Eugeniusz Samojlik

Aminoglutethimide as Treatment of Postmenopausal Women with Advanced Breast Carcinoma

Hormone-dependent breast carcinomas respond to deprivation of biologically active estrogens with objectively quantifiable tumor regression. Aminoglutethimide, a known inhibitor of steroid synthesis, is also a potent blocker of the aromatase enzyme and, thus, of estrogen production. We developed an effective regimen to inhibit estrogen production in postmenopausal women using aminoglutethimide and replacement glucocorticoid. One hundred forty-seven women initially received aminoglutethimide and replacement glucocorticoid as treatment of metastatic breast carcinoma. One hundred twenty-nine women are currently evaluable for assessment of clinical and hormonal responses. Thirty-seven percent of unselected women and 49% of estrogen receptor-positive patients experienced objective tumor regression. Responses occurred predominantly in soft tissue (47%) and bone (35%) and lasted 30 +/- 9.1 months for complete and 14 +/- 1.5 months for partial regressions. Plasma and urinary estrogen levels fell equally in responder versus nonresponder groups whereas androgen levels declined less in patients with progressive disease.

Plasma estrone-sulfate assessment of reduced estrogen production during treatment of metastatic breast carcinoma

Highly sensitive and specific estrogen assays are required to monitor the hormonal effects of surgical adrenalectomy or pharmacologic estrogen suppression in postmenopausal women with breast carcinoma. Because the levels of plasma estrone-sulfate are 10-fold higher than its unconjugated counterpart, we developed a radioimmunoassay for estrone-sulfate to quantitate the minimal estrogen concentrations expected under conditions of endocrine gland ablation. After establishing normal ranges, we compared plasma estrone- sulfate levels and urinary conjugated estrone basally and after surgical adrenalectomy or aminoglutethimide (estrogen suppression) therapy in 23 postmenopausal women with breast carcinoma. In response to either therapy, the plasma levels of estrone-sulfate fell by 63.5-79.2% (p less than .01) and conjugated urinary estrone by 85-94.5% (p less than .01) in all study days over a 12-week period. Correlation analyses yielded r values of 0.77-0.94 between conjugated plasma and urinary estrone concentrations in the surgical adrenalectomy and aminoglutethimide-treated groups, respectively. No significant differences in estrone-sulfate levels were observed when comparing spontaneously menopausal and surgically castrate patients.

Kinetic, hormonal and clinical studies with aminoglutethimide in breast cancer

Approximately one‐third of patients with metastatic breast carcinoma respond to surgical ablative therapy but the morbidity associated with these procedures has limited their use to highly selected patients. Consequently, a chemical method of adrenal suppression was developed using a potent inhibitor of adrenal steroid synthesis, aminoglutethimide, in combination with a synthetic glucocorticoid, dexamethasone. While this regimen effectively blocked adrenal function, it was complicated by a drug interaction in which aminoglutethimide accelerated the metabolism and reduced the bioavailability of dexamethasone. To overcome this problem, a new regime using aminoglutethimide and hydro‐cortisone, a glucocorticoid less susceptible to altered metabolism, was developed. Kinetic studies confirmed that aminoglutethimide does not interact with hydrocortisone to alter its rate of metabolism. Hormone measurements established that 1000 mg of aminoglutethimide and 40 mg of hydrocortisone daily suppressed DHA‐sulfate, androstenedione, estrone, estradiol and aldosterone to a greater extent than the prior protocol using aminoglutethimide and 2–3 mg of dexamethasone. Patients experienced objective tumor regression with equal frequency while receiving the aminoglutethimide‐hydrocortisone regimen or aminoglutethimide and dexamethasone and the overall rate of response in 50 evaluable patients was 38%. Side effects occurred frequently in the first few weeks of treatment but disappeared nearly uniformly thereafter. The present aminoglutethimide‐hydrocortisone regimen is simple, non‐toxic, effective in inhibiting estradiol synthesis and capable of inducing tumor regression as frequently as previously reported with adrenalectomy.

Serum aminoglutethimide levels: studies of serum half-life, clearance, and patient compliance.

