The development of testicular cancers is associated with other testicular abnormalities such as testicular maldescent, testicular atrophy and subfertility (United Kingdom Testicular Cancer Study Group, 1994
; Moller and Skakkebaek, 1999
; Fossa and Kravdal, 2000
). Preorchidectomy sperm counts and LH levels are lower and FSH levels higher than age-matched normal controls and patients presenting with lymphoma in a Danish study (Petersen et al, 1999
). Initial management in most patients is with orchidectomy, so it could be anticipated there would be evidence of gonadal dysfunction in a significant proportion of patients. In this study we have confirmed that indeed gonadal dysfunction is common after treatment for testicular cancer and it is of some concern that we note that over 13% of our patients have either a subnormal testosterone or are on testosterone replacement therapy. There are only limited published data on the hormonal function of patients after orchidectomy alone (summarised in ). The two largest previous studies reported findings similar to ours with subnormal testosterone in 5% (Gerl et al, 2001
) and 16% (Aass et al, 1991
) of patients.
Overview of data on hormonal function of long term survivors of testicular cancer
The deleterious effects of low testosterone are well recognised in a number of patient groups including patients receiving hormone therapy for prostate cancer (Bates et al, 1996
; Simon et al, 1997
; Smith et al, 2001
). Our results clearly show a similar impact on the quality of life of testicular cancer patients with low testosterone. We have already demonstrated in a previous report that low testosterone is associated with increases in body mass index (Huddart and Norman, 2003
) and that elevated LH and FSH are associated on univariate (though not multivariate) analysis with an increased risk of cardiac events (Huddart et al, 2003
). Additionally, in this study we have shown that patients with low testosterone have higher average systolic and diastolic blood pressure. As would be anticipated, we have shown that a low testosterone has a significant effect on the quality of sexual experience, although it is interesting to observe that up to three quarters of men with low testosterone report satisfaction with their sexual life. We do not have direct data on how much this represents satisfaction with their relationships rather than sexual activity per se
or whether lower libido allows satisfaction with lower activity. A similar effect on sexual activity of mild leydig cell insufficiency has also been reported in men after treatment for haematological malignancy (Howell et al, 2000
). Low testosterone was also associated with a reduction in more general aspects on quality of life including physical functioning, role and social effects. The difference between patients with normal and low testosterone in these domains is in the order of 5–6%. The clinical significance of these differences is open to interpretation. It is commonly considered that a difference of 10% on these scales is an important difference for an individual patient. In these averaged results, which contain patients with lesser and greater differences, we believe these statistically significant results represent important and clinically relevant findings. We can only speculate on whether this is a direct effect or secondary to effects on sexual functioning and masculinity. Fatigue was not significantly worse in these patients with a low testosterone, a finding similar to that of Howell et al (2000)
in haematological patients, but, perhaps surprisingly, patients with a low testosterone reported high levels of dyspnoea. The reason for this is unclear.
In addition to low testosterone, we have also noted elevations of LH and FSH in a significant proportion of our patients, a finding similar to other smaller studies (Hansen et al, 1990
; Stuart et al, 1990
; Gerl et al, 2001
). A recent large Norwegian study found similar abnormalities in LH, which were significantly elevated compared to normal controls even in those treated by orchidectomy alone (Nord et al, 2003
In common with other reports we have observed increases in LH and FSH levels following chemotherapy (). However, the level of gonadal dysfunction due to the treatment effect seems to be on average less than that reported in previous studies (). There may be a number of reasons for this. A number of studies have shown that the gonadal dysfunction is greatest immediately after chemotherapy (Stuart et al, 1990
; Brennemann et al, 1997
). For instance, Brennemann et al (1997)
in a cross-sectional study showed a higher rate of elevated LH and FSH levels in the first year compared to the number measured after 8 years of follow-up (LH 32% vs
3.6%, FSH 89% vs
64%). As the median follow-up of our cohort is over 10 years, this lower level of dysfunction may reflect that a degree of recovery of the pituitary–gonadal axis has occurred with time.
However, this may not be the complete explanation as Gerl et al (2001)
could detect no difference in LH, FSH and testosterone levels in patients measured between 24 and 60 months and over 60 months. Our Longitudinal data suggest that for surveillance patients there is little change or even a small rise in levels with follow-up. Seeing a rise in median levels would be unexpected as testosterone levels usually decline with age, but could be explained by temporary reduction in testosterone at diagnosis due to tumour development or the effect of recent orchidectomy, which recovers with follow-up. This contrasts with chemotherapy-treated patients, who have higher baseline levels of testosterone and LH and lower FSH levels at diagnosis. This may be due to an interaction between LH and HCG levels and their younger median age (for FSH and testosterone). On follow-up, on average, both testosterone and LH levels fell after treatment. For most patients this fall is modest, but 25% of patients had a greater than 8
fall in testosterone. As there is difference in baseline values between those who received chemotherapy and patients managed by surveillance, the net effect is to achieve levels similar to that seen in patients treated by orchidectomy alone. The data on testosterone could suggest an effect of chemotherapy on testosterone levels, but could be equally interpreted as being due to a differential effect on baseline results due to disease or age-related factors.
