| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Endocrine Care |
Department of Diabetes and Endocrinology, Royal Liverpool University Hospital (A.M.A., R.G., J.T., J.P.V.), Liverpool, United Kingdom L7 8XP; University Department of Pathological Biochemistry, Glasgow Royal Infirmary (A.M.W.), Glasgow, United Kingdom G4 0SF; and Department of Clinical Chemistry, Royal Liverpool University Hospital (W.D.F.), Liverpool, United Kingdom L69 3GA
Address all correspondence and requests for reprints to: Dr. A. M. Ahmad, Research Fellow, Link 7-C, Department of Diabetes and Endocrinology, Royal Liverpool University Hospital, Prescot Street, Liverpool, United Kingdom L7 8XP. E-mail: draahmad{at}yahoo.com
Abstract
Leptin contributes to the regulation of body weight in healthy individuals and is secreted by adipocytes in a diurnal pattern, with superimposed pulsatility. The circulating leptin concentration is increased in both normally obese and untreated adult GH deficiency, a syndrome characterized by increased adiposity. Leptin circadian rhythm is preserved in adult GH deficiency patients; however, an ultradian rhythm and pulsatility has previously not been reported. Alterations in plasma leptin concentration in obese individuals and adult GH deficiency patients after GH replacement have been attributed to changes in body fat mass. In our present study leptin circadian and ultradian rhythm, leptin pulsatility and its relationship with body fat mass were examined in 12 adult GH deficiency patients (6 men) before and 1 month after GH replacement. All subjects with adult GH deficiency had hypopituitarism subsequent to pituitary surgery and were stabilized on conventional pituitary hormone replacement. Plasma leptin was measured over 24 h at 30-min intervals, and changes in body composition were recorded using bioelectrical impedance.
The 24-h mean leptin concentration decreased from 2.04 ± 0.04 nmol/liter in untreated adult GH deficiency patients to 1.64 ± 0.03 nmol/liter after 1 month of GH replacement (P < 0.0001). Before GH replacement, patients demonstrated a significant mean leptin circadian rhythm (P < 0.001), with a mesor of 2.05 ± 0.03 nmol/liter and a superimposed ultradian frequency of 2.0 ± 0.1 cycles/d. After GH replacement, the circadian rhythm was preserved (P < 0.001), but mesor decreased to 1.65 ± 0.01 nmol/liter (P < 0.0001), and leptin ultradian frequency increased to 16.0 ±0.2 cycles/d (P < 0.0001). Pulse analysis (ULTRA) revealed 3.1 ± 0.9 pulses/24 h in untreated adult GH deficiency patients, which significantly increased to 9.9 ± 2.2 pulses/24 h after 1 month of GH replacement (P < 0.001). There was no significant change in body mass index or body fat mass after 1 month of GH replacement. The body fat percentage significantly reduced from 36.5 ± 2.8% to 35.5 ± 2.7% after 1 month of GH replacement (P < 0.05). This change in body fat percentage was explained by a significant increase in lean body mass, from 56.2 ± 2.8 kg at baseline to 57.4 ± 2.7 kg after 1 month (P < 0.05). A significant correlation was observed between plasma leptin and body fat percentage at baseline and 1 month after GH replacement (both, r = 0.7; P < 0.01) in the absence of a significant correlation between leptin and body fat mass before and after GH replacement (P = 0.13 and P = 0.11, respectively).
Thus, untreated adult GH deficiency is associated with elevated 24-h leptin concentration, preserved circadian rhythm, and decreased pulsatility. The secretory pattern is restored after GH replacement, with a significant reduction in the 24-h mean leptin concentration, maintenance of circadian rhythm, and increased pulsatility. This GH-induced change in the leptin secretory pattern precedes significant changes in body fat mass and may therefore be independent of changes in adipose tissue. Restoration of leptin pulsatility may be of clinical benefit, and our data could lead to novel approaches for leptin manipulation in the future.
PLASMA LEPTIN, an ob gene product (1), appears to play an important role in body weight homeostasis. Increased energy expenditure with decreased food intake and weight loss was observed when leptin was administered to leptin-deficient obese mice (2, 3, 4). The regulation and action of endogenous leptin in humans, however, are less well understood. The leptin concentration is increased in obese compared with lean subjects and is correlated to the degree of obesity (5, 6). Changes in plasma leptin concentration after weight reduction in obese subjects (5, 6, 7) and after overfeeding in normal subjects (8) further suggest a correlation between body fat and plasma leptin. Moreover, plasma leptin is secreted in a circadian pattern with superimposed pulsatility in healthy individuals (9, 10).
