Androgens in Health and Disease.pdf - E Library

Chapter 11/Androgens and Bone 225
insensitivity syndrome (AIS or testicular feminization) are somewhat contradictory.
Patients with AIS are tall, phenotypic females with a male genotype and undescended
testes. They are treated by castration and estrogen replacement. As adults, they do
show a decrease in BMD (65,66). When this is compared with normative male standards,
there is substantial reduction with a Z-score of –1.8. Some of the difference in
AIS patients may be the result of poor compliance with estrogen, but even in the
estrogen-compliant group, the BMD is decreased (67).
ROLE OF ANDROGENS IN THE PATHOGENESIS OF OSTEOPOROSIS
It is well established that men with severe hypogonadism lose bone (68,69). This bone
loss is associated with increased bone turnover and could result not only from the effects
of decreased androgen but from the loss of estrogen, because the majority of endogenous
estrogen in men is derived from gonadal testosterone. Osteopenia is also seen in men
with delayed puberty, although it is less marked (70–72). Hypogonadism acquired later
in life can result in substantial bone loss in patients who have had surgical castration or
been treated with gonadotrophin-releasing hormone (GnRH) analogs for prostate cancer
(73). These individuals may show increased skeletal sensitivity to PTH (74).
The role of testosterone in the age-related decrease in bone density in men is not
clear (75–77). Bioavailable testosterone decreases with age, although total testosterone
may show little or no decrease because SHBG increases with age (24,78). Patients
with hip fractures generally have lower testosterone levels than age-matched controls
(79,80). Studies relating testosterone levels to bone mass or rates of bone loss have
yielded conflicting results (81–85). One confounder is that SHBG is inversely related
to body mass index so that heavier individuals are likely to have lower total testosterone,
and these individuals are also likely to have higher BMDs. This may lead to a
positive association between testosterone levels and BMD (83). However, an inverse
relationship between bioavailable testosterone and femoral neck BMD has been seen
in the subpopulation of elderly men with low bioavailable testosterone levels (84).
Although there was no correlation with estradiol levels and BMD in these studies, this
does not rule out a role for the estrogen produced from testosterone. Circulating estradiol
levels may not fully reflect this production, because, as noted earlier, there is
aromatase activity in bone and, therefore, local production of estrogen may be more
important circulating levels (86).
Studies of men presenting clinically with osteoporosis have shown that the estradiol
level is more likely to be decreased than the testosterone level compared to nonosteoporotic
age-matched controls (87,88). In older men, increased vertebral fracture
incidence, based on lateral spine radiographs, is associated with lower levels of estradiol
but not lower levels total testosterone (89). Morphometric studies of men with osteoporosis
have also suggested that the pattern may be somewhat different from that seen in
women. There is a greater component of decreased bone formation and less loss of
trabeculae in the male patients (17,90,91).
Androgen deficiency may also play a role in the pathogenesis of osteoporosis in
women. Women who have had a hysterectomy and oophorectomy have relative androgen
deficiency because the ovary is a major source of testosterone in postmenopausal
women (92). In addition, there is an age-related decline in adrenal androgens in women
that is greater than that observed in men (93).