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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 5 1543-1548
Copyright © 1997 by The Endocrine Society

Reproductive Endocrinology

Pulsatile Intravenous Gonadotropin-Releasing Hormone Administration Averts Fasting-Induced Hypogonadotropism and Hypoandrogenemia in Healthy, Normal Weight Men1

J. A. Aloi, M. Bergendahl, A. Iranmanesh and J. D. Veldhuis

Division of Endocrinology, Department of Internal Medicine, National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center (J.A.A., J.D.V.), Charlottesville, Virginia 22908; the Departments of Pediatrics and Physiology, University of Turku (M.B.), FIN-20520 Turku, Finland; and the Endocrine Section, Medical Service, Veterans Affairs Medical Center (A.I.), Salem, Virginia 24153

Address all correspondence and requests for reprints to: Dr. J. D. Veldhuis, Division of Endocrinology, Department of Internal Medicine, Box 202, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. E-mail: JDV{at}Virginia.Edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Fasting or severe caloric restriction in the human or experimental animal suppresses serum LH and sex steroid concentrations. In healthy men undergoing prolonged (5-day) nutrient deprivation, the daily LH secretion rate, the mass of LH secreted per burst, and the serum testosterone concentration fall markedly, with no decrease in responsiveness to a single bolus of GnRH. Here we test the hypothesis that the hypogonadotropic hypoandrogenemia accompanying fasting reflects decreased endogenous GnRH release. To this end, six healthy young men were studied on a fed day and during two 83-h fasting sessions with concurrent saline or pulsatile GnRH administration (100 ng/kg, iv, every 90 min for 24 h) followed by a single bolus of 10 µg GnRH, iv, to evaluate pituitary responsiveness. We employed a highly sensitive LH immunoradiometric assay, which correlates well with an in vitro Leydig cell bioassay, and deconvolution analysis to calculate in vivo LH secretory burst frequency, amplitude, duration, mass, and LH half-life. Fasting resulted in 30–50% declines in serum total and free testosterone and LH concentrations, and a 3-fold decrease in the calculated 24-h LH secretion rate (fed, 42 ± 12; fasting, 14 ± 1.9 U/L distribution volume·day; mean ± SEM; P < 0.05, by ANOVA). Reduced LH secretion was accounted for by dual mechanisms, viz. a fall in both the apparent number of computer-resolved LH secretory bursts per 24 h (fed, 16 ± 1.1; fasting, 10 ± 1.2; P < 0.01) and the mass of LH secreted per burst (fed, 2.5 ± 0.5; fasting, 1.5 ± 0.1 U/L; P < 0.05). Fasting also decreased the mean value of the 24-h (nyctohemeral) rhythm in serum LH concentrations and reduced the approximate entropy (disorderliness) of LH release. Exogenous pulsatile GnRH injections prevented both the reduction in the calculated daily LH secretion rate (fed, 42 ± 12; fasting plus GnRH, 64 ± 16 IU/L; P = NS) and the decline in serum testosterone concentrations (fed, 556 ± 71 ng/dL; fasting, 391 ± 41; fasting plus GnRH, 859 ± 65). Pulsatile GnRH treatment also restored the nyctohemeral mesor of serum LH concentrations and the approximate entropy value to baseline. Administration of a submaximal dose of exogenous GnRH (10 µg, iv) at the end of the fasting interval revealed statistically identical LH release in the three study groups, suggesting that pituitary responsiveness to GnRH was unchanged in this paradigm.

