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Differentiated thyroid carcinoma is the most common endocrinological malignancy with an increasing incidence over the last 30 years, with women being more frequently affected. In indicated cases, total thyroidectomy followed by adjuvant radioiodine administration is performed, despite current trends towards less aggressive treatment. We would like to investigate the possible adverse effects of radioiodine (RAI) on ovarian function using a simple serum biomarker. Anti-Müllerian hormone (AMH) appears to be the best endocrine marker for assessing physiological age-related oocyte loss for healthy women. The aim of our ongoing prospective study is to determine serum AMH to estimate ovarian reserve for premenopausal women treated with RAI. Over the course of one year, 33 serum samples from women with thyroid cancer and 3 serum samples from healthy women were examined. AMH levels were compared before radioiodine treatment and at regular intervals after treatment. Mean of the AMH level was 5.4 ng/ml (n=33) prior to RAI. The average level of AMH decreased to 1.8 ng/ml in 4-6 months after treatment. In 22.2 % of patients AMH dropped to 0 ng/ml from a non-zero value. Thereafter, we observed an increase in AMH, the average value was 2.7 ng/ml in 8-12 months. We demonstrated a significant decrease in AMH shortly after radioiodine treatment and a subsequent trend of increase at one year after treatment. Consequently, predicting the adverse effects of radioiodine by assessing a serum biomarker could help to select an appropriate treatment strategy for young women planning pregnancy.

Objective: Patients with pediatric differentiated thyroid carcinoma (DTC) treated with radioiodine (RAI) therapy may experience long-term side effects, such as gonadal dysfunction. Therefore, it is crucial to understand the impact of this therapy on ovarian reserve and future pregnancy rates., Subjects and Methods: Retrospective analysis of 64 female DTC survivors of childbearing age to assess the risk of infertility due to RAI performed before the age of 19 years., Results: Thirty-two out of the 64 DTC survivors had a history of at least one pregnancy during follow-up. No significant differences were observed between the cumulative RAI activity, treatment regimens (multiple versus single RAI treatment), age at first treatment, or presence of lymph node or distant metastases. Notably, the group without a history of pregnancy had a younger age at the time of diagnosis and larger tumors. Age at first pregnancy was slightly higher than that in the general population, but no increase in negative maternal or fetal outcomes was observed., Conclusions: The results of this study show little observational evidence suggesting important adverse effects of RAI on fertility or pregnancy outcomes among female survivors of childhood DTC. Still, studies including larger populations are warranted., Competing Interests: Disclosure: no potential conflict of interest relevant to this article was reported.

Objective: To discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach., Design: Genome-wide association study., Setting: Not applicable., Patients: A discovery cohort of adult female childhood cancer survivors from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nervous system or total body irradiation, or stem cell transplantation. Replication was attempted in the US-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years)., Exposure: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the interindividual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions, and cyclophosphamide equivalent doses were used to quantify alkylation agent exposure., Main Outcome Measure: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function, and the findings were combined in a meta-analysis., Results: Three genome-wide significant (<5.0 × 10 -8 ) and 16 genome-wide suggestive (<5.0 × 10 -6 ) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. On the basis of the effect allele frequency (EAF) (>0.01 if not genome-wide significant), and biologic relevance, 15 single nucleotide polymorphisms were selected for replication. None of the single nucleotide polymorphisms were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated with borderline genome-wide statistical significance (reference/effect allele: C/T; effect allele frequency: 0.04, beta (SE): -0.484 (0.091)., Conclusion: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment because the findings of this genome-wide association study were not statistically significant replicated in the replication cohort. Suggestive evidence for the potential importance of 1 variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. Because the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity as well as fertility preservation options for childhood cancer survivors., Competing Interests: Declaration of Interests M.E.M.v.d.P. reports funding from European Union’s