Present address: Department of Pediatrics, Gyeongsang National University Changwon Hospital, Changwon, Korea
Present address: Department of Pediatrics, Hallym University College of Medicine, Chuncheon, Korea
Present address: Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Few studies have addressed gonadal and sexual dysfunctions in childhood cancer survivors. We evaluated the prevalence rates and risk factors for gonadal failure among adolescent/young adult childhood cancer survivors and their sexual function.
Subjects were childhood cancer survivors aged 15-29 years who had completed therapy more than 2 years ago. Demographic and medical characteristics were obtained from the patients’ medical records. In addition, hormonal evaluation and semen analysis were performed and sexual function was evaluated via questionnaire.
The study included 105 survivors (57 males, 48 females), of which 61 were adults (age > 19 years) and 44 were adolescents. In both males and females, the proportion of survivors with low sex hormone levels did not differ among age groups or follow-up period. Thirteen female subjects (27.1%) needed sex hormone replacement, while five males subjects (8.8%) were suspected of having hypogonadism, but none were receiving sex hormone replacement. Of 27 semen samples, 14 showed azospermia or oligospermia. The proportion of normospermia was lower in the high cyclophosphamide equivalent dose (CED) group (CED ≥ 8,000 mg/m2) than the low CED group (27.3% vs. 62.5%, p=0.047). Among adults, none were married and only 10 men (35.7%) and eight women (34.3%) were in a romantic relationship. Though a significant proportion (12.0% of males and 5.3% of females) of adolescent survivors had experienced sexual activity, 13.6% had not experienced sex education.
The childhood cancer survivors in this study showed a high prevalence of gonadal/sexual dysfunction; accordingly, proper strategies are needed to manage these complications.
According to the 2011 Korea National Cancer Incidence Database, the 5-year event-free survival rate of Korean children aged 0 to 14 years with cancer between 2007 and 2011 was 78.2% [
One of the important late complications of cancer survivors is gonadal dysfunction. In adult survivors of childhood lymphoma, gonadal failure was reported in 11% of males and 44% of females [
This study includes patients who visited an outpatient clinic of the Center for Pediatric Cancer of the National Cancer Center in Korea. Patients were less than 20 years old when diagnosed with cancer and were between 15 and 30 years old during the period when this study was conducted. More than 2 years had passed since the completion of therapy, and there was no evidence of recurrence. This study recruited data describing childhood cancer survivors who visited the hospital between July 2013 and February 2016. The Institutional Review Board of the National Cancer Center approved the study protocol (NCCNCS13741).
Demographic and medical characteristics were obtained from the patient medical records. Radiation records were also reviewed to gather data about radiation area and dose. Information regarding chemotherapy agents used for each patient was obtained from chemotherapy records. Cyclophosphamide equivalent dose (CED) was calculated according to the following formula: CED (mg/m2)=1.0 (cumulative cyclophosphamide dose [mg/m2])+0.244 (cumulative ifosfamide dose [mg/m2])+0.857 (cumulative procarbazine dose [mg/m2])+14.286 (cumulative chlorambucil dose [mg/m2]) +15.0 (cumulative carmustine dose [mg/m2])+16.0 (cumulative lomustine dose [mg/m2])+40 (cumulative melphalan dose [mg/m2])+50 (cumulative thiotepa dose [mg/m2])+100 (cumulative chlormethine dose [mg/m2])+8.823 (cumulative busulfan dose [mg/m2]), as suggested in a previous study [
Hormonal evaluation included follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone or estradiol. In females, the anti-mullerian hormone (AMH) level was also evaluated. To accomplish this, we used electrochemiluminescent immunoassay for FSH/LH, chemiluminescent immunoassay for estradiol, radioimmunoassay for testosterone, and enzyme-linked immunosorbent assay for AMH level.
Male participants collected their semen via masturbation, and samples were processed within 30 minutes of collection. As part of the analysis, semen amount and sperm concentration was checked and the morphology and motility of sperm were evaluated. Azospermia was defined as no sperm observed, and oligospermia was defined as a sperm concentration of less than 15×106/mL based on the World Health Organization reference values [
Questionnaires were presented to participants when they visited our clinic, and were returned either immediately at the clinic or later via mail. Four types of questionnaires were administered, for adolescents younger than 19 years old, adult men, adult women, and parents. Each questionnaire contained questions about quality of life and health behavior. In addition, questions about sexual function were included in questionnaires for adult men and women. Questions regarding sexual function included questions from previously validated questionnaires about male erectile function (Korean version of the International Index of Erectile Function [IIEF-5]) [
Demographic and treatment characteristics of participants were assessed using descriptive statistics. For comparison of continuous variables among groups, an independent t test was used. A chi-squared test and Fisher exact test were used for comparison of categorical variables. SPSS ver. 20 (IBM Corp., Armonk, NY), was used for all quantitative analyses. p-values less than 0.05 were considered significant.
