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Original Studies |
Department of Gynecology and Obstetrics, Skejby Sygehus (P.O.); Medical Department M (Endocrinology and Diabetes), Aarhus Kommunehospital (N.V., J.S.C., J.O.L.J.); and Institute of Experimental Clinical Research, Aarhus University (S.F.), Aarhus, Denmark; and the Endocrinology Division (J.D.V.), National Science Foundation Center for Biological Timing, and University of Virginia Health Sciences Center, Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Per Ovesen, M.D., Department of Gynecology and Obstetrics, Skejby Sygehus, DK-8200 Aarhus N, Denmark.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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To investigate the mechanisms subserving the putative E2-associated increase in GH concentrations in the late follicular phase, we applied the following strategies: 1) a homogeneous group of young healthy premenopausal women was studied, each individual being assessed during two phases of her menstrual cycle to minimize interindividual variation; 2) deconvolution analysis and approximate entropy were used to allow estimation of production rates and patterned regularity of GH in addition to mean GH levels and peak numbers; 3) an arginine stimulation test was performed on each occasion to allow a comparison between spontaneous and stimulated GH levels; and 4) the levels of IGF-I and IGF-binding protein-3 (IGFBP-3) were measured to evaluate the effects of sex steroids on the entire GH-IGF-I axis.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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)
Ten healthy young women with regular menstrual cycles occurring
every 27–29 days were examined. All subjects were nonobese according
to body mass index, waist/hip ratio (W/H), and percent lean body mass
(Table 1). All women were studied twice in random order: in the early
follicular (EF) phase, days 2–5 after the onset of menstrual bleeding;
and in the PO phase, days 13–15 after the onset of menses. Two
subjects had distinctly elevated P values during the PO phase,
suggesting early postovulation. These two subjects exhibited
differences in GH levels that were qualitatively similar to the others.
The tests were separated by at least one normal menstrual cycle.
Volunteers underwent 24-h blood sampling followed by an arginine
stimulation test. All subjects gave their written informed consent, and
the study was approved by the local ethics committee and conducted
according to the Declaration of Helsinki.
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After an overnight fast, the subjects were admitted to the hospital at 0830 h, and an iv cannula was placed in a antecubital vein. Blood sampling was started at 0900 h and continued every 20 min for 24 h. Serum was separated and stored at -20 C until assayed. Subjects were given three meals per day and were allowed normal physical activity but refrained from sleeping during the day. No record of sleep was obtained.
Arginine stimulation test
The test was performed after completion of each 24-h GH sampling profile, and the subjects remained supine during the test. At 0900 h, arginine (0.5 g/kg BW) was infused iv over 30 min, and blood samples were withdrawn every 10 min for 2 h. One of the 10 women only completed 1 arginine stimulation test, so in the paired statistics only 9 women are included.
Hormone analysis
A double monoclonal immunofluorometric assay (Delfia, Wallac, Turku, Finland) was used to measure GH. The lower detection limit was 0.01 mg/L. Serum IGF-I and IGF-II were determined after acid-ethanol extraction by a novel in-house immunofluorometric method using two monoclonal antibodies (9). Dose-dependent within-sample variance was calculated in each 24-h time series using all 73 replicated (duplicated) samples and was used in the pulse analysis. Serum concentrations of FSH, LH, PRL, and progesterone were measured using commercially available RIA kits. Serum concentrations of E2 were analyzed by RIA using the Spectria kits from Orion Diagnostica (Espoo, Finland). The intra- and interassay coefficients of variation were 7.3% and 5.1%, respectively. Serum concentrations of GH-binding protein (GHBP) were measured using a ligand immunofunctional assay (10).
Body composition
Percent body fat and total lean body mass were assessed using bioelectrical impedance (Animeter, HTS, Odense, Denmark) (11). Body mass index was defined as the subject’s weight in kilograms divided by the square of her height in meters. The W/H ratio was defined as the ratio between the circumference of the waist at the umbilicus and that of the hips at throchanter major.
