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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 9 4474-4479
Copyright © 2004 by The Endocrine Society

Pulsatile Intravenous Infusion of Recombinant Human Luteinizing Hormone under Acute Gonadotropin-Releasing Hormone Receptor Blockade Reconstitutes Testosterone Secretion in Young Men

Johannes D. Veldhuis and Ali Iranmanesh

Division of Endocrinology and Metabolism (J.D.V.), Department of Internal Medicine, Mayo Medical and Graduate School of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; and Endocrine Section (A.I.), Medical Services, Veterans Affairs Medical Center, Salem, Virginia 24153

Address all correspondence and requests for reprints to: Dr. Johannes D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate School of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The present study tests the hypothesis that iv infusion of discrete pulses of recombinant human (rh)LH after overnight GnRH-receptor blockade can restore midphysiological concentrations of testosterone (Te) in normal young men. In a pilot time-course analysis, injection of the GnRH antagonist ganirelix (2.0 mg sc) at 2200 h lowered LH concentrations (mean ± SEM) from 3.4 ± 0.7 to 0.8 ± 0.1 IU/liter (P < 0.01) and Te concentrations from 416 ± 48 to 107 ± 16 ng/dl (P < 0.01) (to convert to nmol/liter, multiply by 0.0347) at 0800 h the next morning. LH and Te concentrations remained suppressed thereafter for an additional 15 h (interval, 10–25 h after ganirelix administration) at mean values of 1.2 ± 0.1 IU/liter and 67 ± 10 ng/dl, respectively (P < 0.005 vs. baseline). Based on these data and earlier dose-finding studies, eight men received a single ganirelix injection followed by seven consecutive iv pulses of rhLH (15.3 IU Second International Reference Preparation) each delivered over 6 min every 2 h beginning at 0800 h. Recurrent rhLH stimuli restored mean LH concentrations (IU/liter of homologous standard) to 4.8 ± 0.3, LH peak maxima to 7.1 ± 0.6, incremental LH peak amplitudes to 3.7 ± 0.4, and interpeak nadir LH concentrations to 3.3 ± 0.3 (each P < 0.01 vs. saline infusion after ganirelix). These values were indistinguishable from the normal 95% range established in 23 young adults of comparable age. Injected LH pulses increased total Te concentrations (ng/dl) to 440 ± 52, Te peak maxima to 552 ± 64, incremental Te amplitudes to 188 ± 23, and interpeak nadir Te concentrations to 366 ± 43 (each P < 0.01 vs. saline addback; P value not significant vs. untreated men). Under combined ganirelix inhibition and pulsatile rhLH drive, Te concentrations rose from a nadir of less than 120 ng/dl to an asymptotic plateau of 611 ng/dl with an estimated half-time of 97 ± 9.1 min. Cross-correlation analysis of paired serial LH and Te concentrations verified that infused LH pulses stimulate Te elevations within 40–70 (median 50) min (P < 0.001). Kinetic estimates of the half-life of exogenous rhLH averaged 107 ± 3.8 min, which value exceeded that of secreted LH monitored after pharmacological GnRH stimulation (83 ± 12 min; P = 0.012).

We conclude that intermittent iv pulses of rhLH delivered over 12 h under selective GnRH-receptor blockade can restore young adult-like pulsatile LH and Te concentrations with an appropriate time delay coupling the lutropic stimulus to the steroidogenic response. Whether a comparable near-physiological paradigm can maintain human Leydig-cell testosterone production for a more extended interval is not known.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CONVENTIONAL ASSESSMENT OF Leydig-cell androgen secretion is based on acute injection of human chorionic gonadotropin (hCG) (1, 2, 3). However, compared with endogenous LH pulses, hCG stimulation is supraphysiological. In particular, hCG kinetics and LH/hCG receptor occupancy are prolonged, resulting in steroidogenic desensitization (4, 5, 6). Other means of stimulating human Leydig cells include pulsatile iv infusion of GnRH and oral administration of an antiestrogen or antiandrogen to provoke endogenous LH release (7, 8). Such approaches are less direct, because testis responses depend upon whether stimulated LH release is normal (3).

