Mini Review - sepeap

356 Nader: Adrenarche And Polycystic Ovary Syndrome
advanced bone age, had augmented LH (and also FSH
in one of the boys) during sleep at ages 8.5 and 5.5
years. In the same landmark study 34 quoted above,
there were nine females with idiopathic sexual precocity
with onset between the ages of 6e8 years. All had
Tanner stage 2e3 pubic hair, six had Tanner stage 3
and three Tanner stage 2 breasts. These nine had advanced
bone age and significantly greater DHEA-S
concentrations than chronologic-age-matched controls;
these concentrations were similar to those of normal
children matched for bone age. As written by Sklar
et al., 34 ‘‘These patients exhibited appropriate concordance
between adrenal androgen and gonadal steroid
concentrations. At least some of the patients with onset
of idiopathic precocious puberty between 6 and 8 yr of
age may represent one end of the normal spectrum of
puberty development, their precocious puberty being
part of a more generalized process which includes precocious
activation of both gonadarche and adrenarche.’’
The association between premature pubarche, as
a result of early or amplified adrenarche, and early
menarche was clearly demonstrated in a longitudinal
study of 187 girls with premature pubarche. 43 The authors
showed that menarche before age 12 was twofold
more prevalent in these girls than in normal
controls and was threefold more prevalent in a group
of girls with both premature pubarche and low birth
weight. Thus, while adrenarche and gonadarche can
occur independently, are controlled and initiated by
separate mechanisms, and have separate pathways, 44
there appears to be a temporal link between adrenarche
and gonadarche: early adrenarche is associated
with earlier gonadarche and conversely delayed or
inadequate adrenarche with later gonadarche.
The biochemical evidence supporting a role for
adrenarche in the onset of gonadarche, that is, a role
for androgens in the establishment of gonadal axis
maturation, is circumstantial. The progression of
changes in neuroendocrine function in normal puberty
will first be briefly discussed. This topic was elegantly
reviewed by Blank et al. 45 They stated that the juvenile
period of childhood is characterized by low levels
of LH and FSH with approximately one pulse of
GnRH every 4e6 hours. With the onset of puberty,
nocturnal sleep-associated increases in LH pulse
amplitude and frequency occur and precede pubertal
maturation by about two years. LH pulse frequency
and amplitude increases four- and nine-fold across pubertal
maturation in girls. These nocturnal increases
in LH lead to early morning increase in estradiol, progesterone
and testosterone. 46,47 It has been proposed
that, over time, the morning increases in progesterone
contribute to the reduction in GnRH and LH pulsatility
the following day, favoring FSH synthesis and thus
follicular development, progesterone acting either directly
or indirectly on the GnRH pulse generator. 47
Androgens have been known to play a role in
GnRH pulsatility. As previously stated, testosterone
treatment of adolescent boys with constitutional delay
has been shown to increase the tempo of testicular enlargement,
as compared with control subjects. 42 This
earlier gonadarche can only relate to central axis activation.
In addition, it has long been known that
women with PCOS require higher concentrations of
progesterone to achieve the same degree of suppression
of GnRH pulsatility as normal ovulatory control
subjects. 48 This sensitivity is restored by the antiandrogen
flutamide, implying that decreased progesterone
sensitivity is secondary to hyperandrogenemia. 49
Stated differently, androgens seem to be associated
with a disinhibition of GnRH, with increased GnRH
pulsatility, this also being a marker of the onset of gonadarche.
In light of these observations, it is quite
possible that the gradual increase in androgens characteristic
of normal puberty 50 could potentially mediate
this reduction of feedback sensitivity, leading to
increased GnRH pulsatility, as was suggested by
Blank et al. 45 In support of this possibility, Blank
and colleagues performed a study on normal adolescent
girls given estradiol and progesterone and
showed that hypothalamic progesterone sensitivity
(the ability of progesterone to inhibit GnRH pulsatility)
decreases as puberty progresses, this being coincident
with a rise in serum testosterone. They also
showed that hypothalamic progesterone sensitivity is
further reduced in adolescent girls with androgen
excess (presented at the 88 th annual meeting of the
Endocrine Society, Boston, June 2006, p 2-622).
The hypothesis proposed there is that adrenarche,
which precedes gonadarche, provides the initial
source of androgens, leading to the disinhibition of
GnRH, and hence gonadarche. The progression of
the gonadal events of puberty, as outlined in the section
on reproductive competence, and also above,
would thus naturally follow the production of androgens
at adrenarche, a harbinger of gonadarche. In
the absence of adrenarche, as in patients with
Addison’s disease for example, one would have to
assume that other mechanisms such as the accrual
of body fat and leptin activate the hypothalamic pulse
generator, albeit later. 51,52
Transition from Adrenarche to Full Reproductive
Competence
As outlined in the sections on reproductive competence
and adrenarche, normal pubertal development starts
with adrenarche and ends with the attainment of full reproductive
competence, that is, persistent ovulation, in
women. In the early phase of puberty, there is relative
hyperandrogenism, with high levels of androgens relative
to estrogens, as demonstrated in a study of 56