Solving the puzzle of hormone-dependent breast cancer.
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Breast Neoplasms↗
Biomedical subjects
R J Santen
Publications and source records attributed to R J Santen.
Mechanism of action of aminoglutethimide in breast cancer.
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Adult↗
Pituitary pseudotumor. Mimicry of recurrent prolactinoma by a chronic intrasellar hematoma.
In the increasing cohort of patients being observed after pituitary microneurosurgery for prolactin-secreting adenomas, tumor recurrence remains a concern. We describe a patient with a prolactinoma treated by transsphenoidal pituitary surgery who resumed cyclic menses for one year postoperatively before manifesting progressive headaches, intermittent diplopia, secondary amenorrhea, and anterior pituitary failure. Invasive and noninvasive neuroradiologic procedures suggested recurrent tumor with suprasellar extension. However, reoperation of the pituitary disclosed a chronic intrasellar hematoma expanding under increased pressure within the enclosed sellar space. We discuss a putative mechanism for the pathophysiology of this syndrome, and tentatively designate it "pituitary pseudotumor". Recognition of this entity is important not only because reoperation is required for accurate diagnosis, but also because treatment with radiotherapy or bromocriptine mesylate for presumptive tumor progression or recurrence would be ineffective.
Chronic Disease↗
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.
Adult↗
Enhanced frequency and magnitude of episodic luteinizing hormone-releasing hormone discharge as a hypothalamic mechanism for increased luteinizing hormone secretion.
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Adult↗
Acute effects of aminoglutethimide on testicular steroidogenesis in normal men.
Aminoglutethimide (AG), a known adrenal inhibitor, was administered acutely to normal men in order to study its effects on testicular steroidogenesis. Sixteen subjects between the ages of 21--30 yr received either placebo or 1250 mg AG in divided doses during a 24-h period. To reduce the contribution of adrenal steroids, adrenal function was inhibited in both groups of men by the administration of dexamethasone (2 mg) on the night of the experiment. As a result, mean morning plasma cortisol levels fell to less than 2 micrograms/100 ml. AG blunted the normal diurnal rise in testosterone, which was observed in men receiving placebo, and significantly suppressed the levels of this androgen at 0700 and 0900 h. Estradiol concentrations fell to a greater extent than those of testosterone. The differences between the placebo and drug treatment groups were significant at all time points except 1900 h. A pattern similar to that of estradiol was observed for plasma estrone. When the overall effect of AG administration was examined by analysis of variance, the differences in the levels of all three steroids produced by treatment were highly significant (P less than 0.01 to less than 0.001). After the inhibition of testosterone and estradiol levels, LH and FSH concentrations were significantly (P less than 0.01 and P less than 0.001, respectively) higher in men receiving AG than in those given placebo. However, the data exhibited a large variance due to pulsatile gonadotropin secretion. These observations suggested that AG induces an acute inhibition of testicular steroidogenesis and probably also of the aromatization of testosterone to estradiol.
Adult↗
Abnormalities of the pituitary-gonadal-axis of Hre rats: a study of animals with an inherited disorder of seminiferous tubular and Leydig cell function.
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Aging↗
Medical adrenalectomy with aminoglutethimide: clinical studies in postmenopausal patients with metastatic breast carcinoma.
The use of adrenalectomy and hypophysectomy in the management of postmenopausal patients with metastatic breast carcinoma is reserved for highly selected patients. As an alternate approach, a pharmacologic method of inhibiting adrenal cortical secretion was developed which consisted of the daily administration of 1000 mg of aminoglutethimide to block steroidogensis and either dexamethasone (2.0-3.0 mg/day) or hydrocortisone (40-60 mg/day) as replacement glucocorticoid. This regimen markedly suppressed plasma levels of DHA-S, androstenedione, estrone, and estradiol, and urinary levels of aldosterone. Of 50 patients treated, 19 (38%) demonstrated either a complete (8/19) or a partial (11/19) objective disease remission which lasted for 18.05 +/- 3.1 months (mean +/- SEM). In 10 (20%) patients, there was stabilization of disease (7.8 +/- 1.2 months), accompanied by symptomatic relief of bone pain in six (12%). There was disease progression in 20 (40%) patients. The acute side effects of aminoglutethimide therapy were significant and consisted of transient lethargy (41.5%) and a cutaneous rash (35.8%). Chronic toxicity was negligible. The medical adrenalectomy regimen of aminoglutethimide plus glucocorticoid offers a suitable alternative to surgical adrenalectomy or hypophysectomy in the management of postmenopausal patients with metastatic breast carcinoma.
