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Emotional disorders in testicular cancer survivors in relation to hypogonadism, androgen receptor polymorphism and treatment modality
Journal of Affective Disorders 122 (2010) 260–266
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Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d
Research report
Emotional disorders in testicular cancer survivors in relation to hypogonadism, androgen receptor polymorphism and treatment modality Jakob Eberhard a,b,⁎, Olof Ståhl a,b, Gabriella Cohn-Cedermark d, Eva Cavallin-Ståhl a, Yvonne Giwercman c, Hamideh Rastkhani c, Lars Rylander c,e, Malin Eberhard-Gran f, Ulrik Kvist g,h, Aleksander Giwercman b,c a
Department of Oncology, Lund University Hospital, Lund University, SE 221 85 Lund, Sweden Reproductive Medicine Centre, Malmö University Hospital, Lund University, Malmö, Sweden c Department of Clinical Sciences, Lund University, Lund, Sweden d Department of Oncology–Pathology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden e Division of Occupational and Environmental Medicine, Lund University, Lund, Sweden f Division of Mental Health, Norwegian Institute of Public Health, Oslo, Norway g Center for Andrology and Sexual Medicine, Karolinska University Hospital, S-171 76 Stockholm, Sweden h Department of Medicine Huddinge, Karolinska Institutet, Sweden b
a r t i c l e
i n f o
Article history: Received 12 February 2009 Received in revised form 26 June 2009 Accepted 26 June 2009 Available online 4 August 2009 Keywords: Testicular cancer Hypogonadism Anxiety Depression Androgen receptor polymorphism
a b s t r a c t Purpose: It has been documented that testicular germ cell cancer (TGCC) patients may be at increased risk of developing emotional distress (EMD). Hence, the aim of the present study was to investigate whether EMD is related to the presence of hypogonadism, androgen receptor (AR) polymorphism and/or treatment intensity. Patients and methods: Three to five years after treatment, testosterone and luteinizing hormone (LH) levels were measured in 165 TGCC patients. These patients also completed a questionnaire concerning mental health. EMD was measured by the Hospital Anxiety and Depression Scale (HADS). The androgen receptor (AR) gene has two polymorphic regions in exon I; glutamine encoding CAG and glycine encoding GGN repeats. Association between emotional disorders and AR polymorphisms as well as type of treatment was assessed. Results: Neither anxiety (OR 1.0; 95% CI 0.40–2.4) nor depression (OR 1.1; 95% CI 0.20–6.4) were overrepresented in biochemically hypogonadal TGCC patients and no association between AR polymorphisms and EMD was found. Patients treated with ≥ 5 cycles of cisplatinum based chemotherapy due to refractory or relapsed disease were more prone to experiencing symptoms of anxiety (p = 0.006), but not depression (p = 0.38). Conclusions: Biochemical hypogonadism and AR polymorphism do not seem to be risk factors for EMD in TGCC patients. Patients with refractory or relapsed disease receiving ≥ 5 cycles of cisplatinum based chemotherapy may, to a higher degree than patients receiving less intense therapy, suffer from anxiety. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Testicular germ cell cancer (TGCC) is the most common malignancy in young adult males. Since the introduction of ⁎ Corresponding author. Department of Oncology, Lund University Hospital, SE 221 85 Lund, Sweden. Tel.: +46 46 17 75 20; fax: +46 46 17 60 80. E-mail address: [email protected] (J. Eberhard). 0165-0327/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2009.06.035
cisplatin in the treatment of TGCC in the seventies, the overall survival rate has risen to exceed 95% (Krege et al., 2008a,b) and the quality of life (QoL) of survivors is therefore an important issue. Several studies have focused on general satisfaction and QoL in TGCC patients (Fleer et al., 2004; Joly et al., 2002). Physical and psychological well-being has generally been reported in these patients. Less is known about the specific
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impact of different TGCC therapies on these issues, although a recent study did not find any major impact of different treatment modalities on QoL (Mykletun et al., 2005). It has previously been shown that TGCC patients are at risk of developing Leydig cell insufficiency, biochemically expressed as low serum levels of testosterone and/or elevated LH (Fossa et al., 1995; Nijman et al., 1987; Willemse et al., 1983). We have recently identified risk factors for hypogonadism in TGCC patients, one of which being type of treatment given (Eberhard et al., 2008). The question of whether TGCC patients, following treatment, suffer from emotional distress (EMD) such as depression and anxiety to a larger extent than the normal population has recently been investigated. It has been shown that anxiety is more prevalent in TGCC patients than in the general population (Dahl et al., 2005b), and that both anxiety and depression are associated with chronic fatigue (Fossa et al., 2003). This finding was further confirmed in a large case control study, that also concluded that the Hospital Anxiety and Depression Scale (HADS) can be used as a simple screening test to identify these disorders (Dahl et al., 2005a). Clinically, male hypogonadism is associated with a panorama of symptoms including low levels of resolution, ambivalence, impaired concentration, fatigue and low energy (Carnegie, 2004). Thus, it can be speculated that the increased risk of EMD in TGCC survivors is related to androgen deficiency. Although it has been reported that high LH levels in TGCC survivors are associated with an increased risk of depression (Wiechno et al., 2007), there is a lack of data regarding a possible association between hypogonadism and the risk of EMD in TGCC survivors. The androgen receptor (AR) gene has two polymorphic regions in exon I; glutamine encoding CAG and glycine encoding GGN repeats. The lengths of these polymorphic repeats have been shown to have an impact on androgen sensitivity (Lundin et al., 2006; Tut et al., 1997), and might therefore influence the risk of developing EMD. Thus, in a population of elderly men a positive association between the CAG repeat number and risk of depression, as expressed by the wish to be dead, depressed mood and deterioration of general well-being has been reported (Harkonen et al., 2003). The finding of a link between AR polymorphisms and EMD might point to the role of impaired testosterone effect in development of such symptoms as are encountered in TGCC survivors. Since hypogonadism can be treated by androgen replacement therapy, investigation of a possible association between this hormone deficiency and the risk of EMD is clinically relevant. The intensity of treatment may influence the risk of developing EMD. Men receiving extensive cancer therapy might not only become anxious and depressed as a direct consequence of the therapy, but also as a psychological reaction to the diagnosis of a disseminated cancer disease. To our knowledge, few studies have focused on the impact of treatment intensity on EMD. The aim of this study was to elucidate whether biochemical signs of hypogonadism and/or AR polymorphisms are predictors of EMD in TGCC survivors. In addition we assessed the association between treatment intensity and EMD.
