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Original Studies |
Departments of Pediatrics and Physiology, University of Turku (M.B.), FIN-20520 Turku. Finland; the Division of Endocrinology, Department of Internal Medicine, and National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center (W.S.E., C.P., A.P., J.D.V.), Charlottesville, Virginia 22908; and the Endocrine Section, Medicine Service, Salem Veterans Affairs Medical Center (A.I.), Salem, Virginia 24513
Address all correspondence and requests for reprints to: Dr. J. D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Box 202, McKim Hall, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. E-mail: jdv{at}virginia.edu
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Abstract |
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Thus, short-term (2.5-day) fasting during the sex steroid-replete midluteal phase of the menstrual cycle in healthy young women profoundly suppresses 24-h serum leptin and insulin (and to a lesser degree, IGF-I) concentrations, augments cortisol release, but fails to alter daily LH, estradiol, or progesterone concentrations. In contrast, the GH axis exhibits strikingly amplified pulsatile secretion, increased nyctohemeral rhythmicity, and marked disorderliness of the release process. We conclude that the somatotropic axis is more evidently vulnerable to short-term nutrient restriction than the reproductive axis in steroidogenically sufficient midluteal phase women. This study invites the question of whether normal (nutritionally replete) GH secretory dynamics can be restored in fasting women by human leptin, insulin, or IGF-I infusions.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In recent studies of young menstruating women, Loucks and Heath (11) described reduced LH pulse frequency during waking hours and increased LH pulse amplitude during sleep in response to dietary restriction (10 Cal/kg lean body mass·day). In other studies in the midfollicular phase of the menstrual cycle, a 3-day fast also decreased the number of LH pulses, but failed to affect mean or integrated serum LH concentrations or LH pulse amplitude (9). A recent analysis by Alvero and co-workers (6) revealed that a 3-day fast during the follicular phase in lean (body mass index, 20 kg/m2 or less) healthy young women suppressed the number of LH pulses without altering mean serum LH concentrations, LH peak amplitude, ovarian follicle development, or follicular phase length. In contrast, to our knowledge, there are no detailed studies of pulsatile LH (and GH) secretion in fasting young women evaluated during the midluteal phase of the menstrual cycle. This neuroendocrine interval after ovulation is of particular reproductive interest, because it represents a sex steroid-enriched milieu that occupies approximately 2 weeks of each normal menstrual month and serves necessarily to prepare the endometrium for blastocyst implantation.
Here we investigated the effects of short term (2.5-day) fasting on pulsatile GH and LH secretion in eight healthy young women during the sex steroid-replete midluteal phase of the normal menstrual cycle. We used deconvolution analysis of 24-h serum GH and LH concentration time series to provide estimates of GH and LH secretory activity in vivo (14). In complementary analyses of nonpulsatile features of LH and GH release, we applied cosinor analysis to assess nyctohemeral rhythmicity (15), and the approximate entropy (ApEn) statistic to quantitate the serial orderliness of the LH and GH release process (16, 17, 18).
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Subjects and Methods |
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Eight young healthy women within ±25% of normal body weight (body mass index, 21 ± 1.3 kg/m2; range, 20–24 kg/m2) and aged 21–28 yr were studied after providing written informed consent approved by the human investigation committee of the University of Virginia (Charlottesville, VA). No woman was a smoker, was taking birth control pills or other medications, had undertaken recent transmeridian travel of three or more time zones for at least 2 weeks, or had a remarkable clinical history or physical examination. Each volunteer had normal adult sexual maturation; regular (28 ± 3-day) menstrual cycles; normal biochemical tests of renal, hepatic, metabolic, and hematological function; and normal fasting serum concentrations of total and free T4, TSH, GH, PRL, estradiol, immunoreactive LH and FSH, and insulin-like growth factor I (IGF-I).
