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Effects of Chemotherapy-Induced Testicular Damage on Inhibin, Gonadotropin, and Testosterone Secretion: A Prospective Longitudinal Study

Department of Obstetrics and Gynaecology (E.M.W.), Monash University, Clayton, Victoria 3168, Australia; School of Biological and Molecular Sciences (N.P.G.), Oxford Brookes University, Oxford; Department of Obstetrics and Gynaecology (S.C.R.), University of Edinburgh, Edinburgh EH3 9EW; Department of Haematology (A.C.P.), University of Edinburgh, Western General Hospital; Department of Medicine (F.C.W.W.), University of Manchester, Manchester Royal Infirmary and Department of Reproductive Medicine (F.C.W.W.), St Mary’s Hospital, Manchester, United Kingdom

Address correspondence and requests for reprints to: Dr. E.M. Wallace, Department of Obstetrics and Gynaecology, Monash University, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail: Euan.Wallace{at}med.monash.edu.au

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
To investigate the role of inhibin in the control of follicle-stimulating hormone (FSH) secretion, we have measured levels of immunoreactive inhibin (ir-inhibin), inhibin B, Pro-C containing inhibins, FSH, luteinizing hormone (LH), and testosterone in twelve men with hematological malignancies before, during, and after chemotherapy.

Inhibin B levels fell significantly by 1 month from a mean ± SE baseline level of 273.2 ± 32.8 pg/mL, reaching a nadir of 52.6 ± 15.3 pg/mL at 4 months (P < 0.0001). FSH levels increased within the first month from a baseline level of 3.9 ± 0.6 IU/L, reaching a peak level of 22.4 ± 3.3 IU/L at 4 months (P < 0.0001). FSH and inhibin B were significantly and inversely correlated (r = 0.69, P < 0.0001). Pro-C containing inhibin levels increased significantly (P < 0.05) at 3 months and were significantly and positively correlated with FSH (r = 0.38, P = 0.002). LH levels increased significantly but to a much lesser extent than FSH, the increase becoming evident only 4 months after treatment commenced (P < 0.03). Levels of ir-inhibin and testosterone remained unchanged throughout the study.

These data provide strong support to the hypothesis that inhibin B is the physiologically important form of inhibin in men, negatively regulating FSH secretion at the pituitary. Furthermore, they suggest that FSH stimulates inhibin -subunit secretion by the testis.

	Introduction

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THE REGULATION of follicle-stimulating hormone (FSH) secretion from the anterior pituitary gland in men remains poorly understood. While inhibin has long been regarded as having a physiological role in the negative feedback control of FSH secretion (1, 2), with convincing animal data in support (3, 4), most human studies have been unable to demonstrate the inverse relationship that would be expected between these two hormones, as recently reviewed (5). In men with severe testicular dysfunction, as evidenced by decreased sperm counts and increased FSH, serum levels of immunoreactive inhibin (ir-inhibin) remain within the normal range and are not decreased as might be expected (6, 7, 8). To explain these findings it has been suggested that the elevated FSH levels, thought to be secondary to decreased inhibin negative feedback, in turn induce a compensatory Sertoli cell response, thereby resetting the pituitary-testicular axis, and so maintaining normal inhibin levels (6). However, the earlier studies employed a radioimmunoassay that detected multiple inhibin forms, including the bioactive dimeric inhibins and the non-bioactive free inhibin -subunits (9). Thus, while the levels reported reflected total inhibin, they did not necessarily reflect physiologically important inhibin (9, 10), making interpretation of results difficult (10).

More recently, the development of assays specific for each of the bioactive forms of inhibin, the dimers inhibin-A (11) and inhibin B (12), and for precursor inhibins containing the -subunit fragment pro-C (13), has afforded new insights into inhibin physiology and possible clinical applications (5). It has been shown that, while both dimers are present in the female circulation (14, 15), in human fetal and adult male serum the only dimer detectable is inhibin B (16, 17). Furthermore, serum levels of inhibin B have been shown to correlate with FSH levels in normal and infertile men (17, 18), to increase following FSH administration in healthy men (19), and to be undetectable in orchidectomized men (19). These observations are consistent with inhibin B being a unique testicular product that is both stimulated by FSH and regulates reciprocally the secretion of FSH in men. Therefore, to explore whether reciprocal and dynamic readjustment of inhibin and FSH secretion does occur during testicular damage, we have studied prospectively, changes in ir-inhibin, inhibin B, pro-C containing inhibin, testosterone, and gonadotropin levels in men before, during, and after chemotherapy.

