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Clinical Studies |
Unit of Metabolic Medicine, Imperial College School of Medicine, St. Mary’s Hospital, London, United Kingdom
Address all correspondence and requests for reprints to: Dr. Kamal A. S. Al-Shoumer, Ph.D., M.R.C.P., P.O. Box 49519, 85156 Omariya, Kuwait.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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6.2 and 4.1 mmol/L,
respectively). In the postprandial period (0730–2030 h), the areas
under the curve (AUC) for circulating triglyceride and total
cholesterol were significantly higher in hypopituitary than control
women (P = 0.0089 and P =
0.0016, respectively). The AUC for triglyceride and total cholesterol
over 24 h were also significantly increased (P
= 0.009 and P = 0.0004, respectively). No
significant differences were observed for postprandial and 24-h AUC for
triglyceride and total cholesterol concentrations in men. We conclude
that hypopituitarism with conventional replacement therapy is
associated with unfavorable fasting and postprandial lipid and
lipoprotein concentrations, particularly in women. The changes may
contribute to the observed increased vascular morbidity and mortality. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The association between altered plasma concentrations of lipids and lipoproteins after an overnight fast and risk of cardiovascular or cerebrovascular disorders is well recognized (6, 7). In recent years, abnormal postprandial lipoprotein metabolism has also been considered to play a role (8, 9, 10). Abnormalities of fasting lipids and lipoproteins have been described in hypopituitary adults (11, 12, 13). There is little information on the effect of normal meals on lipid profiles. We, therefore, studied fasting and postprandial lipids and lipoproteins in hypopituitary patients and matched controls. Data for men and women were analyzed separately.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Two groups of subjects underwent two studies. Sixty-seven
hypo-pituitary adults and eighty-seven normal subjects participated
in the first study. Twelve of the 67 patients and 14 of the 87 normal
subjects volunteered for the second study. The patients and controls in
each study were matched for age, sex, and body mass index (Table 1
). Patients were recruited from the endocrine clinic at
St. Mary’s Hospital, and controls were recruited from hospital staff
and friends. The study protocol was approved by the Parkside Health
Authority ethics committee, and patients and control subjects gave
informed written consent.
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Cortisol was taken as hydrocortisone tablets twice daily (at 0730 and
1730 h) in most patients (3 received cortisone acetate and 3
received prednisolone), and the mean daily dose of hydrocortisone (or
equivalent) was 27 (range, 12.5–35) mg/24 h. The mean T4
replacement dosage was 121 (range, 75–200) µg/day in the 41 patients
with TSH deficiency. Male sex hormone was taken as im depot
testosterone (250 mg; Sustanon, Organon, West Orange, NJ) at 2- to
4-week intervals in most men with gonadotropin deficiency, except for 3
patients [2 were taking Primoteston (250 mg; Schering Health, Berlin
Germany) every 3–4 weeks and 1 was taking testosterone undecanoate (80
mg/day)]. Of the female patients, 19 were receiving sex hormone
replacement, of whom 16 were premenopausal; none of the control women
was receiving sex hormone replacement. Sex hormone replacement was
either a combined oral contraceptive preparation or conventional
combined replacement therapy. No patient or control had other known
illness, and none of the patients was taking medications other than
replacement therapy. The data for some of these patients have been
described previously in studies in which fasting lipids were reported
in a smaller number of subjects (3, 15) and 24-h profiles of
intermediary metabolites and insulin were reported (14).
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In the first study, subjects attended the Metabolic Day Ward at St. Mary’s Hospital after an overnight fast of 10–12 h. Their body weights, heights, and waist to hip ratios were measured, and fasting blood was taken for measurements of triglycerides, total cholesterol, and high density lipoprotein (HDL) cholesterol and routine hematological, liver, renal, and thyroid function tests. In the second study, subjects were studied for 24 h after a 10- to 12-h fast. At 0700 h, fasting blood was taken for the measurement of triglycerides, total cholesterol, HDL cholesterol, lipoprotein(a) [Lp(a)], apolipoprotein A1, and apolipoprotein B. Blood was subsequently drawn half-hourly until midnight and then hourly until 0700 h the next morning for measurements of triglycerides and total cholesterol.
During the 24-h study, subjects received mixed meals at 0730, 1230, and 1730 h, had unsweetened coffee or tea at 1000, 1500, and 2100 h, and received their medications at 0730 and 1730 h. Meals were standard hospital meals containing approximately 2200 Cal, with 50% carbohydrate, 35% fat, and 15% protein by weight. All subjects consumed at least 250 g carbohydrate daily for 3 days before the study. They were encouraged to undertake gentle activity during the study period. They retired to bed at 2230 h, and most subjects slept between 2300–0700 h.