The volunteers were admitted to the General Clinical Research Center of the University of Virginia during the midluteal phase (days 5–8 after ovulation) of the menstrual cycle (see below) on the night before blood sampling in the fed state, and again for 1 1/3 days (32 h) before beginning 27 h of blood sampling (32–56 h of fasting) in the 2.5-day fasting session. Ovulation was documented during the study cycle by the development of a normal preovulatory follicle, followed by its disappearance, as characterized via daily or alternate day transvaginal ovarian ultrasonography. The fed and fasting admissions were assigned in randomized order at least 1 month apart.
In both the fed and fasted states, blood sampling was carried out at 10-min intervals for 27 h beginning at 0800 h starting at least 1 h after venipuncture. After sampling for 24 h, a single pulse of 10 µg GnRH was given iv, followed by 3 h more of every 10-min blood withdrawal. Blood was withdrawn through an iv catheter placed in a forearm vein, and samples were allowed to clot at room temperature. The subsequent sera were frozen at -20 C for later hormone assays. Subjects remained in a bed or chair during sampling, except for bathroom privileges. In the fed state, three isocaloric meals were given per day (at 0800, 1200, and 1800 h). During the 2 1/2-day fast, volunteers received caffeine- and calorie-free liquids only, slept in the Clinical Research Center, and had urinary ketone levels monitored daily to assess compliance with the fast. All patients maintained positive urinary ketones consistently throughout the fast. Potassium chloride (40 mEq) and water-soluble vitamins were administered orally daily.
Assays
Serum GH concentrations were measured in each sample in duplicate by an automated ultrasensitive GH chemiluminescence assay (modified Nichols Luma Tag hGH assay; sensitivity, 0.005 µg/L) with human recombinant GH (22,000 Da) as standard, as described previously (19, 20). The median inter- and intraassay coefficients of variation were less than 7.2% in these studies. Serum LH concentrations were measured in each sample in duplicate by a two-site immunoradiometric assay (IRMA; Nichols Institute Diagnostics, San Juan Capistrano, CA), as reported previously (21). The median inter- and intraassay coefficients of variation were less than 8.5% for these studies. The sensitivity of the assay was 0.20 IU/L, using the Second International Reference Preparation. All 169 serum samples from each admission were assayed together. Serum leptin concentrations were measured in a single 24-h pool of serum from each subject in duplicate by RIA, as previously described (22). As control hormones, FSH, estradiol, progesterone, PRL, IGF-I, cortisol, and insulin were also assayed by RIA, chemiluminescence assay, or IRMA in a single 24-h pool of serum from each subject (4, 8, 13).
Deconvolution analysis
Multiparameter deconvolution analysis was used to estimate subject-specific features of pulsatile LH and GH secretion and half-life (14, 23, 24). This technique resolves the serum hormone concentration profile into its constituent secretory contributions and simultaneously estimates the hormone half-life. Daily (24-h) pulsatile secretion rates are derived as the product of secretory burst frequency and the mean mass of GH or LH released per secretory event. The mass of hormone released per burst is the analytical integral of the calculated secretory pulse. Deconvolution analysis was carried out at 95% joint statistical confidence intervals for all calculated secretory burst amplitudes with the technician blinded to the randomized order of the fed vs. fasted admissions. A common half-life and secretory burst duration were calculated for each time series. After deconvolving the entire 27-h time series of serum LH concentrations, statistical analyses were applied to the 24-h baseline (spontaneous) and the 3-h post-GnRH segments separately. Only the 24-h baseline (pre-GnRH) injection serum GH samples were assayed and analyzed.
Nyctohemeral (24-h) rhythmicity
Diurnal rhythms of serum GH and LH concentrations were appraised by cosinor analysis, as described previously (8, 15). Cosinor analysis simply entails trigonometric regression of a 1440-min cosine function on the full 24-h serum hormone concentration vs. time profile.
