Sperm Cryopreservation Prior to Gonadotoxic Treatment

Experience of a Single Academic Centre Over 4 Decades

Nandini Shankara-Narayana; Irene Di Pierro; Carolyn Fennell; Lam P. Ly; Fay Bacha; Ljubica Vrga; Sasha Savkovic; Leo Turner; Veena Jayadev; Ann J. Conway; David J. Handelsman

Disclosures

Hum Reprod. 2019;34(5):795-803. 

In This Article

Discussion

This study represents 4 decades of experience of sperm cryostorage by the same clinic and laboratory involving comprehensive clinical and reproductive data on 2319 men with cancer (n = 2085) or non-cancer (n = 234) diseases together with 398 healthy age-matched controls. Other studies of comparable size include a French study compiling experience of 23 centres over 34 years involving 4345 young males aged 11–20 years (Daudin et al., 2015) and a single centre British sperm bank study of semen analyses with minimal clinical data collated over 37 years from 4362 men undertaking sperm cryostorage (Dearing et al., 2014) (Table III).

The progressive increase in requests for sperm cryopreservation between 1978 and 2017 exceeds the state-wide 3–5-fold increases over the same period for new diagnosis of all, haematological, testicular or other cancers (Figs 1 and 2). This suggests the increasing demand for sperm cryostorage is most likely due by growing awareness among oncologists and oncology nurses of the availability of sperm cryostorage for male fertility preservation and its long established medio-legal significance in avoiding negligence claims (Brahams, 1992) rather than increases in underlying cancer incidence rates (Dearing et al., 2014). Nevertheless, we estimate less than half the target population of men with newly diagnosed cancers in reproductive age group are undertaking sperm cryostorage. This shortfall may be due to men having completed their desired family or attending other facilities but any residual extent of failure to offer cryostorage (Schover et al., 2002a,b) cannot be estimated from this study. This aspect of cancer care remains suboptimal as sperm banking has positive psychological effects in both short-term coping with the diagnosis as well as long-term preparation for survival (Eiser et al., 2011; Hammarberg et al., 2017).

The distribution of diseases, notably between testis and non-testis cancers, for which cryostorage is requested has remained stable over the decades observed. Yet there has been an increase in requests from men about to undergo bone marrow transplantation, a procedure that increased dramatically world-wide from <10 000 to over a million annually in less than the last 3 decades (Gratwohl et al., 2015) as well as a recent mild decrease over the last 5 years for men with testis cancer. The recent reduction in requests for cryostorage from men with testis cancer may reflect both the excellent prognosis for testis cancer treatment (5-year survival rate of 98% (Rockhold, 1993)) with a good fertility prognosis (80% experiencing post-treatment recovery of sperm output within 5 years (Lampe et al., 1997)). This has led to more use of watchful waiting (i.e. surveillance without gonadotoxic treatment) as well platinum-based chemotherapy (Chovanec et al., 2017), which has relatively low toxicity with recoverable impact on spermatogenesis (Howell and Shalet, 2005; Bujan et al., 2013; Suzuki et al., 2013). Nevertheless, gonadotoxicity is dose-dependent (Schrader et al., 2001; Brydoy et al., 2012) and as the ultimate extent of gonadotoxic treatment required is not predictable at first presentation of testis cancer, sperm cryostorage should remain the standard of care.

Sperm cryostorage was feasible for virtually all cancers even in the presence of need for urgent treatment (e.g. superior vena caval syndrome from lymphoma). Sperm output for all cancers and non-cancer diseases was lower, however, than healthy controls (Table I). The healthy controls in this study were men screened as potential sperm donors who provided multiple semen samples comparable with men seeking cryostorage (Handelsman, 1997). The median total sperm output (248 million/ejaculate) of the controls in this study was comparable with WHO reference ranges for unscreened men (196 million/ejaculate) or recent fathers (255 million/ejaculate) (Cooper et al., 2010). Testicular cancers had the lowest total sperm output consistent with previous reports (Lass et al., 1998; Williams et al., 2009; Rives et al., 2012); however, this reduction was accounted for by excision of the tumour-bearing testis as the deficit in sperm output was corrected by adjustment for total testicular volume. Furthermore, patients with non-testis cancers also had impaired sperm output compared with age-matched healthy controls suggesting wider effects associated with a cancer diagnosis on sperm output suggesting that systemic factors rather than specific intra-testicular defects in spermatogenesis or testicular physiology explain the reduction of sperm output in testis or other cancers (van Casteren et al., 2010; Agarwal et al., 2014). These include the impact of known pre-cancer factors that impair sperm production such as cryptorchidism and other testicular pathology, history of infertility, smoking (Hart et al., 2015) and recent weight loss but, surprisingly, not fever (Macleod and Hotchkiss, 1941; Carlsen et al., 2003; Sergerie et al., 2007). Most studies of the effects of weight loss on sperm output are in men undergoing deliberate weight loss for obesity. Yet, obesity itself has deleterious effects on sperm output in some (Hammoud et al., 2008; Oliveira et al., 2017), but not all (MacDonald et al., 2010), studies. Bariatric surgery is reported to decrease (Sermondade et al., 2012), have no effect (Reis et al., 2012; Samavat et al., 2018) or increase (El Bardisi et al., 2016) sperm output whereas non-surgical weight loss for obesity may increase sperm output (Hakonsen et al., 2011). The potential role of radiological and other diagnostic investigations as well as other systemic effects associated with cancer (immune- or cytokine-mediated) should also be considered in future studies. We observed that the first sample was consistently higher than later, though differences were small, where most previous studies report solely the first sample. Analogous small differences in sperm quality between multiple semen samples have been described elsewhere (Jayasena et al., 2018).