We recently examined Leydig-cell responsiveness to biosynthetic LH by administering a long-acting GnRH agonist (leuprolide) to down-regulate LH secretion over several weeks followed by pulsatile iv infusion of recombinant human (rh)LH over a 16-h interval (7). In this hypogonadotropic setting, infusion of successive rhLH pulses failed to restore testosterone concentrations to more than 40% of normal young-adult values. We postulated that subnormal steroidogenesis could reflect limited bioactivity of infused rhLH, an ineffectual paradigm of pulsatile LH delivery, direct inhibition of the testis by leuprolide, and/or impaired Leydig-cell function caused by short-term withdrawal of trophic LH support (3, 8).

To address the foregoing issues, the present investigation tests a novel strategy of exogenous LH drive comprising two sequential steps: 1) acute (overnight) pretreatment with a potent and selective GnRH-receptor antagonist to achieve hypogonadotropic hypogonadism rapidly and 2) stimulation of the testis 10 h later by sequential iv pulses of rhLH.


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

Ten healthy young men ages 18–25 yr with body mass indices of 21–24 kg/m2 participated. Each subject provided voluntary informed consent approved by the Institutional Review Board. The study protocol was reviewed by the General Clinical Research Center (GCRC) and the U.S. Food and Drug Administration. Two subjects were studied twice, once in the pilot time-course analysis and again in the rhLH infusion protocol. Entry criteria included an unremarkable medical history, physical examination, and biochemical measures of renal, hepatic, hematological, and metabolic function. All subjects had normal fasting morning concentrations of LH, FSH, prolactin, testosterone, estradiol, IGF-I, dehydroepiandrosterone sulfate, thyroxine, and TSH (9, 10, 11). Exclusion criteria included acute or chronic systemic disease, alcohol or drug abuse, psychiatric illness, use of any prescription medications, and failure to provide informed voluntary consent. Volunteers were reimbursed for the time spent in participation.

Subjects were admitted to the GCRC in the late afternoon, provided supper at 1800 h, and given a single sc injection of the GnRH-receptor antagonist (ganirelix 2.0 mg) at 2200 h. The latter dose suppresses LH concentrations maximally in young women (viz., by 70–74%) (12, 13). In the pilot time-course analysis, four volunteers received ganirelix and saline infusion only. In the second phase of study, eight men were given ganirelix 2.0 mg sc at 2200 h, followed the next morning by consecutive iv injections of rhLH beginning at 0800 h. The infusion paradigm comprised rhLH (50 IU Serono Laboratory Standard, equivalent to 20 IU First and 15.3 IU Second International Reference Preparation) diluted in sterile water and infused via Harvard syringe pump in 6-min square-wave every 2 h for a total of seven pulses (14, 15). The last dose was infused at 2000 h. To verify competitive inhibition of GnRH receptors by ganirelix, a single bolus of GnRH (500 µ g) was injected iv 3 h after the last rhLH pulse (25 h after ganirelix administration).

Blood was sampled from a contralateral forearm vein every 10 min for a total of 30 h beginning 2 h before ganirelix administration (at 2000 h) and concluding the next night at 0200 h (3 h after the single GnRH pulse). Figure 1Go schematizes the overall timeline.



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  		FIG. 1. Schema of experimental design comprising single administration of a selective GnRH-receptor antagonist (ganirelix, 2 mg sc) at 2200 h, blood sampling every 10 min for 30 h starting 2 h before ganirelix injection (2000 h), iv infusion of seven consecutive 6-min pulses of saline or rhLH (50 IU Serono standard = 15.3 IU Second International Reference Preparation) every 2 h beginning at 0800 h (10 h after ganirelix administration), and subsequent iv injection of GnRH (500-µg bolus) at 2300 h to test the competitive nature of gonadotrope inhibition.

