Case for androgens Giorgio Arnaldi Clinica di Endocrinologia AOU Ospedali Riuniti Ancona Ancona gioarnaldi@gmail.com

Adrenal androgens and bone Agenda Physiology of adrenal androgens , i.e. DHEA Effects of adrenal androgens on bone DHEA treatment in post-menopausal women DHEA treatment and bone effects in Addison

DHEA and DHEAS are the most abundant steroids in humans Adult 6-month old infant 10 000 10 20 30 40 50 60 70 Fetal Period DHEAS nmol l-1 Age (years) Man Woman Birth At 50-60 yr, DHEA has already decreased by 70% The individual variability across adulthood is substantial and the normal range of serum DHEA(S) is therefore very wide at each decade of life

DHEA exerts its primary effects through its estrogenic and androgenic metabolites Labrie 2007

A specific DHEA receptor has not been characterized Although DHEA may be converted to DHEAS by SULT2A1, no relevant amounts of DHEA result from conversion of DHEAS. Therefore, DHEAS levels, which are measured in the routine clinical practice, may not always reflect the amount of available DHEA. In women, exogenous DHEA is mainly converted to androgens. An increase in serum androgens is observed only in men with low androgen levels Lang et al BP&R Clin Endocrinol Metab 2015

Adrenal androgens and bone Agenda Physiology of adrenal androgens , i.e. DHEA Effects of adrenal androgens on bone DHEA treatment in post-menopausal women DHEA treatment and bone effects in Addison

A specific bone DHEA receptor ?

“These findings suggest that the hyperandrogenism observed in Premature Adrenarche may directly or indirectly affect bone mineral mass….”

DHEAS correlates negatively with bone turnover before peak mass DHEA and its metabolites are independent determinants of cortical density, particularly before the activation of pubertal sex hormones Remer, T et al. Adrenarche and bone modeling and remodeling at the proximal radius: weak androgens make stronger cortical bone in healthy children. Journal of Bone and Mineral Research, 18, 1539–1546. 2003 DHEAS correlates negatively with bone turnover before peak mass Walsh, J.S. et al Hormonal determinants of bone turnover before and after attainment of peak bone mass. Clinical Endocrinology (Oxf), 72, 320–327. 2010 DHEAS, androstenedione and estrone were positive predictors of bone age (….but they were not associated with bone density) Vandewalle S et al. Relation of adrenal-derived steroids with bone maturation, mineral density andgeometry in healthy prepubertal and early pubertal boys. Bone. 69:39-46. 2014

Eighty CAH adults (47 classic, 33 nonclassic) low DHEAS may be associated with weak cortical bone independent of glucocorticoid exposure. DHEAS was the only independent significant predictor of BMD at the forearm and spine In a multivariate analysis after adjusting for age, gender, height standard deviation, phenotype and cumulative glucocorticoid exposure, higher DHEAS was independently associated with higher BMD at the spine, radius and whole body.

Adrenal androgens and bone Agenda Physiology of adrenal androgens , i.e. DHEA Effects of adrenal androgens on bone DHEA treatment in post-menopausal women DHEA treatment and bone effects in Addison

Exogenous DHEA treatment When administered to postmenopausal women, DHEA is mainly transformed to androgens rather than estrogens. Using liquid chromatography combined with tandem mass spectrometry, an oral dose of DHEA 50 mg daily for 12 months increases: estrone 34% and estradiol 57% total testosterone about 100%, DHT relatively unchanged Davis et al J Clin Endocrinol Metab, 2011, 96(6):1642–1653

Labrie et al J Clin Endocrinol Metab, 82:3498–3512, 1997 DHEA was administered percutaneously once daily in the morning as a 10% cream 14 women (60 to 70 yr) Total hip +2% at 12 months Labrie et al J Clin Endocrinol Metab, 82:3498–3512, 1997

The effect is small in relation to other treatment Effects of DHEA on bone in postmenopausal women in placebo-controlled trials The effect is small in relation to other treatment No fractures data are available Over 26 weeks 640 women Davis et al J Clin Endocrinol Metab, 2011, 96(6):1642–1653

Adrenal androgens and bone Agenda Physiology of adrenal androgens , i.e. DHEA Effects of adrenal androgens on bone DHEA treatment in post-menopausal women DHEA treatment and bone effects in Addison

Adrenal insufficiency Replacement therapy Glucocorticoid Mineralocorticoid (Addison only) DHEAS (?) In both primary and secondary adrenal insufficiency, DHEA secretion is clearly decreased and often even absent. In women, it results in significant androgen deficiency whereas testicular testosterone is preserved in men.

Gurnell et al Double-blind trial, randomized 106 subjects (44 males, 62 females) with Addison’s disease to receive either 50 mg daily of micronized DHEA or placebo orally for 12 months DHEA reversed ongoing loss of bone mineral density at the femoral neck (P 0.05) but not at other sites. The improvement was modest comparing other treatment

10 female patients (median age 38 10 female patients (median age 38.5 years, range 28–52) with adrenal failure were treated with DHEA 50 mg for 6 months in a double-blind, randomized, placebo-controlled, and crossover study

on muscle, fat, and bone tissue Frequent adverse effects No effects and on fuel metabolism Frequent adverse effects 10 female patients (median age 38.5 years, range 28–52) with adrenal failure were treated with DHEA 50 mg for 6 months in a double-blind, randomized, placebo-controlled, and crossover study

J Intern Med. 2014;275:104-15.