Adult GH deficiency (AGHD) is characterized by abnormal body composition with increased body fat mass (BFM) and decreased lean body mass (LBM) and total body water (TBW) (11, 12, 13, 14, 15). Patients with AGHD have increased levels of plasma leptin with a preserved circadian secretory pattern (16, 17). GH replacement (GHR) has been shown to improve body composition and reduce BFM within 6 months of treatment (11, 18) and to decrease the plasma leptin concentration (16, 19) with no impact on leptin circadian rhythm (16). The decrease in leptin concentration has been attributed to changes in body fat (16, 19). However, none of the studies of either normal individuals (5, 6, 7, 8) or AGHD patients (16, 19) were designed to detect whether the changes in BFM preceded or followed changes in plasma leptin concentration and, therefore, were unable to prove causality. There have been no studies reporting on leptin pulsatility in untreated AGHD patients and the effects of GHR on this pulsatile hormone.
In our present study we investigated the effects of GHR on leptin circadian and ultradian rhythm and pulsatility in AGHD patients. We also aimed to detect whether the changes in leptin concentration precede or follow changes in BFM by measuring both variables as early as 1 month after commencement of GHR.
Subjects and Methods
Patients
Twelve adults (six men and six women) with severe GH deficiency
(GHD), defined as a peak GH response of less than 9 mU/liter (3
µg/liter) to hypoglycemia (blood glucose, <2.2 mmol/liter) induced
during an insulin stress test, were recruited from our Joint Pituitary
Clinic. Eleven patients had a peak GH response of less than 0.5
mU/liter. All patients had undergone pituitary surgery for pituitary
tumors and subsequently developed hypopituitarism. The original
diagnoses and additional pituitary replacement hormones are presented
in Table 1
. No patient received GHR
before inclusion in our study. The mean age at recruitment was
53.4 ± 3.0 yr (mean ± SEM; range, 37–72 yr),
and the time from diagnosis of AGHD to the recruitment in the study was
13.1 ± 2.0 yr (range, 2–21). All patients were trained in the
use of an automated pen device for sc self-injection of GH before
recruitment. After baseline measurements, GH was commenced at a daily
dose of 0.5 IU/d, self-injected at 2200 h every night. GH dose was
titrated at 2 wk after commencement, by increments of 0.25 IU/d,
according to IGF-I concentration with an aim to maintain IGF-I within
the 2 SD score of the age-related reference range.
|
Body composition
Body mass index (BMI) and waist/hip ratio were calculated from height, weight, and waist and hip circumference measurements, respectively. Body composition was analyzed using a whole body bioelectrical impedance analysis (BIA) (Tanita Systems, Skokie, IL), a widely used, relatively simple, noninvasive, and highly reproducible method for estimating body composition. This method has been validated in healthy (20, 21) and AGHD subjects (22, 23) and has demonstrated a strong correlation with other methods used to measure body composition (18). Body fat percentage (BFP), BFM, LBM, and TBW were calculated by the computer program provided by the manufacturer.
Biochemical assays
Total human leptin was measured by RIA. Radioiodinated leptin
was prepared using the solid phase lactoperoxidase procedure
(24). It was purified by Sephadex G-25 gel filtration (on
PD-10 column) followed by G-50 (both from Amersham Pharmacia Biotech, St. Albans, UK) using 0.1 mol/liter phosphate (pH 7.4),
7.7 mmol sodium azide/liter, 1 g/liter BSA, and 0.5 ml/liter Triton
X-100 elution buffer. Test plasma (0.1 ml) was incubated with leptin
standard (0–6.25 nmol/liter in 0.1 ml assay buffer), 0.1 ml donkey
serum, 0.1 ml assay buffer, sheep antileptin antiserum (antibodies were
generated to mature leptin used in an initial dilution, 1:8000 in assay
buffer), and 125I-labeled leptin (
0.06
pmol/tube in 0.1 ml assay buffer) at 4 C for 16 h.