Seventh Framework Programme for research (technological development, and demonstration funding), Dutch Cancer Society (grant no. VU 2006-3622), Princess Máxima Center Foundation, and Stichting Kinderoncologisch Centrum Rotterdam (sKOCR), DCOG-LATER VEVO study was funded by the Dutch Cancer Society (grant no. VU 2006-3622) and by the Children Cancer-Free Foundation (Project no. 20) and the St Jude Lifetime Cohort study by NCI U01 CA195547. L.B. has nothing to disclose. Y.Y. reports funding from National Cancer Institute (NCI) U01CA195547 (MPI: Hudson/Ness), St. Jude Lifetime Cohort Study (SJLIFE), NCI P30CA021765 (PI: Roberts) Cancer Center Support Grant (CCSG), and American Lebanese Syrian Associated Charities for the submitted work; funding from NCI U24CA055727 (PI: Armstrong) Childhood Cancer Survivor Study (CCSS), National Institutes of Health (NIH) R03DE029238 (PI: Li/Sun) Innovative Statistical Analysis for Genome-Wide Data with General Interval Censored Outcomes of Oral Health in Childhood Cancer Survivors, NCI R01CA216354 (MPI: Yasui/Zhang) Late Effects Prediction Using Clinical Phenotypes and Whole Genome Sequencing, St Jude Lifetime Cohort study by NCI U01 CA195547, NCI R01CA270157 (MPI: Bhakta/Yasui) Measuring Lifelong Multimorbidity with Patient Perspectives: Implementing and Visualizing the Cumulative Burden Methodology Across Cohorts, NCI R01CA258193 (MPI: Huang/Yasui) Patient-Generated Health Data to Predict Childhood Cancer Survivorship Outcomes (HEALTHSHARE), NIH &MD Anderson Cancer Center R01CA261750-01A1 (MPI: Howell/Mulrooney/Yasui) Personalized Risk Prediction to Reduce Cardiovascular Disease in Childhood Cancer Survivors, NCI &Northwestern University R01CA261898 (MPI: Burridge/Sapkota) Predicting and Preventing Chemotherapy-Induced Cardiotoxicity in African American Children, NC. J.S.E.L. has nothing to disclose. L.L.R. has nothing to disclose. W.J.E.T. has nothing to disclose. B.V. has nothing to disclose. B.V. has nothing to disclose. D.B. has nothing to disclose. G.J.L.K. has nothing to disclose. C.B.L. has nothing to disclose. A.O. has nothing to disclose. J.J.L. has nothing to disclose. C.C.M.B. has nothing to disclose. J.B. has nothing to disclose. C.B. has nothing to disclose. E.C. has nothing to disclose. E.v.D.-d.B. has nothing to disclose. U.D. has nothing to disclose. H.J.v.d.P. has nothing to disclose. A.C.H.d.V. has nothing to disclose. J.F.W. has nothing to disclose. A.R. has nothing to disclose. S.D.F. has nothing to disclose. D.G. has nothing to disclose. M.M. has nothing to disclose. M.K. has nothing to disclose. T.K. has nothing to disclose. J.K. has nothing to disclose. D.M.-M. has nothing to disclose. C.S. has nothing to disclose. O.Z. has nothing to disclose. P.K. has nothing to disclose. L.C.M.K. has nothing to disclose. R.J.B. has nothing to disclose. F.W. has nothing to disclose. J.L.B. has nothing to disclose. A.G.U. has nothing to disclose. A.M.E.B. has nothing to disclose. F.E.v.L. has nothing to disclose. K.K.N. has nothing to disclose. M.M.H. has nothing to disclose. A.-L.L.F.v.d.K. has nothing to disclose. M.M.v.d.H.E. has nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Research Question: What is the impact of radiation exposure on oocyte quality and female fertility?, Design: Prepubertal mice underwent whole-body irradiation with a single dose (0.02, 0.1, 0.5, 2, 8 Gy) of gamma- or X-rays. Oocytes were quantified in irradiated (n = 36) and sham-treated (n = 8) mice. After a single exposure to 2 Gy, formation of DNA double-strand breaks (n = 10), activation of checkpoint kinase (Chk2) (n = 10) and dynamics of follicular growth (n = 18) were analysed. Fertility assessment was performed in adult irradiated mice and controls from the number of pups per mouse (n = 28) and the fetal abortion rate (n = 24). Ploidy of mature oocytes (n = 20) was analysed after CREST immunostaining, and uterine sections were examined., Results: Radiation exposure induced a massive loss of primordial follicles with LD 50 below 50 mGy for both gamma and X-rays. Growing follicles survived doses up to 8 Gy. This difference in radiosensitivity was not due to a different amount of radio-induced DNA damage, and Chk2 was activated in all oocytes. Exposure to a 2 Gy dose abolished the long-term fertility of females due to depletion of the ovarian reserve. Detailed analysis indicates that surviving oocytes were able to complete folliculogenesis and could be fertilized. This transient fertility allowed irradiated females to produce a single litter albeit with a high rate of fetal abortion (23%, P = 0.0096), related to altered ploidy in the surviving oocytes (25.5%, P = 0.0035)., Conclusions: The effects of radiation on surviving oocyte quality question natural conception as a first-line approach in cancer survivors. Together, the data emphasize the need for fertility preservation before radiation exposure and call for reassessment of the use of cryopreserved