Concentration of Sex Steroids in Adipose Tissue after Menopause

Szymczak, J; Milewicz, Andrzej; Thijssen, J. H. H.; Blankenstein, Marinus A.; Daroszewski, Jacek

doi:10.1016/s0039-128x(98)00019-1

Cited by 154 publications

(102 citation statements)

References 9 publications

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“…Obviously, androgens and androgen precursors must be present in adipose tissue, which was shown by several groups (Feher & Bodrogi 1982, Deslypere et al 1985, Szymczak et al 1998 including ours (Bélanger et al 2006). In the present study, the expression of several enzymes involved in androgen metabolism was detected in fat samples, including 5a-reductase-1, which is necessary for 5a-DHT formation.…”

Section: Discussionsupporting

confidence: 65%

Androgen inactivation and steroid-converting enzyme expression in abdominal adipose tissue in men

Blouin¹,

Richard²,

Brochu³

et al. 2006

Journal of Endocrinology

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We examined 5a-dihydrotestosterone (5a-DHT) inactivation and the expression of several steroid-converting enzymes with a focus on aldoketoreductases 1C (AKR1C), especially AKR1C2, in abdominal adipose tissue in men. AKR1C2 is mainly involved in the conversion of the potent androgen 5a-DHT to its inactive forms 5a-androstane3a/b,17b-diol (3a/b-diol). Subcutaneous (s.c.) and omental (Om) adipose tissue biopsies were obtained from 21 morbidly obese men undergoing biliopancreatic derivation surgery and 11 lean to obese men undergoing general abdominal surgery. AKR1C2 mRNA and 5a-DHT inactivation were detected in both s.c. and Om adipose tissue. After incubation of preadipocytes with 5a-DHT, both 3a-diol and 3b-diol were produced through 3a/b-ketosteroid reductase (3a/b-HSD) activity. In preadipocyte cultures, 3a-reductase activity was significantly predominant over 3b-reductase activity in cells from both the s.c. and Om compartments. Expression levels of AKR1C1, AKR1C3 and of the androgen receptor were significantly higher in s.c. versus Om adipose tissue while mRNA levels of 17b-HSD-2 (hydroxysteroid dehydrogenase type 2) and 3(a/b)-hydroxysteroid epimerase were significantly higher in Om fat. 3a/b-HSD activity was mainly detected in the cytosolic fraction, suggesting that AKR1C may be responsible for this reaction. Experiments with isoform-specific AKR1C inhibitors in preadipocytes showed that AKR1C2 inhibition significantly decreased 3a-HSD and 3b-HSD activities (3a-HSD: 30G24% of control for s.c. and 32G9% of control for Om, 3b-HSD: 44G12% of control for s.c.). When cells were incubated with both AKR1C2 and AKR1C3 inhibitors, no significant additional inhibition was observed. 5a-DHT inactivation was significantly higher in mature adipocytes compared with preadipocyte cultures in s.c. adipose tissue, as expressed per microgram total protein (755G830 versus 245G151 fmol 3a/b-diol per mg protein over 24 h, P!0 . 05 nZ10 cultures). 5a-DHT inactivation measured in tissue homogenates was significantly higher in the s.c. depot compared with Om fat (117G39 versus 79G 38 fmol 3a/b-diol per mg prot over 24 h, P!0 . 0001). On the other hand, Om 3a/b-HSD activity was significantly higher in obese men (body mass index (BMI)R30 kg/m 2 ) compared with lean and overweight men (84G37 versus 52G30 fmol 3a/b-diol per mg protein over 24 h, P!0 . 03). No difference was found in s.c. 3a/b-HSD activity between these groups. Positive correlations were found between s.c. 5a-DHT inactivation rate and circulating levels of the androgen metabolites androsterone-glucuronide (rZ0 . 41, P!0 . 02) and 3a-diol-glucuronide (rZ0 . 38, P!0 . 03) and with the adrenal precursor androstenedione (rZ0 . 42, P!0 . 02). In conclusion, androgen inactivation was detected in abdominal adipose tissue in men, with higher 3a/b-HSD activity in the s.c. versus Om depot. Higher Om 5a-DHT inactivation rates were found in obese compared with lean men. Further studies are required to elucidate whether local androgen inactivation in abdominal adipose tissue ...

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Section: Discussionsupporting

confidence: 65%

Androgen inactivation and steroid-converting enzyme expression in abdominal adipose tissue in men

Blouin¹,

Richard²,

Brochu³

et al. 2006

Journal of Endocrinology

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“…We have recently reported significant elevation of circulating estrogen metabolites with increased fat mass in overweight and obese women in this study population (Mahabir et al, 2006), and this suggests a third system for the observed folate reductions. Although the women did not take HRT, it is established that postmenopausal women aromatize adrenal androsteinedione to estrogen metabolites in adipose tissue (Nevton et al, 1986;Szymczak et al, 1998). Thus, in our overweight and obese subjects, peripheral conversion in the more abundant adipose tissue is a likely source for the elevated estrogen metabolites.…”

