Neuroendocrine Regulation of Growth Hormone and Androgen Axes by Selective Estrogen Receptor Modulators in Healthy Men

Birzniece, Vita; Sata, Akira; Sutanto, Surya

doi:10.1210/jc.2010-1477

Cited by 18 publications

(12 citation statements)

References 28 publications

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“…Hormone replacement therapy with testosterone has been shown to be beneficial in older hypogonadal men, improving sexual function and mild mood symptoms [97]; however, the potential long-term side effects, such as cardiovascular events and prostate cancer [22, 98], are risks of testosterone replacement therapy. Increased testosterone levels are an effect of raloxifene treatment in nonpsychiatric samples [40-43]. Thus, in addition to potentially stimulating abnormal ERs in the brains of people with schizophrenia [99], raloxifene has the potential benefit of increasing testosterone levels in patients with depleted circulating testosterone.…”

Section: Discussionmentioning

confidence: 99%

“…Overall, most studies confirm a relatively beneficial effect of raloxifene in patients with schizophrenia, despite inconsistencies as to which clinical aspects (symptoms or cognition) are ameliorated by the drug [32, 35, 36]. Raloxifene increased sex steroid levels in healthy samples, including estrogen in women [37-39] and testosterone in men [40-43], although several studies found no change in testosterone levels in either sex with raloxifene treatment [39, 44-46]. Modification of circulating testosterone levels may be a mechanism by which raloxifene elicits beneficial effects in patients with schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

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Sex-Specific Associations of Androgen Receptor CAG Trinucleotide Repeat Length and of Raloxifene Treatment with Testosterone Levels and Perceived Stress in Schizophrenia

et al. 2018

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Lower testosterone levels are associated with greater negative symptoms in men with schizophrenia. Testosterone signals via androgen receptor (AR). A functional variant in the AR gene (CAG trinucleotide repeat polymorphism) is associated with circulating testosterone and mood-related symptoms in healthy people. Raloxifene increases testosterone in healthy males and reduces symptom severity and improves cognition in schizophrenia; however, whether raloxifene increases testosterone in men with schizophrenia is unknown. We assessed the interaction of a functional AR gene variant and adjunctive raloxifene on peripheral testosterone and symptom severity in schizophrenia. Patients with schizophrenia (59 males and 38 females) participated in a randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene (120 mg/day). Healthy adults (46 males and 41 females) were used for baseline comparison. Baseline circulating testosterone was decreased in male patients compared to male controls and positively correlated with CAG repeat length in male controls and female patients. Male patients with short, compared to long, CAG repeat length had higher stress scores. Raloxifene treatment increased testosterone in male patients, but was unrelated to AR CAG repeat length, suggesting that raloxifene’s effects may not depend on AR activity. Sex-specific alterations of the relationship between AR CAG repeat length and testosterone suggest that altered AR activity may impact perceived stress in men with schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sex-Specific Associations of Androgen Receptor CAG Trinucleotide Repeat Length and of Raloxifene Treatment with Testosterone Levels and Perceived Stress in Schizophrenia

et al. 2018

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“…E 2 derived from aromatisation also mediates the negative feedback of testosterone on LH secretion (3,24). Thus, by blocking central estrogen action, tamoxifen removes testosterone feedback inhibition, enhancing LH secretion and increasing testosterone production in men (5). Tamoxifen suppressed the GH axis to a lesser degree in men than in women.…”

Section: Discussionmentioning

confidence: 99%

“…Tamoxifen also enhanced LH secretion and increased testosterone levels in men (5). As testosterone stimulates GH secretion (1), it is conceivable that the higher testosterone levels induced by tamoxifen in men mitigated the suppression of GH release.…”

Section: Introductionmentioning

confidence: 99%

Estrogen receptor antagonism uncovers gender-dimorphic suppression of whole body fat oxidation in humans: differential effects of tamoxifen on the GH and gonadal axes

