END2.15 - ‘Hot topic’ DHEAS miraculous potion or snake oil? © Dr S Nussey & IOS
Dec 28, 2015
END2.15 - ‘Hot topic’ DHEAS miraculous potion or
snake oil?
© Dr S Nussey & IOS
Freely available asfood additive
Assays freely available
Adrenarche
Steroid serum concentrations
Steroid Concentration (pmol/l)
Estradiol 200
Aldosterone 300
Testosterone 15,000
DHEA 30,000
Cortisol 300,000
DHEAS 5,000,000
Adrenarche
NB Concentrations of glucocorticoids and mineralocorticoidsdo not change
Effect of age
Males
Females
NB Concentrationsof glucocorticoidsand mineralocorticoidsdo not change
Box 4.14 - Adrenal cortex control
Adrenal hormonesecretion
Q - How can adrenal androgensecretion be controlledindependently?
A - Androgen stimulating peptideor zonation?
Ratios of precursors to products indicatethat maturation of zonation (especially thereticularis) is the most likely aetiology
Metabolism of DHEA
DHEADHEAS Androstenedione Testosterone
5-DHT
EstradiolEstrone
Physiological role of DHEA(S)
• Adrenarche
• Other– Glucocorticoid antagonist– Neurosteroid– Androgen and estrogen precursor
• NB - a receptor has not been identified ?membrane effects
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
DHEA replacement
• 50mg oral DHEA in men aged 49-70 y restored DHEAS to young adult concentrations
• t1/2 DHEA >20h ? as a result of back-conversion
• Circulating concentrations of E2 and T rose to young adult levels
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
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
Summary
Conclusion
Long-term studies of adequate power are required to determinethe benefits and risks of DHEA treatment.
Lancet 2001, 357: 1381
Andropause
Decline in androgens with age
0
5
10
15
20
25
25-34 35-44 45-54 55-64 65-74 75-84 85-100
Age (y)
Ser
um
Tes
tost
ero
ne
(nm
ol/
l)
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
Ser
um
fre
e te
sto
ster
on
e
Testo
free-T
Considerable interindividual variation
• Due to:– Genetic factors– Illness– Obesity– Stress– Physical fitness– Medication
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 concentrationsare weak
? Confounding effect of GH deficiency
Is androgen deficiency diagnosable?
• No clinically useful measure of androgen activity
• ? Increased androgen sensitivity in the elderly
• No increase in gonadotrophins
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 mortalityNB - the numbers of men in trials have been small and the durationshort
Contraindications to testosterone replacement
• Ca prostate
• NB - subclinical carcinoma (>50% of >70y olds) effects unknown
• Polycythaemia
• Sleep apnoea
The future
• The effects of testosterone may be mediated by testosterone itself, 5-DHT (via 5-reductase) or estradiol (via aromatase)
• SARMS such as 17methyl-19-nortestosterone (that does not undergo 5-reduction but is aromatized) may be useful
Androgens in the female
Androgens in the female
Studies in post-menopausal women suggest that the ovary continuesto synthesize and secrete testosterone
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.