Sepharose-donkey antisheep globulin (1 mg in 0.1 ml assay buffer) was
added to the tubes postincubation and reincubated for 1 h at
ambient temperature. Free and bound fractions were then separated by
centrifugation using three 3-ml washes with 0.15 mmol/liter sodium
chloride containing Tween 20. The bound fraction was counted for 60 sec
on a multichannel 
-counter. Calibration curves were calculated, and
unknowns were interpolated using Multicalc (version 2.4, Wallac, Inc., Turku, Finland). The minimum detection limit [analyte
concentration at an intraassay coefficient of variation (CV) of 22%]
was 0.05 nmol/liter, and recovery of exogenous leptin (0.625
nmol/liter) from serum was between 81.1–120.6% (median, 93.9%;
n = 35). The intraassay CV was 5%, and the interassay CV was
5.6% at 0.57 nmol/liter and 9.5% at 1.02 nmol/liter. To demonstrate
that the assay exhibited parallelism, serum samples were diluted
(1:1.33, 1:2, and 1:4) in assay buffer before analysis, and 78.7–119%
of the expected value was achieved postdilution. This assay has been
compared with a commercially available kit (Linco Research, Inc., St. Charles, MO), and the results were highly correlated
(r = 0.96), thus allowing us to validate our assay to provide a
sensitivity of 0.05 nmol/liter (25). Leptin values
obtained as nanograms per ml were converted to Systeme International
units (nanomoles per liter) based on the molecular mass of leptin (16
kDa) (1), using a conversion factor of 0.0625 (1
nmol/liter = 1 ng/ml x 0.0625).
IGF-I was measured with a specific RIA in the presence of a large excess of IGF-II (Mediagnost, Tubingen, Germany) to block the interference of IGF-binding proteins, as described previously (26). Intra- and interassay CVs were 1.6% and 6.4%, respectively (at a sample concentration of half-maximal displacement). The sensitivity was 3 x 10-6 µmol/liter, which was derived from counts 2 SD below B0 (binding of zero standards) (calculated by the program in the counter) (27). Assay-specific normal reference values were used to calculate the IGF-I SD score according to age and gender (28). Values were logarithmically transformed before calculation of the IGF-I SD score. IGF-I values obtained as micrograms per liter were converted to Systeme International units using a conversion factor of 0.131 (1 µmol/liter = 1 µg/liter x 0.131) based on the molecular mass of IGF-I (29).
Statistical analysis
The leptin circadian and ultradian rhythms were analyzed according to single and mean cosinor analyses (30). The rhythms were characterized by the following parameters: 1) mesor (acronym for midline estimating statistic of rhythm), rhythm-adjusted mean; 2) amplitude, the difference between the maximum value measured at acrophase and the mesor in the cosine curve; and 3) acrophase, lag between local midnight and time of highest value of the cosine function used to approximate the rhythm. COSIFIT software (Circesoft, Inc., Waltham, MA), a program that provides an iterative nonlinear least squares analysis of biological rhythm data using Marquardt’s modification of the Gauss-Newton algorithm, was used to analyze the circadian and ultradian rhythms (31, 32). This program provides both parametric and nonparametric estimates of goodness of fit, and the statistical differences between parameter values of select curves were ascertained by ANOVA. Data were initially analyzed for the circadian rhythm parameters, and then, using the demodulation procedure, by subtracting from the data the best fit obtained, the ultradian rhythm parameters were derived. Circadian rhythm data were further validated by CHRONOLAB (Universdade de Vigo, Vigo, Spain), a well validated algorithm that also uses cosinor analysis to determine individual and mean rhythmometric parameters (33).
Pulse analysis for each leptin profile was performed with the pulse-detecting algorithm, ULTRA (34, 35). The general principle of this algorithm is the elimination of all peaks of plasma concentration for which either the increment (difference between peak value and preceding nadir) or the decrement (difference between peak value and following nadir) does not exceed a certain threshold related to measurement error. Peaks that do not meet threshold criteria are eliminated from the data using an iterative process, leaving a clean series in which all remaining peaks are assumed to represent significant pulses. The threshold for pulse detection was set at a value 2 times the leptin intraassay CV. Each pulse was characterized in terms of total duration and absolute (difference between levels at peak and the preceding trough) and relative (absolute peak amplitude divided by the value of the preceding trough) amplitudes.
The t test for paired data was performed to determine the differences in 24-h mean leptin concentrations, leptin pulsatility, body composition, and IGF-I data before and after GHR. Pearson’s test was performed to seek correlations. For all analyses, P < 0.05 was considered significant. Values are expressed as the mean ± SEM unless otherwise stated.
