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In the Adult Male Rhesus Monkey (Macaca mulatta), Unilateral Orchidectomy in the Face of Unchanging Gonadotropin Stimulation Results in Partial Compensation of Testosterone Secretion by the Remaining Testis

Departments of Cell Biology and Physiology (D.R.S., S.R., T.M.P.) and Medicine (G.R.M.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Address all correspondence and requests for reprints to: Dr. Tony M. Plant, Department of Cell Biology and Physiology, University of Pittsburgh, S-828A Scaife Hall, 3550 Terrace Street, Pittsburgh, Pennsylvania 15261. E-mail: plant1{at}pitt.edu.

	Abstract

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This study examined, in adult monkeys, the role that gonadotropin-independent mechanisms play in compensation of testosterone (T) secretion by the testis that remains after unilateral orchidectomy (UO). We employed a model (testicular clamp), in which endogenous gonadotropin secretion was abolished with a GnRH receptor antagonist, and the gonadotropin drive to the testes was concomitantly replaced with an invariant iv pulsatile infusion of recombinant human LH and FSH (1-min pulse every 2.5 h: LH, 0.08–0.12 IU/kg·pulse; FSH, 0.12–0.32 IU/kg·pulse) that provided the Leydig cells with a physiological stimulus. Within 5 h of UO (n = 5), circulating T concentrations had declined to 43% of pre-UO levels. By d 4, however, loss of the first testis was partially compensated, as reflected by the finding that circulating T had reached a plateau of 67% of the pre-UO level, where it remained for the duration of the study (39 d). That the recovery in circulating T was the result of increased T secretion by the remaining testis was suggested by the finding that the pulsatile pattern and decay of T during the intergonadotropin pulse interval before and after UO were indistinguishable. Interestingly, inhibin B production by the remaining testis also showed a delayed, albeit, minor, compensation (13% on d 10–11; P > 0.05) after loss of the first testis. These results suggest that compensation in T production by the remaining testis after UO in adult monkeys may be achieved in part by a gonadotropin-independent mechanism that probably involves direct neural inputs to the primate testis.

	Introduction

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TESTICULAR TESTOSTERONE (T) production in the adult is regulated by the pulsatile discharge of LH from the pituitary gland. In many species, including the rhesus monkey, these two hormones show a tightly coupled temporal pattern of secretion (1, 2, 3, 4, 5). In the rhesus monkey, each LH discharge is followed, approximately 40–60 min later, by an episode of testicular T secretion (6). Pulsatile LH release, in turn, is controlled by circulating T levels through a negative feedback action that is exerted primarily at a hypothalamic site (7).

This feedback mechanism may be perturbed by removing one of the testes. In the adult monkey, unilateral orchidectomy (UO) results within 12 h in an approximately 50% decline of circulating T (8, 9) and is followed within 48 h by a return of T levels to the pre-UO control concentrations, a response that unfolds in the face of only a transient rise in circulating LH (8). This rapid and full compensation in T production by the remaining testis after UO in the absence of a remarkable increase in LH secretion led us to question whether factors other than a change in gonadotropin stimulation may be responsible for the testicular response.

To address this issue, we used an experimental approach in which UO may be performed in the adult male rhesus monkey without changing the gonadotropin stimulation to the remaining testis. In this model, known as a testicular clamp, endogenous gonadotropin release is abolished by daily injections of a GnRH receptor (GnRH-R) antagonist, and the gonadotropin drive to the testis is concomitantly replaced by a pulsatile iv infusion of recombinant human (rh) LH and rhFSH. Here, we describe the impact of UO, in the face of unchanging gonadotropin stimulation, on T secretion by the remaining testis. The results obtained in the present study with the testicular clamp are compared in the Discussion to those previously reported (8) in normal adults not receiving GnRH antagonist treatment (unclamped).

	Materials and Methods

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Animals
Five adult (6.3–11.7 yr of age; 8–12.4 kg body weight) male rhesus monkeys (Macaca mulatta), obtained from laboratories within the U.S. or imported from China, were used. The animals were housed in individual cages and were maintained in accordance with the Guidelines for the Care and Use of Laboratory Animals provided by the NIH. All experimental procedures were approved by the University of Pittsburgh Institutional Animal Care and Use Committee.

