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Endocrine Care |
Department of Endocrinology, Christie Hospital, Manchester, United Kingdom M20 4BX; Department of Endocrinology, St. Bartholomew’s Hospital (W.M.D., L.A.P., G.M.B., J.P.M.), West Smithfield, London, United Kingdom EC1A 7BE; and Department of Clinical Biochemistry, King’s College School of Medicine (N.F.T.), Denmark Hill, London, United Kingdom SE 9RS
Address all correspondence and requests for reprints to: Dr. Peter J. Trainer, Christie Hospital, Wilmslow Road, Manchester, United Kingdom M20 4BX. E-mail: peter.trainer{at}man.ac.uk
Abstract
Pegvisomant is a GH receptor antagonist and highly efficacious new
treatment for acromegaly. The two isoenzymes of 11ß-hydroxysteroid
dehydrogenase are responsible for the interconversion of cortisol and
its inactive metabolite cortisone. We demonstrated previously that the
type I isoform, which is principally responsible for conversion of
cortisone to cortisol, is partially inhibited by GH. The net activity
of the enzyme can be measured by analysis of the urinary ratio of
11-hydroxy/11-oxo cortisol metabolites or of the urinary ratio of
tetrahydrocortisol/tetrahydrocortisone [(tetrahydrocortisol +
5
-tetrahydrocortisol)/tetrahydrocortisone]. We studied the
influence of pegvisomant on cortisol metabolism in patients with active
acromegaly. Seven patients (four women and three men; median age, 58
yr; range, 39–72) were studied at baseline and again after a mean of
46 weeks of treatment. The mean insulin-like growth factor I (IGF-I)
level at baseline fell from 939.7 ± 271.1 to 346.9 ± 379.0
ng/mL on 20 mg/day pegvisomant. The 11-hydroxy/11-oxo ratio increased
from a pretreatment mean value of 0.61 ± 0.18 to 0.88 ±
0.20 (P < 0.02) and when the six patients in whom
serum IGF-I normalized were considered separately, the change was from
0.62 ± 0.19 to 0.90 ± 0.21 (P < 0.04).
The tetrahydrocortisols/tetrahydrocortisone ratio increased from a
pretreatment mean value of 0.64 ± 0.21 to 0.98 ± 0.26
(P < 0.02) and in the six patients in whom serum
IGF-I normalized, the ratio rose from 0.66 ± 0.23 to 1.01 ±
0.26 (P < 0.04). These data 1) indicate that
blockade of GH action with pegvisomant in patients with acromegaly is
associated with reversal of the inhibition of 11ß-hydroxysteroid
dehydrogenase and correction of cortisol metabolism, and 2) suggest
that in active acromegaly, cortisol clearance is accelerated and that
this is reversed by successful treatment. This is further evidence of
the efficacy of pegvisomant in the management of acromegaly and has
important implications for determining optimum glucocorticoid
replacement.
CORTISOL METABOLISM is abnormal in patients with active acromegaly, with alteration of the activity of the 11ß-hydroxysteroid dehydrogenase (11ßHSD) enzymes being implicated as the pathophysiological mechanism. There are two well characterized isoforms of this enzyme responsible for the interconversion of cortisol and cortisone, its inactive metabolite. The type 1 isoform is an NADP-dependent, bidirectional enzyme that predominately acts as a reductase converting cortisone to cortisol and is located principally in liver, adipocytes, and the gonads. Several lines of evidence indicate that GH is an important regulator of 11ßHSD1 and specifically inhibits the conversion of cortisone to cortisol. GH deficiency in adults is associated with decreased net conversion of cortisol to cortisone, an abnormality corrected by GH replacement therapy (1), and in active acromegaly there is accelerated clearance of cortisol, reversed by both transsphenoidal hypophysectomy and octreotide (2).
11ßHSD type 2 is an NAD-dependent, unidirectional enzyme found predominantly in kidney and colon that converts cortisol to cortisone, and defects in this enzyme are responsible for the syndrome of apparent mineralocorticoid excess and the enzyme is not influenced by GH (3).