	Materials and Methods

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Patients

Twelve men (mean age 38.7 ± 3.7 yr) with hematopoietic malignancy were recruited to the study, each giving written informed consent. The study had the approval of the Lothian Research Ethics Committee. Before chemotherapy, and monthly during and subsequent to treatment, 20 mLs of venous blood was collected and separated, and the plasma was stored at -20 C until analysis. Samples were collected over a 12-month period from 6 of the men, while the remaining 6 completed only the first 6 months. The chemotherapy regimens administered depended on the diagnosis in each individual case (Table 1).

Inhibins. Inhibin B was measured using a specific enzyme-linked immunosorbent assay (ELISA) as previously described (12). The assay detection limit was less than 5 pg/mL. Activin-A, activin-B, follistatin, and purified human pro-C had less than 0.1% cross-reaction, while recombinant inhibin-A had a 0.5% cross-reaction. The intra- and interplate coefficients of variation (CV) were 7.3% and 8.4%, respectively. Inhibins containing pro-C were detected using an ELISA described recently (13), with some minor modifications (20). This assay does not detect recombinant human inhibin-A, inhibin B, or follistatin, primarily detecting free inhibin -subunit precursors (21). The intra- and interplate CV were 5.1% and 8.0%, respectively. The detection limit was 3 pg/mL. Immunoreactive inhibin was measured by RIA as previously described (22). This assay utilizes a polyclonal antibody (1989) directed against an epitope on the inhibin C subunit (23) and detects both bioactive dimeric inhibins and free inhibin -subunits (9), reflecting total inhibin. The sensitivity of the assay was 37.5 U/L with intra- and interassay CV of 9% and 11%, respectively.

Other assays. FSH and LH were measured by RIA (24) with a sensitivity, intra- and interassay CV of 0.7 U/L, 4.2% and 4.7%; and 0.6 U/L, 7.3% and 15.4%; for FSH and LH, respectively. Testosterone was measured by an in-house RIA (25). The sensitivity, intra- and interassay CV were 0.3 nmol/L, 8% and 15% respectively.

Normal ranges (mean ±2 [sd] scores) had been previously established for ir-inhibin, FSH, LH, and testosterone from serum from 62 healthy semen donors of known fertility. These samples were not available for inhibin B and pro-C inhibin measurements.

Statistical analyses were performed using Statview 4.1 (Abacus, Berkeley, CA). Changes in hormone levels over time were subjected to ANOVA for repeated measures, and the levels of different hormones were correlated with each other. Changes were recognized as significant when P < 0.05.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
The concentration of inhibin B fell significantly (P < 0.0001) from the baseline level of 273.2 ± 32.8 pg/mL to 123.9 ± 21.5 pg/mL at 1 month and 52.6 ± 15.3 pg/mL at 4 months (Fig. 1A). Thereafter, inhibin B levels did not change further, stabilizing at a level approximately one fifth that of baseline. Serum levels of FSH increased significantly (P < 0.0001) from a pretreatment concentration of 3.9 ± 0.6 IU/L to 9.7 ± 1.9 IU/L at 1 month and to a peak at 4 months (22.4 ± 3.3 IU/L). Thereafter, there was no further increase in FSH, which remained approximately 5-fold higher than baseline (Fig. 1B). The level of pro-C containing inhibins increased significantly (P < 0.05) from a baseline of 553.6 ± 66.1 pg/mL to 817.3 ± 154 pg/mL at 3 months, falling to a level not different from baseline at 10 months (Fig. 1C). There were no significant changes in the level of ir-inhibin with chemotherapy (Fig. 1D). LH levels increased significantly (P < 0.03), but to a much lesser extent and later than FSH, rising from a baseline of 7.4 ± 1.4 IU/L to 12.7 ± 2.0 IU/L at 4 months, returning to baseline at 12 months (Fig. 1F). Although testosterone levels increased significantly (P = 0.04) from a baseline of 14.9 ± 2.0 nmol/L to 23.0 ± 3.9 nmol/L at 1 month, there were no changes at other time points over the 12 months (Fig. 1E).

View larger version (47K): [in this window] [in a new window]   Figure 1. Changes in serum levels of inhibin B (A), FSH (B), pro-C containing inhibins (C), ir-inhibin (D), testosterone (E), and LH (F) in twelve men with a hematological malignancy during and after chemotherapy. Hatched areas represent normal ranges (mean ± 2SDs) derived from 62 known fertile semen donors (mean age 33.2 ± 6.3 yr). *, P < 0.0001 compared with baseline, **, P < 0.05 compared with baseline.

