To our knowledge, this study presents the largest series of patients referred for sperm cryopreservation before potentially gonadotoxic treatment, thus providing sound data on semen quality for various pathological conditions. The extent of poor semen quality is underlined thanks to the calculation of the percentage of normozoospermia as well as the comparison with the level of semen quality in two large groups of healthy fertile men. In addition, our study provides baseline data in cases of brain tumour, Behcet’s disease and multiple sclerosis, three pathological conditions for which possible impact on semen quality has rarely been studied.
The possible direct or indirect role of the pathologies studied on the level of semen quality is briefly discussed below. Then, we discuss the feasibility of sperm banking in the various pathologies as well as its theoretical use for a parental project when a long lasting post-treatment azoospermia is observed.
Semen quality
Although sperm alterations most commonly occur as a result of treatment with gonadotoxic agents, they could also be observed before treatment, and may depend on cancer type. Moreover, only few studies have compared semen quality in different pathologies and healthy volunteers [19–21].
Various pathophysiological hypotheses could be raised to explain spermatogenesis impairment in a context of cancer. Those include direct tumour effects on testis and male reproductive tract, but also indirect impact with endocrine disturbances, or nutritional, autoimmune and systemic effects of cancer (see [22] for review). Sperm chromatin assay (SCSA) [23, 24] revealed sperm DNA damage due to pathology when compared to healthy fertile men. Moreover, in our study, a decrease in seminal volume was also observed for cancer or immunological disease patients, whereas the abstinence delay tends towards being longer than in fertile groups. Because semen volume depends on the contraction of the accessory glands which is influenced by the level of excitement during semen collection, these patients not being in an optimal psychological condition, this may certainly explain most of the observed low semen volumes which simply reflect a lower level of excitement. However, other additional factors such as an hypoandrogenisation for some of the patients cannot be ruled out.
Some differences can be noted according to the type of pathology. For testicular cancer, the majority of authors suggested altered semen parameters, usually sperm concentration and count [3, 4, 21, 25–28], the results being more controversial for motility and morphology. In our series, we observed significantly decreased sperm concentration, count, motility and morphology when compared to semen parameters of both groups of fertile healthy men. Only 50.9 % of men with testicular cancer presented normozoospermia when WHO 2010 reference thresholds were applied. Williams et al. found that 37 % of men with testicular cancer were normozoospermic using previous WHO 1999 criteria [21] and Hotaling et al. reported that only 59 % of TGCT patients had a total motile sperm count of more than five million [20]. However, both of these studies used low sample sizes and other reference values, making results difficult to compare. In addition to common mechanisms in all types of cancer, pre-existing defects in germ cells as part of testicular dysgenesis syndrome could also be involved in case of testicular cancer [29], as suggested by frequent histological modifications that are found in the controlateral testis [30].
For haematological diseases, most of studies revealed impaired sperm parameters. However, results are very difficult to compare because of the wide variety of diseases, leading either to small sample sizes in the studies [20, 21, 27, 28] or to a combination of different pathologies [3, 4, 19]. In our series, we observed moderate but significant decreased sperm concentration, count, motility and morphology in patients presenting lymphomas; 65.1 and 59.5 % of men had normozoospermia in cases of Hodgkin’s lymphoma or non Hodgkin’s lymphoma, respectively. On the contrary, a drastic decrease of motility and morphology were observed for men presenting leukemia, and only 36.9 % presented normozoospermia. Altered general state, hyperthermia (frequently observed during lymphomas) or testicular infiltration (as in acute leukemia), could be additional pathophysiological mechanisms responsible for the impaired spermatogenesis during haematological diseases [6, 31].
Semen quality may be expected to be better in case of chronic forms of leukemia than in case of acute leukemia due to the possible severe deterioration of the general health conditions and the impact of high fever episodes in this form of leukemia. Because we had no mean to a posteriori separate both forms of leukemia we could not provide baseline data for each subcategory. For other solid malignant diseases, literature is scarce, usually showing normal or subnormal sperm parameters [20, 21, 26, 27], but with very small sample sizes (some with a maximum of ten). For men presenting sarcoma, a moderate decrease in all semen parameters was observed in our series. On the contrary, for men presenting cerebral tumours, sperm concentration and counts were comparable to those of healthy fertile men, whereas motility and morphology were drastically reduced.
Finally, little is known about semen parameters of men presenting severe systemic diseases such as Behcet’s disease or multiple sclerosis. Altered semen parameters were pointed out in the only available study comparing 68 men with multiple sclerosis to 48 healthy volunteers [32]. For Behcet’s disease, impaired sperm production was suggested [33]. In our series, we observed moderate alterations in semen parameters for both groups. About 70 % of men presented normozoospermia according to WHO 2010 reference values.
Clinical considerations
There is a number of barriers to sperm banking. One can ask what is the proportion of men actually referred to a sperm bank (who probably do not represent the majority of men of reproductive age likely to be exposed to gonadotoxic treatment) who could effectively benefit from this procedure?
In our series, failure to collect a sperm sample was observed in 5.7 % of men, slightly higher than in other studies with about a 3 % collection failure rate [3, 4]. This difference may be explained by the absence in previous publications of populations more exposed to collection failure, such as men with brain tumours, sarcoma or multiple sclerosis. For these pathological conditions, semen collection failure could be related to stress, but also to severe illness with very impaired general health (especially in leukemia or brain tumour populations), sexual inexperience (especially for very young adults, as in a sarcoma population), or neurological alterations (as seen in men with multiple sclerosis). Azoospermia was observed in 5.7 % of all men, being different according to different pathologies and ranging from 0 % in brain tumours to 13.2 % in leukemia. In leukemia cases, literature showed conflicting results, with azoospermia ranging from 0.8 [4] to 24 % [27], including 12.5 % [28]. Those differences may be due to small sample sizes, making results difficult to compare. In testicular cancer, we observed a rate of azoospermia of 5.0 %, mostly comparable to previously published results in lower sample sizes [3, 4, 19].
The question of the difference in the tolerance of the spermatozoa to the processes of freezing in liquid nitrogen vapours and subsequent thawing to ambient temperature in patients with various cancers compared to other groups of men has rarely been studied [34]. In our study we observed a reduced progressive motility recovery in all groups, except brain tumours and immunological diseases, when compared to fertile candidates for sperm donation. Our results concur with Caponecchia et al. who found that the percentage of surviving sperm cells was significantly lower in oncologic groups of men, especially in a group of men having leukemia, than in a fertile group (32.1 and 50.1 %, respectively) [19]. On the contrary, Agarwal et al. suggested that there was no additional loss of semen quality after thawing beyond that to be expected from any semen cryopreservation [35]. This overall decrease in the motility recovery rate contributes to the constitution of straws with significantly lower NMSPS for men presenting testicular cancer, haematological disease, sarcoma or Behcet’s disease, when compared to fertile sperm donors. Beyond discussion about minimal NMSPS required for ART [36, 37], when evaluating the theoretical use of those straws, decreased NMSPS in cancer patients leads to a less frequent use of IUI and a more frequent use of IVF with or without ICSI, regardless of the female fertility check-up or the number of available straws. For a small number of cases, no motile sperm cells were observed post-thawing, making the use of the stored semen samples uncertain, even for an ICSI attempt. In those situations, the hypo-osmotic swelling test (HOS-test) on a frozen and thawed straw constitutes a very useful adjunct to ascertain if an ICSI attempt may be programmed [38].
