Acromegaly Treatment Is Associated With Lower Lipoprotein(a) and Higher Apolipoprotein A1 and
Low-Density Lipoprotein-Cholesterol Serum Levels

Luciana A. Naves*

Paulo A. Mello†

Aldo Pereira Neto†

Fatima F. Cardoso*

Lucilia Domingues*

Luiz Augusto Casulari‡

 *Divisions of Endocrinology, †Neurosurgery of University of Brasilia, and ‡Endocrinology and Neurosurgery Unit of Hospital de Base do Distrito Federal, Brasília, Brazil.

KEY WORDS: acromegaly, cholesterol, growth hormone, insulin-like growth factor-I, lipoprotein, lipid, treatment, triglyceride

ABSTRACT

Background: The aim was to study the lipid and lipoprotein profiles of patients with actively secreting GH tumors and in previously affected patients considered cured of the acromegaly.

Methods: Experimental design, cross-sectional study. We studied the lipid and lipoprotein profile of 38 patients (21 females; 17 males; aged 42.5 ± 1.7 y) who were divided into three groups: group A–12 patients with active acromegaly in treatment with octreotide (0.2–0.3 mg); group B–11 untreated patients with active acromegaly; and group C–15 previously acromegalic patients considered cured (suppression of serum GH below 1 ng/mL during oral glucose tolerance test and normal serum IGF-I).

Results: GH (0.9 ± 0.4 ng/mL) and IGF-I (199 ± 22.6 ng/mL) serum levels were significantly lower in patients in group C than in those of the A and B groups (GH – A = 14.9 ± 6.7 ng/mL; B = 25.3 ± 11.3 ng/mL; IGF-I – A = 471.8 ± 30 ng/mL; B = 740.7 ± 77.9 ng/mL). Lipoprotein(a) serum levels were higher than 30 mg/dL in 68% of patients with active acromegaly (A + B groups) and only in one patient (6.6%) in group C. Apolipoprotein A1 serum levels were significantly higher in patients in group C (150.5 ± 7.4 mg/dL) than in those in groups A and B (101.8 ± 8.9 mg/dL and 95.4 ± 7.7 mg/dL, respectively). The apolipoprotein B/apolipoprotein A1 ratio was significantly lower in patients in C group (0.71 ± 0.06) than in patients in groups A (1.02 ± 0.14) and B (1.08 ± 0.12), whereas serum low-density lipoprotein cholesterol (LDL-c) was significantly higher in patients in C group (141.3 ± 28.3 mg/dL) than in those in group B (103.5 ± 27.0 mg/dL). A total cholesterol/high-density lipoprotein cholesterol (HDL-c) ratio higher than 5.0 and a LDL-c/ HDL-c ratio higher than 3.5 were most frequent in group C (60% and 50%, respectively) than in group A + B (35.8% and 28.6%, respectively). There were no differences among the three groups in serum levels of apolipoprotein B, HDL-c, VLDL-c, total cholesterol, and triglyceride.

Conclusions: The effective treatment of acromegaly decreases the lipoprotein(a) and increases the apolipoprotein A1 levels, and might be a factor of protection from atherosclerosis and contributes to reduced mortality and morbidity in these patients. The higher LDL-c serum levels after treatment of acromegaly might reflect a deficiency of GH in cured patients.

INTRODUCTION

Acromegaly is a rare disease characterized by an excessive growth hormone (GH) and insulin-like growth factor–I (IGF-I) secretion. It occurs mainly in adult patients.1–3 Treatment of acromegaly includes surgery, usually by the transsphenoidal route, radiotherapy, administration of somatostatin analogs, as octreotide, or of dopamine agonists.3

Cardiovascular disorders are the primary cause of mortality and morbidity in these patients. A specific cardiomyopathy, characterized by ventricular hypertrophy, fibrosis, and myofibrillar degeneration, has been associated with high GH and IGF-I serum levels.4 However, precocious atherosclerosis and coronary heart disease have also been described in acromegalic patients, possibly contributing to the high incidence of cardiovascular diseases.5

Alterations in lipid metabolism and insulin resistance, both present in acromegaly, have been described as important factors in the development of the atherosclerosis and coronary heart disease.6 However, the lipid profiles described in patients with acromegaly are rather inconsistent, and this makes it difficult to understand the true role of the different lipid fractions in the pathogenesis of the atherosclerosis and of the coronary heart disease in acromegalics.

