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Original Studies |
Departments of Growth and Reproduction (P.M.P., A.-M.A., N.E.S.) and Oncology (P.M.P., M.P., G.D.), Finsencenter, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
Address all correspondence and requests for reprints to: Dr. Peter Meidahl Petersen, Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, 9 Blegdamsvej, Copenhagen, Denmark.
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Abstract |
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Thirteen men with verified spermatogenesis and detectable preirradiation levels of serum inhibin B (median, 55; range, 23–193 pg/mL) were investigated before and after testicular irradiation (14–20 Gy). All patients had undetectable levels of inhibin B 2–12 months (median, 5 months) after radiotherapy (<20 pg/mL). Correspondingly, serum FSH increased in all men after radiotherapy [from a median of 9.6 (range, 3.0–24) IU/L to a median of 28 (range, 15–70) IU/L); P < 0.001]. Histological investigation showed a Sertoli cell-only pattern in all patients after radiotherapy. Neither LH nor testosterone showed a significant decrease after radiotherapy.
Our data indicate that inhibin B production sufficient to maintain detectable serum levels in adults requires spermatogenic activity.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-subunit and a ß-subunit, which
exists in two forms, A and B (6, 7, 8). Animal studies have revealed a
complicated interaction between the different cell types in the testis
(9, 10), and inhibin production has been shown to be dependent on the
presence of later stages of germ cells (11). Most studies of blood
levels of inhibin have used heterologous assays that could not
distinguish between the bioactive dimeric inhibin form (inhibin
-ßA) and inactive forms such as free -subunit and
pro-C-related immunoactive peptides (1, 12). Recently, a new
enzyme-linked immunosorbent assay method has been developed for
specific measurement of the bioactive inhibin dimer,
-ßB (inhibin B) (1, 13). This inhibin B has been shown
to be the physiologically important form of inhibin in men. Recent
clinical investigations have indicated a role for inhibin B in the
feedback between the testis and the pituitary in healthy men and
patients with testicular dysfunction due to various causes (1, 13).
However, the relationship between spermatogenesis and inhibin B is
poorly investigated in the human testis. We had the possibility to
study inhibin B before and after testicular irradiation for testicular
carcinoma in situ (CIS). Previous studies in healthy men
have shown eradication of germ cells after testicular irradiation with
a level of more than 6 Gy given as a single dose (14, 15). Thus,
although the treatment in the present study was given to cure CIS, a
side-effect of this treatment is eradication of all nonmalignant germ
cells (16). Thus, this group of patients may serve as a model in the
investigation of physiological changes in the testis after selective
eradication of germ cells, including spermatogenic cells. |
Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twenty-five consecutive patients orchidectomized for unilateral testicular cancer and CIS in the remaining contralateral testis at the time of orchidectomy were considered for this study. Patients with ongoing spermatogenesis and detectable inhibin B levels before radiotherapy (n = 13; age, 19–52 yr) were included. The diagnosis of CIS in the contralateral testis was based on histological examination of a wedge biopsy obtained simultaneously with the orchidectomy. In all but 1 of the 13 patients, histological investigation of the testis harboring CIS also showed complete spermatogenesis in a fraction of seminiferous tubules. One patient had CIS in all tubules of the biopsy, but the histological examination showed a small area of tubules with immature Sertoli cells.
Radiotherapy was given as 14–20 meV electrons to the scrotum placed in a cup of lead in fractionated schedule (2 Gy, 7–10 times) (17). The follow-up examinations include measurements of serum inhibin B, FSH, LH, and testosterone and a histological examination of a biopsy to control the effect of radiotherapy. The first follow-up examination took place a median of 5 (range, 2–12) months after radiotherapy, and the last follow-up occurred a median of 29 (range, 3–67) months after radiotherapy.
None of the patients had elevated serum hCGß levels before treatment or at any time during the follow-up.