This study included survivors who visited the hospital between July 2013 and February 2016 (n=105). Of the 105 survivors, 92 responded to the questionnaire (response rate, 78.6%). Among 61 adults, 50 replied to the questionnaire. Overall, 27 males agreed to the semen analysis.
Demographic and treatment characteristics of participants are presented in
Among 48 females, 13 (27.1%) required sex hormone replacement; 10 were already receiving sex hormone therapy before our study, and three had newly started sex hormone replacement because of amenorrhoea/oligomenorrhoea due to low estradiol levels. One woman showed gonadotropin deficiency in the gonadotropin-releasing hormone (GnRH) stimulation test. The AMH level was below 1.19 ng/mL (fifth percentile cut-off value for Korean women aged 20-31) in 24 women (51.1%). Among women receiving hormone replacement, 11 (84.6%) had an AMH level less than 1.19 ng/mL. Among seven females who received stem cell transplantation, six (85.7%) received sex hormone replacement (data not shown). We divided female survivors into two groups according to median age (13.1 years), and there was no difference in gonadal function between groups. There was also no difference when the results were divided into follow-up periods of 5 years (
Among the 57 male participants, five (8.8%) had testosterone level below 325 ng/dL, suggestive of male hypogonadism (
Semen analysis was performed for 27 males, and azospermia and oligospermia were observed in 11 (37.5%) and three (12.5%) of the semen analysis participants, respectively. We further divided semen analysis participants into two groups according to CED (high CED [CED ≥ 8,000 mg/m2] vs. low CED [CED < 8,000 mg/m2]). The proportion of normospermia was lower in the high CED group than in the low CED group (27.3% vs. 62.5%, p=0.047) (
Sexual function of adult survivors is listed in
Sexual function of adolescent survivors was evaluated in 25 males and 19 females. While adolescent survivors had similar experiences with sexual activity as normal high school students, six (13.6%) had not received any kind of sex education (
In this study, the gonadal and sexual function of adolescent and young adult childhood cancer survivors was evaluated. Gonadal failure is classified into central hypogonadism (due to gonadotropin deficiency) and primary hypogonadism. Childhood cancer survivors are at increased risk of both central and primary hypogonadism because of radiation and chemotherapy. It is not possible to clearly distinguish central from primary hypogonadism because a GnRH stimulation test was only performed for one female in our study. However, it is believed that many patients have combined central and primary gonadal failure since 17 (16.2%) had received both brain radiation and gonadotoxic chemotherapy (data not shown).
Among female participants, 27.1% were taking sex hormones due to ovarian failure. Among female participants of the Childhood Cancer Survivor Study, acute ovarian failure was reported in 215 of 3,390 females (6.3%) [
AMH is used as a marker to evaluate ovarian function because it is not affected by menstrual cycle or exogenous estrogen. Although AMH is not yet recommended as a routine screening tool for gonadal function in childhood cancer survivors, it is believed to be a useful marker to evaluate ovarian reserve in female childhood cancer survivors, especially in those at risk for ovarian failure. Lunsford et al. [
AMH levels vary according to age, and a cut-off value has not been established. Our study used reference values for normal Korean females reported in 2011 [
No male participants had received hormone replacement therapy. The decision to undergo sex hormone replacement may have been more difficult for men than women because there is no clinical indicator of gonadal function, such as menstruation. Testis volume can be a useful marker for gonadal function in males and is known to be related to semen profiles in normal and infertile men [
Risk of gonadal failure is also associated with age at diagnosis or pubertal stage at diagnosis. In females, exposure of the ovaries to chemotherapy or radiotherapy at older age was a significant risk factor for ovarian failure in a previous study [
Fertility after male childhood cancer is most often evaluated based on sperm count determined by semen analysis. In the present study, half of the patients who underwent semen analysis showed azospermia or oligospermia. In a previous report that described the semen profiles of 214 adult childhood cancer survivors, azospermia or oligospermia was reported in 25% and 48% of study participants, respectively, which is similar to our findings [
Sexual dysfunction in childhood cancer survivors can result from impairment of any process associated with sexual intercourse such as desire, erection, ejaculation, or orgasm. Surgery or irradiation (especially of the pelvis), hormonal insufficiencies, and medical comorbidities are possible etiologies of sexual dysfunction in childhood cancer survivors [
Proper sex education is required for childhood cancer survivors and their partners’ health and quality of life. In our study, more than 10% of adolescent survivors had not received official sex education, indicating that strategies to provide such education are needed.
