Adipose aromatase gene expression is greater in older women and is unaffected by postmenopausal estrogen therapy.
ABSTRACT Although natural menopause is associated with loss of ovarian estrogen production, this life phase is followed by a significant increase in estrogen-related cancers, namely breast and endometrial cancer. These tissues, as well as adipose, skeletal, and vascular tissues and the brain are important sites of postmenopausal estrogen production. Circulating C19 steroid precursors are essential substrates for extragonadal estrogen synthesis; however, the levels of these androgenic precursors decline markedly with advancing age. This implies an increase in capacity for extragonadal tissues to produce estrogen with age.
To explore this, and the effects of the menopause transition and postmenopausal estrogen therapy on extragonadal estrogen biosynthesis, we have compared the expression of the aromatase gene and estrogen (ER) and androgen receptors (AR) in subcutaneous abdominal and gluteal fat taken from premenopausal (group 1: n = 11), postmenopausal (group 2: n = 10), and postmenopausal women taking estrogen therapy (group 3: n = 10). All subjects were of normal body mass index, euglycemic, and normolipemic.
The postmenopausal women were older (group 1, 43.1 +/- 5.0 vs groups 2 and 3, 57.9 +/- 7.4 years, P < 0.001 and 56.1 +/- 4.5 years, P < 0.001, respectively) and had lower serum estradiol levels (group 2, 22.2 +/- 3.2 vs group 1, 442.5 +/- 248.2 pmol/L, P < 0.05), which were restored to premenopausal levels with estrogen therapy. Expression analysis revealed that levels of transcripts encoding aromatase were greater in gluteal than abdominal depots in each group in postmenopausal versus premenopausal women (P < 0.05). Use of hormone therapy did not influence aromatase gene expression in either depot. No differences were detected in the expression of ER or AR between groups of between tissue depots.
Thus, the capacity of adipose tissue to produce estrogen seems to increase significantly with age at the time of menopause and to be unaltered by exogenous estrogen therapy. This difference in extragonadal estrogen production with age may play a pivotal role in the increase in estrogen-dependent malignancies in the postmenopausal years.
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ABSTRACT: Androgens play an important role in regulating the central obesity that is a strong risk factor for cardiovascular disease and insulin resistance. This study confirms that androgen receptors are present in subcultured human preadipocytes, with androgen receptor gene expression and saturable specific dihydrotestosterone binding, dissociation constant 1.02 - 2.56 nM and maximal binding capacity 30.8 - 55.7 fmol/mg protein. There was an intrinsic regional difference in androgen receptor complement, with more androgen receptors in visceral than in subcutaneous preadipocytes. Dihydrotestosterone was metabolised by human preadipocytes, with more androstanediol produced by subcutaneous than visceral preadipocytes. While dihydrotestosterone metabolism was insufficient to explain the regional variation in androgen binding, both of these differences would reduce the androgen responsiveness of the subcutaneous preadipocytes compared with visceral preadipocytes. There were no gender differences in androgen binding or metabolism. While the direct effects of androgens on human PAs remain uncertain, these regional differences suggest that AR-mediated regulation of certain PA functions influences adipose tissue distribution.Hormone and Metabolic Research 06/2002; 34(5):223-8. · 2.15 Impact Factor
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ABSTRACT: Family 19 of the P450 superfamily is responsible for the conversion of C19 androgenic steroids to the corresponding estrogens, a reaction known as aromatization, since it involves conversion of the delta 4-3-one A-ring of the androgens to the corresponding phenolic A-ring characteristic of estrogens. Its members occur throughout the entire vertebrate phylum. The reaction mechanism of aromatase is very interesting from a chemical point of view and has been studied extensively; however, a detailed examination of structure-function relationships has not been possible due to lack of a crystal structure. Recent attempts to model the three-dimensional structure of aromatase have permitted a model that accounts for the reaction mechanism and predicts the location of aromatase inhibitors. The gene encoding human aromatase has been cloned and characterized and shown to be unusual compared to genes encoding other P450 enzymes, since there are a number of untranslated first exons that occur in aromatase transcripts in a tissue-specific fashion, due to differential splicing as a consequence of the use of tissue-specific promoters. Thus, expression in ovary utilizes a proximal promoter that is regulated primarily by cAMP. On the other hand, expression in placenta utilizes a distal promoter that is located at least 40 kb upstream of the start of transcription and that is regulated by retinoids. Other promoters are employed in brain and adipose tissue. In the latter case, class I cytokines such as IL-6 and IL-11 as well as TNF alpha are important regulatory factors. PGE2 is also an important regulator of aromatase expression in adipose mesenchymal cells via cAMP and PGE2 appears to be a major factor produced by breast tumors that stimulates estrogen biosynthesis in local mesenchymal sites. In all of the splicing events involved in the use of these various promoters, a common 3'-splice junction is employed that is located upstream of the start of translation; thus, the coding regions of the transcripts- and hence the protein-are identical regardless of the tissue site of expression; what differ in a tissue-specific fashion are the 5'-ends of the transcripts. This pattern of expression has great significance both from a phylogenetic and ontogenetic standpoint as well as for the physiology and pathophysiology of estrogen formation. Recently, a number of mutations of the aromatase gene have been described, which give rise to complete estrogen deficiency. In females this results in virilization in utero and primary amenorrhea with hypergonadotropic hypogonadism at the time of puberty. In men the most striking feature is continued linear bone growth beyond the time of puberty, delayed bone age, and failure of epiphyseal closure, thus indicating an important role of estrogens in bone metabolism in men. In both sexes the symptoms can be alleviated by estrogen administration.Recent Progress in Hormone Research 02/1997; 52:185-213; discussion 213-4.
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ABSTRACT: Circulating androstenedione is converted to estrone in adipose tissue, which is the principal site of estrogen biosynthesis in postmenopausal women. This reaction is catalyzed by a specific form of cytochrome P450 (P450arom; the product of the CYP19 gene). The fractional conversion of plasma androstenedione to estrone as well as the specific activity of aromatase in adipose stromal cells were previously shown to increase with advancing age. To determine whether this positive effect of aging on estrogen biosynthesis is due to an alteration in tissue levels of P450arom transcripts, we quantified P450arom mRNA levels in sc fat biopsy samples (n = 33) from buttocks, thighs, and abdomen of 11 women who ranged in age from 23-61 yr. Competitive polymerase chain reaction linked to reverse transcription was used to quantify P450arom transcripts in total RNA that was isolated from sc fat obtained by needle aspiration. In each sample, primer extension and coamplification of a rat P450arom cRNA as an internal standard were used to control possible differences in amplification efficiencies between samples. The results demonstrate that with advancing age in women, there is a progressive and statistically significant increase in adipose tissue P450arom transcript levels (normalized to total RNA content) in buttocks, thighs, and abdomen (correlation coefficients: r = 0.704, 0.854, and 0.933, respectively). The levels of transcripts observed in the older subjects reach 2- to 4-fold greater than those observed in the young women. Adipose tissue P450arom transcript levels were highest in the buttocks, followed by the thighs, and lowest in the abdomen. This increase in P450arom transcript levels is likely to be a major factor contributing to the increased extragonadal estrogen biosynthesis in elderly women.Journal of Clinical Endocrinology & Metabolism 03/1994; 78(2):428-32. · 6.43 Impact Factor