Hormone analyses
Serum FSH and LH levels were measured by time-resolved
immunofluorometric assay (DELFIA, Wallac, Turku, Finland). LH and
FSH levels were expressed in international units per L. The
sensitivities of the FSH and LH assays were 0.06 and 0.05 IU/L,
respectively. Testosterone was analyzed by RIA (Coat-a-Count,
Diagnostic Products Corp., Los Angeles, CA). The intra- and interassay
variations were below 10% in these assays. Inhibin B was measured by
immunometric assay, as previously described by Illingworth et
al. and Anawalt et al. (1, 13). This assay, which is
specific for bioactive inhibin dimer -ßB, uses
monoclonal capture antibody raised against the ßB-subunit
and a secondary monoclonal enzyme-conjugated antibody raised against a
sequence of the -subunit. The lower detection limit of the inhibin B
assay was 20 pg/mL, and the intra- and interassay variations were 12%
and 17%, respectively. All analyses of FSH and inhibin B were made
during 1996–1997. Blood samples from patients examined before 1996 had
been stored at -20 C. The possible effects of storage by freezing on
inhibin B analysis have been tested, and no effect was detected.
Statistical analysis
The changes in inhibin B, FSH, LH, and testosterone levels after radiotherapy were tested by paired t test if the differences between pre- and posttreatment values were normally distributed and by Wilcoxon’s signed rank test for paired data if they did not show normal distribution. The preirradiation levels were compared with the postirradiation levels at first and last follow-up examinations, respectively.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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and Fig. 1. Of the 13 men with detectable
pretreatment levels of inhibin B, 12 patients had undetectable levels
after irradiation (P < 0.001). One patient had
unmeasurable inhibin B and just detectable inhibin B levels (25 pg/mL),
respectively, at two follow-up visits. The patient was the only
individual with seminiferous tubules with clusters of undifferentiated
Sertoli cells in the biopsies before and after radiotherapy. FSH
increased in all patients after radiotherapy (Table 1 and Fig. 1).
There was a tendency for increased LH levels, but this increase was not
statistically significant, and the levels of testosterone was stable
(Table 1 and Fig. 2). Thus, a significant
Leydig cell function seemed to be preserved in these men. Posttreatment
biopsies were available in 12 patients, and histological investigation
showed a Sertoli cell-only pattern with numerous Leydig cells in the
interstitial tissue in all biopsies.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The observations of undetectable levels of inhibin B in absence of germ cells and the presence of Sertoli cells and Leydig cells suggest that measurable inhibin B production in adults requires the presence of germ cells. We cannot totally rule out the possibility that the Sertoli cells, which apparently are important in the production of inhibin B production (13), could be functionally damaged despite resistance to irradiation, as judged by their apparently unchanged number at histological investigation. However, the observation of undetectable inhibin B levels after selective germ cell depletion is in agreement with our observations that infertile men with histologically verified, idiopathic, Sertoli cell-only pattern had undetectable inhibin B levels (Andersson, A. M., personal communication) and with previous in vitro studies and animal studies that showed that inhibin secretion is stimulated by the presence of late spermatids (11, 18). The exception to the rule that inhibin B production in adult men requires the presence of complete spermatogenesis seems to be the presence of undifferentiated immature Sertoli cells, which apparently may be associated with measurable levels of serum inhibin B. This suggestion is illustrated by the observation of poorly differentiated Sertoli cells in the only individual who had detectable levels of inhibin B after irradiation. This observation is in line with our previous observations that prepubertal children with germ cell depletion have measurable levels of inhibin B (Andersson, A. M., personal communication).
In conclusion, irradiation of the testis with a dose level that eradicates spermatogenesis in men causes undetectable levels of inhibin B in serum. Our observation is in line with the assumption that germ cells in adult men participate in the production of inhibin B in men.
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Footnotes |
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Received June 17, 1998.
Revised September 11, 1998.
Accepted September 17, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-subunit mRNA levels by specific germ cell types. Mol Cell
Endocrinol. 72:13–22.[CrossRef][Medline]
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