Androgens in Health and Disease.pdf - E Library

224 Kenny and Raisz
METABOLISM OF ANDROGEN IN BONE
Bone cells have been shown to contain a number of enzymes that can metabolize
androgens. Because these enzymes that can interconvert androgens and estrogens in
bone cells, it is difficult to assess the specific roles of any single hormone (48). Testosterone
can be converted to DHT by 5α-reductase or to estradiol by aromatase. Bone
cells can also form testosterone from androstenedione (49,50). A genetic defect in
aromatase results in marked skeletal abnormalities because of estrogen deficiency
(51,52), but the specific role of aromatase in bone has not been defined. It seems likely
that 5α-reductase is of less importance for the maintenance of the skeleton, because
deficiency of this enzyme does not result in any gross skeletal abnormalities (53).
ANDROGEN EFFECTS ON BONE IN VIVO:
STUDIES IN ANIMAL MODELS
The role of androgens in bone has been examined in rodent models, including ovariectomized
and orchidectomized rats and mice, animals treated with inhibitors of aromatase
or antiandrogens, and mice with defects in the androgen receptor or the aromatase
enzyme. There are also limited studies in primates (54,55). Orchidectomy in rats produces
bone loss, associated with an increase in turnover similar to the effect of oophorectomy
in females (56,57). However, these changes could be the result of the loss of
estrogen derived from testosterone rather than direct loss of testosterone. In oophorectomized
rats, a high concentration of DHT appeared to decrease bone turnover (58).
Because DHT cannot be converted to estrogen, this indicates an androgen-receptormediated
effect. Moreover, animals treated with either an antiestrogen or antiandrogen
lose less bone than oophorectomized animals, whereas the combination of antiestrogen
and antiandrogen treatment, or antihormonal treatment and oophorectomy results in
equivalent bone loss but not as great an increase in bone turnover (59). Inhibition of
aromatase (60) or knockout of the enzyme (61) produces some bone loss in mice. However,
the picture in male aromatase-deficient mice is somewhat different from that of
orchidectomy, with a decrease in bone turnover and less bone loss (62).
ROLE OF ANDROGENS IN THE SKELETON: HUMAN STUDIES
Both androgens and estrogens are critical for the growth and consolidation of the
skeleton that occurs at puberty. There are sex differences; males show greater periosteal
and endosteal apposition by modeling during puberty, supporting a specific role
of androgen in this process. Studies of androgen insensitivity and estrogen deficiency,
resulting from either defects in aromatase or loss of the estrogen receptor, have shed
further light on the relative roles of these hormones in skeletal development
(51,52,63,64). One male with an inactivating mutation in ERα and two males with
aromatase deficiency have been described as having a quite similar phenotype, with
failure of epiphyseal closure, tall stature, high bone turnover, and decreased bone
mineral density (BMD). With estrogen replacement, the patients with aromatase
deficiency showed epiphyseal closure, decreased bone turnover, and, in one case,
substantial increase in bone mass. These studies indicate that ERα is a critical receptor
for regulation of bone turnover, but that androgen receptors may be sufficient to
stimulate accelerated linear growth of the skeleton at puberty. Findings in androgen-