The most important aspect of our study is that we evaluated gonadal function, sexual function, and romantic relationships altogether, whereas most previous studies have investigated only of these areas. Although one previous study examined both gonadal and sexual function in childhood cancer survivors, it included only male survivors [
It should be noted that our study was limited in that the participants were uniformly young, with many in their early 20s. Additionally, none of the participants were married. Taken together, these factors may have led to underestimation of sexual function. Another limitation is that the follow-up duration after treatment was short and no longitudinal follow-up was conducted. A previous study reported that 8% of 2,819 female childhood cancer survivors experienced premature menopause before the age of 40 [
Moreover, evaluation of sexual function was limited to simple questions about sexual activity, satisfaction and erectile dysfunction. Longitudinal long-term follow-up studies and more detailed investigation of other aspects of sexual function and consideration of the risk factors of sexual dysfunction should be investigated in future studies.
In conclusion, the childhood cancer survivors in this study showed a high prevalence of gonadal/sexual dysfunction. Accordingly, proper strategies for managing these complications, including appropriate sex education, should be established to improve their quality of life.
Supplementary materials are available at Cancer Research and Treatment website (
Conflict of interest relevant to this article was not reported.
This work was supported by a Career Development Award from the National Cancer Center in Goyang, Korea (Grant number 13C0030-1). The study design, data collection and analysis, and writing and submission of the paper were not affected by the funding.
Demographic and medical characteristics of participants
Characteristic | All patients (n=105) | Male |
Female (n=48) | Adult |
||||
---|---|---|---|---|---|---|---|---|
Semen analysis participant (n=27) | Semen analysis non-participant (n=30) | p-value | Questionnaire responder (n=50) | Questionnaire non-responder (n=11) | p-value | |||
19.7 (15.0-26.5) | 20.8 (16.0-25.7) | 19.0 (15.2-26.0) | 0.027 |
19.6 (15.0-26.5) | 22.0 (19.1-26.0) | 21.9 (19.0-26.5) | 0.883 | |
13.3 (0.9-22.6) | 14.5 (7.1-19.3) | 12.6 (0.9-18.9) | 0.098 | 13.0 (2.2-22.6) | 15.5 (2.2-19.3) | 15.5 (10.5-22.6) | 0.981 | |
6.5 (2.2-22.9) | 6.3 (2.6-11.1) | 6.4 (2.6-14.2) | 0.913 | 6.6 (2.2-22.9) | 6.5 (2.5-22.9) | 6.4 (3.4-10.3) | 0.917 | |
5.2 (2.0-12.6) | 5.2 (2.0-10.7) | 5.4 (2.2-12.6) | 0.792 | 5.1 (2.0-10.4) | 5.2 (2.0-10.7) | 4.6 (2.3-10.3) | 0.568 | |
Male | 57 (54.3) | 27 (100) | 30 (100) | - | - | 27 (54.0) | 5 (45.5) | 0.607 |
Female | 48 (45.7) | - | - | 48 (100) | 23 (46.0) | 6 (54.5) | ||
Leukemia | 23 (21.9) | 5 (18.5) | 4 (13.3) | 0.818 | 14 (29.2) | 9 (18.0) | 2 (18.2) | 0.257 |
Lymphoma | 17 (16.2) | 7 (25.9) | 6 (20.0) | 4 (8.3) | 5 (10.0) | 4 (36.4) | ||
Brain tumors | 18 (17.1) | 5 (18.5) | 7 (23.3) | 6 (12.5) | 8 (16.0) | 1 (9.1) | ||
Solid tumors | 46 (43.8) | 10 (37.0) | 12 (40.0) | 24 (50.0) | 27 (54.0) | 4 (36.4) | ||
Histiocytosis | 1 (1.0) | 0 | 1 (3.3) | 0 | 1 (2.0) | 0 | ||
86 (81.9) | 25 (92.6) | 24 (80.0) | 0.258 | 37 (77.1) | 44 (88.0) | 9 (81.8) | 0.627 | |
No SCT | 90 (85.7) | 25 (92.6) | 24 (80.0) | 0.368 | - | 44 (88.0) | 9 (81.8) | 0.860 |
Auto PBSCT | 8 (7.6) | 1 (3.7) | 4 (13.3) | 3 (6.3) | 3 (6.0) | 1 (9.1) | ||
Allo PBSCT | 7 (6.7) | 1 (3.7) | 2 (6.7) | 4 (8.3) | 3 (6.0) | 1 (9.1) | ||
No RT | 66 (62.9) | 15 (55.6) | 18 (60.0) | 0.565 | 33 (68.8) | 31 (62) | 7 (63.6) | 0.401 |
Cranial irradiation | 20 (19.0) | 5 (18.5) | 8 (26.7) | 7 (14.6) | 10 (20.0) | 1 (9.1) | ||
TBI | 5 (4.8) | 2 (7.4) | 0 | 3 (6.3) | 3 (6.0) | 0 | ||
Abdomen-pelvis RT | 4 (3.8) | 1 (3.7) | 1 (3.3) | 2 (4.2) | 2 (4.0) | 2 (18.2) | ||
Other | 10 (9.5) | 4 (14.8) | 3 (10.0) | 3 (6.3) | 4 (8.0) | 1 (9.1) | ||
No alkylating agent | 19 (18.4) | 2 (7.4) | 6 (20.0) | 0.526 | 11 (23.9) | 6 (12.2) | 2 (18.2) | 0.939 |
< 4,000 | 12 (11.7) | 2 (7.4) | 3 (10.0) | 7 (15.2) | 4 (8.2) | 1 (9.1) | ||
4,000-8,000 | 32 (31.1) | 12 (44.4) | 10 (33.3) | 10 (21.7) | 17 (34.7) | 4 (36.4) | ||
≥ 8,000 | 40 (38.8) | 11 (40.7) | 11 (36.7) | 18 (39.1) | 22 (44.9) | 4 (36.4) |
Values are presented as mean (range) or number (%). SCT, stem cell transplantation; PBSCT, peripheral blood stem cell transplantation; RT, radiation therapy; TBI, total body irradiation; CED, cyclophosphamide equivalent dose.
