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Original Studies |
Division of Endocrinology and Metabolism, Department of Internal Medicine, and National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Dr. J. D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Box 202, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. E-mail: jdv{at}virginia.edu
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Abstract |
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In parallel equilibrium infusion studies in men, we administered GH by constant iv infusions for 240 min during octreotide suppression. At doses of 0.5, 1.5, and 4.5 µg/kg·min, steady state GH t1/2 values were 9 ± 1, 12 ± 1, and 15 ± 1 min (at respective steady state serum GH concentrations of 0.5 ± 0.05, 2.1 ± 0.2, and 7.5 ± 0.5 µg/L). In a third analysis in the same volunteers, stopping the constant iv infusions revealed t1/2 values of GH decay from equilibrium of 26 ± 5 and 23 ± 2.3 min for the two higher GH infusion rates. In a fourth paradigm, endogenous GH t1/2 values, as assessed in the same individuals by deconvolution analysis of overnight (10-min sampled) serum GH concentration profiles, averaged 18 ± 1.3 min. This value was intermediate between that of poststeady state decay and iv bolus elimination of GH.
In summary, the foregoing clinical experiments in healthy men and women indicate that 1) the nonequilibrium GH t1/2, (body surface area-normalized) Vo, and MCR are independent of GH dose, sex, menstrual cycle stage, and serum estradiol concentrations; 2) the GH t1/2 calculated after iv bolus injection is significantly (50%) shorter than that assessed during or after steady-state GH infusions or endogenously (overnight) by deconvolution analysis; and 3) the descending rank order of GH t1/2 values in healthy volunteers is approximately: decay from steady state (23 ± 2.3 min) > endogenously secreted GH (18 ± 1.3 min) > during equilibrium infusion (15 ± 1 min) > after bolus infusion (9.8 ± 0.8 min). We thus conclude that for any given body surface area, the elimination properties of GH in men and women reflect predominantly the time mode of hormone entry into the circulation, rather than gender, menstrual cycle stage, or prevailing serum estradiol concentration. Accordingly, differences in serum GH concentrations in premenopausal women compared to those in young men and across the normal menstrual cycle reflect commensurate differences in pituitary GH secretion rates.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The available clinical literature remains unclear about the presumptive
regulation of GH half-life or distribution volume by sex steroid
hormone milieu, gender, and/or menstrual cycle stage. In one analysis,
Rosenbaum and Gertner using constant iv infusions of recombinant human
GH found that young women exhibit an apparently reduced GH MCR (by
30%) compared to men (13). On the other hand, in an unrelated
study, Holl et al. administered human recombinant GH by
bolus iv injections in young men and reported that the serum estradiol
concentration correlates inversely with the GH half-life (14). These
clinical experiments thus offer potentially conflicting inferences, as
women (with higher estrogen concentrations) would be predicted by the
data of Holl et al. to maintain shorter GH half-lives (and
thereby greater, rather than lower, GH MRCs) than men.
The physiological significance of a putative impact of sex, menstrual cycle stage, and/or estrogen on GH kinetics (e.g. GH half-life, metabolic clearance, or distribution volume) arises from important physiological contrasts in the apparent activity of the GH axis across the normal menstrual cycle and (at younger ages) in women compared with men (15, 16, 17, 18). For example, serum GH concentrations typically double during the late follicular phase of healthy young women as serum estradiol concentrations rise (19, 20, 21), and premenopausal women maintain higher 24-h mean serum GH concentrations than comparably aged men (18). In addition, in girls with Turner’s syndrome and/or in postmenopausal women, oral and higher dose transdermal estrogen administration increases mean serum GH concentrations by 1.5- to 3-fold (2, 22, 23, 24). One plausible a priori interpretation of the foregoing literature is that estradiol prolongs the GH half-life, decreases its MCR, and thereby increases serum GH concentrations in estrogen-enriched physiological contexts. This postulated action of estrogen would potentially explicate a variety of sex hormone-dependent variations in serum GH concentrations (2). On the other hand, the severalfold physiological excursions in plasma GH concentrations in different estrogenic milieus might originate from a true augmentation of or diminution in endogenous GH secretion. This mechanistic distinction has fundamental implications, namely in correctly distinguishing whether sex steroids regulate hepatorenal (and/or other) GH removal processes or govern the hypothalamo-pituitary drive of GH secretion.
