end2.15 - ‘hot topic’ dheas miraculous potion or snake oil? © dr s nussey & ios
TRANSCRIPT
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END2.15 - ‘Hot topic’ DHEAS miraculous potion or
snake oil?
© Dr S Nussey & IOS
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Freely available asfood additive
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Assays freely available
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Adrenarche
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Steroid serum concentrations
Steroid Concentration (pmol/l)
Estradiol 200
Aldosterone 300
Testosterone 15,000
DHEA 30,000
Cortisol 300,000
DHEAS 5,000,000
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Adrenarche
NB Concentrations of glucocorticoids and mineralocorticoidsdo not change
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Effect of age
Males
Females
NB Concentrationsof glucocorticoidsand mineralocorticoidsdo not change
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Box 4.14 - Adrenal cortex control
Adrenal hormonesecretion
Q - How can adrenal androgensecretion be controlledindependently?
A - Androgen stimulating peptideor zonation?
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Ratios of precursors to products indicatethat maturation of zonation (especially thereticularis) is the most likely aetiology
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Metabolism of DHEA
DHEADHEAS Androstenedione Testosterone
5-DHT
EstradiolEstrone
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Physiological role of DHEA(S)
• Adrenarche
• Other– Glucocorticoid antagonist– Neurosteroid– Androgen and estrogen precursor
• NB - a receptor has not been identified ?membrane effects
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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
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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
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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
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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
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Summary
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Conclusion
Long-term studies of adequate power are required to determinethe benefits and risks of DHEA treatment.
Lancet 2001, 357: 1381
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Andropause
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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
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Considerable interindividual variation
• Due to:– Genetic factors– Illness– Obesity– Stress– Physical fitness– Medication
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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
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Is androgen deficiency diagnosable?
• No clinically useful measure of androgen activity
• ? Increased androgen sensitivity in the elderly
• No increase in gonadotrophins
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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
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Contraindications to testosterone replacement
• Ca prostate
• NB - subclinical carcinoma (>50% of >70y olds) effects unknown
• Polycythaemia
• Sleep apnoea
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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
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Androgens in the female
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Androgens in the female
Studies in post-menopausal women suggest that the ovary continuesto synthesize and secrete testosterone
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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.