Relative hyperestrogenism in Klinefelter Syndrome: results from a meta-analysis

Santi, Daniele; Vincentis, Sara De; Scaltriti, Sara; Rochira, Vincenzo

doi:10.1007/s12020-019-01850-y

Cited by 12 publications

(8 citation statements)

References 75 publications

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“…It has traditionally been considered a condition of absolute excess circulating E2. However, a recent metaanalysis has reported that this association was driven by studies using inaccurate assay technologies and is not present if only studies using high-quality E2 assays with sufficient accuracy in the low male range are considered (169). In this analysis, men with Klinefelter syndrome did have an increased circulating E2/T ratio, suggesting an increase in aromatization of available testosterone, the mechanism of which is not established.…”

Section: Effects Of Excess E2 In Menmentioning

confidence: 79%

MECHANISMS IN ENDOCRINOLOGY: Estradiol as a male hormone

Russell

Grossmann

2019

European Journal of Endocrinology

108

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Evidence has been accumulating that, in men, some of the biological actions traditionally attributed to testosterone acting via the androgen receptor may in fact be dependent on its aromatization to estradiol (E2). In men, E2 circulates at concentrations exceeding those of postmenopausal women, and estrogen receptors are expressed in many male reproductive and somatic tissues. Human studies contributing evidence for the role of E2 in men comprise rare case reports of men lacking aromatase or a functional estrogen receptor alpha, short-term experiments manipulating sex steroid milieu in healthy men, men with organic hypogonadism or men with prostate cancer treated with androgen deprivation therapy (ADT) and from observational studies in community-dwelling men. The collective evidence suggests that, in men, E2 is an important hormone for hypothalamic–pituitary–testicular axis regulation, reproductive function, growth hormone insulin-like growth factor-1 axis regulation, bone growth and maintenance of skeletal health, body composition and glucose metabolism and vasomotor stability. In other tissues, particularly brain, elucidation of the clinical relevance of E2 actions requires further research. From a clinical perspective, the current evidence supports the use of testosterone as the treatment of choice in male hypogonadism, rather than aromatase inhibitors (which raise testosterone and lower E2), selective androgen receptor modulators and selective estrogen receptor modulators (with insufficiently understood tissue-specific estrogenic effects). Finally, E2 treatment, either as add-back to conventional ADT or as sole mode of ADT could be a useful strategy for men with prostate cancer.

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Section: Effects Of Excess E2 In Menmentioning

confidence: 79%

MECHANISMS IN ENDOCRINOLOGY: Estradiol as a male hormone

Russell

Grossmann

2019

European Journal of Endocrinology

108

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“…The estrogen to testosterone ratio has also been suggested as a potential risk factor for male breast cancer, because this ratio is raised in men with Klinefelter syndrome ( 49 , 50 ) who are known to be at high risk of breast cancer ( 8 ). In a prospective analysis, this ratio showed non-statistically significant evidence of a relation to subsequent breast cancer risk in men but not beyond the association for estrogens alone ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Obesity and Breast Cancer Risk in Men: A National Case-Control Study in England and Wales

Swerdlow

Bruce

Cooke

et al. 2021

JNCI Cancer Spectrum

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Background Breast cancer is rare in men, and information on its causes is very limited, from studies that have generally been small. Adult obesity has been shown as a risk factor but more detailed anthropometric relations have not been investigated. Methods We conducted an interview population-based case-control study of breast cancer in men in England and Wales including 1,998 cases incident during 2005–2017 at ages under 80 years and 1,597 male controls, with questions asked about a range of anthropometric variables at several ages. All tests of statistical significance were two-sided. Results Risk of breast cancer statistically significantly increased with increasing body mass index (BMI) at ages 20 (odds ratio [OR]=1.07, 95% confidence interval [CI] = 1.02 to 1.12 per 2-unit change in BMI), 40 (OR = 1.11, 95% CI = 1.07 to 1.16), and 60 (OR = 1.14, 95% CI = 1.09 to 1.19) years but there was also an indication of raised risk for the lowest BMIs. Large waist circumference 5 years before interview was more strongly associated than was BMI with risk, and each showed independent associations. Associations were similar for invasive and in situ tumors separately and stronger for human epidermal growth factor receptor 2 (HER2)-positive than HER2-negativetumors. Ninety-nine percent of tumors were estrogen receptor-positive. Conclusions Obesity at all adult ages, particularly recent abdominal obesity, is associated with raised risk of breast cancer in men, probably because of conversion of testosterone to estrogens by aromatase in adipose tissue. The association is particularly strong for HER2-expressingtumors.

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“…Moreover, our study did not clarify whether the risk of fractures in KS may be influenced by serum estradiol levels, such as in other forms of hypogonadism 38 . Since the fractures seem to develop in KS despite the favorable estradiol/testosterone ratio, 39 it is reasonable to hypothesize that the possible protective effects of estrogens on bone are not relevant in this specific clinical setting.…”

Section: Discussionmentioning

confidence: 72%

“…30 This study has limitations. 39 it is reasonable to hypothesize that the possible protective effects of estrogens on bone are not relevant in this specific clinical setting.…”

Section: Discussionmentioning

confidence: 98%

Prevalence and determinants of radiological vertebral fractures in patients with Klinefelter syndrome

et al. 2020

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Background Klinefelter syndrome (KS) may induce skeletal fragility, but the studies so far published on this topic were mainly focused on the evaluation of bone mineral density (BMD) and bone microstructure, whereas data on fracture risk are still lacking. Objective To evaluate the prevalence and determinants of vertebral fractures (VFs), that is, the hallmark of osteoporosis, in subjects with KS. Materials and methods Eighty‐seven patients with KS (median age 41 years, range 18‐64) were consecutively evaluated for radiological VFs (by quantitative morphometry) and lumbar spine and femoral neck BMD (by DXA). Fifty‐five patients with KS were also evaluated by the fracture risk assessment (FRAX) tool. Results Low BMD was found in 22/87 (25.3%) patients [12 with osteopenia, three with osteoporosis and seven with “low BMD per age” (subject < 50 years with Z‐score ≤−2.0 SD)] and VFs in 13/87 (14.9%) patients. In patients with VFs, the median spine deformity index was 2 (range 1‐9). Prevalence of VFs was similar between healthy and low‐BMD patients (15.9% vs 13.6%; P = .80). Noteworthy, patients with VFs had significantly higher age at diagnosis of KS as compared to patients who did not fracture (P = .039), without significant differences in age at the time of observation (P = .162), body mass index (P = .234), testosterone replacement therapy (P = .432), duration of testosterone therapy (P = .409), vitamin D therapy (P = 681), and serum testosterone levels (P = .338). Moreover, patients with VFs were more likely to complain back pain in comparison with those without VFs (33.3% vs 7.4%; P = .047). In 55 cases evaluated by the FRAX® tool, no significant differences in 10‐year risk of major fracture (P = .270) and hip fracture (P = .860) were found between fractured and non‐fractured patients. Conclusions This study provides first evidence that KS may be associated with risk of VFs in close relationship with delay in disease diagnosis but independently of BMD values and serum testosterone levels or testosterone therapy.

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Relative hyperestrogenism in Klinefelter Syndrome: results from a meta-analysis

Cited by 12 publications

References 75 publications

MECHANISMS IN ENDOCRINOLOGY: Estradiol as a male hormone

MECHANISMS IN ENDOCRINOLOGY: Estradiol as a male hormone

Obesity and Breast Cancer Risk in Men: A National Case-Control Study in England and Wales

Prevalence and determinants of radiological vertebral fractures in patients with Klinefelter syndrome

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