In summary, a pulsatile iv GnRH infusion in young men averts completely the fasting-induced decline in LH secretory burst mass/amplitude and frequency, reinstates serum total and free testosterone concentrations, and restores the mesor of LH’s nyctohemeral rhythmicity and the approximate entropy of LH release. Rescue of hypogonadism by pulsatile GnRH stimuli supports the thesis that nutrient withdrawal decreases the output of the human hypothalamic GnRH burst generator.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MALNUTRITION suppresses the reproductive axis in mammals (1, 2; for review, see Ref. 3). In humans, short term nutrient deprivation leads to decreased gonadotropin concentrations (4, 5). Suppression of the hypothalamic release of GnRH is a plausible central mechanism subserving fasting-induced hypogonadotropism (4, 5, 6, 7, 8). Indeed, in the rat and sheep, fasting-associated reductions in gonadotropin release are accompanied by decreased pituitary stores of LH and increased hypothalamic content of GnRH, suggesting decreased GnRH secretion (6, 9, 10, 11, 12).

Recently, several investigators have delineated the acute effects of fasting on the physiologically pulsatile mode of secretion of LH and testosterone in the human and rodent (4, 5, 12, 13). The hypothesis that acute caloric restriction attenuates LH secretion by reducing endogenous GnRH release is supported by observations in these species demonstrating that the LH secretory response to exogenous GnRH is similar in the fed and fasting states (4, 14, 15, 16). In addition, as caloric restriction does not appear to alter the half-life or MCR of LH (4, 14), the decline in serum LH concentrations apparently reflects decreased endogenous (GnRH-driven) pituitary gonadotropin secretion.

Deconvolution analysis of the serum LH concentration time series provides an estimate of LH secretory events in vivo and thereby allows an assessment of the effects of fasting on LH (and, thus, indirectly on GnRH) production (17, 18). We have previously shown that 5 days of nutrient deprivation in young men attenuate the mass of LH released per burst without altering LH secretion after a single bolus injection of GnRH or LH half-life, as assessed by 5-min blood sampling over 24 h (4). To investigate the role of GnRH deficiency in the hypogonadism of short term fasting, here we studied six healthy young men during an 83-h fast with and without the concomitant iv administration of pulsatile GnRH during 56–80 h of fasting. We predicted that this experimental paradigm would normalize both LH and testosterone secretion if GnRH deficiency is the primary and immediate basis for hypogonadism.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Clinical protocol

Six healthy men within 25% of normal body weight and with a mean age of 25 ± 2.6 yr (range, 22–37 yr) volunteered for study. Each subject had a normal physical exam, was taking no medications except for acetominophen, and provided written informed consent, as approved by the human investigation committee of the University of Virginia. Volunteers were admitted to the General Clinical Research Center the night before blood sampling in the fed state and again for 2 1/3 days (56 h) before 27 h of 10-min blood sampling (56–83 h) for each of the two fasting sessions (saline vs. GnRH treatment). The admission order was randomized, and studies were separated by at least 4 weeks. For the GnRH (vs. saline) pulsatile infusions, beginning at 0800 h, 100 ng/kg GnRH (or saline) were injected every 90 min by iv bolus during the 24 h spanning 56–80 h of the fasting sessions, followed by a single pulse of 10 µg GnRH and 3 more h of 10-min blood withdrawal (see below). Blood was withdrawn through an indwelling catheter placed in a forearm vein, and samples were allowed to clot at room temperature. The sera obtained were frozen for later analysis. Subjects remained in bed or a chair during sampling and in the fed state were given three meals per day (0800, 1200, and 1800 h).

Each man had normal baseline biochemical tests of renal, hepatic, metabolic, and hematological function and normal morning serum concentrations of T4, TSH, PRL, estradiol, free and total testosterone, immunoreactive LH and FSH, and insulin like growth factor I.

During the fast (total, 83 h), the volunteers received caffeine- and calorie-free beverages only, slept at the General Clinical Research Center, and had urinary ketones and body weights monitored daily to assess compliance with the fast. Potassium chloride (40 mEq) and water-soluble vitamins were administered daily, as described in our prior studies (4, 19, 20, 21).