Pegvisomant, a GH receptor antagonist, is a highly effective new treatment for acromegaly (4). GH contains two distinct receptor-binding sites that interact with identical cell surface receptors. The binding of two receptors to a single GH molecule induces dimerization of the receptors, signal transduction, and insulin-like growth factor I (IGF-I) generation. Pegvisomant is a GH analog and, in common with GH, consists of 191 amino acids differing by the presence of a single amino acid substitution at amino acid 120 that results in total loss of affinity for the second GH receptor, thereby inhibiting dimerization (5). A further 8 amino acid substitutions in the first binding site greatly enhance receptor affinity at that locus, thereby giving the antagonist a kinetic advantage over GH in binding to receptors at site 1. The hydrodynamic volume and consequentially the half-life of the antagonist protein are greatly increased by conjugation with four to five 5000-Da polyethylene glycol moieties. Pegvisomant does not lower circulating GH levels, and hence, GH cannot be used as a marker of disease activity, but, rather, serum IGF-I is used as the primary measure of efficacy.
This study was designed to explore the ability of pegvisomant to correct the abnormality of cortisol metabolism associated with active acromegaly.
Subjects and Methods
Patients
The study included seven patients (four women and three men; median age, 58 yr; range, 39–72), treated at one center, drawn from a multicenter phase II study of pegvisomant in the treatment of acromegaly. The patients initially participated in a double blind, placebo- controlled study, followed by an open label dose titration protocol (6). Four patients were taking hydrocortisone, and five were receiving T4 therapy, in all cases at fixed doses for the duration of the study. The patients were investigated at baseline and subsequently on a maintenance dose of pegvisomant (20 mg/day as a single sc injection).
Study design
The patients gave written informed consent before withdrawal of other medical therapy for acromegaly. At the end of appropriate wash-out periods (2 weeks for short acting octreotide and 5 weeks for dopamine agonists), serum IGF-I was at least 50% above the upper limit of the age-related reference range. A 24-h urine collection was made, and blood samples were drawn after an 8-h fast. Patients were randomized, in a double blind manner, to placebo or 30 or 80 mg pegvisomant once weekly by sc injection for 6 weeks. The patients continued to receive pegvisomant initially weekly then by daily injection. The dose was increased from 10 to 20 mg daily. The patients were restudied after a mean of 46 weeks (range, 45–47 weeks) of treatment when on 20 mg/day pegvisomant. The study was approved by the East London and City Health Authority research ethics committee.
Assays
Serum IGF-I was measured by a competitive binding RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA). Intra- and interassay coefficients of variation (CVs) were between 2–8%.
IGF-binding protein-3 (IGFBP3) was measured by RIA (Endocrine Sciences, Inc., Calabasas Hills, CA). Intra- and interassay CVs were between 5–18%.
Serum CBG was measured by RIA (Biosource Technologies, Inc., Nivelles, Belgium). Intra- and interassay CVs were less than 8% at 30, 60, and 100 µg/mL.
Serum T4, T3, and TSH were measured using an Immuno-1 immunochemistry autoanalyzer (Bayer Diagnostics, Newbury, UK). The imprecision of the T4 measurement was less than 2%, that of T3 was less than 6%, and that of TSH was less than 2%.
Urinary free cortisol was assayed using a Bayer Corp. Immuno-1 immunochemistry autoanalyzer after methylene dichloride extraction. The interassay CV was 11.8%, and the intraassay CV was 9.0%.
Urinary steroid profiles were measured by gas chromotography as previously described (7). The intra- and interassay CVs were between 7.1–21.1%, and 11.2–21.9%, respectively.
Total cortisol metabolites were determined from the sum of
tetrahydrocortisone (THE), tetrahydrocortisol (THF), 5THF,
-cortolone, ß-cortolone, -cortol, and ß-cortol.