Some authors have described increased levels of total serum cholesterol in acromegalic patients,7,8 whereas the great majority of the data in the literature are not indicative of significant changes as compared with appropriate controls.9–15 The same is true with the triglyceride serum levels; some authors have not found significant differences in comparison to the controls,9,14,15 whereas others demonstrated hypertriglyceridemia in all acromegalic patients6,11 or in the majority of them.7,16

Few studies have been performed to analyze the lipoprotein profile in patients with acromegaly and the results have been contradictory. High-density lipoprotein-cholesterol (HDL-c) has been described to be reduced in active acromegaly in some reports,14 but not in others.15 Comparable levels of apolipoprotein A1 (Apo A1), the main component of HDL-c, have been reported in patients with active or controlled acromegaly and in normal control subjects.15 However, a significant increase of Apo A1 levels after pituitary surgery has also been described.13 Apolipoprotein B100 (Apo B) levels are not affected by active acromegaly15 or by its treatment.13,15 The levels of low-density lipoprotein-cholesterol (LDL-c) have been reported to be comparable to those of the controls15 and not affected by surgery10,15 or octreotide treatment.16,17 Very low-density lipoprotein (VLDL) serum levels were described to decrease significantly after surgery.10

Lipoprotein (Lp[a]) is a macromolecular aggregate present in plasma formed by an hydrophobic polypeptide, the apolipoprotein B-100, linked by one or more disulfide bridges to apolipoprotein(a) (apo [a]), which is rich in neuraminic acid residues.18 The sequence of amino acids of the apo(a) is highly homologous to the human plasminogen. Lp(a) serum levels are little affected by age, gender, weight, and diet in comparison to the other lipoproteins classes,18 but several studies have shown that Lp(a) represent an independent risk factor for the development of the atherosclerosis,18 and a close correlation between the Lp(a) levels and the myocardial infarct incidence exists. Values of Lp(a) higher than 30 mg/dL increase approximately three times the risk of developing early coronary artery disease.18 Increased Lp(a) levels have been described in patients with active acromegaly13–15,17,19; moreover, pituitary surgery,13 as well as the treatment with octreotide,14,15 appears to be able to normalize its levels. Some authors have demonstrated only a reduction, but not a complete normalization Lp(a) levels.14,15

As a result of the many discrepancies reported in the lipid and lipoprotein profiles in patients with acromegaly and their importance in the genesis of the atherosclerosis, we have studied these parameters in patients with actively secreting GH tumors in the presence and absence of an octreotide treatment, and in previously affected patients considered cured of the disease.

PATIENTS AND METHODS

Patients

Thirty-eight patients were studied: 21 females and 17 males, aged 42.5 ± 1.7 years (range, 19–73 y). Their clinical characteristics are shown in Table 1. These patients were recruited at the University Hospital of Brasília and at the Hospital de Base of Brasília-Brazil. In all the patients a previous diagnosis of acromegaly had been firmly established by their typical clinical features and biochemical findings: GH serum levels not suppressible below 1 ng/mL during standard oral glucose tolerance test (OGTT). The additional criteria of a paradoxical GH response to TRH and of increased IGF-I serum levels for age and sex had also been used in some of the more recent cases. Computed tomography and/or magnetic resonance imaging had revealed the presence of a microadenoma in two patients, whereas the others had intrasellar or invasive macroadenomas.

The patients were stratified into the following three groups: group A, 12 patients with active acromegaly in treatment with octreotide (0.2–0.3 mg). All the subjects had been submitted to transsphenoidal surgery and radiotherapy (4500–5000 rads) from 2 to 7 years before entering the present study; group B, 11 patients with active acromegaly not treated with octreotide. Ten had been submitted to surgery and three also to radiotherapy from 1 to 5 years before entering the study. One patient has not received any treatment for acromegaly; group C, 15 patients with acromegaly at the moment of the diagnosis and now classified as cured by the following criteria: serum GH suppressed to levels lower than 1.0 ng/mL during OGTT and normal serum levels of IGF-I.1 All had been submitted to transsphenoidal or transcranial surgery 3 months to 30 years before entering the study (mean, 14 y) and 10 were also submitted to radiotherapy.