Assays

Serum LH concentrations were determined in each sample in duplicate by a two-site immunoradiometric assay (IRMA; Nichols Laboratories, San Juan Capistrano, CA), as described previously (22). This assay correlates well (P < 0.001) with an in vitro Leydig cell LH bioassay over the range 2–100 IU/L (22). The median inter- and intraassay coefficients of variation were less than 8.5% for these studies. All samples in each admission were assayed together. The sensitivity of the assay was 0.20 U/L, using the First International Reference Preparation. Serum total and free testosterone, cortisol, and other endocrine parameters were assayed in a single 24-h pool of sera from each subject, as described previously (4, 19).

Deconvolution analysis

Deconvolution analysis was used to express the entire 27-h serum LH concentration vs. time course in terms of four secretory and clearance measures of interest: 1) the number and locations, 2) the amplitudes, and 3) the duration of randomly dispersed LH secretory bursts, acted upon by 4) an endogenous, single component, subject-specific half-life of LH removal (17, 23). A maximal basal secretion rate was estimated concurrently with other secretory measures using stringent peak-amplitude criteria (P < 0.05, by Monte Carlo joint parameter statistical confidence interval). Deconvolution analysis was carried out with the operator blinded to the randomization. After deconvolving the entire 27-h time series of serum LH concentrations, statistical analysis was applied to the 24-h baseline (spontaneous) and the 3-h post-GnRH segments separately.

Statistical analysis

ANOVA was used to test for treatment effects after logarithmic transformation of the LH secretory measures and half-life. P < 0.05 was considered statistically significant. Post-hoc comparisons were made using the Tukey procedure.

Approximate entropy (ApEn) was used as a scale- and model-invariant statistic to quantify the serial orderliness or regularity of the LH release process over 24 h. Here, ApEn parameters of m = 1 and r = 20% of the intraseries SD were used, as previously described (24, 25). ApEn estimates the regularity of subordinate nonpulsatile patterns in the data.

Diurnal rhythms of serum LH concentrations were assessed by cosinor analysis (4, 19, 21). This entails curve-fitting the 24-h LH profile to a 1440-min cosine function, with estimates of the acrophase (time of maximal concentrations), mesor (mean level about which the 24-h rhythm oscillates), and amplitude (difference between maximal LH concentration and mesor, in international units per L).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go summarizes selected endocrine parameters. Both total and free testosterone (see Fig. 1Go) fell by 30% during the fast, whereas serum cortisol increased by 40%. All subjects developed a mild metabolic acidosis with ketonuria.


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  		Table 1. Endocrine-metabolic measures in fed and fasting young men

 


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  		Figure 1. Serum (pooled 24-h) total and free testosterone concentrations in six healthy young men in the fed vs. fasted (56–83 h) states without or with pulsatile iv GnRH treatment during 56–80 h of the fast. Data are the mean ± SEM. *, P < 0.05 vs. fed state. **, P < 0.05 vs. fasted condition. To convert nanograms per dL or picograms per mL testosterone to nanomoles per L or picomoles per L, respectively, multiply by 0.03467 or 3.467.

 
Pulsatile LH secretion

Mean serum LH concentrations over 24 h and daily LH secretory rates fell significantly (Table 1Go). In contrast to testosterone concentrations, estradiol and FSH levels did not vary significantly. Figure 2AGo shows the (24-h) serum LH (IRMA) concentrations in three volunteers with their matching deconvolution-calculated LH secretory profiles (Fig. 2BGo). Specific attributes of deconvolution-estimated LH secretion and half-life are summarized in Table 2Go. Pulsatile GnRH treatment during fasting restored all of the foregoing altered measures of the gonadotropic axis to or above baseline (fed) levels (P = NS vs. baseline). Cortisol concentrations and ketonuria were not influenced by GnRH treatment.