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2. Patients and methods 2.1. Recruitment of TGCC patients All TGCC patients under the age of 50 referred to the Department of Oncology, Lund University Hospital, Lund since March 1996 and to the Department of Oncology, Radiumhemmet and Södersjukhuset, Karolinska University Hospital, Stockholm since November 1998, were asked to participate in a study of reproductive function. Eligible for the current study were those who had passed the 3 year post treatment check-up. By October 2006 a total of 461 patients were eligible for the study of reproductive function. 75 declined to participate and 45 were excluded on the grounds of having linguistic difficulties, bilateral testicular cancer, moving away from the geographical region or being physically handicapped. Seven patients were excluded due to compromising mental conditions: two having schizophrenia, two being mentally disabled, one having Down's syndrome, one being in the process of a severe family crisis and one suffering from anxiety and aggression directed against the medical service. 131 men had not yet passed their three-year check-up. Ten were excluded due to contralateral testicular cancer diagnosed after inclusion in the reproductive function study and three died of progressive disease. Thus, 190 patients were eligible for the current study. Among these, 25 men dropped out (moved to another region; n = 12 or were not coming for planned controls; n = 13). Finally, 165 patients who had gotten through their three-year check-ups were included in the present study (Fig. 1). All participants submitted a written informed consent and the study was approved by the Ethical Board of the University of Lund. 2.2. Patient characteristics All patients (n = 165) were uniformly managed according to the Swedish Norwegian Testicular Cancer Group (SWENOTECA) protocols (www.ocsyd.se). Depending on the stage of the disease, they were exposed to surveillance only (SO), being treated with adjuvant, undergoing 1–2 cycles of chemotherapy (ACT) or a standard 3–4 cycles of chemotherapy (SCT), adjuvant radiotherapy (RT) or higher, ≥5 cycles of chemotherapy (HDCT) (Table 1). The surveillance group (SO) consisted of stage 1 patients only, not receiving any further therapy after orchiectomy (n=13). The adjuvant chemotherapy group (ACT) were all stage 1 patients with only non-seminoma (n = 41) receiving 1–2 cycles of platinum-based chemotherapy. Patients receiving standard doses of chemotherapy (SCT) all had disseminated disease and were receiving 3–4 cycles of cisplatin-based chemotherapy (n=54). The radiotherapy group (RT) were all seminomas stage 1 and treated with adjuvant radiotherapy administered to paraaortic and ipsilateral iliac lymph nodes (n=49). The last group (HDCT) were treated with ≥5 cycles of cisplatinum based chemotherapy±other drugs due to refractory or relapsed disease (n=8). 2.3. Assessment of biochemical hypogonadism Blood samples for analysis of serum levels of testosterone and luteinizing hormone (LH) were obtained between 9 am and
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Fig. 1. Flow chart of the patient material. 461 patients were eligible for a reproductive study. In the current study, the inclusion criteria were (1) participation in the fertility study and (2) to pass the 3–5 years follow-up after finishing treatment. These two criteria left 190 patients eligible, 165 of whom were included in the current study.
3 pm. For patients recruited in Lund (n = 96), details of the hormone analyses and risk factors for being biochemically hypogonadal have been reported previously (Eberhard et al., 2008). In Stockholm (n = 69) LH was determined with an AutoDELFIA automatic immunoassay system (Perkin Elmer, USA) and testosterone with a DxI immunoassay system (Beckman Coulter, USA). The reference levels for testosterone and LH were identical in the two centers and the patients were categorized as being hypogonadal if serum testosterone was below 10 nmol/L and/or serum LH was 10 IU/L or more (Nieschlag et al., 2004).
2.5. Measures of emotional distress The Hospital Anxiety and Depression Scale (HADS) is a well established self-rating scale developed to screen for depression and anxiety (Zigmond and Snaith, 1983). HADS contains fourteen items; seven depression items (HADS-D) and seven anxiety items (HADS-A). Each item is scored from 0 to 3 and the score on each subscale (HADS-D and HADS-A) ranges from 0 to 21. A HADS-D score ≥8 was used as the cutoff score for depression and HADS-A ≥ 8 was used for anxiety. These cut-off levels correspond to those used in prior studies (Bjelland et al., 2002). The scale was filled in at the time of inclusion in the study, and again at the five-year check-up.
2.4. DNA analysis Blood samples for DNA analysis were available from 140 men. These subjects did not differ from the remaining 25 regarding age, disease stage, histological type, biological hypogonadism or emotional disorders (data not shown). Genomic DNA was prepared from peripheral leukocytes, and the CAG (140 subjects) and GGN repeats (135 subjects) were amplified by PCR and subsequently directly sequenced on a Beckman Coulter CEQ 2000XL (Beckman Coulter, Bromma, Sweden) sequencing gear as previously described (Lundin et al., 2003).
Table 1 Treatment and tumor related data on n = 165 testicular cancer patients.
No of patients (n = 165) Age (median) Seminomas (n = 72) Non-seminomas (n = 93) Stage I (n = 116) Stage II–IV (n = 49)
SO
ACT
SCT
RT
HDCT
13 32 4 9 13 0
41 35 0 41 41 0
54 35 16 38 12⁎
49 40 49 0 49 0
8 34 3 5 1⁎ 7⁎
42
Royal Marsden Hospital (RMH) staging system has been used (Horwich et al., 1989). SO: no further therapy after orchiectomy. ACT: 1–2 cycles of adjuvant chemotherapy; SCT: 3–4 cycles of chemotherapy; RT: adjuvant radiotherapy; HDCT ≥ 5 cycles of chemotherapy ± other drugs. ⁎Patients with recurrent or refractory disease.
2.6. Statistical analysis Using binary logistic regression, the odds ratios (OR) with 95% confidence intervals (CI) were calculated to evaluate the association between biochemical signs of hypogonadism, length of CAG repeat, and length of GGN repeat respectively, as potential predictors for EMD. The analyses concerning the impact of hypogonadism were performed both with and without including men on testosterone replacement. Furthermore, these two groups–those treated with testosterone and those not treated–were compared to each other. Testosterone, but not LH, is known to decrease during the day. Therefore, the possible associations between biochemical hypogonadism and EMD were re-tested with LH N 10 IU/L as the only indicator of hypogonadism. The CAG length was evaluated as a continuous variable as well as divided into four categories, (b20, 20–21, 22–23 and N23) using the shortest CAG lengths as the reference. The GGN repeat length was categorized into three groups, (b23, 23 and N23) using the most common length of 23 as the reference. Regarding the impact of hypogonadism, potential confounders such as age, smoking, body mass index (BMI) and laboratory (Lund vs. Stockholm) were included in the models, one at a time. These factors were kept within the model if they changed the risk estimate more than 15%, which was an arbitrary chosen level. A change of less than 15% is considered to be of minor clinical importance.