Results
The GH dose increased from 0.5 to 0.75 IU/d after 1 month, with a
significant increase in IGF-I and IGF-I SD score after 1
month of GHR compared with baseline (P < 0.001; Table 2). The 24-h mean leptin concentration
decreased significantly from 2.04 ± 0.04 nmol/liter at baseline
to 1.64 ± 0.03 nmol/liter after 1 month of GHR (P
< 0.0001; Table 2). Individual cosinor analyses demonstrated
significant circadian rhythms for all subjects before and after GHR
(P < 0.001). Individual leptin profiles before and
after GHR are presented as the percent change in leptin concentrations
at each time point in relation to the baseline 24-h mean in Fig. 1. The leptin mesor was 2.05 ± 0.03
nmol/liter with an amplitude of 0.36 ± 0.01 nmol/liter before
GHR. After GHR, the mesor decreased to 1.65 ± 0.01 nmol/liter
(P < 0.001), and the amplitude to 0.28 ± 0.01
nmol/liter (P < 0.001). The acrophase of the circadian
rhythm shifted from 0408 to 0438 h after treatment
(P = NS; Table 2). An ultradian rhythm was detected
before GHR, oscillating at a frequency of 2.0 ± 0.1 cycles/d
(periodicity, 12 h 17 min ± 54 min) with an amplitude of
0.11 ± 0.02 nmol/liter. The ultradian acrophase (first pulse peak
after local midnight) occurred at 0506 h, with a periodicity of
12 h and 17 min. The ultradian frequency increased significantly
to 16.0 ± 0.2 cycles/d (periodicity, 1 h 29 min ± 1
min) after 1 month of GHR, whereas the amplitude decreased to 0.04
± 0.01 (P < 0.0001). The ultradian acrophase shifted
to 0020 h compared with 0506 h observed before GHR
(P < 0.0001) and subsequently occurred every 1 h
and 29 min (Table 2).
|
|
). No significant
differences were found between the circadian rhythm parameter values
obtained by CHRONOLAB and COSIFIT program (P = NS).
|
) demonstrated
2–5 leptin pulses/24 h/individual (mean ± SD,
3.1 ± 0.9) before GHR, which increased to 6–14 pulses/24 h
(mean ± SD, 9.9 ± 2.2) after 1 month of GHR
(P < 0.001). The mean pulse duration was 393.7 ±
124.7 min before GHR and 136.8 ± 29.3 min after GHR
(P < 0.001). No significant differences in absolute
and relative pulse amplitudes were detected. There was no significant
difference in leptin circadian rhythmicity or pulsatility between 2 of
the 12 patients who were not receiving cortisol replacement and the 10
patients receiving steroid replacement (Table 3 and Fig. 1
).
|
). Although a significant
correlation was observed between the 24-h mean leptin concentration and
BFP at each visit (r = 0.7; P < 0.01), we failed
to detect a correlation between the change in 24-h mean leptin
concentration and changes in BFP that occurred after GHR (r =
-0.3; P = NS). The correlation between 24-h mean
leptin and BMI or BFM was not significant (r = 0.1 and 0.5;
P = 0.71 and 0.13, respectively, at baseline and r
= 0.1 and 0.5; P = 0.70 and 0.11, respectively, after 1
month). LBM was negatively correlated with the 24-h mean leptin
concentration at each visit (r = -0.8; P < 0.001
and r = -0.8; P < 0.001 before and after GHR,
respectively), but the correlation between changes in LBM and 24-h mean
leptin concentration before and after GHR failed to reach significance
(r = -0.2; P = 0.69). Discussion
Our data demonstrate a significant reduction in 24-h mean leptin concentration after 1 month of GHR in the absence of any significant change in body fat, suggesting that GH may have a direct regulatory role in leptin secretion. GHR resulted in a significant increase in leptin pulsatility, which may be important to achieve maximal biological activity and may be related to reported decrease in body fat after GHR (11, 16, 18, 19). These findings may have important clinical and therapeutic implications regarding the roles of GH and leptin in energy homeostasis and obesity.
