Thirty-nine patients with primary hyperparathyroidism were studied four to eight years after their initial operation. In six patients, both the pathologist and surgeon agreed on the diagnosis of solitary adenoma; in 16 patients, the surgeon diagnosed solitary adenoma and the pathologist parathyroid hyperplasia (microscopic hyperplasia). In 16 patients, primary chief cell hyperplasia was agreed upon by the pathologist and surgeon. In the 16 patients with microscopic hyperplasia, there have been no long-term recurrences of hypercalcemia, but, in two patients, plasma parathyroid hormone levels are high. Parathyroid hormone--total calcium regression curves demonstrate significant preoperative correlation in solitary adenoma, p less than 0.01, and primary chief cell hyperplasia, p less than 0.05. After operation, significant correlations were not found between parathyroid hormone and total calcium. T-testing slope differences of pre- and postoperative parathyroid hormone--total calcium regression curves demonstrates a significant (p less than 0.01) shift to the right of the microscopic hyperplasia patients after operation, moving them to a broader range of total calcium per picogram parathyroid hormone. We conclude that 1) in primary hyperparathyroidism, positive regulation of total calcium by autonomously released parathyroid hormone exists in patients with solitary adenoma and chief cell hyperplasia; 2) autonomously functioning parathyroid tissue has been removed by operation for solitary adenoma with coexistent microscopic parathyroid hyperplasia. In this four- to eight-year follow-up period, it is clear that microscopic parathyroid hyperplasia is not associated with recurrent hypercalcemia. Two functionally distinct forms of parathyroid suppression are suggested; positively regulated microscopic hyperplasia and negatively regulated pathologically suppressed glands.
In the absence of functioning gonads, the adrenal is an important source of androgens and estrogens. In order to precisely quantitate the adrenal secretion rates of the sex steroids, we cannulated the adrenal veins and measured venous blood flow and arterial venous steroid gradients in adult male beagle dogs under pentobarbital anesthesia. Celite chromatography and specific radioimmunoassays were utilized to measure steroid levels. During basal conditions, the adrenal produced larger amounts of the androgens (667 ng/min of androstenedione, 5.45 ng/min of testosterone, and 3.43 ng/ min of dihydrotestosterone) than of the estrogens (1.245 ng/min of estradiol and 0.239 ng/min of estrone. These secretion rates were 20- to 50,000-fold less than that of cortisol (12,360 ng/min). Studies were also carried out during adrenal suppression with hydrocortisone to block ACTH release and with the adrenal steroidogenesis inhibitor, aminoglutethimide, plus hydrocortisone. The secretion rates of each androgen measured fell during ACTH inhibition. Significant suppression of estrone and estradiol, however, required addition of aminoglutethimide. This study provides direct evidence that the adrenal in the male dog can secrete estrogens, a previously controversial issue.
SummaryRecent studies suggest that estrogens are the predominant hormones required for the growth of hormonedependent breast cancers in women. Traditional methods of lowering estrogens as treatment of breast cancer involve surgical removal of the ovaries, adrenals, or pituitary. Newer investigative strategies utilize blockade of estrogen action with antiestrogens or inhibition of estrogen synthesis. As reviewed previously, a regimen for pharmacologic suppression of estrogen production was developed which utilizes the aromatase/steroidogenesis inhibitor aminoglutethimide (AG) and replacement hydrocortisone (HC). The current paper updates recent mechanistic, clinical, and hormonal data regarding AG.The preservation of plasma androstenedione levels concomitant with marked estrone and estradiol suppression suggests that AG lowers estrogen production predominantly by blocking aromatization. The mechanism for sustained androstenedione production in the face of suppressed ketosteroids, glucocorticoids, and mineralocorticoids during AG administration was evaluated in dogs fitted with arteriovenous adrenal cannulae. Inhibition of the adrenal secretion of androstenedione with preservation of peripheral plasma levels of this steroid suggests stimulation of extra-adrenal 3/?-ol-dehydrogenase, A 5-A4-isomerase activity by AG.Clinical studies revealed a 32% objective response rate to AG/HC in unselected patients and a 52% response in women with estrogen receptor positive tumors. Randomized trials indicated similar response rates to AG/HC vs hypophysectomy (AG/HC 47% vs Hypox 21%, p = NS), surgical adrenalectomy (AG/HC 52~o vs surgical adrenalectomy 43%, p = NS) and antiestrogen therapy (AG/HC 36~ vs tamoxifen 38%, p = NS). Cross-over data revealed that 50% of 94 patients initially responding to tamoxifen later experienced an objective regression to AG/HC. Only 25% of 93 tamoxifen nonresponders benefited later from AG/HC. Trends indicate that bone metastases may respond better to AG/HC (33%) than to tamoxifen (15%).Use of a computer-based data matrix allowed determination of whether patients escape from AG/HC induced estrogen and androgen suppression at the time of disease relapse. No trends towards escape from
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