11-Hydroxycortisol metabolites (Fm) were derived from the sum of THF,
5THF, -cortol, and [(ß-cortolone +
ß-cortol) x 0.5]. 11-Oxocortisol metabolites (Em) were
determined from the sum of THE, -cortolone, and
[(ß-cortolone + ß-cortol) x 0.5]. 20-Hydroxy
metabolites of cortisol were determined from the sum of -cortolone,
ß-cortolone, -cortol, and ß-cortol, and 20-oxo metabolites of
cortisol were determined from the sum of THE, THF, and 5-THF. The
ratios of Fm/Em and [THF + 5THF/THE] were calculated as indexes of
total net 11ßHSD activity (Fig. 1
).
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Within-subject comparisons were made between baseline and on 20 mg/day pegvisomant. Data relating to each variable tested were shown to have a normal distribution, and subsequent analysis was performed using paired Student’s t test. All results are expressed as the mean ± SD, and significance was taken as P < 0.05.
Results
Serum IGF-I fell with pegvisomant therapy in every patient, with
six of the seven patients reaching a level within the age-related
reference range by the end of the study (Table 1). There was a highly significant
decrease in mean serum IGF-I of 63% from a mean (±SD)
baseline value of 939.7 ± 271.1 to 346.9 ± 379.0 ng/mL
(P = 0.006) during treatment with 20 mg/day. Mean serum
IGFBP-3 fell from 5.2 ± 1.1 ng/mL at baseline to 3.2 ± 1.2
(P < 0.02).
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and Fig. 2), and when considering the six
patients in whom serum IGF-I normalized, the change was from 0.62
± 0.19 to 0.90 ± 0.21 (P < 0.04). The THFs/THE
ratio increased from a pretreatment mean value of 0.64 ± 0.21 to
0.98 ± 0.26 (P < 0.02); for the six patients in
whom serum IGF-I normalized, the change was from 0.66 ± 0.23 to
1.01 ± 0.26 (P < 0.04). Twenty-four-hour urinary
free cortisol excretion was unchanged by pegvisomant therapy
(147.5 ± 92.1 vs. 94.5 ± 51.4; P
= NS).
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Discussion
Pegvisomant has been shown to be a highly effective new therapy for acromegaly. In a double blind, placebo- controlled, phase III study in 112 patients with acromegaly, serum IGF-I fell to the normal age-related reference range in 89% of patients receiving 20 mg/day. Additional measures of activities of the GH axis, namely serum free IGF-I, IGFBP-3, and acid-labile subunit, showed a dose-dependent fall parallel to that in serum IGF-I. The biochemical improvements were accompanied by a significant improvement in patient well-being and a reduction in soft-tissue swelling, reflected by ring size (4). The changes in serum IGF-I and IGFBP-3 in the patients in the study reported here are consistent with the results of the phase III double blind study, with six of seven patients in this study achieving a serum IGF-I within the age-related reference range.
The two isoenzymes of 11ßHSD are important regulators of cortisol
metabolism by the interconversion of cortisol and cortisone within
specific tissues. 11ßHSD1 is found in adipocytes, liver, and gonad
and is bidirectional in normal individuals; the set-point of enzyme
activity favors the conversion of cortisone to cortisol. The
localization of 11ßHSD1 within the liver and visceral fat gives it a
crucial role as a regulator of tissue glucocorticoid exposure.
Short-term inhibition of 11ßHSD1 activity in man results in reduced
hepatic glucose output, and it has been proposed that 11ßHSD1 may be
an important determinant of insulin sensitivity and visceral fat mass
(8). The urinary Fm/Em and THF plus 5THF/THE ratios are
measures of net cortisol to cortisone conversion, whereas the urinary
free cortisol to free cortisone ratio is a specific measure of
11ßHSD2 activity. We and others have previously demonstrated that GH
does not alter the urinary free cortisol to cortisone ratio, indicating
that the changes in Fm/Em and THF plus 5THF/THE ratios due to GH are
specific to 11ßHSD1 (1, 9).