Nine women with ovarian insufficiency as a result of menopause or a lesion of the hypothalamus-pituitary axis were present in the groups with active acromegaly (groups A and B), but none was on replacement hormonal therapy. In the group of cured patients (group C), seven women had ovarian insufficiency and two of them were on replacement hormonal therapy. The patients who had thyroid and/or adrenal hormone deficiency received adequate replacement therapy.

Methods

The study was carried out in accordance with the declaration of Helsinki; informed consent was obtained by all patients.

The subjects came to the laboratory in the morning after 12-hour overnight fast. Blood samples were drawn and after centrifugation the serum was immediately stored at –20˚C. Hormone and lipoprotein assays were performed before 30 days. Glucose, triglyceride, and total cholesterol assays were performed immediately.

Assays

Serum IGF-I levels were determined by a commercial radioimmunoassay kit (Diagnostic System Laboratories) after extraction from serum with formic acid and acetone. GH serum levels were measured by a commercial chemoluminescent kit (Diagnostic Products Corporation, Immulite, 2000). Serum lipoprotein(a), apolipoprotein A1, apolipoprotein B, total cholesterol, and triglyceride were measured by immunoturbidimetric methods using commercial kits (Selectra Merck). LDL-cholesterol was calculated using the Friedewald equation: LDL-c = total cholesterol - (HDL-c + triglycerides). The atherogenic indexes were calculated as described by Castelli et al.20: (a) atherogenic index = total cholesterol/HDL-c; (b) atherogenic index = LDL-c/HDL-c. Another atherogenic index was calculated as described by Berg & Hostmark21:

 

 

HDL ¥ Apo A1

Statistical Analysis

Data are expressed as mean ± standard error (SEM). Data were evaluated by analysis of variance (ANOVA) and by the Chi-square test. The statistical significance of comparisons was assessed by Dunnett test. The level of significance of P <0.05 was adopted.

RESULTS

As shown in Table 1, no statistically significant differences in age, body weight, height, body mass index (BMI), waist and hip circumference, or waist/hip ratio were found among the three groups of patients included in the study.

As presented in the Table 2, IGF-I and GH serum levels were significantly lower in the cured patients (group C; P <0.05) as compared with patients in both groups with active acromegaly (groups A and B). The levels of IGF-I were significantly lower in the group of patients treated with octreotide than in those untreated (group B; P <0.05); GH levels showed the same trend but the difference between the patients in group A and group B was not statistically significant.

Lp(a) levels in the patients of the three examined groups showed consistent variations from 2.0 to 232.6 mg/dL (Table 2). Mean levels were significantly lower in cured patients than in those with an active disease (P <0.05; Table 2). Lp(a) was above 30 mg/dL in nine patients in group A and in six patients in group B (68%), but only in one patient (6.6%) in group C.

Mean of Apo A1 serum levels was significantly higher in the group of cured patients in comparison with the two other groups (P <0.05). In the same group (group C) the increase of Apo A1 caused a significant decrease in the apo B/Apo A1 in comparison with the groups of patients with active acromegaly (P <0.05; Table 2).

Mean of LDL-c levels was significantly (P <0.05) higher in the cured patients than in the patients with active acromegaly not treated with octreotide (group B). LDL-c levels were above 130 mg/dL in 35.8% of the patients with active acromegaly (groups A + B) and in 60% of the patients in group C. This difference is statistically significant (P <0.05).

Mean levels of Apo B, HDL-c, VLDL, triglycerides, and total cholesterol serum levels were not different among the three groups of patients (Table 2).

HDL-c levels were above 40 mg/dL in 68.2% of the patients with active acromegaly (groups A + B) and in 50% of the cured patients, a difference which is not statistically significant. Similarly VLDL levels below 30 mg/dL were found in 50% of the patients in groups A and B and in 55.5% of the cured patients (group C), a distribution which is not statistically different.

The analysis of the triglyceride levels in individual patients showed that 30.7% of the patients in groups A + B and 27.3% in group C had levels higher than normal (>200 mg/dL). Total cholesterol levels were >200 mg/dL in 50% of the patients in groups A + B and 53.3% in group C. Both differences are not statistically significant.