Analytical methods
Blood samples were transferred on ice immediately and centrifuged at 2500 rpm at 4 C for 15 min, and the supernatants were stored at -20 C until analysis. Triglyceride and cholesterol levels were determined enzymatically using a Centrifichem centrifugal analyzer (Baker, Windsor, UK). HDL was analyzed after dextran sulfate extraction (16). Low density lipoprotein (LDL) cholesterol was calculated by Friedewald formula. Lp(a) and apolipoproteins A1 and B were measured by immunonephelometry (Beckman Auto Immuno-Chemical System, Beckman Instruments, High Wycombe, UK). Hemoglobin, packed cell volume, white cell count, and platelets were measured by routine laboratory techniques. Serum insulin-like growth factor I was measured in acid-ethanol serum extract with a polyethylene glycol-assisted second antibody RIA (17).
Statistical analysis
Results are expressed as the mean ± SEM or the
median (range). Patients and controls were compared using Student’s
unpaired t test or the Mann-Whitney U test as appropriate.
Differences in plasma lipids were sought in the prebreakfast (at
0730 h) samples and in the areas under the curve (AUC), calculated
by the trapezoidal rule, for the 24-h and the 13-h postprandial periods
between 0730–2030 h. The proportional frequencies of high fasting
triglyceride, total cholesterol, and LDL cholesterol concentrations in
patients and controls were compared using 
2 test.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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and 2)As expected, the patients had lower insulin-like growth factor I levels than the controls. The waist to hip ratio was significantly higher in patients than controls. The median duration of hypopituitarism was 8 (range, 1–27) yr. The maximum serum GH response to provocative testing was 1.0 (range, 0.1–5.7) mU/L. Hemoglobin, white cell count, packed cell volume, platelets, creatinine, plasma testosterone, and liver function were normal in all patients and controls. Thyroid function was normal in all patients (mean ± SEM, serum total T4, 107 ± 8 nmol/L; reference range, 50–150 nmol/L) and controls (TSH, 2.6 ± 0.3 mU/L; reference range, 0.5–5.0 mU/L). Fasting blood glucose concentrations were normal by WHO criteria in all patients and controls.
Fasting plasma lipids and lipoproteins (Tables 3-6)
Fasting (prebreakfast) concentrations of triglycerides, total
cholesterol, LDL cholesterol, and apolipoprotein B were significantly
higher in patients than in controls. When the subjects were subdivided
by sex, the increases were significant in hypopituitary women, but not
in the men (Table 3). For further analysis, hypopituitary women were
subdivided into those who were receiving cortisol replacement and those
who were not (Table 4), and into those of premenopausal
age (<50 yr) and those who were postmenopausal (Tables 5 and 6). Of the 22 premenopausal
patients, 16 took sex hormone replacement, and the remaining 6 had
normal menstrual cycles. Of the 14 postmenopausal hypopituitary women,
3 were receiving sex hormone replacement and were excluded from further
analysis. The remaining 11 postmenopausal patients were compared with
21 postmenopausal controls, none of whom was receiving sex hormone
replacement.
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). No significant differences were observed between those
requiring cortisol replacement and those not requiring cortisol.
The elevations in circulating total cholesterol and LDL cholesterol
concentrations were observed in premenopausal hypopituitary women
requiring and taking sex hormone replacement and also in those in whom
the menstrual cycle was regular (Table 5). Similarly, elevations in
triglyceride were observed in both groups, although the results did not
achieve statistical significance. The waist to hip ratio, however, was
normal in the premenopausal patients receiving sex hormone replacement,
but was elevated in those with regular cycles. In the postmenopausal
hypopituitary women, the waist to hip ratios and circulating
triglyceride concentrations were elevated significantly, but the
elevations in total and LDL cholesterol were not statistically
significant (Table 6).
The fasting lipid concentrations have been analyzed in the context of
the levels recommended by the National Cholesterol Education Program
(1994). High total cholesterol (6.2 mmol/L) and high risk LDL
cholesterol (4.1 mmol/L) concentrations were observed more frequently
in hypopituitary women than in control women [total cholesterol, 23 of
36 (64%) vs. 12 of 54 (22%; 2 =
15.78; P = 0.0001); LDL cholesterol, 23 of 36 (64%)
vs. 19 of 54 (35%; 2 = 7.15;P = 0.0075]. Similar findings were obtained in men for both
total [16 of 31 (52%) vs. 9 of 33 (27%; 2
= 3.98; P = 0.046] and LDL cholesterol [20 of 31
(65%) vs. 10 of 33 (30%); 2 = 7.69;P = 0.006]. Triglyceride concentrations above the
recommended value (2.3 mmol/L) were observed more frequently only in
hypopituitary women [10 of 36 (28%) vs. 4 of 54 (7%);
2 = 6.82; P = 0.009].
