Assisted reproduction in male cancer survivors: fertility treatment and outcome in 67 couples

Kirsten L. Tryde Schmidt1,3, Elisabeth Larsen1, Susanne Bangsbøll1, Helle Meinertz1, Elisabeth Carlsen2 and Anders Nyboe Andersen1

1 The Fertility Clinic, Section 4071 and 2 Department for Growth and Reproduction, Section 5064, University Hospital of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark

3 To whom correspondence should be addressed. Email: tryde{at}dadlnet.dk


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
BACKGROUND: Many male cancer survivors experience fertility problems due to antineoplastic treatment. We report the fertility outcome in 67 couples referred to assisted reproduction treatment (ART) because of male factor infertility due to cancer. METHODS: This was a retrospective study assessing the following parameters: diagnosis, cancer treatment, type of fertility treatment and type of sperm used, number of pregnancies and pregnancy outcome. RESULTS: Testicular cancer and lymphomas were the most prevalent diagnoses. Adjuvant treatment with chemo- and/or radiation therapy had been given to 90% of the men. Semen was cryopreserved in 82% of the men prior to treatment. Following antineoplastic treatment, 43% of the men had motile spermatozoa in the ejaculate, but 57% were azoospermic. A total of 151 ART cycles were performed [55 intra-uterine insemination (IUI), 82 ICSI and 14 ICSI–frozen embryo replacement (FER)]. The clinical pregnancy rate per cycle was 14.8% after IUI, 38.6% after ICSI and 25% after ICSI–FER. The corresponding delivery rates were 11.1, 30.5 and 21%. Cryopreserved semen was used in 58% of the pregnancies. The delivery rate per cycle was similar after use of fresh or cryopreserved spermatozoa. CONCLUSIONS: Male cancer survivors have a good chance of fathering a child by using either fresh ejaculated sperm or cryopreserved sperm.

Key words: ART/cryopreservation/male cancer survivors/semen


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The number of young men who survive a malignant disease is increasing, since the survival rates of cancers such as testicular cancer and lymphomas have increased considerably over the past decades. Unfortunately, chemo- and radiation therapy may have deleterious effects on spermatogenesis. The degree of testicular damage is drug specific and dose related. Ninety-seven percent of men with Hodgkin's disease (HD) who were treated with MOPP (mechlorethamine, vincristine, procarbazine and prednisone) became azoospermic compared with 54% of those treated with ABVD (adriamycin, bleomycin, vinblastine and dacarbazine). Only 14% of those in the MOPP group recovered spermatogenesis compared with 100% in the ABVD group (Viviani et al., 1985Go). Men with testicular germ cell cancer can expect irreversible impairment of the gonadal function at cumulative cisplatin doses >400 mg/m2 (Pont and Albrecht, 1997Go). In the case of irradiation to the adult male testis, permanent azoozpermia can be induced by doses in excess of 400 cGy, whereas recovery of spermatogenesis is seen at doses of 300 cGy or below (Apperley and Reddy, 1995Go).

In light of this, many clinics routinely offer cryopreservation of sperm prior to chemo- and/or radiation therapy in male cancer patients (Fosså et al., 1989Go; Sanger et al., 1992Go; Lass et al., 1998Go; Audrins et al., 1999Go; Agarwal, 2000Go; Bahadur et al., 2002Go). However, the quality of the sperm at the time of diagnosis may already be considerably impaired because of the underlying disease in the case of both HD (Hendry et al., 1983Go; Viviani et al., 1991Go) and testicular cancer (Berthelsen and Skakkebaek, 1983Go; Hendry et al., 1983Go; Hallak et al., 1999Go). Thus, a lot of male cancer survivors are faced with a fertility problem caused both by the antineoplastic treatment and by the negative impact of the disease itself on spermatogenesis.

