Sex hormone-binding globulin regulation of androgen bioactivity in vivo: validation of the free hormone hypothesis

Laurent, Michaël; Hammond, Geoffrey L.; Blokland, Marco; Jardí, Ferran; LʼAbbate, Antonio; Dubois, Vanessa; Khalil, R; Sterk, S.S.; Gielen, Evelien; Decallonne, Brigitte; Carmeliet, Geert; Kaufman, Jean; Fiers, Tom; Huhtaniemi, Ilpo; Vanderschueren, Dirk; Claessens, Frank

doi:10.1038/srep35539

Cited by 136 publications

(103 citation statements)

References 58 publications

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“…In agreement, wheel running activity, which we have previously established as a sensitive marker of androgen activity, remained unaltered after AR inactivation in neurons. However, seminal vesicle weight, a frequently used readout for androgen levels, was increased in N‐ARKO mice, despite less than in previous N‐ARKO mouse models with a complete neuronal AR inactivation in the hypothalamus . Because seminal vesicle weight might be more sensitive than serum T reflecting changes in androgen activity in male rodents, we determined the bone phenotype of N‐ARKO mice after ORX and hormone replacement in order to rule out potential confounding from subtle alterations in sex steroid levels.…”

Section: Discussionmentioning

confidence: 99%

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Androgen Receptor in Neurons Slows Age-Related Cortical Thinning in Male Mice

Jardí

Kim

Laurent

et al. 2018

Journal of Bone and Mineral Research

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Androgens via the androgen receptor (AR) are required for optimal male bone health. The target cell(s) for the effects of androgens on cortical bone remain(s) incompletely understood. In females, estrogen receptor alpha in neurons is a negative regulator of cortical and trabecular bone. Whether neuronal AR regulates bone mass in males remains unexplored. Here, we inactivated AR in neurons using a tamoxifen‐inducible CreERT2 under the control of the neuronal promoter Thy1. Tamoxifen induced a 70% to 80% reduction of AR mRNA levels in Thy1‐CreERT2‐positive brain regions cerebral cortex and brainstem as well as in the peripheral nervous tissue of male neuronal AR knockout (N‐ARKO) mice. Hypothalamic AR mRNA levels were only marginally reduced and the hypothalamic‐pituitary‐gonadal axis remained unaffected, as determined by normal levels of serum testosterone, luteinizing hormone (LH), and follicle‐stimulating hormone (FSH). In contrast to orchidectomy, deletion of neuronal AR did not alter body weight, body composition, hindlimb muscle mass, grip strength, or wheel running. MicroCT analysis of the femur revealed no changes in bone accrual during growth in N‐ARKO mice. However, 36‐ and 46‐week‐old N‐ARKO mice displayed an accelerated age‐related cortical involution, namely a more pronounced loss of cortical thickness and strength, which occurred in the setting of androgen sufficiency. Neuronal AR inactivation decreased the cancellous bone volume fraction in L5 vertebra but not in the appendicular skeleton of aging mice. MicroCT findings were corroborated in the tibia and after normalization of hormonal levels. Serum markers of bone turnover and histomorphometry parameters were comparable between genotypes, except for a 30% increase in osteoclast surface in the trabecular compartment of 36‐week‐old N‐ARKO mice. Cortical bone loss in N‐ARKO mice was associated with an upregulation of Ucp1 expression in brown adipose tissue, a widely used readout for sympathetic tone. We conclude that androgens preserve cortical integrity in aging male mice via AR in neurons. © 2018 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

“…Total T was measured at the University Hospitals Leuven without derivatization using a two‐dimensional liquid chromatography system and an AB/Sciex QTrap 5500 tandem mass spectrometer in atmospheric pressure chemical ionization positive mode …”

Section: Methodsmentioning

confidence: 99%

Androgen Receptor in Neurons Slows Age-Related Cortical Thinning in Male Mice

Jardí

Kim

Laurent

et al. 2018

Journal of Bone and Mineral Research

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“…First of all, mice and rats lack sex hormone-binding globulin (SHBG) [47], which is the major serum-binding globulin of testosterone and estrogen. SHBG levels regulate the bioavailable levels of these hormones [48] as only estrogen and testosterone that is not bound to SHBG, but rather bound by albumin and other carrier proteins or is circulating freely, are considered available for biological signaling and activity [48]. The importance of SHBG in human bone health has been demonstrated by studies, which show that serum SHBG levels are inversely associated with BMD in both men and women [49, 50].…”

