Hum. Reprod. Advance Access originally published online on November 2, 2007
Human Reproduction 2007 22(12):3215-3222; doi:10.1093/humrep/dem313
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Inhibin B is superior to FSH as a serum marker for spermatogenesis in men treated for Hodgkin’s lymphoma with chemotherapy during childhood
1 Department of Pediatric Oncology/Hematology, Erasmus MC—Sophia Children’s Hospital, Room Sp3435, PO Box 2060, 3000 CB Rotterdam, The Netherlands 2 Department of Pediatric Endocrinology, Erasmus MC—Sophia Children’s Hospital, Room Sp3435, PO Box 2060, 3000 CB Rotterdam, The Netherlands 3 Department of Andrology, Erasmus MC, Rotterdam, The Netherlands 4 Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands 5 Department of Pediatric Oncology, Emma Children’s Hospital, Academic Medical Center, Amsterdam, The Netherlands
6 Correspondence address. Tel: +31-10-4636786; Fax: +31-10-4636811; E-mail: s.demuinckkeizer-schrama{at}erasmusmc.nl
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Abstract |
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BACKGROUND: The aim of this study was to evaluate the long-term gonadal sequelae after treatment for childhood Hodgkin’s lymphoma with combination chemotherapy, using up to date fertility parameters and andrological evaluation, including for the first time inhibin B.
METHODS: There were 56 male patients treated from 1974–1998 for childhood Hodgkin’s lymphoma with combination chemotherapy ABVD or EBVD (adriamycin/epirubicin, bleomycin, vinblastine, dacarbazine) with or without MOPP (mechlorethamine, vincristin, prednisone, procarbazine) with the intention to avoid radiotherapy. These men were studied 15.5 years (range 5.6–30.2 years) after cessation of therapy. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH), inhibin B, testosterone, sex hormone-binding globulin (SHBG), sperm concentration and sperm DNA integrity were determined.
RESULTS: In men treated with MOPP, median FSH and LH were significantly increased (P < 0.001) and inhibin B (17.5 versus 143 ng/l; P < 0.001) and sperm concentration (1.05 versus 49.5 x 106/ml; P < 0.05) were significantly decreased compared with patients treated without MOPP. The number of MOPP courses was significantly correlated with FSH and inhibin B levels. Only inhibin B showed an independent correlation with sperm concentration (r = 0.86; P < 0.001).
CONCLUSIONS: The use of MOPP chemotherapy causes permanent gonadal damage in the far majority of male survivors of childhood Hodgkin’s lymphoma and inhibin B is the most valuable serum marker for gonadal function.
Key words: inhibin B/fertility/Hodgkin’s lymphoma/long-term follow-up
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Introduction |
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The treatment of pediatric Hodgkin’s lymphoma consists of radiotherapy, chemotherapy or a combination of both. With the current treatment strategies, childhood Hodgkin’s lymphoma has an event-free survival rate and an overall survival rate of over 90% (Schellong, 1996
; van den Berg et al., 1997; Schellong, 1998; Hakvoort-Cammel et al., 2004). Consequently, the improved survival rates for Hodgkin’s lymphoma has led to a growing attention for long-term side effects (Oeffinger et al., 2006).
An important long-term effect of both radiotherapy and chemotherapy in males is testicular dysfunction, which may subsequently result in infertility or subfertility (McDowell et al., 2004). Especially, chemotherapy protocols containing alkylating agents (e.g. mechlorethamine or procarbazine) are known to cause severe gonadal damage in both adult and prepubertal patients (McDowell et al., 2004; Hobbie et al., 2005). Even though spermatogenesis is not functional before puberty, the seminiferous epithelium can be damaged irreversibly when alkylating agents are administered during early childhood, due to the ablation of the non-proliferating spermatogonia (Kreuser et al., 1992; Clark et al., 1995; Marmor and Duyck, 1995; Viviani et al., 1999). Up to now, studies on gonadal function after treatment for pediatric Hodgkin’s lymphoma have mainly focused on patients treated with combined modality treatment and not with chemotherapy alone (Ortin et al., 1990; Shafford et al., 1993; Heikens et al., 1996; van den Berg et al., 1997; Gerres et al., 1998; Papadakis et al., 1999; Ben Arush et al., 2000; Cicognani et al., 2000).
