Ten years of experience with semen cryopreservation by cancer patients: follow-up and clinical considerations

Transcription

1 FERTILITY AND STERILITY Copyright., 1985 The American Fertility Society Printed in U.SA. Ten years of experience with semen cryopreservation by cancer patients: follow-up and clinical considerations Edward A. Rhodes, M.D. * Donna J. Hoffman, C.D.R.N. Suzanne H. Kaempfer, R.N., M.N. Denver, Colorado Antineoplastic damage to the testicular germinal epithelium with accompanying infertility or subfertility is now a recognized indication for the use of sperm banking. Thus, issues concerning quality of life now compete with questions of survival in decisions made in oncologic settings. In an attempt to learn what concerns patients who use semen preservation facilities, a lo-year retrospective study was undertaken. Registered mail and phone solicitation was used to determine follow-up characteristics of self-referred male cancer patients who voluntarily banked semen at a private facility before they began cancer treatment. The difficulties encountered in conducting follow-up on this group of patients raise questions about sperm banking practices by cancer populations. Fertil Steril44:51, 1985 Research has documented the occurrence of damage to the testicular germinal epithelium as a consequence of antineoplastic treatment. I - 6 Therefore, storing semen for future artificial insemination has been recommended for patients who are anticipated to experience temporary or permanent sterility from cancer surgery, radio, or chemo. 1, 7-1 To date, attention on this topic has focused on (1) determining culpable cancer treatments; () following up patterns of fertility recovery; (3) assessing patient suitability criteria for use of sperm banking; and (4) evaluating subsequent pregnancy and live birth outcomes when artificial insemination has been attempted. Questions of quality of life and psychologic support regarding when to encourage semen storage by male patients may compete with clinical judgments regarding the futility of accepting poor Received March 1, 1985; revised and accepted June 13, *Reprint requests: Edward A. Rhodes, M.D., 5 East 18th Street, Denver, Colorado 86. quality semen specimens that have little likelihood of successful cryopreservation. 11, 1 Factors that may impede the use of sperm banking by male cancer patients include pretreatment alterations in sperm numbers, morphologic features, and motility incurred through undetermined disease-related mechanisms and manifested by poor trial freeze/postthaw motility recovery. In addition, the need to collect specimens before beginning cytotoxic treatment has resulted in controversy involving delays in cancer treatment in order to assure adequate semen collection. Accessibility to facilities for semen storage and cost may also present barriers to use of sperm banking by male cancer patients. 9 Recent advances in evaluating fertility, gonadal protection, and in vitro fertilization raise questions about limiting consideration of procreative options among cancer patients to traditional semen storage methods For example, improved techniques and availability of in vitro fertilization/embryo transfer for management of infertility among healthy couples has raised the possibility of future use by male cancer patients whose 51 Rhodes et ai. Semen storage by cancer patients Fertility and Sterility

2 pretreatment oligospermia would otherwise render them unsuitable sperm banking candidates. Despite limited chances for successful fertilization when such male factor limitations are involved, in vitro fertilization programs have begun to indicate a willingness to evaluate male cancer patients and their partners for potential participation. A study was undertaken to describe the patterns of use and characteristics revealed during follow-up of male cancer patients who voluntarily elected to bank semen at a private sperm bank before beginning cancer treatment. Because patients in this study were not participating in a sperm banking program as part of a large uni versity-based investigational protocol, both initial referral and long-term follow-up cooperation were subject to patient control. Therefore, an attempt to follow these patients provides more patientcentered perspectives on decisions to maintain semen storage contracts, disposition of unused samples, use of artificial insemination, and willingness to participate in follow-up. This focus may yield information on benefits as determined by patients themselves for using semen storage and may guide future clinician referrals. MATERIALS AND METHODS Patients described in this study represent males with a diagnosed malignancy referred to