Our study could also differ from previous reports due to differences in the chemotherapy utilised. Previous studies have suggested greater dysfunction in patients receiving higher doses of cisplatin chemotherapy (Berger et al, 1996
; Bokemeyer et al, 1996
; Gerl et al, 1997
), vinblastine (Berger et al, 1996
; Bokemeyer et al, 1996
) and ifosphamide (Brennemann et al, 1997
). The majority of our chemotherapy-treated patients received etoposide rather than ifosphamide- or vinblastine-based chemotherapy and additionally almost a third of our patients received carboplatin rather than cisplatin. This view is supported by the greater degree of hormonal dysfunction seen in our intensively treated combination treatment group, many of whom had received intensive salvage treatment.
A number of studies have reported the effects of direct testicular irradiation when applied for carcinoma in situ
, but there is little long-term data on the effect of scattered irradiation from an abdominal field (Fossa et al, 1993
; Brennemann et al, 1997
; Petersen et al, 2002
). Despite statistically significant higher LH levels, our results, like the previous studies, suggest that dogleg radiotherapy probably results in minimal long-term hormonal effects.
In this study we have not undertaken analysis of spermatogenesis, but a number of studies (Fosså et al, 1985
; Kreuser et al, 1989
; Aass et al, 1991
; Brennemann et al, 1998
; Jacobsen et al, 2001
) have emphasised the close correlation between FSH levels and sperm counts. On this basis the elevated level of FSH would suggest that there is a significant long-term impairment of spermatogenesis. In support of this view we were able to observe a clear relationship between FSH elevation and the ability to conceive. However, this is not a clearcut relationship as many patients with elevated FSH do still remain fertile. Our results have shown that though success is less likely with a raised FSH, over 2/3 of such patients were still able to conceive.
The long-term effect of chemotherapy on spermatogenesis at our institution has been previously reported (Lampe et al, 1995
). In this study we noted that 80% of patients who were normospermic before treatment had spermatogenesis by 5 years and the chance of recovery was better if carboplatin and less than four cycles were used. Similar results have been reported by other authors (Drasga et al, 1983
; Fossa et al, 1993
; Petersen et al, 1994
). For instance, Drasga et al (1983)
found that 46% of patients had normal sperm counts 2–3 years after treatment despite only 6.6% having normal spermatogenesis pretreatment. The results of our previous study are reflected in the gratifying success rate of patients attempting to have children despite the substantial evidence of gonadal dysfunction. Although only 25% of patients had successful conception, this represented 77% of the 207 patients who reported attempting conception. This rose to 82% with the aid of infertility treatment. Radiotherapy treatment had no detrimental effect on this success rate, although only a small proportion of patients attempted conception. This is in keeping with the observations in the MRC-randomised trial of dogleg vs
para-aortic radiotherapy that by 3 years 92% of patients treated by dogleg radiotherapy have re-attained sperm counts of 10
Success rate appeared to be lower after chemotherapy, in line with the elevations in FSH that we observed. Most of this is likely to be a direct effect on germ cell function, but there may also be a contribution from dry ejaculation which was reported as ‘quite a bit' or ‘very much' in 3% or more patients after chemotherapy compared to surveillance (). We do not have direct data comparing fertility rates of our patients with normal controls, but in a study of Norwegian registry data (Fossa and Kravdal, 2000
) fertility was approximately 30% lower in testicular cancer patients than the normal population. In line with our findings they reported that lower rates were seen in men who had regional and distant disease (who presumably had more intensive treatment) (fertility rate 0.49 (CI 0.36–0.64) compared to 1.0 for normal population) rather than patients with local disease (0.85 CI 0.67–1.06).
The frequency of hypogonadism observed suggests that screening for testicular dysfunction should be a routine part of testicular cancer follow-up. However, careful thought will need to be given to the issue as to how one manages any detected hypogonadism. Hormone supplementation is indicated for the symptomatic patient with obvious potency problems. The correct management approach for the ‘asymptomatic' man with reasonable sexual activity is more difficult. Testosterone can be replaced by a number of routes (e.g. patches, gels, implanted pellets), but still the most common are by intramuscular injections, which when commenced are likely to be lifelong. Data from other sources have suggested that hypogonadism is associated with the development of osteoporosis and other health effects. Our data have highlighted the, perhaps more subtle, effects of hypogonadism, which affects cardiac risk factors such as BMI and blood pressure and the range of quality of life effects. It is likely that decisions on this will have to be individualised after careful discussion of the issues, but suggests that replacement therapy needs to be considered for this patient group.
In summary, we have found that hormonal dysfunction is frequent after the diagnosis of testicular cancer and treatment can have an additional detrimental effect. This can have a significant impact on the quality of life and contribute to other health problems. Most patients, however, remain fertile though this can be affected by their treatment. Screening for hormonal problems should be considered as a routine part of patient management.