Abstract
Objective
To assess rates of successful testicular sperm retrieval and intracytoplasmic sperm injection (ICSI) outcome in cancer survivors affected by non-obstructive azoospermia (NOA) or retrograde ejaculation (RE)/failure of emission (FOE).
Methods
A retrospective analysis of cancer survivors who did not cryopreserve sperm prior to treatment undergoing testicular sperm extraction (TESE). Non-cancer NOA patients and neurologic RE/FOE were the control group.
Results
A total of 97 cancer survivors were offered TESE and 88 (91%) accepted. Sperm was retrieved and cryopreserved in 34/67 patients with NOA (50.7%) and in 21/21 patients affected by RE/FOE (100%). Sperm retrieval rates were similar in the control group (44.9% in NOA and 100% in RE/FOE). The ICSI cumulative pregnancy rate (60%) and live birth rate (40%) per couple in 30 NOA men did not differ from controls (50.0 and 46.5%, respectively; p = 0.399/0.670). The cumulative pregnancy rate (66.7%) and live birth rate (55.6%) in 18 RE/FOE men did not differ from the control group (38.9 and 33.3%, respectively; p = 0.181/0.315). The cancer type and the resulting infertility disorder (NOA or RE/FOE) were not associated with ICSI outcomes. Female partner age was inversely related to the cumulative live birth rate, being fourfold lower (11.5%) in women ≥ 40 years and 48.8% in younger women (p = 0.0037).
Conclusions
The rate of successful TESE and the ICSI outcome in cancer survivors with NOA and RE/FOE is the same as non-cancer azoospermic patients. Female partner age (older than 40 years) was associated with a significant reduction in live birth rates after TESE-ICSI procedures.
Keywords: Cancer survivorship, Male infertility, Testicular sperm extraction, Intracytoplasmic sperm injection
Introduction
Non-obstructive azoospermia (NOA) is a well-known side effect of chemo/radiotherapy protocols. The gonadotoxic impact and the resulting testicular damage depends on several factors, namely quality of spermatogenesis before treatment, type of malignancy, cancer treatment protocol and patient susceptibility [1–4]. In addition, future fertility may also be compromised by surgical interventions such as retroperitoneal lymph node dissection (RPLND) for treating non-seminomatous germ cell tumours (NSGCT) or after abdominal surgery to resect residual tumours, colorectal cancers, urologic cancers and sarcomas, causing retrograde ejaculation (RE) or failure of emission (FOE) [5].
It is well-known that fertility is an important paradigm for the quality of life post cancer and therefore sperm cryopreservation should always be offered before gonadotoxic treatments [6, 7]. However, in reality, this is not always feasible, as in pre-pubertal boys (< 11 years old) [8], or for patients unable to provide sperm by masturbation, or for those needing immediate chemotherapy or as is often the case, for lack of reproductive counselling and referral [9].
When sequelae of oncological treatments result in persistent azoospermia and no prior sperm was cryopreserved, patients can be offered testicular sperm extraction (TESE) and if successful, assisted reproduction with intracytoplasmic sperm injection (ICSI) [10]. The ICSI treatment can also be offered to cancer survivors affected by RE/FOE using electro ejaculation (EEJ) [11] or by performing TESE if no sperm is obtained by EEJ [12].
The aims of this study are twofold: a) to assess the rate of sperm recovery after TESE in cancer survivors affected by azoospermia or RE/FOE and b) to report the clinical outcome of ICSI with testicular sperm.
Materials and methods
Data collection and patient population
A retrospective selection of patients attending our tertiary referral fertility centre between June 1998 and June 2017, using keywords “male infertility”, “cancer” and “sperm banking” were extracted from our database. The medical information included male and female age, type of malignancy and treatments, reason for the lack of cryopreservation, oncologic follow-up, semen analyses after treatments, FSH and testosterone, testicular sperm extraction and ICSI outcomes.