p < 0.05.
Data were not available for two patients.
Gonadal function of females (n=48)
Gonadal function | All females (n=48) | Age at diagnosis (yr) |
Time since off therapy (yr) |
||||
---|---|---|---|---|---|---|---|
< 13.1 (n=24) | ≥ 13.1 (n=24) | p-value | < 5 (n=30) | ≥ 5 (n=18) | p-value | ||
Gonadotropin deficiency |
1 | 1 | 0 | - | 0 | 1 | - |
AMH < 1.19 ng/mL | 24 (51.1) | 11 (47.8) | 13 (54.2) | 0.773 | 16 (53.3) | 8 (44.4) | 0.679 |
Sex hormone replacement | 13 (27.1) | 6 (25.0) | 7 (29.2) | 0.745 | 8 (26.7) | 5 (27.8) | 1.000 |
Values are presented as number (%). AMH, anti-mullerian hormone.
Evaluated in only one patient.
Gonadal function of males
Gonadal function | All females (n=57) | Age at diagnosis (yr) |
Time since off therapy (yr) |
||||
---|---|---|---|---|---|---|---|
< 14.6 (n=27) | ≥ 14.6 (n=30) | p-value | < 5 (n=31) | ≥ 5 (n=26) | p-value | ||
Testosterone < 325 ng/dL | 5 (8.8) | 2 (7.4) | 3 (10.0) | 1.000 | 3 (9.7) | 2 (7.7) | 1.000 |
Testis volume < 15 cm3, |
5 (8.8) | 1 (3.7) | 4 (13.3) | 0.588 | 5 (16.1) | 0 | 0.026 |
Sex hormone replacement | 0 | 0 | 0 | - | 0 | 0 | - |
Values are presented as number (%).
p < 0.05.
Evaluated in 16 patients.
Semen profile
Semen | All semen analysis participants (n=27) | CED ≥ 8,000 mg/m2 (n=11) | CED < 8,000 mg/m2 (n=16) |
---|---|---|---|
Normospermia | 13 (48.1) | 3 (27.3) | 10 (62.5) |
Oligospermia | 3 (11.1) | 1 (9.1) | 2 (12.5) |
Azospermia | 11 (40.7) | 7 (63.6) | 4 (25) |
Values are presented as number (%). CED, cyclophosphamide equivalent dose.
Including two semen analysis participants who had not received alkylating agent.
Sexual function of adult survivors (≥ 19 years)
Variable | Male (n=28) | Female (n=23) |
---|---|---|
10 (35.7) | 8 (34.8) | |
0 | 0 | |
0-1 per week | 11 (39.3) | 8 (34.8) |
2-3 per week | 7 (25.0) | 5 (21.7) |
4-7 per week | 1 (3.6) | 0 |
No reply | 9 (32.1) | 10 (43.5) |
2 (20) |
Values are presented as number (%).
Sexual activity included not only sexual intercourse, but also kissing/caressing,
Erectile dysfunction was evaluated in 10 males who had a girlfriend.
Sexual function of adolescent survivors (15-18 years)
Variable | Male (n=25) | Female (n=19) |
---|---|---|
Experience of sexual activity |
3 (12.0) |
1 (5.3) |
Experience of sex education | 21 (84.0) | 17 (89.5) |
Values are presented as number (%).
Sexual activity included not only sexual intercourse, but also kissing/caressing,
Reference value for healthy high school students: 9.8% for males and 3.5% for females (from the 11th Korean Youth Risk Behavior Web-based Survey in 2015) [