oocytes., (Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess the proportion of female childhood and adolescent tumor survivors who could benefit from oocyte cryopreservation., Design: Case series of female childhood and adolescent tumor survivors referred for fertility counseling., Setting: A referral cancer center and an infertility unit of an academic hospital., Patient(s): Young female childhood and adolescent tumor survivors who received gonadotoxic treatments., Intervention(s): Patients were prescribed tests of ovarian reserve and a personalized counseling was given. Oocyte cryopreservation was considered in subjects aged ≥18 years who were diagnosed with diminished ovarian reserve (DOR) (antimüllerian hormone level <2 ng/mL or total antral follicle count ≤10)., Main Outcome Measure(s): Rate of women with DOR who stored their oocytes., Result(s): Ninety out of 126 evaluated women completed the assessments. We documented preserved ovarian reserve, DOR, and premature ovarian insufficiency in 36 (40%), 35 (39%), and 19 (21%) cases, respectively. Overall, 13 subjects with DOR were eligible for oocyte cryostorage, of whom 9 (69%) underwent the procedure. Considering the whole cohort of evaluated young women (n = 90), the rate of those who had egg freezing was 10%. Finally, nine women started seeking pregnancy after the counseling (six with DOR), and seven of them became pregnant. When the data were analyzed separately according to most gonadotoxic treatments, considerable differences emerged but the evidence did not support the idea that counseling should be restricted to particular subgroups of women., Conclusion(s): Ovarian reserve impairment is common in female childhood and adolescent tumor survivors. Postcancer oocyte cryopreservation may be part of the armamentarium of fertility preservation options., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Aim: Radioactive iodine (RAI) is frequently used as adjuvant therapy in patients with differentiated thyroid cancer (DTC). However, its effect on ovarian reserve has not been fully elucidated, with studies yielding inconsistent results. The aim of this study was to systematically review and meta-analyze the best available evidence regarding the effect of RAI on ovarian reserve in premenopausal women with DTC., Methods: A comprehensive literature search was conducted in PubMed, Cochrane and Scopus, through to December 6 th , 2020. Data were expressed as weighted mean difference (WMD) with a 95% confidence interval (CI). The I 2 index was used to assess heterogeneity., Results: Four prospective studies were included in the qualitative and quantitative analysis. Anti-Müllerian hormone (AMH) concentrations decreased at three (WMD -1.66 ng/ml, 95% CI -2.42 to -0.91, p<0.0001; I 2 0%), six (WMD -1.58, 95% CI -2.63 to -0.52, p=0.003; I 2 54.7%) and 12 months (WMD -1.62 ng/ml, 95% CI -2.02 to -1.22, p<0.0001; I 2 15.5%) following a single RAI dose compared with baseline (three studies; n=104). With respect to follicle-stimulating hormone (FSH) concentrations, no difference was observed at six (WMD +3.29 IU/l, 95% CI -1.12 to 7.70, p=0.14; I 2 96.8%) and 12 months (WMD +0.13 IU/l, 95% CI -1.06 to 1.32, p=0.83; I 2 55.2%) post-RAI compared with baseline (two studies; n=83). No data were available for antral follicle count., Conclusions: AMH concentrations are decreased at three months and remain low at 6 and 12 months following RAI treatment in women with DTC. No difference in FSH concentrations post-RAI is observed., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: This study sought to evaluate the prevalence of menopausal symptoms in a population of reproductive-aged women remote from cancer therapy compared with a group of healthy similar-aged controls and with a cohort of late reproductive-aged (LR) controls., Methods: Participants were assessed for symptoms of menopause, early follicular phase hormones, and ultrasound examinations. Menopausal symptoms were analyzed in exposed participants and controls using χ 2 analyses, Wilcoxon-Mann Whitney tests, and multivariable logistic regression models., Results: One hundred seventy cancer survivors, 135 similar-aged controls, and 71 LR controls were followed prospectively for an average of 38 months. Compared with similar-aged controls, a greater proportion of survivors reported vasomotor symptoms at some point over the study period (35% vs 19%, p < 0.01), and this proportion was similar to LR controls (44%, p = 0.22). Survivors were more likely to be bothered by vaginal dryness (27%) than similar-aged controls (16%, p = 0.02) or LR controls (14%, p = 0.02). FSH levels were 38.4% higher in those with vasomotor symptoms compared with those without symptoms (p = 0.021)., Conclusions: Reproductive-aged cancer survivors have a higher prevalence of vasomotor symptoms and vaginal dryness than their similar-aged peers., Implications for Cancer Survivors: Providers should be attuned to the high prevalence of menopausal symptoms in cancer survivors.

