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Neuroendocrine Unit (K.K.M., A.K.) and General Clinical Research Center (D.H.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; and Hospital Clinic (G.S.), 08036 Barcelona, Spain
Address all correspondence and requests for reprints to: Anne Klibanski, M.D., Neuroendocrine Unit, Bulfinch 457B, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: aklibanski{at}partners.org
Abstract
Patients with hypopituitarism have increased cardiovascular mortality. A high prevalence of conventional cardiovascular risk factors, including obesity, central fat distribution, insulin resistance, and dyslipidemia, have been described in these patients. The inflammatory markers C-reactive protein (CRP) and IL-6 are predictors of cardiovascular events, and high levels of CRP have been reported in men with hypopituitarism and GH deficiency. However, little is known about inflammatory cardiovascular risk markers in women with hypopituitarism.
We therefore investigated whether inflammatory and traditional cardiovascular risk markers are elevated in women with hypopituitarism. Fifty-three women with hypopituitarism and 111 healthy control women were included in this cross-sectional study. Morning blood samples were drawn after an overnight fast. Serum was assayed for CRP, IL-6, glucose, insulin, IGF-I, triglycerides, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein (HDL) cholesterol, lipoprotein(a), E2, total testosterone (total T) and free testosterone (free T), and dehydroepiandrosterone sulfate.
IL-6 and CRP levels were higher in women with hypopituitarism than in healthy controls (P < 0.0001 for comparison between groups). In a multivariate model, CRP levels depended on hypopituitarism, body mass index (BMI), and estrogen use. There was an interaction between the effect of BMI and hypopituitarism on CRP levels, such that the importance of hypopituitarism in determining CRP levels disappeared at high BMIs. In a similar multivariate model, IL-6 levels depended on hypopituitarism and BMI. Total cholesterol, the total to HDL cholesterol ratio, and triglycerides were higher in hypopituitary patients, but only triglycerides and the total to HDL cholesterol ratio depended on hypopituitarism when controlling for BMI. There was no significant difference in lipoprotein(a) levels between hypopituitary women and control subjects. However, when controlling for estrogen use, lipoprotein(a) levels showed a trend toward being lower in the hypopituitary group (P = 0.075). In patients with hypopituitarism, CRP correlated negatively with IGF-I (r = -0.35; P = 0.010), total T (r = -0.42; P = 0.0020), and free T (r = -0.30; P = 0.031). Similarly, IL-6 correlated negatively with total T (r = -0.39; P = 0.0040) and androstenedione (r = -0.27; P = 0.048) in hypopituitary patients.
In conclusion, hypopituitary women have increased levels of IL-6 and CRP, both of which are inflammatory markers of atherosclerosis. GH deficiency and androgen deficiency may contribute to these findings. Chronic inflammation may contribute to the high cardiovascular risk seen in this population.
HYPOPITUITARISM IS associated with an increase in cardiovascular mortality (1, 2). Patients with hypopituitarism, especially women and patients who have received radiation treatment, are at increased risk of death from coronary artery disease and stroke (3). It has also been reported that patients with pituitary dysfunction have an increased prevalence of conventional cardiovascular risk factors, including obesity with central fat distribution, insulin resistance, and dyslipoproteinemia (4, 5, 6, 7, 8). Endothelial dysfunction (9) and increased intimal-medial thickness (10) have also been described in these patients.
Inflammation plays a central role in the pathogenesis of atherosclerosis (11, 12), and serum inflammatory markers, including C-reactive protein (CRP; determined by a high sensitivity assay) and IL-6, have been shown to predict the risk of acute cardiovascular events in healthy men and women (13, 14, 15, 16, 17). We recently reported that men with hypopituitarism and GH deficiency have increased levels of CRP compared with a reference population (18), but levels of inflammatory cardiovascular risk markers have not been investigated in hypopituitary women.
We therefore investigated conventional and inflammatory cardiovascular risk markers in a population of women with hypopituitarism compared with those in a group of healthy women, controlling for variables that influence inflammatory markers, including body mass index (BMI), age, and estrogen status. In addition, the relationship between inflammatory markers and other hormones, including IGF-I, androgens, and insulin, was assessed.