As presented in the Table 2, the means of the three atherogenic indexes were not different in a statistically significant way among the three studied groups. Analyzing the values of the individual patients, figures higher than 3.5 for LDL-c/HDL-c ratio were observed in 28.6% of the patients with active acromegaly (groups A + B) and in 50% of the patients in group C; this difference is statistically significant (P <0.05). When the cholesterol total/HDL-c ratio is considered, figures >5.0 were calculated in 35.8% of the patients with active acromegaly and in 60% of the cured patients, again a statistically significant difference (P <0.05). On the contrary, the atherogenic index by Berg & Hortmark21 showed a decrease in group C that is not significant as compared with the other two groups.

DISCUSSION

Our data show that the patients considered cured of the acromegaly, according to the criteria of Melmed et al.,1 present levels of Lp(a) below 30 mg/dL, a significant increase of Apo A1 levels, and, as a consequence, a decrease of the apo B/Apo A ratio as compared with the patients with active acromegaly, independently of the octreotide treatment. This improvement of the lipoprotein profile in cured patients can contribute to the prevention of the precocious atherosclerosis occurring in acromegalics.

The results presented here confirm previous studies indicating that active acromegaly is associated with high serum levels of Lp(a)8,13,14,17,19 and that an effective treatment by surgery,13 or by surgery and radiotherapy,14 normalizes Lp(a) levels. In disagreement with the observations gained in this study, the use of octreotide has been reported by some authors8,17,19 to decrease the levels of Lp(a). Differences in dose schedules might explain these differences because, at variance with most literature reports, the great majority of patients on octreotide included in our study have not been treated with doses high enough to normalize the levels of GH and IGF-I.

The mechanisms involved in the maintenance of high levels of Lp(a) in the patients with active acromegaly are not well understood. The effects of GH in increasing the levels of Lp(a) are consistent. It has been shown that the treatment with GH increases the levels of Lp(a) in adults with GH deficiency,22–24 in normal children with short stature,25 in Turner syndrome,22 and during osteoporosis treatment.26 It has been proposed that the increased levels of IGF-I observed in the patients with acromegaly might be casually related in producing high levels of Lp(a). However, a positive correlation between IGF-I and Lp(a) levels has not been clearly established in patients with active acromegaly in previously published reports.13,15,17 Similarly, a lack of a significant correlation was observed in the present study, as indicated by the observation that the decreased levels of IGF-I present in patients with active acromegaly on octreotide are not paralleled by a concomitant decrease of Lp(a) concentrations. Moreover, mean Lp(a) levels and the percentage of patients with levels of Lp(a) above 30 mg/dl are not significantly different in octreotide-treated (group A) and octreotide-untreated (group B) acromegalics. Finally, it has been shown that during treatment with IGF-I the levels of Lp(a) might decrease, as occurs in patients with Laron syndrome22 and with osteoporosis.26

A correlation between the effects of GH on insulin secretion and Lp(a) levels has been proposed.22 During GH treatment of the patients with GH deficiency or with Turner syndrome, insulin and Lp(a) levels are concomitantly increased. However, insulin does not appear to have direct effects on Lp(a); patients with type 1 diabetes treated with a continuous infusion of insulin for 2 weeks do not show significant variations of Lp(a) despite alterations of other lipoproteins.27

The possible effect of ovarian function and Lp(a) levels should also be considered. Menopausal women present an increase of approximately 10% to 30% of Lp(a) levels, and replacement treatment with estrogen causes a significant decrease of these levels.28,29 The great majority of the women included in our study presented an ovarian insufficiency resulting from menopause, lesions of the hypothalamus-pituitary axis (presence of GH-secreting adenomas), or a collateral effect of the treatment (surgery and/or radiotherapy), and only a small number of them were undergoing replacement hormonal therapy. It is possible that the estrogenic deficiency might have contributed to the high levels of Lp(a) in those with active acromegaly. However, five hypogonadal female patients in group C had normal levels of Lp(a), even if they were not on replacement hormonal therapy.