We here examine the null hypothesis that gender, menstrual cycle stage, and estradiol have no significant modulatory effect on human GH kinetics. As GH elimination is controlled by both its distribution volume and its half-life of irreversible removal (25), we have investigated both facets of GH disposal in men and women. Because many earlier studies also differed (and, hence, were not strictly comparable) by way of the mode of GH delivery into the bloodstream, e.g. by steady state infusion (13) or by bolus injection (14), we also directly compared the half-life of GH in the same individuals variously infused with recombinant human GH continuously and (on a separate occasion) by bolus injection. Moreover, inasmuch as other investigations determined the half-life of GH’s removal by yet a third paradigm, viz. after its decay from equilibrium (after abrupt cessation of a constant GH infusion) (8, 11), we further calculated GH’s half-life of decay from the steady state in the same volunteers. We used octreotide to limit potential confounding by variable endogenous GH secretion. Lastly, we concurrently made estimates of the endogenous (secreted) GH half-life by deconvolution analysis of overnight serum GH (pulsatile) concentration profiles (18, 26, 27). Endogenous GH half-lives presumably represent pseudosteady state values, because GH is secreted episodically in short term bursts akin to consecutive brief iv infusions with resultant plasma levels (especially during the night) that do not decay to zero before additional GH release occurs (2).
By implementing the foregoing combined strategies, we unexpectedly provide evidence that the time mode of GH entry into the bloodstream (rather than sex, estradiol, or menstrual cycle status) strongly influences GH half-life, thus harmonizing much of the earlier, otherwise discrepant literature.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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After providing written informed consent, 13 healthy young men (mean ± SEM age, 29 ± 6.6; range, 22–36 yr) and 6 women (age, 25 ± 3.3; range, 22–28 yr) underwent screening history, physical examination, and serum biochemical tests. All volunteers were in excellent health, with normal hematological, renal, hepatic, metabolic, and endocrine function (thyroid panel, PRL, LH, FSH, testosterone, and insulin-like growth factor I levels). Body mass index averaged 25 ± 4.1 (range, 21–31) in men and 20 ± 2.9 (range, 16–25) kg/m2 in women (P = NS). Six different young men participated in the dose-varying iv bolus GH infusion study, and 6 women participated similarly. An additional 7 men underwent both bolus and continuous GH infusions as well as overnight blood sampling and monitoring of GH decay from steady state. Healthy women were studied at each of three stages of the menstrual cycle, as defined by ovarian ultrasonographic criteria; morning serum estradiol, progesterone, and LH concentrations; and menstrual history, as discussed previously (28, 29).
GH infusions
Bolus vs. continuous GH infusions were carried out on separate, randomly ordered (VAX random number generator) occasions at least 1 week apart.
Bolus GH infusion studies. Both men and women were pretreated with octreotide (1 µg/kg) infused continuously iv over 1 h beginning at 0700 h (fasting), 1 h before GH injection. The octreotide infusion was repeated every 5 h twice. This schedule suppresses serum GH concentrations to nearly undetectable in 95% of blood samples (8, 11). One hour after the first octreotide infusion, each volunteer received each of three randomly ordered doses of human recombinant GH by iv bolus infusion over 1 min, namely 1, 2, or 4 µg/kg. Consecutive injections were carried out 4 h apart. Beginning one sample before the bolus GH injection, blood was sampled every 5 min for 30 min and then every 10 min for 3 h to define the serum GH concentration-decay curves.
Continuous iv infusions of GH. Infusions in men were carried out after overnight 10-min blood sampling for 12 h (from 2000 h until 0800 h). GH infusions were preceded by iv octreotide suppression (dose and schedule as described above). Three randomly ordered iv bolus loading doses (1, 2, or 4 µg/kg GH) were given on the same day followed immediately by constant iv GH infusions at corresponding rates of 0.5, 1.5, and 4.5 µg/kg·min, each continued for 240 min. Each dose infusion was stopped for 120 min before starting the next dose. Blood was sampled every 10 min for 4 h during the infusions and also during the 2-h hiatus to monitor GH’s decay from equilibrium. Steady state was determined by ANOVA of the serial serum GH concentrations over the last 90 min showing no significant drift. This inference was confirmed by linear regression defining a zero slope.
Deconvolution analysis
To compare endogenous GH half-lives with those estimated after bolus and steady state infusions (as described above), blood was sampled every 10 min overnight for 12 h (from 2000 h until 0800 h; n = 7 men). The mean (±SEM) overnight serum GH concentration in these subjects was 1.8 ± 0.36 µg/L. Twenty-three additional men were studied by 10-min blood sampling overnight to evaluate a broader range of serum GH concentrations. Multiparameter deconvolution analysis was used to calculate GH half-life, as described previously (30, 31, 32).