Subjects and Methods
Patients
Women with hypopituitarism were identified through a chart review from the Neuroendocrine Clinical Center at Massachusetts General Hospital. Hypopituitarism was defined as the presence of at least one pituitary hormone deficiency, including hypogonadism and/or hypoadrenalism. All patients had to be cured from the condition that led to the hypopituitarism and receiving stable conventional replacement therapy for pituitary hormone deficiencies. Exclusion criteria included diabetes mellitus, supraphysiological thyroid hormone replacement, as defined by a free T4 index above the normal range, high doses of glucocorticoids (>7.5 mg/d prednisone or 30 mg/d hydrocortisone), androgen therapy, and history of oophorectomy. None of the patients suffered from liver disease or malnutrition. Potential participants were identified and contacted, and all patients willing to participate were entered into the study. Two potential subjects contacted did not participate because of a history of diabetes mellitus, four because of time constraints or lack of interest, and two because of free T4 indexes above the normal range.
Controls
Controls were recruited through posters and advertising. All women were in good health, as defined by the absence of any major medical condition, including diabetes mellitus. Women with a history of high blood pressure, if well controlled, were allowed in the study. Premenopausal women all had regular menstrual cycles. Postmenopausal women had all been amenorrheic for at least 1 yr. Exclusion criteria included oophorectomy and abnormal thyroid function, as determined by serum TSH levels. Women receiving estrogen therapy (oral contraceptives or hormone replacement therapy) and those not receiving estrogen were enrolled in the study.
Protocol
Blood was drawn at approximately 0800 h after an overnight fast at the General Clinical Research Center of Massachusetts General Hospital or at a local laboratory and sent to our laboratory. All menstruating women were studied within the first 7 d of the menstrual cycle. A medical history was obtained, height and weight were measured, and BMI was calculated. Fasting blood samples were drawn for glucose, insulin, IGF-I, triglycerides, total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, lipoprotein(a), CRP, IL-6, E2, total testosterone (total T) and free testosterone (free T), androstenedione, and dehydroepiandrosterone sulfate (DHEAS). All specimens were frozen and stored until completion of recruitment and were then measured in the same assay. Androgen levels from a subset of these women have been previously reported (19).
The study was approved by the subcommittee on human studies of the Massachusetts General Hospital, and all patients gave informed consent.
Biochemical assays
Glucose, insulin, triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol, lipoprotein(a), TSH, total T4, thyroid hormone-binding index, and E2 were measured in serum at the Massachusetts General Hospital Clinical Laboratory as previously described (20). The insulin resistance index obtained from the homeostasis model of assessment (IRHOMA) was calculated as glucose (millimoles per liter) x insulin (milliinternational units per liter)/22.5 (21). The free T4 index was calculated as the product of total T4 and thyroid hormone-binding index. CRP was measured on a Behring BNII analyzer (Dade Behring, Newark, DE) using an ultrasensitive and latex-enhanced immunotechnique. The intraassay coefficient of variation was 2.93–4.20%. IL-6 was measured by an ultrasensitive ELISA assay from R & D Systems, Inc. (Minneapolis, MN) with an intraassay coefficient of variation of 5.3–8.3%. Total serum T levels were measured by RIA after extraction and column chromatography (Endocrine Sciences, Inc., Calabasas Hills, CA), with an intraassay coefficient of variation of 2.9–18.8%. Free serum T levels were measured by equilibrium dialysis (Endocrine Sciences, Inc., Calabasas Hills, CA) with an intraassay coefficient of variation of 6.6–9.4%. Androstenedione and DHEAS concentrations were measured by RIA (Diagnostics Systems Laboratories, Inc., Webster, TX), with intraassay coefficients of variation of 2.8–5.6% and 3.8–5.3%, respectively. IGF-I was measured by RIA after acid-alcohol extraction (Nichols Institute Diagnostics, San Juan Capistrano, CA), with an intraassay coefficient of variation of 2.4–3.0%.