Statistical analyses
Differences between fed and fasted deconvolution measures were assessed using a paired two-tailed nonparametric (Wilcoxon) test. Mean (24-h) concentration values were compared via paired two-tailed Student’s t testing. Results are presented as the mean ± SEM (and median). Statistical significance was accepted at P < 0.05.
ApEn
ApEn was used as a scale- and model-independent statistic to quantitate the serial orderliness or regularity of GH and LH release over 24 h. Normalized ApEn parameters of m = 1 and r = 20% of the intraseries SD were used, as previously described (18, 25). ApEn is hence designated ApEn (1, 20%), which estimates the regularity of subordinate sample to sample (nonpulsatile) patterns in the data, and as such yields information complementary to cosinor and deconvolution (pulse) analyses. Higher absolute ApEn values denote greater disorderliness or irregularity of neurohormone release, as observed in acromegaly (17); Cushing’s disease (26, 27); aldosteronoma (28); the aging LH (18), GH (29), and insulin (30) axes; and the GH axis for women compared to men (25).
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Results |
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The 2.5-day fast resulted in a consistent (mean 3.1-fold) increase
in 24-h mean serum GH concentrations (from 1.7 ± 0.27 to 5.3
± 0.76 µg/L; P = 0.0014). Twenty-four-hour
integrated serum GH concentrations rose commensurately
(P < 0.001; Table 1
).
None of the serum GH concentrations in any of the eight women was
undetectable during either admission.
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).
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The 24-h profiles of serum GH concentrations, which were visually
pulsatile in both the fed and fasted state(s), and
deconvolution-resolved GH secretory rates from three women in the
midluteal phase of the menstrual cycle are illustrated in Fig. 1. The quantitative changes in specific
attributes of deconvolution-estimated GH secretion and half-life are
summarized in Table 1
. The half-duration (the duration at half-maximal
amplitude) of computed GH secretory bursts and the calculated GH
half-life did not change significantly in response to fasting for 2.5
days. The number of GH secretory pulses with statistically nonzero
amplitude also remained unchanged in response to a 2.5-day fast,
viz. 24 ± 1.1 (median 23.0) in the fasted state and
20 ± 1.6 (median 18.5) secretory bursts/24 h during the fed study
(P = NS). The mean GH intersecretory burst interval
averaged 75 ± 7.4 (median, 73.2) min in the fed study and 60
± 2.6 (median, 59.7) min in the fasted session (P =
NS; Table 1.). On the other hand, the mass of GH secreted per burst
(area of the calculated GH secretory pulse) rose significantly from
4.9 ± 0.88 (median 4.2) µg/L in the fed session to 11.5 ±
2.1 (median 11.0) µg/L in the fasted environment (P
< 0.01; Fig. 2A). The higher mass
reflected an increase in GH secretory burst amplitude (maximal rate of
calculated GH secretion attained within a release episode) during
fasting [namely, fed amplitude, 0.15 ± 0.02 (median, 0.15);
fasted, 0.35 ± 0.06 (median, 0.34) µg/L·min;
P < 0.01].
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). Nyctohemeral rhythms of GH secretion
The 24-h variation(s) in serum GH levels were appraised using
cosinor analysis. Maximal serum GH concentrations occurred between
(95% confidence intervals) 0052–0252 h in the fed state and between
2305–0133 h in the fasted state (P = NS).
Fasting-induced increases were observed in the mesor (average value
about which the diurnal rhythm oscillates; namely, fed mesor, 0.21
± 0.04; fasted, 3.1 ± 0.69 µg/L; P < 0.01)
and the amplitude (half of the absolute difference between the nadir
and peak value; fed, 0.10 ± 0.04; 1.4 ± 0.43 µg/L;
P < 0.01; see Fig. 3 for
individual values).
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ApEn for GH averaged 0.565 ± 0.047 during the fed admission
and increased significantly to 1.202 ± 0.076 during the fasting
period (P = 0.005; see Fig. 2C for individual
values).