Deconvolution analysis
A pulsatile model of hormone secretion and clearance was assumed, in which the plasma concentration of GH at any given instant is related to four simultaneous secretory and kinetic features of interest: 1) the locations, 2) the amplitudes, and 3) the durations of significant GH secretory bursts, acted upon continuously by 4) an endogenous subject-specific hormone half-life, as previously described (12). A basal (time-invariant) rate of GH secretion was calculated simultaneously to reflect the lowest 5% of sample GH concentrations in any given profile. A distinct secretory burst was defined algebraically as an approximately random (Gaussian) distribution of instantaneous molecular secretory rates, in which the fitted amplitude could be distinguished from zero with 95% certainty. A convolution integral was used to relate the serum GH concentrations to the foregoing specific measure of pulsatile GH secretion and removal, which were quantified by iterative nonlinear least squares parameter estimation. The disappearance function for GH was modeled as a one-component exponential decay function with a subject-specific rate constant (12), assuming that the half-life and distribution volume of GH were approximately constant in each individual throughout the 24 h.
The above deconvolution analysis estimates 1) the daily (endogenous) pulsatile production rate (milligrams per L GH distribution volume/24 h): product of mass per burst and number of bursts (total secretion includes any basal secretion, here found to be approximately zero); 2) secretory burst amplitude (milligrams per L/min): maximal rate of secretion attained within the computed secretory event (mass per distribution volume/min), 3) mass secreted per burst (milligrams per L): area of the calculated secretory burst; hence, amount of hormone secreted per burst per U distribution volume; 4) number of bursts; and 5) t1/2 of (endogenous) GH disappearance (minutes).
All analyses were carried out blinded to the order of admissions.
Cluster analysis
The Cluster analysis (13) was included as a model independent analysis.
Approximate entropy (ApEn) statistic
Normalized ApEn is a scale- and model-independent statistic for assessing the regularity of time-series data. It assigns a single nonnegative number to a time series, quantifying an idea of the serial orderliness or regularity of the data. ApEn measures the logarithmic likelihood that runs of patterns of data length m that are similar remain similar within a tolerance r on next incremental comparisons. Smaller ApEn values indicate a greater likelihood of successive comparisons remaining close and therefore imply greater regularity, and vice versa. It has been demonstrated that ApEn is very stable to repeated small changes in noise characteristics or infrequent, albeit large, data artifacts. The calculation of ApEn has been thoroughly described (14). Two input parameters, m and r, must be fixed to compute ApEn; m is the length of compared runs, and r is effectively a tolerance or filter. In this study, m = 1, and r = 20% of the SD of each GH time series, which serves to normalize ApEn to any differences in absolute serum GH concentrations. These ApEn parameters have been shown to define statistically and biologically significant contrasts in the orderliness of hormone release in various 24-h time series (15, 16, 17).
Statistical analysis
Comparisons among the variables between the two menstrual phases were made using paired Student’s t test and Wilcoxon nonparametric test. Multiple linear regression was used to detect correlations between E2, FSH, LH, IGF-I, GHBP, age, W/H, and fat-free mass (independent variables) and estimates of GH secretion and half-life derived from deconvolution analysis (dependent variables). ANOVA was used to test for changes within and between the two phases during the arginine stimulation test. In addition, the area under the curve (AUC) and the difference between baseline and maximum level postarginine administration were compared by paired t tests. Data are given as the mean ± SEM. Statistical significance was assumed for P < 0.05.
