Estrogens In Peripheral Tissues Research Articles

Second line endocrine treatment of postmenopausal advanced breast cancer. Preliminary endocrine results of a 5-ARM randomized phase II trial of medium vs low dose aminoglutethimide, with or without hydrocortisone vs hydrocortisone alone (EORTC 10861)

The supposed mechanism of action of aminoglutethimide (AG), medical adrenalectomy, has been challenged. AG is now considered to act as an inhibitor of the aromatization of mainly adrenal androgens to estrogens in peripheral tissues and/or breast cancer itself. To further establish the AG dose required to sufficiently reduce estrogen levels in plasma and the possible role of hydrocortisone (HC) in combination with AG or by itself, postmenopausal advanced breast cancer patients received AG low (125 mg bid) or medium (250 mg bid) dose alone or combined with HC (20 mg bid) or HC alone (20 mg bid). Preliminary hormonal data show a similar reduction of serum estrone and estrone sulphate by at least some 50% at 8 wk in all treatment groups. At 6 months these effects persist except for patients treated with HC alone. In the latter a normalization of estrone levels is observed with effective suppression of adrenal androgen precursors, suggesting increased aromatase activity with prolonged glucocorticoid treatment.

Adipose tissue as a source of hormones

Obesity is known to increase the risk for cancer of the reproductive tract in women. The mechanism underlying this association can be explained by increased estrogenic stimulus to estrogen-target tissues as the result of three factors. First, increased adrenal secretory activity makes more androgen precursors available for conversion to estrogen in peripheral tissues. Second, the efficiency of conversion of androstenedione (A) to estrone (E1), is elevated in obese subjects because adipose tissue is the major tissue site of conversion. Third, plasma levels of SHBG, which binds estradiol (E2), are depressed in obese subjects and greater than normal amounts of serum estradiol are therefore available to target tissues from the circulation. Recent studies have shown that the levels of estrogens and other steroid hormones in breast fluids are much higher than in serum, which may be the result of local synthesis or increased uptake from the circulation. No differences in estrogen levels of breast fluid have been found between normal women and those with breast disease. A possible explanation may be differences in the levels of estrogen antagonists, such as progesterone.

Adipose tissue as a source of hormones

Obesity is known to increase the risk for cancer of the reproductive tract in women. The mechanism underlying this association can be explained by increased estrogenic stimulus to estrogen-target tissues as the result of three factors. First, increased adrenal secretory activity makes more androgen precursors available for conversion to estrogen in peripheral tissues. Second, the efficiency of conversion of androstenedione (A) to estrone (E1), is elevated in obese subjects because adipose tissue is the major tissue site of conversion. Third, plasma levels of SHBG, which binds estradiol (E2), are depressed in obese subjects and greater than normal amounts of serum estradiol are therefore available to target tissues from the circulation. Recent studies have shown that the levels of estrogens and other steroid hormones in breast fluids are much higher than in serum, which may be the result of local synthesis or increased uptake from the circulation. No differences in estrogen levels of breast fluid have been found between normal women and those with breast disease. A possible explanation may be differences in the levels of estrogen antagonists, such as progesterone.

Catechol estrogens and the control of gonadotropin and prolactin secretion in man

The catechol estrogens, the 2- or 4-hydroxylated metabolites of estrone and estradiol, have pharmacologic properties of both estrogens and catecholamines and are formed from estrogens in peripheral tissues and in the brain. This has led to speculation that they may mediate some of the feedback effects of estrogens upon gonadotropins and prolactin (PRL). Studies testing these hypotheses are still few and have not been conclusive. There have been reports that the catechol estrogen 2-hydroxyestrone (2-OHE 1) might act as a partial estrogen antagonist, stimulating gonadotropin secretion; and that it might have dopamine-like effects, suppressing the secretion of PRL. In studies testing the chronic and acute effects of catechol estrogens on LH, FSH, and PRL in men and women, we found that they behaved as estrogens, suppressing gonadotropins when given in doses high enough to compensate for their rapid clearance and degradation. We found no evidence that they suppress PRL secretion. The weight of available evidence suggests that these effects are mediated by estrogen receptor interactions; and that the formation of catechol estrogens is not an obligatory step in the feedback effects of estrogens, although it may have a modulatory role. Plasma levels of catechol estrogens are too low for them to exert circulating neuroendocrine effects.