J. Eberhard et al. / Journal of Affective Disorders 122 (2010) 260–266 Table 2 Biochemical signs of hypogonadism, abnormal HADS scores and lengths of CAG and GGN repeat in the androgen receptor gene in TGCC patients 3–5 years after treatment.
Hypogonadal, testosterone b 10 nmol/L and/or LH ≥ 10 IU/L Hypogonadal, LH 10 ≥ IU/L HADS-A ≥ 8 HADS-D ≥ 8 CAG b 20 CAG 20–21 CAG 22–23 CAG N 23 GGN b 23 GGN 23 GGN N 23
Yes/total (n)
%
51/142⁎
36
29/142⁎ 31/165 8/165 36/140 39/140 31/140 34/140 21/135 68/135 46/135
20 19 5 26 28 22 24 16 50 34
HADS-A (Hospital Anxiety and Depression Scale-Anxiety). HADS-D (Hospital Anxiety and Depression Scale-Depression). ⁎Of 165 patients 20 were excluded due to testosterone replacement therapy and three did not want to deliver a blood sample.
A possible interaction between CAG repeat length and testosterone levels in relation to the outcomes of this study was tested in a logistic regression model. The association between the different treatment modalities and EMD was evaluated using Fisher's exact test. One model was applied comparing all treatment groups to each other and one comparing HDCT to all the others. The reason for not using logistic regressions when comparing treatment groups was the low numbers of individuals in some of the treatment modality groups. SPSS 15.0 software (Chicago, IL) was used for all statistical analyses except for Fisher's test where we used StatXact (CYTEL Software Corporation). 3. Results 3.1. Biochemical signs of hypogonadism, emotional distress and androgen receptor polymorphism Of the 165 included patients, three refused to deliver a blood sample and twenty were on testosterone replacement therapy. Among the remaining 142, 36% were biochemically hypogonadal using testosterone b10 nmol/L and/or LH ≥ 10 as the criterion. If using only LH ≥ 10 as the criterion, 20% were hypogonadal (Table 2). Among the 165 patients, 19% scored ≥8 on HADS-A and 5% on the HADS-D. Among the 20 patients on testosterone replacement therapy, 30% scored ≥8 on HADS-A and 10% on the HADS-D (Tables 2 and 3). Patients that scored b8 on HADS-A had a mean testosterone concentration of 13 nmol/L and a mean LH of 7.2 IU/L. For patients with HADS-A ≥ 8 the corresponding values were 14 nmol/L for testosterone and 7.3 IU/L for LH. Patients that scored b8 on HADS-D had a mean testosterone of 13 nmol/L and LH of 7.2, whereas the values were 16 nmol/L and 9.1 IU/L, respectively, for those with HADS-D≥ 8. The AR receptor gene CAG length was measured in 140 and GGN length in 135 patients. Of these, 26% had CAG repeat length b20, 28% had 20–21, 22% had 22–23 and 24% had N23. Sixteen percent had GGN repeat length b23, 50% had 23 and 34 had N23 (Table 2).
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There was no statistically significant interaction between testosterone levels and CAG number in relation to the risk of anxiety or depression. 3.2. Hypogonadism in relation to emotional distress The risk of anxiety (OR 1.0; 95% CI 0.40–2.4) and depression (OR 1.1; 95% CI 0.20–6.4) was not increased in biochemically hypogonadal TGCC patients. The result was the same using LH only as the biochemical marker for hypogonadism whether or not patients on testosterone replacement therapy were included (Table 3). When patients on testosterone replacement therapy (n = 20) were compared to those not on replacement (n = 142) those on androgen therapy were not at significantly higher risk of suffering anxiety (OR 2.0; 95% CI 0.71–5.8), or depression (OR 2.5; 95% CI 0.48–14). 3.3. Androgen receptor polymorphism in relation to EMD The CAG length was not associated with anxiety, neither when tested as a continuous variable (OR 1.1; 95% CI 0.94–1.3) nor as a categorized (p = 0.24) one. The GGN repeat not was associated with anxiety either (p = 0.23). The results were similar irrespective of whether we included or excluded the patients on testosterone replacement in the analyses. There were only five patients with HADS-D ≥8 and with a CAG measurement available for the analyses from the 125 patients remaining after the exclusion of fifteen patients on testosterone replacement therapy, making this comparison less meaningful. 3.4. Emotional distress in relation to treatment modality In the SO group none suffered from EMD, and in the ACT group 10% suffered from anxiety and 2% from depression. In the SCT group 15% had anxiety and 2% depression and the corresponding figures in the RT group were 29% and 10% respectively. Finally, in the HDCT group 62% had anxiety and 12% depression (Table 4). When comparing all treatment groups to each other, there was a significant difference regarding frequency of anxiety (p = 0.002), but not regarding depression (p = 0.19). When the HDCT group, was compared to the other groups, there was a significant difference in the prevalence of anxiety (p = 0.006), but not in the prevalence of depression (p = 0.38). 4. Discussion Using the HADS questionnaire, we found the proportion of TGCC patients with anxiety to be 19%, whereas depression was at 5% 3–5 years after treatment. These figures are well comparable to those in a recent report on a Norwegian cohort of TGCC men (Dahl et al., 2005a). The risk of EMD was neither associated with biochemical signs of hypogonadism–low serum testosterone and/or high LH–nor with polymorphisms in the AR gene. The intensity of treatment given did not influence the risk of having depression, but anxiety was significantly more common in patients treated with ≥5 cycles of chemotherapy, and 62% reported anxiety in this group, compared to 19% for all patients.
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Table 3 Association between biochemical hypogonadism and emotional distress in TGCC patients 3–5 years after treatment. Yes/total⁎ (n) Depression HADS-D ≥ 8 Anxiety HADS-A ≥ 8
Hypogonadal, low testosterone and/or high LH OR (CI)
Adjusted hypogonadal, low testosterone and/or high LH OR (CI)
Hypogonadal, high LH OR (CI)
Adjusted hypogonadal, high LH OR (CI)
6/142⁎
1.1 (0.20–6.4)
2.5 (0.24–25) a
2.0 (0.35–12)
0.77 (0.073–8.1) a
25/142⁎
1.0 (0.40–2.4)
1.0 (0.40–2.4)
2.2 (0.82–5.6)
1.8 (0.66–5.0) b
Hypogonadal, low testosterone and/or high LH: testosterone b 10 nmol/L and/or LH N 10 IU/L. Hypogonadal, high LH: LH N 10 IU/L. HADS-A (Hospital Anxiety and Depression Scale-Anxiety). HADS-D (Hospital Anxiety and Depression Scale-Depression). ⁎Of 165 patients, 20 were excluded due to testosterone replacement therapy and three did not want to deliver a blood sample. When the replaced patients were included, the outcome was similar (data not shown). a Age, smoking and body mass index included in the model. b Body mass index included in the model.