As control group, non-cancer patients affected by NOA or by neurologic RE/FOE (spinal cord injury, juvenile diabetes) were selected during a similar timeframe with age-matched female partners. Azoospermia was defined as the absence of spermatozoa in at least two semen analyses, according to the WHO criteria [13–15]. Failure of emission (FOE) was defined as the complete absence of either antegrade or retrograde seminal emission, while retrograde ejaculation (RE) as the presence of seminal emission into the bladder after orgasm.
In the control group, NOA was diagnosed in patients with small testicles (< 12 ml) and high FSH (> 7.6 mu/ml) [16], after ruling out known causes for azoospermia. Patients with a history of cryptorchidism or mumps orchitis were included, while patients with genetic or chromosomal abnormalities were excluded. Patients with FOE underwent TESE because our centre did not use electro-ejaculation, while the two cases of RE underwent TESE because sperm recovered from the bladder were not viable.
The information collected from female partners included ovarian reserve testing (day 3 estradiol and serum FSH levels until 2010 and antral follicle count (AFC) [17] and serum AMH levels [18] thereafter). Co-existing causes of female infertility were grouped into low ovarian reserve [19], endometriosis, polycystic ovarian syndrome and tubal factor.
This study was approved by our hospital’s Institutional Ethics Committee, and all patients provided written informed consent for the scientific use of their clinical data.
Testicular sperm extraction and intracytoplasmic sperm injection
TESE was performed as an outpatient surgery using open biopsy on both testes under local anaesthesia or deep sedation using propofol [20]. In all cases, a small sample of testicular tissue was sent for histology. Testicular sperm concentration was estimated using a five degree scale as described by Hauser et al. [21] . TESE was considered successful when the sample was ≥ 2 degrees (corresponding to at least a single spermatozoon observed in each microscopic field suitable for ICSI). Failed TESE was considered either the complete absence of spermatozoa or the presence of a single occasional spermatozoon identified after reviewing several microscopic fields (× 200), unusable for ICSI due to severe teratozoospermia. In each case, TESE was carried out before controlled ovarian hyperstimulation (COS) to avoid the risk of not finding spermatozoa on the day of egg retrieval. Testicular sperm was cryopreserved following a rapid two-phase protocol [22]. No complications from TESE were recorded. Testicular pain after biopsy, if present, was managed with oral paracetamol, 1 g every 12 h.
The protocols for controlled ovarian stimulation (COS) consisted of GnRH agonist long protocol.
When at least three follicles with a mean diameter > 18 mm were observed, recombinant human chorionic gonadotropin (Ovitrelle; Merck Serono) was administered 36 h prior to oocyte retrieval.
ICSI procedure was performed as previously described [23]. Embryo transfers took place either on day 2–day 3 or day 5 after ICSI. All patients were given the option of freezing excess oocytes (since during the period 2004–2009 only oocyte cryopreservation was allowed) or embryos [24]. Clinical pregnancy was defined as the ultrasound visualization of one or more gestational sacs. A live birth event was the delivery of singleton or multiple.
Cumulative pregnancy rates and live birth rates were measured per single COS cycle, and positive results were considered clinical pregnancies achieved either in the fresh or in corresponding thawing cycles.
ICSI outcomes in cancer survivors were compared with the results of non-oncologic patients also affected by NOA or by RE/FOE (controls).
Statistical analysis
Data were described as numbers and percentages or means and standard deviations, as appropriate. Differences among groups were explored with the Kruskal Wallis test or chi square test with Fisher correction. Possible risk factors for pregnancy were analysed with logistic regression and stepwise multivariable analysis. A p value less than 0.05 was considered significant. All analyses were performed using Stata13 (2013, Stata Corp, TX, USA, www.stata.com).
Results
Between June 1998 and June 2017, 981 out of 22,173 men (4.4%) seen at our centre either were affected by cancer (n = 826) and referred for sperm banking prior to starting gonadotoxic treatments or were cancer survivors (n = 155). Among the survivors, 58 were oligospermic who needed in-vitro fertilization and 97 were azoospermic who did not bank sperm before antineoplastic therapy. Of these, 75 were diagnosed with NOA and 22 with RE/FOE. Most patients had testicular cancer (54.6%) or haematological malignancies (34%). The remaining cases included sarcomas, gastrointestinal and renal malignancies (Fig. 1). Demographic characteristics of male cancer survivors are reported in Table 1. Age at first reproductive counselling, both in men and in female partners, did not differ statistically between cancer survivors and control group. Interval from cancer diagnosis and reproductive desire was 8.7 ± 8.6 years.