GH assay
Serum GH concentrations during GH infusions were quantitated by immunoradiometric assay (Nichols Institute Diagnostics, San Juan, Capistrano, CA), which had a sensitivity of 0.1 µg/L, an intraassay coefficient of variation of 5.2%, and a between-assay coefficient of variation of 8.3% (26). All serum GH concentrations were detectable during the GH infusions. Serum estradiol and progesterone concentrations were determined by RIA, as previously described (19). Samples from an individual session (involving three bolus injections or three steady state infusion doses) were assayed together.
Analytical methods
A monoexponential equation was fit to the serum GH concentration decay curves, with statistical confidence intervals calculated for the individual GH half-life estimate after each bolus injection (25, 33). The volume of distribution (liters) equals the dose (micrograms) of GH injected divided by the peak serum GH concentration achieved (micrograms per L) thereafter. The MCR (liters per min) calculated after a bolus GH injection equals the dose (micrograms) infused divided by the total area (micrograms per L/min) under the serum GH concentration vs. time (decay) curve. At steady state, the continuous iv GH infusion rate equals the product of the measured serum GH concentration (mean over the last 90 min of infusion) and the MCR, subject to the relationship: MCR = kVo, where k is the rate constant of elimination, and Vo is the distribution volume. The half-life at steady state is determined from t1/2 = ln 2/k.
F ratio testing demonstrated that for the majority (>85%) of fits, as
applied over the (narrower) physiological ranges of GH decay studied
here, addition of at least one other fitting parameter (a second rate
constant) as would be required by a biexponential (vs.
monoexponential) decay model was not justifiable statistically at
P < 0.01 (protected 
for multiple comparisons).
Statistics
Comparisons of group data from men and women were made via unpaired two-tailed Student’s t statistics, assuming unequal variances. In women, data across the same menstrual cycle were assessed by one-way ANOVA for repeated measures. Data are given as the mean ± SEM. P < 0.05 was construed as statistically significant.
The relationships between the GH half-life or MCR and the serum GH concentration at steady state were analyzed by regression of an orthogonal, second degree (quadratic) polynomial, with statistical confidence intervals determined from the joint parameter variance. Simple linear regression and Pearson’s correlation coefficient were used to evaluate an a priori null hypothesis of no relationship between the serum estradiol concentration and GH distribution volume, half-life, or MCR.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Table 1
gives the mean serum estradiol and
progesterone concentrations in the four different study groups.
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Figure 1 summarizes the peak serum
GH concentration (micrograms per L), the calculated volume of
distribution (milliliters per kg), and the monoexponential half-life of
GH elimination after bolus iv injection of each of three randomly
ordered doses (1, 2, and 4 µg/kg) of human recombinant GH in women
and men. Women’s data are means across the three stages of the
menstrual cycle (see below). ANOVA disclosed no effects of GH dose on
any kinetic measure, except (as anticipated) the maximal serum GH
concentration (P < 0.01). Hence, GH half-life values
were pooled across doses of GH. The mean half-life of GH tended to be
slightly, but consistently, lower in women than men, namely by 2.2,
1.8, and 1.1 min at respective bolus GH doses of 1, 2, and 4 µg/kg,
iv (the mean difference across all doses was, thus, 1.7 min).
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). The mean absolute volumes of
distribution (liters per subject) were 6.0 ± 1.2 in men and
4.2 ± 0.3 in women (P = NS). The uncorrected
value of the MCR in men was 748 ± 70 L/day·subject
vs. 475 ± 34 L/day·subject in women
(P < 0.001). However, the MCRs of GH in men and women
corrected per unit surface area (square meters) averaged, respectively,
336 ± 50 (men) and 330 ± 32 (women) L/m2·day
(P = NS). These relationships are summarized in Fig. 2.
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, when GH kinetics
(half-life, volume of distribution, and MCR) in women were analyzed in
relation to each of three different stages of the normal menstrual
cycle and compared with mean values in men, only GH half-life varied
significantly among the four study contexts (P =
0.040). In particular, the GH half-life was significantly lower in the
early follicular phase compared to values in men, but neither of these
two values differed significantly from that in the late follicular or
midluteal phase. GH distribution volumes, expressed as liters per
subject, exhibited no significant variations among the four study
groups. Absolute values tended (by a mean of 1.8 L) to be smaller in
women. The MCR for GH corrected per unit body surface area was
invariant of gender or stage of the menstrual cycle. This reflected the
greater surface area in men, which averaged 2.2 ± 0.2 m2vs. 1.4 ± 0.17 m2 in women
(P < 0.01).