Male hypogonadism and EMD share several symptoms including low levels of resolution, ambivalence, impaired concentration, fatigue and lethargy (American Psychiatric Association, 1995; Carnegie, 2004). It could, therefore, be anticipated that disease and treatment induced hypogonadism is the underlying cause of EMD in TGCC patients. Our results indicate that the EMD symptoms in TGCC patients are not related to hypogonadism. This assumption is also supported by the lack of association between AR CAG and GGN repeat length and EMD. The two conditions seem to be two separate entities which, from a clinical point of view, may represent a problem of differentiating diagnoses. In elderly Finnish men long CAG repeats were found to be associated with the risk of depression (Harkonen et al., 2003) indicating a more important role of androgens in the pathogenesis of EMD in this category of subjects. However, this could not be confirmed in another study on elderly men where testosterone levels and CAG repeat lengths did not have any association with depression (T'Sjoen et al., 2005). Our results are in concordance with those presented by Wiechno et al. (2007) whose study also found no association between the results of the HADS and elevated LH or low testosterone. However, when using another depression scale, the Beck Depression Inventory (BDI), they did find an increased risk for depression when LH levels were increased. Both scales are well validated and the sensitivity and specificity is very high in detecting major depression for both the scales. However, in the case of minor depression there are indications that the Table 4 Emotional distress in relation to treatment in 165 TGCC patients 3–5 years after treatment. HADS-A ≥ 8 Anxiety (n) (%)
HADS-D ≥ 8 Depression (n) (%)
Anxiety (n) (%)
Depression (n) (%)
31 (19)
8 (4.8)
Treatment received SO, n = 13 0 ACT, n = 41 4 (9.8) SCT, n = 54 8 (15) RT, n = 49 14 (29) HDCT, n = 8 5 (62)
0 1 (2.4) 1 (1.9) 5 (10) 1 (12)
All patients
SO: no further therapy after orchiectomy. ACT: 1–2 cycles of adjuvant chemotherapy. SCT: 3–4 cycles of chemotherapy. RT: adjuvant radiotherapy. HDCT ≥ 5 cycles of chemotherapy ± other drugs. HADS-A (Hospital Anxiety and Depression Scale-Anxiety). HADS-D (Hospital Anxiety and Depression Scale-Depression).
HADS demonstrates greater specificity, sensitivity and also a higher positive predictive value, although not a significant one, in cancer patients following curative treatment (Katz et al., 2004). We found patients with more recurrent or refractory disease who had received ≥5 cycles of chemotherapy to be more prone to being anxious 3–5 years after treatment. Therefore, we consider that during follow-up this group should be given special attention with regard to developing anxiety, and appropriate treatment has to be offered to the patient. Whether this is due to psychological factors related to the more uncertain prognosis for these men, or whether it is a direct effect of the cytotoxic drugs on the brain cannot be concluded from this study even though studies done on animals support the latter (Macleod et al., 2007). For the diagnosis of androgen deficiency a blood sample should ideally be obtained before 10 am. For logistical reasons, we obtained blood samples at different time points between 9 am and 3 pm. This might have blurred the difference between truly hypogonadal and eugonadal men, thus reducing the statistical power of that part of the study. However, it has been reported that the diurnal variation in testosterone levels is less pronounced in hypogonadal men (Winters, 1991). Furthermore, we found no increase in the OR for EMD even when LH above 10 IU/L was used as the only indicator of hypogonadism. Unlike testosterone, LH does not decrease during the daytime. Previous studies regarding the association between testosterone levels and metabolic signs of hypogonadism reported no difference in the risk estimates regardless of whether the time of blood sampling was taken into consideration or not (Agledahl et al., 2008). Excluding men on androgen replacement could lead to an underestimation of the frequency of patients with problems related to hypogonadism and TGCC. However, inclusion of patients on testosterone replacement did not influence the magnitude of the risk estimates. In the testosterone replaced group, 30% scored ≥8 on HADS-A, giving a CI on 12–54%. For the whole group, the score was 19% with a CI of 13–26%. Consequently, no difference was seen, but the low number of replaced patients has to be considered. The low prevalence of depression in the study material is a limitation and due to the low statistical power the results needs confirmation in a larger population. The fact that 75 patients declined to participate in the reproductive study and, additionally, that thirteen patients
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withdrew after inclusion in the current study might represent a source of selection bias. However, the study has a relatively high participation rate of 62% even when we include the figure of the 75 men denied participation in the reproductive study as being theoretically eligible for the current study, and we assume that any strong association between hypogonadism and the risk of EMD should be detected in a cohort where 36% of patients present with biochemical signs of androgen deficiency. From the 165 patients answering the HADS, 15 were at the three-year follow-up and 150 at the five-year follow-up. Since all patients answered the questionnaire at inclusion and after 5 years, some were included but had not passed the five-year control yet. We choose to expand the material with the threeyear questionnaires since data from former studies show that after 2–3 years the acute toxicity is reversed concerning most side effects (Eberhard et al., 2009, 2008, 2004). In conclusion, we found that among TGCC patients the risk of EMD was not increased in those with biochemical signs of hypogonadism and since several symptoms are similar, special attention is needed with regard to the possible diagnostic options. The androgen receptor polymorphisms did not predict the risk of anxiety. Patients who had received ≥5 cycles of chemotherapy were at increased risk of developing symptoms of anxiety 3–5 years after completed therapy and special attention should be given to these patients in the follow-up. Role of funding source The study was supported by grants from Swedish Government Funding for Clinical Research, the Swedish Cancer Society (Grant. no. 4857-B05-03XCC), Gunnar Nilssons Cancerstiftelse, Swedish Childhood Cancer Society (Grant nos. 05/056 and RKT04/001), Malmö University Hospital Foundation for Cancer Research and Foundation for Urological Research and King Gustaf V's Jubilee fund for Cancer Research, Stockholm (Grant nos. 44052 and 74061). The donators had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Conflict of interest All authors declare that they have no conflicts of interest.