Pulsatile LH secretion
Specific attributes of deconvolution-estimated LH secretion and
half-life are summarized in Table 3.
Illustrative profiles for three women are shown in Fig. 4. The total daily calculated LH
secretion rate decreased by 33% during the 2.5-day fast (Table 3).
Short term fasting did not affect mean serum LH concentrations or any
other parameter of deconvolution-estimated LH secretion or ApEn (Table 3).
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).
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). The calculated LH secretory burst
amplitude after GnRH increased significantly during fasting.
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As shown in Fig. 5, serum (24-h)
mean concentrations of leptin, IGF-I, and insulin all fell
significantly (respectively, P = 0.0003, 0.027, and
0.0018), whereas cortisol rose (P = 0.0003)
markedly.
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The correlations between serum cortisol and GH concentrations are
shown in Fig. 6 in the fed vs.
fasting states.
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Discussion |
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The fasting-induced rise in the mass of GH secreted per burst suggests, but does not prove, that fasting suppresses the amount (but not necessarily the duration or frequency) of somatostatin released, possibly while concomitantly increasing GHRH secretion (31). In contrast to the midluteal phase women studied here, young women studied during the (early or mid) follicular phase of the menstrual cycle by IRMA failed to show a GH elevation during a 3-day fast (6, 9). We do not know whether this disparity reflects the assay distinctions and/or higher basal (fed) GH secretion rates encountered in the luteal (than early follicular) phase of the menstrual cycle (32). Indeed, the relationship between fasting-induced GH elevations and the sex steroid milieu is not well defined to our knowledge. However, estrogen status critically controls basal pulsatile GH secretion (20, 25, 31, 32, 33, 34, 35, 36).
The calculated GH half-life was unaffected by short term fasting, although GH kinetics are controlled long term by body mass. For example, deconvolution-based and direct estimates of infused GH half-life are shorter in obese subjects (37, 38), and GH half-life correlates negatively with the percent body fat (34). Both fed and fasting GH secretion rates are related to body mass and fat distribution, as the estimated amount of GH secreted per day during fasting even in young normal weight men negatively correlates with the degree of relative adiposity (2). Analogously, analysis of GH secretion in a larger cohort of (fed) middle-aged men and women showed that higher daily GH secretion rates in premenopausal women than in men (35) could be accounted for statistically by sex differences in visceral adiposity (determined by computed tomographic scanning) (39). These data suggest that the known body compositional distinctions between men and women (40) may modulate GH secretory responses to the metabolic stressor of fasting in the two sexes.
The exact metabolic signals that mediate fasting-associated GH hypersecretion in the human remain unknown. Several postulates are that IGF-I, insulin, and/or leptin are involved. For example, the fasting-induced fall in serum IGF-I concentrations may promote GH hypersecretion, because iv IGF-I infusion rapidly inhibits GH hypersecretion in the fasting human (41). Here, short term fasting reduced 24-h mean serum IGF-I concentrations in the midluteal phase women. Analogously, in the follicular stage of the menstrual cycle, Loucks et al. (11) and Olson and colleagues (9) reported a decrease in circulating IGF-I during dietary restriction. As pulsatile GH secretion can rise before total serum IGF-I concentrations fall significantly (7), changes in free IGF-I may be relevant; notably, this may occur as fasting rapidly increases IGF-binding protein-1 concentrations via reduced insulin levels (31). Fasting may also attenuate a putatively direct pituitary inhibitory effect of insulin on GH secretion (42), although moderate hyperinsulinemia did not suppress GH secretion in fasting men (41).
