Wendy van Dorp - Academia.edu (original) (raw)

Papers by Wendy van Dorp

Are genetic polymorphisms, previously identified as being associated with age at menopause in the... more Are genetic polymorphisms, previously identified as being associated with age at menopause in the healthy population, associated with ovarian reserve and predicted age at menopause in adult long-term survivors of childhood cancer? The CT genotype of rs1172822 in the BRSK1 gene is associated with lower serum anti-Müllerian hormone (AMH) levels and a younger predicted age at menopause in adult survivors of childhood cancer. Gonadotoxicity is a well-known late side effect of chemotherapy and radiotherapy in adult survivors of childhood cancer. In the healthy population, several genetic polymorphisms are associated with age at natural menopause. Currently, data on the impact of previously identified variants in gene loci associated with ovarian reserve in adult long-term survivors of childhood cancer are lacking. We performed a pilot study in a single-centre cohort of adult female Caucasian childhood cancer survivors (n = 176). We determined serum AMH levels (a marker of ovarian reserve) in adult survivors of childhood cancer (n = 176) and studied single nucleotide polymorphisms (SNPs) previously reported to be associated with age at natural menopause: BRSK1 (rs1172822), ARHGEF7 (rs7333181), MCM8 (rs236114), PCSK1 (rs271924), IGF2R (rs9457827) and TNF (rs909253). Association analysis was performed using the additive genetic model. Linear regression was conducted to assess the effect of significant polymorphisms in two previously published menopause prediction models. The CT genotype of rs1172822 in the BRSK1 (BR serine/threonine kinase 1) gene was negatively associated with serum AMH levels in our cohort (odds ratio: 3.15, 95% confidence interval: 1.35-7.32, P = 0.008) and significantly associated with the predicted age at menopause (P = 0.04). The other five SNPs were not associated with serum AMH levels. This is a pilot study showing preliminary data which must be confirmed. To confirm our findings and enlarge the project, a nationwide genome-wide association (GWA) project on the ovarian reserve in female survivors of childhood cancer should be performed, including a replication cohort. Our findings support the hypothesis that previously identified genetic polymorphisms associated with age at menopause in healthy women may have an effect on the onset of menopause in female survivors of childhood cancer. Our study highlights a new aspect of the influences on the ovarian reserve after childhood cancer, which should be investigated further in a nationwide GWA study. Eventually, this information can help us to improve counselling on fertility preservation prior to cancer treatment based on genetic factors in individual patients. W.D. is supported by the Paediatric Oncology Centre Society for Research (KOCR), Rotterdam, The Netherlands. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Genovum, Merck-Serono, Organon, Schering Plough and Serono. All other authors have nothing to disclose.

Fertility and Sterility, Jan 7, 2014

Objective: To evaluate the feasibility of electroejaculation to perform semen cryopreservation in... more Objective: To evaluate the feasibility of electroejaculation to perform semen cryopreservation in pubertal boys before gonadotoxic therapy and to review the literature on this topic. Design: Retrospective cohort study and review of the literature. Setting: Academic children's hospital. Patient(s): Boys diagnosed with cancer to whom sperm cryopreservation was offered before the start of gonadotoxic therapy. Intervention(s): We studied the outcome of electroejaculation, including patient characteristics, hormone levels, and pretreatment semen parameters. Main Outcome Measure(s): Semen cryopreservation. Result(s): Pretreatment semen samples were obtained by masturbation in 106/114 boys with cancer, of which 78/106 were adequate for preservation. Electroejaculation was offered to 11 boys, of which three of 11 samples appeared adequate for preservation. Reviewing all reported electroejaculation cases in children with cancer in the literature, 13/29 (45%) cases were successful. Testosterone levels were higher in patients with successful sperm yield obtained by electroejaculation (median, 8.3 nmol/L [5.2-42.4] in successful harvests, vs. median 1.7 nmol/L [0.01-17.9] in unsuccessful harvests). Conclusion(s): Semen cryopreservation should be offered to all pubertal boys diagnosed with cancer. If masturbation fails, electroejaculation can be considered as a useful option for semen cryopreservation and leads to adequate material for cryopreservation in about half of the cases.

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 2015

More than 45 % of long-term childhood cancer survivors (CCS) were diagnosed with osteopenia. Our ... more More than 45 % of long-term childhood cancer survivors (CCS) were diagnosed with osteopenia. Our data suggest that greater awareness for osteopenia is warranted in long-term CCS, especially in survivors who are older than 30 years, male, and underweight and were treated with cranial-spinal radiotherapy and/or steroids. Osteopenia is a potential complication of childhood cancer treatment, but the magnitude of this problem in survivors is unknown. We examined (determinants of) bone mineral density (BMD) status in long-term survivors of adult childhood cancer. This retrospective single-centre cohort study included 346 subjects with the most common types of childhood cancer. Subjects had a median age at diagnosis of 7.0 years (range 0.1-16.8 years), a median age at follow-up of 24.5 years (range 18.0-47.6 years) and a median follow-up time of 16.7 years (range 5.6-39.9 years). Total body BMD (BMDTB) and BMD of the lumbar spine (BMDLS) were measured by dual X-ray absorptiometry. Osteopen...

Tijdschrift voor Urologie, 2014

ABSTRACT De overleving van kinderen met kanker is in de afgelopen decennia sterk verbeterd. Hierd... more ABSTRACT De overleving van kinderen met kanker is in de afgelopen decennia sterk verbeterd. Hierdoor is veel aandacht voor de langetermijneffecten van oncologische behandelingen, zoals infertiliteit.

Reproductive BioMedicine Online, 2014

Little information is available on the use of appropriate comparison groups for studies investiga... more Little information is available on the use of appropriate comparison groups for studies investigating late effects of childhood cancer. Two comparison groups in a nationwide study on reproductive function and ovarian reserve in female childhood cancer survivors were recruited (The Dutch Childhood Oncology Group Long-Term Effects After Childhood Cancer Cohort Study). Experiences of this process are reported. Two types of comparison groups were used: sisters of participating survivors and controls from the general population. A total of 352 out of 580 (61%) of the participating survivors who had a sister gave permission to invite them for the study. The participation rate of sisters was much higher than control participants from the general population (74% versus 21%, respectively), whereas considerably more effort was involved in recruiting controls from the general population. Participants in this group were significantly older and more highly educated than sister controls (P < 0.001 for both groups). No significant differences were observed between both types of comparison groups in several fertility-related characteristics, suggesting minimal bias owing to selective participation. Researchers setting up a study to investigate late effects among survivors of childhood cancer should carefully consider the advantages and disadvantages of using various types of comparison groups.