The reports on male cancer survivors receiving assisted reproduction treatment (ART) for infertility are scarce and the numbers small. We report the fertility outcome in 67 couples referred to ART because of male factor infertility following cancer, which to our knowledge is the largest such study originating from a single clinic.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The study is retrospective, describing the fertility outcome in a consecutive series of 67 couples referred to ART from 1996 to 2003 because of a previous cancer diagnosis in the male. All couples were referred to the same fertility clinic, which is a public clinic serving the citizens of Copenhagen and its suburbs. The following parameters were assessed: diagnosis, cancer treatment, number of men with cryopreserved semen, type of fertility treatment, type and quality of semen used, number of couples obtaining a pregnancy and pregnancy outcome.

Banking of semen
Since 1996 all men with cancer have been offered semen cryopreservation prior to treatment. The samples are collected by masturbation, the aim being to collect several samples from each patient dependent on the severity of the disease with 2 days of abstinence between each collection. The samples are cryopreserved in liquid nitrogen using a combination of egg yolk and glycerol as the medium for cryopreservation (Bie & Berntsen, Rødovre, Denmark).

ART procedures
Public clinics in Denmark offer intra-uterine inseminations (IUIs), and a total of three IVF treatments free of charge to infertile couples. Some counties additionally pay for the second child. The policy of the clinic, when deciding which treatment to offer the individual couples, was as follows: if the fresh ejaculate included motile spermatozoa, it was used for ART. If there were ≥2 x 106 motile spermatozoa after Percoll density gradient centrifugation, IUI was performed. If there were <2 x 106 motile spermatozoa, ICSI was performed. If there was confounding female factor infertility, this was taken into account when deciding which ART procedure would be optimal. In cases of azoospermia, the pre-treatment cryopreserved semen was thawed and used according to the same criteria as above. One patient had obstructive azoospermia after cancer treatment and had failed to bank semen before treatment. A testicular biopsy revealed spermatogenesis in the remaining testis and testicular sperm aspiration (TESA) was performed.

Our patients are offered the chance of having a maximum of two embryos transferred. At the end of the study period, the clinic performed elective single embryo transfer on a selected group of patients with good-quality embryos. Patients with excess good-quality embryos after transfer were offered to have these cryopreserved for later use.

HCG was measured in the woman's serum 2 weeks after embryo transfer or insemination. In the case of a positive HCG, a clinical pregnancy was confirmed by ultrasonography 3 weeks later. Spontaneous abortions were henceforth reported to the clinic by the return of a report form, which the woman was given at the time of transfer/insemination. The women were asked to return this form after delivery or spontaneous abortion. In the present study, all women returned the form. Biochemical pregnancies were followed until HCG was undetectable. Deliveries were registered by using the returned report forms, where the women were also asked to report any congenital anomalies found in the infants.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Clinical data on the male patients
Table I gives the clinical data on the men: age at diagnosis, age at referral, diagnosis, previous treatment and number of men with cryopreserved semen. The majority of patients suffered either from testicular cancer (n=34) or from lymphomas (n=24). Seven patients underwent a surgical procedure as the only treatment, whereas 60 patients received adjuvant therapy. Eight patients received bone marrow transplantation. A total of 55 patients had semen cryopreserved prior to treatment. Twelve men did not have any semen cryopreserved, either because they were too young to produce a sufficient semen sample at the time of diagnosis, or because they were diagnosed with cancer before cryopreservation of semen was routinely offered to cancer patients. Figure 1 is a box plot of the mean concentration of semen prior to cryopreservation according to diagnosis. Figure 2 depicts the percentage of men with motile spermatozoa in the semen after treatment according to diagnosis. The majority of men who had spermatogenesis and thus spermatozoa in the ejaculate after treatment suffered from testicular cancer.


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Table I. Clinical data on 67 men with male factor infertility due to cancer

 


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Figure 1. Mean concentration of spermatozoa (x106/ml) according to diagnosis in 48 out of 55 men who had semen cryopreserved prior to treatment. Data were missing on five patients, and two groups (i.e. colon cancer and testicular cancer + Hodgkin's disease) only contained one patient each and thus could not be included in the box plot.