Section: Serum Folate Concentration and Measures Of Adiposity In Postmentioning

confidence: 88%

Measures of adiposity and body fat distribution in relation to serum folate levels in postmenopausal women in a feeding study

et al. 2007

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Objective: To assess the associations between serum folate concentration and measures of adiposity in postmenopausal women. Design: This study was conducted as a cross-sectional analysis within the control segment of a randomized, crossover trial in which postmenopausal women (n ¼ 51) consumed 0 g (control), 15 g (one drink) and 30 g (two drinks) alcohol (ethanol)/day for 8 weeks as part of a controlled diet. Subjects in one treatment arm were crossed-over to another arm after a 2-to 5-week washout period. Body mass index (BMI) was measured, and dual energy X-ray absorptiometry (DEXA) scan administered to the women during the control (0 g alcohol) treatment, and a blood sample from this group was collected at baseline and week 8 of each diet period and analyzed for folate, B12, homocysteine and methylmalonic acid. Setting: This study was conducted at the Beltsville Human Nutrition Research Center, MD, USA. Results: In multivariate analysis, women who were overweight had a 12% lower, and obese women had a 22% lower serum folate concentrations compared to normal weight women (P-trend ¼ 0.02). Vitamin B12 also decreased with increasing BMI (P-trend ¼ 0.08). Increased BMI, percent body fat, and absolute amounts of central and peripheral fat were all significantly associated with decreased serum folate, but were unrelated to serum B12, homocysteine or methylmalonic acid. Conclusions: Our data show that adiposity is associated with lower serum folate levels in postmenopausal women. With obesity at epidemic proportions, these data, if confirmed by prospective or randomized controlled studies, have important public health implications.

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“…When the tumors reached a measurable size (f300 mm 3 ), f6 weeks after MCF-7Ca cells were inoculated, animals were assigned to four groups with equivalent tumor volumes and injected s.c. daily with androstenedione supplement (100 Ag/d) and vehicle (control; n = 6), or androstenedione along with one of the following treatments: fulvestrant (1 mg/d; n = 7), letrozole (10 Ag/d; n = 18), or letrozole (10 Ag/d) plus fulvestrant (1 mg/d; n = 5). The doses of letrozole and fulvestrant used had been previously determined to be maximally effective in reducing tumor growth (15,22).…”

Section: Methodsmentioning

confidence: 99%

“…Production of estrogens in postmenopausal women occurs mainly via conversion of adrenal androgens mediated by aromatase in peripheral tissue, such as adipose tissue (2). Concentrations of estrogens in the breast are higher than in the circulation and equivalent to those in premenopausal women (3). Current treatments for postmenopausal hormone-dependent breast cancer patients include two strategies to reduce the effects of estrogens on tumor growth.…”

Section: Introductionmentioning

confidence: 99%

Additive Antitumor Effect of Aromatase Inhibitor Letrozole and Antiestrogen Fulvestrant in a Postmenopausal Breast Cancer Model

et al. 2005

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Blocking estrogen receptors with antiestrogens and blocking estrogen synthesis with aromatase inhibitors are two strategies currently being used for reducing the effect of estrogen in postmenopausal estrogen receptor-positive breast cancer patients. To optimize these treatment strategies, we have investigated whether tumor progression can be delayed by combining the pure antiestrogen fulvestrant with the nonsteroidal aromatase inhibitor letrozole. These studies were done in ovariectomized, athymic mice bearing tumors of estrogen receptor-positive human breast cancer cells stably transfected with the aromatase gene (MCF-7Ca). Groups of mice with equivalent tumor volumes were injected s.c. daily with vehicle (control; n = 6), fulvestrant (1 mg/d; n = 7), letrozole (10 Mg/d; n = 18), or letrozole (10 Mg/d) plus fulvestrant (1 mg/d; n = 5). All treatments were effective in suppressing tumor growth compared with controls (P < 0.001). Tumor volumes of the fulvestrant-treated group had doubled in 10 weeks. After 19 weeks of letrozole (10 Mg/d) treatment when tumors had nearly doubled in volume, mice (n = 18) were assigned to second-line therapy with letrozole (100 Mg/d; n = 6), tamoxifen (100 Mg/d; n = 6), or remained on letrozole treatment (10 Mg/d; n = 6). However, tumors continued to increase in volume in these groups. Tumors of animals treated with the combination of letrozole plus Faslodex regressed over 29 weeks of treatment by 45%. Thus, the combination of letrozole plus fulvestrant was more effective in suppressing tumor growth than either letrozole or fulvestrant alone or sequential therapies with tamoxifen or a higher dose of letrozole (100 Mg/d). (Cancer Res 2005; 65(12): 5439-44)

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Concentration of Sex Steroids in Adipose Tissue after Menopause

Cited by 154 publications

References 9 publications

Androgen inactivation and steroid-converting enzyme expression in abdominal adipose tissue in men

Androgen inactivation and steroid-converting enzyme expression in abdominal adipose tissue in men

Measures of adiposity and body fat distribution in relation to serum folate levels in postmenopausal women in a feeding study

Additive Antitumor Effect of Aromatase Inhibitor Letrozole and Antiestrogen Fulvestrant in a Postmenopausal Breast Cancer Model

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