Aromatase Inhibition Reduces Insulin Sensitivity in Healthy Men

Gibb, Fraser; Homer, Natalie; Faqehi, Abdullah M.M.; Upreti, Rita; Livingstone, Dawn E W; McInnes, Kerry J.; Andrew, Ruth; Walker, Brian R.

doi:10.1210/jc.2015-4146

Cited by 37 publications

(27 citation statements)

References 41 publications

(46 reference statements)

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“…This finding suggests that, at least during prepubertal and pubertal years, the lack of estrogens might not affect glucose homoeostasis or the lipid metabolism. In line with these observations, the use of aromatase inhibitors in pubertal boys has been associated with neutral [35] or even beneficial [36] effects on insulin sensitivity, while even short-term use in adult men has been associated with a decrease in insulin sensitivity [37]. In agreement with these observations, mouse aromatase deficiency models progressively developed the metabolic syndrome phenotype (obesity, glucose intolerance, and decreased insulin sensitivity) after the first 10–12 weeks of age (in adulthood) [38].…”

Section: Discussionmentioning

confidence: 91%

Accelerated Pubertal Tempo in a 46,XY Aromatase-Deficient Patient

Costanzo

Garcia-Feyling²,

Saraco

et al. 2018

Horm Res Paediatr

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Background: Aromatase deficiency is a rare autosomal recessive disorder. 46,XY-affected patients often remain undiagnosed until late puberty. Only 2 pediatric cases have been reported. Data on pubertal development in affected males are scarce. Aim: To report the clinical phenotype and hormonal studies of an aromatase-deficient boy during the prepubertal and early pubertal period. Results: The patient was the older brother of a 46,XX girl with aromatase deficiency. Molecular analysis revealed a previously reported homozygous mutation (Arg192Cys) in the CYP19A1 gene. Pubertal onset was at 9.8 years. At 11.3 years of age, signs of rapidly progressive puberty were seen. Laboratory tests revealed normal pubertal basal and GnRH-stimulated gonadotropin levels, normal Sertoli cell markers, and increased testosterone. The prepubertal lumbar spine bone mineral density (BMD) was normal but pubertal bone mineral accrual was incomplete, leading to osteopenia. Conclusion: Estrogen restraint on gonadotropin secretion has been demonstrated in animal and human models. Interestingly, our patient presented with accelerated puberty and apparently normal pituitary gonadal function. These findings suggest that aromatase activity may be required to define pubertal progression in boys. Estrogen deficiency due to aromatase deficiency is responsible for insufficient bone mineral accrual during puberty.

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Section: Discussionmentioning

confidence: 91%

Accelerated Pubertal Tempo in a 46,XY Aromatase-Deficient Patient

Costanzo

Garcia-Feyling²,

Saraco

et al. 2018

Horm Res Paediatr

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“…2008, Guercio et al . 2009), and in healthy men administered anastrozole to suppress aromatase (Gibb et al, 2016). In addition, ERα-null mice develop insulin resistance, glucose intolerance and decreased glucose uptake in skeletal muscle (Bryzgalova et al .…”

Section: Discussionmentioning

confidence: 99%

Estrogen deprivation in primate pregnancy leads to insulin resistance in offspring

Maniu

Aberdeen

Lynch

et al. 2016

Journal of Endocrinology

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This study tested the hypothesis that estrogen programs mechanisms within the primate fetus that promote insulin sensitivity and glucose homeostasis in offspring. Glucose tolerance tests were performed longitudinally in prepubertal offspring of baboons untreated or treated on days 100 to 165/175 of gestation (term is 184 days) with the aromatase inhibitor letrozole which decreased fetal estradiol levels by 95%. Basal plasma insulin levels were over 2-fold greater in offspring delivered to letrozole-treated than untreated animals. Moreover, the peak 1 min, average of the 1, 3 and 5 min, and area under the curve blood glucose and plasma insulin levels after an iv bolus of glucose were greater (P<0.05 and P<0.01, respectively) in offspring deprived of estrogen in utero than in untreated animals and partially or completely restored in letrozole plus estradiol-treated baboons. The value for the homeostasis model assessment of insulin resistance was 2.5-fold greater (P<0.02) and quantitative insulin sensitivity check index lower (P<0.01) in offspring of letrozole-treated versus untreated animals and returned to almost normal in letrozole plus estradiol-treated animals. The exaggerated rise in glucose and insulin levels after glucose challenge in baboon offspring deprived of estrogen in utero indicates that pancreatic beta cells had the capacity to secrete insulin, but that peripheral glucose uptake and/or metabolism were impaired, indicative of insulin resistance and glucose intolerance. We propose that estrogen normally programs mechanisms in utero within the developing primate fetus that lead to insulin sensitivity, normal glucose tolerance and the capacity to metabolize glucose after birth.

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“…Of concern, BMD at the spine decreased significantly after 12 months of anastrozole, presumably because of the decrease in circulating oestradiol . In addition to bone health, oestradiol may be important for of sexual function, prevention of abdominal adiposity and insulin sensitivity . More work is needed before SERMs or AIs can be considered for the treatment of obesity‐associated hypogonadism.…”

Section: Is There a Role For Selective Oestrogen Modulators (Serms) Omentioning

confidence: 99%

Hypogonadism and male obesity: Focus on unresolved questions

Grossmann

2018

Clinical Endocrinology

107

116

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Obesity, increasing in prevalence globally, is the clinical condition most strongly associated with lowered testosterone concentrations in men and presents as one of the strongest predictors of receiving testosterone treatment. While low circulating total testosterone concentrations in modest obesity primarily reflect reduced concentrations of sex hormone binding globulin, more marked obesity can lead to genuine hypothalamic-pituitary-testicular axis (HPT) suppression. HPT axis suppression is likely mediated via pro-inflammatory cytokine and dysregulated leptin signalling and aggravated by associated comorbidities. Whether oestradiol-mediated negative hypothalamic-pituitary feedback plays a pathogenic role requires further study. Although the obesity-hypogonadism relationship is bidirectional, the effects of obesity on testosterone concentrations are more substantial than the effects of testosterone on adiposity. In markedly obese men submitted to bariatric surgery, substantial weight loss is very effective in reactivating the HPT axis. In contrast, lifestyle measures are less effective in reducing weight and generally only associated with modest increases in circulating testosterone. In randomized controlled clinical trials (RCTs), testosterone treatment does not reduce body weight, but modestly reduces fat mass and increases muscle mass. Short-term studies have shown that testosterone treatment in carefully selected obese men may have modest benefits on symptoms of androgen deficiency and body composition even additive to diet alone. However, longer term, larger RCTs designed for patient-important outcomes and potential risks are required. Until such trials are available, testosterone treatment cannot be routinely recommended for men with obesity-associated nonclassical hypogonadism. Lifestyle measures or where indicated bariatric surgery to achieve weight loss, and optimization of comorbidities remain first line.

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Aromatase Inhibition Reduces Insulin Sensitivity in Healthy Men

Cited by 37 publications

References 41 publications

Accelerated Pubertal Tempo in a 46,XY Aromatase-Deficient Patient

Accelerated Pubertal Tempo in a 46,XY Aromatase-Deficient Patient

Estrogen deprivation in primate pregnancy leads to insulin resistance in offspring

Hypogonadism and male obesity: Focus on unresolved questions

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