Background: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to evaluate fertility in female survivors of childhood DTC by assessing various reproductive characteristics combined with anti-Müllerian hormone (AMH) levels (a marker of ovarian reserve). Methods: Female survivors of childhood DTC, diagnosed at ≤18 years of age between 1970 and 2013, were included. Survivors were excluded when follow-up time was less than five years or if they developed other malignancies before or after diagnosis of DTC. Survivors filled out a questionnaire regarding reproductive characteristics (e.g., age at menarche and menopause, pregnancies, pregnancy outcomes, need for assisted reproductive therapy). Survivors aged <18 years during evaluation received an altered questionnaire without questions regarding pregnancy and pregnancy outcomes. These data were combined with information from medical records. AMH levels were measured in serum samples and were compared with AMH levels from 420 women not treated for cancer. Results: Fifty-six survivors with a median age of 31.0 (interquartile range, IQR, 25.1-39.6) years were evaluated after a median follow-up of 15.4 (IQR 8.3-24.7) years. The median cumulative dose of 131 I administered was 7.4 (IQR 3.7-13.0) GBq/200.0 (IQR 100.0-350.0) mCi. Twenty-five of the 55 survivors aged 18 years or older during evaluation reported 64 pregnancies, 45 of which resulted in live birth. Of these 55, 10.9% visited a fertility clinic. None of the survivors reported premature menopause. Age at AMH evaluation did not differ between DTC survivors and the comparison group ( p  = 0.268). Median AMH levels did not differ between DTC survivors and the comparison group [2.0 (IQR 1.0-3.7) μg/L vs. 1.6 (IQR 0.6-3.1) μg/L, respectively, p  = 0.244]. The cumulative dose of 131 I was not associated with AMH levels in DTC survivors ( r s  = 0.210, p  = 0.130). Conclusions: Female survivors of DTC who received 131 I treatment during childhood do not appear to have major abnormalities in reproductive characteristics nor in predictors of ovarian failure.

Context: Many female survivors of adolescent and young adult cancers (AYA survivors) have shortened reproductive lifespans. However, the timing and duration of ovarian function after cancer treatment are largely unknown., Objective: To model the trajectory of ovarian function over two decades following cancer treatment and evaluate how trajectories vary by treatment gonadotoxicity and age., Design: In a prospective cohort, AYA survivors aged 18-39 at variable times since cancer treatment completion provided dried blood spots (DBS) every 6 months for up to 18 months. Anti-Müllerian hormone (AMH) levels were measured using the Ansh DBS AMH enzyme-linked immunosorbent assay. The mean AMH trajectory was modeled for the entire cohort and separately by treatment gonadotoxicity and age using functional principal components analysis., Results: 763 participants, mean (standard deviation) enrollment age 33.3 (4.7) and age at cancer diagnosis 25.9 (5.7) years, contributed 1905 DBS samples. The most common cancers were breast (26.9%), lymphoma (24.8%), and thyroid (18.0%). AMH trajectories differed among survivors by treatment gonadotoxicity (low, moderate, or high) (P < 0.001). Following low or moderately gonadotoxic treatments, AMH levels increased over 2-3 years and plateaued over 10-15 years before declining. In contrast, following highly gonadotoxic treatment, AMH levels were lower overall and declined shortly after peak at 2-3 years. Younger age at treatment was associated with higher trajectories, but a protective effect of younger age was not observed in survivors exposed to highly gonadotoxic treatments (Pinteraction < 0.001)., Conclusions: In this large AYA survivor cohort, timing and duration of ovarian function strongly depended on treatment gonadotoxicity and age at treatment. The findings provide novel, more precise information to guide reproductive decision-making., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Although international guidelines have become more conservative on the use of radioactive iodine (RAI) therapy, it is still one of the cornerstones of the treatment of patients with advanced differentiated thyroid cancer (DTC). As a large proportion of females diagnosed with DTC is in their reproductive years, knowledge about the effect of RAI on their gonadal and reproductive function is important. Earlier studies evaluating Anti-Müllerian hormone (AMH) as a representative of ovarian reserve were either cross-sectional, had relatively low numbers, had no patients with multiple RAI therapies, or had a relatively short follow-up. The primary aim of our study was, therefore, to prospectively evaluate the effect of RAI on AMH in women undergoing treatment for DTC. Methods: We included females, aged 16 years until menopause, who were scheduled to undergo their first RAI treatment for DTC at our hospital. Serum AMH was measured before initial therapy and regularly thereafter. Repeated measurement analysis was used to assess the changes of AMH concentrations over time, and how this is influenced by age and cumulative RAI dose. Results: Longitudinal AMH assessments were available in 65 patients (mean age 32 years, median of five measurements during median follow-up of 34 months). AMH concentrations changed nonlinear over time, decreased until 12 months in the single RAI group (-55%), and stabilized thereafter. In the multiple RAI group, after stabilization, a further decrease occurred (-85% after 48 months). Age in both RAI groups significantly influenced AMH change over time, with younger patients (<35 years of age) showing a less steep decrease. Conclusions: In a population of female DTC patients treated with total thyroidectomy and a single RAI therapy, AMH concentrations significantly dropped during the first year after initial therapy, and thereafter they remained stable. In patients receiving multiple RAI therapies, a further decrease was seen. Age at baseline significantly influenced AMH change over time. These results support a less aggressive treatment with RAI in low-risk patients as is advocated in the current American Thyroid Association (ATA) guidelines, especially in females older than 35 years of age with the desire to have a child.

