Late Effects of the Reproductive System
The treatment of cancer in children and adolescents may adversely affect their subsequent reproductive function. Germ cell survival may be adversely affected by radiation therapy and chemotherapy. Ovarian damage results in both sterilization and loss of hormone production because ovarian hormonal production is closely related to the presence of ova and maturation of the primary follicle. These functions are not as intimately related in the testis. As a result, men may have normal androgen production in the presence of azoospermia.Testis
Surgery, radiation therapy, and/or chemotherapy may damage testicular function. Patients who undergo unilateral orchiectomy for testicular torsion may have subnormal sperm counts at long-term follow-up.[1,2] Retrograde ejaculation is a frequent complication of bilateral retroperitoneal lymph node dissection performed on males with testicular neoplasms,[3,4] and impotence may occur after extensive pelvic dissections to remove a rhabdomyosarcoma of the prostate.
Men treated with whole-abdomen irradiation may develop gonadal dysfunction. In one study, five of ten men were azoospermic, and two were severely oligospermic when evaluated at ages 17 to 36 years after treatment with whole-abdomen irradiation for Wilms tumor at ages 1 to 11 years, with the penis and scrotum either excluded from the treatment volume, or shielded with 3 mm of lead. The testicular radiation doses varied from 796 cGy to 983 cGy. Others reported azoospermia in 100% of ten men 2 to 40 months after radiation therapy doses of 140 cGy to 300 cGy to both testes. Similarly, azoospermia was demonstrated in 100% of ten men after testicular radiation therapy doses of 118 cGy to 228 cGy. Recovery of spermatogenesis occurred after 44 to 77 weeks in 50% of the men, although three of the five with recovery had sperm counts below 20 x 106/ml. Oligospermia or azoospermia was reported in 33% of 18 men evaluated 6 to 70 months after receiving testicular radiation doses of 28 cGy to 135 cGy. In another report, none of five men who received testicular radiation doses of less than 20 cGy became azoospermic. By contrast, two who received testicular radiation doses of 55 cGy to 70 cGy developed temporary oligospermia, with recovery to sperm counts greater than 20 x 106/ml 18 to 24 months after treatment. In summary, a decrease in sperm counts can be seen 3 to 6 weeks after irradiation, and depending on the dosage, recovery may take 1 to 3 years. The germinal epithelium is damaged by much lower dosages (<1 Gy) of radiation than are Leydig cells (20–30 Gy). Complete sterilization may occur with fractionated irradiation greater than doses of 2 Gy to 4 Gy.
Administration of higher radiation doses, such as 2,400 cGy, which was used for the treatment of testicular relapse of acute lymphoblastic leukemia (ALL), results in both sterilization and Leydig cell dysfunction. Craniospinal irradiation produced primary germ cell damage in 17% of 23 children with ALL, but in none of four children with medulloblastoma. Total-body irradiation ([TBI] 950 cGy to 1575 cGy) and cyclophosphamide (60 mg/kg/day for 2 days) produced azoospermia in almost all men.
Cumulative alkylating agent dose is an important factor in estimating the risk of testicular germ cell injury, but limited studies are available that correlate results of semen analyses in clinically well-characterized cohorts. A small cohort study reported normal semen quality in adult long-term survivors of childhood ALL treated with 0 to 10 g/m2 of cyclophosphamide and cranial radiation, whereas no spermatozoa were detected in semen samples from survivors treated with more than 20 g/m2 of cyclophosphamide. Combination chemotherapy that includes an alkylating agent and procarbazine causes severe damage to the testicular germinal epithelium.[16-20] Azoospermia occurred less frequently in adults after treatment with two, rather than six, cycles of MOPP (mechlorethamine, vincristine [Oncovin], procarbazine, prednisone). Elevation of the basal follicle-stimulating hormone (FSH) level, reflecting impaired spermatogenesis, was less frequent among patients receiving two courses of OPPA (vincristine, procarbazine, prednisone, doxorubicin) than among those who received two courses of OPPA in combination with two or more courses of COPP (cyclophosphamide, vincristine, procarbazine and prednisone).
