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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 5 2152-2156
Copyright © 2003 by The Endocrine Society

Endothelial Function and Coagulant Factors in Growth Hormone-Treated Hypopituitary Adults Receiving Desmopressin

J. C. Smith, H. A. Lane, J. Lewis, S. Dann, J. Goodfellow, P. Collins, L. M. Evans, M. F. Scanlon and J. S. Davies

Departments of Medicine (J.C.S., H.A.L., J.L., S.D., L.M.E., M.F.S., J.S.D.), Cardiology (J.G.), and Haematology (P.C.), University Hospital of Wales, Cardiff CF14 4XN, United Kingdom

Address all correspondence and requests for reprints to: Dr. Jamie C. Smith, Department of Diabetes and Endocrinology, Old Building, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom. E-mail: jamie.smith{at}virgin.net.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Although GH deficiency may underlie the increased cardiovascular risk in adult hypopituitarism, other coexisting hormonal deficiencies and/or unphysiological hormone replacement may contribute. L-Deamino-8-D-arginine (DDAVP), when administered parenterally, potentiates hemostasis by increasing plasma procoagulant factors. We investigated whether chronic intranasal DDAVP therapy influences clotting factors (plasma fibrinogen, factor VIII, and von Willebrand factor antigen) and endothelial function (flow-mediated dilation of the brachial artery) in 30 GH-treated hypopituitary subjects, including both DDAVP-treated subjects (group A) (mean age, 46 ± 11 yr) and vasopressin-sufficient subjects (group B) (mean age, 47 ± 16 yr). Fifteen healthy controls (group C) (mean age, 48 ± 12 yr) were also studied. All hypopituitary patients were receiving stable GH replacement (median duration, 19 months). Comparing the three groups, concentrations of fibrinogen (mean ± SD) (A, 3.3 ± 1.0 g/liter vs. B, 3.5 ± 0.9 vs. C, 2.6 ± 0.8, P < 0.05), factor VIII (A, 130% ± 30% vs. B, 128% ± 30% vs. C, 104% ± 35%, P < 0.05) and von Willebrand factor antigen (A, 124% ± 35% vs. B, 134% ± 45% vs. C, 93% ± 36%, P < 0.05) were higher in hypopituitary subjects, compared with controls. However, there were no differences in clotting factors between groups A and B. Flow-mediated dilation did not differ significantly between the two hypopituitary groups (A, 5.9% ± 2.0% vs. B, 4.7% ± 1.6%) and was similar to that in the control group (C, 5.7% ± 2.1%). In conclusion, although endothelium-dependent vasodilation is intact in GH-treated hypopituitary adults, elevated concentrations of hemostatic markers suggest the persistence of a prothrombotic tendency and endothelial dysfunction. Intranasal DDAVP does not appear to influence this proatherogenic profile in hypopituitary adults with vasopressin deficiency.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
ALTHOUGH EPIDEMIOLOGICAL EVIDENCE suggests that hypopituitary adults have an increased mortality from atherosclerotic cardiovascular disease (1, 2, 3), the precise underlying mechanisms remain undetermined. Untreated GH deficiency in adult hypopituitarism is associated with a cluster of cardiovascular risk factors including unfavorable body composition, dyslipidemia, and reduced insulin sensitivity (4, 5). Observations that GH replacement favorably influences this adverse cardiovascular risk profile (6), improves cardiac performance (7), ameliorates proatherogenic changes in the vasculature (8), and improves large artery function (8, 9, 10) all support the tenet that untreated GH deficiency underlies the increased cardiovascular risk in adult hypopituitarism. However, there are conflicting reports concerning the effects of GH replacement on coagulation and fibrinolytic pathways in hypopituitary adults (5, 11). Furthermore, it remains unknown whether GH replacement reduces cardiovascular event rates and improves survival.

Because hypopituitarism is a heterogeneous condition arising from a variety of underlying disorders and characterized by multiple coexisting pituitary hormonal deficiencies, it is possible that unphysiological replacement of other target hormones also contributes significantly to increased cardiovascular risk. Indeed, recent evidence from a study of more than 1000 hypopituitary adults suggests that vasopressin deficiency in hypopituitary adults is a strong predictor of poor cardiovascular outcome, being associated with a 3-fold increase in mortality, compared with the control population (3). Furthermore, patients with an underlying diagnosis of craniopharyngioma, of which as many as 60% receive vasopressin replacement in the postoperative period (12), have a particularly poor cardiovascular outcome (3, 13). The underlying mechanisms responsible for this association are unknown.