Leptin is primarily secreted by adipocytes (1) and acts as a signal to brain regulatory centers controlling energy homeostasis (2, 3, 4). Single time point measurements in normal obese subjects and AGHD patients, who are typically obese (15), has demonstrated increased plasma leptin concentration and BFM compared with lean healthy controls (5, 6, 36, 37). In AGHD patients, 24-h mean plasma leptin concentration and BFM decreased significantly after 1 yr of GHR (19, 37), whereas such changes were not observed after 4 wk of GHR (19). A significant correlation between changes in leptin and BFM was reported in each of these studies (5, 6, 19, 36, 37), and based on correlational analysis it was suggested that the alterations in leptin concentration are a result of changes in body fat. Single time point measurements performed at 1-yr intervals are unable to establish chronology or distinguish whether changes in leptin concentration precede or follow changes in BFM. Additionally, such limited time point measurements are difficult to interpret in light of the new, clearly documented circadian and ultradian leptin rhythm and pulsatility (9, 10). Therefore, it is not possible to conclude from previous studies whether leptin is regulated by changes in adipose tissue. In our current study, a reduction in 24-h mean leptin concentration after 1 month of GHR preceded any significant change in BFM. Our data suggest that alterations in leptin concentration may, in fact, be responsible for the changes in BFM observed after prolonged GHR in previous studies (19, 37).
Healthy individuals demonstrate a circadian leptin rhythm with a superimposed ultradian pulsatility (9, 10). Diurnal rhythm and pulsatility is essential for hormones such as LHRH, GH, steroids, PTH, and the renin-angiotensin system to achieve maximal biological activity (38, 39, 40, 41). Sinha et al. (9) reported a mean of 3.25 pulses/24 h, sampling at 30-min intervals immediately after meals, at 1-h intervals between meals, and at 2-h intervals during the night from 4 lean, 11 obese, and 5 obese noninsulin-dependent diabetic subjects. In another study of 31 healthy subjects, leptin pulsatility was reported to be 3.6 pulses/24 h when plasma leptin was measured at 20-min intervals (42), whereas 13.4 pulses/24 h were detected when 7 healthy men were sample at 10-min intervals (43). Licinio et al. observed 32 pulses/24 h in a small group (6 men) of healthy individuals when measuring leptin every 7 min (10). In our present study we demonstrated 3.1 pulses/24 h in untreated AGHD patients with sampling at 30-min intervals, which significantly increased to 9.9 pulses/24 h after 1 month of GHR when sampling at the same frequency. The increase in leptin pulsatility observed in our study cannot, therefore, be explained by a sampling frequency bias. It is possible that the number of leptin pulses detected at each visit in our study may reflect the short duration of GH treatment these patients were given during this study period. A further increase in leptin pulsatility may, therefore, be observed with longer follow-up.
It is interesting to note that high doses of leptin are required to induce weight loss when administered in a nonpulsatile fashion (2). Reduced leptin pulsatility has been reported in obese subjects compared with healthy lean controls, suggesting a key role for leptin pulsatility in regulating BFM (42). The factors responsible for the regulation of leptin rhythmicity are not clear as yet. However, the presence of leptin receptors in animal (44) and human (45) fetal pituitary and in adult human hypothalamus (46) suggests a role for leptin in regulating GH secretion. This is further supported by evidence from several groups reporting a regulatory role of leptin in GH secretion in rodents (47, 48, 49), sheep (50), and pigs (51). Assuming that leptin participates in the regulation of GH secretion, it would be necessary to establish a classical feedback loop, with GH participating in the regulation of leptin secretion. Studies investigating alterations in plasma leptin concentration in AGHD patients before and after GHR have failed to observe a direct influence of GH on leptin secretion, and the changes observed in leptin secretion were suggested to occur due to changes in BFM (16, 19, 37, 52). None of these studies (16, 19, 52) were designed to examine the pulsatility before and after GHR. As there is increasing evidence of the importance of leptin pulsatility, in our study we measured 24-h leptin profiles at 30-min intervals to explore leptin pulsatility, together with body composition before and 1 month after GHR. We were able to demonstrate that GHR in AGHD patients reduces the mean plasma leptin concentration and increases leptin pulsatility independently of changes in BFM. We can thus propose that GH has a direct influence on the leptin secretory pattern, and a feedback loop between the two hormones may exist. This is in agreement with recent data providing evidence of GH regulation of leptin gene expression in cattle independently of changes in adiposity (53).