Statistical analysis
ANOVA and analysis of covariance were used to compare the
hypopituitary subjects and healthy controls while controlling for
potential confounding covariates in univariate analyses. Confounding
covariates were those shown to have relationships with inflammatory
markers in previous studies (22, 23, 24). The models were fit
twice, initially with covariate by group interactions and then with
nonsignificant interactions removed. Multivariate models were fit for
selected covariates, again removing nonsignificant interactions. ANOVA
was also used to examine the effects of various covariates on outcomes
within the two groups separately. Spearman correlation coefficients
between outcomes were computed within each group. As an additional
check on the model, we matched patients and controls by age, BMI, and
estrogen use. This required the random removal of 2 patients and 60
controls to achieve a one-to-one matching. ANOVA was performed to
compare results between groups in this subset. For ANOVA and analysis
of covariance, the outcome variables that were not normally distributed
were a priori log transformed. For correlation analyses, no
variables were log transformed. Two-sided P 
0.05 was
considered significant. Results are reported as the median and
interquartile ranges in the hypopituitary group vs. the
control group, and P values for comparison between the 2
groups are given. All analyses were performed using SAS version 8 and
JMP 3.2.2 (SAS Institute, Inc., Cary, NC).
Results
Fifty-three women with hypopituitarism and 111 healthy controls
participated in the study. The clinical characteristics of the
hypopituitary patients are shown in Table 1
. Most patients had hypopituitarism
resulting from a pituitary adenoma (72%). Other diagnosis were
craniopharyngioma (9%), hypophysitis (2%), apoplexy (4%), and other
tumors (13%). Patients with a history of Cushing’s disease or
acromegaly had been cured for a mean of 9.5 yr (range, 1–23) and 10 yr
(range 3–17), respectively. Eighty-seven percent of the hypopituitary
patients had secondary hypothyroidism and were receiving conventional
replacement treatment with levo-T4; 76% had
secondary hypoadrenalism and were receiving conventional glucocorticoid
replacement therapy. Hypogonadism was present in 87% of the patients
studied. Of those, 57% were taking estrogen, and 43% were not.
Sixty-seven percent of estrogen-takers received conjugated estrogens,
whereas the rest received oral contraceptives containing ethinyl E2. In
the control group, 53% of estrogen-takers received oral contraceptives
containing ethinyl E2, and 47% received conjugated estrogens. In
addition, 24 patients (45%) had confirmed GH deficiency. Two patients
(4%) had normal GH secretion by stimulation testing. Of the 27
patients (51%) who did not undergo formal stimulation testing for GH
deficiency, 12 patients (45%) had IGF-I levels more than 2
SD below the reference range for the age and sex, and 14
patients (52%) had 3 or more pituitary deficiencies. Seventeen of the
patients (63%) who did not undergo formal stimulation testing had low
IGF-I levels and/or 3 or more pituitary hormone deficiencies.
Therefore, 41 patients (77%) were probably GH deficient. Two patients
with confirmed GH deficiency were receiving GH.
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. Patients with
hypopituitarism had a higher mean BMI [28.7 (range, 25.5–34.5)
vs. 25.0 (range, 22.3–29.0) kg/m2;
P = 0.0007] and were older than controls [48 (range,
40–56) vs. 44 (range, 34–52) yr; P =
0.018; Table 2]. Smoking history was similar in both groups. One
patient in the hypopituitary group had a history of myocardial
infarction more than 1 yr before her participation in the study. IGF-I
and all serum androgen levels were lower in the hypopituitary women
compared with the controls (Table 2).
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CRP levels were higher in women with hypopituitarism than in
controls [6.0 (range, 3.2–9.8) vs. 1.5 (range, 0.6–4.8)
mg/liter, P < 0.0001; Table 3]. CRP depended on
hypopituitarism, BMI, and estrogen use (Table 4). CRP did not depend on age. There was
an interaction between the effects of BMI and hypopituitarism on CRP
serum levels such that the importance of hypopituitarism in determining
CRP levels disappeared at high BMI values (Fig. 1). The regression equation for the
natural logarithm (Ln) of CRP in hypopituitary women was: LnCRP =
-0.35 + 0.66 x EG + 0.06 x BMI. For controls: LnCRP =
-2.77 + 0.66 x EG + 0.1 x BMI. In both equations, EG
= 0 for nonestrogen takers, and EG = 1 for estrogen takers (Table 4).