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Results |
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and 2)The basal secretion of GH was similar during the EF and PO phases (EF, 0.001 ± 0.0 mg/L·min; PO, 0.002 ± 0.0; P = 0.19). Expressed as daily rates, these values are 1.4 and 2.8 mg/L, respectively, which are less than 5% of the pulsatile daily secretion rates and, hence, were omitted from further analysis. The mean 24-h serum GH concentration was significantly higher in the PO than in the EF phase (EF, 0.87 ± 0.1 mg/L; PO, 1.35 ± 0.1; P = 0.004). Furthermore, the mean estimated production rate of GH was increased during the PO phase (EF, 37.0 ± 7.7 mg/L·24 h; PO, 60.6 ± 6.0; P = 0.01). The calculated GH secretory burst amplitude was similar during the two phases (EF, 0.12 ± 0.02 mg/L·min; PO, 0.15 ± 0.02; P = 0.13), whereas the number of GH secretory bursts was significantly increased during the PO phase compared to that during the EF phase [EF, 10.3 ± 0.6 (number of bursts per 24 h); PO, 13.3 ± 0.5; P = 0.004], and thus, the GH interburst interval was significantly shorter in the PO phase than in the EF phase (EF, 134.4 ± 8 min; PO, 107.4 ± 5; P = 0.006). No difference was seen between the two phases in either the mass of GH secreted per burst (EF, 3.7 ± 0.8 mg/L; PO, 4.7 ± 0.6; P = 0.19) or the GH half-life (EF, 17.6 ± 0.8 min; PO, 17.0 ± 0.4; P = 0.92). Cluster analysis revealed a higher maximal peak height (P = 0.037) and total pulse area (P = 0.027) during the PO phase, whereas the peak number did not significantly differ between the two phases. Furthermore, there was no difference between ApEn values during the EF phase compared to those during the PO phase (EF, 0.51 ± 0.04; PO, 0.54 ± 0.05; P = 0.56). Similar ApEn results were obtained when the calculation was repeated after first differencing to remove 24-h trends.
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)Serum GH increased significantly in both phases after arginine infusion (P < 0.001), whereas there was no difference between the two cycle phases (P = 0.20). This was also reflected in the AUCs, expressed as mean GH levels during arginine stimulation (EF, 7.28 ± 1.5 µg/L; PO, 9.51 ± 1.9; P = 0.20). Furthermore, the differences between baseline and maximum level postarginine administration were similar on the two occasions (EF, 12.6 ± 2 mg/L; 15.4 ± 3; P = 0.32).
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)Serum E2 and LH were significantly higher in the PO phase than in the EF phase, whereas serum progesterone and FSH were comparable during the two phases. Serum GHBP levels was similar during the two phases. Serum IGF-I, IGF-II, and IGFBP-3 were measured at 0900, 1500, and 2100 h, and the results reported are the means of these three measurements. Serum IGF-I was significantly increased during the PO phase compared to that during the EF phase. The calculated product of the mean GH concentration and the IGF-I concentration (EF, 191.93 ± 46; PO, 342.32 ± 44; P = 0.002) further increased the difference between the EF and PO phases. Serum IGFBP-3 and IGF-II levels were comparable.
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By multiple regression analysis with features of GH status as the dependent variable and sex steroids, gonadotropins, GHBP, IGF-I, and age as independent variables, no significant determinants of GH status were disclosed in the EF phase. By contrast, in the PO phase the serum E2 concentration was able to significantly predict GH secretory status in most equations. With GH production rate as the dependent variable, the positive association with E2 was significant, with a level of significance between 0.045–0.009 depending on the composition of the other independent variables. In some equations in the PO phase LH appeared as a positive, but weaker, determinant (P = 0.08–0.02) of GH secretory status. Finally, there was no correlation in either the EF phase or the PO phase with measures of body composition.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Earlier studies of GH release in premenopausal women have focused on differences between young and older women and between sexes (18), whereas 24-h GH release during the menstrual cycle has only been investigated in a few studies. Our study partially confirms the study by Faria et al. (4) in which PO levels of mean 24-h GH were increased compared to those during the EF phase of the menstrual cycle, albeit not necessarily in the same women. In their study, which was carried out with a less sensitive GH assay and discrete peak detection without deconvolution analysis, this rise in GH was due to an increased GH pulse amplitude rather than number of pulses. In our study, we found no difference between GH secretory burst mass or amplitude, but there was a significantly increased number of GH secretory pulses. We observed 10.3 and 13.3 pulses/24 h in the EF and PO phases, whereas Faria et al. only detected 8.3 and 7.9 pulses/24 h in the same two phases. This difference probably reflects a greater sensitivity of GH pulse detection by way of both analytical technique (deconvolution vs. Cluster analysis) and assay threshold, especially given that earlier GH assays failed to detect low amplitude secretory bursts. Furthermore, Faria et al. studied different women during the different phases, whereas we investigated the same women during the two phases, thus eliminating interindividual differences. In addition to the higher frequency of GH pulses during the PO phase, the total pulsatile GH production rate was also found to be greater than that in the EF phase. This was not evaluated in the study by Faria et al., but was suggested by increased total pulse area (as confirmed here by deconvolution and independently by Cluster analysis; data not shown). The difference in sampling rates between the two studies (20 and 10 min) could have some implications, but it has recently been shown that a 20-min sampling interval can allow significant information (16), including detection of estrogen-stimulated GH secretory burst frequency (5). As in the Faria study, we detected a positive correlation between E2 and GH secretory pulse amplitude, production rate, and mean 24-h GH in the PO cycle phase and for the first time between E2 and GH secretory burst frequency, collectively suggesting E2 to be a major determinant of GH secretion. This is in accord with the results of studies in postmenopausal women treated with exogenous estrogen, in whom GH levels were increased after both oral and adequately dosed transdermal E2 administration (7).