Surgical procedures
Each monkey was implanted with an indwelling jugular and femoral vein catheter (inner diameter, 0.040 in.; outer diameter, 0.085 in; Stuart’s Bio-Sil, Sil-med Corp., Taunton, MA). One catheter was dedicated for blood sampling, and the other for administration of gonadotropin infusates. The catheters were tunneled sc from the site of venous insertion to the midscapular region, where they were exteriorized via a small cutaneous fistula (10). UO was performed through an inguinal incision. For both procedures, the monkeys were sedated with ketamine hydrochloride (100 mg, iv; Ketaject, Phoenix Scientific, Inc., St. Joseph, MO), and anesthesia was subsequently achieved with 1.5–2% isoflurane (Abbott Animal House, North Chicago, IL) in oxygen. All surgical procedures were performed under aseptic conditions. Postsurgery, animals received a single im injection of penicillin (300,000 U; Bicillin L-A, Wyeth Laboratories, Philadelphia, PA), and a series of iv injections of cefazolin sodium (25 mg/kg body weight; Kefzol, G.C. Hanford Mfg. Co., Syracuse, NY) and an analgesic, either meperidine hydrochloride (1 mg/kg body weight, iv; Demerol, Elkins-Sinn, Cherry Hill, NJ) or ketoprofen (2 mg/kg body weight, im; Ketofen, Fort Dodge Animal House, Fort Dodge, IA), twice daily for 4 d.

Hormones and GnRH-R antagonist
rhFSH (12,296 IU/mg; batch BFDA01522) and rhLH (25,551 IU/mg; batch BLCA0102) were provided by Serono (Aubonne). The GnRH-R antagonist (acyline, Bioqual, Rockville, MD) was provided by the Contraception and Reproductive Health Branch, Center for Population Research, National Institute for Child Health and Human Development. Acyline for injection was prepared in 5% aqueous mannitol (300 µg/ml) and stored at 4 C.

Preparation of the infusate
The gonadotropin infusates were custom-prepared for each monkey using procedures described previously (11). In brief, infusates contained rhLH (0.02–0.17 µg/ml) and rhFSH (0.39–0.58 µg/ml), diluted in Dulbecco’s PBS (Invitrogen Life Technologies, Inc., Grand Island, NY). The infusates contained a broad spectrum antibiotic, cefazolin sodium (1 µg/ml; Kefzol), and the appropriate monkey serum (1%), which had been collected before initiation of the experiments. Infusates were sterilized using a 0.22-µm pore size filter (Fisherbrand, Fisher Scientific, Pittsburgh, PA) and stored at 4 C.

Experimental design
Animals were fitted with a nylon jacket and flexible stainless steel tether and were housed in individual cages that permitted continual access to the venous circulation. The routine care of monkeys housed in the remote sampling laboratory has been described previously (12). To determine the average concentration of circulating T for each animal, plasma samples were collected hourly, either for 12 (0900–2100 h) or 24 h (0900–0900 h) on two or three different occasions. After assessment of each animal’s T status, daily treatment with acyline (60 µg/kg, sc) and intermittent iv replacement with recombinant gonadotropin (1 ml every 2.5 h, delivered at 1 ml/min) were initiated concomitantly. A programmable pump (KDS220P, KD Scientific, New Hope, PA) was used to administer the intermittent gonadotropin infusion. The starting doses of rhLH and rhFSH were 0.15 and 0.2 IU/kg·pulse, respectively. The circulating levels of T and FSH were monitored during two intergonadotropin pulse intervals in samples collected 10 min before and 5, 20, 40, 60, 100, and 140 min after each pulse. If necessary, the dose of rhLH was then adjusted to achieve preclamp concentrations of circulating T. In the case of FSH, however, no robust on-line marker for the bioactivity of this gonadotropin was available. Therefore, we arbitrarily decided to produce circulating levels of rhFSH of approximately 5 mIU/ml, a value in the lower half of the range reported for men (13). Adjustments were made until the desired concentrations were achieved within 4 wk of initiating acyline treatment. The final doses of rhLH and rhFSH were 0.078–0.3 and 0.12–0.32 IU/kg·pulse, respectively. Approximately 4 wk after the final adjustment of the clamp, each animal was subjected to UO, which was performed during an intergonadotropin pulse interval. Animals were immediately returned to their cages, and the pulsatile gonadotropin infusion was continued without interruption. A series of blood samples was collected before UO (d –7 to –2), on the day of UO (d 0; during second and fourth intergonadotropin pulse intervals immediately after UO), and, in general, on d 1, 2, 4, 10–11, 17–18, 24–25, 31–32, and 38–39 after UO. Samples were taken during two consecutive interpulse intervals, except for those collected on the day of UO, when only one interval was sampled. Plasma was separated by centrifugation and stored at –20 C until assayed. Packed cells were resuspended in sterile saline and returned to the respective animals.