Fig. 1.
Schematic description of 97 infertile cancer survivors, with no available cryopreserved sperm, attending our tertiary referral fertility centre between June 1998 and June 2017. TESE = testicular sperm extraction; RE/FOE = retrograde ejaculation/failure of emission. NSGCT = nonseminomatous germ cell tumour
Table 1.
Demographic characteristics of male cancer survivor patients and infertile, non-oncologic control group. RE/FOE = retrograde ejaculation/failure of emission. The asterisk in “Interval between cancer diagnosis and intention to wish a child” means that 13 patients were already looking for children before the diagnosis of cancer. Thus, in these patients, the interval in years between diagnosis and intention to have a child results negative
| Cancer survivors | Controls | p | |
|---|---|---|---|
| No. | 97 | 226 | |
| Age at first reproductive counselling | 37.6 ± 5.9 | 37.8 ± 6.7 | 0.844 |
| Female age at first reproductive counselling | 34.1 ± 4.8 | 34.8 ± 4.8 | 0.195 |
| Age at cancer diagnosis (years) (mean ± SD, range) | 27.4 ± 9.5 (2.1–46.9) | ||
| Interval from cancer diagnosis (years) | 8.7 ± 8.6 (− 5.8–33.1)* | ||
| Failed sperm cryopreservation | 18 (18.5%) | ||
| No cryopreservation | 79 (81.5%) | ||
| Surgery (S) | 19 (19.6%) | ||
| Chemotherapy (C) | 27 (27.8%) | ||
| Radiotherapy (R) | 1 (1%) | ||
| S + C | 21 (21.6%) | ||
| C + R | 15 (15.4%) | ||
| S + R | 6 (6.3%) | ||
| S + C + R | 8 (8.3%) | ||
| Irreversible azoospermia | 75 (77.3%) | 207 (91.6%) | |
| RE/FOE | 22 (22.7%) | 19 (8.4%) | |
| TESE procedures (patients) | 88 (90.7%) | 226 (100%) | |
| Positive TESE (azoospermic) | 34/67 (50.7%) | 93/207 (44.9%) | 0.481 |
| Positive TESE (RE/FOE) | 21/21 (100%) | 19/19 (100%) | – |
| Banked vials (mean ± SD, range) | 4.6 ± 2.3 (1–10) | 3.1 ± 1.8 (1–8) | < 0.001 |
The reasons for the lack of sperm banking were the absence of spermatozoa at the time of the semen collection (18.5%), no reproductive intentions at the time of the diagnosis (23.7%), insufficient/absent counselling before the treatments (51.6%) and finally, the young age (≤ 12 yrs.) (6.2%). Eleven out of 18 patients who were azoospermic when referred for sperm banking were affected by testicular cancer (61%).
The control group consisted of 226 men selected in a similar timeframe for age-matched female partners. Of these, 207 were affected by NOA and 19 by neurologic RE/FOE. The mean age of the male control group was 37.8 ± 6.7 years, while that of their partners was 34.8 ± 4.8 years (34.1 ± 4.8 years in cancer survivors) (p = 0.195). Aetiology of NOA in the control group included 33 cases of cryptorchidism, 3 cases of mumps orchitis, 5 cases of testicular dysgenesis (small testes, high FSH, testicular calcification and nodules at scrotal US) [25], while in the remaining 166 cases the aetiology was unknown (idiopathic NOA).
FSH and testosterone values in cancer survivors and control group are reported in Table 2.
Table 2.