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Krege, S., Beyer, J., Souchon, R., Albers, P., Albrecht, W., Algaba, F., Bamberg, M., Bodrogi, I., Bokemeyer, C., Cavallin-Stahl, E., Classen, J., Clemm, C., CohnCedermark, G., Culine, S., Daugaard, G., De Mulder, P.H., De Santis, M., de Wit, M., de Wit, R., Derigs, H.G., Dieckmann, K.P., Dieing, A., Droz, J.P., Fenner, M., Fizazi, K., Flechon, A., Fossa, S.D., del Muro, X.G., Gauler, T., Geczi, L., Gerl, A., Germa-Lluch, J.R., Gillessen, S., Hartmann, J.T., Hartmann, M., Heidenreich, A., Hoeltl, W., Horwich, A., Huddart, R., Jewett, M., Joffe, J., Jones, W.G., Kisbenedek, L., Klepp, O., Kliesch, S., Koehrmann, K.U., Kollmannsberger, C., Kuczyk, M., Laguna, P., Galvis, O.L., Loy, V., Mason, M.D., Mead, G.M., Mueller, R., Nichols, C., Nicolai, N., Oliver, T., Ondrus, D., Oosterhof, G.O., Ares, L.P., Pizzocaro, G., Pont, J., Pottek, T., Powles, T., Rick, O., Rosti, G., Salvioni, R., Scheiderbauer, J., Schmelz, H.U., Schmidberger, H., Schmoll, H.J., Schrader, M., Sedlmayer, F., Skakkebaek, N.E., Sohaib, A., Tjulandin, S., Warde, P., Weinknecht, S., Weissbach, L., Wittekind, C., Winter, E., Wood, L., von der Maase, H., 2008a. 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Contents lists available at ScienceDirect
Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d
Research report
Emotional disorders in testicular cancer survivors in relation to hypogonadism, androgen receptor polymorphism and treatment modality Jakob Eberhard a,b,⁎, Olof Ståhl a,b, Gabriella Cohn-Cedermark d, Eva Cavallin-Ståhl a, Yvonne Giwercman c, Hamideh Rastkhani c, Lars Rylander c,e, Malin Eberhard-Gran f, Ulrik Kvist g,h, Aleksander Giwercman b,c a
Department of Oncology, Lund University Hospital, Lund University, SE 221 85 Lund, Sweden Reproductive Medicine Centre, Malmö University Hospital, Lund University, Malmö, Sweden c Department of Clinical Sciences, Lund University, Lund, Sweden d Department of Oncology–Pathology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden e Division of Occupational and Environmental Medicine, Lund University, Lund, Sweden f Division of Mental Health, Norwegian Institute of Public Health, Oslo, Norway g Center for Andrology and Sexual Medicine, Karolinska University Hospital, S-171 76 Stockholm, Sweden h Department of Medicine Huddinge, Karolinska Institutet, Sweden b
a r t i c l e
i n f o
Article history: Received 12 February 2009 Received in revised form 26 June 2009 Accepted 26 June 2009 Available online 4 August 2009 Keywords: Testicular cancer Hypogonadism Anxiety Depression Androgen receptor polymorphism
a b s t r a c t Purpose: It has been documented that testicular germ cell cancer (TGCC) patients may be at increased risk of developing emotional distress (EMD). Hence, the aim of the present study was to investigate whether EMD is related to the presence of hypogonadism, androgen receptor (AR) polymorphism and/or treatment intensity. Patients and methods: Three to five years after treatment, testosterone and luteinizing hormone (LH) levels were measured in 165 TGCC patients. These patients also completed a questionnaire concerning mental health. EMD was measured by the Hospital Anxiety and Depression Scale (HADS). The androgen receptor (AR) gene has two polymorphic regions in exon I; glutamine encoding CAG and glycine encoding GGN repeats. Association between emotional disorders and AR polymorphisms as well as type of treatment was assessed. Results: Neither anxiety (OR 1.0; 95% CI 0.40–2.4) nor depression (OR 1.1; 95% CI 0.20–6.4) were overrepresented in biochemically hypogonadal TGCC patients and no association between AR polymorphisms and EMD was found. Patients treated with ≥ 5 cycles of cisplatinum based chemotherapy due to refractory or relapsed disease were more prone to experiencing symptoms of anxiety (p = 0.006), but not depression (p = 0.38). Conclusions: Biochemical hypogonadism and AR polymorphism do not seem to be risk factors for EMD in TGCC patients. Patients with refractory or relapsed disease receiving ≥ 5 cycles of cisplatinum based chemotherapy may, to a higher degree than patients receiving less intense therapy, suffer from anxiety. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Testicular germ cell cancer (TGCC) is the most common malignancy in young adult males. Since the introduction of ⁎ Corresponding author. Department of Oncology, Lund University Hospital, SE 221 85 Lund, Sweden. Tel.: +46 46 17 75 20; fax: +46 46 17 60 80. E-mail address: [email protected] (J. Eberhard). 0165-0327/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2009.06.035
cisplatin in the treatment of TGCC in the seventies, the overall survival rate has risen to exceed 95% (Krege et al., 2008a,b) and the quality of life (QoL) of survivors is therefore an important issue. Several studies have focused on general satisfaction and QoL in TGCC patients (Fleer et al., 2004; Joly et al., 2002). Physical and psychological well-being has generally been reported in these patients. Less is known about the specific
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impact of different TGCC therapies on these issues, although a recent study did not find any major impact of different treatment modalities on QoL (Mykletun et al., 2005). It has previously been shown that TGCC patients are at risk of developing Leydig cell insufficiency, biochemically expressed as low serum levels of testosterone and/or elevated LH (Fossa et al., 1995; Nijman et al., 1987; Willemse et al., 1983). We have recently identified risk factors for hypogonadism in TGCC patients, one of which being type of treatment given (Eberhard et al., 2008). The question of whether TGCC patients, following treatment, suffer from emotional distress (EMD) such as depression and anxiety to a larger extent than the normal population has recently been investigated. It has been shown that anxiety is more prevalent in TGCC patients than in the general population (Dahl et al., 2005b), and that both anxiety and depression are associated with chronic fatigue (Fossa et al., 2003). This finding was further confirmed in a large case control study, that also concluded that the Hospital Anxiety and Depression Scale (HADS) can be used as a simple screening test to identify these disorders (Dahl et al., 2005a). Clinically, male hypogonadism is associated with a panorama of symptoms including low levels of resolution, ambivalence, impaired concentration, fatigue and low energy (Carnegie, 2004). Thus, it can be speculated that the increased risk of EMD in TGCC survivors is related to androgen deficiency. Although it has been reported that high LH levels in TGCC survivors are associated with an increased risk of depression (Wiechno et al., 2007), there is a lack of data regarding a possible association between hypogonadism and the risk of EMD in TGCC survivors. The androgen receptor (AR) gene has two polymorphic regions in exon I; glutamine encoding CAG and glycine encoding GGN repeats. The lengths of these polymorphic repeats have been shown to have an impact on androgen sensitivity (Lundin et al., 2006; Tut et al., 1997), and might therefore influence the risk of developing EMD. Thus, in a population of elderly men a positive association between the CAG repeat number and risk of depression, as expressed by the wish to be dead, depressed mood and deterioration of general well-being has been reported (Harkonen et al., 2003). The finding of a link between AR polymorphisms and EMD might point to the role of impaired testosterone effect in development of such symptoms as are encountered in TGCC survivors. Since hypogonadism can be treated by androgen replacement therapy, investigation of a possible association between this hormone deficiency and the risk of EMD is clinically relevant. The intensity of treatment may influence the risk of developing EMD. Men receiving extensive cancer therapy might not only become anxious and depressed as a direct consequence of the therapy, but also as a psychological reaction to the diagnosis of a disseminated cancer disease. To our knowledge, few studies have focused on the impact of treatment intensity on EMD. The aim of this study was to elucidate whether biochemical signs of hypogonadism and/or AR polymorphisms are predictors of EMD in TGCC survivors. In addition we assessed the association between treatment intensity and EMD.