Obesity, 2014

Objective: Although obesity is associated with gonadal dysfunction in the general population, gon... more Objective: Although obesity is associated with gonadal dysfunction in the general population, gonadotoxic treatment might diminish the impact of obesity in childhood cancer survivors (CCS). The aim was to evaluate whether altered body composition is associated with gonadal dysfunction in male CCS, independent of gonadotoxic cancer treatment. Methods: Three hundred fifty-one male CCS were included. Median age at diagnosis was 5.9 years (0-17.8) and median age at follow-up 25.6 years (18.0-45.8). Total and non-SHBG-bound testosterone, sex hormone-binding globulin, inhibin B, and follicle-stimulating hormone (FSH) were studied. Potential determinants were BMI, waist circumference, waist-hip ratio, and body composition measures (dual energy Xray absorptiometry). Results: Non-SHBG-bound testosterone was significantly decreased in survivors with BMI 30 kg/m 2 (adjusted mean 9.1 nmol/L vs. 10.2 nmol/L, P 5 0.015), high fat percentage (10.0 vs. 11.2, P 5 0.004), and high waist circumference (>102 cm) (9.0 vs. 11.0, P 5 0.020). Survivors with high fat percentage (25%) had significantly lower inhibin B/FSH ratios (inhibin B/FSH ratio: b 234%, P 5 0.041). Conclusion: Obesity is associated with gonadal dysfunction in male CCS, independent of the irreversible effect of previous cancer treatment. Randomized controlled trials are required to evaluate whether weight normalization could improve gonadal function, especially in obese survivors with potential other mechanisms than lifestyle causing their obesity.

Journal of Pediatric Surgery, 2013

Journal of Pediatric Hematology/Oncology, 2013

Background: After a more successful treatment of pediatric cancer, the number of childhood cancer... more Background: After a more successful treatment of pediatric cancer, the number of childhood cancer survivors is progressively increasing. Consequently, awareness of psychological late sequelae is important.

Human Reproduction Update, 2012

BACKGROUND Since childhood cancer survival has increased, long-term effects of treatment have gai... more BACKGROUND Since childhood cancer survival has increased, long-term effects of treatment have gained interest. Childhood Hodgkin's lymphoma has been treated successfully for decades now. We provide an overview of the literature on long-term endocrine side effects, such as gonadal dysfunction and growth retardation, as a result of childhood Hodgkin's lymphoma treatment. METHODS A comprehensive search of the Pubmed database was performed. RESULTS We identified 16 studies (10 studies: 298 male survivors and 6 studies: 230 female survivors) about gonadal dysfunction. In survivors treated with alkylating agents or pelvic radiotherapy, severe gonadal damage is described. Recovery was rarely described. Seven studies (481 survivors) about bone mineral density (BMD) and growth were identified. The effects on BMD appear to be small. Data on growth are scarce, but show that radiotherapy in a dose of >30 Gy including the spine, especially in pre-pubertal children, results in reduced height. We included 10 studies (4012 survivors) about thyroid complications. Hypothyroidism is the most common thyroid disorder after radiotherapy. There is also a significant incidence in thyroid carcinoma after low-dose radiation. In survivors treated with chemotherapy only, hypothyroidism and thyroid cancer have not been reported. CONCLUSIONS The severity of endocrine toxicity after childhood Hodgkin's lymphoma depends on the type of treatment. Gonadal dysfunction seems to be the most severe endocrine long-term effect, especially after treatment with alkylating agents or pelvic radiotherapy. The knowledge obtained in specific follow-up programmes for paediatric cancer survivors will help to find the optimal balance between curability and long-term side effects.

Human Reproduction, 2014

Are anti-Müllerian hormone (AMH) levels reduced in girls with newly diagnosed cancer before the s... more Are anti-Müllerian hormone (AMH) levels reduced in girls with newly diagnosed cancer before the start of treatment? AMH levels are already compromised in girls at the time of cancer diagnosis compared with healthy girls. In women diagnosed with cancer, evidence of reduced ovarian function has been described even before treatment has started. In girls with newly diagnosed cancer, no data are available. We performed an age-matched case-control study in girls with newly diagnosed cancer. We determined serum AMH levels in a cohort of 208 girls with newly diagnosed cancer, up to 18 years of age at diagnosis, and compared them with AMH levels of 250 age-matched healthy girls. The diagnoses included were acute lymphoblastic leukaemia, acute myeloid leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, nephroblastoma, sarcoma and neuroblastoma. The median age was 6.6 years (range 0.0-17.4), comparable with that in the control group (median 6.3 years, range 0.3-18.0). Girls with childhood cancer presented with significantly lower serum AMH levels compared with healthy age-matched controls (standard deviation scores (SDS) -0.8, P < 0.001). Median AMH level in patients was 1.4 μg/l (0.1-10.2) versus 3.0 μg/l (0.1-18.3) in controls. Specifically, 84% of all patients had AMH levels below the 50th percentile of normal AMH levels, and 19% below the 10th percentile. Surrogate markers of general health status (temperature, C-reactive protein and haemoglobin levels at diagnosis) were significantly correlated with AMH SDS. Some caution is warranted because AMH levels increase with age in healthy children but the cases and controls were age-matched in our study. Although our sample size was large, additional studies are still required in an independent cohort. Our study shows that AMH levels are reduced in girls with newly diagnosed cancer even before the cancer treatment has started. AMH levels correlate with impairment of general health status in girls. Therefore, besides (pre) antral follicle number, other factors may influence serum AMH levels. Longitudinal studies during and after childhood cancer are currently being performed in order to evaluate possible ovarian recovery after discontinuation of treatment. W.v.D. is supported by the Paediatric Oncology Centre Society for Research (KOCR), Rotterdam, The Netherlands. J.S.E.L. has received grants from the following companies (in alphabetical order): Ferring, Genovum, Merck Serono, Merck Sharp and Dome, Organon, Serono, Shering Plough and Shering. All other authors have nothing to disclose.