 


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Figure 2. Distribution of diagnoses in 67 men with male factor infertility due to cancer and the percentages of men with motile spermatozoa in the ejaculate after treatment according to diagnosis.

 
Clinical data on the female partners
Of the 67 female partners, 12 had confounding female factor infertility: five had tubal factor infertility, one had anovulation, one had tubal factor and anovulation, two had endometriosis and one had endometriosis and a myoma. The mean age of the women at the time of referral was 29.6 years (range 22–39).

Outcome of ART
The 67 couples underwent a total of 151cycles: 55 IUI, 81 ICSI, 14 frozen embryo transfer (FER) and one ICSI with a TESA cycle. Data on the ICSI cycles, ICSI–FER cycles and IUI cycles are given in Table II. The embryos were evaluated for cleavage stage and scored for morphology prior to transfer as previously described (Ziebe et al., 1997Go).


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Table II. Characteristics of 151 treatment cycles in a total of 67 couples

 
The 151 cycles resulted in 52 pregnancies in 40 couples. Thirty-five of these pregnancies were established clinical pregnancies at week 7, five pregnancies ended in early abortion before week 12, two pregnancies ended in abortion after week 12, eight were biochemical and two were ectopic. So far, 34 deliveries have resulted in a total of 37 babies: 29 singletons, three sets of twins and two stillborn babies at week 25 and 33, respectively, due to severe pre-eclampsia in the mother (same mother). Two pregnancies are ongoing. There were no reports on any congenital anomalies.

The majority of gestations (n=39, 75%) resulted from ICSI, nine (17.3%) resulted from IUI and four (7.7%) from replacement of cryopreserved embryos after ICSI. One of the ICSI pregnancies was established after TESA. Cryopreserved semen accounted for 58% of the pregnancies and fresh ejaculated semen for 42% of the pregnancies.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The fertility of male cancer survivors is known to be impaired. However, the outcome of ART in such patients up until recently has only been addressed in case reports or small studies including only a few patients. In a review of the literature from 1983 to 1992, Sanger et al. (1992)Go described a total of 54 deliveries resulting from cryopreserved semen of male cancer survivors from 12 different clinics. Additionally, another 61 deliveries resulting from the use of cryopreserved semen from male cancer survivors were reported from nine different sperm banks (Sanger et al., 1992Go). A recent study by Agarwal et al. (2004)Go reported the outcome of ART in 29 male cancer survivors. We report the outcome of ART in 67 male cancer survivors and their partners, which, to our knowledge, so far is the most comprehensive study originating from a single fertility clinic.

The importance of cryopreserving semen prior to cancer treatment is clearly illustrated in our study because 57% of the men were azoospermic after treatment. The use of cryopreserved semen in these men resulted in 25 clinical pregnancies and 20 deliveries of a total of 22 babies. The majority of pregnancies obtained using cryopreserved semen were a result of ICSI (86.7%), with IUI accounting for only 13.3% of the pregnancies. These figures could advocate the use of ICSI as first choice in cases in which cryopreserved semen is the only semen available and especially when the number of cryopreserved semen samples is low.

All in all, the patients in our study had a clinical pregnancy rate of 14.8% after IUI, 38.6% after ICSI and 25% after ICSI–FER. The delivery rates per cycle were 11.1, 30.5 and 25% after IUI, ICSI and ICSI–FER, respectively. Importantly, as can be seen in Table II, the delivery rates were independent of whether cryopreserved or fresh semen was used.

The importance of offering semen cryobanking to male cancer patients prior to treatment has been known for a long time and in many clinics it has been offered routinely since the 1970s. In addition to the above-mentioned review (Sanger et al., 1992Go), Khalifa et al. (1992)Go reported the outcome of 12 IVF cycles using the cryopreserved semen from 10 male cancer survivors resulting in a total of four pregnancies.

