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Serum Inhibin B in Combination with Serum Follicle-Stimulating Hormone (FSH) Is a More Sensitive Marker Than Serum FSH Alone for Impaired Spermatogenesis in Men, But Cannot Predict the Presence of Sperm in Testicular Tissue Samples¹

Institute of Reproductive Medicine of the University, D-48129 Münster; and Institute of Veterinarian Anatomy, University of Giessen (M.B.), D-35390 Giessen, Germany

Address all correspondence and requests for reprints to: Prof. Dr. E. Nieschlag, Institute of Reproductive Medicine of the University, Domagkstrasse 11, D-48129 Münster, Germany. E-mail: nieschl{at}uni-muenster.de

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The measurement of serum FSH is useful in the diagnostic workup of the infertile male, but fails to predict the presence of sperm in testicular tissue. We investigated whether inhibin B reflects testicular morphology and the presence of sperm more accurately than FSH. Serum inhibin B and gonadotropin levels were determined in 91 infertile men undergoing diagnostic bilateral testicular biopsy. In 52 of the 91 patients multiple samples were taken for testicular sperm extraction (TESE). Inhibin B levels were (mean ± SEM) 238 ± 32 pg/mL in men with normal spermatogenesis (n = 9), 102 ± 18 pg/mL in men with spermatogenetic arrest (n = 15), 98 ± 16 pg/mL in hypospermatogenesis (n = 23), 41 ± 6 pg/mL in focal Sertoli cell-only syndrome (SCO; n = 26), and 27 ± 8 pg/mL in complete SCO (n = 18). The percentage of SCO tubuli was more strongly correlated to serum inhibin B (r = -0.58; P < 0.01) than to FSH (r = 0.34; P < 0.05). Similarly, the percentage of tubules with elongated spermatids was significantly (P < 0.05) more strongly correlated to serum inhibin B (r = 0.65; P < 0.01) than to FSH (r = -0.4; P < 0.01). Thus, inhibin B is slightly more sensitive than FSH as an index of the spermatogenic status. Neither FSH nor inhibin B alone, however, could predict the type of spermatogenetic damage exactly. The combination of FSH and inhibin B had high diagnostic sensitivity (88%) and specificity (83%) for the presence of elongated spermatids in testicular biopsies. Sperm could be retrieved in 34 (65%) of the TESE patients. The combination of inhibin B and FSH measurement showed a sensitivity of 75% and a specificity of 73% when identifying patients in whom sperm could possibly be retrieved by TESE. We conclude that although the measurement of serum inhibin B improves the sensitivity of predictive tests for the presence of sperm in histology or for TESE, this parameter cannot accurately predict TESE outcome.

	Introduction

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INHIBIN is a heterodimeric glycoprotein consisting of an -subunit and either a ßA-subunit (inhibin A) or a ßB-chain (inhibin B) (1). In men inhibin is secreted from the testis as a product of Sertoli cells involved in the regulation of FSH secretion (2). Classical RIAs for the determination of inhibin, however, were incapable of discriminating among the different inhibin isoforms and yielded conflicting results concerning the function of this hormone in the male reproductive axis (3). A specific immunoassay for inhibin B, developed recently (2), provided more evidence that inhibin B is the physiologically important inhibin form in men. A strong inverse correlation exists between inhibin B and FSH levels in men with normal and disturbed spermatogenesis (4, 5). Inhibin B concentrations are closely related to sperm concentration in the ejaculate (6) and to testicular volume (7). Suppression of spermatogenesis induced by exogenous testosterone (8) or chemotherapy (9) is accompanied by a decrease in serum levels of inhibin B. Based on these observations, it has been suggested that inhibin B could be a good marker for spermatogenesis, and the limited data from men with known testicular histology preliminarily support this hypothesis (7, 10).

In the workup of male infertility, FSH is the classical endocrine parameter to discriminate between testicular impairment of spermatogenesis and obstructive disorders (11). Several studies confirm that FSH levels are a valuable predictive marker of the histological picture of the testis, but a wide overlap between values in states of regular and reduced spermatogenesis limits its diagnostic accuracy (12). As FSH is only an indirect index of the spermatogenic status, the question arises whether inhibin B, as a direct product of the Sertoli cell, may be more accurate. The identification of a parameter that can discriminate between complete absence of germ cells in the testis and less severe disturbances of sperm production would be of considerable prognostic value for assisted reproduction techniques based on sperm retrieval from the testis.

The present study was performed to investigate how serum concentrations of inhibin B reflect different states of spermatogenesis in a large group of men in whom open testicular biopsies were performed either for diagnostic purposes or as a therapeutic intervention [testicular sperm extraction (TESE)] within an assisted reproduction program.