Human Reproduction, 2013

Are genetic polymorphisms, previously identified as being associated with age at menopause in the... more Are genetic polymorphisms, previously identified as being associated with age at menopause in the healthy population, associated with ovarian reserve and predicted age at menopause in adult long-term survivors of childhood cancer? The CT genotype of rs1172822 in the BRSK1 gene is associated with lower serum anti-Müllerian hormone (AMH) levels and a younger predicted age at menopause in adult survivors of childhood cancer. Gonadotoxicity is a well-known late side effect of chemotherapy and radiotherapy in adult survivors of childhood cancer. In the healthy population, several genetic polymorphisms are associated with age at natural menopause. Currently, data on the impact of previously identified variants in gene loci associated with ovarian reserve in adult long-term survivors of childhood cancer are lacking. We performed a pilot study in a single-centre cohort of adult female Caucasian childhood cancer survivors (n = 176). We determined serum AMH levels (a marker of ovarian reserve) in adult survivors of childhood cancer (n = 176) and studied single nucleotide polymorphisms (SNPs) previously reported to be associated with age at natural menopause: BRSK1 (rs1172822), ARHGEF7 (rs7333181), MCM8 (rs236114), PCSK1 (rs271924), IGF2R (rs9457827) and TNF (rs909253). Association analysis was performed using the additive genetic model. Linear regression was conducted to assess the effect of significant polymorphisms in two previously published menopause prediction models. The CT genotype of rs1172822 in the BRSK1 (BR serine/threonine kinase 1) gene was negatively associated with serum AMH levels in our cohort (odds ratio: 3.15, 95% confidence interval: 1.35-7.32, P = 0.008) and significantly associated with the predicted age at menopause (P = 0.04). The other five SNPs were not associated with serum AMH levels. This is a pilot study showing preliminary data which must be confirmed. To confirm our findings and enlarge the project, a nationwide genome-wide association (GWA) project on the ovarian reserve in female survivors of childhood cancer should be performed, including a replication cohort. Our findings support the hypothesis that previously identified genetic polymorphisms associated with age at menopause in healthy women may have an effect on the onset of menopause in female survivors of childhood cancer. Our study highlights a new aspect of the influences on the ovarian reserve after childhood cancer, which should be investigated further in a nationwide GWA study. Eventually, this information can help us to improve counselling on fertility preservation prior to cancer treatment based on genetic factors in individual patients. W.D. is supported by the Paediatric Oncology Centre Society for Research (KOCR), Rotterdam, The Netherlands. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Genovum, Merck-Serono, Organon, Schering Plough and Serono. All other authors have nothing to disclose.

Human Reproduction, 2012

ABSTRACT Introduction: While sperm cryopreservation prior to cancer treatment is regularly utiliz... more ABSTRACT Introduction: While sperm cryopreservation prior to cancer treatment is regularly utilized in adults, the complex ethico-legal issues and knowledge barriers surrounding its use in adolescents mean there is little available data to help inform clinicians deciding which patients should be offered the opportunity. Pre-treatment clinical and biochemical factors and their potential for predicting sperm banking offer, uptake and success rates were analysed in the largest cohort of adolescents to date.Materials and Methods: A retrospective case note analysis of 222 males aged 12-18 years (median 15.0) who attended a tertiary oncology unit over a 10-year period was carried out during three consecutive audit cycles. Patients with new or relapsed malignancy were included in the multivariate analysis which examined the relationship of a range of ‘at diagnosis’ measurements of virilisation with the respective likelihoods of producing a sample suitable for storage; a sample unsuitable for storage, or being unable to produce a sample.Results: 171/222 (77.0%) patients were offered sperm cryopreservation; 117/171 (68.4%) attempted and 76/117 (65.0%) succeeded. Successful sperm cryopreservation was possible as early as 12.6 years, Tanner stage 3 and mean testicular volume of 8 mls. Compared with endocrine biochemistry (70.3%), pubertal stage and testicular volume (24.6%) were poorly assessed pre-treatment. Although oncologists predominantly relied on age in offering sperm banking (p = 0.004), testicular volume (p = 0.031), testosterone (p < 0.001) and LH (p < 0.001) independently predicted success. Commencement of chemotherapy resulted in a higher risk of necrozoospermia (OR 16.5).Conclusion: Sperm cryopreservation in adolescents has a 2 in 3 chance of success, and is therefore a realistic option for consideration in adolescent cancer patients. Oncologists should favour measurements of LH and testosterone, and testicular volume over age as predictors of success. Where possible, chemotherapy should commence only after banking has been attempted.Introduction: There are many cancers that strike young males in their reproductive years, and those who have not the desire to start a family yet. Testicular cancer (TC) is the most frequent tumour diagnosed in men aged 15-39 years. Chemotherapy and radiation are the mainstays of successful cancer treatment, but often lead to diminished fertility and, in some cases, irreversible impairment of spermatogenesis. Treatment is very likely successful with many surviving their cancer and exploring fertility options afterwards.The aim of this study was to assess and compare the semen parameters of males diagnosed with TC attending for semen cryopreservation prior to and post surgery or adjuvant therapy. We also assessed the short and long-term effect of cancer therapy on spermatogenesis.Materials and Methods: A retrospective database and chart review of oncology males who undertook semen cryopreservation at the National Gamete Cryopreservation Centre based in a tertiary academic Centre based at the Rotunda Hospital, Dublin, Ireland, between 1998-2006. We focused only on males diagnosed with TC who had stored samples prior to and returned for follow-up semen analysis post cancer therapy. The criteria for successful fertility preservation at our clinic is the freezing of 3 ejaculates prior to commencement of cancer therapy where possible, therefore due to the known impact of abstinence on semen values the second ejaculate was used for analysis in this study. The following parameters were analysed and compared in all cases pre and post cancer therapy: age, abstinence, semen volume, sperm count and motility. (WHO criteria, 1999). On analysis of post therapy semen anaysis we subgrouped the analysis into time periods t0-1 year, t1-3 years, and t3-t5 years. Quantitative results are expressed as mean and SD for the entire patient group. The Student’s t-test for paired or unpaired data was used to evaluate the differences between two mean values. A two-tailed P-value below 0.05 was considered as statistically significant.Results: A total of 263 males diagnosed with testicular cancer banked samples prior to cancer therapy in this study time period. Of those 47 males (18%) returned for follow up semen analysis post cancer therapy and undertook 78 semen analysis. The mean age ± SD for the pre-therapy group was 28 ± 6.14 and the post therapy group was 31.5 ± 4.93. There was no significance detected for volume, abstinence, count or motility for pre and post therapy (p = 0.54, p = 0.92, p = 0.05, p = 0.46 respectively). One year after therapy was completed 38% of males were azoospermic, 3years after therapy 21% were azoospermic and 5 years after therapy 12% of males were azoospermic.Conclusions: To protect future male fertility, sperm cryopreservation prior to cancer therapy is widely accepted as good clinical practice. The pre-cryopreservation discussion should cover not just the procedure…