In addition to its antidiuretic effect, the long-acting synthetic vasopressin analog, desmopressin (L-deamino-8-D-arginine, DDAVP), used conventionally for vasopressin replacement in diabetes insipidus, is known to have hemostatic properties (14). In normal subjects, iv and sc administration of DDAVP increases plasma concentrations of factor VIII procoagulant and von Willebrand factor (vWF) (14, 15) as well as potentiating platelet aggregation (16) and platelet adhesion to the endothelial cell surface (17). Furthermore, given via the parenteral route in patients with coagulation disorders such as hemophilia or von Willebrand’s disease, DDAVP has an established therapeutic role in increasing plasma levels of endogenous clotting factors and reducing transfusion requirements during surgery or bleeding episodes (14). Reports of DDAVP infusions precipitating myocardial infarction and ischemic stroke in susceptible individuals further highlight its potent thrombotic effects (18).

The hemostatic effects of long-term oral or intranasal DDAVP therapy in hypopituitary adults have not been studied. Although the dosages used intranasally for diabetes insipidus are of a lower order of magnitude than those used either intranasally (approximately, one tenth the dose) or iv for bleeding disorders (14, 19), it is conceivable that long-term DDAVP therapy might produce some prothrombotic effect. Such an effect may adversely influence endothelial function and thus contribute to the proatherogenic state in adult hypopituitarism. The main aims of this cross-sectional study were to assess endothelium-dependent vascular reactivity and coagulant factors in stable GH-treated hypopituitary adults, compared with controls, and assess the influence of intranasal DDAVP therapy on the same parameters for those individuals with diabetes insipidus.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
In this cross-sectional study, 30 GH-deficient hypopituitary patients were recruited from the endocrine clinic at the University Hospital of Wales. All patients had previously undergone diagnostic GH provocative testing using either insulin-induced hypoglycemia or combined GHRH/arginine stimulation and were confirmed to be GH deficient as evidenced by a peak GH response cut-off of less than 3 µg/liter for both stimulatory tests. All patients had been stabilized on GH replacement (median duration 19 months) by self-administered daily injections such that IGF-I concentrations were maintained in the upper half of the age- and sex-adjusted laboratory normal range. The hypopituitary subjects were subdivided into groups A and B according to the presence or absence of vasopressin deficiency. Group A (n = 15) comprised patients with vasopressin deficiency, all of whom were receiving intranasal DDAVP therapy in daily doses ranging from 10–40 µg daily (mean daily dose of 20 µg). Group B (n = 15) comprised only vasopressin-sufficient patients, and these individuals were age and sex matched with group A patients. In addition, 15 healthy controls (group C) were recruited from hospital staff and were also age and sex matched with groups A and B.

All hypopituitary subjects were receiving full, conventional hormonal replacement therapy for other hormone deficiencies including sex hormones. The nature of the underlying pituitary pathology in group A patients was as follows: nonfunctioning pituitary tumor (six patients), craniopharyngioma (three patients), Cushing’s disease (cured) (one patient), acromegaly (two patients), neurosarcoidosis (one patient), and idiopathic hypopituitarism (two patients). The underlying pituitary pathology in group B patients was as follows: nonfunctioning pituitary tumor (eight patients), macroprolactinoma (two patients), pituitary irradiation (two patients), craniopharyngioma (one patient), acromegaly (one patient), and idiopathic (one patient).

Individuals within the three groups were age and sex matched and had similar body weights. There were no individuals with overt coronary heart disease, cerebrovascular disease, or diabetes mellitus. Cigarette smokers were also excluded. Ethical approval for the study was obtained and subjects gave informed consent.

