1 Department of Obstetrics and Gynaecology, University of Thessalia, 2 State Department of Obstetrics and Gynaecology, Larissa and 3 Department of Biological Chemistry, University of Ioannina, Ioannina, Greece
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Abstract |
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Key words: leptin/oestradiol/ovariectomy/ovary/progesterone
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Introduction |
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Although these results suggest that ovarian steroids may play a role in leptin secretion, treatment of normal women with oestrogen plus progesterone in the form of the oral contraceptive pill or hormone replacement therapy did not have any effect on serum leptin concentrations (Kohrt et al., 1996; Castracane et al., 1998
; Cella et al., 2000
). It may be that the doses of the steroids used in these preparations were not sufficient to stimulate leptin secretion. It remains, therefore, to investigate whether induction of `physiological' concentrations of oestradiol and progesterone in blood, similar to those seen in the normal menstrual cycle, can affect leptin secretion. Furthermore, previous data in women have shown a temporal increase in leptin values within the first 24 h after ovariectomy (Messinis et al., 1999
), but the reason for this phenomenon is not known. The present study was undertaken to investigate the mechanisms of changes in leptin values following ovariectomy in normal women and to study further the role of oestrogen and progesterone in the secretion of this protein.
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Materials and methods |
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Statistical analysis
The results were statistically analysed using one-way analysis of variance. To achieve an approximate normal distribution of the data, before the statistical evaluation hormonal values were transformed into logarithms. However, in the results the arithmetic values are presented unless stated otherwise. Correlations between various parameters were calculated by using simple and multiple linear regressions.
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Results |
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Serum oestradiol values declined significantly as early as 12 h after the operation in the control group and remained below the value of 100 pmol/l up to day 7 (Figure 1). In contrast, in the oestradiol group and the oestradiol plus progesterone group serum oestradiol values did not decline, but remained at or above the pre-operative value throughout the whole experimental period. At all points, serum oestradiol concentrations were significantly higher in these two groups than in the control group (Figure 1
).
Serum values of progesterone showed a temporal but significant increase at 12 h after the operation (P < 0.001), returning to the pre-treatment value on day 1 (Figure 1). A significant decrease was seen from days 12 (P < 0.05). From days 27, progesterone values remained very low in the control and the oestradiol groups, while in the oestradiol plus progesterone group, due to the exogenous administration of this hormone, the values increased rapidly from days 27 (P < 0.001) and remained unchanged at this increased value (Figure 1
). A temporal but significant increase (P < 0.001), coincident with that of progesterone, was also seen in serum cortisol values 12 h after the operation in all three groups (Figure 1
). Then, cortisol concentrations declined on day 1 and did not change significantly thereafter, although there was a trend for lower values in the oestradiol plus progesterone group (Figure 1
).
A significant decrease in body weight (mean ± SEM) from days 0 to 7 was seen in the controls (2.7 ± 0.1 kg) and in the oestradiol group (3.6 ± 0.2 kg) (P < 0.001), but not in the oestradiol plus progesterone group (1.0 ± 0.5 kg). Consequently, BMI was decreased in the controls and the oestradiol group but not in the oestradiol plus progesterone group. Serum leptin concentrations before and after the operation were significantly correlated with BMI in all three groups combined (day 0: r = 0.555, P < 0.01, n = 21 and day 7: r = 0.496, P < 0.05, n = 21). Significant positive correlations were found from days 27 between leptin and progesterone values (r = 0.409, P < 0.01, n = 42) and between leptin and oestradiol values (r = 0.363, P < 0.05, n = 42) only in the oestradiol plus progesterone group. In multiple regression analysis, changes in BMI from days 27 was the most important determinant that was significantly correlated with leptin values in all three groups (controls r = 0.419, P < 0.01; oestradiol group r = 0.400, P < 0.01; oestradiol plus progesterone group r = 0.728, P < 0.001, n = 42); however, in the oestradiol plus progesterone group progesterone was significantly correlated with leptin independently of BMI. When all three groups were combined, the log-transformed values of leptin increment from 1224 h following the operation (changes in leptin) were significantly correlated with those of cortisol (r = 0.687, P < 0.001, n = 21) and progesterone (r = 0.637, P < 0.01, n = 21) at 12 h (Figure 2). Between cortisol and progesterone values on day 0 (0 and 12 h) and day 1 there was a significant positive correlation (r = 0.641, P < 0.001, n = 63).
