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Original Studies |
Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital (J.S.M., M.C.S., P.M.S.), Edgbaston, Birmingham, United Kingdom B15 2TH; the Department of Endocrinology, St. Bartholomew’s Hospital (J.P.M., G.K., P.P., G.M.B.), London, United Kingdom EC1A 7BE; the Regional Endocrine Unit, Southampton University Medical School ((P.J.W.), Southampton, United Kingdom S09 4XY; and the Department of Clinical Biochemistry, King’s College School of Medicine (N.F.T.), Denmark Hill, London, United Kingdom SE5 9RS
Address all correspondence and requests for reprints to: Prof. Paul M. Stewart, M.D., F.R.C.P., Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom B15 2TH. E-mail: p.m.stewart{at}bham.ac.uk
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Abstract |
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In 7 acromegalic subjects withdrawing from medical therapy (Sandostatin-LAR; 20–40 mg/month for at least 12 months), GH rose from 7.1 ± 1.5 to 17.5 ± 4.3 mU/L (mean ± SE), and insulin-like growth factor I (IGF-I) rose from 43.0 ± 8.8 to 82.1 ± 13.7 nmol/L (both P < 0.05) 4 months after treatment. There was a significant alteration in the normal set-point of F to E interconversion toward E. The fall in the urinary tetrahydrocortisols/tetrahydocortisone ratio (THF+allo-THF/THE; 0.82 ± 0.06 to 0.60 ± 0.06; P < 0.02) but unaltered urinary free F/urinary free E ratio (a marker for 11ßHSD2 activity) suggested that this was due to inhibition of 11ßHSD1 activity. An inverse correlation between GH and the THF+allo-THF/THE ratio was observed (r = -0.422; P < 0.05). Conversely, in 12 acromegalic patients treated by transsphenoidal surgery (GH falling from 124 ± 49.2 to 29.3 ± 15.4 mU/L; P < 0.01), the THF+allo-THF/THE ratio rose from 0.53 ± 0.06 to 0.63 ± 0.07 (P < 0.05). Patients from either group who failed to demonstrate a change in GH levels showed no change in the THF+allo-THF/THE ratio.
In vitro studies conducted on cells stably transfected with either the human 11ßHSD1 or 11ßHSD2 complementary DNA and primary cultures of human omental adipose stromal cells expressing only the 11ßHSD1 isozyme indicated a dose-dependent inhibition of 11ßHSD1 oxo-reductase activity with IGF-I, but not GH. Neither IGF-I nor GH had any effect on 11ßHSD2 activity.
GH, through an IGF-I-mediated effect, inhibits 11ßHSD1 activity. This reduction in E to F conversion will increase the MCR of F, and care should be taken to monitor the adequacy of function of the hypothalamo-pituitary-adrenal axis in acromegalic subjects and in GH-deficient, hypopituitary patients commencing replacement GH therapy. Conversely, enhanced E to F conversion occurs with a reduction in GH levels; in liver and adipose tissue this would result in increased hepatic glucose output and visceral adiposity, suggesting that part of the phenotype currently attributable to adult GH deficiency may be an indirect consequence of its effect on tissue F metabolism via 11ßHSD1 expression.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionErratumReferences |
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By contrast, the high affinity, NAD-dependent dehydrogenase type 2 11ßHSD enzyme (11ßHSD2), protects the mineralocorticoid receptor from illicit occupancy by F (9, 10, 11). Defects in 11ßHSD2 activity, either congenital in the syndrome of apparent mineralocorticoid excess (2, 12) or acquired after licorice ingestion (13), result in F-induced, mineralocorticoid hypertension. The assessment of activity of these 11ßHSD isozymes in man can be inferred from a 24-h urinary steroid metabolite profile by measuring the excretion of free and A ring-reduced F and E metabolites (14, 15).
It is possible that many of the clinical features observed in patients with aberrant GH secretion may be mediated by altered 11ßHSD activity. A characteristic feature of acromegaly is hypertension, which has been thought to be due to enhanced renal sodium retention (16, 17). Conversely, GH deficiency in adults (GHD) is associated with insulin resistance and visceral obesity (18). In keeping with this hypothesis, recent studies conducted on hypopituitary patients suggested that GH replacement therapy altered the normal set-point of F to E conversion toward E (19, 20, 21). The data analyzing an effect of GH on 11ßHSD2 are conflicting, with studies showing either no change (20) or an increase (21) in the urinary free F/urinary free E ratio, but a common finding was the inhibition of 11ßHSD1 activity, i.e. conversion of E to F after GH replacement. These clinical studies, however, were carried out on patients with additional endocrine deficiencies; many were taking hydrocortisone replacement, which may have confounded the results. Interpretation is further complicated by the fact that net F to E conversion in hypopituitary patients in vivo appears to be directly related to total and regional body fat distribution (22).