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2. Patients and methods 2.1. Recruitment of TGCC patients All TGCC patients under the age of 50 referred to the Department of Oncology, Lund University Hospital, Lund since March 1996 and to the Department of Oncology, Radiumhemmet and Södersjukhuset, Karolinska University Hospital, Stockholm since November 1998, were asked to participate in a study of reproductive function. Eligible for the current study were those who had passed the 3 year post treatment check-up. By October 2006 a total of 461 patients were eligible for the study of reproductive function. 75 declined to participate and 45 were excluded on the grounds of having linguistic difficulties, bilateral testicular cancer, moving away from the geographical region or being physically handicapped. Seven patients were excluded due to compromising mental conditions: two having schizophrenia, two being mentally disabled, one having Down's syndrome, one being in the process of a severe family crisis and one suffering from anxiety and aggression directed against the medical service. 131 men had not yet passed their three-year check-up. Ten were excluded due to contralateral testicular cancer diagnosed after inclusion in the reproductive function study and three died of progressive disease. Thus, 190 patients were eligible for the current study. Among these, 25 men dropped out (moved to another region; n = 12 or were not coming for planned controls; n = 13). Finally, 165 patients who had gotten through their three-year check-ups were included in the present study (Fig. 1). All participants submitted a written informed consent and the study was approved by the Ethical Board of the University of Lund. 2.2. Patient characteristics All patients (n = 165) were uniformly managed according to the Swedish Norwegian Testicular Cancer Group (SWENOTECA) protocols (www.ocsyd.se). Depending on the stage of the disease, they were exposed to surveillance only (SO), being treated with adjuvant, undergoing 1–2 cycles of chemotherapy (ACT) or a standard 3–4 cycles of chemotherapy (SCT), adjuvant radiotherapy (RT) or higher, ≥5 cycles of chemotherapy (HDCT) (Table 1). The surveillance group (SO) consisted of stage 1 patients only, not receiving any further therapy after orchiectomy (n=13). The adjuvant chemotherapy group (ACT) were all stage 1 patients with only non-seminoma (n = 41) receiving 1–2 cycles of platinum-based chemotherapy. Patients receiving standard doses of chemotherapy (SCT) all had disseminated disease and were receiving 3–4 cycles of cisplatin-based chemotherapy (n=54). The radiotherapy group (RT) were all seminomas stage 1 and treated with adjuvant radiotherapy administered to paraaortic and ipsilateral iliac lymph nodes (n=49). The last group (HDCT) were treated with ≥5 cycles of cisplatinum based chemotherapy±other drugs due to refractory or relapsed disease (n=8). 2.3. Assessment of biochemical hypogonadism Blood samples for analysis of serum levels of testosterone and luteinizing hormone (LH) were obtained between 9 am and
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Fig. 1. Flow chart of the patient material. 461 patients were eligible for a reproductive study. In the current study, the inclusion criteria were (1) participation in the fertility study and (2) to pass the 3–5 years follow-up after finishing treatment. These two criteria left 190 patients eligible, 165 of whom were included in the current study.
3 pm. For patients recruited in Lund (n = 96), details of the hormone analyses and risk factors for being biochemically hypogonadal have been reported previously (Eberhard et al., 2008). In Stockholm (n = 69) LH was determined with an AutoDELFIA automatic immunoassay system (Perkin Elmer, USA) and testosterone with a DxI immunoassay system (Beckman Coulter, USA). The reference levels for testosterone and LH were identical in the two centers and the patients were categorized as being hypogonadal if serum testosterone was below 10 nmol/L and/or serum LH was 10 IU/L or more (Nieschlag et al., 2004).
2.5. Measures of emotional distress The Hospital Anxiety and Depression Scale (HADS) is a well established self-rating scale developed to screen for depression and anxiety (Zigmond and Snaith, 1983). HADS contains fourteen items; seven depression items (HADS-D) and seven anxiety items (HADS-A). Each item is scored from 0 to 3 and the score on each subscale (HADS-D and HADS-A) ranges from 0 to 21. A HADS-D score ≥8 was used as the cutoff score for depression and HADS-A ≥ 8 was used for anxiety. These cut-off levels correspond to those used in prior studies (Bjelland et al., 2002). The scale was filled in at the time of inclusion in the study, and again at the five-year check-up.
2.4. DNA analysis Blood samples for DNA analysis were available from 140 men. These subjects did not differ from the remaining 25 regarding age, disease stage, histological type, biological hypogonadism or emotional disorders (data not shown). Genomic DNA was prepared from peripheral leukocytes, and the CAG (140 subjects) and GGN repeats (135 subjects) were amplified by PCR and subsequently directly sequenced on a Beckman Coulter CEQ 2000XL (Beckman Coulter, Bromma, Sweden) sequencing gear as previously described (Lundin et al., 2003).
Table 1 Treatment and tumor related data on n = 165 testicular cancer patients.
No of patients (n = 165) Age (median) Seminomas (n = 72) Non-seminomas (n = 93) Stage I (n = 116) Stage II–IV (n = 49)
SO
ACT
SCT
RT
HDCT
13 32 4 9 13 0
41 35 0 41 41 0
54 35 16 38 12⁎
49 40 49 0 49 0
8 34 3 5 1⁎ 7⁎
42
Royal Marsden Hospital (RMH) staging system has been used (Horwich et al., 1989). SO: no further therapy after orchiectomy. ACT: 1–2 cycles of adjuvant chemotherapy; SCT: 3–4 cycles of chemotherapy; RT: adjuvant radiotherapy; HDCT ≥ 5 cycles of chemotherapy ± other drugs. ⁎Patients with recurrent or refractory disease.