In the rodent, leptin strongly interacts with the GH and LH axes. However, in the male rat, unlike in the human, GH secretion declines with fasting, and leptin infusions then stimulate GH release (43). In contrast, leptin and GH concentrations vary inversely in the fed human (1), suggesting an inverse relationship. In the rat, leptin probably inhibits somatostatin secretion and gene expression acting via full-length leptin receptors expressed in the hypothalamus (43, 44, 45, 46, 47, 48, 49, 50). Leptin also inhibits the hypothalamic expression of orexigenic peptides, such as neuropeptide Y (44, 48, 51), which can regulate both GH and LH secretion. In the latter situation in the mouse and rat, leptin stimulates hypothalamic GnRH secretion (52, 53, 54, 55). Unlike its stimulation of the GH and LH axes, leptin antagonizes stress activation of the rodent corticotropic axis (56, 57). In the human, leptin concentrations also tend to vary inversely with pituitary-adrenal activity (58, 59). Conversely, leptin reverses starvation’s inhibition of the thyroidal axis through its facilitative actions on TRH-secreting neurons (45). Thus, although not established in the human, at least in murine species, prominent stress-adaptive metabolic actions of leptin on hypothalamic regulatory sites may account for various (e.g. fasting) adaptations of the GH, LH, ACTH, TSH, and other axes.
Analyses of the nonpulsatile (entropic) facet of GH release via the ApEn statistic showed greater disorderliness of the GH secretory process in fasting (than fed) women. Irregular GH release was observed recently in fasting follicular phase women who underwent IRMA (rather than chemiluminescence-based assay) of GH (17). Earlier appraisal of entropic GH release revealed a sex difference, in that (fed) young and middle-aged women have more irregular GH release patterns than men (25, 39). Oral administration of ethinyl estradiol to prepubertal girls with Turner’s syndrome elicited greater disorderliness of GH release, indicating that estrogen per se damps the regularity of GH secretion (36). Age and (visceral) adiposity are also associated with reduced orderliness (higher ApEn) of GH release in the human (34, 39). As ApEn is believed to reflect complexity of neuroendocrine feedback inputs within a network (60), the rise in GH ApEn with fasting in women points to altered GHRH/somatostatin-GH-IGF-I feedback control during nutrient withdrawal even in the female human with basally higher ApEn than men.
Although the orderliness of LH release patterns increased significantly (lower ApEn) during a 3.5-day fast in young men and failed to rise similarly in older men (13), here we observed no significant changes in LH ApEn during short term fasting in young midluteal phase women (six of eight women showed a decline in ApEn; P = NS). The latter results may reflect the small group size, or the unchanged serum sex steroid (progesterone and estradiol) concentrations in fasting midluteal phase women. On the other hand, in men, the fasting-associated enhancement in the orderliness of LH release may reflect the evident withdrawal of testosterone’s negative feedback actions on the gonadotropic axis (5, 8, 12, 13). Midluteal phase women seem to be protected from feedback withdrawal by their unvarying progesterone concentrations. According to this speculation, the decreased entropy or LH release in fasting men mirrors sex steroid feedback withdrawal, not fasting per se (60).
Short term fasting significantly increased nyctohemeral rhythmicity of GH release in young midluteal phase women, which, to our knowledge, represents a novel finding. The stability of GH acrophase (timing of maximal serum GH concentration) suggests preservation of sleep-entrained GH secretion in fasting women (61), although sleep was not monitored formally here.
