Androgens in Health and Disease.pdf - E Library

Chapter 17/Androgens and Puberty 339
jects, administration of exogenous testosterone alone leads to a dramatic increase in GH
secretion, plasma IGF-1 concentrations, and growth velocity (see the subsection Constitutional
Delay of Growth and Puberty). Central precocious puberty is characterized by a
significant rise in gonadal steroid hormone levels, GH secretion, and growth velocity. Following
suppression of the hypothalamic–pituitary–gonadal axis with GnRH analogs, a significant
decline in growth velocity, rate of skeletal maturation, GH secretion, and plasma
IGF-1 concentrations are noted (39,40). Girls with Turner syndrome, who lack endogenous
estrogen production, display a twofold to threefold increase in GH secretion following the
administration of very small doses of estrogen (41). Based on the previous clinical observations,
it is clear that the interaction between GH and the sex steroid hormones is necessary
to achieve physiologic growth and sexual development during the pubertal years (42).
THE ROLE OF ANDROGENS VS ESTROGENS
DURING PUBERTY
Individuals with complete androgen insensitivity (formerly termed “testicular feminization”)
demonstrate that androgens are not necessary to support normal adolescent
growth or to achieve pubertal levels of GH and IGF-1, if sufficient levels of estrogens
are present (43). Affected individuals have a normally timed pubertal growth spurt and
attain adult height intermediate between mean heights for men and women. Aromatization
of the high levels of testosterone produces elevated concentrations of estradiol
which correlate positively with plasma IGF-1 levels. Gonadectomy results in a rapid
decline in sex steroid hormone levels as well as GH secretion and IGF-1 levels.
Estrogen plays a pivotal role in skeletal maturation during puberty. Adolescent girls
with Turner syndrome before estrogen therapy and boys with CDGA before testosterone
therapy have a significant delay in skeletal maturation. A 28-yr-old man with an estrogen-receptor
gene mutation who was fully virilized, had a bone age of only 15 yr and
continued to grow in length (44). Similar clinical presentations are described in individuals
with mutations of the aromatase gene. Despite elevated androgen concentrations in
these subjects, levels of estradiol and estrone are very low, resulting in tall stature and
delayed skeletal maturation. Males have eunuchoid skeletal proportions. Taken together,
these observations confirm that estrogens are vital for physiologic bone maturation and
proportions (but not linear growth) in both men and women.
Nonaromatizable Androgens
Unlike testosterone, oxandrolone and dihydrotestosterone (DHT) cannot be converted
to estrogens by the aromatase enzyme system. Studies utilizing these compounds have
helped delineate the differential effects of androgens and estrogens on GH secretion. The
response of DHT and testosterone on GH secretion and IGF-1 levels were compared in
boys with CDGP (45). A significant decrease in the integrated serum GH concentrations,
but no changes in plasma IGF-1 concentrations were found after DHT administration
compared with a significant increase in both parameters following testosterone therapy.
This study suggests that the marked increase in mean and pulsatile GH levels at puberty
is not the result of a direct androgen effect, but perhaps, it results from an estrogenreceptor-dependent
mechanism.
There have been a number of investigations to show the growth-augmenting effects
of oxandrolone. Oxandrolone has been used in the treatment of boys with CDGA to