	Subjects and Methods

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Subjects

In a retrospective analysis we studied 91 patients. All had severely reduced semen parameters (azoospermia or oligozoospermia with sperm concentrations <10⁵/mL). Thirty-nine patients underwent testicular biopsy only as part of the diagnostic workup for infertility. In the remaining 52 patients, beside the diagnostic biopsy, additional testicular samples were taken for direct extraction of sperm to be used for in vitro fertilization therapy. In these patients sperm extraction was performed after enzymatic digestion of tissue following the method described by Salzbrunn et al. (13). Sperm extraction was only performed in a subset of patients because this method was introduced in the middle of the study period. Serum samples were obtained from all patients and stored at -20 C until hormone assays were performed. The age of the patients ranged from 17–52 yr. Eighty-four proven fathers served as the control group for serum hormone levels and were previously described (14). All subjects gave informed consent for this study.

Testicular biopsy

Bilateral, open testicular biopsy was performed under local anaesthesia as previously described (12). All biopsies were fixed in Bouin’s solution. For testicular morphology, at least 25 tubules/testis were evaluated. Scoring of each biopsy was performed by 2 investigators. A mean number of 91.5 tubules (minimal, 67; maximal, 116)/patient was evaluated. The percentage of tubules with elongated spermatids, round spermatids, primary spermatocytes, spermatogonia, or merely Sertoli cells or showing complete absence of cells (tubular atrophy) was calculated. For evaluation we followed the scoring system introduced by Holstein and Schirren (15), which is based on the percentage of seminiferous tubules containing mature spermatids. Details of the scoring system have been described previously (12).

Testicular volume

Determination of testicular volume was performed by sonography using a 7.5-Mhz sector scan (Sonoline versa pro, Siemens, Erlangen, Germany). The procedure for calculation of testicular volume has been described previously (16).

Hormone analysis

Inhibin B was measured using a commercially available, double antibody, enzyme-linked immunoassay (Serotec Ltd., Oxford, UK). Intra- and interassay coefficients of variation were 3.3% and 18%, respectively. The sensitivity of the inhibin B assay, defined as the value 2 SD deviations above the mean of 10 repeated measurements performed with the zero standard, was 7.8 pg/mL, a concentration corresponding to that of the lowest point of the standard curve. The normal range of serum inhibin B concentrations obtained from values in the 84 proven fathers was 94–327 pg/mL.

FSH and LH were analyzed by immunofluometric assays (Autodelfia, Wallac, Inc., Freiburg, Germany). The lower detection limits were 0.12 and 0.25 IU/L, respectively. The normal ranges are 1–7 and 2–10 IU/L for FSH and LH, respectively. Serum testosterone was measured by RIA (Diagnostic Systems Laboratories, Inc., Sinsheim, Germany). The lower limit of the normal range is 12 nmol/L.

Statistical analysis

Statistical analysis was performed using the statistical package SPSS for Windows (version 7.0, SPSS, Inc., Evanston, IL). All variables were checked for normal distribution by Kolmogorov-Smirnov one-sample test for goodness of fit. Descriptive statistics are given as the mean ± SEM. For comparison between two groups, a t test for independent samples was used, whereas comparisons between more than two groups were calculated by one-way ANOVA followed by Dunnett’s post-hoc test for intergroup comparison. Pearson’s coefficient of correlation was used for regression analysis. The diagnostic performance of inhibin B and FSH was described as their ability to discriminate between patients with the presence or absence of sperm, calculating sensitivity and specificity at different cut-off levels for both parameters (17).

	Results

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Sixty-five patients had nonobstructive azoospermia or severe oligozoospermia, 24 men had an obstructive disorder, 1 patient had Reifenstein’s syndrome, and 1 true hermaphroditism. Twenty-nine of the 65 nonobstructed patients had a history of maldescended testes, 4 men had a history of orchitis, 5 patients had been treated with chemotherapy for nontesticular malignancies, and in 27 patients no cause of infertility could be identified (idiopathic). In 4 of the 24 men with obstruction, mutations in the cystic fibrosis gene were found, 2 had associated anomalies of the renal system, two had undergone vasectomy, and in the remaining men obstruction was related to a previous genital inflammation.

Nine of the 91 patients showed histologically normal spermatogenesis. Biopsies of 44 men showed Sertoli cell-only syndrome (SCO), which in 18 cases was present in all tubules evaluated (bilateral complete SCO), whereas in 26 biopsies SCO was found together with some tubules with ongoing spermatogenesis (unilateral or bilateral focal SCO). Mixed atrophy with spermatogenic arrest was diagnosed in 15 patients; in 5 cases spermatogenesis was arrested at the stage of round spermatids, in 9 cases it was stopped at the stage of primary spermatocytes, and in 1 patient only tubules with spermatogonia were present (Reifenstein’s syndrome). In 23 men qualitatively normal, but quantatively reduced, spermatogenesis was found.