Most follow-up studies of long-term survivors of childhood cancer have assessed gonadal function and fertility using combinations of parameters such as testicular volume, semen analysis and/or serum levels of luteinizing hormone (LH), follicle stimulating hormone (FSH) and testosterone. An increase in serum FSH is considered the first indirect indicator of testicular dysfunction (Pierik et al., 1998). In the last decade, inhibin B has been identified as a good direct marker for assessment of spermatogenesis in andrology and fertility clinics. Inhibin B is produced by Sertoli cells, and is strongly correlated with spermatogenesis (Jensen et al., 1997; Klingmuller and Haidl, 1997; Pierik et al., 1998). To date, no studies are available in pediatric Hodgkin’s lymphoma using both inhibin B and semen analysis.
Andrological evaluation of the infertile male routinely consists of classic sperm analysis according to Word Health Organization (WHO) guidelines (WHO, 1999). In recent years, sperm DNA integrity has received growing attention as an additional diagnostic tool for the fertilizing potential of spermatozoa. Several studies have documented increased levels of sperm DNA fragmentation in male infertility (Spano et al., 1998; Evenson et al., 1999; Bungum et al., 2004). Although chemotherapy leads to mutagenic effects in animal studies, little is known about sperm DNA damage that may prevail after childhood Hodgkin’s lymphoma and consequent chemotherapy treatment (Trasler et al., 1985). It might be that persistent sperm DNA damage may either lead to impaired fertility or be transmitted to the offspring causing developmental abnormalities and cancer in the offspring (Morris, 2002), although after treatment with radiotherapy, no such effect has been observed (Winther et al., 2004). Scrotal ultrasound can also be valuable in identifying causes for male infertility (Pierik et al., 1999; Pierik et al., 2000).
The aim of this study is to evaluate the long-term gonadal sequelae after treatment for childhood Hodgkin’s lymphoma with combination chemotherapy only, using up to date fertility parameters and andrological evaluation, including for the first time inhibin B.
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Materials and Methods |
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Patients
A total of 100 male long-term survivors treated from 1974 to 1998 for pediatric Hodgkin’s lymphoma in the Erasmus MC-Sophia Children’s Hospital and AMC-Emma Children’s Hospital were identified. From this group, 13 patients refused participation (13%) and 31 patients were lost to follow-up (31%). There were no differences in age, disease characteristics and treatment between the included 56 male survivors and the 44 not included (Table I). Written informed consent was obtained from all participants, according to protocols approved by the ethical review board of the Erasmus MC. At the time of the study, all patients were in complete remission for more than 5 years after therapy (median follow-up time 15.5 years; range 5.6–30.2 years). The median age at diagnosis was 11.4 years (range 3.7–15.9 years). The median age at follow-up was 27.0 years (range 17.7–42.6 years).
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Therapy
All patients were treated with chemotherapy as previously described (van den Berg et al., 1997
; Hakvoort-Cammel et al., 2004) with ABVD or EBVD [adriamycin 25 mg/m2 (epirubicin 30 mg/m2 in EBVD), bleomycin 10 mg/m2, vinblastine 6 mg/m2 and dacarbazine (DTIC) 250 mg/m2 on day 1 and 8] with or without MOPP [mechlorethamine 6 mg/m2 and vincristine 2 mg/m2 (max 2.5 mg/dose) on day 1 and 8, prednisone 40 mg/m2/day and procarbazine 100 mg/m2/day on days 1–14]. Seven patients needed additional involved field radiotherapy because of treatment failure with chemotherapy only, disease progression or relapse (six treated with MOPP, one treated without MOPP). None of the patients was treated with irradiation to the abdominal or pelvic region. Scatter irradiation to the pelvic region was 
0.5% of the total dose. Patients were categorized into three treatment groups according to the number of administered MOPP cycles: no MOPP (n = 16), 3–4 MOPP (n = 14) and 
6 MOPP cycles (n = 26). None of the patients were treated with 1, 2 or 5 MOPP cycles.
History and measurements
All participants completed a detailed questionnaire regarding fertility-related disease or surgery, paternity and medication. Medical records were reviewed to establish the pubertal stage at diagnosis, the disease stage at diagnosis, the presence of B-symptoms (fever, night sweats and/or loss of >10% of body weight), age at diagnosis and duration of follow-up. Puberty was defined as Tanner stage G2 and higher or age above 14 years.