Patients and controls (both women and men) had similar prebreakfast
concentrations of HDL cholesterol, apolipoprotein A1, and Lp(a) (Table 3).
Concentrations of neither lipids nor lipoproteins were influenced by serum PRL or serum T4 concentrations in the patient group.
24-h serum lipids
Triglycerides (Fig. 1).
Triglyceride
concentrations demonstrated pronounced cyclic variation over 24 h
in the patients, particularly women, with the lowest levels during the
overnight period between 0100–0700 h and the highest levels between
0730–2030 h (13-h postprandial period). During the 13-h postprandial
period, the AUC of circulating triglyceride was significantly higher in
patients than controls (52.33 ± 5.04 vs. 38.20 ±
5.49 mmol/L; P = 0.038). However, over 24 h, the
AUC of triglycerides did not differ significantly between patients and
controls. When subjects were subdivided by sex, postprandial and 24-h
AUC for triglycerides were both significantly higher in hypopituitary
than control women [postprandial AUC, 59.04 ± 7.60
vs. 33.58 ± 4.98 mmol/L (P = 0.0089);
24 h AUC, 87.93 ± 12.40 vs. 49.02 ± 6.58
(P = 0.009)]. These differences in circulating
triglyceride concentrations were not observed in the men. In the
hypopituitary women, hypertriglyceridemia diminished through the night,
with triglyceride concentrations falling from 1.83 ± 0.43 mmol/L
at midnight to 1.39 ± 0.24 mmol/L at 0700 h. In the
controls, triglyceride concentrations remained constant overnight.
During the postprandial period, triglyceride concentrations increased
over the values observed overnight, but the triglyceride elevations
postprandially were similar in patients and controls (with 0700 h
as the baseline, 13 h postprandial AUC, 17.33 ± 3.96
mmol/L.h for patients and 12.54 ± 3.00 mmol/L·h for
controls).
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).
Minor elevations in
serum cholesterol concentrations were observed postprandially in both
patients and controls. As with the fasting values, postprandial and
24-h AUC of total cholesterol were significantly higher in patients
than controls [postprandial AUC, 147.8 ± 5.5 vs.
130.2 ± 5.4 mmol/L (P = 0.017); 24 h AUC,
234.3 ± 8.5 vs. 201.7 ± 8.9 mmol/L
(P = 0.009)]. When men and women were considered
separately, only hypopituitary women had significantly elevated
postprandial cholesterol levels (159.9 ± 4.6 vs.
124.0 ± 7.2 mmol/L; P = 0.0016) and 24-h AUC
(252.7 ± 8.1 vs. 188.8 ± 10.0 mmol/L;
P = 0.0004) for cholesterol concentrations.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Abnormalities of fasting concentrations of lipids and lipoproteins constitute a vascular risk. Increased total and LDL cholesterol levels after an overnight fast have been implicated. In recent years, abnormal postprandial lipoprotein metabolism has been considered to play a role. Under most circumstances, normal subjects spend 50% or more of the time in the postprandial state, and exaggerated lipemia after food intake has been associated with a predominance of small dense LDL and other lipid disturbances that are considered atherogenic (20).
We, therefore, chose to investigate subjects both fasting and in response to normal meals to assess lipid and lipoprotein concentrations during normal physiology in hypopituitary women and men and in matched controls. The fasting data have been analyzed statistically in a conventional manner, comparing patients and controls. In view of the known risks associated with degrees of dyslipidemia, the proportions of patients and controls who exceeded values recommended by the National Cholesterol Education Program (1994) (21) have also been calculated. We have demonstrated increased fasting and postprandial plasma lipid concentrations in hypopituitary women receiving conventional replacement therapy. The increment extended to triglycerides and cholesterol. Much milder abnormalities in fasting cholesterol concentrations were observed in the men.