The cryostorage facility operates without age limits as sufficiently mature adolescents can often provide semen samples after spermarche, which occurs typically at age 12 with a testis volume of 8 ml (Nielsen et al., 1986; Ji and Ohsawa, 2000), so that cryostorage is virtually as feasible for psychologically mature adolescents as for adults. Analogously, older men into the seventh decade were able to cryostore sperm consistent with men's lifelong natural fertility if they have younger female partners.

In this study 7% of cryostored samples were transferred for use to induce a pregnancy at other private fertility clinics after a median time of 2.5 years in cryostorage. This proportion is the same as we reported previously (Kelleher et al., 2001) and similar to a systematic review in 2016 including 30 studies and 11 798 patients showed an aggregated use rate of 8% (Ferrari et al., 2016). The relatively low rate of usage still represents a low cost as a form of fertility insurance which also has positive psychological impact both in the short-term of coping with the cancer diagnosis as well as longer-term planning for their longer-term survival. Although we reported pregnancy outcomes for use of cryostored sperm between 1978 and 2000 (Kelleher et al., 2001), no updated data was available due to more recent privacy restrictions on collecting data from external fertility clinics.

The present study had a high rate of disposal of samples (62.6%) compared to other studies where the systemic review reported an aggregated discard rate of 16% (Table III). This reflects the value of regular follow-up by an experienced cryostorage nurse which reduces the potentially open-ended accumulation of cryostored samples (requiring ever expanding bank capacity) thereby rendering the public service facility more cost-effective.

Although this cryostorage service was provided under the national health scheme without cost or insurance coverage, access still proved limited by geography. Rural and remote areas of the state were markedly under-represented with only 50% as many patients compared to the numbers expected for urban-residing men. The deficit may have been underestimated as many men residing in non-urban areas often travel to Sydney to initiate oncology treatment when they had opportunity for sperm cryostorage. While theoretically possible that the deficit of remote-dwelling men may be due to attendance at other cryostorage facilities the paucity of such alternatives makes this implausible. This underlines the need for an accessible, integrated sperm cryostorage service as an inherent component of a comprehensive care plan for cancer and other serious diseases including men living in non-urban areas.

The post-mortem use of cryostored sperm to induce a pregnancy is an increasingly discussed, controversial medico-legal issue. Within our state, men are required to provide written nomination of their conjugal female partner if they wish to allow use of their stored sperm to create a post-mortem pregnancy. Of 732 men cryostoring sperm who had partners, 630 (86%) chose to nominate a partner for potential post-mortem use of their sperm. Although the nomination can be varied at follow-up visits, this occurs rarely usually due to a change of partner. Unusual requests for post-mortem disposal of cryostored sperm without valid consent have included parents, as executors of the deceased's estate, seeking to obtain the sperm for use with a surrogate; however, the deceased provided no written consent for an unspecified partner and commercial surrogacy remains illegal in this state. Another unusual request was from a nominated female partner to use her deceased partner's stored sperm long after having formed a new conjugal relationship.

Sperm cryopreservation via semen collection by masturbation remains a standard of care for fertility preservation among men with cancer or other diseases requiring gonadotoxic treatment. An important additional consideration is the salvage option of testicular sperm extraction coupled with intracytoplasmic sperm injection which can produce paternity even after severe testicular injury (Zorn et al., 2006; Hsiao et al., 2011). Newly developing non-cytotoxic cancer therapies (e.g. tyrosine kinase inhibitors, immune checkpoint inhibitors) offer possibly less iatrogenic gonadal damage and infertility but data on reproductive effects remains sparse for both men and for pre-pubertal boys, for whom pre-treatment sperm cryostorage will never be feasible. Other possibilities for preserving fertility in pre-pubertal boys include testicular biopsy and cryostorage for future autologous re-implantation into the testis of spermatogonial stem cells or for in-vitro matured sperm for use in in-vitrofertilization. However, re-implantation of germinal stem cells must eliminate the risk of inadvertent transmission of malignant cells. In-vitro spermatogenesis could theoretically be developed from autologous germinal stem cells biopsied from the testis or in-vitro re-programmed, induced pluripotent somatic cells to avoid testicular biopsy; however, all these techniques remain experimental with none achieved in humans at this time with the prospects still remote. In the interim, the safest storage of spermatogonial stem cells remain within the testis rather than as in-vitro cryostorage while the revivification techniques required remain undefined.

We conclude that sperm cryopreservation is a well-established and feasible clinical procedure aiming to preserve male fertility prior to gonadotoxic treatment for cancer or other diseases. As a practical, low cost approach to insure fertility, sperm cryostorage is a readily integrated, best practice component of comprehensive cancer or other medical treatment regimens to overcome iatrogenic damage to spermatogenesis and male fertility for all post-pubertal males. Long recognized in oncology and the law that advising young male cancer patients on sperm cryostorage prior to cancer treatment is an essential component of adequate medical care (Oktay et al., 2018). Although utilization rates are low, such fertility insurance forms a positive psychological support preparing for the man's future survival (Saito et al., 2005; Pacey and Eiser, 2011). Better access to extra-urban areas is required so that sperm cryopreservation becomes universally an integral part of comprehensive cancer treatment programs. This large study over 4 decades shows that sperm cryostorage is feasible for virtually all men, including sufficiently mature adolescents, who can collect semen. Effective clinical follow-up assessing ongoing need for continuing cryostorage is essential to maintain efficiency of storage capacity and avoiding open-ended accumulation of cryostored samples.

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