and accepted for participation in a semen storage program affiliated with a private urology/andrology practice during a 1-year period (1975 to 1984). Patients were self-referred after receiving information on how to contact the semen storage facility from their referring physician (for patients with testicular cancer this tended to be a urologist; oncologists referred patients with other tumor types). Tumor diagnosis and follow-up data for this population of patients are presented in Table 1. At initial referral, split ejaculate samples were collected into preweighed sterile bottles by masturbation after to 3 days abstinence. Specimens were allowed to liquefy at room temperature and were then examined microscopically for suitability. Criteria for cryopreservation were as follows 17 : volume, 1 to 5 ml; motility, > 5% with good forward progression; morphologic features, > 6% normal forms; density, > 5 x 16/m l. Ejaculates accepted for storage were mixed with an egg yolk/glycerol preservative, pipetted into straws containing.5 ml of semen preservative mixture, lowered into a liquid nitrogen storage tank with labeled canes, and gradually brought to a storage temperature of -196 C. Trial freezes were offered to patients but were not used, because time pressure to begin cancer would have precluded collection of additional ejaculates. Patients contracted for storage periods of 1 to 1 years; two copies of the storage contract, one provided to the patient, were completed. The investigators requested that patients stay in contact with the sperm bank to monitor disease status as well as participate in decisions concerning sample storage and disposition. Data for the present study were collected during a 3-month period through registered mail and phone contacts. Of particular interest were current status and treatment of the malignancy; use of semen samples for artificial insemination, including outcome; and current spermatogenesis (evaluation by semen analysis provided at no cost). RESULTS Follow-up letters by certified mail were sent to the 4 cancer patients who stored semen between 1975 and One letter was returned because the patient was deceased, five letters were returned lacking a forwarding address (patients 14 to 18), and five letters were lost in the mail (patients 19 to 3). Subsequently, one of these patients contacted the sperm bank to renew his storage contract (#3). All letters were followed by attempts at reaching the patients by phone. Ten patients were actually reached and were able to provide information on current disease status and desires concerning their semen storage contract. Hodgkin's disease (nine patients) and non Hodgkin's lymphoma (three patients) made up the most frequent tumor diagnosis in this sample. Testicular cancer was the second most common malignancy (seven patients), followed by various hematologic or bone/connective tissue tumors. Patients were receiving a variety of tumor treatments consisting of surgery, radiation, or chemo, alone or in combination. At the time of follow-up, four patients were currently undergoing antineoplastic treatment and eight were disease free; disease status of the remaining patients was unknown because attempts at per- Rhodes et al. Semen storage by cancer patients 513

3 Table 1. Patient Data Semen storage parameters Artificial insemination Follow-up se- Patient Tumor diagno- Current disease Year No. of Range of Range of men evaluation: no. sis/treatment status stored ejaculates sperm No. of attempts! (16/ml ejacumotility outcome iate)/% motility :f;uo~:ii 1 Myeloproliferative Disease free /95; fathered two children after disorder/chemo- completing chemo Metastatic testic- a ular/chemo 3 Hodgkin's disease/ Did not keep folradio, low-up appointchemo ment 4 Hodgkin's disease/ Disease free Azoospermic (1183 and 7/84) radio 5 Chondrosarcoma! Disease free /84, 3/84; two Azoospermic chemo ejaculate samples used for artificial insemination; no pregnancies *b 6 Ewing's sarcoma! Currently re chemo ceiving chemo Currently re * Hodgkin's disease/ 8-9 chemo 1 Hodgkin's disease/ radio, Lymphoma!chemo and 1/8, no pregnancies 15 Metastatic testic ular/chemo 16 Hodgkin's dis- Disease free between / 7 chemo Hodgkin's disease/chemogery Lymphoma!che- Hodgkin's disease/radio- Currently re- Currently receiving ra ~ * * mo ceiving che ceiving chemo dio mo 8 1 Testicular/radio- Testicular/sur- Disease free ~ between 1/ ease/chemo- and 11179, healthy twin daughters 17 Metastatic testic ular/radio, chemo 18 Testicular/un known 19 Hodgkin's dis- Disease free ease/chemo Lymphoma!chemo- Disease free between 1/8 Refused and 1/83, no pregnancies 1 Osteosarcoma! chemo Testicular/ra dio 3 Hodgkin's dis- Disease free Refused ease/chemo a, Unable to establish contact through follow-up. b*, Not applicable, currently undergoing antineoplastic treatment. 514 Rhodes et al. Semen storage by cancer patients Fertility and Sterility