Blood samples, obtained by venous puncture, were processed within 2 h after withdrawal and stored at –20°C until assay. Serum samples were tested for FSH, LH and sex hormone-binding globulin (SHBG) using fluorescence-based immunometric methods (Immulite 2000, Diagnostic Products Corporation, Los Angeles, CA, USA), for inhibin B using an enzyme-immunometric method (Oxford BioInnovation, Oxford, UK) and for total testosterone using a coated tube radioimmunoassay (Diagnostic Products Corporation, Los Angeles, CA, USA). Intra- and interassay coefficients of variation were less than 5% and 15% for LH, less than 3% and 8% for FSH, less than 7% and 9% for SHBG, less than 9% and 15% for Inhibin B and less than 7% and 9% for testosterone. Bioavailable testosterone was calculated according to the method of Sodergard et al. (1982).
Andrological examination
Semen analysis was performed in 21 patients (4 MOPP– and 17 MOPP+). Fresh sperm samples were produced by masturbation after 3–5 days of ejaculatory abstinence. After liquefaction, sperm concentration, motility and morphology were assessed within 1 h according to WHO guidelines (WHO, 1999). An aliquot of the semen sample was stored at –80°C for later analysis of sperm DNA damage.
Further, andrological examination, including scrotal ultrasound, was performed in 18 of these patients (three patients refused participation for this part of the study). Testicular volume was measured using a Prader orchidometer. Scrotal ultrasound was performed using a Toshiba Nemio 20 with a 12 Hz transducer. The ultrasonic volume of each testis was calculated from three perpendicular measurements in the equation V (ml) = 
x length x width x depth (all in cm)/6. The mean bilateral testicular volume was calculated and used for further analysis. Epididymal caput diameter was recorded as indicative for obstruction whenever a diameter above 12 mm was found. A varicocele was diagnosed when at least two venous vessels with a diameter of at least 3 mm were present, in addition to reflux or diameter increase during Valsalva’s maneuver. The testicular parenchyma was scored as normal texture, infertile texture, low-grade microlithiasis (<5 per testis), medium-grade microlithiasis (5–10 per testis), high-grade microlithiasis (>10) or landscape texture microlithiasis (25).
Sperm DNA integrity
Sperm DNA integrity was measured using the Sperm Chromatin Structure Assay (SCSA) as previously described by Evenson et al. (1999). In short, the assay is based on the higher susceptibility of defective sperm chromatin for acid DNA denaturation. Following acid denaturation, sperm DNA is stained with a fluorescent dye, acridine orange (AO), which emits green fluorescence when bound to double stranded DNA but shifts to red fluorescence when bound to single stranded DNA. Sperm DNA damage is quantified by flow cytometric measurements of green and red fluorescence in each sperm cell nucleus. The extent of DNA fragmentation is then calculated as the ratio of red to total (red plus green) fluorescence and is expressed as the DNA fragmentation index (DFI). SCSA was performed in 7 out of the 21 sperm samples. In 10 patients, SCSA could not be performed due to azoospermia, whereas in four patients, no material for SCSA was available after semen analysis.
Statistical analysis
Statistical analysis was performed using SPSS 12.01 software (SPSS, Chicago, IL, USA). Differences in histological subtype and stage of the lymphoma between the included patients and those not included were tested using 
2-test. Differences between treatment groups were tested using Mann–Whitney U-tests and correlations were tested using Spearman’s correlation. Kruskal–Wallis tests were used to test for trends. Regression analysis was performed to test the effect of different parameters on measurements of testicular function i.e. LH, FSH, inhibin B and sperm concentration. P-values <0.05 were considered significant.