Fertility and Sterility, 2014

Objective: To evaluate the feasibility of electroejaculation to perform semen cryopreservation in... more Objective: To evaluate the feasibility of electroejaculation to perform semen cryopreservation in pubertal boys before gonadotoxic therapy and to review the literature on this topic. Design: Retrospective cohort study and review of the literature. Setting: Academic children's hospital. Patient(s): Boys diagnosed with cancer to whom sperm cryopreservation was offered before the start of gonadotoxic therapy. Intervention(s): We studied the outcome of electroejaculation, including patient characteristics, hormone levels, and pretreatment semen parameters. Main Outcome Measure(s): Semen cryopreservation. Result(s): Pretreatment semen samples were obtained by masturbation in 106/114 boys with cancer, of which 78/106 were adequate for preservation. Electroejaculation was offered to 11 boys, of which three of 11 samples appeared adequate for preservation. Reviewing all reported electroejaculation cases in children with cancer in the literature, 13/29 (45%) cases were successful. Testosterone levels were higher in patients with successful sperm yield obtained by electroejaculation (median, 8.3 nmol/L [5.2-42.4] in successful harvests, vs. median 1.7 nmol/L [0.01-17.9] in unsuccessful harvests). Conclusion(s): Semen cryopreservation should be offered to all pubertal boys diagnosed with cancer. If masturbation fails, electroejaculation can be considered as a useful option for semen cryopreservation and leads to adequate material for cryopreservation in about half of the cases.

European Journal of Endocrinology, 2013

Background: Although gonadal toxicity has been reported, no data are available on recovery of gon... more Background: Although gonadal toxicity has been reported, no data are available on recovery of gonadal function in very long-term survivors of childhood cancer. Inhibin B is a novel reliable serum marker which has been shown to be of value in childhood cancer survivor studies to identify risk groups for impaired gonadal function, but consecutive long-term follow-up studies using serum inhibin B as a marker are not available. Objective: To evaluate possible recovery of gonadal dysfunction over time in adult male survivors of childhood cancer. Methods: In this retrospective study, adult male long-term childhood cancer survivors (n = 201) who visited our outpatient late effects clinic were included and we used inhibin B as a surrogate marker for gonadal function. Results: Median age at diagnosis was 5.9 years (range 0.0-17.5) and discontinuation of treatment was reached at a median age of 8.2 years (range 0.0-20.8). Inhibin B levels were first 0959-8049/$ -see front matter Ó

European Journal of Cancer, 2013

Background: Although gonadal toxicity has been reported, no data are available on recovery of gon... more Background: Although gonadal toxicity has been reported, no data are available on recovery of gonadal function in very long-term survivors of childhood cancer. Inhibin B is a novel reliable serum marker which has been shown to be of value in childhood cancer survivor studies to identify risk groups for impaired gonadal function, but consecutive long-term follow-up studies using serum inhibin B as a marker are not available. Objective: To evaluate possible recovery of gonadal dysfunction over time in adult male survivors of childhood cancer. Methods: In this retrospective study, adult male long-term childhood cancer survivors (n = 201) who visited our outpatient late effects clinic were included and we used inhibin B as a surrogate marker for gonadal function. Results: Median age at diagnosis was 5.9 years (range 0.0-17.5) and discontinuation of treatment was reached at a median age of 8.2 years (range 0.0-20.8). Inhibin B levels were first 0959-8049/$ -see front matter Ó

Ovarian infiltration in pediatric non-Hodgkin lymphoma (NHL) at presentation is rare and informat... more Ovarian infiltration in pediatric non-Hodgkin lymphoma (NHL) at presentation is rare and information on outcome is scarce and mainly based on case reports and small series. Evaluation of clinical characteristics and outcome of ovarian infiltrated pediatric NHL cases of a single center, and an extensive review of the all cases reported so far in literature. At presentation, 6/60 female NHL cases of our center had ovarian infiltration, and combining these cases with earlier case reports, a total of 42 cases were identified. Median age at presentation was 10.9 years (range 0-18), and all but one had a B-cell immunophenotype, with 32/42 cases being classified as Burkitt. Bilateral involvement was reported in 26/41 cases, of which 22 were bilaterally ovariectomized as first treatment. All cases were treated with chemotherapy. Relapses were reported in 9/36 and death in 16/36. After follow-up in our center (median 13.4 years), in 2 cases anti-Müllerian hormone (AMH) values were available (2.1 and 0.9 µg/L), in non-ovarian cases median 2.2 µg/L. We conclude that in case of ovarian tumors with negative markers, NHL should be considered in order to avoid unnecessary surgery.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 25, 2016

Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were treated with al... more Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were treated with alkylating agents and/or radiation, with potential exposure of the ovaries, have an increased risk of premature ovarian insufficiency (POI). Clinical practice guidelines can facilitate these survivors' access to optimal treatment of late effects that may improve health and quality of survival; however, surveillance recommendations vary among the existing long-term follow-up guidelines, which impedes the implementation of screening. The present guideline was developed by using an evidence-based approach and summarizes harmonized POI surveillance recommendations for female survivors of CAYA cancer who were diagnosed at age < 25 years. The recommendations were formulated by an international multidisciplinary panel and graded according to the strength of the evidence and the potential benefit gained from early detection and intervention. The harmonized POI surveillance recommendations w...

