Morphological evidence of the possible relevance of aromatase P450 in autoparacrine regulation and pathology of the hypophysis

Aromatase P450, the enzyme responsible for the catabolism of aromatizable androgens to estrogens is involved in sexual dimorphism and several pathologies induced by estrogenic effects. The present work reports evidence of pituitary aromatase synthesis, its regulation by gonadal steroids, and the physiological roles of aromatase on pituitary endocrine cells. The involvement of aromatase, through the auto-paracrine production of estradiol, in the pathogenesis of pituitary tumors -mainly prolactinomas- is reviewed

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Adenocarcinoma pulmonar con ginecomastia dependiente de aromatasa / Aromatase-dependent gynecomastia in a patient with adenocarcinoma of the lung

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Exemestane and aromatase inhibitors in the management of advanced breast cancer.

In metastatic breast cancer, orally-active, potent, selective third-generation nonsteroidal inhibitors and steroidal inactivators have shown superiority over tamoxifen, a selective oestrogen receptor modulator. In advanced breast cancer, aromatase inhibitors and inactivators are becoming established as the standard of care over tamoxifen in postmenopausal female breast cancer patients when hormonal therapy is indicated for first-line treatment. Emerging research evidence and ongoing clinical investigations look likely to further extend the use of these potent agents across several additional treatment settings in the management of breast cancer. Several multi-centre studies are underway examining the role of novel hormonal therapy in the adjuvant treatment of early breast cancer and other investigations will explore possible future applications of these potent antiaromatase agents, including breast cancer prevention.

Gender difference in letrozole pharmacokinetics in rats.

AIM: To study gender difference in letrozole (Letr) pharmacokinetics in rats. METHODS: Letr concentrations in plasma and tissues were determined after ig administration of Letr 2 mg/kg. Recoveries of Letr in urine and feces were also analyzed. RESULTS: Marked gender differences were found 6 h after ig Letr 2 mg/kg, the plasma concentrations of Letr in male rats were significantly (P < 0.01) lower than those in female rats. For example, at 24, 36, 48, and 72 h after administration, plasma concentrations in female rats were about 3.3, 5.6, 10.5, and 7.4-fold of that of male rats, respectively. AUC value of Letr in male was only about one-third of that in female rats. Estimated terminal phase half-lives (T1/2) were 10.5 and 40.4 h, respectively. In female rats, cumulative excreted fractions of Letr in urine and feces were 5.8% +/- 1.4% and 6.6% +/- 1.1% within 120 h after administration, respectively, but in male rats, the excreted fractions of Letr in urine and feces were only 1.30% +/- 0.59% and 0.87% +/- 0.31%. Letr concentrations in female rat tissues were significantly (P < 0.01) higher than those in male rat tissues 24 h after administration. CONCLUSION: There are marked gender differences in Letr pharmacokinetics in rats.

Double-blind, randomised, multicentre endocrine trial comparing two letrozole doses, in postmenopausal breast cancer patients.

Letrozole is an orally competitive aromatase inhibitor. This double-blind, randomised, multicentre trial was carried out to evaluate the endocrine effects of two doses of letrozole, 0.5 mg versus 2.5 mg orally daily, in postmenopausal advanced breast cancer patients progressing after tamoxifen. The pharmacokinetics of letrozole was also assessed. 46 patients entered the trial, 22 on letrozole 0.5 mg and 24 on 2.5 mg. A significant suppression of oestrone and oestradiol levels was achieved by both letrozole doses. Neither letrozole dose induced any changes in cortisol and aldosterone production at rest or after Synacthen stimulation. Androstenedione, testosterone, 17 alpha-OH progesterone, triiodothyronine (T3) thyroxine, (T4) and thyroid-stimulating hormone (TSH) plasma levels did not show any significant changes. Sex hormone binding globulin (SHBG), follicle-stimulating hormone (FSH) and luteinising hormone (LH) levels increased significantly over time. Plasma letrozole concentrations increased until reaching steady-state values after 1 month at the dose of 0.5 mg and after 2 months at 2.5 mg. In conclusion, both letrozole doses suppressed oestrogen levels without affecting adrenal activity.

Widespread tissue distribution of steroid sulfatase, 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD), 17 beta-HSD 5 alpha-reductase and aromatase activities in the rhesus monkey.

Dehydroepiandrosterone-sulfate (DHEA-S), the main secretory product of the human adrenal, requires the presence of steroid sulfatase, 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD), 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), 5 alpha-reductase, and aromatase to form the active androgen dihydrotestosterone (DHT) and the estrogens 17 beta-estradiol (E2) and 5-androst-ene-3 beta,17 beta-diol (delta 5-diol) in peripheral target tissues. Because humans, along with non-human primates are unique in having adrenals that secrete large amounts of DHEA-S, the present study investigated the tissue distribution of the enzymatic activity of the above-mentioned steroidogenic enzymes required for the formation of active sex steroids in the male and female rhesus monkey. Estrone and DHEA sulfatase activities were measured in all 25 tissues examined, and with the exception of the salivary glands, estrogenic and androgenic 17 beta-HSDs were present in all the tissues examined. The adrenal, small and large intestine, kidney, liver, lung, fat, testis, prostate, seminal vesicle, ovary, myometrium, and endometrium all possess the above-mentioned enzymatic activities, thus suggesting that these tissues could possibly form the biologically active steroids E2 and DHT from the adrenal precursor DHEA-S. On the other hand, the oviduct, cervix, mammary gland, heart, and skeletal muscle possess all the enzymatic activities required to synthesize E2 from DHEA-S. The present study describes the widespread tissue distribution of steroid sulfatase, 3 beta-HSD, 17 beta-HSD, 5 alpha-reductase, and aromatase activities in rhesus monkey peripheral tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Aromatase activity in purified Leydig cells from adult rat. Comparative effects of insulin, IGF-I, and hCG.

The comparative effects of insulin and IGF-I on aromatization in adult rat purified Leydig cells were examined to elucidate the mechanism of action of the peptides in testicular steroidogenesis. Aromatase activity was measured in short-time incubations, using the tritiated water release method with [1 beta-3H] and androstenedione as substrate. In the presence of varying concentrations of substrate, the apparent Km for androstenedione was 0.945 mol/l; treatment of cells with insulin, IGF-I and hCG markedly increased the apparent maximal velocity, without modifying Km; peptides were more potent in aromatase stimulation than hCG alone or in combination with either peptides. When related to time (0-4 h) and expressed as percent of control values, aromatase activity in the presence of insulin, IGF-I and/or hCG exhibited a significant and transient increase at 15-30 min. In order to clarify the nature of this early stimulation, the effects of dibutyryl cAMP, various antibiotics, and cytochalasin B on treated Leydig cells were analysed. Results indicated that insulin and IGF-I action on aromatization was not cAMP-dependent; peptides could intervene by increasing RNA and protein, but not DNA, synthesis; they were also effective in glucose transport. These data suggest that insulin and IGF-I are able to modulate aromatization in Leydig cells.