 
Hormone assays

Serum LH and testosterone concentrations were quantitated in duplicate in each 10-min sample in each subject as a batch using an automated random-access chemiluminescence-based assay (ACS:180, Chiron Corp. Diagnostic, Walpole, MA) (16). The LH reference standard is the Second World Health Organization International Standard 80/552. Median within- and between-assay coefficients of variation were 5.1 and 6.8%, respectively. Assay sensitivity is 0.05 IU/liter at 2.5 SD above hypopituitary serum. Earlier assay comparisons in normal men established a strong correlation (r = 0.983; P < 0.001) between the automated chemiluminescence method and an independent immunoradiometric assay (17). Sensitivity and intra- and interassay precision of the chemiluminescent testosterone assay were 18 ng/dl, 5.2%, and 6.5%, respectively.

Analytical methods

Absolute peak, incremental amplitude (maximum minus preceding nadir), and interpulse nadir concentrations of LH and testosterone were computed by model-free cluster analysis (18). Conservative pulse-detection parameters included a 2 x 2 test cluster size and thresholds of t = 2.0 to identify significant upstrokes and downstrokes (8). The decay of testosterone and LH concentrations after ganirelix injection was appraised by monoexponential regression analysis, and the rate of rise of testosterone concentrations after the onset of rhLH infusions was determined by an inverse exponential model (19, 20). The half-life of elimination of infused rhLH and GnRH-stimulated LH release was quantitated by deconvolution analysis (21, 22). Cross-correlation analysis was applied to quantitate the time-lagged relationship between successive LH and testosterone concentrations as described earlier (23, 24).

Statistical methods

Data are presented as the mean ± SEM. Between- and within-subject contrasts were examined via a two-sample and paired Student’s t test, respectively. The null hypothesis asserts that ganirelix does not suppress and LH does not increase testosterone concentrations. Statistical significance was construed for P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Figure 2Go depicts the time course of LH and testosterone concentrations monitored every 10 min for 30 h in two subjects administered ganirelix (2.0 mg sc) and saline. For the four subjects in the pilot analysis, injection of the GnRH-receptor antagonist at 2200 h reduced mean (2000–2200 h) LH concentrations from 3.4 ± 0.7 to 0.8 ± 0.1 IU/liter and total testosterone concentrations from 416 ± 48 to 107 ± 16 ng/dl (P < 0.01 for each effect) the next morning at 0800 h. Based upon 10-min sampling, subsequent mean LH and testosterone concentrations over the next 15 h (0800 to 2300 h) were 1.2 ± 0.1 IU/liter and 67 ± 10 ng/dl, respectively. Accordingly, the same 15-h time interval was used for the rhLH addback phase of the study in eight volunteers.



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  		FIG. 2. Illustrative time course of decline of LH and total testosterone concentrations in two of four young men administered a GnRH-receptor antagonist (ganirelix) at 2200 h (bold arrow) followed by infusion of saline. Blood samples were collected every 10 min for 30 h beginning at 2000 h. The y-axis gives individual (range) LH concentrations and the x-axis clock time (h). A bolus of GnRH was injected at 0130 h in the upper plot. To express testosterone concentrations (ng/dl) as nmol/liter, multiply by 0.0347.

 
Figure 3Go illustrates LH and testosterone concentration time series in three of the eight men administered ganirelix followed by iv infusion of rhLH. In all eight men, injection of ganirelix suppressed LH concentrations from 3.4 ± 0.8 IU/liter at 2000–2200 h to 1.1 ± 0.2 IU/liter at 0800 h and testosterone concentrations over the same interval from 398 ± 51 to 142 ± 40 ng/dl (both P < 0.001). Percentage inhibition averaged 65 ± 5.1% for LH and 67 ± 6.2% for testosterone. Testosterone and LH concentrations declined with half-lives of 82 ± 11 min and 90 ± 9.2 min, respectively, after ganirelix injection.



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  		FIG. 3. LH and testosterone concentrations monitored every 10 min for 30 h in three healthy young men, who received 1) a single sc injection of ganirelix at 2200 h (large arrow), 2) seven consecutive iv pulses of rhLH beginning at 0800 h (vertical series of arrows), and 3) a single supramaximal dose of GnRH at 2300 h. Data are presented otherwise as defined in the legend of Fig. 2Go.

