Adrenal Suppression in the Treatment of Carcinoma of the Prostate

Robinson, M. R. G.; Shearer, R. J.; Fergusson, J. D.

doi:10.1111/j.1464-410x.1974.tb03856.x

Cited by 64 publications

(20 citation statements)

References 14 publications

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“…Aminoglutethimide is an inhibitor of several enzymes involved in adrenal steroid synthesis (Dexter et al, 1967) and in prostaglandin metabolism (Harris et al, 1983c). The combination of aminoglutethimide and hydrocortisone had previously been reported both to reduce circulating levels of adrenal androgen and, in small numbers of patients, to induce responses in hormone-relapsed advanced prostatic cancer (Robinson et al, 1974;Sanford et al, 1976).…”

mentioning

confidence: 99%

Response to aminoglutethimide and cortisone acetate in advanced prostatic cancer

Ponder¹,

Shearer²,

Pocock³

et al. 1984

Br J Cancer

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Summary 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.

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mentioning

confidence: 99%

Response to aminoglutethimide and cortisone acetate in advanced prostatic cancer

Ponder¹,

Shearer²,

Pocock³

et al. 1984

Br J Cancer

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“…Moreover, after adrenal androgen suppression with aminoglutethimide in patients who had become refractory to orchiectomy and exogenous estrogens, a favorable response was observed in three of seven patients [28]. In a similar study, Robinson and coworkers found palliation in 50% of patients [29].…”

Section: Clinical Evidence That Androgen-hypersensitive Tumors Remainmentioning

confidence: 58%

Combination therapy in stage C and D prostatic cancer: rationale and five-year clinical experience

et al. 1987

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In 1941, Huggins and his colleagues discovered that testicular androgens exert a stimulatory effect on prostate cancer growth. Our group has made the key observations that the human adrenals, in addition to the tests, also secrete important amounts of androgens and cancer cells exhibit a marked heterogeneity of androgen sensitivity. In fact, human adrenals secrete large amounts of precursor steroids that are converted into active androgens in peripheral tissues (including the prostate), thus providing 40% to 50% of total androgens in adult men. The action of these androgens remaining after castration can be inhibited in prostatic cancer tissue by administering a pure antiandrogen that also decreases the local concentration of dihydrotestosterone (DHT). The castration levels of serum testosterone left in men after castration have an important stimulatory activity on the growth of androgen-sensitive normal as well as cancer tissues. Cancer cells have markedly different requirements for androgens. Some cell clones can grow in the presence of minimal amounts of androgens, requiring more complete androgen blockade and more potent antiandrogens for inhibiting growth. Among the compounds recommended as antiandrogens, the most unexpected finding is that many of them are devoid of any antiandrogenic activity. In fact, medroxyprogesterone acetate, chlormadinone acetate, and megestrol acetate have androgenic activity, but do not inhibit the peripheral action of DHT in prostatic tissue. These compounds should not be classified as antiandrogens. Cyproterone acetate, on the other hand, is a mixed agonist-antagonist. The only compounds showing pure antiandrogenic activity are Flutamide and its analogues. There is thus a need for a more complete blockade of androgens of both testicular and adrenal origins in order to exert a maximal inhibitory effect on cancer growth. We have therefore performed clinical studies in previously untreated stage D2 and C prostate cancer patients with the combination therapy using the LHRH agonist [D-Trp6, des Gly NH2(10)] LHRH ethylamide and the antiandrogen Flutamide. There was a significant increase in patients with a complete response, as compared with studies limited to the removal or blockade of testicular androgens. There was also a significant decrease in the number of non-responders, an increased duration of positive response, and a decrease in the death rate. This was achieved with minimal or no side effects, thus preserving a good quality of life.

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“…There are several reports of AG + HC achieving both objective (Worgul et al, 1983;Drago et al, 1984;Murray & Pitt, 1984) and subjective (Robinson et al, 1974;Rostom et al, 1982;Ponder et al, 1984) responses in advanced prostatic cancer after relapse from first line therapy (orchiectomy or oestrogen therapy). In addition, we (Ponder et al, 1984) and others (Worgul et al, 1983) have demonstrated that this regimen results in reduced plasma androgen levels as it does in postmenopausal breast cancer patients (Samojlik et al, 1980;Harris et al, 1984).…”

Section: Discussionmentioning

confidence: 99%

“…The demonstration that aminoglutethimide (AG) inhibited the conversion of cholesterol to pregnenolone (Dexter et al, 1967) led to the use of the drug in combination with hydrocortisone (HC) as a so-called 'medical adrenalectomy' in postmenopausal breast cancer patients (Santen et al, 1974) and also with some apparent benefit in prostate cancer patients (Robinson et al, 1974). The mechanism of action of this combination in prostatic cancer has been questioned, since HC is itself an adrenal suppressant and AG is now accepted as acting by aromatase inhibition in breast cancer patients (Santen et al, 1978;Stuart-Harris et al, 1984).…”

mentioning

confidence: 99%

The effects of aminoglutethimide and hydrocortisone, alone and combined, on androgen levels in post-orchiectomy prostatic cancer patients

Dowsett

Shearer²,

Ponder³

et al. 1988

Br J Cancer

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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.

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Adrenal Suppression in the Treatment of Carcinoma of the Prostate

Cited by 64 publications

References 14 publications

Response to aminoglutethimide and cortisone acetate in advanced prostatic cancer

Response to aminoglutethimide and cortisone acetate in advanced prostatic cancer

Combination therapy in stage C and D prostatic cancer: rationale and five-year clinical experience

The effects of aminoglutethimide and hydrocortisone, alone and combined, on androgen levels in post-orchiectomy prostatic cancer patients

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