View larger version (12K): [in this window] [in a new window]   Figure 2. Association of FSH with inhibin B (A) and pro-C (B) in twelve men with a hematological malignancy before, during, and after chemotherapy.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

Following chemotherapy, circulating FSH levels rapidly increased, while inhibin B decreased, with a highly significant negative correlation between FSH and inhibin B levels. These results indicate that progressive testicular damage was being induced with the consequent loss of negative feedback control of FSH. In the absence of any changes in the appropriate direction in other testicular hormones, our data strongly suggest that inhibin B is the missing negative feedback signal in these subjects. These observations provide critical evidence to support the long-held view that inhibin is an important negative regulator of FSH secretion, giving added credence to the "snapshot" inhibin B data recently reported (17, 18, 19) and to the dynamic rebound changes in inhibin B and FSH levels observed following androgen-induced suppression of testicular function (18). Interestingly, the reduction of inhibin B levels to 20% of pretreatment values is similar to the degree of suppression achieved with androgen administration (18) and to that observed in men with untreated idiopathic hypogonadotrophic hypogonadism (28). This may indicate limited constitutive secretion of inhibin B by the testis, possibly from the Leydig cells rather than the Sertoli cells (29).

The design of this study does not allow us to exclude the possibility that some of the change in FSH secretion is secondary to altered production of testosterone (30). While we did not observe any significant changes in circulating testosterone levels, consistent with previous reports (8, 31), the production rate of testosterone may be significantly reduced in men with seminiferous tubular damage even if total testosterone levels are within the normal range (32). It is therefore conceivable that subtle changes in testosterone metabolism resulting in altered circulating free testosterone may account, at least in part, for the raised FSH levels.

The changes in the levels of ir-inhibin and pro-C containing inhibin afford further insight into the gonadotropin control of testicular inhibin secretion in men. That levels of ir-inhibin did not change significantly following testicular damage and increased FSH was not entirely unexpected. In men with severe seminiferous tubular dysfunction, evidenced by azoospermia or oligozoospermia and abnormal gonadotropins, ir-inhibin levels remain within the normal range (6). Similarly, normal ir-inhibin levels after chemotherapy (8) and in critically ill men (33) have been previously reported. However, the increasing levels of pro-C containing inhibin following testicular damage is a novel observation and, together with a recent report that the pro-C ELISA is probably detecting nondimeric precursor inhibin -subunits rather than larger dimeric forms (21), implies increased testicular secretion of free inhibin -subunits secondary to increased FSH. This would be supported by the in vitro finding that, while neither FSH nor LH upregulate inhibin ß-subunit secretion (34), FSH stimulation of Sertoli cell cultures increases inhibin -subunit secretion (35, 36), resulting in a decline in the ratio of bioactive: immunoreactive inhibin secreted (35). Furthermore, in the male Rhesus monkey, administration of recombinant human FSH preferentially increases the secretion of pro-C inhibin (37), and testicular biopsies from infertile men display increased immunostaining for the -subunit relative to biopsies from normal testes (38). Interestingly, staining is present in both the Leydig and Sertoli cells (38), and it is possible that the Leydig cells under increased LH stimulation may contribute to the increased inhibin -subunit secretion we observed. This would be supported by the significant, albeit weak, relationship between LH and pro-C inhibin levels. Thus, the stable ir-inhibin levels in the presence of increased gonadotropins are explained by the composite changes in the inhibins detected, with the changes in both inhibin B (decreasing) and free -subunit (increasing) cancelling out each other. It is likely that the normal ir-inhibin levels reported from the previous studies of testicular failure (6, 7, 8) may be similarly explained.

Importantly, the dynamic changes observed in this study relate the relationships between testicular and pituitary hormones during the progression from normal to severely impaired testicular function. While testicular function can be impaired in hematological malignancy before treatment (39, 40), this was not so for the men in our study as evidenced by pretreatment levels of ir-inhibin, testosterone, LH, and FSH within established normal ranges, and baseline levels of inhibin B similar to those previously obtained in healthy men (18). Further, although we were unable to document changes in semen parameters for ethical reasons, it is well established that the chemotherapeutic regimens used in our 12 men are known to invariably induce significant seminiferous tubular damage (30, 31, 41, 42, 43).

In conclusion, our prospective study has demonstrated a dramatic fall in inhibin B associated with a reciprocal rise in FSH following chemotherapy-induced testicular damage in adult men with hematological malignancies. This provides strong evidence to support the hypothesis that inhibin B is a physiologically important testicular feedback signal negatively regulating FSH secretion at the pituitary. Inhibin B is therefore a potentially useful circulating marker of seminiferous tubule/Sertoli cell function in man, particularly in situations where semen analysis is not possible. We have also shown that the increased FSH in turn increases nondimeric inhibin -subunit secretion, which may confound results derived from nonspecific assays of ir-inhibin.

	Acknowledgments

 
The authors wish to thank Dr. Leslie Russell for helping with the recruitment for the study and Ms. C. Balfour for performing the pro-C inhibin assays.

Received March 10, 1997.

Revised June 3, 1997.

Accepted June 9, 1997.

	References

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