Are genetic polymorphisms, previously identified as being associated with age at menopause in the... more Are genetic polymorphisms, previously identified as being associated with age at menopause in the healthy population, associated with ovarian reserve and predicted age at menopause in adult long-term survivors of childhood cancer? The CT genotype of rs1172822 in the BRSK1 gene is associated with lower serum anti-Müllerian hormone (AMH) levels and a younger predicted age at menopause in adult survivors of childhood cancer. Gonadotoxicity is a well-known late side effect of chemotherapy and radiotherapy in adult survivors of childhood cancer. In the healthy population, several genetic polymorphisms are associated with age at natural menopause. Currently, data on the impact of previously identified variants in gene loci associated with ovarian reserve in adult long-term survivors of childhood cancer are lacking. We performed a pilot study in a single-centre cohort of adult female Caucasian childhood cancer survivors (n = 176). We determined serum AMH levels (a marker of ovarian reserve) in adult survivors of childhood cancer (n = 176) and studied single nucleotide polymorphisms (SNPs) previously reported to be associated with age at natural menopause: BRSK1 (rs1172822), ARHGEF7 (rs7333181), MCM8 (rs236114), PCSK1 (rs271924), IGF2R (rs9457827) and TNF (rs909253). Association analysis was performed using the additive genetic model. Linear regression was conducted to assess the effect of significant polymorphisms in two previously published menopause prediction models. The CT genotype of rs1172822 in the BRSK1 (BR serine/threonine kinase 1) gene was negatively associated with serum AMH levels in our cohort (odds ratio: 3.15, 95% confidence interval: 1.35-7.32, P = 0.008) and significantly associated with the predicted age at menopause (P = 0.04). The other five SNPs were not associated with serum AMH levels. This is a pilot study showing preliminary data which must be confirmed. To confirm our findings and enlarge the project, a nationwide genome-wide association (GWA) project on the ovarian reserve in female survivors of childhood cancer should be performed, including a replication cohort. Our findings support the hypothesis that previously identified genetic polymorphisms associated with age at menopause in healthy women may have an effect on the onset of menopause in female survivors of childhood cancer. Our study highlights a new aspect of the influences on the ovarian reserve after childhood cancer, which should be investigated further in a nationwide GWA study. Eventually, this information can help us to improve counselling on fertility preservation prior to cancer treatment based on genetic factors in individual patients. W.D. is supported by the Paediatric Oncology Centre Society for Research (KOCR), Rotterdam, The Netherlands. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Genovum, Merck-Serono, Organon, Schering Plough and Serono. All other authors have nothing to disclose.

Fertility and Sterility, Jan 7, 2014

Objective: To evaluate the feasibility of electroejaculation to perform semen cryopreservation in... more Objective: To evaluate the feasibility of electroejaculation to perform semen cryopreservation in pubertal boys before gonadotoxic therapy and to review the literature on this topic. Design: Retrospective cohort study and review of the literature. Setting: Academic children's hospital. Patient(s): Boys diagnosed with cancer to whom sperm cryopreservation was offered before the start of gonadotoxic therapy. Intervention(s): We studied the outcome of electroejaculation, including patient characteristics, hormone levels, and pretreatment semen parameters. Main Outcome Measure(s): Semen cryopreservation. Result(s): Pretreatment semen samples were obtained by masturbation in 106/114 boys with cancer, of which 78/106 were adequate for preservation. Electroejaculation was offered to 11 boys, of which three of 11 samples appeared adequate for preservation. Reviewing all reported electroejaculation cases in children with cancer in the literature, 13/29 (45%) cases were successful. Testosterone levels were higher in patients with successful sperm yield obtained by electroejaculation (median, 8.3 nmol/L [5.2-42.4] in successful harvests, vs. median 1.7 nmol/L [0.01-17.9] in unsuccessful harvests). Conclusion(s): Semen cryopreservation should be offered to all pubertal boys diagnosed with cancer. If masturbation fails, electroejaculation can be considered as a useful option for semen cryopreservation and leads to adequate material for cryopreservation in about half of the cases.

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 2015

More than 45 % of long-term childhood cancer survivors (CCS) were diagnosed with osteopenia. Our ... more More than 45 % of long-term childhood cancer survivors (CCS) were diagnosed with osteopenia. Our data suggest that greater awareness for osteopenia is warranted in long-term CCS, especially in survivors who are older than 30 years, male, and underweight and were treated with cranial-spinal radiotherapy and/or steroids. Osteopenia is a potential complication of childhood cancer treatment, but the magnitude of this problem in survivors is unknown. We examined (determinants of) bone mineral density (BMD) status in long-term survivors of adult childhood cancer. This retrospective single-centre cohort study included 346 subjects with the most common types of childhood cancer. Subjects had a median age at diagnosis of 7.0 years (range 0.1-16.8 years), a median age at follow-up of 24.5 years (range 18.0-47.6 years) and a median follow-up time of 16.7 years (range 5.6-39.9 years). Total body BMD (BMDTB) and BMD of the lumbar spine (BMDLS) were measured by dual X-ray absorptiometry. Osteopen...

Tijdschrift voor Urologie, 2014

ABSTRACT De overleving van kinderen met kanker is in de afgelopen decennia sterk verbeterd. Hierd... more ABSTRACT De overleving van kinderen met kanker is in de afgelopen decennia sterk verbeterd. Hierdoor is veel aandacht voor de langetermijneffecten van oncologische behandelingen, zoals infertiliteit.

Reproductive BioMedicine Online, 2014

Little information is available on the use of appropriate comparison groups for studies investiga... more Little information is available on the use of appropriate comparison groups for studies investigating late effects of childhood cancer. Two comparison groups in a nationwide study on reproductive function and ovarian reserve in female childhood cancer survivors were recruited (The Dutch Childhood Oncology Group Long-Term Effects After Childhood Cancer Cohort Study). Experiences of this process are reported. Two types of comparison groups were used: sisters of participating survivors and controls from the general population. A total of 352 out of 580 (61%) of the participating survivors who had a sister gave permission to invite them for the study. The participation rate of sisters was much higher than control participants from the general population (74% versus 21%, respectively), whereas considerably more effort was involved in recruiting controls from the general population. Participants in this group were significantly older and more highly educated than sister controls (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001 for both groups). No significant differences were observed between both types of comparison groups in several fertility-related characteristics, suggesting minimal bias owing to selective participation. Researchers setting up a study to investigate late effects among survivors of childhood cancer should carefully consider the advantages and disadvantages of using various types of comparison groups.