The low urinary cortisol to cortisone metabolites ratio at baseline confirms the findings from our previous studies that in active acromegaly there is accelerated cortisol to cortisone conversion (2). Active acromegaly is associated with salt and water retention and hypertension, but the observation that cortisol clearance is increased excludes the mineralocorticoid action of cortisol as the mechanism. A reduction in serum IGF-I resulting from GH receptor blockade by pegvisomant produced a net increase in cortisone to cortisol conversion, and the improvement seen was greater than has been reported with either octreotide therapy or transsphenoidal surgery (2). The change in cortisol metabolism seen with a GH receptor antagonist in patients with active acromegaly is exactly the opposite of, and therefore mechanistically entirely compatible with, that seen in adults with GH deficiency treated with GH (7). The implication is that the urinary cortisol to cortisone metabolite ratio may be a useful marker of "GH deficiency" due to overtreatment with pegvisomant. The absence of a change in either serum T4 or T3 indicates that this effect is independent of thyroid hormone. In vitro studies indicate the probable mechanism to be a direct action of IGF-I, which has been demonstrated to inhibit 11ßHSD1 reductase activity in cultured HEK93 cells and human omental adipose stromal cells (2). The ability of pegvisomant to completely correct the disturbed cortisol metabolism of acromegaly further reflects the beneficial potency of this new treatment and demonstrates its ability to rectify a major metabolic defect underlying GH excess.
The quantitative consequences of 11ßHSD1 inhibition and the magnitude of the change in circulating cortisol concentration require further study. In patients with an intact hypothalamo-pituitary axis, feedback regulation would suggest that circulating cortisol levels would be unaltered by 11ßHSD1 inhibition, but cortisol concentrations within omental fat and liver may be influenced by pegvisomant. 11ßHSD1 is found in relatively greater concentrations in omental as opposed to sc fat, and as cortisol has a critical role in adipocyte differentiation, local changes in cortisol concentration consequent upon increased 11ßHSD1 activity may influence adipocyte differentiation and visceral fat distribution (10). Further, in vitro, GH antagonists inhibit GH- mediated differentiation of preadipocytes to adipocytes (11, 12). Insulin is another important regulator of 11ßHSD1 activity, an effect that may be modulated by pegvisomant therapy, as it is known to improve insulin sensitivity in patients with acromegaly (13, 14). In addition, 11ßHSD1 activity is inversely proportional to total and regional fat mass (15, 16). The present studies do not permit the precise identification of the interactions between circulating IGF-I and insulin concentrations, fat mass, and 11ßHSD1 activity. Longitudinal studies of body composition and fat distribution changes with pegvisomant therapy are required to determine the complex interplay and net effect of these factors on metabolic homeostasis.
A potential consequence of pegvisomant antagonizing GH-induced inhibition of 11ßHSD1 in patients with ACTH deficiency receiving a fixed replacement dose of hydrocortisone could be overtreatment of adrenocortical insufficiency after the reduction in cortisol clearance. Four patients were receiving a fixed dose of hydrocortisone substitution therapy throughout the study, and there was no clinical evidence of overreplacement. The interpretation of plasma cortisol levels in patients with acromegaly is complex, as approximately 90% of circulating cortisol is bound to cortisol-binding globulin (CBG), and GH is known to lower circulating CBG levels with long-term treatment (7, 17). Octreotide therapy and successful surgery have been reported to increase CBG levels, but no change was seen in this study, implying that the regulation of circulating CBG levels is not directly by GH or IGF-I, but, rather, by some indirect and unidentified mechanism. In general, the changes in circulating free cortisol are probably modest, and the nature of hydrocortisone replacement therapy so crude that it is unlikely to impact on the dose of hydrocortisone replacement. Experience from adults with GH deficiency taking fixed doses of hydrocortisone shows that the introduction of GH replacement therapy and the associated acceleration in cortisol clearance, while a theoretical concern, are rarely if ever associated with hypoadrenalism (18).
In summary, we have confirmed that cortisol clearance is accelerated in patients with active acromegaly and that pegvisomant reverses these changes through alteration of the activity of 11ßHSD1, which may have important clinical consequences.
Acknowledgments
We acknowledge the major contribution of the endocrine nurse specialists, in particular Louise Conrich and Emma Elliot.
Footnotes
1 This work was supported by a grant from Sensus Drug Development
Corp. (Austin, TX). 
Received July 20, 2000.
Revised January 11, 2001.
Revised March 19, 2001.
Accepted March 26, 2001.
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