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, which depicts serum estradiol concentrations in all bolus GH infusion
sessions in both women and men plotted against MCRs corrected per unit
surface area. Statistical analysis revealed no significant regression
in the combined group (or in data from men or women evaluated
separately). Similarly, serum estradiol concentrations were not related
to volumes of distribution regardless of whether they were corrected
for surface area (Fig. 4B). The nonequilibrium GH half-life (bolus
injection) also was statistically independent of the serum estradiol
concentration (Fig. 4C).
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). There was no significant
regression of GH half-life on peak serum GH concentration after iv
bolus GH infusions. However, the converse relationship between the MCR
(corrected per unit surface area) and serum GH concentration was
significantly negative (P < 0.05; Fig. 5B).
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We next evaluated in a subset of seven men the impact of route of
GH delivery on the GH half-life, as summarized in Fig. 6. To this end, each volunteer underwent
a study of GH half-life by each of four strategies (see Materials
and Methods). The resultant descending rank order of mean GH
half-life estimates was 1) monitored decay from equilibrium after
abrupt cessation of continuous iv GH infusions for 4 h, 2)
deconvolution analysis of endogenous (12-h overnight) GH pulsatile
profiles, 3) steady state GH half-life during the last 90 min of
continuous iv GH infusions, and 4) monoexponential disappearance rate
after bolus iv GH injection. The mean corresponding GH half-lives
values for these four paradigms were 23 ± 2.3 min (decay from
equilibrium), 18 ± 1.3 min (endogenous overnight GH secretion),
15 ± 1 min (half-life during steady state infusion), and 9.8
± 0.8 min (bolus iv GH injection; P < 0.01 via
ANOVA).
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plots the mean
(pseudosteady state) overnight serum GH concentrations for each of the
total of 30 men so studied against his individual
(deconvolution-calculated) endogenous GH half-life. Regression analysis
revealed a significantly positive correlation of GH concentration on
endogenous GH half-life (r = 0.727; P < 0.00001).
The linear regression equation was GH t1/2 =
(2.1) x (mean serum GH concentration) + 15.8 min, thus defining a
significant concentration dependence above a baseline endogenous GH
half-life of 15.8 min.
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Discussion |
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Based on the present clinical experiments, we infer that 1) women exhibit a mean nonequilibrium (bolus) GH half-life similar to (or marginally shorter than) that in men; and 2) women and men maintain statistically identical (surface area-normalized) MCRs of human recombinant GH after bolus infusion. Some earlier reported differences in (absolute) GH distribution volumes and/or (uncorrected) MCRs may thus be attributable to gender inequalities in body surface area. By implication, given indistinguishable GH kinetics in men and women across a broad physiological span of serum GH concentrations (0.5–7.5 µg/L at steady state and 17–84 µg/L after bolus GH infusion), the higher mean (24-h) serum GH concentrations that are recognized in premenopausal women vis-à-vis comparably aged men must reflect greater endogenous GH secretion rates (normalized per unit surface area) in women (2, 18, 22, 34). This central inference of increased (endogenous) GH secretion in premenopausal women compared with men was also construed recently independently by deconvolution analysis (18).
By comparing GH kinetics in the same women across the normal menstrual cycle, in which there are varying serum estradiol and progesterone concentrations, we could test for any evident dependencies of the GH distribution volume, MCR, or half-life on the female sex hormone milieu. No such relationship was apparent. Indeed, GH kinetics were invariant of serum estradiol concentrations in women or men considered separately as well as when both groups were combined (n = 70 total patient observations). Accordingly, we infer that the rate of removal of GH from the bloodstream under nonequilibrium conditions does not evidently reflect the prevailing estradiol concentration. Although these new data argue against a dominant impact of estradiol per se on the GH clearance process, to our knowledge available studies have not yet evaluated human recombinant GH removal rates in the same individual before vs. during exogenous estrogen replacement. Hence, our clinical findings do not rule out the possibility that more marked (e.g. pharmacologically induced) extremes in the estrogen milieu could influence GH disposal rates, as estradiol can modify hepatic GH receptor expression in experimental animals (2).
Comparisons of GH distribution volumes, MCRs, and half-lives at three endocrinologically definable phases of the normal menstrual cycle revealed no significant stage of cycle dependence of any of these three principal GH kinetic variables despite the expected rise in serum estradiol concentrations in the late follicular phase, with lesser, but persisting, estradiol elevations in the midluteal phase. Normal ovarian follicular cyclicity was corroborated here in each woman by serial ovarian ultrasonography and by appropriate elevations in serum progesterone concentrations in the midluteal phase. Given this menstrual cycle invariance of GH elimination kinetics, we can infer that the recognized 1.5- to 3-fold variations in (24-h mean) serum GH concentrations that evolve across the normal menstrual cycle (2, 19, 20, 21) arise mechanistically from corresponding 1.5- to 3-fold variations in daily pituitary GH secretion rates.