4 sonal contact through follow-up were unsuccessful. Sixteen patients had been diagnosed with malignancy and had subsequently banked semen since 198, of those in Twelve patients were able to collect three separate ejaculates before beginning cancer treatment; 1 patients managed two pretreatment ejaculates. Fourteen patients were able to produce at least one semen sample with a sperm density of> 5 x 1 6 /mlof ejaculate. Of these patients, only four had produced an ejaculate with a lower density. All demonstrated sperm motilities of 5% or greater in at least one sample. Two to 3 days of abstinence were allowed between the collection of each ejaculate. No consistent patterns emerged relating tumor diagnosis, treatment, sperm density, or sperm motility. Only five patients used follow-up sperm counts to ascertain present spermatogenesis. Of these patients, two had azoospermia, two had oligospermia, and one had normal spermatogenesis. Nine patients initially contracted to bank semen for a period of 1 years, seven for 5 years, five for 3 years, and two for 1 year. Because of the initial length of most of the storage contracts, only four patients needed to renew their contracts in order to keep them current. Two of these were initial 1-year contracts with a subsequent 1-year renewal. One was a 3-year initial and 3-year renewal contract and one was a 3-year initial, 1- year renewal. Four patients had their storage contracts terminated, one because he had his samples shipped to an out-of-state sperm banking facility when he moved and three because they failed to renew their storage contracts. Nine patients who appear to be lost to follow-up still have current storage contracts, three to expire during the coming year. Of the 4 patients, only 4 have used banked semen for artificial insemination; of these, only one was known to be successful, producing healthy twin daughters. Another patient has not yet used his stored semen for artificial insemination but nevertheless fathered two children (normal conceptions) after discontinuing chemo. Another patient intends to attempt insemination during the coming year. DISCUSSION The difficulties encountered in conducting follow-up on cancer patients who banked semen at a private facility were striking. Reports to date on the use of semen storage with male cancer patients have tended to accentuate laboratory values (semen parameters) and outcomes of artificial insemination, with no mention of patient referral or follow-up problems. 7-1 The findings of the present study suggest otherwise, and even these results leave many questions unanswered. Because patients were so difficult to contact for follow-up interviews, interpretation of the data relies more heavily upon patient characteristics that may have contributed to a lack of interest in maintaining contact with the semen storage facility. In particular, privacy issues, as well as reordering oflife priorities in the face oflife-threatening illness, may have accounted for some patient attrition. Three of the patients in the sample had undergone a marital separation or divorce by the time of follow-up. With such a change, fertility may no longer be important to the patient. In a now disease-free patient, follow-up may be resisted because the previous act of banking semen may be too closely associated with the disease experience of cancer diagnosis and treatment. One of the patients was known to be deceased, and considering the severity of disease and length of time since diagnosis, it is feasible that other patients in the sample are also no longer alive. The study facility notifies patients by certified mail of terminating contracts 4 to 6 months in advance of the termination date. Semen specimens are then discarded if the storage contract has not been renewed within 3 days after the termination date. To date, this has occurred with three patients and illustrates inefficient use of sperm banking facility space, not to mention undue patient expense. The length of initial storage contract selected by patients is interesting. Longterm contracts (5 or 1 years) predominated and involved 16 patients. Implications for patient counseling at the time of arranging the initial storage contract period are suggested, although it is possible that patient selection of lengthy contract periods also reflects an expression of hope regarding disease survival. If this is true, admonitions to choose shorter storage periods (1 or 3 years) may interfere with patient coping in the presence of life-threatening illness. After examining the characteristics of this group of patients, it seems noteworthy that during the 1 years of the study, 9 male cancer patients were evaluated for participation in the sperm banking program but were rejected due to Rhodes et ai. Semen storage by cancer patients 515