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We explored correlations of inflammatory parameters with hormonal and
other cardiovascular risk markers. CRP was negatively correlated with
IGF-I in both groups (hypopituitary patients: r = -0.35;
P = 0.010; controls: r = -0.19; P
= 0.044; Fig. 2). CRP was highly
correlated with IL-6 in both groups (hypopituitary patients: r =
0.71; P < 0.0001; controls: r = 0.48;
P < 0.0001). In hypopituitary patients, CRP was
negatively correlated with total T (r = -0.42; P
= 0.0020; Fig. 3) and free T (r =
-0.30; P = 0.031) and showed a trend toward s positive
correlation with insulin (r = 0.24; P = 0.088) and
the insulin to glucose ratio (r = 0.24; P =
0.083). In controls, CRP was negatively correlated with androstenedione
(r = -0.22; P = 0.023) and HDL (r = -0.25;
P = 0.0073), and positively correlated with insulin
(r = 0.33; P = 0.0005), the insulin to glucose
ratio (r = 0.36; P = 0.0001), IRHOMA (r =
0.29; P = 0.0020), triglycerides (r = 0.40;
P < 0.0001), and the total to HDL cholesterol ratio
(r = 0.31; P = 0.0009). CRP showed a trend toward
a negative correlation with total T in controls (r = -0.17;
P = 0.094). Correlations are shown in Table 5.
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IL-6 was higher in hypopituitary patients than in controls [3.7
(range, 2.7–5.5) vs. 1.5 (range, 1.2–2.5) ng/liter;
P < 0.0001; Table 3
]. IL-6 levels depended on both
hypopituitarism and BMI (Fig. 4), but not
on estrogen treatment. The regression equations obtained for the
natural logarithm of IL-6 were: Ln IL-6 = 0.2 + 0.04 x BMI
for hypopituitary women and Ln IL-6 = -0.4 + 0.04 x BMI for
controls (Table 6).
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. Total, LDL, and HDL cholesterol and triglycerides
A personal history of hypercholesterolemia was reported by nine
women in the hypopituitary group and two in the control group. Nine
patients (17%) were taking statins vs. two controls (2%).
Total cholesterol levels were higher in women with hypopituitarism than
in healthy women [5.5 (range, 4.6–6.0) vs. 5.1 (range,
4.4–5.8) mmol/liter; P = 0.041; Table 3], although
the difference was no longer significant when controlling for age or
BMI. LDL and HDL levels were not different in patients vs.
controls (Table 3). HDL cholesterol depended on age and BMI, whereas
LDL depended on BMI. The total to HDL cholesterol ratio was higher in
patients than in controls [3.9 (range, 3.1–5.0) vs. 3.4
(range, 2.8–4.0); P = 0.0025], and this difference
remained significant after controlling for BMI. Triglycerides were
higher in hypopituitary patients than in controls [1.5 (range,
1.2–2.3) vs. 0.9 (range, 0.7–1.4) mmol/liter;
P < 0.0001; Table 3]. Triglyceride levels were found
to depend on both hypopituitarism and BMI. There was no difference in
lipoprotein(a) levels between hypopituitary women and controls.
However, after controlling for estrogen use, lipoprotein(a) levels
showed a trend to be lower in hypopituitary patients (P
= 0.075).
Insulin, glucose, insulin to glucose ratio, and IRHOMA
Glucose was similar in both groups [4.9 (range, 4.6–5.3)
vs. 5.0 (range, 4.7–5.3) mmol/liter; P =
NS; Table 3]. Fasting serum insulin levels showed a trend toward being
higher in hypopituitary patients [38.0 (range, 23.7–68.2)
vs. 32.3 (range, 23.0–53.8) pmol/liter; P =
0.094]. The insulin to glucose ratio [7.8 (range, 5.2–12.9)
vs. 6.5 (range, 5.2–10.3); P = 0.022] and
insulin resistance as determined by IRHOMA [1.21 (range, 0.64–2.28)
vs. 0.98 (range, 0.69–1.63); P = 0.041]
were higher in hypopituitary patients (Table 3). After controlling for
BMI, these levels were no longer significantly different.