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Results |
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A total of 37 patients were prepubertal at diagnosis, whereas 15 patients were pubertal. For four patients (ages 12.3–13.7 years), no data were available on pubertal status at start of therapy. Patients with B-symptoms (n = 16) had a significantly higher disease stage (12.5% stage I; 43.8% stage II; 33.5% stage III; 12.5% stage IV) when compared with patients without B-symptoms (n = 40; 55.2% stage I; 31.0% stage II; 13.8% stage III; 0% stage IV;
2 = 10.4; P < 0.05). In patients without B-symptoms, 65.5% were treated with MOPP, whereas in patients with B-symptoms, this was 81.3%. Table II shows the median values of serum hormone and sperm concentration of patients either treated with MOPP (MOPP+) or without MOPP (MOPP–) and normal reference values as used in the Erasmus MC. Median LH and FSH values were significantly higher in MOPP+ patients when compared with MOPP– patients (P < 0.01), who all had normal to marginally increased LH and FSH levels. Median inhibin B levels were significantly lower in MOPP+ patients when compared with MOPP– patients (P < 0.01). Levels of SHBG were normal in all patients, whereas concentrations of testosterone and bioavailable testosterone were normal to marginally decreased and not different between MOPP+ and MOPP– patients.
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The median sperm concentrations were significantly lower in MOPP+ patients when compared with MOPP– patients (Table II). Compromised sperm concentrations were found in 77% of the men treated with MOPP. In contrast, normospermia was found in all four men treated without MOPP. Azoospermia was found in 9 out of 17 (53%), oligozoospermia (<20 x 106/ml) in 1 out of 17 (6%) and severe oligozoospermia (<5 x 106/ml) in 3 out of 17 (18%) MOPP+ patients. In 4 out of 17 MOPP+ patients (23%), normospermia was found; three of these men were treated with three MOPP cycles and one was treated with six MOPP cycles (age at diagnosis 6.8 years, follow-up time 27.7 years).
Figure 1 shows LH, FSH, inhibin B and sperm concentration in relation to the number of MOPP cycles. LH and FSH increased, and inhibin B levels and sperm concentration decreased significantly with an increasing number of MOPP cycles (Kruskal–Wallis for trend, P < 0.001 for all parameters). No significant differences in LH, FSH, inhibin B or sperm concentration were found between men treated with 3–4 and 6 MOPP courses.
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Laboratory parameters were compared with semen concentrations (Fig. 2). Both LH and testosterone were not significantly related with sperm concentrations. Significant correlations were found between sperm concentration and FSH (r = – 0.67, 95% CI: –0.85 to –0.30; P < 0.001) and inhibin B (r = 0.86, 95% CI: 0.94–0.65; P < 0.001). In a multivariate analysis with inhibin B and FSH as determinants of sperm concentration, inhibin B was the only significant determinant (
= 1.61; P < 0.001).
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The median DFI in the studied men was 10% (5.67–25.55%) and did not differ from 20 healthy controls with normospermia: 12% (6.85 – 34.45%). All participants with normospermia had DFI levels in the normal, fertile range (<15%), whereas the two men with oligozoospermia had moderate DFI levels (15–30%) of 24% and 26%, respectively.
History and andrological examination revealed several confounders for fertility in this Hodgkin’s lymphoma survivor group. Two patients reported a history of bilateral orchidopexy (one MOPP– and one MOPP+), and in one patient, physical examination and scrotal ultrasound revealed a left-sided varicocele grade I. The latter patient was treated with eight MOPP cycles and oligozoospermia was found. Furthermore, scrotal ultrasound revealed low-grade testicular microlithiasis in 4 out of 18 patients (one MOPP– and three MOPP+). In two other patients, a lack of homogeneity of the testicular parenchyma was found unilateraly. These men were diagnosed with respectively azoospermia and severe oligozoospermia. Bilateral infertile testicular parenchyma was found in 3 out of 18 patients of whom two had azoospermia and one was diagnosed with severe oligozoospermia (all MOPP+). None of the results of physical examinations or scrotal ultrasound indicated obstruction of the vas deferens.