Most studies suggest that procarbazine contributes significantly to the testicular toxicity of combination chemotherapy regimens. The combination of doxorubicin, bleomycin, vinblastine, and dacarbazine produced oligospermia or azoospermia in adults frequently during the course of treatment. However, recovery of spermatogenesis occurred after treatment was completed, in contrast to the experience reported after treatment with MOPP. Most studies suggested that prepubertal males were not at lower risk for chemotherapy-induced testicular damage than were postpubertal patients.[17,24-26]
Male survivors of non-Hodgkin lymphoma who underwent pelvic radiation therapy and received a cumulative cyclophosphamide dose greater than 9.5 g/m2 were at increased risk for failure to recover spermatogenesis; in survivors of Ewing and soft tissue sarcoma, treatment with a cumulative cyclophosphamide dose greater than 7.5 g/m2 was correlated with persistent oligospermia or azoospermia. Spermatogenesis was present in 67% of 15 men who received 200 mg/kg of cyclophosphamide before undergoing bone marrow transplantation (BMT) for aplastic anemia. Cyclophosphamide doses exceeding 7.5 g/m2 and ifosfamide doses exceeding 60 g/m2 produced oligospermia or azoospermia in most exposed individuals.[29-31]
Recovery of gonadal function after cytotoxic chemotherapy and radiation therapy is possible. Dutch investigators used inhibin B as a surrogate marker of gonadal function in a cross-sectional, retrospective study of 201 male survivors of childhood cancer, with median follow-up 15.7 years (range, 3–37 years) from diagnosis. The median inhibin B level among the cohort increased based on serial measurements performed over a median of 3.3 years (range, 0.7–11.3 years). The probability of recovery of the serum inhibin B level was significantly influenced by baseline inhibin B level, but not age at diagnosis, age at study evaluation, interval between discontinuation of treatment and study evaluation, gonadal radiation, and alkylating agent dose score. These results suggest that recovery can occur but not if inhibin B is already at a critically low level. Inhibin B and follicle-stimulating hormone levels are correlated with sperm concentration and often used to estimate the presence of spermatogenesis, however, limitations in the specificity and positive predictive value of these tests have been reported. Hence, male survivors should be advised that semen analysis is the most accurate assessment of adequacy of spermatogenesis.Ovary
The frequency of ovarian failure after abdominal radiation therapy is related to both the age of the woman at the time of irradiation and the radiation therapy dose received by the ovaries. Whole-abdomen irradiation produces severe ovarian damage. Seventy-one percent of women in one series failed to enter puberty, and 26% had premature menopause after receiving whole-abdominal radiation therapy doses of 2,000 cGy to 3,000 cGy. Other studies reported similar results in women treated with whole-abdomen irradiation  or craniospinal irradiation [36,37] during childhood.
Ovarian function may be impaired after treatment with combination chemotherapy that includes an alkylating agent and procarbazine such as MOPP; MVPP (nitrogen mustard [mechlorethamine], vinblastine, procarbazine, and prednisone); ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisone); MDP (doxorubicin, prednisone, procarbazine, vincristine, and cyclophosphamide); or the combination of COP (cyclophosphamide, vincristine, and procarbazine) with ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine). Amenorrhea was reported in 11% after MOPP (2 of 18 girls treated at age 2 to 15 years), 31% after MDP (10 of 31 girls treated at age 9.0 to 15.2 years), and 13% after ChIVPP (3 of 23 girls treated at age 6.1 to 20.0 years),[16,38,39] but in 0% after COP/ABVD (0 of 17 girls treated at age 4 to 20 years).
Ovarian function was evaluated in women treated with drug combinations that did not include procarbazine. Ovarian function was normal in all of six women treated for non-Hodgkin lymphoma with a cyclophosphamide-containing drug combination. Others reported that pubertal progression was adversely affected in 5.8% of 17 patients treated before puberty and 33.3% of 18 patients treated during puberty or after menarche. However, the administration of cyclophosphamide did not correlate with the abnormal pubertal progression observed in these patients. Administration of ifosfamide 27 g/m2 to 90 g/m2 to 13 females resulted in evidence of impaired estrogen production in only one patient. Cisplatin administration resulted in amenorrhea in 14% of seven patients.
All women who received high-dose (50 mg/kg/day x 4 days) cyclophosphamide before BMT for aplastic anemia developed amenorrhea after transplantation. In one series, 36 of 43 women had recovery of normal ovarian function 3 to 42 months after transplantation, including all of the 27 patients who were between ages 13 and 25 years at the time of BMT. Most postpubertal women who receive TBI before BMT develop amenorrhea. In one series, recovery of normal ovarian function occurred in only 9 of 144 patients and was highly correlated with age at irradiation in patients younger than 25 years. In a series restricted to patients who were prepubertal at the time of BMT, 44% (7 of 16) had clinical and biochemical evidence of ovarian failure.
Of 3,390 eligible participants in the Childhood Cancer Survivor Study (CCSS), 215 (6.3%) developed acute ovarian failure. Survivors with acute ovarian failure were older (aged 13–20 years vs. aged 0–12 years) at cancer diagnosis and more likely to have been diagnosed with Hodgkin lymphoma or to have received abdominal or pelvic radiation therapy than survivors without acute ovarian failure. Of survivors who developed acute ovarian failure, 75% had received abdominal-pelvic irradiation. Radiation doses to the ovary of at least 2,000 cGy were associated with the highest rate of acute ovarian failure with over 70% of such patients developing acute ovarian failure. In a multivariable logistic regression model, increasing doses of ovarian irradiation, exposure to procarbazine at any age, and exposure to cyclophosphamide at ages 13 to 20 years were independent risk factors for acute ovarian failure.
The presence of apparently normal ovarian function at the completion of chemotherapy should not be interpreted as evidence that no ovarian injury has occurred. Premature menopause is well documented in childhood cancer survivors, especially in women treated with both an alkylating agent and abdominal irradiation.[47-50] A total of 126 childhood cancer survivors and 33 control siblings who participated in the CCSS developed premature menopause. Of these women, 61 survivors (48%) and 31 siblings (94%) had surgically-induced menopause (relative risk [RR], 0.8; 95% confidence interval [CI], 0.52–1.23). However, the cumulative incidence of nonsurgical premature menopause was substantially higher for survivors than for siblings (8% vs. 0.8%; RR, 13.21; 95% CI, 3.26–53.51; P < .001).
