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.