Alterations in cholesterol regulation contribute to the production of intratumoral androgens during progression to castration‐resistant prostate cancer in a mouse xenograft model

León, Carlos; Locke, Jennifer A.; Adomat, Hans; Etinger, Susan L.; Twiddy, Alexis L.; Neumann, Rachel D.; Nelson, Colleen C.; Guns, Emma S. Tomlinson; Wasan, Kishor M.

doi:10.1002/pros.21072

Cited by 147 publications

(170 citation statements)

References 55 publications

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“…"Activation by predecessors" is characteristic of these reactions: an increase in the levels of the preceding substrates stimulates formation of the product of the last stage. This behavior is common to all living organisms [27]. Cholesterol is the main predecessor of the formation of steroid hormones (including testosterone), and at earlier stages -glucose [27].…”

Section: The Influence Of Partial Androgen Deficiency Among Aging Menmentioning

confidence: 99%

“…This behavior is common to all living organisms [27]. Cholesterol is the main predecessor of the formation of steroid hormones (including testosterone), and at earlier stages -glucose [27]. When testosterone production goes down with age, there is a compensatory increase in cholesterol and glucose levels -substrates for the subsequent synthesis of testosterone [8,14,15,16].…”

Section: The Influence Of Partial Androgen Deficiency Among Aging Menmentioning

confidence: 99%

“…Insulin, which is an activator of enzymes of glycolysis, and a suppressor of the enzymes of gluconeogenesis, controls the correlation of activity of these processes [27]. Glucocorticoids serve as an activator of the enzymes of gluconeogenesis and as a suppressor of the enzymes of glycogenesis [30].…”

Section: Role Of Partial Androgen Deficiency Of Aging Men In Developmmentioning

confidence: 99%

“…Glucocorticoids serve as an activator of the enzymes of gluconeogenesis and as a suppressor of the enzymes of glycogenesis [30]. Therefore, in the presence of insulin resistance, which is accompanied by an increase in the incretion of corticosteroids and a decrease in the influence of insulin, the intensity of gluconeogenesis by means of the stimulation of the corresponding enzymes in the liver and the kidneys increases [27]. Insulin resistance, and the increase in insulin which accompanies it, leads to dislipoproteinemia, especially to hypertriglyceridemia, since the surplus of insulin stimulates lipogenesis and the synthesis of low-density lipoprotein in the liver [13].…”

Section: Role Of Partial Androgen Deficiency Of Aging Men In Developmmentioning

confidence: 99%

“…High concentrations of esterified and free cholesterol are collected in the cytoplasm of arterial macrophages, thereby transforming them into foamy cells. When these cells are destroyed, cholesterol is then collected in the walls of the arteries [27]. An increased level of glucose, which is necessary for this process, is supported thanks to insulin resistance.…”

Section: Role Of Partial Androgen Deficiency Of Aging Men In Developmmentioning

confidence: 99%

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Role of Partial Androgen Deficiency of Aging Men in Development of the Metabolic Syndrome

