Biomedical subjects
Publications and source records attributed to R J Santen.
The estrogen receptor, progesterone receptor, and intratumoral aromatase content of 127 breast carcinomas were determined. Patients whose tumor contained either estrogen or progesterone receptors had a longer disease-free interval, but no difference in survival was observed. Measurable aromatase activity was detected in 78 of 113 (69%) tumors. There was no relationship between aromatase activity and disease-free interval or survival.
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CGS 16949A (fadrozole hydrochloride), a potent cytochrome P450-mediated steroidogenesis inhibitor, blocks aromatase at low doses, but other biosynthetic steps at higher concentrations. Recent studies demonstrated inhibition of C11-hydroxylase, corticosterone methyloxidase-II, and deoxycorticosterone to corticosterone conversion with this agent at some-what higher concentrations than those required for blockade of aromatase. Based upon phase I studies, we postulated that relatively selective inhibition of aromatase might be possible if sufficiently low doses of CGS 16949A were used. A phase II study in 54 postmenopausal women with metastatic breast cancer examined the effects of low dose CGS 16949A on estrogen, mineralocorticoid, and glucocorticoid secretion. Two dose schedules and two dose levels were chosen based upon our prior dose escalation protocol study. Plasma estrone, estradiol, and estrone sulfate as well as urinary estrone and estradiol fell equally with 1.8-4 mg CGS 16949A given either on a twice daily or three times daily dose schedule. Isotopic kinetic studies demonstrated an 84% decrease in the rate of conversion of androstenedione to estrone to 0.40 +/- 0.07% (patients receiving 1.8-4 mg CGS 16949A daily). With these three regimens, basal levels of aldosterone and cortisol did not change significantly over a 12-week period of observation. Clinical examination, plasma electrolytes, and urinary sodium/potassium ratios suggested no biological evidence of mineralo-corticoid deficiency. ACTH-stimulated cortisol concentrations, however, were blunted at each dose level compared to pretreatment values. Nonetheless, peak responses exceeded 550 nmol/L, or a basal to peak difference of 190 nmol/L or greater, in 97% of instances. This probably reflected inhibition of C11-hydroxylase, since basal and ACTH-stimulated levels of 11-deoxycortisol were increased in response to CGS 16949A. Androstenedione and 17 alpha-hydroxyprogesterone also exhibited an upward trend in response to drug treatment. ACTH-stimulated aldosterone levels were blunted to a greater extent than those of cortisol, probably as a reflection of corticosterone methyloxidase type II blockade. Overall, the results suggest that CGS 16949A, at doses of 1.8-2 mg daily, blocks aromatase effectively and does not produce clinically important inhibition of cortisol or aldosterone biosynthesis. Thus, this agent can probably be used safely without glucocorticoid or mineralocorticoid supplementation.
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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.
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.
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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.
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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.
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.
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.
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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.