The table compares the main endocrine variables between azoospermic and RE/FOE patients undergoing TESE, according to clinical category (cancer survivors vs. non-oncologic controls). While chemotherapy/radiotherapy causes an increase in FSH and a reduction in testosterone in azoospermic men, the effect in RE/FOE patients is less severe, affecting FSH values only
| Azoospermia with TESE + | p | RE/FOE group with TESE + | s | |||
|---|---|---|---|---|---|---|
| Oncologic | Controls | Oncologic | Controls | |||
| No. | 67 | 207 | 21 | 19 | ||
| Age | 37.3 ± 5.1 | 36.9 ± 5.6 | 0.864 | 39.1 ± 6.3 | 47.6 ± 10.2 | 0.006 |
| FSH (mu/ml) | 21.8 ± 14.2 | 22.0 ± 10.3 | 0.333 | 8.9 ± 6.4 | 4.7 ± 2.5 | 0.016 |
| Testosterone (ng/dl) | 384.3 ± 149.9 | 434.5 ± 160.1 | 0.027 | 492.8 ± 121.7 | 425.9 ± 280.6 | 0.111 |
RE/FOE = retrograde ejaculation/failure of emission
All cancer survivors (n = 97) were offered testicular sperm extraction for ICSI. Nine refused (8/75 in NOA and 1/22 in men affected by RE/FOE).
In the remaining 88 patients, sperm was successfully retrieved and cryopreserved in 34/67 NOA (50.7%), at a rate like the control group (44.9%) (p = 0.48). In patients affected by RE/FOE (cancer survivors and controls) sperm was retrieved in all cases. Among cancer survivors, a previous diagnosis of testicular cancer was associated with a high sperm recovery rate (seminomas 56.5%; NSGCT 73.3%; Hodgkin’s lymphomas 33.3%; non-Hodgkin’s lymphomas 25%; leukaemias 25%) (Table 3). The average number of cryopreserved sperm vials was higher in cancer survivors (4.6 ± 2.3, range 1–10) than in the control group (3.1 ± 1.8, range 1–8) (p < 0.001).
Table 3.
Sperm retrieval rate per oncological diagnosis and sperm characteristics
| Diagnosis | Patients | No. TESE | Sperm retrieval rate (%) | |
|---|---|---|---|---|
| Azoospermia | RE/FOE | |||
| Seminoma | 27 | 26 | 13/23 (56.5%) | 3/3 (100%) |
| NSGCT | 26 | 25 | 11/15 (73.3%) | 10/10 (100%) |
| HL | 18 | 14 | 4/12 (33.3%) | 2/2 (100%) |
| NHL | 9 | 8 | 2/8 (25%) | – |
| Haematological | 6 | 5 | 1/4 (25%) | 1/1 (100%) |
| Other | 11 | 10 | 3/5 (60%) | 5/5 (100%) |
NSGCT = non-seminomatous germ cell tumour; HL = Hodgkin’s lymphoma; NHL = non-Hodgkin’s lymphoma
The usage rate of thawed testicular sperm was 87.2%. Four couples stopped treatment before controlled ovarian stimulations (3 azoospermic, 1 RE/FOE), while COS is still ongoing for three couples (1 azoospermic, 2 RE/FOE). At least 1 ICSI cycle was performed in 48 couples (30 azoospermic and 18 RE/FOE). The mean number of COS per couple was 2 ± 1.3 in azoospermic cancer survivors and 1.8 ± 1.01 in the control group (p = 0.958). In RE/FOE group, it was 1.7 ± 1.09 (cancer survivors) vs. 2.05 ± 1.79 (control group) (p = 0.945).
Compared with controls, female partners of NOA cancer survivors were older (36.7 ± 3.9 years vs. 34.1 ± 5.4, p = 0.001) and younger in RE/FOE cancer survivors (35.3 ± 5.0 vs. 38.7 ± 4.2, p = 0.006). Detailed data are reported in Table 4.
Table 4.