A multiple Poisson regression model showed that risk factors for nonsurgical premature menopause included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent dose score, and a diagnosis of Hodgkin lymphoma. For survivors who were treated with alkylating agents plus abdominal-pelvic radiation, the cumulative incidence of nonsurgical premature menopause approached 30%.
In Europe, survivors of Hodgkin lymphoma treated between the ages 15 years and 40 years and who were not receiving hormonal contraceptives were surveyed for the occurrence of premature ovarian failure. In 460 women, premature ovarian failure was mainly influenced by alkylating chemotherapy use with a linear dose relationship between alkylating chemotherapy and premature ovarian failure occurrence. Premature ovarian failure risk increased by 23% per year of age at treatment. In women treated without alkylating chemotherapy before age 32 years and at age 32 years or older, cumulative premature ovarian failure risks were 3% and 9%, respectively. If menstruation returned after treatment, cumulative premature ovarian failure risk was independent of age at treatment. Among women who ultimately developed premature ovarian failure, 22% had one or more children after treatment, compared with 41% of women without premature ovarian failure who had one or more children after treatment. This report indicates that women with proven fertility after treatment can still face infertility problems at a later stage.
A French cohort study of 1,109 female survivors of childhood solid cancer identified the following as risk factors for nonsurgical menopause: exposure to and dose of alkylating agents, especially during adolescence; radiation dose to the ovaries; and oophorectomy. Women treated with alkylating agents after the onset of puberty, either alone (RR, 9; 95% CI, 2.7–28, P = .0003) or associated with even a low dose of radiation to the ovaries (RR, 29; 95% CI, 8–108, P < .0001), had the highest risk ratio for nonsurgical menopause. Exposure to unilateral oophorectomy was associated with a 7-year-earlier age at menopause. The overall rate of nonsurgical menopause by age 40 years was only 2.1% and substantially lower than the CCSS and European Organization for Research and Treatment of Cancer cohort studies that include survivors of hematological malignancies.Fertility
Fertility was evaluated among the 6,224 male CCSS participants aged 15 to 44 years who were not surgically sterile. They were less likely to sire a pregnancy than siblings (hazard ratio [HR] 0.56; 95% CI, 0.49–0.63). Among survivors, the HR of siring a pregnancy was decreased by radiation therapy greater than 750 cGy to the testes (HR, 0.12; 95% CI, 0.02–0.64), higher summed alkylating agent dose score or treatment with cyclophosphamide (third tertile - HR, 0.42; 95% CI, 0.31–0.57) or procarbazine (second tertile - HR, 0.48; 95% CI, 0.26–0.87; third tertile – HR, 0.17; 95% CI, 0.07–0.41). The HR of siring a pregnancy was inversely related to the summed alkylating agent dose score (P-value for linear trend = <.001). Those who had a summed alkylating agent dose score of 2 (HR, 0.67; 95% CI, 0.51–0.88; P = .004), 3 (HR, 0.48; 95% CI, 0.36–0.65; P <.001), 4 (HR, 0.34; 95% CI, 0.22–0.52; P <.001), 5 (HR, 0.38; 95% CI, 0.22–0.66; P <.001), or 6 to 11 (HR, 0.16; 95% CI, 0.08–0.32; P <.001) were also less likely to ever sire a pregnancy compared with those who did not receive any alkylating agents. Compared with siblings, the HR for ever siring a pregnancy for survivors who had an alkylating agent dose score of 0 and a hypothalamic/pituitary radiation dose of 0 cGy and a testes radiation dose of 0 cGy was 0.91 (95% CI, 0.73–1.14; P = .41).
Fertility was evaluated among the 5,149 female CCSS participants and 1,441 female siblings of CCSS participants, aged 15 to 44 years. The RR for ever being pregnant was 0.81 (95% CI, 0.73–0.90; P < .001), compared with female siblings. In multivariate models among survivors only, those who received a hypothalamic/pituitary radiation dose of greater than 3,000 cGy (RR, 0.61; 95% CI, 0.44–0.83) or an ovarian/uterine radiation dose greater than 500 cGy were less likely to have ever been pregnant (RR, 0.56 for 500–1000 cGy; 95% CI, 0.37–0.85; RR, 0.18 for >1000 cGy; 95% CI, 0.13–0.26). A summed alkylating agent dose score of 3 (RR, 0.72; 95% CI, 0.58–0.90; P = .003) or 4 (RR, 0.65; 95% CI, 0.45–0.96; P = .03) was associated with lower observed risk of pregnancy, compared with those with no alkylating agent exposure. Those with a summed alkylating agent dose score of 3 or 4 or who were treated with lomustine or cyclophosphamide were less likely to have ever been pregnant. A follow-up study of the same cohort demonstrated impaired fertility in female survivors who received modest doses (22–27 Gy) of hypothalamic pituitary radiation and no or very low doses (<0.1 Gy) of ovarian radiation, providing support for the contribution of the role of luteal phase deficiency to infertility in some women.