2.6. Statistical analysis Using binary logistic regression, the odds ratios (OR) with 95% confidence intervals (CI) were calculated to evaluate the association between biochemical signs of hypogonadism, length of CAG repeat, and length of GGN repeat respectively, as potential predictors for EMD. The analyses concerning the impact of hypogonadism were performed both with and without including men on testosterone replacement. Furthermore, these two groups–those treated with testosterone and those not treated–were compared to each other. Testosterone, but not LH, is known to decrease during the day. Therefore, the possible associations between biochemical hypogonadism and EMD were re-tested with LH N 10 IU/L as the only indicator of hypogonadism. The CAG length was evaluated as a continuous variable as well as divided into four categories, (b20, 20–21, 22–23 and N23) using the shortest CAG lengths as the reference. The GGN repeat length was categorized into three groups, (b23, 23 and N23) using the most common length of 23 as the reference. Regarding the impact of hypogonadism, potential confounders such as age, smoking, body mass index (BMI) and laboratory (Lund vs. Stockholm) were included in the models, one at a time. These factors were kept within the model if they changed the risk estimate more than 15%, which was an arbitrary chosen level. A change of less than 15% is considered to be of minor clinical importance.
J. Eberhard et al. / Journal of Affective Disorders 122 (2010) 260–266 Table 2 Biochemical signs of hypogonadism, abnormal HADS scores and lengths of CAG and GGN repeat in the androgen receptor gene in TGCC patients 3–5 years after treatment.
Hypogonadal, testosterone b 10 nmol/L and/or LH ≥ 10 IU/L Hypogonadal, LH 10 ≥ IU/L HADS-A ≥ 8 HADS-D ≥ 8 CAG b 20 CAG 20–21 CAG 22–23 CAG N 23 GGN b 23 GGN 23 GGN N 23
Yes/total (n)
%
51/142⁎
36
29/142⁎ 31/165 8/165 36/140 39/140 31/140 34/140 21/135 68/135 46/135
20 19 5 26 28 22 24 16 50 34
HADS-A (Hospital Anxiety and Depression Scale-Anxiety). HADS-D (Hospital Anxiety and Depression Scale-Depression). ⁎Of 165 patients 20 were excluded due to testosterone replacement therapy and three did not want to deliver a blood sample.
A possible interaction between CAG repeat length and testosterone levels in relation to the outcomes of this study was tested in a logistic regression model. The association between the different treatment modalities and EMD was evaluated using Fisher's exact test. One model was applied comparing all treatment groups to each other and one comparing HDCT to all the others. The reason for not using logistic regressions when comparing treatment groups was the low numbers of individuals in some of the treatment modality groups. SPSS 15.0 software (Chicago, IL) was used for all statistical analyses except for Fisher's test where we used StatXact (CYTEL Software Corporation). 3. Results 3.1. Biochemical signs of hypogonadism, emotional distress and androgen receptor polymorphism Of the 165 included patients, three refused to deliver a blood sample and twenty were on testosterone replacement therapy. Among the remaining 142, 36% were biochemically hypogonadal using testosterone b10 nmol/L and/or LH ≥ 10 as the criterion. If using only LH ≥ 10 as the criterion, 20% were hypogonadal (Table 2). Among the 165 patients, 19% scored ≥8 on HADS-A and 5% on the HADS-D. Among the 20 patients on testosterone replacement therapy, 30% scored ≥8 on HADS-A and 10% on the HADS-D (Tables 2 and 3). Patients that scored b8 on HADS-A had a mean testosterone concentration of 13 nmol/L and a mean LH of 7.2 IU/L. For patients with HADS-A ≥ 8 the corresponding values were 14 nmol/L for testosterone and 7.3 IU/L for LH. Patients that scored b8 on HADS-D had a mean testosterone of 13 nmol/L and LH of 7.2, whereas the values were 16 nmol/L and 9.1 IU/L, respectively, for those with HADS-D≥ 8. The AR receptor gene CAG length was measured in 140 and GGN length in 135 patients. Of these, 26% had CAG repeat length b20, 28% had 20–21, 22% had 22–23 and 24% had N23. Sixteen percent had GGN repeat length b23, 50% had 23 and 34 had N23 (Table 2).
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There was no statistically significant interaction between testosterone levels and CAG number in relation to the risk of anxiety or depression. 3.2. Hypogonadism in relation to emotional distress The risk of anxiety (OR 1.0; 95% CI 0.40–2.4) and depression (OR 1.1; 95% CI 0.20–6.4) was not increased in biochemically hypogonadal TGCC patients. The result was the same using LH only as the biochemical marker for hypogonadism whether or not patients on testosterone replacement therapy were included (Table 3). When patients on testosterone replacement therapy (n = 20) were compared to those not on replacement (n = 142) those on androgen therapy were not at significantly higher risk of suffering anxiety (OR 2.0; 95% CI 0.71–5.8), or depression (OR 2.5; 95% CI 0.48–14). 3.3. Androgen receptor polymorphism in relation to EMD The CAG length was not associated with anxiety, neither when tested as a continuous variable (OR 1.1; 95% CI 0.94–1.3) nor as a categorized (p = 0.24) one. The GGN repeat not was associated with anxiety either (p = 0.23). The results were similar irrespective of whether we included or excluded the patients on testosterone replacement in the analyses. There were only five patients with HADS-D ≥8 and with a CAG measurement available for the analyses from the 125 patients remaining after the exclusion of fifteen patients on testosterone replacement therapy, making this comparison less meaningful. 3.4. Emotional distress in relation to treatment modality In the SO group none suffered from EMD, and in the ACT group 10% suffered from anxiety and 2% from depression. In the SCT group 15% had anxiety and 2% depression and the corresponding figures in the RT group were 29% and 10% respectively. Finally, in the HDCT group 62% had anxiety and 12% depression (Table 4). When comparing all treatment groups to each other, there was a significant difference regarding frequency of anxiety (p = 0.002), but not regarding depression (p = 0.19). When the HDCT group, was compared to the other groups, there was a significant difference in the prevalence of anxiety (p = 0.006), but not in the prevalence of depression (p = 0.38). 4. Discussion Using the HADS questionnaire, we found the proportion of TGCC patients with anxiety to be 19%, whereas depression was at 5% 3–5 years after treatment. These figures are well comparable to those in a recent report on a Norwegian cohort of TGCC men (Dahl et al., 2005a). The risk of EMD was neither associated with biochemical signs of hypogonadism–low serum testosterone and/or high LH–nor with polymorphisms in the AR gene. The intensity of treatment given did not influence the risk of having depression, but anxiety was significantly more common in patients treated with ≥5 cycles of chemotherapy, and 62% reported anxiety in this group, compared to 19% for all patients.