The 8 MOPP– patients and 26 MOPP+ patients for whom data on testicular volume were available did not significantly differ in their testicular volume (Table II). One of eight MOPP– patients had a testicular volume below the normal reference value, whereas 16 of 26 MOPP+ patients had testicular volumes below the normal reference value. None of the fertility-related parameters assessed in this study, i.e. FSH, inhibin B levels and sperm concentration, was associated with testicular volume measurements.
The outcome of fertility parameters did not differ between patients treated during puberty and patients treated before puberty. Patients with B-symptoms at diagnosis had significantly lower inhibin B levels (P < 0.05) and sperm concentration (P = 0.05) when compared with patients who did not present with B-symptoms. A multiple regression analysis was performed on the different hormonal measurements and sperm concentration considering the number of MOPP cycles, number of EBVD/ABVD cycles, radiotherapy (mantlefield or mediastinal), puberty at start of diagnosis, age at diagnosis, disease stage at diagnosis, the presence of B-symptoms and duration of follow-up. Age at diagnosis was a significant determinant of FSH ( = 1.4; P < 0.05) and sperm concentration ( = – 6.18; P < 0.05). The number of MOPP cycles significantly determined LH levels ( = 0.87; P < 0.01), FSH level ( = 2.57; P < 0.01), inhibin B levels ( = – 21.59; P < 0.05) and sperm concentration ( = – 6.25; P < 0.05).
In the questionnaire, all men reported normal pubertal development. Five men reported seven pregnancies. Two of the reported pregnancies were conceived by donor sperm (both in men treated with six MOPP cycles). Of the five spontaneously conceived pregnancies, two men treated without MOPP each fathered one healthy child and the man treated with six MOPP cycles fathered one healthy child and reported two spontaneous abortions.
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Discussion |
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Alkylating agents are known to cause severe gonadal damage in both adults and children (McDowell et al., 2004
; Hobbie et al., 2005). It is well documented that adult men treated with MOPP combination chemotherapy suffer from permanent gonadal damage (Waxman et al., 1982; Shafford et al., 1993; Clark et al., 1995). Several earlier studies reported on gonadal function after treatment for pediatric Hodgkin’s lymphoma (Table III), but these were relatively small and did not include up-to-date markers like inhibin B. The present study shows that inhibin B is a better marker for spermatogenesis than FSH in male survivors of childhood Hodgkin’s lymphoma.
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Previous studies primarily used FSH levels as a marker for fertility. The frequency of elevated FSH levels after chemotherapy with alkylating agents varies from 35% to 100% and depends on the cumulative doses of alkylating agents (Kulkarni et al., 1997
; Gerres et al., 1998; van den Berg et al., 2004). The correlation between FSH levels and the number of MOPP courses was confirmed in the present study. Patients treated without MOPP had normal FSH levels, whereas after treatment with MOPP, 75% of the patients showed increased FSH levels. In addition, we analyzed whether inhibin B would better predict spermatogenesis than FSH. Literature data suggest that the suppression of spermatogenesis by chemotherapy is accompanied by a decrease in serum levels of inhibin B (Wallace et al., 1997). Studies relating testicular histology with spermatogenesis support this assumption (Pierik et al., 1998; Leifke et al., 2000). Our results show that male survivors of Hodgkin’s lymphoma treated at childhood age with alkylating agents have significantly lower levels of inhibin B when compared with men not treated with these agents. In addition, we showed that inhibin B level is a stronger and more independent determinant of sperm concentration compared with FSH level. Inhibin B level therefore appears to be the better fertility marker, which can be used as a screening method to detect gonadal damage in men treated for Hodgkin’s lymphoma in childhood. Our findings in this long-term pediatric Hodgkin’s lymphoma follow-up cohort confirm earlier studies in adults, which showed that inhibin B concentrations are correlated with sperm concentrations in both healthy men (Jensen et al., 1997) as well as in men with fertility problems (Pierik et al., 1998). Pierik et al. (1998) showed that in men with fertility problems, inhibin B is a better marker of spermatogenesis than FSH. A small study of Cicognani et al. (2000) showed comparable results in 11 adult Hodgkin’s lymphoma survivors. Finally, it is noteworthy that in our study, all male survivors with inhibin B levels above 75 ng/ml had normospermia.