The aim of this study, therefore, was to investigate the effect of GH and/or insulin-like growth factor I (IGF-I) on 11ßHSD1 and 11ßHSD2 activities. We have used robust in vitro systems known to express only 11ßHSD1 or 11ßHSD2. Clinically, we have studied patients with acromegaly, all of whom had intact function of the hypothalamo-pituitary-adrenal axis, affter modulation of endogenous GH/IGF-I levels.
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Subjects and Methods |
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Primary cultures of human omental adipose stromal cells. Our earlier studies have demonstrated that 11ßHSD1, but not 11ßHSD2, is expressed in adipose tissue (7). Omental adipose tissue was obtained from 5 patients (mean age, 73 yr) undergoing elective abdominal surgery in accordance with guidelines on the collection and use of surgical tissues obtained from the local hospital ethical committee. Stromal cells were isolated as previously reported (7, 8). Briefly, 2–4 g wet weight of adipose tissue were washed with phosphate-buffered saline containing 50,000 U penicillin and 50,000 µg streptomycin, and then digested with collagenase class 1 (2 mg/ml; Worthington Biochemical Corp., Freehold, NJ) in 1 x Hanks’ Balanced Salt Solution for 45 min at 37 C. After centrifugation at 100 x g for 5 min, the pellet containing the stromal cells was washed with DMEM-nutrient mixture F-12 containing 15% FCS (Life Technologies, Inc., Paisley, UK). Cells were then plated overnight in the above medium, washed with 1 x Hank’s Balanced Salt Solution, and grown in DMEM/F-12 containing 100 nmol/L F. Experiments were carried out on confluent cells 5–7 days later. Twenty-four hours before GH/IGF-I treatments, medium was changed to DMEM/F-12 without phenol red containing 10 µg/ml transferrin along with penicillin and streptomycin. The cells were then treated for 48 h with 1, 10, or 100 ng/ml human recombinant GH (Pharmacia & Upjohn, Inc., Stockholm, Sweden) or 1, 10, or 100 ng/ml human recombinant IGF-I (Sigma Chemical Co., Poole, UK). In each case triplicate assays were run.
Stably transfected fetal kidney cells. HEK 293 cells are derived from human fetal kidney, which is known to express both GH (23) and IGF-I (24) receptors. 293 cells (devoid of endogenous 11ßHSD) were stably transfected with either human 11ßHSD type 1 complementary DNA (cDNA; 293T1) or human 11ßHSD type 2 cDNA (293T2) as previously reported (25). The 11ßHSD cDNAs were donated by Drs. White and Krozowski, respectively (3, 11). Cells were grown in MEM (Life Technologies, Inc.) containing 10% FCS and geneticin until confluence. Twenty-four hours before treatments, medium was changed to serum-free DMEM without phenol red containing 5 ml MEM nonessential amino acids and 150 mg glutamine. Cells were then treated with 1, 10, or 100 ng/ml GH or IGF-I for 8, 24, and 48 h. Each experiment was repeated four times in triplicate.
11ßHSD enzyme assays
11ßHSD activity was assayed by incubating intact cells with either 250 nmol/L E (omental and 293T1 cells) or 50 nmol/L F (293T2 cells) with appropriate tracer for 4 or 2 h, respectively. The steroid concentrations used were based on the substrate affinities of the 11ßHSD1 and two enzymes and ensured first order enzyme kinetics (26). After incubation, steroids were extracted using dichloromethane and then separated using a mobile phase consisting of ethanol and chloroform (8:92) on a TLC plate (Fluka, UK). The fractional conversion of E to F or F to E was calculated after scanning the TLC plate on a Bioscan Autochanger 3000 system (Lablogic, Sheffield, UK).
Cellular protein levels in each incubate was calculated using the Bradford method (27), and enzyme activities were expressed as picomoles per mg protein/h (mean ± SE). Statistical analysis was undertaken using Student’s paired t test.
Clinical studies
Effect of reducing GH on 11ßHSD activity. Twelve patients with active acromegaly (seven women and five men; mean age, 43 yr; range, 22–60 yr) were evaluated before and after transsphenoidal surgery. In each case detailed testing of anterior pituitary function indicated normal adrenal, thyroid, and gonadal function when 11ßHSD activity was analyzed pre- and postoperatively. The time of testing after pituitary surgery varied between 8–16 weeks. GH was measured using an in-house immunoradiometric assay developed by the reference laboratory (NETRIA) based at St. Bartholomew’s Hospital (London, UK). IGF-I was measured as previously reported (28).