Fertility may be impaired by factors other than the absence of sperm and ova. Conception requires delivery of sperm to the uterine cervix, patency of the fallopian tubes for fertilization to occur, and appropriate conditions in the uterus for implantation. Retrograde ejaculation occurs with a significant frequency in men who undergo bilateral retroperitoneal lymph node dissection. Uterine structure may be affected by abdominal irradiation. A study demonstrated that uterine length was significantly shorter in ten women with ovarian failure who had been treated with whole abdomen irradiation. Endometrial thickness did not increase in response to hormone replacement therapy in three women who underwent weekly ultrasound examination. No flow was detectable with Doppler ultrasound through either uterine artery of five women, and through one uterine artery in three additional women.Reproduction
For survivors who maintain fertility, numerous investigations have evaluated the prevalence of and risk factors for pregnancy complications in adults treated for cancer during childhood. Pregnancy complications including hypertension, fetal malposition, fetal loss/spontaneous abortion, preterm labor, and low birth weight have been observed in association with specific diagnostic and treatment groups.[51,52,55-63]
- In a study of 4,029 pregnancies among 1,915 women followed in the CCSS, there were 63% live births, 1% stillbirths, 15% miscarriages, 17% abortions, and 3% unknown or in gestation. Risk of miscarriage was 3.6-fold higher in women treated with craniospinal radiation and 1.7-fold higher in those treated with pelvic radiation. Chemotherapy exposure alone did not increase risk of miscarriage. Survivors were less likely to have live births, more likely to have medical abortions, and more likely to have low-birth-weight babies than were siblings. In the same cohort, another study evaluated pregnancy outcomes of partners of male survivors. Among 4,106 sexually active males, 1,227 reported they sired 2,323 pregnancies, which resulted in 69% live births, 13% miscarriages, 13% abortions, and 5% unknown or in gestation at the time of analysis. Compared with partners of male siblings, there was a decreased incidence of live births (RR, 0.77), but no significant differences of pregnancy outcome by treatment.
- In the National Wilms Tumor Study, records were obtained for 1,021 pregnancies of more than 20 weeks duration. In this group, there were 955 single live births. Hypertension complicating pregnancy, early or threatened labor, malposition of the fetus, lower birth weight (<2,500 g), and premature delivery (<36 weeks) were more frequent among women who had received flank radiation, in a dose-dependent manner.
- In a retrospective cohort analysis from the CCSS of 1,148 men and 1,657 women who had survived cancer, there were 4,946 pregnancies. Irradiation of the testes in men and pituitary gland in women and chemotherapy with alkylating drugs were not associated with an increased risk of stillbirth or neonatal death. Uterine and ovarian irradiation significantly increased the risk of stillbirth and neonatal death at doses higher than 10 Gy. For girls treated before menarche, irradiation of the uterus and ovaries at doses as low as 1 Gy to 2.49 Gy significantly increased the risk of stillbirth or neonatal death.
- Results from a Danish study confirm the association of uterine radiation with spontaneous but not other types of abortion. Thirty-four thousand pregnancies were evaluated in a population of 1,688 female survivors of childhood cancer in the Danish Cancer Registry. The pregnancy outcomes of survivors, 2,737 sisters, and 16,700 comparison women in the population were identified. No significant differences were seen between survivors and comparison women in the proportions of live births, stillbirths, or all types of abortions combined. Survivors with a history of neuroendocrine or abdominal radiation therapy had an increased risk of spontaneous abortion. Thus, the pregnancy outcomes of survivors were similar to those of comparison women with the exception of spontaneous abortion.
Progress in reproductive endocrinology has resulted in the availability of several options for preserving or permitting fertility in patients about to receive potentially toxic chemotherapy or radiation therapy. For males, cryopreservation of spermatozoa before treatment is an effective method to circumvent the sterilizing effect of therapy. Although pretreatment semen quality in patients with cancer has been shown to be less than that noted in healthy donors, the percentage decline in semen quality and the effect of cryodamage to spermatozoa from patients with cancer is similar to that of normal donors.[66-69] For those unable to bank sperm, newer technologies such as testicular sperm extraction may be an option. Further micromanipulative technologic advances such as intracytoplasmic sperm injection and similar techniques may be able to render sperm extracted surgically, or even poor-quality cryopreserved spermatozoa from cancer patients, capable of successful fertilization.