 
Pulsatile iv infusion of rhLH elevated morning testosterone concentrations with a half-time of 97 ± 9.1 min. Testosterone concentrations rose to an asymptotic plateau of 611 ± 59 ng/dl. Intermittent rhLH infusion normalized each primary measure of LH and testosterone pulsatility compared with 23 controls sampled over 24 h (9, 10, 16, 24). Table 1Go summarizes mean, peak, and incremental amplitudes and interpulse nadir concentrations of LH and testosterone over the 15-h infusion interval (0800–2300 h).


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  		TABLE 1. Concentrations of LH and total testosterone measured during pulsatile iv infusion of saline or rhLH after ganirelix administration

 
Injected rhLH decayed with a half-life of 107 ± 3.8 min. The GnRH-stimulated LH pulse disappeared with a half-life of 83 ± 12 min (P = 0.021). Neither value differed from that associated with the overnight fall in LH concentrations induced by ganirelix injection, viz., 90 ± 9.2 min (Fig. 4Go).



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  		FIG. 4. Estimated half-lives of exogenous and endogenous LH monitored after iv injection of rhLH or GnRH, respectively, and of endogenous LH after sc administration of ganirelix in eight healthy young men. The P value denotes the contrast between means labeled A and B. AB does not differ from either A or B.

 
Cross-correlation analysis revealed that rising LH concentrations increase testosterone concentrations significantly within 40–70 min (median 50 min; P < 0.001) (Fig. 5Go).



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  		FIG. 5. Cross-correlation analysis of serial LH and testosterone concentrations sampled during the infusion of discrete 6-min pulses of rhLH under ganirelix blockade. Cross-correlation coefficients (y-axis) are given as the cohort median and absolute range (n = 8 subjects) at each of the indicated time lags (x-axis). A positive lag denotes that there is a time delay (min) between the rise in LH and the increase in testosterone concentrations. P values reject the null hypothesis of chance associations between the two hormones.

 
No significant adverse events occurred after administration of saline, ganirelix, and/or rhLH. Minor side effects included tenderness at the site of sc ganirelix injection in three volunteers (edema < 0.5 cm).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study establishes that overnight GnRH receptor antagonism 1) enforces significant hypogonadotropic hypoandrogenemia within 8–10 h and 2) maintains LH and testosterone depletion for at least an additional 15 h. In this investigational context, midphysiological pulses of rhLH stimulate apparently normal testosterone secretion in young men. The paradigm developed here therefore should provide a basis for examining the steroidogenic actions of multiple randomly ordered doses of rhLH in physiology and pathophysiology.

A single injection of a high dose of a potent and specific GnRH-receptor antagonist peptide (ganirelix) reduced LH and testosterone concentrations during the subsequent 8- to 10-h interval with apparent half-lives of 90 and 82 min, respectively. Values remained greater than 65% suppressed for an additional 15 h. Infusion of discrete iv pulses of rhLH during experimental hypogonadotropism reproduced measures of physiological LH pulsatility. Concomitantly, repeated LH injections increased total testosterone concentrations from the suppressed nadir of less than 120 ng/dl to a predicted asymptotic plateau of 611 ng/dl at a half-time of 97 min. Reconstitution of young-adult testosterone concentrations in this investigative setting diverges vividly from the marked impairment in testicular steroidogenesis observed in response to the same schedule of rhLH addback after GnRH agonist-induced hypogonadotropic hypogonadism (7). The latter outcome putatively reflects the requirement of specific sterol-metabolizing proteins for continuing trophic actions of LH (25, 26).

To assess the time delay between rising LH and testosterone concentrations, we applied classical cross-correlation analysis. Statistical tests showed that rising LH concentrations stimulate testosterone output maximally within 40–70 min. This estimate of response latency mirrors that based on paired serial measurements of LH and testosterone concentrations in peripheral blood of healthy young men and in the spermatic vein of middle-aged patients undergoing varicocele repair (16, 23, 24, 27, 28, 29, 30, 31, 32, 33). hCG, LH, and cAMP also induce Leydig-cell testosterone secretion rapidly (over 5–30 min) in perifusion systems in the experimental animal (4, 5, 6, 26). Recent developments in noninvasive analytical methods of reconstructing nonlinear agonist dose-glandular secretory-response properties in vivo should allow more precise estimation of LH-testosterone coupling under exogenously controlled LH signaling (34, 35).