Hormone assays
The levels of rhFSH in the circulation were measured using an FSH immunoradiometric assay (Coat-A-Count, IKFS1, Diagnostic Products Corp., Los Angeles, CA). The sensitivity of this assay was 0.06 mIU/ml, and the intra- and interassay coefficients of variation were less than 3.8% and less than 5.7%, respectively. The levels of rhLH in the circulation were measured using an LH immunoradiometric assay (ACTIVE, DSL-4600, Diagnostic System Laboratories, Inc., Webster, TX). The sensitivity of this assay was 0.12 mIU/ml, and the intra- and interassay coefficients of variation were both less than 8.9%.

Total T levels in the circulation were measured using an RIA (Coat-A-Count, TKTT5, Diagnostic Products Corp.). The sensitivity of this assay was 0.4 ng/ml, and the intra- and interassay coefficients of variation were less than 7.1% and less than 10.2%, respectively.

Monkey FSH and LH concentrations in plasma were assayed using homologous RIA systems, as described previously (10). In brief, recombinant cynomolgus FSH (NICHD-Rec-Mo-FSH-RP-1, AFP 6940A) and LH (NICHD-Rec-Mo-LH-RP-1, AFP 6936A) were employed for the respective reference preparations and radioiodinated tracers. Appropriate polyclonal rabbit antisera (AFP 782594 and AFP 342994), raised against the recombinant cynomolgus gonadotropins, were used as first antibodies. The average sensitivities of the assays were 0.08 and 0.1 ng/ml, respectively. The intra- and interassay coefficients of variation were less than 3.5% and less than 11.1%, respectively, for FSH, and less than 5.0% and less than 12.3%, respectively, for LH.

Inhibin B levels were assayed using a specific two-site inhibin B ELISA (ACTIVE Inhibin B ELISA, DSL-10-84100, Diagnostic Systems Laboratories, Inc.). The sensitivity was 7 pg/ml, and the intra- and interassay coefficients of variation were less than 5.6% and less than 7.6%, respectively.

Numerical analysis
Baseline and peak T concentrations were defined as the lowest and the highest levels in the interpulse interval. The difference between the peak value and the lowest value preceding the peak was defined as the amplitude. The regression of T concentrations over time was analyzed using a semilog plot after log transformation of the concentrations. Undetectable hormone concentrations were assigned a value equivalent to the sensitivity of the respective assay.

Two monkeys were not sampled on d 4. Therefore, for statistical analyses, values for these times were obtained by interpolation.

The significance of differences among mean concentrations, baseline, peak, and amplitude of T and mean concentrations of inhibin B before and after UO were determined by one-way repeated measure ANOVA, followed by the Student-Newman-Keuls method for all pairwise multiple comparison procedures. SigmaStat (Jandel Corp., San Rafael, CA) was used for this purpose. The regression of log-transformed T concentrations over time was analyzed as described by Zar (14). Statistical significance was accepted at P < 0.05. All data are expressed as the mean ± SEM.

	Results

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Hormone values before and after establishing testicular clamp
Mean (±SEM) circulating T levels from the time of establishing the testicular clamp until the day of UO were comparable to those observed before the administration of acyline (6.2 ± 0.7 vs. 5.3 ± 0.6 ng/ml, respectively; P > 0.05), which indicated that rhLH replacement during acyline administration mimicked the unclamped endogenous LH drive to the testis. After initiating daily acyline injections, endogenous monkey LH concentrations were undetectable (data not shown).

The mean concentration of rhFSH in the circulation during the clamp and before UO was 4.4 ± 0.5 mIU/ml, which compared with the target value of 5.0 mIU/ml. Although inhibin B is not a robust indicator of FSH activity, as T is for LH, the concentrations of inhibin B before and after clamp were 795.0 ± 165.3 and 1238.5 ± 260.9 pg/ml (P > 0.05), respectively.

rhLH and rhFSH levels before and after UO
Before UO, mean levels of circulating rhFSH and rhLH were 4.4 ± 0.5 and 0.7 ± 0.2 mIU/ml, respectively, and corresponding values after UO were 4.4 ± 0.5 and 0.8 ± 0.3 mIU/ml, respectively. These levels were maintained without variation for the duration of the experiment (Table 1 and Fig. 1).