Background: Thyroid carcinoma is the most common endocrine malignancy. Surgery is the standard therapeutic approach for patients with differentiated thyroid carcinoma (DTC), followed by radioiodine (RAI) therapy if indicated. For women with DTC, the effects of RAI therapy on gonadal and reproductive function are an important consideration. This study aimed to evaluate the effects of RAI therapy on ovarian function. Methods: A total of 33 premenopausal women were enrolled in this study. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and anti-Müllerian hormone (AMH) levels during the early follicular phase were measured before and 3, 6, and 12 months after RAI therapy. The Friedman and Wilcoxon tests were used to detect changes in FSH, AMH, LH, and estradiol levels induced by RAI therapy over time. Results: The patients' ages ranged from 21 to 38 years, with a mean age of 31.15 ± 4.83 years. The median follow-up was 19 months (range 4-26 months). The median AMH levels were 3.25 ng/mL (range 0.32-17.42 ng/mL), 1 ng/mL (range 0.01-3.93 ng/mL), 1.13 ng/mL (range 0.08-6.12 ng/mL), and 1.37 ng/mL (range 0.09-6.1 ng/mL) before and at 3, 6, and 12 months after RAI therapy, respectively. The median FSH levels were 6.6 mIU/mL (range 3.78-15.5 mIU/mL), 5.83 mIU/mL (range 4.19-35.36 mIU/mL), 7.71 mIU/mL (range 4.24-16.25 mIU/mL), and 7.04 mIU/mL (range 4.93-19.96 mIU/mL) before and at 3, 6, and 12 months after RAI therapy, respectively. The AMH levels were higher before than after RAI therapy ( p  = 0.001). The AMH levels did not differ significantly between the three time points ( p  > 0.05). The FSH, LH, and estradiol levels were similar before and after RAI therapy ( p > 0.05). Conclusion: AMH is considered an important marker of ovarian reserve. Ovarian reserve decreased after RAI therapy. More attention may be needed when considering RAI therapy for patients with reduced ovarian reserve.

Study Question: Which treatment-related factors are (dose-dependently) associated with abnormal hormonal and ultrasound markers of ovarian reserve in female childhood cancer survivors (CCSs)?, Summary Answer: Cyclophosphamide, procarbazine, a composite group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal radiotherapy (RT), abdominal/pelvic RT and total body irradiation were multivariably associated with abnormal ovarian reserve markers, with dose-effect relationships being established for procarbazine and abdominal/pelvic RT., What Is Known Already: Female childhood cancer survivors are at an increased risk of reduced ovarian function and reserve, but knowledge regarding the long-term effects of individual chemotherapeutic (CT) agents and radiotherapy fields and their respective doses is limited., Study Design, Size, Duration: The DCOG LATER-VEVO is a nationwide retrospective cohort study in which measurements were performed between 2008 and 2014. In total, 1749 female 5-year CCSs, diagnosed before age 18 years between 1963 and 2002 and 1201 controls were invited for the study., Participants/materials, Setting, Methods: Ovarian reserve was assessed by anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B levels, and antral follicle counts (AFC). The study was a multicentre study including all seven Dutch Centers for Paediatric Oncology/Haematology., Main Results and the Role of Chance: In total, 564 CCs and 390 controls participated in the clinical part of the study. Overall, 7.0-17.7% of CCSs and 2.4-13.6% of controls had abnormal ovarian reserve markers. Above age 35, significantly more CCSs than controls had abnormal ovarian reserve markers (AMH: 26% vs. 4%; AFC: 20% vs. 3%; inhibin B: 42% vs. 16%). For AMH and FSH, significant differences were also found below age 35. Cyclophosphamide, procarbazine, a group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal RT, abdominal/pelvic RT and total body irradiation were multivariably associated with at least one abnormal ovarian reserve marker. Dose-effect relationships were established for procarbazine and abdominal/pelvic RT., Limitations, Reasons for Caution: Despite the large scale of the study, dose-effect relationships could not be investigated for all types of treatment due to a limited numbers of participants for specific analyses., Wider Implications of the Findings: This study demonstrated that the majority of CCSs do not show signs of a reduced ovarian reserve. However, specific subgroups of CCSs appear to be associated with a high risk. Our results are important for counselling CCSs and future patients regarding parenthood and fertility preservation., Study Funding/competing Interests: This study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20). Philips Health Systems Benelux supported this study by providing three ultrasound systems and concomitant analytic software. There are no competing interests., Trial Registration Number: NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 2922., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Women of reproductive age with differentiated thyroid cancer (DTC) often need radioactive iodine (RAI) treatment after surgery. In contrast to the well-documented effect of RAI on testicular function, the potential negative effects of this treatment on ovarian