2017

American Research Journal of Urology

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Once people reach 35-40 years of age, they have a decrease in their pool of pluripotent stem cells [1], show a violation of tissue renewal, a decrease in the number of cell-producers of testosterone (Leidig cells), and a reduction in testosterone circulating in the blood [2,3,4]. This reduction of testosterone is named partial androgen deficiency of aging men (PADAM) [5].Cells of a number of tissues have androgen receptors. These cells, in the process of their development from low-differentiated androgen-independent cells, transform into differentiated androgen-dependent cells [6]. Low-differentiated progenitor cells show incipient characters of differentiation, and continue division. When dividing, they produce progeny, a part of which continues to divide, while another part remains low-differentiated [7]. When cells acquire androgen receptors, their further division and differentiation becomes impossible without the availability of a sufficient amount of testosterone increted in the physiological impulse regime by Leidig cells [8,9].PADAM violates division and differentiation of androgen-dependent cells. Deficiency of testosterone production results in atrophy of tissues consisting of these cells [2,10]. The answer to insufficient production of testosterone is given by a series of compensatory-adaptive reactions affecting autocrine, paracrine and endocrine levels [8]. Compensatory reactions are aimed at additional formation of mitogenic factors (cell growth factors, 5α-dihydrotestosterone, 17β-estradiol, insulin, somatotropic hormone and other factors), having a stimulating effect on proliferation of the epithelium and other tissues. A decrease in the level of testosterone induces an increase in mitotic activity, disruption of regulation of cells, as well as inhibition of apoptosis. The intensity of these reactions is proportional to the degree of reduction in testosterone production [8,9,10,11]. An increase in mitogenic stimulation in patients older than 35-40 years old, associated with a decrease in sex hormones, is complemented by an increase in mitogenic stimulation caused by violation of tissue regeneration [2, 3, 4].PADAM provokes a breach of the mechanisms of regulation in the system of the gonads-hypophysis-hypothalamus, including an increase in activity of the hypophysis [12]. In view of the interdependence of the neurohumoral regulatory processes [13], a reduction in the production of testosterone is reflected on endocrinal regulation as a whole [8,9,11,14,15]. Abstract: Insulin resistance, on an equal basis with an increase in proliferative activity, is a manifestation of metabolic syndrome. They reflect a set of compensatory and adaptive reactions that develop in men over 35-40 years old, and are substantially caused by a decrease in testosterone production. The inverse development of the specified compensatory reactions is observed following correction of partial androgen deficiency of aging men.

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Section: The Influence Of Partial Androgen Deficiency Among Aging Menmentioning

confidence: 99%

Section: The Influence Of Partial Androgen Deficiency Among Aging Menmentioning

confidence: 99%

Section: Role Of Partial Androgen Deficiency Of Aging Men In Developmmentioning

confidence: 99%

Section: Role Of Partial Androgen Deficiency Of Aging Men In Developmmentioning

confidence: 99%

Section: Role Of Partial Androgen Deficiency Of Aging Men In Developmmentioning

confidence: 99%

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Role of Partial Androgen Deficiency of Aging Men in Development of the Metabolic Syndrome

2017

American Research Journal of Urology

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Concept and viability of androgen annihilation for advanced prostate cancer

Mohler

2014

Cancer

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There remains no standard of care for patients with a rising prostate-specific antigen (PSA) after radical prostatectomy or radiation therapy but who have no radiographic metastases, even though this is the second largest group of prostate cancer (CaP) patients in the United States. Androgen deprivation therapy (ADT) may cure some men with advanced CaP based on single institution series and a randomized clinical trial of immediate versus delayed ADT for men found to have pelvic lymph node metastasis at the time of radical prostatectomy. ADT may be more effective when initiated for minimal disease burden, which can be detected using PSA after radical prostatectomy or radiation therapy, and if more complete disruption of the androgen axis using newer agents decreases the chance that androgen-sensitive cells survive to adapt to a low androgen environment. Androgens may be “annihilated” sing simultaneously a luteinizing hormone releasing hormone (LHRH) antagonist or agonist to inhibit testicular production of testosterone, a cytochrome P45017A1 (CYP17A1) inhibitor to diminish metabolism of testosterone via the adrenal pathway and dihydrotestosterone (DHT) via the backdoor pathway, a 5α-reductase inhibitor to diminish testosterone reduction to DHT and backdoor metabolism of progesterone substrates to DHT, and a newer anti-androgen to compete better with DHT for the androgen receptor ligand-binding domain. Early initiation of androgen annihilation for induction as part of planned intermittent ADT should be safe, may reduce tumor burden below a threshold that allows eradication by the immune system, and may cure many men who have failed definitive local therapy.

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Serum lipids and prostate cancer

Garrido

Marta

Ribeiro

et al. 2021

Clinical Laboratory Analysis

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Alterations in cholesterol regulation contribute to the production of intratumoral androgens during progression to castration‐resistant prostate cancer in a mouse xenograft model

Abstract: Cellular cholesterol regulation processes are altered during progression to CRPC. Free cholesterol from increased biosynthesis or uptake is likely a precursor for intratumoral de novo androgen synthesis.

Cited by 147 publications

References 55 publications

Role of Partial Androgen Deficiency of Aging Men in Development of the Metabolic Syndrome

Role of Partial Androgen Deficiency of Aging Men in Development of the Metabolic Syndrome

Concept and viability of androgen annihilation for advanced prostate cancer

Serum lipids and prostate cancer

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