Tuesday, July 3, 2007

Regulation of steroid hormone action

Steroid hormones (androgens, oestrogens, progestins
and the corticosteroids) are able to enter cells, bind
to receptors and directly regulate gene transcription.
The synthesized proteins carry out the ultimate effect
of the hormone. Evidence accrued in the following
studies suggest a physiological role for vitamin B6 in
modulating steroid hormone action.
The infl uence of B6 vitamers and analogues on the
physical properties of the glucocorticoid receptor
has been studied using in vitro receptor preparations
(Allgood et al., 1990a). The combined data showed
that, among these compounds, only PLP can directly
associate with the glucocorticoid receptor and alter
several of its properties, including molecular conformation,
surface charge, susceptibility to exogenous
proteolysis, DNA binding capacity and subcellular
localization. The last two properties are requisites for
regulation of target gene expression.
In a number of rat studies, Bender’s group produced
in vivo evidence that vitamin B6 may be involved in the
normal physiological action of steroid hormones. In
male rats, Symes et al. (1984) showed that the uptake
and accumulation of tracer [1,2,6,7–3H]testosterone
in the nucleus of the prostate gland were signifi cantly
increased in vitamin B6-defi cient animals compared
with vitamin B6-adequate controls. In a corresponding
study of female rats (Bowden et al., 1986), the
animals were segregated according to the phase of
the oestrous cycle to avoid the inherent variations of
both plasma concentration of oestrogen and the concentration
of oestrogen receptor in the uterus during
the course of the oestrous cycle. As for testosterone in
the male, uptake and accumulation of tracer [2,4,6,7–
3H]17β-oestradiol in uterine nuclei were signifi cantly
increased in vitamin B6-defi cient animals throughout
the oestrous cycle; there were no signifi cant differences
at anoestrus.
Bender’s group also found evidence of enhanced
sensitivity to steroid hormone action in vitamin B6-
defi cient rats of both sexes. In the male, testosterone is
secreted by the interstitial cells of Leydig in the testes,
but only when these cells are stimulated by luteinizing
hormone (LH) released by the anterior pituitary
gland in response to hypothalamic gonadotropin-releasing
hormone (Gn-RH). Circulating testosterone
exerts negative feedback control at the level of the
hypothalamus, switching off the supply of pituitary
LH and thereby stopping testicular secretion of testosterone
(Fig. 14.9). Symes et al. (1984) found that
the plasma concentration of testosterone in vitamin
B6-defi cient male rats was only 25% of that in vitamin B6-adequate controls. This unexplainable reduction
in plasma testosterone was not accompanied by a
reduction in the relative weight of the prostate gland
as might have been expected; neither was it accompanied
by a rise in plasma LH. These two observations
suggest that there may be enhanced sensitivity of the
hypothalamus to negative feedback by testosterone in
vitamin B6 defi ciency, leading to normal (or reduced)
plasma concentrations of LH and normal growth of
the prostate despite considerably reduced circulating
concentrations of testosterone.
In the female rat, ovarian secretion of oestrogen is
stimulated by LH and follicle-stimulating hormone
(FSH) released from the anterior pituitary gland in
response to hypothalamic Gn-RH. During most of
the oestrous cycle, circulating oestrogen exerts negative
feedback control at the level of the hypothalamus,
suppressing the release of LH and FSH. The major
event of ovulation is preceded by a massive outfl ow
of LH from the pituitary (the pre-ovulatory surge)
caused by positive feedback of oestrogen upon the
hypothalamus. Bowden et al. (1986) reported that in
ovariectomized rats, doses of ethynyl-oestradiol that
had no effect on circulating LH in control animals
(i.e. submaximal doses) lowered plasma LH levels in
vitamin B6-defi cient animals. As in the male rat, this
suggests that vitamin B6 defi ciency leads to enhanced
sensitivity of the hypothalamus to negative feedback
by steroid hormone.
Allgood et al. (1990b) investigated the infl uence of
PLP on glucocorticoid receptor-dependent gene expression
by introducing a reporter gene with a defi ned promoter into a cell culture line. The results showed
that, under conditions of moderate vitamin B6 defi -
ciency, the glucocorticoid receptor becomes a more
effi cient activator of gene transcription. Conversely,
high concentrations of vitamin B6 suppress activation
of transcription. The modulatory effects of PLP
concentration occurred through a novel mechanism
that did not involve changes in glucocorticoid receptor
mRNA or protein levels, or the receptor’s ligand
binding capacity. Analogous effects of PLP were
found with the oestrogen, androgen and progesterone
receptors (Allgood & Cidlowski, 1992). Vitamin
B6 appears to modulate steroid hormone-mediated
gene expression through its infl uence on a functional
or co-operative interaction between steroid hormone
receptors and the transcription factor NF1 (Allgood
et al., 1993).