Obesity, 2014

Objective: Although obesity is associated with gonadal dysfunction in the general population, gon... more Objective: Although obesity is associated with gonadal dysfunction in the general population, gonadotoxic treatment might diminish the impact of obesity in childhood cancer survivors (CCS). The aim was to evaluate whether altered body composition is associated with gonadal dysfunction in male CCS, independent of gonadotoxic cancer treatment. Methods: Three hundred fifty-one male CCS were included. Median age at diagnosis was 5.9 years (0-17.8) and median age at follow-up 25.6 years (18.0-45.8). Total and non-SHBG-bound testosterone, sex hormone-binding globulin, inhibin B, and follicle-stimulating hormone (FSH) were studied. Potential determinants were BMI, waist circumference, waist-hip ratio, and body composition measures (dual energy Xray absorptiometry). Results: Non-SHBG-bound testosterone was significantly decreased in survivors with BMI 30 kg/m 2 (adjusted mean 9.1 nmol/L vs. 10.2 nmol/L, P 5 0.015), high fat percentage (10.0 vs. 11.2, P 5 0.004), and high waist circumference (>102 cm) (9.0 vs. 11.0, P 5 0.020). Survivors with high fat percentage (25%) had significantly lower inhibin B/FSH ratios (inhibin B/FSH ratio: b 234%, P 5 0.041). Conclusion: Obesity is associated with gonadal dysfunction in male CCS, independent of the irreversible effect of previous cancer treatment. Randomized controlled trials are required to evaluate whether weight normalization could improve gonadal function, especially in obese survivors with potential other mechanisms than lifestyle causing their obesity.

Journal of Pediatric Surgery, 2013

Journal of Pediatric Hematology/Oncology, 2013

Background: After a more successful treatment of pediatric cancer, the number of childhood cancer... more Background: After a more successful treatment of pediatric cancer, the number of childhood cancer survivors is progressively increasing. Consequently, awareness of psychological late sequelae is important.

Human Reproduction Update, 2012

BACKGROUND Since childhood cancer survival has increased, long-term effects of treatment have gai... more BACKGROUND Since childhood cancer survival has increased, long-term effects of treatment have gained interest. Childhood Hodgkin&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s lymphoma has been treated successfully for decades now. We provide an overview of the literature on long-term endocrine side effects, such as gonadal dysfunction and growth retardation, as a result of childhood Hodgkin&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s lymphoma treatment. METHODS A comprehensive search of the Pubmed database was performed. RESULTS We identified 16 studies (10 studies: 298 male survivors and 6 studies: 230 female survivors) about gonadal dysfunction. In survivors treated with alkylating agents or pelvic radiotherapy, severe gonadal damage is described. Recovery was rarely described. Seven studies (481 survivors) about bone mineral density (BMD) and growth were identified. The effects on BMD appear to be small. Data on growth are scarce, but show that radiotherapy in a dose of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;30 Gy including the spine, especially in pre-pubertal children, results in reduced height. We included 10 studies (4012 survivors) about thyroid complications. Hypothyroidism is the most common thyroid disorder after radiotherapy. There is also a significant incidence in thyroid carcinoma after low-dose radiation. In survivors treated with chemotherapy only, hypothyroidism and thyroid cancer have not been reported. CONCLUSIONS The severity of endocrine toxicity after childhood Hodgkin&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s lymphoma depends on the type of treatment. Gonadal dysfunction seems to be the most severe endocrine long-term effect, especially after treatment with alkylating agents or pelvic radiotherapy. The knowledge obtained in specific follow-up programmes for paediatric cancer survivors will help to find the optimal balance between curability and long-term side effects.

Human Reproduction, 2014

Are anti-Müllerian hormone (AMH) levels reduced in girls with newly diagnosed cancer before the s... more Are anti-Müllerian hormone (AMH) levels reduced in girls with newly diagnosed cancer before the start of treatment? AMH levels are already compromised in girls at the time of cancer diagnosis compared with healthy girls. In women diagnosed with cancer, evidence of reduced ovarian function has been described even before treatment has started. In girls with newly diagnosed cancer, no data are available. We performed an age-matched case-control study in girls with newly diagnosed cancer. We determined serum AMH levels in a cohort of 208 girls with newly diagnosed cancer, up to 18 years of age at diagnosis, and compared them with AMH levels of 250 age-matched healthy girls. The diagnoses included were acute lymphoblastic leukaemia, acute myeloid leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, nephroblastoma, sarcoma and neuroblastoma. The median age was 6.6 years (range 0.0-17.4), comparable with that in the control group (median 6.3 years, range 0.3-18.0). Girls with childhood cancer presented with significantly lower serum AMH levels compared with healthy age-matched controls (standard deviation scores (SDS) -0.8, P &amp;amp;lt; 0.001). Median AMH level in patients was 1.4 μg/l (0.1-10.2) versus 3.0 μg/l (0.1-18.3) in controls. Specifically, 84% of all patients had AMH levels below the 50th percentile of normal AMH levels, and 19% below the 10th percentile. Surrogate markers of general health status (temperature, C-reactive protein and haemoglobin levels at diagnosis) were significantly correlated with AMH SDS. Some caution is warranted because AMH levels increase with age in healthy children but the cases and controls were age-matched in our study. Although our sample size was large, additional studies are still required in an independent cohort. Our study shows that AMH levels are reduced in girls with newly diagnosed cancer even before the cancer treatment has started. AMH levels correlate with impairment of general health status in girls. Therefore, besides (pre) antral follicle number, other factors may influence serum AMH levels. Longitudinal studies during and after childhood cancer are currently being performed in order to evaluate possible ovarian recovery after discontinuation of treatment. W.v.D. is supported by the Paediatric Oncology Centre Society for Research (KOCR), Rotterdam, The Netherlands. J.S.E.L. has received grants from the following companies (in alphabetical order): Ferring, Genovum, Merck Serono, Merck Sharp and Dome, Organon, Serono, Shering Plough and Shering. All other authors have nothing to disclose.