Serum aminoglutethimide was measured in 13 women with mastastatic breast carcinoma who were treated with 1.0 Gm aminoglutethimide and 40 mg hydrocortisone daily over a period of one year. Serum concentrations of aminoglutethimide were used to evaluate drug half-life, clearance, and patient compliance. Mean half-life and clearance rates were determined in six patients. The mean half-life of aminoglutethimide prior to therapy was 13.3 +/- 2.65 (S.D.) hours and fell significantly (P less than 0.01) to 7.3 +/- 2.14 hours after six to 32 weeks of therapy. The mean clearance rate prior to therapy was 2.58 +/- 0.33 (S.D.) 1./hour and increased significantly (P less than 0.01) to 5.29 +/- 1.4 1./hour after therapy. The mean serum concentration was 11.5 +/- 3.6 microgram/ml in seven patients. No significant variation of mean aminoglutethimide concentration from the overall mean was noted during the course of therapy. We conclude that serum aminoglutethimide concentrations are useful in evaluating patient compliance. Our data also suggest that aminoglutethimide increases its own metabolism, which may explain the absence of toxicity symptoms seen late in the treatment period.

The effect of growth hormone on the Leydig cell response to chorionic gonadotrophin in boys with hypopituitarism.

Eleven boys with growth hormone (hGH) deficiency received human chorionic gonadotrophin (hCG) stimulation tests for the assessment of Leydig cell function before, during, and after 1 year of treatment with somatotrophin. Two patients entered puberty during the course of the study protocol. Analysis of the data in nine prepubertal boys revealed an augmentation of testosterone (T) responses to hCG in the presence of hGH. In six of these individuals in whom dihydrotestosterone (DHT) was determined, a similar augmentation in responsiveness of this steroid was found in the presence of hGH. Three prepubertal boys exhibited poor T responses to the basal hCG test with only partial improvement following hGH. In man growth hormone may be an important permissive factor in Leydig cell activity during periods of changing testicular function such as occur in utero or during puberty.

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.

Clinical and Biochemical Effect of Aminoglutethimide in the Treatment of Advanced Prostatic Carcinoma

Treatment of male patients with advanced prostatic carcinoma and disease progression after initial endocrine therapy frequently is unsatisfactory. However, approximately 20 per cent of these patients respond to surgical adrenalectomy or hypophysectomy, indicating continued hormonal responsiveness. A total of 25 previously castrated men with stage D carcinoma received 1,000 mg. aminoglutethimide and 40 mg. hydrocortisone daily. The patients were evaluated using the criteria of the National Prostatic Cancer Project. One patient has had a complete response and is in remission after 275 weeks of therapy. A partial response was noted in 4 patients, while the disease was objectively stable in 6. Pre-treatment testosterone and dihydrotestosterone levels were measured in 9 of 25 patients and were significantly reduced statistically during aminoglutethimide therapy (p less than 0.01). Response and drug toxicity are discussed.

Treatment of Hirsutism in Women With Flutamide

OBJECTIVE To explore the clinical usefulness of the antiandrogen flutamide in the treatment modality for hirsutism in women. DESIGN Nine women with hirsutism were assessed before and then monthly for 3 months on a regimen of flutamide 250 mg three times a day as the sole therapeutic agent. Blood samples were taken at each assessment time for a battery of androgenic parameters. SETTING Patients were followed in the Out-Patient Department of the Hospital das Clinicas, Sao Paulo, Brazil. Hormonal assays were performed in the Hormone Laboratories of Hospital das Clinicas and the Endocrine Research Laboratory at Newark Beth Israel Medical Center, Newark, New Jersey. PATIENTS Nine women with moderate hirsutism were treated with flutamide. Six women were previously diagnosed as having idiopathic hirsutism, and three women were diagnosed as having polycystic ovary syndrome. INTERVENTION All women were treated with flutamide 250 mg three times a day for 3 months. MAIN OUTCOME MEASURE Improvement of hirsutism was assessed using the Ferriman-Gallwey hair density index. Side effects of drug therapy (deterioration of menses and dry skin) were explored. Androgen parameters included testosterone (T), sex hormone-binding globulin, bound, nonbound, and free T, androstanediol glucuronide, and others. RESULTS After 3 months of flutamide alone, Ferriman-Gallwey scores improved in seven of nine women with mean scores decreasing from 28.1 +/- 0.6 to 24.5 +/- 0.6. None of the androgenic parameters changed during this period of time. Follicle-stimulating hormone and luteinizing hormone response to gonadotropin-releasing hormone was unchanged after flutamide. CONCLUSION Flutamide favorably influenced hirsutism in women, with differences noted after only 3 months of therapy. More prolonged and detailed studies of this drug as the sole therapeutic agent for treatment of hirsutism seems warranted.