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The role of ovarian sex steroids in metabolic homeostasis, obesity, and postmenopausal breast cancer: molecular mechanisms and therapeutic implications.

Boonyaratanakornkit V, Pateetin P - Biomed Res Int (2015)

Bottom Line: The cessation of ovarian function after menopause results in withdrawal of ovarian sex steroid hormones, estrogen, and progesterone.Accumulating evidence suggests that the withdrawal of estrogen and progesterone causes homeostasis imbalances, including decreases in insulin sensitivity and leptin secretion and changes in glucose and lipid metabolism, resulting in a total reduction in energy expenditure.In addition, obese women have a higher risk of insulin insensitivity, and an increase in insulin and other growth factor secretion.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, 154 Rama I Road Patumwan, Bangkok 10330, Thailand.

ABSTRACT
Obese postmenopausal women have an increased risk of breast cancer and are likely to have a worse prognosis than nonobese postmenopausal women. The cessation of ovarian function after menopause results in withdrawal of ovarian sex steroid hormones, estrogen, and progesterone. Accumulating evidence suggests that the withdrawal of estrogen and progesterone causes homeostasis imbalances, including decreases in insulin sensitivity and leptin secretion and changes in glucose and lipid metabolism, resulting in a total reduction in energy expenditure. Together with a decrease in physical activity and consumption of a high fat diet, these factors significantly contribute to obesity in postmenopausal women. Obesity may contribute to breast cancer development through several mechanisms. Obesity causes localized inflammation, an increase in local estrogen production, and changes in cellular metabolism. In addition, obese women have a higher risk of insulin insensitivity, and an increase in insulin and other growth factor secretion. In this review, we describe our current understanding of the molecular actions of estrogen and progesterone and their contributions to cellular metabolism, obesity, inflammation, and postmenopausal breast cancer. We also discuss how modifications of estrogen and progesterone actions might be used as a therapeutic approach for obesity and postmenopausal breast cancer.

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Diagram linking menopause and alterations in cellular metabolism with obesity and breast cancer. FAS: saturated fatty acid; TCA: tricarboxylic acid cycle; TNFα: tumor necrosis factor α; IL-1: interleukin-1; IL-6, interleukin-6; SHBG: sex hormone binding globulin; E2: estradiol; IGF-1: insulin-like-growth-factor-1.
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fig1: Diagram linking menopause and alterations in cellular metabolism with obesity and breast cancer. FAS: saturated fatty acid; TCA: tricarboxylic acid cycle; TNFα: tumor necrosis factor α; IL-1: interleukin-1; IL-6, interleukin-6; SHBG: sex hormone binding globulin; E2: estradiol; IGF-1: insulin-like-growth-factor-1.

Mentions: It is well established that chronic inflammation increases cancer risk [90]. Obesity is associated with adipose tissue inflammation, characterized by macrophage infiltration into the adipose deposit [12]. In addition, large adipose deposits in obese individuals could have limited blood supply resulting in adipose tissue hypoxia [91] and induction of hypoxic-inducible factor 1-α (HIF-α) expression in adipocytes. HIF1α in turn stimulates expression of monocyte chemotactic factor 1 (MCP1), promoting macrophage recruitment to adipose deposits. In addition, production of saturated fatty acids by the breakdown of large fat droplets in large adipocytes in obese individuals can lead to activation of caspase-1, interleukin-1 β, and the NF-κB signaling cascade [92]. Together, adipocytes and macrophages in adipose tissue induce expression of inflammatory cytokines such as TNF-α, IL-6, and prostaglandin-E2 (PGE2) [90] (Figure 1).


The role of ovarian sex steroids in metabolic homeostasis, obesity, and postmenopausal breast cancer: molecular mechanisms and therapeutic implications.

Boonyaratanakornkit V, Pateetin P - Biomed Res Int (2015)

Diagram linking menopause and alterations in cellular metabolism with obesity and breast cancer. FAS: saturated fatty acid; TCA: tricarboxylic acid cycle; TNFα: tumor necrosis factor α; IL-1: interleukin-1; IL-6, interleukin-6; SHBG: sex hormone binding globulin; E2: estradiol; IGF-1: insulin-like-growth-factor-1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383469&req=5

fig1: Diagram linking menopause and alterations in cellular metabolism with obesity and breast cancer. FAS: saturated fatty acid; TCA: tricarboxylic acid cycle; TNFα: tumor necrosis factor α; IL-1: interleukin-1; IL-6, interleukin-6; SHBG: sex hormone binding globulin; E2: estradiol; IGF-1: insulin-like-growth-factor-1.
Mentions: It is well established that chronic inflammation increases cancer risk [90]. Obesity is associated with adipose tissue inflammation, characterized by macrophage infiltration into the adipose deposit [12]. In addition, large adipose deposits in obese individuals could have limited blood supply resulting in adipose tissue hypoxia [91] and induction of hypoxic-inducible factor 1-α (HIF-α) expression in adipocytes. HIF1α in turn stimulates expression of monocyte chemotactic factor 1 (MCP1), promoting macrophage recruitment to adipose deposits. In addition, production of saturated fatty acids by the breakdown of large fat droplets in large adipocytes in obese individuals can lead to activation of caspase-1, interleukin-1 β, and the NF-κB signaling cascade [92]. Together, adipocytes and macrophages in adipose tissue induce expression of inflammatory cytokines such as TNF-α, IL-6, and prostaglandin-E2 (PGE2) [90] (Figure 1).

Bottom Line: The cessation of ovarian function after menopause results in withdrawal of ovarian sex steroid hormones, estrogen, and progesterone.Accumulating evidence suggests that the withdrawal of estrogen and progesterone causes homeostasis imbalances, including decreases in insulin sensitivity and leptin secretion and changes in glucose and lipid metabolism, resulting in a total reduction in energy expenditure.In addition, obese women have a higher risk of insulin insensitivity, and an increase in insulin and other growth factor secretion.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, 154 Rama I Road Patumwan, Bangkok 10330, Thailand.

ABSTRACT
Obese postmenopausal women have an increased risk of breast cancer and are likely to have a worse prognosis than nonobese postmenopausal women. The cessation of ovarian function after menopause results in withdrawal of ovarian sex steroid hormones, estrogen, and progesterone. Accumulating evidence suggests that the withdrawal of estrogen and progesterone causes homeostasis imbalances, including decreases in insulin sensitivity and leptin secretion and changes in glucose and lipid metabolism, resulting in a total reduction in energy expenditure. Together with a decrease in physical activity and consumption of a high fat diet, these factors significantly contribute to obesity in postmenopausal women. Obesity may contribute to breast cancer development through several mechanisms. Obesity causes localized inflammation, an increase in local estrogen production, and changes in cellular metabolism. In addition, obese women have a higher risk of insulin insensitivity, and an increase in insulin and other growth factor secretion. In this review, we describe our current understanding of the molecular actions of estrogen and progesterone and their contributions to cellular metabolism, obesity, inflammation, and postmenopausal breast cancer. We also discuss how modifications of estrogen and progesterone actions might be used as a therapeutic approach for obesity and postmenopausal breast cancer.

Show MeSH
Related in: MedlinePlus