In agreement with the results described in this article, it has been reported that the levels of total cholesterol are not increased in acromegalics9,11,14,15 and are not affected by octreotide treatment12,16 or surgery.13 A single paper has reported a significant decrease of the total cholesterol after treatment with octreotide.8

Our results show that the patients considered cured of the acromegaly possess mean levels of Apo A1 significantly higher than those found in the patients with active acromegaly. These data are in agreement with other reports indicating an increase of Apo A1 after the surgical treatment of acromegaly10,13 or after octreotide treatment19; at variance with these observations other studies have not found alterations of Apo A1 levels either after treatment or in comparison with the controls.15 The main function of Apo A1 is to act as cofactor of the enzyme that esterifies cholesterol in the plasma (cholesterol acyltransferase) and to stimulate the efflux out of cholesterol of the cells.30 These actions are responsible for the protecting effects exerted by these apoproteins in the atherosclerosis. We can, therefore, speculate that the effective treatment of the acromegaly-increasing Apo A1 concentration might counteract the atherogenic tendency present in acromegalic patients.

Because Apo A1 is almost exclusively present in HDL,30 it was expected that the increase in Apo A1 would be accompanied by an increased HDL-c serum concentration; this occurrence has been previously described after surgical treatment of the acromegaly,10 after treatment with octreotide,17 or after the GH administration to patients with GH deficiency.25 However, HDL-c levels were not significantly different in the three groups of patients included in the present study in agreement with other reports.8,15,16 This is only partially surprising because several differential effects of GH on HDL-c and Apo A1 levels have been described. Oscarsson et al.,13 using a continuous infusion of GH in adults with GH deficiency, did not demonstrate alterations in the levels of HDL-c, even if a decrease of Apo A1 was present in the same patients. It is therefore possible that the action of the high levels of GH present in acromegaly would promote a decrease of the Apo A1 concentration present in HDL-c without altering the levels of the lipoprotein fraction. Because the concentrations of Apo A1 in HDL-c are mainly determined by the catabolism of these apoproteins more than by their synthesis,30 it is proposed that high GH levels could increase the metabolic degradation of Apo A1.

Apo B levels were not different in the three studied groups. These data are in agreement with those by others.13,15 As a result of high levels of Apo A1 in the patients in group C, in the presence of unaffected Apo B levels, the Apo B/Apo A1 ratio decreased significantly in the cured patients in comparison with those of the other two groups.

The mean LDL-c serum levels are significantly higher in the cured patients (group C) than in patients in groups A and B; moreover, the percentage of patients in group C with LDL-c above 130 mg/dL was significantly higher than in the other two study groups. In consequence of the LDL-c increase, the number of cured patients with an LDL-c/HDL-c ratio above 3.5 was higher in the patients with active acromegaly. It is possible that the low levels of GH in the patients in group C are responsible for this observation because it has been described that a deficit of GH might be associated with increased LDL-c levels,31 and, recently, it has been suggested that the cure of the acromegaly can produce a GH deficit.32

Total cholesterol/HDL-c and LDL-c/HDL-c ratios are predictive factors of the development of coronary heart disease.20 It has been suggested that individuals who are free of coronary heart disease have an average total cholesterol/HDL-c ratio lower than 5.2 and a LDL-c/HDL-c ratio lower than 3.4.20 We did not observe alterations in the mean levels of these indexes among the groups, with the exception of the above-mentioned slight changes in LDL-c/HDL-c ratio in the cured patients. These results are in disagreement with the reports by other authors indicating that the surgical treatment of the acromegaly is able to affect these indexes.10

The mean levels of triglycerides were not significantly different in the three groups of studied patients. These results are in agreement with those by other authors.7,9,14,15 However, Nikkilä and Pelkonen6 found an incidence three times higher of hypertriglyceridemia in acromegalics in relation to the general population. It has been suggested that the increase of the triglyceride levels in the acromegaly could be mediated, at least partly, by the decreased activity of the lipoprotein lipase and, possibly, of the hepatic lipase induced by the high levels of GH found in acromegaly.7,11

The acromegalic patients included in the present study were overweight, but no statistically significant differences in body weight, BMI, waist and hip circumference, or waist/hip ratio were observed among the three groups of patients. These results are in agreement with previous reports indicating the presence of a moderate overweight, which is not corrected by therapy in acromegalic patients.8,10,16 However, a reduction in the fatty tissue of the members and an increase in the visceral and subcutaneous abdominal fatty tissue after acromegaly treatment has been described.33 We observed a nonsignificant increase of the waist in the cured patients.