Human Reproduction, 2013

Are genetic polymorphisms, previously identified as being associated with age at menopause in the... more Are genetic polymorphisms, previously identified as being associated with age at menopause in the healthy population, associated with ovarian reserve and predicted age at menopause in adult long-term survivors of childhood cancer? The CT genotype of rs1172822 in the BRSK1 gene is associated with lower serum anti-Müllerian hormone (AMH) levels and a younger predicted age at menopause in adult survivors of childhood cancer. Gonadotoxicity is a well-known late side effect of chemotherapy and radiotherapy in adult survivors of childhood cancer. In the healthy population, several genetic polymorphisms are associated with age at natural menopause. Currently, data on the impact of previously identified variants in gene loci associated with ovarian reserve in adult long-term survivors of childhood cancer are lacking. We performed a pilot study in a single-centre cohort of adult female Caucasian childhood cancer survivors (n = 176). We determined serum AMH levels (a marker of ovarian reserve) in adult survivors of childhood cancer (n = 176) and studied single nucleotide polymorphisms (SNPs) previously reported to be associated with age at natural menopause: BRSK1 (rs1172822), ARHGEF7 (rs7333181), MCM8 (rs236114), PCSK1 (rs271924), IGF2R (rs9457827) and TNF (rs909253). Association analysis was performed using the additive genetic model. Linear regression was conducted to assess the effect of significant polymorphisms in two previously published menopause prediction models. The CT genotype of rs1172822 in the BRSK1 (BR serine/threonine kinase 1) gene was negatively associated with serum AMH levels in our cohort (odds ratio: 3.15, 95% confidence interval: 1.35-7.32, P = 0.008) and significantly associated with the predicted age at menopause (P = 0.04). The other five SNPs were not associated with serum AMH levels. This is a pilot study showing preliminary data which must be confirmed. To confirm our findings and enlarge the project, a nationwide genome-wide association (GWA) project on the ovarian reserve in female survivors of childhood cancer should be performed, including a replication cohort. Our findings support the hypothesis that previously identified genetic polymorphisms associated with age at menopause in healthy women may have an effect on the onset of menopause in female survivors of childhood cancer. Our study highlights a new aspect of the influences on the ovarian reserve after childhood cancer, which should be investigated further in a nationwide GWA study. Eventually, this information can help us to improve counselling on fertility preservation prior to cancer treatment based on genetic factors in individual patients. W.D. is supported by the Paediatric Oncology Centre Society for Research (KOCR), Rotterdam, The Netherlands. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Genovum, Merck-Serono, Organon, Schering Plough and Serono. All other authors have nothing to disclose.

Human Reproduction, 2012

ABSTRACT Introduction: While sperm cryopreservation prior to cancer treatment is regularly utiliz... more ABSTRACT Introduction: While sperm cryopreservation prior to cancer treatment is regularly utilized in adults, the complex ethico-legal issues and knowledge barriers surrounding its use in adolescents mean there is little available data to help inform clinicians deciding which patients should be offered the opportunity. Pre-treatment clinical and biochemical factors and their potential for predicting sperm banking offer, uptake and success rates were analysed in the largest cohort of adolescents to date.Materials and Methods: A retrospective case note analysis of 222 males aged 12-18 years (median 15.0) who attended a tertiary oncology unit over a 10-year period was carried out during three consecutive audit cycles. Patients with new or relapsed malignancy were included in the multivariate analysis which examined the relationship of a range of ‘at diagnosis’ measurements of virilisation with the respective likelihoods of producing a sample suitable for storage; a sample unsuitable for storage, or being unable to produce a sample.Results: 171/222 (77.0%) patients were offered sperm cryopreservation; 117/171 (68.4%) attempted and 76/117 (65.0%) succeeded. Successful sperm cryopreservation was possible as early as 12.6 years, Tanner stage 3 and mean testicular volume of 8 mls. Compared with endocrine biochemistry (70.3%), pubertal stage and testicular volume (24.6%) were poorly assessed pre-treatment. Although oncologists predominantly relied on age in offering sperm banking (p = 0.004), testicular volume (p = 0.031), testosterone (p &lt; 0.001) and LH (p &lt; 0.001) independently predicted success. Commencement of chemotherapy resulted in a higher risk of necrozoospermia (OR 16.5).Conclusion: Sperm cryopreservation in adolescents has a 2 in 3 chance of success, and is therefore a realistic option for consideration in adolescent cancer patients. Oncologists should favour measurements of LH and testosterone, and testicular volume over age as predictors of success. Where possible, chemotherapy should commence only after banking has been attempted.Introduction: There are many cancers that strike young males in their reproductive years, and those who have not the desire to start a family yet. Testicular cancer (TC) is the most frequent tumour diagnosed in men aged 15-39 years. Chemotherapy and radiation are the mainstays of successful cancer treatment, but often lead to diminished fertility and, in some cases, irreversible impairment of spermatogenesis. Treatment is very likely successful with many surviving their cancer and exploring fertility options afterwards.The aim of this study was to assess and compare the semen parameters of males diagnosed with TC attending for semen cryopreservation prior to and post surgery or adjuvant therapy. We also assessed the short and long-term effect of cancer therapy on spermatogenesis.Materials and Methods: A retrospective database and chart review of oncology males who undertook semen cryopreservation at the National Gamete Cryopreservation Centre based in a tertiary academic Centre based at the Rotunda Hospital, Dublin, Ireland, between 1998-2006. We focused only on males diagnosed with TC who had stored samples prior to and returned for follow-up semen analysis post cancer therapy. The criteria for successful fertility preservation at our clinic is the freezing of 3 ejaculates prior to commencement of cancer therapy where possible, therefore due to the known impact of abstinence on semen values the second ejaculate was used for analysis in this study. The following parameters were analysed and compared in all cases pre and post cancer therapy: age, abstinence, semen volume, sperm count and motility. (WHO criteria, 1999). On analysis of post therapy semen anaysis we subgrouped the analysis into time periods t0-1 year, t1-3 years, and t3-t5 years. Quantitative results are expressed as mean and SD for the entire patient group. The Student’s t-test for paired or unpaired data was used to evaluate the differences between two mean values. A two-tailed P-value below 0.05 was considered as statistically significant.Results: A total of 263 males diagnosed with testicular cancer banked samples prior to cancer therapy in this study time period. Of those 47 males (18%) returned for follow up semen analysis post cancer therapy and undertook 78 semen analysis. The mean age ± SD for the pre-therapy group was 28 ± 6.14 and the post therapy group was 31.5 ± 4.93. There was no significance detected for volume, abstinence, count or motility for pre and post therapy (p = 0.54, p = 0.92, p = 0.05, p = 0.46 respectively). One year after therapy was completed 38% of males were azoospermic, 3years after therapy 21% were azoospermic and 5 years after therapy 12% of males were azoospermic.Conclusions: To protect future male fertility, sperm cryopreservation prior to cancer therapy is widely accepted as good clinical practice. The pre-cryopreservation discussion should cover not just the procedure…