Preservation of fertility and successful pregnancies may occur after hematopoietic stem cell transplantation (HSCT), though the conditioning regimens that include TBI, cyclophosphamide, and busulfan are highly gonadotoxic. In a group of 21 females who had received a BMT in the prepubertal years, 12 (57%) were found to have ovarian failure when examined between ages 11 and 21 years, and the association with busulfan was significant. One study evaluated pregnancy outcomes in a group of females treated with BMT. Among 708 women who were postpubertal at the time of transplant, 116 regained normal ovarian function and 32 became pregnant. Among 82 women who were prepubertal at the time of transplant, 23 had normal ovarian function and nine became pregnant. Of the 72 pregnancies in these 41 women, 16 occurred in those treated with TBI and 50% resulted in early termination. Among the 56 pregnancies in women treated with cyclophosphamide without either TBI or busulfan, 21% resulted in early termination. There were no pregnancies among the 73 women treated with busulfan and cyclophosphamide, and only one retained ovarian function.Pregnancy outcomes
For childhood cancer survivors who have offspring, there is concern about congenital anomalies, genetic disease, or risk of cancer in the offspring. Children of cancer survivors are not at significantly increased risk for congenital anomalies stemming from their parents' exposure to mutagenic cancer treatments. A retrospective cohort analysis of validated cases of congenital anomalies among 4,699 children of 1,128 male and 1,627 female participants of the CCSS showed no significant associations between gonadal radiation or cumulative exposure to alkylating agents and congenital anomalies in offspring. In a report of 2,198 offspring of adult survivors treated for childhood cancer between 1945 and 1975 compared with 4,544 offspring of sibling controls, there were no differences in the proportion of offspring with cytogenetic syndromes, single-gene defects, or simple malformations. There was similarly no effect of type of childhood cancer treatment on the occurrence of genetic disease in the offspring. A population-based study of 2,630 live-born offspring of childhood cancer survivors versus 5,504 live-born offspring of the survivors' siblings found no differences in proportion of abnormal karyotypes or incidence of Down syndrome or Turner syndrome between survivor and sibling offspring. Survivors treated with abdominal radiation therapy and/or alkylating agents did not have an increased risk of offspring with genetic disease, compared with survivors not exposed to these agents.[75,76]
In a study of 5,847 offspring of survivors of childhood cancers treated in five Scandinavian countries, in the absence of a hereditary cancer syndrome (such as hereditary retinoblastoma), there was no increased risk of cancer. Data from the five-center study also indicated no excess risk of single gene disorders, congenital malformations, or chromosomal syndromes among the offspring of former patients compared with the offspring of siblings. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information about sexuality and reproductive issues and cancer patients.)
Most pregnancies reported by HSCT survivors and their partners result in live births. In female HSCT survivors who were exposed to TBI, there appears to be an increased risk of preterm delivery of low-birth-weight infants. Female HSCT survivors are at higher risk of needing Cesarean sections than are the normal population (42% vs. 16%). Offspring of male and female HSCT recipients do not appear to be at increased risk for birth defects, developmental delay, or cancer.
Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for reproductive late effects information including risk factors, evaluation, and health counseling.References
- Arap MA, Vicentini FC, Cocuzza M, et al.: Late hormonal levels, semen parameters, and presence of antisperm antibodies in patients treated for testicular torsion. J Androl 28 (4): 528-32, 2007 Jul-Aug. [PUBMED Abstract]
- Tryfonas G, Violaki A, Tsikopoulos G, et al.: Late postoperative results in males treated for testicular torsion during childhood. J Pediatr Surg 29 (4): 553-6, 1994. [PUBMED Abstract]
- Narayan P, Lange PH, Fraley EE: Ejaculation and fertility after extended retroperitoneal lymph node dissection for testicular cancer. J Urol 127 (4): 685-8, 1982. [PUBMED Abstract]
- Nijman JM, Jager S, Boer PW, et al.: The treatment of ejaculation disorders after retroperitoneal lymph node dissection. Cancer 50 (12): 2967-71, 1982. [PUBMED Abstract]
- Schlegel PN, Walsh PC: Neuroanatomical approach to radical cystoprostatectomy with preservation of sexual function. J Urol 138 (6): 1402-6, 1987. [PUBMED Abstract]