We verified the competitive nature of gonadotrope inhibition by the GnRH-receptor antagonist by demonstrating marked LH release after acute injection of a supramaximal dose of GnRH (500 µg), when LH and testosterone concentrations were still suppressed in the control condition. Competitive inhibition of LH release was also inferred in the female Rhesus monkey pretreated with another GnRH-receptor antagonist (36). Prominent GnRH-stimulated LH release allowed us to estimate the kinetics of pituitary LH by deconvolution analysis. This approach predicted a half-life of secreted LH of 83 min. The same analysis applied to infused rhLH peaks yielded a half-life of 107 min, which value is significantly prolonged over that of endogenous LH. However, neither estimate differs significantly from that of endogenous LH monitored here after sc ganirelix injection (90 min) or earlier by deconvolution analysis in normal men (14, 15, 20, 37, 38, 39). The detectably longer half-life of biosynthetic than GnRH-stimulated pituitary LH could reflect unequal posttranslational modification of carbohydrate residues in immortalized cells compared with gonadotropes. This is because addition of terminal sialic acid and sulfate residues to oligosaccharide chains varies among cell types. Such residues block rapid uptake of glycoproteins by hepatic lectin-like receptors and thereby prolong the hormone half-life (40).

In summary, a clinical paradigm of single administration of a GnRH-receptor antagonist followed within 10 h by iv infusion of consecutive brief pulses of rhLH 1) recapitulates normal LH pulse amplitude, 2) reinstates midphysiological testosterone concentrations, and 3) drives the expected coupling time between LH and testosterone. These data should provide a platform for further investigation of physiological regulation and pathophysiological disruption of pulsatile LH-dependent drive of Leydig-cell steroidogenesis in the human.


   Acknowledgments
 
We thank Brenda Grisso for performing the immunoassays, the GCRC nursing staff for conducting the research protocols, Nathan J. D. Veldhuis for assisting as a research coordinator, Dr. Christopher Fox for recruiting several patients, and Dr. Louis St. L. O’Dea at Serono Laboratories (Norwalk, MA) for donating rhLH under an FDA-approved Investigator New Drug assignment by the authors.


   Footnotes
 
This work was supported in part by Grants MO1 RR00847 and RR00585 to the General Clinical Research Centers of the University of Virginia and Mayo Clinic and Mayo Foundation from the National Center for Research Resources (Rockville, MD); RO1 AG 23133 from the National Institutes of Health (Bethesda, MD); and a Veterans Affairs Merit Review award.

Abbreviations: hCG, Human chorionic gonadotropin; rh, recombinant human.

Received February 5, 2004.

Accepted June 9, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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P. Y. Liu, P. Y. Takahashi, P. D. Roebuck, A. Iranmanesh, and J. D. Veldhuis
Aging in Healthy Men Impairs Recombinant Human Luteinizing Hormone (LH)-Stimulated Testosterone Secretion Monitored under a Two-Day Intravenous Pulsatile LH Clamp
J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5544 - 5550.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
P. Y. Liu, P. Y. Takahashi, P. D. Roebuck, A. Iranmanesh, and J. D. Veldhuis
Age-specific changes in the regulation of LH-dependent testosterone secretion: assessing responsiveness to varying endogenous gonadotropin output in normal men
Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2005; 289(3): R721 - R728.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
P. Y. Takahashi, P. Y. Liu, P. D. Roebuck, A. Iranmanesh, and J. D. Veldhuis
Graded Inhibition of Pulsatile Luteinizing Hormone Secretion by a Selective Gonadotropin-Releasing Hormone (GnRH)-Receptor Antagonist in Healthy Men: Evidence That Age Attenuates Hypothalamic GnRH Outflow
J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2768 - 2774.
[Abstract] [Full Text] [PDF]

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