Fertility and Sterility, 2014

Objective: To evaluate the feasibility of electroejaculation to perform semen cryopreservation in... more Objective: To evaluate the feasibility of electroejaculation to perform semen cryopreservation in pubertal boys before gonadotoxic therapy and to review the literature on this topic. Design: Retrospective cohort study and review of the literature. Setting: Academic children's hospital. Patient(s): Boys diagnosed with cancer to whom sperm cryopreservation was offered before the start of gonadotoxic therapy. Intervention(s): We studied the outcome of electroejaculation, including patient characteristics, hormone levels, and pretreatment semen parameters. Main Outcome Measure(s): Semen cryopreservation. Result(s): Pretreatment semen samples were obtained by masturbation in 106/114 boys with cancer, of which 78/106 were adequate for preservation. Electroejaculation was offered to 11 boys, of which three of 11 samples appeared adequate for preservation. Reviewing all reported electroejaculation cases in children with cancer in the literature, 13/29 (45%) cases were successful. Testosterone levels were higher in patients with successful sperm yield obtained by electroejaculation (median, 8.3 nmol/L [5.2-42.4] in successful harvests, vs. median 1.7 nmol/L [0.01-17.9] in unsuccessful harvests). Conclusion(s): Semen cryopreservation should be offered to all pubertal boys diagnosed with cancer. If masturbation fails, electroejaculation can be considered as a useful option for semen cryopreservation and leads to adequate material for cryopreservation in about half of the cases.

European Journal of Endocrinology, 2013

Background: Although gonadal toxicity has been reported, no data are available on recovery of gon... more Background: Although gonadal toxicity has been reported, no data are available on recovery of gonadal function in very long-term survivors of childhood cancer. Inhibin B is a novel reliable serum marker which has been shown to be of value in childhood cancer survivor studies to identify risk groups for impaired gonadal function, but consecutive long-term follow-up studies using serum inhibin B as a marker are not available. Objective: To evaluate possible recovery of gonadal dysfunction over time in adult male survivors of childhood cancer. Methods: In this retrospective study, adult male long-term childhood cancer survivors (n = 201) who visited our outpatient late effects clinic were included and we used inhibin B as a surrogate marker for gonadal function. Results: Median age at diagnosis was 5.9 years (range 0.0-17.5) and discontinuation of treatment was reached at a median age of 8.2 years (range 0.0-20.8). Inhibin B levels were first 0959-8049/$ -see front matter Ó

European Journal of Cancer, 2013

Background: Although gonadal toxicity has been reported, no data are available on recovery of gon... more Background: Although gonadal toxicity has been reported, no data are available on recovery of gonadal function in very long-term survivors of childhood cancer. Inhibin B is a novel reliable serum marker which has been shown to be of value in childhood cancer survivor studies to identify risk groups for impaired gonadal function, but consecutive long-term follow-up studies using serum inhibin B as a marker are not available. Objective: To evaluate possible recovery of gonadal dysfunction over time in adult male survivors of childhood cancer. Methods: In this retrospective study, adult male long-term childhood cancer survivors (n = 201) who visited our outpatient late effects clinic were included and we used inhibin B as a surrogate marker for gonadal function. Results: Median age at diagnosis was 5.9 years (range 0.0-17.5) and discontinuation of treatment was reached at a median age of 8.2 years (range 0.0-20.8). Inhibin B levels were first 0959-8049/$ -see front matter Ó

Ovarian infiltration in pediatric non-Hodgkin lymphoma (NHL) at presentation is rare and informat... more Ovarian infiltration in pediatric non-Hodgkin lymphoma (NHL) at presentation is rare and information on outcome is scarce and mainly based on case reports and small series. Evaluation of clinical characteristics and outcome of ovarian infiltrated pediatric NHL cases of a single center, and an extensive review of the all cases reported so far in literature. At presentation, 6/60 female NHL cases of our center had ovarian infiltration, and combining these cases with earlier case reports, a total of 42 cases were identified. Median age at presentation was 10.9 years (range 0-18), and all but one had a B-cell immunophenotype, with 32/42 cases being classified as Burkitt. Bilateral involvement was reported in 26/41 cases, of which 22 were bilaterally ovariectomized as first treatment. All cases were treated with chemotherapy. Relapses were reported in 9/36 and death in 16/36. After follow-up in our center (median 13.4 years), in 2 cases anti-Müllerian hormone (AMH) values were available (2.1 and 0.9 µg/L), in non-ovarian cases median 2.2 µg/L. We conclude that in case of ovarian tumors with negative markers, NHL should be considered in order to avoid unnecessary surgery.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 25, 2016

Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were treated with al... more Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were treated with alkylating agents and/or radiation, with potential exposure of the ovaries, have an increased risk of premature ovarian insufficiency (POI). Clinical practice guidelines can facilitate these survivors' access to optimal treatment of late effects that may improve health and quality of survival; however, surveillance recommendations vary among the existing long-term follow-up guidelines, which impedes the implementation of screening. The present guideline was developed by using an evidence-based approach and summarizes harmonized POI surveillance recommendations for female survivors of CAYA cancer who were diagnosed at age < 25 years. The recommendations were formulated by an international multidisciplinary panel and graded according to the strength of the evidence and the potential benefit gained from early detection and intervention. The harmonized POI surveillance recommendations w...