1. END2.15 - ‘Hot topic’ DHEAS miraculous potion or snake oil? © Dr S Nussey &  IOS

2. Freely available as food additive

3. Assays freely available

5. Adrenarche

6. Steroid serum concentrations

7. Adrenarche NB Concentrations of glucocorticoids and mineralocorticoids do not change

8. Effect of age Males Females NB Concentrations of glucocorticoids and mineralocorticoids do not change

9. Box 4.14 - Adrenal cortex control Adrenal hormone secretion Q - How can adrenal androgen secretion be controlled independently? A - Androgen stimulating peptide or zonation?

10. Ratios of precursors to products indicate that maturation of zonation (especially the reticularis) is the most likely aetiology

11. Metabolism of DHEA DHEADHEASAndrostenedioneTestosterone 5  -DHT EstradiolEstrone

12. Physiological role of DHEA(S) Adrenarche Other –Glucocorticoid antagonist –Neurosteroid –Androgen and estrogen precursor NB - a receptor has not been identified ?membrane effects

13. DHEA replacement in ageing Inverse relationships with DHEAS concentrations and: –mortality and cardiovascular disease in men (but not women) –breast cancer risk (premenopausal women) –bone mineral density in women age 45-69 (but not men) –depressed mood in women (but not men) NB - Cross-sectional data. ?non-specific measure of ageing

14. DHEA replacement 50mg oral DHEA in men aged 49-70 y restored DHEAS to young adult concentrations t 1/2 DHEA >20h ? as a result of back- conversion Circulating concentrations of E2 and T rose to young adult levels

15. DHEA replacement in the elderly RCT data –Increased physical and psychological well- being –Decrease in fat mass and improved muscle strength in men (but not women) –Circulating androgens rose to young adult levels in women (but not men) –Improved bone mineral density NB - small numbers and short follow up

16. DHEA replacement in Addison’s women Reduced anxiety and depression scores Increased overall physical and mental wellbeing Increased sexual thoughts and enhanced physical and mental sexual satisfaction NB - even smaller numbers and shorter follow up

17. Summary

18. Conclusion Long-term studies of adequate power are required to determine the benefits and risks of DHEA treatment. Lancet 2001, 357: 1381

19. Andropause

20. Decline in androgens with age

21. Considerable interindividual variation Due to: –Genetic factors –Illness –Obesity –Stress –Physical fitness –Medication

22. Andropause is predicated on comparisons of the effect of age and hypogonadism in young men Decline in: –muscle mass –sexual function –bone density –cognitive function –body hair Increase in: –fat mass NB - Many of the correlations with serum testosterone concentrations are weak ? Confounding effect of GH deficiency

23. Is androgen deficiency diagnosable? No clinically useful measure of androgen activity ? Increased androgen sensitivity in the elderly No increase in gonadotrophins

24. Effects of androgen supplementation In young androgen deficient men T increases: sexual activity; fat-free mass; muscle strength; insulin sensitivity; bone density; well being In normal elderly men T increases these parameters (but only in those with reduced measures of T) but there are no data on clinical endpoints such as fracture rates or cardiovascular mortality NB - the numbers of men in trials have been small and the duration short

25. Contraindications to testosterone replacement Ca prostate NB - subclinical carcinoma (>50% of >70y olds) effects unknown Polycythaemia Sleep apnoea

26. The future The effects of testosterone may be mediated by testosterone itself, 5  -DHT (via 5  - reductase) or estradiol (via aromatase) SARMS such as 17  methyl-19- nortestosterone (that does not undergo 5  - reduction but is aromatized) may be useful

27. Androgens in the female

28. Studies in post-menopausal women suggest that the ovary continues to synthesize and secrete testosterone

29. Androgen replacement in females RCTs suggest an increase in: –libido and sexual function –bone mineral density –fat-free mass NB - trials have been small and of short duration and have not included the most androgen deficient women. Doubts over replacement androgen.