View larger version (33K): [in this window] [in a new window]   FIG. 1. Time courses of circulating immunoactive concentrations of hLH (top panels), hFSH (middle panels), and T (lower panels) during a selected intergonadotropin pulse interval before UO (Pre-UO), on the day of UO (fourth gonadotropin pulse), and on d 1, 2, 4, 10–11, 17–18, and 38–39 after UO in adult male rhesus monkeys (n = 5) treated daily with a GnRH-R antagonist (acyline) and receiving an invariant iv pulsatile infusion of rhLH and rhFSH. The mean and SEM are shown.

View larger version (13K): [in this window] [in a new window]   FIG. 2. Time course of plasma T concentrations during an intergonadotropin pulse interval before UO () and on 38–39 d after UO () in adult male rhesus monkeys (n = 5), treated daily with a GnRH-R antagonist and receiving an invariant iv pulsatile infusion of rhLH and rhFSH. T concentrations are plotted as a percentage of the peak T concentration observed at 60 min.

Inhibin B levels before and after UO
For the measurement of circulating inhibin B concentrations, plasma pools were made from individual samples collected during selected intergonadotropin pulse intervals. The mean concentration of circulating inhibin B before UO was 1386.8 ± 205.5 pg/ml, and this declined precipitously within the first 6 h after UO to approximately 760 pg/ml on d 1–4. Although inhibin B subsequently increased from 757.8 ± 28.2 pg/ml on d 4 post-UO to 933.3 ± 74.4 pg/ml on d 16, this increase was not significant.

	Discussion

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The efficacy of acyline in reducing endogenous gonadotropin secretion to undetectable levels in adult male rhesus monkeys has been previously established (10), and in the case of LH, this was confirmed in the present study. In the case of FSH, however, we were unable to confirm suppression of endogenous secretion, because rhFSH was found to exhibit significant cross-reactivity in the monkey FSH RIA. Nevertheless, it is reasonable to conclude that endogenous gonadotropin secretion was minimal during acyline treatment.

That the circulating rhLH concentration achieved during the clamp provided the Leydig cells with a physiological stimulus was indicated by the finding that T secretion before and after the clamp were comparable. Although there was no equivalent robust indicator for rhFSH bioactive levels, we did monitor inhibin B levels. The levels of this hormone before and after clamp were also similar (P > 0.05). However, large doses of FSH are required to stimulate inhibin B in both man (15) and monkeys (Ramaswamy, S., G. R. Marshall, and T. M. Plant, unpublished observation). Most importantly, in the context of the present study, the plasma levels of rhFSH as well as those of rhLH exhibited invariant profiles throughout the experiment. Furthermore, there was no evidence for a decline in the bioactivity of rhLH throughout the experiment, and measurement of circulating FSH binding activity failed to demonstrate the formation of FSH antibodies (Parlow, A. F., unpublished observations). Thus, it can be concluded that the testes were rigidly clamped.

Although the dramatic decrease in circulating T concentrations after UO undoubtedly reflects a change in the total T production rate, subsequent compensation in blood T levels could reflect either an increase in T secretion by the remaining testis or a decrease in T clearance. The findings that the profile of the changes in plasma T concentration during an intergonadotropin pulse interval before and 38–39 d after UO was similar, and that the decay in plasma T concentration at these times was identical, suggests that compensation was the result of an increased T secretion by the remaining testis. However, because direct determinations of secretion rate were not performed, the possibility that a decrease in clearance may contribute to the compensation cannot be excluded.

If we assume that T secretion by the two testes before UO was the same, then the following may be proposed. First, T production by the remaining testis immediately after UO decreased to less than half the pre-UO value. The reason for this is unknown, but is probably related to the surgical procedure. Second, restoration in T secretion by the remaining testis was achieved by d 2. Third, in the face of the testicular clamp, T secretion by the remaining testis continued to increase to reach, by d 4, a plateau of approximately 4.2 ng/ml, a value 34% greater than the theoretical value predicted as a result of loss of the first testis. Despite the increased production of T by the remaining testis, circulating T concentrations were restored to only 67% of the pre-UO control concentration.

