clinical Science (1983)65, 99-101
99
SHOR T COMMLNICATION
Normal adrenocortical response to adrenocorticotrophic
hormone in patients with homozygous familial
hypercholesterolaemia
J. M. ALLEN, G . R. THOMPSON* A N D N. B. MYANT*
Endocrinology Unit, Department of Medicine, Royal Postgraduate Medical School, and
*Medical Research Council Lipid Metabolism Unit, Hammersmith Hospital, London
(Received 20 September 1982; accepted 22 February 1983)
summary
1. Plasma cortisol concentration was measured
in three subjects with homozygous familial hypercholesterolaemia immediately before, and 30 and
60 min after, an intramuscular injection of adrenocorticotrophic hormone. The baseline values and
the values at 30 and 60min were within the
normal range.
2. We conclude that in the presence of a genetic
deficiency of low-density lipoprotein receptors,
the human adrenal cortex can respond to a single
injection of adrenocorticotrophic hormone with a
normal increase in corticosteroid production.
Key words: corticosteroid production, familial
hypercholesterolaemia, LDL receptors.
Introduction
The unesterified cholesterol required for the production of steroid hormones in the adrenal cortex
can be derived either from synthesis in situ or
from cholesterol-rich lipoproteins taken up from
the extracellular medium; cholesteryl esters stored
in cytoplasmic droplets provide an additional
source of free cholesterol that can be released in
response to sudden increases in demand for steroid
hormone (see [l]). Observations on rats [2] and
human subjects [ 3 ] in vivo have shown that nearly
all the cholesterol used for steroid hormone synthesis by the adrenals in the basal state is derived
from the plasma rather than from synthesis in
situ. Mouse adrenal cells in culture express specific
Correspondence: Dr N. B. Myant, Director,
MRC Lipid Metabolism Unit, Hammersmith Hospital, DuCane Road, London W12 OHS.
saturable receptors for low-density lipoprotein
(LDL), similar to the LDL receptors discovered
by Brown & Goldstein [4] on human fibroblasts
(see [5]) and Faust et al. [6] have shown that
when these cells are stimulated by adrenocorticotrophic hormone (ACTH), a maximal increase in
corticosteroid production does not occur unless
LDL can be taken up via the LDL receptor pathway. It is not known whether the human adrenal
cortex is equally dependent upon receptor-mediated
uptake of LDL for a maximal response to ACTH,
but Brown et al. [5] have shown that membranes
prepared from human foetal adrenal cortex are
very rich in LDL receptors. If LDL receptors play
an essential role in supplying the adult human
adrenal cortex with cholesterol from the plasma,
it should be possible to demonstrate defective
corticosteroid production in patients with familial
hypercholesterolaemia (FH) in the homozygous
form, a condition characterized by an absence or
marked deficiency of LDL receptors and a greatly
increased plasma LDL concentration. In this study
we have measured the serum cortisol concentration under basal conditions and after a standard
ACTH test in three FH homozygotes.
Methods
Three male homozygotes aged 17 (no. l), 21 (no.
2) and 30 years (no. 3) were investigated. Cultured
skin fibroblasts from all three were receptor
defective according to the criteria of Goldstein
et al. [7]. A blood sample (25 ml) was taken at
09.00 hours after the subjects had fasted for
14 h. Each was then given 0.25 mg of ACTH 1-24
(Synacthen, Ciba Laboratories) by intramuscular
injection and blood samples were taken after
J. M. Allen et al.
100
TABLE1. Serum cortisol concentrations in three
patients with homozygous familial hypercholesteroloemia before and at 30 and 60 min after an
injection o f A C T H 1-24
________
Time
(min)
0
30
60
~_____
~~
Serum cortisol (nmol/l)
Patient no. 1 Patient no. 2 Patient no. 3
254
5 49
621
591
749
867
237
69 1
832
30 min and 60 min. Serum cortisol concentration
was measured by a competitive protein-binding
assay [8] with a pooled sample containing 430
nmol of cortisol/l as qualitycontrol standard.
Results
Table 1 shows the baseline serum cortisol concentrations and the concentrations at 30 min and
6 0 m i n after the injection of ACTH in the three
patients. The baseline values and the increases in
serum cortisol concentration in response to the
standard injection are within the range of values
obtained from adults with normal adrenocortical
function at Hammersmith Hospital, i.e. an increase
in serum cortisol concentration of more than
200 nmol/l to a value exceeding 500 nmol/l after
the standard injection of 0.25 mg of Synacthen.
Discussion
Our finding that the 1 h response to a single injection of Synacthen is normal in FH receptordefective homozygotes suggests that an immediate
.increase in corticosteroid production does not
require the presence of a normal complement of
functioning LDL receptors in the adrenal cortex.
However, it is possible that a brief increase in the
supply of intracellular free cholesterol can be
mediated by hydrolysis of stored cholesteryl
esters, and that if we had given our patients a
more prolonged challenge we would have uncovered a defect in their ability to respond maximally to ACTH. Against this, three of our FH
homozygotes at Hammersmith Hospital have
undergone major surgery for coronary artery
bypass without showing clinical signs of adrenal
insufficiency. It seems more likely that in FH
homozygotes the adrenal cortex obtains the free
cholesterol it needs for increased hormone synthesis, in response t o a brief or prolonged stress,
either by increasing cholesterol synthesis in situ
or by increasing the uptake of lipoproteins from
the plasma by routes other than the LDL receptor
pathway. In keeping with the latter suggestion,
Pittman et al. [9] have concluded that about
90% of the uptake of plasma LDL by the adrenals
of a normal rabbit in vivo is mediated by the
LDL receptor, but that in the WHHL rabbit (a
strain with a genetic deficiency of LDL receptors
leading t o a 10-fold increase in plasma LDL concentration) the adrenals can nevertheless take up
LDL at a rate approaching that observed in the
normal animal. Pittman et al. [9] suggest that at
very high plasma LDL concentrations, as occur
in FH homozygotes, uptake of LDL by nonsaturable mechanisms may partly compensate for
the lack of normal receptor-mediated uptake.
Thus our suggestion that the adrenal cortex in FH
homozygotes responds to stress by increasing its
uptake of LDL via receptor-independent pathways
is compatible with the possibility that in normal
human subjects the LDL receptor pathway makes
a substantial contribution to the supply of cholesterol for hormone synthesis in the adrenal cortex.
Nor does our suggestion exclude the possibility
that there is also an increase in cholesterol synthesis in the adrenal cortex in response to ACTH,
as in the mouse adrenal cells studied by Faust
et al. [6].
Illingworth & Orwoll [ 101 have reported a subnormal increase in corticosteroid output in two
abetalipoproteinaemic patients given intravenous
infusions of ACTH for 24-36 h. However, in
abetalipoproteinaemia there is a total deficiency
of LDL. Hence, neither receptor-independent nor
receptor-mediated uptake of LDL is available to
supply the adrenal cortex with cholesterol from
the plasma.
Acknowledgment
We thank Dr K. Mashiter and his staff (Endocrine
Unit, Hammersmith Hospital) for carrying out the
measurements of plasma cortisol.
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