Assisted reproductive outcomes of male cancer survivors versus non-cancer patients. For couples at risk of ovarian hyper-stimulation syndrome, embryos were cryopreserved and transferred after 1–2 months. Cumulative pregnancy rate and live birth rate were measured per single COS cycle, with positive result counted if at least one pregnancy was archived in the fresh or in corresponding thawing cycles. *Six couples had two pregnancies in different ICSI cycles. **One couple had two pregnancies in different ICSI cycles
| Azoospermic with TESE | RE/FOE group with TESE | |||||
|---|---|---|---|---|---|---|
| Cancer survivors | Controls | p | Cancer survivors | Controls | p | |
| Couples | 30 | 86 | 18 | 18 | ||
| Started cycles (COS) | 60 | 163 | 28 | 37 | ||
| Suspended cycles | 0 | 10 (6.1%) | 0.066 | 0 | 4 (10.8%) | 0.128 |
| Couples with oocyte | 30 | 84 | 18 | 16 | ||
| No. cycles per couple | 2 ± 1.3 (1–6) | 1.8 ± 1.01 (1–6) | 0.958 | 1.7 ± 1.09 (1–5) | 2 ± 1.79 (1–8) | 0.945 |
| Female age at COS | 36.7 ± 3.9 | 34.1 ± 5.4 | 0.001 | 35.3 ± 5.0 | 38.7 ± 4.2 | 0.006 |
| Cycles with oocyte retrieval | 60 | 153 | 28 | 33 | ||
| Retrieved oocytes | 9.7 ± 4.6 | 12.1 ± 7.2 | 0.054 | 11.8 ± 6.3 | 7.8 ± 5.6 | 0.006 |
| Injected oocytes | 5.8 ± 2.8 | 7.3 ± 3.6 | 0.009 | 7.8 ± 4.1 | 4.6 ± 3.0 | 0.002 |
| Fertilized oocytes | 3.6 ± 2.3 | 4.0 ± 2.5 | 0.392 | 4.6 ± 2.8 | 2.9 ± 2.4 | 0.010 |
| Fertilization rate (%) | 59.2 ± 28.3 | 55.1 ± 27.3 | 0.181 | 62.8 ± 23.5 | 62.9 ± 32.4 | 0.759 |
| Fertilization failure | 7 (11.7%) | 13 (8.5%) | 0.447 | 1 (3.6%) | 4 (12.1%) | 0.363 |
| Risk of OHSS | 6 | 18 | 5 | 4 | ||
| No. fresh/cryo ET | 47/18 | 122/52 | 22/13 | 25/8 | ||
| Fresh embryos transferred | 1.9 ± 0.9 | 1.7 ± 0.8 | 0.122 | 1.6 ± 0.9 | 1.7 ± 0.9 | 0.859 |
| Cryo embryos transferred | 1.6 ± 0.6 | 1.5 ± 0.6 | 0.608 | 1.7 ± 0.7 | 1.3 ± 0.5 | 0.135 |
| Cumulative IR (%) (COS) | 16.3 ± 25.7 | 21.2 ± 33.8 | 0.704 | 31.1 ± 37.5 | 13.6 ± 21.7 | 0.079 |
| Cumulative PR (%) (COS) | 18/60 (30.0%) | 50/163 (30.6%) | 0.923 | 15/28 (53.5%) | 9/37 (24.3%) | 0.021 |
| Miscarriages (%) | 6/18 (33.3%) | 4/50 (8.0%) | 0.017 | 5/15 (33.3%) | 2/9 (22.2%) | 0.385 |
| Cumulative LBR/COS | 12/60 (20.0%) | 46/163 (28.2%) | 0.215 | 10/28 (35.7%) | 7/37 (18.9%) | 0.160 |
| Cumulative LBR /couple | 12/30 (40.0%) | 40/86 (46.5%)* | 0.670 | 10/18 (55.6%) | 6/18 (33.3%)** | 0.315 |
| Born children | 13 | 54 | 13 | 7 | ||
| Twin pregnancies | 1 (8.3%) | 8 (17.4%) | 0.677 | 3 (30%) | 0 (0%) | 0.521 |
| Preterm birth (n. child) | 0 | 7 | 0.330 | 2 | 1 | 1.000 |
| Low birth weight (n. child) | 4 | 8 | 0.228 | 5 | 1 | 0.354 |
COS = controlled ovarian stimulation; OHSS = ovarian hyper-stimulation syndrome; PR = pregnancy rate; IR = implantation rate; ET = embryo transfer; IR = implantation rate; LBR = live birth rate
In cancer survivors, 88 ICSI cycles were performed of which 60 in NOA and 28 RE/FOE. Mean number of injected oocytes was 5.8 ± 2.8 and 7.8 ± 4.1, respectively, with a fertilization rate of 59.2 ± 28.3% and 62.8 ± 23.5%. Forty-seven fresh and 18 thawed embryo transfer cycles were performed in azoospermic cancer survivors, 22 fresh and 13 thawed embryo transfer cycles in RE/FOE cancer survivors. Cumulative live birth rates per cycle/patient were 20/40% in NOA vs. 35.7/55.6% in RE/FOE cancer survivors. These outcomes did not differ from the non-oncological controls (NOA 27.0/46.5%, RE/FOE 18.9/33.3%). Noteworthy is the high rate of first trimester (< 12 weeks) miscarriage (33.3%) in both NOA cancer survivors (8% in controls, p = 0.017) and in RE/FOE cancer survivors (22.2% in controls, p = 0.669).
