue alone in these patients.     

Second generation aromatase inhibitor — 4-hydroxyandrostenedione

Summary 4-hydroxyandrostenedione is a steroidal, suicide substrate inhibitor of aromatase, which has been widely tested in postmenopausal breast cancer patients. It is highly specific with the only notable endocrine changes other than oestrogen suppression being a dose-related suppression of sex-hormone binding globulin when the drug is given orally (a reflection of the drug's minor androgenic activity). Intramuscular administration of 250 mg every second week is the schedule of choice. This achieves peripheral aromatase inhibition of about 85% and oestradiol suppression of about 65%. The drug is usually used second-line, after tamoxifen, with an overall response rate in unselected patients of 26%. Side-effects are minimal and consist almost entirely of local reactions at the site of injection. 4-hydroxyandrostenedione is therefore a useful new treatment option as the first selective aromatase inhibitor to have wide clinical availability.     

Effect of two 4-hydroxyandrostenedione doses on serum insulin-like growth factor I levels in advanced breast cancer

Summary A number of endocrine treatments for advanced breast cancer seem to affect serum insulin-like growth factor I (IGF-I). The aim of our study was to investigate IGF-I levels in 33 postmenopausal patients with metastatic disease receiving the selective aromatase inhibitor 4-hydroxyandrostenedione: 250 mg (16 patients) or 500 mg (17 patients) i.m. fortnightly. Blood samples were collected before, and at one month and 3 months after the beginning of treatment for radioimmunoassay determinations. The median patient age was 56 and 60 years in the 250 and 500 mg groups respectively. Most patients had a disease free interval 2 years and were oestrogen receptor positive. Objective responses were obtained in 3 patients (complete response, 1) in the 250 mg group, and in 7 patients (complete response, 3) in the 500 mg group. No significant IGF-I variations were seen in the 250 mg group, whereas a significant increase after 3 months (181.57 ± 84.78 ng/mlversus 272.47 ± 213.22 ng/ml, p = 0.0032) was observed in the 500 mg group. No IGF-I variations were seen between responsive and unresponsive patients in either treatment group. Our results in the 500 mg group are close to those obtained with aminoglutethimide and seem to agree with the hypothesis of an oestrogen-induced suppression of IGF-I circulating levels.