Effect of increasing GH on 11ßHSD activity. Seven patients with acromegaly (two men and five women; mean age, 49 yr) were evaluated after withdrawal of Sandostatin-LAR (Novartis Pharmaceuticals; 20–30 mg every 28 days) (29). Three of the seven patients had microadenomas, and all patients had intact hypothalamo-pituitary-adrenal reserve (as reflected by a serum F >550 nmol/L 30 min after im Synacthen). One patient was receiving replacement T4, but thyroid function tests in every patient were normal and did not change across withdrawal of Sandostatin-LAR. All patients had received a minimum of 12 months of therapy with Sandostatin LAR; the clinical and biochemical responses to withdrawal of therapy and the details of the GH and IGF-I assays employed for this study have been recently published (30). Patients were investigated at 4-week intervals after withdrawal of Sandostatin-LAR for a total of 16 weeks.
Both clinical studies had the approval of the local hospital
ethical committees. In both studies, IGF-I was measured basally, and GH
was determined at hourly intervals for 5 h. Patients completed a
24-h urine collection, which was assayed for F metabolites as
previously described(20), using gas chromatography/mass
spectrometry. The tetrahydrocortisols/tetrahydrocortisone
(THF+allo-THF/THE), 5
-THF/5ß-THF, and urinary free F (UFF)/urinary
free E (UFE) ratios were calculated together with total F metabolite
excretion (THF+allo-THF+THE+cortols+cortolones+UFF) and are expressed
as the mean ± SE. In each case statistical analysis
was undertaken using Student’s paired t test.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionErratumReferences |
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Incubation of both primary cultures of omental adipose stromal
cells (ASC) and 293T1 cells with IGF-I resulted in a
dose-dependent inhibition of reductase activity (E to F conversion). In
the 293T1 cells, no effect was evident after 8 h of incubation
with IGF-I, and some inhibition was observed after 24 h of
incubation (data not shown), but the most marked effect was observed at
48 h of incubation (Fig. 1
). At this
time point, inhibition was observed only with 10 and 100 ng/mL IGF-I;
no effect of 1 ng/mL IGF-I was observed. In contrast, GH had no effect
on 11ßHSD1 activity, even at a concentration of 100 ng/mL, at
incubation times of 48 h.
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For the omental ASC experiments, no differentiation from ASC to adipocytes was observed after incubation with GH or IGF-I for 48 h (longer incubation times with putative differentiation agents are required to induce differentiation of these primary cultures) (8). Furthermore, in all of the experiments, at least over this 48-h period, there did not appear to be a trophic effect of either GH or IGF-I as determined by cellular protein assays.
Clinical studies
The influences of surgery on mean serum GH, IGF-I,
THF+alloTHF/THE, alloTHF/THF, and total F metabolite excretion are
shown in Table 1. Significant increments
in the ratios of THF+alloTHF/THE were observed for the group as a whole
(P = 0.045; Fig. 2) and
were particularly evident in those patients who demonstrated a
substantial reduction in serum GH as a result of surgery. In four
patients there was no discernible change in the THF+alloTHF/THE, and of
these patients, three showed no reduction in GH and/or IGF-I after
surgery (patients 4, 8, and 9 in Table 1). There was no correlation
between either GH or IGF-I and the THF+alloTHF/THE ratio. There was no
change in the ratio of allo-THF/THF or in total F metabolite excretion
after surgery.
