Another article
which shows that we can’t trust anything in our profit first system. It
is as Ben Goldacre says: the devil is in the details. In this case it is the lab tests for
testosterone. Each service does what is
in their financial interest.
https://academic.oup.com/biomedgerontology/article/57/2/M76/547924
Andropause: Clinical Implications of the
Decline in Serum Testosterone Levels With Aging in Men
The Journals
of Gerontology: Series A,
Volume 57, Issue 2, 1 February 2002, Pages M76–M99, https://doi.org/10.1093/gerona/57.2.M76
Because
SHBG levels increase with aging,
many older men with low-normal total T levels have free or bioavailable T
levels that are below the normal range for young men. Therefore, measurements
of bioavailable or free T using ammonium sulfate precipitation or equilibrium
dialysis, respectively, or calculated from measurements of total T and SHBG are
recommended to diagnose androgen deficiency in older men. Unfortunately, these
measurements of free and bioavailable T are not usually performed in local
laboratories and are only available through commercial reference laboratories. Most
local laboratories measure free T using a solid-phase direct analog immunoassay
kit. Although free T measurements using this method correlate with those using
equilibrium dialysis, values obtained differ substantially [e.g., by more than
an order of magnitude in women (53)] from those obtained
by equilibrium dialysis or calculated from SHBG, and vary directly with
alterations in SHBG levels (52)(53)(54)(55)(56). Therefore, free T
measurements using direct analog immunoassay kits may not provide useful clinical
information beyond that of total T levels. They tend to under-diagnose older
men with androgen deficiency and over-diagnose androgen deficiency in men with
low SHBG levels (e.g., moderately obese men). Free T levels measured using a
direct analog immunoassay should not be used in situations where SHBG levels
may be altered (e.g., older men).
Age-Related
Alterations in Androgen Action and Active Metabolism of T
Besides the limited studies of T negative
feedback mentioned
previously, a systematic evaluation of
age-related changes in androgen action in androgen-responsive target organs has
not been performed. Androgen receptor gene expression in the CA1 region of the
hippocampus and the number of androgen receptor binding sites in genital skin
are decreased in older compared with young men (112)(113)(114). Androgen receptor
expression and
nuclear androgen receptor levels in the prostate are unchanged in older men
without benign prostatic hyperplasia (BPH) and are similar to those in young
men (115)(116)(117). However,
prostate androgen receptor expression is reduced, and nuclear androgen receptor
levels are increased in older men with BPH compared with young men.
The length of trinucleotide CAG repeats in
the androgen receptor
gene is variable and is associated with differences in transcriptional
activity, with a shorter CAG repeat length associated with greater androgen
receptor activity and possibly overall greater androgen action (118). In the
Massachusetts Male Aging Study (MMAS),
serum total and free T levels were found to be associated with the CAG repeat
length in the androgen receptor gene (40). Older men
with lower serum T levels had an androgen receptor genotype characterized by a
shorter CAG repeat length, suggesting overall greater androgen activity. It is
hypothesized that, in older men with shorter CAG repeat length, increased
androgen action at the level of the hypothalamic-pituitary axis may result in
greater feedback suppression of gonadotropin and, in turn, endogenous T
secretion. This may be an intrinsic mechanism that underlies the physiological
decline in serum T levels with aging. A shorter CAG repeat length in the
androgen receptor gene also has been associated with an increased risk and
severity of BPH and prostate cancer (119)(120)(121)(122)(123)(124)(125) and
an earlier age at diagnosis and aggressiveness of prostate carcinoma (126)(127)(128)(129).
Androgen action is not simply a function
of androgen receptor
expression in target tissues and CAG repeat length, but involves a complex interaction
among androgen ligands such as T, the androgen receptor, and tissue-specific
coactivators and corepressors with androgen-response elements in specific
genes (130)(131). Age-related alterations of the latter and
other transcription factors in androgen target tissues and their effects on
androgen action have not been investigated. However, the preliminary findings
reviewed suggest that, in addition to circulating T levels, age-associated
changes in androgen action may play important roles in the alterations of
physiological function that occur with normal aging and in the pathophysiology
of age-related pathologies.
T is actively metabolized to the potent estrogen,
estradiol
(E2), by the enzyme aromatase, which is located primarily in adipose tissue,
and to 5 alpha-dihydrotestosterone (DHT), a more potent androgen than T, by the
enzymes 5 alpha-reductase type 1 and 2, which are located predominantly in skin
and the prostate (132)(133)(134). Many
of the actions of T are mediated, at
least in part, by its active metabolites, E2 (e.g., bone, brain, and lipids)
and DHT (e.g., prostate). Despite declining T levels, serum total E2 and
DHT levels do not change or decrease only slightly with aging (24)(26)(34)(37)(38)(135)(136)(137)(138)(139). This
suggests that, with aging, there is a relative increase in aromatization of T
to E2 (perhaps due to increased adipose tissue mass) and 5 alpha-reduction of T
to DHT and/or reductions in the metabolic clearance of E2 and DHT. Because
serum SHBG levels increase with aging, serum bioavailable or free E2 and DHT
levels would be expected to decrease with aging. The physiological significance
of bioavailable E2 and DHT is not clear. However,
recent studies suggest that bioavailable E2 levels decline with aging and
correlate better than T with bone mineral density in men (26)(137)(139)(140).
Serum markers of peripheral androgen action
such as 3 alpha-, 17
beta-androstanediol glucuronide (3 alpha-diol G) decrease markedly with aging,
suggesting an overall decline in the total circulating androgen pool (24)(138)(141). Tissue concentrations of DHT decrease
within the epithelial compartment and E2 increase within the stromal
compartment of the normal and BPH prostate gland with aging, emphasizing the
importance of active metabolism of T in androgen target organs and within
specific regions of these organs (142)(143)(1
https://academic.oup.com/biomedgerontology/article/57/2/M76/547924