- Shalet SM, Beardwell CG, Jacobs HS, et al.: Testicular function following irradiation of the human prepubertal testis. Clin Endocrinol (Oxf) 9 (6): 483-90, 1978. [PUBMED Abstract]
- Speiser B, Rubin P, Casarett G: Aspermia following lower truncal irradiation in Hodgkin's disease. Cancer 32 (3): 692-8, 1973. [PUBMED Abstract]
- Hahn EW, Feingold SM, Nisce L: Aspermia and recovery of spermatogenesis in cancer patients following incidental gonadal irradiation during treatment: a progress report. Radiology 119 (1): 223-5, 1976. [PUBMED Abstract]
- Pedrick TJ, Hoppe RT: Recovery of spermatogenesis following pelvic irradiation for Hodgkin's disease. Int J Radiat Oncol Biol Phys 12 (1): 117-21, 1986. [PUBMED Abstract]
- Kinsella TJ, Trivette G, Rowland J, et al.: Long-term follow-up of testicular function following radiation therapy for early-stage Hodgkin's disease. J Clin Oncol 7 (6): 718-24, 1989. [PUBMED Abstract]
- Blatt J, Sherins RJ, Niebrugge D, et al.: Leydig cell function in boys following treatment for testicular relapse of acute lymphoblastic leukemia. J Clin Oncol 3 (9): 1227-31, 1985. [PUBMED Abstract]
- Sklar CA, Robison LL, Nesbit ME, et al.: Effects of radiation on testicular function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Children Cancer Study Group. J Clin Oncol 8 (12): 1981-7, 1990. [PUBMED Abstract]
- Ahmed SR, Shalet SM, Campbell RH, et al.: Primary gonadal damage following treatment of brain tumors in childhood. J Pediatr 103 (4): 562-5, 1983. [PUBMED Abstract]
- Sanders JE, Buckner CD, Leonard JM, et al.: Late effects on gonadal function of cyclophosphamide, total-body irradiation, and marrow transplantation. Transplantation 36 (3): 252-5, 1983. [PUBMED Abstract]
- Jahnukainen K, Heikkinen R, Henriksson M, et al.: Semen quality and fertility in adult long-term survivors of childhood acute lymphoblastic leukemia. Fertil Steril 96 (4): 837-42, 2011. [PUBMED Abstract]
- Mackie EJ, Radford M, Shalet SM: Gonadal function following chemotherapy for childhood Hodgkin's disease. Med Pediatr Oncol 27 (2): 74-8, 1996. [PUBMED Abstract]
- Shafford EA, Kingston JE, Malpas JS, et al.: Testicular function following the treatment of Hodgkin's disease in childhood. Br J Cancer 68 (6): 1199-204, 1993. [PUBMED Abstract]
- Sherins RJ, Olweny CL, Ziegler JL: Gynecomastia and gonadal dysfunction in adolescent boys treated with combination chemotherapy for Hodgkin's disease. N Engl J Med 299 (1): 12-6, 1978. [PUBMED Abstract]
- Dhabhar BN, Malhotra H, Joseph R, et al.: Gonadal function in prepubertal boys following treatment for Hodgkin's disease. Am J Pediatr Hematol Oncol 15 (3): 306-10, 1993. [PUBMED Abstract]
- Heikens J, Behrendt H, Adriaanse R, et al.: Irreversible gonadal damage in male survivors of pediatric Hodgkin's disease. Cancer 78 (9): 2020-4, 1996. [PUBMED Abstract]
- da Cunha MF, Meistrich ML, Fuller LM, et al.: Recovery of spermatogenesis after treatment for Hodgkin's disease: limiting dose of MOPP chemotherapy. J Clin Oncol 2 (6): 571-7, 1984. [PUBMED Abstract]
- Brämswig JH, Heimes U, Heiermann E, et al.: The effects of different cumulative doses of chemotherapy on testicular function. Results in 75 patients treated for Hodgkin's disease during childhood or adolescence. Cancer 65 (6): 1298-302, 1990. [PUBMED Abstract]
- Viviani S, Santoro A, Ragni G, et al.: Gonadal toxicity after combination chemotherapy for Hodgkin's disease. Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol 21 (5): 601-5, 1985. [PUBMED Abstract]
- Whitehead E, Shalet SM, Jones PH, et al.: Gonadal function after combination chemotherapy for Hodgkin's disease in childhood. Arch Dis Child 57 (4): 287-91, 1982. [PUBMED Abstract]
- Aubier F, Flamant F, Brauner R, et al.: Male gonadal function after chemotherapy for solid tumors in childhood. J Clin Oncol 7 (3): 304-9, 1989. [PUBMED Abstract]
- Jaffe N, Sullivan MP, Ried H, et al.: Male reproductive function in long-term survivors of childhood cancer. Med Pediatr Oncol 16 (4): 241-7, 1988. [PUBMED Abstract]
- Pryzant RM, Meistrich ML, Wilson G, et al.: Long-term reduction in sperm count after chemotherapy with and without radiation therapy for non-Hodgkin's lymphomas. J Clin Oncol 11 (2): 239-47, 1993. [PUBMED Abstract]
- Meistrich ML, Wilson G, Brown BW, et al.: Impact of cyclophosphamide on long-term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas. Cancer 70 (11): 2703-12, 1992. [PUBMED Abstract]
- Kenney LB, Laufer MR, Grant FD, et al.: High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer 91 (3): 613-21, 2001. [PUBMED Abstract]
- Garolla A, Pizzato C, Ferlin A, et al.: Progress in the development of childhood cancer therapy. Reprod Toxicol 22 (2): 126-32, 2006. [PUBMED Abstract]