During the paediatric follow-up, 1 major malformation (congenital cardiac septum malformation) was reported in the cancer survivors group; while one case of hypospadias and one bilateral dislocation of hip in the control group. Two preterm births (27 and 34 weeks) and 9 low birth weights (range 570–2460 g) were observed in the cancer survivors group. In the control group, preterm births and low birth weights were not significantly different (Table 4).
The prognostic factors for successful ICSI outcome were evaluated by univariate logistic regression analysis controlling for cancer; male and female age; NOA vs. RE/FOE; cancer type (testicular and lymphatic/hematologic). Neither cancer type nor infertility disorder (NOA or RE/FOE) were associated with ICSI outcomes. Maternal age however resulted inversely related to the cumulative live birth rate, being 4 times lower (11.1%) when the female partner was ≥ 40 years vs. 48.8% for younger age (p = 0.0037) (Table 5).
Table 5.
Prognostic factors for successful ICSI outcome. Univariate logistic regression analysis. Factors with a p value less than 0.1 were submitted to multivariate logistic regression analysis
| OR (95% CI) | p | OR (95% CI) | p | |
|---|---|---|---|---|
| Cancer (YES) | 0.89 (0.51–1.55) | 0.692 | ||
| Cancer | ||||
| No | 1 | |||
| Seminoma/NSGCT | 0.85 (0.44–1.67) | 0.646 | ||
| Lymphatic/haematologic | 0.96 (0.44–2.11) | 0.918 | ||
| Female age | 0.91 (0.87–0.96) | < 0.001 | 0.89 (0.84–0.96) | 0.001 |
| Male age | 0.96 (0.92–1.00) | 0.054 | – | |
| Azoospermia | 0.99 (0.54–1.82) | 0.983 |
NSGCT non-seminomatous germ cell tumor
Discussion
Sperm banking is a logical solution to preserve fertility in oncologic patients. It is simple and suitable for young patients or for those who have not completed their family when stricken by cancer. Modern cancer treatments offer high chances (> 50%) of being a survivor for 20 years or more after the initial diagnosis, and therefore, it is really important to provide prompt fertility counselling and referrals for sperm banking prior to starting gonadotoxic therapies [26, 27]. However, despite being universally advocated, fertility preservation depends on information provided by oncologists, and regrettably referral rates for sperm banking remain low, as recent surveys reported rates between 38 and 47% [28, 29].
When sperm cryopreservation is not utilized, the risk of future irreversible azoospermia is dependent upon the oncological treatment received. In patient with testicular cancers, the risk of permanent azoospermia ranges between 6 and 18% related to specific treatment protocols (active surveillance vs. chemotherapy vs. RPLND vs. radiotherapy) [30]. However, men with germ cell cancer have the highest rate of azoospermia even before starting cancer treatments, ranging between 15.3 [31], 12 [32], 9 [33] and 4.9% [34], suggesting a role of testicular dysgenesis for both disorders of spermatogenesis and cancer susceptibility [25]. About 20% of testicular cancer survivors with advanced non-seminomatous germ cell tumour (NSGCT) or with late residual mass may be impacted by anejaculation after retroperitoneal lymph node dissection (RPLND) [35].
