Modalities of androgen substitution

As discussed in section 16.5.1, in the absence of convincing evidence that androgen requirements change with age, it can be proposed to aim for the physiological levels in young men. There is no evidence that it is clinically important to mimic the diurnal variations as found in young adults. Nevertheless, it should be appreciated that constant levels in the upper normal range will result in 24-hour mean levels that are supraphysiological as compared to the situation in young men subject to diurnal variations of serum testosterone.

Taken that the hypothalamo-pituitary-testicular axis is very sensitive to negative feedback, and even more so in elderly males (Deslypere et al. 1987; Winters et al. 1984; 1997), it is important to ascertain that the dose administered increases the testosterone levels up to the physiological range and does not merely suppress LH secretion with only replacement of the deficient testosterone production by an inadequate dose of exogenous testosterone. In practical terms, full replacement doses are usually required.

Considering the fact that metabolization of testosterone to DHT and estradiol is important for the regulation and full expression of testosterone effects, treatment with testosterone is the most physiological approach and the preferable option with the currently available evidence, but the debate is certainly not closed in view of data obtained with alternative treatments such as transdermal DHT and in view of ongoing research aimed at the development of "selective androgen receptor modulators" (SARMs) with tissue-specific properties. (The pharmacology and practical aspects of testosterone replacement are discussed in detail in Chapter 13.)

16.6 Key messages

• Mean total serum testosterone decreases progressively in healthy men over the age of 55 years (30% decrease between age 25 and 75 years). Age-associated decrease of the bio-available fractions of serum testosterone is steeper as a consequence of an age-related increase of serum SHBG (50% decrease of free or bio-available testosterone between age 25 and 75 years).

• There is great inter-individual variability of prevailing androgen levels in the elderly, ranging from perfectly preserved to frankly hypogonadal. Part of the inter-individual variability in serum testosterone levels is explained by heredity, physiological factors and lifestyle-related factors.

• The proportion of men with "subnormal" testosterone relative to the levels in young men increases with age (>20% after age 60 years); whether androgen requirements change in aging men remains to be established.

• The age-related decline in Leydig cell function can transiently or more permanently be accentuated by co-morbidity and medication.

• The age-related decline of testosterone production is the result of primary testicular changes as well as of failure of the hypothalamic regulatory mechanisms to respond adequately to the hypoandrogenic state.

• Many of the clinical features of aging in men are reminiscent of the clinical changes seen in hypogonadism in younger men; relative hypoandrogenism may be involved in some, but certainly not all clinical changes.

• Testosterone levels required for normal sexual activity are rather low and although testosterone levels codetermine potency, the factors most commonly involved in sexual dysfunction in elderly men are not hormonal.

• Hypoandrogenism may be involved in the sarcopenia of elderly men.

• The role of hypoandrogenism in male senile osteoporosis remains to be confirmed; recent data indicates that aromatization of testosterone to estradiol plays an important role in the regulation of bone metabolism in elderly men.

• In the present state of the art, androgen supplementation should only be considered in the presence of androgen serum levels clearly below the lower normal limit for younger men, together with unequivocal signs and symptoms of androgen deficiency, in the absence of other reversible causes of decreased androgen levels and after screening for contraindications. The longer term risk-benefit ratio for androgen administration to elderly men is unknown.

• Available questionnaires assessing aging male symptomatology do not predict decreased serum testosterone in elderly men; their use for screening purpose should not be encouraged.

• Possible benefits of the treatment include an improved sense of general well-being, of libido and of muscle strength, with increase of lean body mass and limited decrease of fat mass.

• So far, the limited data on safety of testosterone replacement therapy in the elderly has been rather reassuring: larger scale studies of longer duration are still needed to assess safety, in particular at the prostate level; development of erythrocytosis seems to emerge as one of the most troublesome side-effects, which may be less frequent if largely supraphysiological androgen levels are avoided.

• Androgen replacement therapy in the elderly requires careful monitoring by an experienced physician.

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