Laboratory measurements

Each subject was studied following an overnight fast with measurement of IGF-I, lipid profile, plasma fibrinogen, factor VIII, and vWF antigen (VWF:Ag). Plasma fibrinogen was measured using the Clauss method on a CA6000 coagulometer (Sysmex, Milton Keynes, UK). VWF:Ag was measured using an ELISA assay using antibodies from DAKO Corp. (Glostrup, Denmark). Factor VIII was assayed on a KC10 analyzer using immunodeficient plasma (Technoclene, Vienna, Austria). Total cholesterol and triglyceride concentrations were measured enzymatically using standard techniques. High-density lipoprotein cholesterol was measured after precipitation of apolipoprotein B with phosphotungstate/magnesium. Low-density lipoprotein cholesterol was calculated using the Friedwald equation. IGF-I was measured after prior acid-ethanol extraction by polyethylene glycol-assisted second antibody RIA.

Brachial artery studies

Flow-mediated dilatation (FMD) was measured by ultrasonic wall tracking as reported previously (10). The system comprises an adapted duplex color flow echo machine (Diasonics Spectra, Bedford, UK) with a 7.5-MHz linear phased-array transducer (giving high axial resolution). After obtaining a longitudinal B-mode image of the brachial artery, the radiofrequency signals from the M-mode output are digitized and relayed to the wall-tracking software (Vadirec; Medical Systems Arnhem, Oosterbeek, The Netherlands). Following a 10-sec period of data acquisition, vessel wall movements are tracked using the stored radiofrequency signals to produce displacement waveforms of the anterior and posterior walls together with the distension waveform (diameter change as a function of time) (20). This allows determination of end-diastolic diameter for each beat providing a theoretical resolution of ± 3 µm. Brachial artery blood flow was measured throughout the study using an 8-MHz continuous-wave Doppler probe. The Doppler signals were analyzed by a spectrum analyzer (SciMed Dopstation, Bristol, UK). All studies were performed during the morning in a temperature-controlled room with subjects fasted and supine following a 15-min rest. Measurements were performed at baseline and at 1-min intervals for a period of 5 min during reactive hand hyperemia (produced by releasing a pneumatic wrist cuff inflated for 5 min to suprasystolic pressure). A second cuff inflation was performed and repeat measurements were obtained during reactive hand hyperemia to assess operator reproducibility.

Reproducibility of this technique for a single operator, determined by calculating the mean absolute difference ± SD between paired measurements of FMD, was 0.58% ± 1.7%.

Statistical analysis

All statistical analyses were performed using SPSS for Windows (version 9.0; SPSS, Inc., Chicago, IL). Data are expressed as mean values ± SD. Statistical comparisons among groups were made using ANOVA. Q-Q plots and Blom’s proportional estimation formula were used to determine whether a parameter was normally distributed. The variables IGF-I, triglyceride, and body mass index followed a nonnormal distribution. Correlation among variables was evaluated using Spearman’s and Pearson’s correlation coefficients and multiple regression analysis. A two-sided P value of less than 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The results of comparisons between the two hypopituitary groups (A and B) and healthy controls (C) for coagulant activity and brachial artery vascular reactivity are shown in Table 1Go. Concentrations of fibrinogen (A, 3.3 ± 1.0 g/liter, B, 3.5 ± 0.9 g/liter vs. C, 2.6 ± 0.8 g/liter, P < 0.05), factor VIII (A, 130 ± 30%, B, 128 ± 30% vs. C, 104% ± 35%, P < 0.05), and VWF:Ag (A, 124 ± 35%, B, 134 ± 45% vs. C, 93 ± 36%, P < 0.05) were significantly higher in both groups of hypopituitary subjects (A and B), compared with healthy controls (C) (Fig. 1Go). However, there were no differences in clotting factors between groups A and B. FMD did not differ significantly between the two hypopituitary groups (A, 5.9 ± 2.0% vs. B, 4.7 ± 1.6%) and was similar to that in the control group (C, 5.7 ± 2.1%). There were no differences in brachial artery blood flow increases among the three groups. No correlation was observed between coagulant factors and FMD.


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  		Table 1. Comparisons of coagulant factors and endothelial function between the three groups

 


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  		Figure 1. Comparisons of coagulant activity in study subgroups (mean ± SE). A, DDAVP-treated hypopituitary subjects. B, Vasopressin-sufficient hypopituitary subjects. C, Healthy controls. *, P < 0.05 in comparison with controls (C).