reserve have been largely dismissed. The objective of this pilot study was to examine the possibility that RAI treatment is deleterious to the ovarian reserve by prospectively measuring the concentration of anti-Müllerian hormone (AMH) after RAI treatment., Methods: Thirty premenopausal women (M age  = 34 years; range 20-45 years) with a new diagnosis of DTC scheduled to undergo RAI ablation were recruited for this study. All of them had TNM stage 1 disease (T1-3, N0, or N1, M0), and were scheduled to receive RAI activities ranging from 30 to 150 mCi. AMH was measured at baseline and at 3, 6, 9, and 12 months after the administration of RAI., Results: Of the 30 women, only 24 returned after the baseline assessment. RAI treatment resulted in a significant decrease in AMH concentrations at three months, from 3.25 ± 2.75 to 1.9 ± 1.74 ng/mL (p < 0.0001). Only partial recovery was subsequently documented. Eighty-two percent of subjects had final values below baseline levels, such that at one year, serum AMH was still 32% lower than prior to treatment (2.36 ± 1.88 ng/mL; p < 0.005). The only two continuous variables that correlated with the extent of AMH reduction at three months were the woman's age (r = 0.51; p = 0.02) and the age at menarche (r = 0.48; p = 0.03). Importantly, the RAI dose was not associated with the extent of AMH reduction and neither were smoking or the use of birth control pills. Older subjects (≥35 years) were significantly more likely to experience a marked AMH reduction at three months (63.7 ± 18.5% vs. 33.1 ± 29.2%; p = 0.01). The only predictor of recovery after one year was the extent of AMH decrease at three months: the lower the decline, the higher the chances for recovery., Conclusions: RAI in DTC has a rapid and profound effect on ovarian reserve, with only a partial recovery potential. In an era of declining human fertility, it is of relevance to recognize the potentially adverse effect of RAI in women of reproductive age. AMH measurement may be useful as a tool in this decision-making process.

Objective: To compare markers of fertility and ovarian reserve between cancer survivors and cancer-free women with and without polycystic ovary syndrome (PCOS)., Design: Furthering Understanding of Cancer, Health, and Survivorship in Adult (FUCHSIA) Women's Study-a population-based cohort study., Setting: Not applicable., Patient(s): Female cancer survivors (n = 1,090) aged 22-45 years, diagnosed between ages 20 and 35 years, and at least 2 years after diagnosis; 369 participated in a clinic visit. Three hundred seventy-four reproductive-aged women without cancer also completed a clinic visit., Intervention(s): None., Main Outcome Measure(s): Infertility, time to first pregnancy after cancer diagnosis, and measures of ovarian reserve (antimüllerian hormone [AMH] and antral follicle count [AFC])., Results: Seventy-eight cancer survivors (7.2%) reported a PCOS diagnosis, with 41 receiving gonadotoxic treatment. Survivors with PCOS exposed to gonadotoxic treatment (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.2-4.5) and unexposed (OR 3.4, 95% CI 1.7-6.9) were more likely to report infertility than unexposed survivors without PCOS and were more likely to have fewer children than desired (exposed: OR 2.1, 95% CI 1.0-4.2; unexposed: OR 3.0, 95% CI 1.4-6.8). After adjusting for age, comparison women with PCOS had the highest markers of ovarian reserve (AMH: 2.43 ng/mL, 95% CI 1.22-4.82 ng/mL; AFC: 20.7, 95% CI 15.3-27.8), and cancer survivors without PCOS treated with gonadotoxic agents had the lowest levels (AMH: 0.19 ng/mL, 95% CI 0.14-0.26 ng/mL; AFC: 7.4, 95% CI 6.4-8.5)., Conclusion(s): Despite having higher AMH and AFC on average after cancer treatment, cancer survivors with PCOS were less likely to meet their reproductive goals compared with survivors without PCOS., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Ionizing radiation may cause irreversible ovarian failure, which, therefore, calls for an effective radioprotective reagent. The aim of the present study was to evaluate the potential radioprotective effect of N-acetylcysteine (NAC) on ionizing radiation induced ovarian failure and loss of ovarian reserve in mice. Kun-Ming mice were either exposed to X-irradiation (4 Gy), once, and/or treated with NAC (300 mg/kg), once daily for 7 days before X-irradiation. We examined the serum circulating hormone levels and the development of ovarian follicles as well as apoptosis, cell proliferation, and oxidative stress 24 hours after X-irradiation. In addition, morphological observations on the endometrial luminal epithelium and the fertility assessment were performed. We found that NAC successfully restored the ovarian and uterine function, enhanced the embryo implantation, improved the follicle development, and altered the abnormal hormone levels through reducing the oxidative stress and apoptosis level in granulosa cells while promoting the proliferation of granulosa cells. In conclusion, the radioprotective effect of NAC on mice ovary from X-irradiation was assessed, and our results suggested that NAC can be a potential radioprotector which is capable of preventing the ovarian failure occurrence and restoring the ovarian reserve.