It is possible that the consistent discrepancies described in the literature on the lipid profile of acromegalic patients depend mainly on the different criteria adopted for defining cured patients and on the time interval after treatment. Most of the papers report observations made shortly after treatment by surgery, radiotherapy, or octreotide. On the contrary, patients included in this study, and considered cured according to the criteria of Melmed et al.,1 were analyzed, on the mean, 14 years after treatment. It is possible that the long time elapsed produces the lipid profile described in this article, which is positively characterized by decreased Lp(a) and by increased Apo A1 serum levels, but negatively affected by an increased level of LDL-c.

This double-faced profile of the circulating lipids in patients cured of acromegaly has not been described before, and further investigations are needed both on its mechanisms of development and on its clinical significance.

Acknowledgments

The authors thank Prof. Fabio Celotti for his advice and criticism. They also appreciate the technical assistance of Luiz Gustavo Domingues Casulari da Motta and Laboratorio Sabin.

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16. Simsolo RB, Ezzat S, Ong JM, Mehrnoosh S, Kern PA: Effects of acromegaly treatment and growth hormone on adipose tissue lipoprotein lipase. J Clin Endocrinol Metab 80:3233–3238, 1995.

17. Lam KS, Pang RW, Janus ED, Kung AW, Wang CC: Serum apolipoprotein (a) correlates with growth hormone levels in Chinese patients with acromegaly. Atherosclerosis 104:183–188, 1993.

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19. Wildbrett J, Honefeld M, Fücker K, et al: Abnormalities of lipoprotein pattern and fibrinolysis in acromegalic patients. Relation to GH and IGF–I. Exp Clin Endocrinol Diabetes 105:331–335, 1997.

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21. Berg JE, Hostmark AT: Cardiovascular risk determination: discrepancy between total cholesterol evaluation and two compound laboratory indices in Norway. J Epidemiol Community Health 48:338–343, 1994.

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Table 1. Anthropometric Characteristics of the 38 Acromegalic Patients Included in the Study (mean ± SEM)

 

Groups              A                  B                  C

                                        Without
                  Octreotide   Octreotide       Cured

                    (n = 12)       (n = 11)       (n = 15)

 

Waist/       0.87 ± 0.02  0.85 ± 0.02  0.94 ± 0.03
hip ratio             

 

 

Table 2. Laboratory Characteristics of the 38 Patients With Acromegaly Included in the Study (mean ± SE)

 

                                                     A (n = 12)                B (n = 11)                C (n = 15)            Normal

                                                     Octreotide         Without Octreotide             Cured                Range

                                                                                                                             

IGF-I (ng/mL)                              740.7 ± 77.9*           199.3 ± 22.6†                50–400            471.8 ± 30

GH (ng/mL)                                  25.3 ± 11.3                0.9 ± 0.4†                     <7.0              14.9 ± 6.7

Lipoprotein (a) (mg/dL)               71.9 ± 23.9               17.7 ± 3.0†                     <30              78.8 ± 17.6

(range)                                         6.0–232.6                  2.0-45.5                                            6.0–198.4

Apo A1 (mg/dL)                           95.4 ± 7.7               150.5 ± 7.4†                115–220          101.8 ± 8.9

Apo B (mg/dL)                             100.0 ± 7.7              104.6 ± 8.4                 60–160          105.8 ± 13.8

Apo B/Apo A                               1.08 ± 0.12              0.71 ± 0.06†               0.35–1.25         1.02 ± 0.14

HDL-c (mg/dL)                              43.6 ± 7.8                39.9 ± 3.7                     >40               42.7 ± 4.6

LDL-c (mg/dL)                              103.5 ± 27             141.3 ± 28.3‡                  <130            136.2 ± 17.0

VLDL (mg/dL)                               28.6 ± 4.0                33.8 ± 7.0                     <30               33.0 ± 5.5

Triglyceride (mg/dL)                   156.6 ± 13.8            162.4 ± 30.8                  <200            187.3 ± 32.4

Total cholesterol (mg/dL)           215.4 ± 20.0             201.9 ± 9.9                   <200            203.3 ± 15.3

Total cholesterol/HDL-c                 5.3 ± 0.8                  5.2 ± 0.4                      <5.0               5.0 ± 0.4

LDL-c/HDL-c                                 3.3 ± 0.6                  3.6 ± 0.3                      <3.5               3.3 ± 0.4

Atherogenic index                         3.7 ± 1.3                  2.3 ± 0.8                                            4.0 ± 1.6

 

*P <0.05 vs. A.

†P <0.05 vs. A and B.

‡P <0.05 vs. B.