Because gonadotropin stimulation of the remaining testis was identical before and after UO, it must be concluded that the compensation in T production in the clamped situation was mediated by a mechanism that did not involve the classic negative feedback control system that regulates testicular function. The relatively slow and incomplete compensation in T production by the remaining testis after UO in the clamp situation contrasts with the rapid (within 24 h) and complete (achieved on d 2 after UO) compensation observed after UO in a previous study in the normal intact adult (Fig. 3). Thus, it seems reasonable to conclude that in the normal situation the rapid T compensation is due to a transient hypersecretion of LH triggered by a decrease in the circulating concentration of T, with the negative feedback signal regulating the release of this gonadotropin. The subsequent return to a fully compensated state after UO in the normal adult represents an interesting new steady state, because circulating T and LH concentrations were comparable to those observed before UO. The increased T production by the remaining testis in the face of an LH stimulus comparable to the pre-UO situation is presumably the result of an increase in the responsiveness of the Leydig cells, although an increase in cell number cannot be ruled out. It seems reasonable to posit that this adaptation is in part a manifestation of the slow and partial gonadotropin-independent restoration observed in the present study.

View larger version (15K): [in this window] [in a new window]   FIG. 3. A comparison of the compensation in circulating T concentrations after UO in adult monkeys, in which the testes are clamped with an invariant gonadotropin stimulus (n = 5; present study; ) and the testes are driven by endogenous gonadotropin secretion that is responsive to changes in feedback signals from the testis [; reported previously (8 )]. The horizontal broken line represents the theoretical level of T production by each testis in the testicular clamp model before UO.

In addition to the classical sympathetic outflow to the testis, a hypothalamic-testicular neural pathway has been implicated in the regulation of T secretion. This pathway has been revealed by the finding that pseudorabies virus, a retrograde nerve fiber tracer, was found in spinal cord, brainstem, and hypothalamus after injection into rat testis (24, 25). Disruption of the path by injury of the rat spinal cord impaired the ability of intracerebroventricular injection of IL-1ß, a proinflammatory cytokine, to modulate human chorionic gonadotropin-stimulated testicular T production (26, 27).

The relative importance of these two efferent outflows to the testes in mediating the compensation in testicular T secretion revealed in the present study remains to be determined.

As expected, UO, in the face of an invariant gonadotropin stimulation, resulted in a rapid decline in circulating inhibin B to concentrations approximately half those observed before the removal of the testis. Although there was a suggestion that inhibin B secretion by the remaining testis was restored in the clamped model, as observed previously in the normal adult (12), this was delayed and did not reach statistical significance. Nevertheless, the time course of the changes in circulating inhibin B levels after UO in the testicular clamp model are intriguing, particularly when they are compared with that in normal males (Fig. 4), and at the present time we are therefore reluctant to conclude the testicular inhibin B secretion is totally emancipated from direct neural control.

View larger version (17K): [in this window] [in a new window]   FIG. 4. A comparison of the compensation in circulating inhibin B (Inh B) concentrations after UO in adult monkeys in which the testes are clamped with an invariant gonadotropin stimulus (n = 5; present study; ) and the testes are driven by endogenous gonadotropin secretion that is responsive to changes in feedback signals from the testis [; reported previously (12 )]. The horizontal broken line represents the theoretical level of inhibin B production by each testis in the testicular clamp model before UO.

	Acknowledgments

 
We are most grateful to Serono Laboratories for the gifts of rhFSH and rhLH, and to Dr. Nancy Alexander, Dr. Richard P. Blye, and the National Institute of Child Health and Human Development for the gift of the GnRH receptor antagonist, acyline. The expert technical assistance of Michael A. Cicco, Rachel Roslund, Lisa Nieman-Vento, and Carolyn Phalin from the Primate and Assay Cores of the Center for Research of Reproductive Physiology is also acknowledged.

	Footnotes

 
This work was supported by National Institute of Child Health and Human Development/National Institutes of Health through Cooperative Agreement U54-HD-08610 as part of the Specialized Cooperative Centers Program in Reproduction Research. A preliminary report of this work was presented at the 86th Annual Meeting of The Endocrine Society, New Orleans, LA, June 16–19, 2004 (Abstract P3-334).

Abbreviations: GnRH-R, GnRH receptor; rh, recombinant human; T, testosterone; UO, unilateral orchidectomy.

Received July 2, 2004.

Accepted for publication August 6, 2004.

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