Adrenal Cortex↗
Adrenal suppression with aminoglutethimide. III. Comparison of plasma delta 4- and delta 5-steroids in postmenopausal women treated for breast carcinoma.
A regimen or aminoglutethimide in combination with replacement glucocorticoid has been used to suppress adrenal steroidogenesis in postmenopausal women with metastatic breast carcinoma. During acute and chronic treatment with aminoglutethimide, the levels of the delta 4-steroids [progesterone (P), 17 alpha-hydroxyprogesterone (17-delta 4-P), and androstenedione (delta 4-A)] and the delta 5-steroids [dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), and 17 alpha-hydroxypregnenolone (17-delta 5-P)] were determine. In the total group of women, the plasma levels of P and delta 4-A increased 2- to 3-fold (P less than 0.05) while 17-delta 4-P rose 10-fold (P less than 0.01) from basal concentrations of 0.65 +/- 0.07 to 6.48 +/- 1.46 ng/ml during the initial 2 weeks of therapy with aminoglutethimide (AG) and dexamethasone. These three steroids then fell to basal levels during chronic treatment (P and 17-delta 4-P) or were suppressed (delta 4-A; P less than 0.001). In contrast, the levels of delta 5-steroids (17-delta 5-P, DHEA, and DHEA-S) were reduced 3- to 5-fold during the initial 2 weeks of therapy and remained suppressed throughout. The relative levels of certain delta 5- and delta 4-steroids pairs were then examined. The ratio of 17-delta 5-P to 17-delta 4-P decreased from baseline values of 2.15 +/- 0.35 to 0.38 +/- 0.21 ng/ml (P less .02) with the initiation of therapy and remained low thereafter. A similar pattern for the ratios between DHEA and delta 4-A, and DHEA-S and delta 4-A was observed. This may indicate that the regimen of AG treatment utilized may facilitate the activity of the 3 beta-ol-dehydrogenase, delta 5- to delta 4-isomerase, and accelerate the conversion of delta 5- to delta 4-steroids. The patterns of suppression of the plasma delta 4- and delta 5-steroids in oophorectomized and spontaneously postmenopausal patients with intact ovaries were analyzed separately. The plasma levels of progesterone were higher during the first 2 weeks of therapy in surgically castrate women than in spontaneously postmenopausal women (0.72 +/- 0.25 vs. 0.47 +/- 0.20 ng/ml). A similar pattern was observed for 17-delta 4-P, DHEA, and DHEA-S indicating that the adrenals might contribute to this increase. In contrast, during chronic treatment the levels of all steroids were lower in surgically castrate women than in those with intact ovaries. This suggested residual ovarian steroid during AG administration.
17-alpha-Hydroxypregnenolone↗
Prolonged negative feedback suppression after estradiol administration: proposed mechanism of eugonadal secondary amenorrhea.
The finding of normal gonadotropin and estradiol levels in eugonadal women with secondary amenorrhea suggests a disordered feedback relationship of the hypothalamic-pituitary-ovarian axis. To identify possible defects in negative and positive feedback, we compared the effects of five daily injections of 17 beta-estradiol (E2) in 13 normal women and 11 eugonadal patients with absent cyclic menses. The suppression phase of negative feedback was normal, as LH and FSH were similarly lowered in both groups on day 3. Continued LH (P less than 0.01) and FSH (P less than 0.02) inhibition on day 10 of the protocol, 5 days after the last E2 injection, indicated a defect in the recovery phase of negative feedback in the 11 amenorrheic women. In the 4 patients studied gonadotropin suppression persisted for 3 weeks, E2 did not blunt pituitary responsiveness to GnRH in the amenorrheic women, suggesting a central nervous system site for prolonged gonadotropin inhibition. Nine normal but only 2 amenorrheic women X2 = 4.15; P less than 0.05) exhibited a positive feedback increase in LH on days 4-6. We propose that a defect in the recovery phase of negative feedback to E2 rather than absent positive feedback may be the dominant physiological abnormality which causes secondary amenorrhea by preventing early follicular phase gonadotropin increments and follicular maturation.