5 either inadequate sperm counts, motility, or morphologic features (4 patients) or because their oncologist had referred them after they had begun cancer treatment (5 patients). The problem of posttreatment referrals for sperm banking has not been previously reported but was found by the present investigators to occur rather frequently and to present significant problems to patient/ physician communication and trust. On a more encouraging note, some oncologists have begun to permit greater flexibility in delaying cancer treatment to facilitate adequate semen collection and storage by patients. It is interesting to speculate whether factors such as poor semen quality, posttreatment referral, or treatment time pressure would have influenced patient use of or willingness to be followed by the semen storage facility in the present study. Advances in the technique of in vitro fertilization, as well as a growing receptivity among centers conducting such programs to consider cancer patients for this procedure, prompt a reevaluation of the minimum criteria by which semen samples are judged on suitability for cryopreservation. Should patients with barely acceptable or suboptimal semen quality be permitted to bank sperm and then, at some time in the future, be offered the option of pursuing in vitro fertilization? Many technical and ethicolegal questions of this course of action remain to be articulated. The possibilities for successful reproductive outcomes, should oncologic uses of in vitro fertilization ever become feasible, are encouraging for cancer patients in whom complete loss of fertility would otherwise occur. We examined semen samples stored for 1 years from patients who had used the facility for infertility problems or prevasectomy and whose storage contract had terminated for density, motility, and morphologic features of sperm. The fact that samples were still suitable for use in artificial insemination suggests that semen storage contracts be selectively extended beyond the usual 1-year limit. This flexibility has significant clinical implications for oncologic patients who may store semen during adolescence but not de- sire artificial insemination until they become 3 or older. Patients who in the past would not have used sperm banking because of such time constraints may thereby exercise greater freedom of choice in preserving their procreative capacities. REFERENCES 1. Chapman RM: Effect of cytotoxic on sexuality and gonadal function. Semin Oneal 9:84, 198. Waxman J: Chemo and the adult gonad: a review. J R Soc Med 76:144, Shalet SM: Effects of cancer chemo on gonadal function of patients. Cancer Treat Rev 7:141, Bender R, Young RC: Effects of cancer treatment on individual and generational genetics. Semin OncoI5:47, Sieber SM, Adamson RH: Toxicity of antineoplastic agents in man: chromosomal aberrations, antifertility effects, congenital malformations and carcinogenic potential. Adv Cancer Res :57, Maguire LC: Fertility and cancer. Postgrad Med 65:93, Saunders DM, Medcalf S: Sperm bank potentials in the management of malignancy. Australas Radiol :36, Hendry WF, Stedronska J, Jones CR, Blackmore CA, Barrett A, Peckham MJ: Semen analysis in testicular cancer and Hodgkin's disease: pre- and post-treatment findings and implications for cryopreservation. Br J Urol 55:769, Goldstein G, Howard SS: Cancer trends: in neoplastic diseases, a role for human sperm banking. Va Med 19:514, Rothman C: The usefulness of sperm banking. CA 3:186, Bracken RB, Smith KD: Is semen cryopreservation helpful in testicular cancer? Urology 15:581, Sanger WG, Armitage JO, Schmidt MA: Feasibility of semen cryopreservation in patients with malignant disease. JAMA 44:789, Ross LS: Diagnosis and treatment of infertile men: clinical perspective. J UroI13:847, Mahadevan MM, Trounson AO, Leeton JF: Successful use of human semen cryobanking for in vitro fertilization. Fertil Steril 4:34, Olson M, Alexander NJ: In Vitro Fertilization and Embryo Transfer. Portland, Oregon, The Oregon Health Sciences University, Glode LM, Robinson J, Gould SF: Protection from cyclophosphamide-induced testicular damage with an analog of gonadotropin-releasing hormone. Lancet 1:113, Amelar RD, Dubin L: Semen analysis. In Male Infertility, Edited by RD Amelar, L Dubin, PC Walsh. Philadelphia, W. B. Saunders, 1977, P Rhodes et al. Semen storage by cancer patients Fertility and Sterility