 
There were no significant differences in IGF-I, total cholesterol, low-density lipoprotein cholesterol, or triglyceride concentrations among groups. However, high-density lipoprotein cholesterol was lower in group A (1.2 ± 0.3 mmol/liter, P < 0.05), compared with groups B (1.3 ± 0.3 mmol/liter) and C (1.5 ± 0.4 mmol/liter).

To assess acute effects of DDAVP on the parameters studied, group A subjects were further subdivided into those who had and had not received a DDAVP dose within 4 h of being studied. Of the 15 subjects in group A, six had received DDAVP within 4 h of being studied. Patients within this subgroup were receiving DDAVP as part of a twice-daily dosage regimen. Comparing patients in this latter subgroup vs. those receiving only an evening dose (n = 9), concentrations of fibrinogen were 3.3 ± 0.9 g/liter vs. 3.3 ± 1.1 g/liter (P = NS); factor VIII, 134 ± 36% vs. 128 ± 28% (P = NS); and VWF:Ag, 123 ± 45% vs. 124 ± 30% (P = NS). There were therefore no significant differences in terms of coagulant factors between these two subgroups. In addition, there was no correlation within the whole group between the size of the daily DDAVP dose and coagulant factors or FMD.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Epidemiological evidence suggests that hypopituitary adults have a reduced life expectancy, largely as a result of increased cardiovascular mortality (1, 2, 3). Untreated GH deficiency, a common denominator for the majority of subjects in these studies, is associated with an adverse cardiovascular risk profile (5) together with abnormalities in vascular endothelial function (8, 9, 10, 21). Adult GH deficiency has therefore been implicated as an important contributor to the increased cardiovascular risk associated with hypopituitarism.

In agreement with earlier studies performed at our center (9, 10, 21), the present study demonstrates that endothelium-dependent dilation of the brachial artery in hypopituitary adults receiving stable GH replacement is of a similar magnitude to that of comparable healthy controls. This contrasts with observations in GH-deficient hypopituitary subjects in whom FMD is significantly impaired (9, 10, 21). Thus, stimulated endothelium-derived nitric oxide release in GH-treated hypopituitary adults is intact and might imply healthy large artery function. However, we have also demonstrated elevated levels of vWF, factor VIII, and fibrinogen in these individuals despite stable physiological GH replacement, suggesting the persistence of a prothrombotic tendency.

Following endothelial injury, activation of the coagulation cascade together with platelet activation and adhesion are early events that are prerequisites for thrombogenesis in atheromatous vessels. VWF is a multimeric glycoprotein, synthesized in endothelial cells and platelets (22). Because VWF release is increased when endothelial cells are damaged, plasma levels of VWF have been widely regarded as a marker indicating the extent of endothelial damage and thus the susceptibility to atheromatous complications (22). The validity of this concept has been borne out by results of prospective studies, which have shown that in individuals with overt cardiovascular disease, high plasma levels of VWF are highly predictive of future cardiovascular events including myocardial infarction and death (23, 24). However, rather than merely acting as a marker of endothelial dysfunction, VWF may also play a pivotal role in the pathophysiology of thrombogenesis in atheromatous arteries. At sites of endothelial damage, VWF promotes hemostasis by binding to the exposed subendothelium and bridging this surface with platelet plugs through interactions with glycoprotein complexes on platelet membranes (25). Indeed, VWF-mediated platelet adhesion to the injured endothelium is considered to be an initiating step in physiological thrombus formation (22). Under conditions of high shear stress, similar to those that might occur in diseased arteries, large multimeric forms of VWF stimulate spontaneous platelet aggregation. In addition, VWF stabilizes factor VIII by forming noncovalent complexes with the latter in plasma, thus protecting it from proteolytic inactivation (22, 26). Increased levels of factor VIII and associated acute phase reactants including fibrinogen are also implicated in the development of atherosclerotic disease (27, 28).