Results in a matched subset of patients and controls
Fifty-one women with hypopituitarism and 51 matched controls were
included in a subset analysis. Groups were matched for age, BMI, and
estrogen use (Table 7). In
concordance with the main analysis, CRP, IL-6, triglycerides, and the
cholesterol to HDL ratio were significantly higher in the hypopituitary
women compared with healthy controls, whereas there was no difference
between groups in total cholesterol, HDL, LDL, or lipoprotein(a) levels
(Table 8). IGF-I and androgen
levels were significantly lower in hypopituitary patients, as in the
main analysis (Table 7).
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Discussion
Data from this cross-sectional study indicate that women with hypopituitarism have higher serum levels of IL-6 and CRP than healthy women. This may reflect a higher degree of inflammation in women with hypopituitarism. Inflammation plays an important role in the development of atherosclerosis (11). Serum levels of CRP and IL-6 are thought to reflect chronic inflammation and have been shown to be associated with an increased risk of cardiovascular events in large scale prospective studies (14, 15, 26). Data from the Women’s Health Study have recently demonstrated that high sensitivity CRP is an important predictor of cardiovascular risk in apparently healthy women regardless of the LDL cholesterol level (17). Our data demonstrate that women with hypopituitarism may have higher IL-6 and CRP levels than a healthy control population. Therefore, increased inflammation may contribute to the poor cardiovascular risk profile in this population.
Potential mechanistic explanations for higher levels of IL-6 and CRP in
women with hypopituitarism include the presence of hormonal
deficiencies and/or the hormonal replacement regimens. For example, GH
deficiency may be a contributory factor. It is known that GH exerts
important effects on inflammatory cells (27). The GH
receptor is a member of the cytokine/hemopoietin family and uses the
same molecular pathways as cytokines in signal transduction
(28). We recently reported that men with GH deficiency
have high levels of CRP and that administration of GH compared with
placebo is associated with significant reductions in CRP and IL-6
levels (18). GH may therefore be involved in the
regulation of cytokine or CRP production. In addition to direct effects
of GH on the production of inflammatory markers, there may be important
indirect effects of GH through changes in body composition.
GH-deficient patients have increased fat mass compared with BMI-matched
controls (4). Adipose tissue has been shown to synthesize
IL-6 and TNF
, two cytokines implicated in the stimulation of CRP
production by the liver. It has been estimated that 30% of IL-6 levels
are produced by adipose tissue (29). Forty-five percent of
hypopituitary women who participated in this study were confirmed to
have GH deficiency, and many more were likely to be GH deficient, given
the preponderance of other pituitary hormone deficiencies and the low
IGF-I levels. It is therefore likely that GH, through direct effects on
cytokine production and/or by modifying body composition, may have
contributed to the high levels of inflammatory markers. Consistent with
this hypothesis, CRP levels and IL-6 correlated negatively with IGF-I
levels in the present study. Whether GH replacement in women results in
a decrease in CRP or IL-6 levels merits further investigation.
In addition, androgen deficiency may contribute to the high levels of inflammatory markers seen in women with hypopituitarism. Androgens have been shown in vivo and in vitro to modulate the synthesis of IL-6 (30, 31). Moreover, IL-6 levels rise after orchiectomy in mice (31). We recently reported that women with hypopituitarism are profoundly androgen deficient (19). In this study we report that both CRP and IL-6 correlate negatively with androgens in women with hypopituitarism. These data support the hypothesis that androgen deficiency may contribute to the high serum levels of inflammatory markers seen in this patient population.
Glucocorticoid replacement therapy may also contribute to the elevated levels of inflammatory markers seen in women with hypopituitarism. It is known that glucocorticoids stimulate the synthesis of IL-6. Although the goal of conventional glucocorticoid therapy for patients with hypopituitarism is physiological replacement, the available regimens do not mimic endogenous glucocorticoid production perfectly and may contribute to the elevated levels of inflammatory markers reported.