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  		Figure 2. Illustrative serum LH concentration profiles obtained by sampling blood at 10-min intervals for 24 h in fed and fasting young men without or with pulsatile iv GnRH treatment. Fasting was carried out for 83 h. Intravenous GnRH (vs. saline treatment) was administered during 56–80 h of fasting at a dose of 100 ng/kg every 90 min. Mean data from all six subjects are presented in Table 2Go. A, The observed serum LH concentration profiles and the deconvolution-predicted fits (continuous lines). B, The calculated pulsatile LH secretory rates appraised by deconvolution analysis.

 

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  		Table 2. Deconvolution estimates of LH secretion and half-life in fed and fasting men

 
LH secretion after a single (exogenous) bolus injection of 10 µg GnRH, iv, was unaltered by fasting compared to that during the fed or fasted plus pulsatile GnRH treatment session (see Fig. 3Go).



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  		Figure 3. Individual LH secretory responses to a single bolus injection of 10 µg GnRH, iv, at the conclusion of the studies (80 h of fasting). The deconvolution-calculated mass of LH secretion (international units of LH secreted per L distribution volume/burst) during 80–83 h of the fast is shown as stimulated by the GnRH bolus. The group mean value is represented by an X.

 
ApEn

ApEn averaged 1.222 ± 0.134 during the fed admission and fell to 0.977 ± 0.092 with fasting (P = 0.002), but was restored to the basal value (1.550 ± 0.092) by pulsatile GnRH infusions (P = NS vs. baseline).

Cosinor analysis

The 24-h rhythms of serum LH concentrations had mean amplitudes in the fed, fasting, and treated sessions of 0.90 ± 0.46, 0.50 ± 0.05, and 0.41 ± 0.19 U/L (P = NS). Corresponding clock times of maximal nyctohemeral rhythm values were 0530 (±125 min), 0557 (±129 min), and 0657 (±198 min) h (P = NS). The mesors averaged 3.3 ± 1.2 (fed), 0.88 ± 0.07 (fasting; P = 0.028 vs. fed), and 5.6 ± 1.5 (treated) IU/L.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
More than 60 yr ago, investigators demonstrated a fall in gonadotropic activity in the pituitary glands of malnourished male rats (26). In principle, malnutrition and/or fasting could impair the hypothalamic release of GnRH, decrease the sensitivity of pituitary gonadotrope cells to GnRH, and/or directly suppress gonadal function. A plausible hypothesis posits that a fall in GnRH drive is the proximate cause of hypogonadotropism in undernutrition (4, 6, 27), as LH secretion is preserved or even amplified in response to a single dose of exogenous GnRH administered to malnourished rats or fasting humans in the face of normal or increased hypothalamic GnRH content in the rodent (2, 4, 14, 16, 28, 29). Pituitary GnRH receptor content, which is dependent on GnRH secretion, also declines with fasting in the male rat (29, 30). However, some investigators have described no change in hypothalamic GnRH peptide content after caloric restriction in the rodent (6, 27, 31).

In man as well as the nonhuman primate, short term fasting causes hypogonadotropic hypogonadism (4, 32, 33) despite the preserved responsiveness of the pituitary gland to acute (single dose) stimulation with exogenous GnRH (4, 33). Moreover, treatment of undernourished male monkeys with pulsatile infusions of GnRH can restore circulating gonadotropin levels into the range seen in fed animals (34). Interestingly, in the nonhuman primate, the decline in LH and testosterone concentrations may occur rapidly (e.g. within 24 h), which is quickly reversed with feeding (33). This suggests calorie-dependent regulation of GnRH pulse generator output. The available indirect data suggest that malnutrition could also suppress GnRH neuronal activity in men (4, 35, 36).