The GH/IGF-I system may be directly involved in the regulation of factor VIII and VWF levels (29, 30). Abnormalities of coagulation and fibrinolysis with elevated plasma concentrations of several hemostatic markers have been previously reported in GH-deficient adults (31, 32) but results of earlier studies are inconsistent (5). More recent data in hypopituitary adults with GH deficiency do suggest elevated levels of both fibrinogen (6) and VWF (33) with positive correlations observed between other surrogate markers of endothelial dysfunction (33). Conversely, acutely blocking GH action in healthy males using the GH receptor antagonist, pegvisomant, led to a reduction in VWF levels (34). There has been relatively less study of the effects of GH replacement on hemostatic markers, and these studies have yielded variable results (6, 32). Our observations that hypopituitary adults continue to have elevated levels of the hemostatic markers fibrinogen, VWF, and factor VIII despite stable GH replacement suggest a persistent perturbation of endothelial function and prothrombogenicity in these individuals.

Besides GH deficiency, other target hormonal deficiencies and/or their unphysiological replacement probably contribute to cardiovascular risk in hypopituitarism. Specifically, vasopressin deficiency, necessitating DDAVP treatment, has been identified as a predictor of poor cardiovascular outcome (3). Furthermore, the diagnosis of craniopharyngioma is independently associated with increased cardiovascular mortality (3, 13). Because patients with craniopharyngioma often have posterior pituitary insufficiency, DDAVP replacement therapy is frequently required in this condition. In addition to its antidiuretic effect, it possesses potent hemostatic properties (14). When infused iv or administered sc or intranasally in relatively high doses [approximately 10-fold higher than those used for diabetes insipidus (19)], DDAVP induces a rapid 2- to 3-fold increase in plasma VWF in healthy individuals that lasts 4–6 h (14, 15). The mechanism for this increase in VWF induced by DDAVP probably occurs through direct release of stored factors within endothelial cells (35) and leads to enhanced platelet aggregation and platelet adhesion to the endothelial cell surface.

In addition, release of factor VIII, a cofactor for factor IX in the process of fibrin formation (14), further enhances coagulability. In animal models, DDAVP also exerts direct activating effects on endothelial cells leading to expression of adhesion molecules (P selectin) and margination of leukocytes (36). Although a possible association between venous thromboembolism and low-dose intranasal DDAVP treatment has been reported previously in a patient with diabetes insipidus (37), the influence of DDAVP therapy on coagulation and arterial function in hypopituitary adults has not been examined previously. Our findings suggest that DDAVP treatment using conventional intranasal doses does not affect either endothelium-dependent dilation or VWF concentrations in hypopituitary adults receiving GH replacement. Thus, any hemostatic effect of DDAVP at the conventional doses used to treat diabetes insipidus in hypopituitarism is likely to be minimal and probably has no influence on the susceptibility to atherosclerotic complications.

There are several limitations to the present study. The cross-sectional study design did not allow us to prospectively evaluate the effects of DDAVP therapy on the study parameters over a time period. The numbers of subjects in each group were also relatively small, so small differences that may exist among groups might not have been detected. Despite this, previous experience at our center using the technique of FMD (9, 10, 21, 38) suggests that we would have been able to detect differences in FMD of the order of 2–3% with statistical significance using the chosen sample size. In addition, determining vascular function and cardiovascular risk in hypopituitary adults is complicated because of the heterogeneous nature of hypopituitarism. The imbalance among the groups in terms of nature of underlying pituitary disease could conceivably have influenced endothelial function and coagulation profiles of the subjects.

In conclusion, although endothelium-dependent vasodilation is intact in GH-treated hypopituitary adults, elevated concentrations of hemostatic markers suggest the persistence of a prothrombotic tendency and endothelial dysfunction. Intranasal DDAVP does not appear to influence this proatherogenic profile in hypopituitary adults with vasopressin deficiency. The mechanisms underlying the reported relative increase in cardiovascular risk associated with vasopressin deficiency and craniopharyngioma remain unexplained.


   Acknowledgments
 
We thank the Departments of Haematology and Biochemistry at the University Hospital of Wales for blood sample analysis. N. MacCartney performed the factor VIII and VWF:Ag assays.


   Footnotes
 
Abbreviations: DDAVP, L-Deamino-8-D-arginine; FMD, flow-mediated dilatation; vWF, von Willebrand factor; VWF:Ag, vWF antigen.

Received October 17, 2002.

Accepted February 10, 2003.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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