- Williams D, Crofton PM, Levitt G: Does ifosfamide affect gonadal function? Pediatr Blood Cancer 50 (2): 347-51, 2008. [PUBMED Abstract]
- van Dorp W, van der Geest IM, Laven JS, et al.: Gonadal function recovery in very long-term male survivors of childhood cancer. Eur J Cancer 49 (6): 1280-6, 2013. [PUBMED Abstract]
- Green DM, Zhu L, Zhang N, et al.: Lack of specificity of plasma concentrations of inhibin B and follicle-stimulating hormone for identification of azoospermic survivors of childhood cancer: a report from the St Jude lifetime cohort study. J Clin Oncol 31 (10): 1324-8, 2013. [PUBMED Abstract]
- Wallace WH, Shalet SM, Crowne EC, et al.: Ovarian failure following abdominal irradiation in childhood: natural history and prognosis. Clin Oncol (R Coll Radiol) 1 (2): 75-9, 1989. [PUBMED Abstract]
- Scott JE: Pubertal development in children treated for nephroblastoma. J Pediatr Surg 16 (2): 122-5, 1981. [PUBMED Abstract]
- Hamre MR, Robison LL, Nesbit ME, et al.: Effects of radiation on ovarian function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group. J Clin Oncol 5 (11): 1759-65, 1987. [PUBMED Abstract]
- Wallace WH, Shalet SM, Tetlow LJ, et al.: Ovarian function following the treatment of childhood acute lymphoblastic leukaemia. Med Pediatr Oncol 21 (5): 333-9, 1993. [PUBMED Abstract]
- Ortin TT, Shostak CA, Donaldson SS: Gonadal status and reproductive function following treatment for Hodgkin's disease in childhood: the Stanford experience. Int J Radiat Oncol Biol Phys 19 (4): 873-80, 1990. [PUBMED Abstract]
- Papadakis V, Vlachopapadopoulou E, Van Syckle K, et al.: Gonadal function in young patients successfully treated for Hodgkin disease. Med Pediatr Oncol 32 (5): 366-72, 1999. [PUBMED Abstract]
- Hudson MM, Greenwald C, Thompson E, et al.: Efficacy and toxicity of multiagent chemotherapy and low-dose involved-field radiotherapy in children and adolescents with Hodgkin's disease. J Clin Oncol 11 (1): 100-8, 1993. [PUBMED Abstract]
- Green DM, Yakar D, Brecher ML, et al.: Ovarian function in adolescent women following successful treatment for non-Hodgkin's lymphoma. Am J Pediatr Hematol Oncol 5 (1): 27-31, 1983. [PUBMED Abstract]
- Siris ES, Leventhal BG, Vaitukaitis JL: Effects of childhood leukemia and chemotherapy on puberty and reproductive function in girls. N Engl J Med 294 (21): 1143-6, 1976. [PUBMED Abstract]
- Wallace WH, Shalet SM, Crowne EC, et al.: Gonadal dysfunction due to cis-platinum. Med Pediatr Oncol 17 (5): 409-13, 1989. [PUBMED Abstract]
- Sanders JE, Buckner CD, Amos D, et al.: Ovarian function following marrow transplantation for aplastic anemia or leukemia. J Clin Oncol 6 (5): 813-8, 1988. [PUBMED Abstract]
- Mayer EI, Dopfer RE, Klingebiel T, et al.: Longitudinal gonadal function after bone marrow transplantation for acute lymphoblastic leukemia during childhood. Pediatr Transplant 3 (1): 38-44, 1999. [PUBMED Abstract]
- Chemaitilly W, Mertens AC, Mitby P, et al.: Acute ovarian failure in the childhood cancer survivor study. J Clin Endocrinol Metab 91 (5): 1723-8, 2006. [PUBMED Abstract]
- Sklar CA, Mertens AC, Mitby P, et al.: Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 98 (13): 890-6, 2006. [PUBMED Abstract]
- Byrne J, Fears TR, Gail MH, et al.: Early menopause in long-term survivors of cancer during adolescence. Am J Obstet Gynecol 166 (3): 788-93, 1992. [PUBMED Abstract]
- van der Kaaij MA, Heutte N, Meijnders P, et al.: Premature ovarian failure and fertility in long-term survivors of Hodgkin's lymphoma: a European Organisation for Research and Treatment of Cancer Lymphoma Group and Groupe d'Etude des Lymphomes de l'Adulte Cohort Study. J Clin Oncol 30 (3): 291-9, 2012. [PUBMED Abstract]
- Thomas-Teinturier C, El Fayech C, Oberlin O, et al.: Age at menopause and its influencing factors in a cohort of survivors of childhood cancer: earlier but rarely premature. Hum Reprod 28 (2): 488-95, 2013. [PUBMED Abstract]
- Green DM, Kawashima T, Stovall M, et al.: Fertility of male survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 28 (2): 332-9, 2010. [PUBMED Abstract]
- Green DM, Kawashima T, Stovall M, et al.: Fertility of female survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol 27 (16): 2677-85, 2009. [PUBMED Abstract]
- Green DM, Nolan VG, Kawashima T, et al.: Decreased fertility among female childhood cancer survivors who received 22-27 Gy hypothalamic/pituitary irradiation: a report from the Childhood Cancer Survivor Study. Fertil Steril 95 (6): 1922-7, 1927.e1, 2011. [PUBMED Abstract]
- Critchley HO, Wallace WH, Shalet SM, et al.: Abdominal irradiation in childhood; the potential for pregnancy. Br J Obstet Gynaecol 99 (5): 392-4, 1992. [PUBMED Abstract]