In both women and men, the calculated MCR of GH was inversely related to the peak serum GH concentration after bolus infusion. Our demonstration of the concentration dependence of the MCR of GH under nonequilibrium conditions is also concordant with earlier equilibrium data reported in adults and children (11) as well as with the present deconvolution-based (endogenous) GH half-lives from a total of 30 overnight serum GH pulse profiles in young men. In contrast, the monocomponent GH half-life value estimated after single bolus iv injection was not proportionate to the peak serum GH concentration. This finding might be accounted for by a relatively accelerated half-life value of initial GH disappearance due to rapid diffusion and advection of GH molecules after single bolus iv injection into a GH-deficient (octreotide-suppressed) circulatory pool (35). In contrast, both the continuous GH infusion paradigm and overnight pulsatile (endogenous) GH secretion represent more nearly steady state contexts of GH entry into and removal from the bloodstream, and both show concentration dependence.
A salient observation in the present studies, which can harmonize much of the discrepant GH kinetics literature, is that the particular time course of GH’s entry into the bloodstream strongly conditions the estimate of GH elimination. In healthy men studied by each of four distinct and randomly ordered experimental strategies, we demonstrated a rank order of GH half-lives as follows: 1) monitored decay from established equilibrium infusions (GH half-life, 23 ± 2.3 min), 2) deconvolution analysis of overnight profiles of endogenously secreted GH (18 ± 1.3 min), 3) GH’s removal during continuous (steady state) infusions (15 ± 1 min), and 4) GH’s elimination after bolus iv GH injection (9.8 ± 0.8 min). These significant (mean, 2.4-fold) variations in GH half-life in the same individual may explicate inconsistencies among earlier reports of GH half-lives, which have varied in absolute range from approximately 5–33 min in healthy humans (6, 7, 8, 10, 11, 13, 14, 19, 26, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45). The presence of a physiological, finite capacity, but high affinity, GH-binding protein in human plasma, along with the expected properties of GH’s association with and dissociation from this GH-binding protein and/or relevant tissue GH receptors, probably account for the dependence of half-life estimates on GH’s mode of entry into the bloodstream (25, 46). In addition, assay discrepancies and variable endogenous GH secretion during studies that did not use octreotide probably contribute further to the variability among earlier published reports of GH half-life (47).
Several important considerations emerge from the present clinical studies. First, the 50% reduction in estimates of GH half-life calculated after bolus iv injection (compared with values estimated during decay from steady state) would overestimate the pseudosteady state GH production rate in health and/or pathophysiology by as much as 2-fold. Second, sex and menstrual cycle stage differences in serum GH concentrations mirror true differences in pituitary GH secretion rates. And, third, GH half-lives calculated under different clinical conditions are not interchangeable, as such values can be discrepant by severalfold (mean, 2.4-fold; range, 1.5–3.2-fold) in the same individual. Therefore, we recommend that GH kinetics be determined in clinical contexts that match their later anticipated use when calculating GH secretion.
In summary, menstrual cycle stage, gender, and serum estradiol concentrations in young women and men do not significantly influence estimates of the GH distribution volume, half-life, or MCR. On the other hand, the MCR of GH after bolus injection and at pseudosteady state is inversely correlated to the plasma GH concentration in both men and women, suggesting partial saturability of in vivo GH removal from plasma, processes at higher circulating GH concentrations. The time mode of entry of GH into the bloodstream significantly governs the determinable half-life of GH removal, with the following declining rank order of GH half-lives: decay from (infused) equilibrium, elimination of endogenously secreted GH, removal from plasma of GH during steady state infusion, and disappearance of GH after iv bolus injection. Accordingly, caution should guide any interpretation or application of GH kinetics that are inferred under clinicopathological conditions different from those in which GH secretion is estimated. Clinical extrapolation of GH elimination rates across disparate study contexts could introduce a significant error in estimating GH secretion in human health or disease.
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Acknowledgments |
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Footnotes |
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2 Current address: 95 Bulldog Boulevard, Sheridan Building, Suite
101, Melbourne, Florida 32903.
Received November 30, 1998.
Revised March 4, 1999.
Accepted April 21, 1999.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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