In an earlier study by Zadik et al. (19), 23 normal women were subjected to continuous 24-h sampling in the follicular and again in the luteal phase of the menstrual cycle, with no evident differences in the integrated concentrations of GH during the two phases. Comparable observations were reported in studies based on daily blood samples throughout the menstrual cycle (20, 21, 22), whereas others found a periovulatory rise in serum GH (23, 24). Ovulation induction was also found to result in a severalfold increase in serum GH concentrations during the PO period (25). These 6 studies are all based on single GH values in blood, which do not necessarily reflect endogenous GH secretion.
The observed lack of difference in arginine-stimulated GH release during the menstrual cycle is in accordance with the results of studies using exogenous GHRH as a GH secretagogue (26, 27), whereas higher GH levels in the PO phase have been reported after stimulation with arginine (28) and exercise (22). The reason for this ambiguity is unknown, but it could be a type 2 error in the negative studies.
The serum GHBP level did not differ between the two phases, which is in line with the findings of a previous study (29). It has recently been found that females secrete GH with more process irregularity than males (16) and in a similar immunofluorometric assay secrete more GH per pulse than men (18). Although we found no cycle-dependent difference in GH secretion pattern regularity as quantified by ApEn, estrogen treatment of girls with gonadal dysgenesis increased the disorderliness of GH release (higher ApEn) (30). As estrogen treatment in this context also increases GH pulse amplitude (5), our findings in the PO phase of higher GH pulse frequency and unchanged ApEn are readily distinguished from the GH axis response to exogenous estrogen.
Serum IGF-I levels were significantly increased in the PO phase by our paired comparisons, which contrasts with other recent studies that found no change in serum IGF-I levels throughout the menstrual cycle (29, 31, 32). In postmenopausal women receiving oral estrogen, amplification of endogenous GH levels is usually encountered together with reduced serum IGF-I levels (6). In that context it is, therefore, likely that the increased GH release represents a feedback response to the reduction in peripheral IGF-I levels compar-able to what is observed during fasting (1). In contrast, and much like the combined increase in serum GH and IGF-I that occurs in pubertal vs. prepubertal girls (33), here during the PO phase we find evidence for GH hypersecretion relative to IGF-I levels, thus strongly suggesting central actions of estrogen to stimulate GH production via one or more mechanisms (33). This was also reflected in the calculated product of the mean GH concentration and the IGF-I concentration, which showed an increased value, whereas accommodation of high GH to low IGF-I levels would keep the product nearly constant. The mechanisms underlying this apparent divergence in IGF-I responses after exogenous vs. endogenous elevation in E2 levels are unclear, but it has been suggested that oral estrogen directly inhibits hepatic IGF-I production as a first pass (pharmacological) effect (6).
In conclusion, this study shows that the elevated GH levels during the PO phase of the menstrual cycle are due to an increase in the pulsatile GH production rate and a rise in the GH secretory burst frequency. Furthermore, the concomitant increase in plasma IGF-I concentrations suggests that the ability of endogenous E2 to amplify pituitary GH release is not secondary to the suppression of hepatic IGF-I production.
Received October 6, 1997.
Revised January 7, 1998.
Accepted January 15, 1998.
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) and the PO phase (
). Inset,
AUCs, expressed as mean GH levels during arginine stimulation
(upper panel) and peak GH concentrations (lower
panel).