- Byrne J, Mulvihill JJ, Connelly RR, et al.: Reproductive problems and birth defects in survivors of Wilms' tumor and their relatives. Med Pediatr Oncol 16 (4): 233-40, 1988. [PUBMED Abstract]
- Winther JF, Boice JD Jr, Svendsen AL, et al.: Spontaneous abortion in a Danish population-based cohort of childhood cancer survivors. J Clin Oncol 26 (26): 4340-6, 2008. [PUBMED Abstract]
- Cvancarova M, Samuelsen SO, Magelssen H, et al.: Reproduction rates after cancer treatment: experience from the Norwegian radium hospital. J Clin Oncol 27 (3): 334-43, 2009. [PUBMED Abstract]
- Magelssen H, Melve KK, Skjaerven R, et al.: Parenthood probability and pregnancy outcome in patients with a cancer diagnosis during adolescence and young adulthood. Hum Reprod 23 (1): 178-86, 2008. [PUBMED Abstract]
- Green DM, Lange JM, Peabody EM, et al.: Pregnancy outcome after treatment for Wilms tumor: a report from the national Wilms tumor long-term follow-up study. J Clin Oncol 28 (17): 2824-30, 2010. [PUBMED Abstract]
- Hawkins MM, Smith RA: Pregnancy outcomes in childhood cancer survivors: probable effects of abdominal irradiation. Int J Cancer 43 (3): 399-402, 1989. [PUBMED Abstract]
- Chow EJ, Kamineni A, Daling JR, et al.: Reproductive outcomes in male childhood cancer survivors: a linked cancer-birth registry analysis. Arch Pediatr Adolesc Med 163 (10): 887-94, 2009. [PUBMED Abstract]
- Mueller BA, Chow EJ, Kamineni A, et al.: Pregnancy outcomes in female childhood and adolescent cancer survivors: a linked cancer-birth registry analysis. Arch Pediatr Adolesc Med 163 (10): 879-86, 2009. [PUBMED Abstract]
- Reulen RC, Zeegers MP, Wallace WH, et al.: Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study. Cancer Epidemiol Biomarkers Prev 18 (8): 2239-47, 2009. [PUBMED Abstract]
- Signorello LB, Mulvihill JJ, Green DM, et al.: Stillbirth and neonatal death in relation to radiation exposure before conception: a retrospective cohort study. Lancet 376 (9741): 624-30, 2010. [PUBMED Abstract]
- Lawrenz B, Henes M, Neunhoeffer E, et al.: Fertility preservation in girls and adolescents before chemotherapy and radiation - review of the literature. Klin Padiatr 223 (3): 126-30, 2011. [PUBMED Abstract]
- Agarwa A: Semen banking in patients with cancer: 20-year experience. Int J Androl 23 (Suppl 2): 16-9, 2000. [PUBMED Abstract]
- Hallak J, Hendin BN, Thomas AJ Jr, et al.: Investigation of fertilizing capacity of cryopreserved spermatozoa from patients with cancer. J Urol 159 (4): 1217-20, 1998. [PUBMED Abstract]
- Khalifa E, Oehninger S, Acosta AA, et al.: Successful fertilization and pregnancy outcome in in-vitro fertilization using cryopreserved/thawed spermatozoa from patients with malignant diseases. Hum Reprod 7 (1): 105-8, 1992. [PUBMED Abstract]
- Müller J, Sønksen J, Sommer P, et al.: Cryopreservation of semen from pubertal boys with cancer. Med Pediatr Oncol 34 (3): 191-4, 2000. [PUBMED Abstract]
- Hsiao W, Stahl PJ, Osterberg EC, et al.: Successful treatment of postchemotherapy azoospermia with microsurgical testicular sperm extraction: the Weill Cornell experience. J Clin Oncol 29 (12): 1607-11, 2011. [PUBMED Abstract]
- Teinturier C, Hartmann O, Valteau-Couanet D, et al.: Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure. Bone Marrow Transplant 22 (10): 989-94, 1998. [PUBMED Abstract]
- Sanders JE, Hawley J, Levy W, et al.: Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 87 (7): 3045-52, 1996. [PUBMED Abstract]
- Signorello LB, Mulvihill JJ, Green DM, et al.: Congenital anomalies in the children of cancer survivors: a report from the childhood cancer survivor study. J Clin Oncol 30 (3): 239-45, 2012. [PUBMED Abstract]
- Winther JF, Boice JD Jr, Mulvihill JJ, et al.: Chromosomal abnormalities among offspring of childhood-cancer survivors in Denmark: a population-based study. Am J Hum Genet 74 (6): 1282-5, 2004. [PUBMED Abstract]
- Byrne J, Rasmussen SA, Steinhorn SC, et al.: Genetic disease in offspring of long-term survivors of childhood and adolescent cancer. Am J Hum Genet 62 (1): 45-52, 1998. [PUBMED Abstract]
- Winther JF, Olsen JH, Wu H, et al.: Genetic disease in the children of Danish survivors of childhood and adolescent cancer. J Clin Oncol 30 (1): 27-33, 2012. [PUBMED Abstract]
- Sankila R, Olsen JH, Anderson H, et al.: Risk of cancer among offspring of childhood-cancer survivors. Association of the Nordic Cancer Registries and the Nordic Society of Paediatric Haematology and Oncology. N Engl J Med 338 (19): 1339-44, 1998. [PUBMED Abstract]
- Salooja N, Szydlo RM, Socie G, et al.: Pregnancy outcomes after peripheral blood or bone marrow transplantation: a retrospective survey. Lancet 358 (9278): 271-6, 2001. [PUBMED Abstract]