In this paper the contribution of chronic irradiation at low doses (0.42 mGy/h) and dysgenesis to changing morphological parameters (gonadal atrophy/sterility and ovarian reserve) of the reproductive system of female Drosophild melanogaster is rated. It is shown that the sterilizing effect of dysgenesis is enhanced predominantly by irradiation of the maternal line. The level of ovarian reserve of irradiated females depends on the type of dysgenic system. Unlike I-R females in whom the level of radiation-induced ovarian reserve does not differ from the control, both decrease (in P-M females) and increase (in H-E females) is observed in the ovariole number. The results indicate the important role of mobile genetic elements destabilizing the genome in the modification of reproductive functions of females exposed to chronic-action of low-intensity γ-radiation.

Fertility impairment due to treatments is a major concern for patients who have survived cancer in adolescence or as a young adult. The impact of cancer treatments on fertility depends on the age at treatments, types and cumulative doses of chemotherapy, radiation doses to organs at risk, and on surgeries conducted. Fertility preservation strategies have been developed for many years, and recently diversified thanks to advances in reproductive biology. In female adolescents and young adults, ovarian stimulation followed by oocyte (or embryo) vitrification, ovarian tissue cryopreservation, and sometimes oocyte vitrification after in vitro maturation are options that can be discussed. In some diseases, potential risk of residual disease in cryopreserved ovarian cortex has to be taken into account before ovarian tissue transplantation, which should always be discussed with the oncological team. The use of GnRH agonists for fertility preservation remains controversial. In case of pelvic radiation therapy, intensity-modulated conformal radiotherapy, and ovarian transposition can preserve organs at risk. In male adolescents and young adults, sperm crypopreservation is an established fertility preservation method, which can in most cases, including adolescents, be carried out. In prepubertal or peripubertal patients, testicular tissue cryopreservation can be proposed. Information on the effects of treatments and discussion of fertility preservation options should be systematic in adolescents and young adults with cancer., (Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Radioactive iodine (RAI) ablation treatment is used for patients diagnosed with well-differentiated thyroid cancer in order to reduce the risk of recurrence. RAI ablation treatment can adversely affect gonads in males and females. In this study, we aimed to determine ovary damage and infertility risk due to RAI, using serum anti-Müllerian hormone (AMH) level, in females who received RAI ablation treatment. Materials and Methods: 45 female patients who have not gone through the menopause and had received RAI ablation treatment for well-differentiated thyroid cancer in premenopausal period, and 40 healthy females as control groups were included in this study. The serum AMH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), thyroid stimulating hormone (TSH) and creatinine levels of the patients included in the study were analyzed and compared to those of the control group with similar demographical characteristics. Results: No differences were found between the patient group and control group in terms of age, height, weight, body mass index, LH, E2 and creatinine. The difference in AMH, FSH and TSH between both groups were found to be significant. There was no statistically significant relation between the age and AMH levels. Similarly, no statistically significant relation between RAI exposure duration and AMH levels was determined. When the patients below and above the age of 35 were compared with regard to AMH (2.95±1.79 and 2.75±1.94, respectively) and FSH (5.45±1.63 and 5.99±3.06, respectively), the difference between them was found to be statistically insignificant. Oligo/anovulation was detected in 7 patients (15.6% of the patient group) after RAI treatment, 8 (17.8%) patients became pregnant after RAI treatment, and none of the patients, who were actively trying to get pregnant, were unable to achieve it. Conclusion: According to these results, it may be concluded that low AMH levels due to RAI treatment can cause damage to the ovaries of patients; nevertheless, considering the AMH levels and the absence of infertility in the patients, the infertility risk was found to be low., (© Georg Thieme Verlag KG Stuttgart · New York.)

The effects on human health of electromagnetic field (EMF) have begun to be seriously questioned with the entry into daily life of devices establishing EMF, such as cell phones, wireless fidelity, and masts. Recent studies have reported that exposure to EMF, particularly during pregnancy, affects the developing embryo/fetus. The aim of this study was therefore to examine the effects of exposure to continuous 900-Megahertz (MHz) EMF applied in the prenatal period on ovarian follicle development and oocyte differentiation. Six pregnant Sprague Dawley rats were divided equally into a non-exposed control group (CNGr) and a group (EMFGr) exposed to continuous 900-MHz EMF for 1 h daily, at the same time every day, on days 13-21 of pregnancy. New groups were established from pups obtained from both groups after birth. One group consisting of female pups from CNGr rats was adopted as newborn CNGr (New-CNGr, n = 6), and another group consisting of female pups from EMFGr rats was adopted as newborn EMFGr (New-EMFGr, n = 6). No procedure was performed on New-CNGr or New-EMFGr rats. All rat pups were sacrificed on the postnatal 34th day, and their ovarian tissues were removed. Follicle count, histological injury scoring and morphological assessment with apoptotic index criteria were performed with sections obtained following routine histological tissue preparation. Follicle count results revealed a statistically significant decrease in primordial and tertiary follicle numbers in New-EMFGr compared to New-CNGr (p < 0.05), while atretic follicle numbers and apoptotic index levels increased significantly (p < 0.05). Histopathological examination revealed severe follicle degeneration, vasocongestion, a low level of increased stromal fibrotic tissue and cytoplasmic vacuolization in granulosa cell in New-EMFGr. Prenatal exposure to continuous 900-MHz EMF for 1 h each day from days 13-21 led to a decrease in ovarian follicle reservoirs in female rat pups at the beginning of the prepubertal period.