Inhibin B levels in the patients grouped according to histological findings are shown in Fig. 1a. In men with normal spermatogenesis, inhibin B levels (238 ± 32 pg/mL) were all above the lower normal limit of 94 pg/mL. Compared with this group, patients with quantitative reduction of spermatogenesis had significantly (P < 0.01) lower mean inhibin B levels (98 ± 16 pg/mL) as did those with spermatogenic arrest (102 ± 18 pg/mL). The lowest inhibin B levels were measured in cases with SCO, with the most pronounced reduction in the presence of complete SCO (27 ± 8 pg/mL) compared to that in patients with focal SCO (41 ± 6 pg/mL). The differences between complete and focal SCO did not reach statistical significance. The corresponding distribution of FSH values and bilateral testicular volume is summarized in Fig. 1, b and c. Inhibin B levels were significantly negatively correlated to FSH concentrations (Fig. 2 and Table 1) and were significantly positively correlated to bitesticular volume (Table 1).

View larger version (26K): [in this window] [in a new window]   Figure 1. Distribution of inhibin B (a), FSH (b), and bilateral testicular volume (c) values in the five groups of patients according to histology. Values are given as the median and the first (boxes) and second quartiles below and above the median. Outliers are plotted as points. The dotted line indicates the lower reference limit for inhibin B concentrations (a) and bitesticular volume (c) and the upper limit for FSH (b).

View larger version (22K): [in this window] [in a new window]   Figure 2. Correlation between inhibin B and FSH serum concentrations in 91 men with different histological findings, as documented by open bilateral testicular biopsy. Patients with low inhibin B and normal FSH are grouped in category I (n = 6), patients with low inhibin B and high FSH are grouped in category II (n = 52), patients with normal inhibin B and high FSH are grouped in category III (n = 8), and patients with normal inhibin B and normal FSH are grouped in category IV (n = 25).

TESE results are given in Fig. 3. Sperm could be retrieved from 34 patients (65%) with no obvious correlation to FSH or inhibin B values. No sperm could be obtained from 4 of 16 patients (25%) with normal inhibin B and FSH values. On the other hand, sperm could be extracted from the testicular tissue of 17 of 27 patients (63%) with high FSH and low inhibin B levels. To evaluate the diagnostic power of inhibin B and FSH to predict the presence of sperm or elongated spermatids in histological specimens or during TESE, we calculated sensitivity and specificity at two different cut-off levels for FSH and inhibin B, alone or in combination. Cut-off levels were first set at the lower limit of the normal range for inhibin B and at the upper limit of the normal range for FSH as defined in our laboratory based on the group of proven fathers. The results are summarized in Table 3. The combination of inhibin B and FSH resulted in the highest diagnostic sensitivity (88%) and specificity (83%) for the detection of sperm in histological specimens, whereas both parameters showed a sensitivity below 50% when considered alone. Similarly, the 2 parameters together showed a specificity of 73% from TESE-positive samples, with high sensitivity (75%). Based on receiver operating characteristics analysis, previous investigators had suggested a different cut-off level for the discrimination between men with intact and impaired spermatogenesis (7). If analysis was repeated considering a cut-off for FSH of 4.9 IU/L and for inhibin B of 139 pg/mL, inhibin B alone had a higher specificity (92%) for the presence of sperm in histological samples, but the sensitivity was only 23% (Table 3). Sensitivity for the detection of men with sperm from histological specimens or during TESE was below 50% for either inhibin B or FSH alone. Finally, the positive predictive value for the absence of sperm from histology (84%) or TESE (75%) was best using a reference limit of 94 pg/mL and a FSH concentration of 7 IU/L. The negative predictive value for either histology (92%) or TESE (94%) is better at levels of 139 pg/mL inhibin B and 4.9 pg/mL FSH. Predictive values between single and combined measurements were comparable. In patients with complete SCO on histology, sperm retrieveal was never possible, whereas in the presence of focal SCO, it was successful in 7 of 9 cases. Sperm extraction was not possible in 3 of 35 men with sperm present in the histological specimen.