The mechanism of the triglyceride elevation is unknown. After an overnight fast, most circulating triglyceride resides in very low density lipoprotein, and after food, chylomicrons are the major triglyceride-rich lipoprotein. There is no information on very low density lipoprotein-triglyceride synthesis in hypopituitary subjects. The exaggerated levels throughout the day in women would be compatible with a decrease in clearance of triglyceride-rich lipoproteins. Clearance of these lipoproteins is catalyzed by the intravascular lipolytic enzymes, lipoprotein lipase and hepatic lipase. The activities of both of these lipolytic enzymes tend to be low in both obese and nonobese hyperinsulinemic, insulin-resistant patients (22, 23). Although insulin resistance is common in hypopituitarism, both lipoprotein lipase and hepatic lipase activities are higher in hypopituitary adults than in matched controls (24, 25). The similar postprandial triglyceride excursions in hypopituitary and control women, however, demonstrated that overall absorption and catabolism of triglycerides are qualitatively similar in the two groups, but at a higher threshold in the patients due to the elevated baseline levels.
The observation that fasting total and LDL cholesterol levels were elevated is in accord with other reports (12, 13, 26). An important role for GH in cholesterol metabolism has been suggested. GH therapy has been shown to reduce total and LDL cholesterol in experimental animals (27), GH-deficient children (28), and GH-deficient adults in most (26, 29, 30, 31, 32), but not all (33, 34, 35), studies. Angelin and Rudling (36) have suggested that GH lowers cholesterol by increasing the number of hepatic LDL receptors, thereby increasing the removal of LDL cholesterol.
Our findings of similar fasting HDL cholesterol concentrations in hypopituitary adults and controls contrast with the lower values observed by some investigators (26, 37, 38), but are in agreement with the findings of other workers (12, 13). Although Lp(a) is an independent risk factor for vascular disease and is regulated by hormones, we have shown similar Lp(a) levels in hypopituitary adults and controls.
Our finding of raised apolipoprotein B levels in hypopituitary patients is in agreement with earlier reports (13, 26). Apolipoprotein A-1 levels were similar in the two groups. These observations are compatible with fasting apolipoprotein B levels reflecting LDL cholesterol (39), and apolipoprotein A-1 reflecting HDL cholesterol (40). Their clinical significance, therefore, parallels that of LDL and HDL cholesterol.
The major observation in this study was that the elevations in fasting and postprandial triglyceride concentrations occurred predominantly in the hypopituitary women. Although more male hypopituitary patients than controls had elevated fasting total and LDL cholesterol concentrations, the female patients as a group demonstrated the major abnormalities of fasting and postprandial cholesterol concentrations. We have previously noted gender differences in fasting values in a smaller number of patients (15). Others (38) have also recently demonstrated an adverse effect of hypopituitarism on lipid status in women compared to men (an increase in concentrations of small dense LDL). Although abnormalities induced by inappropriate replacement of glucocorticoids and T4 (14, 41, 42) could contribute to the dyslipidemia, patients in our study received replacement therapy in a conventional manner, and they were clinically euadrenal, with circulating cortisol levels on a diurnal profile within the normal range. They were also clinically euthyroid and had circulating T4 levels within the normal range. After the subgroup analysis based on whether hypopituitary women did or did not require cortisol replacement, fasting lipid levels were equally abnormal in both groups of hypopituitary women. This does not suggest a major contribution of glucocorticoid therapy to the lipid abnormalities. We have demonstrated previously (14) low levels of circulating cortisol overnight in conventionally treated hypopituitarism together with an overnight reduction in circulating nonesterified fatty acid concentrations (NEFA). Overnight insulin levels are similar to those in controls. In contrast to hypopituitarism, circulating NEFA levels in normal subjects increase during the overnight fast. The decline in circulating NEFA in hypopituitarism may contribute to the overnight decline in triglyceride concentrations observed in the patient group through limitation of substrate supply. Finally, GH deficiency may contribute to the lipid disorder, but this does not account for the female preponderance.
Although the gender difference in lipid abnormalities suggests an effect of sex hormone replacement, this conclusion is not sustained by subgroup analysis. Postmenopausal hypopituitary women not receiving sex hormone replacement therapy had fasting triglyceride values double those of postmenopausal controls also not taking sex hormone replacement. There were insufficient postmenopausal subjects receiving sex hormone replacement to permit analysis of the effects of treatment. Premenopausal hypopituitary women with regular menses receiving no sex hormone therapy also demonstrated lipid disorders, particularly elevations in total and LDL cholesterol. Those premenopausal patients who were taking sex hormone replacement continued to have elevated total and LDL cholesterol concentrations. The waist to hip ratio, which was elevated in both men and women with hypopituitarism, tended, in fact, to be normalized by sex hormone replacement in the younger women. Thus, the lipid abnormalities in hypopituitary women occurred regardless of sex hormone replacement, and their mechanisms remain unclear.
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Acknowledgments |
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Footnotes |
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Received October 2, 1996.
Revised January 8, 1997.
Revised April 1, 1997.
Accepted April 28, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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