Birzniece

2015

European Journal of Endocrinology

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Context: Tamoxifen, a selective estrogen receptor modulator, suppresses GH secretion in women but not in men. It increases testosterone levels in men. As GH and testosterone stimulate fat metabolism, the metabolic consequences of tamoxifen may be greater in women than in men. Objective: To determine whether tamoxifen suppresses fat oxidation (Fox) to a greater degree in women than in men.Design: An open-label study of ten healthy postmenopausal women and ten healthy men receiving 2-week treatment with tamoxifen (20 mg/day). Endpoint measures: GH response to arginine stimulation, serum levels of IGF1, testosterone and LH (men only), sex hormone binding globulin (SHBG) and whole body basal and postprandial Fox. Results: In women, tamoxifen significantly reduced the mean GH response to arginine stimulation (D K87%, P!0.05) and circulating IGF1 levels (D K23.5G5.4%, P!0.01). Tamoxifen reduced postprandial Fox in women (D K34.6G10.3%; P!0.05). In men, tamoxifen did not affect the GH response to arginine stimulation but significantly reduced mean IGF1 levels (D K24.8G6.1%, P!0.01). Tamoxifen increased mean testosterone levels (D 52G14.2%; P!0.01). Fox was not significantly affected by tamoxifen in men. Conclusion: Tamoxifen attenuated the GH response to stimulation and reduced postprandial Fox in women but not in men. We conclude that at a therapeutic dose, the suppressive effect of tamoxifen on fat metabolism is gender-dependent. Higher testosterone levels may mitigate the suppression of GH secretion and Fox during tamoxifen treatment in men.

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“…Unlike the GH system, local estrogen derived from aromatization inhibits gonadotrophin secretion [50]. We reported that central estrogen blockade with SERMs enhanced LH secretion, consequently increasing testosterone levels [37,51]. The higher testosterone levels in turn result in secondary stimulation of GH secretion.…”

Section: Gender Differencesmentioning

confidence: 99%

Sex steroids and the GH axis: Implications for the management of hypopituitarism

Birzniece

2017

Best Practice & Research Clinical Endocrinology & Metab

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Growth hormone (GH) regulates somatic growth, substrate metabolism and body composition. Sex hormones exert profound effect on the secretion and action of GH.Estrogens stimulate the secretion of GH, but inhibit the action of GH on the liver, an effect that occurs when administered orally. Estrogens suppress GH receptor signaling by stimulating the expression proteins that inhibit cytokine receptor signaling. This effect of estrogens is avoided when physiological doses of estrogens are administered via a non-oral route. Estrogen-like compounds, such as selective estrogen receptor modulators, possess dual properties of inhibiting the secretion as well as the action of GH. In contrast, androgens stimulate GH secretion, driving IGF-1 production. In the periphery, androgens enhance the action of GH. The differential effects of estrogens and androgens influence the dose of GH replacement in patients with hypopituitarism on concomitant treatment with sex steroids.Where possible, a non-oral route of estrogen replacement is recommended for optimising cost-benefit of GH replacement in women with GH deficiency. Adequate androgen replacement in conjunction with GH replacement is required to achieve the full anabolic effect in men with hypopituitarism.

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Neuroendocrine Regulation of Growth Hormone and Androgen Axes by Selective Estrogen Receptor Modulators in Healthy Men

Abstract: Tamoxifen, but not raloxifene, reduces IGF-I levels. Both SERMs stimulate the gonadal axis, with tamoxifen imparting a greater effect. We conclude that in therapeutic doses, raloxifene perturbs the GH and gonadal axes to a lesser degree than tamoxifen.

Cited by 18 publications

References 28 publications

Sex-Specific Associations of Androgen Receptor CAG Trinucleotide Repeat Length and of Raloxifene Treatment with Testosterone Levels and Perceived Stress in Schizophrenia

Sex-Specific Associations of Androgen Receptor CAG Trinucleotide Repeat Length and of Raloxifene Treatment with Testosterone Levels and Perceived Stress in Schizophrenia

Estrogen receptor antagonism uncovers gender-dimorphic suppression of whole body fat oxidation in humans: differential effects of tamoxifen on the GH and gonadal axes

Sex steroids and the GH axis: Implications for the management of hypopituitarism

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