View larger version (23K): [in this window] [in a new window]   Figure 3. Correlation of serum inhibin B and FSH concentrations to the result of sperm extraction in patients (n = 52) in whom TESE was performed.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

It has been suggested that inhibin B may be a better predictor of spermatogenesis than FSH (6, 7). The diagnostic accuracy of FSH is limited by the fact that spermatogenic arrest at late stages does not lead to changes in FSH secretion and that FSH may be normal in patients with focal SCO or hypospermatogenesis (12). In principle, the present data show that the same limitations hold true for serum inhibin B. In cases of spermatogenic arrest, inhibin B as well as FSH serum concentrations may be normal, except for the cases with a large percentage of SCO tubules. Our data confirm a recent report showing slightly reduced inhibin B levels in men with spermatogenic arrest (20). Most importantly, inhibin B levels could not be related to the stage at which spermatogenesis was arrested. For example, in the patient with Reifenstein’s syndrome, in whom only spermatogonia were present, inhibin B levels were normal. This finding conflicts with the recent description of inhibin ßB-subunit localization in germ cells from pachytene spermatocytes to the early spermatid stage and not in Sertoli cells (20), in contrast to a previous report (21). Moreover, it was suggested that the regulation of inhibin B subunit expression in Sertoli cells or germ cells may depend on the state of testicular maturation (20). We cannot exclude that in Reifenstein’s syndrome maturation may be different from that of the normal postpubertal testis. From our data it cannot be concluded that any specific type of germ cell is involved in the regulation of inhibin secretion, as has been suggested for the adult rat or the human (20, 22).

The analysis of the patients in whom TESE was performed showed that combining inhibin B and FSH serum concentrations yields a high positive predictive value for the presence of sperm in histology or TESE. The addition of serum inhibin B measurement improves the sensitivity of the tests, but only slightly improved the predictive value. No sperm could be retrieved in 25% of cases with normal FSH and inhibin B values. On the other hand, even when inhibin B levels are below 20 pg/ml can sperm still be extracted from the testis in a large percentage of patients (5 of 13 cases, 38%). Other researchers have previously reported that sperm extraction may be successful even in cases with grossly elevated FSH levels (22). Although the measurement of serum inhibin B improves the sensitivity of predictive tests for the presence of sperm in the tissue samples or during TESE, this parameter is not useful for predicting the TESE outcome.

Despite the close correlation between inhibin B and FSH, small subsets of cases exist characterized by either low inhibin B and low FSH levels, or normal inhibin B and elevated FSH. Interestingly, the group of patients with low inhibin B but normal FSH levels had significantly lower LH values in the presence of normal testosterone compared to other patients with a reduction in inhibin B levels. This observation is suggestive of a distinct form of disturbance. Morrow et al. (24) reported comparable findings with a positive correlation between LH and testosterone in infertile men with low FSH values compared to those with high FSH levels, in whom the correlation was negative, suggesting heterogeneous causes for testicular malfunction. The hormonal constellation we found suggests that despite decreased serum inhibin B concentrations, infertile men with normal FSH levels might have a more sensitive feedback regulation of gonadotropin secretion by the peripheral hormones. Alternatively, testosterone could be the only effector of the feedback control of both gonadotropins in such subjects. Finally, these men might have a selective impairment of gonadotropin secretion, which cannot be otherwise recognized. In men with hypogonadotropic hypogonadism, inhibin B levels are low in the presence of low FSH values, and successful stimulation of spermatogenesis with pulsatile GnRH therapy leads to an increase in inhibin B as well as FSH (25). In patients with idiopathic infertility, treatment with FSH (26) not only did not improve sperm counts, but failed to increase inhibin B levels. Whether treatment with FSH may improve inhibin B secretion and or spermatogenesis in this special subgroup of patients deserves further investigation. Our data do not rule out that impaired Sertoli cell function is the primary pathology in these patients.

We conclude that despite the close correlation between inhibin B and FSH, the two parameters together are a more sensitive predictor of the spermatogenic state than either of them alone. However inhibin B, alone or in combination with FSH, is of limited clinical value in patients considered for TESE. Finally, no specific germ cell type can be identified as a predominant regulator of inhibin B secretion. Patients with low inhibin B and low FSH levels may be an important group for further studies of the feedback control of FSH secretion.

	Acknowledgments

 
We are grateful to Prof Dr. L. Hertle and Dr. S. Kliesch, Department of Urology, University of Münster, for performing the biopsies. We thank N. Terwort, R. Sandhowe-Klaverkamp, I. Uppmann, and J. Salzig for technical assistance, and Susan Nieschlag, M.A., for language editing of the manuscript.

	Footnotes

 
¹ This work was supported by the Deutsche Forsehungsgemeinschaft Confocal Research Group "The Male Gamete: Production, Maturation, Function" (Ni 130/15).

Received February 1, 1999.

Revised March 29, 1999.

Accepted April 6, 1999.

	References

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