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and Fig. 2
). The UFF/UFE
ratio, however, did not change (0.64 ± 0.05 and 0.61 ±
0.04, respectively). GH did not rise in one of the seven patients,
remaining between 4.5–5.5 mU/L; this was the only patient in whom no
change in the THF+alloTHF/THE ratio was observed (0.62, 0.63, 0.60, and
0.60, respectively, 4, 8, 12, and 16 weeks after
Sandostatin-LAR). No changes in the allo-THF/THF ratio or
excretion of total F metabolites were seen.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionErratumReferences |
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Two isozymes of 11ßHSD are known to coordinate the interconversion of F and E in human tissues: 11ßHSD1, an oxo-reductase expressed in liver, gonad, adipose tissue, and central nervous system tissues, and 11ßHSD2, a dehydrogenase expressed in the mineralocorticoid target tissues, kidney, and colon. This alteration in the normal set-point of F to E conversion toward E with increasing GH and IGF-I levels could be secondary to either enhanced 11ßHSD2 activity or inhibition of 11ßHSD1 activity. In vivo the urinary THF+allo-THF/THE ratio probably reflects "global" 11ßHSD activity, with contributions from 11ßHSD1 and 11ßHSD2. Indeed, this ratio is grossly elevated in patients with apparent mineralocorticoid excess due to inactivating mutations in the human gene encoding 11ßHSD2 (2). [Such patients have completely normal 11ßHSD1 activity (31).] Similarly, the ratio is equally deranged, but in the opposite direction, in patients with the syndrome of apparent E reductase deficiency, which is thought to be due to loss of 11ßHSD1, but not 11ßHSD2, activity (32). The UFF/UFE ratio may be a more accurate marker of 11ßHSD2 activity; UFE excretion is 2- to 3-fold higher than UFF, reflecting renal conversion of F to E by 11ßHSD2 (15). Thus, our observation of a reduction in the THF+allo-THF/THE ratio, but a normal UFF/UFE ratio, with increasing GH is highly suggestive of inhibition of 11ßHSD1 reductase activity. The lack of change in the UFF/UFE ratio after these alterations in GH/IGF-I status is in keeping with our earlier data (20) and suggests that inhibition of renal 11ßHSD2 activity is not implicated in the pathogenesis of sodium retention observed in patients with acromegaly.
This change in the pattern of F metabolism, however, may have clinical ramifications for glucocorticoid status in both acromegalic and hypopituitary, GH-deficient, patients. By inhibiting 11ßHSD1, GH would effectively increase the MCR of F. As a result we recommend close monitoring of the pituitary-adrenal axis both in patients starting GH replacement therapy and in untreated acromegalic patients. Secondary adrenal failure may be precipitated in such situations, and patients with documented hypothalamo-pituitary-adrenal axis deficiency already taking replacement hydrocortisone may require an escalation of replacement dose.
Our in vitro studies endorse our clinical studies. The effect of GH could be due to a direct effect of GH itself or could be mediated by IGF-I. GH, however, had no effect on 11ßHSD1 (or 11ßHSD2) activity, but IGF-I caused a dose-dependant inhibition of 11ßHSD1 reductase activity. No alteration in 11ßHSD2 dehydrogenase activity after incubation with IGF-I was observed. These data are in keeping with some earlier in vitro studies, but not others. Thus, in rodents, the sexual dimorphic expression of hepatic 11ßHSD1 is thought to be secondary to sex-specific changes in GH secretion (33). The higher expression of 11ßHSD1 activity in male rat liver, for example, can be reduced to female values by a continuous female pattern of GH administration. Such inhibition of 11ßHSD1 could, of course, in an intact animal, be mediated by IGF-I. By contrast, GH itself has been shown to inhibit 11ßHSD1 activity in cultured rat hepatocytes (34), although other studies have failed to confirm these findings (35).
In addition to cells stably transfected with 11ßHSD1, our in vitro studies used primary cultures of omental adipose stromal cells, and these observations may be of considerable relevance. For reasons that are still unclear, 11ßHSD1 is preferentially expressed in omental compared to sc adipose depots (7), where it plays a crucial role in dictating glucocorticoid-induced adipocyte differentiation (8). This may be one mechanism explaining the association of glucocorticoids with visceral, as distinct from generalized, obesity. The observation that IGF-I can modulate this process may have ramifications for patients with adult GH deficiency. Earlier studies suggested that E to F metabolism (i.e. 11ßHSD1 activity) was enhanced in GH-deficient patients with hypopituitarism (19); these data as well as data showing the opposite in patients with GH excess suggest that GH deficiency, through its effect on 11ßHSD1, would increase omental adiposity. Conversely, GH treatment to such a cohort, again through an action on 11ßHSD1, would be expected to reverse this process. Similarly, within the liver, another principal site of 11ßHSD1 expression, increased GH might be expected to inhibit hepatic glucocorticoid levels, thereby reducing gluconeogenesis and hepatic glucose output (5, 6). Thus, it is exciting to speculate that many of the clinical features currently attributed to adult GH deficiency, such as central obesity and insulin resistance (18), may in part be mediated by glucocorticoids through IGF-I modulation of tissue 11ßHSD1 activity.
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Erratum |
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Figure 1, a and c, was omitted. In Figure 2, the bars described as
solid are horizontally hatched (
). The figures and
correct legends appear here.
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Footnotes |
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2 Medical Research Council Senior Clinical Fellow.
Received March 22, 1999.
Revised May 26, 1999.
Accepted July 20, 1999.
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