Plasma Precursors of Estrogen. II. Correlation of the Extent of Conversion of Plasma Androstenedione to Estrone with Age<sup>1</sup>

Hemsell, David L.; Grodin, Jerrold; Brenner, Paul F.; Siiteri, Pentti K.; MacDonald, Paul C.

doi:10.1210/jcem-38-3-476

Cited by 428 publications

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“…The percentage of body fat is higher in women than men and increases with age in both sexes (47,48). The reported age-related increase in androgen aromatization might be attributed to this phenomenon (49). These sex-and age-related changes in body composition might have biased our estimates.…”

Section: Dheas Stratummentioning

confidence: 86%

A direct approach to the estimation of the origin of oestrogens and androgens in elderly men by comparison with hormone levels in postmenopausal women

et al. 2005

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Objective: The origin of oestrogens in men is only partly understood. From infusion studies with radioactively labelled hormones, we know that oestradiol (E2) and oestrone (E1) are either directly secreted by the testes and adrenal glands or peripherally produced from testicular or adrenal androgens. Design and methods: We determined E2, E1, androstenedione, testosterone and dehydroepiandrosterone sulphate (DHEAS) in 292 elderly men and 367 postmenopausal women. We considered postmenopausal women as men without testes, assuming that the postmenopausal ovary is not endocrinologically active and that the testes do not contribute to circulating levels of DHEAS. Subjects were stratified by DHEAS levels to adjust for differences in DHEAS levels between sexes. For men and women separately, mean levels of E2, E1, androstenedione and testosterone were calculated per DHEAS stratum. The relative direct and indirect contributions of the testes to steroid levels in men were calculated by the formula [(C m -C f )/C m ] £ 100%, in which C m and C f represent the mean concentrations of the steroid in men and women respectively. Results: The relative contributions (%) of the testes to hormone levels per DHEAS stratum (, 2, 2-4, 4 -6 and .6 mmol/l) respectively were, for E2, 72%, 60%, 52% and 44%; for E1, 54%, 47%, 35% and 34%; for androstenedione, 14%, 4%, 12% and 0%; and, for testosterone, 88%, 88%, 87% and 83%. Conclusions: We conclude that in elderly men dependent on DHEAS levels, 44-72% of E2 and 34-54% of E1 originate directly or indirectly from the testes.European Journal of Endocrinology 152 261-268

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Section: Dheas Stratummentioning

confidence: 86%

A direct approach to the estimation of the origin of oestrogens and androgens in elderly men by comparison with hormone levels in postmenopausal women

et al. 2005

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“…Incidence of this malignancy increases as women age. In postmenopausal women, the ovaries are no longer the major source of estrogen synthesis and production of estrogens occurs mainly in peripheral tissue, such as adipose tissue (2). Endocrine therapy is the most important treatment for hormone-dependent postmenopausal breast cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Activation of Mitogen-Activated Protein Kinase in Xenografts and Cells during Prolonged Treatment with Aromatase Inhibitor Letrozole

et al. 2005

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Ovariectomized mice bearing tumor xenografts grown from aromatase-transfected estrogen receptor (ER)-positive human breast cancer cells (MCF-7Ca) were injected s.c. with 10 Mg/d letrozole for up to 56 weeks. Western blot analysis of the tumors revealed that ERs (ERA) were increased at 4 weeks but decreased at weeks 28 and 56. Expression of erbB-2 and p-Shc increased throughout treatment, whereas growth factor receptor binding protein 2 (Grb2) increased only in tumors proliferating on letrozole (weeks 28 and 56). In cells isolated from tumors after 56 weeks and maintained as a cell line (LTLT-Ca) in 1 Mmol/L letrozole, ERA was also decreased whereas erbB-2, adapter proteins (p-Shc and Grb2), and the signaling proteins in the mitogen-activated protein kinase (MAPK) cascade were increased compared with MCF-7Ca cells. Growth was inhibited in LTLT-Ca cells but not in MCF7Ca cells treated with MAPK kinase 1/2 inhibitors U0126, and PD98059 (IC 50 f25 Mmol/L). PD98059 (5 Mmol/L) also reduced MAPK activity and increased ERA to the levels in MCF-7Ca cells. Epidermal growth factor receptor kinase inhibitor, gefitinib (ZD1839) inhibited growth of LTLT-Ca cells (IC 50 f10 Mmol/L) and restored their sensitivity to tamoxifen and anastrozole. In xenografts, combined treatment with ER down-regulator fulvestrant and letrozole, prevented increases in erbB-2 and activation of MAPK and was highly effective in inhibiting tumor growth throughout 29 weeks of treatment. These results indicate that blocking both ER-and growth factor-mediated transcription resulted in the most effective inhibition of growth of ER-positive breast cancer cells. (Cancer Res 2005; 65(12): 5380-9)

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“…Although the incidence of breast cancer increases with age, circulating levels of estrogen are low in postmenopausal women as the ovaries are no longer the major source of the estrogen synthesis. 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).…”

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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Plasma Precursors of Estrogen. II. Correlation of the Extent of Conversion of Plasma Androstenedione to Estrone with Age¹

Cited by 428 publications

References 0 publications

A direct approach to the estimation of the origin of oestrogens and androgens in elderly men by comparison with hormone levels in postmenopausal women

A direct approach to the estimation of the origin of oestrogens and androgens in elderly men by comparison with hormone levels in postmenopausal women

Activation of Mitogen-Activated Protein Kinase in Xenografts and Cells during Prolonged Treatment with Aromatase Inhibitor Letrozole

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

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Plasma Precursors of Estrogen. II. Correlation of the Extent of Conversion of Plasma Androstenedione to Estrone with Age1

Cited by 428 publications

References 0 publications

A direct approach to the estimation of the origin of oestrogens and androgens in elderly men by comparison with hormone levels in postmenopausal women

A direct approach to the estimation of the origin of oestrogens and androgens in elderly men by comparison with hormone levels in postmenopausal women

Activation of Mitogen-Activated Protein Kinase in Xenografts and Cells during Prolonged Treatment with Aromatase Inhibitor Letrozole

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

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Plasma Precursors of Estrogen. II. Correlation of the Extent of Conversion of Plasma Androstenedione to Estrone with Age¹