Study Question: Is there any in vitro evidence for or against ovarian protection by co-administration of a GnRH agonist with chemotherapy in human?, Summary Answer: The co-administration of GnRH agonist leuprolide acetate with cytotoxic chemotherapy agents does not preserve ovarian reserve in vitro., What Is Known Already: Randomized controlled trials of the co-administration of gonadotrophin-releasing hormone (GnRH) agonists with adjuvant chemotherapy to preserve ovarian function have shown contradictory results. This fact, together with the lack of a proven molecular mechanism of action for ovarian protection with GnRH agonist (GnRHa) places this approach as a fertility preservation strategy under scrutiny. We therefore aimed in this study to provide in vitro evidence for or against the role of GnRHa in the prevention of chemotherapy-induced damage in human ovary., Study Design, Settings, Size and Duration: This translational research study of ex vivo and in vitro models of human ovary and granulosa cells was conducted in a university hospital between 2013 and 2015., Participants/materials, Setting, Methods: Ovarian cortical pieces (n = 15, age 14-37) and mitotic non-luteinized (COV434 and HGrC1) and non-mitotic luteinized human granulosa cells (HLGC) expressing GnRH receptor were used for the experiments. The samples were treated with cyclophosphamide, cisplatin, paclitaxel, 5-FU, or TAC combination regimen (docetaxel, adriamycin and cyclophosphamide) with and without GnRHa leuprolide acetate for 24 h. DNA damage, apoptosis, follicle reserve, hormone markers of ovarian function and reserve (estradiol (E2), progesterone (P) and anti-mullerian hormone (AMH)) and the expression of anti-apoptotic genes (bcl-2, bcl-xL, bcl-2L2, Mcl-1, BIRC-2 and XIAP) were compared among control, chemotherapy and chemotherapy + GnRHa groups., Main Results and the Role of Chance: The greatest magnitude of cytotoxicity was observed in the samples treated with cyclophosphamide, cisplatin and TAC regimen. Exposure to these drugs resulted in DNA damage, apoptosis and massive follicle loss along with a concurrent decline in the steroidogenic activity of the samples. GnRHa co-administered with chemotherapy agents stimulated its receptors and raised intracellular cAMP levels. But it neither activated anti-apoptotic pathways nor prevented follicle loss, DNA damage and apoptosis induced by these drugs., Limitations, Reasons for Caution: Our findings do not conclusively rule out the possibility that GnRHa may offer protection, if any, through some other mechanisms in vivo., Wider Implications of the Findings: GnRH agonist treatment with chemotherapy does not prevent or ameliorate ovarian damage and follicle loss in vitro. These data can be useful when consulting a young patient who may wish to receive GnRH treatment with chemotherapy to protect her ovaries from chemotherapy-induced damage., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Due to high cure rate in childhood and adolescent cancer, fertility preservation is a major concern. Chemotherapy, radiotherapy and surgery may alter gonadal function, and uterine cavity in women. In women, combined toxicity affecting both endocrine function and ovulation are observed leading to premature ovarian insufficiency. In men, spermatogenesis is frequently affected whereas endocrine function is almost always preserved. The current article focuses on investigations concerning gonadal function after treatment for a cancer during childhood or adolescence and treatment of subsequent infertility or hypogonadism. Nevertheless, those therapeutic are still limited and pretherapeutic preservation of fertility is preferred when possible., (Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Since serum anti-Müllerian hormone (AMH) levels enable quantitative evaluation of ovarian damage, we conducted a computer-based search, using key words, of all articles published in English through the PubMed database from inception until September 2013 to summarize available studies evaluating ovarian reserve after ovarian toxic interventions to discuss the usefulness of serum AMH levels. We found that most of the studies demonstrated a decline in serum AMH levels when compared to control or pretreatment levels, with levels dependent on the type of treatment modality. Measurement of serum AMH levels enables quantitative evaluation of ovarian damage caused by ovarian toxic interventions, such as chemotherapy and radiotherapy, instead of qualitative evaluation using menstrual condition or basal follicle-stimulating hormone levels. Serum AMH levels are becoming indispensable to assess the ovarian reserve of patients who desire preservation of ovarian function for fertility and endogenous sex steroid hormones., (© The Author(s) 2014.)