After the introduction of ICSI in 1992, the chances of fathering a child became a possibility even for men with severe oligospermia, who previously had not had any real chance of impregnating their partner (Palermo et al., 1992Go). One study described the results of 15 couples undergoing ART due to previous testicular cancer in the male. The 15 couples underwent a total of seven IVF cycles and 11 ICSI cycles resulting in 12 pregnancies (Rosenlund et al., 1998Go). Lass et al. (1998)Go described the fertility outcome in six couples undergoing ART following chemotherapy in the male using cryopreserved semen; two couples achieved a pregnancy after IUI, one couple after IVF and two after ICSI. Another study reported that out of 258 men who had their semen cryopreserved due to cancer treatment, only 18 returned for treatment, resulting in six pregnancies (Audrins et al., 1999Go). Ginsburg et al. (2001)Go evaluated an IVF programme in cancer patients. Nineteen of these were men who, together with their partner, underwent a total of 35 cycles; 11 of these cycles used cryopreserved semen resulting in three pregnancies, whilst the remaining 24 cycles used fresh sperm resulting in 11 pregnancies, thus giving a pregnancy rate of 40% per cycle, which is similar to what we found in our study. Recently, Agarwal et al. (2004)Go reported the outcome of ART in 29 male cancer survivors all using cryopreserved semen. A total of 87 cycles were performed with a mean pregnancy rate of 18.3% per cycle (7% after IUI, 23% after IVF and 37% after ICSI). These figures are much in accord with ours as we achieved a pregnancy rate of 14.8% after IUI and 38.6% after ICSI.

The majority of the pregnancies obtained in our study derived after ICSI, i.e. 82.6%. In other studies, pregnancies after ICSI account for a smaller percentage, but at least this difference can be explained to some degree by the fact that other groups use IVF as well, a treatment that the patients in the present study were not offered. Instead we chose to go directly to ICSI, when the sperm count was too poor for IUI or there was confounding female partner infertility. Attempting IVF would give an incresed risk of lack of fertilization and thus exhaust the sparse pool of cryopreserved spermatozoa unnecessarily.

Most of the men in this study (82%) had their semen cryopreserved prior to treatment; of these, 35% regained spermatogenesis after treatment. Men without cryopreserved semen were diagnosed with cancer as children or as young adults before cryopreservation of semen was offered routinely. When looking at the pre-freeze semen quality according to diagnosis, the poorest semen quality seemed to be found in patients suffering from testicular cancer, with a mean concentration of 9.7 x 106 spermatozoa/ml. These results, however, are inconclusive since we lack pre-treatment semen data on 12 patients, who failed to have semen cryopreserved. Previous studies have shown that testicular cancer is associated with impaired spermatogenic function before treatment (Berthelsen and Skakkebæk, 1983; Petersen et al., 1998Go), as is also the case in other cancer forms, although not to the same extent.

Chromosomal damage to the spermatozoa after cancer treatment cannot be ruled out. So far we have received no reports on any congenital malformations in any of the 37 delivered offspring of male cancer survivors. However, any later health problems arising in these infants that can be related to chromosomal damage cannot be excluded completely based on the present findings. It is reassuring, however, that a large Scandinavian epidemiological study found no evidence of a significantly increased risk of non-hereditary cancer among the offspring (Sankila et al., 1998Go). This was also found in an earlier study (Hawkins et al., 1989Go).

At our department we have been offering cryostorage of semen since 1996 and so far 1170 men have had semen cryopreserved. The majority of these men had semen cryopreserved because of a malignant disease, other reasons being due to rheumatological diseases or kidney disease. Sixty-five percent of the men with cryopreserved semen in our study had azoospermia after treatment. We therefore strongly recommend that all young men with a newly diagnosed cancer should be offered semen cryopreservation. In addition, we recommend that male cancer survivors with a fertility wish should be referred to a fertility clinic for ART, since a lot of them will be able to obtain a pregnancy with their partners with either fresh or cryopreserved semen.


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
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Submitted on March 16, 2004; resubmitted on June 25, 2004; accepted on August 18, 2004.





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