The effect of estrogen administration on cardiovascular risk factors is an important consideration. In the present study, women with hypopituitarism and controls who received estrogen had significantly higher mean CRP concentrations than nonestrogen takers. The question of whether estrogen replacement is associated with an improvement in cardiovascular risk has yet to be resolved. Data from the prospective HERS study showed an early increase in the number of cardiovascular events in patients taking hormone replacement therapy as secondary prevention despite a favorable effect on the lipid profile (32). Estrogen alone or in combination with progesterone was associated with an increase in CRP in healthy women in the PEPI trial (22). Women with hypopituitarism were more likely to be receiving lower doses of estrogen (conjugated estrogens vs. ethinyl E2) than women in the control groups (67% vs. 47%). Although there are no randomized clinical trials comparing head to head the effects of the two regimens on inflammatory markers, it is possible that this may have influenced our results. Because our results and those of the PEPI trial, demonstrated increased inflammatory markers in women receiving estrogen, an even greater difference in markers might have been expected if more hypopituitary patients had been receiving oral contraceptives or more controls had been taking hormone replacement dose estrogens. The clinical significance of the finding of increased inflammatory markers in healthy and hypopituitary women who take estrogen has yet to be determined.
Another interesting finding of our study is that the influence of hypopituitarism on CRP was no longer seen when BMI was very high. It is known that BMI is associated with an increase in cardiovascular risk in healthy women and that CRP increases with increases in BMI (24). Severe obesity is also associated with high cardiovascular risk and high CRP levels. Therefore, in the setting of severe obesity, hypopituitarism may not confer additional cardiovascular risk.
In the present study, women with hypopituitarism had significantly higher BMIs than controls, as has been previously described (7, 33). Triglyceride levels were also higher in women with hypopituitarism compared with controls, even after controlling for differences in BMI. This is consistent with the results of a large cross-sectional study in hypopituitary patients (7), but not with a smaller one (34). We also found a higher total to HDL cholesterol ratio, another important predictor of cardiovascular risk, in hypopituitary women compared with controls, consistent with previous observational studies (7, 34). In contrast, we found no differences in indexes of insulin resistance between groups when controlling for BMI and age. As previously described, in the present study both CRP and IL-6 correlated with measures of insulin resistance in healthy women (35, 36). In hypopituitary women, CRP and IL-6 showed a trend toward a positive correlation with insulin and the insulin to glucose ratio.
When we evaluated an age-, BMI-, and estrogen use-matched subgroup of hypopituitary patients and controls, triglycerides, inflammatory markers, and the cholesterol to HDL ratio were higher in patients, supporting the hypothesis that factors unique to hypopituitarism account for the increase in cardiovascular risk markers observed.
Limitations of our study include its cross-sectional design. In addition, our patient and control groups were drawn from different populations. Our patient population was composed of patients referred to the Neuroendocrine Clinical Center of Massachusetts General Hospital from throughout the country, and our control population was largely recruited from the Boston area. However, the distribution of CRP levels in the control group was similar to that published for the general U.S. population based on a large scale epidemiological study (25), which supports our finding of elevated CRP in women with hypopituitarism. Another important consideration is that estrogen treatment in patients and control women is not identical.
Our data demonstrate that women with hypopituitarism have elevated serum IL-6 and CRP levels, inflammatory markers of cardiovascular risk. This suggests that increased inflammation may be a contributory factor to the increased incidence of cardiovascular events seen in this population. Potential mechanisms underlying this increase in inflammatory cardiovascular risk markers include GH deficiency and androgen deficiency. Further studies are needed to investigate the pathophysiological basis and consequences of these findings.
Acknowledgments
We thank Aileen Schiller, Elizabeth Arena, and Senta Burton for patient recruitment and data entry. We thank Gregory Neubauer and Linda Ardisson for their assistance with the performance of hormone assays, the nurses of the General Clinical Research Center for patient care and dedication to research, and the patients who participated in the study.
Footnotes
This work was supported in part by NIH Grant M01-RR-01066, the Fundació la Caixa (to G.S.), and Department of Universities, Research and Information Society of the Generalitat de Catalunya (to G.S.).
Abbreviations: BMI, Body mass index; CRP, C-reactive protein; DHEAS, dehydroepiandrosterone sulfate; HDL, high density lipoprotein; IRHOMA, insulin resistance index obtained from the homeostasis model of assessment; LDL, low density lipoprotein.
Received May 3, 2001.
Accepted August 27, 2001.
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) and controls (
). —-. Regression line in patients;
· · ·, regression line in controls.