Our data allow the new thesis that pulsatile LH secretion, unlike GH release, is relatively resistant to the suppressive effects of short term (2.5-day) fasting in young women in a sex steroid-replete milieu (e.g. midluteal phase). There were no statistically significant changes in deconvolution-analyzed LH pulse frequency, mass, amplitude, duration, or half-life, although the calculated daily total LH secretion rate fell. More prolonged fasting might have suppressed LH release more in some or all individuals, although we have no data on this conjecture. Short term fasting also did not affect 24-h mean serum estradiol or progesterone concentrations, whereas in healthy young men, a 3.5-day or longer fast significantly (by 35–50%) reduces 24-h mean serum total and free testosterone concentrations (5, 12). In contrast, more prolonged food restriction typically inhibits reproductive function in men and women (for review, see Ref. 3). Indeed, prolonged malnutrition, such as that developing in anorexia nervosa and chronic illness, commonly evokes hypothalamic amenorrhea and lowers serum leptin concentrations (62; for review, see Ref. 63). Shorter intervals of food withdrawal seem to suppress reproductive function more variably in women. In the latter context, some studies in women report fasting-induced decreases in LH pulse frequency (6, 9, 11), whereas others disclose no change (present data and Ref. 64). Soules and co-workers (64) reported that nutrient-restricted women maintain physiologically varying concentrations of LH, FSH, estradiol, and progesterone throughout the menstrual cycle and ovulate. Alvero et al. (6) also described preserved mean serum LH concentrations, orderly follicle development, and normal follicular phase length during a 72-h fast. Our analysis disclosed a small, but significant (25%), decrease in serum FSH concentrations (P = 0.044), which would be important to confirm or refute in additional studies. The biological impact of this change in the midluteal phase on the next cycle is not yet known.
Some of the reported nonuniformities of LH axis responses to fasting in women may reflect experimental differences. For example, Loucks et al. (11), Olson et al. (9), and Alvero et al. (6) analyzed pulsatile LH release via the Cluster algorithm, compared to deconvolution analysis in the present study. Olson and co-workers (9) used a relatively short 8-h sampling period, whereas Loucks et al. (11), Alvero et al. (6), and our group collected blood every 10 min for 24 h. In the study of Loucks et al. (11), dietary energy intake was limited to either 10 or 45 Cal/kg lean body weight·day, whereas complete nutrient withdrawal for 2.5–3 days was used here and by Olson et al. (9) and Alvero et al. (6). Alvero and co-workers (6) studied eight lean women (mean age, 28 yr), but only five individuals completed both the fed and fasted sessions. All of the above studies employed a LH IRMA. Despite these paradigmatic differences and the relatively small number of women studied to date, we interpret the available data to indicate that short term fasting in young menstruating women often decreases the frequency of pulsatile LH secretion in the follicular phase, but evidently not in the luteal phase, of the normal menstrual cycle.
A 2.5-day fast markedly suppressed 24-h mean serum leptin concentrations in midluteal phase women. This finding is distinct from but consistent with the recent report of Weigle and co-workers (65), who demonstrated a decrease in leptin in nonobese women in response to a weight reduction. Although phase of the menstrual cycle was not given, other studies also recognized a decline in leptin levels in premenopausal women during short term fasting (66, 67, 68). In relation to possible sex hormone modulation of leptin secretion, Shimizu et al. (69) noted that leptin is significantly higher in the luteal than the follicular phase. This inference was confirmed by Hardie et al. (70), who positively correlated serum leptin and progesterone concentrations. In studies that sampled leptin and LH every 7 min for 24 h in healthy young women, Licinio et al. (22) recently observed an inverse correlation between LH and leptin release, especially at night. Earlier, we discerned a negative statistical correlation between the 24-h serum concentration of this nutritional signaling peptide and GH secretion in older fed women (1). Although results in the fasting male rodent suggest a (positive) neuroendocrine interaction between leptin and the GH axis (43, 46), in fasting women we identify an opposite (inverse) relationship. This contrast probably reflects species distinctions (31). Indeed, food restriction increases GH secretion in the human (2, 7, 10, 41), sheep (71), cow (72), dog (73), rabbit (74), and chicken (74), but paradoxically decreases GH release in the rat (75). In the dog, both GH pulse frequency and amplitude rise during fasting (73), whereas only GH pulse amplitude increases in the sheep (71) and steer (72). Nutritional restriction may increase the GH half-life in sheep and calves (76), but not in chickens (77) or humans (present data and Refs. 2, 10). Thus, dynamic GH axis responses to the stress of fasting show species differences, prompting the need for clinical studies to evaluate human nutritional susceptibilities.
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Acknowledgments |
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Footnotes |
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References |
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