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Discussion |
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The present results, in terms of the effect of oestrogen on leptin secretion, do not confirm earlier studies on rats according to which treatment of the animals with oestradiol prevented the ovariectomy-induced decline in leptin values (Shimizu et al., 1997; Chu et al., 1999
). The reason for this difference is not known. However, in the studies on rats treatment with oestradiol was applied for a few weeks, while in the present study it was applied for only a few days. It is also possible that species differences are important, since administration of oestradiol to female rats significantly elevated within 12 h amounts of leptin mRNA in adipose tissue and plasma leptin concentrations (Brann et al., 1999
), while in the present study in women oestradiol was without any effect. Also, the results of the current study are different from those in previous studies in which treatment of normal women with combinations of oestrogen plus progesterone, in the form of either the oral contraceptive pill or hormone replacement therapy, did not affect leptin values (Kohrt et al., 1996
; Castracane et al., 1998
; Cella et al., 2000
). There are, however, great differences between these and the present study in terms of the design, the aim and the dosages used, which in those preparations may have been insufficient to stimulate leptin secretion.
Although according to the present results, the role of oestradiol in the control of leptin secretion during the normal menstrual cycle is of minor significance, in-vitro data have shown that oestradiol can stimulate leptin production from human adipocytes in cultures (Casabiell et al., 1998), while oestradiol high affinity binding sites have been detected in fat cells (Wade and Gray, 1978
). Additionally, in-vivo data have shown significant positive correlations between oestradiol and leptin values during the follicular phase of the cycle with a significant increase in circulating leptin in the late follicular phase (Messinis et al., 1998
; Cella et al., 2000
). The possibility, therefore, exists that oestradiol may exert a priming effect on adipocytes thus sensitizing these cells to subsequent stimulants, such as progesterone. However, since in the present study a progesterone alone group was not included, this possibility needs to be further examined. Alternatively, oestradiol may exert a delaying effect on leptin secretion, since a trend for higher leptin values during the second part of the post-operative period was seen in the oestradiol-treated women in this study as compared to controls. However, this requires further investigation.
The finding that leptin values were increased when progesterone was added to the oestradiol regimen could be interpreted as indicating that increased concentrations of oestradiol are a prerequisite for progesterone to exert an effect on leptin secretion in women. However, based on further results of the present study this possibility is not likely. In particular, a temporal increase in leptin values occurred in all women within the first 24 h following ovariectomy. This increase, which has been reported previously, does not seem to be related to the type of the operation, because it has also been seen after cholecystectomy in women (Messinis et al., 1999). Since the temporal increase in leptin values was preceded by a significant increase in cortisol concentrations, which were significantly correlated with leptin values, and since dexamethasone can stimulate leptin production in vivo (Larsson and Ahren, 1996
; Papaspyrou-Rao et al., 1997
), it is possible that a stress-related increase in cortisol was responsible for the subsequent increase in circulating leptin values. Coincident with the increase of cortisol was an increase in progesterone concentrations and since the ovaries had already been removed, it is suggested that progesterone at that stage was of adrenal origin. The possibility therefore cannot be excluded that the temporal increase in progesterone values contributed to the temporal increase in leptin, because significant positive correlations were also found between progesterone and leptin values. Since at the time of the progesterone increase oestradiol values declined markedly, it is suggested that progesterone may be able to stimulate leptin secretion even in the presence of low concentrations of oestradiol.
From a physiological point of view, the present findings could explain the previously reported higher concentrations of leptin in the luteal than in the follicular phase of the cycle (Hardie et al., 1997; Mannucci et al., 1998
; Messinis et al., 1998
; Riad-Gabriel et al., 1998
; Quinton et al., 1999
; Ludwig et al., 2000
) as the result of a stimulating effect of progesterone, although there is controversy as to whether leptin and progesterone titres are significantly correlated during the luteal phase (Hardie et al., 1997
; Quinton et al., 1999
; Ludwig et al., 2000
). The disparity between oestradiol plus progesterone group and the other two groups in terms of the decrease in body weight and BMI during the post-operative period is difficult to explain. Nevertheless, it is rather unlikely that this is related to changes in fat stores, since similar dietary restrictions were applied to all three groups of women. It is possible that this is related to water retention, which may happen during the luteal phase of the cycle, although this was not investigated in this study. Finally, the reason for the increase in leptin values in the controls and the oestradiol-treated group during the second half of the experimental period is unclear; however, this may be related to the increased intake of food that was initiated at that stage of the study.
In conclusion, the present study demonstrates for the first time that the temporal increase in leptin values that occurs 24 h after bilateral ovariectomy in pre-menopausal women is preceded by a significant increase in progesterone and cortisol values and a marked decline in oestradiol concentrations. In addition, the subsequent decrease in leptin values below the pre-operative value is prevented by treatment with oestradiol plus progesterone, but not with oestradiol alone. It is suggested that progesterone and cortisol exert stimulating effects on leptin secretion in normal women regardless of the concentrations of oestradiol.
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Acknowledgments |
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Notes |
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References |
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Submitted on March 16, 2000; accepted on August 7, 2000.