In our study, we have shown that half of the men (50.7%) unable to cryopreserve sperm prior to cancer treatment and diagnosed with permanent azoospermia had successful sperm retrieved with TESE and usable for at least one ICSI cycle, a rate similar to the control group. Our data is in line with the results of previous reports (from a total of 258 patients and 283 surgical retrievals, the rate of sperm recovery was 45.9%) [36–43] and also confirm that not all forms of cancer benefit from successful sperm recovery [39].
Cumulative live birth rates per couple in NOA cancer survivors did not differ from non-cancer NOA patients (40 vs. 46.5%), despite the significantly older age of the female partners in cancer survivors. However, compared with data in literature (60 deliveries out of 122 couples = 49.2%) [36–43], we showed a lower live birth rate, and this might reflect the mean older age of the female partners in our dataset [44]. The rate of first trimester (< 12 weeks) miscarriage were higher in both NOA and RE/FOE cancer survivors, than in the non-oncologic controls. One could speculate that the high miscarriage rate could be due to long standing sperm DNA damage from chemo/radiotherapies [45], but in our cases, no specific tests have been carried out on the sperm used for ICSI. Higher miscarriage rates could also be explained by the higher age of the females partners (mean female age in miscarriages was 38.1 years; while in full term pregnancies it was 34.1 years; p = 0.0084). In multivariable analysis, the association cancer-miscarriage disappears in favour of the female age (cancer OR 3, p = 0.199; female age OR 1.5, p = 0.003), thus showing an average increase in miscarriage risk of 50% for each year of age.
With regard to patients with anejaculation, Hsiao et al. (2012) [12] have recently proposed a clinical care pathway, based on their personal experience of 26 testicular cancer survivors (4 with RE and 22 with FOE after chemotherapy and RPLND). They reported oral α-agonist pseudoephedrine as not very effective in RE (1 out of 4 cases converted to antegrade ejaculation with spermatozoa and none in the FOE group), thus proposing the use of electroejaculation (EEJ) with subsequent TESE if EEJ revealed azoospermia or extremely poor sperm quality. In our 16 RE/FOE cancer survivors, we resorted directly to TESE and viable sperm were always recovered.
The limitations of our study are the retrospective design and the relatively low number of patients treated; however, it represents one of the largest case histories for infertile cancer survivors who did not bank sperm ahead of their oncological treatment [36–43]. Another limitation of our study is that ICSI outcome results might have been hampered by Italian Law 40 that banned cryopreservation of embryos during the 2004–2009 period [24].
Conclusions
Our data are in line with previous studies reporting TESE as a successful infertility treatment option after cancer for men diagnosed as NOA and who were unable to cryopreserve sperm ahead of their cancer treatment. To our knowledge, this is the first study comparing TESE and ICSI outcomes of male cancer survivors with a non-cancer control group, showing similar results. Male cancer survivors have excellent chance for paternity using TESE-ICSI, provided that the female age is not older than 40 years. The results obtained in patients with RE/FOE (100% sperm retrieval rate in our sample) suggest that TESE could be considered the first-line treatment, without necessarily trying first off-label medical treatments or electroejaculation.
Acknowledgments
The authors would like to thank Renzo Benaglia, Luca Cafaro and Alessandro Pizzocaro for their surgical and endocrinological support.
Compliance with ethical standards
This study was approved by our hospital’s Institutional Ethics Committee, and all patients provided written informed consent for the scientific use of their clinical data. All the authors are consent to publication. The corresponding author has full control of all primary data. The datasets used and/or analysed during the current study have been sent to the publisher as supplementary material.
Conflict of interest
The authors declare that they have no conflicts of interest.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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