In a prior study employing a 5-day fast in young men, we found by deconvolution analysis that LH secretory pulse frequency, the duration of LH secretory bursts, and the half-life of LH were unchanged, but the mass of LH secreted per burst declined significantly (4). In this earlier study, we sampled blood at 5-min intervals for 24 h and used a high sensitivity LH IRMA. On the other hand, in a 20-min sampling study conducted over 8 h in obese men who were fasted for a longer period (10 days), Klibanski et al. (37) observed a fall in mean serum FSH and testosterone concentrations, but no change in the frequency or amplitude of LH pulsatility. Here, via 10-min blood sampling over 24 h within a shorter period of fasting (~3.5 days or 83 h) in normal weight men, we documented significant decreases in the deconvolution-estimated LH secretory pulse frequency, the amplitude of LH secretory bursts, and the mass of LH secreted per burst. A plausible explanation for the differences in men undergoing a 3.5- vs. a 5-day fast is partial escape or adaptation of the GnRH pulse generator from the suppressive impact of 5 or more days of fasting, as reanalysis of the 10-min subsets of the original 5-min LH series obtained after a 5-day fast also showed no suppression of LH pulse frequency. Thus, the 10-min blood sampling employed in the current study is unlikely to have underestimated the number of LH secretory bursts. A similar inference of reduced LH pulse frequency was made recently based on 15-min blood sampling for 8 h in men fasted for 48 h (5). Thus, we favor an adaptive response to more prolonged fasting over 5 days (4), when serum cortisol concentrations rise more evidently than over 2 days (5, 19).

Most importantly, the present clinical experiments demonstrate for the first time in the human that exogenous pulsatile iv GnRH administration reinstates or preserves LH pulse patterns, the mesor of nyctohemeral LH rhythmicity, and the ApEn or disorderliness of the LH release process over 24 h and also completely prevents the fall in serum testosterone concentrations associated with acute undernutrition. Further, we report that LH secretory responses after a single submaximal GnRH stimulus are no different in subjects fasted, fed, or fasted and treated with pulsatile iv GnRH for 24 h, arguing for an intact pituitary gonadotrope unit and no evident desensitization to the submaximally effective GnRH pulsatile infusion dose (100 ng/kg) and nominal 90-min frequency chosen here (38, 39, 40, 41). More irregular (nonpulsatile) subpatterns of LH release during GnRH replacement (higher ApEn) may reflect the loss of finely adjusted, within-axis feedback in response to a fixed, exogenously imposed GnRH input signal (25). These clinical data in healthy men support earlier experimental work in the rodent (3), sheep (11), and monkey (34) indicating that the mechanism for fasting-induced hypoandrogenemia is probably a defect in GnRH secretion, possibly via endogenous CRH, neuropeptide Y, etc. (for review, see Ref. 3).


   Acknowledgments
 
We thank Patsy Craig for her skillful preparation of the manuscript, Paula P. Azimi for the artwork, Brenda Grisso for performance of the immunoassays, and Sandra Jackson and the expert nursing staff at the University of Virginia Clinical Research Center for conduct of the research protocols.


   Footnotes
 
1 This work was supported in part by NIH Grant RR-00847 (to the Clinical Research Center of the University of Virginia), Research Career Development Award 1-KO4-HD-00634 (to J.D.V.), the Baxter Healthcare Corp. (Round Lake, IL; to J.D.V.), the NIH-supported Clinfo Data Reduction Systems, the University of Virginia Pratt Foundation and Academic Enhancement Program, the NSF Center for Biological Timing (Grant DIR89–20162), the NIH P-30 Center for Reproduction Research (HD-28934), and Veterans Affairs Merit Review Research Funds (to A.I.). Back

Received November 6, 1996.

Revised January 31, 1997.

Accepted February 7, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Zubiran S, Gomez-Mont F. 1953 Endocrine disturbances in chronic human malnutrition. In: Harris P, Marion UF, Thiman KV, eds. Vitamins and hormones. New York: Academic Press; 97–132.
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  4. Veldhuis JD, Iranmanesh A, Evans WS, Lizarralde G, Thorner MO, Vance ML. 1993 Amplitude suppression of the pulsatile mode of immunoradiometric LH release in fasting-induced hypoandrogenemia in normal men. J Clin Endocrinol Metab. 76:587–593.[Abstract]
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