Some studies suggested that the seminiferous cords of the prepubertal testis may be less susceptible to germinal damage from chemotherapy than pubertal or post-pubertal testes (Rivkees and Crawford, 1988), whereas others did not (Heikens et al., 1996). In our study, pubertal stage at diagnosis and start of treatment did not influence gonadal function. However, since older age at diagnosis was an independent determinant of sperm concentration and FSH levels, maturational status of the testis might still be of some influence.
Adult studies showed that 75–100% of the patients treated with alkylating agents have irreversibly compromised spermatogenesis (Waxman et al., 1982; Shafford et al., 1993; Clark et al., 1995). Recovery of spermatogenesis after chemotherapy in adulthood has been reported, but only after chemotherapy without or with low doses of alkylating agents (Pedrick and Hoppe, 1986; Viviani et al., 1999; Dubey et al., 2000). In the present pediatric study, two patients had normal inhibin B and FSH levels and normospermia, despite a high number of MOPP courses. These two men had the longest follow-up times of, respectively, 27 and 28 years. This might indicate that late recovery of spermatogenesis might occur following MOPP chemotherapy. Late recovery has been described earlier in adult patients after a follow-up of more than 10 years (Marmor and Duyck, 1995).
One could raise concern that cytotoxic chemotherapy or the disease itself might result in transmissible genetic damage. Although Kobayashi et al. (2001) found more pronounced sperm DNA damage in 11 Hodgkin’s lymphoma patients prior to treatment when compared with controls, little information is known about sperm DNA damage after chemotherapy (Morris et al., 2002). After chemotherapy for (adult) testicular cancer, sperm DNA damage has been observed (Spermon et al., 2006). Thomson et al. (2002) found that the sperm DNA integrity in survivors of childhood cancer was comparable to that in healthy controls. Our study confirms these results in survivors of childhood Hodgkin’s lymphoma. Although the sperm chromatin structure assay cannot assess chromosomal abnormalities such as aneuploidy or more subtle chromosomal damage or mutations, we showed that the sperm cells produced long after chemotherapeutic treatment for Hodgkin’s lymphoma have a normal chromatin structure.
In our study, all testosterone levels as well as levels of bioavailable testosterone were within the normal range or marginally decreased. However, LH levels were significantly elevated in patients treated with MOPP when compared with patients treated without MOPP. This increase in LH levels indicates that, although testosterone levels are normal, some Leydig cell damage has occurred (Howell et al., 1999; van den Berg et al., 2004). Although these men might be at risk of androgen deficiency in later life, we also showed that LH is inferior to FSH and inhibin B in detecting testicular damage.
Patients presenting with B-symptoms at diagnosis had significantly lower fertility parameters compared with patients who did not present with B-symptoms at diagnosis. This might be related to a lower semen quality before start of therapy associated with B-symptoms (Viviani et al., 1991; Tal et al., 2000; Howell and Shalet, 2001; Gandini et al., 2003), or to the higher number of MOPP courses that these patients received because of higher disease stages. When correcting for other factors in the multivariate analysis, the presence of B-symptoms appeared not to be an independent factor determining a lower fertility on the long term.
We conclude that this is the first study in which both spermatogenesis and serum inhibin B levels were assessed in a group of long-term male survivors of pediatric Hodgkin’s lymphoma. Inhibin B is a good serum marker, superior to FSH, for spermatogenesis in men treated for childhood Hodgkin’s lymphoma with combination chemotherapy. However, since men with mildly decreased inhibin B levels might still have sufficient sperm concentration for assisted reproduction or even natural conception, we recommend that semen analysis should be performed in men with a wish for paternity.
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Funding |
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Research was funded through a grant from the pediatric oncology foundation Rotterdam.
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References |
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Submitted on June 4, 2007; resubmitted on August 20, 2007; accepted on August 29, 2007.
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