Body composition in our study was measured using BIA. In the absence of consensus on a gold standard, body composition measurements are performed using various acceptable methods, such as measurements of skin fold thickness, total body potassium, and dual energy x-ray absorptiometry (DEXA) (54, 55, 56, 57). However, there remain inherent caveats in the calculation of LBM and BFP using these methods. BIA is a relatively new, simple, inexpensive, and reproducible method based on the principle that an electrical current is conducted by electrolytes dissolved in intra- and extracellular water. It has been validated in healthy individuals (20, 21), and more recently, direct comparison studies in AGHD patients have shown no significant differences in body composition measurements obtained by BIA and DEXA methods (22, 23). Further studies measuring changes in body composition in AGHD patients have also reported parallel changes and strong correlations between BIA and other frequently used methods, including DEXA (18, 58, 59, 60). Given such information and the strong correlations between BIA-derived values and other methods, it would appear that BIA is an acceptable technique to determine changes in body composition after GHR. However, BIA does not provide a direct measure of body composition, and the results should therefore be interpreted with care.
In conclusion, we report for the first time that GHR increases leptin pulsatility, which is reduced in AGHD. We also demonstrated that GHR reduces the mean leptin concentration and amplitude of leptin pulses, and that these changes are independent of changes in BFM. We suggest that GH has a direct influence on the leptin secretory pattern, and our data coupled with reports on the regulation of GH secretion by leptin (44, 45, 46, 47, 48, 49, 50, 51) highlight the important link between leptin secretion and the GH axis. Restoration of ultradian leptin pulsatility may be of clinical benefit, and our data could lead to novel approaches for leptin manipulation in the future. Further studies are required to test these hypotheses and to assess the role of leptin pulsatility on body composition.
Acknowledgments
We thank Eli Lilly & Co. (Basingstoke, UK) and Prof. Blum (Endokrinologisches Labor, Giessen, Germany) for analysis of IGF-I. We are grateful to Eli Lilly & Co. and Pharmacia & Upjohn, Inc. (Milton-Keynes, UK), for the help and support they have provided. We are also grateful to Dr. Eve Van Cauter, University of Chicago (Chicago, IL) for providing us with ULTRA algorithm.
Footnotes
Abbreviations: AGHD, Adult GH deficiency; BFM, body fat mass; BFP, body fat percentage; BIA, bioelectrical impedance analysis; BMI, body mass index; CV, coefficient of variation; DEXA, dual energy x-ray absorptiometry; GHD, GH deficiency; GHR, GH replacement; LBM, lean body mass; TBW, total body water.
Received June 5, 2000.
Accepted April 17, 2001.
References
This article has been cited by other articles:
 |
|
 |
|
  J. R. Berggren, M. W. Hulver, and J. A. Houmard Fat as an endocrine organ: influence of exercise J Appl Physiol, August 1, 2005; 99(2): 757 - 764. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Block, R. P. Rhoads, D. E. Bauman, R. A. Ehrhardt, M. A. McGuire, B. A. Crooker, J. M. Griinari, T. R. Mackle, W. J. Weber, M. E. Van Amburgh, et al. Demonstration of a Role for Insulin in the Regulation of Leptin in Lactating Dairy Cows J Dairy Sci, November 1, 2003; 86(11): 3508 - 3515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Leury, L. H. Baumgard, S. S. Block, N. Segoale, R. A. Ehrhardt, R. P. Rhoads, D. E. Bauman, A. W. Bell, and Y. R. Boisclair Effect of insulin and growth hormone on plasma leptin in periparturient dairy cows Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R1107 - R1115. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Koutkia, B. Canavan, M. L. Johnson, A. DePaoli, and S. Grinspoon Characterization of leptin pulse dynamics and relationship to fat mass, growth hormone, cortisol, and insulin Am J Physiol Endocrinol Metab, August 1, 2003; 285(2): E372 - E379. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Ahmad, J. Thomas, A. Clewes, M. T. Hopkins, R. Guzder, H. Ibrahim, B. H. Durham, J. P. Vora, and W. D. Fraser Effects of Growth Hormone Replacement on Parathyroid Hormone Sensitivity and Bone Mineral Metabolism J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2860 - 2868. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ozata, C. Dieguez, and F. F. Casanueva The Inhibition of Growth Hormone Secretion Presented in Obesity Is Not Mediated by the High Leptin Levels: A Study in Human Leptin Deficiency Patients J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 312 - 316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Pan, T. Terada, M. Irie, H. Saito, and K.-I. Inui Diurnal rhythm of H+-peptide cotransporter in rat small intestine Am J Physiol Gastrointest Liver Physiol, July 1, 2002; 283(1): G57 - G64. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Marzullo, C. Buckway, K. L. Pratt, A. Colao, J. Guevara-Aguirre, and R. G. Rosenfeld Leptin Concentrations in GH Deficiency: The Effect of GH Insensitivity J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 540 - 545. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
, Patients
not receiving steroids.