Extraglandular aromatization of androstenedione (δ4-A) to estrone (E1) provides the primary source of estrogen production in spontaneously postmenopausal or surgically castrate women. Estrogens produced by this enzymatic reaction in peripheral tissues can be biologically important, particularly in women with metastatic breast carcinoma. In such patients, an aromatase inhibitor would have potential usefulness clinically. In vitro studies demonstrated that aminoglutethimide (AG), a drug previously used as an adrenal steroidogenesis inhibitor, is also a potent aromatase blocker. A similar in vivo effect of AG was suggested by clinical observations of suppressed plasma E1 without concomitant reductions in δ4-A concentrations in postmenopausal women given this drug. Based upon these considerations, we examined the in vivo effects of AG on the rate of aromatization of δ4-A to E1 by direct radioisotopic kinetic methods. AG inhibited the fractional conversion of δ4-A to E1 in blood from 1.65 ± 0.28% (se) before t...

Aminoglutethimide Inhibits Extraglandular Estrogen Production in Postmenopausal Women with Breast Carcinoma

For many decades, androgens have dominated endocrine research in hair growth control. Androgen metabolism and the androgen receptor currently are the key targets for systemic, pharmacological hair growth control in clinical medicine. However, it has long been known that estrogens also profoundly alter hair follicle growth and cycling by binding to locally expressed high-affinity estrogen receptors (ERs). Besides altering the transcription of genes with estrogen-responsive elements, 17beta-estradiol (E2) also modifies androgen metabolism within distinct subunits of the pilosebaceous unit (i.e., hair follicle and sebaceous gland). The latter displays prominent aromatase activity, the key enzyme for androgen conversion to E2, and is both an estrogen source and target. Here, we chart the recent renaissance of estrogen research in hair research; explain why the hair follicle offers an ideal, clinically relevant test system for studying the role of sex steroids, their receptors, and interactions in neuroectodermal-mesodermal interaction systems in general; and illustrate how it can be exploited to identify novel functions and signaling cross talks of ER-mediated signaling. Emphasizing the long-underestimated complexity and species-, gender-, and site-dependence of E2-induced biological effects on the hair follicle, we explore targets for pharmacological intervention in clinically relevant hair cycle manipulation, ranging from androgenetic alopecia and hirsutism via telogen effluvium to chemotherapy-induced alopecia. While defining major open questions, unsolved clinical challenges, and particularly promising research avenues in this area, we argue that the time has come to pay estrogen-mediated signaling the full attention it deserves in future endocrinological therapy of common hair growth disorders.

The Hair Follicle as an Estrogen Target and Source

There is considerable biologic evidence indicating that testosterone is the most important androgen in women. Testosterone production rates have been elevated in almost every virilized patient studied to date. Clinical evaluation of the hirsute patient, however, is complicated by the observation that plasma testosterone alone may not adequately reflect testosterone production. This relates to the fact that plasma androgen levels in women may be independently influenced by the rate of steroid entry into blood (production rate) as well as removal from blood (clearance). The testosterone production rate must be measured in hirsute women if a complete assessment of androgen metabolism is to be made. The origin of testosterone in normal and virilized women can best be determined by a combination of steroid kinetic studies and direct sampling of adrenal and ovarian venous effluents. In normal women about 65% of plasma testosterone is derived from plasma prehormones (androstenedione and dehydro-epiandrosterone) and 35% is apparently secreted by adrenals and ovaries. In clear-cut cases of adrenal or ovarian disease, excessive androgen production can usually be traced to the abnormal organ. In most women with idiopathic hirsutism, the ovaries, rather than the adrenals, are the most common sites of androgen oversecretion.

Androgen production and metabolism in normal and virilized women

Metabolic clearance and blood production rates of estrogens in postmenopausal women

The secretion of androgens and estrogens by normal and abnormal testes was compared by determining the concentrations of dehydroepiandrosterone (DHEA), androstenedione (Delta(4)A), testosterone (T), estrone (E(1)), and 17beta-estradiol (E(2)) in peripheral and spermatic venous plasma samples from 14 normal men and 5 men with unilateral testicular atrophy. Four normal men and one patient with unilateral atrophy of the testis were given human chorionic gonadotropin (HCG) before surgery. Plasma estrogens were determined by radioimmunoassay; plasma androgens were measured by the double-isotope dilution derivative technique. Peripheral concentrations of these steroids before and after HCG were similar in both the normal men and the patients with unilateral testicular atrophy. In normal men, the mean +/-SE spermatic venous concentrations were DHEA, 73.1+/-11.7 ng/ml; Delta(4)A, 30.7+/-7.9 ng/ml; T, 751+/-114 ng/ml; E(1), 306+/-55 pg/ml; and E(2), 1298+/-216 pg/ml. Three of four subjects with unilateral testicular atrophy had greatly diminished spermatic venous levels of androgens and estrogens. HCG treatment increased the testicular secretion of DHEA and T fivefold, Delta(4)A threefold, E(1) sixfold, and E(2) eightfold in normal men. In the single subject with an atrophic testis who received HCG, the spermatic venous concentrations of androgens and estrogens were much less than in normal men similarly treated. We conclude that: (a) E(1) is secreted by the human testis, but testicular secretion of E(1) accounts for less than 5% of E(1) production in normal men; (b) HCG stimulation produces increases in spermatic venous estrogens equal to or greater than the changes in androgens, including testosterone; and (c) strikingly decreased secretion of androgen and estrogen by unilateral atrophic human tests cannot be appreciated by analyses of peripheral steroid concentrations.

/pdf/secretion-of-unconjugated-androgens-and-estrogens-by-the-589rz55y80.pdf

Secretion of Unconjugated Androgens and Estrogens by the Normal and Abnormal Human Testis before and after Human Chorionic Gonadotropin

Adrenal secretion of androgens and oestrogens.

Concentrations of androgens and oestrogens in human adrenal venous blood

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Adrenal secretion of androgens and oestrogens.

Concentrations of androgens and oestrogens in human adrenal venous blood