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Table 3 Association between biochemical hypogonadism and emotional distress in TGCC patients 3–5 years after treatment. Yes/total⁎ (n) Depression HADS-D ≥ 8 Anxiety HADS-A ≥ 8
Hypogonadal, low testosterone and/or high LH OR (CI)
Adjusted hypogonadal, low testosterone and/or high LH OR (CI)
Hypogonadal, high LH OR (CI)
Adjusted hypogonadal, high LH OR (CI)
6/142⁎
1.1 (0.20–6.4)
2.5 (0.24–25) a
2.0 (0.35–12)
0.77 (0.073–8.1) a
25/142⁎
1.0 (0.40–2.4)
1.0 (0.40–2.4)
2.2 (0.82–5.6)
1.8 (0.66–5.0) b
Hypogonadal, low testosterone and/or high LH: testosterone b 10 nmol/L and/or LH N 10 IU/L. Hypogonadal, high LH: LH N 10 IU/L. HADS-A (Hospital Anxiety and Depression Scale-Anxiety). HADS-D (Hospital Anxiety and Depression Scale-Depression). ⁎Of 165 patients, 20 were excluded due to testosterone replacement therapy and three did not want to deliver a blood sample. When the replaced patients were included, the outcome was similar (data not shown). a Age, smoking and body mass index included in the model. b Body mass index included in the model.
Male hypogonadism and EMD share several symptoms including low levels of resolution, ambivalence, impaired concentration, fatigue and lethargy (American Psychiatric Association, 1995; Carnegie, 2004). It could, therefore, be anticipated that disease and treatment induced hypogonadism is the underlying cause of EMD in TGCC patients. Our results indicate that the EMD symptoms in TGCC patients are not related to hypogonadism. This assumption is also supported by the lack of association between AR CAG and GGN repeat length and EMD. The two conditions seem to be two separate entities which, from a clinical point of view, may represent a problem of differentiating diagnoses. In elderly Finnish men long CAG repeats were found to be associated with the risk of depression (Harkonen et al., 2003) indicating a more important role of androgens in the pathogenesis of EMD in this category of subjects. However, this could not be confirmed in another study on elderly men where testosterone levels and CAG repeat lengths did not have any association with depression (T'Sjoen et al., 2005). Our results are in concordance with those presented by Wiechno et al. (2007) whose study also found no association between the results of the HADS and elevated LH or low testosterone. However, when using another depression scale, the Beck Depression Inventory (BDI), they did find an increased risk for depression when LH levels were increased. Both scales are well validated and the sensitivity and specificity is very high in detecting major depression for both the scales. However, in the case of minor depression there are indications that the Table 4 Emotional distress in relation to treatment in 165 TGCC patients 3–5 years after treatment. HADS-A ≥ 8 Anxiety (n) (%)
HADS-D ≥ 8 Depression (n) (%)
Anxiety (n) (%)
Depression (n) (%)
31 (19)
8 (4.8)
Treatment received SO, n = 13 0 ACT, n = 41 4 (9.8) SCT, n = 54 8 (15) RT, n = 49 14 (29) HDCT, n = 8 5 (62)
0 1 (2.4) 1 (1.9) 5 (10) 1 (12)
All patients
SO: no further therapy after orchiectomy. ACT: 1–2 cycles of adjuvant chemotherapy. SCT: 3–4 cycles of chemotherapy. RT: adjuvant radiotherapy. HDCT ≥ 5 cycles of chemotherapy ± other drugs. HADS-A (Hospital Anxiety and Depression Scale-Anxiety). HADS-D (Hospital Anxiety and Depression Scale-Depression).
HADS demonstrates greater specificity, sensitivity and also a higher positive predictive value, although not a significant one, in cancer patients following curative treatment (Katz et al., 2004). We found patients with more recurrent or refractory disease who had received ≥5 cycles of chemotherapy to be more prone to being anxious 3–5 years after treatment. Therefore, we consider that during follow-up this group should be given special attention with regard to developing anxiety, and appropriate treatment has to be offered to the patient. Whether this is due to psychological factors related to the more uncertain prognosis for these men, or whether it is a direct effect of the cytotoxic drugs on the brain cannot be concluded from this study even though studies done on animals support the latter (Macleod et al., 2007). For the diagnosis of androgen deficiency a blood sample should ideally be obtained before 10 am. For logistical reasons, we obtained blood samples at different time points between 9 am and 3 pm. This might have blurred the difference between truly hypogonadal and eugonadal men, thus reducing the statistical power of that part of the study. However, it has been reported that the diurnal variation in testosterone levels is less pronounced in hypogonadal men (Winters, 1991). Furthermore, we found no increase in the OR for EMD even when LH above 10 IU/L was used as the only indicator of hypogonadism. Unlike testosterone, LH does not decrease during the daytime. Previous studies regarding the association between testosterone levels and metabolic signs of hypogonadism reported no difference in the risk estimates regardless of whether the time of blood sampling was taken into consideration or not (Agledahl et al., 2008). Excluding men on androgen replacement could lead to an underestimation of the frequency of patients with problems related to hypogonadism and TGCC. However, inclusion of patients on testosterone replacement did not influence the magnitude of the risk estimates. In the testosterone replaced group, 30% scored ≥8 on HADS-A, giving a CI on 12–54%. For the whole group, the score was 19% with a CI of 13–26%. Consequently, no difference was seen, but the low number of replaced patients has to be considered. The low prevalence of depression in the study material is a limitation and due to the low statistical power the results needs confirmation in a larger population. The fact that 75 patients declined to participate in the reproductive study and, additionally, that thirteen patients
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withdrew after inclusion in the current study might represent a source of selection bias. However, the study has a relatively high participation rate of 62% even when we include the figure of the 75 men denied participation in the reproductive study as being theoretically eligible for the current study, and we assume that any strong association between hypogonadism and the risk of EMD should be detected in a cohort where 36% of patients present with biochemical signs of androgen deficiency. From the 165 patients answering the HADS, 15 were at the three-year follow-up and 150 at the five-year follow-up. Since all patients answered the questionnaire at inclusion and after 5 years, some were included but had not passed the five-year control yet. We choose to expand the material with the threeyear questionnaires since data from former studies show that after 2–3 years the acute toxicity is reversed concerning most side effects (Eberhard et al., 2009, 2008, 2004). In conclusion, we found that among TGCC patients the risk of EMD was not increased in those with biochemical signs of hypogonadism and since several symptoms are similar, special attention is needed with regard to the possible diagnostic options. The androgen receptor polymorphisms did not predict the risk of anxiety. Patients who had received ≥5 cycles of chemotherapy were at increased risk of developing symptoms of anxiety 3–5 years after completed therapy and special attention should be given to these patients in the follow-up. Role of funding source The study was supported by grants from Swedish Government Funding for Clinical Research, the Swedish Cancer Society (Grant. no. 4857-B05-03XCC), Gunnar Nilssons Cancerstiftelse, Swedish Childhood Cancer Society (Grant nos. 05/056 and RKT04/001), Malmö University Hospital Foundation for Cancer Research and Foundation for Urological Research and King Gustaf V's Jubilee fund for Cancer Research, Stockholm (Grant nos. 44052 and 74061). The donators had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Conflict of interest All authors declare that they have no conflicts of interest.
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