Adult↗
Aminoglutethimide inhibits extraglandular estrogen production in postmenopausal women with breast carcinoma.
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Adult↗
The integrated gonadotrophin test.
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Endocrine System Diseases↗
Pancytopenia induced by aminoglutethimide in the treatment of breast cancer.
Aminoglutethimide is an investigational agent of proven benefit in the treatment of metastatic breast carcinoma. We report herein a case of aminoglutethimide-induced pancytopenia complicated by bleeding and gram-negative septicemia. Severe pancytopenia is a rare but important side effect of this new drug and is rapidly reversible when the agent is withdrawn.
Aged↗
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 hydrocortisone, 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.
Adrenocorticotropic Hormone↗
The effects of castration on adrenal testosterone secretion in men with prostatic carcinoma.
Selective adrenal vein catheterization was done on intact and castrated men with prostatic carcinoma. Adrenal to peripheral venous testosterone gradients were observed in all patients, indicating adrenal production of this hormone. No compensatory adrenal production of testosterone was noted during a 17-month period after orchiectomy. The data suggest that the human adrenal in castrates produces testosterone, which may explain why adrenal ablation can offer palliation in some patients with prostatic carcinoma.
Adrenal Glands↗
Perfusion of rat testes and accessory sex organs: a new method.
Rat testes and accessory sex organs were perfused in situ by recirculating an artificial medium through the hemicorpus preparation previously developed for studies of skeletal muscle. The advantages and limitations of this system for studying the male productive tract were examined. The electrolyte and gas composition of the perfusate remained constant and glucose levels did not fall below normal during 3 h of perfusion. Testicular water content, temperature, and ATP and GTP levels were normal at 90 min. The mean arterial pressure was 40 mm Hg and the flow rates, measured with microspheres, were normal to high to the caput epididymides, ventral prostate and seminal vesicles and approximately half normal to the testes in preparations from 90 day old rats perfused at 35 ml/min. Administration of vasodilators indicated the absence of significant vasoconstriction in the hemicorpus. There was appreciable testosterone metabolism by the preparation and in addition, there was absorption of testosterone by the plastic tubing of the perfusion apparatus. Testosterone levels in the perfusate rose for 90 min in response to hCG. There was a dose-response relationship between hCG (20-1000 mIU/ml of medium) and testosterone levels at 90 min. FSH, prolactin, insulin and vitamins had no significant effect on hCG-stimulated testosterone levels. This perfusion system should prove useful for studies of hormone action.
Animals↗
Nuclear accumulation of androgens in perfused rat accessory sex organs and testes.
The uptake of androgens into the nuclei of caput epididymis, ventral prostate, seminal vesicle and testis was studied by recirculating physiological and pharmacological concentrations of [3H]testosterone in an artificial medium through the lower half (hemicorpus) of castrated or hypophysectomized rats. The accumulation of dihydrotestosterone in accessory sex organ nuclei was saturable, inhibited by perfusion of excess testosterone or cyproterone acetate, and associated with binding to 3S salt-extractable molecules. In castrated preparations the mean saturation levels (pmol/mg DNA) were different in the three organs: seminal vesicle, 2.8; ventral prostate, 1.8; caput epididymis, 0.9. The saturation level was significantly lower in ventral prostate of hypophysectomized rats (1.2) treated with testosterone to regenerate the accessory sex organs. Testosterone was the major nuclear androgen in the testes of mature hypophysectomized preparations perfused with testosterone. Although there was a large amount of nonspecific accumulation, testosterone binding to 3S molecules was shown by sucrose gradient centrifugation. Binding of dihydrotestosterone to 3S molecules in testicular nuclei was also demonstrated. The ratio of dihydrotestosterone to testosterone was different in immature and mature testicular nuclei and was altered by treatments known to affect testicular 5 alpha-reductase activity. The results suggest that in rat accessory sex organs and immature testis the major active androgen is dihydrotestosterone, whereas in mature testis it is testosterone. The shift in the predominant nuclear androgen in the testis from dihydrotestosterone to testosterone is most simply explained by the maturational change in 5 alpha-reductase activity.
Androgens↗