Section: What Is the Normal Physiological Effect Of Androgens On Bmentioning

confidence: 99%

Male Hypogonadism and Osteoporosis: The Effects, Clinical Consequences, and Treatment of Testosterone Deficiency in Bone Health

Golds

Houdek

Arnason

2017

International Journal of Endocrinology

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It is well recognized that bone loss accelerates in hypogonadal states, with female menopause being the classic example of sex hormones affecting the regulation of bone metabolism. Underrepresented is our knowledge of the clinical and metabolic consequences of overt male hypogonadism, as well as the more subtle age-related decline in testosterone on bone quality. While menopause and estrogen deficiency are well-known risk factors for osteoporosis in women, the effects of age-related testosterone decline in men on bone health are less well known. Much of our knowledge comes from observational studies and retrospective analysis on small groups of men with variable causes of primary or secondary hypogonadism and mild to overt testosterone deficiencies. This review aims to present the current knowledge of the consequences of adult male hypogonadism on bone metabolism. The direct and indirect effects of testosterone on bone cells will be explored as well as the important differences in male osteoporosis and assessment as compared to that in females. The clinical consequence of both primary and secondary hypogonadism, as well as testosterone decline in older males, on bone density and fracture risk in men will be summarized. Finally, the therapeutic options and their efficacy in male osteoporosis and hypogonadism will be discussed.

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“…Men without known hypothalamic, pituitary or testicular disease are expected to have total testosterone concentrations ≥10.4 nmol/L up to age 35 years, and ≥6.4 nmol/L at ≥70 years. 46 However, the validity of the free hormone hypothesis to assessing gonadal function in men remains under debate. Age-appropriate reference ranges are provided routinely for other analytes whose distribution varies with age, such as insulin-like growth factor-I, 43 bone turnover markers 44 The interest in free testosterone concentrations stems from the "free hormone hypothesis", which postulates that free or unbound testosterone in the circulation is biologically active.…”

Section: Te S Tos Terone Referen Ce R Ang E Smentioning

confidence: 99%

Clinical practice update on testosterone therapy for male hypogonadism: Contrasting perspectives to optimize care

Yeap

2018

Clinical Endocrinology

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US Endocrine Society (ES) published a clinical practice guideline on testosterone therapy in men with hypogonadism, and Endocrine Society of Australia (ESA) a position statement on management of male hypogonadism. Both emphasize the importance of diagnosing men who are androgen deficient due to organic (classical or pathological) hypogonadism arising from disorders of the hypothalamus, pituitary or testes, who assuredly benefit from testosterone therapy. Both recognize that men with an intact gonadal axis may have low testosterone concentrations, for instance older men or men with obesity or other medical comorbidities. ES guidelines classify such symptomatic men as having organic (advanced age) or functional (obesity, medical comorbidities) hypogonadism, giving an option for testosterone therapy as a shared decision between clinicians and individual patients. ESA did not recommend testosterone therapy in these men. ES offers a reference range for total testosterone established in young men, while ESA cites age‐standardized reference ranges. ES recommends using free testosterone as well as total testosterone to identify men with hypogonadism in conditions where sex hormone‐binding globulin (SHBG) is altered, or when total testosterone is borderline. ESA recommends confirmatory biochemical testing with total testosterone, recognizing that this may be lower than expected if SHBG concentrations are low. Both emphasize the importance of identifying pre‐existing prostate and cardiovascular disease prior to initiating testosterone therapy, with ES providing specific recommendations for PSA measurement, deferring testosterone therapy after major cardiovascular events and indications for pituitary imaging. These contrasting approaches highlight gaps in the evidence base where individualized patient management is required.

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Sex hormone-binding globulin regulation of androgen bioactivity in vivo: validation of the free hormone hypothesis

Cited by 136 publications

References 58 publications

Androgen Receptor in Neurons Slows Age-Related Cortical Thinning in Male Mice

Androgen Receptor in Neurons Slows Age-Related Cortical Thinning in Male Mice

Male Hypogonadism and Osteoporosis: The Effects, Clinical Consequences, and Treatment of Testosterone Deficiency in Bone Health

Clinical practice update on testosterone therapy for male hypogonadism: Contrasting perspectives to optimize care

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